MC1807A1 - 3,5-DISUBSTITUTED DERIVATIVES OF PYROCATECHOL - Google Patents

Description

1

5

3,5-Disubstituted pyrocatechol derivatives 10 Catechol derivatives corresponding to the general formula

)j*a

H0\

• '

\

13

15 H° Rb in which Ra denotes a nitro or cyano group, Rb hydrogen or a halogen, Rc a halogen, a nitro group, cyano group or the group -(A)n-(Q)m-Rl or -(A)n-Q-R2, A a vinylene group 20 substituted where appropriate by a lower alkyl group,

...n the numbers 0 or 1, m the numbers 0- or 1, R1 the group

-COR^, a carbocyclic, aromatic, or carbon-linked heterocyclic group, aromatic or partially unsaturated; R2 denotes hydrogen or a lower carbon hydro-25 radical, substituted if necessary, saturated or partially unsaturated; R-* a hydroxyl, amino, or lower hydrocarbon radical linked by an oxygen atom or by an imino or (lower alkyl)imino group, substituted if necessary, saturated or partially unsaturated, or a nitrogen heterocyclic group linked by a ring nitrogen atom, saturated; Q the -CO~ or >C=N-(Z)p-R4 group, Z an oxygen atom or an imino group, p the numbers 0 or 1, and R4 hydrogen or a lower hydrocarbon radical, substituted if necessary and linked if necessary by a carbonyl group, saturated or partially unsaturated.

The esters and ethers derived from them, hydrolyzable under physiological conditions, and their pharmaceutically acceptable salts, possess valuable pharmacological properties. These compounds, in particular, inhibit the 5-catechol-O-methyltransferase (COMT) enzyme, a soluble, magnesium-dependent enzyme that catalyzes the transfer of the methyl group from S-adenosylmethionine to a catechol substrate, with the formation of the corresponding methyl ethers. Suitable substrates that are 4-methylated by COMT and deactivated by it include, for example, extraneuronal catecholamines and therapeutically active substances having a catechol structure, administered by...

exogenous pathways.

The compounds above corresponding to formula 1a can therefore be used for the prevention and treatment of diseases in which the deactivation of extraneuronal catecholamines by COMT plays a role, for example, in the prevention or treatment of depression. In this case, the compounds corresponding to formula 1a above can be used alone or in combination with other therapeutically active substances that favorably influence the course of the disease. But the compounds corresponding to formula 1a can also be used as co-medication with other therapeutically active substances.

Compounds conforming to formula 1a can, however, also be used to improve the prevention or control of diseases with therapeutically active substances that have a catechol structure. For example, L-dopa, a therapeutically active substance with a catechol structure, can be used to treat Parkinson's disease and parkinsonism. In such cases, compounds conforming to formula 1a can be used as co-medication or in combination. Another possibility for the use of compounds

If the formula above corresponds to the diagnostic domain, after administration of [18p]-6-fluoro-L-dopa, [18p]-dopamine can be made visible in the brain by positron emission tomography. By adding a compound corresponding to the formula above, COMT is inhibited, and consequently the formation of [18p]-3-O-methyldopa is inhibited. In the absence of a COMT inhibitor, the [18p]-3-O-methyldopa formed would penetrate the brain and lead to a very intense background, which would make diagnosis much more difficult.

The formula above covers both known and new compounds. Compounds conforming to the formula known in themselves conform to the general formula

15 ]jta

HCVX x

Axj-Rc"

H0 Rb

20 in which Ra denotes a nitro or cyano group, Rb hydrogen or a halogen, Rc" a nitro, cyano group or the -(A)n-COOH or -(A)n-Q-H group, A a vinylene group substituted where appropriate by a lower alkyl group, n the numbers 0 or 1, Q the -CO- or >C=n-(Z)p-R4 group, Z an oxygen atom or an imino group, p the numbers ~0 or 1 and R4 hydrogen or a lower hydrocarbon radical, where appropriate substituted and where appropriate linked by a carbonyl group, saturated or partially unsaturated, Ra denoting a nitro group, where Rc" denotes a cyano or nitro group,

30 their esters and ethers hydrolyzable under physiological conditions, and their pharmaceutically acceptable salts.

The new compounds conforming to the formula are compounds conforming to the general formula

35

4

H0\

S

II

-Rc'

Ib h0/ HU Rb in which Ra denotes a nitro or cyano group, Rb 11 hydrogen or a halogen, Rc" a nitro, cyano group or the 10 ~(a)nr (q-înirr11 or -(A)n-Q-R21 group, a a vinylene group substituted where appropriate by a lower alkyl group, n the numbers 0 or -1, m the numbers 0 or 1, rH the -COR^l group, a carbocyclic, aromatic or heterocyclic group linked by a carbon atom, aromatic or partially unsaturated, R^l 25 a lower hydrocarbon radical, where appropriate substituted, saturated or partially unsaturated, R^l a hydroxy group,

amino, a lower hydrocarbon radical linked by an oxygen atom or an imino or (lower alkyl) imino group, possibly substituted, saturated or partially unsaturated 20 or a nitrogen heterocyclic group linked by a ring carbon atom, saturated, Q the -CO- group or >C=N-(Z)p-R4, Z an oxygen atom or an imino group, p the numbers 0 or 1 and R4 hydrogen or a lower hydrocarbon radical possibly substituted and possibly linked by a carbonyl group 25, saturated or partially unsaturated, Ra denoting the cyano group, when Rc' denotes a cyano or nitro group, and R^l has a different meaning from the hydroxy group when m denotes the O group,

and their -esters and ethers hydrolyzable under physiological conditions, and their pharmaceutically acceptable salts.

The object of the present invention consists of compounds corresponding to the formula and derivatives thereof indicated for use as therapeutic active substances; medicinal products based on these compounds and

5

their derivatives; the preparation of these medicinal products; the use of the compounds and derivatives in question for the prevention and control of diseases; the use of the compounds and derivatives in question for the preparation of medicinal products 5 which, where appropriate, inhibit the COMT enzyme in the direction of a desired side effect; the compounds corresponding to formula Ib above and their derivatives mentioned as such; the preparation of these compounds and derivatives; and intermediate products for their preparation. 10 The term "lower" refers to radicals and compounds having at most 7, preferably at most 4, carbon atoms. The term "alkyl," taken alone or in combinations such as "alkyl group," "alkoxy," "alkylthio," and "alkyl-imino," refers to linear saturated hydrocarbon radicals 15 or branched radicals, such as methyl, ethyl, propyl,

isopropyl, n-butyl, s-butyl, i-butyl, and t-butyl. The term "saturated or partially unsaturated lower hydrocarbon radical" refers to open-chain and cyclic groups and combinations thereof. Examples of saturated and partially unsaturated lower hydrocarbon radicals include: lower alkyl groups as defined above; lower alkenyl groups, such as 2-propenyl, 2-butanyl, 3-butanyl, and 2-methyl-2-propenyl; C3-C7 cycloalkyl and Cg-Cq bicyclo-alkyl groups, optionally substituted with lower alkyl groups, such as cyclopropyl, cyclopentyl, 2-methylcyclopentyl, cyclohexyl, and 3-methylcyclohexyl; Lower cycloalkenyl groups substituted, where appropriate, by lower alkyl groups, such as 3-cyclopentenyl, 1-methyl-3-cyclopentenyl, and 3-cyclohexenyl groups; lower alkyl or alkenyl groups substituted by lower cycloalkyl or cycloalkenyl groups, such as cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexenyl-35-methyl, and 3-cyclopropyl-2-propenyl groups. Alkenyl groups

The lower groups preferably contain 2 to 4 carbon atoms. The cycloalkyl and cycloalkenyl groups preferably contain 3 to 6 carbon atoms.

As substituents for the lower hydrocarbon radicals above, the following can be considered: hydroxy, cyano, nitro, halogen, amino, (lower alkyl) groups

amino, di(lower alkyl)amino, lower alkoxy, (lower alkyl)carbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, 10-carbamoyl, mono- or dK(lower alkyl)carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, (lower alkyl)amino, (lower alkyl)carbonylamino and (lower alkyl)thio. Saturated or partially unsaturated lower hydrocarbon radicals are preferably unsubstituted or mono- or disubstituted.

The term "aryl" designates carbocyclic aromatic groups, and preferably mono- or bi-cyclic groups. Particularly preferred carbocyclic aromatic groups are phenyl and naphthyl groups, especially phenyl groups. These groups are substituted, where appropriate, by halogens, trifluoromethyl, nitro, amino, ino, mono- or dialkyl groups, lower alkyl amino, lower alkyl, lower alkoxy, lower alkyl thio, lower alkanoyl, lower alkoxy carbonyl, carboxy, hydroxy, cyano, lower alkanoyloxy, carbamoyl, mono- or dialkyl carbamoyl, lower alkyl dioxy, lower alkanoyl amino, or lower alkoxy carbonylamino. Carbocyclic aromatic groups are preferably unsubstituted or mono- or disubstituted.

30 The expression "aromatic or partially unsaturated heterocyclic group" preferably designates a mono- group,

di- or tricyclic, aromatic, or partially unsaturated, a heterocyclic group having up to 5 heteroatoms belonging to the group consisting of nitrogen, sulfur, and oxygen. These heterocyclic groups preferably contain

7

1 to 4 nitrogen atoms and/or 1 oxygen or sulfur atom. They are preferably mono- or bicyclic. The heteroatoms are preferably distributed over one or two rings, with the nitrogen atoms being able to belong to two rings simultaneously. 5 The heterocyclic groups are preferably aromatic. They can be substituted, and in this case, it is preferable that they be mono-, di-, or trisubstituted. As substituents, halogens, trifluoromethyl groups, nitro, carboxy, amino, arylamino, lower alkyl, lower alkoxy, hydroxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, oxo, and (lower alkylene)dioxy groups may be considered. mercapto, (lower alkyl)thio, (lower alkyl)amino, di(lower alkyl)amino, (C3-C7 cycloalkyl)amino, (Cg-Cg bicycloalkyl)amino, (lower alkanoyl)amino, (lower alkoxy)carbonylamino, carbamoyl, mono- or di(lower alkyl)carbamoyl, cyano, aryl, aryl-(lower alkyl), aryl(lower alkyl)amino, heteroaryl, heteroaryl(lower alkyl), heteroarylamino, and C3-C7 cycloalkyl. Monocyclic heterocyclic groups are preferably 5 or 6 members long and contain at most four heteroatoms. Bicyclic heterocyclic groups are preferably 8 to 10 members long, with the various rings preferably having 5 or 6 members.

As examples of such heterocyclic groups, we will cite the following: pyridyl, pyrazinyl~, triazinyl, thiadiazinyl thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, imidazolyl, thienyl, quinoleyl, isoquinoleyl, dihydro-isoquinoleyl, benzoxazinyl, quinoxalinyl, benzopyranyl, benzimidazolyl, indolyl, imidazothiazolyl, imidazothia-30diazolyl, imidazopyridyl, benzothiazinyl, benzoquinoxa-linyl and imidazobenzothiazolyl.

The term "heteroaryl" refers to aromatic, heterocyclic groups as defined above.

The expression "nitrogen heterocyclic group linked by a saturated nitrogen atom" preferably designates an N-hetero-

8

saturated ring with 3 to 7 members, preferably 4 to 6 members, which may contain, in addition to the indicated nitrogen atom, an oxygen, sulfur, or nitrogen atom as a second heteroatom. These saturated N-heterocycles may also be mono-5 or disubstituted with a lower alkyl, hydroxyl, group.

lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, (lower alkoxy)carbonyl, lower alkanoyl, carbamoyl, mono- or di(lower alkyl)carbamoyl, oxo and/or alkylene-10 dioxy.

Examples of these nitrogenous heterocyclic groups include 4-morpholinyl, 1-pyrrolidinyl and 1-azetidinyl.

Esters and ethers that are hydrolyzable under physiological conditions are preferably compounds that meet

to formula 1a, in which at least one of the hydroxyphenolic groups is acylated by a lower fatty acid or etherified by a 1-alkoxycarbonyloxy-1-alkyl, (1-alkanoyloxy)-1-alkyl, or lower 2-oxo-1-alkyl group. 20 The substituent Ra preferably designates a nitro group.

The substituent Rb is preferably located in the p position relative to the substituent Ra and preferably denotes hydrogen, chlorine, or fluorine, with hydrogen being particularly preferred. The substituent Rc' preferably denotes the group -CO-R^, designating an aromatic, monocyclic, carbocyclic, or heterocyclic group with a single ring, linked by a carbon atom, aromatic, having 1 to 3 nitrogen atoms as ring heteroatoms. In a particularly preferred embodiment, it designates

30 a mono- or di-substituted phenyl group, where appropriate by a halogen, a trifluoromethyl, cyano, hydroxy or lower alkyl group, or a pyridyl group.

Within the scope of the present invention, particularly preferred compounds are the following: 35 3,4-Dihydroxy-5-nitrobenzophenone,

9

21-Fluoro-3,4-Dihydroxy-5-nitrobenzophenone and

3,4-Dihydroxy-5-nitrophenyl-4-pyridylketone.

The compounds corresponding to formula Ib, their esters and ethers hydrolyzable under physiological conditions 5, and their pharmaceutically acceptable salts can be prepared according to the invention a) by removing the lower etheralkyl group(s) in a compound corresponding to the general formula

Ra

10 R0\ f'\

11

R'O7 ^ „

K u Rb in which one of the symbols R and R' denotes a lower alkyl group and the other hydrogen or a lower alkyl group, and Ra, Rb and Rc' have the meanings above, or b) by reacting a compound corresponding to the general formula

20 Ra

HCVX x

H0 * Rb

25 in which X denotes a separable group, and Ra, Rb, A and n have the meanings above, with a thioamide, a thiourea, a thiocarboxylic acid hydrazide, a thiosemicarbazide, an amidine, a guanidine, an amidrazone, an aminoguanidine, a cyclic amidine, a 1,2-diamine, a 1,2-aminothiol or a 1,2-amino alcohol and dehydrogenating, if desired, the cyclocondensation product obtained, or c) by reacting a compound corresponding to the general formula

35

10

?

has

HOs / -.

x/ x. 2

/K V*" (A)n-C°-C00R" 15

H0 V*XRb in which R" denotes a lower alkyl group, and Ra, Rb, A and n have the meanings above with a 1,2-diamine, a 1,2-aminothio, a 1,2-amino-10 alcohol; a semicarbazide, a thiosemicarbazide, an amidrazone or an aminoguanidine, and by dehydrogenating, if desired, the cyclocondensation product obtained, or d) by reacting a compound corresponding to formula Ib1 above with a 3-aminocarbonyl compound or e) by transforming it into a compound corresponding to the general formula

9:00

HO

HOxy-V. ""VX 2 '"V\

20 Av-Ro"' 111 ' Av~CH0 Ia °U Av""CH0 IV

HO^-V HO Rb in which Rc''' denotes a nitro, cyano group or the -(A)n-Rl^ group and R^2 i.e. the -COR^l group, an aromatic cyclic carbo-25 group or a carbon-linked heterocyclic group, aromatic or partially unsaturated, and Ra, Rb, A, n and R^l have the above meaning,

or in a di-O-(lower alkanoyl) derivative thereof, the carboxaldehyde group(s) in the cyano group(s), 3 0 or f) by reacting a di-O-(lower alkanoyl) derivative of a carboxylic acid corresponding to the general formula

35

11

That Ra

H°\^'\ ■ ia3 H0\ ^'\ 3

• • - j. a # # YOU

It, . or I II Ib

„n/% V"" (A) n-COOH V'- (A) n-CO-COOH

H° • Rb H0 ' Rb in which Ra, Rb, A and n have the above meaning, in the presence of a condensing agent or a reactive derivative of a di-O-(lower alkanoyl) derivative of a carboxylic acid 10 corresponding to the formulas la3 or Ib3 with a compound corresponding to the general formula

HO-R5 V or HNR6R7 VI

in which R5 designates a lower hydrocarbon radical, possibly substituted, saturated or partially unsaturated, 15 r6 hydrogen or a lower alkyl group and R7 hydrogen or a lower hydrocarbon radical, possibly substituted, saturated or partially unsaturated, or R^ and R? designate, together with the nitrogen atom, a nitrogenous heterocyclic group, or

20 g) by hydrolyzing a compound corresponding to formula Ib2

above or responding to the formula

8

R Vx

25 • \ • — Rc' Ib rV

Rb in which R^ denotes a lower alkanoyl group, and Ra, Rb and Rc' have the meaning above or 30 h) by reacting a compound corresponding to the general formula

35

12

?has

5

L v • -COR'" Ib un W H0 Rb in which Ra and Rb have the above meanings, and R111 denotes hydrogen or a lower alkyl group, or a di-O-(lower alkanoyl) derivative thereof in the presence of a secondary amine, with a compound corresponding to the general formula

CH3CO-R23 VII

in which R^3 denotes a lower hydrocarbon radical, possibly substituted, saturated or partially unsaturated,

15

i) by reacting a compound corresponding to the general formula fa

H0V /V

\ ^ \ a

• • I h

2" To v*-(A)n-CO-CH,-COOR"

H0 " Rb in which Ra, Rb, A, n and R" have the above meaning, with a hydrazine or an amidine, or 25 j) by reacting a compound corresponding to the formula Ib above, in which m denotes the number 1 and Q the -C0- group, with a compound corresponding to the general formula

H2N-(Z)p-R4 VIII

in which Z, p and R4 have the above meaning, 3g and if desired,

k) by transforming a compound corresponding to formula Ib above into an ester or ether hydrolyzable under physiological conditions, or into one of its pharmaceutically acceptable salts.

35 In accordance with variant of process a), the compounds

13

Compounds corresponding to formula Ib can be prepared by removing the ether group(s) from a compound corresponding to formula II. This ether removal can be carried out by processes known per se and familiar to all technicians. For example, the ether can be removed by treatment with hydrobromic acid in a suitable solvent. Suitable solvents include water, acetic acid, and mixtures thereof. Preferably, the reaction is carried out at a high temperature, for example, in a temperature range of approximately 100°C until the boiling point of the reaction mixture is reached. Preferably, 48% hydrobromic acid or mixtures thereof with acetic acid are used.

The removal of the ether can also be achieved by treatment with boron tribromide in a suitable solvent, at temperatures from about -60°C to around room temperature. Suitable solvents include, in particular, lower halogenated hydrocarbons, such as methylene chloride, chloroform, etc. Other suitable methods are treatment with pyridinium hydrochloride at temperatures from about 150°C to about 250°C, and treatment with sodium iodide/silicon tetrachloride in an inert organic solvent, hot, for example, at the reflux temperature of the reaction mixture. Suitable solvents for this latter method include, for example, acetonitrile, aromatic hydrocarbons such as benzene or toluene, mixtures thereof, etc.

According to variant b of the process, compounds corresponding to the general formula can be prepared

35 in which Ra, Rb, A and n possess the following meanings:

30

Ib

7

14

above, and Q1 designates a group corresponding to the formulas

/

V

N=

/

D

-S

(has) ,

/

'V

N=

/

NHRf

-S

(b) ,

/N-Nv x.v

-D

(c) ,

N-N

► «

x-s/

•NHRF

:d),

N—

/

D

-NH

(e) ,

/

Y

N=

/

NHRf

-NH

(f) ,

/N=N\

/N=N\

v „s"Re (g) ' -S ^*-NHRf

-IV

-N

(h) ,

10

15

N=0

•-iLj

Q (i), -

/Rg

^N~V

\ ;*-Rh -<

RF

,Rg

Sn~\

\ /••-Rh (1) •-S

Or

(k) bzw.

m-y s

► • i x-c/

Rg m-y

S *X

Rg

X-=N/

;"-Rh

■Rh (m) ,

(k1 ) ,

Re hydrogen, a lower alkyl group, a C3-C7 cycloalkyl group, aryl, heteroaryl, aryl(lower alkyl) 20 or heteroaryl(lower alkyl), Rf hydrogen, an aryl group, aryl(lower alkyl), lower alkyl, (lower alkoxy)carbonyl, heteroaryl, heteroacyl(lower alkyl), bicycloalkyl in Cg to C]_q or cycloalkyl in C3 to C7, Rg and Rh each hydrogen, a cyano group, lower alkyl, 25 cycloalkyl in C3 to C7, aryl, aryl(lower alkyl), heteroaryl or heteroaryl(lower alkyl), or Rg and Rh denote, with the two hydrogen atoms to which they are bonded, a carbocyclic aromatic group or an aromatic or partially unsaturated heterocyclic group, the line in 30 dashed lines, an optional bond and Q4, at the same time as the carbon atom and the nitrogen atom, an aromatic or partially unsaturated heterocyclic group, which contains at least one nitrogen atom as a ring heteroelement.

35 Suitable solvents for this aspect of the process are a

15

Lower alcohols such as ethanol, n-butanol, n-hexanol, and ethylene glycol; open-chain and cyclic ethers, which may still contain hydroxyl groups, such as tetrahydrofuran, dioxane, methyl δ-butyl ether, dimethyl ethylene glycol ether, dimethyl diethylene glycol ether, monomethyl ethylene glycol ether, and monomethyl diethylene glycol ether; acetonitrile, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide. The desired reaction can also be carried out by dry heating of the reaction partners. The reaction is preferably carried out hot, for example in a range of about 50°C to 150°C, preferably operating at the boiling point of the solvent, provided that one is operating in the presence of a solvent, and that the boiling point is in the range chosen in advance.

According to variant c) of the process, compounds corresponding to the general formula can be prepared

■ ïa

20 HCV\. 0

• y •-(A) - Q 2 k

/ x Yi " ; n u

H0 Rb in which Ra, Rb, A and n have the meaning 25 above and Q2 denotes a group corresponding to the formula

M /R9 K, /R9 /R9

/N-« ,N- •

;*-Rh (n) , */ * - R'1 (o) , -•( ;»-Rh (p) ,

^J~N\ ^'~S ^-°

Cr Rf CT (/

30

35

■< )-0H

CT H

N-N

(q), ;.-SH

CT H

(r) ,

C

16

.N-Nv

• — r o .n-ns

">-<-Re (s: or ->>-NHRf (t. 0 ' H >"N~

</ XH

in which Re, Rf, Rg, Rh and the line in broken lines have the above meaning.

The reaction according to variant c) of the process can be carried out under the same reaction conditions as variant b).

According to variant d) of the process, compounds corresponding to the general formula can be prepared

?has '

HV\ 9

Ay"-(A)n-Q3 ^

H0 Rb in which Q3 denotes the group corresponding to the formula

\yK/Rq l] \\ ( u )

Rey XRh and Ra, Rb, Re, Rf, Rg, Rh, A, n and the line in broken lines have the above meaning.

Variant d) of the process can also be carried out under the same conditions as variant b) of the process.

According to variant of process e), compounds corresponding to formula Ib can be prepared, in which Ra denotes a cyano group, Rc' a nitro, cyano group or the -(A )n-R12 group and r!2 ie -COR^l group, a carbo-cyclic, aromatic or carbon-linked heterocyclic group, aromatic or partially unsaturated, and Rb, A, n and R^l have the above meaning.

17

The transformation of one or more carboxaldehyde groups into one or more cyano groups can be carried out using processes known and familiar to technicians. For example, a compound with the formula Ia2, III, or IV5 can be treated with hot hydroxylamine-O-sulfonic acid, preferably using water as the solvent. The reaction can be carried out within a temperature range of approximately 50°C to approximately 100°C.

According to variant f), di-O-(lower alkanoyl) derivatives of compounds corresponding to formula Ib can be prepared, in which Rc' denotes the -(A)n-(CO)m-COR32 group and R32 an amino group, a lower hydrocarbon radical linked by an oxygen atom or by a lower imino or alkylimino group, optionally substituted, 15 saturated or partially unsaturated, or a nitrogenous heterocyclic group linked by a saturated ring nitrogen atom, and A, n, and m have the meanings above. This reaction can also be carried out by processes known and familiar to technicians. Lower alkyl esters 20 can, for example, be prepared by treating the carboxylic acid in the presence of an acid with the corresponding lower alcohol, preferably using the corresponding lower alcohol as the solvent. Suitable acids include, for example, mineral acids such as hydrochloric acid and organic sulfonic acids, such as p-toluenesulfonic acid. The reaction temperature is preferably within the range of room temperature up to the boiling point of the chosen solvent.

Other esters and amides are preferably pre-prepared from reactive carboxylic acid derivatives. Suitable reactive carboxylic acid derivatives include, for example, the corresponding carboxylic acid halides, in particular carboxylic acid chlorides, the corresponding carboxylic acid anhydrides, and mixed anhydrides (e.g., with trifluoracetic acid).

18

and organic sulfonic acids such as mesitylenesulfonic acid and p-toluenesulfonic acid), suitable imidazolides of carboxylic acids, etc. The process is advantageously carried out in the presence of an acid-fixing agent and in an inert organic solvent. Suitable acid-fixing agents include, for example, tertiary amines such as triethylamine and pyridine. In the preparation of amides, an excess of an amine corresponding to formula VI can also be used as an acid-fixing agent. Suitable solvents include, for example, open-chain and cyclic ethers such as tetrahydrofuran, diethyl ether, β-butyl ether, dioxane, ethylene glycol, dimethyl ether, etc., halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichlor-15 ethane, acetonitrile and dimethylformamide.

The hydrolysis of compounds corresponding to formula Ib^ into the corresponding catechol derivatives according to variant g) of process can be carried out by methods known per se and familiar to technicians. Hydrolysis can, for example, be carried out by treatment with an alkali metal hydroxide such as sodium or potassium hydroxide in a suitable solvent. Suitable solvents include, for example, lower alcohols such as methanol, and water or a mixture thereof. Hydrolysis can, for example, be carried out in a temperature range from about 0°C to the boiling point of the solvent, but preferably at room temperature.

According to variant h), compounds corresponding to the general formula can be prepared

30

?has

"°v

• •

/'x V*-C (R"1) =CH-C0-R H0 Rb

T. 10

23 Ib

35

C

19

in which Ra, Rb, R1, and R2 have the above meanings, and their corresponding lower di-O-alkanoyl derivatives. As a secondary amine, cyclic amines such as pyrrolidine, piperidine, morpholine, and thiomorpholine are preferably used. Suitable solvents for this process include, for example, open-chain and cyclic ethers such as tetrahydrofuran, diethyl ether, β-butylmethyl ether, dioxane, ethylene glycol, and dimethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform, β-dichloroethane, acetonitrile, and dimethylformamide. The reaction temperature is advantageously in the range of about 0°C to the boiling point of the chosen solvent, preferably operating at room temperature. In a particularly preferred embodiment, the reaction is carried out in the presence of an acid, preferably a carboxylic acid, such as acetic acid.

According to variant i) of the process, compounds corresponding to the general formula can be prepared

20

HOW\

To V"(A)n-Q5 Ibl1

H0 Rb

25

in which Q5 designates the group

30

.Rf .Re

N-N /N-*\

(v) or \N (w)

• =: •

\ /

i • — •

noh xoh and Ra, Rb, Re, Rf, A and n have the above meaning.

35 Suitable solvents for this process include, for example

C

20

lower alcohols such as methanol and ethanol, open-chain and cyclic ethers such as tetrahydrofuran, diethyl ether, β-butyl ether, dioxane, ethylene glycol and dimethyl ether, 5-aceto-nitrile and dimethylformamide. Preferably, the process is carried out at

hot, for example in a temperature range of about 50°C to the boiling point of the chosen solvent, we preferably operate at the boiling point of the chosen solvent.

10. According to variant j) of the process, compounds corresponding to the general formula can be prepared

•y'

15 AV-(A)n-S 4

1 H0 Rb NN-(Z)p-R4

in which Ri denotes the -COR^l group, a carbo-cyclic, aromatic group or a heterocyclic group linked by a carbon atom, aromatic or partially unsaturated,

or a substituted hydrocarbon radical where appropriate, saturated or partially unsaturated, and Ra, Rb, r31, r4, a, Z, n and p have the above meaning.

This process can also be carried out using methods known per se and familiar to all technicians. Suitable solvents include, for example, lower alcohols such as methanol and ethanol, dimethylformamide, and water. The reaction is advantageously carried out at room temperature.

30 According to variant k) of the process, compounds of formula Ib can be transformed into their esters and ethers – hydrolyzable under physiological conditions. Suitable esters, hydrolyzable under physiological conditions, are in particular compounds corresponding to formula Ib, 35 in which at least one of the two hydroxyphenolic groups

21

is acylated by a lower fatty acid. These can be prepared by processes known per se and familiar to all technicians. In a preferred embodiment, acylation is carried out with the corresponding lower fatty acid anhydride 5, in the presence of a catalytic amount of a strong acid, preferably using excess fatty acid anhydride as the solvent. Suitable acids are, for example, sulfuric acid and organic sulfonic acids such as p-toluenesulfonic acid. 10 Hydrolyzable ethers under suitable physiological conditions are, for example, compounds corresponding to formula Ib, in which at least one of the two hydroxyphenolic groups is etherified by a lower 1-alkoxycarbonyloxy-1-alkyl group, a lower 1-alcanoyloxy-1-15 alkyl group, or a lower 2-oxo-1-alkyl group. Etherification can be carried out by processes known and familiar to all technicians. For example, a compound corresponding to formula Ib can be reacted with a lower 1-alkoxycarbonyloxy-1-alkyl group, a lower 20-1-alkanoyloxy-1-alkyl group, or a lower 2-oxo-1-alkyl halide. This etherification is advantageously carried out in the presence of a base. Halides, in particular, can be considered. Suitable bases include, for example, alkali metal hydroxides and alkali metal carbonates, such as sodium hydroxide and sodium carbonate.

According to variant k) of the process, compounds corresponding to formula Ib above can also be transformed into pharmaceutically acceptable salts. In particular, salts with pharmaceutically acceptable bases can be considered as such salts. Examples of these salts include alkali metal salts, such as sodium and potassium salts. These salts can be prepared by processes known per se and familiar to all technicians.

C

t. ■

.**■

t- A-'.". 2 2

- HAS '

ï£>' -

The various compounds used as substances of

The starting points are known or can be prepared by processes known in themselves. The following examples contain indications of

% .r, r detailed tions concerning the preparation of these starting substances 5.

A. As previously mentioned, compounds conforming to the formula inhibit the COMT enzyme. This action can be quantitatively assessed as follows: a rat liver homogeisate is incubated in the presence of a suitable substrate, as described in J. Neurochem. 3_8' 191-195 (1982), and COMT activity is measured. In a second

In a series of tests, incubation is carried out in the presence of a compound corresponding to formula 1a. From the difference in GOMT activities determined, the IC50 can be calculated. The IC50 is expressed in nmol/L and is the concentration in the incubation mixture required to lower the activity of COMT by 50%. The following table shows the IC50 values for some compounds corresponding to formula 1a. This table also contains information on the acute toxicity of these compounds (LD50 in mg/kg for a single oral administration to mice).

25

30

35

C

Compound corresponding to the formula

IC50 in LD50 in mg/kg nmoles/1 p.o.

3,4-dihydroxy-5-nitrophenyl-5 2-pyridyl ketone 53.4 1250-2500

3,4-dihydroxy-5-nitrophenyl-

3-pyridyl ketone 47.0 1000-2000 3,4-dihydroxy-5-nitrophenyl-

4-pyridyl ketone 67.0 1000-2000 10 3,4-dihydroxy-5-nitrobenzoate1

butyl 20.0 312-625

n-butyl 3,4-dihydroxy-5-nitrocinnamate 25.9 2500-5000

3,4-Dihydroxy-5-nitrophenyl-15 ethyl glyoxylate 48.1 1250-2500

3,4-dihydroxy-5-nitrobenzo-

Phenone 4 8.0 500-100 0

3.5-dinitropyrocatechol 36.9 500-1000 2 '-fluoro-3, 4-dihydroxy-r5-

20 nitrobenzophenone 42.0 312-625

The substances described can be used as medicinal products, for example in the form of pharmaceutical preparations for enteral or parenteral administration. Compounds meeting the formula 25 can, for example, be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions, emulsions or suspensions, rectally, for example in the form of suppositories, or parenterally, for example in the form of solutions for injections.

The preparation of pharmaceutical preparations can be carried out in a manner familiar to all technicians, by bringing the compounds corresponding to the formula, possibly in combination with other therapeutically interesting substances, along with solid supports.

24

or suitable, non-toxic, inert, therapeutically acceptable liquids, and where appropriate the usual adjuvants in pharmacy, in a galenic administration form.

As carrier materials, both mineral and organic materials can be used. For example, for tablets, coated tablets, dragees, and hard gelatin capsules, carrier materials can include lactose, corn starch or its derivatives, talc, stearic acid, or its salts. For soft gelatin capsules, carriers can include vegetable oils, waxes, fats, and semi-solid and liquid polyols (depending on the formulation of the active substance, however, no carrier is necessary for soft gelatin capsules). For the preparation of solutions and syrups, carrier materials can include water, polyols, sucrose, invert sugar, and glucose. For injectable solutions, carrier materials such as water, alcohols, polyols, glycerol, and vegetable oils can be used. For suppositories, carrier materials such as natural or hardened oils, waxes, fats, and semi-liquid or liquid polyols can be used.

Pharmaceutical adjuvants can be considered, including 25 preservatives, dissolving agents, stabilizers, wetting agents, emulsifiers, and taste-enhancing agents.

such as sweeteners and flavoring agents, colorings, salts to modify osmotic pressure, buffers, coating agents and usual antioxidants.

30 The dosage of the substances described can vary within wide limits depending on the disease being treated, the age and individual condition of the patient, as well as the method of administration, and it is naturally necessary to adapt to individual conditions in each case. In the case of improving 35 the treatment of Parkinson's disease and Parkinsonism

25

For adult patients, a daily dose of L-dopa can be considered, ranging from approximately 25 mg to approximately 1000 mg, particularly from approximately 100 mg to approximately 300 mg. Depending on the dosage, it is advantageous to administer the daily dose in several smaller doses.

Pharmaceutical preparations according to the invention advantageously contain about 25 mg to about 300 mg, preferably about 50 mg to about 150 mg of a compound corresponding to the formula 1a or of an ester or ether thereof 10 hydrolyzable under physiological conditions, or of one of its pharmaceutically acceptable salts.

The following non-limiting examples are given by way of illustration of the invention. All temperatures are in degrees Celsius.

15 Example 1

a) 17.1 g (86.7 mmol) of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde is added to 170 mL of boiling hydrobromic acid at a constant temperature, and the mixture is heated for 3.5 hours under reflux. After cooling, the precipitate formed is drained, washed twice in ice-cold water, and resuspended in ethyl acetate. The organic phase is washed twice with 50 mL of sodium chloride solution each time, dried over magnesium sulfate, and concentrated under vacuum using a vacuum pump. The resulting crystals are resuspended in methylene chloride, after which they are filtered through 10 times their weight of silica gel. The resulting material crystallizes in ethyl acetate/isopropyl ether. 3,4-Dihydroxy-5-nitrobenzaldehyde is obtained in the form of yellow crystals, melting at 142-143°C. 30 b) A solution of 1.83 g (10 mmols) of 3,4-dihydroxy-

5-nitrobenzaldehyde is dissolved in 25 ml of water. A solution of 1.7 g (15 mmol) of hydroxylamine-O-sulfonic acid in 6 ml of water is added, the mixture is stirred for 3.5 hours at 65°C, cooled, the precipitate is drained, and it is resuspended in ethyl acetate. The organic phase is dried on c*

26

Sodium sulfate is used to concentrate the solution under vacuum using a vacuum pump. The resulting crystals are then recrystallized in ethyl acetate/n-hexane. This yields 3,4-Dihydroxy-5-nitrobenzonitrile as yellow crystals that melt at 5°C to 194-195°C.

Example 2

aa) To 4.1 g of 4-(benzyloxy)-3-methoxybromobenzene, dissolved in 40 ml of tetrahydrofuran, 10 ml of solution is added dropwise at -70°C over a period of 10 minutes

10 of tert-butyllithium (1.4 M in hexane). After 2

After stirring at -70°C for 5 hours, 1 mL of pyridine-3-carbal-dehyde is stirred for 5 minutes. The reaction mixture is stirred for 1 hour at -70°C and for 2 hours at 0°C, and then poured over 100 mL of hydrochloric acid (IN). Extracted three times with 15 mL of ether each time. The combined ether phases are washed with 100 mL of hydrochloric acid (IN) and 20 mL of water. The combined aqueous phases are alkalinized with ammonia and extracted three times with 100 mL of methylene chloride each time. The combined methyl-20-lene chloride phases are dried over sodium sulfate and evaporated. Alpha-[4-(benzyloxy-3-methoxyphenyl]-3-pyridine-methanol is obtained as an oil.

ab) In a similar way, using pyridine-4-carbaldehyde, alpha-[4-(benzyloxy)-3-methoxy-25 phenyl1-4-pyridinemethanol is obtained in the form of an oil.

(a) To 3.2 g of alpha-[4-(benzyloxy)-5-methoxyphenyl]-3-pyridinemethanol, suspended in 50 mL of water, 2.5 g of potassium permanganate is added, after which the mixture is stirred for 30 minutes at 90°C. After the addition of a further 1.0 g of potassium permanganate and stirring for another 30 minutes at 90°C, the mixture is cooled to room temperature and extracted twice, each time with 150 mL of ethyl acetate. The combined ethyl acetate phases are washed with a sodium chloride solution, dried over sodium sulfate, and evaporated. The residue is chromatographed as follows

C

27

obtained on 50 g of silica gel with ethyl acetate. By recrystallization in methylene chloride/hexane, 4-(benzyloxy)-3-methoxyphenyl-3-pyridylketone is obtained, melting at 76°.

5 bb) In a similar way, from alpha-[4-(benzyloxy)-3-methoxyphenyl)-4-pyridinemethanol, 4-(benzyloxy)-3-methoxyphenyl-4-pyridylketone melting at 85-87° (methylene chloride/hexane) is obtained.

ca) A 20 g of 4-(benzyloxy)-3-methoxyphenyl-3-pyridyl-

10 ketones are dissolved in 200 ml of methylene chloride. 50 ml of 33% hydrobromic acid in acetic acid is added dropwise at 10°C over a period of 15 minutes. After 3 hours of stirring at 20°C, the reaction mixture is poured onto a mixture of 100 ml of concentrated ammonia and ice.

15. The pH is adjusted to 6 by adding acetic acid. The methylene chloride phase is separated: the aqueous phase is extracted twice more, each time with 100 ml of methylene chloride. The combined methylene chloride phases are dried over sodium sulfate and evaporated. The mixture is then re-

20. Treat the residue in methylene chloride/hexane. The resulting product is 4-hydroxy-3-methoxyphenyl 3-pyridylketone, which melts at 150-151°.

cb) In a similar way, 4-(benzyloxy)-3-methoxyphenyl 4-pyridylketone is obtained from 4-(benzyloxy)-3-methoxyphenyl 4-pyridylketone, 4-hydroxy-

25 3-methoxyphenyl 4-pyridylketone melting at 215-218° (aceto-nitrile).

da) To 1.15 g of 4-hydroxy-3-methoxyphenyl 3-pyridylketone dissolved in 15 ml of acetic acid, 0.38 ml of nitric acid is added dropwise at room temperature

30 to 65%. After stirring for 2 hours, the reaction mixture is poured onto 120 mL of ice water, then adjusted to pH 5 with concentrated ammonia, and the precipitate formed is separated by filtration. The residue thus obtained is heated under reflux in 20 mL of acetonitrile, then filtered.

35 again. We obtain 4-hydroxy-3-methoxy-5-nitrophenyl-3-

28

pyridylketone in the form of brown crystals melting at 193°.

db) Similarly, 4-hydroxy-3-methoxyphenyl-4-pyridylketone, which melts at 240°C, is obtained from 4-hydroxy-3-methoxy-5-nitrophenyl-4-pyridylketone. 5 e) 3.5 g of 4-hydroxy-

3-Methoxy-5-nitrophenyl-3-pyridylketone is dissolved in 70 mL of 48% aqueous hydrobromic acid. The reaction mixture is then evaporated under reduced pressure. The residue is recrystallized in water. The yield is 3,4-Dihydroxy-5-nitrophenyl-3-pyridylketone hydrobromide, which melts at 265°C.

f) Similarly, we obtain from the

4-hydroxy-3-methoxy-5-nitrophenyl-4-pyridylketone, 3,4-dihydroxy-5-nitrophenyl-4-pyridylketone melting at 246° (recris-

15 (planted in water).

g) 13.2 g of 3,4-dihydroxy-5-nitrophenyl-4-pyridylketone are suspended in 500 ml of methanol and 4.88 g of methanesulfonic acid are added while stirring.

The suspension is heated under reflux for 60 minutes. It is then cooled to 10°C, the crystals are drained, and they are washed twice, each time with 30 ml of methanol. The resulting compound is 3,4-dihydroxy-5-nitrophenyl-4-pyridylketone methanesulfonate, which melts at 260-261°C (decomposition).

Example 3

25 a) A solution of

2.6 g (12.2 mmol) of 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 26 ml of boiling hydrobromic acid at a constant temperature. After cooling, the solvent is removed by steam distillation. The crystalline residue is recrystallized in 250 ml of water at boiling temperature. The yield is 3,4-dihydroxy-

5-nitrobenzoic acid in the form of yellow crystals melting at 224-226°.

b) 1.0 g (5 mmol) of 3,4-dihydroxy-35-5-nitrobenzoic acid is added to 20 ml of methanolic acid solution

29

In hydrochloric acid, the mixture is stirred for 3 hours at 45°C, and the residue is resuspended in methylene chloride after solvent removal. The organic phase is washed with sodium chloride solution, dried over sodium sulfate, and evaporated. The resulting crystalline product is resuspended in methylene chloride and filtered through 10 times its weight of silica gel. The material is then recrystallized in ethyl acetate/n-hexane. Methyl 3,4-dihydroxy-5-nitrobenzoate is obtained as 10 yellow crystals melting at 144-145°C.

Similarly, starting from 3,4-dihydroxy-5-nitrobenzoic acid, the following esters are obtained:

c) ethyl 3,4-dihydroxy-5-nitrobenzoate melting at 106-107° (recrystallized in ethyl acetate/n-hexane), 15 d) n-butyl 3,4-dihydroxy-5-nitrobenzoate melting

at 73-74° (recrystallized in methylene chloride, and e) n-hexyl 3,4-dihydroxy-5-nitrobenzoate melting at 44-45° (recrystallized in isopropyl ether.

Example 4

20 a) To 10.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde, dissolved in 150 ml of tetrahydrofuran, 25 ml of a 2 M phenyl-lithium solution (in benzene/ether) (7:3) is added dropwise at -20°C over a period of 15 min, and the reaction mixture is stirred for 1 h at 0°C and for 2 h at 20°C. 25 It is then 150 ml of 2 N sulfuric acid added,

Extraction is performed three times with 150 mL of ether. The combined ether phases are washed with a sodium chloride solution, dried over sodium sulfate, and evaporated. The residue thus obtained is chromatographed on 180 g 30 of silica gel with methylene chloride. 3,4-Dimethoxy-5-nitrobenzhydrol is obtained as an amorphous solid.

b) To 2.5 g of 3,4-dimethylxy-5-nitrobenzhydrol, dissolved in 50 ml of methylene chloride, 2.2 g of pyridinium chloro-35 chromate are added, after which the mixture is stirred for 2 h at

30

at room temperature. Then the insoluble components are separated by filtration. The filtrate is evaporated and the residue is chromatographed on 60 g of silica gel with methylene chloride. After recrystallization in 5-methylene chloride/hexane, 3,4-dimethoxy-5-nitrobenzophenone is obtained, melting at 78-80°C.

c) 0.5 g of 3,4-dimethoxy-5-nitrobenzophenone is stirred for 30 h at 110°C in a mixture of 4 mL of acetic acid and 4 mL of 48% aqueous hydrobromic acid. The reaction mixture is then evaporated to dryness. The residue is resuspended in methylene chloride. It is washed with water, dried over sodium sulfate, and evaporated. After recrystallization in methylene chloride/hexane, 3,4-dihydroxy-5-nitrobenzophenone, which melts at 132°C, is obtained. Example 5

a) 4.9 g (0.2 mol) of magnesium is suspended in 15 mL of absolute ethanol and heated after the addition of 1 mL of carbon tetrachloride until the reaction starts. Then, a solution of 31.8 g (0.2 mol) of diethyl malonate in 19.9 mL of absolute ethanol and 80 mL of absolute toluene is added dropwise, while stirring, so that the temperature is between 50 and 70°C. Stirring continues for 1 h at this temperature, after which the reaction mixture is cooled to -5°C and a solution of 49.3 g (0.2 mol) is added dropwise.

3,4-Dimethoxy-5-nitrobenzoyl chloride (melting point 82-85°C) is dissolved in 300 mL of absolute toluene and 50 mL of absolute tetrahydrofuran, ensuring the temperature does not exceed -5°C. The mixture is then stirred overnight at room temperature. After removing the solvent by distillation, the residue is dissolved in 500 mL of ethyl acetate. With stirring and ice cooling, a solution of 12 mL of concentrated sulfuric acid in 80 mL of water, also ice-cooled, is added. The organic phase is washed with a sodium chloride solution and dried over sulfate.

magnesium is added and evaporated. The resulting oil is chromatographed with methylene chloride in 10 times its weight of silica gel. The crystalline material obtained is recrystallized in isopropyl ether. Diethyl 3,4-Dimethoxy-5-nitrobenzoylmalonate is obtained as light beige crystals that melt at 70°C.

b) 19.0 g (51.4 mmol) of diethyl 3,4-dimethoxy-5-nitrobenzoylmalonate is dissolved in 100 ml of ethyl acetate, and 5 drops of concentrated sulfuric acid are added.

The mixture is heated for 16 hours under reflux. The acetic acid is removed at 60°C under vacuum using a water aspirator, and the residue of 250 mL of toluene is added three times, evaporating it each time. The crystalline residue is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, and evaporated. The resulting crystals are chromatographed with toluene in 30 times their weight of silica gel. The crystalline material obtained is recrystallized in isopropyl ether. 3,4-Dimethoxy-5'-nitroacetophenone is obtained as yellowish crystals melting at 86-87°C.

c) 2 g (8.9 mmols) of 31,41-dimethoxy-5'-nitroacetophenone is added to 30 ml of boiling hydrobromic acid at constant temperature, and stirred for 2.5 h at 140°.

After cooling, pour over 200 ml of ice water.

The mixture is extracted three times, each time with 100 mL of ethyl acetate. The organic phase is washed twice, each time with 25 mL of sodium chloride solution, dried over sodium sulfate, and evaporated. The resulting product is filtered with ethyl acetate through 20 times its weight of silica gel. Recrystallization of the material in water yields 3',4'-dihydroxy-51-nitroacetophenone as yellow crystals melting at 159-160°C.

The same compound is obtained starting from 4'-hydroxy-31-

32

methoxy-5'-nitroacetophenone by treatment with hydrobromic acid at boiling point.

Example 6

a) 100 g (0.8 mole) of guaiacol is dissolved in 136.4 g (0.86 mole) of isobutyric anhydride, and the mixture is then mixed with

120 g (0.88 mol) of anhydrous zinc chloride (all of it dissolves) is used to heat the reaction mixture to 155°C and cool it after 3 minutes. The residue is first steam-strengthened to remove volatile fractions, then extracted three times with 500 mL of ether each time. The organic phase is washed twice with 250 mL of water each time, once with 150 mL of saturated bicarbonate solution, and again with 250 mL of water. It is dried over sodium sulfate and evaporated under vacuum in a water aspirator. The resulting brown resin is distilled under high vacuum. The distillate, boiling at 105-120°C (at 6.67 Pa), is dissolved in ether, after which n-hexane is added until incipient crystallization occurs. The crystals obtained are recrystallized in ether/hexane. 20 4'-hydroxy-3'-methoxy-2-methylpropiophenone is obtained in the form of colorless crystals melting at 86-87 °-.

b) 15.0 g (77.2 mmol) of 4-hydroxy-3'-methoxy-2-methylpropiophenone is dissolved in 300 ml of glacial acetic acid and added dropwise, while stirring, to a

25, duration of 15 minutes, 7.65 ml of 50.5% (11.2N) nitric acid

in 40 ml of glacial acetic acid. After 15 minutes, the reaction mixture is poured onto ice water, the precipitated crystals are drained off, washed with water, and dissolved in methylene chloride. The solution is dried over sodium sulfate and evaporated. The crude product obtained is reconstituted in methylene chloride and filtered through 100 g of silica gel. The resulting crystals are recrystallized in methylene chloride/n-hexane. 4'-Hydroxy-3'-methoxy-2-methyl-5'-nitropropio-35-phenone is obtained as yellow crystals melting at 85-87°C.

33

c) To 8.0 g (33.4 mmol) of 41-hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone, 64 g of pyridine hydrochloride are added and the mixture is stirred for 45 min at 180°C. After cooling, the reaction mixture is poured onto 500 mL of ice-cold water, then acidified with 20 mL of 3N hydrochloric acid, and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate, and evaporated under vacuum using a water aspirator. After recrystallization in methylene chloride/10n-hexane, 3',4'-dihydroxy-2-methyl-5'-nitropropiophenone is obtained as yellow crystals melting at 98-99°C.

Example 7

a) 100 g (805.5 mmol) of guaiacol is dissolved in 15,136.4 g (86.2 mmol) of butyric anhydride, 120 g (880 mmol) of zinc chloride is added, the mixture is heated as indicated in Example 6a for 3 minutes, and then the process is carried out as described in that example. The crude product obtained after distillation is chromatographed under

20 high vacuum with toluene, on 600 g of silica gel.

After recrystallization in ether/n-hexane, 4'-hydroxy-3'-methoxybutyrophenone is obtained in the form of colorless crystals melting at 40-41°.

b) To a solution of 12.7 g (65.4 mmols) of 4'-hydroxy-25 3'-methoxybutyrophenone in 250 ml of glacial acetic acid,

6.5 mL of 11.2N nitric acid is added dropwise while stirring for 10 minutes. The mixture is then stirred for 15 minutes, poured onto ice-cold water, and the precipitate is drained off. It is washed with ice-cold water and resuspended in methylene chloride. The methylene chloride solution is then filtered through 50 g of silica gel.

The material obtained is recrystallized in methylene chloride/n-hexane. 4'-Hydroxy-3'-methoxy-5'-nitrobutyrophenone is obtained in the form of yellow crystals melting at 35 to 92-93°.

1

c) To 10.2 g (42.6 mmol) of 41-hydroxy-3'-methoxy-5'-nitrobutyrophenone, 80 g of pyridine hydrochloride are added and the mixture is stirred for 40 min at 200°C. After cooling, the reaction mixture is poured onto 500 mL of ice-cold water. 30 mL of 3N hydrochloric acid is added, and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The crude product obtained is chromatographed with methylene chloride on 150 g of silica gel. The resulting material is recrystallized in methylene chloride/n-hexane. 3',4'-Dihydroxy-5'-nitrobutyrophenone is obtained as yellow crystals melting at 88-90°C.

Example 8

a) 2.25 g (10 mmol) of 3,4-dihydroxy-5-nitrocinnamic acid is dissolved in 50 mL of methanol, and hydrochloric acid is passed through this solution for 10 minutes. After 1 hour, 50 mL of isopropyl ether is added, the precipitate formed is drained, and it is washed with isopropyl ether. After recrystallization in methanol/ether, methyl 3,4-dihydroxy-5-nitrocinnamate is obtained as yellow crystals melting at 186–187°C.

b) In a similar manner, butyl-3,4-dihydroxy-5-nitrocinnamic acid and a solution of butanolic hydrochloric acid are obtained in the form of yellowish crystals melting at 129-130°.

Example 9

5.0 g (13.5 mmol) of diethyl 3,4-dimethoxy-5-nitrobenzoylmalonate is dissolved in 50 mL of absolute methylene chloride. After cooling to -20°C, a solution of 16.9 g (67.5 mmol) of boron tribromide in 30 mL of methylene chloride is added dropwise while stirring, ensuring that the temperature does not exceed -20°C. The mixture is then stirred overnight at room temperature. After the addition of 80 mL of ethanol, the mixture is stirred for 20 minutes at room temperature.

35

The mixture is heated to room temperature, and the solvent is removed by vacuum distillation using a water aspirator. The residual water is added and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate, and evaporated. The crude product is filtered with ethyl acetate through 50 g of silica gel. The resulting crystalline residue is recrystallized in methylene chloride/n-hexane. Ethyl 3,4-Dihydroxy-5-nitrobenzoylacetate is obtained as 10 yellow crystals melting at 141-142°C.

Example 10

a) To a solution of 1.49 g (12.3 mmols) of 2-phenylethylamine in 100 ml of methylene chloride, 1.26 g of triethylamine is added, while stirring, dropwise.

15. A solution of 3.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 100 mL of methylene chloride is mixed, and the mixture is stirred for 15 minutes. The organic phase is then extracted twice, each time with 50 mL of ice-cold water, dried over sodium sulfate, and evaporated under vacuum using a water aspirator. After recrystallization in methylene chloride/n-hexane, 3,4-dimethoxy-5-nitro-N-phenethylbenzamide is obtained as light beige needles, melting at 121–122°C.

b) 3.6 g (10.9 25 mmol) of 3,4-dimethoxy-5-nitro-N-phenethylbenzamide is heated under reflux for 96 h with

36 ml of phosphorus oxychloride. After removing the excess phosphorus oxychloride by distillation under vacuum in a water aspirator, 100 ml of toluene is added three times at 60°C, with the solvent being distilled 30 ml each time. The residue is resuspended in methylene chloride. The organic phase is washed with water, dried over sodium sulfate, and evaporated under vacuum in a water aspirator. The resulting red resin is chromatographed with methylene chloride/ethyl acetate (1:1) on 35,120 g of silica gel. 1-(3,4-dimethoxy-5-

nitrophenyl)-3,4-dihydroisoquinoline in the form of a yellow resin.

c) To 1.4 g (4.5 mmol) of 1-(3,4-dimethoxy-5-nitrophenyl)-3,4-dihydroisoquinoline, 15 mL of boiling hydrobromic acid at a constant temperature is added, and the mixture is heated to boiling under a nitrogen atmosphere for 1.5 h under reflux. After removal of the hydrobromic acid by vacuum distillation using a water aspirator, the crystalline residue is recrystallized in acetone. The hydrate bromide of 5-(3,4-dihydro-1-isoquinoline) is obtained as yellow crystals that melt at over 250°C (decomposition).

Example 11

a) To 5.0 g (27.7 mmoles) of 4-hydroxy-5-methoxy-iso-phthalaldehyde, 50 ml of boiling hydrobromic acid at constant temperature is added and the mixture is heated under an argon atmosphere for 3 h under reflux and stirring until boiling.

After cooling, 50 mL of ice water is added, the precipitate that forms is drained off, and washed with water. The crude product is then resuspended in ethyl acetate and filtered through 50 g of aluminum oxide (activity stage II). The resulting crystalline material is recrystallized in ethyl acetate/n-hexane. 4,5-Dihydroxyisophthalaldehyde is obtained as faintly orange crystals melting at 201–202°C.

b) To a solution of 2.0 g (12.0 mmols) of 4,5-dihydroxy-isophthalaldehyde in 20 ml of water, a solution of 3.27 g (28.9 mmols) is added drop by drop, while stirring, at 30°

of hydroxylamine-O-sulfonic acid in 12 ml of water, then maintained at 65°C for 10 hours. After cooling,

The precipitate that forms is drained, washed with water, and resuspended in ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, and evaporated under vacuum using a water aspirator. After recrystallization in ethyl acetate, 4,5-dihydroxyisophthalonitrile is obtained in the form of crystals.

37

yellows, which decompose above 300°.

Example 12

a) To a solution of 112.5 g of 2-bromo-41-hydroxy-3'-methoxyacetophenone in 560 ml of glacial acetic acid, 5 drops are added, while stirring, over a period of

For 30 minutes at 20-25°C, a solution of 38 g of fuming nitric acid (96%) in 50 ml of glacial acetic acid is reacted. It separates into brownish-yellow crystals. After 90 minutes, the reaction mixture is poured onto 300 g of ice. The crystals are drained, washed with 1000 ml of water, and dissolved in 1000 ml of water and then in 1000 ml of methylene chloride. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate is evaporated at 50°C under a vacuum in a water aspirator until initial crystallization occurs.

The crystals, cooled to room temperature, are drained and washed with a little methylene chloride. This yields 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone, which melts at 147-149°.

20 b) Process A:

(a) To a suspension of 58 0.1 mg of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 10 ml of ethanol, 443.8 mg of selenium dioxide is added, and the mixture is heated under reflux for 71 h. The mixture is then separated by filtration.

25. The selenium reaction is carried out and evaporated. The residue is dissolved in methylene chloride, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated. The result is...

ethyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate melting point 30 at 165-167° (recrystallized in ethanol).

We obtain in a similar way:

bb) From 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and n-butanol, 4-hydroxy-3-methoxy-

n-Butyl 5-nitrophenylglyoxylate melting at 105-107° (recrystallized in ethanol) and

38

bc) from 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and n-hexanol, hexyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate melts at 103-105° (recrystallized in n-hexanol/petroleum ether).

5 c) Process B:

ca) To a suspension of 29.01 g of 2-bromo-4'-hydroxy-31-methoxy-51-nitroacetophenone in 300 ml of tert-butanol, 27.74 g of selenium dioxide is added and the mixture is heated for 18 h under reflux to boiling. The re-

10. The hot filtration solution is then washed with methylene chloride through a diatomaceous earth filtration aid. The filtrate is evaporated, and the residue is suspended in 150 mL of hot methylene chloride. The crystalline precipitate is drained and washed with a small amount of methylene chloride. The resulting 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid melts at 169–171°C.

2.42 g of 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid is dissolved in 25 mL of dry N,N-dimethylformamide. At room temperature, 50 mg of 4,20-dimethylaminopyridine and 920 mg of dry methanol are added, and the mixture is cooled in an ice bath to 0°C. 2.27 g of N,N-dicyclohexylcarbodiimide is then added. After 10 minutes, the ice bath is removed, and the reaction mixture is stirred for another hour at room temperature. It is then evaporated to dryness. The residue is dissolved in ethyl acetate and separated from the undissolved urea by filtration.

The filtrate is washed four times with water, dried over sodium sulfate, filtered, and evaporated. The yield is methyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate 30, which melts at 155-157°C (recrystallized in methylene chloride/ether).

Similarly, we obtain:

cb) From 4-hydroxy-3-methoxy-5-nitrophenyl-glyoxylic acid and ethanol, 4-hydroxy-3-methoxy-5-nitrophenyl-

35 ethyl glyoxylate melting at 165-167° (recrystallized in

Q

I

39

ethanol) and cc) from 4-hydroxy-3-methoxy-5-nitro-phenylglyoxylic acid and isopropanol, i-propyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate melting at 99-101° (recrystallized in isopropanol).

d) To a suspension of 17.2 g of ethyl 4-hydroxy-3-methoxy-5-nitrophenylflyoxylate in 100 ml of dry acetonitrile and 100 ml of dry toluene, 10.53 g of sodium iodide and 11.9 g of silicon tetrachloride are added, and the mixture is heated

The reaction is carried out for 10 to 47 hours under reflux. The reaction mixture is then evaporated, and the residue is distilled six times, each time with 200 mL of toluene. The resulting residue is divided between water and ether and filtered through a diatomaceous earth filtration aid. The etheric phase is washed four times with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated. The oily residue is treated three times with ether and activated carbon. The yield is ethyl 3,4-dihydroxy-5-nitrophenyl-glyoxylate, melting at 77-79°C (recrystallized in 20% ether/n-hexane).

We obtain in a similar way:

e) From methyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate, methyl 3,4-dihydroxy-5-nitrophenylglyoxylate in the form of a yellow distillate at 145-150° and under 10.67 Pa,

25 f) from isopropyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate, isopropyl 3,4-dihydroxy-5-nitrophenylglyoxylate in the form of a yellow distillate at 155-160° and under 12.0 Pa,

(g) from n-butyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxy-30-late, butyl 3,4-dihydroxy-5-nitrophenylglyoxylate as a yellow distillate at 160-165°C and 10.67 Pa, and (h) from n-hexyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate, 3,4-dihydroxy-5-nitrophenylglyoxylate

35 of hexyl in the form of a yellow distal lattice at 165-170° and

40

under 12.0 Pz.

Example 13

236.1 mg of n-hexyl 3,4-dihydroxy-nitrophenylglyoxylate is dissolved in 15 mL of ethanol, and 7.59 mL of a 0.1 N sodium hydroxide solution is added. After 1 hour, the yellow-red solution is evaporated. The sodium salt of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate is recrystallized in water; it has a melting point of approximately 300°C.

Example 14

To a solution of 3.18 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate in 47.5 mL of ethanol, 1.11 g of O-methylhydroxylamine hydrochloride, 1.95 g of sodium acetate, and 2.5 mL of water are added, and the mixture is heated to boiling for 5 h under reflux. The reaction mixture is then evaporated, and the residue of ether and water is added. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated. The residue is chromatographed on silica gel with methylene chloride. A 7:3 mixture of E- and Z-3,4-dihydroxy-5-nitrophenylglyoxylates of n-hexyl is obtained in the form of a reddish oil; 80 MHz NMR spectrum (CDCI3): signal for O-methyl at 3.96 and 4.05 ppm.

Example 15

To a solution of 5.1 g of ethyl 3,4-dihydroxy-5-nitrophenyl-glyoxylate in dry methylene chloride, 25 g of boron tribromide is added dropwise at -10°C over a period of 15 minutes. The mixture is then stirred for 1 hour at -10°C.

then for 17 hours at room temperature. The reaction mixture is then evaporated, the residual water is carefully added, and the mixture is stirred for another 30 minutes at 50°C. After cooling to room temperature, the flocculent precipitate is drained. The aqueous phase is acidified with 10 mL of hydrochloric acid (IN) and extracted four times with...

41

In ether, the combined organic extracts are washed four times with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated. The crude product is filtered three times successively through ether using a diatomaceous earth filter aid. The yield is 3,4-Dihydroxy-5-nitrophenylglycyoxylic acid, which melts at 172-174°C (in isopropyl ether).

Example 16

a) A mixture of 3.93 g of n-hexyl 3,4-dihydroxy-10 5-nitrophenylglyoxylate and 1.38 g of 2-amino-

phenol at 120°C while stirring. The molten mass crystallizes after 5 minutes. After 2 hours, it is cooled and recrystallized in methanol. This yields 3-(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-one, which melts at 202-204°C. ■ 15 In a similar manner, the following are obtained:

b) From n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 2-amino-p-cresol, 3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-l,4-benzoxazin-2-one melts at 233-235° (recrystallized in a methanol/chloride mixture of

20 methylene). ~

c) from hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 2-amino-4-propylphenol, 3-(3,4-dihydroxy-5-nitrophenyl)-6-propyl-2H-l,4-benzoxazin-2-one melting at 200-202° (recrystallized in methanol),

25 d) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 3-amino-4-hydroxybenzoic acid, 3-(3,4-dihydroxy-5-nitrophenyl)-2-oxo-2H-l,4-benzoxazin-6-carboxylic acid melting at 286-287° (recrystallized in acetone/petroleum ether),

30 e) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 2-amino-4-chlorophenol, 6-chloro-3-(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-one melting at 241-243° (recrystallized in methanol),

f) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 2-amino-4,6-dichlorophenol, 6,8-dichloro-

1

42

3-(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-one melting at 237-239° (recrystallized in ethanol/ether) and g) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 2-amino-5-nitrophenol, the 3-(3,4-dihydroxy-

5 5-nitrophenyl)-7-nitro-2H-l,4-benzoxazin-2-one melting at 253-255° (recrystallized in acetonitrile/ethanol).

Example 17

a) A mixture of 396.0 mg of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 137.6 mg of 1,2-

10 phenylenediamine is heated for 60 minutes at 120°C. It is then suspended in methanol, drained, and recrystallized in an N,N-dimethylformamide/water mixture. This yields 3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxa-linone, which melts at over 300°C.

15. We obtain the following in the same way:

b) From n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and N-methyl-1,2-phenylenediamine, 1-methyl-3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone melts at 271-273° (recrystallized in methanol),

20 c) from 3,4-dihydroxy-5-nitrophenylglyoxylate

- of n-hexyl and N-propyl-1,2-phenylenediamine, 1-propyl-3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone melting at 183-185° (recrystallized in methanol),

d) from 3,4-dihydroxy-5-nitrophenylglyoxylate

25 of n-hexyl and 4,5-dimethyl-l,2-phenylenediamine, the

3-(3,4-dihydroxy-5-nitrophenyl)-6,7-dimethyl-2(1H)-quinoxalinone melting at over 300° (recrystallized in an N,N-dimethylformamide/water mixture),

e) from 3,4-dihydroxy-5-nitrophenylglyoxylate

30 of n-hexyl and 4,5-dichloro-l,2-phenylenediamine, the

6,7-dichloro-3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone melting at over 300° (recrystallized in an N,N-dimethylformamide/water mixture)

f) from 3,4-dihydroxy-5-nitrophenylglyoxylate

35 of n-hexyl and 3-chloro-5-trifluoromethyl-1,2-phenylene-

diamine, a 1:1 mixture of 8 (and 5)-chloro-3-(3,4-dihydroxy-5-nitrophenyl)-6-(and 7 j-trifluoromethyl1-2(1H)-quinoxalinone melting at over 300° (recrystallized in an N,N-dimethylformamide/water mixture),

(g) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 4-methoxy-1,2-phenylenediamine, a 1:1 mixture of 3-(3,4-dihydroxy-5-nitrophenyl)-6(and7)-methoxy-2(1H)-quinoxalinone melting at over 300° (recrystallized in

1'ethanol/ether),

h) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 4-nitro-1,2-phenylenediamine, a 1:1 mixture of 3-(3,4-dihydroxy-5-nitrophenyl)-6(and 7)-nitro-2(1H)-quinoxalinone melting at over 300° (recrystallized in an N,N-dimethylformamide/water mixture) and i) from n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and N-hexyl-1,2-phenylenediamine, 1-hexyl-3-(3,4-dihydroxy-5-nitrophenyl)-2H-quinoxalinone melting at 152-154° (recrystallized in methanol).

Example 18

A solution of 1.07 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 696.3 mg of 2,3-diaminonaphthalene in 3 mL of 1-hexanol is heated to boiling under reflux for 3 h. The reaction mixture is then cooled and diluted with methanol. The crude product is drained and recrystallized from an N,N-dimethylformamide/water mixture. The yield is 3-(3,4-dihydroxy-5-nitrophenyl)-benzo[g]quinoxalin-2(1H)-one, which melts at over 300°C.

Example 19

A suspension of 2.05 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 600.8 mg of thiosemicarbazide is vigorously shaken for 30 min at 90°C. It is then cooled to 40°C and a solution of 870.1 mg of sodium hydroxide in 15 mL of water is added. The solution is then heated for 30 min at 90°C, the reaction mixture is cooled to room temperature, and 2 mL of the solution is added dropwise.

44

concentrated hydrochloric acid. The crystallized product obtained is drained and then dissolved in ethyl acetate. It is washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated.

5 We obtain 6-(3,4-dihydroxy-5-nitrophenyl)-3-mercapto-1,2,4-triazin-5(4H)-one melting at 282-284° (recrystallized in ethanol).

Example 20

aaa) A 2.9 g suspension of 2-bromo-4'-hydroxy-

10 3'-methoxy-5'-nitroacetophenone and 7 61.2 mg of thiourea are reacted in 170 mL of 60° ethanol. 820.3 mg of sodium acetate is added and the mixture is stirred for 6 hours. The reaction mixture is then evaporated, the remaining 170 mL of water is added, and the mixture is heated for 30 minutes at 60°C. After cooling, the product is drained and washed with water. The resulting compound is 4-(2-amino-4-thiazolyl)-2-methoxy-6-nitrophenol, which melts at 248-250°C (recrystallized in ethanol).

We obtain in a similar way:

aab) from 2-bromo-41-hydroxy-3'-methoxy-5'-

20 nitroacetophenone and N-phenylthiourea, 4-(2-anilino-4-thiazolyl)-2-methoxy-6-nitrophenol melting at 185-187° (recrystallized in ether).

aba) To a solution of 4.88 g of 6-amino-4'-(trifluoromethyl)-hexananilide hydrochloride in 70 ml of water, add

25 50 ml of 1,2-dichloroethane and 3.56 g of calcium carbonate. The suspension is then mixed, with stirring at room temperature, with a solution of 2.6 g of thiophosgene in 1.7 ml of toluene. After 16 hours, the precipitate is drained and the organic phase is washed with

30% hydrochloric acid IN and water. After drying over sodium sulfate and filtration, the mixture is evaporated. This yields crude 41-(trifluoromethyl)hexananilide-6-isothiocyanate.

abb) A solution of 5.2 g of crude 4'-(trifluoromethyl)-hexananilide-6-isothiocyanate in 60 ml of ethanol,

35. Add 100 ml of concentrated ammonia. After 30 minutes,

45

The reaction mixture is evaporated. The residue is dissolved in ethyl acetate, washed with water, dried over sodium sulfate, filtered, and evaporated. The product obtained is 1-[5-[(cx,a,a-trif luoro-p-tolyl)carbamoylpentyl]52-thiourea, which melts at 140-142°C (recrystallized in ethanol).

abc) To a suspension of 666.7 mg of 1-[5-(a,a,a-tri-fluoro-p-tolyl)carbamoyl]pentyl]-2-thiourea and 580.2 mg of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 1050 mL of 60% ethanol, 164.2 mg of sodium acetate is added. A yellow-reddish solution is formed. After 90 minutes, the reaction mixture is evaporated, the residual water is added, the precipitate is drained, and it is washed four times with 10 mL of water each time. We obtain 6-[[4- 15 (4-hydroxy-3-methoxy-5-nitrophenyl)-2-thiazolyl]amino1 — 4' — (trifluoromethyl)hexananilide melting at 160-162° (recrystallized in ethanol).

ac) A solution of 2-9.0 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 20 g of 13.5 g of 2-aminoacetophenone is stirred at 90°C for 16 h in 250 mL of dry N,N-dimethyl-formamide. The reaction mixture is then evaporated to approximately two-thirds and poured onto ice. The separating crystals are drained and dissolved in methylene chloride. The mixture is washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated. The yield is 2-(4-hydroxy-3-methoxy-5-nitrobenzoyl)-3-methylindole, which melts at 195-197°C (recrystallized in methylene chloride/methanol).

ada) To a suspension of 14.5 g of 2-bromo-4'-hydroxy-30 3'-methoxy-5'-nitroacetophenone and 5.41 g of 1,2-phenylenediamine in 350 mL of methanol, 4.92 g of sodium acetate are added, and the mixture is heated to boiling under reflux for 22 h. The reaction mixture is then evaporated, the residue is dissolved in methylene chloride, this solution is washed four times with water, and dried on

sodium sulfate is filtered and evaporated. This yields 2-(4-hydroxy-3-methoxy-5-nitrophenyl)quinoxaline, which melts at 195-197° (recrystallized in methylene chloride/methanol).

We obtain in a similar way:

adb) From 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 5-dimethyl-1,2-phenylenediamine, 6,7-dimethyl-2-(4-hydroxy-3~methoxy-5-nitrophenyl)quinoxaline melts at 207-209° (recrystallized in the methylene chloride/methanol mixture.

b) To a suspension of 267.3 mg of 4-(2-amino-4-thiazolyl)-2-methoxy-6-nitrophenol in 10 mL of dry methylene chloride at -20°C, 1.25 g of boron tribromide is added. The mixture is stirred for another 1 h at -20°C after the addition, and without cooling, at room temperature for 18 h. The reaction mixture is then evaporated, the residual water is carefully added, and the mixture is stirred for 20 min at 50°C. After cooling to room temperature, the crude product is drained and washed with a little water. The yield is 5-(2-amino-4-thiazolyl)-3-nitropyrocatechol hydrobromide, which melts at 244-246°C (recrystallized in methanol).

We obtain in a similar way:

c) From 4-(2-anilino-4-thiazolyl)-2-methoxy-6-nitrophenol, 5-(2-anilino-4-thiazolyl)-3-nitropyrocatechol melts at 202-204° (recrystallized in methanol),

d) from 6-[4-(4-hydroxy-3-methoxy-5-nitrophenyl)-

2-thiazolyl)amino|-4'-(trifluoromethyl)hexananilide, 6-

[[4-(3,4-dihydroxy-5-nitrophenyl)-2-thiazolyl]amino i-4'-(tri-fluoromethyl)hexananilide melting at 214-216° (recrystallized in methanol),

e) from 2-(4-hydroxy-3-methoxy-5-nitrobenzoyl)-

3-methylindole, 5-bromo-2-(3,4-dihydroxy-5-nitrobenzoyl)-3-methylindole melting at 265-267° (recrystallized in methanol),

f) from 2-(4-hydroxy-3-methoxy-5-nitrophenyl)-

47

quinoxaline, 2-(3,4-dihydroxy-5-nitrophenyl)quinoxaline melting at 241-243° (recrystallized in methanol) and g) from 6,7-dimethyl-2-(4-hydroxy-3-methoxy-5-nitrophenyl)-quinoxaline, 6,7-dimethyl-2-(3,4-dihydroxy-5-nitrophenyl)quinoxaline melting at 274-276° (recrystallized in methanol).

Example 21

A mixture of 3.12 g of 2-bromo-31,4'-di-hydroxy-51-nitroacetophenone and 859.3 mg of thioacetamide is heated in 40 mL of ethanol for 18 h at refluxing boiling. After cooling, the crystals are drained and recrystallized in a methanol/isopropanol mixture. The resulting hydrobromide of 5-(2-methyl-4-thiazolyl)-3-nitropyrocatechol melts at 280–282°C.

Example 2.2

A solution of 1.38 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 461 mg of thiosemicarbazide in 20 mL of n-butanol is heated to boiling under reflux for 60 minutes. After cooling to room temperature, the crystals are drained and recrystallized in n-butanol. The resulting solution is the hydrobromide of 5-(2-amino-6H-1,3,4-thiadiazin-5-yl)-3-nitropyrocatechol, which melts at 265–267°C.

Example 2 3

A solution of 1.38 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 505.7 mg of 2-amino-1,3,4-thiadiazol in 25 mL of n-butanol is heated to boiling under reflux for 7 h. The reaction mixture is then cooled to room temperature and the crystals formed are drained. The yield is 5-(imidazo[2,1-b]-1,3,4-thiadiazol-6-yl)-3-nitropyrocatechol, which melts at 278–280 °C (recrystallized in methanol).

Example 24

A mixture of 2.78 g of 2-bromo-3',4'-dihydroxy-5'-nitroaceto-

48

Phenone, 1.01 g of 2-aminothiazol, and 40 mL of ethanol are used. The reaction mixture is then cooled to room temperature and the crystals are drained. The resulting hydrobromide of 5-(imidazo[2,1-b1-thiazol-6-yl)-3-nitropyrocatechol, which melts at 286–288°C (recrystallized in methanol), is obtained.

Example 25

A mixture of 1.95 g of 2-bromo-3',41-dihydroxy-5'-nitroacetophenone, 1.06 g of 2-aminobenzothiazol, and 50 mL of ethanol is heated to boiling under reflux for 17 h. The reaction mixture is then cooled to room temperature, after which the crystals are drained. The yield is 5-(imidazo[2,1-β1benzothiazol-2-yl)-3-nitropyrocatechol, which melts at 303–305 °C (recrystallized in an N,N-dimethylformamide/methanol mixture).

Example 26

A mixture of 2.78 g of 2-bromo-31,4'-dihydroxy-5'-nitroacetophenone, 1.51 g of 2-aminothiophenol, and 50 mL of ethanol is heated to boiling under reflux for 1 h. The reaction mixture is then cooled to room temperature, after which the crystals are drained. The yield is 5-(2H-1,4-benzothiazine-3-yl)-3-nitropyrocatechol, which melts at 302–304 °C (recrystallized in N,N-dimethylformamide/methanol).

Example 27

A mixture of 987.5 mg of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 1.01 g of 2-aminopyridine is melted at 110°C. After 30 minutes, 15 ml of ethanol is added, and the mixture is heated to boiling under reflux for 3 hours.

The reaction mixture is then cooled to room temperature and the crystals are drained. The resulting product is 5-(imidazo-[1,2-a]pyridine-3-yl)-3-nitropyrocatechol, which melts at 250-252°C (recrystallized in N,N-dimethylformamide/methanol).

Example 28

a) To a solution of 10.7 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid, in 500 ml of dry tetrahydrofuran, one

49

Add 8.9 g of 1,11-carbonyldiimidazol and then heat the reaction mixture for 5 h at 65-70°C. Then cool it to room temperature and add, over 15 min, a solution of 21.6 g of 6,5-aminohexyl t-butylcarbamate in 50 ml of dry tetrahydrofuran. Then heat the reaction mixture for 18 h at 65-70°C.

It is evaporated, the residue is suspended in ethyl acetate, the material is drained, and the drained material is chromatographed with acetone/methylene chloride (3:1) on silica gel. The t-butylcarbamate of

[6-(4-hydroxy-5-nitro-m-anisamido)hexyl1 melting at 145-147° (recrystallized in isopropanol) .

b) A solution of 4.1 g of t-butylcarbamate of [6-(4-hydroxy-5-nitro-m-anisamido)hexyl) in 80 ml of acid

15. In glacial acetic acid, 5.8 ml of hydrobromic acid is added at room temperature to glacial acetic acid (approximately 33%). The mixture is stirred for 2 hours, the precipitated crystals are drained off, and they are washed with ether. The resulting hydrobromide of N-(6-aminohexyl)-4-hydroxy-5-nitro-m-anisamide 20, which melts at 207-209°C (recrystallized in isopropanol).

c) To a suspension of N-(6(aminohexyl)- hydrobromide

4-hydroxy-5-nitro-m-anisamide in 25 ml of dry methylene chloride, 1.25 g of boron tribromide is added at -20°.

After adding the ingredients, shake for 1 hour at -20°C then for

25 17 hours at room temperature. The reaction mixture is then evaporated, the residue of 10 ml of water is added and the mixture is stirred for 1 hour at room temperature.

After evaporation of the water, the residue is chromatographed with a toluene/ethanol mixture (1:1) on Sephadex LH 20. The hydrobromide of N-6-aminohexyl-3,4-dihydroxy-

5-nitrobenzamide melting at 205-207° (recrystallized in ethanol).

Example 29

aa) A solution 35 of 4.93 g of 5-nitrovanillin and 2.7 g of 1,2-phenylene- is heated to boiling under reflux

c

50

diamine in 45 ml of methanol and 15 ml of nitrobenzene.

After 15 minutes, crystals begin to precipitate from the red solution. After 18 hours, the reaction mixture is cooled to room temperature and diluted with 60 mL of methanol. The crystals are drained and washed with methanol. The yield is 4-(2-benzimidazolyl)-2-methoxy-6-nitrophenol, which melts at 198–200°C (recrystallized in an N,N-dimethylformamide/methanol mixture).

We obtain in a similar way:

ab) From 5-nitrovanillin and 4,5-dichloro-1,2-phenylenediamine, 4-(5,6-dichloro-2-benzimidazolyl)-2-methoxy-6-nitrophenol melts at 258-260° (recrystallized in N,N-dimethylformamide/ether).

b) A suspension of 860.1 mg of 4-(2-benzimidazolyl)-2-methoxy-6-nitrophenol in 10 mL of glacial acetic acid and 10 mL of 48% hydrobromic acid is heated to boiling under reflux for 72 h. The mixture is then evaporated, and the residue is added four times, each time with 50 mL of toluene, which is removed by distillation after each addition. The resulting compound is 5-(2-benzimidazolyl)-3-nitropyrocatechol, which melts at over 300°C (recrystallized in the acetone/water mixture).

We obtain in a similar way:

c) From 4-(5,6-dichloro-2-benzimidazolyl)-2-methoxy-6-nitrophenol, 5-(6-dichloro-2-benzimidazolyl)-3-nitropyrocatechol melts at 282-284° (recrystallized in an acetone/water mixture).

Example 30

To a suspension of 29.0 g of 2-bromo-4'-hydroxy-3'-methoxy-51-nitroacetophenone in 700 ml of dry methylene chloride at -20°C, a solution of 125.3 g of boron tribromide in 300 ml of dry methylene chloride is added over a period of 30 minutes. After the addition, the mixture is stirred for another hour at -20°C and 16 hours at room temperature. It is then evaporated, and the residual water is carefully added while cooling with ice. The mixture is then stirred for 30 minutes at 50°C. After cooling

51

The solution is extracted with ether, the ethereal phase is washed with water, dried over sodium sulfate, filtered, and evaporated. This yields 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone, which melts at 138-140°C (recrystallized in methylene chloride).

Example 31

a) A solution of 3.6 g of ethyl 3,4-dihydroxy-5-nitrophenylglyoxylate is heated in 30 ml of acetic anhydride in the presence of a catalytic amount of sulfu-

10 concentrated ric acid, heated for 30 min at 110°C, cooled to room temperature, poured into 150 ml of water and stirred for 60 min. Extracted with ether, washed with a saturated sodium chloride solution, dried the combined organic extracts over sodium sulfate, filtered and evaporated. The yield is ethyl 3,4-diacetoxy-5-nitrophenylglyoxylate, melting at 87-89°C (recrystallized in ether/petroleum ether).

We obtain in a similar way:

b) From 3-(3,4-dihydroxy-5-nitrophenyl)-2H-2O 1,4-benzoxazin-2-one, 3-(3,4-diacetoxy-5-nitrophenyl)-

2H-1,4-benzoxazin-2-one melting at 186-188° (recrystallized in a methylene chloride/methanol mixture),

c) from 3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone, 3-(3,4-diacetoxy-5-nitrophenyl)-2(1H)-quinoxa-

25 linone melting 241-243° (recrystallized in a methylene chloride/methanol mixture),

d) from 3,4-dihydroxy-5-nitrobenzophenone, 3,4-diacetoxy-5-nitrobenzophenone melting at 141-143° (recrystallized in a methylene chloride/ether mixture),

30 e) from the 2'-fluoro-3,4-dihydroxy-5-nitrobenzo-

phenone, 3,4-diacetoxy-2'-fluoro-5-nitrobenzophenone melting at 122-124° (recrystallized in ether) and f) from 3,4-dihydroxy-5-nitrophenyl-4-pyridylketone, 3,4-diacetoxy-5-nitrophenyl-4-pyridylketone melting at 35 at 148-150° (recrystallized in methylene chloride/ether.

(

52

Example 3.2

a) A solution of 2.0 g of 3,5-dinitropyro-catechol in 25 ml of propionic anhydride is heated in the presence of a catalytic amount of concentrated sulfuric acid, during

At 18 h at 110°C, the excess anhydride is distilled at 70°C under high vacuum (1.33 Pa). The residue is dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered, and evaporated. The yield is 1,2-dipropionyloxy-3,5-dinitrobenzene, melting at 74-76°C (recrystallized in a methylene chloride/petroleum ether mixture).

We obtain in a similar way:

b) From 3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-l,4-benzoxazin-2-one, 3-(3,4-dipropionyloxy-5-nitrophenyl)-6-methyl-2H-l,4-benzoxazin-2-one melting at 158-160° (recrystallized in methylene chloride),

c) from 6-chloro-3~(3,4-dihydroxy-5-nitro-phenyl)-2H-1,4-benzoxazin-2-one, 5-(6-chloro-2-oxo-2H-1,4-benzoxazin-3-yl)-3-nitro-o-phenylene dipropionate melting at 148-150° (recrystallized in methylene chloride/ether),

d) from 3-(3,4-dihydroxy-5-nitrophenyl)7-nitro-2H-1,4-benzoxazin-2-one, 3-nitro-5-(7-nitro-2-oxo-2H-1,4-benzoxazin-3-yl)-o-phenylene dipropionate melting at 177-179° (recrystallized in methanol),

e) from 3-(3,4-dihydroxy-5-nitrophenyl)-2-oxo-2H-1,4-benzoxazin-6-carboxylic acid, 3-[3,4-bis-

(propionyloxy)-5-nitrophenyl]-2-oxo-2H-l,4-benzoxazin-6-carboxylic melting at 192-194° (recrystallized in methylene chloride),

f) from 3-nitro-5-(2-quinoxalinyl)pyrocatechol,

3-nitro-5-(2-quinoxalinyl)-o-phenylene dipropionate melting at 152-154° (recrystallized in methylene chloride/ether),

g) from 5-(2-benzimidazolyl)-3-nitropyrocatechol,

53

5-(2-benzimidazolyl)-3-nitro-o-phenylene dipropionate melting at 179-181° (recrystallized in ether),

h) from 6,7-dichloro-3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone, 5-(6,7-dichloro-3,4-dihydro-

5 3-oxo-2-quinoxalinyl)-3-nitro-o-phenylene dipropionate melting at 260-262° (recrystallized in methylene chloride),

i) from 5-bromo-2-(3,4-dihydroxy-5-nitrobenzyl)-3-methylindole, 5-bromo-2-(3,4-dipropionyloxy-5-nitrobenzoyl)-3-methylindole melts at 196-198° (recrystallized

10 in ether) and j) from 6-(3,4-dihydroxy-5-nitrophenyl)-3-mercapto-1,2,4-triazin-5(4H)-one, 3-nitro-5-(2,3,4,5-tetra-hydro-5-oxo-3-thioxo-as-triazin-6-yl)-o-phenylene-dipropionate melting at 237-239° (recrystallized in ether).

15 Example 3 3

a) A solution of 1.09 g of ethyl 3,4-dihydroxy-5-nitrophenylglyoxylate is heated in 6 ml of isobutyric anhydride in the presence of a catalytic amount of concentrated sulfuric acid for 17 h at 110°C. Then, the following is added:

The reaction mixture was repeated ten times, each time with 10 mL of toluene, evaporating at 80°C and 18.7 mbar. The oily residue was distilled in a sphere at 175–180°C and 8.0 Pa. Ethyl 3,4-diisobutyloxy-5-nitrophenylglyoxylate was obtained.

25. We obtain in a similar way:

b) From 3,5-dinitropyrocatechol, 1,2-diiso-butyryloxy-3,5-dinitrobenzene melts at 78-80° (recrystallized in ether),

c) from 3-(3,4-dihydroxy-5-nitrophenyl)-6-

30 methyl-2H-l,4-benzoxazin-2-one, the 3-(3,4-diisoburyryloxy-

5-nitrophenyl)-6-methyl-2H-l,4-benzoxazin-2-one melting at 142-144° (recrystallized in ether),

d) from 2-(3,4-dihydroxy-5-nitrophenyl)quinoxaline, 2-(3,4-diisobutyryloxy-5-nitrophenyl)quinoxaline

35 melting at 155-157° (recrystallized in ether),

54

e) from l-methyl-3-(3,4-dihydroxy-5-nitro-phenyl)-2(lH)quinoxalinone, l-methyl-3-(3,4-diisobutyryl-oxy-5-nitrophenyl)-2(1H)-quinoxalinone melting at 138-140° (recrystallized in ether),

5 f) from 5-(imidazo[2,1-b]-1,3,4-thiadiazol-6-

yl)-3-nitropyrocatechol, 5-(imidazo[2,1-b]-1,3,4-thia-diazol-6-yl)-3-nitro-o-phenylene-diisobutyrate melting at 169-171° (recrystallized in methylene chloride),

g) from 2-bromo-3',4'-dihydroxy-5'-nitroaceto-10 phenone, 5-(bromoacetyl)-3-nitro-o-phenylene-diisobutyrate melting at 56-58° (recrystallized in methylene chloride/hexane),

h) from 5-(2-amino-4-thiazolyl)-3-nitropyrocatechol hydrobromide, 3-nitro-5-(2-isobutyramido-4-thia-

15 zolyl)-o-phenylene-diisobutyrate melting at 157-159° (recrystallized in methylene chloride/ether),

i) from 5-(2-amino-6H-1,3,4-thia-diazin-5-yl)-3-nitropyrocatechol hydrobromide, 3-nitro-5-(2-isobutyr-amido-4-isobutyryl-1,3,4-thiadiazin-5-yl)-o-phenylene-diiso-

20 butyrate melting at 177-179° "(recrystallized in ether), j) from 3-(3,4-dihydroxy-5-nitrophenyl)-6-propyl-2H-1,4-benzoxazin-2-one, 3-nitro-5-(2-oxo-6-propyl-2H-1,4-benzoxazin-3-yl)-o-phenylene-diisobutyrate melting at 131-133° (melting at 131-133° (recrystallized in 25 methanol),

k) from 5-(imidazo[2,2-α-pyridin-3-yl)-3-nitro-pyrocatechol, 5-(imidazo[1,2-α-pyridin-3-yl)-3-nitro-o-phenylene-diisobutyrate melting at 137-139° (recrystallized in ether),

30 1) from 5-(imidazo[2.1-bJbenzothiazol-2-yl)-3-

nitrotoyrocatechol, 5-(imidazo[2.1-b1benzothiazol-2-yl)-3-nitro-o-phenylene diisobutyrate melting at 197-199° (recrystallized in methylene chloride/ether) and m) from 3,4-dihydroxy-5-nitro-35-phenyl-2-pyridylketone hydrobromide, 3-nitro-5-(2-pyridylcarbonyl)-

o-Phenylene-diisobutyrate melting at 83-85° (recrystallized in 11 ether/hexane).

Example 34

A solution of 613.0 mg of ethyl 3,4-dihydroxy-5-nitrophenylglyoxylate is heated in 4 ml of pivalic anhydride in the presence of a catalytic amount of concentrated sulfuric acid for 17 h at 100°, the cooled solution is diluted with ether, washed with a saturated sodium chloride solution, and dried over sodium sulfate.

It is filtered and evaporated. The residue is added ten times, each time with 10 ml of toluene, re-evaporating after each addition. Distillation in a spherical tube (in an air bath) at 175-180°C and under 4.0 Pa yields ethyl 3,4-dipivaloyloxy-5-nitrophenylglyoxylate.

We obtain in a similar way:

b) From 3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-l,4-benzoxazin-2-one, 3-(3,4-dipivaloyloxy-5-nitrophenyl)-6-methyl-2H-l,4-benzoxazin-2-one melting at 180-182° (recrystallized in ether),

c) from 3,4-dihydroxy-5-nitrobenzophenone, 3,4-dipivaloyloxy-5-nitrobenzophenone melting at 101-103° (recrystallized in β-butylmethyl ether) and d) from 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone, 3,4-dipivaloyoxy-2'-fluorobenzophenone melting

at 74-76° (recrystallized in ts petroleum ether).

Example 35

A solution of 1.7 g of 3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone is heated in 17 mL of oenanthic anhydride in the presence of a catalytic amount of concentrated sulfuric acid for 17 h at 110°C. The excess anhydride is then distilled under high vacuum, the residue is dissolved in methylene chloride, the organic solution is washed with water, dried over sodium sulfate, filtered, and evaporated. The yield is 5-(1,2-dihydro-2-oxo-3-quinoxalinyl)-3-nitro-o-phenylene diheptanoate.

56

at 186-188° (recrystallized in methylene chloride/

ether).

Example 36

a) To a solution of 1.35 g of 2-bromo-3',4'-dihydroxy-

5-Nitroacetophenone is reacted in 25 ml of alcohol, 1.26 g of sodium acetate is added, and the mixture is heated to boiling under reflux. After 6 hours, the reaction mixture is separated from the sodium bromide by filtration and evaporated. The residue is dissolved in ethyl acetate.

10. We wash with a saturated sodium chloride solution, dry over sodium sulfate, filter and evaporate at 50°. We obtain (3,4-dihydroxy-5-nitrobenzoyl)methylacetate which melts at 166-168° (recrystallized in ethyl acetate/ether).

15. We obtain in a similar way:

b) From 2-bromo-31,4'-dihydroxy-5'-nitroacetophenone and sodium isobutyrate, (3,4-dihydroxy-5-nitrobenzoyl)methyl isobutyrate melts at 120-122° (recrystallized in ethyl acetate/ether) and

20 c) from 2-bromo-3',4'-dihydroxy-5'-nitroaceto-

- phenone and sodium 3,4-dihydroxy-5-nitrophenylglyoxylate, 3,4-dihydroxy-5-nitrophenacyl-3,4-dihydroxy-5-nitrobenzoyl)-formate melting at 224-226° ('recrystallized in methanol/ethyl acetate).

25 Example ~3 7

To a suspension of 2.91 g of 2-bromo-3',4'-dihydroxy-51-nitroacetophenone, 1.31 g of thionicotinamide is added in 50 ml of alcohol and heated for 2 h to boiling under reflux. After cooling to room temperature,

30. The crystals are drained and recrystallized in an N,N-dimethylformamide/alcohol mixture. This yields 3-nitro-5-(2-(3-pyridyl)-4-thiazolyl pyrocatechol, which melts at 279-281°.

Example 38

35. A solution of 5.52 g of

57

2-Bromo-3,4'-dihydroxy-5'-nitroacetophenone and 2.7 g of aminoacetophenone in 100 ml of dry N,N-dihydroxyethylformamide. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate, washed with water, dried over sodium sulfate, filtered, and evaporated. The result is 2-(3,4-dihydroxy-5-nitrobenzoyl)

3-methylindole melts at 212-214° (recrystallized in n-butanol).

Example 39

To a suspension of 7.32 g of 2-bromo-31,4'-dihydroxy-5'-nitroacetophenone, 4.06 g of 1-(3-pyridinyl)-2-thiourea is added in 100 mL of n-butanol, and the mixture is heated to boiling under reflux for 3 h. After cooling to room temperature, the crystals are drained and recrystallized in n-butanol. The yield is the hydrobromide of 3-nitro-5-[2-(3-pyridylamino)-4-thiazolyl]pyrocatechol, which melts at over 300°C.

Example 40

To a suspension of 6.35 g of 2-bromo-3',41-dihydroxy-51-nitroacetophenone, 4.68 g of 1-(3-quinolinyl)-2-thiourea is added in 150 mL of n-butanol and heated for 3 h to boiling under reflux. After cooling to room temperature, the crystals are drained and recrystallized in n-butanol. The yield is quinolinylamino)-4-thiazolyl-1-pyrocatechol hydrobromide, which melts at over 300°C.

Example 41

To a suspension of 8.28 g of 2-bromo-3',4'-dihydroxy-51-nitroacetophenone, 6.37 g of racemic 1-(2-exobornyl)-2-thiourea is added in 100 mL of n-butanol, and the mixture is heated to boiling under reflux for 3 h. After cooling to room temperature, the crystals are drained and recrystallized in n-butanol. The yield is the hydrobromide of rac-3-nitro-5-[2-(2-exo-bornylamino)-4-thiazolyl]-pyrocatechol, which melts at 262–264°C.

58

Example 4.2

To 0.875 ml of pyrrolidine in 35 ml of 5° tetrahydrofuran, 605 ml of acetic acid are added, followed by 1.73 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.87 g of 6-oxo-4'-(tri-5-fluoromethyl)heptananilide, and the mixture is stirred for 56 h under argon at 23°. The residue obtained after evaporation of the reaction mixture is divided between ethyl acetate and sodium hydroxide solution (IN). The extracts are acidified with sodium hydroxide combined with concentrated hydrochloric acid, extracted with ethyl acetate, washed with a saturated sodium chloride solution, dried over sodium sulfate, evaporated, and the residue is chromatographed on 120 g of silica gel with methylene chloride/methanol (91:9). After recrystallization in ethyl acetate/petroleum ether, (E)-8-(3,4-dihydroxy-5-nitrophenyl)-6-OXO-4'-(trifluoromethyl)-7-octenanilide is obtained, melting at 194-197°.

Example 4.3

a) 26.0 g of 2-chloro-3-hydroxy-p-anisaldehyde 20 is dissolved in 400 ml of acetic anhydride and 5 ml of pyridine. The mixture is stirred for 8 h at 80°C, then the reaction mixture is evaporated, the residue is divided between ice water and methylene chloride, the organic phase is dried over sodium sulfate, concentrated, and the residue is crystallized in methylene chloride/petroleum ether.

The product obtained is 2-chloro-3-formyl-6;methoxyphenyl-acetate, which melts at 48-50°.

b) 38 g of 2-chloro-3-formyl-6-methoxyphenyl acetate are introduced at a temperature of -5 to -10°, in portions

30 successive stirrings, over a period of 5 minutes, in 150 ml of 98% nitric acid. After 30 minutes of stirring at -5°C, the reaction mixture is poured onto 1.5 L of ice water and extracted three times with 500 ml of methylene chloride. The combined organic phases are washed with ice water, dried over sodium sulfate, and evaporated.

59

Recrystallize the residue in ether. This yields 2-chloro-3-formyl-6-methoxy-5-nitrophenyl acetate, which melts at 84-85°.

c) 35.8 g of 2-chloro-3-formyl-6-methoxy-

5-Nitrophenylacetate in 30 ml of methanol. After adding 145 ml of sodium hydroxide solution (IN), the mixture is stirred for 1 h at 23°C. After evaporation of the methanol, the residue is diluted with ice water, acidified with 2N hydrochloric acid, and extracted twice, each time with 400 ml of acetate.

10 of ethyl. The organic phases are washed with a saturated sodium chloride solution, dried over sodium sulfate, and evaporated. The residue is recrystallized in methylene chloride/petroleum ether. The resulting product is 2-chloro-3-hydroxy-5-nitro-p-anisaldehyde.

15 to 130°.

d) 1.3 g of 2-chloro-3-hydroxy-5-nitro-p-anisaldehyde is dissolved in 80 ml of methylene chloride, 0.82 ml of boron tribromide is added, the mixture is stirred for 18 h at 23°C, and the reaction mixture is then added to

20.5 ml of methanol is cooled with ice, evaporated, the residue is dried under high vacuum, digested in water, filtered, and recrystallized in acetonitrile. The yield is 2-chloro-3,4-dihydroxy-5-nitrobenzaldehyde, which melts at 193-195°C.

25, Example ~4 4

a) A mixture of 30 g of 2-chloro-3-hydroxy-p-anisaldehyde and 230 ml of ethanol is stirred in the presence of 12.3 g of hydroxylamine hydrochloride for 4 h at 70°C. The reaction mixture is then evaporated, and the residue is dried.

30 under high vacuum and it is recrystallized in methanol/water. The resulting product is 2-chloro-3-hydroxy-p-anisaldehyde oxime, which melts at 174-176°.

b) 21 g of 2-chloro-3-hydroxy-p-anisaldehyde-oxime are heated under reflux along with 400 ml of anhydride

35 acetic acid for 20 hours. The mixture is then evaporated.

60

In the reaction, the residue is added to 300 ml of ice water, stirred for 1 hour, decanted, and the cooled residue is divided between methylene chloride and water. The organic phase is dried over sodium sulfate and evaporated. The residue is then dried under high vacuum, chromatographed on 200 g of silica gel with methylene chloride, and recrystallized in methylene chloride/petroleum ether. The yield is 2-chloro-3-cyano-6-methoxyphenyl acetate, which melts at 97-99°C.

10 c) By analogy with examples 43b and 43c, we obtain

from 2-chloro-3-cyano-6-methoxyphenyl acetate 2-chloro-3-hydroxy-5-nitro-p-anisonitrile melting at 157-159° (recrystallized in methylene/hexane chloride).

d) By analogy with example 43d, from 15 of 2-chloro-3-hydroxy-5-nitro-p-anisonitrile, we obtain 2-chloro-

3,4-dihydroxy-5-nitro-benzonitrile melting at 180° (recrystallized in acetonitrile).

Example 4 5

a) 5.5 g of α-chloro-2-fluoro-20 3,4-dimethoxytoluene and 4.05 g of potassium acetate are shaken for 25 h at 80°C in

50 ml of dimethylformamide. Then the reaction mixture is poured onto 150 ml of ice water and extracted with ether. The etheric phases are washed with a sodium chloride solution, dried over sodium sulfate, and evaporated. 2-Fluoro-3,4-Dimethoxybenzyl acetate is obtained as an oil.

b) 5.4 g of 2-fluoro-3,4-dimethoxybenzyl acetate is heated for 1.5 h at 80°C simultaneously with 50 ml of methanol and 50 ml of sodium hydroxide solution (IN). After evaporation

3.0 of the methanol, the residue is extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate, and evaporated. The residue is chromatographed on 80 g of silica gel with a methylene chloride/methanol mixture (95:5). 35 2-Fluoro-3,4-Dimethoxybenzyl alcohol is obtained as an oil.

C.

c) 3.0 g of 2-fluoro-3,4-dimethoxybenzyl alcohol and 5.0 g of manganese dioxide are heated under reflux for 1 h, along with 5 mL of benzene. The insoluble fractions are then separated by filtration after washing with methylene chloride. The filtrate is evaporated, and the residue is recrystallized from methylene chloride/hexane. 2-fluoro-3,4-dimethoxybenzaldehyde, melting at 52-54°C, is obtained.

d) 4.4 g of 2-fluoro-3,4-dimethoxybenzaldehyde and 1.83 g of hydroxylamine hydrochloride are heated for 5 h under reflux with 30 mL of ethanol. The reaction mixture is then evaporated, and the residue, dried at 23°C under high vacuum, is introduced into 40 mL of phosphorus oxychloride. After 2.5 h of stirring at 23°C, the reaction mixture is evaporated, the residue is treated with ice-cold water, the precipitate formed is separated by filtration, washed with water, resuspended in methylene chloride, dried in methylene chloride over sodium sulfate, and evaporated. Recrystallization of the residue in methylene chloride/hexane yields 2-fluoro-3,4-dimethoxybenzonitrile, which melts at 64-65°C.

e) 2.0 g of 2-fluoro-3,4-dimethoxybenzonitrile is dissolved in 60 ml of methylene chloride, and the following are added

1.1 mL of boron tribromide is stirred for 1 h at 23°C. An additional 1.0 mL of boron tribromide is then added, and the mixture is stirred for another 80 min at 23°C. The reaction mixture is then poured onto 100 mL of ice-cooled saturated sodium bicarbonate solution. It is then extracted twice with 300 mL of ether. The combined ether phases are washed twice with sodium chloride solution, dried over sodium sulfate, evaporated, and the residue is chromatographed on 50 g of silica gel with methylene chloride and methylene chloride/methanol (97:3). The resulting product is 2-fluoro-3-hydroxy-p-aniso-

62

nitrile melts at 198-200°.

f) Dissolve 0.9 g of 2-fluoro-3-hydroxy-p-anisonitrile in 10 ml of acetic anhydride and 0.5 ml of pyridine, then stir for 2 h at 120°C. The mixture is then evaporated.

5. The reaction mixture is separated, and the residue is divided between ice water and methylene chloride. The organic phase is dried over sodium sulfate, evaporated, and the residue is recrystallized in methylene chloride/hexane. This yields 3-Cyano-2-Fluoro-6-Methoxyphenyl acetate, which melts at 90-91°C.

(g) 0.8 g of 3-cyano-2-fluoro-6-methoxyphenyl acetate is introduced in three successive portions, at -15°C, into 5 ml of 96% nitric acid, after which the mixture is stirred for

1 h at -10°C. The reaction mixture is then poured onto 50 g of ice. It is extracted twice, each time with 70 mL of ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution, dried over sodium sulfate, and evaporated. The residue thus obtained is dissolved in 50 mL of sodium carbonate solution and 50 mL of methanol, after which it is stirred for 1 h.

The mixture is heated to 23°C and the methanol is removed by distillation. The remaining aqueous phase is acidified to pH 2 with concentrated hydrochloric acid (0°C) and extracted twice with 100 mL of ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution. They are dried over sodium sulfate and evaporated, and the residue is chromatographed on 45 g of silica gel with methylene chloride/methanol (97:3). After recrystallization in ether/hexane, 2-fluoro-3-hydroxy-5-nitro-30 p-anisonitrile, melting at 112-113°C, is obtained.

h) 550 mg of 2-fluoro-3-hydroxy-5-nitro-p-anisonitrile is dissolved in 30 mL of methylene chloride, followed by the addition of 0.44 mL of boron tribromide. After 6 h of stirring at 23°C, an additional 0.1 mL is added.

35 of boron tribromide, then shake for another 1.5 hours

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at 23°C. Then, at -15°C, 3 ml of ethanol is added. The reaction mixture is evaporated and the residue is dried at 23°C.

under high vacuum. By recrystallization in ether/hexane, 2-fluoro-3,4-dihydroxy-5-nitrobenzonitrile is obtained, melting at 154°.

Example 46

a) 9.5 g of 3,4-dimethoxy-5-nitrobenzoic acid is suspended in 95 ml of thionyl chloride. The mixture is stirred for 1 h at 80°C. The solution is then evaporated twice with the addition of toluene.

At 10°C absolute, 10 g of 3,4-dimethoxy-5-nitrobenzoic acid chloride is obtained and dissolved in 100 mL of tetrahydrofuran. This solution is then added dropwise to 300 mL of 28% ammonia. The mixture is stirred for 2 hours at 40°C and cooled to 5°C. The crystalline precipitate is separated by filtration. The resulting 3,4-dimethoxy-5-nitrobenzamide, which melts at 182–185°C, is obtained.

b) After cooling with ice, 2.46 g of chlorine is passed through a mixture of 8.0 g of sodium hydroxide, 50 mL of water, and 30 g of ice. Then, 6.5 g of 3,4-dimethoxy-5-nitrobenzamide is suspended in 5 mL of tetra-

20 hydrofurans are added slowly. The reaction mixture is heated for 30 minutes at 70°C, stirred for 1 hour at 70°C, cooled to 5°C, and the precipitated crystals are filtered. 3,5-Dimethoxy-5-nitroaniline, which melts at 125-131°C, is obtained. By extracting the filtrate with ethyl acetate, drying the extract over sodium sulfate, concentrating and crystallizing the residue with the addition of ether, an additional portion of 3,4-dimethoxy-5-nitroaniline can be obtained.

c) 10 g of finely powdered 3,4-dimethoxy-5-nitro-30 aniline are suspended in 15 ml of hydrochloric acid

12N and 40 ml of water, after which the mixture is stirred for 1 hour at 30°C. Then, 3.8 g of sodium nitrite, dissolved in 20 ml of water, is added dropwise over 15 minutes at -5°C. The mixture is stirred for 30 minutes at -5°C, and the cold diazonium salt solution is added dropwise over a period of

64

The reaction is carried out for 15 minutes in 100 mL of pyridine at 40°C. The mixture is then stirred for 1 hour at 70°C. The reaction mixture is evaporated, and the residue is reconstituted in 300 mL of ethyl acetate. It is extracted three times, each time with 200 mL of 2N hydrochloric acid. The acidic aqueous phase is adjusted with concentrated ammonia to pH 9 and extracted with methylene chloride. The extracts are dried in methylene chloride, combined on sodium sulfate, and evaporated. The residue is then chromatographed on 250 g of silica gel with ethyl acetate. After recrystallization in methylene chloride/hexane, 2-(3,4-dimethoxy-5-nitrophenyl)pyridine is obtained, melting at 89-90°C.

d) 1.5 g of 2-(3,4-dimethoxy-5-nitrophenyl)-pyridine is dissolved in 30 mL of 48% aqueous hydrobromic acid. The reaction mixture is stirred for 16 h at 100°C and for 18 h at 23°C. The precipitate formed is separated by filtration and recrystallized in methanol/ether. The yield is 3-nitro-5-(2-pyridyl)pyrocatechol hydrobromide, which melts at 239-240°C.

20 Example 4 7

a) To 2.76 mL of 2-bromopyridine, dissolved in 30 mL of absolute tetrahydrofuran, 19.2 mL of 1.6 M n-butyllithium solution (in hexane) is added at -60°C for 30 minutes, after which the mixture is stirred for 30 minutes at -60°C. Then, 6.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde, dissolved in 50 mL of tetrahydrofuran, is added dropwise for 30 minutes at -40°C. The reaction mixture is heated for 2 hours at 0°C, poured over ice-cold water, and extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and evaporated, and the residue is chromatographed on 200 g of silica gel with ethyl acetate. α-(3,4-dimethoxy-5-nitrophenyl)-2-pyridinemethanol is obtained in the form of a brown oil.

b) To 4.0 g of a-(3,4-dimethoxy-5-nitrophenyl)-2-pyridine-35 methanol, dissolved in 100 ml of acetone, is added by porC

65

Successive heating cycles, by constantly heating under reflux for 2.5 h, of 7 g of manganese dioxide. The mixture is then heated under reflux for an additional 2 h. The manganese salts are then separated by filtration, and the residue obtained after evaporation is recrystallized in ether/hexane. The resulting compound is 3,4-Dimethoxy-5-nitrophenyl-2-pyridyl ketone, which melts at 113°C.

c) 1.5 g of 3,4-dimethoxy-5-nitrophenyl-2-pyridylketone dissolved in 30 mL of 48% hydrobromic acid is stirred for 18 h at 100°C. The reaction mixture is then evaporated, and the residue is recrystallized from acetonitrile/methanol. The resulting hydrobromide of 3,4-dihydroxy-5-nitrophenyl-2-pyridylketone melts at 213°C.

Example 48

15 a) A 2.25 g of 3',4'-dimethoxy-5'-nitroacetophenone,

Dissolved in 50 mL of ethanol, 11.3 g of tin dihydrate is added, followed by stirring for 30 minutes at 75°C. The reaction mixture is then poured onto 100 g of ice, neutralized with approximately 300 mL of saturated sodium bicarbonate solution, and 150 mL of methylene chloride is added. The mixture is filtered, separating the methylene chloride phase. This phase is dried over sodium sulfate and evaporated, and the residue is recrystallized from petroleum ether. The resulting compound is 5'-amino-2531,4-dimethoxyacetophenone, which melts at 63-65°C.

b) To 14.0 g of 51-amino-3',4'-dimethoxyacetophenone dissolved in 155 mL of hydrochloric acid (IN), a solution of 5.2 g of sodium nitrite in 20 mL of water is added dropwise at 0°C over 20 mins. After 30 mins of stirring at -2°C, the cold diazonium salt solution is added dropwise over 30 mins at 5-10°C to a solution of 8.7 g of copper(I) cyanide and 5.45 g of potassium cyanide in 60 mL of water. When the addition is complete, 200 mL of methylene chloride is added, the reaction mixture is stirred for 3 h at 23°C, and then filtered. The

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The organic phase is washed with water, dried over sodium sulfate, and evaporated. The residue is recrystallized in methylene chloride/petroleum ether. This yields 5'-cyano-3',4'-dimethoxyacetophenone, which melts at 5°C at 125-126°C.

c) 3.75 g of aluminum powder and 28.5 g of iodine are heated in 160 mL of absolute benzene for 2 hours under reflux. At 20°C, 3.0 g of 5'-cyano-3',4'-dimethoxyacetophenone and 0.5 g of tetra-n-butylammonium iodide are added, followed by heating for 1 hour under reflux. 50 g of ice is then added at 20°C and the mixture is filtered. The residue is washed with ethyl acetate. The phases are separated, and the aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are washed with a 20% sodium thiosulfate solution, dried over sodium sulfate, and evaporated. The residue thus obtained is dissolved in 20 mL of acetic anhydride and 0.5 mL of pyridine, and stirred for 6 h at 120°C. The mixture is then evaporated, and the residue is divided between methyl-20-lene chloride and ice-cold water. The methylene chloride phase is dried over sodium sulfate, evaporated, and the residue is chromatographed on 100 g of silica gel with methylene chloride. After recrystallization in ether, 5'-cyano-3',4'-diacetoxyacetophenone is obtained, melting at 25-76-79°C.

Example 49

To 0.33 g of 5'-cyano-3',41-diacetoxyacetophenone dissolved in 3.3 mL of methanol, 2.7 mL of 1.0 N sodium hydroxide solution is added, and the reaction mixture is stirred for 45 min at 23°C. Then, the mixture is acidified with 2 N hydrochloric acid, diluted with 5 mL of saturated sodium chloride solution, and extracted twice, each time with 30 mL of ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate and evaporated. The residue is recrystallized from toluene/acetonitrile. The 5'-

6

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cyano-341-dihydroxyacetophenone in the form of brownish crystals, which decompose above 215°.

Example 5 0

a) To 1.9 g of 5'-cyano-31,4'-dimethoxyacetophenone dissolved in 30 mL of tetrahydrofuran, 3.48 g of phenyltrimethylammonium bromide-dibromide dissolved in 30 mL of tetrahydrofuran are added dropwise at room temperature over 4-5 minutes, after which the mixture is stirred for 30 minutes. The reaction mixture is then poured onto 120 mL of ice-cold water and extracted three times with 70 mL of methylene chloride. The combined methylene chloride phases are washed with 2N sulfuric acid, dried over sodium sulfate, and evaporated. The residue is chromatographed on 20 g of silica gel with methylene chloride.

After recrystallization in methylene chloride/hexane, we obtain 5-(bromoacetyl)-2,3-dimethoxybenzonitrile which melts at 138-141°.

b) 1.45 g of 5-(bromoacetyl)-2,3-dimethoxybenzonitrile and 1.12 g of selenium dioxide are stirred in 10 mL of n-hexanol for 18 h at 120°C. After cooling to room temperature, the mixture is diluted with 20 mL of methylene chloride and filtered. The filtrate is washed with water.

It is dried over sodium sulfate and evaporated. The residue is chromatographed on 70 g of silica gel with hexane/ether (2:1). Hexyl (3-cyano-4,5-dimethoxyphenyl)glyoxylate is obtained as an oil.

c) In 4.0 g of hexyl (3-cyano-4,5-dimethoxyphenyl)glyoxylate dissolved in 100 ml of methylene chloride, 4.8 ml of boron tribromide dissolved in

20 mL of methylene chloride is added, and the reaction mixture is stirred for 18 hours at room temperature. Then, 40 mL of methanol is added dropwise at -60°C, the mixture is stirred for 1 hour at room temperature, and then evaporated. The residue is dissolved in methanol and heated for 10 minutes under

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Under reflux, it is evaporated to dryness and dried under high vacuum. The crude product obtained is recrystallized in acetonitrile. This yields ruethyl (3-cyano-4,5-dihydroxyphenyl)-glyoxylate, which melts at 252°C. Example 51

One 1.075 g of methyl (3-cyano-4,5-dihydroxyphenyl)glyoxylate and 0.60 g of 2-amino-p-cresol are stirred in 2 mL of dimethylformamide. The mixture is then cooled to room temperature and diluted with 15 mL of water. The precipitate is separated by filtration and dried for 6 h at 80°C under vacuum in a water aspirator. After recrystallization in acetonitrile, 2,3-dihydroxy-5-(6-methyl-2-oxo-2H-1,4-benzo-xazin-3-yl)benzonitrile is obtained, which melts at 278–280°C.

Example 5.2

15 a) To a solution of 2.5 g (10.2 mmol) of 3,4-dimethoxy-5-nitrobenzoyl chloride in 10 ml of absolute tetrahydrofuran, 1.1 ml of ethyl isocyanacetate is added, followed by a solution of 3.0 ml of triethylamine in 10 ml of tetrahydrofuran, and the mixture is stirred for 48 h at room temperature. After removal of the solvent by distillation,

Extraction is carried out with an ethyl acetate/water mixture. The crude product obtained after evaporation of 20 times its weight of silica gel with ethyl acetate is chromatographed. After recrystallization in ethyl acetate/hexane, ethyl 5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazolcarboxylate is obtained in the form of yellow crystals melting at 109-110°.

b) To 1.0 g (3.1 mmol) of ethyl 5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazolcarboxylate, 10 mL of boiling hydrobromic acid at a constant temperature is added, and the mixture is stirred for 2 h at 140°C. After removing the excess hydrobromic acid by distillation, the yellow residue is dissolved in ethanol/acetone. The hydrobromide of 2-amino-3',4'-dihydroxy-5'-nitroacetophenone is obtained as yellow crystals that melt at over 250°C (decomposition).

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Gf

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Example 5 3

a) 10 g (34 mmol) of (3,4-di-methoxy-5-nitrobenzoyl)-ethyl acetate is suspended in 100 ml of ethanol, and 1.7 g (37 mmol) of methylhydrazine is added.

5 and they are heated under reflux for 16 h. After removing approximately 50 ml of ethanol by distillation, the mixture is cooled to 0° and the precipitate formed is drained. After recrystallization in ethanol, 3-(3,4-dimethoxy-5-nitro-phenyl)-1-methylpyrazol-5-ol is obtained in the form of yellow crystals melting at 200-202°.

b) 2.0 g (7.2 mmol) of 3-(3,4-dimethoxy-5-nitrophenyl)-1-methylpyrazol-5-ol is suspended in 100 mL of methylene chloride. After cooling to -40°C, a 4.9 mL tribromide solution is added dropwise.

15 ml of boron is dissolved in 60 ml of methylene chloride for 1 hour. The mixture is then stirred for 16 hours at room temperature, cooled to -20°C, and 100 ml of ethanol is added for 30 minutes. After stirring at room temperature for 1 hour, the solvent is removed by distillation under vacuum using a water aspirator. The residue is then added three times to a 100 ml mixture of ethanol/toluene, with the solvent removed by distillation each time. The residue is recrystallized from ethanol. The hydrochloride of 5-(5-hydroxy-1-methylpyrazol-25-3-yl)-3-nitropyrocatechol is obtained as yellow crystals that melt at over 250°C.

Example 5 4

a) To 16.8 g (0.7 atom-g) of magnesium, 15 mL of ethanol is added, and after the addition of 2 mL of 30-carbon tetrachloride, the reaction is started by heating. While stirring, a solution of 130.3 g of tert-butylethyl malonate in 70 mL of ethanol and 600 mL of absolute ether is added dropwise over a period of 30 minutes, such that the reaction takes place at reflux temperature. Stirring is then continued for 3 h at 50°C, and the solution is removed.

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The solvent is removed by distillation at 40°C under vacuum using a water aspirator. The residue is dissolved in 900 mL of tetrahydrofuran. To this solution, a solution of 170 g (0.7 mol) of 3,4-5-dimethoxy-5-nitrobenzoyl chloride in 700 mL of absolute tetrahydrofuran is added dropwise, while stirring at 50°C, and the mixture is stirred for 1 h at reflux temperature. The solvent is removed by distillation at 40°C under vacuum using a water aspirator. 1 L of ether is added to the solvent. While cooling and stirring, 260 mL of 3N sulfuric acid is added, and the mixture is stirred for 30 minutes. The aqueous phase is extracted twice, each time with 600 mL of ether. The organic phase is washed with water until neutral. It is dried over sodium sulfate and evaporated. The brown oil obtained with toluene is filtered through 1 kg of silica gel.

15 The resulting mixture, consisting of ethyl-tert-butyl (3,4-dimethoxy-5-nitrobenzoyl)malonate and ethyl (3,4-dimethoxy-5-nitrobenzoyl)malonate, is dissolved in 600 ml of methylene chloride, and 193 ml of trifluoracetic acid is added over approximately 40 minutes while stirring. 20 The mixture is then stirred for 2 hours at 40°C and evaporated at 40°C under vacuum using a water aspirator. The resulting oil is extracted with ether/water. The organic phase is dried over sodium sulfate and evaporated. After dissolution in diisopropyl ether/hexane and 25 cooling, the precipitated crystals are drained and recrystallized in diisopropyl ether. The resulting (3,4-dimethoxy-5-nitrobenzoyl)ethyl acetate in the form of faintly yellowish crystals melting at 67-68°.

30 b) 10.0 g (33.6 mmol) of (3,4-

ethyl dimethoxy-5-nitrobenzoyl acetate in a manner analogous to Example 53a, with 4.0 g (37 mmols) of phenylhydrazine. After recrystallization in methylene chloride/ethanol, 3-(3,4-dimethoxy-5,35-nitrophenyl)-1-phenyl-2-pyrazolin-5-one is obtained in the form of

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Yellow crystals melting at 190-192°.

c) In a manner analogous to example 53b, from this compound, with boron tribromide, the hydrobromide of 5-(5-hydroxy-l-phenylpyrazol-3-5 yl)-3-nitro-pyrocatechol is obtained in the form of yellow crystals melting at < 220° (decomposition).

Example 55 20.1 g of diethyl (3,4-dimethoxy-5-nitrobenzoyl)malonate is dissolved in 10200 mL of methylene chloride, then cooled to -20°C. At this temperature, a solution of 68.1 g of boron tribromide in 120 mL of methylene chloride is added dropwise, while stirring for 15 minutes. The mixture is then stirred overnight at room temperature. After cooling to -20°C, 300 mL of ethanol is added, and the mixture is stirred for 30 minutes at room temperature. The solvent is removed by vacuum distillation using a water aspirator at 40°C. The residue is then mixed with 300 mL of ice-cold water and methylene chloride. The organic phase is washed with water, dried over sodium sulfate, and evaporated. The crude product obtained is chromatographed over 10 times its weight of silica gel with toluene. After recrystallization in methylene chloride/hexane, 25(3,4-dihydroxy-5-nitrobenzoyl)ethyl acetate is obtained in the form of yellow crystals melting at 136-137°.

Example 56

2.0 g (7.4 mmol) of (3,4-dihydroxy-5-nitrobenzoyl)ethyl acetate is suspended in 50 mL 3Q of ethanol. After the addition of 0.4 g of hydrazine hydrate, the mixture is maintained at reflux temperature for 16 h.

After removing the solvent, the residue is kept at boiling point for 5 minutes along with 50 mL of ethyl acetate. The precipitate formed is drained off, and the filtrate is concentrated to 10 mL. The crystals are then drained off.

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which precipitate when cold. 5-(5-hydroxy-pyrazol-3-yl)-3-nitropyrocatechol is obtained in the form of orange crystals that melt at 228° (decomposition).

Example 57

5 A 7.3 g (36.66 mmol) of 3,4-dohydroxy-5-

nitrobenzol, 30 ml of acetic anhydride are added,

After this, the mixture is maintained at reflux temperature for 8 hours. The reaction mixture is poured onto ice. The precipitate formed is drained, washed with water, and resuspended in methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The resulting residue is recrystallized in methylene chloride/n-hexane at room temperature. 3,4-Diacetoxy-5-nitrobenzoic acid is obtained as colorless crystals melting at 126-127°C.

Example 58

a) To 9.7 g (32.2 mmol) of 3,4-diacetoxy-5-nitrobenzoic acid, 12.5 ml of thionyl chloride is added, after which the mixture is stirred at 100°C for 1.5 h. After elimination-

20 tion of excess thionyl chloride, 5-(chloro-carbonyl)-2-nitro-o-phenylenediacetate distills, boiling point 160° (under 26.7 Pa).

b) 3.2 g (10.6 mmol) of 5-(chloro-carbonyl)-2-nitro-o-phenylenediacetate is dissolved in 50 ml of

25-dimethylformamide. The ice-cooled solution is stirred with a solution of 2.2 mL of diethylamine in 20 mL of dimethylformamide. The mixture is then stirred for 1 hour at room temperature, after which the solvent is removed by distillation under vacuum using a water aspirator at 50°C. Water and methylene chloride are added to the resulting residue. The organic phase is dried over sodium sulfate and evaporated. The resulting yellow resin is recrystallized in methylene chloride/ether. N,N-diethyl-35-3,4-dihydroxy-5-nitrobenzamide is obtained as crystals.

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Melting yolks at 145-146°.

Example 59

3.2 g (10.6 mmol) of 5-(chlorocarbonyl)-2-nitro-o-phenylenediacetate is dissolved in 50 mL of 5-dimethylformamide. This is then added, at 0-5°C, with stirring, for 40 minutes, to a solution of 3.02 mL of 2,2-diethylaminoethylamine in 20 mL of dimethylformamide. The mixture is then stirred for 30 minutes at room temperature. The solvent is removed by 10-second vacuum distillation using a water aspirator at 60°C. The residue is extracted twice, each time with 20 mL of ethanol, dissolved in hot ethanol, and then treated with an excess of ethanolic hydrochloric acid. After recrystallization in ethanol/ethyl acetate, 15 we obtain N-[2-diethyl1zmino)ethyl1]-3,4-dihydroxy-5-nitrobenzamide hydrochloride in the form of yellow crystals melting at 139° (decomposition).

Example 60

a) To 10.0 g (47.4 mmol) of 2,3-dimethoxy-5,20-nitrobenzaldehyde, 50 mL of glacial acetic acid and 50 mL of hydrobromic wetting acid are added at constant temperature and maintained for 7 h at reflux temperature. After adding ice, the precipitate formed is drained, washed with water, and resuspended in ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The crude product obtained is filtered with ethyl acetate through silica gel. After recrystallization in ethyl acetate/hexane, 2,3-dihydroxy-5-nitro-30-benzaldehyde is obtained as brownish crystals melting at 226–228°C.

b) 4.5 g of 2,3-dihydroxy-5-nitrobenzaldehyde is suspended in 75 ml of water. After the addition of

4.2 g of hydroxylamine-o-sulfonic acid is stirred for 35 to 16 hours at 65°C. After cooling, the crystals are drained.

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The precipitates and is washed with water. The filtrate is extracted with ethyl acetate. The crystals and the dried organic phase are combined, after which the residue is evaporated and recrystallized in 5-diisopropyl ether. 2,3-Dihydroxy-5-nitrobenzonitrile is obtained as yellow crystals melting at 186-188°C.

Example 61

a) 4.0 g (19.2 mmols) of 3,4-dimethoxy-10 5-nitrobenzonitrile is dissolved in 50 ml of dimethylformamide,

After which, 1.66 g of ammonium chloride and 2.02 g of sodium azide are added, and the mixture is stirred for 31 h at 125°C. Every 8 and 15 h, the same quantity of ammonium chloride and sodium azide is added again. After cooling, the mixture is poured onto ice. The precipitate formed is drained, washed with water, and dried. 2-Methoxy-6-nitro-4-(1H-tetrazol-5-yl)phenol is obtained in the form of orange crystals that melt at

> 240° (decomposition).

20 k) At 4.0 g (16.9 mmol) of 2-methoxy-6-nitro-4-(1H-

To prepare tetrazol-5-ylphenol, 40 mL of boiling hydrobromic acid at a constant temperature is added, followed by stirring under a nitrogen atmosphere for 8 hours at 140°C. After cooling, the mixture is poured onto ice. The resulting precipitate is drained and recrystallized in ether. 3-Nitro-5-(1H-tetrazol-5-yl)pyrocatechol is obtained as orange crystals that melt at

> 240° (decomposition).

Example 62

3Q In 130 mL of concentrated sulfuric acid, a total of 7.2 g (40 mmols) of 3,4-dihydroxy-5-nitrobenzonitrile is introduced in successive portions, with stirring over a period of 10 minutes. The reaction mixture is poured onto 800 mL of ice-cold water. The precipitate formed is drained, washed with water, and collected.

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in ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. After recrystallization in acetone/ethyl acetate, 3,4-dihydroxy-5-nitrobenzamide is obtained in the form of orange crystals melting at 235-236°.

Example 63

a) To a 3.6 g (82.5 mmol) suspension of a 55% sodium hydride dispersion in 50 ml of absolute dimethylformamide, drop by drop is added,

In an argon atmosphere, for 15 minutes, a solution of 11.25 g (82.6 mmols) of 2-hydroxyacetophenone in 100 mL of absolute dimethylformamide is stirred for 1 hour at room temperature. After cooling to 0°C, a solution of 20.3 g (82.6 mmols) of 3,4- chloride is added dropwise over 20 minutes.

Dimethoxy-5-nitrobenzoyl is dissolved in 100 mL of absolute dimethylformamide and shaken overnight at room temperature. The reaction mixture is poured over ice-cold water, and extracted twice with 250 mL of ethyl acetate each time. The organic phase is extracted twice with 100 mL of sodium chloride solution each time, dried over sodium sulfate, and evaporated. The resulting brown oil is heated in 100 mL of toluene. The precipitate is drained, and the filtrate is chromatographed in 30 times its weight of silica gel with toluene/ethyl acetate (4:1). After recrystallization in ethyl acetate/hexane, o-acetyl-phenyl 3,4-dimethoxy-5-nitrobenzoate is obtained, in the form of yellowish crystals melting at 30 108-109°.

b) 10.0 g (29 mmol) of o-acetylphenyl 3,4-dimethoxy-5-nitrobenzoate is dissolved in 50 ml of pyridine. After adding 8.12 g (144 mmol) of powdered and dried potassium hydroxide, the mixture is stirred for 5 min at 80°C.

35 After cooling, it is poured onto ice.

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The aqueous solution is acidified by adding 3N hydrochloric acid. The precipitate formed is drained. After recrystallization in ethyl acetate/hexane, 1-(o-hydroxyphenyl1)-3-(3,4-dimethoxy-5-nitrophenyl)-1,3-propanedione is obtained in the form of yellowish crystals melting at 188-189°.

c) To a 500 mg (1.45 mmol) solution of

To 1-(o-hydroxyphenyl)-3-(3,4-dimethoxy-5-nitrophenyl)-1,3-propanedione in 50 mL of methylene chloride, a solution of 1.82 g (0.7 mL) of boron tribromide in 20 mL of methylene chloride is added dropwise, while stirring, under an argon atmosphere at -20°C. The mixture is then stirred overnight at room temperature. After cooling to -20°C, 25 mL of ethanol is added dropwise, and the mixture is evaporated at 40°C under vacuum using a water aspirator. After recrystallization from ethanol, 1-(3,4-dihydroxy-5-nitrophenyl)-3-(o-hydroxyphenyl)-1,3-propanedione is obtained as yellow crystals melting at 251-252°C.

Example 64

a) To a solution of 2.0 g (5.79 mmol) of

3,4-dimethoxy-5-nitrobenzoate of o-acetylphenyl is dissolved in 12.5 mL of glacial acetic acid, 0.94 g of sodium acetate is added, and the mixture is maintained at reflux temperature for 4 hours. After cooling, it is poured onto ice-cold water. The crystals that precipitate are drained off. After recrystallization in ethyl acetate/hexane, 2-(3,4-dimethoxy-5-nitrophenyl)-4H-l-benzo-pyran-4-one is obtained as colorless crystals melting at 261–217°C.

b) To a solution of 1.0 g (2.9 mmol) of

2-(3,4-dimethoxy-5-nitrophenyl)-4H-l-benzopyran-4-one in 100 ml of methylene chloride is added dropwise over a period of 30 minutes, at -10°C, under an argon atmosphere, a solution of 10 ml of boron tribromide in 50 ml of

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Methylene chloride is added, after which the mixture is stirred overnight at room temperature. After cooling to -20°C, 20 mL of ethanol is added dropwise, and the mixture is then evaporated at 40°C under vacuum using a water aspirator. The resulting yellow residue is extracted with water/ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, and evaporated. After recrystallization in ethanol/ethyl acetate, 2-(3,4-dihydroxy-5-nitrophenyl)-4H-1-benzo-10-pyran-4-one is obtained as yellow crystals that melt at >240°C (decomposition).

Example 65

a) To 33.0 g of 4-brombenzotrifluoride (dissolved in 150 ml of tetrahydrofuran), add dropwise

15 to -70°C, over a period of 20 minutes, 92 ml of n-butyllithium solution (1.6 M in hexane) is added. After 45 minutes of stirring at -70°C, 36 g of

3-Methoxy-4-Benzyloxybenzaldehyde (dissolved in 100 ml of tetrahydrofuran between -70° and -60°C). The mixture is stirred.

The reaction mixture is heated for 2 hours at -70°C and for 1 hour at 0°C. It is then poured onto a mixture of ice and 100 mL of 2N sulfuric acid and extracted twice with 500 mL of ether. The combined ether phases are washed with a saturated sodium chloride solution, dried over sodium sulfate, and evaporated. The resulting solution is...

4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzhydrol, which can be used directly in the next stage of the reaction.

b) 52.6 g of 4-(benzyloxy)-3-methoxy-41 -(tri-

30-fluoromethylbenzhydrol (dissolved in 500 ml of methylene chloride) is added over a period of 10 minutes at 20°C, along with 0.6 g of pyridinium chlorochromate, and the mixture is stirred for 2 hours at 20°C. The precipitate formed is then separated by filtration and washed with 35-methylene chloride. The filtrate is evaporated and chromato-

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The residue is graphed on 150 g of silica gel with methylene chloride. After recrystallization in methylene chloride/hexane, 4-(benzyloxy)- is obtained.

3-methoxy-41-(trifluoromethyl)benzophenone melts at 120°.

5 c) A 20 ç of 4-(benzyloxy)-3-methoxy-4'-(trifluoro-

methyl)-benzophenone (dissolved in 150 ml of methylene chloride) is mixed with 70 ml of 3% hydrobromic acid in acetic acid at 10°C for 15 minutes. After 1.5 hours of stirring at 20°C, the reaction mixture is poured onto 600 ml of ice water; the methylene chloride phase is separated, and the aqueous phase is extracted twice more with 100 ml of methylene chloride. The combined methylene chloride phases are washed with 600 ml of water, dried over sodium sulfate, and evaporated. The residue is chromatographed on 150 g of silica gel with methylene chloride. After recrystallization in methylene chloride/hexane, the following is obtained:

4-hydroxy-3-methoxy-4'-(trifluoromethyl)benzophenone melting at 97°.

20 d) To 12.8 g of 4-hydroxy-3-methoxy-4'-(trifluoromethyl)benzophenone (dissolved in 160 mL of acetic acid), 3.2 mL of 65% nitric acid are added dropwise over 10 minutes at 20°C. After 1.5 h of stirring, the reaction mixture is poured onto 600 mL of ice-cold water. The precipitate formed is separated by filtration, washed with water, and dissolved in methylene chloride. The solution in methylene chloride over sodium sulfate is dried and evaporated, and the residue is recrystallized in methylene chloride/hexane. 4-hydroxy-3-methoxy-5-nitro-4'-(trifluoromethyl)benzophenone, melting at 172°C, is obtained.

e) 2.0 g of 4-hydroxy-3-methoxy-5-nitro-4'-(trifluoromethyl)-benzophenone (dissolved in 20 ml of 33% hydrobromic acid in 35 ml of acetic acid) is shaken for 18 h at 90°C. Then 20 ml of acid is added.

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48% aqueous hydrobromic solution is stirred for an additional 18 hours at 110°C. The reaction mixture is then evaporated under reduced pressure, and the residue is recrystallized in water. 5-3,4-dihydroxy-5-nitro-4'-(trifluoromethyl)benzophenone is obtained, melting at 116-118°C.

Example 66

a) To 18.7 g of 4-hydroxy-3-methoxy-5-nitro-41-(trifluoromethyl)benzophenone (dissolved in 250 mL of 10 tetrahydrofuran), 27.5 mL of 2N potassium hydroxide solution is added at room temperature, and the mixture is then evaporated. The remaining 200 mL of toluene is added and evaporated again. The mixture is then heated with 400 mL of toluene for 4.15 h under a water separator and reflux. 100 mL of toluene is removed by distillation, and 10 mL of dimethylformamide and 20 mL of freshly distilled dimethyl sulfate are added. The mixture is then heated for 5 h under reflux. Finally, at 20°C, 300 mL of 20 IN sodium hydroxide solution is added. The reaction mixture is stirred for 30 minutes and 200 mL of ether is added. The organic phase is separated; the aqueous phase is extracted twice more with 100 mL of ether; the combined ether phases are dried over sodium sulfate and evaporated for 25 minutes, and the residue is chromatographed on 70 g of silica gel with methylene chloride. After recrystallization in methylene chloride/hexane, 3,4-Dimethoxy-5-nitro-4,1-(trifluoromethyl)benzophenone, melting at 115°C, is obtained.

30 b) To 16.0 g of 3,4-dimethoxy-5-nitro-4'-(trifluoromethyl)benzophenone (dissolved in 300 ml of ethanol), 49.5 g of tin dichloride dihydrate is added, after which the mixture is stirred for 30 min at 75°C. The reaction mixture is then poured onto 800 ml of ice water. It is neutralized with a 28% sodium hydroxide solution, and extracted.

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three times with 600 ml of methylene chloride. The combined methylene chloride phases are washed with water, dried over sodium sulfate, and evaporated. After recrystallization in methylene chloride/hexane, 5-amino-3,4-dimethoxy-4'-(trifluoromethyl)-benzophenone is obtained, melting at 95-96°.

c) 3.25 g of 5-amino-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone (dissolved in 50 ml of acetone) is evaporated under reduced pressure after the addition of 15 ml

10 of 2N sulfuric acid. The residue thus obtained is suspended in 20 ml of acetic acid, diluted with 100 ml of water, and added at 5°C to a solution of 700 mg of sodium nitrite in 10 ml of water. The mixture is stirred for 1 h at 5°C. The diazonium salt solution is then filtered and added at 5°C to a solution of 2.0 g of sodium cyanide and 1.0 g of copper(I) cyanide.

The mixture is mixed in 20 ml of water and stirred for 1 hour at 5°C. Then, 200 ml of methylene chloride is added. The insoluble components are separated by filtration. The 20 phases are separated; the aqueous phase is extracted twice more with 100 ml of methylene chloride. The combined methylene chloride phases are washed with water, dried over sodium sulfate, and evaporated. The residue is chromatographed on 30 g of silica gel with 25 g of methylene chloride. After recrystallization in methylene chloride/hexane, 5-cyano-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone, melting at 130°C, is obtained.

d) To 1.5 g of 5-cyano-3,4-dimethoxy-4'-(trifluoro-30-methyl)benzophenone (dissolved in 75 mL of methylene chloride), 2.18 mL of boron tribromide is added at 5°C, after which the mixture is stirred for 18 h at room temperature. The reaction mixture is then diluted with 50 mL of methylene chloride. It is heated for an additional 4 h 35 min under reflux, and at -70°C, the following is added:

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15 mL of methanol is stirred for 2 hours at room temperature, evaporated, and the residue is dried under vacuum and divided between ethyl acetate and ice-cold water. The aqueous phase is extracted twice more with 5 mL of ethyl acetate. The combined ethyl acetate and ethyl acetate phases are dried over sodium sulfate and evaporated. The resulting material is stirred for 6 hours at 130°C with 10 mL of acetic anhydride and 1 mL of pyridine. It is evaporated and the residue is divided between ice-cold water and 10 mL of methylene chloride. The methylene chloride phase is dried over sodium sulfate and evaporated, and the residue is chromatographed on 30 g of silica gel with methylene chloride. The resulting diacetate is dissolved in 10 mL of methanol. 15 to 4.2 ml of sodium hydroxide solution (IN) is added, the mixture is stirred for 1 h at 0°C, neutralized with acetic acid, evaporated, and divided between ethyl acetate and a saturated sodium chloride solution. The ethyl acetate phases are dried over sodium sulfate and evaporated, and the residue is recrystallized in methylene chloride. The yield is 5-Cyano-3,4-Dihydroxy-4'-(trifluoromethyl)benzophenone, which melts at 204-206°C.

Similarly, we obtain:

a1) From 2'-fluoro-4-hydroxy-3-methoxy-5-25 nitrobenzophenone, 3,4-dimethoxy-2'-fluoro-5-nitro-

benzophenone melting at 86-88° (recrystallized in ether/petroleum ether, etc.),

bl) from 3,4-dimethoxy-2'-fluoro-5-nitro-benzophenone, 5-amino-3,4-dimethoxy-2'-fluorobenzo-30 phenone melting at 93-95° (recrystallized in ether/petroleum ether, etc.),

cl) from 5-amino-3,4-dimethoxy-2'-fluorobenzophenone, 5-benzoyl-2,3-dimethoxy-2'-fluorobenzo-nitrile melting at 132-134° (recrystallized in methylene chloride/petroleum ether, ts.) and

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dl) from 5-benzoyl-2,3-dimethoxy-2'-fluorobenzonitrile, 5-benzoyl-2,3-dihydroxy-2'-fluorobenzonitrile melting at 228-230° (recrystallized in ether/petroleum ether, ts.)

5. We obtain in a similar way:

b2) From 3,4-dimethoxy-5-nitrobenzophenone, 5-amino-3,4-dimethoxybenzophenone in the form of an amorphous solid,

c2) from 5-amino-3,4-dimethoxybenzo-10 phenone, 5-benzoyl-2,3-dimethoxybenzonitrile melting at 98-100°C (recrystallized in ether/hexane) and d2) from 5-benzoyl-2,3-dimethoxybenzonitrile, 5-benzoyl-2,3-dihydroxybenzonitrile melting at 212-214°C (recrystallized in ethyl acetate/ether). 15 Example 67

a) To a solution of 2.68 g (32.64 mmols) of 1-methylimidazole and 6.6 g (65.14 mmols) of triethylamine in 80 ml of pyridine, a solution of 16.0 g (65.14 mmols) of chloride is added dropwise

20 3,4-dimethoxy-5-nitrobenzoyl in 80 ml of pyridine,

After which, the mixture is stirred for 3 hours at 60°C. Following the addition of 1.70 mL of 3N sodium hydroxide solution, the mixture is stirred for another hour, then poured onto ice-cold water. The gray crystals that precipitate are drained off and resuspended in 25 mL of ethyl acetate. The organic phase is then dried over magnesium sulfate, and the solvent is removed by distillation. After recrystallization in ethyl acetate/hexane, 3,4-dimethoxy-5-nitrophenyl(l-methylimidazol-2-yl)ketone is obtained as 30 colorless crystals melting at 144-145°C.

b) To 5.0 g (17.17 mmol) of 3,4-dimethoxy-5-nitro-phenyl(l-methylimidazol-2-yl)ketone, 50 ml of hydrobromic acid (48%) is added, after which the mixture is stirred for 2 hours at reflux temperature. After cooling-

35. The precipitate formed is then squeezed out, washed with water, and q-

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It is recrystallized in ethanol. The hydrobromide of 3,4-dihydroxy-5-nitrophenyl(1-methyl-imidazol-2-yl)ketone is obtained in the form of yellow crystals with a decomposition point > 240°.

5 Example 68

Similar to Example 67, from 3,4-dimethoxy-5-nitrobenzoyl chloride and 1-benzylimidazole, l-benzylimidazol-2-yl(3,4-dimethoxy-5-nitrophenyl)ketone is obtained as colorless crystals melting at 134-135°C (recrystallized in methylene/hexane chloride), and from this, with hydrobromic acid, the hydrobromide of l-benzylimidazol-2-yl-(3,4-dihydroxy-5-nitrophenyl)ketone is obtained as yellow crystals melting at 218-219°C (decomposition). Example 69

a) To a solution of 13.0 g (53.13 mmols) of 3,4-dimethoxy-5-nitrobenzoyl chloride and 5.4 g (53.13 mmols) of triethylamine in 80 ml of acetonitrile, a

20. A solution of 10.0 g (53.13 mmol) of 1-[(benzyloxy)-methyl]imidazole in 50 mL of acetonitrile is prepared by cooling the ice so that the temperature does not exceed 25°C. The mixture is then stirred for 3 hours, after which the solvent is removed by distillation. After the addition of water, the solution is extracted with ethyl acetate. The mixture is washed twice with water, then dried over sodium sulfate and evaporated. The resulting oil is chromatographed on 600 g of silica gel with toluene/ethyl acetate (95:5). 1-[(benzyloxy)methyl]imidazol-2-yl(3,4-dimethoxy-5-nitrophenyl)ketone is obtained as a yellowish oil.

b) In a manner analogous to example 67b, after treatment with hydrobromic acid, the hydrobromide of 3,4-dihydroxy-5-nitrophenyl(imidazol-2-yl)-

35 ketone in the form of yellow crystals melting at 247-248=

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Example 70

a) A solution of 25.0 g (120.16 mmol) of 3-bromoquinoline is dissolved in 200 ml of dry ether and cooled to -60°C. At this temperature, drop by drop is added

75.1 mL (120.16 mmol) of a 1.6 M n-butyllithium solution is added dropwise over 15 minutes, followed by stirring for 10 minutes. At -60°C, a solution of 26.5 g (109.2 mmol) of benzyl vanillin ether in 250 mL of dry ether is then added dropwise. The mixture is stirred for 3 hours at room temperature, poured over approximately 1.5 L of ice-cold water, and extracted three times, each time with 600 mL of ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, and evaporated. The resulting oil is chromatographed on 1 kg of silica gel with methylene chloride/ethyl acetate (1:1). The crude crystalline product obtained is recrystallized in ethyl acetate. The ex-[4-(benzyloxy)-3-methoxyphenyl]-3-quinolinemethanol is obtained in the form of colorless crystals 20 melting at 124-125°.

b) A solution of 6.2 g (16.7 mmol) of α-[benzyloxy)-3-methoxyphenyl]-3-quinolinemethanol in 200 ml of methylene chloride is stirred for 2 h at reflux temperature after the addition of 62 g of hydrogen dioxide.

25 manganese. After cooling, the precipitate is drained and washed with methylene chloride. The filtrate is evaporated, and the resulting oil is dissolved in hot ether, after which a small amount of pentane is added. The crystals that precipitate are drained. The 4-(benzyloxy)-3-methoxyphenyl-(3-quinoline)ketone is obtained as colorless crystals melting at 110-111°.

c) To 11.0 G (29.78 mmol) of 4-(benzyloxy)-3-methoxyphenyl(3-quinoline) ketone, 50 ml are added

35 of trifluoracetic acid, after which it is shaken for 2 hours

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at room temperature. After removing the trifluoracetic acid by distillation, 50 mL of ethanol is added twice, and the solvent is removed by distillation each time. The resulting oil crystallizes upon the addition of ethanol. After recrystallization in ethanol, 4-hydroxy-3-methoxyphenyl(3-quinoleinyl)ketone is obtained as yellowish crystals that melt at 196-197°C.

d) To a solution of 5.5 g (19.69 mmol) of

10 4-hydroxy-3-methoxyphenyl(3-quinoleinyl)ketone is dissolved in 300 mL of glacial acetic acid. A solution of 1.91 mL of 65% nitric acid in 20 mL of glacial acetic acid is added dropwise at 15°C, and the mixture is stirred continuously for 2 hours at this temperature. The mixture is then poured onto ice-cold water and extracted three times, each time with 300 mL of ethyl acetate. The organic phase is washed five times with 100 mL of water, dried over sodium sulfate, and evaporated. After the addition of ethyl acetate to the residue, 4-hydroxy-3-2-O-methoxy-5-nitrophenyl is obtained as yellow crystals that melt at 220-221°C (decomposition).

e) To 820 mg (2.53 mmols) of 4-hydroxy-3-methoxy-5-nitrophenyl(3-quinolineinyl) ketone, 50 ml of 48% hydrobromic acid is added, and the mixture is maintained for 3 h at

25. Reflux temperature. After removing the hydrobromic acid by distillation at 50°C, 70 ml of hot water is added to the residue, and the insoluble portion is drained off. The hydrobromide of 3,4-dihydroxy-5-nitrophenyl(3-quinoleinyl)ketone is obtained in the form of 30 yellow crystals that melt at 270°C (decomposition).

Example 71

By analogy with example 70, o; - [4- (benzyloxy-3-methoxyphenyl ] -4-quinolinemethanol in the form of colorless crystals melting at 117-118° 35 (ethyl acetate), from this, with dioxide

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of manganese, the 4-(benzyloxy)-3-methoxyphenyl(4-isoquinolineinyl)ketone in the form of colorless crystals melting at 126.5-127.5°, from this, with trifluoracetic acid the 4-hydroxy-3-methoxyphenyl-5 (4-isoquinolineinyl)ketone in the form of yellow crystals melting at 197.5-198.5°, and from this, by nitration with nitric acid in glacial acetic acid, then treatment with hydrobromic acid, the hydrobromide of the 3,4-dihydroxy-5-10 nitrophenyl (4-isoquinolineinyl)ketone in the form of yellow crystals melting at 256° (decomposition).

Example 72

By analogy with Example 70, we obtain 1' «-[4-(benzyloxy)-3-methoxyphenyl]-2-naphthalenemethanol in the form of colorless crystals (recrystallized in ethyl acetate/hexane) melting at 113-114°C; from this, with manganese dioxide, we obtain 4-(benzyloxy)-3-methoxy-phenyl(2-naphthyl)-ketone in the form of colorless crystals (recrystallized in ethyl acetate/hexane), melting at 104-105°C; from this, by treatment with trifluoracetic acid and nitration with nitric acid in glacial acetic acid, 4-hydroxy-3-methoxy-5-nitrophenyl(2-naphthyl)ketone in the form of yellow crystals melting at 187-188°, and from 25° this one, by treatment with hydrobromic acid, the

3,4-dihydroxy-5-nitrophenyl(2-naphthyl)ketone in the form of yellow crystals melting at 184-185°.

Example 73

a) To a solution of 20.0 g (100.5 mmol) of 3-phenylpropyl bromide in 300 ml of ether, a solution of 71.8 ml (100.5 mmol) of tert-butyllithium (1.4 molar) in pentane is added at -60°C, with stirring for 15 minutes. After 10 minutes, a solution of 22.14 g (91.36 mmol) of ether is added dropwise at this temperature for 15 minutes.

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Benzyl alcohol of vanillin is dissolved in 200 ml of ether, and the mixture is stirred for 2 hours. The mixture is poured onto 1 liter of ice-cold water and extracted three times, each time with 500 ml of ethyl acetate. The organic phase is washed twice with 200 ml of water, dried over sodium sulfate, and evaporated. The resulting oil is chromatographed on 1 kg of silica gel with methylene chloride. The crystals obtained are recrystallized in ether/pentane. The resulting alcohol is 4-(benzyloxy)-3-methoxy-(3-phenylpropyl)-

benzyl in the form of colorless crystals melting at 71-73°C.

b) To a solution of 9.0 g (24.83 mmols) of 4-(benzyloxy)-3-methoxy-rx-(3-phenylpropyl)benzyl alcohol,

In 250 ml of methylene chloride, 90 g of manganese dioxide are added, and the mixture is maintained at reflux temperature for 2 h. After cooling, the precipitate is drained and washed with methylene chloride. The filtrate is evaporated, and the residue is recrystallized in ethyl acetate/ether. 4'-(benzyloxy)-3'-methoxy-4-phenylbutyrophenone is obtained as colorless crystals melting at 81-82°C.

c) A solution of 7.0 g (19.42 mmols) of 4'-(benzyloxy)- is shaken for 5 h at room temperature

25,31-methoxy-4-phenylbutyrophenone in 40 ml of 33% hydrobromic acid in glacial acetic acid,

then it is poured onto 500 ml of ice water. By adding concentrated ammonia, the solution is adjusted to pH 6.0 and extracted three times, each time with 250 ml of ethyl acetate. The organic phase is washed three times, each time with 50 ml of water, dried over sodium sulfate, and evaporated. The resulting oil is dissolved in 20 ml of ether, then hexane is added until a cloudy consistency is reached, and it is allowed to crystallize. The 4-hydroxy-

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3'-methoxy-4-phenylbutyrophenone colorless, melting at 91-92°.

d) To a solution of 2.2 g (8.14 mmols) of

4-Hydroxy-3'-Methoxy-4-Phenylbutyrophenone is dissolved in 25 mL of glacial acetic acid. A solution of 0.79 mL of 65% nitric acid in 25 mL of glacial acetic acid is added dropwise, and the mixture is stirred continuously for 2 hours at room temperature. The mixture is then poured onto 150 mL of ice-cold water. After adding 20 mL of 3N hydrochloric acid, the solution is extracted three times, each time with 75 mL of ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, and evaporated. The crude product is then reconstituted in ethyl acetate and filtered through 75 g of silica gel. After recrystallization in acetonitrile, 4'-hydroxy-3'-methoxy-5'-niotro-4-phenylbutyrophenone is obtained in the form of yellow crystals melting at 120-121°.

e) 1.0 g (3.2 mmols) of 4'-hydroxy-3'-methoxy-5'-nitro-4-phenyl- is maintained at 200°C for 1 hour

2. Butyrophenone is mixed with 8 g of pyridine hydrochloride. The still-hot mixture is poured onto ice-cold water and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid (IN), then with water, dried over sodium sulfate, and evaporated. 2. The dark residue obtained is chromatographed over three times its weight of silica gel with ethyl acetate. Recrystallization in methylene chloride/hexane yields 3',4'-dihydroxy-5'-nitro-4-phenylbutyrophenone as yellow crystals melting at 118-119°C. 3. Example 74

a) To a solution of 10.0 g (47.4 mmols) of 3,4-dimethoxy-5-nitrobenzaldehyde in 100 ml of dioxane, a solution of 14.68 g (225.4 mmols) of potassium cyanide in 20 ml of water is added. Then, 18.81 ml is added dropwise over 30 minutes.

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(190.76 mmol) of 37% hydrochloric acid, stirring vigorously. After adding 120 mL of ether, the excess hydrocyanic acid is removed by passing argon through the solution. The reaction mixture is filtered through a diatomaceous earth filter, the organic phase is washed with water, dried over sodium sulfate, and evaporated. The 1'-hydroxy-3,4-dimethoxyphenylacetonitrile (yellowish oil) formed is dissolved in 200 mL of ether, after which 20 mL of ethanol is added, the mixture is cooled to 0°C, and gaseous hydrochloric acid is passed through it for 30 minutes. After 3 hours, the colorless precipitate formed is drained off and recrystallized in ethanol/ether. Hydrochloride 1 is obtained from (3,4-dimethoxy-5-nitrophenyl) hydroxyacetimidate.

15 b) 19.7 g (61.46 mmol) of ethyl (3,4-dimethoxy-5-nitrophenyl)hydroxyacetimidate hydrochloride is dissolved in 500 mL of ethanol. After the addition of 6.73 g (61.46 mmol) of o-phenylenediamine, the mixture is stirred for 2 h at room temperature and then held overnight at reflux temperature. After removing the solvent by distillation, 50 mL of water is added, the mixture is alkalinized with a sodium carbonate solution, and the extraction is performed twice, each time with 250 mL of methylene chloride. The organic phase is washed with water, dried over sodium sulfate, and evaporated. The resulting orange residue is chromatographed on 400 g of silica gel with methylene chloride/ethyl acetate (1:1).

After recrystallization in ether/hexane, 1-(3,4-dimethoxy-5-nitrophenyl)-2-benzimidazolmethanol 30 is obtained in the form of yellowish crystals melting at 50° (decomposition).

c) 13.2 g (40.1 mmol) of cx-(3,4-dimethoxy-5-nitrophenyl)-2-benzimidazolmethanol is dissolved in 200 ml of methylene chloride, after which, following the addition of 130 g of manganese dioxide, the mixture is stirred

1

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for 2 h at reflux temperature. After filtration, the solvent is removed by distillation. The 2-benzimidazolyl(3,4-dimethoxy-5-nitrophenyl)ketone is obtained in the form of yellowish crystals melting at 212-213°.

5 d) Maintain 1.0 g at 200°C for 60 minutes

(3.05 mmol) of 2-benzimidazolyl(3,4-dimethoxy-5-nitrophenyl)ketone and 8.0 g of pyridine hydrochloride. The still-hot, dark solution is poured over ice-cold water and extracted three times, each time with 100 mL of ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, and evaporated. After recrystallization in ethyl acetate/hexane, 2-benzimidazolyl(3,4-dihydroxy-5-nitrophenyl)ketone is obtained as yellow crystals melting at 249–250°C.

Example 75

a) 30.0 g (132 mmols) of 3,4-dimethoxy-5-nitrobenzoic acid is dissolved in 250 ml of tetrahydrofuran. After the addition of 21.85 g (135 mmols) of 1,1'-carbonyl-diimidazole, the mixture is stirred for 2 hours at reflux temperature. The mixture is then poured onto 300 ml of ice-cold water, and the crystals that precipitate after 30 minutes of stirring are drained off. These crystals are then collected in methylene chloride, and the organic phase is washed with water, dried over sodium sulfate, and evaporated. After recrystallization in methylene chloride/hexane, 1-(3,4-dimethoxy-5-nitrobenzoyl)imidazole is obtained as colorless crystals melting at 136-137°C. 30 b) At 10.0 g (36.1 mmol) of 1-(3,4-dimethoxy-

In 50 ml of dimethylformamide, add 6.95 g (93.8 mmol) of acetamidoxime, then stir for 1 hour at 70°C. After cooling, pour the mixture onto 500 ml of ice water and stir for 30 minutes. Drain off any crystals that precipitate.

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and we wash them with water. After recrystallization in ethyl acetate, we obtain N'-[(3,4-dimethoxy-5-nitrobenzoyl)oxy]acetamidine in the form of colorless crystals melting at 165-166°.

5 c) 2.0 g (7.2 mmol) of N'-[(3,4-dimethoxy-5-nitrobenzoyl)oxy]acetamidine is maintained in 20 ml of glacial acetic acid for 1 h at reflux temperature. After removal of the glacial acetic acid by distillation, the crystalline residue is recrystallized in ether/hexane. 5-(3,4-dimethoxy-5-nitrophenyl)-3-methyl-1,2,4-oxadiazole is obtained as colorless crystals melting at 111°C.

d) 2.5 g (9.43 mmol) of 5-(3,4-dimethoxy-5-nitrophenyl)-5-methyl-1,2,4-oxadiazole is dissolved in 1570 mL of methylene chloride. After cooling to -60°C, a solution of 23.62 g (94.3 mmol) of boron tribromide in 50 mL of methylene chloride is added dropwise over 20 minutes while cooling. The mixture is then maintained at reflux temperature for 48 hours. After cooling to -60°C, 60 mL of ethanol is added, and the mixture is stirred for 30 minutes at room temperature. The yellow solution is evaporated to dryness, and the residue is then added three times in 100 mL increments of toluene/ethanol (1:1), removing the solvent by distillation each time. After recrystallization in ethanol, 5-(3-methyl-l,2,4-oxadiazol-5-yl)-3-nitropyrocatechol is obtained in the form of yellow crystals melting at 201-202°.

30 Example 7 6

a) To 35.0 g of l-bromo-2-fluorobenzene (dissolved in 600 ml of tetrahydrofuran), 143.8 ml of n-butyllithium solution (1.53 M in hexane) is added dropwise at -70°C for 30 minutes. After 60 minutes and 35 seconds of stirring at -70°C, the remaining solution is added dropwise for

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30 min, 48.5 g of 3-methoxy-4-benzyloxybenzaldehyde (dissolved in 450 mL of tetrahydrofuran). The reaction mixture is stirred for 2 h at -70°C and for 30 min at 0°C, poured onto a mixture of ice and 150 mL of 2N sulfuric acid, and extracted three times with ether. The combined ether phases are washed with a saturated sodium chloride solution, dried over sodium sulfate, and evaporated. 4-(benzyloxy)-2'-fluoro-3-methoxybenzhydrol is obtained as a yellowish oil, which can be used directly in the subsequent stage of the reaction.

We obtain in a similar way:

a) Part of 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-3-fluorobenzene, 4-(benzyloxy)-3'-fluoro-3-15 methoxybenzhydrol in the form of an oil;

a2) from 3-methoxy-4-benzyloxybenzaldehyde and l-bromo-4-fluorobenzene, 4-(benzyloxy)-4'-fluoro-3-methoxybenzhydrol in the form of an oil;

a3) from 3-methoxy-4-benzyloxybenzaldehyde and 20 of l-bromo-2,6-difluorobenzene, 4-(benzyloxy)-2',6'-difluoro-3-methoxybenzhydrol in the form of an oil;

a4) from 3-methoxy-4-benzyloxybenzaldehyde and bromo-2-chlorobenzene, 4-(benzyloxy)-2'-chloro-3-methoxybenzhydrol in the form of an oil; 25 a5) from 3-methoxy-4-benzyloxybenzaldehyde and l-bromo-3-chlorobenzene, 4-(benzyloxy)-31-chloro-3-methoxybenzhydrol in the form of an oil;

a6) from 3-methoxy-4-benzyloxybenzaldehyde and l-bromo-4-chlorobenzene, 4-(benzyloxy)-4'-chloro-3-30 methoxybenzhydrol in the form of an oil;

a7) from 4-benzyloxy-3-methoxybenzaldehyde and 2-bromotoluene, 4-(benzyloxy)-3-methoxy-2'-methyl-benzhydrol in the form of an oil;

a8) from 3-methoxy-4-benzyloxybenzaldehyde and 35 from 4-bromotoluene, 4-(benzyloxy)-3-methoxy-4'-methyl-

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benzhydrol in the form of an oil;

a9) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromobenzonitrile, 4-(benzyloxy)-2'-cyano-3-methoxybenzhydrol in the form of an oil; and 5 a1O) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-2-trifluoromethylbenzene, 4-(benzyloxy)-3-methoxy-2'-(trifluoromethyl)benzhydrol in the form of an oil.

b) To 69.8 g of 4-(benzyloxy)-2'-fluoro-3-methoxy-10 benzhydrol (dissolved in 600 mL of methylene chloride), 45.3 g of pyridinium chlorochromate are added over a period of 30 min at 20°C, and the mixture is stirred for 3 h at 20°C. The precipitate formed is then filtered and washed with methylene chloride. The filtrate is evaporated, and the residue is filtered through 100 g of silica gel with ether. After recrystallization in ether, 4-(benzyloxy)-2'-fluoro-3-methoxybenzophenone, which melts at 118–120°C, is obtained.

In a similar manner, we obtain: 20 kl) From 4-(benzyloxy)-31-fluoro-3-methoxy benzhydrol, 4-(benzyloxy)-3'-fluoro-3-methoxybenzophenone in the form of an amorphous solid;

b2) from 4-(benzyloxy)-4'-fluoro-3-methoxy-benzhydrol, 4-(benzyloxy)-4(-fluoro-3-methoxybenzo-25 phenone melting at 99-101° (recrystallized in ether/hexane);

b3) from 4-(benzyloxy)-2',6'-difluoro-3-methoxybenzhydrol, 4-(benzyloxy)-2',6'-difluoro-3-methoxybenzophenone melting at 139-141° (recrystallized 3 0 in methylene chloride/ether);

b4) from 4-(benzyloxy)-2'-chloro-3-methoxybenzhydrol, 4-(benzyloxy)-21-chloro-3-methoxybenzo-phenone melting at 128-130° (recrystallized in ether);

b5) from 4-(benzyloxy)-3'-chloro-3-methoxy-35 benzhydrol, the 4-(benzyloxy)-3'-chloro-3-methoxybenzo-

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phenomenon in the form of an amorphous solid body;

b6) from 4-(benzyloxy)-41-chloro-3-methoxybenzhydrol, 4-(benzyloxy)-4'-chloro-3-methoxybenzo-phenone melting at 106-108° (recrystallized in 5 methylene chloride/hexane);

b7) from 4-(benzyloxy)-3-methoxy-2'-methyl-benzhydrol, 4-(benzyloxy)-3-methoxy-2'-methylbenzo-phenone melting at 86-88° (recrystallized in isopropyl ether);

10 b8) from 4-(benzyloxy)-3-methoxy-4'-methyl-

benzhydrol, the 4-(benzyloxy)-3-methoxy-4'-methylbenzo-phenone melting at 79-81° (recrystallized in ether/hexane);

b9) from 4-(benzyloxy)-2'-cyano-3-methoxy-15 benzydrol, 4-(benzyloxy)-2'-cyano-3-methoxybenzophenone in the form of an amorphous solid; and bl0) from 4-(benzyloxy)-3-methoxy-2'-(trifluoromethyl)-benzophenone melting at 103-105° (recrystallized in ether).

20 c) To 42.4 g of 4-(benzyloxy)-2•-fluoro-3-methoxybenzophenone (dissolved in 450 mL of methylene chloride), 170 mL of 33% hydrobromic acid in glacial acetic acid is added at 20-25°C for 20 minutes. After stirring for 1.5 hours at 20°C, the reaction mixture is poured onto 750 mL of ice-cold water; the methylene chloride phase is separated, and the aqueous phase is extracted twice more with 200 mL of methylene chloride. The combined methylene chloride phases are washed with 1200 mL of water, dried over sodium sulfate, and evaporated. To remove the benzyl bromide formed, the oily hexane residue is added, and the mixture is decanted. 2'-Fluoro-4-hydroxy-3-methoxybenzophenone is obtained as a yellowish oil, which can be used directly in the next stage of the reaction. The following are obtained in a similar manner:

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cl) From 4-(benzyloxy)-3'-fluoro-3-methoxybenzophenone, 3'-fluoro-4-hydroxy-3-methoxybenzophenone melts at 133-135° (recrystallized in methylene chloride/petroleum ether ts.);

5 c2) from 4-(benzyloxy)-4'-fluoro-3-

methoxybenzophenone, 41-fluoro-4-hydroxy-3-methoxybenzophenone melting at 139-141° (recrystallized in ether);

c3) from 4-(benzyloxy)-2•,6'-difluoro-3-10 methoxybenzophenone, 2',6•-difluoro-4-hydroxy-3-

methoxybenzophenone melting at 130-132° (recrystallized in methylene chloride/petroleum ether ts.);

c4) from 4-(benzyloxy)-21-chloro-3-methoxybenzophenone, 2•-chloro-4-hydroxy-3-methoxy-15 benzophenone in the form of an amorphous solid;

c5) from 4-(benzyloxy)-3'-chloro-3-methoxybenzophenone, 3•-chloro-4-hydroxy-3-methoxybenzophenone melting at 136-138° (recrystallized in methylene chloride);

20 c6) from 4-(benzyloxy)-4'-chloro-3-

methoxybenzophenone, 4'-chloro-4-hydroxy-3-methoxybenzophenone melting at 114-116° (recrystallized in methylene chloride/petroleum ether ts.);

cl) from 4-(benzyloxy)-3-methoxy-2'-25 methylbenzophenone, 4-hydroxy-3-methoxy-2'-methylbenzophenone melting at 103-105° (recrystallized in isopropyl ether);

c8) from 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone, 4-hydroxy-3-methoxy-4'-methyl-30 benzophenone melting at 103-105° (recrystallized in ether/petroleum ether ts.);

c9) from 4-(benzyloxy)-21-cyano-3-methoxybenzophenone, 21-cyano-4-hydroxy-3-methoxybenzophenone melting at 124-126° (recrystallized in n-hexane ether); 35 and t

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clO) from 4-(benzyloxy)-3-methoxy-2'-(trifluoromethyl)benzophenone, 4-hydroxy-3-methoxy-21-(trifluoromethyl)benzophenone melting at 115-117° (recrystallized in ether).

5 d) To 29.4 g of 21-fluoro-4-hydroxy-3-methoxybenzophenone (dissolved in 450 ml of acetic acid), 7.8 ml of 65% nitric acid is added dropwise over 20 min at 20°C. After 1.5 h of stirring, the reaction mixture is poured onto 2 liters of ice-cold water, and the precipitate formed is separated by filtration, washed with water, and dissolved in methylene chloride. The solution in methylene chloride is washed with water, dried over sodium sulfate, and evaporated. The residue is recrystallized in methanol. This yields 2'-fluoro-4-15 *hydroxy-3-methoxy-5-nitrobenzophenone, which melts at 127-129°C. In a similar manner, the following are obtained:

dl) From 3'-fluoro-4-hydroxy-3-methoxybenzophenone, 3'-fluoro-4-hydroxy-3-methoxy-5-nitro-benzophenone melts at 168-170° (recrystallized in 20 methanol);

d2) from 4'-fluoro-4-hydroxy-3-methoxybenzophenone, 4'-fluoro-4-hydroxy-3-methoxy-5-nitro-benzophenone melting at 126-128° (recrystallized in ether);

25 d3) from the 2',, 6'-difluoro-4-hydroxy-3-

methoxybenzophenone, the 2',6'-difluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone melting at 147-149° (recrystallized in methanol);

d4) from 2'-chloro-4-hydroxy-3-methoxy-30 benzophenone, 2'-chloro-4-hydroxy-3-methoxy-5-nitro-benzophenone melting at 123-125° (recrystallized in ether);

d5) from 3'-chloro-4-hydroxy-3-methoxybenzophenone, 3•-chloro-4-hydroxy-3-methoxy-5-nitro-35 benzophenone melting at 152-154° (recrystallized in the

S'7

methanol);

d6) from 41-chloro-4-hydroxy-3-methoxybenzophenone, 4'-chloro-4-hydroxy-3-methoxy-5-nitro-benzophenone melting at 129-131° (recrystallized in methylene chloride/ petroleum ether ts.);

d7) from 4-hydroxy-3-methoxy-2'-methylbenzophenone, 4-hydroxy-3-methoxy-2•-methyl-5-nitro-benzophenone melting at 125-127° (recrystallized in ethanol);

d8) from 4-hydroxy-3-methoxy-41-methylbenzophenone, 4-hydroxy*-3-methoxy-4'-methyl-5-nitro-benzophenone melting at 137-139° (recrystallized in methylene chloride/ether);

d9) from 21-cyano-4-hydroxy-3-methoxybenzophenone, 2'-cyano-4-hydroxy-3-methoxy-5-nitro-benzophenone melting at 163-164° (recrystallized in methanol);

dlO) from 4-hydroxy-3-methoxy-2'-(tri-fluoromethyl)benzophenone, 4-hydroxy-3-methoxy-5-nitro-21-(trifluoromethyl)benzophenone melting at 138-140° (recrystallized in methylene chloride/petroleum ether ts.);

d11) from 4-hydroxy-3,4'-dimethoxybenzophenone, 4-hydroxy-3,41-dimethoxy-5-nitrobenzophenone melting at 134-136° (recrystallized in methanol); and d112) from 4-hydroxy-3,3',4'-trimethoxybenzophenone, 4-hydroxy-5-nitro-3,31,41-trimethoxybenzophenone melting at 178-180° (recrystallized in methanol).

e) 24.8 g of 2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone (dissolved in 120 mL of glacial acetic acid, 100 mL of 33% hydrobromic acid in glacial acetic acid, and 68 mL of 48% aqueous hydrobromic acid) are boiled under reflux for 4 h. The reaction mixture is then evaporated under pressure.

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The product is reduced and distilled with toluene. The residue is dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered, and evaporated. The product is then recrystallized in 5-methylene chloride/petroleum ether. This yields 21-fluoro-3,4-dihydroxy-5-nitrobenzophenone, which melts at 169-171°C.

We obtain in a similar way:

el) from 3'-fluoro-4-hydroxy-3-methoxy-5-10 nitrobenzophenone, 3'-fluoro-3,4-dihydroxy-5-nitro-benzophenone melting at 124-12 6° (recrystallized in methylene chloride);

e2) from 4'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone, 4•-fluoro-3,4-dihydroxy-5-nitro-15 benzophenone melting at 171-173° (recrystallized in methylene chloride);

e3) from 2',6'-difluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone, 2',6'-difluoro-3,4-dihydroxy-5-nitrobenzophenone melting at 194-196° 20 (recrystallized in methanol);

e4) from 2'-chloro-4-hydroxy-3-methoxy-5-nitrobenzophenone, 21-chloro-3,4-dihydroxy-5-nitrobenzophenone melting at 129-131° (recrystallized in methylene chloride/petroleum ether ts.); 25 e5) from 3'-chloro-4-hydroxy-3-methoxy-5-

nitrobenzophenone, 3'-chloro-3,4-dihydroxy-5-nitro-benzophenone melting at 143-145° (recrystallized in methylene chloride/petroleum ether ts.);

e6) from 41-chloro-4-hydroxy-3-methoxy-30 benzophenone, 4'-chloro-3,4-dihydroxybenzophenone melting at 174-176° (recrystallized in methylene chloride);

e7) from 4-hydroxy-3-methoxy-21-methyl-5-nitrobenzophenone, 3,4-dihydroxy-2'-methyl-5-nitro-35 benzophenone melting at 164-166° (recrystallized in the

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methylene chloride);

e8) from 4-hydroxy-3-methoxy-41-methyl-5-nitrobenzophenone, 3,4-dihydroxy-4•-methyl-5-nitro-benzophenone melting at 146-184/ (recrystallized in 5 methylene chloride);

e9) from 21-cyano-4-hydroxy-3-methoxy-5-nitrobenzophenone, 2'-cyano-3,4-dihydroxy-5-nitro-benzophenone melting at 159-161° (recrystallized in methanol);

10 elO) from 4-hydroxy-3-methoxy-5-nitro-2'-

(trifluoromethyl)benzophenone, 3,4-dihydroxy-5-nitro-2'-(trifluoromethyl)benzophenone melting at 146-148° (recrystallized in methanol);

ell) from 15 4-hydroxy-3,4'-dimethoxy-5-nitrobenzophenone, the

5-nitro-3,4,41-trihydroxybenzophenone melting at 212-214° (recrystallized in methanol/methylene chloride); and el2) from 4-hydroxy-5-nitro-3,3',4'-20 trimethoxybenzophenone, 5-nitro-3,3*,4,4'-tetrahydroxybenzophenone melting at 222-224° (recrystallized in ether).

Example 7 7

To a suspension of 13.8 g of 2-bromo-31,4'-25-dihydroxy-5'-nitroacetophenone, 9.0 g of

1-(phenethyl)-2-thiourea is dissolved in 150 ml of n-butanol and heated to boiling under reflux for 3 hours. After cooling to room temperature, the crystals are drained and recrystallized in n-butanol. The resulting 3-nitro-5-[2-(phenethyl-amino)-4-thiazolyl]pyrocatechol hydrobromide melts at 249-251°C.

Example 78

Similar to Example 38, 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone 35 and 2-aminobenzophenone are obtained: 2-(3,4-dihydroxy-5-nitro-

100

benzoyl)-3-phenylindole melting at 196-198° (recrystallized in isopropanol).

Example 79

To a suspension of 8.3 g of 2-bromo-3',4'-5-dihydroxy-5•-nitroacetophenone, l-(l-adamantyl)-2-thiourea is added in 90 ml of n-butanol and heated for 4 h to boiling under reflux. After cooling to room temperature, the crystals are drained and recrystallized in n-butanol. The resulting hydrobromide of 5-[2-(1-adamantylamino)-5-thiazolyl]-3-nitropyrocatechol melts at 245-247°C.

Example 8 0

A suspension of 2.6 g of (3,4-dihydroxy-5-nitrobenzoyl)-15 methyl acetate in 20 mL of ethanol and 20 mL of hydrochloric acid (IN) is heated to boiling under reflux for 5 h. The reaction mixture is then evaporated, distilled again with toluene, and the residue is recrystallized from ethanol. The yield is 2,3',4'-trihydroxy-5'-nitroacetophenone, which melts at 20-210°C.

Example 81

A solution of 4.0 g of n-hexyl 3,4-dihydroxy-5-nitrophenylgly-oxylate and 1.5 g of diaminomaleonitrile in 25–35 mL of ethanol is heated to boiling under reflux for 24 h. The alcohol is then distilled, the residue is distilled in ether, washed with water, dried over sodium sulfate, filtered, and evaporated. The yield is 6-hydroxy-5-(3,4-dihydroxy-5-nitrophenyl)-2,3-pyrazinedicarbonitrile, which melts at >300°C (recrystallized in ether/methylene chloride).

Example 8 2

a) To 4.2 g of 5-(bromacetyl)-2,3-dimethoxybenzo-nitrile, dissolved in 150 ml of methylene chloride, 8.9 ml of boron tribromide is added. The reaction mixture is stirred for 18 h at 20°C. It is then poured onto c

101

220 ml of saturated sodium bicarbonate solution and 100 g of ice are mixed, adjusted to pH 6 with glacial acetic acid, and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate, and evaporated. 5-(bromacetyl)-2,3-dihydroxybenzonitrile is obtained as an amorphous solid.

b) To 3.8 g of 5-(bromacetyl)-2,3-dihydroxybenzonitrile, dissolved in 25 mL of N,N-dimethylformamide, N-phenylthiourea is added and the mixture is stirred for 5 h at 100°C. The solvent is then evaporated. The residue is added to 200 mL of sodium carbonate solution (IN) and extracted three times, each time with 100 mL of methylene chloride. The combined organic phases are washed with water, dried over sodium sulfate, and evaporated. The residue is chromatographed on 30 g of silica gel with ethyl acetate. The crude product thus obtained is added to 40 mL of hydrochloric acid (IN), evaporated, and recrystallized in acetone. The hydrochloride of 5-(2-anilino-4-thiazolyl)-2,3-dihydroxybenzonitrile is obtained, melting at 245-247°.

Example 8 3

a) To 10 g of 4-(benzyloxy)-3-methoxybromobenzene, 25 ml dissolved in 100 mL of tetrahydrofuran, 25 mL of tert-butyllithium solution (1.4 M in hexane) is added dropwise at -70°C over 10 minutes. After 1 hour of stirring at -70°C, 5 g of chinolein-4-carbaldehyde, dissolved in 50 mL of tetrahydrofuran, 30 ml over 30 minutes, is added dropwise. The reaction mixture is stirred for 1 hour at -40°C and for 1 hour at -5°C, then poured onto 200 mL of water and adjusted to pH 4 with acetic acid. It is extracted three times, each time with 50 mL of ether. The 35 combined ethereal phases are washed with water and dried on a sulfate of qs

102

sodium and they are evaporated. We obtain 1'o<-[4-(benzyloxy)-3-methoxyphenyl]-4-guinolinemethanol in the form of an amorphous solid.

b) To 9.4 g of [4-(benzyloxy)-3-methoxyphenyl]-4,5-quinolinemethanol, dissolved in 200 mL of methylene chloride, 6.5 g of pyridinium chlorochromate are added, after which the mixture is stirred for 3 h at room temperature. The insoluble constituents are then separated by filtration. The filtrate is evaporated, and the residue is chromatographed on 150 g of silica gel with ethyl acetate. This yields 4-(benzyloxy)-3-methoxyphenyl-4-quinolineinyl ketone as an amorphous solid.

c) To 7.5 g of 4-(benzyloxy)-3-methoxyphenyl-4-15 quinolineinyl ketone, dissolved in 150 mL of methylene chloride, 15 mL of 33% hydrobromic acid in glacial acetic acid is added at room temperature for 5 minutes. After 4.5 hours of stirring at 20°C, the reaction mixture is added in successive portions to 250 mL of saturated sodium bicarbonate solution. The methylene chloride phase is separated; the aqueous phase is extracted twice more, each time with 100 mL of methylene chloride. The combined methylene chloride phases are dried over sodium sulfate and evaporated. The residue is recrystallized in methylene chloride/hexane. The 4-hydroxy-3-methoxyphenyl-4-quinoleinyl ketone is obtained, melting at 190-192°.

d) 1.3 g of 4-hydroxy-3-methoxyphenyl-4-quinoleinyl ketone, dissolved in 25 ml of acetic acid

At 30°C, 0/37 ml of 65% nitric acid is added dropwise at room temperature. After 3 hours of stirring, the reaction mixture is poured onto ice water, then adjusted to pH 6 with ammonia, and the precipitate formed is separated by filtration. The residue thus obtained is heated under reflux in 20 ml

103

d1acetonitrile, after which the crystals are separated by filtration at 0°. The resulting product is 4-hydroxy-3-methoxy-5-nitrophenyl-4-quinoleinyl ketone, which melts at 246-248°.

e) 1 g of 4-hydroxy-3,5-methoxy-5-nitrophenyl-4-quinoleinyl ketone, dissolved in 30 mL of 48% aqueous hydrobromic acid, is stirred for 18 h at 100°C. After cooling to room temperature, the reaction material is diluted with 30 mL of water, and the precipitate is drained off. The resulting hydrobromide of 3,4-dihydroxy-5,10-nitrophenyl-4-quinoleinyl ketone, which melts at 273-275°C (recrystallized in 1 *acetonitrile), is obtained.

Example 84

a) To 4.03 g of thiophene dissolved in 40 ml of tetrahydrofuran, add dropwise at -50°, on

15. For 10 minutes, 18.8 mL of n-butyllithium solution (1.6 M in hexane) is added. After 30 minutes of stirring at -50°C, 6.3 g of 3,4-dimethoxy-5-nitrobenzaldehyde, dissolved in 100 mL of tetrahydrofuran, is added dropwise over 30 minutes. The reaction mixture is stirred for 1 hour at -50°C and for 30 minutes at 0°C, and then poured onto 100 mL of 2N sulfuric acid. It is extracted three times, each time with 100 mL of ether; the separated etheric phases are washed with sodium chloride solution, dried over sodium sulfate, filtered, and evaporated. We obtain 1^-(3,4-dimethoxy-5-nitro-phenyl)-2-thiophenemethanol, which melts at 79-81°

i

(recrystallized in methylene chloride/hexane).

b) 9.9 g of a-(3,4-dimethoxy-5-nitrophenyl)-2-thiophenemethanol, dissolved in 300 ml of acetone, are heated under reflux for 4 h, 90 g of manganese dioxide are added, and the mixture is heated under reflux for another 4 h. The manganese dioxide is then separated by dewatering, and the filtrate is evaporated. The resulting 3,4-dimethoxy-5-nitrophenyl-2-thienyl ketone melts at 35°C (recrystallized in methylene chloride).

104

hexane).

c) Two g of 3,4-dimethoxy-5-nitrophenyl-2-thienyl ketone are stirred at 100°C for 8 h in a mixture of 20 mL of 30-33% hydrobromic acid in glacial acetic acid and 20 mL of 48% aqueous hydrobromic acid. The reaction mixture is then evaporated to dryness. The residue is resuspended in ethyl acetate, washed with water, dried over sodium sulfate, and filtered, and the filtrate is evaporated. After recrystallization in ethyl acetate/hexane, 3,4-dihydroxy-5-nitrophenyl-2-thienyl ketone, which melts at 155-157°C, is obtained.

Example A

The interlocking gelatin capsules having the following composition can be prepared in a manner known per se:

L-Dopa constituents

Benserazide 3,4-dihydroxy-5-nitrophenyl- hydrochloride

Quantity in m³/capsule 100 29.3

20 4-pyridylketone

25

Avicel Magnesium Stearate Gelatin Mannitol

93.7 100

1 1

25

Capsule filling weight

3 50 mg

30

35

105

Claims (9)

CLAIMS 1. A process for preparing compounds conforming to the general formula Ho\ A I 'J_Rr,. Ib / ^ v c ho *• , Rb 10 in which Ra denotes a nitro or cyano group, Rb hydrogen or a halogen, Rc1 a nitro, cyano group or the -(A)n-(Q)m-RH or -(A)n-(Q)-R2i group, A a vinylene group substituted, if necessary, by a lower alkyl group, n the numbers 0 or 1, m the numbers 0 or 1, 15 rH the -COr31 group, a carbocyclic, aromatic, or carbon-linked heterocyclic group, aromatic or partially unsaturated, r21 a lower hydrocarbon radical, substituted if necessary, saturated or partially unsaturated, r31 a hydroxyl, amino, or lower hydrocarbon radical, 20 a lower hydrocarbon radical linked by an oxygen atom or by a lower imino or alkylimino group, if necessary substituted, saturated or partially unsaturated, or a nitrogen-linked heterocyclic group of the ring, saturated, Q the group -CO- or >C=N-(Z)p-25 r4, z an oxygen atom or an imino group, p the numbers 0 or 1 and R^ hydrogen or a lower hydrocarbon radical substituted where appropriate and linked where appropriate by a carbonyl group, saturated or partially unsaturated, Ra denoting a cyano group when Rc1 denotes a cyano or nitro group, and r31 having a different meaning from the hydroxy group when m denotes the number 0, of esters and ethers hydrolyzable under physiological conditions and of pharmaceutically acceptable salts thereof, characterized in that 35 a) in a compound corresponding to the general formula 106 RO \y*\ ■o/ • -Rc 1 II R' 0 Rb in which one of the symbols R and R1 designates a lower alkyl group and the other hydrogen or a lower alkyl group, and Ra, Rb and Rc' have the above meaning, 10 the lower etheralkyl group(s) are eliminated laughers, or b) a compound corresponding to the general formula is reacted 15 H0x • • v*~ (A)n-C°-CH?-X Ib HO Rb 20 in which X denotes an eliminable group and Ra, Rb, .. A and n have the above meaning, with a thioamide, thiourea, thiocarboxylic acid hydrazide, thiosemicarbazide, amidine, guanidine, amidrazone, aminoguanidine, cyclic amidine 25, 1,2-diamine, 1,2-aminothiol or 1,2-aminoalcohol, and dehydrogenate the cyclocondensation product obtained if desired, or c) react a compound corresponding to the general formula 30 H(VX 2 A JJ-(A)n-co-co°tt" ^ H0 * Rb 35 107 10 HO. in which R" denotes a lower alkyl group, and Ra, Rb, A and n have the meanings above, with a 1,2-diamine, a 1,2-aminothiol, a 1,2-amino alcohol, a semicarbazide, a thiosemicarbazide, an amidrazone, or an aminoguanidine, and dehydrogenate the cyclocondensation product obtained if desired, or d) react a compound corresponding to formula Ib1 above with an O-aminocarbonyl compound, or e) in a compound corresponding to the general formula ÇHO rN PHO V'\. H<V\. 2 Htvx III î II la ou I II pun IV ho-^X Ro'" Av"CH0 /Sx CH0 H° Rb HO7 x-XRb HO 15 in which Rc'11 denotes a nitro, cyano group, or the -(A)n-R^2 group and R^-2 i.e. the -COR^l group, a carbocyclic, aromatic group or a heterocyclic group linked by a carbon atom, aromatic or partially unsealed, and Ra, Rb, A, n and R^l have the above meaning, or in a lower di-O-alkanoylated derivative thereof, the carboxaldehyde group(s) are transformed into the cyano group(s), or 25 f) in a lower di-O-alkanoylated derivative of a carboxylic acid corresponding to the general formula ?a f HOv A 3 H0\ /'■ N. 3 30 /*\ V*~ (A) n-C00H °U /%V"(A) n-CO-COOH Ib HO HO Rb Rb 35 in which Ra, Rb, A and n have the above meaning, in the presence of a condensing agent or a reactive derivative of a lower di-O-alkanoyl derivative of a 108 carboxylic acid corresponding to the formulas la3 or Ib3 with a compound corresponding to the general formula HO-R5 V- or HNR6R7 VI in which R^ denotes a lower hydrocarbon radical, substituted if necessary, saturated or partially unsaturated; R® denotes hydrogen or a lower alkyl group; and R7 denotes hydrogen or a lower hydrocarbon radical, substituted if necessary, saturated or partially unsaturated; or R^ and R7 together with the nitrogen atom denote a saturated nitrogen heterocyclic group; or g) a compound corresponding to formula Ib2 above or to the general formula a F3 R80 is hydrolyzed. Y I II q /*\ V* -Rc ' R O Rb Ib4 in which R^ denotes a lower alkanoyl group and Ra, Rb and Rc1 have the above meaning, or h) a compound conforming to the general formula is reacted HO. J * » Ib5 /*x v * -COR '" 1D HO Rb in which Ra and Rb have the above meanings, and R'1' denotes hydrogen or a lower alkyl group, or a lower di-O-alkanoyl derivative thereof, in the presence of a secondary amine, with a compound corresponding to the general formula CH3CO-R23 VII 109 in which R23 denotes a lower hydrocarbon radical, optionally substituted, saturated or partially unsaturated, or i) a compound conforming to the formula is reacted HOv s K yx. 6 i v"-(A)n-CO-CHn-COOR" Ib H0 -\b in which Ra, Rb, A, n and R" have the above meaning, with a hydrazine or an amidine, or j) a compound corresponding to the formula Ib above is reacted, in which m denotes the number 1 and Q the -CO- group, with a compound corresponding to the general formula H2N-(Z)p-R4 VIII in which Z, p and R4 have the above meaning, and if desired k) a compound corresponding to the formula Ib above is transformed into an ester or ether hydrolyzable under physiological conditions or into one of its pharmaceutically acceptable salts. 2. Method according to claim 1, wherein Rb is in position p relative to Ra. 3. Method according to claims 1 or 2, wherein Ra designates a nitro group. 4. A method according to any one of claims 1 to 3, in which Rb denotes hydrogen, chlorine or fluorine. 5. Method according to claim 4, in which Rb denotes hydrogen. 6. A method according to any one of claims 1 to 5, in which Rc' denotes the -COR-1--'- group and R11 a mononuclear carbocyclic aromatic group, or a hetero- group I 110 cyclic, linked by a carbon atom, aromatic, mononuclear, having 1 to 3 nitrogen atoms as heteroelements in the ring. 7. A method according to claim 6, wherein 5rH designates a phenyl group optionally mono- or disubstituted by a halogen, a trifluoromethyl, cyano, hydroxy or lower alkyl group or a pyridyl group. 8. A method according to claim 1, characterized in what is being prepared: 3,4-dihydroxy-5-nitrobenzophenone. 10 9. A method according to claim 1, characterized in what is being prepared: 2-fluoro-3,4-dihydroxy-5-nitrobenzo-phenone. 10. A method according to claim 1, characterized in what is being prepared is 3,4-dihydroxy-5-nitrophenyl-4-pyridyl-15 ketone. 11. Use of compounds conforming to the general formula Ra HO, .1 20.1. 'J_P_ la CRb / v"-Rc HO in which Ra denotes a nitro or cyano group, Rb hydrogen or a halogen, Rc a halogen, a nitro group, cyano group or the group -(A)n-(Q)m-R1 or -(A)n-Q-R2, A vinylene group, optionally substituted by a lower alkyl group, n the numbers 0 or 1, m the numbers 0 or 1, r! the -COR3 group, a carbocyclic, aromatic, or heterocyclic group linked by a carbon atom, aromatic or partially unsaturated, R2 designates hydrogen or a lower hydrocarbon radical, optionally substituted, saturated or partially unsaturated, R3 designates a hydroxyl, amino, or hydrocarbon radical linked by an oxygen atom or by an imino or (lower alkyl)imino group, optionally substituted, saturated, or partially unsaturated. & 111 saturated, or a nitrogen heterocyclic group linked by a nitrogen atom of the ring, saturated, Q the -CO- group or ^C=N-(Z)p_R^, ^ an oxygen atom or an imino group, p the numbers 0 or 1 and R4 hydrogen or a substituted lower hydrocarbon radical if necessary, and linked where applicable by a carbonyl group, saturated or partially unsaturated, and their esters or ethers hydrolyzable under physiological conditions and their pharmaceutically available salts 10 acceptable for the preparation of agents that inhibit catechol-O-methyltransferase. 12. Use of compounds conforming to the formula defined in claim 11, for the preparation of medicinal products for the treatment of Parkinson's disease 15. Its effects on parkinsonism, in association with L-dopa and a peripheral decarboxylase inhibitor. 13. Use of compounds conforming to the formula defined in claim 11 for the preparation of medicinal packings, consisting of an agent containing 20 a compound conforming to the formula defined in claim 11 and a therapeutically inert carrier material and an agent containing L-dopa, a peripheral decarboxylase inhibitor and a therapeutically inert carrier material. 25 © R1J5WW A L 30 containing .me scratched nut JosV^CURAU Industrial Property Consultant 26*>'«, Princess Charlotte Blvd. MONTE-CARLO 35