JP5212177B2 - Method for producing γ-ketoacetal compound and pyrrole derivative - Google Patents

Description

  The present invention relates to a γ-ketoacetal compound useful as an intermediate for applications such as agricultural chemicals, pharmaceuticals, antibacterial agents, dye materials, optical materials and electronic information materials, and a method for producing a pyrrole derivative using the same.

  γ-Ketoacetal compounds are known as intermediates for the synthesis of pyrrole derivatives, and pyrrole derivatives are important compounds as intermediates for agricultural chemicals, pharmaceuticals, antibacterial agents, dye materials, optical materials, electronic information materials, etc. is there. For example, 4-methyl-1,2-pyrrole derivatives are known as analgesics (see Patent Document 1). Furthermore, since a pyromethene derivative useful as a light-emitting material of an organic electroluminescence device can obtain light emission with high luminance and high light emission efficiency (see Patent Documents 2 and 3), it becomes a pyrrole derivative serving as an intermediate raw material and a raw material thereof. A method for producing a γ-ketoacetal compound with high purity and safety is desired.

  The γ-ketoacetal compound can be obtained using α, β-unsaturated ketones as starting materials. As an example, there is known a method (nitromethane method) in which nitromethane is Michael-added to α, β-unsaturated ketones to obtain a nitro compound, which is led to an acetal derivative by Nef reaction (Non-Patent Document 1). ~ 2).

JP-A-9-323971 Japanese Patent Laid-Open No. 9-289081 JP 2000-208265 A

“Journal of Organic Chemistry”, 2005, Volume 70, p. 5571-5578 “Organic Letters”, 2007, Vol. 9, No. 4, p. 607-609

  However, the methods described in Non-Patent Documents 1 and 2 have a problem in safety because of the use of nitromethane, which has a risk of explosion. In addition, the operability is poor and the environmental load is large in the following points.

  [1] Since a large excess of sulfuric acid, potassium hydroxide, and sodium hydroxide are used in the Nef reaction, a large amount of inorganic salt is by-produced together with γ-ketoacetal. In order to remove them, it is necessary to carry out an extraction operation using a large amount of water, and the waste liquid discharged accordingly increases the environmental load. [2] Although it is necessary to mix a sulfuric acid solution and a potassium hydroxide solution during the reaction, a large exotherm is observed. Therefore, in order to scale up, a slow mixing operation or a particularly powerful cooling facility is required. [3] The reaction is started by cooling to around 0 ° C., and the temperature is raised to room temperature in order to complete the reaction, but it is necessary to cool again when entering the post-treatment step. At the time of scale-up, a significant time loss occurs in this cooling and heating step. [4] Since the product after the Nef reaction is oily, it is difficult to isolate the γ-ketoacetal compound.

  The object of the present invention is to solve such problems and to provide a method for producing a γ-ketoacetal compound excellent in operability and safety.

That is, the present invention is a method for producing a γ-ketoacetal compound having the following steps (A) and (B).
(A) An α, β-unsaturated ketone derivative represented by the general formula (1) and a thioalkylalkyl sulfoxide derivative represented by the general formula (2) are reacted in the presence of a base to give a general formula ( Step (B) for obtaining 1,4-addition product represented by 3) From the 1,4-addition product represented by formula (3), in the presence of acid and alcohol, A step of producing the represented γ-ketoacetal compound.

In formulas (1) to (3), R ^{1 to} R ⁴ each independently represent hydrogen, an alkyl group, or a substituted or unsubstituted aryl group. R ⁵ and R ⁶ each independently represents an alkyl group. Here, the hydrogen on the alkyl group may be substituted with a halogen or an alkoxy group, and the hydrogen on the aryl group may be substituted with a halogen, an alkyl group, an alkoxy group, or a cyano group.

In formula (4), R ^{1 to} R ⁴ represent the same as those in general formulas (1) and (3). R ⁷ and R ⁸ represent an alkyl group and may be bonded to each other to form a ring.

  In another embodiment of the present invention, a pyrrole derivative represented by the general formula (5) is produced by treating a γ-ketoacetal compound represented by the general formula (4) with an ammonium salt in the presence of an acid. Is the method.

In formula (5), R ^{1 to} R ³ represent the same as in general formula (1).

  According to the present invention, a γ-ketoacetal compound useful as an intermediate for agricultural chemicals, pharmaceuticals, antibacterial agents, dye materials, optical materials, electronic information materials, etc. is produced without using nitromethane, which has an explosion risk. Can do. Further, the method of the present invention is superior in operability as compared with the conventional method.

  The method for producing a γ-ketoacetal compound of the present invention mainly has two reaction steps. First, in the first step (step A), an α, β-unsaturated ketone derivative represented by general formula (1) and a thioalkylalkyl sulfoxide derivative represented by general formula (2) are present in the presence of a base. To obtain a 1,4-addition product represented by the general formula (3).

In general formulas (1) to (3), R ^{1 to} R ⁴ each independently represents hydrogen, an alkyl group, or a substituted or unsubstituted aryl group. R ⁵ and R ⁶ each independently represents an alkyl group. Here, the hydrogen on the alkyl group may be substituted with a halogen or an alkoxy group, and the hydrogen on the aryl group may be substituted with a halogen, an alkyl group, an alkoxy group, or a cyano group.

  Among these substituents, the alkyl group is a cyclic or non-cyclic saturated aliphatic carbonization such as methyl group, ethyl group, propyl group, n-butyl group, t-butyl group, cyclopropyl group, cyclopentyl group, and cyclohexyl group. It represents a hydrogen group and preferably has 1 to 16 carbon atoms. An aralkyl group refers to an aromatic hydrocarbon group via an aliphatic hydrocarbon such as a benzyl group or a phenylethyl group.

  The aryl group represents an aromatic hydrocarbon group such as a phenyl group, a naphthyl group, a biphenyl group, an anthranyl group, a phenanthryl group, a terphenyl group, or a pyrenyl group, which may be unsubstituted or substituted. Examples of the substituent include a halogen, an alkyl group, an alkoxy group, or a cyano group. The alkoxy group refers to an aliphatic hydrocarbon group via an ether bond such as a methoxy group or an ethoxy group. Halogen represents fluorine, chlorine, bromine or iodine.

  In addition, when the above group is substituted, the substitution position may be any position. Moreover, even if it has multiple substituents of the same kind, you may have it mixing a different kind of substituent.

Among these, in the general formula (1), R ¹ and R ³ are substituted or unsubstituted aryl groups, and / or R ⁴ is hydrogen, in order to obtain a more useful pyrrole derivative. It is preferable at the point which obtains the (gamma) -ketoacetal compound which is a body.

In the general formula (2), when R ⁵ and / or R ⁶ is a methyl group, it is easy to obtain as a raw material, and in the step B described later, the reaction from the general formula (3) to (4) It is preferable from the viewpoints of proceeding under relatively mild conditions and easy removal of sulfur-containing compounds by-produced at that time.

  Examples of the α, β-unsaturated ketone derivative represented by the general formula (1) include the following. These may be trans or cis.

  These compounds are described in, for example, European Journal Medicinal Chemistry, 2000, Vol. 35, No. 5, p. As described in 499-510, it can be easily produced by aldol condensation of a single carbonyl compound or cross-aldol condensation between different carbonyl compounds.

  Examples of the thioalkylalkyl sulfoxide derivative represented by the general formula (2) include the following.

  These compounds are described in, for example, Journal of Chemical Society, Chemical Communication, 1970, p. 1689 and the like.

  Specific examples of the method of reacting the α, β-unsaturated ketone derivative represented by the general formula (1) and the thioalkylalkyl sulfoxide derivative represented by the general formula (2) in the presence of a base include an appropriate solvent. A thioalkylalkyl sulfoxide derivative is dissolved in the base, and a base is added dropwise to generate a carbon anion. Then, an α, β-unsaturated ketone is added dropwise to achieve a 1,4-addition reaction. Although the method of stopping reaction by adding etc. can be utilized normally, it is not limited to this.

  The operation of step A will be specifically described below. First, a carbon anion is generated. One equivalent of a thioalkylalkyl sulfoxide derivative is dissolved in a solvent, and a base is added for the purpose of extracting a proton on carbon sandwiched between sulfur atoms. The solvent to be selected is not particularly limited as long as it does not inhibit the reaction, but usually diethyl ether, diisopropyl ether, tertiary butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane, 1 Ether solvents such as 1,3-dioxolane, aromatic solvents such as benzene, toluene and xylene, or hydrocarbon solvents such as hexane, heptane and isooctane are preferably used. These solvents may be used alone or in combination of two or more. The amount of the solvent used is preferably 0.5 to 20 times, more preferably 1.0 to 10 times, still more preferably 2 to 5 times the weight of the α, β-unsaturated ketone derivative.

  As described above, a base that can cause a proton abstraction reaction is selected. For example, sodium hydroxide, potassium hydroxide, sodium hydride, calcium hydride, barium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate, potassium fluoride and other inorganic bases, normal butyl lithium, secondary butyl lithium, tertiary Alkyl lithium such as butyl lithium, alkali metal amide compounds such as lithium diisopropylamide, lithium dicyclohexylamide, alkali metal disilazide compounds such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, methylmagnesium Examples include Grignard reagents such as bromide and ethylmagnesium bromide, and metal alkoxides such as sodium methoxide and potassium tertiary butoxide. But it is not limited thereto. In consideration of solubility in organic solvents, operability of post-treatment, and cost, alkyl lithium is preferable among these.

  The amount of the base used is preferably 1 to 5 equivalents by mole with respect to the thioalkylalkyl sulfoxide derivative. More preferably, it is 1-2 equivalents with respect to the thioalkylalkyl sulfoxide derivative. On the other hand, when the excess base inhibits the reaction between the generated carbon anion and the α, β-unsaturated ketone, the amount of the base used is preferably 1 equivalent or less with respect to the thioalkylalkyl sulfoxide derivative. .

  The temperature at which the thioalkylalkyl sulfoxide derivative is reacted with the base depends on the kind of the thioalkylalkyl sulfoxide derivative and the base used, but is usually in the range of -78 ° C to 130 ° C. Preferably it is -40-80 degreeC, More preferably, it is -40 degreeC-50 degreeC. The reaction atmosphere is usually an inert gas atmosphere of 1 atm because carbon anions are generally sensitive to moisture. The reaction time may be as short as 10 hours or so, but considering the productivity, it is preferable to set the conditions so that it is within 3 hours.

  When the generation of the carbon anion by the base is completed, the 1,4-addition reaction proceeds by mixing with the α, β-unsaturated ketone derivative. The mixing order may be to add a carbon anion to the α, β-unsaturated ketone derivative or vice versa. If necessary, the α, β-unsaturated ketone derivative may be mixed or dissolved in a solvent that does not inhibit the addition reaction.

  Examples of the solvent are as described above, ether solvents such as diethyl ether, diisopropyl ether, tertiary butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, benzene, or Aromatic solvents such as toluene and xylene, and hydrocarbon solvents such as hexane, heptane, and isooctane.

  The reaction temperature is usually in the range of -78 ° C to 130 ° C. Preferably it is -40-80 degreeC, More preferably, it is -40 degreeC-50 degreeC. The reaction atmosphere is usually an inert gas atmosphere of 1 atm because carbon anions are generally sensitive to moisture. Although the reaction time is influenced by the raw material to be selected, reaction temperature, concentration, etc., it may take about 10 hours from a very short time, but in consideration of productivity, the reaction time must be within 3 hours. It is preferable to set.

  The progress of the reaction can be monitored by TLC (Thin Layer Chromatography), GC (Gas Chromatography), HPLC (High Performance Liquid Chromatography), etc., confirming the decrease or disappearance of α, β-unsaturated ketone. Thereafter, the reaction can be stopped by adding a compound having active hydrogen such as water. Thereafter, the 1,4-adduct can be isolated by methods known to those skilled in the art, such as extraction. Since 1,4-adducts are stable in the atmosphere, no special care is required for storage and handling.

  By the way, the addition reaction to α, β-unsaturated ketone includes 1,4-addition and 1,2-addition, and depending on the substrate used, one of these can be obtained preferentially or selectively, or simply these Or as a mixture. When a mixture of a 1,4-adduct and a 1,2-adduct is obtained, separation and purification are complicated, and industrial value is particularly lowered. For example, when a dithiane is reacted with an α, β-unsaturated ketone derivative represented by the general formula (1), a 1,2-adduct is preferentially produced. On the other hand, in the method of the present invention, the 1,4-addition of the thioalkylalkyl sulfoxide derivative to the α, β-unsaturated ketone is almost selective, so that separation or purification is unnecessary or very simple. And industrially superior. The thioalkylalkyl sulfoxide derivatives are described in, for example, “Journal of Organic Chemistry”, 1986, Vol. 51, p. 508-512 and “Tetrahedron”, 2003, Vol. 59, p. As described in 2885-2891, 1,2-addition usually occurs preferentially, but in the reaction with the α, β-unsaturated ketone derivative represented by the general formula (1) Therefore, 1,4-addition has priority.

  Next, in the second step (step B), from the 1,4-addition product represented by the general formula (3), in the presence of an acid and an alcohol, γ- represented by the general formula (4) A ketoacetal compound is produced.

In formula (4), R ^{1 to} R ⁴ represent the same as those in general formulas (1) and (3). R ⁷ and R ⁸ represent an alkyl group and may be bonded to each other to form a ring.

  The meanings of the alkyl group, the aralkyl group, the aryl group, the alkoxy group, and the acyl group are the same as those in the general formulas (1) to (3). Examples of the γ-ketoacetal compound represented by the general formula (4) include the following.

  The operation of step B is specifically described below, but the present invention is not limited to this. The 1,4-addition product represented by the general formula (3) can be dissolved in an alcohol, and a γ-ketoacetal compound can be produced by a method such as adding concentrated hydrochloric acid while stirring.

  As the kind of alcohol as the reaction substrate, monovalent liquid alcohol such as methanol and ethanol can be used at room temperature. In this case, the alcohol also functions as a solvent. In addition, dihydric alcohols such as 1,2-ethylene glycol and 1,3-propylene glycol can also be used as a reaction substrate. In this case as well, it is possible to assign a function as a solvent, but it is usually preferable to use another solvent from the viewpoint of cost. It is necessary to use a solvent that can dissolve the 1,4-adduct and the dihydric alcohol and that is not decomposed by an acid. Candidates include ether solvents such as diethyl ether, diisopropyl ether, tertiary butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane and 1,3-dioxolane, and halogen solvents such as dichloromethane and chloroform. However, it is preferable to use an ether solvent. However, it should be noted that ether solvents may be decomposed by acid depending on the conditions.

  Among the above alcohols, monovalent alcohols are preferably used from the viewpoint of ease of pyrrolization in the next step, and methanol is particularly preferably used from the viewpoint of cost. The kind of acid is preferably an inorganic strong acid such as hydrochloric acid, sulfuric acid, perchloric acid or phosphoric acid, or an organic strong acid such as p-toluenesulfonic acid. The amount of acid used is preferably less than the stoichiometric amount relative to the substrate.

  The reaction temperature can be carried out in the range of 0 ° C. to the boiling point of the solvent used, but it is preferably carried out at 0 to 100 ° C. because decomposition reaction of the produced γ-ketoacetal compound may occur at the same time. More preferably, it is 0-50 degreeC. The atmosphere and pressure for the reaction are not particularly limited, but it is usually carried out in an inert gas atmosphere at 1 atm.

  The progress of the reaction can be traced by TLC, GC, HPLC or the like. After confirming the decrease or disappearance of the 1,4-adduct, the reaction is carried out by adding a basic substance such as an aqueous sodium hydroxide solution. Can be stopped. Thereafter, the γ-ketoacetal compound can be isolated by a method known to those skilled in the art, such as extraction.

  According to the method of the present invention, since the acid to be used may be less than the stoichiometric amount with respect to the substrate, the reaction heat can be kept small during the neutralization reaction, and the waste liquid can be greatly reduced. In addition, the product obtained in Step B is solid, and is easy to isolate and purify, so that it is excellent in operability. These improvements improve operability and enable significant cost reduction during scale-up.

  Next, a method for producing a pyrrole derivative represented by the general formula (5) by treating the γ-ketoacetal compound represented by the general formula (4) with an ammonium salt in the presence of an acid will be described. .

In formula (5), R ^{1 to} R ³ represent the same as in general formula (1).

  Although the specific operation method of this process is described below, this invention is not limited to these. This step is achieved by mixing the γ-ketoacetal compound and an ammonium salt in the presence of an acid. Since there is no restriction | limiting in particular about the order of mixing, What is necessary is just to determine according to the property of the (gamma) -ketoacetal compound and ammonium salt to be used. The progress of the reaction can be traced by TLC, GC, HPLC or the like. After the reaction is completed, the target pyrrole derivative can be isolated by a method such as extraction or crystallization. Since pyrrole derivatives are generally easily decomposed under acidic conditions, it is preferable to carry out the isolation operation under neutral to basic conditions as much as possible.

  When using what was obtained by the process A and the process B of this invention as a gamma-ketoacetal compound, since the isolated and refined gamma-ketoacetal compound can be used as a starting material, it is excellent in operativity. As well as improving the purity of the resulting pyrrole.

  Examples of the ammonium salt used include inorganic ammonium salts such as ammonium chloride, ammonium carbonate, ammonium phosphate, and ammonium sulfate, and ammonium carboxylates such as ammonium formate and ammonium acetate. These ammonium salts may be charged in the form of a salt, or may be charged as ammonia and generated in the system by mixing with an acid and used. Among these, ammonium acetate is preferable because the production rate of the target pyrrole is high.

  Although the usage-amount of an ammonium salt can be implemented by 0.5-50 times of (gamma) -ketoacetal compounds by molar ratio, Preferably it is 1-30 times, More preferably, it is 5-20 times. In general, the ammonium salt to be used is often less expensive than the γ-ketoacetal compound, and therefore it is often advantageous in production to add an ammonium salt in excess. On the other hand, if the amount of ammonium salt used is too large, stirring is often difficult. As the kind of solvent used for mixing the γ-ketoacetal compound and the ammonium salt, alcohols such as methanol and ethanol, and carboxylic acids which are liquid at room temperature such as acetic acid and butyric acid are preferably used.

  The amount of the solvent used can be 3 to 100 times that of the γ-ketoacetal compound used in weight ratio, but it is preferably 3 to 30 times, more preferably 3 to 15 times from the viewpoint of reaction rate and cost. Although reaction temperature can be implemented in the range of 20-130 degreeC, since pyrroles are generally not so stable, 20-100 degreeC is preferable. More preferably, it is 20-70 degreeC.

  In order to accelerate the reaction, it is necessary to add an acid. When the selected solvent is a liquid carboxylic acid such as acetic acid or butyric acid, the function as an acid can be assigned to them, so it is not essential to add another acid. When the solvent is other than the above carboxylic acids, an acid is added. The types of acids include inorganic protonic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, organic protonic acids such as acetic acid, butyric acid, p-toluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid, titanium chloride (IV), tin chloride Lewis acids such as (IV), scandium triflate (III), and zirconium (IV) chloride can be used.

  The amount of the acid used depends greatly on the strength of the acid, and can be carried out in a molar ratio of 0.1 to 200 times that of the γ-ketoacetal compound.

  As a combination of an ammonium salt and an acid, a combination of ammonium acetate and acetic acid is preferable. More preferably, the molar ratio of ammonium acetate to acetic acid is ammonium acetate / acetic acid = 0.2 to 0.4.

  By carrying out the steps described above, a pyrrole derivative represented by the general formula (5) is obtained. The obtained pyrrole derivative can be used as an intermediate for agrochemicals, pharmaceuticals, antibacterial agents, dye materials, optical materials, electronic information materials and the like as it is or after further purification as required. Examples of the pyrrole derivative to which the production method of the present invention can be applied include the following.

  EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated, this invention is not limited by these examples. In addition, the apparatus and analysis conditions used in each Example and the comparative example are as follows.

HPLC analysis equipment: SHIMADZU SCL-10Avp (controller), SIL-10Avp (autosampler), LC-10Avp (pump) x 2, CTO-10Avp (column oven), SPD-M10Avp (Diode Array) manufactured by Shimadzu Corporation Ditector)
Column: YMC-Pack ODS-A A-303, S-5μm, 12nm, 250 × 4.6mm I.D.
Column temperature: 45 ° C
Mobile phase A: 0.1% phosphoric acid aqueous solution
Mobile phase B: acetonitrile flow rate: 1 ml / min.
B Gradient: 80% (0min.) → 100% (15min.) → 100% (30min.)
Detector: UV 254nm
Sample: Sample was dissolved in THF. About 1 mg of a sample for purity measurement was weighed, and 10 mL of THF was added to completely dissolve the sample. HPLC measurement was carried out under the above-mentioned conditions, and the ratio of the peak area of the target substance to the total detected peak area was defined as purity.

Example 1
<Synthesis of 1,4-addition product>
A flask substituted with nitrogen was charged with 1.87 g (15.1 mmol) of methyl methylthiomethyl sulfoxide (Tokyo Kasei) and 37 ml of THF, cooled in an ice-water bath, and 5.67 ml of a 2.66 M normal butyl lithium / normal hexane solution (15. 1 mmol) was added dropwise. After stirring at the same temperature for 30 minutes, 3.70 g (12.6 mmol) of 3- (4-t-butylphenyl) -1- (4-methoxyphenyl) prop-2-en-1-one was added in another container. A solution prepared by dissolving in 19 ml of THF was added dropwise. After stirring at the same temperature for 45 minutes, a saturated ammonium chloride aqueous solution was added to the reaction solution to stop the reaction. The organic layer obtained by partition extraction by adding ethyl acetate was dried to obtain 5.2 g (12.4 mmol) of a crude product.

4.9 g of the crude product was recrystallized with 50 ml of cyclopentyl methyl ether to obtain 2.24 g (5.35 mmol) of white crystals. Yield 42.6%. Since this substance was a mixture of two substances having similar structures, they were separated by HPLC in amounts necessary for analysis (hereinafter referred to as component 1 and component 2). ^{From 1} H-NMR, each of these was found to be one diastereomer of the compound represented by the planar structural formula (6), so that the process was directly carried on to the next step.

¹ H-NMR (CDCl ₃ , ppm)
Component 1: 1.27 (s, 9H), 2.33 (s, 3H), 2.62 (s, 3H), 3.55 to 3.79 (m, 3H), 3.85 (s, 3H) ) 4.08-4.20 (m, 1H), 6.88-6.92 (d, 2H), 7.31 (s, 4H), 7.86-7.91 (d, 2H)
Component 2: 1.28 (s, 9H), 2.18 (s, 3H), 2.65 (s, 3H), 3.43-3.59 (m, 1H), 3.72-3.80 (M, 1H), 3.85 (s, 3H), 3.91-4.11 (m, 2H), 6.89-6.95 (d, 2H), 7.31 (s, 4H), 7.91-7.95 (d, 2H)

<Synthesis of γ-ketoacetal compound>
Under a nitrogen atmosphere, the compound shown in (6) (3.58 g, 8.55 mmol) and methanol (35 ml) were charged into a flask, and concentrated hydrochloric acid (350 μl, 4.2 mmol) was added with stirring. After stirring with heating at 40 ° C. for 4 hours, disappearance of the raw material peak was confirmed by HPLC. In an ice bath, an aqueous sodium hydroxide solution (168 mg / 30 ml water) was added, and after confirming that the solution was alkaline, extraction with cyclopentyl methyl ether (150 ml) was performed. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, cyclopentyl methyl ether was distilled off to obtain 3.26 g (8.80 mmol) of pale yellow compound (7). When this was analyzed by HPLC, the retention time was consistent with that of a sample obtained by another method.

Example 2
<Synthesis of pyrrole derivative>
A total of 44.2 g (0.12 mol, 1.00 equivalent) of compound (7) obtained by repeating the method of Example 1, acetic acid 300 ml (5.25 mol, 44.0 equivalent), ammonium acetate 92.1 g (1.19 mol, 10.0 equivalents) was placed in a reaction vessel and stirred at 60 ° C. for 6 hours. Acetic acid was distilled off as much as possible with a rotary evaporator, and an aqueous sodium hydroxide solution was added to the residue to adjust pH = 9. The precipitate obtained by filtration under reduced pressure was washed successively with water, methanol and hexane and dried under reduced pressure to obtain 31.6 g (103.5 mmol) of pale yellow compound (8). . When this was analyzed by HPLC, the retention time was consistent with that of a sample obtained by another method. The purity was 98%, and a high purity product was obtained.

Comparative Example 1
<Synthesis of γ-ketoacetal compound (7) by nitromethane method>
In a reaction vessel, 500 ml of methanol, 3- (4-t-butylphenyl) -1- (4-methoxyphenyl) prop-2-en-1-one 17.0 g (57.7 mmol), diethylamine 21.1 g (290 mmol) And 17.7 g (290 mmol) of nitromethane were charged and stirred at an internal temperature of 63 to 64 ° C. for 15 hours. While paying attention not to give an impact, the solution was concentrated on a rotary evaporator to obtain 42.6 g of a solid. 140 ml of ethanol was added to this solid and dissolved by heating, followed by stirring and crystallization at room temperature. The crystals were filtered under reduced pressure to obtain 16.2 g (45.6 mmol) of compound (9).

  Compound (9) 7.11 g (20.0 mmol) was dissolved in a mixed solvent of 50 ml of methanol and 200 ml of tetrahydrofuran. To this solution was added a prepared potassium hydroxide methanol solution (prepared by dissolving 5.61 g of potassium hydroxide in 50 ml of methanol). Into a reaction vessel equipped with another stirrer, 200 ml of methanol was taken, and concentrated sulfuric acid (73.6 g, 750 mmol) was carefully added dropwise while cooling with an ice bath. The solution of compound (9) prepared above was added dropwise to this sulfuric acid methanol solution in an ice bath. However, since a large exotherm was observed, the dropping rate was adjusted so as to keep the internal temperature at 1 to 3 ° C. Adjusted. The dripping took 45 minutes. After dropping, the temperature was raised to room temperature and disappearance of the raw material was confirmed by TLC at the stage of stirring for 2 hours. Subsequently, the internal temperature was cooled to 5 ° C., and 100 ml of water and 4N aqueous sodium hydroxide solution were successively added dropwise to adjust the pH to about 10. After methanol and tetrahydrofuran were distilled off, 150 ml of cyclopentyl methyl ether was added to the residue, followed by partition extraction. The organic layer was concentrated to obtain 7.6 g (20.5 mmol) of a γ-ketoacetal compound (7) -containing component. There are many operational problems, such as the time required for the cooling and heating process, and the large amount of inorganic salts produced from sulfuric acid, potassium hydroxide and sodium hydroxide, making extraction difficult. It was thought that the solution of these problems was indispensable at the time of up. The product was oily and could not be further purified or dried.

<Synthesis of pyrrole derivative>
Acetic acid 100 ml (1.75 mol) and ammonium acetate 7.7 g (0.1 mol) were added to 7.6 g of the oily γ-ketoacetal compound (7) -containing component obtained in the previous step. The temperature was raised to about 100 ° C. and stirred for 1 hour. To the residue obtained by distilling off acetic acid, 100 ml of water was added and then neutralized with 24 ml of 14% aqueous ammonia. The pH was about 9. 200 ml of cyclopentyl methyl ether was added for partition extraction, and the organic layer was concentrated. The residue was washed with methanol and dried under reduced pressure to obtain 3.03 g (9.92 mmol) of purple crystals of the title compound. The purity was 91%, and a very high purity was not obtained.

Claims (8)

A method for producing a γ-ketoacetal compound, comprising the following steps (A) and (B):
(A) An α, β-unsaturated ketone derivative represented by the general formula (1) and a thioalkylalkyl sulfoxide derivative represented by the general formula (2) are reacted in the presence of a base to give a general formula ( A step of obtaining a 1,4-addition product represented by 3).

(In formulas (1) to (3), R ^{1 to} R ⁴ each independently represents hydrogen, an alkyl group, or a substituted or unsubstituted aryl group. R ⁵ and R ⁶ each independently represents an alkyl group. Wherein the hydrogen on the alkyl group may be substituted with a halogen or an alkoxy group, and the hydrogen on the aryl group may be substituted with a halogen, an alkyl group, an alkoxy group, or a cyano group.)
(B) A step of obtaining a γ-ketoacetal compound represented by the general formula (4) from the 1,4-addition product represented by the general formula (3) in the presence of an acid and an alcohol.

(In the formula (4), R ^{1 to} R ⁴ represent the same as those in the general formulas (1) and (3). R ⁷ and R ⁸ represent an alkyl group and are bonded to each other to form a ring. May be. The method for producing a γ-ketoacetal compound according to claim ^1, wherein R ¹ and R ³ are substituted or unsubstituted aryl groups. The method for producing a γ-ketoacetal compound according to claim 1 or 2, wherein R ⁴ is hydrogen. The method for producing a γ-ketoacetal compound according to any one of claims 1 to 3, wherein R ⁵ and / or R ⁶ is a methyl group. The method for producing a γ-ketoacetal compound according to any one of claims 1 to 4, wherein the base is alkyllithium. The γ-ketoacetal compound represented by the general formula (4) obtained by the method according to any one of claims 1 to 5 is treated with an ammonium salt in the presence of an acid and represented by the general formula (5). A method for producing a pyrrole derivative, wherein the pyrrole derivative is produced.

(In the formula (5), R ^{1 to} R ³ represent the same as those in the general formula (1).) The method for producing a pyrrole derivative according to claim 6, wherein the ammonium salt is ammonium acetate. The method for producing a pyrrole derivative according to claim 6 or 7, wherein the acid is acetic acid.