JP2007191446A - Biphenylmethylhydantoin compound, method for producing the same, and method for producing biphenylalanine compound using the same - Google Patents

Abstract

【選択図】なしThe present invention provides a compound useful as an intermediate for producing a biphenylalanine compound.
A biphenylmethylhydantoin compound represented by the formula (1) (wherein R ¹ and R ² represent a hydrogen atom, a halogen atom, etc.). A method for producing a biphenylmethylhydantoin compound (1), comprising reducing the biphenylmethylenehydantoin compound (2). A method for producing a biphenylalanine compound (3), comprising hydrolyzing the biphenylmethylhydantoin compound (1).

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Description

  The present invention relates to a biphenylmethylhydantoin compound useful as an intermediate for producing a biphenylalanine compound, a production method thereof, and a production method of a biphenylalanine compound using the same.

  A compound having a biphenylalanine structure is a compound useful as an intermediate of a pharmaceutical such as a neutral endopeptidase inhibitor (see Patent Documents 1 and 2).

  The following methods are known as methods for producing biphenylalanine. 4-biphenylmethyl halide and diethyl malonate are reacted to form diethyl 4-phenylbenzylmalonate, which is hydrolyzed to 4-phenylbenzylmalonic acid, which is decarboxylated and brominated to give 4-phenyl-α -Bromohydrocinnamic acid, which is reacted with ammonia to obtain biphenylalanine (see Non-Patent Document 1). However, this method is not a suitable method for industrial production because the process is complicated and bromine is difficult to handle.

Moreover, the following method is known as a manufacturing method of optically active biphenylalanine.
(1) 4-biphenylmethyl bromide and N-carbobenzyloxy- (2R, 3S)-(−)-6-oxo-2,3-diphenylmorpholine are reacted in the presence of sodium bistrimethylsilylamide to form N -Carbobenzyloxy-2 (R), 3 (S), 5 (S) -6-oxo-2,3-diphenyl-5- (4-biphenylylmethyl) morpholine was obtained by catalytic hydrogenation Reduction to obtain optically active (S)-(+)-4-biphenylalanine (see Patent Document 3)
(2) Triflation of D-Boc-tyrosine methyl ester, Suzuki coupling, ester hydrolysis (see Patent Document 3)

  However, the method (1) is a reaction that requires an ultra-low temperature of −78 ° C., sodium bistrimethylsilylamide used as a base, and N-carbobenzyloxy- (2R, 3S)-(−) as a raw material. Since -6-oxo-2,3-diphenylmorpholine is expensive, it is not an industrially advantageous method. The method (2) is an industrially advantageous method in that the reagent for triflation is expensive and a palladium catalyst is used in Suzuki coupling, so that palladium remains in the product and is difficult to remove. That's not true. Accordingly, there is a demand for a method that can produce biphenylalanine with high yield and can be used for industrial production.

As a method for producing an amino acid derivative, there is a method of hydrolyzing an alkyl hydantoin derivative. The following methods are known as methods for producing alkyl hydantoin derivatives or amino acid derivatives.
Patent Document 4 describes a method for producing a 5-alkylhydantoin derivative by reducing a 5-alkylidenehydantoin derivative using formic acid or a salt thereof in the presence of a palladium catalyst.
In Patent Document 5, alkylidene hydantoin is reacted with pressurized hydrogen in the presence of an alkali and a metal catalyst to perform reduction and hydrolysis simultaneously, and an acetylating agent is added to the reaction system to produce an acetylated amino acid derivative. A method is described.
Patent Document 6 describes a method for producing 5-pyridylmethylhydantoin by reduction of 5-pyridylmethylenehydantoin.
Patent Document 7 describes a method for producing a 5-cyclohexylmethylhydantoin derivative by reduction of a 5- (3-cyclohexen-1-yl) methylenehydantoin derivative.
In Patent Document 8, 5- (4-methyl-4-nitropentylidene) hydantoin is reduced to obtain 5- (4-methyl-4-nitropentyl) hydantoin, which is hydrolyzed to give 2 A process for producing amino-6-methyl-6-nitroheptanoic acid is described.
Patent Document 9 describes a method of producing an amino acid derivative by reducing a substituted alkylidene hydantoin derivative to obtain a substituted alkylhydantoin derivative and hydrolyzing it.

  However, these documents do not describe an example in which hydrolysis of an alkylhydantoin derivative is applied to the synthesis of a biphenylalanine derivative.

  Non-Patent Document 2 and Patent Document 10 describe 5- (4-biphenylylmethylene) hydantoin obtained by condensing 4-phenylbenzaldehyde and hydantoin. However, these documents do not describe the production of biphenylmethylhydantoin derivatives.

JP-A-6-228187 JP 2003-261522 A Japanese Patent Laid-Open No. 5-170792 JP-A-5-255273 JP-A-8-277252 JP 2003-81970 A JP-A-6-199808 JP 2003-2872 A JP 2000-327665 A JP-A 62-45553 Ber. 1933, 66, 1464-1470 J. Med. Chem., 2004, 47 (6), 1527-1535

  An object of the present invention is to provide a novel compound useful as an intermediate for producing a biphenylalanine compound. Another object of the present invention is to provide a method for producing the novel compound and a method for producing a biphenylalanine compound using the same.

As a result of intensive studies to solve the above problems, the present inventors have found that a biphenylalanine compound can be produced in a high yield by using a biphenylmethylhydantoin compound represented by the following formula (1). The headline and the present invention were completed.
That is, the present invention is as follows.

[1] Formula (1)

(In the formula, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, a hydroxy group, an alkoxy group, a cyano group, or a nitro group.)
(Hereinafter, also referred to as biphenylmethylhydantoin compound (1)).
[2] The compound according to [1], wherein R ¹ and R ² are hydrogen atoms.
[3] Formula (2)

(Wherein R ¹ and R ² have the same meanings as described above,
The broken line indicates that the compound represented by the formula (2) is an isomer of Z configuration or E configuration or a mixture thereof. )
A method for producing a biphenylmethylhydantoin compound (1), comprising reducing a compound represented by formula (hereinafter also referred to as a biphenylmethylenehydantoin compound (2)).
[4] Biphenylmethylhydantoin compound (1) is hydrolyzed, the formula (3)

(In the formula, each symbol has the same meaning as described above.)
(Hereinafter also referred to as a biphenylalanine compound (3)).
[5] (a) Biphenylmethylenehydantoin compound (2) is reduced to obtain biphenylmethylhydantoin compound (1),
(B) A method for producing a biphenylalanine compound (3), comprising hydrolyzing the biphenylmethylhydantoin compound (1).

The biphenylmethylhydantoin compound (1) of the present invention is useful as an intermediate for producing the biphenylalanine compound (3). According to the production method of the present invention, the biphenylalanine compound (3) can be produced in a high yield from the biphenylmethylhydantoin compound (1). Moreover, according to the production method of the present invention, the biphenylmethylhydantoin compound (1) can be produced from the biphenylmethylenehydantoin compound (2) in a high yield.
The production method of the present invention is an industrially advantageous production method because it uses the biphenylmethylhydantoin compound (1) that can be produced from an inexpensive raw material.

The definition of the substituent used in this specification is described below.
As the “alkyl group”, a linear or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Hexyl etc. are mentioned, Preferably it is methyl or ethyl.

  Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.

  The “haloalkyl group” is an “alkyl group” as defined above substituted with a “halogen atom” as defined above. Although the number of substitution of the halogen atom is not particularly limited, 1 to 3 is preferable. Examples of the “haloalkyl group” include chloromethyl, bromomethyl, fluoromethyl, dichloromethyl, dibromomethyl, difluoromethyl, trichloromethyl, tribromomethyl, trifluoromethyl, 2,2-dichloroethyl, 2,2,2- Trichloroethyl etc. are mentioned, Preferably it is trifluoromethyl.

  As the “alkoxy group”, a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyl Examples thereof include oxy, neopentyloxy, hexyloxy and the like, preferably methoxy or ethoxy.

R ¹ and R ² are preferably a hydrogen atom.

  A method for producing the biphenylmethylhydantoin compound (1) and the biphenylalanine compound (3) will be described below.

(In the formula, each symbol has the same meaning as described above.)

Process 1
Biphenylmethylene hydantoin compound (2) can be obtained by reacting compound (4) and hydantoin (5) in the presence of a base.
The amount of hydantoin (5) to be used is generally 1 to 3 mol, preferably 1.05 to 2 mol, per 1 mol of compound (4).
Examples of the base include ammonium acetate, sodium acetate, piperidine, triethylamine and the like, preferably ammonium acetate.
The amount of the base to be used is generally 0.1 to 10 mol, preferably 0.5 to 2 mol, per 1 mol of compound (4).
Examples of the reaction solvent include acetic acid, acetic anhydride, N, N-dimethylformamide and the like, preferably acetic acid.
Although the usage-amount of a solvent is not specifically limited, It is 1-50 mL normally with respect to 1 g of compounds (4), Preferably it is 2-6 mL.
The reaction temperature is usually 30 to 200 ° C, preferably 100 to 200 ° C. The reaction time is usually 1 to 24 hours, preferably 3 to 10 hours.

Process 2
The biphenylmethylhydantoin compound (1) can be obtained by reducing the biphenylmethylenehydantoin compound (2).
The reduction can preferably be carried out by catalytic hydrogenation.
Examples of the catalyst used in the catalytic hydrogenation include palladium-carbon, palladium hydroxide-carbon, platinum-carbon, rhodium-carbon, ruthenium-carbon, Raney nickel, and preferably palladium-carbon.
The usage-amount of a catalyst is 0.2-15 mg normally with respect to 1 g of biphenyl methylene hydantoin compounds (2) as a metal amount, Preferably it is 0.5-10 mg.
As the hydrogen source, hydrogen, formic acid or a salt thereof can be used. Examples of formate include sodium formate, potassium formate, ammonium formate, and monomethylammonium formate.
When formic acid or a salt thereof is used as a hydrogen source, the amount used is usually 2 to 15 mol, preferably 4 to 10 mol, per 1 mol of the biphenylmethylenehydantoin compound (2).
Examples of the reaction solvent include ethers such as tetrahydrofuran, tert-butyl methyl ether, 1,2-dimethoxyethane, and 1,4-dioxane; alcohols such as methanol, ethanol, isopropanol, n-butanol, and tert-butanol; ethyl acetate And esters such as methyl acetate and butyl acetate; organic acids such as acetic acid and propionic acid; water; and mixed solvents thereof. In particular, it is preferable to use a mixed solvent of water and tetrahydrofuran because the raw materials and products dissolve and the reaction proceeds rapidly.
Although the usage-amount of a solvent is not specifically limited, It is 3-30 mL normally with respect to 1 g of biphenyl methylene hydantoin compounds (2), Preferably it is 5-20 mL. When using the mixed solvent of water and tetrahydrofuran, 5-20 mL is preferable with respect to 1 mL of water, and, as for the usage-amount of tetrahydrofuran, 6-15 mL is more preferable.
Catalytic hydrogenation can be carried out under normal pressure or pressurized conditions. The reaction pressure is usually from normal pressure to 5 MPa, preferably from normal pressure to 2 MPa.
The reaction temperature is 20 to 100 ° C, preferably 40 to 70 ° C. The reaction time is usually 1 to 24 hours, preferably 3 to 10 hours.
The purification method of the obtained biphenylmethylhydantoin compound (1) is not particularly limited, and general methods such as recrystallization, crystallization, and column chromatography can be used. For example, the biphenylmethylhydantoin compound (1) can be obtained by removing the catalyst from the reaction solution and then concentrating.

Process 3
Biphenylalanine compound (3) can be obtained by hydrolyzing biphenylmethylhydantoin compound (1).
Hydrolysis is usually performed by treating with a base in a solvent.
Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate and the like, preferably sodium hydroxide and potassium hydroxide.
The usage-amount of a base is 2-10 mol normally with respect to 1 mol of biphenyl methyl hydantoin compounds (1), Preferably it is 3-8 mol.
Examples of the reaction solvent include alcohols such as methanol, ethanol and ethylene glycol; ethers such as tetrahydrofuran, tert-butyl methyl ether, 1,2-dimethoxyethane and 1,4-dioxane; water; mixed solvents thereof and the like. It is done. Among these, a mixed solvent of water and alcohols is preferable, and a mixed solvent of water and ethylene glycol is more preferable. Use of ethylene glycol having a high boiling point is preferable because the reaction can be performed at a high temperature and the reaction proceeds rapidly.
Although the usage-amount of a solvent is not specifically limited, It is 2-20 mL normally with respect to 1 g of biphenyl methyl hydantoin compounds (1), Preferably it is 3-10 mL. When using the mixed solvent of water and ethylene glycol, 10-100 mL is preferable with respect to 1 mL of water, and, as for the usage-amount of ethylene glycol, 20-50 mL is more preferable.
The reaction temperature is 80 to 200 ° C, preferably 100 to 170 ° C. The reaction time is usually 1 to 24 hours, preferably 3 to 10 hours.
The purification method of the obtained biphenylalanine compound (3) is not particularly limited, and general methods such as recrystallization, crystallization, column chromatography and the like can be used. For example, the biphenylalanine compound (3) is precipitated by adjusting the pH of the reaction solution to 4 to 9, preferably 5 to 8, with a suitable pH adjuster such as hydrochloric acid. A biphenylalanine compound (3) can be obtained by filtering this.

  The biphenylmethylhydantoin compound (1) of the present invention is useful as an intermediate for producing the biphenylalanine compound (3). The biphenylalanine compound (3) is useful as an intermediate for producing a medicament such as a neutral endopeptidase inhibitor. For example, the N-phosphonomethyl-biaryl substituted dipeptide derivative described in the publication can be produced from the biphenylalanine compound (3) using the method described in JP-A-6-228187.

  The present invention will be described in more detail below with reference to production examples and examples, but the present invention is not limited to these examples.

Production example
Preparation of 5-([1,1'-biphenyl] -4-ylmethylene) -2,4-imidazolidinedione
4-phenylbenzaldehyde (100.0 g, 0.55 mole), hydantoin (82.4 g, 0.82 mole) and ammonium acetate (63.5 g, 0.82 mole) were added to acetic acid (360 mL), and the mixture was stirred at an internal temperature of 108 to 124 ° C. for 5 hours. . The reaction mixture was cooled to 50 ° C., water (360 mL) was added, and the mixture was further cooled to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with a mixture of isopropanol and water (1: 1, 400 mL) and dried to give the title compound (143.1 g, yield 98.7% from 4-phenylbenzaldehyde).
¹ H-NMR (DMSO-d ₆ ) δ; 6.47 (1H, s), 7.39 (1H, t, J = 7 Hz), 7.48 (2H, t, J = 7 Hz), 7.67-7.73 (6H, m ).

Example 1
Preparation of 5-([1,1'-biphenyl] -4-ylmethyl) -2,4-imidazolidinedione
5-([1,1'-biphenyl] -4-ylmethylene) -2,4-imidazolidinedione (62.9 g) was dissolved in a solvent consisting of tetrahydrofuran (THF) (540 mL) and water (60 mL) in an autoclave. Suspended and 5% palladium-carbon (3.1 g, 50% water content) was added. After replacing the inside of the autoclave with nitrogen, hydrogen was introduced to a gauge pressure of 0.4 to 0.5 MPa. The internal temperature was adjusted to 59.5 to 60.1 ° C. and a hydrogen pressure of 0.4 to 0.5 MPa was maintained for 5 hours. Then, the catalyst was removed by filtration, and the catalyst was further washed with THF (200 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (62.64 g, yield 98.8%).
¹ H-NMR (DMSO-d ₆ ) δ; 2.94 (1H, dd, J = 5.6, 15.6 Hz), 2.99 (1H, dd, J = 5.6, 15.6 Hz), 4.36 (1H, t, J = 5.6 Hz ), 7.27 (2H, d, J = 8 Hz), 7.34 (1H, t, J = 8 Hz), 7.44 (2H, t, J = 8 Hz), 7.58 (2H, d, J = 8 Hz), 7.64 (2H, d, J = 8 Hz), 7.94 (1H, s), 10.45 (1H, s).

Example 2
Production of DL-biphenylalanine
5-([1,1'-biphenyl] -4-ylmethyl) -2,4-imidazolidinedione (59.7 g, 0.224 mole) was dissolved in ethylene glycol (300 mL), and water (10 mL) was added. Sodium hydroxide (36.65 g, 0.916 mole) was added. The resulting mixture was stirred at an internal temperature of 133.8 to 140.3 ° C. for 5 hours, cooled to room temperature, and water (130 mL) was added. Further, hydrochloric acid consisting of 35% hydrochloric acid (85 g) and water (99 g) was added dropwise to adjust the pH of the solution to 6.9. The resulting crystals were collected by filtration and further washed successively with water (300 mL) and methanol (300 mL) to give the title compound (53.25 g, yield 98.4%).
Melting point: 212 ° C (decomposition)

Claims (5)

Formula (1)

(In the formula, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, a hydroxy group, an alkoxy group, a cyano group, or a nitro group.)
A compound represented by The compound according to claim 1, wherein R ¹ and R ² are hydrogen atoms. Formula (2)

(Wherein R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, a hydroxy group, an alkoxy group, a cyano group or a nitro group;
The broken line indicates that the compound represented by the formula (2) is an isomer of Z configuration or E configuration or a mixture thereof. )
A compound represented by formula (1):

(In the formula, each symbol has the same meaning as described above.)
The manufacturing method of the compound represented by these. Formula (1)

(In the formula, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, a hydroxy group, an alkoxy group, a cyano group, or a nitro group.)
The compound represented by formula (3) is hydrolyzed:

(In the formula, each symbol has the same meaning as described above.)
The manufacturing method of the compound represented by these. (A) Formula (2)

(Wherein R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, a hydroxy group, an alkoxy group, a cyano group or a nitro group;
The broken line indicates that the compound represented by the formula (2) is an isomer of Z configuration or E configuration or a mixture thereof. )
A compound represented by the formula (1)

(In the formula, each symbol has the same meaning as described above.)
To obtain a compound represented by
(B) Hydrolyzing the compound represented by Formula (1), Formula (3)

(In the formula, each symbol has the same meaning as described above.)
The manufacturing method of the compound represented by these.