JPH09208514A - Production of optically active carboxylic acids - Google Patents

Abstract

PROBLEM TO BE SOLVED: To selectively produce optically active carboxylic acids of high optical purity useful in industrial fields such as medicines, agrochemicals, perfumes, food additives and electronics in high yield. SOLUTION: An optically active 4,5-diphenyl-2-imidazolidinone derivative represented by formula II (R<1> is an alkyl, etc.; R<2> is a dialkoxyphosphoryl or a halogen; * indicates the position of asymmetric carbon) is reacted with an aldehyde represented by the formula R<3> CHO (R<3> is an organic group) to afford an α,β-unsaturated acyl compound represented by formula III. The Michael addition reaction or Michael type addition reaction of the resultant α,β-unsaturated acyl compound represented by formula III is then carried out by using a reagent having an organic group R<4> different from R<3> to provide a diastereomer represented by formula IV (R<4> is the organic group different from R<3> ), which is then hydrolyzed to afford optically active carboxylic acids represented by formula I, e.g. (4S,5S)-1-cinnamoyl-4,5-diphenyl-3-methyl-2-imidazolidinone.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing optically active carboxylic acids.

[0002]

2. Description of the Related Art Enantiomers (enantiomers) exist in organic compounds having an asymmetric carbon. When such an organic compound is used as a flavoring agent or a food additive, it is known that the odor and taste differ depending on each enantiomer. In addition, it is known that, as clearly shown in the example of thalidomide, the efficacy and toxicity of pharmaceuticals differ greatly depending on both isomers. Further, for the ferroelectric liquid crystal, a compound having a pure chiral molecular structure is required, and it is said that a decrease in optical purity causes a remarkable decrease in function.

As described above, in the industrial fields such as medicines, agricultural chemicals, flavors, food additives, and electronics, any enantiomer is required, and those having higher optical purity are also required.

Further, in order to produce carboxylic acids having high optical purity, the method of producing by ordinary chemical reaction using an optically active starting material is the easiest and most common. Therefore, optically active raw material compounds are industrially important, and inexpensive and large-scale supply is required.

[0005]

As a method for producing such an optically active carboxylic acid, a method of separating a racemic body obtained by a usual reaction using an optically active resolving agent, an enzyme or a biological method. A method is known in which only one of the isomers is converted to the desired product by using.

[0006] However, in such a method, half of the isomers that cannot be industrially used remain, so that the resources cannot be effectively used and it is uneconomical. Therefore, a method for producing only necessary optical isomers is desired, and several examples using asymmetric synthesis reagents have been reported at present. Among these asymmetric synthesis reagents, 4-chiral-2-oxazolidinone derivatives are widely used because of their easy availability and wide application range.

4,5-Diphenyl-1-methyl-2-imidazolidinone is known as a derivative of optically active 1,2-diphenyl-1,2-ethanediamine which is widely used as an asymmetric synthesis reagent. However, as an example of application to its asymmetric synthesis reaction, 4,5-diphenyl-1-methyl-3
-The only asymmetric aldol reaction of propionyl-2-imidazolidinone with aldehydes has been reported [Bull. Chem. Soc. Jpn. , 64 , 14
25-1427 (1991)].

Therefore, it is an object of the present invention to provide a method capable of selectively producing an optically active carboxylic acid with good yield using a good asymmetric synthesis reagent.

[0009]

In view of such circumstances, the inventors of the present invention have conducted diligent research, and as a result, have shown that the optically active 4,5-diphenyl-2-imidazolidinone represented by the following general formula (1) is obtained. The inventors have found that the use of a derivative as an asymmetric synthesis reagent allows the reaction to proceed in a highly diastereoselective manner, thereby producing an optically active carboxylic acid selectively and in high yield, and completed the present invention.

The present invention can be represented by the following reaction formula.

[0011]

Embedded image

[In the formula, R ¹ represents an alkyl group, R ² represents a dialkoxyphosphoryl group or a halogen atom,
³ and R ⁴ represent different organic groups, and * represents the position of the asymmetric carbon.]

That is, in the present invention, an optically active 4,5-diphenyl-2-imidazolidinone derivative represented by the general formula (1) is reacted with an aldehyde represented by R ³ CHO (R ³ represents an organic group). Let (Step 1) General formula (2)
An α, β-unsaturated acyl compound represented by the formula (1) is obtained, and a Michael addition reaction or a Michael type addition reaction using a reagent having an organic group R ⁴ different from R ³ is carried out (step 2)
The present invention provides a method for producing an optically active carboxylic acid represented by the general formula (4), which comprises obtaining a diastereomer represented by the general formula (3) and then hydrolyzing the diastereomer (step 3). .

[0014]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The method of the present invention will be described below for each of the above steps. In addition, the optically active 4,5-
The method for producing the diphenyl-2-imidazolidinone derivative (1) will be described later.

(1) Step 1 Optically active 4,5-diphenyl-used as a raw material
In the 2-imidazolidinone derivative (1), the alkyl group in the general formula (1) includes those having 1 to 12 carbon atoms, more preferably those having 1 to 6 carbon atoms, specifically, Examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group and a t-butyl group. In the present invention, those having 1 to 4 carbon atoms are particularly preferable. Moreover, as the dialkoxyphosphoryl group, for example, a diC ₁ -C ₁₂ alkoxyphosphoryl group is preferable, and a dimethoxyphosphoryl group, a diethoxyphosphoryl group and the like are more preferable. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Aldehyde (R
The organic group in ³ CHO) is a group corresponding to the β-position of the objective optically active carboxylic acid (4), and is not particularly limited, and examples thereof include a hydrocarbon group and a heterocyclic group. Here, the hydrocarbon group and the heterocyclic group may be substituted with a halogen atom, an alkoxy group, an amino group, a nitro group, a cyano group or the like. The hydrocarbon group includes linear, branched and cyclic groups, and may be saturated or unsaturated (including aromatic). The heterocyclic group may be either saturated or unsaturated, and the heteroatoms constituting the heterocycle include one or more kinds of nitrogen atom, oxygen atom and sulfur atom.

The reaction of step 1 is preferably carried out in the presence of a base such as n-butyllithium and sodium hydride,
It is preferably carried out at -20 to 50 ° C for 1 to 24 hours in an inert solvent such as tetrahydrofuran or dimethylformamide.

(2) Step 2 Step 2 is a β addition reaction to the α, β-unsaturated acyl compound (2), which is a Michael addition reaction or a Michael type addition reaction.

The reagent used here is not particularly limited as long as it has an organic group R ⁴ different from R ³ and is usually used in a Michael addition reaction or a Michael type addition reaction, but (R ⁴ ) ₂ CuMgX ( X is a halogen atom),
(R ⁴ ) ₂ CuLi, R ⁴ MgX, (R ⁴ ) ₃ B, R ⁴ Al
(R ⁵ ) ₂ (R ⁵ represents a lower alkyl group), an organic metal reagent such as R ⁴ K; R ⁶ COCH ₂ COR ⁷ (wherein R ⁶ and R ⁷ are a hydrocarbon group, a hydrocarbon oxy group, a heterocyclic group) Active methylene compounds such as cyclic groups and heterocyclic oxy groups). Here, as R ^4, the a group listed as R ^3, include organic groups different from R ^3.

[0020] The reaction of step 2 may vary depending on the type of the reagent with R ^4, carried out under the conditions of a Michael addition reaction or Michael-type addition reaction, when the reagent with R ⁴ is an organic metal reagent such as ethers In an inert solvent such as -10
It is preferably carried out at 0 to 20 ° C. for 1 to 24 hours.

This reaction proceeds in a diastereoselective manner, and one of the obtained diastereomers (3) has a high diastereomer ratio.

(3) Step 3 Step 3 is a reaction for obtaining the desired optically active carboxylic acid (4) by hydrolysis of the diastereomer (3).
The hydrolysis reaction is carried out by a conventional method, but it is preferably carried out in the presence of a base. Sodium hydroxide as the base,
Lithium hydroxide, potassium hydroxide or the like can be used, but a metal alkoxide may be used. When a metal alkoxide is used, an alkyl ester of an optically active carboxylic acid is produced, and therefore it is necessary to further perform hydrolysis using sodium hydroxide or the like.

The starting compound (1) can be obtained, for example, according to the following reaction formula, using optically active 1,2-diphenyl-1,2-ethanediamine (5) as a starting material in four steps to obtain 4,5-diphenyl. -1-Alkyl-2-imidazolidinone (12) with halogenocarboxylic acid halogenide (1
When 3) is reacted, a halogenoacyl-4,5-diphenyl-2-imidazolidinone derivative (1a) is obtained, which is further reacted with a trialkyl phosphite (14) to give a dialkoxyphosphoryl compound (1b). ) Can be manufactured.

[0024]

[Chemical 6]

[Wherein R ¹ and * are the same as defined above, R ⁸ and R ⁹ are alkyl groups, and X ¹ , X ² and X are
³ and X ⁴ represent a halogen atom]

The above reaction will be described below step by step.

(1) Step a Optically active 1,2-diphenyl-1,2-ethanediamine (5) is cyclized with urea (6) and water to give 4,5-diphenyl-2-imidazo. The ridinone (7) is obtained. Examples of the optically active 1,2-diphenyl-1,2-ethanediamine (5) used as a raw material include (1R, 2R) -1,2-diphenyl-1,2
-Ethanediamine and (1S, 2S) -1,2-diphenyl-1,2-ethanediamine. This reaction is carried out by heating while distilling off water.

(2) Step b 1-acyl-4,5-diphenyl-2 by reacting 4,5-diphenyl-2-imidazolidinone (7) with fatty acid halogenide (8) represented by propionyl chloride. -Imidazolidinone (9) is obtained. This reaction is carried out in the presence of a base such as sodium hydride.

(3) Step c 1-Acyl-4,5-diphenyl-2-imidazolidinone (9) is reacted with alkyl halide (10) to give 3-acyl-1-alkyl-4,5-. Diphenyl-2-imidazolidinone (11) is obtained. Specific examples of the alkyl halide (10) include methyl iodide, ethyl iodide, ethyl bromide, n-propyl iodide,
N-propyl bromide, n-propyl chloride, i-propyl iodide, i-propyl bromide, n-butyl iodide, n-bromide
Butyl, i-butyl iodide, i-butyl bromide, t-chloride
Butyl and the like. This reaction is carried out in the presence of a base such as sodium hydride.

(4) Step d 3-acyl-1-alkyl-4,5-diphenyl-2-
Hydrolysis of imidazolidinone (11) yields 1-alkyl-4,5-diphenyl-2-imidazolidinone (1
2) is obtained. This reaction is carried out in the presence of a base such as sodium alkoxide under the condition where only the acyl group is eliminated.

(5) Step e 1-Alkyl-4,5-diphenyl-2-imidazolidinone (12) to halogenocarboxylic acid halogenide (13)
The halogenoacyl-4,5-diphenyl-2-imidazolidinone derivative (1a) is obtained by reacting Specific examples of the halogenocarboxylic acid halogenide include:
Examples thereof include chloroacetyl chloride and bromoacetyl chloride. This reaction is carried out by dimethylformamide,
A metal salt of compound (12) is prepared using an organometallic compound such as n-butyllithium or lithium diisopropylamide, sodium hydride or lithium hydride in an inert solvent such as tetrahydrofuran or diethyl ether, and then cooled to room temperature or cooled. It is carried out by dropping the solution of the metal salt of the compound (12) into the solution of the halogenocarboxylic acid halogenide (13) below.

(6) Step f The halogenoacyl-4,5-diphenyl-2-imidazolidinone derivative (1a) is added to the trialkyl phosphite (14).
Compound (1b) is obtained by reacting Specific examples of the trialkyl phosphite (14) include trimethyl phosphite, triethyl phosphite, tripropyl phosphite and the like. This reaction is carried out by dissolving the compound (1a) and the trialkyl phosphite (14) in a solvent such as toluene, xylene, dimethylformamide and heating.

[0033]

Industrial Applicability According to the present invention, optically active carboxylic acids can be produced selectively and in high yield.

[0034]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto.

Production Example 1 Production of (4S, 5S) -1-acetyl-4,5-diphenyl-2-imidazolidinone:
Sodium hydride 0.10 in 10 ml dimethylformamide.
73 g (55% 16.8 mmol) and (4S, 5S)-
4,5-diphenyl-2-imidazolidinone 2.00g
(8.4 mmol) was added and the mixture was stirred for 30 minutes, and then 0.66 g (8.4 mmol) of acetyl chloride in 3 ml of dimethylformamide was slowly added dropwise, and the mixture was stirred for another 30 minutes after completion. The reaction solution was added to a dilute aqueous hydrochloric acid solution and extracted with methylene chloride. The extract solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (solvent: chloroform) to give 1.49 g of the title compound (yield 63%).
Obtained.

IRν ^KBr _max cm ⁻¹ : 3270, 1745, 1660 ¹ H-NMR (CDCl ₃ ) δ: 2.53 (3H, s), 4.51 (1H, d, J = 3.3Hz), 5.
13 (1H, d, J = 3.3Hz), 5.77 (1H, s), 7.24 ~ 7.41 (10H, m)

Preparation Example 2 Preparation of (4S, 5S) -1-acetyl-3-n-butyl-4,5-diphenyl-2-imidazolidinone: 0.24 g (55%) of sodium hydride in 12 ml of dimethylformamide. 5.5 mmol) and (4S, 5S) -1-acetyl-4,5-diphenyl-
2-Imidazolidinone 1.40 g (5.0 mmol) was added and stirred for 30 minutes, then n-butyl iodide 0.92
g (5.0 mmol) was added dropwise, and the mixture was further stirred at room temperature for 28 hours after completion. The reaction solution was added to a dilute aqueous hydrochloric acid solution and extracted with methylene chloride. The extract solution was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a red oily substance. This oily substance was purified by silica gel chromatography (solvent: chloroform) to give 1.7 g of the title compound (yield: 10
0%).

IR ν ^neat _max cm ⁻¹ : 1720, 1685 ¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, t, J = 6.6Hz), 1.24 to 1.44 (4
H, m), 2.59 (3H, s), 2.70 ~ 2.75 (1H, m), 3.64 ~ 3.69 (1H,
m), 4.34 (1H, d, J = 2.6Hz), 5.06 (1H, d, J = 2.6Hz), 7.17 ~
7.41 (10H, m)

Preparation Example 3 Preparation of (4S, 5S) -1-n-butyl-4,5-diphenyl-2-imidazolidinone: (4S, 5S) -1-acetyl-3-n- in 5 ml of methanol. 1.16 g (3.5 mmol) of butyl-4,5-diphenyl-2-imidazolidinone was dissolved, and 1.3 g of sodium methoxide 28% methanol solution was dissolved therein.
(6.7 mmol) was added, and the mixture was stirred at room temperature for 50 minutes. The reaction solution was added to a dilute aqueous hydrochloric acid solution and extracted with methylene chloride. The extract solution was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1.01 g (yield 100%) of the title compound. It was

IR ν ^neat _max cm ⁻¹ : 3220, 1695

Preparation Example 4 Preparation of (4S, 5S) -1-chloroacetyl-4,5-diphenyl-3-methyl-2-imidazolidinone: 95 mg (55% 2.2 mmol) of sodium hydride in 5 ml of dimethylformamide. ) And (4
S, 5S) -4,5-Diphenyl-1-methyl-2-imidazolidinone (500 mg, 2.0 mmol) was added, and the mixture was stirred at room temperature for 45 minutes to prepare a sodium salt. 330 mg of this sodium salt solution under ice cooling
(2.9 mmol) was slowly added to a solution of 5 ml of dimethylformamide. Then, after stirring at room temperature for 1 hour, the reaction solution was added to a dilute hydrochloric acid aqueous solution and extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate. The viscous oily substance obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (solvent: chloroform) to obtain 270 mg (yield 41%) of the title compound.

Mp 109.5 to 112.3 ° C. [α] ^22.5 _D = −98.24 ° (c = 1.00, CHCl ₃ ) UVλ ^MeOH _max nm: 210.0 (ε 23900) IRν ^KBr _max cm ⁻¹ : 1725, 1700 ¹ H-NMR ( CDCl ₃ ) δ: 2.81 (3H, s), 4.34 (1H, d, J = 3.7Hz), 4.
78 (1H, d, J = 15.0Hz), 4.90 (1H, d, J = 15.0Hz), 5.05 (1H, d,
J = 3.7Hz), 7.16 to 7.46 (10H, m) ¹³ C-NMR (CDCl ₃ ) δ: 29.12, 43.84, 63.75, 67.85, 125.
53, 126.15, 128.48, 129.19, 129.21, 129.56, 137.93,
139.71, 154.32, 165.80

Preparation 5 Preparation of (4S, 5S) -1-bromoacetyl-4,5-diphenyl-3-methyl-2-imidazolidinone: 190 mg sodium hydride (55% 4.3 mmol) in 10 ml dimethylformamide. ) And (4S, 5S) -4,5-diphenyl-1-methyl-2
-Adding 1.00 g (4.0 mmol) of imidazolidinone,
The sodium salt was prepared by stirring at room temperature for 50 minutes. This sodium salt solution was added to bromoacetyl chloride 9 under ice cooling.
Slowly added to a solution of 10 mg (5.8 mmol) of dimethylformamide in 10 ml. Then, stirring was continued at room temperature for 1.5 hours. The same operations as in Production Example 4 were carried out to obtain 680 mg (yield 46%) of the title compound.

Mp 99.5-101.8 ° C. [α] ^26.6 _D = −93.03 ° (c = 1.00, CHCl ₃ ) UVλ ^MeOH _max nm: 209.6 (ε 25100) IRν ^KBr _max cm ⁻¹ : 1720, 1695 ¹ H-NMR ( CDCl ₃ ) δ: 2.82 (3H, s), 4.63 (1H, d, J = 3.7Hz), 4.
78 (1H, d, J = 15.0Hz), 4.90 (1H, d, J = 15.0Hz), 5.05 (1H, d,
J = 3.7Hz), 7.16 to 7.46 (10H, m) ¹³ C-NMR (CDCl ₃ ) δ: 29.12, 43.78, 63.77, 67.88, 125.
53, 126.16, 126.20, 128.48, 129.19, 129.56, 137.96,
139.72, 154.32, 165.80

Preparation 6 Preparation of (4S, 5S) -1-Bromoacetyl-4,5-diphenyl-3-n-butyl-2-imidazolidinone: 0.25 g (55 g) of sodium hydride in 13 ml of dimethylformamide. % 5.6 mmol)
And (4S, 5S) -4,5-diphenyl-1-n-butyl-2-imidazolidinone 1.50 g (5.1 mmol)
Was added and stirred at room temperature for 1 hour to prepare a sodium salt. This sodium salt solution was slowly added to a solution of 1.20 g (7.6 mmol) of bromoacetyl chloride in 13 ml of dimethylformamide under ice cooling. Then, stirring was continued at room temperature for 3.5 hours. Thereafter, the same operation as in Production Example 4 was carried out to obtain 0.69 g (yield 33%) of the title compound.

Viscous oil [α] ^26.4 _D = −83.55 ° (c = 1.00, CHCl ₃ ) UVλ ^MeOH _max nm: 209.6 (ε 25000) IRν ^neat _max cm ⁻¹ : 1720 ¹ H-NMR (CDCl ₃ ). δ: 0.87 (3H, t, J = 7.5Hz), 1.25〜1.31 (2
H, m), 1.39 ~ 1.52 (2H, m), 2.70 ~ 2.79 (1H, m), 3.61 ~ 3.7
1 (1H, m), 4.42 (1H, d, J = 2.9Hz), 4.78 (1H, d, J = 15.2Hz),
4.92 (1H, d, J = 15.2Hz), 5.05 (1H, d, J = 2.9Hz), 7.17 ~ 7.43
(10H, m) ¹³ C-NMR (CDCl ₃ ) δ: 13.54, 19.58, 28.96, 41.36, 43.8
5, 63.66, 65.46, 125.33, 126.17, 128.35, 129.07, 12
9.11, 129.43, 138.45, 140.02,154.09, 165.62

Preparation Example 7 Preparation of (4S, 5S) -1-diethoxyphosphorylacetyl-4,5-diphenyl-3-methyl-2-imidazolidinone: Obtained in Preparation Example 5 (4S) in 20 ml of toluene. , 5S) -1-Bromoacetyl-4,5-diphenyl-3-methyl-2-imidazolidinone 470 mg (1.26 mmol) and triethyl phosphite 419 mg (2.52 mmol) were added, and heating under reflux was continued for 30 hours. It was After cooling, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (solvent chloroform / methanol) to give 370 mg of the title compound (yield 68
%)Obtained.

Viscous oil [α] ^27.6 _D = −71.50 ° (c = 1.13, CHCl ₃ ) UVλ ^MeOH _max nm: 210.4 (ε 24600) IRν ^neat _max cm ⁻¹ : 1725, 1685, 1260, 1020 ¹ H -NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3Hz), 1.30 (3H, t, J =
7.3Hz), 2.80 (3H, s), 3.87 (0.5H, d, J = 13.6Hz), 3.95 (0.5
H, d, J = 13.6Hz), 3.97 (0.5H, d, J = 13.6Hz), 4.04 (0.5H, d, J
= 13.6Hz), 4.11 to 4.17 (4H, m), 4.26 (1H, d, J = 3.5Hz), 5.1
0 (1H, d, J = 3.5Hz), 7.22-7.44 (10H, m) ¹³ C-NMR (CDCl ₃ ) δ: 16.26, 16.28, 16.34, 16.36, 29.1
4, 33.63, 35.35, 62.48, 62.50, 62.55, 62.58, 63.83,
67.20, 125.48, 126.40, 128.14,129.01, 129.06, 12
9.45, 138.32, 140.28, 154.40, 164.37, 164.45

Preparation Example 8 Preparation of (4S, 5S) -1-n-butyl-3-diethoxyphosphorylacetyl-4,5-diphenyl-2-imidazolidinone: Toluene 15 ml
(4S, 5S) -1-bromoacetyl-3-n-butyl-4,5-diphenyl-2-imidazolidinone obtained in Preparation Example 6 (709 mg, 1.71 mmol) and triethyl phosphite (568 mg, 3.42 mmol) was added and heating under reflux was continued for 27 hours. After cooling, the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel chromatography (solvent: chloroform / methanol) to obtain 400 mg (yield 50%) of the title compound.

Viscous oil [α] ^27.0 _D = −65.83 ° (c = 1.00, CHCl ₃ ) UV λ ^MeOH _max nm: 210.8 (ε 23200) IRν ^neat _max cm ⁻¹ : 1725, 1685, 1260, 1025 ¹ H -NMR (CDCl ₃ ) δ: 0.85 (3H, t, J = 7.3Hz), 1.28 (3H, t, J =
7.1Hz), 1.30 (3H, t, J = 7.1Hz), 1.24 ~ 1.44 (4H, m), 2.77
(1H, dt, J = 14.1 and 7.9Hz), 3.67 (1H, dt, J = 14.1 and 7.9
Hz), 3.82 (0.5H, d, J = 13.5Hz), 3.89 (0.5H, d, J = 13.5Hz),
4.03 ~ 4.20 (5H, m), 4.34 (1H, d, J = 2.9Hz), 5.12 (1H, d, J =
2.9Hz), 7.26 ~ 7.41 (10H, m) ¹³ C-NMR (CDCl ₃ ) δ: 13.56, 11.64, 16.33, 19.75, 29.0
0, 33.56, 35.27,41.36, 62.35, 62.40, 62.43, 62.48,
63.79, 64.87, 125.29, 126.41, 128.10, 128.98, 129.
39, 138.78, 140.55, 154.17, 164.18, 164.27

Preparation 9 Preparation of (4S, 5S) -1-dimethoxyphosphorylacetyl-3-methyl-4,5-diphenyl-2-imidazolidinone: Obtained in Preparation 5 (4S, 5S) in 12 ml of toluene. 5S) -1-Bromoacetyl-4,5-diphenyl-3-methyl-2-imidazolidinone (520 mg, 1.39 mmol) and trimethyl phosphite (346 mg, 2.79 mmol) were added, and the mixture was heated under reflux for 22 hours. . After cooling, the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel chromatography (solvent: chloroform / methanol) to obtain 360 mg of the title compound (yield: 64).
%)Obtained.

Viscous oil [α] ^29.4 _D = −59.12 ° (c = 1.00, CHCl ₃ ) UV λ ^MeOH _max nm: 210.8 (ε 21100) IRν ^neat _max cm ⁻¹ : 1725, 1680, 1265, 1025 ¹ H -NMR (CDCl ₃ ) δ: 2.80 (3H, s), 3.74 (1.5H, s), 3.75 (1.
5H, s), 3.78 (1.5H, s), 3.88 (0.5H, d, J = 13.7Hz), 3.95 (0.
5H, d, J = 13.7Hz), 4.00 (0.5H, d, J = 13.7Hz), 4.07 (0.5H, d,
J = 13.7Hz), 4.28 (1H, d, J = 3.4Hz), 5.10 (1H, d, J = 3.4Hz),
7.22-7.42 (10H, m) ¹³ C-NMR (CDCl ₃ ) δ: 29.12, 32.74, 34.47, 53.00, 53.0
8, 63.79, 67.13, 125.41, 126.30, 128.19, 129.02, 12
9.06, 129.46, 138.25, 140.17,154.33, 164.10, 164.1
9

Example 1 (1) (4S, 5S) -1-Cinnamoyl-4,5-
Preparation of diphenyl-3-methyl-2-imidazolidinone: 37.1 mg (55% 0.85 mmol) sodium hydride and 4S, 5 in 4 ml anhydrous tetrahydrofuran.
S) -1-Diethoxyphosphorylacetyl-4,5-diphenyl-3-methyl-2-imidazolidinone 366 mg
(0.85 mmol) was added and stirred at 0 ° C. for 15 minutes,
90 mg (0.85 mmol) of benzaldehyde was added, and the temperature was 0 ° C.
The stirring was continued for 1 hour at room temperature and for 15 hours at room temperature. Next, water was added to the reaction solution, which was extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel chromatography (solvent n-hexane / ethyl acetate) to obtain 265 mg (yield 82%) of the title compound.

Mp 144.9-146.0 ° C. [α] ^21.0 _D = + 29.82 ° (c = 1.00, CHCl ₃ ) UVλ ^MeOH _max nm: 293.6 (ε 27200) 208.0 (ε 23700) IRν ^KBr _max cm ⁻¹ : 1710, 1665, 1610 ¹ H-NMR (CDCl ₃ ) δ: 2.84 (3H, s), 4.33 (1H, d, J = 3.5Hz), 5.
20 (1H, d, J = 3.5Hz), 7.20 ~ 7.63 (15H, m), 7.74 (1H, d, J = 1
5.9Hz), 8.23 (1H, d, J = 15.9Hz)

(2) (4S, 5S) -4,5-diphenyl-1-methyl-3- (3-phenylbutyryl) -2
-Production of imidazolidinone: 0.62 g (95% 95%) cuprous bromide in 4.8 ml anhydrous tetrahydrofuran under a stream of nitrogen.
(4.11 mmol) was added and the mixture was cooled to -40 ° C, 2.72 ml (8.16 mmol) of a 3.0 M solution of methylmagnesium bromide in diethyl ether was added, and the mixture was cooled to -40 ° C at 1 ° C.
The mixture was further stirred for 5 minutes at −10 ° C. for 20 minutes. Then, (4
S, 5S) -1-Cinnamoyl-4,5-diphenyl-
1.04 g of 3-methyl-2-imidazolidinone (2.7
2 mmol) was added, and stirring was continued at −10 ° C. for 1.5 hours, 0 ° C. for 20 minutes, and room temperature for 16 hours. 12 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.25 g of residue. The residue was purified by silica gel chromatography (solvent n-hexane / ethyl acetate) to obtain 0.55 g (yield 51%) of the title compound as a mixture of diastereomers. When the mixture was analyzed by HPLC, the diastereomer ratio was 77:23.

HPLC analysis conditions Column: Capcell pak ODS UG-120Å 5 μm (4.6 mm ID × 250 mm L) Mobile phase: CH ₃ OH: H ₂ O = 7: 3 Flow rate: 1.0 ml / min Detector: UV 210 nm

(3) Preparation of 3-phenylbutanoic acid: (4S, 5S) -4,5-diphenyl-1-methyl-3- (3-phenylbutyryl) -2-imidazolidinone 0 in 5 ml of methanol. 0.52 g (1.31 mmol) and sodium methoxide 28% methanol solution 0.51 g (2.
64 mmol) and stirred at room temperature for 45 minutes, then 1 ml of water
(55.56 mmol) was added, and the mixture was stirred at room temperature for 16 hours.
Water was added to the reaction solution and extracted with methylene chloride. The methylene chloride layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure (4S, 5S) -4,5-diphenyl-1-methyl. 0.32 g of -2-imidazolidinone was recovered. The aqueous layer was acidified with hydrochloric acid and then extracted with ethyl acetate,
The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 0.21 g of the title compound (yield 10
0%).

IRν ^neat _max cm ^-1 : 2960, 1705

Example 2 (1) Production of (4S, 5S) -4,5-diphenyl-1-methyl-3- (3-phenylvaleryl) -2-imidazolidinone: anhydrous tetrahydrofuran 2 under nitrogen stream
132 mg (95% 0.87 mmol) of cuprous bromide was added to the solution and cooled to -40 ° C, and 0.58 ml of a 3.0 M solution of ethyl magnesium bromide in diethyl ether (1.
75 mmol) was added, and the mixture was stirred at -40 ° C for 25 minutes and further at -10 ° C for 15 minutes. Then, 223 mg (0.58 mmol) of (4S, 5S) -1-cinnamoyl-4,5-diphenyl-3-methyl-2-imidazolidinone was added, and -10
Stirring was continued at ~ 0 ° C for 35 minutes and then at room temperature for 22 hours. Then, the same operation as in Example 1 (2) was carried out to give 120 mg (yield 50%) of the title compound as a mixture of diastereomers.
Obtained. When the ¹ H-NMR spectrum analysis of this mixture was performed and the integrated values were compared, the diastereomeric ratio was 73:
27.

Analytical value of main product IRν ^neat _max cm ⁻¹ : 1725, 1685 ¹ H-NMR (CDCl ₃ ) δ: 0.77 (3H, t, J = 7.1Hz), 1.62 to 1.70 (2
H, m), 2.75 (3H, s), 3.12 ~ 3.24 (2H, m), 3.65 ~ 3.75 (1H,
m), 4.17 (1H, d, J = 3.3Hz), 4.92 (1H, d, J = 3.3Hz), 6.94 to 7.
42 (10H, m)

(2) Production of 3-phenylpentanoic acid:
(4S, 5S) -4,5-diphenyl-1-methyl-3- (3-phenylvaleryl) -2- in 5 ml of methanol
60 mg (0.15 mmol) of imidazolidinone and 84.5 mg (0.4% of sodium methoxide 28% methanol solution)
(4 mmol) was added and the mixture was stirred at room temperature for 18.5 hours, then 0.3 ml of water (16.67 mmol) was added and the mixture was stirred at room temperature for 4.5 hours. Then, the same operation as in Example 1 (3) was carried out to obtain 20 mg (yield 77%) of the title compound.

IR ν ^neat _max cm ⁻¹ : 2920, 1705

Example 3 (1) (4S, 5S) -1-n-butyl-4,5-diphenyl-3- [3- (2-thienyl) propenoyl]
Preparation of 2-imidazolidinone: Sodium hydride 39.2 mg (55% 0,5% in anhydrous tetrahydrofuran 5 ml).
90 mmol) and (4S, 5S) -1-n-butyl-3-
Diethoxyphosphorylacetyl-4,5-diphenyl-
After adding 424 mg (0.90 mmol) of 2-imidazolidinone and stirring at 0 ° C for 30 minutes, 101 mg (0.90 mmol) of 2-thiophenaldehyde was added, and stirring was continued at 0 ° C for 40 minutes and further at room temperature for 20 hours. . Hereinafter, Example 1 (1)
The same operation as in the above was performed to give 250 mg of the title compound (yield: 65
%)Obtained.

IRν ^KBr _max cm ⁻¹ : 1700, 1655, 1595 ¹ H-NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 7.5Hz), 1.26 to 1.55 (4
H, m), 2.73 to 2.77 (1H, m), 3.65 to 3.72 (1H, m), 4.38 (1H, d,
J = 3.1Hz), 5.19 (1H, d, J = 3.1Hz), 7.02-7.42 (13H, m), 7.
83 (1H, d, J = 15.7Hz), 8.04 (1H, d, J = 15.7Hz)

(2) Production of (4S, 5S) -1-n-butyl-4,5-diphenyl-3- [3- (2-thienyl) butyryl] -2-imidazolidinone: under nitrogen stream
129 mg of cuprous bromide in 2 ml of anhydrous tetrahydrofuran
(95% 0.86 mmol) was added, and the mixture was cooled to -40 ° C, and 0.57 ml (1.71 mmol) of a 3.0 M solution of methylmagnesium bromide in diethyl ether was added to this, and -40
The mixture was stirred at ℃ for 20 minutes and further at -10 ° C for 5 minutes. Then
245 mg (0.57 mmol) of (4S, 5S) -1-n-butyl-4,5-diphenyl-3- [3- (2-thienyl) propenoyl] -2-imidazolidinone was added, and -1
Stirring was continued at 0 ° C. for 15 minutes, 0 ° C. for 50 minutes and room temperature for 9 hours. Then, the same operation as in Example 1 (2) was carried out to obtain 125 mg (yield 49%) of the title compound as a mixture of diastereomers. When the ¹ H-NMR spectrum analysis of this mixture was performed and the integrated values were compared, the diastereomeric ratio was 79:21.

Analysis value of main product ¹ H-NMR (CDCl ₃ ) δ: 0.85 (3 H, t, J = 7.3 Hz), 1.23 to 1.43 (4
H, m), 2.66 ~ 2.78 (1H, m), 3.19 ~ 3.30 (1H, m), 3.57 ~ 3.76
(3H, m), 4.31 (1H, d, J = 3.1Hz), 5.03 (1H, d, J = 3.1Hz), 6.8
3 to 7.39 (13H, m)

(3) Preparation of 3- (2-thienyl) butanoic acid: (4S, 5S) -1-n-butyl-4,5-diphenyl-3- [3- (2-thienyl) in 1 ml of methanol. Butyryl] -2-imidazolidinone 125 mg (0.
28 mmol) and 162 mg (0.84 mmol) of a sodium methoxide 28% methanol solution were added, and the mixture was stirred at room temperature for 1.5 hours, then 0.3 ml of water (16.7 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Then, the same operation as in Example 1 (3) was carried out to obtain 34.5 mg (yield 73%) of the title compound.

IRν ^neat _max cm ^-1 : 2960, 1705

Example 4 (1) Preparation of (4S, 5S) -4,5-diphenyl-1-methyl-3- (3-methylpentanoyl) -2-imidazolidinone: 4 ml of anhydrous tetrahydrofuran under a nitrogen stream. 333 mg (95% 2.21 mmol) of cuprous bromide was added and cooled to -40 ° C., and 1.47 ml of a 3.0 M solution of ethyl magnesium bromide in diethyl ether was added.
(4.42 mmol) was added, and further -1 was added at -40 ° C for 30 minutes.
Stirred at 0 ° C. for 30 minutes. Then, (4S, 5S) -1
-Crotonoyl-4,5-diphenyl-3-methyl-2
-Adding 471 mg (1.47 mmol) of imidazolidinone,
The stirring was continued at -10 ° C for 40 minutes and further at room temperature for 26 hours.
Thereafter, the same operation as in Example 1 (2) was carried out to obtain 148.2 mg (yield: 29) of the title compound as a mixture of diastereomers.
%)Obtained. When the ¹ H-NMR spectrum analysis of this mixture was performed and the integrated values were compared, the diastereomeric ratio was 7
It was 6:24.

Analysis value of main product IR ν ^neat _max cm ⁻¹ : 1725, 1685 ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, d, J = 6.8Hz), 0.89 (3H, t, J =
5.4Hz), 1.21 ~ 1.43 (2H, m), 1.98 (1H, m), 2.79 (1H, dd, J =
8.6 and 15.0Hz), 2.80 (3H, s), 3.10 (1H, dd, J = 5.7 and 1
5.0Hz), 4.26 (1H, d, J = 3.5Hz), 5.06 (1H, d, J = 3.5Hz), 7.1
6〜7.44 (10H, m)

(2) Preparation of 3-methylpentanoic acid: (4S, 5S) -4,5-diphenyl-1-methyl-3- (3-methylpentanoyl) -2- in 5 ml of methanol.
Imidazolidinone 100 mg (0.29 mmol) and sodium methoxide 28% methanol solution 162 mg (0.8
4 mmol) and stirred at room temperature for 1.5 hours, and then water 0.3
ml (16.7 mmol) was added, and the mixture was stirred at room temperature for 16 hours.
Then, the same operation as in Example 1 (3) was carried out to obtain 31.5 mg (yield 95%) of the title compound.

IR ν ^neat _max cm ^-1 : 2960, 1700

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 333/24 C07D 333/24 409/06 233 409/06 233 // C07D 233/38 C07D 233 / 38 C07M 7:00

Claims (1)

[Claims] 1. The following general formula (1):[Wherein, R¹Represents an alkyl group;^TwoIs a dialkoxy
Indicates a phosphoryl group or a halogen atom, * indicates an asymmetric carbon
The position of the optically active 4,5-dipheny
R-2-imidazolidinone derivative with R ^ThreeCHO (R^ThreeIs
(Representing an organic group) is reacted with
The general formula (2)[Wherein, R¹, R^TwoAnd * indicate the same as above]
The α, β-unsaturated acyl compound represented is obtained, to which R
^ThreeDifferent organic group R^FourWith Michael using reagent with
Addition reaction or Michael type addition reaction
(3)[Wherein, R¹, R^Three, R^FourAnd * are the same as above
A diastereomer represented by
The following general formula (4) characterized by being hydrolyzed[Wherein, R^Three, R^FourAnd * have the same meanings as above]
Process for producing optically active carboxylic acids represented.