JPH06298751A - Production of diltiazem hydrochloride - Google Patents

Abstract

PURPOSE:To obtain diltiazem hydrochloride without carrying out optical resolution during this production using a new (-)-(2R*,3S*)-2,3-epoxy-3-(4- methoxyphenyl)propionic acid ester. CONSTITUTION:A new optically active compound of formula I (R is 1-4C alkyl) used as a starting substance is led to (+)-(2S,3S)-3-(2-aminophenylthio)-2- hydroxy-3-(4-methoxyphenyl)propionic acid and then, well-known reaction is carried out while keeping optical activity to provide the objective product. The compound of formula I is obtained by esterifying a (-)-(2R*,3S*)-2,3- epoxy-3-(4-methoxyphenyl)propionic acid salt of formula II (A<+> is a conjugate acid of organic base or an alkali metal ion) with a lower alcohol in the presence of a dialkyl sulfate or a 1-methyl-2-halopyridinium salt.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing diltiazem hydrochloride.

[0002]

2. Description of the Related Art The following chemical formula (1)

[0003]

[Chemical 2] The benzothiazepine derivative represented by the formula has two asymmetric carbon atoms in the molecule, and theoretically has four types of optical isomers. And among these four types of optical isomers, only the (+)-(2S, 3S) form has already been found to have a medicinal effect as a strong coronary vasodilator. This (+)-(2S, 3S) form is known by the name of diltiazem hydrochloride.

A typical method for producing the benzothiazepine derivative of the above chemical formula (1) is, for example, Japanese Patent Publication No. 46-4.
The following method described in Japanese Patent No. 3785 is known. First, β− represented by the following general formula (2)
Phenylglycidic acid ester:

[0005]

[Chemical 3] (However, in the above general formula (2), R ¹ represents an ester residue) and 2-aminothiophenol represented by the following chemical formula (3):

[0006]

[Chemical 4] And are reacted by heating to give a 1,5-benzothiazepine derivative represented by the following chemical formula (3):

[0007]

[Chemical 5] Then, the 1,5-benzothiazepine derivative was converted to a fatty acid such as acetic acid or propionic acid represented by the following general formula (4):

[0008]

[Chemical 6] (However, in the general formula (4), R ² represents an alkyl group) and condensed to give 1,
5-benzothiazepine derivative:

[0009]

[Chemical 7] And then using the 1,5-benzothiazepine derivative as an alkali metal salt at the 5-position nitrogen site,
An amine derivative represented by the following general formula (6):

[0010]

[Chemical 8] (However, in the general formula (6), R ³ and R ⁴ both represent an alkyl group, and X represents a halogen atom) to undergo a condensation reaction to give the desired benzothiazepine derivative of the chemical formula (1). obtain.

However, since the benzothiazepine derivative of the above chemical formula (1) is a mixture of four kinds of optical isomers as described above, it has a medicinal effect as a strong coronary vasodilator and is diltiazem hydrochloride. , That is, (+)-(2S, 3S)
In order to obtain the body, it is necessary to optically resolve the produced benzothiazepine derivative of the chemical formula (1). However, when the method of optically resolving this product is used, it results in wasting most of the products other than the desired optical isomer among the products manufactured through complicated manufacturing processes. Therefore, it is not advantageous as an industrial production method, and a suitable optical resolving agent for optically resolving the benzothiazepine derivative of the chemical formula (1) to obtain only the desired optical isomer with high purity has not been found. For this reason, methods other than optical resolution of this product have been investigated. Japanese Patent Publication 53-
In Japanese Patent No. 18038, β represented by the general formula (2) is used.
-Optical resolution of racemic α-2-hydroxy-3- (p-alkoxyphenyl) -3- (O-nitrophenylthio) -propionic acid obtained by reacting phenylglycidic acid ester with 2-nitrothiophenol To give optically active α-2-hydroxy-3- (p-alkoxyphenyl) -3- (O-nitrophenylthio) -propionic acid, which is reduced to give optically active α-2-hydroxy-3.
-(P-Alkoxyphenyl) -3- (O-aminophenylthio) -propionic acid, which is subjected to an intramolecular ring closure reaction to give an optically active α-2- (p-alkoxyphenyl)-
3-Hydroxythio-2,3-dihydro-1.5-benzothiazepin-4 (5H) -one was prepared by condensation reaction with ω-dialkylaminoalkyl halide in the presence of a condensing agent to give optically active α- 2- (p-alkoxyphenyl)
-3-Hydroxy-5- (ω-dialkylaminoalkyl) -2,3-dihydro-1.5-benzothiazepine-
4 (5H) -one, which is then reacted with a fatty acid acylating agent to give an optically active α-2- (p-alkoxyphenyl) -3-acyloxy-5- (ω-dialkylaminoalkyl) -2,3. Disclosed is a method for obtaining -dihydro-1.5-benzothiazepin-4 (5H) -one (diltiazem). This method involves reacting a β-phenylglycidic acid ester with 2-nitrothiophenol,
Racemic α-2-hydroxy-3- (p-alkoxyphenyl) -3- (O-nitrophenylthio) -propionic acid was once produced, optically resolved into an optically active substance, and then reduced. This is a process for producing an optically active amino compound, and subjecting it to a ring-closing reaction, a condensation reaction, and an acylation reaction while maintaining the optical activity to obtain diltiazem as an objective optically active compound.

[0012]

DISCLOSURE OF THE INVENTION The present invention provides a more advantageous production method as compared with various known production methods of diltiazem.

That is, the present inventor has made the above-mentioned Japanese Patent Publication No.
An intermediate having an optical activity corresponding to diltiazem is obtained at a step further ahead of the method for producing diltiazem described in Japanese Patent No. 18038, and the starting material is used as a starting material without any troublesome optical resolution operation. Based on the idea that if the desired diltiazem can be obtained, a more advantageous production method as a production method of diltiazem can be developed. First, an optically active free (-)-(2R *, 3S *)-2 , 3-
It was considered to obtain epoxy-3- (4-methoxyphenyl) propionic acid, but it is very difficult to isolate and handle this compound because it is considered to be an unstable compound like its racemate. I reached the conclusion.

[0014]

For the above-mentioned reason, the present inventor has carried out optical resolution at the stage of 2,3-epoxy-3- (4-methoxyphenyl) propionate to obtain a stable optically active substance. Is obtained, which is esterified in the presence of dialkyl sulfuric acid or the like to obtain a novel optically active (−)-(2R *, 3S *)-2,3-epoxy-3-
It has been found that (4-methoxyphenyl) propionic acid ester can be stably obtained. Then, they have found that if this novel optically active compound is used as a starting material, diltiazem hydrochloride can be obtained without performing optical resolution on the way.

Therefore, the present invention provides the general formula (7):

[0016]

[Chemical 9] (In the general formula (7), R represents an alkyl group having 1 to 4 carbon atoms.) (-)-(2R *, 3
It is a method for producing diltiazem hydrochloride using S *)-2,3-epoxy-3- (4-methoxyphenyl) propionic acid ester as a starting material without performing optical resolution on the way.

The above (-)-(2R *, 3S *)-2,
3-epoxy-3- (4-methoxyphenyl) propionic acid ester has the following formula (8).

[0018]

[Chemical 10] (In the above formula, A ⁺ represents a conjugate acid of an organic base or an alkali metal ion.) (-)-(2R *, 3
S *)-2,3-epoxy-3- (4-methoxyphenyl) propionate was added to a lower alcohol (alcohol having 1 to 4 carbon atoms) in the presence of dialkyl sulfuric acid or 1-methyl-2-halopyridinium salt. Can be obtained by esterification.

In the general formula (7) of the present invention, (-)-(2R
*, 3S *)-2,3-Epoxy-3- (4-methoxyphenyl) propionate (-)-(2R *, 3S *)-2,3-epoxy- which is the starting material for the production of 3- (4-methoxyphenyl) propionate is
Patent application of the same applicant as this case (Japanese Patent Application No. 59-26743)
No. 3), which is the title of the invention "Novel optically active epoxypropionic acid derivative and method for producing the same" (specific examples are described as reference examples in the present specification). Then, the obtained optically active propionate is subjected to esterification to give the optically active (-) compound of the present invention.
-(2R *, 3S *)-2,3-epoxy-3- (4-
Methoxyphenyl) propionic acid ester. For example, in the reaction for obtaining the methyl ester, sodium hydrogencarbonate may be added in a dimethylformamide solvent, and dimethyl sulfate and the propionate may be reacted for several hours. Alternatively, 1-methyl-2-chloropyridinium methylsulfate, triethylamine, and methanol may be used in equimolar amounts with respect to the propionate, and the reaction may be performed in dichloromethane.

The optically active (-)-(2R
*, 3S *)-2,3-epoxy-3- (4-methoxyphenyl) propionic acid ester is a known optically active intermediate in the synthesis of diltiazem hydrochloride while maintaining the optical activity by utilizing the following chemical reaction. Body (+)-
(2S, 3S) -3- (2-aminophenylthio) -2
-Hydroxy-3- (4-methoxyphenyl) propionic acid could be derived. Then, using this optically active intermediate, while maintaining the optical activity, Japanese Patent Publication No. 53-1803.
Diltiazem hydrochloride can be easily obtained by carrying out the reaction described in JP-B-8.

[0021]

[Chemical 11]

[0022]

【Example】

[Reference Example 1] 108 ml of acetonitrile and 12 m of water
(±)-(2RS, 3S well ground in 1 mixed solvent
R) -2,3-Epoxy-3- (4-methoxyphenyl) propionic acid potassium salt 11.61 g (50.0 mmol) and (-)-(S) -α-methylbenzylamine.1 / 2 sulfate 8.51 g (50.0 mmol) is added and the mixture is vigorously stirred at room temperature for 30 minutes. The insoluble matter was filtered off, and the filtrate was cooled at -20 ° C for 2 hours, and colorless needle-like crystals were precipitated. Therefore, this was filtered to give (-)-(2R *, 3S
*)-2,3-Epoxy-3- (4-methoxyphenyl) propionic acid. (-)-(S) -α-methylbenzylamine salt [hereinafter abbreviated as (-)-1. (-)-2 salt. To obtain 5.60 g. Yield [calculated with half of total salt as 100%, the same applies hereinafter] 71.0%. mp: 127.5-
128.5 ° C (decomposition). [Α] _D ²³ : −120 ° (c =
1.02, methanol) Further, the insoluble matter filtered off previously was washed with methanol, and the solid obtained by concentrating and drying the washing liquid under reduced pressure was washed with acetonitrile to obtain (-)-1. (- ) -2 salt 0.60
g (7.6%) were obtained. The IR spectrum of this salt coincided with that of the above salt. mp: 126.5-127 ° C (decomposition). [Α] _D ²³ : -117 ° (c1.07, methanol)

IR (KBr) cm ^-1 : 3440,300
0-2950, 2700, 2520, 2200, 163
0,1610,1565,1535,1510,141
0,1290,1250,880,765,700 ¹ H-NMR (CDCl ₃ / CD ₃ OD = 6/1) δ: 1.62 (d, 3H, J = 7 Hz, —CHC H ₃ ) 3.35 ( d, 1H, J = 2Hz, epoxy ring protons) 3.73 (d, 1H, J = 2Hz, epoxy ring protons) 3.80 (s, 3H, -OC H 3) 4.36 (q, 1H, J _{= 7Hz, -C H CH 3)} 6.8-7.2 (m, 4H, aromatic protons) 7.2-7.5 (m, 5H, aromatic protons)

Reference Example 2 4.41 g (14.0 mmol) of (-)-1. (-)-2 salt was added to dry benzene 14
It is suspended in ml and a solution of 0.80 g of 95% sodium methoxide in dry methanol (14 ml) is gradually added thereto at room temperature. After stirring at room temperature for 1 hour, the reaction solution was filtered and washed with benzene to obtain (-)-(2R * · 3S *)-2,
2.68 g of 3-epoxy-3- (4-methoxyphenyl) propionic acid sodium salt was obtained. Yield: 88.4
%. mp: about 220 ° C. (decomposition). [Α] _D ²³ : -158
° (c = 0.697, acetone: water = 1.0: 1.0)

IR (KBr) cm ^-1 : 3040,300
5,2950,2900,2835,1605,151
0,1435,1415,1245,1020,89
0.830 ¹ H-NMR ((CD ₃ ) ₂ CO: D ₂ O = 1: 1; internal standard DSS) δ; 3.47 (d, 1H, J = 2 Hz, epoxy ring proton) 3.83 (s) _{, 3H, -OC H 3) 3.95} (d, 1H, J = 2Hz, epoxy ring protons) 6.96 (d, 2H, J = 8.6Hz, aromatic protons) 7.31 (d, 2H, J = 8.6Hz, aromatic proton)

[Reference Example 3] 2-chloropyridine 11.3
6 g (100.0 mmol) of dry dichloroethane 15
ml was added, and under heating under reflux, 12.61 g of dimethylsulfate was added.
A solution of (100.0 mmol) in 15 ml of dichloroethane is added dropwise. After heating under reflux for 1 hour, cool to room temperature and
A methyl-2-chloropyridinium methylsulfate solution was obtained. This was transferred to a volumetric flask and the volume was adjusted to exactly 100 ml using dichloromethane. It was used in the following examples without further purification.

[Example 1] (-)-(2R * / 3S *)
-2,3-Epoxy-3- (4-methoxyphenyl) propionic acid sodium salt [abbreviated as (-)-3 hereinafter]
2.59 g (12.0 mmol) of methylene chloride 12 m
1.3 l g of triethylamine (13.2
Mmol) and 13.2 ml of a methanol / methylene chloride solution (containing 1 mmol / ml of methanol), and the mixture is stirred well. 1-Methyl-obtained in Reference Example 3 at room temperature
13.2 ml of 2-chloropyridinium methylsulfate solution
(13.2 mmol) is added slowly. The reaction solution is stirred overnight at room temperature, the solvent is evaporated under reduced pressure, ethyl acetate is newly added, and the mixture is washed with water and saturated brine. After drying with Glauber's salt, the solvent was distilled off and the residue was distilled to obtain (-)-(2R *
3S *)-2,3-epoxy-3- (4-methoxyphenyl) propionic acid methyl ester (2.08 g) was obtained. Yield: 83.2%. bp: 99-101 ° C / 2.5
× 10 ^-1 torr. [Α] _D ²³ : -160 ° (c = 0.892, chloroform)

IR (neat) cm ^-1 : 3020, 29
60, 2920, 2840, 1760, 1615, 15
15, 1440, 1250, 1030, 835 ¹ H-NMR (CDCl ₃ ) δ: 3.50 (d, 1H, J = 2 Hz, epoxy ring proton) 3.80 and 3.81 (s × 2.6H, −) OC H ₃ and —CO ₂ C H ₃ ) 4.04 (d, 1H, J = 2 Hz, epoxy ring proton) 6.86 (d, 2H, J = 8.8 Hz, aromatic proton) 7.19 (d , 2H, J = 8.8Hz, aromatic proton)

[Example 2] 4.32 g (2) of (-)-3
Dimethylformamide (20 ml) and powdery sodium hydrogencarbonate (6.72 g, 80.0 mmol) are added to (0.0 mmol) and the mixture is stirred. Dimethyl sulfate 5.0
4 g (40.0 mmol) are added. After 16 hours, the reaction mixture is poured into 200 ml of ice water, extracted with ether and washed with water. The ether layer was dried over sodium sulfate and the solvent was distilled off, followed by (-)-(2R *, 3S *)-2,3-epoxy-3-.
2.45 g of (4-methoxyphenyl) propionic acid methyl ester was obtained. Yield: 58.9%. IR and ¹ H-N
The MR device data completely matched the data of Example 1. [Α] _D ²³ : −155 ° (c = 0.897, chloroform). bp: 107-113 ° C / 0.12 torr

[Example 3] 3.89 g (1) of (-)-3
8.0 mmol) in 30 ml of methylene chloride,
2.00 g (19.8 mmol) of triethylamine and 0.91 g (19.8 mmol) of ethanol are added rapidly and stirred well. At room temperature, 19.8 ml (19.8 mmol) of the 1-methyl-2-chloropyridinium methylsulfate solution obtained in Reference Example 3 was gradually added thereto. The reaction solution is stirred overnight at room temperature, the solvent is evaporated under reduced pressure, ethyl acetate is newly added, and the ethyl acetate layer is washed with water and then with saturated brine. After drying with mirabilite, the solvent was distilled off, and the residue was distilled to obtain (-)-(2R *, 3S *)-
3.33 g of 2,3-epoxy-3- (4-methoxyphenyl) propionic acid ethyl ester was obtained. Yield: 8
3.3%. bp: 110-111 ° C./2.5×10 ^-2 torr. [Α] _D ²³ : -152 ° (c = 1.10, chloroform)

IR (neat) cm ⁻¹ : 2990, 29
50, 2910, 2840, 1760, 1615, 15
15, 1440, 1300, 1250, 1200, 11
_{^{75,1030,835,780 1 H-NMR (CDCl 3}} ) δ; 1.32 (t, 3H, J = 7Hz, -OCH 2 C H 3) 3.48 (d, 1H, J = 2Hz, epoxy ring proton) 3.80 (s, 3H, -OC H 3) 4.03 (d, 1H, J = 2Hz, epoxy ring protons) 4.27 (q, 2H, J = 7Hz, -OC H 2 CH 3) 6.87 (d, 2H, J = 8.8Hz, aromatic proton) 7.21 (d, 2H, J = 8.8Hz, aromatic proton)

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] May 6, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] Full text

[Correction method] Change

[Correction content]

[Document name] Statement

Title of the invention Method for producing diltiazem hydrochloride

[Claims]

[Chemical 1] (In the above general formula, R represents an alkyl group having 1 to 4 carbon atoms.) (-)-(2R *, 3S *)
A method for producing diltiazem hydrochloride using 2,3-epoxy-3- (4-methoxyphenyl) propionic acid ester as a starting material without performing optical resolution during the process.

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing diltiazem hydrochloride.

[0002]

2. Description of the Related Art The following chemical formula (1)

[0003]

[Chemical 2] The benzothiazepine derivative (α-2- (p-
(Methoxyphenyl) -3-acetoxy-5- (β-methylaminoethyl) -2,3-dihydro-1.5-benzothiazepin-4 (5H) -one hydrochloride) has two asymmetric groups in the molecule. Since it has carbon, theoretically there are four types of optical isomers. Among these four types of optical isomers, only the (+)-(2S, 3S) isomer has already been found to have a medicinal effect as a strong coronary vasodilator. This (+)-(2S, 3S) form is known by the name of diltiazem hydrochloride.

A typical method for producing the benzothiazepine derivative of the above chemical formula (1) is, for example, Japanese Patent Publication No. 46-4.
The following method described in Japanese Patent No. 3785 is known. First, β− represented by the following general formula (2)
Phenylglycidic acid ester:

[0005]

[Chemical 3] (However, in the above general formula (2), R ¹ represents an ester residue) and 2-aminothiophenol represented by the following chemical formula (3):

[0006]

[Chemical 4] And are reacted by heating to give a 1,5-benzothiazepine derivative represented by the following chemical formula (3):

[0007]

[Chemical 5] Then, the 1,5-benzothiazepine derivative was converted to a fatty acid such as acetic acid or propionic acid represented by the following general formula (4):

[0008]

[Chemical 6] (However, in the above general formula (4), R ² represents an alkyl group) to undergo a condensation reaction to obtain 1, of the following chemical formula (5).
5-benzothiazepine derivative:

[0009]

[Chemical 7] And then using the 1,5-benzothiazepine derivative as an alkali metal salt at the 5-position nitrogen site,
An amine derivative represented by the following general formula (6):

[0010]

[Chemical 8] (However, in the general formula (6), R ³ and R ⁴ both represent an alkyl group, and X represents a halogen atom) to undergo a condensation reaction to give the desired benzothiazepine derivative of the chemical formula (1). obtain.

However, since the benzothiazepine derivative of the above chemical formula (1) is a mixture of four kinds of optical isomers as described above, it has a medicinal effect as a strong coronary vasodilator and is diltiazem hydrochloride. , That is, (+)-(2S, 3S)
In order to obtain the body, it is necessary to optically resolve the produced benzothiazepine derivative of the chemical formula (1). However, when the method of optically resolving this product is used, it results in wasting most of the products other than the desired optical isomer among the products manufactured through complicated manufacturing processes. Therefore, it is not advantageous as an industrial production method, and a suitable optical resolving agent for optically resolving the benzothiazepine derivative of the chemical formula (1) to obtain only the desired optical isomer with high purity has not been found. For this reason, methods other than optical resolution of this product have been investigated.

In Japanese Examined Patent Publication No. 53-18038, racemic α-2-hydroxy-3 obtained by reacting β-phenylglycidic acid ester represented by the above formula (2) with 2-nitrothiophenol. Optically active α-2-hydroxy-3-by optically resolving-(p-alkoxyphenyl) -3- (O-nitrophenylthio) -propionic acid.
(P-Alkoxyphenyl) -3- (O-nitrophenylthio) -propionic acid, which is reduced to give optically active α-2-hydroxy-3- (p-alkoxyphenyl)
-3- (O-aminophenylthio) -propionic acid was prepared, which was subjected to an intramolecular ring closure reaction to give an optically active α-2- (p
-Alkoxyphenyl) -3-hydroxythio-2,3-
Dihydro-1.5-benzothiazepin-4 (5H) -one was prepared by condensation reaction with ω-dialkylaminoalkyl halide in the presence of a condensing agent to give an optically active α-2-
(P-Alkoxyphenyl) -3-hydroxy-5-
(Ω-dialkylaminoalkyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one,
Then, this is reacted with a fatty acid acylating agent to give an optically active α-2- (p-alkoxyphenyl) -3-acyloxy-5- (ω-dialkylaminoalkyl) -2,3-
A method for obtaining dihydro-1.5-benzothiazepin-4 (5H) -one (diltiazem) is disclosed. This method involves reacting β-phenylglycidic acid ester with 2-nitrothiophenol to give racemic α-2-hydroxy-3- (p-alkoxyphenyl) -3- (O-nitrophenylthio) -propion. An acid is once produced, which is optically resolved into an optically active form, and then reduced to an optically active amino form, which is then subjected to a ring closure reaction, a condensation reaction, and an acylation reaction while maintaining the optical activity,
This is a production method for obtaining diltiazem which is an objective optically active substance.

[0013]

DISCLOSURE OF THE INVENTION The present invention provides a more advantageous production method as compared with various known production methods of diltiazem hydrochloride.

That is, the present inventor has made the above-mentioned Japanese Patent Publication No.
The intermediate having an optical activity corresponding to diltiazem hydrochloride is obtained at a step further ahead of the method for producing diltiazem hydrochloride described in Japanese Patent No. 18038, and using this as a starting material, a troublesome optical resolution operation is performed on the way. Based on the idea that a more advantageous production method can be developed as a production method of diltiazem hydrochloride if the desired diltiazem hydrochloride can be obtained, the optically active free (-)-(2R *, 3
S *)-2,3-epoxy-3- (4-methoxyphenyl) propionic acid was considered to be obtained, but since this compound is considered to be an unstable compound like its racemate, it was isolated. It has been concluded that it is very difficult to handle.

[0015]

For the above-mentioned reason, the present inventor has carried out optical resolution at the stage of 2,3-epoxy-3- (4-methoxyphenyl) propionate to obtain a stable optically active substance. Is obtained, which is esterified in the presence of dialkyl sulfuric acid or the like to obtain a novel optically active (−)-(2R *, 3S *)-2,3-epoxy-3-
It has been found that (4-methoxyphenyl) propionic acid ester can be stably obtained. Further, they have found that if this novel optically active compound is used as a starting material, diltiazem hydrochloride can be obtained without any particular optical resolution in the intermediate step.

Therefore, the present invention provides the general formula (7):

[0017]

[Chemical 9] (In the general formula (7), R represents an alkyl group having 1 to 4 carbon atoms.) (-)-(2R *, 3
It is a method for producing diltiazem hydrochloride using S *)-2,3-epoxy-3- (4-methoxyphenyl) propionic acid ester as a starting material without performing optical resolution on the way.

The above (-)-(2R *, 3S *)-2,
3-epoxy-3- (4-methoxyphenyl) propionic acid ester has the following formula (8).

[0019]

[Chemical 10] (In the above formula, A ⁺ represents a conjugate acid of an organic base or an alkali metal ion.) (−) − (2R *, 3
S *)-2,3-epoxy-3- (4-methoxyphenyl) propionate was added to a lower alcohol (alcohol having 1 to 4 carbon atoms) in the presence of dialkyl sulfuric acid or 1-methyl-2-halopyridinium salt. Can be obtained by esterification.

(-)-(2R of the general formula (7) of the present invention.
*, 3S *)-2,3-Epoxy-3- (4-methoxyphenyl) propionate (-)-(2R *, 3S *)-2,3-epoxy- which is the starting material for the production of 3- (4-methoxyphenyl) propionate is
Patent application of the same applicant as this case (Japanese Patent Application No. 59-26743)
No. 3), which is the title of the invention "Novel optically active epoxypropionic acid derivative and method for producing the same" (specific examples are described as reference examples in the present specification). Then, the obtained optically active propionate is subjected to esterification to give the optically active (-) compound of the present invention.
-(2R *, 3S *)-2,3-epoxy-3- (4-
Methoxyphenyl) propionic acid ester. For example, in the reaction for obtaining the methyl ester, sodium hydrogencarbonate may be added in a dimethylformamide solvent, and dimethyl sulfate and the propionate may be reacted for several hours. Alternatively, 1-methyl-2-chloropyridinium methylsulfate, triethylamine, and methanol may be used in equimolar amounts with respect to the propionate, and the reaction may be performed in dichloromethane.

The optically active (-)-(2R
*, 3S *)-2,3-epoxy-3- (4-methoxyphenyl) propionic acid ester is a known optically active intermediate in the synthesis of diltiazem hydrochloride while maintaining the optical activity by utilizing the following chemical reaction. Body (+)-
(2S, 3S) -3- (2-aminophenylthio) -2
-Hydroxy-3- (4-methoxyphenyl) propionic acid could be derived. Then, using this optically active intermediate, while maintaining the optical activity, Japanese Patent Publication No. 53-1803.
8 or the reaction described in JP-A-57-1365.
By carrying out the reaction described in JP-A-81, the desired diltiazem hydrochloride can be easily obtained.

[0022]

[Chemical 11]

[0023]

Examples [Reference Example 1] (±)-(2RS, 3S well ground in a mixed solvent of 108 ml of acetonitrile and 12 ml of water.
R) -2,3-Epoxy-3- (4-methoxyphenyl) propionic acid potassium salt 11.61 g (50.0 mmol) and (-)-(S) -α-methylbenzylamine.1 / 2 sulfate Add 8.51 g (50.0 mmol) and stir vigorously for 30 minutes at room temperature. The insoluble matter was filtered off, and the filtrate was cooled at -20 ° C for 2 hours to precipitate colorless needle crystals. This is filtered and (-)-(2R *, 3S *)
-2,3-Epoxy-3- (4-methoxyphenyl) propionic acid. (-)-(S) -α-methylbenzylamine salt [hereinafter abbreviated as (-)-1. (-)-2 salt. ]
Obtained 5.60 g. Yield [calculated with half of total salt as 100%, the same in the following examples. ]: 71.0%.
mp: 127.5-128.5 ° C (decomposition). [Α] _D ²³ : −120 ° (c = 1.02, methanol) Further, the insoluble matter filtered off previously was washed with methanol, and the washing liquid was concentrated to dryness under reduced pressure to give a solid obtained from acetonitrile. Washed and (-)-1. (-)-2 salt 0.60
g (7.6%) were obtained. The IR spectrum of this salt coincided with that of the above salt. mp: 126.5-127 ° C (decomposition). [Α] _D ²³ : -117 ° (c = 1.07, methanol)

IR (KBr) cm ^-1 : 3440,30
00-2950, 2700, 2520, 2200, 16
30, 1610, 1565, 1535, 1510, 14
_{^{10,1290,1250,880,765,700 1 H-NMR (CDCl 3}} / CD 3 OD = 6/1) δ: 1.62 (d, 3H, J = 7Hz, -CHC H 3) 3.35 ( d, 1H, J = 2Hz, epoxy ring protons) 3.73 (d, IH, J = 2Hz, epoxy ring _{protons) 3.80 (s, 3H, -OC} H 3) 4.36 (q, 1H, J _{= 7Hz, -C H CH 3)} 6.8-7.2 (m, 4H, aromatic protons) 7.2-7.5 (m, 5H, aromatic protons)

Reference Example 2 4.41 g (14.0 mmol) of (-)-1. (-)-2 salt was added to dry benzene 14
It is suspended in ml and a solution of 0.80 g of 95% sodium methoxide in dry methanol (14 ml) is gradually added thereto at room temperature. After stirring at room temperature for 1 hour, the reaction solution was filtered and washed with benzene to obtain (-)-(2R * · 3S *)-2,
2.68 g of 3-epoxy-3- (4-methoxyphenyl) propionic acid sodium salt was obtained. Yield: 88.4
%. mp: about 220 ° C. (decomposition). [Α] _D ²³ : -15
8 ° (c = 0.697, acetone: water = 1.0: 1.
0)

IR (KBr) cm ^-1 : 3040, 30
05, 2950, 2900, 2835, 1605, 15
10, 1435, 1415, 1245, 1020, 89
0.830 ¹ H-NMR ((CD ₃ ) ₂ CO: D ₂ O = 1: 1; internal standard DSS) δ; 3.47 (d, 1H, J = 2 Hz, epoxy ring proton) 3.83 (s _{, 3H, -OC H 3) 3.95} (d, 1H, J = 2Hz, epoxy ring protons) 6.96 (d, 2H, J = 8.6Hz, aromatic protons) 7.31 (d, 2H, J = 8.6Hz, aromatic proton)

[Reference Example 3] 2-chloropyridine 11.3
6 g (100.0 mmol) of dry dichloroethane 15
ml was added, and under heating under reflux, 12.61 g of dimethylsulfate was added.
A solution of (100.0 mmol) in 15 ml of dichloroethane is added dropwise. After heating under reflux for 1 hour, cool to room temperature and
A methyl-2-chloropyridinium methylsulfate solution was obtained. This was transferred to a volumetric flask and the volume was adjusted to exactly 100 ml using dichloromethane. It was used in the following examples without further purification.

[Example 1] (-)-(2R * / 3S *)
2.59 g (12.0 mmol) of 2,2,3-epoxy-3- (4-methoxyphenyl) propionic acid sodium salt [abbreviated as (-)-3 below] was suspended in 12 ml of methylene chloride. Later, triethylamine 1.34
g (13.2 mmol) and methanol / methylene chloride solution (containing 1 mmol / ml of methanol) 13.2 m
Add 1 and stir well. At room temperature, 13.2 ml (13.2 mmol) of the 1-methyl-2-chloropyridinium methylsulfate solution obtained in Reference Example 3 was gradually added. The reaction mixture is stirred overnight at room temperature, the solvent is evaporated under reduced pressure, ethyl acetate is newly added, and the mixture is washed successively with water and saturated brine. After drying over anhydrous sodium sulfate,
The solvent was distilled off and the residue was distilled to give (-)-(2R * .3
2.08 g of S *)-2,3-epoxy-3- (4-methoxyphenyl) propionic acid methyl ester was obtained. Yield: 83.2%. bp: 99-101 ° C./2.5×10
^-1 torr. [Α] _D ²³ : −160 ° (c = 0.89)
2, chloroform).

IR (neat) cm ^-1 : 3020,2
960, 2920, 2840, 1760, 1615, 1
515, 1440, 1250, 1030, 835 ¹ H-NMR (CDCl) δ: 3.50 (d, 1H, J = 2 Hz, epoxy ring proton) 3.80 and 3.81 (s × 2.6H, -OC). H ₃ and _{-CO 2 C H 3) 4.04 (} d, IH, J = 2Hz, epoxy ring protons) 6.86 (d, 2H, J = 8.8Hz, aromatic protons) 7.19 (d, 2H, J = 8.8Hz, aromatic proton)

[Example 2] 4.32 g (2) of (-)-3
Dimethylformamide (20 ml) and powdery sodium hydrogencarbonate (6.72 g, 80.0 mmol) are added to (0.0 mmol) and the mixture is stirred. Dimethyl sulfate 5.0
4 g (40.0 mmol) are added. After 16 hours, the reaction mixture is poured into 200 ml of ice water, extracted with ether and washed with water. The ether layer is dried over sodium sulfate and the solvent is distilled off to give (-)-(2R *, 3S *)-2,3-epoxy-3-.
2.45 g of (4-methoxyphenyl) propionic acid methyl ester was obtained. Yield: 58.9%. IR and ¹ H-N
The MR data were completely in agreement with the data of Example 1.
[Α] _D ²³ : −155 ° (c = 0.897, chloroform). bp: 107-113 ° C / 0.12 torr.

[Example 3] 3.89 g (1) of (-)-3
8.0 mmol) in 30 ml of methylene chloride,
2.00 g (19.8 mmol) of triethylamine and 0.91 g (19.8 mmol) of ethanol are added rapidly and stirred well. To this, at room temperature, 19.8 ml (19.8 mmol) of the 1-methyl-2-chloropyridinium methylsulfate solution obtained in Reference Example 3 was gradually added. The reaction solution is stirred overnight at room temperature, the solvent is evaporated under reduced pressure, ethyl acetate is newly added, and the ethyl acetate layer is washed with water and then with saturated brine. After drying with mirabilite, the solvent was distilled off, and the residue was distilled to obtain (-)-(2R *, 3S *)-
3.33 g of 2,3-epoxy-3- (4-methoxyphenyl) propionic acid ethyl ester was obtained. Yield: 8
3.3%. bp: 110-111 ° C./2.5×10 ⁻²
Thor. [Α] _D ²³ : −152 ° (c = 1.10, chloroform).

IR (neat) cm ^-1 : 2990,2
950, 2910, 2840, 1760, 1615, 1
515, 1440, 1300, 1250, 1200, 1
_{^{175,1030,835,780 1 H-NMR (CDCl 3}} ) δ; 1.32 (t, 3H, J = 7Hz, -OCH 2 C H 3) 3.48 (d, 1H, J = 2Hz, epoxy ring _{proton) 3.80 (s, 3H, -OC} H 3) 4.03 (d, 1H, J = 2Hz, epoxy ring protons) 4.27 (q, 2H, J = 7Hz, -OC H 2 CH 3) 6.87 (d, 2H, J = 8.8Hz, aromatic proton) 7.21 (d, 2H, J = 8.8Hz, aromatic proton)

Example 4 2.69 g (21.5 mmol) of 2-aminothiophenol and (-)-(2R *, 3S *)-2,3-epoxy-3-under a nitrogen atmosphere.
4.48 g (21.5 mmol) of (4-methoxyphenyl) propionic acid methyl ester was dissolved in toluene,
Heat to reflux for 10 hours. After cooling, the solvent was distilled off under reduced pressure, the residue was recrystallized with 70% ethanol and (+)-
(2R *, 3R *)-3- (2-aminophenylthio)
2-hydroxy-3- (4-methoxyphenyl) propionic acid methyl ester 5, 15 g was obtained. Yield 71.
8%. mp: 109-112 ° C. [Α] _D ²³ : +10
2 ° (c = 0.536, chloroform).

IR (KBr) cm ⁻¹ : 3530, 34
40, 3350, 3060, 2960, 2840, 17
30, 1610, 1505, 1290, 1245, 11
_{^{80,1090,1020,745 1 H-NMR (CDCl 3}} ) δ; 3.56 (s, 3H, -CO 2 C H 3) 3.78 (s, 3H, -OC H 3) 4.0~4 .4 (br, s, 3H, -N H 2 and -O
H , disappears when heavy water is added) 4.49 (s, 2H,> C = C <) 6.4 to 7.4 (m, 8H, aromatic proton)

[Embodiment 5] (+)-(2R *, 3R *)
-3- (2-aminophenylthio) -2-hydroxy-
To 333 mg (1.0 mmol) of methyl 3- (4-methoxyphenyl) propionic acid, 2.0 ml of a 1N aqueous sodium hydroxide solution was added, 5 ml of water and 1 ml of methanol were added, and the mixture was stirred at 50 ° C for 30 minutes. After cooling, 2.0 ml of 1N hydrochloric acid is added and left overnight. The precipitated crystals were filtered, washed well with water, and then (+)-(2
278 mg of S, 3S) -3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid was obtained. Yield 87.1%. mp: 138-1
39 ° C. [Α] _D ²³ : + 346 ° (c = 0.355,
ethanol).

[Embodiment 6] (+)-(2S, 3S) -3
-(2-Aminophenylthio) -2-hydroxy-3-
(4-methoxyphenyl) propionic acid (ie, d
-Α-2-hydroxy-3- (p-methoxyphenyl)
-3- (O-aminophenylthio) -propionic acid)
100 ml of xylene is added to 5.8 g, and the mixture is refluxed for 12 hours while removing water. After the reflux was completed, xylene was distilled off and the residue was recrystallized from ethanol to give a melting point of 196-
198 ° C, [α] _D ²⁴ : + 129 ° (c = 0.48)
6, ethanol) d-α-2- (p-methoxyphenyl) -3-hydroxy-2 / 3-dihydro-1.5-benzothiazepin-4 (5H) -one with a yield of 4.5 g. can get.

[Example 7] 64% sodium hydride 1.
Add 07 g to 77 ml of dimethyl sulfoxide, and add 70 ° C.
Heat and stir for 1 hour. D-α-2 was added to the obtained reaction solution.
-(P-Methoxyphenyl) -3-hydroxy-2.3
-Dihydro-1.5-benzothiazepine-4 (5H)-
Add 7.8g on at room temperature. 1 at 25-26 ℃
After stirring for an hour, 3.06 g of β-dimethylaminoethyl chloride is added dropwise, and the mixture is stirred overnight at room temperature. Then, after heating at about 45 ° C. for 30 minutes, the reaction solution is added to ice water and extracted with benzene. The benzene layer is extracted with 10% hydrochloric acid, the hydrochloric acid layer is made alkaline with sodium hydroxide, and extracted again with benzene. After the benzene extract was dried, the solvent was distilled off to give d-α-2- (p-methoxyphenyl) -3-hydroxy-5- (β-dimethylaminoethyl) -2,3-dihydro-1.5. -Benzothiazepine-
8 g of 4 (5H) -one are obtained as an oil. 170 ml of acetic anhydride is added to the above oily substance, heated in a water bath for 4 hours, and then acetic anhydride is distilled off under reduced pressure. The residue is dissolved in benzene, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried and then benzene is distilled off. The residue is dissolved in ether, hydrochloric acid / methanol is added, and the precipitated hydrochloride crystals are collected by filtration. This crystal was recrystallized from ethanol to give [α] _D ²⁷ : + 96.6 ° (c = 0.61, methanol), d-α-2- (p-methoxyphenyl).
-3-acetoxy-5- (β-dimethylaminoethyl)
-2.3-Dihydro-1.5-benzothiazepine-4
7.76 g of (5H) -one hydrochloride ((+)-(2S, 3S) form, that is, the target diltiazem hydrochloride) is obtained.

Claims (1)

[Claims] 1. A general formula: (In the above general formula, R represents an alkyl group having 1 to 4 carbon atoms.) (-)-(2R *, 3S *)
A method for producing diltiazem hydrochloride using 2,3-epoxy-3- (4-methoxyphenyl) propionic acid ester as a starting material without performing optical resolution during the process.