JPH107668A - Production of optically active glycidic ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently and safely obtain the subject ester useful as an intermediate for synthesizing e.g. diltiazem by reaction of a specific compound with an aldol condensation reagent and a specific compound followed by epoxidation. SOLUTION: (A) A compound of formula I (R1 is H, an alkyl, alkoxy or halogen; R2 is an alkyl or alkoxy; X is a halogen) is reacted with an aldol condensation reagent and (B) a compound of formula II (R3 is H, an alkyl, alkoxy or halogen) in a hydrocarbon-based solvent (e.g. dichloromethane) to form a compound of formula III, which, in turn, is epoxidized to obtain the objective glycidic ester of formula IV (R4 is an alkyl). By this method, the objective compound with desired optical activity can be obtained. Using the objective compound, a (+)-cis type 1,5-benzothiazepine derivative having vasodilative activity can be obtained.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to diltiazem (Diltiazem).
The present invention relates to a method for producing an optically active 3- (p-methoxyphenyl) glycidic acid ester, which is a useful synthetic intermediate of a (+)-cis 1,5-benzothiazepine derivative having a vasodilating action represented by zem). .

[0002]

2. Description of the Related Art A general method for producing diltiazem (V), which is a 1,5-benzothiazepine derivative of the (+)-cis type, includes, for example, the following reaction formula:

Embedded image Are known (Pharmaceutical Magazine, 19
1988, 108, 716). According to this synthetic route, o-nitrothiophenol (VI) and (-)-3
After the addition reaction with-(p-methoxyphenyl) glycidic acid methyl ester (VII), the nitro group of the obtained threo-type intermediate is reduced, and the methyl ester is hydrolyzed.
The desired diltiazem (V) is obtained through cyclization, N-alkylation and acetylation. Compounds having two asymmetric carbons in the molecule, such as compound (V), can theoretically have four types of optical isomers. In the case of compound (V),
Since it has been revealed that only the (+)-cis form has a strong pharmaceutical effect, in order to efficiently produce the desired (+)-cis type 1,5-benzothiazepine derivative (V),
Optically active form (VII) is used as a starting material.

[0003] Thus, the development of an efficient method for producing the optically active compound (VII) is expected to lead to an improved method for producing a (+)-cis 1,5-benzothiazepine derivative more efficiently. Is done. As a method for producing compound (VII), an enzymatic method utilizing a biochemical reaction and a chemical synthesis method are already known. In chemical method synthesis, there are two methods, a further optical resolution method and an asymmetric synthesis method. It has been reported.
As a method for obtaining the optically active compound (VII) via optical resolution, an optically active amine is allowed to act on racemic 3- (p-methoxyphenyl) glycidic acid to perform optical resolution (44% yield), followed by esterification. (Japanese Unexamined Patent Publication No.
0-13775, JP-A-60-13776). Further, optical resolution is performed by reacting a mineral salt of an optically active organic amine with a racemic alkali metal salt of 3- (p-methoxyphenyl) glycidic acid (yield 71%), followed by esterification or racemic formation. 3- (p-methoxyphenyl) in the form
After adding an optically active organic amine to the alkali metal glycidate, the solution is optically separated by dropwise addition of hydrochloric acid (yield 8).
0%), and then a method of esterification is also known (Japanese Patent Publication No. 4-61867 and JP-A-2-17168).

[0004] However, the method using the optical division has the following problems. That is,
According to the method described in JP-A No. 0-13775, since 3- (p-methoxyphenyl) glycidic acid, which is generally known to be unstable, is isolated, the yield is remarkably reduced. It is. In addition, Japanese Patent Publication 4-6186
In the method described in 7, the mineral salt of the amine must be prepared, and furthermore, the operation is complicated, for example, the inorganic salt generated at the time of resolution must be crystallized after filtering off. on the other hand,
In the method of adding hydrochloric acid at the end described in JP-A-2-17168, especially when a large amount of reaction is carried out as an industrial method, a large amount of diluted acid is used for a long time in order to suppress the formation of decomposition products under strongly acidic conditions. It is necessary to add over time, which is also unsuitable for industrialization.

On the other hand, a method involving asymmetric synthesis involves a method involving a coupling reaction between a halogenoacetic acid ester and benzaldehyde in the presence of an optically active lithium amide compound and alkyllithium (Japanese Patent Laid-Open No. 1-268881), and 2-halogeno. Asymmetric reduction of 3-oxo-3-phenylpropionic acid derivative (JP-A-3-19086)
5) and the like are known. However, the methods involving these asymmetric syntheses have problems of reaction yield and optical yield, or cost problems that asymmetric sources are wasted, and are unsuitable for industrialization. Also, a method of subjecting an oxazolidinone derivative to a reaction with a condensation reagent and an aldehyde compound (Te
Although trahedron Letters, Vol. 28, No. 1, 39-42, 1987) is known, this method is not suitable as an industrial method because diethyl ether is used as a solvent.

In the enzymatic method, a method using an esterase (Japanese Patent Laid-Open No. Hei 4-228070) is known. However, this method also requires the use of a special apparatus, and it is difficult to perform post-treatment. There is a problem. As described above, in any of the conventional methods, the optically active compound (VII)
Leaves many problems for industrial production.

[0007]

Means for Solving the Problems The present inventor has calculated the formula (IV)
As a result of intensive studies aimed at an efficient and safe production method of the (-)-3- (p-methoxyphenyl) glycidic acid ester represented by the formula (I), the compound represented by the formula (I) was converted into a hydrocarbon solvent Wherein the aldol condensation reagent and the formula (II)
The compound represented by formula (III) was reacted with the compound represented by formula (III), and was further epoxidized to successfully lead to an optically active compound (IV), thereby completing the present invention.

That is, the present invention provides a compound of the formula (I):

Embedded image Wherein R ₁ is hydrogen, alkyl, alkoxy or halogen; R ₂ is alkyl or alkoxy; X is halogen) in a hydrocarbon solvent in an aldol condensation reagent and a compound of formula (II):

Embedded image Wherein R ₃ is hydrogen, alkyl, alkoxy or halogen, reacting with a compound of formula (III):

Embedded image Wherein R ₁ , R ₂ , R ₃ and X are as defined above, and then epoxidizing the compound;

Embedded image (Wherein R ₄ represents alkyl, and R ₃ has the same meaning as described above).

As used herein, "alkyl" refers to straight or branched C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, n-pentyl, n-
It means hexyl and the like, and particularly preferably C1-C3 alkyl.

"Alkoxy" means a straight or branched C1-C6 alkoxy, such as methoxy,
Ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-
Examples include pentyloxy, n-hexyloxy and the like.
"Halogen" means fluorine, chlorine, bromine or iodine.

The present invention provides a compound represented by the formula (I):
The glycidic acid ester represented by the formula (IV) is produced by reacting an aldol condensation reagent and a compound represented by the formula (II) in a hydrocarbon solvent in the presence of a base, followed by epoxidation. The optically active oxazolidinone derivative (I), which is a starting material of the present invention, is a known compound, for example, J. Am. Chem. Soc. 1981, 103, 2127-21.
It can be produced according to the method described in 29. Examples of the base used when condensing the aldehyde derivative (II) with the compound (I) include triethylamine, N, N-diisopropyl-N-ethylamine, pyridine and the like. Examples of the aldol condensation reagent include n-dibutylboron triflate, zinc chloride, and tin (II) triflate. Examples of the hydrocarbon solvent include dichloromethane, toluene, hexane, a mixed solvent of toluene and hexane, and a mixed solvent of dichloromethane and hexane. The compound (I) is reacted with 1 to 5 equivalents, preferably 1.3 to 2 equivalents, and 1 to 2 equivalents, preferably 1 to 1.5 equivalents of an aldol condensation reagent. The reaction is carried out at a temperature of -78 ° C to 20 ° C. Preferably, it is −20 ° C. The formula (II) used in the present invention
Specific examples of the compound represented by include p-methoxybenzaldehyde, p-ethoxybenzaldehyde, p-methylbenzaldehyde, p-chlorobenzaldehyde and the like. Epoxidation is performed in an alcoholic solvent in the presence of a base. Examples of the alcohol solvent include methanol and ethanol. Examples of the base include sodium methoxide, sodium ethoxide, potassium methoxide, potassium butoxide and the like.

The method of the present invention will be specifically described with reference to the following examples. Reference Example 1

Embedded image (4R, 5S)-(+)-4-Methyl-5-phenyl-
Dissolve 10.5 ml (1.1 equivalents) of ethyl 2-oxazolidone (1) chloroformate in 20 ml of toluene, and dissolve (1S, 2R)-(+)-norephedrine 15.12 g (100 mmol), triethylamine 15.3 ml (1. 1 equivalent) in toluene 120
It was added over 10 minutes to the solution dissolved in ml. After stirring the reaction mixture for 30 minutes, water was added and extracted with toluene. The organic layer was washed successively with water, dilute hydrochloric acid, sodium carbonate-water and water, then dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain 22.03 g of a ethoxycarbonyl compound crystal residue.
(98.7%). Ethoxycarbonyl compound 21.3
6 g (95.7 mmol) was dissolved in 210 ml of toluene, cooled to −20 ° C., and potassium tert-butoxide 1 was added.
2.88 g (1.2 eq) were added. The reaction mixture was stirred at the same temperature for 1 hour and ice-cooled for 1 hour, diluted with water, the organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystal residue was recrystallized from 120 ml of toluene and 60 ml of hexane to obtain 15.2 g of Compound (1) (yield: 89.6%). 124-125 ° C (pillar) [α] _D ²⁴ = + 164.7 ° (c 1.96, CHCl ₃ ) [Lit. (Aldrich pp. 869 1992-1993) mp 121-123 ° C;
[α] _D ²⁵ = + 170 ° (c 2, CHCl ₃ )] IR (Nujol): 3260, 3160 (sh), 1758, 1715, 1500 cm ^-1 NMR (CDCl ₃ ): δ 0.82 (d, J = 6.4Hz, 3H), 4.21 (m, 1H)
5.4 (bs, 1H), 5.72 (d, J = 8.0 Hz, 1H), 7.25-7.4 (m,
5H)

Example 1 (4R, 5S)-(+)-3-chloroacetyl-4-me
Cyl-5-phenyl-2-oxazolidinone (2) 49.61 g of the compound (1) obtained in Reference Example 1 (280 mm
ol) is dissolved in 450 ml of anhydrous tetrahydrofuran,
After cooling to −65 ° C., 166 ml (1.07 equivalent) of a 1.8 M n-butyllithium / hexane solution was added dropwise for 15 minutes. After stirring at the same temperature for 15 minutes, 25.4 ml (1.1 equivalents) of chloroacetyl chloride was dissolved in 50 ml of anhydrous tetrahydrofuran, and added at the same temperature over 30 minutes. The reaction mixture was stirred at -65 ° C for 45 minutes and under ice-cooling for 20 minutes, and then added with water and dry ice, and extracted with dichloromethane. The organic layer was washed with water, sodium carbonate-water and water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was chromatographed on silica gel (500 g) with dichloromethane-hexane (1: 1), and the oily compound (2) showing a single spot in thin layer chromatography was 63.98.
g (90.1% yield). A part was recrystallized after crystallization from ether-hexane. Melting point 62.5-63 ° C (prism crystal) Elemental analysis (%) C ₁₂ H ₁₂ NO ₃ Cl Calculated: C, 56.82; H, 4.77; N, 5.52; Cl, 13.97 Found: C, 56.76; H , 4.80; N, 5.70; Cl, 13.88 IR (Nujol): 1780, 1611, 1498 cm ^-1 NMR (CDCl ₃ ): δ 0.95 (d, J = 6.8 Hz, 3H), 4.77 (s, 2
H), 4.81 (six, J = 6.8 and 7.4Hz, 1H), 5.76 (d, J = 7.
4Hz, 1H), 7.25-7.5 (m, 5H) [α] _D ²⁴ = + 25.3 ° (c 1.016, CHCl ₃ )

(4R, 5S, 2R ′, 3S ′) — (—)
-3- (2'Chloro-3'-hydroxy-3'-
(4 "-methoxyphenyl) -1-oxopropyl-
4-methyl-5-phenyl-2-oxazolidinone
(3) 10.16 g (40 mmol) of the compound (2) obtained above
l), 8.63 ml of triethylamine (1.55 equivalent)
Is dissolved in 180 ml of toluene-hexane (1: 2),
Cool to −22 ° C., add 1 M n-dibutyl boron triflate, 50 ml of dichloromethane solution (1.25 equivalents) to 1
It was dropped for 2 minutes. After the pale yellow reaction solution was stirred at room temperature for 1 hour, it was cooled again to -20 to -23 ° C, 7.08 g (1.3 equivalents) of p-anisaldehyde was added for 10 minutes, and the mixture was stirred at the same temperature for 1.5 hours. After 0.5 hour under ice cooling, methanol 50m
1, 80 ml of a 0.2 M pH 7 phosphate buffer solution was added.
Five minutes later, 40 ml of 30% aqueous hydrogen peroxide was added under ice cooling.
After vigorously stirring the reaction mixture for 30 minutes, the precipitated crystals were collected by filtration, washed with water, and dried to obtain 9.27 g of compound (3) (yield: 59.4%). 135-137 ° C. [α] _D ²⁴ = −39.8 ° (c 1.016, CHCl ₃ ) The filtrate consisting of two layers is separated and the organic layer is separated into water, 10% sodium bisulfite (three times), sodium carbonate, water And dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained oil was chromatographed on silica gel (70 g) using hexane-acetone (5: 1 to 4: 1), and the residue was recrystallized from toluene-hexane. 5.5%). A portion was further recrystallized from acetone-hexane. Mp 138-139 ° C. (HashiraAkira) Elemental analysis _{(%) C 20 H 20 NO} 5 Cl Calculated: C, 61.62; H, 5.17 ; N, 3.59; Cl, 9.09 Found: C, 61.64; H, 5.16 ; N, 3.59; Cl, 8.86 [α] _D ²² = −39.4 ° (c 1.020, CHCl ₃ ) IR (Nujol): 3460, 1794, 1788 (sh), 1718, 1613 158
9, 1510 cm ^-1 NMR (CDCl ₃ ): δ 0.88 (d, J = 6.6 Hz, 3H), 3.81 (s, 3
H), 4.54 (quint, J = 7.0Hz, 1H), 5.14 (d, J = 6.8Hz, 1
H), 5.32 (d, J = 7.2Hz, 1H), 5.96 (d, J = 6.8Hz, 1H),
6.92 (d, J = 9.0Hz, 2H), 7.22 (m, 2H), 7.4 (m, 5H)
[α] _D ²² = −39.4 ° (c 1.020, CHCl ₃ )

Methyl (2R, 3S)-(-)-3-
(4-methoxyphenyl) glycidate (4 ) 1.330 g (3.41 mmol) of the compound (3) obtained above.
l) was suspended in 6 ml of methanol, and 16.5 ml of a methanol solution of 0.5 M sodium methylate (2.4 ml) was added under ice-cooling.
Equivalent). After stirring at the same temperature for 1.5 hours, dry ice and ice were added, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 10 ml of diisopropyl ether, the seed nucleus of compound (1) was added, and the mixture was allowed to stand. The precipitated crystals were filtered to give 498 mg of compound (1) (yield: 82.4).
%; Melting point 124-125 ° C). After the mother liquor was distilled off under reduced pressure, the residue was recrystallized from 2 ml of t-butyl alcohol to obtain 567 mg (yield: 79.9%) of glycidate. Melting point 88-89 ° C. [α] ₅₇₈ ²⁴ = −211.8 ° (c 0.501, CH ₃ OH) [(JP-A-2-17168) Melting point 89.2 ° C .;
₅₇₈ ²² = −212.2 ° (c 0.504, CH ₃ OH)] The NMR spectrum was consistent with that of the standard.

[0016]

Industrial Applicability The present invention provides a method for efficiently and safely producing an optically active compound (IV), and can contribute to the production and development of pharmaceuticals such as diltiazem.

Claims (1)

[Claims] 1. A compound of formula (I): Wherein R ₁ is hydrogen, alkyl, alkoxy or halogen; R ₂ is alkyl or alkoxy; X is halogen) in a hydrocarbon solvent in an aldol condensation reagent and a compound of formula (II): ] Wherein R ₃ is hydrogen, alkyl, alkoxy or halogen, reacting with a compound of formula (III): Wherein R ₁ , R ₂ , R ₃ and X have the same meanings as described above, and then the compound is epoxidized. (Wherein R ₄ represents alkyl, and R ₃ has the same meaning as described above).