JPH03190865A - Production of optically active 3-phenylglycidic ester compound - Google Patents

Abstract

PURPOSE:To simply obtain in high efficiency the title compound useful as an intermediate for synthesizing medicines by selective asymmetric reduction of the ketone segment of a 2-halogeno-3-oxo-3-phenylpropionic acid derivative followed by intramolecular ring closure. CONSTITUTION:A compound of formula I (ring A is phenyl; R is lower alkyl; X is halogen) is put to asymmetric reduction with a metal hydride (e.g. boron lithium hydride) in a solvent such as THF in the presence of an optically active amino acid derivative (e.g. amino group-protected serine) and a lower aliphatic alcohol (e.g. isopropanol) to produce a 2-halogeno-3-hydroxy-3-phenylpropionic acid derivative of formula II. Thence, this compound is put to intramolecular ring closure at -10 to 50 deg.C in a solvent such as methanol in the presence of a base (e.g. sodium methoxide) to obtain the objective optically active trans-3- phenylglycidic ester of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel method for producing optically active trans-3-phenylglycidate ester compounds useful as pharmaceutical synthesis intermediates.

(Prior art) Trans-3-phenyl glycidate compounds (optically active) are important compounds as raw materials for the synthesis of diltiazem hydrochloride, which is useful as a coronary vasodilator, and various other pharmaceutical compounds. A method for producing (P-methoxyphenyl) glycidic acid or its alkali metal salt by optically resolving it with an optically active amine and then esterifying it (JP-A-61-145160. JP-A No. 61-145160.
775) is known. - (Problem to be Solved) The present invention aims to provide a new method for producing optically active 3-phenylglyzide acid ester compounds that is different from such known methods and is industrially advantageous.

(Means for Solving the Problems) According to the present invention, the general formula (however, a phenyl group which may have a substituent on the ring,
R represents a lower alkyl group. ) The optically active trans-3-phenylglyzide acid ester compound is a 2-halogen compound represented by the general formula (wherein the ring and R represent the same meanings as above, and X represents a halogen atom). -3-oxo-3-phenylpropionic acid derivative is asymmetrically reduced with a metal hydride in the presence of an optically active amino acid derivative and a lower aliphatic alcohol, and the general formula (however, rings A, R and X are It can be produced by preparing a 2-halogeno-3-hydroxy-3=phynylpropionic acid derivative represented by the following and then intramolecularly ring-closing this.

As an example of the object of the present invention, in general formula (1),
Examples include compounds in which ring A is a phenyl group which may have a substituent selected from a lower alkyl group, a lower alkoxy group, and a halogen atom, and compounds in which R is a linear or branched lower alkyl group, and more specific , ring A is a phenyl group, 4
-methylphenyl group, 4-methoxyphenyl group or 4-
Examples thereof include a chlorophenyl group, and compounds in which R is a methyl group, an ethyl group, an isopropyl group, a t-butyl group, and the like.

The asymmetric reduction reaction of the first step of the present invention is 2-halogeno-3
This can be carried out by reacting the -oxo-3-phenylpropionic acid derivative [11] with a metal hydride in the presence of an optically active amino acid derivative and a lower aliphatic alcohol in an appropriate solvent.

As the optically active amino acid derivative, serine, cysteine, cystine with a protected amino group, or derivatives thereof in which the carboxyl group is reduced to alcohol can be suitably used. As the protecting group for the amino group, commonly used ones may be used, such as benzoyl group, acetyl group, tosyl group, benzyloxycarbonyl group, L-butoxycarbonyl group, L-amyloxycarbonyl group, 2-nara1
-yl group, p-nitrocarbobenzoxy group, etc., and benzoyl group is particularly preferred. These optically active amino acid derivatives have a molecular weight of 1 to 5 with respect to starting compound (II).
It is preferable to use twice the mole, especially 2 to 3 times the mole.

Examples of lower aliphatic alcohols include those having 1 or more carbon atoms, such as methanol, ethanol, isopropanol, and L-butanol.
Among them, lower aliphatic alcohols having a branched group such as isopropanol and butanol can be preferably used. The amount of alcohol to be used is preferably 1 to 5 times the mole, particularly 1 to 2 times the mole of the starting compound (II).

Examples of the metal hydride include lithium borohydride, sodium borohydride, lithium aluminum hydride, and lithium borohydride is particularly preferred. The amount used is preferably 1 to 5 times the mole, particularly 3 to 4 times the mole of the starting compound (II).

Examples of the solvent include hydrocarbon solvents such as hexane,
Any inert solvent that does not participate in the reaction may be used, such as aromatic solvents such as benzene, toluene, and xylene, and ether solvents such as ethyl ether, tetrahydrofuran, dioxane, and diglyme, and these may be used alone or in appropriate mixtures. .

In this asymmetric reduction reaction, first, an optically active amino acid derivative and a lower aliphatic alcohol are dissolved in a solvent under an inert gas atmosphere such as nitrogen or argon, and a metal hydride is added.
(1st reaction) with heating if necessary, then 2nd reaction with cooling.
This reaction can be suitably carried out by adding a -halogeno-3-oxo-3-phenylpropionic acid derivative (second reaction). The first reaction is preferably carried out at room temperature to reflux temperature, the second reaction is carried out at -150 to 0 °C, especially at 10
Preferably, the temperature is 0 to -30°C.

The subsequent intramolecular ring-closing reaction of the 2-halogeno-3-hydroxy 3-phenylpropionic acid derivative (III) in the second step can be suitably carried out in a solvent in the presence of a base. As the solvent, lower alkanols such as methanol and ethanol can be suitably used. In addition, as the base, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and lithium methoxide can be suitably used, and the amount used is 2-halogeno-3-hydroxy-3-phenylpropionic acid derivative In(III). It is preferably about 0.8 to 1.2 times the molar amount. This reaction is carried out at 10°
C to 50° C1, particularly preferably at 0° C to room temperature.

In addition, 2-halogeno-3- which is a raw material compound for the method of the present invention
Oxo-3-phenylpropionic acid derivative (II) is
An acetophenone compound represented by the general formula (however, ring A has the same meaning as above) is reacted with di-lower alkyl carbonate in the presence of a base, and It can be produced by preparing a 3-oxo-3-phenylpropionic acid derivative represented by the following formula and then halogenating it.

(Example) (1) To a suspension of 1.614 g of N, N'-dibenzoyl=L-cystine, 357 μg of t-butanol, and 20 ml of tetrahydrofuran, 237 μg of lithium borohydride was added to 1 ml of tetrahydrofuran under an argon atmosphere.
6ml of the solution was added and the mixture was refluxed for 1 hour. Then, 728 μl of 2-chloro-3-oxo-3-(4-methoxyphenyl)propionic acid methyl ester in tetrahydrofuran 1
The solution was added at -65 to -70°C and stirred at the same temperature for 1 hour. After the reaction, 10% hydrochloric acid was added to the reaction solution for decomposition, and then 5% aqueous sodium hydrogen carbonate solution was added to adjust the pH to 9-10, followed by extraction with ethyl ether. After washing the extract with water and drying, the solvent was distilled off and the resulting yellow oily residue was purified by silica gel column chromatography (solvent: hexane: ethyl acetate = 3: 1) to obtain 2-chloro -3-hydroxy-3(4
660 mg of a mixture of threo (2R, 3S) and erythro (2S, 33) forms of -methoxyphenyl)propionate methyl ester was obtained as colorless crystals.

IR (liquid): 34B0.1750
．． 1610.1515°1250, 1175.1030
．． 830 cm-'NMRδ (CDCh): (threo body) 2.89 (III, d, 3.9 Hz
) 3.67 (311, s ), 3.80 (311,
s ) + 4.42 (III, d.

6.8 Hz), 5.08(ill, dd, 3.9
and 6.8 Hz).

6.89(21Ld, 8.81(z), 7.30(
2tl, d, 8.8] (z) (erythro body) 2.8
9 (ill, d, 4.611z), 3.80 (611
, s ), 4.35 (III, d, 8.1 ] (z )
, 5.00 (ill.

dd, 4.6 and 8.11(z), 6.91
(211,d,8.811z)+7.32(2H,d
, 8.8) fz ) (2) To a solution of the crystals obtained in (1) above dissolved in 16 m2 of methanol, a solution of 153 μm of sodium methoxide in 5 rnl of methanol was added at 0°C, and after stirring at the same temperature for 90 minutes. and stirred at room temperature for 10 minutes. Then, water was added to the reaction solution, and the mixture was extracted with ethyl ether. After washing the extract with saturated brine and drying, the solvent was distilled off. The resulting oily residue was purified by silica gel column chromatography (solvent: hexane:ethyl acetate = 3:1) to obtain 506 mg of (2R,3S)-3-(4-methoxyphenyl)glycid acid methyl ester. Obtained.

[α) =, -143,3' (C=0.30, methanol) (optical purity: 82%, from HPLC) IR (Nujol): 2920.1730.
1615.15201440, 1250 1030.8
40cmNMRδ (CDCl5): 3.50 (II
I, d, 1.811y, )3.80(3H,s )+
3.81 (3H, s), 4.04 (LH, d.

1.811z)+6.87(28,d, 9.01
1z), 7.20 (2H.

d, 9.011z) Mass (ET): 208 (M) Reference example (1-a) 30.7 g of sodium was added to 30 g of toluene
After heating to 93°C, the mixture was allowed to cool while stirring vigorously, and the sodium was formed into a sandwich. A solution of 300 g of dimethyl carbonate in 600 ml of toluene was added to this, and then a solution of 250 mEI of toluene containing 100 g of p-methoxyacetophenone was added at 84 to 86°C for 2 hours.
The dropwise addition took 5 minutes. 1.5 at 82-83℃ after dropping
After heating and stirring for an hour, the solvent was distilled off, isopropyl ether 11 was added to the residue, and the crystals were collected by filtration. Washed with. Add this crystal to 100% acetic acid.
The mixture was added to an ice-ethyl acetate mixture containing g and extracted with ethyl acetate.

The extract was washed with 5% sodium hydrogen carbonate, washed with water, dried, and the solvent was distilled off to give 3-oxo-3-(
4-Methoxyphenyl)propionic acid methyl ester 1
31.6 g were obtained as an oil.

Yield: 94.9% T R (liquid): 3625-3450.
1740.1665 cm-'NMRδ(CDCl3
): 3.74 (311, S ) + 3.87 (311,
S ) 1 2 3.95 (2H, s ), 6.94 (2+1.d,
9.2H7)+7.92(211,d, 9
．． 211z ) (1-b) Sodium hydride (6
0x oil suspension) 2.7g in tetrahydrofuran 25ml
5. Suspend in p-methoxyacetophenone.
Add 0g of dimethyl carbonate at 55°C.
g was added over 10 minutes. After refluxing for 6 hours, 3-oxo-3 was prepared in the same manner as in (1-a) below.
6.3 g of -(4-methoxyphenyl)propionic acid methyl ester were obtained as an oil.

Yield: 91.3% (2) 131 g of 3-oxo-3-(4methoxyphenyl)propionic acid methyl ester obtained in (1) above was converted to 1.37 g of carbon tetrachloride! Sulfuryl chloride 85
g was added dropwise at 45 to 50°C over 1 hour. After dripping,
After stirring at the same temperature for 1 hour, cooling, washing with water, and drying,
By distilling the oily residue obtained by distilling off the solvent under reduced pressure, 2-coro-3-oxo-3-(4-
methoxyphenyl)propionic acid methyl ester 140
I got g.

Yield: 92.1% b, p, 143.5-145°C 10.3 mmmm1
l R (liquid); 1750.1660
c+n-'NMRδ(CDCl3): 3.82(3
+1. S), 3.88 (3tl,s).

5.9D IILs), 6.96(2H,d, 9
．． 0tlz ) + 7.97 (2tl, d, 9.01
1z) (Effect of the invention) According to the method of the present invention, 2-halogeno-3-oxo-3-
Optically active trans-3-phenyl glycidate compounds can be efficiently produced by a simple reaction operation of selectively asymmetrically reducing the ketone moiety of a phenylpropionic acid derivative and then performing intramolecular ring closure.

3 4

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [II] (However, ring A is a phenyl group that may have a substituent,
R represents a lower alkyl group, and X represents a halogen atom. ) is asymmetrically reduced with a metal hydride in the presence of an optically active amino acid derivative and a lower aliphatic alcohol to obtain the general formula ▲ mathematical formula, chemical formula, There are tables, etc. ▼ [III] (However, rings A, R and X have the same meanings as above.) A 2-halogeno-3-hydroxy-3-phenylpropionic acid derivative is prepared, and then, The optically active trans- Method for producing 3-phenylglycidic acid ester compounds.