JPS61145159A - Novel optically active propionic acid ester derivative and preparation thereof - Google Patents

Abstract

NEW MATERIAL:(+)-(2R*,3R*)-3-(2-aminophenylthio)-2-hydrox-y-3-(4-met-hoxy- phenyl)propionic acid ester of formula I (R is 1-4C lower alkyl). USE:An intermediate of diltiazem hydrochloride useful as a coronary vasodilator. PREPARATION:The compound of formula I can be prepared by reacting (-)-(2 R*,3R*)-2,3-epoxy-3-(4-methoxyphenyl)propi-onic acid ester of formula II with 2-aminothiophenol in a solvent (e.g. toluene) at 100-140 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an optically active propionic acid ester 1! It concerns conductors. More specifically, a novel ←)- represented by the general formula 1 (where R represents a lower alkyl group having 1 to 4 carbon atoms) is important as an intermediate raw material for diltiazem hydrochloride, a coronary vasodilator that is useful as a pharmaceutical. (2R", aR") -3-
(2-aminophenylthio)-2-hydroxy-3-(
The present invention relates to a 4-1 t+diphenyl)propionic acid ester and a method for producing the same.

Since the compound (1) represented by the following formula has two asymmetric carbon atoms in the molecule, it theoretically exists in four types of optical isomers. Among these, ←)
Only the -(2s,38) form has strong medicinal efficacy and is known as diltiazem hydrochloride.

Therefore, when synthesizing diltiazem hydrochloride, it is necessary to use some method in the synthesis intermediate or the final compound.
A method for inducing the desired optical isomer, such as optical resolution, is required. Conventionally, optical resolution of intermediates has been carried out in various ways.
-136581 and JP-A-58-32872.

These methods use (t)-(2R8,3SR) as the starting material.
It is thought that -2,3-epoxy-3-(4-methoxyphenyl)furopionic acids, that is, racemic forms, are used, and are optically resolved in a later step to derive the desired optical isomer. In a manufacturing method that uses a method called optical resolution,
If one of the enantiomers is unnecessary and cannot be recovered due to racemization or the like, at least half of the enantiomer will be wasted, so it is advantageous to use the optically active form at an early stage when asymmetric carbon is generated.

As a result of extensive studies, the present inventors have discovered that a new important intermediate can be created by using optically active epoxypropionate esters in the initial step of synthesizing diltiazem hydrochloride and allowing 2-aminothiophenol to act on the optically active epoxypropionic esters. (→−(2
R", 3R")-3-(2-aminophenylthio)-2
-Hydroxy-3-(4-methoxyphenyl)furopionic acid ester (I) was successfully induced.

The present invention will be explained in further detail.

(-)-(2R", 3S") -2,3 represented by the general formula (-)-(2R", 3S") -2,3 in which R represents a lower alkyl group having 1 to 4 carbon atoms
-Epoxy-3-(4-methoxyphenyl)furopionate ester is produced according to the title of the invention entitled "Novel optically active epoxypropionate ester derivative and method for producing the same" related to a patent application filed on the same date by the same applicant as the present case.

Compound (I) can be obtained by reacting Compound (Goods) and 2-aminothiophenol in a solvent at 100 to 140°C. For example, in toluene under a nitrogen atmosphere, the desired ←)-(2
R", 3R")-3-(2-aminophenylthio)-2
-Hydroxy-3-(4-methoxyphenyl)propionic acid ester (I) 75f i Rare. ■ is a known compound that is an important intermediate of diltiazem polyhydrochloride by hydrolysis, i.e. ←)-l'2s, 3S)-3-
(2-aminophenylthio)-2-hydroxy-3-(
It was possible to derive 4-methoxyphenyl)propionic acid (2).

(g)-(2R8,38R)-2,3 well ground in a medium
-Epoxy-3-(4-methoxyphenyl)furopionic acid potassium salt t 1.61 F! (so, ommo
g) and ←)-(S)-α-methylbenzylamine・
'/2 Add 8.519 (50.0 mmol) of sulfate and stir vigorously at room temperature for 30 minutes.

Insoluble matter was filtered off and the filtrate was cooled at -20°C for 2 hours. Colorless needle crystals were precipitated, which were filtered and (→-(2R")
, 3S”)-2,3-epoxy-3-(4-methoxyphenyl)flopionic acid ←)-(S)-α-methylbenzylamine salt [hereinafter abbreviated as ←)-saki・←)-misioic acid )
5.609 was obtained. Yield (calculated with half of the gold salt as 100%, the same applies hereinafter) 71.0%. mp127.5-128
．． 5℃ (axe M-) 1,000-H x 10 times ζ-1200 (C1,02, methanol) Also, a solid obtained by washing the previously filtered insoluble matter with methanol and concentrating the washing liquid to dryness under reduced pressure. Wash with acetonitrile and add ←)-↓・←)-and salt 0.60 &('7
．． 6%). The IR of this salt matched that of the above fence. m
p126.5-127°G (min M-) (d), ”-1
17°(C1,07,Meta)-R”)IR(KBr)
c*.

3.440.3000~2950.2700.252n
, 2200°1630 , 1G10.1565.153
5.1510.1410°1290.1250. 88
0. 765. 700” HNMR (CD (J/CD
OD= 6/1) δ: 1.62 (d, 3H, J=
7Hz, -CHCH,)3.35(d,IH,J=
2Hz, x boxy ring proton) 3.73 (d, IH, J
= 2Hz, x boxy ring proton) 3.80 (S, 3H
, -QC,) 4.36 (q, IH, J=7Hz, -CIjCH,
) 6.8-7.2 (m, 4H, aromatic proton) 7.2
-7.5 (m, 5H, aromatic proton) Reference example 2゜←)-1・←)-2 salt 4.419 (14,0 mmol
) was suspended in 14 m of dry benzene, and at room temperature,
A solution of 0.809% of sodium methoxide in dry methanol (14111) is slowly added. After stirring at room temperature for 1 hour, the reaction solution was filtered and washed with benzene (→-(2R
2.68 g of sodium salt of ",3s")-2,3-epoxy-3-(4-methoxyphenyl)propionate were obtained. Yield 88.4%, mp approx. 220°C (decomposition) U”-t
sso(C0,697, acetone:water=1.O:1.
0) IR(KBr)cllL.

3040.3005, 2950, 2900, 2835,
1605°1510.1435,1415,1245,
1020. 890゜"H'MMR ((■3)2CO:
D20=1=1; internal standard DSS) δ; 3.47 (d
r I H, J==2 Hz, epoxy ring proton)3j33 (s, 3H, -0CH3)3.95(
d, IH, J=2Hz, x boxy ring proton) 6.96
(d, 2H, J=8.6Hz, aromatic proton) 7.31 (d, 2H, J=8.6Hz, aromatic 7'
o) 7) Reference example 3゜2-chloropyridine 11.36g (100.0mmo
15 ml of dry dichloroethane was added to J), and 12.61 g (100.0 mmol) of dimethyl sulfate was added under heating under reflux.
15 m/solution of dioxtan was added dropwise. After heating under reflux for 1 hour, the mixture was cooled to room temperature to obtain a 1-methyl-2-chloropyridinium methyl sulfate solution. Transfer this to a volumetric flask and add exactly 100% using dichloromethane.
4゜←)-(2R", 3S")-2,3-epoxy-3-
(4-methoxyphenyl)propionate sodium salt C
Hereinafter abbreviated as (-)-3) 2.51 (12, □mm
ol) in methylene chloride 12a/l, triethylamine 1.349 (13,2 mm0l) and methanol-methylene chloride solution (methylene chloride/l/1 mmol)
Add 13.21 (containing l/rnl) and stir well. To this was added 13.2 ml of the 1-methyl-2-chloropyridinium methyl sulfate solution obtained in Reference Example 3 at room temperature.
mol) gradually.

After stirring the reaction solution overnight at room temperature, the solvent was distilled off under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline water.

After drying with Glauber's salt, the solvent was distilled off and the residue was distilled to give ←)-(2R
8,38”) -2,3-epoxy-3-(4-methoxyphenyl)propionic acid methyl ester 2. Os
& got. Yield 832 bp 99-101°G/
2,5 X 10-” Torr @J23-1600 (
CO, 892, chloroform) IR(neat) tx.

3020.2960, 2920, 2840.176Q,
1615°1515.1440,1250,1030.
835'HNMR (CDCl 3) δ; 3.50 (d, tH, J = 2Hz, epoxy ring proton) 3.80 and 3.81 (sX2 r 6Hr-
OCH3and-Co2CH3)4, Q4(d, IH
, J=2Hz, -c baud + cy ring proton)6.86 (
d, 2H, J=8.8Hz, aromatic proton)7
．． 19 (d, 2H, J=13.8Hz, aromatic proton) Reference example 5゜←) -a 4.32g (20.0mmol) of dimethylformamide 20d and powdered sodium hydrogen carbonate 6.722 (80.0mmol) ) and stir 6.
To this, dimethyl sulfur Ml 5.04 f (40,0 m
Add rmA). After 16 hours, the reaction mixture was poured into ice water for 20 hours.
0-, extracted with ether, and washed with water. After drying the ether layer with Glauber's salt and distilling off the solvent, (c)-(2R", 3S
”)-2,3-epoxy-3-(4-methoxy7!nyl)propionic acid methyl ester 2.45?f was obtained. Yield 58.9%, IR and 1H NMR instrument data were as described in Reference Example 4. and completely iL*. (a), 7-155° (C
0,897, chlorophor A) bp 107-113
℃ / 0.12 Torr Example atmosphere 2-aminothiophenol 2.69t
(21,5mmoz) and H-(2R", 3S")
-2,3-epoxy-3-(4-methoxyphenyl)furopionic acid methyl ester 4.48 f (21,5
mmoz) in 21.5 mm of toluene and heated under reflux for 10 hours.

After cooling, the solvent was distilled off under reduced pressure and the residue was recrystallized from 70% ethanol.
Aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionic acid methyl ester 5.1
I got 5f. Yield 71.8%, mp109-112℃
(<, ”+xo2° (C01536, Chloroform) IR (KBr ) aR.

3530.3440, 3350.3060.2960,
2840.

1730.1610, 1505, 1290, 1245,
1180°1090.1020. 745 1HNMR (CD(J3)δ; 3.56 (S, 3H, -Co2OH3) 3.78
(8,3H,-0CH3) 4.0~4.4 (brs p 3Hy-NH2and
-OH, disappears by adding heavy water) 4.49 (S, 2H, =CH-c!!: )6.
4-7.4 ("mt8Hj aromatic 7'o) 7)
Reference example 6゜

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (+)-(2R^*, 3R^*)- (in the formula, R represents a lower alkyl group having 1 to 4 carbon atoms) 3-(2
-aminophenylthio)-2-hydroxy-3-(4-
methoxyphenyl)propionate ester. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (-)-(2R^*, 3S^*)- represented by (R in the formula represents a lower alkyl group having 1 to 4 carbon atoms) 2,3-
A general formula characterized by the action of 2-aminothiophenol on epoxy-3-(4-methoxyphenyl)propionate ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R has 1 to 4 carbon atoms) (+)-(2R^*,3R^*)-3-(2
-aminophenylthio)-2-hydroxy-3-(4-
Method for producing methoxyphenyl)propionate ester.