JPS61145160A - Production of optically active propionic acid derivative - Google Patents

Abstract

NEW MATERIAL:(+)-(2R*,3R*)-3-(2-aminophenylthio)-2-hydrox-y-3-(4-met-hoxy- phenyl)propionic acid derivative of formula I (R is H or 1-4C lower alkyl). USE:An intermediate of filtiazem hydrochloride useful as a coronary vasodilator. PREPARATION:The compound of formula I can be prepared according to the reaction formula, by (1) reacting the compound of formula III (M is alkali metal) with a mineral acid salt of an optically active organic amine, (2) decomposing the resultant diastereomer salt to the compound of formula IV (A1(+) is conjugated acid of organic base) taking advantage of the solubility difference in a solvent, (3) treating the compound with a base (e.g. alkali metal alkoxide, etc.), (4) esterifying the resultant compound of formula V (A2 is alkali metal) to the compound of formula VI, (5) reacting the compound of formula VI with 2-aminothiophenol, and if necessary, (6) hydrolyzing the product.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active propionic acid derivatives. In more detail, it is represented by the general formula (1), which is important as an intermediate raw material for diltiazem hydrochloride, a coronary vasodilator that is useful as a pharmaceutical. -(2R", 3R")
-3-(2-7minophenylthio)-2-hydroxy-
The present invention relates to a method for producing a 3-(4-methoxyphenyl)propionic acid derivative.

Since the compound (6) represented by the following formula has two asymmetric carbon atoms in the molecule, there are theoretically four types of optical isomers of Fi. Among these, (
Only the g)-(28,38) form has strong medicinal efficacy and is known as diltiazem hydrochloride. Therefore, it is necessary to induce the desired optical isomer in a synthetic intermediate or final compound by some method. Hitherto, various reports have been made regarding the synthesis of diltiazem hydrochloride, such as those described in Japanese Patent Publication No. 53-18038, Japanese Patent Application Publication No. 57-136581, and Japanese Patent Application Publication No. 58-32872. These methods use (t)-(2R8,3SR)-2,
It is thought that 3-epoxy-3-(4-methoxyphenyl)furopionic acids, that is, racemic forms, are used.
In a later step, optical resolution is performed to derive the desired optical isomer. In production methods that use optical resolution, if one of the enantiomers is unnecessary and cannot be recovered due to racemization, at least half of the enantiomer is wasted. It is more advantageous to use

As a result of intensive studies, the present inventors found that optically active ←) -(2R", 38"), which is a raw material for the synthesis of diltiazem hydrochloride.
After synthesizing -2,3-epoxy-3-(4-methoxyphenyl)propionate and esterifying it, 2-
It is an important intermediate that is industrially advantageous by reacting with aminothiophenol and optionally hydrolyzing it.
(2Rゝ,3R“)-3-(2-aminophenylthio)
-2-Hydroxy-3-(4-methoxyphenyl)propionic acid derivative (1) was successfully derived.

That is, according to the present invention, (G) represented by the general formula ■ (in the formula, MFi represents an alkali metal)
-(2R8,3SR) -2,3-epoxy-3-(4
-Methoxyphenyl)propionic acid is reacted with a mineral acid salt of an optically active organic amine, and the resulting diastereomeric salts are separated using their solubility in the solvent. ←)-(2R",38")-2,3-epoxy-3-(4-methoxyphenyl)propionate, which is represented by A1 organic ersu), and this is converted into an alkali metal alkoxy form or water. ←)-
(2R", 3s") -2,3-epoxy-3-(4-
methoxyphenyl)propionate, which is represented by the general formula (where R represents a lower alkyl group having 1 to 4 carbon atoms) -(2R", 3s") -2,3-epoxy-3-(4-methoxyphenyl)propionic acid ester and reacting it with 2-aminothiophenol,
(T)-(2R", 3R")-3 represented by (in the formula R, H"! represents a lower alkyl group having 1 to 4 carbon atoms) by hydrolysis if desired.
-(2-aminophenylthio)-2-hydroxy-3-
A (4-methoxyphenyl)propionic acid derivative is obtained.

This reaction can be diagrammed as shown below.

[IV V
The present invention will be explained in more detail.

The compound (■) used is its ester form (AnnyJ+11
0 (1953)) by reacting with an alkoxy form or hydroxide of an alkali metal such as lithium, sodium, or potassium in an alcoholic solvent such as methanol or ethanol).

Add to this an equimolar amount of an optically active organic amine mineral acid.
□ Allow the salt to react in a suitable solvent. Examples of optically active organic amines include α-methylbenzylamine and its analogs, 1-(1-naphthyl)ethylamine, 1-(2-naphthyl)ethylamine, ephedrine, and N-substituted ephethrin. Solvent F used in reaction
Examples include, but are not limited to, water, methanol, ethanol, 1-glopanol, 2-glopanol, 1-butanol, 2-butanol, acetone, methyl ethyl ketone, ethylene glycol, methyl cellosolve, ethyl cell. Solv, acetonitrile, dioxane, etc. may be used alone or in a suitable mixture thereof, and preferably a mixed solvent of acetonitrile-water, acetone-water, or methylcellosolve-water is used. The reaction temperature is not particularly limited, but is preferably 10° to 60°C, preferably 20 to 30°C. The reaction proceeds in several minutes to several hours, and after removing the formed inorganic salt by filtration, 1) rv is obtained by cooling the filtrate or drying the filtrate under reduced pressure and crystallizing it from a suitable solvent.The cooling temperature of the filtrate varies depending on the type of solvent, but is 5° to -30°C. ℃, preferably -1
The temperature is preferably 0 to -20°C. In addition, the solvent for crystallization is acetone, acetonitrile, dioxane, ethyl acetate, butyl acetate, methyl ethyl ketone, ethylene glycol,
Methyl cellosolve, ethyl cellosolve and the like may be used alone or in appropriate mixtures thereof.

Next, (1) is dissolved in a solvent such as water, methanol, or alcohol-containing benzene or toluene, and treated with an alkali metal alkoxy or hydroxide (#).
■ Get.

The obtained V is then subjected to esterification to form (2). This reaction may be carried out using a conventional esterification reaction, and a suitable esterifying agent may be used to form (2).

For example, in a reaction to obtain a methyl ester, dimethyl sulfate and V may be reacted for several hours in a dimethylformamide solvent by adding sodium hydrogen carbonate. Alternatively, V may be reacted with imole of 1-methyl-2-chloropyridinium methyl sulfate, triethylamine, and methanol in dichloromethane.

Next, mix ■ke■ and 2-aminothiophenol in a solvent, i
It is obtained by reacting at oo' to 140°C. For example, compound (I) can be obtained by heating and refluxing 2-aminothiophenol and (2) in toluene under a nitrogen atmosphere for several hours and hydrolyzing as desired.

Example 1゜(t)-(2R8,3SR)-2,3- well ground in a mixed solvent of 108M acetonitrile and 12mt of water
3-(4-methoxyphenyl)propionic acid potassium salt 11.619 (50, Ommol) 3 at room temperature.
Stir vigorously for 0 minutes. Insoluble matter was filtered off and the filtrate was diluted with -2 (
When cooled for 2 hours at No. 1, colorless needle crystals precipitate, which are filtered and treated with ←)-(2R",3S")-2,3-epoxy-3-(4-methoxyphenyl)furopionic acid. (
→−■−α-methylbenzylamine salt [hereinafter ←) −1・
←)-2 salt) 5.6ON was obtained. Yield [calculated assuming that half of the gold salt is 100 g, the same applies hereinafter] 71.0%.

mP127.5-128.5℃ (Nashian@knee x2o°
(C1,02, m/-l) In addition, the previously filtered insoluble matter was washed with methanol, the washing liquid was concentrated to dryness under reduced pressure, and the obtained solid was washed with acetonitrile ←)-1・←
)-2 salt 0.609 (7.6 t) was obtained. The IR of this salt matched the above. mP I26.5-127℃(/
kM-di-117 (C1,07, methanol) IR
+'KBr)α; 3440.3000~2950, 2700, 252
0,2200.

1630, 1610.1565.1535.1510.
1410°1290.1250. 880. 765.
700′HNMR (CDC et al./CD30D=%) δ;
1.62 (d, 3H, J=7Hz, -CHCH3)3.
35 (d, IH, J=2Hz, x boxy ring proton)
3.73 (d, IH, J = 2Hz, epoxy ring proton) 3.80 (g, 3H, -0CH3) 4.36 (
q, IH, J=7Hz, -C'1jCH3)6.
8-7.2 (rn, 4H, aromatic proton) 7.2-7
．． 5 (m15H1 aromatic proton) Example 2 Mixed bath of acetonitrile 43.2 me and water 4.8 tlXKj <milled L&l) - (2R8, aSR) -
2,3-epoxy-3-(4-methoxyphenyl)propionic acid potassium salt 4.65g (2o, ommol)
and ←)-(S)-α-methylbenzylamine bi
Add 3.401 (20, Ommol) of the acid salt and stir at room temperature.
Stir vigorously for 0 minutes. The reaction solution was cooled at -20°C overnight, and the precipitated solid was filtered. Acetonitrile 4.8
After washing with 1 nl, this solid is further washed with methanol, and the washed methanol solution is concentrated to dryness under reduced pressure. The dried solid was further diluted with 4.8 rRl of acetonitrile.
and washed with ←)-1/←)-2 salt L, 149 was obtained.

Yield 55.2%. mP 126.5-127°C (
Decomposition) times ζ-120° (C1,02, methanol) Example 3 (t)-(2R8,38R)-2,3-epoxy-3 well ground in a mixed solvent of 18d acetone and 2ml of water
-(4-methoxyphenyl)furopionic acid potassium salt 1
．． 09 (4,3 mmol) and 0.73 g (4,
3 mm0A') and stir vigorously for 40 minutes at room temperature. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain beef oil-like crystals. Add 6M of ethyl acetate to this, leave it to stand, and collect the precipitated crystals by filtration to obtain ←)-1 and ←)-2 salt 02491
I got it. Yield 72.0%, mP 122-123°C (decomposition) rm knee x 1° (CO, 322, m/-l) Example 4° Thoroughly ground in a mixed solvent of Methyl Cellsolve 200d and water 5QR1 (T) -(2R8,3SR) -2,3
-Epoxy-3-(4-methoxyphenyl)propionic acid potassium salt 11.69 (50, Ommol) and ←) -■-α-methylbenzylamine・”/2 sulfate 8.50 g (50, Qmmol/) and stirred at 40°C for 15 minutes.The reaction solution was concentrated under reduced pressure, and methanol 80#I7 was added thereto, and the precipitated solid was separated by filtration.The methanol solution was concentrated under reduced pressure, and 50 mt of ethyl acetate was added to the residue, and the mixture was allowed to stand. Filter the precipitated crystals, ←)-1・←)
-2 salt 3. 'Obtained 70g. Yield 47.2%, mp12
1-12 members-Episode 4: -107° (C0,337,) evening/-ru) Sen 14dK! ! ! Let it become cloudy and stir it at room temperature for 95 minutes.
Slowly add a dry methanol solution of sodium methoxide (141111). After stirring at room temperature for 1 hour, the reaction solution was filtered and washed with benzene.
-(2R”.

3S")-2,3-epoxy-3-(4-methoxyphenyl)propionic acid sodium salt 2.68.!i' was obtained.

Yield 88.4%, mp approx. 220°C (decomposition) decomposition ÷ (ro) 158° (CO, 697, acetone:water = 1.0
:1.0) IR(KBr)tx-”; 3040, 3005, 2950, 2900, 2
835, 1605.

1510.1435.1415.1245.1020.
890"HNMR ((CD3) 2Co:D20=1
: 1; internal standard DSS) δ; 3.47 (d, IH1J = 2Hz, epoxy ring proton) 3.83 (3,3, -0CH3) 3.95 (dllHIJ = 2Hz + j-bo + cy ring proton) 6 .96 (d, 2H, J=+3.6Hz,
aromatic proton) 7.31 (d, 2H, J = 8.6Hz
, aromatic proton) Reference example 1゜2-rioo viridi 711.36 & (100,0mm
od) to dry dichloroethane 151R1! was added and heated under a stream of dimethyl sulfate (10o, ommo
d) dikuoo ethane 15. d solution 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. This was transferred to a volumetric flask and dichloromethane was used to make it exactly 100-. This was used in the following examples without further purification.

Example 6゜←)～(2R", 3S")-2,3-epoxy-3-(
4-methoxyphenyl)propionate sodium salt (hereinafter abbreviated as ←)-mi) 2.59 g (12,Qmmo
71.349 (13.2 mm 0 l) and a methanol-methylene chloride solution (add 1 ml of methanol and stir well. Tokutoku 1
-Methyl-2-chloropyridinium Methyl sulfate solution 1 3.2 ml (1 3.2 mmoz) is gradually added. After stirring the reaction solution overnight at room temperature, the solvent was distilled off under reduced pressure.
Add ethyl acetate to the solution, and wash with water and saturated brine. After drying with Glauber's salt, the solvent was distilled off and the residue was distilled ←)-(
2R″,3S″)-2.3-epoxy-3-(4-methoxyphenyl)propionic acid methyl ester2. 0
Got 8 F. Yield 8 3. 2%, bp 99-
101°C / 2.5X10 Torr @1D
-160.

(C0.892, chloroform) Ding R (neat) α.

3020, 29 (30, 2920, 2840.1760
1615, 1515, 1440, 1250, 1030.
835'H NMR (CDC13) δ; 3,
50 (d, IH, J==2Hz, epoxy ring proton) 3, 80 and 3.81 (s X 2
+ 6 H, C) CT(3 nnd CO2 0I
3) 4, 04 (d, iH, J = = 2Hz, epoxy ring proton) 6, 8 6 (d, 2H, J = 8
．． 8) Iz, aromatic proton) 7,19 (d,
2H, J==8.8 Hz, aromatic proton)
Example 7.

(to) - 4.3 2 1 (2 0.0 mmoz)
20 rrlt of dimethylformamide and powdered sodium bicarbonate 6,7 2 9 (8 0.0 mm
oz) and stir it [dimethyl 5.0
Add 4 fl (40.0 mmot). 16
After an hour, the reaction mixture is poured into 200 ml of ice water, extracted with ether and washed with water. After drying the ether layer with Glauber's salt and distilling off the solvent, (to)-(2R'', 3S'')-2.3-
Epoxy-3-(4-methoxyphenyl)propionic acid methyl ester 2.452 was obtained, yield 58.9%, IR
, 1H NMR instrument data completely matched that of Example 6. [αKo 3-155 (C 0.897.

rioo form), hp107 ~ 113℃/0.12
Torr ritual practice.

(to) - 3.89t (18.0mmoz)
Suspend in 30 mt of methylene chloride, quickly add triethylamine 2.00 F (19.8 mmoz) and ethanol 0.915' (19.8 m mo L), and stir well. To this, 19.8 rr+z (19.8 mrnoz) of the l-methyl-2-chloropyridinium methyl sulfate solution obtained in Reference Example 1 was gradually added at room temperature. After stirring the reaction solution overnight at room temperature, the solvent was distilled off under reduced pressure, new ethyl acetate was added, and the ethyl acetate layer was continuously washed with saturated brine. After drying with Glauber's salt, the solvent was distilled off and the residue was distilled to give ←)-(2R'', 3S'')-2
, 3.33 g of 3-epoxy-3-(4-methoxyphenyl)furopionic acid ethyl ester was obtained. Yield 83
．． 3%, bpH0-111'C/2.5X10-2To
rr (-dJ”3-152°(C1,10, rio
o form) I R(neat) cat.

2990.2950, 2910, 2840.1760,
1615°1515.1440,1300,1250,
1200,1175°1030.835,780'HNMR(CDCl3)δ; 1.32 (t, 3H, J=7Hz, -0CR
20H,) 3.48 (drIH, J: 2Hz, x boxy ring proton) 3.80 (s, 3H, -0CH3)
4.03 (d, IHJ=2Hz, x boxy ring proton)
4.27 (q, 2H, J=7Hz, -00 (2 parts,)6
．． 87 (d, 2H, J=8.8Hz, aromatic proton) 7.21 (d, 2H, J=8.8Hz, aromatic proton) Example 9° Under nitrogen atmosphere 2-aminothiophenol 2.69'
i (21,5 mmol) and ←)-(2R”, 3S
”) -2゜3-epoxy-3-(4-methoxyphenyl)propionic acid methyl ester 4.48J9 (21,
5 mmol) was dissolved in toluene 21.5 RA', and 10
Heat to reflux for an hour. After cooling, the solvent was distilled off under reduced pressure, and the residue was recrystallized from 70% ethanol ←)-(2R", 3R"
) -3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propionic acid methyl ester 5.159 was obtained. Yield 71.8%, mp
109-112℃ @:, 3+ 102°(C・
0.536. Chloroform ) IR (KBr) tx
; 3530, 3440, 3350, 3060, 2
960, 2840.

1730.1610, 1505, 1290, 1245,
1180゜1090, 1020, 745'' HNMR (CDC/3) δ; 3.56 (S, 3H, -Co2CH3) 3.78
(S, 3H, -0CH3)4.0~4.4 (b
r S + 3H, -NH2and -OH, disappeared by adding heavy water) 4.49 (S, 2H, -cH-ca) 6.4-7.
4 (m, BH, Yoshi8M1) o ) N) Reference example 2
゜

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, M indicates an alkali metal) (±) −
The alkali metal salt of (2RS,3SR)-2,3-epoxy-3-(4-methoxyphenyl)propionic acid is reacted with a mineral acid salt of an optically active organic amine, and the resulting diastereomeric salt is oxidized into a solvent. By separating using solubility, there are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. *) -2,3-epoxy-3-(4-methoxyphenyl)propionate, which is treated with a base, gives the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A_2 represents an alkali metal. ) is represented by (−
)-(2R^*,3S^*)-2,3-epoxy-3-
(4-methoxyphenyl)propionate,
This is subjected to esterification and is expressed by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a lower alkyl group having 1 to 4 carbon atoms) 3S^*)-2,3-
The general formula is characterized by epoxy-3-(4-methoxyphenyl)propionic acid ester, which is reacted with 2-aminothiophenol and hydrolyzed as desired▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Formula R represents H or a lower alkyl group having 1 to 4 carbon atoms) (+)-(2R^*, 3R^*)-
3-(2-aminophenylthio)-2-hydroxy-3
- A method for producing a (4-methoxyphenyl)propionic acid derivative.