JPS58183669A - Method for producing optically active propionic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 and R2 are H or lower alkyl; X is halogen). EXAMPLE:(+)-Erythro-2-hydroxy-3-( p-methoxyphenyl )-3-( o-iodophenylthio )-propionic acid. USE:Raw material for the intermediate of pharmaceuticals. PROCESS:The compound of formula I can be prepared by reacting the racemic erythro-type compound of formula II [e.g. (+ or -)-erythro-2-hydroxy-3-(p-methoxyphenyl)-3-(o-iodophenylthio)propionic acid] with an optically active compound (e.g. cinchonidine) in a solvent such as tetrahydrofuran under refluxing, filtering the precipitated crystals, concentrating and cooling the filtrate to precipitate the crystals and to effect the optical resolution, and extracting with ether under acidic condition with hydrochloric acid.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a new optically active propionic acid derivative compound.

More specifically, formula (1) [wherein R1 and R2 are the same or different and represent a hydrogen atom, a lower alkyl group, or a halogen atom. ] Compounds represented by, especially optically active compounds IJ).

This invention relates to a method for producing type compounds.

The novel compounds provided by the present invention are used as critical intermediate raw materials for useful medical compounds.

The present invention will be explained in detail below.

The compound represented by formula (1) provided by the present invention is produced as follows. That is, formula (1) [where x
, R+ Id same as above]
An erythro-type compound is reacted with an optically active resolving reagent in a solvent, and the products are optically resolved using the difference in solubility. The resolving reagents used here include cinchonidine, cinchonine, quinine, quinidine, strychnine, brucine, etc., and the solvents used include tetrahydrofuran, dioxane, chloroform, dimethyl cellosolve, choleratoacetone, toluene, benzene, and methyl alcohol. Examples include mixed solvents with etc. The resolution is carried out by subjecting the racemic-erythro compound represented by formula l) to a heating dissolution reaction with the resolving reagent in a solvent, and then cooling, the solubility of the product reacted with the resolving reagent in the dextrorotatory form and the levorotatory form. Since there is a difference of 3-, this becomes possible by utilizing this difference. For example, when cinchonidine is used as a resolving reagent, the levorotatory form precipitates as crystals, and the dextrorotatory form remains dissolved in the solvent, so that both are separated.

Surprisingly, the fact that a compound with extremely high optical purity was obtained through only one splitting operation can be said to be an advantage of the present invention.

The optically active reaction products thus obtained (reaction products of the compound represented by the formula (fi) and the resolving reagent) include ethyl ether, isopropyl ether, benzene, toluene, and trifluorocarbons. , mix a solvent and water to form nine layers, suspend the reaction product therein, make it acidic with hydrochloric acid, sulfuric acid, etc., separate the organic layer, and extract the optically active formula (]) from the organic layer. The compound shown is obtained.

The thus obtained optically active compound represented by formula (j) is dissolved in an AR alcohol such as methyl alcohol, ethyl alcohol, flobyl alcohol, isopropyl alcohol, or methyl alcohol, and then mixed with sulfuric acid, hydrogen chloride, benzenesulfonic acid, and P. - When heated under reflux with toluenesulfonic acid, etc., optically active elimide in which R2 is a lower alkyl group in formula (1)
type compounds can be obtained.

1, if the optically resolved product of the reaction product of the compound represented by the formula (1) and the resolving reagent is heated under reflux with sulfuric acid or hydrogen chloride in a lower alcohol, the formula (1) can be obtained. An optically active eli)o-type compound in which R2 is a lower alkyl group can be obtained.

Incidentally, the new raw material compound of the present invention is synthesized according to Reference Examples.

The present invention will be described in more detail with reference to Examples. Example 1 (Th)-Erythro-2-hydroxy-3-(P-methoxyphenyl)-3-(0-iodophenylthio)-propion A mixture of acid 20y1, cinchonidine 14.1y-, and tetrahydrofuran 160 ml was heated under reflux for 1 hour. After the reaction mixture was cooled and stirred with ice water for 2.5 hours and 5 minutes, the precipitated crystals were collected and washed with 20 tnl of tetrahydrofuran to obtain white crystals. Prefix 18.04 yo This was recrystallized with methyl alcohol (→-erythro-2-hydroxy-3-(P-methoxyphenyl)-3-(0-iodophenylthio)-furopionic acid cinchonidine salt to obtain white needle-like crystals. Obtained.

Tatami volume 12.63y, yield 75.0%, m, P 203℃
+ IRm-': 3420, 3070 (OH), 2630 (
NN) 1605 (carpogysylate -COO->specific optical rotation [α] 8--137.4° (C=1.O chloroform) On the other hand, the tetrahydrofuran F solution from which the crystals were separated previously was concentrated and cooled. Precipitation The resulting crystals were separated to obtain white crystals.Preliminary 15.07y0 This was recrystallized from methyl alcohol to give U→-erythro-2-hydroxy-3-(P-methoxyphenyl)=3-(0-iodophenyl). --10
Cinchonidine pionate salt was obtained. Tatami amount 12.96y1 Yield 76.9%, m, P 196-198℃, I Rty
n-': 6-3380, 3070(OH), 2600-200
0 (old 1600 (carboxylate-COO-) specific optical rotation [α3o = -13,3° (C = 1.0 methanol) Example 2 (''→-erythro 2-hydroxy-3-(P-methoxyphenyl) -1-(0-iodophenylthio)-phropionic acid cinchonidine salt 2y was suspended in a mixture of ether and water and acidified with hydrochloric acid.The ether layer was separated, washed with water, dried and charged, and the ether was distilled off. 5 ml of benzene and 5 ml of hexane were added and the precipitated crystals were collected to give ←→-erythro-2-hydroxy-3-(P-methoxyphenyl)-3-(0-iodophenylthio)-furopionic acid. 1.11y, yield 93.3%, m, p 12
9-130℃, TLC (black o/L/mu:methy/
l/7/L/co/l/:acetic acid=20:2
: IV/V) Single spot, I Rcm-' :
3500 (OH), 3200-2000 (carboxylic acid OH), 1710 (carciboxylic acid C20), 1600
, 1515 (benzene ring), specific optical rotation [α] et al. 2 = +1
12.6° (C=1.0 methyla/l/v-/l/
), N M R,)S',',”: 3.74 (
31□, 8°0CHa), 4.56.4.74 (IH,
d, C2f(,]H1d,C3H), 6.0-7.9(
101(,m aromatic ring hydrogen Of(,C0OH) Example 3 Instead of the compound used in Example 2, The treatment was carried out in the same manner as in Example 2 using cinchonidine thio)-fropionate salt 2y.

White crystals of (→-erythro-2-hydroxy-3- ())-methoxyphenyl)-3-(0-iodophenylthio)-propionic acid were obtained. Tatami volume 1.14y, storage #9
5.8%, m, p129-130°C, TLC (chloroform: methyl alcohol: acetic acid = 20:2: IV/V)
Single spot TRrg': 3510 (OH), 3200
-2000 (carboxylic acid OH), 1710 (carboxylic acid c = 0), 1610.1515 (benzene ring), specific optical rotation [α) = -112,1° (C = 1.0. Methyl Al'
” ) , N M Rr￥上°°工 3.7 (3H,
S. . H3), 4.51.4.69 (LH, d, C
2-H, IH, d, Ca H), 6, O-7,9 (1
0H, m, aromatic ring OH, C00H) Example 4 (→-Erythro 2-hydroxy-3-(P-methoxyphenyl)-43-(0-iodophenylthio)-propionic acid cinchonidine salt 7.25y was dissolved in 40rnl of methyl alcohol. After adding 2.06y of sulfuric acid,
The mixture was heated to reflux for an hour.

The reaction mixture was concentrated under reduced pressure, and benzene and water were added to the residue. The benzene layer was separated, further washed with water, and diluted with m bicarbonate l-I.
After washing with an aqueous solution of Jumium, washing with water and drying, benzene was distilled off. Isopropyl ether was added to the residue, and the precipitated crystals were collected and recrystallized from isopropyl alcohol to give ((P-methoxyphenyl)-3-(0-iodophenylthio)-) Propionate methyl ester was obtained. Obtained fi3.709-y1 yield 83.3%, m, p 80 °C, TLC (
, chloroform:methanol:acetic acid=20:2:IV/
V) Single spot, I RcM-': 3540 (O
H), 1745 (ester c=o), 1610.15
15 (benzene ring), specific optical rotation [α]” -1108.
6°. . =1. . + l f /L/A/L/ v −
/l/ ), N M RJ” ”’”°.

TMS' 3.30 (II-I, d, OH), 3.55 (3H
, s , C00CH3), 3.70 (3H, S ,
0CH3), 4.3-4.8 (2H, m.

C2HXC3H), 6.5 to 7.9 (8H, aromatic ring hydrogen) Example 5 phenylthio)-propionic acid cinchonidine salt,
The same treatment was carried out in the same manner except that levorotatory form 20y of the same compound was used (→-erythro-2-hydroxy-3-(P-methoxyphenyl)-3-(0-iodophenylthio)-propionic acid methyl ester was obtained. .Weight 1.o, 44y1
Yield 85.1%, m, p 79.5-80 °C, TLC
10- (chloroform: methyl alcohol: acetic acid = 20:2:
IV/V) Single spot, IRl:1n-”:3540
(OH), 1740 (ester C=0), 1610°1
510 (benzene ring), specific rotation [α] = -107,8
°(C=1.0.Methyl alcohol) NMRf 0D”
': 3.30 (IH, d, OH), 3.55 (3H.

MS s, COOCH3), 3.70 (3H, S, 0
CH3), 4.3-4.8 (2H, m, C2H, C3
-H), 6.5-7.9 (8H aromatic ring hydrogen) Reference example 1 (a) P-methoxyphenylglycid acid methyl ester 4. Add to 6 ml of Ofl f acetonitrile,
Add 8 ml of 0-iodothiophenol 4-Oywo to this.
of acetonitrile.

Let it react for 4 days at room temperature, count the precipitated crystals, and (to) -
Erythro-2-hydroxy-3-(P-methoxyphenyl)-3-(0-iodophenylthio)-propionic acid methyl ester is 4. , tatami volume 4.8y1 yield 60.4
%, m, p 133-134 °C TLC (benzene: acetone-95:5 V/V) R (single spot at 0,43,
I Rcrn-': 3500 (OH), 1720 (xste/l/C:O), 1600. 1510 (benzene ring), 1240.1025 (methoxyC-0-C) (C:+)(t)-erythro-2-hydroxy-3-(
P-methoxyphenyl)-3-(0-iodophenylthio)-propionic acid methyl ester 5(1', 95% sodium hydroxide 5.71y, water 15o-, toluene 10
The mixed solution of 0- was stirred at 60 to 70°C for 1 hour. During heat,
After adding 28.31 nl of 6N hydrochloric acid, the mixture was cooled at room temperature and further cooled with ice water. The precipitated white crystals were washed several times with water and dried to give Yama-erythro-2-hydroxy-3-(P-methoxyphenyl)-3-(0-iodophenylthio)-
Propionic acid was obtained. Co-location 47.46y, yield 97.6
%, m, p 117-120°C, TLC (Chloroform: Methyl a/l/Nia-/L/: Acetic acid = 20:
2: IV/V) Single spot, IRcm-”:
3550 (OH), 3200-200o (carboxylic acid OH), 171° (carboxylic acid C-0), 1600.
1510 (Benzene ring) Applicant Teikoku Kagaku Sangyo Co., Ltd. 13- Procedural amendment (method) % formula % 1. Case description 1982 Patent Application No. 66125 2. Title of the invention Method for producing optically active propionic acid derivatives 3. Relationship with the case of the person making the amendment Patent Applicant Address: 1-18 Kitahorie, Nishi-ku, Osaka Representative Einosuke Nagase 4, Agent (43 Building River Center 6, 3-57 Kyobashi, Higashi-ku, Osaka) , Number of inventions increased by amendment - 7 amendments 0 subject specification', b There is no amendment to the typed printed specification.

Amendment to power of attorney procedure September 8, 1982 2 Title of the invention Process for producing optically active propionic acid derivatives 3 Person making the amendment Case “0 related Patent applicant 711 Kanao t #Shinishiki Kitanerie Address Nishi-ku, Osaka Kitahorie 1-1-18-4, Agent 7, Subject of amendment Contents of specification Q 〪ill: .1.1.-1-1゜1, Lines 9 and 10 of page 11 of the specification Insert the following between.

Example 6 75 g of (±)-erythro 2-hydroxy-3-(p-methoxyphenyl)-3-(o-bromphenylthio)-propionic acid, 59.43 g of cinchonidine.

A mixture of chloroform 338+al was heated under reflux for 1 hour. The reaction mixture was cooled and stirred in ice water for 3 hours, and then the precipitated crystals were collected by filtration and washed with 75 ml of chloroform to give (-)-erythro 2-hydroxy-3-(p-methoxyphenyl).
-3-(o-bromphenylthio)-propionic acid cinchonidine salt-roloform adduct 60.04 g (yield 7
6.9%) of white crystals were obtained.

If you recrystallize with methanol, chloroform will be released.)
-Erythro 2-hydroxy-3-(P-methoxyphenyl)-3-(o-bromphenylthio)-propionic acid cinchonidine salt 39.68 g (yield 59.7%) of white needle crystals were obtained.

m, p, 203.5-204.5℃ 8° 1lu--+ 1 +-man 1' as listed in 10TRcm-1: 3430, 3070 (OH), 265
0 (-NH).

1610 (Carboxylate-〇(I)-)-Concentrate the chloroform filtrate and add 385ml of methanol to the residue.
1. After adding 25.9 g of sulfuric acid, the mixture was heated under reflux for 5 hours. After the reaction mixture was stirred and cooled in ice water for 3 hours, the precipitated crystals were collected by filtration and washed with 50 ml of methanol to give (±)-erythro 2-hydroxy-3-(p-methoxyphenyl)-3-.
17.33 g of white crystals of (o-bromphenylthio)-propionic acid methyl ester were recovered. m, p, TL
ClIR and NMR were completely consistent with Reference Example 2 in the latter part.

The methanol filtrate was concentrated under reduced pressure, and benzene water was added to the residue to make a homogeneous solution. The benzene layer was separated, washed twice with water, washed with dilute aqueous sodium bicarbonate solution, washed with water and dried,
Benzene was distilled off to obtain 29.44 g of white crystals. Recrystallized from isopropyl alcohol +)-erythro 2-hydroxy-3-(p-methoxyphenyl)-3-
(o-bromphenylthio)-propionic acid methyl ester 26.35g (Yield 1-rate 67.7%, 87°0% if recovered ester is taken into account)
White needle-like crystals were obtained.

m, p, 84~5℃ 4 [α) = +132.7″ (c = 1.0 methanol) IRcm': 3500 (OH), 17
30 (ester C=O).

3,55 (3H,s, C(X)Ct13) 3.
70 (311, s, 0C113) 4.3-4.65
(m) 4.70(d) (]+I, C2-I+.

III, c3-tg Example 7 32.66 g of cinchonidine salt of (=)-erythro 2-hydroxy-3-(P-methoxyphenyl)-3-(o-bromphenylthio)-propionic acid was dissolved in methanol 18
After adding 9.89 g of sulfuric acid to the suspension, the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and benzene water was added to the residue to make a homogeneous solution. The benzene layer was separated, washed twice with water, washed with a dilute aqueous sodium bicarbonate solution, washed with water, dried, and distilled off the benzene to obtain 18.72 g of white crystals. Recrystallized from isopropyl alcohol =)-erythro 2-hydroxy-3-(P-methoxyphenyl)-
17.41 g (yield 91.3%) of 3-(0-bromphenylthio)-propionic acid methyl ester were obtained as white needles.

m, p, 84-85°C 4 [α] = -134,0° (c = 1.0 methanol) IRcm': 3500 (OH), 1.730
(Esteno 1c=0), 16103, 55 (311,
s, C00C) 13) 3.70 (3H.

s, 0CH3) 4.3-4.65(m) 4.7
0 (d) (Ill C2-H, IJI ca-H
) 2. Insert the following from line 3 on page 13.

Reference Example 2 (a) A mixture of 280 g of 0-bromthiophenol, 323.9 g of p-methoxyphenylglycidic acid methyl ester, and 280 ml of dry acetonitrile was heated to 66°C at 45°C.
Stir for hours. After cooling, the precipitated crystals were collected by filtration and washed with methanol to give (±)-erythro 2-hydroxy-3-(p-
methoxyphenyl)-3-(0-bromphenylthio)
-345.4 g of propionic acid methyl ester (yield: 5
8.7%) of white crystals were obtained.

m, p, 132-3°C IRcm-': 3500 (OH), 1.730
(ester), 1610 (4,64(m), 4.6
9 (d) (+, 1lC2-H, IHC3H) (b)
(±)-erythro 2-hydroxy-3-(P-methoxyphenyl)-3-(o-bromphenylthio)-propionic acid methyl ester 360 g, 95% sodium hydroxide 45.78 g, water 850 ml, toluene 580 ml
The mixture was stirred at around 70°C for 1 hour. 6N-H when hot
After adding 1.96+ nl of Cl, the mixture was stirred and cooled to room temperature, and then stirred for 1.5 hours while cooling with ice water. The precipitated crystals were collected by filtration, washed with water and dried to give (±)-erythro 2-hydroxy-
3-(p-methoxyphenyl)-3-(o-bromphenylthio)-propionic acid 339.7 g (yield 97.
8%).

4-m, p, 133-4℃ IRcm': 3550 (OH), 2625
(carboxylic acid OH).

1720 (Carbon Chen=O) 1605.1510
(Ben 5 - Procedural amendment (spontaneous) February 7, 1980 Commissioner of the Japan Patent Office1, Indication of the case Patent Application No. 66125 of 19822, Name of the invention Process for producing optically active propionic acid derivatives3, Relationship with the case of the person making the amendment Patent applicant address 1-1-18 Kitahorie, Nishi-ku, Osaka Name fbohana''+
ri Midori Shiki Company 4, Agent address: 3-57 Kyobashi, Higashi-ku, Osaka Building (1) Claims (2) Detailed description of the invention in the specification (typed print) (3) 1981 Procedural amendment dated September 8th 6. Contents of the Amendment As shown in the attached sheet 1, the scope of the claims is amended as follows.

"An optically active propionic acid derivative characterized in that an optically active erythro-type compound represented by the formula is obtained by treating the racemic-erythro type compound represented by the formula with an optically active compound and optically resolving it. manufacturing method.

(In the formula, R1 and R2 are the same or different and represent a hydrogen atom or a lower alkyl group, and X represents a halogen atom.)
Isamu 2, insert the following between lines 12 and 13 on page 5 of the specification.

``In addition, ``Erythro'' as used in the specification of this application
This is a representation for a compound having the structure shown below, following the Fisher projection method when determining the steric configuration of a compound.

(References Chem, Pharm, Bull, 18
．． 2284 (1970)) [In the formula, X represents a halogen atom, R1 represents a hydrogen atom or a lower alkyl group, and R2 represents a lower alkyloxy group or a hydroxyl group]
'-1 = 3, page 1, line 4 of the procedural amendment dated September 8, 1980, 1
Lines 0 and 15; page 2, lines 8 and 18; page 3, line 12; page 4, lines 1 and 20; Correct it to J.

that's all

Claims (1)

[Scope of Claims] An optical system characterized in that an optically active IJ)0 type compound represented by the formula is obtained by treating the racemic-erythro type compound represented by the formula with an optically active compound and performing optical resolution. Method for producing active propionic acid derivatives. [In the formula, R+, Rzl'j- and Rzl'j- each represent a hydrogen atom or a lower alkyl group, and X represents a halogen atom. ]