JPS61260059A - Production of d-isomer of propionic acid derivative - Google Patents

Abstract

PURPOSE:To obtain a compound useful as a synthetic intermediate for coronary vasodilators in good yield, by carrying out the optical resolution of dl-isomer of a propionic acid derivative using an optically active benzylamine compound as a resolving agent. CONSTITUTION:The dl-isomer of a compound expressed by formula I (A is aryl which may be substituted by lower alkoxy; R<1> is lower alkyl) is reacted with an optically active benzylamine compound expressed by formula II (R<2> is lower alkyl; Y is phenyl which may be substituted), particularly the l-isomer to form two kinds of diastereomer salts, and the aimed substance is obtained. The compound expressed by formula II is used in an amount of 1-1.1 equivalents based on the compound expressed by formula I and isopropyl ether, etc., may be used as a solvent.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention provides d-cis-5-(
2-(dimethylamino)ethyl)-2,3-dihydro-
General formula useful as a synthetic intermediate such as 2-(4-methoxyphenyl)-1゜5-benzothiazepin-4(5H)-one (wherein A represents allyl which may be substituted with lower alkoxy) , R1 represents lower alkyl) [Compound (■)]

[Conventional technology]

Compound (1) is d-cis-5-(2-(dimethylamino)ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5H)-
It is a compound useful as a synthetic intermediate for the compound [compound (■)] represented by the general formula (in the formula, R3 and R4 each represent lower alkyl, and A and R1 have the same meanings as above), including [Japanese Patent Publication No. 58-29779, Patent Application No. 60-65197 (Sawai Pharmaceutical Co., Ltd.)] Among these compounds (Iff), the d-isomer thereof has particularly excellent coronary vasodilatory action (Japanese Patent Publication No. 1982-2977- No. 18038).

On the other hand, as a method for producing compound (I), the method represented by the following formula is generally used, but optical resolution at the stage of compound (1) is not yet known.

1 Cyclization [α) l' 239.20°↓ N-alkylation (α)! ' : 110.03 '↓ [α) I' : 97.03 ” (wherein A and R1 have the same meanings as above) [Problems to be solved by the invention] The purpose of this study is to industrially split the 46-isomer to produce the d-isomer of compound (r).

[Means for solving problems]

After conducting various studies to solve these problems, we discovered that the d-form of compound (1) can be efficiently obtained by using the optically active form of compound (I[) as an optical resolution agent. As a result, the present invention was completed.

That is, the present invention converts 411 compounds of compound (1) into compound (n)
The present invention relates to a method for producing the d-form of compound (1), which is characterized by optically resolving the optically active form of compound (1) as a resolving agent.

In this specification, examples of lower alkyl include those having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, 1so-propyl, n-butyl, and t-butyl.

In addition, examples of lower alkoxy include methoxy, ethoxy,
n-propoxy, 1so-propoxy, n-butoxy,
Examples include those having 1 to 4 carbon atoms such as t-butoxy.

Furthermore, phenyl is exemplified as allyl.

Regarding the general formula (If), examples of the substituent on the optionally substituted phenyl represented by Y include lower alkyl.

In the present invention, a desired optical isomer is obtained by reacting 61 forms of compound (1) with an optically active form of compound (11), especially one form, to generate two types of diastereomer salts. It is carried out by

In the above reaction, the optically active form of compound (II) is preferably used in an amount of 1 to 1.1 equivalents relative to compound (1). Examples of the solvent include isopropyl ether. If the obtained diastereomeric salt is collected by filtration or the like and recrystallized from a mixed solvent of isopropanol and isopropyl ether, an optically pure compound can be obtained when two forms of compound (II) are used. A monosalt of compound (If) in the d form of (1) can be obtained.

The salt thus obtained is decomposed by a conventional method, for example, with a mineral acid (hydrochloric acid, sulfuric acid, etc.) to obtain the d-isomer of the desired compound (-■).

On the other hand, from the easily soluble diastereomeric salt contained in the mother liquor from which the poorly soluble diastereomeric salt is separated, one compound (1) can be recovered by adding a mineral acid to the mother liquor for decomposition.

[Action/Effect]

The compound (U) used in the production method of the present invention is one that can efficiently optically resolve the dj form of the compound (R), and the production method of the present invention can industrially and efficiently produce compound (1). The d-body of is obtained.

, thus obtained compound (1)
The six compounds are useful as intermediates for the d-isomer synthesis of compound (III), which has excellent activity as a coronary vasodilator.

〔Example〕

Next, an example will be given and explained.

Example 1: Synthesis of d-threo-2-acetoxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)-propionic acid.

(11 At room temperature, dl-threo-2-acetoxy-3-(
2-aminophenylthio)-3-(4-methoxyphenyl)-propionic acid [hereinafter abbreviated as compound (1)] 1.
55 g (4,29ms+ol) was dissolved in dry isopropyl ether 80- and dry ethanol 4- (any insoluble matter was removed by filtration), and added to this solution under the same conditions!
-α-methylbenzylamine 0.593d (4,5m
mol) of dry isopropyl ether (1d) was added dropwise, and after a solid was precipitated, the mixture was stirred at room temperature for 1 hour and collected by suction filtration. Crystallization is performed to obtain d-compound (1) .l-α-methylbenzylamine salt.

Yield 700mg, white crystals, m, p, 169-174°C
(α) l'? 320.15° (C-0,532
, methanol) IR, (νHB, Cm-'): 3450, 3350.3200-2400.1728'
H-NMR (D0-d, δ); u3 1.5 (d, 38.-"CI-)NH.

2.0 (S, 3H, -0COCjj*) 3.67
(5,3B, -0CH3)4.67 (d, 18.
-Cfi-CI-, J-3Hz) 5.05 (d, I
H, -CH-岨-1J-3Hz) 5.20-7.67
(m+ 18L arom, -Null-
COOH) In addition, when d-α-methylbenzylamine is used in the above reaction, one compound (1)・d-α
-Methylbenzyl amii salt is obtained. Seagull, p. 159~
165℃.

(α) i' i -319,13" (C-0,5
04, methanol)) Dissolve the d-form compound (1) l-α-methylbenzylamine obtained in (1) above in distilled water by heating (70°C). Under the same conditions
After adding 0.52 m (0.52 -.l) of IN-HCl, the mixture was cooled in a water bath. This solution was extracted with ether and saturated NaCj! Wash with solution and dry. After distilling off the solvent, d-compound (1) was obtained.

Yield: 179.7 mg (95.6% yield), white foamy solid, m.p. p. 60-73℃.

(α)! ' ? 300.22° (C -0.505
, methanol) IR (νWB+ell-'): 3450, 3350. 3300-2200. 17
40. 1610'H NMR (CDCjs.δ
);2,13 (S. 3H. -OCOC)Is)3
, 73 (S. 3H, -0(ljs) 4, 50 (
d, 1B, -Cjj-CB-, J-4Hz)5,
37 (d. 1B, -CI-CI-, J=4Hz
)6, 27~7.33 axis + 1LH + ar
om. Null -COOH) In addition, 200 mg (0.41 maol) of the monomer compound (1) d-α-methylbenzylamine salt obtained above and IN-
When the same procedure is carried out using 0.41 d (0.41 mmol") of HCl, a monomer compound (1) is obtained.

Yield 138 mg (yield 93.2%), white foamy solid [α
) I'? -300.22° (C-0.514
, methanol) Reference Example 1: d-2-(4-methoxyphenyl)-3-acetoxy-
Cis-2,3-dihydro-1,5-benzothiazepine-
Synthesis of 4(5H)-one.

6-body - Compound (1) 5 0 6.4-g (1.4
On+sol) and 4-dimethylaminopyridine 34.5
mg (0.28-1 of) in dry methylene chloride 70a
Dissolved in Z. Dicyclohexylcarbodiimide 346,6 mg (1.68 m
mol) of dry methylene chloride (1-) solution was added dropwise, the temperature was returned to room temperature, and the mixture was stirred for 30 minutes. The precipitated solid in the reaction mixture was collected by suction filtration, and the solvent was distilled off from the filtrate. The residue was dissolved in chloroform and applied to a silica gel column (developing solvent: benzene:
Purification was carried out with ethyl acetate (7:3) and d-2-
(4-methoxyphenyl)-3-acetoxy-cis-2
．． 3-dihydro-1,5-benzothiazepine-4 (5H
) - get on.

Yield 451.9 mg (yield 94%), white crystals, -0p
.

149-150°C.

[α] Todoro': 39.20" (C-0,511, chloroform) Reconsolidation solvent (ethanol-water) I R (SiH: C, cm-'): 3300.29
50. 1760. 1700'H-NMR (CDC1
m, δ): 1.90 (3,3B, -0COCHi)3.73
(S, 3H, -0CHs)5.07 (d, 11.
-CI-CH-, J=7Hz)5.31 (d,
IH, -CI-Cdan+, J=71Lz) 6.60~
7.77 (m, 8H, arom) 8.73 (br
s, 18. -CON and) Procedures Principal Ho Masaaki 1) June 5, 1985 Commissioner of the Patent Office -°宕：t゛″
1. 2. Title of the invention: Process for producing 4 propionic acid derivatives 3. Relationship with the amended person's case Name of patent applicant: Sawai Pharmaceutical Co., Ltd. 4, Agent: 541 Address: 4-chome, Hirano-cho, Higashi-ku, Osaka 53-3 New Life Hirano-cho 406 Telephone (06) 227-1156 Contents of amendment to column 6 of "Detailed Description of the Invention" of the specification (1) The entire text of page 2 of the specification is corrected as shown in the attached sheet.

(2) On page 3, line 9 of the circular, ``common name'' is corrected to ``known name''.

(3) On page 3, line 10 of the circular, “optically resolving” means “optically resolving to efficiently produce compounds (
The method for producing In) is corrected to ``.

(4) Page 3 of the same book, second line from the bottom, “[α]Otsu’
: 39.20 ” Delete J.

(5) Same book No. 4 true [α] divination': 11G, 03 "↓ [α)!': 97.03° (in the formula, A and R1 have the same meanings as above)".

(6) On page 4 of the same book, in the 8th line from the bottom, after “4 bodies”, “
"Industrial and efficient" is added.

(7) Circular page 8, lines 8-10 r CHs 1.5 (d, 3H,-”CH-)NHt
Correct J to .

[Industrial Application Field] The present invention provides d-cis-3-acetoxy-5-(2-(dimethylamino)ethyl)- which is useful as a coronary vasodilator.
2,3-dihydro-2-(4-methoxyphenyl)-1
, 5-benzothiazepin-4(5H)-one, etc., which are useful as synthetic intermediates (in the formula, A represents allyl which may be substituted with lower alkoxy, and R1 represents lower alkyl). propionic acid derivative [compound (■
)].

(Conventional technology)

Claims (1)

[Claims] Represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, A represents allyl which may be substituted with lower alkoxy, and R^1 represents lower alkyl) The dl form of the compound [compound (I)] is expressed by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, R^2 is a lower alkyl group, and Y is an optionally substituted phenyl group. 1. A method for producing the d-isomer of compound (I), which comprises optically resolving an optically active form of a benzylamine compound [compound (II)] represented by the following as a resolving agent.