JPS6013776A - Production of optically active 3-(p-alkoxyphenyl)-glycidic acid derivative - Google Patents

Abstract

PURPOSE:To produce the titled optically active compound useful as an intermediate of coronary vasodilator, by reacting the novel optically active 3-(p-alkoxyphenyl)glycidic acid alkali metal salt with an alkyl halide, etc. CONSTITUTION:The optically active compound of formula I (A is OR<3> or SR<3>) can be produced economically, by reacting the novel optically active compound of formula VI (R<1> is alkoxy; M is alkali metal) with the compound of formula R<2>X<1> (R<2> is alkyl; X<1> is halogen) or formula R<3>SCOX<2> (R<3> is alkyl or aryl; X<2> is halogen). The above novel substance of formula VI is obtained by (1) hydrolyzing the racemic compound of formula III (R is lower alkyl), (2) neutralizing the obtained racemic compound of formula IV (M is alkali metal), and (3) subjecting the obtained racemic compound of formula V to optical resolution with an optically active amine. The optically active compound of formula IIuseful as the above drug can be produced from the optically active compound of formula I with little reagent loss, in high efficiency.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing optically active 3-(P-alkoxyphenyl glycidate derivatives, especially ester derivatives).

3-(p-methoxyphenyl) glycidate derivative [compound (■)] is a d-cis-2-(4-methoxyphenyl)-3-acetoxy- 5-(2-dimethylamineethyl)-2,3-dihydro-1゜5-benzothiazepine-4
It is used as a starting material for (5H)-one [hereinafter referred to as compound (i)] (Japanese Patent Publication No. 45-41392.46
-8982 etc.).

According to the above-mentioned patent publications, in synthesizing compound (I), route 1 (in the formula, K means an alkyl group) is used to synthesize compound (■a) (racemic form) as shown in route 1 below. Intermediate compound (■) (racemic form) of compound (I) is synthesized by acting with orthonitrothiophenol and subsequently hydrolyzing. Compound (II) was then optically resolved (Japanese Patent Publication No. 53-18
038), and then reduction, cyclization, acetylation and alkylation to synthesize compound (I).

However, in the above method for synthesizing compound (I), compound (■a) is used as the starting material in its racemic form, and optical resolution is performed during the synthesis route, so 2 is separated and removed by optical resolution. This method has the disadvantage that all of the d-isomer products and unreacted d-isomer raw materials are discarded, resulting in large reagent loss.

Therefore, the present inventors investigated a method for synthesizing compound (I) that would reduce reagent loss, and as a result, the starting compound (■) was converted to 1
; 1sR3), where R2 is an alkyl group, and R' is an alkyl group or an aryl group, respectively. Since only the optically active raw material compound (■) is handled, the loss of reagents in the subsequent synthesis process can be suppressed to a very small amount, and the above-mentioned drawbacks can be eliminated.

In order to realize this concept, the present invention was completed as a result of repeated research on the method of synthesizing the optically active raw material compound (■). This is what we are trying to provide.

The method of the present invention, which has achieved the above object, is based on an optically active alkali metal salt of 3-(P-alkoxyphenyl) glycidate represented by the general formula (wherein R1 means an alkoxy group and M means an alkali metal). , R2X' (R2 means an alkyl group, xl means a halogen) or O R''5CX2 (R'i; t 7 alkyl group or haf')
The general formula (wherein, kl is an alkoxy group, and A is OR2 or SR1, respectively) is represented by the following formula: The purpose of this method is to obtain an optically active 3-(P-alkoxyphenyl)grind acid derivative.

The starting compound (VI) in the method of the present invention is a new optically active compound, and it is advantageous to produce it according to the following method (route 2).

Route 20 (wherein, R1 is an alkoxy group, k is a lower alkyl group, M
3-(P-alfkydiphenyl) glycidic acid ester (racemic form, compound (
(2)] is hydrolyzed by adding an alkali metal hydroxide, an alkali metal alcoholade, etc. to obtain an alkali metal salt of 3-(P-alkoxyphenyl) glycidate [racemic form, compound (IV)]. The starting material for the above reaction, compound (III), is a carboxylic acid ester, and the lower alkyl represented by k is methyl, ethyl,
Examples include hydrocarbon residues having 1 to 6 carbon atoms such as propinopeisopropyl, butyl, pentyl, and hexyl. Also 1
The alkoxy group represented by C (j includes methoxy group, ethoxy group, propoxy group, etc.).The reaction proceeds equimolarly in ethanol or other solvents that do not adversely affect the progress of the reaction.Reaction temperature There are no particular limitations, and the reaction is generally carried out under ice-cooling to room temperature.

Then, by neutralizing the compound (IV) by adding, for example, a dilute acid, 3-(p-alkoxyphenyl)glycidic acid [racemic form, compound (V)] is obtained.

Examples of the dilute acid provided in the above reaction include mineral acids such as hydrochloric acid and sulfuric acid. The reaction proceeds smoothly under mild conditions of cooling to room temperature in an organic solvent that does not adversely affect the progress of the reaction. As the above-mentioned organic solvent, ether, methylene chloride, and other solvents are used, but among them, ethyl acetate gives the most preferable results.

Next, compound (V) is dissolved in an organic solvent that does not affect the reaction and placed under mild temperature conditions ranging from cooling to room temperature, and to this is added an optically active amine that has been separately dissolved in the same organic solvent under the same temperature conditions. The amine salt of optically active 3-(p-alkoxyphenyl)crizidic acid [compound (V
a)] is obtained. As the organic solvent, general-purpose solvents such as ether and methylene chloride are used, but among them, ethyl acetate gives the most favorable results. In addition, various optically active amines can be used as the optically active amine provided in the reaction, and representative examples include α-methylbenzylamine, α-(1-naphthyl)ethylamine, α-( 2-NaphthinoL) Ethylamine, purusin, ephedrine, etc. are preferred, among which primary aralkylamine is preferred, and specifically, the most favorable results are obtained when optically active α-methylbenzylamine is used.

In the above reaction, when 6 optically active amines are used as optical resolution agents, 6 compounds (Vl) are obtained from the racemic compound e1m, and when 1 optically active amine is used, 1 compound (Vl) is obtained. @](v+) can be obtained.

Next, after separating the compound (V+), it was poured into a separately prepared organic solvent and diluted with dilute acid etc. at ice-cooling to room temperature.
and optically active 3-(P-alkoxyphenyl) glycidic acid. Examples of the organic solvent include the same solvents as mentioned above, such as ether, methylene chloride, and ethyl acetate, and examples of the dilute acid include mineral acids such as hydrochloric acid and sulfuric acid. Next, an anhydrous alcohol solution of an alkali metal hydroxide, an alkali metal alcoholade, an alkali metal carbonate, etc. is allowed to act on the optically active 3-(P-alkoxyphenyl) glycidic acid dissolved in a specific solvent such as ether or ethyl acetate. Optically active 3-(P-alkoxyphenyl)glycidic acid alkali metal salt [Compound (■)]
get.

Next, in the optically active raw material compound (VI) to be explained regarding method 1 of the present invention, examples of the alkoxy group represented by R1 include methoxy, ethoxy, propoxy, impropoxy, butoxy, pentyloxy, hexyloxy, etc. Examples of the alkali metal represented by M include potassium and sodium. An optically active 3-(P-alkoxyphenyl) glycidic acid derivative [compound (■)] is obtained from such compound (Vl),
The compound (■) can be divided into two types: an ester derivative in which the substituent represented by A is OR' [compound (■3)], and a thioester derivative in which the substituent represented by A is Sk'. I'll explain the toughest one.

++>Compound (VI)-→Compound (■a) Optical activity 3-
A strong acid metal salt such as silver nitrate is reacted with the alkali metal salt of (P-alkoxyphenyl) cricid acid [Compound (■)] to form the corresponding metal salt of optically active 3-(P-alkoxyphenyl) cricid acid [Compound (VI)]. obtain a).

The reaction is carried out in a hydrophilic solvent such as water or an organic solvent that does not affect the reaction under mild temperature conditions of cooling to room temperature, with light shielding as necessary. Next, compound (VI) a separated from the reaction mixture was dispersed in an organic solvent and R2XI (
R2 is an alkyl group,
). As R2XI to be subjected to the reaction, R2 is any hydrocarbon residue having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, and , iodine and other halogen elements, but the best results are obtained especially when iodide is used. As the above-mentioned organic solvent, general-purpose solvents such as alcohols, ethers, and esters that do not affect the reaction may be used, and among them, ethers are preferred. The reaction is carried out for 10 to 24 hours under mild temperature conditions ranging from cooling to room temperature, blocking light if necessary, and stirring if necessary.

In the above, compound (VI) is once converted into a metal salt represented by compound (Vl) a, and then alkyl halide (R'
Compound (Vl[)a was obtained by reacting with X'), but due to the selection of the reaction solvent, compound (VI) was directly reacted with /% alkyl rogenide CR2Xi) to obtain compound (■)a. It can also happen.

In this case, Compound (■) 3 is obtained by dissolving Compound (Vl) in a polar solvent such as HMPA or DMF, and reacting the same alkyl halide with the above solution.

The reaction is carried out at a temperature of room temperature to 100°C for 24 to 72 hours with stirring if necessary. Note that HMPA is particularly preferred as the polar solvent.

(11) Compound (VI) → Compound (■) b Optical activity 3-
(P-alkoxyphenyl)glycidic acid alkali metal salt [compound (■)] and an organic base as a reaction promoter are dispersed in an anhydrous organic solvent, and 0 (in the formula
is an alkyl group R3S CX2 or an aryl group, x2 is a halogen) is added dropwise to the alkylhalothioformate or arylhalothioformate under a temperature condition of cooling to room temperature, and then heated to room temperature overnight. When reacted, optically active 3-(P
-Alkylthioester or arylthioester of glycidic acid (alkoxyphenyl) [compound (■) b)
As the 0 obtained from the above and subjected to the reaction, R3 is a hydrocarbon residue having 1 to 6 carbon atoms such as methyl, ethyl, furoyl, isopropyl, butyl, pentyl, hexyl, or phenyl, tolyl, xylyl, naphthyl, Examples include compounds in which the compound is an aryl group such as methylnaphthyl, ethylnaphthyl, or anthranyl, and x2 is any halogen element such as fluorine, chlorine, bromine, or iodine. In addition, examples of organic bases used as reaction accelerators include pyridine, triethylamine,
N-methylpyrrolidine, etc., can be used as a reaction solvent. Examples of organic solvents include anhydrous tetrahydrofuran, anhydrous ether,
Examples include anhydrous methylene chloride and the like.

Optically active compound (■) a or (
(2) Compound (I) etc. useful as a coronary vasodilator can be obtained by using b as a raw material and subjecting it to the same operations as in route 1 (however, excluding the optical resolution operation).

The present invention is constructed as described above, and has an optically active 3-(p
-Alkoxyphenyl) glycidic acid derivatives, particularly ester derivatives or thioester derivatives, can be produced easily and in good yields, and since these are used as raw materials, subsequent steps can be carried out efficiently.

The present invention will be described in detail below.+11 Synthesis Example 1 of optically active 3-(P-methoxyphenyl)glyzide acid methyl ester [compound (■) a] d-3-(P-methoxyphenyl)glyzide acid potassium salt [ Dissolve 0.6 f of compound (VI) in 3 ml of water, add 0.439 f of copper nitrate while stirring at room temperature and shield from light.
A solution prepared by dissolving this in 4rnl of water is added dropwise. After 10 minutes, the precipitate formed was separated and washed with water and then ether.
0.6'l of silver salt of d-3-(P-methoxyphenyl)glycidic acid was obtained. Add this silver salt to 5 mt of anhydrous ether.
After adding 2.4 ml of methyl iodide, leave at room temperature.
Stir for 16 hours in the dark.

Insoluble matter is filtered and washed with ether, and the washing solution and P
When ether is distilled off from the combined liquid, d-3-(
P-methoxyphenyl) glycitic acid methyl ester [
Compound (■)) 0.436 (yield: 81%) was obtained.

Oily substance [1 (liquid film method, σ-'): 1740 (-COOC
H,) NMR (CDCA',, δ): 3.80 (
8, 3H) 3.45 (d, J-2, IH) 4.01 (d,, J=2, IH) 6.76-7
．． 26 (m, 4H) 2 [α): +179.37 (C-=0.5136.k';'/-l) Example 2 Same as Example 1, l-3-(P-methoxyphenyl)
When the reaction is carried out using glidate potassium salt, /
-3-(P-methoxyphenyl)glycidic acid methyl ester was obtained.

Oily substance, yield near 7% 22°[α)D, -179,61 (Cm0.5185, ethanol) Example 3 d-3-(P-methoxyphenyl)glycidic acid potassium salt 0.59 and methyl iodide 1.6 ml of HMPA5
After reacting in mt at room temperature for 48 hours and drying, and distilling off the ether, d-3-(P-methoxyphenyl)glycidic acid methyl ester 0.224IC yield: 50%
)was gotten.

(2) Synthesis of optically active 3-(P-methoxyphenyl)glycidic acid thiophenyl ester [compound (■) b].

Example 4! - 1.0 g of potassium salt of 3-(P-methoxyphenyl) glycidate is suspended in anhydrous tetrahydrofuran,
Add a drop of pyridine while cooling to 0° C. under a stream of N2. Then, separately, 0.74 phenylchlorothioformate
A solution of 39 dissolved in anhydrous tetrahydrofuran was added dropwise to the mixture, and the mixture was stirred at 0'C for 30 minutes and then allowed to react overnight at room temperature.The reaction mixture was transferred to a mixed solution of 86 ml of ice water and 86 ml of needles, and extracted with ether. Then, the aqueous layer is separated and extracted with 40 rnl of ether.The ether layer is dyed, washed with saturated sodium chloride water, dried with Glauber's salt, and the ether is distilled off. 0.995g of yellow oily crude product of phenyl ester
(Yield: 81%) is obtained. When the crude product is heated and dissolved in a mixed solvent of n-hexane and ether and then cooled in an acetone-dry ice system, a part of the oily substance is separated and precipitated. The astringent supernatant is collected and slowly stirred again to obtain the desired white crystals. The same operation is repeated on the separated oil to obtain white crystals. Collecting these white crystals gives 0.518
g (yield: 42%).

Melting point: 65-66゛C 1R (KB r , Cm'): 1680 (-co
sc6H5) NMR (CT) (J), , δ: 3.8
0 (S, 3H)3.70 (d, J=2,
IH) 4.13 (d, J=2.IH) 6.73-7.42 (m, 9H) 22° [α] IJl-20,76 (c-o5o9IcHcI!
,) Elemental analysis (as CT60I4035) (weight and %) Reference Example When the reaction is carried out using racemic 3-(P-methoxyphenyl) glycidic acid metal salt in the same manner as in Example 4,
Racemic 3-(P-methquinphenyl)clidic acid naophenyl ester was obtained.

Yield: 43% Melting point near 0-72°C From the comparison between Example 4 and Reference Example, the ester reaction of the optically active starting compound [compound (■)] gives a yield comparable to that of the ester reaction of the racemic starting compound. It can be seen that it progresses in a similar manner.

Applicant: Sawai Pharmaceutical Co., Ltd. -T''-Continued amendment (spontaneous) 1-2 (October 141, 1981) 1 Indication of case Special revision application No. 123041 of 1982, Title of invention Optically active 3-(P-alkoxy) Process for producing (phenyl)glycine F acid derivatives 3, relationship with the amended case Patent applicant 1-4-25 Akayo, Asahi-ku, Osaka City Representative: Osamu Sawai Department 4 Agent: Osamu Sawai, Osaka 530 Osaka Shinko Hill, 2-3-7 Dojima, Ichikita-ku Contents of amendment to column 6 of "Detailed explanation of the invention" in the specification (1) Specified parts of the specification will be corrected as shown in the attached errata.

hoe 恕

Claims (1)

[Scope of Claims] R"X' (R2 means an alkyl group, X means a halogen) or 1 R3S CX2 (R' means an alkyl group or an aryl group, x
2 means halogen) to form a general formula (wherein, kl is an alkoxy group, A is 0R2X (I S R'
An optically active 3-(P-alkoxyphenyl) glycidic acid derivative represented by:
A method for producing a (P-alfkydiphenyl) glycidic acid derivative.