KR830001653B1 - Method for preparing basic ester of hexane carboxylic acid with hydroxy cycle - Google Patents

Abstract

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Description

Method for preparing basic ester of hexane carboxylic acid with hydroxy cycle

The present invention relates to a process for the preparation of basic esters of hexane carboxylic acids with substituted hydroxy cycles having the general formula (I)

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In particular the invention relates to 2- (diethylamino) -1-methylethyl-cis-1-hydroxy- (bicyclohexyl) -2-carboxylate and 2- (diethylamino-1-methylethyl-cis-2 It relates to an improved process for the preparation of hydroxy-2-phenyl-cyclohexane carboxylate.

The esters of the invention known as anti-convulsants are described in U.K. Part of the basic esters described in German Patent No. 1,168,624 to Specification No. 1.167,386. According to known conventional methods for the preparation of such esters there is a general method of reacting with an amino alkyl chloride of hexane carboxylic acid with a substituted hydroxy cycle.

Two other methods that are practical because of the low yield of the desired product are: reacting the potassium salt of hexane carboxylic acid with substituted hydroxy cyclohexane with an alkylene dihalide followed by reacting an alkyl halide ester with a primary amine or under mild conditions It is known to react the acyl chloride obtained with chlorination of hexane carboxylic acid with a substituted hydroxy cycle with an amino alcohol.

From the industrial point of view, only one effective method is the first described method, and the detailed description of the method is described in U.K. In particular, given in Example IV of Specification 1,167,386.

If the method of the present invention is applied to the preparation of the compound and the crude oily product is subjected to two-step distillation or fractional rectification instead of one step, a product that can meet the analytical needs can be obtained.

In the case of the title compound (as shown in formula (I)), a receptor for hydrogen chloride (e.g. K ₂ CO ₃ , NaOH

Cis-1-hydroxy- [bicyclohexyl] -2-kiric acid or cis-2-hydroxyphenyl-cyclohexane carboxylic acid and 1-diethyl amino-2 in the presence of KoCH ₃ , NaOCH _3, etc. During the reaction of -chloropropane, two products were formed according to the following reaction scheme, which was divided into B of A for convenience.

It is known that 1-diethylamino-2-chloropropane reacts in the following cyclic form to break the bond at position (a) to form product (A) and break the bond at position (b) to result in product (B) Is due to the fact that it produces.

By varying the reaction temperature of the solvent, the ratio of product (A) and product (B) is obtained, but the amount of undesired isomer (B) can be reduced to below 28-30% when R = C ₆ H ₁₁ and R = When C ₆ H ₅ can be reduced to less than 16-17%.

Solvents and temperatures involved in the reaction with cis-1-hydroxy- [bicyclohexyl] -2-carboxylic acid are as follows.

When using K ₂ CO ₃ as anhydrous toluene hydrogen acceptor:

When using K ₂ CO ₃ as hydrogen acceptor in anhydrous dimethylformromide:

Using Potassium Methirate as the Hydrogen Receptor for Isopropane:

When isopropane is used and K ₂ CO ₃ is used as a hydrogen acceptor frame:

Separation of product A and product B obtained in the above reaction is carried out by fractionation. Of course, the yield of desired product A is significantly reduced compared to the theoretical value. Therefore, the main object of the present invention is to provide a reaction mixture comprising product A and product B by heating at least 3 hours at a temperature of 160 ° C.-240 ° C. followed by fractional distillation at a temperature not lower than the temperature of the heating interval. The above problem is solved.

In fact, by the method of the present invention the final product was estimated to represent a content of R = C ₆ H ₁₁ when not more than 1% and R = C1 ₆ H ₅ .5% very low product B under the following optimized conditions.

An advantage of the process according to the invention is that the yield of the desired compound can be obtained almost theoretically by further processing the reaction mixture instead of separating the undesired isomers from the reaction mixture through the difficult operation of reducing the yield.

According to the practical method of the present invention, after the usual glass step, the mixture of compounds A and B is heated at a temperature of 160-240 ° C., especially below 180 ° C. for at least 3 hours. Since the heating temperature and heating time are inversely proportional, yields of near 100% of the yield can be obtained by heating at 180 ° C. for 6 hours, distilling at 180 ° C., and heating at 220-230 ° C. for 3 hours and then splitting distillation at 230-240 ° C. Obtained by

The following examples, for purposes of illustration and not limitation, illustrate the method of the present invention in more detail.

Example 1

200 g of cis-1-hydroxy- [bicyclohexyl] -2-carboxylic acid dissolved in 1000 ml of isopropyl alcohol were mixed with 188 g of anhydrous potassium carbonate and the mixture was heated to reflux (82 ° C.). Then, while maintaining this temperature, 164 g of 1-dimethylamino-2-chlorofurophane hydrocoolide dissolved in 500 ml of isopropyl alcohol is added.

After the addition, the reaction mixture was kept at reflux for 7 hours, and then the reaction mixture was cooled to filter out the salts (KCl and KHCO ₃ ) and thermally isomerized with an isopropyl solution containing 70% of product A and 30% of product B in the following manner. Is carried out.

The solvent is evaporated, the residue (300 g) is dissolved in ethyl ether, the ether solution is extracted with dilute hydrogen chloride at 0 ° C., and the aqueous phase is alkoxylated with dilute sodium hydroxide at 0 ° C. and then repeatedly extracted with ether. The ether extract is washed repeatedly with water until neutral and the solvent is evaporated. The residue (275 g) comprising 70% of product A and 30% of product B was gradually heated from 25 ° C. to 180 ° C. for 6 hours and then distilled in an oil bath at 210 ° C. under reduced pressure (0.1-0.2 mmHg) to 0.5 267 g of 2- (diethylamino) -1-methylethyl-cis-1) hydroxy- [bicyclohexyl] -2-carboxylate containing up to% Isomer B are obtained.

Example 2

The process of Example 1 is repeated until 275 g of residue containing 70% of product A and product B is obtained.

The mixture is heated from 25 ° C. to 220-240 ° C. for 3 hours and then distilled under reduced pressure (0.1-0.2 mmHg) in an oil bath at 230-240 ° C. to give 267 g of Product A containing up to 1% of Product B. .

Example 3

200 g of cis-2-hydroxy-2-phenyl-cyclohexane dissolved in 1000 ml of isopropyl alcohol was added 188 g of anhydrous potassium carbonate and the mixture was heated to reflux (82 ° C.) While maintaining, add 164 g of 1-diethylamino-2-chloropropane hydrochloride dissolved in 500 ml of isopropyl alcohol and let the mixture reflux for 7 hours. After half the mixture was cooled, salts (KCl and KHCO ₃ ) were filtered and an isopropyl solution containing 83.5% Product A and 16.5% Product B was subjected to thermal isomerization in the following manner.

The solvent is evaporated and the residue (296 g) is dissolved in ethyl ether, then the ether solution is treated with dilute hydrochloric acid at 0 ° C. and the separated aqueous phase is alkalined with dilute sodium hydroxide at 0 ° C. and repeatedly extracted with ethyl ether. The ether extract is washed repeatedly with water until neutral and the solvent is evaporated.

Residue (288 g) containing 83.5% of product A and 16.5% of product B was gradually heated from 25 ° C. to 180 ° C. for 6 hours and then distilled in an oil bath at 210 ° C. under vacuum (0.1-0.2 mmHg) to 1.5%. 260 g of product A containing the following product B is obtained.

Similar results were obtained by heating at 25 ° -200 ° C. and then distilling the mixture in an oil bath at 220-230 ° C. under reduced pressure (0.2 mmHg).

Claims (1)

The hydroxy cyclohexane carboxylic acid is reacted with aminoisopropylhydrochloride to accept a reaction mixture containing the desired basic ester having the general formula (1) and the isomers thereof having the general formula (1a), and then After the thermal isomerization by heating the reaction mixture at a temperature of 160 ° C.-240 ° C. for at least 3 hours, the heated mixture is fractionated at a temperature not lower than the heating temperature under the general formula (1). A method for producing a basic ester of hydroxy cyclohexane carboxylic acid having.