KR790001358B1 - Process for the preparation of substituted phenoxy - -methyl propionic acid derivatives - Google Patents

Abstract

Title compds. [I; Y = CH2-, CH2O-, -CH2CH2-, -CH=CH, R = lower alkyl group or -(CH2)n N-(R1)2 group(n = integer, R' = lower alkyl group) useful as cholesterol-lowering agents, were prepd. by reaction of α-(halogeno-α-methylpropionic acid and P-substituted metal salt of phenol to give α-(P-substituted phenoxy)-α-methyl propionic acid or reactive derivs. (II; X = hydroxyl group or reactive group) followed by reaction with lower alcohols or dimethylamino alcohol.

Description

Method for preparing substituted phenoxy-α-methylpropionic acid derivative

The present invention is a novel substituted phenoxy-α-methylpropionic acid derivative having cholesterol lowering action, more specifically general formula

(n은 정수, R₁은 저급알킬기)를 표시함.]으로 표시되는 치환페녹시-α-메틸프로피온산유도체(I)의 제조방법에 관한 것이다.[In the above formula, Y represents -CH _2- , CH ₂ O-, -CH ₂ CH _2- , -CH = CH-, R is a lower alkyl group or

(n represents an integer and R ₁ represents a lower alkyl group). The present invention relates to a method for producing a substituted phenoxy-α-methylpropionic acid derivative (I).

In human arteriosclerosis, especially atherosclerosis, it is well known that cholesterol in blood has a significant effect. Therefore, the inventors have studied in various ways about the compound that lowers cholesterol, and the compound of the general formula (I) mentioned above is very low in reducing the concentration of cholesterol in rat serum and acute toxicity in rats. I learned.

It is therefore an object of the present invention to provide a novel compound (I) which is very useful for the treatment and prevention of atherosclerosis, particularly hypercholesterolemia, in humans and animals.

The method of the present invention is represented by the following scheme.

(In the above scheme, X represents a hydroxyl group or a reactive group, and Y and R are the same as mentioned above.)

In other words, the method of the present invention produces a substituted phenoxy-α-methylpropionic acid derivative (I) by reacting α- (P-substituted phenoxy) -α-methyl propionic acid or its reactive derivative (II) with alcohols (III). That's how.

The present invention is explained in more detail below.

The raw material compound (II) used in the present invention is a novel compound, for example, is easily prepared by reacting α-halogeno-α-methyl propionic acid with a metal salt of P-substituted phenol. Moreover, as a compound in which X in general formula (II) is represented by a reactive group, the borolides, such as bromine and chlor, an acid anhydride, mixed acid anhydride, ester, etc. are mentioned.

As alcohols (III) which are one of the starting materials, for example, lower alcohols such as methanol, ethanol, n-propanol and isopropanol, N.N- such as dimethylaminoethyl alcohol, diethylaminoethyl alcohol and dimethylaminoethyl alcohol Di lower alkylamino lower alcohol is exemplified.

In carrying out the process of the present invention, when an acid halide is used as the compound (II) as one of the starting materials, the reaction is generally carried out in an organic solvent. As an organic solvent, basic solvents, such as pyridine and quinoline, neutral solvents, such as bezel, toluene, and xylene, etc. are mentioned. The reaction proceeds under ice-cooling or at room temperature, and in some cases, the reaction time may be shortened by heating to 40-140 ° C. In the case of using a neutral solvent, it may be a good result to react in the presence of a tertiary amine and a heterocyclic compound.

In addition, when using the carboxylic acid represented by the hydroxyl group as X as a starting material (II), it carries out according to the normal dehydration esterification method, ie, the compound (III) which is the starting material (III) of the other side, In the case of lower alcohols such as methanol and ethanol, the raw material compound (II) and the raw material compound (III) are reacted under reflux or reflux reaction in the presence of an esterification catalyst such as P-toluenesulfonic acid. In the case of N-N-di lower alkali amino lower alcohol, the reaction is carried out while removing by-product water under reflux out of the reaction system using a water separator in an organic solvent such as benzene, toluene, and xylene.

In the case of using an acid anhydride as the raw material compound (II), the reaction proceeds without a solvent, but in general, it is preferable to use an organic solvent. Suitable organic solvents include nitrogen-containing heterocyclic compounds such as pyridine and quinoline, Basic solvents, such as tertiary amine, neutral solvents, such as benzene, toluene, ether, dioxane, and xylene, are mentioned. When using a neutral solvent, it is sometimes desirable to use a mixed solvent of tertiary amines and nitrogen-containing heterocyclic compounds. Moreover, catalysts, such as a sulfuric acid and boron fluoride, can also be used.

In the compound (I) obtained as mentioned above, the compound in which R is represented by the N * N-di lower alkylamino lower alkyl group can also be formed with the salt of the corresponding organic acid or inorganic acid by a conventional method.

The pharmacological effect of the compound (I) obtained by making it above is as follows.

(1) Effect on Cholesterol in Serum

A normal SD rat (male of about 160 g body weight) is used as a group of 10 rats and a group of 10 rats is prepared for control.

16 hours are fasted before administering a sample, and various samples and control solutions are orally administered in the stomach. After 8 hours, pickled radish was collected and centrifuged to separate serum. Cholesterol in serum is measured by Zurkowski-Shibata method. The results are shown in the first table.

However, the dose of the sample compound was 100 mg / kg rat body weight, and each value expressed the percentage of inhibition by the test drug against the serum cholesterol value of normal rats.

[Table 1]

(2) Acute Toxicity in Rats

Drugs were orally administered using dd rats (males) at around 20 g of body weight and subjected to the Lichfilcl-Wilconzon method [J. Pharmac. Exp. Ther, 96, 99 (1949)], respectively, to find the value of LD ₅₀ . The results are shown in the second table. Provided that Y and R are the same as (1).

[Table 2]

(3) Pharmacological activity and toxicity comparison between known compounds and compounds of the present invention

(I) the effect on cholesterol in serum:

Wistar rats (males) (about 250g body weight) were formed in groups of 10, and 12 groups were used. For each group of the 11 groups, the drug was 360 mg / kg (each test drug in 5% Arabic gum solution). Forced administration was carried out at the ratio of (suspended form). And 5% Arabian gum is administered to the control as described above. 24 hours after the end of the administration, anesthesia was collected and collected from the total carotid artery, and serum was separated after centrifugation. The total amount of cholesterol in serum was quantified by the Rudel-Morris method (J.Lipid Res. 14,354 (1973)), and the inhibitory degree of the test drug to the control group was expressed as a percentage.

The results are as shown in the third table.

[Table 3]

(II) Acute Toxicity in Mice:

Using healthy rats (males) at around 20 g body weight, the drug is orally administered and the values of LD ₅₀ are determined by the Lichfild Wilcoxon method. The results are shown in the fourth table. Drug AI described in the table is the same as those in the third table.

[Table 4]

Next, it demonstrates with an Example.

Example 1

3.1 g of α- [P- (P'-chlorbenzyl) phenoxy] -α-methylpropionic acid is dissolved in 40 ml of ethanol anhydride, and 0.2 g of P-toluenesulfonic acid is added and heated to reflux for 3 hours. After completion of the reaction, the excess solvent was distilled off, the residue was dissolved in ether, washed with water, the solvent was distilled off, the residue was distilled off under reduced pressure, and the boiling point was 18-186 ° C./2 mmHg. Obtain a transparent liquid which is (P'-chlorbenzyl) phenoxy]-(alpha)-methyl propionic acid ethyl ester.

Elemental Analysis Value: C ₁₉ H ₂₁ O ₃ Cl

Theoretic value (%): C 68.57, H 6.36

Analytical Value (%): C 68.38, H 6.53

Example 2

4.0 g of α- [P- (P'-chlorbenzyloxy) phenoxy] -α-methylpropionic acid is dissolved in 40 ml of anhydrous methanol, and 0.2 g of P-toluenesulfonic acid is added and heated to reflux for 4 hours.

After the completion of the reaction, excess methanol was distilled off, and the crystal obtained by treating the residue as in Example 1 was recrystallized with methanol to give?-[P- (P'-chlorbenzyloxy) having a melting point of 86-87 占 폚. ) Phenoxy] -α-methylpropionic acid methyl ester is obtained.

Elemental Analysis Value: C ₁₈ H ₁₀ O ₄ Cl

Theoretic value (%): C 64.58, H 5.72

Analytical Value (%): C 64.47, H 5.57

Example 3

To 40 ml of xylene, 3.2 g of α- [P- (P'-chlorstyryl) phenoxy] -α-methylpropionic acid and 1.2 g of N, N-diethylaminoethanol were added, and a water separator was installed. The mixture was refluxed for 6 hours. Stir. The reaction mixture is added to water and extracted with ether. The ether extract is washed with dilute aqueous sodium carbonate solution and then washed with water and dried. Next, the precipitated crystals were introduced by the introduction of dry hydrogen chloride gas, and the precipitates were collected by filtration and recrystallized with ethanol to give α- [P- (P'-chlorstyryl) phenoxy] -α-methylpropionic acid N, N-diethylaminoethyl ester hydrochloride is obtained as white crystals.

Elemental Analysis Value: C ₂₄ H ₃₁ O ₃ NCl ₂

Theoretic value (%): C 63.86, H 6.70, H 3.10

Analytical Value (%): C 63.90, H 7.00, N 2.92

Example 4

To 50 ml of xylene, 1.6 g of α- [P- (P'-chlorbenzyloxy) phenoxy] -α-methylpropionic acid and 0.5 g of N and N-dimethylaminoethanol were added, and a water separator was installed under reflux stirring for 6 hours. React. After completion of the reaction, the crystals obtained by treatment in the same manner as in Example 3 were recrystallized from isopropyl alcohol to have a melting point of 101-103 ° C. α- [P- (P'-chlorbenzyloxy) phenoxy] -α-methylpropionic acid N, N-dimethylaminoethyl ester hydrochloride is obtained as white crystals.

Elemental Analysis Value: C ₂₁ H ₂₇ O ₄ Cl ₂ N

Theoretic value (%): C 58.88, H 6.35, H 3.27

Experimental value (%): C 58.10, H 6.41, N 2.97

Example 5

6.0 g of α- [P- (P'-chlorstyryl) phenoxy] -α-methylpropionic acid was dissolved in 40 ml of benzene, and 1.0 g of N, N-dimethylaminoethanol was dissolved in 20 ml of benzene while stirring at room temperature. Emphatically in minutes. Next, the reaction was stirred under reflux for 1.5 hours. After completion of the reaction, the resulting crystal filtration was cooled to room temperature, dried and recrystallized from isopropyl alcohol to give a melting point of 188-191 ° C α- [P- (P'-chlorstyryl) phenoxy] -α-methylpropionic acid N, N -Dimethylaminoethyl ester hydrochloride is obtained as white crystals.

Elemental Analysis Value: C ₂₂ H ₂₇ O ₃ Cl ₂ N

Theoretic value (%): C 62.27, H 6.41, H 3.30

Experimental value (%): C 62.04, H 6.40, N 3.12

Example 6

To 80 ml of acetonitrile, 5.0 g of α- [P- (P'-chlorbenzyloxy) phenoxy] -α-methylpropionic acid and 2.0 g of N and N-dicyclohexylcarbodiimide were added and stirred at room temperature for 2 hours. And leave for 1 night. The precipitated N, N-dicyclohexyl urea is filtered off and the filtrate is distilled under reduced pressure to remove the solvent. The distillation residue is recrystallized with an ether: ligroin mixed solvent to obtain α- [P- (P'-chlorbenzyloxy) phenoxy] -α-methylpropionic anhydride having a melting point of 116-117 ° C. as a white crystal.

Elemental Analysis Value: C ₃₄ H ₃₂ O ₇ Cl ₂

Theoretic value (%): C 65.49, H 5.17

Experimental value (%): C 65.66, H 5.23

Example 7

1.0 g of α- [P- (P'-chlorbenzyloxy) phenoxy] -α-methylpropionic anhydride and 1.2 g of n-propane were dissolved in 4 ml of pyridine, and heated at 80-95 ° C. for 4 hours, and then left to stand overnight. do. The reaction solution is concentrated under reduced pressure, and the residue is dissolved in ether, and then washed with water with dilute sodium bicarbonate solution and then dried with water. The ether was distilled off and the residue was recrystallized from isopropyl alcohol to obtain α- [P- (P'-chlorbenzyloxy) phenoxy] -α-methylpropionic acid n-propyl ester having a melting point of 42-43.5 ° C as white crystals.

Elemental Analysis Value: C ₂₀ H ₂₃ O ₄ Cl

Theoretic value (%): C 66.20, H 6.39

Experimental value (%): C 65.37, H 6.43

Claims (1)

General formula

(In the above general formula, Y represents -CH _2- , CH ₂ O-, -CH ₂ CH _2- , CH = CH-, etc., X represents a hydroxyl group or a reactive group.) P-substituted phenoxy) -α-methylpropionic acid or its reactive derivative is represented by the formula ROH (wherein R is a lower

Is. Provided that n is an integer and R ₁ represents a lower alkyl group.

(Y and R in the general formula is as described above.) A method for producing a substituted phenoxy-α-methylpropionic acid derivative.