JPS593466B2 - Chikan alkyl chikan phenoxy carbon sanruio seizousuruhouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention is based on the general formula (wherein R1 and R2 are hydrogen or an alkyl group, R3
is a carboxy group or a carboxy group esterified with a lower alkyl group, and X is a hydrogen or hydroxy group, respectively) or its salts are reacted with a reagent capable of converting X into a halogen to form a general compound. A carboxylic acid derivative or a salt thereof represented by the formula (wherein R1, R2 and R3 have the same meanings as before and Y means a halogen) is obtained, and then a carboxylic acid derivative or a salt thereof represented by the general formula (wherein R4 is an alkyl group, cyclo An aryl group or benzyl group with or without a halogen or alkoxy group as an alkyl group or a substituent, R5 means hydrogen, an alkyl group, or a benzyl group, respectively, and when R4 and R5 are both alkyl groups, they are bonded. Substituted alkyl-substituted phenoxycarbonyl represented by the general formula (wherein R1, R2, R3, R4 and R5 each have the same meaning as above) by reacting with amines represented by The present invention relates to a method for producing substituted alkyl-substituted phenoxycarboxylic acids, which comprises obtaining acid derivatives or salts thereof.

The reaction of this invention is carried out by first reacting carboxylic acid (1) or a salt thereof with a reagent capable of converting X into halogen.

Carboxylic acids are represented by the above general formula (1), and more specifically, have hydrogen or alkyl groups such as methyl, ethyl, propyl, etc. as R1 and R2, and are esterified with a carboxy group or a lower alkyl group. It means a compound having a carboxy group as R3 and a hydrogen or hydroxy group as X.

Here, the carboxy group esterified by the lower alkyl group of R3 is, for example, a chain-like or Examples include those that are cyclic lower alkyl groups. Salts of carboxylic acids (1) include salts with inorganic bases such as sodium salts, potassium salts, calcium salts, magnesium salts, trimethylamine salts, triethylamine salts, N-N-dimethylaniline salts, pyridine salts, picoline salts, Salts with organic bases such as N-N' dibenzylethylenediamine salts are mentioned. When X is hydrogen, examples of reagents that can convert X into halogen include N-promosuccinimide, N-chlorosuccinimide, Br
When X is a hydroxy group, it is used to halogenate hydroxy groups such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, phosphorus pentabromide, etc. Examples include halogenating agents.

This reaction is usually carried out in a solvent, and examples of the solvent include, but are not limited to, carbon tetrachloride, chloroform, benzene, etc. Any solvent that does not adversely affect this reaction can be used. can. The reaction temperature is not particularly limited, and can be carried out under cooling to heating at about the boiling point of the solvent.
) or is appropriately selected depending on the type of reagent that can convert X into a halogen. When N-promosuccinimide, N-chlorosuccinimide, etc. are used in this reaction, it is advantageous to carry out the reaction by adding a reaction accelerator such as benzoyl peroxide or azobisisobutylnitrile. This X
Examples of the halogen Y produced by the reaction of X with a reagent capable of converting into a halogen include chloro, brome, and the like.

) The reaction of this invention is carried out by reacting the thus obtained carboxylic acid derivative () or its salt with an amine ().

Amines are represented by the above general formula (), and more specifically include alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. , phenyl, tolyl, with or without a cycloalkyl group such as cycloheptyl, or a halogen such as chloro, fluoro, brome, or an alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy as a substituent; It means a compound having an aryl group or a benzyl group such as xylyl, tantyl, naphthyl, etc. as R4, and hydrogen, an alkyl group as described above, or a benzyl group as R5, where R4 and R5 are both alkyl groups. The two may be bonded to each other at °C. In this case, the amines () include pyrrolidine, piperidine, homopiperidine, and the like.

This reaction is usually carried out in a solvent, and examples of the solvent include, but are not limited to, ethanol, acetone, ether, dimethylformamide, etc. Any solvent that does not adversely affect this reaction may be used. I can do it.

Although the reaction temperature is not particularly limited, it is usually carried out under cooling to room temperature.

This reaction generally involves alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogencarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and trimethylamines such as trimethylamine and triethylamine. The reaction proceeds easily if carried out in the presence of a base such as an alkylamine, but amines () can also serve as a base, and liquid bases can also be used as a solvent.

The substituted aminoalkyl-substituted phenoxycarboxylic acid derivative () obtained in this way and its salts can be used, as necessary, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, acetate, maleate, fumarate, etc. Acid salts such as organic acid salts such as acid salts, tartrates, benzenesulfonates, and toluenesulfonates may also be introduced.

Substituted aminoalkyl-substituted phenoxycarboxylic acid derivatives () and their salts, which are the target substances of this invention, are new substances, have cholesterol-lowering effects, and are useful as pharmaceuticals.

Next, the present invention will be explained with reference to examples.

Example 1 (a) Ethyl ester of 2-(P-tolyloxy)-2-methylpropionic acid 20y,. A mixture of 17.7f7 of N-promosuccinimide, 0.2y of benzoyl peroxide and 140 TRI of anhydrous carbon tetrachloride is heated under reflux for 4 hours.

After the reaction, the reaction solution is left to stand, cooled, and then washed with water. After drying the carbon tetrachloride layer, it was concentrated to obtain an oily substance (
When 28f) is distilled under reduced pressure, Ppl46~148℃/1~
2-(4-bromomethylphenoxy)-2 at 211Hg
- Ethyl ester of methylpropionic acid 18.3f7 is obtained. (b) 40% ethylamine ethanol solution 50%
1 m and 4.58 y of potassium carbonate were added to 5 ml of absolute ethanol.
A solution of 10r of ethyl ester of 2-(4-promomethylphenoxy)-2-methylpropionic acid dissolved in 207 to 11 of absolute ethanol was added to this suspension under ice-cooling and stirring for 1.25 hours. The mixture was added dropwise over a period of time, and then stirred for 1 day while cooling with water.

After the reaction, ethanol is distilled off, water is added to the residue, and the mixture is extracted three times with benzene.The extract is washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After drying, the pale yellow oil obtained by distilling off the solvent (8.87r) was subjected to column chromatography using silica gel 88r, and eluted with a 2% methanol/benzene solution and then a 5% methanol/benzene solution. . Mpll converting 3.93y of oil obtained by distilling off the solvent of 5% methanol/benzene eluate into hydrochloride using a mixture of hydrochloric acid/ethanol
4.14r of the hydrochloride of the ethyl ester of 2-(4-ethylaminomethylphenoxy)-2-methylpropionic acid is obtained at 7-119°C.

Example 2 Pyrrolidine 15WL1 was stirred under ice cooling, and Example 1 was added to it.
- Ethyl ester of 2-(4-promomethylphenoxy)-2-methylpropionic acid obtained in the same manner as in (a) 5
, 0f were added dropwise, and then stirred at room temperature for 30 minutes.

After adding an aqueous sodium bicarbonate solution and ether to the reaction solution and extracting, the extract is thoroughly washed 7 to 8 times with water, and then extracted twice with dilute hydrochloric acid. The diluted hydrochloric acid extract is washed three times with ether, made basic by adding an aqueous sodium bicarbonate solution, and extracted twice with ether. The extract was washed twice with water and then dried over magnesium sulfate. After drying, the solvent was distilled off to obtain 2.9 f of oil. This oil is alumina 15
After adsorption on V and elution with benzene, the solvent was distilled off under high vacuum to obtain 2.63y of ethyl ester of 2-[4-(1-pyrrolidinylmethyl)phenoxy]-2-methylpropionic acid as a colorless oil. get. Infrared absorption spectrum (liquid film) 1725, 1280, 123011175, 1135,
1020 (17!-1) The following compound is obtained in the same manner.

(1) 2-(4-anilinomethylphenoxy)-2-
Ethyl ester of methylpropionic acid, Mp45-46
℃.

(2) Hydrochloride of ethyl ester of 2-(4-anilinomethylphenoxy)-2methylpropionic acid, Mpl5
8-163℃.

(3) Hydrochloride of ethyl ester of 2-[4-(P-anisidinomethyl)phenoxy]-2-methylpropionic acid, Mpll 9-120°C.

(4) Hydrochloride of ethyl ester of 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionic acid, Mpl 43-145°C.

(5) ethyl ester of 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionic acid,
Mp58-60°C. (6) Hydrochloride of the ethyl ester of 2-(4-cyclohexylaminomethylphenoxy)-2-methylpropionic acid, Mpl4O~142°C.

(7) Hydrochloride of ethyl ester of 2-(4-isobutylaminomethylphenoxy)-2-methylpropionic acid, Mpll8-119℃o(8) 2-(4-benzylaminomethylphenoxy)-2 - Hydrochloride of the ethyl ester of methylpropionic acid, Mpl 38-139°C.

(9) Hydrochloride of ethyl ester of 2-[4-(P-druidinomethyl)phenoxy]-2-methylpropionic acid, Mpl33-135°C o (112-[4-(3-chloroanilinomethyl)phenoxy]- Hydrochloride of ethyl ester of 2-methylpropionic acid, Mpl46-148
℃0002-[4-{N-(4-chlorophenyl)-N
-methylaminomethyl}phenoxy]-2-methylpropionic acid ethyl ester, oil.

Infrared absorption spectrum (liquid film) 1730, 1280, 1
235, 11751140, 1020CTIL-1 02) 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionic acid, Mpl55-15
8°C003) Hydrochloride of the ethyl ester of 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylbutyric acid, Mpl 35-137°C.

04) 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylbutyric acid, Mpl52-153℃o(
Self) Ethyl ester of 2-[4-(4-chloroanilinomethyl)phenoxy]propionic acid, oil.

Infrared absorption spectrum (liquid film) 341011740c1-1 Nuclear magnetic resonance absorption spectrum (CDCl3, δ) Ppm6
．． 3-7.3 (8H,.m) 4.65 (1H,.q,.
J-7Hz) 4.15 (2H, .q, .J=7Hz) 4.13 (2H, .s) 3.6-4.0 (1H, .br0ads) 1.55 (3
H,. d,. J=7Hz) 1.20 (3H,.t,.J=7Hz) 6) 2-[4-(4-chloroanilinomethyl)phenoxy]propionic acid, Mpl48-149°C.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 and R_2 are hydrogen or an alkyl group,
R_3 means a carboxyl group or a carboxyl group esterified with a lower alkyl group, and Y means a halogen, respectively.) Carboxylic acid derivatives or their salts have the general formula ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (formula Among them, R_4 is an alkyl group, a cycloalkyl group, or an aryl group or benzyl group with or without a halogen or alkoxy group as a substituent, R_5
means hydrogen, an alkyl group, or a benzyl group, and when R_4 and R_5 are both alkyl groups, they may be bonded) to form the general formula ▲mathematical formula, There are chemical formulas, tables, etc.▼ (In the formula, R_1, R_2, R_3, R_4 and R_5
A method for producing substituted alkyl-substituted phenoxycarboxylic acids, characterized in that a substituted alkyl-substituted phenoxycarboxylic acid derivative or a salt thereof is obtained, each of which has the same meaning as above). 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 and R_2 are hydrogen or alkyl groups,
R_3 is a carboxy group or a carboxy group esterified with a lower alkyl group, and X is hydrogen or a hydroxy group, respectively). General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R
_1, R_2 and R_3 have the same meanings as before, Y means halogen respectively), and then we obtain the carboxylic acid derivatives or their salts represented by the general formula ▲ mathematical formula, chemical formula, table etc. ▼ (in the formula, R_4 is an alkyl group, a cycloalkyl group, or an aryl group or benzyl group with or without a halogen or alkoxy group as a substituent, R_5
means hydrogen, an alkyl group, or a benzyl group, and when R_4 and R_5 are both alkyl groups, they may be bonded) to form the general formula ▲mathematical formula, There are chemical formulas, tables, etc.▼ (In the formula, R_1, R_2, R_3, R_4 and R_5
1. A method for producing substituted alkyl-substituted phenoxycarboxylic acids, characterized in that a substituted alkyl-substituted phenoxycarboxylic acid derivative or a salt thereof is obtained as shown in (the same meaning as above).