JPS5929579B2 - Method for producing substituted alkyl-substituted phenoxycarboxylic acids - Google Patents

Description

[Detailed description of the invention] This invention is based on the general formula Nin-CH2□O-IC! -R_5(I)R_.

(In the formula, R_1 and R_2 are hydrogen, an alkyl group, a phenyl group or a benzyl group having a halogen as a substituent, R_3 and R_4 are hydrogen or an alkyl group, R_5
each means an esterified carboxy group)
A compound represented by formula R_ is obtained by hydrolyzing the compound represented by formula R_.

Substituted alkyl substitution consisting of obtaining a substituted alkyl-substituted phenoxycarboxylic acid or a salt thereof represented by Neen N-CH200~÷1COoH R_4 (■) (wherein R_1, R_2, R_3 and R_4 each have the same meaning as before) This invention relates to a method for producing phenoxycarboxylic acids.

Compound (I) used as a raw material in this invention is a new compound, among which, for example, ethyl ester of 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionic acid is 4-[N- (4-chlorophenyl)formimidoyl]phenol is reacted with ethyl ester of 2-bromo-2-methylpropionic acid, and the resulting 2-[4-{N-(4-chlorophenyl)formimidoyl}phenoxy]- By reducing the ethyl ester of 2-methylpropionic acid or
2-[4-{N-(4-chlorophenyl)formimidoyl}phenoxy]-2- is obtained by reacting ethyl ester of (4-formylphenoxy)-2-methylpropionic acid with 4-chloroaniline. Alternatively, by reducing the ethyl ester of methylpropionic acid, 4-(
4-chloroanilinomethyl)phenol to 2-bromo-2
- It can be produced by reacting ethyl ester of methylpropionic acid, and it can also be produced by reacting 2-[4-{N-(
Ethyl ester of 4-chlorophenyl)-N-benzylaminomethyl}phenoxy]-2-methylpropionic acid is 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropion obtained by the above method. It can be produced by reacting benzyl bromide with ethyl ester of an acid, and other compounds can be produced in the same manner.

The reaction of this invention is carried out by hydrolyzing compound (1).

Same or different from the compound represented by general formula (1), hydrogen, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, etc., chloro, fluoro, bromine as substituents. A phenyl group or benzyl group having a halogen such as R
1 and R2, the same or different hydrogen or alkyl groups as described above as R3 and R4, and an esterified carboxy group as R5.

As the esterified carboxy group in R5,
For example, the ester moiety is methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, tertiary pentyl, cyclohexyl, cycloheptyl, vinyl, 1
-propenyl, allyl, 1,1-dimethyl-2-flopenyl, 3-butenyl, ethynyl, 1,1-dimethyl-2
- Saturated or unsaturated, linear or cyclic alkyl such as propynyl, aryl such as phenyl, xylyl, tolyl, naphthyl, aralkyl such as benzyl, phenethyl, trityl, diphenylmethyl, or the above saturated or unsaturated, linear or cyclic methoxymethyl in which the carbon atom of the alkyl part of the alkyl and aralkyl is interrupted with a sulfur atom, nitrogen atom, oxygen atom or carbonyl, etc.
Ethoxymethyl, methylthioethyl, methylthiomethyl, dimethylaminoethyl, diethylaminoethyl, phenoxymethyl, phenylthiomethyl, methylsulfinylmethyl, phenylsulfinylmethyl, benzoylmethyl, toluoylmethyl, acetamidoethyl, etc. Chloromethyl, bromomethyl, in which the group has one or more suitable substituents, such as halogen such as cyano, nitro, hydroxy, fluoro, chloro, bromo, iodo, alkoxy such as methoxy, ethoxy, pukapoxy, alkanesulfonyl, phenylazo, etc. , iodoethyl, trichloroethyl, cyanomethyl, 2-cyano-1,1 dimethylethyl, p-nitrophenyl, 2
・4,5-trichlorophenyl, 2,4,6-trichlorophenyl, pentachlorophenyl, p-mesylphenyl, 4-(phenylazo)phenyl, 2,4-dinitrophenyl, p-chlorobenzyl, 0-nitrobenzyl, p
-Methoxybenzyl, p-nitrobenzyl, 3, 4, 5
-trimethoxybenzyl, bis(p-methoxyphenyl)methyl, pentachlorobenzyl, trichlorobenzyl, 3,5-ditertiary butyl-4-hydroxybenzyl,
Esterified carboxy groups such as p-nitrophenylthiomethyl, p-chlorophenylthiomethyl, p-nitrobenzoylmethyl, p-chlorobenzoylmethyl, other thioalcohols substituted or unsubstituted with carboxy groups, N -Hydroxysuccinimide, N-hydroxyphthalimide, tetrahydropyranol, 1-cyclopropylethanol, 1,3-propanediol, 1
-Phenyl-3-methyl-5-pyrazolone, 3-hydroxypyridine, 3-hydroxymethylpyridine, 2-hydroxymethylpyridine-1-oxide, 1-hydroxypiperidine, 1-methyl-4-hydroxypiperidine, 1-hydroxy- 2(1H)-pyridone, dimethylhydroxylamine, diethylhydroxylamine, glycolamide, 8-hydroxyquinoline, oxime,
2-hydroxymethylquinoline-1-oxide, methoxyacetylene, ethoxyacetylene, N-N dimethyl-
3,3-dimethyl-1-butynylamine, N-N-diethyl-3,3-dimethyl-1-butynylamine, N-N-
Diethyl-1-butynylamine, 2-ethyl-5-(3
-sulfophenyl) isoxazolium hydroxide inner salt, 1,5,9,9,10-pentachloro-9,1
0-dihydroanthracene, 9,9,10-tricaro-9,10-dihydroanthracene, 1,8,9,10
- Esterified carboxy groups obtained by reaction with halogeno-9,10-dihydroanthracene derivatives such as 10-pentachloro-9,10-dihydroanthracene.

In this invention, the method of hydrolyzing compound (1) usually uses an acid or a base, and the acids used in the acid method include dic acid, trichloroacetic acid, trifluoroacetic acid, etc. trihaloacetic acid, hydrochloric acid, acetic acid,
Examples include hydrobromic acid, hydrofluoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, mixed acid of hydrochloric acid and acetic acid, acidic ion exchange resin, etc. When using a solvent in this method, a hydrophilic organic solvent , water or mixed solvents are often used. Examples of bases used in the base method include inorganic bases such as hydroxides, carbonates, and bicarbonates of alkali metals such as sodium and potassium, and alkaline earth metals such as magnesium and calcium. , trialkylamines such as trimethylamine and triethylamine, organic bases such as picoline, N-methylpyrrolidine, and N-methylmorpholine, and basic ion exchange resins. Basic methods are often carried out in water or a hydrophilic solvent or a mixture thereof. Further, in the present invention, when the esterified carboxy group is an active ester, the reaction often proceeds not only under normal hydrolysis conditions but also under mild hydrolysis conditions such as contact with water. The target product () obtained in this way is a salt of the carboxy group with an inorganic base such as sodium salt, potassium salt, calcium salt, magnesium salt, trimethylamine salt, triethylamine salt, N/N-dimethylaniline salt, pyridine salt, picoline salt, etc. salts, salts with organic bases such as N'merized benzylethylenediamine salts, or inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, acetates, maleates, fumarates, tartrates in their amino groups; , benzenesulfonate,
It may also be introduced into an acid salt such as an organic acid salt such as toluenesulfonate.

Substituted alkyl-substituted phenoxycarboxylic acids () and their salts, which are the target substances of this invention, are new substances, have cholesterol-lowering effects, and are useful as medicines.

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

Example 1 2-[4-(4-chloroanilinomethyl)phenoxy]
-2-Methylpropionic acid ethyl ester 6.147
A mixture of 130 ml of 95% ethanol and 52 ml of 1N aqueous sodium hydroxide solution was stirred at 70° C. for 50 minutes.

After concentrating the reaction solution under reduced pressure, the residue was dissolved in water and washed five times with ether. 55 ml of 1N hydrochloric acid is added to the aqueous layer while cooling, and the precipitated crystals are extracted twice with ether. The extract is washed twice with water and then dried over magnesium sulfate. After drying, the solvent is distilled off to obtain 5.67 g of 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionic acid. Colorless crystals, Mpl 55-158°C o Example 2 2-[4-(4-chloroanilinomethyl)phenoxy]
10.0 V of ethyl ester of propionic acid and 1.68 y of potassium hydroxide are dissolved in 50 ml of dry methanol and stirred for 5 hours at room temperature.

After concentrating the reaction solution, water is added to the residue to dissolve it, and this solution is washed with ether. The aqueous layer is acidified with hydrochloric acid and extracted with ether. The extract is washed with water, dried over magnesium sulfate, and then the solvent is distilled off. The obtained crystalline residue is recrystallized from benzene to obtain 8.0y of 2-[4-(4-chloroanilinomethyl)phenoxy]propionic acid. Mpl48-149℃O Example 3 1.27 ethyl ester of 2-[4-{N-(4-chlorophenyl)-Nmethylaminomethyl}phenoxy]-2-methylpropionic acid was dissolved in 20 ml of ethanol, and this solution Then 1N aqueous sodium hydroxide solution 15
Add m1 and stir at room temperature for 4 hours.

Ethanol was distilled off from the reaction solution under reduced pressure, the residue was dissolved in water, the pH was adjusted to 4 with 10% hydrochloric acid, and the precipitated crystals were collected and dried to give 2-[4-{N-(4-chlorophenyl)-N
-methylaminomethyl}phenoxy]-2-methylpropionic acid 0.94f is obtained. Mp63-65°C. Example 4 2.3y of ethyl ester of 2-[4-{N-(4-chlorophenyl)-N-benzylaminomethyl}phenoxy]-2-methylpropionic acid was dissolved in 40ml of ethanol, and 1N water was added to this solution. Sodium oxide aqueous solution 25m
1 and heated under reflux for 2 hours.

The reaction solution was concentrated under reduced pressure, the residue was dissolved in water, the pH was adjusted to 4 with 10% hydrochloric acid, and the precipitated crystals were collected and dried to give 2-[4
-{N-(4-chlorophenyl)-N-benzylaminomethyl}phenoxy]2-methylpropionic acid 1.9t
get. Mp65-67°C. Example 5 The following compound is obtained analogously to the previous example.

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. Alkyl group, R_5
each means an esterified carboxy group)
By hydrolyzing the compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. 1. A method for producing substituted alkyl-substituted phenoxycarboxylic acids, characterized by obtaining salts.