JPS5929578B2 - Method for producing substituted phenoxy fatty acids - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention is based on the general formula [wherein R1 is an alkyl group or a cycloalkyl group; A group represented by the formula -CH2=( )÷0H, R
2 means hydrogen, an alkyl group, a cycloalkyl group, a phenyl group or a benzyl group with or without a halogen, alkoxy group, or lower alkyl group as a substituent, and when R1 and R2 are both alkyl groups, both may be bonded] to the substituted phenols or their salts represented by the general formula (wherein,
R3 and R4 are hydrogen or an alkyl group, R5 is a carboxy group or an esterified carboxy group whose ester moiety is a lower alkyl, x is a halogen), or a salt thereof is reacted with the general formula [In the formula, K is an alkyl group, a cycloalkyl group, a phenyl group or benzyl group with or without a halogen, alkoxy group or lower alkyl group as a substituent, or a formula -0-C-R5 (in the formula, R3, R4 and R5 have the same meanings as before), R2, R3, R4 and R5 have the same meanings as before, and when K and R2 are both alkyl groups, they are bonded. The present invention relates to a method for producing substituted phenoxy fatty acids, which comprises obtaining substituted phenoxy fatty acid derivatives or salts thereof shown in [1].

The reaction of this invention is carried out by reacting the substituted phenol (1) or its salt with the fatty acid derivative (1) or its salt.

Substituted phenols are represented by the general formula (), and more specifically include alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, Cycloalkyl groups such as cyclohexyl and cycloheptyl, halogens such as chloro, fluoro, and bromine, alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tertiary butoxy, or lower alkyl groups such as methyl as substituents. phenyl or benzyl group with or without the formula -
Having a group represented by CH2=《 》-0H as R1,
It means a compound having as R2 hydrogen, an alkyl group, a cycloalkyl group as described above, a phenyl group or a benzyl group with or without a halogen, alkoxy group or lower alkyl group as a substituent, where R1 and R2 are When both are alkyl groups, they may be bonded to each other to form a group such as pyrrolidinyl, piperidino, homopiperidino, etc. together with the nitrogen atom.

Further, the number of the above-mentioned substituents in the phenyl group and benzyl group of R1 and R2 may be two or more, and in that case, those substituents may be different from each other. Salts of these substituted phenols 1) include salts with inorganic bases such as sodium salts, potassium salts, calcium salts, magnesium salts, salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates, and acetic acid. Examples include salts with organic acids such as salts, maleates, fumarates, tartrates, benzenesulfonates, and toluenesulfonates. The fatty acid derivative is represented by the above general formula (11), and more specifically, R and R4
It means a compound having as R5 an esterified carboxy group whose carboxy group or ester moiety is lower alkyl, and having a halogen such as chloro, bromo, or iodo as x.

Here, the esterified carboxy group in which the ester moiety of R5 is lower alkyl includes esterified carboxy groups in which the ester moiety is lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, Examples include groups.

Salts of these fatty acid derivatives (11) include salts with inorganic bases such as sodium salts, potassium salts, calcium salts, and magnesium salts, trimethylamine salts, triethylamine salts, N/N-dimethylaniline salts, pyridine salts, and vicolin salts. salts, and salts with organic bases such as N-mardibenzylethylenediamine salts. This reaction is usually carried out in a solvent, which includes, but is not limited to, water, ethanol, acetone, methyl isobutyl ketone, dimethylformamide, ether, benzene, etc., and does not adversely affect the reaction. Any solvent can be used.

In addition, this reaction usually involves alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, calcium carbonate, Alkaline earth metal carbonates such as magnesium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, inorganic bases such as alkali metal hydrides such as sodium hydride and potassium hydride, sodium methoxide, sodium ethoxide, etc. alkali metal alkoxides, trimethylamine, triethylamine, triethanolamine, N-N-dimethylaniline, N-N-dimethylbenzylamine, N-N-dimethylpiperazine,
It is preferable to carry out the reaction in the presence of an organic base such as pyridine or quinoline, and these bases may be used in combination, and a liquid base may also be used as a solvent. The reaction temperature is not particularly limited, and the reaction can be carried out at any temperature from room temperature to heating.

The thus obtained substituted phenoxy fatty acid derivatives and their salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, acetate, maleate, fumarate, tartrate, benzenesulfonate, Acid salts of organic acid salts such as toluene sulfonate or salts with inorganic bases such as sodium salts, potassium salts, calcium salts, magnesium salts, organic bases such as triethylamine salts, N-N-dimethylaniline salts, pyridine salts, etc. It may also be converted into a salt with a base such as a salt with.

The object substance (e) of the present invention and its salts are novel substances, have a cholesterol-lowering effect, and are useful as medicines.

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

Example 1 4-(4-chloroanilinomethyl)phenol 1500
A mixture of 632 mmol of ethyl ester of 2-bromo-2-methylpropionic acid, 7.5 ml of methyl isobutyl ketone and 448 tons of potassium carbonate is heated under reflux for 6 hours.

Remove insoluble materials from the reaction solution, wash the solution with water, dry it, and then concentrate. The residue (730') Wl9) was purified by column chromatography using silica gel 227 and chloroform as a developing solvent to obtain 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionic acid. 410% of the ethyl ester was obtained. Mp58-605℃
. Example 2 To a solution of 0.256 fl of sodium dissolved in 30 ml of ethanol, 27 g of 4-(4-chloroanilinomethyl)phenol was added, and then 2.02 g of ethyl ester of 2-promopropionic acid was added dropwise at room temperature. Heat to reflux for 5 hours.

Ethanol was distilled off from the reaction solution, 20 ml of water was added to the residue, and the mixture was extracted with ether. The extract is washed twice with a saturated aqueous sodium chloride solution, dried, and then the solvent is distilled off. The residue (2.97) was purified by column chromatography using silica gel 607 and chloroform as the developing solvent, resulting in an oil component of 2-[4-(4-chloroanilinomethyl)].
Ethyl ester of phenoxy]propionic acid 2.17 is obtained. Nuclear magnetic resonance absorption spectrum (CDCl3, δ) P
pm6.4-7.5 (8H,.m) 4.77 (1H,.m)
q,. J=7Hz) 4.23 (2H.q.J-7Hz) 4,20 (2H,.s) 4.1 (1H,.br0ads) 1.57 (3H,.d.J-7Hz) 1.22 (3H..t,.J-7Hz) Example 3 The following compound is obtained in the same manner as in the previous example.

(1) 2-(4-ethylaminomethylphenoxy)-
Hydrochloride of ethyl ester of 2-methylpropionic acid, M
pll7-119℃. (2) Ethyl ester of 2-[4-(1-pyrrolidinylmethyl)phenoxy]-2-methylpropionic acid, colorless oil.

Infrared absorption spectrum (liquid film) 1725, 1280, 1230, 1175, 1135,
1020C! RL-1(3) Ethyl ester of 2-(4-anilinomethylphenoxy)-2-methylpropionic acid, Mp 45-46°C.

(4) 2-(4-anilinomethylphenoxy)-2-
Hydrochloride of ethyl ester of methylpropionic acid, Mpl
58-163℃ o(5) Hydrochloride of ethyl ester of 2-[4-(p-anisidinomethyl)phenoxy]-2-methylpropionic acid, Mpll9-12'CO(6)
2-[4-(4-chloroanilinomethyl)phenoxy]
- hydrochloride of ethyl ester of 2-methylpropionic acid,
Mpl43-145°C.

(7) Hydrochloride of the ethyl ester of 2-(4-cyclohexylaminomethylphenoxy)-2-methylpropionic acid, Mpl4O~142°C. (8) Hydrochloride of ethyl ester of 2-(4-isobutylaminomethylphenoxy)-2-methylpropionic acid, Mpll 8-119°C
o]) 2-(4-benzylaminomethylphenoxy)
Hydrochloride of ethyl ester of 2-methylpropionic acid, M
pl38-139°C.

0) Hydrochloride of the ethyl ester of 2-[4-(p-toluidinomethyl)phenoxy]-2-methylpropionic acid, Mpl 33-135°C.

1) Hydrochloride of ethyl ester of 2-[4-(3-chloroanilinomethyl)phenoxy]-2-methylpropionic acid, Mpl46-148℃02) 2-[4-{N-
(4-chlorophenyl)1N-methylaminomethyl}phenoxy]-2methylpropionic acid ethyl ester,
Oil.

Infrared absorption spectrum (liquid film) 17301128011
235, 1175, 114011020c1n-13)
2-[4-chloroanilinomethyl)phenoxy]-2
-Methylpropionic acid, Mpl 55-158°C.

4) N-N-bis[4-(1-methyl-1-ethoxycarbonylethoxy)benzyl]ethylamine hydrochloride, Mpl 64-165°C.

5) Hydrochloride of the ethyl ester of 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylbutyric acid, M
pl35-137℃.

6) Hydrochloride of ethyl ester of 2-[4-{N-benzyl-N-(4-chlorophenyl)aminomethyl}phenoxy]-2-methylpropionic acid, Mpl37-14
1℃.

7) 2-[4-(4-chloroanilinomethyl)phenoxy]propionic acid, Mpl48-1490C~ 8) 2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylbutyric acid, Mpl52-153 ℃.

9) 2-[4-{N-methyl-N-(4-chlorophenyl)aminomethyl}phenoxy]-2methylpropionic acid, Mp 63-65°C.

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. group or benzyl group or a group represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼, R_2 is hydrogen, alkyl group, cycloalkyl group, phenyl with or without halogen, alkoxy group, or lower alkyl group as a substituent or a benzyl group, and when R_1 and R_2 are both alkyl groups, they may be bonded.] to the substituted phenols or their salts represented by the general formula etc.▼ (In the formula, R_3 and R_4 are hydrogen or an alkyl group,
R_5 is a carboxy group or an esterified carboxy group where the ester moiety is lower alkyl, and X is a halogen. ▼ [In the formula, R'_1 is an alkyl group, a cycloalkyl group, a phenyl group or a benzyl group with or without a halogen, alkoxy group, or lower alkyl group as a substituent, or a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_3, R_4 and R_5 have the same meanings as before), R_2, R_3, R_4 and R_5 have the same meanings as before, and when R'_1 and R_2 are both alkyl groups, both A method for producing substituted phenoxy fatty acids, which comprises obtaining a substituted phenoxy fatty acid derivative or a salt thereof, which may be bonded.