JPS5929575B2 - Method for producing substituted phenoxy fatty acids - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing substituted phenoxy fatty acids, and the outline thereof is shown by the following formula.

(In the formula, X is a halogen, R1 and R2 are hydrogen, an alkyl group, a phenyl group or a benzyl group having a halogen as a substituent, and R3 and R4 are hydrogen or an alkyl group, respectively) Used as a raw material in the method of this invention The substituted phenol (1) is, for example, the general formula (wherein R1
and R2 have the same meanings as above) are reacted with hydroxy-substituted benzaldehyde, and then reduced.

The method of this invention is carried out by reacting the substituted phenol (1) or its salt with the compound () in the presence of a strong base.

Substituted phenols are represented by the general formula (1) above, and more specifically include hydrogen, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, and pentyl hexyl, and chloro, fluoro, etc. as substituents. , refers to a compound having a halogen-containing phenyl group or benzyl group such as bromine as R1 and R2.

These substituted phenols (1) can also be used in the form of salts, such as alkali metal salts such as sodium salts, potassium salts, acid salts such as hydrochlorides and hydrobromides. Examples include. The compound (), which is the other raw material, refers to a compound having hydrogen or the above-mentioned alkyl group as R3 and R4 in the general formula (), and having rogene such as chlor, bromine, etc. as X. means. The reaction between the substituted phenol (1) or its salt and the compound () is carried out in the presence of a strong base, and such strong bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydroxide, etc. Alkoxides, alkali metal alkoxides such as potassium alkoxide, etc. are frequently used.

This reaction is usually carried out in a solvent, and acetone, dioxane, ether, benzene, etc. are often used as the solvent, but any other solvent that does not adversely affect this reaction can be used.

Although the reaction temperature is not particularly limited, the reaction is usually carried out with or under heating in many cases. The reaction product is isolated and collected by conventional methods. The method of the present invention can also be carried out by reacting the substituted phenol (1) or its salt with a chloride () and a compound () in the presence of a strong base.

Chloroform or bromoform is often used as the rogen compound () used as a raw material in this reaction.

Further, the compound () means a compound having hydrogen or the above-mentioned alkyl groups as R3 and R4 in the general formula ().

Note that the substituted phenol (1
), its salts, and strong bases, those exemplified in the above reaction are also exemplified here. This reaction is usually carried out in a solvent, and dioxane, ether, benzene, etc. are often used as the solvent, but any other solvent that does not adversely affect this reaction can be used.

Note that when the compound () used as a raw material in this reaction is liquid, it can also be used as a solvent.
Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature, with heating, or under heating. The reaction product is isolated and collected by conventional methods. In addition, in this reaction, halide ()
and Compound () react in advance to produce Compound (), and the target compound (V) is obtained via this reaction product.

The substituted phenoxy fatty acid (V) obtained in this way can be optionally inorganic acid salts such as hydrochloride, hydrobromide, sulfate, or acetate, maleate, fumarate, tartrate, benzenesulfonate. , acid salts such as organic acid salts such as toluene sulfonate, sodium salts, potassium salts,
Triethylamine salts and synchhexylamine salts may be converted into salts with inorganic or organic bases.

Substituted phenoxy fatty acid (V) which is the object substance of this invention
and its salts are new substances that have cholesterol-lowering effects and are useful as medicines.

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

Example 1 4-(4-chloroanilinomethyl)phenol 11.7
7 and 16.8 V of powdered potassium hydroxide are suspended in 176 ml of acetone.

To this, 1-trichloromethyl-1-methylethanol 1
After dropping a solution consisting of 0.7y and acetone 8111, the mixture was heated under reflux for 55 hours. Filter the reaction solution and wash with acetone.

Combine the washing solution and the washing solution, and distill off the acetone under reduced pressure. Add 100 ml of water to the residue and diisopropyl ether 5
Wash twice with 0111. 150 d of ethyl acetate in aqueous solution
were laminated, and the pH was adjusted to 4 with 10% hydrochloric acid. The ethyl acetate layer is separated, and the aqueous layer is extracted with 50 ml of ethyl acetate. The extract was combined with the above ethyl acetate solution, washed with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate.
Removal of the solvent under reduced pressure yields residue 1567. Add 130 U1 of 5% sodium hydrogen carbonate aqueous solution to this,
Heat and dissolve at 50-55°C. After allowing this to cool, it is washed three times with 50 ml of ethyl acetate. Layer 100 ml of ethyl acetate on the aqueous solution, adjust the pH to 4 with 10% hydrochloric acid, and separate the ethyl acetate layer. Ethyl acetate 50TfL1
and combine the extract with the ethyl acetate solution. After washing this with a saturated aqueous solution of sodium chloride and drying with magnesium sulfate, the solvent was distilled off under reduced pressure.
2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionic acid 12.6 at 160 to 162°C
Get 7. Example 2 17 4-(4-chloroanilinomethyl)phenol and 1.44 f of powdered potassium hydroxide were added to 10 m of acetone.
1.

Add 0.54 ml of chloroform to this dropwise at room temperature, and
Stir at ℃ for 5.5 hours. Acetone is distilled off from the reaction solution, water is added to the residue, and the mixture is washed with ether. 1 aqueous solution
Adjust the pH to 4 with 0% hydrochloric acid and extract with ethyl acetate. The extract is back-extracted with a saturated aqueous solution of sodium hydrogen carbonate, and the pH of this extract is adjusted to 4 with 10% hydrochloric acid. This is extracted again with ethyl acetate, the extract is washed with water, dried, and the solvent is distilled off under reduced pressure. Recrystallization of the residue from ethanol yields 2-[4-(4-
0.87 of chloroanilinomethyl)phenoxy]-2-methylpropionic acid is obtained. Example 3 27 4-(4-chloroanilinomethyl)phenol is dissolved in 80 mj of dioxane.

4.8 y of powdered potassium hydroxide is added to this while stirring. 3.04f7 of 1-trichloromethyl-1-methylethanol was added little by little to this solution, and the mixture was stirred at 55°C for 3 hours. Dioxane is distilled off from the reaction solution under reduced pressure, water is added to the residue, and the residue is washed with ether. The aqueous solution was adjusted to pH 4 with 10% hydrochloric acid and extracted with ethyl acetate. 5% extract
Back-extract with aqueous sodium carbonate solution, and reduce this extract to 10%
Adjust the pH to 4 with hydrochloric acid. This is extracted again with ethyl acetate, and the ethyl acetate extract is washed with water, dried, and then the solvent is distilled off under reduced pressure. When the residue is washed with ethanol, M
2-[4-(4-chloroanilinomethyl)phenoxy]-2-methylpropionic acid with a pl of 58-161°C 0.7
Get 47. Example 4 4-(4-chloroanilinomethyl)phenol 107,
To a solution consisting of methyl ethyl ketone 50 WLI1, 13.87 ml of powdered potassium hydroxide and 100 ml of dioxane, 18.6 ml of tribromomethane is added dropwise at room temperature.

After heating and refluxing this for 5 hours, the solvent was distilled off under reduced pressure. After adding water to the residue and washing with Kotel, 10%
Adjust the pH to 4 with hydrochloric acid and extract with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off under reduced pressure. The residue was dissolved in 2.83y of sodium bicarbonate and 1007n1 of water.
Dissolved in an aqueous solution consisting of
Wash twice. Separate the aqueous layer, adjust the pH to 4 with 10% hydrochloric acid,
Extract twice with ethyl acetate. After washing this extract with water and drying, the solvent is distilled off. When the residue was washed with diisopropyl ether and the precipitated crystals were collected, Mpl52
4.27 of 2-methyl 2-{4-(4-chloroanilinomethyl)phenoxy}butyric acid at ˜153° C. is obtained. Example
5 The following compound was obtained in the same manner as above.

(1) 2-{4-(4-chloroanilinomethyl)phenoxy}propionic acid Mpl48-149℃o(2)
2-Methyl-2-[4-{N-(4-chlorophenyl)
-N-methylaminomethyl}phenoxy]propionic acid Mp 63-65°C.

(3) 2-Methyl-2-[4-{N-(4-chlorophenyl)-N-benzylaminomethyl}phenoxy]propionic acid Mp 65-67°C.

Claims (1)

[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. The substituted phenol or its salt represented by the general formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ (in the formula, R^3 and R^4 are hydrogen or an alkyl group,
(X means halogen) is reacted with a compound represented by a strong base in the presence of a strong base to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1, R^2, R^3 and A method for producing substituted phenoxy fatty acids, characterized in that a substituted phenoxy fatty acid or a salt thereof is obtained (R^4 has the same meaning as above). 2 Substitution represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. Phenol or its salts are combined with halides represented by the general formula CHX_3 (wherein, X means halogen) and the general formula R^3-CO-R^4 (wherein, R^3 and R^4 are hydrogen or The general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R^1, R^2, R^3 and R^ 4 has the same meaning as above) A method for producing substituted phenoxy fatty acids, characterized in that a substituted phenoxy fatty acid or a salt thereof is obtained.