SU286643A1 - METHOD OF OBTAINING SUBSTITUTE PHENOXYL ACID - Google Patents

Description

The invention relates to a process for the preparation of 4- (2-methylene alkanoyl) -phenoxan-acetic acids and their non-toxic amides used in pharmacology. The invention also relates to 4- (2-hydroxymethylalkanoyl) -phenoxy-acetic acid intermediates, from which 4- (2-methylenealkanoyl) phenoxy-acetic acid is obtained. Pogde R is hydrogen, alkyl with Ci-Cj, trifluoromethyl, trifluoroethyl, 2,2,2-trifluoropropyl.

The usefulness of 4- (2-ox 1methylalkanoylphenox sp-acetic acids as intermediates, they also have physiologically active properties.

The process, based on the well-known formaldehyde condensation method, proceeds according to the following scheme: ts benzene cores can form hydrocarbonylene chain {t. e. divalent ortetramethylene, 1,3-butadienylene (-CHI CH- - CH CH-),

n is an integer from 1 to 2.

m is an integer higher than 1.

Condensation (i.e., the study of compound II) should be carried out with an aqueous solution of formaldehyde or its functional equivalent, for example paraformaldehyde, trioxa, etc., in the presence of an acid and, preferably, in an appropriate solvent, for example dioxane. The reaction is expediently carried out by heating, for example by heating the reaction mixture under reflux for a long time. The process is carried out without isolation of the intermediate hydroxylated product, since the optimum conditions for preparing 4- (2-hydroxymethylalkanoyl) phenoxy acetic acid (II) are also optimal for converting said intermediate II to their respective end products I. It should be noted that compounds II it is difficult to isolate, since their conversion into the target compounds I occurs very quickly, and therefore at any time there is a small amount of intermediate compound P. in the reaction mixture.

4- (2-Methylene alkanoyl) -phenoxy acetic acid (I) is usually obtained in the form of crystals. If necessary, they can be purified by recrystallization from appropriate solvents or a mixture of solvents, for example, from carbon tetrachloride, chlorobutyl, beizole, cyclohexane, etc., or mixtures thereof.

The acids obtained according to the invention can be converted by lime to various derivatives: amides, esters, salts, for example alkali or alkaline earth metals.

Example 1. 2,3-Dichloro-4- (2-methylenebutyryl) -feioxy-acetic acid.

A mixture of (2,3-dichloro-4-butyrylphenox) -acetic acid (11.6 g or 0.04 mol), paraformaldehyde (4.88 g or 0.163 mol), p-toluenesulfonic acid monohydrate (7.6 g or 0, 04 mol) and dioxaia (100 ml) stirred, heating on a steam bath, 20 hours. The temperature inside the reaction mixture is 86 ° C.

Taking small samples of the reaction mixture at determined time intervals, it is possible to determine the presence of intermediate {2,3-dichloro-4 (oxymethyl) -butyryl-phyoxy} acetic acid by thin layer chromatography and infrared spectroscopy.

The solvent is distilled off under vacuum (in a rotary evaporator), and the residue is dissolved in dichloromethane and washed with water.

The organic phase is present over magnesium sulfate, and the solvent is distilled off in a rotary evaporator. A solid residue of 9.2 g (76%) is 2,3-dichloro-4- (2 methylenebutyryl) phenoxy acetic acid. By recrystallization from carbon tetrachloride, a pure product with m.p. 124-125 ° C. Example 2. 2,3-Dichloro-4- (2-methylenebutyryl) -phenoxy-acetic acid.

The reaction is carried out as described in example 1, with the difference that instead of iaraformaldehyde take trioxane (4.88 g or 0.16 mol.), Instead of my hydrate-toluene sulfonic acid, co-nitrivium sulfuric acid (22 g or 0.04 mol-same .). The reaction mixture is heated for 11.5 hours. The yield after one crystallization is 6.5 g (54%) of 2,3-dichloro-4- (2-methylenebutyryl) - feioxy-acetic acid.

acid. The products are purified by recrystallization from carbon tetrachloride, so pl. 124-125 ° C.

Example 3. 2,3-Dichloro-4- (2-methylenebutyryl) -phenoxy-acetic acid.

The reaction is carried out in example 2 using sioosob, but instead of trioxane, they take a 38% aqueous formaldehyde solution (12.64 g or 0.16 mol.). The reaction is conducted 25 hours. Output after one crystallization of 6.45 g (53%)

2,3-dichloro - 4 (2 - methylenebutyryl) - phenoxy acetic acid. Recrystallization gives the purified product with an mp. 124-125 ° C. PRI me R 4. 2,3-Dichloro-4- (2-methylenebutyryl) -phenoxy-acetic acid.

The reaction is carried out using O1i-1 batch in example 1, but instead of l-toluenesulfonic acid monohydrate, boron trichloride etherate (5.68 g or 0.04 mol) is taken and heated for 7 hours.

2,3-Dichloro-4- (2 methylenebutyryl) -phenoxy-acetic acid thus obtained

melts at 124-125 ° C after several

recrystallization.

Analog to example 1 can be obtained

other substituted 4- (2-methylenalkanoyl) -phenoxy-acetic acid (I) compounds. So, take in the appropriate (4-alkaioylpheoxy) -acetic acid instead of (2,3-dichloro4-butyrylphenoxy) -acetic acid from example 1, using paraformaldehyde or its functional equivalent and leading further to the reaction described in example 1 4- (2-methylene alkanoyl) phenoxy-acetic acid (derivatives) and

and intermediate (2-hydroxymethyl) alkaioyl phenoxy} acetic acids of the invention. According to the scheme below, compounds are prepared analogously to example 1. The values of the radicals in the starting compounds and the constants

Whole products p) are presented in the table.

Xs X

3 lg

R-CH - S SU-O-SNg-S

SNGON O

R-C-C Wo-SNg-C

CH, O

0 OSI, -C + (SNGO).

HE

he

AZ

/

HE