RU2192408C2 - Method of synthesis of substituted aryloxyacetic acid - Google Patents

Abstract

FIELD: organic chemistry, chemical technology. SUBSTANCE: invention relates to method of synthesis of aryloxyacetic acid of the general formula (I)

where X means -C(Et)=C(Et)-; -CH(Et)- -CH(Et)- . Method involves condensation of phenol of the general formula (II)

Description

 The invention relates to the field of organic chemistry - a method for producing substituted aryloxyacetic acid of the general formula (I).

где Х=-С(С₂Н₅)=С(С₂Н₅)- (а); СН(С₂Н₅)СН(С₂Н₅)- (б).

where X = —C (C ₂ H ₅ ) = C (C ₂ H ₅ ) - (a); CH (C ₂ H ₅ ) CH (C ₂ H ₅ ) - (b).

с последующим омылением полученных эфиров водным или водно-спиртовым раствором щелочи и подкислением минеральной кислотой [ Патент ФРГ 1643460 (кл. 12q, 14/04); Патент ФРГ 1668896 (кл. 12q, 14/04; МКИ С 07 с 59/24); J. Org. Chem. 38, 20, 3525-3533 (1973); J.A. Katzenellbogen, H.N. Myers, H.J. Johnson (прототип)].A known method for producing aryloxyacetic acids (II) in two stages, based on the condensation of phenols with esters of haloacetic acids under the action of bases

followed by saponification of the obtained esters with an aqueous or aqueous-alcoholic solution of alkali and acidification with mineral acid [German Patent 1643460 (CL 12q, 14/04); German patent 1668896 (CL 12q, 14/04; MKI C 07 with 59/24); J. Org. Chem. 38, 20, 3525-3533 (1973); JA Katzenellbogen, HN Myers, HJ Johnson (prototype)].

 However, when using this method for the synthesis of aryloxyacetic acids (I), a number of difficulties arise. Even if an equimolar amount of the base is used, a difficult to separate mixture of three products is obtained: the starting phenol (III), monoester (IV) and diester (V), which are separated by preparative chromatography [J. Org. Chem. 38, 20, 3525-3533 (1973); J.A. Katzenellbogen, H.N. Myers, H.J. Johnson].

(III-V), X=-C(C₂H₅)=C(C₂H₅)- (а);
-CH(C₂H₅)-CH(C₂H₅)- (б),
y = Cl или Br.

(III-V), X = —C (C ₂ H ₅ ) = C (C ₂ H ₅ ) - (a);
-CH (C ₂ H ₅ ) -CH (C ₂ H ₅ ) - (b),
y = Cl or Br.

 In addition, the work is complicated by the need for saponification of ether (IV), which is accompanied by a decrease in the yield of the target product and an additional expenditure of working time.

In order to eliminate these disadvantages, we have developed a new, one-step method for producing aryloxyacetic acid of the general formula (I), characterized in that the phenol of the general formula (III) is condensed with a haloacetic acid ester in the presence of an alkaline agent in an organic solvent medium or in a mixture thereof, followed by acidification of the reaction mixture and extraction of reaction products with a 3-20% aqueous alkali solution, keeping the obtained alkaline extract at 20-100 ^o C for 8-12 hours, neutralizing to a pH of 6-8, separating you fallen starting phenol, acidifying the extract to pH 1 and isolating the target product in the usual manner. The reaction mass is extracted with ether or a mixture of ether with dioxane or tetrahydrofuran.

 The minimum concentration of alkali (caustic soda or caustic potassium) should be such that it allows extraction of compounds having a phenolic group. The optimal concentration of alkali is 3-20%.

An alkaline extract containing the starting phenol (III) and monoester (IV) is kept at 20 ^° C for several hours or heated to 100 ^° C in order to saponify the ether (IV).

 After alkaline extraction, diester (V) can be isolated from the organic solvent.

 The progress of the reaction and the extraction process is controlled by thin layer chromatography on silica gel plates "Silufol-254". A mixture of chloroform and ether in a ratio of 97: 3 is used as the mobile phase during chromatography at the stage of the reaction, while a mixture of chloroform and methanol in a ratio of 90:10 is used to control the formation and purity of aryloxyacetic acids (I). The plates are viewed in UV light or sprayed with 0.1% alcohol solution of bromphenol blue.

The PMR spectrum was recorded on a Bruker-300 instrument, the solvent was DMSO-d ₆ , and the standard was tetramethylsilane.

 The invention is illustrated by the following examples.

 Example 1

A solution of 0.536 g (2 mmol) of diethylstilbestrol (IIIa) in 24 cm ^{3 of} absolute ethyl alcohol is treated with 1.7 cm ³ 2 N. sodium ethoxide solution, mixed with 1.0 g (6 mmol) of ethyl bromoacetic acid, incubated for 1 hour at 20 ^° C, diluted with 30 cm ^{3 of} ether, 30 cm ^{3 of} water, the reaction mixture was acidified with concentrated hydrochloric acid to pH 1, shaken and the upper ether layer is separated. The ether extract is washed with three portions of water, 5 cm ³ each, and extracted with 3% potassium hydroxide solution until the extract no longer becomes cloudy upon acidification.

Alkaline extracts are combined, incubated for 8-12 hours at 20 ^o C in nitrogen atmosphere and acidified to pH 6-8. The precipitate of the starting phenol (IIIa) was separated by filtration. The filtrate was acidified with concentrated hydrochloric acid to pH 1. The precipitate of acid (Ia) was washed three times with water on a filter and dried in air.

Obtain 0.27 g (41%) of 4- [1-ethyl-2 (4-hydroxyphenyl) -1-butenyl] phenoxyacetic acid (Ia) with T. pl. 153-154 ^o C (benzene). Rf 0.45. 1 H-NMR: δ (ppm) 0.7t (6H), 2.08 m (4H), 4.65 s (2H), 6.8-7.4 m (8H), 7.36 s (1H).

 Example 2

A solution of 0.54 g (2 mmol) of hexestrol (IIIb) in a mixture of 24 cm ^{3 of} methanol and 6 cm ^{3 of} tetrahydrofuran is treated with 1 equivalent of 2 N. methanol solution of sodium methylate, mixed with 1 equivalent of methanol solution of ethyl ester of chloroacetic acid, boiled for 8 hours, cooled and diluted with 30 cm ^{3 of a} 20% solution of tetrahydrofuran in ether. Next, the reaction is treated in the same way as in the preparation of acid (Ia). A 20% sodium hydroxide solution is used for extraction. Saponification is carried out by heating at 90-100 ^o C for one hour.

Obtain 0.25 g (39%) of 4 [1-ethyl-2- (4-hydroxyphenyl) butyl] phenoxyacetic acid (IB) with T. pl. 135 - 137 ^o C (benzene). Literature data: So pl. 137-140 ^o With (benzene) [J. Org. Chem. 38, 20, 3525-3533 (1973); JA Katzenellbogen, HN Myers, HJ Johnson].

 The obtained aryloxyacetic acids (I) can be used as starting materials for the preparation of conjugates with proteins in the development of immunochemical methods for the determination of hormones (for example, diethylstilbestrol, hexestrol).

 In addition, aryloxyacetic acids of this type exhibit antioxidant and anti-inflammatory properties.

Claims (1)

The method of obtaining aryloxyacetic acid of the General formula

where X = —C (Et) = C (Et) -; -CH (Et) -CH (Et) -,
characterized in that the phenol of the general formula

subjected to condensation with a haloacetic acid ester in the presence of an alkaline agent in an organic solvent or a mixture thereof, followed by acidification of the reaction mixture and extraction of the reaction products with a 3-20% aqueous alkali solution, keeping the obtained alkaline extract at 20-100 ^o C for 8-12 hours , neutralization to pH 6-8, separation of the precipitated starting phenol, acidification of the extract to pH 1 and the selection of the target product.