RU2214995C1 - Method for preparing ortho-arylglycolic acids - Google Patents

Abstract

FIELD: organic chemistry, chemical technology. SUBSTANCE: invention relates to the improved method for preparing o-arylglycolic acids of the formula: ArOCH₂COOH. Method involves condensation of haloidacetic acid esters with phenols in the presence of bases and saponification of synthesized o-arylglycolic acid esters to the end product at 10-30 C in medium of aprotonic bipolar solvent by treatment with equivalent amount of alkali aqueous solution to pH 9-10. Method allows to coincide two stages in preparing o-arylglycolic acids to a single stage. Method allows carrying out process under the more mild conditions, to enhance yield and to synthesize o-arylglycolic acids comprising labile groups. Some of synthesized o-arylglycolic acids can be used for preparing antisera in development of immunochemical methods for assay of anabolic steroids. EFFECT: improved preparing method.

Description

 The invention relates to the field of organic chemistry - a method for producing o-aryl glycolic acids [1].

 A known method for producing o-aryl glycolic acids (I) by condensation of a haloacetic acid ester with phenols under the action of a base (sodium ethylate, potassium carbonate, sodium iodide, etc.), followed by the isolation of synthesized esters of o-aryl glycol acids (II) and saponification them to o-aryl glycolic acids (I) using an excess of an aqueous alkali solution when heated in an aqueous-alcoholic medium (Scheme 1) [1, 2], (given at the end of the description).

 Thus, for example, o-aryl glycolic acid (Ia) is synthesized based on estradiol (III) [1].

 However, it is difficult to extend this method to obtaining o-aryl glycolic acid (IB) containing an oxyacetylene moiety.

 It is known that compounds containing a similar group are easily hydrolyzed in the presence of aqueous solutions of bases, and in the presence of alcohols they are attached via a triple bond (Scheme 2) [3] (shown at the end of the description).

In order to eliminate these shortcomings, we developed a new method for producing o-aryl glycolic acids (I), characterized in that o-aryl glycolic acids are obtained in one step and saponification of o-aryl glycolic acid esters (II) formed during the reaction is carried out at 10-30 ^o With an aprotic bipolar solvent in the medium with an equivalent amount of an aqueous solution of alkali, gradually adjusting the pH of the mixture at the end of the reaction to 9-10 units.

 Essentially, the process of saponification of o-aryl glycolic acid esters (II) is reduced to the process of titration at room temperature.

 The high hydrolysis rate of o-aryl glycolic acid esters (II) is due to the use of highly polar solvents and a significantly higher degree of dissociation of o-aryl glycolic acids (I) compared to the corresponding benzoic acids.

 Selected mild conditions for the saponification of esters (II) make it possible to obtain o-aryl glycolic acid (Ib) containing a labile hydroxyacetylene group in high yield.

 Using the developed method of saponification of esters (II), it is possible to replace the two-stage method for producing o-aryl glycolic acids (I) with a single-stage. A new method for producing o-aryl glycolic acids (I) is characterized in that the condensation of esters of haloacetic acids with phenols and the subsequent conversion of esters of o-aryl glycol acids (II) into the target product are carried out in one stage.

So, o-aryl glycolic acid (Ia) is obtained in good yield by treating a solution of methyl ester of chloroacetic acid and estradiol (III) in dimethyl sulfoxide with an equivalent amount of an aqueous solution of potassium hydroxide at 20 ^o C.

The proposed method is of general importance and can be extended to obtain various o-aryl glycolic acids (I). For example, n-chlorophenyl glycolic acid (Ic) is obtained in up to 96% yield. The reaction is already at a temperature of 10 ^o C.

The invention is illustrated by the following examples.
Example 1

Obtain o- [19-nor-17α-ethynyl-17β-hydroxypregn-1,3,5 (10) -trien-3-yl] glycolic acid (IB)
A solution of 29.6 mg (0.1 mmol) of ethinyl estradiol (IV) in 0.4 cm ^{3 of} dimethyl sulfoxide is added with stirring to a suspension of 22 mg (0.4 mmol) of powdered caustic potassium in 0.4 cm ^{3 of} dimethyl sulfoxide. After 30 minutes, a solution of 22 mg (0.2 mmol) of chloroacetic acid methyl ester in 0.1 cm ^{3 of} dimethyl sulfoxide was added, stirred for 1 hour, then 0.1 cm of water was added and stirring was continued for 30 minutes. The reaction mass is diluted with 5 cm ^{3 of} cold water (pH 9.0-9.5), transferred to a separatory funnel, acidified with 5% hydrochloric acid and extracted with 2, 1 and 1 cm ^{3 of} ethyl acetate sequentially. The combined ethyl acetate extracts are washed with 2 portions of 5 cm ^{3 of} water, shaken with 0.5 cm ^{3 of} saturated brine, dried over sodium sulfate, clarified with activated carbon and evaporated in vacuo in a water bath at 100 ^° C. The oily residue crystallizes upon cooling.

297 mg (84%) of o-aryl glycolic acid (Ib) are isolated, mp. 180-181 ^o C.

IR spectrum (KBr), cm ^-1 : 1736 s, 1215 s (COOH), 1610 sr (Ar), 1500 sr, 1160 sr, 3280 s (OH, C = CH).

1 H-NMR spectrum (CDCl ₃ ), ppm: 0.88 (3H, CH ₃ ), 2.62 s (1H, C = CH), 2.86 s (2H, CH ₂ ), 4.65 s (2H, OCH ₂ ), 6.67 s (1H, Ar), 6.72 d (1H, Ar), 7.28 m (1H, Ar).

 Example 2

 Obtain o- (p-chlorophenyl) glycolic acid (Ic).

A solution of 130 mg (1 mmol) of p-chlorophenol and 214 mg (1 mmol) of ethyl ester of iodoacetic acid in 3 cm ^{3 of} dimethyl sulfoxide is treated with cooling (8-10 ^° C) 112 mg (2 mmol) of potassium hydroxide in 0.2 cm ³ water, stirred for 2 hours at 10 ^o C and evaporated in vacuo. The residue was diluted with water, shaken with ethyl acetate and acidified with 10% hydrochloric acid to pH 2.

 The precipitated o- (p-chlorophenyl) glycolic acid (Ic) was separated by filtration.

Obtain 67 mg (36%) of acid (Ic), so pl. 155-156 ^o With (water-methanol). Literature data: so pl. l55-156 ^o C [4].

 Example 3

Obtain o- (p-chlorophenyl) glycolic acid (Ic)
A solution of 130 mg (1 mmol) of p-chlorophenol and 428 mg (2 mmol) of ethyl ester of iodoacetic acid in 3 cm ^{3 of} dimethyl sulfoxide is treated at 8-10 ^{° C.} with 224 mg (4 mmol) of potassium hydroxide in 0.4 cm ^{3 of} water. After a few hours, the excess dimethyl sulfoxide is distilled off in vacuo, and the mixture is diluted with water and acidified to pH 2.

The yield of acid (Ic) 110 mg (59%), so pl. 154-155 ^o C.

 Example 4

 Obtain o- (p-chlorophenyl) glycolic acid (Ic).

A solution of 215 mg (1 mmol) of ethyl p-chlorophenoxyacetic acid in 4 cm ^{3 of} dimethyl sulfoxide is treated with stirring with a solution of 40 mg (1 mmol) of sodium hydroxide in 0.3 cm ^{3 of} water at a temperature of 30 ^o C, incubated for 30 minutes (pH 10) and processed as described in example 3.

The yield of o- (p-chlorophenyl) glycolic acid (Ic) 185 mg (86%), so pl. 155-156 ^o C.

 Example 5

Obtain o- [17β-hydroxy-estra-1,3,5 (10) trien-3-yl] glycolic acid (Ia)
To a solution of 272 mg (1 mmol) of estradiol (III) and 0.22 cm ³ (334 mg, 2 mmol) of ethyl bromoacetate in 8 cm ^{3 of} dimethyl sulfoxide, a solution of 224 mg (4 mmol) of potassium hydroxide is added dropwise with vigorous stirring 0.7 cm ^{3 of} water for an hour, incubated for 30 minutes at 20 ^o C (pH 9.5-10.0), diluted with 60 cm ^{3 of} water and extracted with 3 portions of 15 cm ^{3 of} ethyl acetate. Further processing is carried out as described in example 1.

Get o-arylglycolic acid (Ia) with a yield of 95%, so pl. 186-187 ^o C. Literature data: so pl. 187-188 ^o C [1].

 Example 6

Obtain o- [19-nor-17α-ethynyl-17β-hydroxy-pregna-1,3,5 (10) -trien-3-yl] glycolic acid (IB)
A solution of 382 mg (1 mmol) of ethyl ester (IIb) in 6 cm ^{3 of} dimethyl sulfoxide was treated at 20 ^° C. dropwise twice with 220 mg of 10% sodium hydroxide solution (1.1 mmol) with vigorous stirring. The contents of the flask gradually thicken. After two hours, the reaction mass was diluted with 50 cm ^{3 of} cold water (pH 9.0-9.5) and treated as described in Example 1. 326 mg (92%) of o-aryl glycolic acid (Ib) were obtained, so pl. 181-182 ^o C (ethyl acetate-hexane).

 Example 7

Obtain o- [19-nor-17α-ethynyl-17β-hydroxy-pregna-1,3,5 (10) -trien-3-yl] glycolic acid (IB)
A solution of 38.2 mg (0.1 mmol) of ethyl ether (IIb) in 1 cm ^{3 of} dimethylacetamide is treated twice with 22 mg (0.11 mmol) of a solution of sodium hydroxide in 0.05 cm ^{3 of} water with vigorous stirring, incubated for 1 hour at 30 ^o C and diluted with water (pH 9.5-10.0). The reaction mixture is treated as described in example 2.

Get 78% of o-arylglycolic acid (IB), so pl. 179-180 ^o C.

 Example 8

O- [19-nor-17α-ethynyl-17β-hydroxy-pregn-1,3,5- (10) trien-3-yl] glycolic acid ethyl ester is obtained (IIb)
A mixture of 296 mg (1 mmol) of ethinyl estradiol (IV), 200 mg of finely ground potassium carbonate, 10 mg of benzyltriethylammonium bromide, 0.22 cm ³ (334 mg, 2 mmol) of ethyl bromoacetate and 4 cm ^{3 of} acetone are boiled for several hours in a water bath .

Acetone is distilled off, and the oily residue is triturated with 10 cm ^{3 of} hexane. The precipitated crystals are separated by filtration. The yield of ethyl ether (IIb) 350 mg (94%), so pl. 95-96 ^o C (methanol).

IR spectrum (KBr), cm: 1760 s, 1225 s (COOC ₂ H ₅ ), 1610 cp (Ar), 3330 s, 3390 s. w. (OH, CH≡CH).

1 H-NMR spectrum (CDCl ₃ ,), ppm: 0.88 s (3H, CH ₃ ), 1.38 t (3H, CH ₃ ), 2.62 s (1H, CHCH), 2.83 s (2H , CH ₂ Ar), 4.25 kV (2H, OCH ₂ ), 4.62 s (2H, OCH ₂ COOEt), 6.63 s (1H, Ar), 6.72 d (1H, Ar), 7.26 m (1H , Ar).

 O-aryl glycolic acids (I) are of great practical importance. For example, o-aryl glycolic acid (Ia) is used as a hapten in the preparation of antisera for the determination of the anabolic steroid estradiol (III) in physiological fluids and tissues of animals and humans by immunochemical methods [1].

 In a similar way, o-aryl glycolic acid (Ib) can be used to determine the anabolic steroid, ethinyl estradiol (IV), which is illegally used in animal husbandry.

Sources of information
1. US patent 3966744, cl. 546-125, 1976.

 2. S.A. 72, p. 66698 c.

 3. Volkov AN, Skvortsov Yu.M. et al. - Organic Chemistry, 1970, v.6, 5, p. 897-902.

 4. Chemical Reference Aldrich, 1990, c. 311.

Claims (1)

A method of producing o-aryl glycolic acids of the general formula:
ArOSN ₂ COOH,
where Ar is a substituted phenyl or steroid radical

where R = H or C≡CH,
by condensation of haloacetic acid esters with phenols in the presence of alkaline agents and subsequent saponification of the isolated o-aryl glycolic acid esters with an aqueous or aqueous-alcoholic alkali solution by heating and acidification, characterized in that the o-aryl glycolic acids are obtained in one step and the saponification is formed during the reaction esters of o-aryl glycolic acids are carried out at 10-30 ^o C in an aprotic bipolar solvent with an equivalent amount of an alkaline aqueous solution so that the pH of the mixture at the end of the reaction and did not exceed 9-10 units.

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