RU2026855C1 - Method of synthesis of 2-methoxyisobutyric acid - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product 2-methoxyisobutyric acid, empirical formula is C₅H₁₀O₃, b. p. is 98-100 C/20 mm mercury column; n $\genfrac{}{}{0ex}{}{\text{2}}{\text{D}}$ ⁰ = 1.4208; d $\genfrac{}{}{0ex}{}{\text{2}}{\text{4}}$ ⁰ = 1.0589; MR_D = 28.24. Reagent 1: chloroform. Reagent 2: acetone. Reagent 3: spirituous alkali solution. Reaction conditions: 0 C, exposition at 20-22 C, mole ratio chloroform:acetone:alkali = 1:(1.2-2.5):(4-6), respectively. EFFECT: improved method of synthesis. 2 tbl

Description

 The invention relates to the field of the pharmaceutical industry, specifically to an improved method for producing 2-methoxyisobutyric acid, which finds application as an intermediate in the synthesis of various drugs.

 A known method of producing 2-methoxyisobutyric acid, which consists in the fact that sodium methylate is added to a methacrylic acid ester followed by hydrolysis of the resulting product. The disadvantages of this method include the low quality of the target product due to the presence in it of an impurity by-product of the reverse addition of sodium methylate.

 There is also known a method for producing 2-methoxyisobutyric acid, which consists in the fact that the nitrile of 2-hydroxyisobutyric acid is esterified with the simultaneous saponification of the nitrile group. The disadvantages of this method are the use of highly toxic nitrile 2-hydroxyisobutyric acid, especially when carrying out the process in an acidic environment created by phosphorus pentoxide and difficulty in working with large quantities of phosphorus pentoxide. The yield of the target acid is 67%.

The closest in technical essence and attainable result is a method for producing 2-metoksiizomaslyanoy acid, comprising reacting hloretona with alkali in alcoholic medium at their molar ratio of 1: 4 respectively, wherein hloreton added in an alcoholic solution of alkali at a temperature not higher than ⁰ ° C, after which the reaction mixture was kept for 1 hour at 20-22 ° ^C. The yield of the target product 71%.

 The disadvantage of this method is the inaccessibility of the original - chloroethone, which is usually obtained from chloroform and acetone under alkaline conditions with a yield of about 40%, and to increase this yield additional conditions are required, for example, the use of liquid ammonia.

 The purpose of the invention is to simplify the process.

The goal is achieved by the proposed method for producing 2-methoxyisobutyric acid, which consists in the interaction of a mixture of chloroform and acetone with alkali in methanol at a molar ratio of chloroform: acetone: alkali of 1: 1.2-2.5: 4-6, respectively, while chloroform and acetone is added to the alcoholic solution of alkali at a temperature not higher than ⁰ ° C, then the reaction mixture was kept at 20-22 ^{° C} overnight. The yield of the target product is 58%.

 Distinctive features of the process are the use of a chlorine-substituted chloroform derivative, which is introduced into the process simultaneously with acetone, and hydrolysis at a molar ratio of chloroform: acetone: alkali of 1: 1.2-2.5: 4-6, respectively, which simplifies the process.

 A change in the molar ratio of the reagent, as well as an increase in the process temperature above that indicated, leads to a sharp decrease in the yield of the target product.

 PRI me R s 1-15.

H+3MetCl где Met=Na или К.CH ₃ COCH ₃ + CHCl ₃ + MetOH + CH ₃ OH _____ (CH ₃ )

H + 3MetCl where Met = Na or K.

A mixture of chloroform and acetone is added dropwise to an intensely stirred solution of caustic alkali in methanol while cooling. Upon completion of the addition the mixture temperature is observed precipitation and spontaneous increase, the reaction mixture vigorously cooled to the temperature of the reaction mixture did not exceed 45 ^C. The reaction mixture was left at room temperature overnight, the inorganic precipitate was filtered off, washed with methanol, methanol was evaporated, the residue was adjusted with sulfuric acid to pH 1, the inorganic precipitate is filtered off, the mother liquor is extracted with ether. The ether layer was dried, the ether was evaporated, and the residue was distilled. Get 2-methoxyisobutyric acid with so Kip. 98-100 ^about C / 20 mm Hg .; n _D ²⁰ 1.4208; d ₄ ²⁰ 1.0589; MR _D 28.24; MR _Habit. 28.47.

 Found,%: C 50.78; H, 8.39.

C ₅ H ₁₀ O ₃ .

 Calculated,%: C 50.84; H, 8.47.

(Literature data: b.p. 98-99 ^{° C} at 20 mm Hg.).

 The process parameters are summarized in table. 1.

 PRI me R s 16-18. Obtaining methyl ester of 2-methoxyisobutyric acid.

To a solution of 2-methoxyisobutyric acid in methanol is added the resin KU-2-8 in the H ⁺ form. At the end of the reaction, the resin is filtered off, washed with methanol, the methanol is evaporated, the residue is washed with concentrated brine and distilled. Get methyl ester of 2-methoxyisobutyric acid with so Kip. 136-137 ° ^C / 760 mm Hg .; n _D ²⁰ 1.4036; d ₄ ²⁰ 0.9815; MR _D 32.86; MR _Habit. 33.20.

 Found,%: C 54.20; H, 8.94.

C ₆ H ₁₂ O ₃ .

 Calculated,%: C 54.54; H, 9.10.

(Literature data: b.p. 134-135 ° ^C / 760 mm Hg.).

 The conditions for esterification and yield are given in table. 2.

 PRI me R 19. Obtaining the amide of 2-methoxyisobutyric acid.

To 108 ml of concentrated ammonia solution, 19.5 g (0.15 mol) of 2-methoxyisobutyric acid methyl ester and the minimum amount of methanol required to obtain a homogeneous solution (30 ml) are added. The reaction mixture was left at room temperature for 48 hours, after evaporation of the solvents, the residue was recrystallized from benzene-acetone (2: 3). 13 g (75%) of 2-methoxyisobutyric acid amide are obtained with a melting point of 116-118 ^about S.

 Found,%: C 51.30; H, 9.33; N, 11.95.

C ₅ H ₁₁ NO ₂ .

 Calculated,%: C 51.78; H, 9.40; N, 11.96.

Chromatogram on silufol UV-254 in the system ammonia: chloroform: isopropanol 1: 8: 4 - one spot with R _f - 0.25.

 PRI me R 20. Obtaining 2-methoxyisobutylamine.

To a suspension of 13 g of lithium aluminum hydride in 400 ml of dry diethyl ether, 20.0 g (0.17 mol) of 2-methoxyisobutyric acid amide are added portionwise and the reaction mixture is boiled for 10 hours. After cooling, the excess lithium aluminum hydride is decomposed by successive addition of 13 ml of water, 13 ml of a 15% aqueous sodium hydroxide solution and 39 ml of water, the precipitate is filtered off and washed with ether. The ether solution was dried with magnesium sulfate and evaporated, and the residue was distilled. 16.4 g (93%) of 2-methoxyisobutylamine are obtained with b.p. 122-123 ^{° C} (762 mm Hg..); n _D ²⁰ 1.4204; d ₄ ²⁰ 0.8661; MR _D 30.12; MR _Habit. 30.36.

 Found,%: C 58.00; H 12, 52; N, 13.74.

C ₅ H ₁₃ NO.

 Calculated,%: C 58.25; H, 12.62; N, 13.59.

(Published data:. Bp 124-125 ^{° C,} 123-124 ° ^C).

Chromatogram on silufol UV-254 in the system ammonia: chloroform: isopropanol 1: 8: 4 - one spot with R _f 0.48.

 As can be seen from the above examples, the proposed method is simple to implement, based on the use of available starting compounds.

Claims (1)

METHOD FOR PRODUCING 2-METHODSI-BASIC ACID using the interaction of alkali and a chlorine-substituted aliphatic compound in methanol at a temperature not higher than 0 ^o С followed by keeping the reaction mass at 20-22 ^o С, characterized in that, in order to simplify the process, as a chlorine-substituted compound use chloroform, which is introduced into the alcohol solution of alkali simultaneously with acetone and the process is carried out at a molar ratio of chloroform: acetone: alkali of 1: 1.2-2.5: 4-6, respectively.

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