RU2080317C1 - Process for preparing $$$-bromosubstituted fatty acid esters - Google Patents

Abstract

FIELD: fine organic synthesis. SUBSTANCE: fatty acid bromoanhydrides are prepared by mild bromination of aliphatic aldehydes with bromine first in clark and than in light with good yield. The resulting bromoanhydrides are then subjected to esterification with alcohol. EFFECT: more efficient preparation process. 4 cl

Description

 The invention relates to the field of fine organic synthesis, namely to the production of esters of α-bromo-substituted fatty acids, used, in particular, for the production of drugs, such as corvalol, valocardine, etc.

 It is known that esters are obtained by the reaction of esterification of acids with alcohols or by the action of alcohols on the halides of the corresponding acids [1]. The difficulty lies in the preparation of a-bromo-substituted fatty acids halides.

A known method of producing ethyl ester of a-bromisovalerianic acid by two-stage bromination of isovalerianic acid, moreover, in the first stage, the reaction is carried out in the presence of bromine and PCl ₃ at 70-80 ^o C for 10-20 hours and in the second stage in the presence of additional bromine at 100-105 ^o C for 1.5-2 hours

The resulting a-bromisovalerianic acid is converted to the acid chloride, which is subjected to esterification with aliphatic alcohol [2]
The disadvantage of this method is the multi-stage and complexity, insufficient purity of the final product, due to the presence of optically active impurities in the initial isovalerianic acid. In addition, the process is uneconomical (carried out at high temperature).

 The objective of the invention is to simplify the process of producing esters of a-bromo-substituted fatty acids and to increase the purity of the final products, which are intermediate substances for the synthesis of medicinal substances.

The problem is solved by the fact that aliphatic aldehydes are subjected to bromination (for example, isovalerianic, butyric). Bromination is carried out as follows: to a solution of aldehyde and an organic solvent (hexane, heptane, chloroform, carbon tetrachloride) in the dark with stirring, add bromine in an amount of 0.8-1 mol per 1 mol of aldehyde. The rate of addition of bromine is determined by the temperature range of the reaction. The temperature of the reaction medium should remain in the range of 20-35 ^o C. In this case, a-bromo-substituted aldehyde is formed. After decolorization of the reaction mixture, lighting (incandescent lamp) is turned on, the temperature is raised to 40-60 ^° C and 0.7-0.9 mol of bromine per mole of aldehyde is added. After bleaching, the temperature is raised to 70 ^° C., the corresponding alcohol (ethanol, menthol, etc.) is added in an amount of 1 to 1.5 mol per mol of aldehyde. After the completion of the isolation of HBr, the reaction mixture was kept at 70-75 ^° C for 5-10 minutes with stirring, then cooled to room temperature or lower (up to 10 ^° C), an approximately equal volume of water was added to the reaction mixture, the organic layer was separated, dry it and fractionate.

 Ethyl esters of the corresponding acids (a-bromo-substituted isovalerianic or butyric) are obtained from the a-bromo-substituted acid ethyl ester by transesterification with menthol.

The direct way is not known in the literature for the preparation of esters of a-bromo substituted acids from aldehydes by gentle bromination of aliphatic aldehydes for their subsequent esterification [3]
Example 1. In a reactor equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel with a tube reaching the bottom, 12 ml (0.1 mol) of 3-methylbutanal (isovalerian aldehyde), 18 ml of hexane are added and 5 are added with stirring in the dark ml (0.1 mol) of bromine at 20 ^o C. The first 3 drops of bromine are provided for 1 min, and the temperature rises to 28 ^o C. The entire amount of bromine (5 ml) is added in 5 minutes Isolation of HB a very insignificant bulk of hydrogen bromide remains in the reaction mass. The thermal effect is negligible. After bleaching, the temperature was raised to 50 ^° C., a 40 watt incandescent lamp was turned on, and 3 ml (60% of theory) of bromine were introduced over 4 minutes. The last drops of bromine are discolored slowly. Then the reaction mass is heated to 70 ^° C. and 8 ml of ethanol are introduced over a period of 2-3 minutes.

After the completion of the evolution of hydrogen bromide, the mixture was kept at 70 ^° C for several more minutes, then cooled, 40 ml of cold water containing 1 g of sodium sulfite was added, stirred, transferred to a separatory funnel, the organic layer was separated, dried with anhydrous sodium sulfate and distilled under vacuum. 12.0 g (58% of theory) of ether are obtained with b.p. 75-83 ^o / 15 ml, n ²⁰ = 1.1448. Re-distillation produces ethyl ester of a-bromosovalerianic acid with so on. 76 ^o / 15 mm, n $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{D}}$ 1,4478, D $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{4}}$ 1.2643, MP _D 44.25 (calc. 43.81).

Found, C, 40.55; H 6.42; Br 37.8;
Calculated, C 40.21; H 6.27; Br 38.22.

Example 2. In the reactor load 24 ml (0.2 mol) of isovaleriandehyde and 30 ml of heptane; at 30 ^° C. in the dark, 9 ml of bromine (0.18 mol) are added dropwise with stirring. After bleaching, the temperature was raised to 42 ^° C. and, under illumination with an incandescent lamp, 7.7 ml of bromine (0.15 mol) was gradually introduced. The solution is stirred until discoloration, the reaction mass is heated to 70 ^o C and injected with 10 ml of ethanol. Further, all operations are carried out as in example 1 (50 ml of water are added). 22.5 g (54% of theory) of α-bromisovalerianic acid ethyl ester are obtained with b.p. 75-78 ^o C / 15 mm, n $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{D}}$ 1.4560 .. By distillation, pure ethyl ester of α-bromisovalerianic acid with t. 77-78 ^o C / 15 mm, n $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{D}}$ = 1,4495, d $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{4}}$ 1.2813 ..

Example 3. 9.2 ml of butanal (0.1 mol) and 17 ml of hexane are charged into the reactor, 5 ml (0.1 mol) of bromine are gradually added in the dark with stirring at 25 ^° C. After the reaction mixture is discolored (about 5 minutes) ) turn on the incandescent lamp and when illuminated at 50 ^o C, another 5 ml of bromine is introduced. After bleaching the solution, the temperature was raised to 70 ^° C. and 8 ml of ethanol was added. After completion of the evolution of hydrogen bromide, the mixture was stirred for several more minutes at 70 ^° C, then cooled, 40 ml of water were added and the product was separated as in Example 1. 12.6 g (64% of theory) of α-bromobutyric acid ethyl ester with t were obtained. .kip. 75 ^o C / 20 mm, n $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{D}}$ 1,4487, d $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{4}}$ 1.3392. Content Br.

 Calculated, 40.96.

 Found, 40.2.

 Chromatography-mass spectroscopy data confirm the production of α-bromobutyric acid ethyl ester.

Example 4. 9.2 ml of butanal (0.1 mol), 18 ml of hexane are charged into the reactor; in the dark, 5 ml of bromine (0.1 mol) are added dropwise with stirring at 28 ^° C. After bleaching, the temperature is raised to 60 ^° C and in the light, another 5 ml of bromine (0.1 mol) is added dropwise, after bleaching, the temperature is again raised to 70 ^° C. and 8 ml of ethanol are introduced. Further, all operations are carried out as in example 1. Obtain 11.5 g (59% of theory.) Of ethyl ester of a-bromobutyric acid with so Kip. 70-78 ^o C / 20 mm, n $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{D}}$ 1.4500.
Example 5. The experiment is carried out similarly to experiment 1, but the esterification is carried out with menthol, having previously removed HBr from the reaction medium by purging the reactor with nitrogen. Obtain 15 g of methyl ester of α-bromisovalerianic acid (52% of theory.). The product is chromatographically pure.

 The invention due to the soft bromination of aliphatic aldehydes allows one to significantly simplify the known method for producing esters of a-bromo-substituted fatty acids and to obtain, in particular, optically inactive ethyl ester of a-bromisovalerianic acid, which is essential for obtaining high-quality drugs.

Information sources:
1. Chichibabin A.E. Gos. Scientific and technical publishing house of chemical literature, Moscow, 1963, v. 1, p. 308.

 2. Industrial regulations for the production of ethyl ester of a-bromisovalerianic acid. Project 64-0115-21-88 TsHLS VNIHFI.

 3. R. Garth Pews and Zenon Lyzenko. Synthetic Communications, 1985, 15/11 977-984.

Claims (4)

1. A method of producing an ester of α-bromosubstituted acid by two-stage bromination by heating an oxygen-containing compound to obtain an acid halide and its esterification with alcohol, characterized in that an aliphatic aldehyde is used as the oxygen-containing compound, which is brominated in the first stage at 20 35 ^o C in the dark at the molar ratio of bromine and aldehyde is 0.8 1.0, and in the second stage at 40 to 60 ^{° C.} under illumination and the molar ratio of bromine to aldehyde is 0.6 0.9, whereby α-bromohydride is obtained, which t esterification.  2. The method according to p. 1, characterized in that the bromination is subjected to isovalerian aldehyde, and the esterification is carried out with ethyl alcohol.  3. The method according to p. 1, characterized in that the bromination is subjected to isovalerian aldehyde, and the esterification is carried out with menthol.  4. The method according to p. 1, characterized in that the bromination is subjected to butyric aldehyde.