CS199274B2 - Process for the asymetric concersion of 2-deutero-3-fluor-l-alanine into corresponding d-isomer - Google Patents

Abstract

2-Deutero-3-fluoro-L-alanine is converted into its D-isomer in an asymmetrical manner. In this process, the L-isomer is reacted with sodium nitrite to give the corresponding L-2-deutero-2-halo-3-fluoro-propionic acid in solution in an aqueous hydrohalic acid. This L-2-deutero-2-halo-3-fluoropropionic acid is then reacted either with ammonia or with sodium azide with replacement of the 2-halogen substituent by a 2-azido group and subsequent catalytic hydrogenation to give 2-deutero-3-fluoro-D-alanine. 2-Deutero-3-fluoro-L-alanine can be converted into pharmaceutically acceptable salts. The resulting compound can be used for inhibition of the growth of Gram-positive and Gram-negative pathogenic bacteria.

Description

The invention generally relates to a process for the preparation of 2-deutero-3-fluoro-D-alanine and pharmaceutically acceptable salts thereof which are potent antibacterial agents useful in inhibiting the growth of pathogenic bacteria of both the Gram-positive and Gram-negative type. More specifically, the invention relates to a novel asymmetric process in which 2-deutero-3-fluoro-L-alanine is converted to its D-isomer.

2-Deutero-3-fluoro-L-alanine is dissolved in strong (6N) hydrobromic acid or hydrochloric acid, sodium nitrite is added in portions, and the resulting solution is maintained at about 0 ° C for about three hours to give thus, L-2-bromo-2-deutero-3-fluoropropionic acid or L-2-chloro-2-deutero-3-fluoropropionic acid. 2-Halogen-2-deutero-3-fluoropropionic acid is conveniently isolated from the acidic reaction solution by extraction with a water immiscible organic solvent such as methylene chloride and evaporation of the extract in vacuo. The L-2-halo-2-deutero-3-fluoropropionic acid obtained as a residue is purified by vacuum fractional distillation. ‘

The ld-broin-dimethoxy-4-fluoropropionic acid or the corresponding 2-chloro analog is then reacted with sodium azide.

The reaction of the L-2-chloro- or L-2-bromo intermediate with sodium azide is preferably carried out by contacting the reaction components in dimethylformamide and stirring the reaction mixture at room temperature. Under these conditions, the reaction is complete after one day. The D-2-azido-2-deutero-3-fluoropropionic acid thus formed is then catalytically hydrogenated, whereby the 2-azido group is reduced to the 2-amino group to give 2-deutero-3-fluoro-D-alanine. the isomer of 2-deutero-3-fluoroaniline to the D-isomer.

As mentioned above, 2-deutero-3-fluoro-D-alanine is an effective and useful antibacterial agent, while the isomeric 2-deutero-3-fluoro-L-alanine (although exhibiting an antibacterial effect) is generally an undesirable isomer. Thus, instead of the racemization of the Ldsomer obtained by resolution of 2-deutero-3-fluoro-DL-alanine and subsequent resolution to form DL mixtures, the L-isomers of 2-deutero-3-fluoro-L-alanine can be asymmetrically converted directly to 2-deutero-3. -fluoro-D-alanine.

The following examples illustrate the process of the invention, but it is to be understood that these examples are given for the purpose of illustration only and are not intended to limit the invention in any way.

Example 1

2-Deutero-3-fluoro-L-alanine (21.4 g) was dissolved in 250 mL of 6N aqueous hydrobromic acid, cooled to 0 ° C and sodium nitrite (22 g) was added in small portions at room temperature. The reaction mixture was maintained at 0-5 [deg.] C. After the addition was complete, the reaction mixture was maintained at 0 [deg.] C. for three hours, the solution was extracted with methylene chloride and then dried over MgSO4, and the methylene chloride was evaporated in vacuo to leave L-2-bromo-2-deutero-3. The fluoropropionic acid is then purified by traction distillation in vacuo.

L-2-bromo-2-deutero-3-fluoropropionic acid (3.0 g) was dissolved in 20 ml of dimethylformamide, sodium azide (1.0 g) was added, and the mixture was stirred at 25 ° C for 24 hours. The mixture was poured into water and extracted with ether. The ether extract was washed with water and dried. About 20 ml of ethanol are added to the filtrate and the resulting D-2-azido-2-deutero-3-fluoropropionic acid solution is treated with hydrogen in the presence of 0.5 g of 5% palladium on carbon. The catalyst was filtered off and the solvent was evaporated in vacuo. Crude 2-deutero-3 is obtained

-fluoro-D-alanine, which is purified by crystallization from aqueous isopropanol.

Example 2

2-Deutero-3-fluoro-L-alanine (21.4 g) was dissolved in 250 mL of 6N aqueous hydrochloric acid. The solution was cooled to 0 ° C and sodium nitrite (22 grams) was added in small portions while maintaining the temperature at 0-5 ° C. After the addition was complete, the reaction solution was kept at 0 ° C for three hours. The methylene chloride was evaporated in vacuo, and the L-2-chloro-2-deutero-3-fluoropropionic acid obtained as a residue was purified by vacuum fractional distillation.

L-2-chloro-2-deutero-3-fluoropropionic acid (2.0 µg) was dissolved in 20 ml of dimethylformamide. Sodium azide (1.0 g) was added and the mixture was stirred at 25 ° C for 24 h. The mixture was poured into water and D-2-azido-2-deutero-3-fluoropropionic acid was catalytically hydrogenated and the product was purified by crystallization from 50% aqueous isopropanol. There was thus obtained 2-deutero-3-fluoro-D-alanine.

Claims (1)

Method for asymmetric conversion of 2-deutero-3-fluoro-L-alanine to the corresponding D-isomer, characterized in that the L-isomer is reacted in a solution of aqueous hydrohalic acid with sodium nitrite to give the corresponding L-2-deutero-2-halogen -3-fluoro-propionic acid, whereupon this L-2-deutero-2-halo-3-fluoropropionic acid is reacted with sodium azide to form 2-azido substituent instead of 2-halogen substituent and catalytic hydrogenation then 2-deutro-3- fluoro-D-alanine.