IE43351B1

IE43351B1 - Processes for asymmetric conversion of 3-fluoro-l-alanine and 2-deutero-3-fluoro-l-alanine to their d-isomers

Info

Publication number: IE43351B1
Application number: IE335/76A
Authority: IE
Original assignee: Merck & Co Inc
Priority date: 1975-02-24
Filing date: 1976-02-20
Publication date: 1981-02-11
Also published as: DK55976A; PT64805B; IE43351L; NO760448L; CH620194A5; CS199274B2; DE2607252A1; ES445381A1; AU1117876A; JPS51110513A; FR2301513B1; GB1488332A; CA1045157A; FR2301513A1; AU500536B2; AR207277A1; PT64805A; GR59306B; ZA761045B; YU41876A

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

PAIENT APPLICATION BY (71) MERCK & CO., INC., A CORPORATION ORGANISED UNDER THE LAWS OF THE STATE OF NEW JERSEY, UNITED STATES OF AMERICA, OF RAHWAY, NEW JERSEY, UNITED STATES OF AMERICA. prtet 12|p This invention is concerned generally with the production of 2-deutero-3-fluoro-D-alanine and its pharmacologically acceptable salts, which are potent antibacterial agents useful in inhibiting the growth of pathogenic bacteria of both the gram-positive and gram-negative type. More particularly, it concerns a novel asymmetric procedure whereby 2-deutero-3fluoro-L-alanine is transformed to its D-isomer.

In accordance with the present invention, there is provided a method of asymmetrically converting 2-deutero-3fluoro-L-alanine to the corresponding D-isomer, which comprises reacting the said L-isomer in solution in agueous hydrohalic acid with sodium nitrite thereby forming the corresponding L-2-deutero-2-halo-3-fluoropropionic acid, and reacting this L-2-deutero-2-halo-3-fluoropropionic acid (a) with ammonia; or (b) with sodium azide, thereby replacing the 2-halo substituent by 2-azido, followed by catalytic hydrogenation; to produce 2-deutero-3-fluoro-D-alanine.

In a practical method of carrying out this procedure 2-deutero-3-fluoro-L-alanine is dissolved in strong (6N) aqueous hydrobromic acid or hydrochloric acid, sodium nitrite is added portionwise to the solution, and the resulting solution is maintained at about 0°C., for a period of about 3 hours, to produce L-2-bromo-2-deutero-3-fluoropropionic acid or L-2-chloro-2 deutero-3-fluora-propionic acid, respectively. The 2-halo-2deutero-3-propionic acid is conveniently recovered from the acidic reaction solution by extraction with a water-immiscible organic solvent such as methylene chloride, and evaporating the extract in vacuo; the residual L-2-halo-2-deutero-3-fluoropropionic acid is purified by vacuum fractional distillation.

The L-2-bromo-2-deutero-3-fluoro-propionio acid, or its 2-chloro analogue, is then reacted with ammonia or sodium azide. The reaction of the L-2-halo-2-deutero-3-fluoropropionic acid with ammonia is preferably carried - 2 4-3 3a! out in a pressure vessel using liquid ammonia at about room temperature, under which conditions the reaction is ordinarily complete in about five days. Evaporation of the ammonia gives 2-deutero-3-fluoro-D-alanine which is conveniently purified by recrystallization from isopropanol-water.

The reaction of the L-2-chloro or L-2-bromo intermediate with sodium azide is preferably carried out by bringing the reactants together in dimethylformamide, and agitating the reaction mixture at substantially room temperature, under which conditions the reaction is substantially complete in about one day; the D-2-azido2-deutero-3-fluoro-propionic acid thus formed is then subjected to catalytic hydrogenation whereby the 2azido grouping is reduced to 2-amino thereby forming 2-deutero-3-fluoro-D-alanine. This procedure makes possible the direct conversion of the L-isomer of 2deutero-3-£luoroalanine to the D-isomer.

As noted hereinabove, the 2-deutero-3-fluoroD-alanine is a potent and useful antibacterial, whereas the isomeric 2-deutero-3-fluoro-L-alanine (although possessing antibacterial action) is generally an unwanted isomer; thus, instead of racemizing the L-isomer obtained by resolution of 2-deutero-3-fluoro-DL-alanine, followed by a further resolution of the DL-mixture thus produced, the L-isomers, 2-deutero-3-fluoro-L-alanine, can be 433 31 asymetrically converted directly to 2-deutero3-fluoro-D-alanine.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

EXAMPLE 1 2-Deutero-3~fluoro-L-alanine (21.4 g.) is dissolved in 250 ml. of 6N aqueous hydrobromic acid.

The solution is cooled to 0°C. and sodium nitrite (22 g.) is added in small portions with maintenance of temperature at 0-5°C. After completing the addition, the reaction is maintained at 0°C. for 3 hours. The solution is extracted with methylene chloride which L5 is then dried over magnesium sulfate. The methylene chloride is evaporated in vacuo. The residual L-2bromo-2-deutero-3-fluoropropionic acid is purified by vacuum fractional distillation.

L-2-Bromo-2-deutero-3-fluoropropionic acid iO (3.0 g.) is charged to a steel bomb and 30 ml. of liquid ammonia is added. The bomb is sealed and allowed to stand at room temperature for five days. The ammonia / / 433 is evaporated and the crude 2-deutero-3-£luoro-Dalanine is purified by recrystallization from 50% isopropanol-watcr.

Alternatively, the L-2-bromo-2-deutero-3fluoropropionic acid (2.0 g.) is dissolved in 20 ml. of dimethyl formamide. Sodium azide (1.0 g.) is added, and the mixture stirred at 25°C. for 24 hours. The mixture is poured into water and extracted with ether. The ethereal extract is washed with water and dried. About 20 ml. of ethanol is added to the filtrate, and the resulting solution of D-2-azido-2-deutero-3fluoropropionic acid is reacted with hydrogen in the presence 0.5 g. of 5% palladium-on-carbon. The catalyst is filtered, and the solvent is evaporated in vacuo to give crude 2-deutero-3-fluoro-D-alanine, which is purified by crystallization from aqueous isopropanol.

EXAMPLE 2 2-Deutero-3-fluoro-L-alanine (21.4 g.) is dissolved in 250 ml. of 6N aqueous hydrochloric acid.

The solution is cooled to 0°C. and sodium nitrite (22 g.) is added in small portions with maintenance of temperature at 0-5°C. After completing the addition, the reaction solution is maintained at 0°C. for 3 hours. The resulting solution is extracted with methylene chloride, the methylene chloride extract is dried over magnesium - 5 43351 sulfate, and the methylene chloride is evaporated in vacuo. The residual L-2-chloro-2-deutero-3-fluoropropionic acid is purified by vacuum fractional distillation.

L-2-Chloro-2-deutero-3-fluoropropionic acid (3.0 g.) is charged to a steel bomb and 30 ml. of liquid ammonia is added. The bomb is sealed and allowed to stand at room temperature for five days. The ammonia is evaporated and the crude 2-deutero-3-fluoro-D-alanine is purified by recrystallization from 50% isopropanolwater .

Alternatively, the L-2-chloro-2-deutero-3fluoropropionic acid (2.0 g.) is dissolved in 20 ml. of dimethyl formamide. Sodium azide (1.0 g.) is added, and the mixture stirred at 25°C. for 24 hours. The mixture is poured into water and the D-2-azido-2deutero-3-fluoropropionic acid is catalytically hydrogenated and the product purified by recrystallization from 50% aqueous isopropanol to give 2-deutero-3-fluoro20 D-alanine.

Claims

1. CLAIMS:1. A method of asymmetrically converting

2. -deutero-

3. -fluoroL-alanine to the corresponding. D-isomer, which comprises reacting the said L-isomer in solution in aqueous hydrohalic acid with sodium nitrite thereby forming the corresponding 5 L-2-deutero-2-halo-3-fluoropropionic acid, and reacting this L-2-deutero-2-halo-3-fluoropropionic acid (a) with ammonia; or (b) with sodium azide, thereby replacing the 2-halo substituent by 2-azido, followed by catalytic hydrogenation; to produce 2-deutero-3-fluoro-D-alanine. 10 2. A method as claimed in Claim 1 in which the aqueous hydrohalic acid is aqueous hydrobromic acid and the intermediate L-2-deutero-2-bromo-3-fluoro-propionic acid thus formed is reacted with liquid ammonia to produce 2-deutero-3-fluoro-Dalanine. 15 3. A method as claimed in Claim 1 substantially as hereinbefore described in Example 1 or 2.

4. 2-Deutero-3-fluoro-D-alanine when prepared by a method as claimed in any· one of the preceding claims.