CA1045157A - Processes for asymmetric conversion of 3-fluoro-l-alanine and 2-deutero-3-fluoro-l-alanine to their d-isomers - Google Patents
Processes for asymmetric conversion of 3-fluoro-l-alanine and 2-deutero-3-fluoro-l-alanine to their d-isomersInfo
- Publication number
- CA1045157A CA1045157A CA246,060A CA246060A CA1045157A CA 1045157 A CA1045157 A CA 1045157A CA 246060 A CA246060 A CA 246060A CA 1045157 A CA1045157 A CA 1045157A
- Authority
- CA
- Canada
- Prior art keywords
- deutero
- fluoro
- alanine
- acid
- isomer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C265/00—Derivatives of isocyanic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/19—Acids containing three or more carbon atoms
- C07C53/21—Acids containing three or more carbon atoms containing fluorine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/185—Saturated compounds having only one carboxyl group and containing keto groups
- C07C59/19—Pyruvic acid
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A B S T R A C T
The invention is concerned with a process for converting 2-deutero-3-fluoro-L-alanine to the corresponding D-isomer by reacting the L-isomer in solution in aqueous hydrohalic acid with sodium nitrite to form the L-2-deutero-2-halo-3-fluoropropionic acid and reacting the latter with ammonia or sodium azide to replace the 2-halo by 2-azido, followed by catalytic hydrogenation.
The invention is concerned with a process for converting 2-deutero-3-fluoro-L-alanine to the corresponding D-isomer by reacting the L-isomer in solution in aqueous hydrohalic acid with sodium nitrite to form the L-2-deutero-2-halo-3-fluoropropionic acid and reacting the latter with ammonia or sodium azide to replace the 2-halo by 2-azido, followed by catalytic hydrogenation.
Description
- _ f ` 1~938IA
.:
l This invention is concerned generally with
.:
l This invention is concerned generally with
2 the production of 2-deutero-3-fluoro-D-alanine and its
3 pharmacologically acceptable salt, which are potent
4 antibacterial agents useful in inhibiting the growth
5 of pathogenic bacteria of both the gram-positive and
6 gram-negative type. More particularly, it relates
7 to a novel asymmetric procedure whereby 2-deutero-3- -~
8 fluoro-L-alanine is transformed to its D-isomer.
g 2-Deutero-3-fluoro-L-alanine is dissolved in strong (6N) aqueous hydrobromic acid or hydrochloric 11 acid, sodium nitrite is added portionwise to the solution, 12 and the resulting solution is maintained at about 0C., ';' 13 for a period of about 3 hours, to produce L-2-bromo-2- -l~ deutero-3-fluoro-propionic acid or L-2-chloro-2-deutero- -: ,: .
15 3-fluoro propionic acid, respectively. The 2-halo- ;
,~ :.
16 2-deutero-3-fluoro-propionic acid is conveniently 17 re overed from the acidic;reaction eolution by extraction . .
; 18 with a water-immiscibIe organi~c solvent such as methylene ~ ~
::
l9 chloride, and evapGrating the extract in vacuo; the 20~ residua1 L-2-haLo-2-deutero-3-fluoro-propion1c acid is 2~1 ~purified~by~vacuum fractional distillation.
~22~ The~L-2-bromo-2-deutero-3-fluoro-propionic ,.. ..
~23; acid, or its 2-chloro analog, is then reacted with ammonia 24 or sodium azide. The reaction of the L-2-halo-2-deutero-3-f~luoro-propionlc acid with~a~monia is preferably carried : ~: ' ' '' 1~93~1~
~)4S~S7 1 out in a pressure vessel using liquid ammonia at about 2 room temperature, under which conditions the reaction 3 is ordinarily complete in about five days. Evaporation 4 of the ammonia gives 2-deutero~3-fluoro-D-alanine which is conveniently purified by recrystallization from 6 isopropanol-water.
7 The reaction of the L~2-chloro or L-2-bromo 8 intermediate with sodium azide is preferably carried
g 2-Deutero-3-fluoro-L-alanine is dissolved in strong (6N) aqueous hydrobromic acid or hydrochloric 11 acid, sodium nitrite is added portionwise to the solution, 12 and the resulting solution is maintained at about 0C., ';' 13 for a period of about 3 hours, to produce L-2-bromo-2- -l~ deutero-3-fluoro-propionic acid or L-2-chloro-2-deutero- -: ,: .
15 3-fluoro propionic acid, respectively. The 2-halo- ;
,~ :.
16 2-deutero-3-fluoro-propionic acid is conveniently 17 re overed from the acidic;reaction eolution by extraction . .
; 18 with a water-immiscibIe organi~c solvent such as methylene ~ ~
::
l9 chloride, and evapGrating the extract in vacuo; the 20~ residua1 L-2-haLo-2-deutero-3-fluoro-propion1c acid is 2~1 ~purified~by~vacuum fractional distillation.
~22~ The~L-2-bromo-2-deutero-3-fluoro-propionic ,.. ..
~23; acid, or its 2-chloro analog, is then reacted with ammonia 24 or sodium azide. The reaction of the L-2-halo-2-deutero-3-f~luoro-propionlc acid with~a~monia is preferably carried : ~: ' ' '' 1~93~1~
~)4S~S7 1 out in a pressure vessel using liquid ammonia at about 2 room temperature, under which conditions the reaction 3 is ordinarily complete in about five days. Evaporation 4 of the ammonia gives 2-deutero~3-fluoro-D-alanine which is conveniently purified by recrystallization from 6 isopropanol-water.
7 The reaction of the L~2-chloro or L-2-bromo 8 intermediate with sodium azide is preferably carried
9 out by bringing the reactants together in dimethylformamide, and agitating the reaction mixture at substantially room 11 temperature, under which conditions the reaction is 12 substantially complete in about one day; the D-2-azido-13 -2-deutero-3-fluoro-propionic acid thus formed is then 14 subjected to catalytic hydrogenation whereby the 2-azido grouping is reduced to 2-amino thereby forming 16 2 deutero-3-fluoro-D-alanine~ This procedure makes 17 possible the direct conversion of the L-isomer of 2-18 deutero-3-fluoroalanine to the D-isomer.
19 As noted hereinabove, the 2-deutero-3-fluoro-D-alanine is a potent and useful antibacterial, whereas `
21 ~the isomeric 2-deutero-3-fluoro-L alanine (although 22 possessing antibacterial action) is generally an unwanted 23 isomer; thus, instead of racemizing the L-isomer obtained 24 by resolution of 2-deutero-3-fluoro-DL-alanine, followed by a further re~olution of the DL-mixture thus produced, 26 the~ L-isomers, 2-deutexo-3-flu¢ro-L-alanine, can be : -~ 2-.
:
1~93~I~
11)451~i7 1 assymetrically converted directly to 2-deutero-2 3-fluoro-D-alanine.
3 The following examples illustrate methods 4 of carrying out the present invention, but it is to be understood that these examples are given for purposes 6 of illustration and not of limitation. , ' ~ , ~ '.
.. ' ~':
- ~
.
8 2-Deutero-3-fluoro-L-alanine (21.4 g.) is 9 dissolved in 250 ml. of 6N aqueous hydrobromic acid.
The solution is cooled to 0C. and sodium nitrite ;. .
11 ~22 g.) is added~in small portions with maintenance 12 of temperature at 0-5C. After completing the addition, : :.:
13 the reaction is maintained at 0C. for 3 hours. The ~. ~
: ~ :, : ,. : .
I4 solution is extracted with methylene chloride which . .: :
~ 15 is then dried over magnesium sulfate. The methylene , ...
16 chloride is evaporated ln vacuo. The residual L-2 ~17~ bromo-2 deutero-3-~luoropropionic acid is purified by ~`~
` 13~ vaouum fr.actional distillation.
~- ~ 19~ L-2-Bromo-2-deutero-3-fluoropropionic acid - 20~ (~3.0 g.)~ is charged to a~steel~bomb and 30 ml. o~ liquid 21~ ammonia is addecl. The bomb is s~ealed and allowed to ~. : :: .
~ ~ ~ 22~ stand at room temperature~for fi~e~ days. The ammollia `
.~ : ~ . . . . ..
~ ~3~
: ~ : ~ : . :
:~ ~
'' - . : ` .`" .' ;~ " ~ .'',,'"' ~ 93~1~
~4S~LS~
l is evaporated and the crude 2-deutero-3-fluoro-D-2 alanine is purified by recrystallization from 50%
3 isopropanol-water.
4 Alternatively, the L-2-bromo-2-deutero-3-fluoropropionic acid (2.0 g.) is dissolved in 20 ml.
6 f dimethyl formamide. Sodium azide (l.0 g.) is added, 7 and the mixture stirred at 25C. for 24 hours. The 8 mixture is poured into water and extracted with 9 ether. The ether extract is washed with water and dried. About 20 ml. of ethanol is added to thè filtrate, 11 and the resulting solution of D-2-azido-2-deutero-3-: . .
12 fluoropropionic acid is reacted with hydrogen in the 13 presence 0.5 g. of 5%~palladium-on-caxbon The catalyst 14 is filtered, and the solvent is evaporated in v _ o to give ¢rude 2-deutero-3-fluoro-D-alaniner which is 16 purified by cr~stallization from aqueous isopropanol.
17 EXAMPLE 2 ~ ~
: .
18 ~ 2-Deutero-3-fluoro-L-alanine (21.4 g.) is 19 dissolved in 250~ml. of ~6N aqueous hydrochloric acid.
: : ~ .
20~ The solut1on~ lS~ cooled to 0C.~and sodium nitrite (22 g.) ;~ ---21 ~is~added in sma~ll portionsjwith maintenance of tempera-22~ture at~0-5C.~ After completing the addition, the 23~ reaction~ solutLon ~is maintailled at 0C. for 3 hcurs. The 24 resulti~ng solution is extracted with methylene chloride, ,: ~
the;methylene chloride extrac~t is dried over~ ma~nesiu~
- : ,:
,f ~ , '~ , .
14938I~ ~
J,~4~i~S7 1 sulfate, and the methylene chloride is evaporated ln 2 vacuo. The residual L-2-chloro-2-deutero-3-fluoro- i, 3 propionic acid is purified by vacuum ~ractional dis-4 tillation. -L-2-Chloro-2-deutero-3-fluoropropionic acid 6 ~3.0 g.) is charged to ~ steel bomb and 30 ml. of liquid 7 ammonia is added. The bomb is sealed and allowed to 8 stand at room temperature for five days. The ammonia 9 is evaporated and the crude 2-deutero-3-fluoro-D-alanine is purified by recrystallization from 50% isopropanol-11 water. .
12 Alternatively, the L-2-chloro-2-deutero-3-13 fluoropropionic acid (2.0 g.) is dissolved in 20 ml.
14 of dimethyl~formamide. Sodium azide (1.0 g.) is added, and the mixture stirred at 25C. for 24 hours. The 16 mixture is poured into water and the D-2-azido-2-17 deutero-3-fluoropropionic acid is catalytically 18 hydrogenated and the product purified by recrystallization 19 from 50% aqueous isopropanol to give 2-deutero-3-~luoro-D-alanine.
.
, ~ ~ , ":
. ~ .. ...
: ~ : : . :
_5- :
: .
.
., ..
19 As noted hereinabove, the 2-deutero-3-fluoro-D-alanine is a potent and useful antibacterial, whereas `
21 ~the isomeric 2-deutero-3-fluoro-L alanine (although 22 possessing antibacterial action) is generally an unwanted 23 isomer; thus, instead of racemizing the L-isomer obtained 24 by resolution of 2-deutero-3-fluoro-DL-alanine, followed by a further re~olution of the DL-mixture thus produced, 26 the~ L-isomers, 2-deutexo-3-flu¢ro-L-alanine, can be : -~ 2-.
:
1~93~I~
11)451~i7 1 assymetrically converted directly to 2-deutero-2 3-fluoro-D-alanine.
3 The following examples illustrate methods 4 of carrying out the present invention, but it is to be understood that these examples are given for purposes 6 of illustration and not of limitation. , ' ~ , ~ '.
.. ' ~':
- ~
.
8 2-Deutero-3-fluoro-L-alanine (21.4 g.) is 9 dissolved in 250 ml. of 6N aqueous hydrobromic acid.
The solution is cooled to 0C. and sodium nitrite ;. .
11 ~22 g.) is added~in small portions with maintenance 12 of temperature at 0-5C. After completing the addition, : :.:
13 the reaction is maintained at 0C. for 3 hours. The ~. ~
: ~ :, : ,. : .
I4 solution is extracted with methylene chloride which . .: :
~ 15 is then dried over magnesium sulfate. The methylene , ...
16 chloride is evaporated ln vacuo. The residual L-2 ~17~ bromo-2 deutero-3-~luoropropionic acid is purified by ~`~
` 13~ vaouum fr.actional distillation.
~- ~ 19~ L-2-Bromo-2-deutero-3-fluoropropionic acid - 20~ (~3.0 g.)~ is charged to a~steel~bomb and 30 ml. o~ liquid 21~ ammonia is addecl. The bomb is s~ealed and allowed to ~. : :: .
~ ~ ~ 22~ stand at room temperature~for fi~e~ days. The ammollia `
.~ : ~ . . . . ..
~ ~3~
: ~ : ~ : . :
:~ ~
'' - . : ` .`" .' ;~ " ~ .'',,'"' ~ 93~1~
~4S~LS~
l is evaporated and the crude 2-deutero-3-fluoro-D-2 alanine is purified by recrystallization from 50%
3 isopropanol-water.
4 Alternatively, the L-2-bromo-2-deutero-3-fluoropropionic acid (2.0 g.) is dissolved in 20 ml.
6 f dimethyl formamide. Sodium azide (l.0 g.) is added, 7 and the mixture stirred at 25C. for 24 hours. The 8 mixture is poured into water and extracted with 9 ether. The ether extract is washed with water and dried. About 20 ml. of ethanol is added to thè filtrate, 11 and the resulting solution of D-2-azido-2-deutero-3-: . .
12 fluoropropionic acid is reacted with hydrogen in the 13 presence 0.5 g. of 5%~palladium-on-caxbon The catalyst 14 is filtered, and the solvent is evaporated in v _ o to give ¢rude 2-deutero-3-fluoro-D-alaniner which is 16 purified by cr~stallization from aqueous isopropanol.
17 EXAMPLE 2 ~ ~
: .
18 ~ 2-Deutero-3-fluoro-L-alanine (21.4 g.) is 19 dissolved in 250~ml. of ~6N aqueous hydrochloric acid.
: : ~ .
20~ The solut1on~ lS~ cooled to 0C.~and sodium nitrite (22 g.) ;~ ---21 ~is~added in sma~ll portionsjwith maintenance of tempera-22~ture at~0-5C.~ After completing the addition, the 23~ reaction~ solutLon ~is maintailled at 0C. for 3 hcurs. The 24 resulti~ng solution is extracted with methylene chloride, ,: ~
the;methylene chloride extrac~t is dried over~ ma~nesiu~
- : ,:
,f ~ , '~ , .
14938I~ ~
J,~4~i~S7 1 sulfate, and the methylene chloride is evaporated ln 2 vacuo. The residual L-2-chloro-2-deutero-3-fluoro- i, 3 propionic acid is purified by vacuum ~ractional dis-4 tillation. -L-2-Chloro-2-deutero-3-fluoropropionic acid 6 ~3.0 g.) is charged to ~ steel bomb and 30 ml. of liquid 7 ammonia is added. The bomb is sealed and allowed to 8 stand at room temperature for five days. The ammonia 9 is evaporated and the crude 2-deutero-3-fluoro-D-alanine is purified by recrystallization from 50% isopropanol-11 water. .
12 Alternatively, the L-2-chloro-2-deutero-3-13 fluoropropionic acid (2.0 g.) is dissolved in 20 ml.
14 of dimethyl~formamide. Sodium azide (1.0 g.) is added, and the mixture stirred at 25C. for 24 hours. The 16 mixture is poured into water and the D-2-azido-2-17 deutero-3-fluoropropionic acid is catalytically 18 hydrogenated and the product purified by recrystallization 19 from 50% aqueous isopropanol to give 2-deutero-3-~luoro-D-alanine.
.
, ~ ~ , ":
. ~ .. ...
: ~ : : . :
_5- :
: .
.
., ..
Claims (2)
1. The process of asymmetrically converting 2-deutero-3-fluoro-L-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 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.
2. The process as defined in Claim 1 wherein the L-isomer is 2-deutero-3-fluoro-L-alanine, 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-D-alanine.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/552,474 US3950411A (en) | 1972-02-03 | 1975-02-24 | Processes for asymmetric conversion of 3-fluoro-L-alanine and 2-deutero-3-fluoro-L-alanine to their D-isomers |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1045157A true CA1045157A (en) | 1978-12-26 |
Family
ID=24205490
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA246,060A Expired CA1045157A (en) | 1975-02-24 | 1976-02-18 | Processes for asymmetric conversion of 3-fluoro-l-alanine and 2-deutero-3-fluoro-l-alanine to their d-isomers |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS51110513A (en) |
| AR (1) | AR207277A1 (en) |
| AU (1) | AU500536B2 (en) |
| CA (1) | CA1045157A (en) |
| CH (1) | CH620194A5 (en) |
| CS (1) | CS199274B2 (en) |
| DE (1) | DE2607252A1 (en) |
| DK (1) | DK55976A (en) |
| ES (1) | ES445381A1 (en) |
| FI (1) | FI760302A (en) |
| FR (1) | FR2301513A1 (en) |
| GB (1) | GB1488332A (en) |
| GR (1) | GR59306B (en) |
| HU (1) | HU173362B (en) |
| IE (1) | IE43351B1 (en) |
| NL (1) | NL7601511A (en) |
| NO (1) | NO760448L (en) |
| PT (1) | PT64805B (en) |
| SE (1) | SE7601423L (en) |
| YU (1) | YU41876A (en) |
| ZA (1) | ZA761045B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3880922A (en) * | 1972-02-03 | 1975-04-29 | Merck & Co Inc | Process for preparing 3-fluoro-D-alanine by asymmetric rearrangement of 2-(azidocarbonyl)-3-fluoro-propionic ester or nitrile |
-
1976
- 1976-01-01 AR AR262279A patent/AR207277A1/en active
- 1976-02-09 FI FI760302A patent/FI760302A/fi not_active Application Discontinuation
- 1976-02-10 SE SE7601423A patent/SE7601423L/en unknown
- 1976-02-11 DK DK55976*#A patent/DK55976A/en unknown
- 1976-02-12 NO NO760448A patent/NO760448L/no unknown
- 1976-02-13 NL NL7601511A patent/NL7601511A/en not_active Application Discontinuation
- 1976-02-16 PT PT64805A patent/PT64805B/en unknown
- 1976-02-17 AU AU11178/76A patent/AU500536B2/en not_active Expired
- 1976-02-17 CH CH193076A patent/CH620194A5/en not_active IP Right Cessation
- 1976-02-17 GR GR50072A patent/GR59306B/en unknown
- 1976-02-18 CA CA246,060A patent/CA1045157A/en not_active Expired
- 1976-02-19 GB GB6655/76A patent/GB1488332A/en not_active Expired
- 1976-02-19 YU YU00418/76A patent/YU41876A/en unknown
- 1976-02-20 FR FR7604715A patent/FR2301513A1/en active Granted
- 1976-02-20 ES ES445381A patent/ES445381A1/en not_active Expired
- 1976-02-20 IE IE335/76A patent/IE43351B1/en unknown
- 1976-02-23 ZA ZA761045A patent/ZA761045B/en unknown
- 1976-02-23 CS CS761182A patent/CS199274B2/en unknown
- 1976-02-23 DE DE19762607252 patent/DE2607252A1/en not_active Withdrawn
- 1976-02-24 HU HU76ME1954A patent/HU173362B/en unknown
- 1976-02-24 JP JP51018580A patent/JPS51110513A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| FR2301513B1 (en) | 1979-02-02 |
| CS199274B2 (en) | 1980-07-31 |
| ZA761045B (en) | 1977-09-28 |
| AU1117876A (en) | 1977-08-25 |
| YU41876A (en) | 1982-02-28 |
| FI760302A (en) | 1976-08-25 |
| AR207277A1 (en) | 1976-09-22 |
| NO760448L (en) | 1976-08-25 |
| CH620194A5 (en) | 1980-11-14 |
| JPS51110513A (en) | 1976-09-30 |
| GR59306B (en) | 1977-12-12 |
| NL7601511A (en) | 1976-08-26 |
| PT64805B (en) | 1978-02-06 |
| PT64805A (en) | 1976-03-01 |
| AU500536B2 (en) | 1979-05-24 |
| ES445381A1 (en) | 1977-06-01 |
| FR2301513A1 (en) | 1976-09-17 |
| DK55976A (en) | 1976-08-25 |
| IE43351L (en) | 1976-08-21 |
| IE43351B1 (en) | 1981-02-11 |
| SE7601423L (en) | 1976-08-25 |
| DE2607252A1 (en) | 1976-09-02 |
| HU173362B (en) | 1979-04-28 |
| GB1488332A (en) | 1977-10-12 |
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