NO753750L - - Google Patents

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Publication number
NO753750L
NO753750L NO753750A NO753750A NO753750L NO 753750 L NO753750 L NO 753750L NO 753750 A NO753750 A NO 753750A NO 753750 A NO753750 A NO 753750A NO 753750 L NO753750 L NO 753750L
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Norway
Prior art keywords
fluoro
reacted
alanine
deutero
acid
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NO753750A
Other languages
Norwegian (no)
Inventor
D F Reinhold
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Merck & Co Inc
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Priority claimed from US05/525,708 external-priority patent/US3976689A/en
Application filed by Merck & Co Inc filed Critical Merck & Co Inc
Publication of NO753750L publication Critical patent/NO753750L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/20—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Description

Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av/ 3-f luor-D-alanin og dets deutero-analoger, som er virksomme antiba.kterielle midler som er verdifulle til å inhib-ere veksten av patogene bakterier av både den gram-positive og gr am-negative type. Mere spesielt angår oppfinnelsen fremstil-lingen av 3-fluor-D-alaninforbindelser ved asymmetrisk syntese hvori fluor-pyruvinsyre omsettes med et D-optisk aktivt amin som D-a-methylbenzyl-amin for å danne det tilsvarende ketimin som omsettes med et alkalimetallborhydrid- eller -bordeuterid-reduksjonsmiddel, som natriumborhydrid, natriumbordeuterid og lignende, for å danne et N-(D-a-methy1benzy1 )-derivat fulgt av hydrogenolyse av methylbenzylgruppen for å danne 3-fluor-D-alanin eller 2-deutero-3-fluor-D-alanin. The present invention relates to a process for the production of 3-fluoro-D-alanine and its deutero-analogs, which are effective antibacterial agents that are valuable for inhibiting the growth of pathogenic bacteria of both the gram-positive and gram-positive am-negative type. More particularly, the invention relates to the preparation of 3-fluoro-D-alanine compounds by asymmetric synthesis in which fluoro-pyruvic acid is reacted with a D-optically active amine such as D-a-methylbenzylamine to form the corresponding ketimine which is reacted with an alkali metal borohydride or bordeuteride reducing agent, such as sodium borohydride, sodium bordeuteride and the like, to form an N-(D-a-methy1benzy1 ) derivative followed by hydrogenolysis of the methylbenzyl group to form 3-fluoro-D-alanine or 2-deutero-3-fluoro-D- alanine.

I henhold til foreliggende oppfinnelse omsettes en D-optisk aktiv aminf orbindelse som D-oc-methylbenzyl amin., R(D)-f enylglyein , 1-amino-( S )-2- \_( R )-l-hydroxyethyl 1 -indolin , og lignende, med fluorpyruvinsyre, fortrinnsvis i oppløsning i en lavere alkanol som ethanol, isop ropanol. og lignende.- Reaksjonr en utføres til å begynne med koldt, og tillates å oppvarmes til ca. værelsetempéråtur under hvilke betingelser reaksjonen er i det vesentlige fullstendig i løpet av en time. Det dannede D-ketimin som 2-(D-a-methylbenzylimino )-3-fluorpropionsyre, 2-(D-a-carboxybenzy1imino)-3-fluorpropionsyre og lignende, omsettes så med et alkalimetallborhydrid-reduksjonsmiddel, fortrinnsvis i isopropanol ved 10 - 25°C, under hvilke betingelser reduksjon av D-ketiminet er i det vesentlige fullstendig i løpet av ca. 3 timer. Det foretrekkes i alminnelighet å anvende den erholdte oppløsning inneholdende reduksjonsproduktet direkte, eller eventuelt efter fortynning med vann, i den på-følgende hydrognolysereaksjon. According to the present invention, a D-optically active amine compound is reacted as D-oc-methylbenzyl amine, R(D)-phenylglyein, 1-amino-(S)-2-(R)-1-hydroxyethyl 1 -indoline, and the like, with fluoropyruvic acid, preferably in solution in a lower alkanol such as ethanol, isotropanol. and the like.- Reactions are initially carried out cold, and allowed to warm up to approx. room temperature under which conditions the reaction is substantially complete within one hour. The D-ketimine formed as 2-(D-α-methylbenzylimino)-3-fluoropropionic acid, 2-(D-α-carboxybenzy1imino)-3-fluoropropionic acid and the like is then reacted with an alkali metal borohydride reducing agent, preferably in isopropanol at 10 - 25°C, under which conditions reduction of the D-ketimine is essentially complete within approx. 3 hours. It is generally preferred to use the obtained solution containing the reduction product directly, or possibly after dilution with water, in the subsequent hydrognolysis reaction.

På tilsvarende måte kan D-ketiminet omsettes med et alkalimetallbordeuterid under anvendelse av de ovenfor angitte betingelser for reaksjonen som anvender alkalimetallborhydrid, og opp-løsningen inneholdende det reduserte (deutererte) .produkt kan anvendes som i den påfølgende hydrogenolyseoperasjon, eller om ønskes, kan det deutererte produkt utvinnes for å få 2-deutero-(D -a-methylbenzyl )-3-f luor-D-alanin , 2-deu tero-N-( D-a-:Carboxybenzy.l )-3-fluor-D-alanin og lignende. In a similar way, the D-ketimine can be reacted with an alkali metal borodeuteride using the above stated conditions for the reaction using alkali metal borohydride, and the solution containing the reduced (deuterated) product can be used as in the subsequent hydrogenolysis operation, or if desired, it can deuterated product is recovered to obtain 2-deutero-(D -a-methylbenzyl )-3-fluoro-D-alanine, 2-deutero-N-(D-a-:Carboxybenzy.l )-3-fluoro-D-alanine and such.

En oppløsning av dette N-substituerte derivat i ethanol eller isopropanol, fortynnet med vann om ønskes, omsettes så med hydrogen ved forhøyet trykk, f.eks. 2,8 kg/cm 2, under anvendelse av en hydrogeneringskatalysator som p all.adi umhy droxyd-på-trekullkatalysatdr, hvorved N-substituenten hydrogenolyser.es. Efter at hydrogenopptagelsen er opphørt, frafiltreres katalysatoren, filtratet inndampes til tørrhet i vakuum og det gjen-værende materiale omkrystalliseres fra vandig isopropanol hvorved man får 3-fluor-D-alanin eller 2-deutero-3-fluor-D-alanin. A solution of this N-substituted derivative in ethanol or isopropanol, diluted with water if desired, is then reacted with hydrogen at elevated pressure, e.g. 2.8 kg/cm 2 , using a hydrogenation catalyst such as p all.adi umhydroxide-on-charcoal catalystdr, whereby the N-substituent is hydrogenolyzed.es. After the hydrogen uptake has ceased, the catalyst is filtered off, the filtrate is evaporated to dryness in a vacuum and the remaining material is recrystallized from aqueous isopropanol whereby 3-fluoro-D-alanine or 2-deutero-3-fluoro-D-alanine is obtained.

De følgende eksempler illustrerer fremgangsmåten ifølge oppfinnelsen. The following examples illustrate the method according to the invention.

Eksempel 1Example 1

En kold oppløsning av 12,1 g D-a-methylbenzylamin i 100 ml isopropanol tilsettes langsomt til en oppløsning av 5,3 g fluor-pyruvinsyre i 250 ml isopropanol, mens den dannede oppløsning holdes ved 0°C. Oppløsningen får så lov til å oppvarmestil 25°C og holdes ved 25°C i 1 time. Oppløsningen inneholdende D-a-methylbenzyl-aminsaltet av 2-(D-a-methylbenzy1imino)-3-fluor-propionsyre avkjøles så til ca. 10°C og 0,66 g natriumbordeuterid tilsettes. Reaksjonsblandingen omrøres ved 25°C i 3 timer. Ca. 100 ml vann tilsettes for å danne en vandig iso-propanoloppløsning inneholdende N-(D-a-methylbenzyl )-a-deutero-3-fluor-D-alaninet, og pH innstilles på 4,5 med fortynnet van - dig saltsyre. Plethy lbenzylgr uppen . hy drogenoly seres så ved 2,8 kg/cm under anvendelse av 5,0 g 10^-ig palladiumhydroxyd-på-trekullkatalysator. Efter at hydrogenopptagelsen er opphørt, oppvarmes blandingen til 70°C og katalysatoren fjernes ved filtrering. Filtratet inndampes til tørrhet i vakuum, og residuet omkrystalliseres fra 50^-ig isopropanol-vann, og derpå fra vann, hvorved "man får i det vesentlige rent 2-deutero-3-fluor-D-alanin. A cold solution of 12.1 g of D-α-methylbenzylamine in 100 ml of isopropanol is slowly added to a solution of 5.3 g of fluoropyruvic acid in 250 ml of isopropanol, while the resulting solution is kept at 0°C. The solution is then allowed to warm to 25°C and held at 25°C for 1 hour. The solution containing the D-α-methylbenzylamine salt of 2-(D-α-methylbenzylimino)-3-fluoro-propionic acid is then cooled to approx. 10°C and 0.66 g of sodium bordeuteride are added. The reaction mixture is stirred at 25°C for 3 hours. About. 100 ml of water is added to form an aqueous iso-propanol solution containing N-(D-α-methylbenzyl)-α-deutero-3-fluoro-D-alanine, and the pH is adjusted to 4.5 with dilute aqueous hydrochloric acid. Plethy lbenzylgr uppen . hy drogenoly is then seen at 2.8 kg/cm using 5.0 g of 10 2 palladium hydroxide on charcoal catalyst. After the hydrogen uptake has ceased, the mixture is heated to 70°C and the catalyst is removed by filtration. The filtrate is evaporated to dryness in vacuo, and the residue is recrystallized from 50 µg of isopropanol-water, and then from water, whereby essentially pure 2-deutero-3-fluoro-D-alanine is obtained.

Eksempel 2Example 2

En kold oppløsning av 12,1 g D-ot-methylbenzyl-amin ,i 100 ml isopropanol tilsettes langsomt til en oppløsning av 5,3 g fluor-pyruvinsyre i 250 ml isopropanol, mens den dannede blanding holdes ved 0°C. Oppløsningen får lov til å oppvarmes til 25°C og holdes ved 25°C i 1 time. Oppløsningen inneholdende D-oc-methylbenzylaminsaltet av 2-(D-a-methylbenzylimino)-3-fluor-propionsyre avkjøles så til ca. 0°C og 0,60 g natriumborhydrid tilsettes. Reaksjonsblåndingen omrøres så ved 25°C i 3 timer. Ca. 100 ml vann tilsettes for å danne en vandig isopropanol-oppløsning inneholdende (D-a-meth<y>lbenz<y>1)-3-f luor-D-alaninet, og pH innstilles på 4,5 med fortynnet vandig saltsyre. Methylbenzylgruppen hydrogenolyseres ved 2,8 kg/cm under anvendelse av 5,0 g 10%-ig palladiumhydroxyd-på-trekullkatalysator . Efter. at hydrogenopptagelsen er opphørt, oppvarmes blandingen til 70°C og katalysatoren fjernes ved filtrering. Filtratet inndampes til tørrhet i vakuum, og residuet omkrystalliseres fra 50% isopropanol-vann, og derpå fra vann, hvorved man får i det vesentlige rent 3-fluor-D-alanin. A cold solution of 12.1 g of D-o-methylbenzylamine in 100 ml of isopropanol is added slowly to a solution of 5.3 g of fluoropyruvic acid in 250 ml of isopropanol, while the resulting mixture is kept at 0°C. The solution is allowed to warm to 25°C and held at 25°C for 1 hour. The solution containing the D-oc-methylbenzylamine salt of 2-(D-α-methylbenzylimino)-3-fluoro-propionic acid is then cooled to approx. 0°C and 0.60 g of sodium borohydride are added. The reaction mixture is then stirred at 25°C for 3 hours. About. 100 ml of water is added to form an aqueous isopropanol solution containing the (D-α-meth<y>lbenz<y>1)-3-fluoro-D-alanine, and the pH is adjusted to 4.5 with dilute aqueous hydrochloric acid. The methylbenzyl group is hydrogenolysed at 2.8 kg/cm using 5.0 g of 10% palladium hydroxide on charcoal catalyst. After. that the hydrogen absorption has ceased, the mixture is heated to 70°C and the catalyst is removed by filtration. The filtrate is evaporated to dryness in vacuo, and the residue is recrystallized from 50% isopropanol-water, and then from water, whereby essentially pure 3-fluoro-D-alanine is obtained.

I stedet for å anvende D-a-methylbenzylamin i reaksjonen med fluorpyruvinsyre, kan også andre optisk aktive arninofor-bindelser anvendes, som R(D )-feny1 glycin eller 1-amino-(S)-2-[[(R)-l-hydroxyethyl3-indolin. Instead of using D-a-methylbenzylamine in the reaction with fluoropyruvic acid, other optically active amino compounds can also be used, such as R(D)-phenylglycine or 1-amino-(S)-2-[[(R)-1- hydroxyethyl3-indoline.

Claims (1)

1. Fremgangsmåte ved fremstilling av 3-fluor-D-alanin eller 2- deutero-3-fluor-D-alanin, karakterisert ved at fluorpyruvinsyre omsettes med et optisk aktivt D-amin, under dannelse av det tilsvarende D-ketimin, som omsettes med et alkalimetallborhydrid eller alkalimetallbordeuterid, hvorved ketiminet reduseres til det tilsvarende N-substituerte 3-fluor-D-alanin eller det N-substituerte 2-deutero-3-fluor-D-alanin, og at den erholdte N-substituerte forbindelse omsettes med hydrogen i nærvær av palladiumhydroxyd-på-trekull-hydrogeneringskatalysator hvorved N-substituenten hydrogenolyseres.1. Process for the production of 3-fluoro-D-alanine or 2-deutero-3-fluoro-D-alanine, characterized in that fluoropyruvic acid is reacted with an optically active D-amine, forming the corresponding D-ketimine, which is reacted with an alkali metal borohydride or alkali metal borodeuteride, whereby the ketimine is reduced to the corresponding N-substituted 3-fluoro-D-alanine or the N-substituted 2-deutero-3-fluoro-D-alanine, and that the obtained N-substituted compound is reacted with hydrogen in the presence of palladium hydroxide-on-charcoal hydrogenation catalyst whereby the N-substituent is hydrogenolysed. 2. Fremgangsmåte ifølge krav 1, karakterisert ved at 3-fluor-D-alanin fremstilles ved å omsette fluorpyruvinsyre med et optisk aktivt D-amin under dannelse av det tilsvarende D-ketimin, som omsettes med et alkalimetallborhydrid hvorved ketiminet reduseres til det tilsvarende N-substituerte 3- fluor-D-alanin, og at denne N-substituerte forbindelse omsettes med hydrogen i nærvær av palladiumhPydroxyd-på-trekull-hydrogeneringskatalysator hvorved N-substituenten hydrogenolyseres .2. Method according to claim 1, characterized in that 3-fluoro-D-alanine is produced by reacting fluoropyruvic acid with an optically active D-amine to form the corresponding D-ketimine, which is reacted with an alkali metal borohydride whereby the ketimine is reduced to the corresponding N -substituted 3-fluoro-D-alanine, and that this N-substituted compound is reacted with hydrogen in the presence of palladium hPydroxyd-on-charcoal hydrogenation catalyst whereby the N-substituent is hydrogenolysed. 3. Fremgangsmåte ifølge- krav 1, karakterisert ved at 2-deutero-3-fluor-D-alanin fremstilles ved å omsette fluorpyruvinsyre med et optisk aktivt D-amin, under dannelse av det tilsvarende D-ketimin, som omsettes med et alkalimetallbordeuterid hvorved ketiminet reduseres til det tilsvarende N-substituerte 2-deutero-3-fluor-D-alanin, og at den erholdte N-substituerte forbindelse omsettes med hydrogen i nærvær av pall adiumhydroxyd-på-trekull-hydrogeneringskatalysator hvorved N-substituenteh hydrogenolyseres.3. Method according to claim 1, characterized in that 2-deutero-3-fluoro-D-alanine is produced by reacting fluoropyruvic acid with an optically active D-amine, forming the corresponding D-ketimine, which is reacted with an alkali metal bordeuteride whereby the ketimine is reduced to the corresponding N-substituted 2-deutero-3-fluoro-D-alanine, and that the obtained N-substituted compound is reacted with hydrogen in the presence of palladium hydroxide-on-charcoal hydrogenation catalyst whereby the N-substituent is hydrogenolysed. 4. Fremgangsmåte ifølge krav 1, karakterisert ved at f luorpy ru vi nsy re omsettes med D-oc-methylbenzylamin under dannelse av 2-(D-a-methylbenzy1 imi no )-3-fluor-propionsyre, som omsettes med natriumborhydrid under dannelse av N-(D-a-methylbenzyl )-3-fluor-D-alanin, som omsettes med hydrogen i nærvær av palladiumhydroxyd-på-trekullkatalysator hvorved methylbenzylsubstituenten hydrogenolyseres.4. Method according to claim 1, characterized in that fluoropyruvic acid is reacted with D-oc-methylbenzylamine to form 2-(D-a-methylbenzy1imino)-3-fluoro-propionic acid, which is reacted with sodium borohydride to form N -(D-α-methylbenzyl )-3-fluoro-D-alanine, which is reacted with hydrogen in the presence of palladium hydroxide on charcoal catalyst whereby the methylbenzyl substituent is hydrogenolysed. 5. Fremgangsmåte ifølge krav 1, karakterisert ved at 2-deutero-3-fluor-D-alanin fremstilles ved å omsette fluorpyruvinsyre med D-a-methylbenzylamin under dannelse, av 2-( D-a-methylbenzylimino}- 3-f luor-propionsyre , sam omsettes med natriumbor.deuterid under dannelse av N-(D-a-methylbenzy 1 )-1 2-deutero-3-fluor-D-alanin, som omsettes med hydrogen i nærvær av palladiumhydroxyd-på-trekullkatalysator hvorved methylbenzylsubstituenten hydrogenolyseres.5. Method according to claim 1, characterized in that 2-deutero-3-fluoro-D-alanine is produced by reacting fluoropyruvic acid with D-α-methylbenzylamine during the formation of 2-(D-α-methylbenzylimino}-3-fluoro-propionic acid, together is reacted with sodium boron deuteride to form N-(D-α-methylbenzy 1 )-1 2-deutero-3-fluoro-D-alanine, which is reacted with hydrogen in the presence of palladium hydroxide on charcoal catalyst whereby the methylbenzyl substituent is hydrogenolysed. 6. Fremgangsmåte ifølge krav 1, karakterisert ved at fluorpyruvinsyre omsettes med R(0 )-fenylglycin under dannelse av 2-(D-a-carboxybenzylimino)-3-fluor-propionsyre, som omsettes med natriumborhydrid under dannelse av N-(D-a-carboxybenzy1 )-3-f1uor-D-alanin, som omsettes med hydrogen i nærvær av palladiumhydroxyd-på-trekullkatalysator hvorved carboxybenzylsubstituenten hydrognolyseres.6. Method according to claim 1, characterized in that fluoropyruvic acid is reacted with R(0)-phenylglycine to form 2-(D-a-carboxybenzylimino)-3-fluoropropionic acid, which is reacted with sodium borohydride to form N-(D-a-carboxybenzylimino) -3-fluoro-D-alanine, which is reacted with hydrogen in the presence of palladium hydroxide-on-charcoal catalyst whereby the carboxybenzyl substituent is hydrogenolysed. 7. Fremgangsmåte ifølge krav 1, karakterisert ved at 2-deutero-3-fluor-D-alanin fremstilles, ved å omsette fluorpyruvinsyre med R(D )-fenylglycin under dannelse av 2-(D-a-carboxybenzylimino )-3-fluor-propionsyre, som omsettes med natriumbordeuterid under dannelse av N-(D-a-carboxybenzyl )-2- deuter.o-3-f luor-D-alanin, som omsettes med hydrogen i nærvær av palladiumhydroxyd-på-trekullkatalysator hvorved carboxybenzylsubstituenten hydrogenolyseres.7. Process according to claim 1, characterized in that 2-deutero-3-fluoro-D-alanine is prepared by reacting fluoropyruvic acid with R(D)-phenylglycine to form 2-(D-a-carboxybenzylimino)-3-fluoro-propionic acid , which is reacted with sodium bordeuteride to form N-(D-a-carboxybenzyl)-2-deuter.o-3-fluoro-D-alanine, which is reacted with hydrogen in the presence of palladium hydroxide on charcoal catalyst whereby the carboxybenzyl substituent is hydrogenolysed. 8. Fremgangsmåte ifølge krav 1, karakterisert ved at der som optisk aktivt D-amin anvendes 1-amino-(S )-2-|_(R.)-l-hydroxyethylJ -indolin.. q Fremgangsmåte ved fremstilling av et N-substituert 3-fluor-D-alanin eller N-substituert 2-deutero-3-fluor-D-alanin, karakterisert ved at fluorpyruvinsyre omsettes med et optisk aktivt D-amin, under dannelse av det tilsvarende D-ketimin, som omsettes' med et alkalimetallborhydrid eller alkalimetallbordeuterid, hvorved ketiminet reduseres.8. Method according to claim 1, characterized in that 1-amino-(S )-2-|_(R.)-1-hydroxyethylJ -indoline is used as optically active D-amine.. q Method for the preparation of an N- substituted 3-fluoro-D-alanine or N-substituted 2-deutero-3-fluoro-D-alanine, characterized in that fluoropyruvic acid is reacted with an optically active D-amine, forming the corresponding D-ketimine, which is reacted with an alkali metal borohydride or alkali metal borodeuteride, whereby the ketimine is reduced. 10. Fremgangsmåte ved fremstilling av N-(D-a-methylbenzyl)-3- fluor-D-alanin, karakterisert ved at 2-(D-a-methylbenzylimino)-3-fluor-propionsyre omsettes med natriumborhydrid.10. Process for the production of N-(D-α-methylbenzyl)-3-fluoro-D-alanine, characterized in that 2-(D-α-methylbenzylimino)-3-fluoro-propionic acid is reacted with sodium borohydride. 11. Fremgangsmåte v/ed fremstilling au N-( D-a-methy lben zyl ) - 2-deutero-3-f luor-D-alanin, karakterisert v/ ed at 2-(D-a-methylbenzylimino)-3-fluor-propionsyre omsettes med natriumbordeuterid.11. Process for the production of N-(D-a-methylbenzyl)-2-deutero-3-fluoro-D-alanine, characterized by reacting 2-(D-a-methylbenzylimino)-3-fluoro-propionic acid with sodium bordeuteride. 12. Fremgangsmåte v/ed fremstilling av/ ( D-a-carboxybenzy 1.)-2-deutero-3-f luor-D-alanin, karakterisert v/ed at 2-(D-a-carboxybenzylimino)-3-fluor-propionsyre omsettes med natriumbordeuterid.12. Process for the production of (D-α-carboxybenzyl 1.)-2-deutero-3-fluoro-D-alanine, characterized in that 2-(D-α-carboxybenzylimino)-3-fluoro-propionic acid is reacted with sodium bordeuteride.
NO753750A 1974-11-20 1975-11-10 NO753750L (en)

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US05/525,708 US3976689A (en) 1972-02-03 1974-11-20 Process for preparing 3-fluoro-D-alanine and its deutero analogs

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JP (1) JPS5175020A (en)
CH (1) CH619685A5 (en)
DD (1) DD124972A5 (en)
DK (1) DK515575A (en)
ES (1) ES442779A1 (en)
FI (1) FI753167A (en)
NL (1) NL7513137A (en)
NO (1) NO753750L (en)
SE (1) SE7512699L (en)

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JPS5175020A (en) 1976-06-29
FI753167A (en) 1976-05-21
NL7513137A (en) 1976-05-24
DK515575A (en) 1976-05-21
CH619685A5 (en) 1980-10-15
DD124972A5 (en) 1977-03-23
ES442779A1 (en) 1977-09-16
SE7512699L (en) 1976-05-21

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