DE2229245A1 - Decomposition of 3 fluorine DL alanine - Google Patents

Description

Decomposition of J-

The invention relates to new antibacterial agents and methods of making the same. In particular, the invention relates to the new stereoisomeric compound 3-I ¹ IuOr-D-. alanine, their deutero analogs, such as 2-Deutero-3-fluoro-D-alanine and 2,3,3-trideutero-3-fluoro-D-alanine, derivatives thereof protected on the carboxyl or amino group, salts of the above compounds with optically active acids and bases, processes for the production of 3-i'luoro-D-alanine and its deutero analogs or derivatives substituted by protective groups from these optically active salts and processes for the preparation of 3-3? luoro-D-alanine or its deutero analogs from a derivative substituted on the carboxyl or amino group by a protective group by reaction of this derivative substituted by a protective group with a cleavage agent, such as a hydrolyzing or hydrogenating agent. The 3-I ^t luor-D-alanine and its deutero analogues are potent antibacterial agents and are suitable for inhibiting the growth of gram-positive and gram-negative pathogenic bacteria.

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The new stereoisomers are expediently prepared by asymmetric synthesis or by decomposition of a derivative of 3-I ¹ IuOr-diialanine which is protected on the carboxyl or on the amino group.

As protecting groups for the carboxyl group, amides and substituted amides, ester substituents, e.g. Alkyl esters, such as methyl, ethyl and tert-butyl esters, aryl esters, Aralkyl esters such as benzyl esters, p-nitrobenzyl esters and the like.

Acyl substituents, such as formyl, acetyl, benzoyl, phthaloyl, are usually used as protective groups for the amino group, Trifluoroacetyl, 1-menthoxyacetyl, toluenesulfonyl, dibenzylphosphoryl, 2-nitrobenzenesulfenyl, tritylsulfenyl, o-nitrophenoxyacetyl and the like, protective urethane substituents, such as benzyloxycarbonyl (carbobenzoxy), methyloxycarbonyl, Ethyloxycarbonyl, p-methoxycarbobenzoxy, p-nitrocarbobenzoxy, tert-butyloxycarbonyl, tert-amyloxycarbonyl, adamantyloxycarbonyl, 2- (p-biphenylyl) -2-propyloxycarbonyl, isonicotinyloxycarbonyl, diisopropylmethyloxycarbonyl and the like, -alkyl- or aralkyl substituents such as benzyl, dibenzyl, a-phenylethyl (oc-methylbenzyl), triphenylmethyl, trialkylsilyl, Trimethylsilyl and the like.

If 3-Pluör-D-alanine compounds by decomposition of a derivative (not a salt) of 3-I ¹ luor-DL-alanine with the help of an optically active group, such as the 1-menthoxyacetyl group, or by asymmetric synthesis, such as by reaction of fluoroacetaldehyde with an optically active amine, such as Da-methylbenzylamine, R (D) -phenylglycine, 1-amino- (5) -2- / TR) -1-hydroxyethyl7-indoline ^{and the} like, or by reacting one protected on the amino group oc-Amino-ß-fluoroacrylic acid, such as a-benzamido-ß-fluoroacrylic acid, with hydrogen or deuterium in the presence of an asymmetric catalyst.

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or if 3-fluoro-D-alanine compounds by asymmetric rearrangement of a 2- (azidocarbonyl or aminocarbonyl) -3-fluoropropionic acid ester or nitrile or from N _T acyl-3-fluoro-D-alanine by selective enzymatic ^ deacetylation of the 1-isomer, a derivative of 3-fluorine-D-alanine which is protected at the amino and / or carboxyl group, e.g. U-1-menthoxyacetyl-3-fluoro-D-alanine, N- (Da-methylbenzyl) -3-fluoro-D-alanine, N- (D-oc-carboxybenzyl) -3-fl "and or-D-alanine, F-benzyl-3-fluoro-D-alanine, N -Carboriyl-3-fluoro-D-alanine methyl ester, N-ethoxycarbonyl-3-fluoro-D-alanine, li-chloroacetyl-3-fluoro-D-alanine and the like.

If 3-fluoro-D-alanine compounds are prepared by decomposing salts of an optically active base with a derivative of 3-i ¹ luoro-DL-alanine protected on the amino group, the corresponding compound is finally obtained (after acidification) the amino group-protected derivative of 3-fluoro-D-alanine such as B-carbobenzoxy-3-fluoro-D-alanine, N, N-dibenzyl-3-fluoro-D-alanine and the like.

If 3-luoro-D-alanine compounds are prepared by decomposing salts of an optically active acid with a carboxyl-protected derivative of 3-I ¹ IuOr-Dl-alanine, the corresponding carboxyl-protected derivatives are finally obtained 3-fluoro-D-alanine, such as (after decomposition using tartaric acid, camphor-10-sulfonic acid, dibenzoyl-d-tartaric acid and the like as a decomposition agent) the benzyl ester of 3-fluoro-D-alanine, D-2-amino 3-fluoro-propionitrile, D-2-amino-3-fluoro-propionic acid amide and the like ...

These derivatives substituted by protective groups are all converted into the free 3-fluorine-D-alanine compound by reaction with a cleavage agent convicted. For example one uses at

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the one on the amino group through the N-1-menthoxyacetyl, the N-benzoyl, the H-carbonyl, the N-ethoxycarbonyl or the N-chloroacetyl substituted derivatives are usually preferred an acidic hydrolyzing agent, such as aqueous hydrochloric acid, aqueous hydrobromic acid and the like, as a splitting agent, while basic hydrolyzing agents are generally unsuitable because they have the 3-position fluorine substituent can react.

In the case of the other derivatives protected on the amino group, namely those substituted on the amino group by the N- (Da-methylbenzyl), the N-fD-a-oxybenzyl), the N-carbobenzoxy or the NN-dibenzyl radical Derivatives are preferably used as a cleavage agent, a hydrogenation agent, such as hydrogen in the presence of clay palladium on carbon or palladiufihydroxide on charcoal as a catalyst. If the protective group can easily be split off, such as, for example, the carbobenzoxy group, the hydrogenation is expediently carried out at approximately atmospheric pressure _} during aiaa. in the case of protective groups that are difficult to split off, such as ΪΤ, Ε-dibenzyl, N- (D-oc-methylbenzyl; '^ - (D-oc-carboxybenzyl) and the like, when using palladium hydroxide for bridges up to 2.8 kg / cm and when using palladium on carbon, hydrogenated at pressures up to 70 kg / cm '"'.

In the case of the above, protected on the carboxyl group Derivatives, e.g. of the benzyl ester, of D-2-amino-3-fluoropropionic acid amide (and nitrile), the splitting agent used is preferably an aqueous acidic hydrolyzing agent, such as aqueous Hydrochloric acid and the like.

The invention also comprises, as a further embodiment, the decomposition of ^ -fluoro-DI-alanine, its deutero analogs and its derivatives protected on the amino group using optically active bases, such as D + I-oc-phenethylamine,

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Quinine, brucine, ohinidine, cinchonine, I-lysine, cinchonidine, strychnine, morphine, 1-menthylarain, L-arginine, d-2-amino-lhydroxyhydrinden, ephedrine, atdetylainine, amphetamine, D + L-threo-ip-nitrophenyl- 2-amino-i, 3-propanediol, D ₊ L-thre0-1-phenyl-2-amino-1,3-propanediol, D + LN-dimethyloc-phenethylamine, dehydroabietylamine, D + L-1- (1-naphthyl ) -ethylamine, D + L-1- (2-ITaphthyl) -ethylamine, D + L-tyrosine hydrazide, D + L-oc-1-penchylamine, · D + L-threo ~ 2,2-dimethyl-4-phenyl-5 -amino-1,3-dioxane, optically active "basic polymers, such as the quaternary ammonium compound of dimethyl- (l-phenethyl) -polystyrene-divinylbenzene, and the decomposition of J-fluoro-DL-alanine, its deutero analogs and its derivatives protected on the carboxyl group using optically active acids, such as d + 1-camphor-10-sulfonic acid, 3-bromocamphor-8-sulfonic acid, D + L-tartaric acid, d + 1-camphor-10-sulfonic acid, 3-bromocamphor -8-sulfonic acid, D + L-dibenzoyltartaric acid, D + L-ditoluoyltartaric acid, D + L-tartranilic acid, D + LN-Cl-phenylethylJ-succinamic acid, 3D + LN- (1-phenylethyl) -phthalamic acid, U-acetylalanine, H-acetylleucine, pyroglutamic acid, glutamic acid, 1-menthoxyacetic acid, mandelic acid, malic acid, LN-acetyldibromo tyrosine, D ¹ + ltyrosine -1-acetyl-amethyl-3,4-dimethoxyphenylalanine, D + LN-acetyl-ix-ynethyl-3,4-methylenedioxyphenylalanine and the like.

Example 1

A solution of 20 g of 3-I ¹ IuOr-DL-alanine in 200 ml of water and 56 ml of 2.5N sodium hydroxide solution is admixed with a total of 62.0 g of carbobenzoxychloride in five equal portions at intervals of 15 minutes with vigorous stirring and cooling in a bis bath . The mixture is stirred for a further 3 hours while cooling. During the reaction, the pH is kept at 10 to 11 by adding 2.5N aqueous sodium hydroxide solution. The reaction mixture is extracted with ethyl acetate and the extract is discarded. The aqueous phase is adjusted to a pH of 2 with dilute aqueous hydrochloric acid and the solution obtained in this way is adjusted several times

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extracted with ethyl acetate «The ethyl acetate extracts are dried over anhydrous magnesium sulfate and dried to dryness evaporated. The residue is made from 400 ml of moist carbon tetrachloride recrystallized and dried. 33 g of! I-öar'bo'bensoxy ~ 3-xluoro-DL-alanine are obtained.

A mixture of 22.3 g of L-tjrosine hydrazide and 24.1 g of N-carbobensoxy-3-fluoro-DL-alanine-v / ird dissolved with heating in 50 percent aqueous ethanol and the solution under reduced Druck au ai Geraiacii the diastereoisomeric L-tyrosine hydrazide s evaporated. which then, by fractional crystallization separated from each other from ethanol.

The L-tyrosine hydrazide-H-ca, rbobenzoxy-3-fluoro-D-alanine salt is suspended in dilute aqueous hydrochloric acid and the suspension extracted mehnnals with ethyl acetate. After evaporation of the ethyl acetate leaves N-carbobenzoxy-3-fluoro-D-alanine.

1 g N-Garbobenzoxy-3-fluoro-D-alanJri is dissolved in 50 ml methanol and the solution at atmospheric pressure in the presence ύοπ reacted with hydrogen 1 g of 5-percent palladium on carbon. The catalyst is filtered off and the methanol is evaporated from the piltrate in vacuo. The residue is recrystallized from water, practically pure 3-fluoro-D-alanine being obtained.

Example 2

To a solution of 20.4 g of 3-fluorine-DL-alanine in 200 ml of v / water and 56 ml of 2.5-D. aqueous sodium hydroxide solution are under rapid Stirring 28.0 g of levorotatory menthoxyacetyl chloride were added dropwise. A further 2.5N aqueous sodium hydroxide solution is added to adjust the pH between 10 and 11. The reaction solution is then slowly poured into ice-containing dilute aqueous hydrochloric acid. Of the Precipitate is filtered off, and the mixed diastereo-

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isomers are obtained by fractional crystallization from aqueous Ethanol separated from each other.

The stereoisomeric N1-menthoxyacetyl-3-fluoro-dalanine obtained in this way is heated to reflux temperature with aqueous 6N hydrochloric acid, which contains a little ethanol for the purpose of volatilization. After boiling for 18 hours using a reflux condenser, the solution is partially evaporated and extracted twice with ether. The aqueous solution is then evaporated to dryness, where the excess hydrochloric acid is driven off. The 3- ^l) luoro-D-alanine hydrochloride that remains as a residue is dissolved in the smallest possible amount of water and the solution is adjusted to pH with concentrated aqueous ammonium hydroxide solution value of 4.8 adjusted. The mixture is cooled to 0 ° C, followed by optically pure by filtration 3-3 ¹ IuOr-D-alanine wins..

Another method is the 3-I'l'uor-D-alanine-hydrochloride dissolved in water and the solution passed through a strongly acidic cation exchange resin (in the hydrogen ion form). The chlorine ions are extracted from the ionic acid column with water washed out, and then the column is eluted with dilute aqueous ammonium hydroxide solution and the Bluat evaporated. That 3-E'luoro-D-alanine which precipitates out is filtered off and dried.

Example 3

A suspension of 20.7 g of 3-fluoro-DL-alanine in 200 ml of benzyl alcohol is passed through with dry hydrogen chloride heated to 100 ° C. The reaction mixture is kept at 100 ° C. until a clear solution has formed. then the benzyl alcohol is evaporated off under reduced pressure, the remaining oil is dissolved in 50 ml of water and 200 ml are added Methylene chloride too. Solid sodium carbonate is then added while stirring. until the effervescence stops. the

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The methylene chloride layer is separated and washed with water. Then the methylene chloride layer is evaporated in vacuo, whereby the benzyl ester of J-fluoro-DL-alanine as viscous Oil remains behind.

10 g of the benzyl ester of 3-fluoro-DL-alanine thus prepared and 9.0 g of dibenzoyl-d-tartaric acid are mixed together in 100 ml of ethanol, and the mixture is gently heated until solution has occurred. The solution is evaporated to dryness. The residue will be in the least amount possible dissolved hot ethanol and the mixture of diastereoisomers separated by fractional crystallization.

The dibenzoyl-d-tartaric acid salt of the benzyl ester of 3-3? Luoro-D-alanine thus obtained is added to dilute aqueous hydrochloric acid and the mixture is extracted five times with 25 ml of methylene chloride each time, whereby the dibenzoyl-d-tartaric acid from the hydrochloride of the benzyl ester from 3-i ¹ luoro-D-alanine containing acidic aqueous solution is extracted. The benzyl ester is hydrolyzed by heating the aqueous acidic solution to boiling for 5 hours. The reaction solution is cooled and extracted with methylene chloride. The aqueous solution is then evaporated to dryness, the excess hydrochloric acid being driven off. The remaining 3-i ^1- luoro-D-alanine hydrochloride is dissolved in the smallest possible amount of water, the pH is adjusted to 4.8 with concentrated aqueous ammonium hydroxide and the precipitate of S-fluoro-D-alanine is collected by filtration.

According to another method, after the dibenzoyl-d-tartaric acid has been extracted, the aqueous acidic solution of the benzyl ester of 3-I'luoro-D-alanine by hydrogenolysis using of 1.0 g of 10 percent palladium on carbon as a catalyst in 3-fluoro-D-alanine hydrochloride, which then by treatment with concentrated aqueous ammonia

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nitrous hydroxide solution, as described above, into the free amino acid 3 -]? Luor-rD-alanine is converted.

Example 4

39 »4 g of dibenzylamine become a solution of 17» 1 g of 2-bromo-3-fluoropropionic acid in 50 ml. isopropanol added. The mixture is left to stand at 25 ° C. for 5 minutes and then heated another 3 hours at reflux temperature. The isopropanol is evaporated in vacuo and the residue is added to 200 ml 10 percent aqueous sodium carbonate solution is added. The aqueous solution thus obtained is five times with 100 ml of ether extracted. The aqueous layer is then acidified with acetic acid and extracted twice with 50 ml of chloroform each time. That Chloroform is evaporated off in vacuo and the residue is recrystallized from cyclohexane. H, N-dibenzyl-3-fluoro-DL-alanine is obtained.

5.7 g of F, E-dibenzyl-3-fluoro-DL-alanine and 4.24 g of D (-) - threo-1-p-nitrophenyl-2-aminopr.opandxol-1,3 are mixed together in 150 ml of hot 50 percent aqueous ethanol. You get a mixture of the diastereoisomeric salts. This is obtained by fractional crystallization from aqueous ethanol D (-) ~ threo-1-p-nitrophenyl-2-aminopropanediol-1,3-salt of N, N-dibenzyl-3-fluoro-D-alanine. The salt is made by further Purified recrystallization from 50 percent aqueous ethanol.

2 g of D (-) - threo-1-p-nitrophenyl-2-aminopropanediol-1,3-salt of 2i, N ~ dibenzyl-3-fluoro-D-alanine with 10 ml 10 percent aqueous sodium carbonate solution is added, and the D (-) - threo-1-p-Mtrophenyl-2-aminopropanediol-1,3-diol which precipitates is filtered off. The filtrate is acidified with acetic acid and the N, N-dibenzyl-3-fluoro-D-alanine is extracted with chloroform. Evaporation of the chloroform extract gives N, N-dibenzyl-3-fluoro-D-alanine.

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A solution of 1.0 g of N, N-dibenzyl-3-fluoro-D-alanine in 10 ml of ethanol and 10 ml of 6N hydrochloric acid is taken at 2.8 kg / cm. Use of 1.0 g of 10 percent palladium hydrogenated on carbon as a catalyst. If no more hydrogen is taken up, the catalyst is filtered off and the Mltrat evaporated to dryness. The hydrochloride of 3-fluoro-D-alanine is obtained. This salt is dissolved in water and the aqueous solution is passed through a strongly acidic cation exchange resin (in the hydrogen ion form). The chlorine ions are washed out of the column with water and the column is then eluted with dilute aqueous ammonium hydroxide solution. After the ammonia has been driven off, a precipitate separates out of the eluate and is filtered off and dried. This material is 3-fluoro-D-alanine.

Example 5

A solution of 2 g of 3-i ¹ luoro-DL-alanine in 20 ml of water and 5.6 ml of aqueous 2.5N sodium hydroxide solution is mixed with a total of 6 g of carbobenzoxychloride in five equal portions at intervals of 15 minutes, stirring vigorously and cools in an ice bath. Stirring and cooling are continued for a further 3 hours. During the reaction, the pH is kept between 10 and 11 by adding aqueous 2.5N sodium hydroxide solution. The reaction mixture is extracted with ethyl acetate and the aqueous phase is adjusted to a pH of 2 with dilute aqueous hydrochloric acid. The aqueous acidic solution is then extracted several times with ethyl acetate and these extracts are combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is recrystallized from 40 ml of moist carbon tetrachloride and dried. Ma.n receives 3 g of N-carbobenzoxy-3-fluoro-DL-alanine.

• A solution of 0.150 g of N-carbobenzoxy-3-fluoro-DL-alanine in 5 ml of ethyl acetate are mixed with 0.094 g of 1-ct-phenylethylamine. The mixture is evaporated to dryness, the residue

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dissolved in 1 ml of ethyl acetate and the mixture thus obtained, subjected to fractional crystallization. The la ~ phenylethylamine salt of N-carbobenzoxy ~ 3-fluoro-D-alanine is obtained. 0.100 g of this salt are dissolved in water, the solution is acidified to a pH of 2, extracted with ethyl acetate and the ethyl acetate extract is evaporated to dryness. The residue left behind is K-carbobenzoxy-3-fluoro-I) -alanine.

0.255 g of N-carbobenzoxy-3-fluoro-D-alanine are in -10 ml Dissolved methanol, and 0.3 g of 5 percent palladium on charcoal is added to the solution. Through the mixture is Passed Vfassstoff for 12 hours at room temperature. The catalyst is then filtered off and the filtrate is evaporated to dryness. The residue is recrystallized from a mixture of water and isopropanol. The product is 3-3? Luor-D ~ alanin.

Example 6

12.4 g of freshly prepared ITuoraeetaldehyd are slowly un ter cooling in an ice-methanol bath in 24 »3 g of D (+) -a-methylbenzylamine distilled into it. The mixture is slowly added with 50 g; added anhydrous calcium sulfate and the resultant Mixture stirred overnight at room temperature. After adding 200 ml of ether, the calcium sulfate is filtered off. The ether filtrate is evaporated in vacuo and the residue remaining N-CD-a-methylbenzylJ-ß-fluoroacetaldimine in anhydrous Dissolved ethanol, cooled the ethanolic solution to -10 ° C and treated with 7.9 ml of hydrogen cyanide. The mixture is stirred for 16 hours at room temperature, whereupon the Ethanol evaporates in vacuo. 2- (D-oc-methylbenzylamino) -3-fluoro-D-propionitrile is obtained. The cooled nitrile is mixed with 200 ml of cold concentrated aqueous hydrochloric acid, the Mixture stirred overnight at room temperature, then heated to reflux temperature for 8 hours and the reaction solution in vacuo evaporated to dryness. The excess hydrochloric acid will

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removed from the residue by adding 100 ml of tert-butanol and repeated evaporation to dryness. It remains behind the hydrochloride of N- (D-oc-methylbenzyl) -3-fluoro-D-alanine. This salt is dissolved in absolute ethanol and the solution is filtered and 16 ml of propylene oxide were added to set the amino acid free from its hydrochloride. You leave that Mixture stand overnight at room temperature so that the reaction is complete and N- (D-oc-methylbenzyl) -3-fluoro-D-alanine forms, which is then filtered off, washed with ethanol and recrystallized from aqueous ethanol.

The N- (D-oc-methylbenzyl) -3-fluoro-D-alanine is dissolved in ethanol, which contains an equivalent amount of hydrogen chloride, and at 2.8 kg / cm in the presence of 10 percent palladium hydroxide on charcoal as a catalyst Subjected to hydrogenolysis. The oc-methylbenzyl group is split off as a result. The catalyst is filtered off and the filtrate is evaporated to dryness. 3-5 ¹ luoro-D-alanine hydrochloride remains as a residue. This hydrochloride is dissolved in the smallest possible amount of water and the pH is adjusted to 4.8 with concentrated aqueous ammonium hydroxide solution. The mixture is cooled to 0 ° 0, whereupon optically pure 3-i ^1- luoro-D-alanine is obtained.

The mixture is cooled to 0 ° 0, whereupon it is filtered off

Another method is to dissolve the 3-3? Luoro-D-alanine hydrochloride in water and pour the solution through strongly acidic cation exchange resin (in the hydrogen ion form) pass through. The chlorine ions are washed out of the exchange column with water, whereupon the column with dilute aqueous ammonium hydroxide solution eluted. When evaporating 3-fluoro-D-alanine precipitates out of the eluate, which is filtered off and dried.

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Example 7

A cold solution of 12.1 g of D-α-methylbenzylamine in 100 ml Ethanol slowly becomes a solution of 5.3 g of "fluoropyruvic acid added in 250 ml of ethanol, keeping the temperature at 0 ° G. The solution is allowed to rise to 25 ° C heat and keep it at 25 ° C. for one hour. The 2 ~ (D-oc-methylbenzylimino) -3-fluoropropionic acid containing solution is

then at 2.8 kg / cm using 5.0 g of 10 percent palladium on carbon as a catalyst with hydrogen implemented, the hydrogenation being continued until no more hydrogen is taken up. The catalyst is filtered and constricts the liltrate to half its volume a. An aqueous ethanol mixture is obtained by adding 100 ml of water Solution containing N- (D-oc-methylbenzyl) -3-fluoro-D-alanine. The methylbenzyl group is made by hydrogenolysis at 2.8 kg / cm using 5.0 g of 10 percent Cleaved off palladium hydroxide on charcoal as a catalyst. When the hydrogen uptake ceases, the catalyst becomes filtered off, the filtrate evaporated to dryness in vacuo and the residue from 50 percent isopropanol in Water and then recrystallized from water. You get practically pure 3 -]? luoro-D-alanine.

Example 8

A cold solution of 12.1 g of D-cc-methylbenzylamine in 100 ml Ethanol is slowly converted into a solution of 5.3 g of fluoropyruvic acid in 250 ° C. while maintaining a temperature of 0 ° C. ml of ethanol added. The solution is allowed to warm to 25 ° 0 and keeps it at this temperature for an hour. The solution containing 2- (D-a ~ methylbenzylimino) -3-fluoropropionic acid

holds, is then at 2.8 kg / cm using 5.0 g of catalyst (10 percent palladium on carbon) reacted with deuterium, with the deuterium sb being initiated for a long time until no more deuterium is absorbed. Then the catalyst is filtered off and the piltrate on the

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Half of its volume constricted. By adding 100 ml of vat an aqueous-ethanolic solution is obtained, the N- (B-a-methylbenzyl) ~ 2-deutero-3-fluoro ~ D-alanine contains, and the methylbenzyl group is then split off by hydrogenolysis on a charcoal catalyst. When the hydrogen uptake has stopped, the catalyst is filtered off, the piltrate evaporated to dryness in vacuo and the residue from a 50 percent solution of isopropanol in water and then off Uracrystallized water. Practically pure 2-deutero-3-fluoro-D-alanine is obtained.

Example 9

0.1 millimole asymmetric diphosphine rhodium catalyst (prepared according to "Chem. Comm", 1971, page 481) is in 50 ml a mixture of 1 part of benzene and 2 parts of ethanol and 11.0 g of cc-benzamido-ß-fluoroacrylic acid are added to the solution. The mixture is reacted with hydrogen at 7 kg / cm 2 and 25 ° C. The reaction solution is evaporated to dryness and the residue dissolved in chloroform. The chloroform extract is washed with water, treated with charcoal, filtered and evaporated to dryness. N-benzoyl-3-fluoro-D-alanine is obtained. After adding concentrated aqueous hydrochloric acid, the mixture is heated to reflux temperature for 8 hours. whereby the benzoyl group is split off.

The solution is evaporated to dryness and the residue is dissolved in the smallest possible amount of water. The pH of the aqueous solution is adjusted to 4.8 with concentrated aqueous ammonium hydroxide, the solution is cooled and the precipitate is filtered off. The crude 3-i ¹ luor-D ~ alanine is / stirred 24 hours at 25 ° C with five times its volume of V ater. By filtering off, practically pure 3-fluoro-D-alanine is obtained.

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Example 10

0.1 millimole asymmetric diphosphine rhodium catalyst (manufactured according to "Chem. Comm.", 1971, page 481) is in 50 ml a mixture of 1 part of benzene and 2 parts of ethanol and 11.0 g of α-benzamido-ß-fluoroacrylic acid are added to the solution. The mixture becomes "at 7 kg / cm and 25 C with deuterium implemented. The reaction solution is evaporated to dryness and the residue is dissolved in chloroform. The chloroform extract is washed with water, treated with adsorption charcoal, filtered and the filtrate is evaporated to dryness N-Benzoyl-2,3-dideütero-3-fltior-D-ralanine. After adding concentrated aqueous hydrochloric acid, the mixture is heated to reflux temperature for 8 hours, where the benzoyl group is split off will. The solution is then evaporated to dryness and the residue dissolved in the smallest possible amount of water. The pH of the aqueous solution is adjusted to 4> 8 with concentrated aqueous ammonium hydroxide, the solution cooled and the precipitate filtered off. The crude 2,3-dideutero-3-fluoro-D-alanine obtained as pilter residue turns 24 Stirred for hours at 25 ° C with five times its volume of water. By filtering off one obtains practically pure .2,3-Dideutero-3-fluoro-D-alanine.

Example 11

50 g of dimethylmethylene malonate (ie methyl 2-methoxycarbonylacrylate) are added to 200 ml of anhydrous hydrogen fluoride at a temperature below -20 ° C. After the hydrogen fluoride has evaporated, 500 ml of ether are added. The ether solution is washed with ice water, dried and filtered. The filtrate is evaporated to dryness and the oil which remains as residue is distilled in vacuo. Virtually pure 3-fluoromethylmalonic _{acid dimethyl ester is obtained (ie 0} 2-methoxycarbonyl-3-fluoropropionic acid methyl ester).

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16.4 g of ethyl 2-metlioxycarbonyl-3-i'luoropropionate become dissolved in 100 ml of methanol, and the solution is paused a temperature of 0 ° C with 10 ml of 1N aqueous sodium hydroxide solution offset. This gives an aqueous-methanolic solution containing the sodium salt of methyl 2-carbaxy-3-fluoropropionate contains. This solution is neutralized with dilute aqueous hydrochloric acid and extracted with chloroform and the chloroform solution dried and evaporated in vacuo. Methyl 2-carboxy-3-fluoropropionate is obtained.

15g of this ester are in a mixture of methanol and Benzene dissolved, whereupon the stoehiometrically equivalent amount of L-oc-methylbenzylamine is added and the diastereoisomers Salts of methyl 2-carboxy-3-fluoropropionate are separated from one another by fractional crystallization. The thus obtained L-α-methylbenzylamine salt of S-2-carboxy-3-fluoropropionic acid methyl ester is reacted in aqueous solution with the stoehiometrically equivalent amount of aqueous hydrochloric acid, the aqueous solution extracted with chloroform and the chloroform extract dried and evaporated in vacuo. Main receives methyl S-2-carboxy-3-fluoropropionate.

3.0 g of S-2-carboxy-3-fluoropropionic acid methyl ester are in 25 ml of acetone gelös.t, and the solution is first with 2.02 g of triethylamine and then with excess ethyl chloroformate at 0 C offset. 10 ml of water are added to the mixture and the solution is stirred for 30 minutes at 0 ° C., during which an aqueous acetone solution is obtained which contains the corresponding carboethoxy ester mixed anhydride of methyl S-2-carboxy-3-fluoropropionate contains. This solution is mixed with 1.3 g of sodium azide and the mixture for a further two hours -5 to 0 C stirred. The reaction mixture is poured into ice-cold saturated aqueous sodium chloride solution and the aqueous Mixture extracted several times with ether. The methyl S-2-azidocarbonyl-3-fluoropropionate containing solution is

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dried over anhydrous sodium sulfate, filtered, mixed with 100 ml of dioxane, the ether then evaporated and the dioxane solution carefully heated to boiling (behind a protective window), during which the azide decomposes and converts to methyl S-2-isocyanato-3-fluoropropionate, i.e. N-carbonyl-3-fluoro-D-alanine methyl ester, surrounded.

100 ml of water and 50 ml of concentrated aqueous hydrochloric acid are added to this isocyanate, and the mixture is heated to reflux temperature for 2 hours. Under these conditions, both the isocyanate group and the methyl ester group are split off by hydrolysis. By evaporating the aqueous reaction solution in vacuo; you get crude 3-3 ¹ luor-D-alanine hydr ο chloride (S-3-i ^l luoralanine hydrochloride).

The hydrochloride of 3-3? Luoro-D-alanine is dissolved in water and the solution passed through a strong cation exchange resin (in the hydrogen ion form). The ion exchange column is washed with water to remove the chlorine ions and then eluted with dilute aqueous ammonium hydroxide solution. The eluate is evaporated and the precipitate is filtered off, dried and recrystallized from 50 percent aqueous isopropanol. Practically pure 3-fluoro-D-alanine (S-3-I ^v luoralanine) is obtained.

If the S-2-azido carbonyl-3-fluoropropionic acid methyl ester is decomposed in ethanol solution, the corresponding one is formed Xthyl urethane of the 3-fluoro-D-alanine methyl ester (ethyl urethane of S-3-3? luoralanine methyl ester). The latter is then with aqueous hydrochloric acid converted to J-Sluor-D-alanine hydrochloride, which, as described above, is converted into 3 -]? luoro ~ D-alanine.

The optically active connections in this example are sometimes marked with "R" or "S" according to the "IUPAC Tentative Rules for

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the Nomenclature of Organic Chemistry; Section E Fundamental Stereochemistry ", Journal of Organic Chemistry, Volume 35 (1970), Page 2863-2867, "inscribed.

In a similar way, the carboethoxy ester mixed anhydride of S-2-carboxy-3-fluoropropionic acid methyl ester (instead of sodium azide) with ammonia to S-2-aminocarbonyl-3-fluoropropionic acid methyl ester implemented, which is then made to react with sodium hypobromite, whereby the amido group rearranges and, when using dioxane as solvent, S ^ -Isocyanato ^ -fluorpropionäuremethylester, and when one Ethanol used as solvent, the corresponding ethyl urethane of 3-i'luoro-D-alanine, namely N-ethoxycarbonyl-3-fluoro-D-alanine, arises.

On the other hand, 2-cyanoacrylic acid can be converted into 2-carboxy-3-fluoropropionitrile with hydrogen fluoride by the process described above convert, which is broken down into its stereoisomers using L-oc-methylbenzylamine as a decomposition agent, whereby R-2-carboxy-3 ~ fluoropropionitrile obtained, which is then converted into the mixed anhydride. The latter is made with sodium azide, as described above, converted to R-2-azidocarbonyl-3-fluoropropionitrile and the latter is heated, the azide decomposing and S-2-isocyanato-3-fluoropropionitrile arises, which is then heated with aqueous hydrochloric acid on the reflux condenser (as with the Hydrolysis of S-2-isocyanato-3-fluoropropionic acid methyl ester). Here are the isocyanate group and the nitrile group split off by hydrolysis, and 3-fluoro-D-alanine hydrochloride is formed.

Another method gives D-2-amino-3-fluoropropionitrile compounds by decomposition of the corresponding DL-2-amino-3-fluoropropionitrile compounds. DL-2-amino-3-fluoropropionitrile itself is e.g. using an op-

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15 056

table-active decomposing agent, me tartaric acid, camphor-10-sulfonic acid and the like, decomposed, where "the optically active salt of D-2-amino-3-fluoropropionitrile is obtained, which by treatment with aqueous ammonia is converted into the free D-2- amino-3-fluorpropionitril is transferred. the latter is extracted from the aqueous solution with ether. the D-2-amino-3-fluorpropionitril is then "at temperatures below 0 C and enriched in hydrogen chloride aqueous hydrochloric acid (50 fo HGL) to D -2-Aroino-3-fluoropropionamide reacted and the latter heated to reflux temperature with concentrated aqueous hydrochloric acid, the hydr'ochloride of 3-luoro-D-alanine being obtained.

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Claims (23)

Merck & Co., Inc. 15 056 Claims / π .j Process for the preparation of 3-I'luoro-D-alanine or Deutero analogs of the same, characterized in that one of a derivative substituted by protective groups of 3-i'luoro-D-alanine or a Deutero analogue thereof. ben splits off the protective groups by reaction with a splitting agent. 2. The method according to claim 1, characterized in that one protected on the amino group derivative of 3-fluoro-D-alanine with a cleavage agent that causes hydrolysis or hydrogenolysis » 3 ^; . Process according to claim 1, characterized in that an N-acyl derivative of 3-fluorine-D-alanine is reacted with a hydrolysis-causing cleavage agent. ^{4. The method according to claim 1, characterized in that a derivative of 3-S 1} luoro ~ D-alanine which is substituted on the nitrogen atom of the amino group by a hydrocarbon radical or a substituted hydrocarbon radical is reacted with a hydrogenolysis-causing cleavage agent. 5. The method according to claim 1, characterized in that N-carbobenzoxy-3-fluoro ~ D-alanine with a hydrolysis or hydrogenolysis causing cleavage agent. - 20 209857/118 056 6. The method according to claim 1, characterized in that an N- (benzyl) -, an N, N- (dibenzyl) -, an N- (cc-methylbenzyl) - or an N - («- carboxy" benzyl) -derivative of 3-I ¹ IuOr-D-alanine or a · Deutero analogue thereof with a hydrogenolysis-causing cleavage agent. 7. The method according to claim 1, characterized in that one-an N- (benzoyl) -, an N- (chloroacetyl) - or a> N- (l-menthoxyacetyl) derivative of 3-I ¹ luoro-D-alanine or a Deutero analogue thereof with a hydrolysis-causing cleavage agent. 8. The method according to claim 1, characterized in that a derivative of 3-3? luoro-D-alanine protected on the carboxyl group or a deutero analogue thereof, which an ester group as a protective substituent of the carboxyl group, has an amide group or a nitrile group, is reacted with a hydrolysis-causing cleavage agent. 9. A method for breaking down 3-I ¹ luoro-DL-alanine, Deutero analogs of the same or protected on the carboxyl or amino group derivatives of these compounds into the stereoisomers, characterized in that a mixture of the salts with an optically active base or an optically active acid broken down by fractionation. 10. Method for resolving a DL racemate of 3-fluoroalanine or a Deutero analogue of the same into the individual stereoisomers, characterized in that a mixture the salts of the L and D components of the racemate or one protected on the amino or on the carboxyl group Produces derivative of these L and D components with an optically active base or an optically active acid and the salt mixture is broken down by fractionation. - 21 209852/1183 ; 2279245 056 34 11. The method according to claim 9, characterized in that one a mixture of the salts of 3-fluoro-DL-alanine with an optical active base produces the salt of 3-fluoro-D-alanine by fractional crystallization of the salt mixture separates in practically pure form and the 3-fluoro-d ~ alanine from this salt by treatment with a strong acid in Freedom sets. 12. The method according to claim 9> characterized in that a mixture of the salts of 3-fluoro-DL-alanine with an optically active acid is prepared by fractional crystallization of the salt mixture separates the salt of 3-fluoro-D-alanine in practically pure form and the 3-fluoro-D-alanine sets free from this salt by treatment with a strong base. 13 · Process for the preparation of 3-fluoro-D-alanine or one Deutero analogs thereof, characterized in that; a mixture of the salts of an amino-protected derivative of 3-fluoro-DL-alanine or a deutero analog the same made with an optically active acid, by fractional decomposition of the salt mixture the salt of the corresponding 3-fluoro-D-alanine protected on the amino group is obtained in practically pure form, the 3-fluoro-D-alanine derivative protected on the amino group sets free from the salt by means of a strong acid and this; Reacts derivative with a cleavage agent. 14. Salt of 3-fluoro-D-alanine or a deutero analogue thereof with an optically active base. 15. Salt of a 3-fluoro-D-alanine protected on the amino group or a deutero analog thereof with an optically active base. - 22 209857M 183 2279245 16. Salt according to claim 15, characterized in that the optically active base is 1-a-ehenylethylamine. 17. Salt of 3-fluoro-D-alanine or a deutero analogue thereof with an optically active acid. 18. Salt according to claim 17, characterized in that the optically active acid is d-camphor-10-sulfonic acid. 19. Salt of a 3-3J ¹ IuOr-D-alanine protected on the carboxyl group or a deutero analog thereof with an optically active acid. 20. Amino-protected derivative of 3-S ¹ IuOr-D- - alanine. 21. A derivative according to claim 20, characterized in that the Amino group through an H-benzyl-, Ϊϊ, ϊϊ-dibenzyl--, H- (cc-methylbenzyl) -, N- (cc-carboxybenzyl) -, N-benzoyl-, N-chloroacetyl or N- (l-menthoxyacetyl) radical substituted is. 22. A derivative of 3-ITu.or-D-alanine protected on the carboxyl group or a Deutero analogue of the same 23. A derivative according to claim 22, characterized in that: the Carboxyl group by an amide, a substituted Araid group, a methyl, ethyl, propyl, tert-butyl or Benzyl ester group is substituted. - 23 209852/1183