CA2083108A1 - Process for the production of .alpha.-hydroxy-.beta.-aminocarboxylic acids - Google Patents
Process for the production of .alpha.-hydroxy-.beta.-aminocarboxylic acidsInfo
- Publication number
- CA2083108A1 CA2083108A1 CA002083108A CA2083108A CA2083108A1 CA 2083108 A1 CA2083108 A1 CA 2083108A1 CA 002083108 A CA002083108 A CA 002083108A CA 2083108 A CA2083108 A CA 2083108A CA 2083108 A1 CA2083108 A1 CA 2083108A1
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- Prior art keywords
- group
- alpha
- protected
- process according
- amino protective
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- 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
- C07C227/30—Preparation of optical isomers
- C07C227/32—Preparation of optical isomers by stereospecific synthesis
-
- 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
- C07C229/28—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 saturated and containing rings
-
- 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
- C07C229/34—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 containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
ABSTRACT OF THE DISCLOSURE
A process is disclosed for the production of .alpha.-hydroxy-.beta.-aminocarboxylic acids of the formula:
(I) starting from N-protected .alpha.-amino acid halides of the formula:
(II) The process comprises converting the halides (II) with trimethylsilyl cyanide into novel .alpha.-oxonitriles (acyl cyanides). In a second step, the acyl cyanides are converted into novel .alpha.-oxo-carboxylic acid esters and then reduced selectively to .alpha.-hydroxycarboxylic acid esters.
The .alpha.-hydroxycarboxylic acid esters are optionally separated into their diastereomers and/or are subjected to a cleaving off of the N-protective group and/or to an ester hydrolysis. The .alpha.-hydroxy-.beta.-amino-carboxylic acids (I) are structural elements of peptides with enzyme inhibiting effect.
A process is disclosed for the production of .alpha.-hydroxy-.beta.-aminocarboxylic acids of the formula:
(I) starting from N-protected .alpha.-amino acid halides of the formula:
(II) The process comprises converting the halides (II) with trimethylsilyl cyanide into novel .alpha.-oxonitriles (acyl cyanides). In a second step, the acyl cyanides are converted into novel .alpha.-oxo-carboxylic acid esters and then reduced selectively to .alpha.-hydroxycarboxylic acid esters.
The .alpha.-hydroxycarboxylic acid esters are optionally separated into their diastereomers and/or are subjected to a cleaving off of the N-protective group and/or to an ester hydrolysis. The .alpha.-hydroxy-.beta.-amino-carboxylic acids (I) are structural elements of peptides with enzyme inhibiting effect.
Description
o ~
This lnvention relates to a process for the production of ~-hydroxy-~-aminocarboxylic acids and the esters thereof.
Some a-hydroxy-~-aminocarboxylic acids are of interest as structural elements of natural or synthetic peptides, which are effective as inhibitors of specific enzymes. They include, in particular, (2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid ("Norstatin") and (2R,3S)-3-amino-2-hydroxy-4-cyclohexyl butyric acid ("Cyclohexylnorstatin") [see, e.g., K. Iizuka et al., J.
Med. Chem., 33, (1990), 2707-2714].
Processes for the production of these compounds are known. Starting from the corresponding oe-aminocarboxylic acid having a chain with one less carbon atom, these processes yield the desired products via the N-protected a-amino alcohol. The corresponding N-protected o!-amino aldehyde and the ryanohydrin are obtained by hydrolysis of the cyano group to the carboxyl group with hydrocyanic acid [Iizuka et al., loc. cit.; see also D.H.
Rich et al., J. Org. Chem., 45, (1980), 2288-2290]. A
drawback of these processes is the use of an aldehyde as an intermediate step, which must be produced either by a reduction oxidation sequence from the carboxylic acid or by reduction with diisobutyl aluminum hydride from the methyl ester, which is difficult for synthesising on a large scale. Other problems follow from the use of hydrocyanic acid. Moreover, the production of esters of a-hvdroxy-~-amino acids employing these processes requires an additional esterification step.
The main ohjective of the invention is to provide a novel process for the production of a-hydroxy-~-aminocarboxylic acids and their esters that avoids the disadvantage of the prior art and is also suitable for production on an industrial scale.
.~ .
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Accordingly, the invention provides a process for the production of an ~-hydroxy-~-amino carboxylic aoid, an ester thereof or a salt thereof of the formula:
N~3R4 OH
R~C H - C~H - COOR~ (I) wherein Rl is a linear or branched alkyl group having 1 to 6 carbon atoms, capable of being optionally substituted with an aryl group or a cycloalkyl group having 3 to 8 ring members, R2 is hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, and R3 and R4, independent of one another, are hydrogen or an amino protective group or R3 and R4 together form a bifunctional amino protective group, which process comprises:
(a) reacting an N-protected ~-aminocarboxylic acid halide of the formuJa:
NR5R6 o 1 1* 11 R -C H - C - X (II) wherein Rl has the above-mentioned meaning, X is chlorine or bromine, and R5 and R6 have the same meanings as the above-mentioned meanings for R3 and R4, provided that Rs and R6 are not both hydrogen at the same time, with trimethylsilyl cyanide to form the corresponding ~-oxonitrile of the formula:
NR5R6 o ~ 1* 11 R - C H - C -CN (III) wherein Rl, R5 and R6 have the above-mentioned meanings, (b) converting the cyano group of a compound (III) into an alkoxy carbonyl group to form the corresponding ~ oxocarboxylic acid ester of the formula:
NR5R~ O
F~1 _ C * H-- C--CoOR7 ( IV ) ` . - ' ~ ' ` ' ' ' ` `
~` ' . , ` .
This lnvention relates to a process for the production of ~-hydroxy-~-aminocarboxylic acids and the esters thereof.
Some a-hydroxy-~-aminocarboxylic acids are of interest as structural elements of natural or synthetic peptides, which are effective as inhibitors of specific enzymes. They include, in particular, (2R,3S)-3-amino-2-hydroxy-5-methylhexanoic acid ("Norstatin") and (2R,3S)-3-amino-2-hydroxy-4-cyclohexyl butyric acid ("Cyclohexylnorstatin") [see, e.g., K. Iizuka et al., J.
Med. Chem., 33, (1990), 2707-2714].
Processes for the production of these compounds are known. Starting from the corresponding oe-aminocarboxylic acid having a chain with one less carbon atom, these processes yield the desired products via the N-protected a-amino alcohol. The corresponding N-protected o!-amino aldehyde and the ryanohydrin are obtained by hydrolysis of the cyano group to the carboxyl group with hydrocyanic acid [Iizuka et al., loc. cit.; see also D.H.
Rich et al., J. Org. Chem., 45, (1980), 2288-2290]. A
drawback of these processes is the use of an aldehyde as an intermediate step, which must be produced either by a reduction oxidation sequence from the carboxylic acid or by reduction with diisobutyl aluminum hydride from the methyl ester, which is difficult for synthesising on a large scale. Other problems follow from the use of hydrocyanic acid. Moreover, the production of esters of a-hvdroxy-~-amino acids employing these processes requires an additional esterification step.
The main ohjective of the invention is to provide a novel process for the production of a-hydroxy-~-aminocarboxylic acids and their esters that avoids the disadvantage of the prior art and is also suitable for production on an industrial scale.
.~ .
" ~
. ~ --. .. . .
' ::
Accordingly, the invention provides a process for the production of an ~-hydroxy-~-amino carboxylic aoid, an ester thereof or a salt thereof of the formula:
N~3R4 OH
R~C H - C~H - COOR~ (I) wherein Rl is a linear or branched alkyl group having 1 to 6 carbon atoms, capable of being optionally substituted with an aryl group or a cycloalkyl group having 3 to 8 ring members, R2 is hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, and R3 and R4, independent of one another, are hydrogen or an amino protective group or R3 and R4 together form a bifunctional amino protective group, which process comprises:
(a) reacting an N-protected ~-aminocarboxylic acid halide of the formuJa:
NR5R6 o 1 1* 11 R -C H - C - X (II) wherein Rl has the above-mentioned meaning, X is chlorine or bromine, and R5 and R6 have the same meanings as the above-mentioned meanings for R3 and R4, provided that Rs and R6 are not both hydrogen at the same time, with trimethylsilyl cyanide to form the corresponding ~-oxonitrile of the formula:
NR5R6 o ~ 1* 11 R - C H - C -CN (III) wherein Rl, R5 and R6 have the above-mentioned meanings, (b) converting the cyano group of a compound (III) into an alkoxy carbonyl group to form the corresponding ~ oxocarboxylic acid ester of the formula:
NR5R~ O
F~1 _ C * H-- C--CoOR7 ( IV ) ` . - ' ~ ' ` ' ' ' ` `
~` ' . , ` .
2 ~
wherein Rl, Rs and R6 have the above-mentioned meanings, and R7 has the same meaning as the above-mentioned meaning for R2, provided that R7 is not hydrogen, (c) selectively reducing the keto group of a compound (IV) to form the corresponding N-protected a-hydroxycarboxylic acid ester of the formula:
R1 _C~H-- C~H--CoOR7 (V) wherein Rl, R5, R6 and R7 have the above-mentioned meanings;
and, optionally, (d) cleaving the amino protective group and/or hydrolysing the ester function.
Preferably, the N-protected a-aminocarboxylic acid halide (II) is employed in the L configuration.
Preferably, an N-protected a-aminocarboxylic acid chloride is used as the N-protected a-aminocarboxylic acid halide (II). Preferably, an N-protected L-phenylalanyl chloride is used as the N-protected a-aminocarboxylic acid chloride.
Preferably, a phthaloyl group is used as the amino protective group R5R6. Preferably, the cleaving-off of the phthaloyl group is performed with hydrazine hydrate or concentrated hydrochloric acid. Preferably, the reaction with trimethylsilyl cyanide is performed in the presence of zinc iodide. Preferably, the conversion of the cyano group in an alkoxy carbonyl group is performed by reaction with the corresponding alcohol R70H in the presence of a strong acid and subsequent hydrolysis of the iminoester salt for~ed as an intermediate product. Preferably, methanol is used as the alcohol. Preferably, a diastereomer separation of a-hydroxycarboxylic acid ester (V) is performed between step (c) and step (d). Preferably, the selective reduction of the keto group is performed with a borohydride selected from the group consisting of LiBH4, NaBH4, Ca(B~4)2 and Zn(BH4)2, as the reducing agent. Also preferably, the . ., : :. ~
. . . . .
selective reduction of the keto group is performed by catalytic hydrogenation on a platinum/rhodium mixed catalyst.
The invention also provides N-protected ~-oxo-~-aminonitriles of the general formula:
NR5R6 o R - C*H ~ C - CN (III) wherein R~ is a linear or branched alkyl group having 1 to 6 carbon atoms, capable of being optionally substituted with an aryl group or a cycloalkyl group having 3 to 8 ring members, and either R5 is an amino protective group and R6 is hydrogen or an amino protective group or R5 and R6 together form a bifunctional amino protective group.
Preferably, the N-protected ~-oxo-~-aminonitrile has the (S) configuration. Preferably, R5 and R6 together form a phthaloyl group. Preferably, Rl is selected from the group consisting of isobutyl, benzyl, p-hydroxybenzyl and cyclohexylmethyl.
The invention further provides N-protected ~-oxo-~-aminocarboxylic acid esters of the general formula:
NR5p,6 o * 7 R --C H-- C--COOR (IV) wherein the asymmetric center has the ~S) configuration, Rl is a linear or branched alkyl group having 1 to 6 carbon atoms, capable of being optionally substituted with an aryl group or a cycloalkyl group having 3 to 8 ring members, and R7 is a linear or branched alkyl group having 1 to 4 carbon atoms and either R5 is an amino protective group and R6 is hydrogen or an amino protective group or Rs and R6 together form a bifunctional amino protective group.
Preferably, R7 is methyl. Preferably, R5 and R6 together are a phthaloyl group. Preferablyr Rl is selected ~3~8 from the group consisting of isobutyl, benzyl, p-hydroxybenzyl and cyclohexylmethyl.
The process according to the invention is suitable for the production of ~-hydroxy-~-aminocarboxylic acids and their esters of the general formula:
F11--C*~l-- C~H--COOR2 (I) wherein Rl is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. The alkyl group can be substituted with aryl groups, for example, phenyl, o-, m- and p-tolyl, chlorophenyl, hydroxyphenyl, methoxyphenyl and cycloalkyl groups having 3 to 8 ring members, for example, cyclopropyl, cyclopbutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Especially preferred groups for Rl are isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl and cyclohexylmethyl. Basically Rl may comprise any substituent which remains non-reactive in the applied reaction conditions. R2 is hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, i.e., methyl, , :
;', ~ . . ~
, :"' ' ; , - \
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, preferably methyl. R3 and R~, independent from each other, are hydrogen or amino protective groups, or R3 and R4 together form a bifunctional amino protective group. Herein, bifunctional amino protective groups are to be understood in this connection to be those Whi Ch form a heterocyclic ring by substitution of both hydrogen atoms of an amino group together with the amino nitrogen atom. Amino protective groups are especially in use in the peptide synthesis and are known in the art; a survey of their properties and the methods for their introduction and cleavage are provided, for example, by E. Wunsch, Methoden Org. Chem., (Houben-Weyl), 4th Ed., (1974), Vol. XV/l, pp. 46-305.
The compounds produced according to the process of the invention have two chiral centers (wlless other chiral centers are present in R1 and/or R2), thus each can occur in four stereoisomeric forms. Since only one of the two chiral centers is newly formed in the reaction sequence according to the invention, while the configuration of the other chiral center is maintained, generally diastereomeric mixtures result with the use of optically active ~-amino acid derivatives as the initial material,whjch however, can easily be separated because of the different physical properties. Therefore, the process according to the invention is especially suitable for the production of configurationally homogeneous ~-hydroxy-~-amlno aclds.
:
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According to the invention, a chloride or bromide, preferably chloride, of an ~-amino carboxylic acid with protected amino function corresponding to general formula:
NR5R6 o Rl-C*H - C - X (II) is used as starting material. In formula (II), X is chlorine or bromine, Rl has the same meaning as in formula (I), and Rs and R6 have the same meaning as R3 and R4 in formula (I~, provided that R5 and R6 are not both hydrogen at the same time.
Basically the process can be per~ormed with any of the amino protective group which is only slightly sensitive to acids and bases as well as trimethylsilyl cyanide and halides and is not cleaved off by the reaction conditions of steps (a) to (c) of the inv~ntion process.
Suitable protective groups are, for example, p toluene sulfonyl (tosyl), and the bifunctional protective groups, the so-called diacyl protective groups, such as maleoyl or especially phthaloyl. The phthaloyl protective group can be easily introduced in ~-amino acids according to or analogously to known processes and again cleaved off with hydrazine hydrate or strong acids (E. Wunsch, loc. cit., pp. 250-263).
, , .:
::
.
8 2~3~8 The thus obtained N-phthaloyl-~-aminocarboxylic acids can be converted also by known methods with halides of inorganic acids, such as, thionyl chloride, into the amino acid halides re~lired for the process according to the invention (see, e.g., P. Stetzel, Methoden Org. Chem., (Houben-Weyl), 4th Ed., (1974), Vol. XV/2, pp 355-364).
The N-protected ~-aminocarboxylic acid halides (II) according to the invention are converted in the first stage (a) with trimethylsilyl cyanide (cyanotrimethyl silane) into the corresponding ~-oxonitriles (acyl cyanides) (III), having the formula:
NR R O
wherein Rs and R6 are defined above. These compounds (III) are nov~l and also constitute ~a~t of tliis invention.
No racemization takes place in the reaction with trimethylsilyl cyanide in contrast to the previously known process of the reaction of carboxylic acid halides with copper(I)-cyanide, according to which phthaloylglycyl c~anide is prodllced, for example, from phthaloylglycyl bromide; but racemization was observed in the case of optically active -amino acid derivatives (P. ~tetzel, loc. cit. p. 364).
~.
' : ~
~.
, The reaction with trimethylsilyl cyanide is preferably performed in the presence of a catalytic amount of zinc iodide. A solvent is not necessary, however for better handling an inert solvent, such as dioxane, diethyl acetate or tetrahydrofuran, is added. The reaction temperature is advantageously from about 20 to 100C, preferably from about 40 to 70C. The trimethylsilyl chloride or bromide resulting in the reaction can optionally be distilled off because of its lower boiling point, and used again for the production of trimethylsilyl cyanide.
The ~-oxonitriles (III) according to the invention are converted in step (b) into the ~-oxocarboxylic acid esters (IV). The ~-oxocarboxylic acid esters (IV) are novel and also constitute part of the invention. The ~-oxocarboxylic acid esters (IV) are of the formula:
NR5R~ O
R1 _C~ H-- C--CoOR7 ( IV) wherein Rl, R2, R5 and R6 are defined above. It is not necessary to purify the ~-oxonitrile (III) for the production o~ the ~-oxocarboxylic acid esters (IV), since the crude product or even the unworked-up reaction mixture of the first synthesis step can be used.
Preferably, this reaction is performed in the manner of the Pinner reaction with an alcohol that corresponds to the desired ester, i.e., preferably methanol, and a strong acid. Thus, first a salt of the corresponding imino ester is formed which readily hydrolyses with water to the normal ester. The reaction is preferably performed in an inert polar solvent, such as diethyl ether or tetrahydrofuran. Because of the substitution of the cyano group by an alkoxy group as a possible secondary reaction which leads to an ~-aminocarboxylic acid ester, it is advantageous not to use - . . ..:
., ;, : ::
~ '. .
~3~
an excessive amount of alcohol. By choosing suitable reaction conditions the portion of the substitution product can be limited, for example, to 5 to 10 percent. Hydrogen chloride is preferably used as the acid which can be introduced in a gaseous state. Because of the high reactivity of the ~-o~onitriles (III) the Pinner reaction can be performed at a comparatively low temperature.
The reaction temperature is suitably from about -~0 to +20C, preferably from about -20 to 0C. It is also within the scope of this invention to produce ~-oxocarboxylic acid esters (IV) from ~-oxonitriles (III) according to another method, for example, by hydrolysis to ~-oxocarboxylic acid and subsequent esterification.
According to the invention in step (c), the keto-carbonyl group of the ~-oxocarboxylic acid esters (IV) are selectively reduced to the N-protected ~-hydroxycarbo~ylic acid esters (V~. Preferably, borohydrides, especially lithium borohydride, so~ium borohydride, calcium borohydride, zinc borohydride, or hydrogen in the presence of a platinum/rhodium mixed catalyst are used as the reducing agent.
From the reduction process a second asymmetric center is formed such that depending on whether it was started from an optically active or from a racemic carboxylic acid halide (II) generally two diastereomers or diastereomer pairs result. The proportiGn of the diastereomers, i.e., the diastereoselectivity of the reduction, depends on the reduction agent used and the temperature. Especially high diastereoselectivities were observed when LiBH4 and Zn(BH4)2 are used as the reducing agents. Preferably, in each case the diastereomer with opposite configuration is formed on both asymmetric centers, i.e., the (2R,3S)- or (2S,3R)-diastereomer.
The reduction with borohydrides, preferably with Zn(BH4)2, is performed suitably at a temperature of from about -50 to +25C, preferably from about -30 to 0C.
.
:;
The reduction wlth hydrogen at a platinum/rhodium mixed catalyst is preferably performed at a hydrogen pressure of from about 10 to 200 bars, and a temperature of from about 20 to 80C in a non-polar solvent, such as toluene, or a polar solvent, such as ethyl acetate or tetrahydrofuran.
It was found that the diastereomers resulting from the reduction can easily be separated at this step, for example, by column chromatography or recrystallization.
: .
l2 Then, optionally in another step (d), the amino protective group is cleaved off and/or the ester function is hydrolyzed. For example, the phthaloyl protective group can be cleaved off while maintaining the ester function with hydrazine hydrate or by hydrolysis of the ester with a strong acid. However, it is possible under less drastic conditions to hydrolyze only the ester group with acid while maintaining the phthaloyl protective group.
The following Examples illustrate the performance of the process according to the invention.
Example 1 N-Phthaloyl-L-phenYlalanyl chloride ((S)-3-~henyl~~p'l~hai.imidopropionyl chloride) A mixture of 138.2 g (0.47 mol) of ll-phthaloyi~L~
phenylalanine (produced according to A.K. Bose, Org.
Syntheses, Coll., Vol. 5, p. 973) and 167 g (1.4 mol) of thionyl chloride was refluxed for 3 hours. Then the excess thionyl chloride was distilled off. The residue was mixed with 200 ml of toluene and hea~ted to about 80C. After addition of 380 ml of hexane the solution was cooled for crystallization to about 4C~ The ~rystallized product was filtered off and dried. The yield of the product was 143.9 g (98% of theory). The melting point oE the product was from 81.9 to 82.4àC. Other data regarding the product was:
[~]D: -226.7 (c = 2.0; benzene) .;
' ~:
13 2 ~
H-NMR (CDCl3, 300 MHz) ~: 3.50-3.72 (m, 2H);
5.35 (dd, lH);
7.10-7.24 (m, 5H);
7.65-7.79 (m, 4H).
F.xample 2 (S)-2-Oxo-4-phenyl-3-phthalimidobutane nitrile A mixture of 25 g (79.7 mmol) of N-phthaloyl-L-phenylalanyl chloride (produced according to Example 1), 9.5 g (95.7 mmol) of trimethylsilyl cyanide and 255 mg (0.80 mmol) of zinc iodide was heated to 60C. After 35 minutes, 30 ml of tetrahydrofuran was added. The mixture was refluxed for another 80 minutes, then mixed with 200 ml of hexane and cooled to about 4C. The precipitated product was filtered off, washed with hexane and dried in a vacuum. The yield of the product was 21.06 g (87% of theory). Other data regarding the product was:
[~]D0: -264.2 (c = 1.0; THF) H-NMR (CDCl3, 300 MHz) ~: 3.38 (dd, lH);
wherein Rl, Rs and R6 have the above-mentioned meanings, and R7 has the same meaning as the above-mentioned meaning for R2, provided that R7 is not hydrogen, (c) selectively reducing the keto group of a compound (IV) to form the corresponding N-protected a-hydroxycarboxylic acid ester of the formula:
R1 _C~H-- C~H--CoOR7 (V) wherein Rl, R5, R6 and R7 have the above-mentioned meanings;
and, optionally, (d) cleaving the amino protective group and/or hydrolysing the ester function.
Preferably, the N-protected a-aminocarboxylic acid halide (II) is employed in the L configuration.
Preferably, an N-protected a-aminocarboxylic acid chloride is used as the N-protected a-aminocarboxylic acid halide (II). Preferably, an N-protected L-phenylalanyl chloride is used as the N-protected a-aminocarboxylic acid chloride.
Preferably, a phthaloyl group is used as the amino protective group R5R6. Preferably, the cleaving-off of the phthaloyl group is performed with hydrazine hydrate or concentrated hydrochloric acid. Preferably, the reaction with trimethylsilyl cyanide is performed in the presence of zinc iodide. Preferably, the conversion of the cyano group in an alkoxy carbonyl group is performed by reaction with the corresponding alcohol R70H in the presence of a strong acid and subsequent hydrolysis of the iminoester salt for~ed as an intermediate product. Preferably, methanol is used as the alcohol. Preferably, a diastereomer separation of a-hydroxycarboxylic acid ester (V) is performed between step (c) and step (d). Preferably, the selective reduction of the keto group is performed with a borohydride selected from the group consisting of LiBH4, NaBH4, Ca(B~4)2 and Zn(BH4)2, as the reducing agent. Also preferably, the . ., : :. ~
. . . . .
selective reduction of the keto group is performed by catalytic hydrogenation on a platinum/rhodium mixed catalyst.
The invention also provides N-protected ~-oxo-~-aminonitriles of the general formula:
NR5R6 o R - C*H ~ C - CN (III) wherein R~ is a linear or branched alkyl group having 1 to 6 carbon atoms, capable of being optionally substituted with an aryl group or a cycloalkyl group having 3 to 8 ring members, and either R5 is an amino protective group and R6 is hydrogen or an amino protective group or R5 and R6 together form a bifunctional amino protective group.
Preferably, the N-protected ~-oxo-~-aminonitrile has the (S) configuration. Preferably, R5 and R6 together form a phthaloyl group. Preferably, Rl is selected from the group consisting of isobutyl, benzyl, p-hydroxybenzyl and cyclohexylmethyl.
The invention further provides N-protected ~-oxo-~-aminocarboxylic acid esters of the general formula:
NR5p,6 o * 7 R --C H-- C--COOR (IV) wherein the asymmetric center has the ~S) configuration, Rl is a linear or branched alkyl group having 1 to 6 carbon atoms, capable of being optionally substituted with an aryl group or a cycloalkyl group having 3 to 8 ring members, and R7 is a linear or branched alkyl group having 1 to 4 carbon atoms and either R5 is an amino protective group and R6 is hydrogen or an amino protective group or Rs and R6 together form a bifunctional amino protective group.
Preferably, R7 is methyl. Preferably, R5 and R6 together are a phthaloyl group. Preferablyr Rl is selected ~3~8 from the group consisting of isobutyl, benzyl, p-hydroxybenzyl and cyclohexylmethyl.
The process according to the invention is suitable for the production of ~-hydroxy-~-aminocarboxylic acids and their esters of the general formula:
F11--C*~l-- C~H--COOR2 (I) wherein Rl is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. The alkyl group can be substituted with aryl groups, for example, phenyl, o-, m- and p-tolyl, chlorophenyl, hydroxyphenyl, methoxyphenyl and cycloalkyl groups having 3 to 8 ring members, for example, cyclopropyl, cyclopbutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Especially preferred groups for Rl are isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl and cyclohexylmethyl. Basically Rl may comprise any substituent which remains non-reactive in the applied reaction conditions. R2 is hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, i.e., methyl, , :
;', ~ . . ~
, :"' ' ; , - \
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, preferably methyl. R3 and R~, independent from each other, are hydrogen or amino protective groups, or R3 and R4 together form a bifunctional amino protective group. Herein, bifunctional amino protective groups are to be understood in this connection to be those Whi Ch form a heterocyclic ring by substitution of both hydrogen atoms of an amino group together with the amino nitrogen atom. Amino protective groups are especially in use in the peptide synthesis and are known in the art; a survey of their properties and the methods for their introduction and cleavage are provided, for example, by E. Wunsch, Methoden Org. Chem., (Houben-Weyl), 4th Ed., (1974), Vol. XV/l, pp. 46-305.
The compounds produced according to the process of the invention have two chiral centers (wlless other chiral centers are present in R1 and/or R2), thus each can occur in four stereoisomeric forms. Since only one of the two chiral centers is newly formed in the reaction sequence according to the invention, while the configuration of the other chiral center is maintained, generally diastereomeric mixtures result with the use of optically active ~-amino acid derivatives as the initial material,whjch however, can easily be separated because of the different physical properties. Therefore, the process according to the invention is especially suitable for the production of configurationally homogeneous ~-hydroxy-~-amlno aclds.
:
.` ' 2~3: ~
According to the invention, a chloride or bromide, preferably chloride, of an ~-amino carboxylic acid with protected amino function corresponding to general formula:
NR5R6 o Rl-C*H - C - X (II) is used as starting material. In formula (II), X is chlorine or bromine, Rl has the same meaning as in formula (I), and Rs and R6 have the same meaning as R3 and R4 in formula (I~, provided that R5 and R6 are not both hydrogen at the same time.
Basically the process can be per~ormed with any of the amino protective group which is only slightly sensitive to acids and bases as well as trimethylsilyl cyanide and halides and is not cleaved off by the reaction conditions of steps (a) to (c) of the inv~ntion process.
Suitable protective groups are, for example, p toluene sulfonyl (tosyl), and the bifunctional protective groups, the so-called diacyl protective groups, such as maleoyl or especially phthaloyl. The phthaloyl protective group can be easily introduced in ~-amino acids according to or analogously to known processes and again cleaved off with hydrazine hydrate or strong acids (E. Wunsch, loc. cit., pp. 250-263).
, , .:
::
.
8 2~3~8 The thus obtained N-phthaloyl-~-aminocarboxylic acids can be converted also by known methods with halides of inorganic acids, such as, thionyl chloride, into the amino acid halides re~lired for the process according to the invention (see, e.g., P. Stetzel, Methoden Org. Chem., (Houben-Weyl), 4th Ed., (1974), Vol. XV/2, pp 355-364).
The N-protected ~-aminocarboxylic acid halides (II) according to the invention are converted in the first stage (a) with trimethylsilyl cyanide (cyanotrimethyl silane) into the corresponding ~-oxonitriles (acyl cyanides) (III), having the formula:
NR R O
wherein Rs and R6 are defined above. These compounds (III) are nov~l and also constitute ~a~t of tliis invention.
No racemization takes place in the reaction with trimethylsilyl cyanide in contrast to the previously known process of the reaction of carboxylic acid halides with copper(I)-cyanide, according to which phthaloylglycyl c~anide is prodllced, for example, from phthaloylglycyl bromide; but racemization was observed in the case of optically active -amino acid derivatives (P. ~tetzel, loc. cit. p. 364).
~.
' : ~
~.
, The reaction with trimethylsilyl cyanide is preferably performed in the presence of a catalytic amount of zinc iodide. A solvent is not necessary, however for better handling an inert solvent, such as dioxane, diethyl acetate or tetrahydrofuran, is added. The reaction temperature is advantageously from about 20 to 100C, preferably from about 40 to 70C. The trimethylsilyl chloride or bromide resulting in the reaction can optionally be distilled off because of its lower boiling point, and used again for the production of trimethylsilyl cyanide.
The ~-oxonitriles (III) according to the invention are converted in step (b) into the ~-oxocarboxylic acid esters (IV). The ~-oxocarboxylic acid esters (IV) are novel and also constitute part of the invention. The ~-oxocarboxylic acid esters (IV) are of the formula:
NR5R~ O
R1 _C~ H-- C--CoOR7 ( IV) wherein Rl, R2, R5 and R6 are defined above. It is not necessary to purify the ~-oxonitrile (III) for the production o~ the ~-oxocarboxylic acid esters (IV), since the crude product or even the unworked-up reaction mixture of the first synthesis step can be used.
Preferably, this reaction is performed in the manner of the Pinner reaction with an alcohol that corresponds to the desired ester, i.e., preferably methanol, and a strong acid. Thus, first a salt of the corresponding imino ester is formed which readily hydrolyses with water to the normal ester. The reaction is preferably performed in an inert polar solvent, such as diethyl ether or tetrahydrofuran. Because of the substitution of the cyano group by an alkoxy group as a possible secondary reaction which leads to an ~-aminocarboxylic acid ester, it is advantageous not to use - . . ..:
., ;, : ::
~ '. .
~3~
an excessive amount of alcohol. By choosing suitable reaction conditions the portion of the substitution product can be limited, for example, to 5 to 10 percent. Hydrogen chloride is preferably used as the acid which can be introduced in a gaseous state. Because of the high reactivity of the ~-o~onitriles (III) the Pinner reaction can be performed at a comparatively low temperature.
The reaction temperature is suitably from about -~0 to +20C, preferably from about -20 to 0C. It is also within the scope of this invention to produce ~-oxocarboxylic acid esters (IV) from ~-oxonitriles (III) according to another method, for example, by hydrolysis to ~-oxocarboxylic acid and subsequent esterification.
According to the invention in step (c), the keto-carbonyl group of the ~-oxocarboxylic acid esters (IV) are selectively reduced to the N-protected ~-hydroxycarbo~ylic acid esters (V~. Preferably, borohydrides, especially lithium borohydride, so~ium borohydride, calcium borohydride, zinc borohydride, or hydrogen in the presence of a platinum/rhodium mixed catalyst are used as the reducing agent.
From the reduction process a second asymmetric center is formed such that depending on whether it was started from an optically active or from a racemic carboxylic acid halide (II) generally two diastereomers or diastereomer pairs result. The proportiGn of the diastereomers, i.e., the diastereoselectivity of the reduction, depends on the reduction agent used and the temperature. Especially high diastereoselectivities were observed when LiBH4 and Zn(BH4)2 are used as the reducing agents. Preferably, in each case the diastereomer with opposite configuration is formed on both asymmetric centers, i.e., the (2R,3S)- or (2S,3R)-diastereomer.
The reduction with borohydrides, preferably with Zn(BH4)2, is performed suitably at a temperature of from about -50 to +25C, preferably from about -30 to 0C.
.
:;
The reduction wlth hydrogen at a platinum/rhodium mixed catalyst is preferably performed at a hydrogen pressure of from about 10 to 200 bars, and a temperature of from about 20 to 80C in a non-polar solvent, such as toluene, or a polar solvent, such as ethyl acetate or tetrahydrofuran.
It was found that the diastereomers resulting from the reduction can easily be separated at this step, for example, by column chromatography or recrystallization.
: .
l2 Then, optionally in another step (d), the amino protective group is cleaved off and/or the ester function is hydrolyzed. For example, the phthaloyl protective group can be cleaved off while maintaining the ester function with hydrazine hydrate or by hydrolysis of the ester with a strong acid. However, it is possible under less drastic conditions to hydrolyze only the ester group with acid while maintaining the phthaloyl protective group.
The following Examples illustrate the performance of the process according to the invention.
Example 1 N-Phthaloyl-L-phenYlalanyl chloride ((S)-3-~henyl~~p'l~hai.imidopropionyl chloride) A mixture of 138.2 g (0.47 mol) of ll-phthaloyi~L~
phenylalanine (produced according to A.K. Bose, Org.
Syntheses, Coll., Vol. 5, p. 973) and 167 g (1.4 mol) of thionyl chloride was refluxed for 3 hours. Then the excess thionyl chloride was distilled off. The residue was mixed with 200 ml of toluene and hea~ted to about 80C. After addition of 380 ml of hexane the solution was cooled for crystallization to about 4C~ The ~rystallized product was filtered off and dried. The yield of the product was 143.9 g (98% of theory). The melting point oE the product was from 81.9 to 82.4àC. Other data regarding the product was:
[~]D: -226.7 (c = 2.0; benzene) .;
' ~:
13 2 ~
H-NMR (CDCl3, 300 MHz) ~: 3.50-3.72 (m, 2H);
5.35 (dd, lH);
7.10-7.24 (m, 5H);
7.65-7.79 (m, 4H).
F.xample 2 (S)-2-Oxo-4-phenyl-3-phthalimidobutane nitrile A mixture of 25 g (79.7 mmol) of N-phthaloyl-L-phenylalanyl chloride (produced according to Example 1), 9.5 g (95.7 mmol) of trimethylsilyl cyanide and 255 mg (0.80 mmol) of zinc iodide was heated to 60C. After 35 minutes, 30 ml of tetrahydrofuran was added. The mixture was refluxed for another 80 minutes, then mixed with 200 ml of hexane and cooled to about 4C. The precipitated product was filtered off, washed with hexane and dried in a vacuum. The yield of the product was 21.06 g (87% of theory). Other data regarding the product was:
[~]D0: -264.2 (c = 1.0; THF) H-NMR (CDCl3, 300 MHz) ~: 3.38 (dd, lH);
3.65 (dd, lH);
5.20 (dd, lH);
7.08-7.23 (m, 5H);
7.70-7.90 (m, 4H).
- . , , . ~ .
, ~ , , , , .: :
-. .: ., , ~:
l4 ~31Q8 ExamPle 3 (S)-2-Oxo-4-Phenyl-3-~hthalimidobutYric acid methyl ester A mixture of 100 ml of diethyl ether and 4 ml of methanol was saturated with HCl gas at -10C. Then 9.0 g (30 mmol) of (S)-2-oxo-4-phenyl-3-phthalimidobutane nitrile (produced according to Example 2) was added. The mixture was stirred for 45 minutes at -10C and then mixed with 170 ml of water at -20 to 0C. The aqueous phase was extracted three times with 200 ml of diethyl ether each. The combined ether phases were washed three times with 150 ml of saturated sodium bicarbonate solution each and the washing solution was extracted back with diethyl ether. The combined ether phases were then drled on magnesium sulfate, concentrated by evaporation on a rotary evaporator and finally freed of the remaining solvent in a high vacuum. The yield of the product (viscous oil) was 6.8 9 (68% of theory). Other data regarding the product was:
H-NMR (CDCl3, 300 MHz) ~: 3.40 (dd, lH);
3.60 (dd, lH);
3.84 (s, 3H);
5.57 (dd, lH);
7.10-7.25 (m, 5H);
7.65-7.87 (m, 4H).
: .; ~ . : -' . . .
' ~3~
After chromatographic purification the product was able to be crystallized. The melting point of the product was 75D to 7 6C~ Other data regarding the product was:
[~]D0: -200.4 (c = 1.0; CHCl3) _ample 4 (2R,3S)- and (2S,3S)-~-HydroxY-4-phenvl _ Phthalimidobutyric acid methyl ester
5.20 (dd, lH);
7.08-7.23 (m, 5H);
7.70-7.90 (m, 4H).
- . , , . ~ .
, ~ , , , , .: :
-. .: ., , ~:
l4 ~31Q8 ExamPle 3 (S)-2-Oxo-4-Phenyl-3-~hthalimidobutYric acid methyl ester A mixture of 100 ml of diethyl ether and 4 ml of methanol was saturated with HCl gas at -10C. Then 9.0 g (30 mmol) of (S)-2-oxo-4-phenyl-3-phthalimidobutane nitrile (produced according to Example 2) was added. The mixture was stirred for 45 minutes at -10C and then mixed with 170 ml of water at -20 to 0C. The aqueous phase was extracted three times with 200 ml of diethyl ether each. The combined ether phases were washed three times with 150 ml of saturated sodium bicarbonate solution each and the washing solution was extracted back with diethyl ether. The combined ether phases were then drled on magnesium sulfate, concentrated by evaporation on a rotary evaporator and finally freed of the remaining solvent in a high vacuum. The yield of the product (viscous oil) was 6.8 9 (68% of theory). Other data regarding the product was:
H-NMR (CDCl3, 300 MHz) ~: 3.40 (dd, lH);
3.60 (dd, lH);
3.84 (s, 3H);
5.57 (dd, lH);
7.10-7.25 (m, 5H);
7.65-7.87 (m, 4H).
: .; ~ . : -' . . .
' ~3~
After chromatographic purification the product was able to be crystallized. The melting point of the product was 75D to 7 6C~ Other data regarding the product was:
[~]D0: -200.4 (c = 1.0; CHCl3) _ample 4 (2R,3S)- and (2S,3S)-~-HydroxY-4-phenvl _ Phthalimidobutyric acid methyl ester
4.92 g of (S)-2-oxo-4-phenyl-3-phthalimidobutyric acid methyl ester (produced according to Example 3) was dissolved in 50 ml of tetrahydrofuran. The solution was cooled to -25C
and mixed with 95 mg of lithium borohy~rice The reaction mixture was stirred for 30 minutes at -25 to -20C. Then 200 ml of diethyl ether was added and the mixtllre was washed twice with 100 ml of 0.1 M hydrochloric acid each. The washing solution was extracted back twice wlth 100 ml of diethyl ether each. The combined organic phases were dried on magnesium sulfate, concentrated by evaporation on a rotary evaporator and finally freed of the remaining solvent in a high vacuum.
The yield of the produ~t (oil ) was 4.78 9 (96% of theory) .
By integration of the lH-NMR signals the diastereomer ratio of (2R,3S):(2S,3S) was founc to be about 5:1. (The configuration a~sign~ent took place after separation, cleavage of the phthaloyl groups and derivatization with phosgene to the corresponding oxazolidinone based on the coupling constants in the 1H-NMR, cf. in this connection K.
. ;; -. .
:.. : , . .
, ,, , . :
.: , .. .
16 ~''3 ~
Iizuka et al., J. Med. Chem., (1990), 33, 2707-2714.) The diastereomer mixture was able to be pu~ ~iec and se~-dted by cnrc~atography on silica gel (mobile solvent hexane/dichloromethane/diethyl ether 2:2:1).
Data for the (2R,3S)-compound was:
Melting point: 91.9-92.9C
[~]D : -107.6 (c = 1.0; CHCl3) H-NMR (CDCl3, 300 MHz) ~ 3.20-3.40 (m, 2H);
3.63 (s, 3~);
4.48-4.60 (m, 2H);
4.90-5.00 (m, l~I);
7.10-7.30 (m, 5H);
7.67 7.~5 (m, 4H).
Exam~le 5 (2R,3S)-3-Amino-2-hvdroxy-4-phenylbutyric acid h~drochloride 13.25 g (39.1 mmol) of (2R,3S)-/(2S,3S)-2-hydroxy-4-phenyl-3-phthalimidobutyric acid methyl ester (diastereomeric ratio = 3:1) was dissolved in 60 ml of acetic acid. The solution was mixed with 380 ml of concentrated hydrochloric acid and refluxed for 8 hours. After cooling the mixture was extracted with diethyl ether continuously for 18 hours in a liquid-liquid extractor (according to Kutscher-Steudel). The ether extract and the aqueous phase were separately concentrated by evaporation. The residue of the ether phase (7.41 g of brown powder) consisted basically of phthalic acid.
~31~8 The residue of the a~ueous phase (6.38 g) was suspended in 200 ml of acetonitrile and refluxed for about 15 minutes. The undissolved part (2.6 g) was filtered off, it consisted basically of (2R,3S)-diastereomer. Data for the (2R,3S)-diastereomer was:
H-NMR tDMSO-d6, 300 MHz) ~: 2.90 (dd, lH);
3.05 (dd, lH);
3.40 (br.m, lH);
3.90 (d, lH);
7.20-7.43 (m, 5H);
8.20 (br.m, 3H).
Example 6 f2R 3S~-3-Am no-4-c~clohexyl-2-hydr~xybutyric acid hydrochloride (cyclohexylnorstatin hydrochloride) 500 mg of (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid hydrochloride was dissolved in 5 ml of acetic acid and 5 ml of water, mixed with 50 mg of rhodium/activated carbon (5~ Rh) and hydrogenated for 24 hours at room temperature at 20 bars hydrogen pressure. The catalyst was then filtered off and the filtrate concentrated by evaporation on a rotary evaporator.
The residue was dried in a high vacuum. The yield of the .
.. : .,.~ ....
-.
;. ~ ' product was quantitative. Other data regarding the product was:
H-NMR (DMSO-d6, 300 MHz) ~: 0.75-1.80 (m, 13H);
3.40 (br.m, lH);
4.08 (d, lH).
Example 7 (2R 3S)-2 HYdroxy-4-phenyl-3-phthalimidobut~ric acid 16.8 g of (2R,3S)-2-hydroxy-4-phenyl-3-phthalimidobutyric acid methyl ester (content according to HPLC 49.6%) was dissolved in 50 ml of acetic acid and mixed with 100 ml of 32%
hydrochloric acid. The mixture was stirred for 28 hours at room temperature, and a white solid precipitated. The precipitate was filtered off and washed with cold water. The yield of the product was 10.2 g. Other data regarding the product was:
H-NMR (CDCl3, 300 MHz) ~: 3.15-3.40 (m, 2H);
4.50 (d, lH);
4.95-5.05 (m, lH);
7.08-7.20 ~m, 5H);
7.60-7.80 (m, 4H).
~ o ~
Example 8 (2R.3S)-2-Hvdroxy-~-Phenvl-3-Phthalimidobutyric acid methyl ester ~reduction with Zn(BH4)2~
2.85 g of sodium borohy~ride and 12.83 g of anhydrous zinc chloride were stirred for 18 hours at room temperature in 585 ml of anhydrous tetrahydrofuran. Then the resultant suspension was cooled to -25C and mixed with a solution of 63.5 g of (S)-2-oxo-4-phenyl-3-phthalimidobutyric acid methyl ester in 50 ml of tetrahydrofuran. The mixture was stirred for another 1.5 hours at 25C, then diluted with 500 ml of toluene and extracted three times with 350 ml of o.1 M
hydrochloric acid each. The organic phase was washed three times with 350 ml of saturated sodium bicarbonate solution each. The combined aqueous phases were extracted with toluene. After drying the combined oryanic phases over magnesium sulfate the solvent was distilled off on a rotary evaporator and the residue was recrystallized from 160 ml of toluene. The yield of the product was 33.9 g (53% of theory).
Exam~le 9 (2R,3S)-2-Hydroxy-4-phenYl-3-phthalimidobutyric acid methyl ester (reduction with Ca(BH4)2) 1.12 g of sodium boronydride and 1.23 g of anhydrous calcium chloride were stirred for 16 hours at room temperature in 210 ml of anhydrous tetrahydrofuran. Then the mixture was ,: " ~'~' ,' , ! ; :
2~83~g cooled to -25C. A solution of 25 g of (S)-2-oxo-4-phenyl-3-phthalimidobutyric methyl ester in 40 ml of tetrahydrofuran was lnstilled in this mixture. The reaction mlxture was s-tirred for another 30 minutes at -25C, then diluted ~lith 250 ml of toluene,and washed first with 200 ml of 0.1 M hydrochloric acid and then three times with 250 ml of saturated sodium bicarbonate solution each. The further working-up took place as des~ribed in Example 8 but without recrystallization. The yield of the product was 22.5 g (89.5% of theory). Other data for the product was:
~iastereomeric ratio: (2R,3S)/(2S,3S) - 4:1.
Example 10 (2R,3S)-2-Hydroxy-4-phenyl-3-phthalimidobutyric acid methyl ester (reduction with H2/Pt/Rh) 100 mg of a Pt/Rh mixed catalyst (4% Pt, 1% Rh on activated carbon) was suspended in a solution of 1 g of (S)-2-oxo-4-phenyl-3-phthalimidobutyric acid methyl ester in 10 ml of ethyl acetate. The mixture was hydrogenated for 24 hours at 50 bars hydrogen pressure and 50C, then filtered off from the catalyst and concentrated by evaporation on a rotary evaporator. The yield of the product was 1.0 g, with a conten~ (HPLC) of 53.5 percent. Other data for the product was:
Diastereomeric ratio: (2R,3S) ~ 5.
and mixed with 95 mg of lithium borohy~rice The reaction mixture was stirred for 30 minutes at -25 to -20C. Then 200 ml of diethyl ether was added and the mixtllre was washed twice with 100 ml of 0.1 M hydrochloric acid each. The washing solution was extracted back twice wlth 100 ml of diethyl ether each. The combined organic phases were dried on magnesium sulfate, concentrated by evaporation on a rotary evaporator and finally freed of the remaining solvent in a high vacuum.
The yield of the produ~t (oil ) was 4.78 9 (96% of theory) .
By integration of the lH-NMR signals the diastereomer ratio of (2R,3S):(2S,3S) was founc to be about 5:1. (The configuration a~sign~ent took place after separation, cleavage of the phthaloyl groups and derivatization with phosgene to the corresponding oxazolidinone based on the coupling constants in the 1H-NMR, cf. in this connection K.
. ;; -. .
:.. : , . .
, ,, , . :
.: , .. .
16 ~''3 ~
Iizuka et al., J. Med. Chem., (1990), 33, 2707-2714.) The diastereomer mixture was able to be pu~ ~iec and se~-dted by cnrc~atography on silica gel (mobile solvent hexane/dichloromethane/diethyl ether 2:2:1).
Data for the (2R,3S)-compound was:
Melting point: 91.9-92.9C
[~]D : -107.6 (c = 1.0; CHCl3) H-NMR (CDCl3, 300 MHz) ~ 3.20-3.40 (m, 2H);
3.63 (s, 3~);
4.48-4.60 (m, 2H);
4.90-5.00 (m, l~I);
7.10-7.30 (m, 5H);
7.67 7.~5 (m, 4H).
Exam~le 5 (2R,3S)-3-Amino-2-hvdroxy-4-phenylbutyric acid h~drochloride 13.25 g (39.1 mmol) of (2R,3S)-/(2S,3S)-2-hydroxy-4-phenyl-3-phthalimidobutyric acid methyl ester (diastereomeric ratio = 3:1) was dissolved in 60 ml of acetic acid. The solution was mixed with 380 ml of concentrated hydrochloric acid and refluxed for 8 hours. After cooling the mixture was extracted with diethyl ether continuously for 18 hours in a liquid-liquid extractor (according to Kutscher-Steudel). The ether extract and the aqueous phase were separately concentrated by evaporation. The residue of the ether phase (7.41 g of brown powder) consisted basically of phthalic acid.
~31~8 The residue of the a~ueous phase (6.38 g) was suspended in 200 ml of acetonitrile and refluxed for about 15 minutes. The undissolved part (2.6 g) was filtered off, it consisted basically of (2R,3S)-diastereomer. Data for the (2R,3S)-diastereomer was:
H-NMR tDMSO-d6, 300 MHz) ~: 2.90 (dd, lH);
3.05 (dd, lH);
3.40 (br.m, lH);
3.90 (d, lH);
7.20-7.43 (m, 5H);
8.20 (br.m, 3H).
Example 6 f2R 3S~-3-Am no-4-c~clohexyl-2-hydr~xybutyric acid hydrochloride (cyclohexylnorstatin hydrochloride) 500 mg of (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid hydrochloride was dissolved in 5 ml of acetic acid and 5 ml of water, mixed with 50 mg of rhodium/activated carbon (5~ Rh) and hydrogenated for 24 hours at room temperature at 20 bars hydrogen pressure. The catalyst was then filtered off and the filtrate concentrated by evaporation on a rotary evaporator.
The residue was dried in a high vacuum. The yield of the .
.. : .,.~ ....
-.
;. ~ ' product was quantitative. Other data regarding the product was:
H-NMR (DMSO-d6, 300 MHz) ~: 0.75-1.80 (m, 13H);
3.40 (br.m, lH);
4.08 (d, lH).
Example 7 (2R 3S)-2 HYdroxy-4-phenyl-3-phthalimidobut~ric acid 16.8 g of (2R,3S)-2-hydroxy-4-phenyl-3-phthalimidobutyric acid methyl ester (content according to HPLC 49.6%) was dissolved in 50 ml of acetic acid and mixed with 100 ml of 32%
hydrochloric acid. The mixture was stirred for 28 hours at room temperature, and a white solid precipitated. The precipitate was filtered off and washed with cold water. The yield of the product was 10.2 g. Other data regarding the product was:
H-NMR (CDCl3, 300 MHz) ~: 3.15-3.40 (m, 2H);
4.50 (d, lH);
4.95-5.05 (m, lH);
7.08-7.20 ~m, 5H);
7.60-7.80 (m, 4H).
~ o ~
Example 8 (2R.3S)-2-Hvdroxy-~-Phenvl-3-Phthalimidobutyric acid methyl ester ~reduction with Zn(BH4)2~
2.85 g of sodium borohy~ride and 12.83 g of anhydrous zinc chloride were stirred for 18 hours at room temperature in 585 ml of anhydrous tetrahydrofuran. Then the resultant suspension was cooled to -25C and mixed with a solution of 63.5 g of (S)-2-oxo-4-phenyl-3-phthalimidobutyric acid methyl ester in 50 ml of tetrahydrofuran. The mixture was stirred for another 1.5 hours at 25C, then diluted with 500 ml of toluene and extracted three times with 350 ml of o.1 M
hydrochloric acid each. The organic phase was washed three times with 350 ml of saturated sodium bicarbonate solution each. The combined aqueous phases were extracted with toluene. After drying the combined oryanic phases over magnesium sulfate the solvent was distilled off on a rotary evaporator and the residue was recrystallized from 160 ml of toluene. The yield of the product was 33.9 g (53% of theory).
Exam~le 9 (2R,3S)-2-Hydroxy-4-phenYl-3-phthalimidobutyric acid methyl ester (reduction with Ca(BH4)2) 1.12 g of sodium boronydride and 1.23 g of anhydrous calcium chloride were stirred for 16 hours at room temperature in 210 ml of anhydrous tetrahydrofuran. Then the mixture was ,: " ~'~' ,' , ! ; :
2~83~g cooled to -25C. A solution of 25 g of (S)-2-oxo-4-phenyl-3-phthalimidobutyric methyl ester in 40 ml of tetrahydrofuran was lnstilled in this mixture. The reaction mlxture was s-tirred for another 30 minutes at -25C, then diluted ~lith 250 ml of toluene,and washed first with 200 ml of 0.1 M hydrochloric acid and then three times with 250 ml of saturated sodium bicarbonate solution each. The further working-up took place as des~ribed in Example 8 but without recrystallization. The yield of the product was 22.5 g (89.5% of theory). Other data for the product was:
~iastereomeric ratio: (2R,3S)/(2S,3S) - 4:1.
Example 10 (2R,3S)-2-Hydroxy-4-phenyl-3-phthalimidobutyric acid methyl ester (reduction with H2/Pt/Rh) 100 mg of a Pt/Rh mixed catalyst (4% Pt, 1% Rh on activated carbon) was suspended in a solution of 1 g of (S)-2-oxo-4-phenyl-3-phthalimidobutyric acid methyl ester in 10 ml of ethyl acetate. The mixture was hydrogenated for 24 hours at 50 bars hydrogen pressure and 50C, then filtered off from the catalyst and concentrated by evaporation on a rotary evaporator. The yield of the product was 1.0 g, with a conten~ (HPLC) of 53.5 percent. Other data for the product was:
Diastereomeric ratio: (2R,3S) ~ 5.
Claims (20)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of an .alpha.-hydroxy-.beta.-amino carboxylic acid, an ester thereof or a salt thereof of the formula:
(I) wherein R1 is a linear or branched alkyl group having 1 to 6 carbon atoms, capable of being optionally substituted with an aryl group or a cycloalkyl group having 3 to 8 ring members, R2 is hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, and R3 and R4, independent of one another, are hydrogen or an amino protective group or R3 and R4 together form a bifunctional amino protective group, which process comprises:
(a) reacting an N-protected .alpha.-aminocarboxylic acid halide of the formula:
(II) wherein R1 has the above-mentioned meaning, X is chlorine or bromine, and R5 and R6 have the same meanings as the above-mentioned meanings for R3 and R4, provided that R5 and R6 are not both hydrogen at the same time, with trimethylsilyl cyanide to form the corresponding .alpha.-oxonitrile of the formula:
(III) wherein R1, R5 and R6 have the above-mentioned meanings, (b) converting the cyano group of a compound (III) into an alkoxy carbonyl group to form the corresponding .alpha.-oxocarboxylic acid ester of the formula:
(IV) wherein R1, R5 and R6 have the above-mentioned meanings, and R7 has the same meaning as the above-mentioned meaning for R2, provided that R7 is not hydrogen, (c) selectively reducing the keto group of a compound (IV) to form the corresponding N-protected .alpha.-hydroxycarboxylic acid ester of the formula:
(V) wherein R1, R5, R6 and R7 have the above-mentioned meanings;
and, optionally, (d) cleaving the amino protective group and/or hydrolysing the ester function.
(I) wherein R1 is a linear or branched alkyl group having 1 to 6 carbon atoms, capable of being optionally substituted with an aryl group or a cycloalkyl group having 3 to 8 ring members, R2 is hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, and R3 and R4, independent of one another, are hydrogen or an amino protective group or R3 and R4 together form a bifunctional amino protective group, which process comprises:
(a) reacting an N-protected .alpha.-aminocarboxylic acid halide of the formula:
(II) wherein R1 has the above-mentioned meaning, X is chlorine or bromine, and R5 and R6 have the same meanings as the above-mentioned meanings for R3 and R4, provided that R5 and R6 are not both hydrogen at the same time, with trimethylsilyl cyanide to form the corresponding .alpha.-oxonitrile of the formula:
(III) wherein R1, R5 and R6 have the above-mentioned meanings, (b) converting the cyano group of a compound (III) into an alkoxy carbonyl group to form the corresponding .alpha.-oxocarboxylic acid ester of the formula:
(IV) wherein R1, R5 and R6 have the above-mentioned meanings, and R7 has the same meaning as the above-mentioned meaning for R2, provided that R7 is not hydrogen, (c) selectively reducing the keto group of a compound (IV) to form the corresponding N-protected .alpha.-hydroxycarboxylic acid ester of the formula:
(V) wherein R1, R5, R6 and R7 have the above-mentioned meanings;
and, optionally, (d) cleaving the amino protective group and/or hydrolysing the ester function.
2. A process according to claim 1, wherein the N-protected .alpha.-aminocarboxylic acid halide (II) is in the L
configuration.
configuration.
3. A process according to claim 1 or 2, wherein an N-protected .THETA.-aminocarboxylic acid chloride is used as the N-protected .alpha.-aminocarboxylic acid halide (II).
4. A process according to claim 3, wherein an N-protected L-phenylalanyl chloride is used as the N-protected .alpha.-aminocarboxylic acid chloride.
5. A process according to claim 1 or 2, wherein a phthaloyl group is used as the amino protective group R5R6.
6. A process according to claim 5, wherein the cleaving-off of the phthaloyl group is performed with hydrazine hydrate or concentrated hydrochloric acid.
7. A process according to claim 1, 2, 4 or 6, wherein the reaction with trimethylsilyl cyanide is performed in the presence of zinc iodide.
8. A process according to claim 1, 2, 4 or 6, wherein the conversion of the cyano group into an alkoxy carbonyl group is performed by reaction with the corresponding alcohol R7OH in the presence of a strong acid and subsequent hydrolysis of the iminoester salt formed as an intermediate product.
9. A process according to claim 8, wherein methanol is used as the alcohol.
10. A process according to claim 1, 2, 4, 6 or 9, wherein a diastereomer separation of .alpha.-hydroxycarboxylic acid ester (V) is performed between step (c) and step (d).
11. A process according to claim 1, 2, 4, 6 of 9, wherein the selective reduction of the keto group is performed with a borohydride selected from the group consisting of LiBH4, NaBH4, Ca(BH4)2 and Zn(BH4)2, as reducing agent.
12. A process according to claim 1, 2, 4, 6 or 9, wherein the selective reduction of the keto group is performed by catalytic hydrogenation on a platinum/rhodium mixed catalyst.
13. An N-protected .alpha.-oxo-.beta.-aminonitrile of the formula:
(III) wherein R1 is a linear or branched alkyl group having 1 to 6 carbon atoms, capable of being optionally substituted with an aryl group or a cycloalkyl group having 3 to 8 ring members, and either R5 is an amino protective group and R6 is hydrogen or an amino protective group or R5 and R6 together form a bifunctional amino protective group.
(III) wherein R1 is a linear or branched alkyl group having 1 to 6 carbon atoms, capable of being optionally substituted with an aryl group or a cycloalkyl group having 3 to 8 ring members, and either R5 is an amino protective group and R6 is hydrogen or an amino protective group or R5 and R6 together form a bifunctional amino protective group.
14. A compound according to claim 13, wherein the N-protected .alpha.-oxo-.beta.-aminonitrile has (S) configuration.
15. A compound according to claim 13 or 14, wherein R5 and R6 together form a phthaloyl group.
16. A compound according to claim 13 or 14, wherein R1 is isobutyl, benzyl, p-hydroxybenzyl or cyclohexylmethyl.
17. An N-protected .alpha.-oxo-.beta.-aminocarboxylic acid ester of the general formula:
(IV) wherein the asymmetric center has the (S) configuration, R1 is a linear or branched alkyl group having 1 to 6 carbon atoms, capable of being optionally substituted with an aryl group or a cycloalkyl group having 3 to 8 ring members, R7 is a linear or branched alkyl group having 1 to 4 carbon atoms and either R5 is an amino protective group and R6 is hydrogen or an amino protective group or R5 and R6 together form a bifunctional amino protective group.
(IV) wherein the asymmetric center has the (S) configuration, R1 is a linear or branched alkyl group having 1 to 6 carbon atoms, capable of being optionally substituted with an aryl group or a cycloalkyl group having 3 to 8 ring members, R7 is a linear or branched alkyl group having 1 to 4 carbon atoms and either R5 is an amino protective group and R6 is hydrogen or an amino protective group or R5 and R6 together form a bifunctional amino protective group.
18. A compound according to claim 17, wherein R7 is methyl.
13. A compound according to claim 17 or 18, wherein R5 and R6 together are a phthaloyl group.
20. A compound according to claim 17 or 18, wherein R1 is isobutyl, benzyl, p-hydroxybenzyl or cyclohexylmethyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH3373/91 | 1991-11-19 | ||
| CH337391 | 1991-11-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2083108A1 true CA2083108A1 (en) | 1993-05-20 |
Family
ID=4254557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002083108A Abandoned CA2083108A1 (en) | 1991-11-19 | 1992-11-17 | Process for the production of .alpha.-hydroxy-.beta.-aminocarboxylic acids |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0543343A3 (en) |
| JP (1) | JPH06184069A (en) |
| CA (1) | CA2083108A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5591885A (en) * | 1994-09-23 | 1997-01-07 | Hoffman-La Roche Inc. | Process for the preparation of halogenated α-aminoketone compounds |
| US5919949A (en) * | 1993-03-24 | 1999-07-06 | Hoffmann-La Roche Inc. | α-hydroxy acid esters useful as intermediates in the production of β-amino alcohols |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5786500A (en) * | 1993-10-22 | 1998-07-28 | Abbott Laboratories | Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane |
| US5491253A (en) * | 1993-10-22 | 1996-02-13 | Abbott Laboratories | Process for the preparation of a substituted 2,5-diamino-3-hydroxyhexane |
| DE4431530C2 (en) * | 1994-09-03 | 2002-01-31 | Degussa | Process for the preparation of 2- [3 (S) -amino-2 (R) -hydroxy-4-phenylbutyl] -N-tert-butyl-decahydro- (4aS, 8aS) -isoquinolin-3 (S) -carboxamide |
| US5523463A (en) * | 1994-09-23 | 1996-06-04 | Hoffmann-La Roche Inc. | Method of producing halogenated and alpha-aminoalchohols |
| ES2158997T3 (en) * | 1995-10-04 | 2001-09-16 | Ajinomoto Kk | ESTERES ALFA-ACILOXI-BETA-AMINOTIOLCARBOXILICOS AND METHOD AND INTERMEDIATES FOR THEIR PRODUCTION. |
| SG10201502642TA (en) | 2006-10-12 | 2015-05-28 | Bhi Ltd Partnership | Methods, Compounds, Compositions And Vehicles For Delivering 3-Amino-1-Propanesulfonic Acid |
-
1992
- 1992-11-13 JP JP4303629A patent/JPH06184069A/en not_active Withdrawn
- 1992-11-17 CA CA002083108A patent/CA2083108A1/en not_active Abandoned
- 1992-11-17 EP EP19920119634 patent/EP0543343A3/en not_active Withdrawn
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5919949A (en) * | 1993-03-24 | 1999-07-06 | Hoffmann-La Roche Inc. | α-hydroxy acid esters useful as intermediates in the production of β-amino alcohols |
| US5591885A (en) * | 1994-09-23 | 1997-01-07 | Hoffman-La Roche Inc. | Process for the preparation of halogenated α-aminoketone compounds |
| US5684176A (en) * | 1994-09-23 | 1997-11-04 | Hoffmann-La Roche Inc. | Process for manufacturing an α, α'-diaminoalcohol |
| US5847144A (en) * | 1994-09-23 | 1998-12-08 | Hoffmann-La Roche Inc. | Process for manufacturing α,α'-diaminoalcohol |
| US5965733A (en) * | 1994-09-23 | 1999-10-12 | Hoffmann-La Roche Inc. | Process for manufacturing an αα'-diaminoalcohol |
| US5977388A (en) * | 1994-09-23 | 1999-11-02 | Hoffmann-La Roche Inc. | Compounds useful for preparing an α,α'-diaminoalcohol |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0543343A2 (en) | 1993-05-26 |
| JPH06184069A (en) | 1994-07-05 |
| EP0543343A3 (en) | 1993-07-21 |
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