WO2014153113A2

WO2014153113A2 - Processes and intermediates for the preparation of 3 amino-n-cyclopropyl-2 hydroxypropionamide derivatives

Info

Publication number: WO2014153113A2
Application number: PCT/US2014/029125
Authority: WO
Inventors: Anantha Sudhakar
Original assignee: Virobay, Inc.
Priority date: 2013-03-14
Filing date: 2014-03-14
Publication date: 2014-09-25
Also published as: WO2014153113A3

Abstract

The present invention relates to a process for the preparation of 3-amino-N cyclopropyl-2 hydroxypropionamide derivatives as well as novel compounds prepared or used in the process.

Description

PROCESSES AND INTERMEDIATES FOR THE PREPARATION OF 3-AMINO-JV- CYCLOPROPYL-2-HYDROXYPROPIONAMIDE DERIVATIVES

CROSS REFERENCE TO RELATED APPLICATION

[0001] The instant patent application claims priority to U.S. Provisional Patent Application Serial No. 61/785,883. filed March 14, 2013, the entire contents of which are herein incorporated by reference for all purposes.

FIELD OF THE INVENTION

[0002] The present invention relates to processes and intermediates for the preparation of 3-amino-N-cyclopropyl-2-hydroxypropionamid6 derivatives, which are intermediates useful in the synthesis of serine and cysteine protease inhibitors.

BACKGROUND

[0003] Compounds having a 3-amino-N-cyc3opropyl-2-oxoalkanamide group, for example a 3-amino-N-cyclopropyl-2-oxopentanamide have been shown to be useful for the treatment of hepatitis C and related disorders. See, for example, U.S. Patent Application

2007/0054864, the complete disclosure of which is hereby incorporated by reference.

Compounds having a 3-amino-N-cyclopropyl-2-oxoalkan amide group are also useful in preparing inhibitors of Cathepsin S. Accordingly, it would be desirable to have a facile synthesis of common intermediates useful in the preparation of such compounds, particularly a synthesis suitable for large scale preparation of this and similar intermediates.

SUMMARY OF THE INVENTION

[Θ004] first aspect of the invention is a compound which is a dicyclohexylamine salt of a racemic mixture of anti-isomers of a 3-nitro-2-hydroxypropionic acid derivative having the following formula:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentvl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms.

[0005] A second aspect of the invention is a compound which is a racemic mixture of anti- isomers of a 3-nitro-2-hydroxypropionic acid derivative having the following formula.:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms.

[0006] A third aspect of the invention is a compound which is an S-phenylglycinol salt of a 3-nitro-2-hydroxypropionic acid derivative having the following formula;

OH

[0007] A fourth aspect of the invention is compound which is a 3-nitro-2-hydroxypropionic acid derivative having the following formula:

OH

in which. R¹ is alky] of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexvl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexvl additionally may be further substituted with 1-5 halogen atoms. 10008] A fifth aspect of the invention is compound which is a 3-nitro-N-cyclopropyl- 2-hydroxyproprionamide acid derivative having the following formula:

in which R¹ is alky] of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexvl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexvl additionally may be further substituted with 1-5 halogen atoms and R² is alkyl of 1 -6 carbon atoms, alkenyl or 2-6 carbon atoms or eycloalkyl of 3-6 carbon atoms,

[0009] A sixth aspect of the invention is process for preparing a compound which is a dicyclohexylamine salt of a racemic mixture of the anti-isomers of a 3-nitro- 2 -hydroxy-propionic acid derivative having the following formula:

in which R¹ is alkyl of 1 -6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexvl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexvl additionally may be further substituted with 1 -5 halogen atoms, which process comprises contacting a mtroalkane derivative having the following formula;

with glyoxylic acid in the presence of dicyclohexylamine. [Θ010] A seventh aspect of the invention is a process for preparing a compound which is a diastereomer of a 3-nitro-2-hydroxypropionic acid derivative having the following formula:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms, which process comprises treating the dicyclohexylamine salts of a racemic mixture of anti-isomers of a 3-nitro-2 -hydroxy-propionic acid derivative having the following formula:

with resolving agent to form a salt of the diasteromer of the 3-nitro-2-hydroxypoprionic acid derivative and then converting the salt to the free acid.

[0011] An eight aspect of the invention is a process for preparing a diastereomer of a 3-nitro-N-cyclopropyl-2-hydroxypropionamide acid derivative having the following formula.:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2 -6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1 -5 halogen atoms and R² is alkyl of 1-6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, which process comprises contacting a 3-nitro-2-hydroxypropionic acid derivative having the following formula: OH

with an amine of formula NH₂R .

[0012] A ninth aspect of the invention is a process for preparing a diastereomer of a 3- amino-N-cyclopropyl-2-hydrQxypropionamide derivative having the following formula:

OH

which process comprises reducing a diastereomer of a 3-nitro-N-cyclopropyl- 2-hydroxypropionamide derivative having the following formula:

OH

in which R¹ is alky] of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms and R² is alkyl of 1 -6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms.

[0013] A tenth aspect of the invention is a process for preparing a diastereomer of a 3- amino-N-cyclopropyl-2-hydrQxypropionamide derivative having the following formula:

OH

in which. R¹ is alky] of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms and R² is alkyl of 1 -6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, which process comprises:

(a) contacting a nitroalkane derivative having the following formula:

with glyoxylic acid in the presence of dicyclohexylamine to give dicyclohexylamine salts of a racemic mixture of anti-isomers of a 3-nitro-2-hydroxypropionie acid derivative having the following formula:

and then converting the dicyclohexylamine salts to the corresponding free acids;

(b) treating the mixture of anti-isomers of the free acid with resolving agent to form the salt of a diasteromer of the 3-nitro-2-hydroxypropionic acid derivative having of the following formula:

OH

and then converting the salt to the corresponding tree acid;

(c) con tac ting the diastereomer of the free acid with an amine of formula Nt^R" to gi ve a diastereomer of a 3-nitro-'V-cyclohexyl-2-hydroxypropionamide derivative having the following formula:

(d) reducing the 3-nitro-N-cyclopropyl-2 iydroxypropionamide derivative.

[Θ014] An eleventh aspect of the invention is a compound which is a 3-nitro-2- hydroxypropionic acid derivative having one of the following formulae:

in which R¹ is alkyl of .1 -6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cvclohexyi additionally may be further substituted with 1 -5 halogen atoms. [Θ015] A twelfth aspect of the invention is a compound which is a 3-nitro-N-cyclopropyl- 2 -hydroxy-propionic acid derivative having one of the following formulae:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyi, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms and R² is alkyl of 1-6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms.

10016] A thirteenth aspect of the invention is a compound which is an amine or alkali salt of a racemic mixture of anti-isomers or syn-isomers of a 3-nitro-2-hydroxypropionic acid derivative having the following formula:

in which R¹ is alkyl of 1 -6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyf wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cvclohexyl additionally may be further substituted with 1-5 halogen atoms.

[0017] A fourteenth aspect of the invention is a process for preparing a compound which is an amine or alkali salt of a racemic mixture of anti-isomers or syn-isomers of a 3-nitro- 2-hydroxypropionic acid derivative having the following formula:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cvclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cvclohexyl additionally may be further substituted with 1-5 halogen atoms, which process comprises contacting a nitroalkane derivative having the following formula: l/\

R N0₂ with glyoxylic acid in the presence of amine or alkali base, wherein for the preparation of a racemic mixture of anti-isomers the amine or alkali base selectively forms salts with the anti-isomers and said anti-isomer salts are insoluble in the solvent in which said anti-isomer salts are formed and for the preparation of the racemic mixture the syn-isomers the amine or alkali base selectively forms salts with the syn-isomers and said syn-isomers salts are insoluble in the solvent in which said syn-isomers salts are formed,

10018] A fifteenth aspect of the invention is a process for preparing a compound which is a diastereonier of a 3-nitro-2-hydroxypropionic acid derivative having one of the following formula:

in which R is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cycloliexyi wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cycloliexyi additionally may be further substituted with 1 -5 halogen atoms, which process comprises treating a racemic mixture of anti-isomers or syn-isomers of a 3- nitro-2-hydroxypropionic acid derivative having the following formula:

with resolving agent to form a salt of the diasteromer of the 3-nitro-2-l ydrox.yproprionic acid derivative and then converting the salt to the free acid.

[0019] A sixteenth aspect of the invention is a process for preparing a diastereonier of a 3-nitro-N-cyclopropyl-2-hydroxypropionamide derivative having one of the following formulae:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cvclohexyl wherein aikyl, alkenyl, cyclopropyi, cyclopentvl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms and R² is aikyl of 1 -6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, which process comprises contacting a. 3--nitro--2--hydroxypropionie acid derivative having one of the following formulae:

respectively , with an amine of formula NH₂R².

[0020] A seventeenth aspect of the invention is a process for preparing a diastereomer of a 3-amino-N-cyclopropyl-24iydroxypropionamide derivative having one of the following formulae:

which process comprises reducing a diastereomer of a 3-nitro-N-cyclopropyl- 2. -hydroxy-propionic acid derivative having one of the following formulae:

respectively, in which R is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionaliy may be further substituted with 1 -5 halogen atoms and is alkyl of 1-6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms.

[0021] An eighteenth aspect of the invention is a process for preparing a diastereomer of a 3-amino-N-cyclopropyl-2-hydroxypropionarmde derivative having one of the following formulae:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyeiopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyeiopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms and R² is alkyl of 1 -6 carbon atoms, alkenyl or 2-6 carbon atoms or eycloalkyl of 3-6 carbon atoms, which process comprises:

(a) contacting a nitroalkane derivative having the following formula:

R NO, with glyoxylic acid in the presence of amine or alkali base to give an amine or alkali salt of a racemic mixture of anti-isomers or syn-isomers of a 3-nitro-2-hydroxypropionic acid derivative having the following formula:

wherein for the preparation of a racemic mixture of anti-isomers the amine or alkali base selectively forms salts with the anti-isomers and said anti-isomer salts are insoluble in the solvent in which said anti-isomer salts are formed and for the preparation of a racemic mixture of the syn-isomers the amine or alkali base selectively forms salts with the syn-isomers and said syn-isomers salts are insoluble in the solvent in which said syn-isomers salts are formed, and then converting the amine or alkali salts to the corresponding free acids; (b) treating the mixture of anti-isomers or syn-isomers of the free acid with chiral resolving agent to form the salt of a diastereomer of the 3-nitro-2-hydroxypropionic acid derivative having one of the following formulae:

respectively, and converting the salt to the corresponding free acid;

(c) contacting the diastereomer of the free acid with an amine of formula NHaR^{^} to give a diastereomer of a 3-nitro-N-cyclohexyl-2 iydroxypropionamide deri vative having one of the following formulae:

respectively, and

(d) reducing the 3-nit.ro-A^r-cyclopropyl-2-hydroxypropionamide derivative,

10022] A nineteenth aspect of the invention is a process for preparing a. diastereomer of protected 3-ammo-N-cyclopropyl-2 iydroxypropionamide derivative having the following formula:

which process comprises reducing a diastereomer of a 3 -nitro-N-cyclopropy 1- 2-hydroxypropionamide derivative having the following formula:

in the presence of an amine protecting group in which R¹ is alkyl of 1 -6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl

1.) or cyclohexyl wherein alkyl, alkenyi, cyclopropyi, cyclopentyl and cyclohexyl additionally may be further substituted with 1 -5 halogen atoms and R" is alkyl of 1-6 carbon atoms, alkenyi or 2-6 carbon atoms or cycioalkyl of 3-6 carbon atoms and Z is an amine protecting group.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0023] "Anti-isomers" are diastereomers where the configuration of certain functional groups are on opposite sides of the carbon chain. For example, the anti-isomers of 3 -nitro - 2-hydroxypentanoic acid are represented by the compounds having the following formulae:

R,R S,S

in which the nitro and hydroxyl groups are configured on the opposite sides of the carbon chain, namely 35-nitro-25-3iydroxypentanoic acid and 3i?-nitro-2 ?-hydi xypentanoic acid. The anti-isomers can exist individually or together as a mix ture. For the purposes of this application a racemic mixture of anti-isomers includes a mixture of equal amounts of the individual anti-isomers or any ratio of the individual anti-isomers.

10024] "Syn-isomers" are diastereomers where the configuration of certain functional groups are on the same side of the carbon chain. For example, the syn-isomers of 3-nit.ro- 2-hydroxypentanoic acid are represented by the compounds having the following formulae:

in which the nitro and hydroxyl groups are configured on the same side of the carbon chain, namely 36-nitro-2i?-hydroxypentanoic acid and 3i?-nitro-2S-hydroxypentanoic acid. The syn-isomers can exist individually or together as a mixture. For the purposes of this application a racemic mixture of syn-isomers includes a mixture of equal amounts of the individual syn-isomers or any ratio of the individual syn-isomers.

10025] "Alley!" represented by itself means a straight or branched, saturated aliphatic radical containing the number of carbon atoms indicated, e.g., alky] includes methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, fcri-butyi, and the like.

"Alkenyl" represented by itself means a straight or branched, unsaturated aliphatic radical containing the number of carbon atoms indicated, e.g., alkenyl includes vinyl, prop-1 - enyl, isopropenyl, but-l,3-dienyl, _tyi¾>buten-2-yl, isobutenyl, tert-butyl, and the like.

[Θ027] "Halogen atom" means f!uoro, ehloro, bromo or iodo.

[Θ028] "Amine base" means any amine which can selectively form an acid salt with a racemic mixture of anti-isomers or syn-isomers and which is insoluble in the particular solvent in which the anti-isomer or syn-isomer is formed. For example, amine base which selectively forms the acid salt of anti-isomers is dicyclohexylamine and a solvent in which dicyclohexylamine salts are insoluble is methyl teri-butyl ether or mixtures of toluene and ethanol. Other suitable amine bases include, but are not limited to, primary aliphatic amine compounds such as ethylamine, n -propylamine, isopropylamine, n-butylamine, sec- butylamine, tert-butylamine, pentylamine, hexyiamme, heptylamine, octylamine, decylamine, iaurylamine, 3 -pentylamine, 2-ethyihexyla,mine, 1,2-dimethylhexylamine,

aminomethylbicycloheptane, cyclopentylamine, cyclohexylamine,

2,3-dimethylcyclobexylamine, aminomethylcyclohexane, ethylenediamine,

1 ,2-propylenediamine, 1 ,6-hexamethylenediamine, isophoronediamine,

bis(4-aminoeyclohexyl)methane and 2,7-diaminofluorene; primary aromatic amine compounds such as aniline, benzylamine, phenetylamine, meta(or para)-xylylenediamine, 1 ,5-, 1,8- or 2,3-diaminonaphthalene, and 2,3-, 2,6- or 3,4-diaminopyridine; secondary aliphatic amine compounds such as diethylamine, dipropylamine, di-n-butylamine, di-sec- butylamine, dicyclohexylamine, di(2-ethylhexyl)amine, piperidine, pyrrolidine, piperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 2,6-dimethylpiperazine, 1 , 1 -di(4- piperidyl)methane, 1 ,2-(4-piperidyl)ethane, 1 ,3 -(4-piperidyl)propane and l,4-di(4- piperidyl)buiane; and secondary aromatic amine compounds such as diphenylamine, dibenzylamine, N-methylbenzylamine and N-ethylbenzylamine. [Θ029] "Alkali base" means any alkali which can selectively form an acid salt with a racemic mixture of anti-isomers or syn-isomers and which is insoluble in the particular solvent in which the anti-isomer or syn-isomer is formed,

10030] "Resolving agent" means any agent which can resolve an individual stereoisomer from a mixture of stereoisomers.

[0031] "Isomers" mean compounds of the invention having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed

"diastereomers" and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers" or sometimes "optical isomers." A carbon atom bonded to four nonidentical substituents is termed a "chiral center." A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture." A compound that has more than one chiral center has 2"^"1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see "Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992). It is understood that the names and illustration used in this application to describe compounds of the invention are meant to be encompassed ail possible stereoisomers. When referring to compounds of the invention as individual diastereomers in the disclosure or claims it is meant that the individual diastereomer exists in at least 90% purity in a mixture with other diastereomers.

Preferred Embodiments

[0032] Some embodiments described herein set forth a compound which is a

dicyclohexylamme salt of a racemic mixture of anti-isomers of a 3-nitro-2-hydroxypropionic acid derivative having the following formula: R ^ , in which R¹ is alkyl of

1- 6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cycfohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms. In some of these embodiments, R¹ is alkyl of 1 -6 carbon atoms. Irs some other embodiments, R¹ is alkyl of 1 -6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms. In yet other embodiments, R¹ is alkenyl of 2-6 carbon atoms. In still other embodiments, R¹ is alkenyl of 2-6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms. In certain embodiments, R⁵ is ethyl. In certain other embodiments, R¹ is n -propyl.

[Θ033] Some embodiments described herein set forth a compound which is a racemic mixture of anti-isomers of a 3-nitro-2-hydroxypropionic acid derivative having the following

formula

in which R³ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms. In some of these embodiments, R¹ is alkyl of 1-6 carbon atoms. In some other embodiments, R¹ is alkyl of 1-6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms, in yet other embodiments, R¹ is alkenyl of 2-6 carbon atoms. In still other embodiments, R¹ is alkenyl of

2- 6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms. In certain embodiments, R⁵ is ethyl. In certain other embodiments, R⁵ is n-propyl. [Θ034] Some embodiments described herein set forth a compound which is an S- phenylglycinol salt of a 3-nitro-2-hydroxypropionic acid derivative having the following

formula:

[_{n w}hich R^! is alkyl of 1 -6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein aikyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1 -5 halogen atoms. In some of these embodiments, R¹ is alkyl of 1 -6 carbon atoms. In some other embodiments, R¹ is alkyl of 1-6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms. In yet other embodiments, R¹ is alkenyl of 2-6 carbon atoms. In still other embodiments, R¹ is alkenyl of 2-6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with

1 - 5 halogen atoms. In certain embodiments, R¹ is ethyl. In certain other embodiments, R¹ is n-propyl.

[Θ035] Some embodiments described herein set forth a compound which is a 3-nitro-2- hydroxypropionic acid derivative having the following formula:

, in which R^! is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1 -5 halogen atoms. In some of these embodiments, R^l is alkyl of 1 -6 carbon atoms. In some other embodiments, R¹ is alkyl of 1-6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms. In yet other embodiments, R^! is alkenyl of 2-6 carbon atoms. In still other embodiments, R^! is alkenyl of

2- 6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1 -5 halogen atoms. In certain embodiments, R¹ is ethyl. Irs certain other embodiments, R¹ is n-propyl.

Some embodiments described herein set forth a compound which is a 3-nitro-N yclopropyl-2-hydroxyproprionamide acid derivative having the following formula:

, in which R³ is alkyl of 1 -6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms and R^" is alkyl of 1 -6 carbon atoms, alkenyl or 2-6 carbon atoms or cvcloalkyl of 3-6 carbon atoms. In some of these embodiments, R¹ is alkyl of 1-6 carbon atoms. In some other embodiments, R¹ is alkyl of 1 -6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms. In y et other embodiments, R^! is alkenyl of 2-6 carbon atoms. In still other embodiments, R¹ is alkenyl of 2-6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally maybe further substituted with 1-5 halogen atoms. In certain embodiments, R⁵ is ethyl. In certain other embodiments, R¹ is n-propyl.

Certain processes and compounds of the invention within the broadest scope set forth in the Summary of the Invention are preferred.

[0038] Preferred is a compound which is a racemic mixture of the dicyclohexylamine salts of anti-isomers of the 3-nitro-2-hydroxypropionic acid derivative of the invention in which R^! is ethyl, namely a mixture of 3S-nitro-25-hydroxypentanoic acid and 3i?-nitro- 2 i-hydroxypentanoic acid dicyclohexylamine salts.

[0039] Preferred is a compound which is a racemic mixture of anti-isomers of the 3-nitro- 2 -hydroxy-propionic acid derivative of the invention in which R¹ is ethyl, namely 35-nitro- 25'-hydroxypen†.anoic acid and 3/?-nitro-2/?-hydroxypentanoic acid.

)] Preferred is a compound which is a racemic mixture of anti-isomers of the 3-nitro- 2 - ydroxy-propionic acid derivative of the invention in which R¹ is «-propyl, namely 35-nitro- 2S-hydroxyhexanoic acid and 3i?-nitro-2i?-hydroxyhexanoic acid. [Θ04Ϊ ] Preferred is a compound which is ars S-phenylglycinol salt of a 3-nitro- 2-hydroxypropionic acid derivative of the invention in which R¹ is ethyl, namely liS-mtro- 2S'-hydiOxypentanoic acid 5-phenyglycinoi salt.

[0042] Preferred is a compound which is an S-phenyl giycinoi salt of a 3-nitro- 2-hydroxypropionic acid derivative of the invention in which R¹ is «-propyl, namely 3/S-nitro- 2,5-hydroxyhexanoic acid S-phenylglycinol salt.

[0043] Preferred is a compound which is the 3 -nitro-2-hydroxypropionie acid derivative of the invention in which R¹ is ethyl, namely 3S-nitro-2S-hydroxypentanoic acid,

[0044] Preferred is a compound which is the 3-nitro-2-hydroxypropionic acid derivative of the invention in which R^! is «-propyl, namely 3S-nitro-2S-hydroxyhexanoic acid.

[Θ045] Preferred is a compound which is the 3-nitro-N-cyclopropyl-2-hydroxypropionic acid derivative of the invention in which R¹ is ethyl and IV is cyclopropyl, namely N- cyclopropyi-25^,-hydroxy-35¹-niiropenianoic acid.

[0046] Preferred is a compound which is the 3-niiro-N-cyclQpiOpyl-2-hydroxypropionic acid derivative of the invention in which R¹ is κ -propyl and R' is cyclopropyl, namely N- cyclopropyi-2S-hydroxy-3S-nitrohexanoic acid,

[0047] Preferred is a process for preparing a compound which is a dicyclohexyiamine salt of a racemic mixture of anti-isomers of the 3-nitro-2-hydroxypropionic acid derivative of the invention in which R¹ is ethyl, namely 35'-nitro-25-hydroxypentanoic acid and 3/?-nitro- 2 ?-hydroxypeotanoic acid, which process comprises contacting nitroethane with glyoxylic acid in the presence of dicyclohexyiamine.

[0048] Preferred is a process for preparing a compound which is a diasiereomer of a 3- nitro-2-hydroxypropionic acid derivative having the following formula:

in which R¹ is alky] of 1-6 carbon atoms or alkenyl of 2.-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyi wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cycloiiexyl additionally may be further substituted with 1 -5 halogen atoms, which process comprises treating the dicycloliexylamine salts of a racemie mixture of anti-isomers of a 3 -nitro-2-hy droxypropionic acid derivative having the following formula:

with S-phenylglycinol to form the S-phenylglycinol salt of the diasteromer of the 3-nitro- 2-hydroxypropionic acid derivative and then converting the salt to the free acid; more preferably a process for preparing said compound in which R³ is ethyl, namely 35-nitro- 2S-hydrox}ⁱpentanoic acid. In some of these embodiments, R¹ is alkyl of 1-6 carbon atoms. In other of these embodiments, R¹ is alkenyl of 2-6 carbon atoms. In some of these embodiments, R^! is alkenyl of 2-6 carbon atoms optionally substituted by cyclopropyi, cyclopentyl or cycloiiexyl wherein alkenyl, cyclopropyi, cyclopentyl and cycloiiexyl additionally may be further substituted with 1-5 halogen atoms. In some of these embodiments, R¹ is alkyl of 1 -6 carbon atoms optionally substituted by cyclopropyi, cyclopentyl or eyciohexyi wherein alkyl, cyclopropyi, cyclopentyl and cyclohexyl additionaliy ma}' be further substituted with 1-5 halogen atoms. In certain embodiments, R¹ is ethyl. In certain other embodiments, R¹ is n-propyl.

[0049] Preferred is a process for preparing a diastereomer of a 3-nitro-N-cyclopropyl- 2 -h droxypropionic acid derivative of the invention in which R¹ is ethyl, namely 35-amino- N-cyclopropyl-2S-hydroxypentanoic acid, which process comprises contacting a 3-riitro- 2-hydroxypropionic acid derivative of the invention in which R¹ is ethyl, namely liS-nitro- 25'-hydroxypentanoic acid, with an amine of formula NH₂R², in which R² is cyclopropyi.

10050] Preferred is a process for preparing a diastereomer of a 3-amino-N-cyclopropyl- 2-hydroxypropionamide derivative of the invention in which R¹ is ethyl and R² is cyclopropyi, namely 3S-amino-N-cyclopropyl-2S-hydroxypentanoic acid, which process comprises reducing a diastereomer of a 3 -nitro-N-cyclopropyl-2-hy droxypropionic acid derivative of the invention in which R¹ is ethyl and R² is cyclopropyi, namely 35-nitro- 2.5'-hydroxypentanoic acid, namely N-cyclopropyl^S-hydroxy-SS-nitropentanoic acid. Preferred is a process for preparing a diastereomer of a 3-amino-N-cyclopropy]- 2-hydroxypropionamide derivative having the following formula:

OH

in which R is alky! of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by eyeiopropyl, cyclopentyl or cyclohexyi wherein alkyl, alkenyl, cyclopropyi, cyclopentyl and cyclohexyi additionally may be further substituted with 1-5 halogen atoms and R² is alkyl of 1-6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, which process comprises:

(a) contacting a nitroalkane derivative having the following formula:

R ^'NO, with glyoxylic acid in the presence of dicyclohexylamine to give dicyclohexylamine salts of racemic mixture of anti-isomers of a 3-nitro-2-hydroxypropionic acid derivative having the following formula:

(b) treating the mixture of anti-isomers of the free acid with S-phenylglycinol to form the S-phenylglycinol salt of a diastereomer of the 3-nitro-2-hydroxypropionic acid derivative having of the following formula:

OH

and then converting the salt to the corresponding free acid;

(c) contacting the diastereomer of the free acid with an amine of formula NtbR ^' to give diastereomer of a 3-nitro-N-cyclohexyl-2-hydroxypropionamide derivati ve having the following formula:

OH

(d) reducing the 3-nitro-A^r-cyclopropyl-2-hydroxyproprionamide derivative; more preferably the process for preparing the compound of the invention in which R³ is ethyl and R² is cyclopropyl, namely 35-amino-N-cyclopropyl-25-hydroxypentanoic acid. In some of these embodiments, R¹ is alkyl of 1-6 carbon atoms. In other of these embodiments, R¹ is alkenyl of 2-6 carbon atoms. In some of these embodiments, R¹ is alkenyl of 2-6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1 -5 halogen atoms. In some of these embodiments, R¹ is alkyl of 1-6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms. In certain embodiments, R¹ is ethyl. In certain other embodiments, R¹ is n-propyl.

[0052] Preferred is a compound which is an amine of a racemic mixture of anti- isomers of a 3-nitro-2-hydroxypropionic acid derivative having the following formula:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms; preferably in which R¹ is ethyl or «-propyi. [Θ053] Preferred is a compound which is an amine salt of a racemic mixture of anti-isomers of a 3-mtro-2-hydroxypropiomc acid derivative having the following formula;

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms and the amine used to make the salt selectively form salts with the anti-isomers and said anti-isomers salts are insoluble in the solvent in which said anti-isomers salts are formed; more preferably in which the amine is dicylcohexylamine; more preferably in which R¹ is ethyl or κ-propyl.

10054] Preferred is a process for preparing a compound which is an amine salt of a racemic mixture of anti-isomers of a 3-nitro-2-hydroxypropionic acid derivative having the following formula:

in which R^! is alkyl of 1-6 carbon atoms or alkenyl of 2 -6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alley!, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1 -5 halogen atoms, which process comprises contacting a nitroaikane derivative having the following formula:

R N0₂

with glyoxylic acid in the presence of amine base, wherein the amine base selectively forms salts with the anti-isomers and said anti-isomers salts are insoluble in the solvent in which said anti-isomers salts are formed; more preferably in which the amine base is

dicyclohexylamine; more preferably in which R¹ is ethyl. [Θ055] Preferred is a process for preparing a compound which is a diastereom

nitro-2-hydroxypropionic acid derivative having one of the foll owing formulae:

in which R¹ is alky! of 1-6 carbon atoms or alkcnyl of 2-6 carbon atoms optionally substituted in either case by cyciopropyL cyclopentyl or cyclohexyi wherein alkyl, alkenyL cyclopropyi, cyclopentyl and cyclohexyi additionally may be further substituted with 1 -5 halogen atoms, which process comprises treating a racemic mixture of anti-isomers of a 3-nitro- 2 -hydroxy-propionic acid derivative having the following formula:

with a resolving agent to form a salt of the diastereomer of the 3-nirro-2-hydroxypropionic acid derivative and then converting the salt to the free acid; preferabiy in which the resolving agent is S-phenylglycinol and the diastereomer of the 3 -nitro-2- ydroxypropionic acid derivative has the following formula;

preferably in which R^l is ethyl.

[Θ056] Preferred is a process for preparing a diastereomer of a 3-amrao-N-cyclopropyl- 2-hydroxypropionamide derivative having one of the following formulae:

(a) contacting a nitroalkane derivative having the following formula:

with glyoxylic acid in the presence of amine base to give an amine salt of a racemic mixture of anti-isorners of a 3-nitro-2-hydroxypropionic acid derivative having the following formula:

wherein the amine base selectively forms salts with the anti-isorners and said anti-isomers salts are insoluble in the solvent in which said anti-isomers salts are formed, and then converting the amine salts to the corresponding free acids;

(b) treating the mixture of anti-isomers of the free acid with chiral resolving agent to form the salt of a diastereomer of the 3-nitro-2-h.ydroxypropiomc acid derivative having one of the following formulae:

respectively, and converting the salt to the corresponding free acid;

( c) contacting the diastereomer of the free acid with an amine of formula NH?R² to give a diastereomer of a 3-nitro-N-cyc3ohexyl-2-hydroxypropionamide derivative having the following formula:

respectively, and

(d) reducing the 3-nitro-N-cyclopropyl-2-hydroxypropionamide derivative.

Chemistry

10057] The follow scheme illustrates a process for making and isolating one of the anti - isomers of the 3-nitro-N-cyclopropyl-2-hydroxypropionic acid derivatives of the invention.

Scheme 1

or alkali base

resolving agent

in which R¹ and R^z are as defined in the Summary of the Invention.

[0058] In some of these processes for making and isolating one of the anti-isomers of the 3 - nitro-N-cyclopropyl-2-hydroxypropionic acid derivatives, R¹ is alkyl of 1-6 carbon atoms. In other of these embodiments, R¹ is alkenyl of 2-6 carbon atoms. In some of these

embodiments, R' is alkenyl of 2-6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyciohexyi wherein alkenyl, cyclopropyl, cyeiopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms. In some of these

embodiments, R¹ is alkyl of 1 -6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, cyclopropyl, cyclopentyl and cyclohexyl additionally m }' be further substituted with 1-5 halogen atoms. In certain embodiments, R¹ is ethyl. In certain other embodiments, R¹ is n-propyl.

[0059] In some of these processes for making and isolating one of the anti-isomers of the 3- nitro-N-cyclopropyl-2-hydroxypropionic acid derivatives, R² is alkyl of 1-6 carbon atoms. In some other embodiments, R is alkenyl. In some other embodiments, R² is cycloalkyl of 3-6 carbon atoms.

[0060] The amine or alkali salts of the 3-mtro-2-hydroxypropionic acid derivatives of the invention are prepared by reacting a nitroalkane of formula R¹C1¾N0₂ with glyoxylic acid in the presence a suitable amine or alkali base (e.g., dicyclohexylamine in the case of the anti- isomers). The reaction is carried out in a suitable solvent (e.g., toluene, ethanol, and the like or any combinations thereof) at temperatures of about 0 to 25°C and requires about 24 hours to complete.

[0061] The diastereomers 3-nitro-2-hydroxypropionic acid derivatives are prepared by converting an amine or alkali salt of an anti-isomeric or syn-isomeric racemic mixture of a 3-nitro-2-hydroxypropionic acid derivative to its corresponding free acid and then treating the free acid with a resolving agent (e.g., S-phenylglycinol in the case of the 5,5-isomers) to form a salt of the diasteroraer of the 3-nitro-2-hydroxypropionic acid derivative and converting the diastereomeric salt to its corresponding free acid. Conversion of the amine or alkali salt to its free acid can be carried out by treating with acid (e.g., concentrated hydrochloric acid) in a suitable solvent (e.g., TBE) at a temperature of about 10 to 25°C and requires about 1 to 2 hours to complete. The treatment with the resolving agent is carried out in a suitable solvent (e.g., isopropyi alcohol) at temperatures of about 20 to 25°C and requires about 1 to 2 hours to complete. Conversion of the diastereomeric salt to its free acid is carried out by treating with, acid (e.g., concentrated hydrochloric acid) in a suitable solvent (e.g., MTBE) at a temperature of about 10 to 25°C and requires about 1 to 2 hours to complete.

[Θ062] The 3-nitro-N-cyclopropyl-2-hydroxypropionic acid derivatives can be prepared by reacting a corresponding 3-nitro-2-hydroxypropionic acid derivative with amine of formula 1¾R². The reaction is carried out in a suitable solvent (e.g., ethyl acetate, THF, and the like or any combinations thereof) in the presence of an appropriate coupling agent (e.g.EDC.HCl/ HOBt monohydrate) at temperatures of about 0 to 25°C and requires 1 to 2 hours to complete.

[0063] Other anti-isomers and syn-isomers of the in vention can be prepared by proceeding as Scheme 1 but varying the amino or alkali base and resolving agent to achieve the desired product.

[0064] The 3-nitro-N-cyclopropyl-2-hydroxypropionic acid derivatives of the invention are useful as intermediates in the preparation of 3-amino-N-cyclopropyl-2-hydroxypropionamide derivatives that in turn are useful in the preparation of pharmaceutical agents. The following scheme illustrates a process for making compounds which are the anti-isomers of the 3- amino-N-cyclopropyl-2-hydroxypropionamide derivatives.

in which R¹ and R^z is as defined in the Summary of the Invention.

[Θ065] The 3-ammo-N-cyclopropyl-2-hydroxypropionamide derivatives are prepared by reducing a corresponding 3-nitro-N-cyclopropyl-2-hydroxypropionamide derivative. The reduction can be carried out in a suitable solvent (e.g., methanol) with an appropriate reducing agent (e.g., hydrogen and palladium hydroxide) at temperatures of about 20 to 25°C and requires about 8 hours to complete.

[0066] In some of these processes for making compounds which are the anti-isomers of the 3-amino-N-cyclopropyl-2-hydroxypropionamide derivatives, R¹ is alkyl of 1-6 carbon atoms. In other of these embodiments, R^l is alkenyl of 2-6 carbon atoms. In some of these embodiments, R¹ is alkenyl of 2-6 carbon atoms optionally substituted by cyclopropyl, cyclopentyl or cyclohexyl wherein alkenyl, cyclopropyi, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms. In some of these embodiments, R¹ is aik i of 1-6 carbon atoms optionally substituted by cyclopropyi, cyclopentyl or cyclohexyl wherein alkyl, cyclopropyi, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms. In certain embodiments, R^! is ethyl. In certain other embodiments, R^! is n-propyl.

[0067] In some of these processes for making compounds which are the anti-isomers of the 3-amino-N-cyclopropyl-2-hydroxypropionamide derivatives, is alkyl of 1-6 carbon atoms. In some other embodiments, R² is alkenyl. In some other embodiments, R² is cycloalkyl of 3-6 carbon atoms.

Examples

10068] Tlie following examples are included to demonstrate preferred embodiments of the invention, it should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1

[0069] Mixture of 3,S-Nitro-2S-hydroxypentanoic Acid and 3 ?-Nitro-2i?-hydroxypentanoic Acid Dicyciohexylamine Salts

[0070] A 4-neck round bottom flask (20 L) fitted with mechanical stirrer under ₂, was charged 1-nitropropane {500 g, 5.61 mol), toluene (9 L) and ethanol ( 1 L) and the mixture was stirred for 15 rain at 20-25 C. A solution of 50% glyoxylic acid in water (920 g, 6.21 mol) was added to the mixture at 20-25°C. The reaction mixture was cooled to 0°C and then dicyciohexylamine (5.1 Kg, 28.06 mol) was added slowly via an addition funnel over a period of 30 minutes at < 25°C. The reaction mixture was maintained for 24 hours at 20- 25°C. Progress of the reaction was monitored by HPLC. Solids were filtered and washed with a mixture of 9: 1 toluene: e iianol (0.5 L). The product was dried under vacuum at 50°C for 12 hours to give a mixture of 35^,-nitro-2S-hydroxypentanoic acid and 3i?-nitro-2i?- hydroxy-pentanoic acid dic clohexylarnine salts (1700 g, 4,9 mo3, 87%) as a light yellow solid. Purity by HPLC: 87.84%. Chiral purity: 92.6%.

Example 2

[Θ07Ϊ ] Mixture of 35- itro-25-hydroxypentanoic Acid and 3/?-Nitro-2/?~hydroxype tanoic Acid

[0072] A 4-neck round bottom flask (20 L) fitted with the mechanical stirring and thermometer was charged with a mixture of 35-nitro-25-hydroxypentanoic acid and 3i?-nitro- 2/?-hydroxypentanoic acid dicyclohexylarnine salts (1.7 Kg, 4.93 moi), prepared as in Example 1, and methyl tert-bv yl ether ( 17 L). The mixture was stirred for 15 minutes at 20- 25°C and then cooled to 10°C. A solution of IN HC1 (8.5 L) was added to the mixture at < 25°C. The mixture was stirred for 1 hour at 20-25°C. The mixture was filtered and the wet cake was slurry washed with methyl feri-butyf ether (1 L). The solid was re-extracted with methyl ¾?ri-butyi ether (4.25 L) and IN HQ solution (4.25 L). The combined organic layer was washed with water (8.5 L), dried with sodium sulfate and concentrated completely under vacuum at 50°C to afford a mixture of 3S-nitro-2S-hydroxypentanoic acid and 3i?-nitro-2/?- hydroxypentanoic acid (650 g, 3.96 mol, 81%) as a light yellow liquid. Purity by HPLC: 87.84%. Chiral purity: 92.6%.

Example 3

[0073] 3.S-NitrO"2S"3iydroxypentanoic Acid S-Phenylglycinoi Salt

.) 1

10074] A 4-neck round bottom flask (20 L) fitted with mechanical stirrer was charged with a mixture of 3S-nitro-2S-hydroxypentanoic acid and 37?-mtro-2i?-hydroxypentanoic acid (500 g, 3,06 mol), prepared as in Example 2, in isopropyl alcohol (10 L) and the solution was stirred for 10 minutes at 20-25°C. S-Phenylglycinol (420 g, 3.06 mol) was added to the solution at 20-25°C and the mixture was stirred for 1 hour. Solids were filtered and washed with isopropyl alcohol (0,5 L). The product was dried under vacuum at 50°C for 12 hours to afford 35'-nitro-2S-hydroxypentanoic acid S-phenylglycinol salt (260 g, 0.86 mol, 28.5%) salt as an off-white solid. Purity by HPLC: 96.84%. Chiral purity: 93.73%.

Example 4

[0075] 3S-Nitro-25'-hydroxypentanoic Acid

10076] A 4-neck round bottom flask (20 L) fitted with the mechanical stirrer and thermometer was charged with 3S-nitro-2S-hydroxypentanoic acid S-phenyl glycinol salt (40 g, 0, 133 mol), prepared as in Example 3, and methyl ferf-butyl ether (400 mL). The mixture was stirred for 15 minutes at 20-25°C and then cooled to 10°C, IN HQ (400 mL) was added to the mixture at < 25°C. The mixture was stirred for 30 minutes and allowed to settle for 15 minutes. The layers were separated. The organic layer was washed with water (200 mL), dried under sodium sulfate and concentrated completely under vacuum at 50°C to afford 3S-nitro-2S-hydiOxypentanoic acid (20 g, 0.12 mol, 92%) as a light yellow colored oil.

Example 5

[0077] N-Cyclopropyl-2S-hydroxy-3S-nitropentanoic Acid

[0078] A -i -neck round bottom flask (250 mL) fitted with a mechanical stirrer, thermometer and N? U-Tube, was charged with 3S-nitro-2S iydroxypentanoic acid (5 g, 0.030 mol), prepared as in Example 4, and ethyl acetate (60 mL). Cyclopropylamine (2.63 g, 0,046 mol) was added drop-wise over 15 minutes. The mixture was stirred for 15 minutes at 25°C and then cooled to between 0 and -5°C. A solution of HOBt monohydrate / THF / water (7.04 g, / 20 mL / 1 mL) and EDC.HC1 / water (8.83 g / 8.9 mL) was prepared separately and added drop-wise to the reaction mixture over ~ 30 minutes while maintaining the temperature < 0°C. The reaction mixture was maintained for 16 hours at between 0 and -5°C. Progress of the reaction was monitored by HPLC. The IPC after 30 minutes indicated about 0.91% of unreacted i-nitro propane and 90.85% of the product. A 5% NaHC0₃ solution (25 mL) was slowly added to the reaction mixture at < 10°C. The layers were separated. The organic layer was washed twice with 5% NaHC0₃ solution (25 mL) and then with water (25 mL) at < 10°C, dried with sodium sulfate and concentrated completely under vacuum at 50°C. The residue was combined with n-heptane (12.5 ml,) and the resultant solution was concentrated under vacuum at 30°C. The residue was taken up into «-heptane (25 mL) and the resultant solution was stirred for 1 hour at 0°C. Solids were filtered, washed with n-heptane (2.5 mL) and dried under vacuum at 30°C for 12 hours to afford N-cyclopropyl-25'-hydroxy-35- nitropentanoic acid (4.2 g, 0.02 mol, 68.5%) as a yellow solid. Purity by HPLC: 94.47%. Chiral purity: 92.45%.

Example 6

[0079] 3S-Amino-A^/-cyclopropyl-2,5'-hydroxypentanoic Acid

[0080] N-Cyclopropyl-2£-bydroxy-3S-nitTopentanoic acid (1 g, 0.0049 mol), prepared as in Example 5, was dissolved in methanol (40 mL) and the solution was placed in a Parr Shaker hydrogenator. Pd(OH)₂ (0.3 g, 20% in 50% wet) was added and H₂ pressure (3 kg/cm²) was applied. The reaction mixture was maintained for 8 hours at 20-25°C. Progress of the reaction was monitored by HPLC. The IPC after 30 minutes indicated about 0,75% of unreacted 1 -nitro propane and 80.57% of the product formation. The reaction mixture was filtered through ceiite, washed with methanol ( 10 mL) and distilled under vacuum at 30°C. Isopropyl alcohol (~ 10 mL) was added and the mixture was stirred for 5 minutes at 25°C. Concentrated HCl was added slowly to the mixture at 25°C. A resultant slurry was stisred for 5 hours at 0°C, filtered, washed with isopropyl alcohol (2 mL) and dried under vacuum at 30°C for 12 hours to afford 3S-amino-A-cyclopropyi-25-hydroxypentanoic acid (0.65 g, 62%) as an off-white solid. Purity by HPLC: 98.2%.

Claims

Claims:

1. A compound which is a dicyclohexylamine salt of a racemic mixture of anti-isomers of a 3-nitro-2-hydroxypropionic acid derivative having the following formula:

in which R¹ is alky] of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyi or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyi and cyclohexyl additionally may be further substituted with 1-5 halogen atoms.

2. The compound of Claim 1 in which R¹ is ethyl, namely a racemic mixture of 3S-nitro-2S-hydroxypentanoic acid and 3 ?-nitro-2J?-hydroxypentanoic acid

dicyclohexylamine salts.

3. The compound of Claim 1 in which R¹ is «-propyl, namely a racemic mixture of 3£-nitro-2£-hydroxyhexanoic acid and 3ii-nitro-2i?-hydroxyhexa.noic acid

dicyclohexylamine salts.

4. A compound which is a racemic mixture of anti-isomers of a 3-nitro- 2-hydroxypropionic acid derivative having the following formula:

in which R is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyi or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyi and cyclohexyl additionally may be further substituted with 1 -5 halogen atoms.

5. The compound of Claim 4 in which R¹ is ethyl, namely a racemic mixture of 35'-nitro-25'-hydroxypentanoic acid and 3 ?-mtro-2ii-hydroxypentanoic acid.

6. The compound of Claim 4 in which R¹ is « -propyl, namely a racemic mixture of 3S'-nitro-2S'-hydroxypentanoic acid and 37?-nitro-2i?-hydroxypentanoic acid.

7. A compound which is an 5-phenylglycinol salt of a. 3-nitro-2- hydroxypropionic acid derivative having the following formula:

in which R^! is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1 -5 halogen atoms.

8. The compound of Claim 7 in which R¹ is ethyl, namely 35-nitro- 25-hydroxypentanoic acid 5-phenylglycinol salt,

9. The compound of Claim 7 in which R¹ is M-propyl, namely 35-nitro- 2S^,-hydroxyhexanoic acid S-phenylglycinol salt.

10. A compound which is a 3-nitro-2-hydroxypropionic acid derivative having the following formula:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl addiiionally may be further substituted with 1-5 halogen atoms. , The compound of Claim 10 in which R¹ is ethyl, namely SS-nitro-

2S^,-hydiOxypentanoic acid,

12. The compound of Claim 10 in which R¹ is «-propyl, namely 3S'-nitro- 2S-bydroxyhexanoic acid.

13. A compound which is a 3-nitro-N-cyclopropyl-2-hydroxypropionamide derivative having the following formula:

OH

in which R¹ is alkyl of 1 -6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cvciopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms and R² is alkyl of 1-6 carbon atoms, alkenyl or 2-6 carbon atoms or cvcloalkyl of 3-6 carbon atoms.

14. The compound of Claim 13 in which R¹ is ethyl and R² is cyclopropyl, namely N-cycl opropy 1-25-hy droxy - 35-ni tropen tanami de.

15. The compound of Claim 13 in which R' is w-propyl and R:^' is cyclopropyl, namely N-cyclopropyl-25-hydroxy-3S-nitrohexanamide.

16. A. process for preparing a compound which is a dicyclohexylamine salt of a racemic mixture of anti-isomers of a 3-nitro-2~hydroxypropionic acid derivative having the following formula:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyciopropyl, cyclopentyl or eyclohexyi wherein alkyl, alkenyl, cyclopropyi, cyclopentyl and eyclohexyi additionally may be further substituted with 1-5 halogen atoms, which process comprises contacting a nitroalkane derivative having the following formula:

1 -

R N0₂

with glyoxylic acid in the presence of dicyclohexylamine.

17, The process of Claim 16 for preparing the compound in which R is ethyl, namely a mixture of 35^l-nitro-2<S'-hydroxypentanoic acid and 3i?-nitro-2 ?-hydroxy-pentanoic acid dicyclohexylamine salts.

18. A process for preparing a compound which is a diastereomer of a 3-nitro- 2-hydroxypropionic acid derivative having the following formula:

OH

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyciopropyl, cyclopentyl or eyclohexyi wherein alkyl, alkenyl, cyclopropyi, cyclopentyl and eyclohexyi additionally may be further substituted with 1-5 halogen atoms, which process comprises treating the dicyclohexylamine salts of a racemic mixture of anti-isomers of a 3-mtro-2-hydroxypropionic acid derivative having the following formula:

with a resolving agent to form a salt of the diastereomer of the 3-nitro-2-hydroxypropionic acid derivative and then converting the salt to the free acid.

19. The process of Claim 18 in which the resolving agent is S-phenylglycinol.

20. The process of Claim 18 for preparing the compound in which R is ethyl, namely 3S~nitro~25-hydroxypentanoic acid.

21. A process for preparing a diastereomer of a 3-nitro-N-cyclopropyl- 2-hydroxypropionamide derivative having the following formula:

OH

in which R is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyciopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms and R² is alkyl of 1-6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, which process comprises contacting a. 3-nitro-2-hydroxypropionic acid derivative having the following formula:

OH

with an amine of formula \ i ί >R. .

The process of Claim 21 for preparing the compound in which

R¹ is ethyl and R ⁷ is cyclopropyl, namely N-cyclopropyl-2S'-liydroxy-3<S'-nitropentanamide

23. A process for preparing a diastereomer of a 3-amino-iY-cyclopropyl- 2-hydroxyproprionamide derivative having the following formula: OH

which process comprises reducing a diastereomer of a 3-niiro-N-cyclopropyl- 2-hydroxypropionamide derivative having the following formula:

OH

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyi wherein alkyl, alkenyl cyclopropyl, cyclopentyl and cyclohexyi additionally may be further substituted with 1 -5 halogen atoms and R² is alkyl of 1-6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms.

24. The process of Claim 23 for preparing the compound in which

R^l is ethyl and R² is cyclopropyl, namely 35'-amino-iV-cyclopropyl-25'-hydroxypentanamide.

25. A process for preparing a diastereomer of a 3-amino-N-cyclopropyl- 2-hydroxypropionamide derivative having the following formula:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyi wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyi additionally may be further substituted with 1-5 halogen atoms and R" is alkyl of 1-6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, which process comprises: (a) contacting a nitroalkane derivative having the following formula:

with glvoxylic acid in the presence of dicyclohexylamme to give dicyclohexylamine salts of a racemic mixture of anti-isomers of a 3 -nitro-2-hydroxypropionic acid derivative having the following formula:

(b) treating the mixture of anti-isomers of the free acid with resolving agent to form the salt of a diastereomer of the 3-nitro-2-hydroxypropionic acid derivative having of the following formula:

and then converting the salt to the corresponding free acid;

(c) contacting the diastereomer of the free acid with an amine of formula ¾R² to give a diastereomer of a. 3-nitro-N-cyclohexyl-2-hydroxypropionamide derivative having the following formula:

(d) reducing the 3-nitro-N-cyclopropyl-2-liydroxypropionamide derivative.

26. The process of Claim 25 in which the resolving agent is S-phenylglycinol. 27, The process of Claim 26 for preparing the compound in which R is ethyl anc R² is cyciopropyl, namely 3S-aminO"N-cyclopropyi"2S-hydroxypentanamide,

28. A compound which is an amine or alkali salt of a racemic mixture of anti- isomers or syn-isomers of a 3-nitro-2-hydroxypropionic acid derivative having the following formula:

in which R is alky! of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyciopropyl cyclopentyl or cyclohexyi wherein alkyl, alkenyl, cyciopropyl, cyclopentyl and cyclohexyi additionally may be further substituted with 1 -5 halogen atoms.

29. The compound of Claim 28 which is the amine salt of a racemic mixture of the anti-isomers of the 3 -nitro-2-hydroxypropionic acid deri vative.

30. The compound of Claim 29 in which R' is ethyl.

31. The compound of Claim 29 in which R¹ is «-propyl.

32. A compound which is a 3-nitro-2-hydroxypropionic acid derivative having one of the following formulae:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyciopropyl, cyclopentyl or eyclohexyi wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and eyclohexyi additionally may be further substituted with 1-5 halogen atoms.

33. A compound which is a 3-nitro-N-cyclopropyl-2-hydroxypropionamide derivative having one of the following formulae:

in which R is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or eyclohexyi wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and eyclohexyi additionally may be further substituted with 1 -5 halogen atoms and R² is alkyl of 1-6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloaikyl of 3-6 carbon atoms.

34. A process for preparing a compound which is an amine or alkali salt of a racemic mixture of anti -isomers or syn-isomers of a 3-nitro-2-hydroxypropionic acid derivative having the following fo

in which R is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyciopropyl cyclopentyl or eyclohexyi wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and eyclohexyi additionally may be further substituted with 1 -5 halogen atoms, which process comprises contacting a nitroalkane derivative having the following formula: N0₇ with glyoxylic acid in the presence of amine or alkali base, wherein for the preparation of a racemic mixture of anti-isomers the amine or alkali base selectively forms salts with the anti-isomers and said anti-isomer salts are insoluble in the solvent in which said anti-isomer salts are formed and for the preparation of the racemic mixture the syn-isomers the amine or alkali base selectively forms salts with the syn-isomers and said syn-isomers salts are insoluble in the solvent in which said syn-isomers salts are formed,

35. The process of Claim 34 in which the compound is an amine salt of a mixture of anti-isomers of the 3-nitro-2-hydroxypropionic acid derivative.

36. A process for preparing a compound which is a diastereomer of a 3-nitro- 2-hydroxypropionic acid derivative having one of the following formulae:

in which R is alkyl of 1-6 carbon atoms or aikenyl of 2 -6 carbon atoms optionally substitutei in either case by cyciopropyl, cyclopentyl or cyclohexyl wherein alkyl, aikenyl, cyclopropyi, cyclopentyl and cyclohexyl additionally may be further substituted with 1 -5 halogen atoms, which process comprises treating a racemic mixture of anti-isomers or syn-isomers of a 3- nirro-2-hydroxypropionic acid derivative having the following formula:

with resolving agent to form a salt of the diasteromer of the 3 -nitro-2-hydroxypropionic acid derivative and then convertins the salt to the free acid.

37. A process for preparing a diastereomer of a 3~nitro-N~cyclopropyl~

2-hydroxypropionamide derivative having one of the following formulae:

in which R¹ is alky] of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, eyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms and R² is alkyl of 1 -6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, which process comprises contacting a 3-nitro-2-hydroxypropionic acid derivative having one of the following formulae:

respectively, with an amine of formula NH?R^"'.

38. A process for preparing a diastereomer of a 3-amino-N-cyclopropyl- 2-hydroxyproprionamide derivative having one of the fol lowing formulae:

which process comprises reducing a diasiereomer of a 3-nitro-N-cyclopropyl- 2-hydroxypropionamide derivative having one of the following formulae:

respectively, in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyciopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyciopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms and R² is alkyl of 1-6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms.

39. A process for preparing a diastereomer of a 3-amino-N-cyclopropyl- 2-hydroxypropionamide derivative having one of the following formulae:

in which R¹ is alkyl of 1-6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyclopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyclopropyl, cyclopentyl and cyclohexyl additionally may be further substituted with 1-5 halogen atoms and R² is alkyl of 1-6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, which process comprises:

(a) contacting a nitroalkane derivative having the following formula:

R N0₂ with glvoxylic acid in the presence of amine or alkali base to give an amine or alkali salt of a racemic mixture of anti-isomers or syn-isomers of a 3-mtro-2-hydroxypropionic acid derivative having the following formula:

wherein for the preparation of a racemic mixture of anti-isomers the amine or alkali base selectively forms salts with the anti-isomers and said anti-isomer salts are insoluble in the solvent in which said anti-isomer salts are formed and for the preparation of a racemic mixture of the syn-isomers the amine or alkali base selectively forms salts with the syn-isomers and said syn-isomers salts are insoluble in the solvent in which said syn-isomers salts are formed, and then converting the amine or alkali salts to the corresponding tree acids; (b) treating the mixture of anti-isomers or syn-isomers of the free acid with chiral resolving agent to form the salt of a diasteromer of the 3-nitro-2-hydroxypropionic acid derivati ve having one of the following formulae:

respectively, and converting the salt to the corresponding free acid;

(c) contacting the diastereomer of the free acid with an amine of formula NtfeR" to give a diastereomer of a 3-nitro-N-cyclohexyl-2-hydroxypropionamide derivative having one the following formulae:

respectively, and

(d) reducing the 3-nitro-N-cyclopropyl-2-hydroxypropionamide derivative.

40, The process of Claim 39 in which the nitroalkane is contacted with glyoxylic acid in the presence of amine base to give an amine salt of a racemic mixture of anti-isomers wherein the amine base selectively forms salts with the anti-isomers and said anti-isomers salts are insoluble in the solvent in which said anti-isomers salts are formed.

41. A process for preparing a diastereomer of protected 3 -amino-N-cyclopropyl-2- hydroxyproprionamide derivative having the following formula:

OH

which process comprises reducing a diasiereomer of a 3-nitro-N-cyclopropyl- 2 -hydroxy-propionic acid derivative having the following formula:

OH

in the presence of an amine protecting group in which R is alley! of 1 -6 carbon atoms or alkenyl of 2-6 carbon atoms optionally substituted in either case by cyciopropyl, cyclopentyl or cyclohexyl wherein alkyl, alkenyl, cyciopropyl, cyclopentyl and cyclohexyl additionally may be fuiiher substituted with 1-5 halogen atoms and R² is alkyl of 1-6 carbon atoms, alkenyl or 2-6 carbon atoms or cycloalkyl of 3-6 carbon atoms and Z is an amine protecting group.

42. The process of Claim 41 wherein the amine protecting group is tert- butoxycarbonyl.