Claims: We Claim:
1. A process for the preparation of compound of Formula 1,

Formula 1
wherein R1and R2are different and individually represent alkyl, aryl group, cycloalkyl; “ * ” denotes a chiral center which encompasses both “R” and “S” isomers or dextro and levo rotary compounds which comprises reacting an alkyl amine of compound of formula 2

Formula 2
with a chiral acidoptionally in the presence of base in a suitable solvent.

2. A process as claimed in claim 1, wherein the compound of Formula 2 is prepared by
i) hydrogenating compound of Formula 3 or its salts

Formula 3
wherein R1, R2, R3 and R4 are as defined above, using a catalyst in suitable solvent optionally in the presence of an acid to obtain compound of Formula 2 or its salts.

Formula 2

3. A process as claimed in claim 2, wherein the compound of Formula 3 or its salts,

Formula 3
wherein R1, R2, R3 and R4 are as defined above, which comprises

i) reaction of compound of Formula 4

Formula 4
with a-amine of Formula 5 or its salts

Formula 5
using titanium isopropoxide, P-TSA, titanium tetrachloride in presence of base in a suitable solvent to give a compound of formula 6,

Formula 6
ii) reducing the compound of formula 6 using a reducing agent in a suitable solvent to give compound ofFormula 3 or its salts.

4. A process for the preparation of compound of Formula 1,

Formula 1
wherein R1 and R2 are as defined above; which comprises:
i) hydrogenating compound of Formula 3 or its salts

Formula 3
wherein R1, R2 are as defined above; R3 represents substituted or unsubstituted alkyl group and R4 represents substituted or unsubstituted aryl groups using a catalyst in suitable solvent optionally in the presence of an acid to obtain compound of Formula 2 or its salts,

Formula 2
ii) reacting alkyl amine compound of formula 2with a chiral acid in presence of base in suitable solvent to obtain alkyl amine compound of formula 1.

5. A process for the preparation of compound of Formula 3or its salts,

Formula 3
wherein R1, R2, R3 and R4 are as defined above, which comprises

i) reaction of compound of Formula 4

Formula 4
with a-amine of Formula 5 or its salts

Formula 5
using titanium isopropoxide, P-TSA, titanium tetrachloridein presence of base in a suitable solvent to give a compound of formula 6,

Formula 6
ii) reducing the compound of formula 6 using a reducing agent in a suitable solvent to give compound ofFormula 3 or its salts.

6. A process for the preparation of compound of Formula 1,

Formula 1
wherein R1 and R2as defined above, which comprises
i) condensing a compound of Formula 4

Formula 4
with a-amine of Formula 5 or its salts

Formula 5
using titanium isopropoxide, P-TSA, titanium tetrachloride in presence of a base in suitable solvent to give a compound of formula 6,

Formula 6
ii) reducing the compound of formula 6 using a reducing agent in a suitable solvent to give compound of Formula 3 or its salts,

Formula 3
iii) hydrogenating compound of Formula 3 or its salts using a catalyst in a suitable solvent optionally in the presence of an acid to obtain compound of Formula 2 or its salts,
iv) reacting compound of Formula 2with a chiral acid optionally in the presence of base in a suitable solvent to give compound of Formula 1.

7. A compound of Formula 1,

Formula 1
wherein R1 and R2 are different and individually represent hydrogen, alkyl, aryl group, cycloalkyl; “ * ” denotes a chiral center which encompasses both “R” and “S” isomers or dextro and levo rotary compounds.

8. A compound as claimed in claim 7, wherein the compound of Formula 1 is

Formula 1a.
9. The process as claimed in claim 1, 4 & 6 - 7 the chiral acid is selected from a-hydroxy acid, camphor sulfonic acid and (R)-(-)-1,1'-Binaphthalene-2,2'-diyl hydrogen phosphate.

10. The process as claimed in claim 9 a-hydroxy acid is selected from lactic acid, malic acid, tartaric acid, Dibenzoyl-D-tartaric acid, di-Toluoyl tartaric acid and mandelic acid.

11. The process for the preparation of compound of Formula 1a,

Formula 1a

wherein R1 and R2as defined above, which comprises:
i) condensing a compound of Formula 4

Formula 4

with a-amine of Formula 5 or its salts

Formula 5
using titanium isopropoxide, P-TSA, titanium tetrachloride in presence of a base in suitable solvent to give a compound for formula 6,

Formula 6
ii) reducing the compound of formula 6 using a NaBH4 in a suitable solvent to give compound of Formula 3 or its salts,

Formula 3
iii) hydrogenating compound of Formula 3 or its salts using Pd/C in suitable solvent optionally in the presence of acid to obtain compound of Formula 2 or its salts,
iv) reacting compound of Formula 2with a chiral acid optionally in the presence of a base in a suitable solvent to give compound of Formula 1a.

12. The process as claimed in claim 1-6 and 11, wherein the solvents isselected from water, "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane, or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone, or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methylt-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone or "glycol ethyl ethers" such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, Ethylene glycol monobutyl ether , ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol mono-n-butyl ether or "halogenated solvents" such as CCl4, dichloroethane, hexafluoro-2-propanol, trichloroethane, dichloromethane, trichloromethane,diiodomethane, tetrachloroethane, chlorobenzene, tetrabromomethane or mixtures thereof.

13. The process as claimed in claim 1, 3-6 and 11, wherein the base is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or organic bases such as triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine,di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole,1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO).
14. The process as claimed in claim 3, 5, 6 and 11, wherein the reducing agent LiAlH4, NaHg, ZnHg, ZnCl2, MgCl2, diborane, NaBH4, iron sulfate, tin chloride, dithionates, DIBAL-H, phosphonic acid, hypophosphite, phosphite, tetrakis{3,5-trifluoromethyl}phenyl borate and 1,4-Dithio-D-threitol.

15. The process as claimed in 3, 5, 6 and 11, wherein the catalyst is selected from Raney nickel, platinum, Pd/C, rhodium, ruthenium, Dichlorotris(triphenylphosphine) ruthenium(II), RhCl(PPh3)3, phosphonium borate, copper chromite and chromium oxide.

16. The process as claimed in claim 2, 4, 6 and 11, wherein the acids used in hydrogenation is selected from inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, polyphosphoric acid, H2SO4; organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid.
Dated this Twenty-first (21st) day of January 2017.

_________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883 , Description:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)
&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE ALKYL AMINE COMPOUNDS

We, SUVEN LIFE SCIENCES LIMITED,
a company incorporated under the companies act, 1956 having address at Serene Chambers, Road No 5, Avenue 7, Banjara Hills, Hyderabad, Telangana 500034, India

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of optically active alkyl amine compounds of Formula 1,

Formula 1
wherein R1 and R2 are different and individually represent alkyl, aryl group, cycloalkyl; “ * ” denotes a chiral center which encompasses both “R” and “S” isomers or dextro and levo rotary compounds.

BACKGROUND OF THE INVENTION
Alkyl amines are used as intermediates in the preparation of Pharmaceutical and agrochemical active compounds.

Specifically, cycloalkyl alkyl amine compounds are used as intermediates in the preparation of JAK Kinase inhibitor’s such as those disclosed in WO 2009/075830 A1 andJournal of Medicinal Chemistry, 2011, Vol 54, pg 7334-7349.

Process for the preparation of chiral cyclopropylamines is disclosed in Journal of American Chemical Society, 1966, Vol 88, pg 2262-2271, by resolution of racemic amine with optically active tartaric acid in water.

Scheme-I
Process for the preparation of chiral primary amines is disclosed in Journal of Organic Chemistry, 1996, vol.61, pg 4130-4135, which involves stereoselective ring opening of perhydrobenzoxazines by cyclopropylmagnesium bromide at reflux/room temperatures in diethyl ether or benzene at 78°C to (-)-8-(benzylamino)menthol derivative, followed by transformation into the chiral primary amines. The process is shown in the scheme given below:

Scheme-II
Process for the preparation of cyclopropyl ethylamine is disclosed in US 2008/ 0167500 A1 which is shown in the scheme given below:

Scheme-III
Process for the preparation of chiral 1-cyclopropyl-ethanaminium chloride is disclosed in WO 2009/075830 A1and Journal of Medicinal Chemistry, 2011, Vol 54, pg 7334-7349, which involves reaction of cyclopropanecarboxaldehyde with (S)-(-)2-methyl-2-sulfinamide to give tert-butanesulfinylketimine, which is further alkylated with Methyl magnesium bromide to give N-[(1S)-1-cyclopropylethyl]-(S)-2-methylpropane-2-sulfinamide, followed by hydrolysis with hydrochloric acid in methanol/dioxane to yield (1S)-1-cyclopropyl ethanaminiumHCl. The process is shown in the scheme given below:

Scheme-IV
The process disclosed in the prior art references suffers from drawback, especially the use of expensive chemicals like (S) & (R) tert-butanesulfinamides; chiral auxiliaries such as (-)-8-(benzylamino)menthol, which has to be prepared from (+)-pulegone and benzene in two steps.
Further, the process suffers from other drawbacks such as low optical purity and requires multiple recrystallizations for purifying the compound with low yield of about 15%. Therefore the processes are not suitable for commercial scale production.

In view of the commercial importance of alkyl amines, there is a need for developing a commercially feasible process which involves use of inexpensive, environmental friendly reagents which are easily available or prepared from commercially available sources easily. Further, there is a need for a process for the preparation of alkyl amines which yields the compound with high chemical purity and chiral purity with high enantiomeric excess.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a process for the preparation of chiral alkyl amine compounds.

Another objective of the present invention is to provide a process for the preparation of optically active cycloalkyl alkyl amine compounds of Formula 1, which are useful as intermediates in the preparation of JAK inhibitors.

In a more preferred objective of the present invention is to provide an improved process for the preparation of optically active cycloalkyl alkyl amine compounds, which is commercially feasible / industrially scalable.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of compound of Formula 1,

Formula 1
wherein R1and R2are different and individually represent alkyl, aryl group, cycloalkyl; “ * ” denotes a chiral center which encompasses both “R” and “S” isomers or dextro and levo rotary compounds; which comprises reacting an alkyl amine compound of formula 2

Formula 2

with a chiral acidoptionally in the presence of base in a suitable solvent.

Another embodiment of the present invention relates to a process for the preparation of compound of Formula 1,

Formula 1

wherein R1 and R2 are different and individually represent alkyl, aryl group, cycloalkyl; “ * ” denotes a chiral center which encompasses both “R” and “S” isomers or dextro and levo rotary compounds; which comprises:
i) hydrogenating compound of Formula 3 or its salts

Formula 3

whereinR1and R2are as defined above; R3represents substituted or unsubstituted alkyl group, and R4 represents substituted or unsubstituted aryl groups, using a catalyst in suitable solvent optionally in the presence of an acid to obtain compound of Formula 2 or its salts,
ii) reacting alkyl amine compound of formula 2

Formula 2

with a chiral acid in presence of base in suitable solvent to obtain alkyl amine compound of formula 1.

Yet another embodiment of the present invention relates to a process for the preparation of compound of Formula 3 or its salts,

Formula 3

wherein R1, R2, R3 and R4 are as defined above, which comprises:
i) condensinga compound of Formula 4

Formula 4

with a-amine of Formula 5 or its salts

Formula 5

using titanium isopropoxide, P-TSA, titanium tetrachloride in presence of base in a suitable solvent to give a compound of formula 6,

Formula 6

ii) reducing the compound of formula 6using a reducing agent in a suitable solvent to give compound of Formula 3 or its salts.

Still yet another embodiment of the present invention relates to a process for the preparation of compound of Formula 1,

Formula 1

wherein R1 and R2as defined above, which comprises:
i) condensing a compound of Formula 4

Formula 4

with a-amine of Formula 5 or its salts

Formula 5

using titanium isopropoxide, P-TSA, titanium tetrachloride in presence of a base in suitable solvent to give a compound of formula 6,

Formula 6

ii) reducing the compound of formula 6using a reducing agent in a suitable solvent to give compound of Formula 3 or its salts,

Formula 3

iii) hydrogenating compound of Formula 3 or its salts using a catalyst in suitable solvent optionally in the presence of an acid to obtain compound of Formula 2 or its salts,
iv) reacting compound of Formula 2with a chiral acid optionally in the presence of base in a suitable solvent to give compound of Formula 1.

Still another embodiment relates to compound of Formula 1,

Formula 1

wherein R1 and R2 are different and individually represent hydrogen, alkyl, aryl group, cycloalkyl; “ * ” denotes a chiral center which encompasses both “R” and “S” isomers or dextro and levo rotary compounds.

Still another embodiment relates to a process for the preparation of alkyl amines which yields the compound with high chemical purity and chiral purity with high enantiomeric excess.

In still yet another embodiment relates to a process for the preparation of alkyl amines with 95%-100% chiral purity as measured by Gas Chromatography.

In still yet another embodiment relates to a process for the preparation of alkyl amines with 99%-100% chiral purity as measured by Gas Chromatography.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of compound of Formula 1a,

Formula 1a

wherein R1and R2are different and individually represent alkyl, aryl group, cycloalkyl; “ * ” denotes a chiral center which encompasses both “R” and “S” isomers or dextro and levo rotary compounds; which comprises reacting an alkyl amine compound of Formula 2

Formula 2

with mandelic acid, optionally in the presence of base in a suitable solvent.

Another embodiment of the present invention relates to a process for the preparation of compound of Formula 1a,

Formula 1a

wherein R1 and R2 are different and individually represent alkyl, aryl group, cycloalkyl; “ * ” denotes a chiral center which encompasses both “R” and “S” isomers or dextro and levo rotary compounds; which comprises:
i) hydrogenating compound of Formula 3 or its salts

Formula 3
whereinR1and R2are as defined above; R3represents substituted or unsubstituted alkyl group, and R4 represents substituted or unsubstituted aryl groups, using Pd/C in suitable solvent optionally in the presence of an acid to obtain compound of Formula 2 or its salts,
ii) reacting alkyl amine compound of formula 2

Formula 2

with mandelic acid in presence of base in suitable solvent to obtain alkyl amine compound of formula 1a.

Yet another embodiment relates to a process for the preparation of compound of Formula 3 or its salts,

Formula 3

wherein R1, R2, R3 and R4 are as defined above; which comprises:
i) condensing a compound of Formula 4

Formula 4

with a-amine of Formula 5 or its salts

Formula 5

using titanium isopropoxide; P-TSA, titanium tetrachloride in presence of a base in a suitable solvent to give a compound of formula 6,

Formula 6

ii) reducing the compound of formula 6 using a NaBH4 in a suitable solvent to give compound of Formula 3 or its salts.

Still another embodiment of the present invention relates to a process for the preparation of compound of Formula 1a,

Formula 1a

wherein R1 and R2are as defined above; which comprises:
i) condensing a compound of Formula 4

Formula 4

with a-amine of Formula 5 or its salts

Formula 5

using titanium isopropoxide, P-TSA, titanium tetrachloride in presence of a base in suitable solvent to give a compound of formula 6,

Formula 6

ii) reducing the compound of formula 6 using a NaBH4 in a suitable solvent to give compound of Formula 3 or its salts,

Formula 3

iii) hydrogenating compound of Formula 3 or its salts using Pd/C in suitable solvent optionally in the presence of acid to obtain compound of Formula 2 or its salts,
iv) reacting compound of Formula 2with a chiral acid optionally in the presence of base in a suitable solvent to give compound of Formula 1a.

Still another preferred embodiment relates to compound of Formula 1a,

Formula 1a

wherein R1 and R2 are different and individually represent hydrogen, alkyl, aryl group, cycloalkyl; “ * ” denotes a chiral center which encompasses both “R” and “S” isomers or dextro and levo rotary compounds.

Still another preferred embodiment relates to a process for the preparation of alkyl amines which yields the compound with high chemical purity and chiral purity with high enantiomeric excess.

In a preferred embodiment relates to a process for the preparation of alkyl amines with 95%-100% chiral purity as measured by Gas Chromatography.

In a more preferred embodiment relates to a process for the preparation of alkyl amines with 99%-100% chiral purity as measured by Gas Chromatography.

Compound of Formula 2, 4 and 6may be isolated or used in later without isolation. Specifically, the compound of formula 6 shall be carried out in-situ which steps further converted to compound Formula 1a without isolation.

The present invention mainly focuses on the preparation of optically pure cycloalkyl alkyl amine. The preparation and isolation of cycloalkyl alkyl amine compound in the form of mandelic acid yields a compound having less alkyl impurity and with good yield.

Alkyl as used herein is and not limited to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, octyl, isopentyl and t-butyl and substitutions on alkyl are selected from hydroxyl, cyano, halogen such as fluorine, chlorine, bromine and iodine.

Aryl as used herein is and not limited tobenzyl, phenyl, naphthyl, thienyl, indolyl, toluene, xylene and O-xylyl.

Cycloalkyl as used herein is and not limited tocyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclohexylmethane.

Chiral acid represents a-hydroxy acid, camphor sulfonic acid and (R)-(-)-1,1'-Binaphthalene-2,2'-di-yl hydrogen phosphate.

a-hydroxy acids as used herein is and not limited to are lactic acid, malic acid, tartaric acid, Dibenzoyl-D-tartaric acid,di-Toluoyl tartaric acid and mandelic acid.

“Solvent” as defined in the presence invention isselected from water, "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methylt-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone or "glycol ethyl ethers" such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol mono-n-butyl ether or "halogenated solvents" such as CCl4, dichloroethane, hexafluoro-2-propanol, trichloroethane, dichloromethane,trichloromethane, diiodomethane, tetrachloroethane, chlorobenzene, tetrabromomethane and the likeand/or mixtures thereof.

Base as used herein in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or organic bases such as triethylamine, triethanolamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine,di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole,1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

Reducing agent as used herein is and not limited to LiAlH4, NaHg, ZnHg, ZnCl2, MgCl2, diborane, NaBH4, iron sulfate, tin chloride, dithionates, DIBAL-H, phosphonic acid, hypophosphite, phosphite, tetrakis{3,5-trifluoromethyl}phenyl borate and 1,4-Dithio-D-threitol.

The term “salts” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloride salt.

Catalyst as used herein is and not limited to Raney nickel, platinum, Pd/C, rhodium, ruthenium, Dichlorotris(triphenylphosphine)ruthenium(II), RhCl(PPh3)3, phosphonium borate,
copper chromite and chromium oxide.

Acids used in hydrogenation herein is and not limited toinorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, poly phosphoric acid, Conc. H2SO4; organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example-1:
Preparation of (S)-1-cyclopropylethan-1-amine (R)-2-hydroxy-2-phenylacetate
Step-1: Preparation of (S)-(1-cyclopropylethyl)-(1-phenylethyl)amine HCl
To a stirred solution of cyclopropyl methyl ketone (100 g, 1.19 mol) in ethanol (500ml) was added titanium isopropoxide (422.3 g, 1.48 mol), triethylamine (150.4 g, 1.48 mol) and (S)-(-)-a-methylbenzylamine (173.0 g, 1.43 mol) at 15-20°C. The resulting mixture was stirred for 24h at room temperature. Then the solution was cooled to 0-5°C andsodium borohydride (65.2 g, 1.72 mol) was added and the resulting mixture was stirred for 3h at 0-5°C. The reaction was quenched by pouring into aqueous ammonia, resulting inorganic salts filtered off, and washed with ethyl acetate. The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 1N HCl and 2N sodium hydroxide solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give optically active secondary amine crude (225g) as syrup. The crude product in isopropanol (700ml) was added to IPA.HCl (16%, 338.6g) at 0-5°C and stirred for 1h at the same temperature. Then the solid was filtered and washed with a small amount of IPA and dried to obtain 160 g of optically active secondary amine as crystalline solid, which is represented by the following formula.

The diastereomeric excess of the crystals was determined by gas chromatography in a manner that the hydrochloride salt turned into free base with 2N sodium hydroxide solution.
de: 99.72% (by GC).
IR (KBr cm-1): 3432, 2974, 2708, 2478, 2341, 2173, 1968, 1831, 1587, 1455, 1378, 1214, 1079, 955, 939, 766, 707.
1H NMR (400MHz, CDCl3):d 10.24 (brs, 1H), 9.80 (brs, 1H), 7.72 (d, 2H, J=8.0Hz), 7.42 (t, 2H, J=7.5Hz), 7.32 (t, 1H, J=7.3Hz), 4.71 (t, 1H, J=7.7Hz), 2.27 (m, 1H), 1.94 (d, 3H, J=6.8Hz), 1.63 (d, 3H, J=6.7Hz), 1.34 (m, 1H), 0.74 (m, 1H), 0.57 (m, 1H), 0.26 (m, 1H), 0.04 (m, 1H).

Step-2: Preparation of (S)-1-cyclopropylethylamine HCl
(S)-(1-cyclopropylethyl)-(1-phenylethyl)amine HCl (100g) was dissolved in 2N sodium hydroxide solution (500ml), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, followed by concentration and vacuum drying to give 84g of secondary amine free base as syrup.
To the above free base in methanol (630ml), acetic acid (50ml) and 10% Pd/C (16.8 g) were added. The mixture was stirred under hydrogen pressure (5.0 atm) at 50-55°C for 10h. After completion of the reaction, the mixture was cooled to room temperature, filtered to remove the catalyst and washed with methanol. Ethyl acetate HCl (13%, 186g) was added to methanol layer and stirred for 30min, concentrated under reduced pressure to give the crude, which was crystallized from methyl t-butylether and acetone to get cyclopropylamine HCl (42 g) as white to off white crystalline solid, which is represented by the following formula.

The enantiomeric ratio was determined via derivatization with TFAA. Product is analyzed as a trifluoroacetamide after TFAA derivatization.
Chiral purity: 99.0% (by GC).
IR (KBr cm-1): 3393, 3010, 2928, 2009, 1682, 1604, 1504, 1410, 1386, 1307, 1239, 1196, 1113, 1043, 935, 829.
1H NMR (400MHz, DMSO-d6):d 8.08 (brs, 3H), 2.48 (m, 1H), 1.23 (d, 3H, J=6.6Hz), 0.91 (m, 1H), 0.52 (m, 2H), 0.42 (m, 1H) 0.28 (m, 1H).

Step-3: Preparation of (S)-1-cyclopropylethan-1-amine (R)-2-hydroxy-2-phenylacetate
To a stirred solution of cyclopropyl ethylamine HCl (25g) in ethanol (375 ml) was added 50% sodium hydroxide solution (10.9 ml) and water (16.5ml). The resulting slurry was stirred for 1h at 20-25°C.Filter the mixture through celite to remove sodium chloride and wash the celite with a small amount of ethanol.
To the above free base in ethanol was added R(-)-Mandelic acid (31.25g) at room temperature. The resulting mixture was distilled under vacuum to 4vol ethanol. Methyl t-butyl ether (300ml) was added to the reaction mixture at 55-60°C, and stirred for 3h. Cooled the reaction mass temperature to 10-15°C, and maintained for 3h, filtered the solid, washed with methyl t-butyl ether and ethanol and dried to obtain 41g of optically active (S)-1-cyclopropylethan-1-amine(R)-2-hydroxy-2-phenylacetate, represented by the following formula.

The enantiomeric ratio was determined via derivatization with TFAA.
Chiral purity: 100% (by GC).
IR (KBr cm-1): 3419, 2995, 2138, 1636, 1573, 1340, 1198, 1084, 1055, 931, 749, 701, 531
1H NMR (400MHz, DMSO-d6):d 7.36 (d, 2H, J=7.4 Hz), 7.22 (t, 2H, J=7.5Hz), 7.13 (t, 1H, J=7.2Hz), 4.47 (s, 1H), 2.42 (m, 1H), 1.19 (d, 3H, J=6.6Hz), 0.87 (m, 1H), 0.47 (m, 2H), 0.33 (m, 1H), 0.23 (m, 1H).
13C NMR (400MHz, DMSO-d6): d 175.607, 144.146, 127.806, 126.750, 126.535, 74.081, 51.882, 18.781, 15.560, 4.328, 3.284.

Example-2:
Preparation of (R)-1-cyclopropylethan-1-amine (R)-2-hydroxy-2-phenylacetate
Step-1:Preparation of (R)-(1-cyclopropylethyl)-(1-phenylethyl)amine HCl
To a stirred solution of cyclopropyl methyl ketone (100 g, 1.19 mol) in ethanol (500ml) was added titanium isopropoxide (422.3 g, 1.48 mol), triethylamine (150.4 g, 1.48 mol) and (R)-a-methylbenzylamine (173.0 g, 1.43 mol) at 15-20°C. The resulting mixture was stirred for 24h at room temperature. Then the solution was cooled to 0-5°C andsodium borohydride (65.2 g, 1.72 mol) was added and the resulting mixture was stirred for 3h at 0-5°C. The reaction was quenched by pouring into aqueous ammonia, resulting inorganic salts filtered off, and washed with ethyl acetate. The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 1N HCl and 2N sodium hydroxide solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give optically active secondary amine crude (225g) as syrup. The crude product in isopropanol (700ml) was added to IPA.HCl (16%, 338.6g) at 0-5°C and stirred for 1h at the same temperature. Then the solid was filtered and washed with a small amount of IPA and dried to obtain 160 g of optically active secondary amine as crystalline solid, which is represented by the following formula.

The diastereomeric excess of the crystals was determined by gas chromatography in a manner that the salt turned into free base with 2N sodium hydroxide solution.
de: 97.7% (by GC).

Step-2: Preparation of (R)-1-cyclopropylethylamine HCl
(R)-(1-cyclopropylethyl)-(1-phenylethyl)amine HCl (100g) was dissolved in 2N sodium hydroxide solution (500ml), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, followed by concentration and vacuum drying to give 84g of secondary amine free base as syrup.
To the above free base in methanol (630ml), acetic acid (50ml) and 10% Pd/C (16.8 g) were added. The mixture was stirred under hydrogen pressure (5.0 atm) at 50-55°C for 10h. After completion of the reaction, the mixture was cooled to room temperature, filtered to remove the catalyst and washed with methanol. Ethyl acetate HCl (13%, 186g) was added to methanol layer and stirred for 30min, concentrated under reduced pressure to give the crude, which was crystallized from methyl t-butylether and acetone to get cyclopropylamine HCl (42 g) as white to off white crystalline solid, which is represented by the following formula.

The enantiomeric ratio was determined via derivatization with TFAA.
Chiral purity: 99.0% (by GC).

Step-3: (R)-1-cyclopropylethan-1-amine (R)-2-hydroxy-2-phenylacetate
To a stirred solution of cyclopropyl ethylamine HCl (25g) in ethanol (375 ml) was added 50% sodium hydroxide solution (10.9 ml) and water (16.5ml). The resulting slurry was stirred for 1h at 20-25°C.Filter the mixture through celite to remove sodium chloride and wash the celite with a small amount of ethanol.
To the above free base in ethanol was added R(-)-Mandelic acid (31.25g) at room temperature. The resulting mixture was distilled under vacuum to 4vol ethanol. Methyl t-butyl ether (300ml) was added to the reaction mixture at 55-60°C, and stirred for 3h. Cooled the reaction mass temperature to 10-15°C, and maintained for 3h, filtered the solid, washed with methyl t-butyl ether and ethanol and dried to obtain 41g of optically active (R)-1-cyclopropylethan-1-amine (R)-2-hydroxy-2-phenylacetate, represented by the following formula.

The enantiomeric ratio was determined via derivatization with TFAA.
Chiral purity: 100% (by GC).