FORM 2
THE PATENT ACT 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
Novel process for reductive animation of prochiral ketones
APPLICANT
(a) Name: Embio Limited
(b) Nationality: Indian
(c) Address: #501, Sentinel, Central Avenue Road,
Hiranandani Gardens,
Powai, Mumbai- 400 076, India

FIELD OF THE INVENTION
[0001] The present invention relates to a novel process of reductive amination
of prochiral ketones to optically active secondary amines. The process is particularly useful where the substrate ketones are themselves chiral and liable to undergo racemization during conventional processes of reductive amination.
BACKGROUND OF THE INVENTION
[0002] Reductive amination (also known as reductive alkylation) is a form of
amination that involves the conversion of a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. The amines, thus obtained are very useful in industry that are found to have a widespread applications such as intermediates for pharmaceuticals, dyes, resins, fine chemicals, solvents, textile additives, disinfectants, rubber stabilizers, corrosion inhibitors, and in the manufacture of detergents and plastics.
[0003] Reductive amination is one of the most versatile methods for the
preparation of amines in chemical and biological system. Typically, reductive amination of ketones is depicted by a general reaction as shown below:

[0004] The amine used can be primary or secondary amine, in which case, the
product could be secondary or tertiary amine respectively. The source of chirality could come from the substrate ketone or the reactant, primary or secondary amine. The reducing agent used in the process of reductive amination could be metal hydrides, formic acid or formate salts of metals or amines, elemental hydrogen, silicon hydrides etc. The induction of chirality in the product could also come from either chirally modified reducing agent or a separate chiral catalyst.

[0005] Reductive animation process may also be used to prepare Ephedrine and
norephedrine by using L-phenylacetylcarbinol as a chiral substrate ketone. Many methods of making L-norephedrine compound are known, such as, European Patent EP1735266 (Bl) which provides a process for preparation of L-erythro-2-amino-l-phenyl-1-propanol from the corresponding oxime of 1-1-phenyl-l-hydroxy-2-propanol using nickel aluminium catalyst alloy as a reducing agent (Scheme 1). The product resulted by the process is substantially free from optical antipodes and diasteromeric impurities.

[0006] Although the chemistry of the process is very efficient, there have been
some concerns especially about safety and environment impact of the process as the effluent from the reduction process contains huge quantities of aluminium in salt form. Moreover, the reduction process is highly exothermic and is sometimes uncontrollable.
[0007] Another Patent Application (JP 2003-252837) discloses a method to
convert a -hydroxyketones of general formula I to corresponding a -aminoalcohols of formula II (A) as shown in Scheme II below. The preparation of optically active erythro-a-aminoalcohols, starting from the corresponding substituted L-phenylacetylcarbinol of formula I (R1 -C1-10 alkyl, phenyl, furyl, thiophenyl, substituted phenyl) with primary amine R3NH2 (R3 = H, C1-10 alkyl, C1-10 phenyl alkyl, naphthyl, (subst) phenyl C1-10 alkyl) using palladium catalysts. However, both the optical purity (50-55% ee) and diasteromeric purity (50-55% ee) of a-aminoalcohols failed to achieve the similar result when an unsubstituted L-phenylacetylcarbinol is

used. Moreover, to obtain pure L-norephedrine [erythro-(-)-norephedrine], extensive purification by the way of crystallization and salt formation is required which in turn reduces the yield to commercially unviable levels.
Scheme II

[0008] Another patent Application elaborates a process wherein L-
phenylacetylcarbinol is reductively aminated by catalytic hydrogenation using benzylamine using either platinum or palladium catalysts EP1142864 (Al) (Scheme III). In the former case, the product is N-benzyl-1-norephedrine and in the latter case, the product is l-norephedrine. It further discloses a process to convert the intermediate N-benzyl-1-norephedrine to l-norephedrine by hydrogenation. The said process could either be carried out in two stages or else could be done in a single stage. When the process is carried out in two stages, i.e. first with Pt catalyst and then with Pd catalyst, excellent optical purity and diastereomeric purity is obtained. [erythro:threo ratio 92:8; optical purity 97% ee]. Whereas, when the same process is repeated as a one-stage process with Pd catalyst, the optical purity suffers (85% ee). While the former two-stage process is attractive from the point of view of optical and diastereomeric purity, it involves two different noble metal catalysts which inherently increases the cost of operation and requirement of two different metal recovery streams which makes the process lengthy and costly. Scheme III


[0009] US Patent Application Number US20040249212 Al, involves a
preliminary step of acyolin condensation between an aldehyde and a ketone mediated by yeast in presence of supercritical fluid, resulting in an 2-hydroxy ketone derivative as depicted in Scheme IV. The resultant hydroxy ketone is further treated with an amine for reductive animation process using yeast and palladium or platinum catalyst in presence of a supercritical fluid or liquefied gas resulting in an amine of formula III. It also reports a process for imine intermediate formation. However, the process involved is lengthy as temperature and pressure required for the reaction completely depends upon the choice of supercritical fluid or liquefied gas. Also ammonia or nitrogen based supercritical fluid or liquefied ammonia needs to be avoided as it may interfere with imine formation or reductive amination. Thus, process reported seems to be lengthy thereby less cost effective due to racemization and finally may be inconvenient for large scale developments.
Scheme IV

R2 = Optionally substituted C1- C6 Alkyl;
R4 = H, OH, Optionally substituted C1- C6 Alkyl or optionally substituted
C1- C6 Alkyoxy; R5 = Optionally Substituted aryl, Optionally aryl alkyl, Optionally Substituted alkyl R6 = Optionally substituted C1- C6 Alkyl
[0010] Another European Patent Application Number EP2055379 (Al)
discloses a catalytic hydrogenation process for the preparation of optically active L-

norephedrine which is substantially free from its optical antipodes and diastereomeric impurities (Scheme V). L-phenylacetylcarbinol oxime is catalytically hydrogenated using novel catalyst comprising of finely divided nickel metal with a group IIIA metal of the periodic table such as Aluminium as an activator and group VIB or VIII of the periodic table such as iron or chromium resulting in L-norephedrine. The process gives an excellent conversion of L-phenylacetylcarbinol oxime to L-norephedrine with excellent diasteremoeric and enantiomeric purity of L-norephedrine. However, the method is best suitable for oxime of L-phenylacetylcarbinol and not for L-phenylacetylcarbinol and also the usage of three metals and the overall process is time consuming and not cost effective.
Scheme V

[0011] Thus, there is a significant need for a more efficient, cost-effective
process for reductive amination of prochiral ketones to optically active secondary amines, illustratively, reductive amination of L-Phenylacetylcarbinol to give optically active L-norephedrine such that the process gives high diastereoselecrivity and enantioselectivity. Moreover the said product should exhibit high diastereomeric purity (not less than 99.5 % erythro isomer) and also has a high optical purity (not less than 99 % ee of erythro isomer).
SUMMARY OF THE INVENTION
[00012] The object of the present invention is to provide a novel process for
reductive amination of prochiral ketones to optically active secondary amines wherein the prochiral ketone such as L-phenylacetylcarbinol is used to obtain a secondary amine, L-Norephedrine having high diastereoselectivity and optical purity.

[0013] Another aspect of the present invention is to avoid racemization during
reductive amination of L-phenylacetylcarbinol with benzylamine.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention provides an efficient process for reductive
amination of L-phenylacetylcarbinol to produce L-norephedrine with high diastereomeric and enantiomeric purity.
[0015] L-phenylacetylcarbinol, being an a-hydroxy ketone, is liable to undergo
racemization through keto-enol tautomerization under basic conditions as depicted in Scheme VI. Scheme VI

[0016] If the imine formed from L-phenylacetylcarbinol and benzylamine does
not undergo reduction as soon as it is formed, then it is liable to undergo imine-enamine tautomerization. The enamine tautomer would be a non-chiral molecule and would lead to other side reactions as shown below Scheme VII:

Scheme VII

[0017] Use of benzylamine as a reactant in reductive amination, makes the
reaction medium strongly basic when mixed with L-phenylacetylcarbinol. Thus it is essential to preserve the optical purity of the starting material, L-phenylacetylcarbinol. This is achieved by rapidly increasing the rate of reaction of L-phenylacetylcarbinol reaction with benzylamine such that it is not exposed to the basic conditions for an appreciable time. Secondly, it was also realized that the rate of reduction of the inline intermediate needs to be very high such that it is not allowed to equilibrate with the optically inactive enamine intermediate.
[0018] Therefore, it was envisaged that benzylamine may not be a preferred
substrate as amine donor due to its high basicity. However, if benzylamine could be generated in-situ under reductive conditions (as in catalytic hydrogenation) such that L-phenylacetyl carbinol can be avoided from exposure to the basic condition. Moreover, the benzylamine still could be used if the catalytic system was so active that very high rates of hydrogenation of the imine intermediate could be achieved.

[0019] The present invention employed following measures:
1. By using substrate compounds of the general formula R-CH(R')N02 wherein R is phenyl, (subst) phenyl, naphthyl, and R' is C1- C8 alkyl or -COOR1, (where R1 is C1- C8 alkyl).
2. By using substrate compound of the general formula R-CH(R')NH2 wherein R is phenyl, subst phenyl, naphthyl, and R' is C1- C8 alkyl or -COOR1, (where R1 is C1- C8 alkyl).
3. Use of highly efficient catalytic system comprising noble metals such as palladium and platinum catalysts supported on carbon used either individually or in combination.
[0020] The preferred process according to the present invention is illustrated
below (Scheme VIII)
Scheme VIII

[0021] According to one embodiment of the present invention, L-
phenylacetylcarbinol is hydrogenated with a compound of the general formula R-CH(R') N02 (R-CH(R')N02 wherein R is phenyl, (subst) phenyl, naphthyl, and R' is C1- C8 alkyl or -COOR1, (where R1 is C1- C8 alkyl). in the presence of catalyst containing a

mixture of palladium and platinum metals supported on activated carbon. Further, product obtained 1-norephedrine is isolated by evaporation of solvent and purified by salt formation. The yield of isolated L-norephedrine HC1 is 85% of theory. Diasteromeric purity: erythro isomer: > 99.5%, threo isomer < 0.5 %; enantiomeric purity: l-norephedrine: > 99.6%, d-norephedrine: < 0.4 %.
[0022] The solvents used for this reaction includes toluene, benzene and C1- C3
aliphatic alcohols or a mixture of any two of them. The catalyst composition is of particular importance to achieve very high rates of hydrogen absorption. Content of platinum on carbon is between 0.2 and 4.0% by weight. The content of palladium on carbon is between 1.0 and 15.0%. The temperature of reaction is between ambient and 100°C. The pressure of hydrogen employed is between atmospheric and 20 kg/cm2.
[0023] In yet another embodiment of the present invention, the solvent used is toluene or methanol or a mixture thereof, the content of platinum on carbon is between 1.0 and 3.0% by weight, the content of palladium on carbon is between 3.0 and 7.0%), the temperature of reaction is between 45 and 65°C and the pressure of hydrogen employed is between 4.0 and 6.0 kg/cm . The isolation of product is done by treatment with an organic acid as detailed in EP 1735266 (incorporated herein by reference in its entirety).
[0024] According to another mode of operation of the present invention, L-
phenylacetylcarbinol can be converted to L-norephedrine by following procedure same as above, but replacing the compound of the general formula R-CH(R')N02 by a compound of the general formula R-CH(R')NH2, wherein R is phenyl, (subst) phenyl, naphthyl, and R' is C1-8 alkyl or-COOR1, (where R1 is C1-8 alkyl).
[0025] According to yet another mode of operation of the invention, the
conversion of L-phenylacetylcarbinol may be stopped at erythro-N-(a-
alkyl)arylmethyl-l-norephedrine stage by utilizing procedure same as above but
replacing the catalyst containing palladium and platinum metals by a catalyst

containing platinum alone. Thus, L-phenylacetylcarbinol is hydrogenated with a compound of the general formula R-CH(R')NH2, wherein R is phenyl, (subst) phenyl, naphthyl, and R' is C1-8 alkyl or -COOR1, (where R1 is C1-8 alkyl) in the presence of catalyst containing platinum supported on activated carbon. The product is isolated by evaporation of solvent and formation of a hydrochloride salt by treatment with hydrogen chloride. Here, the isolated product is erythro-N-(a-alkyl)arylmethyH-norephedrine. The yield of erythro-N-(a-alkyl)arylmethyl-l-norephedrine is almost quantitative. Diastereomeric purity: erythro isomer: > 90 %, threo isomer < 10 %. The crude product, if desired in pure form, may be purified through salt formation. However, for the purpose of conversion to L-norephedrine, crude product may be directly taken to a further step of conversion.
[0026] In yet another mode of the present invention, the hydrogenative reaction
between L-phenylacetylcarbinol and a compound of the general formula R-CH(R')NH2 may be catalyzed by Lewis acid catalysts such as titanium tetraisopropoxide.
[0027] The solvents used for the above-mentioned reaction includes toluene,
benzene and C1-3 aliphatic alcohols or a mixture of any two of them. The catalyst composition is of particular importance to achieve very high rates of hydrogen absorption. Content of platinum on carbon is between 0.2 and 4.0% by weight. The temperature of reaction is between ambient and 80°C. The pressure of hydrogen employed is between atmospheric and 20 kg/cm2.
[0028] In one of the preferred embodiments of the invention, the solvent used is
toluene or methanol or a mixture thereof, the content of platinum on carbon is between 1.0 and 3.0% by weight, the temperature of reaction is between 45 and 65°C, the pressure of hydrogen employed is between 4.0 and 6.0 kg/cm2.
[0029] The product, erythro-N-(a-alkyl)arylmethyl-l-norephedrine is converted
to l-norephedrine by another hydrogenation reaction. The erythro-N-(a-

alkyl)arylmethyl-l-norephedrine is hydrogenated in the presence of a catalyst containing palladium supported on activated carbon. The product 1-norephedrine is isolated by evaporation of solvent and purified by salt formation by treatment with an organic acid as detailed in EP 1735266. The isolated yield of L-norephedrine HC1 (starting from L-phenylacetylcarbinol) is 85 % of theory. Diastereomeric purity: erythro isomer: > 99.5 %; threo isomer < 0.5 %; enantiomeric purity: L-norephedrine: > 99.6%, d-norephedrine: < 0.4 %. The solvents used for the reaction include toluene, benzene and C1-3 aliphatic alcohols or a combination thereof. Content of palladium on carbon is between 1.0 and 15.0% by weight. The temperature of reaction is between ambient and 80°C. The pressure of hydrogen employed is between atmospheric and 20 kg/cm2.
[0030] In another preferred embodiment of the present invention, the solvent
used is toluene or methanol or a mixture thereof, the content of palladium on carbon is between 3.0 and 7.0% by weight, the temperature of reaction is between 45 and 65°C, the pressure of hydrogen employed is between 4.0 and 6.0 kg/cm .
[0031 ] In accordance with yet another aspect of the invention, the reductive
amination and removal of arylmethyl group are achieved in a single operation without the need for isolation of the intermediate erythro-N-arylmethyl-1-norephedrine compound wherein the L-phenylacetylcarbinol is hydrogenated with a compound of the general formula R-CH(R')NH2 (wherein R is phenyl, (subst) phenyl, naphthyl, and R' is C1-8 alkyl or -COOR1, (where R1 is C1-8 alkyl) in the presence of catalyst containing palladium supported on activated carbon containing nano-sized particles. The method of operation is exactly similar to the first mode of operation.
[0032] The solvents used for this reaction includes toluene, benzene and C1-3
aliphatic alcohols or a combination thereof. Content of palladium on carbon is between 5.0 and 17.0 % by weight. The temperature of reaction is between ambient and 80°C. The pressure of hydrogen employed is between atmospheric and 20 kg/cm .

[0033] In another preferred embodiment of the invention, the solvent used is
toluene or methanol or a combination thereof. The content of palladium on carbon is between 11.0 and 15.0% by weight. The temperature of reaction is between 45 and 65°C, the pressure of hydrogen employed is between 4.0 and 6.0 kg/cm .
[0034] Further advantage of the present invention is that the catalysts i.e. Pd-Pt
mixtures on carbon, Pd on carbon or Pd on nano carbon can be recycled after careful washing of the catalyst after filtration of the reaction mass with the solvent of reaction followed by a wash with acetic acid. The catalysts were found to have same activity upto 10th recycle. Thus this makes the process highly economical in terms of the catalyst cost.
[0035] Further, the diastereomeric purity was ascertained by HPLC analysis
using the following methods:
1. For analysis at N-arylmethyl-norephedrine stage:
i. Column: Phenyl S5P 250 X 4.6 mm, 5 \x.
ii. Detection: 210 nm
hi. Flow rate: 1 ml/min
iv. Injection volume: 20 u, L
v. Run temp: 60 min.
vi. Column temp.: 30°C
vii. Mobile phase:
A. Solution A: 16 ml of 25% aq. solution of tetramethylammonium hydroxide + 5 ml orthophosphoric acid + 500 ml water, make up to 1000 ml with water

B. Mobile phase: 40 ml methanol + 4 ml THF, make up to 1000 ml with solution A.
viii. Sample solution: 50 mg sample dissolved in 100 ml mobile phase.
[0036] 2. For analysis at norephedrine stage:
i. Column: CI8, 250 X 4.6 mm, 5 \i
ii. Detection: 210 nm
iii. Flow rate: 1 ml/min
iv. Injection volume: 20 u L
v. Run temp: 60 min.
vi. Column temp.: 30°C
vii. Mobile phase:
A. Solution A: 16 ml of 25% aq. solution of tetramethylammonium
hydroxide + 5 ml orthophosphoric acid + 500 ml Water, make up to
1000 ml with water
B. Mobile phase: 40 ml methanol + 4 ml THF, make up to 1000 ml with
solution A.
viii. Sample solution: 25 mg sample dissolved in 100 ml mobile phase.
3. The enantiomeric purity was ascertained by HPLC analysis using the following method:
i. Column: Chiralpak AD-H 250 X 4.6 mm, 5 u.
ii. Detection: 210 nm
iii. Flow rate: 0.5 ml/min
iv. Injection volume: 20 u L

v. Run time: 30 min.
vi. Column temp.: ambient
vii. Mobile phase: 150 ml ethanol + 1 ml methanesulphonic acid make up volume to 1000 ml with n-hexane.
EXAMPLES
[0037] The details of the invention, its objects, and its advantages are explained
hereunder in great detail. The examples given below are merely illustrative and do not limit the scope of this invention and it would be obvious that any modifications or changes in the steps by those skilled in the art without departing from the scope of the invention shall be consequently encompassed within the ambit and spirit of this approach and scope thereof.
EXAMPLE 1: Preparation of L-norephedrine by hydrogenation of L-phenylacetyl carbinol with phenylnitromethane
[0038] 20 g (133 mmol) of L-phenylacetylcarbinol (as a 30% solution in
methanol) was charged to a 1 L SS autoclave. 22 g (160 mmol; 1.2 eq) of phenylnitromethane was charged to it followed by 2 g (dry basis; 50% water wet) of a carbon catalyst containing 2% Pt and 5 % Pd metal was added as a slurry in water at ambient temperature. The autoclave was evacuated and then filled with hydrogen to 2 kg/cm2. The cycle of evacuation and filling with hydrogen was repeated two times. Finally the autoclave was pressurized to 6 kg/cm with hydrogen. The temperature rapidly rises to 40-45°C. It is maintained at this level and hydrogen pressure maintained between 5 and 6 kg/cm2 until tendency to drop the pressure ceases." After this phase, the autoclave is heated to raise the temperature to 75-80°C. The hydrogen pressure maintained between 5 and 6 kg/cm until tendency to drop the pressure ceases. The autoclave is cooled to room temperature and vented. The reaction mass is filtered and the catalyst is washed with 50 ml methanol. The filtrate is concentrated in vacuum to give crude L-norephedrine base. Yield: 17 g; purity: assay: 75 % w/w (titrimetric); diastereomeric purity: erythro:threo::88.3:11.7

EXAMPLE 2: Preparation of L-norephedrine by hydrogenation of L-phenylacetyl carbinol with benzylamine: (Using catalytic system: 2% Pt and 5 % Pd)
[0039] 20 g (133 mmol) of L-phenylacetylcarbinoI (as a 30% solution in
methanol) was charged to a 1 L SS autoclave. 15 g (140 mmol; 1.05 eq) of benzylamine was charged to it followed by 2 g (dry basis; 50% water wet) of a catalyst containing 2% Pt and 5 % Pd metal on carbon and another 2 g (dry basis; 50% water wet) of a catalyst containing 10% palladium on carbon was added as slurry in water at ambient temperature. The autoclave was evacuated and then filled with hydrogen to 2 kg/cm . The cycle of evacuation and filling with hydrogen was repeated two times. Finally the autoclave was pressurized to 6 kg/cm with hydrogen. The temperature rapidly rises to 40-45°C. It is maintained at this level and hydrogen pressure maintained between 5 and 6 kg/cm until tendency to drop the pressure ceases. After this phase, the autoclave is heated to raise the temperature to 75-80°C. The hydrogen pressure maintained between 5 and 6 kg/cm until tendency to drop the pressure ceases. The autoclave is cooled to room temperature and vented. The reaction mass is filtered and the catalyst is washed with 50 ml methanol. The filtrate is concentrated in vacuum to give crude L-norephedrine base. Yield: 18 g; purity: assay: 88 % w/w (titrimetric); diastereomeric purity: erythro:threo::94:6
EXAMPLE 3: Preparation of L-N-benzyl-norephedrine by hydrogenation of L-phenylacetyl carbinol with benzylamine: (Using catalytic system: 2% Pt and 5 % Pd)
[0040] 20 g (133 mmol) of L-phenylacetylcarbinol (as a 30% solution in
methanol) was charged to a 1 L SS autoclave. 15.7 g (146.5 mmol; 1.1 eq) of benzylamine was charged to it followed by 2 g (dry basis; 50%) water wet) of a carbon catalyst containing 2% Pt and 5 % Pd metal was added as a slurry in water at ambient temperature. The autoclave was evacuated and then filled with hydrogen to 2 kg/cm . The cycle of evacuation and filling with hydrogen was repeated two times. Finally the autoclave was pressurized to 6 kg/cm2 with hydrogen. The temperature rapidly rises to 40-45°C. It is maintained at this level and hydrogen pressure maintained between 5

and 6 kg/cm2 until tendency to drop the pressure ceases. The autoclave is cooled to room temperature and vented. The reaction mass is filtered and the catalyst is washed with 50 ml methanol. The filtrate is concentrated in vacuum to give crude L-N-benzyl-norephedrine base. Yield: 29 g; purity: assay: 93 % w/w (titrimetric); diastereomeric purity: erythro: threo::92.3:7.7
EXAMPLE 4: Preparation of L-norephedrine from L-N-benzyl-norephedrim
[0041] 25 g of the product of example 2 is dissolved in 200 mL methanol and
charged to a 1 L SS autoclave. 2.5 g (dry basis; 50 % water wet) of 10% Pd-C catalyst is added as water slurry. The autoclave was evacuated and then filled with hydrogen to 2 kg/cm2. The cycle of evacuation and filling with hydrogen was repeated two times. Finally the autoclave was pressurized to 6 kg/cm2 with hydrogen. The autoclave is heated to raise the temperature to 75-80°C. It is maintained at this level and hydrogen pressure maintained between 5 and 6 kg/cm2 until tendency to drop the pressure ceases. The autoclave is cooled to room temperature and vented. The reaction mass is filtered and the catalyst is washed with 50 ml methanol. The filtrate is concentrated in vacuum to give crude L-norephedrine base. Yield: 14 g; purity: assay: 95 % w/w (titrimetric); diastereomeric purity: erythro: threo:: 91.1:8.9
EXAMPLE 5: Preparation of L-norephedrine by hydrogenation of L-phenylacetylcarbinol with benzylamine (Pd catalyst)
[0042] 25 g of the product of example 2 is dissolved in 200 mL methanol and
charged to a 1 L SS autoclave. 1 g (dry basis; 50 % water wet) of 10% Pd-C catalyst is added as water slurry. The autoclave was evacuated and then filled with hydrogen to 2 kg/cm2. The cycle of evacuation and filling with hydrogen was repeated two times. Finally the autoclave was pressurized to 6 kg/cm2 with hydrogen. The autoclave is heated to raise the temperature to 75-80°C. It is maintained at this level and hydrogen pressure maintained between 5 and 6 kg/cm2 until tendency to drop the pressure ceases. The autoclave is cooled to room temperature and vented. The reaction mass is

filtered and the catalyst is washed with 50 ml methanol. The filtrate is concentrated in vacuum to give crude L-norephedrine base. Yield: 14 g; purity: assay: 95 % w/w (titrimetric); diastereomeric purity: erythro: threo:: 91.1:8.9

CLAIMS
We Claim,
1. A process for reductive animation of L-phenylacetylcarbinol of formula I with arylnitrometane of the general formula R-CH(R')N02 or an arylmethylamine of general formula R-CH2(R')NH2 wherein R = Phenyl, (subst) phenyl, naphfnyl and R' is CI-8 alkyl or COOR', (where Rl is CI-8 alkyl) with hydrogen and reduction is conducted in the presence of noble catalysts supported on carbon used either alone or in combination to produce L-norephedrine of formula II. Formula I

and Formula II

2. The process as mentioned in claim 1, wherein the product L-norephedrine results in high diasteromeric and enatiomeric purity.
3. The process as mentioned in claim 1, wherein the arylnitromethane used is phenylnitromethane.
4. The process as mentioned in claim 1, wherein the arylmethylamine used is benzylamine.
5. The process as mentioned in claim 1, wherein the noble catalyst used is a combination of palladium and platinum metals supported on carbon with the

palladium content on carbon is between 1 and 15% and that of platinum on carbon is between 0.2 and 4%.
6. The process as mentioned in claim 1 wherein the catalyst used is palladium metal supported on nano-carbon further wherein the palladium content on carbon is between 1 and 15 %
7. The process as mentioned in claim 1, wherein the hydrogen pressure used is between atmospheric and 20kg/cm .
8. The process as mentioned in claim 1, wherein the solvent used for the process is selected from the group consisting of toluene, benzene, lower aliphatic alcohol or a combination thereof.
9. The process as mentioned in claim 1, wherein the temperature of the process is ambient and 100°C.
10. The process as mentioned in claim 1, wherein the temperature of the process is ambient and 45°C.