WO2020129087A1

WO2020129087A1 - NOVEL PROCESS FOR THE PREPARATION OF R-PHENYLACETYLCARBINOL AND β-AMINOALCOHOLS

Info

Publication number: WO2020129087A1
Application number: PCT/IN2019/050935
Authority: WO
Inventors: Gopalkrishnan V.N.; Shreya S.; Saravanan R.; Perumal S.; Balamurugan K.
Original assignee: Malladi Drugs and Pharmaceuticals Ltd
Current assignee: Malladi Drugs and Pharmaceuticals Ltd
Priority date: 2018-12-22
Filing date: 2019-12-19
Publication date: 2020-06-25
Anticipated expiration: 2021-06-22
Also published as: DE112019006382T8; DE112019006382T5; CN113784945A

Abstract

Disclosed herein is a process for the manufacture of (R)-phenylacetylcarbinol ((R)-PAC), (1R,2S). Ephedrine and its salts, (1R,2S)-norephedrine and its salts and 1-(Phenyl/Substituted phenyl)-2-(amino/alkylamino/dialklyamino) propan-1-ol and its salts, by enzymatic reduction of α-isonitrosopropiophenone (INP) and substituted α-isonitrosopropiophenone (substituted INP). The β-amino alcohols, produced by the process of present invention gives their corresponding diastereomers on Walden inversion. The present preparation process of (R)-PAC with (R)-PAC oxime as an intermediate has the advantage, that propiophenone as a key raw material which is easily available and has a low-price, operationally simple with high yield and a single process leading to the synthesis of several 1,2-aminoalcohol/ β- aminoalcohols active pharmaceutical ingredients. The design approach of the process is to reduce environmental impact of the product by comparing to the present manufacturing process.

Description

Novel process for the preparation of R-Phenylacetylcarbinol and b-aminoalcohols

FIELD OF THE INVENTION:

The present invention generally relates to phenylacetylcarbinol synthesis and more particularly, it relates to a novel process for the preparation of (R)-phenylacetylcarbinoland (R)- 1 -hydroxy- 1- phenylpropan-2-one oxime, an intermediate b-amino alcohol more specifically for ephedrine, norephedrine & other drug substances.

BACKGROUND:

(R)-phenylacetylcarbinol (hereinafter referred to as (R)-VhC) is a typical precursor for the chemical synthesis of (lR,2S)-l-ephedrine, (lS,2S)-d-pseudoephedrine, (lR,2S)-l-norephedrine, (15,25)-d-norpseudoephedrine and other b-amino alcohols. Pseudoephedrine and ephedrine are the two major pharmaceutical ingredients which are useful for treating nasal congestion. They are found as ingredients in many cough and cold suppressant drug product preparations, sinus medications, nasal syrups, allergy and antipyretic medications.

Norephedrine, also known as phenylpropanolamine (PPA), is often used as decongestant and appetite suppressant. It is used as an intermediate in the preparation of potent central nervous system(CNS) stimulant like amphetamine, besides used as a starting material for several chemical synthesis.

Commercially, the optically active b-aminoalcohols including 1-ephedrine are manufactured by chemical conversion of (R)-phenylacetylcarbinol. For example, IN249376 discloses a process of preparation of several b-aminoalcohols using (R)-PAC which is produced from fermentation process.

Generally, (R)-PAC is produced by fermentation process, in which benzaldehyde is converted to (R)-PAC. For example, in US7074966, (R)-phenylacetylcarbinol is produced by an enzymatic process in which benzaldehyde is reacted with pyruvate decarboxylase (PDC) in a liquid bi-phasic- system (scheme 1).

Benzaldehyde (R)-Phenylacetyl carbinol

Scheme 1

On the other hand, (R)-PAC or its derivatives prepared via other routes are also known in existing art. For example, CN106543013and JPH054948 relate to a process for the preparation of norephedrine and norpseudoephedrine from isonitrosopropiophenone, with (R)- 1 -hydroxy- 1- phenylpropan-2-one oxime (hereinafter referred to as (R)-PAC oxime) as an intermediate. CN 106543013 discloses the biotransformation of isonitrosopropiophenone to produce (R)-PAC oxime. In this, optical purity of (R)-PAC oxime is not revealed. The obtained (R)-PAC is used in the preparation of norephedrine and norpseudoephedrine as a diastereomeric mixture (scheme 2).

.

Scheme 2

JPH054948 discloses the synthesis of (Zv’)-PAC oxime by hydrogenation of ketoxime in the presence of Rhodium complex with optically active ferrocene as chiral catalyst (scheme 3). The disadvantage of the process is handling the expensive rhodium complexes and also selectivity during the hydrogenation.

(£)-2-(hydroxyimino)-1- (£)-1 -hydroxy-1 -phenylpropan-2-one oxime 2-amino-1 -phenylpropan-1 -ol phenylpropan-1 -one C_QH^ NO-, C₉H₁₃NO

CgHgN0₂ Mol Wt: 165.19 Mol Wt: 151.21 Mol Wt: 163.17

Scheme 3

However, none of the existing prior art discloses an efficient chemical synthesis of ( R )- phenylacetylcarbinol using propiophenone as a starting material, involving (Zv’)-PAC oximeas an intermediate.

Thus, the present invention aims to provide simple, cost-effective, green chemistry method to produce! /?)-PACand ( ?)-PAC oxime in a single process having increased productivity and lower energy consumption, to act as intermediates for preparing ephedrine, norephedrine and other drug substances.

SUMMARY: The primary objective of the present invention is to provide analternate route to synthesis of ( R )- PAC of Formula I without involving fermentation process. In addition, the process of this invention makes it possible to produce PAC with high purity and very high enantiomeric excess.

I Another objective of the invention is to provide a process which enables the economic production of enantiomerically pure and, respectively, enantiomericahy enriched intermediates of formula II and III in high yields and with high enantiomeric purity without any byproducts.

To achieve the above objectives, the present invention provides a process for the preparation of (R)-PAC from a simple, commercially available chemical propiophenone. The preparation process comprising of converting isonitrosopropiophenone compound (III) from propiophenone compound (IV). Further, enantioselective reduction in the presence of ketoreductase & in the presence of co-enzyme in a buffer solution at 20-50 °C, produces an intermediate ( A ) - 1 -hydroxy- l-phenylpropan-2-one oxime compound (II). The (R) - hydroxy oxime is hydrolyzed in acidic medium to obtain (R)-phenylacetylcarbinol (I) with substantially high purity and very high chiral purity. The key starting material propiophenone is a commodity chemical, obtained in low-price and easily available substrate, the ketoreductase is utilized for performing asymmetric reduction and is commercially available. (R)-phenylacetylcarbinol (I) and the intermediate (A)- 1 -hydroxy- l-phenylpropan-2-one oxime (II) are used to synthesize 1,2-aminoalcohol or b-aminoalcohols of the type ephedrine and norephedrine derivatives and also other drug substances.

IV II in

Other objectives, advantages and features of the present invention will become more apparent from the following detailed description and claims.

OFT ATT /FT) DESCRIPTION OF THE INVENTION:

The present invention discloses an efficient process to produce (R)-phenylacetylcarbinol in high yield with high purity and very high enantiomeric purity. The invention provides a novel efficient process of producing (R)-phenylacetylcarbinol (hereinafter referred to as (i?)-PAC) from propiophenone, involving a-isonitrosopropiophenone (INP) and (i?)-l -hydroxy- 1 -phenylpropan- 2-one oxime (hereinafter referred to as (A’)-PAC oxime) as intermediates.

The preferred process according to the present invention is shown in the reaction scheme depicted in reaction Scheme 4. Stage- 1:

II I Scheme 4

The so produced (R)-PAC and (R)-PAC oxime are used for the manufacture of 1 ,2-aminoalcohol or b-aminoalcohols of the type ephedrine and norephedrine derivatives and also other drug substances. The preferred salt form of ephedrine and norephedrine is hydrochloride.

According to the preferred embodiment of the invention, a stepwise synthesis of (R)-PAC is further described in detail for illustrative purposes.

Step 1: Preparation of Isonitrosopropiophenone (IP)

In the first step of the preparation process, propiophenone IV in the presence of acid catalyst is reacted with alkyl nitrites (Ci to C4) preferably methyl nitrite at temperature of 40 °C to 50 °C preferably 40 to 45 °C. The reaction is carried out with suitable aliphatic alcohol Ci to C4preferably, methanol or ethanol. The reaction can be monitored by High Performance Liquid Chromatography (HPLC) to monitor the reaction conversion. The conventional work up of reaction mass gives pure isonitrosopropiophenone III with high yield.

Step 2: Preparation of (/?)-l-hydroxy-l-phenylpropan-2-one oxime (II)

Step 2 comprises, enantioselective reduction of keto function using enzyme along with a suitable co factor. According to the invention, the enzymatic reduction proceeds under mild reaction conditions so that the degradation of the unstable compounds of formula II and thus the significant formation of undesired byproducts can be avoided. The isolated compound of formula P ((/?)- compound) according to the invention has an enantiomeric purity of 99%, at least. The enantio selective enzymatic reduction of a-isonitrosopropiophenone (INP) IP to the corresponding (R)-l- Hydroxy-l-phenylpropan-2-one oxime ((R)-Oxime) is catalyzed by an IEP-oxidoreductase i.e. IEP 0x162 in combination with IEP 0x152 and a solvent with secondary alcoholic group. The oxidoreductase transfers the hydrogen from NADH to the keto group of INP, thereby the NADH is oxidized to NAD and the substrate is reduced to (R)-Oxime II.

In a preferred embodiment of the invention, the cofactor used in the process is continuously reduced with a co-substrate. Preferably, b-NAD is used as the cofactor which reduces to NADH by transferring the hydrogen from co-substrate, and the enzyme oxidoreductase transfer hydrogen from NADH to INP and is oxidized to NAD.

In the processes according to the invention, the oxidized cofactor NAD formed by the oxidoreductase/dehydrogenase is preferably regenerated continuously with another enzyme IEP Ox 152.

According to a preferred embodiment of all processes according to the invention, the oxidized cofactor NAD or NADP is regenerated by oxidation of a secondary alcohol.

Secondary alcohols such as 2-propanol, 2-butanol, 2-pentanol, 3-pentanol, 4-methyl-2-pentanol, 2-heptanol, 2-octanol are preferably used as co-substrates. More preferably, 2-propanol or 2- butanol is used as co-substrates for cofactor regeneration. The amount of co-substrate for the regeneration ranges from 5 to 95% by volume, based on the total volume.

The concentration of both the enzyme IEPOxl62 and IEP 0x152 is chosen in such a way to achieve best conversion rate. Concentration of IEPOxl62 is preferably from 50g/Kg of the INP to 125 g/Kg of INP, particularly and preferably from 60g/Kg of INP to 80g/Kg of INP. IEPOxl52 is preferably from 50 g/Kg to 60g/Kg of the substrate INP (Table -1). The co factor NAD is required for the conversion preferably from 0.05% to 0.3%.

In the processes according to the invention, the compound of formula III used in the reaction batch in an amount ranging from 10 g/1 to 500 g/1, preferably from 25 g/1 to 300 g/1, more preferably from 50 g/1 to 200 g/1, based on the total volume.

The aqueous portion of the reaction mixture in which the enzymatic reduction proceeds preferably contains a buffer, e.g., a potassium phosphate, tris/HCl or triethanolamine buffer, having a pH value ranging from 5 to 10, preferably a pH ranging from 6 to 9. In addition, the buffer can contain ions for stabilizing or activating the enzymes such as, for example, zinc ions or magnesium ions.

While carrying out the process according to the invention, the temperature suitably ranges from about 20° C to 50° C, preferably from 25° C to 35° C. After completion of the reduction, the reaction mixture is processed. For this purpose, Water immiscible solvents like ether, tert-butylmethylether, ethyl acetate, isopropylacetate, toluene, dichloromethane, cyclohexane, etc., are added to the mass and filtered. The aqueous phase is optionally separated from the organic phase. Optionally, the aqueous phase can also be processed further like the organic phase. Thereupon, the solvent is evaporated from the organic phase and the product of formula II is obtained as a crude product. Optionally, the product can then be used directly without isolation of formula II for the synthesis of a resultant product.

Step 3: Preparation of R)-PAC (I)

The hydrolysis process of formula II of the present invention is performed using inorganic acid like sulfuric acid, hydrochloric acid, phosphoric acid and organic acid chosen from formic acid and organic acid having carbon chain C-l to C4, trifluoroacetic acid, etc., preferably, hydrochloric acid or sulfuric acid is chosen as an inorganic acid.

Hydrolysis is carried out in bi-phasic system where water and organic phase immiscible solvents like ether, TBME, toluene, cyclohexane, dichloromethane preferably toluene as medium. While carrying out the invention, the temperature suitably ranges from 5 °C to 60 °C and preferably from 5 °C to 20 °C.

After completion of the hydrolysis, the organic phase containing the (R)-PAC I is separated, and aqueous phase can also be extracted till complete absence of (R)-PAC.

The organic layer is evaporated to complete dryness for resultant product or used directly for next step after partial evaporation of organic solvent.

The process of the present invention is further illustrated in the way of following examples.

Example 1:

Example 1A:

Preparation of isonitrosopropiophenone (III)

In a round bottom flask, 120 mL of methanol and lOOg of propiophenone IV was taken, which is the key raw material in this process. To the solution dry hydrochloric acid gas of about 10 g at 15 °C to 20 °C is purged to it. In another reaction vessel, 40 mL of water, 60 g of sodium nitrite, 45 mL of methanol is taken. Sulphuric acid 50 % is added to the above sodium nitrite solution in mixture of water and methanol for about 3 hours at below 45°C. The liberated methyl nitrite gas was purged to the reaction vessel containing propiophenone in methanol. The mass was stirred for about an hour at 35 °C to 45 °C and the progress of the reaction are monitored by Gas chromatography (GC). To the reaction mass, 120 mL of water was added at 30 °C to 45 °C. The mass was cooled to 0 °C to 5 °C, maintained for about an hour, filtered and washed with 100 mL of water. The wet product on drying yields, a-Isonitrosopropiophenone III (100 g, 82%) as white crystalline powder.

Example IB:

Preparation of (/?)-l-hydroxy-l-phenylpropan-2-one oxime (P) from

isonitrosopropiophenone (III)

100 g of 0.613 mole of a-isonitrosopropiophenone III was suspended in 170 mL of 2-propanol at 20 to 25 °C and agitated for about 20 min.

To the suspension of 7.5 g of oxidoreductase IEPOxl62 and 5.0 g of IEPOxl52 inl20 mL of phosphate (pH 8.0) buffer solution added 0.1 g of charged b- nicotinamide adenine dinucleotide (NAD)is also suspended inlO mL of phosphate (pH 8.0) buffer solution under vigorous stirring at 20 °C to 25 °C. The contents are agitated vigorously at 25 °C to 30 °C to get uniform suspension of enzymes. The suspension of enzymes are transferred in to the suspension of a- isonitrosopropiophenone IP in 2-propanol at 25 °C to 30 °C. The resulting reaction mass was agitated for about 24 - 48 hours at 25 °C to 30 °C. The progress of the reaction is monitored by HPLC. After complete conversion, 300 mL of toluene was charged and the resulting mass was filtered through celite and the celite bed was washed with 100 mL of toluene. The organic layer is further concentrated in reduced pressure by keeping the temperature less than 50 °C. The concentrated syrup was stirred with hexane to facilitate the precipitation. The precipitated product was filtered and dried to give 96 g (95%) of (i?)-PAC oxime II. Purity: 99.56% GC

(R)-l -hydroxy- 1 -phenylpropan-2-one oxime: 99.9%

(S)-Isomer: 0.1%

Specific optical rotation: 142.8° (2%, ethanol): ¾ NMR (CDC13,400MHz): dH: 1.75 (3H, s, C=N-CH₃), 5.32 (1H, s, CH-OH), 7.29 - 7.38 (5H, m, CeHs).

¹³C NMR (CDC13 , 100MHz) : 5C: 10.15 (C=N-CH₃), 75.04 (CH-OH), 126.52 - 139.48

(aromatic carbons), 159.67 (C=N-CH₃).

Example 1C:

Preparation of (R)-pheylacetylcarbinol (I) from(R)-l-hydroxy-l-phenylpropan-2-one oxime (P)

The (R)-PAC oxime II obtained in the example IB is dissolved in 500 mL of toluene and then cooled to 10 °C. 250 mL of Hydrochloric acid diluted with 350 mL of water is added to it for about 3 to 4 hours at 10 °C to 15 °C. The resulting reaction mass was agitated for about 2 hours at 10 °C to 15 °C. The completion of hydrolysis reaction of oxime is monitored by GC. The organic layer was separated and product in aqueous layer was extracted twice with 200 mL of toluene. The toluene layers were combined and washed with 200 mL of water and concentrated completely under reduced pressure at below 40 °C to yield (R)-PAC (85 g) as golden yellow oil with 88% yield. The analytical details are as below.

Purity: 96.7 % (GC)

(R)-Phenylacetylcarbinol: 99.2% (GC)

S-Phenylacetylcarbinol: 0.8%

Example 2:

Repetition of example IB by replacing 2-propanol with 2-butanol

100 g of 0.613 mole of a-isonitrosopropiophenone III was suspended in 170 mL of 2-butanol at 20 to 25 °C and agitated for about 20 min.

To the suspension of 7.5 g of oxidoreductase IEPOxl62 and 5.0 g of IEPOxl52 in 120 mL of phosphate (pH 8.0) buffer solution added 0.1 g of charged b- nicotinamide adenine dinucleotide (b-NAD) is also suspended inlO mL of phosphate (pH 8.0) buffer solution under vigorous stirring at 20 °C to 25 °C. The contents are agitated vigorously at 25 °C to 30 °C to get uniform suspension of enzymes. The suspension of enzymes are transferred into the suspension of a- isonitrosopropiophenone PI in 2-butanol at 25 °C to 30 °C. The resulting reaction mass was agitated for about 24 - 48 hours at 25 °C to 30 °C. The progress of the reaction was monitored by HPLC. After complete conversion, 300 mL of toluene was charged and the resulting mass was filtered through celite and the celite bed was washed with 100 mL of toluene. The organic layer is further concentrated in reduced pressure by keeping the temperature less than 50 °C. The concentrated syrup was stirred with hexane to facilitate the precipitation. The precipitated product was filtered and dried to give 96 g (95%) of (Z?)-PAC-oxime showing purity > 99% (GC) and > 99 % ee (GC).

Example 3:

Repetition of example IB except isolating (R)-PAC oxime followed by hydrolysis

To the suspension of 7.5 g of oxidoreductase IEPOxl62 and 5.0 g of IEPOxl52 in 120 mL of phosphate (pH 8.0) buffer solution added 0.1 g of charged b- nicotinamide adenine dinucleotide (b-NAD) is also suspended inlO mL of phosphate (pH 8.0) buffer solution under vigorous stirring at 20 °C to 25 °C. The contents are agitated vigorously at 25 °C to 30 °C to get uniform suspension of enzymes. The suspension of enzymes are transferred in to the suspension of a- isonitrosopropiophenone PI in 2-propanol at 25 °C to 30 °C. The resulting reaction mass was agitated for about 24 - 48 hours at 25 °C to 30 °C. The progress of the reaction was monitored by HPLC. After complete conversion 800 mL of toluene was charged and the resulting mass was filtered through celite and the celite bed was washed with 100 mL of toluene.

The total filtrate along with the aqueous phase was cooled to 10 °C. Hydrochloric acid (30%) 250 mL diluted with 350 mL of water was added for about 3 to 4 hours at 10 °C to 15 °C. The resulting reaction mass was agitated for about 2 hours at 15 °C to 10 °C. The complete hydrolysis reaction of (Zv’)-PAC oxime was monitored by GC. The organic layer was separated and the product in aqueous layer was extracted twice with 200 mL of toluene. The combined toluene layers are combined and washed with water 200 mL and concentrated till residual volume of 600 mL volume under reduced pressure at below 40 °C to yield (Z?)-PAC in toluene as golden yellow oil of in toluene layer estimated as 82 g (89%) having purity 94.8% with > 99% ee. Example 4

Hydrolysis of the (R)-PAC oxime (Il)with organic acid

The (R)-PAC oxime II 10 g obtained in the example IB was dissolved in 60 mL of toluene and then cooled to 10 °C. 50 mL of acetic acid diluted with 100 mL of water was added to it for about 3 to 4 hours at 10 °C to 15 °C. The resulting reaction mass was agitated for about 2 hours at 35 °C to 40 °C. The completion of hydrolysis reaction of oxime was monitored by GC. The organic layer was separated and the product in aqueous layer was extracted twice with 200 mL of toluene. The toluene layers are combined and washed with water 50 mL and concentrated completely under reduced pressure at below 40 °C to yield (R)-PAC I 8.0 g (88 %) as golden yellow oil with purity 93.5% and 98.8% ee.

Comparative Example 1:

Preparation of (1/f ,25)-l-ephedrine HC1

To the 600 mL of concentrated mass of toluene containing (R)-phenylacetylcarbinol I, 40% solution of aqueous monomethylamine 62 g was added. The resulting mass was hydrogenated at 30 °C to 55 °C at 2 kg/cm² to 4 kg/cm² of hydrogen pressure in the presence of 5% platinum on carbon (8 g) till hydrogen consumption ceases. The mass was maintained at 40 °C to 55 °C in 2 kg/cm² to 4 kg/cm² of hydrogen gas pressure. The progress of the reaction mass was monitored by GC and mass was cooled to 30 °C to 35 °C. The platinum catalyst was filtered off and to the filtrate water of 150 mL was added. The pH of the reaction mass was adjusted to about 2.0 with hydrochloric acid and the aqueous layer was separated. The separated aqueous layer was concentrated under reduced pressure and the precipitated product was isolated using acetone 160 mL at 20 °C to 25 °C. The isolated ephedrine hydrochloride was washed with acetone 100 mL to yield crude ephedrine hydrochloride. The crude ephedrine hydrochloride on re-crystallisation with water yields (80 g, 74 %), (1R,2S)-Ephedrine hydrochloride as white crystalline solid. Purity by HPLC > 99.5 % with 99.5 % ee, Specific optical rotation: (-) 32.4 °.

Comparative Example 2:

Preparation of (l/f,25)-phenylpropanolamine (Norephedrine) In a hydrogenation flask taken (R)-phenylacetylcarbinol oxime II prepared in example IB, methanol700 mL followed by Nickel-L(+)-tartaric acid complex prepared by conventional method. The mass charged with aqueous ammonia solution and hydrogenated at 30 °C to 40 °C at 3 kg/cm² to 4 kg/cm² of hydrogen pressure till hydrogen consumption ceases. The mass was maintained at 30 °C to 40 °C in 3 kg/cm² to 4 kg/cm² of hydrogen gas pressure. The progress of the reaction mass was monitored by HPLC and mass was cooled to 30 °C to 35 °C. The Nickel- Tartaric acid was filtered off and the filtrate was concentrated under reduced pressure. The above mass was diluted with 2-propanol and pH adjusted was adjusted 2.0 - 3.0 with IPA. HC1 and the precipitated product was filtered and washed with 2-propanol (with ee 99.3% and de 97%). The crude (lR,2S)-phenlpropanolamine hydrochloride on recrystallisation with 2-propanol yields (70 g, 69%) (lR,2S)-phenylpropanolamine hydrochloride, as white crystalline solid. Purity by HPLC: > 99.5 %, Enantiomericpurity> 99 %, Diasteromeric impurity: < 0.2%, Specific optical rotation: (-) 34.2 °.

TABLE 1 : Input and output data of the major compounds used in the present invention with their respective yields.

The advantages of process of the present invention including, but not limited to, are: high enantioselectivity process leading chiral purity > 99%, high purity of about > 95%, decreased effluent load and increased in productivity due to lesser cycle time, much lower energy consumption and a single process leading to the synthesis of two API.

Thus, the present invention provides an efficient process to yield (Z?)-phenylacetylcarbinol ((/?)- PAC) and (Z?)-l -hydroxy- 1 -phenylpropan-2-one oxime ((Z?)-PAC oxime), an intermediate for ephedrine, norephedrine & other drug substances.

While the foregoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiment, method, and examples herein. The invention should therefore not be limited by the above described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention as claimed.

Claims

We Claim:

1. A process for preparing (i?)-l -hydroxy- l-phenylpropan-2-one, of chemical formula I:

the process comprises of converting propiophenone(IV) in presence of methanol and sodium nitrite in acidic medium to form a-isonitrosopropiophenone (III): subjecting the a- isonitrosopropiophenone (III) to biotransformation reaction with oxidoreductase in the presence of regeneration enzyme and cofactor nicotinamide adenine dinucleotide (NAD) in aliphatic alcohols solvent system at a temperature ranging from 20°C to 50 °C and pH ranging from 7 to 9 to produce (R)-l -hydroxy- 1 -phenylpropan-2-one oxime of formula (II) with high chiral purity

and hydrolyzing the(Z?)-l -hydroxy- 1 -phenylpropan-2-one oxime (II) in acidic medium at temperature ranging from 5°C to 60 °C to obtain the formula I with optical purity greater than 99%.

2. The process as claimed in claim 1, wherein the solvent used in the biotransformation reduction is selected from carbon chain C-3 to C-8.

3. The process as claimed in claim 1 or 2, wherein the solvent is an isopropylalcohol.

4. The process as claimed in claim 1, wherein the co factor b-NAD acts as hydrogen donor.

5. The process as claimed in claim 1, wherein the temperature selected for the enzymatic reduction is 30° C to 35° C.

6. The process as claimed in claim 1, wherein an optimized pH for the enzymatic reduction is 8 0

7. The process as claimed in claim 1, wherein the hydrolysis is performed using inorganic and organic acids having carbon chain C-l to C-4 at temperature ranging from 5°C to 60 °C.

8. The process as claimed in claim 7, wherein the acid is hydrochloric acid.

9. The process as claimed in 1 or 7, wherein the temperature range is fromlO°C to 15 °C.

10. The process as claimed in claim 1, wherein comprising utilizing the (R)- 1 -hydroxy- 1- phenylpropan-2-one oxime as a precursor for production of norephedrine.

11. The process as claimed in claim 1, wherein comprising utilizing synthesis of optically active ephedrine hydrochloride from propiophenone without involving fermentation process.

12. The process as claimed in claim 1, wherein comprising utilizing the (R)- 1 -hydroxy- 1- phenylpropan-2-one for synthesis of b-aminoalcohols.