Claims:We claim

1. An improved process for the preparation of enantiomerically pure Metaraminol Bitartrate of a compound of formula (1)

Comprising the steps of :
a) reacting 3’-Hydroxypropiophenoneof compound of formula (2)

with n-Butyl nitrite in the presence of a solvent and an acid to form alpha oximinoketonecompound of formula (4);

b) reducing the compound of formula (4) to form isomeric mixture of Metaraminol of formula (5);

c) separation of the isomeric mixture of metaraminol of compound of formula (5) with L -(+)- tartaric acid using a solvent to form crude product Metaraminol Bitartrate;

d) crystallizing the Metaraminol Bitartrate using a solvent and
e) Isolating the enantiomerically pure Metaraminol Bitartrate.

2. The process as claimed in claim 1, wherein the solvent in reaction step (a) is selected from ether, tert-Butyl methyl ether (MTBE), acetone, N,N-Dimethylformamide (DMF), tetrahydrafuran (THF), toluene, methanol and mixtures thereof.

3. The process as claimed in claim 1, wherein the reaction in step (a) is carried out at a temperature in the range of 5 to 60 °C for a period of 10 minutes to 6h.

4. The process as claimed in claim 1, wherein the acid in reaction step (a) is selected from sulfuric acid, nitric acid, hydrochloric acid or mixture thereof.

5. The process as claimed in claim 1, wherein the reduction is carried out using a catalyst selected from Raney nickel, Pd/C in the presence of hydrogen gas.

6. The process as claimed in claim 1, wherein the resolution in step (c) is carried out without isolation of compound of formula (5) and is carried out in situ.

7. The process as claimed in claim 1, wherein the solvent for resolution in step (c) is selected from alcohol, acetonitrile, acetone, dichloromethane, ether, ethyl acetate and mixture thereof.

8. The process as claimed in claim 1, wherein the solvent for crystallization step (d) is selected from water, alcohol, acetone and mixture thereof.

9. An improved process for the preparation of Metaraminol Bitartrate of a compound of formula (1)

Comprising the steps of :
f) reacting 3’-Hydroxypropiophenone of compound of formula (2)

with n-Butyl nitrite in the presence of a solvent selected from ether, tert-Butyl methyl ether (MTBE), acetone, N,N-Dimethylformamide (DMF), tetrahydrafuran (THF), toluene, methanol and mixtures thereof and an acid selected from hydrochloric acid to form alpha oximinoketonecompound of formula (4),

g) reducing the compound of formula (4) using a catalyst selected from Raney nickel or Pd/C in the presence of hydrogen gas to form isomeric mixture of Metaraminol of formula (5),

h) resolving the isomeric mixture of metaraminol of compound of formula (5)

with L -(+)- tartaric acid using a solvent selected from alcohol, acetonitrile, acetone, water and mixture thereof to form crude product Metaraminol Bitartrate,
i) crystallizing the Metaraminol Bitartrate using a solvent selected from alcohol, acetonitrile, acetone, water and mixture thereof and
j) Isolating the enantiomerically pure (>98% ee) Metaraminol Bitartrate.

10. Metaraminol Bitartrate having chiral purity in the range of 99 to 100% ee

11. Metaraminol Bitartrate having the PXRD pattern as shown Fig. 3 and table 1
, Description:Field of the invention
The present invention provides an improved process for the preparation of Metaraminol Bitartrate with high enantiomeric purity of a compound of formula (1).

Backgroud of the invention
Metaraminol Bitartrate is a potent sympathomimetic amine used in the prevention and treatment of hypotension, particularly as a complication of anesthesia. Metaraminol Bitartrate is chemically known as [R-(R*,S*)]-a-(1-aminoethyl)-3-hydroxybenzenemethanol [R-(R*, R*)]- 2,3-dihydroxybutanedioate (1:1) (salt), which is levorotatory. It is structurally represented as

Metaraminol Bitartrate is approved and marketed under the trade name ARAMINE* in the form of injectable dosage form.

R.S. Vardanyan et.al synthesis of essential drugs (2006) disclosed preparation of metaraminol in two ways. The first way is synthetic, which involves, protecting the hydroxyl group in 3-hydroxypropiophenone by alkylation with benzyl chloride, giving 3-benzyloxypropiophenone. Nitrosation of propiophenone with n-Butyl nitrite to form isonitrosoketone, which by reduction using hydrogen over Raney nickel yields 1-(3-benzyloxyphenyl)-2-aminopropan-1-ol, deprotecting the benzyl group using hydrogen over palladium catalyst to give isomeric mixture of metaraminol. The reaction is shown in the Scheme -1 below:

The above synthetic approach involves protection of hydroxyl and deprotection, thus adding two additional steps. Further the disclosed information does not teach the preparation of optically pure Metaraminol.

The second way is semi synthetic, consisting of fermentation of D-glucose in the presence of 3-1-acetoxybenzaldehyde, which form (-)-1-hydroxy-1-(3-hydroxyphenyl)-acetone, the carbonyl group of which is reduced by hydrogen over a palladium catalyst in the presence of ammonic, giving metaraminol. The reaction is shown in the Scheme -2 below:

The above fermentation process is tedious and difficult to isolate the pure product.

Chinese patent application No. CN103739504 A discloses a synthesis method of Metaraminol Bitartrate, comprises the steps: catalyzing a chiral addition reaction of hydroxybenzaldehyde and nitroethane by using a chiral catalyst system consisting of cinchona alkaloid, copper acetate hydrate and less imidazole to obtain an addition product with a dominant required spatial configuration, and then reducing nitro compound by using hydrogen in the presence of Pd-C to obtain amine and saltifying the amine with L(+)-tartaric acid to obtain a final product Metaraminol Bitartrate. The reaction is shown in the Scheme -3 below:

The above synthetic process involves the use of expensive cinchona alkaloids as catalyst and the use of nitroethane at lower temperatures making it undesirable for commercial production. Further the overall yield of the synthetic scheme is about 7%. Thus there is a need to develop a cost effective and scalable process.

Summary of the invention
Accordingly, the present invention provides an improved process for the preparation of Metaraminol Bitartrate in high enantiomerically pure of a compound of formula (1)

Comprising the steps of:
a) reacting 3’-Hydroxypropiophenone of compound of formula (2)

With n-Butyl nitrite in the presence of a solvent and an acid to form alpha oximinoketone compound of formula (4),

b) reducing the compound of formula (4) to form isomeric mixture of Metaraminol of formula (5);

c) separation of the isomeric mixture of metaraminol of compound of formula (5) with L -(+)- tartaric acid using a solvent to form crude product of Metaraminol Bitartrate;
d) crystallizing the Metaraminol Bitartrate using a solvent; and
e) Isolating the high enantiomerically pure Metaraminol Bitartrate.

Brief Description of the Figures
Fig.1 shows the chiral HPLC chromatogram of racemic mixture of Metaraminol Bitartrate.

Fig.2 shows the chiral HPLC chromatogram of enantiomerically pure compound of Metaraminol Bitartrate.

Fig. 3 shows the PXRD pattern of Metaraminol Bitartrate.
Detailed Description of the invention
An improved process for the preparation of Metaraminol Bitartrate of a compound of formula (1)

wherein the solvent in reaction step (a) is selected from ether, tert-Butyl methyl ether (MTBE), acetone, N,N-Dimethylformamide (DMF), tetrahydrafuran (THF), toluene, methanol and mixtures thereof. The reaction is carried out at a temperature in the range of 5 to 60 °C for a period of 10 minutes to 6h.

The acid in reaction step (a) used is selected from sulfuric acid, nitric acid, hydrochloric acid or mixture thereof.

The reduction according to the present invention is carried out using a catalyst selected from Raney nickel, Pd/C in the presence of hydrogen gas.

The separation of the isomeric mixture of metaraminol of compound of formula (5) is carried with isolation of compound of formula (5) and is carried out in situ using L -(+)- tartaric acid in the presence of a solvent selected from alcohol, acetonitrile, acetone, dichloromethane, ether, ethyl acetate and mixture thereof to form crude Metaraminol Bitartrate;

The crystallization step (d) is carried out using the solvent selected from water, alcohol, acetonitrile, acetone and mixture thereof.

In a preferred embodiment, the present invention provides an improved process for the preparation of Metaraminol Bitartrate with high enantiomeric purity of a compound of formula (1)

Comprising the steps of :
a) reacting 3’-Hydroxypropiophenone of compound of formula (2)

with n-Butyl nitrite in the presence of a solvent selected from ether, tert-Butyl methyl ether (MTBE), acetone, N,N-Dimethylformamide (DMF), tetrahydrafuran (THF), toluene, methanol and mixtures thereof and an acid selected from hydrochloric acid to form alpha oximinoketonecompound of formula (4),

b) reducing the compound of formula (4) using a catalyst selected from Raney nickel or Pd/C in the presence of hydrogen gas to form isomeric mixture of Metaraminol of formula (5),

c) resolving the isomeric mixture of metaraminol of compound of formula (5)

with L -(+)- tartaric acid using a solvent selected from alcohol, acetonitrile, acetone, water and mixture thereof to form crude product Metaraminol Bitartrate,
d) crystallizing the Metaraminol Bitartrate using a solvent selected from alcohol, acetonitrile, acetone, water and mixture thereof and
e) Isolating the enantiomerically pure (>98% ee) Metaraminol Bitartrate.

In yet another embodiment, the present invention provides Metaraminol Bitartrate having chiral purity in the range of 99 to 100% as shown in Fig.1 & Fig.2 (Fig.1 is chiral HPLC chromatogram of racemic mixture and Fig.2 is chiral HPLC chromatogram of enantiomerically pure compound).

In another preferred embodiment, the present invention provides Metaraminol Bitartrate having the PXRD pattern as shown in Fig. 3 and table 1

Table 1: Theta values (PXRD) of Metaraminol Bitartrate
S. No. Peak Pattern (°?) Relative Intensity %
1 7.0824 29.6
2 12.6296 20.7
3 6.24866 6.3
4 16.1435 33.8
5 17.6275 100.0
6 19.3708 13.7
7 20.7425 30.9
8 21.2896 42.6
9 21.6912 13.3
10 23.6065 6.7
11 24.1557 15.8
12 25.4427 16.0
13 27.0015 8.8
14 27.8089 14.1
15 28.3314 10.8
16 32.5673 12.7
17 32.7500 10.8
18 35.8181 6.7
19 37.5545 11.0

The process of the present invention is explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be constructed as limit to the scope of the claims in any manner.

Example-1: (Stage-1 procedure): Preparation of 3'-hydroxy-a-isonitroso-propiophenone (4): To a stirred solution of 3’-Hydroxypropiophenone (2, 10.0 g, 66.6 mmol) in tert-Butyl methyl ether (MTBE) (90.0 mL) at 25-35°C. The mixture was stirred at this temperature for 15 min. Cool the reaction mass to 0-20°C and slowly passed the dry HCl gas to the reaction mass for 15 min at 10-20°C. Slowly added the solution of n-Butyl nitrite (0.8 to 3 eq.) (3) in MTBE (10.0 mL) to the reaction mass at 0-20°C while passing HCl gas. Reaction mass stirred for 5-7 h at 0-20°C. Slowly added DM water (50.0 mL) to the reaction mass at 0-20°C and stirred for 15 min at 25-30°C. Both layers were separated and aqueous layer extracted with MTBE for 2 times (2X200 mL). Combined organic layers were washed with D M water for 2 times (2X20.0 mL). Organic layer was concentrated under vacuum. Reaction mass was cooled to 40-45°C and added n-hexane (20.0 mL) at below 45°C. Reaction mass was further cooled to 25-30°C and stir for 30 min at 25-30°C. Filtered the reaction mass and cake was washed with toluene. The solid was dried under atmospheric pressure at 60°C for 2 h to afford 60-90 % yields with >99 % purity by HPLC. 1H-NMR (DMSO-d6): d 12.36 (s, 1H, Ar-OH), 9.70 (s, 1H, N-OH), 7.28-7.20 (m, 3H, Ar-3H), 6.99-6.96 (m, 1H, Ar-H), 2.01 (s, 3H, CH3).

Example 2: Preparation of 3'-hydroxy-a-isonitroso-propiophenone (4) in THF (stage-1): To a stirred solution of 3’-Hydroxypropiophenone (50 g, 33.3 mmol) in Tetrahydrofuran (THF) (50 mL) at 25-30°C. The mixture was stirred at this temperature for 15 min. Cool the reaction mass to 20-25°C and slowly passed the dry HCl gas to the reaction mass for 15 min at 20-25°C. Slowly added the solution of n-Butyl nitrite in tetra hydro furan (THF) (5 mL) to the reaction mass at 20-25°C while passing HCl gas (exothermicity was observed up to 3-5°C while reagent addition to the reaction mass). Stirred the reaction mass for 1.5-2.0 h at 20-25°C under continuous HCl gas passing to the reaction mass, the reaction progress was monitored by TLC, only 50% progress was observed. Further, reaction mass was stirred for 3.0 h at 20-25°C under continuous HCl gas passing to the reaction mass, the reaction mass progress monitored by TLC, there is no change in the reaction mass. The reaction mass poured into ice-cold water (50 mL) (slightly exothermic, temperature increases from 5-10°C) and stirred for 30 min at 25-30°C. Charged ethyl acetate (100 mL) to the reaction mass and stirred for 20-30 min. separated the both layers and aqueous layer extracted with ethyl acetate for 3 times (3X50 mL). Combined the all the organic layers and washed with DM water for 1 time (1X50 mL) followed by washing with 20% brine solution (1X50 mL). The crude product was purified by column chromatography by using ethyl acetate/hexane as eluents to get 25 % yields.

Example 3: Preparation of 3'-hydroxy-a-isonitroso-propiophenone (4) in toluene (stage-1): To a stirred solution of 3’-Hydroxypropiophenone (50.0 g, 333.3 mmol) in toluene (150 mL) at 25-30°C. The mixture was stirred at this temperature for 15 min. Cool the reaction mass to 20-25°C and slowly passed the dry HCl gas to the reaction mass for 15 min at 20-25°C. Slowly added the solution of n-Butyl nitrite in toluene (50 mL) to the reaction mass at 20-25°C while passing HCl gas (exothermicity was observed up to 3-5°C while reagent addition to the reaction mass). Reaction mass was stirred for 1.0 h at 20-25°C under continuous HCl gas passing to the reaction mass. After 1.0 h, solid formation was observed. The reaction mass was filtered and solid washed with toluene (50 mL). The solid was dried under atmospheric pressure at 75-80°C for 6 h to afford 36.2 g (60.7 %) of the desired product.

Example 4: Preparation of 3'-hydroxy-a-isonitroso-propiophenone (4) in methanol (stage-1): To a stirred solution of 3’-Hydroxypropiophenone (5.0 g, 33.3 mmol) in methanol (50 mL) at 25-30°C. The mixture was stirred at this temperature for 15 min. Cool the reaction mass to 20-25°C and slowly passed the dry HCl gas to the reaction mass for 15 min at 20-25°C. Slowly added the solution of n-Butyl nitrite in methanol (5 mL) to the reaction mass at 20-25°C while passing HCl gas (exothermicity was observed up to 3-5°C while reagent addition to the reaction mass). Stirred the reaction mass for 2.0-2.5 h at 20-25°C under continuous HCl gas passing to the reaction mass, the reaction mass progress monitored by TLC, starting material was absent. The reaction mass distilled under vacuum and filtered the solid and washed with toluene. The solid isolation in methanol was very difficult.

Example-5: (Stage-1 procedure): Preparation of 3'-hydroxy-a-isonitroso-propiophenone (4): To a stirred solution of 3’-Hydroxypropiophenone (2, 100 g, 666.6 mmol) in tert-Butyl methyl ether (MTBE) (900 mL) at 25-35°C. The mixture was stirred at this temperature for 15 min. Cool the reaction mass to 0-20°C and slowly passed the dry HCl gas to the reaction mass for 15 min at 10-20°C. Slowly added the solution of n-Butyl nitrite (1.0 to 3 eq.) (3) in MTBE (100 mL) to the reaction mass at 0-20°C while passing HCl gas. Reaction mass was stirred for 5-7 h at 0-20°C. Slowly added DM water (500 mL) to the reaction mass at 0-20°C and stirred for 15 min at 25-30°C. Both layers were separated and aqueous layer was extracted with MTBE for 2 times (2X200 mL). Combined organic layers were washed with DM water for 2 times (2X200 mL). Organic layer was concentrated under vacuum and cooled to 40-45°C and added n-hexane (200 mL) at below 45°C. Reaction mass was further cooled to 25-30°C and stirred for 30 min at 25-30°C. Filtered the reaction mass and cake was washed with toluene. The solid was dried under atmospheric pressure at 60°C for 2 h to afford 75-85 % yields with >99 % HPLC purity. 1H-NMR (DMSO-d6): d 12.36 (s, 1H, Ar-OH), 9.70 (s, 1H, N-OH), 7.28-7.20 (m, 3H, Ar-3H), 6.99-6.96 (m, 1H, Ar-H), 2.01 (s, 3H, CH3). Melting point: 136.8-138.2°C.

Example 6: Preparation of 3'-hydroxy-a-isonitroso-propiophenone (4) in DMF (stage-1): To a stirred solution of 3’-Hydroxypropiophenone (200 g, 1333.3 mmol) in N, N-Dimethyl formamide (DMF) (900 mL) at 25-30°C. The mixture was stirred at this temperature for 15 min. Cool the reaction mass to 20-25°C and slowly passed the dry HCl gas to the reaction mass for 15 min at 20-25°C. Slowly added the solution of n-Butyl nitrite in N, N-Dimethyl formamide (DMF) (200 mL) to the reaction mass at 20-25°C while passing HCl gas (exothermicity was observed up to 3-5°C while reagent addition to the reaction mass). Stirred the reaction mass for 1.5-2.0 h at 20-25°C under continuous HCl gas passing to the reaction mass, after 2h the reaction mass kept overnight at 25-30°C without stirring. The reaction mass poured into ice-cold water (7.2 Lit) (slightly exothermic, temperature increases from 5-10°C) and stirred for 1-2h at 25-30°C. Charged ethyl acetate (2.0 Lit) to the reaction mass and stirred for 20-30 min. separated the both layers and aqueous layer extracted with ethyl acetate for 3 times (3X1000 mL). Combined the all the organic layers and washed with DM water for 1 time (1X1000 mL) followed by washing with 20% brine solution (1X1000 mL). Separated the organic layer and concentrated under vacuum up to 80 % at below 50°C (~20% remains in the mass). Added toluene (200 mL) to the slurry mass at below 50°C and stirred for 15 min. Reaction mass further cooled to 25-30°C and stir for 30 min at 25-30°C. Filtered the reaction mass and cake washed with toluene (100 mL). The solid was dried under atmospheric pressure at 75-80°C for 6 h to afford 168.5 g (71.7 %) of the desired product in 99.97 % purity by HPLC.

Example 7: Preparation of 3'-hydroxy-a-isonitroso-propiophenone (4) (stage-1) scale up batches on 3.5 Kg scale: To a stirred solution of 3’-Hydroxypropiophenone (2, 3.5 Kg, 23.3 mmol) in tert-Butyl methyl ether (MTBE) (31.5 Lt) at 25-30°C. The mixture was stirred at this temperature for 15 min. Cool the reaction mass to 0-20°C and slowly passed the dry HCl gas to the reaction mass for 15 min at 10-20°C. Slowly added the solution of n-Butyl nitrite (3) in MTBE (3.5 Lt) to the reaction mass at 0-20°C while passing HCl gas. The reaction mass was stirred for 5-6 h at 0-20°C under continuous HCl gas passing to the reaction mass. Slowly added DM water (17.5 Lt) to the reaction mass at 0-20°C and stirred for 15 min at 25-30°C. Combined organic layers were washed with D M water and Organic layer was concentrate and cooled to 40-45°C. n-Hexane (7.0 Lt) was added at below 45°C. Reaction mass was further cooled to 25-30°C and stirred for 30 min. Filtered the reaction mass and cake was washed with n-hexane. The solid was dried under atmospheric pressure at 50°C for 6 h to afford 85.0 % of the desired product (4) in >99.50 % purity by HPLC. Melting range: 136.8-138.2°C.

Example-8: (Stage-2 procedure): Preparation of Metaraminol Bitartrate crude (6): In clean and dried autoclave, charged a solution of stage-1 (4, 10.0 g, 55.86 mmol), Raney-Nickel (10.0 g) and methanol (100 mL) at 25-30°C. Pressurize the autoclave with 1-5 kg of hydrogen and maintain the reaction for 2-9 h under 2 to 8 kg of hydrogen pressure at 25-50°C. Upon completion of the reaction, filtered the reaction mass through celite bed and washed the bed with methanol (Raney-Nickel filtration is highly flammable should maintain nitrogen blanket and attention). To the filtrate, 3.25 g of activated charcoal was added to the reaction mass (filtrate ML’s) and stir for 30 min at 25-30°C. Filtered the reaction mass through celite bed and wash the bed with methanol followed by concentrated under vacuum at below 50°C. In a separate RBF, charge methanol and L-(+)-Tartaric acid (5) (5.4 g, 55.86 mmol) at 25-30°C, stirred the reaction mass for 30 min at 25-30°C. Slowly added the L-(+)-tartaric acid in methanol solution to the reaction mass at 25-30°C. Stirred the reaction mass for 1h at 25-30°C. Reaction mass was filtered and cake washed with methanol. The solid was dried under atmospheric pressure at 50-75°C for 3-5 h to afford 18-30 % yield of the desired product (6) with >98 % HPLC purity. Chiral purity was observed >98 % and other isomer was observed <2.0 %. For free base 1H-NMR (DMSO-d6): d 7.11 (t, 1H, Ar-1H), 6.75-6.61 (m, 3H, Ar-3H), 4.37 (s, 1H, CH-OH), 3.17 (s, 3H, CH-NH2, CH-OH), 0.85 (s, 3H, CH3). Melting point: 171-172.2.

Example-9: Preparation of Metaraminol Bitartrate crude (6) with 0.5 w/w Raney-Ni (stage-2): In clean and dried autoclave charged a solution of stage-1 (50 g, 279.3 mmol), Raney-Nickel (25 g, 0.5 w/w) and methanol (500 mL) at 25-30°C. Pressurize the autoclave with 6 kg of hydrogen and maintain the reaction for 2-2.5 h under 5.5 to 6 kg of hydrogen pressure at 25-40°C (during the maintained temperature raising observed up to 10-15°C). Up on completion of the reaction, filtered the reaction mass through celite bed and washed the bed with methanol (Raney-Nickel filtration is highly flammable should maintain nitrogen blanket and attention). In a separate RBF, charge methanol and L-(+)-Tartaric acid (37.5 g, 250.0 mmol) at 25-30°C, stirred the reaction mass for 30 min at 25-30°C. The L-(+)-Tartaric acid in methanol solution filter through 0.45 micron filtered and wash with methanol. Slowly added the L-(+)-tartaric acid in methanol solution drop by drop with the help of additional funnel to the reaction mass at 25-30°C (slight exothermicity was observed) during addition. Stirred the reaction mass for 1h at 25-30°C, solid formation was observed. Filtered the reaction mass and cake was washed with methanol (50 mL). The solid was dried under atmospheric pressure at 80°C for 5 h to afford 15 % yield.

Example-10: (Stage-2): Preparation of Metaraminol Bitartrate crude (6) : In clean and dried autoclave, charged a solution of stage-1 (4, 100 g, 558.6 mmol), Raney-Nickel (100 g, 558.6 mmol, w/w) and methanol (1000 mL) at 25-30°C. Pressurize the autoclave with 3-6 kg of hydrogen and maintain the reaction for 2-8 h under 3 to 6 kg of hydrogen pressure at 25-30°C. Up on completion of the reaction, filtered the reaction mass through celite bed and washed the bed with methanol (Raney-Nickel filtration is highly flammable should maintain nitrogen blanket and attention). To the filtrate added 3.25 g of activated charcoal to the reaction mass (filtrate ML’s) and stir for 30 min at 25-30°C. Filtered the reaction mass through celite bed and wash the bed with methanol followed by 0.45 micron filter and wash with methanol. Concentrated the filtrate reaction mass under vacuum at below 50°C. In a separate RBF, charge methanol and L-(+)-Tartaric acid (5) (54.4 g, 558.6 mmol) at 25-30°C, stirred the reaction mass for 30 min at 25-30°C. L-(+)-tartaric acid was added slowly in methanol solution at 25-30°C. Reaction mass was stirred for 1h at 25-30°C. Reaction mass was filtered and cake was washed with methanol. The solid was dried under atmospheric pressure at 60-85°C for 3-5 h to afford 18-23 % yield (6) with 99.1 % HPLC purity. For free base 1H-NMR (DMSO-d6): d 7.11 (t, 1H, Ar-1H), 6.75-6.61 (m, 3H, Ar-3H), 4.37 (s, 1H, CH-OH), 3.17 (s, 3H, CH-NH2, CH-OH), 0.85 (s, 3H, CH3).

Example-11: (Stage-2): Preparation of Metaraminol Bitartrate crude (6) scale up batches on 3.2 Kg scale: In clean and dried autoclave, charged a solution of stage-1 (4, 3.2 Kg, 17.8 mmol), Raney-Nickel (3.2 Kg) and methanol (32 L) at 25-30°C. Pressurize the autoclave with 3-6 kg of hydrogen and maintain the reaction for 2-8 h under 3 to 6 kg of hydrogen pressure at 25-30°C. Upon completion of the reaction, filtered the reaction mass through celite bed and washed the bed with methanol (Raney-Nickel filtration is highly flammable should maintain nitrogen blanket and attention). To the filtrate added 175 g of activated charcoal to the reaction mass (filtrate ML’s) and stir for 30 min at 25-30°C. Filtered the reaction mass through celite bed and wash the bed with methanol followed by 0.45 micron filter and wash with methanol. Concentrated the filtrate reaction mass under vacuum at below 50°C. In a separate RBF, charge methanol and L-(+)-Tartaric acid (5) (2.68 Kg, 17.8 mmol) at 25-30°C, stirred the reaction mass for 30 min at 25-30°C. L-(+)-tartaric acid was slowly added in methanol solution at 25-30°C. Reaction mass was stirred for 1h at 25-30°C. Reaction mass was filtered and cake washed wash with methanol. The solid was dried under atmospheric pressure at 60-85°C for 3-5 h to afford 20-25 % yield (6) with 99.3 % purity by HPLC.

Example-12: (Stage-3): Preparation of Metaraminol Bitartrate (1):
Aqueous ethanol solution (46 mL) and stage-2 (6, 4.6 g, 14.51 mmol) were taken in to a RBF. The reaction mass temperature was raised to 60-80°C and maintained for 30 min. Reaction mass was slowly cooled and filtered through 0.45 micron filter and wash with hot aqueous ethanol solution (11.5 mL). In a separate RBF, filtrate ML’s were charged and slowly cooled the reaction mass to 25-30°C (solid formation was observed in between 36-44°C) and stirred for 1h at 25-30°C. Reaction mass was filtered and cake washed with ethanol (4.6 mL). The solid was dried under vacuum at 60-80°C for 3-5 h to afford 60-85 % of the desired product (1) in >99.9 % purity by HPLC. Chiral purity was observed >99.9 % ee (fig. 2) and other isomer was observed <0.1 %. 1H-NMR (DMSO-d6): d 7.90 (5H, 2COOH & 3OH), 7.14-7.11 (t, 1H, Ar-1H), 6.79-6.64 (m, 3H, Ar-3H), 4.86 (d, 1H, CH-OH), 3.98 (s, 2H, CH-NH2), 3.39-3.33 (m, 1H, CH-NH2), 0.91-0.89 (d, 3H, CH3). Melting point: 172.1-174.1°C, SOR (C:100 mg/mL in 0.5 N HCl solution at ?=405: -33.1°

Example-13: (Stage-3): Preparation of Metaraminol Bitartrate (1):
Aqueous ethanol solution (460 mL) and stage-2 (6, 46 g, 145.1 mmol) were taken in to a RBF. The reaction mass temperature was raised to 60-80°C and maintained for 30 min. Reaction mass was slowly cooled and filtered through 0.45 micron filter and wash with hot aqueous ethanol solution (115 mL). In a separate RBF, filtrate ML’s were charged and slowly cooled the reaction mass to 25-30°C (solid formation was observed in between 36-44°C) and stirred for 1h at 25-30°C. Reaction mass was filtered and cake washed with ethanol (46 mL). The solid was dried under vacuum at 60-80°C for 3-5 h to afford 60-85 % of the desired product (1) in >99.9 % purity by HPLC. Chiral purity was observed >99.9 % ee and other isomer was observed <0.1 %.

Example-14: (Stage-3): Preparation of Metaraminol Bitartrate (1) scale up batches on 1.35 Kg scale:
Aqueous ethanol solution (13.5 Lt) and stage-2 (6, 1.35 Kg, 4.25 mmol) were taken in to a reactor. The reaction mass temperature was raised to 60-80°C and maintained for 30 min. Reaction mass was slowly cooled and filtered through 0.45 micron filter and wash with hot aqueous ethanol solution (875 mL). In a separate reactor, filtrate ML’s were charged and slowly cooled the reaction mass to 25-30°C (solid formation was observed in between 36-44°C) and stirred for 1h at 25-30°C. Reaction mass was filtered and cake washed with ethanol (5.25 Lt). The solid was dried under vacuum at 60-80°C for 3-5 h to afford 70-85 % of the desired product (1) in >99.9 % purity by HPLC. Chiral purity was observed >99.9 % ee and other isomer was observed <0.1 %.