• Field of the invention

The objective of the present invention relates to improved process for the preparation of (1R, 2S)-methoxamine, its salts and stereoisomers with high chiral purity. The invention also provides a complete method for synthesis of therapeutically active (1R,2S)-isomer of 1 -(2,5-dimethoxyphenyl)-2-amino-1 -propanol also called as (1R, 2S)methoxamine hydrochloride of formula (1), with high enantiomeric purity from 2,5-dimethoxy benzene. The (1R, 2S)-Methoxamine, prepared by the process of the present invention is used as a pressor agent, as a vasoconstrictor, as a nasal decongestant, in ophthalmology and also found very effective in the treatment of faecal incontinence.

• Background of invention

Methoxamine contains two chiral carbons and thus exists in four isomeric forms. Of all the isomeric forms, the studies revealed (1R,2S)- isomer to be therapeutically active.

Though the molecule possesses varied range of applications, there have been fewer methods reported for the synthesis of these compounds.

US patent 2359707 describes the process for the synthesis of racemic β-(2,5-dimethoxy phenyl)-P-hydroxy-isopropyl amine in neutral, acid salt and its derivative from 2,5- dimethoxy propiophenone by treatment with methylnitrite in diethyl ether medium to obtain 2,5-dimethoxy-a-isonitrosopropiophenone hydrochloride. It is further reduced with palladium on carbon to yield β-(2,5-dimethoxyphenyl)-p-ketoisopropylamine hydrochloride and then with platinum black to get p-(2,5-dimethoxyphenyl)-β- hydroxyisopropyl amine hydrochloride. The described process for di-methoxamine HC1 is not cost-effective, due to the use of two expensive catalysts (platinum black and palladium carbon), solvent diethyl ether and involves more number of steps. The other drawback being it is racemic mixture and cannot be used directly as drug. The process described did not specify the quality of the product.

In US patent 3284490 the processes for racemic N-alkyl derivatives of methoxamine are described from dl-methoxamine.

JP 63165348 describes process for production of optically active l-(2,5- dimethoxyphenyl)-2-aminophenol by resolving racemic compound with the use of optically active L-N-acetylleucine as resolving agent. The disadvantages of the process are less yield, low quality and use of expensive naturally occurring amino acid, which prevents from employing this method on commercial scale.

WO 03/055474 A1 discloses mainly, the use of (1R, 2S)-methoxamine in the treatment of faecal incontinence at low doses without local or systemic side effects when used topically. The patent also described the synthesis of (1R, 2S)-methoxamine, from L- alanine, by protecting the amino group using methylchloroformate, converting carboxy
group of the N-protected alanine into an acid chloride insitu followed by reaction with an amine to produce an N-protected (S)-alanine amide and coupling that compound with a brominated 2,5-dimethoxybenzene in the presence of n-butyllithium or a magnesium based reagent to give (S)-amino-l-(2,5-dimethoxy-phenyl)-l-propanone, the amino group of which is protected .The reduction of the N-protected propanone was carried out using dimethylphenylsilane and the protecting group was removed by treatment with potassium hydroxide. Other method adopted in the patent to isolate (1R,2S)methoxamine is by separation of racemic methoxamine using chiral column.

The prior art suffers with some of the disadvantages like using n-butyllithium, which is pyrophoric, expensive and causes hazards to commercial scale. Also, the separation of racemic Methoxamine using chiral column mentioned in the patent can be considered for
isolating small quantities of the required isomer for analytical purposes but cannot be adopted on commercial scale for production of the drug.

US Patent 5962737 described stereospecific synthesis of the racemic threo isomers of 2- nitro-1 -phenylpropanols by reacting benzaldehyde derivative with nitroalkane in the presence of a tertiary amine and reducing 2-nitro-l-phenylpropanols with lithium aluminium hydride to 2-amino-l-phenylpropanols. Also described is phase transfer resolution of racemic mixtures of 2-amino-l-phenylpropanol and its derivatives into their optically pure isomers by reacting with the mono alkali metal salt of tartaric acid ester in a two phase system of a hydrocarbon and water. The specification further describes optically pure isomer D-threo 2-amino-( 1 -dialkoxy or alkoxy)phenylpropanol by resolution of dl- threo 2-amino-( 1 -dialkoxy or alkoxy)phenylpropanol by using dibenzoyltartaric acid. The synthesis of the product (lS,2S)-threo 2-amino-(l-dialkoxy or alkoxy) phenyl propanol involves the use of expensive and hazardous chemicals like LAH making the process technically and commercially difficult for implementation.

To over the drawbacks of the prior art processes, the present invention relates to provide a efficient, cost effective, easily scaleable at large, commercial production process, for the preparation of (1R, 2S)-Methoxamine, its salts and stereoisomers. It is also an objective of the present invention to provide (1R, 2S)methoxamine HC1 of formula (1) with high optical purity.

The present invention provides an improved process for preparing (1R, 2S)-Methoxamine, its salts and stereoisomers.

The method of the present invention is quite preferable and economical for the preparation of (1R, 2S)Methoxamine HC1 as an industrial procedure and gives (1R,2S)- methoxamine HC1 with high optical purity. The 1R, 2S-methoxamine HC1 so prepared has wide applications namely as a pressor agent, as a vasoconstrictor, as a nasal decongestant, in ophthalmology and also in the treatment of faecal incontinence.


Objectives of the invention

The main objective of the present invention is to provide an improved process for commercial synthesis of (1R, 2S)-methoxamine HC1 (1) and its stereoisomers in high
optical purity of >99%.

Another objective of the present invention is to provide an improved process for the preparation of (1R, 2S)-methoxamine HC1 (1) and (1S, 2R)-methoxamine HC1 (2) by resolving the dl-erythro-methoxamine of formula (3) with chiral carboxylic acid as the resolving agent and avoiding the use of expensive and hazardous chemicals (platinum oxide, n-butyllithium, LAH).

Another objective of the present invention is to provide an improved process for the preparation of 1R, 2S-methoxamine hydrochloride by resolving the dl-erythro- methoxamine using stoichiometric quantity of the resolving agent.

Yet another objective of the present invention is to provide an improved process for the preparation of dl-threo-methoxamine of formula (4) by treatment of dl-erythro- methoxamine with acetic anhydride followed by hydrolysis and basification.

Another objective of the present invention is to provide an improved process for the preparation of (IR, 2R)-methoxamine HC1 of the formula (5) from (1R, 2R)methoxamine HC1 by converting into base, treating further with acetic anhydride followed by hydrolysis, basification and acidification with hydrochloric acid.

Another objective of the present invention is to provide an improved process for the preparation of (1S,2S)-methoxamine HC1 of the formula (6) from (1R, 2S)-methoxamine HC1 by converting into base, treating further with acetic anhydride followed by hydrolysis, basification and acidification with hydrochloric acid.

Further objective of the present invention is to overcome the problems associated with prior art processes and to prepare (1R, 2S)-Methoxamine its pharmaceutical^ acceptable salts and its stereoisomers by simple, cost-effective, non-hazardous and easily scaleable way.

• Summary of the invention

According to the present invention there is provided an improved process for the
preparation of (IR, 2S)Methoxamine HC1 of the formula (1) and its enantiomer (1S,2R)-
Methoxamine HC1 of the formula (2)

The said process comprising the steps of

a) treating a compound 1,4-dimethoxy benzene (7) with propionyl chloride in the presence of Lewis acid (aluminium chloride) in solvent medium at a temperature in the range of-30 °C to +30 °C to produce l-(2,5-dimethoxyphenyl)propan-l-one (8)

b) reacting l-(2,5-dimethoxyphenyl)propan-l-one (8) with alkyl nitrite in the presence of solvent to give l-(2,5-dimethoxyphenyl)-2-nitrosopropan-l-one (9)

c) reducing l-(2,5-dimethoxyphenyl)-2-nitrosopropan-l-one (9) in the presence of polar solvent by using noble metal catalyst to give dl-erythro-methoxamine (3)

d) resolving dl-erythro-methoxamine (3) with tartaric acid in presence of mixture of polar solvents to give (1R, 2S)-methoxamine tartrate and (1S, 2R)-methoxamine tartrate and further acidification with HC1 to (1R, 2S)-methoxamine hydrochloride (1) and (1S, 2R)-methoxamine HC1 (2). The acidification of methoxamine tartrate with other acids gives respective salts.

According to the preferred embodiment, 1,4-dimethoxy benzene of formula (7) in step (a) is treated with propionyl chloride in the presence of Lewis acid in a solvent medium at a temperature ranging from -30 °C to +30 °C, preferably carried out at about 0 °C to -5 °C.

The Lewis acid used is selected from Boron trifluoride, Tin (IV) chloride, Aluminium chloride and Iron (III) chloride, preferably Aluminium chloride. The solvent used for the reaction is selected from dichloroethane, carbon tetrachloride, dichloromethane, chloroform and trichloroethylene, more particularly dichloromethane.

According to another preferred embodiment, the alkyl nitrite used in step (b) is selected from methylnitrite, ethylnitrite, propylnitrite and butylnitrite, preferably butylnitrite. The solvent used in step (b) is selected from acetone, dichloromethane, diethyl ether, ethyl acetate, more particularly dichloromethane.

According to another preferred embodiment, the polar solvent used for reducing l-(2,5- dimethoxyphenyl)-2-nitrosopropan-l-one of formula (9) in step (c) is selected from ethanol, methanol, n-butanol, iso-propyl alcohol, iso-butanol, preferably iso-propyl alcohol. The noble metal catalyst used is selected from palladium, platinum, Rhodium, Raney nickel, Ruthenium, more particularly Raney Nickel.

Yet another preferred embodiment, dl-erythw-methoxamine (3) is resolved in step (d) using acids selected from tartaric acid, mandelic acid, lactic acid, Dibenzoyl-tartaric acid, Ditoluoyl tartaric acid, preferably tartaric acid. The mixture of polar solvents are selected from acetone, methanol, iso-propyl alcohol, DMSO, more preferably methanol-DMSO (4:1).

According to another aspect of the present invention; there is provided an improved process for the preparation of dl-threo-methoxamine HC1 of formula (11) which comprising the steps of

(i) treating dl-erythro-methoxamine HC1 (10) with a base in aqueous medium to give dl-erythro-methoxamine (3)

(ii) reacting dl-erythro-methoxamine (3) with acetic anhydride in solvent medium followed by acid hydrolysis and basification to obtain dl-threo-methoxamine(4)

(iii) treating dl-threo-methoxamine with acid to give its HC1 salt (11).

The base used in step (i) includes sodium hydroxide, potassium carbonate, potassium hydroxide, sodium carbonate, sodium acetate, potassium acetate, sodium bicarbonate, sodium methoxide, potassium methoxide, sodium etboxide, potassium ethoxide, potassium tert.butoxide, preferably sodium hydroxide.

The solvent used in step (ii) includes hexane, dichloromethane, toluene, benzene, MIBK, xylene, dioxane, preferably toluene. The acid used for hydrolysis is selected from conc.sulphuric acid, conc. hydrochloric acid, conc. hydrobromic acid, conc. hydroiodic acid, conc. nitric acid, acetic acid, preferably conc.sulphuric acid. The base used for basification includes potassium carbonate, potassium hydroxide, sodium carbonate, sodium acetate, potassium acetate, sodium bicarbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert.butoxide, preferably sodium hydroxide.

The acid used in step (iii) includes hydrochloric acid, hydroiodic acid, hydrobromic acid, sulphuric acid, preferably hydrochloric acid.

The present invention further provides an improved process for the preparation of (JS, 2S)-Methoxamine HC1 of formula (6) from (1R, 2S)-methoxamine by treating with acetic anhydride in toluene medium followed by acid hydrolysis and basification to obtain (IS, 2S)-Methoxamine base which is further acidified to form (1S,2S)- Methoxamine HC1 (6).

The present invention further provides an improved process for the preparation of (1R, 2R)-Methoxamine HC1 of formula (5) from its diastereomer (1S, 2R)-methoxamine HC1 of formula (2) by treating with acetic anhydride in toluene medium followed by acid hydrolysis and basification to obtain (1R, 2R)-Methoxamine base which is further acidified to form (1R, 2R)-Methoxamine HC1 (5).

The following examples illustrate the invention.

EXAMPLES

Example 1
Preparation of l-(2,5-Dimethoxyphenyl)propan-l-one (8)
Aluminium chloride (127.4 g; 0.955 mol) was added to dichloromethane (420 mL) in a round bottomed flask under nitrogen atmosphere. The reaction mixture was cooled to -5 °C; 1,4-dimethoxybenzene (100 g; 0.724 mol) was added slowly within 15-30 minutes. Propionic chloride (87 g; 0.94 mol) dissolved in dichloromethane (245 mL) was added slowly within 2 hours. The reaction mass was allowed to stir for 2 hours and then was quenched in crushed ice (1 kilo) and HC1 (75 mL) at 0 - 5 °C. Separated the layers and the organic layer was washed with 5% sodium hydroxide solution, dried and concentrated (140 g; colorless liquid); Purity by HPLC : 99.04%

Spectroscopic interpretation

The structure of the product, l-(2,5-Dimethoxyphenyl)propan-l-one was confirmed with the help of the following spectroscopic data.

a) IR (cm-1) (KBr)
Aromatic C-H stretch at 3071, aliphatic C - H stretch at 2938, C = O stretch at 1674, benzenoid bands at 1609 and 1584, C - O stretch at 1223, C - H out of plane bending of tri-substituted benzene ring at 814,719.

b) 1H NMR(CDCb, 300 MHz) (δH)
1.16 (3H, t, -CH2-CH3), 3.0 (2H, q, -CH2-CH3), 3.78 (3H, s, -OCH3), 3.85 (3H, s, -OCH3), 6.83 - 7.72 (3H, m, aromatic protons)

c) 13C NMR (CDCb, 300 MHz) (δC)
8.44 (-CH2-CH3), 37.03 (-CH2-CH3), 55.74 (-OCH3), 56.01 (-OCH3), 113.09 - 153.41 (aromatic carbons), 202.96 (C=O)

d) Mass spectrum (ESI, methanol)
[M+Na]+ at m/z 217 (9), [M+H]+ at m/z 195 (100).

Example 2
Preparation of l-(2,5-Dimethoxyphenyl)-2-nitrosopropan-l-one (9) l-(2,5-Dimethoxyphenyl)propan-l-one (100 g; 0.515 mol) was added to dichloromethane (660 mL) in a round bottomed flask under nitrogen atmosphere. Butylnitrite (46.6 g; 0.52 mol) was slowly added in about 30 minutes at 30 - 35 °C. Diethyl ether (60.2 mL) was added to the reaction mixture and dry HC1 gas was purged for about 4 hours at 30 - 35 °C. The reaction mass was maintained for 12 hours and then concentrated under vacuum The residue obtained (60 g; Pale yellow crystalline powder); Purity by HPLC: 99.81%; mp: 104-107 °C

Spectroscopic interpretation

The structure of the product, l-(2,5-Dimethoxyphenyl)-2-nitrosopropan-l-one was confirmed with the help of the following spectroscopic data

a) IR (cm1) (KBr)
O-H stretch at 3250 (broad), aromatic C-H stretch at 3024, aliphatic C - H stretch at 2934, C = O stretch at 1688, C = N stretch at 1645, benzenoid bands at 1589 and 1504, C-O stretch at 1231, C-H out of plane bending of tri-substituted benzene ring at 745,702.

b) 1H NMR(CDCb, 300 MHz) (δh)
2.07 (3H, s, -C-CH3), 3.72 (3H, s, -OCH3), 3.76 (3H, s, -OCH3), 6.84-6.99 (3H, m, aromatic protons), 8.89 (1H, bs, OH)

c) 13C NMR (CDCb, 300 MHz) (δC)
9.16 (-C-CH3), 55.81 (-OCH3), 56.34 (-OCH3), 113.09 - 153.27 (aromatic carbons), 157.07 (C=N-OH); 193.32 (CO)

d) Mass spectrum (ESI, methanol) [M+H]+ at m/z 224 (100)

Example 3
Preparation of dl-erythro-methoxamine HC1 (10)
Raney nickel (50 g); iso-propyl alcohol (250 mL) were added to the autoclave. l-(2,5- Dimethoxyphenyl)-2-nitrosopropan-1 -one (100 g; 0.448 mol) was added slowly at 50 - 55 °C by simultaneously purging the flask with hydrogen at 2-3 Kilo pressure. When hydrogen consumption ceases, the catalyst was filtered and the filtrate was concentrated. iso-Propyl alcohol (200 mL) was added to the concentrated mass followed by acidification with HC1 to obtaindl-erythro-methoxamine HC1 (70 g; white crystalline solid)

Spectroscopic interpretation
The structure of the product, dl-erythro-methoxaxmne HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3409, aromatic C-H stretch at 3010, aliphatic C - H stretch at 2914, HN-H str. at 2574 and 2467, benzenoid bands at 1615 and 1569, C-N stretch at 1279, C-O stretch at 1216, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 812.

b) 1H NMR (DMSO-d6, 300 MHz) (δH)
1.0 (3H,d, -CH-CH3), 3.74 (3H, s, -OCH3), 3.77 (3H, s, -OCH3), 4.89 (1H, q, -CH-CH3),6.1 (1H, d, -CH-OH), 6.87-7.01 (3H, m, aromatic protons), 8.06 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δc)
14.75 (-CH-CH3), 52.12 (-OCH3), 55.70 (-OCH3), 55.70 (-CH-CH3), 67.25 (CH-OH), 111.89 - 153.16 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H)+ at m/z 212 (100), [M-H2O]+ at m/z 194 (56).

Example 4
Preparation of(JR,2S)-Metboxamine HC1 (1) and (1S, 2R)-Methoxamine HC1 (2) dl-erythro-methoxamine HC1 (117g; 0.47 mol) was dissolved in water (350 mL) at 30-35 °C. The clear solution obtained was basified using 50% sodium hydroxide solution. dl-erythro-Methoxaumne (3) was extracted into dichloromethane (150 mL) and concentrated. Mixture of methanol/DMSO (4:1; 1650 mL) was added and the mass was heated to 50 °C. L-(+)-Tartaric acid (71.1g; 0.47mol) was added slowly and the temperature of the mass was further raised to 70 °C for complete dissolution. The mass was cooled to 35 °C and maintained for 48 hours. (IR,2.S)-Methoxamine tartrate complex (80 g) precipitated was filtered. From the filtrate on concentration was obtained (1S,2R)- methoxamine tartrate complex (82 g) (IR,25)-Methoxamine tartrate complex was added to water (250 mL) at 35 °C, basified to 12 - 13 pH with 50% sodium hydroxide solution. Dichloromethane (200 mL) was added and stirred for 30 min. Separated the org layer, dried over sodium sulphate and concentrated completely under vacuum at 45° C. Iso-Propyl alcohol (150 mL) was added, charcaolized and filtered. The clear filtrate was acidified with 20%IPA HC1 to yield (1R, 2S)-Methoxamine HC1 which was filtered and dried (48 g); White crystalline powder; Purity by HPLC : 100%; Chiral purity : 100 %; mp : 172-175 °C; [α]D: -47.94° (c = 2% in MeOH)

Spectroscopic interpretation

The structure of the product, (1R,2S)-Methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3300, aromatic C-H stretch at 3065, aliphatic C-H stretch at 2938, HN-H str. at 2693 and 2580, benzenoid bands at 1609 and 1578, C-N stretch at 1277, C-O stretch at 1217, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 818.

b) 1H NMR (DMSO-d6 300 MHz) (δH)
0.91 (3H,d, -CH-CH3), 3.71 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 5.14 (1H, m, -CH- NH3+), 5.95 (1H, d, -CH-OH), 6.83-7.01 (3H, m, aromatic protons), 8.25 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δC)
II. 44 (-CH-CH3), 49.22 (-OCH3), 55.24 (-OCH3), 55.70 (-CH-CH3), 66.49 (CH-OH),

III. 41 - 153.03 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (15).
(IS, 2i?)-Methoxamine tartrate complex was added to water (275 mL) at 35 °C, basified

to 12 - 13 pH with 50% sodium hydroxide solution. Dichloromethane (250 mL) was added and stirred for 30 min. Separated the organic layer, dried over sodium sulphate and concentrated completely under vacuum at 45 °C. Iso-Propyl alcohol (175 mL) was added, charcaolized and filtered. The clear filtrate was acidified with 20%IPA HC1 to yield (1S, 2R)-Methoxamine HC1 which was filtered and dried (51 g) White crystalline powder; Purity by HPLC : 99.99%; Chiral purity . 100 %; mp . 172-175 °C;[α]D : + 47.9° (c = 2% in MeOH)

Spectroscopic interpretation

The structure of the product, (1S, 2R)-Methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) m (cm1) (KBr)
O-H stretch at 3265, aromatic C-H stretch at 3059, aliphatic C-H stretch at 2997, HN-H str. at 2658 and 2567, benzenoid bands at 1611 and 1587,
C-N stretch at 1294, C-O stretch at 1217, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 818.

b) 1H NMR (DMSO-d6,300 MHz) (δH)
0.91 (3H,d, -CH-CH3), 3.71 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 5.14 (1H, m, -CH- NH3+), 5.97 (1H, d, -CH-OH), 6.83-7.01 (3H, m, aromatic protons), 8.19 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6,300 MHz) (δc)

II. 46 (-CH-CH3), 49.18 (-OCH3), 55.23 (-OCH3), 55.68 (-CH-CH3), 66.45 (CH-OH),

III. 42 - 153.02 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (15).

Example 5
Preparation of dl-threo-methoxamine HC1 (11)
dl-erythro-methoxamine HC1 (120g; 0.48 mol) was dissolved in DM water (500 mL) at 30 - 35 °C and cooled to 10 - 15 °C. The clear solution was basified using 50 % sodium hydroxide solution and extracted in dichloromethane (250 mL). The organic layer was separated and concentrated under vacuum. The residue thus obtained was dissolved in toluene (200 mL) and was added slowly to acetic anhydride (120 g; 1.17mol) at 65 - 70 °C. The reaction mass was maintained under stirring and further cooled to 10 - 20 °C. Conc.Sulphuric acid (57.6g; 0.58mol) was added to the reaction mass slowly by maintaining the reaction mass at 10 - 200 C. The reaction mass was heated to 35 - 400 C for 3 hours and concentrated under vacuum at below 80 °C.

The reaction mass was cooled to 10 - 15 °C and was dissolved in DM water (250 mL). The mass was maintained for 3 h at reflux temperature and again cooled to 10 - 15 °C.

The pH was adjusted to 12 - 13 using 50% sodium hydroxide solution and extracted the d/-threo-Methoxamine base in dichloromethane (250 mL). Separated the organic layer and concentrated under vacuum. The concentrated mass was triturated with iso-Propyl alcohol (150 mL); acidified using 20% HC1 in iso-propyl alcohol. Distilled the iso- propyl alcohol completely to the final traces and acetone (300 mL) was added. The material precipitated, crude dl-threo-methoxamine HC1 was filtered. (85 g) Off white powder; Purity by HPLC: 99.4%; mp: 221-223 °C Spectroscopic interpretation

The structure of the product, di-threo-methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm"1) (KBr)
O-H stretch at 3401, aromatic C-H stretch at 3005, aliphatic C-H stretch at 2924, HN-H str. at 2581 and 2490, benzenoid bands at 1609 and 1578, C-N stretch at 1277, C-0 stretch at 1215, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 802.

b) NMR (DMSO-d6,300 MHz) (δH)
1.2 (3H,d, -CH-CHs), 3.72 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 4.87 (1H, q, -CH-CH3),6.3 (1H, d, -CH-OH), 6.83-6.99 (3H, m, aromatic protons), 8.03 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δC)
14.76 (-CH-CH3), 52.15 (-OCH3), 55.89 (-OCH3), 67.34 (CH-OH), 111.96 - 153.21 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (52).

Example 6
Preparation of (1S,2S)- Methoxamine HC1 (6)
(IR, 2S)-Methoxamine HC1 (120 g; 0.48 mol) was dissolved in DM water (500 mL) at 30 -35 °C and cooled to 10 - 15 °C. The clear solution was basified using 50 % sodium hydroxide solution and extracted in dichloromethane (250 mL). The organic layer was separated and concentrated under vacuum. The residue thus obtained was dissolved in toluene (200 mL) and was added slowly to acetic anhydride (120 g; 1.17 mol) at 65 - 70 °C. The reaction mass was maintained under stirring and further cooled to 10 - 20 °C. Conc.sulphuric acid (57.6 g; 0.58 mol) was added to the reaction mass slowly by maintaining the reaction mass at 10 - 20 °C. The reaction mass was heated to 35 - 40 °C for 3 hours and concentrated under vacuum at below 80 °C.

The reaction mass was cooled to 10-15°C and was dissolved in DM water (250 mL). The mass was maintained for 3 h at reflux temperature and again cooled to 10 - 15 °C. The pH was adjusted to 12-13 using 50% sodium hydroxide solution and extracted the (1S, 2S)-Methoxamine base in dichloromethane (250 mL). Separated the organic layer and concentrated under vacuum The concentrated mass was triturated with iso-Propyl alcohol (150 mL); acidified using 20% HC1 in iso-propyl alcohol. Distilled the iso- propyl alcohol completely to the final traces and acetone (300 mL) was added. The material precipitated, crude (IS, 2S)-methoxamine HC1 was filtered. (86 g); White crystalline powder; Purity by HPLC . 99.8%; Chiral purity : 99.7%; mp : 172-175 °C; [α]D: + 30.739° (c = 2% in MeOH)

Spectroscopic interpretation
The structure of the product, (IS, 2S)-methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3356, aromatic C-H stretch at 3080, aliphatic C-H stretch at 2999, HN-H str. at 2641 and 2583, benzenoid bands at 1611 and 1506, C-N stretch at 1302, C-O stretch at 1229, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 812.

b) 1H NMR (DMSO-d6 300 MHz) (δH)
1.04 (3H,d, -CH-CH3), 3.72 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 4.90 (1H, m, -CH- CH3),6.07 (1H, d, -CH-OH), 6.84-7.01 (3H, d, aromatic protons), 8.15 (3H, bs, HN-H)
The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δC)
14.75 (-CH-CH3), 52.18 (-OCH3), 55.21 (-OCH3), 55.69 (-CH-CH3), 67.32 (CH-OH), 111.38 -153.01 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (48).

Example 7
Preparation of (1R, 2R)-Methoxamine HC1 (5)
(IS, 2R)Methoxamine HC1 (120g; 0.48 mol) was dissolved in DM water (500 mL) at 30 - 35 °C and cooled to 10 - 15 °C. The clear solution was basified using 50 % sodium hydroxide solution and extracted in dichloromethane (250 mL). The organic layer was separated and concentrated under vacuum. The residue thus obtained was dissolved in toluene (200 mL) and was added slowly to acetic anhydride (120 g; 1.17mol) at 65 - 70 °C. The reaction mass was maintained under stirring and further cooled to 10 - 20 °C. Cone.Sulphuric acid (57.6g; 0.58mol) was added to the reaction mass slowly by maintaining the reaction mass at 10 - 20 °C. The reaction mass was heated to 35 - 40 °C for 3 hours and concentrated under vacuum at below 80 °C.

The reaction mass was cooled tol0-15°C and was dissolved in DM water (250 mL). The mass was maintained for 3 h at reflux temperature and again cooled to 10 - 15 °C. The pH was adjusted to 12-13 using 50% sodium hydroxide solution and extracted the (IR, 2i?)-Methoxamine base in dichloromethane (250 mL). Separated the organic layer and concentrated under vacuum. The concentrated mass was triturated with iso-Propyl alcohol (150 mL); acidified using 20% HC1 in iso-propyl alcohol Distilled the iso- propyl alcohol completely to the final traces and acetone (300 mL) was added. The material precipitated, crude (1R, 2R)-methoxamine HC1 was filtered. (90 g) White crystalline powder; Purity by HPLC: 99.1%, Chiral purity. 100%; mp: 172-175 °C;[α]D: -29.04° (c - 2% in MeOH)

Spectroscopic interpretation

The structure of the product, (1R, 2R)methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3356, aromatic C-H stretch at 3078, aliphatic C-H stretch at 2999, HN-H str. at 2619 and 2500, benzenoid bands at 1611 and 1508, C-N stretch at 1302, C-O stretch at 1229, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 812.

b) 1H NMR(DMSO-d6 300 MHz) (δH)
I. 04 (3H,d, -CH-CHa), 3.72 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 4.90 (1H, m, -CH- CH3),6.07 (1H, d, -CH-OH), 6.83-7.01 (3H, d, aromatic protons), 8.13 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6 300 MHz) (δe)
II. 41 (-CH-CH3), 52.16 (-OCH3), 55.22 (-OCH3), 55.70 (-CH-CH3), 67.32 (CH-OH), III. 39-153.15 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (44).

We Claim

1. An improved process for the preparation of (1R, 2S)-Methoxamine HC1 of the formula (1) and its enantiomer (1S, 2R)-Methoxamine HC1 of the formula (2) which comprises of

a) treating 1,4-dimethoxy benzene (7) with propionyl chloride in the presence of Lewis acid in solvent medium at a temperature in the range of -30 °C to +30 °C to produce l-(2,5-dimethoxyphenyl)propan-l-one (8)

b) reacting l-(2,5-dimethoxyphenyl)propan-l-one (8) with alkyl nitrite in the presence of solvent to give l-(2,5-dimethoxyphenyl)-2-nitrosopropan-l-one (9)

c) reducing 1 -(2,5-dimethoxyphenyl)-2-nitrosopropan-1 -one (9) in the presence of polar solvent by using noble metal catalyst to give dl-erythro-methoxamine (3)
and

d) resolving dl-erythro-methoxanime (3) with tartaric acid in presence of mixture of polar solvents to give (1R, 2S)-methoxamine tartrate and (1S, 2R)-methoxamine tartrate and further acidification with HC1 to (1R, 2S)-methoxamine hydrochloride
(1) and (1S, 2R)-methoxamine HC1 (2). The acidification of methoxamine tartrate with other acids gives respective salts.

2. An improved process claimed in claim 1, wherein the 1,4-dimethoxy benzene of formula (7) in the step (a) is treated with propionyl chloride in the presence of Lewis acid in a solvent medium at a temperature ranging from -30 °C to +30 °C, preferably carried out at about 0 °C to -5 °C. The Lewis acid used is selected from Boron trifluoride, Tin (IV) chloride, Aluminium chloride and Iron (III) chloride, preferably Aluminium chloride. The solvent used for the reaction is selected from Dichloroethane, Carbon tetrachloride, Dichloromethane, Chloroform and Trichloroethylene, more particularly dichloromethane.

3. An improved process as claimed in claims 1 & 2, wherein the alkyl nitrite used in step (b) is selected from methylnitrite, ethylnitrite, propylnitrite and butylnitrite, preferably butylnitrite. The solvent used in step (b) is selected from acetone, dichloromethane, diethyl ether, ethyl acetate, more particularly dichloromethane.

4. An improved process as claimed in claims 1 to 3, wherein the polar solvent used for reducing 1 -(2,5-dimethoxyphenyl)-2-nitrosopropan-1 -one of formula (9) in step (c) is selected from ethanol, methanol, n-butanol, iso-propyl alcohol, iso-butanol, preferably iso-propyl alcohol. The noble metal catalyst used is selected from palladium, platinum, Rhodium, Raney nickel, Ruthenium, more particularly Raney Nickel.

5. An improved process as claimed in claims 1 to 4, wherein the dl-erythro- methoxamine (3) is resolved in step (d) using acids selected from tartaric acid, mandelic acid, lactic acid, esters of tartaric acid, preferably tartaric acid. The mixture of polar solvents are selected from acetone, methanol, iso-propyl alcohol, DMSO, more preferably methanol-DMSO (4:1).

6. An improved process for the preparation of dl-threo-methoxamine HC1 of formula (11) which comprising the steps of

(i) treating dl-erythro-methoxamine HC1 (10) with a base in aqueous medium to give dl-erythro-methoxamine (3)

(ii) reacting dI-erythro-methoxamine (3) with acetic anhydride in solvent medium followed by acid hydrolysis and basification to obtain dl-threo-methoxamine (4)

(iii) treating methoxamine with acid to give its HC1 salt of formula (11).

7. A process claimed in Claim 6, wherein the base used in step (i) includes sodium hydroxide, potassium carbonate, potassium hydroxide, sodium carbonate, sodium acetate, potassium acetate, sodium bicarbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert.butoxide, preferably sodium hydroxide.

8. A process claimed in Claim 6, wherein the solvent used in step (ii) includes hexane, dichloromethane, toluene, benzene, MIBK, xylene, dioxane, preferably toluene. The acid used for hydrolysis includes Cone. Sulphuric acid, Cone. Hydrochloric acid, Cone. Hydrobromic acid, Cone. Hydroiodic acid, Cone. Nitric acid, acetic acid, preferably conc. sulphuric acid. The 4 base used for basification is selected from potassium carbonate, potassium hydroxide, sodium carbonate, sodium acetate, potassium acetate, sodium bicarbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert.butoxide, preferably sodium hydroxide.

9. A process claimed in Claim 6, wherein the acid used in step (iii) includes hydrochloric acid, hydroiodic acid, hydrobromic acid, sulphuric acid, preferably hydrochloric acid.

10. An improved process for the preparation of (1S, 2S)-methoxamine HC1 of formula (6) and (1R, 2R)-methoxamine HC1 of formula (5) from their diastereomers (1R,2S) methoxamine and (1S, 2R)-methoxamine by treating with acetic anhydride in toluene medium followed by acid hydrolysis and basification to obtain respective bases (1S,2S)-methoxamine & (1R, 2R)-methoxamine which are further acidified to form (1S.2S)- methoxamine HC1 and (1R,2R)- methoxamine HC1.