WO2016147132A1

WO2016147132A1 - A process for the preparation of droxidopa

Info

Publication number: WO2016147132A1
Application number: PCT/IB2016/051491
Authority: WO
Inventors: Murali Rajappa; Arnab ROY; Amit Kumar MANDAL; Dhileepkumar Krishnamurthy; Mahesh Ramrao KULKARNI; Kamlesh Harichandra CHAVAN; Suresh Kumar SYTHANA; Sanjeev Kumar Aavula; Chirag Navinchandra PATEL
Original assignee: Piramal Enterprises Limited
Priority date: 2015-03-18
Filing date: 2016-03-17
Publication date: 2016-09-22

Abstract

The present invention provides a novel process for the preparation of droxidopa, a synthetic amino acid precursor of norepinephrine. The process is a stereoselective process for the preparation of droxidopa using asymmetric induction and thus avoids synthetic process involving chiral resolution. The present invention also provides novel intermediates of formula V and formula VI.

Description

A PROCESS FOR THE PREPARATION OF DROXIDOPA

Field of the invention

The present invention relates to a process for the preparation of (2S,3 ?)-2-amino-3-(3,4- dihydroxyphenyl)-3-hydroxypropanoic acid, which is known as Droxidopa, a synthetic amino acid precursor of norepinephrine. The present invention also relates to novel intermediates for the preparation of Droxidopa.

Background of the invention Droxidopa is chemically known as (2S,3 ?)-2-amino-3-(3,4-dihydroxyphenyl)-3- hydroxypropanoic acid and it is structurally represented by the following formula I. It is also known as L-i/zreo-dihydroxyphenylserine. Droxidopa is available in the market as Northera® capsules with dosages of 100 mg, 200 mg and 300 mg for oral administration.

Droxidopa (Formula I)

Droxidopa is an orally active, synthetic norepinephrine precursor that was originally launched in 1989 in Japan by Sumitomo Dainippon Pharma for the oral treatment of frozen gait or dizziness associated with Parkinson's disease and for the treatment of orthostatic hypotension, syncope or dizziness associated with Shy-Drager syndrome and familial amyloidotic polyneuropathy. In 2011, the product was filed for approval in the U.S. and in 2014 Northera® was approved for the treatment of orthostatic dizziness, light headedness, or the "feeling that you are about to black out" in adult patients with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure, dopamine beta- hydroxylase deficiency, and non-diabetic autonomic neuropathy. Droxidopa is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopadecarboxylase, which is extensively distributed throughout the body. Chirality has acquired increasing importance for the pharmaceutical industry, as evidenced by the fact that more than 80% of the drugs developed hitherto have chiral properties. The various enantiomers may develop completely different effects in the body, so that only one of two or more enantiomeric forms administered may be effective. In the case of droxidopa, the compound of formula I, it has been observed that the h-threo enantiomer is the desired isomer having desired activity. Administration of the active h-threo enantiomer of the compound of formula I, substantially free of its other isomers, would essentially enable a reduction in the dose of drug. Due to the importance of the h-threo enantiomer of the compound of formula I as an oral, synthetic norepinephrine precursor, there exists a need to develop an economical and efficient synthetic process for its production. Droxidopa is disclosed in US Patent No. 3,920,728 (hereinafter referred to as US'728 patent). The US'728 patent also provides a process for the preparation of droxidopa comprising the steps of (i) reaction of 3,4-dibenzyloxybenzaldehyde with glycine, followed by treatment with sodium acetate trihydrate and diethylamine to obtain racemic- i zreo/er i zro-3-(3,4-dibenzyloxyphenyl)-serine; (ii) treatment of the compound obtained in step (i) with carbobenzoxy chloride to obtain racemic-threo/erythro-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserine; (iii) treatment of the compound obtained in step (ii) with freshly distilled dicyclohexylamine to obtain racemic-i/zreo-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserinedicyclohexylamine salt, which on treatment with HC1 gas in the presence of ethyl acetate yields racemic-threo-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserine; (iv) treatment of the compound obtained in step (iii) with (+)-ephedrine to yield (+)-ephedrine salt of h-threo-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserine; (v) hydrolysis of the compound obtained in step (iv) to yield L-i/zreo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and (vi) reduction of the compound obtained in step (v) over Pd/C to yield h-threo-3-(3,4- dibenzyloxyphenyl)-serine. The process disclosed in US'728 patent is an elaborate and tedious process for commercial manufacturing. Also, the chiral resolution to obtain threo/erythro isomer results into 50% loss of the undesired isomer, which affects the overall yield of the process. The US Patent No. 4,319,040 discloses a process for preparation of droxidopa comprising reaction of racemic threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine with resolving agent of formula A, followed by decomposition using hydrochloric acid to yield (-)-3-(3,4- dibenzyloxyphenyl) -N-c arbobenzoxy serine .

Formula A wherein R is methyl, isopropyl or isobutyl.

The US Patent No. 4,562,263 (hereinafter referred to as US'263 patent) discloses a process for preparation of droxidopa comprising optical resolution of N-phthaloyl-3-(3,4- methylenedioxyphenyl) serine using optically active amine selected from the group consisting of strychinine, cinconidine, L-norephedrine, S-2-amino-l,l-diphenyl-l-propanol and L-3-hydroxy-3-(4-nitrophenyl)-2-amino-l-propanol to yield L-N-phthaloyl-3-(3,4- methylenedioxyphenyl) serine, reacting the resulting compound with a Lewis acid selected from the group consisting of aluminium trichloride, aluminium tribromide, boron trichloride and boron tribromide to form N-phthaloyl-3-(3,4-dihydroxyphenyl)-serine; which is then deprotected by removal of phthaloyl group with hydrazine to yield L-threo- 3-(3,4-dihydroxyphenyl)-serine. The process involves use of complex agents for isomer separation, which also results in < 50 % of desired isomer. Also, the hydrazine used for the deprotection of phthaloyl group is known to be genotoxic and thus it is required to remove traces of hydrazine from the final product, droxidopa. However, the limitation of the process described in US'263 patent is that it is unable to remove traces of hydrazine.

The prior art processes for the preparation of droxidopa involve a resolution method involving significant processing. The use of resolving agent renders the process costly. Partial recycling of the resolving agent is feasible but such recycling is costly as it requires additional processing and is also associated with waste generation. The undesired enantiomer cannot be recycled and is discarded. The maximum theoretical yield of the key intermediate obtained is just 50 % on a laboratory scale synthesis due to loss of half of the racemate. This yield may be further reduced due to the need for high chiral purity (> 95% enantiomeric excess). Thus, there is a clear need to develop an alternative asymmetric synthesis which would provide the desired L-threo isomer in an efficient and more specific manner. The said prior art processes are therefore disadvantageous for commercial manufacturing due to non-feasibility of the reaction process owing to use of genotoxic reagents, and due to the elaborate and tedious nature of the process, providing low yield of the desired isomer.

Thus, there is a need to develop a process for preparation of droxidopa, which avoids the synthetic process involving chiral resolution to obtain desired L-threo isomer, thereby making the process of the present invention simple, efficient, cost-effective and industrially feasible process. The object of this invention is to provide an alternative process for the preparation of the L-threo isomer of droxidopa, the compound represented by formula I, which is an enantioselective process. The process of the present invention allows efficient large-scale synthesis by overcoming the drawbacks of the conventional resolution technique.

Objects of the invention

An object of the present invention is to provide a process for the preparation of L-threo- dihydroxyphenylserine (droxidopa) represented by formula I, which improves upon the limitations of the prior art process.

An object of the present invention is to provide a stereoselective process for the preparation of droxidopa using asymmetric induction, thereby avoiding synthetic process involving chiral resolution.

An object of the present invention is to provide a process for the preparation of droxidopa involving novel intermediates of formula V and formula VI. An object of the present invention is to provide novel intermediates of formula V and formula VI and a process for their preparation.

Another object of the present invention is to provide a process for preparation of droxidopa, wherein the desired -threo isomer is obtained with selectivity > 95 %.

Still another object of the present invention is to provide a process for the preparation of droxidopa which is simple, efficient, cost-effective and industrially feasible process. Summary of the invention

In accordance with an aspect of the present invention, there is provided a process for the preparation of L-i/zreo-dihydroxyphenylserine (droxidopa) represented by formula I comprising the steps of:(a) reacting compound of formula II with compound of formula III using a catalyst in the presence of a solvent to yield compound of formula IV; (b) reacting the compound of formula IV, obtained in step (a) with haloacetate in the presence of a base and a solvent to yield compound of formula V; (c) deprotecting the compound of formula V, obtained in step (b) using an acid in the presence of a solvent to yield the compound of formula VI or its pharmaceutically acceptable salt; (d) reacting compound of formula VI, obtained in step (c) with an acid in the presence of a solvent to obtain desired isomer of formula VII; (e) reacting compound of formula VII, obtained in step (d) with a base in the presence of a solvent to yield compound of formula VIII; (f) reacting compound of formula VIII, obtained in step (e) with amine protecting compound in the presence of a base and a solvent to yield the compound of formula IX; and (g) deprotecting the compound of formula IX, obtained in step (f) to yield the compound of formula I.

The process of the present invention is depicted in the following scheme:

Step a

Catalyst

Solvent

Formula II Formula III

Formula V Formula VI

Step d

Acid, solvent

Selectivity > 95% O o ven

Formula VII Formula VIII

Formula IX wherein Ri is selected from a group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl and heterocyclyl;

R₂ is selected from a group consisting of unsubstituted or substituted alkyl and aryl; and R₃ is absent; or R₃ is an aryl ring selected from phenyl or naphthyl.

In accordance with another aspect of the present invention, there is provided a novel intermediate of formula V or its pharmaceutically acceptable salt

Formula V

wherein Ri and R₂ are as defined herein. In accordance with another aspect of the present invention, there is provided a novel intermediate of formula VI or i le salt

Formula VI wherein R₂ is as defined herein.

In accordance with yet another aspect of the present invention, there is provided a process for the preparation of the novel intermediate of formula V; and the intermediate of formula VI or its pharmaceutically acceptable salt.

In accordance with another aspect of the present invention, the process of the present invention overcomes the disadvantages associated with the processes described in the prior art references, which is mainly concerned with the use of a synthetic process involving chiral resolution using chiral resolving agents to obtain desired L-threo isomer, wherein the selectivity to separate the desired isomer is very low. Also, the processes described in the prior arts teach the use of genotoxic reagents; and are elaborate and tedious processes. The process of the present invention is a stereoselective process utilizing asymmetric induction involving novel intermediates to obtain desired L-threo isomer in droxidopa with selectivity > 95 %, thereby making the process of the present invention simple, efficient, cost-effective and industrially applicable.

Detailed description of the invention

The present invention relates to a process for the preparation of L-threo- dihydroxyphenylserine (droxidopa) of formula I,

Formula I

comprising the steps of:

a) reacting compound of formula II

Formula II with compound of formula III

O

H₂N * ^ R,

Formula III

wherein Ri is as defined herein,

using a catalyst in the presence of a solvent to yield compound of formula IV,

Formula IV

wherein Ri is as defined herein; reacting the compound of formula IV, obtained in step (a) with haloacetate presence of a base and a solvent to yield compound of formula V,

Formula V

wherein Riand R₂ are as defined herein; deprotecting the compound of formula V, obtained in step (b) using an acid in the presence of a solvent to yield compound of formula VI or its pharmaceutically acceptable salt,

Formula VI

wherein R₂ is as defined herein; d) reacting compound of formula VI, obtained in step (c) with an acid in the presence of a solvent to obtain compound of formula VII as desired isomer,

Formula VII

wherein R₂ is as defined herein; e) reacting compound of formula VII, obtained in step (d) with a base in the presence of a solvent to yield compound of formula VIII;

Formula VIII f) reacting compound of formula VIII, obtained in step (e) with amine protecting compound using a base in the presence of a solvent to yield compound of formula IX; and

Formula IX

wherein R₃ is absent; or R₃ is an aryl ring selected from phenyl or naphthyl; deprotecting the compound of formula IX, obtained in step (f) to yield the compound of formula I.

The present invention relates to a compound of formula V or its pharmaceutically acceptable salt

Formula V

wherein Ri is selected from a group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl and heterocycyl;

R₂ is selected from a group consisting of unsubstituted or substituted alkyl and aryl.

The present invention also relates to a process for preparation of a compound of formula V

wherein Ri and R₂ are as defined herein, comprising reacting compound of formula IV

Formula IV

wherein Ri is as defined herein,

with haloacetate in the presence of a base and a solvent to yield compound of formula V.

The present invention relates to a compound of formula VI or its pharmaceutically acceptable salt

Formula VI

wherein R₂ is selected from a group consisting of unsubstituted or substituted alkyl and aryl. The present invention also relates to a process for the preparation of compound of formula VI or a pharmaceutically acceptable salt thereof

Formula VI

wherein R₂ is as defined herein,

comprising deprotecting compound of formula V

Formula V

wherein Ri and R₂ are as defined herein,

using an acid in the presence of a solvent to yield compound of formula VI pharmaceutically acceptable salt.

The present invention relates to a process for the preparation of formula VII

Formula VII

wherein Ri and R₂ are as defined herein,

comprising reacting compound of formula VI or a pharmaceutically acceptable salt thereof

Formula VI with an acid in the presence of a solvent to obtain desired isomer of formula VII having > 95 % of selectivity of desired L-threo isomer. The obtained compound of formula VII is further treated with a base to yield compound of formula VIII. In accordance with the embodiments of the present invention Ri is selected from a group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl and heterocyclyl.

In accordance with the embodiments of the present invention, the unsubstituted or substituted alkyl is (Ci-Cio)-alkyl, which may be a straight-chain or branched chain alkyl; for example, Ci-Cio for straight chain and C₃-C₁₀ for branched chain. Suitable alkyl groups containing from one to ten carbon atoms, include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3- pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl, 3-hexyl, n-heptyl, isoheptyl, 2-heptyl, 3- heptyl, n-octyl, isooctyl, 2-octyl, 3-octyl, n-nonyl, isononyl, 2-nonyl, 3-nonyl, n-decyl, isodecyl, 2-decyl and 3-decyl.

Furthermore, the alkyl groups may be unsubstituted or substituted with one or more substituents. A substituted alkyl refers to a (Ci-Cio)-alkyl substituted with one or more groups, preferably 1-3 groups, independently selected from halogen, hydroxy, (Ci-C₆)- alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)₂-alkyl.

In accordance with the embodiments of the present invention, the cycloalkyl is (C₃-C₁₂)- cycloalkyl, wherein a saturated or partially unsaturated cyclic hydrocarbon radical including 1, 2 or 3 rings and including a total of 3 to 12 carbon atoms forming the rings. The term cycloalkyl includes bridged, fused and spiro ring systems. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, bicyclo[2.1.0]pentane, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]hept-2- ene, spiro[3.3]heptanes and l,2,3,3a-tetrahydropentalene.

Furthermore, the cycloalkyl group may be unsubstituted or substituted with one or more groups, preferably 1-3 groups independently selected from halogen, hydroxy, (C₁-C6)- alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)₂-alkyl. In accordance with the embodiments of the present invention, the aryl is (C₆-Ci₄)-aryl, which refers to monocyclic or bicyclic hydrocarbon groups having 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system. Examples of (C₆-Ci₄)-aryl residues are phenyl, naphthyl, fluorenyl and anthracenyl. Aryl groups can be unsubstituted or substituted with one or more groups, for example 1, 2, 3, 4 or 5 groups independently selected from halogen, hydroxy, (Ci-C₆)-alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)₂-alkyl.

In accordance with the embodiments of the present invention, the heterocyclyl is a 3- to 9- membered saturated or partially unsaturated monocyclic or bicyclic ring system containing one to four identical or different hetero atoms selected from a nitrogen (N), a sulphur (S) or an oxygen (O) atom. Heterocyclyl includes saturated heterocyclic ring systems, which do not contain any double bond. Partially unsaturated heterocyclic ring systems containing at least one double bond, but do not form an aromatic system containing hetero atom. Suitable saturated and partially unsaturated heterocyclic groups include, but are not limited to, aziridine, oxirane, oxiridine, thiirane, oxetane, azetidine, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dihydropyran, tetrahydropyran, thio- dihydropyran, thio-tetrahydropyran, piperidine, piperazine, morpholine, 1,3-oxazinane, 1,3-thiazinane, 4,5,6-tetra hydropyrimidine, 2,3-dihydrofuran, dihydrothiene, dihydropyridine, tetrahydro pyridine, isoxazolidine, pyrazolidine, azepane, oxepane, thiepane and azocane.

Further, the heterocycyl having an aromatic ring containing heteroatom/s are herein referred to by the customary term "heteroaryl". Within the context of the present invention and as used herein, the term "heteroaryl" refers to a 5 to 10-membered aromatic monocyclic or bicyclic ring system containing one to four identical or different hetero atoms selected from N, S or an O atom. Examples of heteroaryl include, but are not limited to pyrrole, pyrazole, imidazole, triazole, pyrazine, furan, thiophene, oxazole, thiazole, benzimidazole, benzoxazole, benzothiazole, benzofuran, indole, indazole, isoindole, isoquinoline, isooxazole, triazine, purine, pyridine, quinoline, oxadiazole, thiene, pyridazine, pyrimidine, isothiazole, quinoxaline (benzopyrazine), tetrazole, azepine, oxepine, thiepine and azocine. The oxidized form of the ring nitrogen atom of the heteroaryl to provide N-oxide is also encompassed. Furthermore, the heterocyclic group may be unsubstituted or substituted with one or more groups, preferably 1-3 groups independently selected from halogen, hydroxy, (CrC₆)- alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)₂-alkyl. In accordance with the embodiments of the present invention, R₂ is selected from a group consisting of unsubstituted or substituted alkyl and aryl.

In accordance with the embodiments of the present invention, the unsubstituted or substituted alkyl is selected from (Ci-C₆)-alkyl, which may be a straight-chain or branched chain alkyl; for example, Ci-C₆ for straight chain and C3-C₆ for branched chain. Suitable alkyl groups containing from one to ten carbon atoms, include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl and 3-hexyl. Furthermore, the alkyl groups may be unsubstituted or substituted with one or more substituents. A substituted alkyl refers to a (Ci-C₆)-alkyl substituted with one or more groups, preferably 1-3 groups, independently selected from halogen, hydroxy, (CrC₆)- alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)₂-alkyl. In accordance with the embodiments of the present invention, the aryl is (C₆-Ci₄)-aryl, which refers to monocyclic or bicyclic hydrocarbon groups having 6 to 14 ring carbon atoms, preferably 6 to 10 carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system. Examples of (C₆-Ci₄)-aryl residues are phenyl, naphthyl, fluorenyl and anthracenyl. Aryl groups can be unsubstituted or substituted with one or more groups, for example 1, 2, 3, 4 or 5 groups independently selected from halogen, hydroxy, (Ci-C₆)-alkoxy, nitro, cyano, amino, substituted amines, C(O) and C(0)₂-alkyl.

In an embodiment of the present invention, in the step (a) of the process, said compound of formula II is reacted with said compound of formula III using a catalyst in the presence of a solvent to yield compound of formula IV.

In accordance with an embodiment of the present invention, in the step (a) of the process the said catalyst is selected from a group consisting of metal alkoxides, metal oxides, metal halides and metal triflates. In accordance with an embodiment of the present invention, the said metal is selected from a group consisting of transition metals and inner- transition metals. The examples of metal alkoxide include, but are not limited to, aluminium alkoxide, tin alkoxide, titanium alkoxide, scandium alkoxide, zinc alkoxide, zirconium alkoxide and vanadium alkoxide.

The examples of metal oxides include, but are not limited to aluminium oxide, tin oxide, titanium oxide, scandium oxide, palladium oxide, iron oxide, zinc oxide, zirconium oxide and vanadium oxide.

The examples of metal halides include, but are not limited to aluminium halide, bismuth halide, boron halide, iron halide, manganese halide, zinc halide, titanium halide and zirconium halide .

In accordance with an embodiment of the present invention, the said halide of metal halides is selected from chloride, bromide, fluoride or iodide. The examples of metal triflates include, but are not limited to zinc triflate, ytterbium triflate, yttrium triflate and scandium triflateln accordance with an embodiment of the present invention, in the step (a) of the process the said solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, hydrocarbon solvents, dimethyl sulfoxide, toluene, and acetonitrile, or a mixture thereof.

In accordance with an embodiment of the present invention, the said ethereal solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di- isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole.

In accordance with an embodiment of the present invention, the said amide solvent is selected from dimethylformamide, dimethylacetamide, formamide, N-methyl-2- pyrrolidone, N-methylformamide or 2-pyrrolidone. In accordance with an embodiment of the present invention, the said ketonic solvent is selected from acetone, methylethyl ketone, cyclohexanone, methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone or methyl isopropyl ketone. In accordance with an embodiment of the present invention, the said halogenated solvent is selected from dichloromethane, chloroform, carbon tetrachloride or carbon tetrabromide.

In accordance with an embodiment of the present invention the said hydrocarbon solvent is selected from pentanes, hexanes, heptanes, octanes or nonanes.

In accordance with an embodiment of the present invention, in the step (a) of the process the reaction is carried out at a temperature range of 40 °C to 80 °C.

In accordance with an embodiment of the present invention, in the step (a) of the process the reaction is carried out at a temperature range of 40 °C to 80 °C for 0.5 h to 5 h.

In an embodiment of the present invention, in the step (b) of the process, said compound of formula IV, obtained in step (a) is reacted with haloacetate in the presence of a base and a solvent to yield compound of formula V.

In accordance with an embodiment of the present invention, in the step (b) of the process the said haloacetate is selected from chloroacetate, bromoacetate, fluoroacetate or iodoacetate. In accordance with an embodiment of the present invention, in the step (b) of the process the said haloacetate is selected from alkyl haloacetate having 1 to 6 carbon atoms in the ester group.

The examples of said alkyl haloacetate include, but are not limited to, methyl chloroacetate, methyl bromoacetate, methyl iodoacetate, methyl fluoroacetate, ethyl chloroacetate, ethyl bromoacetate, ethyl iodoacetate, ethyl fluoroacetate, n-propyl chloroacetate, n-propyl bromoacetate, propyl iodoacetate, propyl fluoroacetate, n-butyl chloroacetate, n- butyl bromoacetate, isopropyl chloroacetate, isopropyl bromoacetate, t- butyl chloroacetate and t-butyl bromoacetate. In accordance with an embodiment of the present invention, in the step (b) of the process the said haloacetate is selected from aryl haloacetate having 6 to 14 carbon atoms.

In accordance with an embodiment of the present invention, the said aryl is unsubstituted or substituted.

The examples of said aryl haloacetate include, but are not limited to, 4-phenylbutyl chloroacetate, o-butoxyphenyl chloroacetate, benzyl bromoacetate, 4-bromophenyl chloroacetate, tolylchloroacetate, benzyl iodoacetate, 6-phenylhexyl chloroacetate, xylylchloroacetate, 2,3-dimethylphenyl iodoacetate, 2,5-dibromophenyl chloroacetate and p-butylphenylbromoacetate.

In accordance with an embodiment of the present invention, in the step (b) of the process the said base is selected from a group consisting of metal silylamide, metal hydroxides and metal alkoxides.

In accordance with an embodiment of the present invention, the said metal silylamide is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, calcium bis[bis(trimethylsilyl)amide], magnesium bis[bis(trimethylsilyl)amide], titanium tris[bis(trimethylsilyl)amide], manganese bis[bis(trimethylsilyl)amide], manganese tris[bis(trimethylsilyl)amide], zinc bis[bis(trimethylsilyl)amide], iron bis[bis(trimethylsilyl)amide], iron tris[bis(trimethylsilyl)amide] or scandium tris[bis(trimethylsilyl)amide]. In accordance with an embodiment of the present invention, the said metal of metal hydroxide and metal alkoxide is selected from a group consisting of alkali metals and alkaline earth metals.

The examples of metal hydroxide include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide and calcium hydroxide.

The examples of metal alkoxides include, but are not limited to, sodium alkoxide, potassium alkoxide, lithium alkoxide, magnesium alkoxide and calcium alkoxide. The process for preparation of compound of formula V from compound of formula IV can optionally be carried out in the presence of a phase transfer catalyst selected from a group consisting of a quaternary ammonium salt and a quaternary phosphonium salt. The examples of quaternary ammonium salt phase transfer catalyst include, but are not limited to benzyltriethylammonium halide, hexadecyltrimethylammonium halide, tetrabutylammonium halide, tetramethylammonium halide and tetraethylammonium halide or a mixture thereof. The examples of quaternary phosphonium salt phase transfer catalyst include, but are not limited to tetra-n-butyl-phosphonium chloride, tetraphenylphosphonium bromide, tetraphenylphosphonium chloride, triphenylmethylphosphonium bromide and triphenylmethylphosphonium chloride or a mixture thereof. In accordance with an embodiment of the present invention, in the step (b) of the process the said solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, hydrocarbon solvents, dimethyl sulfoxide, toluene, and acetonitrile, or a mixture thereof. In accordance with an embodiment of the present invention, the said ethereal solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di- isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole. In accordance with an embodiment of the present invention, the said amide solvent is selected from dimethylformamide, dimethylacetamide, formamide, N-methyl-2- pyrrolidone, N-methylformamide or 2-pyrrolidone.

In accordance with an embodiment of the present invention, the said ketonic solvent is selected from acetone, methylethyl ketone, cyclohexanone, methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone or methyl isopropyl ketone.

In accordance with an embodiment of the present invention, the said halogenated solvent is selected from dichloromethane, chloroform, carbon tetrachloride or carbon tetrabromide. In accordance with an embodiment of the present invention the said hydrocarbon solvent is selected from pentanes, hexanes, heptanes, octanes or nonanes. In accordance with an embodiment of the present invention, in the step (b) of the process the reaction is carried out at a temperature range of -78 °C to 25 °C.

In accordance with an embodiment of the present invention, in the step (b) of the process the reaction is carried out at a temperature range of-78 °C to 25 °C for 0.5 h to 5 h.

The step (b) of the process comprises reaction of compound of formula IV with haloacetate in the presence of a base to yield compound of formula V. The formation of compound of formula V is a stereoselective reaction, wherein the desired R,R-isomer of formula V is exclusively formed. The reaction may result into a S,S-isomer to some extent. The compound of formula V, as R,R-isomer plays a crucial role in the reaction. The presence of S,S-isomer in the reaction mixture may contaminate the desired isomer in the subsequent steps of the preparation of droxidopa. The formation of undesired S,S-isomer in the reaction may require additional step of purification for removal and to avoid any formation of impurities.

In an embodiment of the present invention, in the step (c) of the process the said compound of formula V, obtained in step (b) is deprotected using an acid in the presence of a solvent to yield compound of formula VI or its pharmaceutically acceptable salt. In accordance with an embodiment of the present invention, in the step (c) of the process the said acid is an inorganic acid.

The examples of inorganic acid include, but are not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid and sulphuric acid or a mixture thereof.

In accordance with an embodiment of the present invention, in the step (c) of the process the said acid is an organic acid. The examples of organic acid include, but are not limited to acetic acid, formic acid, trifluoroacetic acid, /?-toluenesulphonic acid, trifluoromethane sulphonic acid and phenylsulfinic acid or a mixture thereof. In accordance with an embodiment of the present invention, in the step (c) of the process the said acid is a lewis acid.

The examples of lewis acid include, but are not limited to titanium tetrachloride, boron trichloride, boron tribromide, boron trifluoride, tin tetrachloride and aluminium chloride or a mixture thereof.

The acid used for the deprotection of said compound of formula V is may be used in the acid form or as a solution of acid in a solvent. The said solvent is selected from water or an organic solvent or a mixture thereof. The said organic solvent is selected from alcohol, ether or a mixture thereof.

The ether solvent may be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di-isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole or a mixture thereof.

The alcohol may be selected from methanol, ethanol, isopropanol or n-butanol or a mixture thereof. In accordance with an embodiment of the present invention, in the step (c) of the process the said solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, hydrocarbon solvents, dimethyl sulfoxide, toluene, and acetonitrile, or a mixture thereof. In accordance with an embodiment of the present invention, the said ethereal solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di- isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane or anisole. In accordance with an embodiment of the present invention, the said amide solvent is selected from dimethylformamide, dimethylacetamide, formamide, N-methyl-2- pyrrolidone, N-methylformamide or 2-pyrrolidone. In accordance with an embodiment of the present invention, the said ketonic solvent is selected from acetone, methylethyl ketone, cyclohexanone, methyl isobutyl ketone, methyl tert-butyl ketone, diethyl ketone or methyl isopropyl ketone.

In accordance with an embodiment of the present invention, the said halogenated solvent is selected from dichloromethane, chloroform, carbon tetrachloride or carbon tetrabromide.

In accordance with an embodiment of the present invention the said hydrocarbon solvent is selected from pentanes, hexanes, heptanes, octanes or nonanes. In accordance with an embodiment of the present invention, in the step (c) of the process the reaction is carried out at a temperature range of 0 °C to 40 °C.

In accordance with an embodiment of the present invention, in the step (c) of the process the reaction is carried out at a temperature range of 0 °C to 40°C for 0.5 h to 5 h.

In accordance with an embodiment of the present invention, the compound of formula VI is obtained as a free base or as its pharmaceutically acceptable salt.

In accordance with an embodiment of the present invention, the pharmaceutically acceptable salt is selected from formula VI salt with inorganic acids or organic acids.

The inorganic acid salt of compound of formula VI may be selected from hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid. The organic acid salt of compound of formula VI may be selected from sulphonic acid, oxalic acid, formic acid, acetic acid, trifluoro acetic acid, propionic acid, maleic acid, succinic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, mandelic acid, methane sulphonic acid, ethanesulphonic acid, benzene sulphonic acid, toluenesulphonic acid, or naphthalenedisulphonic acid. In an embodiment of the present invention, in the step (d) of the process, the said compound of formula VI or its pharmaceutically acceptable salt, obtained in step (c) is treated with an acid in the presence of a solvent to obtain compound of formula VII having > 95 % selectivity towards obtaining of L-threo isomer.

In accordance with an embodiment of the present invention, in the step (d) of the process the said acid is selected from a group consisting of inorganic acid and organic acid.

In accordance with an embodiment of the present invention, the said inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid or sulphuric acid.

In accordance with an embodiment of the present invention, the said organic acid is selected from acetic acid, formic acid, oxalic acid, trifluoroacetic acid, maleic acid, succinic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, mandelic acid, /?-toluenesulphonic acid, methanesulphonic acid, trifluoromethanesulphonic acid, phenylsulfinic acid, benzenesulphonic acid, benzoic acid, nitrobenzoic acid or naphthalenedisulphonic acid.

In accordance with an embodiment of the present invention, in the step (d) of the process the acid may be used in the acid form or as a solution of acid in a solvent. The said solvent is selected from water or an organic solvent or a mixture thereof. The said organic solvent is selected from alcohol, ether or a mixture thereof.

The ether solvent may be selected from tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, diethyl ether, di-isopropyl ether, di-n-butyl ether, di-iodopropyl ether, methyl-tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether, dioxane, or anisole or a mixture thereof.

The alcohol may be selected from methanol, ethanol, isopropanol or n-butanol or a mixture thereof.

In accordance with an embodiment of the present invention, in the step (d) of the process the said solvent is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, hydrocarbon solvents, dimethyl sulfoxide, toluene and acetonitrile or a mixture thereof.

In accordance with an embodiment of the present invention, the said amide solvent is selected from dimethylformamide, dimethylacetamide, formamide, N-methyl-2- pyrrolidone, N-methylformamide or 2-pyrrolidone.

In accordance with an embodiment of the present invention, the said halogenated solvent is selected from dichloromethane, chloroform, carbon tetrachloride or carbon tetrabromide. In accordance with an embodiment of the present invention the said hydrocarbon solvent is selected from pentanes, hexanes, heptanes, octanes or nonanes.

In accordance with an embodiment of the present invention, in the step (d) of the process the reaction is carried out at a temperature range of 10 °C to 60 °C.

In accordance with an embodiment of the present invention, in the step (d) of the process the reaction is carried out at a temperature range of 10 °C to 60 °C for 0.5 h to 12 h.

In an embodiment of the present invention, in the step (e) of the process, the said compound of formula VII, obtained in step (d) is treated with a base in the presence of a solvent to yield compound of formula VIII. In accordance with an embodiment of the present invention, in the step (e) of the process the said base is selected from a group consisting of metal hydroxide, metal carbonates, metal bicarbonates and metal oxides. In accordance with an embodiment of the present invention, the said metal is selected from a group consisting of alkali metals and alkaline earth metals.

The examples of metal hydroxides include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide and calcium hydroxide.

The examples of metal carbonates include, but are not limited to, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate and magnesium carbonate.

The examples of metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate and magnesium bicarbonate.

The examples of metal oxides include, but are not limited to, sodium oxide, potassium oxide, magnesium oxide and calcium oxide. In accordance with an embodiment of the present invention, in the step (e) of the process the said solvent is selected from an alcohol, acetonitrile or water; or a mixture thereof.

In accordance with an embodiment of the present invention, the said alcohol is selected from methanol, ethanol, isopropanol or n-butanol or a mixture thereof.

In accordance with an embodiment of the present invention, in the step (e) of the process the reaction is carried out at a temperature range of -10 °C to 25 °C.

In accordance with an embodiment of the present invention, in the step (e) of the process the reaction is carried out at a temperature range of - 10 °C to 25 °C for 0.5 h to 5 h.

In step (d) of the process, only the desired isomer is obtained in a very high yield of greater than 95 %), which is specific to the reaction condition and substrate. The SN (nucleophilic substitution) aziridine ring opening reaction occurs predominantly, which depends on the reaction conditions and is substrate-specific. Therefore, step (d) of the process involves an asymmetric induction reaction and constitutes the key step in the process for the preparation of droxidopa. In an embodiment of the present invention, in the step (f) of the process, the said compound of formula VIII, obtained in the step (e) is treated with an amine protecting compound in the presence of a base and a solvent to yield compound of formula IX.

In accordance with an embodiment of the present invention, in the step (f) of the process the said amine protecting compound is selected from a group consisting of phthalic acid, succinic acid, phthaloyl chloride, succinoyl chloride, phthalic anhydride, succinic anhydride, N-carbomethoxy phthalimide, N-carbomethoxy succinimide, N-carboethoxy phthalimide, N-carboethoxy succinimide, monomethyl phthalate, monomethyl succinate, monoethyl phthalate, monoethyl succinate, dimethyl phthalate, dimethyl succinate, diphenyl phthalate and diphenyl succinate.

In accordance with an embodiment of the present invention, in the step (f) of the process the said base is selected from a group consisting of metal hydroxide, metal carbonates and metal bicarbonates.

In accordance with an embodiment of the present invention, the said metal is selected from a group consisting of alkali metals and alkaline earth metals.

The examples of metal carbonates include, but are not limited to, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate and magnesium carbonate. The examples of metal bicarbonates include, but are not limited to, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate and magnesium bicarbonate. In accordance with another embodiment of the present invention, in the step (f) of the process the said solvent is selected from an alcohol, acetonitrile or water; or a mixture thereof. In accordance with an embodiment of the present invention, the said alcohol is selected from methanol, ethanol, isopropanol or n-butanol; or a mixture thereof.

In accordance with an embodiment of the present invention, in the step (f) of the process, the reaction is carried out at a temperature range of 20 °C to 40 °C.

In accordance with an embodiment of the present invention, in the step (f) of the process, the reaction is carried out at a temperature range of 20 °C to 40 °C for 0.5 h to 5 h.

In an embodiment of the present invention, in the step (g) of the process the said compound of formula IX, obtained in the step (f) is deprotected to yield droxidopa, the compound of formula I.

The compound of formula IX can be deprotected to yield droxidopa of formula I by following the processes known in the art. For example the compound of formula IX can be deprotected to yield droxidopa, the compound of formula I by following the process disclosed in the US Patent Application Publication No. 2013/0253061. The process involves reaction of L-i zreo-(N-phthaloyl-3-(3,4-methylenedioxyphenyl)serine) with aluminium chloride and octanethiol in the presence of dichloromethane at a temperature range of 10 °C to 15 °C for 1.5 h to 2.5 h to yield droxidopa, the compound of formula I.

The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be considered in anyway to limit the scope of the present invention. Examples

Example- 1: Process for preparation of compound IV

E)-N-(benzo[d][l,3]dioxol-5-ylmethylene)-2-methylpropane-2-sulfinamide

In a round bottom flask was charged the compound of formula II (5.0 g, 33 mmol) and isopropyl (S)-sulfinamide (4.0 g, 33 mmol) and then dissolved in tetrahydrofuran (250 mL). To the reaction mixture then added solution titanium tetraethoxide (13.97 mL, 66 mmole) under nitrogen atmosphere. The resulting reaction mixture was then refluxed at a temperature of 60 °C for 1.5 h. The reaction mixture was then cooled to room temperature and then diluted with ethyl acetate (125 mL) and water. The precipitated solid was filtered through celite bed and the resulting filtrate was treated with ethyl acetate and water. The organic layer was separated and dried over anhydrous sodium sulphate. The resulting product was evaporated under reduced pressure to yield a crude product. The crude product was then purified by column chromatography (silica gel, hexane:ethyl acetate; 1: 1) to yield pure product of formula III. Yield: 7.44 g, 88 %; 1H-NMR (400MHz, DMSO-d₆):□ (ppm) 8.47 (s, 1H), 7.43 (d, = 1.6 Hz, 1H), 7.32 (m, 1H), 6.91 (d, = 8 Hz, 1H), 6.07 (s, 2H), 1.27 (s, 9H); LCMS: RT. 2.28 min., Area % 99.53, MS (ES+) m/z: 254.13 (M + 1).

Example-2: Process for preparation of compound V

2 -methyl 3-(benzo[d][l,3]dioxol-5-yl)-l -( tert-butylsulfinyl)aziridine-2-carboxylate

To a round bottom flask was charged a solution of lithium bis(trimethylsilyl)amide (LiHMDS) (3.67 mL, 3.67 mmol) in tetrahydrofuran (10 mL) at a temperature of -78 °C and methyl bromoacetate (0.510 g, 3.35 mmol). The resulting solution was stirred for 30 min at a temperature of -78 °C. To the reaction mixture, was charged a solution of compound III (obtained in example 1) (0.425 g, 1.67 mmol) in tetrahydrofuran (1 mL) and stirred at a temperature of -78 °C for 30 min. Then slowly the temperature of the reaction mixture was raised to 25-30 °C and maintained for 1 h. The reaction mixture was then quenched by adding water and the water layer was extracted with ethyl acetate. The organic layers were combined and washed with brine. The resulting organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield crude product. The crude product was purified by column chromatography (silica gel, hexane:ethyl acetate; 8:2) to yield pure compound V. Yield 0.450 g, 83 %; ¹H-NMR (400MHz, CDC1₃): □ (ppm) 6.91-6.88 (m, 2H), 6.78 (d, J = 8.0 Hz, 1H), 5.97 (d, J = 0.8Hz, 2H), 3.65 (d, J = 7.2 Hz, 1H), 3.61 (s, 3H), 3.48 (d, J = 7.2 Hz, 1H), 1.34 (s, 9H); LCMS: RT.2.273 min., Area % 100.00, MS (ES+) m/z: 326.0 (M + 1).

Example-3: Process for preparation of compound VI

2R,3R)-methyl 3-(benzo[d][l,3]dioxol-5-yl)aziridine-2-carboxylate

To a round bottom flask, was charged a solution of compound V (obtained in example 2) (1.5 g, 4.6 mmol) in tetrahydrofuran (15 mL) and 4 M hydrochloric acid solution in dioxane (3 mL) dropwise at a temperature of 0 °C. Then the resulting reaction mixture was stirred at a temperature of 0 °C for 5 min and at a temperature of 25-35 °C for 1 h. The reaction mixture was then concentrated under reduced pressure to obtain crude product. The crude product was triturated with diethyl ether (30 mL) and filtered to yield hydrochloride salt of compound VI. Yield: 0.907 g, 76 %; 1H-NMR (400MHz, DMSO-d₆): □ (ppm) 8.99 (s, 2H), 7.16 (d, = 1.6 Hz, 1H), 6.95-6.94 (m, 2H), 6.08 (d, = 4.2 Hz, 2H),5.48 (d, = 7.6 Hz, 1H), 4.74 (d, = 7.6 Hz, 1H), 3.60 (s, 3H); LCMS: RT. 2.81 min., Area % 39.49, MS (ES+) m/z: 222.05 (M + 1).

Example-4: Process for preparation of compound VII

(2S,3R)-methyl 2-amino-3-(benzo[d][l,3]dioxol-5-yl)-3-hydroxypropanoate

To a reaction flask, was charged compound VI (obtained in example 3) (900 mg, 3.49 mmol) and 50 % aq. acetic acid solution (9 mL) and heated in dichloromethane (45 mL) at a temperature of 55 °C for 6 h. The reaction mixture was then cooled to a temperature of 10 °C and the resulting reaction mixture was diluted with water (10 mL). The pH of the reaction mixture was adjusted to -10 with 25 % aqueous ammonia solution. The resulting layers were separated and the aqueous layer was further extracted with dichloromethane (25 mL). The organic layers were combined and washed with brine (25 mL and then dried over anhydrous sodium sulphate. The resulting liquid evaporated under reduced pressure to provide crude solid which was purified by trituration in diethyl ether (10 mL) to yield compound VII. Yield 0.405 g, 49 %; 1H-NMR (400MHz, DMSO-d₆): D D (ppm) D 6.90 (d, J = 1.2 Hz, 1H), 6.83 (d, = 8.0 Hz, 1H), 6.76 (dd, = 8.0 Hz, 0.8 Hz, 1H), 5.98 (s, 2H), 5.47 (d, = 5.2 Hz, 1H), 4.70 (t, = 4.8 Hz, 1H), 3.57 (s, 3H), 3.42 (d, = 4.4 Hz, 1H), 1.66 (s, 2H); LCMS: RT.2.729 min., Area % 98.71, MS (ES+) m/z: 239.98 (M + 1)

Example-5: Process for preparation of compound VIII

(2S,3R)-2-amino-3-(benzo[d][l,3]dioxol-5-yl)-3-hydroxypropanoic acid

To a round bottom flask charged compound VII (obtained in example 4) (0.14 g, 0.585 mmol) dissolved in methanol (1.5 mL) and cooled at a temperature of 0 °C. To the resulting reaction mixture was added 5N sodium hydroxide solution (0.2 mL) and stirred at a temperature of 0 °C for 3 h. The resulting reaction mixture was washed with diethyl ether and the aqueous layer was acidified to pH 5 with 0.1 N aqueous solution of hydrochloric acid. The reaction mixture was stirred for further 1 h at a temperature of 0 °C. The precipitated solid was filtered and dried over vacuum to yield compound VIII. 1H-NMR (400MHz, DMSO-d₆):□ (ppm) 7.40 (bs, 2H), 6.94 (s, 1H), 6.86-6.81 (m, 2H), 5.99 (d, = 2.4 Hz, 2H),4.97 (d, = 3.6 Hz, 1H), 3.32 (bs, 1H), 3.31 (d, = 3.6 Hz, 1H); LCMS: RT.2.85 min., Area % 98.95, MS (ES+) m/z: 226.0 (M + 1).

Example-6: Process for preparation of compound IX

(2S,3R)-3-(benzo[d][l,3]dioxol-5-yl)-2-(l,3-dioxoisoindolin-2-yl)-3-hydroxypropanoic acid

To a reaction flask, was charged compound VIII (obtained in example 5) (20 mg, 0.08 mmol); sodium carbonate (10 mg, 0.1 mmol) solution in water (0.4 mL) at a temperature of 0 °C, and carboethoxypthalimide (19 mg, 0.09 mmol). The resulting reaction mixture was stirred at a temperature of 25-35 °C for 2 h. The resulting reaction mixture was then washed with diethyl ether and the pH of the reaction mixture was adjusted to 5 using 0.1 N hydrochloric acid. Then the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield compound IX. Yield 0.008 g, 25 %; 1H-NMR (400MHz, DMSO-d₆):□ (ppm) 7.89-7.83 (m, 4H), 6.91 (s, 1H), 6.85-6.80 (m, 2H), 6.41 (bs, 1H), 5.97 (d, = 4.4 Hz, 2H), 5.23 (d, = 7.6 Hz, 1H), 4.81 (d, = 7.2 Hz, 1H); LCMS: RT.2.25 min., Area % 100, MS (ES+) m/z: 354.04 (M + 1).

Claims

We claim:

1. A process for preparation of L-i zreo-dihydroxyphenylserine (droxidopa) of formula I;

comprising the steps of: a) reaction of compound of formula II

Formula II with compound of formula III

O

H₂N R-i

Formula III using catalyst in the presence of a solvent to yield compound of formula IV,

Formula IV wherein Ri is selected from a group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl and heterocycyl; which are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, (Ci-C6)-alkoxy, nitro, cyano, amino, substituted amines, C(O) or C(0)₂-alkyl; reacting the compound of formula IV, obtained in step (a) with halo acetate the presence of a base and solvent to yield compound of formula V,

Formula V wherein R₂ is selected from an alkyl or aryl; which are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, (CrC₆)- alkoxy, nitro, cyano, amino, substituted amines, C(O) or C(0)₂-alkyl; the compound of formula V, obtained in step (b) is deprotected using acid in the presence of a solvent to yield compound of formula VI or its pharmaceutically accept

Formula VI treating compound of formula VI, obtained in step (c) with acid

presence of a solvent to obtain desired isomer of formula VII,

Formula VII reacting compound of formula VII, obtained in step (d) with metal hydroxides in the presence of a solvent to yield compound of formula VIII,

Formula VIII f) reacting compound of formula VIII, obtained in step (e) with an amine

protecting compound, using a base in the presence of a solvent to yield compound of formula IX,

Formula IX wherein R₃ is absent; or R₃ is an aryl ring selected from phenyl or naphthyl; g) deprotecting the compound of formula IX, obtained in step (f) to yield

compound of formula I.

The process according to claim 1, wherein in step (a), the catalyst is selected from a group consisting of metal alkoxides, metal oxides, metal halides and metal triflates.

The process according to claim 2, wherein the metal is selected from a group consisting of transition metals and inner-transition metals.

The process according to claim 1, wherein in step (a), the reaction is carried out at a temperature range of 40 °C to 80 °C.

The process according to claim 1, wherein in step (b), the haloacetate is selected from chloroacetate, bromoacetate, fluoroacetate or iodoacetate.

The process according to claim 1, wherein in step (b), the haloacetate is an alkyl haloacetate having 1 to 6 carbon atoms in the ester group.

The process according to claim 1, wherein in step (b), the haloacetate is an aryl haloacetate having 6 to 14 carbon atoms.

8. The process according to claim 1, wherein in step (b), the base is selected from a group consisting of metal silylamides, metal hydroxides and metal alkoxides.

9. The process according to claim 8, wherein the metal silylamide is selected from lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, calcium bis[bis(trimethylsilyl)amide], magnesium bis[bis(trimethylsilyl)amide], titanium tris[bis(trimethylsilyl)amide], manganese bis[bis(trimethylsilyl)amide], manganese tris[bis(trimethylsilyl)amide], zinc bis[bis(trimethylsilyl)amide], iron bis[bis(trimethylsilyl)amide], iron tris[bis(trimethylsilyl)amide] or scandium tris[bis(trimethylsilyl)amide].

10. The process according to claim 8, wherein the metal of metal hydroxide and metal alkoxide is selected from a group consisting of alkali metals and alkaline earth metals.

11. The process according to claim 10, wherein the metal of metal hydroxide and metal alkoxide is selected from sodium, potassium, lithium, magnesium or calcium.

12. The process according to claim 1, wherein in step (b), the process is carried out in the presence of a phase transfer catalyst selected from a group consisting of a quaternary ammonium salt and a quaternary phosphonium salt.

13. The process according to claim 12, wherein the quaternary ammonium salt phase transfer catalyst is selected from benzyltriethylammonium halide, hexadecyltrimethylammonium halide, tetrabutylammonium halide, tetramethylammonium halide and tetraethylammonium halide or a mixture thereof.

14. The process according to claim 12, wherein the quaternary phosphonium salt phase transfer catalyst is selected from tetra-n-butyl-phosphonium chloride, tetraphenylphosphonium bromide, tetraphenylphosphonium chloride, triphenylmethylphosphonium bromide and triphenylmethylphosphonium chloride or a mixture thereof.

15. The process according to claim 1, wherein in step (b), the reaction is carried out at a temperature range of -78 °C to 25 °C.

16. The process according to claim 1, wherein in step (c), the acid is selected from an inorganic acid, organic acid or a lewis acid, wherein the acid may be used in the acid form or as a solution of acid in a solvent selected from water or an organic solvent or a mixture thereof.

17. The process according to claim 1, wherein in step (d), the compound of formula VII is obtained with greater than 95 % selectivity towards the L-threo isomer.

18. The process according to claim 1, wherein in step (d), the acid is selected from a group consisting of inorganic acid and organic acid, wherein the acid may be used in the acid form or as a solution of acid in a solvent selected from water or an organic solvent or a mixture thereof.

19. The process according to claim 1, wherein in step (d), the reaction is carried out at a temperature range of 10 °C to 60 °C. 20. The process according to claim 1, wherein in step (e), the base is selected from a group consisting of metal hydroxide, metal carbonates, metal bicarbonates and metal oxides.

21. The process according to claim 1, wherein in step (e), the reaction is carried out at a temperature range of -10 °C to 25 °C.

22. The process according to claim 1, wherein in step (f), the amine protecting compound is selected from a group consisting of phthalic acid, succinic acid, phthaloyl chloride, succinoyl chloride, phthalic anhydride, succinic anhydride, N-carbomethoxy phthalimide, N-carbomethoxy succinimide, N-carboethoxy phthalimide, N- carboethoxy succinimide, monomethyl phthalate, monomethyl succinate, monoethyl phthalate, monoethyl succinate, dimethyl phthalate, dimethyl succinate, diphenyl phthalate and diphenyl succinate.

23. The process according to claim 1, wherein in step (f), the base is selected from a group consisting of metal hydroxide, metal carbonates and metal bicarbonates.

24. The process according to claim 20 or claim 23, wherein the metal is selected from a group consisting of alkali metals and alkaline earth metals.

25. The process according to claim 1, wherein in step (f), the reaction is carried out at a temperature range of 20 °C to 40 °C.

26. The process according to claim 1, wherein the solvent used in steps (a) to (d) is selected from a group consisting of ethereal solvents, amide solvents, ketonic solvents, halogenated solvents, hydrocarbon solvents, dimethyl sulfoxide, toluene, and acetonitrile, or a mixture thereof.

27. The process according to claim 1, wherein the solvent used in steps (e) and (f) is selected from an alcohol, acetonitrile or water; or a mixture thereof.

28. The process according to claims 16 or 18, wherein the organic solvent is selected from alcohol, ether or a mixture thereof.

29. A compound of formula V or its pharmaceutically acceptable salt;

Formula V wherein Ri is selected from a group consisting of alkyl, cycloalkyl, aryl and heterocycyl; which are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, (Ci-C₆)-alkoxy, nitro, cyano, amino, substituted amines, C(O) or C(0)₂-alkyl; and

R₂ is selected from an alkyl or aryl; which are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, (Ci-C₆)-alkoxy, nitro, cyano, amino, substituted amines, C(O) or C(0)₂-alkyl.

30. A compound of formula VI or its pharmaceutically acceptable salt;

Formula VI

wherein R₂ is selected from an alkyl or aryl; which are unsubstituted or substituted with one or more groups selected from halogen, hydroxy, (Ci-C6)-alkoxy, nitro, cyano, amino, substituted amines, C(O) or C(0)₂-alkyl.