DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATIONOF DROXIDOPA

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
KONDAPUR, HITECH CITY,
HYDERABAD, 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the nature of this invention and the manner in which is to be performed:
FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of threo-3-(3,4-dihydroxyphenyl)-L-serine commonly known as Droxidopa of a Compound of Formula (1).

Formula1
BACKGROUND OF THE INVENTION
Droxidopa is chemically known as (-)-(2S,3R)-2-Amino-3-hydroxy-3-(3,4-dihydroxyphenyl)propanoic acid and/or threo-3-(3,4-dihydroxyphenyl)-L-serine. Droxidopa is a drug that has been known to be useful as an agent for treatment of peripheral orthostatic hypotension or an agent for treatment of Parkinson's disease. Droxidopa is marketed under the brand name Northera®.
Droxidopa is disclosed first time in US 3,920,728. This patent also discloses a process for the preparation of Droxidopa (1) using a multiple-step synthesis starting from 3,4-dibenzyloxybenzaldehydeandglycine. Applicant found that the process is not viable for large-scale production as it involves large number of steps and de-protection benzyl protected compound with Pd/C resulted with Droxidopa contaminated with catalyst and hence tedious purification required thereby affecting the overall yield. The process as shown below:

Scheme-I
US 4,562,263 discloses variant process for the preparation of Droxidopa (1). The process comprises, reacting racemic threo-3-(3,4-methylenedioxyphenyl)serine(2)with N-carbethoxyphthalimide to produce racemic threo-N-phthaloyl-3-(3,4-methylenedioxyphenyl)serine (3). The obtained compound (3)is further resoluted with cinchonidine or l-norephedrine to produce L-threo-N-phthaloyl-3-(3,4-methylenedioxyphenyl)serine (4), which is further treated with ethyl mercaptan and anhydrous aluminum chloride to produce threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine (5). The obtained compound (5) is de-protected by treating with hydrazine to produce Droxidopa (I). The use of hydrazine, a genotoxic material, in the last step is industrially not viable as it is expected to yield Droxidopa with genotoxic impurities. The process as shown below:

Scheme-II
US 8,598,370disclosesanother process for the preparation of Droxidopa (1). The process comprises, reacting threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine(Compound 5) with methyl amine as de-protection of N-phthaloyl group to produce Droxidopa (1).The process as shown below:

Scheme-III

During the examination of US 8,598,370, applicant indicated that the use of other amines like ethylenediamine; ethylamine; dimethylamine; piperidine; organic bases for example sodium hydroxide; hydroxylamine; and sodium borohydride etc are failed to de-protect N-phthaloyl group. However applicant observed that the usage of 40% aqueous solution of methylamine has produced a poor conversion of Droxidopa (1), even with a complete consumption of Compound 5. Furthermore, methylamine as a gas and available as a 40% aqueous solution having a low boiling point requires special attention towards its storage and handling. Further in US 2013/0253061 it has mentioned that the use of methylamine for the de-protection of L-threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)serine (Compound 5) did not produce the desired Droxidopa.
Considering the importance of Droxidopa in the pharmaceutical field, there is always a need for an alternative preparative routes, which for example, involve fewer steps, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity. The present invention is related to a process for the preparation of Droxidopa (1) with high yield and high purity.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple and cost effective process for the preparation of Droxidopa (1) or a pharmaceutically acceptable salt thereof; with high purity and good yield (without genotoxic impurities) on commercial scale.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides an improved process for the preparation of threo-3-(3,4-dihydroxyphenyl)-L-serine known as Droxidopa of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof:

Formula 1
which comprises step of reacting threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine of Formula (5);

Formula 5
with alkanolamine of formula (6).

Formula 6
wherein R is same or different and independently selected from hydrogen or alkyl groups; and n is numerical number varies from 1 to 8.

In another embodiment, the present invention provides an improved process for the preparation of threo-3-(3,4-dihydroxyphenyl)-L-serine known as Droxidopa of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof:

Formula 1

comprising a step of reacting threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine of a Compound of Formula (5):

Formula 5

with ethanolamine.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides an improved process for the preparation of threo-3-(3,4-dihydroxyphenyl)-L-serine known as Droxidopa of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof:

Formula 1

which comprises step of reacting threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine of a Compound of Formula (5);

Formula 5
with alkanolamine of formula (6).

Formula 6

wherein R is same or different and independently selected from hydrogen or alkyl groups; and n is numerical number varies from 1 to 8. The alkyl group is selected from methyl, ethyl, propyl, butyl and the like.

In an embodiment of the invention, alkanolamine of formula (6) is selected from methanolamine, ethanolamine, N-methylethanolamine, N,N-dimethylethanolamine and the like or mixtures thereof.

In an embodiment of the invention, alkanolamine of formula (6) is ethanolamine. The use of ethanolamine when compared to methylamine has many advantages as the use of methylamine requires certain special care with respect to handling, the use of methylamine leads to degradation of starting material with no product formation and applicant found that the yield of Droxidopa is significantly high when ethanolamine is employed. Applicant has repeated the examples given in US 8598370 and observed that the use of ethanolamine produces the Droxidopa in good quality and quantity over the reported methyl amine as shown in the below table:

Amine Used Result Purity
40 % aq. Methyl amine solution as per US 8598370 No reaction
(no starting material, but product is not isolable) Not applicable
Ethanolamine Reaction proceeds smoothly More than 98 %

In still another embodiment, the reaction of a Compound of Formula (5) with alkanolamine of formula (6) is carried out in the presence of a solvent.
In another embodiment, the solvent used in the reaction step comprises polar protic solvent or polar aprotic solvent or non-polar solvents and/or mixtures thereof.
In another embodiment, polar protic solvent comprises water, methanol, ethanol, isopropanol n-butanol, and/or mixtures thereof; polar aprotic solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, N-methylpyrrolidoneand/or mixtures thereof; and non-polar solvents comprises hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane (CH2Cl2) and/or mixtures thereof.

In still another embodiment of the invention, about 1-10 mole equivalents of alkanolamine of formula (6) is used for the reaction; preferably 2-7 mole equivalents more preferably 3-5 mole equivalents is used.
In one more embodiment, the reaction is carried out at a temperature of 0oC to 50°C preferably 20 to 50°C more preferably 20 to 30°C for a time period of 1-5 hours.
In another embodiment, the present invention provides an improved process for the preparation of threo-3-(3,4-dihydroxyphenyl)-L-serine known as Droxidopa of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof:

Formula 1

comprising a step of reacting threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine of a Compound of Formula (5):

Formula 5

with ethanolamine.

In still another embodiment, a step of neutralizing a reaction solution with an acid after a completion of the reaction of threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine of a Compound of Formula (5) with ethanolamine.
In still another embodiment, an acid comprises hydrochloric acid or sulfurc acid.

In another embodiment, after completion of the reaction, Compound (1) is isolated and optionally purified by conventional methods.

In still another embodiment, the Compound (5) is prepared by the methods known in the literature.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES:
EXAMPLE 1: PREPARATION OF THREO-3-(3,4-DIHYDROXYPHENYL)-L-SERINEOR DROXIDOPA (Compound 1)
To the suspension of threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine (Compound 5) (10 g, 0.029 moles) in methanol (20 ml) at 25-30°Cwas added, ethanolamine (8.9 g, 0.145 moles) and stirred the solution at 35-40°C. The solution was cooled to room temperature and neutralized with concentrated hydrochloric acid and stirred. The solid obtained was filtered and washed with methanol (10 ml) to give threo-3-(3,4-dihydroxyphenyl)-L-serine (Droxidopa) (3.74 g).

EXAMPLE 2: PREPARATION OF THREO-3-(3,4-DIHYDROXYPHENYL)-L-SERINE OR DROXIDOPA (Compound 1)
To the suspension of threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine (Compound 5) (2 g, 0.0058 moles) in methanol (4 ml) at 25-30°C, was added ethanolamine (2.54 g, 0.040 moles) and stirred the solution at 35-40°C.The solution was cooled to 25 °C and neutralized with concentrated hydrochloric acid. The solid obtained was filtered and washed with methanol (5 ml) to give threo-3-(3,4-dihydroxyphenyl)-L-serine (Droxidopa) (0.75 g).

EXAMPLE 3: PREPARATION OF THREO-3-(3,4-DIHYDROXYPHENYL)-L-SERINE OR DROXIDOPA (Compound 1)
To the suspension of threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine (Compound 5) (2 g, 0.0058 moles) in methanol (4 ml) at 25°C, was added ethanolamine (1.78 g, 0.029 moles) and stirred the reaction mixture at 25-30°C. Thereafter the solution was neutralized with concentrated hydrochloric acid. After stirring the contents for 2 h at 25-30°C, the reaction mixture was filtered and washed with methanol (5 ml) to give threo-3-(3,4-dihydroxyphenyl)-L-serine (Droxidopa).

EXAMPLE 4: PREPARATION OF THREO-3-(3,4-DIHYDROXYPHENYL)-L-SERINE OR DROXIDOPA (Compound 1)
To the suspension of threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine (Compound 5) (2 g, 0.0058 moles) in methanol (4 ml) at 25°C, was added ethanolamine (1.78 g, 0.029 moles) and stirred the reaction mixture at 10-15°C. Thereafter, the solution was neutralized with concentrated hydrochloric acid. After stirring the contents for 2 h at 25-30°C, the reaction mixture was filtered and washed with methanol (5 ml) to give threo-3-(3,4-dihydroxyphenyl)-L-serine (Droxidopa).
EXAMPLE 5: PREPARATION OF THREO-3-(3,4-DIHYDROXYPHENYL)-L-SERINE OR DROXIDOPA (Compound 1)
To the suspension of threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine(Compound 5) (2 g, 0.0058 moles) in methanol (4 ml) at 25°C, was added ethanolamine (1.78 g, 0.029 moles) and stirred the reaction mixture at 0-5°C. Thereafter, the solution was neutralized with concentrated hydrochloric acid. After stirring the contents for 2 h at 25-30°C, the reaction mixture was filtered and washed with methanol (5 ml) to give threo-3-(3,4-dihydroxyphenyl)-L-serine (Droxidopa) (0.81 g). ,CLAIMS:WE CLAIM:

1. An improved process for the preparation of threo-3-(3,4-dihydroxyphenyl)-L-serine known as Droxidopa of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof:

Formula 1
which comprises step of reacting threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine of Formula (5);

Formula 5
with alkanolamine of formula (6);

Formula 6
wherein R is same or different and independently selected from hydrogen or C1-C4 alkyl groups; and n is numerical number varies from 1 to 8.

2. The process according to claim 1, alkanolamine of formula (6) is selected from methanolamine, ethanolamine, N-methylethanolamine, N,N-dimethylethanolamine and the like or mixtures thereof.

3. The process according to claim 1, alkanolamine of formula (6) is ethanolamine.

4. The process according to claim 1, the reaction of a Compound of Formula (5) with alkanolamine of formula (6) is carried out in the presence of a solvent comprises polar protic solvent or polar aprotic solvent or non-polar solvents and/or mixtures thereof.

5. The process according to claim 4, polar protic solvent comprises water, methanol, ethanol, isopropanol, n-butanol, and/or mixtures thereof; polar aprotic solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, N-methylpyrrolidone and/or mixtures thereof; and non-polar solvents comprises hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane (CH2Cl2) and/or mixtures thereof.

6. An improved process for the preparation of threo-3-(3,4-dihydroxyphenyl)-L-serine known as Droxidopa of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof:

Formula 1

comprising a step of reacting threo-N-phthaloyl-3-(3,4-dihydroxyphenyl)-L-serine of a Compound of Formula (5):

Formula 5

with ethanolamine.

7. The process according to claim 6, the reaction of a Compound of Formula (5) with alkanolamine of formula (6) is carried out in the presence of a solvent comprises polar protic solvent or polar aprotic solvent or non-polar solvents and/or mixtures thereof.

8. The process according to claim 6, the reaction of a Compound of Formula (5) with ethanolamine is carried out in the presence of a methanol solvent.