TITLE OF THE INVENTION
Improved process for the preparation of Droxidopa.
FIELD OF THE INVENTION
The present invention relates to the improved process for the preparation of Droxidopa having the structural formula I
BACKGROUND OF THE INVENTION
Droxidopa is a prodrug of norepinephrine which by the action of dopa decarboxylase enzyme, is converted to norepinephrine in the body. It is used in the treatment of orthostatic hypotension. It is also useful in treating certain symptoms associated with Parkinson's disease. Droxidopa is commercialized under the trade name Northera by Chelsea Therapeutics.
Droxidopa is chemically known as L-threo-dihydroxyphenylserine
Droxidopa was first disclosed in US 4,480,109 A of Sumitomo Chemical Company.
Several process for the preparation of Droxidopa of formula-I have been disclosed in EP 0112606 Bl, EP 201039 Bl, EP 3168208 Al, IN 201641017019, US 4480109 B2, US 2013/0253061 Al, WO 2013142093 Al, WO 2013167998 A2, WO 2017081206 Al and WO 2018090670 Al.

The process disclosed in prior art failed to provide efficient methods for obtaining Droxidopa in high purity and high yields. The lack of efficient manufacturing processes increases the cost of the final Droxidopa and the pharmaceutical compositions containing it, which has already resulted in expensive medications. In view of the pharmaceutical value of the compound of formula I, it is thus desirable to develop an efficient and safe process for the preparation of Droxidopa in high purity and high yield, which can be easily applied at an industrial scale with low energy requirements and costs.
SUMMARY OF THE INVENTION
The present invention provides a cost effective, novel and an efficient process for the preparation of Droxidopa with higher yield and purity.
In one embodiment, the present invention provides the process for preparation of Droxidopa compound of Formula-I.
which comprises:
a) tert-butoxycarbonyl protection of compound of FormuIa-II
in presence of catalyst, solvent and base to obtain compound of Formula-Ill;

b) coupling compound of Formula-Ill with nickel complex of FormuIa-IV
c) conversion of compound of Formula-V in presence of a base and solvent to obtain compound of Formula I.

In stage-I, tert-butoxycarbonyl protection of compound of Formula- II in presence of catalyst, solvent and base to obtain compound of Formula- III.
The reaction temperature may range from 5 to 25 °C and preferably at a temperature in the range from 10 to 15 °C. The duration of the reaction may range from 0.5 to 3 hours, preferably for a period of 1 to 2 hours.
The catalyst used in the reaction is selected from group consisting of 4-dimethylaminopyridine, 4-Pyrrolidinylpyridine, pyridine, dimethylamine, and the like; Preferably 4-dimethylaminopyridine.

The solvent used in the reaction is selected from the group consisting of Tetrahydrofuran, MeTHF, dioxane, methanol, isopropyl alcohol, ethanol, propanol; preferable Tetrahydrofuran.
The base used in the reaction is selected from the group consisting of diisopropylethylamine, triethylamine, pyridine, lutidine derivatives, sodium methoxide, potassium methoxide, sodium methoxide or potassium hydroxide, preferable diisopropylethylamine
In stage-11, the compound of formula-Ill is reacted with Nickle complex of formula-IV amination catalyst solvent and an organic solvent to obtain compound of Formula -V.
Nickle complex preparation was carried out as disclosed in WO2005085178A1.
Base used in the reaction is selected from the group consisting of sodium methoxide, potassium methoxide, sodium hydroxide or potassium hydroxide and the like. Preferably using sodium methoxide.
Solvent used in the reaction is selected from the group consisting of methanol, isopropyl alcohol, ethanol, propanol and the like. Preferably using methanol and isopropyl alcohol.
Chelating agent used in the reaction is selected from the group consisting
of ammonium pyrrolidine dithiocarbamate, ammonium piperidine
dithiocarbamate, ammonium morpholine dithiocarbamate, ammonium 4-
methylpiperazinedithiocarbamate, ammonium, N,N-dialkylamine
dithiocarbamate, ammonium, N,N-diarylamine dithiocarbamate, and the like. Preferably using ammonium pyrrolidinedithiocarbamate.

The duration of the reaction may range from 12 tol9 hours, preferably for a period of 14 to 17 hours.
In stage-Ill, the compound of formula-V that is Droxidopa hydrochloride is treated with base and solvent to obtain compound of Formula I.
Solvent used in the reaction is selected from methanol, isopropyl alcohol, ethanol, butanol, acetonitrile or acetone preferably using methanol.
Alcohol used in the reaction is selected the group consisting of methanol, isopropyl alcohol, ethanol or butanol;
Base used in the reaction is selected from the group consisting of triethanolamine ortetraethylammonium, diisopropylethylamine and the like, preferably using triethylamine.
The cooling temperature may range from -5 to 10 °C and preferably at a temperature in the range from 0 to 5 °C. The duration of the stirring may range from 5 to 10 hours, preferably for a period of 7 to8 hours.
EXPERIMENTAL PORTION
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.
Exam pie-1: Process for preparation of Droxidopa
Stage-I: Process for preparation of Carbonic acid 2-tert-butoxyc arbonyloxy-
4-formylphenyl ester tert-butyl ester
To a solution of 3,4-dihydroxy benzaldehyde (50.0 grams, 0.362 mol, 1.0 eq) in to the THF (500 mL, 10 v/g of 3,4-dihydroxy benzaldehyde) and cooled to 10-15 QC. DMAP (2.21 grams, 0.018 mol, 0.05 eq) was added to the reaction mixture at 10-

15 °C and stirred for 5 minutes. DIPEA (52 mL, 0.362 mol, 1.0 eq) was added to the reaction mixture at 10-15 °C and stirred for 10 min. Boc anhydride (210 mL, 0.905 mol, 2.5 eq) was added to the reaction mixture at 10-15 °C over 30 minutes. After addition, reaction mixture was stirred at 10-15 °C for 1-2 hours. The aliquot taken and checked TLC, 3,4-dihydroxy benzaldehyde was completely consumed and new non-polar spot formation observed. MTBE (500 mL, 10 v/g of 3,4-dihydroxy benzaldehyde) was added to the reaction mixture and stirred for 15 min at 25-30 °C and added 10% citric acid aqueous solution (500 mL, 10 v/g of 3,4-dihydroxy benzaldehyde) to the MTBE solution and stirred for 10 min. Allowed to separate the layers and washed the organic layer with water (500 mL, 10 v/g of 3,4-dihydroxy benzaldehyde). Resulted organic layer was distilled out under vacuum at below 25 °C to obtained stage-I product as yellow liquid. The stage-I material used for stage-II without any further purification.
'HNMR (CDC13) 400 MHz): 9.96 (s, 1H), 7.81 (d, 7=1.6 Hz, 1H), 7.78 (dd, 1H), 7.46 (d, J= 6.8 Hz, 1H), 1.56 (s, 18H); ,3C-NMR (CDC13> 100 MHz): 189.9, 150.2, 149.7, 147.2, 143.1, 134.5, 127.9, 123.8, 123.6,27.4.
Stage-II: Process for preparation of Droxidopa hydrochloride
To a solution of 48 mL of 30%NaOMe solution in MeOH (200 mL, 2 v/g of Ni-ligand) and stirred for 15 minutes at 25-30 °C, cooled the reaction mixture up to 10-15 °C, added Ni-Ligand (100 grams, 0.200 mol, 1.0 eq) to the reaction mixture at 10-15 °C. Reaction mixture was stirred for 30 minutes at 10-15 °C and added the stage-I in methanol solution (72 grams, 0.210 mol, 1.05 eq, stage-I intermediate was dissolved in 100 mL of MeOH) over 30 min at 10-15 °C. Reaction mixture was stirred for 1 hour at 10-15 °C. The aliquot taken and checked TLC, Ni-Ligand was completely consumed and new non-polar spot formation observed. After completion of the reaction, cooled to 0-5 °C and added 85 mL of cone. HC1 to the reaction mixture slowly at 0-5 °C over a period of 30-45 minutes, stirred the reaction mixture for 14-17hours at 0-5 °C. 300 mL of MDC added to the reaction mixture and stirred for 15-20 min at 15-20 °C. 150 mL of IN

HC1 added to the reaction mixture and stirred for 15-20 min at 15-20 °C. Allowed to separate the layers and washed the aqueous layer with MDC (2X300 mL). Distilled the aqueous layer to remove the MeOH at below 25 °C under vacuum (500 mmHg). Ammonium pyrrolidine dithiocarbamate (33.0 grams, 0.2 mol, 1.0 eq.) was added to aqueous layer and heated up to 50-55 °C and stirred for 1 hour at 50-55 °C and allowed to 25-30 °C and filtered the solid and washed with 50 mL of IN HC1. Charged IPA (200 mL, 2 v/g of Ni-!igand) to the filtrate and cooled to 0-5 °C and stirred for lOhours at 0-5 °C.
Stage-Ill: Process for preparation of Droxidopa
The above obtained Droxidopa hydrochloride salt (10.0 grams, obtained in stage-II) was dissolved in 30 mL of IN HC1 and converted the'free base by adjusting the pH to 6.0-6.5 of its aqueous solution using triethylamine:MeOH (1:2). The solid was precipitated and cooled to 0-5 °C and stirred for 7-8 hours at same temperature. Filtered and washed with water (10 mL) followed by washing with methanol (10 mL) to obtain desired product (4.0 grams).