DESC:Field of the Invention:
The present application relates to an alternative process for (2S)-2-amino-3-[3-hydroxy-4-(phosphonooxy)phenyl] propanoic acid and intermediates thereof, which is represented by the following structural formula-I.

Formula-I

Background of the Invention:
Foslevodopa is also known as Levodopa-4´-monophosphate with the chemical name of (2S)-2-amino-3-[3-hydroxy-4-(phosphonooxy)phenyl] propanoic acid for the treatment of motor fluctuations in patients with advanced levodopa-responsive Parkinson’s disease who do not have satisfactory control of severe, debilitating motor fluctuations and hyper /dyskinesia despite optimized treatment with available combinations of Parkinson’s medicinal products.
The product is developed by AbbVie Corporation with brand name of VYALEV™ approved as combination with Foscarbidopa in Canada and European Union.

The US patent US9446059B2 (herein after US’059B2) first reported foscarbidopa and foslevodopa and process for intermediates thereof.
The said US’059B2 patent reported process for preparation foslevodopa by separating the isomers by column chromatography and also reported various processes for foslevodopa and intermediated thereof involves multiple conventions and purifications.

Based on draw back of the prior art processes, there is a need for providing an alternative / improved process for the preparation of foslevodopa which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords high pure foslevodopa.
The present invention provides an alternative and improved process for preparation of foslevodopa, which is efficient, industrially viable and cost effective.
Brief Description:
The first aspect of the present invention provides an alternative process for the preparation of the Foslevodopa (Scheme-I).
The second aspect of the present invention provides an improved process for the preparation of the Foslevodopa.

Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.

As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, Di isopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “protecting” agent / group (PG) used in the present invention refers to a suitable protecting reagents that are selected from di-tert-butyl dicarbonate, chlorobenzyl format, benzoyl chloride, benzyl bromide, benzyl chloride, acetyl chloride, fluorenyl methyloxy carbonyl chloride; The term “phase transfer catalyst (PTC)” used in the present invention refers are selected from triethyl benzyl ammonium chloride, tetra butyl ammonium bromide, tetra butyl ammonium chloride, tetra butyl ammonium acetate, methyl tributyl ammonium chloride, tetra butyl ammonium hydroxide, tributylbenzylammonium chloride;
The first aspect of the present invention provides an improved process for the preparation of compound of formula-I.

Formula-I
Comprising of:
a) reacting the compound of formula-1,

Formula-1

with suitable reagent, solvent to provide compound of formula-2,


Formula-2
b) reacting the compound of formula-2 with suitable reagents, solvents to get compound of formula-3,

Formula-3
c) reacting the compound of formula-3 with suitable reagents, solvents to get compound of formula-4,

Formula-4
d) reacting the compound of formula-4 with suitable reagents, solvents to get compound of formula-5,

Formula-5
e) reacting the compound of formula-5 with suitable reagents, suitable solvents to get compound of formula-I,
f) optionally purifying the compound obtained in step-e) with suitable reagents, suitable solvents to provide compound of formula-I.

Formula-I
Wherein in step-a), b), c), d), e) and f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvent, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, ketone solvent, alcohol solvent, acetic acid, water or any mixture thereof; the suitable temperature is 0-150°C.
Wherein in step-a) suitable reagents are selected from HBr-Acetic acid, bromine, N-bromo succinimide, bromine in acetic acid, ammonium bromide and mixed thereof; suitable temperature is 0-125°C.
Wherein in step-b) suitable reagents are selected from benzyl chloroformate, benzyl bromide, benzyl chloride and mixture thereof.
Wherein in step-c) suitable reagents are selected from tetra benzyl pyrophosphate, dibenzyl phosphoryl chloride, organic base and mixture thereof.
Wherein in step-d and e) suitable reagents are selected from inorganic base, organic base, Conc. HCl, dil. HCl, palladium carbon, platinum oxide, Pd(OH)2 , Pd(OAc)2, Raney nickel, hydrogen gas atmosphere and mixture thereof.
Wherein in step-f) suitable reagents are selected from Conc. HCl, dil. HCl, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, oxalic acid, tartaric acid, para toluene sulfonic acid, acetic acid, trifluoro acetic acid, organic base, inorganic base and mixture thereof.

The second aspect of the present invention provides an improved process for the preparation of compound of formula-I.

Formula-I
Comprising of:
a) reacting the compound of formula-1,

Formula-1
with suitable reagent, suitable solvent to provide compound of formula-2A,


Formula-2A
b) reacting the compound of formula-2A with suitable reagents, suitable solvents to get compound of formula-3A [Where X: chloro, bromo, iodo; where PG: nitrogen protecting groups such as benzyl and substituted benzyl groups, or more frequently carbamates such as tert-butyl, benzyl or fluorenyl methyl carbamates, acetyl, hydrogen; where R: alkyl (methyl, ethyl, propyl, t-butyl, isopropyl), benzyl, substituted benzyl groups, hydrogen, carbamates such as tert-butyl, benzyl or fluorenyl methyl carbamates)

Formula-3A

c) reacting the compound of formula-3A with suitable reagents, solvents to get compound of formula-4A,

Formula-4A
d) reacting the compound of formula-4A with suitable reagents, solvents to get compound of formula-5A,

Formula-5A

e) reacting the compound of formula-5A with suitable reagents, solvents to get compound of formula-I,
f) optionally purifying the compound obtained in step-e) with suitable reagents, solvents to provide compound of formula-I.

Formula-I
wherein in step-a), b), c), d), e) and f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvents, nitrile solvents, ketone solvents, alcohol solvents, acetic acid, water or any mixture thereof; the suitable temperature is 0-150°C.
wherein in step-a) suitable reagents are selected from HBr-Acetic acid, bromine, N-bromo succinimide, bromine in acetic acid, ammonium bromide and mixed thereof; suitable temperature is 0-155°C.
Wherein in step-b) suitable reagents are selected from benzyl chloroformate, benzyl bromide, benzyl chloride, methyl chloroformate, ethyl chloroformate, F-MoC, (BOC)2O, acetyl chloride, triphenylmethyl chloride and mixture thereof.
Wherein in step-c) suitable reagents are selected from tetra benzyl pyrophosphate, dibenzyl phosphoryl chloride, organic base and mixture thereof.
Wherein in step-d and e) suitable reagents are selected from inorganic base, organic base, Conc. HCl, dil. HCl, palladium carbon, platinum oxide, Pd(OH)2 , Pd (OAc)2, Raney nickel, hydrogen gas atmosphere and mixture thereof;
Wherein in step-f) suitable reagents are selected from Conc. HCl, dil. HCl, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, oxalic acid, tartaric acid, para toluene sulfonic acid, acetic acid, trifluoro acetic acid, organic base, inorganic base and mixture thereof.

The other preferred embodiment of the present invention is a compound of formula- 3A .

Formula-3A

[where X: chloro, bromo, iodo; where PG: nitrogen protecting groups such as benzyl and substituted benzyl groups, or more frequently carbamates such as tert-butyl, benzyl or fluorenyl methyl carbamates, acetyl, hydrogen; where R: alkyl (methyl, ethyl, propyl, t-butyl, isopropyl), benzyl, substituted benzyl groups, hydrogen, carbamates such as tert-butyl, benzyl or fluorenyl methyl carbamates].

The other preferred embodiment of the present invention is a compound of formula- 4A.

Formula-4A

[Where X: chloro, bromoe, iodo; where PG: nitrogen protecting groups such as benzyl and substituted benzyl groups, or more frequently carbamates such as tert-butyl, benzyl or fluorenyl methyl carbamates, acetyl, hydrogen; where R: alkyl (methyl, ethyl, propyl, t-butyl, isopropyl), benzyl, substituted benzyl groups, hydrogen, carbamates such as tert-butyl, benzyl or fluorenyl methyl carbamates].

The other preferred embodiment of the present invention is a compound of formula- 5A.
Where X : chloro, bromo, iodo.

Formula-5A

The present invention described as follows in a schematic representation (Reaction scheme-I)

The other aspect of the present invention provides an improved process for the preparation of compound of formula-I as mentioned in scheme-II
Reaction scheme-II

The process for the preparation of foslevodopa developed by the present inventors produces highly pure levodopa with good yield. All the related substances and residual solvents are controlled well within the limits as suggested by ICH guidelines and most of the related substances are controlled in non-detectable levels.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:
Example-1: Preparation of compound of formula-2.
A round bottom flask was charged with L-tyrosine (1000 g), acetic acid (10L), aq. 50 % HBr (2500 g) and dimethylsulfoxide (500 mL) are heated to 60-70°C and stirred for 5 hr. The reaction mixture was distilled off, cooled the reaction to 25-35°C and charged with water and heated to 60-75°C further stirred for 1 hr. The reaction cooled, adjusted the pH to 7.0 with sodium carbonate solution and stirred for 6 hr. The obtained solid was filtered and dried to get the title compound.
Yield: 956. g
Example-2: Preparation of compound of formula-3.
A round bottom flask was charged with sodium hydroxide (40 g, in water ) was added drop-wise to a solution of compound 2 (100 g) in water over a period of 20 minutes at 0° C. Benzyl chloroformate (103.9 g) in dioxane (400 mL) was added drop-wise to the suspension and then the reaction mass was stirred at 25-35°C for 16 hours. The reaction mass was basified using aq. sodium hydroxide and extracted with ethyl acetate. The organic layer was separated, and the aqueous layer was acidified using dil. HCl and extracted with ethyl acetate. The combined organic layer was washed with water, saturated sodium chloride solution, dried over sodium sulfate, and concentrated to provide crude compound.
A round bottom flask was charged with cesium carbonate (113 g) and a solution of the above crude compound in dimethylformamide at 0° C. Benzyl bromide (95 mL,) was added dropwise to this mixture over a period of 30 minutes at 0° C and the reaction mass was stirred at 25-35°C for 16 hours. The reaction mass was diluted with water and extracted with methyl tert-butyl ether. The combined organic layer was washed with water, saturated sodium chloride solution, dried over sodium sulfate, and concentrated under vacuum to provide crude compound 3.
Yield: 154 g
Example-3: Preparation of compound of formula-4.
A round bottom flask was charged with potassium tert-butoxide (40 g) was added compound 3 (100 g) in tetrahydrofuran at 0° C. A solution dibenzylphosphoryl chloride in toluene (1 mol) was added dropwise to this mixture over a period of 30 minutes at 0° C and the reaction mass was stirred at 25-35°C for 2 hours. The reaction mass was cooled to 0° C and quenched with water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, dried over sodium sulfate, and concentrated to get the crude product.
Example-4: Preparation of compound of formula-I.
An autoclave was charged with 10% Pd/C (3 g, wet), Compound 4 (10 g) in methanol and water under nitrogen atmosphere. The reaction flask was hydrogenated at 4 Kg/cm2 pressure for 16 h at 30-40°C. The reaction mixture catalyst was removed by filtration and the filtrate was concentrated to get the crude compound. The crude compound was charged with ethanol (10 v), potassium hydroxide (1 eq) was stirred for 8 h at 50-60°C. Cooled the reaction mixture, acidified with dil. HCl and stirred for 2h. Filtered the solid compound and dried under suction to give the title compound.
Yield: 2.2 g.

,CLAIMS:We claim:
1. An alternative process for the preparation of compound of formula-I.

Formula-I
comprising of:
a) reacting the compound of formula-1,

Formula-1

with suitable reagent, solvent to provide compound of formula-2,


Formula-2
b) reacting the compound of formula-2 with suitable reagents, solvents to get compound of formula-3,

Formula-3
c) reacting the compound of formula-3 with suitable reagents, solvents to get compound of formula-4,

Formula-4
d) reacting the compound of formula-4 with suitable reagents, solvents to get compound of formula-5,

Formula-5
e)reacting the compound of formula-5 with suitable reagents, solvents to get compound of formula-I,
f) optionally purifying the compound obtained in step-e) with suitable reagents, solvents to provide compound of formula-I.

Formula-I
2. A process for compound of formula-I as per claim 1, wherein in step-a), b), c), d), e) and f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvents, nitrile solvents, ketone solvents, alcohol solvents, acetic acid, water or any mixture thereof; the suitable temperature is 0-150°C.
3. A process for compound of formula-I as per claim 1, Wherein in step-a) suitable reagents are selected from HBr-Acetic acid, bromine, N-bromo succinimide, bromine in acetic acid, ammonium bromide and mixed thereof; suitable temperature is 0-125°C.
Wherein in step-b) suitable reagents are selected from benzyl chloroformate, benzyl bromide, benzyl chloride, F-MoC, (BOC)2O, acetyl chloride, triphenylmethyl chloride and mixture thereof.
Wherein in step-c) suitable reagents are selected from tetra benzyl pyrophosphate, dibenzyl phosphoryl chloride, organic base and mixture thereof.
Wherein in step-d and e) suitable reagents are selected from inorganic base, organic base, Conc. HCl, dil HCl, palladium carbon, platinum oxide, Pd(OH)2 , Palladium acetate, Raney nickel, hydrogen gas atmosphere and mixture thereof;
Wherein in step-f) suitable reagents are selected from Conc. HCl, dil. HCl, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, oxalic acid, tartaric acid, para toluene sulfonic acid, acetic acid, trifluoro acetic acid, organic base, inorganic base and mixture thereof.
4. An improved process for the preparation of compound of formula-I

Formula-I
comprising of:
a) reacting the compound of formula-1,

Formula-1
with suitable reagent, solvent to provide compound of formula-2A,


Formula-2A
b) reacting the compound of formula-2A with suitable reagents, solvents to get compound of formula-3A [Where X: chloro, bromo, iodo; where PG: nitrogen protecting groups such as benzyl and substituted benzyl groups, or more frequently carbamates such as tert-butyl, benzyl or fluorenylmethyl carbamates, acetyl, hydrogen; where R: alkyl (methyl, ethyl, propyl, t-butyl, isopropyl), benzyl, substituted benzyl groups, hydrogen, carbamates such as tert-butyl, benzyl or fluorenylmethyl carbamates)

Formula-3A
c) reacting the compound of formula-3A with suitable reagents, to get compound of formula-4A,

Formula-4A
d) reacting the compound of formula-4A with suitable reagents, to get compound of formula-5A,

Formula-5A
e) reacting the compound of formula-5A with suitable reagents, solvents to get compound of formula-I,
f) optionally purifying the compound obtained in step-e) with suitable reagents, solvents to provide compound of formula-I.

Formula-I

5. A process for compound of formula-I as per claim 4, wherein in step-a), b), c), d), e) and f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvents, nitrile solvents, ketone solvents, alcohol solvents, acetic acid, water or any mixture thereof; the suitable temperature is 0-150°C; Wherein in step-a) suitable reagents are selected from HBr-Acetic acid, bromine, N-bromo succinimide, bromine in acetic acid, ammonium bromide and mixed thereof; suitable temperature is 0-125°C.
Wherein in step-b) suitable reagents are selected from benzyl chloroformate, benzyl bromide, benzyl chloride, F-MoC, (BOC)2O, acetyl chloride, triphenylmethyl chloride and mixture thereof.
Wherein in step-c) suitable reagents are selected from tetra benzyl pyrophosphate, dibenzyl phosphoryl chloride, organic base and mixture thereof.
Wherein in step-d and e) suitable reagents are selected from inorganic base, organic base, Conc. HCl, dil HCl, palladium carbon, platinum oxide, Pd(OH)2 , Palladium acetate, Raney nickel, hydrogen gas atmosphere and mixture thereof;
Wherein in step-f) suitable reagents are selected from Conc. HCl, dil. HCl, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, oxalic acid, tartaric acid, para toluene sulfonic acid, acetic acid, trifluoro acetic acid, organic base, inorganic base and mixture thereof.

6. A compound of formula- 3A

Formula-3A
[where X: chloro, bromo, iodo; where PG: nitrogen protecting groups such as benzyl and substituted benzyl groups, or more frequently carbamates such as tert-butyl, benzyl or fluorenyl methyl carbamates, acetyl, hydrogen; where R: alkyl (methyl, ethyl, propyl, t-butyl, isopropyl), benzyl, substituted benzyl groups, hydrogen, carbamates such as tert-butyl, benzyl or fluorenyl methyl carbamates]

7. A compound of formula- 4A

Formula-4A
[where X: chloro, bromo, iodo; where PG: nitrogen protecting groups such as benzyl and substituted benzyl groups, or more frequently carbamates such as tert-butyl, benzyl or fluorenyl methyl carbamates, acetyl, hydrogen; where R: alkyl (methyl, ethyl, propyl, t-butyl, isopropyl), benzyl, hydrogen, substituted benzyl groups, carbamates such as tert-butyl, benzyl or fluorenyl methyl carbamates]

8.A compound of formula- 5A [where X: chloro, bromo, iodo]

Formula-5A