DESC:FIELD OF INVENTION
The present invention provides a process for preparation of threo-3-(3,4-dihydroxyphenyl)serine derivatives (IIa and IIb) substantially free of erythro-3-(3,4- dihydroxyphenyl)serine derivatives (IIc and IId). The present invention further provides conversion of threo-3-(3,4-dihydroxyphenyl)serine derivatives (IIa and IIb) to Droxidopa.

BACKGROUND OF THE INVENTION
The (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)serine compound (Ia)

is known as Droxidopa is pharmacologically active towards the circulatory system and the central nervous system, and, when administered to a patient, has efficacy against certain ailments, such as peripheral orthostatic hypotension and Parkinson disease, and has efficacy as an antidepressant. In the United States, it is marketed under the name Northera™.

3-(3,4-dihydroxyphenyl)serine compounds (I) or a mineral acid salt thereof

* represents asymmetric carbon
have two asymmetric carbon atoms, due to which four optical isomers are possible. Two optical isomers are “threo” isomers are a 2S, 3R compound and a 2R, 3S compound; while another two optical isomers are “erythro” isomers are a 2R, 3R compound and a 2S, 3S compound.

Several methods have been disclosed in the literature for preparing the Droxidopa (Ia).

U.S. Patent No. 3,920,728 discloses a method of separating isomers, including droxidopa, from four isomeric forms. The process involves condensation of 3,4-Di(benzyloxy)benzaldehyde with glycine in aqueous NaOH solution followed by treatment with benzyl chloroformate to give mixture of erythro and threo isomers of 3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine which is then separated to remove erythro isomers by fractional crystallization in acetonitrile containing dicyclohexylamine followed by decomposition with acid to give threo isomers of 3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine. Resolving threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine via salt formation with optically active threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol or ephedrine followed by decomposition with acid to give (–) threo-(2S, 3R)-3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine, which on hydrogenation gives (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)serine (Droxidopa). However, the maximum yield after separation of four isometric forms cannot exceed 25%. Further purity and yield of the intermediates and final product is also poor.

U.S. Patent No. 4,480,109 discloses a selective production of threo-3-(3,4-methylenedioxyphenyl)serine by condensing glycine and piperonal in the presence of a base and subsequent addition of acetic acid in solvent or mixture of solvent with water. After completion of the condensation, the intermediate products of the reaction are decomposed by the addition of water and acetic acid to obtain threo form in the form of acetate.

Japanese Patent No. 2,740,959 discloses a selective production of threo-3-(3,4-dialkoxyphenyl)serine by condensing a 3,4-dialkoxybenzaldehyde and glycine in the presence of an inorganic base using a mixed solvent of a lower alcoholic solvent and an aprotic solvent and the resultant product is then treated with an acid. However, use of the mixed solvent system has limitations of maintaining the solvent ratio and their separation.

In view of the above, it is therefore, desirable to provide an efficient process for the preparation of droxidopa with high yield and better impurity profile.

SUMMARY OF THE INVENTION
The main object of the present invention is to provide, a process for the preparation of threo-3-(3,4-dihydroxyphenyl)serine derivatives (IIa and IIb)

wherein R1 and R2 represent hydrogen, alkyl, aryl, aralkyl; or R1 and R2 jointly form a methylene group;
which is substantially free of erythro-3-(3,4-dihydroxyphenyl)serine derivatives (IIc and IId),
comprises condensing 3-(3,4-dihydroxyphenyl)-benzaldehyde derivative (III) with glycine in the presence of a base in organic solvent under substantially anhydrous conditions.

wherein R1 and R2 are as defined above.

Another object of the present invention is to provide, a process for conversion of the threo derivatives (IIa and IIb) obtained according to present invention, to Droxidopa (Ia).

DETAILED DESCRIPTION OF THE INVENTION
The main object of the present invention is to provide, a process for the preparation of threo-3-(3,4-dihydroxyphenyl)serine derivatives (IIa and IIb) as shown in scheme 1

wherein R1 and R2 represent hydrogen, alkyl, aryl, aralkyl; or R1 and R2 jointly form a methylene group;
which is substantially free of erythro-3-(3,4-dihydroxyphenyl)serine derivatives (IIc and IId),
comprises condensing 3-(3,4-dihydroxyphenyl)-benzaldehyde derivative (III) with glycine in the presence of a base in organic solvent under substantially anhydrous conditions.

In another aspect, the present invention provides a process for the preparation of (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)serine (Ia) or its pharmaceutically acceptable salts

comprises condensing 3-(3,4-dihydroxyphenyl)-benzaldehyde derivative (III) with glycine in the presence of a base in organic solvent under substantially anhydrous conditions to obtain threo-3-(3,4-dihydroxyphenyl)serine derivatives (IIa and IIb), substantially free of erythro-3-(3,4-dihydroxyphenyl)serine derivatives (IIc and IId);
followed by conversion of threo-3-(3,4-dihydroxyphenyl)serine derivatives (IIa and IIb) to (-) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)serine (Ia) or its pharmaceutically acceptable salts.

In another aspect, the present invention provides a process for the preparation of (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)serine (Ia) or its pharmaceutically acceptable salts
comprises:
a) condensing 3-(3,4-dihydroxyphenyl)-benzaldehyde derivative of formula (III)

wherein R1 and R2 represent hydrogen, alkyl, aryl, aralkyl; or R1 and R2 jointly form a methylene group;
with glycine in the presence of a base in organic solvent under substantially anhydrous conditions to obtain threo-3-(3,4-dihydroxyphenyl)serine derivatives of formula (IIa and IIb)

wherein R1 and R2 are as defined above
substantially free of erythro-3-(3,4-dihydroxyphenyl)serine derivatives of formula (IIc and IId),
b) protecting free amine group of threo-3-(3,4-dihydroxyphenyl)serine derivatives of formula (IIa and IIb) obtained in step a) to obtain threo-3-(3,4-dihydroxyphenyl)-N-protected serine derivatives of formula (IVa and IVb)

wherein R1 and R2 are as defined above; R3 represent amino protecting group,
c) optically resolving threo-3-(3,4-dihydroxyphenyl)-N-protected serine derivatives of formula (IVa and IVb) obtained in step b) with resolving agent to obtain (–) threo-(2S, 3R)-3-(3,4-dibenzyloxyphenyl)-N-protected serine derivative salt of formula (Va)

wherein 'HA' refers to resolving agent; R1 and R2 are as defined above; and R3 represent amino protecting group,
d) treating the salt obtained in step c) with mineral acid to obtain (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)-N-protected serine derivative of formula (VIa)

e) deprotecting (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)-N-protected serine derivative of formula (VIa) to obtain (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)-serine of formula (Ia) or its pharmaceutically acceptable salts.

The organic solvent used in step a) is selected from the group consisting of alcohols selected from methanol, ethanol, n-propanol, isopropanol, n-butanol; nitriles selected from acetonitrile, propionitrile, butyronitrile; ketones selected from acetone, methyl ethyl ketone; esters selected from ethyl acetate, propyl acetate, isopropyl acetate; ethers selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane; hydrocarbons selected from hexane, heptane; amides selected from dimethyl formamide, dimethylacetamide, dimethylsulphoxide and mixtures thereof; preferably absolute ethanol.

The reaction in accordance with this invention should be carried out in a substantially anhydrous condition because the presence of water causes formation of undesirable erythro derivatives and reduces the yield of the desired threo derivative. According to the present invention the term “Substantially anhydrous conditions” refers to a water content of the reaction medium less than 10%, preferably less than 5%, more preferably less than 2% by weight based on the amount of the entire reaction mixture. Experiment has shown that if the amount of water is larger than 10% by weight, the yield of the final product markedly decreases and formation of erythro derivatives increases.

In the present invention, the term “substantially free of erythro-3-(3,4-dihydroxyphenyl)serine derivatives” means that the amount of erythro-3-(3,4- dihydroxyphenyl)serine derivatives (IIc and IId) is less than 10%, preferably less than 7%, more preferably less than 5% when measured by HPLC.

The base used in step a) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate and mixture thereof; preferably sodium hydroxide.

The amino protecting group is selected from carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), acetyl, benzyl (Bn), p-methoxybenzyl (PMB), benzoyl (Bz), tosyl (Tos), carbamate, p-methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxycarbonyl (FMOC), phthaloyl; more preferably carbobenzyloxy (Cbz). The protection can be carried out by the methods known in the art under those conditions which are generally used, including molar ratio, solvent, reaction temperature, and reaction time.

The threo-3-(3,4-dihydroxyphenyl)-N-protected serine derivatives (IVa and IVb) obtained is resolved with resolving agent which are chiral bases selected from quinidine, quinine, strychnine, cinchonidine, cinchonine, ephedrine, norephedrine, 1-methylamine, dehydroabietylamine, (R)-2-amino-1,1-diphenyl-1-propanol, (S)-2-amino-1,1-diphenyl-1-propanol, and L-3-hydroxy-3(4-nitrophenyl)-2-amino-1-propanol; preferably ephedrine or (S)-2-amino-1,1-diphenyl-1-propanol.

In general, the resolution is done in presence of more of organic solvents. The organic solvent used for resolution is selected from the group consisting of alcohols selected from methanol, ethanol, n-propanol, isopropanol, and n-butanol; nitriles selected from acetonitrile, propionitrile, butyronitrile; ketones selected from acetone, methyl ethyl ketone; esters selected from ethyl acetate, propyl acetate, isopropyl acetate; ethers selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and dioxane; hydrocarbons selected from hexane, heptane; amides selected from dimethyl formamide, dimethylacetamide, and dimethylsulphoxide; preferably methanol.
During the resolution process the undesired (–) threo-(2R, 3S)-3-(3,4-dibenzyloxyphenyl)-N-protected serine derivative salt (Vb)

wherein, R1, R2 and R3 are as defined above;
remains in the solution and desired (–) threo-(2S, 3R)-3-(3,4-dibenzyloxyphenyl)-N-protected serine derivative salt (Va) gets precipitated.

The precipitated resolved salt (Va) is then treated with mineral acid selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; preferably hydrochloric acid to obtain (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)-N-protected serine derivative (VIa).

The (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)-N-protected serine derivative (VIa) obtained is subjected to deprotection of hydroxyl group and amino group to obtain (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)-serine (Ia) or its pharmaceutically acceptable salts.
Deprotection of the amino group and hydroxyl group can be carried independently or simultaneously under acidic, basic, hydrogenating, oxidative or reductive conditions, or by combination thereof e.g. treatment with acid selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, aluminium trichloride, boron trifluoride, aluminum bromide, ferric chloride, stannic chloride, boron trichloride, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid; treatment with base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, butyl lithium, ammonia, hydrazine, sodium hydride, sodium borohydride, lithium aluminium hydride; hydrogenolysis using catalyst selected from PtO2, Pd/carbon, Raney nickel, Rh/carbon.

The organic solvent used for deprotection is selected from the group consisting of alcohols selected from methanol, ethanol, n-propanol, isopropanol, and n-butanol; nitriles selected from acetonitrile, propionitrile, butyronitrile; ketones selected from acetone, methyl ethyl ketone; esters selected from ethyl acetate, propyl acetate, isopropyl acetate; ethers selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and dioxane; hydrocarbons selected from hexane, heptane, toluene and benzene; amides selected from dimethyl formamide, dimethylacetamide, and dimethylsulphoxide; halogenated hydrocarbon solvents selected from dichloromethane, chloroform, dichloroethane, and chlorobenzene.

The (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)-serine (Ia) can be converted to pharmaceutically acceptable salts with acids selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, boric acid, formic acid, acetic acid, ascorbic acid, oxalic acid, lactic acid, citric acid, monochloroacetic acid, trichloroacetic acid, benzoic acid, phtahlic acid, hydroxybenzoic acid, benzenesulfonic acid, toluenesulfonic acid and naphthalene sulfonic acid; preferably hydrochloric acid.

The process of the present invention is as shown in Scheme 2:

wherein, R1, R2 and R3 are as defined above

Following are the advantages of the process of the present invention:
i) Use of substantially anhydrous conditions formed threo derivatives not less than 90%.
ii) No separate step required for removal of erythro derivatives.
iii) Purity of intermediate threo derivatives is not less than 90%.
iv) Numbers of reaction steps are also reduced.
v) Yield and purity of the Droxidopa is improved.

Droxidopa (Ia) obtained by the process of the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers, excipients, or diluents.

To understand the present invention following preparative and testing examples are set forth, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

EXAMPLES:
Example 1: Preparation of 3,4-di(benzyloxy)benzaldehyde (III, wherein R1=R2= benzyl)
500 gm 3, 4-dihydroxy benzaldehyde and methanol reacted with 825 gm K2CO3 and 1259 gm benzyl chloride at 60-65 °C, after completion of reaction cooled and filter the solids. Solids washed with methanol and water to obtain 1010 gm of 3,4-di(benzyloxy)benzaldehyde. Yield- 88 %, Purity-99.78%.

Example 2: Preparation of threo-3-(3,4-dibenzyloxyphenyl)-serine (IIa and IIb, wherein R1=R2= benzyl)
300 g of 3,4-di(benzyloxy)benzaldehyde (water content < 0.89%) in 1200 ml absolute ethanol (water content is < 0.21%), 36.7 of glycine (water content < 0.20%) and 48.9 g of sodium hydroxide stirred at 72?. After cooling to 42? added 1104 ml 2N HCl for 1 to 1.5 hours then cool to room temperature and filtered and washed with 150 mL 1:1 mixture of ethanol and 3N HCl. Sodium acetate 500 g is added in the filtrate, cooled, filtered, washed with water 300 ml and then this solid was taken in 1500 MTBE at 55? and cooled, filtered, washed with MTBE 300 ml to obtain 105 g of threo-3-(3,4-dibenzyloxyphenyl)-serine. Yield - 32.40 %, Purity-91%. Content of erythro-3-(3,4-dibenzyloxyphenyl)-serine (IIc and IId) less than 5%.

Example 3: Preparation of threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine (IVa and IVb, wherein R1=R2= benzyl, R3= carbobenzyloxy (Cbz))
80 gm threo-3-(3,4-dibenzyloxyphenyl)-serine and 8 gm NaOH 400 ml water are added in reaction flask followed by dropping 38.50 gm benzyl chloroformate after dropping adjust pH 8.5-9.0 using 3N NaOH & stirred reaction mass added 800 gm chilled water & 160 ml conc HCl. Reaction mass extracted with 1600 ml ethyl acetate and organic layer washed with 800 ml 1N HCl and isolated by using ethyl acetate and cyclohexane to obtain 96.0 gm threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine. Yield- 90 %, Purity-74.41 %.

Example 4: Preparation of (–) threo-(2S, 3R)-3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine (S)-2-amino-1,1-diphenyl-1-propanol salt (Va, wherein R1=R2= benzyl and R3= carbobenzyloxy (Cbz))
90 gm threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine and 38.76 gm (S)-2-amino-1,1-diphenyl-1-propanol in 450 ml methanol stirred at ambient temperature. Filtered the solids and washed with methanol to obtain 50.4 gm of (–) threo-(2S, 3R)-3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine (S)-2-amino-1,1-diphenyl-1-propanol salt isomer with 100% ee. Yield- 40 %, Purity 98.23 %.

Example 5: Preparation of (–) threo-(2S, 3R)-3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine (VIa, wherein R1=R2= benzyl and R3= carbobenzyloxy (Cbz))
45 gm of salt of (–) threo-(2S, 3R)-3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine & 450 ml ethyl acetate mixed and treated with 180 ml 1N Aq HCl, separated the layers. Distilled out the solvent to obtain 30 gm desired isomer with 100% ee. Yield- 96 %.

Example 6: Preparation of droxidopa hydrochloride (Ia.HCl)
25 gm (–) threo-(2S, 3R)-3-(3,4-dibenzyloxyphenyl)-N-carbobenzyloxyserine and methanol mixed with mixed with 1N HCl and hydrogenated in presence of 10% Pd/C. Filtered out reaction mass on celite bed and washed with methanol. Solvents distilled off under reduced pressure. Solids stirred with acetone and filtered out, to obtain 11.25 gm Droxidopa.HCl. Yield- 95 %, Purity-99.92%.

Example 7: Preparation of droxidopa (Ia)
10 gm Droxidopa.HCl neutralized with water and aq NaHCO3 filtered the solids and washed with water to obtain 8 gm of Droxidopa. Yield- 94 %, Purity-99.94 %.
,CLAIMS:1. A process for preparation of threo-3-(3,4-dihydroxyphenyl)serine derivative of compound of formula (IIa and IIb)

wherein R1 and R2 represent hydrogen, alkyl, aryl, aralkyl; or R1 and R2 jointly form a methylene group;
which is substantially free of erythro-3-(3,4-dihydroxyphenyl)serine derivative of compound of formula (IIc and IId)
comprises condensing 3-(3,4-dihydroxyphenyl)-benzaldehyde derivative of formula (III) with glycine in the presence of a base in organic solvent under substantially anhydrous conditions.

wherein R1 and R2 are as defined above.
2. A process for the preparation of (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)serine of formula (Ia) or its pharmaceutically acceptable salts

comprises condensing 3-(3,4-dihydroxyphenyl)-benzaldehyde derivative compound of formula (III) as defined in claim 1, with glycine in the presence of a base in organic solvent under substantially anhydrous conditions to obtain threo-3-(3,4-dihydroxyphenyl)serine derivative of compound of formula (IIa and IIb) as defined in claim 1, substantially free of erythro-3-(3,4-dihydroxyphenyl)serine derivative of compound of formula (IIc and IId) as defined in claim 1;
followed by conversion of threo-3-(3,4-dihydroxyphenyl)serine derivative of compound of formula (IIa and IIb) as defined in claim 1 to (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)serine of formula (Ia) or its pharmaceutically acceptable salts.
3. A process for the preparation of (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)serine of formula (Ia) or its pharmaceutically acceptable salts

comprises:
a) condensing 3-(3,4-dihydroxyphenyl)-benzaldehyde derivative of formula (III)

wherein R1 and R2 represent hydrogen, alkyl, aryl, aralkyl; or R1 and R2 jointly form a methylene group;
with glycine in the presence of a base in organic solvent under substantially anhydrous conditions to obtain threo-3-(3,4-dihydroxyphenyl)serine derivatives of formula (IIa and IIb)

wherein R1 and R2 are as defined above
substantially free of erythro-3-(3,4-dihydroxyphenyl)serine derivatives of formula (IIc and IId),
b) protecting free amine group of threo-3-(3,4-dihydroxyphenyl)serine derivatives of formula (IIa and IIb) obtained in step a) to obtain threo-3-(3,4-dihydroxyphenyl)-N-protected serine derivatives of formula (IVa and IVb)

wherein R1 and R2 are as defined above; R3 represent amino protecting group,
c) optically resolving threo-3-(3,4-dihydroxyphenyl)-N-protected serine derivatives of formula (IVa and IVb) obtained in step b) with resolving agent to obtain (–) threo-(2S, 3R)-3-(3,4-dibenzyloxyphenyl)-N-protected serine derivative salt of formula (Va)

wherein 'HA' refers to resolving agent; R1 and R2 are as defined above; and R3 represent amino protecting group,
d) treating the salt obtained in step c) with mineral acid to obtain (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)-N-protected serine derivative of formula (VIa)

e) deprotecting (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)-N-protected serine derivative of formula (VIa) to obtain (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)-serine of formula (Ia) or its pharmaceutically acceptable salts.
4. The process according to claim 1, claim 2 and claim 3 a), wherein content of erythro-3-(3,4-dihydroxyphenyl)serine derivative of compound of formula (IIc and IId) is less than 10% when measured by HPLC.
5. The process according to claim 1, claim 2 and claim 3 a), wherein water content of the reaction medium is less than 10%.
6. The process according to claim 1, claim 2, and claim 3 a), wherein the base is selected from the sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
7. The process according to claim 1, claim 2 and claim 3 a), wherein organic solvent is selected from alcohol, nitrile, ketone, ester, ether, hydrocarbon, amide & mixtures thereof.
8. The process according to claim 7, wherein said solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, propionitrile, butyronitrile, acetone, methyl ethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, hexane, heptane, dimethyl formamide, dimethylacetamide, dimethylsulphoxide and mixtures thereof.
9. The process according to claim 3 b), wherein amino protecting group is selected from carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), acetyl, benzyl (Bn), p-methoxybenzyl (PMB), benzoyl (Bz), tosyl (Tos), carbamate, p-methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxycarbonyl (FMOC), phthaloyl.
10. The process according to claim 3 c), wherein resolving agent is selected from cinchonidine, cinchonine, ephedrine, norephedrine and (S)-2-amino-1,1-diphenyl-1-propanol.
11. The process according to claim 3 d), wherein the mineral acid is selected from hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
12. threo-3-(3,4-dihydroxyphenyl)serine derivative of compound of formula (IIa and IIb) as defined in claim 1, substantially free of erythro-3-(3,4-dihydroxyphenyl)serine derivative of compound of formula (IIc and IId) as defined in claim 1.
13. (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)serine of formula (Ia) or its pharmaceutically acceptable salts obtained according to the process of claim 2 and claim 3.
14. A pharmaceutical composition comprising (–) threo-(2S, 3R)-3-(3,4-dihydroxyphenyl)serine of formula (Ia) obtained according to the process of claim 2 and claim 3 with pharmaceutically acceptable carrier, excipient, or diluent.