Claims:We Claim:
1) A process for the preparation of D-Penicillamine (I)
(I)
comprising the steps of:
a. reacting phenyl hydrazine with (4S)-2-isopropyl-5,5-dimethyl thiazolidine -4-carboxylic acid (IV) or salt thereof in water miscible organic solvent to obtain Racemic-Penicillamine (III);

b. resolving the D-penicillamine from racemic –penicillamine (III), wherein the process of resolving comprising the steps of:
(i) reacting the racemic-penicillamine (III) with D-(-)-Tartaric acid in aqueous solvent;

(ii) treating the D-Penicillamine hemitartarate (II) with organic base in a water miscible organic solvent to get D-Penicillamine (I).

2) The process for the preparation of D-Penicillamine (I) according to claim 1, wherein suitable aqueous solvent is water or mixture with water miscible organic solvents or mixture of water miscible organic solvents and organic acids.

3) The process for the preparation of D-Penicillamine (I) according to claim 2, wherein water miscible organic solvents selected from alcohols as methanol, ethanol, isopropanol, n-propanol, n-butanol or mixture thereof.

4) The process for the preparation of D-Penicillamine (I) according to claim 2, wherein organic acids selected from methanoic acid, acetic acid, propionic acid, butyric acid, oxalic acid or mixture thereof.

5) The process for the preparation of D-Penicillamine (I) according to claim 1, wherein base is selected from organic base as methyl amine, dimethyl amine, trimethylamine, monoethylamine, diethylamine and triethylamine.

6) The process for the preparation of D-Penicillamine (I), according to claim 1, wherein the acid used for the salt of compound of Formula IV selected from hydrochloride, sulphuric acid and phosphoric acid.

7) The process for the preparation of D-Penicillamine (I) according to claim 1, wherein step a. comprising steps of:
i. reacting phenyl hydrazine with (4S)-2-isopropyl-5,5-dimethyl thiazolidine -4-carboxylic acid (IV) or salt thereof in water miscible organic solvents at temperature ranging between 30-60°C for a time duration ranging between 30 minutes to 120 minutes;
ii. separating the solid obtained in step i. and washed with alcoholic solvent to get racemic-Penicillamine (III).

8) The process for the preparation of D-Penicillamine (I) according to claim 1, wherein step b (i). comprising steps of:
i. D-tartaric acid dissolved in water or in methanol and added to the racemic-Penicillamine solution (III) in water or in acetic acid;
ii. the solution obtained in step i maintained for a time duration ranging between 30 minutes to 60 minutes at a temperature ranging between 20-80°C;
iii. the solution obtained in step ii treated with alcoholic solvent and maintained for 1-3 hours at temperature 0-10°C to get solid;
iv. filtered solid obtained in step iii. and washed with alcoholic solvent followed by drying to get D-Penicillamine hemitartarate (II).

9) The process for the preparation of D-Penicillamine (I) according to claim 1, wherein step b(ii). comprising steps of:
i. D-Penicillamine hemitartarate (II) is treated with organic base in a suitable water miscible organic solvent and maintained at temperature 20-40°C for time duration 30 minutes to 120 minutes to obtain solid;
ii. filtered solid obtained in step i. and washed with alcoholic solvent;
iii. isolate the solid and water added;
iv. filtered solid obtained in step iii.;
v. separating the solid obtained in step iv. and maintained for 10 minutes to
60 minutes in alcoholic solvent at temperature 20-50°C;
vi. filtered the solid and washed with water miscible organic solvents to get D-Penicillamine (I).
, Description:FIELD OF THE INVENTION
The present invention relates to improved process for the preparation of D-Penicillamine of formula I.
(I)
D-Penicillamine (I) and salts thereof are well known to be useful in the treatment of Wilson’s disease, rheumatoid disease and cystinuria.

BACKGROUND OF THE INVENTION
D-Penicillamine of formula (I), is chemically known as (2S)-2-Amino-3-methyl-3-sulfanylbutanoic acid. The molecular formula is C5H11NO2S and the molecular weight for the drug substance is 149.212.
(I)
Friedrich Asinger et.al in the patent US 3,966,752 discloses process for the preparation of D-penicillamine by treating N-formyl-isopropylidene, D,L-penicillamine with 1-norephedrine to get N-formyl-isopropylidene-D-penicillamine and 1-norephedrine. The obtained compound was treated with Concentrated hydrochloric acid to separate N-formyl-isopropylidene-D-penicillamine. Further, N-formyl-isopropylidene-D-penicillamine was treated with 15% Aq.HCl to get D-penicillamine.HCl. D-penicillamine.HCl was treated with triethylamine to get D-penicillamine.

Kaoru Sota et.al in the patent US 4,150,240 discloses process for the preparation D-Penicillamine using Benzylpenicilloic acid, N,N’-diphenylethylene-diamine and acetic acid in water. The product is acidified with hydrochloric acid to get D-penicillamine hydrochloric acid salt. Treating the HCl salt with dimethylamine to give D-penicillaime.

Friedrich Asinger et.al. in the patent US4,060,548 discloses the process for the preparation of reacting i-butyraldehyde with elemental sulfur or a sulfur-containing compound and gaseous ammonia or NH4 NO3.2NH3 so as to form 2-isopropyl-5.5-dimethyl-thiazoline-?3. The obtained compound was reacted with substantially anhydrous hydrogen cyanide so as to form 2-isopropyl-5.5-dimethylthiazolidine-4-carbonitrile. The obtained compound was treated with an excess of concentrated hydrochloric acid at an elevated temperature followed by separating the components of the resulting mixture of 2-isopropyl-5.5-dimethyl-thiazolidine-4-carboxylic acid hydrochloride, ammonium chloride and D,L-penicillamine hydrochloride and recovering the penicillamine hydrochloride therefrom. The free D,L-penicillamine may be obtained in conventional manner from the hydrochloride.

Various procedures were reported by varying substances utilizing N-formyl-isopropylidene, D,L-penicillamine and 1-norpheredene as key materials. There is a need to have alternate procedures which are industrially feasible. The process of this invention provides D-Penicillamine in substantially pure form. Thus, present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of D-Penicillamine, which provides high overall yield.

SUMMARY OF INVENTION
Particular aspects of the present invention relates to preparation of D-Penicillamine (I):
(I)
comprising the steps of:
a. reacting phenyl hydrazine with (4S)-2-isopropyl-5,5-dimethyl thiazolidine -4-carboxylic acid (IV) or salt thereof in water miscible organic solvent to obtain Racemic-Penicillamine (III);

b. resolving the D-penicillamine from racemic –penicillamine (III), wherein the process of resolving comprising the steps of:
(i) reacting the racemic-penicillamine (III) with D-(-)-Tartaric acid in aqueous solvent;

(ii) treating the D-Penicillamine hemitartarate (II) with organic base in a water miscible organic solvent to get D-Penicillamine (I).

DETAILED DESCRIPTION
As set forth herein, embodiments of the present invention provide an efficient process for the preparation of D-Penicillamine (I).

In another embodiment according to present application, it provides a process for the preparation of D-Penicillamine (I)
(I)
comprising the steps of:
a. reacting phenyl hydrazine with (4S)-2-isopropyl-5,5-dimethyl thiazolidine -4-carboxylic acid (IV) or salt thereof in water miscible organic solvent to obtain Racemic-Penicillamine (III);

b. resolving the D-penicillamine from racemic –penicillamine (III), wherein the process of resolving comprising the steps of:
(i) reacting the racemic-penicillamine (III) with D-(-)-Tartaric acid in aqueous solvent;

(ii) treating the D-Penicillamine hemitartarate (II) with organic base in a water miscible organic solvent to get D-Penicillamine (I).

Individual steps of the embodiments are detailed herein below.

In process step of reacting phenyl hydrazine with (4S)-2-isopropyl-5,5-dimethyl thiazolidine -4-carboxylic acid (IV) or salt in a suitable aqueous solvent was water or mixture with water miscible organic solvents or organic acids. Water miscible organic solvents selected from alcohols as methanol, ethanol, isopropanol, n-propanol, n-butanol or mixture thereof and mixtures thereof. Further, the salt of the (4S)-2-isopropyl-5,5-dimethyl thiazolidine -4-carboxylic acid (IV) can be selected from the group consisting of hydrochloride, sulphuric acid and phosphoric acid and the reaction was performed at temperature ranging between 30-60°C for a time duration ranging between 30 minutes to 120 minutes. Scheme of Step a. process as shown below:

In one of the particular embodiment according to present invention in step a, salt of (4S)-2-isopropyl-5,5-dimethyl thiazolidine -4-carboxylic acid (IV) was (4S)-2-isopropyl-5,5-dimethyl thiazolidine -4-carboxylic acid (IV) hydrochloride salt.

In one of the particular embodiment according to present application, steps a. process comprising the following steps:
i. reacting phenyl hydrazine with (4S)-2-isopropyl-5,5-dimethyl thiazolidine -4-carboxylic acid (IV) or salt thereof in a water miscible organic solvent at temperature ranging between 30-60°C for a time duration ranging between 30 minutes to 120 minutes;
ii. separating the solid obtained in step i. and washed with alcoholic solvent to get racemic-Penicillamine (III).

In another particular embodiment according to the present invention, step a. was performed at 40-45°C for 60 minutes in methanol as water miscible organic solvent.

In process step b. of resolving the D-penicillamine from racemic –penicillamine (III), wherein the process of resolving, comprising the steps of:
(i) reacting the racemic-penicillamine (III) with D-(-)-Tartaric acid in a suitable aqueous solvent was water or mixture with water miscible organic solvents or organic acids. Scheme of Step b(i). process as shown below:

(ii) treating the D-Penicillamine hemitartarate (II) with organic base in a water miscible organic solvent to get D-Penicillamine (I). Scheme of Step b(ii). process as shown below:

In one of the particular embodiment of the present invention, step b(i) of reacting the racemic-penicillamine (III) with D-(-)-Tartaric acid was carried in a suitable aqueous solvent as water or in mixture with water miscible organic solvents or in mixture of water miscible organic solvent and organic acid.

In one of the particular embodiment of the present invention, step b(i) was carried in water miscible organic solvents selected from alcohols as methanol, ethanol, isopropanol, n-propanol, n-butanol or mixture thereof.

In one of the particular embodiment of the present invention, step b(i) was carried in methanol as water miscible organic solvent.

In one of the particular embodiment of the present invention, step b(i) was carried in in mixture of water miscible organic solvent and organic acid wherein water miscible organic solvent selected from alcohols as methanol, ethanol, isopropanol, n-propanol, n-butanol or mixture thereof and organic acid selected from methanoic acid, acetic acid, propionic acid, butyric acid, oxalic acid or mixture thereof.

In one of the particular embodiment of the present invention, step b(i) was carried in mixture of methanol and acetic acid wherein methanol and acetic acid were in the ratio of 1:1 to 6:1.

In one of the particular embodiment of the present invention, process step b (i) comprising the steps of:
i. D-tartaric acid dissolved in water or in methanol and added to the racemic-Penicillamine solution (III) in water or in acetic acid;
ii. the solution obtained in step i maintained for a time duration ranging between 30 minutes to 60 minutes at a temperature ranging between 20-80°C;
iii. the solution obtained in step ii treated with alcoholic solvent and maintained for 1-3 hours at temperature 0-10°C to get solid;
iv. filtered solid obtained in step iii. and washed with alcoholic solvent followed by drying to get D-Penicillamine hemitartarate (II).

In still another particular embodiment of the present invention, process step (iii) of step b (i) of resolving the D-penicillamine from racemic –penicillamine (III) was carried at temperature 0-5°C for 120 minutes in methanol as solvent.

In one of the embodiment of the present invention, in step b (ii), treating the D-Penicillamine hemitartarate (II) with organic base in a water miscible organic solvent to get D-Penicillamine (I) comprising the steps of:
i. D-Penicillamine hemitartarate (II) is treated with organic base in a suitable water miscible organic solvent and maintained at temperature 20-40°C for time duration 30 minutes to 120 minutes to obtain solid;
ii. filtered solid obtained in step i. and washed with alcoholic solvent;
iii. isolated the solid and add water to it;
iv. filtered solid obtained in step iii.;
v. separating the solid obtained in step iv. and maintained for 10 minutes to 60 minutes in alcoholic solvent at temperature 20-50°C;
vi. filtered the solid and washed with water miscible organic solvent to get D-Penicillamine (I).

In one of the embodiment of the present invention, in step b (ii), treating the D-Penicillamine hemitartarate (II) with organic base selected from methyl amine, dimethyl amine, trimethylamine, monoethylamine, diethylamine and triethylamine in water miscible organic solvents selected from methanol, ethanol, isopropanol, n-propanol, n-butanol or mixture thereof and the reaction was performed at temperature 25-40°C for 45-60 minutes to get D-Penicillamine (I).

In one of the particular embodiment of the present invention, in step b (ii), treating the D-Penicillamine hemitartarate (II) with triethylamine as organic base in methanol as water miscible organic solvent and the reaction was maintained at temperature 25-40°C for 45-60 minutes to get D-Penicillamine (I) free of L- Penicillamine determined by using HPLC.

In yet another embodiment according to present invention, obtained compounds are purified by initiating either by cooling or concentration of the reaction mixture followed by cooling of the remaining solution or by using column chromatography. The purified product is then isolated from the reaction mixture by suitable techniques such as filtration, centrifugation and the like.

The disulfide impurities of the D-Penicillamine samples were measured using Chromatography. Chromatography was performed with Waters Alliance HPLC system (MILD, USA) that consists of quaternary pump equipped with a 2695 separation module with inbuilt auto injector and 2996 photodiode array detector. The output signal was monitored and processed using chromelean software version 6.8.

The invention was further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES:
Example 1: Synthesis of 2-amino-3-mercapto-3-methylbutanoic acid:
2-isopropyl-5,5-dimethylthiazolidine-4-carboxylic acid hydrochloride (0.0417 moles) was added to methanol (100.0 ml) and then charged Phenyl hydrazine (0.0933 moles) at room temperature. After 10 minutes stirring, the reaction mass was heated to 40-45°C. Maintained for 60 minutes at 40-45°C. Cooled to 25-35°C and stirred for 60 minutes. The obtained solid was filtered and washed with methanol (30.0 ml) and dried in vacuum oven to give the title compound.
Yield: 99.32%,
Disulfide - 0.02% (by HPLC)
Example 2: Synthesis of (S)-2-amino-3-mercapto-3-methylbutanoic acid hemi tartrate
To a stirred mixture of 2-amino-3-mercapto-3-methylbutanoic acid (0.335 moles) in acetic acid (300.0 ml) was added D(-)Tartaric acid (0.5026 moles) solution in methanol (50.0 ml) and the mixture was stirred for 10 minutes at room temperature and then heated to 50-55°C, stirred for 30-40 minutes. Cooled to 25-35°C and charged methanol (100 ml). Further cooled to 0-5°C and stirred for 90 minutes and filtered, washed with methanol (25 ml) and dried in vacuum oven to give the title compound.
Yield: 50.0 %.
Example 3: Synthesis of (S)-2-amino-3-mercapto-3-methylbutanoic acid hemi tartrate
To a stirred mixture of 2-amino-3-mercapto-3-methylbutanoic acid (0.0670 moles) in water (25.0 ml) was added D(-)Tartaric acid (0.1005 moles) solution in water (25.0 ml) and the mixture was stirred for 10 minutes at room temperature and then heated to 50-55°C, stirred for 30-40 minutes. Cooled to 25-35°C and charged methanol (40 ml). Further cooled to 0-5°C and stirred for 2 hrs and Filtered, washed with methanol (10.0ml) and dried in vacuum oven to give the title compound.
Yield: 50.0 %.
Disulfide: 0.08% (by HPLC)

Example 4: Synthesis of D-Penicillamine
Charged (S)-2-amino-3-mercapto-3-methylbutanoic acid hemi tartrate (0.0668 moles) in to methanol (140.0 ml) and slowly added Triethylamine (0.1136 moles) at room temperature. Stirred for 45-60 minutes. Filtered and washed with methanol (20.0ml). Charged the above wet material in to water (80.0 ml) and stirred for 10 minutes. Filtered through hyflo bed and washed with water (10.0 ml) Distilled the filtrate completely under vacuum. Cooled to 25-35°C and charged methanol (40.0 ml), stirred for 30 minutes. Filtered the solid and washed with methanol (10.0 ml) then dried in vacuum oven to give the title compound.
Yield: 80.24 %.
Melting Point: 208.3°C.
Disulfide (S,S'-Bi(D-penicillamine)) - 0.09 % (by HPLC) & L-isomer – Not detected (by HPLC).
Purity: 98.8% (by HPLC)
Specific Optical Rotation: -62.6°

S,S'-Bi(D-penicillamine) L-isomer

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.