NOVEL PROCESS FOR THE PREPARATION OF ARGATROBAN MONOHYDRTAE

FIELD OF INVENTION

The present invention is related to a novel process for the preparation of Argatroban monohydrate, which acts as an anticoagulant in individuals with thrombosis and heparin induced thrombocytopenia, more particularly preparation of Argatroban monohydrate in high purity.

BACKGROUND OF THE INVENTION

Shosuke Okamoto, et.al in US patent 4201863 (1980), disclosed a method for the preparation of Argatroban which comprises the synthesis of NG -substituted-N2-quinolinesulphonyl-L-arginamide and its hydrogenation catalyzed by palladium black in ethanol under 10 kg/cm2 hydrogen pressure at 100°C to yield Argatroban.

In US patent 4258192, Shosuke Okamoto, et.al modified the conditions for hydrogenation wherein the solvent used was ethanol containing acetic acid using 5% palladium on carbon under 50 kg/cm^ hydrogen pressure at 80°c for 4 hrs.

Argatroban was approved by US PDA and was reported to be a diastereoisomeric mixture of 21R & 21S isomers in the ratio of 65:35 ( hereafter referred to as" Diastereoisomeric ratio"

Another US patent 5925760 (1999), described the synthesis of Argatroban using a new intermediate N2 - (3-methylquinolinesulfonyl)-NG- nitro - L-Arginine.

A Chinese patent CN1951937 (2006) described a method for preparation of Argatroban monohydrate using water as solvent for final crystallization.

WO 2009/124906 disclosed a method for preparing argatroban monohydrate using aqueous methanol as the solvent for crystallization.

Therefore, it is an object of the present invention to provide a method for preparing argatroban monohydrate in highly purified form.

BRIEF SUMMARY OF THE INVENTION

The primary aspect of the present invention is to provide a method for the preparation of argatroban monohydrate in highly purified form.

Another aspect of the invention is to provide an industrially viable method for the preparation of argatroban monohydrate.
Still another aspect of the invention is to provide a novel process for the preparation of Argatroban monohydrate comprising following steps:

a) hydrogenating 2R, 4R-4-methyl-1[N2-(3-methyl- 8-quinolinesulfonyl)-L-arginyl-2-piperidine carboxylic acid (I) to 2R, 4R-4-methyl-1 [N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl-2-piperidine carboxylic acid (II) (Argatroban) using 10% palladium on carbon in 2-methoxyethanol and acetic acid under pressure, to yield crude Argatroban with the required diastereoisomeric ratio.

b) recrystallizing the crude product obtained in step (a) using 2-methoxyethanol to get pure argatroban with desired proportion of diastereoisomers.

c) adding low boiling solvent such as diethyl ether, methyl tertiary butyl ether, diisopropyl ether, most preferably diethyl ether was added to the mixture obtained in step
(b) to facilitate filtration.

d) treating pure argatroban obtained in step (b) with aqueous 2-methoxyethanol for obtaining argatroban monohydrate with desired proportion of diastereoisomers.

DETAILED DESCRIPTION OF PRESENT INVENTION:

The present invention involves,

a. hydrogenating 2R, 4R-4-methyl-1[N2-(3-methyl- 8-quinolinesulfonyl)-L-
arginyl-2-piperidine carboxylic acid (I) to 2R, 4R-4-methyl-1[N2-(3-methyl-
1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl-2-piperidine carboxylic
acid (II) (Argatroban) using 10% palladium on carbon in 2-methoxyethanol
and acetic acid under pressure, to yield crude Argatroban with the
required diastereoisomeric ratio.

b. recrystallizing the crude product obtained in step (a) using 2-
methoxyethanol to get pure argatroban with desired proportion of
diastereoisomers.

c. adding low boiling solvent such as diethyl ether, methyl tertiary butyl ether,
diisopropyl ether, most preferably diethyl ether was added to the mixture
obtained in step (b) to facilitate filtration.

d. treating pure argatroban obtained in step (b) with aqueous 2-methoxyethanol for preparing argatroban monoliydrate with desired proportion of diastereoisomers.

The solvent for hydrogenation used in step (a) is a mixture of hydroxy solvent and acetic acid. The hydroxy solvents include ethanol, methanol, isopropyl alcohol and 2-methoxyethanol, preferably 2-methoxyethanol.

The concentration of acetic acid in the hydroxy solvent is between 10 to 50%, most preferably 20%. The catalyst used for hydrogenation is 5% to 10% palladium on carbon, platinum oxide, preferably 10% palladium on carbon. The temperature used for the hydrogenation is between 50 and 100°C, most preferably between 70 and 80°C.

In the present invention, the hydroxy solvents used for crystallization are ethanol, isopropyl alcohol, n-butanol and 2-methoxyethanol, preferably 2-methoxy ethanol.

Preparation of argatroban monohydrate is accomplished using aqueous hydroxy solvents for crystallization. The hydroxy solvents used are ethanol, isopropyl alcohol, n-butanol and 2-methoxy ethanol, most preferably 2-methoxyethanol.

The proportion of 2-methoxyethanol in water is between 10 and 50%, most preferably between 20 and 30%.


According to the present invention, hydrogenation was carried out using 2-methoxy ethanol. This yielded Argatroban with diastereoisomeric ratio of about 65:35 (R:S). 2-methoxyethanol is a safe solvent for hydrogenation, therefore the method is industrially viable and safe.

Recrystallization from 2-methoxy ethanol gave argatroban with purity greater than 99% and maintained diastereoisomeric ratio is about 64:36.

After crystallization and before filtration of the resulting thick mass low boiling solvent like diethyl ether, methyl tertiary butyl ether, diisopropyl ether, most preferably diethyl ether was added to the mixture to facilitate filtration; the same solvent was used to wash the crystals to remove traces of 2-methoxyethanol.

Water containing 2-methoxyethanol was employed for final crystallization to facilitate the formation of argatroban monohydrate crystals. This crystallization improves the purity of the product to greater than 99.5 and maintained diastereoisomeric ratio.

The diastereoisomeric ratio of the argatroban is between 63 to 65 and 35 to 37
Accordingly, a process for the preparation of argatroban monohydrate with a diastereoisomeric ratio of about 65:35 comprising following steps;

(a) hydrogenating 2R, 4R-4-methyl-1[N2-(3-methyl- 8-quinolinesulfonyl)-L-arginyl-2-piperidine carboxylic acid (I) to 2R, 4R-4-methyl-1[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl-2-piperidine carboxylic acid (II) using 10% palladium on carbon in hydroxyl solvent and acetic acid under pressure, to yield crude Argatroban with the required diastereoisomeric ratio.

(b) recrystallizing the crude product obtained in step (a) using hydroxyl solvent to get pure argatroban with desired proportion of diastereoisomers (65:35).
(c) adding non-polar solvent to the mixture obtained in step (b) to facilitate filtration and removing residual 2-methxoyethanol from the product.

(d) treating pure argatroban obtained in step (b) with aqueous 2-methoxyethanol for preparing argatroban monoliydrate with desired proportion of diastereoisomers.

The solvent for hydrogenation used in step (a) is a mixture of hydroxy solvent and acetic acid; the hydroxy solvents include ethanol, methanol, isopropyl alcohol and 2-methoxyethanol, preferably 2-methoxyethanol. The concentration of acetic acid in the hydroxy solvent is between 10 to 50%, most preferably 20%; the catalyst used for hydrogenation is 5% to 10% palladium on carbon, platinum oxide, preferably 10% palladium on carbon and the temperature used for the hydrogenation is between 50 and 100°C, most preferably between 70 and 80°C.

The hydroxy solvent used in step (b) and (d) selected from ethanol, isopropyl alcohol, n-butanol and 2-methoxyethanol, preferably 2-methoxy ethanol.

The proportion of 2-methoxyethanol in water used for preparing argatroban monohydrate in step (d) is between 10 and 50%, most preferably between 20 and 30%.

The process claimed in any preceding claims, wherein the non-polar solvent used in step (c) is such as diethyl ether, methyl tertiary butyl ether, diisopropyl ether, most preferably diethyl ether.

The purity of the product is more than 99.5% and the diastereoisomeric ratio R: S of argatroban is between 63 to 65 and 35 to 37.

Examples I:

Synthesis of 2R, 4R-4-methyl-1[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolJnesuifonyl)-L-arginyl-2-piperJdine carboxylic acid (II)

2R, 4R-4-methyl-1 [N^-(3-methyl- 8-quinolinesulfonyl)-L-arginyl-2-piperidine carboxylic acid (I) (1.0kg) dissolved in a mixture 2-methxoyethanoi containing 20% acetic acid (50 lit) was hydrogenated using 10% palladium on carbon (100g) under hydrogen pressure of 600psi at 70°C for 8hrs. After completion of the reaction, the catalyst was filtered and the solvent from the filtrate distilled out almost completely. The gummy material obtained was dissolved in dichloromethane (20 lit) washed with water (5lit) and dichloromethane from the organic layer was distilled out completely to yield crude Argatroban.

Yield: 900g (w/w: 90%) Purity by HPLC: >95% DIastereoisomeric ratio: 64.5:35.5

Purification:

The crude material obtained was dissolved in 2-methoxyethanol (4.5lit) at 80-90°C and the solution cooled to 2-8°C and left at that temperature for 12 hrs. To the mixture, diethyl ether (4.5lit) was added and stir for 5 minutes at 2-8°C. The crystallized material was filtered, washed with diethyl ether and dried to yield pure Argatroban.
Yield: 675g (75%w/w) Purity by HPLC: >99% Diastereoisomeric ratio: 64:36

Example tl:
Synthesis of Argatroban monohydrate (III)
Argatroban obtained from Example I (675 g) was dissolved in water containing 20% 2-methoxyethanol at 80-90°C, filtered. The clear solution was kept at 2-8°C for 12 hrs. The crystallized material was filtered, and dried to yield pure Argatroban monohydrate.
Yield: 540g (85%w/w) Purlty by HPLC: >99.5% Diastereoisomeric ratio: 64.5:35.5

We claim:

A process for the preparation of argatroban monohydrate with a diastereoisomeric ratio of about 65:35 comprising following steps;

a. hydrogenating 2R, 4R-4-methyl-1[N2-(3-methyl- 8- quinolinesulfonyl)-L-arginyl-2-piperidine carboxylic acid (I) to 2R, 4R-4-methyl-1 [N2-(3-methyl-1 ,2, 3,4-tetrahydro-8- quinolinesulfonyl)-L-arginyl-2-piperid me carboxylic acid (II) using 10% palladium on carbon in hydroxyl solvent and acetic acid under pressure, to yield crude Argatroban with the required diastereoisomeric ratio;
b. recrystallizing the crude product obtained in step (a) using hydroxyl solvent to get pure argatroban with desired proportion of diastereoisomers(65:35);

c. adding non-polar solvent to the mixture obtained in step (b) to facilitate filtration and removing residual 2-methxoyethanol from the product;

d. treating pure argatroban obtained in step (b) with aqueous 2- methoxyethanol for preparing argatroban monohydrate with desired proportion of diastereoisomers.

2. The process as claimed in claim 1, wherein the solvent for hydrogenation used in step (a) is a mixture of hydroxy solvent and acetic acid; the hydroxy solvents include ethanol, methanol, isopropyl alcohol and 2-methoxyethanol, preferably 2-methoxyethanol.

3. The process as claimed in any preceding claims, wherein the concentration of acetic acid in the hydroxy solvent is between 10 to 50%, most preferably 20%.

4. The process as claimed in any preceding claims, wherein in step (a) the catalyst used for hydrogenation is 5% to 10% palladium on carbon, platinum oxide, preferably 10% palladium on carbon and the temperature used for the hydrogenation is between 50 and 100°C, most preferably between 70 and 80°C.

5. The process claimed in any preceding claims, wherein the hydroxy solvent used for crystallization in step (b) selected from ethanol, isopropyl alcohol, n-butanol and 2-methoxyethanol, preferably 2-methoxy ethanol.

6. The process claimed in any preceding claims, wherein the proportion of 2-methoxyethanol in water used for preparing argatroban monohydrate in step (d) is between 10 and 50%, most preferably between 20 and 30%.

7. The process claimed in any preceding claims, wherein the non-polar solvent used in step (c) is such as diethyl ether, methyl tertiary butyl ether, diisopropyl ether, most preferably diethyl ether.

8. The process claimed in any preceding claims, wherein the purity of the product is more than 99.5%.

9. The process claimed in any preceding claims, wherein the diastereoisomeric ratio R: S of argatroban is between 63 to 65 and 35 to37.

10. A novel process for the preparation of Argatroban monohydrate such as herein described and exemplified.