This application claims priority to Indian patent application number 3872/CHE/2010 filed on Dec 20, 2010 the contents which are incorporated by reference in their entity.

FIELD OF THE INVENTION:

The present invention relates to novel impurities of Pitavastatin calcium i.e. monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}.

BACKGROUND OF THE INVENTION:

Pitavastatin calcium i.e. monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}, having the Formula-I is approved, under the trade name Livalo®, by the United States Food and Drug Administration. Livalo® is a HMG-CoA reductase inhibitor indicated for the treatment of patients with primary hyperlipidemia and mixed Dyslipidemia.

Pitavastatin was first disclosed in United States patent number US 5753675 and this patent does not disclose calcium salt of Pitavastatin.

United States patent number US 5856336 specifically discloses calcium salt of Pitavastatin and this patent does not discloses process for the preparation of Pitavastatin calcium.

Journal of Pharmaceutical and Biomedical analysis discuss about the photostability of the Pitavastatin calcium and this journal discloses four photodegradation products namely PP-l,PP-2,PP-3andPP-4.

Like any synthetic compound, Pitavastatin calcium can contain impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products.

It is also known in the art that impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products.

It is well known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.

Thus, there is a need in the art for managing impurities in Pitavastatin calcium, thus developing a method of producing Pitavastatin calcium free of various impurities.

OBJECT AND SUMMARY OF THE INVENTION:

Principle object of the present invention is to provide pure Pitavastatin calcium.

Another object of the present invention is to provide novel impurities of Pitavastatin calcium i.e. monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}.

One more object of the present invention is to provide a process for producing the novel impurities of Pitavastatin calcium.

One aspect of the present invention is to provide Pitavastatin calcium novel impurities i.e. hydrogenated impurity of Formula-A, two degradation products of Formulae Bl and B2, two Dehydroxyl Impurities of Formulae CI and C2 and amide impurity of Formula-D.

Another aspect of the present invention is to provide process for the preparation of the novel Pitavastatin impurities i.e. hydrogenated impurity of Formula-A, two degradation products of Formulae Bl and B2, two Dehydroxyl Impurities of Formulae CI and C2 and amide impurity of Formula-D.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides pure Pitavastatin calcium i.e. monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}.

The present invention provides novel impurities of Pitavastatin calcium i.e. monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}.

The present invention further provides process for the preparation of impurities of Pitavastatin calcium.

The main aspect of the present invention is to provide pure Pitavastatin calcium, monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate}.

One embodiment of the present invention provides, pure Pitavastatin calcium having less than 0.15% of hydrogenated impurity of Formula-A.

Another embodiment of the present invention provides, pure Pitavastatin calcium having less than 0.15% of degradation product of Formula B1.

Another embodiment of the present invention provides, pure Pitavastatin calcium having less than 0.15% of degradation product of Formula B2.

Another embodiment of the present invention provides, pure Pitavastatin calcium having less than 0.15% of Dehydroxyl Impurity of Formula CI.

Another embodiment of the present invention provides, pure Pitavastatin calcium having less than 0.15% of Dehydroxyl Impurity of Formula C2.

Another embodiment of the present invention provides, pure Pravastatin calcium having less than 0.15% of an amide impurity of Formula-D.

Another aspect of the present invention is to provide Pitavastatin calcium novel impurities i.e. hydrogenated impurity of Formula-A, two degradation products of Formulae Bl, B2, two Dehydroxyl Impurities of Formulae CI, C2 and an amide impurity of Formula-D.

Another aspect of the present invention is to provide a process for the preparation of Pitavastatin hydrogenated impurity of Formula-A comprising, adding reducing agent to Pitavastatin in a solvent such as methanol, and isolating Pitavastatin hydrogenated impurity of Formula-A.

Another aspect of the present invention is to provide a process for the preparation of Pitavastatin two degradation products of Formulae Bl, B2 comprising, dissolving the Pitavastatin calcium in a mixture of acetonitrile and water, irradiating with visible light, acidified with HC1, followed by purification by column chromatography / preparative HPLC/ Crystallization to isolate degradation products of Formulae Bl, B2.

Another aspect of the present invention is to provide a process for the preparation of Pitavastatin two Dehydroxyl Impurities of Formulae CI, C2 comprising, dissolving the Pitavastatin calcium in a mixture of acetonitrile and water, adding Potassium hydrogen sulphate, acidified with HC1, followed by purification by column chromatography / preparative HPLC/ Crystallization to isolate Dehydroxyl Impurities of Formulae CI, C2.

One more aspect of the present invention is to provide a process for the preparation of Pitavastatin amide impurity of Formula-D comprising, adding Dicyclohexyl carbodiimde to a solution of Pitavastatin Acid and a-methyl benzyl amine in dichloromethane, stirring, followed by purification by column chromatography / preparative HPLC/ Crystallization to isolate amide impurity of Formula-D.

One more aspect of the present invention is to provide an improved process for the preparation of pure Pitavastatin calcium having less than 0.15% of each of impurities of Formulae A, Bl, B2, CI, C2 and D comprising the steps of:

a) dissolving (S)-a-methyl benzyl amine salt of Pitavastatin in water;
b) adding Sodium hydroxide solution to the resultant mixture;
c) adding t-butyl methyl ether solvent to the aqueous layer;
d) adding calcium chloride; and
e) isolating the Pitavastatin calcium.

According to the present invention (S)-a-methyl benzyl amine salt of Pitavastatin is suspended in water and Sodium hydroxide solution and stirred at room temperature, t-butyl methyl ether (1000 ml) is added to the aqueous layer. The reaction mixture is stirred and layers are separated. Water is added to aqueous layer and partial amount of water is distilled out from aqueous layer. The reaction mass is filtered through Celite bed and Calcium chloride solution is added. The solid is filtered and washed with DM water. The obtained solid is dried under vacuum to get pure Pitavastatin calcium.

In another embodiment, (S)-a-methyl benzyl amine salt of Pitavastatin is purified by suspending (S)-a-methyl benzyl amine salt of Pitavastatin in a mixture of water and ethyl acetate. The pH of the reaction mixture is adjusted by using aq. hydrochloric acid. (S)-a-methyl benzyl amine is added to the organic layer. The solid is filtered, washed with ethyl acetate and dried to get pure (S)-a-methyl benzyl amine salt of Pitavastatin.

The following examples are provided to illustrate the process of the present invention. They are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

Example-1: Process for the preparation of hydrogenated impurity of Formula-A
To a solution of Pitavastatin Calcium (2.0 g) in methanol (200 ml), 10 % Palladium on Charcoal was added and hydrogen gas was passed through the reaction mixture. The reaction mixture was filtered through hyflow bed, and washed with methanol. The filtrate was concentrated under reduced pressure to yield hydrogenated impurity of Formula-A.

Example-2: Process for the preparation of degradation products of Formulae Bl, B2
Pitavastatin Calcium (2.0 g) was dissolved in a mixture of acetonitrile and water and irradiated with visible light (750 w) at 50°C for 30 days. The obtained product was acidified with HC1 and concentrated under vacuum. The obtained residue was purified by preparative HPLC to yield degradation products of Formulae Bl, B2.

Example-3: Process for the preparation of Dehydroxyl Impurities of Formulae CI, C2
Pitavastatin Calcium (2.0 g) was dissolved in a mixture of acetonitrile and water and to this Potassium hydrogen sulphate was added. The reaction mixture was stirred for 8-12 hours at 60°C. The obtained product was acidified with HC1 and concentrated under vacuum. The obtained residue was purified by preparative HPLC to yield Dehydroxyl Impurities of Formulae CI, C2.

Example-4: Process for the preparation of amide impurity of Formula-D
To a solution of Pitavastatin Acid (5.0 g) and a-methyl benzyl amine (3.0 g) in dichloromethane (200 ml), Dicyclohexyl carbodiimde (10.0 g) was added, stirred for 20 -24 hours at room temperature and filtered. The filtrate was concentrated and purified by preparative HPLC to yield amide impurity.

Example-5: Process for the purification of (S)-a-methyl benzyl amine salt of Pitavastatin calcium 100g of (S)-a-methyl benzyl amine salt of Pitavastatin was suspended in a mixture of 500ml of water and l000rnl of ethyl acetate. The pH of the reaction mixture was adjusted to 2-5 by adding aq. hydrochloric acid. The layers were separated and sodium chloride solution was added to the organic layer and stirred at room temperature. (S)-a-methyl benzyl amine (22.4 g) was added to the organic layer and cooled to 5 °C. The solid was filtered, washed with ethyl acetate and dried to yield (S)-a-methyl benzyl amine salt of Pitavastatin.

Example-6: Process for the preparation of pure Pitavastatin calcium
100g of (S)-a-methyl benzyl amine salt of Pitavastatin obtained from example 5 was suspended in 500ml of water. To this Sodium hydroxide solution (8.1g sodium hydroxide in 200 ml DM water) was added and stirred at room temperature for 2 hours. The layers were separated and t-butyl methyl ether (1000 ml) was added to the aqueous layer. The reaction mixture was stirred and layers were separated. To the aqueous layer 800 ml of water was added and 200 ml of water was distilled out from aqueous layer. The reaction mass was filtered through Celite bed and to this Calcium chloride solution (16.25 g calcium chloride dihydrate in 500 ml DM water) was added and stirred for 24 hours. The solid was filtered and washed with DM water. The solid was dried under vacuum to yield Pitavastatin calcium.

We claim:

1. Pitavastatin impurities of Formulae A, Bl, B2, CI, C2 and D having the following structures

2. Pitavastatin calcium having less than 0.15% of hydrogenated impurity of Formula-A.

3. Pitavastatin calcium having less than 0.15% of degradation product of Formula Bl.

4. Pitavastatin calcium having less than 0.15% of degradation product of Formula B2.

5. Pitavastatin calcium having less than 0.15% of Dehydroxyl Impurity of Formula CI.

6. Pitavastatin calcium having less than 0.15% of Dehydroxyl Impurity of Formula C2.

7. Pitavastatin calcium having less than 0.15% of an amide impurity of Formula-D.

8. A process for the preparation of pure Pitavastatin calcium comprising the steps of:

a) dissolving (S)-a-methyl benzyl amine salt of Pitavastatin in water;
b) adding Sodium hydroxide solution to the resultant mixture;
c) adding t-butyl methyl ether solvent to the aqueous layer;
d) adding calcium chloride; and
e) isolating the Pitavastatin calcium.

9. Pure Pitavastatin calcium obtained by the process as claimed in claim 8.

10. A process for the preparation of pure Pitavastatin calcium having less than 0.15% of each of impurities of Formulae A, B1, B2, CI, C2 and D substantially as herein described with reference to the foregoing examples.