FIELD OF THE INVENTION

The present invention relates to novel organic acid salt of Pitavastatin alkyl ester of Formula I.

wherein R represents C1-3 alkyl; X represents monobasic or dibasic acid

The present invention is an improvement of the invention disclosed and claimed in our co-pending application no IN 2458/CHE/2011.

BACKGROUND OF THE INVENTION

Pitavastatin calcium is a synthetic lipid lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase inhibitor), chemically known as (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid, calcium (2:1) salt.

Pitavastatin is being marketed under the brand name Livalo®, as an oral tablet in 1 mg, 2 mg and 4 mg strengths. Pitavastatin calcium is used to lower the lipid levels including cholesterol in blood and can be used for the prevention or treatment of hyperlipidemia and artheriosclerosis.

In view of the importance of Pitavastatin as a Lipid-lowering agent, several synthetic methods have been reported in the literature to prepare Pitavastatin, some of which are as summarized below.

US 4,761,419, US 5,011,930, US 5,753,675 discloses a process, which is as shown below:

wherein R is hydrogen or protecting group.

US 6,835,838 B2 discloses a process for the preparation of Pitavastatin calcium, which is as shown below:

However, it has been observed that the above process of lactonization results in -10-15% of unreacted Pitavastatin ethyl ester and therefore results in low yield. Further, -10% of Pitavastatin acid results during the above lactonization process and therefore does not produce a single product which is required to keep adequate control for an intermediate through specifications to have consistently better quality of the finished product.

US 6,875,867 B2 discloses a process for the preparation of Pitavastatin arginine salt, which is as shown below.

During the above process Trifluoroacetic acid or hydrochloric acid is used to break the acetonide and the product Pitavastatin ester formed in situ converted to its corresponding alkali salt by treating with base, such as sodium hydroxide.

US 2012/0101126 Al discloses crystalline polymorphic Forms A, B, C, D, E, F and an amorphous form of Pitavastatin calcium.

US 2011/0319624 Al discloses crystalline Form A of Pitavastatin calcium and also Pitavastatin calcium having crystallinity, which is close to amorphous state, water content less than 4% having PXRD pattern shown in Figure 1. The present inventors have designated this crystalline form as crystalline Form I.

The crystalline form shown in Figure 1 of US 2011/0319624 Al is also disclosed in Chinese patent CN 101195603 A and WO 2012/025939 Al.

It is known that Pitavastatin is enantiomerically pure compound having two chiral centers in side chain of the molecule. All four isomers of Pitavastatin can be separated by HPLC and the Pitavastatin is (3R, 5S)-isomer.

The process shown above carries out diastereomeric purification of Pitavastatin calcium through its lactone hydrochloride intermediate or forming different salts of Pitavastatin like arginine salt, which makes the process economically unviable.

Further, it is well understood from the prior art that crystallization of Pitavastatin esters to remove diastereomers is practically a difficult process because of their lesser solubility in most of the organic solvents as compared to the required (3R, 5S)-isomer.

However, the present inventors have now found that the diastereomer can be reduced by making Pitavastatin alkyl ester as organic acid salt, which is industrially feasible.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide Pitavastatin alkyl ester organic acid salt.

Yet another objective of the present invention is to provide an improved process for
preparing (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3,5-
dihydroxy-6-heptenoic acid, calcium salt (2:1) using Pitavastatin alkyl ester organic acid salt, which is simple, industrially applicable and economically viable.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 - Powder X-ray diffraction (PXRD) of Pitavastatin calcium crystalline
Form 1

Figure 2 - Powder X-ray diffraction (PXRD) of Pitavastatin calcium crystalline
Form I, 2M at 25°C-60%RH

Figure 3 - Powder X-ray diffraction (PXRD) of Pitavastatin calcium crystalline Form I, 2M at 40°C-75%RH

SUMMARY OF THE INVENTION

The present invention relates to novel organic acid salt of Pitavastatin alkyl ester of Formula I.

wherein R represents C1-3 alkyl; X represents monobasic or dibasic acid

The present invention also relates to a process to prepare organic acid salt of Pitavastatin alkyl ester of Formula I, which comprises: a) reacting Pitavastatin ester of Formula III,
wherein R represents C1-3 alkyl with an organic acid in the presence of inert solvent; b) isolating the compound of Formula I.

The present invention also relates to a process for preparing (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3,5-dihydroxy-6-heptenoic acid, calcium salt (2:1) of Formula II,

which comprises:

a) reacting Pitavastatin alkyl ester of Formula III,

wherein R represents C1-3 alkyl

with an organic acid selected from monobasic acid or dibasic acid in the presence of inert solvent to obtain organic acid salt of Pitavastatin alkyl ester of Formula I;

wherein R represents C1.3 alkyl; X represents monobasic or dibasic acid

b) optionally, purifying the compound of Formula I;

c) treating compound of formula I with aqueous inorganic base to obtain pure Pitavastatin alkyl ester of Formula III;

d) hydrolyzing Pitavastatin alkyl ester of formula III with strong base to obtain the corresponding alkali metal salt of compound of Formula IV;

wherein M represents Na, K, Li

e) treating compound of formula IV with a calcium source to obtain Pitavastatin calcium of Formula II; and

f) isolating the Pitavastatin calcium of Formula II.

In another embodiment the Pitavastatin calcium obtained as per the present invention is crystalline Form I having water content less than 4%.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel organic acid salt of Pitavastatin alkyl ester of Formula I.

wherein R represents C1-3 alkyl; X represents monobasic or dibasic acid

The organic acid salt of Pitavastatin ester is selected from trifluoroacetic acid, trifiuoromethane sulfonic acid, acetic acid, methanesulfonic acid, perchloric acid, periodic acid, oxalic acid, mandelic acid, malic acid, tartaric acid, camphorsulfonic acid, benzenesulfonic acid, p-toluenebenzenesulphonic acid, 4-nitrobenzenesulfonic acid etc.

In another embodiment of the present invention, the process to prepare organic acid salt of Pitavastatin alkyl ester of Formula I,

wherein R represents C1-3 alkyl; X represents monobasic or dibasic acid comprises, reacting Pitavastatin ester in an organic solvent selected from C1-C5 alcohol such as methanol, ethanol, butanol; C3-C8 esters such as ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate; C3-C8 ketones such as methyl ethyl ketone, methyl isobutyl ketone, acetone; C6-C10 aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, methyl ethyl ether; acetonitrile and mixture thereof, with an organic acid selected from monobasic or dibasic acid, such as trifluoroacetic acid, trifluoromethane sulfonic acid, acetic acid, methanesulfonic acid, perchloric acid, periodic acid, oxalic acid, mandelic acid, malic acid, tartaric acid, camphorsulfonic acid, benzenesulfonic acid, p-toluenebenzene sulphonic acid, 4-nitrobenzene sulfonic acid; preferably trifluoroacetic acid at temperature below 15°C, preferably at 0-5°C, for 15 min to 2 hr, preferably 15-20 min. Non-polar solvent selected from hexane, heptane, cyclohexane ethers such as diisopropyl ether etc., is added and isolated the organic acid salt of Pitavastatin alkyl ester of Formula I.

The organic acid salt of formula I is prepared by combining organic acid and ester compound of III in molar ratio within the range from 1.25:1 to 0.8:1; preferably 1.1:1.

In another aspect, the present invention provides Pitavastatin ester organic acid salt of formula I, containing less than ~0.3% of its anti-isomer of formula 1(a), Pitavastatin lactone salt of formula V and Pitavastatin acid salt of formula VI.

The present invention also provides Pitavastatin ester of Formula III, having ~0.3% of diastereomeric purity.

wherein X represents monobasic or dibasic acid

In another embodiment of the present invention, the process for preparing (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3,5-dihydroxy-6-heptenoic acid, calcium (2:1) salt of Formula II, comprises, reacting Pitavastatin ester in an organic solvent selected from C1-C5 alcohol such as methanol, ethanol, butanol; C3-C8 esters such as ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate; C3-C8 ketones such as methyl ethyl ketone, methyl isobutyl ketone, acetone; C6-C10 aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, methylethyl ether; acetonitrile and mixture thereof, with an organic acid selected from monobasic or dibasic acids, such as trifluoroacetic acid, trifluoromethane sulfonic acid, acetic acid, methanesulfonic acid, perchloric acid, periodic acid, oxalic acid, mandelic acid, malic acid, tartaric acid, camphorsulfonic acid, benzenesulfonic acid, p-toluenebenzenesulphonic acid, 4-nitrobenzenesulfonic acid; preferably trifluoroacetic acid at temperature below 15°C, preferably at 0-5°C, for 15 min to 2 hr, preferably 15-20 min. Non-polar solvent selected from hexane, heptane, cyclohexane ethers such as diisopropyl ether, etc. is added and isolated the organic acid salt of Pitavastatin alkyl ester of Formula I. Optionally, purifying the obtained organic acid salt of Pitavastatin alkyl ester of Formula I using organic solvent or from a mixture of solvent, selected from ethanol, methanol, isopropyl alcohol, tert-butyl alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, toluene, acetonitrile, water, hexanes, heptane, pentane, cyclohexane etc.

Organic acid compound of formula I is treated with aqueous inorganic base selected from sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium hydroxide, lithium bicarbonate, lithium carbonate; in the presence of an organic solvent selected from ethyl acetate, isopropyl acetate, toluene, tetrahydrofuran, acetonitrile and water is added to obtain Pitavastatin alkali ester of formula III.

Pitavastatin alkali ester of formula III is then treated with strong base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium hydroxide, etc. to obtain Pitavastatin alkali salt of Formula IV, which is then in situ converted to Pitavastatin calcium of Formula II by treating with a source of calcium selected from calcium chloride, calcium acetate, calcium carbonate.

In another embodiment of the present invention, the Pitavastatin calcium obtained has water content less than 4%, has Powder X-Ray Diffraction (PXRD) pattern as Figure I, stable (Figures 2 and 3), which is designated as Crystalline Form I.

The Pitavastatin calcium obtained is packed under nitrogen atmosphere and in a double polythene bag or triple bag with a desiccant.

The Pitavastatin calcium obtained as per present invention is stable, which is as shown below:

In another aspect, the Pitavastatin ethyl ester of Formula III of the present invention is prepared by process, which comprises preparing a solution of Pitavastatin keto ester of Formula VII, in an organic solvent or a mixture of organic solvents, selected from the group consisting of an etheral solvent selected from C2-C8 ethers or cyclic ethers such as diethyl ether, dimethyl ether, tetrahydrofuran; alcoholic solvent selected from C1-C4 alcohol such as methanol, ethanol, butanol, and protic solvents such as toluene, alkyl esters such as ethyl acetate, methyl acetate, and adding to a solution of mixture of dialkylalkoxyborane, selected from diethylmethoxyborane, dimethylmethoxyborane, dimethylethoxyborane and a hydride ion source, selected from sodium borohydride, potassium borohydride, lithium borohydride and sodium triacetoxyborohydride, in a mixture of three or more organic solvents, group consisting of an ethereal solvent selected from C2-C8 ethers or cyclic ethers such as diethyl ether, dimethyl ether, tetrahydrofuran; alcoholic solvents selected from C1-C4 alcohol such as methanol, ethanol, butanol and protic solvents such as toluene, alkyl ester such as ethyl acetate, methyl acetate, propyl acetate at low temperature in the range of -50°C to -95°C, more preferably -70°C to -80°C. Thereafter, the reaction mass is stirred at same temperature.

Reaction is quenched at -80°C to -50°C by adding quenching agents to the reaction mass.

The quenching agent is selected from water, acetic acid, aqueous hydrochloric acid, acetone, sodium bicarbonate, aqueous acetic acid buffer or mixture thereof. Preferred agents are acetic acid buffer or acetic acid. After quenching the reaction mass is diluted with water and extracted with solvents like ethyl acetate, toluene, methylene chloride preferably with ethyl acetate. Distillation of solvents results Pitavastatin ethyl ester having (3S,5S)-diastereomer ~1 %.

Preferably, the total volume of solvent used for the reaction of Pitavastatin keto ester of Formula VII and dialkylalkoxyborane is about 10 volumes to 80 volumes (based on per gram of Pitavastatin keto ester of Formula VII) in the reaction mixture, more preferably 30-40 volumes; the source of hydride ion is present in an amount of 1 to about 4 equivalents (based on per mole of Pitavastatin keto ester of Formula VII).

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE -1

PREPARATION OF ETHYL (3R,5S,6E)-7-[2-CYCLOPROPYL-4-(4-FLUORO-PHENYL)QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOATE
[PITAVASATTIN ETHYL ESTER]

A solution of diethylmethoxyborane in tetrahydrofuran (8.95 g, 50% solution, 0.044 mole) was added to a cold mixture of tetrahydrofuran (300 ml), methanol (65 ml) and ethyl acetate (25 ml) at -75°C to -80°C. Sodium borohydride (1.36 gm,0.033 mole) was added to the above solution in one lot and stirred for 5 min. at the same temperature.

Thereafter, a solution of Ethyl (5S,6E)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3-hydroxy-5-oxo-6-heptenoate (10 gm, 0.022 mole) prepared in a mixture of tetrahydrofuran, (25 ml), methanol (10 ml) and ethyl acetate (5 ml) was added to the above reaction mixture, while maintaining the temperature at -75 °C to -80°C. The reaction mass was further stirred at the same temperature till starting material content less than 0.1% monitored by qualitative HPLC. Thereafter, excess borohydride was quenched by adding acetone (15 ml) and thereafter acetic acid (10 ml) was added to it. The reaction mass was diluted with water and brought to 25-30°C. The product was extracted using ethyl acetate (2 x 250 ml) and the combined organic extract was washed with saturated sodium bicarbonate (250 ml) followed by with water (250 ml) and aqueous sodium chloride (250 ml). Solvents were removed and the crude Pitavastatin ethyl ester was co-distilled with ethyl acetate. Yield: l0gm Anti-isomer (3S,5S-lsomer): 0.85%

EXAMPLE -2

PREPARATION OF ETHYL (5R,5S,6E)-7-[2-CYCLOPROPYL-4-(4-FLUORO-PHENYL)QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOATE,
TRIFLUORO-ACETATE SALT [PITAVASATTIN ETHYL ESTER, TRIFLUOROACETATE SALT]

The crude Pitavastatin ethyl ester (10 gm, 0.022), as obtained from example 1, was dissolved in ethyl acetate (50 ml) and cooled to 0-5°C. Trifluoacetic acid (1.89 ml, 0.024 mole) was added to the above solution maintaining the temperature below 5°C. The reaction mixture was stirred for 15 min. at 0-5°C and thereafter temperature was raised to 20-30°C. Heptane (10 ml) was added to it and stirred for 1 hr. The precipitated trifluoroacetate salt of Pitavastatin ethyl ester was isolated by filtration. Yield: 6 gm.
Anti-isomer (3S,5S-lsomer): 0.38%

EXAMPLE -3
PREPARATION OF ETHYL (5R,5S,6E)-7-[2-CYCLOPROPYL-4-(4-FLUORO-PHENYL)QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOATE, TRIFLUORO-ACETATE SALT [PITAVASATTIN ETHYL ESTER, TRIFLUOROACETATE SALT]

The crude Pitavastatin ethyl ester (10 gm, 0.022 mole, anti isomer: 0.85%), was
dissolved in a mixture of ethyl acetate (25 ml) and ethanol (10 ml). It was cooled to
0-5°C. Trifluoacetic acid (1.89 ml, 0.024 mole) was added to the above solution
maintaining the temperature below 5°C. The reaction mixture was stirred for 15 min
at 0-5°C and thereafter temperature was raised to 20-30°C. Heptane (150 ml) was
added to it and stirred for 1 hr. The precipitated Pitavastatin ethyl ester
trifluoroacetate salt was isolated by filtration.

Yield: 8.6 gm.

Anti-isomer (5S,5S-Isomer): 0.60%

1H NMR (300 MHz, CDC13): δ 1.28 -1.39 (m, 7H), 1.69-1.71 (m, 2H), 2.42-2.45
(m, 2H), 2.52-2.55 (m, 1H), 4.15-4.22 (m, 3H), 4.40-4.43 (m, 1H), 5.63 (dd, J = 18,

6 Hz, 1H), 6.62 (d, J = 18 Hz, 1H), 7.24-7.49 (m, 4H), 7.52-7.56 (m, 2H), 7.81-7.83 (m, 1H), 8.46 (d,J= 9 Hz, 1H).

EXAMPLE -4

PREPARATION OF ETHYL (5R,5S,6E)-7-[2-CYCLOPROPYL-4-(4-FLUORO-PHENYL)QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOATE, TRIFLUORO-ACETATE SALT [PITAVASATTIN ETHYL ESTER, TRIFLUOROACETATE SALT]

The crude Pitavastatin ethyl ester (10 gm, 0.022 mole), as obtained from example 1, was dissolved in a mixture of ethyl acetate (25 ml) and ethanol (15 ml). It was cooled to 0-5°C. Trifluoacetic acid (1.89 ml, 0.024 mole) was added to the above solution maintaining the temperature below 5°C. The reaction mixture was stirred for 15 min at 0-5°C and thereafter temperature was raised to 20-30°C. Heptane (150 ml) was added to it and stirred for 1 hr. The precipitated Pitavastatin ethyl ester trifluoroacetate salt was isolated by filtration. Yield: 6.0 gm.

Anti-isomer(5S,5S-Isomer): 050%

1H NMR (300 MHz, CDC13): δ 1.28 -1.39 (m, 7H), 1.69-1.71 (m, 2H), 2.42-2.45 (m, 2H), 2.52-2.55 (m, 1H), 4.15-4.22 (m, 3H), 4.40-4.43 (m, 1H), 5.63 (dd, J = 18, 6 Hz, 1H), 6.62 (d, J = 18 Hz, 1H), 7.24-7.49 (m, 4H), 7.52-7.56 (m, 2H), 7.81-7.83 (m, 1H), 8.46 (d, J- 9 Hz, 1H).

EXAMPLE -5

CRYSTALLIZATION OF PITAVASATTIN ETHYL ESTER, TRIFLUOROACETATE SALT

The Pitavastatin ethyl ester, trifluoroacetate salt (10 gm, anti isomer: 0.51%) was dissolved in a mixture of ethyl acetate (25 ml) and ethanol (10ml). n-Heptane (150 ml) was added to it slowly over a period of 30 min. at 20-30°C. The product precipitated was further stirred for 2 hr and filtered.

Yield: 6.0 gm

Anti-isomer (5S,5S-Isomer): 0.31%

EXAMPLE -6

PREPARATION OF (5R,5S,6E)-7-[2-CYCLOPROPYL-4-(4-
FLUOROPHENYL)-QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOIC ACID, CALCIUM SALT [PITAVASATATIN CALCIUM]

Pitavastatin ethyl ester, trifluoroacetate salt (6 gm, 0.010 mole, Anti isomer: 0.38%) was suspended in water (215 ml) and ethyl acetate (25 ml) and cooled to 0-5°C. The pH was adjusted to 7.5 with saturated sodium bicarbonate. The organic layer was separated and washed with water (25 ml). The ethyl acetate layer was concentrated to obtain Pitavastatin ethyl ester having anti content 0.38%.

The above Pitavastatin ethyl ester was dissolved in ethanol (25 ml) and THF (2.5 ml) and cooled to 0-5°C. ~\N aqueous Sodium hydroxide (11 ml, 0.010 mole) was added to it over a period of 20 min and the hydrolysis of Pitavastatin ethyl ester was monitored by qualitative HPLC till the unhydrolyzed Pitavastatin ethyl ester was less than 0.1%.

Thereafter, solvents were evaporated and water (100 ml) was added to it. The resulted solution was extracted once with methyl tert-butyl ester (25 ml). The aqueous layer was concentrated partially to ensure complete removal of solvents. Thereafter, the temperature of the aqueous layer was raised to 40-45°C and aqueous Calcium chloride dihydrate solution (0.86 gm. 0.005 mole, dissolved in 25 ml of water) was added to it slowly over a period of 30 min, with slow stirring. The resulted Pitavastatin calcium was further stirred at 20-30°C and was filtered, washed with water (25 ml x 2). The product was dried under vacuum to remove the filtrate for one hour and further at 20-3 0°C till a moisture content of-10% w/w. Yield: 3.8 gm. Anti-isomer (3S.5S-lsomer): 0.36%

EXAMPLE - 7

PREPARATION OF CRYSTALLINE FORM 1 OF (3R,5S,6E)-7-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL)-QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOIC ACID, CALCIUM SALT [PRAVASTATIN CALCIUM FORM 1]

Pitavastatin ethyl ester, trifluoroacetate salt (100 gm) was dissolved in a mixture of ethyl acetate (1.0 Lt) and water (1.0 Lt) and it was cooled to 0-5°C. The pH was adjusted to 7.5-8.0 by adding aqueous sodium bicarbonate (~400 ml). The ethyl acetate layer was separated and washed with water. Solvent was evaporated at 35-45 °C under reduced pressure to obtain Pitavastatin ethyl ester. It was subsequently co-distilled with ethanol (200 ml) at about 50°C.

Pitavastatin ethyl ester obtained above was dissolved in a mixture of ethanol (500 ml) and THF (50 ml) at 20-30°C. The above solution was cooled to 0-5°C and aqueous sodium hydroxide (7.32 g, 97% w/w assay, on as is basis, dissolved in 200 ml of water) was added to it slowly in about 20 min maintaining the temperature at 0-5°C. After completion of the reaction, monitored by qualitative HPLC, the reaction mass was concentrated at 35-40°C and dissolved in water (1.0 Lt). The obtained aqueous solution of Pitavastatin sodium was extracted with methyl tert-butyl ether (500 ml) and treated with carbon enoanticromos (5 g). It was filtered through hyflo and concentrated under reduced pressure to a volume of~700 ml. The above concentrated mass was diluted with water (1300 ml) and heated to 30-35°C. Aqueous calcium chloride (14.36 g, dihydrate, dissolved in 500 ml of water) was added to the above aqueous Pitavastatin sodium slowly over a period of lh at 30-35°C during which product was precipitated out. Subsequently, the above suspension was cooled to 25-30°C and stirring was continued at this temperature for ~3h. The product was filtered and washed with water (2 x 100 ml).

Thereafter, the product was kept under suction for ~lh to squeeze last traces of filtrate and dried at 35-40°C under reduced pressure till the water content is < 4% w/w. Yield: 65 g

EXAMPLE - 8

PREPARATION OF CRYSTALLINE FORM 1 OF (3R,5S,6E)-7-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL)-QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOIC ACID, CALCIUM SALT [PRAVASTATIN CALCIUM FORM 1]

Pitavastatin ethyl ester, trifluoroacetate salt (300 gm) was dissolved in a mixture of ethyl acetate (3.0 Lt) and water (3.0 Lt) and it was cooled to 0-5°C. The pH was adjusted to 7.5-8.0 by adding aqueous sodium bicarbonate (~1.2Lt). The ethyl acetate layer was separated and washed with water. Solvent was evaporated at 35-45°C under reduced pressure to obtain Pitavastatin ethyl ester. It was subsequently co-distilled with ethanol (600 ml) at about 50°C.

Pitavastatin ethyl ester obtained above was dissolved in a mixture of ethanol (1.5 Lt) and THF (150 ml) at 20-30°C. The above solution was cooled to 0-5°C and aqueous sodium hydroxide (21.96 g, 97% w/w assay, on as is basis, dissolved in 600 ml of water) was added to it slowly in about 20 min maintaining the temperature at 0-5°C. After completion of the reaction, monitored by qualitative HPLC, the reaction mass was concentrated at 35-40°C and dissolved in water (3.0 Lt). The obtained aqueous solution of Pitavastatin sodium was extracted with methyl tert-Butyl ether (1.5 Lt) and treated with carbon enoanticromos (15 g). It was filtered through hyflo and concentrated under reduced pressure to a volume of ~2Lt. The above concentrated mass was diluted with water (5.0Lt) and heated to 30-35°C. Aqueous calcium chloride (14.36 g, dihydrate, dissolved in 1.5Lt of water) was added to the above aqueous Pitavastatin sodium slowly over a period of lh at 30-35°C during which product was precipitated out. Subsequently, the above suspension was cooled to 25-30°C and stirring was continued at this temperature for ~3h. The product was filtered and washed with water (2 x 300 ml).

Thereafter, the product was kept under suction for ~lh to squeeze last traces of filtrate and dried at 35-40°C under reduced pressure till the water content is < 4% w/w. Yield: 200 g

WE CLAIM

1. A process for the preparation of Pitavastatin calcium of formula II, comprising:

a) reacting compound of formula III,

wherein R2 represents C1-4 straight chain or branched chain alkyl, aryl, substituted aryl or aralkyl group with an organic acid selected from monobasic acid or dibasic acid in the presence of organic solvent to obtain organic acid salt of compound of formula I,
wherein R2 is same as defined above and X represents monobasic or dibasic acid;

b) optionally, purifying compound of formula I;

c) treating compound of formula I with aqueous inorganic base to obtain pure compound of formula III;

d) hydrolyzing the compound of formula III with a base to obtain the corresponding alkali metal salt of compound of formula IV,

wherein M represents Na, K, Li;

e) treating compound of formula IV with a calcium source to obtain Pitavastatin calcium of formula II; and

f) isolating the Pitavastatin calcium of formula II.

2. The process according to claim 1, wherein monobasic or dibasic acid is selected from the group consisting of trifluoroacetic acid, trifluoromethane sulfonic acid, acetic acid, methanesulfonic acid, perchloric acid, periodic acid, oxalic acid, mandelic acid, malic acid, tartaric acid, camphorsulfonic acid, benzenesulfonic acid, p-toluenebenzene sulphonic acid and 4-nitrobenzene sulfonic acid.

3. The process according to claim 1, wherein step (a) is carried out in an organic solvent selected from the group consisting of C1-C5 alcohols, C3-C8 esters, C3-C8 ketones, C6-C10 aromatic hydrocarbons, ethers, acetonitrile and mixtures thereof.

4. The process according to claim 1, wherein purification of organic acid salt of formula I is carried out using organic solvent.

5. The process according to claim 4, wherein, organic solvent is selected from the group consisting of ethanol, methanol, isopropyl alcohol, tert-butyl alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, toluene, acetonitrile, water, hexanes, heptane, pentane, cyclohexane and mixture thereof

6. The process according to claim 1, wherein step (c) is carried out using inorganic base selected from sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium hydroxide, lithium bicarbonate or lithium carbonate.

7. The process according to claim 1, wherein step (d) is carried out using a base selected from sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium hydroxide, lithium bicarbonate or lithium carbonate.

8. The process according to claim 1, wherein Pitavastatin calcium is crystalline Form I having water content less than 4%.

9. Organic acid salt of compound of formula I,

wherein R2 represents C1-4 straight chain or branched chain alkyl, ar yl, substituted aryl, aralkyl and X represents monobasic or dibasic acid.

10. The organic acid salt of compound of formula I according to claim 8, wherein acid is selected from the group consisting of trifluoroacetic acid, trifluoromethane sulfonic acid, acetic acid, methanesulfonic acid, perchloric acid, periodic acid, oxalic acid, mandelic acid, malic acid, tartaric acid, camphorsulfonic acid, benzenesulfonic acid, p-toluenebenzene sulphonic acid and 4-nitrobenzene sulfonic acid.