FIELD OF THE INVENTION

The present invention relates to a novel process for preparing Pitavastatin calcium salt of Formula I.

BACKGROUD OF THE INVENTION

Pitavastatin calcium, chemically known as (3/?,55,6£)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid calcium (2:1) salt, is a synthetic lipid lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase).
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.

Pitavastatin was disclosed for the first time in US patents US 4,761,419, US 5,011,930 and US 5,753,675. The process disclosed in these patents for the preparation of Pitavastatin is as shown below:

wherein R is hydrogen or protecting group.

US 5,284,953 discloses a process for the preparation of Pitavastatin calcium, which employs optically active a-methylbenzylamine as a resoluting agent.

The above processes are economically not viable, as resolution is carried out in final stage.

Bioorganic & Medicinal Chemistry Letters (1999), 9(20), 2977-2982 discloses a process for the preparation of pitavastatin epimers, which is as shown below:

The above process gives Pitavastatin calcium of less chiral purity.

WO 1995/11898 Al discloses a process for the preparation of Pitavastatin, which is as shown below:

wherein Y represents P"^RiiRi2Ri3Har or P(W)Ri4Ri5; Rpa, R9b and Rio are protecting groups.

The above process would result in 2-5% of Cis Pitavastatin which would require further purification and therefore results in poor yield.

As mentioned above though there are number of processes available still there is a continuing need to identify alternative process for the manufacture of Pitavastatin and its pharmaceutically acceptable salts, such processes may, for example, when compared to previously known processes, be more convenient to use, be more suitable for large scale manufacture, give the product in a better yield, use intermediates which are more easily isolated, require less complex purification techniques, use less expensive reagents and/or be more environmentally friendly.

We have now found a process for preparing (3/f,55',6£)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3,5-dihydroxy-6-heptenoic acid, calcium (2:1) salt of Formula I, which is industrially feasible.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide novel process for preparing (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid, calcium (2:1) salt with high yield and high purity.

Another objective of the present invention is to provide novel process for preparing (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid, calcium (2:1) saU, which is simple, industrially applicable and economically viable.
Yet another objective of the present invention is to provide novel process for preparing (3i?,5S',6£r)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid, calcium (2:1) salt with novel intermediates.

SUMMARY OF THE INVENTION
The present invention relates to process for preparing (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid, calcium (2:1) salt of Formula I,

which comprises:

a) protecting the compound of Formula II with a suitable hydroxy protecting group,

in an organic solvent to obtain a compound of Formula III,

wherein R1 represents a hydroxy protecting group;

b) activating the acid group of the compound of Formula III with an acid activator, followed by treating the resulting intermediate with a metal complex of formula IV,

wherein R2 represents CM straight chain or branched chain alkyl, aryl, substituted aryl, aralkyl; M represents Mg, Zn, Ca Cu; n represents an integer selected from 1-2; R3 represents alkyl or alkoxy; m represents an integer selected from 0 or 1 in an organic solvent to obtain a compound of Formula V,
wherein R1 and R2 are same as defined above;

c) deprotecting the compound of formula V with a suitable reagent in an organic solvent, water or mixture thereof to obtain compound of Formula VI,

wherein R2 is same as defined above; d) reducing the compound of Formula VI to obtain a compound of Formula VII,

wherein R2 is same as defined above;

e) hydrolyzing the compound of Formula VII; and
f) treating the compound obtained in step (e) with calcium salt to give the compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The process to prepare pitavastatin calcium comprises protecting (3S,4E)-5-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3-hydroxypentenoic acid of Formula II with a suitable hydroxy protecting group selected from tertiarybutyldimethylsilyl, dihydropyran, trimethylsilyl, methoxymethyl, more preferably tert-butyldimethylsilyl in the presence of an organic solvent selected from toluene, N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, N-methylpyrrolidinone, sulfolane, with or without an acid or base catalyst at a temperature ranging from 0 to 50°C; preferably at 0-30°C. The acid catalyst is selected from pyridinixmi p-toluene sulfonate, p-toluene sulfonic acid, acetic acid, etc. and base catalyst is selected from triethylamine, pyridine, imidazole, etc. Optionally, during the silylation reaction a suitable additive is added to accelerate the silylation reaction, which is selected from sodium iodide, potassium iodide, lithium iodide, etc.

(3S,4E,)5- [2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3-(protected hydroxy )pentenoic acid of Formula III is treated with acid activator like 1,1-carbonylimidazole, methyl chloroformate, ethyl chloroformate, phenyl chloroformate, 4-methoxyphenylchloroformate, 2,4-dinitrophenyi chloroformate, 4-trifluoromethylchloroformate, 4-nitrophenylchloroformate, etc., more preferably with 1,1-carbonylimidazole in the presence or absence of organic base which is selected from triethylamine, pyridine, etc. The resulting activated imidazolimide intermediate is subsequently treated with metal complex of mono-alkyl malonate, wherein metal is selected from zinc, magnesium, calcium and copper.

Magnesium complex of monoalkyi malonate can be prepared by treating 2 moles of malonic acid mono alkyl ester with 1 mole of magnesium ethoxide in the presence of an organic solvent selected from tetrahydrofuran, N,N-dimethylformamide, methylene chloride, acetonitrile or mixture thereof and the reaction is conducted at a temperature between 0-100°C, preferably at ambient temperature.

Zinc complex of monoalkyi malonate can be prepared by using different methods such as processes I or II.

Process I:
Zinc complex is prepared by reacting dialkyl zinc with 2 moles of lower alcohol, preferably ethanol in an inert solvent selected from tetrahydrofuran, toluene, hexane, methyl tert-butyl ether, isopropyl ether or mixture thereof, at -10°C to 40°C. 1-5 mole of monoalkyi malonate, preferably 2 to 3 mole are added to this reaction mixture and stirred for 1 -15 h, preferably for 1-3 h.

Process II:

Zinc complex is prepared by reacting zinc oxide with 1 to 5 moles of monoalkyl malonate in an inert solvent selected from tetrahydrofuran, toluene, hexane, methyl tert-butyl ether, isopropyl ether or mixture thereof, at ambient temperature for 2h to 6h. The water formed during the course of reaction is co-distilled with an inert solvent such as toluene.

The metal complex of Formula IV is reacted with acid activated compound of Formula III in an inert solvent such as tetrahydrofuran, acetonitrile, toluene, methyl tert-butyl ether, isopropyl ether or mixture thereof, at 0°C to 40°C, preferably 10°C to 25°C for 8h to 24h, preferably lOh to 24h to yield (5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-5-(protectedhydroxy)-3-oxo-6-heptenoate of Formula V. During the work-up of this reaction, a compound of Formula Va, which is generated in situ gets decarboxylated giving directly ketoester of Formula V.

(5S,6E)- [2-Cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-5-(protectedhydroxy) -3-oxo-6-heptenoate of Formula V is deprotected using acids having a general formula HX wherein X represents halide or MX wherein X represents halogen, M is a cation derived from inorganic metal like Na"*", K"^, Li"^ etc organic ammonium salt like N^(R)4 wherein R represents C1-C4 alkyl, straight or branched chain alkyl, sulphonic acid, organic acids selected from /7-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, trifluoroacetic acid, acetic acid in an aqueous solvent or in an organic solvents selected from tetrahydroftiran, acetonitrile, methanol, ethanol, dichloromethane, ethylene dichloride, toluene, xylene, etc. or a mixture thereof at room temperature to yield (5S',6£)-7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-5-hydroxy-3-oxo-6-heptenoate of Formula VI.

(5S,6E)-7- [2-Cyclopropyl-4-(4-fluorophenyl)-quinolin-3 -yl] -5 -hydroxy-3 -0x0-6-heptenoate of Formula VI is stereoselectively reduced with metal borohydrideselected from sodium borohydride, more preferably sodium borohydride in thepresence of chelating agents like trialkylborane or boronates selected from
dialkylalkoxyborane such as diethylmethoxyborane, diethylethoxyborane,dimethylmethoxyborane, more preferably with diethylmethoxyborane, in a mixture of inert solvent selected from tetrahydrofiiran, a lower alkanol, more preferably methanol and CM alkyl ester like methyl acetate, ethyl acetate, propyl
acetate, more preferably ethyl acetate at -78°C to -0°C. After completion of the reaction, excess sodium borohydride is destroyed by adding acetic acid and resulting (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-3,5-dihydroxy-6-heptenoate of Formula VII is isolated by extracting into an organic solvent. The organic layer is concentrated under reduced pressure to give crude compound, which is purified by crystallization or is used as such for hydrolysis.

Saponification of (3R,5S,6E)- [2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-3,5-dihydroxy-6-heptenoate of Formula VII is carried out using a base, selected from alkali or alkali earth metal hydroxide selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide preferably sodium hydroxide. The sodium salt of Pitavastatin thus obtained can be optionally isolated or the solution containing Pitavastatin sodium is treated with a calcium ion source such as calcium chloride, calcium acetate, etc. to yield Pitavastatin calcium.

(35',4E)-5-[2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3-hydroxypentenoic acid of Formula II is prepared by following the prior-art process, which is as shown below:

wherein R7 selected from (=O), CM alkyl, aralkyl, phenyl, substituted phenyl, Re and R5 are selected from ORs, CM alkyl, aralkyl, phenyl, substituted phenyl; R4 and R8 are selected from CM alkyl, aralkyl, phenyl, substituted phenyl; "—" represents an optional bond with a provision that when R7 is =O, "—" is not a bond and when R7 represents C1-4 alkyl, phenyl, substituted phenyl, then "—" is a bond; R', R", R'" and R"" are selected from alkyl, aralkyl, cycloalkyl, aryl, heterocyclic reissue.

2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxaldehyde of formula VIII is reacted with a phosphorous compound of Formula IX optionally in the presence of a base such as organic base selected from sodium methoxide, lithium diisopropylamide, n-Butyllithium, lithium hexamethyldisilazane, sodium hexamethyldisilazane, etc. or inorganic base selected from sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate.

potassium carbonate, a solvent selected from acetonitrile, dichloromethane, tetrahydrofUran, methanol, ethanol, isopropyl alcohol and mixture thereof, at a temperature ranging from 20-90°C, preferably 40-80°C for 1-8 h to yield (2E)-3-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]acrylate of Formula X, which is reduced using a reducing agent such as diisobutylaluminium hydride (DIBAL), Vitride, Lithium aluminium hydride (LAH), etc. in an organic solvent selected from toluene, tetrahydrofuran, at 35°C to -80°C, preferably at -78°C to yield (2E)-3-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]propen-l-ol of Formula XI.

(2E)-3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]propen-l-ol of Formula XI is oxidized using an oxidizing agent such as pyridinium dicromate (PDC), Pyridinium chlorocromate (FCC), manganese dioxide (Mn02), and tetrapropylammoniumperrutheniante (TPAP), sodium hypochlorite (NaOCl) / TEMPO, N-Methylmorpholine N-Oxide (MNO) and the like, at a temperature ranging from 0-100°C preferably at 0-25°C to yield (2E)-3-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-2-propenal of Formula XII, which is condensed with a compound of Formula Xllla or Xlllb in presence of base selected from n-butyllithium, lithium hexamethyldisilazane, sodium hexamethyldisilazane, lithium diisopropylamine, etc. more preferably lithium hexamethyldisilazane in an organic solvent selected from tetrahydrofiiran, ether, hydrocarbon solvents such as heptane, hexane or mixture thereof, preferably tetrahydroftiran and hexane and the reaction is carried out at a temperature ranging from -78°C to 25°C.

After completion the reaction is quenched with 5N hydrochloric acid and extracted with an organic solvent to give a diastereomeric mixture of compounds of Formula XlVa or XlVb and is hydrolyzed to its corresponding acid, (4E)-5-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-3-hydroxypentenoic acid of Formula XV, which is then resolved using optically pure precipitating agents, for example (+) or (-) phenylalkylamine or substituted phenylalkylamine, preferably (R)-l-phenylethylamine is a suitable organic solvent selected from acetonitrile, tetrahydroftiran, ethyl acetate, methanol, ethanol, isopropyl alcohol or a mixture of organic solvent and water to obtain enantiomerically pure (35,4E)-5-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-3-hydroxypentenoic acid, (R)-a-methylbenzylamine salt of Formula XVI, which then converted to the free acid (3S,4Er)-5-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-3-hydroxypentenoic acid by treating with dilute inorganic acid, such as aqueous hydrochloric acid.

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 METHYL (2E)-3-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL)-QUINOLIN-3YL]ACRYLATE

Mixture of 2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxaldehyde (50 g, 0.171 mole) and methyl(triphenylphosphoranylidene)acetate (68.86 g, 0.205 mole) was suspended in isopropyl alcohol (250 ml) at 25-30°C. The contents were heated to 78-82°C during which a clear solution was obtained. The completion of the reaction was confirmed by TLC. After completion of the reaction, the temperature was subsequently lowered to 25-30°C during which product was precipitated out. The product was cooled to 0-5°C, filtered, washed with precooled isopropyl alcohol and dried at 40-45°C under reduced pressure (-20 mm Hg) till water content is < 0.3%. Yield: 58.0 g (97%) 'H NMR (CDCI3, 300 MHz): 5 1.06-1.09 (m, 2H), 1.38-1.40 (m, 2H), 2.37-2.39 (m, IH), 3.73 (s, 3H), 6.04 (d, J = 16.2 Hz, IH), 7.19-7.25 (m, 4H), 7.33-7.36 (m,2H), 7.63-7.66 (m, IH), 7.78 (d, J = 16.2 Hz, IH), 7.96 (d, J = 8.7 Hz, IH).

EXAMPLE 2
PREPARATION OF (2E)-3-[2-CYCLOPROPYL-4-(4-FLUOROPHENY) QUINOLIN-3-YL]-2-PROPENAL

Methyl (2£)-3-[2-cycIopropyl-4-(4-fIuorophenyI)quinoIine-3-yl]acryIate (50 g, 0.144 mole) was dissolved in toluene (600 ml) at 25-30°C. It was cooled to -50 to -60°C under nitrogen atmosphere. Diisobutylaluminium hydride (82 g, -25% w/w solution in toluene) was added slowly in ~ 2 h by keeping the temperature of the reaction mass between -50°C and -60°C. The completion of the reaction was confirmed by TLC and thereafter, water (300 ml) was added to the above reaction mass slowly in -30 min at -50°C and temperature was raised to 25-30°C. The precipitated inorganic salt was filtered through hyflow. From the filtrate, toluene layer was separated and the aqueous layer was extracted with toluene (300 ml). The combined toluene layer was washed with water. Thereafter the toluene layer was partially concentrated to control the water content below 0.1% w/w. Manganese dioxide (100 g) was added to the above partially distilled toluene layer and stirred at 25-30°C for ~ 24 h. Thereafter the reaction mass was filtered and the residue was washed with preheated toluene (2 x 150 ml). The filtrate was concentrated at 35-45°C. The crude mass obtained was crystallized fi-om hexanes (250 ml) and dried at 40-45°C till the loss on drying is less than 3% w/w.

Yield: 45 g (99.80%)
1HNMR(CDC13,300MHZ):5 1.08-1.34 (m, 2H), 1.42-1.61 (m, 2H), 2.33-2.36 (m, IH), 6.56-6.49 (m, IH), 7.22-7.27 (m, 4H), 7.27-7.37 (m, 2H), 7.56 (d, J= 15.6 Hz, 7.66-7.97 (m, IH), 7.99 (d, J = 6 Hz, IH), 9.50, (d, J = 7.8 Hz, IH).

EXAMPLE 3
PREPARATION OF (1S)-2-HYDROXY-l,2,2-TRIPHENYLETHYL (3S,4E)(3R,4E)-5-[2-CYCLOPROPYL-4-(4-FLUOFOPHENYL)QUINOLIN-3-YL]-3-HYDROXY-4-PENTE-NOATE
Hexamethyldisilazane (73.31 g, 0.454 mole) was added to n-Butyl lithium (272 ml, -15% w/w solution in hexanes) at 0-5°C over a period of -15 min and thereafter temperature was raised to 20-30°C and stirred for 30 min. The above contents were diluted with tetrahydrofiiran (450 ml) and the reaction mass was cooled to -35°C. A slurry of (2S)-2-acetoxy-l,l,2-triphenylethanol (83.78 g, 0.252 mole) in tetrahydrofiiran (400 ml) was added to the above reaction mass. Thereafter, the temperature of the reaction mass was increased to -15°C and stirred for 1 h at this temperature. Subsequently, the temperature was lowered to -75°C and a solution of (2E)-3-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-2-propenal (45 g, 0.142 mole) in tetrahydrofiiran (200 ml) was added slowly over a period of 1 h keeping the temperature between -75°C to -80°C. After addition, stirring was continued for 15 min and progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was quenched by adding ~5N hydrochloric acid (500 ml). The organic layer was separated and aqueous layer was extracted with ethyl acetate (250 ml). The combined organic layer was washed with water (250 mlj and evaporated to obtain the product as a solid residue. Yield: 115 g.

EXAMPLE 4
PREPARATION OF (3S,4E)-5-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL)QUINO-LIN-3-YL]-3-HYDROXYPENTENOIC ACID, (R)-a-METHYLBENZYLAMINE SALT
(1S)-2-Hydroxy-l,2,2-triphenyIethyl (35,4E)(3S,4E)-5-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3-hydroxy-4-pentenoate (115 g, crude) was suspended in tetrahydrofuran (500 ml) and ~1M sodium hydroxide (520 ml) was added slowly to the above suspension. The reaction mass was stirred at 20-30°C for -24 h. The completion of the reaction was confirmed by TLC. Thereafter, solvent was evaporated and water (500 ml) was added to it. The resulting aqueous layer was extracted with methylene chloride (2 x 250 ml) at 25-30°C. The pH of the resulting aqueous layer was lowered to 1.5 to 2 with aqueous hydrochloric acid and the product was extracted with methylene chloride (2 x 250 ml). The combined methylene chloride extracts was washed with water (250 ml) and solvent was evaporated. The residue obtained was dissolved in acetonitrile (600 ml) and (R)-a-Methylbenzyl amine (17.0 g) was added to it. The product precipitated was filtered, washed with acetonitrile (950 ml) and dried at 40-45°C under reduced pressure for 8 h.

Yield: 65 g (92.8%)
1H NMR (300 MHz, DMSO-d^ + D2O): 5 1.06-1.09 (m, 2H), 1.19 (brs, IH), 1.46 (d, J = 6 Hz,3H), 1.81-1.98 (m, 2H), 2.47-2.50 (m, IH), 4.21-4.31 (m, 2H), 5.62 (dd, J = 12 Hz, 6 Hz, IH), 6.49( d = 15 Hz, IH), 7.28-7.44 (m, IIH), 7.64-7.69 (m, lH),7.89(d,J = 6Hz, IH).

EXAMPLE 5
PREPARATION OF (2S,3E)-4-[2-CYCLOPROP YL-4-(4-FLUOROPHENYL)QUINOLIN-3-YL]-2-(tert-BUTYLDIMETHYL SILYLOXY)-l-CARBONYLIMIDAZOL-3-BUTENE
Part A: (35,4J?)-5-[2-Cylopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3-hydroxy pentenoic acid, (R)-a-methylbenzylamine salt (50 g) was suspended in a mixture of methylene chloride (150 ml) and water (150 ml) and cooled the suspension to 0-5°C. The contents were acidified with ~1N hydrochloric acid (-100 ml) to pH 2.0 - 2.5. Thereafter, the temperature of the reaction mass was raised to 20-30°C and methylene chloride layer was separated. The aqueous layer was extracted with methylene chloride (150 ml) and the combined methylene chloride extracts was washed with water (250 ml). The washed methylene chloride layer was concentrated to obtain a viscous oily residue.

Part B: Anhydrous potassium iodide (41.66 g) was suspended in N,N-dimethylformamide (160 ml) at 25-3 0°C under nitrogen atmosphere, tert-butyldimethylsilyl chloride (37.65 g) was added to the above suspension and temperature was raised to 60-65°C. It was stirred for 45 min at 60-65°C and triethyl amine (30.42 g) was added to it slowly over a period of 30 min. The part A product was dissolved in N,N-dimethylformamide (100 ml) and added to the above reaction mass at 60-65°C. The reaction mass was stirred for 30 min and the completion of the reaction was confirmed by TLC. Thereafter it was quenched by pouring into pre-cooled water (1.0 Lt, 0-5°C). The temperature was raised to 20-30°C and the product was extracted with toluene (2 x 250 ml). The combined toluene extracts was washed with -0.35% w/v aqueous hydrochloric acid (250 ml). Finally, it was washed with water (250 ml) and evaporated to obtain the product as an oily residue.

Part C: The Part B product was dissolved in methylene chloride at 25-30°C and cooled to 15-20°C. Carbonyldiimidazole (48.80 g) was dissolved in methylene chloride (500 ml) and added to the above reaction mass over a period of 15 min. at 15-20°C. The stirring was continued at this temperature for ~ 3h and the completion of the reaction was confirmed by TLC. Thereafter it was quenched by pouring into pre-cooled water (1.0 Lt, 2-5°C). The methylene chloride layer was separated and the aqueous layer was extracted with methylene chloride (250 ml). The combined methylene chloride layer was washed with water (250 ml), with -5% w/w aqueous citric acid solution and finally with water (250 ml). The methylene chloride layer was concentrated at 40-45°C under vacuum to obtain the product as an oily residue.
Yield: -60 g

EXAMPLE 6
PREPARATION OF ETHYL (5S,6E)-7-l2-CYCLOPROPYL-4-(4-FLUOROPHENYL)-QUINOLIN-3-YL]-5-(tert-BUTYLDIMETHYL SILYLOXY)-3-OXO-6-HEPTENOATE
Under nitrogen atmosphere, zinc oxide (16.26 g) was suspended in toluene (300 ml) at 25-30°C. Mono-Ethyl malonate (79.5 g) in tetrahydrofuran (100 ml) was added to the above suspension in one lot and the mixture was stirred for 2 h at 25-30°C during which a clear solution was obtained. The solvents were evaporated and the concentrated mass was re-dissolved in toluene (250 ml). (2IS',3JE)-4-[2-Cyclopropyl-4-[4-fluorophenyl)quinoline-3-yl]-2-(tert-butyldimethylsilyloxy)-l-carbonylimidazol-2-butene (~60 g, - as obtained from example 4) was dissolved in tetrahydrofuran (250 ml) and added to the above zinc monoethyl malonate complex. The reaction mass was stirred for -12 h and the completion of the reaction was confirmed by TLC. Thereafter water (1.0 Lt) was added to it. The organic layer was separated and the aqueous layer was extracted with toluene (250 ml). The combined organic layer was washed with water 9250 ml) and evaporated to obtain the product as an oily mass. Yield: -55 g.

EXAMPLE 7
PREPARATION OF ETHYL (5S,6E)-7-[2-CYCLOPROPYL-4-(4-FLUOROPHENYL)-QUINOLIN-3-YL]-5-HYDROXY-3-OXO-6-HEPTENOATE
Ethyl (5iS',6£)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-5-(tert-
butylsilyIoxy)-3-oxo-6-heptenoate (~55g) was dissolved in acetonitrile (750 ml) and cooled the solution to -10°C. Hydrochloric acid (-35% w/w, 17 ml) was added slowly to it. The reaction mass was stirred at this temperature for - 4h and the completion of the reaction was confirmed by TLC. Thereafter pH of the reaction mass was raised to 7.5 to 7.0 by adding -7% w/w aqueous sodium bicarbonate solution. The reaction mass was diluted with ethyl acetate (500 ml) and temperature of the reaction mass was raised to 15-20°C. The organic layer was separated. The aqueous layer was extracted with ethyl acetate (250 ml) and the combined organic layer was washed with water. Solvent was evaporated to obtain a viscous residue which was re-dissolved in toluene (250 ml), washed with -2% w/w aqueous potassium carbonate solution (2 x 75 ml) and finally with water (75 ml). The toluene layer was concentrated imder vacuum to obtain the product as viscous residue which was subsequently crystallized from ethyl acetate- hexane (2:8 ; v/v). The product was dried under vacuum at 40-45°C till the loss on drying is<0.5%w/w.

Yield: 32.5 g (73%).
'H NMR (CDCI3, 300 MHz): 5 1.01-1.05 (m, 2H), 1.26-1.35 (m, 5H), 2.34-2.39 (m, IH), 2.53-2.55 (m, 2H), 2.67-2.68 (m, IH), 3.42 (s, 2H), 4.17-4.24(q, J = 7.2 Hz, 2H), 4.59 (brs, IH), 5.58( dd, J = 16.2 Hz, 5.7Hz, IH), 6.67 (dd, J = 16.2 Hz, 1.2Hz), 7.17-7.35 (m, 6H), 7.56-7.61 (m, IH), 7.95 (d, J = 8.4 Hz, IH).

EXAMPLE 8
PREPARATION OF ETHYL (3R,5S,6E)-7-[2-CYCLOPROPYL-4-(4-FLUORO-PHENYL)QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOATE
Under nitrogen atmosphere, a mixture of tetrahydrofuran (900 ml), ethyl acetate (75 ml) and methanol (200 ml) was cooled to -80°C. Diethylmethoxyborane (50% w/w solution in tetrahydrofuran, 15.0 g) was added to the above mixture of solvents at -75°C to -80°C. Sodium borohydride (3.8 g) was added to the above reaction mass and thereafter a solution of ethyl (5S',6£0-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3-oxo-6-heptenoate (30 g) dissolved in a mixture of tetrahydroftiran (75 ml), ethyl acetate (45 ml) and methanol (30 ml) was added to the above reaction mass maintaining the temperature between -80°C to -75°C. The reaction mass was stirred at this temperature for ~ 5h and the completion of the reaction was confirmed by TLC. Thereafter, acetone (45 ml) was added to quench the reaction. Acetic acid (30 ml) was added to the reaction mass and temperature was raised to -30°C.

Thereafter, water (750 ml) and ethyl acetate (750 ml) were added to it. -20% w/w Sodium chloride solution (75 ml) was added to the above content to facilitate the separation of the layers. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (9500 ml). The combined organic extracts was washed with water (500 ml) followed by ~7% w/w aqueous sodium bicarbonate (500 ml). The ethyl acetate layer was concentrated under vacuum at 40-45°C to obtain the crude product. It was co-distilled with methanol (80 ml X 2) and finally with n-heptane (80 ml). The residue obtained after distillation was dissolved in ethyl acetate (50 ml) and ethanol (25 ml) at 20-30°C. n-Heptane (200 ml) was added to it for crystallization. The product was filtered, washed with n-heptane (25 ml) at 0-5°C and dried at 40-45°C under vacuum for 8 h till the loss on drying is less than 0.5% w/w. Yield: 25 g (83%).
'H NMR (CDCI3, 300 MHz): 6 1.01-1.05 (M, 2H), 1.27-1.43 (m, 7H), 1.44-1.61 (m, IH), 2.38-2.44 (m, 2H), 4.11-4.21 (m, 3H), 4.22-4.32(m, IH), 5.60-5.65 (m, IH), 6.63 (d, J = 15 Hz, IH), 7.17-7.56 (m, 6H), 7.56-7.60 (m, IH), 7.95 (d, J = 8Hz, IH).

EXAMPLE 9
PREPARATION OF (3R,5S,6E)-7-[2-CYCLOPROPYL-4-(4-FLUORO-PHENYL)-QUINOLIN-3-YL]-3,5-DIHYDROXY-6-HEPTENOIC ACID, CALCIUM SALT
Ethyl (3R,5S,6E)- [2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3,5-dihydroxy-6-heptenoate (25 g, 0.055 mole) was suspended in ethanol (125 ml) and cooled to 0-5°C. Sodium hydroxide (2.28 g, 97% w/w assay, 0.055 mole) in water (50 ml) was added to the above suspension at 0-5°C and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, solvent was evaporated and water (240 ml) was added to it. The resulted aqueous layer was extracted with methyl tert-butyl ether (2 x 50 ml). Carbon (1 g) was added to the aqueous layer and stirred for 30 min. It was filtered through hyflo and a solution of calcium chloride (4.5 g, dihydrate, 0.030 mole) in water (25 ml) was added to it. The Pitavastatin calcium, which precipitated out was filtered and washed with water (2 x 25 ml). The product was dried under vacuum at 40-45°C for 8 h.

Yield: 22 g (90%).

WE CLAIM:

1. A process for the preparation of Pitavastatin calcium of formula I,

Which comprises:

a)Protecting compound of formula

with a suitable hydroxy protecting group in an organic solvent to obtain a compound of formula III,

wherein R1 represents a hydroxy protecting group;

b) activating the acid group of the compound of formula III with an acid activator, followed by treating the resulting intermediate with a metal complex of formula IV,

wherein R2 represents CM straight chain or branched chain alkyl, aryl, substituted aryl or aralkyl; M represents Mg, Zn, Ca or Cu; n represents an integer selected from 1-2; R3 represents alkyl or alkoxy; m represents an integer selected from 0 or 1 in an organic solvent to obtain a compound of formula V,

wherein R2 is same as defined above;

d) reducing the compound of formula VI to obtain a compound of formula VII,

wherein R2 is same as defined above;

e) hydrolyzing the compound of formula VII; and

f) treating the compound obtained in step (e) with calcium salt to give the Pitavastatin calciimi of formula I.

2. The process according to claim 1, wherein hydroxy protecting group is selected from the group consisting of tert-butyldimethylsilyl, dihydropyran, trimethylsilyl and methoxymethyl.

3. The process according to claim 1, wherein organic solvent used in step (a) is selected from the group consisting of toluene, N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, N-methylpyrrolidinone, sulfolane and mixtures thereof

4. The process according to claim 1, wherein acid activator is selected from the group consisting of 1,1-carbonylimidazole, methyl chloroformate, ethyl chloroformate, phenyl chloroformate, 4-methoxyphenylchloroformate, 2,4-dinitrophenyl chloroformate, 4-trifluoromethylchloroformate and 4-nitrophenylchloroformate.

5. The process according to claim 1, wherein step (b) is carried out in an organic solvent selected from the group consisting of tetrahydrofuran, acetonitrile, toluene, methyl tert-butyl ether, isopropyl ether and mixtures thereof.

6. The process according to claim 1, wherein compound of formula V is deprotected using suitable reagent selected from the group consisting of acids having a general formula HX, wherein X represents halogen; MX wherein X represent halogen and M is a cation derived from inorganic metals selected from Na+, K+, Li+; organic ammoniym salts selected from N+(R)4, wherein R represents C1-C4 alkyl, straight or branched chain alkyl; sulphonic acid and

organic acid selected from p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, trifluoroacetic acid, acetic acid.

7. The process according to claim 1, wherein step (c) is carried out in solvent selected from an aqueous solvent or organic solvent selected from tetrahydroforan, acetonitrile, methanol, ethanol, dichloromethane, ethylene dichloride, toluene, xylene or mixtures thereof.

8. The process according to claim 1, wherein compoimd of formula VI is reduced using metal borohydride.

9. The process according to claim 1, wherein compound of formula VII is hydrolysed using a base selected from alkali or alkali earth metal hydroxides,

10. The process according to claim 1, wherein calcium ion source is selected from the group consisting of calcium chloride and calcium acetate.