This application claims priority to Indian patent application 1351/CHE/2010 filed on May 13, 2010 the contents of which are incorporated by reference in their entity.

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of intermediates of HMG-CoA reductase inhibitors and further conversion to HMG-CoA reductase inhibitors and pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION:

The HMG-CoA reductase inhibitors (Statins) have been used in reducing blood levels of LDL cholesterol. Cholesterol is produced via the mevalonic acid pathway. Reducing the formation of mevalonic acid, a precursor to cholesterol, leads to a corresponding decrease in hepatic cholesterol biosynthesis with a reduction in the cellular pool of cholesterol. The HMG-CoA reductase inhibitors (Statins) represented by the following general Formula-I,

wherein R is a residue of HMG-CoA reductase inhibitor; M represents hydrogen or pharmaceutically acceptable salts like sodium, potassium, magnesium and calcium.. Bis[(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]Calcium Salt of Formula-A (Rosuvastatin Calcium) is an HMG-CoA reductase inhibitor, developed by shionogi for the treatment of hyperlipidemia

Formula-A
Rosuvastatin and its pharmaceutically acceptable salts were first disclosed in European patent publication EP 0,521,471. It also discloses process for the preparation of Rosuvastatin calcium.

Bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptenoate} monocalcium of Formula-B (Pitavastatin Calcium) is an HMG-CoA reductase inhibitor, developed by Nissan Chemical Industries for the treatment of hyperlipidemia.

Pitavastatip and its pharmaceutically acceptable salts were first disclosed in European patent publication EP 0,304,063. It also discloses process for the preparation of Pitavastatin sodium.

United States Patent No. 5,260,440 and PCT publication No. WO 03/097614, disclose the
synthesis of Rosuvastatin from the intermediate 3(R)-3(tert-butyldimethylsilyloxy)-5-
oxo-6-triphenyl-phosphoranylidenehexanoate.

PCT publication No. WO 03/087112 discloses the synthesis of Rosuvastatin from a
different intermediate, (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxo-
hexanoate.

US 5,117,039 discloses the process for the preparation of (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester by the ring opening of 3-[(tert-Butyldimethylsilyl)oxy] pentanedioic anhydride using benzyl D-mandelate gives by products.

US 20090076292 discloses process for the preparation of Rosuvastatin by using the intermediates 3(R)-3(tert-butyldimethylsilyloxy)-5-oxo-6-triphenyl-phosphoranylidene hexanoate and (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxo-hexanoate. These intermediates are prepared by a novel intermediate i.e. chiral base salt of hydroxy protected diethyl glutarate.

US 2005/0070605 Al discloses the enantioselective opening of 3-hydroxy protected glutaric anhydride by phenylethylamine to form an amide bond, and further conversion to obtain the HMG-CoA reductase inhibitor.

Above mentioned processes involves the usage of the expensive and hazardous materials in the preparation of HMG-CoA reductase inhibitors. HMG-CoA reductase inhibitors obtained by the above processes are having impurities in the final product.

Thus the present invention provides process for the preparation of HMG-CoA reductase inhibitors with high yield and purity.

OBJECT AND SUMMARY OF THE INVENTION:

The principle object of the present invention is to provide an improved process for the preparation of compound of Formulae-IXa and IXb having the following structures

wherein P is hydroxy protecting group; R2 is C1-C5 alkyl or substituted C1-C5 alkyl group; R3, R4 and R5, each independently, are selected from C6-C10 aryl group, preferably phenyl group or substituted phenyl groups; Alk is alkyl preferably C1-C5 alkyl.

Another object of the present invention is to provide a compound of Formula-VI having the following structure

wherein the base is a non-chiral base; P is hydroxy protecting group and R2 is C1-C5 alkyl or substituted C1-C5 alkyl group.

Another object of the present invention is to provide further conversion of compound of Formulae- IXa or IXb into HMG-CoA reductase inhibitors by the conventional methods.

One aspect of the present invention provides, process for the preparation of the compound of Formulae-IXa or IXb comprising the steps of:

a) ring opening of hydroxyl protected glutaric anhydride of compound of Formula-II in presence of chiral auxiliary;

b) reacting with alkalimetal alkoxide to get monoester derivative of formula V;

c) optionally purifying the compound of Formula-V by using a base to obtain pure compound of Formula-V;

d) converting the compound of Formula-V to mixed anhydride of Formula-VIII; and

e) converting the compound of formula VIII into compound of formulae IXa or IXb.
Another aspect of the present invention provides, a process for the purification of compound of Formula-V comprising: a) reacting a crude compound of Formula-V having the structure

with a non-chiral base to obtain the compound of Formula-VI having the structure
and; b) reacting the compound of Formula-VI with an acid to obtain pure compound of
Formula-V.

One more aspect of the present invention provides further conversion of compound of
Formula-V into compound of Formula-I by conventional methods.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of compound of Formulae- IXa or IXb, by ring opening of the Hydroxyprotected glutaricanhydride by using chiral auxiliary and conversion to monoester, and purification with non chiral amine base and conversion to mixed anhydride which is further converted to compound of formulae IXa or IXb. The present invention further relates to conversion of compound of formulae IXa or IXb to HMG-CoA reductase inhibitors.

Accordingly the present invention provides a process for the preparation of compound of Formulae- IXa or IXb through the compound of Formula-II is summarized in scheme-I.

In one embodiment, the process for the preparation of compound Formulae-IXa or IXb comprising the steps of:

a) ring opening of the compound of Formula-II by using the compound of Formula-Ill in the presence of chiral auxiliary and deprotecting to produce compound of Formula-IV, wherein P is hydroxy protecting group; Ra is alkyl, aryl or optionally substituted aryl and Rb is hydrogen, optionally substituted alkyl, or optionally substituted aryl alkyl.

b) reacting the compound of Formula-IV with Alkalimetal alkoxide to get the compound of Formula-V, wherein R2 is C1-C5 alkyl or substituted C1-C5 alkyl group.

c) optionally purifying the compound of Formula-V by using a base to obtain pure compound of Formula-V

d) converting the compound of Formula-V into compound of Formula- VIII, wherein Y is an alkoxy or alkyl group of C1 to C5 carbons; and

e) converting the compound of Formula-VIII into compound of Formula-IXa or Formula IXb, wherein R3, R4 and R5, independently, are selected from C6-C10 aryl group, preferably phenyl group or substituted phenyl groups.

In one embodiment of the present invention, chiral auxiliary used for the ring opening of the compound of Formula-II is selected from N-pyrrolidinyl norephedrine, (1R, 2S)-N-methylephedrine, ephedrine, N,N-dibenzylnorephedrine, (lR,2R)-pseudoephedrine, (lS,2S)-N-methylpseudoephedrine, (1R, 2S)-N-piperidinyl norephedrine, preferably N-pyrrolidinyl norephedrine. The prior art US 5117039 discloses ring opening of compound of Formula-II without using chiral auxiliary. If chiral auxiliary is not used, 20 % of the unwanted isomer is formed. By using chiral auxiliary the unwanted isomer is controlled.

In another embodiment of the present invention, ring opening of the compound of Formula-II is carried out with compound of Formula-Ill, which is selected from benzyl(R)-mandelate, ethyl (R)-mandelate, Trityl (R)-mandelate, preferably benzyl(R)-mandelate.

In another embodiment of the present invention, the compound of Formula-IV is reacted with Alkalimetal alkoxide. Alkalimetal alkoxide used in this reaction is selected from sodiumalkoxide, potassiumalkoxide, preferably sodium methoxide. In another embodiment of the present invention, the compound of Formula-V is purified by using base wherein the base is chiral or non-chiral base. The non-chiral base is selected from cyclohexylamine, terf-butylamine, cyclopropylamine, cyclopentylamine, benzyl amine, Dicyclohexyl amine, 2-ethyl hexylamine, ethanolamine, methylamine, ethylene amine, preferably cyclohexylamine, tert-butylamine, benzyl amine.

In one more embodiment of the present invention, the compound of formula-VIII can be prepared by reacting the compound of formula-V with ethylchlorocarbonate or pivaloyl chloride, preferably ethylchlorocarbonate.

In one more embodiment of the present invention, the compound of formula-IXa can be prepared by reacting the compound of formula-VIII with triarylphosphonium alkyl halide like methyltriphenyl phosphonium bromide. Alternatively compound of formula VIII is reacted with dialkylmethylphophonate to get compound of formula-IXb.

In one more embodiment of the present invention, the compound of Formulae-IXa or IXb are further converted into HMG CoA reductase inhibitors of Formula-I by conventional methods as disclosed in US RE 37,314 and CN 100506796, the disclosers of which are incorporated by reference in their entirety herein.

For example the compound of formula-IXa can be converted into the Rosuvastatin calcium by the way as summarized in the following scheme-II.

SCHEME-II

For example the compound of formula-IXa can be converted into the Pitavastatin calcium by the way as summarized in the following scheme-Ill.

SCHEME-III

In one aspect the present invention provides, a compound of Formula-VI having the following structure

wherein the base is a non-chiral base; and P is hydroxy protecting group and R2 is C1-C5 alkyl or substituted C1-C5 alkyl group.

In another aspect the present invention provides, a process for the preparation of compound of Formula-VI comprising: reacting a compound of Formula-V having the
structure

Formula-V with a non-chiral base to obtain the compound of Formula-II having the structure

Formula-VI wherein the base is a non-chiral base; and P is hydroxy protecting group and R2 is C1-C5 alkyl or substituted C1-C5 alkyl group.

One embodiment of the present invention provides, the base used is non-chiral base selected from cyclohexylamine, tert-butylamine, cyclopropylamine, cyclopentylamine, benzyl amine, Dicyclohexylamine, 2-ethylhexylamine, ethanolamine, methylamine, ethylene amine, preferably cyclohexylamine, /erf-butylamine, benzyl amine.

Another aspect of the present invention provides, a process for the purification of compound of Formula-V comprising: a) reacting crude compound of Formula-V having the structure

Formula-V with a non-chiral base to obtain the compound of Formula-VI having the structure and; b) reacting the compound of Formula-VI with an acid to obtain pure compound of Formula-V.

In one embodiment of the present invention, the acid used in the above process is selected from hydrochloric acid, acetic acid, formic acid, preferably hydrochloric acid.

Another aspect of the present invention provides, a process for preparing a compound of
Formula-I comprising the steps of:

a) reacting a non-chiral base with a compound of formula-V to obtain a salt of
formula-VI;

Formula-V Formula-VI
wherein P and R2 is defined as above

b) reacting compound of Formula-VI with an acid to obtain pure compound of
formula-V;

Formula-VI Formula-V

c) converting the compound of formula-V into compound of formula-VIII by known
methods;

Formula-V Formula-VIII

d) converting the compound of formula VIII into compound of formula-IXa;

Formula-VIII Formula-IXa

wherein Y, P, R2, R3, R4 and R5 is defined as above

e) converting compound of formula-IXa into compound of formula-X by reacting
with an aldehyde compound of Formula R-CHO.

i) deprotecting the compound of Formula-X into compound of Formula-XI; and g) converting the compound of Formula-XI into compound of Formula-I by
conventional methods, wherein R is a residue of HMG-CoA reductase inhibitor selected from

In one embodiment, the present invention provides one-pot synthesis of compound of Formula-XI starting with the compound of Formula-V without isolating the intermediate compounds of Formulae VI, VIII, IXa and X.

Formula-XI wherein R and R2 as defined above.
The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way

Experimental procedure:

Example 1: Process for the preparation of (3R)-3-[(tert-Butyldimethylsilyl) oxy]
pentanedioic acid, 1-[(R)-Mandelic acid] Ester

A solution of N-pyrrolidinyl norephedrine in toluene and catalytic amount of triphenyl methane in tetrahydrofuran (750 ml) was cooled to -78 °C, and to this a solution of 1.6 M BuLi in hexane (257 ml) was added drop wise, and the reaction mixture was stirred for 1 hr. To this reaction mixture a solution of benzyl(R)-mandelate (100 g) in THF (500 ml) was added and stirred for 1 hr. To this a solution of 3-[(tert-butyldimethylsilyl)oxy] pentanedioic anhydride (101 g) in THF (250 ml) was added and the resulting reaction mass was stirred for 2-3 Hrs. The reaction mixture was acidified with Aq hydrochloric acid and the product was extracted with ethylacetate. The organic layer was washed with water and sodium chloride solution and concentrated. The concentrated reaction mass taken into ethyl acetate and to this solution 10 % Palladium on Charcoal was added and the reaction mass was stirred at room temperature in a hydrogen atmosphere. The reaction mass was filtered and the filtrate was extracted with sodium bicarbonate solution

The resulting Aq layer was washed with ethyl acetate, dichloromethane and acidified with Aq hydrochloric acid solution. The Aq layer was extracted with dichloromerthane and the organic layer was washed twice with DM water. The combined organic extracts were dried and concentrated. The concentrated mass was crystallized in toluene to give (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester. The above crude product was purified in Ethylacetate/ hexane to give (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester (130 g).

Example 2: Preparation of (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester

A solution of ethyl-(R)-mandelate (25 g) in tetrahydrofuran (375 ml) was cooled to -78 °C, and a solution of 1.6 M BuLi in hexane (87 ml) was added drop wise, and stirred for 1 hr .To this reaction mixture a solution of 3-[(tert-butyldimethylsilyl)oxy] pentanedioic anhydride (33.6 g) in THF (125 ml) was added, and the resulting reaction mass was stirred for 2-3 Hrs. The reaction mixture was acidified with Aq hydrochloric acid and the product was extracted with ethyl acetate. The organic layer was washed with water and sodium chloride solution. The organic layer was concentrated. The concentrated reaction mass taken into 100 ml methanol and to this 100 ml of DM water was added. To this sodium hydroxide (0.55 g) solution in DM water (50 ml) was added and the reaction mass was stirred at room temperature for 2-3 hrs. The reaction mass was concentrated. To the concentrate a mixture of DM water and dichloromethane was added and acidified with Aq hydrochloric acid solution. The Aq layer was extracted with dichloromethane and the organic layer was washed twice with DM water. The combined organic extracts were dried and concentrated. The concentrated mass was crystallized in toluene to give (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester. The above crude product was purified in Ethyl acetate/ hexane to give (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester (45.0 g).

Example 3: Preparation of (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester

A solution of Trityl-(R)-mandelate (25 g) in tetrahydrofuran (375 ml) was cooled to -78 °C, and a solution of 1.6 M BuLi in hexane (40 ml) was added drop wise, and the reaction mixture was stirred for 1 hr. To the reaction mixture a solution of 3-[(tert-butyldimethylsilyl)oxy] pentanedioic anhydride (15.5 g) in THF (125 ml) was added, and the resulting reaction mass was stirred for 2-3 Hrs. The reaction mixture was acidified with Aq hydrochloric acid and the product was extracted with ethyl acetate. The organic layer was washed with water and sodium chloride solution. The organic layer was concentrated. Concentrated reaction mass taken into 100 ml methanol and to this 100 ml DM water added. To this Aq hydrochloric acid solution (50 ml) was added and the reaction mass was stirred at room temperature for 2-3 hrs. The reaction mass was concentrated. To the concentrate a mixture of DM water and dichloromethane was added, Stirred and separated the layers. The Aq layer was extracted with dichloromethane and the organic layer was washed twice with DM water. The combined organic extracts were dried and concentrated. The concentrated mass was crystallized in toluene to give (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester. The above crude product was purified in Ethyl acetate/ hexane to give (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester (22.0 g).

Example 4: Preparation of Hydrogen (3R)-1-Methyl 3-[(tert-Butyldimethylsilyl)-oxy] pentanedioate

To an ice cold solution of sodium methoxide (80 g) and methanol (300 ml) a solution of (3R)-3-[(tert-Butyldimethylsilyl) oxy] pentanedioic acid, 1-[(R)-Mandelic acid] Ester (100 g) in 150 ml methanol was added drop wise at 0-5 °C. Stirred the reaction mixture for 1-3 hr and the mixture was poured into the mixture of ~ 35 % Aq HC1 (140 ml), Water (500 ml), Dichloromethane (1000 ml). To the organic layer DM water added and pH was adjusted to ~ 6.5 with sodium bicarbonate solution. The organic layer was washed with water, dried the organic layer over sodium sulphate and concentrated to give Hydrogen (3R)-1-Methyl 3-[(tert-Butyldimethylsilyl)-oxy] pentanedioate (70 g).

Example 5: Preparation of Cyclohexylamine salt of Hydrogen (3R)-l-methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate

To the solution of Hydrogen-(3R)-l-methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (50.0 g) in hexane (375 ml), a solution of cyclohexylamine amine (18 g) in hexane (125 ml) was added drop wise over 20 min. Reaction mixture was Stirred for 1-3 hr. The solid was filtered and washed with hexane. Solid was dried to give Cyclohexylamine salt of Hydrogen-(3R)-l-methyl 3-[(tert-butyldimethylsilyl)-oxy]pentanedioate (63 g)

Example 6: Preparation of t-butyl amine salt of Hydrogen (3R)-l-methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate

To a solution of Hydrogen-(3R)-l-methyl 3-[(tert-butyldimethylsilyl)-oxy]
pentanedioate (50.0 g) in hexane (375 ml), a solution of t-butyl amine (13.2 g) in hexane (125 ml) was added drop wise over 20 min. Reaction mixture was stirred for 1-3 hr. The reaction mixture was filtered and washed with hexane. The obtained solid was dried to give t-butyl amine salt of Hydrogen-(3R)-l-methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (57.5 g)

Example 7: Preparation of Benzyl amine salt of Hydrogen (3R)-l-methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate

To a solution of Hydrogen-(3R)-l -methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (50.0 g) in hexane (375 ml), a solution of benzyl amine (19.4 g) in hexane (125 ml) was added drop wise over 20 min. Reaction mixture was stirred for 1-3 hr. The reaction mixture was filtered and washed with hexane. The obtained solid was dried to give benzyl amine salt of Hydrogen-(3R)-l-methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (63 g)

Example 8: Preparation of Hydrogen (3R)-l-methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate

To cyclohexylamine salt of Hydrogen-(3R)-l-methyl-3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (63 g), mixture of DM water and dichloromethane was added, cooled and acidified with Aq HC1 solution at 15-20 °C. The reaction mass was stirred and layers were separated. The organic layer was washed thrice with DM water, dried the organic layer over sodium sulphate and concentrated to give Hydrogen-(3R)-l-Methyl-3-[(tert-Butyldimethylsilyl)-oxy] pentanedioate (46 g).

Example 9: Preparation of Methyl (3R)-3-(t-butyldimethylsiIyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoate

A solution of Hydrogen-(3R)-l-Methyl 3-[(tert-Butyldimethylsilyl)-oxy] pentanedioate (25 g), triethylamine (12.0 g) in hexane was cooled to -40 °C, and to this ethylchlorocarbonate (11.0 g) was added drop wise. The reaction mass was stirred for 1-3 hr to give anhydride. In another flask a suspension of methyltriphenyl phosphonium bromide(71 g) in THF was cooled to 0°C, and to this a solution of 1.6 M BuLi solution( 120 ml) in hexane was added drop wise over 60 min. The mixture was cooled to -78 °C and the anhydride obtained in above was added drop wise. The resulting reaction mass was stirred for 1-3 hr. The reaction mass was poured into DM water. The reaction mass was stirred and layers were separated. Organic layer was concentrated under u/v at 40-45 °C. The concentrated mass was taken into diisopropyl ether, washed the diisopropyl ether with DM water and brine solution. The organic layer was dried and concentrated to give

Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenyl phosphoranylidenehexanate (55 g)

Example 10: Preparation of Methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl] - (3R)-3hydroxy-5-oxo-(E)-6-heptenate (Rosuvastatin intermediate)

A solution of 25 g 4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino)-5-pyrimidine carbaldehyde, 55 g Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoate and acetonitrile was refluxed for about 20 hrs. The reaction mass was concentrated under vacuum. To this cyclohexane was added. The reaction mass was stirred and filtered. Filtrate was Concentrated under u/v and taken into acetonitrile, cooled to 0 °C. To this solution of hydrogen fluoride (100 ml) was added drop wise in acetonitrile under ice cooling, and the mixture was warmed to room temperature and stirred for 1-3 hrs. To this a mixture of DM water and dichloromethane was added and neutralized with sodium bicarbonate solution. The reaction mixture was stirred and layers were separated. The organic layer was washed with water and brine solution. To the concentrated IPA was added, stirred, and filtered. The obtained solid was washed IPE and dried to give Methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl] - (3R)-3-hydroxy-5-oxo-(E)-6-heptenate(32 g).

Example 11: Preparation of Methyl (E)-7-[2-cyclopropyl-4-(4-flurophenyl)-3-quinolinyl]- 3-hydroxy-5-oxo-6-heptenate (Pitavastatin intermediate)

A solution of 20 g 2-cyclopropyl-4-(4-fluorophenyl)-quinolyl-3-carboxaldehyde, 55 g Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoate and acetonitrile was refluxed for about 20 hrs. The reaction mass was concentrated under vacuum. To this cyclohexane was added, Stirred and filtered. The filtrate was concentrated under u/v. The concentrated mass was taken into acetonitrile and cooled to 0 °C. To this a solution of hydrogen fluoride (100 ml) in acetonitrile was added under ice cooling, and the mixture was warmed to room temperature and stirred for 1 -3 hrs. To this a mixture of DM water and dichloromethane was added and neutralized with sodium bicarbonate solution. The reaction mass was stirred and layers were separated. The organic layer was washed with water and brine solution and concentrated. To this concentrated IPA was added, stirred, and filtered. The obtained solid was washed with hexane and dried to give Methyl (E)-7-[2-cyclopropyl-4-(4-flurophenyl)-3-quinolinyl]-3-hydroxy-5-oxo-6-heptenate (27 g).

Example 12: Preparation of Methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methyl sulfonylamino)-pyrimidin-5-yl] - (3R)-3-hydroxy-5-oxo-(E)-6-heptenate (Rosuvastatin intermediate)

To a solution of hydrogen (3R)-1-methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (50.0 g) in hexane (375 ml), cyclohexylamine (18 g) in hexane (125 ml) solution was added drop wise over 20 min. The reaction mixture was stirred, filtered and washed with hexane. The obtained solid was dried to give Cyclohexylamine salt. To the obtained Cyclohexylamine salt a mixture of DM water and dichloromethane added, cooled and acidified with Aq HC1 solution at 15-20 °C. The layers are separated and organic layer was washed thrice with DM water, and dried to give Hydrogen (3R)-1 -Methyl 3-[(tert-Butyldimethylsilyl)-oxy] pentanedioate. The solution of hydrogen (3R)-1-Methyl 3-[(tert-Butyldimethylsilyl)-oxy] pentanedioate (25 g), triethylamine (12.0 g) in hexane was cooled to -40°C, and to this ethyl chlorocarbonate (11.0 g) was added drop wise and stirred for 1-3 hr to give anhydride. A suspension of methyltriphenyl phosphonium bromide(71 g) in THF was cooled to 0 °C, and 1.6 M BuLi solution( 120 ml) in hexane was added drop wise over 60 min. The mixture was cooled to -78 °C and the anhydride obtained in above was added drop wise. The resulting reaction mass was stirred for 1-3 hr. The reaction mass was poured into DM water, stirred and layers were separated. The organic layer was Concentrated under u/v at 40-45 °C. The concentrated mass was taken into diisopropyl ether, washed with DM water and brine solution. The organic layer was concentrated to give Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoate as residue. To this residue 25 g 4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino)-5-pyrimidine carbaldehyde and acetonitrile (100 ml) was added and refluxed for about 20 hrs. The reaction mass was concentrated under vacuum. To the concentrated mass cyclohexane was added, stirred and filtered. The concentrated mass was taken into acetonitrile and cooled to 0 °C. To this a solution of hydrogen fluoride (100 ml) in acetonitrile was added under ice cooling, and the mixture was warmed to room temperature and stirred for 1-3 hrs. To the reaction mixture a mixture of DM water and dichloromethane was added and neutralized with sodium bicarbonate solution. The layers were separated and the organic layer was washed with water and brine solution. To the concentrated IPA was added, stirred, and filtered. The obtained solid was washed with IPE and dried to give Methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl] - (3R)-3hydroxy-5-oxo-(E)-6-heptenate (34 g).

Example 13: Preparation of Methyl (E)-7-[2-cyclopropyl-4-(4-flurophenyl)-3-quinolinyl]- 3-hydroxy-5-oxo -6-heptenate (Pitavastatin intermediate)

To a solution of hydrogen (3R)-1-methyl 3-[(tert-butyldimethylsilyl)-oxy] pentanedioate (50.0 g) in hexane (375 ml), cyclohexyl amine (18 g) in hexane (125 ml) solution was added drop wise over 20 min. The reaction mixture was for 1-3 hr. The reaction mass was filtered and washed with hexane. The solid was dried to give Cyclohexylamine salt. To the obtained cyclohexyl amine salt a mixture of DM water and dichloromethane was added, cooled and acidified with Aq HC1 solution at 15-20 °C. The layers were separated and the organic layer was washed thrice with DM water. The organic layer was dried over sodium sulphate and concentrated to give residue. The obtained residue and a solution of triethylamine (12.0 g) in hexane was cooled to -40 °C, and to this ethylchlorocarbonate (11.0 g) was added drop wise and stirred for 1-3 hr to give anhydride. A suspension of methyltriphenyl phosphonium bromide(71 g) in THF was cooled to 0 °C, and 1.6 M BuLi solution( 120 ml) in hexane was added drop wise over 60 min. The mixture was cooled to -78 °C and to this above obtained anhydride was added drop wise. The resulting reaction mass was stirred for 1-3 hr. The reaction mass was poured into DM water, stirred and layers were separated. The organic layer was concentrated under u/v at 40-45 °C. The concentrated mass was taken into diisopropyl ether, washed with DM water and brine solution. The organic layer was dried and concentrated to give Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoate. To this residue 2-cyclopropyl-4-(4-fluorophenyl)-quinolyl-3-carboxaldehyde (20 g) & acetonitrile was added and refluxed for about 15-24 hrs. The reaction mass was concentrated under vacuum. To the reaction mas cyclohexane was added, stirred and filtered. The obtained concentrate was taken into acetonitrile and cooled to 0 °C. To this a solution of hydrogen fluoride (100 ml) in acetonitrile was added under ice cooling, and the mixture was warmed to room temperature and stirred for 1-3 hrs. To the reaction mixture a solution of DM water and dichloromethane was added and neutralized with sodium bicarbonate solution. The layers were separated and the organic layer was washed with water and brine solution. To the concentrated IPA was added, stirred, and filtered. The obtained solid was washed with hexane and dried to give Methyl (E)-7-[2-cyclopropyl-4-(4-flurophenyl)-3-quinolinyl]-3-hydroxy-5-oxo-6-heptenate(29g).

We claim:

1. A process for the preparation of compounds of Formulae-IXa or IXb

wherein P is hydroxy protecting group; R2 is C1-C5 alkyl or substituted C1-C5
alkyl group; R3, R4 and R5, independently, are selected from C6-C10 aryl group,
preferably phenyl group or substituted phenyl groups; Alk is alkyl preferably C1-
C5 alkyl comprising the steps of:

a) ring opening of the compound of Formula-II by using the compound of
Formula-Ill in the presence of chiral auxiliary and deprotecting to produce
compound of Formula-IV, wherein P is hydroxy protecting group; Ra is alkyl,
aryl or optionally substituted aryl and Rb is hydrogen, optionally substituted
alkyl, or optionally substituted aryl alkyl;

Formula-II Formula-IV

b) reacting the compound of Formula-IV with Alkalimetal alkoxide to get the
compound of Formula-V, wherein R2 is C1-C5 alkyl or substituted C1-C5 alkyl
group;

Formula-V

c) optionally purifying the compound of Formula-V by using a base to obtain
pure compound of Formula-V;

Formula-V

d) converting the compound of Formula-V into compound of Formula- VIII,
wherein Y is an alkoxy or alkyl group of C1 to C5 carbons; and

e) converting the compound of Formula-VIII into compound of Formula-IXa or Formula-IXb by reacting with triarylphosphonium alkyl halide or dialkylmethylphosphonate respectively.

2. The process according to claim 1, wherein chiral auxiliary used for the ring opening of the compound of Formula-II is selected from N-pyrrolidinyl norephedrine, (1R, 2S)-N-methylephedrine, ephedrine, N,N-dibenzylnorephedrine, (lR,2R)-pseudoephedrine, (1S,2S)-N-methylpseudoephedrine and (1R, 2S)-N-piperidinyl norephedrine.

3. The process according to claim 1, wherein ring opening of the compound of Formula-II is carried out with compound of Formula-Ill, which is selected from benzyl(R)-mandelate, ethyl (R)-mandelate and Trityl (R)-mandelate.

4. The process according to claim 1, wherein alkalimetal alkoxide used in step-b is selected from sodiumalkoxide or potassiumalkoxide.

5. The process according to claim 1, wherein the compound of Formula-V is purified in the presence of chiral or non-chiral base.

6. The process according to claim 5, wherein non-chiral base is selected from cyclohexylamine, tert-butylamine, cyclopropylamine, cyclopentylamine, benzyl amine, Dicyclohexyl amine, 2-ethyl hexylamine, ethanolamine, methylamine and ethylene amine.

7. The process according to claim 1, wherein the conversion of compound of formula-V to compound of formula VIII is carried out by reacting the compound of formula-V with ethylchlorocarbonate or pivaloyl chloride.

8. The process according to claim 1, wherein the triarylphosphonium alkyl halide
used in the preparation of Formula-IXa is methyltriphenyl phosphonium bromide.

9. The process according to any of the preceding claims, wherein the compounds of
Formulae-IXa or IXb is further converted into HMG-CoA reductase inhibitors.

10. The process according to claim 9, wherein the HMG-CoA reductase inhibitor is
selected from Rosuvastatin or Pitavastatin.

11. The compound of Formula-VI

Formula-VI wherein the base is a non-chiral base; and P is hydroxy protecting group and R.2 is C1-C5 alkyl or substituted C1-C5 alkyl group.

12. A process for the preparation of HMG-CoA reductase inhibitors intermediate of
the following formula-XI

Formula-XI wherein R is Rosuvastatin or Pitavastatin residue of formula

and R2 is C1-C5 alkyl or substituted C1-C5 alkyl group comprising the steps of:

a) reacting crude compound of formula-V with a non-chiral base to obtain a salt
of formula-VI;

wherein P is hydroxy protecting group and R2 is defined as above
b) reacting compound of Formula-VI with an acid to obtain pure compound of
formula-V;

c) converting the compound of formula-V into compound of formula-VIII;

Formula-V Formula-VIII
wherein Y is an alkoxy or alkyl group of C1 to C5 carbons and P, R2 is defined as above

d) converting the compound of formula VIII into compound of formula-IXa;
Formula-VIII Formula-IXa
wherein Y, P, R2, and R5 is defined as above and R3, R4 and R5, independently, are selected from C6-C10 aryl group, preferably phenyl group or substituted phenyl groups

e) converting compound of formula-IXa into compound of formula-X by
reacting with an aldehyde compound of Formula R-CHO wherein R, P, R2,
R3, R4 and R5 are as defined above; and

Formula-IXa Formula-X

f) deprotecting the compound of Formula-X into compound of Formula-XL

13. The process according to claim 12, wherein the compound of Formula-XI is further converted into Rosuvastatin calcium.

14. The process according to claim 12, wherein the compound of Formula-XI is further converted into Pitavastatin calcium.

15. The process according to claim 12, wherein the compound of Formula-XI is prepared from the compound of Formula-V without isolating the intermediate compounds of Formulae VI, VIII, IXa and X.