This application claims priority to Indian patent application No. 1007/CHE/2010 filed on April 12, 2010

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and their intermediates thereof represented by the following formula-I

wherein R represents a residue of HMG-CoA reductase inhibitor; M represents hydrogen or pharmaceutically acceptable salts like sodium, potassium, magnesium and calcium.

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.
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.

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.

Pitavastatin 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.

US Pat No. US 6,844,437 discloses process for the preparation of Rosuvastatin by the
condensation of diphenyl[4-(4-fluorophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl] phosphine oxide with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl}acetate in presence of a base in a suitable solvent to provide tertiary butyl ester compound of Rosuvastatin which is further converted into free acid or salt by conventional methods.

US Pat No. US 7,312,329 discloses another process for the preparation of Rosuvastatin by the condensation of Wittig reagent like triphenyl[4-(4-fiurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl] phosphonium bromide or other reagent with tert-butyl 2-[(4R,6S)-6-formyl- 2,2-dimethy 1-1,3 -dioxan-4-yl} acetate in a suitable solvent in presence of a base to provide tertiary butyl ester compound of Rosuvastatin which is further converted into free acid or salt by conventional methods.
WO 1995011898 discloses process for the preparation of Pitavastatin by the condensation
of {2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}methyltriphenylphosphonium
bromide with t-butyl (3R,5S)-6-oxo-3,5-isopropylidenedioxy-6- heptenoate in a suitable solvent in presence of a base to provide tertiary butyl ester compound of Pitavastatin which is further converted into free acid or salt by conventional methods.

Above mentioned processes involves the usage of the base for the preparation of diol protected ester intermediate compound, which tends to hydrolysis of ester group during the reaction hence leads to the formation of impurities.

Thus the present invention provides process for the preparation of HMG-CoA reductase inhibitors by avoiding the impurities formed by the ester hydrolysis.

OBJECT AND SUMMARY OF THE INVENTION:

The principle object of the present invention is to provide an improved process for the preparation of an intermediate compound of Formula-II

wherein R is residue of HMG-CoA reductase inhibitor as defined above, R1 and R2 are alcohol protecting groups, or R1 and R2 taken together is a 1,3-diol protecting group, and R is a carboxylic acid protecting group.

Another object of the present invention is to provide, an improved process for the preparation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors from the intermediate of formula II.

One aspect of the present invention provides, a process for the preparation of compound of formula-II comprising: reacting either of compounds of Formula-III(a), 111(b) or III(c) having the structures

wherein X is any halogen and Alk is alkyl group; with an aldehyde compound of the Formula-IV

wherein R1, R2 and R3 are as defined above, in a solvent without using the base.

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

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides an improved process for the preparation of compound of Formula-II, which is used an intermediate in the preparation of HMG-CoA reductase inhibitors, having the following structure

wherein R is a residue of HMG-CoA reductase inhibitor selected from

and R1 and R2 are alcohol protecting groups, or R1 and R2 taken together is a 1,3-diol protecting group, and R is a carboxylic acid protecting group.

In one aspect the present invention provides, an improved process for the preparation of compound of formula-II comprising reacting either of compounds of Formula-III(a), 111(b) or III(c) having the structures

wherein X is any halogen and Alk is alkyl group; with an aldehyde compound of the Formula-IV

wherein R1, R2 and R3 are as defined above, in a solvent without using the base.

In one embodiment of the present invention, R is Rosuvastatin residue having the following structure

In another embodiment of the present invention, R is Pravastatin residue having the following structure

In another embodiment of the present invention, the compounds of formulae 111(a), 111(b) or III(c) is reacted with compound of formula-IV optionally in presence of salts such as Potassium iodide, Sodium iodide, Sodium bromide, Sodium chloride, preferably Potassium iodide.

In another embodiment of the present invention, the compounds of formulae 111(a), IH(b) or III(c) is reacted with compound of formula-IV optionally in presence of Phase transfer catalyst such as tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, crown ethers, preferably tetrabutyl ammonium bromide.

In another embodiment of the present invention, the compounds of formulae III (a), III (b) or III(c) is reacted with compound of formula-IV in presence of polar solvents such as acetonitrile, water, acetone and dimethyl acetamide.

In one more embodiment of the present invention, process for the preparation of diol protected ester intermediate compound of Rosuvastatin is as depicted in scheme-I.
SCHEME-I

In one more embodiment of the present invention, diol protected ester intermediate compound of Rosuvastatin is further converted into Rosuvastatin calcium by conventional methods.

In one more embodiment of the present invention, process for the preparation of diol protected ester intermediate compound of Pitavastatin is as depicted in scheme-II

SCHEME-II

In one more embodiment of the present invention, diol protected ester intermediate compound of Pitavastatin is further converted into Pitavastatin calcium by conventional methods.

In another aspect the present invention provides, a process for the preparation of compound of formula-I from compound of formula-II by conventional methods. For example the process is as given in scheme-Ill.

SCHEME-III

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:

Triphenyl{4-(4-fluorophenyl)-6-isopropyl-2-[(2-n-methyl-n-methylsulfonyl)amino] pyrimidine-5-yl-methyl]phosphine bromide (lOg), tert-butyl-(3R, 5S)-6-oxo-3, 5-isopropylidene-3,5-dihydroxy hexonate ( 3.9g), potassium iodide (O.lg) was added to 50 ml acetonitrile and reaction mass was refluxed for 2 days. Progress of reaction was monitored by TLC and solvent was removed from the reaction mass under reduced pressure. The obtained residue was stirred with isopropyl alcohol (40 ml), filtered &dried to give t-butyl-(+)7-[4-(4-fluorophenyl)-6-isopropyl-2-(n-methyl, n-methylsulphonylamino)pyrimidine-5-yl]- (3R, 5S)-dioxane-(E)-6-heptane ( 5g)

Example 2:

Triphenyl{4-(4-fluorophenyl)-6-isopropyl-2-[(2-n-methyl-n-methylsulfonyl) amino]
pyrimidine-5-yl-methyl]phosphine bromide (5g), tert-butyl-(3R, 5S)-6-oxo-3, 5-isopropylidene-3,5-dihydroxy hexonate ( 1.9g) , potassium iodide (lg) was added to 50 ml water and reaction mass was refluxed for 2 days. Progress of reaction was monitored by TLC and solvent was removed from the reaction mass under reduced pressure. The obtained residue was stirred with isopropyl alcohol (40 ml), filtered & dried to give t-butyl-(+)7-[4-(4-fluorophenyl)-6-isopropyl-2-(n-methyl, n-methylsulphonylamino)pyrimidine-5-yl]- (3R, 5S)-dioxane-(E)-6-heptane (2.5g).

Example 3:

Triphenyl{4-(4-fluorophenyl)-6-isopropyl-2-[(2-n-methyl-n-methylsulfonyl)amino]
pyrimidine-5-yl-methyl]phosphine bromide (5g), tert-butyl-(3R, 5S)-6-oxo-3, 5-
isopropylidene-3,5-dihydroxy hexonate ( 1.9g) , was added to 50 ml acetone and
reaction mass was refluxed for 4 days. Progress of reaction was monitored by TLC. The reaction mass was cooled, filtered & dried to give t-butyl-(+) 7-[4-(4-fluorophenyl)-6-isopropyl-2-(n-methyl, n-methylsulphonylamino) pyrimidine-5-yl]- (3R, 5S)-dioxane-(E)-6-heptane (3.5g).

Example 4:

Triphenyl{4-(4-fluorophenyl)-6-isopropyl-2-[(2-n-methyl-n-methylsulfonyl)amino]
pyrimidine-5-yl-methyl]phosphine bromide (5g), tert-butyl-(3R, 5S)-6-oxo-3, 5-
isopropylidene-3,5-dihydroxy hexonate ( 1.9g) was added to 50 ml dimethyl acetamide
and reaction mass was refluxed for 4 days. Progress of reaction was monitored by TLC
and the solvent was removed from the reaction mass under reduced pressure. The
obtained residue was stirred with isopropyl alcohol (40 ml), filtered & dried to give t-
butyl-(+)7-[4-(4-fluorophenyl)-6-isopropyl-2-(n-methyl, n-methylsulphonyl
amino)pyrimidine-5-yl]- (3R, 5S)-dioxane-(E)-6-heptane ( 2.5g).

We claim:

1. A process for the preparation of HMG-CoA reductase inhibitor intermediate of general formula-II,

wherein, R is a residue of HMG-CoA reductase inhibitors of formulae

and R1 and R2 are alcohol protecting groups, or R1 and R2 taken together is a 1,3-diol protecting group, and R is a carboxylic acid protecting group, comprising reacting either of compounds of Formula-III(a), 111(b) or III(c) having the structures

wherein X is any halogen;
with an aldehyde compound of the Formula-IV

wherein R1, R2and R3 are as defined above, in a solvent without using base.

2. The process according to claim 1, wherein the solvent is polar solvent.

3. The process according to claim 2, wherein the polar solvent is acetonitrile, water, acetone or dimethyl acetamide.

4. The process according to claim 1, wherein R is of formula

5. The process according to claim 1, wherein R is of formula

6. The process according to claim 1, wherein the HMG-CoA reductase inhibitor intermediate of general formula-II is further converted into HMG-CoA reductase inhibitors.

7. The process according to claim 6, wherein the HMG-CoA reductase inhibitor is Rosuvastatin.

8. The process according to claim 6, wherein the HMG-CoA reductase inhibitor is Pitavastatin.

9. The process for the preparation of HMG-CoA reductase inhibitor intermediate of general formula-II as herein described in the specification and examples.