This application claims priority to Indian patent application No. 2291/CHE/2013 filed on May 27, 2013 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to a novel process for the preparation of intermediates of HMG-CoA reductase inhibitors and further conversion to HMG-CoA reductase inhibitors.

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) are represented by the following general Formula-I,
OH OH O
IT ^^ ^~^ ^^ OM
Formula-I wherein R is a residue of HMG-CoA reductase inhibitor; and 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 used for the treatment of hyperlipidemia.

- F
S=^ OH OH O
N^w^^v^v^0- Ca++
H3CNAN"VCH3
0=S=0 CH3
CH3
Formula-A Rosuvastatin calcium is marketed under the proprietary name CRESTOR for treatment of mammals such as humans and is administrated as a daily dosage form of 5 mg, 10 mg, 20 mg and 40 mg. Rosuvastatin and its pharmaceutically acceptable salts are disclosed in European patent publication EP 0521471, which also discloses a 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 (pravastatin calcium) is an HMG-CoA reductase inhibitor used for the treatment of hyperlipidemia.
F
^p OH OH O
Formula-B Pravastatin and its pharmaceutically acceptable salts are disclosed in European patent publication EP 0304063, which also discloses a process for the preparation of pitavastatin. 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-phosphoranylidenehexanate. PCT publication No. WO 03/087112 discloses the synthesis of rosuvastatin from intermediate, (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxo-hexanate. US 5,117,039 discloses a process for the preparation of (3R)-3-[(tert-butyldimethylsilyl) oxy] pentanedioic acid, l-[(R)-mandelic acid] ester by the ring opening of 3-[(tert-butyldimethylsilyl)oxy] pentanedioic anhydride using benzyl D-mandelate. US 20090076292 discloses a process for the preparation of rosuvastatin by using the intermediates 3(R)-3(tert-butyldimethylsilyloxy)-5-oxo-6-triphenyl-phosphoranylidene hexanate and (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5-oxo-hexanate. These intermediates are prepared from a 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.

The present invention provides an improved process for the preparation of compounds of Formula-II, which are important intermediates in the preparation of HMG-CoA reductase inhibitors
R2 O OX O
^^ ^^ ^^ OR,
R4
Formula-II wherein X is hydrogen or hydroxy protecting group, Ri is carboxyl protecting group and R2, R3 and R4 are independently selected from substituted or unsubstituted C6-C10 aryl group.

OBJECT AND SUMMARY OF THE INVENTION: The present invention provides an improved process for the preparation of compounds of Formula-II, which are important intermediates in the preparation of HMG-CoA reductase inhibitors
R2 o ox o
^^ \x" \^ ^0R]
R4 Formula-II wherein X is hydrogen or hydroxy protecting group, Ri is carboxyl protecting group and R2, R3 and R4 are independently selected from substituted or unsubstituted C6-C10 aryl group. One aspect of the present invention provides, an improved process for the preparation of compounds of Formula-II comprising the steps of:
a) reacting a compound of Formula-Ill with dimethylformamide dimethylacetal in the presence of a base to get a compound of Formula-IV,
o ox o o ox o
HO ^^ ^^ NH2 HO ^^ ^^ OR,
Formula-Ill Formula-IV wherein X is hydrogen or hydroxy protecting group and Ri is carboxyl protecting group;
b) reacting the compound of formula-IV with alkyl chloroformate in the presence of a base to get a compound of Formula-V,

o ox o ° o ox o
FKT ^^^^^^^OR, o o ^-^ ^-^ OR!
Formula-IV Formula-V wherein X and Ri are defined above and Alk represents C1-C4 alkyl; and c) converting the compound of Formula-V into a compound of Formula-II,
0 o ox o R2 o ox o
"vwA—-"-JNXAA.,
Formula-V ^ Formula-II wherein X is hydrogen or hydroxy protecting group, Ri is carboxyl protecting group and R2, R3 and R4 are independently selected from substituted or unsubstituted C6-C10 aryl group; wherein compounds of Formula-IV and Formula-V are not isolated. Another aspect of the present invention provides an improved process for the purification of compound of Formula-II. Another aspect of the present invention provides further conversion of a compound of Formula-II into HMG-CoA reductase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides an improved process for preparation of compounds of Formula-II, which are important intermediates in the preparation of HMG-CoA reductase inhibitors,
R2 O OX O
— \^ \/^ ^OR!
R4
Formula-II wherein X is hydrogen or hydroxy protecting group, Ri is carboxyl protecting group and R2, R3 and R» are independently selected from substituted or unsubstituted C6-C10 aryl group. The invention further provides a process for conversion of compounds of Formula-II to HMG-CoA reductase inhibitors. The Ri of Formula-II is carboxyl protecting group and X is hydrogen or hydroxy protecting group. Suitable protecting groups are available in the literature and well familiar to the person skilled in the art. Examples of suitable protecting groups can be found in standard works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry," Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," Third edition, Wiley, New York 1999; "The Peptides," Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; "Methoden der organischen Chemie", Houben-Weyl, 4th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974; H.D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine," Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate," Georg Thieme Verlag, Stuttgart 1974.

Suitable hydroxy protecting groups include, without limitation, alkyl, aryl, arylalkyl, trialkylsilyl and diarylalkylsilyl. Preferred hydroxyl protecting groups include trialkylsilyl and diarylalkylslyl. Especially preferred protecting groups are trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or diphenyl(tert-butyl)silyl group. One aspect of the present invention provides, an improved process for the preparation of compounds of Formula-II comprising the steps of:

a) reacting a compound of Formula-Ill with dimethylformamide dimethylacetal in the presence of a base to get a compound of Formula-IV,
o ox o o ox o
HO ^"^ ^~^ NH2 HO ^^ ^^ ORj
Formula-Ill Formula-IV wherein X is hydrogen or hydroxy protecting group and Ri is carboxyl protecting group;

b) reacting the compound of formula-IV with alkyl chloroformate in presence of a base to get a compound of Formula-V,
o ox o ° o ox o
.^U. —. A AAA.
Formula-IV Formula-V wherein X and Ri are defined above and Alk represents C1-C4 alkyl; and

c) converting the compound of Formula-V into a compound of Formula-II,
5 o ox 0 R2 o ox o
"\A-^AAOT|—--fvXAA-,
Formula-V ^ Formula-II wherein X is hydrogen or hydroxy protecting group, Ri is carboxyl protecting group and R2, R3 and R4 are independently selected from substituted or unsubstituted C6-C10 aryl group, and wherein compounds of Formula-IV and Formula-V are not isolated. In one embodiment of the present invention, the compound of Formula-Ill is converted into the compound of Formula-II without isolating the compounds of Formula-IV and Formula-V. Step a described above involves reacting a compound of Formula-Ill with dimethylformamide dimethylacetal in the presence of a base. Under mild basic conditions dimethylformamide dimethylacetal converts the amide to a reactive acylformamidine, which then reacts with alcohols to form the corresponding ester, while it suppresses the esterification of the free carboxylic acid group. In some embodiments, the base used in this reaction may be selected from alkali metal alkoxides like sodium methoxide or potassium methoxide, preferably sodium methoxide. Preferred compounds of Formula-Ill used in this invention can be a compound of Formula-Ill, wherein X is tert-butyl dimethylsilyloxy protecting group.

Step b described above involves reaction of a compound of Formula-IV with alkyl chloroformate in the presence of a base. In some embodiments, the alkyl chloroformate used in this reaction may be selected from ethyl chloroformate and methyl chloroformate, preferably methyl chloroformate. In some embodiments, the base used in this reaction may be selected from organic amine bases like triethylamine. A preferred compound of Formula-IV used in this invention can be a compound of Formula-IV, wherein X is tert-butyl dimethylsilyloxy protecting group and Ri is Methyl. Step c described above involves conversion of a compound of Formula-V into a compound of Formula-II by reacting the compound of Formula-V with triarylphosphonium alkyl halide in presence of a base. Suitable triarylphosphonium alkyl halides include triarylphosphonium methyl halide, preferably triphenylphosphonium methyl bromide. In one embodiment, the base used in this step may be selected from organolithium bases such as phenyllithium or n-butyllithium. A preferred compound of Formula-V used in this invention can be a compound of Formula-V, wherein X is tert-butyl dimethylsilyloxy protecting group, Ri is Methyl and R2, R3 and R4 are phenyl.

Another aspect of the present invention is to provide purification of a compound of Formula-II by using hydrocarbon solvents. In one embodiment of the present invention, hydrocarbon solvents are selected from hexanes and heptanes. Preferably cyclohexane is used. In an embodiment of the present invention, a hydrocarbon solvent, preferably selected from hexanes and heptanes, most preferably cyclohexane, is added to the compound of Formula-II (wherein X is tert-butyl dimethylsilyloxy protecting group, Ri is Methyl and R2, R3 and R4 are phenyl) and the temperature is raised to about 40-65° C, preferably about 45-60° C. The reaction mass is cooled to about 10-30° C, preferably about 15-25° C. The solid is filtered and dried to get pure compound of Formula-II. The compound of Formula-Ill is prepared by the prior art process for example as disclosed in our co-pending Indian patent application IN 4102/CHE/2011. The compound of Formula-II is further converted into HMG-CoA reductase inhibitors of Formula-I by the conventional methods as disclosed in US RE37,314, US 5,260,440, WO 2003087112, US 2007037979 and CN 100506796.

For example the compound of Formula-II is further converted into rosuvastatin calcium by the following procedure.
F
R2 O OX O K^ \^ O OX O
R_L X X X tAr^o N^^^AA-J'-OR,
** Fonnula-II °:?=° CH3 0=S=0 CH3
CH3 CH3
Deprotection I"
(Tj ^r o OH o
J^^J^SSSA^ ^OR, Reduction H3C.XIAXI«L,CH3
II I "* N N T^
H3C-N'^N,^YCH3 0=S=0 CH3
0=S=0 CH3 CH3
CH3
Hydrolysis Salt formation
Rosuvastatin Calcium

In another example, the compound of Formula-II is further converted into pravastatin calcium by the following procedure.

X F
«2 O OX O |A| ,-A*.
i l I 1 v Q
R3—P-^^\ ^\ ^\ + T T^ P. ox P
i, ill \\ \ I '
^ Formula-II V-^-./^ \^ *1\_
Deprotection
y o" 2H ° ^r o OH o
/\A^/^>A./\A„ Reduction I - II T II
(i ^r ^r ^^ ^^ ^-^ OR, -« /vV^AAAnn
Hydrolysis Salt formation
Pravastatin Calcium 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.

Experimental procedure: Example 1: Process for the preparation of compound of Formula-II (Ri=Me, X=OTBDMS, R2, Rs and R4= phenyl) (S)-3-(tert-butyl dimethylsilyloxy) glutaric acid monoamide (100 g) was dissolved in methanol (650 ml) under nitrogen atmosphere. To this solution, sodium methoxide solution (~ 25% in methanol) (22.73 gm) was added under cooling. The reaction mass was heated to ~ 25° C, and to this dimethyl formamide dimethylacetal (100 g) was slowly added. The mixture was stirred and cooled to 8° C. To the reaction mass, a stirred mixture of toluene, water and diluted phosphoric acid solution was added. The layers were separated. The organic phase was washed thrice with water, and anhydrous sodium sulphate was added to the organic layer. Sodium sulphate was filtered and washed with toluene. To the filtrate, triethylamine (43.94 gm) was added and cooled to -45° C. To this, methylchloroformate solution (40.0 g methylchloroformate diluted in 800 ml toluene) was slowly added and stirred for 6 hours. The reaction mixture was added to a mixture of tetrahydrofuran (950 ml), methyltriphenyl phosphonium bromide (361.8 gm) and n-Butyl lithium (62.5 gm) solution in hexanes at a temperature of -90 °C.

The reaction mass temperature was slowly raised to 30 °C and water (500 ml) was added. Layers were separated and the organic layer was concentrated until almost no solvents remained. To the concentrated organic layer, a mixture of tert-butylmethyl ether and cyclohexane was added. To this mixture, water was added and layers were separated. To the organic layer 10% sodium chloride solution was added, and the layers were separated. The organic layer was dried over sodium sulphate, and activated carbon and silica gel were added to the organic layer. The reaction mass was filtered through a Hyflo bed, and the filtrate was concentrated until almost no solvents remained. To the concentrated mass cyclohexane was added and heated to a temperature of 50° C. The reaction mass was cooled to 20° C, filtered and dried to yield the compound of Formula-II (Methyl (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidenehexanate).

We Claims:

1. A process for the preparation of a compound of Formula-II comprising the steps of:

a. reacting a compound of Formula-Ill with dimethylformamide dimethylacetal in the presence of a base to get a compound of Formula-IV,
o ox o o ox o
HO ^"^ ^~^ NH2 HO ^^ ^^ ORj
Formula-Ill Formula-IV wherein X is hydrogen or hydroxy protecting group and Ri is carboxyl protecting group;

b. reacting the compound of formula-IV with an alkyl chloroformate in the presence of a base to get a compound of Formula-V,
o ox o ° o ox o
HOT ^^ ^^ ^OR, O^ \T ^-^ ^^ OR,
Formula-IV Fonnula-V wherein X and Ri are as defined above and Alk represents C1-C4 alkyl; and

c. converting the compound of Formula-V into a compound of Formula-II,
0 O OX O |2 O OX O
Formula-V Formula-II wherein X is hydrogen or hydroxy protecting group, Ri is carboxyl protecting group and R2, R3 and R4 are independently selected from the group consisting of substituted and unsubstituted C6-C10 aryl groups; and wherein compounds of Formula-IV and Formula-V are not isolated.

2. The process according to claim 1, wherein the base used in step-a is an alkali metal alkoxide.

3. The process according to claim 1, wherein the alkyl chloroformate used in step b is selected from the group consisting of ethyl chloroformate and methyl chloroformate.

4. The process according to claim 1, wherein the base used in step b is an organic amine base.

5. The process according to claim 4, wherein the organic amine base is triethylamine.

6. A process for the purification of a compound of Formula-II
R2 O OX O
R4
Formula-II comprising:

a. adding a hydrocarbon solvent to the compound of Formula-II;

b. heating the mixture to a temperature from about 40° C to about 65° C;

c. cooling the mixture to a temperature from about 10° C to about 30° C; and

d. filtering and drying the mixture to obtain a purified compound of Formula-II, wherein X is hydrogen or hydroxy protecting group, Ri is carboxyl protecting group and R2, R3 and R4 are independently selected from the group consisting of substituted and unsubstituted C6-C10 aryl groups.

7. The process according to claim 6, wherein the hydrocarbon solvent is selected from the group consisting of hexanes and heptanes.

8. The process according to claims 1 to 7, further comprising converting the compound of Formula-II into an HMG-CoA reductase inhibitor.

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

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