Indian Patents. 217177:"PROCESS FOR THE PREPARATION OF METHYL ANALOGS OF SIMVASTATIN AS NOVEL HMG-CoA REDUCTASE INHIBITORS"

Title of Invention	"PROCESS FOR THE PREPARATION OF METHYL ANALOGS OF SIMVASTATIN AS NOVEL HMG-CoA REDUCTASE INHIBITORS"
Abstract	The present invention relates to a process for the synthesis of novel methyl analogs of simvastatin, which have the ability to inhibit the synthesis of cholesterol.

Full Text	The present invention relates to a process for the synthesis of novel methyl analogs of simvastatin, which have the ability to inhibit the synthesis of cholesterol. The compounds of the present invention hold promise for the treatment and prophylaxis of hypercholesterolemia and of various cardiac disorders. Hypercholesterolemia is a known primary risk factor for the progression of atherosclerosis. High serum cholesterol is regarded as a major risk factor for the development of ischaemic heart disease and there is, therefore, a need for drugs which have the effect of reducing the blood cholesterol levels. Over the past several years a number of structurally related anti-hypercholesterolemic agents acting by inhibition of HMG-CoA reductase have been developed and are now commercially available. The compounds have varied from the natural fermentation products, compactin of structural formula I (as shown in the accompanied drawings) and mevinolin of structural formula II (as shown in the accompanied drawings) (GB 1,555,831; 2,055,100; 2,073,199) to di- and tetrahydro derivatives thereof (EP 0,052,366); to analogs with different esters in the 8-position of the polyhydronaphthalene moiety, to totally synthetic analogs, wherein the polyhydronaphthalene moiety is replaced by substituted mono-and bicylic aromatics, and biphenyls (EP 0,068,038). In all of these compounds, the homochiral p-hydroxypyranone ring of structural formula III as shown in the accompanied drawings, or its corresponding ring - opened dihydroxy acid of structural formula IV as shown in the accompanied drawings was preserved, thereby establishing it as a key structural feature responsible for its HMG-CoA reductase inhibitory activity. Soon afterwards, intense efforts were directed to the design and development of synthetic strategies for selectively modifying the side-chain ester and the lactone moieties of mevinolin. Analogs of mevinolin by the modification of the 2(S) - methylbutyryl side chain and hexahydronaphthalene nucleus have been exensively studied (W.F. Hoffman et. al J. Med. Chem, 1986, 29, 849 and Gerald E. Stokker, J. Org. Chem, 1994, 59, 5983). These studies led to a series of side chain ester derivatives, the new analogs with more pronounced or reduced activity e.g. simvastatin, which has an extra methyl group in the methylbutyryl side chain is twice as potent as mevinolin. Synthetic strategies for modifying the side chain ester and lactone moieties of mevinolin have been described by Ta-Jyh-Lee in J. Org. Chem. 1982, 47, 4750. Mevalonate analogues of structural formula V and VI by substituting hydroxy bearing carbon in the HMG-CoA and mevinolinic acid with a methyl group have been prepared. However, mevalonate analogues with a methyl group at the 3-position of the pyranone ring have not been reported earlier in the literature. The present invention relates to a process for the synthesis of novel methyl analogs of simvastatin, having HMG-CoA reductase inhibitor activity. Compounds of this invention possess a methyl group in both the orientation (R) and (S), substituted at the 3-position of the ß-hydroxy pyranone ring. These may be in the lactone or corresponding dihydroxy acid forms (closed or open). In the hydrophobic bonding which accounts for the major part of drug receptor bond energy, the methyl groups in a drug molecule plays an important role. However, the biological consequences of methyl groups in the ß-hydroxy pyranone ring position of statins has been rarely studied. An object of the present invention is to provide a process for the preparation of a novel compound that exhibit significant HMG-CoA reductase inhibitory activity. Accordingly, the present invention provides a process for the preparation of hydroxymethylglutaryl coenzyme A reductase inhibitor, methyl simvastatin having the general Formula VII, as shown in the accompanied drawings, wherein R1 is a ß-hydroxy pyranone ring, as shown in the accompanied drawings of structural formula Vlla-d wherein R2 is Na, K or NH4; R3 is a methyl group, which comprises reacting simvastatin of Formula VII as shown in the accompanied drawings in which R1 and R2 are same as defined above, and R3 is hydrogen, with a methylating agent and isolating methyl simvastatin having the general Formula VII.. Methyl simvastatin is prepared by reacting a solution of simvastatin with a methylating agent in the presence of a base at a temperature from about -10°C to about -60°C under an atmosphere of nitrogen followed by a suitable aqueous work up and crystallization from organic solvents. Methylating agent used is an alkyl halide, preferably methyl iodide. The base required is used in the form of an alkali metal salt, like lithium pyrrolidide or lithium hexamethyldisilazane (Li-HMDS). Lithium pyrrolidide is generated in situ by the reaction of n-butyl lithium with pyrrolidine in tetrahydrofuran. Methylation of α-methylene site in the pyranone ring is achieved via ester enolate formed with bases like hexamethyldisilazane (Li-HMDS) or lithium pyrrolidide. Enolization with lithium pyrrolidone during methylation afforded a mixture of (3R) and (3S) methyl simvastatin isomers of structural formula (VIIc) and (VIIa), respectively as shown in the accompanied drawings. This low stereoselectivity using lithium pyrrolidone may be attributed to the lower bulk of pyrrolidone group allowing entry from both the faces of pyranone ring. However, due to more steric bulk of Li-HMDS it approaches the pyranone ring from less hindered side, and enolization with Li-HMDS followed by methylation led stereospecifically to the formation of (3R) methyl isomer of simvastatin of structural formula (VIIc) as shown in the accompanied drawings. Methylation reaction is preferably performed without protecting the two hydroxy groups of the open pyranone ring of simvastatin at a temperature from about -25°C to about -55°C. Suitable aqueous work-up involves the addition of water to the reaction mixture after the methylation is completed followed by extraction with organic solvents. Any organic solvent may be used for extraction and such solvents are known to a person who is skilled in the art and include water immisicible and partially miscible solvents such as chloroform, dichloromethane, 1,2-dichloroethane, hexanes, cyclohexane, toluene, methyl acetate, ethyl acetate, and the like. Most preferably, ethyl acetate is used. The organic phase is washed with mineral acid to remove the basic impurities. Acids may include hydrochloric acid, sulfuric acid and phosphoric acid, hydrochloric acid being the preferred acid. The product may be obtained by reducing the volume of the organic solvent containing methyl simvastatin by evaporation, adding a miscible polar solvent and precipitating the desired product by addition of an anti-solvent. The addition of polar solvent greatly reduces the presence of impurities, in the final product. Polar solvent may be selected form a group consisting of a lower alkanol, denatured spirit, isopropanol and the like , ketones such as acetone or esters such as methyl acetate or ethyl acetate, and mixture thereof. Precipitation may be effected by the addition of appropriate quantities of anti-solvent and include water, alkanes, mixture of alkanes, such as hexane, cyclohexane or cyclopentane, ethers such as isopropyl ethers or aromatic hydrocarbons such as benzene or toluene. The polar solvent and the anti-solvent should be at least partially miscible and preferably completely miscible. Methods known in the art may be used with the process of this invention to enhance any aspect of this process. The product (isomers) obtained may further be purified by any technique known to a person skilled in the art for example filtration, crystallization, column chromatography, preparative HPLC, TLC or a combination of these procedures. Biological activity in vivo and in vitro of the above described methyl simvastatin isomeric compounds of structural formula VIlc and VIIa was carried out on a HMG-CoA reductase inhibitory model. Compounds were tested at three concentrations (10-5, 10-7 and 10-9 M) for in vitro activity. The results indicated that compound VIIc possess significant HMG-CoA reductase inhibitory activity. In vivo experiments were conducted using radiolabelled (14C) acetate which was administered to the rats converting it into (14C) cholesterol. This synthesis was measured by quantitating (14C) cholesterol inhibited by HMG-CoA reductase inhibitor. In vivo results indicated that compounds (VIIc) and (VIIa) have cholesterol lowering activity. The results of the above experiment have been summarized in Table 1 and Table 2 in the accompanied drawings. In the following section preferred embodiments are described by way of examples to illustrate the process of this invention. However, these are not intended in any way to limit the scope of the present invention. EXAMPLE 1 6(R)-[2-[8(SH[2,2-Dimethylbutanoyl]oxyl]-2(S))6(R)-dimethyl-1I2,6,7l8,8a(R)-hexahydro-1(S)-napthyl]ethyl]-3(S)-methyl,4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (VIlc) To a solution of simvastatin (10 g, 0.023 mol) in tetrahydrofuran (130 ml) was syringed in lithium hexadimethylsilazane (1.3 M in hexane, 55.14 ml, 0.05 mol) maintaining temperature at -40 to -45°C under an atmosphere of nitrogen. The mixture was stirred at this temperature for 1 hour. Methyl iodide (3.72 g, 0.026 mol) was charged via syringe maintaining temperature below -30°C. The mixture was further stirred at -40 to -45°C for 1 hour and reaction was quenched by addition of water (50 ml). Layers were separated and aqueous layer was extracted with ethyl acetate (50 ml x 2). Combined organic phase was washed with pre-cooled 2N hydrochloric acid (25 ml) and finally with water (30 ml). Concentration of the organic layer gave an oil which on crystallization from ethylacetate/hexane afforded a crude solid. It was further purified from methanol/water to yield the titled compound (Vile) (7.5 g, 72% yield) in 99.37% purity (HPLC); m.pt. = 148.5 - 150°C (uncorrected). 1H NMR (CDCI3); δ 0.80-0.89 (m, 2-Me), 1.07-1.12(m, 3-Me), 1.30-1.33 (d,1-Me), 1.87-1.94 (m, 6H) 2.2-2.3 (m,3H), 2.59-2.60 (m,2H), 3.85 (m, 1H), 4.46-4.48 (m, 1H), 5.36 (s, 1H), 5.5 (s, 1H), 5.74-5.80 (m, 1H), 5.97-6.0 (m,1H), MS m/z : 433.5, 317.2 (M-116), 299.3 (317.2-18), 281.3 (299.3-18) IR (KBr pellet) : v max 3485, 2980, 1760, 1490, 1260, 850 cm-1. EXAMPLE 2 6(R)-[2-[8(S)-[[2,2-Dimethyl butanoyl] oxyl]-2(S), 6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydro-1(S)-napthyl]ethyl]-3(R)-methyl,4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (Vila) N-butyl lithium (1.6M, 23 ml, 0.036 ml) was syringed in to a solution of pyrrolidine (2.73 g, 0.038 mol) in THF (15ml) at -30 to -25°C under nitrogen. Mixture was stirred at -25°C for 30 min. and a solution of simvastatin (5g, 0.012 mol) was charged at -40°C. The mixture was stirred at -30°C for about 1 hour and methyl iodide (5.12g, 0.036 mol) was added. The mixture was further stirred at -30°C for 1 hour and at -15°C for 20 min. Reaction was quenched by addition of water (30 ml). Layers were separated and aqueous layer extracted with ethyl acetate (20ml). Combined organic phase was washed with 1N hydrochloric acid (30 ml), evaporated in vacuo to give an oil (4.2 g). It was found to be a mixture of (Vila) and (Vile) in 1:5 ratio, respectively as determined by HPLC. Isomer (Vila) (500 mg) was isolated in pure form (99%) from the mixture using preparative HPLC. WE CLAIM: 1. A process for the preparation of hydroxyrnethylglutaryl coenzyme A reductase inhibitor, methyl simvastatin having the general Formula VII, as shown in the accompanied drawings, wherein RI is a p-hydroxy pyranone ring, as shown in the accompanied drawings of structural formula Vlla-d wherein R2 is Na, K or NH4; R3 is a methyl group, which comprises reacting simvastatin of Formula VII as shown in the accompanied drawings in which R1 and R2 are same as defined above, and R3 is hydrogen, with a methylating agent and isolating methyl simvastatin having the general Formula VII. 2. The process of claim 1 wherein methylation is performed without protecting the two hydroxy groups of the open pyranone ring of simvastatin. 3. The process of claim 1 wherein said methylating agent is methyl iodide. 4. The process of claim 1 wherein methylation reaction requires the presence of a base. 5. The process of claim 4 wherein the said base is lithium pyrrolidide or lithium hexadimethyldisilazane. 6. The process of claim 1 wherein the methylation reaction is carried out at a temperature from about -10° to about - 60°C. 7. The process of claim 6 wherein preferred temperature range being from about -25°C to about -55°C. 8. The process of claim 1 wherein the isolation comprises suitable aqueous work up after the methylation reaction is complete. 9. The process of claim 8 wherein the aqueous work up includes extraction with an organic solvent. 10. The process of claim 9 wherein an organic solvent is water - immiscible or partially miscible with water. 11. The process of claim 10 wherein an organic solvent is selected from choloroform, dichloromethane, 1,2-dichloroethane, hexanes, cyclohexane, toluene, methyl acetate or ethyl acetate. 12. The process of claim 11 further comprises adding a polar solvent to the solvent system containing methyl simvastatin. 13. The process of claim 12 wherein polar solvent is selected from a lower alkanol ketone, ester, or mixtures thereof. 14. The process of claim 13 wherein solvent is methanol, ethanol, denatured spirit, isopropanol, acetone, methyl acetate, ethyl acetate, or mixtures thereof. 15. The process of claim 12 wherein the polar solvent is added to said solvent system after the amount of the solvent has been reduced. 16. The process of claim 1 wherein the isolation comprises adding an antisolvent to the polar solvent containing methyl simvastatin. 17. The process of claim 16 wherein an anti-solvent is at least partially miscible. 18. The process of claim 17 wherein an anti-solvent includes water, alkanes, mixture of alkanes, ethers or aromatic hydrocarbons. 19. The process of claim 18 wherein solvent is hexane, cyclohexane, cyclopentane, isopropyl ether, benzene or toluene. 20. The process of claim 1 wherein the isolation comprises purifying methyl simvastatin by recrystallization from solvent(s). 21 . The process for the preparation of methyl simvastatin of structural formula VII substantially as herein described and exemplified by the examples.

Full Text

The present invention relates to a process for the synthesis of novel methyl analogs of simvastatin, which have the ability to inhibit the synthesis of cholesterol. The compounds of the present invention hold promise for the treatment and prophylaxis of hypercholesterolemia and of various cardiac disorders.
Hypercholesterolemia is a known primary risk factor for the progression of atherosclerosis. High serum cholesterol is regarded as a major risk factor for the development of ischaemic heart disease and there is, therefore, a need for drugs which have the effect of reducing the blood cholesterol levels.
Over the past several years a number of structurally related anti-hypercholesterolemic agents acting by inhibition of HMG-CoA reductase have been developed and are now commercially available. The compounds have varied from the natural fermentation products, compactin of structural formula I (as shown in the accompanied drawings) and mevinolin of structural formula II (as shown in the accompanied drawings) (GB 1,555,831; 2,055,100; 2,073,199) to di- and tetrahydro derivatives thereof (EP 0,052,366); to analogs with different esters in the 8-position of the polyhydronaphthalene moiety, to totally synthetic analogs, wherein the polyhydronaphthalene moiety is replaced by substituted mono-and bicylic aromatics, and biphenyls (EP 0,068,038). In all of these compounds, the homochiral p-hydroxypyranone ring of structural formula III as shown in the accompanied drawings, or its corresponding ring - opened dihydroxy acid of structural formula IV as shown in the accompanied drawings was preserved, thereby establishing it as a key structural feature responsible for its HMG-CoA reductase inhibitory activity. Soon afterwards, intense efforts were directed to the design and development of synthetic strategies for selectively modifying the side-chain ester and the lactone moieties of mevinolin.
Analogs of mevinolin by the modification of the 2(S) - methylbutyryl side chain and hexahydronaphthalene nucleus have been exensively studied (W.F. Hoffman et. al J. Med. Chem, 1986, 29, 849 and Gerald E. Stokker, J. Org. Chem, 1994, 59, 5983). These studies led to a series of side chain ester derivatives, the new analogs with

more pronounced or reduced activity e.g. simvastatin, which has an extra methyl group in the methylbutyryl side chain is twice as potent as mevinolin.
Synthetic strategies for modifying the side chain ester and lactone moieties of mevinolin have been described by Ta-Jyh-Lee in J. Org. Chem. 1982, 47, 4750. Mevalonate analogues of structural formula V and VI by substituting hydroxy bearing carbon in the HMG-CoA and mevinolinic acid with a methyl group have been prepared.
However, mevalonate analogues with a methyl group at the 3-position of the pyranone ring have not been reported earlier in the literature.
The present invention relates to a process for the synthesis of novel methyl analogs of simvastatin, having HMG-CoA reductase inhibitor activity. Compounds of this invention possess a methyl group in both the orientation (R) and (S), substituted at the 3-position of the ß-hydroxy pyranone ring. These may be in the lactone or corresponding dihydroxy acid forms (closed or open).
In the hydrophobic bonding which accounts for the major part of drug receptor bond energy, the methyl groups in a drug molecule plays an important role. However, the biological consequences of methyl groups in the ß-hydroxy pyranone ring position of statins has been rarely studied.
An object of the present invention is to provide a process for the preparation of a novel compound that exhibit significant HMG-CoA reductase inhibitory activity. Accordingly, the present invention provides a process for the preparation of hydroxymethylglutaryl coenzyme A reductase inhibitor, methyl simvastatin having the general Formula VII, as shown in the accompanied drawings, wherein R1 is a ß-hydroxy pyranone ring, as shown in the accompanied drawings of structural formula Vlla-d wherein R2 is Na, K or NH4; R3 is a methyl group, which comprises reacting simvastatin of Formula VII as shown in the accompanied drawings in which R1 and R2 are same as defined above, and R3 is hydrogen, with a methylating agent and isolating methyl simvastatin having the general Formula VII..

Methyl simvastatin is prepared by reacting a solution of simvastatin with a methylating agent in the presence of a base at a temperature from about -10°C to about -60°C under an atmosphere of nitrogen followed by a suitable aqueous work up and crystallization from organic solvents.
Methylating agent used is an alkyl halide, preferably methyl iodide. The base required is used in the form of an alkali metal salt, like lithium pyrrolidide or lithium hexamethyldisilazane (Li-HMDS). Lithium pyrrolidide is generated in situ by the reaction of n-butyl lithium with pyrrolidine in tetrahydrofuran.
Methylation of α-methylene site in the pyranone ring is achieved via ester enolate formed with bases like hexamethyldisilazane (Li-HMDS) or lithium pyrrolidide. Enolization with lithium pyrrolidone during methylation afforded a mixture of (3R) and (3S) methyl simvastatin isomers of structural formula (VIIc) and (VIIa), respectively as shown in the accompanied drawings. This low stereoselectivity using lithium pyrrolidone may be attributed to the lower bulk of pyrrolidone group allowing entry from both the faces of pyranone ring. However, due to more steric bulk of Li-HMDS it approaches the pyranone ring from less hindered side, and enolization with Li-HMDS followed by methylation led stereospecifically to the formation of (3R) methyl isomer of simvastatin of structural formula (VIIc) as shown in the accompanied drawings.
Methylation reaction is preferably performed without protecting the two hydroxy groups of the open pyranone ring of simvastatin at a temperature from about -25°C to about -55°C.
Suitable aqueous work-up involves the addition of water to the reaction mixture after the methylation is completed followed by extraction with organic solvents. Any organic solvent may be used for extraction and such solvents are known to a person who is skilled in the art and include water immisicible and partially miscible solvents such as chloroform, dichloromethane, 1,2-dichloroethane, hexanes, cyclohexane, toluene, methyl acetate, ethyl acetate, and the like. Most preferably, ethyl acetate is used. The organic phase is washed with mineral acid to remove the basic impurities.

Acids may include hydrochloric acid, sulfuric acid and phosphoric acid, hydrochloric acid being the preferred acid.
The product may be obtained by reducing the volume of the organic solvent containing methyl simvastatin by evaporation, adding a miscible polar solvent and precipitating the desired product by addition of an anti-solvent. The addition of polar solvent greatly reduces the presence of impurities, in the final product. Polar solvent may be selected form a group consisting of a lower alkanol, denatured spirit, isopropanol and the like , ketones such as acetone or esters such as methyl acetate or ethyl acetate, and mixture thereof. Precipitation may be effected by the addition of appropriate quantities of anti-solvent and include water, alkanes, mixture of alkanes, such as hexane, cyclohexane or cyclopentane, ethers such as isopropyl ethers or aromatic hydrocarbons such as benzene or toluene. The polar solvent and the anti-solvent should be at least partially miscible and preferably completely miscible.
Methods known in the art may be used with the process of this invention to enhance any aspect of this process. The product (isomers) obtained may further be purified by any technique known to a person skilled in the art for example filtration, crystallization, column chromatography, preparative HPLC, TLC or a combination of these procedures.
Biological activity in vivo and in vitro of the above described methyl simvastatin isomeric compounds of structural formula VIlc and VIIa was carried out on a HMG-CoA reductase inhibitory model. Compounds were tested at three concentrations (10-5, 10-7 and 10-9 M) for in vitro activity.
The results indicated that compound VIIc possess significant HMG-CoA reductase inhibitory activity.
In vivo experiments were conducted using radiolabelled (14C) acetate which was administered to the rats converting it into (14C) cholesterol. This synthesis was measured by quantitating (14C) cholesterol inhibited by HMG-CoA reductase inhibitor. In vivo results indicated that compounds (VIIc) and (VIIa) have cholesterol

lowering activity. The results of the above experiment have been summarized in Table 1 and Table 2 in the accompanied drawings.
In the following section preferred embodiments are described by way of examples to illustrate the process of this invention. However, these are not intended in any way to limit the scope of the present invention.
EXAMPLE 1
6(R)-[2-[8(SH[2,2-Dimethylbutanoyl]oxyl]-2(S))6(R)-dimethyl-1I2,6,7l8,8a(R)-hexahydro-1(S)-napthyl]ethyl]-3(S)-methyl,4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (VIlc)
To a solution of simvastatin (10 g, 0.023 mol) in tetrahydrofuran (130 ml) was syringed in lithium hexadimethylsilazane (1.3 M in hexane, 55.14 ml, 0.05 mol) maintaining temperature at -40 to -45°C under an atmosphere of nitrogen. The mixture was stirred at this temperature for 1 hour. Methyl iodide (3.72 g, 0.026 mol) was charged via syringe maintaining temperature below -30°C. The mixture was further stirred at -40 to -45°C for 1 hour and reaction was quenched by addition of water (50 ml). Layers were separated and aqueous layer was extracted with ethyl acetate (50 ml x 2). Combined organic phase was washed with pre-cooled 2N hydrochloric acid (25 ml) and finally with water (30 ml). Concentration of the organic layer gave an oil which on crystallization from ethylacetate/hexane afforded a crude solid. It was further purified from methanol/water to yield the titled compound (Vile) (7.5 g, 72% yield) in 99.37% purity (HPLC); m.pt. = 148.5 - 150°C (uncorrected). 1H NMR (CDCI3); δ 0.80-0.89 (m, 2-Me), 1.07-1.12(m, 3-Me), 1.30-1.33 (d,1-Me), 1.87-1.94 (m, 6H) 2.2-2.3 (m,3H), 2.59-2.60 (m,2H), 3.85 (m, 1H), 4.46-4.48 (m, 1H), 5.36 (s, 1H), 5.5 (s, 1H), 5.74-5.80 (m, 1H), 5.97-6.0 (m,1H), MS m/z : 433.5, 317.2 (M-116), 299.3 (317.2-18), 281.3 (299.3-18) IR (KBr pellet) : v max 3485, 2980, 1760, 1490, 1260, 850 cm-1.

EXAMPLE 2
6(R)-[2-[8(S)-[[2,2-Dimethyl butanoyl] oxyl]-2(S), 6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydro-1(S)-napthyl]ethyl]-3(R)-methyl,4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (Vila)
N-butyl lithium (1.6M, 23 ml, 0.036 ml) was syringed in to a solution of pyrrolidine (2.73 g, 0.038 mol) in THF (15ml) at -30 to -25°C under nitrogen. Mixture was stirred at -25°C for 30 min. and a solution of simvastatin (5g, 0.012 mol) was charged at -40°C. The mixture was stirred at -30°C for about 1 hour and methyl iodide (5.12g, 0.036 mol) was added. The mixture was further stirred at -30°C for 1 hour and at -15°C for 20 min. Reaction was quenched by addition of water (30 ml). Layers were separated and aqueous layer extracted with ethyl acetate (20ml). Combined organic phase was washed with 1N hydrochloric acid (30 ml), evaporated in vacuo to give an oil (4.2 g). It was found to be a mixture of (Vila) and (Vile) in 1:5 ratio, respectively as determined by HPLC.
Isomer (Vila) (500 mg) was isolated in pure form (99%) from the mixture using preparative HPLC.

WE CLAIM:
1. A process for the preparation of hydroxyrnethylglutaryl coenzyme A reductase
inhibitor, methyl simvastatin having the general Formula VII, as shown in the
accompanied drawings, wherein RI is a p-hydroxy pyranone ring, as shown in
the accompanied drawings of structural formula Vlla-d wherein R2 is Na, K or
NH4; R3 is a methyl group, which comprises reacting simvastatin of Formula
VII as shown in the accompanied drawings in which R1 and R2 are same as
defined above, and R3 is hydrogen, with a methylating agent and isolating
methyl simvastatin having the general Formula VII.
2. The process of claim 1 wherein methylation is performed without protecting
the two hydroxy groups of the open pyranone ring of simvastatin.
3. The process of claim 1 wherein said methylating agent is methyl iodide.
4. The process of claim 1 wherein methylation reaction requires the presence of
a base.
5. The process of claim 4 wherein the said base is lithium pyrrolidide or lithium
hexadimethyldisilazane.
6. The process of claim 1 wherein the methylation reaction is carried out at a
temperature from about -10° to about - 60°C.
7. The process of claim 6 wherein preferred temperature range being from about
-25°C to about -55°C.
8. The process of claim 1 wherein the isolation comprises suitable aqueous work
up after the methylation reaction is complete.
9. The process of claim 8 wherein the aqueous work up includes extraction with
an organic solvent.
10. The process of claim 9 wherein an organic solvent is water - immiscible or
partially miscible with water.
11. The process of claim 10 wherein an organic solvent is selected from
choloroform, dichloromethane, 1,2-dichloroethane, hexanes, cyclohexane,
toluene, methyl acetate or ethyl acetate.

12. The process of claim 11 further comprises adding a polar solvent to the
solvent system containing methyl simvastatin.
13. The process of claim 12 wherein polar solvent is selected from a lower alkanol
ketone, ester, or mixtures thereof.
14. The process of claim 13 wherein solvent is methanol, ethanol, denatured
spirit, isopropanol, acetone, methyl acetate, ethyl acetate, or mixtures thereof.
15. The process of claim 12 wherein the polar solvent is added to said solvent
system after the amount of the solvent has been reduced.
16. The process of claim 1 wherein the isolation comprises adding an antisolvent
to the polar solvent containing methyl simvastatin.
17. The process of claim 16 wherein an anti-solvent is at least partially miscible.
18. The process of claim 17 wherein an anti-solvent includes water, alkanes,
mixture of alkanes, ethers or aromatic hydrocarbons.
19. The process of claim 18 wherein solvent is hexane, cyclohexane,
cyclopentane, isopropyl ether, benzene or toluene.
20. The process of claim 1 wherein the isolation comprises purifying methyl
simvastatin by recrystallization from solvent(s).
21 . The process for the preparation of methyl simvastatin of structural formula VII substantially as herein described and exemplified by the examples.

Documents:

659-del-2001-abstract.pdf

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659-del-2001-correspondence-others.pdf

659-del-2001-correspondence-po.pdf

659-del-2001-description (complete).pdf

659-del-2001-drawings.pdf

659-del-2001-form-1.pdf

659-del-2001-form-19.pdf

659-del-2001-form-2.pdf

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Patent Number

217177

Indian Patent Application Number

659/DEL/2001

PG Journal Number

15/2008

Publication Date

11-Apr-2008

Grant Date

26-Mar-2008

Date of Filing

13-Jun-2001

Name of Patentee

RANBAXY LABORATORIES LIMITED

Applicant Address

19,NEHRU PLACE,NEW DELHI-110 019,INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	RAJESH KUMAR THAPER	RANBAXY LABORATIRIES LIMITED PLOT No.20,SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA,GURGAON -122001(HARYANA)INDIA
2	S.M.DILEEP KUMAR	RANBAXY LABORATIRIES LIMITED PLOT No.20,SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA,GURGAON -122001(HARYANA)INDIA
3	YATENDRE KUMAR	RANBAXY LABORATIRIES LIMITED PLOT No.20,SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA,GURGAON -122001(HARYANA)INDIA

PCT International Classification Number

a61k 31/35

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA