Title of Invention

"PROCESS FOR PRODUCING SIMVASTATIN USING NOVEL HYDRAZIDE INTERMEDIATES"

Abstract

This invention relates to an industrially feasible process for producing HMG-CoA reductase inhibitor, simvastatin via novel intermediates, wherein the process comprises treating lovastatm or lovastatm ammonium salt with hydrazine or hydrazine derivatives to obtain lovastatin hydrazide intermediate, which is further used to produce simvastatin. Further, the hydroxyl groups of said intermediate are optionally protected to obtain protected lovastatin hydrazide intermediate and use the same to produce simvastatin.

Full Text

Field of the Invention This invention in general relates to a process for producing HMG-CoA reductase inhibitor. More particularly the present invention provides a novel process for producing simvastatin by treating lovastatin or lovastatin ammonium salt with hydrazine or hydrazine derivatives to produce novel hydrazide intermediates, which are further used in the production of simvastatin. Background of the Invention Compactin, lovastatin and pravastatin are natural fermentation products, which possess a 2-methylbutyrate side chain at C-8 carbon of their hexahydronaphthalene nucleus. It is known that simvastatin [1] inhibits cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase. It possesses a 2,2-dialkylbutyrate C-8 side chain and is a better inhibitor of HMG-CoA reductase than its 2-alkylbutyrate counterpart. (Formula Removed) There are two major approaches for the alkylation of 2-methyl butyrate chain reported in the prior art. The first approach involves indirect alkylation by doing deacylation of the C-8 side chain followed by reacylation through several chemical steps as described in US Pat. No. 4,444,784, US Pat. No. 5,159,104, US Pat. No. 6,294,680. The process comprises de-esterification of 2-methylbutyrate side chain; protection of the 4-hydroxyl group of the pyranone ring; re-esterification of the protected lactone compound with 2,2-dimethylbutyric acid and deprotection of the hydroxyl group of the pyranone ring. This approach has several disadvantages, like drastic conditions for the reaction, low yield and low purity of simvastatin due to degradation and thus not industrially feasible. The other approach is direct alkylation of the 2-methylbutyrate chain which involves six steps: (a) deactivation of a- methylene protons at C-5 position of pyranone moiety by protection of the carboxyl group e.g. by making amide derivative; (b) protecting the two hydroxyl groups e.g. via silyl protection; (c) alkylation of a -hydrogen atom of butyrate chain preferably using lithium pyrrolidide; (d) deprotection of hydroxyl groups in acidic medium; (e) hydrolysis of carboxyl protecting group e.g. amides under basic condition to restore simvastatin dihydroxy acid derivative and isolating it preferably as ammonium salt; and (f) relactonization to give lactonized compound. US Pat. No. 4,582,915 discloses a process for the preparation of simvastatin, by direct methylation of the 2-methylbutyrate side chain of lovastatin, using methyl halide in the presence of a strong base such as alkali metal amide. This process has several disadvantages including low conversion, resulting in contamination of the final product by a significant concentration of unconverted starting material and relatively high concentration of by-products. This will result in the low yield and poor purity of the final product and thus not industrially feasible. U S Pat. No. 4,820,850, U S Pat. No. 5,393,893, U S Pat. No.6,100,407, U S Pat. No. 6,472,542 and International Patent Publication No WO03/000673 describes a process for the preparation of simvastatin, by treating lovastatin with substituted amine to form lovastatin amide followed by the protection of the hydroxyl-groups using protecting agents e.g. TBDMS, boronic acid etc. The resulting protected intermediate was then methylated with alkyl halide followed by removal of the protecting group and hydrolysis of the alkyl amide under basic condition to obtain carboxylate salt, which undergo lactonization in a hydrocarbon solvent under heating or with organic or inorganic acid in presence of solvent. However, the above-mentioned processes have certain disadvantages such as that simvastatin has been prepared in multiple steps hence affecting the overall yield and thus not economical. Another disadvantage of these processes is that deprotection of the hydroxyl group and hydrolysis of the carboxyl protecting group is done in two separate steps, which increases the manufacturing time and effect the overall yield of the final product. Beside these, the hydroxyl groups of the lactone ring are protected using expensive reagent, which increases the production cost. These processes disclosed in the prior art suffer from drawbacks ranging from multiple steps, low yields and poor purity of the final product and use of expensive reagents. Therefore, there is a need for an industrially feasible process for the preparation of simvastatin, which involves minimum chemical steps, is less time consuming, is economical by use of inexpensive reagents and gives overall good yield. The present invention addresses these needs. Summary of the Invention It is the principal aspect of the present invention to provide an industrially feasible process for producing simvastatin [1] via novel intermediates, which involves minimum steps, consumes less time and is cost effective. According to another aspect of the present invention, there are provided novel intermediates [3] and [4] to produce simvastatin [1], which are prepared by treating lovastatin [2] or lovastatin ammonium salt [2'] with hydrazine or hydrazine derivatives. In another preferred embodiment, disclosed herein is a process for producing simvastatin [1], wherein the process comprises treating lovastatin [2] or lovastatin ammonium salt [2'] with hydrazine or hydrazine derivatives to obtain lovastatin hydrazide intermediate [3], methylating the lovastatin hydrazide [3] by methyl halide to prepare simvastatin hydrazide formed in situ, hydrolyzing the resultant simvastatin hydrazide to form simvastatin ammonium and lactonizing the same to obtain crude simvastatin. In another embodiment of the present invention, there is provided a process for producing simvastatin [1], wherein the process comprises treating lovastatin [2] or lovastatin ammonium salt [2'] with hydrazine or hydrazine derivatives to obtain lovastatin hydrazide [3], protecting said lovastatin hydrazide [3] with hydroxyl protecting group to obtain protected lovastain hydrazide [4], methylating the protected lovastatin hydrazide [4] by methyl halide to prepare protected simvastatin hydrazide formed in situ, deprotecting and hydrolyzing the resultant simvastatin hydrazide to form simvastatin ammonium and lactonizing the same to obtain crude simvastatin. Description of the Invention The disclosed embodiment of the present invention deals with a process for the preparation of novel intermediates to produce HMG-CoA reductase inhibitor simvastatin [1], which is economically viable, suitable for large scale manufacturing and obviates the disadvantages mentioned in prior arts. Synthetic Scheme (Scheme Removed) R1 and R2= hydrogen, substituted or unsubstituted alkyl, aryl, cyclolkyl hetroaryl, or combined to form a cyclic structure R3= hydroxyl protecting group R'= NH4+ According to the present invention, there is provided a process for producing simvastatin of the Formula [1] comprising treating lovastatin [2] or lovastatin ammonium salt [2'] with hydrazine or hydrazine derivatives to obtain lovastatin hydrazide [3], methylating the lovastatin hydrazide intermediate [3] with methyl halide to prepare simvastatin hydrazide formed in situ and hydrolyzing the resultant methylated hydrazide intermediate followed by relactonization of the corresponding ammonium salt. The process for preparation of an intermediate disclosed in the invention, wherein reaction of lovastatin [2] or lovastatin ammonium salt [2'] with hydrazine or hydrazine derivatives takes place in presence of inert organic solvent. The hydrazine derivatives are selected from substituted or unsubstituted alkyl, cycloalkyl, aryl, heteroaryl group. The reaction takes place in presence of acid catalyst selected from formic acid, acetic acid, methane sulphonic acid, p-toluene sulphonic acid, benzene sulphonic acid or trifluoroacetic acid. The reaction is performed at a temperature of 60-90°C under inert atmosphere. The process disclosed herein also provides an optional process step where the hydroxyl groups of lovastatin hydrazide intermediate [3] are protected with hydroxyl protecting groups in presence of a base e.g. imidazole to obtain protected lovastatin hydrazide intermediate [4] which can participate in the further process step for producing simvastatin [1], wherein the hydroxyl protecting group is selected from a silyloxy group, borate group, cyclic ether group, cyclic thioether group, cyclic sulphate, cyclic phosphate, as an acetal, a ketal, cyclic acetals, cyclic ketals and the like. More preferably the protecting groups are selected from trimethylsilyl, triethylsilyl, dimethylhexylsilyl, diethylisopropylsilyl, tribenzylsilyl, tri-p-xylylsilyl, dimethylisopropylsilyl, tert-butyldimethylsilyl, tert- butylmethoxyphenylsilyl, t-butyldiphenylsilyl, diisopropylmethylsilyl, (triphenylmethyl)dimethylsilyl, diphenylmethylsilyl, triisopropylsilyl, triphenylsilyl, t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, phenyl boronic acid, tetrahydropyran-2-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydropyran-2-yl, l,4-dioxane-2-yl, tetrahydrofuran-2-yl, acetonide and the like. The reaction takes place optionally in presence of solvent selected from inert organic solvent. The reaction is carried out at an elevated temperature, preferably at the reflux temperature of the reaction mixture depending upon the solvent used. The resulting protected lovastatin hydrazide [4] is taken for methylation reaction without purification. Methylation of the protected lovastatin hydrazide [4] is carried out by forming an anion by reaction with an alkali metal amide in an inert organic solvent e.g. tetrahydrofuran, followed by the addition of an alkylating agent. The alkali metal amide used in the methylation is prepared by reacting a secondary amine, e.g. pyrrolidine, piperidine or a dialkylamine with an n-butyl or n-hexyl alkali metal compound preferably n-hexyl lithium or n-butyl lithium in an anhydrous inert solvent medium e.g. tetrahydrofuran, diethyl ether etc, at a temperature of about -10°C to -50°C, preferably about -20°C to about -30°C. Preferably the alkali metal amide is prepared by the combination of n-butyl lithium in hexane solution with about an equimolar amount of pyrrolidine in tetrahydrofuran. When the alkali metal amide, e.g. lithium pyrrolidide, is formed, it is added to an organic solvent solution of a protected lovastatin hydrazide to form an anion. The alkylating agent used herein is selected from methyl halide wherein the halide is selected from chloride, bromide or iodide preferably iodide at a temperature of about -30°C to -60°C under inert atmosphere. The resulting methylated hydrazide intermediate is further subjected to deprotection and hydrolysis in a single step, by treating with a mixture of water and acid catalyst, wherein the acid catalyst is selected from formic acid, acetic acid, methane sulphonic acid, p-toluene sulphonic acid, benzene sulphonic acid or trifluoroacetic acid. The reaction is performed at a temperature below 50°C. These hydrazide intermediates have several advantages at the commercial scale, e.g. these hydrazides are quite stable in the basic conditions and thus used as such for hydroxyl protection without work-up. Another advantage of these compounds is that these hydrazide protecting groups are readily removed under the acidic conditions, thus the removal of the hydroxyl protecting groups and hydrolysis of the hydrazide group is done in a single step. This reduces the number of operations involved in simvastatin preparation and thereby increases the operational efficiency and convenience on large-scale manufacturing. The simvastatin dihydroxy acid may be precipitated out as a crude simvastatin ammonium salt by the treatment with ammonium hydroxide. The resulting simvastatin ammonium salt is relactonized according to the processes reported in the prior art, e.g. taken in toluene and heated at 100-105°C while removing the water azeotropically in an inert atmosphere to obtain crude simvastatin [1]. The lactonization reaction is carried out optionally in presence of antioxidant selected from butylated hydroxyanisole or butylated hydroxytoluene. Crude simvastatin is purified, according to the known processes, using a mixture of methanol and water. The present invention is further described in greater detail as illustrated in non-limiting examples. It should be understood that variation and modification of the process are possible within the ambit of the invention broadly disclosed herein. Infrared measurements were done on Thermo Nicolet FT IR spectrometer using KBr pellets and absorption bands are reported in reciprocal centimeter. 1H NMR spectra were recorded at 400 MHz NMR spectrometer. LC-MS was done on Finnigan LCQ Advantage Max using Phenomenex C-18 column with the dimension 250x4.6 mm. Example-1 Preparation of lovastatin phenyl hydrazide [3] A mixture of lovastatin (50 g) and phenyl hydrazine (20 ml) was taken in tetrahydrofuran (100 ml). To this mixture, acetic acid (5 ml) was added under an inert atmosphere. The mixture was heated at 65-70°C for 2-3 hours. The solvent was distilled off and water (125 ml) was added to the reaction mass and extracted with dichloromethane (250 ml). The organic layer was washed with NaHCO3 solution (10%) and water (250 ml) was added and then evaporated under vacuum to obtain the title compound. IR (KBr, cm-1): 3334, 2966, 2934, 2873, 1723, 1658, 1381 1307, 1189, 754. 1H NMR (400MHz, CDC13, δ ppm): 0.87 (m, 3H, d-H), 1.47 (d, 2H,C2-H), 2.29 (m, 1H, C3-H), 1.09 (m, 3H, C4-H), 5.27 (d, 1H, C6-H), 1.2-1.4 (m, 2H, C7-H), 2.37 (m, 1H, C8-H), 1.07 (d, 3H, C9-H), 5.5 (m, 1H, C10-H), 6.0 (m, 1H, C12-H), 5.8 (m, 1H, CB-H), 2.2 (m, 1H, CH-H), 0.89(d, 3H,Ci5-H), 1.6 (m, 1H, Cie-H), 2.3(m, 1H, C17-H), 1.2-1.8 (m, 2H, C18-H), 1.2-1.8 (m, 2H, C19-H) 3.56(m, 1H, C20-H), 4.5 (s, 1H, C20-OH), 1.5-2.0(m, 2H, C21-H), 4.04(m, 1H, C22-H), 4.8 (s, 1H, C22-OH) l.l-2.5(m, 2H, C23-H), 6.7-7.1(m, 5H, aromatic-H), 9.6 (s, 1H, CONH), 7.7(s, 1H, aromatic C25-NH). LC-MS: 535 (M++23). Example-2 Preparation of lovastatin phenyl hydrazide [3] A mixture of lovastatin ammonium salt (50 g) and phenyl hydrazine (20 ml) was taken in tetrahydrofuran (100 ml). To this mixture, acetic acid (5 ml) was added under an inert atmosphere. The mixture was heated at 65-70°C for 8-12 hours. The solvent was distilled off under vacuum and after distillation, water (125 ml) was added to the reaction mass and extracted with dichloromethane (250 ml). The organic layer was washed with NaHC03 solution (10%) and subsequently with water (250 ml) and then evaporated under vacuum to obtain the title compound. Example-3 Preparation of protected lovastatin phenyl hydrazide [4] Lovastatin phenyl hydrazide (50 gm) was taken in tetrahydrofuran (100 ml). To this mixture, hexamethyldisilazane (HMDS) (35 ml) and imidazole (5.0 gm) was added. The mixture was heated at 50-55°C under stirring for 1-2 hours. The reaction mass was dissolved in cyclohexane (300 ml) and washed with water. The organic phase was separated off and distilled under vacuum to obtain the title compound. IR(KBr, cm-1): 3293,2957,2827,1728,1682,1603,1496,1450,1116,1093, 841. 'H NMR (400MHz, CDC13, 5 ppm): 0.01 (m, 18H, Si(CH3)6), 0.76 (m, 3H, C1-H), 1.48 (d, 2H,C2-H), 2.26 (m, 1H, C3-H), 1.08 (m, 3H, C4-H), 5.16 (s, 1H, broad), 1.2-1.4 (m, 2H, C7-H), 2.33 (m, 1H, C8-H), 1.06 (m, 3H, C9-H), 5.4 (m, 1H, C10-H), 5.9 (m, 1H, Ci2-H), 5.7 (m, 1H, C13-H), 2.2 (m, 1H, C14-H), 0.96(m, 3H, C15-H), 1.7 (m, 1H, C16-H), 2.2 (m, 1H, C17-H), 1.2-1.8 (m, 2H, Ci8-H), 3.5(m, 1H, C20-H), 1.5-2.0(m, 2H, C21-H), 4.0(m, 1H, C22-H), 1.1-2.5 (m, 2H, C23-H), 7.5 (s, 1H, aromatic C25-NH), 6.6-7.0 (m, 5H, aromatic-H), 9.5 (s, 1H, CONH). LC-MS: 679 (M++23) Example-4 Preparation of protected lovastatin phenyl hvdrazide[4] Lovastatin phenyl hydrazide (50 gm) was taken in hexamethyldisilazane (HMDS) (100 ml). The mixture was heated at 55-60°C for 4-8 hours. After reaction completion hexamethyldisilazane (HMDS) was evaporated off under vacuum. To the resulting residue, cyclohexane (300 ml) was added and distilled under vacuum to obtain the title product. Example-5 Preparation of protected lovastatin phenyl hydrazide[4] Lovastatin (50 gm) was taken in dimethylformamide (100 ml). To the resulting solution, phenyl hydrazine (20 ml) and acetic acid (5 ml) was added. The reaction mixture was stirred for 4-5 hours at 60-65°C. Hexamethyldisilazane (HMDS) (92 ml) was added and stirred for 5-6 hours. Solvent was distilled off under vacuum, cyclohexane (300 ml) and water (250 ml) was added. The organic layer was separated off, washed with water and distilled under vacuum. To the resulting mass, tetrahydrofuran (150 ml) was added and distilled under vacuum to obtain the title compound. Example-6 Preparation of simvastatin ammonium salt A solution of pyrrolidine (58 gm) was taken in anhydrous tetrahydrofuran (300 ml) and cooled to about -20°C to -25 °C under a nitrogen atmosphere. To the resulting solution n-butyl lithium (502 ml) (1.6M in hexane) was added. Protected lovastatin phenyl hydrazide (90 gm) taken in tetrahydrofuran (300 ml) was added to the reaction mixture at -35° to -40°C. Methyl iodide (79 g) was added at the above temperature. After completion of the reaction, the resulting mixture was quenched with ammonium chloride solution (20%). The phases were separated and the organic phase was washed with water, separated and concentrated. The resulting mass was dissolved in acetonitrile (150 ml) and cooled to 0 to 5°C. To the resulting solution, a mixture of methane sulphonic acid and water (1:1) was added dropwise and stirred for 5-6 hours at room temperature. To the resulting mixture, methanol (100 ml) and sodium hydroxide solution (30%, 150 ml) was added and stirred for one hour. The solvent was distilled off under vacuum and water (500 ml) was added. The reaction mass was cooled to about 0-5°C and solution of hydrochloric acid (3N) was added to obtain a pH of about 5 to 6. The product was extracted with ethyl acetate (500 ml) and pH was again adjusted of about 3-4. The organic layer was separated off and the aqueous layer was extracted with ethyl acetate. A mixture of ammonium hydroxide and methanol in 1:1 mixture was added. The solid was filtered off to obtain the title compound. Example-7 Preparation of simvastatin [1] Simvastatin ammonium salt (50 gm) was taken in toluene (1250 ml) and heated at 100-105°C while removing water azeotropically under a constant flow of nitrogen. After reaction completion, toluene was distilled off under vacuum and cyclohexane (800 ml) was added. The resulting reaction mass was cooled to 10-15°C and stirred for one hour. The resulting solid was filtered off, dried under vacuum to obtain crude simvastatin. Example-8 Preparation of pure simvastatin Crude simvastatin (30 gm) was dissolved in methanol (450 ml). To this solution, water (450 ml) was added and stirred for one hour. The resulting solution was cooled to 10-15°C and stirred for one more hour. The resulting solid was filtered off and dried under vacuum to obtain pure simvastatin. Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims. We Claim: 1. A process for producing simvastatin of Formula [ 1 ] (Formula Removed) employing a novel intermediate lovastatin hydrazide of Formula [3], the process comprising: (a) treating lovastatin of Formula [2] or lovastatin salt of Formula [2'] (Formula Removed) with hydrazine or hydrazine derivative to obtain the intermediate lovastatin hydrazide of Formula [3], (Formula Removed) wherein R1 and R2 are selected from hydrogen atom, substituted or unsubstituted alkyl, cycloalkyl, aryl or heteroaryl moiety or R1 and R2 are combined to form a cyclic structure and R' is NH4+; (b) methylating the intermediate lovastatin hydrazide of Formula [3] by methyl halide and hydrolyzing the resultant to form ammonium salt of simvastatin; and lactonizing the same to produce simvastatin of Formula [1]. 2. The process according to claim 1, wherein the hydrazine derivative is selected from substituted or unsubstituted alkyl group, cycloalkyl group, aryl group or heteroaryl group. 3. The process according to claim 1, wherein the preparation of intermediate lovastatin hydrazide of Formula [3] is carried out in presence of an acid catalyst. 4. The process according to claim 3, wherein the said acid catalyst is selected from a group comprising formic acid, acetic acid, methane sulphonic acid, p-toluene sulphonic acid, benzene sulphonic acid or trifluoroacetic acid. 5. The process according to claim 1, wherein the preparation of the intermediate lovastatin hydrazide of Formula [3] is carried out at a temperature of about 60-90°C. 6. The process according to claim 1, the process further comprising: (a) protecting the hydroxyl groups of the intermediate lovastatin hydrazide of Formula [3] with a hydroxyl protecting group to obtain a novel intermediate protected lovastatin hydrazide of Formula [4], (Formula Removed) wherein R1 and R2 are selected from hydrogen atom, substituted or unsubstituted alkyl, cycloalkyl, aryl or heteroaryl moiety or R1 and R2 are combined to form a cyclic structure and R3 is a hydroxyl protecting group; (b) methylating the protected lovastatin hydrazide of Formula [4] employing methyl halide to prepare a protected simvastatin hydrazide intermediate, deprotecting and hydrolyzing the resultant to form ammonium salt of simvastatin of Formula [1] and lactonizing the same to obtain simvastatin of Formula [1]. 7. The process according to claim 6, wherein the hydroxyl protecting group is selected from the silyloxy group, borate group, cyclic ether group, cyclic thioether group, cyclic sulphate, cyclic phosphate, as an acetal, a ketal, cyclic acetals, cyclic ketals and the like. 8. The process according to claim 7, wherein the said hydroxyl protecting group is selected from the group comprising trimethylsilyl, triethylsilyl, dimethylhexylsilyl, diethylisopropylsilyl, tribenzylsilyl, tri-p-xylylsilyl, dimethylisopropylsilyl, tert-butyldimethylsilyl, tert-butylmethoxyphenylsilyl, t-butyldiphenylsilyl, diisopropylmethylsilyl, (triphenylmethyl)dimethylsilyl, diphenylmethylsilyl, triisopropylsilyl, triphenylsilyl, t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, phenyl boronic acid, tetrahydropyran-2-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydropyran-2-yl, l,4-dioxane-2-yl, tetrahydrofuran-2-yl, acetonide and the like. 9. The process according to claim 1, wherein the hydrolysis and deprotection of resultant methylated hydrazide is carried out in the presence of an acid catalyst and water. 10. The process according to claim 9, wherein the said acid catalyst is selected from a group comprising formic acid, acetic acid, methane sulphonic acid, p-toluene sulphonic acid, benzene sulphonic acid or trifluoro acetic acid. 11. The process according to claim 1, wherein the hydrolysis and deprotection of resultant methylated hydrazide is carried out at a temperature below 50°C. 12. The process according to claim 1, wherein said methyl halide is methyl iodide or methyl bromide.

Documents:

108-del-2004-abstract.pdf

108-del-2004-claims.pdf

108-del-2004-Correspondence-Others-(27-09-2012).pdf

108-del-2004-correspondence-others.pdf

108-del-2004-correspondence-po.pdf

108-del-2004-description (complete).pdf

108-del-2004-description (provisional).pdf

108-del-2004-form-1.pdf

108-del-2004-form-13.pdf

108-del-2004-form-19.pdf

108-del-2004-form-2.pdf

108-del-2004-form-3.pdf

108-del-2004-form-5.pdf

108-del-2004-pct-210.pdf

108-del-2004-pct-220.pdf

108-del-2004-pct-237.pdf