FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARATION OF FLUVASTATIN SODIUM AND INTERMEDIATE THEREFOR
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an efficient process for the preparation of Fluvastatin sodium.
The following specification particularly describes the invention and the manner
in which it is to be performed.
4. DESCRIPTION
The present invention relates to an efficient process for the preparation of Fluvastatin sodium.
Fluvastatin is [R*,S*-(E )]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H -indol-2-yl]-3,5-dihydroxy-6-heptenoic acid of Formula I. Fluvastatin, is commercially available as Lescol® Capsules and extended release Tablets in form of its sodium salt. It is indicated for the treatment of hypercholesterolemia (heterozygous familial and non familial), mixed dyslipidemia, secondary prevention of coronary events and atherosclerosis.
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US Patent No 5,354,772 discloses the process for synthesis of fluvastatin, its sodium salt and pharmaceutical compositions thereof.
US Patent No 5,189,164 (the '164 Patent) discloses process for synthesizing syn (E)-3,5-dihydroxy-7-substituted hept-6-enoic acid and heptanoic acid derivatives and intermediates thereof wherein p ketoester intermediate of Formula II

wherein R is Ci.8 alkyl is prepared by the condensation of fluvaldehyde of Formula VI

wherein R is as described above and alkyl acetoacetate of Formula VII,
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wherein R is Ci.8alkyl in the presence of sodium hydride and n-butyl lithium. After completion of reaction, the pH of the reaction mixture is adjusted with cold dilute hydrochloric acid until the pH is 3-4. At this pH the p ketoester decomposes and the resulting product has purity of about 70%. This p ketoester is reduced to dihydroxy intermediate of Formula IV

wherein R is as describe above in the presence of diethylmethoxy borane, followed by hydrolysis using sodium hydroxide to obtain fluvastatin and salts thereof.
Several other processes are known in the art for preparation of fluvastatin or salt thereof, viz. US Patent No 4,870,199; US Patent No 6,743,926; US Patent No 6,875,867 (the '867 Patent).
The present inventors have now surprisingly found an efficient method of minimizing the decomposition of p-ketoester of Formula II as mentioned above thereby increasing its purity, p-ketoester intermediate of fluvastatin is prepared by the condensation reaction of fluvaldehyde and alkyl acetoacetate in the presence of sodium hydride and n-butyl lithium. After the completion of the reaction, the pH of the reaction mixture is adjusted with dilute organic or inorganic acid or a buffer to 6.0 or more. At this pH the p ketoester decomposition is minimized and the resulting p ketoester has purity of 95% or
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more. This β ketoester is reduced to dihydroxy intermediate in the presence of trialkyl or dialkylalkoxy borane from which fluvastatin or salts thereof are isolated by hydrolysis.
One of the aspects of the present invention provides a process for preparation of fluvastatin or salt thereof wherein the said process comprises of
a) reacting fluvaldehyde of Formula VI,

wherein R is as mentioned above in presence of sodium hydride and n-butyl lithium,
b) adjusting the pH of reaction mixture of step a) after completion of reaction to 6.0 or more,
c) reducing the β-ketoester intermediate of Formula II,

wherein R is as mentioned above is obtained in step b) to dihydroxy intermediate of Formula IV,
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in the presence of trialkyl borane or dialkylalkoxy boranes.
d) hydrolyzing the dihydroxy intermediate to fluvastatin or salt thereof,
e) isolating fluvastatin or salt thereof from the reaction mass.
Fluvaldehyde and alkyl acetoacetate are condensed in the presence of sodium hydride and n-butyl lithium in an organic solvent such as tetrahydrofuran (THF). After completion of the reaction, the pH of the reaction mixture is adjusted with organic or inorganic acid or with a buffer to 6.0 or more. The organic acid comprises of carboxylic acid or sulphonic acids and inorganic acids comprises of mineral acids. A suitable buffer can also be used for adjusting the pH. At pM 6.0 or more the decomposition of p ketoester intermediate is minimized and the product obtained has a purity of 95% or more.
The p-ketoester is reduced in the presence of diethylmethoxy borane or triethyl borane to get dihydroxy intermediate. The dihydroxy intermediate so obtained is then hydrolysed using sodium hydroxide to get crude fluvastatin and salts thereof from which pure fluvastatin or salts thereof are isolated.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
Preparation of β ketoester of Formula II wherein R is t-butyl
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To a suspension of sodium hydride (25 g, 60% by weight in mineral oil) in THF was added solution of t-butyl acetoacetate (124 g) in THF (125 ml), followed by n-butyl lithium (610 ml) solution in hexane and then fluvaldehyde (200 g) in THF (350 ml) at -10 to 0 °C. After the completion of the reaction, the pH of reaction mixture is adjusted dilute hydrochloric acid to about 7.5. The organic phase is separated and washed with brine solution (800 ml). The organic layer is concentrated to syrupy mass under vacuum to give p ketoester. Yield: 332 g Purity: above 95% w/w by HPLC
EXAMPLE 2
Preparation of dihydroxy intermediate of Formula IV wherein R is t-butyl
Sodium borohydride (47.6 g) were added to a solvent comprising THF (1.32 Lit) and methanol (356 ml) under nitrogen at about -77°C. To the resulting solution was added diethylmethoxy borane (102 ml of 50% (4.0M) solution in THF) over a 15 minutes period and thus formed mixture was stirred for an additional 10 minutes.
p-Ketoester intermediate of Formula IV wherein R is t-butyl (300.5 g) was mixed in THF (104 ml) methanol (26 ml) at a temperature about -74 to -77°C. To this mixture was added the previously prepared reducing mixture drop-wise over the period of 1.5 hours, and the resulting mixture was stirred for an additional 30 minutes. Saturated sodium bicaronate (120 ml) and heptane (1.75 Lit) were added to quench the reaction, followed by addition of ethyl acetate (1.5 Lit) and water (3.5 Lit) with stirring. The organic layer was separated and washed twice with saturated sodium chloride solution (1.5 Lit) to get a pH of about 7.5 and the organic layer was concentrated under high vacuum under 45°C. To the residue was added 375 ml of toluene and solvent is distilled at again at about 45°C. Ethyl acetate (3.73 Lit) was added to the residue followed by addition of hydrogen peroxide solution (50 ml, 30% w/w) while maintaining the internal temperature at
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about 25-30°C. The reaction mixture was stirred for 2 hours at 20-25°C until the TLC shows absence of boronate ester. The organic layer was washed twice with saturated sodium chloride solution and the solvent was distilled under high vacuum at about 45°C. The residue was dissolved in hot ethyl acetate (1.17 Lit) and the mixture was filtered while hot. The clear filtrate was stirred at 20-25°C for 18 hours. The solids were filtered and dried under reduced pressure at 25°C, washed with of ethyl acetate/heptane (550 ml, 1:4) and re-dissolved in ethyl acetate and stirred for 18 hours at ambient temperature. The solids were filtered and washed with ethyl acetate/heptane (480 ml, 1:2), dried to get the title compound. Yield: 114.5 g.
EXAMPLE 3
Preparation of Fluvastatin sodium
To a mixture of dihydroxy intermediate of Formula IV wherein R is t-butyl (35 g)
and ethanol (175 ml) under nitrogen was added sodium hydroxide solution (74 ml, 1N) while maintaining the internal temperature at about 15°C. The suspension was stirred at 30-35°C for 1 hour or until the pH was between 7-8. The solvent was evaporated under reduced pressure at 45°C and the residue was dissolved in water (250 ml). The distillation is continued until the remaining volume is about 115 ml. De-ionized water (315 ml) was added to the solution which is then gently washed in three portions with t-butyl methyl ether (525 ml). The solution was concentrated to about 245 ml, to which de-ionized water (185 ml) was added. The aqueous solution was lyophilized to obtain the title compound. Yield: 29.75 g
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WE CLAIM:
1. A process for preparation of fluvastatin or salt thereof wherein the said process comprises of a) reacting fluvaldehyde of Formula VI,

with alkyl acetoacetate of Fomula VII,

wherein R is as mentioned above in presence of sodium hydride and n-butyl lithium,
b) adjusting the pH of reaction mixture of step a) after completion of reaction to 6.0 or more,
c) reducing the β-ketoester intermediate of Formula II,

wherein R is as mentioned above is obtained in step b) to dihydroxy intermediate of Formula IV,
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in the presence of trialkyl borane or dialkylalkoxy boranes.
d) hydrolyzing the dihydroxy intermediate to fluvastatin or salt thereof,
e) isolating fluvastatin or salt thereof from the reaction mass.

2. A process as claimed in claim 1 having compound of Formula II wherein R is t-butyl.
3. A process as claimed in claim 1 wherein the pH is adjusted with dilute hydrochloric acid.
4. A process as claimed in claims 1 wherein the reduction is carried out in the presence of diethylmethoxy borane or triethyl borane.
5. A process as claimed in claims 1 wherein the hydrolysis is carried out using sodium hydroxide.
6. A process as claimed in claims 1 wherein fluvastatin sodium salt is isolated.
Dated this28th day of March, 2006
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