FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARATION OF FLUVASTATIN SODIUM USING TRIALKYL BORANE
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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Formula 1 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 the reduction of b-ketoester intermediate to the dihydroxy intermediate is carried out in presence of dialkylalkoxy boranes such as diethylmethoxy borane (DEMBO) to achieve a greater chiral selectivity for erythro enantiomer over threo enantiomer.
Several other processes are known in the art for preparation of fluvastin 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 that when trialkyl boranes are used for the reduction of the p-ketoester intermediate to the dihydroxy intermediate, chiral selectivity can still be obtained with enantiomer ratio of erythro isomer to threo-isomer of 96:4. This selectivity is imparted at a very low molar ratio of trialkyl borane in the reaction much less than that reported in the 772 Patent. As compared to the '164 Patent which uses about 0.8 moles of DEMBO, the present inventors have noticed that with trialkyl borane the same reaction can be carried out in less than 0.6 moles.
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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) reducing p-ketoester of II,

wherein R is C1-5 alkyl, aryl, aralkyl; with a trialkyl borane of Formula III,
B(Ri)(R2)(R3)
Formula III
wherein R1( R2, R3 are independently C1-8 alkyl and sodium borohydride in presence of a lower alkanol and polar aprotic solvent to get the dihydroxy intermediate of IV,
,F

Formula IV wherein R is as defined above
b) hydrolysing the dihydroxy intermediate of Formula IV to Fluvastatin or salt thereof,
c) isolating Fluvastatin or salt thereof from the reaction mass.
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The p-ketoester intermediate used as starting material can be prepared by any process known in the art. It is then reduced by using trialky borane and sodium borohydride in presence of a mixture of lower alkanol and a polar aprotic solvent at-25 to-100°C.
Some examples of trialkyl borane are trimethyl borane, triethyl borane, tri-t-butyl borane and the like. The polar aprotic solvent can be selected from a group comprising of tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide or N-methylpyrrolidone. The lower alkanol can be methanol, ethanol, n-propanol, isopropanol or the like.
After the completion of reaction, the mass is quenched and extracted in suitable organic solvent in presence of water and the organic layer is concentrated to get the residue, which is purified to get the desired dihydroxy intermediate.
The so obtained dihydroxy intermediate has less than 5% of the unwanted threo-isomer. This product is further hydrolyzed using sodium hydroxide to get sodium salt of fluvastatin.

Formula II
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In yet another aspect of the present invention there is provided a process for preparation of Fluvastatin or salt thereof wherein the said process comprises of a) reducing p-ketoester of Formula II,

wherein R is C1.5 alkyl, aryl, aralkyl; with a borane compound of Formula V,
B(Ri)(R2)(R3)
Formula V
wherein R1 and R2 are independently C1-8 alkyl and R3 is C1.8 alkyl or C1_8 alkoxy and sodium borohydride in presence of a lower alkanol and polar aprotic solvent to get the dihydroxy intermediate of Formula IV,

Formula IV
wherein R is as defined above
b) hydrolyzing the dihydroxy intermediate of Formula IV to Fluvastatin or salt thereof,
c) isolating Fluvastatin or salt thereof from the reaction mass.
wherein the process is characterized by the fact that less than 0.6 moles of compound of Formula V is used for reduction in step a).
The p-ketoester intermediate used as starting material can be prepared by any process known in the art. The p-ketoester intermediate is reduced using less than 0.6 moles of a borane compound having Formula V R1 and R2 are independently C1-8 alkyl and R3 is independently C1_8 alkyl or C1.8 alkoxy; along with sodium borohydride in presence of a mixture of lower alkanol and a polar aprotic solvent at -25 to -100°C.
The compound of Formula V comprises of trialkyl boranes such as triethyl borane, trimethyl borane, tri-t-butyl borane or dialkylalkoxy boranes such as DEMBO. The polar aprotic solvent can be selected from a group comprising of
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tetrahydrofuran (THF), 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide or N-methylpyrrolidone. The lower alkanol can be methanol, ethanol, n-propanol, isopropanol or the like.
After the completion of reaction, the mass is quenched and extracted in suitable organic solvent in presence of water and the organic layer is concentrated to get the residue, which is purified to get the desired dihydroxy intermediate.
The so obtained dihydroxy intermediate has less than 5% of the unwanted threo-isomer. This product is further hydrolyzed using sodium hydroxide to get sodium salt of fluvastatin.
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 dihydroxy intermediate:
A solution of p-ketoester of Formula II wherein R is t-butyl (42 g), in THF (28 ml) and methanol (8 ml) was added to the mixture of sodium borohydride (3.9 g) and triethyl borane (33.0 ml, 0.1 M solution in THF and methanol) at -85 to -75 °C. After the completion of the reaction, sodium bicarbonate (90 ml, 10% aqueous solution) was added to the reaction mixture at the same temperature. The dihydroxy intermediate so formed was separated from the reaction mixture by addition of n-heptane (190 ml) and ethyl acetate (55 ml), and water (425 ml). The organic phase was separated and washed with brine and sodium sulfite solution. The organic layer was concentrated and the residue was slurried in a mixture of
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isopropanol : n-heptane for about 3 hrs. The material was filtered and dried in oven to get title compound. Yield: 18 g Purity: 99.2%.
EXAMPLE 2
Preparation of dihydroxy intermediate:
A solution of p-ketoester of Formula II wherein R is t-butyl (42 g), in THF (28 ml) and methanol (8 ml) was added to the mixture of sodium borohydride (3.9 g) and triethyl borane (41.0 ml, 0.1 M solution in THF and methanol) at -85 to -75 °C. After the completion of the reaction, sodium bicarbonate (90 ml, 10% aqueous solution) was added to the reaction mixture at the same temperature. The dihydroxy intermediate so formed was separated from the reaction mixture by addition of n-heptane (190 ml) and ethyl acetate (55 ml), and water (425 ml). The organic phase was separated and washed with brine and sodium sulfite solution. The organic layer was concentrated and the residue was slurried in a mixture of isopropanol : ri-heptane for about 3 hrs. The material was filtered and dried in oven to get title compound. Yield: 16 g Purity: 99.1%.
EXAMPLE 3
Preparation of dihydroxy intermediate:
A solution of p-ketoester of Formula II wherein R is t-butyl (330 g), in THF (224 ml) and methanol (64 ml) was added to the mixture of sodium borohydride (31 g) and diethylmethoxy borane (65.0 ml, 4 M solution in THF) at -85 to -75 °C. After the completion of the reaction, sodium bicarbonate (725 ml, 10% aqueous solution) was added to the reaction mixture at the same temperature. The
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dihydroxy intermediate so formed was separated from the reaction mixture by addition of n-heptane (1.5 Lit) and ethyl acetate (450 ml), and water (3.4 Lit). The organic phase was separated and washed with brine and sodium sulfite solution. The organic layer was concentrated and the residue was slurried in a mixture of isopropanol : n-heptane for about 3 hrs. The material was filtered and dried in oven to get title compound. Yield: 215 g
Purity: 99.38% w/w by HPLC Threo-isomer: 0.2% by HPLC.
EXAMPLE 4
Preparation of Fluvastatin sodium:
To a suspension of dihydroxy intermediate of Formula IV wherein R is t-butyl (15 g) in methanol (225 ml) at ambient temperature was added sodium hydroxide solution (1.4 g/15 ml of water). The contents were heated to 28-32 °C for 5 hours under nitrogen. After the completion of the reaction, concentrated the reaction mixture under vacuum at 38-42 °C to residue then co distilled the reaction mixture with methanol (50 ml), THF (100 ml) respectively to reduce the moisture content of the residue to below 15%. The residue was dissolved in THF (120 ml) and cooled to 8-12 °C for about 4 hours. The separated solids were filtered and washed with chilled THF (20 ml) and dried under vacuum at 45-50 °C to yield title compound. Yield: 13 g
Purity: 99.4% w/w by HPLC Threo-isomer: 0.23% by HPLC.
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WE CLAIM:
1. A process for preparation of Fluvastatin or salt thereof wherein
a. p-ketoester intermediate of Formula II, wherein R is C1-5 alkyl, aryl,
aralkyl; is reduced with a borane compound of Formula III, wherein
R1 is C1-8 alkyl and R2 is C1-8 alkyl or C1-8 alkoxy and sodium
borohydride in presence of a lower alkanol and polar aprotic solvent
to get the dihydroxy intermediate of Formula IV, wherein R is as
defined above and
b. hydrolysing the dihydroxy intermediate of Formula IV to Fluvastatin
or salt thereof.
c. isolating Fluvastatin or salt thereof from the reaction mass.
2. A process for preparation of Fluvastatin or salt thereof wherein the said
process comprises of
a. reducing p-ketoester of Formula II, wherein R is C1.-5 alkyl, aryl,
aralkyl; with a borane compound of Formula V, wherein R1 and R2
are independently C1-8 alkyl and R3 is independently C1-8 alkyl or C1.
8 alkoxy and sodium borohydride in presence of a lower alkanol and
polar aprotic solvent to get the dihydroxy intermediate of Formula
IV, wherein R is as defined above
b. hydrolysing the dihydroxy intermediate of Formula IV to Fluvastatin
or salt thereof,
c. isolating Fluvastatin or salt thereof from the reaction mass,
wherein the process is characterized by the fact that less than 0.6 moles
of compound of Formula III is used for reduction in step a).
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3. A process as claimed in claim 1 or 2 having compound of Formula II wherein R
is t-butyl.
4. A process as claimed in claim 1 or 2 wherein the polar aprotic solvent is tetrahydrofuran.
5. A process as claimed in claims 1 or 2 wherein the lower alkanol is methanol.
6. A process as claimed in claim 1 wherein trialkyl borane is triethyl borane.
7. A process as claimed in claim 2 wherein the boron compound of Formula V is
triethyl borane or DEMBO.
8. A process as claimed in claims 1 or 2 wherein the hydrolysis is carried out
using sodium hydroxide.
9. A process as claimed in claims 1 or 2 wherein fluvastatin sodium salt is
isolated.
10. A process as claimed in claim 2 and 7 wherein 0.4 moles of boron compound
is used for reduction.

Dated this 28th day of March, 2006

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