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
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.
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 β-ketoester intermediate to the dihydroxy intermediate is carried out in presence of dialkylalkoxy boranes. The dihydroxy intermediate is isolated and purified from a solvent system containing ethyl acetate and hydrogen peroxide with a yield of 42%.
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 that after reduction of the p-ketoester using a suitable reducing agent, when the product dihydroxy intermediate is purified using two or more polar organic solvents, the yield is increased to 67%. Also the purity of the desired isomer of dihydroxy intermediate, i.e. erythro isomer is increased to 99.7%. When this enriched intermediate is further hydrolyzed to fluvastatin or salts thereof the yield and purity of the resulting product is greatly enhanced.
2

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 Formula II

wherein R is C1-6 alkyl with a suitable reducing agent to get dihydroxy intermediate of Formula IV

wherein R is as described above,
b) purifying the dihydroxy intermediate of Formula IV from two or more polar organic solvents,
c) hydrolysing the dihydroxy intermediate of Formula IV to Fluvastatin or salt thereof,
d) isolating Fluvastatin or salt thereof from the reaction mass.
The β-ketoester intermediate used as starting material can be prepared by any process known in the art. It is then reduced to dihydroxy intermediate by using dialkyl borane such as diethylmethoxy borane and sodium borohydride in presence of a mixture of lower alkanol and a polar aprotic solvent at -25 to -100°C.
3

After the completion of reaction, the dihydroxy intermediate is isolated using two or more polar organic solvents. Some examples of organic solvents are methanol, dimethyl ketone, diethyl ketone, methyl ethyl ketone (MEK), methylacetate, ethylacetate, propylacetate, methylpropylate, ethylpropylate and the like. Present inventors used a number of organic solvent combinations as tabulated in Table 1.

S. No Input(g) Solvents Yield(g) Purity Antiisomer(%) Other impurities (>0.05%)
1 5 Methanol (10 vol) 3.5 95.9 2.8 0.40 0.60
2 5 Methyl ethyl ketone (10 vol) 2.2 98.7 1 0.07 0.07
3 37 Ethyl acetate (10 vol) 18 95.9 0.9 2.7 0.18 0.12
4 5 Methanol/lsopropanol (1:4) 3.5 97.8 1.6 0.16 0.4
5 3 Ethyl acetate: Isopropanol (1:1) Methyl ethyl ketone / 1.6 98.8 0.92 0.09 0.13
6 5 methyl t-butyl ether (1:1)Ethylacetate / 2.2 98.6 1 0.07 0.1
7 235 methyl ethyl ketone (1:1) 204 99.7 0.2 - -
Table 1
The maximum yield of 67% is achieved when dihydroxy intermediate is purified using methyl ethyl ketone and ethylacetate.
The so obtained dihydroxy intermediate is hydrolyzed using sodium hydroxide to get sodium salt of fluvastatin. Fluvastatin and salts thereof are further purified from the crude form.
4

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
Purification of dihydroxy intermediate:
β-ketoester of Formula II wherein R is t-butyl (330 g) in tetrahydrofuran (224 ml) and methanol (64 ml) was added to a mixture of sodium borohydride (31 g) suspended in to a mixture of tetrahydrofuran and methanol and diethylmethoxy borane (65 ml, 4.0 M solution in tetrahydrofuran) at -85 to -75°C. After the completion of the reaction, it was quenched with saturated solution of sodium bicarbonate (725 ml) and a mixture of n-heptane (1.5 Lit) and ethyl acetate (450 ml), and water (3.4 Lit). The organic phase was separated and concentrated to residue under vacuum. This residue was dissolved in ethyl acetate (3.0 Lit) and stirred in a solution of hydrogen peroxide (600 ml) at 20-25°C. The organic phase is separated and washed with brine (2.0 L), sodium sulfite solution (2X2.7 L) and then again with brine solution (2.0 L) at 20-25 °C. The organic layer is concentrated to residue under vacuum at 40-45 °C. The residue was slurried in a mixture of isopropanokn-heptane at 8-12 °C. The material was filtered and dried in oven at 50-55 °C under vaccum. This crude was recrystallized by dissolving at 60-65 °C in 1:1 mixture of ethyl acetate/methyl ethyl ketone (940 ml), cooled slowly to 8-12 °C and stirred. The crystallized material was filtered and washed with 200 ml of 1:1 mixture of ethyl acetate/methyl ethyl ketone and dried in oven at 50-55 °C under vacuum to get title compound. Yield: 204 g Purity: 99.7%
5

EXAMPLE 2
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
6

WE CLAIM:
1. 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 Ci-6 alkyl with a
suitable reducing agent to get dihydroxy intermediate of Formula
IV wherein R is as described above,
b. purifying the dihydroxy intermediate of Formula IV from two or
more polar organic solvents,
c. hydrolysing the dihydroxy intermediate of Formula II to Fluvastatin
or salt thereof,
d. 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 polar organic solvent comprises of methyl ethyl ketone, ethyl acetate, methanol, ethanol, isopropanol or tetrahydrofuran.
4. A process as claimed in claims 1 wherein the hydrolysis is carried out using sodium hydroxide.
5. A process as claimed in claims 1 wherein fluvastatin sodium salt is
isolated.

Dated this 28th day of March, 2006