FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARATION OF FLUVASTATIN INTERMEDIATE
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 a process for the preparation of Fluvastatin intermediate. More over it related to cyclization process for 3-(4'-fluorophenyl)-1-(1'-methylethyl) indole intermediate.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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4. DESCRIPTION
The present invention relates to a process for the preparation of Fluvastatin intermediate. More over it related to cyclization process for 3-(4'-fluorophenyl)-1-(1'-methylethyl) indole intermediate.
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.

Formula I
U.S. Patent No. 5,354,772 discloses the process for synthesis of Fluvastatin, its sodium salt and pharmaceutical compositions thereof. The 722 patent disclosed the use of anhydrous zinc chloride in the formation of 3-(4'-fluorophenyl)-1-(1'-methylethyl) indole intermediate.
U.S. Patent No. 5,189,164 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 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%.
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Several other processes are known in the art for preparation of Fluvastatin or salt thereof, for eg. U.S. Patent No. 4,870,199; U.S. Patent No. 6,743,926; U.S. Patent No. 6,875,867.
Several polymorphic forms of Fluvastatin are disclosed in the art, for eg. U.S. Patent No. 6,696,479; U.S. Patent No. 6,858,643; PCT Application No. WO 2006021967; WO Application No 2006030304 and PCT Application No. WO 2007039784
Anhydrous zinc chloride tends to absorb water and leads to formation of zinc oxychloride, the main hydrolysis product. Anhydrous zinc chloride can also be prepared by heating the hydrated zinc chloride upto 400 °C for 4-5 hrs. Commonly the moisture present in the anhydrous zinc chloride is less than 1.0% It is difficult to get and manufacture anhydrous zinc chloride at commercial stage.
While working on the process for intermediates of Fluvastatin, It was found by the present inventors that hydrated zinc chloride can also be used for the formation of 3-(4'-fluorophenyl)-1-(1'-methylethyl) indole intermediate of formula III.

Formula III
Thus omitting one simple step of formation of anhydrous zinc chloride has the advantages includes: significant reduction in equipment demand (eg. driers, dehumidifiers etc.); and significant reduction of the process time and hence increase the process economy.
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One of the aspects of the present invention provides a process for preparation of 3-(4'-fluorophenyl)-1-(1'-methylethyl) indole of formula III, wherein the said process includes the cyclization of N-(4-fluorobenzoylmethyl)-N-(1-methylethyl) aniline of formula II, using hydrated zinc chloride in alcoholic solvent.

Formula II
The N-(4-fluorobenzoylmethyl)-N-(1-methylethyl) aniline of formula II, can be obtained by any process known to the skilled artisan, for eg. reacting 4-chloroacetyl 1- fluorebenzene, and N-isopropyl aniline. The so obtained N-(4-fluorobenzoylmethyl)-N-(l-methylethyl) aniline of formula II, is cydized to indole intermediate of formula III in presence of hydrated zinc chloride in alcoholic solvent at reflux temperature. After completion of reaction, the hydrochloric acid is added to the reaction mixture. The reaction mass is than extracted with methylene chloride which is completely removed under vacuum. The residue obtained is suspended in isopropanol isolated and dried.
The 3-(4'-fluorophenyl)-1-(1'-methylethyl) indole, can be used an intermediate in synthesis of Fluvastatin and salt thereof by the method known in the art.
The hydrated zinc chloride may contain the moisture between 1 to 10% w/w.
The non-limiting examples of alcoholic solvents include for example, n-butanol, isopropanol, n-propanol, ethanol, methanol and mixtures thereof.
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The 3-(4'-fluorophenyl)-1-(1'-methylethyl) indole intermediate has the purity of 99.0% or more
Removing the solvents may include, for example, one or more of filtration, filtration under vacuum, distillation, distillation under vacuum, evaporation, decantation and centrifugation.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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.
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Example 1: 3-(4'-fluorophenvl)-1-(1'-methylethvl) indole intermediate:
Hydrated Zinc chloride (562 g) was suspended in IPA (800 ml) at 25-40 °C and stirred. Then N-(4-Fluorobenzoyl methyl)-N-(1 -methyl ethyl) aniline (160 g) was added. The content was heated to reflux. After completion of reaction, the reaction mixture was cooled, quenched with 1 N hydrochloric acid (950 ml) slowly below 30° C. The compound was extracted with methylene chloride and the combined methylene chloride layer was washed with water and the organic layer was concentrated at 40CC under vacuum to get residue. The residue so obtained was slurred in isopropanol, filtered and dried to get the title compound.
Yield: 126 gm
Purity: 99.2%
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WE CLAIM:
1. A process for preparation of 3-(4'-fluorophenyl)-1-(1'-methylethyl) indole intermediate comprising the cyclization of N-(4-fluorobenzoylmethyl)-N-(1-methylethyl) aniline, in presence of hydrated zinc chloride in an alcoholic solvent.
2. The processes according to claim 1, wherein the hydrated zinc chloride is having moisture content more than 1%.
3. The processes according to claim 2, wherein the hydrated zinc chloride is having moisture content of upto 10%.
4. The process according to claim 1, wherein the alcoholic solvent is selected from the group consisting of n-butanol, isopropanol, n-propanol, ethanol, methanol and mixtures thereof.
5. The process according to claim 4, wherein the alcoholic solvent is Isopropanol.
6. The process according to claim 1, wherein the 3-(4'-fluorophenyl)-1-(1'-methylethyl) indole intermediate has the purity of 99.0% or more.
7. The process for preparation of 3-(4'-fluorophenyl)-1-(1'-methylethyl) indole of claim 1, as an intermediate in synthesis of Fluvastatin and salt thereof.

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Abstract:
The present invention relates to a process for the preparation of Fluvastatin intermediate. More over it related to cyclization process for 3-(4'-fluorophenyl)-1-(1'-methylethyl) indole intermediate using hydrated zinc chloride having moisture content more than 1% in presence of an alcoholic solvent.
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