Field of the Invention
The present invention relates to a novel process for the preparation of Fluvastatin and its pharmaceutically acceptable salts, preferably sodium salt. Fluvastatin sodium salt chemically known as sodium salt of (±) (E)-7-[3-(p-fluorophenyl)-l-isopropyl-lH indol-2- yl]-3,5-dihydroxy-6-heptenoic acid. It can be represented as the following Formula (I). This invention further relates to Fluvastatin intermediates and the processes for the preparation thereof.

Fluvastatin, an HMG-CoA reductase inhibitor, that is, a cholesterol-biosynthesis inhibitor, is an important indole derivative that is used in the treatment of hyperlipoproteinaemia and arteriosclerosis.
Background of the Invention
Fluvastatin, an HMG-CoA reductase inhibitor, that is, a .cholesterol-biosynthesis inhibitor, is an important indole derivative that is used in the treatment of hyperlipoproteinaemia and arteriosclerosis. Indole derivatives of the formula (I) known as pharmaceutical active ingredients (e.g. from US Patent 4,739,073).
U.S Patent 4,739,073 is disclosed [Erythro-E)]-(±)-7-[3'-(4"-fluorophenyl)-l-isopropyl)-l H-indol-2'-yl]-3,5-dihydroxy-6-heptenoic acid and its sodium salt (Formula (I)). (Hereinafter referred to collectively as "The Agent") as inhibitors of HMG CoA reductase. The Agent is obtained therein via reduction of methyl- (E)-7-[3'-4"-fluoro phenyl)-1-isopropyl indol-2'-yl]-5-hydroxy-3-oxo hept-6-enoate and subsequent processing. However the agent may be obtained from the compound of formula (i) (BEM) by treatment with acid (to cleave acetonide-protecting group) followed by base hydrlysis (to cleave the ester as described in WO 03/01855) conversion of the initially formed salt to the free acid (Fluvastatin) or its pharmaceutically acceptable salts preferably sodium salt.
Many other patents disclose the process for the preparation of Fluvastatin and its intermediates but none of those patents are related to the process of the present invention. Known processes for the preparation of the indole compounds of formula (I) do not in all cases meet the demands made in terms of yield and economy of the process.
It is accordingly the aim of the present invention to provide a novel process for the preparation of Fluvastatin sodium of formula (I) using novel intermediates of compound of formula (g) and compound of formula (h), by means of which such compounds can be obtained in as high yield as possible.
The main object of the present invention is to synthesize the compound of formula (I) using novel intermediate compounds of formula (h) and compound of formula (g).
Advantages over the prior art process
> This invention provides a commercially viable process for the manufacture of the intermediate compound of formula (g) and compound of formula (h)
> Always convergence synthesis is preferable than linear synthesis
> Compound of formula (I) can be easily prepared by convergence synthesis, i.e. condensation of two novel compounds instead of synthesizing the compound in linear synthesis.
> Effluent generation in the preparation of compound of formula (h) which is disclosed in US Patent 4,739,073 is very high, due to usage of PBr3 for bromination.
> Reduction of cycle time
> Cost effective and eco-friendly process
Summary of the Invention
The present invention relates to a novel process for the preparation of Fluvastatin and its novel intermediates. The present invention further relates to processes for preparing such intermediate compounds, Fluvastatin sodium which is chemically known as sodium salt of (±) (E)-7-[3-(p-fluorophenyl)-l-isopropyl-lH indol-2-yl]-3,5-dihydroxy-6-heptenoic acid.
Accordingly, a first aspect of the present invention provides the novel intermediate i.e., (+) tert-butyl 2-[6-formyl -2,2-dimethyl-l, 3-dioxane-4-yl] acetate (BFA) (formula-g).

A second aspect of the present invention provides the novel intermediate i.e., diphenyl -(4 Fluoro phenyl)-!-isopropyl)-! H- indol-2-yl]-phosphine oxide (DPPO) (formula-h).

A third and fourth aspects of the present invention provides processes for the respective preparation of the Fluvastatin intermediates of the first and second aspects of the invention.
Fifth aspect of the invention provides the process for the preparation of Fluvastatin sodium salt (Formula-I).
The present invention provides a novel process for the preparation of compound of formula (g) (BFA). Which comprises of
a) Reducing Ethyl -4-chloro aceto acetate with an alkali or alkaline earth metal borohydride to give (+) ethyl -4-chloro-3-hydroxy butanoate of compound of formula (a).
b) Reacting the compound of formula (a) with tert.butyl acetate in presence of a strong base like Li HMDS, LDA to give compound of formula (b).
c) Selectively reducing the compound of formula (b) with an alkali or alkaline earth metal borohydride and trialkyl or dialkyl alkoxy borane or mixtures there of to give compound of formula (c),
d) Protecting the hydroxy groups of the compound of formula (c) with 2,2-dimethoxy propane in presence of an acid catalyst to give compound of formula (d).
e) Reacting compound of formula (d) with an alkali acetate like sodium acetate in presence of a phase transfer catalyst to give compound of formula (e).
f) Hydrolyzing the compound of formula (e) in presence of inorganic base like sodium carbonate, potassium carbonate to give compound of formula (f)
g) Oxidizing the compound of formula (f) with a mild-oxidizing agent like sodium hypochlorite in presence of TEMPO (2,2,6,6-tetramethyl piperidinyloxy free radical) to give the desired compound of formula (g).
Another aspect of the present invention is to provide a novel process for the preparation of a compound of formula (h) (DPPO), which comprises of:
i) The reaction of 2-methyl-2-chloro acetyl chloride with Fluorobenzene in presence of Lewis acid gives the 4-(2-methyl-2-chloroacetyl)-l-fluorobenzene (Formula-1).
ii) Reacting the Compound of formula-1 with N-isopropyl aniline which is in situ ring
closure in presence of Zinc chloride and ethanol or methanol gives 3-(4'- Fluorophenyl) -2-methyl-l-(l'-methylethyl) indole (Formula-2),
iii) Bromination of compound of formula-2 with N-halosuccinimide like N-
bromosuccinimide/DBDMH (Dibromodimethyl hydontion) in the presence of catalytic amount of Azo bis isobutyronitrile gives 3-(4'-Fluorophenyl) -2- bromomethyl-l-(l'-methylethyl) indole (Formula-3),
iv) Reaction of compound of formula-3 with Ethoxy diphenylphosphine gives the desired compound DPPO (Formula-h), in which R,R' are hydrogen or alkyl or cycloalkyl or aryl.
A further aspect of the present invention is to provide a novel process for the preparation of formula (I), which comprises of:
a) Condensation of diphenyl -(4 Fluoro phenyl)-1-isopropyl)-1 H- indol-2-yl]-phosphine oxide of formula (h) (DPPO) with (±) tort-butyl 2-[6-formyl -2,2-dimethyl-l, 3- dioxane-4-yl] acetate of formula (g) (BFA) in presence of a strong base to give the compound of formula (i). •
b) The compound of formula (i) on acid and base hydrolysis gives the Fluvastatin free acid which is optionally converted into its organic amine salts of compound of formula (j) for getting very high pure compound or Fluvastatin free acid can be converted into its sodium salt (Formula (I)) using sodium hydroxide.
c) Compound of formula (j) is further converted into its sodium salt compound of Formula (I) using sodium hydroxide.
The compound of formula (I) was analyzed by HPLC, using a liquid chromatograph equipped with variable wavelength UV-Detector, set at 242 nm. The coloumn is inertsil, CI8 ODS-3V 250X 4.6 mm; 5 ^m and the eluent 20% acetonitrile,40% methanol,40% 0.05 M Na H2P04 2 H20 buffer at pH 2.0, flow rate of 1.0 ml per minute, injection volume 20 microliters. The sample is prepared by diluting 0.025 gm of the sample to 100 ml with 4:5:1 water, acetonitrile, methanol. The product peak elutes at 11-14 minutes and diene impurity elutes at RRT -1.1.
Detailed description of the Invention
The present invention relates to a novel and improved process for the preparation of Fluvastatin and its novel intermediates. The present invention further relates to processes for preparing such intermediate compounds, Fluvastatin sodium which is chemically known as sodium salt of(±)-(E)-7-[3-(p-fluorophenyl)-l'-isopropyl-lH indol-2-yl]-3,5- dihydroxy-6-heptenoic acid.
The present invention schematically represented as follows.


The present invention provides a novel process for the preparation of compound of
formula (g) which comprises of
a) Reduction of ethyl-4-chloro aceto acetate with alkali hydrides or alkaline borohydrides like sodium hydride, potassium hydride or sodium borohydride, lithium borohydride with suitable organic acid like acetic acid in appropriate solvent selected from ethereal or aromatic solvents as mixtures thereof, tetrahydrofuran (THF), dimethoxy ethane and toluene, or mixtures thereof, preferably THF or THF and toluene, preferably tetrahydrafuran, methylene chloride or mixture of tetrahydrafuran, methylene chloride to give (+) ethyl -4- chloro-3-hydroxy butanoate (formula (a)). The reaction is carried out at -30 to 40°C, preferably at -15 to -10 °C temperature, for 30 minutes to 10 hrs, preferably for 30 minutes to 3hrs.
b) Compound of formula (a) is further condensation with tertiary butyl acetate to give compound of formula (b), in appropriate solvent such as ethers, hexanes, dioxane, toluene, cyclohexane, or any other inert organic solvent, the solvent is most preferably tetrahydrofuran, the reaction is carried out with strong base like, NaNH2, KHMDS, KNH2, a lithium amide compound such as lithium di isopropyl amide or Li HMDS, most preferably LiHMDS (Lithium hexa methyl disilazide), the reaction is carried out at a temperature of 25 °C to -90°C, most preferably at ^0°C to -78°C, and it is conducted under an inert atmosphere such as nitrogen or argon.
c) Compound of formula (b) is further selectively reduced to compound of formula (c) by using a reducing agent which include sodium borohydride , zinc borohydride, lithium borohydride, preferably sodium borohydride, Stereospecificity of the reduction reaction may be achieved by the use of a hydride reducing agent, particularly high stereospecificity may be achieved by the use of a combination of sodium borohydride and a trialkyl borane. The reducing agent employed is most preferably a mixture of triethyl borane or an alkoxydialkylborane such as methoxy diethyl borane and sodium borhydride. The stereospecific reduction is preferably carried out by addition of borane reagent followed by sodium borohydride, at the end of the reduction, the formed borane complex may be hydrolyzed by a peroxide such as hydrogen peroxide or by alkaline solution, the reaction is carried out at a temperature of from about -30 °C to about -90°C, most preferably from about -60°C to about- 80°C, and it is conducted under an inert atmosphere such as nitrogen or argon,
d) Protection of hydroxy groups in the compound of formula (c) with dimethoxy propane in presence of methane sulfonic acid as a catalyst in an appropriate solvent like acetone, tetrahydrafuran or dichloro methane to give the compound of formula (d), the reaction is carried out at 0 to 50°C, preferably at around 25-35°C for 10 minutes to 10 hrs, preferably for 30 minutes to 3hrs. The obtained protected compound of formula (d) is subjected to reaction with sodium acetate in presence of tetrabutyl ammonium bromide in toluene as a solvent or without using a solvent to give the compound of formula (e). The reaction is performed for 1-30 hrs preferably for 10-15 hrs at 105- 110°C.
e) The compound of formula (e) is subjected to hydrolysis in appropriate solvent such as an alcoholic solvent like methanol, ethanol isopropyl alcohol, butanol, in presence of a mild base like sodium carbonate or potassium carbonate to give the compound of formula (f).
f) The compound of formula (f) is oxidized with a mild oxidizing agent like sodium hypochlorite in presence of a free radical initiator in appropriate solvent such as dichloromethane, toluene, tetrahydrofuran. This reaction is conducted preferably at -30 to 50°C and more preferably at -10 to 20°C for 10 minutes to 5 hrs, preferably for 30 minutes to 2 hrs to give the desired compound of formula (g) (BFA).
Another aspect of the present invention is to provide a novel process for the preparation of
compound of formula (h) (DPPO) which comprises of
i) 2-methyl-2-chloro acetyl chloride reacts with fluorobenzene in presence of Lewis acid such as anhydrous aluminium chloride gives the compound of formula-1 in a suitable solvent such as non polar solvents like toluene, chlorobenzene and fluorobenzene preferably fluorobenzene at a temperature 45-85°C preferably at 55-65°C for 1-5 hours, preferably 2 hours,
ii) Compound of formula -1 on condensation with N-isopropyl aniline in a suitable aprotic solvent like dimethylformamide at a temperature of 50-100°C for 24 hours under nitrogen atmosphere, which is in situ converted into compound of formula-2 in presence of Zinc chloride and ethanol or methanol, the ethanol or methanol and Zinc chloride mixture is prepared at a temperature of about 25-80°C, and the reaction conducted at a temperature of 80-120°C preferably at 100-105°C for about 2-5 hours preferably for 3 hours.
iii) Bromination of compound of Formula-2 with NBS (N-bromosuccinimide) or DBDMH (dibromodimethyl hydontoin) in presence of catalytic amount of AIBN(Azo bis isobutyronitrile) in a suitable chloro solvent like methylene chloride, carbon tetrachloride or chlorobenzene preferably methylene chloride at a temperature of about 20-40°C gives the compound of formula-3.
iv) The compound of formula-3 on reaction with Ethyl diphenylphosphinite in a suitable non polar solvent like toluene at a temperature of about 40-90°C preferably at 65- 75 °C for about 2 hours to give the desired compound of Formula-(h) (DPPO)
Further aspect of the present invention is to provide a novel process for the preparation of
formula (I) which comprises of
a) Compound of formula (g) (BFA) is condensed with an aromatic intermediate i.e. diphenyl -(4 Fluoro phenyl)-l-isopropyl)-l H- indol-2-yl]-phosphine oxide of compound (h) (DPPO) in presence of a strong base like amide bases, alkyl metals and metal hydrides. Particular bases include, sodium bis (trimethyl silyl) amide, potassium bis (trimethyl silyl) amide, lithium bis (trimethyl silyl) amide, and butyllithium and sodium hydride. Particularly more preferred base is sodium bis (trimethyl silyl) amide (Na HMDS), in a suitable solvent or mixture of solvents like ethereal or aromatic solvents as mixtures thereof, tetrahydrofuran (THF), dimethoxy ethane and toluene, or mixtures thereof, preferably THF or THF and toluene to give the compound of formula (i), The reaction is carried out at a temperature in the range of -20°C to -90°C, such as -40°C to - 90°C,^0°C to-80°C preferably -75to -80°C,
b) Cleavage of the dihydroxy (acetonide) protecting group in the compound of formula (i) by acid hydrolysis, such as by using hydrochloric acid in suitable solvent like tetrahydrofuran, acetone, acetonitrile, this reaction is carried out at -10 to 35°C. Preferably at -10 to 20 °C more preferably at -5 to 15°C, and cleavage of the tert- butyl ester group under basic conditions by using a solution of a metallic hydroxide in a polar solvent, such as using aqueous sodium hydroxide in ethanol, acetone, THF or acetonitrile, then pH of the reaction mixture adjusted to below 4 to get Fluvastatin free acid, which is optionally converted into its amine salts with a organic amine bases like cyclic amines such as cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, dicyclohexyl amine, pyrrolidine or morpholine or alkyl amines such as methyl amine, isopropyl amine, disiopropyl amine, tert-butyl amine, n-octyl glucamine or aryl amines such as phenyl ethyl amine, phenyl propyl amine to give a respective salt of compound of formula (j)- This respective salt optionally recrystallized in the solvents like acetone, acetonitrile or mixture of acetonitrile and isopropyl alcohol to get very high
pure compound or Fluvastatin free acid can be converted into compound of Fomula (I) using sodium hydroxide.
c) Compound of formula (j) is further converted into its sodium salt compound of formula (I) using sodium hydroxide in a suitable solvent selected from alcoholic solvents like methanol, ethanol at a temperature 20-40°C for 2-5 hours.
The invention is further illustrated in the following examples, but not limited by the following examples
Experimental section
Example: 1
Preparation of (+) ethyl -4- chloro-3-hydroxy butanoate.(formula-a).
A solution of ethyl-4-chloro aceto acetate (500 gm), methylene chloride (1000 ml) and tetrahydrofuron (500 ml) is cooled to -15°C to -10°C and added sodium borohydride (86.5 gm) lot wise at -15 to -10°C, stirred for 2 hrs at -15 to -10°C. Quenched the reaction mixture with chilled water. Separated the organic layer and aqueous layer extracted twice with methylenechloride (2x500 ml ). Combined organic layer washed with 10% sodium bicarbonate solution, followed by washed with water. Distilled the solvent completely under reduced pressure to get the title compound as a residue. Residue weight (400 gm), which can be used for the next stage without any further purification.
Example:2
Preparation of (+) 6-chloro -5-hydroxy-3-oxo hexanoic acid 1,1-dimethyl ethyl ester (formula-b).
3511 ml of 1 molar LiHMDS solution and tetrahydrofuran (666 ml) cooled to - 75°C and tert-butyl acetate (70 ml) is added slowly in 45 minutes and maintained for 25
minutes at -72°C. (+) Ethyl -A- chloro-3-hydroxy butanoate (185 gm) obtained from example (1), solution in tetrahydrofuran (185 ml ) is added in 40 minutes at -73 °C and stirred for 1 hr 45 minutes at -73°C to -75°C. Raised the temperature to -45°C and stirred for 1 hr at -48 to -45°C. Quenched the reaction mixture with chilled water (3552 ml) and hydrochloric acid (888ml) solution. Separated the organic layer and washed with 10% sodium bicarbonate solution (100 ml). Finally dried the organic layer using sodium sulfate and distilled the solvent completely under reduced pressure. Residue is purified using pet- ether at -10 to -5° to get title compound formula (b). Yield (240 gm).
Example:3
Preparation of (+) 6-chloro-3, 5-dihydroxy hexanoic acid 1,1-dimethyl ethyl ester, (formula-c).
A solution of (+) 6-chloro -5-hydroxy-3-oxo hexanoic acid 1,1-dimethyl ethyl ester (500 gm), 3.5 lits of tetrahydrofuran and methanol (1 lit) is cooled to -70°C and diethyl methoxy borane (433 ml) is added slowly in 25 minutes to the reaction mixture. Stirred the reaction mixture at -70°C for another 25 minutes and sodium borohydride (86.5gr) is added in 9 lots. Stirred the reaction mixture for 2 hrs at -75°C. Quenched the reaction mixture with hydrogen peroxide solution and separated the organic layer washed with 10% sodium bicarbonate solution followed by water and brine solution. Finally organic layer is dried over sodium sulfate and solvent completely distilled under reduced pressure to get title compound of formula (c). Residue weight (446 gm).
Example:4
Preparation of (±) 6-(chloromethyl)-2,2-dimethyl-l,3-dioxane-4-acetic acid- l,ldimethyl ethyl ester.(formula-d)
A solution of (±) 6-chloro-3,5-dihydroxy hexanoic acid 1,1-dimethyl ethyl ester (280 gm) and acetone (1560 ml) is cooled to 25-30°C. Added 2,2-dimethoxy propane (1039 ml), methanesulfonic aicd (2.6 ml) to the reaction mixture and stirred at 25-35°C for 9 hrs. Quenched the reaction mass with sodium bicarbonate solution, separated the organic layer. Extracted the aqueous layer with pet-ether and washed the total organic layer with brine solution. Finally organic layer dried over sodium sulfate and distilled the solvent completely under reduced pressure to get title compound. Residue weight:254 gm.
Example:5
Preparation of (±) 6-[(Acetyloxy) methyl]-2,2-dimethyl-l,3-dioxane-4-acetic acid- l,ldimethyl ethyl ester. (Formula-e)
250 gms of (+) 6-(chloromethyl)-2,2-dimethyl-l,3-dioxane-4-acetic acid- 1,1 dimethyl ethyl ester, sodium acetate (225 gm) and tetrabutyl ammonium bromide (290 gm) are heated to 110-115°C and stirred for 12 hrs. Reaction mixtrue is diluted with pet- ether and filtered the byproduct. Organic layer washed with water. Distilled the solvent completely under reduced pressure and material isolated in pet-ether and dried the solid at 40-45°C. yield (100 gm). M.R: 62-65°C.
Example:6
Preparation of (+) 6-(Hydroxymethyl)-2,2-dimethyl-l,3-dioxane-4acetic acid,1,1- dimethylethyl ester (formula-f)
50 gms of (+) 6-[(Acetyloxy) methyl]-2,2-dimethyl-l,3-dioxane-4-acetic acid- 1,1 dimethyl ethyl ester is dissolved in methanol (250 ml), added potassium carbonate and cooled to 0-5°C. Stirred the reaction mixture at 0-5°C for 2 hrs. Quenched the reaction mixture with chilled water and stirred for 20 minutes. Extracted the reaction mixture thrice with dichloromethane (3x100 ml). Combined organic layer washed with brine solution and water (50ml). The total organic layer dried over sodium sulfate and distilled the solvent completely under reduced pressure to get title compound, yield (35 gm).
Example: 7
Preparation of (+) tert-butyl 2-[6-formyl -2,2-dimethyl-l, 3-dioxane-4-yl] acetate (formula-g).
A solution of (+) 6-(Hydroxymethyl)-2,2-dimethyl-l,3-dioxane-4aceticacid,l,l- dimethylethyl ester (25 gm) and methylene chloride is cooled to 0-5°C. KBr (lgm),
TEMPO (0.1 gm) (2,2,6,6-tetramethyl piperidinyloxy free radical) were added to the above reaction mixture. Sodium hypochlorite is added to the reaction mixture at 0-5°C in 60 minutes and stirred for another 30 minutes at 0-5°C. Quenched the reaction mixture with sodiumthiosulphate solution (10%) (50 ml), separated the organic layer and washed the organic layer with water (50 ml). Organic layer dried over sodium sulfate and distilled completely under reduced pressure to get title compound, yield (10 gm).
Example 8 :
Preparation of 4-(2-methyl-2-chloroacetyl)-l-fluorobenzene (Formula-1)
260 gr of 2-methyl-2-chloro acetyl chloride (2.04 moles) is added over a 50 minutes period to a mixture of 410 gr of fluorobenzene (4.22 moles) and 300 gr of anhydrous aluminium chloride (2.25 moles) stirred at 75°C under nitrogen. The reaction mixture is stirred at 80°C under nitrogen for 1 hour, cooled to 50°C, 500 ml of fluorobenzene is added and the reaction mixture is cooled to 0°C and gradually (over a 30 minutes period) added 1 lit of 6N hydrochloric acid and stirred at 0°C (The temperature of the aqueous hydrochloric acid is maintained at or below 25°C throughout the addition). The quenched, acidified reaction mixture is stirred for 15 minutes, and the aqueous phase is separated and extracted with 350 ml of fluorobenzene. The two organic phases are combined and washed twice with 500 ml portions of 3N hydrochloric acid and once with 500 ml of water. The fluorobenzene is distilled under reduced pressure at 60°C and upon cooling, the obtained oily residue solidifies to give title compound, Yield 185gr.
Example 9 :
Preparation of 3-(4'-Fluorophenyl) -2-methyl-l-(l'-methylethyl) indole (Formula-2)
562.9 gr (4.08 moles) of N-isopropylaniline is rapidly added to a solution of the crude product of 4-(2-methyl-2-chloroacetyl)-l -fluorobenzene in 500 ml of dimethyl formamide stirred at 50°C under nitrogen atmosphere for 10 hours and allowed to cool to room temperature overnight. The reaction mixture is heated to 60°C, 2.0 lit. of water is added, and the mixture is cooled to 10°C. The obtained solids are collected, washed twice with 500 ml portions of water and dissolved in 550 ml of 95% ethanol at 75°C. The solutions is cooled to 0°C, and the obtained solids are collected, and 1250 gr (9.3 moles) of anhydrous Zinc chloride is added portionwise to 1.90 lit. of absolute methanol stirred at 25-3 5 °C under nitrogen. The addition is exotherimc. The above obtained solid is added to the resulting hot (70°C) solution, and the reaction mixture is stirred at 100-103°C under nitrogen for 3 hours and cooled to 25°C, 1.5 lit of IN. hydrochloric acid is added, followed by 1.0 lit. of methylene chloride. The resulting two phase system is stirred for 5 minutes, the organic phase is separated, and the aqueous phase is washed twice with 250 ml portions of methylene chloride. The three methylene chloride phases are combined, the volume is reduced by about 50% by partial evaporation .of the methylene chloride at 40°C under reduced pressure, and 1.0 lit. of 95% of ethanol is added. The reaction mixture is distilled at atmospheric pressure until a vapor temperature of 75 °C is reached and cooled to 0°C. The obtained solids are collected, washed three times with 100 ml portions of cold ethanol and reduced pressure dried overnight at 25-35°C to obtain the title compound as a white powder, Yield 350gr.
Example 10:
Preparation of 3-(4'-Fluorophenyl) -2-bromomethyl-l-(l'-methylethyl) indole (Formula-3)
61.9 gr (0.348 moles) of N-bromo succinimide is added to the solution of 77.5 gr (0.29 moles) of 3-(4'-Fluorophenyl) -2-methyl-l-(l'-methylethyl) indole, 500 ml of Dichloromethane and 8.2 gr (0.05 moles) of Azo bis iso butyronitrile, reaction mixture heated to 35-40°C and stirred for 8 hours, cooled the reaction mixture to 25-35°C, 1.0 lit. of chilled water added to the reaction mixture, filtered the unwanted solids, take the filtrate and add 1.0 lit. of methylene chloride stirr for 15-20 mintues, separated the organic and aqueous phases and washed the aqueous phase twice with methylene chloride, combined the organic phases and washed with 250 ml portions of 5% sodium bicarbonate solution, followed by 250 ml portions of water. Distilled the organic phase completely under reduced pressure and isolated the title compound using hexanes, Yield 51gr.
Example 11:
Preparation of diphenyl -(4 Fluoro phenyl)-l-isopropyl)-l H- indol-2-yl]-phosphine oxide (Formula-4)
Ethyl diphenylphosphinite (8 gm) was added to the solution of 8 gr of 3-(4'- Fluorophenyl) -2-bromomethyl-l-(l'-methylethyl) indole and 50 ml o f Toluene. The mixture was stirred at 65-75°C for 2 hrs, then heated to 105-110°C and stirred for another 2 hrs. Distilled the solvent completely under reduced pressure and the material is isolated using n-hexane and dried under reduced pressure at 50-60°C to give title compound, Yield 8.0gr.
Example: 12
Preparation of (E)- (±)--6-{2-(l-isopropyl-3- (4- fluoro phenyl)-l H- indol-2-yl)- vinyl]-2,2- dimethyl- [l,3]-dioxane-4-yl}-acetic acid tert-butyl ester (Formula-i)
A mixture of DPPO formula- (h) (12 gm) and THF (120 ml) were warmed briefly to 40°C until a clear solution observed, then inserted by the sequential application of reduced pressure and nitrogen. The mixture was cooled to -75°C. Sodium bis (trimethyl silyl) amide (30 ml) was added to the reaction mixture over 30 minutes through dropping funnel maintaining the temperature below -75°C. The mixture stirred for further 1 hr at - 76°C. BFA compound of formula (g) (6 gm in 50 ml of toluene) was added in portions to the suspension over 30 minutes through dropping funnel maintaining the temperature below -73°C. The mixture stirred for further 15 minutes at -76°C. The suspension allowed to warm to 10°C over 1.0 hr. Glacial Acetic acid (3 ml) in water (30 ml) was added in one portion raising the temperature to 18°C and dissolving all solids and the mixture was stirred for further 5 minutes. Further reaction mixture diluted with water and organic layer separated. Organic layer washed with sodium bicarbonate solution (10%) (60ml) and followed by washing with saturated sodium chloride solution (50 ml). Organic layer distilled under reduced pressure and crude product isolated using n-hexane. The crude product taken into diisopropyl ether and filtered the unwanted, Filtrate is concentrated by distillation under reduced pressure and product of formula (i) is isolated in acetonitrile. (Yield: 5 gm. M.R: 133-137°C)
Example-13:
Preparation of Dicyclohexyl amine salt of (±) (E)-7-[3-(p-fluorophenyl)-l- isopropylindol-2-yl]-3,5-dihydroxy-6-heptenoic acid, (formula-j)
A solution of (E)- (±)--6-{2-(l-isopropyl-3- (4- fluoro phenyl)-l H- indol-2-yl)- vinyl]-2,2- dimethyl- [ 1,3]-dioxane^-yl} -acetic acid tert-butyl ester (10 gm) and acetonitrile (400ml) is cooled to 20-25°C, added aqueous hydrochloric acid solution (0.75 ml in 58 ml water) slowly in 30 minutes. Stirred for 1.5 hrs, sodiumhydroxide (1.5 gm) in water (75 ml) solution is added slowly in 20 minutes and stirred the reaction mixture for 3 hrs at 30-35°C. Reaction mixture is cooled to 0-10°C and pH is adjusted to 4 with 10% hydrochloric acid and organic layer washed with brine solution. Dicyclohexyl amine(3 gm) is added to the reaction mixture at 0-10°C and reaction mixture is further diluted with 100 ml of acetonitrile and raised the temperature to 25-35°C, further stirred for 2 hrs at 25- 35°C, filtered the cake and washed with acetonitrile (50 ml). It is re crystallized in a mixture of acetonitrile and isopropyl alcohol solvents and dried the obtained product at 40-45°C for 5 hrs. Yield (7.5 gm). HPLC Purity: 99.84%.
Example: 14
Preparation of sodium salt of (±) (E)-7-[3-(p-fluorophenyI)-l-isopropylindol-2-yl]- 3,5-dihydroxy-6-heptenoic acid. (formula-I)
A solution of 4.5 ml of IN sodium hydroxide, 2.0 gr of compound of formula (j) and 150 ml of methanol is stirred at 25-35°C for 2 hours, the solvent is evaporated under reduced pressure, and the product isolated using acetone, Yield 1.5 gr.

We Claim :
1. Process for the preparation of compound of formula (I) using the compound of formula (g) and the compound of formula (h), which comprises of:

a) Condensation of Compound of formula (g) (BFA) with an aromatic intermediate i.e. diphenyl -(4 Fluoro phenyl)- l-isopropyl)-l H- indol-2-yl]-phosphine oxide of compound of formula (h) (DPPO) in a suitable solvent or mixture of solvent selected from ethereal or aromatic solvents as mixtures thereof, tetrahydrofuran (THF), dimethoxy ethane and toluene, or mixtures thereof, preferably THF or THF and toluene, in the presence of a suitable bases like amide bases, alkli metals and metal hydrides, particular bases like sodium bis (trimethyl silyl) amide, potassium bis (trimethyl silyl) amide, lithium bis (trimethyl silyl) amide, and butyllithium and sodium hydride, more preferred base is sodium bis (trimethyl silyl) amide (Na HMDS), U oVVo^
b) deprotection of the compound of formula (i) obtained from step (a) using inorganic or organic acid such as hydrochloric acid or acetic acid in a suitable solvent like THF or Acetone or Acetonitrile, which is in situ hydralyzing to cleave the tert-butyl ester
group using inorganic or organic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide to give Fluvastatin free acid which is further converted into its organic amine salts of compound of formula (j) using organic amine bases like cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, dicyclohexyl amine, pyrrolidine or morpholine or alkyl amines such as methyl amine, isopropyl amine,disiopropyl amine, tert-butyl amine, n-octyl glucamine or aryl amines such as phenyl ethyl amine, phenyl propyl amine, preferably dicyclohexyl amine or methyl amine,
c) reacting the compound of formula (j) with sodium hydroxide in a suitable solvent selected from alcoholic solvents like methanol, ethanol, preferably methanol to give compound of formula (I).
2. Process for the preparation of compound of formula (g), which comprises of i e
V , \ .S,
a) Reduction of ethyl-4-chloro aceto acetate with alkali or alkaline borohydrides like sodium borohydride, lithium borohydride, preferably sodium borohydride with suitable organic acid like acetic acid in appropriate solvent selected from ethereal or aromatic solvents or halo solvents or mixtures thereof, tetrahydrofuran (THF), dimethoxy ethane and toluene, or mixtures thereof, preferably THF or THF and toluene, preferably tetrahydrafuran, dichloro methane or mixture of tetrahydrafuran, dichloro methane, h> C / * - e •
b) condensation of (+) ethyl -4- chloro-3-hydroxy butanoate obtained from step (a) with tertiary butyl acetate in presence of strong base like, NaNH2, KHMDS, KNH2, lithium amide compound such as lithium di isopropyl amide or Li HMDS, most preferably LiHMDS (Lithium hexa methyl disilazide),in an appropriate solvent such as ethers,
hexanes, dioxane, toluene, cyclohexane, or any other inert organic solvent, preferably tetrahydrofuran,
c) reducing the compound of formula (b) obtained from step (b) with alkali hydrides or alkaline borohydrides like sodium hydride, potassium hydride or sodium borohydride, lithium borohydride, zinc borohydride, preferably sodium borohydride, and mixtures thereof, the reducing agent employed is most preferably a mixture of alkyl borane or an alkoxydialkylborane such as methoxy diethyl borane and sodium borhydride,
d) protecting the hydroxy groups of compound of formula (c) obtained from step (c) with dimethoxy propane in the presence of methane sulfonic acid as a catalyst in appropriate solvent selected from chloro solvents like methylene chloride, carbon tetra chloride, acetone, tetrahydrafuran, reaction of compound of formula (d) obtained above, with alkali salts like sodium acetate in presence of phase transfer catalyst like tetrabutyl ammonium bromide, tetra butyl ammonium fluoride in neat reaction or using non polar solvents like chlorobenzene, toluene; cyclohexane as a solvent, preferably toluene,
e) hydorlyzing the compound of formula (e) obtained from step (d) in appropriate solvent such as an alcoholic solvent like methanol, ethanol isopropyl alcohol, butanol, in the presence of a mild base selected from carbonate bases like sodium carbonate, potassium carbonate, preferably sodium carbonate,
f) oxidation of compound of formula (f) obtained from step (e) with a mild oxidizing agent hypochlorite like sodium hypochlorite in presence of a free radical initiator like TEMPO (2,2,6,6-tetramethyl piperidinyloxy free radical) in appropriate solvent selected from chloro solvent such as methylene chloride, toluene, tetrahydrofuran, preferably methylene chloride to give the desired compound of formula (g) (BFA).
3. Process for the preparation of compound of formula (h) which comprises of
/
ri>
y
a) Reacting 2-methyl-2-chloro acetyl chloride with Fluorobenzene in presence of lewis acids like anhydrous aluminium chloride in an appropriate solvent like halo benzene, toluene preferably toluene,
b) condensation of compound of formula-1 obtained in step (a) with N-isopropyl aniline and in situ ring closure in presence of Zinc chloride and ethanol,
c) compound of formula-2 obtained in step (b) on reaction with N-halo succinimide like N-bromosuccinimide or DBDMH, preferably N-bromosuccinimide in the presence of catalytic amount of Azo bis isobutyronitrile in a solvent selected from methylene chloride, carbon tetrachloride, 1,4-dioxane, preferably methylene chloride,
d) compound of formula-3 obtained in step (c) on reaction with ethyl diphenylphosphinite in an appropriate solvent selected from toluene, chlorobenzene, preferably toluene.
4. A compound of general formula .

Wherein R is halogen, acetyloxy, hydroxy, and formyl • R' is tertiary butyl.
5. A compound of general formula vv*' 1
O^T
/
Wherein R is tertiary butyl.
6. A compound of general formula • I.
w
V-
f.
' . I I
# / '
Wherein R is halogen, acetyloxy, hydroxy, and formyl ^ C > v
R' is tertiary butyl.
7. A compound of general formula . k
i
Wherein R and R' are C1-C4 alkyl, aryl. , a
; f
8. A compound of general formula (j) I
/
Wherein R,R' are Dicyclohexyl and R is Hydrogen and R' is Methyl.