PREPARATION OF ATORVASTATIN

INTRODUCTION

The present disclosure relates to processes for the preparation of (4R-cis)-1,1-dimethylethyl-6-[2[2-(4-fluorophenyl]-5-(1-methylethyl)-3-phenyl-4[(phenylamino) carbonyl]-1H-pyrrole-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate, which is an intermediate for preparation of atorvastatin. The present disclosure also relates to processes for the preparation of an intermediate of Formula II which is used in for the preparation of atorvastatin and its salts.

Atorvastatin is described chemically as [R-(R*,R*)]-2-(4-fluorophenyl)-p,5-dihydroxy-5-(1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 -heptanoic acid and is represented structurally by Formula I.

Atorvastatin is useful as a selective and competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme to mevalonate, a precursor of sterols such as cholesterol. The conversion of HMG-CoA to mevalonate is an early and rate-limiting step in cholesterol biosynthesis.

Atorvastatin as well as some of its metabolites are pharmacologically active in humans and are thus useful as a hypolipidemic and hypocholesterolemic agent. Atorvastatin is commercially available as Lipitor® in USA, in the form of its hemicalcium salt.

U.S. Patent No. 5,273,995 discloses atorvastatin, its pharmaceutically acceptable salts. The patent also gives processes for its preparation. Various processes for the preparation of atorvastatin, its salts, and its intermediates have been described in subsequent patents and applications.

Processes for the preparation of the Formula II provided in the art involve the reaction of a 1,4-diketone of Formula III with a primary amine of Formula IV. The reaction of the amine with the 1,4-diketone is known as the Paal-Knorr pyrrole synthesis. It involves addition of a primary amine to both ketone groups of the 1,4diketone and elimination of two moles of water to achieve aromaticity as shown in Scheme 1.

U. S. Patent No. 5,298,627 discloses Paal Knorr condensation of amine with 1,4-diketone in 2:1:1 heptane:THF:toluene in the presence of pivalic acid as a catalyst. Baumann, K. L. et al. Tet. Lett. 1992, 33, 2283-84 describes a process for preparing atorvastatin, which involves preparing a pyrrole intermediate, in 75% yield from (4R-cis)-1, 1- dimethylethyl-6-aminomethyl-2, 2-dimethyl-1, 3-dioxane-4-acetate tert-butyl ester. The Paal Knorr reaction is carried out in a ternary solvent mixture of toluene-heptane-tetrahydrofuran (THF) (1:4:1) in the presence of a pivalic acid catalyst. Another similar condensation between a diketone and amine is described in U. S. Patent No. 5,397, 792 where the condensation is carried out in a 6:10:5 toluene:heptane:tetrahydrofuran solvent mixture in the presence of pivalic acid as catalyst.

U. S. Patent No. 5,216,174 teaches generally that the Paal Knorr reaction can be performed on an acetonide-protected 7-amino-3, 5-dihydroxy heptanoic acid tert-butyl ester in an inert solvent or solvents such as, for example, hexane, toluene and the like for about 24 hours at about the reflux temperature of the solvent or solvents and that the product is not isolated but is treated directly with acid to remove the acetonide protecting group. International Application Publication No. WO 2006/097909 A1 describes Paal Knorr condensation of diketone compound III with primary amine IV in presence of a catalyst, the catalyst comprising a salt wherein the salt comprises an amine salt or an inorganic salt of an organic acid.
The present inventors have developed an improved process for the preparation of compound of Formula II involving the use of a phase transfer catalyst and a secondary amine during condensation thus providing a process which affords shorter reaction time, better yield than all the known processes and can be practiced on an industrial scale.

SUMMARY

The present disclosure provides processes for the preparation of the compound (4R-cis)-1,1-dimethylethyl-6-[2[2-(4-fluorophenyl]-5-(1-methylethyl)-3-phenyl-4[(phenyl amino)carbonyl]-1 H-pyrrole-1 -yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate of Formula II by the Paal-Knorr condensation of 1,4-diketone of Formula III with a primary amine of Formula IV in the presence of catalytic acid, phase transfer catalyst and an organic amine.

Another aspect of the present disclosure provides processes for the preparation of atorvastatin or its salts of Formula I using the intermediate of Formula II.

DETAILED DESCRIPTION

The present disclosure provides processes for the preparation of the compound (4R-cis)-1,1 -dimethylethyl-6-[2[2-(4-fluorophenyl]-5-(1 -methylethyl)-3-phenyl-4[(phenyl amino)carbonyl]-1 H-pyrrole-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate of Formula II by the Paal-Knorr condensation of 1,4-diketone of Formula III with a primary amine of Formula IV in the presence of catalytic acid, phase transfer catalyst and an organic amine.
According to the disclosure there are provided processes for preparing a compound of formula II:

comprising reacting a 1,4-diketone of the formula III:

with a primary amine of the formula IV:

silyl or R1 and R2 together are CRaRb wherein Ra and Rb may be same or different and are independently an C1-C11 alkyl group or Ra and Rb, together with the carbon atom to which they are attached, may form a ring, and R3 is an C1-C6 alkyl group; in the presence of a catalytic acid, organic amine, and phase transfer catalyst.

Suitable catalytic acids include, but are not limited to, carboxylic acids such as
acetic acid, butyric acid, pivalic acid, benzoic acid, , toluenesulphonic acid,
trichloroacetic acid, or isobutyric acid. Suitable organic amines are primary,
secondary, or tertiary amines. Suitable primary amines which can be used for the
reaction step include, but are not limited to, methylamine, ethylamine, ethanolamine,
or the like. Suitable secondary amines which can be used for the reaction step
include, but are not limited to, dialkylamine, N-alkylaniline, N-alkylbenzylamine, N-
alkyl-o-tolylamine, pyrrolidine, piperidine, morpholine, or proline. Suitable tertiary
amines which can be used for the reaction step include, but are not limited to,
triethylamine, pyridine, 1-butylimidazole, n-ethylmorpholine, N-methylmorpholine, or
the like. In one embodiment, the organic amine is a secondary amine.

Suitable phase transfer catalysts which can be used include, but are not limited to
salts of onium ions (e.g. tetraalkyl ammonium salts) or agents that complex inorganic
cations (e.g. crown ethers). Examples of such catalysts include, but are not limited
to, benzyltrimethylammonium chloride, benzyltributyl ammonium bromide,
benzyltrioctyl ammonium bromide, benzyltriphenylphosphonium bromide,
benzyltriethylammonium chloride, benzyltriethylammonium bromide, hexadecyltributylphosphonium bromide, hexadecyltrimethylammonium bromide, methyltrioctylammonium chloride, methyltrioctyl ammonium bromide, tetrabutyl ammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, tetramethyl ammonium hydrogen sulfate, tetramethylammonium bromide, tetramethylammonium chloride, tetramethyl ammonium iodide, tetraethylammonium bromide, tetraethyl ammonium chloride, tetraethylammonium iodide, tetraethylammonium hydrogen sulfate, tetrapropyl ammonium bromide, tetrapropylammonium chloride, tetrapropylammonium iodide, tetrapropylammonium hydrogen sulfate, triethylbutylammonium bromide, trimethylbenzylammonium bromide, thethylbenzylammonium chloride, tripropylbenzyl ammonium chloride, dodecyltrimethylammonium bromide, tricetylmethyl ammonium chloride, crown ethers such as 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane), and polyethylene glycols.

Suitable solvents which can be used for the reaction steps include, but are not limited to alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, or 2-butanol; nitriles such as acetonitrile or propionitrile; halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane, or the like; ketones like acetone; aliphatic hydrocarbons like cyclohexane or hexane; aromatic hydrocarbons like toluene or xylene; dimethyl sulphoxide; ethers like THF or dioxane; or mixtures thereof.

Suitable temperature at which the reaction can be carried out is in the range of about 40°C to about 100°C In one embodiment, the temperature is in the range of about 50°C to about 85°C. The mole ratio of the reactants of Formula III to Formula IV lies in the range of from about 1:2 to about 2:1. In one embodiment the mole ratio of reactants is in the range of about 1:1.

Suitably, the reaction is completed in a time from about 10 hours to about 25 hours. There is a substantial decrease in the time for reaction completion when compared to the processes described in the art. WO2006097909 A1 discloses about 48-50 hours and WO2004046105 A3 discloses about 96 hours for the completion of reaction.

Isolation and purification of the intermediate of Formula II described above can be effected, if desired, by any suitable separation or purification procedure such

as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.

The yield of the obtained product ranges from about 80% to about 85% with respect to the starting material. The yield is substantially improved over the yields mentioned in the prior art procedures. WO2004046105 A3 discloses about 65-75% yield and WO2006097909 A1 about 75-80% yield of the intermediate of Formula II.

Another aspect of the present disclosure is to provide a process for the preparation of atorvastatin or its salts of Formula I comprising:

a) condensing compound of Formula III with the compound of Formula IV in presence of catalytic acid, phase transfer catalyst, and organic amine in a suitable solvent to give intermediate of Formula II;
Formula II

b) removing the acetonide protecting group of the open chain compound of
Formula II with a strong acid in a suitable solvent to give atorvastatin of Formula I; and

c) optionally converting atorvastatin to a pharmaceutically acceptable salt.
Step a) can be performed as defined in the first embodiment of the disclosure.

In step b) the compound of Formula II is treated with a strong acid such as
hydrochloric acid, trifluoroacetic acid, ortho phosphoric acid or the like in a suitable solvent to remove the diol protecting group. Suitable solvents which can be used for the deprotection reaction include, but are not limited to aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide, acetonitrile or the like; hydrocarbons such as toluene or the like; or mixtures thereof.

Atorvastatin obtained after deprotection may then be converted, if so desired, to a metal salt by contacting it with a source of the metal cation. Pharmaceutically acceptable metal salts include sodium, potassium, calcium, magnesium, aluminum, iron and zinc salts. Preparation of metal salt of the 3, 5-dihydroxy-7-pyrrol-1-yl heptanoic acid of Formula (I), is carried out according to prior art. Atorvastatin or its salts obtained using the process of the present disclosure have a purity of more than about 99.5% or more than about 99.9 % by HPLC. The starting compounds of Formula III and formula IV can be prepared by any known methodology of the prior art.

Still another aspect of the present disclosure provides a pharmaceutical composition comprising atorvastatin or its salts prepared according to the process of the present disclosure along with one or more pharmaceutically acceptable carriers, excipient, or diluents.
The pharmaceutical composition comprising atorvastatin or its salts and its combination with a pharmaceutically acceptable carrier of this disclosure may further formulated as solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in tha form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation, or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present disclosure may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that find use in the present disclosure include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

DEFINITIONS

The following definitions are used in connection with the present disclosure unless the context indicates otherwise. HPLC is high pressure liquid chromatography and TLC is thin layer chromatography. A "phase transfer catalyst" is a catalyst that facilitates the migration of a reactant from one phase into another phase where reaction occurs. This catalyst is used when the reaction takes place in a heterogeneous reaction medium. Suitable phase transfer catalysts which can be used include, but are not limited to salts of onium ions (e.g. tetraalkyl ammonium salts) or agents that complex inorganic cations (e.g. crown ethers). Examples of such catalysts include, but are not limited to, benzyltrimethylammonium chloride, benzyltributyl ammonium bromide, benzyltrioctyl ammonium bromide, benzyltriphenylphosphonium bromide, benzyltriethylammonium chloride, benzylthethylammonium bromide, hexadecyltributylphosphonium bromide, hexadecyltrimethylammonium bromide, methyltrioctylammonium chloride, methyltrioctyl ammonium bromide, tetrabutyl ammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, tetramethyl ammonium hydrogen sulfate, tetramethylammonium bromide, tetramethylammonium chloride, tetramethyl ammonium iodide, tetraethylammonium bromide, tetraethyl ammonium chloride, tetraethylammonium iodide, tetraethylammonium hydrogen sulfate, tetrapropyl ammonium bromide, tetrapropylammonium chloride, tetrapropylammonium iodide, tetrapropylammonium hydrogen sulfate, triethylbutylammonium bromide, trimethylbenzylammonium bromide, triethylbenzylammonium chloride, tripropylbenzyl ammonium chloride, dodecyltrimethylammonium bromide, tricetylmethyl ammonium chloride, crown ethers such as 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane), and polyethylene glycols.

"Alkoxy-" refers to the group R-O- where R is an alkyl group, as defined below. Exemplary CrC6alkoxy- groups include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy, and t-butoxy.

"Alkyl-" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a C|-C|0alkyl-group may have from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, "alkyl" is a chain (straight or branched) having 1 to 6 (inclusive) carbon atoms in it. Examples of Ci-C6alkyl- groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
Representative "pharmaceutically acceptable acids" include but are not limited to those capable of making water-soluble and water-insoluble salts, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, butyrate, camsylate (camphorsulfonate), carbonate, citrate, clavulariate, dihydrochloride, diphosphate, edisylate (camphorsulfonate), esylate (ethanesulfonate), fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, glutamate, hexafluorophosphate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, iodide, isothionate (2-hydroxyethanesulfonate), lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pamoate (4,4'-methylenebis-3-hydroxy-2-naphthoate, or embonate), pantothenate, phosphate, picrate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, and valerate salts.

Certain specific aspects and embodiments of the present disclosure will be explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present disclosure.

EXAMPLES

EXAMPLE 1: Preparation of (4R-cis)-1,1-dimethyl ethyl-6-[2[2-(4-fluorophenyl]-5-(1 -methylethyl)-3-phenyl-4[(phenyl amino) carbonyl]-1 H-pyrrole-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate (Formula II) using phase transfer catalyst. To a solution of pivalic acid (13.95 g, 0.136 mol) in cyclohexane (700 ml) was added morpholine (16.06 g, 0.184 mol) and stirred for 10-15 minutes. 4-Fluoro-a-2-methyl-1-oxopropyl-Y-oxo-N-p-diphenylbenzene butanamide (III) (100 g, 0.23 mol) and tetrabutyl ammonium hydrogen sulfate (15.44 g, 0.045 mol) were added to the reaction mass, which was heated to 50-60°C. (4R-Cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (IV) (65.48 g, 0.23 mol) was added and reaction mixture heated at reflux at 80°C. Refluxing was continued for 20 hours and water removed azeotropically using a Dean-Stark trap. Reaction mass was cooled to 40-45°C, charged with water (200 ml), and stirred for 15-30 minutes. The bottom aqueous layer was discarded and organic layer was evaporated off under vacuum below 70°C. Isopropanol (130 ml) was added to the reaction mass at 55-60°C and solvent evaporated under vacuum below 70°C. The reaction mass was cooled to 55-60°G and isopropyl alcohol {400 ml) added. The resulting reaction mass was heated at reflux at 80°C and was cooled to 65°C. Seeding material of (4R-cis)-1,1-dimethyl ethyl-6-[2[2-(4-fluorophenyl]-5-(1-methylethyl)-3-phenyl-4[(phenyl amino) carbonyl]-1 H-pyrrole-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate (II) (2.0 g) was added and stirred at 65°C for 1 hour. The reaction mass was cooled to 25-35°C and stirred at same temperature for 2-3 hours. After reaction completion, the reaction mass was cooled to 0-5°C and stirred at 0-5°C for 2-3 hours. The solid obtained, was isolated by filtration, washed with isopropanol (300 ml) at 0-10°C, and then dried by suction for 10-15 min. The wet solid obtained was dried at 70-75°C for 4-5 hours to obtain (4R-cis)-1,1-dimethyl ethyl-6-[2[2-(4-fluorophenyl]-5-(1 -methylethyl)-3-phenyl-4[(phenyl amino) carbonyl]-1H-pyrrole-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate. (Yield: 125 g, % yield: 80%, HPLC: 98.97%).

EXAMPLE 2: Preparation of Atorvastatin calcium. Step 1: Preparation of [R-(R*,R*)]-2-(4-fluoro phenyl)-p,8 dihydroxy -5-[(1 -methyl ethyl)-3-phenyl- 4-[(phenyl amino)-carbonyl] -1H-pyrrole-1-heptanoic acid, tert butyl ester. (4R-Cis)-1,1-dimethyl ethyl-6-[2[2-(4-fluorophenyl]-5-(1-methylethyl)-3-phenyl-4[(phenyl amino) carbonyl]-1 H-pyrrole-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate obtained according to the step above (110 g, 0.16 mol) was added to acetonitrile at 30-35°C and stirred for 10-15 minutes. Hydrochloric acid solution containing concentrated hydrochloric acid (44 ml) and water (396 ml) was added to the reaction mass at 25-30°C in 30-45 minutes. The reaction mixture was maintained at 25-30°C in 45-60 minutes. After completion of reaction (TLC monitored), water (1100 ml) was added and the reaction mixture cooled to 10-15°C. The pH of reaction mass was adjusted to 7.0-8.0 at 10-15°C by adding sodium carbonate solution containing sodium carbonate (31.6 g) and water (165 ml). Reaction mixture was stirred at 10-15°C for 10-20 minutes. The solid obtained, was isolated by filtration, washed with water (550 ml) at dried by suction for 1-2 hours. The wet solid obtained was taken in acetonitrile (924 ml) and water (365 ml) and heated at 70-75°C for complete dissolution and then heated at reflux for 10-20 minutes. The reaction mass was cooled to 25-30°C and maintained at same temperature for 1-2 hours. The solid obtained, was isolated by filtration,, washed with amixture of water (77 ml) and acetonitrile (154 ml) and dried at 50-60°C for 8-12 hours to obtain [R-(R*,R*)]-2-(4-fluoro phenyl)-|3,5 dihydroxy -5-[(1-methyl ethyl)-3-phenyl- 4-[(phenyl amino)-carbonyl] -1H-pyrrole-1-heptanoic acid, tert butyl ester. (Yield: 85 g, HPLC: 98.2%)

Step 2: Preparation of Atorvastatin calcium. The t-butyl ester of atorvastatin (220 g, 0.32 mol) was treated with sodium hydroxide (14.3 g) in acetonitrile (1600 ml) and water (500 ml) at 40-45° C, followed by an aqueous solution of calcium acetate ((CH3COO)2Ca0.5H2O) (31.8 g, 020 mol) in water (318 ml) at 40-45° C. Sodium hydroxide (1 g) in water (10 ml) was added to the reaction mixture and the temperature was raised to 70-80° C. The reaction mixture was filtered hot and the filter cake washed with acetonitrile (200 ml). Water (2000 ml) was added to the filtrate at 25-35° C, followed by aqueous NaOH (0.4 g NaOH and 4 ml water) and the temperature was raised to 70-80° C. The solution was cooled to 25-35° C to DreciDitate the Droduct. which was filtered and washed with water (500ml). The solid was first dried at 50-60° C, and then under vacuum, at 55-65° C, to obtain Atorvastatin calcium (Yield: 100 g, HPLC: 99.6%).

EXAMPLE 3: Preparation of (4R-cis)-1,1-dimethyl ethyl-6-[2[2-(4-fluorophenyl]-5-(1-methylethyl)-3-phenyl-4[(phenyl amino) carbonyl]-1 H-pyrrole-1 -yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate (Formula II) in absence of catalytic acid and organic amine
To a solution of (4R-Cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (IV) (32.7 g, 0.119 mol) and 4-Fluoro-a-2-methyl-1-oxopropyl-v-oxo-N-B-diphenylbenzene butanamide (III) (50 g, 0.119 mol) in cyclohexane (500 ml) was added tetrabutyl ammonium hydrogen sulfate (40.6 g, 0.119 mol) and heated to reflux azeotropically at 80-85°C for 4-5 hours. Water (50 ml) were added to the reaction mass and stirred at 65-70°C for 10-20 minutes. Bottom aqueous layer was separated and to the top organic layer was added water (50 ml) and stirred at 65-70°C for 10-20 minutes. Separated the aqueous layer and the organic layer was distilled off completely. To the reaction mass was added isopropanol (65 ml) and distilled off solvent. Isopropanol (200 ml) was added and heated to reflux at 80-85°C for 20-30 minutes. Reaction mass was cooled gradually to 60-65°C and charged seeding material of compound II dissolved in isopropanol (5 ml) and stirred.at 60- ... 65°C for 45-60-minutes. Reaction mass was cooled gradually to 45-50°C in 60 minutes and stirred at same temperature for 45-60 minutes. Reaction mass was again cooled gradually to 30-35°C in 60 minutes and stirred at same temperature for 45-60 minutes. Reaction mass was further cooled gradually to 25-30°C in 60 minutes and stirred at same temperature for 4-5 hours. Finally reaction mass was cooled to 0-5°C and maintained at same temperature for 4-5 hours. The reaction mixture was filtered and wet cake obtained was washed with chilled isopropanol (150 ml). The wet solid obtained was dried at 70-75°C for 4-5 hours to obtain (4R-cis)-1,1-dimethyl ethyl-6-[2[2-(4-fluorophenyl]-5-(1 -methylethyl)-3-phenyl-4[(phenyl amino) carbonyl]-1 H-pyrrole-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate. (Yield: 52.9 g, % yield: 70.7%, HPLC: 98.48%).

EXAMPLE 4: Preparation of (4R-cis)-1,1-dimethyl ethyl-6-[2[2-(4-fluorophenyl]-5-(1-methylethyl)-3-phenyl-4[(phenyl amino) carbonyl]-1 H-pyrrole-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate (Formula II) in absence of organic amine

To a solution of (4R-Cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (IV) (32.7 g, 0.119 mol) and 4-Fluoro-a-2-methyl-1-oxopropyl--oxo-N--diphenylbenzene butanamide (III) (50 g, 0.119 mol) in cyclohexane (500 ml) at 60-65°C was added tetrabutyl ammonium bromide (15 g) and pivalic acid (6.5 g) and heated to reflux azeotropically at 80-85°C for 4-5 hours. Water (50 ml) were added to the reaction mass and stirred at 65-70°C for 10-20 minutes. Bottom aqueous layer was separated and to the top organic layer was added water (50 ml) and stirred at 65-70°C for 10-20 minutes. Separated the aqueous layer and the organic layer was distilled off completely. To the reaction mass was added isopropanol (65 ml) and distilled off solvent. Isopropanol (200 ml) was added and heated to reflux at 80-85°C for 20-30 minutes. Reaction mass was cooled gradually to 60-65°C and charged seeding material of compound II dissolved in isopropanol (5 ml) and stirred at 60-65°C for 45-60 minutes. Reaction mass was cooled gradually to 45-50°C in 60 minutes and stirred at same temperature for 45-60 minutes. Reaction mass was again cooled gradually to 30-35°C in 60 minutes and stirred at same temperature for 45-60 minutes. Reaction mass was further cooled gradually to 25-30°C in 60 minutes and stirred at same temperature for 4-5 hours. Finally reaction mass was cooled to 0-5°C and maintained at same temperature for 4-5 hours. The reaction mixture was filtered and wet cake obtained was washed with chilled isopropanol (150 ml). The wet solid obtained was dried-at 70-75°C for 4-5 hours to obtain (4R-cis)-1,1-dimethyl ethyl-6-[2[2-(4-fluorophenyl]-5-(1-methylethyl)-3-phenyl-4[(phenyl amino) carbonyl]-1 H-pyrrole-1 -yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate. (Yield: 53.2 g, % yield: 71.1%, HPLC: 98.64%).

EXAMPLE 5: Preparation of (4R-cis)-1,1 -dimethyl ethyl-6-[2[2-(4-fluorophenyl]-5-(1-methylethyl)-3-phenyl-4[(phenyl amino) carbonyl]-1H-pyrrole-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate (Formula II) in absence of phase transfer catalyst.

To a solution of (4R-Cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (IV) (65.4 g, 0.239 mol) and 4-Fluoro-a-2-methyl-1-oxopropyl-Y-oxo-N-B-diphenylbenzene butanamide (III) (100 g, 0.239 mol) in cyclohexane (1000 ml) at 25-30°C was added morpholine (28 g) and pivalic acid (14 g, 0.136 mol) and heated to reflux azeotropically at 80-85°C for 64 hours. The reaction mixture heated at 55-60°C and solvent distilled off at reduced pressure. Isopropanol (130 ml) was added at 55-60°C and solvent distilled off at reduced pressure. Isopropanol (400 ml) was added to reaction mass and heated to reflux for 30-40 minutes. Reaction mixture was cooled to 65-70°C and seeding material of compound II (0.3 g) added. Reaction mixture was allowed to cool to room temperature and maintained at same for 15-16 hours. The reaction mixture was cooled to 0-5°C and maintained at same temperature for 3-4 hours. The reaction mixture was filtered and wet cake obtained was washed with chilled isopropanol (300 ml). The wet solid obtained was dried at 70-75°C for 12-15 hours to obtain (4R-cis)-1,1-dimethyl ethyl-6-[2[2-(4-fluorophenyl]-5-(1-methylethyl)-3-phenyl-4[(phenyl amino) carbonyl]-1H-pyrrole-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate. (Yield: 105 g, % yield: 67.3%, HPLC: 98.5%).

We Claim:

Claim 1: A process for preparing a compound of formula II:

comprising reacting a 1,4-diketone of the formula III:

with a primary amine of the formula IV:

wherein R1 and R2 may be same or different and are H, C1-C6 alkyl, C1-C6 alkoxy, or R1 and R2 together are CRaRb wherein Ra and Rb may be same or different and are independently an C1-C11 alkyl group or Ra and Rb, together with the carbon atom to which they are attached, may form a ring, and R3 is an C1-C6 alkyl group in the presence of a catalytic acid, organic amine, and phase transfer catalyst.

Claim 2: A process according to Claim 1 wherein Ra and Rb are each methyl and R3 is tertiary butyl.

Claim 3: The primary amine of the formula IV according to claims 1or 2 is 1,1-dimethyl-(4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.

Claim 4: The catalytic acid used in claim 1 is a weak organic carboxylic acid having a C1-C6 alkyl group which may be straight or branched having pKa greater than or equal to 2.

Claim 5: The weak organic acid according claim 4 which is one or more of pivalic acid, formic acid, acetic acid, or butyric acid.

Claim 6: The organic amine according to claim 1 which is secondary amine.

Claim 7: Secondary amine in claim 6 which is one or more of dialkylamine, N-alkylaniline, /V-alkylbenzylamine, /V-alkyl-o-tolylamine, pyrrolidine, piperidine, morpholine, or proline.

Claim 8: The phase transfer catalyst according to claim 1 is selected from tetraalkylammonium hydrogen sulphate, tetraalkylammonium or phosphonium halide such as tetrabutylammonium bromide, tetrabutylammonium fluoride, crown ethers like 15-crown-5, 18-crown-6, preferably tetrabutylammonium hydrogen sulphate.

Claim 9: The process according to claim 1 wherein the reaction is carried out in presence of solvent selected from alcohol solvents such as methanol, ethanol, isopropanol or the like; aliphatic hydrocarbons like cyclohexane or, hexane; aromatic hydrocarbons such as toluene or xylene; ethers like THF or, dioxane; or mixtures thereof.

Claim 10: A process according to claim 1 optionally in absence of catalytic acid and organic amine.

Claim 11: A process according to claim 1 optionally in absence of phase transfer catalyst.

Claim 12: Process for preparation of atorvastatin and its pharmaceutically acceptable salts comprising:

a) condensing a compound of Formula III with the compound of Formula IV in presence of catalytic acid, phase transfer catalyst, and organic amine in a suitable solvent to give intermediate of Formula II;

Formula II

b) removing the protecting group acetonide of the open chain compound of
Formula II with a strong acid in a suitable solvent to give atorvastatin of Formula I; and

c) optionally converting atorvastatin to a pharmaceutically acceptable salt.