DESC:FIELD OF INVENTION
The present invention provides an improved process for preparation of a Key intermediate of Atorvastatin Calcium and more particularly for preparation of compound ((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]ethyl}-2,2-dimethyl- 1,3- dioxane-4-acetate (Formula II).

BACKGROUND OF THE INVENTION

Atorvastatin calcium is a drug compound that is used as a lipid-lowering agent, for treating hypercholesterolemia. The compound of Formula I, has the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-ß, d-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrrole-l-heptanoic acid, calcium salt (2:1). Pharmaceutical products containing crystalline atorvastatin calcium trihydrate are sold using the trademark LIPITOR & many other names.
Racemic trans-5-(4-fluorophenyl)-2-( 1-methylethyl)-N,4-diphenyl- 1-[2-tetrahydro-4-4- hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-carboxamide("racemic atorvastatin lactone") or its hydroxy acid form or pharmaceutically acceptable salts thereof and methods for its preparation is reported in U.S. Pat. No. 4,681,893.

U.S. Pat. No. 5,273,995 discloses atorvastatin, the pure enantiomer of Formula I. Also disclosed are hemi calcium, hemi magnesium, hemi zinc, monosodium, monopotassium, N-methylglucamine and l-deoxy-l-(methylamino)-D-glucitol salts of atorvastatin. The patent is expired now. It led to allowance of generic Atorvastatin in regulated as well as non-regulated marked.

U.S. Pat. No. 5,969,156 discloses atorvastatin hemi calcium crystalline forms I, II and IV and their preparation process. It was one of the key patents for Atorvastatin. It claimed the most important & widely used Trihydrate Form of Atorvastatin calcium Crystalline (Form I). Later patent like (US patents No. 6,121,461), discloses crystalline forms of atorvastatin, suggest that the product obtained according to the original patents was amorphous. According to the XRD studies of Atorvastatin obtained according to previous patents (US 4,681,893; 5,298,627 and 5273995) is not perfectly amorphous and according to an X-ray diffraction analysis it shows the presence of crystalline components, as described in WO03/068739.
Atorvastatin Calcium (formula I) is manufactured according to published patents (US patents Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,397,792; 5,342, 952) usually from the sodium salt of [R-(R*,R*)]-2-(4-fluorophenyl)-ß,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid and a suitable, water soluble calcium salt, preferably from calcium acetate or chloride.

A number of patents and published International Patent Applications have issued describing atorvastatin calcium in amorphous as well as in crystalline forms, formulations of atorvastatin calcium, as well as processes for atorvastatin calcium and key intermediates for preparing atorvastatin calcium. These include: United States Patent Numbers 4,681,893; 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,273,995; 5,280,126; 5,298,627; 5,342,952; 5,397,792; 5,446,054; 5,470,981; 5,489,690; 5,489,691; 5,510,488; 5,686,104; 5,969,156; 5,998;633; 6,087,511; 6,121,461; 6,126,971; 6,433,213; 6,476,235; 6,528,660; 6,600,051 ; 6,605,759; 6,613,916; 6,646,133; 6,730,797; 6,867,306; 6,891,047; WO99/32434; WO01/36384; WO02/41834; WO02/43667; WO02/43732; WO02/051804; WO02/057228; WO02/057229; WO02/057274; WO02/059087; WO02/083637; WO02/083638; WO03/011826; WO03/050085; WO03/07072 and WO 04/022053.

Patent US6,528,660; US6,613,916; US6,646,133; WO03/018547 and WO03/078379 described the preparation of amorphous Atorvastatin calcium.

Applicant itself has been granted many patents on Atorvastatin. Various patents are described herein. US 7,563, 911, CA2456095, IN196737 & EP1572638 patents describepreparation of Amorphous Atorvastatin Calcium in MDC/IPE Solvent system. WO2004022053, RU2294924 & ZA2005/01802 describes Atorvastatin Calcium Crystalline Form VI. WO2006048894 also describes yet another crystalline form of Atorvastatin Calcium. WO2006048893 focusses on the large particle size Statins such as Atorvastatin Calcium. WO2006059346 discloses high purity Atorvastatin Calcium. IN287549 discloses various Amine salts of Atorvastatin Acid. IN331925 provides Improved Processes for the preparation as well as purification of Atorvastatin Calcium & its intermediate.

There are various key patents related to development of Atorvastatin & its various salts of polymorphs. Since the inception of Atorvastatin in above mentioned patents, there has been tremendous research on this molecule. More than 50 polymorphic Form, Uncountable patents & non patented journals reviews & articles have been published. It is virtually impossible to incorporate all here for reference. We will focus on the area of our invention only.

There are several routes to atorvastatin disclosed in the art but the most prominent approach available till date is the pyrrole ring construction (Paal-Knorr pyrrole synthesis), which process involves reacting tert-butyl [(4R ,6R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl] acetate ("amino ketal") with 4-(4-Fluorophenyl)-2-isobutyl-3-phenyl-4-oxo-N-phenyl butyramide ("1,4-diketone") to obtain diol protected atorvastatin ester of formula II, followed by deprotection of the diol functionality and carboxylic acid functional group and then conversion to atorvastatin, for example, in US 5,003,080, WO 2005/092852 and many other references. The above-mentioned reaction is typically carried out at elevated temperatures for about 72 hours. The yield of this typical reaction disclosed herein is quite low due to lot of impurities formation. This reaction is the key area of our invention. We have devised an improved method for carrying out this reaction which is disclosed herein. Benefits of our improved process has been provided in the further part of the invention.

Two other different approaches for preparation of compound of Formula II are described in next lines.

ES2289945 (2008) patent describes preparation of compound of Formula II as pe scheme as given below. It involves Reagents: Pivalic acid, 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU) in Solvents: Cyclohexane & reaction conditions: 60 min, 80 - 84 °C; 24 h, reflux

WO2017060885 A1 by Laurus Labs describes preparation of Compound of Formula II, as per reaction scheme as given below using reagents Pivalic acid, 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU), Solvents: Cyclohexane & Reaction conditions: 60 min, 80 - 84 °C; 24 h, reflux

SUMMARY OF THE INVENTION

The present invention provides an improved process for preparation of compound of Formula II. It is an improved version of existing (Paal-Knorr pyrrole synthesis), which involves reacting tert-butyl [(4R ,6R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl]acetate with 4-(4-Fluorophenyl)-2-isobutyl-3-phenyl-4-oxo-N-phenyl butyramide to obtain diol protected atorvastatin ester of formula II. The reaction is catalyzed using catalysts selected from Diazabicyclo(5.4.0)undec-7-ene (DBU), 1,4-Diazabicyclooctane (DABCO) or 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN) or a mixture thereof.

In particular 1,5-Diazabicyclo [4.3.0] non-5-ene (DBN) & 1,8-Diazabicyclo (5.4.0) undec-7-ene (DBU) were used to catalyze the reaction and reduce the overall batch time cycle from 72 hours to 10-12 hours along with improved yield and quality of compound of Formula II. It also discloses subsequent purification process to give high purity key intermediate of Formula II. The material obtained is of high purity having HPLC > 99.85. The yield as reported in prior art, as discussed already varies from 60-70% whereas the current invention yields compound of formula II around 85-89%, which is huge gain. So the process disclosed herein is not only industrially viable, but also economical and gives ideal quality consistently.

The detailed description of their application is disclosed in sections of patent ahead:

4-Fluoro-a-[2-methyl-1-oxo propyl]?-oxo-N-ß-diphenyl benzene Butanamide (Formula III)

(4R-Cis)-1,1-Dimethylethyl-6-(2-aminomethyl)-2,2-dimethyl-1,3-dioxane -4-Acetate (Formula IV)

DETAILED DESCRIPTION OF THE INVENTION

Numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention. Hence, the following specification is intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations and variations thereof.
The main aspect of this invention is to provide an improved process for highly pure ((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-lH-pyrrol-l-yl]ethyl}-2,2-dimethyl- 1,3- dioxane-4-acetate compound of formula (II):

1) Dissolving 4-Fluoro-a-[2-methyl-1-oxopropyl] ?-oxo-N-ß-diphenylbenzene Butan amide (Formula III), (4R-Cis)-1,1-Dimethylethyl-6-(2-aminomethyl)-2,2-dimethyl-1,3-dioxane -4-Acetate (Formula IV), Pivalic acid in cyclic aliphatic hydrocarbon selected from Cyclopentane, cyclohexane, cycloheptane, Aliphatic ether like 2-Methyl Tetrahydrofuran or a mixture thereof.
2) Adding an catalyst selected from Diazabicyclo(5.4.0)undec-7-ene (DBU), 1,4-Diazabicyclooctane (DABCO) or 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN) or a mixture thereof.
3) stirring the reaction mass & heating to reflux azeotropically for 10-20 hours.
4) Cooling the reaction mass to 55-65°C
5) Adding water to reaction mass
6) Stirring, settling & layer separation
7) Removing solvent under vacuum to get solid residue
8) Triturating with an aliphatic alcohol, selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol, diethylene glycol or aliphatic ketone like Acetone, Methyl ethyl ketone, or a mixture thereof & removing solvent under vacuum again
9) Dissolving residue in aliphatic alcohol or aliphatic ketone of step 8) & water mixture at 25-30°C.
10) Cooling the reaction mass to 5-15°C
11) Stirring for 3-6 hours.
12) Isolating product as wet cake by filtration
13) Drying the wet cake at 60-70°C for 10-15 hours to get ((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-lH-pyrrol-l-yl] ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate (Formula II) having purity > 99.50%.
14) Re-dissolving the dried material of step 13) in a solvent & water mixture at 25-30°C.
15) Adding water & stirring reaction mass
16) Cooling the reaction mass to 5-15°C & stirring further
17) Isolating product as wet cake by filtration
18) Drying the wet cake at 60-70°C for 10-15 hours to get highly pure ((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenyl amino)carbonyl]-lH-pyrrol-l-yl]ethyl}-2,2-dimethyl- 1,3- dioxane-4-acetate (Formula II) having purity > 99.90%.

According to one embodiment of the present invention, the quantity of catalysts used in step 2 for fast reaction completion is between 0.10-0.70 Times w.r.t. compound IV, more preferably 0.15-0.50, most preferably 0.20-0.40.

According to another embodiment of this invention, the solvent used in step 14 can an aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof or an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof.

Key advantages of the current invention:
1. It reduces the BTC (Batch time cycle) from 72 hours to 10-12 hours only. Hence highly cost effective.
2. The overall yield of product (compound II) is also increased from 60-70% (as per processes disclosed in prior art) to 85-89%.
3. The material obtained by this invention is highly pure, having HPLC purity in excess of 99.85%.

The invention is further illustrated by non-limiting examples. Thus, the following examples should not construe the scope of the protection sought in this invention.
Example 1: Process for the preparation of ((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]ethyl}-2,2-dimethyl- 1,3- dioxane-4-acetate (Formula II)
To a solution of 4-Fluoro-?-[2-Methyl-1-Oxopropyl]-?-Oxo-N-?-Diphenyl Benzene Butanamide (Formula III) (150 g) in Cyclohexane (700 ml), (4R-Cis)-1,1-Dimethylethyl-6-(2-Aminomethyl)-2,2-Dimethyl-1,3-Dioxane-4-Acetate (Formula IV) (100 g), Pivalic acid (24 g) and DBN (20 g) are added at ambient temperature and reaction mixture was heated to reflux and removing water azeotropically. The resulting reaction mixture was further refluxed, removing water azeotropically for 20-24 hrs. After completion of reaction, the reaction mixture was cooled to 55-65°C and Water (500 ml) was added with stirring. The layers were separated and the organic layer was washed with Water and concentrated to get the residue. Isopropyl alcohol (100 ml) was then added to it and the solvent recovered under vacuum, followed by repeated addition of Isopropyl alcohol (100 ml) and solvent recovery under vacuum to get residue. The residue was dissolved in Isopropyl alcohol (500 ml) and Water (150 ml) was added at ambient temperature. The reaction mixture was cooled to 5-15°C with stirring for 3-6 hrs. The product was filtered, washed with a mixture of Isopropyl alcohol (50ml) & Water (50 ml) and dried at 60-70°C to yield 231g of the product of formula II. (HPLC purity >99%).
The resulting product was purified by dissolving in a mixture of Acetone-Water at ambient temperature followed by addition of Water with stirring. The resulting mass was cooled to 5-15°C. The solid, thus obtained, was filtered and dried at 60-70°C to yield 215g of pure of Formula II. (HPLC purity 99.90%).

Example 2: Process for the preparation of ((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl] ethyl}-2,2-dimethyl- 1,3- dioxane-4-acetate (Formula II)
To a solution of 4-Fluoro-?-[2-Methyl-1-Oxopropyl]-?-Oxo-N-?-Diphenyl Benzene Butanamide (Formula III) (150 g) in Cyclohexane (700 ml), (4R-Cis)-1,1-Dimethylethyl-6-(2-Aminomethyl)-2,2-Dimethyl-1,3-Dioxane-4-Acetate (Formula IV) (100 g), Pivalic acid (24 g) and DBN (15 g) are added at ambient temperature and reaction mixture was heated to reflux and removing water azeotropically. The resulting reaction mixture was further refluxed, removing water azeotropically for 20-24 hrs. After reaction completion, the reaction mixture was cooled to 55-65°C and Water (500 ml) was added with stirring. The layers were separated and the organic layer was washed with Water and concentrated to get the crude. Isopropyl alcohol (100 ml) was then added to crude, and the solvent recovered under vacuum, followed by repeated addition of Isopropyl alcohol (100 ml) and solvent recovery under vacuum to get residue. The residue was dissolved in Isopropyl alcohol (500 ml) was added at ambient temperature and heated to reflux to get clear solution. The reaction mixture was cooled to 35-45°C and Water (150 ml) was added with stirring for 1-2 hrs. The reaction mass was further cooled to 5-15°C with stirring for 3-6 hrs. The product was filtered and dried at 60-70°C to yield 224g of Formula II.
(HPLC purity >99%).
The crude product was purified by dissolving in mixture of Acetone-Water and cooled at ambient temperature. The solid thus obtained was filtered and dried at 60-70°C to yield 211g of pure of formula II. (HPLC purity 99.50%).
Example 3: Process for the preparation of ((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl] ethyl}-2,2-dimethyl- 1,3- dioxane-4-acetate (Formula II)
To a solution of 4-Fluoro-?-[2-Methyl-1-Oxopropyl]-?-Oxo-N-?-Diphenyl Benzene Butanamide (Formula III) (150 g) in Cyclohexane (700 ml), (4R-Cis)-1,1-Dimethylethyl-6-(2-Aminomethyl)-2,2-Dimethyl-1,3-Dioxane-4-Acetate (Formula IV) (100 g), Pivalic acid (24 g) and DBU (20 g) are added at ambient temperature and reaction mixture was heated to reflux and removing water azeotropically. The resulting reaction mixture was further refluxed, removing water azeotropically for 20-24 hrs. After completion of reaction, the reaction mixture was cooled to 55-65°C and Water (500 ml) was added with stirring. The layers were separated, and the organic layer was washed with Water and concentrated to get the residue. Isopropyl alcohol (100 ml) was then added to it and the solvent recovered under vacuum, followed by repeated addition of Isopropyl alcohol (100 ml) and solvent recovery under vacuum to get residue. The residue was dissolved in Isopropyl alcohol (500 ml) and Water (150 ml) was added at ambient temperature. The reaction mixture was cooled to 5-15°C with stirring for 3-6 hrs. The product was filtered, washed with a mixture of Isopropyl alcohol (50ml) & Water (50 ml) and dried at 60-70°C to yield 229 g the product of formula II (HPLC purity >99%).
The resulting product was purified by dissolving in a mixture of Isopropyl Alcohol-Water at ambient temperature followed by addition of Water with stirring. The resulting mass was cooled to 5-15°C. The solid, thus obtained, was filtered and dried at 60-70°C to yield 214 g of pure of formula II. (HPLC purity 99.80%).

Example 4: Process for the preparation of ((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl] ethyl}-2,2-dimethyl- 1,3- dioxane-4-acetate (Formula II)
To a solution of 4-Fluoro-?-[2-Methyl-1-Oxopropyl]-?-Oxo-N-?-Diphenyl Benzene Butanamide (Formula III) (150 g) in Cyclohexane (700 ml), (4R-Cis)-1,1-Dimethylethyl-6-(2-Aminomethyl)-2,2-Dimethyl-1,3-Dioxane-4-Acetate (Formula IV) (100 g), Pivalic acid (24 g) and DBU (30 g) are added at ambient temperature and reaction mixture was heated to reflux and removing water azeotropically. The resulting reaction mixture was further refluxed, removing water azeotropically for 20-24 hrs. After reaction completion, the reaction mixture was cooled to 55-65°C and Water (500 ml) was added with stirring. The layers were separated and the organic layer was washed with Water and concentrated to get the crude. Isopropyl alcohol (100 ml) was then added to crude, and the solvent recovered under vacuum, followed by repeated addition of Isopropyl alcohol (100 ml) and solvent recovery under vacuum to get residue. The residue was dissolved in Isopropyl alcohol (500 ml) was added at ambient temperature and heated to reflux to get clear solution. The reaction mixture was cooled to 35-45°C and Water (150 ml) was added with stirring for 1-2 hrs. The reaction mass was further cooled to 5-15°C with stirring for 3-6 hrs. The product was filtered and dried at 60-70°C to yield 227 g of formula II.
(HPLC purity >99%).
The crude product was purified by dissolving in mixture of Isopropyl Alcohol-Water and cooled at ambient temperature. The solid thus obtained was filtered and dried at 60-70°C to yield 210 g of pure of Formula II. (HPLC purity 100%).
Example 5: Process for the preparation of ((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl] ethyl}-2,2-dimethyl- 1,3- dioxane-4-acetate (Formula II)
To a solution of 4-Fluoro-?-[2-Methyl-1-Oxopropyl]-?-Oxo-N-?-Diphenyl Benzene Butanamide (Formula III) (150 g) in Cyclohexane (700 ml), (4R-Cis)-1,1-Dimethylethyl-6-(2-Aminomethyl)-2,2-Dimethyl-1,3-Dioxane-4-Acetate (Formula IV) (100 g), Pivalic acid (24 g), DBU (10 g) and DBN (5 g)are added at ambient temperature and reaction mixture was heated to reflux and removing water azeotropically. The resulting reaction mixture was further refluxed, removing water azeotropically for 20-24 hrs. After reaction completion, the reaction mixture was cooled to 55-65°C and Water (500 ml) was added with stirring. The layers were separated and the organic layer was washed with Water and concentrated to get the crude. Isopropyl alcohol (100 ml) was then added to crude, and the solvent recovered under vacuum, followed by repeated addition of Isopropyl alcohol (100 ml) and solvent recovery under vacuum to get residue. The residue was dissolved in Isopropyl alcohol (500 ml) was added at ambient temperature and heated to reflux to get clear solution. The reaction mixture was cooled to 35-45°C and Water (150 ml) was added with stirring for 1-2 hrs. The reaction mass was further cooled to 5-15°C with stirring for 3-6 hrs. The product was filtered and dried at 60-70°C to yield 228 g of product of formula II.
(HPLC purity> 99%).
The crude product was purified by dissolving in mixture of Isopropyl alcohol -Water and cooled at ambient temperature. The solid thus obtained was filtered and dried at 60-70°C to yield 211 g of pure of Formula II. (HPLC purity 99.90%).
Example 6: Process for the preparation of ((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl] ethyl}-2,2-dimethyl- 1,3- dioxane-4-acetate (Formula II)
To a solution of 4-Fluoro-?-[2-Methyl-1-Oxopropyl]-?-Oxo-N-?-Diphenyl Benzene Butanamide (Formula III) (150 g) in Cyclohexane (700 ml), (4R-Cis)-1,1-Dimethylethyl-6-(2-Aminomethyl)-2,2-Dimethyl-1,3-Dioxane-4-Acetate (Formula IV) (100 g), Pivalic acid (24 g), DBU (10 g) and DBN (10 g) are added at ambient temperature and reaction mixture was heated to reflux and removing water azeotropically. The resulting reaction mixture was further refluxed, removing water azeotropically for 20-24 hrs. After reaction completion, the reaction mixture was cooled to 55-65°C and Water (500 ml) was added with stirring. The layers were separated, and the organic layer was washed with Water and concentrated to get the crude. Isopropyl alcohol (100 ml) was then added to crude, and the solvent recovered under vacuum, followed by repeated addition of Isopropyl alcohol (100 ml) and solvent recovery under vacuum to get residue. The residue was dissolved in Isopropyl alcohol (500 ml) was added at ambient temperature and heated to reflux to get clear solution. The reaction mixture was cooled to 35-45°C and Water (150 ml) was added with stirring for 1-2 hrs. The reaction mass was further cooled to 5-15°C with stirring for 3-6 hrs. The product was filtered and dried at 60-70°C to yield 225 g of product of Formula II.
(HPLC purity >99%).
The crude product was purified by dissolving in mixture of Isopropyl alcohol -Water and cooled at ambient temperature. The solid thus obtained was filtered and dried at 60-70°C to yield 213 g of pure OF Formula II.
(HPLC purity 99.90%).

CLAIMS:

WE CLAIM:

1.

An improved and industrially viable process for preparing highly pure ((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]ethyl}-2,2-dimethyl- 1,3- dioxane-4-acetate, which comprises:
i. dissolving 4-Fluoro-a-[2-methyl-1-oxopropyl] ?-oxo-N-ß-diphenylbenzene Butan amide, (4R-Cis)-1,1-dimethylethyl-6-(2-aminomethyl)-2,2-dimethyl-1,3-dioxane -4-Acetate & Pivalic acid in cyclic aliphatic hydrocarbon selected from cyclopentane, cyclohexane, cycloheptane, 2-methyltetrahydrofuran or a mixture thereof;
ii. adding a suitable catalyst or a mixture of catalysts;
iii. stirring and heating the reaction mass to reflux azeotropically for 10-24 hours;
iv. cooling the reaction mass to 55-65°C and adding water;
v. separating the layer;
vi. removing the solvent under vacuum to get residue;
vii. dissolving the residue of step vi) in an aliphatic alcohol, selected from methanol, ethanol, 1-propanol, isopropyl alcohol, butanol, monoethylene glycol, diethylene glycol or aliphatic ketone selected from Acetone, Methyl ethyl ketone, , diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or a mixture thereof;
viii. Cooling the reaction mass to 5-15°C;
ix. Stirring for 3-6 hours;
x. Isolating the material as wet cake by filtration followed by its drying at 60-70°C for 10-15 hours;
xi. re-dissolving the dried material of step x) is solvent of step vii);
xii. Adding water & stirring;
xiii. Cooling the reaction mass to 5-15°C;
xiv. Stirring for 3-6 hours; and
xv. Isolating the material as wet cake by filtration followed by its drying at 60-70°C for 10-15 hours to get highly pure ((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenyl amino)carbonyl]-lH-pyrrol-l-yl]ethyl}-2,2-dimethyl- 1,3- dioxane-4-acetate having purity > 99.80% on HPLC.

2. A process as claimed in claim 1, wherein the catalyst used in claim 1(ii) is selected from Diazabicyclo(5.4.0)undec-7-ene (DBU), 1,4-Diazabicyclooctane (DABCO) or 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN) or a mixture thereof.

3. A process as claimed in claim 1, wherein quantity of catalysts used in claim 1(ii) is 0.10-0.70 times of (4R-Cis)-1,1-Dimethylethyl-6-(2-aminomethyl)-2,2-dimethyl-1,3-dioxane -4-Acetate.
4. A process as claimed in claim 1, wherein quantity of catalyst used in claim 1(ii) is specifically 0.15-0.50 times of (4R-Cis)-1,1-Dimethylethyl-6-(2-aminomethyl)-2,2-dimethyl-1,3-dioxane -4-Acetate.

5. A process as claimed in claim 1, wherein quantity of catalyst used in claim 1(ii) is more specifically 0.20-0.40 times of (4R-Cis)-1,1-Dimethylethyl-6-(2-aminomethyl)-2,2-dimethyl-1,3-dioxane -4-Acetate.

6. A process as claimed in claim 1, wherein the reaction time is 10-24 hrs, more preferably 10-20 hrs, most preferably 10-12 hrs for completion of reaction to get minimum unreacted 4-Fluoro-a-[2-methyl-1-oxopropyl]?-oxo-N-ß-diphenylbenzene Butanamide resulting in reduced reaction Time from 72 hours in prior art to 10-12 hrs in present invention along with huge yield gain & improved quality of Atorvastatin intermediate((4R-cis)-l,l-dimethylethyl-6-{2-[2-[(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenyl amino) carbonyl]-lH-pyrrol-l-yl]ethyl}-2,2-dimethyl- 1,3- dioxane-4-acetate .