FIELD OF THE INVENTION
The present invention relates to process for the preparation of inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, Atorvastatin calcium of formula I, and intermediates thereof.

Particularly, the present invention relates to an improved, efficient, and industrially advantageous process for the preparation of key intermediate, 2-[2-(4-Fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide, of atorvastatin, marked as formula IV:

More particularly, the present invention provides an improved process for the preparation of compound of Formula IV, the diketone intermediate of atorvastatin, for better yield and higher purity which can be employed for preparation of atorvastatin calcium of high purity.

BACKGROUND OF THE INVENTION
2-[2-(4-Fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenyl amide compound of formula IV is a key intermediate in the synthesis of atorvastatin calcium.
Atorvastatin calcium of the formula I, marketed under the trade name LIPITOR®, is an inhibitor of HMG-CoA reductase and is a therapeutic agent for hyperlipidemia, arteriosclerosis, hypercholesterolemia, osteoporosis, benign prostatic hyperplasia, and Alzheimer’s disease. Its structural formula is:
Atorvastatin calcium is chemically described as [R-(R*, R*)]-2-(4-fluorophenyl)-ß,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is (C33H34 FN2O5)2Ca•3H2O.
Atorvastatin and its pharmaceutically acceptable salts were first disclosed in US patent 5273995 (US’995).
US patent 5155251 (US’251) has described a process for the preparation of (±) 4-Fluoro-a-2-methyl-1-oxopropyl]?-oxo-N-ß-diphenylbenzene butaneamide by Knoevenagel condensation of 4-methyl-3-oxo-N-phenylpentanamide with benzaldehyde to obtain 4-methyl-3-oxo-N-phenyl-2-[phenylmethylene] pentanamide. The resulting condensation product reacts with p-fluoro benzaldehyde in the presence of the catalyst thiazole salt to obtain (±) 4-Fluoro-a-2-methyl-1-oxopropyl]?-oxo-N-ß-diphenylbenzene butaneamide.
The process is schematically represented as follows:

The above process involves additional steps for the preparation of catalyst which ultimately makes the whole process lengthy and industrially inefficient.
PCT patent publication 2003004457 (WO’457) has described a process for the preparation of atorvastatin including the process for the preparation of compound of formula IV.
The process of the diketone intermediate of formula IV is schematically represented as follows:

In the above process, 2-bromo-1-(4-fluorophenyl)-2-phenylethanone undergoes nucleophilic substitution reaction with 4-methyl-3-oxo-N-phenyl pentanamide in the presence of base preferably potassium carbonate and in the presence of polar solvent, especially methanol, ethanol or DMF to obtain compound of formula IV. Product is isolated by precipitation by slow addition of solvent like n-hexane. The remaining soluble material is recovered by chromatographic separation.
Further, it involves use of bromine which is difficult to operate due to its volatility, and strong toxicity as it causes disturbances of the respiratory, nervous, and endocrine systems during bromination process. It also involves relatively harsh reaction conditions.
Bromo compound starting material is very expensive and unsafe as compared to chloro compound used for the same purpose in the instant application.
It also uses column chromatographic technique for isolation of product, which is not conducive to industrial production.
Moreover, in this process the compound is obtained as diastereomeric mixture as well as other impurities which affect yield and purity of the desired product. The above WO’457 does not characterize any impurity formed in above reaction and the control of impurities such as desfluoro diketone is also ignored.
The above process needs to be carried out under controlled conditions to avoid impurities.
PCT patent publication 2009144736 (WO’736) has described a process for preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-?-oxo-N-ß-diphenyl benzenebutanamide, a key intermediate of atorvastatin by reacting 2-halo-1-(4-fluorophenyl)-2-phenylethanone with 4-methyl-3-oxo-N-phenylpentamide in the presence of base such as sodium carbonate, potassium carbonate, caesium carbonate, diisopropylethylamine, triethylamine, sodium hydride and C3-C5 alcohol as solvent.
The process is schematically represented as follows:

PCT patent publication 2012143933 (WO’933) has described a process for the preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-?-oxo-N-ß-diphenylbenzene butane amide, the diketone intermediate, by Friedel-craft condensation of fluorobenzene with phenylacetyl chloride in the presence of Lewis acid catalyst to obtain 1-(4-Fluorophenyl)-2-phenyl ethenone. Further, halogenation of resulting compound is performed in the presence of inert solvent like methylene chloride followed by addition of bromine solution to obtain 2-halo-1-(4-fluorophenyl)-2-phenylethanone. In the next step, nucleophilic substitution of 2-halo-1-(4-fluorophenyl)-2-phenylethanone in the presence of appropriate base and solvent with 4-methyl-3-oxo-N-phenyl pentanamide is performed to obtain diketone intermediate.
Although the above process avoids the use of expensive metal catalysts, the use of liquid bromine reagent is not suitable being strongly irritating and corrosive, and also not eco-friendly.
The process is schematically represented as follows:

Indian patent application, 2012MU01728, has also described a process for preparation of 4-fluoro-a-[2-methyl-l-oxopropyl]-?-oxo-N-ß-diphenylbenzenebutanamide, a key intermediate by involving use of high vacuum distillation of 2-chloro-1-(4-fluorophenyl)-2-phenone.
The process is schematically represented as follows:

Chinese patent application 111909048 has also disclosed following one pot process for preparation of 4-(4-fluorophenyl)-2-(2-methylpropionyl)-3-phenyl-4-oxo-N-phenyl butanamide (formula IV) by reacting compound of formula II with fluorobenzaldehyde, and isobutyraldehyde in the presence of Cu(SbF6)2 and under the action of catalyst A; wherein catalyst A is N-hydroxyaminocyclohexylcarboxamide derivative ligand and PdCl2.

The above process involves the use of expensive catalysts, which is unsuitable for industrial production.
Therefore, it is necessary to seek a more effective, improved purification technique and inexpensive synthetic route to avoid use of large amount of solvent and tedious reaction conditions.
There is need to develop a more economical and convenient new method in which the formation of reaction impurities is minimized, and yield is maximize for synthesizing a-isobutyryl-ß-p-fluorobenzoyl-ß-phenylpropionanilide.
The purpose of the present invention is to overcome the disadvantages of complex reaction operation, low yield, difficult removal of by-products, and to provide suitable route for industrial production of atorvastatin and intermediates thereof.
OBJECT OF THE INVENTION
The object of the present invention is to provide an improved, efficient, and industrially advantageous process for the preparation of Atorvastatin calcium of formula I, and intermediates thereof.
Another object of the present invention is to provide commercially viable and eco-friendly process for the preparation of key intermediate of atorvastatin, marked as formula IV:

The main object of the present invention is to provide an improved process for the preparation of compound of Formula IV, for better yield and higher purity which can be employed for preparation of atorvastatin calcium of high purity.
Yet another object of the present invention is to provide improved purification technique for the preparation of diketone intermediate by reducing amount of solvent to enhance yield of desired product.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of Atorvastatin calcium of formula I, and intermediates thereof.

In an embodiment, the present invention provides a process for the preparation of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of formula IV,

comprising the steps of:
a) reacting 2-chloro-1-(4-fluorophenyl)-2-phenylethanone compound of formula II

with 4-methyl-3-oxo-N-phenyl pentanamide compound of formula III

in the presence of suitable base in a mixture of a suitable solvent with water at a suitable temperature to obtain wet crude compound of formula IV;
b) purifying the crude compound of formula IV with a suitable solvent at a suitable temperature; and
c) isolating pure compound of formula IV.
In another aspect, the present invention provides a process for the preparation of pure 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of formula IV,

comprising the steps of:
a) purifying wet crude compound of formula IV with a suitable solvent at a suitable temperature; and
b) isolating pure 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of formula IV.
wherein suitable solvent used in step a) is selected from isopropanol and ethanol.

In another aspect, the present invention provides a process for the preparation of diketone intermediate of the formula IV substantially free of 2-Acetyl-4-(4-Fluorophenyl)-4-oxo-3,N-diphenylbutyramide impurity (acetyl impurity) of formula V.

In another aspect, the present invention provides a process for the preparation of substantially pure diketone intermediate of the formula IV.
In another aspect, the present invention provides a process for the preparation of atorvastatin calcium of formula I from substantially pure diketone intermediate of the formula IV.
DETAILED DESCRIPTION OF THE INVENTION
The present disclosure encompasses an improved process for the preparation of Atorvastatin of formula I, and intermediates thereof.

As discussed above, the processes described in the literature have significant disadvantages. More particularly, the process described in prior art have disadvantages of complex reaction operation, low yield, and difficult removal of by-products and impurities. Therefore, the reported prior art processes may not be considered suitable for commercial production.
As used herein, the modifier term "about" should be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 5 to about 10" also discloses the range "from 5 to 10." When used to modify a single number, the term "about" may refer to plus or minus 10% of the indicated number and includes the indicated number e.g., "about 10%" may indicate a range from 9% to 11%, and "about 1" may be from 0.9-1.1.
As used herein, and unless specified otherwise, the term "alcohol solvents" include, but are not limited to, substituted or unsubstituted C1-C6 alcohols, methanol, ethanol, 1-propanol, isopropyl alcohol (IPA), 2-nitroethanol, 2-fluoroethanol, ethylene glycol, 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, tert-butyl alcohol, 2-ethoxyethanol, di-ethylene glycol, pentanol, neo-pentyl alcohol, tert-pentyl alcohol, cyclohexanol, benzyl alcohol, phenol, glycerol, or the like.
As used herein, and unless otherwise specified, the term "isolated" in reference to the compounds of the present invention, their salts or solid-state forms thereof corresponds to compounds that are physically separated from the reaction mixture in which they are formed.
As used herein, and unless otherwise specified, the term "substantially free" is meant that the atorvastatin of formula I or any other intermediate thereof of the present invention contain about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w) or less, or about 0.2% (w/w) or, or about 0.1% (w/w) less of a specified or unspecified impurity.
As used herein, and unless otherwise specified, the term "substantially pure" relates to compounds having a purity of about 95% or more. In other words, the term relates a compound, having a purity, measured as % area normalization by HPLC, of about 95% or more. In other aspects, the term relates to compounds having a purity of about more than 97% area normalization by HPLC. In preferred embodiments, the term relates to compounds having a purity of about more than 98% (by HPLC; area normalization).
In an aspect, the present invention provides a process for the preparation of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of formula IV,

comprising the steps of:
a) reacting 2-chloro-1-(4-fluorophenyl)-2-phenylethanone compound of formula II

with 4-methyl-3-oxo-N-phenyl pentanamide compound of formula III

in the presence of suitable base in a mixture of a suitable solvent with water at a suitable temperature to obtain wet crude compound of formula IV;
b) purifying crude compound of formula IV with a suitable solvent at a suitable temperature; and
c) isolating pure compound of formula IV.
The suitable base in step (a) is preferably an inorganic base, selected from, but not limited to, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide or the like. Most preferably, the base is potassium carbonate.
The suitable solvent in step (a) may include but are not limited to polar solvent. Preferably, the polar solvent is alcohol solvent or the like. Most preferably, the alcohol solvent is ethanol and methanol.
The process of step (a) may be carried out for about 10-20 hours at a temperature from about 20°C to about 60°C, preferably at about 40°C to about 55°C, and most preferably at about 45°C to about 50°C.
The suitable solvent for purification in step (b) may include but are not limited to polar solvent. Preferably, the polar solvent is alcohol solvent or the like. Most preferably, the alcohol solvent is isopropanol and ethanol.
The purification step (b) may be carried out at a temperature from about 0°C to about 80°C, preferably at about 40°C to about 80°C, and most preferably at about 60°C to about 70°C.
In another aspect, the present invention provides a process for the preparation of pure 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of formula IV,

comprising the steps of:
a) purifying crude compound of formula IV with a suitable solvent at a suitable temperature; and
b) isolating pure 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of formula IV.
wherein suitable solvent used in step a) is selected from isopropanol and ethanol.
The purification step a) may be carried out at a temperature from about 0°C to about 80°C, preferably at about 40°C to about 80°C, and most preferably at about 60°C to about 70°C.
In another aspect, the present invention provides a process for the preparation of diketone intermediate of the formula IV substantially free of 2-Acetyl-4-(4-Fluorophenyl)-4-oxo-3,N-diphenylbutyramide impurity (acetyl impurity) of formula V.

In another aspect, the present invention provides a process for the preparation of substantially pure diketone intermediate of the formula IV.
In another aspect, the present invention provides process of Scheme 1 for the preparation of substantially pure diketone intermediate of the formula IV.

In another aspect, the present invention provides a process for the preparation of atorvastatin calcium of formula I from substantially pure diketone intermediate of the formula IV.
In another aspect, the present invention provides a process of Scheme 2 for the preparation of atorvastatin calcium of formula I from substantially pure diketone intermediate of the formula IV.

The progress of the reaction can be monitored by suitable chromatographic techniques such as high-pressure liquid chromatography (HPLC), gas chromatography (GC), ultra-pressure liquid chromatography (UPLC), thin layer chromatography (TLC) and the like.
The following examples are provided to describe the invention in further detail.
Although, the following examples illustrate the present invention in more detail but should not be construed as limiting the scope of the invention.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES:
Preparation of 2-[2-(4-Fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide (IV)

Reference example (As per patent no. WO 03/004457): - 20 g (0.0804 mole) 2-Chloro-1-(4-fluorophenyl)-2-phenyl ethenone (II) and 16.34 g (0.0796 mole) 4-methyl-3-oxo-N-phenylpentanamide of (III) were dissolved in 205 ml ethanol with stirring. 11.45 g (0.0828 mole) potassium carbonate was added to the reaction mixture. Reaction was stirred for 48 hours at 25-30ºC and monitored by HPLC. After 48 hours, Formula-II: 12.33%, Formula-III: 8.82% and Formula-IV: 59.57% were observed in reaction mixture. Thereafter, reaction mixture was diluted with water and ethyl acetate. Layers were settled and separated. Organic layer was distilled out under vacuum at 45-50ºC to get 36.0 g of compound of Formula-IV having purity 69.05%, Formula- II: 9.93%, Formula-III: 7.03%, single highest impurity: 5.31%.
Example- 1: - 20 g (0.0804 mole) of 2-Chloro-1-(4-fluorophenyl)-2-phenyl ethenone (II) and 16.34 g (0.0796 mole) 4-Methyl-3-oxo-N-phenylpentanamide of (III) were dissolved in 205 ml ethanol with stirring. 11.45 g (0.0828 mole) potassium carbonate was added to the reaction mixture. Reaction was stirred for 48 hours at 45-50ºC and monitored by HPLC. After 48 hours, Formula-II: 4.95%, Formula-III: 4.36% and Formula-IV: 62.70% were observed in reaction mixture. Thereafter, reaction mixture was diluted with water and ethyl acetate. Layers were settled and separated. Organic layer was distilled out under vacuum at 45-50ºC to get 36.0 g compound of Formula-IV having purity 73.92%, Formula- II: 3.57%, Formula-III: 3.67%, single highest impurity: 9.70%.
Example- 2: - 16.34 g (0.0796 mole) 4-Methyl-3-oxo-N-phenylpentanamide (III) was dissolved in 175 ml ethanol with stirring. 11.45 g (0.0828 mole) potassium carbonate was added. Temperature was raised to 45-50ºC. Solution of 20 g (0.0804 mole) 2-Chloro-1-(4-fluorophenyl)-2-phenyl ethenone (II) in ethanol, 30 ml was added in reaction mixture in 5-6 hours at 45-50ºC. Reaction was stirred for 48 hours at 45-50ºC and monitored by HPLC. After 48 hours, Formula-II: 4.04%, Formula-III: 2.58% and Formula-IV: 66.22% were observed in reaction mixture. Thereafter, reaction mixture was diluted with water and ethyl acetate. Layers were settled and separated. Organic layer was distilled out under vacuum at 45-50ºC to get 36.0 g compound of Formula-IV having purity: 72.60%, Formula-II: 3.53%, Formula-III: 4.47%, single highest impurity: 10.53%.
Example- 3: - 45.41 g (0.2212 mole) 4-Methyl-3-oxo-N-phenylpentanamide (III) was dissolved in 100 ml ethanol followed by addition of 40.0 g (0.2894 mole) potassium carbonate and 75 ml water under stirring. Temperature was raised to 45-50ºC. Solution of 50 g (0.2011 mole) 2-Chloro-1-(4-fluorophenyl)-2-phenyl ethenone (II) in 75 ml ethanol was added slowly in 5-6 hours at 45-50ºC. Reaction was stirred for 15-16 hours at 45-50ºC and monitored by HPLC. After 16 hours, Formula-II: 0.64%, Formula-III: 6.12% and Formula-IV: 73.61% were observed in reaction mixture. Thereafter, reaction mass was cooled to 30-35ºC and filtered. Wet material was running washed with mixture of ethanol and water followed by water. Material was dried to obtained 56.4 g (Yield- 1.13 w/w) crude compound of Formula-IV having purity: 99.26%, Formula- II: 0.01%, Formula-III: 0.04%, single highest impurity- 0.25%.
Example- 4: - 17.34 g (0.0844 mole) 4-Methyl-3-oxo-N-phenylpentanamide (III) was dissolved in 40 ml ethanol followed by addition of 16 g (0.1158 mole) potassium carbonate and 20 ml water. Temperature was raised to 45-50ºC. Solution of 20 g (0.0804 mole) 2-Chloro-1-(4-fluorophenyl)-2-phenyl ethenone (II) in 30 ml ethanol was added slowly in 5-6 hours at 45-50ºC. Reaction was stirred for 15-16 hours at 45-50ºC and monitored by HPLC. After 16 hours, Formula-II: 0.19%, Formula-III: 1.59% and Formula-IV: 79.81% were observed in reaction mixture. Thereafter 20 ml water was added. Reaction mixture was cooled to 10-15ºC and filtered. Wet material was running washed with mixture of ethanol and water followed by water. Material was dried to obtained 23.0 g (Yield- 1.15 w/w) crude compound of Formula-IV having purity 98.69%, Formula- II: 0.02%, Formula-III: 0.13%, single highest impurity- 0.32%.
Example- 4a: - 216.76kg 4-Methyl-3-oxo-N-phenylpentanamide (III) was dissolved in 500 L ethanol followed by addition of 200g potassium carbonate and 250L water. Temperature was raised to 45-50ºC. Solution of 250 kg 2-Chloro-1-(4-fluorophenyl)-2-phenyl ethenone (II) in 375L ethanol was added slowly in 5-6 hours at 45-50ºC. Reaction was stirred for 14-16 hours at 45-50ºC and monitored by HPLC. After 14 hours, Formula-II: 0.15%, Formula-III: 6.83% and Formula-IV: 79.09% were observed in reaction mixture. Thereafter 250L water was added. Reaction mixture was cooled to 25-30ºC and filtered. Wet material was running washed with mixture of ethanol and water followed by water to obtained 282.5 kg crude compound of Formula-IV having purity 100%.
Example- 5: - 43.33 g (0.211 mole) 4-Methyl-3-oxo-N-phenylpentanamide (III) was dissolved in 100 ml ethanol followed by addition of 40 g (0.2894 mole) potassium carbonate and 75 ml water under stirring. Temperature was raised to 45-50ºC. Solution of 50 g (0.2011 mole) 2-Chloro-1-(4-fluorophenyl)-2-phenyl ethenone (II) in 75 ml ethanol was added slowly in 5-6 hours at 45-50ºC. Reaction was stirred for 14-16 hours at 45-50ºC and monitored by HPLC. After 14 hours, Formula-II 0.45%, Formula-III 1.01%, Formula-IV 81.17% were observed in reaction mixture. Thereafter 50 ml water was added. Reaction mixture was cooled to 25-30ºC and filtered. Wet material was running washed with mixture of ethanol and water followed by water. Again, wet material was slurry washed with water at 60-65ºC to get wet crude compound of Formula-IV having purity: 99.61%, Formula-II: 0.01%, Formula-III: 0.03%, Desfluoro imp. 0.05%, single highest impurity: 0.18%.
Wet crude compound of Formula-IV was taken in 112.5 ml IPA and heated to 65-70ºC under stirring. Reaction mixture was maintained for 1 hour at 65-70ºC. Thereafter, reaction mixture was cooled to 10-15ºC and stirred for 1 hour. Material was filtered at 10-15ºC and washed with chilled 25 ml IPA. The wet material was dried to obtain 53 g (Yield: 1.06 w/w) of pure compound of Formula-IV having purity: 99.88%, Formula-II: ND, Formula-III: 0.02%, Desfluoro imp. 0.05%, single highest impurity: 0.03%.
Preparation of tert-Butyl-2-((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl] ethyl}-2,2-dimethyl-1,3-dioxan-4-yl) acetate (VII)

Example- 6: - 20.0 g (0.073 mole) (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate (VI) and 30.53 g (0.073 mole) crude compound of Formula-IV was taken in 175 ml cyclohexane. In the reaction mixture, 4.8 g (0.047 mole) pivalic acid, 5.18 g (0.051 mole) diisopropylamine and 3.79 g (0.011 mole) tetra butyl ammonium hydrogen sulphate were added under stirring. Reaction mixture was heated to 75-85ºC. Reaction was maintained for 40 hrs. at 75-85ºC, and water was removed azeotropically. Reaction was monitored by HPLC. After completion of reaction, reaction mixture was cooled to 65-70ºC and quenched with sodium bicarbonate solution. Organic layer was separated and washed with water. Organic layer was distilled off under vacuum below 65ºC. Traces of cyclohexane were removed by addition and distillation of isopropyl alcohol under vacuum below 65ºC. Residue so obtained was dissolved in isopropyl alcohol and product was crystallized by addition of water. Product was filtered and dried. Dried material was further purified in the mixture of isopropyl alcohol and water. Material was dried to obtained 40.4 g of compound of formula VII. Yield- 2.02 w/w.
Preparation of Atorvastatin Calcium Trihydrate: (3R, 5R) -7- [2-(4-Fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate calcium trihydrate (I)
Example- 7: - 20 g (0.031 mole) tert-Butyl-2-((4R,6R)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl] ethyl}-2,2-dimethyl-1,3-dioxan-4-yl) acetate (VII) was taken into 200 ml methanol. Reaction mixture was heated to 45-55ºC till clarity. Solution was cooled to 33-38ºC and 27.7 ml water was added. Thereafter solution of 4.2 ml hydrochloric acid in 9.0 ml water was added. Reaction mixture was maintained for 6 hours and monitored. After the completion of reaction, solution of 3.88 g (0.097 mole) sodium hydroxide in 40 ml water was added till the pH of reaction mass reached to more than 12.0. Reaction mass was slowly heated to 40-45ºC. Reaction mixture was maintained for 4 hrs. and monitored. After completion of reaction, reaction mass was concentrated under vacuum at temperature below 60ºC. Concentrated mass thus obtained was diluted with 141.6 ml water, 30 ml methanol and 40 ml methyl tertiary butyl ether at 25-35ºC. Reaction mixture was stirred till clarity. pH of reaction mixture was adjusted to 8.5-9.5 with dilute HCl solution. Temperature was raised to 45-50ºC followed by addition of solution of 2.7g (0.017 mole) calcium acetate in 78.34 ml water till turbidity. After turbidity, 2.0 g Atorvastatin calcium was added as seeding followed by addition of remaining qty. of calcium acetate solution. After the calcium salt formation, reaction mass was cooled to 30-35ºC and filtered out. Wet material was slurry washed with mixture of 60 ml ethyl acetate and 40 ml cyclohexane at 60-65ºC. Wet material thus obtained was further slurry washed with 200 ml water at 35-40ºC and dried to obtained 19.0 g of Atorvastatin Calcium (I). Yield- 0.95 w/w.
Advantages of present invention over prior art:
• Cost effective as well as green chemistry involving less consumption of solvent and selecting eco-friendly solvent.
• Crude compound of formula IV is isolated in the mixture of ethanol and water; and purified in IPA which is suitable and viable for industrial scale.
• Isolated compounds are of superior quality over prior art reported, having purity = 99%.
• Isolated compound of formula IV is purified in isopropyl alcohol only, hence recovered solvent can be used which makes the process cost effective and eco-friendly.
• Isolated compound of formula IV is substantially free of acetyl impurity of formula V.

CLAIMS:

WE CLAIM
Claim 1. A process for the preparation of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of formula IV,

comprising the steps of:
a) reacting 2-chloro-1-(4-fluorophenyl)-2-phenylethanone compound of formula II,

with 4-methyl-3-oxo-N-phenyl pentanamide compound of formula III,

in the presence of base in a mixture of a solvent with water at a suitable temperature to obtain wet crude compound of formula IV;
b) purifying the crude compound of formula IV with solvent at a suitable temperature; and
c) isolating pure 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of formula IV.
Claim 2. A process for the preparation of pure 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of formula IV,

comprising the steps of:
a) purifying crude compound of formula IV with solvent at a suitable temperature; and
b) isolating pure 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of formula IV.
wherein solvent used in the step (a) is selected from isopropanol and ethanol.

Claim 3. The process as claimed in claim 1, wherein base used in the step (a) is an inorganic base selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide.
Claim 4. The process as claimed in claim 1, wherein solvent used in the step (a) is polar solvent selected from alcohol solvent.
Claim 5. The process as claimed in claim 1, wherein in the step (a) suitable temperature is selected from 20°C to 60°C.
Claim 6. The process as claimed in claims 1, wherein the solvent used in purification of crude compound of formula IV is alcohol solvent.
Claim 7. The process as claimed in claim 6, wherein the alcohol solvent is selected from isopropanol and ethanol.
Claim 8. The process as claimed in claim 1, wherein in the step (b) purification is carried out at a suitable temperature from 0°C to 80°C and preferably at 40°C to 80°C.
Claim 9. The process as claimed in claim 1, wherein in the step c) isolated pure compound of formula IV is substantially free of 2-acetyl-4-(4-fluorophenyl)-4-oxo-3,N-diphenylbutyramide impurity (acetyl impurity) of formula V.
.
Claim 10. A process for the preparation of atorvastatin calcium of formula I from pure compound of the formula IV, prepared by the process as claimed in claim 1.
Ind-Swift Laboratories Ltd.