DESC:INTRODUCTION
The present disclosure relates to one pot process for preparation of Atorvastatin calcium crystalline form I.
Atorvastatin calcium is described chemically 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 and is represented structurally by Formula I.

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 generically and specifically Atorvastatin and its related compounds along with their pharmaceutically acceptable salts, pharmaceutical composition and a method of treatment.
U.S. Patent No. 5,969,156 discloses the process for the preparation of crystalline Form I wherein a mixture of (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide (atorvastatin lactone), methyl tertiary-butyl ether (MTBE) and methanol is reacted with an aqueous solution of sodium hydroxide to form the ring-opened sodium salt. Followed by cooling, and converting to sodium salt and further converting to calcium salt hemihydrate and seeded with a slurry of crystalline Form I atorvastatin water and methanol, followed by drying the resultant solid to give crystalline Form I atorvastatin.
WO2006032959A1 discloses the use of ion-exchange resin for acetal deprotection of (4R-cis)-6-[2-[3-[phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(l- methylethyl)-pyrrol- 1 -yl]-ethyl]-2,2-dimethyl-[l ,3]-dioxane-4-yl-acetic acid-t-butyl ester in the process for preparation of Atorvastatin calcium.
There remains a need for a process which is cost effective, eco-friendly and commercially suitable to get of Atorvastatin calcium and its stable crystalline Form I.
SUMMARY
In an aspect, the present application provides a one pot process for the preparation of Atorvastatin calcium crystalline Form I comprising the steps of:
i) dissolving compound of formula II in a mixture of water and isopropanol ;
ii) passing the solution of step (i) in to a preheated column packed with ion-exchange resin to provide compound of formula III; wherein R=alkyl, aryl
iii) reacting the solution of step (ii) with aqueous sodium hydroxide solution to form the sodium salt of atorvastatin;

iv) adding calcium acetate solution to step (iii) to form atorvastatin calcium salt;

v) filtering the atorvastatin calcium solution of step (iv);
vi) optionally adding pure crystalline atorvastatin calcium Form–I seed;
vii) isolating crystalline Form-I of atorvastatin calcium.

In another aspect, the present application one pot process for the preparation of atorvastatin calcium crystalline Form I comprising the steps of:
i) combining compound of formula II with a mixture of water and isopropanol;
ii) adding ammonium chloride to the reaction mixture of step (i) and refluxing to provide compound of formula III;

wherein R= alkyl, aryl
iii) reacting the solution of step (ii) with aqueous sodium hydroxide solution to form the sodium salt of atorvastatin;

iv) adding calcium acetate solution to step (iii) to form atorvastatin calcium salt;

v) filtering the atorvastatin calcium solution of step (iv);
vi) optionally adding pure crystalline atorvastatin calcium Form–I seed;
vii) isolating crystalline Form-I of atorvastatin calcium.

In another aspect, the present application one pot process for the preparation of atorvastatin calcium, containing less than 0.1% of heptenoic acid impurity, comprising the steps of:
i) combining compound of formula II with a mixture of water and isopropanol;
ii) adding ammonium chloride to the reaction mixture of step (i) and refluxing to provide compound of formula III;

wherein R= alkyl, aryl
iii) reacting the solution of step (ii) with aqueous sodium hydroxide solution to form the sodium salt of atorvastatin;

iv) adding calcium acetate solution to step (iii) to form atorvastatin calcium salt;

v) filtering the atorvastatin calcium solution of step (iv);
vi) optionally adding pure crystalline atorvastatin calcium Form–I seed;
vii) isolating crystalline Form-I of atorvastatin calcium.

In another aspect, the present application provides a one pot process for the preparation of atorvastatin calcium comprising the steps of:
i) dissolving compound of formula II in acetonitrile ;
ii) adding ion-exchange resin to the solution of step (i) at room temperature to provide compound of formula III;
wherein R= alkyl, aryl
iii) reacting the solution of step (ii) with aqueous sodium hydroxide solution to form the sodium salt of atorvastatin;

iv) adding calcium acetate solution to step (iii) to form atorvastatin calcium salt;

v) filtering the atorvastatin calcium solution of step (iv);
vi) isolating atorvastatin calcium.

In another aspect, the present application provides intermediate compound of formula III, IV and Atorvastatin calcium, obtained according to any of the processes of previous aspects, containing less than 0.1 % of Heptenoic acid impurity, as detected by HPLC.

In another aspect, the present application provides intermediate compound of formula III, IV and Atorvastatin calcium containing less than 0.1 % of Heptenoic acid impurity, as detected by HPLC.

In another aspect, the present application provides the intermediate compound of formula II, obtained according to any of the processes of present application, containing less than 0.15 % of precursor of diamino impurity with RRT 0.96, as detected by HPLC.
In another aspect, the present application provides Atorvastatin, obtained according to any of the processes of present application, containing less than 0.15 % of diamino impurity, as detected by HPLC.

In another aspect, the present application provides the intermediate compound of formula II containing less than 0.15 % of precursor of diamino impurity with RRT 0.96, as detected by HPLC.

In another aspect, the present application provides Atorvastatin calcium, containing less than 0.15 % of diamino impurity, as detected by HPLC.

In sixth aspect, the present application provides a pharmaceutical composition comprising crystalline form I of Atorvastatin calcium prepared according to the present invention and atleast one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF DRAWINGS
Figure 1 is an XRPD pattern of the crystalline Form I of Atorvastatin calcium prepared according to Example 1.
Figure 2 is an XRPD pattern of the crystalline Form I of Atorvastatin calcium prepared according to Example 2.

DETAILED DESCRIPTION
In an aspect, the present invention provides a one pot process for the preparation of atorvastatin calcium crystalline Form I comprising the steps of:
i) dissolving compound of formula II in a mixture of water and isopropanol;
ii) passing the solution of step (i) in to a preheated column packed with ion-exchange resin to provide compound of formula III;

wherein R=alkyl, aryl
iii) reacting the solution of step (ii) with aqueous sodium hydroxide solution to form the sodium salt of atorvastatin;

iv) adding calcium acetate solution to step (iii) to form atorvastatin calcium salt;

v) filtering the atorvastatin calcium solution of step (iv);
vi) optionally adding pure crystalline atorvastatin calcium Form–I seed;
vii) isolating crystalline Form-I of atorvastatin calcium.

In another aspect, the present application provides a one pot process for the preparation of Atorvastatin calcium crystalline Form I comprising the steps of:
i) combining the compound of formula II with a mixture of water and isopropanol ;
ii) adding ammonium chloride to the reaction mixture of step (i) and refluxing to provide compound of formula III;

wherein R= alkyl, aryl
iii) reacting the solution of step (ii) with aqueous sodium hydroxide solution to form the sodium salt of atorvastatin;

iv) adding calcium acetate solution to step (iii) to form atorvastatin calcium salt;

v) filtering the atorvastatin calcium solution of step (iv);
vi) optionally adding pure crystalline atorvastatin calcium Form–I seed;
vii) isolating crystalline Form-I of atorvastatin calcium.

In another aspect, the present application one pot process for the preparation of atorvastatin calcium, containing less than 0.1% of heptenoic acid impurity, comprising the steps of:
i) combining compound of formula II with a mixture of water and isopropanol;
ii) adding ammonium chloride to the reaction mixture of step (i) and refluxing to provide compound of formula III;

wherein R= alkyl, aryl
iii) reacting the solution of step (ii) with aqueous sodium hydroxide solution to form the sodium salt of atorvastatin;

iv) adding calcium acetate solution to step (iii) to form atorvastatin calcium salt;

v) filtering the atorvastatin calcium solution of step (iv);
vi) optionally adding pure crystalline atorvastatin calcium Form–I seed;
vii) isolating crystalline Form-I of atorvastatin calcium.

In another aspect, the present application provides a one pot process for the preparation of Atorvastatin calcium comprising the steps of:
i) dissolving compound of formula II in acetonitrile ;
ii) adding ion-exchange resin to the solution of step (i) at room temperature to provide compound of formula III;
wherein R= alkyl, aryl
iii) reacting the solution of step (ii) with aqueous sodium hydroxide solution to form the sodium salt of atorvastatin;

iv) adding calcium acetate solution to step (iii) to form atorvastatin calcium salt;

v) filtering the atorvastatin calcium solution of step (iv);
vi) isolating atorvastatin calcium.

Step i) of the above processes may be carried out by dissolving or combining the compound of formula II in a mixture of isopropanol-water or acetonitrile. The reaction mixture of step i) may be either homogeneous or heterogenous. The step i) solution can be prepared at room temperature, under heating or can be carried forward from the previous step.
Step ii) of the above processes may be carried out either in the presence of ion-exchange resin or with ammonium chloride.
Suitable ion-exchange resin in step ii) include, but are not limited to cross linked polystyrene such as cation-exchange resin. Examples of such ion-exchange resins include TULSION 57-H, Amberlite(R) IRA 120, Amberlyst(R) 15, Indion 525 and mixtures thereof. The ion-exchange resin is ordinarily present in an amount ranging from about four times to about ten times with respect to starting material.
In the step ii) of the first aspect, the column is preheated from about 75°C to about 90°C. The solution of step i) was circulated through the column at temperature from about 75°C to about 90°C for about 12 hours to about 20 hours or longer.
In the step ii) of the second aspect, ammonium chloride was added to the solution of step i) and refluxed for about 20 hours to about 45 hours or longer.
In the step ii) of the third aspect, the ion-exchange resin was added to the solution of step i) at about 25°C to about 35°C and maintained for about 30 hours to about 35 hours or longer.
Steps iii) of the aspects of the present inventions involves the formation of sodium salt of atorvastatin on treatment of step ii) solution with sodium hydroxide. The nature of sodium hydroxide can be either in solid form or as an aqueous solution.
Steps iv) of the three aspects of the present inventions involves the formation of calcium salt of atorvastatin on treatment of step iii) solution with calcium acetate. The nature of calcium acetate can be either in solid form or as an aqueous solution.
Steps v) of the three aspects of the present inventions involves the filtration of step iv) solution. The filtration can be done by methods know in the art.
Step vi) of first and second aspects involve the optional addition of crystalline Form I seeds of atorvastatin calcium to the solution of step v). Optionally, similar seeding can be used in the third aspect of the invention. The seed of atorvastatin calcium is ordinarily present in an amount ranging from about 0.02 times to about 0.1 times with respect to starting material.
Steps vi) of the third aspect involves the isolation of solid atorvastatin calcium. The isolation can be carried by methods known in the art such as filtration, crystallization, distillation, evaporation, rotavapor drying, freeze-drying, fluidized bed drying, flash drying, spin flash drying or the like.
Steps vii) of the first and second aspect involves the isolation of crystalline form I atorvastatin calcium. The isolation can be carried by methods known in the art such as filtration, crystallization, distillation, evaporation, rotavapor drying, freeze-drying, fluidized bed drying, flash drying, spin flash drying or the like. Atorvastatin calcium crystalline Form I obtained by the processes of the present invention is characterized by XRD pattern as shown in Fig. 1 and Fig. 2.
Atorvastatin calcium obtained by any of the processes described in this application may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, Nutch filter dryers such as Agitated nutch filter dryer or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 80°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
Suitable temperature at which the above processes can be carried out is in the range from about 20°C to about 100°C.
Atorvastatin calcium obtained by any of the processes described in this application may be purified to obtain the required physical and chemical attributes such as purity, particle size, surface area, polymorph, etc. The purification can be done using any of the known methods in the art.
Atorvastatin calcium obtained according to the process of present application is having purity of greater than about 99% or greater than about 99.5% and the impurities are at the acceptable limit as measured by HPLC.
Atorvastatin calcium obtained according to the processes of the present application may be milled or micronized by any of the processes known in the art, such as ball milling, jet milling, wet milling and the like, to produce desired particle sizes and particle size distributions.
Atorvastatin calcium crystalline Form I obtained by the processes of the present invention is characterized by XRD pattern as shown in Fig. 1 and Fig. 2.
The Atorvastatin calcium crystalline Form I of present invention is stable and useful for the pharmaceutical formulations.
Starting materials used in any aspect of the instant application may be obtained from either commercially available sources or prepared according to the methods known in the art. Starting materials used in any aspect of the instant application may be purified according to the methods known in the art such as recrystallization, acid – base treatment, chromatography, fractional distillation, slurrying or the like, before using.
In another aspect, the present application provides intermediate compound of formula III, IV and Atorvastatin calcium, obtained according to any of the processes of previous aspects, containing less than 0.1 % of Heptenoic acid impurity, as detected by HPLC.

In another aspect, the present application provides intermediate compound of formula III, IV and Atorvastatin calcium containing less than 0.1 % of Heptenoic acid impurity, as detected by HPLC.

In embodiments, the content of Heptenoic acid impurity was measured in the reaction mass (containing compound of formula III) samples obtained through the processes of present application i.e., using ion exchange resin or ammonium chloride for the deprotection of acetonide compound of formula II and in the samples obtained through the use of known deprotection conditions, as tabulated below.
Deprotection reagent Solvent Purity in reaction mass (%) Heptenoic acid impurity in reaction mass
(%)
PTSA Aq. Methanol 96.5 0.31
Trifluoroacetic acid Aq. Methanol 98.26 0.39
HCl Aq. Methanol 98.12 0.47
NH4Cl Aq. Methanol 98.38 0.18
Amberlist-15 Aq. IPA 98.90 0.13
Cross linked polystyrene resin Aq. IPA 99.18 0.12
NH4Cl Aq. IPA 99.32 0.06
NH4Cl Aq. IPA 99.39 0.07
NH4Cl Aq. IPA 99.33 0.07

As illustrated above, the use of ammonium chloride for the deprotection of acetonide compound of formula II results in the control of Heptenoic acid impurity effectively, as low as 0.06%, at this stage itself and avoids downstream purifications or isolation at subsequent steps.

In another aspect, the present application provides Atorvastatin calcium containing less than 0.1 % of Heptenoic acid impurity, as detected by HPLC.

In another aspect, the present application provides the intermediate compound of formula II, obtained according to any of the processes of present application, containing less than 0.15 % of precursor of diamino impurity with RRT 0.96, as detected by HPLC.

In another aspect, the present application provides Atorvastatin, obtained according to any of the processes of present application, containing less than 0.15 % of diamino impurity, as detected by HPLC.

In another aspect, the present application provides the intermediate compound of formula II containing less than 0.15 % of precursor of diamino impurity with RRT 0.96, as detected by HPLC.

In embodiments, the process for the preparation of intermediate compound of formula II or Atorvastatin calcium, containing less than 0.15 % of diamino impurity, as detected by HPLC, comprises the step of controlling the impurity in the preparation of tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate from tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate. In embodiments, tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate may be prepared according to the procedures described at example 4 of the present application.

In another aspect, the present application provides the intermediate compound of formula II or Atorvastatin calcium containing less than 0.15 % of diamino impurity, as detected by HPLC.

In another aspect, the present application provides a pharmaceutical composition comprising crystalline form I of Atorvastatin calcium prepared according to the present invention and atleast one pharmaceutically acceptable excipient.
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.
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 the 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.
DEFINITIONS
“Ion-exchange resin or ion-exchange polymer” is a resin or polymer that acts as a medium for ion exchange. It is an insoluble matrix (or support structure) normally in the form of small (0.25–0.5 mm radius) microbeads, usually white or yellowish, fabricated from an organic polymer substrate.
EXAMPLES
EXAMPLE 1: Preparation of Atorvastatin Calcium Crystalline Form I
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 (50g) was added to a mixture of isopropanol (600 mL) and water (150mL) and heated at 77-85°C for 3hours. Cross-linked polystyrene resin (250g) was loaded into column and the jacket temperature was raised to 80-85°C. The reaction mass was circulated through the column for two hours at 77-85°C. Water (100 mL) was added to reaction mass at 77-85°C and continuously the reaction mass was circulated through column for 15 hours at 77-85°C. The reaction mass was cooled to 50-60°C and aqueous sodium hydroxide solution (3.36g of sodium hydroxide dissolved in 37.5 mL of water) and isopropanol (50 mL) was added. The reaction mixture was maintained at 50-60°C for two hours. Aqueous calcium acetate solution (7.55 g of calcium acetate dissolved in 62.5 mL of water) was added to reaction mass at 50-60°C and maintained for one hour. Aqueous sodium hydroxide solution (0.92g of sodium hydroxide dissolved in 7.5 mL of water) was added to reaction mixture at 50-60°C and maintained for two hours. The reaction mixture was filtered on hyflo bed and washed with isopropanol (50mL). The reaction mass maintained at 50-60°C was added to a mixture of water (1273.5mL) and Atorvastatin calcium crystalline Form-I seed (2.5g) at 40-50°C and maintained for one hour. The reaction mass was cooled to 30-35°C and maintained for two hours. The compound was filtered, washed with a mixture of isopropanol (83mL) and water (167mL). Solid material was dried at 25-35°C followed by 60-70°C in air tray drier to yield the title compound.
Yield: 37.04g (80.34%); HPLC purity: 99.49%

EXAMPLE 2: Preparation of Atorvastatin Calcium Crystalline Form I
tert-butyl-2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenyl carbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (20 g) in isopropanol (240ml) was added to a mixture of ammonium chloride (4.91g) in water (60ml) and refluxed for 40 hours. To the reaction mass sodium hydroxide (5.5g) dissolved in water (15mL) was added and maintained at 50-60 °C for 2 hours. Calcium acetate (3.21g) dissolved in 25 mL of water was added and maintained for 1 hour at 50-60 °C. Solution of sodium hydroxide (0.37g) in water (3mL) was added to the reaction mass and maintained for two hours at 50-60°C. Reaction mass was filtered through hyflo bed and 0.45 micron filter paper and further washed with isopropanol (50mL). The filtrate was added to mixture of water (840mL) and atorvastatin calcium form-1 seed (1g) at 40-50°C. Reaction mass was cooled to 30-35°C after maintaining for 1 hour at 40-50 °C. Precipitated material was filtered and washed with mixture of isopropanol (33mL) and water (67mL). Solid material was dried at 25-35°C followed by 60-70°C in air tray drier to yield the title compound.
Yield: 13.5g (73%); HPLC purity: 99.59%;

Example 3: One pot process for preparation of Atorvastatin Calcium
Cross-linked polystyrene resin (50g) was added to a mixture of tert-butyl-2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenyl carbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (5g) in acetonitrile (150 mL) and maintained at 25-35°C for 31 hours. Resin was separated by decantation and solution of sodium hydroxide (0.5g) in water (7.5mL) was added to reaction mixture maintained for 2 hours at 25-35 °C. Calcium acetate (0.88g) dissolved in water (10mL) was added to reaction mass and maintained for 60 minutes at 50-60 °C. Reaction mixture was filtered through hyflo bed and 0.45 micron filter paper, further washed acetonitrile (2.5 ml). Precipitated material was filtered. Solid material was dried at 25-35°C followed by 60-70°C in air tray drier to yield the title compound.
Yield: 1.3g; HPLC purity: 99.24%

Example 4: Preparation of tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate
Charge tert-butyl 2-((4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (200 kg) and methanolic ammonia (150 kg) in to reactor. Cool the reaction mass to 4.2 °C. Charge the Raney Ni (16 .14 kg) (washed with water (56 L X 6 times)), water (12 L) and methanolic ammonia (900 kg) in to reactor. Apply hydrogen pressure 0.4 kg/cm2 and stir for 7 minutes. Maintain the reaction mass at 39.3 °C under hydrogen pressure 3.0 – 3.5 kg/cm2 for 3 hours and filter the reaction mass and wash with methanol (200 L and 100 L). Evaporate the solvent under vacuum at 42.6 °C and charge methanol (15 L). Evaporate the solvent completely under vacuum at 47.9 °C to obtain the title compound.

Example 5: 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
Cyclohexane (2280 L), pivalic acid (46 kg), Morpholine (53 kg) and (±)-fluoro-a-2-methyl-1-oxopropyl]-?-oxo-N-ß-diphenyl benzene butaneamide are added to the product obtained in example 4. The reaction mass is heated and stirred for 25 hours at 77.2 °C. The reaction mass is cooled to 68.6 °C and washed with water (165 L X 2 times). The solvent (1728 L) is evaporated under vacuum at 68.6 °C. Isopropyl alcohol (650 L) is added and evaporated the solvent (1728 L) under vacuum at 53.9 °C. Isopropyl alcohol (650 L) and evaporated the solvent (1728 L under vacuum at 58.7 °C. Isopropyl alcohol (650 L) and evaporated the solvent (1728 L under vacuum at 53.0 °C. Isopropyl alcohol (650 L) is added and heat to 82 °C. Stirred the reaction mass for 20 minutes and cooled to 63.8 °C in 60 minutes. tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (4.9 kg) is added and stirred for 60 minutes. The reaction mass is cooled to 49.6 °C in 75 minutes and maintain for 60 minutes. The reaction mass is cooled to 33.6 °C in 75 minutes and maintain for 60 minutes. The reaction mass is cooled to 29.2 °C and stirred for 4 hours at same temperature. The reaction mass is further cooled to 4.8 °C and stirred for 4 hours. Filtered the compound and washed with chilled isopropyl alcohol (1000 L).The solid was dried at 70 -75 °C under vacuum for 6 hours to obtain the title compound.
Yield: 410.26 kg; HPLC purity: 99.00%; Impurity at 0.96 RRT (precursor of diamino impurity): 0.10%.

EXAMPLE 6: Preparation of Atorvastatin Calcium Crystalline Form I
tert-butyl-2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenyl carbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (80 g) in isopropanol (760 ml) was added to a mixture of ammonium chloride (39.2 g) in water (480 ml) and refluxed for 23 hours. Charge the above reaction mass to solution of sodium hydroxide (36.0 g) dissolved in water (140 mL) was added and maintained at 45-55 °C for 1 hours. Calcium acetate (12.85 g) dissolved in 100 mL of water was added and maintained for 1 hour at 45-55 °C. Reaction mass was filtered through hyflo bed and 0.45 micron filter paper and further washed with isopropanol (60mL). The filtrate was added to mixture of water (1920 mL) and atorvastatin calcium form-1 seed (4.0 g) at 40-50°C. Reaction mass was cooled to 30-35°C after maintaining for 1 hour at 40-50 °C. Heated the reaction mass to 70-75 °C and maintained for 20-30 minutes. Cool the reaction 30-35 °C and maintained for 2 hours. Precipitated material was filtered and washed with water (160 mL X 2 times). Solid material was dried at 25-35°C followed by 60-70°C in air tray drier to yield the title compound.
Yield: 67.2 g (90.9%); HPLC purity: 99.74%; Diamino impurity: 0.02%; Heptenoic acid impurity: 0.03% nd XRPD: Crystalline Form I
,CLAIMS:Claims
1. One pot process for the preparation of Atorvastatin calcium crystalline Form I, comprising the steps of:
i) dissolving compound of formula II in a mixture of water and isopropanol ;
ii) passing the solution of step (i) in to a preheated column packed with ion-exchange resin to provide compound of formula III; wherein R=alkyl, aryl

iii) reacting the solution of step (ii) with aqueous sodium hydroxide solution to form the sodium salt of atorvastatin;

iv) adding calcium acetate solution to step (iii) to form atorvastatin calcium salt;
v) filtering the atorvastatin calcium solution of step (iv);
vi) optionally, adding pure crystalline atorvastatin calcium Form–I seed;
vii) isolating crystalline Form-I of atorvastatin calcium.

2. One pot process for the preparation of atorvastatin calcium crystalline Form I, comprising the steps of:
i) combining compound of formula II with a mixture of water and isopropanol;
ii) adding ammonium chloride to the reaction mixture of step (i) and refluxing to provide compound of formula III;

wherein R= alkyl, aryl
iii) reacting the solution of step (ii) with aqueous sodium hydroxide solution to form the sodium salt of atorvastatin;

iv) adding calcium acetate solution to step (iii) to form atorvastatin calcium salt;
v) filtering the atorvastatin calcium solution of step (iv);
vi) optionally adding pure crystalline atorvastatin calcium Form–I seed;
vii) isolating crystalline Form-I of atorvastatin calcium.

3. In another aspect, the present application provides a one pot process for the preparation of atorvastatin calcium comprising the steps of:
i) dissolving compound of formula II in acetonitrile ;
ii) adding ion-exchange resin to the solution of step (i) at room temperature to provide compound of formula III;

wherein R= alkyl, aryl
iii) reacting the solution of step (ii) with aqueous sodium hydroxide solution to form the sodium salt of atorvastatin;

iv) adding calcium acetate solution to step (iii) to form atorvastatin calcium salt;

v) filtering the atorvastatin calcium solution of step (iv);
vi) isolating atorvastatin calcium.

4. One pot process for the preparation of atorvastatin calcium, containing less than 0.1% of heptenoic acid impurity, comprising the steps of:
i) combining compound of formula II with a mixture of water and isopropanol;
ii) adding ammonium chloride to the reaction mixture of step (i) and refluxing to provide compound of formula III;

wherein R= alkyl, aryl
iii) reacting the solution of step (ii) with aqueous sodium hydroxide solution to form the sodium salt of atorvastatin;

iv) adding calcium acetate solution to step (iii) to form atorvastatin calcium salt;

v) filtering the atorvastatin calcium solution of step (iv);
vi) optionally adding pure crystalline atorvastatin calcium Form–I seed;
vii) isolating crystalline Form-I of atorvastatin calcium.

5. The process of claims 1 and 3, wherein the ion-exchange resin used at step ii) is selected from the group consisting of TULSION 57-H, Amberlite(R) IRA 120, Amberlyst(R) 15 and Indion 525.

6. Compound of formula III, IV and Atorvastatin or its calcium salt, obtained according to any of the processes of claim 1 to 3, containing less than 0.1 % of Heptenoic acid impurity, as detected by HPLC.

7. Compound of formula III, IV and Atorvastatin or its calcium salt, containing less than 0.1 % of Heptenoic acid impurity and less than 0.15 % of diamino impurity, as detected by HPLC.

8. Compound of formula II, obtained according to the processes of claim 1 to 3, containing less than 0.15 % of precursor of diamino impurity with RRT 0.96, as detected by HPLC.

9. Atorvastatin or its calcium salt, obtained according to the processes of claim 1 to 3, containing less than 0.15 % of diamino impurity, as detected by HPLC.

10. Compound of formula II containing less than 0.15 % of precursor of diamino impurity with RRT 0.96, as detected by HPLC.