New amine salts of Atorvastatin Acid, process thereof and its use for the preparation of highly pure amorphous and crystalline Atorvastatin Hemi
Calcium salt (2:1)
The present invention relates to new amine salts of Atorvastatin Acid, process for their preparation and a new method of manufacturing highly pure i.e. almost impurity free amorphous as well as crystalline atorvastatin hemi calcium salt (formula 1) by using amine salt of Atorvastatin acid, which is marketed under the brand name LipitorTM. Chemically atorvastatin calcium is [R-(R*,R*)]-2-(4-fluorophenyl)-p,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid calcium salt (2:1), known under the non-proprietary name Atorvastatin. Atorvastatin is an important representative of hypolipidemic and hypocholesteric medicaments.

(Formula Removed)

BACKGROUND OF THE INVENTION
In general, depending on the mode of carrying out, atorvastatin is obtained in some of its crystalline forms or as amorphous atorvastatin. In the original patents (for instance US patents Nos. 4,681,893 and 5,273,995), the polymorphic form of the product obtained under this patents is not mentioned. Later patents (US patents Nos. 5,969,156 and 6,121,461), disclosing crystalline forms of atorvastatin, suggest that the product obtained according to the original patents was amorphous.
According to our knowledge, 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)-P,8-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-l-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; W099/32434; WOOl/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.
Although Atorvastatin hemi calcium salt of formula (1) can be prepared by various methods described in the above mentioned patents but the product obtained is not of high purity. The purity of the active ingredient is an important factor for manufacturing the safe and effective pharmaceutical formulation, especially if the product is taken on a longer term basis in the treatment or prevention of high plasma cholesterol. The accumulation of the impurities from the pharmaceutical product of lower purity may cause many side effects during the medical treatment. Therefore, there is a need to develop a process for preparation and purification of compound of formula (I) and its amine salts which can produce highly pure Atorvastatin hemi calcium salt in lab as well as commercial scale in high yield.
SUMMARY OF THE INVENTION

The present invention provides new amine salts of Atorvastatin acid, process for their preparation and their use in the preparation of highly pure i.e. almost impurity free amorphous as well as crystalline atorvastatin calcium in high yields. Particularly the amine salt preparation of atorvastatin acid provides method for the purification of atorvastatin and preparation of highly pure amorphous as well as crystalline atorvastatin calcium. It resulted in the increased purity of atorvastatin hemi calcium salt of formula 1 in amorphous as well as in crystalline form. The increased purity will ultimately result in the better stability of the product.
BRIEF DESCRIPTION OF THE FIGURES
A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawing of which:
Fig I : shows the synthetic route for preparation of amorphous as well as crystalline Atorvastatin hemi calcium salt of formula (I).
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 highly pure new amine salts of Atorvastatin acid which ultimately result in the preparation of amorphous as well as crystalline atorvastatin calcium salt of high purity i.e. almost impurity free in high yields.

According to the first aspects of the invention, it provides new amine salts of atorvastatin acid, process for their preparation as well as purification, which comprises:
(a) hydrolysis of 1,3-dioxane ring 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-l,3-dioxane-4-acetate having formula (II),
(b) in situ hydrolysis of t-butyl group to form Atorvastatin sodium salt solution,
(c) addition of acetic acid to Atorvastatin sodium salt solution, followed by extraction of Atorvastatin acid in organic solvent and preparation of Atorvastatin amine salt by adding an organic amine,
(d) optionally purifying Atorvastatin amine salt in organic solvents,
Alternatively Atorvastatin amine salt can be prepared directly by reacting any form of Atorvastatin calcium with an organic amine in the presence of organic solvent.
According to one embodiment of this invention, the organic amines used in the above step (c) are dicyclohexylamine, benzylamine, phenylhydrazine, a,a-Diphenyl-4-piperidinemethanol, 2-(2-methoxyphenoxy) ethyl amine, tris(hydroxymethyl)aminomethane, cyclohexylamine, dibenzylamine, phenyl ethyl amine, di-n-propyl amine, diisopropyl amine, t-butyl amine, isopropyl amine and alfa-methyl benzyl amine.
The second aspect of the present invention is to provide a process for the preparation of highly pure amorphous atorvastatin calcium, which comprises
(I) converting Atorvastatin amine salt of step (c) or (d) into Atorvastatin acid by addition
of acetic acid in an organic solvent,
(II) recovery of solvent and dissolving crude mass in water miscible solvent with the help
of aq. caustic solution to form Atorvastatin sodium solution,
(III) addition of an aqueous calcium acetate solution into Atorvastatin sodium salt solution,
(IV) seeding with amorphous atorvastatin calcium,
(V) filtering the slurry to get wet cake,
(VI) dissolving the wet product of step (V) in ethyl acetate followed by addition of
antioxidant and optionally concentrating the solution by recovery of ethyl acetate,
(VII) addition of mass of step (VI) to n-heptane or addition of an n-heptane to the mass
of step (VI),

(VIII) filtering and drying the product by conventional methods to afford amorphous Atorvastatin hemi calcium salt of formula (I) of high purity i.e. almost impurity free product.
The third aspect of the present invention is to provide a process for the preparation of highly pure Atorvastatin calcium Morepen's Form VI which comprises:
1. Converting Atorvastatin amine salt of step (c) or (d) into Atorvastatin acid using acetic acid in an organic solvent.
2. recovery of solvent and dissolving crude mass in acetone using aq. caustic solution to form Atorvastatin sodium solution.
3. addition of an aqueous calcium acetate solution into Atorvastatin sodium salt solution.
4. filtering and drying the product by conventional methods to afford Atorvastatin calcium Morepen's Form VI of very high purity with excellent yield.
The fourth aspect of the present invention is to provide a process for highly pure Atorvastatin calcium Form I which comprises:
(A) converting Atorvastatin amine salt into Atorvastatin acid using acetic acid in organic solvent,
(B) recovery of solvent and dissolving crude mass in methanol using aq. caustic solution to form Atorvastatin solution followed by washing of aq. layer with t-butyl methyl ether.
(C) addition of an aqueous calcium acetate solution to Atorvastatin sodium salt solution,
(D) seeding with Atorvastatin Form 1 seeds.
(E) filtering and drying the product by conventional method to afford highly pure
Atorvastatin calcium Form I in excellent yield.
Similarly any polymorphic Form of Atorvastatin calcium can be prepared by conventional methods using Atorvastatin amine salt.
According to yet another aspect of this invention, the organic solvent used in step (c), (d), (I), (1) and (A) are selected from aliphatic halogenated hydrocarbons preferably dichloromethane, chloroform & carbontetra chloride, aromatic hydrocarbons preferably toluene, xylene & benzene, aliphatic esters preferably ethyl acetate &. propyl acetate, cyclic

or acyclic aliphatic ethers preferably tetrahydrofuran, dioxane, diisopropyl ether, t-butylmethyl ether & diethyl ether or a mixture thereof.
According to still another aspect of this invention, the water miscible organic solvent used in step (II) is selected from C1-C4 aliphatic alcohols preferably methanol, ethanol, propanol, butanol, monoethylene glycol & diethylene glycol, aliphatic cyclic ethers preferably tetrahydrofuran & dioxane, aliphatic amides preferably N,N-dimethylfonnamide & N,N-dimethylacetamide or a mixture thereof
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 Preparation of Atorvastatin acid dicyclohexylamine salt
The compound (4R-Cis)-1-1 -dimethylethyl-6-[2-(2-(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]ethyl-2,2-dimethyl-l,3-dioxane-4-acetate (lOOg) is dissolved in methanol (l.Sltr) at 40-45°C. After dissolution, the solution is cooled to 15-20°C and 1.5N aq. hydrochloric acid (170ml) is added and stirred for 30-36hrs at 35-40°C. Then 15% aq. NaOH solution (170ml) is added at 15-20°C and stirred for 30-36hrs at 35-40°C.
Activated charcoal (25g) is added and reaction mixture is stirred for 30minutes. The reaction solution is filtered through hyflo bed. The solvent is removed at reduced pressure to reduce the volume to one third and a mixture of methanol (180ml) and water (900ml) is added and stirred for 30minutes. A mixture of n-hexane (500), ethyl acetate (500ml) is added, stirred for ISminutes and aq. layer is separated followed by washing of aq layer with t-butyl methyl ether. The pH of aq. layer is adjusted to 4.0-4.5 using acetic acid and stirred for 30minutes at 15-25°C. The product is extracted in ethyl acetate (500ml) followed by addition of dicyclohexylamine (34g) dissolved in toluene (500ml) to the ethyl acetate layer. The resulting reaction mixture is stirred for 2-5 hrs to get white solid. The solid is filtered and washed with chilled ethyl acetate followed by drying to get Atorvastatin dicyclohexylamine salt. (Yield = 11 Og, HPLC purity =99.80%)

EXAMPLE-2 Preparation of Atorvastatin acid benzylamine salt
The compound (4R-Cis)-1 -1 -dimethyletiiyi-6-[2-(2-(4-fluorophenyl)-5-( 1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yi]ethyl-2,2-dimethyl-l,3-dioxane-4-acetate (100g) is dissolved in methanol (1.5ltr) at 40-45°C. After dissolution, the solution is cooled to 15-20°C and 1.5N aq. hydrochloric acid (170ml) is added and stirred for 30-36hrs at 35-40°C. Then 15% aq. NaOH solution (170ml) is added at 15-20°C and stirred for 30-36hrs at 35-40°C.
Activated charcoal (25g) is added and reaction mixture is stirred for 30minutes. The reaction solution is filtered through hyflo bed. The solvent is removed at reduced pressure to reduce the volume to one third and a mixture of methanol (180ml) and water (900ml) is added and stirred for 30minutes. A mixture of n-hexane (500), ethyl acetate (500ml) is added, stirred for 15minutes and aq. layer is separated followed by washing of aq layer with t-butyl methyl ether. The pH of aq. layer is adjusted to 4.0-4.5 using acetic acid and stirred for 30minutes at 15-25°C. The product is extracted in ethyl acetate (500ml) followed by addition of benzylamine (30g) dissolved in toluene (500ml) to the ethyl acetate layer. The resulting reaction mixture is stirred for 2-5 hrs to get white solid. The solid is filtered and washed with chilled ethyl acetate followed by drying to get Atorvastatin benzylamine salt. (Yield = 1 lOg, HPLC purity =99.80%)
EXAMPLE-3 Preparation of Atorvastatin acid phenylhydrazine salt
The compound (4R-Cis)-1 -1 -dimethylethyl-6-[2-(2-(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrol-l-yl]ethyl-2,2-dimethyl-l,3-dioxane-4-acetate (100g) is dissolved in methanol (1.51tr) at 40-45°C. After dissolution, the solution is cooled to 15-20°C and 1.5N aq. hydrochloric acid (170ml) is added and stirred for 30-36hrs at 35-40°C. Then 15% aq. NaOH solution (170ml) is added at 15-20°C and stirred for 30-36hrs at 35-40°C.
Activated charcoal (25g) is added and reaction mixture is stirred for 30minutes. The reaction solution is filtered through hyflo bed. The solvent is removed at reduced pressure to reduce the volume to one third and a mixture of methanol (180ml) and water (900ml) is added and stirred for 30minutes. A mixture of n-hexane (500), ethyl acetate (500ml) is added, stirred for 15minutes and aq. layer is separated followed by washing of aq layer with t-butyl methyl ether. The pH of aq. layer is adjusted to 4.0-4.5 using acetic acid and stirred for 30minutes at

15-25°C. The product is extracted in ethyl acetate (500ml) followed by addition of phenylhydrazine (30g) dissolved in toluene (500ml) to the ethyl acetate layer. The resulting reaction mixture is stirred for 2-5 hrs to get white solid. The solid is filtered and washed with chilled ethyl acetate followed by drying to get Atorvastatin phenylhydrazine salt. (Yield = 1 lOg, HPLC purity =99.80%)
EXAMPLE-4 Preparation of Atorvastatin acid 2-(2-methoxyphenoxv) ethyl amine salt The compound (4R-Cis)-1 -1 -dimethylethyl-6-[2-(2-(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrol-1 -yl]ethyl-2,2-dimethyl-1,3-dioxane-4-acetate (100g) is dissolved in methanol (1.51tr) at 40-45°C. After dissolution, the solution is cooled to 15-20°C and 1.5N aq. hydrochloric acid (170ml) is added and stirred for 30-36hrs at 35-40°C. Then 15% aq. NaOH solution (170ml) is added at 15-20°C and stirred for 30-36hrs at 35-40°C.
Activated charcoal (25g) is added and reaction mixture is stirred for 30minutes. The reaction solution is filtered through hyflo bed. The solvent is removed at reduced pressure to reduce the volume to one third and a mixture of methanol (180ml) and water (900ml) is added and stirred for 30minutes. A mixture of n-hexane (500), ethyl acetate (500ml) is added, stirred for 15minutes and aq. layer is separated followed by washing of aq layer with t-butyl methyl ether. The pH of aq. layer is adjusted to 4.0-4.5 using acetic acid and stirred for 30minutes at 15-25°C. The product is extracted in ethyl acetate (500ml) followed by addition of 2-(2-methoxyphenoxy) ethyl amine (35g) dissolved in toluene (500ml) to the ethyl acetate layer. The resulting reaction mixture is stirred for 2-5 hrs to get white solid. The solid is filtered and washed with chilled ethyl acetate followed by drying to get Atorvastatin 2-(2-methoxyphenoxy) ethyl amine salt. (Yield = 110g, HPLC purity =99.80%)
EXAMPLE-5 Preparation of Atorvastatin acid α,α-Diphenvl-4-piperidinemethanol salt The compound (4R-Cis)-l-l-dimethylethyl-6-[2-(2-(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrol-1 -yl]ethyl-2,2-dimethyl-1,3-dioxane-4-acetate (100g) is dissolved in methanol (1.51tr) at 40-45°C. After dissolution, the solution is cooled to 15-20°C and 1.5N aq. hydrochloric acid (170ml) is added and stirred for 30-36hrs at 35-

40°C. Then 15% aq. NaOH solution (170ml) is added at 15-20°C and stirred for 30-36hrs at 35-40°C.
Activated charcoal (25g) is added and reaction mixture is stirred for 30minutes, The reaction solution is filtered through hyflo bed. The solvent is removed at reduced pressure to reduce the volume to one third and a mixture of methanol (180ml) and water (900ml) is added and stirred for 30minutes. A mixture of n-hexane (500), ethyl acetate (500ml) is added, stirred for 15minutes and aq. layer is separated followed by washing of aq layer with t-butyl methyl ether. The pH of aq. layer is adjusted to 4.0-4.5 using acetic acid and stirred for SOminutes at 15-25°C. The product is extracted in ethyl acetate (500ml) followed by addition of a,a-Diphenyl-4-piperidinemethanol (50g) dissolved in toluene (500ml) to the ethyl acetate layer. The resulting reaction mixture is stirred for 2-5 hrs to get white solid. The solid is filtered and washed with chilled ethyl acetate followed by drying to get Atorvastatin a,a-Diphenyl-4-piperidinemethanol salt. (Yield = 1 lOg, HPLC purity =99.80%)
EXAMPLE-6 Preparation of Atorvastatin acid tris(hydroxymethyl)aminomethane salt The compound (4R-Cis)-1 -1 -dimethylethyl-6-[2-(2-(4-fluorophenyl)-5-( 1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrol-1-yl]ethyl-2,2-dimethyl-1,3-dioxane-4-acetate (10g) is dissolved in methanol (1.51tr) at 40-45°C. After dissolution, the solution is cooled to 15-20°C and 1.5N aq. hydrochloric acid (170ml) is added and stirred for 30-36hrs at 35-40°C. Then 15% aq. NaOH solution (170ml) is added at 15-20°C and stirred for 30-36hrs at 35-40°C.
Activated charcoal (25g) is added and reaction mixture is stirred for 30minutes. The reaction solution is filtered through hyflo bed. The solvent is removed at reduced pressure to reduce the volume to one third and a mixture of methanol (180ml) and water (900ml) is added and stirred for 30minutes. A mixture of n-hexane (500), ethyl acetate (500ml) is added, stirred for 15minutes and aq. layer is separated followed by washing of aq layer with t-butyl methyl ether. The pH of aq. layer is adjusted to 4.0-4.5 using acetic acid and stirred for SOminutes at 15-25°C. The product is extracted in ethyl acetate (500ml) followed by addition of tris(hydroxymethyl)aminomethane (30g) dissolved in toluene (500ml) to the ethyl acetate layer. The resulting reaction mixture is stirred for 2-5 hrs to get white solid. The solid is filtered and washed with chilled ethyl acetate followed by drying to get Atorvastatin tris(hydroxymethyl)aminomethane salt.

(Yield = 1 lOg, HPLC purity =99.80%)
EXAMPLE-7 Preparation of Atorvastatin acid from Atorvastatin dicvclohexylamine salt To a suspension of Atorvastatin dicyclohexylamine salt (100g) in methylene chloride (500ml) and water (500ml) is added followed by addition of acetic acid to get pH 4.0-4.5. The organic layer is separated and washed with water (100ml). The solvent is removed at reduced pressure to get Atorvastatin acid as white solid. (Yield = 70g)
EXAMPLE-8 Preparation of Atorvastatin acid from Atorvastatin benzvlamine salt
To a suspension of Atorvastatin benzylamine salt (lOOg) in methylene chloride (500ml) and water (500ml) is added followed by addition of acetic acid to get pH 4.0-4.5. The organic layer is separated and washed with water (100ml). The solvent is removed at reduced pressure to get Atorvastatin acid as white solid. (Yield = 78g)
EXAMPLE-9 Preparation of Atorvastatin acid from Atorvastatin phenylhydrazine salt To a suspension of Atorvastatin phenylhydrazine salt (100g) in methylene chloride (500ml) and water (500ml) is added followed by addition of acetic acid to get pH 4.0-4.5. The organic layer is separated and washed with water (100ml). The solvent is removed at reduced pressure to get Atorvastatin acid as white solid. (Yield = 73g)
EXAMPLE-10 Preparation of Atorvastatin acid from Atorvastatin 2-(2-methoxvphenoxv) ethyl amine salt To a suspension of Atorvastatin 2-(2-methoxyphenoxy) ethyl amine salt (100g) in methylene chloride (500ml) and water (500ml) is added followed by addition of acetic acid to get pH 4.0-4.5. The organic layer is separated and washed with water (100ml). The solvent is removed at reduced pressure to get Atorvastatin acid as white solid. (Yield = 77g)

EXAMPLE-11 Preparation of Atorvastatin acid from Atorvastatin a,a-Diphenvl-4-piperidinemethanol salt To a suspension of Atorvastatin a,a-Diphenyl-4-piperidinemethanol salt (100g) in methylene chloride (500ml) and water (500ml) is added followed by addition of acetic acid to get pH 4.0-4.5. The organic layer is separated and washed with water (100ml). The solvent is removed at reduced pressure to get Atorvastatin acid as white solid. (Yield = 69g)
EXAMPLE-12 Preparation of Atorvastatin acid from tris(hydroxvmethvl)aminomethane salt To a suspension of Atorvastatin tris(hydroxymethyl)aminomethane salt (lOOg) in methylene chloride (500ml) and water (500ml) is added followed by addition of acetic acid to get pH 4.0-4.5. The organic layer is separated and washed with water (100ml). The solvent is removed at reduced pressure to get Atorvastatin acid as white solid. (Yield = 80g)
EXAMPLE-13 Preparation of Atorvastatin calcium Form-I
The Atorvastatin acid (50g) is dissolved in methanol (250ml) by addition of aq. caustic solution (pH 12.0-1.5). The reaction mixture stirred for 30-45°C. Then pH of solution is adjusted to 8.0-8.5 followed by addition of calcium acetate solution. The reaction solution Is seeded with Atorvastatin calcium Form-I and stirred at 40-45°C for 3-4 hrs. The product is filtered and dried to get Atorvastatin calcium Form-I as white crystalline solid. (Yield = 52g, HPLC purity = 99.90%)
EXAMPLE-14 Preparation of Atorvastatin calcium Form-VI
The Atorvastatin acid (50g) is dissolved in acetone (500ml) by addition of aq. caustic solution (pH 12.0-1.5). The reaction mixture stirred for 30-35 minutes at 40-45°C. Then pH of solution is adjusted to 8.0-8.5 followed by addition of calcium acetate solution. The reaction mass is stirred for 2-3 hrs and product is filtered followed by drying to get Atorvastatin calcium Form-VI as white crystalline solid. (Yield = 46g, HPLC purity = 99.95%)

EXAMPLE-15 Preparation of Atorvastatin calcium amorphous
The Atorvastatin acid (50g) is dissolved in methanol (250ml) by addition of aq. caustic solution (pH 12.0-1.5). The reaction mixture stirred for 30-45°C. Then pH of solution is adjusted to 8.0-8.5 followed by addition of calcium acetate solution. The solid thus obtained is extracted in methylene chloride (750ml) followed by washing of organic layer with water (250ml). The organic layer is dried over anhydrous sodium sulphate and reduced to 250ml by vacuum. Then diisopropyl ether (750ml) is added to it and the solid is filtered and dried to get amorphous Atorvastatin calcium. (Yield = 50g, HPLC purity = 99.80%)
EXAMPLE-16 Preparation of amorphous Atorvastatin hemicalcium salt
The Atorvastatin acid (50g) is dissolved in methanol (250ml) by addition of aq. caustic solution (pH 12.0-1.5). The reaction mixture stirred for 30-45°C. Then pH of solution is adjusted to 8.0-8.5 followed by addition of calcium acetate solution. The resulting solid mass is extracted in ethyl acetate (500ml) followed by washing of organic layer with water (250ml). The ethyl acetate layer is dried over anhydrous sodium sulphate. Then ethyl acetate is removed completely at 40-50°C at reduced pressure. Then traces of ethyl acetate are removed using n-heptane (100ml). Then n-heptane (250ml) is added to the resulting mass and stirred for 2-5 hrs. The solid is filtered and dried at 40-50°C in a vacuum dryer for 24-48 hrs. (Yield = 50g, HPLC purity = 99.85%).
EXAMPLE-17
Preparation of (3S.5R')-7-[2-(4-Fluorophenvl)-5-isopropyl-3-phenyl-4-(phenyl carbamoyl)-pyrrol-l-yl]-3,5-dihydroxyheptanoate calcium salt (Trans atorvastatin calcium) by purification of the mixture of two isomers.
A mixture of [R-(R*,R*)]2-(4-Fluorophenyl)-b,d-dihydroxy-5- (l-methylethyl)-3-phenyl-4-
[(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid ;calcium salt (Atorvastatin Calcium)
& (3S,5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(phenyl carbamoyl)-pyrrol-l-yl]-3,5-
dihydroxyheptanoate calcium salt (Trans atorvastatin calcium) (100 g) is dissolved in Methanol (100
ml). It is crystallized by ethyl acetate (600 ml). Stirred followed by its filtration to get pure (3S,5R)-
7-[2-(4-Fluorophenyl)-5-isopropyi-3-phenyl-4-(phenylcarbamoyl)-pyrrol-l-yI]-3,5-dihydroxy
heptanoate calcium salt (Trans atorvastatin calcium)

Advantages:
1. The present invention describes new amine salts of atorvastatin acid and process for their preparation.
2. The main advantage of the atorvastatin amine salts preparation is that they resulted in the increased purity along with improved yield of atorvastatin calcium.
3. The preparation of amine salts of atorvastatin acid results in highly pure i.e. almost impurity free amorphous as well as crystalline atorvastatin calcium which will result in increased stability of product.
4. The present invention describes the preparation and isolation of atorvastatin acid in solid form.

We claim:
1. New amine salts of atorvastatin acid.
2. A process for preparation of atorvastatin amine salts which comprises:

a) dissolving atorvastatin acid in an organic solvent
b) adding an organic amine
c) filtering the resulting solid
d) drying of wet cake of step (c) to get atorvastatin amine salt.

3. A process of claim 2, wherein the organic solvent used in step(a) is selected from Ci-C4 aliphatic esters, e.g. ethyl acetate, propyl acetate etc; aromatic hydrocarbons, e.g. Toluene, xylene etc; C1-C4 aliphatic alcohols eg methanol, ethanol etc. halogenated aliphatic hydrocarbons, eg. methylene chloride, chloroform etc. or a mixture thereof
4. A process of claim 2, where in organic amine used in step(b) is selected from dicyclohexylamine, benzylamine, phenylhydrazine, a,a-diphenyl-4-piperidinemethanol, 2-(2-methoxyphenoxy)ethylamine, tris(hydroxymethyl)aminomethane, cyclohexylamine, dibenzylamine, phenylethylamine, di-n-propylamine, diisopropylamine, t-butylamine, isopropylamine and a-methyl benzylamine.
5. A process of claim 2, wherein the drying of wet cake in step(a) is done at 40-60 °C under vaccum.
6. A process for the preparation of amorphous atorvastatin which comprises

a) treating atorvastatin amine salt with acetic acid in an organic solvent
b) recovery of solvent at reduced pressure
c) dissolving of atorvastatin acid of step(b) in aq. caustic solution

d) addition of aq. calcium acetate to the reaction mass of step(c) to get
atorvastatin calcium as white solid
e) dissolving wet cake of step(d) in methylene chloride
f) adding diisopropyl ether to the methylene chloride layer of step(e)
containing atorvastatin calcium.
g) filtering and drying the wet cake to get pure atorvastatin calcium in
amorphous form.
7. A process of claim 6 wherein organic solvent used in step(a) is selected from halogenated aliphatic hydrocarbons, e.g. methylene chloride, ethylene chloride etc; aliphatic esters e.g. ethyl acetate, propyl acetate etc; aromatic hydrocarbon e.g. toluene, xylene etc or a mixture thereof
8. A process for the preparation of Atorvastatin calcium polymorphic form I which comprises

a) treating atorvastatin amine salt with acetic acid in organic solvent
b) recovery of solvent at reduced pressure
c) dissolving atorvastatin acid of step(b) in aq. caustic solution.
d) adding aq. calcium acetate to the reaction mass of step(c) followed by seeding with Atorvastatin calcium crystalline form I
e) drying the wet cake of step(d) at 45-60 °C to get highly pure Atorvastatin calcium crystalline form I.
9. A process for the preparation of Atorvastatin calcium form VI which comprises
a) treating atorvastatin amine salt with acetic acid in organic solvent
b) recovery of solvent at reduced pressure
c) dissolving of atorvastatin acid of step(b) in caustic in methanol
d) complete recovery of methanol

e) dissolving product of step (d) in acetone
f) addition of aq. calcium acetate in the reaction mass of step (e)
g) filtration & drying of wet cake at 45-60 °C to get highly pure atorvastatin calcium crystalline form VI.

10. New amine salts of Atorvastatin Acid, process thereof and its use for the preparation of highly pure amorphous and crystalline Atorvastatin Hemi Calcium salt (2:1) as herein described with reference to the accompanying specification, examples and drawings.