FIELD OF THE INVENTION
The field of the invention relates to the preparation of amorphous atorvastatin calcium in high yield and high purity from (3R, 5R) tert.-butyl (6-{2-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-( 1 -methyl ethyl)-pyrrol-1 -yl] -ethyl} -2,2-dimethyl (l,3-}dioxan-4-yl) acetate.
BACKGROUND OF THE INVENTION
Atorvastatin calcium of Formula I, is a selective inhibitor of the enzyme 3-hydroxy-3-

(Formula Removed)
methyl glutaryl CoA reductase (HMG-CoA reductase) and is chemically known as (|3R. 8R)-2-(4-fluorophenyr)-P,8-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt. As such Atorvastatin calcium is a potent lipid-lowering compound and is thus useful as a hypocholesterolemic agent.
Atorvastatin was disclosed in U.S. Pat. No. 5,273,995 as ring opened dihydroxy acid form. US patents 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; 5,280,126; 5,397,792 and 5,342,952, which are herein incorporated by reference, disclose various processes and key intermediates for preparing Atorvastatin calcium. The processes described in the above mentioned US patents do not give amorphous Atorvastatin calcium consistently but give a mixture of
its crystalline and amorphous forms, which has unsuitable filtration and drying characteristics.
US patent 6,087,511 describes the preparation of amorphous Atorvastatin calcium by dissolving the compound in a non-hydroxylic solvent and removing solvent by vacuum drying.
US patent 6,274,740 describes the method for conversion of crystalline form of Atorvastatin calcium to amorphous form which comprises of using two solvents such as tetrahydofuran and toluene. The process involves complete removal of solvent under high vacuum and at high temperature and further vacuum drying at high temperature leads to degradation of the product.
US patent 6,528,660 describes preparation of amorphous Atorvastatin calcium by solvent precipitation. Atorvastatin calcium is dissolved in tetrahydrofuran and an anti solvent is added to obtain amorphous material. However, this process makes use of large quantities of solvents thus requiring efficient solvent recovery.
US patent application 2002/0183527 also describes the preparation of amorphous Atorvastatin calcium by solvent precipitation. Crystalline Atorvastatin calcium is dissolved in alcohol and ether is added to precipitate the amorphous product. US patent application 2004/0242670 describes the process for the preparation of amorphous Atorvastatin calcium from crystalline Atorvastatin calcium by spray drying using hydroxylic solvent
US patent application 2005/0131055 describes the method for the preparation of amorphous atorvastatin calcium from (3R, 5R) tert.-butyl (6-{2-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-(l-methylethyl)-pyrrol-l-yl]-ethyl}-2,2-dimethyl {l,3-}dioxan-4-yl) acetate by acidic hydrolysis followed by alkaline hydrolysis and then treating the resulting salt with calcium source and precipitating the product in hydrocarbons or ethers.
US patent application 2005/0165242 describes a process for amorphous atorvastatin calcium which comprises hydrolysis of precursor lactone with sodium hydroxide and then treating the atorvastatin sodium salt with calcium chloride or calcium acetate.
PCX patent application WO 01/028999 describes an alternate process wherein amorphous Atorvastatin calcium was prepared by crystallization from a lower alkanol containing 2-4 carbon atoms
PCX patent application WO 02/083638 discloses the preparation of amorphous Atorvastatin calcium directly from diol protected tert.-butyl ester through atorvastatin sodium salt. But disadvantage of this process is that amorphous Atorvastatin calcium prepared is contaminated with calcium hydroxide and needs purifications.
PCX patent application WO 03/009975 discloses another process for the preparation of amorphous Atorvastatin by dissolving Atorvastatin calcium in aliphatic acyclic ketone filtering the solvent and removing the solvent at 40-50°C under vacuum.
PCX patent application WO 03/078379 discloses the preparation of amorphous Atorvastatin calcium having particle size 1 to 150 microns by dissolving Atorvastatin calcium in a hydroxylic solvent and removing the solvent by freeze drying or by spray drying and subsequently subjecting the product to milling.
PCX patent application WO 03/093233 describes the process for preparation of amorphous Atorvastatin Calcium by dissolving Atorvastatin calcium in an organic solvent miscible in water and gradually adding the said solution to water.
PCX patent application WO 03/018547 describes a process for the preparation of amorphous Atorvastatin calcium which comprises hydrolyzing the lactone form of Atorvastatin with aqueous base, extracting with organic solvent and adding the same to an anti-solvent to precipitate the product and finally filtering the product to afford amorphous Atorvastatin calcium. Alternatively, amorphous Atorvastatin calcium is prepared from crystalline Atorvastatin calcium, which comprises dissolving the
crystalline Atorvastatin calcium in an organic solvent, distilling off half of the solvent and adding the same to an anti solvent to precipitate the amorphous product.
PCT patent application WO 04/085391 describes a process for the preparation of amorphous atorvastatin calcium from salt of atorvastatin with a basic amino acid.
Thus, it is evident that most of the methods described in the prior art to prepare amorphous Atorvastatin calcium have some disadvantages such as involving use of large volumes of solvents as mixtures, which are difficult to separate and thus amounting to increase in cost. Numbers of steps are more, leading to low yields and make these processes industrially unattractive from economical and handling point of view.
It is therefore an object of the present invention to provide a process for the preparation of amorphous Atorvastatin calcium in high yields and high purity directly from diol protected tert.-butyl ester of Formula II, without isolating crystalline or mixture of crystalline and amorphous Atorvastatin calcium. The process is economical and capable of being practiced on a commercial scale.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of amorphous atorvastatin calcium which comprises
i) acidic hydrolysis of diol protected tert.-butyl ester of Formula II,
(Formula Removed)
in water miscible solvent, at a temperature of 25-50°C to prepare a compound of Formula III,

(Formula Removed)
ii) heating the resulting reaction mass with calcium hydroxide at a temperature of 50-75°C till complete hydrolysis of ester group,
iii) filtering the reaction mixture,
iv) distilling the water miscible solvent,
v) diluting the reaction mass with water immiscible solvent,
vi) adding water to separate the layers.
vii) distilling out the water immiscible solvent and
viii) isolating the amorphous atorvastatin calcium in pure form.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 X-ray powder diffractogram of amorphous atorvastatin calcium (Example 1)
The horizontal axis presents 20 and vertical axis corresponds to peak intensity. Fig 2 X-ray powder diffractogram of amorphous atorvastatin calcium (Example 2)
The horizontal axis presents 20 and vertical axis corresponds to peak intensity. Fig 3 X-ray powder diffractogram of amorphous atorvastatin calcium (Example 3)
The horizontal axis presents 20 and vertical axis corresponds to peak intensity. Fig 4 X-ray powder diffractogram of amorphous atorvastatin calcium (Example 3) The horizontal axis presents 29 and vertical axis corresponds to peak intensity. Fig 5 X-ray powder diffractogram of amorphous atorvastatin calcium (Example 4)
The horizontal axis presents 20 and vertical axis corresponds to peak intensity. Fig 6 X-ray powder diffractogram of amorphous atorvastatin calcium (Example 4)
The horizontal axis presents 20 and vertical axis corresponds to peak intensity. Fig 7 Infrared spectrum of amorphous atorvastatin calcium (Example 1) Fig 8 Infrared spectrum of amorphous atorvastatin calcium (Example 2)
DETAILED DESCRIPTION OF THE INVENTION
The instant invention relates to an improved simple, efficient and industrially advantageous process for the preparation of highly pure amorphous atorvastatin calcium in high yield directly from diol protected tert.-butyl ester, namely (3R, 5R) tert.-butyl (6-{2-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-(l-methylethyl)-pyrrol-l-yl]-ethyl}-2,2-dimethyl {l,3-}dioxan-4-yl) acetate of Formula II.
The diol protected tert.-butyl ester of Formula II may be prepared by the methods described in the previously mentioned US Patents, which are incorporated herein by reference.
Preferably, diol protected tert.-butyl ester of Formula II, is hydrolyzed in water miscible solvent using acid to de-protect diol group. The water miscible solvent is selected from alcoholic solvent methanol, ethanol, isopropanol and the like, tetrahydrofuran and
mixture thereof and preferably methanol is used. Specifically, acidic hydrolysis of diol protected tert.-butyl ester of Formula II is carried out using hydrochloric acid in alcoholic solvent at a temperature of 25 to 50°C and preferably at 30 to 35°C. The reaction takes about 3-5 hours for complete removal of protecting group; thus leading to preparation of tert.-butyl ester of atorvastatin of Formula III.
The removal of tert.-butyl group and calcium salt formation was carried out simultaneously using calcium hydroxide. The calcium hydroxide is employed in the molar ratio* of 1-2 with respect to compound of formula II. The reaction is conducted at a temperature of 50°C to 75°C and it takes about 2 to 5 hours for completion. The progress of reaction can be monitored by high performance liquid chromatography (HPLC) as well as by thin layer chromatography (TLC). When compound of formula III is absent in HPLC or TLC, reaction mass is subjected to carbon treatment.
Thereafter, water miscible solvent is distilled out and residue is dissolved in water immiscible solvent such as halogenated solvent, esters or the like. It is advantageous to distill the water miscible solvent partially and the reaction mass is diluted with water immiscible solvent such as halogenated solvent, esters or the like. The halogenated solvent can be selected from chloroform, methylene chloride, ethylene chloride and the like and esters can be ethyl acetate, methyl acetate and the like. The reaction mixture is washed with water. Specifically the reaction mixture is stirred at a temperature 20 -40°C for 1-2 hours and preferably at 30-35°C for 1/2 hour. Thereafter layers are separated and solvent is distilled out completely and pure amorphous product is isolated in good yields. Alternatively the isolation of pure amorphous atorvastatin calcium can be carried out by slurring the amorphous product in non polar solvent followed by filtration. Non polar solvent can be selected from cyclohexane, hexane, heptane, diisopropyl ether and the like and mixture thereof. The wet product is dried at a temperature 60 - 65°C under vacuum till residual solvent level is below allowable limits. The product obtained is having purity and assay of greater than 99% by high performance liquid chromatography.
The product is characterized by powdered X-ray diffraction and infrared analyses. X-ray diffraction patterns were determined on PANalytical X'Pert X-ray powder diffraction system using a copper target X-ray tube, a nickel filter, X'celerator detector and PW1770/10 powder complex. The infrared spectra of atorvastatin calcium were determined on Perkin Elmer-spectrum ONE infrared spectrophotometer.
In another embodiment of the present invention pure amorphous atorvastatin calcium can be prepared by dissolving any crystalline form of atorvastatin calcium in water immiscible solvent such as halogenated solvents, esters or the like at reflux temperature and thereafter removing the solvent completely to obtain pure amorphous atorvastatin calcium. Alternatively the isolation of pure amorphous atorvastatin calcium can be carried out by slurring the amorphous product in non polar solvent followed by filtration. Non polar solvent can be selected from cyclohexane, hexane, heptane, diisopropyl ether and the like and mixture thereof.
Major advantages realized in the present invention are the high yields and high product purity with assay more than 99%. Further number of steps is also less, thus reducing time cycle in commercial batches. Mixture of solvents were not used therefore solvent recovery is quantitative which makes the process cost effective. Amorphous atorvastatin calcium is isolated directly starting from diol protected tert.-butyl ester of Formula II without isolating lactone compound.
The examples will illustrate the process of this invention, which is not intended in anyway to limit the scope of the invention
Example 1
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM
Diol protected tert.-butyl ester of Formula II (10.0 gm) was taken in methanol (200 ml) at room temperature and the reaction mixture was heated at 40-45 °C till dissolution. The reaction mixture was cooled to 30-35 °C, IN hydrochloric acid solution (21 ml) was added at same temperature and stirred for 2-3 hours at 30-35 °C. After completion of the reaction, calcium hydroxide (2.25 gm) was added at 30-35 °C. The reaction mass was refluxed for 2-3 hours at 65-70 °C, 1.0 gm activated carbon was added and stirred for '/a hour at same temperature. The reaction mixture was filtered through celite and washed with methanol (20 ml). Methanol was distilled out till 30 ml left in flask, the reaction mass was cooled to 30-35 °C and methylene chloride (100 ml) was added followed by addition of water (50 ml). The reaction mixture was stirred for 15 minutes at 30-35 °C. The layers were separated, the organic layer was washed with water and filtered. Methylene chloride was distilled out completely, the product was dried under vacuum below 45 °C to obtain 8.3 gm of pure amorphous atorvastatin calcium.
X-ray powder diffraction patterns are given in Fig 1.
Infrared spectrum is similar as shown in Fig 7.
Example 2
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM
Diol protected tert.-butyl ester of Formula II (20.0 gm) was taken in methanol (400 ml) at room temperature and the reaction mixture was heated at 40-45 °C till dissolution. The reaction mixture was cooled to 30-35 °C, IN hydrochloric acid solution (42 ml) was added and was stirred for 2-3 hours at 30-35 °C. After completion of the reaction.
calcium hydroxide (4.5 gm) was added at 30-35 °C. The reaction mass was refluxed for 2-3 hours at 65-70 °C, 2.0 gm activated carbon was added and stirred for Vi hour at same temperature. The reaction mixture was filtered tlirough celite and washed with methanol (50 ml). Methanol was distilled out, till 60 mi of solution left in the flask. The reaction mass was cooled to 30-35 °C and methylene chloride (200 ml) was added followed by addition of water (100 ml). The reaction mixture was stirred for 15 minutes at 30-35 °C. The layers were separated, the organic layer was washed with water (100ml) and filtered. Methylene chloride was distilled out completely, dried the product under vacuum below 45 °C. To the residue cyclohexane (100ml) was added at 30-35 °C and stirred for 1 hour. The product was filtered, washed with cyclohexane (40ml) and dried at temperature 60 - 65°C under vacuum to obtain 16.8 gm of pure title compound having purity of 99.59 % by HPLC,
XRD data given in Fig. 2 shows that product is amorphous in nature. Infrared spectrum is shown in Fig 8.
Example 3
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM
Diol protected tert.-butyl ester of Formula II (10.0 gm ) was taken in methanol (200 ml) at room temperature and the reaction mixture was heated at 40-45 °C till dissolution. The reaction mixture was cooled to 30-35 °C, IN hydrochloric acid solution (21 ml) was added and stirred for 2-3 hours at 30-35 °C. After completion of reaction, calcium hydroxide (2.25 gm) was added at 30-35 °C. The reaction mass was refluxed for 2-3 hours at 65-70 °C, 1.0 gm activated carbon was added and stirred for lA hour at same temperature. The reaction mixture was filtered tlirough celite and washed with methanol (20 ml). Methanol was distilled out till 30 ml left in the flask, the reaction mass was cooled to 30-35 °C and methylene chloride (100 ml) was added followed by addition of water (50 ml). The reaction mixture was stirred for 15 mints at 30-35 °C. The layers were separated; the organic layer was washed with water and filtered. Methylene
chloride was distilled out completely; dried the product under vacuum below 45 °C. XRD was checked and given in Fig 3. To the residue cyclohexane (50ml) was added at 30-35 °C and stirred for 1 hour. The product was filtered, washed with cyclohexane (20ml) and dried at temperature 60 - 65°C under vacuum to obtain 8.3 gm of pure title compound.
XRD data is given in Fig. 4 which shows that product is amorphous in nature.
Example 4
PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM
Crystalline atorvastatin calcium (20.0 gm) was suspended in methylene chloride (240 ml) and heated to reflux till dissolution. After complete dissolution, the reaction mixture was filtered through celite and washed with methylene chloride (20 ml). Methylene chloride was distilled out completely and the product was dried under vacuum below 45 °C. XRD was checked and given in Fig 5. To the residue cyclohexane (100ml) was added at 30-35 °C and stirred for 1 hour. The product was filtered, washed with cyclohexane (40ml) and dried at temperature 60 - 65°C under vacuum to obtain 16.6 gm of pure title compound.
XRD data is given in Fig. 6 which shows that product is amorphous.

WE CLAIM
1. An improved process for the preparation of amorphous atorvastatin calcium of formula I,

(Formula Removed)
which comprises;
i) acidic hydrolysis of diol protected tert.-butyl ester of Formula II,
(Formula Removed)
in water miscible solvent, at a temperature of 25-50°C to prepare a compound of Formula III,
(Formula Removed)

ii) heating the resulting reaction mass with calcium hydroxide at a temperature of 50-75°C till complete hydrolysis of ester group,
iii) filtering the reaction mixture.
iv) distilling the water miscible solvent,
v) diluting the reaction mass with water immiscible solvent,
vi) adding water to separate the layers,
vii) distilling out water immiscible solvent and
viii) isolating the amorphous atorvastatin calcium in pure form.
2. The process according to claim 1, wherein in step-i, acidic hydrolysis is carried out using hydrochloric acid.
3. The process according to claim 1, wherein in step-i, water miscible solvent is methanol, ethanol, isopropanol or tetrahydrofuran.
4. The process according to claim 1, wherein in step-iv, water miscible solvent is distilled out completely.

5. The process according to claim 1, wherein in step-iv, water miscible solvent is distilled out partially.
6. The process according to claim 1. wherein in step-v, water immiscible solvent is chloroform, methylene chloride, ethylene chloride or ethyl acetate.
7. The process according to claim 1, wherein in step-viii, amorphous atorvastatin is isolated as such.
8. The process according to claim 1, wherein in step-viii, amorphous atorvastatin is isolated by slurring the residue obtained in step vii, with non-polar solvent and filtering the product, followed by drying.
9. The process according to claim 8, wherein in non-polar solvent is cyclohexane, hexane, heptane and diisopropyl ether.
10 A process for producing amorphous atorvastatin calcium, which comprises the steps of:
dissolving crystalline atovastatin calcium in water immiscible solvent,
distilling out water immiscible solvent and isolating the amorphous atorvastatin calcium in pure form.