FIELD OF THE INVENTION
The field of the invention relates to the preparation of amorphous atorvastatin hemicalcium in high yield and high purity from (4R-cis)-(6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-( 1 -methylethyl)-pyrrol-1 -yl]-ethyl]-2,2-dimethyl-[l,3]-dioxan-4-yl-acetic acid tertiary-butyl ester.
BACKGROUND OF THE INVENTION
Atorvastatin hemicalcium 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 (pR,8R)-2-(4-fluorophenyl)-p,6-dihydroxy-5-(l-methylethyl)-3-phenyl-4-
[(phenyl amino)carbonyl]-lH-pyrrole-l-heptanoic acid hemicalcium salt. As such atorvastatin hemicalcium is a potent lipid-lowering compound and is thus useful as a hypocholesterolemic agent.
Racemic atorvastatin and pharmaceutically acceptable salts thereof have been first disclosed in US Patent 4,681,893 as a useful inhibitor of cholesterol biosynthesis. Subsequent US Patent 5,273,995 (herein referred to as '995) discloses [R(R*,R*)] enantiomer of atorvastatin and hemicalcium salt thereof. The '995 patent describes a process for the preparation of atorvastatin hemicalcium, which is the salt form of the drug that has been approved by the U.S. Food and Drug Administration for
oral administration to human patients. To prepare atorvastatin hemicalcium, the '995 patent teaches that the sodium salt is prepared first by dissolving the lactone in methanol and water and adding a little less than one equivalent of sodium hydroxide to the solution until the lactone has been opened as determined by high performance liquid chromatography (HPLC). The '995 patent then teaches that the hemicalcium salt may be prepared from the sodium salt by treating it with one equivalent or a slight excess of calcium chloride dihydrate (CaCl2.2H2O). To an atorvastatin sodium salt solution whose exact concentration has been determined by HPLC is slowly added an equivalent or slight excess of CaCl2.2H2O at elevated temperature while agitating the solution. After completing the addition, atorvastatin hemicalcium is obtained as a precipitate by cooling the solution.
The above patent teaches the use of sodium hydroxide which is a strong base and is very corrosive. It is difficult to handle and causes severe burns and may cause serious permanent eye damage and is harmful by skin contact or by inhalation of dust.
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 hemicalcium. These processes do not give amorphous atorvastatin hemicalcium consistently but give a mixture of its crystalline and amorphous forms, which has unsuitable filtration and drying characteristics.
Atorvastatin hemicalcium is known to exist in a number of crystalline and amorphous forms. The amorphous form is of interest, due at least in part to its enhanced solubility as compared to crystalline forms, a higher solubility thought to provide an improved bioavailability profile.
US Patent 6,087,511 describe the procedures for converting the crystalline form of atorvastatin calcium to the amorphous form. The process disclosed therein involve dissolving form I atorvastatin calcium in a non hydroxylic solvent like
tetrahydrofuran or a mixture of tetrahydrofuran and toluene. None of these processes disclosed therein is suitable for large scale production as solvent has to be removed at high temperature of about 85-90°C and under high vacuum (5-10 mm of mercury) and the product thus obtained is in the form of a brittle glassy foam which has to be broken into a free flowing powder. The process disclosed therein takes very long time for the removal of solvents.
A number of subsequent patents and applications relate to different processes for producing amorphous atorvastatin hemicalcium which are herein incorporated by reference.
US Patent 6,528,660 describes the procedure for converting the crystalline form-I of atorvastatin hemicalcium to amorphous form thereof by dissolving it in a non-hydroxylic solvent like tetrahydrofuran and precipitating amorphous atorvastatin hemicalcium by the addition of non-polar hydrocarbon like, n-hexane cyclohexane or n-heptane. The method disclosed in this patent is not suitable for large scale production of amorphous atorvastatin hemicalcium as the process requires very large amount of non polar hydrocarbon solvents making the process uneconomical on the commercial scale.
US Patent 6,528,661 provides a process for preparing atorvastatin hemicalcium trihydrate (crystalline form) from an acetonide protected, ester protected p, 8-dihydroxy heptanoic acid precursor compound using calcium hydroxide.
US patent application 2005/0131055 discloses a process for the preparation of amorphous atorvastatin hemicalcium from diol protected tertiary-butyl ester by acidic hydrolysis followed by alkaline hydrolysis and then treating the resulting salt with a calcium source such as calcium salt, calcium hydroxide or alcoholate thereof and precipitating the product in hydrocarbons or ethers.
US patent application 2005/0165242 discloses a process for the preparation of amorphous atorvastatin hemicalcium which comprises hydrolysis of precursor
lactone with sodium hydroxide and then treating the atorvastatin sodium salt with calcium chloride or calcium acetate.
PCT patent application WO 02/083638 discloses a process for the preparation of amorphous atorvastatin hemicalcium from diol protected tertiary-butyl ester through atorvastatin sodium salt and convertion thereof to calcium salt using calcium chloride.
PCT patent application WO 03/018547 describes a process for the preparation of amorphous atorvastatin hemicalcium 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 hemicalcium. Alternatively, amorphous atorvastatin hemicalcium is prepared from crystalline atorvastatin hemicalcium, which comprises dissolving the crystalline atorvastatin hemicalcium in an organic solvent, distilling off half of the solvent and adding the same to an anti solvent to precipitate the amorphous product.
Thus, it is evident that most of the methods described in the prior art to prepare amorphous atorvastatin hemicalcium have some disadvantages such as involving the use of large volumes of solvents as mixtures, which are difficult to separate and thus amounting to increase in cost. Further most of the processes involve the alkaline hydrolysis of tertiary-butyl ester of atorvastatin first and thereafter conversion to calcium salt and results in more number of steps and more reaction time.
OBJECT OF THE INVENTION
It is therefore an object of the present invention to provide a process for the preparation of amorphous atorvastatin hemicalcium in high yields and high purity directly from diol protected tertiary-butyl ester of formula II without performing alkaline hydrolysis step in-between.
It is a further object of the present invention to provide a process for the preparation of amorphous atorvastatin hemicalcium consistently and which avoids production of a mixture of amorphous and crystalline forms.
It is yet another object of the present invention to provide a process for the preparation of amorphous atorvastatin hemicalcium, which 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 hemicalcium which comprises:
i) acidic hydrolysis of diol protected tertiary-butyl ester of formula II,
(Formula Removed)
in a water miscible solvent, at a temperature of 25-50°C to form a compound of formula III,
(Formula Removed)
ii) treating the resulting reaction mass containing compound of formula III formed insitu with a calcium source such as calcium oxide till complete hydrolysis of ester group,
iii) distilling the water miscible solvent,
iv) diluting the reaction mass with water immiscible solvent and water,
v) separating the layers,
vi) distilling out water immiscible solvent and
vii) isolating the amorphous atorvastatin hemicalcium in pure form.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1. X-ray powder diffractogram of amorphous atorvastatin hemicalcium.
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 hemicalcium in high yield directly from diol protected tertiary-butyl ester, namely (4R-cis)-(6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(l-methyl ethyl)-pyrrol-l-yl]-ethyl]-2,2-dimethyl-[ 1,3]-dioxan-4-yl-acetic acid tertiary-butyl ester of formula II.
The diol protected tertiary-butyl ester of formula II may be prepared by the methods described in the previously mentioned U.S. Patents, which are incorporated herein by reference.

Preferably, diol protected tertiary-butyl ester of formula II, is hydrolyzed in water miscible solvent using acid to de-protect the diol group to form a compound of formula III,
(Formula Removed)
Specifically, acidic hydrolysis of diol protected tertiary-butyl ester of formula II is carried out by dissolving the compound of formula II in water miscible solvent preferably methanol at a temperature of 35 to 50°C. The water miscible solvent can be selected from tetrahydrofuran or alcoholic solvent such as methanol, ethanol, isopropanol, the like and mixtures thereof. The reaction mass is then cooled to a temperature of about 20 to 45°C with constant stirring. This is followed by the slow addition of acid preferably hydrochloric acid with constant stirring. The reaction takes about 2-10 hours for complete removal of protecting group; thus leading to the preparation of tertiary-butyl ester of atorvastatin of formula III. Compound of formula III can be isolated of the reaction mixture. But it is advantageous not to isolate the intermediate compounds, as it lowers the processing time and product is achieved in high yield.
The removal of tertiary-butyl group and calcium salt formation was carried out simultaneously using calcium oxide. The calcium oxide is employed to the reaction mixture formed above in the molar ratio of 1-3 with respect to compound of formula II at a temperature of about 20 to 45°C. The reaction mass is then heated at a temperature of 50°C to 75°C, preferably at the reflux temperature of the solvent with stirring. It takes about 2 to 20 hours for completion of the reaction. 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 less than 1.0% in HPLC or TLC, reaction mass is subjected to carbon treatment.
Thereafter, water miscible solvent is completely or partially 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 immiscible solvent such as halogenated solvent, esters or the like. The halogenated solvent can be selected from chloroform, dichloromethane, dichloroethane 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 of 20-40°C for 1-2 hours and preferably at 20-45°C for about half hour. The washing can be repeated with water or a mixture of water and water miscible solvent. Thereafter layers are separated and solvent is distilled out completely. The product is then washed with halogenated solvent preferably dichloromethane followed by distillation of the solvent to afford a thick viscous mass which is then slurried in non polar solvent at a temperature of 30-50°C followed by cooling the reaction mass to a temperature of 20-3 0°C to isolate amorphous atorvastatin hemicalcium in high yield and purity. Non polar solvent can be selected from cyclohexane, hexane, heptane and the like and mixture thereof. The amorphous atorvastatin hemicalcium is then isolated by the methods well known in art like centrifugation, filtration and the like. The product can optionally be washed with non-polar solvent and dried at a temperature 70-85°C under vacuum till residual solvent level is below allowable limits. The product obtained is having purity 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.
Amorphous atorvastatin hemicalcium so formed can be converted to crystalline form I by suspending the amorphous atorvastatin hemicalcium in water.
Major advantages realized in the present invention are: The use of calcium oxide is advantageous over the prior art calcium sources as it is inexpensive and is easily available. Also, the hemicalcium salt of atorvastatin is obtained directly from diol protected tertiary butyl ester of atorvastatin without the need for making sodium salt using strong base like sodium hydroxide or any other intermediates and thereby reducing number of steps, thus reducing time cycle in commercial batches. Also, the product is achieved in high yields and high purity with assay more than 98% by HPLC.
The examples will illustrate the process of this invention, which is not intended in anyway to limit the scope of the invention
EXAMPLES
EXAMPLE 1: PREPARATION OF AMORPHOUS ATORVASTATIN HEMICALCIUM
Diol protected tertiary-butyl ester ( 20g) was taken in methanol (400 ml) at room temperature and the reaction mixture was heated at 40-45°C till complete dissolution. The reaction mixture was cooled to 30-35°C, IN hydrochloric acid solution (42 ml) was added slowly and stirred for 2-3 hours at 30-35°C. Completion of the reaction was monitored by TLC. After completion of the reaction, calcium oxide (4.5 g) was added at 30-35°C. The reaction mass was stirred under reflux for 6 hours. Completion of the reaction was monitored by TLC. After completion of the reaction, activated carbon (2.0 g) was added and stirred for half hour at reflux temperature. The reaction mixture was filtered through hyflo bed and washed with methanol (40 ml). Methanol was distilled out till 60-70 ml was left in reactor, the reaction mass was cooled to 30-35°C and dichloromethane (200 ml) was added followed by addition of water (100 ml) with stirring. The reaction mixture was stirred for 30 minutes at 30-35°C. The layers were separated; the organic layer was washed with demineralized water (100 ml)
and methanol (25 ml). The organic layer was filtered through hyflo bed. Dichloromethane was distilled out completely at atmosphere pressure. XRD was checked which showed product was amorphous in nature. Cyclohexane (100 ml) was added to the resulting residue at 30-35°C. The reaction mass was stirred for 2 hours at 40-45°C followed by cooling to 25-30°C. The reaction mass was centrifuged at 25-30°C. The product was washed with cyclohexane and dried at 75-80°C to obtain 16.4 g of amorphous atorvastatin hemicalcium.
EXAMPLE 2; PREPARATION OF AMORPHOUS ATORVASTATIN HEMICALCIUM
Diol protected tertiary-butyl ester (40g) was taken in methanol (800 ml) at room temperature and the reaction mixture was heated at 40-45°C till complete dissolution. The reaction mixture was cooled to 30-35°C; IN hydrochloric acid solution (84 ml) was added slowly and stirred for 2-3 hours at 30-35°C. Completion of the reaction was monitored by TLC. After completion of the reaction, calcium oxide (9.0 g) was added at 30-35°C. The reaction mass was stirred under reflux for 6 hours. Completion of the reaction was monitored by TLC. After completion of the reaction, activated carbon (4.0 g) was added and stirred for half hour at reflux temperature. The reaction mixture was filtered through hyflo bed and washed with methanol (80 ml). Methanol was distilled out till 60-70 ml was left in reactor, the reaction mass was cooled to 30-35°C and dichloromethane (400 ml) was added followed by addition of water (200 ml) with stirring. The reaction mixture was stirred for 30 minutes at 30-35°C. The layers were separated; the organic layer was washed with demineralized water (200 ml) and methanol (50 ml). The organic layer was filtered through hyflo bed. Dichloromethane was distilled out at atmosphere pressure. Cyclohexane (200 ml) was added to the resulting residue at 30-35°C. The reaction mass was stirred for 2 hours at 40-45°C followed by cooling to 25-30°C. The reaction mass was centrifuged at 25-3 0°C. The product was washed with cyclohexane and dried at 75-80°C to obtain 33.2 g of amorphous atorvastatin hemicalcium.

WE CLAIM
1. A process for the preparation of amorphous atorvastatin hemicalcium of formula I,
(Formula Removed)
which comprises:
i) acidic hydrolysis of diol protected tertiary-butyl ester of formula II,
(Formula Removed)
in a water miscible solvent, at a temperature of 25-50°C to form a compound of formula III,
(Formula Removed)
ii) treating the resulting reaction mass containing compound of formula III formed insitu with a calcium source such as calcium oxide till complete hydrolysis of ester group,
iii) distilling the water miscible solvent,
iv) diluting the reaction mass with water immiscible solvent and water,
v) separating the layers,
vi) distilling out water immiscible solvent and
vii) isolating the amorphous atorvastatin hemicalcium 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-iii, water miscible solvent
is distilled out completely.
5. The process according to claim 1, wherein in step-iii, water miscible solvent
is distilled out partially.
6. The process according to claim 1, wherein in step-iv, water immiscible
solvent is chloroform, dichloromethane and dichloroethane.
7. The process according to claim 1, wherein in step-vii, amorphous
atorvastatin hemicalcium is isolated as such.
8. The process according to claim 1, wherein in step-vii, amorphous
atorvastatin hemicalcium is isolated by slurring the residue obtained in step
vi, with a 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 and heptane.
10. The process according to claim 1, wherein amorphous atorvastatin
hemicalcium so formed is converted to crystalline form I by suspending
amorphous atorvastatin hemicalcium in water.