The present invention relates to a process for the preparation of [R-(R* R*)]-2-(4-fluorophenyl)-P,§-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-IH-pyrrole-l-heptanoic acid hemi calcium salt (atorvastatin. Lipitor). which is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA). an important coenzyme catalyzing the intracellular synthesis of cholesterol, and thus is used as hypolipidemic and hypocholesterolemic agents.
Cardiovascular disease and its associated maladies, dysfunctions and complications are a principal cause of disability and the chief cause of death. One specific factor significantly contributing to this pathophysiologic process is atherosclerosis, which has been generally recognized as the leading health care problem both with respect to mortality and health care costs.
Atherosclerosis is characterized by the deposition of fatty substances, primarily cholesterol, resulting in plaque formation on the inner surface of the arterial wall and degenerative change within it.
It is now well established that vascular blockage and cardiovascular disorders including myocardial infarction, coronary heart disease, hypertension and hypotension, cerebrovasular disorders including stroke, cerebral thrombosis and memory loss due to stroke; peripheral vascular disease and intestinal infarction are caused by blockage of arteries and arterioles by atherosclerotic plaque. Atherosclerotic plaque formation is multi-factorial in its production, flypercholesterolemia. especially elevated level of low-
density lipoprotein cholesterol (LDL) is an important risk factor for atherosclerosis and arteriosclerosis and associated diseases.
The HMG-CoA reductase inhibitors (statins) have been used in reducing blood levels of LDL cholesterol level. Cholesterol is produced via the mevalonic acid pathway. Reducing the formation of mevalonic acid, a precursor to cholesterol, leads to a corresponding decrease in hepatic cholesterol biosynthesis with a reduction in the cellular pool of cholesterol.
U.S. Patent No. 4.681. 893 discloses a route using resolution of the racemic product using R (+) a-methyl benzyl amine.
U.S. Patent No. 5.003,080 discloses a synthetic route for the preparation of the chiral form of atorvastatin.
U.S. Patent Nos. 5,216.174; 5.097.045: 5,103.024: 5,124.482; 5.149.837: 5.155.251: 5.245,047: 5.273.995: 5.248.793 and 5.397.792 describe various minor modifications in the procedure for the preparation of atorvastatin calcium salt.
WO 02/057274 discloses a process for the synthesis of atorvastatin form V and phenylboronates as intermediate compounds.
The object of the present invention is to provide an alternate and scalable route for the preparation of [R-(R* R*)]-2-(4-t1uorophenyl)-p.8-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-l H-pyrrole-1-heptanoic acid hemi calcium salt
(atorvastatin. Lipitor). which is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyiTie A reductase (HMG-CoA). an important coenzyme catalyzing the intracellular synthesis of cholesterol, and thus is used as hypolipidemic and hypocholesterolemic agents.
In order to achieve the above-mentioned objective and in accordance with the purpose of the invention as embodied and broadly described herein, there is provided a process for the preparation of [R-(R* R*)]-2-(4-fluorophenyl)-p,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyiTole-l-heptanoic acid hemi calcium salt of Formula I. as shown in the accompanied drawings.
Scheme I
[R-(R*R*)]-2-(4-fluorophenyl)-p.5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenyl amino)carbonyl]-IH-pyrrole-l-heptanoic acid hemi calcium salt of Formula 1 can be prepared according to scheme I. as shown in the accompanied drawings, which method comprises reacting 4-methyl-3-oxo-pentanoic acid benzyl ester of Formula 11 with benzaldehyde to give 4-methyl-3-oxo-2-[l-phenyl-methylidene]-pentanoic acid benzyl ester of Formula III. which on reaction with 4-fluorobenzaldehyde gives 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-pentanoic acid benzyl ester of Formula IV. which on reaction with 7-amino-3.5-dimethoxy-heptanoic acid tert-butyl ester of Formula V gives l-[2-(6-tert-butoxycarbonylmethyl-2.2-dimethyl-[1.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-l H-pyrrole-3-carboxylic acid benzyl ester of Formula VI. which on debenzylation gives l-[2-(6-tert-butoxycarbonyliTiethyl-2.2-dimethyl-[l.3]dioxan-4-yl)-ethyl]-5-(4-tluorophenyl)-2-isopropyl-4-phenyl-l H-pyiTole-3-carboxylic acid of Formula VII. which on
(a) conversion to corresponding acid chloride followed by reaction with aniline (Path a) or
(b) reaction with aniline in the presence of a coupling agent (Path b) gives (6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrole-l-yl]-ethyl}-2,2-dimethyl-[1.3]dioxan-4-yl)-acetic acid tert-butyl ester of Formula VIII. which on hydrolysis gives compound of Formula IX. which can be further converted to hemi calcium salt of Formula I by following the procedure well known in the art.
The reaction of 4-methyl-3-oxo-pentanoic acid benzyl ester of Formula II with benzaldehyde to give 4-methyl-3-oxo-2-[l-phenyl-methylidene]-pentanoic acid benzyl ester of Formula III can be carried out in a solvent, for example, xylene, toluene, heptane, hexane or dichloromethane. in the presence of an organic base, for example, triethylamine. pyridine, piperidine or P-alanine. and an organic acid, for example, glacial acetic acid or benzoic acid.
The reaction of 4-methyl-3-oxo-2-[l-phenyl-methylidene]-pentanoic acid benzyl ester of Formula III with 4-tluorobenzaldehyde can be carried out in a solvent, for example, methanol, ethanol. propanol or isopropanol. in the presence of an organic base, for example, triethylamine or pyridine, and a catalyst, for example, sodium cyanide. 3-ethyl-5- (2-hydroxyethyl)-4-methyl thiazolium bromide or 3-benzyl-5- (2-hydroxyethyl)-4-methyl thiazolium chloride.
The reaction of 2-[2-(4-tluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-pentanoic acid benzyl ester of Formula IV with 7-amino-3.5-dimethoxy-heptanoic acid tert-butyl
ester of Formula V can be carried out in a solvent, for example, hexane, heptane, toluene, tetrahydrofuran or a mixture thereof in various combination in the presence of an acid, for example, pivalic acid or p-toluene sulfonic acid.
The debenzylation of l-[2-(6-tert-butoxycarbonylmethyl-2,2-dimethyl-[l.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-IH-pyrrole-3-carboxylic acid benzyl ester of Formula VI can be carried out in a solvent, for example, methanol, ethanol. propanol. dioxane or a mixture thereof in the presence of a catalyst, for example, palladium on carbon and hydrogen.
The conversion of l-[2-(6-tert-butoxycarbonylmethyl-2.2-dimethyl-[l.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-l H-pyrrole-3-carboxylic acid of formula VII to its corresponding acid chloride (Path a) can be carried with any chlorinating agent, for example, oxalyl chloride, in a solvent, for example, benzene, dichloromethane. tetrahydrofuran. toluene or xylene, followed by reaction with aniline to give {6-{2-[2-(4-fIuorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrole-l-yl]-ethylj-2.2-dimethyl-[l.3]dioxan-4-yl)-acetic acid tert-butyl ester of Formula VIII in a solvent, for example, benzene, and in the presence of an organic base, for example, triethylamine or pyridine.
The reaction of I-[2-(6-tert-butoxycarbonylmethyl-2.2-dimethyl-[1,3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid of Formula VII with aniline can be carried out in the presence of a coupling agent, for example. O-benzotriazol-l-yl-N.N.N'.N'-tetramethyl uronium hexatluorophosphate (HBTU). bis(2-oxo-3-oxazolidinyl)phosphine (BOP). 1.3-dicyclohexycarbodiimide (DCC). 2-(IH-
benzotriazole-l-yl)-l.l.3.3-tetramethyluronium tetrafluoroborate (TBTU). benzotriazole-
l-yl-oxy-tris-pyrrolidino-phosphoniLim hexafluorophosphate (PyBOP) or
carbonyldiimidazole (CD!) (Path b) in a solvent, for example, dimethylformamide, and a base, for example, diisopropylethylamine or the coupling reaction can also be achieved following any method described in the prior art.
The conversion of (6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyiTole-l-yl]-ethyl}-2.2-dinethyl-[l.3]dioxan-4-yl)-acetic acid tert-butyl ester of Formula VIII to 7-[2-(4-f1uorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyiTole-l-yl]-3.5-dihydroxy-heptanoic acid of Formula IX can be carried out in a two step manner involving an initial acid catalyzed cleavage of ketal followed by base catalyzed hydrolysis of tert-butyl ester. The said acid can be a mineral acid, for example, hydrochloric acid. The cleavage of ketal can be carried out by any other cleavage method known in the prior art. The said base can be. for example, lithium hydroxide, sodium hydroxide or potassium hydroxide.
7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrole-l-yl]-3.5-dihydroxy-heptanoic acid of Formula XI can be converted into its corresponding hemi calcium salt of Formula i by following the procedures well known to a person ordinary skilled in the art.
In the above synthetic method where specific solvents, acids, bases, catalysts, etc.. are mentioned, it is to be understood that the other solvent, acids, bases, catalysts, etc.. may be used. Similarly, the reaction temperature and duration of reaction can be adjusted.
While the present invention has been described in terms of its specific embodiments.
certain modifications and equivalents will be apparent to those skilled in the art and are
intended to be included within the scope of the present invention.
EXPERIMENTALS
Example I: Preparation of 4-methvl-3-oxo-2-[l-phenyl-meth-(Z)-vlidene]-pentanoic acid benzyl ester of Formula 111.
To a solution of 4-methyl-3-oxo-pentanoic acid benzyl ester of Formula II (4.5 mmoles)
in toluene (15 ml) added benzaldehyde (4.9 mmoles), piperidine (0.02 ml) and acetic acid
(0.054 ml). The mixture was heated at reflux with azeotropic removal of water for about
4 to 6 hours. The reaction mixture was concentrated and residue extracted in
dichloromethane. Organic layer washed with IN hydrochloric acid solution, sodium
bicarbonate solution, brine, dried over anhydrous sodium sulphate and concentrated. The
crude product was purified on column (silica gel, 100-200 mesh, 2% EtOAc-hexane)
Example 2: Preparation of 2-r2-(4-fluorophenvl)-2-oxo-l-phenvlethvl1-4-methvl-3-oxo-pentanoic acid benzyl ester of Formula IV.
4-methyl-3-oxo-2-[l-phenyl-meth-(Z)-ylidene]-pentanoic acid benzyl ester of Formula
III (6.49 mmoles), 4-tluorobenzaldehyde (7.14 mmoles), 3-ethyl-5- (2-hydroxyethyl)-4-
methyl thiazolium bromide (1.298 mmoles) triethylamine (6.49 mmoles) and ethanol (0.6
ml) were placed in a 30 ml vial, flush with argon and sealed the vial properly. Stirred the
reaction mixture at 70°C for about 12 to 15 hours. To the reaction mixture added ethyl
acetate, washed with water, 6N hydrochloric acid, again with water and brine, dried over
anhydrous sodium sulphate, and concentrated to give crude product. The crude product
was purified on column (silica gel 100-200 mesh) using 7% ethyl acetate in hexane.
(a) To a solution of (6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyiTole-l-yl]-ethyll-2.2-dimethyl-[1.3]dioxan-4-yl)-acetic acid tert-butyl ester of Formula Vlll in methanol and tetrahydrofuran (1:1) was added IN hydrochloric acid (3 equiv) and the mixture stirred at an ambient temperature. After the complete hydrolysis of ketal, reaction mixture was cooled to 0°C and sodium hydroxide pellet (6 equiv) were added. The reaction was then allowed to stir at an ambient temperature. At the end of ester hydrolysis, solvents were removed and residue dissolved in water: aqueous layer was washed with ether, and neutralized with IN hydrochloric acid. Organics were extracted into ethyl acetate, and concentrated. The residue was then purified on column (silica gel 100-200 mesh).
(b) To an aqueous solution of sodium salt of acid (prepared by adding 1 equivalent IN sodium hydroxide solution) was added drop wise an aqueous solution (IM) of calcium acetate (0.55 equiv). A little white precipitate was obtained which was filtered off and washed with copious amount of water, dried in vacuo.
Example 3: Preparation of l-[2-(6-tert-butoxvcarbonylmethyl-2.2-dimethyl-[l3]dioxan-4-vl)-ethyl]-5-(4-fluorophenvl)-2-isopropyl-4-phenvl-IH-pyrrole-3-carboxvlic acid benzyl ester of Formula VI
To a solution of 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-pentanoic
acid benzyl ester Formula IV (4.62 mmles) in heptane: toluene: tetrahydrofuran (4:1:1)
added 7-amino-3,5-dimethoxy-heptanoic acid tert-butyl ester of Formula V (6.99
mmoles) and pivalic acid (4.768 mmoles). The mixture was refluxed with azeotropic
removal of water for about 22 to 25 hours. The reaction mixture concentrated, added
ethyl acetate, washed with sodium bicarbonate solution and brine, dried over anhydrous
sodium sulphate and concentrated to give the crude product. The crude product was
purified on column (silica gel. 100-200 mesh) using 7% ethyl acetate in hexane.
Example 4: Preparation of l-[2-(6-tert-butoxycarbonymethyl-2.2-diiTiethyl-[l.3]dioxan-4-yn-ethvl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-IH-pyrrole-3-carboxylic acid of Formula VII.
To a solution 1 -[2-(6-tert-butoxycarbonylmethyl-2,2-dimethyl-[1.3]dioxan-4-yl)-ethyl]-5-
(4-fluorophenyl)-2-isopropyl-4-phenyl-l H-pyrrole-3-carboxylic acid benzyl ester of
Formula VI (0.8g) in methanol: dioxan (2:8) mixture was added 10% palladium carbon
(50% wet. 60%) vv/w). The resulting reaction mixture was hydrogenated at 40 psi for
about 2.5 hours. After the reaction was over, the reaction mixture was passed through
celite and the resulting solution was concentrated under vaccum to give the required
product, which was further used as such for next step.
Example 5: Preparation of (6-!2-[2-(4-t1uorophenyl)-5-isop|•opyl-3-phenvl-4-phenylcarbamovl-pyrl•ole-l-yl]-ethyl]-2.2-dimethyl-[l.31dioxan-4-yl)-acetic acid tert-butvl ester of Formula VIII
Path a: To a solution of l-[2-(6-tert-butoxycarbonyliTiethyl-2.2-dimethyl-[!.3]dioxan-4-yl)-ethyl]-5-(4-tluorophenyl)-2-isopropyl-4-phenyl-l H-pyrrole-3-carboxylic acid of Formula Vll (1 equiv) in benzene at 0°C under argon, oxalyl chloride (2.0 equiv) was added dropvvise. After the evolution of gas had ceased, the reaction mixture was heated on oil bath at 70°C for about 2 hours. Reaction mixture was evaporated to dryness. The residue was dissolved in benzene (dry) and added at ambient temperature to a solution of aniline (I.I equiv.) in benzene. The reaction mixture was then heated at 70°C till completion of reaction. Volatiles were removed in vacuo & the residue was purified on column (silica gel, 100-200 mesh).
Path b: To a solution of l-[2-(6-tert-butoxycarbonylmethyl-2,2-dimethyl-[l.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-l H-pyrrole-3-carboxylic acid of Formula VII (1.2 mmole) in dimethylformamide (2.5 ml) was added diisopropylethylamine (2.4 mmole) and 0-benzotriazol-l-yl-N,N.N'.N'-tetramethyl uronium hexafluorophosphate (HBTU) (1.2 mmoles). To the resulting clear solution was then added aniline (1.2 mmoles) in dimethylformamide (0.5 ml), stirred the reaction mixture at 50 0C to 60 0C overnight. To the reaction mixture was added water and extracted with dicloromethane. organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated to get the crude product. The crude product was purified by column chromatography (silica gel. 100-200 mesh) using 10 % ethyl acetate in hexane.
Example 6: Preparation of [R-(R* R*)]-2-(4-fluorophenvl)-|3. 5-dihvdroxy-5-(l-methylethyl)-3-phenvl-4-[(phenylamino)carbonvl]-l H-pyrrole-1-heptanoic acid hemi calcium salt of Formula I

WE CLAIM:
1. A process for the preparation of [R-(R* R*)]-2-(4-fluorophenyl)-P, 5-dihydroxy-5-(i-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-IH-pyrrole-l-heptanoic acid hemi calcium salt, as shown in scheme I of the accompanied drawings, which method comprises reacting 4-methyl-3-oxo-pentanoic acid benzyl ester of Formula II with benzaldehyde to give 4-methyl-3-oxo-2-[l-phenyl-iTiethylidene]-pentanoic acid benzyl ester of Formula III. which on reaction with 4-tluorobenzaldehyde gives 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-pentanoic acid benzyl ester of Formula IV. which on reaction with 7-amino-3.5-dimethoxy-heptanoic acid tert-butyl ester of Formula V gives l-[2-(6-tert-butoxycarbonylmethyl-2.2-dimethyl-[l.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-l H-pyrrole-3-carboxylic acid benzyl ester of Formula VI. which on debenzylation gives l-[2-(6-tert-butoxycarbonylmethyl-2.2-dimethyl-[l.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid of Formula VII. which on (a) conversion to corresponding acid chloride followed by reaction with aniline (Path a) or (b) reaction with aniline in the presence of a coupling agent (Path b) gives (6-(2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrole-1 -yl]-ethyl j -2.2-dimethyl-[ 1,3]dioxan-4-yl)-acetic acid tert-butyl ester of Formula VIII. which on hydrolysis gives compound of Formula IX. which can be further converted to hemi calcium salt of Formula I by following the procedure well known in the art.
2. The process according to claim 1 wherein the reaction of 4-methyl-3-oxo-pentanoic acid benzyl ester of Formula II with benzaldehyde to give 4-methyl-3-oxo-2-[l-phenyl-methylidenej-pentanoic acid benzyl ester of Formula III is carried out in a solvent

selected from the group consisting of xylene, toluene, heptane, hexane and dichloromethane.
3. The process according to claim I wherein the reaction of 4-methyl-3-oxo-pentanoic acid benzyl ester of Formula II with benzaldehyde is carried out in the presence of an organic base selected from the group consisting of triethylamine. pyridine, piperidine and P-alanine.
4. The process according to claim 1 wherein the reaction of 4-methyl-3-oxo-pentanoic acid benzyl ester of Formula II with benzaldehyde is carried out in the presence of an organic acid selected from the group consisting of glacial acetic acid and benzoic acid.
5. The process according to claim 1 wherein the reaction of 4-methyl-3-oxo-2-[l-phenyl-methylidenej-pentanoic acid benzyl ester of Formula III with 4-fluorobenzaldehyde to give 2-[2-(4-fluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-pentanoic acid benzyl ester of Formula IV is carried out in a solvent selected from the group consisting of methanol, ethanol. propanol and isopropanol.
6. The process according to claim 1 wherein the reaction of 4-methyl-3-oxo-2-[l-phenyl-methylidene]-pentanoic acid benzyl ester of Formula 111 with 4-fluorobenzaldehyde is carried out in the presence of an organic base selected from the group consisting of triethylamine and pyridine.
7. The process according to claim 1 wherein the reaction of 4-methyl-3-oxo-2-[l-phenyl-methylidene]-pentanoic acid benzyl ester of Formula 111 with 4-fluorobenzaldehyde is carried out in the presence of a catalyst selected from the group consisting of 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide and 3-benzyl-5- {2-hydroxyethyl)-4-methyl thiazolium chloride.
8. The process according to claim I wherein the reaction of 2-[2-(4-tluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-pentanoic acid benzyl ester of Formula IV with 7-amino-3.5-dimethoxy-heptanoic acid tert-butyl ester of Formula V to give I-[2-(6-tert-butoxycarbonylmethyl-2.2-dimethyl-[I.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-IH-pyiTole-3-carboxylic acid benzyl ester of Formula VI is carried out in a solvent selected from the group consisting of hexane, heptane, toluene, tetrahydrofuran and a mixture thereof in various combination.
9. The process according to claim 1 wherein the reaction of 2-[2-(4-tluorophenyl)-2-oxo-I-phenylethyl]-4-methyl-3-oxo-pentanoic acid benzyl ester of Formula IV with 7-amino-3.5-dimethoxy-heptanoic acid tert-butyl ester of Formula V is carried out in the presence of an acid selected from the group consisting of pivalic acid and p-toluene sulfonic acid.

10. The process according to claim I wherein the debenzylation of i-[2-(6-tert-butoxycarbonylmethyl-2.2-dimethyl-[1.3]dioxan-4-yl)-ethyl]-5-(4-tluorophenyl)-2-isopropyl-4-phenyl-IH-pyrroIe-3-carbo,xylic acid benzyl ester of Formula VI to give 1-[2-(6-tert-butoxycarbonylmethyl-2.2-dimethyl-[l.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-lH-pyiTole-3-carboxylic acid of Formula VII is carried out in a solvent selected from the group consisting of methanol, ethanol. propanol. dioxane and a mixture thereof
11. The process according to claim I wherein the debenzylation of l-[2-(6-tert-butoxycarbonylmethyl-2.2-dimethyl-[1.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-l H-pyrrole-3-carboxylic acid benzyl ester of Formula VI is carried out in the presence of a catalyst selected as palladium on carbon and hydrogen.
12. The process according to claim I wherein the conversion of l-[2-(6-tert-
butoxycarbonylmethyl-2.2-dimethyl-[l.3]dioxan-4-yl)-ethyl]-5-(4-fIuorophenyr)-2-
isopropyl-4-phenyl-IH[-pyrrole-3-carboxylic acid of formula VII to its corresponding acid
chloride is carried out with a chlorinating agent selected as oxalyl chloride in a solvent
selected from the group consisting of benzene, dichloromethane, tetrahydrofuran, toluene
and xylene.
13. The process according to claim I wherein the reaction of acid chloride of 1-[2-(6-tert-butoxycarbonylmethyl-2,2-dimethyl-[l.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid of formula VII with aniline to give (6-{2-[2-(4-tluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbaiTioyl-pyrrole-l-yl]-ethyl}-2.2-dimethyl-[l.3]dioxan-4-yl)-acetic acid tert-butyl ester of Formula VIII is carried out in a solvent selected as benzene.
14. The process according to claim 1 wherein the reaction of acid chloride of l-[2-(6-tert-butoxycarbonylmethyl-2.2-dimethyl-[l.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid of formula VII with aniline is carried out in the presence of an organic base selected from the group consisting of triethylamine and pyridine.
15. The process according to claim I wherein the reaction of I-[2-(6-teil;-
butoxycarbonylmethyl-2.2-dimethyl-[I.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-
isopropyl-4-phenyl-lH-pyrrole-3-carboxylic acid of Formula VII with aniline to give (6-
{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbaiTioyl-pyrrole-l-yl]-ethyl}-
2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester of Formula VIII is carried out
in a solvent selected as dimethylformamide.
16. The process according to claim I wherein the reaction of I-[2-(6-tert-butoxycarbonylmethyl-2.2-dimethyl-[l,3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-IH-pyrrole-3-carboxylic acid of Formula VII with aniline is carried out in a base selected as diisopropylethylamine.
17. The process according to claim I wherein the reaction of I-[2-(6-tert-butoxycarbonylmethyl-2.2-dimethyl-[1.3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-IH-pyrrole-3-carboxylic acid of Formula VII with aniline is carried out in the presence of a coupling agent selected from the group consisting of 0-benzotriazol-l-yl-N,N.N'.N'-tetramethyl uronium hexafluorophosphate (HBTU), bis(2-oxo-3-oxazolidinyl)phosphine (BOP). 1.3-dicyclohexycarbodiimide (DCC). 2-(lH-benzotriazole-l -yl)-1.1.3.3-tetramethyluronium tetrafluoroborate (TBTU). benzotriazole-l-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) and carbonyldiimidazole (CDI).

18. The process according to claim 1 wherein the hydrolysis of 6-{2-[2-(4-tluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrole-1-yl]-ethyl)-2.2-dimethyl-[ 1.3]dioxan-4-yl)-acetic acid tert-butyl ester of Formula VIII to give 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrole-1 -yl]-3.5-dihydi"oxy-heptanoic acid of Formula XI is carried out in the presence of a mineral acid selected as hydrochloric acid.
19. The process according to claim I wherein the hydrolysis of 6-{2-[2-(4-fIuorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrole-1-yl]-ethyl J-2.2-dimethyl-[ 1.3]dioxan-4-yl)-acetic acid tert-butyl ester of Formula Vlli to give 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbainoyl-pyrrole-l-yl]-3.5-dihydi"oxy-heptanoic acid of
Formula XI is carried out in the presence of a base selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide.
20. The process according to claim 1 wherein 7-[2-(4-fluorophenyl)-5-isopropyl-3-
phenyl-4-phenylcarbamoyl-pyrrole-l-yl]-3.5-dihydroxy-heptanoic acid of Formula XI is
converted into its corresponding hemi calcium salt of Formula 1 by following the
procedures well known to a person ordinary skilled in the art.
21. The process for the preparation of [R-(R* R*)]-2-(4-fluorophenyl)-|3. 6-dihydroxy-5-
(l-methylelhyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid hemi
calcium salt, substantially as herein described and illustrated by example herein.