FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
POLYMORPHS OF (4R-CIS)-6- [2- [3-PHENYL-4-{PHENYLCARBAMOYL) -2-(4-
FLUOROPHENYL)-5-(1-METHYLETHYL)-PYRROL-1-YL]-ETHYL]-2,2 -DIMETHYL-[1,3]-
DIOXANE-4-YL-ACETIC ACID TERTIARY BUTYL ESTER, FOR THE PREPARATION OF ATORVASTATIN AND SALTS THEREOF
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh Hall,
Ahmedabad 380 009, Gujarat, India
The following specification describes the nature of the invention and the manner in which it is to
be performed:

POLYMORPHS OF (4R-CIS)-6- [2- [3-PHENYL-4-(PHENYL CARBAMOYL) -2-(4-FLUOROPHENYL)-5-(1-METHYLETHYL)-PYRROL-1-YL]-ETHYL]- 2,2 -DIMETHYL-[1,3]-DIOXANE-4-YL-ACETIC ACID TERTIARY BUTYL ESTER, FOR THE PREPARATION OF ATORVASTATIN AND SALTS THEREOF
FIELD OF THE INVENTION
This invention relates to new polymorphs of (4R-Cis)-6-[2-[3-phenyl-4- (phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methy[ethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dtoxane-4-yl-acetic acid tertiary butyl ester, process for its preparation, as well as use of the polymorphs for the preparation of atorvastatin or its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
{4R-Cis)-6-[2-[3-phenyl-4-{phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methyl ethyl)-pyrrol-1-ylJ-ethyl]-2,2-dimethyl- [1,3]- dioxane-4-yl-acetic acid tertiary butyl ester is a known and valuable pharmaceutical intermediate useful for the preparation of atorvastatin calcium.

and its use as an intermediate for the preparation of atorvastatin by using specific synthesis procedure. EP 330172 describes the preparation of (4R-Cis)-6- [2-[3-phenyl-4-
EP 330172 discloses (4R-Cis)-6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-{4-fluorophenyl)-5-(1-methylethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-yl-acetic acid tertiary butyl ester of formula (I)

(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-pyrrol-1-yl]-ethyl]-2, 2-dimethyl- [1, 3] -dioxane-4-yl-acetic acid tertiary butyl ester (I) by reacting [(4R, 6R)-6-(2-aminoethyl)-2,2-dimethyl-[1,3]-dioxan-4-yl]acetic acid tertiary butyl ester (II) of the formula

with 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide (III) of the formula

in a 9: 1 mixture of heptane and toluene with heating to reflux for 24 hours, cooling the reaction mixture, adding 2- propano! and isolating the precipitated product by filtration.
U.S. Pat. No 5,155,251 and U.S. Pat. No 5,103,024 disclose the process of preparation of (4R-Cis)-6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl) -5-(1-methylethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-yl-acetic acid tertiary butyl ester (I) as per details given in EP 330172.
The reference, Tetrahedron Letters Vol. 33. no. 17, 2283-2284 (1992) discloses the reaction of [(4R, 6R)-6-{2-aminoethyl)-2,2-dimethyl-[1,3]-dioxan-4-yl]acetic acid tertiary butyl ester (II) with 2- [2- (4-fluorophenyl)- 2- oxo- 1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide (III) in a 1: 4: 1 mixture of toluene, heptane and tetrahydrofuran in the presence of pivalic acid as catalyst. The isolation of the product from the reaction mixture is not described and the physical form of the product is not mentioned.

WO 03/024959 publication discloses new crystalline Forms I and II of the compound of formula (I), and a process of preparation thereof. The disclosed process uses organic solvents for the preparation of crystal polymorphs of compound shown in the formula (I).
However, the existence, and possible numbers, of polymorphic forms for a given compound cannot be predicted. In addition, there are no "standard" procedures that can be used to prepare polymorphic forms of a substance.
It has always been a challenge to the synthetic chemist to produce stable, pure amorphous form of atorvastatin or its pharmaceutical^ acceptable salts.
Thus, there is a need to provide novel crystalline forms of (4R-Cis)-6- [2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-{1-methylethyl)-pyrrol-1-yl]- ethyl] -2,2-dimethyl-[1, 3]-dioxane-4-yl-acetic acid tertiary butyl ester (I) and its use for the preparation of atorvastatin or its pharmaceutically acceptable salts.
SUMMARY OF THE INVENTION
In one aspect, the specification discloses a crystalline Form X of (4R-Cis)-6- [2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-pyrrol-1-yl] ethyl]-2, 2-dimethyl-[1,3]-dioxane-4-yl-acetic acid tertiary butyl ester having an X-ray powder diffraction substantially the same as shown in Fig. 1.
In another aspect, the specification discloses a crystalline Form Y of (4R-Cis)-6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-yl-acetic acid tertiary butyl ester having an X-ray powder diffraction substantially the same as shown in Fig. 2.
In one aspect, the specification discloses a process for the preparation of crystalline Form X comprising the steps of:

(a) mixing (4R-Cis)-6- [2- [3-phenyl-4-(phenylcarbamoyl)-2- {4-fluorophenyl)-5-1-methylethyl)-
pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]- dioxane-4-yl-acetic acid tertiary butyl ester with isopropyl
alcohol;
(b) heating the mixture of step (a);
(c) cooling the solution of step (b) gradually to room temperature and below room temperature;
(d) filtering the solution of step (c);
(e) optionally washing solid filtered in step (d) with isopropyl alcohol;
(f) drying the solid obtained in step (e) to obtain the crystalline Form X.
In another aspect, the specification discloses a process for the preparation of crystalline Form Y comprising the steps of:
(a) mixing crystalline Form X of (4R-Cis)-6-[2-[3-phenyl-4- (phenylcarbamoyl)-2-(4-
fluoropheny!)-5-(1-methylethyl)-pyrrol-1-yl]-ethyl]-2, 2-dimethyl-[1,3]-dioxane-4-yl-acetic acid
tertiary butyl ester or (4R-Cis)-6- [2- [3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-
methylethyl)-pyrrol-1-yl]-ethyl] -2,2-dimethyl-[1,3]-dioxane-4-yl-acetic acid tertiary butyl ester in
methanol;
(b) heating the mixture of step (a);
(c) cooling the solution of step (b) gradually to room temperature and below room temperature;
(d) filtering the solution of step (c);
(e) optionally washing solid filtered in step (d) with methanol;
(f) drying the solid obtained in step (e) to obtain the crystalline Form Y.
In another aspect, the specification discloses a process for preparing a atorvastatin calcium comprising:
a) providing a solution in a solvent of crystalline Form X, crystalline Form Y or mixture thereof;
b) deprotecting two hydroxy groups;
c) deprotecting the carboxylic acid group; where steps b) and c) may be performed in either order;
d) adding a salt solution;
e) precipitating the salt of atorvastatin.

DESCRIPTION OF THE DRAWINGS
Figure 1: An X-ray powder diffraction pattern of crystalline Form X (4R-Cis)-6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1t3]-dio-xane-4-yl-acetic acid tertiary butyl ester (compound of the formula I) obtained from Example 2.
Figure 2; An X-ray powder diffraction pattern of crystalline Form Y (4R-Cis)-6-f2-(3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[113]-dio-xane-4-yl-acetic acid tertiary butyl ester (compound of the formula I) obtained from Example 3.
DETAILED DESCRIPTION OF THE INVENTION
The terms "crystalline Form X, crystalline Form Y" means crystalline forms X, Y of (4R-Cis)-6-[2-
[3-phenyl-4-(phenylcarbamoyl)-2-(4-fiuorophenyl)-5-(1-methylethyl)-pyrrol-1-yl]-ethylI-2,2-
dimethyl-[1,3]-dioxane-4-yl-acetic acid tertiary butyl ester, respectively.
The powder diffraction patterns of crystalline Forms X and Y were obtained with X'Pert PRO
Panalytical X-ray powder diffractometer.
(4R- Cis) -6- [2 - [3-phenyl - 4 - (phenylcarbamoyl) - 2 - (4 - fluorophenyl) - 5-(1-methylethyl)-
pyrrol-1-yl]- ethyl] -2, 2-dimethyl- [1, 3]- dioxane-4-yI-acetic acid tertiary butyl ester can be
prepared by process as described in EP 330172 or Tetrahedron Letters, Vol. 33, No. 17, 2283-
2284(1992).
One embodiment of the specification discloses a crystalline Form X of (4R-Cis)-6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5- <1-methylethyl)-pyrrol-1-yl]- ethyl] -2, 2-dimethyl- [1, 3]- dioxane-4-yl-acetic acid tertiary butyl ester. The crystalline Form X has an X-ray powder diffraction pattern as expressed in Table 1 and Fig. 1.
Table 1:
[°28] d-spacing[°
A] Relative Intensity. [%]
6.5409 13.51361 4.68
7.0676 12.50757 100.00
7.1842 12.30491 5.64
9.5817 9.23068 0.67
10.4604 8.45722 0.36
11.5844 7.63903 25.04
11.7980 7.50122 1.44
12.2864 7.20411 6.74
12.6914 6.98056 36.46

13.2861
6.66418 8.61
14.3979 6.15198 74.82
15.1259 5.85750 10.91
15.2504 5.80997 6.67
16.5269 5.36397 7.92
16.6940 5.31066 3.58
17.3881 5.10020 9.40
17.5370 5.05723 13.46
17.6803 5.01655 15.29
17.9901 4.93086 24.09
18,7044 4.74414 10.89
18.8924 4.69735 7.67
19.1414 4.63682 10.20
19.4061 4.57415 4.92
20.0012 4.43940 7.34
20.3091 4.37277 23.22
20.9334 4.24375 3.76
21.4744 4.13804 26.45
21.8838 4.06155 7.35
22.4025 3.96866 8.62
22.7810 3.90359 24.67
23.0230 3.86354 19.20
23,9713 3.71238 2.26
24.4807 3.63627 4.12
24.9772 3.56510 3.30
25.5107 3.49174 19.50
25.8053 3.45255 2.79
26.2295 3.39767 4.72
26.5482 3.35759 2.69
27.7631 3.21337 4.89
28.1623 3.16873 4.92
28.5619 3.12529 6.54
29.4335 3.03470 2.49
29.8956 2.98884 3.38
30.4928 2.93165 0.85
32.1340 2.78556 2.55
32.7975 2.73072 1.54
33.7431 2.65632 1.30
34.6296 2.59033 1.42
36.0654 2.49043 3.67
36.4988 2.46185 1.81
37.5785 2.39356 1.39
39.3825 2.28798 1.37
The crystalline Form X of (4R-Cis)-6-[2- [3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-pyrro!-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-yl-ace-tic acid tertiary butyl ester

may be characterized by X-ray powder diffraction pattern having peaks at 9.5, 16.6 ,24.9 and 34.6 ±0.1 °2θ.
In another embodiment, the specification discloses a crystalline Form Y of (4R-Cis)-6-[2-[3-phenyl-4-(phenylcarbamoyl)'2-(4-fluorophenyl)-5-(1-methyl-ethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-yl-acetic acid tertiary butyl ester. The X-ray powder diffraction pattern of a crystalline Form Y is as expressed in Table 2 and Fig. 2. Table 2:

[o2θ] d-spacing[° A] Relative Intensity. [%]
7.1253 12.40647 1.41
9.1054 9.71250 2.29
9.9791 8.86395 100.00
11.2821 7.81303 3.32
11.4652 7.71816 2.07
12.3693 7.15602 0.49
13.2917 6,66140 3.11
14.3504 6.17226 1.03
14.9793 5.91449 2.62
15.4442 5.73750 4.42
16.0025 5.53397 1035
17.7671 4.98813 7.07
17.9421 4.93985 9.84
18.4296 4.81029 18.70
18.8297 4.70895 11.64
19.3066 4.59369 27.01
19.8232 4.47515 6.86
20.3801 4.35410 5.86
20.6339 4.30110 2.60
21.2294 4.18178 3.96
21.6337 4.10454 5.76
22.2415 3.99372 3.93
23.0821 3.85014 4.55
23.9026 3.71981 2.72
24.3990 3.64524 1.66
25.1929 3.53241 3.01
26.2015 3.39841 2.86
27.0610 3.29240 2.94
27.8836 3.19711 4.72
28.1877 3.16330 6.40
28.4792 3.13159 1.75
28.7544 3.10224 1.56
29.4867 3.02684 1.06
30.7788 2.90265 3.08
31.3671 2.84954 0.87

32.3729 2.76327 0.83
33.0455 2.70854 2.24
33.7108 2.65660 1.81
34.1326 2.62472 1.33
35.4817 2.52796 0.93
36.9718 2.42942 1.41
38.1546 2.35678 0.72
38.9371 2.31120 0.30
The crystalline Form Y of (4R-Cis)-6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methy[ethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyI-[1,3]'dioxane-4-yl acetic acid tertiary butyl ester (crystalline Form Y), may be characterized by X-ray powder diffraction pattern having peaks at 10.0,20.6,26.2 and 28.7 ± 0.1 ° 2θ.
Another embodiment of the specification discloses a process for the preparation of crystalline Form X comprising the steps of:
(a) mixing (4R-Cis)-6- [2- [3-phenyl-4- (phenylcarbamoyl)-2- (4-fluorophenyl)-5- (1-methylethyl)-pyrrol-1-yl]- ethyl] -2, 2-dimethyl- [1, 3]- dioxane-4-yl-acetic acid tertiary butyl ester with isopropyl alcohol;
(b) heating the mixture of step (a);
(c) cooling the solution of step (b) gradually to room temperature and below room temperature;
(d) filtering the solution of step (c);
{e) optionally washing solid filtered in step (d) with isopropyl alcohol; (f) drying the solid obtained in step (e) to obtain the crystalline Form X.
The starting material, (4R-Cis)-6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4- fluorophenyl)-5-{1-methylethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-yl-acetic acid tertiary butyl ester, can be prepared by processes well known in art, is mixed with isopropyl alcohol. The dissolution by heating may be carried out at any temperature range. Preferably, the dissolution may be carried out by heating at 20° - 85° C, more preferably at 45° - 50° C,
The solution may be cooled gradually or stepwise. The solution may be cooled to a first temperature of about 20° - 30° C over a period of 1 - 2 hours with stirring, followed by further cooling to a second temperature range of about 0° - 5°C over a period of 1-2 hours with stirring.

(4R-Cis)-6- [2- [3- [phenylcarbamoyl)-2- (4-fluorophenyl)-5- (1-methylethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-yl acetic acid tertiary butyl ester can be isolated from the reaction mixture by filtration. After filtration, the solid can be optionally washed with isopropyl alcohol. After washing, the solid can be dried. Any drying technique known to a person skilled }n the art may be used. Preferably, suck drying for about 20 to 40 minutes, more preferably for 30 minutes, followed by further drying under vacuum at about 40° - 45° C for about 8 hours to obtain crystalline Form X.
In another aspect, the specification discloses a process for the preparation of crystalline Form Y comprising the steps of:
(a) mixing crystalline Form X of (4R-Cis)-6- [2- [3-phenyl-4- (phenylcarbamoyl)-2- (4-
fluorophenyl)-5- (1-methylethyl)-pyrrol-1-yl]- ethyl] -2, 2-dimethyl- [1, 3]- dioxane-4-yl-acetic acid
tertiary butyl ester or (4R-Cis)-6- [2- [3-phenyl-4- (phenylcarbamoyl)-2- (4-fluorophenyl)-5- (1-
methylethyl)-pyrrol-1-yl]- ethyl] -2, 2-dimethyl- [1, 3]- dioxane-4-yl-acetic acid tertiary butyl ester
in methanol;
(b) heating the mixture of step (a);
(c) cooling the solution of step (b) gradually to room temperature and below room temperature;
(d) filtering the solution of step (c);
(e) optionally washing solid filtered in step (d) with methanol;
(f) drying the solid obtained in step (e) to obtain the crystalline Form Y.
The specification provides a process for the preparation of a crystalline Form Y wherein (4R-Cis)-6-[2-[3-phenyl-4-(phenylcarbarnoyl)-2-(4-fluorophenyl)-5- (1-methylethyl)-pyrrol-1-yl]-ethyl] -2,2-dimethyl-[1,3]-dioxane-4-yl-acetic acid tertiary butyl ester or Form X of (4R-Cis)-6- [2- [3-phenyl-4- (phenylcarbamoyl)-2- (4-fluorophenyl)-5- (1-methylethyl)-pyrro!-1-yl]- ethyl] -2, 2-dimethyl- [1,3]- dioxane-4-yl-acetic acid tertiary butyl ester is mixed with methanol.
The dissolution may be carried out by heating at any temperature range. Preferably, the dissolution may be carried out by heating at 20° - 65° C, more preferably at 60° - 65° C.
The solution can be filtered over hyflow bed and the residue on the filter bed can optionally be washed with a solvent, preferably methanol.

The solution may be cooled gradually or stepwise. The solution may be cooled to a first temperature of about 20° - 35° C over a period of 1 - 2 hours with stirring, followed by further cooling to a second temperature range of about 0° - 5oC over a period of 1-2 hours with stirring.
The Form Y may be isolated by filtration, followed by washing with chilled methanol. The drying may be carried out at temperature of about 40° - 50° C, preferably at about 40° - 45° C, under vacuum for about 6 to 8 hours.
In another embodiment, the specification discloses a process for preparing a atorvastatin calcium comprising:
a) providing a solution in a solvent of crystalline Form X, crystalline Form Y or mixture thereof;
b) deprotecting the two hydroxy groups;
c) deprotecting the carboxylic acid group; where steps b) and c) may be performed in either order;
d) adding a salt solution;
e) precipitating atorvastatin calcium.
The crystalline Forms X, Y or mixture thereof may be used as a starting material for the preparation of atorvastatin salt. Preferably, the crystalline Form Y is dissolved in a non-hydroxyltc solvent. Preferably, the crystalline Form Y is dissolved in 100 ml to 300 ml per 10 g of crystalline Form Y of a non-hydroxylic solvent. The solvent may be cyclohexane, acetonitrile, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, toluene, n-heptane, n-hexane or a mixture of these solvents.
The deprotection of the two hydroxy groups in the side-chain (in the 3-and 5-positions) of the compound of Formula (I) can be conveniently performed by the addition of an acid such as diluted hydrochloric acid or sulfuric acid, trifluoroacetic acid, formic acid, propanoic acid, or para-toluenesulfonic acid. The resulting solution may be kept, preferably while being mixed by stirring, agitating or shaking the solution, at a temperature from about 5° - 40° C, preferably at a room temperature so that the compound (I), may no longer be detectable by thin-layer chromatography (TLC). Then, the deprotection of the carboxylic acid group, can be carried out by adding a base. The base may be an alkali metal hydroxide or alkaline earth metal hydroxide, for example sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and

the tike, to the solution to adjust the pH value of the solution at pH = 12-12.5. The resulting solution may be kept, preferably while being mixed by stirring, agitating or shaking the solution, at a temperature of from 5° - 60° C, preferably 40° - 45° C. till the carboxylic acid group protected compound is no longer detectable by thin-layer chromatography (TLC). Deprotection of carboxyl and hydroxy groups can be performed in either order.
0.01 M to 1M, preferably 0.5M aqueous solution of a salt can be added to the reaction mixture containing the free atorvastatin acid to obtain the preferred salt form of atorvastatin. A suitable calcium salt, preferably calcium acetate, calcium citrate, calcium oxalate, calcium chloride or calcium iodide can be used. The addition can be carried out over a period of 0.5 to 1 hour at about 25°-60° C.
After the addition water is complete, the resulting the reaction mass may be then filtered after cooling to about 20° - 30° C. The resulting wet cake can be dried under vacuum to give the atorvastatin salt. The preferred salt is atorvastatin calcium.
Atorvastatin or salts thereof can also be prepared as process disclosed in U.S.Pat.No.5,273,995.
The polymorphic forms of (4R-Cis)-6-[2-[3-[phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl) pyrrole-1-y1]-ethyl]-2, 2-dimethyl-[1,3]-dioxane-4-ylacetic acid-t-butyl ester produced by the above process are highly pure, suitable for industrial scale-up and can be used to prepare atorvastatin or salts thereof.
The following examples illustrate certain embodiments in greater detail, and are not intended to limit the scope of the invention.
Example 1
Preparation of (4R-Cls)-6-[2-[3-[phenylcarbamoyl)-2-{4-fluorophenyl}-5-(1 -methylethyl)
pyrrole-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-ylacetic acid tert-butyl ester:
Tetrahydrofuran (252 ml), toluene (252 ml) and 2- [2-(4-fluorophenyl) - 2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide (150 g) were charged at room temp in a reaction vessel. [(4R, 6R)-6-(2-Aminoethy!)-2,2-dimethyl-[1,3]-dioxan-4-yl]acetic acid tertiary butyl ester (102 g) was added to the reaction mixture. Subsequently, n-heptane (1011 ml) and pivalic acid

(22.66 g) were added to the reaction mixture at room temperature. The reaction mixture was
heated to reflux (83° - 86° C) in 30 minutes and stirred at reflux (83° - 86° C) for 48 hrs. The
reaction mass was cooled to 20° C and toluene (1500 ml) and 0.5 N aqueous sodium hydroxide
solution (510 ml) was added at 20° C to the cooled mass. The reaction mass was stirred for 15
minutes at 20° C and allowed to settle. The aqueous and organic layers were separated. 0.5 N
hydrochloric acid (710 ml) was added to the organic layer at 20° C. The reaction mass was
stirred for 15 minutes at 20° C and settled to subsequently separate the aqueous and organic
layers. The organic layer was treated twice by adding 10% of calcium chloride solution (510 ml)
at 20° C, stirring for 15 minutes and settling to subsequently separate the aqueous and organic
layers. Activated charcoal (5.1 g) was added to the organic layer at 30° - 33° C and stirred for 10
minutes. The solution was filtered over hyflow bed followed by washing the bed with toluene (50
ml). Toluene was distilled out under vacuum at 60° - 70° C till 500 g material was left in the
flask. Isopropyl alcohol (510 ml) was added to the reaction mixture and subsequently distilled
out under vacuum at 45° - 50° C till 500 g material was left in the flask. Isopropyl alcohol (810
ml) was added to the reaction mixture and stirred for 15 minutes to get clear solution at room
temperature. Water (600 ml) was added slowly to the reaction mixture at 30° - 35° C in 1 hour.
The solution was cooled slowly to 24° - 26° C in 2 hours and filtered at 24° - 26° C to obtain (4R-
Cis)-6-[2-[3-[phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl) pyrrole-1-yl]-ethyl]-2,2-
dimethyl-[1,3]-dioxane-4-ylacetic acid tert-butyl ester as solid. The solid was added into a reaction vessel and isopropyl alcohol (20 ml) and water (160 ml) were added to it. The reaction mixture was stirred for 5 minutes, filtered and suck dried for 30 minutes. The product obtained was dried under vacuum at 40° - 45° C for 8 hours till the moisture content was less than 0.5% to obtain crystalline Form X.
Example 2
Preparation of (4R-Cis)-6-[2-[3-[phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1 -methylethyl)
pyrrole-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-ylacetic acid tert-butyl ester:
Cyclohexane (800 ml) and ±4-fluoro-a-(2-methyl-1-oxopropyl)-Y-oxo-N,(3-
diphenylbenzenebutaneamide (100 gm) were charged in round bottom flask at 25-30°C. Subsequently (4R-cis)-1, 1-dimethylethyl-6-(2-aminoethyf)-2,2-dimethyl-1,3-dioxane]-4-acetate (65.5 gm) and cyclohexane (100 ml) solution were charged to the reaction mass at 25-30° C. The temperature was raised to 50-55oC. Pivalic acid (15.5 gm) and cyclohexane (100 ml) solution was added at 50-55°C within 30 minutes. The temperature was raised to reflux (80-85oC). The reaction mass was refluxed for 48 hours and cooled to 60-65°C. Cyclohexane was

completety distilled out at 60 - 65° C under vacuum. The residue was cooled to 45-50°C. Isopropanol (200 ml of) was charged to the residue at 45-50°C.The reaction mass was further stirred for 30 minutes at 45-50°C. Isopropanol was completely distilled out at 45 - 50°C under vacuum to obtain {4R-Cis)-6-[2-[3-[phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl) pyrrole-1-yl]-ethyl]-2, 2-dimethyl-[1, 3]-dioxane-4-ylacetic acid tert-butyl ester as residue. The residue was added into a reaction vessel and isopropyl alcohol (400 ml) was added to it. The solution was heated to 45 - 50° C for 30 minutes under stirring. The solution was cooled to 25° -30° C slowly in 1 hour under stirring. The solution was further cooled to 0° - 5° C in 1 hour under stirring. The reaction mass was then filtered and the bed was washed with chilled isopropyl alcohol (50 ml). The solid was dried at 40° - 45° C for six hours under vacuum to obtain crystalline Form X. Dry weight: 100 g.
Example 3
Preparation of {4R-Cis)-6-[2-[3-[phenylcarbamoyl)-2-(4-fluorophenyl)-5-{1 -methylethyl)
pyrrole-1-yl]-ethyl]-2, 2-dlmethyl-[1, 3]-dioxane-4-ylacetic acid tert-butyl ester (Crystalline
Form Y):
Crystalline Form X (100 g) of example 1 or 2 was dissolved in methanol (400 mi) at room temperature. The solution was heated to 60° - 65° C for 30 minutes. The solution was filtered at a temperature of 60° - 65° C over hyflow bed and the bed was washed with methanol (25 ml). The solution was cooled to 25° - 30° C slowly in 1 hour under stirring. The solution was further cooled to 0° - 5° C. in 1 hour under stirring. The reaction mass was then filtered and the bed was washed with chilled methanol (50 ml). The residue was dried at 40° - 45° C for 6 hours under vacuum to obtain crystalline Form Y. Dry weight: 82 g.
Example 4
Preparation of atrovastatin calcium
Acetonitrile (750 ml) and crystalline form Y of (4R-Cis)-6-[2-[3-[phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)pyrrole-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-ylacetic acid tert-butyl ester (100 gm) were charged to the reaction vessel at 25-30sC. The temperature was raised to 35-40°C (Clear solution observed). The reaction mass was cooled to 25-30°C. Conc. HCI (20.0 gm) and R.O. water (180 ml) were added within 30 minutes at 25-30°C.The reaction mass was stirred for 4.0 hours at 25-30°C. Sodium hydroxide solution (20 gm sodium hydroxide

was added to 50 ml water) was added to the above reaction mixture slowly. The temperature was raised to 40-45°C. The reaction mass was further stirred at 40-45°C for 2.0 hours. The reaction mass was cooled to 40°C. The solvent was distilled out completely under vacuum at below 40°C. Methanol (200 ml) was charged to the residue and stirred for 30 minutes at below 40°C. Methanol was distilled out completely under vacuum at below 40°C. Methanol (700 ml) was charged to the residue and stirred for 30 minutes at below 40°C to get clear solution and cooled to 25 - 30°C. Water (800 ml) and TBME (tertiarybutylmethylether) (900 ml) were added to the reaction mass at 25 - 30°C. The reaction mass was stirred for 15 minutes at 25-30°C and settled for 5 minutes at 25-30°C. The layers were separated. TBME (300 ml) was charged to the aqueous layer at 25-30°C. The reaction mass was stirred and settled for 15 minutes at 25-30°C. The layers were separated. The pH of aqueous layer was adjusted to 8.3-8.7 with 1 N HCi solution at 25-30°C. The temperature was raised to 50-55°C. Calcium acetate (13.3 gm) and water (480 ml) was added to reaction mass within 30-40 minutes. The reaction mass was stirred for 30 minutes at 50-55°C and cooled to 25-30°C within 2.0 hours. Water (110 ml) was charged to the reaction mass for 4.0 hours at 25-30°C and the reaction mass was stirred for 6.0 hours at 25-30°C. The product was filtered over buchner funnel. The wet cake was washed with methanol: water (1:2) and dried for 30 minutes. Wet weight: 210.0-220.0 gm. The compound was dried under vacuum at 25-30°C for 6.0 hours and was dried under vacuum at 40-45°C till KF is 6-8%. Dry Weight: 65.0 to 70.0 gm.
Ethyl acetate (1000 ml) and crude atorvastatin calcium (100 gm) obtained from above were charged at 25-30° C. The temperature was raised to 60-65° C and stirred for 30 minutes at 60-65° C. The reaction mass was cooled to 25-30°C. The reaction mass was filtered over hyflow bed at 25-30° C and washed the bed with ethyl acetate (50 ml) at 25-30°C (Solution A). Cyclohexane (2000 ml) was charged in other round bottom flask at 25-30° C and cyclohexane was stirred at 25-30° C. So)ution-A was added to the cyclohexane within 30-40 minutes at 25-30° C. The reaction mass was stirred for 1.0 hour at 25-30X. The product was filtered over Buchner funnel. The wet cake was washed with cyclohexane (100 ml) and dried for 30 minutes. Wet weight: 110.0 gm. The compound was dried under vacuum at 25-30° C for 8.0 hours. Dry weight: 95.0 to 98.0 gm. The compound was sieved with 100 mess sieve at 25-30° C. The compound was milled at 25-30° C for 2 times. The milled compound was dried under vacuum at 50-55° C. Dry Weight: 45 to 47 gm.

WE CLAIM:
1. A crystalline Form X of (4R-Cis)-6- [2- (3-phenyf-4- (phenylcarbamoyf)-2- (4-fluorophenyl)-5-(1-methylethyl)-pyrrol-1-yl]- ethyl] -2, 2-dimethyl- [1, 3]- dioxane-4-yl-acetic acid tertiary butyl ester having an X-ray powder diffraction pattern substantially the same as shown in Fig. 1.
2. The crystalline Form X of (4R-Cis)-6- [2- [3-phenyl-4- (phenylcarbamoyl)-2- (4-fluorophenyl)-5- (1-methylethyl)-pyrrol-1-yl]- ethyl] -2, 2-dimethyl- [1, 3]- dioxane-4-yl-acetic acid tertiary butyl ester of claim 1, having an X-ray powder diffraction pattern comprising peaks at about 9.5, 16.6, 24.9 and 34.6 ±0.1o2θ.
3. A crystalline Form Y of (4R-Cis)-6-[2-[3-phenyl-4-(phenylcarbarnoyl)-2-(4-fluorophenyl)-5- (1-methylethyl)-pyrrol-1-yl]-ethyf]-2,2-dimethyt-[1,3]-dioxane-4-yl-acetic acid tertiary butyl ester having an X-ray powder diffraction pattern substantially the same as shown in Fig. 2.
4. The crystalline Form Y of (4R-Cis)-6-[2-[3-phenyl-4- (phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dioxane-4-yl-acetic acid tertiary butyl ester of claim 2, having an X-ray powder diffraction pattern comprising peaks at about 10.0, 20.6, 26.2 and 28.7 ±0.1 "2θ.
5. A process for the preparation of crystalline Form X of (4R-Cis)-6-[2-l3-phenyl-4-
(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]-dio-
xane-4-yl-acetic acid tertiary butyl ester comprising steps of:
(a) mixing (4R-Cis)-6-[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(1 -
methylethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl-[1,3]- dioxane-4-yl-acetic acid tertiary butyl
ester with isopropyl alcohol;
(b) heating the mixture of step (a);
(c) cooling the solution of step (b) gradually to room temperature and below room temperature;