IMPROVED PROCESSES FOR THE PREPARATION AS WELL AS PURIFICATION
OF ATORVASTATIN CALCIUM & ITS INTERMEDIATE
FIELD OF INVENTION:
The present invention relates to the improved process for the preparation as well purification of
Atorvastatin key intermediate tert-Butyl(4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-
4-(phenylcarbarnoyl) pyrrol- 1 -yl]ethyl]-2,2-dimethyl- 1,3-dioxan-4-yllacetate (Formula 11) which
results in high purity of this intermediate and can be used for preparation of various polymorphic
forms of Atorvastatin calcium of high purity. Furthermore the present invention reports the
improved process for Atorvastatin calcium which results in critical impurities especially (4Rcis)-
1 , 1 -dimethylethyl-6-[2-[2-(4-fluoropheny1)-5-(1 -methylethyl)-3 -phenyl-
4[(phenylamino)carbonyl] 1 H-pyrrol- 1 -yl] ethyl]- 1,3-dioxane-4-heptanoic acid calcium salt
impurity (Imp I) or (~~GR)-2-(4-Fluorophenyl)-6-hydroxy-~-Methoxy-5--M(e1t hylethyl)-3-
phenyl-4-[(phenylamino)-carbonyll- 1 H-pyrrole- 1 -heptanoic Acid Calcium Salt impurity (Imp
11) below the specified limit during the reaction. It ultimately avoids the yield loss during
purification of Atorvastatin calcium, to remove these impurities (I & 11). The present invention
also relates to an improved purification process for atorvastatin calcium to reduce / remove all
the critical impurities.
Imp I
Imp I1
BACKGROUD OF INVENTION:
Atorvastatin Calcium (Formula I) is manufactured according to published patents (US patents
Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,25 1; 5,216,174;
5,245,047 ; 5,248,793; 5,397,792; 5,342, 952) usually from the sodium salt of [R-(R*,R*)]- 2-
(4-fluoropheny1)-P,G-dihydroxy-5-(1 -methylethyl)-3-phenyl-4-[(phenylarnino)carbonyl]- 1 Hpyrrole-
1-heptanoic acid and a suitable, water soluble calcium salt, preferably fiom calcium
acetate or chloride.
A number of patents and published International Patent Applications have issued describing
atorvastatin calcium in amorphous as well as in crystalline forms, formulations of atorvastatin
calcium, as well as processes for atorvastatin calcium and key intermediates for preparing
atorvastatin calcium. These include: United States Patent Numbers 4,681,893; 5,003,080;
5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,25 1 ; 5,216,174; 5,245,047; 5,248,793;
5,273,995; 5,280,126; 5,298,627; 5,342,952; 5,397,792; 5,446,054; 5,470,981; 5,489,690;
5,489,691; 5,5 10,488; 5,686,104; 5,969,156; 5,998;633; 6,087,511; 6,121,461; 6,126,971;
6,433,213; 6,476,235; 6,528,660; 6,600,05 1 ; 6,605,759; 6,613,916; 6,646,133; 6,730,797;
6,867,306; 6,891,047; W099132434; W001136384; W002141834; W002143667; WOO2143732;
WOO21051804; W0021057228; WOO21057229; W0021057274; W002/059087; WOO21083637;
WOO21083638; WOO3101 1826; WOO31050085 and WOO3107072 .
Patent US 6,528,660; US 6,613,916; US 6,646,133; WOO31018547 and WOO31078379 described
the process for the preparation of amorphous Atorvastatin calcium.
US Patent US 7,674,923 of Teva describes the process of manufacturing of Atorvastatin calcium
free from impurities specially Atorvastatin epoxy dihydroxy.
US 7,193,090 of Apotex describes a novel method of preparation of Atorvastatin calcium via
novel intermediates. This process claims to use cost effective and safe reagents in the preparation
of the API unlike the patents as described above.
U.S. Pat. No. 7,208,608 B2 discloses a method of manufacturing an amorphous form of the
hemi-calcium salt of (3R,5R)-7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophe-nyl)-5-isopropylpyr-
rol- 1 -yl]-3,5-dihydroxyheptanoic acid.
U.S. Pat. No. 7,208,608 of Zentiva provides the process for preparation of atorvastatin calcium in
amorphous form. However, the patent discloses the extraction of sodium salt with ethyl acetate
or crystallization of sodium salt of atorvastatin in ethanol followed by treatment with ethyl
acetate, which results in increased atorvastatin lactone content due to acid produced during
hydrolysis of ethyl acetate.
WO 201 11131605 & WO 201 11131601 of DSP IP also report several methods to reduce the
different impurities such as Atorvastatin o-methyl, Atorvastatin ketal & Atorvastatin lactone.
Both Ketal and o-Methyl are reduced by extending the recovery time at different temperature
after deprotection of tert-Butyl(4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenyl carbamoyl) pyrrol- 1 -yl]ethyl]-2,2-dimethyl- 1,3 -dioxan-4-yllacetate (Formula 11) with dil
hydrochloric acid and lactone is reduced by provision of additional washing after hydrolysis of
deprotected starting material. It deploys use of ether such as dibutyl ether, diethyl ether, methyl
ether etc for washing.
Another patent US 8,115,015 of Cadila Healthcare described the preparation amorphous
Atorvastatin calcium using tert-Butyl(4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenylcarbamo yl) pyrrol- 1 -yl]ethyl]-2,2-dimethyl- 1,3-dioxan-4-yllacetate (Formula 11) as
starting raw material and using acetonitrile as solvent for its deprotection & further hydrolysis
with caustic and reaction with an calcium salt to give atorvastatin calcium. This was extracted by
ethyl acetate & its recovery was done. Finally the material was crystallized in cyclohexane and
filtered & dried to give pure Atorvastatin calcium amorphous. Use of various antioxidants such
as Butylated hydroxy anisole, Butylated hydroxy toluene etc is also done.
Although Atorvastatin hemi calcium salt of formula (I) can be prepared by various methods
described in the above mentioned patents but the product obtained is not of high purity. The
purity of the active ingredient is an important factor for manufacturing the safe and effective
pharmaceutical formulation, especially if the product is taken on a longer term basis in the
treatment or prevention of high plasma cholesterol. The accumulation of the impurities from the
pharmaceutical product of lower purity may cause many side effects during the medical
treatment. Therefore, there is a need to develop improved processes for preparation as well as
purification of compound of Atorvastatin and its key intermediate tert8utyl(4R,6R)-2-[[[6-(2-4-
fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pynol-1 - yl]ethyl]-2,2-dimethyl- 1,3-
dioxan-4-yllacetate (Formula 11), which can produce highly pure Atorvastatin hemi calcium salt
in lab as well as commercial scale in high yield.
SCOPE OF THE INVENTION:
The present invention describes improved processes for the preparation of Atorvastatin calcium.
This invention also describes the purification process for its key intermediate to improve its
I
purity. The aim of the present invention is to provide improved processes for control of critical
impurities (Imp I & 11) during manufacturing of Atorvastatin calcium. This involves control on
these critical impurities using different solvent systems during reaction.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, an improved process for the
I purification of Atorvastatin intermediate tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-
isopropyl-3-phenyl-4-(phenylcarbamoy1)pyrrol1- - yl]ethyl]-2,2-dimethyl-1 ,3-dioxan-4-yllacetate
(Formula 11) which comprises:
1) dissolving tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenylcarbamoy1)pyrrol- 1 -yl]ethyl]-2,2-dimethyl- 1,3-dioxan-4-yllacetate (Formula 11)
in an aliphatic ketone at elevated temperature
2) charcolization of resulting layer of step (1) followed by its filtration through hyflowbed
3) recrystallization of product from filtrate of step (2) by adding water
4) isolation of product by usual filtration
5) drying of wet cake of step (4) at 55-60 "C to get highly pure tert-Butyl(4R6R)-2-[[[6-(2-
4-fluorophenyl)-5-isopropyl-3-phenyl-4-@henylcarbamoyl)pyrrol-1 - yl]ethyl]-2,2-
dimethyl- l,3-dioxan-4-yllacetate (Formula 11).
According to one aspect of present invention, the aliphatic ketone used in step (1) above may be
selected from acetone, methyl ethyl keone, 2-butanone, methyl isobutyl ketone, diethyl ketone,
dipropyl ketone, dibutyl ketone or a mixture thereof.
According to another aspect of present invention, the most suitable aliphatic ketone used is
acetone.
According to yet another aspect of present invention, the temperature used for dissolution in step
(1) is preferably 30-60 "C, more preferably 30-40 "C & most preferably 35-40 "C.
The atorvastatin intermediate tert-Butyl(4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-
4-(phenylcarbamoyl)pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate (Formula 11) used
for purification was prepared as per process reported in literature, which comprises:
1) dissolving (4R-Cis)-l , 1 -Dimethylethyl-6-(2-aminomethyl)-2,-dimethyl-1 , 3 d o x e -4-
Acetate & 4-Fluoro-a-[2-methyl-1-oxopropyl]y-oxo-N-~-diphenylbenzenebutaiind e
cyclohexane.
2) heating to 75-80 "C and addition of pivalic acid.
3) heating under reflux for 60-72 hours for reaction completion.
4) cooling the reaction mass to 35-40 "C.
5) quenching of reaction mass in sodium bicarbonate followed by layer separation and
washing of organic layer with water and sodium bicarbonate 10% solution, followed by
complete recovery of cyclohexane to get residue.
6) Isolating tert-Butyl(4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenyl
carbamoy1)pyrrol- 1 -yl]ethyl]-2,2-dimethyl- 1,3-dioxan-4-yllacetate (Formula 11) by
recrystallization in isopropyl alcohol.
According to the second embodiment of the present invention, an improved process for the
preparation of Atorvastatin calcium which comprises:
1) dissolving pure tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenylcarbamoy1)pyrrol- 1 -yl]ethyl]-2,2-dimethyl-l,3-dioxan-4-yl]acetate (Formula 11)
in CI-C4 aliphatic alcohol and an aliphatic organic nitrile.
9
2) heating to get clear solution and stirring further for 1 hour
3) cooling to 15-20 OC and addition of aq. hydrochloric acid at 20-30 "C.
4) stirring at 30-40 "C till reaction completion.
5) dropwise addition of caustic solution to the reaction mass of step (4).
6) Stirring at 30-40 "C for 4-5 hrs till reaction completion.
7) complete recovery of solvent from reaction mass to get semi solid material.
8) addition of mixture of methanol & water at 30-40 "C.
9) extraction of aqueous reaction solution at 30-40 "C with methyl tert butyl ether.
10) adjustment of pH of aq layer of step (a) to 8-9 with dil hydrochloric acid (30 %)
1 1) heating aq. layer followed by addition of calcium acetate solution at 40-45 "C.
12) stirring at 30-40 "C till complete crystallization
13) isolation of product by filtration of resulting solid of step (12) & drying of wet cake at
50-60 "C for 24-36 hours to get atorvastatin calcium having controlled contents of Imp I
& Imp 11.
According to one aspect of the present invention, the C1'C4 aliphatic alcohols used in step (1) are
selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol &
diethylene glycol or a mixture thereof.
According to another aspect of present invention, the aliphatic organic nitrile used in step (1)
above is selected from acetonitrile, propionitrile or a mixture thereof.
According to yet another aspect of present invention, the temperature in step (2) above is 45-50
"C.
According to the third embodiment of the present invention, an improved process for the
preparation of Atorvastatin calcium which comprises:
1) dissolving pure tertButy1 (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenylcarbamoy1)pyrrol- 1 -yl]ethyl]-2,2-dimethyl- 1,3-dioxan-4-yllacetate (Formula 11)
in C1'C4 aliphatic alcohol and an aliphatic ether solvent.
2) heating to get clear solution and stirring further for 1 hour
3) cooling to 15-20 "C and addition of aq. hydrochloric acid at 20-30 "C.
4) stirring at 30-40 "C till reaction completion.
5) dropwise addition of caustic solution to the reaction mass of step (4).
6) Stirring at 30-40 "C for 4-5 hrs till reaction completion.
7) complete recovery of solvent from reaction mass to get semi solid material.
8) addition of mixture of methanol & water at 30-40 "C.
9) extraction of aqueous reaction solution at 30-40 "C with methyl tert butyl ether.
10) adjustment of pH of aq layer of step (9) to 8-9 with dil hydrochloric acid (30 %)
11) heating aq. layer followed by addition of calcium acetate solution at 40-45 "C.
12) stirring at 30-40 "C till complete crystallization
13) isolation of product by filtration of resulting solid of step (12) & drying of wet cake at
50-60 "C for 24-36 hours to get atorvastatin calcium having controlled contents of Imp I
& Imp 11.
According to one aspect of the present invention, the CI-C4 aliphatic alcohols used in step (1) are
selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol &
diethylene glycol or a mixture thereof.
According to another aspect of present invention, the aliphatic ether solvent used in step (1)
above is selected from tetrahydrofwran or 2-methyl tetrahydrofuran or a mixture thereof.
According to yet another aspect of present invention, the temperature in step (2) above is 45-50
"C.
According to fourth embodiment of the present invention, an improved process for the
preparation of Atorvastatin calcium which comprises:
1) dissolving pure tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenylcarbamoy1)pyrrol- 1 - yl]ethyl]-2,2-dimethyl- 1,3-dioxan-4-yllacetate (Formula 11)
in C1'C4 aliphatic alcohol.
2) addition of sodium chloride
3) heating to get clear solution and stirring further for 1 hour
4) cooling to 15-20 "C and addition of aq. hydrochloric acid at 20-30 "C.
5) stirring at 30-40 "C till reaction completion.
6) dropwise addition of caustic solution to the reaction mass of step (4).
7) stirring at 30-40 "C for 4-5 hrs till reaction completion.
8) complete recovery of solvent from reaction mass to get semi solid material.
9) addition of mixture of methanol & water at 30-40 "C.
10) extraction of reaction solution at 30-40 "C with methyl tert butyl ether.
13
11) adjustment of pH of aq layer of step (10) to 8-9 with dil hydrochloric acid (30 %)
12) heating aq. layer followed by addition of calcium acetate solution at 40-45 "C.
13) stirring at 30-40 "C till complete crystallization
14) isolation of product by filtration of resulting solid & drying of wet cake at 50-60 "C for
24-36 hours.
According to one aspect of the present invention, the C1-C4 aliphatic alcohols used in step (1)
are selected fiom methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol &
diethylene glycol or a mixture thereof.
According to yet another aspect of present invention, the temperature in step (2) above is 45-50
"C.
Atorvastatin calcium (API) produced using these processes is having (4R-cis)- 1 , 1 -dimethylethyl-
6- [2-[2-(4-fluoropheny1)-5-(1 -methylethyl)-3 -phenyl-4[(phenylamino)carbonyl] 1 H-pyrrol- 1 -yl]
ethyl]--1,3-dioxane-4-heptanoic acid calcium (Impurity I) & (PR,GR)-2-(4-Fluoropheny1)-6-
hydroxy-P-Methoxy-5-(1 -Methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-l H-pyrrole- 1 -
heptanoic acid calcium salt (Impurity-11) < 0.10 % is produced.
Although the invention has been described with reference to several to a specific example, it will
be appreciated by those skilled in the art that the invention may be embodied in many other
14
forms. The processes of the present invention will be explained in more detail with reference to
the following non limiting examples, which are provided by the way of illustration only and
should not be constructed as limit to the scope of the claims in any manner.
EXAMPLES:
Example 1:
Preparation of crude tert-Butyl(4~6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenyl carbamoyl)pyrrol-l-y1]ethyl]-2J-dimethyl-l~-dioxan-4-yl]acetate( Formula 11)
100 g of (4R-Cis)- 1,l- dimethylethyl-6-(2-aminomethyl)-2,2-dimethyl-ld,3io xane-4Acetate is
charged in cyclohexane (1000 ml), followed by addition of 4-Fluoro-a-[2-methyl-1 -oxopropyl]y-
0x0-N-P-diphenylbenzenebutanarnide (140 g) and pivalic acid (30 g). Then refluxed the reaction
mass till reaction completion for 72 hours. After confirmation of reaction completion by
TLC/HPLC, the reaction mass is quenched in 10% sodium bicarbonate solution at 35-40 "C
followed by layer separation and washing of organic layer with 10% sodium chloride solution
followed by layer separation and complete recovery of solvent and resulting residue is
recrystallized in isopropyl alcohol (300 ml) and water (400 ml) to get 192 g tert-Butyl (4R,6R)-
2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbmoyl)pyrrol- 1 -yl]ethyl]-2,2-
dimethyl- 1,3 -dioxan-4-yllacetate (Formula 11).
Purity by HPLC = 96.30%, Single highest impurity = 0.88%; Assay = 93.50 %.
15
Example 2:
Purification of crude tert-Butyl(4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenyl carbamoyl)pyrrol-l-y1]ethyl]-2~-dimethyl-l~dioxan-4-yl]aceta(tFeo rmula 11)
100 g of crude tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenylcarbamoy1)pyrrol- 1 -yl]ethyl]-2,2-dimethyl- 1,3 -dioxan-4-yllacetate (Formula 11) is
dissolved in acetone (250 ml) at 35-40 "C, followed by carbon treatment. The reaction mass is
filtered through celite or hyflow bed. The filtrate is heated to 35-40 OC and material is
crystallized by the addition of 75 ml water. The solid material is filtered and washed with DM
I water & dried at 55-60 OC to get pure tert-Butyl(4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl
-3-phenyl-4-(phenylcarbamoy1)pyrrol-1 - yl]ethyl]-2,2-dimethyl- 1,3-dioxan-4-yllacetate (Formula
11).
I I Purity by HPLC = 99.80%, Single highest impurity < 0.10%, Assay = 99.50 %.
Example 3:
Preparation of Atorvastatin calcium having controlled critical impurities I & I1 (Process I)
100 g of pure tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenyl
carbamoy1)pyrrol- 1 -yl]ethyl]-2,2-dimethyl- 1,3-dioxan-4-yllacetate (Formula 11) is taken in
methanol (1800 ml) & acetonitrile (200 ml) heated to 45-50 "C to get clear solution. The reaction
mass is cooled to 15-20 "C & 300 ml of 1N-hydrochloric acid is added dropwise at max 30 OC &
16
reaction mass is stirred for 4-5 hours. The reaction monitoring is done by TLCIHPLC. (The
content of starting material should be less than 0.50% wlw). To the reaction mass, 10% sodium
hydroxide is added and stirring for 4-5 hours. The reaction monitoring is done by TLCIHPLC
(Atorvastatin tert butyl ester impurity NMT 0.20% wlw). The solvents recovery under vacuum to
get viscous mass. To the reaction mass methanol (200 ml) water (800 ml) methyl tertiary butyl
ether (400 mi), are added at 35-40 "C. The reaction mass is stirred at 30-40 "C followed by layer
separation. After layer separation the pH of aq. phase is adjusted to 8.0-9.0 with dil hydrochloric
acid. Then the reaction mass is fine filtered through hyflow bed. The reaction mass is now
heated to 40-45 "C followed by addition of calcium acetate solution (25g in 425 ml water) and
stirring till complete crystallization. The resulting solid is filtered & given running washing with
water followed by drying of wet cake at 50-60 "C to get final product Atorvastatin calcium
having critical impurities (I & 11) < 0.10% wlw.
Purity by HPLC = 99.92%, Single highest impurity = 0.04%.
Example 4:
Preparation of Atorvastatin Calcium to get reduced level of impurities I & I1 (Process 11)
100 g of pure tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenyl
carbamoy1)pyrrol- 1 - yl]ethyl]-2,2-dimethyl- 1,3-dioxan-4-yllacetate (Formula 11) is taken in
methanol (1800 ml) & tetrahydrofuran (200 ml) heated to 45-50 "C to get clear solution. The
17
reaction mass is cooled to 15-20 "C & 300 ml 1-N hydrochloric acid is added dropwise at max 30
"C & reaction mass is stirred for 4-5 hours. The reaction monitoring is done by TLC/HPLC (The
content of starting material should be less than 0.50% wlw). To the reaction mass, 10% sodium
hydroxide is added & stirred for 4-5 hours. The reaction monitoring is done by TLC/HPLC
(Atorvastatin tert butyl ester impurity NMT 0.20% wlw). The solvent recovery is done under
vacuum to get viscous mass. To the reaction mass methanol (200 ml), water (800 ml) & methyl
tertiary butyl ether (400 ml), is added at 35-40 "C. The reaction mass is stirred at 30-40 "C
followed by layer separation. After layer separation, the pH of aq. phase is adjusted to 8.0-9.0
with dil hydrochloric acid. After this, the reaction mass is fine filtered through hyflow bed. The
reaction mass is now heated to 40-45 "C followed by addition of calcium acetate solution (25g in
425 ml water) and stirring till complete crystallization. The resulting solid is filtered & given
running washing with water, followed by drying of wet cake at 50-60 "C to get final product
Atorvastatin calcium having critical impurities (I & 11) < 0.10% wlw.
Purity by HPLC = 99.95%, Single highest impurity = 0.03%.
Example 5:
Preparation of Atorvastatin Calcium to get reduced level of impurities I & I1 (Process-111)
100 g of pure tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-~henyl
carbarnoy1)pyrrol- 1 -yl]ethyl]-2,2-dimethyl- 1,3 -dioxan-4-yllacetate (Formula 11) is taken in
18
I methanol (1800 ml) & sodium chloride (5 grn) is added to it and heated to 45-50 "C to get clear
solution. The reaction mass is cooled to 15-20 "C & 1N-hydrochloric acid (300 ml) is added
dropwise at max 30 "C & stirred for 4-5 hours. The reaction monitoring is done by TLC/HPLC
after 4-5 hours (the content of starting material should be less than 0.50% wtw). To the reaction
mass, 10% sodium hydroxide is added and reaction mass is stirred for 4-5 hours. The reaction
monitoring is done by TLCIHPLC (Atorvastatin tert butyl ester impurity NMT 0.20% wlw). The
solvents recovery under vacuum to get viscous mass. To the reaction mass methanol (200 ml),
water (800 ml) & methyl tertiary butyl ether (400 ml), is added at 35-40 "C. The reaction mass is
stirred at 30-40 "C followed by layer separation. After layer separation, the pH of aq. phase is
adjusted to 8.0-9.0 with dil hydrochloric acid. Then the reaction mass is fine filtered through
hyflow bed. The reaction mass is then heated to 40-45 "C followed by addition of calcium
acetate solution (25g in 425 ml water) and stirring till complete crystallization. The resulting
solid is filtered & given running washing with water, The wet cake is dried at 50-60 "C to get
final product Atorvastatin calcium having critical impurities (I & 11) < 0.10% wlw.
Purity by HPLC = 99.89%, Single highest impurity = 0.04%.

We Claim:
1. An improved process for the purification of Atorvastatin intermediate tert-Butyl(4R,6R)-
2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-henylcarboyl)pyol1-- yl]ethyl]-
2,2-dimethyl-1,3-dioxan-4-yllacetatwe hich comprises
i) Dissolving tert-Butyl(4~6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-
(phenylcarbamoy1)pyrrol- 1 -yl]ethyl]-2,2-dimethyl- 1,3-dioxan-4-yllacetate in an
aliphatic ketone at elevated temperature.
ii) charcoaling of resulting layer of step (i) above.
iii) recrystallization of product from filtrate of step (ii) by addition of water
iv) isolation of product by usual filtration
v) drying of wet cake of step (iv) at 55-60 "C to get pure tert-Butyl(4R,6R)-2-[[[6-
(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol1-- yl]ethyl]-
2,2-dimethyl- 1,3 -dioxan-4-yllacetate
2. The process of claim 1, wherein the aliphatic ketone used in step (i) can be selected from
acetone, butanone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone,
dibutyl ketone or a mixture thereof.
3. The process of claim 1, wherein the temperature for dissolution in step (i) & charcoaling
in step (ii) is 35-40 "C.
4. An improved process for the preparation of Atorvastatin calcium which comprises:
i) dissolving pure tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-
phenyl-4-(phenylcarbamoy1)pyrrol- 1 -yl]ethyl]-2,2-dimethyl- 1,3-dioxan-4-
yllacetate in C1'C4 aliphatic alcohol and an aliphatic organic nitrile.
ii) mher heating to get clear solution and stirring further for 1 hour
iii) cooling to 15-20 "C and addition of aq. hydrochloric acid at 20-30 "C.
iv) stirring at 30-40 "C till reaction completion.
v) dropwise addition of caustic solution to the reaction mass of step (4).
vi) stirring at 30-40 "C for 4-5 hours till reaction completion.
vii) complete recovery of solvent from reaction mass to get semi solid mass.
viii) addition of mixture of methanol and water at 30-40 "C.
ix) extraction of reaction solution at 30-40 "C with methyl tertiary butyl ether
x) adjustment of pH of aq layer to 8-9 with dil. hydrochloric acid (30 %)
xi) heating of aq layer followed by addition of calcium acetate solution at 30-40 "C.
xii) stirring at 30-40 "C till complete crystallization.
xiii) isolation of product by filtration & drying at 50-60 "C for 24-36 hours.
5. A process of claim 4, wherein the organic nitrile used in step (i) is selected from
acetonitrile, propionitrile or a mixture thereof.
6. An improved process for the preparation of Atorvastatin calcium which comprises:
i) dissolving pure tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-
phenyl-4-(phenylcarbamoy1)pyrrol- 1 -yl]ethyl]-2,2-dimethyl- 1,3-dioxan-4-
yllacetate in C1-C4 aliphatic alcohol and an aliphatic ether solvent.
ii) fhther heating to get clear solution and stirring further for 1 hour
iii) cooling to 15-20 "C and addition of aq. hydrochloric acid at 20-30 "C.
iv) stirring at 30-40 "C till reaction completion.
v) dropwise addition of caustic solution to the reaction mass of step (4).
vi) stirring at 30-40 "C for 4-5 hours till reaction completion.
vii) complete recovery of solvent fiom reaction mass to get semi solid mass.
viii) addition of mixture of methanol and water at 30-40 "C.
ix) extraction of reaction solution at 30-40 "C with methyl tertiary butyl ether
x) adjustment of pH of aq layer to 8-9 with dil. hydrochloric acid (30 %)
xi) heating of aq layer followed by addition of calcium acetate solution at 30-40 "C.
xii) stirring at 30-40 "C till complete crystallization.
xiii) isolation of product by filtration & drying at 50-60 "C for 24-36 hours.
7. A process of claim 6, wherein the aliphatic ether used in step (i) is selected fiom
tetrahydrofuran or 2-methyltetrahydrofuran or a mixture thereof.
8. An improved process for the preparation of Atorvastatin calcium which comprises:
i) dissolving pure tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-
phenyl-4-(phenylcarbamoy1)pyrrol-1 -yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-
yllacetate in C1'C4 aliphatic alcohol.
ii) Addition of sodium chloride
iii) further heating to get clear solution and stirring further for 1 hour
iv) cooling to 15-20 "C and addition of aq. hydrochloric acid at 20-30 "C.
v) stirring at 30-40 "C till reaction completion.
vi) dropwise addition of caustic solution to the reaction mass of step (4).
vii) stirring at 30-40 "C for 4-5 hours till reaction completion.
viii) complete recovery of solvent from reaction mass to get semi solid mass.
ix) addition of mixture of methanol and water at 30-40 "C.
x) extraction of reaction solution at 30-40 "C with methyl tertiary butyl ether
xi) adjustment of pH of aq layer to 8-9 with dil. hydrochloric acid (30 %)
xii) heating of aq layer followed by addition of calcium acetate solution at 30-40 "C.
xiii) stirring at 30-40 "C till complete crystallization.
xiv) isolation of product by filtration & drying at 50-60 "C for 24-36 hours.
9. A process of claim 4, 6, & 8 wherein the aliphatic alcohol used in 4(i), 6(i) & 8 (i) is
selected from C1-C4 aliphatic alcohols preferably methanol, ethanol, propanol, butanol or
a mixture thereof.
10. A process of claim 4, 6 & 8 wherein the temperature in step 4(ii), 6 (ii) & 8 (iii) is 45-50
"C.