FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10, rule 13)
"PROCESS FOR THE PREPARATION OF PYRROLE DERIVATIVES"
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road
Post Box No. 26511
Mumbai- 400 026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND
THE MANNER IN WHICH IT IS TO BE PERFORMED

PRIORITY
This application claims the benefit to Provisional Application No. 848/MUM/2004,
filed August 6, 2004 and entitled "PROCESS FOR THE PREPARATION OF
ATORVASTATIN", and from Provisional Application No. 849/MUM/2004, filed August 6,
2004 and entitled "PROCESS FOR THE PREPARATION OF ÏNTERMEDIATES OF
ATORVASTATIN", the contents of which are incorporated by reference herein.
BACKGROUND OF THE INVENTIQN
1. Technical Field
The present invention generally relates to improved processes for the preparation of
pyrrole derivatives or pharmaceutically acceptable salts thereof and intermediates thereof.
2. Description of the Related Art
The present invention is directed to an improved process for the preparation of pyrrole
derivatives such as atorvastatin (also known as [R-(R*,R*]-2-(4-fluorophenyl)-p, d-
dihydroxy-5 -(l -methylethyl)-3 -phenyl-4- [(phenylamino)carbonyI] -1 H-pyrrole-1 -heptanoic
acid) of Formula I:

Generally, atorvastatin is a synthetic lipid-lowering agent that acts as an inhibitor of 3-
hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMG-CoA Reductase
inhibitor). This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and
rate-limiting step in cholesterol biosynthesis. HMG-CoA reductase inhibitors are commonly
referred to as "statins." Statins are therapeutically effective drugs used for reducing low
density lipoprotein (LDL) partiële concentration in the blood stream of patients at risk for
2

cardiovascular disease. Atorvastatin is indicated for use for reducing elevated total
cholesterol (tptal-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B),
and high plasma triglycerides (TG) in patients with primary hypercholesterolemia
(heterozygous familial and nonfamilial) and mixed hyperlipidemia (Fredrickson types Ha and
IIb). Atorvastatin calcium (calcium salt (2:1) trihydrate) is sold under the trade name
LIPITOR®.
U.S. Patent No. 5,003,080 ("the '080 patent"), herein incorporated by reference,
discloses a process for preparing atorvastatin. The process includes producing a key
intermediate (4R-cis)-6-[2-[3-[phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(l-
methylethyl)-pyrrol-l-yl]-ethyl]-2,2-dimethyl-[l,3]-dioxane-4-yl-acetic acid-t-butyl ester of
Formula IV by reacting (4R-cis)-l,l-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-l,3-
dioxane-4-acetate of Formula II with 2-[l-phenyl-2-(4-fluorphenyl)-2-oxoethyl]-4-methyl-N-
methyl-N-phenyl-3-oxo pentamide of Formula III in a 9:1 mixture of heptane and toluene
under reflux for 24 hours as set forth below in Scheme I:
3
SCHEME I


The deprotection of the acetal intermediate of Formula IV to produce atorvastatin is
disclosed in, for example, Tetrahdron Letters, Vol. 33, No. 17, p. 2283-2284 (1992), U.S.
Patent No. 5,149,837 and WO 01/72706.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, a process for the
preparation of a pyrrole derivative or a racemic mixture, an enantiomer, a diastereoisomer, a
mixture thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof is provided
comprising reacting an amino compound of the general formula

wherein each R is independently hydrogen or a hydrolyzable protecting group, or each R,
together with the oxygen atom to which each is bonded, form a hydrolyzable cyclic protecting
group, or each R is bonded to the same substituent which is bonded to each oxygen atom to
form a hydrolyzable protecting group and R1 is hydrogen, a lower alkyl or a cation capable of
forming a non-toxic pharmaceutically acceptable salt, with a di-oxo compound of the general
formula

\-S
wherein R2 is 1-naphthyl, 2-naphthyl, cyclohexyl, cyclohexylmethyl, norbornenyl, a
substituted or unsubstituted aryl group, benzyl, 2-, 3-, or 4-pyridinyI, or 2-, 3-, or 4-pyridinyl-
N-oxide, R3 and R4 are independently hydrogen, a lower alkyl, a C3-C25 cycloalkyl group, a
substituted or unsubstituted aryl group, cyano, trifluoromethyl, or -CONR6R7 wherein R6 and
R7 are independently hydrogen, a lower alkyl or a substituted or unsubstituted aryl group and
R5 is a lower alkyl, a C3-C25 cycloalkyl or trifluoromethyl; in the presence of a catalyst and in
at least one solvent,
4

In a seconó emboóïment of the present 'mvention, a process for the preparation of a
pyrrole derivative is provided comprising the step of hydrolyzjng a pyrrole derivative of the
general formula

wherein R, R1, R2, R3, R4, and R5 have the aforestated meanings or a racemic mixture, an
enantiomer, a diastereoisomer, a mixture thereof, a tautomer thereof,, or a pharmaceutically
acceptable salt thereof with at least one ion-exchange resin in at least one solvent to provide a
pyrrole derivative of the general formula

The advantage of the present invention includes at least;
l. A less time consuming process for the transformation of (4R-cis)-6-[2-[3[phenyI-4-
(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(l -methylethyO-pytrol-1 -yl]-ethyl]-2,2-dimethyl-
[l,3]-dioxane-4-yl-acetic acid-t-butyl ester to atorvastatin.
2. Easy removal of atorvastatin from the transformation catalyst.
3. The catalyst is recyclable which reduces costs.
DEFINITIONS
Representative lower alkyls include, but are not limited to, straight or branched C| to
C8 alkyls such as, for exampie, methyl, ethyl, n-propyl, isoprOpyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl and isohexyl, tert-amyl, n-
heptyl, n-octyl and the like. The lower alkyls may be substituted with l to 3 substituents such
5

as a halogen, amino, and cyano. Suitable halogens include, but are not limited to, fluorine,
chlorine, bromine, iodine and the like.
Representative aryl groups include, but are not limited to, C6 to C12 aromatic
group such as, for example, phenyl, tolyl, xylyl, biphenyl, naphthyl, and the like. The aryl
groups may be substituted with l to 3 substituents such as lower alkyls, halogens, hydroxyl
groups, trifluoromethyl, alkoxy groups, or alkanoyloxy groups, amino groups, cyano groups
and the like. A preferred aryl group is phenyl substituted with l to 3 halogens.
Representative aralkyl groups include, but are not limited to, C1 to C6 lower
alkyls substituted with C6 to C12 aryl groups as defined above. Examples include benzyl,
phenethyl, phenylpropyl and the like, each of which may be substituted with l to 3
substituents such as lower alkyls, halogens, amino, cyano, and the like.
Representative cycloalkyl groups include, but are not limited to, three- to
twenty five-membered saturated hydrocarbon rings such as, for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Representative alkoxy groups include 0-alkyl in which the alkyl group is as
defined above.
Representative alkanoyloxy groups include an alkyl group, as defined above,
attached to a carbonyl group and thence, through an oxygen atom, to the parent molecular
residue.
Norbornenyl is a group derived by the removal of a hydrogen atom (other than
at a bridgehead carbon atom) from bicyclo[2.2.1]hept-2-ene.
Representative halogens include, but are not limited to, fluorine, iodine,
bromine, chlorine and the like.
The term "a cation capable of forming a non-toxic pharmaceutically acceptable
salt" refers to alkali metal ions, alkaline earth metal ions, ammonium ions and the like.
Examples of alkali metals include lithium, sodium, potassium, and cesium. Examples of
alkaline earth metals include, but are not limited to, beryllium, magnesium, and calcium.
Preferred cations are sodium and calcium.
6

The hydrolyzable protecting groups used are preferably hydrolyzable under
acidic or basic conditions. Examples of hydrolyzable protecting groups include, for example,
silyl groups such as trialkylsilyl, e.g., t-butyl-dimethyl-silyl, and alkyldiarylsilyl and cyclic
protecting groups such that each R form, for example, a djoxane. In one embodiment, the
hydrolyzable protecting group is wherein each R5 is bonded to the same substituent which is
bonded to each oxygen atom to form a hydrolyzable protecting group, e.g.,

rtierein each R is a lower alkyl as defined above.
DETAÏLED DESCRIPTION OF THE PREFERRED EMBODIMENTS
One aspect of the present invention provides an improved process for the preparation
of pyrrole derivatives or a racemic mixture, an enantiomer, a diastereo i somer, a mixture
thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof of the general
formula

wherein each R is independently hydrogen or a hydrolyzable protecting group, or each R,
together with the oxygen atom to which each is bonded, form a hydrolyzable cyclic protecting
group, or each R is bonded to the same substituent which is bonded to each oxygen atom to
form a hydrolyzable protecting group and R1 is hydrogen, a lower alkyl or a cation capable of
forming a non-toxic pharmaceutically acceptable salt, R2 is l -naphthyl, 2-naphthyl,
cyclohexyl, cyclohexylmethyl, norbornenyl, a substituted or unsubstituted aryl group, benzyl,
2-, 3-, or 4-pyridinyl, or 2-, 3-, or 4-pyridinyl-N-oxide, R3 and R4 are independently hydrogen,
7

a straight or branched aJky] of l to 6 carbon atoms, a C3-C25 cycloalkyl, phenyl optionally
substituted with a halogen, hydroxyl, trifluoromethyl, alkyl of l to 4 carbon atoms, or alkoxy
of l to 4 carbon atoms, cyano, trifluoromethyl, or -CONR R wherein R and R are
independently hydrogen, a straight or branched alkyl of l to 4 carbon atoms, phenyl
optionally substituted with a halogen, cyano, or trifluoromethyl and R5 is a straight or
branched alkyl of l to 6 carbon atoms, a C3-C25 cycloalkyl or trifluoromethyl. All
stereoisomers of the compounds prepared by the process of the present invention are
contemplated, either in admixture or in pure or in substantially pure form. The compounds
can have asymmetrie centers at any of the carbon atoms. Consequently, the compounds
prepared herein can exist in enantiomeric or diastereoisomeric forms or in mixtures thereof.
When enantiomeric or diastereoisomeric products are prepared, they can be separated by
conventional techniques, e.g., chromatographic or fractional crystallization.
In accordance with one embodiment of the present invention, a process for the
preparation of a pyrrole derivative or a racemic mixture, an enantiomer, a diastereoisomer, a
mixture thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof is provided
comprising reacting an amino compound of the general formula

wherein R and R1 have the a forestated meanings with a di-oxo compound of the general
formula
`
wherein R , R , R and R have the aforestated meanings in the presence of a catalyst and in at
least one solvent.
Useful catalysts in the process of the present invention include, but are not limited to,
aliphatic carboxylic acids, cycloaliphatic carboxylic acids, aromatic carboxylic acids and the
8

like and mixtures thereof. Suitable aliphatic carboxylic acids include those having from 2 to
18 carbon atoms such as, for example, propionic acid, butyric acid, n-heptanoic acid, 2, 2-
dimethylbutanoic acid and the like and mixtures thereof. Suitable cycloaliphatic carboxylic
acids mclude those having from 7 to 15 carbon atoms, e.g., cydohexanoic acid. Suitable
aromatic carboxylic acids include those having from 7 to 15 carbon atoms, e.g., benzoic acid).
In one embodiment, the catalysts are n-heptanoic acid and/or 2, 2-dimethylbutanoic acid.
Useful solvents may be an organic solvent or a mixture of organic solvents. Suitable
organic solvents include, but are not limited to, aliphatic hydrocarbons, e.g., heptane, aromatic
hydrocarbons, e.g., xylene or toluene, ethers such as cyclic ethers, e.g., tetrahydrofuran, and
the like and mixtures thereof. The solvent will ordinarily be present in an amount ranging
from about 17 to 19 volume as mixture with respect to amino compound. When more than
one solvent is employed, the mixture of solvents may be present in a ratio of from about
10:4:3 to about 15:5:3 and preferably about 10:5:2.2 of aliphatic hydrocarbon: cyclic ether:
aromatic hydrocarbon. In one embodiment of the present invention, the solvent mixture is a
10:5:2.2 mixture of heptane, tetrahydrofuran and toluene.
The reaction of the amino compound with the di-oxo compound can be carried out at a
temperature ranging from about 60°C to about 105°C, and preferably at a temperature of
about 100°C. The reaction time can range from about 7 hours to about 15 hours, and
preferably about 8 hours. Generally, the amino compound is present in a stoichiometric
amount sufficient to couple with the di-oxo compound and form a pyrrole derivative, e.g., in
an amount ranging from about l .0 to l .05 equivalents.
In a preferred embodiment, a process of the present invention involves reacting (4R-
cis)-l,l-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate of Formula II
with 2-[l-phenyl-2-(4-fluorphenyl)-2-oxoethyl]-4-niethyl-N-inethyl-N-phenyl-3-oxo
pentamide of Formula III in a solvent with a catalyst to produce the intermediate (4R-cis)-6-
[2-[3-phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyI)-5-(l-methylethyl)-pyrrol-l-yl]-ethyl]-
2,2-dimethyl-[l,3]-dioxane-4-yl-acetic acid-t-butyl ester of Formula IV as generally shown
below in Scheme II:
9


Following the formation of the pyrrole derivative, the pyrrole derivative can be
hydrolyzed to obtain the hydrolyzed pyrrole derivatives herein such as, for example, an
intermediate of atorvastatin salt, of the general formula

wherein R, R1, R , R3, R4 and R5 have the aforestated meanings; or a racemic mixture, an
enantiomer, a diastereoisomer, a mixture thereof, a tautomer thereof, or a pharmaceutically
acceptable salt thereof. In one embodiment, the pyrrole derivative can be hydrolyzed using at
least one ion-exchange resin in at least one solvent. Useful ion-exchange resins include, but
are not limited to, cation-exchange resin, anion-exchange resin, and the like mixtures thereof.
Examples of such ion-exchange resins include Amberlite® IRA 120, Amberlyst® 15,Indion
525 and the like and mixtures thereof. The ion-exchange resin is ordinarily present in an
amount ranging from about 0.8 to 1.0 w/w.
Useful solvents may be an organic solvent or a mixture of organic solvents. Suitable
organic solvents include, but are not limited to, nitriles, e.g., acetonitrile (ACN), cyclic ethers,
10

e.g,, tetrahydrofuran (THF), lower alcohols, e.g., methanol, ethanol and isopropanol, and the
]ike and mixtures thereof. In one embodiment of the process of the present invention, ACN
can be used. The step of hydrolyzing may be performed at a temperature ranging from about
25°C to about 30°C for a time period ordinarily ranging from about 2 to about 5 hours, and
preferably about 3 hours.
11
In one embodiment, a process of the present involves producing atorvastatin. By the
transformation of the intermediate (4R-cis)-6-[2-[3-[phenyl-4-(phenylcarbamoyl)-2-(4-
fluorophenyl)-5-(l-methylethyl)-pyrrol-l-yl]-ethyl]-2,2-dimethyl-[l,3]-dioxane-4-yl-acetic
acid-t-butyl ester of Formula IV using at least one of the foregoing ion-exchange resin in at
least one sol vent to form atorvastatin of Formula V as generally shown below in Scheme III:


After the completion of the hydrolysis, the hydrolyzed pyrrole derivative can be
cooled and then filtered off, e.g., by crystallization. The crude solid obtained can be purified
in substantially pure form, e.g., a purity greater than about 90%, preferably greater than about
95% and most preferably greater than about 99%.
As one skilied in the art will readily appreciate, the hydrolyzed pyrrole derivative can
then be converted to a pharmaceutically acceptable salt such as a sodium or calcium salt, e.g.,
atorvastatin salt, using techniques known in the art. For example, the hydrolyzed pyrrole
derivative can be converted to a salt using IN sodium hydroxide solution at room temperature
for about 4 to about 5 hours in a suitable solvent medium such as an alcohol solvent, e.g.,
methanol, ethanol, or isopropanol, or in a mixture of an alcohol, e.g., isopropanol, and
tetrahydrofuran, in such a marmer that there is substantially no free alkali present in the
reaction mixture and the sodium salt formation is complete. After stripping the solvent
carefully under high vacuüm at room temperature, an ether-type solvent, e.g., a dialkyl ether
such as diisopropyl ether, can be added and stirred to crystallize out the sodium salt. The
sodium salt can be filtered off under totally anhydrous conditions in a dehumidified area and
washed with the same or a different solvent to remove slight excess of the ester present.
The following examples are provided to enable one skilled in the art to practice the
invention and are merely illustrative of the invention. The examples should not be read as
limiting the scope of the invention as defmed in the claims.
EXAMPLE l
Preparation of (4R-cis)-6-[2-[3-[phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(l-
methylethyl)-pyrrol-l-yl]-ethyl]-2,2-dimethyl-[l,3]-dioxane-4-yl-aceticacid-t-butyl-ester
(4R-cis)-l, l -dimethy]ethy]-6-(2-amïnoethyl)-2,2-dimethyI-l ,3-dioxane-4-acetate (5.0
g), 2-[l-phenyl-2-(4-fluoro phenyl)-2-oxo ethyl]-4-methyl-N-methyl-N-phenyl-3-oxo
pentanamide (7.2 g) were charged in a heptane (50 ml),tetrahydrofuran (25 ml) and toluene
(l l ml) mixture, n-heptanoic acid (2.5 g) was then added to the reaction mixture, The
reaction mixture was azeotropically refluxed for about 8 hours and the reaction progress was
12

monitored by TLC, The solvents were removed under reduced pressure. An isopropyl alcohol
("IPA") (12.5 ml) was added to the residue at a temperature of about 60°C. The reaction
mixture was then stirred at room temperature (a temperature ranging from about 25°C to
about 30°C) for about 10 hours. The reaction mixture was then cooïed to a temperature of
about 15°C and hexane (10-30 ml) added. A yellowish solid was produced and was filtered.
The solid was dried in an oven at a temperature of about 55°C for about 12 hours to get the
intermediate. Yield = 6.5 g.
IR (cm-1): OH str. 3393, CH str. Ar 3100, CH Str aliph. 2981, CO-O Str. 1720. PMR
(in delta): (in CDC13), 1.0-1.7 (m, 5H), 1.30 (s, 3H), 1.36 (s, 3H), 1.43 (s, 9H), 1.53 (d, 6H),
2.23 (dd, l H), 2.39 (dd, 1H), 3.5-3.9 (m, 3H), 4.0-4.2 (m, 2H), 6.8-7.3 (m, 14H) The Cl mass
shows m/z 655 [M 1]+.
EXAMPLE 2
Preparation of Atorvastatin Calcium Salt
(4R-cis)-6-[2-[3-phenyl-4-(phenylcarbamoyI)-2-(4-fluorophenyl)-5-(ï-methy]ethyl)-
pyrrol-l-yl]-ethyl]-2,2-dimethyl-[l,3]dioxane-4-yl-acetic acid-t-butyl ester (3.4g) was
dissolved in an acetonitrile (70 ml). Indion 525 (H+ form) (3.4g) was added and the reaction
mixture was stirred at room temperature. The reaction was monitored by TLC. The reaction
mixture was decanted to remove the Indion 525 resin. Solid sodium hydroxide (0.34 g) was
dissolved in water (5 ml) and added to the reaction mixture and stirred for about 2 hours. The
reaction was monitored by TLC. The solvents were then removed under reduced pressure.
The sodium salt obtained was dissolved in methanol (55 ml) at a temperature of about 50°C
and then water (42 ml) was added. The solution was filtered and the clear solution was stirred
at a temperature of about 55°C. A solution of calcium acetate (0.6 g) in water (7 ml) was
added at 55°C. The reaction mixture was maintained for about 30 minutes. The reaction
mixture was cooled to room temperature and then to a temperature of about 15°C. The off-
white solid obtained was filtered. The solid was dried at a temperature of about 50°C under
vacuüm to obtain the calcium salt of atorvastatin (2.4 g).
13

IR (cm-1): OH str. 3412, CH Str aliph. 2960.
PMR (in delta): (in CDC13), 1.26 (m, 2H), 1.37 (m, 6H), 1.59 (m, 2H), 2.04 (m, 2H),
3.24-3.96 (m, 5H), 4.80 (brs., l H), 5.75(brs., 1H), 7.0-7.22 (m, 12H), 7.52 (d, 2H), 9.82 (s,
l H).
The Cl mass shows m/z 558 [M-Ca+],
It will be understood that various modifications may be made to the embodiments
disclosed herein. Therefore the above description should not be construed as limiting, but
merely as exemplifications of preferred embodiments. For example, the functions described
above and implemented as the best mode for operating the present invention are for
illustration purposes only. Other arrangements and methods may be implemented by those
skilled in the art without departing from the scope and spirit of this invention. Moreover,
those skilied in the art will envision other modifications within the scope and spirit of the
claims appended hereto.
14

We claim:
1. A process for the preparation of a pyrrole derivative or a racemic mixture, an
enantiomer, a diastereoisomer, a mixture thereof, a tautomer thereof, or a pharmaceutically
acceptable salt thereof comprising reacting an amino compound of the general formula

wherein each R is independently hydrogen or a hydrolyzable protecting group, or each R,
together with the oxygen atom to which each is bonded, form a hydrolyzable cyclic protecting
group, or each R is bonded to the same substituent which is bonded to each oxygen atom to
form a hydrolyzable protecting group and R1 is hydrogen, a lower alkyl or a cation capable of
forming a non-toxic pharmaceutically acceptable salt, with a di-oxo compound of the general
formula

wnerem K is 1-napntnyl, 2-napntnyl, a C3-C25 cycloalkyl group, norbornenyl, a substituted or
unsubstituted aryl group, benzyl, 2-, 3-, or 4-pyridinyl, or 2-, 3-, or 4-pyridinyl-N-oxide, R3
and R4 are independently hydrogen, a lower alkyl, a C3-C25 cycloalkyl group, a substituted or
unsubstituted aryl group, cyano, trifluoromethyl, or -CONR6 R7 wherein R6 and R7 are
independently hydrogen, a lower alkyl or a substituted or unsubstituted aryl group and R5 is a
lower alkyl, a C3-C25 cycloalkyl or trifluoromethyl; in the presence of a catalyst and in at least
one solvent.
2. The process of Claim l, wherein R2 is a substituted aryl group, R3 is an
unsubstituted aryl group, R4 is -CONR6R7 wherein R6 is hydrogen and R7 is a substituted or
unsubstituted aryl group and R5 is a lower alkyl.
15

3. The process of Claim l, wherein R2 is a phenyl group substituted with one or
halogens, R3 is a phenyl group, R4 is -CONR6R7 wherein R6 is hydrogen and R7 is a
substituted or unsubstituted aryl group and R5 is a lower alkyl.
4. The process of Claim l, comprising reacting (4R-cis)-l,l-dimethylethyl-6-(2-
aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate of the formula

with 2-[l-phenyl-2-(4-fluorphenyl)-2-oxoethyl]-4-methyl-N-methyl-N-phenyl-3-oxo
pentamide of the formula

in the presence of a catalyst and in at least one solvent to produce the intermediate (4R-
cis)-6-[-[3-pheny]-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(l-methyJethyl)-pyrrol-l-
yl]-ethyI]-2,2-dimethyl-[l,3]-dioxane-4-yl-acetic acid-t-butyl ester of the formula

16

5. The process of Claims 1-4, wherein the catalysl is a carboxylic acid.
6. The process of Claims 1-5, wherein the cat^lyst is selected from the group
consisting of an aliphatic carboxylic acid, cycloaliphatic carboxylic acid, aromatic carboxylic
acid and mixtures thereof.
7. The process of Claim 6, wherein the aliphatic carboxylic acid contains 2 to 18
carbon atoms.
8. The process of Claims 6 and 7, wherein the aliphatic carboxylic acid is selected
from the group consisting of propionic acid, butyric acid, n-heptanoic acid, 2, 2-
dimethylbutanoic acid and mixtures thereof.
9. The process of Claims 1-8, wherein the solvent is selected from the group
consisting of an aliphatic hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent
and mixtures thereof.
10. The process of Claims 1-9, wherein the solvent is a mixture of organic solvents.

11. The process of Claims 1-10, wherein the solvent is a mixture of aliphatic
hydrocarbon solvent, cyclic ethers and aromatic hydrocarbon solvent.
12. The process of Claim 11, wherein the mixture of aliphatic hydrocarbon solvent
and aromatic hydrocarbon solvent is present in a ratio of about 10:4:3 to about 15:5:3 of
aliphatic hydrocarbon, cyclic ethers and aromatic hydrocarbon.
13. The process of Claims 1-12, wherein the solvent is a mixture of heptane,
tetrahydrofuran and toluene.
17

14. The process of Claim 13, wherein the mixture of heptane ,tetrahydrofuran and
toluene is present in a 10:5:2.2 ratio of heptane, tetrahydrofuran and toluene.
15. The process of Claim l, wherein the reaction is performed at a temperature
ranging trom about 60°C to about 105°C.
16. The process of Claims 1-15, further comprising the step of hydrolyzing the
product pyrrole derivative.
17. The process of Claim 16, wherein the step of hydrolyzing comprises, reacting the
intermediate pyrrole derivative with at least one ion-exchange resin in one or more second
solvents.
18. The process of Claim 17, wherein the ion-exchange resin is selected from the
group consisting of cation-exchange resin, anion-exchange resin, and mixtures thereof.
19. The process of Claim 17, wherein the ion-exchange resin is selected from the
group consisting of Amberlite® IRA 120, Amberlyst® 15,Indion 525 and mixtures thereof.
20. The process of Claims 16-19, wherein the second solvent is a mixture of organic
solvents.
21. The process of Claim 20, wherein the organic solvent is acetonitrile.
22. The process of Claim 4, thereafter converting the intermediate (4R-cis)-6-[2-
[3[phenyl-4-(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(l-methylethyl)-pyirol-l-yl]-ethyl]-2,2-
dimethyl-[l,3]-dioxane-4-yl-acetic acid-t-butyl ester to atorvastatin or a pharmaceutically
acceptable sak thereof.
18

23. A process for the preparation of a pyrroïe derivative or a racemic mixture, an
enantiomer, a diastereoisomer, a mixture thereof, a tautomer thereof, or a pharmaceutically
acceptable salt thereof of the general formula

wherein each R is independently hydrogen or a hydrolyzable protecting group, or each R,
together with the oxygen atom to which each is bonded, form a hydrolyzable cyclic protecting
group, or each R is bonded to the same substituent which is bonded to each oxygen atom to
form a hydrolyzable protecting group and R1 is hydrogen, a lower alkyl or a cation capabie of
fomirng a non-toxrc pharmaceuticatfy acceptaö/e salt, R2 is 1-napthyl, 2-naphthyl,
cyclohexyl, cyclohexylmethyl, norbornenyl, a substituted or unsubstituted aryl group, benzyl,
2-, 3-, or 4-pyridinyl, or 2-, 3-, or 4-pyridinyl-N-oxide, R3 and R4 are independently hydrogen,
a straight or branched alkyl of l to 6 carbon atoms, a C3-C25 cycloalkyl, phenyl optionally
substituted with a halogen, hydroxyl, trifluoromethyl, alkyl of l to 4 carbon atoms, or alkoxy
of l to 4 carbon atoms, cyano, trifluoromethyl, or -CONR6R7 wherein R6 and R7 are
independently hydrogen, a straight or branched alkyl of l to 4 carbon atoms, phenyl
optionally substituted with a halogen, cyano, or trifluoromethyl and R5 is a straight or
branched alkyl of l to 6 carbon atoms, a C^-C^ cycloalkyl or trifluoromethyl, the process
comprising hydrolyzing the pyrroïe derivative with at least one ion-exchange resin in at least
one solvent.
24. The process of Claim 23, wherein R2 is a substituted aryl group, R3 is an
unsubstituted aryl group, R4 is -CONR6R7 wherein R6 is hydrogen and R7 is a substituted or
unsubstituted aryl group and R5 is a lower alkyl.
19

25. The process of Claim 23, wherein R is a phenyl group substituted with one or
halogens, R3 is a phenyl group, R4 is -CONR6R7 wherein R6 is hydrogen and R7 is a
substituted or unsubstituted aryl group and R5 is a lower alkyl.
26. The process of Claim 23, comprising hydrolyzing (4R-cis)-6-[2-[3[phenyl-4-
(phenylcarbamoyl)-2-(4-fluorophenyl)-5-(l-methylethyl)-pyrrol-l-yl]-ethyl]-2)2-dimethyl-
[l,3]-dioxane-4-yI-acetic acid-t-butyl ester with at least one ion-exchange resin in at least one
solvent.
27. The process of Claims 23-26, wherein the ion-exchange resin is selected from the
group consisting of cation-exchange resin, anion-exchange resin, and mixtures thereof.
28. The process of Claims 23-26, wherein the ion-exchange resin is selected from the
group consisting of Amberlite® IRA 120, Amberlyst® 15,Indion 525 and mixtures thereof.
29. The process of Claims 23-28, wherein the solvent is organic solvent.
30. The process of Claim 29, wherein the organic solvent is nitrile.
31. The process of Claim 29, wherein the organic solvent is acetonitrile.
32. The process of Claim 30, wherein the quantity of nitrile is 20 volume.
33. The process of Claims 23-32, wherein the reaction is carried out for a time period
of about 2 to about 5 hours.
34. The process of Claims 23-33, and thereafter converting the hydrolyzed pyrrole
derivative to a salt thereof.
20

21
35. The process of Ciaim 34, wherein the salt is a sodium or calcium salt.
Dated this fifth (05th) day of August, 2005