Note: Descriptions are shown in the official language in which they were submitted.
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PROCESSES FOR PREPARING CALCIUM SALT FORMS OF STATINS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of provisional application Serial Number
60/312,812, filed August 16, 2001 and U.S. Patent Application Serial No.
10/037,412,
filed October 24, 2001, which claims the benefit of provisional application
Serial Number
60/249,319, filed November 16, 2000.
FIELD OF THE INVENTION
The present invention relates to processes for preparing calcium salt forms of
statins.
BACKGROUND OF THE INVENTION
is The class of drugs called statins are currently the most therapeutically
effective
drugs available for reducing low-density lipoprotein (LDL) particle
concentration in the
blood stream of patients at risk for cardiovascular disease and thus, statics
are used in the
treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis.
A high
level of LDL in the bloodstream has been linked to the formation of coronary
lesions that
obstruct the flow of'blood and can rupture and promote thrombosis. Goodman and
Gilman, The Pharmacological Basis of Therapeutics, page 879 (9th Ed. 1996).
Statins inhibit cholesterol biosynthesis in humans by competitively inhibiting
the
3-hydroxy-3-methyl-glutaryl-coenzyme A ("HMG-CoA") reductase enzyme. HMG-CoA
reductase catalyzes the conversion of IIMG to mevalonate, which is the rate
determining
step in the biosynthesis of cholesterol. Decreased production of cholesterol
causes an
increase in the number of LDL receptors and corresponding reduction in the
concentration
of LDL particles in the bloodstream. Reduction in the LDL level in the
bloodstream
reduces the risk of coronary artery disease. I.A.M.A. 1984, 251, 351-74.
Currently available statins include lovastatin, simvastatin, pravastatin,
fluvastatin,
cerivastatin and atorvastatin. Lovastatin (disclosed in U.S. Pat. No.
4,231,938) and
simvastatin (ZQCOR; disclosed in U.S. Pat. No. 4,444,784 and WO 00/53566) are
administered in the lactone form. After absorption, the lactone ring is opened
in the liver
by chemical or enzymatic hydrolysis, and the active hydroxy acid is generated.
1.
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Pravastatin (PRAVACHOL; disclosed in U.S. Pat. No. 4,346,227) is administered
as the
sodium salt. Fluvastatin (LESCOL; disclosed in U.S. Pat. No. 4,739,073) and
cerivastatin
(disclosed in U.S. Pat. No. 5,006,530 and 5,177,080), also administered as the
sodium salt,
are entirely synthetic compounds that are in part structurally distinct from
the fungal
derivatives of this class that contain a hexahydronaphthalene ring.
Atorvastatin and two
new "superstatins," rosuvastatin and pitavastatin, are administered as calcium
salts. The
structural formulas of these statins are shown below.
HO O
HO O ,,,Cr HO COON
O \ /0 O 0 ~OH
Y
H3- CYrH H3' CYCH3 H H3C "'H
H CH3 CH3 H CH3
H3C H3C. HO.
Lovastatm Sirrtvastatin Pravastatm
= HO`^COOH =
TIVOH
N
F \ - CH30HzC ~ \COOH
/ N HO H H OH
\
F
Fluvastatin
F F Cerivastatin
F OH
COON
OH OH
N OH OH N
NH N \ H 0
O O
O HO 01~S\ CHs OH N
0
Rosuvastatin Pitavastatin
Atorvastatin
Atorvastatin is the common chemical name for [R-(R*, R*)]-2-(4-fluorophenyl)-
13,5-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-
pyrrole- l -
heptanoic acid. The free acid of atorvastatin is prone to lactonization. The
systematic
chemical name of atorvastatin lactone is (2R-trans)-5-(4-fluorophenyl)-2-(1-
methylethyl)-
N,4-diphenyl- l -[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1 H-
pyrrole-3-
carboxamide. Atorvastatin and its corresponding racemic lactone are disclosed
in U.S.
Patent No. 4,681,893.
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The lactone form is disclosed in U.S. Patent No. 5,273,995. In Examples 4 and
5
of the `995 patent, the lactone is prepared by dissolving 1,1-dimethylethyl
(R)-7-[2-(4-
fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrol-
l -yl]-5-
hydroxy-3-oxo-l-heptanoate in tetrahydrofuran and triethyl borane, followed by
the
addition of t-butylcarboxylic acid. After cooling, methanol is added followed
by sodium
borohydride. The mixture is poured into an ice/hydrogen peroxide/water
mixture.
Trichloromethane is added and the mixture is partitioned. The organic layer is
dried over
magnesium sulfate, filtered, and the solvent is evaporated. The product is
dissolved in
tetrahydrofuran and methanol and added to a solution of sodium hydroxide. The
mixture
is concentrated to remove organic solvent, added to water, and extracted with
diethyl
ether. The aqueous layer is acidified with hydrochloric acid and extracted
with ethyl
acetate. The organic layer is dried with anhydrous magnesium sulfate,
filtered, and the
solvent evaporated. The residue is dissolved in toluene and concentrated. The
product is
recrystallized from ethyl acetate and hexane to produce the lactone.
The lactone can also be prepared according to the procedures disclosed in U.S.
Patent No. 5,00,080. For instance, in Example 2, Method A, cis-2-(4-
I'luorophenyl)- 3,s-
dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)carbonyl-1 H-pyrrole- l -
heptanoic
acid, methyl ester is treated with sodium hydroxide, and after dilution with
water and
separation, the remaining layer are washed with hexane and ethyl acetate
followed by
concentrated hydrochloric acid solution. Upon separation, the upper layer is
washed with
hydrochloric acid and concentrated. The residue is dissolved in toluene.
As disclosed in the `080 patent, the lactone can also be prepared by mixing (
)-cis-
6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid (Example 2, Method B);
( )-
(2a,4a,6a) or ( )-(2a,4f3,6(3)-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetic
acid
(Example 2, Method C); ( )-cis-9-(2-aminoethyl)-6,10-dioxaspiro[4.5]decane-7-
acetic
acid (Example 2, Method D); ( )-cis-(4-(2-aminoethyl)-1,5-
dioxaspiro[5.5]undecane-2-
acetic acid (Example 2, Method E); or ( )-(2a,4a,6a) or ( )-(2a,413,613)-6-(2-
aminoethyl)-2-methyl-1,3-dioxane-4- acetic acid (Example 2, Method F and G)
with ( )-
4-fluoro-a-[2-methyl- l -oxopropyl]-y-oxo-N, 13-diphenylbenzenebutaneamide in
dimethyl
sulfoxide. After heating, the solution is poured into a mixture of diethyl
ether and
saturated ammonium chloride in water. After separation, the organic layer is
washed with
water and sodium hydroxide. The aqueous layer is acidified with dilute
hydrochloric acid
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and extracted with ethyl acetate, to which hydrochloric acid is added, and the
solution is
concentrated. The residue is dissolved in toluene.
Another method of making the lactone, according to the `080 patent, includes
mixing ( )-cisl,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-
acetate
(Example 2, Method H); ( )-(2a,4a,6a) or ( )-(2a,413,613)-1,1-dimethyl-6-(2-
aminoethyl)-2-phenyl-1,3-dioxane-4-acetate (Example 2, Method I); or ( )-cis-
l,l-
dimethylethyl (4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetate (Example
2,
Method J) with ( )4-fluoro-a-[2-methyl-l-oxopropyl]-y-oxo-N,13-diphenylbenzene
butaneamide in heptane:toluene (9:1). After heating, the solution is poured
into a mixture
of tetrahydrofuran and ammonium chloride in water. After separation, the
organic layer is
washed with brine, followed by the addition of hydrochloric acid. After
stirring, sodium
hydroxide is added to the organic layer. The reaction is stopped by adding a
mixture of
water and hexane. After separation, the aqueous layer is acidified with dilute
hydrochloric
acid, extracted with ethyl acetate, and concentrated. The residue is dissolved
in toluene.
The lactone or the free acid may be used to prepare the pharmaceutically
acceptable calcium salt, [R-(R*,R*)]-2-(4-fluorophenyl)-[3,S-dihydroxy-5-(1-
methylethyl)-
3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-l-heptanoic acid calcium salt
(2:1)
trihydrate. In animal models, atorvastatin calcium salt has been shown to
lower plasma
cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and
cholesterol
synthesis in the liver. Atorvastatin is marketed by PFIZER as the hemicalcium
salt
trihydrate under the trade name LIPITOR, as 10, 20, 40 and 80 mg tablets.
Atorvastatin
hemicalcium salt has the following structure:
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F
OH OH 0 *Ca 2+
=3 HZO
NH
O
2
Atorvastatin Hemicalcium Salt
The hemicalcium salt is disclosed in U.S. Patent No. 5,273,995, which teaches
that
the calcium salt is obtained by crystallization from a brine solution
resulting from the
transposition of the sodium salt with calcium chloride and further purified by
recrystallization from a 5:3 mixture of ethyl acetate and hexane.
U.S. Patent No. 5,298,627, also discloses a process for making the hemicalcium
salt. In Example 1 of this patent, (4R-cis)-1-[2-[6-[2-(diphenylamino)-2-
oxoethyl]-2,2-
dimethyl-1,3-dioxan-4-yl] ethyl] -5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-
diphenyl-1 H-
pyrrole-3-carboxamide is dissolved in methanol and reacted with hydrochloric
acid to
form [R-(R*,R*)]-5-(4-fluorophenyl)-R,8-dihydroxy-2-(1-methylethyl)-N,N,4-
triphenyl-3-
[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamide, which is mixed with methanol
and
sodium hydroxide. The filtrate is washed with tert-butyl methyl ester and the
aqueous
layer is acidified using aqueous hydrochloric acid and extracted with tert-
butyl methyl
ester to form the sodium salt of [R-(R*,R*)]-2-(4-fluorophenyl)-[i,8-dihydroxy-
5-(1-
methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-l-heptanoic acid.
The
sodium salt is converted to the hemicalcium salt by the addition of calcium
acetate in
water.
In an analogous process, (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-N,N-
bis(phenylmethyl)- 1,3-dioxane-4 -acetamide is converted to [R-(R*,R*)]-5-(4-
fluorophenyl)-(3,6-dihydroxy-2-(1-methylethyl)-4-phenyl-3-
[(phenylamino)carbonyl]-
N,N-bis(phenylmethyl)-1H-pyrrole-l-heptanamide which is further converted to
the
hemicalcium salt (Example 2); (4R-cis)-6-(2-aminoethyl)-N,N-diethyl-2,2-
dimethyl-1,3-
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dioxane-4-acetamide is converted to [R-(R*,R*)]-N,N-diethyl-5-(4-fluorophenyl)-
[3,8-
dihydroxy-2-(1-methylethyl)-4-phenyl-3-[(phenylamino)carbonyl]-1 H-pyrrole- l -
heptanamide which is further converted to the hemicalcium salt (Example 3);
(4R-cis)-6-
(2-aminoethyl)-N-butyl-N,2,2-trimethyl-1,3-dioxane-4-acetamide is converted to
[R-
(R*,R*)]-N-butyl-5-(4-fluorophenyl)-[i,8-dihydroxy-N-methyl-2-(1-methylethyl)-
4-
phenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-l-heptanamide which is further
converted
to the hemicalcium salt (Example 4); (4R-cis)-6-(2-aminoethyl)-N-(l,1-
dimethylethyl)-
2,2-dimethyl-N-(phenylmethyl)-1,3-dioxane-4-acetamide is converted to [R-
(R*,R*)]-N-
(1,1-(dimethylethyl)-5-(4-fluorophenyl)-[3,8-dihydroxy-2-(1-methylethyl)-4-
phenyl-3-
[(phenylamino)carbonyl]-N-(phenylmethyl)-1H-pyrrole-l-heptanamide which is
further
converted to the hemicalcium salt (Example 5); and (4R-cis)-1-[[6-(2-
aminoethyl)-2,2-
dimethyl-1,3-dioxan-4-yl]-acetyl]piperidine is converted to [R-(R*,R*)]-1-[3,5-
dihydroxy-
7-oxo-7-(1-piperidinyl)heptyl]-5-(4-fluorophenyl-2-(1-methylethyl)-N-4-
diphenyl-1 H-
pyrrole-3-carboxamide which is further converted to the hemicalcium salt
(Example 6).
Rosuvastatin is the common chemical name for [S-[R*,S*-(E)]]-7-[4-(4-
fluorophenyl)-6-(1-methylethyl)-2- [methyl(methylsulfonyl)amino]-5-
pyrimidinyl] -3, 5-
dihydroxy-6-heptenoic acid. Rosuvastatin is in the process of being approved
for
marketing under the name CRESTOR, which contains rosuvastatin calcium.
Rosuvastatin,
its calcium salt (2:1), and its lactone form are disclosed and claimed in U.S.
Patent No.
5,260,440. The process of the `440 patent prepares rosuvastatin by reacting 4-
(4-
fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-
pyrimidinecarbardehyde with methyl (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-
triphenylphosphoranylidene hexanate in acetonitrile under reflux. The silyl
group is then
cleaved with hydrogen fluoride, followed by reduction with NaBH4 to obtain a
methyl
ester of rosuvastatin.
The ester is then hydrolyzed with sodium hydroxide in ethanol at room
temperature, followed by removal of ethanol and addition of ether, to obtain
the sodium
salt of rosuvastatin. The sodium salt is then converted to the calcium salt
with a multi-step
process. The sodium salt is dissolved in water and maintained under a nitrogen
atmosphere. Calcium chloride is then added to the solution, resulting in
precipitation of
rosuvastatin calcium (2:1). Hence, the process of the `440 patent prepares
rosuvastatin
calcium through the sodium salt intermediate.
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U.S. Pat. No. 6,316,460 discloses a pharmaceutical composition of
rosuvastatin.
The pharmaceutical compositions contain rosuvastatin or its salt and a
multivalent tribasic
phosphate salt. The `460 patent does not disclose any methods for preparing
the calcium
salt of rosuvastatin.
Pitavastatin is the common chemical name for (E)-3,5-dihydroxy-7-[4'-(4"-
fluorophenyl)-2'-cyclopropyl-quinolin-3'-yl]-hept-6-enoic acid. Pitavastatin,
its calcium
salt (2:1), and its lactone are disclosed in three related U.S. Pat. Nos.
5,011,930, 5,856,336
and 5,872,130.
The `930 patent prepares pitavastatin ethyl ester in accordance with Example
1.
First 4-(4'-fluorophenyl-2'-(1'-cyclopropyl)-quinolin-3'-yl-carboxylate is
prepared by
reacting 2-amino-4'-fluorobenzophenone with ethyl isobutyrylacetate, which is
then
converted to 4-(4'-fluorophenyl)-3-hydroxymethyl-2-(1'-cyclopropyl)-quinoline,
which is
converted to 4-4'-fluorophenyl-2-(1'-cyclopropyl)-quinolin-3'-yl-
carboxyaldehyde, which
is converted to 3-(3'-ethoxy-1'-hydroxy-2'-propenyl)-4-(4'-fluorophenyl)-2-(1'
cyclopropyl)-quinoline, which is converted to (E)-3-[4'-(4"-fluorophenyl)-2'-
(1-
cyclopropyl)-quinolin-3'-yl]propenaldehyde, which is converted to ethyl (E)-7-
[4-(4"-
fluorophenyl-2'-(1 "-cyclopropyl)-quinolin-3'-yl]-5-hydroxy-3-oxohepto-6-
enoate, which is
converted to ethyl (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-(1"-
cyclopropyl)-quinolin-
3'-yl]-hept-6-enoate.
The resulting ester, ethyl (E)-3,5-dihodroxy-7-[4'-(4"-fluorophenyl)-2'-(1"-
cyclopropyl)-quinolin-3'-yl]-hept-6-enoate, is converted to the sodium salt in
accordance
to Example 2 by using an aqueous solution of sodium hydroxide. The compound is
dissolved in ethanol, to which an aqueous solution of sodium hydroxide is
added. The
resulting mixture is stirred and the ethanol is removed under reduced
pressure. Water is
then added, and the mixture is further extracted with ether. The aqueous layer
is then
lyophilized to obtain the final product, or the aqueous layer is weakly
acidified with a
dilute solution of hydrochloric acid. The acidified aqueous layer is then
extracted with
ether. After extraction, the ether layer is dried over magnesium sulphate.
Then the ether
is removed under reduced pressure to obtain the sodium salt. The `930 patent
and its
related patents do not disclose preparing the calcium salt of any compound.
These patents prepare the lactone by dissolving the sodium salt prepared in
dry
toluene, refluxing the solution and removing the toluene under reduced
pressure. The
crude solid is then recrystallized from diisopropyl ether to obtain the
lactone, [4'-(4"-
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fluorophenyl)-2' -(1 "-methylethyl)quinolin-3' -ylethynyl] -4-hydroxy-3,4,5,6-
tetrahydro-
2H-pyran-2-one. The lactone is further reduced using palladium/carbon under
nitrogen
atmosphere.
U.S. Pat. No. 6,335,449 improves the prior art process for preparing
pitavastatin by
reacting an aldehyde quinoline with diethyl cyanomthylphosphonate to obtain a
nitrile
intermediate for the synthesis of pitavastatin. U.S. Pat. No. 6,335,449 does
not disclose
how to prepare the calcium salt or any other salt of pitavastatin.
Simvastatin is the common medicinal name of the chemical compound
butanoicacid,2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-
(tetrahydro-4-hydro
1o xy-6- oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S*-[1a,3
a,7b,8b(2S*,4S),-8ab]].
(CAS Registry No. 79902-63-9.). Simvastatin is marketed as ZOCOR, and is
disclosed in
U.S. Patent Nos. 4,444,784 and 6,002,021, as well as WO 00/53566. These
references
disclose preparing the lactone, and the open form of simvastatin.
Of these references, only WO 00/53566 discloses preparing the calcium salt of
the
open form of simvastatin. In a typical example, the process of WO 00/53566
hydrolyzes
the lactone of simvastatin with sodium hydroxide, followed by addition of a
calcium
source, such as calcium acetate hydrate.
The above prior art processes of making calcium statin salts, such as
atorvastatin,
pitavastatin, rosuvastatin and simvastatin, all either do not disclose how to
prepare the
calcium salt, or proceed through a sodium salt intermediate. Further, some of
the
processes are highly sensitive and are not consistently reproducible and have
unsuitable
filtration and drying properties for large-scale production. It is desirable
to obtain a stable
product in fewer steps than previous methods using a process that is easily
reproducible
and is amenable to large-scale production.
SUMMARY OF THE INVENTION
The present invention provides a novel process for preparing statin calcium
salts
having the formula:
OH OH 0
Ca 2+
R O-
2
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wherein R represents an organic radical, comprising contacting an ester
derivative of
the statin selected from the group consisting of:
OR2 OR3 0
R OR1
and
Rao O
O
with a sufficient amount of calcium hydroxide,
wherein R1 is a C1 to a C8 alkyl group, and
R2, R3 and R4 each independently represent hydrogen, or the same or different
hydrolyzable protecting group, or R2 and R3, together with the oxygen atom to
which each
is bonded, form a hydrolyzable cyclic protecting group.
The reaction can be carried with or without a phase transfer catalyst.
Preferred
phase transfer catalysts are quaternary ammonium salts such as
tetrabutylammonium
bromide (TBAB) and triethylbenzylammonium chloride (TEBA). The reaction is
preferably heated to accelerate the conversion.
Preferred statins are atorvastatin, rosuvastatin, pitavastatin and
simvastatin. In a
preferred embodiment, R2, R3 and R4 are hydrogen. Each of R2, R3 or R4 can
also be the
same or different protecting group, which are hydrolyzed by use of calcium
hydroxide in
one step together with hydrolysis of the ester group, i.e., -COORI, or
hydrolyzed by using
an acid catalyst, followed by hydrolysis of the ester group -COOR1. Preferred
protecting
groups are silyl groups such as trialkylsilyl, which can be hydrolyzed by
calcium
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hydroxide, and acetonide, which can be hydrolyzed by an acid catalyst.
Acetonide forms a
cyclic hydrolyzable protecting group, i.e., a dioxane.
In another aspect, the present invention provides a process for preparing a
calcium
salt of a statin having the formula:
OH OH O
R OH
wherein R represents an organic radical, comprising the steps of:
adding calcium hydroxide and an ester derivative of the statin as described
above to a
mixture of water and a C, to a C4 alcohol, heating the mixture, precipitating
the calcium
salt of the statin and separating the calcium salt.
DETAILED DESCRIPTION OF THE INVENTION
Forming an ester is a well known way of protecting a carboxylic acid group and
masking its acidic proton. Green, T.W.; Wuts, P.G.M. Protective Groups in
Organic
Synthesis 3rd. ed., chapter 5 (John Wiley & Sons: New York 1999) ("Greene &
Wuts").
It is also known, generally, that carboxylic acids that have been protected as
esters may be
deprotected by hydrolyzing the ester with a strong base. Id. at 377-78.
Sodium hydroxide is a strong base with a dissociation constant of 6.37
(pKb= -0.80), Handbook of Chemistry and Physics 81st ed. 8-45 (CRC Press: Boca
Raton
2000-01), and its use as a reagent for deprotecting ester-protected carboxylic
acids is
taught in the art. Green & Wuts, p. 377. Calcium hydroxide (Ca(OH)2), with a
first
dissociation constant of 3.74 x 10-3 (pKb=2.43) and second dissociation
constant of 4.0 x
10-2 (pKb= 1.40), is a much weaker base than sodium hydroxide. Handbook of
Chemistry
and Physics 63rd ed. D-170 (CRC Press: Boca Raton 1983).
Calcium hydroxide is not listed among the reagents that have been used to
hydrolyze esters in a well known compendium of functional group
transformations in
organic synthesis. Larock R.C. Comprehensive Organic Transformations 2nd ed.,
Section
NITRILES, CARBOXYLIC ACIDS AND DERIVATIVES, Sub-sect. 9.17, pp. 1959-68
(Wiley-VCH: New York 1999). Its use as a general reagent for deprotecting
ester-
protected carboxylic acids is not taught by a well known reference book on
methods for
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protecting and deprotecting organic functional groups. Greene & Wuts. pp. 377-
79. In
fact, U.S. Pat. No. 5,273,995 cautions against using an excess of sodium
hydroxide to
prepare the sodium salt in order to prevent forming calcium hydroxide when
calcium
chloride is later added to a solution of the sodium salt. It appears not to
have been
appreciated that ester-protected forms of statins such as atorvastatin can be
converted
directly to the respective hemi-calcium salts, such as atorvastatin hemi-
calcium, without
first treating the ester with a strong base like sodium hydroxide to hydrolyze
it, then
displacing the sodium ion by contacting the sodium salt with a calcium salt
such as
calcium chloride or calcium acetate.
As used herein, an "ester derivative" is a compound resulting from replacement
of
the hydroxyl proton of the carboxylic acid group in the ring-opened or
dihydroxy acid
form of the statin with a substituent bonded to the hydroxyl oxygen atom
through carbon.
Such ester derivatives include, e.g., compounds wherein the substituent bonded
to the
hydroxyl oxygen of the carboxylic acid is a C1-C8 alkyl group. The ester
derivative used
for conversion can be a mixture of derivatives containing various esters. For
example, a
methyl ester derivative can be added to ethanol, resulting in the conversion
of some of the
methyl esters to ethyl esters. The ester derivative of the statin can be
produced by
methods known in the art or can be purchased commercially. An ester derivative
also
includes the lactone or closed-ring form of the statin. The lactone form is a
cyclic ester in
which the ester group of the statin is incorporated into the ring. A mixture
of ester
derivatives also includes a mixture of the open- and closed-ring forms of the
statin.
The present invention is directed to statins having the general formula:
OH OH 0
R OH
in which an organic radical R is attached to a diol-pentanoic acid group.
These statins
include, e.g., pravastatin, fluvastatin, cerivastatin, atorvastatin,
rosuvastatin, pitavastatin,
lovastatin and simvastatin. Of these, atorvastatin, rosuvastatin, pitavastatin
and
simvastatin are preferred.
R refers to an organic radical that is bonded to the diol pentanoic acid
group.
Depending on the statin, the R radical can be:
pravastatin: 1,2,6,7,8,8a-Hexahydro-6-hydroxy-2-methyl-8-(2-methyl- l -
oxobutoxy)-1-
naphthalene ethyl radical.
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fluvastatin: 3-(4-fluorophenyl)-1 -(1-methylethyl)-1H-indol-2-yl]-ethylene
radical.
cerivastatin: 4-(4-fluorophenyl)-5-methoxymethyl)-2,6bis(1-methylethyl)-3-
pyridinyl-
ethylene radical.
atorvastatin: 2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]-
1H-pyrrole-ethyl radical
rosuvastatin: [4-(4-fluorophenyl)-6-(1-methylethyl)-2-
[methyl(methylsulfonyl)amino]-5-
pyrimidinyl]-ethylene radical.
pitavastatin: [4'-(4 " -fluorophenyl)-2'-cyclopropyl-quinolin-3'-yl] -ethylene
radical.
The R radical can also be that of the open ring form, i.e., the dihydroxy
acid, of
simvastatin or lovastatin. These open ring forms also have a diol pentanoic
acid group. As
used herein, the terms simvastatin and lovastatin include both the lactone
form and the
open-ring form. When the statin is simvastatin or lovastatin, the R radical
is:
simvastatin: 1,2,6,7,8,8a-Hexahydro-2,6-dimethyl-8-(2,2-dimethyl-l -oxobutoxy)-
1-
naphthalene ethyl radical.
lovastatin: 1,2,6,7,8,8a-Hexahydro-2,6-dimethyl-l-8-(2-methyl- l -oxobutoxy)-1-
naphthalene ethyl radical.
The calcium salt of these and other statins can be made by the processes of
the
present invention such that the organic radical bonded to the diol pentanoic
acid group or
corresponding lactone, defines a compound that is a statin, i.e., a compound
that inhibits 3-
hydroxy-3-methyl-glutaryl-coenzyme A ("HMG-CoA") reductase enzyme. See e.g. WO
00/53566. Thus, R should not be construed as limited to the organic radical
bonded to the
diol pentanoic acid group or corresponding lactone of the statins expressly
disclosed or
exemplified herein. All hydrates, solvates and anhydrates of the calcium salt
and other
polymorphic forms thereof, crystalline or amorphous, of these statins are
within the scope
of the present invention.
The present invention illustrates preparation of calcium salt of these statins
by
using preparation of atorvastatin hemi-calcium as an example. To the extent
that an aspect
in the preparation of atorvastatin hemi-calcium is different than that for
another statin, one
of skill in the art would appreciate that atorvastatin is being used merely
for illustrative
purposes; and that the various aspects in the preparation of atorvastatin hemi-
calcium can
be readily modified to prepare the other statins, while still being within the
spirit and
scope of the present invention.
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WO 03/016317 PCT/US02/26012
The present invention provides a process for preparing a statin hemi-calcium
salt
by converting a statin ester derivative of formula:
OH OH 0
'Ij~
R OR1
or
OH
O
R
wherein R represents an organic radical and R1 is a C1 to C8 alkyl group, to
the
corresponding hemi-calcium salt having the formula:
OH OH 0
Ca 2+
R O-
2
by contacting the ester derivative with a sufficient amount of calcium
hydroxide. A
"sufficient amount" as used herein refers to the amount of calcium hydroxide
that
substantially converts the ester derivative to the corresponding hemi-calcium
salt. By
"substantially converts" as used herein is meant an amount such that greater
than about
50% (molar basis), preferably greater than about 70%, and more preferably
greater than
about 90% of the statin ester derivative is converted to the corresponding
hemi-calcium
salt. Most preferably, greater than about 95% of the statin ester derivative
is converted to
the corresponding hemi-calcium salt.
An unexpected advantage of this process is that the calcium hydroxide fulfills
two
roles. It functions as a basic catalyst for hydrolysis of the ester and
supplies calcium ions
for forming the hemi-calcium salt. Another significant practical advantage of
the process
is that the amount of calcium hydroxide does not have to be as carefully
controlled as the
amount of sodium hydroxide and calcium chloride/acetate used in other
processes which,
in contrast to the present invention, involve a sequential process of
hydrolyzing the ester
derivative with NaOH followed by displacement of the sodium ion with calcium
ions.
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WO 03/016317 PCT/US02/26012
The statin ester derivative may be provided in pure form or in mixture with
other
statin ester derivatives. The statin ester derivative, optionally in mixture
with other statin
ester derivatives, is dissolved or suspended preferably in a mixed solvent
comprising a C,-
C4 alcohol and water. Preferred alcohols are ethanol and isopropyl alcohol
("IPA") and a
preferred solvent mixture contains about 5% to about 15% water in ethanol or
IPA, more
preferably about 10% water and about 90% ethanol (v/v) or IPA. Whether the
statin ester
derivative dissolves in the mixed solvent depends upon such factors as the
choice of C,-C4
alcohol, the proportion of water, the temperature and the purity of the statin
ester
derivative. Calcium hydroxide is then suspended in the solvent and the base
hydrolysis
reaction mixture is maintained until the statin ester derivative has been
consumed.
Consumption of the statin ester derivative may be monitored by any
conventional means
such as TLC, HPLC and NMR. After the statin ester derivative has been
consumed, statin
hemi-calcium is recovered from the base hydrolysis reaction mixture by
conventional
means. It is unnecessary to add another source of calcium to provide a Caz+
ion for the
atorvastatin hemi-calcium salt.
According to a preferred procedure foi practicing the base hydrolysis process,
the
statin ester derivative is added in an amount sufficient to provide about 10
mmoles L-' to
about 1 mole L"' of the mixed solvent.
Preferably, about 1 equivalent to about 6 equivalents of calcium hydroxide
with
respect to the ester derivative 1 is used. More preferably, from about 1 to
about 2
equivalents is used.
Calcium hydroxide is only sparingly soluble in the C1-C4 alcohol:water mixed
solvent and only a minor proportion of it will be in solution available to
catalyze the
hydrolysis at any one time. To accelerate the base hydrolysis, a phase
transfer catalyst
may be added to increase the solubility of the calcium hydroxide. Phase
transfer catalysts
are well known in the art and include, for instance, tetra-n-butylammonium
bromide
("TBAB"), benzyltriethylammonium chloride ("TEBA"), tetra-n-butylammonium
chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide,
tetra-etylammonium chloride, benzyltributylammonium chloride,
benzyltributylammonium bromide, benzyltri ethyl ammonium bromide,
tetramethylammonium chloride and polyethylene glycol. A most preferred phase
transfer
catalyst is TBAB. When used, the phase transfer catalyst should be used in a
14
CA 02450820 2010-02-25
substoichiometric amount, preferably from about 0.05 to about 0,25
equivalents, more
preferably about 0.1 equivalents, with respect to statin ester derivative.
The mixture maybe heated to up to the reflux temperature of the mixed solvent
in
order to accelerate the reaction. A preferred temperature range is at an
elevated
temperature of from about 40 C to about 70 C.
After consumption of the statin ester derivative, statin hemi-calcium or
solvate
thereof is recovered from the base hydrolysis reaction mixture. As part of
recovering the
statin hemi-calcium, the reaction mixture is preferably filtered to remove
excess
suspended calcium hydroxide. The reaction mixture preferably is filtered while
hot to
prevent precipitation of statin hemi-calcium on the calcium hydroxide
filtercake.
After filtration to remove suspended calcium hydroxide, statin hem-calcium may
be recovered from the filtrate by precipitation. According to a preferred
recovery
technique, statin hemi-calcium is caused to precipitate from the filtrate by
slow addition of
water. A volume of water roughly equivalent to the volume of the filtrate is
added over
about an hour's time. Preferably, the slow water addition is also conducted at
elevated
fiemperatures, e.g. from about 40 C to about 65 C. Precipitating statin hemi-
calcium by
slow water addition yields statin hemi-ealoium in a crystalline form and
prevents
formation of a gelatinous precipitate. Alternatively, statin hemi-calcium may
be recovered
by any conventional means. After any necessary purification steps, the
recovered statin
hemi-calcium may be used as an active ingredient to formulate a pharmaceutical
product.
The filtering characteristics and purity of the statin hemi-calcium may be
further
improved by redissolving the crystalline product in the aqueous alcohol
reaction mixture
by heating to a temperature sufficient to cause all the precipitate to
dissolve, resulting in a
clear solution. The solution is preferably cooled slowly over several hours
and held,
preferably at ambient temperature, until no more crystals are observed to
form. After
filtering and drying, and any further optional purification steps, the statin
harm-calcium or
solvate thereof may be used as an active ingredient in a pharmaceutical
product.
Statins are sometimes prepared through an intermediate in which one or both of
the
hydroxyls in the pentanoic acid diol group (open-ring form) or the hydroxyl of
the lactone
(closed-ring form) are protected via a hydrolyzable protecting group and the
carboxyl
group is protected via an ester derivative as described hereinabove. For
example, U.S_ Pat.
No. 5,260,440 uses a silyl protecting group during
synthesis of rosuvastatin. U.S. Pat. Nos. 6,002,021 and 4,444,784
CA 02450820 2010-02-25
use a silyl protecting group during the synthesis of simvastatin. Brower, P.L.
et
al. Tet. Lett. 1992,33,2279-82 and Baumann, K.L. at al. T. Len 1992,33,2283-
2284,
prepare atorvastatin through a dioxane intermediate that
has an acetonide protecting group, i.e., R2 and R3, together with the oxygen
atom to which
each is bonded, form a hydrolyzable cyclic protecting group.
These compounds, referred to herein as "protected static ester derivatives"
may
be converted in accordance with the present invention to the corresponding
hemi-calcium
salt. Thus, in another embodiment, the present invention is directed to a
process for
preparing a calcium salt of a statin having the formula:
OH OH 0
bH
wherein R represents an organic radical, comprising contacting an ester
derivative of
the statin selected from the group consisting of
RZ OR3 O
OR1
and
R40 O
O
with a sufficient amount of calcium hydroxide, wherein R1 is a C1 to a Cg
alkyl
group, and R2, R3 and B4 each independently represent hydrogen, or the same or
different
hydrolyzable protecting group, or R2 and R3, together with the oxygen atom to
which each
is bonded, form a hydrolyzable cyclic protecting group- The.protecting group
used is
preferably hydrolyzable under acidic or basic conditions. Preferred protecting
groups R2,
R3 and R4 in accordance with this embodiment of the present invention include,
for
example, silyl groups, with trialkylsilyl and alkyldiarylsilyl being more
preferred, and with
t-butyl-dimethyl-silyl being the most preferred; and, cyclic protecting groups
such that R2
and R3 form, for example, a dioxane.
16
CA 02450820 2010-02-25
U.S. Pat. No. 6,294,680. discloses additional
protecting groups used in the synthesis of statins, particularly simvastatin.
Disclosed
cyclic protecting groups include a dioxane, a cyclic sulfate, a cyclic
phosphate or
borylidene, which are optionally substituted with alkyl and aryl groups. Other
protecting
s groups include boronic acid, disclosed in WO 95113283,
and esterification with an acetic anhydride, disclosed in U.S. Pat. No.
5,159,104,
U.S. Pat. No. 6,100,407
discloses additional protecting groups. The protecting groups disclosed in
these
references may be used in accordance with the present invention.
It has surprisingly been found that a silyl group can be hydrolyzed and
removed by
contact with calcium hydroxide. Hence the use of a silyl group allows for
removal of the
protecting group and conversion of the ester to a calcium salt in one step, in
the same
solvent. The use of calcium hydroxide eliminates the need for a separate step
of acid
hydrolysis of the silyl protecting group with, e.g., a hydrogen halide such as
hydrogen
fluoride, to remove the protecting group, as required by the processes of U.S.
Pat. No.
5,260,440 and U.S. Pat. No. 4,444,784. Thus, the process of the present
invention applies
to any statin with a silyl or other protecting group R2, R3 and R4 capable of
being
hydrolyzed by calcium hydroxide. The protected rosuvastatin disclosed in U.S.
Pat. No.
5,260,440, e.g., can be used, with a modification of reducing the ketone to
obtain
hydrogen as R2. The silyl protected simvastatin disclosed in U.S. Pat. Nos.
4,444,784 and
6,002,021 can also be used.
Some of the protecting groups are best hydrolyzed under acidic conditions.
Thus,
before contacting the protected statin ester derivative with calcium
hydroxide, an acid
catalyst is added to hydrolyze the protecting group. Examples of such acid
catalysts
include acetic acid, trifluoroacetic acid, p-toluenesulfbnic acid, zinc
bromide and
hydrochloric acid or other hydrogen halide, with acetic acid and hydrochloric
acid being
preferred. The resulting diol ester is then converted to the calcium salt by
contact with
calcium hydroxide. The process can also be carried out in one pot. The diol-
ester is
formed as described above, and is then reacted with calcium hydroxide to form
atorvastatin hemi-calcium in the same pot, without changing solvent. A
preferred solvent
is a mixture of water and a C, to a C4 alcohol, with ethanol being preferred.
A preferred
pH for the reaction is less than about 3, more preferably less than about 1.
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CA 02450820 2003-12-11
WO 03/016317 PCT/US02/26012
A preferred protecting group that is removed with an acid catalyst is an
acetonide,
i.e., a compound in which the diol forms a cyclic hydrolyzable protecting
group, i.e., a
dioxane. Preferably, any acetone formed during the reaction of the acetonide
with the acid
catalyst is removed, e.g., by evaporation under reduced pressure.
The one pot process with use of acid catalyst is illustrated as follows:
F F
0
0 0 acid y OH OH 0
NH NH
0 0 +
Acetortide Ester (1) Diol-Ester (II)
Ca(OH)2
F
OH OH 0 =Ca2+
=3 H2O
NH
O
2
Atorvastatin Hemicalcitan Salt
Pharmaceutical compositions may be prepared as medicaments to be administered
orally, parenterally, rectally, transdermally, bucally, or nasally. Suitable
forms for oral
administration include tablets, compressed or coated pills, dragees, sachets,
hard or gelatin
capsules, sub-lingual tablets, syrups and suspensions. Suitable forms of
parenteral
administration include an aqueous or non-aqueous solution or emulsion, while
for rectal
administration suitable forms for administration include suppositories with
hydrophilic or
hydrophobic vehicle. For topical administration, the invention provides
suitable
transdermal delivery systems known in the art, and for nasal delivery there
are provided
suitable aerosol delivery systems known in the art.
18
CA 02450820 2010-02-25
Pharmaceutical compositions of the present invention contain statin
hemicalcium,
particularly atorvastatin hemicalcium, rosuvastatin hemicalcium, pitavastatin
hemicalcium, simvastatin hemicalcium and lovastatin hemicalcium. In addition
to the
active ingredient(s), the pharmaceutical compositions of the present invention
can contain
one or more excipients. Selection of excipients and the amounts to use can be
readily
determined by the formulation scientist based upon experience and
consideration of
standard procedures and reference works in the field. U.S. Pat. No. 6,316,460,
and the most recent edition of Handbook of
Pharmaceutical Excipients, American Pharmaceutical Association, can be used as
a
guidance. The dosage and formulation of LIPJTORD (atorvastatin hem-calcium)
and
the other pharmaceuticals can also be used as a guidance.
EXAMPLES
Gene
Unless otherwise indicated, reagents were used as received. [R-(R*,R*)] 2-(4-
fluorophenyl)-I,5-dioxane-5 -(1-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]-1 H-
pyrrole-1-test-butylheptanoic ester (dioxane 2, R, - t-Butyl) was prepared by
a
condensation reaction between the corresponding diketone and the corresponding
chiral
amine to form the pyrrole ring. It also may be prepared by known methods.
Brower, P.L.
at al. Tat. Lett. 1992, 33, 2279-82; Baumann, K.L. at al. Tat. Lett. 1992, 33,
2283-84. The
following HPLC conditions were used to determine the composition of mixtures
obtained
in the acid hydrolyses reported in the examples: Waters Spherisorb S3
ODS1(7.6x100
mm), 70:30 acetonitrile:water, 0.6 ml min.-', 20 tl sample, UV detection x254.
Example 1 '
Preparation of aM astatio calcium from a dioxane ester derivative
In a flask equipped with a magnetic stirrer, [R-(R*,R*)]-2-(4-fluorophenyl)-
R,S-
dioxane-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH pyrrole-l-tent-
butylheptanoic ester (2.0 g) was suspended in an 80% aqueous solution of
acetic acid (50
ml). The mixture was stirred at ambient temperature for about 20 hours until a
clear
solution was obtained. The clear solution was evaporated to dryness and the
traces of
19
CA 02450820 2003-12-11
WO 03/016317 PCT/US02/26012
acetic acid were removed by azeotropic distillation with toluene (3x50 ml) to
obtain a
powder.
The above obtained powder (200 mg, 0.32 10-3 mole) was dissolved in ethanol (8
ml), to which a saturated solution of calcium hydroxide (8 ml) containing
tetrabutyl
ammonium bromide (10 mg) was added. The mixture was stirred and heated at a
temperature of about 45 C for about 24 hours. Additional saturated solution
of calcium
hydroxide (4 ml) was added. After about 20 minutes of stirring at ambient
temperature,
the reaction was completed. The purity of the resulting product was analyzed
by HPLC.
The white precipitate was filtered under vacuum and dried at a temperature of
about 65 C
for about 18 hours. After drying, a 77% yield of atorvastatin calcium salt was
obtained
(142 mg).
Example 2
Preparation of atorvastatin calcium from a dioxane ester derivative
In a flask equipped with a magnetic stirrer, [R-(R*,R*)]-2-(4-fluorophenyl)-
[i,8-
dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole- l -
tert-
butylheptanoic ester (10.0 g, 15.29 10"3mmole) was suspended in an 80% aqueous
solution
of acetic acid (150 ml). The mixture was stirred at ambient temperature
overnight until a
clear solution was obtained. The clear solution was evaporated and the traces
of acetic
acid were removed by azeotropic distillation with toluene (3x100 ml) to obtain
an oily
product containing toluene.
The oily product was placed in a mixture of ethanol (100 ml) and water (20
ml). A
mixture of calcium hydroxide (5.5 eq., 6.22g, 84.0 10"3 mmole) and 5% (w/w of
the
dioxane ester derivative) tetrabutyl ammonium bromide (0.46 g) was added. The
mixture
was heated to a temperature of about 45 C for about 3 hours until the
reaction was
completed. While the mixture was hot, filtration was done under vacuum to
remove the
excess calcium hydroxide. The mixture was then cooled to ambient temperature,
after
which, while stirring, water (200 ml) was added. After about 20 minutes of
stirring at
ambient temperature, the reaction was completed. The purity of the resulting
product was
analyzed by HPLC. The white precipitate was filtered under vacuum and dried at
a
temperature of about 65 C for about 18 hours. After drying, an 84% yield of
atorvastatin
calcium salt was obtained (7.44 g).
CA 02450820 2003-12-11
WO 03/016317 PCT/US02/26012
Example 3
Preparation of atorvastatin lactone from a dioxane ester derivative
To a flask equipped with a magnetic stirrer, [R-(R*,R*)]-2-(4-fluorophenyl)-
[3,8-
dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole- l -
tert-
butylheptanoic ester (0.5 g, 0.76 10-3mmole) was dissolved in a 1:1 mixture of
trifluoroacetic-tetrahydrofuran (4 ml) in the presence of catalytic amount of
water. The
reaction mixture was stirred at ambient temperature for about 24 hours. The
solution
obtained was evaporated and the traces of trifluoroacetic were removed by
azeotropic
1o distillation with ether (3x10 ml). A white solid was obtained (0.3 g).
Based on HPLC
analysis, the white solid was a mixture of atorvastatin and atorvastatin
lactone in the ratio
of 40:60, respectively.
Example 4
Preparation of atorvastatin lactone from a dioxane ester derivative
To a flask equipped with a magnetic stirrer, [R-(R*,R*)]-2-(4-fluorophenyl)-
R,S-
dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole- l -
tert-
butylheptanoic ester (0.2g, 0.30 10-3mmole) and zinc bromide (3.5 eq, 1.07 10-
3 mole)
were dissolved in dichloromethane (5 ml). The reaction mixture was stirred at
ambient
temperature for about 24 hours. Water (30 ml) was added and the mixture was
stirred for
about 3 hours. The aqueous layer was extracted with dichloromethane (3x10 ml),
whereas
the organic layer was dried with sodium sulfate and filtrated. The organic
layer was then
evaporated under reduced pressure to give the resulting product (150 mg).
Based on
HPLC analysis, the resulting product was a mixture of atorvastatin and
atorvastatin lactone
in the ratio of 57:43, respectively.
Example 5
Preparation of atorvastatin lactone from a dioxane ester derivative
In a flask equipped with a magnetic stirrer, [R-(R*,R*)]-2-(4-fluorophenyl)-
[3,8-
dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-l-tert-
butylheptanoic ester (0.2 g) was suspended in a 90% aqueous solution of acetic
acid (4
ml). The mixture was stirred at a temperature of about 50 C for about 5 days.
The
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WO 03/016317 PCT/US02/26012
resulting solution was evaporated to dryness and the traces of acetic acid
were removed by
azeotropic distillation with toluene (3x15 ml) to obtain a powder. Based on
HPLC
analysis, the product was a mixture of atorvastatin and atorvastatin lactone
in the ratio of
54:46, respectively.
Example 6
Preparation of atorvastatin lactone from a dioxane ester derivative
In a flask equipped with a magnetic stirrer, a 3% aqueous solution of
hydrochloric
to acid (1 ml) and [R-(R*,R*)]-2-(4-fluorophenyl)-(3,8-dioxane-5-(1-
methylethyl)-3-phenyl-
4-[(phenylamino)carbonyl]-1H-pyrrole-l-tert-butylheptanoic ester (0.2 g) were
dissolved
in methanol (2 ml). The mixture was stirred at a temperature of about 110 C
for about 4
hours and then stirred overnight at ambient temperature. The resulting
solution was
evaporated to dryness to obtain a powder. Based on HPLC analysis, the powder
was a
mixture of atorvastatin and atorvastatin lactone in the ratio 54:46,
respectively.
Example 7
Preparation of rosuvastatin calcium from an ester derivative
In a flask equipped with a magnetic stirrer, methyl 7-[4-(4-fluorophenyl)-6-
iso-
propyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-
6-
heptenoate is dissolved in ethanol, to which a saturated solution of calcium
hydroxide
containing 5% (w/w of the ester derivative) tetrabutyl ammonium bromide is
added. The
mixture is stirred and heated at a temperature of about 45 C for about 24
hours.
Additional saturated solution of calcium hydroxide is added. After about 20
minutes of
stirring at ambient temperature, the reaction is completed, resulting in
rosuvastatin
calcium.
Example 8
Preparation of rosuvastatin calcium from an ester derivative
In a flask equipped with a magnetic stirrer, methyl 7-[4-(4-fluorophenyl)-6-
iso-
propyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl] -(3R,5 S)-dihydroxy-
(E)-6-
heptenoate is placed in a mixture of ethanol and water. A mixture of calcium
hydroxide
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WO 03/016317 PCT/US02/26012
and 5% (w/w of the ester derivative) tetrabutyl ammonium bromide is added. The
mixture
is heated to a temperature of about 45 C for about 3 hours until the reaction
is completed.
While the mixture is hot, filtration is done under vacuum to remove the excess
calcium
hydroxide. The mixture is then cooled to ambient temperature, after which,
while stirring,
water is added. After about 20 minutes of stirring at ambient temperature, the
reaction is
completed, resulting in rosuvastatin calcium.
Example 9
Preparation of pitavastatin calcium from an ester derivative
In a flask equipped with a magnetic stirrer, ethyl (E)-3,5-dihydroxy-7-[4'-(4"-
fluorophenyl)-2'-cyclopropyl-quinolin-3'-yl]-hept-6-enoate is dissolved in
ethanol, to
which a saturated solution of calcium hydroxide containing 5% (w/w of the
ester
derivative) tetrabutyl ammonium bromide is added. The mixture is stirred and
heated at a
temperature of about 45 C for about 24 hours. Additional saturated solution
of calcium
hydroxide is added. After about 20 minutes of stirring at ambient temperature,
the
reaction is completed, resulting in pitavastatin calcium.
Example 10
Preparation of pitavastatin calcium from an ester derivative
In a flask equipped with a magnetic stirrer, ethyl (E)-3,5-dihydroxy-7-[4'-(4"-
fluorophenyl)-2'-cyclopropyl-quinolin-3'-yl]-hept-6-enoate is placed in a
mixture of
ethanol and water. A mixture of calcium hydroxide and 5% (w/w of the ester
derivative)
tetrabutyl ammonium bromide is added. The mixture is heated to a temperature
of about
45 C for about 3 hours until the reaction is completed. While the mixture is
hot, filtration
is done under vacuum to remove the excess calcium hydroxide. The mixture is
then
cooled to ambient temperature, after which, while stirring, water is added.
After about 20
minutes of stirring at ambient temperature, the reaction is completed,
resulting in
pitavastatin calcium.
Having thus described the invention with reference to particular preferred
embodiments and illustrated it with Examples, those in the art can appreciate
modifications to the invention as described and illustrated that do not depart
from the spirit
and scope of the invention as disclosed in the specification. The Examples are
set forth to
23
CA 02450820 2010-02-25
aid in understanding the invention but are not intended to, and should not be
construed to,
limit its scope in any way. The examples do not include detaiied descriptions
of
conventional methods. Such methods are well known to those of ordinary skill
in the an
and are described in numerous publications.
24
