U.S. patent application number 11/120567 was filed with the patent office on 2005-09-08 for processes for preparing calcium salt forms of statins.
This patent application is currently assigned to Teva Pharmaceutical Industries Ltd.. Invention is credited to Lidor-Hadas, Rami, Lifshitz-Liron, Revital, Niddam-Hildesheim, Valerie.
Application Number | 20050197501 11/120567 |
Document ID | / |
Family ID | 34589908 |
Filed Date | 2005-09-08 |
United States Patent
Application |
20050197501 |
Kind Code |
A1 |
Niddam-Hildesheim, Valerie ;
et al. |
September 8, 2005 |
Processes for preparing calcium salt forms of statins
Abstract
Processes for preparing a calcium salt of a statin from an ester
derivative or protected ester derivative of the statin by using
calcium hydroxide are provided. The ester or protected ester
derivative is contacted with calcium hydroxide to obtain the
calcium salt. Preferred statins are rosuvastatin, pitavastatin and
atorvastatin, simvastatin and lovastatin. In processes beginning
with a protected statin ester derivative, the protecting group is
hydrolyzed during salt formation by contact with calcium hydroxide,
or is contacted with an acid catalyst followed by contact with
calcium hydroxide.
Inventors: |
Niddam-Hildesheim, Valerie;
(Even-Yeouda, IL) ; Lifshitz-Liron, Revital;
(Herzlia, IL) ; Lidor-Hadas, Rami; (Kafar-Saba,
IL) |
Correspondence
Address: |
KENYON & KENYON
ONE BROADWAY
NEW YORK
NY
10004
US
|
Assignee: |
Teva Pharmaceutical Industries
Ltd.
Teva Pharmaceuticals USA, Inc.
|
Family ID: |
34589908 |
Appl. No.: |
11/120567 |
Filed: |
May 2, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11120567 |
May 2, 2005 |
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10803414 |
Mar 18, 2004 |
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10803414 |
Mar 18, 2004 |
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10222556 |
Aug 16, 2002 |
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6777552 |
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10222556 |
Aug 16, 2002 |
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10037412 |
Oct 24, 2001 |
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6528661 |
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60312812 |
Aug 16, 2001 |
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60249319 |
Nov 16, 2000 |
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Current U.S.
Class: |
548/537 ;
549/292; 560/179 |
Current CPC
Class: |
C07D 309/30 20130101;
C07D 213/55 20130101; C07D 207/34 20130101; C07D 405/06 20130101;
C07D 239/42 20130101; Y02P 20/55 20151101; C07D 209/24 20130101;
C07D 215/14 20130101 |
Class at
Publication: |
548/537 ;
560/179; 549/292 |
International
Class: |
C07D 309/30; C07C
069/66 |
Claims
1. A process for preparing a calcium salt of a statin having the
formula: 13wherein R represents and organic radical, comprising
contacting an ester derivative of the statin selected from the
group consisting of: 14with a sufficient amount of calcium
hydroxide, wherein R.sub.1 is a C.sub.1 to a C.sub.8 alkyl group,
and R.sub.2, R.sub.3 and R.sub.4 each independently represent
hydrogen, or the same or different hydrolyzable protecting group,
or R.sub.2 and R.sub.3, together with the oxygen atom to which each
is bonded, form a hydrolyzable cyclic protecting group.
2-42. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of provisional
application Ser. No. 60/312,812, filed Aug. 16, 2001 and U.S.
patent application Ser. No. 10/037,412, filed Oct. 24, 2001, which
claims the benefit of provisional application Ser. No. 60/249,319,
filed Nov. 16, 2000, all of which are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to processes for preparing
calcium salt forms of statins.
BACKGROUND OF THE INVENTION
[0003] 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, statins 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).
[0004] 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 HMG 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. J.A.M.A. 1984, 251,
351-74.
[0005] Currently available statins include lovastatin, simvastatin,
pravastatin, fluvastatin, cerivastatin and atorvastatin. Lovastatin
(disclosed in U.S. Pat. No. 4,231,938) and simvastatin (ZOCOR;
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. 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. Nos. 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. 12
[0006] Atorvastatin is the common chemical name for
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-
-3-phenyl-4-[phenylamino)carbonyl]-1H-pyrrole-1-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-methyl-
ethyl)-N,4-diphenyl-1-[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. Pat. No. 4,681,893.
[0007] The lactone form is disclosed in U.S. Pat. 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]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-hepta-
noate 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.
[0008] The lactone can also be prepared according to the procedures
disclosed in U.S. Pat. No. 5,003,080. For instance, in Example 2,
Method A,
cis-2-(4-Fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3-ph-
enyl-4-(phenylamino)carbonyl-1H-pyrrole-1-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.
[0009] 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); (.+-.)-(2.alpha.,4.alpha.,6.alpha.) or
(.+-.)-(2.alpha.,4.beta.,6.beta.)-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-
-acetic acid (Example 2, Method C);
(.+-.)-cis-9-(2-aminoethyl)-6,10-dioxa- spiro[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 (.+-.)-(2.alpha.,4.alpha.,6.alpha.)
or
(.+-.)-(2.alpha.,4.beta.,6.beta.)-6-(2-aminoethyl)-2-methyl-1,3-dioxane-4-
-acetic acid (Example 2, Method F and G) with
(.+-.)-4-fluoro-.alpha.-[2-m-
ethyl-1-oxopropyl]-.gamma.-oxo-N,.beta.-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 and extracted with ethyl acetate, to which hydrochloric acid
is added, and the solution is concentrated. The residue is
dissolved in toluene.
[0010] Another method of making the lactone, according to the '080
patent, includes mixing (.+-.)-cis
,1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimeth-
yl-1,3-dioxane-4-acetate (Example 2, Method H);
(.+-.)-(2.alpha.,4.alpha.,- 6.alpha.) or
(.+-.)-(2.alpha.,4.beta.,6.beta.)-1,1-dimethyl-6-(2-aminoethy-
l)-2-phenyl-1,3-dioxane-4-acetate (Example 2, Method I); or
(.+-.)-cis 1,1-dimethylethyl
(4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetate (Example 2,
Method J) with (.+-.)4-fluoro-.alpha.-[2-methyl-1-oxopropyl]--
.gamma.-oxo-N,.beta.-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.
[0011] The lactone or the free acid may be used to prepare the
pharmaceutically acceptable calcium salt,
[R-(R*,R*)]-2-(4-fluorophenyl)--
.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbon-
yl]-1H-pyrrole-1-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: 3
[0012] The hemicalcium salt is disclosed in U.S. Pat. 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.
[0013] U.S. Pat. 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-(diphe-
nylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl]-5-(4-fluoropheny-
l)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide is
dissolved in methanol and reacted with hydrochloric acid to form
[R-(R*,R*)]-5-(4-fluorophenyl)-.beta.,.delta.-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)-.beta.,.delta.-dihydroxy-5--
(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic
acid. The sodium salt is converted to the hemicalcium salt by the
addition of calcium acetate in water.
[0014] 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)-.beta.,.delta.-dihydroxy-2-(1-methylethyl)-
-4-phenyl-3-[(phenylamino)carbonyl]-N,N-bis(phenylmethyl)-1H-pyrrole-1-hep-
tanamide which is further converted to the hemicalcium salt
(Example 2);
(4R-cis)-6-(2-aminoethyl)-N,N-diethyl-2,2-dimethyl-1,3-dioxane-4-acetamid-
e is converted to
[R-(R*,R*)]-N,N-diethyl-5-(4-fluorophenyl)-.beta.,.delta-
.-dihydroxy-2-(1-methylethyl)-4-phenyl-3-[(phenylamino)carbonyl]-
1H-pyrrole-1-heptanamide which is further converted to the
hemicalcium salt (Example 3);
(4R-cis)-6-(2-aminoethyl)-N-butyl-N,2,2-trimethyl-1,3-d-
ioxane-4-acetamide is converted to
[R-(R*,R*)]-N-butyl-5-(4-fluorophenyl)--
.beta.,.delta.-dihydroxy-N-methyl-2-(1-methylethyl)-4-phenyl-3-[(phenylami-
no)carbonyl]-1H-pyrrole-1-heptanamide which is further converted to
the hemicalcium salt (Example 4);
(4R-cis)-6-(2-aminoethyl)-N-(1,1-dimethylet-
hyl)-2,2-dimethyl-N-(phenylmethyl)-1,3-dioxane-4-acetamide is
converted to
[R-(R*,R*)]-N-(1,1-(dimethylethyl)-5-(4-fluorophenyl)-.beta.,.delta.-dihy-
droxy-2-(1-methylethyl)-4-phenyl-3-[(phenylamino)carbonyl]-N-(phenylmethyl-
)-1H-pyrrole-1-heptanamide which is further converted to the
hemicalcium salt (Example 5); and
(4R-cis)-1-[[6-(2-aminoethyl)-2,2-dimethyl-1,3-diox-
an-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-diphe-
nyl-1H-pyrrole-3-carboxamide which is further converted to the
hemicalcium salt (Example 6).
[0015] Rosuvastatin is the common chemical name for
[S-[R*,S*-(E)]]-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl(methyls-
ulfonyl)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. Pat. 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 NaBH.sub.4 to obtain a methyl ester of
rosuvastatin.
[0016] 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.
[0017] 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.
[0018] 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.
[0019] 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-carbo-
xyaldehyde, 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]propenaldeh-
yde, which is converted to ethyl
(E)-7-[4-(4"-fluorophenyl-2'-(1"-cyclopro-
pyl)-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)-quino-
lin-3'-yl]-hept-6-enoate.
[0020] The resulting ester, ethyl
(E)-3,5-dihydroxy-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.
[0021] 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"-fluorophenyl)-2'-(1"-met-
hylethyl)quinolin-3'-ylethynyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on-
e. The lactone is further reduced using palladium/carbon under
nitrogen atmosphere.
[0022] U.S. Pat. No. 6,335,449 improves the prior art process for
preparing pitavastatin by reacting an aldehyde quinoline with
diethyl cyanomethylphosphonate 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.
[0023] 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-(tetr-
ahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester,
[1S*-[1a,3a,7b,8b(2S*,4S),-8ab]]. (CAS Registry No. 79902-63-9.).
Simvastatin is marketed as ZOCOR, and is disclosed in U.S. Pat.
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.
[0024] 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.
[0025] 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
[0026] The present invention provides a novel process for preparing
statin calcium salts having the formula: 4
[0027] wherein R represents an organic radical, comprising
contacting an ester derivative of the statin selected from the
group consisting of: 5
[0028] with a sufficient amount of calcium hydroxide,
[0029] wherein R.sub.1 is a C.sub.1 to a C.sub.8 alkyl group,
and
[0030] R.sub.2, R.sub.3 and R.sub.4 each independently represent
hydrogen, or the same or different hydrolyzable protecting group,
or R.sub.2 and R.sub.3, together with the oxygen atom to which each
is bonded, form a hydrolyzable cyclic protecting group.
[0031] 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.
[0032] Preferred statins are atorvastatin, rosuvastatin,
pitavastatin and simvastatin. In a preferred embodiment, R.sub.2,
R.sub.3 and R.sub.4 are hydrogen. Each of R.sub.2, R.sub.3 or
R.sub.4 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., --COOR.sub.1, or
hydrolyzed by using an acid catalyst, followed by hydrolysis of the
ester group --COOR.sub.1. Preferred protecting groups are silyl
groups such as trialkylsilyl, which can be hydrolyzed by calcium
hydroxide, and acetonide, which can be hydrolyzed by an acid
catalyst. Acetonide forms a cyclic hydrolyzable protecting group,
i.e., a dioxane.
[0033] In another aspect, the present invention provides a process
for preparing a calcium salt of a statin having the formula: 6
[0034] wherein R represents an organic radical, comprising the
steps of:
[0035] adding calcium hydroxide and an ester derivative of the
statin as described above to a mixture of water and a C.sub.1 to a
C.sub.4 alcohol, heating the mixture, precipitating the calcium
salt of the statin and separating the calcium salt.
DETAILED DESCRIPTION OF THE INVENTION
[0036] 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.
[0037] Sodium hydroxide is a strong base with a dissociation
constant of 6.37 (pK.sub.b=-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).sub.2), with a first dissociation constant of
3.74.times.10.sup.-3 (pK.sub.b=2.43) and second dissociation
constant of 4.0.times.10.sup.-2 (pK.sub.b=1.40), is a much weaker
base than sodium hydroxide. Handbook of Chemistry and Physics 63rd
ed. D-170 (CRC Press: Boca Raton 1983).
[0038] 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 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.
[0039] 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 C.sub.1-C.sub.8 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.
[0040] The present invention is directed to statins having the
general formula: 7
[0041] 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.
[0042] R refers to an organic radical that is bonded to the diol
pentanoic acid group. Depending on the statin, the R radical can
be:
[0043] pravastatin:
1,2,6,7,8,8a-Hexahydro-6-hydroxy-2-methyl-8-(2-methyl--
1-oxobutoxy)-1-naphthalene ethyl radical.
[0044] fluvastatin:
3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-et- hylene
radical.
[0045] cerivastatin:
4-(4-fluorophenyl)-5-methoxymethyl)-2,6bis(1-methylet-
hyl)-3-pyridinyl-ethylene radical.
[0046] atorvastatin:
2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phe-
nylamino)carbonyl]-1H-pyrrole-ethyl radical
[0047] rosuvastatin:
[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl(methy-
lsulfonyl)amino]-5-pyrimidinyl]-ethylene radical.
[0048] pitavastatin:
[4'-(4"-fluorophenyl)-2'-cyclopropyl-quinolin-3'-yl]-- ethylene
radical.
[0049] 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:
[0050] simvastatin:
1,2,6,7,8,8a-Hexahydro-2,6-dimethyl-8-(2,2-dimethyl-1--
oxobutoxy)-1-naphthalene ethyl radical.
[0051] lovastatin:
1,2,6,7,8,8a-Hexahydro-2,6-dimethyl-1-8-(2-methyl-1-oxo-
butoxy)-1-naphthalene ethyl radical.
[0052] 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.
[0053] 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.
[0054] The present invention provides a process for preparing a
statin hemi-calcium salt by converting a statin ester derivative of
formula: 8
[0055] wherein R represents an organic radical and R.sub.1 is a
C.sub.1 to C.sub.8 alkyl group, to the corresponding hemi-calcium
salt having the formula: 9
[0056] 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.
[0057] 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.
[0058] 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.sub.1-C.sub.4 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.sub.1-C.sub.4
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 Ca.sup.2+
ion for the atorvastatin hemi-calcium salt.
[0059] According to a preferred procedure for practicing the base
hydrolysis process, the statin ester derivative is added in an
amount sufficient to provide about 10 mmoles L.sup.-1 to about 1
mole L.sup.-1 of the mixed solvent.
[0060] 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.
[0061] Calcium hydroxide is only sparingly soluble in the
C.sub.1-C.sub.4 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-ethylammonium chloride,
benzyltributylammonium chloride, benzyltributylammonium bromide,
benzyltriethylammonium 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
substoichiometric amount, preferably from about 0.05 to about 0.25
equivalents, more preferably about 0.1 equivalents, with respect to
statin ester derivative.
[0062] The mixture may be 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.degree. C. to about 70.degree. C.
[0063] 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.
[0064] After filtration to remove suspended calcium hydroxide,
statin hemi-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
temperatures, e.g. from about 40.degree. C. to about 65.degree. C.
Precipitating statin hemi-calcium by slow water addition yields
statin hemi-calcium 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.
[0065] 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 hemi-calcium or solvate thereof may be used as an active
ingredient in a pharmaceutical product.
[0066] 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, incorporated
herein by reference, uses a silyl protecting group during synthesis
of rosuvastatin. U.S. Pat. Nos. 6,002,021 and 4,444,784,
incorporated herein by reference, 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. et al. Tet. Lett. 1992,
33, 2283-2284, incorporated herein by reference, prepare
atorvastatin through a dioxane intermediate that has an acetonide
protecting group, i.e., R.sub.2 and R.sub.3, together with the
oxygen atom to which each is bonded, form a hydrolyzable cyclic
protecting group.
[0067] These compounds, referred to herein as "protected statin
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: 10
[0068] wherein R represents an organic radical, comprising
contacting an ester derivative of the statin selected from the
group consisting of: 11
[0069] with a sufficient amount of calcium hydroxide, wherein
R.sub.1 is a C.sub.1 to a C.sub.8 alkyl group, and R.sub.2, R.sub.3
and R.sub.4 each independently represent hydrogen, or the same or
different hydrolyzable protecting group, or R.sub.2 and R.sub.3,
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 R.sub.2, R.sub.3 and R.sub.4 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 R.sub.2 and
R.sub.3 form, for example, a dioxane.
[0070] U.S. Pat. No. 6,294,680, incorporated herein by reference,
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 groups include boronic acid, disclosed in
WO 95/13283, incorporated herein by reference and esterification
with an acetic anhydride, disclosed in U.S. Pat. No. 5,159,104,
incorporated herein by reference. U.S. Pat. No. 6,100,407,
incorporated herein by reference, discloses additional protecting
groups. The protecting groups disclosed in these references may be
used in accordance with the present invention.
[0071] 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 R.sub.2, R.sub.3 and R.sub.4 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 R.sub.2.
The silyl protected simvastatin disclosed in U.S. Pat. Nos.
4,444,784 and 6,002,021 can also be used.
[0072] 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-toluenesulfonic 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.sub.1 to a C.sub.4 alcohol, with ethanol
being preferred. A preferred pH for the reaction is less than about
3, more preferably less than about 1.
[0073] 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.
[0074] The one pot process with use of acid catalyst is illustrated
as follows: 12
[0075] 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.
[0076] 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, incorporated herein by reference, and the most recent
edition of Handbook of Pharmaceutical Excipients, American
Pharmaceutical Association, can be used as a guidance. The dosage
and formulation of LIPITOR.RTM. (atorvastatin hemi-calcium) and the
other pharmaceuticals can also be used as a guidance.
EXAMPLES
[0077] General
[0078] Unless otherwise indicated, reagents were used as received.
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic
ester (dioxane 2, R.sub.1=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. et al. Tet. Lett. 1992, 33, 2279-82;
Baumann, K. L. et al. Tet. 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 (7.6.times.100 mm), 70:30 acetonitrile:water,
0.6 ml min..sup.-1, 20 .mu.l sample, UV detection .gamma.=254.
Example 1
Preparation of Atorvastatin Calcium from a Dioxane Ester
Derivative
[0079] In a flask equipped with a magnetic stirrer,
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-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 acetic acid
were removed by azeotropic distillation with toluene (3.times.50
ml) to obtain a powder.
[0080] The above obtained powder (200 mg, 0.32 10.sup.-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.degree. 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.degree. 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
[0081] In a flask equipped with a magnetic stirrer,
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic
ester (10.0 g, 15.29 10.sup.-3 mmole) 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
(3.times.100 ml) to obtain an oily product containing toluene.
[0082] The oily product was placed in a mixture of ethanol (100 ml)
and water (20 ml). A mixture of calcium hydroxide (5.5 eq., 6.22 g,
84.0 10.sup.-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.degree. 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.degree. C. for about 18 hours. After
drying, an 84% yield of atorvastatin calcium salt was obtained
(7.44 g).
Example 3
Preparation of Atorvastatin Lactone from a Dioxane Ester
Derivative
[0083] To a flask equipped with a magnetic stirrer,
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic
ester (0.5 g, 0.76 10.sup.-3 mmole) 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 distillation with ether (3.times.100 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
[0084] To a flask equipped with a magnetic stirrer,
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic
ester (0.2 g, 0.30 10.sup.-3 mmole) and zinc bromide (3.5 eq, 1.07
10.sup.-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
(3.times.10 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
[0085] In a flask equipped with a magnetic stirrer,
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dioxane-5-(1-methylethyl)-3-
-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-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.degree. C. for about 5 days. The resulting solution was
evaporated to dryness and the traces of acetic acid were removed by
azeotropic distillation with toluene (3.times.15 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
[0086] In a flask equipped with a magnetic stirrer, a 3% aqueous
solution of hydrochloric acid (1 ml) and
[R-(R*,R*)]-2-(4-fluorophenyl)-.beta.,.de-
lta.-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrro-
le-1-tert-butylheptanoic ester (0.2 g) were dissolved in methanol
(2 ml). The mixture was stirred at a temperature of about
110.degree. 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
[0087] In a flask equipped with a magnetic stirrer, methyl
7-[4-(4-fluorophenyl)-6-iso-propyl-2-(N-methyl-N-methylsulfonylamino)pyri-
midin-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.degree. 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
[0088] In a flask equipped with a magnetic stirrer, methyl
7-[4-(4-fluorophenyl)-6-iso-propyl-2-(N-methyl-N-methylsulfonylamino)pyri-
midin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoate 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.degree. 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
[0089] 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.degree. 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
[0090] 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.degree. 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.
[0091] 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 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 detailed descriptions
of conventional methods. Such methods are well known to those of
ordinary skill in the art and are described in numerous
publications. All references mentioned herein are incorporated in
their entirety
* * * * *