PREPARATION OF ROSUVASTATIN

ELABORATION DE LA ROSUVASTATINE

English Abstract

Provided are processes for preparing intermediates of rosuvastatin and their
use in preparation of rosuvastatin and rosuvastatin salts thereof.

French Abstract

La présente invention concerne des procédés permettant l'élaboration d'intermédiaires de la rosuvastatine, et leur utilisation pour l'élaboration de la rosuvastatine, et de certains de ses sels.

Claims

What is claimed is:
1. A process for preparing Compound 20 of the following structure by a Wittig-
Homer
reaction,
<IMG>
comprising combining Compound 19A of the following structure:
<IMG>
a base and Compound 14 of the following structure:
<IMG>
to obtain the Compound 20;
wherein W is a carboxyl protecting group, T1 and T2 are independently aryl or
alkoxy, and X is a hydroxyl protecting group.
2. The process of claim 1, wherein the process comprises:
(a) providing a dry solvent and the Compound 19A;
(b) combining the base with the dry solvent and the Compound 19A to obtain a
first reaction mixture;
(c) combining the Compound 14 with the first reaction mixture at a reduced
temperature to obtain a second reaction mixture;
(d) maintaining the second reaction mixture for a sufficient time to obtain
the
Compound 20.
3. The process of claim 2, further comprising quenching the reaction after
step (d).
38

4. The process of any of claims 1-2, further comprising recovering the
Compound 20.
5. The process of claim 4 wherein the recovering comprises:
(i) combining the quenched second reaction mixture with a water immiscible
solvent and water to obtain a 2 phase system;
(ii) washing the first organic phase with a base and a solvent to obtain a
three
phase system; and
(iii) recovering Compound 20.
6. The process of claim 4 wherein the recovering comprises:
(i) combining the quenched second reaction mixture with a water immiscible
solvent and water to obtain an first organic and aqueous phase;
(ii) washing the first organic phase with a solvent to obtain a second organic
and
second phase;
(iii) combining the first organic phase and the second organic phase with a
base
and an alcohol and optionally adding the extracted product of the first
aqueous phase and the second aqueous phase, to obtain a three phase system
comprising a upper, middle and lower phase;
(iv) isolating the upper phase;
(v) washing the upper phase with first with an alcohol/water mixture, then a
base,
then an alcohol and subsequently water; and
(vi) recovering Compound 20.
7. The process of any of claims 5-6 further comprising filtering and washing
the
Compound 20 prior to the combining the quenched second reaction mixture with a
water
immiscible solvent and water.
8. The process of any of claims 3-7 wherein the quenching comprises adding
water and/or
an acid.
9. The process of any of claims 2-8 wherein the reduced temperature is about
room
temperature to about the freezing point of the solvent.
10. The process of any of claims 1-9 wherein the base is combined in the
presence of a
phase transfer catalyst.
11. The process of any of claims 1-10 wherein the Compound 19A is in an amount
of from
about 1 to about 5 molar equivalents relative to Compound 14.
12. The process of claim 11 wherein the Compound 19A is in an amount of from
about 1 to
about 2 molar equivalents relative to Compound 14.
39

13. The process of any of claims 1-12 wherein the base is selected from the
group consisting
of a metal hydride, NaOMe, KOtBu, NaOtBu, NaOH, K2C03, a lithiated base, 1,8-
diazabicyclo[5.4.0]undec-7-ene, diazabicyclo[2.2.2] octane and mixtures
thereof.
14. The process of any of claims 1-13 wherein the Compound 19A is 19TBPO:
<IMG>
15. A process for preparing Compound 21 of the following structure:
<IMG>
comprising:
i. preparing Compound 20 according to the process of any of claims 1-14; and
ii. converting the Compound 20 to the Compound 21;
wherein W is a carboxyl protecting group.
16. A process for preparing rosuvastatin or a pharmaceutically acceptable salt
thereof,
comprising:
i. preparing Compound 20 according to the process of any of claims 1-14; and
ii. converting the Compound 20 to the rosuvastatin or pharmaceutically
acceptable salt thereof.
17. A process for preparing rosuvastatin or a pharmaceutically acceptable salt
thereof,
comprising:
a. providing a solution of Compound I of the following structure
<IMG>
wherein Y is a C1-C4 ester, W is a carboxyl protecting group and X is a
hydroxyl protecting group, and a polar solvent;

b. combining the solution with a base to obtain a pH of about 10 to
about 13 to form a first solution comprising Compound 17 of the
following structure
<IMG>
wherein W is a carboxyl protecting group and X is a hydroxyl protecting
group;
c. adding a second solution comprising a mono-, di-, tri-(C1 to C4)
alkyl substituted benzene chloroformate, saturated or aromatic C5-C12
chloroformate or C1-8 alkyl chloroformate and an organic solvent to
obtain a first reaction mixture while maintaining a temperature of
about -50°C to about -10°C;
d. maintaining the first reaction mixture for a sufficient period of time
to obtain Compound 18 of the following structure
<IMG>
wherein W is a carboxyl protecting group, X is a hydroxyl protecting group
and Z is a C1-8 alkyl or aryl;
e. providing a dry solvent and Compound 19A of the following
structure
<IMG>
wherein W is a carboxyl protecting group, T1 and T2 are independently aryl or
alkoxy, and X is a hydroxyl protecting group;
f. combining a base with the dry solvent and the Compound 19A to
obtain a second reaction mixture;
41

g. combining Compound 14 with the second reaction mixture at a
reduced temperature to obtain a third reaction mixture;
<IMG>
h. maintaining the third reaction mixture for a sufficient time to obtain
the Compound 20;
<IMG>
wherein W is a carboxyl protecting group and X is a hydroxyl protecting
group;
i. optionally, quenching the reaction;
j. converting Compound 20 into Compound 21 of the following
structure
<IMG>
wherein W is a carboxyl protecting group;
k. optionally recovering Compound 21 by providing a two-phased
system comprised of a mixture of a non-polar aliphatic solvent and a
non-polar aromatic solvent and a mixture of a mixture of a lower
aliphatic alcohol and water, each in an amount of about 4 to about 6
42

volumes relative to Compound 21 and crude Compound 21, washing
the non-polar phase with a mixture of lower aliphatic alcohol and
water, and recovering Compound 21 from the organic phase;
l. optionally crystallizing Compound 21;
m. converting Compound 21 into Compound 22 of the following
structure
<IMG>
wherein W is a carboxyl protecting group; and
n. converting Compound 22 into rosuvastatin.
18. The process of claim 17 further comprising:
(i) combining the quenched second reaction mixture with a water immiscible
solvent and water to obtain a 2 phase system;
(ii) washing the first organic phase with a base and a solvent to obtain a
three
phase system; and
(iii) recovering Compound 20.
19. The process of claim 17 further comprising:
(i) combining the quenched second reaction mixture with a water immiscible
solvent and water to obtain an first organic and aqueous phase;
(ii) washing the first organic phase with a solvent to obtain a second organic
and
second phase;
(iii) combining the first organic phase and the second organic phase with a
base
and an alcohol and optionally adding the extracted product of the first
aqueous phase and the second aqueous phase, to obtain a three phase system
comprising a upper, middle and lower phase;
(iv) isolating the upper phase;
(v) washing the upper phase with first with an alcohol/water mixture, then a
base,
then an alcohol and subsequently water; and
(vi) recovering Compound 20.
43

CLAIMS
20. The process of any of claims 17-19, wherein the rosuvastatin obtained is
further
converted to a pharmaceutically acceptable salt of rosuvastatin.
21. The process of claim 16 or 20, wherein the salt of rosuvastatin is the
calcium salt.
22. A pharmaceutical composition comprising rosuvastatin or pharmaceutically
acceptal
salt thereof prepared according to the process of any claims 16-21 and a
pharmaceutically acceptable excipient.
23. Use of the pharmaceutical composition of claim 22 in the manufacture of a
medicam
for lowering cholesterol.
24. Substantially pure 21TB having a purity of greater than about 80%.
25. Substantially pure 21TB having a purity of greater than about 90%.

Description

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PREPARATION OF ROSUVASTATIN
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No.
60/723,491,
filed October 3, 2005; U.S. Provisional Application No. 60/723,875, filed
October 4, 2005;
U.S. Provisional Application No. 60/732,979 filed November 2, 2005; U.S.
Provisional
Application No. 60/751,079, filed December 15, 2005; U.S. Provisional
Application No.
60/760,506, filed January 19, 2006; U.S. Provisional Application No.
60/762,348, filed
January 25, 2006, and U.S. Application No. 11/360,725, filed February 22,
2006, all of which
are herein incorporated by reference.
FIELD OF THE INVENTION
The invention is directed to processes for preparing intermediates of
rosuvastatin and
their use in preparation of rosuvastatin and rosuvastatin salts thereof.
BACKGROUND
Complications of cardiovascular disease, such as myocardial infarction,
stroke, and
peripheral vascular disease account for half of all deaths in the United
States. A high level of
low density lipoprotein (LDL) in the bloodstream has been linked to the
formation of
coronary lesions which obstruct the flow of blood and promote thrombosis. [See
Goodman
and Gilman, The Pharmacological Basis of Therapeutics, 9th ed., p. 879
(1996)]. Reducing
plasma LDL levels has been shown to reduce the risk of clinical events in
patients with
cardiovascular disease and in patients who are free of cardiovascular disease
but who have
hypercholesterolemia. [Scandinavian Simvastatin Survival Study Group, 1994;
Lipid
Research Clinics Program, 1984a, 1984b.]
Statin drugs are currently the most therapeutically effective drugs available
for
reducing the level of LDL in the blood stream of a patient at risk for
cardiovascular disease.
This class of drugs includes, irater- alia, compactin, lovastatin,
simvastatin, pravastatin and
fluvastatin.
The mechanism of action of statin drags has been elucidated in some detail.
The
statin drugs disrupt the synthesis of cholesterol and other sterols in the
liver by competitively
inhibiting the 3-hydroxy-3-methyl-gh.itaryl-coenzyme A reductase enzyme ("HMG-
CoA
reductase"). HMG-CoA reductase catalyzes the conversion of HMG-CoA to
mevalonate,

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which is the rate determining step in the biosynthesis of cholesterol.
Consequently, HMG-
CoA reductase inhibition leads to a reduction in the rate of formation of
cholesterol in the
liver. 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].
Currently available statins include: lovastatin, simvastatin, pravastatin,
fluvastatin,
cerivastatin and atorvastatin, which are administered in their lactone form,
as sodium salts or
as calcium salts.
Rosuvastatin (7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-
methylsulfonylamino) pyrimidin-5-yl]-(3R, 5S)-dihydroxy-(E)-6-heptenoic acid)
calcium, an
HMG-CoA reductase inhibitor can lower LDL-cholesterol and triglycerides levels
more
effectively than first generation statin drugs. Rosuvastatin calcium has the
following
chemical formula:
F
cct 2+
ca
N
SOzCHs 2
Rosuvastatin calcium
A number of relevant processes for preparation of rosuvastatin and salts
thereof are
disclosed. Rosuvastatin calcium, intermediates and their preparation are
disclosed in U.S.
Patent No. 5,260,440, herein '440. WO 03/097614 discloses the synthesis of
rosuvastatin
from the late intermediate (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-
triphenyl-
phosphoralydene hexanate, an intermediate disclosed in '440. WO 03/087112
discloses the
synthesis of rosuvastatin from a different intermediate, (3R)-3-(t-
butyldimethylsilyloxy)-6-
dimethoxyphosphinyl-5-oxohexanate. WO/0049014 discloses the synthesis of
rosuvastatin
using intermediates with other side chains via a Wittig reaction. EP 850,902
describes the
removal of triphenylphosphine derivatives in mixtures.
Nevertheless, there remains a need in the art for processes of preparing
rosuvastatin
that are both cost effective, have fewer purification steps, and/or result in
higher purity of the
final product, thereby malcing them more suitable for industrial scale
preparation.
2

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SUMMARY OF THE INVENTION
In one embodiment, the invention provides a process for preparing Compound 20
of
the following structure by a Wittig-Homer reaction,
F
O OX
N~ Cw
NN I
SO2CH3
5 comprising combining Compound 19A of the following structure:
O O OX
T, I",P CW
x
T2
19A,
a base and Compound 14 of the following structure:
F
N CHO
NN
SO2CH3
14
10 to obtain the Compound 20;
wherein W is a carboxyl protecting group, T1 and T2 are independently aryl or
alkoxy, and X
is a hydroxyl protecting group.
In another embodiment, the invention provides a process for preparing
rosuvastatin or
a pharmaceutically acceptable salt thereof, comprising:
15 a, providing a solution of Compound I of the following structure
ox
Y CW
(I)
wherein Y is a C1-C4 ester, W is a carboxyl protecting group and X is a
hydroxyl protecting group, and a polar solvent;
3

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b. combining the solution with a base to obtain a pH of about 10 to about
13 to form a first solution comprising Compound 17 of the following
structure
ox
HOOC CW
17
wherein W is a carboxyl protecting group and X is a hydroxyl protecting
group;
c. adding a second solution comprising a mono-, di-, tri-(C1 to C4) alkyl
substituted benzene chloroformate, saturated or aromatic C5-C 12
chloroformate or C1-8 alkyl chloroformate and an organic solvent to
obtain a first reaction mixture while maintaining a temperature of
about -50 C to about -10 C;
d. maintaining the first reaction mixture for a sufficient period of time to
obtain Compound 18 of the following structure
O O Ox
Zo~O)t"'J'cw
18
wherein W is a carboxyl protecting group, X is a hydroxyl protecting group
and Z is a C1_$ alkyl or aryl;
C. providing a dry solvent and Compound 19A of the following structure
O O OX
T1 I", //
P CW
T2
19A
wherein W is a carboxyl protecting group, T1 and T2 are independently aryl or
alkoxy, and X is a hydroxyl protecting group;
f. combining a base with the dry solvent and the Compound 19A to
obtain a second reaction mixture;
g. combining Compound 14 with the second reaction mixture at a
reduced temperature to obtain a third reaction mixture;
4

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F
N CHO
N'J"N
SO2CH3
14
h. maintaining the third reaction mixture for a sufficient time to obtain
the Conipound 20;
F
' ~.
O ox
N Cw
N')II N
SO2CH3
20
wherein W is a carboxyl protecting group and X is a hydroxyl protecting
group;
i. o.ptionally, quenching the reaction;
j. converting Compound 20 into Compound 21 of the following structure
F
~ 0 OH
N~ CW
N'ILI~ N
SO2CH3
21
wherein W is a carboxyl protecting group;
k. optionally recovering Compound 21 by providing a two-phased system
comprised of a mixture of a non-polar aliphatic solvent and a non-polar
aromatic solvent and a mixture of a mixture of a lower aliphatic
alcohol and water, each in an amount of about 4 to about 6 volumes
relative to Compound 21 and crude Compound 21, washing the non-
polar phase with a mixture of lower aliphatic alcohol and water, and
recovering Compound 21 from the organic phase;
5

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1. optionally crystallizing Compound 21;
M. converting Compound 21 into Compound 22 of the following structure
F
OH OH
N CW
NN
SO2CH3
22
wherein W is a carboxyl protecting group; and
n. converting Compound 22 into rosuvastatin.
DETAILED DESCRIPTION
As used herein, RT refers to room temperature and includes temperatures of
about 25
~ 5 C.
As used herein, "dry solvent" is meant to include any solvent which contains
substantially no water, preferably less than 0.5% water.
As used herein a "reduced temperature" is meant to indicate a temperature of
less than
about 25 5 C.
As used herein, unless otherwise noted, "substantially pure" is meant to
indicate a
purity of at least about 80%, preferably at least about 85%, and more
preferably at least about
95% pure by weight as measured by assay against standard.
The carboxyl protecting group in the structures within the present application
may be
any suitable carboxyl protecting group, such as esters, amides, benzenes or
hydrazides. More
preferably, the carboxyl protecting group is an ester, and most preferably is
a tert-butyl ester
in the structures of the present inventions. Some typical examples of a
hydroxyl protecting
group include methoxymethyl esters, tetrahydropyranyl ether, trimethylsilyl
ether, tertbutyl
diphenyl silyl, Stannum derivatives, and acetate ester. Preferably the tri(C1-
C6 alkyl)silyl is
tri(C1 to C4 alkyl)silyl, even more preferably trimethylsilyl, or tert-
butyldimethylsilyl
(TBDMS), with TBDMS being especially preferred. More carboxyl or hydroxyl
protecting
groups are described in "Protective Groups in Organic Synthesis" by T. W.
Greene, John
Wiley & Sons, Inc. (1981).
As used herein, "lower aliphatic alcohols" include C1 to C4 alcohols.
6

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When used herein, the suffix "TB" describes intermediate compounds described
in the
summary, wherein R is t-butyl. For example, the term "17TB" refers to
intermediate
Compound 17 wherein R is t-butyl. The suffix "M" describes intermediate
compounds
wherein R is methyl. For example, the term "17M" refers to intermediate
Compound 17,
wherein R is methyl. The suffix "TBPH" describes compounds herein wherein R is
t-butyl
and PH is phenyl. The suffix "TBRE" describes compounds herein wherein R is
tert-butyl
and RE is rosuvastatin ester. The suffix "TBDMS" describes compounds herein
wherein R is
t-butyl and TDMS is tert-butyl dimethyl silyl.
As used herein, "aryl", "aryl group" or "Ar" refer to an unsaturated aromatic
carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g.,
phenyl) or multiple
condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may
not be
aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7y1, and the
like) provided
that the point of attachment is through an aromatic ring atom. Preferably, the
aryl is phenyl,
naphthyl or 5,6,7,8-tetrahydronaphth-2-yl. The aryl may be substituted or
unsubstituted. The
substituents may be, for example, an alkyl group, an alkenyl group, a cyclic
alkyl group, an
aralkyl group, a cyclic alkenyl group, a cyano group, an aryl group, an alkoxy
group, an
aryloxy group, an alkylthio group, an arylthio group, an alkylsulfonyl group,
or an
arylsulfonyl group.
The invention provides improved processes for the preparation of rosuvastatin
and
intermediates thereof in high yield using cost effective reagents. The
processes of the
invention provide for the quantitative conversion of reagents and decreased
formation of by-
products, resulting in a process for preparing rosuvastatin requiring fewer
purification steps.
Examples in specific cases are dispersed throughout.
In one aspect of the present invention, a process is provided for preparing
intermediate Compound 17, of the following structure:
ox
HOOC CW
Compound 17
by partial hydrolysis of the diester, Compound I, of the following structure:
ox
Y CW
Compound (I)
7

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wherein Y is a C1-C4 ester, W is a carboxyl protecting group, and X is a
hydroxyl protecting
group. The process comprises: providing a solution of Compound I and a polar
solvent;
combining the solution with a base to obtain a pH of about 10 to about 13; and
recovering
Compound 17. In this process, the synthesis of Compound 17 allows for the
production of a
monoacid derivative with little contamination of the diacid derivative.
Polar solvents can be selected from the group consisting of: Cl_4 alcohols,
nitriles,
acetone, dioxane, and THF, most preferably, methanol and ethanol. The polar
solvent is in
amount of about 2 to about 15 volumes, preferably about 5 to about 10, and
most preferably 5
volumes relative to Compound I.
The base used is any suitable base, which can be selected from the group
consisting
of: mono-, di-, tri-(C1_4 alkyl)amino pyridines, mono-, di-, tri-(C1_4
alkyl)amines, alkali
metals, alkali earth hydroxides, alkali earth alkooxides, and C1_4 alkyl
lithium carbonates.
Preferably, the base is at least one of sodium hydroxide, potassium hydroxide,
or lithium
hydroxide, most preferably sodium hydroxide. Preferably, the base is in a
concentration of
about 0.9 to about 1.8 volumes, most preferably about 1.2 volumes relative to
Compound I.
In a particularly preferred embodiment, the base is added drop-wise to a
solution of
Compound (I). The base may be added in portions to maintain the pH at this
level. The
amount of base required to effect the reaction will depend on the scale of the
reaction, and
may easily be determined by one skilled in the art with little or no
experimentation using such
20. techniques as TLC.
Preferably, the reaction mixture is heated at a temperature of about 30 C to
about
70 C. Most preferably, the reaction mixture is heated at about 45 C to about
55 C. Heating
is for a period of time, will depend on scale and mixing procedures, and can
be determined by
one skilled in the art by measuring the absence of the limiting reagent using
such techniques
such as HPLC or TLC. For example, when about 288 mmol of Compound I is used,
the
heating time is about 1 hour to about 10 hours, and preferably about 7 hours.
In another aspect of the present invention, a process for recovery of Compound
17
from the reaction mixture is provided. This process comprises: providing crude
Compound
17; partially evaporating the solvent; adding water; washing with a C5_7
alkyl; extracting
using an organic solvent selected from the group consisting of: saturated or
aromatic C5-C12
hydrocarbons, mono-, di-, tri-(CI to C4) alkyl substituted benzene; acidifying
the mixture
using an inorganic acid to a pH of about 7 to about 5; and recovering Compound
17 from the
organic phase.
8

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The water used is preferably in an amount of about 2 to about 10 volumes, most
preferably 4 volumes relative to the crude Compound 17. Preferably, the C5_7
alkyl is hexane.
The washing may be in portions, preferably about 2. The organic solvent is
preferably
toluene. Any inorganic acid may be used for acidification, preferably HCI.
Preferably,
acidifying is to a pH of about 6. Recovery from the organic phase may be by
drying, such as
over MgSO4.
In another aspect of the present invention, Compound 17 prepared by the
process of
the present invention is used to prepare any downstream intermediate,
rosuvastatin and
pharmaceutically acceptable salts thereof by conventional means, for example
as depicted in
US 5,260,440. For example, the following reaction scheme describes one method
of
converting Compound 17 into rosuvastatin calcium, wherein Compounds 17 to 22
are
represented by number
Base 0x Ohloroformate 0 0 034
ox alcohol HO2OI'JII- Ct+v Orga in base 70 )~ O'k"J" Ow
cw
17
h~
0 ox
CH3PPh3halide Ph3P~ f GbU
Base
19
F F F
0 OX I .r
0 OH
H GHO cV1r CW
~ -~~ H
~ ~H H ,-11 H
SO2OH3 SO2Gf 43 802CH3
14 20 21
F F
OH OH [oHoH]
--~ H~ OVit H~ G02- ~
Ga
N ~+
-il-N N 'N
S02GH3 SO2CH3 2
22 ROSU
9

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wherein W represents a carboxyl protecting group, Z is a C1- C$ alkyl group or
aryl, Y is a
C1-C4 ester, and X is an hydroxyl protecting group.
In one embodiment, in the above scheme, Compound 19 is replaced with Compound
19A, shown below, wherein X and W are as defined above and Tl and T2 are
independently
aryl or alkoxy. Compound 19A can be prepared from Compound 18 by, e.g.,
reaction, in a
base, of Compound 18 with POQ3, wherein Q is alkoxy or aryl (e.g.,
(OEt)2POEt).
O O OX
Tl I" õ I
P CW
T2
Compound 19A
Preparation of Rosuvastatin through Intermediates
~
In another aspect of the present invention, a process is provided for
preparing
intermediate Compound 18, as shown in the following structure:
0 0 ox
Zo ~ 0 cw
Compound 18
wherein W is a carboxyl protecting group, and X is a hydroxyl protecting
group, and Z is a
C1_8 alkyl or aryl. The process comprises: adding of a first solution
comprising Compound 17,
a first organic solvent and a base, to a second solution comprising a mono-,
di-, tri-(C1 to C4)
alkyl substituted benzene chloroformate, saturated or aromatic C5-C12
chloroformate or CI_g
alkyl chloroformate and a second organic solvent to obtain a reaction mixture
while
maintaining a temperature of about -50 C to about -10 C; and maintaining the
reaction
mixture for a sufficient period of time to obtain Compound 18.
The base may be any suitable organic base, including, but not limited to, di-
(Ci to C4
alkyl) pyridine, wherein the alkyl group may be the same or different, mono-,
di-, or tri-(C1
toC4 alkyl) amines, wherein the alkyl groups can be the same or different,
alkaline earth
metals, allcaline earth hydroxides, allcaline earth alkoxides, C1.4 alkyl
lithium. Preferably, the
base is a Cl_C4 trialkylamine, and most preferably is triethylamine.
The first and second organic solvents suitable for use in the process of the
invention
include, but are not limited to, saturated or aromatic C5_12 hydrocarbons,
mono-, di-, tri-,(C1_4)
alkyl substituted benzenes, and benzenes. For example, THF, toluene, methylene
chloride,

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diethylether, benzene, and chlorofbrm may be used. Toluene and THF are
preferred organic
solvents. The same organic solvent is preferably used for both the first and
second organic
solvent.
Preferably the mono-, di-, tri-(C1 to C4) alkyl substituted benzene
chloroformate,
saturated or aromatic C5-C12 chloroformate or C1_8 alkyl chloroformate is a
C1_4 alkyl
chloroformate, more preferably ethyl chloroformate or methyl chloroformate,
with ethyl
chloroformate being particularly preferred. The molar ratio of the
chloroformate to
Compound 17 in the reaction mixture is about 1 mole to about 3 moles, and is
preferably
about 1 mol to about 1.5 mol.
The first solution is combined with the second solution at a temperature of
about
-50 C to about -10 C, more preferably at a temperature of -50 to about -30 C
and most
preferably at a temperature of about -45 C to about -40 C. Preferably the
solutions are
combined over a period of about 30 minutes.
The reaction mixture is maintained by gradual heating to about -10 C to about
30 C,
and more preferably to about 0 C. The sufficient period of time required to
obtain
Compound 18 will depend on, for example, scale and mixing procedures. This can
be
determined by one skilled in the art by measuring the absence of the limiting
reagent using
such techniques such as HPLC or TLC, preferably TLC. Optionally, the reaction
mixture can
then be quenched, preferably with water.
Optionally, Compound 18 may be recovered from the reaction mixture using
techniques known to those skilled in the art. Preferably, Compound 18 is
recovered by
separating the organic layer formed during quenching from the reaction mixture
and washing
the organic layer with a mild base (pH 7-11), such as NaHCO3. The reaction
mixture may be
washed by adding NaCl. The organic layer is then dried, for example with a
metal salt,
preferably Na2SO4 or MgSO4. The solvent is then evaporated to obtain Compound
18.
Alternatively, the reaction mixture is filtered to remove the salts formed
during the reaction.
Preparing Compound 18 according to the process of the invention reduces the
formation of a symmetric anhydride impurity and allows a quantitative
formation of a mixed
anhydride product. In addition, the process of this invention can be used
easily on an
industrial scale as extreme temperatures need not be used, in
contradistinction to US
5,260,440 where -70 C to -85 C are ideally used.
11

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In another aspect of the present invention, Compound 18 prepared by the
process of
the present invention is used to prepare any downstream intermediate of
rosuvastatin or
pharmaceutically acceptable salts thereof.
Compound 18 may be converted into Compound 19 or Compound 19A, of the
following structures:
0 OX
Ph3P~ CW
Compound 19
O O OX
T,I", ~~ I
P CW
T2
Compound 19A
wherein X is any hydroxyl protecting group, T1 and T2 are independently aryl
or alkoxy and
W is any carboxyl protecting group, by methods known in the art. For example,
a solution of
Compound 18 in toluene may be gradually added to a cooled solution comprising:
methyl
triphenylphosphonium bromide, THF, and a butyllithium while maintaining the
temperature
at about -60 C to obtain a reaction mixture; and maintaining the reaction
mixture at a
maximum temperature of about -20 C for a sufficient amount of time to obtain
Compound
19. [See US Patent No. 5,260,440].
In another aspect of the present invention, Compound 19 or Compound 19A
prepared
by the process of the present invention can be used to prepare any downstream
intermediate
in the synthesis of, e.g., rosuvastatin and phamiaceutically acceptable salts
thereof.
In another aspect of the present invention, a process is presented for the
preparation of
Compound 20. In one aspect, Compound 20 is prepared through the Wittig
condensation of
Compound 19 and Compound 14, as shown below:
F F
O~~ ox 0 ox
N CHO + Ph3P/\/\iCW CW N N N N N
SO2CH3 $OZCH3
14 19 20
12

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WO 2007/041666 PCT/US2006/038921
wherein W is a carboxyl protecting group and X is a hydroxyl protecting group.
This process
comprises: providing Compound 19, Compound 14 and a suitable organic solvent
other than
acetonitrile, to obtain a reaction mixture in an inert atmosphere such as
argon or nitrogen; and
heating the reaction mixture at about 70 C to about reflux for period to
obtain Compound 20.
The organic solvent can be any suitable organic solvent including, but not
limited to,
saturated or aromatic C5-Cla hydrocarbons, mono-, di-, tri-(Cl to C4 alkyl
substituted
benzenes, and benzenes. Preferably, the organic solvent is toluene.
Compound 19 is in an amount of 1.5 equivalents relative to Compound 14, while
the
organic solvent other than acetonitrile is about 10 volumes relative to
Compound 14. Heating
the reaction mixture is preferably to about 70 C to about 110 C, most
preferably about
100 C. The period of time necessary depends on the scale and temperature of
the process and
may be determined easily by anyone skilled in the art.
Compound 20 may alternatively be prepared by use of a Wittig-Horner reaction
(also
known as a Horner-Wadsworth-Emmons reaction). (See -Maryanoff et al. "The
Wittig
olefination reaction", Chem. Rev. (1989) 89, 863-927; Boutagy et al. "Olefin
synthesis with
organic phosphonate carbanions", Chem. Rev. (1974), 74 (1), 87-99; Wadsworth
et al." The
utility of phosphonate carbanions in olefin synthesis", JACS (1961), 83, 1733-
1738; Tsuge et
al. "Homer-Emmons Olefination", Bull. Chem. Soc. Jpn. (1987), 60, 4091-4098.)
The
Wittig-Horner reaction can be applied to Compound 19A and Compound 14, as
shown
below:
F
F
ox 0 O}~
,,,..PI + H ~ CHf} ---~ ~I - I ~ CV~
T2 I I ~-,H H
T1 -N -~-_H ~
i ~O~H3
19A SQzCH3
14
wherein X and W are as defined for Compound 19 and T1 and T2 are independently
alkoxy
or aryl. For example, Compound 19A may be 19TBPO as shown below.
13

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a 0 OTBDN1S
EtO
~~ II I~~p~~4H9
~ '"'~ f
EtO
19TBPO
In one aspect of the present invention, a Wittig-Horner reaction is presented
which
comprises combining Compound 19A, a base, and Compound 14 to obtain Compound
20.
Preferably, the Wittig-Horner reaction for preparing Compound 20 comprises:
(a) providing a dry solvent and the Compound 19A;
(b) combining the base with the dry solvent and the Compound 19A to obtain a
first reaction mixture;
(c) combining the Compound 14 with the first reaction mixture at a reduced
temperature to obtain a second reaction mixture;
(d) maintaining the second reaction mixture for a sufficient time to obtain
the
Compound 20.
Compound 19A is, e.g., in an amount of about 1 to 5 molar equivalents relative
to
Compound 14. Preferably, about 1 to about 2 and more preferably about 1.3 to
1.6 molar
equivalents are used.
Examples of dry solvents include, but are not limited to, ethereal solvents
such as
tetrahydrofuran, aromatic solvents such as toluene, chlorinated solvents and
acetonitrile.
Preferably, the dry solvent and Compound 19A are provided in a homogeneous
mixture. In one example, the dry solvent and compound 19A are mixed for about
20 minutes
to obtain a homogenous mixture. Preferably, the dry solvent and compound 19A
are at a
temperature below room temperature and above the freezing point of the solvent
used, for
example, a temperature of 5 to about -5 C.
Preferably combining the dry solvent and Compound 19A is performed at a
temperature between about room temperature and about the freezing point of the
solvent
used, it being noted that the freezing point of any solvent can be easily be
obtained by the
skilled artisan. Preferably, the dry solvent and Compound 19A are combined
until a
homogeneous suspension is obtained.
Suitable bases for the Wittig-Horner reaction, include but are not limited to,
NaH or
other metal hydrides, NaOMe, NaOH, KOtBu, NaOtBu, K-2C03, BuLi or other
lithiated
bases, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and DABCO (diazabicyclo
[2.2.2] octane).
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When necessary, suitable bases are in the presence of a phase transfer
catalyst. Preferably
bases such as lithiated bases, and metal hydrides are used. A sufficient
amount of base, for
example, is from about 1 to 5 molar equivalents relative to Compound 14,
preferably, about 1
to about 2 molar equivalents. Preferably, the base and first reaction mixture
are at a reduced
temperature of below about 20 C, more preferably below about 10 C, so as to
prevent an
exothermic reaction. Preferably, the base is added gradually over time.
Preferably, Compound 14 is added gradually over time. Preferably, the
temperature is
maintained at about less than 20 C, more preferably less than 10 C.
Maintaining the second reaction mixture is preferably for a period of time to
allow the
reaction to proceed to completion as measured by HPLC. As one skilled in the
art will
appreciate, the time required to allow the reaction to proceed to completion
will vary
depending upon, among other factors, the amount of starting materials and the
temperature,
and can be determined by periodic HPLC measurements. Preferably, more than
about 70%
of the reaction has gone to completion, more preferably, more than about 85%
and most
preferably, more than about 95% has gone to completion.
Preferably, once the reaction has gone to completion, quenching of the
reaction is
performed by addition of water and/or an acid. The acid may be organic or
inorganic, strong
or weak. For example, acetic acid, hydrochloric acid or ammonium chloride may
be used.
Preferably, once the reaction is quenched, Compound 20 is recovered.
As assay may be performed which measures contamination of Compound 20 by salts
or impurities, primarily from excess of Compound 19A and the phosphonate
derivative after
condensation with the aldehyde (1 equivalent). Regardless of these impurities,
Compound 20
formed from this process may be used directly without further purification in
the next step to
form Compound 21. Recovery maybe performed by any suitable means, such as by
filtering,
washing and drying. In one embodiment, Compound 20 is extracted with a brine
solution; the
organic phase is washed with a saturated solution of NaHCO3 and brine
solution; and the
mixture is evaporated to obtain a viscous oil.
In another embodiment, substantially pure Compound 20 is presented.
In yet another embodiment, a method of recovering Compound 20 is presented
comprising:
a. combining the quenched second reaction mixture, which is optionally
filtered
and washed, with a water immiscible solvent (e.g. hexane, heptane, or toluene)
and water to
obtain a 2 phase system;

CA 02625290 2008-04-04
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b. washing the first organic [upper] phase with a base (e.g., potassium
carbonate
(K2C03)) and a solvent (to bring the aqueous base in contact with the organic
compound, e.g.
an alcohol) to obtain a three phase system; and
c. recovering Compound 20.
In a particularly preferred embodiment, Compound 20 is recovered by a process
comprising:
a. combining the quenched second reaction mixture, which is optionally
filtered
and washed, with a water immiscible solvent and water to obtain an first
organic and aqueous
phase;
b. washing the first organic phase with a suitable solvent to obtain a second
organic and second phase;
c. combining the first organic phase and the second organic phase with a base
and an alcohol and optionally adding the extracted product of the first
aqueous phase and the
second aqueous phase, to obtain a three phase system comprising a upper,
middle and lower
phase;
d. isolating the upper phase;
e. washing the upper phase with first with an alcohol/water mixture, then a
base
(e.g. sodium bicarbonate, triethylamine, diisopropylamine, sodium hydroxide),
then an
alcohol and subsequently water and
f. recovering Compound 20.
The inventors have discovered that the above Wittig-Homer reaction leads to a
higher
purity downstream products, e.g. Compound 20, as compared to the Wittig
reaction.
The by-products obtained from the Wittig-Homer reaction may be separated
easily at
the end of the reaction after work-up.
Overall, the reaction of Compound 19A with Compound 14 results in a
quantitative
conversion of starting materials. Preferably, Compound 14 is present in a
quantity of less than
5% as measured by HPLC, and most preferably less than 2% as measured by HPLC.
Triphenylphosphine oxide is formed as a by-product of the reactions, and can
be
removed from the reaction mixture. Preferably, triphenylphosphine oxide is
removed by
forming a complex with a metal salt by combining a metal salt, preferably
anhydrous
magnesium chloride with the reaction mixture, as disclosed in EP Patent No.
0850902A1, and
isolating Compound 20 by heating to about 100 C, cooling to about 0 C,
filtering, washing
with water or toluene and evaporating the solvent.
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In another aspect of the present invention, Compound 20 prepared by the
process of
the present invention is used to prepare any downstream intermediate of
rosuvastatin and
pharmaceutically acceptable salts thereof.
Compound 21 may be prepared by the deprotection of the hydroxyl group of
Compound 20, as disclosed in WO 2003/097614 A2 as shown below:
F F
0 OX 0 OH
N cw N cw
N N N N
i i
SO2CH3 S02CH3
20 21
wherein W is a carboxyl protecting group and X is a hydroxyl protecting group.
In one
example, a solution of Compound 20 in methanol, THF or acetonitrile is
combined with a
deprotecting agent, such as a fluoride ion source or an inorganic acid aside
from HF, to obtain
a reaction mixture; and the reaction mixture is maintained for a sufficient
time and
temperature to obtain Compound 21.
In another aspect of the present invention, a process for recovery of Compound
21 is
provided. This process comprises:
a. providing a two-phased system comprised of a mixture of a non-polar
aliphatic
solvent and a non-polar aromatic solvent and a mixture of a mixture of a lower
alipliatic alcohol and water, each in an amount of about 4 to about 6 volumes
relative to Compound 21 and crude Compound 21;
b. washing the non-polar phase with a mixture of lower aliphatic alcohol and
water;
and
c. recovering Compound 21 from the organic phase.
Compound 21, having a purity of greater than about 80%, preferably about 90%
(as
determined by HPLC) and a yield of greater than about 90%, preferably greater
than about
95%, may be obtained using this recovery method.
Preferably, the non-polar aliphatic solvent, non-polar aromatic solvent, lower
aliphatic
alcohol and water in step a. are each in an equal volume of about 5 volumes
relative to
Compound 21. Preferably, the non-polar aliphatic solvent is heptane.
Preferably, the non-
polar aromatic solvent is toluene. Preferably, the lower aliphatic alcohol is
ethanol.
Preferably, providing the two-phase system of step a. includes mixing the
reagents of step a.
17

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at room temperature until a clear solvent is obtained and allowing the mixture
to separate into
phases.
Washing the non-polar phase with the mixture of polar solvent and water is
preferably
in stages, where 5 times should be sufficient. In a more preferred embodiment,
4 portions of
ethanol and water is used. Preferably, the ratio of ethanol to water is in a
ratio of about 2:1 by
volume. Preferably, the ethanol is in an amount of about 4 to about 6 volumes,
preferably 5
volumes relative to Compound 21 while the water is in an amount of about 8 to
about 12
volumes relative to Compound 21, preferably about 10 volumes. Preferably,
fractions 2
through 5 from 5 fractions are collected, combined and concentrated,
preferably under
reduced pressure, to obtain an oily residue of Compound 21.
The recovery process of Compound 21 described above allows for the
crystallization
of Compound 22 after stereoselective reduction of Compound 21. The production
of
Compound 22 in solid form resulting from the purification of Conipound 21
allows
rosuvastatin to be further purified, if desired. Crystallization of Compound
21 may further
reduce the impurities present; however, such crystallization may not provide a
satisfactory
yield.
Subsequent reduction of intermediate Compound 21 to form Compound 22, shown in
the following:
F F
0 OH OH OH
N~ CW
N N N N
i i
SO2CH3 SO2CH3
21 22
wherein W is a carboxyl protecting group and X is a hydroxyl protecting group.
This process
is performed under conditions known to those skilled in the art, and is
preferably performed
using diethylmethoxyborane in THF and sodium borohydride.
Rosuvastatin may be obtained upon saponification of Compound 22.
In another aspect, the present invention provides a process for preparing
rosuvastatin,
and pharmaceutically acceptable salts thereof, by converting Compound 17 into
rosuvastatin.
This process comprises:
a. providing a solution of Compound I and a polar solvent;
18

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b. combining the solution with a base to obtain a pH of about 10 to about 13
to
form a first solution comprising Compound 17;
c. adding a second solution comprising a mono-, di-, tri-(C1 to C4) alkyl
substituted benzene chloroformate, saturated or aromatic C5-C12 chloroformate
or C1_8 alkyl chloroformate and an organic solvent to obtain a first reaction
mixture while maintaining a temperature of about -50 C to about -10 C;
d. maintaining the first reaction mixture for a sufficient period of time to
obtain
Compound 18;
e. converting Compound 18 into Compound 19;
f. providing Compound 19, Compound 14 and a suitable organic solvent other
than acetonitrile, to obtain a first reaction mixture in an inert atmosphere
such
as argon or nitrogen;
g. heating the first reaction mixture at about 70 C to about reflux for period
to
obtain Compound 20;
h. converting Compound 20 into Compound 21;
i. optionally recovering Compound 21 by providing a two-phased system
comprised of a mixture of a non-polar aliphatic solvent and a non-polar
aromatic solvent and a mixture of a mixture of a lower aliphatic alcohol and
water, each in an amount of about 4 to about 6 volumes relative to Compound
21 and crude Compound 21, washing the non-polar phase with a mixture of
lower aliphatic alcohol and water, and recovering Compound 21 from the
organic phase;
j. converting Compound 21 into Compound 22; and
k. converting Compound 22 into rosuvastatin.
Optionally, steps e, f, and g are replaced with:
(aa) providing a dry solvent and Compound 19A;
(bb) combining a base with the dry solvent and the Compound 19A to obtain a
second reaction mixture;
(cc) combining Compound 14 with the second reaction mixture at a reduced
temperature to obtain a third reaction mixture;
(dd) maintaining the third reaction mixture for a sufficient time to obtain
Compound 20;
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(ee) optionally, quenching the reaction to obtain a fourth reaction mixture
comprising Compound 20; and,
(ff) optionally recovering the Compound 20.
Optionally, step (ff) comprises:
(i) combining the quenched second reaction mixture, which is optionally
filtered
and washed Compound 20, with a water immiscible solvent (e.g. hexane, heptane,
or toluene)
and water to obtain a 2 phase system;
(ii) washing the first organic [lower] phase with a base (e.g., potassium
carbonate
(K2CO3)) and a solvent (to bring the aqueous base in contact with the organic
compound, e.g.
an alcohol) to obtain a three phase system; and
(iii) recovering Conzpound 20.
Optionally step (ff) comprises:
(i) combining the quenched second reaction mixture, which is optionally
filtered
and washed Compound 20, with a water immiscible solvent and water to obtain an
first
organic and aqueous phase;
(ii) washing the first organic phase with a suitable solvent to obtain a
second
organic and second phase;
(iii) combining the first organic phase and the second organic phase with a
base
and an alcohol and optionally adding the extracted product of the first
aqueous phase and the
second aqueous phase, to obtain a three phase system comprising a upper,
middle and lower
phase;
(iv) isolating the upper phase;
(v) washing the upper phase with first with an alcohol/water mixture, then a
base
(e.g. sodium bicarbonate, triethylamine, diisopropylamine, sodium hydroxide),
then an
alcohol and subsequently water and
(vi) recovering Compound 20.
Optionally, Compound 17 may be recovered from step b. by partially evaporating
the
solvent from the first solution, adding water, washing with a C5_7 alkyl,
extracting using an
organic solvent selected from the group consisting of: saturated or aromatic
C5-C12
hydrocarbons, mono-, di-, tri-(C1 to C4) alkyl substituted benzene, acidifying
the mixture
using an inorganic acid to a pH of about 7 to about 5; and recovering Compound
17 from the
organic phase. The recovered Compound 17 may then be combined with a first
organic
solvent and a base to form the first solution comprising Compound 17.

CA 02625290 2008-04-04
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Rosuvastatin obtained by the processes of the invention may be converted to a
pharmaceutically acceptable salt of rosuvastatin, preferably the calcium salt.
[See e.g. U.S.
patent No. 5,260,440]. The process of converting rosuvastatin into its
pharmaceutically
acceptable salt includes contacting rosuvastatin with calcium hydroxide, or
with a stronger
base such as sodium hydroxide. The base is preferably combined dropwise with a
reaction
mixture of rosuvastatin at a suitable temperature, such as a temperature of
about 25 C ~: 5 C.
The reaction mixture may be washed with a suitable water immiscible organic
solvent.
Suitable water immiscible organic solvents include, but are not limited to,
hydrocarbons;
preferably the water immiscible organic solvent is toluene. The water
immiscible organic
solvent may be removed by phase separation. Remaining water immiscible organic
solvent
may be removed by distillation of the reaction mixture, preferably at a
temperature of about
40 C to about 45 C under reduced pressure (below about 50 mmHg).
The reaction mixture may then be combined with an alkali metal, including a
source
of calcium such as calcium chloride or calcium acetate, to form the salt of
rosuvastatin. [See
e.g. U.S. patent No. 6,777,552]. For example, calcium chloride may be added
dropwise to a
reaction mixture of rosuvastatin at a suitable temperature, such as a
temperature of about
35 C to about 45 C, and preferably at about 40 C, over a period of about
thirty to about
ninety minutes. Active carbon may be combined with a reaction mixture of
rosuvastatin to
remove impurities from the reaction mixture. If active carbon is used during
the conversion
of rosuvastatin into its pharmaceutically acceptable salt, the active carbon
may be used before
or after contacting rosuvastatin with an alkali metal.
The conversion of rosuvastatin into its pharrnaceutically acceptable salt may
also
include filtering the reaction mixture. The reaction mixture may be filtered,
such as with
Synter and Hyflo , before or after washing with a water immiscible organic
solvent.
Other embodiments of the invention encompass pharmaceutical compositions
containing rosuvastatin or rosuvastatin salts made by the processes of the
invention and
methods of making pharmaceutical compositions comprising converting Compound
17 into
rosuvastatin or one or more of the above-mentioned intermediates - e.g.
Compounds 18, 19,
19A, 20, 21 and 22.
Pharmaceutical compositions of the invention may include excipients. Diluents
increase the bulk of a solid pharmaceutical composition, and may make a
pharmaceutical
dosage form containing the composition easier for the patient and care giver
to handle.
Diluents for solid compositions include, for example, microcrystalline
cellulose (e.g.
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Avicelo), microfine cellulose, lactose, starch, pregelatinized starch, calcium
carbonate,
calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium
phosphate dihydrate,
tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide,
maltodextrin,
mannitol, polyinethacrylates (e.g. Eudragit ), potassium chloride, powdered
cellulose,
sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compacted into a dosage form, such
as a
tablet, may include excipients whose functions include helping to bind the
active ingredient
and other excipients together after compression. Binders for solid
pharmaceutical
compositions include acacia, alginic acid, carbomer (e.g. carbopol),
carboxymethylcellulose
sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable
oil, hydroxyethyl
cellulose, hydroxypropyl cellulose (e.g. Klucel ), hydroxypropyl methyl
cellulose (e.g.
Methocel ), liquid glucose, magnesium aluminum silicate, maltodextrin,
methylcellulose,
polymethacrylates, povidone (e.g. Kollidon , Plasdone ), pregelatinized
starch, sodium
alginate and starch.
The dissolution rate of a coinpacted solid pharmaceutical composition in the
patient's
stomach may be increased by the addition of a disintegrant to the composition.
Disintegrants
include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose
sodium (e.g.
Ac-Di-Sol , Primellose ), colloidal silicon dioxide, croscarmellose sodium,
crospovidone
(e.g. Kollidon , Polyplasdone ), guar gum, magnesium aluminum silicate, methyl
cellulose,
microcrystalline cellulose, polacrilin potassium, powdered cellulose,
pregelatinized starch,
sodium alginate, sodium starch glycolate (e.g. Explotab) and starch.
Glidants can be added to improve the flowability of a non-compacted solid
composition and to improve the accuracy of dosing. Excipients that may
function as glidants
include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose,
starch, talc and
tribasic calcium phosphate.
When a dosage form such as a tablet is made by the compaction of a powdered
composition, the composition is subjected to pressure from a punch and dye.
Some
excipients and active ingredients have a tendency to adhere to the surfaces of
the punch and
dye, which can cause the product to have pitting and other surface
irregularities. A lubricant
can be added to the composition to reduce adhesion and ease the release of the
product from
the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl
monostearate,
glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil,
mineral oil,
polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl
fumarate, stearic
acid, talc and zinc stearate.
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Flavoring agents and flavor enhancers make the dosage form more palatable to
the
patient. Common flavoring agents and flavor enhancers for pharmaceutical
products that
may be included in the coinposition of the present invention include maltol,
vanillin, ethyl
vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
Solid and liquid compositions may also be dyed using any pharmaceutically
acceptable colorant to improve their appearance and/or facilitate patient
identification of the
product and unit dosage level.
In liquid pharniaceutical compositions of the present invention, rosuvastatin
and any
other solid excipients are dissolved or suspended in a liquid carrier such as
water, vegetable
oil, alcohol, polyethylene glycol, propylene glycol or glycerin. Liquid
pharmaceutical
compositions may contain emulsifying agents to disperse uniformly throughout
the
composition an active ingredient or other excipient that is not soluble in the
liquid carrier.
Emulsifying agents that may be useful in liquid compositions of the present
invention
include, for example, gelatin, egg yolk, casein, cholesterol, acacia,
tragacanth, chondrus,
pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
Liquid pharmaceutical compositions may also contain a viscosity enhancing
agent to
improve the mouth-feel of the product and/or coat the lining of the
gastrointestinal tract.
Such agents include acacia, alginic acid bentonite, carbomer,
carboxymethylcellulose calcium
or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar
gum,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl
cellulose,
maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene
glycol alginate,
sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose,
aspartame,
fructose, mannitol and invert sugar may be added to improve the taste.
Preservatives and chelating agents such as alcohol, sodium benzoate, butylated
hydroxyl toluene, butylated hydroxyanisole and ethylenediamine tetraacetic
acid may be
added at levels safe for ingestion to improve storage stability.
According to the invention, a liquid composition may also contain a buffer
such as
guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium
lactate, sodium
citrate or sodium acetate. Selection of excipients and the amounts used may be
readily
determined by the formulation scientist based upon experience and
consideration of standard
procedures and reference works in the field.
The solid compositions of the present invention include powders, granulates,
aggregates and compacted compositions. The dosages include dosages suitable
for oral,
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buccal, rectal, parenteral (including subcutaneous, intramuscular, and
intravenous), inhalant
and ophthalmic administration. Although the most suitable administration in
any given case
will depend on the nature and severity of the condition being treated, the
most preferred route
of the present invention is oral. The dosages may be conveniently presented in
unit dosage
form and prepared by any of the methods well-known in the pharmaceutical arts.
Dosage forms include solid dosage forms like tablets, powders, capsules,
suppositories, sachets, troches and losenges, as well as liquid syrups,
suspensions and elixirs.
The dosage form of the present invention may be a capsule containing the
composition,
preferably a powdered or granulated solid composition of the invention, within
either a hard
or soft shell. The shell may be made from gelatin and optionally contain a
plasticizer such as
glycerin and sorbitol, and an opacifying agent or colorant.
The active ingredient and excipients may be formulated into compositions and
dosage
forms according to methods known in the art.
A composition for tableting or capsule filling may be prepared by wet
granulation. In
wet granulation, some or all of the active ingredients and excipients in
powder form are
blended and then further mixed in the presence of a liquid, typically water,
that causes the
powders to clump into granules. The granulate is screened and/or milled, dried
and then
screened and/or milled to the desired particle size. The granulate may then be
tableted, or
other excipients may be added prior to tableting, such as a glidant and/or a
lubricant.
A tableting composition may be prepared conventionally by dry blending. For
example, the blended composition of the actives and excipients may be
compacted into a slug
or a sheet .and then comminuted into compacted granules. The compacted
granules may
subsequently be compressed into a tablet.
As an alternative to dry granulation, a blended composition may be compressed
directly into a compacted dosage form using direct compression techniques.
Direct
compression produces a more uniform tablet without granules. Excipients that
are
particularly w ell suited for direct compression tableting include
microcrystalline cellulose,
spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The
proper use of
these and other excipients in direct compression tableting is known to those
in the art with
experience and skill in particular formulation challenges of direct
compression tableting.
= A capsule filling of the present invention may comprise any of the
aforementioned
blends and granulates that were described with reference to tableting,
however, they are not
subjected to a final tableting step. The oral dosage form of the invention is
preferably in the
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form of an oral capsule having a dosage of about 5 mg to about 40 mg, more
preferably
capsules of 5, 10, 20 and 40 mg.
The present invention, in certain of its embodiments, is illustrated by the
following
non-limiting examples.
All purities mentioned herein refer to a yield per weight quantification,
measured by
comparing HPLC of the product versus known standard.
EXAMPLES
Example 1: Preparation of Compound 17TB
OTBDMS NaOH OTBDMS
EtO2C~~CO2C4H9-Y HO2C,_,JCO2C4H9
EtOH
Diester 17TB
A 1 liter flask, equipped with a condenser, a mechanical stirrer, a pH-meter
and a
thermometer, was charged with t-butylethyl glutaric acid TBDMS protected (100
g, 288
mmol) and absolute EtOH (500 ml),'forming a reaction mixture. The reaction
mixture was
heated to 50 C, and NaOH 1N (115.2 ml) was added dropwise. The pH measured
12.8.
After 1 hour at this temperature, the pH measured 10.59. Additional NaOH 1N
(115.2
ml) was added. The pH measured 12.25. After 1 hour, additional NaOH 1 N (115.2
ml) was
added.
The reaction mixture was maintained at 50 C for 7 hours, until the starting
material
was not detected by TLC. The reaction mixture was cooled to room temperature,
and
evaporated to a final volume of 300 ml. H20 (400 ml) and EtOH (95%, 50 ml)
were added to
the reaction mixture. The reaction mixture was washed twice with hexane (300
ml each).
Toluene was added (300 ml) to the aqueous phase, and the reaction mixture was
neutralized with HCl (32%) to a pH of 6. Two additional extractions with
toluene were
performed (300 ml each). The toluene layers were combined, dried with MgSO4
(approx 12
g), and evaporated, yielding 78.3 g (85% yield) of a yellow oil.

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Example 2: Preparation of Compound 18TB
OTBDMS CIC02Et O O OTBDMS
HO2C,,j,CO2C4H9 Et0'k0)~'~C02C4H9
NEt3
17TB Tol. 18TB
A 2 L flask was charged with a first solution of ethyl chloroformate (16.44
ml) in 900
ml of dry toluene (KF = less than 0.01%) and the solution was cooled to -45 C.
A reaction
mixture was formed by adding dropwise through a dropping fitmiel a second
solution of
Compound 17TB (50 g) and Et3N (26.06 ml) in 100 ml of toluene dropwise through
a
dropping funnel to the first solution over a period of about 30 minutes, so
that the
temperature of the reaction mixture was maintained at -45 to -40 C.
The reaction mixture was slowly heated to 0 C over a period of 1.5 hours and
then
quenched with water. The reaction mixture was immediately transferred to a 2L
separation
funnel, and the organic layer was washed with NaHCO3 (saturated, 250 ml) and
NaCI
(saturated, 250 ml), and dried with MgSO4. The solvent was evaporated and the
residue was
used for the next stage without any purification.
Example 3: Preparation of Compound 19TBPH
0 0 OTBDMS 0 OTBDMS
Et0-k0'k~CO2C4Hg CH3PPh3Br Ph3P'- CO2Cq.Hg
BuLi
18TB 19TBPH
Methyl triphenyl phosphonium bromide (224.3 g) was suspended in THF(600 ml),
and BuLi (1.6 M, 392.5 ml) was added over a period of 30 minutes at a
temperature of about
-55 to -50 C. The reaction mixture was then heated to about 0 C over a period
of 1.5 hours,
and then cooled to about -60 C.
A solution of anhydride Compound 18TB (122.6 g, 314 mmol) in toluene (360 ml)
was added dropwise to the reaction mixture over a period of about two hours,
while the
temperature of the reaction mixture was maintained at about -55 to -65 C. The
reaction
mixture was heated to about 0 C over a period of 1.5 hours, and quenched with
water (250
ml). The aqueous phase was separated, and the product was extracted from the
aqueous
phase using toluene (100 ml). Both organic layers were mixed together and
washed with
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NaHCO3 (saturated, 2 x 100 ml) and NaC1(2 x 100 ml). The organic phase was
kept
overnight on NaaSO4 at about -25 C and the solvent evaporated before use.
Example 4: Preparation of Compound 20TB by Wittig reaction from 19TBPH
F F
0 OTBDMS 0 OTBDMS
Ph3P, C02C4H9 + N CHO N~ C02C4H9
N N
SO2CH3 SO2CH3
19TBPH 14 20TB
A 100 ml flask, protected from light and provided with N2 flow was charged
with
Compound 14 (3.6 g, 10.5 mmol), Compound 19TBPH (9.05 g, 15.7 mmol), and dry
toluene
(36 ml, 10 vol relative to Compound 14). The reaction mixture was heated to
about 100 C
for 19.5 hrs. A sample of the reaction mixture was analyzed by HPLC, and
contained 1.7% of
Compound 14.
Anhydrous MgCla (2 g, 2 equivalents relative to Compound 19TBPH) was added to
the reaction mixture and the reaction mixture was stirred at 100 C for 2 hrs.
The reaction
mixture was cooled to 0 C for 2 hours, and filtered without washing the solid.
A filtrate was
obtained and was washed twice with H20 (100 ml each) and the solvent was
evaporated,
yielding 7.56 g of a brown solid.
Example 5: Preparation of Compound 20M by Wittig Reaction from 19M
F F
I I
0 OTBDMS 0 OTBDMS
N/ CHO + Ph3P~ C02CH3 N~ CO2CH3
N
S02CH3 N
S02CH3
14 19M 20M
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A 250 ml flask, protected from light and provided with N2 flow was charged
with
Compound-14 (4.38 g, 12.5 mmol), Compound 19M (10 g, 18.7 mmol), and extra dry
toluene
(100 ml). The reaction mixture was heated to about 100 C for 15 hrs. After the
completion
of the reaction, anhydrous MgC12 (4.8 g, 2.7 eq.) was added to the reaction
mixture and the
reaction mixture was heated for 2 hours at about 100 C. The reaction mixture
was cooled to
0 C over a period of about 2 hours, filtered, and washed with 45m1 of toluene,
yielding
12.73g of a viscous oil.
Example 6: Preparation of Compound 21TB in HCl/ methanol
F F
I "~'
I
0 OTBDMS 0 OH
N I \ C02C4H9 N C02C4H9
~
NN NN
SO2CH3 SO2CH3
20TB 21TB
A mixture of HC1(32% in water, 1 mL), water (0.5 mL) and methanol (8 mL) was
added dropwise to a solution of Compound 20TB (2 g) in methanol (10 mL). The
reaction
mixture was stirred at 30 C for about 1.5 hours, until TLC (Hexane/EtAc, 4:1)
indicated full
consumption of the starting material.
Ethyl acetate (150 mL) was added to the reaction mixture and the reaction
mixture
was washed with a saturated NaHCO3 solution (50 mLx2), forming an organic
layer. The
organic layer was dried over MgSO4 and the solvent was removed under reduced
pressure,
yielding Compound 21TB (1.72 g).
Example 7: Preparation of Compound 21TB in HCI/THF
A mixture of HCl (32% in water, 0.57 g), water (2 mL), and THF (17.5 mL) was
prepared. 5.4 mL of this mixture were added dropwise to a solution of Compound
20TB
(2.7g) in THF (8.1 mL). The reaction mixture was stirred at ambient
temperature overnight,
until monitoring of the reaction by TLC indicated completion of the reaction.
Ethyl acetate (20 mL) was added to the reaction mixture and the reaction
mixture was
washed witli water (20 mL). An aqueous layer formed, and was extracted with
ethyl acetate
(20 mL). The organic layers were combined and washed with an aqueous solution
of Et3N (2
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x 5 mL) at a pH of about 10.5. The organic layer was dried over MgSO4 and the
solvent was
removed under reduced pressure, yielding an oil of Compouiid 21 TB (2.03 g).
Example 8: Preparation of Compound 21TB with tetrabutylammonium fluoride/THF
Compound 20TB (5 g) was dissolved in THF (40 mL). Tetrabutylaininonium
fluoride
in THF (8.46 ml, 1 M solution) was added dropwise to the solution, forming a
reaction
mixture. The reaction mixture was stirred for about 1 hour at room
temperature. The solvent
was removed under reduced pressure. Toluene (300 ml) was added to the
solution. The
solution was washed three times with a NaHCO3 saturated solution (50 mL) and
concentrated
under reduced pressure, yielding Compound 21TB.
Example 9: Preparation of Compound 21TB by TBDMS deprotection with CsF,
K2C03 and NH2OH.HC1
Compound 20TB (0.3 g) was dissolved in acetonitrile (10 ml) at room
temperature.
CsF (70 mg), K2CO3 (300 mg), and NH2OH.HCI (160 mg) were added to the
solution,
forming a reaction mixture. The reaction mixture was heated at about 75 C.
Partial
deprotection of the compound was observed after heating for about 4.5 hours.
Example 10: Preparation of Compound 21TB by TBDMS deprotection with CsF
Compound.20TB (300 mg) was dissolved in acetonitrile (10 ml). CsF (70 mg) was
added to the solution, forming a slurry. The slurry was heated at about 75 C
for about 17
hours, at which point a complete deprotection of the material was observed.
Example 11: Preparation of Compound 21TB by TBDMS deprotection with
tetrabutylammonium fluoride of 20TB
Compound 20TB (5g) was dissolved in THF (40 mL) and tetrabutylammonium
fluoride was added dropwise as 1M solution in THF (8.46 mL). The mixture was
stirred for
1 hour at room temperature and the solvent was removed under reduced pressure.
Toluene
(300 ml) was added to the residue. The solution was washed with NaHCO3
saturated solution
(50 mL x 3) and concentrated under reduced pressure resulting in crude 21TB.
Example 12: Preparation of Compound 21TB in methanesulfonic acid/methanol
A solution of methanesulphonic acid (15 mL, 0.2M in methanol/water, 10:1) was
added to a solution of Compound 20TB (3 g) in methanol (15 mL). The reaction
mixture was
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stirred at 30 C for about 3 hours, until monitoring by TLC (Hexane/EtAc, 4:1)
indicated full
consumption of the starting material.
Toluene (200 mL) was added to the reaction mixture and the reaction mixture
was
washed with a saturated NaHCO3 solution (50 mL x2), forming an organic layer.
The
organic layer was dried over MgSO4 and the solvent was removed under reduced
pressure to
yield Compound 21TB (2.97 g).
Example 13: Preparation of Compound 21TB by TBDMS deprotection with
methanesulphonic acid in methanol
A solution of inethanesulphonic acid (1.66 g) in methanol (200 ml) and water
(19 ml)
was added to a solution of 20TB (20.26 g, 81.2 % assay) in methanol (185 ml).
The resulting
mixture was stirred at about 30 C. After 10.5 hours the HPLC indicated that
the level of the
starting material was 6% (on area), and the solution was cooled to room
temperature.
EtOAc (400 mL) was added and the solution was washed with brine (400 mL). The
organic layer was then washed with a saturated solution of NaHCO3 (2 x 200 mL)
and finally
with brine (2 x 100 ml).
The organic layer was dried over Na2SO4 and the solvent was removed under
reduced
pressure to obtain 21TB (19.9g).
Example 14: Preparation of Compound 21M by TBDMS deprotection with
methanesulphonic acid in methanol
F F
I \
I
0 OTBDMS 0 OH
N~ CO2CH3 N~ CO2CH3
~ -~
N N NN
S02CH3 S02CH3
20M 21 M
A solution of inethanesulphonic acid (50 mL, 0.2 M in methanol/water, 10:1)
was
added to a solution of Compound 20M (10 g) in methanol (50 mL), forming a
reaction
mixture. The reaction mixture was stirred at about 30 C for about four hours.

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Methanesolfonic acid was added (0.35 ml) to the reaction mixture and the
reaction mixture
was stirred until completion of the reaction.
A product was extracted with toluene (2 x100 mL) and washed with a saturated
NaHCO3 solution (100 mL), forming an organic layer. The organic layer was
dried over
MgSO4 and the solvent was removed under reduced pressure, yielding 9.15 g of
an oil.
Example 15: Extraction of Compound 21TB
A 1 L flask equipped with a mechanical stirrer was charged with crude 21TB
(41.6 g,
assay = 40.8%), toluene (200 mL), ethanol (200 mL), heptane (200 mL), and
water (200 mL),
forming a suspension. The suspension was stirred at room temperature until a
clear solution
was obtained. The solution was then poured into a separating funnel to allow
phase
separation. The EtOH/ H20 phase was removed. The toluene/heptane phase was
then washed
4 times with a mixture of EtOH/ H20 (400 mL:200 mL), and the fractions were
collected.
Fractions 2-5 were combined and concentrated under reduced pressure to obtain
an oily
residue of purified 21TB(24.2 g, assay= 56.0%, yield of 80%).
Example 16: Preparation of Compound 22TB (TBRE)
F F
I \ \
0 OH OH OH
N CO2C4H9 N CO2C4H9
NN NN
SO2CH3 S02CH3
21 TB 22TB
To a solution of 21TB (1 g) in dry THF (26 mL) and dry methanol (7 mL), a
solution
of diethylmethoxyborane (1M) in THF (2 mL) was added at about -78 C, forming a
reaction
mixture. The reaction mixture was stirred for 0.5 hour, NaBH4 was added, and
the stirring
was continued for 3 hours. Acetic acid (1.2 mL) was added to the reaction
mixture and the
reaction mixture was warmed to ambient temperature.
Ethyl acetate (150 mL) was added to the reaction mixture and the pH was
adjusted to
8 by addition of concentrated NaHCO3 water solution. The layers were
separated, and water
was extracted by adding an additional amount of ethyl acetate (50 mL). The
organic layers
were combined and dried over MgSO4. The solvents were then evaporated under
reduced
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pressure, leaving a residue. The residue was treated with methanol and then
the methanol
was evaporated. Methanol treatment and evaporation was performed two more
times,
yielding crude Compound 22TB (TBRE) (0.87 g, 86%).
Example 17: Conversion of Compound 22TB into rosuvastatin Ca with extraction
in
ethyl acetate
A 1 L reactor equipped with a mechanical stirrer was charged with EtOH (3 L),
water
(1800 mL), and TBRE (600 g), forming a reaction mixture. NaOH (47%, 1.2 eq,
114 g) was
slowly added to the reaction mixture, at RT. The reaction mixture was stirred
at about RT for
two hours. The reaction mixture was filtered under reduced pressure with
Synter and Hyflo
to eliminate the small particles present. The reaction mixture was
concentrated under reduced
pressure at about 40 C until half the volume of the reaction mixture remained.
Water (2000 mL) was added to the reaction mixture and the reaction mixture was
stirred at about RT for 5 minutes. An aqueous phase and an organic phase
formed. The
phases were separated, and the aqueous phase was washed with ethyl acetate
(3000 mL) and
stirred at RT for half an hour. The organic phase was discarded.
The aqueous phase was concentrated under reduced pressure at about 40 C until
half
the volume remained. Water (2800 mL) was added to the aqueous phase and the
aqueous
phase was stirred at about RT for 5 minutes. CaC12 (124 g) was added to the
aqueous phase
in portions over a period of about 10 minutes at a temperature of about RT.
The aqueous
phase was then stirred at about RT for about 1 hour, filtered, and washed with
1200 mL of
water, yielding a powdery compound (491 g, 88%).
Example 18: Conversion of Compound 22TB into rosuvastatin Ca with extraction
in
toluene
A 500 mL reactor equipped with a mechanical stirrer was charged with EtOH (150
mL), water (90 mL), and 22TB (30 g), forming a reaction mixture. NaOH (47%,
1.2 eq, 5.7
g) was slowly added to the reaction mixture at a temperature of about RT. The
reaction
mixture was stirred at RT for about 2 hours. The reaction mixture was filtered
under reduced
pressure with Synter and Hyflo to eliminate the small particles present. The
reaction mixture
was washed with toluene (150 mL) and stirred at RT for about half an hour,
forming an
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aqueous phase and an organic phase. The two phases were separated, and the
organic phase
was discarded.
The aqueous phase was concentrated under reduced pressure at about 40 C until
half
the volume remained. Water (104 mL) was added to the aqueous phase and the
aqueous
phase was stirred at about RT for 5 minutes. CaC12 (6.2 g) was added dropwise
to the
aqueous phase over 1 minute at about RT. The aqueous phase was then stirred at
RT for
about 1 hour, filtered, and washed with 1200 mL of water, yielding a powdery
compound (26
g, 92%).
Example 19: Conversion of Compound 22TB (TBRE) into rosuvastatin Ca with
extraction in toluene
A 1 L reactor equipped with a mechanical stirrer was charged with EtOH (300
mL),
water (90 ml), and 22TB (60 g), forming a reaction mixture. NaOH (47% 1.2eq,
11.4 g) was
added dropwise to the reaction mixture at RT. The reaction mixture was stirred
at about RT
for two hours. The reaction mixture was filtered under reduced pressure with
Synter and
Hyflo to eliminate the small particles present. Water (420 ml) was added to
the reaction
mixture.
The mixture was then extracted with toluene (3000 mL) and stirred at RT for
half an
hour. An aqueous phase formed and was isolated. The aqueous phase was
concentrated
under reduced pressure at 40 C to half of the volume. Half of the remaining
aqueous phase
was transferred to a 500 mL reactor and water (110 mL) was added, creating a
solution. The
solution was stirred at RT for 5 minutes. Ca(OAc)2 (8.8 g) was added dropwise
to the
solution over 1 min. at RT. The solution was stirred at RT for 1 hour,
filtered, and washed
with 60 mL of water, yielding a powdery compound (26 g, 94%).
Example 20: Synthesis of TB-20 by Wittig-Horner reaction and Purification
Thereof
A 1000 mL 3-necked flask equipped with a mechanical stirrer and nitrogen
bubbler was charged with 19TBPO (100 g, 1.5 eq.) and tetrahydrofuran (500 mL).
The
mixture so-obtained was stirred at 0 C-2 C for 20 minutes. Potassium tert-
Butoxide (24.7 g,
1.5 eq.) was added in 3 portions while keeping the temperature below 10 C and
the solution
was stirred for 15 minutes. ROSU-14 (Compound 14) (51 g, 1.0 eq.) was added
and the
suspension was further stirred at 0 C-2 C for 2 hours. The suspension was then
allowed to
reach ambient temperature and further stirred for 16-18 hours. Glacial acetic
acid (3 mL) was
added and the solution was evaporated to dryness to obtain an oily residue.
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. ..... ... ......
Heptane (350 mL) and water (250 mL) were added to the oily residue and the
organic
phase was separated and washed with NaHCO3 sat. (250 mL). The aqueous phases
were
combined and extracted with heptane (100 mL). The organic phases were combined
and
further washed with K2C03 (20%, 350 mL) together with ethanol (350 mL) to
obtain 3
phases. The 2 bottom phases were discarded and the remaining organic phase was
washed
twice with a mixture ethanol (275 mL)/water (275 mL), then again with K2C03
(20%, 275
mL) together with ethanol (275 mL) and finally with water (200 mL). The
organic phase was
then evaporated to dryness to obtain an oily residue of TB-20. (83.2 g, 82.0%
based on 92%
assay).
Example 21: Preparation of Compound 20TB
A 2 L flask under N2 flow was charged with 19TBP0 (100 g, 1.5 eq.) and THF
(500
ml, 9.7 vol) and cooled to -5 C. Potassium tert-butoxide (22.97 g, 1.4 eq.)
was added through
a tube over 15 min. The mixture was stirred for additional 15 min. at this
temperature and
then Rosu-14 (51.49 g, 1 eq) was added. The bath was removed and the mixture
stirred at
room temperature for 8 hours.
The reaction was quenched by adding AcOH (6 ml, until pH 5-6). Brine solution
(240
ml, 4.6 vol) was added and phases were separated. The organic phase was washed
with a
saturated solution of NaHCO3 (300 ml, 5.8 vol) and brine solution (240 ml, 4.6
vol). The
organic solvent was evaporated to obtain 136.4g of a viscous oil. (assay
=59.6%, y = 81.3% )
Example 22: Crystallization of Compound 21TB
Oily TB-21 (100 g, assay 65%) was charged in a reactor at ambient temperature
with
toluene (100 ml). The mixture was stirred until dissolution of all the
material (it maybe
heated to 50 C if the oil does not go into the toluene). At ambient
temperature hexane (150
ml) was added with a dropping funnel over 30 minutes under slow stirring. A
solid started to
precipitate after the initial addition of hexane. Additional amount of hexane
(250 ml) was
added dropwise over 45 minutes at the same temperature. After 3 hrs of
stirring, the solid was
filtered under reduced pressure, washed with precooled hexane (50 ml, 12-15 C)
and dried
under vacuum for 1 hour at about 50 C to obtain 82 g of a solid material
(assay 80%)
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Example 23: Preparation of Compound 22M
F F
( \ \
0 OH OH OH
N CO2CH3 -= N __ C02CH3
N N N N
S02CH3 S02CH3
21 M 22M
To a solution of Compound 21M (8 g; prepared by a Witig-Homer reaction) in dry
THF (210 mL) and dry methanol (56 mL), a solution of diethylmethoxyborane (1M)
in THF
(17 mL) was added at -78 C, forming a reaction mixture. The reaction mixture
was stirred
for 0.5 hour, NaBH4 (0.76 g) was added, and stirring was continued for 3
hours. Acetic acid
(9.6 mL) was added to the reaction mixture and the reaction mixture was warmed
to ambient
temperature. Water (100 mL), ethyl acetate (100 mL), and a saturated solution
ofNaHCO3
were added, forming layers. The layers were separated, and water was extracted
with
additional ethyl acetate (100 mL). The organic layers were combined and the
solvents were
evaporated under reduced pressure, leaving a residue. The residue was treated
with methanol
and methanol was evaporated. Methanol treatment and evaporation was performed
two more
times, yielding crude compound 22M (4.78 g).
Example 24: Conversion of Compound 22TB into rosuvastatin Ca with extraction
in
toluene using active carbon
A 1 L reactor equipped with a mechanical stirrer was charged with EtOH (100
mL),
water (60 ml), and TBRE (20 g), forming a reaction mixture in suspension. NaOH
(47%
1.2eq, 3.8 g) was added dropwise to the reaction mixture at 25 C 5 C. The
reaction
mixture was stirred at about 25 C 5 C for two hours. Water (140 mL) was
added to the
reaction mixture and the reaction mixture was washed with toluene (100 mL).
The reaction
mixture was stirred at 25 C I 5 C for half an hour, and then the aqueous phase
was isolated.
The aqueous phase was concentrated under reduced pressure at 40 C to half of
its
volume. Active carbon was added to the aqueous phase and the aqueous phase was
stirred
for about half an hour at 25 C 5 C. The aqueous phase was filtered under
reduced pressure
with Synter and Hyflo to eliminate the active carbon present. Water (50 ml)
was added and

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the aqueous phase was heated to 40 C. CaC12 (4.13 g) was added dropwise to the
aqueous
phase over a period of about 30-90 minutes at a temperature of about 38 C - 45
C. The
aqueous phase was then cooled to 25 C 5 C, and stirred at 25 + 5 C for 1
hour. The
aqueous phase was then filtered and washed with water (4 x 20 ml), yielding a
powdery
compound (16.7 g dry, 90%).
Example 25: Conversion of Compound 22TB into rosuvastatin Ca with extraction
in
toluene using active carbon
A 1 L reactor equipped with a mechanical stirrer was charged with EtOH (100
mL),
water (60 ml), and TBRE (20 g), forming a reaction mixture in suspension. NaOH
(47%,
1.2eq, 3.8 g) was added dropwise to the reaction mixture at 25 5 C. The
reaction mixture
was stirred at 25 2= 5 C for about two hours. Water (140 ml) was added to the
reaction
mixure, and the reaction mixture was washed with toluene (100 mL). The
reaction mixture
was stirred at 25 C 5 C for half an hour, and then the aqueous phase was
isolated.
Active carbon was added to the aqueous phase and the aqueous phase was stirred
at
5 C for 30 minutes. The aqueous phase was filtered under reduced pressure with
Sinter
and Hyflo to eliminate the active carbon present. The aqueous phase was then
concentrated
under reduced pressure at 40 C to half of its volume.
Water (50 mL) was added to the aqueous phase, forming a solution. The solution
was
20 heated to about 40 C. CaC12 (4.13 g) in water (20 ml) was added dropwise to
the solution
over 30-90 minutes at 38-45 C. The solution was then cooled to 25 5 C,
stirred at 25 5 C
for 1 hour, filtered, and washed with water (4 x 20 ml), yielding a powdery
compound (16.7g
dry, 90%).
25 Example 26: Conversion of Compound 22TB into rosuvastatin Ca with
extraction in
toluene using active carbon
A 1 L reactor equipped with a mechanical stirrer was charged with EtOH (150
mL),
water (90 ml), and TBRE (30 g), forming a reaction mixture. NaOH (47% 1.2eq,
5.7 g) was
added dropwise to the reaction mixture at 25 5 C. The reaction mixture was
stirred at 25 ~
5 C for two hours.
Active carbon was added to the reaction mixture and the reaction mixture was
stirred
at 25 + 5 C for 30 minutes. The reaction mixture was filtered under reduced
pressure with
Synter and Hyflo to eliminate the active carbon present.
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WO 2007/041666 PCT/US2006/038921
Water (210 ml) was added to the reaction mixture, and the reaction mixture was
.
washed with toluene (150 mL). The reaction mixture was stirred at 25 5 C for
half an hour,
and then the aqueous phase was isolated.
The aqueous phase was concentrated under reduced pressure at 40 C to half its
volume. Water (75 mL) was added to the aqueous phase, forming a solution, and
the solution
was heated to 40 C.
CaC12 (6.2 g) was added dropwise to the solution over 30-90 minutes at 38-45
C. The
solution was then cooled to 25 5 C, stirred at 25 + 5 C for 1 hour,
filtered, and washed with
water (4 x 30 ml), yielding a powdery compound (25 g dry, 90%).
Example 27: Conversion of Compound 22TB into rosuvastatin Ca with extraction
in
toluene using active carbon
A 1 L reactor equipped with a mechanical stirrer was charged with EtOH (100
mL),
water (60 ml), and TBRE (20 g), forming a reaction mixture. NaOH (47% 1.2eq,
3.8 g) was
added dropwise to the reaction mixture at 25 + 5 C, and the reaction mixture
was stirred at 25
:L 5 C for two hours.
Water (140 ml) was added to the reaction mixture, and the reaction mixture was
washed with toluene (100 mL). The reaction mixture was stirred at 25 5 C for
half an hour
and the aqueous phase was isolated.
Active carbon was added to the aqueous phase and the aqueous phase was stirred
at
5 C for 30 minutes. The aqueous phase was filtered under reduced pressure with
Sinter
and Hyflo to eliminate the active carbon present.
The aqueous phase was then concentrated urider reduced pressure at 40 C to
half its
25 volume. Water (50 mL) was added to the aqueous phase, forming a solution.
The solution
was heated to 40 C. CaC12 (4.13 g) was added dropwise to this solution over 30-
90 minutes
at 38-45 C. The solution was then cooled to 25 5 C, stirred at 25 5 C for
1 hour, filtered,
and washed with water (4 x 20 ml), yielding a powdery compound (16.7 g dry,
90%).
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