Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR PREPARING SIMVASTATIN AND INTERMEDIATES THEREOF
[0001] This application claims the benefit of U.S. Provisional Patent
Applications
Ser. Nos. 60/717,006, filed September 13, 2005, and 60/742,541, filed December
6, 2005,
which are incorporated herein by reference, in their entirety.
FIELD OF INVENTION
[0002] The invention relates to processes for preparing simvastatin and
intennediates of such processes.
BACKGROUND OF THE INVENTION
[0003] Simvastatin, marketed under the name ZOCOR by Merck & Co., is a
lipid-lowering agent. After oral ingestion, it is believed that simvastatin,
an inactive
lactone, is hydrolyzed to the corresponding 3,5-dihydroxy acid form, which
then inhibits
the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA) reductase. This
enzyme is believed to catalyze the conversion of HMG-CoA to mevalonate, an
early rate-
limiting step in the biosynthesis of cholesterol.
[0004] Simvastatin is also known as butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-
hexahydro-3,7-dimethyl- 8- [2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-
ethyl] -1-
naphthalenyl ester, [1S-[1(alpha),3(alpha),7(beta),8(beta)(2S*,4S*),-
8(alpha)(beta)].
Simvastatin (m.w. 418.57) has the structure represented in formula I below.
HO 0
O
O
O
simvastatin
[0005] Simvastatin can be synthetically prepared from the fermentation product
lovastatin, shown in formula II, by "methylation" processes.
1
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HO 0
O
O
O
II
lovastatin
[0006] For example, U.S. Patent No. 4,582,915 describes a process for
preparing
simvastatin by first converting lovastatin to an alkali metal salt, preferably
the potassium
salt, of the dihydroxycarboxylate, then methylating the 2-methylbutyryloxy
group at the
C2-position.
[0007] Acidity of the a-protons of the 3,5-dihydroxyheptanoic acid moiety can
be
decreased by formation of a lovastatin hydroxy acid amide. This dihydroxy
amide
derivative can be methylated without further protection, as disclosed in U.S.
Patent No.
5,763,646, or after protection of the 1,3-diol moiety by (1) tert-
butyldimethylsilylation, as
disclosed in U.S. Patent No. 4,820,850; (2) the formation of phenylboronic
acid
derivatives, as disclosed in U.S. Patent No. 5,393,893; (3) the formation of
acetonides as
disclosed in U.S. Patent No. 6,100,407; or (4) protection using
hexamethyldisilazane
(HMDS), as disclosed in U.S. Patent No. 6,472,542.
[0008] The above processes, however, suffer from several disadvantages. Thus,
there is a continuing need for processes for preparing simvastatin.
SUMMARY OF THE INVENTION
[0009] In one aspect, the present invention provides a process for the
preparation
of simvastatin and intermediates useful in making simvastatin.
[00010] In one embodiment, the invention relates to a process for the
preparation
of lovastatin amide of formula III,
O R1
N, R2
OH
j <:OH
H CH H CH
3
HC\"
a
2
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which includes:
(a) combining a lovastatin compound selected from the group consisting of
(i) lovastatin of formula II,
HO O O
O
= H
O
HCH - H CH3 II
H3C"
(ii) lovastatin acid of formula VII,
0
OH
OH
O OH
H CH - H VII
CH3
H C ",
3
(iii) a salt of lovastatin of formula II,
(iv) a salt of lovastatin acid of formula VII, and
(v) mixtures thereof,
an inert organic solvent, and an amine of formula HNR1R2 to obtain a first
reaction
mixture; and
(b) obtaining a second reaction mixture comprising the lovastatin amide of
formula III by
maintaining the first reaction mixture at a temperature and for a period of
time sufficient
to convert substantially all of the lovastatin compound to the lovastatin
amide of formula
III.
[00011] In such a process, the molar ratio of the amine of formula HNR1R2 to
the
lovastatin compound is no more than about 1.5, and R' and R2 are independently
selected
from hydrogen, straight or branched C2_$ alkyl, aryl, aryalkyl, and C3_$
cycloalkyl groups,
or together form a ring optionally containing a heteroatom.
[00012] The period of time can be, e.g., from about 3 hours to about 5 hours
and
the temperature can be from about 60 C to about 120 C. The amine of formula
HNR1R2
can be, e.g., selected from the group consisting of n-butylamine,
diethylamine,
3
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cyclohexylamine, morpholine, benzylamine and mixtures thereof, e.g.,
cyclohexylamine,
benzylamine or mixtures thereof. In certain embodiments, the molar ratio of
the amine of
formula HNRiR2 to the lovastatin compound is no more than about 1.2, or from
about 1
to about 1.2.
[00013] The lovastatin compound can be, e.g., an ammonium salt of formula
VIII.
0
O-NH4
OH
0 OH
O
H CH - H CH3 VIII
H 3 C
In certain embodiments, the process can further comprise:
(c) converting the lovastatin amide of formula III to simvastatin of formula
I.
HO O
O
O
= H
H3C CH
H CH
3
H3C~
[00014] In certain embodiments, the process can further comprise:
(c) combining the lovastatin amide of forinula III, a silylation catalyst and
hexamethyldisilazane (HMDS) to obtain a third reaction mixture; and
(d) maintaining the third reaction mixture at a temperature and for a period
of
time sufficient to convert substantially of the lovastatin amide of formula
III to the bis
(TMS)-lovastatin amide derivative of formula IV;
R1
' R2
OSiMe3
0 OSiMe3
H
14 Me Me
Me'
IV
4
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wherein Rl and R2 are as defined previously.
[00015] In a certain embodiment, the second reaction mixture comprising the
lovastatin amide of formula III of step (b) is directly combined with the
silylation catalyst
and the HMDS. In such a process, the period of time in step (b) is, e.g., from
about 3 to
about 5 hours, the period of time in step (d) is from about 0.5 to about 10
hours, the
temperature of step (b) is'from about 60 to about 120 C and the temperature
of step (d)
is from about 0 C to about 40 C. The molar ratio of the silylation catalyst to
the
lovastatin compound can be, e.g., from about 0.0001 to about 0.05. The
silylation
catalyst can be, e.g., silylhalide or iodine and the molar ratio of the
silylhalide or iodine to
the lovastatin compound can be, e.g., about 0.02 (if silylhalide), or about
0.004 (if iodine).
The molar ratio of the HMDS to the lovastatin compound can be, e.g., from
about 1 to
about 1.7. In a certain embodiment, this process can further comprise:
(e) combining the bis (TMS)-lovastatin amide derivative of formula IV with
an aprotic organic solvent to obtain a fourth reaction mixture;
(f) combining the fourth reaction mixture with a strong base at a temperature
of from about -10 C to about -80 C to obtain a fifth reaction mixture;
(g) maintaining the fifth reaction mixture at a temperature of from about 0 C
to about -40 C for a period of time of at least about 1 hour (e.g. about 1-5
hours) to obtain
a sixth reaction mixture;
(h) combining the sixth reaction mixture with a methylating agent at a
temperature of from about 0 C to about -60 C to obtain a seventh reaction
mixture;
(i) maintaining the seventh reaction mixture at a temperature of from about -
20 C to about -40 C for a period of time of at least about 0.5 hours (e.g.
about 0.5-3
hours) to obtain an eighth reaction mixture;
(j) quenching the eighth reaction mixture at a temperature of from about 0 C
to about -20 C; and, optionally
(k) recovering simvastatin dihydroxy acid amide derivative of formula V;
wherein Rl and Ra are as defined in formula III.
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O R1
NR2
OH
O OH
H
Nle Me Me
Me"
v
[00016] In one embodiment, the above process further comprises:
(1) combining the simvastatin dihydroxy acid amide derivative of formula V,
a water miscible organic solvent and an aqueous solution of an alkali base to
obtain a
ninth reaction mixture; and
(m) maintaining the ninth reaction mixture at a temperature of from about 50 C
to about 100 C for a period of time of at least about 2 hours (e.g. about 2-8
hours) to
obtain an alkali salt of formula IX;
0
0 M+
OH
0 _ OH
/ ='1 ~ H
H3C CH _ CH3 lX
H3C~ ~
wherein M is alkali metal atom.
[00017] In an embodiment, the above process further comprises:
(n) converting the alkali salt of formula IX to simvastatin dihydroxy acid of
formula X.
0
OH
OH
0 OH
H C.=1CH : H
O
3 CH3 X
HC~
3
[00018] Once the simvastatin dihydroxy acid of formula X is obtained, it may
be,
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e.g., further converted into simvastatin ammonium salt of formula VI, which is
then
recovered.
0
0- NH4+
OH
O _ OH
O
H3C CH ' H CH VI
3
H C,,
3
[00019] In various embodiments, the simvastatin ammonium salt of formula VI
can
be converted to simvastatin of formula I.
[00020] Certain embodiments relate to a process for the preparation of bis
(TMS)-
lovastatin amide derivative of formula IV, which may comprise:
(a) combining lovastatin amide of formula III, a silylation catalyst and
hexamethyldisilazane (HMDS) to obtain a first reaction mixture; and
(b) obtaining a second reaction mixture comprising the bis (TMS)-lovastatin
amide derivative of formula IV by maintaining the first reaction mixture at a
temperature
and for a period of time sufficient to convert substantially all of the
lovastatin anlide of
formula III to the bis (TMS)-lovastatin amide derivative of formula IV.
[00021] The period of time can be, e.g., from about 0.5 to about 10 hours and
the
temperature can be from about 0 C to about 40 C. The silylation catalyst can
be, e.g.,
selected from the group consisting of silylhalide, molecular halogen,
inorganic salt,
organic salt, transition metal phosphonic acid derivative, saccharin and
mixtures thereof,
e.g., silylhalide, molecular halogen, saccharin or mixtures thereof, e.g.,
trimethylsilyl
iodide, iodine or mixtures thereof.
[00022] The molar ratio of the silylation catalyst to the lovastatin amide of
formula
III can be, e.g., from about 0.0001 to about 0.06. The silylation catalyst can
be, e.g.,
silylhalide and the molar ratio of silylhalide to the lovastatin amide of
formula III can be
from about 0.02 to about 0.025. The silylation catalyst can be, e.g., iodine
and the molar
ratio of the iodine to the lovastatin amide of formula III can be from about
0.004 to about
0.005. The molar ratio of the HMDS to the lovastatin amide of formula III can
be, e.g.,
from about 1 to about 2.
[00023] If desired, the bis (TMS)-lovastatin amide derivative of formula IV
can be
converted to simvastatin of formula I using any suitable method.
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[00024] Certain embodiments relate to a process for the preparation of
simvastatin
dihydroxy acid amide derivative of formula V, which may comprise:
(a) combining the bis (TMS)-lovastatin amide derivative of formula IV, an
aprotic organic solvent, and an amine derivative to obtain a third reaction
mixture;
(b) combining the third reaction mixture and a strong base at a temperature of
from about -10 C to about -80 C to obtain a fourth reaction mixture;
(c) maintaining the fourth reaction mixture at a temperature of from about 0 C
to about -40 C for a period of time of at least about 1 hour (for example,
about 1-5 hours)
to obtain a fifth reaction mixture;
(d) combining the fifth reaction mixture with a methylating agent at a
temperature of from about 0 C to about -60 C to obtain a sixth reaction
mixture;
(e) maintaining the sixth reaction mixture at a temperature of from about
-20 C to about -40 C for a period of time of at least about 0.5 hours (for
example, about
0.5-3 hours) to obtain a seventh reaction mixture; and
(f) quenching the seventh reaction mixture at a temperature of from about 0 C
to about -20 C to obtain the simvastatin dihydroxy acid amide derivative of
formula V.
Preferably, the process also includes:
(g) recovering the simvastatin dihydroxy acid amide derivative of formula V.
[00025] Any suitable methylating agent may be used. Examples of methylating
agents include methyl halide (e.g., methyl iodide, etc.), methyl sulfate and
mixtures
thereof. The seventh reaction mixture can be quenched, for example, with
water. If
desired, the simvastatin dihydroxy acid amide derivative of formula V can be
converted
to simvastatin of formula I.
[00026] In certain embodiments, the bis (TMS)-lovastatin amide derivative of
formula IV is prepared by a process comprising:
(aa) combining lovastatin amide of formula III, a silylation catalyst and
hexamethyldisilazane (HMDS) to obtain a first reaction mixture; and
(bb) obtaining a second reaction mixture comprising the bis (TMS)-lovastatin
amide derivative of formula IV by maintaining the first reaction mixture at a
temperature
and for a period of time sufficient to convert substantially all of the
lovastatin amide of
fonnula III to the bis (TMS)-lovastatin amide derivative of formula IV.
[00027] The period of time can be, e.g., about 0.5-10 hours and the
temperature can
be from about 0 C to about 40 C.
[00028] If desired, the second reaction mixture comprising the bis (TMS)-
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lovastatin amide derivative of formula IV can be directly combined with the
aprotic
organic solvent and the amide derivative.
[00029] The process may further comprise:
(h) combining the simvastatin dihydroxy acid ainide derivative of formula V,
a water miscible organic solvent and an aqueous solution of an alkali base to
obtain an
eighth reaction mixture;
(i) maintaining the eighth reaction mixture at a temperature of from about
50 C to about 100 C for a period of time of at least about 2 hours (e.g.,
about 2-8 hours)
to obtain an alkali salt of formula IX;
(j) converting the alkali salt of formula IX to simvastatin dihydroxy acid of
formula X; and
(k) converting the simvastatin dihydroxy acid of formula X to simvastatin
ammonium salt of formula VI.
The process can also comprise:
(1) recovering the simvastatin ammonium salt of formula VI.
[00030] The alkali base can be, e.g., sodium hydroxide, potassium hydroxide or
mixtures thereof.
[00031] The invention also relates to certain novel compounds, which are
useful as
synthetic intermediates in the preparation of simvastatin. For example, such
compounds
include a compound of formula IV-a:
R1
' R2
OSi Me3
0 OSiMe3
9 H
lq Me ' Me
Me
IV-a
wherein one of Rl and R2 is H and the other of R' and Ra is selected from the
group
consisting of benzyl radical and cyclohexyl radical; for example, one of R'
and R2 is H
and the other of Rl and R2 is benzyl radical, or one of R' and Ra is H and the
other of Rl
and R2 is cyclohexyl radical.
[00032] Certain embodiments of the invention also relate to a process for the
preparation of simvastatin of formula I, the process comprising:
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(a) providing a compound of formula IV-a; and
(b) converting the compound of formula IV-a to simvastatin of formula I.
DETAILED DESCRIPTION OF THE INVENTION
[00033] As used herein, the phrase "at a temperature and for a period of time
sufficient to convert substantially all of ' a particular starting material to
another
compound means that at least about 80%, preferably at least about 85%, more
preferably
at least about 90%, even more preferably at least about 95%, of the starting
material is
converted to the another compound.
[00034] In one embodiment, the invention relates to a synthesis of simvastatin
(I)
from lovastatin (II) according to the following general scheme. (It will be
appreciated
that the invention also relates to the individual steps and compounds involved
therein).
O R1 O
R1
HO 0 fl- NR2 NR2
OH O-S/~
O O
H O = OH O
O'S",
~O ~
CHO H CHa H CH = H CHa -~ H H~ H CH
a
'= / / / /
H3C HaC' HaC
ii
iii iV
O R1 0
N, R2 O NH4+
OH OH
O OH O OH
O
Ha = H CHa Ha'~ - H
CHa
HaC./ H Cr
3
v vi
HO~
0
O
= H
O
H3C CH 5 H CH
3
HaC,=
[00035] In preferred embodiments, this process affords a simple and economical
way for commercial scale production of simvastatin in high yield and purity.
In one
embodiment, the first four steps of the process may be combined in a "one-pot"
process in
which the simvastatin ammonium salt (VI) is the first isolated intermediate.
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Antidatiota ofLovastatiya
[00036] The amidation of lovastatin includes combining a lovastatin compound,
an
inert organic solvent, and an amine of formula HNR'R2 to obtain a first
reaction mixture,
which is then converted to a second reaction mixture comprising the lovastatin
amide of
formula III by maintaining the first reaction mixture at a temperature and for
a period of
time sufficient to convert substantially all of the lovastatin compound to the
lovastatin
compound of formula III.
[00037] For example, the temperature can be from about 60 C to about 120 C and
the period of time of can be at least about 3 hours (preferably about 3-5
hours). In certain
embodiments, the temperature is from about 80 C to about 110 C, more
preferably from
about 80 C to about 90 C.
[00038] Preferably, a Dean-Stark apparatus is used to remove water, which is a
by-
product.
[00039] The lovastatin compound can be selected from the group consisting of
(i) lovastatin of formula II,
HO O
O
O
H
H CH = H CH3 II
H3C~
(ii) lovastatin acid of formula VII,
0
OH
OH
0 OH
H' CH H VII
CH3
HC,
3
(iii) a salt of lovastatin of formula II,
(iv) a salt of lovastatin acid of formula VII (e.g. the ammonium salt of
formula
VIII), and
(v) mixtures thereof.
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0
O -NH4
OH
0 OH
H CH = H CH3 VIII
HCa'
3
[00040] In the amidation reaction, preferably the inert organic solvent is
benzene,
toluene, xylene, tetrahydrofuran (TBF), or mixtures thereof. More preferably,
the inert
organic solvent is toluene.
[00041] The R' and R2 groups of HNR1R2 are independently selected in each
instance from hydrogen, straight or branched CZ_g alkyl, aryl, arylalkyl, and
C3_$
cycloalkyl groups, or together form a ring optionally containing a heteroatom
such as 0,
S, or N.
[00042] "Aryl", "aryl group" or "Ar" refers 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-7yl, 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.
[00043] "Arylalkyl" refers to an aryl group with at least one alkyl
substituent, such
as a linear or branched alkyl group preferably having from 1 to 10 carbon
atoms and more
preferably 1 to 6 carbon atoms. The substituent is exemplified by groups such
as methyl,
t-butyl, n-heptyl, octyl and the like.
[00044] Preferably, the amine of formula HNR1R2 is n-butylamine, diethylamine,
cyclohexylamine, morpholine, benzylamine, or mixtures thereof. More
preferably, the
amine of formula HNR1R2 is cyclohexylamine, benzylamine or mixtures thereof.
Indeed,
the inventor has surprisingly discovered that the amidation reaction works
well with
amines having relatively large groups - i.e. cyclohexyl and benzyl groups.
[00045] The molar ratio of the amine of formula HNR1R2 to the lovastatin
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compound is no more than about 1.5, more preferably, no more than about 1.2,
e.g., a
molar ratio of from about 1 to about 1.2 or about 1 to about 1.5. Indeed, the
use of no or a
slight excess of amine is advantageous, because, e.g., the silylation reaction
can be
performed without the need to first remove the excess amine by, e.g.,
distillation, a time-
consuming operation that can lead to formation of impurities.
[00046] Preferably, the lovastatin of formula II and the amine of formula
HNRiRa
are commercially available. Preferably, the lovastatin compound is the
ammonium salt of
formula VIII.
[00047] Preferably, the lovastatin amide of formula III is converted to
simvastatin
of formula I by a suitable process, e.g., the silylation, methylation,
deprotection, and/or
lactonization reactions of the general scheme.
Silylation Reaction
[00048] In the silylation reaction, the alcohol groups of the lovastatin amide
of
formula III are protected. In a preferred embodiment, bis (TMS)-lovastatin
amide
derivative of formula IV is prepared. The silylation reaction is carried out
by:
(a) combining lovastatin amide of formula III, a silylation catalyst and
hexamethyldisilazane (HMDS) to obtain a reaction mixture; and
(b) maintaining the reaction mixture at a teinperature and for a period of
time
sufficient to convert substantially all of the lovastatin amide of formula III
to the bis
(TMS)-lovastatin amide of formula IV (wherein R' and Ra are as defined in
formula III):
R1
' 2
OSiMe3
O OSiMe3
9 H =
14 Me Me
Me"0
IV
[00049] For example, the temperature can be from about 0 C to about 40 C
(preferably about room temperature to about 40 C) and the period of time can
be at least
about 0.5 hours (preferably about 0.5-10 hours, more preferably about 1-4
hours).
[00050] Preferably, the silylation catalyst is silylhalide, molecular halogen,
inorganic salt, organic salt, transition metal phosphonic acid derivative,
saccharin or
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mixtures thereof. Preferably, the silylhalide is trimethylsilyl iodide,
trimethylsilyl
bromide, trimethylsilyl chloride, or mixtures thereof, more preferably,
trimethylsilyl
iodide. Preferably, the molecular halogen is iodine, bromine, or mixtures
thereof, more
preferably, iodine. Preferably, the inorganic salt is zinc chloride,
tetrabutylammonium
fluoride, lithium perchlorate, copper triflate, or mixtures thereof. Preferred
transition
metal phosphonic acid derivative include phosphonomolybdenic acid,
tungstenophosphonic acid, and mixtures thereof. The more preferred silylation
catalysts
are iodine, trimethylsilyl iodide, saccharin and mixtures thereof. The most
preferred
silylation catalyst is iodine. Surprisingly, the inventor has discovered that
silylation
catalysts not only improve the rate of reaction, but also decrease the amount
of starting
material necessary, which is both unexpected and advantageous.
[00051] Preferably, the bis (TMS)-lovastatin amide derivative of formula IV is
subsequently converted to simvastatin of formula I by a suitable process,
e.g., the
methylation, deprotection, and/or lactonization steps of the general scheme.
[00052] Preferably, the molar ratio of the silylation catalyst to the
lovastatin amide
of formula III is from about 0.0001 to about 0.06. More preferably, the
silylation catalyst
is silylhalide and the molar ratio of silylhalide to the lovastatin amide of
formula III is
from about 0.02 to about 0.025, or the silylation catalyst is iodine and the
molar ratio of
the iodine to the lovastatin amide of formula III is from about 0.004 to about
0.005.
Preferably, the molar ratio of the HMDS to the lovastatin amide of formula III
is from
about 1 to about 2. Thus, in a preferred embodiment, the silylation reaction
of the present
invention is performed with no or a slight excess of HMDS. This is
advantageous
because, for example, 1) HMDS can decompose to ammonia; 2) the excess HMDS
does
not have to be removed by isolation steps; and 3) isolation steps to remove
the excess
HMDS can expose the trimethyl-silyl protecting groups to water, which can
remove the
protecting groups and also lead to insufficient conversion in the methylation
step.
[00053] Preferably, the lovastatin amide of formula III is prepared by an
amidation
reaction, e.g., the amidation reaction discussed above. More preferably, the
lovastatin of
formula III is prepared by the amidation reaction discussed above, and the
reaction
mixture comprising the amidation reaction product (i.e., the lovastatin amide
of formula
III) is directly combined with the silylation catalyst and HMDS. That is, the
reaction
mixture comprising the lovastatin amide of formula III is combined with the
silylation
catalyst and the HMDS without recovering or purifying the lovastatin amide of
formula
III from the reaction mixture comprising the lovastatin amide of formula III.
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[00054] In this preferred embodiment, preferably, the molar ratio of the
silylation
catalyst to the lovastatin compound is 0.0001 to about 0.05, depending on the
catalyst.
More preferably, silylhalide is the silylation catalyst and the molar ratio of
the silyl halide
to the lovastatin compound is about 0.02. More preferably, iodine is the
silylation
catalyst and the molar ratio of the iodine to the lovastatin compound is about
0.004.
[00055] Preferably, the molar ratio of the HMDS to the lovastatin compound is
from about 1 to about 1.7, more preferably, from about 1 to about 1.2.
[00056] In another aspect, the present invention relates to 2 novel compounds:
N-
cyclohexyl-7-[ 1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2(S)-
methylbutanoyl]oxy]-1(S)-naphtyl]-3(R),5(R)-bis(trimethylsilyloxy)heptanamide;
and N-
benzyl-7-[ 1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2(S)-
methylbutanoyl]oxy]-1(S)-naphtyl]-3(R),5(R)-bis(trimethylsilyloxy)heptanamide.
These
compounds are embraced by formula IV-a:
R'
N'R2
OSiMe3
0 OSiMe3
II o H =
14'' Me Me
Me'
IV-a
wherein one of Rl and R2 is H and the other of R' and R- is benzyl radical or
cyclohexyl radical.
[00057] The compound of formula IV-a wherein one of Rl and R2 is H and the
other of R' and R~ is cyclohexyl radical can be characterized by data selected
from an 1H-
NMR spectrum having hydrogen chemical shifts at about 0.05, 0.73, 0.76, 0.93,
0.97,
1.01-1.09, 1.13, 1.20-1.31, 1.38-1.59, 1.72-1.81, 1.85, 2.05, 2.10, 2.19,
2.25, 2.31, 3.49,
3.63, 4.09, 5.15, 5.37, 5.65, 5.85 and 6.07 ppm, and MS (ESI) spectrum having
peaks at
about 648.44 (MH+).
[00058] Meanwhile, the compound of fonnula IV-a wherein one of Rt and Ra is H
and the other of Rl and R2 is benzyl radical can be characterized by data
selected from an
1H-NMR spectrum having hydrogen chemical shifts at about 0.06, 0.11, 0.84,
0.86, 1.05,
1.07, 1.12, 1.14, 1.33, 1.39, 1.52, 1.62-1.64, 1.89, 1.96, 2.19-2.45, 3.58,
4.16, 4.41, 5.31,
5.48, 5.76, 5.95, 6.60 and 7.18-7.33 ppm; and MS (ESI) spectrum having peaks
at about
656.42 (MH+).
CA 02619236 2008-01-24
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[00059] The compounds of formula IV-a can be prepared by any suitable process,
e.g., the arnidation reaction and silylation reaction described above.
[00060] Preferably, the compound of formula IV-a is converted to simvastatin
by a
suitable process, e.g., the methylation, deprotection and/or lactonization
steps of the
general scheme.
Metlzylation Reaction
[00061] In one embodiment, a methylation reaction involving the bis (TMS)-
lovastatin amide derivative of formula IV can be carried out as follows:
(a) combining the bis (TMS)-lovastatin amide derivative of formula IV with
an aprotic organic solvent to obtain a third reaction mixture;
(b) combining the third reaction mixture and a strong base at a temperature of
from about -10 C to about -80 C to obtain a fourth reaction mixture;
(c) maintaining the fourth reaction mixture at a temperature of from about 0 C
to about -40 C for a period of time of at least about 1 hour (preferably about
1-5 hours) to
obtain a fifth reaction mixture;
(d) combining the fifth reaction mixture with a methylating agent at a
temperature of from about 0 C to about -60 C to obtain a sixth reaction
mixture;
(e) maintaining the sixth reaction mixture at a temperature of from about
-20 C to about -40 C for a period of time at least about 0.5 hours (preferably
about 0.5-3
hours) to obtain a seventh reaction mixture;
(f) quenching the seventh reaction mixture at a temperature of from about 0 C
to about -20 C; and, optionally,
(g) recovering the simvastatin dihydroxy acid amide derivative of formula V
(wherein Rl and Ra are as defined in formula III):
O /R1
NR2
OH
0 OH
9 H
Nle Me Me
Me""
V
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WO 2007/100351 PCT/US2006/035824
[00062] Preferably, the bis (TMS)-lovastatin amide derivative of formula IV is
prepared according to the silylation reaction, and the reaction mixture
comprising the bis
(TMS)-lovastatin amide derivative of formula IV is directly combined with the
aprotic
organic solvent. That is, the reaction mixture comprising the bis (TMS)-
lovastatin amide
derivative of formula IV is combined with the aprotic organic solvent without
recovering
or purifying the bis (TMS)-lovastatin amide derivative of formula IV.
[00063] Preferably, the aprotic solvent is aromatic hydrocarbon, ether, or
mixtures
thereof. Preferably, the aromatic hydrocarbon is toluene. Preferably, the
ether is
tetrahydrofuran (THF), diethyl ether, diisopropyl ether, dioxane, or mixtures
thereof.
More preferably, the ether is THF. A preferred mixture is that of toluene and
THF.
[00064] Preferably, if methylation is preceded by amidation of lovastatin, the
amount of the strong base used in the methylation reaction is such that the
molar ratio of
the strong base to the lovastatin compound is from about 3 to about 6.
[00065] Preferably, the strong base is commercially available. More
preferably,
the strong base is an alkali amide. Preferably, the alkali amide is lithium
amide, sodium
amide, lithium diethylamide, lithium N-isopropyl-N-cyclohexylamide, lithium
diisopropylamide (LDA), lithium pyrrolidide, or mixtures thereof. More
preferably, the
base is LDA, lithium pyrrolidide or mixtures thereof.
[00066] In a particularly preferred embodiment, the strong base is prepared in-
situ
by adding alkyllithium, alkali hydride, or mixtures thereof to a third
reaction mixture that
includes, in this embodiment, the bis (TMS)-lovastatin amide derivative and an
amine
derivative. Preferably, the alkali hydride is sodium hydride, potassium
hydride or
mixtures thereof. Preferred alkyllithiums include n-butyllithium, n-
hexyllithium and
mixtures thereof. More preferably, n-butyllithium is used to prepare the
strong base.
Preferably, the amine derivative is pyrrolidine. Thus, in this preferred
einbodiment, the
alkyllithium, the alkali hydride or mixtures thereof is directly added to the
bis (TMS)-
lovastatin amide derivative of formula IV, instead of preparing the strong
base in a work-
up reaction and then combining it witli the bis (TMS)-lovastatin amide
derivative of
formula IV.
[00067] Preferably, the temperature of step (b) is from about -30 C to about -
60 C,
more preferably, from about -40 C to about -60 C. Preferably, the temperature
of step (c)
is from about -30 C to about -40 C.
[00068] Preferably, the methylating agent is methyl halide, methyl sulfate or
mixtures thereof. Preferably, the methyl halide is methyl iodide, methyl
bromide, methyl
17
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WO 2007/100351 PCT/US2006/035824
chloride or mixtures thereof. A preferred methylsulfate is methyl tosylate,
methyl
mesylate or mixtures thereof. The more preferred methylating agent is methyl
iodide.
[00069] Preferably, the methylation reaction is preceded by the amidation
reaction
described above. In this preferred embodiment, preferably, the amount of the
methylating
agent used is such that the molar ratio of the methylating agent to the
lovastatin
compound is from about 1.5 to about 3.
[00070] Preferably, the temperature of step of step (d) is from about -30 C to
about
-50 C. Preferably, the temperature of step (f) is from about -10 C to about -
20 C.
[00071] Preferably, in step (f), the step of quenching the seventh reaction
mixture
includes the use of water as a quenching reagent. Preferably, the water also
removes the
silyl groups to produce the desired product, simvastatin dihydroxy acid amide
derivative
of formula V.
[00072] Preferably, simvastatin dihydroxy acid arnide derivative of formula V
is
recovered in step (g) by acidifying the organic phase followed by washing with
water and
evaporating the solvents.
[00073] Preferably, simvastatin dihydroxy acid amide derivative of formula V
is
subsequently converted to simvastatin by a suitable process, e.g., the
deprotection and/or
lactonization steps disclosed in the general scheme.
Deprotection Step
[00074] In certain embodiments, the amine protecting group of the simvastatin
dihydroxy acid amide derivative of formula V can be removed to provide the
simvastatin
ammonium salt of formula VI. For example, such a process can include:
(a) combining simvastatin dihydroxy acid amide derivative of formula V, a
water miscible organic solvent and an aqueous solution of an alkali base to
obtain a first
reaction mixture;
(b) maintaining the first reaction mixture at a temperature of from about 50 C
to about 100 C (preferably about 75-80 C) for a period of time of at least
about 2 hours
(preferably about 2-8 hours, more preferably 4-8 hours) to obtain second
reaction mixture
comprising an allcali salt of formula IX;
(c) converting the alkali salt of formula IX to simvastatin dihydroxy acid of
formula X; and
(d) converting the simvastatin dihydroxy acid of formula X to simvastatin
ammonium salt of formula VI.
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WO 2007/100351 PCT/US2006/035824
[00075] Preferably, the process also includes: (e) recovering the simvastatin
ammonium salt of formula VI.
[00076] Preferably, the simvastatin dihydroxy acid amide derivative of formula
V
is prepared according to a process set forth previously.
[00077] Preferably, the water miscible organic solvent is C1-4 alcohol,
ketone, ether
or mixtures thereof. Preferred C1-4 alcohols are methanol, ethanol and
mixtures thereof.
The more preferred water miscible organic solvent is methanol. Preferably, the
ketone is
acetone. A preferred ethers include THF, dioxane and mixtures thereof.
[00078] Preferably, the alkali base is sodium hydroxide, potassium hydroxide
or
mixtures thereof.
[00079] The alkali salt of formula IX can be converted to simvastatin
dihydroxy
acid of formula X
0
OH
OH
0 OH
0
H3C C H
H CH
3 X
H3C r"
by, e.g., concentrating the second reaction mixture, then adding an acid to
adjust the pH
of the organic phase to a range of about 2 to about 6, preferably from about 3
to about 5.
[00080] Simvastatin dihydroxy acid of formula X can be converted to
simvastatin
ammonium salt of formula VI
0
O- NH4+
OH
0 _ OH
O
H= H =
3 CH3 vi
H3C /
by, e.g., adding ammonium hydroxide to simvastatin dihydroxy acid of formula
X.
[00081] Simvastatin ammonium salt of formula VI can be recovered by any
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WO 2007/100351 PCT/US2006/035824
suitable method, such as cooling to induce precipitation followed by filtering
to obtain a
wet solid that is then washed.
Lactonization Step
[00082] In certain embodiments, the lactonization of simvastatin ammonium salt
of
formula VI to simvastatin of formula I, may be performed by, for example, a
thermally-
induced lactonization process, as disclosed in PCT Publication No. WO
2004/071456 A2,
which is incorporated herein by reference.
[00083] Simvastatin of formula I can be further purified by, e.g., a process
involving crystallization from a mixture of an aromatic hydrocarbon and a C5_$
aliphatic
hydrocarbon.
EXAMPLES
General
[00084] In the examples below, the HPLC chromatographic measurements were
made on an AGILENT 1100 with a ZORBAX SB C18 4,6*'75mm' 3,5 m, or Hypersil
ODS 100*4 mm column, and eluted with a 0.1 % aqueous phosphoric acid solution
(eluant A)/acetonitrile (eluant B) mixture as described below, with detection
at 240 mn, a
flow rate of 1.2mL/min, and an injection volume of 10 l. The colunm
temperature was
25 C and the sample temperature was 5 C.
[00085] The following gradient program was used with the HPLC:
Time (min) eluent A(%) eluent B(%)
0.0 50.0 50.0
5.0 50.0 50.0
25.0 5.0 95.0
34.0 5.0 95.0
35.0 50.0 50.0
40.0 50.0 50.0
[00086] Retention times under these conditions are the following:
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WO 2007/100351 PCT/US2006/035824
RT/min RRT
Simvastatin hidroxy acid 5.8 0.55
Lovastatin 8.3 0.78
Simvastatin 10.5 1.00
Anhidro-Simvastatin 16.3 1.55
Simvastatin-dimer 27.3 2.59
Example 1:Prenaration of lovastatin cyclohexylamide
[00087] Lovastatin (10.1 g, 25 mmol) was suspended in a mixture of
cyclohexylamine (2.6 g, 3.0 ml, 26.3 mmol) and toluene (25 ml) and the
reaction mixture
was heated to a temperature of 80 - 90 C to obtain a solution. The solution
was stirred at
this temperature for 5 hours under nitrogen atmosphere to complete the
reaction and
obtain a solution including lovastatin cyclohexamide.
Example 2: Preparation of bis(TMS)-lovastatin cyclohexylamide
[00088] Trimethylsilyl iodide (100 mg, 0.5 mmol) and hexamethyldisilazane
(HMDS) (6.03 g, 7.8 ml, 37 mmol) were added to the solution including
lovastatin
cyclohexamide obtained in Example 1. The resulting reaction mixture was
stirred at a
temperature of 30-40 C for 4 hours, to complete the reaction and obtain a
reaction
mixture including bis(TMS)-lovastatin cyclohexamide.
Example 3: Methylation of bis(TMS)-lovastatin cyclohexylamide
[00089] The reaction mixture including bis(TMS)-lovastatin cyclohexamide
obtained in Example 2 was diluted with THF (100 ml) and cooled to a
temperature of-30
to -40 C. Lithium diisopropylamide (60 m12 molar solution, 120 mmol) was added
to
the reaction mixture while stirring at the above temperature under nitrogen.
After the
addition, the reaction mixture was aged at a temperature of -30 to -35 C for
1.5 hours.
The mixture was then cooled to -50 C and methyl iodide (8.9 g, 3.8 ml, 62.5
mmol) was
added (after which the temperature increased to 14 C). Then, the reaction
mixture was
stirred at a temperature of -30 to -35 C for 1 hour. The temperature was
allowed to
increase to -10 C and the reaction mixture was stirred at this temperature for
30 min
followed by the addition of water (50 ml). Toluene (50 ml) was added after the
water and
the organic phase were separated. 1M solution of hydrochloric acid (150 ml)
was added
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to the organic phase to obtain a mixture, which was stirred for 15 min and the
phases
were separated again. After separation of the aqueous phase, the organic phase
was
washed twice with water (2x 50 ml). The organic phase was concentrated in
vacuum to
give an oil (about 14 g) containing a simvastatin dihydroxy acid amide
derivative.
Example 4 :Preparation of lovastatin benzylamide
[00090] Lovastatin (10.1 g, 25 mmol) was suspended in a mixture of benzylamine
(2.94 g, 3 ml, 27.5 mmol) and toluene (25 ml) and the resulting mixture was
heated to 80
- 90 C to obtain a solution. The solution was stirred at this temperature for
4 hours under
nitrogen atmosphere to complete the reaction and obtain a solution including
lovastatin
benzylamide.
Example 5: Preparation of bis(TMS)-lovastatin-benzylamide
[00091] Iodine (25 mg, 0.1 mmol) and hexamethyldisilazane (H1VIDS) (6.03 g,
7.8
ml, 37 mmol) were added to the reaction mixture including lovastatin
benzylamide
obtained in Example 4. The reaction mixture then was stirred at room
temperature for 1
hour. After the 1 hour period, there was no starting material detected by TLC
in the
reaction mixture.
Example 6: Methylation of bis(TMS)-lovastatin benzylamide
[00092] The reaction mixture obtained in Example 5 was diluted with THF (50
ml)
and toluene (50 ml) followed by addition of pyrrolidine (8.9 g, 10.3 ml; 125
mmol) under
nitrogen to give a mixture. The mixture was then cooled to -60 C. A solution
of n-butyl
lithium (78 ml; 125 mmol) was added over 60 minutes while the temperature was
kept at
-50 to -60 C. After the addition, the reaction mixture was aged at a
temperature of -30 to
about -40 C for 2 hours. The mixture was then cooled to -50 to -60 C, methyl
iodide (8.9
g, 3.8 ml; 62.5 mmol) was added over about 10 min at the above temperature,
and then
the reaction mixture was stirred at -30 to -35 C for 1 hour. The temperature
was allowed
to increase to -10 C and the reaction mixture was stirred at this temperature
for 30 min
followed by the addition of water (50 ml) to give two phases. After phase
separation, 1M
solution of sulfuric acid (100 ml) was added to the organic phase and the
mixture was
stirred for 30 min. Then, the phases were separated again. After separation of
the
aqueous phase, the organic layer was washed with water (50 ml) and
concentrated under
vacuum to give an oil (about 15 g) containing a simvastatin dihydroxy acid
amide
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WO 2007/100351 PCT/US2006/035824
derivative.
Example 7: Caustic hydrolysis and preparation of ammonium salt
[00093] The oil of Example 6 was dissolved in methanol (120 ml). Sodium
hydroxide (6.4 g, 160 mmol) in water (80 ml) was added to this solution
followed by
stirring at reflux temperature (75 - 80 C) for 4 hours. The obtained solution
was then
concentrated under vacuum to about half of its original volume. The
concentrated mixture
was cooled to 5 C and the pH was adjusted to about 7 by addition of aqueous
hydrochloric acid solution. Ethyl acetate (175 ml) was added and the pH was
adjusted to
3-5. Then, the water phase was separated and the organic phase was diluted
with
methanol (50 ml) and the pH was adjusted to 9-11 by adding aqueous ammonia
solution
(6 ml).
[00094] The basic mixture was cooled in a refrigerator and the precipitated
material was collected, washed with ethyl acetate and dried to yield
simvastatin
ammonium salt (9.3 g, 82 % yield based on the starting material, lovastatin),
in a purity
of 97% area by HPLC.
Example 8: Preparation of simvastatin
[00095] Simvastatin ammonium salt (6.0 g) in toluene (300 ml) in the presence
of
butylhydroxytoluene (BHT) (0.08 g) was refluxed for 2 hours, under nitrogen,
using a
Dean-Stark condenser for removing water. After reflux, the reaction mixture
was stirred
at 85-90 C for 3 hours. The reaction mixture was then evaporated to dryness to
form a
solid residue.
[00096] The solid residue was then dissolved in toluene (20 ml) at about 60 C.
The solution was treated with charcoal (0.3 g). The charcoal was removed by
filtration,
and the solution was washed with toluene (4 ml). The solution was then charged
into a
four-necked round bottomed flask fitted with nitrogen inlet, thermometer,
dropping
funnel and reflux condenser. The solution was heated to about 60 C and n-
hexane (55
ml) was added in a dropwise manner for 1 hour, while stirring. The reaction
mixture was
then cooled to 0 - 5 C in 1.5 hours and a new portion of hexane (41 ml) was
added to the
slurry over an hour. The slurry was then stirred at this temperature for
another hour and
the product was collected, washed with the mixture of toluene (4 ml) and
hexane (16 ml)
containing BHT (butylated hydroxytoluene) (0.007 g) and dried at 48 C in a
vacuum
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WO 2007/100351 PCT/US2006/035824
oven to yield simvastatin (5.0 g, 90 % yield, based on the starting material,
simvastatin
ammonium salt) in a purity of 98 %(HPLC).
Example 9: Preparation of lovastatin benzylamide
[00097] Lovastatin ammonium salt (11.0 g, 25 mmol) was suspended in a mixture
of benzylamine (3.2 g, 3.3 ml, 30 mmol) and toluene (30 ml) and the mixture
was heated
to reflux temperature. The mixture was stirred at reflux temperature for 3
hours under
nitrogen atmosphere using a Dean-Stark water separator to complete the
formation of the
lovastatin benzylamide.
[00098] While the present invention has been described with reference to the
specific embodiments thereof, it should be understood by those skilled in the
art that
various changes may be made and equivalents may be substituted without
departing from
the true spirit and scope of the invention. In addition, many modifications
may be made
to adapt a particular situation, material, composition of matter, process,
process step or
steps, to the objective, spirit and scope of the present invention. All such
modifications
are intended to be within the scope of the invention.
24
