Title: Process for preparing simvastatin having controlled ranges of simvastatin dimer content
Abstract: The present invention relates to a process for preparing simvastatin, wherein the simvastatin dimer content is controlled. More particularly, the present invention relates to a process for preparing simvastatin having a simvastatin dimer content of about 0.2 to about 0.4% wt. The present invention also relates to a process for preparing simvastatin having a simvastatin dimer content of less than about 0.2% wt. The present invention also discloses a commercial scale process of preparing simvastatin having a specified simvastatin dimer content which is reproducible.
Patent Number: 6,995,277 Issued on 02/07/2006 to Korodi, et al.
| Inventors:
|
Korodi; Ferenc (Debrecen, HU);
Szabo; Csaba (Debrecen, HU);
Salyi; Szabolcs (Debrecen, HU);
Bodi; Istvan (Balmazujvaros, HU)
|
| Assignee:
|
Plus Chemicals, B.V. (Mijdrecht, NL)
|
| Appl. No.:
|
777535 |
| Filed:
|
February 11, 2004 |
| Current U.S. Class: |
549/292 |
| Current Intern'l Class: |
C07D 309/30 (20060101) |
| Field of Search: |
549/292
|
References Cited [Referenced By]
U.S. Patent Documents
| 4444784 | Apr., 1984 | Hoffman et al.
| |
| 4582915 | Apr., 1986 | Sleteinger et al.
| |
| 4820850 | Apr., 1989 | Verhoeven et al.
| |
| 6797831 | Sep., 2004 | Dandala et al.
| |
| 2002/0115712 | Aug., 2002 | Szabo et al.
| |
| Foreign Patent Documents |
| 0 351 918 | Jan., 1990 | EP.
| |
| 511 867 | Nov., 1992 | EP.
| |
| 0 864 560 | Sep., 1998 | EP.
| |
| WO 98/3275/1 | Jul., 1998 | WO.
| |
| WO 00/5356/6 | Sep., 2000 | WO.
| |
| WO 01/3459/0 | May., 2001 | WO.
| |
| WO 01/4548/4 | Jun., 2001 | WO.
| |
| WO 02/2045/1 | Mar., 2002 | WO.
| |
| WO 02/2045/7 | Mar., 2002 | WO.
| |
| WO 03/018570 | Mar., 2003 | WO.
| |
Primary Examiner: Dentz; Bernard
Attorney, Agent or Firm: Kenyon & Kenyon
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the U.S. Provisional Application Ser.
Nos. 60/446,764 filed Feb. 11, 2003 and 60/463,065 filed Apr. 15, 2003, the disclosures
of which are incorporated by reference in their entirety herein.
Claims
What is claimed is:
1. A process for preparing simvastatin with a specified simvastatin dimer content,
comprising the steps of:
a) lactonizing an ammonium salt of simvastatin in aromatic hydrocarbon at a concentration
of less than about 60 g/l to form a simvastatin;
b) dissolving the simvastatin in at least one solvent selected from the group
consisting of toluene, ethylacetate, tetrahydrofuran, and benzene and precipitating
the dissolved simvastatin with an anti-solvent selected from the group consisting
of pentane, hexane, heptane, cyclohexane and petroleum ether;
c) isolating the crystallized simvastatin;
d) dissolving the crystallized simvastatin in at least one solvent selected from
the group consisting of toluene, ethylacetate, tetrahydrofuran, and benzene and
precipitating the dissolved simvastatin with an anti-solvent selected from the
group consisting of pentane, hexane, heptane, cyclohexane and petroleum ether; and
e) isolating the recrystallized simvastatin,
wherein the recrystallized simvastatin contains a simvastatin dimer content of
less than 0.2% wt.
2. The process of claim 1, wherein the steps d) and e) are repeated.
3. The process of claim 1, wherein the concentration of the ammonium salt of
simvastatin is from about 30 to about 35 g/l.
4. The process of claim 3, wherein the concentration of the ammonium salt of
simvastatin is about 35 g/l.
5. The process of claim 1, wherein the lactonizing step is performed by refluxing
the ammonium salt of simvastatin in the aromatic hydrocarbon.
6. The process of claim 5, wherein the aromatic hydrocarbon is selected from
the group consisting of benzene, ethylbenzene, xylene and toluene.
7. The process of claim 5, wherein the aromatic hydrocarbon is toluene.
8. The process of claim 5, wherein the lactonizing step is performed for about
3 to about 5 hours.
9. The process of claim 8, wherein the lactonizing step is performed for 4 hours.
10. The process of claim 1, wherein the lactonizing step is performed in the
presence of butyl hydroxytoluene.
11. The process of claim 1, after step a) and before step b), further comprising
the step of drying the simvastatin obtained in step a).
12. The process of claim 11, wherein the drying step is performed by evaporation.
13. The process of claim 11, wherein the simvastatin obtained in step a) is dried
to residue by drying.
14. The process of claim 11, wherein the dissolving step in b) or d) is performed
at about 60° C.
15. The process of claim 1, after step e), further comprises the steps of:
f) dissolving the simvastatin obtained in step e) in a water miscible organic
solvent selected from the group consisting of methanol, ethanol, acetone, acetonitrile
and tetrahydrofuran; and
g) adding an anti-solvent to induce precipitation to obtain recrystallized simvastatin.
16. The process of claim 15, wherein the steps f-g) are repeated.
17. The process of claim 15, wherein the water miscible organic solvent is methanol.
18. The process of claim 15, wherein the anti-solvent is water.
19. The process of claim 1, wherein the crystallized simvastatin contains a simvastatin
dimer content of less than about 0.19% wt.
20. A process for preparing simvastatin with a specified simvastatin dimer content,
comprising the steps of:
a) lactonizing an ammonium salt of simvastatin in toluene at a concentration
of less than about 60 g/l to form a simvastatin;
b) dissolving the simvastatin in toluene and precipitating the dissolved simvastatin
with hexane;
c) isolating the crystallized simvastatin;
d) dissolving the crystallized simvastatin intoluene and precipitating the dissolved
simvastatin with hexane; and
e) isolating the recrystallized simvastatin,
wherein the recrystallized simvastatin contains a simvastatin dimer content of
less than 0.2% wt.
21. The process of claim 20, wherein the steps d) and e) are repeated.
22. The process of claim 20, after step e) further comprises the steps of:
f) dissolvieng the simvastatin obtained in step e) in methanol; and
g) adding water to induce precipitation to obtain recrystallized simvastatin.
23. A process for preparing simvastatin as in claim 1, wherein the ammonium salt
of simvastatin is at least about 100 grams.
Description
FIELD OF THE INVENTION
The present invention relates to a process for preparing simvastatin, wherein
the simvastatin dimer content is controlled. More particularly, the present invention
relates to a process for preparing simvastatin having a simvastatin dimer content
of about 0.2 to about 0.4% wt. The present invention also relates to a process
for preparing simvastatin having a simvastatin dimer content of less than about
0.2% wt. The present invention further relates to a commercial scale process for
preparing the same.
BACKGROUND OF THE INVENTION
Simvastatin, a cholesterol-lowering agent, is chemically designated
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-napthalenyl
ester, [1S-[1α,3α,7β,8β(2S*, 4S*),-8a β. Simvastatin
dihydroxy acid is a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme
(HMG-CoA) reductase, which catalyzes the rate-limiting step conversion of HMG-CoA
to mevalonate in cholesterol synthesis. Simvastatin is sold under the tradename
ZOCOR® and is marketed by Merck & Co., Inc. There is a need for a high yield
and efficient commercial scale processes for preparing simvastatin.
U.S. Pat. No. 4,444,784 describes heating the dihydroxy acid in neutral solvent
with continuous removal of the water by-product in order to drive the equilibrium
reaction toward lactone formation. However, heating promotes an undesirable esterification
reaction between the 3-hydroxy group of the 3-hydroxylactone with the precursor
free acid to increase the amount of dimer.
PCT/EP 98/00519 describes preparing simvastatin with a low level of dimer
impurity. The lactonization process uses the ammonium salt of simvastatin as the
starting material and involves refluxing in toluene followed by crystallizations
to obtain pure simvastatin. The simvastatin prepared in accordance with this procedure
is found to have a low dimer content of about 0.1 to about 0.12% wt.
Lactonization reaction of simvastatin ammonium salt to simvastatin
is an equilibrium reaction which is illustrated as follows:
##STR1##
Lactonization as an intramolecular esterification can be accompanied
by the esterification of the reaction product with starting material present in
the reaction mixture. This intermolecular esterification leads to the formation
of simvastatin dimer byproduct having the structure shown in the scheme above.
The European and U.S. pharmaceutical industry standards for certain simvastatin
products requires that simvastatin cannot contain more than 0.4% wt dimer. This
relatively high amount of impurity accepted by pharmaceutical authorities may be
due to the understanding that not only simvastatin but also the simvastatin dimer
are precursors of the pharmacologically active dihydroxy open acid form of the
compound (PCT/US 01/27466).
Efforts to produce simvastatin containing less than 0.2% of the simvastatin
dimer have been made. EP 351 918 discloses a method for acid catalyzed lactonization
leading to a simvastatin crude product containing less than 0.2% wt of simvastatin
dimer. This reference discloses that attempts to produce simvastatin of this quality
by purification had failed.
For other applications, it is desirable that purified simvastatin active ingredient
contain about 0.2 to about 0.4% wt simvastatin dimer; more preferably, about 0.25
to about 0.34% wt. Accordingly, a reproducible process for preparing simvastatin
active ingredient having a controllable dimer content in the specified ranges,
as well as acceptable impurity profile, is desirable.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing simvastatin, wherein the
simvastatin dimer content is controlled.
In one embodiment, the present invention provides a process for preparing simvastatin
with a specified simvastatin dimer content, comprising the steps of:
- a) lactonizing an ammonium salt of simvastatin in aromatic hydrocarbon
at a concentration from about 25 to about 40 g/l to form a simvastatin;
- b) dissolving the simvastatin in at least one solvent selected from
the group consisting of toluene, ethylacetate, tetrahydrofuran, and benzene and
precipitating the dissolved simvastatin with an anti-solvent selected from the
group consisting of pentane, hexane, heptane, cyclohexane and petroleum ether; and
- c) isolating the crystallized simvastatin,
wherein the crystallized simvastatin contains a simvastatin dimer content
of about 0.2 to about 0.4% wt.
Preferably, the concentration of the ammonium salt of simvastatin is
from about 30 to about 35 g/l. More preferably, the concentration of the ammonium
salt of simvastatin is about 35 g/l.
Preferably, the lactonizing step is performed by refluxing the ammonium
salt of simvastatin in the aromatic hydrocarbon. Preferably, the aromatic hydrocarbon
is selected from the group consisting of benzene, ethylbenzene, xylene and toluene.
More preferably, the aromatic hydrocarbon is toluene.
Preferably, the lactonizing step is performed for about 3 to about 5
hours. More preferably, the lactonizing step is performed for 4 hours.
Preferably, the lactonizing step is performed in the presence of butyl hydroxytoluene.
Preferably, the crude simvastatin is dried. Preferably, the drying step
is performed by evaporation. Preferably, the simvastatin is dried to residue.
Preferably, the crude simvastatin is dissolved in a solvent followed
by precipitation. Preferably, the dissolving step is performed at about 60°
C. Preferably, the precipitation is induced by adding an anti-solvent to the solution
containing the dissolved simvastatin.
Preferably, the anti-solvent is at lease one solvent selected from the
group of pentane, hexane, heptane, cyclohexane and petroleum ether.
Preferably, the process further comprises the steps of:
- d) dissolving the simvastatin obtained in step c) in a water miscible
organic solvent selected from the group consisting of methanol, ethanol, acetone,
acetonitrile and tetrahydrofuran; and
- e) adding an anti-solvent to induce precipitation to obtain recrystallized simvastatin.
Preferably, the recrystallization steps of d-e) are repeated. Preferably,
the anti-solvent is water.
Preferably, the crystallized simvastatin contains a simvastatin dimer
content of about 0.25 to about 0.34% wt.
In another embodiment, the present invention provides a process for preparing
simvastatin with a specified simvastatin dimer content, comprising the steps of:
- a) lactonizing an ammonium salt of simvastatin in aromatic hydrocarbon
at a concentration of less than about 60 g/l to form a simvastatin;
- b) dissolving the simvastatin in at least one solvent selected from
the group consisting of toluene, ethylacetate, tetrahydrofuran, and benzene and
precipitating the dissolved simvastatin with an anti-solvent selected from the
group consisting of pentane, hexane, heptane, cyclohexane and petroleum ether;
- c) isolating the crystallized simvastatin;
- d) dissolving the crystallized simvastatin in at least one solvent selected
from the group consisting of toluene, ethylacetate, tetrahydrofuran, and benzene
and precipitating the dissolved simvastatin with an anti-solvent selected from
the group consisting of pentane, hexane, heptane, cyclohexane and petroleum ether; and
- e) isolating the recrystallized simvastatin,
- wherein the recrystallized simvastatin contains a simvastatin dimer
content of less than 0.2% wt.
Preferably, the concentration of the ammonium salt of simvastatin is
less than about 40 g/l. More preferably, the concentration of the ammonium salt
of simvastatin is about 35 g/l.
Preferably, the lactonizing step is performed by refluxing the ammonium
salt of simvastatin in the aromatic hydrocarbon. Preferably, the aromatic hydrocarbon
is selected from the group consisting of benzene, ethylbenzene, xylene and toluene.
More preferably, the aromatic hydrocarbon is toluene.
Preferably, the lactonizing step is performed for about 3 to about 5
hours. More preferably, the lactonizing step is performed for 4 hours.
Preferably, the lactonizing step is performed in the presence of butyl hydroxytoluene.
Preferably, the crude simvastatin is dried. Preferably, the drying step
is performed by evaporation. Preferably, the simvastatin is dried to residue.
Preferably, the dissolving step is performed at about 60° C. Preferably,
the crystallizing step is performed by adding an anti-solvent to the solvent after
simvastatin is dissolved. Preferably, the anti-solvent is at lease one solvent
selected from the group pentane, hexane, heptane, cyclohexane and petroleum ether.
Preferably, the process further comprises the steps of:
- f) dissolving the simvastatin obtained in step e) in a water miscible
organic solvent selected from the group consisting of methanol, ethanol, acetone,
acetonitrile and tetrahydrofuran; and
- g) adding an anti-solvent to induce precipitation to obtain recrystallized simvastatin.
Preferably, the recrystallization steps of f-g) are repeated. Preferably,
the anti-solvent is water.
Preferably, recrystallized simvastatin contains a simvastatin dimer content
of less than about 0.19% wt.
In yet another embodiment, the present invention provides a commercial scale
process
for preparing simvastatin with a specified simvastatin dimer content, comprising
the steps of:
- a) lactonizing an ammonium salt of simvastatin in aromatic hydrocarbon
at a concentration from about 25 to about 40 g/l to form a simvastatin;
- b) dissolving the simvastatin in at least one solvent selected from
the group consisting of toluene, ethylacetate, tetrahydrofuran, and benzene and
precipitating the dissolved simvastatin with an anti-solvent selected from the
group consisting of pentane, hexane, heptane, cyclohexane and petroleum ether; and
- c) isolating the crystallized simvastatin,
- wherein the crystallized simvastatin contains a simvastatin dimer content
of about 0.2 to about 0.4% wt.
Preferably, the commercial scale process further comprises the steps of:
- d) dissolving the simvastatin obtained in step e) in a water miscible
organic solvent selected from the group consisting of methanol, ethanol, acetone,
acetonitrile and tetrahydrofuran; and
- e) adding an anti-solvent to induce precipitation to obtain recrystallized simvastatin.
Preferably, the recrystallization steps of f-g) are repeated. Preferably,
the anti-solvent is water.
In yet another embodiment, the present invention provides a commercial scale
process
for preparing simvastatin with a specified simvastatin dimer content, comprising
the steps of:
- a) lactonizing an ammonium salt of simvastatin in aromatic hydrocarbon
at a concentration of less than about 60 g/l to form a simvastatin;
- b) dissolving the simvastatin in at least one solvent selected from
the group consisting of toluene, ethylacetate, tetrahydrofuran, and benzene and
precipitating the dissolved simvastatin with an anti-solvent selected from the
group consisting of pentane, hexane, heptane, cyclohexane and petroleum ether;
- c) isolating the crystallized simvastatin;
- d) dissolving the crystallized simvastatin in at least one solvent selected
from the group consisting of toluene, ethylacetate, tetrahydrofuran, and benzene
and precipitating the dissolved simvastatin with an anti-solvent selected from
the group consisting of pentane, hexane, heptane, cyclohexane and petroleum ether; and
- e) isolating the recrystallized simvastatin,
- wherein the recrystallized simvastatin contains a simvastatin dimer
content of less than 0.2% wt.
Preferably, the commercial scale process further comprises the steps of:
- f) dissolving the simvastatin obtained in step e) in a water miscible
organic solvent selected from the group consisting of methanol, ethanol, acetone,
acetonitrile and tetrahydrofuran; and
- g) adding an anti-solvent to induce precipitation to obtain recrystallized simvastatin.
Preferably, the recrystallization steps of f-g) are repeated. Preferably,
the anti-solvent is water.
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
As used herein: "HMG-CoA reductase" refers to 3-hydroxy-3-methyl-glutarylcoenzyme
A reductase; "an inhibitor of HMG-CoA reductase" refers to statins which can exists
either as a 3-hydroxyl lactone ring or as the corresponding ring dihydroxy open
acid; "RRT" refers to relative retention time (relative to that of simvastatin)
of an impurity in HPLC; "RRT 0.68" refers to an impurity of simvastatin having
a relative retention time of 0.68; "RRT 1.87" refers to the impurity of simvastatin
dimer; "Lov" refers to lovastatin; "E-Lov" refers to epi-lovastatin; "Sim-OH-Ac"
refers to dihydroxy open acid simvastatin; "Simv" refers to simvastatin; "Anhyd"
refers to anhydrosimvastatin; "BHT" refers to butylhydroxytoluene; "DMBA" refers
to dimethybutyric acid; "ammonium salt of simvastatin" includes the ammonium salt
of 3,5-dihydroxy acid simvastatin; and, "commercial scale" refers to a simvastatin
manufacturing process starting with at least about 100 gram (can be as high as
hundreds of kilograms) of ammonium salt of simvastatin in the lactonization process.
"Anti-solvent" is generally known to the art to be a solvent, when
added to a solution containing a dissolved solute, will induce the precipitation
of the solute from the solution. "Water miscible organic solvent" refers to an
organic solvent that is miscible with water.
Unless otherwise specified, "%" refers to % wt and "A %" refers to % area
under HPLC. For the purposes of this application, "dimer" refers to simvastatin
dimer, e.g., the ester of the 3-hydroxyl simvastatin lactone and free acid lactone precursor.
Without being bound by any theory or mechanism of the invention, it is believed
that simvastatin formation is an intramolecular reaction and is independent of
the concentration of the simvastatin ammonium salt in the reaction mixture. Simvastatin
dimer formation, however, is an intermolecular reaction and can be accelerated
by increasing the concentration of simvastatin salt in the reaction mixture.
The present invention provides a process for controlling simvastatin dimer content
by lactonizing an ammonium salt of simvastatin at a specified concentration range.
The concentration of ammonium simvastatin salt is less than about 60 g/l. Preferably,
the concentration of ammonium simvastatin salt is about 25 to about 40 g/l. More
preferably, the concentration of ammonium simvastatin salt is about 30 to about
35 g/l. Most preferably, the concentration of ammonium simvastatin salt is about
35 g/l.
Lactonization may be brought about by any means known in the art including
thermal induction. Lactonization of ammonium salt of simvastatin at a concentration
of about 20 g/l yields simvastatin which, after drying, results in a simvastatin
containing about 0.50% to about 0.55% wt simvastatin dimer. Lactonization of ammonium
salt of simvastatin at a concentration of about 30 to about 60 g/l yields increasing
amount of simvastatin dimers in evaporated residues (0.7% to 1.2%; see Table 1).
The lactonizing step is preferably performed by refluxing the ammonium salt of
simvastatin in aromatic hydrocarbon. Aromatic hydrocarbon includes, but not limited
to, benzene, ethylbenzene, xylene, toluene and the like. Preferably, the aromatic
hydrocarbon is toluene. Preferably, the lactonizing step is performed for about
3 to about 5 hours. More preferably, the lactonizing step is performed for 4 hours.
Preferably, the lactonizing step is performed in the presence of butyl hydroxytoluene.
Preferably, the crude simvastatin is dried. Preferably, the drying step is performed
by evaporation. Preferably, the simvastatin is dried to residue.
The crude simvastatin is preferably dissolved in a solvent followed by precipitation.
Preferably, the dissolving step is performed at about 60° C. Preferably, the
precipitation is induced by adding an anti-solvent to the solution containing the
dissolved simvastatin. Preferably, the anti-solvent is at lease one solvent selected
from the group of pentane, hexane, heptane, cyclohexane and petroleum ether.
In addition to regulating the concentration of ammonium salt of simvastatin during
the lactonization process, the present invention further provides another means
for controlling simvastatin dimer content. The means involves purification of simvastatin
using the steps of crystallization. According to the present invention, the process
of controlling simvastatin dimer content may involve using a combination of the
reaction conditions and crystallization strategy from different solvent systems.
One embodiment of the present invention involves crystallizing an evaporated
solid residue of simvastatin derived from the lactonization reaction mixture. Preferably,
the crystallization comprises the initial step of dissolving crude simvastatin
in a crystallization solvent. Preferably, the solvent is at least one solvent selected
from the group consisting of toluene, ethylacetate, tetrahydrofuran, and benzene.
Precipitation may be induced by adding an anti-solvent to the solution. Preferably,
an anti-solvent is exemplified, but not limited to, pentane, hexane, heptane, cyclohexane
and petroleum ether.
Solution of crude simvastatin in toluene, ethylacetate, tetrahydrofuran
and/or benzene followed by precipitation by addition of an anti-solvent (e.g.,
hexane) greatly reduce simvastatin dimer content. Such crystallization system is
desirable for controlling simvastatin dimer at a specified range of less than about
0.2% wt. For example, a first crystallization of the evaporated simvastatin residue
(obtained using simvastatin ammonium salt of about 30 g/l to about 60 g/l) from
toluene-hexane mixture leads to crude simvastatin with a dimer content of about
0.3% to about 0.5% wt. (see Table 1).
A second crystallization of crude simvastatin from toluene-hexane mixture leads
to purified simvastatin containing less than about 0.2%wt of simvastatin dimer
(see Table 2).
Preferably, the apolar solvent-anti-solvent system uses toluene as an
apolar solvent and hexane as an anti-solvent. More preferably, the ratio of toluene
and hexane is 1:4 (v/v).
The recrystallization of crystallized simvastatin (e.g., crude simvastatin after
crystallized with toluene-hexane) with a water miscible organic solvent does not
change significantly the amount of simvastatin dimer. For example, a methanol solvent/water
anti-solvent crystallization of either the crude simvastatin (obtained after the
first toluene-hexane crystallization) or crystallized simvastatin (obtained after
the second toluene-hexane crystallozation) has limited effect on dimer content;
but, effectively removes other impurities. Therefore, final crystallization from
methanol-water does not effect the amount of dimer.
Preferably, the water miscible organic solvent includes, but not limited
to, methanol, ethanol, acetone, acetonitrile and tetrahydrafuran. Preferably, the
crystallization solvent is ethanol or acetone. Most preferably, the crystallization
solvent is methanol. Preferably, the anti-solvent used is water. Preferably, the
polar solvent-anti-solvent system uses methanol as a polar solvent and water as
an anti-solvent. More preferably, the ratio of methanol and water is 1:1 (v/v).
In accordance with the present invention, the lactonization using an ammonium
salt of simvastatin of about 25 to 40 g/l followed by purification steps of toluene-hexane
crystallization results in simvastatin containing a simvastatin dimer content of
about 0.2 to about 0.4% wt.
In accordance with the present invention, the lactonization using an ammonium
salt of simvastatin of less than 60 g/l followed by purification steps of repeated
toluene/hexane crystallization results in simvastatin containing a simvastatin
dimer content of less than 0.2% wt.
According to another embodiment, the present invention provides a commercial
scale process by using ammonium salt of simvastatin of at least about 100 grams.
The simvastatin prepared according to the process of the invention contains a
very low level of other impurities, typically less than about 0.1%.
The present invention will be more fully understood from the following examples.
These examples are intended for illustration purposes, but do not in any way limit
the scope of the invention.
EXAMPLES
Example 1
Effect of Varying Ammonium Simvastatin Concentrations on Simvastatin Impurity Profile
a) Lactonization
Simvastatin ammonium salt (9.0 grams) was refluxed in toluene (300 ml)
for 2 hours under nitrogen in the presence of butylhydroxytoluene (BHT) (0.08 gram)
using an oil bath for heating in a Dean—Stark condenser for removing water
formed in the reaction. 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. The dimer in the simvastatin solid residue was 0.70% (see Table 1, exp. 3).
b) First Crystallization With Toluene-Hexane Solvent
Solid simvastatin residue was dissolved in toluene (20 ml) at about 60°
C. The solution was treated with charcoal (0.3 gram), which was removed by filtration
and was washed with toluene (4 ml). The solution was charged into a four-necked
round bottom flask fitted with nitrogen inlet, thermometer, dropping funnel and
reflux condenser. The solution was then heated to 58-62° C. and n-hexane (55
ml) was added dropwise at this temperature for 1 hour while stirring. The reaction
mixture was then cooled to 0-5° C. in 1.5 hours and new portion of hexane
(41 ml) was added to the slurry after 1 hour. The mixture was then stirred at this
temperature for 1 additional hour. Product was collected, washed with the mixture
of toluene (4 ml) and hexane (16 ml) containing BHT (0.007 gram) and dried at 48°
C. in a vacuum oven to yield crude simvastatin. The dimer in the crude simvastatin
was 0.32% (see Table 1, exp. 3).
Using the above lactonization conditions, we examined how varying concentrations
of ammonium simvastatin salt affected the simvastatin impurity profile. Varying
concentrations, 2% (exp. nos. 1-2), 3% (exp. no. 3), 4% (exp. no. 4), 6% (exp.
no. 5) of ammonium simvastatin salt were tested. Lactonization was performed at
reflux temperature of 3 hours (exp. no. 1) or 5 hours (exp. no. 2). The oil bath
temperature was set at 125° C. (exp. no. 1) or 150° C. (exp. no. 6).
Dimethybutyric acid (DMBA) (5% wt/wt) was added with ammonium simvastatin salt
(exp. no. 7) to evaluate the effect of acid on simvastatin purity.
Table 1 summarizes the results of 20 to 60 g/l ammonium simvastatin salt concentration
on the simvastatin impurity profile. As is evident in Table 1, increasing the concentration
of the ammonium simvastatin salt from 20 to 60 g/l increases the amount of dimer,
without significantly changing the amount of other impurities. Increasing lactonization
temperature from 125° C. to 150° C. does not change the dimer content
(exp. nos. 1 and 6), but addition of dimethyl butyric acid increases the dimer
content (exp. nos. 1 and 7).
Example 2
Comparative
a) Second Crystallization With Toluene-Hexane
Crude simvastatin, from exp. 5, in Table 1, was dissolved in toluene (20 ml)
at about 60° C. and the solution was charged into a four-necked round bottomed
flask fitted with nitrogen inlet, thermometer, dropping funnel and reflux condenser.
The solution was then heated to 58-62° C. and n-hexane (46 ml) was added dropwise
at this temperature for 1 hour while stirring. The reaction mixture was then cooled
to 0-5° C. in 1.5 hours and new portion of hexane (34 ml) was added to the
slurry in 1 hour. The mixture was then stirred at this temperature for 1 additional
hour. Product was collected, washed with the mixture of toluene (3 ml) and hexane
(12 ml) containing BHT (0.007 gram) and dried at 48° C. in a vacuum oven to
yield a purified simvastatin (exp. 5a).
b) Third Crystallization With Methanol-Water
Purified simvastatin from the second toluene-hexane crystallization was
dissolved in methanol (49 ml), treated with charcoal (0.25 gram) which was filtered.
The purified simvastatin was washed with methanol (15 ml). BHT (0.004 gram) and
water (23 ml) were added to the solution, which was then heated to 35-40°
C. while stirring. The solution was cooled to 13-17° C. gradually in 2 hours.
Precipitation began at about 30° C. The suspension was then heated to 35-40°
C. again to dissolve most of the crystals. New portion of water (46 ml) was then
added dropwise at 35-40° C. in 45-50 min and the slurry was stirred for 1
hour at this temperature, then cooled to 5-10° C. in 2 hours and stirred at
this temperature for 1 hour. The resulting crystalline material was collected,
washed with the mixture of water (7 ml) and methanol (6 ml) and dried at 48°
C. for a night in a vacuum oven to provide the simvastatin final product (exp. 5b).
Table 2 summarizes the results of the second toluene/hexane crystallization
(exp. 5a) followed by a methanol/water crystallization (exp. 5b) steps on the simvastatin
impurity profile. As is evident in Table 2, a second toluene-hexane crystallization
step significantly decreases dimer from 0.48% to 0.19% and a third methanol/water
crystallization step does not further significantly reduce dimer (0.18%) (see Table
2). The methanol-water crystallization does not significantly affect the dimer
content but efficiently removes polar impurities, (e.g., RRT=0.58 and RRT=0.76
(simvastatin hydroxy acid).
Example 3
Different Simvastatin Ammonium Salt Starting Material
The experiments described above (Examples 1 to 7) used recrystallized simvastatin
ammonium salt as starting material. Since impurities of the starting ammonium salt
can also influence the impurity profile of the simvastatin product, this effect
was also studied.
Recrystallized simvastatin ammonium salt starting material from a
laboratory batch and crude simvastatin ammonium salt from commercial production
were used and the lactonization and crystallization steps were performed as in
Example 1.
The impurity profile of crude simvastatin obtained from different quality simvastatin
ammonium salt (i.e., (1) laboratory ammonium simvastatin salt described above,
and (2) production plant ammonium simvastatin salt) are summarized in Table 3.
Table 3 summarizes the impurity profile of the crude simvastatin (i.e., obtained
after first toluene/hexane crystallization) prepared from the simvastatin ammonium
salt from laboratory batch or commercial production. As evident in Table 3, the
quality of the ammonium salt does not effect the amount of the dimer in the crude
simvastatin. As also evident in Table 3 that the amount of other impurities can
depend on the purity of the ammonium salt.
Example 4
Effect of Repeated Methanol-Water Crystallization on Impurity Profile
The crude simvastatin products described in Table 3 were subjected to repeated
methanol-water crystallizations, after the toluene/hexane crystallization of Example
3, to yield the final product. The yield, assay and impurity profile of the products
are summarized in Table 4.
Changing the crystallization steps affects the impurity profile of the final
product. The second toluene-hexane crystallization (see example 2) effectively
removed both polar (RRT=0.68, simvastatin hydroxy acid) and apolar (RRT=1.40) impurities
(see Table 2) and dimer. The data in Table 4 shows that methanol-water crystallization
does not significantly affect the dimer content but efficiently removes the polar
impurities (e.g., RRT=0.68 and RRT=0.76 (simvastatin hydroxyl acid).
Example 5
Scaled-up Process for Preparing Simvastatin
The procedure elaborated in the foregoing examples; i.e., 10 gram scale was scaled-up
in the laboratory to 100 gram scale using a 4 L jacketed reactor instead of round
bottomed flasks. A process for preparing simvastatin starting from 105.0 grams
ammonium salt of commercial production plant origin is set forth below:
Step a) Lactonization Process
Simvastatin ammonium salt (105.0 grams) was stirred at reflux temperature
(109-111° C.) in toluene (3,000 ml) for 2 hours under nitrogen in the presence
of butylhydroxytoluene (BHT) (0.8 gram) in a 4 L jacketed reactor fitted with nitrogen
inlet, thermometer in a Dean-Stark condenser for removing of water formed in the
reaction. 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
(exp. no. 15, Table 5).
Step b) Preparation of Crude Simvastatin
Evaporation residue (112.0 grams) was dissolved in toluene (370 ml) at
about 60° C. The solution was treated with charcoal (5.0 grams) which was
removed by filtration and washed with toluene (50 ml). The solution was charged
into a four-necked round bottom flask fitted with nitrogen inlet, thermometer,
dropping funnel and reflux condenser. The solution was then heated to 58-62°
C. and n-hexane (968 ml) was added dropwise at this temperature for 1 hour while
stirring. The reaction mixture was then cooled to 0-5° C. in 1.5 hours and
new portion of n-hexane (712 ml) was added to the slurry in 1 hour. The mixture
was then stirred at this temperature for an additional 1 hour. The product was
collected, washed with the mixture of toluene (60 ml) and hexane (240 ml) containing
BHT (0.13 gram) and dried at 48° C. in a vacuum oven to yield 89.0 grams of
crude simvastatin (exp. no. 16, Table 5).
Separation of Crude Simvastatin
Crude simvastatin was divided into two equal parts. One part was subjected
to one toluene-hexane recrystallization followed by a methanol-water final crystallization
according to one purification strategy, the other part was subjected to a methanol-water
recrystallization followed by a methanol-water final crystallization according
to an alternative purification strategy.
Purification Strategy of Applying Toluene-hexane Recrystallization Followed by
Methanol-water Final Crystallization
Step c) Purification by Toluene-Hexane Recrystallization
Crude simvastatin ((43.75 grams) from step b) was dissolved in toluene (150
ml) at about 60° C., treated with charcoal (2.25 grams) which was washed with
toluene (24 ml). The filtrate was charged into a four-necked round-bottom flask
fitted with nitrogen inlet, thermometer, dropping funnel and reflux condenser.
The solution was then heated to 58-62° C. and n-hexane (400 ml) was added
dropwise at this temperature for 1 hour while stirring. The reaction mixture was
then cooled to 0-5° C. in 1.5 hour and a new portion of hexane (296 ml) was
added to the slurry in 1 hour. The mixture was then stirred at this temperature
for an additional 1 hour. The product was collected, washed with a mixture of toluene
(29 ml) and hexane (116 ml) containing BHT (0.067 gram), and dried at 48°
C. in a vacuum oven to yield 42.5 gram of purified simvastatin (exp. no. 17, Table 5).
Step d) Methanol-Water Final Crystallization
Purified simvastatin (41.0 grams) from step c) was dissolved in methanol
(438 ml), treated with charcoal (2.25 grams) which was filtered and washed with
methanol (137 ml). BHT (0.033 gram) and water (203 ml) were added to the solution,
which was heated to 35-40° C. while stirring. The solution was cooled to 13-17°
C. gradually in 2 hours. Precipitation began at about 30° C. The suspension
was then heated to 35-40° C. again to dissolve most of the crystals and an
additional portion of water (415 ml) was then added dropwise at 35-40° C.
in 45-50 min. The slurry was stirred for 1 hour at this temperature, then was cooled
to 5-10° C. in 2 hours and stirred at this temperature for 1 hour. Crystalline
material was collected, washed with the mixture of water (61 ml) and methanol (54
ml) and dried at 48° C. for a night in a vacuum oven to afford 39.16 grams
of simvastatin final product (exp. no. 18, Table 5).
Purification Strategy of Applying Methanol-water Recrystallization Followed by
Methanol-water Final Crystallization
Step e) Purification by First Methanol-Water Crystallization
Another portion of the crude from step b) crude simvastatin (43.75 grams)
was dissolved in was dissolved in methanol (438 ml), treated with charcoal (2.25
grams) which was filtered and washed with methanol (137 ml). BHT (0.033 gram) and
water (203 ml) were added to the solution and then it was heated to 35-40°
C. while stirring. The solution was cooled to 13-17° C. gradually in 2 hours.
Precipitation begins at about 30° C. The suspension was then heated to 35-40°
C. again to dissolve most of the crystals and new portion of water (415 ml) was
then added dropwise at 35-40° C. in 45-50 min. The slurry was stirred for
1 hour at this temperature then was cooled to 5-10° C. in 2 hours and stirred
at this temperature for 1 hour. Crystalline material was collected, washed with
the mixture of water (61 ml) and methanol (54 ml) and dried at 48° C. for
a night in a vacuum oven to yield 42.5 grams of simvastatin final product (exp.
no.19, Table 5).
Toluene (150 ml) at about 60° C., treated with charcoal (2.25 grams)
which was washed with toluene (24 ml). The filtrate was charged into a four-necked
round bottomed flask fitted with nitrogen inlet, thermometer, dropping funnel and
reflux condenser. The solution was then
The data in Table 6 show that scaling-up the process (e.g., commercial process),
when using about 3.5% ammonium salt simvastatin followed by crystallization of
the crude simvastatin with a first methanol/water solvent results in simvastatin
with the specified range of dimer content (see, exp. 19, Table 5).
Step f) Purification by Second Methanol-Water Crystallization
Purified simvastatin (41.0 grams) from step e) was dissolved in methanol
(438 ml), treated with charcoal (2.25 grams) which was filtered and washed with
methanol (137 ml). BHT (0.033 grams) and water (203 ml) were added to the solution
then it was heated to 35-40° C. while stirring. The solution was cooled to
13-17° C. gradually in 2 hours. Precipitation begins at about 30° C.
The suspension was then heated to 35-40° C. again to dissolve most of the
crystals and new portion of water (415 ml) was then added dropwise at 35-40°
C. in 45-50 min. The slurry was stirred for 1 hour at this temperature then was
cooled to 5-10° C. in 2 hours and stirred at this temperature for 1 hour.
Crystalline material was collected, washed with the mixture of water (61 ml) and
methanol (54 ml) and dried at 48° C. for a night in a vacuum oven to afford
39.55 grams of simvastatin final product.
The data in Table 5 also show that a second methanol/water crystallization results
in simvastatin with the specified range of dimer content (see, exp. 20, Table 5).
The present invention is not to be limited in scope by the specific embodiments
described herein. It will be understood that various modifications may be made
without departing from the spirit and scope of the invention. Various publications
and patents are cited herein, the disclosures of which are incorporated by reference
in their entireties.
| TABLE 1 |
|
| Effect of the Lactonization Conditions on Impurity |
| Profile of Crude Simvastatin |
| |
|
Dimer in |
|
|
[0.76] |
|
|
|
|
|
| Exp. |
|
Solid |
Yield |
|
Sim-OH— |
[0.86] |
[0.88] |
|
[1.40] |
[1.87] |
| No. |
Conditions |
Residue |
(%) |
[0.68] |
Ac |
Lov |
E-Lov |
Simv |
Anhyd |
Dimer |
|
| 1 |
Conc. 2%(a) |
0.55 |
91 |
0.04 |
0.43 |
0.11 |
0.05 |
98.94 |
0.02 |
0.24 |
| 2 |
Conc. 2%(b) |
0.51 |
91 |
0.04 |
0.22 |
0.09 |
0.04 |
99.14 |
0.04 |
0.23 |
| 3 |
Conc. 3% |
0.70 |
90 |
0.04 |
0.33 |
0.08 |
0.046 |
98.93 |
0.04 |
0.32 |
| 4 |
Conc. 4% |
0.91 |
93 |
0.04 |
0.59 |
0.10 |
0.05 |
98.53 |
0.02 |
0.43 |
| 5 |
Conc. 6% |
1.2 |
93 |
0.04 |
0.18 |
0.09 |
0.05 |
98.92 |
0.05 |
0.48 |
| 6 |
Conc. 2% |
0.58 |
93 |
0.05 |
0.47 |
0.11 |
0.05 |
98.84 |
0.03 |
0.26 |
| |
Higher oil |
| |
bath |
| |
temperature(c) |
| 7 |
Conc. 2% |
0.94 |
84 |
0.04 |
0.73 |
0.11 |
0.05 |
97.76 |
0.63 |
0.45 |
| |
Added |
| |
DMBA(d) |
|
| (a)laboratory procedure for lactonization described above, the oil
bath temperature was 125° C. |
| (b)lactonization was performed at a reflux temperature for 5 hours |
| (c)the oil bath temperature was 150° C. |
| (d)DMBA (5% wt/wt) was added with ammonium simvastatin salt to the
reaction mixture |
| TABLE 2 |
|
| Crystallization of the Crude Simvastatin Obtained in Exp. No. 5 (in Table 1) |
| Exp. |
|
Yield |
|
[0.76] Sim- |
[0.86] |
[0.88] |
|
[1.40] |
[1.87] |
| No. |
Conditions |
(%) |
[0.68] |
OH—Ac |
Lov |
E-Lov |
Simv |
Anhyd |
Dimer |
|
| 5a |
2nd Toluene-Hexane cryst. |
95 |
0.03 |
0.06 |
0.09 |
0.05 |
99.46 |
— |
0.19 |
| 5b |
Methanol-water cryst. |
94 |
— |
— |
0.09 |
0.04 |
99.51 |
0.01 |
0.18 |
|
| TABLE 3 |
|
| Characterization of Lactonisation and Crude Simvastatin starting from |
| Different Quality of Simvastatin Ammonium Salt |
| |
|
Dimer in |
Yield |
|
[0.76] Simv- |
[0.86] |
[0.88] |
|
[1.40] |
[1.87] |
| Exp. No. |
Conc. |
Solid Res. |
(%) |
[0.68] |
OH—Ac |
Lov |
E-Lov |
Simv |
Anhyd |
Dimer |
|
| 8(a) |
3% |
0.61 |
90 |
0.03 |
0.26 |
0.13 |
0.04 |
99.09 |
0.03 |
0.26 |
| 9(a) |
3% |
0.54 |
84 |
— |
0.23 |
0.09 |
0.04 |
98.03 |
0.16 |
0.24 |
| 10(a) |
3.5% |
0.83 |
89 |
0.04 |
0.22 |
0.08 |
0.04 |
98.98 |
0.03 |
0.33 |
| 11(a) |
3.5% |
0.75 |
91 |
0.03 |
0.29 |
0.08 |
0.03 |
99.01 |
0.03 |
0.30 |
| 12(b) |
3.5% |
0.80 |
89 |
0.20 |
0.15 |
0.17 |
0.08 |
98.78 |
0.03 |
0.32 |
| 13(b) |
3.5% |
0.78 |
90 |
0.25 |
0.19 |
0.18 |
0.09 |
98.44 |
0.04 |
0.33 |
|
| (a)starting from recrystallized ammonium salt of simvastatin from
laboratory batches |
| (b)starting from recrystallized ammonium salt of simvastatin from
commercial production plant |
| TABLE 4 |
|
| Characterization of Impurity Profile in Simvastatin Obtained After |
| First and/or Second Methanol-Water Crystallization |
| |
Yield |
Assay |
|
[0.76] Simv- |
[0.86] |
[0.88] |
[1.40] |
[1.87] |
| Exp. No. [recryst] |
(%) |
(%) |
[0.68] |
OH—Ac |
Lov |
E-Lov |
Anhyd |
Dimer |
|
| 8 [2nd] |
96 |
100.5 |
0.00 |
0.00 |
0.09 |
0.04 |
0.03 |
0.24 |
| 9 [2nd] |
94 |
100.1 |
0.00 |
0.04 |
0.09 |
0.05 |
0.15 |
0.22 |
| 10 [1st] |
93 |
99.5 |
0.00 |
0.00 |
0.08 |
0.04 |
0.03 |
0.30 |
| 10 [2nd] |
94 |
99.2 |
0.00 |
0.00 |
0.08 |
0.04 |
0.04 |
0.28 |
| 11 [1st] |
93 |
99.8 |
0.00 |
0.01 |
0.08 |
0.05 |
0.03 |
0.27 |
| 11 [2nd] |
93 |
99.9 |
0.00 |
0.00 |
0.08 |
0.04 |
0.03 |
0.26 |
| 12 [1st] |
95 |
100.1 |
0.06 |
0.00 |
0.12 |
0.08 |
0.03 |
0.26 |
| 12 [2nd] |
95 |
100.6 |
0.01 |
0.00 |
0.12 |
0.08 |
0.03 |
0.25 |
| 13 [1st] |
95 |
100.7 |
0.08 |
0.02 |
0.13 |
0.08 |
0.04 |
0.28 |
| 13 [2nd] |
94 |
100.1 |
0.01 |
0.00 |
0.13 |
0.08 |
0.04 |
0.26 |
|
| [1st] refers to first crystallization from Methanol-Water |
| [2nd] refers to second crystallizations (i.e., repeated crystallization)
from Methanol-Water |
| TABLE 5 |
|
| Impurity Profile at Different Stages of Lactonization and Purification |
| of Scaled-Up Product |
| |
|
Yield |
Assay |
|
[0.76] Sim- |
[0.86] |
[0.88] |
|
[1.40] |
[1.87] |
| Exp. No. |
Stage |
(%) |
(%) |
[0.68] |
OH—Ac |
Lov |
E-Lov |
Simv |
Anhyd |
Dimer |
|
| 14 |
End of the lact. |
|
|
0.46 |
1.60 |
0.02 |
0.01 |
95.8 |
0.26 |
0.67 |
| 15 |
Evap. solid res. |
|
|
0.48 |
1.14 |
0.06 |
0.02 |
96.1 |
0.26 |
0.73 |
| 16 |
Crude simv. |
91.8 |
|
0.18 |
0.20 |
0.07 |
0.04 |
98.8 |
0.04 |
0.30 |
| 17 |
Recrystallization from |
97.1 |
|
0.07 |
0.07 |
0.07 |
0.07 |
99.5 |
0.00 |
0.11 |
| |
toluene-hexane |
| 18 |
Recrystallization from |
95.5 |
|
0.02 |
0.00 |
0.07 |
0.04 |
99.7 |
0.00 |
0.11 |
| |
methanol-water |
| 19 |
1st crystallization from |
97.1 |
97.0 |
0.04 |
0.00 |
0.07 |
0.04 |
98.4 |
0.04 |
0.31 |
| |
methanol-water |
| 20 |
2nd crystallization from |
96.5 |
99.0 |
0.01 |
0.00 |
0.07 |
0.04 |
99.5 |
0.04 |
0.28 |
| |
methanol-water |
|
*
