U.S. patent application number 10/054727 was filed with the patent office on 2003-09-04 for new process.
This patent application is currently assigned to Pfizer Inc.. Invention is credited to Ogilvie, Ronald James.
Application Number | 20030166704 10/054727 |
Document ID | / |
Family ID | 27808338 |
Filed Date | 2003-09-04 |
United States Patent
Application |
20030166704 |
Kind Code |
A1 |
Ogilvie, Ronald James |
September 4, 2003 |
New process
Abstract
The present invention provides an improved process for the
preparation of the anti-migraine drug,
(R)-5-(2-benzenesulphonylethyl)-3-N-methylpyrroli-
din-2-ylmethyl)-1H-indole (eletriptan), available commercially as
the hydrobromide salt, and an intermediate and dimer-free products
obtained from such process.
Inventors: |
Ogilvie, Ronald James;
(Kent, GB) |
Correspondence
Address: |
PFIZER INC
150 EAST 42ND STREET
5TH FLOOR - STOP 49
NEW YORK
NY
10017-5612
US
|
Assignee: |
Pfizer Inc.
|
Family ID: |
27808338 |
Appl. No.: |
10/054727 |
Filed: |
November 13, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60260752 |
Jan 10, 2001 |
|
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|
Current U.S.
Class: |
514/414 ;
548/465 |
Current CPC
Class: |
A61K 31/404 20130101;
C07D 403/06 20130101 |
Class at
Publication: |
514/414 ;
548/465 |
International
Class: |
A61K 031/405; C07D
43/02 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 20, 2000 |
GB |
0031094.6 |
Claims
1. A process for the preparation of a compound of formula (I)
5which comprises hydrolysis of a compound of formula (II) 6
2. A process according to claim 1 which is carried out under basic
conditions.
3. A process according to claim 2 wherein said hydrolysis is
performed using potassium carbonate in methanol/water.
4. A process according to claim 1 wherein the compound of formula
(II) is obtained by catalytic reduction of a compound of formula
(III) 7
5. A process according to claim 4 wherein said reduction is carried
out using hydrogen or a hydrogen source in the presence of a
suitable catalyst.
6. A process according to claim 5 wherein said reduction is carried
out using hydrogen at a pressure of from 1 to 15 atmospheres.
7. A process according to claim 5 wherein said reduction is carried
out using a hydrogen source which is ammonium formate or formic
acid.
8. A process according to according to claim 4 wherein said
catalyst is palladium on carbon, Raney nickel, platinum oxide,
rhodium, or ruthenium.
9. A process according to claim 8 wherein said catalyst is 5% w/w
palladium on carbon.
10. A process according to claim 4 wherein the catalytic reduction
is carried out in the presence of an acid.
11. A process according to claim 10 wherein said acid is
methanesulphonic acid, acetic acid, or trifluoroacetic acid.
12. A process according to claim 4 wherein the compound of formula
(II) obtained by catalytic reduction is slurried with cold aqueous
tetrahydrofuran before hydrolysis to the compound of formula
(I).
13. A process according to claim 4 wherein the compound of formula
(III) is obtained by treating a compound of formula (IV) 8with
phenyl vinyl sulphone in the presence of a palladium catalyst, a
triarylphosphine and a base.
14. A process according to claim 13 wherein the compound of formula
(IV) is obtained by N-acetylating
(R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl- )-1H-indole.
15. A process according to claim 1 wherein the compound of formula
(I) so obtained is converted to a pharmaceutically acceptable acid
addition salt by treatment with an appropriate acid.
16. A process according to claim 15 wherein said conversion is
carried out in situ without isolation of the compound of formula
(I).
17. A process according to claim 15 wherein the acid is hydrobromic
acid and the resulting salt is the hydrobromide.
18. The compound of formula (II): 9
19. Eletriptan which is substantially free of 10
20. A pharmaceutically acceptable acid addition salt of eletriptan
which is substantially free of 11
21. A pharmaceutically acceptable acid addition salt of eletriptan
according to claim 20 which is the hydrobromide.
22. A pharmaceutical composition comprising eletriptan or a
pharmaceutically acceptable acid addition salt thereof which is
substantially free of 12and a suitable carrier or excipient.
23. A composition according to claim 22 wherein said
pharmaceutically acceptable acid addition salt is the hydrobromide.
Description
[0001] The present invention is concerned with an improved process
for the preparation of the anti-migraine drug,
(R)-5-(2-benzenesulphonylethyl)-3--
N-methylpyrrolidin-2-ylmethyl)-1H-indole (eletriptan), available
commercially as the hydrobromide salt: 1
[0002] and with an intermediate and dimer-free products obtained
thereby.
[0003] European Patent No. 0592438 describes the preparation of
eletriptan by the catalytic reduction of
(R)-5-(2-benzenesulphonylethenyl)-3-(N-meth-
ylpyrrolidin-2-ylmethyl)-1H-indole, which compound is prepared by
(i) reacting N-benzyloxycarbonyl-D-proline acid chloride with
5-bromoindole in the presence of a Grignard reagent, (ii) reducing
the resulting
(R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole
to give (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and
(iii) reacting same with phenyl vinyl sulphone in the presence of a
palladium catalyst, a triarylphosphine and a base.
[0004] The complete sequence may be represented as follows: 2
[0005] While the foregoing sequence produces eletriptan of formula
(I) in reasonable yield, it has been found that the
(R)-5-(2-benzenesulphonyleth-
enyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole precursor is
prone to dimerise when attempting to recrystallise in impure form
and/or drying prior to catalytic reduction: 3
[0006] Not only does the formation of this dimeric impurity reduce
the yield of eletriptan, but, perhaps more importantly, it requires
the costly and time-consuming removal of said dimer in order to
provide hydrobromide salt of sufficient purity to meet the
stringent standards required for regulatory approval.
[0007] As a result of this difficulty, we have now developed an
alternative route to eletriptan which avoids the use of a precursor
which is prone to dimerisation. Specifically, the process of the
invention comprises the preparation of eletriptan by the hydrolysis
of
(R)-1-acetyl-5-(2-benzenesulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl-
)-1H-indole, which compound may conveniently be prepared by (i)
N-acetylating
(R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, (ii)
reacting the resulting
(R)-1-acetyl-5-bromo-3-(N-methylpyrrolidin-2-- ylmethyl)-1H-indole
with phenyl vinyl sulphone in the presence of a palladium catalyst,
a triarylphosphine and a base to give
(R)-1-acetyl-5-(2-benzenesulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmeth-
yl)-1H-indole and (iii) catalytically reducing same.
[0008] The complete sequence may be represented as follows: 4
[0009] By the use of this process, it is possible to avoid the
formation of unwanted dimer and thereby obtain eletriptan of high
purity in good yield without the subsequent costly and
time-consuming purification steps needed to remove the dimeric
impurity. Thus according to the present invention, there is
provided a process for the preparation of a compound of formula (I)
which comprises hydrolysis of a compound of formula (II), typically
under basic conditions, more especially potassium carbonate in
methanol/water.
[0010] According to another aspect of the invention, the compound
of formula (II) used in the process may be obtained by catalytic
reduction of a compound of formula (III), typically using hydrogen
or a hydrogen source in the presence of a suitable catalyst. The
reduction is typically carried out using hydrogen at a pressure of
from 1 to 15 atmospheres or using a hydrogen source such as
ammonium formate or formic acid. Suitable catalysts include
palladium on carbon, for example, 5% w/w Pd/C, Raney nickel,
platinum oxide, rhodium, or ruthenium. The reduction is
conveniently carried out in the presence of an acid, for example,
methanesulphonic acid, acetic acid, or trifluoroacetic acid. The
compound of formula (II) so obtained is conveniently slurried with
cold aqueous tetrahydrofuran before hydrolysis to the compound of
formula (I).
[0011] The invention specifically provides the aforementioned
compound of formula (II) which has not hitherto been described.
[0012] According to yet another aspect of the invention, the
compound of formula (III) used in the process may be obtained by
treating a compound of formula (IV) with phenyl vinyl sulphone in
the presence of a palladium catalyst, a triarylphosphine and a base
in accordance with the process described in Example 57 of U.S. Pat.
No. 5,607,951.
[0013] According to yet a further aspect of the invention, the
compound of formula (IV) used in the process may be obtained by the
N-acetylation of
(R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, also in
accordance with the process described in Example 57 of
aforementioned U.S. Pat. No. 5,607,951.
[0014] Eletriptan obtained by the process of the invention may be
converted to a pharmaceutically acceptable acid addition salt by
treatment with an appropriate acid; said conversion may
conveniently be carried out in situ without isolation of the
compound of formula (I). A particularly preferred salt is the
hydrobromide obtained by treatment with hydrobromic acid.
[0015] Thus according to the present invention, there is also
provided dimer-free eletriptan and pharmaceutically acceptable
salts thereof, particularly the hydrobromide, and pharmaceutical
compositions comprising same.
EXAMPLE
[0016] The process of the invention may be illustrated by the
following example of the preparation of
(R)-5-(2-benzenesulphonylethyl)-3-N-methylp-
yrrolidin-2-ylmethyl)-1H-indole (I) and its hydrobromide salt:
[0017] (a) Preparation of
(R)-1-acetyl-5-(2-benzenesulphonylethyl)-3-(N-me-
thylpyrrolidin-2-ylmethyl)-1H-indole (II)
[0018] To a solution of the compound of formula (III) (200 g)
prepared by the method described in Example 57 of aforementioned
U.S. Pat. No. 5,607,951 in acetone (2.0L) was added water (0.5L).
Methanesulphonic acid (43.2 g, 0.95 equiv.) was added dropwise and
the resulting solution stirred for 5 minutes before adding 5% w/w
Pd/C catalyst (89.0 g, Johnson Mattey Type 58, 50% wet). The
solution was hydrogenated at room temperature at 200 psi hydrogen
for 18 hours.
[0019] The catalyst was removed by filtration and the filtrate
stripped to give an acetone-free slurry. To this was added dropwise
40% aqu. NaOH (30 mL) followed by water (1.5L). The resulting
slurry was stirred for 20 minutes and further 40% aqu. NaOH (20 mL)
added. After granulation for 2 hours under vigorous stirring, the
suspension was filtered and sucked dry for 30 minutes to give a
beige damp solid which was either
[0020] (i) dried at 45.degree. C. to give the desired product
(193.0 g, yield 95%) or
[0021] (ii) taken up in tetrahydrofuran (1.6L) to which was added
water (1.5L in total) over 10 minutes. The resulting suspension was
stirred vigorously for 18 hours, filtered and sucked dry for 30
minutes to give the desired product as a beige damp solid
(corrected weight 129.0 g, yield 67%).
[0022] Either form may be used directly in step (b):
[0023] (b) Preparation of
(R)-5-(2-benzenesulphonylethyl)-3-N-methylpyrrol-
idin-2-ylmethyl)-1H-indole (I)
[0024] To a solution of the compound of formula (II) (95.9 g) from
step (a)(i) or (ii) in acetone (1L) and methanol (0.1L) was added
K.sub.2CO.sub.3 (46.8 g, 1.5 equiv.) and the resulting mixture
stirred for 24 hours. To this was added charcoal (50 g) followed an
hour later by anhy. MgSO.sub.4 (300 g). The resulting suspension
was stirred for 1 hour and filtered. The filtrate was stripped to
give a damp solid which was dried in vacuo at 45.degree. C. to give
the desired product (79.3 g, 91.8%).
[0025] In the case where the compound of formula (I) is to be
converted to a pharmaceutically acceptable acid addition salt,
isolation of the compound of formula (I) may be avoided by directly
treating the solution obtained by hydrolysis with the appropriate
acid, for example, hydrobromic acid to give the hydrobromide
salt:
[0026] (c) Preparation of
(R)-5-(2-benzenesulphonylethyl)-3-N-methylpyrrol-
idin-2-ylmethyl)-1H-indole (I) and in situ hydrobromination
thereof
[0027] To a solution of the compound of formula (II) (95.9 g) from
step (a)(i) or (ii) in acetone (1L) and methanol (0.1L) was added
K.sub.2CO.sub.3 (46.8 g, 1.5 equiv.) and the resulting mixture
stirred for 24 hours. To this was added charcoal (50 g) followed an
hour later by anhy. MgSO.sub.4 (300 g). The resulting suspension
was stirred for 1 hour and filtered.
[0028] The filtrate was partially concentrated by azeotropic
distillation to remove methanol and the volume readjusted to 0.45L
with acetone. A solution of 48% w/v HBr (33.2 g, 0.95 equiv.) in
acetone (50 mL) was added dropwise and the resulting suspension
stirred for 72 hours. This was filtered, sucked dry for 30 minutes
and dried in vacuo at 45.degree. C. to give the desired product as
slightly beige crystals (71.8 g, 68.5%).
[0029] In a preferred embodiment of the invention, certain steps
may be `telescoped` in order to reduce handling and accelerate
processing time. For example, as indicated in step (a)(ii), drying
the compound of formula (II) prior to hydrolysis may be avoided by
using damp material slurried in aqueous tetrahydrofuran. Likewise,
as indicated in step (c), isolation of the compound of formula (I)
before conversion to a salt may be avoided by forming the salt in
situ.
* * * * *