U.S. patent application number 10/818301 was filed with the patent office on 2004-09-30 for process for the preparation of an indole derivative.
This patent application is currently assigned to SmithKline Beecham p.l.c.. Invention is credited to Fedouloff, Michael, Strachan, John Bryce.
Application Number | 20040192911 10/818301 |
Document ID | / |
Family ID | 26314042 |
Filed Date | 2004-09-30 |
United States Patent
Application |
20040192911 |
Kind Code |
A1 |
Fedouloff, Michael ; et
al. |
September 30, 2004 |
Process for the preparation of an indole derivative
Abstract
A process for the preparation of methyl
2-(3-chloropropoxy)-indole-3-carbo- xylate, which comprises
reacting a 3-chloro-3-carboxylate indole compound with
3-chloropropanol in the presence of an acid having a pKa of from 0
to 2.
Inventors: |
Fedouloff, Michael; (London,
GB) ; Strachan, John Bryce; (Bishop's Stortford,
GB) |
Correspondence
Address: |
GLAXOSMITHLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham p.l.c.
|
Family ID: |
26314042 |
Appl. No.: |
10/818301 |
Filed: |
April 5, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10818301 |
Apr 5, 2004 |
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10354865 |
Jan 30, 2003 |
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10354865 |
Jan 30, 2003 |
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10094285 |
Mar 8, 2002 |
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10094285 |
Mar 8, 2002 |
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09743820 |
Mar 28, 2001 |
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09743820 |
Mar 28, 2001 |
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PCT/EP99/04944 |
Jul 13, 1999 |
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Current U.S.
Class: |
544/89 |
Current CPC
Class: |
C07D 209/42
20130101 |
Class at
Publication: |
544/089 |
International
Class: |
C07D 491/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 16, 1998 |
GB |
9815481.8 |
Claims
1 and 2 (Cancelled)
3. A process for preparing
N-[(1-.sup.nbutyl-4-piperidyl)methyl]-3,4-dihyd-
ro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide, i.e. the compound
of Formula (I): 5or a pharmaceutically acceptable salt thereof,
which process comprises (a) preparing methyl
2-(3-chloropropoxy)-indole-3-carbo- xylate, i.e. the compound of
formula (B): 6by reacting a compound of formula (C) 7with
3-chloropropanol in the presence of an acid having a pKa of from 0
to 2; and (b) using the resulting methyl
2-(3-chloropropoxy)-indole-3-carboxylate of formula (B) in the next
stage in the synthesis of the
N-[(1-.sup.nbutyl-4-piperidyl)methyl]-3,4-dihydro-
-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide or the
pharmaceutically acceptable salt thereof.
4. A process as claimed in claim 3 wherein in step (a) the acid is
trichloroacetic acid, dichloroacetic acid and/or trifluoroacetic
acid.
5. A process as claimed in claim 3 wherein in step (a) the acid is
trichloroacetic acid.
6. A process as claimed in claim 3 wherein the reaction in step (a)
is effected in an organic solvent.
7. A process as claimed in claim 6 wherein in step (a) the organic
solvent is dichloromethane or chloroform.
8. A process as claimed in claim 3 wherein the reaction in step (a)
is effected in an organic solvent at a temperature in the range
-20.degree. C. to +10.degree. C.
9. A process as claimed in claim 4 wherein the reaction in step (a)
is effected in an organic solvent at a temperature in the range
-20.degree. C. to +10.degree. C.
10. A process as claimed in claim 8 wherein in step (a) the organic
solvent is dichloromethane or chloroform.
11. A process as claimed in claim 9 wherein in step (a) the organic
solvent is dichloromethane or chloroform.
12. A process as claimed in claim 6 wherein the reaction in step
(a) is effected using a catalytic amount of the acid.
13. A process as claimed in claim 8 wherein the reaction in step
(a) is effected using a catalytic amount of the acid.
14. A process as claimed in claim 9 wherein the reaction in step
(a) is effected using a catalytic amount of the acid.
15. A process as claimed in claim 11 wherein the reaction in step
(a) is effected using a catalytic amount of the acid.
16. A process as claimed in claim 3 comprising, in step (b),
cyclisation of the intermediate (B) (the methyl
2-(3-chloropropoxy)-indole-3-carboxyl- ate) by treatment with base
in a solvent to prepare a compound of formula (A): 8wherein R is
methyl, which compound of formula (A) is methyl
3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate.
17. A process as claimed in claim 16, comprising, in step (b):
reacting N-(1-.sup.nbutyl-4-piperidyl)methylamine with the methyl
3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate of formula
(A) to prepare the
N-[(1-.sup.nbutyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]-
oxazino[3,2-a]indole-10-carboxamide of formula (I); and optionally
preparing a pharmaceutically acceptable salt of the
N-[(1-.sup.nbutyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]i-
ndole-10-carboxamide.
18. A process as claimed in claim 13 comprising, in step (b),
cyclisation of the intermediate (B) (the methyl
2-(3-chloropropoxy)-indole-3-carboxyl- ate) by treatment with base
in a solvent to prepare a compound of formula (A): 9wherein R is
methyl, which compound of formula (A) is methyl
3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate.
19. A process as claimed in claim 18, comprising, in step (b):
reacting N-(1-.sup.nbutyl-4-piperidyl)methylamine with the methyl
3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate of formula
(A) to prepare the
N-[(1-.sup.nbutyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]-
oxazino[3,2-a]indole-10-carboxamide of formula (I); and optionally
preparing a pharmaceutically acceptable salt of the
N-[(1-.sup.nbutyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]i-
ndole-10-carboxamide.
20. A process as claimed in claim 3, wherein step (b) comprises
preparing the hydrochloride salt of
N-[(1-.sup.nbutyl-4-piperidyl)methyl]-3,4-dihyd-
ro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide.
21. A process as claimed in claim 13, wherein step (b) comprises
preparing the hydrochloride salt of
N-[(1-.sup.nbutyl-4-piperidyl)methyl]-3,4-dihyd-
ro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide (SB-207266-A).
22. A process as claimed in claim 17, wherein step (b) comprises
preparing the hydrochloride salt of
N-[(1-.sup.nbutyl-4-piperidyl)methyl]-3,4-dihyd-
ro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide (SB-207266-A).
23. A process as claimed in claim 19, wherein step (b) comprises
preparing the hydrochloride salt of
N-[(1-.sup.nbutyl-4-piperidyl)methyl]-3,4-dihyd-
ro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide.
Description
[0001] This invention relates to a new synthetic process to a
compound having pharmacological activity.
[0002] WO 93/18036 (SmithKline Beecham plc) describes certain
indole compounds having 5-HT.sub.4 receptor antagonist activity
including the compound of formula (I) 1
[0003] and its pharmaceutically acceptable salts. This compound is
N-[(1-.sup.nbutyl-4-piperidyl)
methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]- indole-10-carboxamide,
referred to herein by its code number SB-207266, (the hydrochloride
salt is SB-207266-A), which is being developed by SmithKline
Beecham plc as the active ingredient in a medicament for treatment
of irritable bowel syndrome.
[0004] Example 3 of WO 93/18036 describes a method of preparation
of SB-207266-A from
N-[(1-.sup.nbutyl-4-piperidyl)methyl]indole-3-carboxamid- e (i.e.
the compound corresponding to SB-207266, without the oxazino
moiety), by reacting with N-chlorosuccinimide and
3-bromo-1-propanol, followed by treatment with sodium carbonate.
N-[(1-.sup.nbutyl-4-piperidy- l)methyl]indole-3-carboxamide is
prepared by coupling N-(1-.sup.nbutyl-4-piperidyl)methylamine with
a indole-3-carboxylic acid.
[0005] WO 98/07728 (SmithKline Beecham plc) describes a process for
preparing SB-207266-A which involves the use of the
N-(1-.sup.nbutyl-4-piperidyl)methylamine intermediate at a later
stage in the process thus resulting in an increased yield of
SB-207266-A relative to the amount of this intermediate, which is
relatively expensive to produce. In particular, the alternative
process comprises the reaction of of
N-(1-.sup.nbutyl-4-piperidyl)methylamine with a compound of formula
(A): 2
[0006] wherein R is alkyl, such as methyl or ethyl.
[0007] The compound of formula (A) wherein R is methyl is methyl
3,4-dihydro-2H-[1,3]-oxazino[3,2-.alpha.]indole-10-carboxylate.
[0008] WO98/07728 also describes the preparation of the
oxazinoindole compound of the formula (A) from the corresponding
indole by reaction with N-chlorosuccinimide and a 3-halo-propanol,
such as 3-chloropropanol or 3-bromopropanol followed by cyclisation
of the intermediate (B) by treatment with base in a suitable
solvent. 3
[0009] The Description in the latter specification describes in
more detail the the preparation of compound (B) from the
corresponding methyl indole-3-carboxylate by reaction of the latter
with N-chlorosuccinimide in the presence of
1,4-diazabicyclo[2.2.2]octane (DABCO) to form an intermediate of
formula (C): 4
[0010] and subsequent reaction of (C) with 3-chloropropanol in the
presence of methanesulphonic acid.
[0011] We have now found that the use of an acid having a pKa of
from 0 to 2, especially trichloroacetic acid, in place of
methanesulphonic acid results in significant advantages for the
commercial operation of the process.
[0012] According to a feature of the present invention we provide a
process for the preparation of the compound of formula (B) above,
namely methyl 2-(3-chloropropoxy)-inodole-3-carboxylate, which
comprises reacting a compound of formula (C) with 3-chloropropanol
in the presence of an acid having a pKa of from 0 to 2, especially
trichloroacetic acid.
[0013] Other acids which may be used in accordance with the
invention in addition to trichloroacetic acid include
dichloroacetic acid and trifluoroacetic acid.
[0014] The use of the above-defined acid such as trichloroacetic
acid in place of methanesulphonic acid has been found to increase
significantly the overall yield of the process. The former acid
also has the advantage over the latter that its use results in the
formation of lower levels of the corresponding 2-methoxy compound,
as an impurity.
[0015] The reaction is conveniently effected in an organic solvent
such as dichloromethane or chloroform, at a temperature in the
range -20.degree. C. to +10.degree. C., for example using a
catalytic amount of the acid. The resulting product of formula (B)
can be used for the next stage in the synthesis of SB-207266 e.g as
described in WO 98/07728.
[0016] The following Example illustrates the invention.
EXAMPLE
Methyl 2-(3-Chloropropoxy)-Indole-3-Carboxylate (Formula (B))
[0017] A mixture of methyl indole-3-carboxylate and dichloromethane
is cooled to 0.degree. C. 1,4-dimethylpiperazine (0.55 eq.) and
N-chlorosuccinimide (1.1 eq) are added and the mixture left to stir
for two hours to give a slurry containing the compound of formula
(C) above. The resulting slurry is added to a solution of
3-chloropropanol (1.1 eq) and trichloroacetic acid (0.12 eq) in
dichloromethane, maintaining the temperature below 0.degree. C. The
reaction mixture is left to stir for half an hour, then washed with
10% aqueous sodium carbonate, 0.5 M hydrochloric acid and water.
The organic solution is dried over sodium sulphate, filtered and
the solvent evaporated. Toluene is added and the mixture stirred at
0-5.degree. C. for one hour. The product is then filtered, washed
with toluene and dried to give the title product in 83% yield.
* * * * *