Process for the preparation of an indole derivative

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

Reexamination Certificate

active

06583294

ABSTRACT:

This invention relates to a new synthetic process to a compound having pharmacological activity.
WO 93/18036 (SmithKline Beecham plc) describes certain indole compounds having 5-HT
4
receptor antagonist activity including the compound of formula (I)
and its pharmaceutically acceptable salts. This compound is N-[(
1-
n
butyl4-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.
Example 3 of WO 93/18036 describes a method of preparation of SB-207266-A from N-[(
1-
n
butyl-4-piperidyl)methyl]indole-3-carboxamide (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-
n
butyl-4-piperidyl)methyl]indole-3-carboxamide is prepared by coupling N-(
1-
n
butyl-4-piperidyl)methylamine with a indole-3-carboxylic acid.
WO 98/07728 (SmithKline Beecham plc) describes a process for preparing SB-207266-A which involves the use of the N-(
1-
n
butyl-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-
n
butyl-4-piperidyl)methylamine with a compound of formula (A):
wherein R is alkyl, such as methyl or ethyl.
The compound of formula (A) wherein R is methyl is methyl 3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate.
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.
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):
and subsequent reaction of (C) with 3-chloropropanol in the presence of methanesulphonic acid.
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.
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)-indole-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.
Other acids which may be used in accordance with the invention in addition to trichloroacetic acid include dichloroacetic acid and trifluoroacetic acid.
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.
The reaction is conveniently effected in an organic solvent such as dichloromethane or chloroform, at a temperature in the range −20° C. to +10° 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.


REFERENCES:
patent: 5852014 (1998-12-01), Gaster et al.
patent: 5998409 (1999-12-01), Gaster et al.
patent: 0884319 (1998-12-01), None
patent: WO 98/07728 (1998-02-01), None
patent: WO 93/18036 (1993-09-01), None
patent: WO 98/07728 (1998-02-01), None
patent: WO 98/11067 (1998-03-01), None
patent: WO 99/29697 (1999-06-01), None
patent: WO 00/03983 (2000-01-01), None
L.M. Gaster, et al.,J. Med. Chem., 38(24), 1995, pp. 4760-4763.
L. Gaster,Drugs of the Future, 1997, 22(12), pp. 1325-1332.
K.A. Wardle, et al., Br. J. Pharmacol., 1996, 118, pp665-670.

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Process for the preparation of an indole derivative does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the preparation of an indole derivative, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of an indole derivative will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-3127017

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.