Process for the production of indole derivatives

Details Process for the production of indole derivatives Process for the production of indole derivatives

2000-03-24

2001-08-28

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C548S468000, C548S503000, C548S504000

Reexamination Certificate

active

06281357

ABSTRACT:

This invention relates to a novel process for the production of a known class of compounds, some of which are known to be pharmacologically active.
For example, International Patent Application WO 92/06973 discloses a series of indole derivatives that are potent serotonin (5-HT) agonists. These compounds are indicated for treating disorders arising from deficient serotonergic neurotransmission comprising hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders. The compounds covered by WO 92/06973 include (R)-5-(methylaminosulphonylmethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (Example 5A, known as CP-122,288), which has the following structure:
UK Patent N
o
2,162,522 discloses an indole derivative (known as sumatriptan) which is sold for the treatment of migraine under the trade mark IMIGRAN, and which has the following structure:
European Patent Application 0548813 discloses another indole derivative (see Example 29, known as BMS-180048) which is indicated in the treatment of migraine, and which has the following structure:
In the prior art, synthesis of these compounds begins with a substituted benzyl halide, which then undergoes displacement with a suitable sulphur nucleophile (for example sodium sulphite). The product is then oxidised to the corresponding sulphonyl chloride and condensed with methylamine to give the desired secondary sulphonamide group. The resulting compound then undergoes an intramolecular cyclisation to form the desired indole ring. In the case of CP-122,288, this cyclisation is a Heck reaction according to the following scheme:
wherein P is a protecting group.
Reactions of this type can have a low yield (often around 25%) and result in a mixture of products, which require column chromatography to purify. This makes the production of the desired products expensive and inefficient.


REFERENCES:
patent: 5037845 (1991-08-01), Oxford
patent: 500086 A1 (1992-08-01), None
Sammes, M. P.; Wylie, C. M.; Hoggett, J. G, J. Chem. Soc. C (1971), (11), 2151-5.

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