Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-23
2001-07-31
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S112000, C546S126000
Reexamination Certificate
active
06268498
ABSTRACT:
The present invention relates to a new process for preparing pharmaceutically active compounds and intermediates therefor.
EP-A-0200 444 (Beecham Group plc) describes certain 5-HT (5-hydroxytryptamine) antagonists which are described as possessing a number of therapeutic utilities, inter alia the prevention of vomiting following the administration of cytotoxic agents. The compound described in Example 6 is endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methylindazole-3-carboxamide, and this compound has been assigned the INN granisetron. EP-A-0200 444 discloses that granisetron can be prepared by reacting 1-methylindazole-3-carboxylic acid chloride with endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane.
A new process has been devised which can be used to prepare granisetron in a high state of purity. Accordingly, the present invention provides a process for preparing granisetron (1) or a pharmaceutically acceptable salt thereof:
which process comprises cyclising a compound of structure (2).
The cyclisation proceeds spontaneously under the conditions of deprotection.
The compound of structure (2) is conveniently prepared from a compound of structure (3)
in which R
1
and R
2
together form the group ═CHR in which R is C
1-4
alkyl such as methyl or ethyl or aryl such as optionally substituted phenyl, or R
1
and R
2
together form an oxygen atom:
(a) the compound is prepared in situ by deprotecting a hydrazone, suitably by carrying out deprotection under aqueous acidic conditions; or
(b) by the reduction of a nitroso compound of structure (3) in which R
1
and R
2
together are an oxygen atom, for example with either a solution of tin (II) chloride in dilute hydrochloric acid or a solution of sodium dithionite.
The intermediate compound of structure (2) and compounds of structure (3) in which R
1
and R
2
together form the group ═CHR and in which R
1
and R
2
together are an oxygen atom are novel and form a part of this invention.
The hydrazones of structure (3) in which R
1
and R
2
together form the group ═CHR can be prepared according to the procedure described in Annalen (1978) (2) pages 280-282 by reacting a compound of structure (4) with endo-3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (5) and methylating the resulting product.
The compound of Structure (3) in which R
1
and R
2
together form an oxygen atom may be prepared by reacting a compound of structure (6) with a solution of sodium nitrite and acidifying the mixture.
Compound (6) may be prepared by, for example, Friedel-Crafts reaction of a dichloroborane derivative of N-methylaniline with methyl oxalyl chloride, followed by reaction with endo-3-amino-9-methyl-9-azabicyclo[3.3.1 ]nonane (5) in DMSO; an alternative process is by direct Friedel-Crafts reaction of a dichloroborane derivative of N-methylaniline with a suitably activated derivative of the oxalamide of structure (7).
In this specification compounds are shown in the boat-chair form. It will be recognised that these conformations will be in equilibrium with the corresponding chair-chair forms which are shown in EP-A-0200444.
REFERENCES:
patent: 0 200 444 A2 (1986-04-01), None
Jacewicz Victor Witold
Jones David Alan
Ward Neal
Hoffmann-La Roche Inc.
Johnston George W.
Rocha-Tramaloni Patricia S.
Rotman Alan L.
Silverman Robert A.
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