Process for the preparation of...

Details Process for the preparation of... Process for the preparation of...

2002-04-17

2003-04-01

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06541643

ABSTRACT:

This application is a 371 of PCT/HU00/00079 filed Jul. 13, 2000.
The subject of the present invention is a process for the preparation of spiro[cis-4-(&bgr;-hydroxyethyloxy)cyclohexane-[3H]indol]-2′[1′H]-one derivatives of general formula I.
The spiro[cis-4-(&bgr;-hydroxyethyloxy)cyclohexane-1,3′-(5′-ethoxy)-[3H]indol]-2′[1′H]-one is an important intermediate to the vasopressin V
2
antagonistic agent, SR 121463. Preparation of. the latter compound and its intermediate of formula I are described in patent application of WO 9715556.
According to the process described in the above patent application, the compounds of general formula I are prepared from the compounds of general formula II
using zinc borohydride reducing agent in the presence of chlorotrimethylsilane in the mixture of dichloromethane and diethyl ether. By this method the desired cis-isomer is obtained in 50-54% yield. The reaction time is long, approximately 20 hours, the zinc borohydride reagent has to be prepared in situ (it also takes approximately 20 hours) and the diethyl ether can not be substituted by an other solvent.
Surprisingly, we have found that the reaction can be accomplished under more simple conditions.
The subject of our invention is a process for the preparation of spiro[cis-4-(&bgr;-hydroxyethyloxy)cyclohexane-[3H]indol]-2′[1′H]-one derivatives of the formula I,
wherein
R
1
and R
2
stand independently from each other for hydrogen, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylthio, C
1-4
polyfluoroalkyl, C
1-4
polyfluoroalkoxy, C
3-7
cycloalkyloxy, C
3-7
cycloalkylthio, phenoxy, benzyloxy or nitro group by reduction of a dispiro[(1,3-dioxolane)-2,4′-cyclohexane-1′,3″-[3H]indol]-2″[1″H]-one derivative of the general formula II,
 wherein R
1
and R
2
are as defined above, which comprises carrying out the reduction
a) with sodium cyanoborohydride in the presence of a Lewis acid, or
b) with sodium borohydride in the presence of a strong acid.


REFERENCES:
patent: 5994350 (1999-11-01), Foulon et al.
patent: WO 97 15556 (1997-05-01), None

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