Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
2002-04-17
2003-07-29
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
Reexamination Certificate
active
06600039
ABSTRACT:
The subject of the present invention is a process for the preparation of N-(1,1-dimethylethyl)-4-[[5′-ethoxy-4-cis-[2-(4-morpholino)ethoxy]-2′-oxospiro[cyclohexan- 1,3′-[3H]indol]-1′(2′H)-yl]-sulfonyl]-3-methoxybenzamide (SR 121463) of formula I
and its salts, compounds having vasopressine V
2
antagonistic effect.
According to patent application WO 9715556 the compound of formula I is prepared by reacting the spiro/cis-4-(beta-morpholino-ethyloxy)cyclohexan-1,3′-(5′-ethoxy)-[3H]indol-2′[1′H]one of formula II
with the 2-methoxy-4-(N-t-butylaminocarbonyl)benzenesulfonyl chloride of formula III
using potassium-t-butylate in tetrahydrofuran.
Because of the applied solvent (tetrahydrofuran) and reaction temperature (between −60° C. and 40° C.) it is not easy to carry out the process under industrial conditions, the yield is low, the product is contaminated, its purification requires repeated crystallization.
To our surprise, we have found that by stirring in dimethyl sulfoxide at room temperature the reaction proceeds in very good yield (85-92%). The work-up procedure is simple, while in the original process the product is obtained by extraction, in the present process the base precipitates on diluting the reaction mixture with water, and it can be filtered off. The purity of the resulting base is 93-96% and the salt formed from it is appropriately pure.
In accordance with the above, the subject of the invention is a process for the, preparation of the compound of the formula I
and the salts thereof, by reacting the compounds of the formula II
and III,
which comprises carrying out the reaction in dimethyl sulfoxide at a temperature between 10° C. and 40° C., preferably at room temperature and transforming the resulting base of formula I into its salt by a method known per se.
REFERENCES:
patent: 5994350 (1999-11-01), Foulon et al.
patent: 6090818 (2000-07-01), Foulon et al.
patent: WO 98/25901 (1998-06-01), None
patent: WO 97 15556 (1997-05-01), None
Serradeil-Le C, Lacour C, Valette G, et al. Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist. J Clin Invest 1996; 98:2729-38.
Csikós Éva
Csutor Andrea Sántáné
Gönczi Csaba
Halász Judit
Heja Gergely
Alexander Michael D.
Dupont Paul E.
Lambkin Deborah C.
Sanofi-Synthelabo
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