Process for the synthesis of ritonavir

Details Process for the synthesis of ritonavir Process for the synthesis of ritonavir

2001-05-21

2002-06-18

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S205000

Reexamination Certificate

active

06407252

ABSTRACT:

This application is a 371 of PCT/IT00/00368 Sep. 18, 2000.
BACKGROUND OF THE INVENTION
Ritonavir (CAS Number [155213-67-5]), the structural formula of which is given below,
is an inhibitor of human HIV protease which was described for the first time by Abbott in International Patent Application WO 94/14436, together with the process for the preparation thereof.
In the synthesis scheme given in WO 94/14436, Ritonavir is manufactured starting from valine and from compounds 1, 4 and 7, the structural formulae of which are also given below.
The synthesis process in question was subsequently optimised in its various parts by Abbot, who then described and claimed the individual improvements in the patent documents listed below: U.S. Pat. No. 5,354,866, U.S. Pat. No. 5,541,206, U.S. Pat. No. 5,491,253, WO 98/54122, WO 98/00393 and WO 99/11636.
The process for the synthesis of Ritonavir carried out on the basis of the abovementioned patent documents requires, however, a particularly large number of intermediate stages; it is also unacceptable from the point of view of so-called “low environmental impact chemical synthesis” (B. M. Trost Angew. Chem. Int. Ed. Engl. (1995) 34, 259-281) owing to the increased use of activating groups and protective groups which necessitate not inconsiderable additional work in disposing of the by-products of the process, with a consequent increase in the overall manufacturing costs.
SUMMARY OF THE INVENTION
The object of the present invention is therefore to find a process for the synthesis of Ritonavir which requires a smaller number of intermediate stages and satisfies the requirements of low environmental impact chemical synthesis, thus limiting “waste of material”.
A process has now been found which, by using as starting materials the same compounds as those used in WO 94/14436, leads to the formation of Ritonavir in only five stages and with a minimum use of carbon atoms that are not incorporated in the final molecule.


REFERENCES:
patent: 5354866 (1994-10-01), Kempf et al.
patent: 5491253 (1996-02-01), Stuk et al.
patent: 5541206 (1996-07-01), Kempf et al.
patent: 5559158 (1996-09-01), Al-Razzak et al.
patent: 5567823 (1996-10-01), Tien et al.
patent: 0 748 801 (1996-12-01), None
patent: WO 94/14436 (1994-07-01), None
patent: 9604232 (1996-02-01), None
patent: WO 98/00393 (1998-01-01), None
patent: WO 98/54122 (1998-12-01), None
patent: WO 99/11636 (1999-03-01), None
PCT Search Report
L. Cotarca et al., Bis(Trichloromethyl) Carbonate in Organic Synthesis, XP-002090854, pp. 553-576, 1996.

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