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Synfacts 2017; 13(12): 1227
DOI: 10.1055/s-0036-1591624
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Raltegravir

Rezensent(en):
P. J. Kocienski
Stathakis CI. * Koftis TV. * et al. Pharmathen S.A., Thessaloniki, Greece
(Chloromethyl)dimethylchlorosilane−KF: A Two-Step Solution to the Selectivity Problem in the Methylation of a Pyrimidone Intermediate en Route to Raltegravir.

Org. Process Res. Dev. 2017;
21: 1413-1418
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Publikationsverlauf

Publikationsdatum:
17. November 2017 (online)

 
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Key words

Raltegravir - HIV integrase inhibitor - N-methylation - Chapman rearrangement

Significance

Raltegravir potassium (Isentress®) is an HIV integrase inhibitor manufactured by ­Merck & Co. (G. R. Humphrey et al. Org. Process Res. Dev. 2011, 15, 73). A major challenge in the synthesis of raltegravir is the selective N-methylation of the pyrimidone intermediate A. Conventional methylating agents such as MeI produced mixtures of N- and O-methylated pyrimidones that were difficult to separate.


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Comment

Highly selective N-methylation of A was achieved by the three-step sequence developed by workers at Pharmathen involving (1) N-alkylation of B with C to give F, (2) amidation of F with amine G, and (3) desilylation of H with potassium fluoride in methanol. By this procedure, the desired N-methylpyrimidone I was obtained in 82% overall yield on a 420 mmol scale. For a mechanism for the formation of I, see: V. A. Pestunovich and co-workers J. Organomet. Chem. 1989, 361, 147.


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