Synthesis of Fused Oxepane HIV Integrase Inhibitor MK-1376

Published as part of the Special Topic Synthesis in Industry

Abstract

Controlling the absolute and relative stereochemistry of a seven-membered oxepane in the formation of HIV integrase inhibitor MK-1376 was accomplished through a strategy involving the use of asymmetric allylation and stereoconvergent, substrate-directed installation of an amine fragment. Surprising reactivity was demonstrated during the asymmetric allylation in which the allyl-pyrimidone product was formed reversibly. The stereoconvergent amine addition was accomplished through an elimination/addition sequence involving a quinone methide reactive intermediate, and nucleophilic trapping of the reactive quinone methide intermediate with methylamine. This novel approach delivered MK-1376, offering 100-fold greater productivity and 50-fold less waste than the initial synthetic chemistry route.

Key words

HIV integrase inhibitor - oxepane - pyrimidine - π-allyl cyclization - quinone methide

• References

• 1 New address: Arrowhead Biopharmaceuticals, 502 South Rosa Road, Madison, WI 53719, USA
• 2 New address: Colgate Palmolive Company, 909 River Rd, Piscataway, NJ 08854, USA
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• 10 Even under these optimized conditions for the π-allyl cyclization, Boc-methylamine species 6 still gave only racemic trans-product.
• 11 Interestingly, when 1 equiv K₂CO₃ was added to the asymmetric allylation reaction, the rate increased and the sense of enantioselectivity completely switched from 96% ee (R) to –45% ee (S). This reversal in selectivity could signal a change in mechanism from one involving attack of the pyrimidone on Pd followed by reductive elimination to one involving intermolecular attack of the pyrimidone anion directly on the Pd-bound allyl fragment.
• 12 No hydrogenation reaction was observed in dichloromethane.
• 13 During this oxidation screen an interesting unprecedented oxidation was discovered using Tl(NO₃)₃ in HOAc, which oxidized the oxepane to the olefin (Scheme 11). This olefin could then be converted into the dibromide, which gave the vinyl bromide regioselectively upon base-mediated elimination. Further pursuit of this method was not attempted due to the toxicity of thallium; but, it was encouraging to note traces of the desired C-10 halogenated compound were observed after halogenations in the presence of Tl(NO₃)₃ using NBS, NCS and t-BuOCl. At this point, evidence from the thallium(III) catalyzed and Pyr₂INO₃ halogenations indicated an auxiliary oxidant may be beneficial in driving the halogenation to completion.
• 14 Process mass intensity (PMI) was decreased from >60,000 to 1200.
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