Development of practical syntheses of potent non-nucleoside reverse transcriptase inhibitors

Lithium Diisopropylamide: Nonequilibrium Kinetics and Lessons Learned about Rate Limitation

“…Lithiations of 2-fluoropyridines (eq ) , proved to be among the most challenging within the series because they revealed all of the trappings of nonequilibrium kineticsautocatalysis, LiCl catalysis, rate-limiting and partially rate-limiting deaggregations (Scheme ), strange time-dependent decays of substrates, and biphasic kinetics in the competitive KIE (see Section ). They also included some subtleties that would not be understood until subsequent studies were completed. , …”

Use of 3-(trifluoromethyl)-1H-pyrazolo-[3,4-b]pyridine as a versatile building block

“…1H-Pyrazolo [3,4-b]pyridines, when appropriately substituted, exert potent and selective actions at diverse sets of protein targets, including G proteincoupled receptors, lyases and DNA polymerases. Besides their well-known vasodilatatory activity found in therapeutics such as Riociguat (A) 7 1H-pyrazolo [3,4-b]pyridines have also demonstrated activities as reverse transcriptase inhibitors represented by B, 8 phosphodiesterase IV inhibitors such as C, 9 and adenosine A 2B receptor antagonists exemplified by D. In one of our drug discovery projects we required 1H-pyrazolo [3,4-b]pyridine-3-carbonitrile (4) as a key building block. 11 Initially, the synthesis was established via 3-amino-pyrazolo-pyridine 2, prepared from commercially available 2-chloro-3-cyanopyridine (1) and hydrazine hydrate (Scheme 1).…”

Process Development and Large-Scale Synthesis of MK-6186, a Non-Nucleoside Reverse Transcriptase Inhibitor for the Treatment of HIV

“…Bromo compound 8 was readily available using chemistry previously described at Merck. 4 Hydrazone 13 was anticipated to be formed by palladium mediated cross-coupling of bromide 12 with benzophenone hydrazone. Bromide 12 itself would be accessed by an adaptation of the medicinal chemistry route to 5.…”

“…Second-generation NNRTIs, such as etravirene have recently been developed specifically for treatment-experienced adult patients with HIV resistance to an NNRTI. Merck recently reported on the discovery and development of a novel class of second-generation NNRTIs containing the pyrazolo­[3,4- b ]­pyridine and biaryl ether key structural features. , In a further elaboration of this sequence, compound 1 , now with a central indazole moiety was brought forward for development . Herein, the evolution of a robust synthesis of 1 which is amenable to scale, will be discussed.…”

“…Once formed, 14 could then be treated with aqueous acid to invoke a tandem acid hydrolysis and cyclisation, to afford the desired indazole product 1 regio-selectively. Bromo compound 8 was readily available using chemistry previously described at Merck . Hydrazone 13 was anticipated to be formed by palladium mediated cross-coupling of bromide 12 with benzophenone hydrazone.…”