An Improved Preparation of (R)-3-Aminobutanol, a Key Intermediate for the Synthesis of Dolutegravir Sodium

Rao, Y. Srinivasa; Babu, B. Hari; Aminual, I.; Nageshwar, D.; Satyanarayana, P.

doi:10.2174/1570180814666170602083756

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“…Integrase medicines can keep HIV from entering into DNA, 1 and thus they enable to avoid the replication of the DNA infected by HIV 2 . Dolutegravir (DTG, I in Scheme 1), that is, the second generation of integrase inhibitor, has the advantages of lower doses, 3 stronger resistance, 4 and fewer side effects 5 than the first generation. GlaxoSmithKline published the preparation method of DTG (Scheme 1) starting from methyl 4‐(methoxy)‐3‐carbonylbutyrate 6 .…”

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confidence: 99%

Mechanism and kinetic study for the intensification of two‐step synthesis of a dolutegravir intermediate in microreactor

et al. 2022

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Multi-step reaction processes are frequently encountered in the synthesis of pharmaceuticals, separate study on each step however is easily neglected. Herein, we separately investigated two reaction steps for the synthesis of an intermediate (DTG-6) of an anti-HIV drug dolutegravir (DTG) in microreactors. The first step (i.e., deprotection of DTG-4) was optimized to achieve a high DTG-5 yield (i.e., 96.7%) in the microreactor after the parametric screening on the DTG-4 concentration, methanesulfonic acid loading, molar ratio of reaction components, and so forth. Reaction kinetics was revealed based on substantial experimental data and mechanism cognition. Validation experiments showed the accuracy of this reaction kinetics. After thoroughly understanding this deprotection step, we combined it with the following annelation step in a cascade microreactor system for the twostep synthesis of DTG-6 with a much higher yield even at a remarkably shorter residence time compared with literature reports, thus indicating efficient process intensification.

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