Abstract
The development of a scalable telescoped continuous flow procedure for the acetylation and nitration of 4-fluoro-2-methoxyaniline is described. A subsequent batch deprotection then affords 4-fluoro...
Highlights
Osimertinib (1) is an active pharmaceutical ingredient (API)developed by AstraZeneca
The application of microreaction technology to perform nitration reactions was reported as early as 1956.14 Nitration reactions within continuous flow environments have received significant attention since that time, with recent developments encompassing the nitration of important API building blocks.[10,15,16]
The continuous flow nitration of benzyl-protected vanillin to O-benzyl-6-nitrovanillin on a multikilogram scale has been described by a group at Bristol-Myers Squibb (BMS).[17]
Summary
Within a continuous flow reactor, only a small amount of chemical inventory is processed at any one time, which considerably minimizes the risk and potential scale of explosions or thermal runaway These advantages make continuous processes inherently safer and more controlled than operation within a batch environment, at larger scales.[13] The application of microreaction technology to perform nitration reactions was reported as early as 1956.14 Nitration reactions within continuous flow environments have received significant attention since that time, with recent developments encompassing the nitration of important API building blocks.[10,15,16] In particular, a team from Novartis developed a protocol using fuming nitric acid that resulted in improved safety, higher product quality, and a straightforward scale-up.[10] The continuous flow nitration of benzyl-protected vanillin to O-benzyl-6-nitrovanillin on a multikilogram scale has been described by a group at Bristol-Myers Squibb (BMS).[17] The protection of the hydroxyl group provided the desired selectivity for the process and reduced the formation of the undesired 5-nitrovanillin. We describe the optimization of the nitration reaction within continuous flow, the development of a telescoped continuous flow acetylation and nitration procedure, and subsequent technology transfer from laboratory to pilot scale
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