op8b00387_si_001.pdf (31.33 MB)
Rapid On-Demand Synthesis of Lomustine under Continuous Flow Conditions
journal contribution
posted on 2019-02-12, 16:38 authored by Zinia Jaman, Tiago J. P. Sobreira, Ahmed Mufti, Christina R. Ferreira, R. Graham Cooks, David H. ThompsonLomustine,
an important agent for treatment of brain tumors and
Hodgkin’s lymphoma, has been synthesized using continuous flow
methodology. Desorption electrospray ionization mass spectrometry
(DESI-MS) was used to quickly explore a large number of reaction conditions
for one of the reaction steps and guide the efficient translation
of optimized conditions to continuous lomustine production. Using
only four inexpensive commercially available starting materials and
a total residence time of 9 min, lomustine was prepared via a linear
sequence of two chemical reactions performed separately in two telescoped
flow reactors. Sequential offline extraction and filtration resulted
in a 63% overall yield of pure lomustine at a production rate of 110
mg/h. The primary advantages of this approach are the rapid manufacture
of lomustine with two telescoped steps to avoid isolation and purification
of a labile intermediate and the mild conditions used in the nitrosylation
step, thereby significantly increasing the purity and yield of this
active pharmaceutical ingredient.
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reaction conditions9 minSequential offline extractionlomustine productionbrain tumorsflow reactorsproduction ratenitrosylation stepDesorption electrospray ionization mass spectrometryDESI-MSRapid On-Demand Synthesisflow methodologychemical reactionsreaction stepsContinuous Flow Conditions Lomustineresidence timeoptimized conditions
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