2022
DOI: 10.1021/acs.oprd.1c00481
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Development and Process Intensification of an Efficient Flow–Cascade Reaction Sequence in the Synthesis of Afizagabar

Abstract: Aromatic nitration and catalytic hydrogenation are among the most dangerous reactions in the chemical industry. The traditional, batchwise pilot plant manufacturing process of a key intermediate of our drug candidate afizagabar (S44819) involved these kinds of transformations (besides a Dakin−West-type reaction, a ring closure, and a keto reduction step). To mitigate some of the hazards associated with this sequence, a flow chemical approach was developed. First, a flow−cascade process was elaborated, which fu… Show more

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Cited by 4 publications
(2 citation statements)
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“…In continuation of our efforts aiming at the technological and analytical , development of drug substance manufacturing processes, we also tried to achieve economical improvements in the synthetic procedure leading to levomepromazine [( R )- 1 ]. In order to obtain recovered 2-methoxyphenothiazine ( 2 ) in a reasonable yield and required purity, we aimed to transform the one-pot procedure (see above, Scheme ) into an easily scalable process by isolating and purifying certain intermediates.…”
Section: Resultsmentioning
confidence: 99%
“…In continuation of our efforts aiming at the technological and analytical , development of drug substance manufacturing processes, we also tried to achieve economical improvements in the synthetic procedure leading to levomepromazine [( R )- 1 ]. In order to obtain recovered 2-methoxyphenothiazine ( 2 ) in a reasonable yield and required purity, we aimed to transform the one-pot procedure (see above, Scheme ) into an easily scalable process by isolating and purifying certain intermediates.…”
Section: Resultsmentioning
confidence: 99%
“…1 In the last step, among the wide arsenal of oxidants available in the literature, a stoichiometric amount of the two electron acceptor DDQ 2 in dichloromethane was used to support early clinical batches of API S44819 on a multi-kilogram scale. 3 Despite the efficiency and selectivity of the process, the stoichiometric use of DDQ causes some purification issues on a large scale, associated with the concomitant formation of the corresponding hydroquinone (DDHQ) in equimolar quantities. Indeed, the huge quantity of DDQ (1.28 kg/kg of 2) involved in the process induces the use of a massive volume of aqueous NaHCO 3 to remove all the DDQH.…”
mentioning
confidence: 99%