A batch process was developed to produce 1-(azidomethyl)-3,5-bis-(trifluoromethyl)benzene, 1, in 94% yield by an efficient nucleophilic substitution reaction between 3,5-bis-(trifluoromethyl)benzyl chloride, 4, and sodium azide. Hydrazoic acid (HN3), a toxic volatile compound with explosive properties, can be formed in the reactor headspace during conventional batch processing that requires significant engineering controls. In order to improve the overall safety profile, the process to produce azide 1 was optimized for operation in a microcapillary tube reactor. In addition, azide 1 was prepared in a simple biphasic solvent system using phase-transfer catalysis which results in an overall low e-factor. The product was purified via wiped film evaporation (WFE) technology.
A key pharmaceutical intermediate (1) for production of edivoxetine•HCl was prepared in >99% ee via a continuous Barbier reaction, which improves the greenness of the process relative to a traditional Grignard batch process. The Barbier flow process was run optimally by Eli Lilly and Company in a series of continuous stirred tank reactors (CSTR) where residence times, solvent composition, stoichiometry, and operations temperature were optimized to produce 12 g h −1 crude ketone 6 with 98% ee and 88% in situ yield for 47 hours total flow time. Continuous salt formation and isolation of intermediate 1 from the ketone solution was demonstrated at 89% yield, >99% purity, and 22 g h −1 production rates using MSMPRs in series for 18 hours total flow time. Key benefits to this continuous approach include greater than 30% reduced process mass intensity and magnesium usage relative to a traditional batch process. In addition, the flow process imparts significant process safety benefits for Barbier/Grignard processes including >100× less excess magnesium to quench, >100× less diisobutylaluminum hydride to initiate, and in this system, maximum long-term scale is expected to be 50 L which replaces 4000-6000 L batch reactors.
A concise and scalable synthesis of LY231514 (1), a new pyrrolo[2,3-d]pyrimidine-based antitumor agent, is presented. Reaction
of 2-bromo-4-arylbutanal 9 with 2,4-diamino-6-hydroxypyrimidine (10) regioselectively provided pyrrolo[2,3-d]pyrimidine
11, representing the core structure of the drug, in good yield.
Assimilation of the glutamic acid residue by conventional means
completed the synthesis. Development of the optimized synthetic
route emphasized avoiding isolation of the relatively unstable
aldehyde and bromoaldehyde intermediates.
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