Thomas M. Koenig

A convenient method for preparing enantiomerically pure norfluoxetine, fluoxetine and tomoxetine

Abstract A convenient synthesis for enantiomers of norfluoxetine, fluoxetine and tomoxetine is described. All final products were derived from a common intermediate, 3-phenyl-3-hydroxypropylamine.

Synthesis of R- and S- Fluoxetine, Norfluoxetine and Related Compounds from Styrene Oxide

Abstract A facile, high yield synthesis of R—or S—fluoxetine and norfluoxetine is described. This synthetic route utilizes readily available starting materials.

Regiospecific opening of 1,2-expoxides with acetone cyanohydrin under mildly basic conditions

Acetone cyanohydrin with stoichiometic triethylamine opens epoxides regiospecifically to give β-hydroxy nitriles. As expected, addition of cyanide occurs at the least substituted carbon.

Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions.

Continuous-flow technology is devised and implemented for manufacture of a drug candidate in clinical trials. Go with the flow in drug manufacturing Although many commodity chemicals are manufactured using continuous flow techniques, pharmaceuticals are still mostly produced in large single batches. Cole et al. report a protocol for the small-volume continuous preparation of multi-kilogram quantities of a cancer drug candidate, prexasertib monolactate monohydrate, under current good manufacturing practices. Advantages of the approach include safer handling of hazardous reagents and intermediates, as well as yield and selectivity improvements in both the reaction and purification stages. Concurrent analytical monitoring also facilitated rapid trouble-shooting during the manufacturing process. Science, this issue p. 1144 Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.

Ortho-hydroxyl assisted deoxygenation of phenones. Regiochemical control in the synthesis of monoprotected resorcinols and related polyphenolic hydroxyl systems

A method for the selective protection of polyphenolic hydroxyls is described. This approach relies on the deoxygenation of a benzylic ketone ortho to at least one of the phenolic hydroxyl groups.