A convergent synthesis of (S)-(4-benzylmorpholin-2-yl)(morpholino)methanone methanesulfonate (1), a key regulatory starting material for edivoxetine·HCl, was developed at Eli Lilly & Company. This novel synthesis utilizes d-serine as the source of chirality, which is preserved throughout the synthesis. Key features include the development of a scalable diazotization process to produce (S)-epoxy acid 7, which was optimized to improve the process safety profile. The final (S)-morpholino acid intermediate 11 was converted to the title compound using T3P with >99.9% purity in 75% yield. Life cycle analysis of the new route revealed a 69% reduction in global warming potential (GWP) for solvent usage relative to the prior route of manufacture.

Serotonin norepinephrine reuptake inhibitor (SNRI) pyrrolidinyl ether 2 was synthesized by employing a dynamic kinetic resolution (DKR) with enantio- and diastereoselective hydogenation on β-keto-γ-lactam 8 to afford β-hydroxy-γ-lactam 9 with 96% ee and 94% de. Reduction of 9 and purification via the dibenzoyl-(l)-tartaric acid diastereomeric salt 16 enriched the ee and de to 100%. While screening hydrogenation reaction systems with ruthenium-BINAP catalysts to prepare 9, it was found that adding catalytic HCl and LiCl enabled higher yields. In addition, the rate and equilibrium of the DKR-hydrogenation of 8 to give 9 was studied by online NMR and chiral HPLC, which indicated that one of the enantiomers of 8 was reducing faster to 9 than the equilibration of the stereocenter of 8.

This article describes chemistry that was developed to give access to multigram quantities of the selective peroxisome proliferator activated receptor modulator (SPPARM), compound 1.(1) Fischer esterifications, phase transfer-catalyzed alkylations, amide couplings, crystallizations, and a new synthesis were developed to accomplish this task. In addition, an efficient method for preparing 2-(4-alkoxyphenyl)ethylamines 7a-d from tyramine 9 was developed that involves O-alkylation of intermediate Schiff base 11 and subsequent acid-catalyzed hydrolysis to afford the target molecules as crystalline hydrochloride salts.

Echinocandin B (ECB) analog 1c was methylphosphonylated with the new reagent dimethyldiphosphonate 7. Selective functionalization of the phenol group was achieved in the presence of 11 other reactive alcohol and amide groups. The phosphonylation was best conducted in a mixture of THF and DMF using lithium t-butoxide as base. Methylphosphonate diester 1d was deprotected by hydrogenolysis to afford methylphosphonate monoester 1e, a potential prodrug for ECB analog 1c.

The scope of the phthalimido protecting group (PhthN-) is extended by reaction with pyrrolidine. The resulting o-pyrrolidinocarbonylbenzamide (“OPCB-”) represents a base/nucleophile stable derivative of the parent, which reverts to the imide form upon treatment with acid. This methodology allows utilization of this protecting group (as the OPCB form in synthetic sequences requiring basic/nucleophilic reaction conditions.