Continuous Process Improvement in the Manufacture of Carfilzomib, Part 2: An Improved Process for Synthesis of the Epoxyketone Warhead

Abstract

The development and kilogram-scale demonstration of an improved process for the synthesis of the epoxyketone warhead of carfilzomib is described. Critical to the success of this process was: (1) development of a scalable asymmetric epoxidation protocol; (2) identification of a crystalline intermediate with improved physical properties for isolation; (3) discovery and optimization of epimerization conditions to set the target stereochemistry; and (4) introduction of a seeded-bed coaddition crystallization to facilitate isolation of the final low-melting target. The results of kilogram-scale demonstration runs are shared, including details of a continuous process for the safe execution of an exothermic Barbier-type Grignard process.

Recent Trends and Prospects in Homogeneous Manganese‐Catalysed Epoxidation

“…More recently, Beaver et al . had developed an asymmetric epoxidation procedure for the synthesis of the epoxyketone fragment of the drug, Carfilzomib used in the treatment of cancer [59] . They modified the catalytic complex in the earlier method reported by Sun and coworkers for asymmetric enone epoxidation [60] .…”

“…More recently, Beaver et al had developed an asymmetric epoxidation procedure for the synthesis of the epoxyketone fragment of the drug, Carfilzomib used in the treatment of cancer. [59] They modified the catalytic complex in the earlier method reported by Sun and coworkers for asymmetric enone epoxidation. [60] Herein, they utilized the chiral Mnnonheme complex with H 2 O 2 and AcOH affording good yield (> 95% assay yield) and high selectivity (91:9 dr) in the preparation of (R,R)-epoxyketone (Scheme 41).…”

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

“…There are other publications that report on reactions performed in CSTRs-in-series [71][72][73][74][75][76][77], which are not discussed in detail here.…”

“…For example, Wernik et al [ 75 ] used ReactIR in the second CSTR to monitor the formation of diazoketone at 2107 cm −1 . The concentration of CH 2 N 2 cannot be monitored because the overlap of the characteristic stretch between CH 2 N 2 (2097 cm −1 ) and diazoketone; Hu et al [ 8 , 16 ] used ReactIR in the last stage of CSTRs-in-series to monitor the concentration of reactant in the mother liquor; Beaver et al [ 74 ] developed ReactIR method to monitor both the consumption of 2-bromopropene and the generation of product to reduce the safety risk relevant to the accumulation of the Grignard precursor.…”

Improved Synthesis of Bioactive Molecules Through Flow Chemistry

“…Carfilzomib has an epoxyketone moiety, commonly synthesized from L-Boc-leucine and its production involves the morpholine amide formation as the first step, followed by enone formation with the addition of isopropenylmagnesium bromide and epoxidation in the last step. In 2020, the Amgen company [96,97] developed a huge project for the preparation of this epoxyketone on industrial scale, employing a three-step telescoped continuous flow process to improve the commercial route (Fig. 55).…”