Synthesis of Vixotrigine, a Voltage- and Use-Dependent Sodium Channel Blocker. Part 2: Development of a Late-Stage Process

Abstract

As vixotrigine (1) entered a later clinical phase for trigeminal neuralgia (ZakrzewskaJ. M. Zakrzewska, J. M. Lancet Neurol.201716291300), the development of a sustainable late-stage process was required to meet the supply needs for formulation optimization, phase 3 clinical trials, and registration stability batches (this is the expected commercial formulation). In this article, we describe how the process was streamlined from the early supply route (GiblinG. Giblin, G. 10.1021/acs.oprd.0c00382Org. Process Res. Dev.2020) and a comprehensive control strategy was established. Process improvements included improving safety and scalability for a temperature-sensitive Grignard reaction, simplifying unit operations, removal of heterogenous conditions, and route redesign to afford a high yielding, one-pot sequential alkylation and amidation. Improvement in the salt formation step, combined with wet milling, resulted in improved particle properties with enhanced flow properties of the final active pharmaceutical ingredient. The process mass intensity was improved 65% while maintaining drug substance purity at more than 99.8%. This new process has been scaled up to generate metric ton quantities of drug substance.

Nickel-catalyzed reductive coupling of unactivated alkyl bromides and aliphatic aldehydes

“…Benzyl ethers and straight-chain aldehydes were shown to couple effectively. Substrates with b-branching, such as citronellal (7) and isovaleraldehyde (8), delivered the desired products in good yield. Aldehydes bearing protected amines such as carbamates were well tolerated, showing no activation or cleavage of the Boc group in 9. a-Branched aldehydes showed comparable reactivity to linear substrates (10-13), however, aldehydes bearing a-quaternary centers did not afford meaningful amounts of coupled product.…”

“…These processes are attractive due to the generation of metalated intermediates of lower nucleophilicity, a higher control of selectivity by tuning the catalytic systems, and ability to be applied on process scales. [6][7][8] Net reductive couplings using organohalide feedstocks have been developed using stoichiometric reductants to enable catalyst turnover, obviating the need for pre-generation of the organometallic nucleophile. [9][10][11][12][13][14][15][16] Among the most common systems are Rh 10 , Ni 11,[14][15][16] and Cr [17][18][19][20][21][22][23][24] -catalyzed couplings of aldehydes and organohalides.…”

Simple Methods to Predict Particle Size for Growth-Only Systems Undergoing One or More Temperature Cycles

“…Temperature-cycling a suspension may increase the final particle size by partial fine dissolution and then growth on undissolved material during non-rapid cooling. Chen et al 2 and Durak et al 3 demonstrate this well-known technique to implement wet milling followed by temperature cycling to control particle size to a desired range.…”

Nickel-Catalyzed Decarboxylative Coupling of Redox-Active Esters with Aliphatic Aldehydes

“…An attractive approach to deliver organohalide feedstocks to carbonyl compounds that obviates the need for preformed organometallic reagents is transition-metal-catalyzed reductive coupling reactions . To date, the coupling of aldehydes with organohalides using a stoichiometric reducing agent can be catalyzed by Cr, Rh, Co, and Ni, but current systems are often restricted to aryl, allylic, or propargylic halides and aromatic aldehydes.…”