Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine

Abstract

A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.

Enzymatic synthesis of fluorinated compounds

“…To overcome the poor water solubility and photostability of piperine, a threo -difluoropiperine analog was synthesized and showed higher potency and selectivity than piperine for the treatment of AD (Lizarme-Salas et al 2020 ). Similarly, fluorinated compounds are also the key building blocks of antibiotic, antimalarial, antiinflammatory, asthma, antagonists, migraine, and central nervous system drugs, such as 2,2-bis(6-fluoro-1H-indol-3-yl)ethan-1-amine, fluorinated steroidal, Trifluorothymidine and fluorouracil polytoxin, fluorinated cholesterol, fluorinated galegine, fluorinated bastimolide A, 6(R/S)-fluoropenibruguieramine, fluorinated cyclopropanecarboxylic acid derivatives, aryl-fluoro sulfates, 3-fluoro-4-aminopiperidine, and β-fluoramines (Adler et al 2019 ; Bakhotmah and Abdel-Rahman 2017 ; Campana et al 2020 ; Frank et al 2016 ; Fujino et al 2017 ; Gambini et al 2019 ; Liu et al 2018 ; Molinaro et al 2019 ; Munck Af Rosenschold et al 2019 ; Pupo et al 2019 ; Quintard et al 2018 ; Shao et al 2015 ; Wu et al 2020d ). Accordingly, fluorinated compounds will pay more and more attention to the research and development of new pharmaceutical intermediates.…”

Recent Developments in Transition-Metal-Catalyzed Asymmetric Hydrogenation of Enamides

“…In 2019, Phillips and Xiang, at Process Research & Development Merck & Co, and co-workers developed a practical and efficient enantioselective route to prepare the calcitonin gene-related peptide receptor antagonist involving Ru-catalyzed asymmetric hydrogenation of a fluoridesubstituted enamide to provide the corresponding cis-1,2aminofluoropiperidine as the key intermediate for the active pharmaceutical ingredient (API). 48 Careful optimization by varying the metal precursors and the additives demonstrated that the catalyst formed by a combination of 3% of (COD)Ru(Me-allyl) 2 and MeO-BIPHEP ligand (L24) provided, in THF under 34 bar of hydrogen in the presence of HBF 4 •OEt 2 , the desired product in 97% yield and 86% ee and 3% of a defluorinated by-product. Notably, to avoid potential catalyst poisoning during the formation of the by-product, a stoichiometric amount of HBF 4 •OEt 2 in the presence of Ti(O i Pr) 4 was employed with 1 mol% of catalyst loading (Scheme 45).…”

Large Scale Practical Synthesis of Enantiomerically Pure cis-4-Amino-3-fluoro-1-methylpiperidine via Rhodium-Catalyzed Asymmetric Hydrogenation of a Tetrasubstituted Fluoroalkene

“…Enantiomerically pure fluoro-containing molecules are important intermediates for the synthesis of active pharmaceutical ingredients (APIs) due to their improved physiological properties. The cis -4-amino-3-fluoropiperidine moiety is an important fragment that appears in many pharmaceutical drug candidates such as antibacterials, PTK2 inhibitors, JAK inhibitors, CGRP receptor antagonists, gyrase inhibitors, and antimigraine compounds (Figure ). As part of one of our development programs for a drug candidate, we needed multikilogram amounts of enantiomerically pure (3 S ,4 R )-1-methyl-3-fluoropiperidin-4-amine 1 as a regulatory starting material of API.…”

“…However, asymmetric hydrogenation on fluoro-containing tetrasubstituted alkenes often suffers from unsatisfactory enantioselectivity and diastereoselectivity together with generation of the hydrodefluorination impurity. These pose significant purification challenges with a great deal of yield loss to obtain the targeted specification. , Herein, we report a sustainable manufacturing process of compound 1 by engineering a highly enantioselective rhodium-catalyzed reduction of fluoroencarbamate. The reduction step furnished the product 4 in >99% enantiomeric and diastereomeric excess, with <1.0% of the hydrodefluorination impurity ( 12 ).…”

“…When the amount of regioisomer 3a was controlled to 0.6% in the purification process, the enantiomeric ratio of product 4 was eventually increased to 99.5:0.5 (entry 6). As mentioned earlier, asymmetric hydrogenation of fluoro-containing tetrasubstituted piperidine enamides and encarbamates often suffers from unsatisfactory diastereoselectivity and generation of des-fluoro impurities that are very difficult to purge with significant yield loss. , Fortunately, enantioselective reduction of the compound 3·HCl utilizing the catalyst system of Rh­(NBD) 2 (BF 4 ) with W003-1 has resulted in <1.0% of des-fluoro impurity 12 (Table , entry 6). Furthermore, isolation of high-purity compound 3·HCl followed by asymmetric hydrogenation also resulted in a minimal amount of trans -isomer 11 at <0.3%, which was within the specification of API synthesis.…”