An Efficient, Direct Bis-ortho-chlorination of 4-(Difluoromethoxy)aniline and Its Application to the Synthesis of BMS-665053, a Potent and Selective Pyrazinone-Containing Corticotropin-Releasing Factor-1 Receptor Antagonist

Abstract

An efficient scale-up synthesis of (S)-5-chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(difluoromethoxy)phenylamino)-pyrazin-2(1H)-one, 1 (BMS-665053), is described. This new process features a one-step direct bis-orthochlorination of 4-(difluoromethoxy)aniline with HCl and H 2 O 2 , and a palladium-catalyzed coupling of 2,6-dichloro-4-(difluoromethoxy)aniline 2 and (S)-3,5-dichloro-1-(1-cyclopropylethyl)pyrazin-2(1H)-one 3. The process was applied to the preparation of batches of 1 for preclinical toxicology studies.

An aza-Diels–Alder approach to chlorinated quinolines, benzoquinolines, and polybenzoquinolines

“…To enable the preparation of chlorinated benzoquinolines and polybenzoquinolines, we next synthesized multiple functionalized naphthalene derivatives, as shown in Scheme 1 . Initially, we directly chlorinated commercially-available 4-nitronaphthalen-1-amine according to reported protocols, 44 furnishing 2-chloro-4-nitronaphthalen-1-amine 3 in a high yield of ∼94 % ( Scheme 1 and Fig. S25 † ).…”

2(1H)-Pyrazinones from acyclic building blocks: methods of synthesis and further derivatizations

“…Starting from 3,5-dihalo-2(1H)-pyrazinones, Bristol-Myers Squibb researchers developed a family of N-3-(hetero)aryl-2(1H)-pyrazinones as corticotropin-releasing factor-1 receptor (CRF 1 R) antagonists that could be useful for the treatment of psychiatric disorders. 18,82,83,[88][89][90] The general structure 58 of this family of 2(1H)-pyrazinones and two of the most representative members, BMS-665053 (59) and BMS-764459 (11), are depicted in Fig. 3.…”

“…88,89 Based on this activity as CRF 1 R antagonists, later they prepared uorinated analogues and explored their potential as Positron Emission Tomography (PET) radioligands. 91,92 The synthesis of this family of compounds, with general structure 58, was achieved via a base-mediated reaction or a palladium-catalyzed site-selective coupling of the corresponding (hetero)aryl amine with the 3,5-dihalo-2(1H)-pyrazinone 60a or 60b (Scheme 17), 18,82,83,[88][89][90] which were prepared as shown in Scheme 16. 5-Bromo-2(1H)-pyrazinone 58b served as a starting material for the incorporation of substituents at C-5 of the pyrazinone via palladium-catalyzed cross-coupling reactions (Scheme 18).…”

“…Researchers from Bristol-Myers Squibb described an optimized procedure that allowed the synthesis of 3,5-dihalo-2(1 H )-pyrazinones in multigram quantities, involving lower reaction temperatures and the use of lower boiling point solvents. 82,83 This procedure consists of the preparation of the α-aminonitrile via the nucleophilic substitution of chloroacetonitrile with a primary amine in the presence of KI and K 2 CO 3 in MeCN followed by acidification and final treatment with oxalyl chloride or oxalyl bromide in toluene (Scheme 16).…”

“…93 The corresponding pyrazinones were prepared on multigram scale following the procedure described by Bristol Myers Squibb researchers (Scheme 16) . 82,83 The cycloaddition was carried out at 180 °C in the absence of solvent for <2 h and provided the expected 2-pyridone boronic acid derivatives as a 2 : 1 mixture of regioisomers. These could be separated using high performance counter-current chromatography (HPCC) and were further derivatized to provide a range of functionalized 2-pyridones.…”