The Development of a Robust Process for a CRF₁ Receptor Antagonist

Abstract

A scalable and robust process was developed for the preparation of pexacerfont (2), a pyrazolotriazine corticotropin-releasing factor receptor 1 antagonist (CRF1). The formation of the core hydroxypyrazolotriazine moiety was achieved through two consecutive cyclizations of a semicarbazide, employing reaction conditions that are significantly milder than those reported in the literature. Further conversion to the key chloropyrazolotriazine intermediate was accomplished through a novel catalytic process using phosphorous oxychloride as the chlorinating agent. The active pharmaceutical ingredient 2 was obtained in >99.5% purity with a 68% overall yield for the six synthetic steps.

Development of a Practical Synthesis of a Functionalized Pyrrolo[2,1-f][1,2,4]triazine Nucleus

“…The major impurity was identified as the condensate 27 (up to 10%, Scheme 5). Addition of catalytic DABCO 22 significantly increased the rate of conversion while suppressing the formation of 27, resulting in an improved yield of chloride 24 (90% in-process yield). Mechanistic studies indicated that multiple phosphoryl intermediates rapidly formed in the first stage of the reaction.…”

“…It is recommended that this compound be handled at lower than 50 °C.) This process was successfully implemented at our contract manufacturing site (five batches, 75 kg input of benzyl carbazate), providing 563 kg of the product with >99% HPLC purity: Diethyl 1-(Benzyloxycarbonylamino)-1H-pyrrole-2,3dicarboxylate (22). To a slurry of sodium diethyl oxalacetate (516 g, 2.33 mol) in toluene (8.0 L) was added glacial acetic acid (7.4 mL, 0.13 mol) at 20 °C.…”

Scalable Process Design for a PDE10A Inhibitor Consisting of Pyrazolopyrimidine and Quinoxaline as Key Units

“… This reaction condition was simple, but the low solubility of monochloride as the intermediate was taken into consideration to establish the addition method of the reagents; thereby, each quarter of 11 was added to the reaction mixture at regular intervals. Unfortunately, i -Pr 2 NEt as an additive to the reaction mixture accelerated the dimerization of 12 (up to 20% relative HPLC area %) . Dichloride 12 was crystallized from the resulting mixture after quenching the remaining POCl 3 by pouring it to another reactor containing water (584 kJ/mol per 11 ) with control of the pH of the resulting suspension (pH 4–5)…”

N‐N migration of a carbamoyl group in a pyrazole derivative revealed by NMR

“…The compound 1 is an intermediate in the synthesis of 8‐(6‐methoxy‐2‐methylpyridin‐3‐yl)‐2,7‐dimethylpyrazolo[1,5‐ a ][1,3,5]triazin‐4‐ol ( 5 ) as shown in Scheme . While monitoring the conversion of 1 to 5 (Scheme ), approximately 10% of an unknown species is observed within 1–2 h; however, it disappears over time (>3 h).…”