Development of a Multikilogram Scale Synthesis of a TRPV1 Antagonist

Abstract

A highly efficient, regioselective five-step synthesis of the TRPV1 antagonist 1 is described. The coupling of piperazine 7 with dichloropyrimidine 8 proceeded via a regioselective Pd-mediated amination affording product 11 in excellent yield. Conversion of the penultimate product 14 afforded 1 through formation of a magnesium ate complex and trapping with CO2.

Impurity Occurrence and Removal in Crystalline Products from Process Reactions

“…The solvate was isolated, dissolved in DMAc/water, aq. NaOH added, and warmed to 45 °C to achieve dissolution; MsOH was added and cooled to crystallize the mesylate salt of 96 without impurity 101 …”

“…The final product was found to contain the impurity 101 in 3% quantity carried through from previous steps in which it had not been rejected by crystallization by salt formation (Scheme 22). 61 However, target compound 96 was also found to form a crystalline DMSO solvate which rejected impurity 101. Hence, the aqueous reaction extract (after washing to remove other impurities) was extracted into MTBE and the solvent switched to DMSO, which resulted in a slurry of the DMSO solvate with stirring at room temperature.…”

“…NaOH added, and warmed to 45 °C to achieve dissolution; MsOH was added and cooled to crystallize the mesylate salt of 96 without impurity 101. 61 2.7. Class I, Class II, and Class III.…”

Natural-Product-Derived Transient Receptor Potential Melastatin 8 (TRPM8) Channel Modulators

“…[4][5][6] TRPM8, which is expressed in nearly 15 percent of all somatosensory neurons, is of particular interest in terms of druggability as it was also found in the epidermis, bladder, and prostate. [6][7][8] TRPM8 is selective to calcium and is activated by a range of cold temperatures (8-28 °C) and by both natural and synthetic cooling compounds such as menthol (1), cubebol (2), and icilin (3) (Figure 1). [3][4][5][6][7][8] In addition to its role as the primary cold receptor of the somatosensory system, TRPM8 has been suggested as a potential target for cancer therapy, due to the presence of TRPM8 mRNA in prostate tissue and in elevated levels in tumours of the prostate, breast, colon, lung and skin.…”

Highly Regioselective Organocatalytic SNAr Amination of 2,4‐Dichloropyrimidine and Related Heteroaryl Chlorides

“…Generally, amination reactions of DCP are highly sensitive to changes of reaction conditions, in particular to the combination of nucleophile and base . The C‐4 position of DCP tends to be more reactive towards nucleophilic substitution, but the exclusive formation of a single regioisomer remains challenging, and this is further complicated by separation issues and loss of product . These challenges are further increased when weakly nucleophilic amines are used; most existing methods are limited to reactive primary and secondary amines.…”