Development of a Practical Synthesis of the Progesterone Receptor Antagonist 4-{[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile

Abstract

The development and implementation of a scaleable process for the manufacture of the nonsteroidal progesterone receptor antagonist 8 is described. Key aspects of the synthesis include (i) a telescoped chlorination−etherification sequence to prepare diketone 4 and (ii) separation of pyrazole regioisomers 6 and 7 through formation of their hydrogen sulfate salts and selective crystallization, followed by oxidation to 8.

The Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

“…1) is an orally active nonsteroidal PR antagonist. The synthesis of PF-02413873 has been described elsewhere (Bradley et al, 2009). RU-486/mifepristone was purchased from Sigma-Aldrich (St. Louis, MO).…”

Work-Up Optimization en Route to an Improved Process To Prepare a Progesterone Receptor Antagonist

“…We recently disclosed our initial synthetic route to the nonsteroidal progesterone receptor antagonist, 4-{[3-cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile, 5, and the application of this process to deliver ∼2.5 kg of 5 for initial clinical investigations (Scheme 1). 1 As this project advanced through development, additional supplies were required, and this route was supplied to an external vendor in order to prepare 15 kg of 5. While some minor difficulties were encountered with the early steps to prepare pyrazole 2, in particular the chlorination/displacement sequence (Scheme 1, steps a, b), these were readily resolved, and these steps performed as expected, delivering a 50% yield, comparable to that seen previously (56%).…”

Reaction of 3-(Alkylsulfanylmethyl)pentane-2,4-diones and 4-(Alkylsulfanyl)-3-(alkylsulfanylmethyl)butan-2-ones with Phenylhydrazine in the Presence of Zinc Chloride

“…Functionally substituted pyrazole ring is a structural unit of natural compounds [1] and modern medicines with a lower number of side effects [2,3]; pyrazole derivatives exhibit a broad spectrum of biological activity [2][3][4][5][6][7][8][9] and are used to obtain mixed-ligand coordination compounds necessary for homogeneous catalysis [10]. Some 4(2)-[alkyl(aryl)sulfanylmethyl]substituted 1H-pyrazoles were found to inhibit N-myris toyl transferase [11] and α-amylase [12] and act as progesterone receptor antagonists [13], antioxidants [14], fungicides [15], and efficient and selective extractants and ligands in the synthesis of sulfur-containing platinum(II) and palladium(II) complexes [16][17][18]. 4-[Alkylsulfanyl(sulfonyl)methyl]-1H-pyrazoles can be synthesized from the corresponding halogen-substituted pyrazoles [13,18].…”