Rational Design and Synthesis of 4-((1R,2R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile (PF-998425), a Novel, Nonsteroidal Androgen Receptor Antagonist Devoid of Phototoxicity for Dermatological Indications

Abstract

4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.

Kinetic Resolution of Secondary Alcohols Catalyzed by Chiral Phosphoric Acids

“…Herein we present the first kinetic resolution of secondary alcohols by chiral phosphoric acid catalyzed acylation 6. This method provides effective access to optically pure 2‐arylcycloalkanols,7 which are structural motifs of biologically significant compounds, such as lycorine ( 1 ),8 epicatechin ( 2 ),9 PF‐998,425 ( 3 ),10 and L‐733,060 ( 4 )11 (Scheme ).…”

Achieving Vinylic Selectivity in Mizoroki–Heck Reaction of Cyclic Olefins

“…The latter showed promising activity in reducing hair loss in animal models. [13] In the reported synthesis, classic transformations were used including addition of an organolithium reagent to a cyclic ketone and subsequent acidic dehydration. By comparison, our Heck method displayed excellent tolerance of sensitive functional groups and can avoid the use of strongly basic and acidic conditions.…”

Kinetic Resolution of Secondary Alcohols Catalyzed by Chiral Phosphoric Acids

“…[5] Herein we present the first kinetic resolution of secondary alcohols by chiral phosphoric acid catalyzed acylation. [6] This method provides effective access to optically pure 2-arylcycloalkanols, [7] which are structural motifs of biologically significant compounds, such as lycorine (1), [8] epicatechin (2), [9] 425 (3), [10] and L-733,060 (4) [11] (Scheme 2).Although Brønsted acids promote the acylation of alcohols with an acid anhydride, [12] a systematic study of their catalytic activity has not been reported. At the outset of this study, several Brønsted acids were tested in the acylation of cis-2-phenylcyclohexanol (5 a) with isobutyric anhydride (6 a).…”

“…[5] Herein we present the first kinetic resolution of secondary alcohols by chiral phosphoric acid catalyzed acylation. [6] This method provides effective access to optically pure 2-arylcycloalkanols, [7] which are structural motifs of biologically significant compounds, such as lycorine (1), [8] epicatechin (2), [9] PF-998,425 (3), [10] and L-733,060 (4) [11] (Scheme 2).…”

“…Alcohols (AE)-5 c, 5 d, and 3 with an electron-deficient aryl group were also good substrates, affording a high selectivity (s = 120-135; entries 3-5). PF-998,425 (3) [10] was obtained with a high optical purity in an almost ideal yield (entry 5). cis-Arylcycloalkanols with different ring sizes, such as (AE)-5 f and (AE)-5 g, were also resolved with a high selectivity (s = 55 and 151; entries 6 and 7, respectively).…”