A Practical Synthesis of the PDE4 Inhibitor, KW-4490

Abstract

A practical and scalable synthesis of a PDE4 inhibitor KW-4490 (1) was developed. This improved synthesis features the construction of the 1-arylcyclohexene ( 9) by the Diels-Alder reaction followed by a newly established Brønsted acid-promoted hydrocyanation. Subsequent crystallization-induced dynamic resolution enabled the high-yield production of the desired cis-isomer (cis-8). The synthesis was achieved in seven steps in 37% overall yield.

Transition Metals Catalyzed Element-Cyano Bonds Activations

“…Representatively, one of the interesting cases is shown below in Scheme 10. During the synthesis of PDE 4 inhibitor, TMSCN is the source of cyano group (Scheme 10) (14). On the top of Scheme 10, Lewis acid catalyzed dehydroxylation of free hydroxyl group occurred and corresponding replacement with cyano group was realized in excellent yield.…”

“…Several notable examples of palladium or nickel catalyzed regio-and stereo-selective addition reactions to alkynes with several X-CN groups have been previously reported. These included: X = H (hydro-cyanation), 6–13 X = C (carbo-cyanation) (18–38), X = Si (cyano-silylation) (14–17), X = Ge (cyano-germylation) (47,48), X = Sn (cyano-stannylation) (49–52), X = B (cyano-boration) (39–46), and X = S (cyano-thiolation) (53–56). …”

“…Other element-cyano bond cleavages, such as silyl-cyano (14–17), germyl-cyano (47,48), stannyl-cyano (49–52), boryl-cyano (39–46), sulfur-cyano (53–56), and halo-cyano (57,58) have also been achieved, a useful synthetic transformation of oxy-cyano has not been reported until recently (59). …”

Determination of Sudan IV in hot chilli powder with luminol/dissolved oxygen chemiluminescence system

“…KW‐4490 ( 333 ), a PDE4 inhibitor, was a clinical candidate investigated in 2002 by Kyowa Hakko Kirin for the treatment of asthma 190. The low yield and poor reproducibility of the first generation approach and the need to isolate the desired compound by column chromatography called for an alternative route (see Scheme S10 in the Supporting Information).…”

“…The low yield and poor reproducibility of the first generation approach and the need to isolate the desired compound by column chromatography called for an alternative route (see Scheme S10 in the Supporting Information). A new process based on a DA cycloaddition was thus developed, which proved robust enough for the delivery of kilogram amounts of the drug (Scheme ) 190. The unstable 2‐aryl‐1,3‐butadiene 330 required for the build‐up of the cyclohexene ring within KW‐4490 was prepared in situ by dehydration of benzyl vinyl alcohol 329 through a DA reaction with ethyl acrylate as the dienophile in the presence of a catalytic amount of PPTS.…”