A New Route for Manufacture of 3-Cyano-1-naphthalenecarboxylic Acid

Abstract

3-Cyano-1-naphthalenecarboxylic acid is an intermediate required for manufacture of tachykinin receptor antagonists. The 1,3-disubstitution pattern on the naphthalene skeleton complicates the synthesis of this cyano acid. Previous literature-based chemistry is unattractive for large-scale manufacture due to stoichiometric use of mercury salts, low yield, and other operational difficulties. An attractive new route has been developed by establishing the 1,3-substitution on the carbon atoms destined for only one-half of the naphthalene 2-ring system, via 3-bromocoumalate, and then building up the rest of the naphthalene ring system by Diels-Alder addition of 3-bromocoumalate to in situ-generated benzyne. The resulting 4-bromo-2-naphthoate was converted to the required cyanoacid by transformation of ester to nitrile followed by carbonylation of the bromo substituent. The new route has been scaled up successfully and offers significant advantages over previous literature chemistry in terms of improved process environmental implications, improved yield, lower cost, and improved robustness and ease of operation at larger scales of operation.

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

“…Cheap and readily available malic acid ( 1.57 ) undergoes self-condensation to yield coumalic acid under strongly acidic dehydrating conditions [37–40]. The mechanism is believed to progress by initial dehydration/decarbonylation of malic acid to give an aldehyde acid enol 1.60 which then condenses by Michael addition of the enol to the corresponding enone to give after further dehydration and lactonisation coumalic acid (Scheme 10).…”

Standard molar enthalpies of formation of 1- and 2-cyanonaphthalene

“…The 1-cyanonaphthalene is used in the synthesis of chiral derivatives of Butenafine and Terbinafine; well established antimicotic agents used among others in the treatment of dermatocytes invading skin and nails, with antifungal activity [10,11]. The 3-cyano-1-naphthalenecarboxylic acid is an intermediate required for the manufacture of tachykinin receptor antagonists; such as ZD60211, under investigation for treatment of depression, asthma, urinary incontinence, and other disease conditions [12].…”

Selective Cyclodimerization and Cyclotrimerization of Acetals Bearing Electron‐Withdrawing Groups Catalyzed by Lewis Acids

“…Recently, 3-cyano-1-naphthalenecarboxylic acid, which is an important intermediate required for the manufacture of tachykinin receptor antagonists, was synthesized using coumalic acid as a starting material. [4] In spite of the synthetic importance of coumalic acids, however, there have been few methods on the synthesis of coumalic acids so far. The most frequently used method is based on the condensation of malic acid by strong acids like fuming sulfuric acid.…”