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.
A new, dynamic diastereomeric crystallization method has been developed, in which the mother liquors are continuously separated, racemized over a fixed-bed catalyst, and recirculated to the crystallizer in a resolution−racemization−recycle (R 3 ) process. Separating the racemization from crystallization overcomes problems of using catalysts in situ, that suffer conflicting sets of conditions, inhibition, and separation. Continuous racemization has been achieved through the covalent attachment of [IrCp*I 2 ] 2 SCRAM catalyst to Wang resin solid support to give a fixed-bed catalyst. One tertiary and a variety of secondary optically enriched amines have been racemized efficiently, with residence times compatible with the crystallization (2.25−30 min). The catalyst demonstrates lower turnover (TOF) than the homogeneous analogue but with reuse shows a long lifetime (e.g., 40 recycles, 190 h) giving acceptable turnover number (TON) (up to 4907). The slow release of methylamine during racemization of N-methyl amines was found to inactivate the catalyst, which could be partially reactivated using hydroiodic acid. Dynamic crystallization is achieved in the R 3 process through the continual removal of the more soluble diastereomer and supply of the less soluble one. The solubility of the diastereomers was determined, and the difference correlates to the rate of resolution but is also affected by the rates of racemization, crystal growth, and dissolution. A variety of cyclic and acyclic amine salts were resolved using mandelic acid (MA) and ditoluoyl tartaric acid (DTTA) with higher resolvability (S = yield × d.e.) than the simple diastereomeric crystallization alone. Comparing resolvabilities, resolutions were 1.6−44 times more effective with the R 3 process than batch, though one case was worse. Further investigation of this revealed an unusual thermodynamic switching behavior: rac-N-methylphenethylamine was initially resolved as an (S,S)-bis-alkylammonium tartrate crystal but over time became the equivalent (R,S) salt. Thermal, mixing, concentration, stoichiometry, and seeding conditions were all found to affect the onset of the switching behavior which is only associated with difunctional resolving reagents.
Three routes to 6-(trifluoromethyl)pyrid-2-one involving de noWo synthesis of the pyridine ring have been investigated which would potentially allow rapid semi-technical scale manufacture. A route starting from ethyl 4,4,4-trifluoroacetoacetate (β-keto ester route) has been demonstrated. Development of the route was attempted; however, poor yields at a number of stages and scale-up difficulties made this route unattractive for commercial use. A four-stage route starting from trifluoroacetic anhydride and an alkyl vinyl ether (TFAA route) has been developed which gives good yields and productivity for all stages. The final stage of this route is a difficult decarboxylation of a nicotinic acid derivative, but an 80% yield of the required pyridone with a purity of >99.5% could be achieved without a separate purification stage. The route was scaled up to 2000 L, and several hundred kilograms of product was prepared.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.