Muneo Takatani

Large-scale synthesis of new cyclazines, 5-thia-1,8b-diazaacenaphthylene-3-carboxylic acid derivatives having the peripheral 12π-electron ring system

Abstract The 5-thia-1,8b-diazaacenaphthylenes ( 2 and its ester, 8 ) are new cyclazines, in which a paramagnetic ring is present in the peripheral 12π-electron ring system. Three convenient methods of preparing 8 have been developed. One involved thioglycolation of a new compound, 5-fluoroimidazo[1,2- a ]pyridine ( 6b ), followed by the Duff reaction gave 8 in 64% yield without chromatographic purification.

A Practical Synthesis of the Chronic Renal Disease Agent, 4,5-Dihydro-3H-1,4,8b-triazaacenaphthylen-3-one Derivatives, Using Regioselective Chlorination of Ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxylate with N-Chlorosuccinimide

Abstract A convenient synthesis of the chronic renal disease agent, trifluoro-N-[4-(3-oxo-3,5-dihydro-4H-1,4,8b-triazaacenaphthylen-4-yl)butyl]methanesulfonamide (1a), for large scale has been developed via ethyl 5-(chloromethyl)imidazo[1,2-a]pyridine-3-carboxylate (3), which was given by the regioselective chlorination of ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxylate (6) with N-chlorosuccinimide (NCS) using AcOEt as a solvent in 83% yield. The condensation of 3 and primary amines gave 4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one derivatives (1) in good yields. The present synthesis of 1a was accomplished in five steps from 2-amino-6-methylpyridine (4) without requiring a chromatographic method.

Efficient syntheses of a novel 5-thia-1-azacycl[3.3.2]azine ring system and 3H-1,4-diazacycl[3.3.2]azine derivatives

Novel 5-thia-1-azacycl[3.3.2]azine derivatives 1 , 5-thia-1,8b-diazaacenaphthylenes, have successfully been prepared. An X-ray crystallographic analysis of 1c revealed that the 5-thia-1-azacycl[3.3.2]azine ring system adopts a planar structure as to the internal ring nitrogen atom. The 1 H NMR spectrum for unsubstituted ring system 1d implies contribution of a paramagnetic ring current in the peripheral 12π-electron ring system. Also, 3 H -1,4-diazacycl[3.3.2]azine derivatives, 4-benzyl-4,5-dihydro-3 H -1,4,8b-triazaacenaphthylen(e)-3-ones 2 and -3,5-diones 3 were synthesized with high efficiency via 3-(trichloroacetyl)imidazo[1,2- a ]pyridine derivatives as new useful synthetic intermediates.

From East to West: A Japanese Pharma perspective on establishing a global research capability

Takeda (http://www.takeda.com) is one of the oldest Pharmaceutical companies in the world and has been the largest Japanese Pharmaceutical company for over a decade. Although many of its operations such as development and marketing have been conducted on a global basis for a number of years, research has historically been focused on in-house activities inside Japan, which have a successful track record in generating pioneer blockbuster drugs. To meet the ever-increasing challenge of maintaining a robust pipeline and a continuous stream of INDs, Takeda has embarked on a program to globalize its internal drug discovery capability through the integration of world-class research entities. We outline the strategies, opportunities and challenges of building a global research network from the perspective of a Japanese Pharmaceutical company.