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3,3-Dichloro-1-azaallylic anions, generated by deprotonation of alpha,alpha-dichloroketimines 10 with lithium diisopropylamide, reacted with N-sulfonylaldimines 7 to produce the Mannich-type products N-[2,2-dichloro-3-(N-alkylimino)-1,3-diarylpropyl]benzenesulfonamides 11. The latter stable compounds were hydrolyzed at the imino functionality to afford N-[2,2-dichloro-3-oxo-1,3-diarylpropyl]benzenesulfonamides 12 in excellent yields. N-[2,2-Dichloro-3-(N-alkylimino)-1,3-diarylpropyl]benzenesulfonamides 11 were cyclized to cis-3-aryl-2-chloro-2-imidoylaziridines 19 in 81-99% yield with high diastereoselectivity, representing a novel and readily available class of stable 2-chloroaziridines. Finally, a highly stereoselective entry to 2-(aminomethyl)-2-chloroaziridines 27 (70-98% yield; de > 95-99) was worked out from the reaction of cis-3-aryl-2-chloro-2-imidoylaziridines 19 and sodium cyanoborohydride in the presence of acetic acid. The latter 2-(aminomethyl)aziridines 27 represent stereochemically defined small azaheterocyclic rings which were scarcely reported in the literature.

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An efficient scalable route to synthesize the enantiomerically pure tert-butyl-(1R,4S,6R)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate is described. Compared to the original routes, significant improvements were made by using an innovative approach starting from commercially available chiral lactone. In this approach, one of the key steps described is an elegant epimerization/hydrolysis of the undesired diastereoisomer avoiding tedious purification. The chemistry has been scaled up to produce kilogram amounts of tert-butyl-(1R,4S,6R)-4-(hydroxymethyl)-3azabicyclo[4.1.0]heptane-3-carboxylate in 43% yield over nine chemical transformations.

The synthetic potential of lithio 3-halo-1-azaallylic anions as building blocks in organic chemistry and especially in heterocyclic chemistry will be highlighted by the synthesis of functionalized imines, obtained after reaction of 3-halo-1-azaallylic anions with het- eroatom-substituted electrophiles. Thus, the latter generated functionalized imines are suitable building blocks for the synthesis of a whole range of heterocycles and physiologically active compounds, including agrochemicals and pharmaceuticals. 3-Halo-1-azaallylic anions were used in the synthesis of N-alkyl-3,3-dichloroazetidines, 2,3-disubstituted pyrroles, piperidines, 2-substituted pyridines, 2-alkoxytetrahydrofurans,etc., from which a large range of useful and interesting chemicals can be produced, e.g., 2-azetines and 9-alkyl- 2-phenyl-3a-beta,4,6,7,8,9,9a-beta,9b-beta-octahydro-1H-pyrrolo [3,4,h]quinoline-1,3-diones. The utility of the present methodology is demonstrated by the synthesis of the pheromone (S)-manicone, the sulfur-containing flavor compound 2-[(methylthio)methyl ]-2-butenal, and some agrochemical and pharmaceutical compounds.

The development and scale-up of an optimized synthesis for a novel drug candidate for depression and anxiety is presented. The updated synthesis represents a convergent and efficient four-stage approach to the API, overcoming high cost of goods (COG), general lack of convergence, and low yield of previous routes. A lower cost of goods resulted from using 3-nitrosalicylaldehyde as a starting material and introducing the expensive side chain (2-methyl-5-(piperazin-1-yl)quinoline) at a later stage. Green chemistry principles were applied when a direct amidation enabled a straightforward conversion of the 4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxylate to the corresponding amide in the last step. In addition, the total number of stages was reduced from seven to four, and solvent usage was greatly minimized. The modified synthesis was demonstrated on a kilogram pilot scale, allowing the isolation of the API in 17% overall yield with the required purity.

The family of phosphodiesterase (PDE) enzymes hydrolyse cyclic nucleotides, cAMP and cGMP, leading to their inactivation as intracellular second messengers. Inhibition of these enzymes leads to an elevation of levels of cyclic nucleotides in the cell and prolongs their action on downstream signaling pathways. PDE4, of which there are four subtypes, is widely expressed throughout the brain but is also abundant in the periphery in inflammatory and immune cells, in the gastrointestinal tract, and in cardiac myocytes. GSK356278 1 is a potent, selective, and competitive inhibitor of PDE4 enzymes currently under investigation for the treatment of CNS disorders. The initial synthetic route developed by Medicinal Chemistry Department, used several hazardous and/or expensive reagents and harsh conditions and gave relatively low yields. By targeted process of research and development plus application of analytical techniques to identify byproduct and extensive route scouting, a novel synthetic route for 1 has been developed. This contribution reports the optimisation of the chemical synthesis of 1 to develop a large-scale process suitable for its synthesis.