Synthesis of a muscarinic receptor antagonist via a diastereoselective Michael reaction, selective deoxyfluorination and aromatic metal-halogen exchange reaction.

An efficient synthesis of a structurally unique, novel M(3) antagonist 1 is described. Compound 1 is conveniently disconnected retrosynthetically at the amide bond to reveal the acid portion 2 and the amine fragment 3. The synthesis of key intermediate 2 is highlighted by a ZnCl(2)-MAEP complex 19 catalyzed diastereoselective Michael reaction of dioxolane 7 with 2-cyclopenten-1-one (5) to establish the contiguous quaternary-tertiary chiral centers and a subsequent geminal difluorination of ketone 17 using Deoxofluor in the presence of catalytic BF(3).OEt(2). The synthesis of the amine moiety 3 is highlighted by the discovery of a novel n-Bu(3)MgLi magnesium-halogen exchange reaction for selective functionalization of 2,6-dibromopyridine. This new and practical metalation protocol obviated cryogenic conditions and upon quenching with DMF gave 6-bromo-2-formylpyridine (26) in excellent yield. Further transformations afforded the amine fragment 3 via reductive amination with 35, Pd-catalyzed aromatic amination, and deprotection. Finally, the highly convergent synthesis of 1 was accomplished by coupling of the two fragments. This synthesis has been used to prepare multi-kilogram quantities of the bulk drug.

Practical asymmetric synthesis of a selective endothelin A receptor (ETA) antagonist.

[structure: see text]. A practical, chromotography-free asymmetric synthesis was developed for the large scale preparation of an endothelin receptor antagonist 2. This synthesis includes a new efficient process for the preparation of 6-bromo-2,3-dihydrobenzofuran, a stereoselective conjugate addition of an aryllithium followed by stereospecific addition of the Grignard reagent of the top aryl bromide, and an aminophosphate-mediated sterospecific intramolecular enolate alkylation, which led to the formation of the five-membered ring bearing three contiguous asymmetric centers.

Flux growth and crystal structure of pyromorphite.

Single crystals of pyromorphite, Pb5(PO4)3Cl, were grown by standard flux growth technique with excess lead chloride used as the flux. Pyromorphite was first prepared by heating an intimate mixture of lead hydrogen phosphate and lead chloride in the molar ratio 6:4 at 100 degrees C for 1 h. A mixture of 60 wt% of pyromorphite and 40 wt% of lead chloride was heated at 850 degrees C for 15 h and then cooled at the rate of 3.4 degrees C/h. Hexagonal prismatic crystals of length 1 mm were obtained. The chemical composition has close to the theoretical value. The crystal is hexagonal, space group P6(3)/m with a = 9.9981(8), c = 7.344(1) A and Z = 2. The structure was refined to R = 0.058 and Rw = 0.053 with 502 independent reflections. The structure is in principal the same as that of barium chlorapatite; the chlorine ions occupy the (0, 0, 0) position.