A facile and large-scale preparation of the antitumor agent R116010 has been developed. The new synthetic process requires four steps: (i) Friedel−Crafts reaction of N-phenyl-2-benzothiazolamine with 2-chloropropionyl chloride, (ii) conversion of the α-chloroketone into the corresponding α-(dimethylamino)ketone and resolution of the latter, (iii) reduction of the chiral aminoketone with resultant formation of the β-amino alcohol and finally (iv) conversion of the amino alcohol into the β-aminoimidazole R116010. The key strategic improvement is the crystallization-induced diastereomeric dynamic resolution of the aminoketone, leading to the chiral ketone in 90% yield and 90% enantiomeric purity. This new process improves the overall yield from 0.26 to 18.8% without tedious chromatographic separations and hazardous reaction conditions.

A scalable and safe process for the oxidative rearrangement of β-carboline to quinolone derivatives, intermediates in the synthesis of PDE-V inhibitors RWJ387273 (R301249) and RWJ444772 (R290629), has been developed.

A practical and scalable synthesis was developed that was used to prepare multikilogram batches of gastrazole, a selective cholecystokinin-2 receptor antagonist. In addition, evidence was found to indicate an amide bond-forming reaction proceeded via the isoimide of a benzimidazoleamide acid derivative.

A scalable process to produce enantiomeric R 83842, (S)-6-[(4-chlorophenyl) (1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole, is developed and described as a lecture* transcript. Cheap and safe reagents have been used. A typical procedure for oxidative destruction of aqueous cyanide waste, and stability data on N-acetyl hydrazine are provided. Special focus is on cost analysis as an important tool in developing performant synthetic methods. The method consists of preparing a chiral monosubstituted hydrazine which is ring closed to the chiral 1-alkylated 1,2,4-triazole title compound.

Alternative Synthesis of the PDE5 Inhibitor RWJ387273 (R290629). -(LEMAIRE, S.; WILLEMSENS, B.; MARKO*, I. E.; Synlett 2007, 5, 709-712; Unite Chim. Org. Med., Univ. Cathol. Louvain, B-1348 Louvain-la-Neuve, Belg.; Eng.) -Mais 30-112