Challenging couplings of hindered carboxylic acids with non-nucleophilic amines to form amide bonds can be accomplished in high yields, and in many cases, with complete retention of the adjacent stereogenic centers using the combination of N, N, N', N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI). This method allows for in situ generation of highly reactive acyl imidazolium ions, which have been demonstrated to be intermediates in the reaction. The reagent delivers high reactivity similar to acid chlorides with the ease of use of modern uronium reagents.

4-Cyanobenzenesulfonamides of secondary amines were found to cleave to the parent amine cleanly under the action of thiol and base. This feature readily lends itself to the use of this motif as an amine protecting/activating group within a broader context of amine synthesis. The crystalline sulfonamides could be further elaborated by alkylation and arylation similarly to nitrobenzenesulfonamides. The sulfonamides could withstand conditions that functionalize nitroarenes, such as reductions and vicarious nucleophilic substitution reactions.

We report research and development conducted to enable the safe implementation of a highly enantioselective palladium-catalyzed desymmetrization of a meso−bis-ester using trimethylsilylazide (TMSN 3 ) as the nucleophile. This work is used as a case example to discuss safe practices when considering the use of azide reagents or intermediates, with a focus on the thermodynamic and quantitative analysis of the hazards associated with hydrazoic acid (HN 3 ).

A regioisomeric impurity is routinely formed during preparation of the first intermediate of the fosinopril sodium side chain. This first step, the radical-initiated condensation of 4-phenyl-1-butene (1) and aqueous hypophosphorous acid, provides low levels of the phosphinic acid (8) resulting from carbon−phosphorus bond formation to the internal olefin carbon. This impurity was isolated by preparative chromatography, and its structure was proven by independent synthesis. Subsequent reactions of 8 in the two following steps produce the corresponding regioisomeric impurities. Pure samples of these impurities were prepared for HPLC analysis to determine potential impact on the quality of intermediates downstream. The initial regioisomer averages 2 area % in manufacturing batches, and the levels of regioisomeric impurities diminish sharply with sequential conversion to further side-chain intermediates. After two steps, the levels of the regioisomeric impurities have been less than 0.08 area % in production batches; therefore, no significant amount of side-chain regioisomeric impurities (i.e., <0.1%) is expected to be found in production batches of fosinopril sodium side chain.

5-Fluoro-3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1H-indole dihydrochloride (1) facilitates 5-HT neurotransmission and was an antidepressant drug candidate. The development of a safe, rugged process for the large-scale, chromatography-free preparation of this compound is described. The main areas of optimization included a Fischer indole synthesis, preparation and chlorination of a monohydroxypyrimidine, and coupling of the resultant fragments to prepare the drug substance.