The ACS Green Chemistry Institute® Pharmaceutical Roundtable has assembled an updated list of key research areas to highlight transformations and reaction media where more sustainable technologies would be most impactful.
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.
The process development and the kilogram-scale synthesis of linrodostat (BMS-986205, 1) are described. The synthesis features several highly efficient
telescoped processes and the use of Evans auxiliary to install a methyl-bearing
stereocenter. The target was prepared in 12 steps with 7 isolations
in an overall yield of 31%.
Diacid formation is a major problem in the conventional chemical hydrolysis of a diester to a monoester. Enzymecatalyzed hydrolysis of dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate (1) by lipases from Candida antarctica and Burkholderia cepacia gave the corresponding monoester 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid (2) in excellent yields with negligible amounts of diacid 3. About 100 kg of monoester 2 was prepared in 78% yield by hydrolysis of diester 1 with a commercially available lipase from B. cepacia. A more efficient process for the hydrolysis of 1 that give monoester 2 in 82% yield was subsequently developed using significantly lower amounts of the commercially available immobilized lipase B from C. antarctica. The commercially available immobilized lipase B from C. antarctica and porcine liver esterase were also efficient for the selective hydrolysis of dimethyl cyclobut-1-ene-1,2-dicarboxylate (4) to the corresponding monoester 5 in yields of 78% and 87%, respectively.
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