With the redesign of three chemical steps, the throughput of the valsartan manufacturing process could be significantly increased, and with the substitution of chlorobenzene with cyclohexane in the bromination of 4′-methyl-biphenyl-2-carbonitrile (6) to 4′bromomethyl-biphenyl-2-carbonitrile (5), halogenated solvents are no longer used in the whole valsartan production process. The alkylation of (S)-2-amino-3-methyl-butyric acid benzyl ester (8) with 4′-bromomethyl-biphenyl-2-carbonitrile (5), and the acylation of (S)-2-[(2′-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid benzyl ester (4) to (S)-2-[(2′-cyano-biphenyl-4-ylmethyl)pentanoyl-amino]-3-methyl-butyric acid benzyl ester (3) were thoroughly modified. In the acylation of 4 to 3, N-ethyldiisopropylamine was replaced by aqueous sodium hydroxide by using the conditions of the Schotten-Baumann reaction, leading to a better quality of intermediate 3. In the alkylation of 8 with 5, N-ethyldiisopropylamine was indirectly replaced by aqueous sodium hydroxide. The reaction runs under homogenous conditions with (S)-2-amino-3-methyl-butyric acid benzyl ester (8) acting as acceptor for hydrobromic acid; recycling of 8 is performed by extraction with aqueous sodium hydroxide.

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A novel industrial process for the antiepileptic drug oxcarbazepine 1 has been developed. Unlike the old process, the new process is free from halogenated solvents and can be performed in standard production equipment. It starts from commercially available 1,3-dihydro-1-phenyl-2H-indol-2-one 10. In the key step, an electrophilic ring closure reaction of 2-[(methoxycarbonyl)phenylamino] benzeneacetic acid 5 to 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxylic acid methyl ester 6 in poly phosphoric acid was applied. For the manufacture of 5, a highly efficient process using a dianion strategy was developed.

The development of the robust synthesis of quinolin-1-yl]-phenyl]propionitrile (dactolisib) on a commercial scale is described. The key step is a Pd-catalyzed Suzuki coupling of 2-[4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile to 3-quinoline boronic acid. A special focus is placed on reducing the amount of Pd catalyst used in the Suzuki coupling and purifying the crude drug substance, including removing traces of Pd.