Process mass intensity (PMI) is a key metric for evaluating the sustainability of a manufacturing process. Within Eli Lilly and Co. (Lilly), a process based on the molecular complexity and the projected market demand has been adopted to set PMI targets for prospective drugs. This strategy is described. PMIs for relevant molecules from publications in this journal were also calculated and compared to the model. These data illustrate the strengths and weaknesses of the model.
An efficient synthesis of 4-chloro-2-pyrrolino[2,3-d]pyrimidin-6-one was achieved in four steps starting from dimethyl malonate in 23% overall yield. This synthesis was demonstrated on 100 g scale to obtain 4-chloro-2-pyrrolino[2,3-d]pyrimidin-6-one in 98.5% purity. Similarly, 7-[(2,4-dimethoxyphenyl)methyl]-4-chloro[2,3-d]pyrimidin-6-one and 7-(α-methylbenzyl)-4-chloro[2,3-d]pyrimidin-6-one were synthesized by the reaction of methyl 2-(4,6-dichloropyrimidin-5-yl)acetate with an appropriately substituted benzylamine.
The synthesis of Pemetrexed Disodium Heptahydrate has consistently resulted in a very low level (ca. 0.02%) unknown impurity. To ensure long-term control, the identity and source of the impurity were desired. Isolation and characterization identified the impurity as the N-methyl derivative. The source was identified as the methyl groups on the peptide coupling agent, 2,6-Dimethoxy-1,3,5-triazine (CDMT). Further work assured the current conditions provide adequate control.
A practical synthesis of the title compound was accomplished by hydrogenation of 2-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-2-(pyridin-4-yl)-1H-imidazol-1-yl}-N,N-dimethylethanamine. The latter was obtained by N-alkylation of 4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}pyridine. Treatment of N-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}isonicotinamide hydrochloride with ammonium acetate in acetic acid provided 4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}pyridine. Coupling of 2-amino-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone 4-methylbenzene sulfonate with pyridine 4-carboxylic acid using either T 3 P or EDCI-HOBt provided N-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}isonicotinamide hydrochloride.
A high-yielding five-step synthesis of the title compound, methyl 7,9-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylate, starting from 2,4-dimethylaniline was developed. This synthesis involved N-alkylation of 2,4-dimethylaniline with ethyl 4-bromobutyrate to obtain ethyl 4-[(2,4-dimethylphenyl)amino]butanoate. Carbamoylation of the latter followed by hydrolysis of the resulting ester provided 4-[(2,4-dimethylphenyl)(methoxycarbonyl)amino]butanoic acid. Activation of the carboxylic acid using thionyl chloride followed by intramolecular cyclization via a Friedel-Crafts reaction using aluminum trichloride provided the title compound in good yield. Analogues of the title compound were also prepared similarly.
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