N-H ketoimines 3a-3v are readily prepared in high yield via organometallic addition to nitriles and isolated as corresponding bench-stable hydrochloride salts. Homogeneous asymmetric hydrogenation of unprotected N-H ketoimines 3a-3v using Ir-(S,S)-f-binaphane as catalyst provides chiral amines 4a-4v in 90-95% yield with enantioselectivities up to 95% ee.

This manuscript provides the results of an in-depth survey assessment of the capabilities, experience, and perspectives on continuous processing in the pharmaceutical sector, with respondents from both pharmaceutical companies and Contract Manufacturing Organizations (CMOs). The survey includes staffing (personnel), chemistry, reaction platforms, postreaction processing, analytical, regulatory, and factors that influence the adoption of continuous manufacturing. The results of the survey demonstrate that the industry has been increasing, and will continue to increase, the portion of total manufacturing executed as continuous processes with a decrease in batch processing. In general, most of the experience with continuous processing on scale have been enabling reaction chemistry, while postprocessing and analytical remain in the very early stages of development and implementation.

No abstract

The potential for N -nitrosamine impurities in pharmaceutical products presents a challenge for the quality management of medicinal products. N -Nitrosamines are considered cohort-of-concern compounds due to the potent carcinogenicity of many of the structurally simple chemicals within this structural class. In the past 2 years, a number of drug products containing certain active pharmaceutical ingredients have been withdrawn or recalled from the market due to the presence of carcinogenic low-molecular-weight N , N -dialkylnitrosamine impurities. Regulatory authorities have issued guidance to market authorization holders to review all commercial drug substances/products for the potential risk of N -nitrosamine impurities, and in cases where a significant risk of N -nitrosamine impurity is identified, analytical confirmatory testing is required. A key factor to consider prior to analytical testing is the estimation of the daily acceptable intake (AI) of the N -nitrosamine impurity. A significant proportion of N -nitrosamine drug product impurities are unique/complex structures for which the development of low-level analytical methods is challenging. Moreover, these unique/complex impurities may be less potent carcinogens compared to simple nitrosamines. In the present work, our objective was to derive AIs for a large number of complex N -nitrosamines without carcinogenicity data that were identified as potential low-level impurities. The impurities were first cataloged and grouped according to common structural features, with a total of 13 groups defined with distinct structural features. Subsequently, carcinogenicity data were reviewed for structurally related N -nitrosamines relevant to each of the 13 structural groups and group AIs were derived conservatively based on the most potent N -nitrosamine within each group. The 13 structural group AIs were used as the basis for assigning AIs to each of the structurally related complex N -nitrosamine impurities. The AIs of several N -nitrosamine groups were found to be considerably higher than those for the simple N , N -dialkylnitrosamines, which translates to commensurately higher analytical method detection limits.

Pure (Z)-enamines readily prepared from beta-ketoesters and amides using (S)-phenylglycine amide were hydrogenated with very high diastereoselectivities (up to 200:1) using heterogeneous catalysis. Hydrogenolytic cleavage of the (S)-phenylglycine amide afforded the corresponding chiral beta-aminoesters and amides. The high geometrical purity of the (Z)-enamine and a simple activation procedure for the PtO2 catalyst are essential in achieving high selectivity.

The scope of thermolytic, N-Boc deprotection was studied on 26 compounds from the Pfizer compound library, representing a diverse set of structural moieties. Among these compounds, 12 substrates resulted in clean (≥95% product) deprotection, and an additional three compounds gave ≥90% product. The thermal de-Boc conditions were found to be compatible with a large number of functional groups. A combination of computational modeling, statistical analysis, and kinetic model fitting was used to support an initial, slow, and concerted proton transfer with release of isobutylene, followed by a rapid decarboxylation. A strong correlation was found to exist between the electrophilicity of the N-Boc carbonyl group and the reaction rate.

No abstract

Taranabant (1) is a cannabinoid-1 receptor (CB1R) inverse agonist that was recently in late-stage clinical development for the treatment of obesity. The previously employed synthesis exhibited a number of shortcomings for continuing development, and in this paper we report an improved synthesis of the target molecule that is suitable for large-scale implementation. Palladium-catalyzed amidation of an enol tosylate afforded a stereodefined tetrasubstituted enamide, and asymmetric hydrogenation thereof provided the target molecule.