1180132-17-5Relevant articles and documents
Development of a Leuckart-Wallach Reaction in Flow for the Synthesis of Abemaciclib
Frederick, Michael O.,Pietz, Mark A.,Kjell, Douglas P.,Richey, Rachel N.,Tharp, Gregg A.,Touge, Taichiro,Yokoyama, Naota,Kida, Michio,Matsuo, Toshiyasu
, p. 1447 - 1451 (2017)
The development of a route for a key building block in the synthesis of abemaciclib is described. The route proceeds through a Leuckart-Wallach reductive amination in flow followed by an Ullmann amination with aqueous ammonia. Key to the Leuckart-Wallach reductive amination was the addition of trimethyl orthoformate for water removal, running the reaction continuously in a pipes-in-series reactor for rapid heat-up, and building a kinetic model to understand time and temperature parameters for the feed tank storage. The product of the Leuckart-Wallach reductive amination is forward processed in batch and telescoped with the Ullmann amination and subsequent workup. The development resulted in a robust process that has successfully been run on the production scale.
Discovery of novel and orally bioavailable CDK 4/6 inhibitors with high kinome selectivity, low toxicity and long-acting stability for the treatment of multiple myeloma
Yuan, Kai,Kuang, Wenbin,Chen, Weijiao,Ji, Minghui,Min, Wenjian,Zhu, Yasheng,Hou, Yi,Wang, Xiao,Li, Jiaxing,Wang, Liping,Yang, Peng
supporting information, (2021/12/09)
Multiple myeloma (MM) ranks second in malignant hematopoietic cancers, and the most common anti-MM drugs easily generate resistance. CDK4/6 have been validated to play determinant roles in MM, but no remarkable progress has been obtained from clinical trials of CDK4/6 inhibitors for MM. To discover novel CDK6 inhibitors with better potency and high druggability, structure-based virtual screening was conducted to identify compound 10. Further chemical optimization afforded a better derivative, compound 32, which exhibited strong inhibition of CDK4/6 and showed high selectivity over 360+ kinases, including homologous CDKs. The in vivo evaluation demonstrated that compound 32 possessed low toxicity (LD50 > 10,000 mg/kg), favorable bioavailability (F% = 51%), high metabolic stability (t1/2 > 24 h) and strong anti-MM potency. In summary, we discovered a novel CDK4/6 inhibitor bearing favorable drug-like properties and offered a great candidate for MM preclinical studies.
Sustainable synthesis of potential antitumor new derivatives of Abemaciclib and Fedratinib via C-N cross coupling reactions using Pd/Cu-free Co-catalyst
Khorsandi, Zahra,Keshavarzipour, Fariba,Varma, Rajender S.,Hajipour, Abdol R.,Sadeghi-Aliabadi, Hojjat
, (2021/11/24)
Herein, chitosan as an inexpensive, abundant, and biodegradable bio-material, produced from a key constituent of the exoskeletons of crustaceans, was used to generate the cobalt-based magnetic silica nanocomposite for the performance of the C-N cross-coupling reaction as the main step of the synthesis of Abemaciclib and Fedratinibs. Several derivatives of these recently FDA-approved anti-cancer drugs were synthesized for the first time by using Pd/Cu-free co-catalyzed under both, the conventional heating and microwave (MW) irradiation conditions. The potential anticancer activity of synthesized compounds was investigated by molecular docking study.
