1802434-18-9Relevant articles and documents
Methyl-2,2-difluoro-2-(fluorosulfonyl) acetate (MDFA)/copper (I) iodide mediated and tetrabutylammonium iodide promoted trifluoromethylation of 1-aryl-4-iodo-1,2,3-triazoles
Arunachalam, Pirama Nayagam,Chandran, Thirumurugan Kothandarama,Corte, James R.,Gupta, Anuradha,Kumar, Hemantha,Mathur, Arvind,Nimje, Roshan Y.,Panja, Chiradeep,Puttaramu, Jayashankara Vaderapura
, (2020)
While several methods are available for the synthesis of a host of trifluoromethylated heterocycles, very few of them have been applied to access 4-trifluoromethylated 1,2,3-triazoles. We report herein a general methodology for the trifluoromethylation of 1-aryl-4-iodo-1, 2, 3-triazoles. Tetrabutylammonium iodide (TBAI) has been shown to provide enhanced conversion in these CuI-mediated reaction using methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (MDFA). The method exhibited broad functional group tolerance and was applied to the synthesis of a library of 1-aryl-4-trifluoromethyl-1,2,3-triazoles on the multi-gram scale.
Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy
Dilger, Andrew K.,Pabbisetty, Kumar B.,Corte, James R.,De Lucca, Indawati,Fang, Tianan,Yang, Wu,Pinto, Donald J. P.,Wang, Yufeng,Zhu, Yeheng,Mathur, Arvind,Li, Jianqing,Hou, Xiaoping,Smith, Daniel,Sun, Dawn,Zhang, Huiping,Krishnananthan, Subramaniam,Wu, Dauh-Rurng,Myers, Joseph E.,Sheriff, Steven,Rossi, Karen A.,Chacko, Silvi,Zheng, Joanna J.,Galella, Michael A.,Ziemba, Theresa,Dierks, Elizabeth A.,Bozarth, Jeffrey M.,Wu, Yiming,Crain, Earl,Wong, Pancras C.,Luettgen, Joseph M.,Wexler, Ruth R.,Ewing, William R.
, (2021/09/28)
Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7-12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2′ moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian (BMS-986177/JNJ-70033093, 17, FXIa Ki = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.
NOVEL SYNTHETIC OPTIONS TOWARDS THE MANUFACTURE OF (6R,10S)-10- {4-[5-CHLORO-2-(4-CHLORO-1H-1,2,3-TRIAZOL-1-YL)PHENYL]-6-OXO-1(6H)- PYRIMIDINYL}- 1-(DIFLUOROMETHYL)-6-METHYL-1,4,7,8,9,10-HEXAHYDRO-11,15 -(METHENO)PYRAZOLO [4,3-B] [1,7] DIAZACYCLOTETRADECIN-5(6H)-ONE
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Paragraph 00124; 00273-00276, (2020/10/21)
Highly efficient methods are provided for preparing key intermediates in the synthesis of Compound (I), which are broadly applicable and can provide selected components having a variety of substituents groups.
