149549-11-1Relevant articles and documents
Discovery of N -(4-(3-(2-Aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine (AMG 900), A Highly Selective, Orally Bioavailable Inhibitor of Aurora Kinases with Activity against Multidrug-Resistant Cancer Cell Lines
Geuns-Meyer, Stephanie,Cee, Victor J.,Deak, Holly L.,Du, Bingfan,Hodous, Brian L.,Nguyen, Hanh Nho,Olivieri, Philip R.,Schenkel, Laurie B.,Vaida, Karina R.,Andrews, Paul,Bak, Annette,Be, Xuhai,Beltran, Pedro J.,Bush, Tammy L.,Chaves, Mary K.,Chung, Grace,Dai, Yang,Eden, Patrick,Hanestad, Kelly,Huang, Liyue,Lin, Min-Hwa Jasmine,Tang, Jin,Ziegler, Beth,Radinsky, Robert,Kendall, Richard,Patel, Vinod F.,Payton, Marc
, p. 5189 - 5207 (2015)
Efforts to improve upon the physical properties and metabolic stability of Aurora kinase inhibitor 14a revealed that potency against multidrug-resistant cell lines was compromised by increased polarity. Despite its high in vitro metabolic intrinsic cleara
Synthesis of 4-Substituted Phthalazin-1(2H)-ones from 2-Acylbenzoic Acids: Controlling Hydrazine in a Pharmaceutical Intermediate through PAT-Guided Process Development
Mennen, Steven M.,Mak-Jurkauskas, Melody L.,Bio, Matthew M.,Hollis, L. Steven,Nadeau, Kelly A.,Clausen, Andrew M.,Hansen, Karl B.
, p. 884 - 891 (2015/07/27)
A simple one-pot, two-step process for the conversion of 2-acylbenzoic acids to phthalazin-1(2H)-ones was developed. A robust process was required that delivered the final isolated solid with consistently low levels of residual hydrazine, for further processing to the final drug substance. An in situ formed intermediate was critical to control reactivity and allowed for the controlled crystallization that prevented entrainment of hydrazine. Leveraging Process Analytical Technology (PAT), we investigated the reaction profile with in situ IR and Power Compensation Calorimetry (PCC) to aid development prior to a successful scale-up.
Practical access to metallo thiophenes: Regioselective synthesis of 2,4-disubstituted thiophenes
Asselin, Sylvie M.,Bio, Matthew M.,Langille, Neil F.,Ngai, Ka Yi
supporting information; experimental part, p. 1427 - 1431 (2011/09/20)
This report describes a protocol for functionalization of thiophenes, utilizing a regioselective magnesiation mediated by commercial Grignard reagents and catalytic 2,2,6,6-tetramethylpiperidine. This metalation provides practical access to metallo thiophenes, avoiding cryogenic conditions, prolonged reaction times, and prohibitively expensive reagents. Application to a target thiophene-phthalazinone 6 was accomplished by addition of 2-magnesio-4- methylthiophene to phthalic anhydride, providing the product with >40:1 regioselectivity. This also solved a chemoselectivity issue encountered with analogous lithio-thiophene reagents and cyclic anhydrides, or with magnesio-thiophene generated by simultaneous lithium-to-magnesium transmetalation/anhydride acylation. These alternative in situ transmetalation sequences were plagued by an age effect dictated by the kinetic solubility of MgCl2/THF complexes.
