- Development of an Efficient Synthesis of (2-Aminopyrimidin-5-yl) Boronic Acid
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A practical and cost-effective synthesis of (2-aminopyrimidin-5-yl) boronic acid 1b has been developed. Key features of the synthesis include the inexpensive in situ protection of the amine via bis-silylation using TMSCl followed by metal-halogen exchange using n-BuLi and trapping with B(Oi-Pr)3. The water-soluble boronic acid is isolated by a well-designed acid-base sequence providing the target in 80% yield and high purity for the two-step process. The large-scale (15 kg) implementation of a Suzuki-Miyaura borylation to form the pinacol boronic ester is also described.
- Patel, Nitinchandra D.,Zhang, Yongda,Gao, Joe,Sidhu, Kanwar,Lorenz, Jon C.,Fandrick, Keith R.,Mulder, Jason A.,Herbage, Melissa A.,Li, Zhibin,Ma, Shengli,Lee, Heewon,Grinberg, Nelu,Song, Jinhua J.,Busacca, Carl A.,Yee, Nathan K.,Senanayake, Chris H.
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- PROCESS FOR MAKING THIENOPYRIMIDINE COMPOUNDS
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Process methods for making the dual mTOR/PI3K inhibitor GDC-0980, named as (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, having the structure: and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof.
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Page/Page column
(2014/04/18)
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- PROCESS FOR THE PREPARATION OF BORONIC ACID INTERMEDIATES
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The present invention relates to an improved process for the preparation of 2- pyrimidine-5-boronic acid of formula (I). or salts or esters thereof.
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Page/Page column 36; 40; 45; 46; 48; 49
(2014/12/09)
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- PROCESS FOR THE PREPARATION OF BORONIC ACID INTERMEDIATES
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The present invention relates to a process for the preparation of 2-amino-pyrimidine-5-boronic acid of formula (I). or salts or esters thereof.
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Paragraph 0295-0299
(2014/11/13)
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- Identification of NVP-BKM120 as a potent, selective, orally bioavailable class i PI3 kinase inhibitor for treating cancer
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Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
- Burger, Matthew T.,Pecchi, Sabina,Wagman, Allan,Ni, Zhi-Jie,Knapp, Mark,Hendrickson, Thomas,Atallah, Gordana,Pfister, Keith,Zhang, Yanchen,Bartulis, Sarah,Frazier, Kelly,Ng, Simon,Smith, Aaron,Verhagen, Joelle,Haznedar, Joshua,Huh, Kay,Iwanowicz, Ed,Xin, Xiaohua,Menezes, Daniel,Merritt, Hanne,Lee, Isabelle,Wiesmann, Marion,Kaufman, Susan,Crawford, Kenneth,Chin, Michael,Bussiere, Dirksen,Shoemaker, Kevin,Zaror, Isabel,Maira, Sauveur-Michel,Voliva, Charles F.
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supporting information; experimental part
p. 774 - 779
(2011/12/03)
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- New pyrimidylboronic acids and functionalized heteroarylpyrimidines by Suzuki cross-coupling reactions
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We report the synthesis of 2-chloro-5-pyrimidylboronic acid (6) and 2-amino-5-pyrimidylboronic acid (8) by lithium-halogen exchange followed by reaction with triisopropylborate. Their reactivity with heteroaryl halides in Suzuki-Miyaura cross-coupling reactions has been evaluated. New highly functionalized 5-heteroarylpyrimidine derivatives 24-33 (heteroaryl = quinoline, pyridine, pyrimidine, pyrazine, thiophene, benzothiazole) have been obtained in synthetically useful yields. The X-ray structure of 6 reveals extensive intermolecular O-H...N hydrogen bonding in the crystal. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
- Clapham, Kate M.,Smith, Amy E.,Batsanov, Andrei S.,McIntyre, Laura,Pountney, Adam,Bryce, Martin R.,Tarbit, Brian
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p. 5712 - 5716
(2008/09/17)
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