A Practical, Protecting-Group-Free Synthesis of a PI3K/mTOR Inhibitor

We report a practical and protecting-group-free synthesis amenable to produce multikilogram amounts of PI3K/mTOR inhibitor GDC-0980. The route employed metalation/formylation and reductive amination followed by a metal catalyzed Suzuki–Miyaura cross-coupling. The metalation was performed via triarylmagnesiate intermediates allowing formylation under noncryogenic conditions. 2-Picoline·BH3 was employed to replace Na(OAc)3BH in the reductive amination and to eliminate the use of molecular sieves. A concise one-step synthesis was developed for the selective monoamidation of piperazine with (S)-lactate to produce the piperazine lactamide starting material. The boronic acid was produced from 2-amino-5-bromopyrimidine in a one-step and protecting-group-free approach. The final crystallization in 1-propanol and water afforded the API in 59% overall yield in four steps and >99% purity by HPLC.

[1]  H. Federsel.  En route to full implementation: driving the green chemistry agenda in the pharmaceutical industry , 2013 .

[2]  F. Gosselin,et al.  A Practical Synthesis of a PI3K Inhibitor under Noncryogenic Conditions via Functionalization of a Lithium Triarylmagnesiate Intermediate , 2013 .

[3]  K. Mashima,et al.  Sodium methoxide: a simple but highly efficient catalyst for the direct amidation of esters. , 2012, Chemical communications.

[4]  BinQing Wei,et al.  Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. , 2011, Journal of medicinal chemistry.

[5]  H. Noorman,et al.  Key Green Engineering Research Areas for Sustainable Manufacturing: A Perspective from Pharmaceutical and Fine Chemicals Manufacturers , 2011 .

[6]  R. Abraham,et al.  Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402. , 2010, Journal of medicinal chemistry.

[7]  Kaushik Raha,et al.  Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. , 2010, ACS medicinal chemistry letters.

[8]  D. Sabatini,et al.  mTOR signaling at a glance , 2009, Journal of Cell Science.

[9]  Jeffrey A. Engelman,et al.  Targeting PI3K signalling in cancer: opportunities, challenges and limitations , 2009, Nature Reviews Cancer.

[10]  J. Wasylak,et al.  The Process Development of Ravuconazole: An Efficient Multikilogram Scale Preparation of an Antifungal Agent(1) , 2009 .

[11]  P. Baran,et al.  Protecting-group-free synthesis as an opportunity for invention. , 2009, Nature chemistry.

[12]  M. Bradley,et al.  Amide bond formation: beyond the myth of coupling reagents. , 2009, Chemical Society reviews.

[13]  Daniela Gabriel,et al.  Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity , 2008, Molecular Cancer Therapeutics.

[14]  J. Bazureau,et al.  Deprotonation of furans using lithium magnesates , 2005 .

[15]  F. Mongin,et al.  Deprotonation of benzoxazole and oxazole using lithium magnesates. , 2005, The Journal of organic chemistry.

[16]  F. Mongin,et al.  Deprotonation of thiophenes using lithium magnesates , 2005 .

[17]  Shinya Sato,et al.  One-pot reductive amination of aldehydes and ketones with α-picoline-borane in methanol, in water, and in neat conditions , 2004 .

[18]  L. Cantley,et al.  Targeting the PI3K-Akt pathway in human cancer: rationale and promise. , 2003, Cancer cell.

[19]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.

[20]  P. Wu,et al.  Homodienyl [1,5]-Hydrogen Shift ofcis- andtrans-N-Acyl-2-alkylcyclopropylimines , 1997 .

[21]  Barry M. Trost,et al.  Atom Economy—A Challenge for Organic Synthesis: Homogeneous Catalysis Leads the Way , 1995 .

[22]  A. Tasaka,et al.  Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-b utanol and its stereoisomers. , 1993, Chemical & pharmaceutical bulletin.