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New Brunswick, United States

Guz N.R.,Exelixis Inc. | Leuser H.,Chemical Development | Goldman E.,Exelixis Inc.
Organic Process Research and Development | Year: 2013

Route scouting, process development, and multikilogram syntheses of an IGF-1R/Src/Bcr-Abl inihibitor are reported. Key aspects of the developed route are a regioselective [3 + 2] isoxazole formation on a pyrimidine core and a selective SNAr addition of an aryl amine to a symmetrical dichloro substituted pyrimidine. The route contains six synthetic steps and was demonstrated twice on scale, delivering 4.6 and 11.2 kg (25% and 16% overall yield), for Phase I clinical studies. © 2013 American Chemical Society. Source

Zhu D.,Scripps Research Institute | Yang G.,Scripps Research Institute | He J.,Scripps Research Institute | Chu L.,Scripps Research Institute | And 5 more authors.
Angewandte Chemie - International Edition | Year: 2015

2,4,6-Trimethoxypyridine is identified as an efficient ligand for promoting a Pd-catalyzed ortho-C-H amination of both benzamides and triflyl-protected benzylamines. This finding provides guidance for the development of ligands that can improve or enable PdII-catalyzed Csp2-H activation reactions directed by weakly coordinating functional groups. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Amin R.,Chemical Development | Chen J.-X.,Chemical Development | Cotterill I.C.,Fermentation and Biotransformations | Emrich D.,Chemical Development | And 9 more authors.
Organic Process Research and Development | Year: 2013

A practical synthesis targeting the C16-C20 segment of the endogenous metabolite Resolvin E1 (RvE1) is described. The original route was revised to avoid the use of source-constrained raw materials and chemistries that were problematic on larger scale. The revised route utilizes commercially available (E)-1-chloropent-1-en-3-one as the key raw material to replace (S)-glycidol. The (E)-vinyl iodide functionality was installed by an addition/elimination sequence to prepare the segment required for a subsequent Sonogashira coupling. The chiral secondary hydroxyl group at C18 was established by Corey-Bakshi-Shibata (CBS) reduction followed by lipase-catalyzed acetylation to achieve chiral purity in excess of 98% ee. The revised route offered a viable multikilogram process to support early clinical production of this pro-resolution therapeutic agent. © 2013 American Chemical Society. Source

Mortensen M.A.,Chemical Development | Guo C.,Discovery RandD | Reynolds N.T.,Chemical Development | Wang L.,Chemical Development | And 8 more authors.
Organic Process Research and Development | Year: 2012

Process development and production of a novel tubulin inhibitor are described. The desired API was obtained through selective iodination of the 12′ position of vinblastine and subsequent thiomethylation. Most of the impurities were identified, and process parameters were adjusted to control such impurities. The optimized process was scaled up under cGMP conditions to afford 230 g of the desired API. © 2012 American Chemical Society. Source

Deshpande P.P.,Chemical Development | Singh J.,Process Research and Development | Pullockaran A.,Process Research and Development | Kissick T.,Process Research and Development | And 25 more authors.
Organic Process Research and Development | Year: 2012

A practical synthesis of the SGLT-2 inhibitor β-C-aryl-d-glucoside (1) has been developed. The route employed 2,3,4,6-tetra-O-trimethlysilyl-d- glucano-1,5-lactone as the key chiral building block, prepared efficiently from the commercially available, inexpensive raw materials, d-gluconolactone and trimethylsilyl chloride. The salient step in the synthesis is the Lewis acid-mediated stereoselective reduction of a methyl C-aryl peracetylated glycoside using a silyl hydride to set the stereochemistry of the crucial anomeric chiral center. Several novel cocrystalline complexes of 1 with l-phenylalanine and l-proline were discovered. Single-crystal structures of these complexes and several synthetic intermediates have been determined. The l-phenylalanine complex was developed and used to purify and isolate the API. All steps were implemented at multikilogram scale. © 2012 American Chemical Society. Source

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