- Enantiospecific Synthesis of (3 R,4 R)-1-Benzyl-4-fluoropyrrolidin-3-amine Utilizing a Burgess-Type Transformation
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Manufacture of an EGFR inhibitor required the asymmetric synthesis of a key 3,4-trans-substituted pyrrolidine suitable for pilot-plant scale. The initial synthetic route utilized reagents and intermediates that posed safety concerns due to their energetic potential and then required supercritical fluid chromatography to access the desired single enantiomer. Burgess-type reagents provide tremendous utility in organic synthesis but see limited use on large scales because of their high cost and instability. Nevertheless, extensive process development led to a scale-friendly process where in situ formation of a Boc-Burgess reagent enabled access to a chiral cyclic sulfamate from inexpensive materials. ReactIR monitoring was used to study intermediate stability and enabled processing on a multikilogram scale. The sulfamate was converted to trans-3-fluoro-4-aminopyrrolidine 1 with complete stereospecificity. Intermediate crystallinity offered purity control points where byproducts and impurities were rejected, avoiding the need for chromatography.
- Widlicka, Daniel W.,Gontcharov, Alexander,Mehta, Ruchi,Pedro, Dylan J.,North, Robert
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Read Online
- AMINOPYRROLOTRIAZINES AS KINASE INHIBITORS
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The disclosure relates to compounds of formula I which are useful as kinase modulators including RIPK1 modulation. The disclosure also provides methods of making and using the compounds for example in treatments related to necrosis or inflammation as well as other indications.
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Page/Page column 170
(2019/08/12)
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- Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants
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Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechani
- Planken, Simon,Behenna, Douglas C.,Nair, Sajiv K.,Johnson, Theodore O.,Nagata, Asako,Almaden, Chau,Bailey, Simon,Ballard, T. Eric,Bernier, Louise,Cheng, Hengmiao,Cho-Schultz, Sujin,Dalvie, Deepak,Deal, Judith G.,Dinh, Dac M.,Edwards, Martin P.,Ferre, Rose Ann,Gajiwala, Ketan S.,Hemkens, Michelle,Kania, Robert S.,Kath, John C.,Matthews, Jean,Murray, Brion W.,Niessen, Sherry,Orr, Suvi T. M.,Pairish, Mason,Sach, Neal W.,Shen, Hong,Shi, Manli,Solowiej, James,Tran, Khanh,Tseng, Elaine,Vicini, Paolo,Wang, Yuli,Weinrich, Scott L.,Zhou, Ru,Zientek, Michael,Liu, Longqing,Luo, Yiqin,Xin, Shuibo,Zhang, Chengyi,Lafontaine, Jennifer
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supporting information
p. 3002 - 3019
(2017/04/24)
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- SELECTIVELY SUBSTITUTED QUINOLINE COMPOUNDS
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Embodiments of the disclosure relate to selectively substituted quinoline compounds that act as antagonists or inhibitors for Toll-like receptors 7 and/or 8, and their use in pharmaceutical compositions effective for treatment of systemic lupus erythematosus (SLE) and lupus nephritis.
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Paragraph 0447; 0452
(2015/04/21)
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- BENZIMIDAZOLYL-METHYL UREA DERIVATIVES AS ALX RECEPTOR AGONISTS
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The present invention relates to benzimidazolyl-methyl urea derivatives of formula (I), wherein n, D, E, R1, R2, R3, R4, R6, R7, R8 and R9 are as defined in the description, their preparation and their use as pharmaceutically active compounds.
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Page/Page column 126
(2015/02/25)
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- PURINE DERIVATIVES
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The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Q, G, ring A, ring B, R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, and m are defined herein. The novel purine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.
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- FLUORINATED BRIDGED SPIRO[2.4]HEPTANE DERIVATIVES AS ALX RECEPTOR AGONISTS
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The present invention relates to fluorinated bridged spiro[2.4]heptane derivatives of formula (I), wherein n and R1 are as defined in the description, their preparation and their pharmaceutically active compounds.
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Page/Page column 33
(2013/12/03)
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- Design of novel aminopyrrolidine factor Xa inhibitors from a screening hit
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Starting from a hit identified by focused screening, 3-aminopyrrolidine factor Xa inhibitors were designed. The binding mode as determined by X-ray structural analysis as well as the pharmacokinetic behaviour of selected compounds is discussed.
- Zbinden, Katrin Groebke,Anselm, Lilli,Banner, David W.,Benz, Joerg,Blasco, Francesca,Decoret, Guillaume,Himber, Jacques,Kuhn, Bernd,Panday, Narendra,Ricklin, Fabienne,Risch, Philippe,Schlatter, Daniel,Stahl, Martin,Thomi, Stefan,Unger, Robert,Haap, Wolfgang
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body text
p. 2787 - 2795
(2009/10/17)
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