- Syntheses of (Z)- and (E)-4-amino-2-(trifluoromethyl)-2-butenoic acid and their inactivation of γ-aminobutyric acid aminotransferase
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(Z)- and (E)-4-amino-2-(trifluoromethyl)-2-butenoic acid (4Scheme 1Proposed mechanism of inactivation of GABA-AT by 1 or 4.Scheme 2Synthesis of 4 and 5. (i) Zn, CO2, DMF; (ii) aq. HCl; (iii) (CH3)2C=CH2, concd H2SO4, CH2Cl2; (iv) KOH, EtOH; (v) allyl bromide, DMF, 100°C; (vi) O3, -78°C, CH2Cl2; (vii) Me2S; (viii) Zn-Cu, Ac2O, 4 A molecular sieves, THF, 66°C; (ix) C18 reversed-phase HPLC; (x) TFA, CH2Cl2; (xi) Dowex 50.Scheme 3Proposed mechanism of inactivation of GABA-AT by 4 with release of activated species. and 5, respectively) were synthesized and investigated as potential mechanism-based inactivators of γ-aminobutyric acid aminotransferase (GABA-AT) in a continuing effort to map the active site of this enzyme. The core α-trifluoromethyl-α,β-unsaturated ester moiety was prepared via a Reformatsky/reductive elimination coupling of the key intermediates tert-butyl 2,2-dichloro-3,3,3-trifluoropropionate and N,N-bis(tert-butoxycarbonyl)glycinal. Both 4 and 5 inhibited GABA-AT in a time-dependent manner, but displayed non-pseudo-first-order inactivation kinetics; initially, the inactivation rate increased with time. Further investigation demonstrated that the actual inactivator is generated enzymatically from 4 or 5. This inactivating species is released from the active site prior to inactivation, and as a result, 4 and 5 cannot be defined as mechanism-based inactivators. Furthermore, 4 and 5 are alternate substrates for GABA-AT, transaminated by the enzyme with K(m) values of 0.74 and 20.5 mM, respectively. Transamination occurs approximately 276 and 305 times per inactivation event for 4 and 5, respectively. The enzyme also catalyzes the elimination of the fluoride ion from 4 and 5. A mechanism to account for these observations is proposed. Copyright (C) 1999 Elsevier Science Ltd.
- Johnson, Theodore R.,Silverman, Richard B.
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- Evaluation of kilogram-scale Sonagashira, Suzuki, and Heck coupling routes to oncology candidate CP-724,714
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The synthesis of the anti-cancer compound 2-methoxy-N-(3-{4-[3-methyl-4-(6- methyl-pyridin-3-yloxy)phenylamino]quinazolin-6-yl}-E-allyl)acetainide (CP-724,714) (1) on multikilogram scale using several different synthetic routes is described. Application of the Sonogashira, Suzuki, and Heck couplings to this synthesis was investigated to identify a safe, environmentally friendly, and robust process for the production of this drug candidate. A convergent and selective synthesis of the candidate was identified which utilizes a Heck coupling of a protected allylamine to install the critical olefin.
- Ripin, David H. Brown,Bourassa, Dennis E.,Brandt, Thomas,Castaldi, Michael J.,Frost, Heather N.,Hawkins, Joel,Johnson, Phillip J.,Massett, Stephen S.,Neumann, Karin,Phillips, James,Raggon, Jeffery W.,Rose, Peter R.,Rutherford, Jennifer L.,Sitter, Barbara,Stewart III, A. Morgan,Vetelino, Michael G.,Wei, Lulin
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- Potent, orally bioavailable somatostatin agonists: Good absorption achieved by urea backbone cyclization
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Backbone cyclization of urea-based somatostatin agonists resulted in novel, orally bioavailable agonists. Binding assays confirmed that the resulting conformationally constrained cyclic ureas retained the potency of their acycyclic counterparts. SAP, studies subsequently led to highly potent analogs, selective for receptor subtype 2, and having good oral bioavailability.
- Pasternak, Alexander,Pan, Yanping,Marino, Dominick,Sanderson, Philip E.,Mosley, Ralph,Rohrer, Susan P.,Birzin, Elizabeth T.,Huskey, Su-Er Wu,Jacks, Tom,Schleim, Klaus D.,Cheng, Kang,Schaeffer, James M.,Patchett, Arthur A.,Yang, Lihu
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- NITROGENOUS HETEROCYCLIC COMPOUND, PREPARATION METHOD, INTERMEDIATE, COMPOSITION, AND APPLICATION
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A nitrogenous heterocyclic compound, a preparation method, an intermediate, a composition, and an application. The present invention provides a nitrogenous heterocyclic compound as represented by formula I, pharmaceutically acceptable salts thereof, enantiomers thereof, diastereoisomers thereof, tautomers thereof, solvates thereof, metabolites thereof, or prodrugs thereof. The compound has high inhibitory activity against ErbB2 tyrosine kinase, has good inhibitory activity against human breast cancer cells BT-474, human gastric cancer cells NCI-N87 and the like with high expression of ErbB2, and in addition has relatively weak inhibitory activity against EGFR kinase, that is, the compound is an EGFR/ErbB2 double target inhibitor that attenuates EGFR kinase inhibitory activity or a small-molecule inhibitor having selectivity for an ErbB2 target. (I)
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Paragraph 0532-0533
(2020/07/07)
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- NITROGENOUS HETEROCYCLIC COMPOUND, PREPARATION METHOD, INTERMEDIATE, COMPOSITION AND USE
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Disclosed are a nitrogenous heterocyclic compound, intermediates, a preparation method, a composition and use thereof. The nitrogenous heterocyclic compound in the present invention is as shown in formula I. The compound has a high inhibitory activity towards ErbB2 tyrosine kinase and a relatively good inhibitory activity towards human breast cancer BT-474 and human gastric cancer cell NCI-N87 which express ErbB2 at a high level, and at the same time has a relatively weak inhibitory activity towards EGFR kinase. Namely, the compound is a highly selective small-molecule inhibitor targeted at ErbB2, and hence it has a high degree of safety, and can effectively enlarge the safety window in the process of taking the drug.
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Paragraph 0202
(2019/01/17)
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- Substrate-directable heck reactions with arenediazonium salts. The regio- and stereoselective arylation of allylamine derivatives and applications in the synthesis of naftifine and abamines
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The palladium-catalyzed, substrate-directable Heck-Matsuda reaction of allylamine derivatives with arenediazonium salts is reported. The reaction proceeds under mild conditions, with excellent regio- and stereochemical control as a function of coordinating groups present in the allylamine substrate. The distance between the olefin moiety and the car-bonylic system seems to play a key role regarding the regiocontrol. The method presents itself as robust, as simple to carry out, and with wide synthetic scope concerning the allylic substrates and the type of arenediazonium employed. The synthetic potential of the method is illustrated by the short total syntheses of the bioactive compounds naftifine, abamine, and abamine SG.
- Prediger, Patricia,Barbosa, Lais Ferreira,Genisson, Yves,Correia, Carlos Roque Duarte
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experimental part
p. 7737 - 7749
(2011/12/01)
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- Synthesis of a platform to access bistramides and their analogues
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The platform C14-C40, which can be used to prepare bistramide C and 39-oxobistramide K, was synthesized in 19 steps with an overall yield of 6.2%. Furthermore, the chemoselective reduction of the ketone at C-39 was performed giving an easy access to bistramides A, B, D, K, and L. Finally, the versatility of the synthesis of the C14-C40 fragment can allow the preparation of a large variety of stereoisomers to produce bistramide analogues.
- Commandeur, Malgorzata,Commandeur, Claude,Cossy, Janine
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supporting information; experimental part
p. 6018 - 6021
(2011/12/16)
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- Rhodium-catalyzed asymmetric hydroformylation of n-allvlamides: Highly enantioselective approach to β2-amino aldehydes
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(Figure Presented) You're having a lahf I The asymmetric hydroformylation (AHF) of allylic compounds, catalyzed by a rhodium-yanphos complex, is a direct and concise route to ss2-amino aldehydes, acids, and alcohols with excellent enantioselectivity (see scheme; TON =turnover number, acac = acetylacetonate).
- Zhang, Xiaowei,Cao, Bonan,Yu, Shichao,Zhang, Xumu
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supporting information; experimental part
p. 4047 - 4050
(2010/08/07)
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- PROCESSES FOR THE PREPARATION OF N-((((PYRIDINYLOXY) -PHENYLAMINO) QUINAZOLINYL)- ALLYL) ACETAMIDE DERIVATIVES AND RELATED COMPOUNDS AS WELL AS INTERMEDIATES OF SUCH PROCESSES AND PROCESSES FOR THE PREPARATION OF SUCH INTERMEDIATES
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The invention relates to processes for preparing compounds of the formula (1) and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein R1, R3, R4, R6 R11, R13 R14 R15, R16, R17, k, I, and m are as defined herein. The present invention also relates to intermediates represented by the formula (3a) wherin R4, and R5 are independently selected from hydrogen and C1-C6alkyl; each R13, R14, R15 and R16 is independently selected from hydrogen, C1-C6alkyl and CH2OH, R17 and R18 are independently C1-C6 alkyl, and k and I are independently an integer from 1 to 3, as well as to a process for preparing these intermediates.
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- COMPOUNDS USEFUL AS ANTIPROLIFERATIVE AGENTS AND GARFT INHIBITORS
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The invention relates to compounds, such as compound (1) in equilibrium with its 4-hydroxy tautomer, and its pharmaceutically acceptable salts. Such compounds are useful as inhibitors of glycinamide ribonucleotide formyl transferase (GARFT) or as antiproliferative agents. The invention also pertains to pharmaceutical compositions and methods employing such compounds as GARFT inhibitors or antiproliferative agents. The invention also relates to compounds useful as intermediates for preparing such compounds.
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- 2-Methyltetrahydrofuran as an Alternative to Dichloromethane in 2-Phase Reactions
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2-Methyltetrahydrofuran (MTHF) has proven to be a superior solvent to methylene chloride in some 2-phase reactions from process and environmental perspectives.
- Ripin, David H. Brown,Vetelino, Michael
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p. 2353 - 2353
(2007/10/03)
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- Processes for preparing antiproliferative garft-inhibiting compounds
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The invention generally relates to compounds of the formula I, which are in equilibrium with their 4-hydroxy tautomers, and their pharmaceutically acceptable salts: STR1 where n is 0 to 2; A is S, CH2, O, NH or Se, and when n is 0, A is not CH2, and when n is 1, A is not CH2 or NH; X is a substituted or unsubstituted C1 -C3 alkyl, C2 -C3 alkenyl, C2 -C3 alkynyl or amino, or sulfur or oxygen; Ar is a substituted or unsubstituted monocyclic carbocycle or heterocycle, or fused or nonfused polycyclic carbocycle or heterocycle; and R1 and R2 are hydrogen or a moiety that forms together with the attached CO2 a readily hydrolyzable ester group. These compounds and their salts are useful as inhibitors of GARFT or as antiproliferative agents. The invention also pertains to pharmaceutical compositions and methods employing such compounds as GARFT inhibitors or antiproliferative agents. The invention also relates to compounds useful as intermediates for preparing such compounds, and to their synthesis.
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- Synthesis of N-Protected Amino Esters via Palladium Catalysed Allylic Substitution
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N-protected allylamines were prepared by palladium catalysed allylic substitution of the corresponding allyl acetates with a range of nitrogen nucleophiles.The so-formed N-protected allylamines were subjected to oxidative cleavage of the alkene to afford N-protected amino acids or esters.
- Jumnah, Roshan,Williams, Jonathan M. J.,Williams, Andrew C.
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p. 6619 - 6622
(2007/10/02)
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- AN EFFICIENT ROUTE FOR THE STEREOSELECTIVE CONVERSION OF KETONES INTO THREE-CARBONS HOMOLOGATED PRIMARY E-ALLYLAMINES: THE PALLADIUM-CATALYSED REACTION OF VINYL TRIFLATES WITH N,N-DI-TERT-BUTOXYCARBONYL-N-ALLYAMINE.
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E-Allylamines N-protected with the easily removable tert-butoxycarbonyl group are stereoselectively prepared in good to high yield through the palladium-catalysed reaction of vinyl triflates with N,N-di-tert-butoxycarbonyl-N-allylamine in the presence of AcOK and n-Bu4NCl.The reaction is very sensitive to the nature of the base.The use of bases other than AcOK has been examined and proved to be unsuccessful.
- Arcadi, A.,Bernocchi, E.,Cacchi, S.,Caglioti, L.,Marinelli, F.
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p. 2463 - 2466
(2007/10/02)
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