101894-60-4Relevant articles and documents
Gas phase retro-Michael reaction resulting from dissociative protonation: Fragmentation of protonated warfarin in mass spectrometry
Zhang, Jia,Chai, Yunfeng,Jiang, Kezhi,Yang, Huameng,Pan, Yuanjiang,Sun, Cuirong
, p. 1059 - 1064 (2012)
A mass spectrometric study of protonated warfarin and its derivatives (compounds 1 to 5) has been performed. Losses of a substituted benzylideneacetone and a 4-hydroxycoumarin have been observed as a result of retro-Michael reaction. The added proton is initially localized between the two carbonyl oxygens through hydrogen bonding in the most thermodynamically favorable tautomer. Upon collisional activation, the added proton migrates to the C-3 of 4-hydroxycoumarin, which is called the dissociative protonation site, leading to the formation of the intermediate ion-neutral complex (INC). Within the INC, further proton transfer gives rise to a proton-bound complex. The cleavage of one hydrogen bond of the proton-bound complex produces the protonated 4-hydroxycoumarin, while the separation of the other hydrogen bond gives rise to the protonated benzylideneacetone. Theoretical calculations indicate that the 1, 5-proton transfer pathway is most thermodynamically favorable and support the existence of the INC. Both substituent effect and the kinetic method were utilized for explaining the relative abundances of protonated 4-hydroxycoumarin and protonated benzylideneacetone derivative. For monosubstituted warfarins, the electron-donating substituents favor the generation of protonated substituted benzylideneacetone, whereas the electron-withdrawing groups favor the formation of protonated 4-hydroxycoumarin. Copyright
Synthesis and pharmacological investigations of some 4-hydroxycoumarin derivatives
Manolov, Ilia,Danchev, Nicolay D.
, p. 83 - 94 (2003)
The synthesis of ten coumarin derivatives of 4-hydroxycoumarin and various unsaturated ketones and aldehydes is described. The structures of the synthesized compounds were confirmed by IR, 1H-NMR, and mass-spectral data. Acute toxicity studies of the compounds were performed on mice by oral and intraperitoneal administration. A comparative pharmacological study of the in vivo anticoagulant effects of the derivatives with respect to warfarin, showed that the compounds have anticoagulant activity. Compounds 4-hydroxy-3-[1-phenyl-2-(4′-chlorobenzoyl)-ethyl]-2H-1-benzopyran-2-one 2b, 4-hydroxy-3-[1-(4-fluorophenyl)-3-oxobutyl]-2H-1-benzopyran-2-one 3a, and 3,3′-p-bromobenzylidene-bis-(4-hydroxy-2H-1-benzopyran-2-one) 4 b showed slight acute toxicity and a greater anticoagulant effect than warfarin.
First aromatic amine organocatalysed activation of α,β-unsaturated ketones
Sonsona, Isaac G.,Marqués-López, Eugenia,Gimeno, M. Concepción,Herrera, Raquel P.
, p. 12233 - 12240 (2019/08/12)
This work provides an unprecedented example of a chiral aromatic amine used to activate α,β-unsaturated ketones in asymmetric aminocatalysis. Chiral aromatic diamine VII has been efficiently employed, as a proof of concept, in the Michael addition reaction between benzylideneacetones (1a-f) and coumarins (2a-d). The reaction gives rise to warfarin derivatives 3 with promising results using this family of catalysts for the first time. The additional studies performed supported the bifunctional mode of activation of the chiral catalyst VII and the covalent nature of the interactions between the catalyst VII and benzylideneacetones 1.
Atom-economic synthesis of optically active warfarin anticoagulant over a chiral mof organocatalyst
Shi, Tao,Guo, Zhiwei,Yu, Huixian,Xie, Jianwu,Zhong, Yijun,Zhu, Weidong
supporting information, p. 2538 - 2543 (2013/10/21)
A novel chiral metal-organic framework (MOF) organocatalyst has been developed, based on readily available MIL-101 and the chiral primary diamine (1R,2R)-1,2-diphenylethylenediamine, by the post-synthetic modification. Over the developed chiral heterogeneous catalyst the asymmetric synthesis of (S)-warfarin with high enantioselectivity can be fulfilled on a gram-scale (2.8 g) with excellent yield (92%) at low cost, making the synthesis method an ideal alternative to existing methods. Copyright
Highly enantioselective synthesis of Warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalysts
Dong, Juan,Du, Da-Ming
, p. 8125 - 8131 (2012/11/06)
An efficient enantioselective Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones catalysed by primary amine-phosphinamide bifunctional catalysts has been developed. This reaction afforded Warfarin and its analogs in moderate to excellent yie
Microbial models of mammalian metabolism: Conversion of warfarin to 4'-hydroxywarfarin using Cunninghamella bainieri
Rizzo,Davis
, p. 183 - 189 (2007/10/02)
Warfarin, an anticoagulant and 'metabolic probe' for cytochrome P-450 isozyme multiplicity, is metabolized to 4'-hydroxywarfarin, a principle mammalian metabolite, using the fungus Cunninghamella bainieri (UI-3065). The metabolite was isolated from cell suspension cultures and characterized by analytical (TLC, HPLC, GC-MS) and spectral (HRMS, EI-MS, PMR) comparisons with authentic 4'-hydroxywarfarin. The mechanism of aromatic hydroxylation was examined in C. bainieri using 4'-deuterowarfarin. The absence of a primary isotope effect (K(H)/K(D) = 1.13), migration and retention of deuterium in the phenolic product [80% migration and retention (M&R)], and inhibition of the hydroxylation by carbon monoxide (93% inhibition in a 50:50 CO:O2 atmosphere) are consistent with a cytochrome P-450-mediated hydroxylation involving the classic NIH shift (arene oxide) pathway.
