- Inexpensive Radical Methylation and Related Alkylations of Heteroarenes
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A simple method for the introduction of a methyl and higher aliphatic group to various heteroarenes using very inexpensive reagents is described. It is based on the radical addition of a carboxylic xanthate followed by decarboxylation. Depending on the heteroarene structure, the decarboxylation can be spontaneous or induced by heating in N,N-dimethylacetamide or N-methyl pyrrolidone in a microwave oven.
- Huang, Qi,Zard, Samir Z.
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supporting information
p. 1413 - 1416
(2018/03/09)
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- Synthesis of substituted 5-bromomethyl-4-nitroimidazoles and use for the preparation of the hypoxia-selective multikinase inhibitor SN29966
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5-Bromomethyl-4-nitroimidazoles have utility as bioreductive trigger precursors for the preparation of hypoxia-selective prodrugs. Here we describe an efficient two-step synthesis of 5-(bromomethyl)-1-methyl-4-nitro-1H- imidazole, a preferred precursor, employing an N-bromosuccinimide mediated radical bromination. Use of this precursor to prepare SN29966, a promising hypoxia-selective irreversible pan-ErbB inhibitor is reported along with the preparation of four other prodrug candidates. 5-Bromomethyl-4-nitroimidazole analogues bearing electron-donating and electron-withdrawing substituents at the N-1 and C-2 positions are also described.
- Lu, Guo-Liang,Ashoorzadeh, Amir,Anderson, Robert F.,Patterson, Adam V.,Smaill, Jeff B.
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p. 9130 - 9138
(2013/09/24)
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- PRODRUG FORMS OF KINASE INHIBITORS AND THEIR USE IN THERAPY
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The invention provides novel prodrug compounds comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, where the compound carries a positive charge. In preferred embodiments, the compounds are of Formula I: where: X is any negatively charged counterion; R1 is a group of the formula —(CH2)nTr, where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and —(CH2)nTr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6; R2, R3 and R4 may each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R2)(R3)(R4)N, or two of R2, R3, and R4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R2, R3 and R4 may be absent and two of R2, R3 and R4 form an aromatic heterocyclic amine ring of a kinase inhibitor. The compounds of the invention are useful in treating proliferative diseases such as cancer.
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Page/Page column 36; 83
(2010/10/03)
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- Carbanion Stabilization in C,N-Dimethylnitroimidazoles
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Kinetics of base-catalyzed exchange of C-methyl protons have been investigated for the six position isomers of C,N-dimethylnitroimidazoles (at 60 deg C in D2O-CD3OD, 1:1).Rates of exchange were based on the decrease in 1H NMR signals relative to those for the nonexchanging N-methyl groups.Values of kOD covered a range of 5*104; in 0.01 N NaOD, values of t1/2 range from 2.8 s to 38 h.The greatest kinetic acidity was found in 1,5-dimethyl-4-nitroimidazole and the least in 1,2-dimethyl-4-nitro- and 1,4-dimethyl-2-nitroimidazole.In the latter two compounds, the methyl and nitro groups have a "meta" relationship, their resistance to exchange indicates weak resonance stabilization of the respective carbanions.The value of kOD for 1,5-dimethyl-4-nitroimidazole (1485 M-1 min-1) is 4.8*106 as great as that for o-nitrotoluene but only 27-fold less than that for nitromethane.The result suggests that there may be significant localization in the 4,5-double bond of N-substituted imidazoles.The order of kinetic acidities for the C-methyl groups is consistent with the order of reactivities of the same compounds in aldol condensations.
- Rav-Acha, C.,Cohen, Louis A.
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p. 4717 - 4720
(2007/10/02)
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