95082-75-0Relevant articles and documents
Synthesis of Monoamides of Methotrexate from L-Glutamic Acid Monoamide t-Butyl Esters
Antonjuk, David J.,Boadle, Deborah K.,Cheung, H.T.Andrew,Tran, Trung Q.
, p. 1989 - 2004 (2007/10/02)
Analoques of methotrexate (amethopterin) (1) with α- or γ-monoamide functions were synthesized starting with t-butyl L-isoglutamine (12a), t-butyl L-glutamine (22a), or the appropriate N'-alkyl or N'N'-dialkyl analoques (12b-k), (22d), (22k), (22l), and (22m).The corresponding N-benzyloxycarbonyl compounds (11) and/or (21) from which the above L-glutamic acid derivatives were obtained were generally synthesized by mixed-anhydride coupling of N-benzyloxycarbonyl-L-glutamic acid (9) with the appropriate amine, conversion into the t-butyl ester, and chromatographic separation.The resulting α-monoamide γ-t-butyl ester (11) and γ-monoamide α-t-butyl ester (21) are unambiguously distinguished by mass spectrometry and 13C n.m.r. spectroscopy.Factors which affect the γ-amide/α-amide product ratio are discussed.The N-deprotected L-glutamic acid monoamide t-butyl esters (12) or (22) were individually coupled to N-trifluoroacetyl-p-methylaminobenzoic acid, and the resulting α- or γ-monoamide t-butyl esters (13) or (23) of N-(p-methyl(trifluoroacetyl)aminobenzoyl)-L-glutamic acid was hydrolysed.The N-deprotected product, viz. t-butyl N-(p-methylaminobenzoyl)-L-glutamate α- or γ-monoamide (14) or (24) was converted into the appropriate methotrexate-monoamide t-butyl ester (15) or (25), and thence the desired methotrexate-monoamide (16) or (26), by reaction with 2,4-diamino-6-bromomethylpteridine (17) or by the Taylor procedure.Features of the mass and 13C n.m.r. spectra of the intermediates are discussed.
