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Synthesis of [C 2 H 3 ]methotrexate and [C 2 H 3 ]7‐hydroxymethotrexate

Elmore, Charles S. ; Dean, Dennis C. ; Zhang, Yong ; Gibson, Carter ; Jenkins, Herb ; Jones, Allen N. ; Melillo, David G.

Journal of Labelled Compounds and Radiopharmaceuticals, January 2002, Vol.45(1), pp.29-36 [Peer Reviewed Journal]

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  • Title:
    Synthesis of [C 2 H 3 ]methotrexate and [C 2 H 3 ]7‐hydroxymethotrexate
  • Author: Elmore, Charles S. ; Dean, Dennis C. ; Zhang, Yong ; Gibson, Carter ; Jenkins, Herb ; Jones, Allen N. ; Melillo, David G.
  • Description: Stable label analogues of methotrexate (MTX) and 7‐hydroxymethotrexate (7‐OH‐MTX) were required for use as internal standards for LC/MS quantitation. A minimum incorporation of stable isotopes to produce a mass increase of 3 in the non‐glutamate derived portion of the molecule was necessary for adequate MS detection. The commercial availability of des‐methyl MTX (aminopterin, ) made methylation with CHI an attractive option. Surprisingly, all attempted methylations of and the dimethyl ester of failed to provide a significant amount of the methylated aniline, apparently due to attenuated reactivity of the secondary amine towards alkylation. However, reductive amination of diacid with CHO and NaBHCN gave [CH]MTX in 52% yield. A previously reported method was utilized to convert [CH]MTX to [CH]7‐OH‐MTX. Preparative HPLC purification of [CH]7‐OH‐MTX resulted in extremely low recovery from the column; this was resolved by switching to a column with few free silanols. Copyright © 2002 John Wiley & Sons, Ltd.
  • Is Part Of: Journal of Labelled Compounds and Radiopharmaceuticals, January 2002, Vol.45(1), pp.29-36
  • Identifier: ISSN: 0362-4803 ; E-ISSN: 1099-1344 ; DOI: 10.1002/jlcr.537
  • Subjects: Methotrexate ; 7‐Hydroxymethotrexate ; Rofecoxib ; Cyclooxygenase Ii ; Reductive Amination
  • Language: English

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