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Synthesis of methotrexate‐1‐ 15 N and methotrexate‐4‐ 15 NH 2
Author(s) -
Degraw Joseph I.,
Ryan Kenneth J.,
Tracy Michael,
Colwell William T.,
Arnold John R. P.,
Roberts Gordon C. K.
Publication year - 1989
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.2580271004
Subject(s) - chemistry , ammonium hydroxide , hydrolysis , amide , medicinal chemistry , carboxamide , ring (chemistry) , nuclear chemistry , organic chemistry
This paper describes an application of the pterin synthesis of Taylor and co‐workers for preparation of methotrexate specifically labelled at the N 1 ‐ring nitrogen and at the 4‐amino group with 99 atom percent 15 N. Oximination of ethyl cyanoacetate‐ 15 N followed by reduction afforded ethyl 2‐aminocyanoacetate‐C 15 N ( 3 ). Condensation with 3‐bromopyruvaldoxime and 4‐methylaminobenzoic acid afforded 2‐amino‐3‐carbethoxy‐5‐N‐methyl‐p‐carboxy‐anilinomethylpyrazine‐1‐oxide‐2‐ 15 NH 2 ( 4 ). Treatment of 4a with ammonium hydroxide at room temperature gave the 3‐carboxamide ( 5a ). Reduction of the N‐oxide (PCl 3 ), esterification, and dehydration of the amide (POCl 3 ) afforded the 2‐amino‐3‐cyano‐pyrazine benzoate ester ( 8 ). Ring closure with guanidine followed by benzoate ester hydrolysis, glutamate coupling and hydrolysis of the glutamate diester yielded methotrexate‐1‐ 15 N ( 12a ). Amination of the unlabeled 2‐amino‐3‐carbethoxy pyrazine intermediate ( 4b ) with 15 N‐labelled ammonium hydroxide gave the 15 N‐carboxamide ( 5b ) which was carried through the process described above to afford methotrexate‐4‐ 15 NH 2 ( 12b ).