Abstract: There is disclosed a process for the preparation of the pyrazine precursor of methotrexate or an N-substituted derivative thereof and/or a di(lower)alkyl ester thereof having the formula: ##STR1## wherein R and R' may each be hydrogen or a lower alkyl group, e.g., ethyl. In a preferred embodiment, the process comprises reacting in one step the compounds aminomalononitrile, .beta.-halopyruvaldoxime and a di(lower)alkyl p-methylaminobenzoyl-L-glutamate to form the di(lower)alkyl ester of the pyrazine oxide precursor of methotrexate having the formula: ##STR2## This compound is then treated with either titanium trichloride oriodoformamidinium iodide to deoxygenate the compound. There is also disclosed a process for the preparation of a di(lower)alkyl ester of methotrexate having the formula: ##STR3## by treating the di(lower)alkyl ester of the pyrazine precursor of methotrexate with a guanidine salt of a weak organic acid, e.g., guanidine acetate.

Abstract: There is disclosed a process for the preparation of the pyrazine precursor of methotrexate or an N-substituted derivative thereof and/or a di(lower)alkyl ester thereof having the formula: ##STR1## wherein R and R' may each be hydrogen or a lower alkyl group, e.g., ethyl. In a preferred embodiment, the process comprises reacting in one step the compounds aminomalononitrile, .beta.-halopyzuvaldoxime and a di(lower)alkyl p-methylaminobenzoyl-L-glutamate to form the di(lower)alkyl ester of the pyrazine oxide precursor of methotrexate having the formula: ##STR2## This compound is then treated with either titanium trichloride or iodoformamidinium iodide to deoxygenate the compound. There is also disclosed a process for the preparation of a di(lower)alkyl ester of methotrexate having the formula: ##STR3## by treating the di(lower)alkyl ester of the pyrazine precursor of methotrexate with a guanidine salt of a weak organic acid, e.g., guanidine acetate.