Ethyl 4-(methylamino)benzoate → HCID 21465302, compound

Participants

Reaction Steps

The method of synthesizing 7-NR1R2 -MTX wherein either R1 or R2 is hydrogen, and the other is C1 -C5 alkyl, is also outlined in FIGS. 1A and 1B. This method comprises (a) reacting phosphorus oxychloride with 3-amino-6-(chloromethyl)-2-pyrazinecarbonitrile 4-oxide (1) to yield 3-amino-5-chloro-6-(hydroxymethyl)-2-pyrazinecarbonitrile (2); (b) reacting 3-amino-5-chloro-6-(hydroxymethyl)-2-pyrazinecarbonitrile with thionyl chloride to form 3-amino-5-chloro-6-(chloromethyl)-2-pyrazinecarbonitrile (4); (c) reacting 3-amino-5-chloro-6-(chloromethyl)-2-pyrazinecarbonitrile with ethyl 4-methylaminobenzoate (3) to form ethyl 4-[N-(2-amino-3-cyano-6-chloro-5-pyrazinylmethyl)-N-methylamino]benzoate (5); (d) reacting ethyl 4-[N-(2-amino-3-cyano-6-chloro-5-pyrazinylmethyl)-N-methylamino]benzoate with guanidine to form 4-[N-(2,4-diamino-7-chloro-6-pteridinylmethyl)-N-methylamino]benzoate (6); (e) reacting 4-[N-(2,4-diamino-7-chloro-6-pteridinylmethyl)-N-methylamino]benzoate with methylamine to form 4-[N-(2,4-diamino-7-methylamino-y-pteridinylmethyl)-N-methylamino]benzoic acid (7b); and (f) coupling 4-[N-(2,4-diamino-7-methylamino-y-pteridinylmethyl)-N-methylamino]benzoic acid and diethyl L-glutamate to form the diethyl ester of 7-methylamino-MTX.

Provenance & Evidence