ethyl 4-(methylamino)benzoate → HCID 21465302, compound
Reaction equation
[NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9]Cl)=[C:6]([Cl:8])[N:7]=1.[CH3:13][NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1>>[NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9][N:14]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH3:13])=[C:6]([Cl:8])[N:7]=1Participants
Procedure
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.
Sources & evidence
- ORD record
- ord-b327f958547a4d689d8ae77bc4a95657
- Source dataset
- uspto-grants-1997_12
- Patent number
- US05698556
Reaction notes
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