Hydrochloric Acid → 4-[(4-methylpiperazin-1-yl)methyl]benzoic Acid Dihydrochloride
Reaction equation
[CH:1]1[C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=[C:3]([C:9]([OH:11])=[O:10])[CH:2]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[ClH:19]>[Pd].C(O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:9]([OH:11])=[O:10])=[CH:2][CH:1]=2)[CH2:15][CH2:14]1.[ClH:8].[ClH:19]Participants
Procedure
The synthesis of WBZ4, as shown in scheme 3 below, begins with treatment of 2-methyl-5-nitroaniline (1) with 65% nitric acid in ethanol followed by the addition of cyanoamide to give the corresponding 2-methyl-5-nitroaniline-guanidine nitrate (2). Once completed, nicotinate (3) was first treated with sodium hydrate and refluxed with ethyl acetate to form methyl 6-methylnicotinylacetate. The intermediate acetate was then hydrolyzed to form 3-Acetyl-6-methylpyridine (4). The product (4) was treated with methyl dimethoxyforamide to give 3-dimethylamino-1-(3-(6-methyl-pyridyl)-2-propene-1-one (5). The nitrate salt (2) is treated with (5) and sodium hydroxide in refluxing isopropanol to give N-(2-Methyl-5-nitrophenyl)-4-(3-(6-methyl-pyridyl))-2-pyrimidine-amine (6) which is subsequently hydrogenated with 10% palladium on carbon to give N-(2-Methyl-5-aminophenyl)-4-(3-6-methyl-pyridyl)-2-pyrimidine-amine (7). The WBZ4 synthesis will consist of the reaction of α-chloro-p-toluylic acid (8) with 4-methyl-piperazine in ethanol followed by treatment with concentrated HCl to give the corresponding dihydrochloride 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (9) which is subsequently treated with thionyl chloride to give the corresponding acid chloride dihydrochloride (10). Subsequent condensation with N-(2-Methyl-5-aminophenyl)-4-(3-(6-methyl)-pyridyl)-2-pyrimidine-amine (7) in pyridine affords Formula 5 (WBZ4).
Workup
- customThe WBZ4 synthesis
Sources & evidence
- ORD record
- ord-54ba5ca357354676abf60520bbd039b5
- Source dataset
- uspto-grants-2013_06
- Patent number
- US08466154B2
Reaction notes
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