Hydrochloric Acid → 4-[(4-methylpiperazin-1-yl)methyl]benzoic Acid Dihydrochloride

HRID 1258161Notes

Reaction equation

HRID 1258161 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

6

Reactant 3

HCID 313Hydrochloric AcidHCID 531671-MethylpiperazineHCID 742344-(Chloromethyl)benzoic acid

Product 1

HCID 103353464-[(4-methylpiperazin-1-yl)methyl]benzoic Acid Dihydrochloride

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 702EthanolSolvent

Procedure

Referencing scheme 1 below, the synthesis 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, 3-acetylpyridine (3) is first reacted with phenyl chloroformate at nitrogen position and then regioselectively alkylated using Grignard reagents and catalytic amounts of copper (I) iodide to obtain intermediate dihydropyridine. The dihydropyridine was further deprotected to obtain 3-acetyl-4-methyl-pyridine(4) (Tanis et al., 1996). Product (4) was treated with methyl dimethoxyforamide to give 3-dimethylamino-1-(3-(4-methyl-pyridyl)-2-propene-1-one (5). Nitrate salt (2) is treated with (5) and sodium hydroxide in refluxing isopropanol to give N-(2-Methyl-5-nitrophenyl)-4-(3-(4-methyl-pyridyl))-2-pyrimidine-amine (6) which is subsequently hydrogenated with 10% palladium on carbon to give N-(2-Methyl-5-aminophenyl)-4-(3-4-methyl-pyridyl)-2-pyrimidine-amine (7). The first WBZ1 synthesis consists 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-(4-methyl)-pyridyl)-2-pyrimidine-amine (7) in pyridine affords the Gleevec analog WBZ1 (PCT publication WO2004108699).

Workup

  1. customThe first WBZ1 synthesis

Sources & evidence

ORD record
ord-6841bb7fd5204372b616a74877c37c82
Source dataset
uspto-grants-2013_06
Patent number
US08466154B2

Reaction notes

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