Thiazole → 4-[5-Fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzoic acid
Reaction equation
S1C=CN=C1.C[O:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH:16](Br)[F:17])=[CH:11][CH:10]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28](=[S:30])[NH2:29])[CH2:24][CH2:23]1>>[F:17][C:16]1[S:30][C:28]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[N:29][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([C:8]([OH:7])=[O:20])=[CH:10][CH:11]=1Participants
Procedure
The starting material, methyl 4-acetylbenzoate, is commercially available. Bromination at the α-position to the ketone is achieved with bromine in acetic acid to provide the desired 4-(2-bromo-acetyl)-benzoic acid methyl ester. Subsequent treatment of 4-(2-bromo-acetyl)-benzoic acid methyl ester with potassium fluoride in the presence of 18-crown-6 at 90° C., provides 4-(2-fluoro-acetyl)-benzoic acid methyl ester after column chromatography. Repeated bromination at the α-position to the ketone is achieved with bromine in acetic acid to provide the desired 4-(2-bromo-2-fluoro-acetyl)-benzoic acid methyl ester. Formation of the thiazole is typically carried out by heating 4-(2-bromo-2-fluoro-acetyl)-benzoic acid methyl ester with 4-methylpiperazine-1-carbothioamide at 70° C. for 2 hours. On cooling, the desired 4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]benzoic acid methyl ester precipitates out. Deprotection of the methyl ester is carried out using a lithium hydroxide solution and the desired acid, 4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzoic acid is generally obtained in good yield as the dihydrochloride salt on workup with hydrochloric acid.
Workup
- temperatureOn cooling
- customthe desired 4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]benzoic acid methyl ester precipitates out
Sources & evidence
- ORD record
- ord-a8cdfd34bb884d2c91b2a8efb2f7c7a1
- Source dataset
- uspto-grants-2013_04
- Patent number
- US08426421B2
Reaction notes
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