Chlorodifluoromethane → 4-Difluoromethoxy-6-methoxypyrimidin-2-amine
Reaction equation
FF.[NH2:3][C:4]1[N:9]=[C:8]([O:10]C)[CH:7]=[C:6]([O:12][CH3:13])[N:5]=1.Cl[CH:15]([F:17])[F:16]>>[NH2:3][C:4]1[N:9]=[C:8]([O:10][CH:15]([F:17])[F:16])[CH:7]=[C:6]([O:12][CH3:13])[N:5]=1Participants
Procedure
Because of the difficulty of handling fluorine, which is extremely reactive, non-selective and toxic, to date no methods for the direct fluorination of alkoxypyrimidines have been disclosed. Trifluoro- and chlorodifluoromethoxypyrimidines have not been disclosed either. Difluoromethoxypyrimidines have been obtained by a circuitous route, for example by ester cleavage of 2-amino-4,6-dimethoxypyrimidine to give the corresponding 4-hydroxy compound and subsequent reaction with chlorodifluoromethane to give 2-amino-4-difluoromethoxy-6-methoxypyrimidine in 10% yield (EP-A-70,804, Example 6). Since the starting material is prepared from trichloropyrimidine by reaction with ammonia and methanol, and then the methyl group has to be eliminated again, this is not an economic route. Direct reaction of 2-amino-4,6-dihydroxypyrimidine with chlorodifluoromethane yields the corresponding 4,6-bis(difluoromethoxy) compound in 6.4% yield (EP-A-70,804, Example 3). Finally, special safety measures are required when handling harmful chlorodifluoromethane in order to prevent escape into the atmosphere.
Workup
- customto give
Sources & evidence
- ORD record
- ord-64dc62f26053481e8a6b89af308c6789
- Source dataset
- uspto-grants-1993_08
- Patent number
- US05237063
Reaction notes
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