2,6-Lutidine → N-methoxycarbonyl ethoxycarboimidoylbiphenyl benzimidazole
Reaction equation
CCO[C:4]1[N:12](CC2C=CC(C3C=CC=CC=3C3N=C(O)ON=3)=CC=2)[C:11]2[C:10](C(O)=O)=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.N1C2C=CC=CC=2NC=1.[CH2:44]([O:46][C:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[NH:48])[CH3:45].[CH2:61]([O:63][C:64](Cl)=[O:65])C.CC1C=CC=C(C)N=1>>[N:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[NH:12][CH:4]=1.[CH3:61][O:63][C:64]([N:48]=[C:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[O:46][CH2:44][CH3:45])=[O:65]Participants
Procedure
According to another method disclosed in U.S. '054 for the preparation of azilsartan (Scheme 2), ethoxycarboimidoyl biphenyl benzimidazole derivative of compound of formula (6) reacts with ethylchloroformate in presence of 2,6-dimethylpyridine as base gives N-methoxycarbonyl ethoxycarboimidoylbiphenyl benzimidazole derivative of compound of formula (7). The resulting N-methoxycarbonyl ethoxycarboimidoyl biphenyl benzimidazole compound of formula (7) can be converted to 1,2,4-oxadiazol derivative compound of formula (4) by either of the two ways: (i) by treating the compound of formula (7) with hydroxylamine hydrochloride in presence of sodium methoxide; (ii) by reacting compound of formula (7) with methyl chloroformate in presence of 2,4,6-trimethylpyridine to obtain a residue, which on further addition to a mixture of hydroxylamine hydrochloride and sodium methoxide under reflux yielded compound of formula (4). 1,2,4-Oxadiazol derivative compound of formula (4) thus obtained is further hydrolyzed in presence of a base to obtain azilsartan (5).
Sources & evidence
- ORD record
- ord-2b23953323634ccd9e52768dcd0cf107
- Source dataset
- uspto-grants-2016_01
- Patent number
- US09233955B2
Reaction notes
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