Hydroxylamine → HCID 178513246, compound
Reaction equation
BrC1C=CC2C3N(C=C(C4N(C(C)C)N=C(C)N=4)N=3)CCOC=2C=1.[Br:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:34])[CH:27]=1.[NH2:35][OH:36]>>[Br:25][C:26]1[CH:33]=[CH:32][C:29]([C:30](=[NH:31])[NH:35][OH:36])=[C:28]([F:34])[CH:27]=1Participants
Procedure
Scheme 10 shows the synthesis of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine III from 4-bromo-2-fluorobenzonitrile 11. Addition of hydroxylamine to the nitrile of 11 gave 4-bromo-2-fluoro-N-hydroxybenzimidamide 24. Michael addition of 24 to ethyl propiolate gave ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25. Heating 25 in a high-boiling solvent such as toluene, xylene, ethylbenzene, or diphenyl oxide gave cyclized imidazole, ethyl 2-(4-bromo-2-fluorophenyl)-1H-imidazole-4-carboxylate 26, along with by-product pyrimidine, 2-(4-bromo-2-fluorophenyl)pyrimidin-4-ol. Alternatively, 25 can be cyclized to 26 with catalytic Lewis acids such as Cu(I) or Cu(II) salts. Alkylation of 26 with a 2-hydroxyethylation reagent, such as 1,3-dioxolan-2-one, in a base, such as N-methylimidazole or cesium carbonate, gave ethyl 2-(4-bromo-2-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazole-4-carboxylate 27. Ring-cyclization of 27 with an aqueous basic reagent, such as potassium hydroxide, lithium hydroxide, and methyl tributylammonium hydrochloride, gave 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid 28. Addition of acetamidine to 28 with triphenylphosphine gave 9-bromo-N-(1-iminoethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide 29. Ring-cyclization of 29 with isopropylhydrazine hydrochloride 4 in acetic acid gave 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine III.
Sources & evidence
- ORD record
- ord-fae53f8ec2c84e4bbd9d456ccf64278f
- Source dataset
- uspto-grants-2016_04
- Patent number
- US09303043B2
Reaction notes
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