Ammonia → 10-bromo-3-(cyclopropanecarboxamidomethyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide

HRID 575323Notes

Reaction equation

HRID 575323 reaction equation
[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13](C=O)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[C:23]([O-:26])(=O)[CH3:24].[NH4+].[C:28]([BH3-])#[N:29].[Na+].N.[CH2:33](O)[CH3:34]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:28][NH:29][C:23]([CH:24]4[CH2:34][CH2:33]4)=[O:26])=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1

Participants

6

Reactant 5

HCID 222AmmoniaHCID 702EthanolHCID 517165Ammonium AcetateHCID 5003444Sodium cyanoborohydrideHCID 8669316110-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide

Product 1

HCID 8669335910-bromo-3-(cyclopropanecarboxamidomethyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide

Procedure

10-bromo-9-fluoro-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (50 mg) was added into a saturated solution of ammonium acetate in Ethanol (2.7 mL) at which point sodium cyanoborohydride (3 eq) and 30% aqueous ammonia solution (1 mL) were added. The mixture was stirred at reflux for 1 hr, until reaction was deemed complete by LC-MS. The reaction was cooled to room temperature, concentrated to dryness and suspended in Methanol. The slurry was loaded onto a biotage scx-2 cartridge, rinsed with Methanol and crude 3-(aminomethyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was then eluted with a 4N ammonia in methanol solution and concentrated to an orange oil. The crude intermediate was reacted with cyclopropane carboxylic acid similarly to as described in Example 2 to afford crude 10-bromo-3-(cyclopropanecarboxamidomethyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was directly reacted with 2-Methyl-3-butyne-ol via General Procedure E to afford 12 mg (33%) of 3-[(cyclopropanecarbonylamino)methyl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.

Workup

  1. additionwere added
  2. temperatureat reflux for 1 hr, until reaction
  3. concentrationconcentrated to dryness
  4. washrinsed with Methanol and crude 3-(aminomethyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide
  5. washwas then eluted with a 4N ammonia in methanol solution
  6. concentrationconcentrated to an orange oil
  7. customThe crude intermediate was reacted with cyclopropane carboxylic acid similarly

Sources & evidence

ORD record
ord-a93c110df05c426ca7508e619c189e61
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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