Dichloromethane → HCID 86693400, compound

HRID 575361Notes

Reaction equation

HRID 575361 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20]O)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.ClCCl.P(Br)(Br)[Br:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:20][Br:27])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1

Participants

4

Reactant 3

HCID 6344DichloromethaneHCID 24614Phosphorus tribromideHCID 86693391HCID 86693391, compound

Product 1

HCID 86693400HCID 86693400, compound

Procedure

To a solution of methyl 10-bromo-3-(hydroxymethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate in dichloromethane (1 eq) was added phosphorus tribromide. After 20 minutes of stirring at room temperature, the reaction was extracted with a saturated ammonium chloride solution and the organic layer was dried, filtered and concentrated to afford crude methyl 10-bromo-3-(bromomethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxy late. To this intermediate in a solution of N,N-dimethylformamide (5 mL/mmol) was added 2-chlorophenol (2 eq) and cesium carbonate (1.5 eq). The reaction was stirred at 50° C. and monitored by LC-MS until complete, whereupon the reaction mixture was extracted with dichloromethane and a saturated ammonium chloride solution and the organic layer was dried, filtered and concentrated to afford 147 mg (59%) crude methyl 10-bromo-3-((2-chlorophenoxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. Methyl 10-bromo-3-((2-chlorophenoxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was subjected to General Procedure L to afford 124 mg (91%) of 10-bromo-3-((2-chlorophenoxy)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide, 50 mg of which was directly reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 31 mg (55.4%) of 3-[(2-chlorophenoxy)methyl]-10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.

Workup

  1. extractionthe reaction was extracted with a saturated ammonium chloride solution
  2. customthe organic layer was dried
  3. filtrationfiltered
  4. concentrationconcentrated

Sources & evidence

ORD record
ord-7a872427cd314d6096e7579e0b020357
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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