4-Methylmorpholine → 9-Fluoro-5-(2-hydroxyethyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]diazepine-1-carboxylic acid 2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylamide

HRID 558952Notes

Reaction equation

HRID 558952 reaction equation
[F:1][C:2]1[C:12]2[N:11]([C:13](=[O:36])[NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:30][CH2:29][CH2:28][CH2:27][C:26]5[CH:31]=[CH:32][CH:33]=[CH:34][C:25]4=5)=[O:23])=[CH:18][C:17]=3[CH3:35])[CH2:10][CH2:9][C:8](=[O:37])[N:7]([CH2:38][C:39](O)=[O:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[BH4-].[Na+].[Cl-].[NH4+]>C1COCC1.O>[CH3:35][C:17]1[CH:18]=[C:19]([C:22]([N:24]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]3[CH:31]=[CH:32][CH:33]=[CH:34][C:25]2=3)=[O:23])[CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][C:13]([N:11]1[CH2:10][CH2:9][C:8](=[O:37])[N:7]([CH2:38][CH2:39][OH:40])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:12]1=2)=[O:36]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 25517Ammonium ChlorideHCID 4311764Sodium borohydrideHCID 11699686{6-Fluoro-5-[2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylcarbamoyl]-2-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl}-acetic acid

Product 1

HCID 115195689-Fluoro-5-(2-hydroxyethyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]diazepine-1-carboxylic acid 2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of {6-fluoro-5-[2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylcarbamoyl]-2-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl}acetic acid from Example 2 (170 mg, 0.30 mmol) in THF (6 ml) were added N-methylmorpholine (47 μl, 0.43 mmol) and isobutyl chlroroformate (57 μl, 0.43 mmol) while cooling in an ice/water bath. The mixture was stirred for 1 h, filtered and added to a solution of sodium borohydride (27 mg, 0.70 mmol) in water (1.5 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature slowly and stirred for 2 h. Saturated ammonium chloride solution (2 ml) was added and the mixture evaporated in vacuo. The residue was partitioned between choroform and water and the organic layer was washed with brine, dried over magnesium sulphate and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant methanol:dichloromethane 6:94) to give a white solid; yield 104 mg, 64%.

Workup

  1. temperaturewhile cooling in an ice/water bath
  2. filtrationfiltered
  3. temperaturewhile cooling in an ice/water bath
  4. stirringstirred for 2 h
  5. customthe mixture evaporated in vacuo
  6. customThe residue was partitioned between choroform and water
  7. washthe organic layer was washed with brine
  8. dry with materialdried over magnesium sulphate
  9. customevaporated in vacuo
  10. customThe residue was purified by flash chromatography on silica (eluant methanol:dichloromethane 6:94)
  11. customto give a white solid

Sources & evidence

ORD record
ord-a316d339508643829dbe890e0b3d972a
Source dataset
uspto-grants-2011_11
Patent number
US08063038B2

Reaction notes

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