Pyridine → tert-butyl(2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate

HRID 1486039Notes

Reaction equation

HRID 1486039 reaction equation
[CH3:1][C@@H:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[C@H:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].N1C=CC=CC=1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1>C(Cl)Cl>[CH3:1][C@@H:2]1[N:8]([C:34]([CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[O:35])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[C@H:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]

Participants

5

Reactant 3

HCID 1049PyridineHCID 2795505Oxane-4-carbonyl chloride2×HCID 90082343tert-butyl(2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate

Product 1

HCID 118292727tert-butyl(2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamateYield 46.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a 0° C. solution of tert-butyl(2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (prepared as in Example 1, 330 mg, 1.13 mmol) in methylene chloride (10 ml) was added pyridine (277 μl, 3.4 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (185 mg, 1.25 mmol). It was stirred at 0° C. for one hour and then warmed to room temperature and stirred overnight. After this time another portion of tetrahydro-2H-pyran-4-carbonyl chloride (252 mg, 1.70 mmol) was added and the reaction mixture was stirred at room temperature another 3 h. After this time the reaction mixture was diluted with methylene chloride (30 mL), washed with a saturated aqueous sodium bicarbonate solution (30 mL), and saturate aqueous sodium chloride solution (30 mL), the organic layer was then dried over sodium sulfate, filtered to remove the drying agent, and concentrated in vacuo. The crude material was then purified on an Intelliflash 280 system (12 g silica gel column, 20-65% ethyl acetatehexanes) to afford tert-butyl(2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (210 mg, 46%) as a white foam: LC-MS m/z 426 [M+Na]+.

Workup

  1. temperaturewarmed to room temperature
  2. stirringstirred overnight
  3. stirringthe reaction mixture was stirred at room temperature another 3 h
  4. washwashed with a saturated aqueous sodium bicarbonate solution (30 mL)
  5. concentrationsaturate aqueous sodium chloride solution (30 mL)
  6. dry with materialthe organic layer was then dried over sodium sulfate
  7. filtrationfiltered
  8. customto remove the drying agent
  9. concentrationconcentrated in vacuo
  10. customThe crude material was then purified on an Intelliflash 280 system (12 g silica gel column, 20-65% ethyl acetatehexanes)

Sources & evidence

ORD record
ord-a0b1ac09cbb8467ea95e20446c5c7a03
Source dataset
uspto-grants-2016_08
Patent number
US09422331B2

Reaction notes

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