Methanol → tert-butyl (8R,9aR)-8-[(5-cyclopropylpyrazin-2-yl)oxy]-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate

HRID 1050311Notes

Reaction equation

HRID 1050311 reaction equation
[OH:1][C@H:2]1[CH2:19][N:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@H:4]2[CH2:3]1.CC(C)([O-])C.[K+].Br[C:27]1[CH:32]=[N:31][C:30]([CH:33]2[CH2:35][CH2:34]2)=[CH:29][N:28]=1.CO>O1CCCC1>[CH:33]1([C:30]2[N:31]=[CH:32][C:27]([O:1][C@H:2]3[CH2:19][N:5]4[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C@H:4]4[CH2:3]3)=[N:28][CH:29]=2)[CH2:35][CH2:34]1

Participants

6

Reactant 4

HCID 887MethanolHCID 23665647Potassium tert-butoxideHCID 457876352-Bromo-5-cyclopropylpyrazineHCID 86723190tert-butyl (8R,9aR)-8-hydroxy-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate

Product 1

HCID 86723196tert-butyl (8R,9aR)-8-[(5-cyclopropylpyrazin-2-yl)oxy]-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylateYield 58.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

tert-Butyl (8R,9aR)-8-hydroxy-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (60 mg, 0.222 mmol, 1.0 equivalent, Example 46, Part D) was dissolved in tetrahydrofuran (1.0 mL). Potassium tert-butoxide (0.311 mL, 0.311 mmol, 1 M in tetrahydrofuran, 1.4 equivalents) was added at room temperature, and the resulting yellow solution was stirred for five minutes. Then 2-bromo-5-cyclopropylpyrazine (57.4 mg, 0.289 mmol, 1.3 equivalents) was added as a solution in tetrahydrofuran (0.5 mL), and the reaction mixture was stirred for 16 hours at the same temperature. The reaction mixture was quenched with 1 drop of saturated sodium bicarbonate, the solvent was removed in vacuo, and the crude material was loaded onto a 12 g silica column with 5% methanol/dichloromethane and eluted with 100:0 to 95:5 dichloromethane:methanol over 20 minutes to give the titled compound (50 mg, 0.129 mmol, 58.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (s, 1H), 7.94 (d, J=1.1 Hz, 1H), 5.38 (br s, 1H), 4.23 (br s, 2H), 3.95 (t, J=7.2 Hz, 1H), 3.90-3.73 (m, 2H), 3.00 (br s, 2H), 2.71-2.45 (m, 3H), 2.18-1.86 (m, 2H), 1.47 (s, 9H), 1.05-0.85 (m, 4H); MS (ESI+) m/z 333.0 (M-tBu+H)+.

Workup

  1. stirringthe reaction mixture was stirred for 16 hours at the same temperature
  2. customThe reaction mixture was quenched with 1 drop of saturated sodium bicarbonate
  3. customthe solvent was removed in vacuo
  4. washeluted with 100:0 to 95:5 dichloromethane

Sources & evidence

ORD record
ord-0c7d2eaa6712460ab65d43bb69d8017e
Source dataset
uspto-grants-2016_07
Patent number
US09382258B2

Reaction notes

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