Phosgene → Cyclobutyl-6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

HRID 2205924Notes

Reaction equation

HRID 2205924 reaction equation
[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.[CH:17]1([O:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18]1.C1(O)CCC1.C(Cl)(Cl)=O>CN(C=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH:17]1([O:21][C:22]([N:10]2[C:4]3[CH:3]=[C:2]([Br:1])[N:7]=[CH:6][C:5]=3[CH:8]=[C:9]2[C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)=[O:23])[CH2:20][CH2:19][CH2:18]1

Participants

9

Reactant 4

HCID 6371PhosgeneHCID 76218CyclobutanolHCID 5362587Cyclobutyl chloroformateHCID 867062766-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine

Product 1

HCID 86706314Cyclobutyl-6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylateYield 70.2%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 122, 100 mg, 0.36 mmol) was dissolved in dry DMF (1 ml). The solution was degassed and a solution of sodium bis(trimethylsilyl)amide (0.54 ml of a 1M solution in THF, 0.54 mmol) was added. After 20 minutes reaction, a solution of cyclobutylchloroformate [freshly prepared by stirring 40 mg of cyclobutanol with one equivalent of a 20% phosgene solution in toluene (0.275 ml) for 3 h, 0.55 mmol] was added. The reaction was stirred for 2 hours at room temperature then was diluted with ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulphate and concentrated in vacuum. The crude product was purified on silica gel column chromatography eluting with 20% hexane in ethyl acetate to afford the title compound as a white powder (95 mg, 70.2%). 1H-NMR (500 MHz, CDCl3): δ 1.69 (m, 1H), 2.12 (m, 1H), 2.15 (m, 2H), 2.4 (m, 2H), 3.94 (s, 3H), 5.17 (quin, J=7.2 Hz, 1H), 6.54 (s, 1H), 7.6 (s, 1H), 7.62 (s, 1H), 8.14 (s. 1H), 8.51 (s, 1H)

Workup

  1. customThe solution was degassed
  2. additiona solution of sodium bis(trimethylsilyl)amide (0.54 ml of a 1M solution in THF, 0.54 mmol) was added
  3. customAfter 20 minutes reaction
  4. addition0.55 mmol] was added
  5. washThe organic solution was washed with brine
  6. dry with materialdried over sodium sulphate
  7. concentrationconcentrated in vacuum
  8. customThe crude product was purified on silica gel column chromatography
  9. washeluting with 20% hexane in ethyl acetate

Sources & evidence

ORD record
ord-677ce9854cf44d1c92384232267d91b0
Source dataset
uspto-grants-2016_06
Patent number
US09371319B2

Reaction notes

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