Cesium carbonate → tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate

HRID 246506Notes

Reaction equation

HRID 246506 reaction equation
[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:39][CH:40]1[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH:40]4[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:41]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 53249943tert-Butyl 3-(iodomethyl)azetidine-1-carboxylateHCID 712795662-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide

Product 1

HCID 71280303tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylateYield 82.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 188 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (56.0 mg, 188 μmol) and cesium carbonate (184 mg, 565 μmol) in dimethylformamide (2 mL) were heated in a microwave at 150° C. for 30 min. The mixture was cooled, partitioned between ethyl acetate and water, and the organic phase washed with water 3 times then dried and concentrated. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (108 mg, 82%). MS (M+H)+=700; 1H NMR (CDCl3) δ: 9.18 (s, 1H), 8.34 (s, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.00 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.35 (dd, J=9.0, 2.1 Hz, 1H), 6.24-6.81 (m, 1H), 5.72 (s, 3H), 5.30 (s, 2H), 4.66 (d, J=7.5 Hz, 2H), 3.89 (dd, J=8.9, 5.2 Hz, 2H), 3.58 (dd, J=8.8, 7.6 Hz, 2H), 3.21-3.33 (m, 1H), 1.61 (s, 9H), 1.45 (s, 9H), 0.88-1.00 (m, 2H), −0.08-−0.01 (m, 9H).

Workup

  1. temperatureThe mixture was cooled
  2. custompartitioned between ethyl acetate and water
  3. washthe organic phase washed with water 3 times
  4. customthen dried
  5. concentrationconcentrated
  6. customPurification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-dd16b7184862407eb69a5b1f162470a7
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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