Cesium carbonate → (R)-3-methyl-2-(5-(5-((2-(pyrrolidin-1-yl)ethoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-N-(2,2,2-trifluoroethyl)butanamide

HRID 510214Notes

Reaction equation

HRID 510214 reaction equation
Cl[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][C@H:18]([CH:27]([CH3:29])[CH3:28])[C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3C=C(N[C@H](C(NCC(F)(F)F)=O)C(C)C)C=NC=3)=CN(COCC[Si](C)(C)C)C2=NC=1.[N:75]1([CH2:80][CH2:81][O:82][CH2:83][B-](F)(F)F)[CH2:79][CH2:78][CH2:77][CH2:76]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[CH3:28][CH:27]([CH3:29])[C@@H:18]([NH:17][C:13]1[CH:14]=[N:15][CH:16]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([CH2:83][O:82][CH2:81][CH2:80][N:75]4[CH2:79][CH2:78][CH2:77][CH2:76]4)[CH:3]=3)[N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=2)[CH:12]=1)[C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20]

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 49761739Potassium 2-(pyrrolidin-1-YL)ethoxymethyltrifluoroborateHCID 131733258N2-[5-(5-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)valinamideHCID 131733263(R)-2-(5-(5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide

Product 1

HCID 89495580(R)-3-methyl-2-(5-(5-((2-(pyrrolidin-1-yl)ethoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-N-(2,2,2-trifluoroethyl)butanamide

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

In a microwave vial purged with nitrogen containing (R)-2-(5-(5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide, 2-1a (52 mg, 0.094 mmol), Potassium 2-(pyrrolidin-1-yl)ethoxymethyltrifluoroborate (CA) (44.4 mg, 0.189 mmol), cesium carbonate (105.3 mg, 0.323 mmol), palladium acetate (4.2 mg, 0.019 mmole) and RuPhos catalyst (17.45 mg, 0.037 mmol) was added a degassed mixture of 10:1 dioxane (500 μl)/water (50 μl). The reaction vessel was sealed and heated at 150° C. for 15 minutes in the microwave. LC/MS indicated product as a major peak. The reaction was cooled, passed through a celite cartridge, to remove water, the cartridge was washed with dichloromethane, ethyl acetate and the filtrate concentrated. The crude product 9-1a (60.7 mg) was used directly in the next step. LRMS (ESI) m/z 649.2 [(M+H)+; calcd for C32H47F3N6O3Si: 649.35].

Workup

  1. customIn a microwave vial purged with nitrogen
  2. additionwas added
  3. customThe reaction vessel was sealed
  4. temperatureThe reaction was cooled
  5. customto remove water
  6. washthe cartridge was washed with dichloromethane, ethyl acetate
  7. concentrationthe filtrate concentrated

Sources & evidence

ORD record
ord-87726d65836a49068d00898342b7b367
Source dataset
uspto-grants-2015_08
Patent number
US09096598B2

Reaction notes

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