Cesium carbonate → tert-butyl trans-3-methyl-4-{[(2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]methyl}pyrrolidine-1-carboxylate

HRID 577673Notes

Reaction equation

HRID 577673 reaction equation
Cl[C:2]1[N:3]=[C:4]([O:19][CH2:20][C@H:21]2[C@H:25]([CH3:26])[CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.[CH3:34][N:35]1[CH:39]=[C:38]([NH2:40])[CH:37]=[N:36]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][C@H:25]1[C@H:21]([CH2:20][O:19][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=3[N:7]=[C:2]([NH:40][C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)[N:3]=2)[CH2:22][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 47709901-methyl-1H-pyrazol-4-amineHCID 86679617tert-butyl trans-3-{[(2-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]methyl}-4-methylpyrrolidine-1-carboxylate

Product 1

HCID 86679618tert-butyl trans-3-methyl-4-{[(2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]methyl}pyrrolidine-1-carboxylateYield 59.8%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

To a mixture of tert-butyl trans-3-{[(2-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]methyl}-4-methylpyrrolidine-1-carboxylate (1.34 g, 2.7 mmol), 1-methyl-1H-pyrazol-4-amine (0.397 g, 4.05 mmol), Cs2CO3 (2.7 g, 8.4 mmol) and Xantphos (138 mg, 0.27 mmol) in 1,4-dioxane (30 mL) was added Pd2(dba)3 (247 mg, 0.27 mmol). The reaction was irradiated at 140° C. in three microwave tubes for 1 hr. TLC (petroleum ether/EtOAc=5:1) showed the reaction was complete. The mixture was concentrated and diluted with water (20 mL), then extracted with EtOAc (two×20 mL). The combined organic layers were washed with brine (four×20 mL), dried over Na2SO4 and concentrated. The residue was purified by Biotage flash chromatography (petroleum ether/EtOAc=1:1, Rf: 0.3) to yield the title compound (0.9 g, 59% yield) as a brown oil. m/z (APCI+) for C27H43N7O4Si 558.3 (M+H)+.

Workup

  1. customThe reaction was irradiated at 140° C. in three microwave tubes for 1 hr
  2. concentrationThe mixture was concentrated
  3. additiondiluted with water (20 mL)
  4. extractionextracted with EtOAc (two×20 mL)
  5. washThe combined organic layers were washed with brine (four×20 mL)
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customThe residue was purified by Biotage flash chromatography (petroleum ether/EtOAc=1:1, Rf: 0.3)

Sources & evidence

ORD record
ord-20ca2bb0a5914ed39fea9b1a3efc3bc2
Source dataset
uspto-grants-2015_05
Patent number
US09040547B2

Reaction notes

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