Cesium carbonate → tert-butyl {3-[(5-cyano-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamate

HRID 577677Notes

Reaction equation

HRID 577677 reaction equation
Cl[C:2]1[N:3]=[C:4]([O:21][CH:22]2[CH2:25][CH:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[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>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].O1CCOCC1>[C:11]([C:10]1[C:5]2[C:4]([O:21][CH:22]3[CH2:25][CH:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23]3)=[N:3][C:2]([NH:40][C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)=[N:7][C:6]=2[N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=1)#[N:12]

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 86679622tert-butyl {3-[(2-chloro-5-cyano-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamate

Product 1

HCID 86679623tert-butyl {3-[(5-cyano-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamateYield 86.5%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
140 °C

Procedure

To a microwave reaction vial was added tert-butyl {3-[(2-chloro-5-cyano-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamate (508 mg, 1.0 mmol), 1-methyl-1H-pyrazol-4-amine (110 mg, 1.1 mmol), 1,4-dioxane (10 mL), Cs2CO3 (670 mg, 2.1 mmol, 2 mol eq), Xantphos (62 mg, 0.1 mmol) and Pd2(dba)3 (94 mg, 0.1 mmol). The reaction vial was flushed with nitrogen, capped, stirred and heated to 140° C. in a Biotage microwave reactor for 1 hr and 45 min. The reaction was diluted with EtOAc (120 mL) and water (20 mL). The organic layer was separated, washed with water (20 mL), brine (10 mL), and dried over Na2SO4. After concentrating the extract to dryness, the product was purified via flash chromatography eluting with a gradient of 0%-60% EtOAc in heptanes to afford the title compound (480 mg, 84 yield) as a light yellow solid. 1:1 cis:trans mixture: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.42 (s, 1H) 8.11 (s, 1H) 7.96 (br. s., 1H) 7.49-7.60 (m, 1H) 7.20-7.46 (m, 1H) 5.53 (br. s., 2H) 4.11-5.13 (m, 1H) 3.82 (s, 3H) 3.56 (t, J=7.55 Hz, 2H) 2.83 (d, J=6.80 Hz, 1H) 2.39-2.48 (m, 2H) 2.02-2.16 (m, 1H) 1.39 (d, J=5.54 Hz, 9H) 0.84 (t, J=8.06 Hz, 2H) −0.12 (br. s., 9H). m/z (APCI+) for C26H38N8O4Si 555.1 (M+H)+.

Workup

  1. customTo a microwave reaction
  2. customThe reaction
  3. customvial was flushed with nitrogen
  4. customcapped
  5. additionThe reaction was diluted with EtOAc (120 mL) and water (20 mL)
  6. customThe organic layer was separated
  7. washwashed with water (20 mL), brine (10 mL)
  8. dry with materialdried over Na2SO4
  9. concentrationAfter concentrating the
  10. extractionextract to dryness
  11. customthe product was purified via flash chromatography
  12. washeluting with a gradient of 0%-60% EtOAc in heptanes

Sources & evidence

ORD record
ord-0e091708cb0c4b359b6cd0527333e080
Source dataset
uspto-grants-2015_05
Patent number
US09040547B2

Reaction notes

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