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 577677노트

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HRID 577677 반응식
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]

참가 물질

7

반응물 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

생성물 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}carbamate수율 86.5%

시약·촉매·용매 2

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 312751,4-Dioxane용매

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온도
140 °C

실험 절차

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)+.

후처리

  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

출처 및 근거

ORD 기록
ord-0e091708cb0c4b359b6cd0527333e080
출처 데이터셋
uspto-grants-2015_05
특허 번호
US09040547B2

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