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HRID729629

反应详情

EQUATION

反应方程式

HRID 729629 的结构方程式

REACTANTS

反应物

3
结构：C1CCOC1
HCID8028

Tetrahydrofuran

C4H8O

2 次

结构：CC1(C(=O)N2CCC(Oc3ncc(N)c4ccccc34)CC2)CC1
HCID57832814

未命名化合物

结构：Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
HCID57832815

未命名化合物

PRODUCTS

生成物

1
结构：Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)C4(C)CC4)CC3)c3ccccc23)cc1
HCID16061469

未命名化合物

收率 68%

CONDITIONS

反应条件

温度
46.5 °C

PROCEDURE

实验过程

Add [4-(4-Amino-isoquinolin-1-yloxy)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone (Preparation 23, 331.00 g, 1.02 moles), THF (3.97 L, 48.79 moles), [5-(1-Methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Preparation 18, 410.00 g, 1.02 moles), and DIPE (159.00 g, 1.22 moles) to a 12 L Morton flask equipped with overhead stirrer, thermocouple, and reflux condenser. Reflux the mixture for 22 hours. Cool reaction to <50° C. and treat with carbon (Darco G-60; 33.00 g, 2.75 moles). Stir the slurry for 30 minutes at 43-50° C., then filter over micro fiber paper and Hyflo Super Cel® (27.00 g). Seed the filtrate and allow to cool at ambient temperature during precipitation. Pack the resulting slurry in ice and stir overnight. Filter the solids, wash with THF (300.00 mL, 3.69 moles), and dry under reduced pressure at 40° C. Subject residue to silica gel chromatography eluting with 1:3 acetone/DCM, then 30% acetone in DCM to obtain 401 g (68%) 1-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea as a white solid 1H NMR (300 MHz, DMSO-d6): δ 0.56 (t, J=6.0 Hz, 2H), 0.73 (t, J=6.0 Hz, 2H), 0.84 (t, J=6.0 Hz, 2H), 0.92 (t, J=6.0 Hz, 2H), 1.27 (s, 3H), 1.41 (s, 3H), 1.73-1.81 (m, 2H), 1.99-2.08 (m, 2H), 2.41 (s, 3H), 3.52-3.65 (m, 2H), 3.83-3.96 (m, 2H), 5.47-5.58 (m, 1H), 6.22 (s, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.65-7.71 (m, 1H), 7.78-7.83 (m, 2H), 8.12 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.58 (s, 1H), 8.69 (s, 1H).

WORKUP

后处理

  1. customequipped with overhead stirrer
  2. temperaturethermocouple, and reflux condenser
  3. temperatureReflux the mixture for 22 hours
  4. temperatureCool
  5. customreaction to <50° C.
  6. additiontreat with carbon (Darco G-60; 33.00 g, 2.75 moles)
  7. filtrationfilter over micro fiber paper and Hyflo Super Cel® (27.00 g)
  8. temperatureto cool at ambient temperature during precipitation
  9. stirringstir overnight
  10. filtrationFilter the solids
  11. customdry under reduced pressure at 40° C
  12. washSubject residue to silica gel chromatography eluting with 1:3 acetone/DCM