huagongshe.com
HRID1396348

反应详情

EQUATION

反应方程式

HRID 1396348 的结构方程式

REACTANTS

反应物

5
结构：O=C(O)C(F)(F)F
HCID6422

未命名化合物

结构：CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
HCID1514389

tert-Butyl [(1S,2R)-2-aminocyclohexyl]carbamate

C11H22N2O2

2 次

结构：CC(C)c1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)n1
HCID71626822

未命名化合物

结构：CC(C)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
HCID86689717

未命名化合物

结构：CC(C)c1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
HCID86689718

未命名化合物

PRODUCTS

生成物

2
结构：[NH4+].[OH-]
HCID14923

Ammonium hydroxide

H5NO

结构：CC(C)c1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)n1
HCID71626822

未命名化合物

收率 9%

AUXILIARIES

试剂、催化剂与溶剂

2
结构：ClCCl
溶剂HCID6344

Dichloromethane

CH2Cl2

结构：CN1CCCC1=O
溶剂HCID13387

N-Methyl-2-pyrrolidone

C5H9NO

CONDITIONS

反应条件

温度
150 °C

PROCEDURE

实验过程

To a solution of 6-chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (102 mg, 350 μmol) in N-methyl-2-pyrrolidinone (6 ml) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (150 mg, 699 μmol) and the mixture heated to 150° C. for 3 d. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (150 mg, 699 μmol) was added and the reaction heated to 150° C. for an additional 2 d, then cooled, concentrated, and purified by chromatography (silica, 50 μm, 40 g, Analogix, 96:3.8:0.2 to 84:15.2:0.8; dichloromethane:MeOH:NH4OH) to give a mixture of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate and 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (33 mg). This mixture was dissolved in dichloromethane (2 mL) then TFA (370 mg, 250 μL, 3.24 mmol) was added. After 18 h, the mixture was concentrated in vacuo and the residue obtained was purified by chromatography (spherical silica, 20-45 μm, 25 g, Versaflash Supelco, 96:3.8:0.2 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 25 min gradient to afford 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (12 mg, 9%) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.35 (br. s., 1H) 8.33 (s, 1H) 7.96 (br. s., 1H) 7.44 (t, J=7.83 Hz, 1H) 6.70 (d, J=7.58 Hz, 1H) 6.61 (d, J=8.08 Hz, 1H) 5.61 (br. s., 1H) 5.31 (br. s., 1H) 3.75 (br. s., 1H) 3.19 (d, J=3.28 Hz, 1H) 2.89-3.01 (m, 1H) 1.32-1.80 (m, 8H) 1.27 (d, J=6.82 Hz, 6H). LCMS (EI/CI) m/z: 370 [M+H].

WORKUP

后处理

  1. temperaturethe reaction heated to 150° C. for an additional 2 d
  2. temperaturecooled
  3. concentrationconcentrated
  4. custompurified by chromatography (silica, 50 μm, 40 g, Analogix, 96:3.8:0.2 to 84:15.2:0.8; dichloromethane:MeOH:NH4OH)
  5. customto give
  6. concentrationthe mixture was concentrated in vacuo
  7. customthe residue obtained
  8. customwas purified by chromatography (spherical silica, 20-45 μm, 25 g, Versaflash Supelco, 96:3.8:0.2 to 84:15.2:0.8 dichloromethane