Cesium carbonate → tert-Butyl 3-(3-(6-Chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-1H-pyrazol-1-yl)azetidine-1-carboxylate

HRID 872158노트

반응식

HRID 872158 반응식
[NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH:7]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]2)[N:3]=1.Br[C:19]1[C:20](=[O:27])[N:21]([CH3:26])[N:22]=[C:23]([Cl:25])[CH:24]=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>C(OCC)(=O)C.O.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>[Cl:25][C:23]1[CH:24]=[C:19]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH:7]3[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10]3)[N:3]=2)[C:20](=[O:27])[N:21]([CH3:26])[N:22]=1

참가 물질

9

반응물 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 592164744-Bromo-6-chloro-2-methyl-2,3-dihydropyridazin-3-oneHCID 66634616tert-Butyl 3-(3-Amino-1H-pyrazol-1-yl)azetidine-1-carboxylate

생성물 1

HCID 66634723tert-Butyl 3-(3-(6-Chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-1H-pyrazol-1-yl)azetidine-1-carboxylate수율 73.4%

시약·촉매·용매 4

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 962Water용매HCID 8857Ethyl Acetate용매HCID 312751,4-Dioxane용매

실험 절차

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 105b (677 mg, 2.84 mmol), 103a (635 mg, 2.84 mmol), cesium carbonate (1.85 g, 5.68 mmol) and 1,4-dioxane (14 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (246 mg, 0.426 mmol) and tris(dibenzylideneacetone)dipalladium(0) (260 mg, 0.284 mmol) were added. A reflux condenser was attached to the flask, and the reaction mixture was heated at reflux for 2.5 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (200 mL) and water (75 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL), and the combined organic layers were dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 95:5 methylene chloride/methanol) to afford a 73% yield of 105c (794 mg) as an amorphous white solid: mp 154-156° C.; 1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.60 (s, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.01 (d, J=2.5 Hz, 1H), 5.00-4.95 (m, 1H), 4.39-4.32 (m, 4H), 3.79 (s, 3H), 1.48 (s, 9H); MS (ESI+) m/z 403.1 (M+Na).

후처리

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet
  2. customAfter bubbling nitrogen through the resulting suspension for 30 min
  3. customA reflux condenser was attached to the flask
  4. temperaturethe reaction mixture was heated
  5. temperatureat reflux for 2.5 h
  6. customthe layers were separated
  7. extractionThe aqueous layer was extracted with ethyl acetate (50 mL)
  8. dry with materialthe combined organic layers were dried over sodium sulfate
  9. customThe drying agent was removed by filtration
  10. concentrationThe filtrate was concentrated under reduced pressure
  11. customthe resulting residue was purified by flash column chromatography (silica, 95:5 methylene chloride/methanol)

출처 및 근거

ORD 기록
ord-0add878569d044b5984ce53c3fb9b9a2
출처 데이터셋
uspto-grants-2015_03
특허 번호
US08975260B2

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