Cesium carbonate → N-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropanecarboxamide

HRID 2366198노트

반응식

HRID 2366198 반응식
Cl[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:19]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20]1.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(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:24][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1

참가 물질

7

반응물 4

HCID 10796Cesium carbonateHCID 80376Cyclopropanecarboxamide2회HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)2회HCID 867233054-Chloro-2-(2-chloro-6-fluorophenyl)-thiazolo[5,4-c]pyridine

생성물 1

HCID 56953389N-(2-(2-Chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4-yl)cyclopropanecarboxamide수율 30.4%

시약·촉매·용매 2

HCID 9811564Bis(dibenzylideneacetone)palladium촉매2회HCID 312751,4-Dioxane용매

실험 절차

A mixture of 4-chloro-2-(2-chloro-6-fluoro-phenyl)-thiazolo[5,4-c]pyridine (0.050 g, 0.17 mmol), cyclopropanecarboxamide (0.016 g, 0.18 mmol), Pd2(dba)3 (0.008 g, 0.009 mmol), XantPhos (0.010 g, 0.017 mmol) and cesium carbonate (0.139 g, 0.43 mmol) in dioxane (1.7 mL) was degassed with nitrogen then subjected to microwave irradiation at 170° C. for 60 minutes. Further cyclopropanecarboxamide (0.006 g, 0.08 mmol), Pd2(dba)3 (0.010 g, 0.010 mmol) and XantPhos (0.012 g, 0.021 mmol) were added. The mixture was degassed with nitrogen then subjected to microwave irradiation at 200° C. for 90 minutes. Water and DCM were added and the resulting mixture was filtered through Celite®. The layers of the filtrate were separated via a phase separator and the organic phase concentrated under reduced pressure. The residue was loaded onto an Isolute® SCX-2 cartridge that was washed with MeOH and the product eluted with 2M ammonia in MeOH. The relevant fractions were combined, concentrated under reduced pressure and the resultant residue was purified by silica gel flash chromatography (0-30% EtOAc in DCM) to give the desired compound as an off-white solid (0.018 g, 30% yield). 1H NMR (300 MHz, DMSO-d6): δ 11.40 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 7.92 (d, J=5.6 Hz, 1H), 7.69 (dd, J=8.3, 6.1 Hz, 1H), 7.59-7.58 (m, 1H), 7.52-7.49 (m, 1H), 2.13-2.03 (s, 1H), 0.91-0.90 (m, 4H). LCMS (Method D): RT=3.36 min, m/z: 348 [M+H+].

후처리

  1. customwas degassed with nitrogen
  2. customirradiation at 170° C. for 60 minutes
  3. customThe mixture was degassed with nitrogen
  4. customirradiation at 200° C. for 90 minutes
  5. additionWater and DCM were added
  6. filtrationthe resulting mixture was filtered through Celite®
  7. customThe layers of the filtrate were separated via a phase separator
  8. concentrationthe organic phase concentrated under reduced pressure
  9. washwas washed with MeOH
  10. washthe product eluted with 2M ammonia in MeOH
  11. concentrationconcentrated under reduced pressure
  12. customthe resultant residue was purified by silica gel flash chromatography (0-30% EtOAc in DCM)

출처 및 근거

ORD 기록
ord-ba3cfe03474646ebb2266b806d39b0e2
출처 데이터셋
uspto-grants-2014_04
특허 번호
US08697708B2

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