Cesium carbonate → {6-[2-(2-Chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-2-methylpyrimidin-4-yl}-methanol hydrochloride salt

HRID 626798노트

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HRID 626798 반응식
Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH3:28])[N:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:50]C2C(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]>[ClH:18].[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[N:9]1[CH:8]=[C:7]2[C:2]([NH:20][C:21]3[N:22]=[C:23]([CH3:28])[N:24]=[C:25]([CH2:27][OH:50])[CH:26]=3)=[N:3][CH:4]=[C:5]([F:19])[C:6]2=[N:10]1

참가 물질

7

반응물 4

HCID 10796Cesium carbonateHCID 680392,6-Dimethyl-4-aminopyrimidineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866970814-Bromo-2-(2-chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine

생성물 1

HCID 69674838{6-[2-(2-Chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-2-methylpyrimidin-4-yl}-methanol hydrochloride salt수율 696.6%

시약·촉매·용매 2

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

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온도
80 °C

실험 절차

A mixture of 4-bromo-2-(2-chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (172 mg, 0.5 mmol), 4-amino-2,6-dimethylpyrimidine (83 mg, 0.6 mmol), Pd2(dba)3 (11 mg, 0.013 mmol), Xantphos (29 mg, 0.05 mmol) and cesium carbonate (326 mg, 1.0 mmol) in dioxane (5 mL) was de-gassed and purged with nitrogen and the reaction mixture was heated at 80° C. in a sealed vial overnight. The resultant mixture was allowed to cool to room temperature, before being partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (80-100% ethyl acetate in cyclohexane). The resultant residue was stirred with HCl (1.25 N in propan-2-ol, 5.0 mL) for 1 hour. The resultant mixture was concentrated under reduced pressure and the solid obtained was triturated with diethyl ether, filtered and dried to afford the title compound as a white solid (153 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.25 (br s, 1H), 9.48 (s, 1H), 8.25 (br s, 1H), 8.15 (d, J=3.6 Hz, 1H), 7.83-7.76 (m, 1H), 7.74-7.66 (m, 2H), 4.70 (s, 2H), 2.67 (s, 3H). LCMS (Method B): RT=2.96 min, m/z: 403 [M+H+].

후처리

  1. customwas de-gassed
  2. custompurged with nitrogen
  3. temperatureto cool to room temperature
  4. custombefore being partitioned between ethyl acetate and water
  5. customThe layers were separated
  6. washthe organic layer was washed with brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by silica gel flash chromatography (80-100% ethyl acetate in cyclohexane)
  11. concentrationThe resultant mixture was concentrated under reduced pressure
  12. customthe solid obtained
  13. customwas triturated with diethyl ether
  14. filtrationfiltered
  15. customdried

출처 및 근거

ORD 기록
ord-d6bcb314bb3748c58d86fbe5245337b0
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09309240B2

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