Cesium carbonate → [2-(2-Chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-(2,6-dimethylpyrimidin-4-yl)amine hydrochloride salt

HRID 626797Notes

Reaction equation

HRID 626797 reaction equation
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)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]>[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[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH3:28])[N:22]=3)=[N:3][CH:4]=[C:5]([F:19])[C:6]2=[N:10]1

Participants

7

Reactant 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

Product 1

HCID 69671544[2-(2-Chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-(2,6-dimethylpyrimidin-4-yl)amine hydrochloride saltYield 134.2%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

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 (74 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 (ethyl acetate). The resultant residue was stirred with HCl (1.25 N in propan-2-ol, 5.0 mL) for 1 hour. The solid obtained was collected by filtration and dried to afford the title compound as an off-white solid (142 mg, 67% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.36 (s, 1H), 8.15 (br s, 1H), 8.11 (d, J=3.4 Hz, 1H), 7.81-7.73 (m, 1H), 7.73-7.62 (m, 2H), 2.65 (s, 3H), 2.59 (s, 3H). LCMS (Method B): RT=3.14 min, m/z: 387 [M+H+].

Workup

  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 (ethyl acetate)
  11. customThe solid obtained
  12. filtrationwas collected by filtration
  13. customdried

Sources & evidence

ORD record
ord-e72dc4e2a57a479ab3000e9d8c1b28a3
Source dataset
uspto-grants-2016_04
Patent number
US09309240B2

Reaction notes

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