Hydrochloric Acid → 3-Chloro-5-fluoro-2-{7-fluoro-4-[6-(2-hydroxyethylamino)-2-methylpyrimidin-4-ylamino]pyrazolo[4,3-c]pyridin-2-yl}benzonitrile hydrochloride salt

HRID 626786Notes

Reaction equation

HRID 626786 reaction equation
[Cl:1][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]#[N:14])[N:10]=[C:6]2[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][CH2:30][CH2:31][OH:32])[CH:23]=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+].[ClH:81]>O1CCOCC1.CC(O)C.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:1].[Cl:81][C:18]1[C:11]([N:9]2[CH:8]=[C:7]3[C:2]([NH:21][C:22]4[CH:23]=[C:24]([NH:29][CH2:30][CH2:31][OH:32])[N:25]=[C:26]([CH3:28])[N:27]=4)=[N:3][CH:4]=[C:5]([F:20])[C:6]3=[N:10]2)=[C:12]([CH:15]=[C:16]([F:19])[CH:17]=1)[C:13]#[N:14]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 696711852-((6-Amino-2-methylpyrimidin-4-yl)amino)ethanolHCID 866970772-(4-Chloro-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-5-fluorobenzonitrile

Product 1

HCID 696711063-Chloro-5-fluoro-2-{7-fluoro-4-[6-(2-hydroxyethylamino)-2-methylpyrimidin-4-ylamino]pyrazolo[4,3-c]pyridin-2-yl}benzonitrile hydrochloride saltYield 28%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 3776IsopropanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 2-(4-chloro-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-5-fluorobenzonitrile (185 mg, 0.5 mmol), 2-(6-amino-2-methylpyrimidin-4-ylamino)ethanol (101 mg, 0.6 mmol), Pd2(dba)3 (11 mg, 0.0125 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. The reaction mixture was heated at 80° C. in a sealed vial overnight. After cooling, the resultant mixture was diluted with ethyl acetate and washed with water. 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 (0-2% methanol in ethyl acetate) to afford crude product. This was dissolved in 1.25 N HCl in propan-2-ol solution (10 mL) and was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and diethyl ether was added and the mixture was stirred for 5 minutes. The precipitate was filtered off and dried to afford the title compound as an off-white solid (68 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.52 (br s, 1H), 8.35-8.29 (m, 2H), 8.07 (s, 1H), 7.13 (br s, 1H), 3.66-3.59 (m, 2H), 3.59-3.49 (m, 2H), 2.59 (s, 3H). LCMS (Method B): RT=3.13 min, m/z: 457 [M+H+].

Workup

  1. customwas de-gassed
  2. custompurged with nitrogen
  3. temperatureAfter cooling
  4. additionthe resultant mixture was diluted with ethyl acetate
  5. washwashed with water
  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 (0-2% methanol in ethyl acetate)
  11. customto afford crude product
  12. concentrationThe solvent was concentrated under reduced pressure, and diethyl ether
  13. additionwas added
  14. stirringthe mixture was stirred for 5 minutes
  15. filtrationThe precipitate was filtered off
  16. customdried

Sources & evidence

ORD record
ord-4c77290aa28445b7a1d5bc8f2ec09e10
Source dataset
uspto-grants-2016_04
Patent number
US09309240B2

Reaction notes

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