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

HRID 626799Notes

Reaction equation

HRID 626799 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]([CH2:28][OH:29])[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]([CH2:28][OH:29])[N:22]=3)=[N:3][CH:4]=[C:5]([F:19])[C:6]2=[N:10]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 69671946(4-Amino-6-methylpyrimidin-2-yl)methanolHCID 866970814-Bromo-2-(2-chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine

Product 1

HCID 69675050{4-[2-(2-Chloro-6-fluoro-phenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-6-methyl-pyrimidin-2-yl}-methanol hydrochloride salt

Reagents, catalysts & solvents 2

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

Conditions

Temperature
150 °C

Procedure

A mixture of 4-bromo-2-(2-chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (100 mg, 0.29 mmol), (4-amino-6-methylpyrimidin-2-yl)-methanol (42 mg, 0.31 mmol), Pd2(dba)3 (13 mg, 0.015 mmol), Xantphos (17 mg, 0.03 mmol) and cesium carbonate (189 mg, 0.58 mmol) in dioxane (2.0 mL) was de-gassed and purged with nitrogen and the reaction mixture was heated under microwave irradiation at 150° C. for 45 minutes. The resultant mixture was allowed to cool to room temperature and was then filtered through a pad of Celite® washing with further dioxane and then ethyl acetate. The combined washings were concentrated under reduced pressure and the resultant residue was purified by silica gel flash chromatography (40-100% ethyl acetate in cyclohexane). The resultant residue was further purified by HPLC (gradient: 10 to 98% MeOH (0.1% NH4OH) in water (0.1% NH4OH)], to afford the free base of the title compound. To this crude residue was added a solution of HCl (1.25 N in propan-2-ol, 2.0 mL) and the resulting mixture was stirred at room temperature for 1 hour. The resultant mixture was concentrated under reduced pressure and dried in vacuo to afford the title compound as a white solid (42 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.24 (br s, 1H), 9.45 (s, 1H), 8.14 (d, J=3.3 Hz, 1H), 8.12 (br s, 1H), 7.83-7.75 (m, 1H), 7.74-7.63 (m, 2H), 4.71 (s, 2H), 2.63 (s, 3H). LCMS (Method B): RT=3.03 min, m/z: 403 [M+H+].

Workup

  1. customwas de-gassed
  2. custompurged with nitrogen
  3. temperatureto cool to room temperature
  4. filtrationwas then filtered through a pad of Celite®
  5. washwashing with further dioxane
  6. concentrationThe combined washings were concentrated under reduced pressure
  7. customthe resultant residue was purified by silica gel flash chromatography (40-100% ethyl acetate in cyclohexane)
  8. customThe resultant residue was further purified by HPLC (gradient

Sources & evidence

ORD record
ord-dd39ca9083ff4c26aedd80f9854adbec
Source dataset
uspto-grants-2016_04
Patent number
US09309240B2

Reaction notes

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