Cesium carbonate → 1-{6-[2-(2,6-Dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-ethanol

HRID 626751

Reaction equation

HRID 626751 reaction equation
Cl[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([CH:26]([OH:28])[CH3:27])[CH:21]=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]([Cl:17])[C:11]=1[N:9]1[CH:8]=[C:7]2[C:2]([NH:19][C:20]3[N:25]=[CH:24][N:23]=[C:22]([CH:26]([OH:28])[CH3:27])[CH:21]=3)=[N:3][CH:4]=[CH:5][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 696711341-(6-Aminopyrimidin-4-yl)-ethanolHCID 866970364-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine

Product 1

HCID 696718161-{6-[2-(2,6-Dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-ethanolYield 21%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
150 °C

Procedure

A mixture of 4-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (133 mg, 0.445 mmol), 1-(6-aminopyrimidin-4-yl)-ethanol (65 mg, 0.467 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (26 mg, 0.045 mmol) and cesium carbonate (290 mg, 0.89 mmol) in dioxane (3.5 mL) was de-gassed and purged with nitrogen and the reaction mixture was heated at 150° C. in the microwave for 30 minutes. The resultant mixture was filtered and washed with dioxane. The filtrate was concentrated under reduced pressure and the resultant residue was purified by silica gel flash chromatography (0-100% ethyl acetate in cyclohexane) to afford a yellow solid. This was re-purified by HPLC [gradient: 5 to 98% acetonitrile (0.1% ammonium hydroxide) in water (0.1% ammonium hydroxide)], to afford the title compound as a white solid (31 mg, 21% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.53 (d, J=0.9 Hz, 1H), 9.07 (d, J=1.1 Hz, 1H), 8.09 (d, J=7.3 Hz, 1H), 7.88-7.86 (m, 2H), 7.78 (dd, J=9.2, 7.1 Hz, 1H), 7.68-7.61 (m, 2H), 4.83-4.76 (m, 1H), 1.46 (d, J=6.7 Hz, 3H). LCMS (Method B): RT=2.74 min, m/z: 401 [M+H+].

Workup

  1. customwas de-gassed
  2. custompurged with nitrogen
  3. filtrationThe resultant mixture was filtered
  4. washwashed with dioxane
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customthe resultant residue was purified by silica gel flash chromatography (0-100% ethyl acetate in cyclohexane)
  7. customto afford a yellow solid
  8. customThis was re-purified by HPLC [gradient: 5 to 98% acetonitrile (0.1% ammonium hydroxide) in water (0.1% ammonium hydroxide)]

Sources & evidence

ORD record
ord-035dbd663cb34395878ff0a08ddfd968
Source dataset
uspto-grants-2016_04
Patent number
US09309240B2

Linked notes

Loading…