Hydrochloric Acid → 1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone dihydrochloride

HRID 2271845Notes

Reaction equation

HRID 2271845 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][N:19]([CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:20]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:52]>O1CCOCC1.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:28].[ClH:52].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:20]=2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 667151272,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenolHCID 667160841-(6-bromo-4-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone

Product 1

HCID 667161791-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone dihydrochlorideYield 42.5%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a suspension of 1-(6-bromo-4-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone (50 mg, 0.116 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80° C. for 2 h. The solution was allowed to cool to room temperature, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded a residue that was dissolved in methanol (4 mL) and HCl (1.25 M in methanol, 1.0 mL, 1.25 mmol) was added. The resultant solution was concentrated to give the desired product (18.6 mg, 27%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.26 (s, 1H), 8.25-8.18 (m, 1H), 8.18-8.07 (m, 2H), 8.00 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.36-7.32 (m, 2H), 4.70-4.61 (m, 1H), 3.68 (d, 2H), 3.53-3.45 (m, 1H), 3.41-3.22 (m, 1H), 2.94 (s, 3H), 2.80 (s, 3H), 2.53-2.33 (m, 4H). ESI MS m/z 510 [C26H25Cl2N5O2+H]+; HPLC 97.4% (AUC), tR=9.46 min.

Workup

  1. customN2 gas was bubbled through the reaction mixture
  2. temperatureto cool to room temperature
  3. additiondiluted with a saturated NaHCO3 solution
  4. extractionextracted with ethyl acetate
  5. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  6. concentrationconcentrated
  7. customPurification by column chromatography (silica, 0-20% methanol/dichloromethane)
  8. customafforded a residue that
  9. concentrationThe resultant solution was concentrated

Sources & evidence

ORD record
ord-93682d8e9841411c8db203f7b8d4c1fb
Source dataset
uspto-grants-2015_09
Patent number
US09120749B2

Reaction notes

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