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

HRID 2271842Notes

Reaction equation

HRID 2271842 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[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22]2)[CH:20]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:51]>O1CCOCC1.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:27].[ClH:51].[Cl:27][C:28]1[CH:33]=[C:32]([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[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22]3)[CH:20]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 667151272,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenolHCID 667163161-(6-bromo-4-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone

Product 1

HCID 667166241-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone dihydrochlorideYield 83.1%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
80 °C

Procedure

To a suspension of 1-(6-bromo-4-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone (80 mg, 0.19 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (80 mg, 0.28 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 further purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The resultant residue was dissolved in methanol (8 mL) and HCl (6 M in water, 1.0 mL, 6 mmol) was added. The resultant solution was concentrated to give the desired product (66.2 mg, 60%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.27 (br s, 1H), 8.26-8.17 (m, 2H), 8.11 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.79 (s, 1H), 7.37 (s, 2H), 5.41 (br s, 1H), 4.25-3.93 (m, 2H), 3.84-3.32 (m, 2H), 3.21-3.03 (m, 3H), 2.82-2.78 (br s, 1H), 2.80 (3, 3H), 2.39 (br s, 1H). ESI MS m/z 496 [C25H23Cl2N5O2+H]+; HPLC>99% (AUC), tR=9.56 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. customwas further purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA)
  10. dissolutionThe resultant residue was dissolved in methanol (8 mL)
  11. concentrationThe resultant solution was concentrated

Sources & evidence

ORD record
ord-f934692b0024426c897772c13710e97d
Source dataset
uspto-grants-2015_09
Patent number
US09120749B2

Reaction notes

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