Hydrochloric Acid → (6-(3-Chloro-5-fluoro-4-hydroxyphenyl)-4-((6-(3-(methylamino)pyrrolidin-1-yl)pyridin-3-yl)amino)quinolin-3-yl)(cyclopropyl)methanone trihydrochloride

HRID 2271839Notes

Reaction equation

HRID 2271839 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]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([N:29]([CH3:37])C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:62].C(O)(C(F)(F)[F:66])=O>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:38].[ClH:62].[ClH:38].[Cl:54][C:41]1[CH:42]=[C:43]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[N:22][C:21]([N:24]3[CH2:28][CH2:27][CH:26]([NH:29][CH3:37])[CH2:25]3)=[CH:20][CH:19]=2)[CH:44]=[C:39]([F:66])[C:40]=1[OH:55]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 10796Cesium carbonateHCID 667151272,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenolHCID 86692971HCID 86692971, compound

Product 1

HCID 66716564(6-(3-Chloro-5-fluoro-4-hydroxyphenyl)-4-((6-(3-(methylamino)pyrrolidin-1-yl)pyridin-3-yl)amino)quinolin-3-yl)(cyclopropyl)methanone trihydrochlorideYield 47%

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 tert-butyl (1-(5-((6-bromo-3-(cyclopropanecarbonyl)quinolin-4-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (88 mg, 0.155 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (68 mg, 0.25 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 brown solid. This solid was dissolved in TI-IF (3 mL) and TFA (2 mL). The reaction mixture was heated at 65° C. for 16 h, cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The 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 (46.5 mg, 47%) as an orange solid. 1H NMR (500 MHz, MeOD) δ 9.34 (s, 1H), 8.36 (s, 1H), 8.31 (dd, J=8.8, 1.9 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 8.02-7.95 (m, 1H), 7.41-7.33 (m, 2H), 7.20 (dd, J=9.6, 2.5 Hz, 1H), 4.17-4.07 (m, 2H), 3.99-3.88 (ddd, J=m, 2H), 3.85-3.76 (m, 1H), 2.84 (s, 3H), 2.83-2.75 (m, 1H), 2.72-2.61 (m, 1H), 2.49-2.38 (m, 1H), 1.24-1.12 (m, 4H). ESI MS m/z 532 [C29H27ClFN5O2+H]+; HPLC 98.8% (AUC), tR=10.10 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 brown solid
  9. temperatureThe reaction mixture was heated at 65° C. for 16 h
  10. temperaturecooled to room temperature
  11. concentrationconcentrated
  12. customThe resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA)
  13. dissolutionThe residue was dissolved in methanol (8 mL)
  14. concentrationThe resultant solution was concentrated

Sources & evidence

ORD record
ord-635b5285335e46aea2fc344eadb31057
Source dataset
uspto-grants-2015_09
Patent number
US09120749B2

Reaction notes

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