Hydrochloric Acid → HCID 178478882, compound

HRID 2271975Notes

Reaction equation

HRID 2271975 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@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:54]>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:30].[ClH:54].[Cl:30][C:31]1[CH:36]=[C:35]([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[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:20][CH2:19]2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 667160792-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenolHCID 178519792HCID 178519792, compound

Product 1

HCID 178478882HCID 178478882, compoundYield 72.1%

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 (6-bromo-4-((trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)amino) quinoline-3-yl)(cyclopropyl)methanone (60 mg, 0.13 mmol), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (54 mg, 0.20 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). The reaction mixture was degassed with nitrogen and heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with a satd. aq. NaHCO3 (20 mL) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired fractions were combined and concentrated and the residue was dissolved in methanol (4 mL) and HCl (1.25 M in methanol, 1.5 mL, 1.9 mmol). The mixture was concentrated to obtain the desired product (42.9 mg, 55%) as an off-white solid. 1H NMR (500 MHz, MeOD) δ 9.35 (br s, 1H), 8.47 (br s, 1H), 8.27 (dd, J=8.8, 1.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.60 (br s, 1H), 7.53 (d, J=11.1 Hz, 1H), 4.51 (br s, 1H), 3.74-3.66 (m, 2H), 3.18-3.07 (m, 4H), 2.85 (br s, 1H), 2.44 (br s, 2H), 2.24-1.96 (m, 5H), 1.83-1.71 (m, 2H), 1.36-1.18 (m, 6H). ESI MS m/z 522 [C30H33ClFN3O2+H]+; HPLC 98.9% (AUC), tR=10.35 min.

Workup

  1. customThe reaction mixture was degassed with nitrogen
  2. temperatureThe reaction mixture was cooled to room temperature
  3. additiondiluted with a satd
  4. extractionaq. NaHCO3 (20 mL) and extracted with ethyl acetate
  5. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  6. concentrationconcentrated
  7. custompurified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA)
  8. concentrationconcentrated
  9. dissolutionthe residue was dissolved in methanol (4 mL)
  10. concentrationThe mixture was concentrated

Sources & evidence

ORD record
ord-a3ce9dd9d4644106b32ab97f7bcc3a82
Source dataset
uspto-grants-2015_09
Patent number
US09120749B2

Reaction notes

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