Hydrochloric Acid → HCID 178467106, compound

HRID 2271976Notes

Reaction equation

HRID 2271976 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@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F: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@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]

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 178467065HCID 178467065, compound

Product 1

HCID 178467106HCID 178467106, compoundYield 91.2%

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-((trans-4-(2-(dimethylamino)ethyl)cyclohexyl)amino)quinolin-3-yl)ethanone (63 mg, 0.15 mmol), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61 mg, 0.22 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 a mixture of CHCl3/isopropanol (3:1). The desired fractions were concentrated and dissolved in methanol and resultant residue was dissolved in methanol (4 mL) and HCl (1.25 M in methanol, 1.5 mL, 1.9 mmol) was added. The resulting solution was concentrated to give the desired product (55.9 mg, 67%) as an off-white solid NMR (500 MHz, MeOD) δ 9.10 (s, 1H), 8.50 (s, 1H), 8.27 (dd, J=8.7, 1.7 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.52 (dd, J=11.4, 2.3 Hz, 1H), 4.54-4.50 (m, 1H), 3.25-3.17 (m, 2H), 2.90 (s, 6H), 2.73 (s, 3H), 2.42 (d, J=12.2 Hz, 2H), 2.04 (d, J=12.9 Hz, 2H), 1.80-1.68 (m, 4H), 1.59 (br s, 1H), 1.39-1.27 (m, 2H). ESI MS m/z 484 [C27H31ClFN3O2+H]+; HPLC>99% (AUC), tR=10.01 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
  8. additionwith a mixture of CHCl3/isopropanol (3:1)
  9. concentrationThe desired fractions were concentrated
  10. dissolutiondissolved in methanol
  11. dissolutionresultant residue was dissolved in methanol (4 mL)
  12. concentrationThe resulting solution was concentrated

Sources & evidence

ORD record
ord-966b011c07f04458b4c865028e800502
Source dataset
uspto-grants-2015_09
Patent number
US09120749B2

Reaction notes

Loading…