Hydrochloric Acid → (2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid

HRID 1622498Notes

Reaction equation

HRID 1622498 reaction equation
Br[C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:13][CH2:12]3)[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:3]=1.[B:32]1(B2OC(C)(C)C(C)(C)O2)[O:36]C(C)(C)C(C)(C)[O:33]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+].Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH:11]1([C:8]2[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[C:16]=3[CH3:25])[C:6]3[CH:5]=[C:4]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:3]=[C:2]([B:32]([OH:36])[OH:33])[C:10]=3[N:9]=2)[CH2:13][CH2:12]1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 866878534-(4-bromo-2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine

Product 1

HCID 71599551(2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acidYield 20.9%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of 4-(4-bromo-2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (1.01 g, 2.043 mmol), bis(pinacolato)diboron (1.556 g, 6.13 mmol), Pd2(dba)3 (0.094 g, 0.102 mmol), X-Phos (0.097 g, 0.204 mmol) and potassium acetate (0.602 g, 6.13 mmol) in 1,4-Dioxane (20 mL) in a 40 mL scintillation vial was heated for 1 hr at 95° C. When cooled the reaction contents were poured into 1N HCl (10 ml) and H2O (10 mL) mixture, swirled and then extracted with EtOAc, dried over MgSO4 and concentrated in-vacuo. The residue was dissolved in MeOH and the material was purified by reverse phase chromatography eluting with a gradient 30% CH3CN to 60% CH3CN over 10 minutes. The fractions containing clean desired compound were combined and concentrated in-vacuo to provide the desired product (196 mg, 0.427 mmol, 20.89% yield) as a clear oil after drying in a vacuum oven at 50° C. The oil was triturated to provide an analytically pure off-white powder (2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid (115 mg, 0.250 mmol, 12.26% yield). m/e: 459.2, 460.3 [M+H]+; 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.67 (d, J=8.08 Hz, 1H), 7.50 (br. s., 1H), 7.28 (t, J=7.83 Hz, 1H), 7.08 (d, J=2.27 Hz, 1H), 6.73 (d, J=8.08 Hz, 1H), 5.90 (s, 2H), 3.72-3.92 (m, 4H), 3.10-3.23 (m, 4H), 2.21-2.42 (m, 1H), 1.22-1.37 (m, 4H).

Workup

  1. temperatureWhen cooled
  2. customthe reaction contents
  3. extractionextracted with EtOAc
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in-vacuo
  6. dissolutionThe residue was dissolved in MeOH
  7. customthe material was purified by reverse phase chromatography
  8. washeluting with a gradient 30% CH3CN to 60% CH3CN over 10 minutes
  9. additionThe fractions containing clean desired compound
  10. concentrationconcentrated in-vacuo

Sources & evidence

ORD record
ord-216b1058dcab4ded9269291df4c43d7a
Source dataset
uspto-grants-2014_07
Patent number
US08778937B2

Reaction notes

Loading…