Potassium Phosphate, Tribasic → HCID 89980399, compound

HRID 532931Notes

Reaction equation

HRID 532931 reaction equation
Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH:12]=[C:7]12.CO[C:28]1C=CC=C(OC)[C:33]=1[C:34]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C1(B(O)O)CC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:34]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]2[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]4[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]4)[CH:12]=[C:7]23)[CH2:33][CH2:28]1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 89979803HCID 89979803, compound

Product 1

HCID 89980399HCID 89980399, compoundYield 306.8%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

Example 96-1. 9-bromo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (7.73 g, 19.26 mmol) was dissolved in toluene (155 mL) and S-Phos (2.58 g, 6.16 mmol), cyclopropylboronic acid (3.45 g, 38.5 mmol) and K3PO4 (8.59 g, 40.5 mmol) were added. The suspension was degassed, Pd(OAc)2 (0.87 g, 3.85 mmol) was added under Argon and the mixture was heated at 100° C. for 1 h. The mixture was allowed to warm to RT and filtered through a pad of celite. The residue was diluted with DCM and extracted with water, saturated aqueous NaHCO3 solution and brine. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 1% MeOH in DCM for 5 min, then from 1% MeOH in DCM to 5% MeOH in DCM in 60 min, 5% MeOH in DCM for 10 min) to yield a beige foam (6.85 g). The residue was crystallized from AcOEt to afford the title compound as white crystals (5.8 g). UPLC-MS: MS 363.3 (M+H+); UPLC rt 0.95 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 0.50-0.72 (m, 2 H), 0.79-1.06 (m, 2 H), 1.77-2.08 (m, 1 H), 2.93-3.14 (m, 2 H), 3.24 (s, 3 H), 3.87 (br. s, 2 H), 4.13-4.39 (m, 4 H), 7.09-7.21 (m, 2 H), 7.24-7.35 (m, 1 H), 7.62 (s, 1 H), 7.84-7.94 (m, 1 H), 8.20 (s, 1 H).

Workup

  1. customThe suspension was degassed
  2. temperatureto warm to RT
  3. filtrationfiltered through a pad of celite
  4. additionThe residue was diluted with DCM
  5. extractionextracted with water, saturated aqueous NaHCO3 solution and brine
  6. dry with materialThe combined organic layers were dried with sodium sulfate
  7. filtrationfiltered
  8. customthe solvent was removed under reduced pressure
  9. customThe crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent
  10. waitfrom 1% MeOH in DCM to 5% MeOH in DCM in 60 min

Sources & evidence

ORD record
ord-ff4f1cb331a548e8b8e1967c2b1bfb89
Source dataset
uspto-grants-2014_10
Patent number
US08853203B2

Reaction notes

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