Potassium Phosphate, Tribasic → HCID 86711417, compound

HRID 926343Notes

Reaction equation

HRID 926343 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)[CH2:12][CH: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)[CH2:12][CH:7]23)[CH2:33][CH2:28]1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 86711418HCID 86711418, compound

Product 1

HCID 86711417HCID 86711417, compoundYield 70.4%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

Example 143. 9-bromo-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-1,7,8,12b-tetrahydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (148 mg, 0.367 mmol) was dissolved in toluene (3.6 mL) and S-Phos (49 mg, 0.117 mmol), cyclopropylboronic acid (66 mg, 0.734 mmol) and K3PO4 (164 mg, 0.771 mmol) were added. The suspension was degassed, Pd(OAc)2 (17 mg, 0.073 mmol) was added under Argon and the mixture was heated at 100° C. for 1.5 h. The mixture was allowed to warm to RT and filtered through a pad of celite 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 3 min, then from 1% MeOH in DCM to 4% MeOH in DCM in 12 min, 4% MeOH in DCM for 3 min) to yield a yellow foam. Further purification by SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60 A, Princeton; eluent: 11% MeOH/CO2 for 1 min, then from 11% MeOH/CO2 to 16% MeOH/CO2 in 6 min; flow 100 mL/min; UV detection at 220 nm) gave the title compound as white foam (30 mg). UPLC-MS: MS 365.3 (M+H+); UPLC rt 0.85 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.51-0.66 (m, 2 H), 0.86-0.98 (m, 2 H), 1.86-2.00 (m, 1 H), 2.97-3.09 (m, 2 H), 3.21 (s, 3 H), 3.54-3.66 (m, 1 H), 3.67-3.77 (m, 1 H), 4.11-4.30 (m, 3 H), 5.26 (d, J=15.31 Hz, 1 H), 5.73 (dd, J=9.91, 4.89 Hz, 1 H), 6.95 (d, J=7.28 Hz, 1 H), 7.12-7.21 (m, 1 H), 7.21-7.27 (m, 1 H), 7.57 (s, 1 H), 8.10 (s, 1 H).

Workup

  1. customThe suspension was degassed
  2. temperatureto warm to RT
  3. filtrationfiltered through a pad of celite
  4. customthe solvent was removed under reduced pressure
  5. customThe crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent
  6. waitfrom 1% MeOH in DCM to 4% MeOH in DCM in 12 min
  7. custom4% MeOH in DCM for 3 min) to yield a yellow foam
  8. customFurther purification by SFC (column
  9. waiteluent: 11% MeOH/CO2 for 1 min
  10. waitfrom 11% MeOH/CO2 to 16% MeOH/CO2 in 6 min

Sources & evidence

ORD record
ord-a17eee32184048ef80f1ab48c04aa36f
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

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