Potassium Phosphate, Tribasic → HCID 73336213, compound

HRID 926305Notes

Reaction equation

HRID 926305 reaction equation
Br[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:17](=[O:18])[CH2:16][N:15]=[C:14]([N:19]3[CH:23]=[C:22]([CH2:24][O:25][CH3:26])[N:21]=[CH:20]3)[CH:13]=[C:7]12.CO[C:29]1C=CC=C(OC)[C:34]=1[C:35]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.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].CO>[CH:35]1([C:2]2[C:11]([F:12])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]2[C:17](=[O:18])[CH2:16][N:15]=[C:14]([N:19]4[CH:23]=[C:22]([CH2:24][O:25][CH3:26])[N:21]=[CH:20]4)[CH:13]=[C:7]23)[CH2:34][CH2:29]1

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2760897Cyclopropylboronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 86711377HCID 86711377, compound

Product 1

HCID 73336213HCID 73336213, compound

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 887MethanolSolvent4×HCID 1140TolueneSolventHCID 6344DichloromethaneSolvent4×

Conditions

Temperature
100 °C

Procedure

Example 96-2. 9-bromo-10-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (1.5 g, 3.58 mmol) was dissolved in toluene (36 mL) and S-Phos (0.47 g, 1.14 mmol), cyclopropylboronic acid (0.615 g, 7.16 mmol) and K3PO4 (1.59 g, 7.51 mmol) were added. The suspension was degassed, Pd(OAc)2 (0.16 g, 0.72 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. 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: 50% AcOEt in DCM for 5 min, then from 50% AcOEt in DCM to 100% AcOEt in DCM in 40 min, followed by 100% AcOEt in DCM for 10 min)) to yield a foam. A second flash-column chromatography over silicagel was done (Biotage Isolera Four, eluent: 0.5% MeOH in DCM for 4 min, then from 0.5% MeOH in DCM to 4% MeOH in DCM in 60 min, 4% MeOH in DCM for 20) to yield the title compound as a yellow solid. The residue was dissolved in DCM and MP-TMT resin (0.71 mmol/g) was added and the mixture was stirred for 2.5 h. The resin was filtered off and the solvent was removed under reduced pressure to yield a yellow foam. The foam was crystallized from hot n-butanol to afford the title compound as white crystals (683 mg). UPLC-MS: MS 381.3 (M+H+); UPLC rt 3.53 min (10 min method). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.55-0.64 (m, 2 H), 0.94-1.04 (m, 2 H), 1.67-1.78 (m, 1 H), 3.08 (t, J=5.99 Hz, 2 H), 3.23 (s, 3 H), 3.77-3.88 (m, 2 H), 4.22 (br. s., 2 H), 4.27 (s, 2 H), 7.10-7.20 (m, 2 H), 7.63 (s, 1 H), 7.98 (dd, J=8.93, 5.01 Hz, 1 H), 8.20 (d, J=1.47 Hz, 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 50% AcOEt in DCM to 100% AcOEt in DCM in 40 min
  11. waitfollowed by 100% AcOEt in DCM for 10 min
  12. custom)) to yield a foam

Sources & evidence

ORD record
ord-b1dff079a2d341fb8538b57e4cb1d8f1
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

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