HCID 86711365, compound → HCID 73335824, compound

HRID 926292Notes

Reaction equation

HRID 926292 reaction equation
I[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]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:19]3)[CH:12]=[C:7]12.[CH2:26]([Zn]CC)[CH3:27]>O1CCOCC1.CCOC(C)=O.Cl.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].C(Cl)Cl>[CH2:26]([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]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:19]3)[CH:12]=[C:7]12)[CH3:27]

Participants

7

Reactant 2

HCID 86711365HCID 86711365, compoundHCID 178418750HCID 178418750, compound

Product 1

HCID 73335824HCID 73335824, compoundYield 31.9%

Reagents, catalysts & solvents 4

HCID 178418807HCID 178418807, compoundCatalystHCID 313Hydrochloric AcidSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a degassed solution of 9-iodo-2-(4-isopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (20 mg, 0.045 mmol) and PdCl2(dppf)-CH2Cl2 adduct (2 mg, 2.24 μmol) in dioxane (1 mL) was added diethylzinc (135 μL, 0.135 mmol, 1M in hexane) and the mixture was heated in the microwave at 80° C. for 44 h. The reaction mixture was allowed to warm to rt and then diluted with AcOEt and 2M aqueous HCl. The organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by SFC (column: Diol 5 μm, 250×30 mm, 60 A, Princeton; eluent: 7% MeOH/CO2 for 1 min, then from 7% MeOH/CO2 to 12% MeOH/CO2 in 6 min; flow 100 mL/min; UV detection at 220 nm) to yield the title compound (5 mg). UPLC-MS: MS 349.2 (M+H+); UPLC rt 1.01 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.21-1.28 (m, 9 H) 2.72 (q, J=7.4 Hz, 2 H) 2.85-2.92 (m, 1 H) 2.96 (t, J=6.2 Hz, 2 H) 3.91 (t, J=6.3 Hz, 2 H) 4.35 (br. s., 2 H) 6.61 (s, 1 H) 7.18 (s, 1 H) 7.27-7.38 (m, 2 H) 7.52 (d, J=7.3 Hz, 1 H) 7.93 (s, 1 H).

Workup

  1. temperatureto warm to rt
  2. customThe organic phase was separated
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customThe crude product was purified by SFC (column
  6. waitfrom 7% MeOH/CO2 to 12% MeOH/CO2 in 6 min

Sources & evidence

ORD record
ord-072b62110c9b46288f7a22b572b5cf44
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

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