Dimethylformamide → HCID 90386902, compound

HRID 1476863Notes

Reaction equation

HRID 1476863 reaction equation
Cl[C:2]1[N:3]=[C:4]([O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[CH3:26][N:27](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([C:2]1[N:3]=[C:4]([O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2)#[N:27]

Participants

5

Reactant 2

HCID 6228DimethylformamideHCID 90387231HCID 90387231, compound

Product 1

HCID 90386902HCID 90386902, compoundYield 65%

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
160 °C

Procedure

To a solution of (S)-tert-butyl 3-((3-chloro-7-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (1 g, 2.73 mmol) in DMF (10 mL) was added Zn(CN)2 (0.64 g, 5.46 mmol) and Pd(PPh3)4 (0.316 g, 0.273 mmol) under N2. The mixture was heated at 160° C. for 30 minutes in a microwave reactor and was subsequently partition between EtOAc (50 mL) and water (50 mL). The aqueous phase was back-extracted with EtOAc (3×50 mL) and the organic layers were combined and washed with saturated aqueous NaCl (3×50 mL) and concentrated in vacuo. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=20:1-5:1 gradient) to give the title compound (0.65 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 8.19-8.16 (dd, J1=5.2 Hz, J2=3.6 Hz, 1H), 7.97-7.95 (m, 2H), 5.73-5.69 (d, J=16 Hz, 1H), 3.71-3.67 (m, 1H), 3.58-3.50 (m, 3H), 2.25-2.24 (d, J=4 Hz, 2H), 1.42-1.39 (d, J=12 Hz, 9H).

Workup

  1. customwas subsequently partition between EtOAc (50 mL) and water (50 mL)
  2. extractionThe aqueous phase was back-extracted with EtOAc (3×50 mL)
  3. washwashed with saturated aqueous NaCl (3×50 mL)
  4. concentrationconcentrated in vacuo
  5. customThe crude product was purified by column chromatography
  6. washeluting with petroleum ether and ethyl acetate (PE/EtOAc=20:1-5:1 gradient)

Sources & evidence

ORD record
ord-984fc0613fe24c3d875ac11bee2c76da
Source dataset
uspto-grants-2016_08
Patent number
US09402841B2

Reaction notes

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