Dimethylformamide → HCID 90387218, compound

HRID 1476887Notes

Reaction equation

HRID 1476887 reaction equation
Cl[C:2]1[N:3]=[C:4]([NH: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]([NH: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 90387035HCID 90387035, compound

Product 1

HCID 90387218HCID 90387218, compoundYield 72%

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)amino)pyrrolidine-1-carboxylate (0.5 g, 1.37 mmol) in DMF (15 mL) was added Zn(CN)2 (0.48 g, 4.1 mmol), and Pd(PPh3)4(0.16 g, 0.14 mmol) under a nitrogen atmosphere. The mixture was heated to 160° C. for 30 minutes in a microwave reactor. The mixture was partition between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The organic layers were combined, 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=10:1-5:1 gradient) to give the title compound (0.36 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38-8.35 (d, J=10.8 Hz, 1H), 8.01-7.97 (m, 1H), 7.77-7.72 (m, 3H), 4.66-4.58 (m, 1H), 3.69-3.67 (m, 1H), 3.48-3.46 (m, 1H), 3.39-3.37 (m, 1H), 3.28-3.27 (m, 1H), 2.2 (s, 1H), 1.97-1.91 (m, 1H), 1.40 (s, 9H).

Workup

  1. customThe mixture was partition between EtOAc (50 mL) and water (50 mL)
  2. extractionThe aqueous layer was 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=10:1-5:1 gradient)

Sources & evidence

ORD record
ord-26d71569f9ac470b92ecbec9aa9eb3bd
Source dataset
uspto-grants-2016_08
Patent number
US09402841B2

Reaction notes

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