Triethylamine → (S)-tert-butyl 3-((3-cyano-8-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate

HRID 1476877Notes

Reaction equation

HRID 1476877 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[CH:5]=[C:4]([C:13]#[N:14])[N:3]=1.CCN(CC)CC.[NH2:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1>CN1C(=O)CCC1>[C:13]([C:4]1[N:3]=[C:2]([NH:22][C@H:23]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])#[N:14]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 854071tert-butyl (3S)-3-aminopyrrolidine-1-carboxylateHCID 903868251-Chloro-8-fluoroisoquinoline-3-carbonitrile

Product 1

HCID 90387010(S)-tert-butyl 3-((3-cyano-8-fluoroisoquinolin-1-yl)amino)pyrrolidine-1-carboxylateYield 81%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
160 °C

Procedure

To a suspension of 1-chloro-8-fluoroisoquinoline-3-carbonitrile (0.8 g, 3.88 mmol) and Et3N (0.78 g, 7.76 mmol) in NMP (5 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.87 g, 4.66 mmol) at RT. The resulting mixture was heated at 160° C. for 30 minutes in a microwave reactor. The reaction was quenched with water and the mixture was extracted with EtOAc (3×30 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate and petroleum ether (EtOAc/PE=1:50-1:9 gradient) on silica gel to give the title compound (1.12 g, 81%). 1H NMR (400 MHz, CDCl3) δ ppm 7.56-7.52 (m, 1H), 7.44-7.42 (d, 1H, J=8.0 Hz), 7.29 (s, 1H), 7.21-7.18 (m, 1H), 6.47-6.43 (m, 1H), 4.73 (br s, 1H), 3.77-3.72 (dd, J1=6.4 Hz, J2=11.6 Hz, 1H), 3.48-3.19 (m, 3H), 2.26 (br s, 1H), 1.90 (br s, 1H), 1.41 (s, 9H); ESI-MS m/z [M+H-tert-butyl]+ 301.2.

Workup

  1. customThe reaction was quenched with water
  2. extractionthe mixture was extracted with EtOAc (3×30 mL)
  3. dry with materialThe organic phase was dried over Na2SO4
  4. concentrationconcentrated in vacuo
  5. customThe crude product was purified by column chromatography
  6. washeluting with ethyl acetate and petroleum ether (EtOAc/PE=1:50-1:9 gradient) on silica gel

Sources & evidence

ORD record
ord-135c3ce5decd479ea301483974657220
Source dataset
uspto-grants-2016_08
Patent number
US09402841B2

Reaction notes

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