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

HRID 1476907Notes

Reaction equation

Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[CH:5]=[C:4]([C:14]#[N:15])[N:3]=1.[NH2:16][C@H:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1.CCN(CC)CC>CN1C(=O)CCC1>[C:14]([C:4]1[N:3]=[C:2]([NH:16][C@H:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH3:13])#[N:15]

Participants

Conditions

Temperature: 130 °C

Procedure

To a solution of 1-chloro-8-methoxyisoquinoline-3-carbonitrile (230 mg, 1.05 mmol) in NMP (5 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (294 mg, 1.57 mmol) and Et3N (212 mg, 2.1 mmol). The reaction mixture was heated to 130° C. for 45 minutes in a microwave reactor and was subsequently quenched with H2O (20 mL). The aqueous phase was extracted with EtOAc (3×10 mL). The organic layers were combined and concentrated in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate and petroleum ether (EtOAc/PE=1:20-1:2 gradient) to give the title compound (380 mg, 2 batches, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (s, 1H), 7.55 (t, 1H, J=8.0 Hz), 7.25 (s, 1H), 6.97 (d, 1H, J=8.0 Hz), 4.60-4.80 (m, 1H), 4.01 (s, 3H), 3.78-3.79 (m, 1H), 3.27-3.57 (m, 3H), 2.29-2.34 (m, 1H), 1.94-1.99 (m, 1H), 1.48 (s, 9H).

Workup

customwas subsequently quenched with H2O (20 mL)
extractionThe aqueous phase was extracted with EtOAc (3×10 mL)
concentrationconcentrated in vacuo
customThe crude product was purified by column chromatography
washeluting with ethyl acetate and petroleum ether (EtOAc/PE=1:20-1:2 gradient)

Sources & evidence

ORD record: ord-68e795d2ba5045479ee68e922b0851a3
Source dataset: uspto-grants-2016_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09402841B2

Reaction notes

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