2,6-Lutidine → 3-[8-chloro-1-[[(3S)-1-prop-2-enoylpyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,4-dihydro-1,2,4-triazol-5-one

HRID 1476906Notes

Reaction equation

Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([NH:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[N:10][C:9]([C:19]1[NH:23][C:22](=[O:24])[NH:21][N:20]=1)=[CH:8]2.CC1C=CC=C(C)N=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([N:16]1[CH2:17][CH2:18][C@H:14]([NH:13][C:11]2[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[Cl:2])[CH:8]=[C:9]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:10]=2)[CH2:15]1)(=[O:36])[CH:34]=[CH2:35]

Participants

Conditions

Temperature: -40 °C

Procedure

To a mixture of (S)-3-(8-chloro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (100 mg, 0.3 mmol) in DCM (20 mL) was added 2,6-dimethylpyridine (97 mg, 0.91 mmol). The resulting mixture was cooled to −40° C. Acryloyl chloride (51 mg, 0.6 mmol, 10 mg/mL in dry DCM) was added dropwise and the mixture was stirred at −40° C. for 30 minutes. The reaction was subsequently quenched with MeOH (5 mL) and the mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (57 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 11.80 (s, 1H), 7.85-7.83 (m, 1H), 7.61-7.59 (m, 3H), 7.49-7.47 (m, 1H), 6.6-6.5 (m, 1H), 6.17-6.13 (m, 1H), 5.67-5.63 (m, 1H), 5.18-5.16 (m, 1H), 4.18-4.17 (m, 0.5H), 3.69-3.65 (m, 0.5H), 3.42 (m, 0.5H), 3.32-3.31 (m, 1.5H), 2.31-2.29 (m, 1H), 2.04-2.01 (m, 1H); ESI-MS m/z [M+H]+ 385.1.

Workup

customThe reaction was subsequently quenched with MeOH (5 mL)
concentrationthe mixture was concentrated in vacuo
customThe crude product was purified by preparative HPLC

Sources & evidence

ORD record: ord-88b9a72357b8415d92a756ca2ec6116c
Source dataset: uspto-grants-2016_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09402841B2

Reaction notes

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