Morpholine → (S)-4-(2-oxo-3-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

HRID 420797Notes

Reaction equation

FC1C=CC(S([N:11]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:30][CH2:29][C@@H:28](O)[C:27]3=[O:32])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=O)=O)=CC=1.CCN(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:68]=[C:67]2[C:62]([CH2:63][CH2:64][NH:65][CH2:66]2)=[CH:61][CH:60]=1.N1CCOCC1>C(Cl)Cl>[O:32]=[C:27]1[C@@H:28]([N:65]2[CH2:64][CH2:63][C:62]3[C:67](=[CH:68][C:59]([C:58]([F:57])([F:70])[F:69])=[CH:60][CH:61]=3)[CH2:66]2)[CH2:29][CH2:30][N:26]1[C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:19])=[O:18])=[CH:21][CH:22]=1

Participants

Conditions

Temperature: -25 °C

Procedure

A solution of (R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide (12.4 g, 24.9 mmol) in DCM (80 mL) was stirred under nitrogen at −25° C. To the reaction mixture was added DIEA (9.6 g, 13 mL, 74.6 mmol) followed by dropwise addition of triflic anhydride (10.5 g, 6.30 mL, 37.3 mmol). The reaction mixture was stirred at −25° C. for 90 minutes. A solution of 7-trifluoromethyl-tetrahydroisoquinoline (5.0 g, 24.9 mmol) in DCM (10 mL) was added to the reaction mixture and stirring was continued under nitrogen at −25° C. for 1 h. Morpholine (4.33 g, 4.3 mL, 49.7 mmol) was added and the cooling bath was removed. The reaction mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure and purified by silica gel column chromatography (0.5-10% MeOH in DCM). The product obtained was taken up in DCM and precipitated by addition of Et2O providing a white solid (5.25 g, 40%), which was collected by filtration. 1H NMR (400 MHz, DMSO-d6) δ: 12.0 (s, 1H), 7.84 (dd, J=9.0, 22.8 Hz, 4H), 7.46 (bs, 2H), 7.32-7.30 (m, 1H), 7.26 (d, J=4.6 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 4.12 (d, J=15.3 Hz, 1H), 3.92-3.78 (m, 4H), 3.15-3.10 (m, 1H), 2.90-2.83 (m, 3H), 2.34-2.27 (m, 1H) and 2.19-2.10 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=523.3; tR=1.18 minMS (ESI) m/e (M+H+) 523.3, retention time: 1.18 min (10-99% CH3CN in H2O).

Workup

stirringstirring
waitwas continued under nitrogen at −25° C. for 1 h
customthe cooling bath was removed
stirringThe reaction mixture was stirred at room temperature for 30 minutes
concentrationconcentrated under reduced pressure
custompurified by silica gel column chromatography (0.5-10% MeOH in DCM)
customThe product obtained
customprecipitated by addition of Et2O providing a white solid (5.25 g, 40%), which
filtrationwas collected by filtration

Sources & evidence

ORD record: ord-0af46116ae504f8496c7959544b6eb49
Source dataset: uspto-grants-2012_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08097636B2

Reaction notes

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