1,1'-Carbonyldiimidazole → (2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a (cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15, 16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate

HRID 2069175Notes

Reaction equation

[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][C:37]=4[F:40])[CH2:32]3)=[O:30])[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19][C@:18]2([C:43](O)=[O:44])[CH2:42][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.S([O-])(O)(=O)=O.[K+]>C1(C)C=CC=CC=1.O>[F:40][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:38]=1[CH2:39][N:31]([C:29]([O:28][C@H:26]1[CH2:25][N:22]3[C:23](=[O:24])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH:15]=[CH:16][C@@H:17]4[CH2:42][C@@:18]4([C:43](=[O:44])[NH:64][S:61]([CH:58]4[CH2:60][CH2:59]4)(=[O:63])=[O:62])[NH:19][C:20](=[O:41])[C@@H:21]3[CH2:27]1)=[O:30])[CH2:32]2

Participants

Conditions

Temperature: 60 °C

Procedure

(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecine-14a-carboxylic acid (0.072 g, 0.11 mmol) in toluene (3 mL) was added di(1H-imidazol-1-yl)methanone (0.024 g, 0.15 mmol) in rt. The reaction was stirred at 60° C. for 3 hrs. Cyclopropanesulfonamide (0.021 g, 0.17 mmol) was added, followed by addition of DBU (0.043 ml, 0.29 mmol). The reaction was then stirred at rt for 17 hrs. Water (5 mL) was added and acidified with saturated potassium hydrogen sulfate until pH=2˜3. The mixture was extracted with ethyl acetate (20 mL), washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Ethyl acetate) to (2R,6S, 13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.057 g, 68%). MS: Calcd.: 733. Found: [M+H]+ 734. 1H NMR (400 MHz, d6-DMSO) δ 1.08 (s, 1H), 9.03 (d, J=10.8 Hz, 1H), 7.34 (m, 1H), 7.11-7.33 (m, 3H), 5.46 (m, 1H), 5.30 (s, 1H), 5.23 (m, 1H), 4.67 (s, 4H), 4.42 (m, 1H), 4.28 (m, 1H), 3.95 (m, 1H), 3.69 (m, 1H), 3.56 (m, 1H), 3.41 (m, 1H), 3.32 (m, 1H), 3.26 (m, 1H), 2.91 (m, 1H), 2.18-2.40 (m, 5H), 1.92 (m, 1H), 1.75 (m, 1H), 1.61 (m, 2H), 1.00-1.28 (m, 13H).

Workup

stirringThe reaction was then stirred at rt for 17 hrs
extractionThe mixture was extracted with ethyl acetate (20 mL)
washwashed with brine
dry with materialdried over sodium sulfate
customAfter removal of solvent
customthe residue was purified by chromatography (Ethyl acetate) to (2R,6S, 13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.057 g, 68%)

Sources & evidence

ORD record: ord-8bda0bcfd4d34938b83ebbc80098c7c1
Source dataset: uspto-grants-2012_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08299021B2

Reaction notes

Loading…