1,1'-Carbonyldiimidazole → (2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-9-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a, 14,14a,15,16,16a-hexadecahydrocyclopropa(n)pyrrolo[2,1-c][1,4,9]triazacyclopentadecine-2-yl 4-fluoroisoindoline-2-carboxylate

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Reaktionsgleichung

[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH2:20][CH2:19][CH:18]=[CH:17][C@@H:16]2[CH2:36][C@@:15]2([C:37](O)=[O:38])[NH:14][C:13](=[O:40])[C@@H:12]2[CH2:41][C@@H:42]([O:44][C:45]([N:47]3[CH2:55][C:54]4[C:49](=[CH:50][CH:51]=[CH:52][C:53]=4[F:56])[CH2:48]3)=[O:46])[CH2:43][N:11]2[C:10]1=[O:57])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH:70]1([S:73]([NH2:76])(=[O:75])=[O:74])[CH2:72][CH2:71]1.C1CCN2C(=NCCC2)CC1.S([O-])(O)(=O)=O.[K+]>C1(C)C=CC=CC=1.O>[F:56][C:53]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:54]=1[CH2:55][N:47]([C:45]([O:44][C@H:42]1[CH2:43][N:11]3[C@H:12]([C:13](=[O:40])[NH:14][C@:15]4([C:37](=[O:38])[NH:76][S:73]([CH:70]5[CH2:72][CH2:71]5)(=[O:75])=[O:74])[CH2:36][C@H:16]4[CH:17]=[CH:18][CH2:19][CH2:20][N:21]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH2:22][CH2:23][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]3=[O:57])[CH2:41]1)=[O:46])[CH2:48]2

Komponenten

Reaktionsbedingungen

Temperatur: 60 °C

Versuchsvorschrift

(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-9-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa(n)pyrrolo[2,1-c][1,4,9]triazacyclopentadecine-14a-carboxylic acid (0.71 g, 0.87 mmol) in toluene (10 mL) was added di(1H-imidazol-1-yl)methanone (0.18 g, 1.13 mmol) in rt. The reaction was stirred at 60° C. for 3 hrs. Cyclopropanesulfonamide (0.16 g, 1.31 mmol) was added, followed by addition of DBU (0.26 ml, 1.74 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 give (2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-9-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa(n)pyrrolo[2,1-c][1,4,9]triazacyclopentadecine-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.41 g, 51%). MS: Calcd.: 917. Found: [M+H]+ 918. 1H NMR (400 MHz, d6-DMSO) δ 0.99 (s, 1H), 9.12 (s, 1H), 8.04 (m, 1H), 7.98 (m, 1H), 7.87 (m, 2H), 7.33 (m, 2H), 7.08-7.21 (m, 2H), 5.48 (m, 1H), 5.32 (m, 1H), 5.27 (m, 1H), 4.67 & 4.65 (s, 4H), 4.42 (m, 1H), 4.33 (m, 1H), 4.00 (m, 1H), 3.70 (m, 1H), 3.61 (m, 1H), 3.43 (m, 1H), 3.32 (m, 1H), 3.03 (m, 1H), 2.90 (m, 2H), 2.48 (m, 2H), 2.13 (m, 1H), 1.99 (m, 2H), 1.63 (m, 1H), 083-1.24 (m, 15H).

Aufarbeitung

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)

Quellen und Nachweise

ORD-Eintrag: ord-8309f27cd4be434baeba9efa8415afa5
Quelldatensatz: uspto-grants-2012_10
DOI: 10.6084/m9.figshare.5104873.v1
Patentnummer: US08299021B2

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