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

HRID 2069180노트

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HRID 2069180 반응식
[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

참가 물질

8

반응물 5

HCID 682631,1'-CarbonyldiimidazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 516920Potassium bisulfateHCID 15765418CyclopropanesulfonamideHCID 68792524(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

생성물 1

HCID 44187034(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-carboxylate수율 51.3%

시약·촉매·용매 2

HCID 962Water용매HCID 1140Toluene용매

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온도
60 °C

실험 절차

(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).

후처리

  1. stirringThe reaction was then stirred at rt for 17 hrs
  2. extractionThe mixture was extracted with ethyl acetate (20 mL)
  3. washwashed with brine
  4. dry with materialdried over sodium sulfate
  5. customAfter removal of solvent
  6. customthe residue was purified by chromatography (Ethyl acetate)

출처 및 근거

ORD 기록
ord-8309f27cd4be434baeba9efa8415afa5
출처 데이터셋
uspto-grants-2012_10
특허 번호
US08299021B2

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