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 2069180ノート

反応式

HRID 2069180 の反応式
[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

参加物

8

反応物 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

生成物 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-carboxylate収率 51.3%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 1140Toluene溶媒

反応条件

温度
60 °C

実験手順

(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).

後処理

  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)

出典と根拠

ORDレコード
ord-8309f27cd4be434baeba9efa8415afa5
出典データセット
uspto-grants-2012_10
特許番号
US08299021B2

反応ノート

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