tert-butyl ((2S,3S)-3-((R)-hex-5-en-2-yloxy)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-1-oxopentan-2-yl)carbamate → tert-butyl ((2R,6S,7S,9R,13aS,14aR,16aS,Z)-7-ethyl-2-hydroxy-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa[i]pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecin-6-yl)carbamate

HRID 523182

反応式

HRID 523182 の反応式
[CH3:1][C@@H:2]([O:7][C@@H:8]([CH2:44][CH3:45])[C@H:9]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18](=[O:35])[NH:19][C@:20]1([C:25](=[O:34])[NH:26][S:27]([C:30]2([CH3:33])[CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH2:22][C@H:21]1C=C)=[O:11])[CH2:3][CH2:4][CH:5]=[CH2:6]>CC1C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru](Cl)(Cl)=CC1C=CC=CC=1OC(C)C.ClCCCl>[CH2:44]([C@H:8]1[C@H:9]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:42])[CH3:41])[C:10](=[O:11])[N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[C:18](=[O:35])[NH:19][C@:20]2([C:25](=[O:34])[NH:26][S:27]([C:30]3([CH3:33])[CH2:31][CH2:32]3)(=[O:29])=[O:28])[CH2:21][C@H:22]2[CH:6]=[CH:5][CH2:4][CH2:3][C@@H:2]([CH3:1])[O:7]1)[CH3:45]

参加物

4

反応物 1

HCID 118425558tert-butyl ((2S,3S)-3-((R)-hex-5-en-2-yloxy)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-1-oxopentan-2-yl)carbamate

生成物 1

HCID 90132196tert-butyl ((2R,6S,7S,9R,13aS,14aR,16aS,Z)-7-ethyl-2-hydroxy-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa[i]pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecin-6-yl)carbamate

試薬・触媒・溶媒 2

HCID 11763533(1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene)(dichloro)((2-((propan-2-yl)oxy)phenyl)methylidene)ruthenium触媒HCID 111,2-Dichloroethane溶媒

反応条件

温度
80 °C

実験手順

To a round-bottom flask equipped with a stir bar was added tert-butyl ((2S,3S)-3-((R)-hex-5-en-2-yloxy)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-1-oxopentan-2-yl)carbamate (all material from step 4, 569 mg, 0.869 mmol) and DCE (100 mL). The solution was sparged with nitrogen for 30 min. and then to the solution was added (1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium (“Hoveyda-Grubbs Catalyst 2nd Generation”, 27 mg, 0.043 mmol). The solution was stirred at 80° C. for 2 h and then cooled to 45° C. and stirred for 3 days. The solution was concentrated in vacuo and the resulting residue was subjected to silica gel purification (hexanes:acetone 80:20 to 40:60). The product containing fractions were pooled; concentrated; and re-subjected to silica gel chromatography (hexanes:acetone 80:20 to 40:60) to afford tert-butyl ((2R,6S,7S,9R,13aS,14aR,16aS,Z)-7-ethyl-2-hydroxy-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa[i]pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecin-6-yl)carbamate as a light-brown solid foam (90 mg, 10% over 5 steps). 1H-NMR (500 MHz, CD3OD) δ 8.93 (s, 1H), 5.61 (td, J=10.1, 6.2 Hz, 1H), 5.03 (t, J=10.3 Hz, 1H), 4.58 (br. s., 1H), 4.47-4.37 (m, 2H), 3.92 (br. s., 2H), 3.86-3.79 (m, 1H), 3.58-3.49 (m, 1H), 2.75 (q, J=9.5 Hz, 1H), 2.64-2.52 (m, 1H), 2.23-2.11 (m, 2H), 1.92-1.80 (m, 2H), 1.75 (dd, J=8.5, 5.5 Hz, 1H), 1.66-1.60 (m, 1H), 1.59-1.52 (m, 2H), 1.49 (s, 4H), 1.43 (s, 9H), 1.41-1.32 (m, 2H), 1.15 (d, J=6.3 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H), 0.88-0.84 (m, 2H).

後処理

  1. customTo a round-bottom flask equipped with a stir bar
  2. customThe solution was sparged with nitrogen for 30 min.
  3. temperaturecooled to 45° C.
  4. stirringstirred for 3 days
  5. concentrationThe solution was concentrated in vacuo
  6. customthe resulting residue was subjected to silica gel purification (hexanes:acetone 80:20 to 40:60)
  7. additionThe product containing fractions
  8. concentrationconcentrated

出典と根拠

ORDレコード
ord-0f40bc58e2ce4249815c092e2b578bda
出典データセット
uspto-grants-2016_05
特許番号
US09334279B2

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