4-Methylmorpholine → Tert-Butyl (3R,4S)-3-({cyclopropyl[3-({(1R,2R)-2-[(2,3-dihydro-1H-inden-5-yloxy)-carbonyl]cyclopropyl}methoxy)-5-(3-methoxypropyl)benzyl]amino}-carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate

HRID 1798466ノート

反応式

HRID 1798466 の反応式
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33]([N:35]([CH2:39][C:40]2[CH:41]=[C:42]([CH:51]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:53]=2)[O:43][CH2:44][C@@H:45]2[CH2:47][C@H:46]2[C:48]([OH:50])=[O:49])[CH:36]2[CH2:38][CH2:37]2)=[O:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:74]1[C:82]2[C:77](=[CH:78][C:79](O)=[CH:80][CH:81]=2)[CH2:76][CH2:75]1.[H-].[Na+]>C(Cl)Cl.C1COCC1>[CH:36]1([N:35]([CH2:39][C:40]2[CH:53]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:51]=[C:42]([O:43][CH2:44][C@@H:45]3[CH2:47][C@H:46]3[C:48]([O:50][C:79]3[CH:78]=[C:77]4[C:82](=[CH:81][CH:80]=3)[CH2:74][CH2:75][CH2:76]4)=[O:49])[CH:41]=2)[C:33]([C@@H:10]2[C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]4[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[Cl:32])=[CH:16][CH:15]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]2)=[O:34])[CH2:37][CH2:38]1

参加物

8

反応物 5

HCID 79724-MethylmorpholineHCID 151185-IndanolHCID 24758Sodium hydrideHCID 62365Isobutyl chloroformateHCID 68488708(1R,2R)-2-{[3-{[[((3R,4S)-1-(tert-Butoxycarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl](cyclopropyl)amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylic Acid

生成物 1

HCID 86641741Tert-Butyl (3R,4S)-3-({cyclopropyl[3-({(1R,2R)-2-[(2,3-dihydro-1H-inden-5-yloxy)-carbonyl]cyclopropyl}methoxy)-5-(3-methoxypropyl)benzyl]amino}-carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate

試薬・触媒・溶媒 2

HCID 6344Dichloromethane溶媒HCID 8028Tetrahydrofuran溶媒

反応条件

温度
-20 °C

実験手順

To a solution of (1R,2R)-2-{[3-{[[((3R,4S)-1-(tert-butoxycarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl](cyclopropyl)-amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylic acid (1 eq.) from Example 4/Step 1 in DCM (0.1 M) at −20° C. was added N-methylmorpholine (1.3 eq.) and isobutylchloroformate (1.3 eq.). The reaction was stirred at −20° C. for 45 min. Meanwhile, a solution of indan-5-ol (2 eq) in THF (0.2) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1 eq.), stirred for 30 min at rt, and added to the reaction at −15° C. The reaction was stirred at rt for 18 h and then quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 35% EtOAc in Hex) to afford the title compound as an oil.

後処理

  1. customat −20° C.
  2. stirringstirred for 30 min at rt
  3. additionadded to the reaction at −15° C
  4. stirringThe reaction was stirred at rt for 18 h
  5. customquenched with saturated aqueous NaHCO3 solution
  6. extractionThe aqueous layer was extracted with EtOAc
  7. washThe combined organic extracts were washed with brine
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated in vacuo
  10. customThe crude product was purified by flash column chromatography (SiO2, 35% EtOAc in Hex)

出典と根拠

ORDレコード
ord-bc8c38e03d1446c38348ab772d692f74
出典データセット
uspto-grants-2013_01
特許番号
US08343968B2

反応ノート

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