Dabco → N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R)-4-hydroxy-4-phenylpyrrolidin-2-yl)propan-2-yl)-N1-methylisophthalamide

HRID 1014880

反応式

HRID 1014880 の反応式
[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:30])[NH2:29])[CH:23]=1)[CH2:11][C:12]1[CH:17]=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.C(OC([C@@H:58]([CH2:81][C:82]1[CH:87]=[C:86]([F:88])[CH:85]=[C:84]([F:89])[CH:83]=1)[C@@H:59]([C@H:68]1[CH2:72][C@@H:71]([OH:73])[CH2:70][N:69]1C(OC(C)(C)C)=O)[O:60][Si](C(C)(C)C)(C)C)=O)C1C=CC=CC=1.C(O[C@H]1CN(C(OC(C)(C)C)=O)[C@@H]([C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](C(OCC2C=CC=CC=2)=O)C[C:109]2[CH:114]=[C:113](F)[CH:112]=[C:111](F)[CH:110]=2)C1)C=C.[CH2:135]1N2CCN(CC2)C1.[OH-].[Na+].[O-][Mn](=O)(=O)=O.[K+]>O.CCO.CCOC(C)=O.CCCCCC.CO>[CH2:10]([N:20]([CH3:135])[C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH:29][C@@H:58]([CH2:81][C:82]2[CH:83]=[C:84]([F:89])[CH:85]=[C:86]([F:88])[CH:87]=2)[C@H:59]([OH:60])[C@H:68]2[CH2:72][C:71]([OH:73])([C:109]3[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=3)[CH2:70][NH:69]2)=[O:30])[CH:23]=1)[CH2:11][CH2:12][CH3:17]

参加物

10

反応物 6

HCID 9237DabcoHCID 14798Sodium HydroxideHCID 516875Potassium PermanganateHCID 67315032(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylateHCID 67316089(2R,4R)-tert-butyl 2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-hydroxypyrrolidine-1-carboxylateHCID 67316571(2R,4R)-tert-butyl 4-(allyloxy)-2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)pyrrolidine-1-carboxylate

生成物 1

HCID 11848528N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R)-4-hydroxy-4-phenylpyrrolidin-2-yl)propan-2-yl)-N1-methylisophthalamide収率 77%

試薬・触媒・溶媒 3

HCID 887Methanol溶媒HCID 19096565Water ethanol溶媒HCID 21226206Ethyl acetate hexane溶媒

反応条件

温度
140 °C

実験手順

Step 6 (A): (2R,4R)-tert-butyl 2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-hydroxypyrrolidine-1-carboxylate. To a solution of (2R,4R)-tert-butyl 4-(allyloxy)-2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)pyrrolidine-1-carboxylate (Preparation A, 730 mg, 1.11 mmol) in H2O/EtOH (0.8/7 mL) were added RhCl(PPh3)3 (77 mg, 0.083 mmol) and DABCO (25 mg, 0.22 mmol). The mixture was stirred at 140° C. for 3 h and then cooled to rt. MeOH (20 mL) and 1N NaOH solution (5 mL) were added followed by 0.1% KMnO4 solution (5 mL) dropwise. The reaction mixture was stirred at rt for 1.5 h and quenched with H2O. The mixture was extracted with ethyl acetate (300 mL) twice and solvent was removed. Flash chromatography (silica gel, 0% to 10% to 20% to 35% EtOAc/Hexane step gradient) gave the title compound (530 mg, 77% yield): 1H NMR (CDCl3, 500 MHz) δ 0.10-0.13 (6H, m), 0.93 (9H, s), 1.22-1.27 (2H, m), 1.46 (9H, s), 2.13 (2H, s), 3.23-3.25 (2H, m), 3.54-3.89 (2H, m), 4.12 (1H, m), 4.22 (1H, s), 4.32 (1H, m), 4.86-5.03 (3H, m), 6.60-6.70 (3H, m), 7.17 (2H, s), 7.27-7.28 (3H, m). MS (ESI) (M+H)+ 621.25.

後処理

  1. temperaturecooled to rt
  2. stirringThe reaction mixture was stirred at rt for 1.5 h
  3. customquenched with H2O
  4. extractionThe mixture was extracted with ethyl acetate (300 mL) twice
  5. customsolvent was removed

出典と根拠

ORDレコード
ord-c38f696e426b408db32d14eab08d6407
出典データセット
uspto-grants-2011_07
特許番号
US07981913B2

関連ノート

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