Water → 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 20960

反応式

HRID 20960 の反応式
[Si]([O:8][C@H:9]([C@H:32]1[CH2:36][C:35]([OH:43])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][N:33]1C(OC(C)(C)C)=O)[C@@H:10](NC(=O)C1C=CC=C(C(=O)N)C=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H]([NH:70][C:71](=[O:88])[C:72]1[CH:77]=[CH:76][CH:75]=[C:74]([C:78]([N:80]2[CH2:84][CH2:83][CH2:82][C@@H:81]2COC)=[O:79])[CH:73]=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.[C:105]1([Mg]Br)C=CC=CC=1.O>C1COCC1>[CH2:84]([N:80]([CH3:105])[C:78](=[O:79])[C:74]1[CH:75]=[CH:76][CH:77]=[C:72]([C:71]([NH:70][C@@H:10]([CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)[C@H:9]([OH:8])[C@H:32]2[CH2:36][C:35]([OH:43])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:34][NH:33]2)=[O:88])[CH:73]=1)[CH2:83][CH2:82][CH3:81]

参加物

6

反応物 4

HCID 962WaterHCID 67316242(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylateHCID 68558510(2R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylateHCID 178418255HCID 178418255、化合物3 回

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 42%

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

反応条件

温度
0 °C

実験手順

Step 6 (E): Preparation of (2R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate. To a solution of (R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-oxopyrrolidine-1-carboxylate (Step 6 (D), 25 mg, 0.036 mmol) in THF (1 mL) was added phenylmagnesium bromide (3.0 M in diethyl ether, 0.0144 mL, 0.0432 mmol) at −20° C. After stirring for 20 min, the reaction mixture was warmed up to 0° C. and stirred for 30 min and another portion of phenylmagnesium bromide (3.0 M in diethyl ether, 0.0144 mL, 0.0432 mmol) was added and the reaction mixture was stirred at rt for 2 h. Another portion of phenylmagnesium bromide (3.0 M in diethyl ether, 0.024 mL, 0.072 mmol) was added and the reaction mixture was stirred at rt for 2 days. H2O (50 mL) was added and the mixture was extracted with ethyl acetate, dried (Na2SO4) and concentrated. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% EtOAc/Hexane step gradient) to give 12 mg of the title compound (42% yield): 1H NMR (CDCl3, 500 MHz) δ 0.15 (3H, s), 0.20 (3H, s), 0.72-0.79 (1H, m), 0.86 (1H, m), 0.96 (9H, s), 1.08-1.11 (1H, m), 1.45 (9H, s), 1.58-1.62 (1H, m), 1.77 (3H, s), 2.52 (2H, d, J=5 Hz), 2.63 (1H, m), 2.87-3.04 (3H, m), 3.16 (1H, brd s), 3.28 (1H, d, J=10 Hz), 3.51 (1H, brd s), 3.66 (1H, d, J=15 Hz), 3.78 (1H, d, J=10H), 3.95 (1H, m), 4.30 (1H, s), 4.56 (2H, s), 6.59 (1H, t, J=10 Hz), 6.78 (2H, d, J=5 Hz), 7.14 (1H, m), 7.24-7.27 (1H, m), 7.34 (2H, m), 7.39 (1H, m), 7.46-7.50 (3H, m), 7.68 (2H, m). MS (ESI) (M+H)+ 780.49.

後処理

  1. stirringstirred for 30 min
  2. stirringthe reaction mixture was stirred at rt for 2 h
  3. stirringthe reaction mixture was stirred at rt for 2 days
  4. extractionthe mixture was extracted with ethyl acetate
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. customThe crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% EtOAc/Hexane step gradient)

出典と根拠

ORDレコード
ord-e8219be87f814c8594729607d0806901
出典データセット
uspto-grants-2010_06
特許番号
US07745470B2

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