Reaktionsgleichung
[Si]([O:8][C@H:9]([C@H:44]1[CH2:48][C@@H:47]([O:49][CH2:50][CH2:51][CH3:52])[CH2:46][N:45]1C(OC(C)(C)C)=O)[C@@H:10](NC(=O)C1C=C(C2OC=CN=2)C=C(C(N2CCC[C@@H]2COC)=O)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:68]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H:69]([NH:79][C:80](=[O:90])[C:81]1[CH:86]=[CH:85][CH:84]=[C:83]([C:87](=[O:89])[NH2:88])[CH:82]=1)[CH2:70][C:71]1[CH:76]=[C:75]([F:77])[CH:74]=[C:73](F)C=1)(C(C)(C)C)(C)C.C(OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](NC(C1C=C(C=CC=1)C(O)=O)=O)CC1C=C(F)C=C(F)C=1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC1C=CC(C(N)C)=CC=1>ClCCl>[F:19][C:14]1[CH:13]=[C:12]([CH2:11][C@H:10]([NH:88][C:87](=[O:89])[C:83]2[CH:84]=[CH:85][CH:86]=[C:81]([C:80]([NH:79][CH:69]([C:70]3[CH:71]=[CH:76][C:75]([F:77])=[CH:74][CH:73]=3)[CH3:68])=[O:90])[CH:82]=2)[C@H:9]([OH:8])[C@H:44]2[CH2:48][C@@H:47]([O:49][CH2:50][CH2:51][CH3:52])[CH2:46][NH:45]2)[CH:17]=[C:16]([F:18])[CH:15]=1Komponenten
Edukt 6
HCID 81531Diisopropylethylamine
HCID 1230631-(4-Fluorophenyl)ethylamine
HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)
HCID 67315032(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate
HCID 673161403-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acid
HCID 67316383(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylateProdukt 1
Reagenzien, Katalysatoren, Lösungsmittel 1
Versuchsvorschrift
Step 16 (A): (2R,4R)-tert-Butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl) propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acid (Step 1 (C), 40 mg, 0.06 mmol) in dichloromethane (1.5 mL) was added Hunig's base (24 mg, 0.18 mmol) to make a clear solution and HATU (28 mg, 0.072 mmol) was then added. After stirring for 20 min, the reaction mixture was added 1-(4-fluorophenyl)ethanamine (17 mg, 0.12 mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under vacuum and purified by silica gel Flash Chromatography (0% to 15% to 30% EtOAc/Hexane step gradient) to give 38 mg of the title compound (84% yield): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.05 (3H, s), 0.84 (9H, s), 0.89 (3H, m), 1.47 (9H, s), 1.50 (2H, m), 1.58 (3H, d, J=5 Hz), 2.00-2.05 (1H, m), 2.22 (1H, m), 2.64 (1H, m), 2.86-2.92 (1H, m), 3.28-3.37 (3H, m), 3.76 (1H, m), 4.00 (1H, m), 4.07-4.12 (2H, m), 4.61 (1H, m), 5.31 (1H, m), 6.51-6.52 (1H, m), 6.60 (1H, m), 6.77 (2H, d, J=10 Hz), 7.00 (2H, m), 7.34 (2H, dd, J=5, 10 Hz), 7.49 (1H, m), 7.99-8.02 (2H, m), 8.20 (1H, s), 8.33 (1H, m). MS (ESI) (M+H)+ 798.46.
Aufarbeitung
- additionwas then added
- stirringthe reaction mixture was stirred at rt overnight
- concentrationThe reaction mixture was concentrated under vacuum
- custompurified by silica gel Flash Chromatography (0% to 15% to 30% EtOAc/Hexane step gradient)
Quellen und Nachweise
- ORD-Eintrag
- ord-14c0020543a843d68a4a0064666dd7f4
- Quelldatensatz
- uspto-grants-2010_06
- Patentnummer
- US07745470B2
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