1-Phenethylamine → N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-N3-(1-phenylethyl)isophthalamide

HRID 20969

Reaktionsgleichung

Reaktionsgleichung von HRID 20969
[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]([NH:20][C:21](=[O:43])[C:22]1[CH:27]=[C:26](C2OC=CN=2)[CH:25]=[C:24]([C:33]([N:35]2[CH2:39][CH2:38][CH2:37][C@@H:36]2[CH2:40]OC)=[O:34])[CH:23]=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](NC(=O)C1C=CC=C(C(=O)N)C=1)CC1C=C(F)C=C(F)C=1)([C:63](C)([CH3:65])[CH3:64])(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.C1(C(N)C)C=CC=CC=1>ClCCl>[F:19][C:14]1[CH:13]=[C:12]([CH2:11][C@H:10]([NH:20][C:21](=[O:43])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:33]([NH:35][CH:36]([C:37]3[CH:65]=[CH:63][CH:64]=[CH:39][CH:38]=3)[CH3:40])=[O:34])[CH:23]=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]=1

Komponenten

8

Edukt 6

HCID 74081-PhenethylamineHCID 81531DiisopropylethylamineHCID 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-carboxylateHCID 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 acidHCID 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-carboxylate

Produkt 1

HCID 11848638N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-N3-(1-phenylethyl)isophthalamideAusbeute 87 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel

Versuchsvorschrift

Step 15 (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-phenylethanamine (15 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 40 mg of the title compound (87% yield): 1H NMR (CDCl3, 500 MHz) δ 0.01 (3H, s), 0.05 (3H, s), 0.85 (9H, s), 0.89 (3H, m), 1.46 (9H, s), 1.50 (2H, m), 1.58 (3H, d, J=5 Hz), 2.02-2.05 (1H, m), 2.20 (1H, dd, J=5, 10 Hz), 2.64 (1H, m), 2.88-2.94 (1H, m), 3.30-3.37 (3H, m), 3.78 (1H, dd, J=5, 15 Hz), 4.00 (1H, m), 4.07-4.13 (2H, m), 4.60 (1H, m), 5.33 (1H, m), 6.56-6.61 (2H, m), 6.77 (2H, d, J=10 Hz), 7.25 (1H, m), 7.32 (2H, m), 7.37 (2H, m), 7.48 (1H, m), 7.97-8.01 (2H, m), 8.20 (1H, m), 8.24-8.31 (1H, m). MS (ESI) (M+H)+ 780.49.

Aufarbeitung

  1. additionwas then added
  2. stirringthe reaction mixture was stirred at rt overnight
  3. concentrationThe reaction mixture was concentrated under vacuum
  4. custompurified by silica gel Flash Chromatography (0% to 15% to 30% EtOAc/Hexane step gradient)

Quellen und Nachweise

ORD-Eintrag
ord-ec40ef2253214084936caf1b296c4d2a
Quelldatensatz
uspto-grants-2010_06
Patentnummer
US07745470B2

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