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

HRID 20971

Reaktionsgleichung

Reaktionsgleichung von HRID 20971
[Si](O[C@H:9]([C@H]1CC(O)(C2C=CC=CC=2)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:16]([F:18])[CH:15]=[C:14](F)C=1)(C(C)(C)C)(C)C.[Si]([O:58][C@H:59]([C@H:94]1[CH2:98][C@@H:97]([O:99][CH2:100][CH2:101][CH3:102])[CH2:96][N:95]1C(OC(C)(C)C)=O)[C@@H:60](NC(=O)C1C=C(C2OC=CN=2)C=C(C(N2CCC[C@@H]2COC)=O)C=1)[CH2:61][C:62]1[CH:67]=[C:66]([F:68])[CH:65]=[C:64]([F:69])[CH:63]=1)(C(C)(C)C)(C)C>Cl.O>[F:69][C:64]1[CH:63]=[C:62]([CH2:61][C@H:60]([NH:29][C:28](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([NH:20][CH:10]([C:11]3[CH:12]=[CH:17][C:16]([F:18])=[CH:15][CH:14]=3)[CH3:9])=[O:31])[CH:23]=2)[C@H:59]([OH:58])[C@H:94]2[CH2:98][C@@H:97]([O:99][CH2:100][CH2:101][CH3:102])[CH2:96][NH:95]2)[CH:67]=[C:66]([F:68])[CH:65]=1

Komponenten

5

Edukt 2

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-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-carboxylate

Produkt 1

HCID 11848639N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-N3-(1-(4-fluorophenyl)ethyl)isophthalamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterKatalysatorHCID 313Hydrochloric AcidLösungsmittel

Versuchsvorschrift

Step 16 (B): N1-((1R,2 S)-3-(3,5-Difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propran-2-yl)-N3-(1-(4-fluorophenyl)ethyl)isophthalamide. The solution of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyoxy)-2-(3-(carbonyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (Step 16 (A), 38 mg) in HCl (4.0 M solution in dioxane, 1 mL) was added 2 drops of H2O and the mixture was stirred at rt for 1 h. The solvent was removed and the mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S5 column, 34-90% methanol/H2O/0.1% TFA) to give 30 mg of the title compound: 1H NMR (CD3OD, 500 MHz) δ ppm 0.97 (3H, m), 1.58 (3H, d, J=5 Hz), 1.62 (2H, m), 2.17 (1H, m), 2.50 (1H, m), 2.86 (1H, m), 3.34-3.49 (5H, m), 3.81 (1H, m), 4.06 (1H, dd, J=5, 10 Hz), 4.22-4.25 (2H, m), 5.21-5.27 (1H, m), 6.73 (1H, m), 6.89-6.90 (2H, m), 7.07 (2H, m), 7.41-7.44 (2H, m), 7.53 (1H, t, J=10 Hz), 7.79-7.82 (1H, m), 7.96 (1H, m), 8.12-8.14 (1H, m), MS (ESI) (M+H)+ 584.32.

Aufarbeitung

  1. customThe solvent was removed
  2. customthe mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S5 column, 34-90% methanol/H2O/0.1% TFA)

Quellen und Nachweise

ORD-Eintrag
ord-57999718f56e48d58498c538ec308c46
Quelldatensatz
uspto-grants-2010_06
Patentnummer
US07745470B2

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