Tetrahydrofuran → 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid

HRID 1948493Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1948493
[OH:1][C@@H:2]([C:16]1[CH:21]=[CH:20][C:19](/[C:22](=[N:24]/O)/[NH2:23])=[CH:18][CH:17]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][C:11]([O:13]CC)=[O:12])[CH2:5]1.CCN(C(C)C)C(C)C.[C:35]1([C:41]2[C:45]([C:46]([F:49])([F:48])[F:47])=[C:44]([C:50](F)=[O:51])[O:43][N:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(#N)C.C(OCC)(=O)C>[OH:1][CH:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:24]=[C:50]([C:44]3[O:43][N:42]=[C:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:45]=3[C:46]([F:49])([F:48])[F:47])[O:51][N:23]=2)=[CH:18][CH:17]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][C:11]([OH:13])=[O:12])[CH2:5]1

Komponenten

8

Edukt 5

HCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 2724141Tetrabutylammonium FluorideHCID 58374067HCID 58374067, VerbindungHCID 58374196ethyl 2-[(3R)-1-[(2S)-2-hydroxy-2-[4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]ethyl]piperidin-3-yl]acetate

Produkt 1

HCID 669554722-((3R)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6342AcetonitrileLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

To a mixture of ethyl 2-((R)-1-((S)-2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate (198 mg, 0.567 mmol) and DIEA (0.198 mL, 1.133 mmol) in acetonitrile (10 mL) was added 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride, Int-I-G (147 mg, 0.567 mmol). The reaction mixture was stirred at room temperature. After 1 hr, TBAF in THF (0.567 mL, 0.567 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated. The resulting solids were purified on a silica gel cartridge using an EtOAc/hexanes gradient. Isolated fractions with correct mass by LCMS were concentrated in vacuo. The product was then treated with 6N HCl/MeCN at 50° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 107 mg of 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.13 (2H, d, J=8.35 Hz), 7.57-7.64 (4H, m), 7.44-7.55 (3H, m), 5.17 (1H, dd, J=9.23, 4.39 Hz), 3.81 (1H, d, J=11.86 Hz), 3.56 (1H, d, J=11.42 Hz), 3.24-3.31 (2H, m), 2.82-2.95(1H, m), 2.72 (1H, t, J=11.86 Hz), 2.16-2.40 (3H, m), 1.79-1.95 (3H, m), 1.10-1.34 (1H, m). MS (m+1)=543. HPLC Peak RT=3.26 minutes. Purity=98%.

Aufarbeitung

  1. stirringthe reaction mixture was stirred overnight
  2. washwashed with H2O
  3. dry with materialThe organic layer was dried with MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe resulting solids were purified on a silica gel cartridge
  7. concentrationIsolated fractions with correct mass by LCMS were concentrated in vacuo
  8. additionThe product was then treated with 6N HCl/MeCN at 50° C. overnight
  9. filtrationThe reaction mixture was filtered
  10. custompurified by HPLC
  11. custom25 minute
  12. customIsolated fractions with correct mass were freeze-dried overnight

Quellen und Nachweise

ORD-Eintrag
ord-476207a3d7dd4e2c9324a844b0551ef6
Quelldatensatz
uspto-grants-2013_03
Patentnummer
US08399451B2

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