Trifluoroacetic acid → 2-(2-(3-(4-((S)-2,3-dihydroxypropoxy)-3,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-2-(4-fluorophenyl)cyclohexanone

HRID 71231Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 71231
[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1([CH2:14][CH2:15][C:16]([OH:18])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC1(C)[O:24][C@H:23]([CH2:25][O:26][C:27]2[C:36]([CH3:37])=[CH:35][C:30]([C:31](=[NH:34])[NH:32]O)=[CH:29][C:28]=2[CH3:38])[CH2:22][O:21]1.C(N=C=NC(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(O)(C(F)(F)[F:75])=O>ClCCl>[OH:24][C@@H:23]([CH2:22][OH:21])[CH2:25][O:26][C:27]1[C:36]([CH3:37])=[CH:35][C:30]([C:31]2[N:34]=[C:16]([CH2:15][CH2:14][C:3]3([C:8]4[CH:9]=[CH:10][C:11]([F:75])=[CH:12][CH:13]=4)[CH2:4][CH2:5][CH2:6][CH2:7][C:2]3=[O:1])[O:18][N:32]=2)=[CH:29][C:28]=1[CH3:38]

Komponenten

8

Edukt 6

HCID 6422Trifluoroacetic acidHCID 8028Tetrahydrofuran2×HCID 12734DiisopropylcarbodiimideHCID 2008413-(2-Oxo-1-phenylcyclohexyl)propanoic acidHCID 2724141Tetrabutylammonium Fluoride2×HCID 178426656HCID 178426656, Verbindung

Produkt 1

HCID 566439532-(2-(3-(4-((S)-2,3-dihydroxypropoxy)-3,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-2-(4-fluorophenyl)cyclohexanoneAusbeute 34 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel

Versuchsvorschrift

A solution of 3-(1-(4-fluorophenyl)-2-oxocyclohexyl)propanoic acid (30 mg, 0.114 mmol, Preparation 1B) and (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-hydroxy-3,5-dimethylbenzimidamide (33.4 mg, 0.114 mmol) in dichloromethane (900 μL) was treated with N,N′-diisopropylcarbodiimide (19 μL, 0.125 mmol). The reaction mixture was stirred at room temperature for 1.5 h and concentrated. The residue was dissolved in acetonitrile (900 μL) and treated with a solution of 1N tetra-n-butylammonium fluoride in THF (57 μL, 0.057 mmol). After 2.5 h, additional 1N tetra-n-butylammonium fluoride solution in THF (28 μL, 0.028 mmol) was added and stirring was continued for 16 h. The reaction mixture cooled to 0° C. and treated with TFA (1.5 mL). After 1 min, the ice bath was removed and stirring was continued for additional 55 min. The reaction mixture was concentrated and the residue was purified by reversed-phase autoprep HPLC (Phenomenex S10 30×100 mm, 40 min gradient time, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.1% TFA; Final solvent: 90% aq. MeOH—0.1% TFA) to obtain 2-(2-(3-(4-((S)-2,3-dihydroxypropoxy)-3,5-dimethylphenyl)-1,2,4-oxadiazol-5-yl)ethyl)-2-(4-fluorophenyl)cyclohexanone (23.2 mg, 34% yield) as a white solid. LC/MS: m/e 483.16 (M+H)+. 1H NMR (400 MHz, CD3OD): δ ppm 7.59 (s, 2H), 7.20-7.23 (m, 2H), 7.06-7.10 (m, 2H), 3.91-3.99 (m, 1H), 3.82-3.89 (m, 1H), 3.74-3.81 (m, 1H), 3.59-3.72 (m, 2H), 2.75-2.86 (m, 1H), 2.33-2.2 (m, 2H), 2.56-2.74 (m, 2H), 2.30-2.42 (m, 2H), 2.29 (s, 6H), 2.19-2.26 (m, 1H), 2.00-2.12 (m, 1H), 1.90-2.00 (m, 1H), 1.63-1.85 (m, 4H).

Aufarbeitung

  1. concentrationconcentrated
  2. dissolutionThe residue was dissolved in acetonitrile (900 μL)
  3. waitAfter 2.5 h
  4. stirringstirring
  5. waitwas continued for 16 h
  6. temperatureThe reaction mixture cooled to 0° C.
  7. waitAfter 1 min
  8. customthe ice bath was removed
  9. stirringstirring
  10. waitwas continued for additional 55 min
  11. concentrationThe reaction mixture was concentrated
  12. customthe residue was purified by reversed-phase autoprep HPLC (Phenomenex S10 30×100 mm, 40 min gradient time, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.1% TFA; Final solvent: 90% aq. MeOH—0.1% TFA)

Quellen und Nachweise

ORD-Eintrag
ord-45375eed5e69498e89706b9bf271c499
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08822510B2

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