Butyl vinyl ether → 3-(4-Acetyl-phenyl)-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester

HRID 1520787Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1520787
[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]([O:22]CCCC)=[CH2:21].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Komponenten

7

Edukt 4

HCID 8108Butyl vinyl etherHCID 812191,3-Bis(diphenylphosphino)propaneHCID 516892Sodium BicarbonateHCID 58079744Tert-butyl 3-(4-bromophenyl)-3-fluoroazetidine-1-carboxylate

Produkt 1

HCID 716803193-(4-Acetyl-phenyl)-3-fluoro-azetidine-1-carboxylic acid tert-butyl esterAusbeute 57,66 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 167845palladium(II) acetateKatalysatorHCID 702EthanolLösungsmittel

Reaktionsbedingungen

Temperatur
96 °C

Versuchsvorschrift

In 100 mL autoclave vessel, a solution of 3-(4-bromo-phenyl)-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (Intermediate from Step 5a; 5 g, 15.142 mmol, 1 eq) in ethanol (17.5 mL) was degassed with nitrogen gas for 30 minutes at room temperature. TEA (3.79 mL, 27.256 mmol, 1.8 eq), butyl vinyl ether (BVE, 3.91 mL, 30.282 mmol, 2 eq), 1,3-bis(diphenylphosphino)propane (DPPP, 0.375 g, 0.909 mmol, 0.06 eq) were added followed by addition of Pd(OAc)2 (0.102 g, 0.454 mmol, 0.03 eq.) at room temperature. Resulting reaction mixture was heated at 96° C. for 16 hours in an autoclave. After complete consumption of starting material, the reaction mixture was quenched with 1N HCl (5 mL, pH˜2-3) and stirred for 2 hours at room temperature. After 2 hours, the pH of reaction mixture was adjusted to 7 by addition of saturated NaHCO3 solution and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (250 mL), dried over sodium sulphate and concentrated under reduced pressure to get crude compound as dark brown sticky oil (6.1 g, Crude). Crude compound was purified by column chromatography on silica gel using 230-400 silica mesh. Desired compound was eluted in 10% ethyl acetate in n-hexane to give product as off white semisolid (2.56 g, 57.66%). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 9H), 2.61 (s, 3H), 4.20 (dd, J1=0.88 Hz, J2=10.28 Hz, 1H), 4.24 (dd, J1=0.92 Hz, J2=10.36 Hz, 1H), 4.39 (dd, J1=1.28 Hz, J2=10.24 Hz, 1H), 4.44 (dd, J1=1.28 Hz, J2=10.20 Hz, 1H), 7.55 (dd, J1=1.48 Hz, J2=8.48 Hz, 2H), 8.00 (d, J=7.96 Hz, 2H), LC-MS (m/z): 294.1 (M+H).

Aufarbeitung

  1. customResulting
  2. customreaction mixture
  3. customAfter complete consumption of starting material
  4. customthe reaction mixture was quenched with 1N HCl (5 mL, pH˜2-3)
  5. waitAfter 2 hours
  6. customthe pH of reaction mixture
  7. extractionextracted with ethyl acetate (3×50 mL)
  8. washThe combined organic layer was washed with brine (250 mL)
  9. dry with materialdried over sodium sulphate
  10. concentrationconcentrated under reduced pressure
  11. customto get crude compound as dark brown sticky oil (6.1 g, Crude)
  12. customCrude compound was purified by column chromatography on silica gel using 230-400 silica mesh
  13. washDesired compound was eluted in 10% ethyl acetate in n-hexane

Quellen und Nachweise

ORD-Eintrag
ord-80c3adb00b944307aa31cff9b6e3b74d
Quelldatensatz
uspto-grants-2015_07
Patentnummer
US09073912B2

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