Morpholine → HCID 68513627, Verbindung

HRID 1948372

Reaktionsgleichung

Reaktionsgleichung von HRID 1948372
C([Li])CCC.[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[Cl:12][C:13]1[CH:18]=[C:17](C(OC)=O)[N:16]=[C:15]([C:23](OC)=[O:24])[CH:14]=1.O1CCN([Li])CC1.C(O[CH:38]([O:43]C(C)C)[O:39][CH:40]([CH3:42])[CH3:41])(C)C>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:23]([N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[O:24])[N:16]=[C:17]([C:38]([O:39][CH:40]([CH3:41])[CH3:42])=[O:43])[CH:18]=1

Komponenten

7

Edukt 5

HCID 8083MorpholineHCID 78191Propane, 2,2',2''-[methylidynetris(oxy)]tris-HCID 2378452,6-Dimethyl 4-chloropyridine-2,6-dicarboxylate2×HCID 178418339ButyllithiumHCID 178506921HCID 178506921, Verbindung

Produkt 1

HCID 68513627HCID 68513627, VerbindungAusbeute 16,7 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel2×

Versuchsvorschrift

n-butyllithium (1.92 mL, 2.5M in hexanes) was added dropwise to a −78° C. solution of morpholine (0.42 mL, 4.8 mmol) in anhydrous THF followed by slow warming to room temperature. The solution was transferred to an addition funnel via cannulation and then added dropwise to a solution of dimethyl 4-chloropyridine-2,6-dicarboxylate (1.0 g, 4.4 mmol, Intermediate 251) in anhydrous THF. A slight precipitate was observed during the addition. After stirring two hrs at room temperature an additional 0.5 equivalence of the morpholino-lithium reagent was added to the reaction and after an additional two hrs of stirring another 0.5 equivalence was added followed by stirring one hour to reach completion. The solvent was removed under reduced pressure and the residue was suspended in methylene chloride and the product was extracted with a sat. sodium bicarbonate solution (×3). The sodium bicarbonate portion was acidified with conc. HCl to pH 3 and then extracted with EtOAc (×10), followed by drying with MgSO4 and concentrating to a solid (0.8 g, 70%). MS (ES) MH+: 271 for C11H11ClN2O4. The solid was suspended in anhydrous toluene (75 mL) and to this was added triisopropylorthoformate (1.97 mL, 8.9 mmol) slowly followed by heating to reflux for 12 hours. After cooling to room temperature the solvent was removed under reduced pressure and the residue was suspended in 1N HCl. Basification to pH8 with saturated sodium bicarbonate followed by extraction with EtOAc (×3), drying with MgSO4 and removal of solvent yielded a tan solid. Purification by silica gel flash column (gradient elution to 3:1 EtOAc:CH2Cl2) yielded a white solid (0.23 g) MS (ES) MH+: 313 for C14H17ClN2O4; NMR: 1.33 (s, 3 H) 1.35 (s, 3 H) 3.41 (s, 2 H) 3.44 (d, 2 H) 3.58 (d, 2 H) 3.68 (s, 4 H) 5.17 (dt, 1 H) 8.01 (d, 1H) 8.13 (d, 1 H).

Aufarbeitung

  1. customThe solution was transferred to an addition funnel via cannulation
  2. additionA slight precipitate was observed during the addition
  3. additionwas added to the reaction and after an additional two hrs
  4. additionwas added
  5. stirringby stirring one hour
  6. customThe solvent was removed under reduced pressure
  7. extractionthe product was extracted with a sat. sodium bicarbonate solution (×3)
  8. extractionextracted with EtOAc (×10)
  9. dry with materialby drying with MgSO4
  10. concentrationconcentrating to a solid (0.8 g, 70%)
  11. temperatureby heating
  12. temperatureto reflux for 12 hours
  13. temperatureAfter cooling to room temperature the solvent
  14. customwas removed under reduced pressure
  15. extractionBasification to pH8 with saturated sodium bicarbonate followed by extraction with EtOAc (×3)
  16. dry with materialdrying with MgSO4 and removal of solvent
  17. customyielded a tan solid
  18. customPurification
  19. washby silica gel flash column (gradient elution to 3:1 EtOAc:CH2Cl2)

Quellen und Nachweise

ORD-Eintrag
ord-66c2e2c8718d46e5b4bc031517e1cdb7
Quelldatensatz
uspto-grants-2013_03
Patentnummer
US08399489B2

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