Water → 6-[5-(1-methoxy-1-methyl-ethyl)-3-pyridyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide

HRID 712688Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 712688
CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)O1.Br[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([C:30]([O:33][CH3:34])([CH3:32])[CH3:31])[CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH3:34][O:33][C:30]([C:28]1[CH:29]=[C:24]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)[CH:25]=[N:26][CH:27]=1)([CH3:32])[CH3:31]

Komponenten

7

Edukt 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 667881343-Bromo-5-(2-methoxypropan-2-yl)pyridineHCID 1231626313,4-Dihydro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-1(2h)-carboxamide

Produkt 1

HCID 1176669436-[5-(1-methoxy-1-methyl-ethyl)-3-pyridyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178477754HCID 178477754, VerbindungKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

To a sealed tube which contained the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (generated according to the procedure for Step 3 of Example 16 in 5 mL 1,4-dioxane, 0.78 mmol) is added 3-bromo-5-(1-methoxy-1-methyl-ethyl)-pyridine (216 mg, 0.937 mmol), Na2CO3 (166 mg, 1.56 mmol) and water (0.5 mL). The mixture is bubbled with Ar for 5 min. Then PdCl2(DPPF) (57 mg, 0.078 mmol) is added. The mixture is then bubbled with Ar for 5 min. The cap is sealed and the mixture is heated at 90° C. for 1 h and then is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtration is partitioned between water and DCM. The aqueous phase is extracted with DCM. The combined DCM phases are concentrated. The crude is separated by flash silica gel column (MeOH/DCM 0 to 5% gradient, then 5%) and then separated by C-18 prep HPLC ((MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 65% gradient over 10 min run). The resulting material is further purified by C-18 HPLC (31% CH3CN in 2.5 mM NH4HCO3 aqueous solution, isocratic for 15 min plus 5 min wash at 17 ml/min) to obtain 66 mg of the title compound.

Aufarbeitung

  1. customTo a sealed tube which contained
  2. customThe mixture is bubbled with Ar for 5 min
  3. customThe mixture is then bubbled with Ar for 5 min
  4. customThe cap is sealed
  5. temperatureis cooled to room temperature
  6. filtrationThe reaction mixture is filtered through diatomaceous earth
  7. washwashed with DCM
  8. filtrationThe filtration
  9. customis partitioned between water and DCM
  10. extractionThe aqueous phase is extracted with DCM
  11. concentrationThe combined DCM phases are concentrated
  12. customThe crude is separated by flash silica gel column (MeOH/DCM 0 to 5% gradient
  13. custom5%) and then separated by C-18 prep HPLC ((MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 65% gradient over 10 min run)
  14. customThe resulting material is further purified by C-18 HPLC (31% CH3CN in 2.5 mM NH4HCO3 aqueous solution, isocratic for 15 min plus 5 min wash at 17 ml/min)

Quellen und Nachweise

ORD-Eintrag
ord-25b5334106c1431481b5cf10f133589f
Quelldatensatz
uspto-grants-2015_11
Patentnummer
US09181272B2

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