Diisopropylamine → 2-(3-(3-((3-Methyloxetan-3-yl)ethynyl)pyrazin-2-yloxy)azetidin-1-yl)quinoline

HRID 454936

Reaktionsgleichung

Reaktionsgleichung von HRID 454936
Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(NC(C)C)(C)C.C[Si](C)(C)[C:32]#[C:33][C:34]1([CH3:38])[CH2:37][O:36][CH2:35]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:38][C:34]1([C:33]#[C:32][C:2]2[C:3]([O:8][CH:9]3[CH2:12][N:11]([C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[CH2:10]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:37][O:36][CH2:35]1

Komponenten

6

Edukt 3

HCID 7912DiisopropylamineHCID 585476972-(3-(3-Chloropyrazin-2-yloxy)azetidin-1-yl)quinolineHCID 58547788Trimethyl((3-methyloxetan-3-yl)ethynyl)silane

Produkt 1

HCID 546705782-(3-(3-((3-Methyloxetan-3-yl)ethynyl)pyrazin-2-yloxy)azetidin-1-yl)quinolineAusbeute 12,11 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 178418397HCID 178418397, VerbindungKatalysator

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

Tetrakis(triphenylphosphine)palladium (288 mg, 0.249 mmol), copper(i) iodide (190 mg, 0.998 mmol) and 2-(3-(3-chloropyrazin-2-yloxy)azetidin-1-yl)quinoline (see PREPARATION P2.6; 312 mg, 0.998 mmol) were combined in a microwave vial which was degassed and backfilled with nitrogen (procedure was repeated three times). DMF (1663 μL) was added followed by diisopropylamine (2097 μL, 14.96 mmol) and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (840 mg, 4.99 mmol). The tube was sealed and heated to 85° C. for 16 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with brine and water. The aqueous layer was back extracted with EtOAc (3×) and the combined organic phase was dried over Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide 2-(3-(3-((3-methyloxetan-3-yl)ethynyl)pyrazin-2-yloxy)azetidin-1-yl)quinoline (45 mg, 0.121 mmol, 12.11% yield) as orange powder. 1H NMR (400 MHz, chloroform-d) δ ppm 1.76 (s, 3H) 4.28 (dd, J=9.88, 4.21 Hz, 2H) 4.47 (d, J=5.48 Hz, 2H) 4.67 (dd, J=9.59, 6.65 Hz, 2H) 4.97 (d, J=5.48 Hz, 2H) 5.52-5.62 (m, 1H) 6.63 (d, J=8.80 Hz, 1H) 7.21-7.41 (m, 2H) 7.45-7.65 (m, 1H) 7.76 (d, J=8.22 Hz, 1H) 7.90 (d, J=8.80 Hz, 1H) 8.03 (d, J=2.74 Hz, 1H) 8.17 (d, J=2.54 Hz, 1H). ESI (M+1) 373.1; calc for C22H20N4O2 372. (PDE10 IC50=0.0446 nM).

Aufarbeitung

  1. customwas degassed
  2. additionDMF (1663 μL) was added
  3. customThe tube was sealed
  4. customThe solvent was removed under reduced pressure
  5. dissolutionThe residue was dissolved in EtOAc
  6. washwashed with brine and water
  7. extractionThe aqueous layer was back extracted with EtOAc (3×)
  8. dry with materialthe combined organic phase was dried over Na2SO4
  9. customThe solvent was removed under reduced pressure
  10. customThe crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g)
  11. washeluting with a gradient of 0% to 50% EtOAc in hexane

Quellen und Nachweise

ORD-Eintrag
ord-73301116193c4ef1a1092bd24f1fcae0
Quelldatensatz
uspto-grants-2013_07
Patentnummer
US08497265B2

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