Acetic Acid → [5-(1-Cyclobutyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

HRID 19895

Reaktionsgleichung

Reaktionsgleichung von HRID 19895
[F:1][C:2]1([F:26])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.C(O)(=O)C.[C:31]1(=O)[CH2:34][CH2:33][CH2:32]1.C(O[BH3-])(=O)C.[Na+]>O1CCCC1.O.C(OCC)(=O)C>[CH:31]1([N:23]2[CH2:24][CH2:25][CH:20]([O:19][C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[NH:11][C:10]([C:8]([N:5]3[CH2:6][CH2:7][C:2]([F:1])([F:26])[CH2:3][CH2:4]3)=[O:9])=[CH:18]4)[CH2:21][CH2:22]2)[CH2:34][CH2:33][CH2:32]1

Komponenten

8

Edukt 4

HCID 176Acetic AcidHCID 14496CyclobutanoneHCID 23670382SodiumacetoxyborohydrideHCID 67017913(4,4-Difluoro-piperidin-1-yl)-[5-(piperidin-4-yloxy)-1H-indol-2-yl]-methanone

Produkt 1

HCID 67017911[5-(1-Cyclobutyl-piperidin-4-yloxy)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
55 °C

Versuchsvorschrift

A mixture of (4,4-difluoro-piperidin-1-yl)-[5-(piperidin-4-yloxy)-1H-indol-2-yl]-methanone (example 43, step 6, 350 mg, 1.0 eq.), acetic acid (0.17 mL, 3.0 eq.) and cyclobutanone (138 mg, 2.0 eq.) in tetrahydrofuran (6 mL) was stirred at 55° C. for 1 h. At room temperature, sodium acetoxyborohydride (421 mg, 2.0 eq.) was added and the mixture stirred for 16 h at 65° C. The reaction mixture was partitionned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate and the combined organic fractions were washed twice with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered, evaporated to dryness and purified on silica gel, eluting with a 49:1:0 to 95:5:0.25 gradient of dichloromethane/methanol/ammonium hydroxide, to yield 265 mg (65%) from the desired product as off-white solid. MS (m/e): 418.1 (MH+, 100%).

Aufarbeitung

  1. stirringthe mixture stirred for 16 h at 65° C
  2. extractionThe aqueous layer was extracted twice with ethyl acetate
  3. washthe combined organic fractions were washed twice with saturated sodium bicarbonate solution
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. customevaporated to dryness
  7. custompurified on silica gel
  8. washeluting with a 49:1:0 to 95:5:0.25 gradient of dichloromethane/methanol/ammonium hydroxide

Quellen und Nachweise

ORD-Eintrag
ord-dacabf58836542c1aa82874a9bbf70eb
Quelldatensatz
uspto-grants-2010_06
Patentnummer
US07745479B2

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