Reaktion #48173

Reaktionsgleichung

sodium acetoxyborohydride

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

(4,4-Difluoro-piperidin-1-yl)-[5-(piperidin-4-yloxy)-1H-indol-2-yl]-methanone

acetic acid

cyclobutanone

→

desired product

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

Lösungsmittel

water

ethyl acetate

tetrahydrofuran

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.STIRRINGthe mixture stirred for 16 h at 65° C
2. 2
   ExtraktionThe aqueous layer was extracted twice with ethyl acetate
3. 3
   Waschenthe combined organic fractions were washed twice with saturated sodium bicarbonate solution
4. 4
   Trocknendried over sodium sulfate
5. 5
   Filtrationfiltered
6. 6
   Sonstigeevaporated to dryness
7. 7
   Sonstigepurified on silica gel
8. 8
   Wascheneluting with a 49:1:0 to 95:5:0.25 gradient of dichloromethane/methanol/ammonium hydroxide

Vorschrift

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%).

Quelle