Реакция #48173

Уравнение реакции

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

Растворители

water

ethyl acetate

tetrahydrofuran

Условия реакции

Обработка

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

Методика

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%).

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