Reacción #59660

Ecuación de reacción

sodium tert-butoxide

4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine

4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine

carbamate

4-hydroxy-piperidine-1-carboxylic acid isopropyl ester

4-Hydroxy-Piperidine-1-Carboxylic Acid Isopropyl Ester

→

product ( 6 )

Rendimiento 74.4%

4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester

Rendimiento 74.4%

Disolventes

Toluene

Condiciones de reacción

Tratamiento posterior

1. 1
   Otroreaction vessel
2. 2
   Otrofitted with a mechanical stirrer, nitrogen inlet
3. 3
   Otroa slurry was obtained
4. 4
   workup.STIRRINGwith stirring
5. 5
   TemperaturaThe internal temperature gradually increased to 34° C. due to an exotherm
6. 6
   Otrowas brought down to 23-25° C
7. 7
   workup.STIRRINGwas stirred at room temperature for 2.5 h
8. 8
   FiltraciónThe precipitate from the reaction mixture was filtered
9. 9
   Lavadowashed with toluene (250 mL)
10. 10
    Otrodried overnight at room temperature
11. 11
    Otrowas slurried in EtOH (500 mL) at room temperature
12. 12
    Filtraciónfiltered
13. 13
    Lavadowashed with water (2.5 L) until the filtrate
14. 14
    workup.DISSOLUTIONThe washed solid product was dissolved
15. 15
    Temperaturain refluxing EtOH (1.3 L)
16. 16
    Temperaturathe resulting clear solution was gradually cooled to room temperature
17. 17
    OtroThe product (6) crystallized out and
18. 18
    Otrowas isolated by filtration
19. 19
    Otrodried overnight in a vacuum oven at 40° C.

Procedimiento

Toluene (1.6 L) was transferred to a 4 L jacketed reaction vessel fitted with a mechanical stirrer, nitrogen inlet and a temperature probe. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (7) (97.0 g, 0.297 mol) was added with stirring into the reaction vessel under nitrogen, and a slurry was obtained. The carbamate, 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (5) (66.57 g, 0.356 mol), was added at room temperature. The reactor was cooled to 12° C. and sodium tert-butoxide (37.09 g, 0.386 mol) was added with stirring. The internal temperature gradually increased to 34° C. due to an exotherm. Then the internal temperature was brought down to 23-25° C. The reaction mixture became a thick slurry and was stirred at room temperature for 2.5 h. The precipitate from the reaction mixture was filtered, washed with toluene (250 mL) followed by water (3×500 mL), and vacuum dried overnight at room temperature. The dried solid product was slurried in EtOH (500 mL) at room temperature, filtered, and washed with water (2.5 L) until the filtrate was neutral. The washed solid product was dissolved in refluxing EtOH (1.3 L), and the resulting clear solution was gradually cooled to room temperature. The product (6) crystallized out and was isolated by filtration and dried overnight in a vacuum oven at 40° C., 20 torr to provide 105.5 g of product (6) (74%). HPLC analysis, >99% (purity, by peak area). 1H NMR (Bruker 400 MHz, CDCl3) δ 8.62 (s, 1H, Ar—H), 8.32 (s, 1H, Ar—H), 7.93 (m, 3H, Ar—H), 5.62 (m, 1H, —O—CH—), 4.95 (m, 1H, CH3—CH—CH3), 3.91 (m, 2H, —CH2—), 3.37 (m, 2H, —CH2—), 3.12 (s, 3H, —SO2CH3), 2.09 (m, 2H, —CH2—), 1.87 (m, 2H, —CH2—), 1.27 (d, 6H, J=8 Hz, CH3—CH—CH3); mass spec. (electrospray) m/z 478 (M+H).

Fuente