반응 #59660

반응 방정식

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 )

수율 74.4%

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

수율 74.4%

용매

Toluene

반응 조건

후처리

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

실험 절차

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).

출처