반응 #74534

반응 방정식

formaldehyde

formaldehyde

sodium triacetoxyborohydride

sodium triacetoxyborohydride

Acetic acid

4-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide trifluoroacetate salt

→

title compound

4-{4-Chloro-2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

용매

water

ethanol

methanol

dichloromethane

반응 조건

후처리

1. 1
   기타An alternative method of preparing Example 811
2. 2
   온도The solution was then cooled in an ice bath
3. 3
   workup.STIRRINGstirred
4. 4
   온도whilst warming to room temperature over 1.5 hours
5. 5
   workup.STIRRINGstirred for 30 minutes
6. 6
   workup.STIRRINGstirred at room temperature for 1.5 hours
7. 7
   기타The reaction was quenched
8. 8
   workup.ADDITIONby adding water (552.25 mL)
9. 9
   workup.STIRRINGstirred for 30 minutes
10. 10
    workup.ADDITION0.880 aqueous ammonia solution (100 mL) was added in two equal portions
11. 11
    workup.STIRRINGstirred for a further 30 minutes
12. 12
    여과The resulting solid was filtered off
13. 13
    기타dried
14. 14
    기타to give the crude title compound as a white solid, (135 g)
15. 15
    온도heated
16. 16
    온도to reflux for 1 hour
17. 17
    workup.STIRRINGthe resulting slurry was stirred at 90° C. for 30 minutes
18. 18
    온도to cool to 35° C
19. 19
    여과The solid was filtered off
20. 20
    기타dried

실험 절차

An alternative method of preparing Example 811 is as follows: 4-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide trifluoroacetate salt, (Example 801, 110.45 g, 0.1558 mol) was dissolved in dichloromethane (1050 mL) and methanol (110.45 mL). Acetic acid (17.86 mL, 2.73 mol) was added followed by aqueous formaldehyde solution (58.54 mL of 37 wt % in water, 0.779 mol), stirred at room temperature for 30 minutes. The solution was then cooled in an ice bath and sodium triacetoxyborohydride (82.56 g, 0.3895 mol) was added, stirred whilst warming to room temperature over 1.5 hours. Aqueous formaldehyde solution (29.27 mL of 37 wt % in water, 0.3895 mol) was added, stirred for 30 minutes then sodium triacetoxyborohydride (82.56 g, 0.3895 mol) was added and stirred at room temperature for 1.5 hours. The reaction was quenched by adding water (552.25 mL) and stirred for 30 minutes then 0.880 aqueous ammonia solution (100 mL) was added in two equal portions and stirred for a further 30 minutes. The resulting solid was filtered off and dried to give the crude title compound as a white solid, (135 g). The crude product was suspended in ethanol (405 mL) and heated to reflux for 1 hour then water (405 mL) was added and the resulting slurry was stirred at 90° C. for 30 minutes before being allowed to cool to 35° C. The solid was filtered off and dried to give the title compound as a white solid, (67.5 g).

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