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

HRID 46256Notes

Reaction equation

HRID 46256 reaction equation
F[C:2](F)(F)C(O)=O.[NH:8]1[CH2:11][CH:10]([N:12]2[C:16]([C:17]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:18]=3[O:19][C:20]3[C:25]([F:26])=[CH:24][C:23]([S:27]([NH:30][C:31]4[S:35][N:34]=[CH:33][N:32]=4)(=[O:29])=[O:28])=[C:22]([F:36])[CH:21]=3)=[CH:15][CH:14]=[N:13]2)[CH2:9]1.C(O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO.C(O)C.O>[Cl:41][C:39]1[CH:38]=[CH:37][C:18]([O:19][C:20]2[C:25]([F:26])=[CH:24][C:23]([S:27]([NH:30][C:31]3[S:35][N:34]=[CH:33][N:32]=3)(=[O:28])=[O:29])=[C:22]([F:36])[CH:21]=2)=[C:17]([C:16]2[N:12]([CH:10]3[CH2:9][N:8]([CH3:2])[CH2:11]3)[N:13]=[CH:14][CH:15]=2)[CH:40]=1

Participants

9

Reactant 4

HCID 176Acetic AcidHCID 712Formaldehyde2×HCID 5049666Sodium triacetoxyborohydride2×HCID 866665194-[2-(1-Azetidin-3-yl-1h-pyrazol-5-yl)-4-chlorophenoxy]-2,5-difluoro-n-1,2,4-thiadiazol-5-ylbenzenesulfonamide trifluoroacetate salt

Product 1

HCID 468414994-{4-Chloro-2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

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).

Workup

  1. customAn alternative method of preparing Example 811
  2. temperatureThe solution was then cooled in an ice bath
  3. stirringstirred
  4. temperaturewhilst warming to room temperature over 1.5 hours
  5. stirringstirred for 30 minutes
  6. stirringstirred at room temperature for 1.5 hours
  7. customThe reaction was quenched
  8. additionby adding water (552.25 mL)
  9. stirringstirred for 30 minutes
  10. addition0.880 aqueous ammonia solution (100 mL) was added in two equal portions
  11. stirringstirred for a further 30 minutes
  12. filtrationThe resulting solid was filtered off
  13. customdried
  14. customto give the crude title compound as a white solid, (135 g)
  15. temperatureheated
  16. temperatureto reflux for 1 hour
  17. stirringthe resulting slurry was stirred at 90° C. for 30 minutes
  18. temperatureto cool to 35° C
  19. filtrationThe solid was filtered off
  20. customdried

Sources & evidence

ORD record
ord-f98988c6d47a4d088f4a43373a85e94b
Source dataset
uspto-grants-2013_09
Patent number
US08541588B2

Reaction notes

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