Ammonia → CP 547632

HRID 335521Notes

Reaction equation

HRID 335521 reaction equation
C[O:2][C:3]([C:5]1[C:6]([O:23][CH2:24][C:25]2[C:30]([F:31])=[CH:29][C:28]([Br:32])=[CH:27][C:26]=2[F:33])=[N:7][S:8][C:9]=1[NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:12])=O.[NH3:34]>CO.O1CCCC1>[Br:32][C:28]1[CH:29]=[C:30]([F:31])[C:25]([CH2:24][O:23][C:6]2[C:5]([C:3]([NH2:34])=[O:2])=[C:9]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:12])[S:8][N:7]=2)=[C:26]([F:33])[CH:27]=1

Participants

5

Reactant 2

HCID 222AmmoniaHCID 11519603HCID 11519603, compound

Product 1

HCID 9811611CP 547632Yield 76%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

In a 1 Liter autoclave 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid methyl ester (1.00 equiv, 27.0 g) was slurried in methanol (270 mL, 10 volumes) and tetrahydrofuran (270 mL, 10 volumes). The mixture was cooled to 0° C. and stirred at 600 rpm. Anhydrous ammonia gas was charged carefully, keeping the temperature below 10° C. Once a steady pressure of around 10 psi was maintained, the mixture was heated to 40° C. The pressure increased to about 45 psi. The pressure was adjusted to 50 psi and stirred at 600 rpm and 40° C. for 90 hours. The stir rate was then adjusted to 1000 rpm and stirred for an additional 24 hours. The ammonia was removed by vacuum, and the mixture was cooled to 20° C. and transferred out of the reactor. The mixture was filtered to remove insoluble solids (non-product related). The filtrate was diluted with 2-propanol (270 mL, 10 volumes), and the tetrahydrofuran and methanol were distilled atmospherically. Additional 2-propanol (135 mL, 5 volumes) were added, then the mixture was distilled to approximately 250 mL total volume. The slurry was cooled to 20° C. and stirred 18 hours. The solids were filtered and then dried under vacuum to give 19.9 grams of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide (76% yield). 1H NMR (DMSO-d6): δ 10.98 (s, 1H); 8.18 (m, 1H); 7.55 (m, 3H); 6.80 (s, 1H); 5.41 (s, 2H); 3.08 (m, 2H); 2.47 (m, 6H); 1.62 (m, 4H); 1.42 (m, 4H). MS (API-ES pos) 532/534 (M+H)+, base.

Workup

  1. customthe temperature below 10° C
  2. temperatureOnce a steady pressure of around 10 psi was maintained
  3. temperaturethe mixture was heated to 40° C
  4. temperatureThe pressure increased to about 45 psi
  5. stirringstirred at 600 rpm and 40° C. for 90 hours
  6. stirringstirred for an additional 24 hours
  7. customThe ammonia was removed by vacuum
  8. temperaturethe mixture was cooled to 20° C.
  9. filtrationThe mixture was filtered
  10. customto remove insoluble solids (non-product related)
  11. additionThe filtrate was diluted with 2-propanol (270 mL, 10 volumes)
  12. distillationthe tetrahydrofuran and methanol were distilled atmospherically
  13. additionAdditional 2-propanol (135 mL, 5 volumes) were added
  14. distillationthe mixture was distilled to approximately 250 mL total volume
  15. temperatureThe slurry was cooled to 20° C.
  16. stirringstirred 18 hours
  17. filtrationThe solids were filtered
  18. customdried under vacuum

Sources & evidence

ORD record
ord-4f8ff711267c4c649f553a06ec3faa17
Source dataset
uspto-grants-2014_11
Patent number
US08884025B2

Reaction notes

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