Dimethyl Sulfoxide → HCID 11519603, compound

HRID 335520Notes

Reaction equation

HRID 335520 reaction equation
CS(C)=O.[N:5]1([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](N2C=CN=C2)=[O:16])[CH2:9][CH2:8][CH2:7][CH2:6]1.O1CCCC1.[CH3:27][O:28][C:29]([C:31]1[C:32]([O:37][CH2:38][C:39]2[C:44]([F:45])=[CH:43][C:42]([Br:46])=[CH:41][C:40]=2[F:47])=[N:33][S:34][C:35]=1[NH2:36])=[O:30].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH3:27][O:28][C:29]([C:31]1[C:32]([O:37][CH2:38][C:39]2[C:40]([F:47])=[CH:41][C:42]([Br:46])=[CH:43][C:44]=2[F:45])=[N:33][S:34][C:35]=1[NH:36][C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:16])=[O:30]

Participants

7

Reactant 4

HCID 679Dimethyl SulfoxideHCID 11430Potassium CarbonateHCID 11494622HCID 11494622, compoundHCID 86626437HCID 86626437, compound

Product 1

HCID 11519603HCID 11519603, compoundYield 90%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
20 °C

Procedure

Dimethylsulfoxide (105 mL, 5 volumes) was added to the imidazole-1-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide/tetrahydrofuran mixture, the tetrahydrofuran was removed by distillation under vacuum. The mixture was cooled to 20° C. then 5-Amino-3-(4-bromo-2,6-difluoro-benzyloxy)-isothiazole-4-carboxylic acid methyl ester (1.00 equiv, 21.0 g) was added, followed by potassium carbonate (2.0 equiv, 15.2 g). The mixture stirred at 20° C. for 21.5 hours. Ethyl acetate (210 mL, 10 volumes) then water (210 mL, 10 volumes) were added. The slurry was stirred at 20° C. for 3-4 hours. The solids were filtered and the filter cake was rinsed with ethyl acetate (63.0 mL, 3 volumes). The solids were dried in a vacuum oven for 17 hours to give 27.36 grams of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid methyl ester (90% yield). 1H NMR: (DMSO-d6) δ 10.38 (s, 1H); 8.11 (m, 1H); 7.54 (m, 2H); 5.30 (s, 2H); 3.70 (s, 3H); 3.12 (m, 2H); 2.48 (m, 6H); 1.63 (m, 4H); 1.44 (m, 4H). MS (API-ES pos): 547/549 (M+H)+, base.

Workup

  1. customthe tetrahydrofuran was removed by distillation under vacuum
  2. stirringThe slurry was stirred at 20° C. for 3-4 hours
  3. filtrationThe solids were filtered
  4. washthe filter cake was rinsed with ethyl acetate (63.0 mL, 3 volumes)
  5. customThe solids were dried in a vacuum oven for 17 hours

Sources & evidence

ORD record
ord-350093dc4bf442ac988ba1282e34a6c1
Source dataset
uspto-grants-2014_11
Patent number
US08884025B2

Reaction notes

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