Dichloromethane → Methyl 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(methylsulfonyl)-4-isothiazolecarboxylate

HRID 2205431Notes

Reaction equation

HRID 2205431 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:14])=[N:7][S:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:21][C:22]1[CH:39]=[C:38]([F:40])[C:25]([CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)=[C:24]([F:41])[CH:23]=1.ClCCl.ClCCl>CS(C)=O.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:14][CH2:26][C:25]2[C:38]([F:40])=[CH:39][C:22]([Br:21])=[CH:23][C:24]=2[F:41])=[N:7][S:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])=[O:4]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 86626436HCID 86626436, compoundHCID 178498985HCID 178498985, compound

Product 1

HCID 11568422Methyl 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(methylsulfonyl)-4-isothiazolecarboxylateYield 70%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

In a separate vessel, 3-Hydroxy-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester (1.00 equiv, 18.5 g) was taken up in dimethylsulfoxide (185 mL, 10 volumes) and potassium carbonate (1.0 equiv, 10.8 g) was added. The toluene-4-sulfonic acid 4-bromo-2,6-difluoro-benzyl ester/dichloromethane solution from Example 6 was added to the 3-Hydroxy-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl/potassium carbonate/dimethylsulfoxide slurry dropwise over 1 hour. The mixture was stirred at 25° C. for 16.5 hours. Dichloromethane (185 mL, 10 volumes) then water (185 mL, 10 volumes) were added and the layers were separated. The organic layer was dried over magnesium sulfate and filtered. The dichloromethane was removed under vacuum to leave an orange paste. The orange paste was diluted with 10 volumes of 1:1 EtOAc:Hexanes (v/v) and slurried at 25° C. for 16 hours. The mixture was filtered and the filter cake washed with 55-60 mL of 1:1 EtOAc:Hexanes (v/v) and dried to give 24.22 g of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester (70% yield). 1H NMR: (DMSO-d6) δ 7.57 (m, 2H); 5.46 (s, 2H); 3.80 (s, 3H); 3.57 (s, 3H). MS (API-ES pos): 442/444 (M+H)+; 205/207 (1,5-difluoro-3-bromotropylium ion), base.

Workup

  1. customthe layers were separated
  2. dry with materialThe organic layer was dried over magnesium sulfate
  3. filtrationfiltered
  4. customThe dichloromethane was removed under vacuum
  5. customto leave an orange paste
  6. filtrationThe mixture was filtered
  7. washthe filter cake washed with 55-60 mL of 1:1 EtOAc
  8. dry with materialHexanes (v/v) and dried

Sources & evidence

ORD record
ord-8f36b92505fd4c02ae1f91acc7b2ff12
Source dataset
uspto-grants-2016_06
Patent number
US09371298B2

Reaction notes

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