Lithium Hexamethyldisilazide → 7-((2-Fluoro-4-(methylthio)phenyl)amino)benzo[d]isothiazole-6-carboxylic acid

HRID 79035Notes

Reaction equation

HRID 79035 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:22]1[C:30]2[S:29][N:28]=[CH:27][C:26]=2[CH:25]=[CH:24][C:23]=1[C:31]([OH:33])=[O:32]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:22]1[C:30]2[S:29][N:28]=[CH:27][C:26]=2[CH:25]=[CH:24][C:23]=1[C:31]([OH:33])=[O:32]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 220256172-Fluoro-4-(methylsulfanyl)anilineHCID 583743747-Fluoro-benzo[d]isothiazole-6-carboxylic acid

Product 1

HCID 670835707-((2-Fluoro-4-(methylthio)phenyl)amino)benzo[d]isothiazole-6-carboxylic acidYield 30%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 2-fluoro-4-methylsulfanyl-phenylamine (628 mg, 4.0 mmol) in anhydrous THF (15 mL) at −78° C. was added a 1.0M solution of LHMDS in hexanes (6.0 mL, 6.0 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and a suspension of 7-fluoro-benzo[d]isothiazole-6-carboxylic acid (394 mg, 2.0 mmol) in anhydrous THF (15 mL) was added dropwise. The resultant mixture was stirred at −78° C. for 30 minutes, then allowed to reach room temperature and stirred for 18 hours before being quenched by addition of a 1M aqueous HCl (ca. 50 mL) and extracted with ethyl acetate. The organic layer was separated and washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 10%, MeOH in DCM) to give the title compound as a brown solid (200 mg, 30%). LCMS (method B): RT=3.67 min, [M+H]+=335

Workup

  1. additionwas added dropwise
  2. customto reach room temperature
  3. stirringstirred for 18 hours
  4. custombefore being quenched by addition of a 1M aqueous HCl (ca. 50 mL)
  5. extractionextracted with ethyl acetate
  6. customThe organic layer was separated
  7. washwashed with water
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. customevaporated in vacuo

Sources & evidence

ORD record
ord-e2318b5052d94542818ab0fc37e85e57
Source dataset
uspto-grants-2014_09
Patent number
US08841462B2

Reaction notes

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