Lithium Hexamethyldisilazide → 7-((4-Cyclopropyl-2-fluorophenyl)amino)benzo[d]isothiazole-6-carboxylic acid

HRID 79034Notes

Reaction equation

HRID 79034 reaction equation
[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([F:11])[CH:5]=2)[CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:23]1[C:31]2[S:30][N:29]=[CH:28][C:27]=2[CH:26]=[CH:25][C:24]=1[C:32]([OH:34])=[O:33]>C1COCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:23]3[C:31]4[S:30][N:29]=[CH:28][C:27]=4[CH:26]=[CH:25][C:24]=3[C:32]([OH:34])=[O:33])=[C:6]([F:11])[CH:5]=2)[CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 201000714-Cyclopropyl-2-fluoroanilineHCID 583743747-Fluoro-benzo[d]isothiazole-6-carboxylic acid

Product 1

HCID 673534187-((4-Cyclopropyl-2-fluorophenyl)amino)benzo[d]isothiazole-6-carboxylic acidYield 32.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 4-cyclopropyl-2-fluoro-phenylamine (445 mg, 2.94 mmol) in anhydrous THF (10 mL) at −78° C. was added a 1.0 M solution of LHMDS in hexanes (4.4 mL, 4.4 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes and a suspension of 7-fluoro-benzo[d]isothiazole-6-carboxylic acid (290 mg, 1.47 mmol) in anhydrous THF (10 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 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 triturated with diethyl ether to give the title compound as a brown solid (155 mg, 32%). LCMS (method B): RT=3.79 min, [M+H]+=329.

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
  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
  11. customThe resultant residue was triturated with diethyl ether

Sources & evidence

ORD record
ord-3b1ff5c9657b4342ac4b51eb3e4e219b
Source dataset
uspto-grants-2014_09
Patent number
US08841462B2

Reaction notes

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