Acetic Acid → Etamicastat HCl salt

HRID 854704Notes

Reaction equation

HRID 854704 reaction equation
[ClH:1].[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:13])[CH:12]=1)[O:9][CH2:8][C@H:7]([NH2:14])[CH2:6]2.C(OC(=O)[NH:21][CH2:22][CH2:23][C:24](=O)[CH2:25]O[Si](C(C)(C)C)(C)C)(C)(C)C.[S-:36][C:37]#[N:38].[K+].O.C(O)(=O)C>C(OCC)(=O)C>[ClH:1].[NH2:21][CH2:22][CH2:23][C:24]1[N:14]([C@@H:7]2[CH2:6][C:5]3[C:10](=[C:11]([F:13])[CH:12]=[C:3]([F:2])[CH:4]=3)[O:9][CH2:8]2)[C:37](=[S:36])[NH:38][CH:25]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 962WaterHCID 516872Potassium thiocyanateHCID 11493428[4-(Tert-butyldimethylsilanyloxy)-3-oxobutyl]carbamic acid tert-butyl esterHCID 11615490(R)-6,8-difluorochroman-3-ylamine hydrochloride

Product 1

HCID 10450386Etamicastat HCl salt

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

A stirred mixture of (R)-6,8-difluorochroman-3-ylamine hydrochloride (1.68 g, 7.58 mmol), [4-(tert-butyldimethylsilanyloxy)-3-oxobutyl]carbamic acid tert-butyl ester (3.13 g, 9.85 mmol), potassium thiocyanate (0.96 g, 9.85 mmol), water (0.18 mL, 10 mmol) and acetic acid (3.0 mL, 50 mmol) in ethyl acetate (30 mL) was refluxed for 7 hours, cooled to room temperature, washed by sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography on silica using ethyl acetate—petroleum ether mixture as eluent. The resulting oil (2.15 g) was dissolved in ethyl acetate (20 ml), 2M HCl solution in ethyl acetate was added (20 mL, 40 mmol) and the mixture was stirred for 2 hours at room temperature. The precipitate was removed by filtration and washed with ethyl acetate to give crystals, which decomposed without melting.

Workup

  1. temperaturewas refluxed for 7 hours
  2. washwashed by sodium bicarbonate solution
  3. dry with materialdried over anhydrous magnesium sulphate
  4. customevaporated in vacuo
  5. customThe residue was purified by column chromatography on silica
  6. dissolutionThe resulting oil (2.15 g) was dissolved in ethyl acetate (20 ml)
  7. addition2M HCl solution in ethyl acetate was added (20 mL, 40 mmol)
  8. customThe precipitate was removed by filtration
  9. washwashed with ethyl acetate
  10. customto give crystals, which

Sources & evidence

ORD record
ord-df33cdcc8d434ef1ad1a31d36688c222
Source dataset
uspto-grants-2007_08
Patent number
US07259271B2

Reaction notes

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