Acetyl chloride → (S)-tert-Butyl-4-{(R)-2-acetoxy-3,3-dimethylbutanoyl}-3-[2-{(tert-butoxycarbonyl amino)methyl}-5-chlorobenzylcarbamoyl]piperazine-1-carboxylate

HRID 2277089Notes

Reaction equation

HRID 2277089 reaction equation
[OH:1][C@H:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3](O)=[O:4].[C:10](Cl)(=[O:12])[CH3:11].S(Cl)(Cl)=O.C(N(CC)CC)C.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:35]=1[CH2:36][NH:37][C:38]([C@H:40]1[NH:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]1)=[O:39])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:49]([O:48][C:46]([N:42]1[CH2:43][CH2:44][N:45]([C:3](=[O:4])[C@H:2]([O:1][C:10](=[O:12])[CH3:11])[C:6]([CH3:9])([CH3:8])[CH3:7])[C@H:40]([C:38](=[O:39])[NH:37][CH2:36][C:35]2[CH:53]=[C:54]([Cl:57])[CH:55]=[CH:56][C:34]=2[CH2:33][NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:41]1)=[O:47])([CH3:50])([CH3:51])[CH3:52]

Participants

7

Reactant 5

HCID 6367Acetyl chlorideHCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 11344038(2R)-2-hydroxy-3,3-dimethylbutanoic acidHCID 89835591(S)-tert-Butyl 3-[2-{(tert-butoxycarbonylamino)methyl}-5-chlorobenzylcarbamoyl]piperazine-1carboxylate

Product 1

HCID 89826538(S)-tert-Butyl-4-{(R)-2-acetoxy-3,3-dimethylbutanoyl}-3-[2-{(tert-butoxycarbonyl amino)methyl}-5-chlorobenzylcarbamoyl]piperazine-1-carboxylateYield 50.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of (R)-2-hydroxy-3,3-dimethylbutanoic acid (86.2 mg, 0.65 mmol) in acetyl chloride (0.15 mL, 2.11 mmol) was heated to 60° C. for 15 min. Excess acetyl chloride was removed under reduced pressure and the residue was dried under high vacuum. The residue was dissolved in thionyl chloride (0.15 mL, 2.06 mmol) and the mixture was heated at refluxed for 2 h. Volatile impurities were dissolved in THF (5 mL) and triethylamine (0.45 mL, 3.26 mmol) was added. A solution of (S)-tert-Butyl 3-[2-{(tert-butoxycarbonylamino)methyl}-5-chlorobenzylcarbamoyl]piperazine-1carboxylate (0.30 g, 0.62 mmol) in THF (2 mL) at −5° C. was then added and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine solution (50 mL) then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile:water) to afford the title compound (0.2 g) as a white solid.

Workup

  1. customExcess acetyl chloride was removed under reduced pressure
  2. customthe residue was dried under high vacuum
  3. temperaturethe mixture was heated
  4. temperatureat refluxed for 2 h
  5. customThe reaction mixture was quenched with water (50 mL)
  6. extractionextracted with EtOAc (3×25 mL)
  7. washThe combined organic layers were washed with brine solution (50 mL)
  8. dry with materialthen dried over anhydrous Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile:water)

Sources & evidence

ORD record
ord-3013ae4df53845f8aeed14408d88f03e
Source dataset
uspto-grants-2015_09
Patent number
US09133147B2

Reaction notes

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