Acetic Acid → tert-Butyl 3-amino-4-(hydroxymethyl)-3-isothiazol-5-yl-pyrrolidine-1-carboxylate

HRID 1619014Notes

Reaction equation

HRID 1619014 reaction equation
[S:1]1[C:5]([C:6]23[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH:10]2[CH2:9][O:8][NH:7]3)=[CH:4][CH:3]=[N:2]1.C(O)(=O)C>C(OCC)(=O)C.[Zn]>[NH2:7][C:6]1([C:5]2[S:1][N:2]=[CH:3][CH:4]=2)[CH:10]([CH2:9][OH:8])[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:13]1

Participants

5

Reactant 2

HCID 176Acetic AcidHCID 86697926tert-Butyl 6a-isothiazol-5-yl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate

Product 1

HCID 86697925tert-Butyl 3-amino-4-(hydroxymethyl)-3-isothiazol-5-yl-pyrrolidine-1-carboxylateYield 65.1%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
40 °C

Procedure

tert-Butyl 6a-isothiazol-5-yl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (400.0 g, 1.35 mol), acetic acid (4.00 L) and zinc (439.78 g, 6.73 mol) are added together. The reaction mixture is heated to 40° C. and stirred at 40° C. for 8 hours and then cooled to room temperature. The reaction mixture is diluted with ethyl acetate (4 L), filtered through diatomaceous earth, washed with ethyl acetate, and evaporated under reduced pressure. The yellow oily residue is dissolved in toluene (2 L) and concentrated. The dissolution process with toluene is repeated 3 times. The foamy oil residue is suspended in 10% w/w aq. citric acid (3.2 L), MTBE (4 L) is added and the mixture is stirred for 15 minutes at room temperature. The biphasic mixture is filtered through diatomaceous earth (slow filtration) to remove the gel-like solids. The layers are separated and the aqueous layer is washed with MTBE (4×600 mL). The aqueous layer (pH 4.0) is added to ethyl acetate (3.0 L), and the mixture is neutralized with NaOH 50% w/w to adjust the pH=9.0-9.5 and the mixture is vigorously stirred. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (3×1 L). The organic layers are combined, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the title compound as a white solid, (262.00 g, 65.1%). ES/MS (m/e): 300 (M+H).

Workup

  1. temperaturecooled to room temperature
  2. filtrationfiltered through diatomaceous earth
  3. washwashed with ethyl acetate
  4. customevaporated under reduced pressure
  5. dissolutionThe yellow oily residue is dissolved in toluene (2 L)
  6. concentrationconcentrated
  7. additionis added
  8. stirringthe mixture is stirred for 15 minutes at room temperature
  9. filtrationThe biphasic mixture is filtered through diatomaceous earth (slow filtration)
  10. customto remove the gel-like solids
  11. customThe layers are separated
  12. washthe aqueous layer is washed with MTBE (4×600 mL)
  13. additionThe aqueous layer (pH 4.0) is added to ethyl acetate (3.0 L)
  14. stirringthe mixture is vigorously stirred
  15. customThe organic layer is separated
  16. extractionthe aqueous layer is extracted with ethyl acetate (3×1 L)
  17. dry with materialdried over sodium sulfate
  18. filtrationfiltered
  19. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-c88e514d4c8f4e9bbfdf0403ec47d6f4
Source dataset
uspto-grants-2014_07
Patent number
US08772282B2

Reaction notes

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