Citric Acid → tert-Butyl 6a-isothiazol-5-yl-1-[(4-methoxyphenyl)methyl]-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate

HRID 1619012Notes

Reaction equation

HRID 1619012 reaction equation
[CH2:1]([N:4]([CH2:12][C:13]([C:15]1[S:19][N:18]=[CH:17][CH:16]=1)=O)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][OH:30])=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[S:19]1[C:15]([C:13]23[CH2:12][N:4]([C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])[CH2:1][CH:2]2[CH2:3][O:30][N:29]3[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[CH:16][CH:17]=[N:18]1

Participants

8

Reactant 4

HCID 311Citric AcidHCID 81531DiisopropylethylamineHCID 10909770N-(4-Methoxybenzyl)hydroxylamineHCID 86697894tert-Butyl N-allyl-N-(2-isothiazol-5-yl-2-oxo-ethyl)carbamate

Product 1

HCID 86697924tert-Butyl 6a-isothiazol-5-yl-1-[(4-methoxyphenyl)methyl]-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylateYield 82.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

tert-Butyl N-allyl-N-(2-isothiazol-5-yl-2-oxo-ethyl)carbamate (610.1 g, 2.16 mol) is dissolved in toluene (6.10 L) under an atmosphere of nitrogen. N-[(4-methoxyphenyl)methyl]hydroxylamine (532.68 g, 2.81 mol) is added followed by diisopropylethylamine (489.86 mL, 2.81 mol). Ti(OEt)4 (640.78 g, 2.81 mol) is added and the yellow reaction solution is heated to 100° C. with stiffing for 2 hours. The reaction is cooled to room temperature and diluted with ethyl acetate (3.05 L). A solution of citric acid 50% w/w in water (5.49 L) is added. A solid precipitates which then re-dissolves on stirring. The biphasic mixture is separated and the aqueous layer is extracted with ethyl acetate (2×1 L). The combined organic layers are washed with water (2×2 L), brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue is dissolved in ethyl acetate (3 L) and concentrated under reduced pressure again. The crude product is triturated in ethyl acetate (1.2 L) and isohexane (4.8 L) for 40 minutes. The suspension is filtered and washed with hexane (4 L). The solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours to give the title product (741.51 g, 82.2%). ES/MS (m/e): 418 (M+H). The mother liquor from the trituration is concentrated under reduced pressure to give a brown solid, which is re-crystallized from methanol (150 mL) to obtain a second crop of product as a off-white solid, (26.02 g, 62.32 mmol, 2.9% yield).

Workup

  1. temperatureThe reaction is cooled to room temperature
  2. customA solid precipitates which
  3. dissolutionthen re-dissolves
  4. customThe biphasic mixture is separated
  5. extractionthe aqueous layer is extracted with ethyl acetate (2×1 L)
  6. washThe combined organic layers are washed with water (2×2 L), brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated to dryness
  10. dissolutionThe residue is dissolved in ethyl acetate (3 L)
  11. concentrationconcentrated under reduced pressure again
  12. customThe crude product is triturated in ethyl acetate (1.2 L)
  13. waitisohexane (4.8 L) for 40 minutes
  14. filtrationThe suspension is filtered
  15. washwashed with hexane (4 L)
  16. customThe solid is dried under vacuum for 3 hours and in a vacuum oven at 40° C. for 16 hours

Sources & evidence

ORD record
ord-5d95717f1cd9417b9121468f40e7a811
Source dataset
uspto-grants-2014_07
Patent number
US08772282B2

Reaction notes

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