tert-Butyl methyl ether → Sulopenem Etzadroxil

HRID 1712890Notes

Reaction equation

HRID 1712890 reaction equation
COC(C)(C)C.I[CH2:8][O:9][C:10](=[O:16])[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13].[CH3:17][C@@H:18]([OH:37])[C@H:19]1[C:22](=[O:23])[N:21]2[C:24]([C:34]([OH:36])=[O:35])=[C:25]([S:27][C@@H:28]3[CH2:32][S+:31]([O-:33])[CH2:30][CH2:29]3)[S:26][C@H:20]12.C(N(CC)C(C)C)(C)C>CC(C)=O.C(OCC)(=O)C.CCCCCCC.O>[OH:37][C@@H:18]([C@H:19]1[C:22](=[O:23])[N:21]2[C@@H:20]1[S:26][C:25]([S:27][C@H:28]1[CH2:29][CH2:30][S@@:31](=[O:33])[CH2:32]1)=[C:24]2[C:34]([O:36][CH2:8][O:9][C:10](=[O:16])[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:35])[CH3:17]

Participants

9

Reactant 4

HCID 15413tert-Butyl methyl etherHCID 81531DiisopropylethylamineHCID 23449337Iodomethyl 2-ethylbutanoateHCID 178462320HCID 178462320, compound

Product 1

HCID 23642298Sulopenem EtzadroxilYield 60%

Reagents, catalysts & solvents 4

HCID 180AcetoneSolvent2×HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 8900HeptaneSolvent

Procedure

The semi-crude tert-butyl methyl ether solution of 2-ethyl butyric acid iodomethyl ester from Step 3 was added to a slurry of sulopenem (750 g) in acetone (5.9 L). N,N-Diisopropylethylamine (DIEA) (319 g) in acetone (0.5 L) was added and the mixture was stirred at ambient temperature until reaction completion. Low pyrogen water (6.5 L) and heptane (3.75 L) were added and the phases were separated. The aqueous layer was extracted first with heptane (5 L) and then with ethyl acetate (2×6 L). The ethyl acetate extracts were combined and washed with 5% aqueous sodium thiosulfate (6 L), low pyrogen water (6 L) and 10% aqueous sodium chloride (6 L). The organic extract was treated with activated carbon (75 g) and magnesium sulfate (150 g), then was filtered. The filter cake was washed with ethyl acetate (2×1 L) and the filtrate was evaporated to dryness to provide the crude product (0.8 kg). Ethyl acetate (2.4 L) was added and the solution was heated (45° C.) to achieve dissolution. This solution was then hot-filtered and tert-butyl methyl ether (4.7 L) was added. The resulting slurry was granulated for 10 minutes at 40° C. to 50° C. and was then cooled slowly to less than 10° C. The resulting solid was collected, washed with a 1:2 mixture of ethyl acetate and tert-butyl methyl ether (4×0.5 L) and dried to constant weight under vacuum at up to 50° C. to give 0.57 kg of the desired product (60% yield).

Workup

  1. customthe phases were separated
  2. extractionThe aqueous layer was extracted first with heptane (5 L)
  3. washwashed with 5% aqueous sodium thiosulfate (6 L), low pyrogen water (6 L) and 10% aqueous sodium chloride (6 L)
  4. extractionThe organic extract
  5. additionwas treated with activated carbon (75 g) and magnesium sulfate (150 g)
  6. filtrationwas filtered
  7. washThe filter cake was washed with ethyl acetate (2×1 L)
  8. customthe filtrate was evaporated to dryness
  9. customto provide the crude product (0.8 kg)
  10. temperaturethe solution was heated (45° C.)
  11. dissolutiondissolution
  12. filtrationThis solution was then hot-filtered
  13. additiontert-butyl methyl ether (4.7 L) was added
  14. temperaturewas then cooled slowly to less than 10° C
  15. customThe resulting solid was collected
  16. washwashed with a 1:2 mixture of ethyl acetate and tert-butyl methyl ether (4×0.5 L)
  17. customdried to constant weight under vacuum at up to 50° C.

Sources & evidence

ORD record
ord-3c9aa67ffd6940e1b7a26312f105589c
Source dataset
uspto-grants-2010_09
Patent number
US07795244B2

Reaction notes

Loading…