Bromochloromethane → Sulbactam

HRID 246869Notes

Reaction equation

HRID 246869 reaction equation
[CH3:1][C:2]1([CH3:15])[S:6](=[O:8])(=[O:7])[C@@H:5]2[CH2:9][C:10](=[O:11])[N:4]2[C@H:3]1[C:12]([O-:14])=[O:13].[Na+].ClCBr.C(N(C(C)C)CC)(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1([CH3:15])[S:6](=[O:7])(=[O:8])[C@@H:5]2[CH2:9][C:10](=[O:11])[N:4]2[C@H:3]1[C:12]([OH:14])=[O:13]

Participants

5

Reactant 3

HCID 6333BromochloromethaneHCID 81531DiisopropylethylamineHCID 23663973Sulbactam Sodium

Product 1

HCID 130313SulbactamYield 84%

Reagents, catalysts & solvents 1

HCID 94433Tetrabutylammonium hydrogen sulfateCatalyst

Procedure

The tetrabutylammonium salt of sulbactam (53 g of an oil) was prepared from sulbactam sodium salt (20.0 g, 0.078 mol) and tetrabutylammonium hydrogen sulfate (33.2 g) according to the method of Example 1. The entire 53 g batch was taken into 1280 ml of chlorobromomethane containing 1.70 ml (0.0098 mol) of diisopropylethylamine. After 5 hours, the reaction mixture was extracted with 3×100 ml of water. By optical rotation assay, the first, second and third extracts contained 5.7%, 1.1% and 0.3% of recovered sulbactam. The organic layer was stripped to a volume of 300 ml, and the BrCH2Cl displaced with 2×500 ml of ethyl acetate to a final volume of 275 ml, diluted with 100 ml fresh ethyl acetate, extracted 1×275 ml H2O, 1×275 ml saturated Na2SO4, 1×275 H2O and 1×275 ml brine, dried over 20 g MgSO 4, stirred with 4 g of activated carbon for 30 minutes, and filtered over diatomaceous earth with 100 ml of ethyl acetate wash. The filtrate and wash liquor were combined, stripped to 100 ml, cooled to 0°-5° C., diluted dropwise with 90 ml of hexane, maintaining 0°-5° C. (leading to an oil), warmed back to ambient temperature (causing the oil to form crystals), diluted dropwise over 1.5 hours with 150 ml of additional hexane, cooled and granulated at 0°-5° C. for 1 hour, and title product recovered in two crops (the second following evaporation of the mother liquor and trituration with hexane), 13.8 g and 4.7 g, both melting at 89°-95° C., a yield of 84% uncorrected, a yield of 80% corrected for purity by hplc.

Workup

  1. extractionthe reaction mixture was extracted with 3×100 ml of water
  2. additiondiluted with 100 ml fresh ethyl acetate
  3. extractionextracted 1×275 ml H2O, 1×275 ml saturated Na2SO4, 1×275 H2O and 1×275 ml brine
  4. dry with materialdried over 20 g MgSO 4
  5. filtrationfiltered over diatomaceous earth with 100 ml of ethyl acetate
  6. washwash
  7. washThe filtrate and wash liquor
  8. temperaturecooled to 0°-5° C.
  9. additiondiluted dropwise with 90 ml of hexane
  10. temperaturemaintaining 0°-5° C. (
  11. additiondiluted dropwise over 1.5 hours with 150 ml of additional hexane
  12. temperaturecooled
  13. waitgranulated at 0°-5° C. for 1 hour
  14. customtitle product recovered in two crops (the
  15. customevaporation of the mother liquor and trituration with hexane), 13.8 g and 4.7 g

Sources & evidence

ORD record
ord-91146a72a0144dc6a51f74b462ae73cf
Source dataset
uspto-grants-1987_11
Patent number
US04704456

Reaction notes

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