Ethyl Acetate → Cefuroxime Axetil

HRID 638542Notes

Reaction equation

HRID 638542 reaction equation
[C:1]([O:4][CH:5](Br)[CH3:6])(=[O:3])[CH3:2].[CH3:8][O:9]/[N:10]=[C:11](\[C:17]([NH:19][C@@H:20]1[C:23](=[O:24])[N:22]2[C:25]([C:34]([O-:36])=[O:35])=[C:26]([CH2:29][O:30][C:31]([NH2:33])=[O:32])[CH2:27][S:28][C@H:21]12)=[O:18])/[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1.[Na+].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>[CH3:6][CH:5]([O:35][C:34]([C:25]1[N:22]2[C:23]([C@@H:20]([NH:19][C:17](/[C:11](/[C:12]3[O:16][CH:15]=[CH:14][CH:13]=3)=[N:10]\[O:9][CH3:8])=[O:18])[C@H:21]2[S:28][CH2:27][C:26]=1[CH2:29][O:30][C:31]([NH2:33])=[O:32])=[O:24])=[O:36])[O:4][C:1]([CH3:2])=[O:3]

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 516892Sodium BicarbonateHCID 111375051-Bromoethyl acetateHCID 23670318Cefuroxime Sodium

Product 1

HCID 6321416Cefuroxime AxetilYield 84.4%

Reagents, catalysts & solvents 2

HCID 11430Potassium CarbonateCatalystHCID 31374DimethylacetamideSolvent

Procedure

(RS)-1-Acetoxyethylbromide (12.5 g) was added to a stirred mixture of sodium cefuroxime (20 g) in dimethyl acetamide (110 ml) at 0° C. The mixture was stirred at +1° for 90 minutes and potassium carbonate (0.5 g) was added. Stirring was continued for a further 2 hours at 1°-3° when the reaction mixture was added to a rapidly stirred mixture of ethyl acetate (200 ml) and aqueous 3% sodium bicarbonate (200 ml) to destroy any excess 1-acetoxyethylbromide. After 1 hour the organic layer (1.5% Δ2 isomer by HPLC) was separated, washed with N hydrochloric acid (100 ml) and aqueous 20% sodium chloride containing 2% sodium bicarbonate (30 ml). All three aqueous phases were sequentially washed with ethyl acetate (100 ml). The combined organic extracts were stirred for 30 minutes with charcoal (NOrit SX Plus; 2 g), filtered through a kieselguhr bed which was washed with ethyl acetate (2×25 ml). The combined filtrate and washes were evaporated in vacuo to 150 g and stirred at ambient temperature for 1 hour until the crystallisation was well established. Di-isopropyl ether (250 ml) was added over 45 minutes to complete the crystallisation and stirring was continued for an additional 1 hour. The product was collected by filtration, washed with 2:1 diisopropyl ether/ethyl acetate (150 ml) and dried for a weekend in vacuo at 50° to give crystalline cefuroxime axetil (19.3 g).

Workup

  1. stirringStirring
  2. waitwas continued for a further 2 hours at 1°-3°
  3. customto destroy any excess 1-acetoxyethylbromide
  4. customAfter 1 hour the organic layer (1.5% Δ2 isomer by HPLC) was separated
  5. washwashed with N hydrochloric acid (100 ml) and aqueous 20% sodium chloride containing 2% sodium bicarbonate (30 ml)
  6. washAll three aqueous phases were sequentially washed with ethyl acetate (100 ml)
  7. stirringThe combined organic extracts were stirred for 30 minutes with charcoal (NOrit SX Plus; 2 g)
  8. filtrationfiltered through a kieselguhr bed which
  9. washwas washed with ethyl acetate (2×25 ml)
  10. customThe combined filtrate and washes were evaporated in vacuo to 150 g
  11. stirringstirred at ambient temperature for 1 hour until the crystallisation
  12. additionDi-isopropyl ether (250 ml) was added over 45 minutes
  13. customthe crystallisation
  14. stirringstirring
  15. waitwas continued for an additional 1 hour
  16. filtrationThe product was collected by filtration
  17. washwashed with 2:1 diisopropyl ether/ethyl acetate (150 ml)
  18. customdried for a weekend in vacuo at 50°

Sources & evidence

ORD record
ord-0bfe0479d5d44f48993e4a19280ba673
Source dataset
uspto-grants-1985_12
Patent number
US04562181

Reaction notes

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