Phosphorus oxychloride → Benzhydryl 7-[2-(4-aminopyrimidin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate

HRID 905474Notes

Reaction equation

HRID 905474 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[N:12][O:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:9]([OH:11])=O)[N:3]=1.P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.[NH2:35][CH:36]1[C:61](=[O:62])[N:38]2[C:39]([C:45]([O:47][CH:48]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:46])=[C:40]([CH:43]=[CH2:44])[CH2:41][S:42][C@H:37]12>C(OCC)(=O)C.C(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[N:12][O:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:9]([NH:35][CH:36]2[C:61](=[O:62])[N:38]3[C:39]([C:45]([O:47][CH:48]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)=[O:46])=[C:40]([CH:43]=[CH2:44])[CH2:41][S:42][C@H:37]23)=[O:11])[N:3]=1

Participants

8

Reactant 4

HCID 24813Phosphorus oxychloride2×HCID 357676Acetamide, 2-(trimethylsilyl)-2×HCID 12818000Benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylateHCID 541766642-(4-Aminopyrimidin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid

Product 1

HCID 131713337Benzhydryl 7-[2-(4-aminopyrimidin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylateYield 17.7%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

To a suspension of 2-(4-aminopyrimidin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer) (1.3 g) in ethyl acetate (25 ml) was added phosphorus oxychloride (0.5 ml) under ice-cooling with stirring, followed by stirring at 0° to 5° C. for half an hour. After trimethylsilylacetamide (28 mg) was added thereto, the mixture was stirred at the same temperature for half an hour. To the mixture was added phosphorus oxychloride (0.5 ml) at 0° to 5° C., followed by stirring at the same temperature for 15 minutes. Thereto was added N,N-dimethylformamide (0.37 ml) at 0° to 5° C., followed by stirring under ice-cooling for half an hour to prepare the activated acid solution. This solution was added at a time to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (1.32 g) and trimethylsilylacetamide (3.5 g) in methylene chloride (30 ml) at -20° C., followed by stirring at -10° C. for 40 minutes. The reaction mixture was poured into ethyl acetate, and the separated organic layer was washed with 5% aqueous sodium bicarbonate and 5% aqueous sodium chloride, followed by drying over magnesium sulfate. After removal of the solvent, the residual oil was subjected to column chromatography on silica gel (100 ml) using a mixed solvent of diisopropyl ether and ethyl acetate as an eluent. The fractions containing a desired compound were collected and then evaporated to obtain benzhydryl 7-[2-(4-aminopyrimidin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (0.4 g), mp 155° to 158° C.

Workup

  1. temperaturecooling
  2. stirringby stirring at 0° to 5° C. for half an hour
  3. stirringthe mixture was stirred at the same temperature for half an hour
  4. stirringby stirring at the same temperature for 15 minutes
  5. stirringby stirring under ice-
  6. temperaturecooling for half an hour
  7. customto prepare the activated acid solution
  8. stirringby stirring at -10° C. for 40 minutes
  9. washthe separated organic layer was washed with 5% aqueous sodium bicarbonate and 5% aqueous sodium chloride
  10. dry with materialby drying over magnesium sulfate
  11. customAfter removal of the solvent
  12. additionThe fractions containing a desired compound
  13. customwere collected
  14. customevaporated

Sources & evidence

ORD record
ord-95ee80a60ec04bb29cf265f5ffa8d3d2
Source dataset
uspto-grants-1983_12
Patent number
US04423213

Reaction notes

Loading…