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

HRID 1494491Notes

Reaction equation

HRID 1494491 reaction equation
C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([OH:23])=O)[N:19]=1)=[O:13].[NH2:34][CH:35]1[C:61](=[O:62])[N:37]2[C:38]([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:39]([CH2:42][S:43][CH3:44])[CH2:40][S:41][C@H:36]12.C[Si](CC(N)=O)(C)C>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([NH:34][CH:35]2[C:61](=[O:62])[N:37]3[C:38]([C:45]([O:47][CH:48]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:46])=[C:39]([CH2:42][S:43][CH3:44])[CH2:40][S:41][C@H:36]23)=[O:23])[N:19]=1)=[O:13]

Participants

11

Reactant 5

HCID 24813Phosphorus oxychlorideHCID 77311Chloro-N,N-dimethylformiminium chlorideHCID 357676Acetamide, 2-(trimethylsilyl)-HCID 543909512-t-Butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acidHCID 67712714Benzhydryl 7-amino-3-methylthiomethyl-3-cephem-4-carboxylate

Product 1

HCID 131713151Benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-methylthiomethyl-3-cephem-4-carboxylateYield 99.2%

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Vilsmeier reagent prepared from phosphorus oxychloride (1.23 ml) and N,N-dimethylformamide (1.1 ml) was suspended in dry tetrahydrofuran (40 ml). To the suspension was added 2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer) (4.0 g) under ice-cooling with stirring, and the mixture was stirred at the same temperature for 50 minutes to prepare the activated acid solution. On the other hand, benzhydryl 7-amino-3-methylthiomethyl-3-cephem-4-carboxylate (4.66 g) and trimethylsilylacetamide (8.6 g) were dissolved in methylene chloride (50 ml). To the solution was added the activated acid solution at -20° C. at a time, and the mixture was stirred at the same temperature for an hour. Water (100 ml) and ethyl acetate (200 ml) were added to the resultant solution, and the organic layer was separated, washed with 5% aqueous sodium bicarbonate and an aqueous sodium chloride, and then dried over magnesium sulfate, followed by evaporation under reduced pressure to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]- 3-methylthiomethyl-3-cephem-4-carboxylate (syn isomer) (8.0 g), mp 132°-138° C.

Workup

  1. temperaturecooling
  2. stirringthe mixture was stirred at the same temperature for 50 minutes
  3. customto prepare the activated acid solution
  4. additionTo the solution was added the activated acid solution at -20° C. at a time
  5. stirringthe mixture was stirred at the same temperature for an hour
  6. customthe organic layer was separated
  7. washwashed with 5% aqueous sodium bicarbonate
  8. dry with materialan aqueous sodium chloride, and then dried over magnesium sulfate
  9. customfollowed by evaporation under reduced pressure

Sources & evidence

ORD record
ord-876b78edb8b044d89b74dd3abd27bd84
Source dataset
uspto-grants-1991_06
Patent number
US05026695

Reaction notes

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