Phosphorus oxychloride → Benzhydryl 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate

HRID 1262761Notes

Reaction equation

HRID 1262761 reaction equation
C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[S:16][C:17]([Cl:34])=[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].Cl.[NH2:36][CH:37]1[C:62](=[O:63])[N:39]2[C:40]([C:46]([O:48][CH:49]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[S:47])=[C:41]([CH2:44][CH3:45])[CH2:42][S:43][C@H:38]12.C(=O)(O)[O-].[Na+]>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][C:17]([Cl:34])=[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:36][CH:37]2[C:62](=[O:63])[N:39]3[C:40]([C:46]([O:48][CH:49]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[S:47])=[C:41]([CH2:44][CH3:45])[CH2:42][S:43][C@H:38]23)=[O:23])[N:19]=1)=[O:13]

Participants

11

Reactant 5

HCID 24813Phosphorus oxychlorideHCID 77311Chloro-N,N-dimethylformiminium chlorideHCID 516892Sodium BicarbonateHCID 540757552-(2-Formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acidHCID 131713539Benzhydryl 7-amino-3-ethylthio-3-cephem-4-carboxylate hydrochloride

Product 1

HCID 131713538Benzhydryl 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylateYield 378.3%

Reagents, catalysts & solvents 5

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

Procedure

Vilsmeier reagent prepared from N,N-dimethylformamide (0.42 ml) and phosphorus oxychloride (0.527 ml) was suspended in dry tetrahydrofuran (30.5 ml). To a suspension was added 2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer, 2.8 g) under ice-cooling with stirring and then the solution was stirred at the same temperature for an hour to prepare the activated acid solution. To the solution of benzhydryl 7-amino-3-ethylthio-3-cephem-4-carboxylate hydrochloride (2.0 g) and monotrimethylsilylacetamide (5.7 g) in methylene chloride (40 ml) was added the activated acid solution obtained above all at once at -0° C. and the mixed solution was stirred at -20° to -10° C. for an hour. After water and ethyl acetate (150 ml) were added to the resultant solution, the mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give benzhydryl 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 12.8 g), mp. 143° to 148° C.

Workup

  1. temperaturecooling
  2. stirringthe solution was stirred at the same temperature for an hour
  3. customto prepare the activated acid solution
  4. customobtained above all at once at -0° C.
  5. stirringthe mixed solution was stirred at -20° to -10° C. for an hour
  6. washThe organic layer was washed with a saturated aqueous solution of sodium chloride
  7. dry with materialdried over magnesium sulfate
  8. customThe solvent was evaporated under reduced pressure

Sources & evidence

ORD record
ord-72e7034cb4fc4065b53d00b78984a646
Source dataset
uspto-grants-1984_06
Patent number
US04452851

Reaction notes

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