Phosphorus oxychloride → Benzhydryl 7-[2-(6-formamidopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate

HRID 1262762Notes

Reaction equation

HRID 1262762 reaction equation
C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[N:20]=[C:19]([C:21](=[N:25][O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22]([OH:24])=O)[CH:18]=[CH:17][CH:16]=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>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[N:20]=[C:19]([C:21](=[N:25][O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22]([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:24])[CH:18]=[CH:17][CH:16]=1)=[O:13]

Participants

10

Reactant 4

HCID 24813Phosphorus oxychlorideHCID 77311Chloro-N,N-dimethylformiminium chlorideHCID 536951302-(6-Formamidopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acidHCID 131713539Benzhydryl 7-amino-3-ethylthio-3-cephem-4-carboxylate hydrochloride

Product 1

HCID 131713541Benzhydryl 7-[2-(6-formamidopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylateYield 78.1%

Reagents, catalysts & solvents 5

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

Procedure

Vilsmeier reagent prepared from phosphorus oxychloride (0.52 ml) and N,N-dimethylformamide (0.44 ml) was suspended in dry tetrahydrofuran (16.5 ml). To the stirred suspension was added 2-(6-formamidopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer, 1.67 g) under ice-cooling and then the solution was stirred for an hour at the same temperature 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 (5.67 g) in methylene chloride (40 ml) was added the activated acid solution all at once at -20° C., and then the mixed solution was stirred for an hour at -20° to -10° C. To the resultant solution were added water (50 ml) and ethyl acetate (100 ml). The organic layer was separated and washed with 5% aqueous solution of sodium bicarbonate. The solution 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-(6-formamidopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 2.5 g), mp. 113° to 123° C.

Workup

  1. temperaturecooling
  2. customto prepare the activated acid solution
  3. stirringthe mixed solution was stirred for an hour at -20° to -10° C
  4. customThe organic layer was separated
  5. washwashed with 5% aqueous solution of sodium bicarbonate
  6. washThe solution 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-7fc0f2282feb45f993fe7bd34aa1d6d6
Source dataset
uspto-grants-1984_06
Patent number
US04452851

Reaction notes

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