Phosphorus oxychloride → Benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate

HRID 1731689Notes

Reaction equation

HRID 1731689 reaction equation
P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH:21]=[CH2:22])[C:15]([OH:17])=O)[N:13]=1)=[O:7].Cl.[NH2:24][CH:25]1[C:50](=[O:51])[N:27]2[C:28]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:29]([CH2:32][Cl:33])[CH2:30][S:31][C@H:26]12.C[Si](NC(N[Si](C)(C)C)=O)(C)C>O1CCCC1.O.C(OCC)(=O)C.CN(C)C=O>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH:21]=[CH2:22])[C:15]([NH:24][CH:25]2[C:50](=[O:51])[N:27]3[C:28]([C:34]([O:36][CH:37]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:35])=[C:29]([CH2:32][Cl:33])[CH2:30][S:31][C@H:26]23)=[O:17])[N:13]=1)=[O:7]

Participants

9

Reactant 4

HCID 24813Phosphorus oxychlorideHCID 875621,3-Bis(trimethylsilyl)ureaHCID 13239629Benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochlorideHCID 542025522-Allyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid

Product 1

HCID 131714951Benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylateYield 88.2%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Phosphorus oxychloride (7.0 ml) was added under ice-cooling to a solution of N,N-dimethylformamide (5.8 ml) in tetrahydrofuran (11 ml). The mixture was cooled until the precipitate appeared. Tetrahydrofuran (107 ml) was then added to this mixture, and the mixture was stirred for 20 minutes at 0° C. 2-(2-Formamidothiazol-4-yl)-2-allyloxyiminoacetic acid (syn isomer) (13.2 g) was added to the mixture. The resultant mixture was stirred at 0° C. to give an activated acid solution. On the other hand, to a suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate monohydrochloride (20 g) in tetrahydrofuran (200 ml) was added bis(trimethylsilyl)urea (36.2 g) at ambient temperature. The mixture was stirred at 36°-38° C. for 40 minutes to give a clear solution. To this solution was added the activated acid solution obtained above at once at -20° C. The mixture was stirred at -20°~12° C. for 40 minutes. To this mixture was added a mixture of ethyl acetate (700 ml) and water. The separated organic layer was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated to give a solid. The solid was recrystallized from diisopropyl ether to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-allyloxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (25.5 g).

Workup

  1. temperatureThe mixture was cooled until the precipitate
  2. customto give an activated acid solution
  3. stirringThe mixture was stirred at 36°-38° C. for 40 minutes
  4. customto give a clear solution
  5. additionTo this solution was added the activated acid solution
  6. customobtained above at once at -20° C
  7. stirringThe mixture was stirred at -20°~12° C. for 40 minutes
  8. additionTo this mixture was added
  9. washThe separated organic layer was washed with an aqueous solution of sodium bicarbonate
  10. dry with materialdried over magnesium sulfate
  11. concentrationconcentrated
  12. customto give a solid
  13. customThe solid was recrystallized from diisopropyl ether

Sources & evidence

ORD record
ord-f24aae7e5b964c52a705bf22fcb2ef25
Source dataset
uspto-grants-1986_11
Patent number
US04622318

Reaction notes

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