Dimethylformamide → 7-[2-(2-Tritylaminothiazol-4-yl)-2-(2-tetrahydropyranyloxyimino)acetamido]-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate

HRID 1607949Notes

Reaction equation

HRID 1607949 reaction equation
CN(C)C=O.P(Cl)(Cl)(Cl)=O.[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34]([C:36](=[N:40][O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[C:37](O)=[O:38])[N:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.Cl.[NH2:50][CH:51]1[C:68](=[O:69])[N:53]2[C:54]([C:65]([O-:67])=[O:66])=[C:55]([CH2:58][N+:59]3([CH3:64])[CH2:63][CH2:62][CH2:61][CH2:60]3)[CH2:56][S:57][C@H:52]12>O1CCCC1.O>[C:11]([NH:30][C:31]1[S:32][CH:33]=[C:34]([C:36](=[N:40][O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[C:37]([NH:50][CH:51]2[C:68](=[O:69])[N:53]3[C:54]([C:65]([O-:67])=[O:66])=[C:55]([CH2:58][N+:59]4([CH3:64])[CH2:63][CH2:62][CH2:61][CH2:60]4)[CH2:56][S:57][C@H:52]23)=[O:38])[N:35]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 24813Phosphorus oxychlorideHCID 538028372-(2-Tritylamino-4-thiazolyl)-2-tetrahydropyranyloxyimino-acetic acidHCID 1317161277-Amino-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate dihydrochloride

Product 1

HCID 1317161367-[2-(2-Tritylaminothiazol-4-yl)-2-(2-tetrahydropyranyloxyimino)acetamido]-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylateYield 175.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-20 °C

Procedure

To a mixture of dimethylformamide (5.28 ml) and tetrahydrofuran (15 ml) wasadded phosphorus oxychloride (6.6 ml) under cooling. The mixture was stirred for 30 minutes under ice-cooling. To the mixture was added a solution of 2-(2-tritylaminothiazol-4-yl)-2-(2-tetrahydropyranyloxyimino)acetic acid (syn isomer) (30.4 g) in tetrahydrofuran (300 ml) with stirring under ice-cooling. The mixture was stirred for 40 minutes at 3° to 5° C. to produce an activated acid solution. On the other hand, to a solution of a salt of 7-amino-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate dihydrochloride (20 g) in tetrahydrofuran containing monotrimethylsilylacetamide (107 g) was added at once. The activated acid solution obtained above under cooling at -20° C. and the resulting mixture was stirred for 2 hours at -20° C. to -10° C. To thereaction mixture was added water. The insoluble materials were filtered offand the organic layer in the filtrate was separated. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate several times. The combined extract was washed with water, aqueous sodium bicarbonate and saturated aqueous sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (250 g) eluting with a mixture of ethyl acetate and isopropyl ether (1:3). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated in diisopropyl ether to give 7-[2-(2-tritylaminothiazol-4-yl)-2-(2-tetrahydropyranyloxyimino)acetamido]-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate (syn isomer) (75.0 g).

Workup

  1. temperatureunder cooling
  2. temperaturecooling
  3. stirringwith stirring under ice-
  4. temperaturecooling
  5. stirringThe mixture was stirred for 40 minutes at 3° to 5° C.
  6. customto produce an activated acid solution
  7. additionwas added at once
  8. customThe activated acid solution obtained above
  9. stirringthe resulting mixture was stirred for 2 hours at -20° C. to -10° C
  10. filtrationThe insoluble materials were filtered
  11. customthe organic layer in the filtrate was separated
  12. extractionextracted with ethyl acetate several times
  13. extractionThe combined extract
  14. washwas washed with water, aqueous sodium bicarbonate and saturated aqueous sodium chloride successively
  15. dry with materialdried over magnesium sulfate
  16. distillationThe solvent was distilled off
  17. washeluting with a mixture of ethyl acetate and isopropyl ether (1:3)
  18. additionThe fractions containing the object compound
  19. concentrationconcentrated under reduced pressure
  20. customThe residue was triturated in diisopropyl ether

Sources & evidence

ORD record
ord-0a76def4898a45ddb26f9010da93f39e
Source dataset
uspto-grants-1989_09
Patent number
US04868174

Reaction notes

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