Dimethylformamide → Benzhydryl 3-chloromethyl-7-[2-isopropoxyimino-2-(2-tritylaminothiazol-4-yl) acetamido]-3-cephem-4-carboxylate

HRID 1194604Notes

Reaction equation

HRID 1194604 reaction equation
P(Cl)(Cl)(Cl)=O.CN(C)C=O.[CH:11]([O:14][N:15]=[C:16]([C:20]1[N:21]=[C:22]([NH:25][C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:23][CH:24]=1)[C:17]([OH:19])=O)([CH3:13])[CH3:12].[NH2:45][CH:46]1[C:71](=[O:72])[N:48]2[C:49]([C:55]([O:57][CH:58]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])=[C:50]([CH2:53][Cl:54])[CH2:51][S:52][C@H:47]12.[OH-].[Na+]>O.C(OCC)(=O)C.C(Cl)Cl>[Cl:54][CH2:53][C:50]1[CH2:51][S:52][C@@H:47]2[CH:46]([NH:45][C:17](=[O:19])[C:16](=[N:15][O:14][CH:11]([CH3:12])[CH3:13])[C:20]3[N:21]=[C:22]([NH:25][C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[S:23][CH:24]=3)[C:71](=[O:72])[N:48]2[C:49]=1[C:55]([O:57][CH:58]([C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56]

Participants

9

Reactant 5

HCID 6228DimethylformamideHCID 14798Sodium HydroxideHCID 24813Phosphorus oxychlorideHCID 13239626Benzhydryl 7-Amino-3-chloromethyl-3-cephem-4-carboxylateHCID 542516492-(2-Tritylamino-4-thiazolyl)-2-(1-methylethoxyimino)-acetic acid

Product 1

HCID 131715762Benzhydryl 3-chloromethyl-7-[2-isopropoxyimino-2-(2-tritylaminothiazol-4-yl) acetamido]-3-cephem-4-carboxylateYield 66.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

0.41 ml (4.4 mmol) of phosphorous oxychoride was added to 5 ml of ethyl acetate, and 0.35 ml (4.5 mmol) of N,N-dimethylformamide was dropwise added thereto under cooling with ice. Then, the mixture was stirred at room temperature for 15 minutes. To the solution, 20 ml of a methylene chloride solution containing 1.59 g (3.38 mmol) of 2-isopropoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (syn-isomer) was added, and the mixture was stirred for 30 minutes. To the reaction solution, 1.4 g (3.37 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate was added under cooling with ice, and the mixture was stirred for 2 hours. To the reaction solution, 50 ml of ethyl acetate and 20 ml of water were added, and the mixture was adjusted to pH 7.0 with a 5N sodium hydroxide aqueous solution. The organic layer was separated and washed sequentially with a 5% sodium hydrogen carbonate aqueous solution, water and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The oily residue was purified by silica gel column chromatography to obtain 1.94 g (yield: 66%) of benzhydryl 3-chloromethyl-7-[2-isopropoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn-isomer).

Workup

  1. additionwas dropwise added
  2. temperatureunder cooling with ice
  3. additionwas added
  4. stirringthe mixture was stirred for 30 minutes
  5. temperatureunder cooling with ice
  6. stirringthe mixture was stirred for 2 hours
  7. customThe organic layer was separated
  8. washwashed sequentially with a 5% sodium hydrogen carbonate aqueous solution, water
  9. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  10. concentrationconcentrated under reduced pressure
  11. customThe oily residue was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-068925ad35ce4e6da0206f1b070b321e
Source dataset
uspto-grants-1989_03
Patent number
US04814328

Reaction notes

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