Hydrochloric Acid → Benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylate

HRID 569368Notes

Reaction equation

HRID 569368 reaction equation
NC1C(=O)N2C(C(O)=O)=C(CO)CS[C@H]12.C(=O)([O-])[O-].[Na+].[Na+].Cl.[C:23]([O:27][C:28]([CH2:30][O:31][N:32]=[C:33]([C:51]1[N:52]=[C:53]([NH:56][CH:57]=[O:58])[S:54][CH:55]=1)[C:34]([NH:36][CH:37]1[C:49](=[O:50])[N:39]2[C:40]([C:46]([OH:48])=[O:47])=[C:41]([CH2:44][OH:45])[CH2:42][S:43][C@H:38]12)=[O:35])=[O:29])([CH3:26])([CH3:25])[CH3:24].[C:59]1([C:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[N+]=[N-])[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>C(=O)(O)[O-].[Na+].O.CC(C)=O.C(OCC)(=O)C>[C:23]([O:27][C:28]([CH2:30][O:31][N:32]=[C:33]([C:51]1[N:52]=[C:53]([NH:56][CH:57]=[O:58])[S:54][CH:55]=1)[C:34]([NH:36][CH:37]1[C:49](=[O:50])[N:39]2[C:40]([C:46]([O:48][CH:65]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:47])=[C:41]([CH2:44][OH:45])[CH2:42][S:43][C@H:38]12)=[O:35])=[O:29])([CH3:26])([CH3:24])[CH3:25]

Participants

10

Reactant 5

HCID 313Hydrochloric Acid2×HCID 10340Sodium CarbonateHCID 612301,1'-(Diazomethylene)bis(benzene)HCID 129054807-Amino-3-hydroxymethyl-3-cephem-4-carboxylic AcidHCID 1317133337-[2-Tertbutoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid

Product 1

HCID 131713332Benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylate

Reagents, catalysts & solvents 4

HCID 180AcetoneSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Procedure

On the other hand, 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid (11.5 g) was dissolved in a solution of sodium bicarbonate (8.4 g) in water (50 ml) and acetone (50 ml). To this solution was added dropwise the activated acid solution obtained above at 3° to 8° C. while keeping the pH value of the mixture to 7-8 with 20% aqueous sodium carbonate, and the mixture was stirred at the same temperature for an hour. The reaction mixture was adjusted to pH 6.0 with 10% hydrochloric acid and then washed with ethyl acetate to give an aqueous solution containing 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer). To this aqueous solution was added a solution of diphenyldiazomethane in ethyl acetate (1 mmol/ml) (100 ml), and the mixture was acidified to pH 2.5 with 10% hydrochloric acid. After stirring at ambient temperature for 2 hours, the solution was extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1). The extract was washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, followed by drying over magnesium sulfate. The solution was evaporated and the residue was pulverized with diethyl ether to give benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylate (syn isomer) (18.5 g).

Workup

  1. additionTo this solution was added dropwise the activated acid solution
  2. customobtained above at 3° to 8° C.
  3. washwashed with ethyl acetate
  4. customto give an aqueous solution
  5. stirringAfter stirring at ambient temperature for 2 hours
  6. extractionthe solution was extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1)
  7. washThe extract was washed with a saturated aqueous sodium bicarbonate
  8. dry with materialby drying over magnesium sulfate
  9. customThe solution was evaporated

Sources & evidence

ORD record
ord-35a8874586b84c4bbcbbfd37e4cdd0d2
Source dataset
uspto-grants-1988_03
Patent number
US04731443

Reaction notes

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