Diketene → Benzhydryl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate

HRID 905430

Reaction equation

HRID 905430 reaction equation
[CH2:1]=[C:2]1[O:6][C:4](=O)[CH2:3]1.BrBr.BrCC(=O)CC(Br)=O.Cl.[NH2:18][CH:19]1[C:44](=[O:45])[N:21]2[C:22]([C:28]([O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]12.C[Si](CC(N)=O)(C)C.[NH2:54][C:55]([NH2:57])=[S:56]>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.C(O)C.O1CCCC1.O>[NH2:57][C:55]1[S:56][CH:1]=[C:2]([CH2:3][C:4]([NH:18][CH:19]2[C:44](=[O:45])[N:21]3[C:22]([C:28]([O:30][CH:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[O:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]23)=[O:6])[N:54]=1

Participants

12

Reactant 6

HCID 12661DiketeneHCID 24408BromineHCID 357676Acetamide, 2-(trimethylsilyl)-HCID 2723790ThioureaHCID 12818005Benzhydryl 7-amino-3vinyl-3cephem-4-carboxylate hydrochlorideHCID 128310484-Bromo-3-oxobutanoyl bromide

Product 1

HCID 88469409Benzhydryl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylateYield 86.3%

Reagents, catalysts & solvents 5

HCID 702EthanolSolventHCID 962WaterSolventHCID 5943Carbon TetrachlorideSolvent2×HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

To a solution of diketene (1.26 g) in carbon tetrachloride (12 ml) was added a solution of bromine (2.40 g) in carbon tetrachloride (3 ml) at -30° to -25° C., and the mixture was stirred at the same temperature for half an hour to prepare a solution of 4-bromoacetoacetyl bromide. This solution was added dropwise to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (6.43 g) and trimethylsilylacetamide (7.82 g) in ethyl acetate (129 ml) at -30° C. with stirring, and the stirring was continued at -30° to -10° C. for 2 hours. To the reaction mixture were added water at -20° C. and ethyl acetate, followed by separating out the organic layer, which was washed with water, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, dried over anhydrous magnesium sulfate and then evaporated. The residue obtained was dissolved in a mixture of ethanol (100 ml) and tetrahydrofuran (100 ml), and to this solution was added thiourea (3.42 g), followed by stirring at ambient temperature for an hour. After evaporation of the reaction mixture, to the residue were added water and ethyl acetate, and then adjusted to pH 7 with sodium bicarbonate. The separated ethyl acetate layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to give benzhydryl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (6.89 g).

Workup

  1. stirringwith stirring
  2. customby separating out the organic layer, which
  3. washwas washed with water
  4. dry with materialan aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, dried over anhydrous magnesium sulfate
  5. customevaporated
  6. customThe residue obtained
  7. stirringby stirring at ambient temperature for an hour
  8. customAfter evaporation of the reaction mixture
  9. additionto the residue were added water and ethyl acetate
  10. washThe separated ethyl acetate layer was washed with an aqueous solution of sodium chloride
  11. dry with materialdried over anhydrous magnesium sulfate
  12. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-bb49785a49a948b5bed000dd91962f31
Source dataset
uspto-grants-1983_12
Patent number
US04423213

Linked notes

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