反应详情

A solution of bromine (43.0 g.) in methylene chloride (30 ml.) was dropwise added to a solution of diketene (22.6 g.) in methylene chloride (30 ml.) at -30° C. over 35 minutes, and stirred at the same temperature for 30 minutes. The solution was dropwise added to a stirred solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (75.1 g.) and bis(trimethylsilyl)acetamide (68.4 g,) in tetrahydrofuran (1.5 l) at -15° C. over 10 minutes, and the solution was stirred at the same temperature for 50 minutes. Water (35 ml.) and an aqueous solution (35 ml.) of sodium nitrite (18.6 g.) were added to the resultant solution while keeping at pH 2.0, and the solution was stirred at 10° to 15° C. for 15 minutes. After the solution was adjusted to pH 4.5 with a saturated aqueous solution of sodium bicarbonate, an aqueous solution (150 ml.) of thiourea (17.1 g.) was added to the solution, adjusted to pH 6.0 with a saturated aqueous solution of sodium bicarbonate, and stirred for 20 minutes. The organic layer was separated and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1.5 l), and washed with water three times. The solution was dried over magnesium sulfate, treated with activated charcoal and concentrated under reduced pressure. After the residue was triturated with diethyl ether (200 ml.), the precipitates were collected by decantation and washed with ether acetate (300 ml.), a mixture of tetrahydrofuran (500 ml.) and ethyl acetate (1 l) at 60° C. and then with ethyl acetate (100 ml.) three times, and dried to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 55.5 g.).

1. stirringthe solution was stirred at the same temperature for 50 minutes
2. stirringthe solution was stirred at 10° to 15° C. for 15 minutes
3. stirringstirred for 20 minutes
4. customThe organic layer was separated
5. concentrationconcentrated under reduced pressure
6. dissolutionThe residue was dissolved in ethyl acetate (1.5 l)
7. washwashed with water three times
8. dry with materialThe solution was dried over magnesium sulfate
9. additiontreated with activated charcoal
10. concentrationconcentrated under reduced pressure
11. customAfter the residue was triturated with diethyl ether (200 ml.)
12. customthe precipitates were collected by decantation
13. washwashed with ether acetate (300 ml.)
14. additiona mixture of tetrahydrofuran (500 ml.) and ethyl acetate (1 l) at 60° C.
15. dry with materialwith ethyl acetate (100 ml.) three times, and dried