反应详情

A stirred suspension of phosphorus pentachloride (156 g, 0.75 mole) in dry dichloromethane (1.5 liters) was cooled in an ice-bath and treated with pyridine (60.5 ml, 0.75 mole) at such a rate that the temperature of the mixture remained at ca. 20° to 25°. The mixture was stirred and cooled to 8° and diphenylmethyl (6R,7R)-7-(thien-2-yl)acetamido-3-trichloroacetylcarbamoyloxymethylceph-3-em-4-carboxylate (354.5 g, 0.5 mole) was added in portions over 10 minutes. The mixture was stirred at ca. 8° for 1.75 hours and then added over 10 minutes to a stirred mixture of butane-1,3-diol (225 ml, 2.5 mole) and dichloromethane (500 ml) precooled to -20° so that the temperature of the mixture was kept in the range -15° to -20°. The cooling bath was removed and the mixture was stirred at ca. -10° for 20 minutes. Water (1 liter) was added and the two-phase mixture was stirred for 30 minutes. The aqueous phase was extracted with dichloromethane (2×500 ml), and the organic phases were washed sequentially with 2N hydrochloric acid (1 liter), combined and evaporated to a brown gum. The gum was dissolved in methanol (3.6 liters) and this solution was stirred and treated with saturated aqueous sodium hydrogen carbonate solution (1.2 liters) over a period of 10 minutes. The mixture was stirred at ca. 20° for 1.5 hours and a small quantity of brown solid was removed by filtration. The yellow filtrate was concentrated in vacuo (bath temp. not greater than 40°) to ca. 1.5 liters and water (1.5 liters) was added. The resulting suspension was refrigerated for 1 hour, and the yellow solid was filtered off, washed well with water, sucked as dry as possible and dried in vacuo at 40° for 24 hours. The greasy solid thus obtained, followed by toluene-p-sulphonic acid monohydrate (81 g, 0.425 mole), were added to stirred chloroform (2 liters). After several minutes the toluene-p-sulphonic acid salt began to crystallise. Stirring was continued for a further 30 minutes, after which the water was removed azeotropically in vacuo with continuous replacement of the chloroform so as to maintain a volume of 2 liters. The suspension was refrigerated overnight and the product was filtered off, slurry washed with chloroform (2×250 ml), refiltered, washed by displacement with chloroform (250 ml) and dried in vacuo at 40° to give the title compound as an off-white crystalline solid (237.8 g, 74.1%); λmax (EtOH) 262 nm (ε 7,250); the NMR spectrum (Me2SO-d6) indicated the presence of 0.25 mole of chloroform.

1. temperaturewas cooled in an ice-bath
2. customremained at ca. 20° to 25°
3. temperaturecooled to 8°
4. stirringThe mixture was stirred at ca. 8° for 1.75 hours
5. customprecooled to -20° so that the temperature of the mixture
6. customwas kept in the range -15° to -20°
7. customThe cooling bath was removed
8. stirringthe mixture was stirred at ca. -10° for 20 minutes
9. additionWater (1 liter) was added
10. stirringthe two-phase mixture was stirred for 30 minutes
11. extractionThe aqueous phase was extracted with dichloromethane (2×500 ml)
12. washthe organic phases were washed sequentially with 2N hydrochloric acid (1 liter)
13. customevaporated to a brown gum
14. dissolutionThe gum was dissolved in methanol (3.6 liters)
15. stirringthis solution was stirred
16. additiontreated with saturated aqueous sodium hydrogen carbonate solution (1.2 liters) over a period of 10 minutes
17. stirringThe mixture was stirred at ca. 20° for 1.5 hours
18. customa small quantity of brown solid was removed by filtration
19. concentrationThe yellow filtrate was concentrated in vacuo (bath temp. not greater than 40°) to ca. 1.5 liters and water (1.5 liters)
20. additionwas added
21. filtrationthe yellow solid was filtered off
22. washwashed well with water
23. customas dry as possible and
24. customdried in vacuo at 40° for 24 hours
25. customThe greasy solid thus obtained
26. additionwere added
27. customto crystallise
28. stirringStirring
29. waitwas continued for a further 30 minutes
30. customafter which the water was removed azeotropically in vacuo with continuous replacement of the chloroform so as
31. temperatureto maintain a volume of 2 liters
32. waitThe suspension was refrigerated overnight
33. filtrationthe product was filtered off
34. washslurry washed with chloroform (2×250 ml)
35. washwashed by displacement with chloroform (250 ml)
36. customdried in vacuo at 40°