Bromine → 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-[2-(pyrid-3-yl-amino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene

HRID 2413446Notes

Reaction equation

HRID 2413446 reaction equation
BrBr.[CH:3]([O:16][C:17]([C:19]1[N:20]2[CH:23]([S:24][CH2:25][C:26]=1[CH:27]=[CH:28]N(C)C)[CH:22]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:21]2=[O:40])=[O:18])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([NH:47][C:48]([NH2:50])=[S:49])[CH:42]=1>C(Cl)Cl.O1CCCC1.O>[CH:3]([O:16][C:17]([C:19]1[N:20]2[CH:23]([S:24][CH2:25][C:26]=1[C:27]1[S:49][C:48]([NH:47][C:43]3[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=3)=[N:50][CH:28]=1)[CH:22]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C:21]2=[O:40])=[O:18])([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1

Participants

7

Reactant 3

HCID 24408BromineHCID 27605153-PyridylthioureaHCID 539143342-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylamino-vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene

Product 1

HCID 204024442-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-[2-(pyrid-3-yl-amino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of bromine (35.96 g) in dry methylene chloride (40 cc) is added dropwise to a solution, cooled to -75° C., of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylamino-vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, E-form, (107.1 g) in dry tetrahydrofuran (600 cc). The mixture is stirred at this temperature for 10 minutes and pyrid-3-yl-thiourea (30.64 g) dissolved in a mixture (400 cc) of water and tetrahydrofuran (50:50 by volume) is then added. The cooling bath is removed and the mixture is stirred at 20° C. for 17 hours. The brown solution is diluted with ethyl acetate (1.5 liters) and is then washed successively with distilled water (1 liter), a half-saturated sodium bicarbonate solution (1 liter), distilled water (1 liter) and a saturated sodium chloride solution (500 cc). The organic phase is dried over anhydrous magnesium sulphate. After evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C., the residue is chromatographed on a column (height: 46 cm, diameter: 8.1 cm) of silica gel (0.06-0.20 mm), elution being carried out successively with a mixture (5 liters) of cyclohexane and ethyl acetate (50:50 by volume), a mixture (5 liters) of cyclohexane and ethyl acetate (25:75 by volume) and ethyl acetate (7 liters), 1 liter fractions being collected. Fractions 8 to 17, containing the pure product, are combined and concentrated to a residual volume of 250 cc. A yellow suspension is obtained, which is kept at 5° C. for 12 hours. The solid is filtered off, washed with ethyl ether (3×100 cc) and dried under reduced pressure (1 mm Hg; 0.13 kPa). 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-[2-(pyrid-3-yl-amino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (14.5 g) is thus obtained in the form of a yellow powder.

Workup

  1. additionis then added
  2. customThe cooling bath is removed
  3. stirringthe mixture is stirred at 20° C. for 17 hours
  4. additionThe brown solution is diluted with ethyl acetate (1.5 liters)
  5. washis then washed successively with distilled water (1 liter)
  6. distillationa half-saturated sodium bicarbonate solution (1 liter), distilled water (1 liter)
  7. dry with materialThe organic phase is dried over anhydrous magnesium sulphate
  8. customAfter evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C.
  9. customthe residue is chromatographed on a column (height: 46 cm, diameter: 8.1 cm) of silica gel (0.06-0.20 mm), elution
  10. customa mixture (5 liters) of cyclohexane and ethyl acetate (25:75 by volume) and ethyl acetate (7 liters), 1 liter fractions being collected
  11. additionFractions 8 to 17, containing the pure product
  12. concentrationconcentrated to a residual volume of 250 cc
  13. customA yellow suspension is obtained
  14. waitwhich is kept at 5° C. for 12 hours
  15. filtrationThe solid is filtered off
  16. washwashed with ethyl ether (3×100 cc)
  17. customdried under reduced pressure (1 mm Hg; 0.13 kPa)

Sources & evidence

ORD record
ord-ad76c885ba914a57ae8db15e2029a535
Source dataset
uspto-grants-1985_01
Patent number
US04496560

Reaction notes

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