Dicyclohexylcarbodiimide → 2-Benzhydryloxycarbonyl-7-[2-(2-t-butoxycarbonylprop-2-yl-oxyimino)-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-[2-(pyridin-3-yl-amino)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene

HRID 1980424Notes

Reaction equation

HRID 1980424 reaction equation
ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:26][CH:27]1[C:34](=[O:35])[N:33]2[CH:28]1[S:29][CH2:30][C:31]([C:52]1[S:56][C:55]([NH:57][C:58]3[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=3)=[N:54][CH:53]=1)=[C:32]2[C:36]([O:38][CH:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37].[C:64]([NH:83][C:84]1[S:85][CH:86]=[C:87]([C:89](=[N:93][O:94][C:95]([C:98]([O:100][C:101]([CH3:104])([CH3:103])[CH3:102])=[O:99])([CH3:97])[CH3:96])[C:90](O)=[O:91])[N:88]=1)([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C)C=O.C(O)(=O)C>[CH:39]([O:38][C:36]([C:32]1[N:33]2[CH:28]([S:29][CH2:30][C:31]=1[C:52]1[S:56][C:55]([NH:57][C:58]3[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=3)=[N:54][CH:53]=1)[CH:27]([NH:26][C:90](=[O:91])[C:89](=[N:93][O:94][C:95]([C:98]([O:100][C:101]([CH3:104])([CH3:103])[CH3:102])=[O:99])([CH3:97])[CH3:96])[C:87]1[N:88]=[C:84]([NH:83][C:64]([C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=3)([C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=3)[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)[S:85][CH:86]=1)[C:34]2=[O:35])=[O:37])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1

Participants

7

Reactant 4

HCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 139605317-Amino-2-benzhydryloxycarbonyl-3-[2-(pyrid-3-yl-amino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-eneHCID 534453442-(2-Tritylaminothiazol-4-yl)-2-[(2-t-butoxycarbonylprop-2-yl)-oxyimino]-acetic acid

Product 1

HCID 538049402-Benzhydryloxycarbonyl-7-[2-(2-t-butoxycarbonylprop-2-yl-oxyimino)-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-[2-(pyridin-3-yl-amino)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-eneYield 21.2%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
22 °C

Procedure

1-Hydroxybenzotriazole (3.24 g) and N,N'-dicyclohexylcarbodiimide (4.95 g) are added to a solution, cooled to +5° C., of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-[2-(pyridin-3-yl-amino)-thiazol-5-yl]-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene (10.83 g) and the syn isomer of 2-(2-tritylaminothiazol-4-yl)-2-[(2-t-butoxycarbonylprop-2-yl)-oxyimino]-acetic acid (13.72 g) in anhydrous N,N-dimethylformamide (200 cc). The mixture is stirred for 30 minutes at 5° C. and for 3 hours 30 minutes at 22° C. Acetic acid (1 cc) is added, the mixture is then filtered, the precipitate is washed with dimethylformamide (20 cc) and the filtrate is diluted with ethyl acetate (900 cc). The organic phase is washed with distilled water (2×500 cc), a 0.1 N aqueous solution of hydrochloric acid (500 cc), a semi-saturated solution of sodium bicarbonate (500 cc), distilled water (2×500 cc) and a saturated solution of sodium chloride (500 cc). It is dried over anhydrous magnesium sulphate; the mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is purified by chromatography on a column (height=63 cm, diameter=4.8 cm), containing silica gel (0.06-0.20 mm), elution being carried out under a pressure of 0.4 bar with a mixture of cyclohexane and ethyl acetate (50/50 by Volume) (4 liters) and 250 cc fractions being collected. Fractions 8 to 14, containing the pure product, are combined and concentrated under reduced pressure (30 mm Hg: 4 kPa) at 30° C. to give the syn isomer of 2-benzhydryloxycarbonyl-7-{2-[(2-t-butoxycarbonylprop-2-yl)-oxyimino]-2-(2-tritylaminothiazol-4-yl)-acetamido}-8-oxo-3-[2-(pyridin-3-yl-amino)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0] oct-2-ene (4.65 g) in the form of a hard yellow foam.

Workup

  1. filtrationthe mixture is then filtered
  2. washthe precipitate is washed with dimethylformamide (20 cc)
  3. additionthe filtrate is diluted with ethyl acetate (900 cc)
  4. washThe organic phase is washed with distilled water (2×500 cc)
  5. distillationa 0.1 N aqueous solution of hydrochloric acid (500 cc), a semi-saturated solution of sodium bicarbonate (500 cc), distilled water (2×500 cc)
  6. dry with materialIt is dried over anhydrous magnesium sulphate
  7. filtrationthe mixture is filtered
  8. concentrationthe filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C
  9. customThe residue is purified by chromatography on a column (height=63 cm, diameter=4.8 cm)
  10. additioncontaining
  11. washsilica gel (0.06-0.20 mm), elution
  12. additionbeing carried out under a pressure of 0.4 bar with a mixture of cyclohexane and ethyl acetate (50/50 by Volume) (4 liters) and 250 cc fractions
  13. custombeing collected
  14. additionFractions 8 to 14, containing the pure product
  15. concentrationconcentrated under reduced pressure (30 mm Hg: 4 kPa) at 30° C.

Sources & evidence

ORD record
ord-cfd2af102a0043e480ef87698d2ddcb9
Source dataset
uspto-grants-1985_04
Patent number
US04508717

Reaction notes

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