Chlorotrimethylsilane → (6R,7R)-7-[[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-hydroxyiminoacetyl]amino]-8-oxo-3-(1H-pyrazol-4-ylmethylsulfanyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

HRID 619238Notes

Reaction equation

HRID 619238 reaction equation
C[Si](CC(N)=O)(C)C.C[Si](C)(C)Cl.[NH2:14][C@@H:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([S:22][CH2:23][C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)[CH2:20][S:21][C@H:16]12.C(=O)=O.C([O-])(=O)C.[Cl:41][C:42]1[S:46][C:45]([NH:47]C=O)=[N:44][C:43]=1/[C:50](=[N:54]/[O:55]C(=O)C)/[C:51](Cl)=[O:52]>ClCCl.CO>[NH2:47][C:45]1[S:46][C:42]([Cl:41])=[C:43](/[C:50](=[N:54]/[OH:55])/[C:51]([NH:14][C@@H:15]2[C:32](=[O:33])[N:17]3[C:18]([C:29]([OH:31])=[O:30])=[C:19]([S:22][CH2:23][C:24]4[CH:28]=[N:27][NH:26][CH:25]=4)[CH2:20][S:21][C@H:16]23)=[O:52])[N:44]=1

Participants

8

Reactant 5

HCID 6397ChlorotrimethylsilaneHCID 357676Acetamide, 2-(trimethylsilyl)-HCID 10614869[(Z)-[2-chloro-1-(5-chloro-2-formamido-1,3-thiazol-4-yl)-2-oxoethylidene]amino] acetateHCID 701245417beta-Amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acidHCID 131721386Dry ice acetate

Product 1

HCID 9871187(6R,7R)-7-[[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-hydroxyiminoacetyl]amino]-8-oxo-3-(1H-pyrazol-4-ylmethylsulfanyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acidYield 40.6%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Under nitrogen atmosphere, trimethylsilylacetamide (39.4 g) and trimethylchlorosilane (0.76 ml) were added successively to a suspension of 7β-amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid (9.4 g) in dichloromethane (100 ml) at 0° C. The mixture was refluxed for 1.5 hours, then cooled again to -15° C. with dry ice-acetate. 2-(5-Chloro-2-formylaminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetyl chloride (12.6 g) was added portionwise to the mixture over 10 minutes at the same temperature. The whole mixture was stirred for 12 hours at 0° C., then poured into 100 ml of ice-cooled methanol. After the solvent was concentrated in vacuo, 17 ml of concentrated hydrogen chloride was added at 0° C., and stirred for 7 hours. The mixture was poured into water (400 ml) and the pH was adjusted to between 3.4 and 3.6 with 28% ammonium hydroxide, and stirred for 12 hours at 0° C. The resulting precipitate was collected by filtration, and chromatographed on HP-20 to afford 7β-[2-(2-amino-5-chlorothiazol-4-yl)-2-(Z)-(hydroxyimino)-acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid (6.30 g) as crystals. The physical data was identical with that the object compound of Example 3.

Workup

  1. temperatureThe mixture was refluxed for 1.5 hours
  2. concentrationAfter the solvent was concentrated in vacuo, 17 ml of concentrated hydrogen chloride
  3. additionwas added at 0° C.
  4. stirringstirred for 7 hours
  5. additionThe mixture was poured into water (400 ml)
  6. stirringstirred for 12 hours at 0° C
  7. filtrationThe resulting precipitate was collected by filtration
  8. customchromatographed on HP-20

Sources & evidence

ORD record
ord-84e20a2bd0ac4c8192dd3264258735f3
Source dataset
uspto-grants-1999_09
Patent number
US05958914

Reaction notes

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