p-Toluenesulfonic acid monohydrate → 7-(Imidazol-2-yl)amino-3-(1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylic acid

HRID 1463162Notes

Reaction equation

HRID 1463162 reaction equation
O.C1(C)C=CC(S(O)(=O)=O)=CC=1.F[C:14]1[N:15](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=[CH:17][N:18]=1.FC1NC=CN=1.[NH2:44][CH:45]1[C:62](=[O:63])[N:47]2[C:48]([C:59]([OH:61])=[O:60])=[C:49]([CH2:52][S:53][C:54]3[S:55][CH:56]=[N:57][N:58]=3)[CH2:50][S:51][C@H:46]12>CN(C=O)C>[NH:15]1[CH:16]=[CH:17][N:18]=[C:14]1[NH:44][CH:45]1[C:62](=[O:63])[N:47]2[C:48]([C:59]([OH:61])=[O:60])=[C:49]([CH2:52][S:53][C:54]3[S:55][CH:56]=[N:57][N:58]=3)[CH2:50][S:51][C@H:46]12

Participants

6

Reactant 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 5595422-Fluoro-1H-imidazole2×HCID 128891877-Amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3cephem-4-carboxylic acidHCID 204324542-Fluoro-1-trityl-1H-imidazole

Product 1

HCID 705083937-(Imidazol-2-yl)amino-3-(1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylic acidYield 11.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of toluene-p-sulphonic acid hydrate (54 mg.) in dry DMF (1 ml.) was added 2-fluoro-1-triphenylmethylimidazole (110 mg.) and the solution heated in a preheated bath at 80°. After 5 minutes, to allow complete formation in situ of 2-fluoroimidazole, 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylic acid (110 mg.) was added and heating continued for 2.5 hours. A further portion of the fluoroimidazole (50 mg.) was then added, heating was continued for a further 30 minutes, and the mixture was cooled and evaporated at room temperature. To the residue was added water (10 ml.) and ethyl acetate (25 ml.) and the mixture filtered and the phases separated. The aqueous layer was concentrated to 4 ml., filtered and subjected to preparative HPLC on Whatman "Partisil 10" using water/MeOH/HOAc 80:20:1 v/v/v as eluant. The product crystallised on addition of acetone. It was washed with acetone and ether to give 7-(imidazol-2-yl)amino-3-(1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylic acid (15 mg.) having the following n.m.r. in d6DMSO+CD3COOD: 3.52 (d, 1H); 3.79 (d, 1H); 4.33 (d, 1H); 4.6 (d, 1H); 5.12 (d, 1H); 5.58 (d, 1H); 6.83 (s, 2H); 9.49 (s, 1H).

Workup

  1. temperaturethe solution heated in a preheated bath at 80°
  2. additionwas added
  3. temperatureheating
  4. waitcontinued for 2.5 hours
  5. temperatureheating
  6. waitwas continued for a further 30 minutes
  7. temperaturethe mixture was cooled
  8. customevaporated at room temperature
  9. additionTo the residue was added water (10 ml.) and ethyl acetate (25 ml.)
  10. filtrationthe mixture filtered
  11. customthe phases separated
  12. concentrationThe aqueous layer was concentrated to 4 ml
  13. filtration, filtered
  14. customThe product crystallised on addition of acetone
  15. washIt was washed with acetone and ether

Sources & evidence

ORD record
ord-fe78007221a147b780f40b5a6d6e77a1
Source dataset
uspto-grants-1984_07
Patent number
US04463173

Reaction notes

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