Acetic Acid → 3-(1,3,4-Thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2(2-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid

HRID 325403Notes

Reaction equation

HRID 325403 reaction equation
[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[S:6][CH2:7][C:8]1[CH2:9][S:10][C@@H:11]2[CH:18]([NH:19][C:20](=[O:37])[CH:21]([OH:36])[C:22]3[N:23]=[C:24]([NH:27]C(OC(CC)(C)C)=O)[S:25][CH:26]=3)[C:17](=[O:38])[N:12]2[C:13]=1[C:14]([OH:16])=[O:15].C(O)=O.C(O)(=O)C>C(=O)(O)[O-].[Na+].C([O-])(=O)C>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[S:6][CH2:7][C:8]1[CH2:9][S:10][C@@H:11]2[CH:18]([NH:19][C:20](=[O:37])[CH:21]([OH:36])[C:22]3[N:23]=[C:24]([NH2:27])[S:25][CH:26]=3)[C:17](=[O:38])[N:12]2[C:13]=1[C:14]([OH:16])=[O:15]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 284Formic AcidHCID 704900353-(1,3,4-Thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acidHCID 178447171HCID 178447171, compound

Product 1

HCID 704905123-(1,3,4-Thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2(2-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid

Reagents, catalysts & solvents 2

HCID 175AcetateSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A mixture of 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (2.1 g.) and 98 to 100% formic acid (40 ml.) was stirred for 2.5 hours at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure. The residue was pulverized in acetonitrile, collected by filtration and then washed with ether to produce brown powder (1.3 g.). The powder was dissolved in 5% sodium bicarbonate aqueous solution (20 ml.) and then adjusted to pH 6 with acetic acid. The mixture was subjected to neutral almina column chromatography by using pH 5.0 acetate buffer as an eluent. The eluates containing object compound (230 ml.) were collected, adjusted to pH 2.8 to 3.0 with 10% hydrochloric acid, washed with ethyl acetate, and then remaining ethyl acetate was distilled off from the eluates under reduced pressure. The resulting aqueous layer was subjected to column chromatography (Amberlite XAD-4 prepared by Rohm & Haas Co.), and the column was washed with water and then eluted with 20% methanol (80 ml.), 50% methanol (80 ml.) and 70% methanol (300 ml.) in turn. The eluates containing the object compound were collected and then methanol was distilled off under reduced pressure. The remaining aqueous solution was lyophillized to give pale brown powder of 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.40 g.), mp. 151° to 180° C. (dec.).

Workup

  1. customAfter the reaction
  2. concentrationthe reaction mixture was concentrated under reduced pressure
  3. filtrationcollected by filtration
  4. washwashed with ether
  5. customto produce brown powder (1.3 g.)
  6. additionThe eluates containing object compound (230 ml.)
  7. customwere collected
  8. washwashed with ethyl acetate
  9. distillationremaining ethyl acetate was distilled off from the eluates under reduced pressure
  10. customThe resulting aqueous layer was subjected to column chromatography (Amberlite XAD-4 prepared by Rohm & Haas Co.)
  11. washthe column was washed with water
  12. washeluted with 20% methanol (80 ml.), 50% methanol (80 ml.) and 70% methanol (300 ml.) in turn
  13. additionThe eluates containing the object compound
  14. customwere collected
  15. distillationmethanol was distilled off under reduced pressure

Sources & evidence

ORD record
ord-09e519f2939e417ba99df864619d101b
Source dataset
uspto-grants-1984_04
Patent number
US04440766

Reaction notes

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