Abstract:-Development of an industrial process for producing 7432-S, a new oral cephem antibiotic, is outlined. The required components, 2-(2-benzyloxycarbonylamino-4-thiazolyl )-4-(3-methylbut-2-enyloxycarbonyl )but-2-enoic acid (2b) and diphenylmethyl 7-amino-3-cephem-4-carboxylate (3b) (or its precursor 3'), were prepared starting from methyl 2-(2-amino-4-thiazolyl)acetate T12) and penicillin G, respectively. Condensation of the two components followed by deprotection (after reduction or elimination) and epimerizati… Show more
“…Cefaclor and ceftibuten are in a class of medications called cephalosporin antibiotics. Earlier Shionogi Research Laboratories described a synthesis on industrial scale for producing ceftibuten . In an effort to develop commercial routes to these valuable compounds, researchers at the Schering Plough Research Institute utilized an ozonolysis reaction to provide a key intermediate used to produce ceftibuten and cefaclor …”
Section: Industrial-scale Ozonolysismentioning
confidence: 99%
“…A substantial number of reducing reagents have been employed including zinc−acetic acid, sulfite ion, bisulfite ion, iodide, dimethyl sulfide, thiourea, and lithium aluminum hydride or sodium borohydride to afford alcohols. −, The reductions themselves are generally exothermic and dose-controlled, requiring efficient cooling to dissipate the heat of reaction. The use of dimethyl sulfide offers several advantages including the ability to safely reduce peroxides to carbonyl products, and the excess sulfide can be removed by evaporation, provided that an efficient scrubbing system is in place. , Dimethyl sulfide is also a milder reducing reagent causing less of an exothermic event . Trimethyl phosphite also has been used as an efficient reducing agent for quenching ozonolysis reactions and offers the advantage of less odor than dimethyl sulfide.…”
“…Cefaclor and ceftibuten are in a class of medications called cephalosporin antibiotics. Earlier Shionogi Research Laboratories described a synthesis on industrial scale for producing ceftibuten . In an effort to develop commercial routes to these valuable compounds, researchers at the Schering Plough Research Institute utilized an ozonolysis reaction to provide a key intermediate used to produce ceftibuten and cefaclor …”
Section: Industrial-scale Ozonolysismentioning
confidence: 99%
“…A substantial number of reducing reagents have been employed including zinc−acetic acid, sulfite ion, bisulfite ion, iodide, dimethyl sulfide, thiourea, and lithium aluminum hydride or sodium borohydride to afford alcohols. −, The reductions themselves are generally exothermic and dose-controlled, requiring efficient cooling to dissipate the heat of reaction. The use of dimethyl sulfide offers several advantages including the ability to safely reduce peroxides to carbonyl products, and the excess sulfide can be removed by evaporation, provided that an efficient scrubbing system is in place. , Dimethyl sulfide is also a milder reducing reagent causing less of an exothermic event . Trimethyl phosphite also has been used as an efficient reducing agent for quenching ozonolysis reactions and offers the advantage of less odor than dimethyl sulfide.…”
“…Since Schönbein first studied ozonolysis in 1855, this reaction has been applied to many types of industrial production, for example, for the preparation of antibiotics such as ceftibuten and cefaclor. , Ozonolysis is a useful reaction for obtaining carbonyl compounds directly from olefins, and ozone is a very “green” oxidant because it only produces oxygen as a coproduct after the reaction. However, ozonolysis is known to be a very dangerous reaction which may cause explosions.…”
Safety evaluation for ozonolysis of β-pinene was conducted using DSC, ARC, and RC1e. ARC measurement showed that the concentration of the ozonized mixture affects its thermal stability. The sample at a high concentration of 1.83 mol/L was very unstable even at room temperature and decomposed rapidly. ADT24 of the diluted sample of 0.73 mol/L was 28.2 °C. Although reductive decomposition of the ozonized mixture at extremely low temperature is very dangerous because of accumulation of the heat of reaction, its process temperature was validated to not exceed the ADT24. As a result, pilot manufacturing on a 300-L reactor scale could be achieved.
“…The orally active third generation cephalosporin antibiotic, Ceftibuten ( 1 ) has been manufactured using a long process based on producing the key intermediate diphenylmethyl 7 ( R )-amino-3-cephem-4-carboxylate ( 2 ) from a penicillin starting material via diphenylmethyl 3-hydroxy-7( R )-phenylacetamidoceph-3-em-4-carboxylate ( 3 ) (Scheme ). 1 Shionogi synthesis of Ceftibuten…”
Analysis of several options for the synthesis of Ceftibuten from
cephalosporin C-derived starting materials led to the conclusion
that the most practical option, leading to the lowest costs, would
be realized by trying to resurrect the previously discarded
electrochemical reduction process. This contribution describes
the preparation of 3-exomethylene-7(R)-glutaroylaminocepham-4-carboxylic acid 1(S)-oxide (10,1(S)-oxide) in almost quantitative yield by the electrochemical reduction of 3-acetoxymethyl-7(R)-glutaroylaminoceph-3-em-4-carboxylic acid 1(S)-oxide
(9,1(S)-oxide) using a high-surface area tin mesh cathode. The
new product has been shown (see Bernasconi, E.; Lee, J.; Sogli,
L.; Walker, D. Org. Process Res. Dev.
2002, 6, 169) to be a
superior new intermediate for the preparation of orally active
cephalosporins such as Ceftibuten.
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