- Microwave-assisted solid-phase synthesis of cephalosporin derivatives with antibacterial activity
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The reaction of heterocyclic acids with 7-amino-cephalosporanic acid adsorbed on basic alumina under microwave irradiation afforded the N-acylated cephalosporin analogues in satisfactory yield. All compounds were tested for their antibacterial activity; some of them showed significant antibacterial properties. Cefotaxime and cephalothin were used as reference drugs.
- Kidwai, Mazaahir,Misra, Preeti,Bhushan, Kumar R.,Saxena, Rajendra K.,Singh, Meena
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- Cefazolin acetoxy analogue preparation method
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The invention discloses a cefazolin acetoxy analogue preparation method, wherein the cefazolin acetoxy analogue finished product is prepared by using a 7-ACA solution and a tetrazoleacetic acid mixedanhydride solution as reaction raw materials and carrying out matched control on the raw material ratio, the reaction temperature and the pH value of the system. According to the present invention, the process method for preparing the cefazolin acetoxy analogue by using the chemical synthesis method is provided, such that the cefazolin acetoxy analogue standard substance can be stably and efficiently obtained so as to improve the production quality of cefazolin sodium.
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Paragraph 0028-0029; 0031-0032; 0033-0034; 0035-0042
(2019/02/13)
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- Influence of substrate structure on PGA-catalyzed acylations. Evaluation of different approaches for the enzymatic synthesis of cefonicid
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The influence of the substrate structure on the catalytic properties of penicillin G acylase (PGA) from Escherichia coli in kinetically controlled acylations has been studied. In particular, the affinity of different β-lactam nuclei towards the active site has been evaluated considering the ratio between the rate of synthesis (vs) and the rate of hydrolysis of the acylating ester (vhl). 7-Aminocephalosporanic acid (7-ACA) and 7-amino-3-(1-sulfomethyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (7-SACA) showed a good affinity for the active centre of PGA. The enzymatic acylation of these nuclei with R-methyl mandelate has been studied in order to evaluate different approaches for the enzymatic synthesis of cefonicid. The best results have been obtained in the acylation of 7-SACA. Cefonicid (8) was recovered from the reaction mixture as the disodium salt in 65% yield and about 95% of purity. Furthermore, through acylation of 7-ACA, a "one-pot" chemo-enzymatic synthesis was carried out starting from cephalosporin C using three enzymes in sequence: D-amino acid oxidase (DAO), glutaryl acylase (GA) and PGA. Cefonicid disodium salt was obtained in three steps, avoiding any intermediate purification, in 35% overall yield and about 94% purity. This approach presents several advantages compared with the classical chemical processes.
- Terreni, Marco,Tchamkam, Joseph Gapesie,Sarnataro, Umberto,Rocchietti, Silvia,Fernandez-Lafuente, Roberto,Guisan, Jose M.
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p. 121 - 128
(2007/10/03)
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- One-pot chemoenzymatic synthesis of 3'-functionalized cephalosphorines (cefazolin) by three consecutive biotransformations in fully aqueous medium
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We illustrate a new chemoenzymatic synthesis of cefazolin from cephalosporin C, involving three consecutive biotransformations in full aqueous medium. This one-pot three-step synthesis includes the D-amino acid oxidase catalyzed oxidative deamination of the cephalosporin C side chain, hydrolysis of the resulting glutaryl derivative catalyzed by glutaryl acylase, and the final penicillin G acylase (PGA)-catalyzed acylation of 7- aminocephalosporanic acid (1, 7-ACA). The product, 7-[(1H-tetrazol-1- yl)acetamido]-3-(acetoxymethyl)-Δ3-cephem-4-carboxylic acid (5), was used as an intermediate for cefazolin synthesis by 3'-acetoxy group displacement with 2-mercapto-5-methyl-1,3,4-thiadiazole. Very high yields have been achieved with all the enzymatic reactions performed; high product concentrations were obtained in short reaction times. This synthetic approach presents several advantages when compared with the conventional chemical processes. The use of the toxic reagents and chlorinated solvents is avoided, while the substrate specificity and chemoselectivity of the enzymes makes reactive group protection and intermediate purification unnecessary. The enzymatic deacylation of cephalosporin C was performed by the simultaneous use of D-amino acid oxidase and glutaryl acyclase. The substrate specificity of PGA allowed the acylation of 7-ACA (1) to be performed without purification from the glutaric acid produced during the enzymatic deacylation. These results were achieved by optimization and correct assembly of the different biotransformations involved. Special attention has been applied to the kinetically controlled acylation reaction. High yields were obtained through a careful selection of the enzyme catalyst, experimental conditions, and synthetic strategy.
- Justiz,Fernandez-Lafuente,Guisan
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p. 9099 - 9106
(2007/10/03)
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- Chemoenzymatic one-pot synthesis of cefazolin from cephalosporin C in fully aqueous medium, involving three consecutive biotransformations catalyzed by D-aminoacid oxidase, glutaryl acylase and penicillin G acylase
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A new chemoenzymatic synthesis of Cefazolin through the correct assembly of three biotransformations catalyscd by D-aminoacid oxidase, glutaryl acylase and penicillin G acylase is described. This multienzymatic synthesis has been performed from the natural Cephalosporin C in fully aqueous medium without intermediate purification stages. Almost quantitative yields have been achieved in all the enzymatic reactions.
- Fernandez-Lafuente, Roberto,Guisan, Jose M.,Pregnolato, Massimo,Terreni, Marco
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p. 4693 - 4696
(2007/10/03)
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- Process for N-acylation of 7 amino cephem compounds
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A compound having the formula: EQU1 and a 7-amihocephalosporanic acid derivative having the formula: SPC1 Are reacted in a homogeneous aqueous solution of the reactants to prepare a reaction of the formula: SPC2 In the formulas, R may be H or other defined substituents such as carboxyl group; R1 is H, an alkyl of 1-4 carbons or other defined substitents; R2 is H or phenyl or when taken together with R1 form a defined cyclicradical; R3 is H or other defined substituents and M is an alkali metal cation, ammonium cation or H.
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