“…For example, the maximal conversion and yield were 61% and 53%, respectively, with the substrate molar ratio of 1.0, while being 90% and 83%, respectively, with the substrate molar ratio of 2.0. Nonetheless, using lower substrate molar ratios seemed to be favorable for synthesis, resulting in the higher S/H ratio, which is in good agreement with the previous results (Ferreira et al 2007; Ribeiro et al 2005). Fig.…”
Section: Resultssupporting
confidence: 92%
“…Besides, the substrate conversions were more than 95% after 7 h. It suggests that the two esters tested are good acyl donors for the enzymatic N -acylation of 7-ACA. In addition to the conversions and yields, the S/H ratios (the molar ratios of N -bromoacetyl-7-ACA to bromoacetic acid, the selectivity toward synthesis), a parameter that is often used to assess the economics of the enzymatic process (Bruggink et al 1998; Wegman et al 2002; Ribeiro et al 2005; Cao et al 2000), were also tracked (Fig. 3).…”
BackgroundEnzymatic approaches have become promising alternatives to chemical methods for the production of semi-synthetic β-lactam antibiotics. In this work, enzymatic synthesis of N-bromoacetyl-7-aminocephalosporanic acid (N-bromoacetyl-7-ACA), the key intermediate for the production of cefathiamidine, was reported for the first time.ResultsOf the immobilized penicillin acylases (PAs) tested, PGA-750 was the best biocatalyst. Optimization of the biocatalytic process was conducted. The optimal acyl donor, molar ratio of acyl donor to 7-ACA, pH, temperature, 7-ACA concentration, and enzyme dosage were methyl bromoacetate, 3, 7.5, 20 °C, 50 mmol/L and 4 U/mL, respectively. Under the optimal conditions, enzymatic N-acylation of 7-ACA with methyl bromoacetate afforded the desired product with the yield of 85% in 2 h, where the synthesis/hydrolysis (S/H) ratio was approximately 1.5. The immobilized enzyme PGA-750 exhibited good operational stability, and the relative yields of approximately 90% and 63% were achieved, respectively, when it was reused in 7th and 11th batch.ConclusionsAn enzymatic approach to N-bromoacetyl-7-ACA, the key intermediate for the industrial production of cefathiamidine, has been developed successfully in a fully aqueous medium. The present work may open up a novel opportunity for the production of cefathiamidine through a simple and green process.Graphical abstractEnzymatic synthesis of N-bromoacetyl-7-ACA, the key intermediate for the production of cefathiamidine, was reported for the first time.
Electronic supplementary materialThe online version of this article (doi:10.1186/s40643-016-0127-3) contains supplementary material, which is available to authorized users.
“…For example, the maximal conversion and yield were 61% and 53%, respectively, with the substrate molar ratio of 1.0, while being 90% and 83%, respectively, with the substrate molar ratio of 2.0. Nonetheless, using lower substrate molar ratios seemed to be favorable for synthesis, resulting in the higher S/H ratio, which is in good agreement with the previous results (Ferreira et al 2007; Ribeiro et al 2005). Fig.…”
Section: Resultssupporting
confidence: 92%
“…Besides, the substrate conversions were more than 95% after 7 h. It suggests that the two esters tested are good acyl donors for the enzymatic N -acylation of 7-ACA. In addition to the conversions and yields, the S/H ratios (the molar ratios of N -bromoacetyl-7-ACA to bromoacetic acid, the selectivity toward synthesis), a parameter that is often used to assess the economics of the enzymatic process (Bruggink et al 1998; Wegman et al 2002; Ribeiro et al 2005; Cao et al 2000), were also tracked (Fig. 3).…”
BackgroundEnzymatic approaches have become promising alternatives to chemical methods for the production of semi-synthetic β-lactam antibiotics. In this work, enzymatic synthesis of N-bromoacetyl-7-aminocephalosporanic acid (N-bromoacetyl-7-ACA), the key intermediate for the production of cefathiamidine, was reported for the first time.ResultsOf the immobilized penicillin acylases (PAs) tested, PGA-750 was the best biocatalyst. Optimization of the biocatalytic process was conducted. The optimal acyl donor, molar ratio of acyl donor to 7-ACA, pH, temperature, 7-ACA concentration, and enzyme dosage were methyl bromoacetate, 3, 7.5, 20 °C, 50 mmol/L and 4 U/mL, respectively. Under the optimal conditions, enzymatic N-acylation of 7-ACA with methyl bromoacetate afforded the desired product with the yield of 85% in 2 h, where the synthesis/hydrolysis (S/H) ratio was approximately 1.5. The immobilized enzyme PGA-750 exhibited good operational stability, and the relative yields of approximately 90% and 63% were achieved, respectively, when it was reused in 7th and 11th batch.ConclusionsAn enzymatic approach to N-bromoacetyl-7-ACA, the key intermediate for the industrial production of cefathiamidine, has been developed successfully in a fully aqueous medium. The present work may open up a novel opportunity for the production of cefathiamidine through a simple and green process.Graphical abstractEnzymatic synthesis of N-bromoacetyl-7-ACA, the key intermediate for the production of cefathiamidine, was reported for the first time.
Electronic supplementary materialThe online version of this article (doi:10.1186/s40643-016-0127-3) contains supplementary material, which is available to authorized users.
“…The eluent flow rate was 1 mL min –1 and the UV detector wavelength was 254 nm. The method is common for the determination of antibiotic concentration. , …”
The hydrophobic adsorption is an alternative to traditional organic solvent extraction for the recovery and purification of Penicillin G (PenG). However, there is a lack of information concerning the effect of process variables and technical feasibility while balancing product degradation. After assessing the integrity of PenG under different conditions, Amberlite XAD-4 was selected from among three different adsorbents. During the batch process using only 0.05 g XAD-4 /mL medium , the adsorption yield increased from 36% at pH 6 to 44% at pH 4. More than 90% of the antibiotic was captured from the fermentation broth using 0.083 g XAD-4 /mL medium in a 45 min batch performed at pH 4 and 4 °C. Moreover, there was no PenG degradation. The desorption conditions were evaluated, and 95% of the antibiotic could be recovered in only one batch using water−ethanol, which is an unexplored PenG desorption process. The results showed selective adsorption, indicating that the process can also be useful for purification purposes. Hydrophobic adsorption with ethanol desorption is efficient, scalable, and green and could be used in place of traditional methods or in extractive fermentation.
“…In the past several decades, the enzymatic synthesis of these antibiotics has been intensively studied as an option with lower environmental impact than traditional chemical synthesis [1,2]. Among the many strategies proposed for increasing the process effectiveness of aminopenicillin and aminocephalosporin enzymatic synthesis, use of the reagents at high concentrations is the most prevailing practice at last time [2][3][4][5][6][7][8][9]. Since enzymes used for antibiotic synthesis converts only dissolved reagents, their solubility has a great influence on the reaction rate and level of enzymatic transformation.…”
The article deals with experimental determination of ionization constants and solubility for the compounds (target products, initial β-lactams, acylating agents and by-products) involved in enzymatic synthesis of some therapeutically used aminopenicillins and aminocephalosporins, namely ampicillin, amoxicillin, cephalexin, cephadroxil, cephaloglycin, cefaclor, cefprozil, cefatrizine. Methodology of investigations and the evaluation of experimental data for the determination of ionization constants and solubility of the different type electrolytes are presented. Applications of the methods based on acid-base potentiometric titration and on determination of solubility-pH dependence of assayed substances are discussed. The original data on ionization constants and solubility of amoxicillin, cefprozil, cefatrizine, cephadroxil and initial β-lactams for production of cefaclor, cefprozil and cefatrizine, as well as solubility of by-product D-(-)-p-hydroxyphenylglycine are presented. Experimentally determined parameters and constants available in the literature for all abovementioned aminopenicillins and aminocephalosporins are collected. These data might be used for choice of the conditions of both processes: the enzymatic synthesis and the isolation of the product from reaction mixture.
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