- Preparation method of cefalexin
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The invention belongs to the field of medicine synthesis, in particular to an improved method of a beta-lactam antibiotic cefalexin synthesis process. According to the method, 7-ADCA is used as a rawmaterial and is protected by carboxyl silane; after activation with alpha-aminophenylacetic acid hydrochloride and trifluoroacetic acid succinimide, condensation reaction is carried out; cefalexin isobtained through hydrolysis after-treatment, the proper pH value is controlled through hydrochloric acid after organic solvent and alkali adjustment treatment, and cefalexin crystals with extremely high purity are obtained. The method has the advantages of being easy and convenient to operate, mild in reaction condition, not prone to causing side reaction and capable of effectively removing impurities and preparing high-purity cefalexin.
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Paragraph 0048-0051
(2020/05/05)
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- PROCESS FOR THE PRODUCTION OF CEPHALOSPORINS
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The present invention relates to a composition comprising ≥85 wt% of an N-deacylated cephalosporin, a process for making the same and the use of said N-deacylated cephalosporin in the preparation of highly pure semi synthetic cephalosporins.
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Page/Page column 12
(2012/03/27)
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- MANUFACTURING METHOD AND APPARATUS OF ULTRAFINE PARTICLES HAVING UNIFORM PARTICLE SIZE DISTRIBUTION
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The present invention relates to a novel technology for forming fine particles with a size of 0.02?3 microns from a solid that can be dissolved in a liquid solvent and is not decomposed by heat. The particle preparation technology according to the present invention may be applicable to the fields of food, cosmetics, biopolymer, polymer compositions, and pharmaceuticals.
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- Amino ester hydrolase from Xanthomonas campestris pv. campestris, ATCC 33913 for enzymatic synthesis of ampicillin
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α-Amino ester hydrolases (AEH) are a small class of proteins, which are highly specific for hydrolysis or synthesis of α-amino containing amides and esters including β-lactam antibiotics such as ampicillin, amoxicillin, and cephalexin. A BLAST search revealed the sequence of a putative glutaryl 7-aminocephalosporanic acid (GL-7-ACA) acylase 93% identical to a known AEH from Xanthomonas citri. The gene, termed gaa, was cloned from the genomic DNA of Xanthomonas campestris pv. campestris sp. strain ATCC 33913 and the corresponding protein was expressed into Escherichia coli. The purified protein was able to perform both hydrolysis and synthesis of a variety of α-amino β-lactam antibiotics including (R)-ampicillin and cephalexin, with optimal ampicillin hydrolytic activity at 25 °C and pH 6.8, with kinetic parameters of kcat of 72.5 s-1 and KM of 1.1 mM. The synthesis parameters α, βo, and γ for ampicillin, determined here first for this class of proteins, are α = 0.25, βo = 42.8 M-1, and γ = 0.23, and demonstrate the excellent synthetic potential of these enzymes. An extensive study of site-directed mutations around the binding pocket of X. campestris pv. campestris AEH strongly suggests that mutation of almost any first-shell amino acid residues around the active site leads to inactive enzyme, including Y82, Y175, D207, D208, W209, Y222, and E309, in addition to those residues forming the catalytic triad, S174, H340, and D307.
- Blum, Janna K.,Bommarius, Andreas S.
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experimental part
p. 21 - 28
(2010/12/19)
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- Synthesis of cephalosporin-type antibiotics by coupling of their β-lactam nucleus and racemic amino acid side chains using a clathration-induced asymmetric transformation
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The cephalosporin-type antibiotics Cephalexin, Cephradine and Cefadroxil have been prepared by coupling of their β-lactam nucleus and racemic amino acid side chain precursors. The initially obtained mixture of cephalosporin epimers is subjected to a clathration-induced asymmetric transformation which results in the epimerization of the epi-cephalosporin into the cephalosporin with the correct diastereomeric configuration.
- Kemperman, Gerardus J.,Zhu, Jie,Klunder, Antonius J. H.,Zwanenburg, Binne
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p. 1817 - 1820
(2007/10/03)
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- Process and device for producing liquid dosage formulations of medicinal compounds on demand from tablets and capsules
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The present invention provides a process for preparing liquid pharmaceutical formulations on demand from tablets and capsules.
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- Complexes of cephalosporins and carbacephalosporins with parabens
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The invention provides complexes of the formula: STR1 wherein X is chloro, hydrogen, vinyl, or --CH3, Z is CH2 or S; n is 0-5; Y is phenyl or 1,4-cyclohexadien-1-yl; R1 and R2 are hydrogen or hydroxy, with the proviso that R1 and R2 are not both hydrogen and R3 is --COO-, --COO(C1 -C4 alkyl), --NO2 or STR2 wherein R4 is C1 -C4 alkyl.
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- Penicillin acylase in the industrial production of β-lactam antibiotics
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Immobilized penicillin acylase is a biocatalyst suitable for the kinetically controlled industrial synthesis of semi-synthetic antibiotics in aqueous environments. Amoxiciliin and ampicillin are obtained by condensing 6-aminopenicillanic acid with the amide or ester of D-( - )-4-hydroxyphenyIglycine and D-( - )phenylglycine, respectively. Similarly, the cephalosporin antibiotics cefadroxil and cephalexin can be obtained from 7-aminodesacetoxycephalosporanic acid.
- Brugging, Alle,Roos, Eric C.,De Vroom, Erik
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p. 128 - 133
(2013/09/08)
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- Synthesis of potential impurities of cefalexin and cefradine
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The synthesis of some impurities of the cephalosporin antibiotics cefalexin and cefradine is described. These impurities which may be present in commercial samples are formed during the semi-synthetic preparation of these antibiotics or upon their degradation. The preparation of these compounds enables the validation of selective quantitative analytical methods, such as column liquid chromatography and thin layer chromatography.
- Hendrix,Roets,Bervoets,Thomas,Pijcke,Busson,Janssen,Hoogmartens
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p. 215 - 219
(2007/10/02)
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- Prodrug derivatives of carboxylic acid drugs
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Novel ester derivatives of carboxylic acid medicaments of formula (I), wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integrer from 1 to 3, and R1 and R2 are the same or different and are selected from a group consisting of an alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may be unsubstituted or substituted, or R1 and R2 together with the N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which heterocyclic group may be substituted. These compounds are highly biolabile prodrug forms of the corresponding carboxylic acid compounds and are highly susceptible to undergoing enzymatic hydrolysis in vivo whereas they are highly stable in aqueous solution. The novel derivatives are less irritating to mucosa than the parent carboxylic acids and may provide an improved bio-availability of the drugs.
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- Novel drug delivery system
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A unique pharmaceutical delivery system comprising a physiologically acceptable nonaqueous liquid such as an edible oil and a thickening agent such as colloidal silicon dioxide which together form a semi-solid having the consistency of a pudding is provided. This novel system masks unacceptable taste, does not adversely affect the stability of the drug, and accommodates large doses. Its primary advantage is its ease of administra-tion to very young or debilitated patients.
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- CONVERSION OF PENICILLIN G INTO CEPHALEXIN EMPLOYING A SECOND-ORDER ASYMMETRIC TRANSFORMATION
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2'S- and 2'R- and S- cephalexin, (5b) and (5c) respectively, both available in six stages from penicillin G, have each been converted to the more useful 2'R-isomer (5a) by a base catalysed epimerization and selective crystallization process involving the N-nitrosoimidazolidinyl derivatives (7).
- Cooper, John,Humber, David C.,Long, Alan G.
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p. 1469 - 1478
(2007/10/02)
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- Synthesis of functionalized penicillins and cephalosporins by photo-initiated bromination. A novel route to ampicillin and cephalexin from penicillin G
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Potoinitiated bromination of the 1S-oxide ester 9, available in two stages from penicillin G6, gave the diastereometic bromides 10a and 10b. Both isomers have been utilized in further transformations to give the established antibiotics ampicillin 7 and cephalexin 8.
- Cooper,Humber,Laundon,et al.
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p. 4153 - 4157
(2007/10/02)
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- Process for preparing derivatives of 7-amino-desacetoxy cephalosporanic acid
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Process for preparing cephalexine monohydrate and cephadroxyl monohydrate, according to which a reaction is carried out of a mixed anhydride prepared from a Dane salt of phenylglycine or p-hydroxyphenyl-glycine with a chloroformiate, with an aqueous solution of 7-ADCA in a solvent selected from the group comprising dimethyl sulphoxide, dimethylacetamide, formamide, dimethylformamide and dioxane.
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- Substrate Specificity of α-Amino Acid Ester Hydrolase from Xanthomonas citri
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Enzymological properties of the purified α-amino acid ester hydrolase from Xanthomonas citri IFO 3835 were studied.The enzyme catalyzed both hydrolysis of α-amino acid esters (e.g.D-α-phenylglycine methyl ester (D-PG-OMe)) and transfer of the acyl group from the amino acid esters to amine nucleophiles (e.g. 7-aminocephalosporanic acid, 7-amino-3-deacetoxycephalosporanic acid (7-ADCA) and 6-aminopenicillanic acid).The substrate specificity of the enzyme in hydrolysis was parallel with that in transfer.The enzyme required a free amino group on the α-carbon of the donor ester, but did not exhibit absolute stereospecificity. α-Amino acid derivatives having an acid-amide bond were hydrolyzed at much lower rates than the corresponding ester derivatives.The optimum pH for both hydrolysis and transfer was 6.4, and the optimum temperature, 35 deg C.The enzyme was inactivated completely within 15 min at pH 6.0 and 50 deg C.FeSO4, CuSO4 and HgCl2 inhibited the enzyme.At pH 6.4 and 30 deg C, the Michaelis constants were estimated to be 8,26 mM for D-PG-OMe and 2.99 mM for cephalexin.The apparent Michaelis constant for 7-ADCA was estimated to be 5.08 mM.With D-PG-OMe as an acyl donor, the molecular activity (k0) for hydrolysis was calculated to be 1.11E4*sec-1.
- Kato, Koichi,Kawahara, Kenji,Takahashi, Takeshi,Kakinuma, Atsushi
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p. 1075 - 1082
(2007/10/02)
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- Kinetics of Acyl Transfer by α-Amino Acid Ester Hydrolase from Xanthomonas citri
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Kinetics of the acyl transfer catalyzed by Xanthomonas α-amino acid ester hydrolase was studied.The enzyme hydrolyzed D-α-phenylglycine methyl ester (D-PG-OMe) to give equimolar amounts of D-α-phenylglycine and methanol.With D-PG-OMe as an acyl donor and 7-amino-3-decetoxycephalosporanic acid (7-ADCA) as an acyl acceptor, the enzyme transferred the acyl group from D-PG-OMe to 7-ADCA in competition with water.The addition of amino nucleophiles (7-ADCA and 7-aminopenicillanic acid) decreased the molecular activity (k0) of the enzyme-catalyzed hydrolysis of D-PG-OMe, whereas it did not alter the Michaelis constant (KM), and plots of 1/k0 against the initial concentration of a nucleophile (n0) gave a straight line.These results support the assumptions that the overall process for hydrolysis and acyl transfer proceeds through a common acyl-enzyme intermediate, that the acylation step of the enzyme is rate-limiting, and that the transfer competes with the hydrolysis of the acyl donor.
- Kato, Koichi
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p. 1083 - 1088
(2007/10/02)
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- Selective conversion of benzyl alcohol carboxylates to the free acid form
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A process for preparing free carboxylic acids which comprises treating an optionally substituted benzyl ester with a Lewis acid, preferably in the presence of a cation acceptor, followed by hydrolysis, if required.
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- De-esterification process for cephalosporins
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p-Nitrobenzyl esters of cephalosporins are reductively cleaved with zinc and α-hydroxycarboxylic acids, e.g., the p-nitrobenzyl ester of the cephalosporin antibiotic, cephalexin, is reacted in an inert solvent with zinc and mandelic acid to provide the antibiotic, cephalexin, as the free acid in yields greater than 85 percent.
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- β-1,3-Glucan derivatives
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β-1,3-Glucan derivatives, which are produced by reacting a water-insoluble β-1,3-glucan with a cyanogen halide, are a useful water-insoluble carrier of high reactivity for the production of water-insoluble enzymes and of carrier-ligand products suitable for affinity chromatography.
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- Pharmaceutical formulations
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Microcapsules which have an average diameter of from 100μ to 300μ and which comprise 94% to 99.9% of a medicament coated by 0.1% to 6% of a coating agent may be formed into a powder with 0% to 95% excipients or a tablet or capsule with a carrier.
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- Method of preparing a sparingly soluble complex of cephalexin
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Method of recovering high purity cephalexin in high yields from a solution containing cephalexin comprising the steps of reacting said solution with a non-substituted or substituted naphthalene to form a complex with cephalexin, isolating said complex, and decomposing said complex to recover cephalexin or a salt thereof.
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- Process for preparing cephalosporins
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An improved process for preparing antibacterially active 7-α-aminoacetamido cephalosporin-4-carboxylic acids in which a 7-aminocephalosporin-4-carboxylic acid ester is reacted with an activated form of an α-aminoacetic acid, the amino group of which is protected by a β-dicarbonyl group, this amino group being removed after the acylation in the presence of a sufficient amount of a hydrazine derivative to prevent re-reaction of the β-dicarbonyl protecting agent with the cephalosporin.
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