- A novel and efficient synthesis of (6R,7R)-7-amino-3-hydroxymethyl cephalosporanic acid: A versatile precursor of cefuroxime acid
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A novel process has been developed for the synthesis of (6R,7R)-7-amino-3-hydroxymethyl cephalosporanic acid (7-AHCA) using a combination of reagents [triethyl amine/tetrabutyl ammonium hydroxide (TBAH)] at ambient temperature, with improved yield. This intermediate was exploited for the synthesis of cefuroxime acid and its sodium salt.
- Singh, Santosh Kumar,Tiwari,Jain, Praveen
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- Substituent Effects on Reactivity and Spectral Parameters of Cephalosporins
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The chemical reactivity of a series of cephalosporins is examined as a function of the substituents at positions 3 and 7.In most cases, the nature of the C7 side chain has a minor influence on the β-lactam reactivity.But in the case of the amino-containing C7 substituents, when intramolecular nucleophilic attack may occur, the reactivity may be greatly increased.The spectroscopic and structural characteristics of the β-lactam linkage do not correlate with the chemical reactivity of studied compounds.The hydrolysis rates are linked neither with the IR frequency or 13C NMR chemical shift of the carbonyl β-lactam nor with the geometry of the β-lactam ring.However, a relationship is confirmed between the β-lactam ring opening rate and the polarity of the C3-C4 double bond, reflected in the different 13C NMR chemical shifts of those atoms.The results are an experimental verification of the theoretical calculations of Boyd et al. on cephalosporin model compounds, which foresee that a C3 substituent could favor the opening of the β-lactam cycle by stabilizing a transition state involved in alkaline hydrolysis.
- Coene, Bernard,Schanck, Andre,Dereppe, Jean-Marie,Meerssche, Maurice Van
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- An improved process for the preparation of diphenylmethyl7β- Phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate
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An efficient and improved process for the preparation of diphenylmethyl 7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate was developed. With the commercially available 7-aminocephalosporanic acid (7-ACA) as starting material, up to 73.5% overall isolated yield of the titled compound was synthesized in two steps via direct phenylacetylation with phenylacetyl chloride, followed by basic hydrolysis and esterification with diphenyldiazomethane. The newly developed process obviated the use of protecting groups, reduced the environmental footprint, and could be easily controlled and conveniently scaled up for this pivotal intermediate in cephalosporin chemistry.
- Keping, Yu,Nan, Sun,Shanzong, Fang,Weimin, Mo,Baoxiang, Hu,Zhenlu, Shen,Xinquan, Hu
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- FLUOROGENIC BETA-LACTAMASE SUBSTRATE AND ASSOCIATED DETECTION METHOD
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This invention relates to probes for the detection of β-lactamase-type enzymatic activity. In particular, the invention relates to novel fluorogenic substrates for detecting the presence of a catalytically active β-lactamase and a detection method using such substrates.
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Page/Page column 40; 42-43
(2021/06/04)
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- Synthesis method of dimer impurity D produced by cefazolin sodium production
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The invention discloses a dimer impurity D produced by cefazolin sodium, and a synthesis method of the dimer impurity D produced by cefazolin sodium production. The method comprises: carrying out a reaction on an initial raw material A and sodium hydroxide in a solvent ethanol and water, adjusting the pH value with diluted hydrochloric acid, extracting, and distilling to obtain an intermediate B;adding the intermediate B into dichloromethane, adding a Dess-Martin Periodinane reagent, quenching the reaction solution, and filtering to obtain the mother liquor of a compound C so as to be spare;and sequentially adding a compound A and sodium triacetoxyborohydride into dichloromethane, adding the mother liquor of the product C, quenching after completing the reaction, extracting, and purifying by using a chromatographic silica gel column to obtain a dimer impurity D. According to the present invention, the synthesized dimer impurity D can provide impurity control for the reaction.
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Paragraph 0015; 0018
(2020/01/03)
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- A hydrochloric acid Cefcapene pivoxil preparation method
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The invention belongs to the technical field of antibiotic synthesis, and relates to a preparation method for cefcapene pivoxil hydrochloride. The preparation method comprises the following steps: (1) reacting 7-ACA with sodium hydroxide in a solution with quaternary ammonium salt under the temperature of (-5 DEG C)-5 DEG C to generate 7-DACA; (2) adding (cefcapene pivoxil side chain acid, compound 5) into the solution containing 7-DACA, diisopropylamine and phenyltriethylammonium chloride under the temperature of 0-10 DEG C to react with a methylsufonyl chloride reaction solution under the temperature of (-15 DEG C)-0 DEG C to obtain a compound (4); reacting the compound 4 and chlorosulfonyl isocyanate to obtain a compound (3); further reacting the compound (3) with iodomethyl pivalate to obtain a compound (2); removing the protection base of the compound (2) in a hydrochloric acid methanol solution to obtain the cefcapene pivoxil hydrochloride (compound 1).
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Paragraph 0041-0042
(2018/06/19)
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- Nitrocefin synthesis method
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The invention relates to a nitrocefin synthesis method and belongs to the field of drug synthesis. The invention provides a novel process for preparing nitrocefin from a compound I as a raw material. The compound I is prepared from 7-ACA. The nitrocefin synthesis method can realize synthesis of nitrocefin from 7-ACA as an initial raw material through seven processes. The 7-ACA as an initial raw material is a key intermediate of a cephalosporin, has already been industrialized and has a low market price. The nitrocefin synthesis method has the advantages of simple processes, easy reaction treatment, easy product purification, high yield, easy industrialization and low production cost.
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Paragraph 0045; 0054; 0055; 0056; 0057
(2017/04/08)
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- Synthesis method of antibacterial drug cefoxitin
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The invention discloses a synthesis method of an antibacterial drug cefoxitin. The synthesis method comprises the following steps: taking 7-amino cephalosporanic acid as a raw material; adding a curing enzyme into an alkaline solution to hydrolyze; after hydrolyzing, filtering the curing enzyme; after adding ethyl acetate, starting to drop 2-thiophene acetylation reagent to react; after introducing thiophene acetyl, dropping a benzathine diacetate solution and separating out crystals to obtain a compound I; taking the compound I to react with an aminomethoxyl acylation reagent to react and introducing aminoformylmethoxyl at a site 3 of the compound I, so as to obtain a compound II; taking the compound II to react with tertiary-butyl hypochlorite and sodium methoxide to react to introduce methoxyl at a site 7 of the compound II to obtain the cefoxitin. The synthesis method has the advantages of low cost of raw materials, high yield, moderate reaction conditions, good powder crystallinity and small granularity of synthesized powder. The synthesis method needs simple equipment, has a simple reaction process, is easy to implement and is suitable for large-scale production.
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Paragraph 0043
(2017/01/26)
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- A practical synthesis of cefcapene pivoxil
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Cefcapene pivoxil monohydrochloride monohydrate, a broad spectrum third-generation cephalosporin for oral administration, was prepared by reacting three centers of 7-amino-3-(hydroxymethyl)cephalosporinic acid (7-HACA), derived from 7-aminocephalosporanic acid. The coupling of 7-HACA and (Z)-2-[2-(Boc-amino)thiazol-4-yl]pent-2-enoic acid, followed by carbamylation with chlorosulfonyl isocyanate, and precipitation with diisopropylamine gave the key intermediate, in which thiazole side chain and carbamoyl group had been introduced into the 7-amino and 3-hydroxymethyl groups of 7-HACA, respectively, in a continuous procedure. Afterwards, the intermediate was esterified with pivaloyloxymethyl iodide to complete the modification of the C4 carboxy group affording Boc-cefcapene pivoxil, from which the desired product was finally obtained by an economical Boc removal and successive formation of the hydrochloride in 36% overall yield on a decagram scale. This synthesis promises an easy entry to cefcapene pivoxil monohydrochloride monohydrate with convenient manipulation, simple isolation, and good yields; it is of potential value for production on an industrial scale. Georg Thieme Verlag Stuttgart · New York.
- Jiang, Jian-An,Zhai, Jiao-Jiao,Yu, Xin-Hong,Teng, Xin,Ji, Ya-Fei
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experimental part
p. 207 - 214
(2012/04/17)
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- Syntheses and studies of quinolone-cephalosporins as potential anti-tuberculosis agents
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The syntheses and anti-tuberculosis activity of quinolone-cephalosporin conjugates (1 and 2) are described. Both showed broad-spectrum antibacterial activity and significant anti-TB activity. The carbamate-linked quinolone-cephem 2 showed better antimycobacterial activity, including anti-TB activity, than the direct amine-linked quinolone-cephem 1, while quinolone-cephem 1 was slightly more effective against some Gram-negative bacterial strains.
- Zhao, Gaiying,Miller, Marvin J.,Franzblau, Scott,Wan, Baojie,Moellmann, Ute
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p. 5534 - 5537
(2007/10/03)
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- An alternative procedure for preparation of cefdinir
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Cefdinir, a broad spectrum third-generation cephalosporin for oral administration, was prepared by the following synthetic pathway: synthesis of diphenylmethyl 7β-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride from 7-aminocephalosporanic acid (7-ACA), preparation of sodium 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(tritylhydroxyimino) acetate from ethyl acetoacetate, coupling of both intermediaries to obtain diphenylmethyl 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-tritylhydroxyimino-3- vinyl-3-cephem-4-carboxylate and final cleavage of trityl and diphenylmethyl protective groups. This procedure allows to obtain better yields of cefdinir and to avoid the use of diketene during the synthesis of this antibiotic by the previously reported method.
- Gonzalez, Maritza,Rodriguez, Zalua,Tolon, Blanca,Rodriguez, Juan C.,Velez, Herman,Valdes, Barbara,Lopez, Miguel A.,Fini, Adamo
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p. 409 - 418
(2007/10/03)
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- Improvement of the synthesis of diphenylmethyl 7β-(o-hydroxy)benzylideneamino-3-hydroxymethyl-3-cephem-4-carboxylate
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The title product (I) is synthesized currently from 7-aminocephalosporanic acid, and diphenyldiazomethane (DDM) is used as a protective reagent of the acid function for further reactions. When DDM was prepared from benzophenone hydrazone by reaction with chloramine T, it was resulted impure by p-toluenesulfonamide, formed as side product, which cannot be removed during the final purification step carried out according to the literature procedure. Two simple methods are proposed here to obtain I with the suitable degree of purity necessary for a drug.
- Lopez, Miguel,Rodriguez, Zalua,Valdes, Barbara,Velez, Herman,Agueero, Juan,Fini, Adamo,Gonzalez, Maritza
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p. 629 - 631
(2007/10/03)
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- The synthesis and evaluation of 3-substituted-7-(alkylidene)cephalosporin sulfones as β-lactamase inhibitors
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A series of 3-substituted-7-(alkylidene)cephaloporin sulfones were prepared and evaluated as inhibitors of representative class A and class C serine β-lactamase. Appropriate substituents resulted in a 1000-fold improvement in the inhibition of the class A enzymes and a simultaneous 20-fold improvement in the inhibition of class C. These new compounds have achieved the goal of creating broad scale inhibitors in the cephalosporin series. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Buynak, John D.,Doppalapudi, Venkata Ramana,Adam, Greg
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p. 853 - 857
(2007/10/03)
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- Cephalosporin C acylase in the autolysis of filamentous fungi
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Cephalosporin C acylase activity was studied using fluorescamine determination of free - NH2 groups produced in the deacylation of cephalosporin C by the enzyme. Fourteen fungi from different genera were studied and low extracellular cephalosporin C acylase activity was found in the genera Aspergillus, Fusarium and Penicillium. Forty one fungi of these genera were checked but not all presented acylase activity. The enzyme was generally found to be an extracellular enzyme and during the process of autolysis its activity increased with incubation time and with increasing pH of the medium. In no case was β-lactamase activity detected. Penicillium rugulosum and Penicillium griseofulvum were identified as good cephalosporin C acylase producers. Deacetyl esterase activity was also detected in these fungi.
- Reyes,Martinez,Alfonso,Copa-Patino,Soliveri
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p. 128 - 131
(2007/10/02)
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