- Method for synthesizing azorithromycin by utilizing erythromycin thiocyanate oxime
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The invention relates to a method for synthesizing azithromycin by utilizing erythromycin thiocyanate oxime. The method comprises the following process steps: removing thiocyanate radicals through erythromycin thiocyanate oxime dissociation, performing rearrangement reaction, performing continuous back extraction, performing continuous reduction reaction and separation, and performing azithromycin crystallizing. According to the invention, the thiocyanate radicals are removed before the rearrangement reaction and then the rearrangement is performed, the reduction reaction adopts a continuous reaction process, the reaction mode is changed, and the process is high in reaction efficiency, low in production cost, small in environmental pollution, high in product yield and good in product quality.
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Paragraph 0037; 0041-0043; 0044; 0048-0051; 0055-0057
(2021/05/05)
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- Chemical synthesis method for azithromycin intermediate
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The invention relates to a chemical synthesis method for an azithromycin intermediate. According to the chemical synthesis method for the azithromycin intermediate,erythromycin 6,9-imino ether is usedas a raw material and reduced by potassium borohydride and zinc trifluoromethanesulfonate, hydrolysis is assisted through IR.A-743 or ZXC-700 resin, and 9-deoxo-9-alpha-aza-9[alpha]-homoerythromycinA is obtained with a high yield.
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Paragraph 0006-0007
(2020/02/10)
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- Novel crystal-form compound of dihydroerythromycin and preparation method thereof
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The invention relates to a novel crystal-form compound of dihydroerythromycin and a preparation method thereof, and belongs to the technical field of synthesis of heterocyclic compounds. Erythromycinimide ether is dissolved in methanol, a catalyst Pt/C is added after acid adjustment, and a hydrogenation reaction is performed; after the reaction is finished, the catalyst is filtered, and a set amount of methanol is recovered; the temperature is dropped and the alkalinity is adjusted to the pH value of 10-12, a set amount of water is added drop by drop, and the novel crystal-form compound of dihydroerythromycin is obtained by filtration and drying. The preparation method is applied in synthesis of dihydroerythromycin and has the advantages of good fluidity, easy packaging, high liquid content and the like.
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Paragraph 0026-0031
(2019/02/13)
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- Mild, calcium catalysed Beckmann rearrangements
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A mild calcium catalysed Beckmann rearrangement has been realised, which forgoes the more traditional harsh reactions conditions associated with the transformation. The catalyst system is shown to be tolerant towards a wide variety of functional groups relevant to natural product synthesis and medicinal chemistry and the synthetic utility of the reaction has also been investigated. A preliminary mechanistic investigation was performed to understand the nature of the incoming nucleophile and a possible reaction pathway is described.
- Kiely-Collins,Sechi,Brennan,McLaughlin
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supporting information
p. 654 - 657
(2018/02/06)
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- Macrolide derivative and application thereof
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The invention provides a macrolide derivative of a novel structure. Experiments show that the macrolide derivative has a good promoting effect on alimentary motility and is capable of enhancing intestine peristalsis, increasing defecation quantity and accelerating passing of intestinal content; on such basis, it is further discovered that the macrolide derivative is low in antibiotic activity and small in side effect and can be taken as a gastrointestinal motility promoting drug. Particularly, a compound III-3 screened with the optimal efficacy is subjected to further efficacy evaluation as well as acute toxicity and cardiotoxicity evaluation by domestic rabbits, beagles and marmosets. Experiments show that the compound III-3 is safe and capable of effectively promoting gastrointestinal motility, thereby being excellent in druggability.
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- Preparation method of norazithromycin
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The invention discloses a preparation method of norazithromycin and relates to the technical field of macrolide antibiotics. The preparation method comprises the following steps: reducing erythrocin A 6,9-imino ether in water at 0 DEG C to room temperature under the pH of 7.0-9.0 by using a reducing agent sodium borohydride or potassium borohydride; then in the presence of an organic solvent and water, performing continuous hydrolysis at 0 DEG C to room temperature under the pH of 2.0-3.0; then adding two-phase reaction liquids after continuous hydrolysis into an alkaline aqueous solution, adjusting the pH to be greater than or equal to 12, stirring, layering and abandoning the aqueous phase, wherein the organic solvent is dichloromethane, chloroform, 1,2-dichloromethane, ethyl acetate or butyl acetate; and after the last hydrolysis reaction in continuous hydrolysis, performing layering, directly adding the aqueous phase into the alkaline aqueous solution, adjusting the pH to be greater than or equal to 12, and performing stirring and separating out norazithromycin. The method increases the utilization ratio of the reducing agent, can control reverse reactions of borate, and reduces unnecessary separating process to obtain high quality norazithromycin.
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Paragraph 0058-0097
(2017/10/26)
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- Synthesis method of azithromycin
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The invention relates to a synthesis method of azithromycin. The synthesis method is characterized by comprising the process steps of firstly adding sodium bicarbonate and a rearrangement reaction reagent to erythromycin oxime in a reaction system employing water as a reaction solvent for rearrangement reaction, carrying out heat preservation for 2-3 hours, dropwise adding a reduction reaction regent for reduction reaction and stirring for 1-2 hours during heat preservation; adding a competitive inhibitor for removing boron through reduction hydrolysis for reduction and boron removal reaction; and finally separating out crystal, and cooling and filtering to obtain the azithromycin. Rearrangement and reduction are simultaneously carried out in the same reaction system. Compared with a sodium borohydride reduction method in the prior art, the synthesis method has the advantages that the process is simplified, use of an organic solvent and the like is omitted, the environmental pollution and the product cost are reduced, the influence of a complicated process on the quality of a product is reduced, the quality and the yield of the product are finally improved and the synthesis method is suitable for technological production.
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Paragraph 0003; 0025-0026
(2017/08/29)
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- Dihydrokainate high method for preparing ycin (by machine translation)
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The invention provides a method for the preparation of erythromycin the hydrogen is high, including, the boiling method: the erythromycin A9-oxime, water and rearrangement reagent for a BECKMANN rearrangement, reaction end, adjusting with alkali liquor pH3.0-7.0, by adding reducing agent to reducing, by acid hydrolysis, crystallization get dihydrokainate high ycin. The invention uses water as solvent the BECKMANN rearrangement and reduction reaction to boiling, is greatly shortened from the erythromycin A9-oxime or erythromycin A9- [...] cyanate to dihydrokainate high production of time, have reduced the process, at the same time reduces the three waste emissions, improved than that of the prior process yield 1-3%, further reduce the cost of production of Azithromycin. Without extracting erythromycin intermediate A6,9 imines ether, mild reaction conditions; water as a reaction solvent, there are few three wastes, green. (by machine translation)
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Paragraph 0029-0030
(2017/03/28)
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- Chemistry and biology of macrolide antiparasitic agents
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Macrolide antibacterial agents inhibit parasite proliferation by targeting the apicoplast ribosome. Motivated by the long-term goal of identifying antiparasitic macrolides that lack antibacterial activity, we have systematically analyzed the structure-activity relationships among erythromycin analogues and have also investigated the mechanism of action of selected compounds. Two lead compounds, N-benzylazithromycin (11) and N-phenylpropylazithromycin (30), were identified with significantly higher antiparasitic activity and lower antibacterial activity than erythromycin or azithromycin. Molecular modeling based on the cocrystal structure of azithromycin bound to the bacterial ribosome suggested that a substituent at the N-9 position of desmethylazithromycin could improve selectivity because of species-specific interactions with the ribosomal L22 protein. Like other macrolides, these lead compounds display a strong "delayed death phenotype"; however, their early effects on T. gondii replication are more pronounced.
- Lee, Younjoo,Choi, Jun Yong,Fu, Hong,Harvey, Colin,Ravindran, Sandeep,Roush, William R.,Boothroyd, John C.,Khosla, Chaitan
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p. 2792 - 2804
(2011/06/24)
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- A COST EFFECTIVE PROCESS FOR PREPARING 6,9-IMINO ETHER
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The present invention relates to an improved process for the preparation of 6,9-imino ether of formula (I) an intermediate used in preparation of Azithromycin. The present invention further provides a process for preparation of Azithromycin.
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Page/Page column 8
(2010/01/30)
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- Using chemical probes to investigate the sub-inhibitory effects of azithromycin
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The antibacterial drug azithromycin has clinically beneficial effects at sub-inhibitory concentrations for the treatment of conditions characterized by chronic Pseudomonas aeruginosa infection, such as cystic fibrosis. These effects are, in part, the result of inhibition of bacterial biofilm formation. Herein, the efficient synthesis of azithromycin in 4 steps from erythromycin and validation of the drug's ability to inhibit biofilm formation at sub-MIC (minimum inhibitory concentration) values are reported. Furthermore, the synthesis of immobilized and biotin-tagged azithromycin analogues is described. These chemical probes were used in pull-down assays in an effort to identify azithromycin's binding partners in vivo. Results from these assays revealed, as expected, mainly ribosomal-related protein binding partners, suggesting that this is the primary target of the drug. This was further confirmed by studies using a P. aeruginosa strain containing plasmid-encoded ermC, which expresses a protein that modifies 23S rRNA and so blocks macrolide entry to the ribosome. In this strain, no biofilm inhibition was observed. This work supports the hypothesis that the sub-inhibitory effects of azithromycin are mediated through the ribosome. Moreover, the synthesis of these chemical probes, and proof of their utility, is of value in global target identification in P. aeruginosa and other species.
- Glansdorp, Freija G.,Spandl, Richard J.,Swatton, Jane E.,Loiseleur, Olivier,Welch, Martin,Spring, David R.
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supporting information; experimental part
p. 4120 - 4124
(2009/02/07)
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- PROCESSES FOR THE PREPARATION OF AZITHROMYCIN
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The invention relates to processes for the preparation of anhydrous azithromycin. The invention also relates to a one-pot process for the preparation of azithromycin without isolation of intermediates. The invention also relates to pharmaceutical compositions that include the anhydrous azithromycin or a pharmaceutically acceptable salt thereof.
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Page/Page column 11
(2008/06/13)
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- A PROCESS FOR PREPARING 9-DEOXO-9A-AZA-9A-HOMOERYTHROMYCIN A
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The invention relates to a process for preparing 9-Deoxo-9a-aza-9a- homoerythromycin A of formula (III), which is an intermediate in the preparation of Azithromycin dihydrate.
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Page/Page column 10-11
(2008/06/13)
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- A PROCESS FOR PREPARING 6,9-IMINO ETHER
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A process for preparing 6,9-Imino ether from Erythromycin thiocyanate without isolating Erythromycin base and Erythromycin oxime and Beckmann's rearrangement of erythromycin oxime is carried in the presence biphasic solvent system comprising methylene chloride and water in the presence of triethylamine along with sodium bicarbonate to obtain 87-96 % pure 6,9-Imino ether. Further the 6,9-Imino ether is hydrogenated to 9-Deoxo-9a-aza-9a-homoerythromycin A followed by reductive methylation to obtain Azithromycin dihydrate.
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Page/Page column 12
(2008/06/13)
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- Novel 9a-carbamoyl- and 9a-thiocarbamoyl-3-decladinosyl-6-hydroxy and 6-methoxy derivatives of 15-membered macrolides
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An efficient method for the synthesis of diverse 9a-carbamoyl- and 9a-thiocarbamoyl-3-decladinosyl-6-hydroxy and 3-decladinosyl-6-methoxy derivatives of 15-membered azalides has been developed. These derivatives bear various alkyl and aryl groups attached to macrolide scaffold through urea or thiourea moieties at 9a position. Chemical transformations of hydroxy group at position C-3 afforded range of ketolides, anhydrolides, hemiketals, cyclic ethers, and acylides. It has been shown that 6-hydroxy and 6-methoxy derivatives undergo different chemical transformations under otherwise identical reaction conditions. Antimicrobial properties of prepared compounds were evaluated.
- Istuk, Zorica Marusic,Mutak, Stjepan,Kujundzic, Nedjeljko,Kragol, Goran
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p. 4498 - 4510
(2008/03/13)
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- Macrolides
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Azithromycin in the form of a stable monohydrate and processes for the preparation of azithromycin in the form of an, e.g. stable, monohydrate.
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Page/Page column 11
(2008/06/13)
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- 9A-AZALIDES WITH ANTI-INFLAMMATORY ACTIVITY
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Macrolides with anti-inflammatory activity are described, and more particularly, 9a-azalides without cladinose in position 3 with anti-inflammatory activity, their pharmaceutically acceptable salts and pharmaceutical compositions that contain them as active principle.
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- Hybrids of macrolides and nucleobases or nucleosides
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A few examples of hybrids/conjugates/chimeras of erythromycin A derivatives and nucleobases (uracil and thymine) or thymidine-derived nucleosides are reported. Linkers and reaction conditions have been investigated to avoid the degradation of the macrolide moiety (glycoside hydrolysis, ring cleavage, dehydration, etc.). (C) 2000 Elsevier Science Ltd.
- Costa, Anna M.,Vilarrasa, Jaume
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p. 3371 - 3375
(2007/10/03)
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- Synthesis of 9-deoxo-9a-aza-11,12-deoxy-9a-methyl-9a-homoerythromycin A 11,12 Hydrogenorthoborate dihydrate and a process for the preparation of azitromicin dihydrate
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The preparation of azitromycin dihydrate from 9-deoxo-9a-aza-11,12-deoxy-9a-methyl-9a-homoerythromycin A 11,12-hydrogenorthoborate, obtained by a step by step process starting from 9-deoxo-6-deoxy-6,9-epoxy-9,9a-dihydro-9a-azahomoerythromycin A is a process which takes place under mild conditions and with good yields.
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- Intermediate for azithromycin
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A compound having formula (III). Also, a process of making azithromycin comprising reducing the compound of formula (III) and N-methylating the reduced product.
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- Erythromycin Series. Part 11. Ring Expansion of Erythromycin A Oxime by the Beckmann Rearrangement
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The synthesis of 10-dihydro-10-deoxo-11-azaerythromycin A (11) by the Beckmann rearrangement of erythromycin A oxime (2) and reduction of the imino ether so obtained (5) is described.The structure elucidation of the new ring-expanded semisynthetic erythromycins (5) and (11) has been established on the basis of their analytical and spectral data and acid-catalysed degradation into the aglycones (7) and (13), respectively.Finally, the complete structure of ring-expanded erythronolides (7) and (13) has been determined by X-ray crystallography.
- Djokic, Slobodan,Kobrehel, Gabrijela,Lazarevski, Gorjana,Lopotar, Nevenka,Tamburasev, Zrinka,et al.
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p. 1881 - 1890
(2007/10/02)
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