- Improved method of preparation process of oxo-fluoro cyclization ester or levo-oxo-fluoro cyclization ester
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The invention discloses an improved method of a preparation process of oxo-fluoro cyclization ester or levooxo-fluoro cyclization ester. Existing preparation methods of some levofloxacin intermediateshave many side reactions and are low in yield. According to the technical scheme in the invention, by means of 2,3,4,5-tetrafluorobenzoyl chloride, N,N-dimethylaminoethyl acrylate and (L-)aminopropanol as starting raw materials and toluene and N, N-dimethylformamide added with a water removal agent organic ester or anhydride as solvents, the oxygen-fluorine cyclization ester is prepared through aone-pot reaction. According to the method, organic ester or anhydride is added, so that the loss of raw materials and the generation of by-products are reduced, the reaction yield is increased, the product quality is ensured, and the yield of the (L-)oxo-fluoro cyclization ester can be increased from 75-80% to about 90%.
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- ANTIBIOTIC RESISTANCE BREAKERS
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The invention relates to antibiotic compounds of formula (A1) and pharmaceutically acceptable salts, solvates, tautomers and combinations thereof, wherein X and L are optional linkers and one of RA or R1 comprises Ar1, wherein Ar1 is an antibiotic resistance breaker moiety which comprises an optionally substituted C6-10 aryl, C7-13 aralkyl, C5-10 heteroaryl, C6-13 heteroaralkyl, C5-10 heterocyclyl, C6-13 heterocyclalkyl, C3-10 carbocyclyl, C4-13 carbocyclalkyl, -C(=NR')-NR'R'' or –CH2- CH=CH2 group; wherein after administration of the compound to a bacterial infection this moiety reduces or prevents efflux. The invention also discloses pharmaceutical compositions comprising compounds of formula (A1) and the use of such compounds as medicaments, in particular, to treat bacterial infections, such as drug-resistant bacterial infections.
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Page/Page column 76; 77
(2019/01/05)
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- Synthesizing method of levofloxacin drug intermediate
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The invention discloses a synthesizing method of a levofloxacin drug intermediate. The synthesizing method uses sodium hydride, toluene, ethyl acetate, ethyl formate, sodium formyl ethyl acetate, tetrafluorobenzyl chloride, S-(+)-2-amino-1-propanol, Co(NO3)2 6H20 and Zn(NO3)2 6H2O as the raw materials. The synthesizing method has the advantages that the intermediate (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7-hydropyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester is prepared by subjecting the sodium formyl ethyl acetate and the tetrafluorobenzyl chloride to addition elimination, S-(+)-2-amino-1-propanol replacement and cyclization under the effect of a catalyst; the sodium formyl ethyl acetate is used to replace traditional N,N-dimethylamino ethyl acrylate DMA, so thatthe synthesizing route is shortened, preparation cost is lowered, pollution caused by dimethylamine gas generated during amino-1-propanol reaction is avoided, and the method is green, environmentallyfriendly and capable of greatly increasing the yield of the intermediate.
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Paragraph 0008; 0010-0015; 0016-0018; 0029
(2018/09/13)
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- Environment-friendly method for preparing levofloxacin hydrochloride
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The invention provides an environment-friendly method for preparing levofloxacin hydrochloride. The method comprises the following steps: preparing 3-(2-hydroxy-1-methyl-ethylamino)-2-(2,3,4,5-tetrafluorobenzoyl)-ethyl acrylate, preparing levo-oxy main naphthenic acid, and preparing the levofloxacin hydrochloride. The method provided by the invention is concise, low in production cost, high in product yield, good in quality, economic and environment-friendly, fewer three wastes are discharged, and most byproducts are effectively separated and recycled, so that the method is convenient for industrial production and has great popularization significance.
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- Method for preparing high-quality levofloxacin hydrochloride
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The invention provides a method for preparing high-quality levofloxacin hydrochloride. The method comprises the following steps: preparation of 3-(2-hydroxy-1-methyl-ethylamino)-2-(2,3,4,5-tetrafluorobenzoyl)-ethyl acrylate, preparation of levo naphthenic acid and preparation of levofloxacin hydrochloride; the method is concise, the production cost is low, the product yield is high, quality is good, the method has the advantages of economic performance and environmental protection, three waste discharge capacity is little, effective separating and recycling on most by-product can be simultaneously realized, the method is convenient for industrial production, and has large popularization meaning.
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- Method for preparing levofloxacin hydrochloride
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The invention provides a method for preparing levofloxacin hydrochloride. The method comprises preparation of 3-(2-hydroxyl-1-methyl-ethylamino)-2-(2,3,4,5-tetrafluorobenzoyl)-ethyl acrylate, preparation of levo-oxygen main naphthenic acid, and preparation of the levofloxacin hydrochloride. The method is simple, low in production cost, high in product yield, good in product quality, economical, environmentally friendly, and low in three-waste emission load, and realizes effective separation and recycling of most byproducts, is convenient for industrial production and has great significance of promotion.
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- Synthesis process of levofloxacin acid ester
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The invention discloses a synthesis process of levofloxacin acid ester, comprising the following steps: (1) sequentially putting toluene, organic alkali and acyl chloride into an acylation reaction kettle, starting stirring, then adding N,N-dimethylaminoethyl acrylate into a dropping device, starting stirring and dropping, and then heating and stirring after dropping is completed; (2) after the completion of step (1), adding L-amino propanol, adding saturated salt water after the completion of reaction, adjusting the PH value through dropping, implementing static stratification after the PH value is stable, recovering toluene from a toluene layer in a decompression mode until no toluene solution exists in the reaction kettle, adding DMF, stirring and dissolving, and then transferring to a cyclization kettle head tank for later use; (3) adding DMF into a cyclization kettle, stirring, adding KF, heating to recover front cut fractions at atmospheric pressure, adding an amination reaction solution, and heating to maintain continuous refluxing; and (4) ending heat preservation, cooling, recovering DMF in a decompression mode, adding high-purity water after recovery, stirring, filtering, washing with the high-purity water, rinsing with methanol, and drying to obtain a product. The synthesis process disclosed by the invention adopts one-pot reaction, and is mild in reaction condition, simpler to operate and high in utilization rate of raw materials.
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- Ofloxacin preparation method (by machine translation)
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The invention provides a preparation method of ofloxacin. The preparation method comprises the following steps of: reacting (N,N)-dimethylamino ethyl acrylate with aminopropanols in methylbenzene; directly adding lewis base serving as a catalyst and trimethylchlorosilane to protect hydroxyl and amido; after reaction is completely finished, dropwise adding (2,3,4,5)-tetrafluorobenzoyl chloride; preserving heat; performing acid washing; removing protecting groups; concentrating an organic layer to obtain an oil layer; adding a proper amount of dimethyl formamide (DMF); diluting and dropwise adding backflow DMF having anhydrous potassium fluoride; recovering DMF and adding water to centrifuge; adding acid water into a solid to hydrolyze to obtain difluorocarboxylic acid; and completely reacting difluorocarboxylic acid and N-methyl piperazine in dimethylsulfoxide (DMSO) by using triethylamine as an acid-binding agent at 90-100 DEG C to obtain ofloxacin. According to the process, hydroxyl and amido are protected by using trimethylchlorosilane, so that the utilization degree of (2,3,4,5)-tetrafluorobenzoyl chloride is effectively increased, and the generation of impurities is reduced to ensure that the reaction yield of intermediate difluorocarboxylic acid is increased by 10 percent.
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Paragraph 0019; 0027; 0028; 0029
(2016/10/09)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF LEVOFLOXACIN HEMIHYDRATE
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The present invention relates to an improved process for preparation of Levofloxacin hemihydrate having single individual impurity not more than 0.1% and free from particulate matter and from the other enantiomer (R-form) which comprises dissolving levofloxacin technical grade in aqueous alkaline solution, treating the resulting solution with activated carbon at room temperature, removing the undissolved particulate matter filtration, bringing the pH of the aqueous alkaline levofloxacin solution to neutral using dilute mineral acid, removing the precipitated particulate matter by filtration, acidifying the resulting solution, treating the acidified solution with activated carbon at room temperature, filtering the undissolved particulate matter by filtration, neutralizing the acidic solution, filtering again to remove any particulate matter present and, extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydrofuran or in admixture with other organic solvents to get highly pure levofloxacin hemihydrate having single individual impurity is less than 0.1% and fee from particulate matter and from the other enantiomer (R-form).
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Page/Page column 16-17
(2008/06/13)
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- Optically active pyridobenzoxazine derivatives and intermediates thereof
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An optically action pyridobenzoxazine derivative, a process for preparing the same and a novel intermediate useful for preparing the optically active pyridobenzoxazine derivative are disclosed. The optically active pyridobenzoxazine derivative possesses increased antimicrobial activity and reduced toxicity. The intermediate is useful for preparing such optically active pyridobenzoxazine derivatives such as Ofloxacin and anolog compounds.
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- Optically active benzoxazines and bezothiazines and a process for their stereospecific preparation
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Optically active 7,8-difluoro-3,4-dihydro-3--methyl-2H-[1,4]benzoxazines and 7,8-difluoro-3,4-dihydro-2--methyl-2H-[1,4]benzoxazines and the corresponding benzothiazines of formula III, where, one of the substituents R1, R2, R3 and R4 is CH2OH or -CH2Z, the remaining being hydrogen, X denotes fluoro, chloro, methyl or hydrogen, Y is oxygen or sulfur and Z is hydrogen, fluoro or protected hydroxyl are obtained as the stereochemically pure products of a stereospecific synthesis using a 3,4-difluoronitrobenzene substituted with a stereochemically pure 2-(1-hydroxyisopropoxy), 2-(2--hydroxypropoxy), 2-(1-hydroxyisopropylthio) or 2-(2--hydroxypropylthio) substituent. The obtained compounds are suited for the production of optically active pyridobenzoxazines and pyridobenzothiazines, among which are useful antibacterial optically active quinolones, particularly (S)-(-)-ofloxacin.
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