182 results about "Pleuromutilin" patented technology

The invention relates to an extraction process of microorganism source compounds, in particular to a pleuromutilin solvent extraction process; the process comprises the following steps: mycelium is separated out from pleuromutilin producing bacterium total-fermentation broth, is dried, crushed and sifted out, the total water content of the mycelium is baked to be lower than 5 percent, so as to obtain baking mycelium for spare; the obtained baking mycelium is mixed with butyl acetate, the mixture is shaken out and extracted, the extracting solution is filtered, the filtrate is washed, dehydrated and dried, and decolorized by activated carbon, the solvent is recovered until being crystallized, crystallization is carried out by standing, so as to obtain the pleuromutilin; the process has theadvantages of stability, having easy operation, convenient operation, low solvent toxicity, high safety, low solvent consumption level, short extraction time, easy purification of products and low cost.

The invention discloses a pleuromutilin derivate, a preparation method and medical use thereof. The pleuromutilin derivate is a compound, which is obtained by coupling pleuromutilin to alkyl acylamino-thiazole-4-methyl merecaptan with 2-different substitutional amino. Pharmacological experimental results show that: compared with the pleuromutilin, the pleuromutilin derivate disclosed by the invention has better antimicrobial and antibiotic resistant bacteria activities; and therefore, the compound is possibly applicable for curing a plurality of infection and inflammatory diseases on clinic.

The invention discloses a method for synthesizing valnemulin hydrochloride. The method taking pleuromytilin a raw material comprises the following steps: synthesizing sulfonated pleurin; then, preparing 14-O-[(1-amido-2-methyl-propyl-2-yl)acetyl] mutelin by the sulfonated pleurin; synthesizing D-valine deng salt by D-valine; and finally, mixing the 14-O-[(1-amido-2-methyl-propyl-2-yl)acetyl] mutelin, the D-valine deng salt, N-methylmorpholine and allyl chloroformate by a certain sequence and a certain condition and reacting to generate mixed anhydride so as to obtain the valnemulin hydrochloride by the subsequent steps of acidylating, hydrolyzing, separating, drying and the like. The invention realizes the accurate control of the reaction by controlling the technological parameters of the reaction temperature, the drying condition, the reaction pH and the like and enhances the reaction efficiency and the quality and the purity of a product effectively. The obtained valnemulin hydrochloride can be used for medicines and meets the market requirement.

The invention discloses a method for preparing valnemulin. The method comprises the following steps of: preparation of chloridized pleuromutilin, preparation of N-allyloxycarbonyl-valine; preparation of 1, 1-dimethyl-2-(N-allyloxycarbonyl valyl amino) ethanethiol and preparation of the valnemulin. The method can effectively improve the product quality and the yield.

The invention discloses a method for fermenting, extracting and preparing high purity pleuromutilin raw material, comprising: filtering fermentation liquor used for fermenting and culturing pleurotusmutilus, and obtaining wet thallus containing the pleuromutilin; after drying the wet thallus, obtaining dry thallus; then, taking methyl isobutyl ketone as solvent for extracting for a plurality of times, and obtaining extracted filtrate; concentrating the filtrate, and obtaining concentrated solution containing the pleuromutilin; after carrying out temperature reduction and crystallization on the concentrated solution, obtaining crystalloid containing the pleuromutilin; and finally, vacuum drying and grinding the crystalloid, and obtaining the raw material powder of the pleuromutilin. The method has simple technique and easy operation, and the obtained pleuromutilin has high yield, good quality and the content reaching more than 95%; furthermore, the methyl isobutyl ketone which is adopted as solvent has good dissolubility, can be recycled, is high in recovery rate, saves the using quantity of the solvent by about 15% compared with the existing technique, and has little environmentalpollution.

The invention belongs to the field of medicinal chemistry, and discloses a pleuromulin-like compound and with an acyl piperazine side chain and a preparing method and application of the pleuromulin-like compound. The pleuromulin derivative is a compound and an officinal salt of which the structure can be shown in the formula 3, formula 4 or formula 5, wherein R1, R2, and R3 are independently chosen from one of hydrogen atom, hydroxide radical, amidogen, sulfydryl, hydroxymethyl, amine methyl, nitro, halogen, trihalogenated methyl, methyl, natural amino acid acylamino, and alkoxy of which the number of carbon atoms is 1-6. The pleuromulin-like compound and with the acyl piperazine side chain has good property of inhibiting staphylococcus aureus and mycoplasma activities, and is particularly suitable for being used as a novel anti-microbial agent to prevent infectious diseases of human or animal caused by infection of mycoplasma or multidrug resistant microorganisms.

The invention relates to a preparation method of tiamulin base. The preparation method includes: filtering pleuromulin fermentation broth, drying mycelium, performing leaching by using methanol as solvent, using acetone to extract leach liquor after vacuum concentration, concentrating extract, transferring concentrate into a synthetic reactor, adding paratoluensulfonyl chloride, allowing for synthetic reaction at pH of 11-12 and reaction temperature of 20-30 DEG C, allowing for standing and layering after complete reaction, adding tetrabutylammonium bromide and diethylaminoethyl mercaptide into ketone phase respectively , allowing for full reaction at pH of 9-10 and the reaction temperature of 50-60 DEG C, adding water for extraction, discarding aqueous phase, filtering the ketone phase, and reducing the original volume to 60-70% by vacuum concentration to obtain tiamulin base. The original process is improved, the salifying and crystallization process is omitted, the tiamulin base is used to produce preparations directly, and accordingly equipment investment cost and production cost are lowered, product quality is improved, and the content of tiamulin base reaches 80-90%. Organic solvents used in the preparation method are recyclable, environmental pollution is reduced, and the preparation method has promising development prospect.

The invention discloses a method for extracting and purifying pleuromutilin. The method comprises the following steps: leaching pleuromutilin dry hypha with methyl isobutyl ketone to obtain a crude product; and dissolving the crude product with methanol, sequentially extracting with petroleum ether and butyl acetate, concentrating, crystallizing, washing with aether, and decoloring with activatedcarbon to obtain the finished pleuromutilin product. In the process of leaching the crude pleuromutilin product, the methyl isobutyl ketone is used instead of butyl acetate, thereby increasing the extraction yield (higher than 90%); and in the purification process, proper technical steps and extracting and washing agents are selected to remove impurities contained in the pleuromutilin, thus, the degree of purification is high, and the purity of the pleuromutilin is higher than 98%.

The invention discloses a valnemulin synthesis method which comprises the following steps of: 1. pleuromutilin sulphonic acid ester synthesis: using pleuromutilin as raw materials to react with sulfonic acid chloride under the alkaline condition for converting the pleuromutilin into pleuromutilin sulphonic acid ester; 2. sulpho-pleuromutilin synthesis: using penicillamine to substitute sulphonic acid ester in the product in the step 1 under the alkaline condition to obtain sulpho-pleuromutilin; 3. amino-protected D-R-valine synthesis; and 4. valnemulin synthesis. The mainly used raw materials of the valnemulin synthesis method are fermentation products of the pleuromutilin and cysteine which can be easily obtained in the market and have low cost, and in addition, the valnemulin synthesis method has simple process operation, has no danger, has the characteristics of low cost, high yield and the like, is applicable to enlargement and industrial production and has industrialization value.

The invention belongs to the field of medicinal chemistry and discloses a pleuromutilin derivative with a 2-amino phenyl mercaptan side chain and a preparing method and application of the pleuromutilin derivative. The compound has the structures shown in formula 2 and formula 3, wherein R1, R2 and R3 are respectively and independently selected from the hydrogen atom, the hydroxyl, the amino, the sulfydryl, the hydroxymethyl, the amine methyl, the nitro, the halogen, the trihalogenated methyl, the methyl, the natural amino acid acylamino and the C1-6 alkoxy. The pleuromutilin derivative with the 2-amino phenyl mercaptan side chain has good activity for inhibiting the drug resistant staphylococcus aureus and the mycoplasma and is particularly suitable for serving as a novel antibacterial medicine for preventing infectious diseases caused by the human or animal mycoplasma or drug resistant staphylococcus aureus or multidrug resistant bacteria.

The invention discloses a chemical synthesis method of valnemulin hydrochloride, which comprises the following steps of: taking refined pleuromutilin as raw material, carrying out sulfonation by paratoluensulfonyl chloride, and reacting with dimethyl cysteamine hcl, to obtain the pleuromutilin dimethyl cysteamine substitute; reacting D-valine, methyl acetoacetate and potassium hydroxide to obtain (R)-2-(1-methoxycarbonyl group-2-allyl) amino-3-methyl potassium butyrate, activating by ethyl chloroformate and reacting with the pleuromutilin dimethyl cysteamine substitute, adjusting PH value, carrying out reverse phase extraction, and carrying out freeze-drying to obtain the valnemulin hydrochloride. The method has the advantages that due to the refining of the raw material pleuromutilin, the impurities in the product can be effectively removed, and the purifying process can be simplified from the source; the carboxyl of D-valine can be activated by the ethyl chloroformate, so that the reaction is easier to carry out; and due to the pH adjustment, the reverse phase extraction, and the freeze-drying, the product can be obtained, so that the product is stable in quality, and high in purity.

The invention belongs to the field of pharmaceutics, and provides pleuromutilin phosphate compounds shown as a right general formula (I), a medicinal composition thereof, a preparation method thereofand application thereof. The pleuromutilin phosphate compounds have good water solubility, quickly release parent medicaments in vivo after intravenous administration, achieve higher blood concentration, and have excellent anti-infectious activity, so the pleuromutilin phosphate compounds can be used for treating infectious diseases, particularly infectious diseases caused by multi-medicament andmedicament-resistant bacteria.

The invention discloses a pleuromutilin derivative with a pyrimidine side chain. The structural formula of the derivative is shown in the specification, wherein R1 is C1-C4 alkoxy groups or hydroxyl groups; R2 is an amino group or an amide group; R3 is hydrogen or C1-C4 alkyl groups. The compound can be applied to preparation of antibacterial drugs, particularly to preparation of MRSA (methicillin-resistant staphylococcus aureus), MRSE (methicillin-resistant staphycoccus epidermidis) and / or antagonistic bacillus subtilis drugs, and the antibacterial effect is superior to that of tiamulin.

The invention provides a reagent for eliminating mycoplasma contamination in cell culture and a use method thereof. The reagent is prepared by mixing liquid A and liquid B isometrically or mixing liquid A, liquid B and liquid C isometrically, wherein the liquid A is prepared by mixing semisynthetic pleuromutilin derivatives and 0.01MPBS, and the mass-volume percentage concentration of the solute after mixing is 0.5-1.5%; the liquid B is prepared by mixing quinolone derivatives and 0.01MPBS, and the mass-volume percentage concentration of the solute after mixing is 0.5-1.5%; and the liquid C is prepared by mixing tetracycline derivatives and 0.01MPBS, and the mass-volume percentage concentration of the solute after mixing is 0.25-0.75%. The reagent and method provided by the invention havethe following beneficial effects: if contamination is not severe, the effect can be displayed within a week; and after the treatment cycle is finished, black spots do not exist among the treated contaminated cells, the growth cycles of the cells return to normal, the cell morphology is normal, and aggregated growth and netting phenomena are avoided.

The invention relates to a preparation method of valnemulin hydrochloride. The preparation method comprises the following steps: reacting pleuromutilin with p-toluenesulfonyl chloride, substituting with 1-amino-2-methyl propyl-2-mercaptan hydrochloride so as to obtain [(2-amino-1,1-dimethyl S, 6S, 8R,9R, 9aR, 10R)-6-vinyl decahydro-5-hydroxyl-4,6,9,10-tertamethyl-1-oxo-3a, 9-propanol-3aH-cyclopentacyclooctene-8-yl ester for later use; reacting D-valine with methyl acetoacetate; synthesizing the product with isobutyl chloroacetate so as to generate anhydride; and reacting anhydride with [(2-amino-1,1-dimethyl ethyl) sulfenyl] acetic acid (3aS, 4R, 5, 6S, 8R,9R, 9aR, 10R)-6-vinyl decahydro-5-hydroxyl-4,6,9,10-tertamethyl-1-oxo-3a, 9-propanol-3aH-cyclopentacyclooctene-8-yl ester so as to generate amide, and then carrying out deprotection with hydrochloric acid so as to prepare valnemulin hydrochloride. The method has the advantages that (1) reaction temperature is mild, thereby being applicable to large-scale production; (2) post-treatment is simple, thereby directly obtaining the product; (3) used solvents are less, thereby reducing environmental pollution; and (4) the valnemulin hydrochloride content and yield of the obtained product are high.

The present invention relates to pleuromutilin antibiotics represented by a general formula (I), pharmaceutically acceptable salts, prodrugs, solvates or stereoisomers thereof, wherein R<1>, R<2>, R<2a>, R<2b>, m, X and Y are defined in an instruction. The present invention further relates to preparation methods of the compounds, drug compositions containing the compounds, drug preparations containing the compounds, and applications of the compounds in preparation of drugs for treatment and / or prevention of diseases caused by microorganisms.

The invention belongs to the field of pharmaceutical chemistry, and discloses pleuromutilin derivatives with piperazine side chain, and a preparation method and application thereof. The derivatives have the structure disclosed as Formula 2 or Formula 3, wherein R1 is hydrogen atom, methoxy, methyl, hydroxy, nitro or chlorine atom; R2 is hydrogen atom, methoxy, methyl, hydroxy, nitro or chlorine atom; R3 is hydrogen atom, methoxy, methyl, hydroxy, nitro or chlorine atom; and R4 is phenyl or methyl. The pleuromutilin derivatives with piperazine side chain have favorable in-vitro antimicrobial activity, have the advantage of lower preparation cost than valnemulin and retapamulin, and thus, are specially suitable to be used as a novel antibacterial drug for preventing and treating human or animal bacterial infective diseases.

The present invention relates to a class of pleuromytilin compounds represented by the following general formula (I), pharmaceutically acceptable salts and preparation methods thereof, and compositions comprising the compound represented by the general formula (I) as an active component. The compounds have excellent antibacterial activities and can be adopted as the active substance for infectious disease treatment.

The invention discloses pleuromutilin derivatives with the structure as shown in a formula (I) in the specification and the antibacterial activity, salts, solvates, optical isomers and polymorphism compounds thereof acceptable in pharmacy and / or veterinary medicines as well as a preparation method and an application of the pleuromutilin derivatives and the salts, solvates, optical isomers and polymorphism compounds thereof in antibacterial compositions. The preparation method has the beneficial effects that two different lead compounds are connected together by covalent bonds so as to generate a synergistic effect, an additive effect or new pharmacological activity in vivo; sulfonamides are spliced into side chains of pleuromutilin so as to generate new pleuromutilin derivatives, the antibacterial activity of the obtained new compounds can be enhanced, the obtained new compounds have obvious antibacterial activity for gram-positive bacterium, gram-negative bacterium and mycoplasma and an obvious inhibiting effect on drug-resistance bacteria such as MRSA, and the antibacterial spectrums of the obtained new compounds are effectively expanded.

The invention discloses a pleuromutilin derivative with a thiadiazole skeleton and a preparation method thereof. The preparation method comprises the following steps: 1, synthesizing 22-O-(4-tosyl)acetoxyl mutilin; 2, synthesizing 14-O-( iodoacetyl)mutilin; 3, synthesizing 14-O-[(4, 2-amino-1-thiadiazole-5yl)thioacetyl]mutilin; 4, synthesizing an end product. The compound synthesis method is easily available in raw materials, cheap in price, simple in operation, easy in product separation and purification and high in yield, wherein the total yield is 32-40%.

The present invention relates to pleuromutilin antibiotic derivatives represented by a general formula (I), pharmaceutically acceptable salts, prodrugs, solvates or stereoisomers thereof, wherein R<2>, Q<1>, Q<2>, m and X are defined in an instruction. The present invention further relates to preparation methods of the compounds, drug compositions containing the compounds, drug preparations containing the compounds, and applications of the compounds in preparation of drugs for treatment and / or prevention of diseases caused by microorganisms.

The invention belongs to a process for preparing a valnemulin hydrochloride premix of pleuromutilin antibiotics specially used for animals, and in particular relates to a method for preparing a valnemulin hydrochloride coating granule. The method comprises the following process steps of pre-granulation of the valnemulin hydrochloride, preparation of coating solution, coating of the valnemulin hydrochloride and the like. The method has the advantages of solving the problems existing in the prior art that the valnemulin hydrochloride materials are hygroscopic, sensitive to light and strong in powder irritation, and are easily decomposed when being mixed with feed and the like, effectively achieving the aim of odor masking and the like; moreover, after coating, the coating granule is stable under conditions of a light accelerating experiment.

The invention discloses a process for extracting pleuromutilin in tiamulin synthetic process. The process comprises the following steps: mixing pleuromutilin mycelium with methanol or ethanol, and continuously stirring the mixture at the temperature of 20-40 DEG C for 3-6h to prepare leach liquor; and allowing the leach liquor to pass through a closed inorganic membrane filtering system at a certain pressure, sending the obtained filtrate to a subsequent processing system, allowing part of the residual filtrate to return to a lixiviating tank and the other part thereof to run through a circulating pump for being circularly filtered by the closed inorganic membrane. The process can effectively separate and clarify the pleuromutilin leach liquor, shorten process flow by 6-10h for each day, improve the yield by 5-7% compared with a traditional plate-and-frame filtering process, and has fast filtering rate, high filtering precision and low energy consumption. The closed inorganic membrane filtering system can help reduce the loss of organic solvents caused by volatilization and realize clean production, thus lowering production cost of enterprises, greatly improving working environment, being favorable for health of operators, and having significant social and economic benefits.

The invention relates to a medium of producing pleuromutilin by fermenting Pleurotus sp and its fermentation method. The medium comprises a primary seed medium, a secondary seed medium and a fermentation medium, and is characterized in that the primary seed medium and the secondary seed medium contains cold pressing yellow bean cake powder and an organosilicon antifoaming agent; the fermentation seed medium contains cold pressing yellow bean cake powder, the organosilicon antifoaming agent and corn oil. According to the invention, corn oil and cold pressing bean cake powder can replace soya-bean oil and heat pressing bean cake powder, a medium formula can be optimized, the technical defects of low fermentation unit, less quantity of single pot mycelium and the like. The invention provides a fermentation unit, the thalline fermentation quality can be improved, the original accessory source can be maximally reduced without environmental influence, the sufficient supply can be guaranteed, and the production with stabilization and high efficiency of pleuromutilin can be realized.

The invention relates to a synthesis method of p-toluene sulfonic acid pleuromutilin ester. Especially, the method includes: under catalysis of three inorganic alkalis, i.e. sodium hydroxide, potassium hydroxide or sodium carbonate, reacting pleuromutilin with p-toluenesulfonyl chloride for 0.5-1.5h in a methyl isobutyl ketone solvent at 50-65DEG C, conducting washing and distillation of the solvent, thus obtaining the p-toluene sulfonic acid pleuromutilin ester with yield of 95-96.5% and chromatographic purity of 97-98.1%. The method has the advantages of environmental-friendliness, worker health promotion, low production cost, short synthesis reaction time and high yield.

The invention discloses a synthesis method of tiamulin. According to the method, firstly, p-toluene sulfonic acid pleuromutilin ester prepared by pleuromutilin is converted into sulpho-pleuromutilin. After that, sulpho-pleuromutilin reacts with the salt of an ethyl amino ethane derivative to generate tiamulin. The method is simple to operate, low in cost, and environment-friendly. The total recovery of tiamulin is over 80%. Therefore, the method is applied to the industrial production of tiamulin.

The invention discloses new pleuromutilin derivatives which have a structural formula (I) or a structural formula (II) shown in the specification, wherein in the formula (I), when n=0, R1 is Cl, CH3, OCH3 or NH2; and when n=1, R1=H, and R2=NH2. The compounds have favorable inhibiting action on Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Streptococcus mastitidis; the antibacterial activity of one compound having a phenyl group with ortho-substituting groups or para-substituting groups (such as Cl, CH3, OCH3 or NH2) is superior to the antibacterial activity of one compound having a phenyl group with meta-substituting groups; and part of compounds having para-substituting aryl groups or ortho-substituting aryl groups are the same with valnemulin in the antibacterial activity on Staphylococcus epidermidis or Streptococcus mastitidis, and can be used for the preparation of antibacterial drugs. The synthesis method of the compounds has the advantages that the raw materials are accessible, the price is low, the operation process is simple, the products are easy to separate and purify, the yield is high and the total yield is 35-45%.

The present invention belongs to the field of chemical medicines, and concretely relates to a pleuromutilin derivative, and a preparation method and an application thereof. The preparation method of the pleuromutilin derivative includes the following steps: 1, preparing 22-O-(4-tosyl)oxoacetylmutilin powder; 2, preparing 14-O-(iodoacetyl)mutilin; 3, synthesizing 14-O-[(2-amino-1,2,3,4-thiadiazole-5-yl)mercaptoacetyl]mutilin; and 4, synthesizing an end product. The synthesis method of like compounds has the advantages of easily available raw materials, low price, simple operation, easy separation and purification of the product, and high yield, and realizes a total yield of 30-38%.

An adsorption chromatograph based method for recovering pleuromutilin from a crystallization mother liquor, belongs to the technical field of separation and purification of antibiotic. The method is characterized by comprising steps of: carrying out a vacuum concentration on a pleuromutilin crystallization mother liquor, heating to 90 DEG C gradually until no distillate, adding water-soluble organic solvent and stirring uniformly; pumping into nonpolar macroporous adsorption resin column for adsorption; preparing an eluant by a water-soluble organic solvent with volume percentage of 20-70% and pumping into an adsorption resin column for desorption; carrying out vacuum condensation on the obtained eluate, adding organic solvent, dissolving, recrystallizing and carrying out vacuum drying to obtain a finished product. The invention has beneficial effects that the adsorption chromatograph based method for recovering pleuromutilin from the crystallization mother liquor has simple technique, low production costs, and a residual pleuromutilin recovery rate from the crystallization mother liquor reaches 85-92%, and a total production recovery rate reaches 95-98%, so as to increase industrial production efficiency.

A method of preventing or treating diseases caused by Mycobacterium, comprising administering to a subject in need of such treatment an effective amount of a pleuromutilin.