54 results about "Roxadustat" patented technology

The invention provides a preparation method of Roxadustat intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate (IV), comprising the step of subjecting 2-(1-(3-phenoxyphenyl)ethylimide)dimalonate (III) as a starting material to condensation and cyclization. The preparation method of the Roxadustat intermediate IV has the advantages that material is easy to obtain, operating steps are few, the process is simple, the reaction yield is high, atom utilization rate is high, and the method is easy for industrial production. The reaction general formula is shown in the specification.

The invention provides a preparation method for an intermediate VI of Roxadustat. The preparation method comprises the following steps: reacting 3-methyl-5-bromoisobenzofuran-1(3H)-one (I), which serves as a starting raw material, with phenol so as to prepare an intermediate II, then, subjecting the II to a ring-opening substitution reaction so as to prepare a compound III, and subjecting the compound III to a substitution reaction so as to prepare a key intermediate V; and subjecting the V to alkali condensation, deprotection and aromatization, thereby preparing the target intermediate VI. The preparation method for the intermediate VI of the Roxadustat, provided by the invention, has the advantages that the raw materials are readily available, the process is simple, the operation is convenient, the reaction yield is high, the atom utilization ratio is high, and the industrial production is facilitated. The reaction general formula is represented by the formulae shown in the description.

The invention discloses a synthesis method for a drug Roxadustat for chronic anemia. The synthesis method comprises the following steps: hydrolyzing and acidifying a compound shown as a formula 6 under the action of alkali to obtain a key intermediate compound shown as a formula 7; carrying out condensation reaction on the compound shown as the formula 7 and carbonyl diimidazole under suitable conditions to obtain an intermediate compound shown as a formula 8, and separating or not separating the compound shown as the formula 8 from a system to directly take part in subsequent reaction; and finally, reacting the product with glycine to obtain a final product Roxadustat shown as a formula 9. The preparation method has the advantages that the route efficiency is improved, the process cost isreduced, side products are reduced and the purity of a final product is favorably improved (The formula is shown in the description), wherein R2 in the compound shown as the formula 6 represents alkyl, and includes but not limited to methyl, ethyl, isopropyl, tertiary butyl or benzyl.

The invention discloses a preparation method of Roxadustat, compound 1 and bis(dimethylamino)methane are heated in a mixed solvent of acetic acid and trifluoroacetic acid for reaction to form compound2; acetic anhydride is added to the obtained reaction solution of the compound 2 for completing reaction by heating to form compound 3; the compound 3 is dissolved in ethyl acetate and heated, then is catalyzed by Pd / C, and reduced by hydrogen to obtain compound 4; the compound 4 and glycine are dissolved in a solvent, and heated under the action of an organic base for reaction to obtain compound5; wherein the solvent is one or more of dioxane, ethylene glycol monomethyl ether, toluene, acetonitrile and n-propanol, the organic base is one or more of triethylamine, 1,8-diazabicyclo undecane-7-ene, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, and ethylenediamine; the preparation method has the advantages of shorter reaction time, low reaction temperature, low equipment condition requirements and high crude product purity, is suitable for large-scale industrial production, and has a good industrialization prospect.

The invention discloses a method for purifying roxadustat by using a mixing solvent. The concrete process comprises: (a) dissolving a roxadustat crude product in a first solvent, carrying out heating stirring, carrying out cooling filtering at a room temperature, and collecting the filter cake; (b) adding a second mixing solvent to the collected filter cake, carrying out heating stirring, and cooling at a room temperature; and (3) filtering, washing the filter cake, and carrying out vacuum drying to obtain the pure roxadustat product. According to the present invention, the impurity removing effect of the purification method is significant, wherein the total impurity content of about 5.5% can be reduced to 0.20% and below, the purity of the purified roxadustat can be about more than 99.80%, the maximum single impurity is less than 0.1%, the yield is more than 75%, and the obtained roxadustat can meet the bulk drug level, and can meet the clinical and commercial use quality and management standards.

The invention relates to a process for the preparation of roxadustat, namely [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid. The preparation method is low cost, simple in method and good in safety, and is suitable for industrial production.

The invention provides a synthesis method of roxadustat. The roxadustat is prepared from 2-amino-3-hydroxyl-3-(4-phenoxyphenyl)propionic acid through the steps of acetic anhydride protection, esterification, cyclization, aromatic ring oxidation, hydrolysis and glycine condensation. The material used in the synthesis method is simple and easy to obtain, reaction operation is simple, the reaction conditions are mild, the product purity is high, the generation cycle is short, cost is low, and the method is suitable for large-scale industrial production.

The invention provides a preparation method of Roxadustat. The preparation process provided by the invention has the advantages of cheap and easily available initial raw materials, short synthetic route, short reaction period, no environmental pollution, simple operation, avoidance of harsh reaction conditions, simple operation and post-treatment, high yield and product purity, easy purifying of intermediates in each step, low production cost, suitability for industrial large-scale production, and accordance with the principle of green chemistry.

The invention relates to a roxadustat pharmaceutical preparation. The pharmaceutical preparation specifically comprises roxadustat, a cyclodextrin derivative, polacrilin potassium, a diluent and a disintegrating agent. The particle size d0.9 of the roxadustat is not greater than 30 [mu] m. The roxadustat pharmaceutical preparation prepared by the invention has better dissolution rate, thereby ensuring quality and curative effect of the medicine.

The invention discloses a preparation method of a roxadustat intermediate, which comprises the following steps of: firstly, reacting methyl nitroacetate with trimethyl orthoformate to obtain a product I, and performing catalytic hydrogenation reduction to obtain a product II; then reacting the product II with m-phenoxyacetophenone to obtain a product III; carrying out a Pomeranz-Fritsch reaction on the product III, and completing intramolecular ring closing to obtain a product IV; finally, carrying out an oxidation reaction on the product IV to obtain the roxadustat intermediate 1-methyl-4-hydroxy-7-phenoxy isoquinoline-3-methyl carboxylate. According to the preparation method of the roxadustat intermediate, the raw materials are easy to obtain, and the production cost can be remarkably reduced. The whole process is simple, the whole consumed time is short, the production efficiency is high, the yield is high, the reaction condition is mild, the post-treatment is simple and convenient, and the method is suitable for large-scale preparation and has a great application prospect.

The invention relates to the field of medicinal preparations, and particularly discloses a medicinal composition containing a roxadustat solid dispersion and a preparation method of the medicinal composition. The preparation method comprises the steps of firstly, preparing a roxadustat carrier solution containing roxadustat from a medicinal carrier material with a solubilizing effect and the roxadustat through an ethanol solution with a certain concentration; and preparing the medicinal preparation containing the roxadustat solid dispersion from the roxadustat solid dispersion and other pharmaceutically acceptable auxiliary materials through the steps of one-step granulation, size stabilization and the like. The medicinal composition containing the roxadustat solid dispersion has good dissolution performance, the preparation process is simple and easy to operate, energy is saved, the input cost is reduced, raw materials do not need to be micronized, the solubility of the roxadustat medicine is improved, the content uniformity is improved, the in-vitro dissolution rate and the bioavailability are further improved, besides, the one-step granulation process avoids material exposure, and the preparation has good light stability and is convenient for industrial production.

The invention relates to a method for analyzing related substances of Roxadustat. The method is carried out on a high performance liquid chromatograph. The method comprises the following steps: adopting an Ultra XB chromatographic column; taking a trifluoroacetic acid aqueous solution and an organic solvent as mobile phases; enabling the liquid phase diode array detector or the ultraviolet detector to carry out gradient elution detection so as to effectively separate and detect the Roxadustat-related substances. According to the invention, the related substances in the Roxadustat can be comprehensively controlled, the drug safety can be improved, and the basis can be provided for the establishment of the quality standard of the Roxadustat bulk drug.

The invention belongs to the field of preparation of drug intermediates, and relates to a preparation method of an important intermediate 3e of roxadustat. According to the method, 3c is used as an initial raw material and reacts with acetic acid and metal powder in a solvent under the action of the acetic acid and the metal powder to prepare 3e. The method is mild in reaction condition; high temperature and high pressure are not needed; the reaction can be carried out under normal pressure; the method is suitable for industrial amplification; and the yield and purity of the method are equivalent to those of a contrast patent of which the number is CN103435546B.

The invention discloses an application of roxadustat in a medicine for treating migraine and the medicine containing the roxadustat, and relates to the technical field of medicines, wherein the migraine is chronic migraine. The used roxadustat can significantly inhibit nitroglycerin-induced pain sensitivity related to mouse migraine and improve the central sensitization state of the trigeminal nerve spine tail nucleus part, the new application of the roxadustat in the aspect of migraine resistance can expand the research of the roxadustat in the field of medicine, and a new theoretical direction is provided for clinical application.

The invention discloses a preparation method of a roxadustat intermediate. The method comprises the following steps: anhydride ring opening, esterification, ring closing, aromatization, deprotection, chlorination and methylation to obtain the roxadustat intermediate. According to the invention, the preparation method provided by the invention makes full use of the atom economy theory, is easy to operate, low in cost and low in pollution, and is suitable for large-scale industrial production; and only one-time refining is carried out, the chromatographic purity can reach 99.5% or above, and the total yield of the six-step reaction is 30% or above.

The invention discloses new medical uses of roxadustat, specifically applications in preparation of a pharmaceutical preparation for assisted treatment of diabetic foot. According to the present invention, the uses of roxadustat in the diabetic foot treating pharmaceutical preparation are firstly disclosed; and the clinical test research results show that the foot ulcers of diabetic foot patientscan be significantly treated, hyperlipidemia, hypertension, inflammation and other systemic symptoms can be improved, the recurrence rate can be reduced, and the life quality of patients is exactly improved after the diabetic foot patients are treated with roxadustat.

The invention relates to usage of Roxadustat in preparation of drugs for treating sepsis. In order to solve the problem of lack of therapeutic drugs for treating sepsis and organ dysfunction, such asheart dysfunction, liver heart dysfunction and the like, the invention provides novel usage of Roxadustat in preparation of drugs for treating sepsis as well as organ dysfunction, such as heart dysfunction, liver heart dysfunction and the like, thereby effectively reducing fatality rate of sepsis as well as treating organ dysfunction, such as cardiovascular dysfunction, liver dysfunction and the like, caused by sepsis.

The present invention provides crystalline Roxadustat Form-γ, crystalline Roxadustat Form-δ, process for the preparation of crystalline Roxadustat Form-γ, crystalline Roxadustat Form-δ and its pharmaceutical compositions thereof. The present invention also provides co-crystals of Roxadustat Form RLP, Roxadustat Form RNM and Roxadustat Form RU, process for their preparation and pharmaceutical composition thereof.

The invention relates to a crystallization process of a Roxadustat bulk drug with a controlled particle size. The process comprises the steps of salifying the Roxadustat (I) with alkali, filtering, heating, adding a first part of an acetic acid aqueous solution to adjust the pH value to 6.4-6.7, adding a Roxadustat seed crystal and a second part of the acetic acid aqueous solution, crystallizing, centrifuging, and drying to obtain the Roxadustat bulk drug with a controlled particle size. The particle size D (90) of the Roxadustat bulk drug prepared by the process method is 25-45 [mu] m, and the Roxadustat bulk drug meets the requirements of preparations and is suitable for industrial production.

The invention discloses application of an HIF2alpha agonist and an ACER2 agonist in preparation of a medicine for treating and / or preventing atherosclerosis. Wherein the HIF2alpha agonist can be an adipose cell HIF2alpha agonist, and the ACER2 agonist can be a visceral fat ACER2 enzyme activator. The invention also discloses an application of Roxadustat in preparing a medicine for treating and / orpreventing atherosclerosis. The HIF2alpha agonist, the ACER2 agonist and the Roxadustat can be used for inhibiting or alleviating the occurrence and development of atherosclerosis.

The invention belongs to the field of preparation of drug intermediates, and relates to a preparation method of an important intermediate 3e of roxadustat. According to the method, 3c is used as an initial raw material and reacts with a hydrogen-donating compound and palladium carbon or raney nickel in a solvent to prepare 3e, and the hydrogen-donating compound is selected from one or more of formate, formic acid, triethyl silicon hydrogen and the like; and the molar ratio of the hydrogen-donating compound to the 3c raw material is 1-100, preferably 5-50, and more preferably 10-30. The reaction conditions of the method are mild; high temperature and high pressure are not needed, the reaction can be carried out under normal pressure. The method is suitable for industrial amplification, andthe yield of the method is equivalent to that of a contrast patent of which the number is CN103435546B.

The invention relates to application of roxadustat in preparation of a drug for preventing and / or treating narcotic or drug addiction. The invention discloses that the roxadustat can prevent formation of narcotic or drug addiction behavior after being applied, and can promote regression of the narcotic or drug addiction behavior, so that the prevention and treatment of narcotic or drug addiction or dependence are realized.

The invention belongs to the technical field of chemical preparation, and discloses a method for synthesizing a roxadustat intermediate. The method comprises the following steps: mixing 4-bromo-2-methylbenzoic acid and a solvent to obtain a mixture 1, adding N-bromosuccinimide and an initiator into the mixture 1, performing uniform mixing to obtain a mixture 2, and performing a reaction to obtainthe roxadustat intermediate 5-bromophthalide. The method provided by the invention has the following advantages: the method for synthesizing the roxadustat intermediate provided by the invention adopts the 4-bromo-2-methylbenzoic acid as the reaction raw material, the raw material is simple and easy to obtain, the costs are low, the reaction is easy to control, and the final product 5-bromophthalide has a yield of 96.5% or more and purity of 98.5% or more.

The invention provides a preparation method of Roxadustat intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinecarboxylate (IV), comprising the step of subjecting 2-(1-(3-phenoxyphenyl)ethylimide)dimalonate (III) as a starting material to condensation and cyclization. The preparation method of the Roxadustat intermediate IV has the advantages that material is easy to obtain, operating steps are few, the process is simple, the reaction yield is high, atom utilization rate is high, and the method is easy for industrial production. The reaction general formula is shown in the specification.

The invention provides an application of rosustat in a medicine for inhibiting acute alcoholic fatty liver. Roxasstat can significantly inhibit liver injury and lipid accumulation caused by acute alcohol. According to the mechanism, rosustat plays a role in inhibiting mouse liver lipid accumulation mainly by regulating and controlling the expression of lipid synthesis key genes. The medicine is expected to become an effective medicine for clinically treating the alcoholic fatty liver.

The invention relates to a preparation method of roxadustat. In the method, methyl 4-hydroxy-7-phenoxyisoquinoline-3-formate and N,N,N',N'-tetramethyldiaminomethane as raw materials are reacted in glacial acetic acid and methyl 1-((dimethylamino) methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate is obtained after the reaction is finished; the obtained methyl 1-((dimethylamino) methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate is dissolved into glacial acetic acid, zinc is added, diluted hydrochloric acid is added, and after the reaction is finished, methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate is obtained; the obtained methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate is mixed with glycine, and dissolved into methanol, sodium methoxide is added, and after the reaction is finished, the target product roxadustat is obtained. The method is mild in reaction condition, simple and controllable in operation, low in preparation cost and suitable for large-scale industrial production, the obtained target product is high in purity, and the production requirements of enterprises are met.

The invention relates to a preparation method of an isoquinolinone compound. Specifically, the method for preparing the compound shown in the formula 2 comprises the step that a compound shown in a formula b reacts with a methylation reagent to obtain the compound shown in the formula 2. The method provided by the invention is used for preparing the isoquinolinone compound (such as Roxadustat), and has the excellent effects of reasonable route, convenience, feasibility, high yield, high purity, suitability for industrial production and the like.

The invention discloses a crystal form of rosustat, a preparation method of the crystal form, a pharmaceutical composition of rosustat and an application of rosustat in treating diseases such as chronic renal anemia. The structure of rosustat is as follows in the specification.

The invention discloses a preparation method of a roxadustat intermediate IV. The method comprises the following steps: 1, carrying out addition reaction on 4-bromo-phthalic anhydride (compound I) anda methyl Grignard reagent to obtain an intermediate II; 2, carrying out sodium borohydridereduction on the intermediate II first, and then, carrying outcyclization under an acid condition to obtain an intermediate III; and 3, carrying out an aryl alkylation reaction on the intermediate III and phenol to obtain the roxadustat intermediate IV. According to the preparation method of the roxadustat intermediate IV, the raw materials are simple and easy to obtain, a plurality of suppliers exist in China, and the cost is low; and methyl is introduced in advance, the methyl introduction process is mild in reaction condition, hydrogenation special reaction, ultralow temperature and other dangerous unit operation reactions are avoided, and the method is more suitable for industrial production.

The invention discloses a synthesis method of roxadustat and an intermediate thereof and the intermediate of roxadustat. Specifically, the invention discloses a synthesis method of a compound M1, which comprises the following step: under the action of an oxidizing agent, a compound SM and a compound SM-A are subjected to a reaction as shown in the specification. The method provided by the invention has the advantages of cheap and easily available raw materials, short reaction steps, high yield and simple post-treatment process, and is suitable for industrial production.