24 results about "Roxadustat" patented technology

This invention provides an intermediate impurity of roxadustat and a method for preparing the impurity. The method for preparing roxadustat impurity I includes: dissolving compounds II and III in an organic solvent, and conducting a coupling reaction under a nitrogen atmosphere and a reaction temperature of 40–60°C in the presence of a base to obtain roxadustat impurity I. This preparation method features mild reaction conditions, simple operation, low time cost, high yield, and high product purity. It can efficiently obtain sufficient quantities of high-purity impurity reference standards, playing a positive role in the quality control of roxadustat intermediates and roxadustat active pharmaceutical ingredients, and has good application prospects.

The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of a lutrombopag intermediate, which comprises the step of preparing an intermediate I p-toluenesulfonate by using a new salifying system.

The invention discloses a rosaxostat orally disintegrating tablet and a preparation method thereof. The preparation method of the orally disintegrating tablet is selected from one of a freeze-drying method, a tabletting method and a melting method. The prescription of the freeze-drying method comprises the rosaxostat or rosaxostat salt, a skeleton supporting agent, an adhesive, a suspending aid and a surfactant. According to the preparation formula and the preparation process, the defect that the content uniformity of the prepared tablets is poor due to the fact that the uniformity of intermediate liquid medicine is poor in the preparation process can be overcome, and the disintegration time limit of the rosaxostat orally disintegrating tablets, especially the rosaxostat freeze-dried orally disintegrating tablets, is further prolonged; the medicine is especially suitable for old people, children, patients with dysphagia and people with inconvenience in taking water to take medicine; the bioavailability is high; the rosaxostat orally disintegrating tablet is simple in material, moderate in tablet weight, good in appearance, good in taste, fast in disintegration, simple in preparation process and suitable for industrial mass production.

The invention provides a preparation method of a rosaxostat impurity. The preparation method specifically comprises the following steps: S1, carrying out a substitution reaction on a compound 14-hydroxy-7-phenoxy isoquinoline-3-methyl formate and NCS under an acidic condition to generate an impurity A; s2, carrying out methylation reaction on the impurity A and a compound 2-methylboronic acid under an alkaline condition to generate an impurity B; s3, carrying out condensation reaction on the impurity B and a compound 3, namely glycine methyl ester hydrochloride to generate an impurity C. The synthesis method adopted by the invention is simple, the obtained sample is high in purity, and the synthesis method has great significance in process research, impurity analysis and quality control of the rosaxostat.

1. Name of the product of this design: Packaging box (Rosuvastatin Capsules). 2. Application of this design product: for pharmaceutical packaging. 3. The key design point of this design product lies in the combination of shape and pattern. 4. The picture or photo that best illustrates the design points: three-dimensional picture.

1. Name of the product in this design: Drug Packaging Box (Roxadustat Capsules). 2. Purpose of this design: for product packaging. 3. The key design features of this product are the combination of pattern and color. 4. The picture or photo that best illustrates the key design points: Design 1 front view. 5. The design for which protection is sought includes color. 6. Design 1 is designated as the basic design.

The present invention provides a novel process for preparing the compound I containing the compound [I(A)] (vadadustat) and the compound [I(B)] (roxadustat) which are useful as a medicine in an industrially advantageous manner, and a process for preparing the compound I which comprises reacting the compound (a1) or the compound (b1), the compound (2) or salts of the compound (2), with carbon monoxide in the presence of a palladium catalyst, in the presence or absence of a ligand, in the presence of a base, in a solvent to prepare the compound I (wherein structure formulae of the compound (a1), the compound (b1) or the compound (2), and the definitions of groups in the formulae are defined in the description.

Disclosed are a method for the synthesis of roxadustat and an intermediate thereof, and an intermediate thereof. In particular, disclosed is a method for the synthesis of compound M1, the method comprising the following steps: carrying out a reaction as shown below between compound SM and compound SM-A under the action of an oxidizing agent. The method of the present invention uses cheap and easily available raw materials, has short reaction steps, produces a high yield, has simple and convenient post-treatment procedures, and is suitable for industrial production.

The application provides a method for preparing roxadustat intermediate III, i.e. 3-methyl-5-phenoxyisobenzofuran-1(3H)-one, which comprises the following steps: generating 5-bromo-3-methylisobenzofuran-1(3H)-one through self-cyclization by taking 4-bromo-2-ethylbenzoic acid as a raw material; and generating roxadustat intermediate III through carbon-oxygen coupling reaction of 5-bromo-3-methylisobenzofuran-1(3H)-one and phenol. The method can significantly shorten the reaction time, improve the reaction yield, and simplify the reaction conditions, and is suitable for industrial production.

The present invention provides a new crystalline form of Roxadustat which is chemically known as 2-[(4-Hydroxy-l-methyl-7-phenoxy- iso quinoline-3-carbonyl)-amino]-acetic acid and preparation of its stable crystalline polymorph "Form X".

The invention relates to a ribosilil precursor and a continuous flow preparation method of ribosilil. The continuous flow preparation method of the ribosilil comprises the following steps: S1, providing a reaction solution I; the reaction liquid I contains a ribosilil precursor; s2, reacting the reaction liquid I and the feed liquid C in a second microreactor to obtain a reaction liquid II; the feed liquid C is an acid solution; s3, carrying out a reaction on the reaction liquid II and a feed liquid D; the feed liquid D is an alkali solution. The method is good in yield, the ribosilil with the purity of 99% or above can be obtained by refining and purifying the obtained crude product when the ribosilil is prepared through the method, and the method is easy to operate, high in safety and short in production period.

The application relates to the technical field of roxadustat, and particularly discloses a preparation method of roxadustat, which comprises the following steps: S1, taking 4-bromobenzyl bromide as a starting raw material, refluxing 4-bromobenzyl bromide and sodium methoxide in methanol to prepare an intermediate 2; S2, subjecting the intermediate 2 to a Friedel-Crafts acylation reaction with acetic anhydride to prepare an intermediate 3; S3, subjecting the intermediate 3 to an Ullmann coupling reaction with phenol in toluene by using glycine copper as a catalyst to prepare an intermediate 4; the starting raw material is 4-bromobenzyl bromide, the raw material is easy to obtain and low in price, a low-cost conventional reagent is used as a catalytic system, and cheap catalytic systems are used in key reactions, and low-cost alkali-solvent combinations are selected for steps such as aminolysis, so that the preparation cost is greatly compressed from the aspects of raw materials and reagents.

The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a class of NO donor type roxadustat derivatives, a preparation method, a composition and purposes. In the application, an ester group is used to connect an NO donor into a roxadustat structure to synthesize the NO donor type roxadustat. The NO donor type roxadustat can release NO rapidly under the action of enzymes in vivo, and exert the beneficial pharmacological activity of NO. Then, the released roxadustat can stabilize HIF-1 alpha, activate the downstream related genes of HIF-1, and exert the effects of inducing brain tissue hypoxia tolerance, promoting angiogenesis and promoting the survival of neurons. Thus, a new drug with the pharmacological activities of both nitric oxide molecules and roxadustat is obtained, and the new drug can exert better effects of preventing cerebral ischemia, treating and protecting brain tissues after cerebral ischemia, and improving the prognosis.

The present application relates to a compound preparation for treating alopecia areata, active ingredient A is a direct or indirect EPO receptor agonist, active ingredient B is tofacitinib or its pharmaceutically acceptable salt, and the EPO receptor agonist is preferably roxadustat. The beneficial effect is that roxadustat and tofacitinib or its pharmaceutically acceptable salt are both limited when used alone for alopecia areata treatment, but they act on different target points in the pathogenesis of alopecia areata respectively, so they are made into a compound preparation, the key signal pathway in the pathogenesis of alopecia areata is inhibited by roxadustat to compensate for the defect of tofacitinib in insufficient curative effect on moderate and severe patients from the etiology, and the hair repair effect of tofacitinib is improved from the symptom by the good hair growth promoting effect of roxadustat, the curative effects of the two are complementary, the alopecia areata is treated both from the etiology and the symptom, and the side effect risk can be reduced by appropriately reducing the dose of tofacitinib according to the synergistic effect.

The present application relates to the technical field of organic chemistry, and provides a roxadustat intermediate, a preparation method thereof and a preparation method of roxadustat.The roxadustat intermediate provided by the present application has high activity, can be hydrolyzed at the same time of ring closure, and does not need additional protection and deprotection steps of amino group, thereby shortening the synthesis route.The preparation method of roxadustat provided by the present application has a short synthesis route, and roxadustat can be prepared through 5 reaction steps, so that the production efficiency of roxadustat can be significantly improved;the reagent used in the present application is cheap, and can greatly reduce the production cost and the amount of solid waste and waste water;the obtained roxadustat product is easy to separate and purify, which is beneficial to reduce the refining times, improve the yield and production efficiency.

The application provides a Roxadustat intermediate and a preparation method thereof, and relates to the technical field of organic synthesis. The preparation method comprises the following steps: condensation of m-phenoxybenzaldehyde and an amino acid under catalysis of an alkali to generate an imine, reduction of the imine to obtain an amine, ring formation of the amine, hydrolysis, Friedel-Crafts acylation, ring opening, oxidation and esterification to obtain a target product. The synthesis line of the application is novel, all the raw materials and reagents used are easy to obtain or prepare, no high-risk and high-pollution reagents are used, the application is safe, environment-friendly, the reaction condition is mild, the operation is convenient and controllable, the Roxadustat intermediate prepared has high purity and high yield, has obvious cost advantage, and is suitable for industrial production.

The application discloses a preparation method of Roxadustat, which comprises the following steps: firstly, condensing compound 1 with a condensing agent under the action of an organic base to obtain a hydroxyl acylation intermediate; and secondly, directly coupling the hydroxyl acylation intermediate with methyl boronic acid under the catalysis of a catalyst to obtain a key intermediate compound 2. The improvement avoids the use of phosphorus oxychloride or phosphorus tribromide, effectively reduces the generation of three wastes, shortens the reaction steps, and improves the reaction yield. In the condensation step with a glycine segment, glycine sodium is used to replace glycine, and the amidation reaction of the glycine sodium with the intermediate compound 2 is studied to obtain the final product roxadustat 3. The improvement also greatly reduces the alkaline decomposition by-product of the intermediate compound 2, improves the reaction yield and the purity of the finished product.

The application provides a preparation method of roxadustat, and the roxadustat (compound 1) is prepared from 4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (compound 2) through condensation reaction with N,N-dimethylformamide dimethyl acetal, reduction reaction and ammonolysis reaction. The synthesis method has the advantages of short steps, low cost, safety, environmental protection, simple operation and industrialization value. The roxadustat prepared by the method has good quality, and can be used for preparing roxadustat preparations for clinical use.

The application provides a preparation method of a key intermediate 4-hydroxy-1-methyl-7-phenoxy-3-isoquinoline formate (LT-D3) of roxadustat, which is prepared from 3-oxo-3-(4-phenoxyphenyl) propionate (MQC) through aldehyde groupization, imidization and reduction reaction. The method is novel, the synthesis line is relatively simple, all raw materials and reagents used are easy to obtain or prepare, the reagent used in the imidization step, substituted aniline, can be obtained through a reduction reaction, the cyclic utilization of the aniline reagent can be realized, the atomic economy of green chemistry is realized, no high-risk and high-pollution reagent is used in the preparation method, the method is safe, environment-friendly, the reaction condition is mild, the operation is convenient and controllable, the prepared roxadustat intermediate LT-D3 has good purity and yield, and is suitable for industrial production.

The application relates to the field of biological medicine, and discloses application of a treatment target in preparation of a drug for treating heart function after myocardial infarction, and the treatment target is NR1D1. The application discloses that NR1D1 is a key target for treating heart dysfunction after myocardial infarction, and it is proved that by exciting NR1D1, the heart function can be significantly improved, the myocardial injury can be reduced, the fibrosis and cell apoptosis can be inhibited, NR1D1 plays a protection role by directly activating RABGAP1L, a "HIF-PHIs-NR1D1-RABGAP1L" signal shaft is formed, a new target and mechanism are provided for the treatment of myocardial infarction, an experimental basis is provided for a new use of Roxadustat in the protection of heart function after myocardial infarction, and the application has a good clinical application prospect.

The objective of the present invention is to provide a method for preparing Roxadustat that economically viable, suitable for industrial-scale production and achieving high purity and high yield.

The application provides a Roxadustat intermediate and a preparation method thereof, and relates to the technical field of organic synthesis. The preparation method comprises the following steps: condensation of m-phenoxybenzaldehyde and an amino acid under catalysis of an alkali to generate an imine, then reduction to obtain an amine, and then hydrolysis, substitution, Friedel-Crafts acylation, substitution and aromatization to obtain a target product. The synthesis line of the application is novel, all the raw materials and reagents used are easy to obtain or prepare, no high-risk and high-pollution reagents are used, it is safe and environmentally friendly, the reaction conditions are mild, the operation is convenient and controllable, the prepared Roxadustat intermediate has good purity, and can be applied to industrial production.

The application belongs to the technical field of medicine synthesis, and particularly relates to a Roxadustat intermediate compound and a preparation method and application thereof. The compound is prepared by ring formation of acryloyl glycine methyl ester and m-phenoxyphenylacetone oxime; the reaction condition is mild, and the yield and purity are relatively high. The compound is used for preparing a key intermediate (1-methyl-4-hydroxy-7-phenoxyisoquinoline-3-carbonyl) glycine methyl ester of Roxadustat, and has relatively high reaction stability, and the obtained product has relatively high yield and purity, and is suitable for industrial production.

The invention provides blood vessel promoting and antibacterial double-effect composite bone cement and a preparation method thereof, and belongs to the technical field of medical biological materials. The preparation method comprises the following steps: carrying out esterification reaction on methacrylic anhydride and hydroxyl of bacterial cellulose (BC) in anhydrous N, N-dimethylformamide to prepare modified cellulose (BC-MA) of which the surface contains methylacryloyl; the preparation method comprises the following steps: mixing BC-MA with an ethanol solution containing Roxadustat, and carrying out vacuum drying, so as to obtain a medicine carrying material BC-MA (at) Roxa; then spraying a high-concentration gentamicin sulfate aqueous solution on the BC-MA-coated Roxa, and carrying out freeze drying and grinding, so as to obtain a double-drug carrier BC-MA-coated Roxa-coated Genta; and mixing the powder with PMMA bone cement powder in proportion, adding a liquid-phase monomer, stirring and curing to obtain the BC-MA-coated Roxa-coated Genta / PMMA composite bone cement. The BC-MA (at) Roxa (at) Genta / PMMA composite bone cement prepared by the invention has relatively high porosity and connectivity, high drug loading capacity, stable release process and long duration time. The material realizes the functionalization of antibiosis and blood vessel promotion, and provides good biological activity and tissue integration performance for bone repair.