154 results about "Vildagliptin" patented technology

The invention relates to medical composition containing metformin and Vildagliptin and a preparation method thereof. The medical composition is formed by taking metformin chloride and Vildagliptin as medical active components and blending with pharmaceutically acceptable auxiliary materials; the invention adopts the metformin chloride and Vildagliptin as materials and adds auxiliary materials with some special kinds and proportions to prepare and develop diversified oral preparations such as tablets, capsules, granules, dispersible tablets, chewable tablets, buccal tablets, effervescent tablets, effervescent granules according to the technical method of the invention. The medical composition of the invention can be used for treating diabetes type II that can not be properly cured by alimentary control and sports and also for diabetes type II that can not be controlled by simply using metformin chloride or Vildagliptin.

The present invention provides a pharmaceutical composition for the prevention and treatment of a non-alcoholic fatty liver disease (NAFLD), containing an active ingredient selected from the group consisting of Compound 1 represented by formula 1, sitagliptin, vildagliptin, linagliptin or a pharmaceutically acceptable salt thereof. Further, the present invention provides a method for the prevention or treatment of a non-alcoholic fatty liver disease, including administering an effective amount of an active ingredient selected from the group consisting of Compound 1 represented by formula 1, sitagliptin, vildagliptin, linagliptin or a pharmaceutically acceptable salt thereof to a mammal including a human in need thereof.; Further, the present invention provides use of Compound 1 represented by formula 1, sitagliptin, vildagliptin, linagliptin or a pharmaceutically acceptable salt thereof, for manufacturing a pharmaceutical composition for the prevention or treatment of a non-alcoholic fatty liver disease.

The invention belongs to the field of drug synthesis and discloses a novel method for preparing vildagliptin. The process comprises the following steps: dehydrating N-fluorenylmethoxy carbony-L-prolinamide (raw material) to form nitrile; removing the Fmoc- protective group and carrying out N-chloracetylation to obtain an intermediate (S)-1-(chloracetyl)-2-cyan pyrrolidine; further carrying out condensation on the intermediate and 3-amino-1-adamantanol to obtain a coarse vildagliptin product; and recrystallizing to obtain a refined vildagliptin product. The process flow used for synthesizing vildagliptin is simple in method and low in impurity content, thereby facilitating industrial production of vildagliptin.

The invention relates to a process for preparing Vildagliptin by a one-pot method. The one-pot method is adopted, so the purification steps are reduced, the product yield is improved, and the process is particularly suitable for industrial production.

The invention belongs to the field of pharmaceutical preparations, and provides a compound tablet composition of vildagliptin and melbine and a preparation method thereof. The composition comprises an adhesive which accounts for 20-30% of the composition based on dry weight and has apparent viscosity of 2-4 mpas in 1% water solution. According to the provided composition, the compressibility of the melbine is improved and the compressibility of the vildagliptin is improved at the same time, the compressibility and the mobility of the powder are good, the between-run content difference of the prepared compound tablets is small, the tablets are qualified in friability and rapid in digestion, and the technological feasibility is high.

The present invention relates to an efficient synthesis method of vildagliptin. According to the method, L-prolinamide is adopted as a raw material, N-chloro acetylation and amide dehydration are performed to generate an intermediate (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile, and the (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile and 3-amino adamantanol are subjected to condensation in acetonitrile in the presence of an organic base to obtain the target product vildagliptin. According to the present invention, the synthesis method operation only requires the separation of the one key intermediate, and the method has characteristics of simple and feasible operation, high efficiency, environmental protection, and easy industrial production achieving.

The invention discloses a preparation method of high-purity vildagliptin, which comprises the following steps: carrying out nucleophilic substitution reaction on an intermediate (2S)-1-(2-chloracetyl)-2-pyrrolidine formonitrile and 3-amino-1-adamantanol in a certain reaction solvent by using potassium iodide as a catalyst and potassium carbonate as an acid-binding agent, carrying out after-treatment to obtain grease, and carrying out solvent crystallization to obtain a vildagliptin crude product; and refining the vildagliptin crude product by using a purified solvent to obtain the refined product. The synthesis method by controlling the vildagliptin crude product obtains favorable technical effects, and can obviously lower the impurity content in the vildagliptin crude product. A refinement technique different from the documents is adopted, and isopropanol and 2-butanone impurity removal is performed to obtain favorable technical effects, thereby obviously lowering the content of the main impurity 3-amino-1-adamantanol and vildagliptin bis-substituted impurity in the vildagliptin crude product. The vildagliptin purity detected by HPLC (high performance liquid chromatography) and GC (gas chromatography) is up to 99.8% or above, and the contents of the two impurities are respectively lower than 0.1%.

The invention relates to a vildagliptin composition. Specifically the composition comprises vildagliptin, (a) at least one medicinal diluent, (b) at least one disintegrating agent, and (c) lubricant, optionally comprises other pharmaceutical adjuvant, and does not use fatty acid magnesium salts as the lubricant. The composition has a better stability and drug dissolution.

The invention relates to a sugar-lowering drug composition and application thereof. The composition comprises 1) medicinal dosage of vildagliptin, 2) medicinal dosage of any one or combination of thiazolidinedione sugar-lowering drugs or medicinal salt thereof, sulfonylurea sugar-lowering drugs or medicinal salt thereof or biguanide sugar-lowering drugs or medicinal salt thereof and 3) B vitamins. The invention relates to application of the sugar-lowering drug composition to preparing the drugs for treating and / or controlling diabetes or diabetic complications. The composition can effectively overcome the defect that type 2 diabetes can not be controlled by singly taking the commonly used sugar-lowering drugs or vildagliptin in the prior art and simultaneously addition of the B vitamins is conductive to enhancing the treatment effect of the drug, effectively controlling the blood sugar, protecting the endothelial cell functions in a synergic manner, slowing rising of plasma homocysteine of the diabetes patients, especially the diabetes patients associated with chronic complications and reducing the diabetic complications.

The invention relates to a preparation method for Vildagliptin. The preparation method comprises the following steps: using L-prolinamide as a raw material, performing the dehydration reaction with cyanuric chloride, and generating (S)-2-cyanopyrrolidine; performing the salt forming reaction to the (S)-2-cyanopyrrolidine and hydrogen chloride, to obtain intermediate-1; enabling the intermediate-1 to react with chloroacetic acid under the conditions of using EDCI as a condensing agent, using HOBt as a catalyst, and using DIEA as an acid-binding agent, to obtain intermediate-2; enabling the intermediate-2 to react with 3-amino-1-adamantanol, to obtain the Vildagliptin, filtering, concentrating, crystallizing, and re-filtering to obtain a Vildagliptin crude product; and preparing the Vildagliptin finished product by the acetone refining. The preparation method is capable of providing a new method, and reducing the generation of by-products in each step. The content of the disubstitution product of the Vildagliptin by-product and the 3-amino-1-adamantanol are reduced to less than 0.1%, the yield and purity of the Vildagliptin are effectively improved, the raw materials are easily obtained, the conditions are moderate, and the preparation method is suitable for the industrial large-scale production.

The invention relates to a method for preparing 3-amino-1-adamantane alcohol. The method comprises the following steps of: adding amantadine hydrochloride into a nitrating agent in batches, performing reaction for 1 to 2 hours in an ice-water bath and performing reaction for 1 to 30 hours at room temperature to obtain yellowish liquid; pouring the yellowish liquid into ice, continuously reacting for 0.5 to 2 hours with stirring to obtain blue-green liquid; and adding solid base into solution obtained by the step 2 with stirring, keeping temperature below 80 DEG C, regulating pH to be between 10 and 12, performing reaction for 30 minutes with stirring, leaching, extracting reaction liquid by using dichloromethane, drying the obtained product with anhydrous sodium sulfate, steaming off the dichloromethane and performing recrystallization by using ethyl acetate to obtain white solid. The preparation method has the advantages of readily available starting raw materials, simple reaction operation, short route, environmental friendliness, easy industrial production and good application prospect, and also reduces cost for the synthesis of Vildagliptin serving as a medicament for treatingdiabetes; and the yield of products reaches 75 percent.

The invention relates to a pharmaceutical composition which takes metformin hydrochloride and vildagliptin as the active ingredients and the preparation method and usage thereof. The invention takes metformin hydrochloride and vildagliptin as the pharmaceutical active ingredients and mixed with pharmaceutically acceptable excipients to form the pharmaceutical composition. The invention can be used for diet control and the treatment of type 2 diabetes can not be controlled appropriately by movements, and the invention can also be used in the type 2 diabetes which can not be controlled by the single administration of metformin hydrochloride or vildagliptin. The contents of the invention take metformin hydrochloride and vildagliptin as the raw materials and are added with given type and proportion of excipients, then the invention is prepared and developed into tablets, capsules, granules, dispersion tablets, chew tablets, buccal tablets, effervescent tablets, effervescent granules and other various oral preparations according to the technical means illustrated by the invention.

The invention relates to a Vildagliptin impurity compound and a preparation method thereof, a detection method and application. The Vildagliptin impurity compound has a structure as shown in the formula (I), wherein R1 is polyhalogenated C1-C4 lower alkyl or CH2R3, and R3 is five-membered / six-membered heterocyclic radical containing an N atom. The heterocyclic radical can be optionally replaced with CN or CONH2. The compound, as a reference substance or standard substance of related substances, can be used in quality control of a Vildagliptin preparation.

The invention discloses a method for preparing a midbody (2S)-N-chloracetyl-2-cyano tetrahydropyrrole of vildagliptin, belonging to the field of medical technology. According to the method, L-proline is taken as the main starting material, the L-proline and chloroacetyl chloride are amidated so as to produce a midbody I(2S)-N-chloracetyl-2-carboxylic acid tetrahydropyrrole, the midbody I is amidated by carboxyl so as to obtain a midbody II (2S)-N-chloracetyl-2-amide tetrahydropyrrole, the midbody II is further dehydrated by amide so as to obtain the (2S)-N-chloracetyl-2-cyano tetrahydropyrrole. The method for preparing the midbody (2S)-N-chloracetyl-2-cyano tetrahydropyrrole of vildagliptin has advantages of short synthetic route, mild reaction conditions, environment protection, and low cost, and is applicable to mass production in factories.

The invention provides a method for preparing (S)-1-(2-halogenated acetyl)pyrrolidine-2-formonitrile as shown in the formula (I). Optionally in the presence of a diluent, (S)-1-(2-halogenated acetyl)pyrrolidine-2-formamide and a dehydrating agent propanephosphonic acid cyclic anhydride (T3P) react with each other. The invention also provides a method for preparing vildagliptin by using S-prolinamide involving the above reaction. The method for preparing the compound as shown in the formula (I) has the following advantages: use of expensive trifluoroacetic anhydride is not required, yield is increased, and cost is reduced; use of cyanuric chloride prepared from highly toxic raw materials is not required, and the reaction is more environmentally friendly; and an improved method for preparing vildagliptin is then obtained. In the formula (I) and formula (II), X1 is halogen.

The invention discloses a composition containing vildagliptin and metformin and a preparation method of the composition. The composition contains more than 20% of a binding agent in terms of dry weight, wherein the metformin is prepared by virtue of a fluidized bed in a mode of hot-melting granulating. According to the composition provided by the invention, the compressibilities and the liquidities of the vildagliptin and the metformin are improved, and the method is simple and convenient to operate, low in production cost, environment-friendly and efficient. A prepared composite tablet is qualified in friability and rapid to dissolve out.

The invention discloses a preparation method of a vildagliptin and metformin hydrochloride compound preparation. The method includes: subjecting metformin hydrochloride, an adhesive and vildagliptin to sieving mixing, performing dry granulation, adding a lubricant, conducting total blending, carrying out sampling detection, tabletting and other processes. The tablet prepared by the process solves the content uniformity problem of vildagliptin, also improves the tablet compressibility and fluidity, the friability and hardness are accord with the quality standards of Pharmacopoeia, and the stability is good. Also the method has the characteristics of simple operation and low production cost, and can realize industrialization.

The invention relates to a vildagliptin tablet and a preparation method thereof, belonging to the technical field of medicinal preparations. The vildagliptin tablet is prepare from vildagliptin, a diluent, a disintegrating agent, a lubricant, etc. According to verification results of a great amount of experiments, the vildagliptin tablet prepared in the invention and the preparation method thereof have the following substantial advantages compared with the prior art: vildagliptin amide impurity included in the vildagliptin tablet has stable quality in the processes of acceleration and long-term storage compared with an untreated vildagliptin tablet; and the preparation method is simple and can easily realize industrial mass production.

The invention relates to a sugar-lowering drug composition and application thereof. The composition comprises 1) medicinal dosage of vildagliptin and 2) medicinal dosage of any one or combination of thiazolidinedione sugar-lowering drugs or medicinal salt thereof, sulfonylurea sugar-lowering drugs or medicinal salt thereof and biguanide sugar-lowering drugs or medicinal salt thereof. The invention relates to application of the sugar-lowering drug composition to preparing the drugs for treating and / or preventing diabetes or diabetic complications. The composition can effectively overcome the defect that type 2 diabetes can not be controlled by singly taking the commonly used sugar-lowering drugs or vildagliptin in the prior art and can reduce the diabetic complications.

The invention discloses a preparation method of vildagliptin, and the preparation method comprises the following steps: 1) in the presence of a first solvent and a reducing agent, a formula II compound reacts with a formula III compound to obtain a formula IV compound; 2) in the presence of a second solvent, an alkali and a halide, the formula IV compound reacts with a formula V compound to obtain a formula VI compound; and 3); in the presence of a third solvent, the vildagliptin is obtained by debenzylation of the formula VI compound. The preparation method avoids generation of bi-substituted and other by-products of synthesis methods in the prior art, has the advantages of simple operation and low cost, and is suitable for industrial production.

The invention provides a vildagliptin preparation method, and relates to a drug compound preparation method. According to the preparation method, L-proline is adopted as a raw material, and is subjected to reactions such as N-chloroacetylation, carbonyl amination and nitrile formation through amide dehydration to obtain an intermediate (S)-1-(2-chloroacetyl)pyrrolidine-2-formonitrile; and an amantadine hydrochloride is adopted as a raw material, and is subjected to mixing acid nitration and alkali hydrolysis to obtain the other intermediate 3-amino-adamantanol, and the two key intermediates are subjected to condensation to obtain the target product vildagliptin. The preparation method has characteristics of simpleness, easy performing, simple reaction operation, convenient time and environmental protection, and is suitable for industrial production.

The invention discloses a novel preparation method of Vildagliptin. The preparation method comprises that L-prolinamide as a raw material, chloroacetyl chloride and tetrahydrofuran undergo an acylation reaction, the reaction product is subjected to suction filtration, the filtrate and trifluoroacetic anhydride directly undergo a dehydration reaction without filtrate separation purification to produce (-)-(2S)-1-chloroacetylpyrrolidine-2-carbonitrile (II), the refined (-)-(2S)-1-chloroacetylpyrrolidine-2-carbonitrile, 3-amino-1-adamantanol (III), potassium carbonate and potassium iodide undergo a reaction to produce (-)-(2S)-1-[[(3-hydroxytricyclo[3.3.1.1[3,7]]dec-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (I) in acetone, and the (-)-(2S)-1-[[(3-hydroxytricyclo[3.3.1.1[3,7]]dec-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (I) is refined by calcium double salt, ethyl acetate and butanone to form pure Vildagliptin (compound wg-0). The improved synthesis technology has the advantages of less reaction steps, operation simpleness, after-treatment simpleness, low employee cost, equipment cost and time cost, high yield, high product quality and industrialization feasibility.

The invention provides a pharmaceutical composition containing vildagliptin and metformin. In the pharmaceutical composition, vildagliptin is good in content uniformity, high in dissolution rate and stable in product. A preparation method of the pharmaceutical composition comprises the steps that metformin hydrochloride and an adhesive are prepared into granules through a fluidized bed granulation technology; the granules, vildagliptin and a filler are mixed to be uniform, and then dry granulation is conducted; the mixture is mixed with a lubricant, and tablets are prepared. By means of the fluidized bed granulation technology, the fluidity and compressibility of metformin hydrochloride are greatly improved, the granularity of vildagliptin is controlled to be within a certain range, direction contact of metformin hydrochloride and vildagliptin is reduced, and degradation of vildagliptin is reduced; by means of dry granulation, the content uniformity, a tablet weight difference and the like of the granules all meet the requirements. By means of the preparation process, compound preparations with small differences between batches can be obtained, the friability, content uniformity and stability of the tablets all meet the requirements, and the pharmaceutical composition can be subjected to scale-up production in a workshop.

The invention discloses a preparation method of isomer impurities of vildagliptin, and relates to the technical fields of medicine and chemical industry. The preparation method comprises the steps: S1: enabling D-prolinamide (I) serving as a raw material to react with chloroacetyl chloride to obtain a reaction product (II), and then enabling the reaction product (II) to react with trifluoroacetic anhydride to obtain a reaction product (III); S2: enabling the reaction product (III) to react with 3-amino-1-adamantanol to generate a target product (IV). The preparation method disclosed by the invention has the advantages that the preparation process is simple, the operation is simple and convenient, reaction time is short, and the post-treatment purification is simple and effective, which is beneficial to industrialized production. The purity of manufactured impurities of the vildagliptin is high and is as high as 99.1% through HPLC (high-performance liquid chromatography) detection. By further studying the isomer impurities of the vildagliptin, the quality of the vildagliptin can be better controlled, and the drug safety is improved.

The invention provides a preparing process for a vildagliptin / metformin hydrochloride compound preparation. The preparing process comprises the following steps: (1) adding vildagliptin, metformin hydrochloride, magnesium aluminosilicate and hydroxy propyl cellulose into ethanol or isopropanol to form a dispersion liquid; (2) spraying and drying the dispersion liquid obtained in the step (1) to obtain spherical active matter-containing powder; (3) sieving and selecting the active matter-containing powder with particle size of 75 to 150 microns, which is obtained through the method, adding 1% of magnesium stearate, and directly pressing to form a tablet. The preparing process has the advantage that the unexpected satisfaction effects of uniform fluidity of integral materials and storage stability of the preparation are realized.

The invention discloses a method for detecting enantiomer in a vildagliptin midbody. The chromatographic conditions of the method are that a CHIRALPAK IC chromatographic column is adopted, the column temperature is 25-40 DEG C, the detection wavelength is 210nm, the mobile phase is a mixture of n-butyl alcohol, ethanol and diethylamine, and the flow velocity is 0.8-1.2mL / min. By adopting the method disclosed by the invention, quantitative analysis on the enantiomer (2R)-1-(2-chloracetyl)-2-pyrrolidine formonitrile in (2S)-1-(2-chloracetyl)-2-pyrrolidine formonitrile can be implemented, the enantiomer can be effectively separated and detected, peak patterns are in symmetry without trailing, aspects such as the separation degree, the specificity, the limit of quantitation, the detection limit, the linearity, the precision degree, the accuracy degree, the solution stability and the durability need to be specifically verified, various verification results meet requirements of related rules and guidance principles, and a good detection effect can be achieved.

The invention relates to a method for analyzing and measuring a Vildagliptin intermediate-5 enantiomer through high performance liquid chromatography. The method comprises the steps that a CHIRALPAK-AD-H type chiral chromatographic column is adopted, and after normal hexane-ethyl alcohol-methyl alcohol is adopted as a flow phase for chromatographic column separation, an ultraviolet detector is used for detecting the Vildagliptin intermediate-5 enantiomer. By means of the method, the enantiomer in Vildagliptin intermediate-5 can be effectively detected, and the quality of the Vildagliptin intermediate-5 can be better ensured. The method has the advantages of being high in specificity, high in accuracy and good in reproducibility.

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of an important vildagliptin intermediate (S)-1-(2-chloracetyl) pyrrolidine-2-methyl cyanogens. The synthetic method has the advantages that the intermediate is not separated in a reaction process, the workload is reduced, the operation is easy; di-tert-butyl dicarbonate ester is used as a condensing agent of amide, so that the production cost is reduced, and POCl3 is used as a dehydrating condensation agent, so that the reaction yield is increased.

The invention specifically relates to a vildagliptin compound and a preparation method thereof, belonging to the technical field of medicine. The vildagliptin compound with a novel crystal form obtained in the invention has the advantages of high purity and good stability, wherein maximal impurity content is less than 0.05%. The preparation method for the vildagliptin compound has good reproducibility and enables the purity and the crystal form of the vildagliptin compound to be perfectly reproduced when carried out in pilot scale. The invention also relates to application of the vildagliptin compound with the novel crystal form is preparation of a drug used for treating diabetes type 2.