56 results about "Trelagliptin" patented technology

The present invention relates to solid forms of trelagliptin, a preparation method therefor and applications thereof, and relates specifically to six new solid forms of the dipeptidyl peptidase-4 inhibitor trelagliptin and preparation methods therefor, as well as to pharmaceutical compositions comprising said solid forms of trelagliptin, and uses of same in the preparation of medicines for the treatment of diseases mediated by dipeptidyl peptidase-4.

The invention discloses a method for measuring related substances in succinic acid Trelagliptin raw materials and relates to the field of analytic chemistry. According to the method, high performance liquid chromatography is adopted, a sample solution is injected into a high performance liquid chromatograph, and the related substances in the succinic acid Trelagliptin raw materials are measured; according to chromatographic conditions, a 100-5C18 chromatographic column of the Kromasil company is adopted as a chromatographic column, a flowing phase A and a flowing phase B are both a mixed solution of an acid aqueous solution and an organic solvent, the sum of the volume percentage of the flowing phase A and the volume percentage of the flowing phase B is kept 100% all the time, and linear gradient elution is performed. According to the method, the 100-5C18 chromatographic column of the Kromasil company is adopted, the gradient elution program of the flowing phases is optimized, and the related substances in the succinic acid Trelagliptin raw materials can be effectively separated. The method solves the separation and measurement problem of the related substances in the succinic acid Trelagliptin raw materials, and therefore it is guaranteed that the mass of the succinic acid Trelagliptin raw materials is controllable.

The invention discloses a trelagliptin and a preparation method of succinate thereof. The preparation method includes the following steps that a trelagliptin intermediate II and a trelagliptin intermediate III perform nucleophilic substitution reaction in an organic solvent in the presence of phosphate and a phase transfer catalyst to obtain trelagliptin I, and then trelagliptin I reacts with the succinate to produce salt. The operation process of the preparation method is simple and safe, special devices are not needed, the impurity contents of bis-substituted and primary amine substituted isomers can significantly reduced, only one-time recrystallization is needed, the purity of the obtained trelagliptin succinate I' can be above 99.5%, the impurity contents of the bis-substituted and primary amine substituted isomers are both below 0.05%, the contents of all the other impurities are all below 0.05%, the prepared trelagliptin succinate I' is high in purity, the production cost is low, and the trelagliptin and the preparation method are suitable for industrialized production.

The invention provides a novel high-purity trexagliptin crystal. The high-purity trexagliptin prepared by the present invention can form a salt with an acid to obtain a high-purity trexagliptin salt, and at the same time provide a high-purity trexagliptin crystal preparation and purification crystallization process, including the following steps: Step 1: Condensation reaction, that is, compound 1 and (R)-3-aminopiperidine dihydrochloride 2 are used as raw materials, and are heated to reflux in an organic solvent and in the presence of a base to undergo a condensation reaction to obtain the crude product of trexagliptin; Step 2: Recrystallization, that is, recrystallize the crude trexagliptin obtained in step 1 in an organic solvent to obtain high-purity trexagliptin. The method of the invention has the advantages of simple operation, high yield and low cost, and is very suitable for large-scale industrial production.

The invention discloses succinic acid trelagliptin orally-disintegrating tablets and a preparing method thereof. The orally-disintegrating tablets are a medicine composition prepared from succinic acid trelagliptin, filler, a disintegrating agent, a wetting agent, a binding agent, a flavoring agent and a lubricating agent. Wet granulation and tabletting methods are adopted for the preparing method. The succinic acid trelagliptin orally-disintegrating tablets are simple in preparing process, low in cost, convenient to take, quick in effect taking and high in bioavailability, the medicine taking compliance of patients can be improved through the dosage form, and treatment on diseases is facilitated.

The invention provides a method for determining related substances in Trelagliptin tablets, and relates to the field of analytical chemistry. The method comprises the steps that a high-performance liquid chromatography method is adopted, a sample solution is injected into a high-performance liquid chromatographic instrument, determination of the related substances in the Trelagliptin tablets is completed, and the chromatographic conditions are that a chromatographic column takes silica gel of which the surface is provided with electric hybrid particles as a filler, a mobile phase A is an acidic aqueous solution, a mobile phase B is an organic solvent, the sum of the volume percent of the mobile phase A and the volume percent of the mobile phase B maintains 100% all the time, and linear gradient elution is conducted. According to the method for determining the related substances in the Trelagliptin tablets, an Xselect C18 chromatographic column is adopted, optimization is conducted on the mobile phase gradient elution program, and the related substances in the Trelagliptin tablets can be effectively separated. The separation determination problem of the related substances in the Trelagliptin tablets is solved, and therefore it is guaranteed that the quality of the Trelagliptin tablets is controllable.

The invention discloses a synthetic method of trelagliptin, trelagliptin synthesized through the method and a trelagliptin synthesis intermediate. The synthetic method of trelagliptin comprises the following steps: 1, taking 2-hydroxymethyl-4-fluorobenzonitrile as a starting raw material, and conducting a chlorination reaction, so that 2-chloromethyl-4-fluorobenzonitrile is obtained; 2, taking the 2-chloromethyl-4-fluorobenzonitrile as an intermediate, and conducting a condensation reaction, so that 2-[(6-chlorine-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-4-fluorobenzonitrile is obtained; 3, taking the 2-[(6-chlorine-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-4-fluorobenzonitrile as an intermediate, and conducting an ammonolysis reaction, so that trelagliptin alkali is obtained. By means of the method, use of high-toxicity copper cyanide is avoided, safety of the synthesis process is improved, environment friendliness is achieved, the formed chloro intermediate is more stable, and no irritation is caused.

The invention relates to a method for preparing trelagliptin. The method comprises the following steps: 1) in a reaction solvent, adding 2-(6-chlorine-3-methyl-2,4-dione-3,4-dihydropyrimidine-dihydro-1-methyl)-4-F-benzonitrile into R-3-piperidinamine dihydrochloride, dropwise adding 1,8-diazabicyclo[5,4,0]-undec-7-ene in ice bath, at temperature of 15-25 DEG C, insulating the materials for reacting for 2 hours, 2) using hydrochloric acid to adjust a reaction solution to acidity, 3) adding an organic solvent and adjusting a pH value of a water phase to alkalescence, extracting the material to obtain a trelagliptin crude product, and 4) using a solvent for recrystallization to obtain trelagliptin. The obtained trelagliptin can effectively control chromatographic purity being no less than 99.0% and yield being no less than 75%, process is simple, and cost is low.

The invention discloses a method for separating and analyzing trelagliptin succinate and preparation related substances thereof. According to the method, the chromatographic conditions comprise that an octadecyl bonded silica gel is adopted as a stationary phase, a buffer liquid is adopted as a mobile phase A and an organic solvent is adopted as a mobile phase B to carry out gradient elution, and the gradient elution conditions comprise that the mobile phase A is 85-50 (V%) and the mobile phase B is 15-50 (V%) at the time of 0-10 min, the mobile phase A is 50 (V%) and the mobile phase B is 50 (V%) at the time of 25-30 min, and the mobile phase A is 85-50 (V%) and the mobile phase B is 15-50 (V%) at the time of 31-35 min; the sample solution preparation comprises that the sample to be detected is prepared into the sample solution by using the mobile phase A; and separating and analyzing are performed, wherein the sample solution is injected into a high performance liquid chromatography so as to complete the detection of the trelagliptin succinate and the preparation related substances thereof. With the method of the present invention, the trelagliptin and the related substances can be rapidly and effectively separated under the same chromatographic conditions. The detection method of the present invention has advantages of high specificity, high precision, strong accuracy, convenient operation, and effective control of drug quality.

The present invention relates to a trelagliptin succinate crystal form A preparation method, and belongs to the technical field of the chemistry. The technical scheme comprises: preparing a trelagliptin fine product, and preparing a trelagliptin succinate bulk drug. The invention provides the trelagliptin succinate crystal form A preparation method suitable for industrial production, wherein the purity of the product prepared through the method is more than 99.95%; and the used single solvent anhydrous ethanol can be recovered and applied, is the optimal solvent for preparing the trelagliptin succinate crystal form A, is the bulk drug refining solvent recommended in ICH, and has characteristics of low prices and environmental protection.

The invention belongs to the technical field of medicine analysis and particularly relates to a succinic acid trelagliptin raw medicine and a testing method of a preparation enantiomer thereof. A chiral chromatographic column with the silica gel surface coated with ADMPC as filler is used, and the uccinic acid trelagliptin enantiomer is measured with a lower alcohol mixed solution and lower aliphatic amine or lower alcohol amine as mobile phases. The method is easy and quick to operate, good in reproducibility and high in sensitivity.

The invention provides a preparation method of succinic acid Trelagliptin tablets. The method includes: taking succinic acid Trelagliptin, adding sorbitol, microcrystalline cellulose and crosslinking sodium carboxymethyl cellulose, mixing, placing mixture under a condition with certain temperature and relative humidity, moving into a vacuum kettle, rising the temperature under a vacuum condition, adding binder, performing wet granulation, drying obtained granules in a fluidized bed granulation coating machine to obtain dried granules, adding lubricant into the dry granules, mixing, tableting, and coating to obtain the succinic acid Trelagliptin tablets. The preparation method has the advantages that the succinic acid Trelagliptin tablets prepared by the method is stable in quality and good in in-vitro dissolution performance, the method is simple in production process, and large-scale industrial production can be achieved.

The invention discloses a preparation method for trelagliptin and belongs to the field of organic synthesis. The preparation method comprises the following steps: (1) taking methylurea and diethyl malonate as initial raw materials and performing cyclization and chlorination reaction, thereby acquiring 3-methyl-6-chlorouracil; (2) acquiring 2-(6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-methyl)-4-fluorobenzonitrile from the nucleophilic substitution reaction of 3-methyl-6-chlorouracil and 2-bromine methyl-4-fluorobenzonitrile; (3) generating a target compound (R)-2-((6-(3-aminopiperidines-1-group)-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-group) methyl-4-fluorobenzonitrile (trelagliptin) through the reaction of 2-(6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-methyl)-4-fluorobenzonitrile and (R)-3-aminopiperidine. The preparation method has the characteristics of low-cost and easily acquired initial raw materials, convenient after-treatment, mild condition, operation convenience, and the like.

The invention provides a trelagliptin clathrate, which is composed of trelagliptin and cyclodextrin or derivatives of cyclodextrin, and the weight ratio of trelagliptin to cyclodextrin or derivatives of cyclodextrin is 1:1-1:30. The invention also provides a preparation method of the trelagliptin clathrate. According to the preparation method, cyclodextrin or derivatives of cyclodextrin is taken as the subject, trelagliptin is taken as the object, and through the clathration in the presence of a solvent, trelagliptin is included or embedded into cyclodextrin or derivatives of cyclodextrin to from the clathrate. The invention also provides an application of the trelagliptin clathrate in the preparation of drugs for treating diabetes. The trelagliptin clathrate is a new solid state of trelagliptin, the problems of multiple crystal forms or mixed crystals of trelagliptin are solved, thus the production technology is simplified, at the same time, trelagliptin clathrate has the advantages of increased water solubility and good stability, moreover, the preparation method has the advantages of simple and convenient operation, little material loss, and low cost.

The invention belongs to the technical field of medicinal chemistry and particularly relates to a preparation method of Trelagliptin. The equation is shown in the specification. In the method, 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-methyl)-4-fluorobenzonitrile and (R)-3-aminopiperidine dihydrochloride are subjected to a normal-pressure reaction in a single organic solvent or a mixed solvent under the alkaline condition of an acid-binding agent, and then a Trelagliptin compound is obtained. By means of the method, a high-pressure reaction is avoided, and thus reaction safety is greatly enhanced. The reaction condition of the method is mild and easy to control, and the method can be applied to industrial production and preparation of Trelagliptin.

The invention provides a succinic acid trelagliptin solid preparation and a preparation method thereof. The succinic acid trelagliptin solid preparation comprises 13-84wt% of succinic acid trelagliptin and 10-84wt% of mixture of mannitol and pregelatinized starch. The preparation method of the solid preparation is wet granulation and comprises the following concrete processes: (1) uniformly mixing succinic acid trelagliptin, a diluting agent and a disintegrating agent, then adding a wetting agent for wet granulation, and drying to obtain a mixture I; and (2) adding a lubricating agent into the mixture I, totally blending, and tabletting. According to the solid preparation, by wet granulation of the raw materials and auxiliary materials, the problems of loose and light properties and poor liquidity and compressibility of the raw materials are solved; and by adopting the specific auxiliary materials, the generation of impurities of the raw materials under hygrothermal conditions is avoided.

The invention discloses a trelagliptin succinate solid preparation and a preparation method thereof. The method comprises the following steps that by mass, 50-80 parts of trelagliptin succinate, 5-20parts of a filling agent, 1-10 parts of an adhesive, 3-15 parts of a disintegrating agent and 0-5 parts of a lubricant are prepared; trelagliptin succinate, the filling agent and the adhesive are mixed proportionally, and pre-mixed powder is obtained; then, water is added into the pre-mixed powder for granulation to obtain medicated granules; the medicated granules are dried by a fluidized bed fordrying, and dried medicated granules are obtained; the disintegrating agent and the lubricant are added into the dried medicated granules, and uniform mixing is performed to obtain total mixed granules; then, pressing and tableting are performed to obtain trelagliptin tablet cores. The method is simple and feasible in technology, the dissolution of the obtained solid preparation meets the requirement of a quick release agent, the tablet wright difference is small, and stability is good.

The invention provides a novel dipeptidyl peptidase IV inhibitor trelagliptin compound, hemi-succinate, hydrates and novel crystal-form drugs thereof, a pharmaceutical composition containing them and applications thereof in preparing medications for treating diabetic diseases. A novel crystal form provided by the invention contains 0.5 succinate molecule, so that the intake of inactive ingredients is reduced, then the relative toxicity is low, and the effective composition content is high, therefore, the novel crystal-form is safer and more effective when applied to preparations, and more applicable to the clinical application of high-dose preparations. Compared with the succinate crystal form of existing trelagliptin, the novel crystal form provided by the invention is good in stability and conducive to the wet granulation of solid preparations or the preparation of liquid preparations, and facilitates the manufacturing, storage and transportation of medications; and the novel crystal form provided by the invention is high in purity and safer in usage of medication.

The invention relates to a preparation method for degraded trelagliptin impurity. The method comprises the following steps: adding 2-[[6-[(3R)-3-amino-1-piperidyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl] methyl]-5-fluorobenzonitrile, an oxidizing agent and an acid catalyst into an organic solvent, and then reacting for 6-48h, thereby acquiring the degraded trelagliptin impurity, namely, 2-[[6-[(3R)-3-amino-1-piperidyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl] methyl]-5-fluorobenzamide, wherein the organic solvent is selected from at least one of C1-C4 alcohol, C2-C6 ether, tetrahydrofuran and dichloromethane and the oxidizing agent is selected from at least one of hydrogen peroxide, metachloroperbenzoic acid, t-butylhydroperoxide and peracetic acid. The method has the advantages of few steps, simple operation, mild reaction condition, and high product yield and purity.

The invention discloses a method for refining trelagliptin, the method comprises the following steps: S1, evenly mixing crude trelagliptin, ethyl acetate and ethanol, refluxing and stirring for 2-4h, adding a molecular sieve, continuing refluxing and stirring for 1-2h, hotly filtering to obtain filtrate, cooling to 0-5 DEG C, stirring for 2-3h, filtering to obtain a filtering cake, and drying to obtain an intermediate; and S2, evenly mixing the intermediate obtained by the step 1 with ethyl acetate and isopropanol, refluxing and stirring for 3-5h, cooling to 0-5 DEG C, stirring for 3-4h, filtering to obtain a filtering cake, and drying to obtain the trelagliptin. The trelagliptin prepared by the method has the advantages of high purity, good yield, simple operation and low cost, and is suitable for industrial production.