52 results about "Alogliptin Benzoate" patented technology

The invention discloses an industrial production method of Alogliptin benzoate raw material medicine. According to the method, ethanol/water mixed solvents are used as crystallization solvents; the ethanol/water mixed solvents and Alogliptin benzoate crude products are heated and flow back to a state that the solution is clear; the temperature is lowered, and crystal seeds are added; the gradient temperature reduction crystal separation is carried out; centrifugation and drying are carried out, and the Alogliptin benzoate raw material medicine is obtained. The adopted mixed solvents have low toxicity, and a better environment-friendly effect can be achieved. Compared with the method in the prior art, the industrial production method provided by the invention has the advantages that the solvent use type is reduced, the process is simple, the yield is high, and the production cost is reduced; through the method, the purity of the obtained Alogliptin benzoate finished product is at least 99.8 percent, the single impurity content is lower than or equal to 0.05 percent, the ethanol residue is low (lower than or equal to 0.1 percent) and is much lower than the limit of 0.5 percent of medical raw material medicine; impurities X generated by the reaction between phthalic acid and Alogliptin can be removed.

The invention discloses a novel method for preparing alogliptin benzoate ((R)2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)methyl]benzonitrile benzoate). The method comprises the steps of alkylation, phase transfer catalysis reaction, catalytic hydrogenation, salt formation protection and the like. The process is novel in routes, short in the steps, high in reaction yield, and low in production costs; the method has larger implementing value and social economic benefit.

The invention discloses a preparation method of alogliptin benzoate (formula 1). The method is easily available in raw materials, mild in reaction conditions, simple in operation and applicable to large-scale industrial production.

The present invention provides an alogliptin benzoate preparation method, which comprises treating an intermediate IV reaction solution, and specifically comprises: heating the intermediate IV reaction solution to a temperature of 50-80 DEG C, adding a diluted alcohol while hot, cooling to a temperature of 0-40 DEG C to make the crystal be crystallized, adding water after a lot of the crystals are crystallized, carrying out stirring washing, filtering, and drying to obtain the intermediate IV. According to the present invention, the intermediate IV is prepared by using the one-pot method, a certain amount of the diluted alcohol is added at the high temperature, the saturated solution is formed after the cooling, and the cooling is continuously performed to crystallize, such that the crystal caking problem caused by the direct water precipitation is avoided, the intermediate IV crystal is uniformly dispersed, sticking on the wall and the agglomeration do not exist, the sticking onto the stirring slurry does not exist, the operation is convenient, and the method is suitable for industrial production.

The invention provides a method for separating and analyzing alogliptin benzoate and its related substance. The method takes octyl bonded silica gel as a fixed phase and takes a mixed solvent of a mobile-phase A-buffer, a mobile-phase B-organic solvent as a mobile phase for gradient elution. The method can rapidly and efficiently separate alogliptin benzoate and its related substance under same chromatographic condition, and the detection method has the advantages of strong specialization, high precision, strong accuracy and convenient operation, and can effectively control the medicine quality.

The invention discloses a synthesis method of alogliptin benzoate. The synthesis method comprises the following steps: putting 2-cyano benzyl bromide, 3-3metyl-6-chlorouracil and tri-n-butylamine in methylbenzene and stirring for reaction; cooling, adding water and stirring for crystallization; filtering and washing with water to obtain 2-(6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimdine-1-metyl)-benzonitrile; adding 2-(6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimdine-1-metyl)-benzonitrile, (R)-3-piperidinamine dihydrochloride and alkali into ethyl alcohol and stirring for reaction; purifying and salifying with benzoic acid to obtain alogliptin benzoate. The synthesis method disclosed by the invention is mild in condition, easy to control, non-toxic, environment-friendly, high in purity and high in yield.

The invention relates to a method for preparing a DPP-IV inhibitor, and concretely relates to a method for preparing a modified alogliptin benzoate intermediate (R)-t-butyl{1-[3-(2-cyanbenzyl)-1-methyl-2,6-dioxo-1-1,2,3,6-tetrahydro-4-yl]piperidyl-3-yl}-t-butyl carbamate. The method comprises the following steps: 1, carrying out a nucleophilic substitution reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in N,N-dimethyl formamide or N,N-dimethyl acetamide or an N,N-dimethyl formamide and N,N-dimethyl acetamide mixed solvent in the presence of an alkali metal carbonate; and 2, directly adding (R)-3-Boc-aminopiperidine and the alkali metal carbonate into the reaction solution obtained in step 1 for continuous reaction. The preparation method allows the reactions to be carried out in a same reactor and the intermediate to undergo a next step reaction without separation, so the method is simple to operate.

The present invention provides new amorphous forms of alogliptin benzoate, pharmaceutical compositions comprising same, methods for their preparation and use thereof in treating conditions mediated by DPP-IV, in particular, type 2 diabetes.

The invention discloses a method for separating Alogliptin benzoate and an enantiomer thereof through high performance liquid chromatography. The method comprises the following steps: dissolving an Alogliptin benzoate raw material medicine containing Alogliptin benzoate and the enantiomer thereof in a dilution solution until the concentration is 0.1-2mg/mL; and separating Alogliptin benzoate and the enantiomer thereof by using a high performance liquid chromatography system adopting silica with the surface being covalently bonded with cellulose-tri(3,5-dichlorophenylcarbamate) as a stationary phase and an n-hexane, ethyl acetate, anhydrous ethanol and triethylamine mixed solution as a mobile phase, wherein the dilution solution is one selected from or a mixture composed of two or more of acetonitrile, methanol and ethanol. The method effectively realizes separation and determination of Alogliptin benzoate and the enantiomer thereof, and guarantees the effectiveness and the safety of Alogliptin benzoate products.

The invention provides a method for detecting dissolution rate of alogliptin benzoate tablets. The method comprises the following steps: by adopting a Welch Ultimate AQ-C18 5-micron chromatographic column of 4.6*150mm, taking a mixed solution of phosphate aqueous solution with the pH value of 5.5-6.5 and acetonitrile as a mobile phase, performing isocratic elution, and detecting the dissolution rate of the alogliptin benzoate tablets on the liquid chromatography system. The detection method provided by the invention is economic, rapid and high-efficiency, has high specificity and is suitable for detecting the dissolution rate of the alogliptin benzoate tablets under different dissolution medium conditions.

The invention relates to the field of pharmaceutical chemistry, and discloses a method for refining alogliptin benzoate. The method comprises the following steps: S1. A alogliptin benzoate crude product is added into an organic solvent for dissolving according to a proportion, wherein the proportion of alogliptin benzoate crude product to the organic solvent is 1g:2-10mL, the crude product is heated at 40-60 DEG C with stirring for dissolved clarification, wherein the organic solvent is selected from any one of acetone, tetrahydrofuran, alcohols and acetonitrile; S2. an aqueous solution of tartrate is added into liquid with dissolved clarification in the step S1, the aqueous solution of tartrate is added according to a proportion, wherein the proportion of the alogliptin benzoate crude product and the aqueous solution of tartrate is 1g:2-6mL, and heating is carried out at 40-60 DEG C with stirring for 1 hour; S2. cooling, crystallization and filtering are carried out in order to obtain solid without tartrate, the solid and benzoic acid form salt, crystallization and filtering are carried out, pressure reduction and drying are carried out for filter cakes, and a refined product of alogliptin benzoate is obtained. The refining method can reduce the content of enantiomer to 0.05% or below, refining yield reaches 89% or above, and safety and effectiveness of clinic application are guaranteed.

The invention provides an alogliptin-metformin sustained-release tablet consisting of a metformin hydrochloride sustained-release portion and an alogliptin benzoate immediate-release portion. The alogliptin-metformin sustained-release tablet comprises the following ingredients by weight percentage as shown in the description. Through series of experiments, the alogliptin-metformin sustained-release tablet provides favorable conditions for rapid absorption of alogliptin benzoate in vivo, and metformin hydrochloride achieves more sustained and stable sustained-release effect. Compared with common preparations, the alogliptin-metformin sustained-release tablet has the advantages that the alogliptin-metformin sustained-release tablet is rapider and more stable in release and can enable a diabetes patient to keep stable blood sugar concentration for the whole day. The alogliptin-metformin sustained-release tablet is taken once per day conveniently and has the combination medication advantage and high clinical application value. A preparation method of the alogliptin-metformin sustained-release tablet is good in reproducibility and stability and suitable for industrial production.

The invention provides an alogliptin benzoate tablet and a preparation method thereof. The alogliptin benzoate tablet of the invention comprises alogliptin benzoate tablet, a disintegrating agent, a filler, an adhesive, a flow aid and a lubricant, wherein the disintegrating agent is selected from crosslinked polyvinylpyrrolidone or low-substituted hydroxy propyl cellulose. The method of the invention adopts wet granulation, is low in requirements for equipment and auxiliary materials, and reduces cost; the preparation steps are simple; the effective component of alogliptin benzoate in the tablet of the invention does not interact with the disintegrating agent; the tablet is good in dissolubility; in the preparation process, the adding mode of the disintegrating agent can be selected randomly; the alogliptin benzoate tablet of the invention has good stability, and can keep stable under conditions of high temperature and high humidity.

The invention discloses a preparation method of alogliptin benzoate. The preparation method of alogliptin benzoate comprises the following steps of, firstly, reacting 3-methyl-6-chlorouracil with 2-cyanobenzyl bromide to obtain 2-(6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-methyl)-benzonitrile; secondly, reacting 2-(6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-methyl)-benzonitrile with (R)-3-aminoperidine dihydrochloride to obtain alogliptin; thirdly, salifying alogliptin with benzoic acid to obtain alogliptin benzoate. According to the preparation method of alogliptin benzoate, condensation reaction in the first step is implemented in dichloromethane solvent and under reflux conditions, thereby being mild in conditions and capable of achieving a yield higher than 90%; condensation reaction in the second step is implement in water or water-methylbenzene mixed solution to avoid production of disubstituted impurities and achieving high product purity.

The invention discloses a novel preparation process of alogliptin benzoate. The method comprises the steps: reacting 3-methyl-6-chlorouracil serving as an initial raw material with 2-cyanobenzyl bromide under an alkaline condition by taking toluene as a solvent to obtain 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]benzonitrile, then reacting the solvent system with (R)-3-Boc-aminopiperidine under an alkaline condition, dissociating a protecting group by using acid to obtain alogliptin, and carrying out salifying reaction on the alogliptin and benzoic acid to finally prepare the alogliptin benzoate which is an anti-type 2 diabetes medicine. The preparation method adopts a one-pot method, has the advantages of low raw material cost, high yield, reduction of post-treatment operation of each chemical reaction in multi-step reaction, great shortening of the production period, few impurities generated in the reaction, high product quality, relative reduction of the use amount of chemical reagents, relatively environmental protection and the like, and is beneficial to industrial production.