246 results about "Sitagliptin" patented technology

Intermediate compounds in the synthesis of Sitagliptin, 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester, and amino protected-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester, and the stereoselective reduction of these compound to give Synthon I, or the amino-protected Synthon I, are provided.

A novel crystalline form of sitagliptin sulfate is provided. In addition, a method for obtaining the crystalline form, pharmaceutical compositions comprising the novel crystalline form and the crystalline form for use as a medicament are provided.

The invention discloses a method for preparing trifluoro-phenylacetic acid. The method comprises the following steps: (1) in the presence of an evocating agent, trifluoro-benzyl halides and magnesium in an organic solvent react to obtain a Grignard reagent; (2) carbon dioxide gas is introduced into the Grignard reagent for reaction; and (3) a product obtained in the step (2) is hydrolyzed to obtain the trifluoro-phenylacetic acid. The invention also discloses a method for preparing sitagliptin. The method has the characteristics of high yield, good purity, low cost, simple process, mild condition, few three wastes and good safety, and is suitable for industrialized production.

The invention discloses aminotransferase, a mutant and application to Sitagliptin preparation. According to the application, wet thalli obtained by performing fermentation culture on recombinant escherichia coli containing aminotransferase encoding genes are used as biocatalysts; Sitagliptin precursor ketone is used as a substrate; dimethyl sulfoxide is used as a latent solvent; phosphopyridoxal is used as a coenzyme; isopropylamine is used as an auxiliary substrate; a trolamine buffer solution with the pH being 8 to 9 is used as a reaction medium; a reaction system is formed; the biocatalytic reaction is performed under the conditions of the temperature being 30 to 45 DEG C and the stirring speed being 100 to 250 r/min; after the reaction is completed, the reaction liquid is separated and purified; the Sitagliptin is obtained. The aminotransferase and the mutant are used as biocatalysts; the latent carbonyl compound of Sitagliptin precursor ketone is directly used as the substrate; meanwhile, biocatalytic reaction is performed by using isopropylamine as the auxiliary substrate and using the pyridoxal phosphate as the coenzyme; the separation and purification is performed; Sitagliptin with high optical purity is prepared. The method has the advantages that the total yield is 76 percent; the product e.e. value reaches 99 percent.

Disclosed are pharmaceutical compositions comprising fixed-dose combinations of an extended-release form of metformin, or a pharmaceutically acceptable salt thereof, coated with an immediate-release form of the DPP-4 inhibitor sitagliptin, or a pharmaceutically acceptable salt thereof.

The invention discloses sitagliptin and an enzyme-chemical preparation method of an intermediate of the sitagliptin. The method comprises the steps of mixing 3-carbonyl-4-(2, 4, 5-trifluoro-phenyl)butyrate, D-amino acid dehydrogenase, a cofactor, cofactor-catalyzing cyclophorase, an amino doner, a cosolvent and a buffer solution according to a certain ratio to obtain a product (R)-3-amino-4-(2, 4, 5 trifluoro-phenyl)butyrate; enabling the (R)-3-amino-4-(2, 4, 5 trifluoro-phenyl)butyrate to be subjected to the steps of amino protection, condensation and deprotection to obtain sitagliptin free alkali. Compared with the prior art, the method adopted by the invention is less in process route, shorter in reaction time, improved in product purity and yield and lower in production cost, and is suitable for industrial production.

The invention discloses a preparation method of sitagliptin, comprising the following steps: reacting 2, 4, 5-trifluoro-phenylacetic acid with malonic cyclo (sub) isopropyl ester; reacting 3-oxo-4-(2, 4, 5-trifluorophenyl) methyl butyrate with ammonium acetate; reacting 3-amino-4-(2, 4, 5-trifluorophenyl) methyl crotonate with hydrogen; performing hydrolysis reaction to (R)-3-amino-4-(2, 4, 5-trifluorophenyl) methyl butyrate; and reacting (R)-3-amino-4-(2, 4, 5-trifluorophenyl) butyric acid with 3-(trifluoromethyl)-5, 6, 7, 8-tetrahydro-[1, 2, 4] triazol [4, 3-a] pyrazine hydrochloride to obtain sitagliptin. According to the invention, EE value greater than 90% is obtained through high-efficiency catalytic hydrogenation; sitagliptin is prepared by only five steps; yield is higher; technical conditions are mild; operations are simple; cost is low; and yield and purity of products are high.

The invention discloses a preparation method of sitagliptin intermediate, sitagliptin or salts thereof. The method comprises the following steps of: (1) preparing a compound, namely 2,4,5-trifluorobromobenzene shown as a formula (II) into a Grignard reagent; (2) reacting the Grignard reagent with boric acid trimester in an organic solvent under the action of a catalyst to obtain a compound, namely 2,4,5-trifluorobenzolc acid shown as a formula (III); and (3) preparing a compound, namely (3R)-3-substituted amido-4-bromine-butyric ester shown as a formula (IV) and the 2,4,5-trifluorobenzolc acid shown as the formula (II) into a compound, namely (3R)-3-substituted amido-4-(2,4,5-trifluorophenyl)-butyric ester shown as a formula (V) under the action of a transition metal catalyst and alkali. By using the method, the synthesis efficiency is increased, and the cost is lowered.

The invention provides immobilized transaminase. The immobilized transaminase is obtained by fixing transaminase, with histidine tag, derived from Mycobacterium vanbaalenii PYR-1 onto an enzyme immobilization carrier; the enzyme immobilization carrier is obtained by derivatization of epoxy resin through IDA (imino diethyl acetic acid) and cobalt chloride or derivatization of ionic chelate resin through cobalt chloride. The immobilized transaminase has the advantages of firmness in combination, low enzyme activity loss, simplicity in separation and high reusability; low cost of an asymmetric conversion process, mild reaction conditions, environment friendliness, simplicity and convenience in operation, easiness in industrial expanding and promising industrial application prospect are realized.

The invention discloses an omega-transaminase mutant and application thereof in preparation of sitagliptin intermediate. The omega-transaminase mutant is obtained by performing single mutation on the56 position or the 134 position of an amino acid sequence as shown in a SEQ ID No.2; the 56 phenylalanine is substituted by valine, histidine or tyrosine; and the 134 threonine is substituted by glycine. The omega-transaminase mutant has relatively high enzyme activity which is higher than 300U/g and is at least 2.7 times that of a wild type since the omega-transaminase mutant is subjected to site-specific mutagenesis by acquiring certain sites possibly influencing the catalytic activity of the omega-transaminase mutant through molecular docking, homologous modeling and other modes, can be used for efficiently catalyzing precursor ketone 1-piperidine-4-(2,4,5-trifluorophenyl)-1,3-dibutanone of the sitagliptin intermediate to synthesize the sitagliptin intermediate (R)-3-amino-1-piperidine-4-(2,4,5-trifluorophenyl)-1-butanone, and has a conversion rate of 85 percent.

The invention discloses a transaminase mutant as well as application thereof to preparation of sitagliptin midbody. The application adopts a wet thallus obtained by fermenting and culturing recombinant escherichia coli comprising aminotransferase coded gene as a biological catalyst, adopts sitagliptin midbody precursor ketone as a substrate, adopts dimethyl sulfoxide as a co-solvent and , adopts phosphopyridoxal as co-enzyme, adopts isopropylamine as an auxiliary substrate, adopts a pH 8-9 triethanolamine buffering solution as a reaction medium to form a reaction system to perform the biological catalytic reaction under the conditions that the temperature is 30 to 45 DEG C, and the stirring rate is 100 to 250 r/min, after the reaction is ended, the reaction solution is separated and purified to obtain sitagliptin; and the total yield of the method is about 81 percent, and a e.e. value of the product reaches 99 percent.

The invention provides a compound shown by a formula I, a purpose of a stereoisomer, a geometrical isomer, a tautomer, an oxynitride, a hydrate, a solvate, a metabolite, a pharmacologically acceptable salt or prodrug of the compound in Sitagliptin preparation, and a Sitagliptin preparation method. The formula I is shown in the description, wherein R1 is a substitutional group containing the hydroxyl group. The compound shown by the formula I or the stereoisomer, the geometrical isomer, the tautomer, the oxynitride, the hydrate, the solvate, the metabolite, the pharmacologically acceptable salt or the prodrug of the compound shown by the formula I has high water solubility, and is used for obtaining a chiral amino intermediate to further obtain the Sitagliptin. Compared with the prior art, the compound has the advantages that the amino group conversion rate is greatly improved; the yield of the Sitagliptin is also greatly improved.

The invention discloses a synthetic method of sitagliptin and a salt thereof. The synthetic method comprises the steps: carrying out an esterification reaction, a reduction reaction, an oxidizing reaction and a witting reaction on 2,4,5-trifluorophenylacetic acid as a starting raw material to obtain 4-(2,4,5-trifluorophenyl)-2-ethyl crotonate; then carrying out a hydroamination reaction on 4-(2,4,5-trifluorophenyl)-2-ethyl crotonate and chiral amine in the presence of butyl lithium or hexamethyldisilazane sodium to form a chiral hydroamination product; carrying out an esterolysis reaction, a condensation reaction and a hydrogenation reaction to obtain sitagliptin. The raw materials used in the synthetic method of sitagliptin are low in price and easy to obtain; the synthetic method of sitagliptin is less in step, easy to operate and capable of effectively reducing cost. By the use of the method, high-purity sitagliptin can be obtained, a sitgliptin phosphate obtained through salifying has an HPLC (High Performance Liquid Chromatography) and an ee (enantiomeric excess) value of more than 99% and can be applied to the field of medicine.

The invention provides a preparation method of sitagliptin. The preparation method comprises the following steps of: performing condensation reaction on hydrochloride of 3-trifluoromethyl-[1,2,4] triazol [4,3-a] piperazine serving as a starting raw material and methyl malonyl chloride under a normal temperature condition; reacting an obtained product with 2,4,5-trifluorophenylacetic acid under an alkaline condition and then performing condensation reaction with (S)-phenylglycinamide under normal temperature condition to obtain a product; reducing the obtained product through a reducing agent; removing an ester group through heating reflux; and reacting with a hydrogenation reducing reagent to obtain the sitagliptin. The preparation method has the advantages of low cost, high yield, easiness in operation, all used reagents of conventional reagents, simple post-treatment and convenience for industrial production.

The invention relates to a medicinal composition. The medicinal composition comprises sitagliptin, pharmaceutically acceptable salt thereof and/or hydrate of the salt, and anhydrous calcium hydrogen phosphate. The medicinal composition is further used for preparing a solid preparation, and is especially prepared into a tablet by a direct tabletting method. Through selection of the medicinal composition, especially selection of the specific anhydrous calcium hydrogen phosphate as a raw material, the quality control way of the medicinal composition using the sitagliptin, the pharmaceutically acceptable salt thereof and/or the hydrate of the salt as an active component can be significantly improved, and even production of related impurities in the medicinal composition can be significantly improved so as to improve the stability of the medicinal composition and relevant dosage forms.

The present invention relates to pharmaceutical compositions comprising {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (FRI-1) in combination with an anti-diabetic drug selected from the group consisting of metformin, sitagliptin or exenatide. The present invention also relates to the use of the pharmaceutical compositions in restoring insulin sensitivity and treating type II diabetes, including reducing body weight in subjects undergoing type II diabetes treatment.

The invention discloses a drug composition containing sitagliptin and melbine. A melbine sustained release tablet core is coated with sitagliptin in a mixed suspension mode. The invention also discloses composition of a sitagliptin suspension. By carefully selecting preparation prescriptions, antioxidants are not used in the prescriptions, a production process is simple, and meanwhile and the technical advantages of uniform preparation content, consistent dissolution, good stability and the like are also achieved.

The invention relates to a transaminase-PLP co-immobilized enzyme and a preparation and application thereof, and application of the co-immobilized transaminase for preparing a Sitagliptin medicine chiral midbody. Epoxy resin is adopted as a carrier, and the transaminase-PLP co-immobilized enzyme is obtained by covalence immobilizing of transaminase and coenzyme pyridoxal phosphate (PLP for short).The transaminase-PLP co-immobilized enzyme is adopted as a catalyst, the stability is good, the service life is long, the organic solvent tolerance is good, the transaminase-PLP co-immobilized enzymecan be repeatedly used, no expensive exogenous coenzymes are added in the reaction process, and the production cost is greatly lowered. The method is simple in technology, low in cost, and high in product yield and purity, and the enzyme has the great application value in industrial production of the Sitagliptin medicine chiral midbody.