12 results about "Edoxaban" patented technology

The invention provides a preparation method of an edoxaban key intermediate I. According to the method, a compound II serves as a raw material, a compound III is obtained through an azidation reaction of hydroxyl, then a target compound I is obtained through hydrogenation reduction, and the compound is the key intermediate of an anticoagulant drug edoxaban. The'one-pot method 'is high in reaction yield, obviously reduces the cost, obviously reduces'three wastes', is more environment-friendly, and is suitable for large-scale industrial production.

The present invention provides a preparation method for Edoxaban or a salt or hydrate thereof. The method comprises the following steps: step 1: under acidic conditions and in a polar solvent, removing the N-Boc protecting group of chemical compound 1 so as to generate chemical compound 2; step 2: adding to the reaction solution obtained in step 1 triethylamine, a protic solvent, a condensing agent, and 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-C]pyridine-2-carboxylic acid or a salt thereof, and reacting to obtain Edoxaban. Adding a certain amount of protic solvent during the reaction accelerates the reaction process, shortens the reaction time, improves reaction efficiency, and reduces the impurity content in the obtained Edoxaban. The purification method is simple and convenient, produces high purity, and is suited for large-scale industrial production.

The invention provides a crystal form of an edoxaban intermediate and a preparation method thereof, and relates to the field of medicinal chemistry. The structural formula of the edoxaban intermediate is as shown in formula I; the crystal form of the edoxaban intermediate comprises a crystal form A, a crystal form B or a mixture of the crystal form A and the crystal form B in any proportion. The X-ray powder diffraction pattern of the crystal form A of the edoxaban intermediate has characteristic absorption peaks at the positions of 2theta angles of 11.20 degrees, 17.66 degrees, 18.61 degrees, 19.29 degrees and 27.40 degrees; the X-ray powder diffraction pattern of the crystal form B of the edoxaban intermediate has characteristic absorption peaks at the positions of 2 theta angles of 7.99 degrees, 10.82 degrees, 13.33 degrees, 18.22 degrees, 18.48 degrees, 19.34 degrees and 20.02 degrees. The stable crystal form of the compound shown in the formula I can be successfully obtained, the crystal form of the compound shown in the formula I can be directly used as an intermediate to be stored and used, and the synthesis route of edoxaban is simplified.

The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an edoxaban intermediate. The method takes 2,5-dimethyl-4,5,6,7-tetrahydrothiazole[5,4-c]pyridine (compound 1) as raw material, and first performs an oxidation reaction with an oxidant to obtain 5-methyl-4,5,6,7-tetrahydrothiazole[5,4-c]pyridine-2-methanal (compound 2), then performs a reaction with chlorite to obtain 5-methyl-4,5,6,7-tetrahydrothiazole[5,4-c]pyridine-2-carboxylic acid (compound 3), and finally performs a salt formation in an organic solution of hydrochloric acid to obtain the edoxaban intermediate (compound 4). The reaction route of the application is short, the material is cheap and easy to obtain, the reaction condition is mild, the atomic economy is high, the obtained product has high purity, the product quality can meet the subsequent requirements, and the yield is high.

The present invention discloses an edoxaban intermediate and a method for preparing the same. The general structural formula of the edoxaban intermediate is: [Formula 1] TIFF2024543705000030.tif27170 or [Case 2] TIFF2024543705000031.tif27170, where R1 is OH, an alkoxy group or an N,N-dialkyl group, and R2 is hydrogen, an alkoxycarbonyl group or an amino protecting group. [C3] and mixing the compound of formula II, transaminase, transaminase coenzyme and phosphate buffer solution for enzyme catalysis or further amine derivatization to obtain the compound of formula I. Compared with the chemical synthesis methods of the prior art, the key intermediate of edoxaban and the preparation method thereof provided by the present invention have a novel structure, mild reaction conditions, high yield and good industrial value.

The present invention relates to an efficient and industrially advantageous process for the preparation of Edoxaban of Formula-I or salt thereof. The present invention also relates to a process for preparation of Edoxaban intermediates namely methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride of Formula-II, tert-Butyl [(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylaminocarbonyl)cyclohexyl]carbamate of Formula-IV, and their use for the preparation of Edoxaban or salt thereof.

The present invention provides a method for preparing edoxaban, or its salt or hydrate. This method involves step 1: removing the N-Boc protecting group from compound 1 in a polar solvent under acidic conditions to produce compound 2; and step 2: adding triethylamine, a protic solvent, a condensing agent, and 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-C]pyridine-2-carboxylic acid or a salt thereof to the reaction mixture obtained in step 1 to produce edoxaban. Adding a certain amount of protic solvent to the reaction system accelerates the reaction process, shortens the reaction time, improves reaction efficiency, and reduces the content of impurities in the resulting edoxaban. The purification method is simple, allowing for high-purity production, making the compound suitable for industrial mass production.

The present invention provides a solid pharmaceutical composition in the form of tablet, comprising edoxaban particles having specific particle size distribution with D90 value less than 20 µm, having specific disintegrants to obtain desired dissolution profile, stability and in-vitro results.

The application belongs to the technical field of medicine purification, and particularly discloses a preparation method of a high-purity edoxaban intermediate. The preparation method comprises the following steps: a synthesis process: raw materials EDB070, triethylamine and a solvent are mixed, first-time heating is performed to dissolve and clear, second-time heating is performed to react, and a product EDB080 is obtained; pyridine and water are added, third-time heating is performed to react, and a product EDB090 is obtained; a purification process: NaCl solution is added to EDB090 to break emulsion, and then NaOH solution is added; extraction and concentration are performed, and then toluene is added to dissolve and clear; finally, normal heptane is added dropwise to perform crystallization, and after filtration, the purified EDB090 is obtained. In the post-treatment and purification process, the system of toluene / normal heptane is used for crystallization, good impurity removal effect is achieved, the purity of the edoxaban intermediate EDB090 is 92.21-93.69%, and the yield can reach 70-78%.

The application belongs to the technical field of medicine synthesis, and particularly relates to an intermediate compound of edoxaban. The application takes 2-bromo-5-methyl-3a, 4, 5, 6, 7, 7a-hexahydrothiazolo[5, 4-c] pyridine as a starting material, and a lactam product is obtained by undergoing a carbonylation reaction with (3R, 4R)-3-amino-4-hydroxy-N, N-dimethylcyclohexane-1-carboxamide under the action of a catalyst, and the obtained lactam product undergoes a Mitsunobu reaction with N-(4-chlorophenyl) oxamide to obtain edoxaban. The preparation method of edoxaban provided by the application introduces a lactam by using a copper-catalyzed carbonylation reaction, and the whole synthesis method is simple in operation, high in reaction yield and purity; can effectively avoid the addition of n-butyllithium and low-temperature operation required by the carboxylation in the prior art, improve the operation safety, and has the advantages of mild use conditions, high conversion rate and simple operation.

The application discloses a synthesis method of an intermediate for preparing edoxaban, wherein N-methyl-4-piperidone, monocyannamide, tetrahydropyrrole and sulfur powder are used as reactants to generate compound A, the compound A is dissolved in a hydrobromic acid solution, reacts with hypophosphorous acid and sodium nitrite to generate compound B, and the compound B reacts with acetyl chloride under the action of an acid binding agent to generate the intermediate of edoxaban. The application selects suitable reaction conditions and reactants to improve the yield of each step, the product exists in the form of hydrochloride, has higher stability, is convenient to store and use, and has a purity meeting the requirement of further preparation of edoxaban.

The objective is to provide an orally disintegrating tablet containing edoxaban with improved dissolution properties in the neutral region. [Solution] To provide granulated granules containing 45% or more edoxaban tosylate hydrate, and orally disintegrating tablets containing pharmaceutical additives and free of organic acids.