20 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 invention relates to an Edoxaban tosylate calibrator and quality control product as well as a preparation method and application thereof, and relates to the technical field of analysis and detection, and the Edoxaban tosylate calibrator is prepared from an international standard reference substance NIBSC: 11 / 176 indirectly traced to low molecular weight heparin LMWH. According to the present invention, the existing LMWH international standard reference substance NIBSC: 11 / 176 is adopted to assign the researched and developed EDOX calibrator and the researched and developed EDOX quality control product so as to obtain the reference approach in the tracing chain, such that the blank of the EDOX calibrator and the EDOX quality control product in the prior art is filled, the expansion field of the Xa inhibitor activity determination is promoted, and the Xa inhibitor activity determination method can be used for the Xa inhibitor activity determination. And a feasible scheme and basis are provided for standardized determination and commercial production of EDOX, and the method has practical application value.

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 present invention discloses a method for synthesizing an edoxaban intermediate. First, the raw material (S)-(−)-3-cyclohexene carboxylic acid is oxidized by potassium permanganate to generate intermediate 2; intermediate 2 reacts with methanesulfonyl chloride to generate intermediate 3; intermediate 3 reacts with ammonia in ethanol to generate intermediate 4; intermediate 4 undergoes a self-cyclization reaction under the catalysis of EDCI and HOBt to generate intermediate 5; intermediate 5 reacts with benzyl chloride to generate intermediate 6; intermediate 6 is hydrolyzed under alkaline conditions and reacts with Boc2O simultaneously to generate intermediate 7; intermediate 7 undergoes a condensation reaction with dimethylamine to generate intermediate 8; intermediate 8 is hydrogenated to remove the benzyl group to generate the edoxaban intermediate. The synthesis method of the present invention has simple operation steps, high chiral selectivity, is beneficial to improving the product yield and reducing the production cost, and does not use the dangerous reagent sodium azide, reducing the production risk and ensuring the safety and operability of the reaction.

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 invention discloses an edoxaban intermediate chiral amine and a synthesis method thereof, and relates to the technical field of medicines. A synthesis method of an edoxaban intermediate chiral amine comprises the following steps: adding a compound shown as 01A into a solvent A, adding benzylamine, and heating for reaction to obtain a compound shown as 02B; adding the compound as shown in 02B into a solvent B, and adding an oxidizing agent to react to obtain a compound as shown in 03C; adding the compound as shown in 03C and S-tert-butyl sulfonamide into a solvent C, and adding a condensing agent to react to obtain a compound as shown in 04D; adding the compound as shown in 04D into a solvent D, and adding a reducing agent for reaction to obtain a compound as shown in 05E; and adding the compound as shown in 05E into a solvent E, and reacting in an acid environment to obtain the edoxaban intermediate chiral amine as shown in 06F. According to the invention, phosphorus-containing reagents, easy-to-produce explosive sodium azide, hydrazine hydrate and the like are avoided, and the problems of safety risk, low productivity and the like are solved.

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 invention discloses a method for recovering an edoxaban intermediate resolving agent R-phenylethylamine, which comprises the following steps: S1, adding an organic solvent A into a mother solution containing free R-phenylethylamine salt, cooling to 5-15 DEG C, adding inorganic acid to adjust the pH value to acidity, heating to 25-30 DEG C, and collecting a water phase; s2, cooling the water phase to 5-15 DEG C, adding inorganic alkali to adjust the pH to be alkaline, heating to 25-30 DEG C, adding an organic solvent B, and collecting an organic phase; and carrying out reduced pressure desolventizing distillation under the vacuum of-0.09 to-0.1 MPa at the temperature of less than or equal to 50 DEG C until no fraction exists, heating to 50-110 DEG C, carrying out reduced pressure distillation, and collecting the fraction with the top temperature of 80-100 DEG C, thereby obtaining the (R)-(+)-phenylethylamine. According to the method, the mother liquor is subjected to acid adjustment, solvent extraction, water phase alkali adjustment, solvent extraction and reduced pressure distillation and concentration, so that the yield and the recovery purity of the product can be improved, and the method is stable in process, easy to operate, short in time consumption and low in cost.

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.

The invention belongs to the field of medicinal chemistry, and provides a synthesis method of an edoxaban key chiral intermediate A. According to the synthesis method, 3-cyclohexene-1-formic acid is taken as a starting raw material, bromine ring esterification is carried out, selective hydrolysis is carried out by using specific biocyclic ester hydrolase, and solid-liquid separation is carried out, so that a target compound A is obtained, post-treatment is simple and convenient, the synthesis route is shortened, the used bio-enzyme mother liquor can be reused, the activity is maintained for 9-10 times, and the whole process is environment-friendly, low in cost and suitable for large-scale production; and the molar yield of the produced key chiral intermediate A is high, the ee value of a crude product after resolution reaches 95% or above, and the ee value exceeds 99.0% after refining.

The present invention relates to a process for preparation of Edoxaban intermediate namely alkyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate compound of Formula-I. The present invention also relates to a process for the preparation of Edoxaban of Formula-IV or salt thereof from alkyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate compound of Formula-I.

A computer implemented method for determining a dosage of edoxaban for administering to a patient, the method comprising: receiving patient data relating to a patient, wherein the patient data includes a kidney function metric; processing the patient data with a dosage calculator to determine the dosage of edoxaban for administering to the patient, wherein the dosage calculator is derived from a plasma level prediction model; and indicating the dosage.

A computer implemented method for determining a dosage of edoxaban for administering to a patient, the method comprising: receiving patient data relating to a patient, wherein the patient data includes a kidney function metric; processing the patient data with a dosage calculator to determine the dosage of edoxaban for administering to the patient, wherein the dosage calculator is derived from a plasma level prediction model; and indicating the dosage.