16 results about "Apixaban" patented technology

New derivatives of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl) phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo [3,4c] pyridine-3-carboxamide (Apixaban) able to increase its water solubility. These derivatives are cocrystals derivatives ofApixaban of different acids, from which the most outstanding are the following: Apixaban Malonic Acid derivative, Apixaban-a-Ketoglutaric Acid derivative, Apixaban-Gallic Acid derivative, Apixaban-Maleic Acid derivative, Apixaban-L-Tartaric Acid derivative, and Apixaban Citric Acid derivative.

This invention relates to the field of pharmaceutical impurity preparation technology, and discloses a method for synthesizing apixaban genotoxic impurity I. The steps include: S1. performing an addition reaction of compound II in an alkaline system to generate compound III; S2. subjecting the product of S1 to elimination and isomerization reactions under heating, separating the reaction product to obtain apixaban genotoxic impurity I. The synthesis method of this invention has high safety, low raw material cost, and can achieve a one-pot reaction while ensuring yield and product purity (no product separation and purification is required between each reaction step; only one separation and purification is needed after obtaining the final product).

This invention provides a solid preparation containing apixaban that exhibits stable dissolution properties and suppresses the formation of related substances, a method for producing the solid preparation, and an apixaban-containing composition that serves as a raw material for the solid preparation. [Solution] An apixaban-containing composition comprising crystalline apixaban particles, wherein the primary particles of the crystalline apixaban particles comprise crystalline apixaban and a swelling agent; and a dispersion preparation step of preparing a dispersion containing crystalline apixaban particles and a surfactant; a granulation step of granulating the dispersion and an excipient as raw materials after the dispersion preparation step; and a formulation step of manufacturing a solid preparation using the obtained granulated powder as raw materials after the granulation step, wherein the primary particles of the crystalline apixaban particles comprise crystalline apixaban and a swelling agent.

The application provides a synthesis method of apixaban. The synthesis method adopts a heterogeneous Pd monatomic catalyst to catalyze the reaction of 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide to obtain apixaban. The method is simple in operation process, the Pd monatomic catalyst has high reaction selectivity to N-H substrates, and the yield of apixaban is more than 94%. Compared with the traditional method, the synthesis method provided by the application can select water as a solvent, can also react under normal pressure, directly utilizes a Pd monatomic catalyst to synthesize a target product in one step, is more fast and efficient, and is environment-friendly and mild.

The invention discloses a fully continuous flow chemical synthesis method of an apixaban intermediate (Z)-2-chloro [(4-methoxyphenyl) hydrazono] ethyl acetate. The fully continuous flow chemical synthesis method comprises the following steps: introducing a sodium nitrite solution, a solution of a compound as shown in a formula (I) and acid into a dynamic tubular reactor, and carrying out diazotization reaction under the condition that the temperature is not higher than 0 DEG C; and introducing a sodium acetate solution and an ethyl 2-chloroacetoacetate solution into the microchannel reactor, mixing with the diazotization reaction solution, carrying out a Jappp-Klingemann reaction at-5-2 DEG C, and concentrating to obtain the apixaban intermediate compound shown in the formula (II). The invention provides a full-continuous flow chemical synthesis method of an apixaban intermediate (Z)-2-chloro [(4-methoxyphenyl) hydrazono] ethyl acetate. The target product can be efficiently prepared in dozens of seconds in a high-purity and high-yield manner.

The present invention relates to an orally disintegrating pharmaceutical dosage forms of apixaban or a pharmaceutically acceptable salt or prodrug thereof. The present invention specifically relates to a stable orally disintegrating pharmaceutical composition comprising apixaban and one or more pharmaceutically acceptable excipients. Further, the present invention relates to an orally disintegrating dosage form comprising apixaban, at least one disintegrating excipient and optionally one or more pharmaceutically acceptable excipients for treatment of disorders associated with Factor Xa.

The application provides a synthesis method of apixaban and a preparation method of an intermediate thereof. The method takes a key intermediate IX as a raw material, and obtains apixaban (formula I) through oxidation, elimination, addition, reduction and aminolysis successively. The synthesis route of the application is rationally designed, reaction conditions are mild, operation is simple, the yield is high, the process is economical, and the route is easy to be produced on an industrial scale.

The present invention is related to an oral liquid formulation of apixaban. The present invention is specifically related to an oral liquid formulation of apixaban which is comprising a therapeuticall

The invention discloses a preparation method of an apixaban pyridone intermediate. The preparation method comprises the following steps: with 1, 4-dioxane as a solvent and iodide as a catalyst, carrying out a condensation-elimination reaction on a compound 1c and morpholine at 50-90 DEG C to prepare a compound 1d. According to the preparation method provided by the invention, a condensation-elimination reaction can be carried out at a relatively low temperature, an apixaban pyridone intermediate compound 1d is efficiently synthesized, excessive morpholine does not need to be adopted, byproducts are few in the reaction process, the product separation yield is high, and the purity is high; as the reaction temperature is lower, the safety risk level is lower than third level, and the safety risk is almost avoided.

To provide an orally disintegrating tablet containing apixaban that maintains its disintegration properties even after storage. [Solution] A pharmaceutical composition containing the following components (a) and (b). (a) Apixaban or its salt or solvate (b) D-mannitol characterized by having a D90 of 200-400 μm

The present invention relates to an injectable pharmaceutical composition comprising apixaban. The invention particularly relates to a ready to dilute injectable composition comprising apixaban, and pharmaceutically acceptable excipients. The present invention also relates to a ready to use injectable composition comprising apixaban, and pharmaceutically acceptable excipients The invention also particularly relates to a process of preparing the composition.

The utility model discloses a novel high-precision purification device for an apixaban intermediate, and relates to the technical field of medicine preparation. The device comprises a base, a purification tank is fixedly mounted on the base, a mounting cover is mounted at the top of the purification tank, a vertically-arranged rotating shaft is rotatably arranged at the middle end of the mounting cover, and a plurality of stirring pieces distributed at equal intervals are fixedly mounted at the end, located in the purification tank, of the rotating shaft. A horizontally-arranged cross rod is fixedly arranged at the top of the rotating shaft, a vertically-arranged first scraping plate is fixedly arranged at the end, away from the rotating shaft, of the cross rod, and an obliquely-arranged second scraping plate is fixedly arranged at the bottom of the first scraping plate; high-pressure water flow flushing of the fancy spraying head is combined with mechanical scraping of the first scraping plate and the second scraping plate, the double functions of spraying flushing and physical stripping are achieved, compared with a traditional single spraying mode, medicine impurities attached to the inner wall can be more thoroughly removed, and the cleaning efficiency is improved.

This invention provides a solid preparation containing apixaban that exhibits stable dissolution properties and suppresses the formation of related substances, a method for producing the solid preparation, and an apixaban-containing composition that serves as a raw material for the solid preparation. [Solution] An apixaban-containing composition comprising crystalline apixaban particles, wherein the primary particles of the crystalline apixaban particles comprise crystalline apixaban and a swelling agent; and a dispersion preparation step of preparing a dispersion containing crystalline apixaban particles and a surfactant; a granulation step of granulating the dispersion and an excipient as raw materials after the dispersion preparation step; and a formulation step of manufacturing a solid preparation using the obtained granulated powder as raw materials after the granulation step, wherein the primary particles of the crystalline apixaban particles comprise crystalline apixaban and a swelling agent.

The application discloses a kind of full continuous flow chemical synthesis methods of apixaban intermediate (Z)-2-chloro [(4-methoxyphenyl) hydrazono] ethyl acetate.The full continuous flow chemical synthesis method includes the following steps: sodium nitrite solution, formula (I) compound solution, acid is passed into dynamic tubular reactor, and diazotization reaction occurs under the condition that temperature is not higher than 0 DEG C;Sodium acetate solution, 2-chloroacetoacetic acid ethyl ester solution is passed into microchannel reactor, and Japp-Klingemann reaction occurs with diazotization reaction liquid mixture under the condition that temperature is-5~2 DEG C, concentration, to obtain apixaban intermediate formula (II) compound.The application provides a kind of full continuous flow chemical synthesis method of apixaban intermediate (Z)-2-chloro [(4-methoxyphenyl) hydrazono] ethyl acetate, can be efficiently, high purity, high yield in a few tens of seconds to prepare target product.

The invention belongs to the field of medicine preparation, and particularly relates to a synthesis method of apixaban, which comprises the following steps: (1) synthesis of an intermediate I: taking 4-aminobenzoic acid and 5-chlorovaleryl chloride as raw materials, adding a polar solvent and a strong alkali reagent, and preparing the intermediate I, namely 1-(4-carboxyphenyl) piperidine-2-ketone, by a one-pot method; (2) synthesis of an intermediate II: adding trifluoromethanesulfonic anhydride into the intermediate I obtained in the step (1) to obtain an OTf activated intermediate, and carrying out Suzuki reaction on the OTf activated intermediate and a pyrazole borate derivative in the presence of a palladium composite catalyst and alkali to obtain the intermediate II; and (3) synthesis of apixaban: taking the intermediate II, adding a cyclization reagent and a third solvent, and reacting under a microwave condition to obtain apixaban. According to the apixaban, the total yield and purity are remarkably improved, the reaction time is greatly shortened, the production efficiency is improved, operation is easy, and the apixaban is suitable for large-scale production.

This invention belongs to the field of pharmaceutical cocrystal technology, specifically relating to an apixaban-gallic acid cocrystal solvate and its preparation method. The cocrystal solvate is formed by apixaban and gallic acid in a 1:1 molar ratio, simultaneously binding one molecule of acetone and one molecule of water. Its X-ray powder diffraction pattern exhibits characteristic peaks at 2θ values ​​of 8.3±0.2°, 11.3±0.2°, 12.7±0.2°, 13.8±0.2°, 16.8±0.2°, 18.3±0.2°, 22.0±0.2°, and 26.9±0.2°. The crystal form provided by this invention significantly improves the solubility of apixaban, resulting in tablets prepared with it as the active ingredient exhibiting high dissolution rate and high bioavailability, making it more suitable for oral formulations.