162 results about "Ibrutinib" patented technology

Discussed herein are pharmaceutical compositions containing Ibrutinib and processes for preparing them. The compositions may be utilized in the treatment of a variety of conditions including, without limitation, B-cell proliferative disorders such as non-Hodgkin lymphoma (diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma or burkitt lymphoma), Waldenstrom macroglobulinemia, plasma cell myeloma, chronic lymphocytic leukemia, lymphoma, or leukemia. These compositions are designed for oral ingestion. The compositions are contained within a capsule such as a standard or sprinkle or in a liquid formulation such as a suspension. In one embodiment, the pharmaceutical composition contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. In another embodiment, the pharmaceutical composition contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, concentrated hydrochloric acid, sodium hydroxide, and water.

The invention provides two crystal forms of ibrutinib, a preparation method and applications thereof. Specifically, the invention provides crystal forms of 1-[(3R)-3-[4-amino-3-(4-phenoxylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl]-1-piperidyl]-2-propylene-1-one, a preparation method and applications thereof.

The present invention relates to a novel crystal form of ibrutinib and a preparation method thereof, and belongs to the technical field of pharmacy. The differential scanning calorimetry curve of the novel crystal form has endothermic peak at 194-204 DEG C; and the novel crystal form has good physical and chemical properties, is conducive to the production operation, and can be used in the preparation of pharmaceutical preparations.

The invention discloses a crystal form F of ibrutinib. The crystal form F is characterized in that X-ray powder diffraction (X-RPD) which adopts Cu-Kalpha radiation and is represented with a 2theta angle has diffraction peaks in positions at angles of 3.7 degrees plus or minus 0.2 degrees, 6.7 degrees plus or minus 0.2 degrees, 13.2 degrees plus or minus 0.2 degrees, 16.1 degrees plus or minus 0.2 degrees, 19.1 degrees plus or minus 0.2 degrees, 20.0 degrees plus or minus 0.2 degrees, 23.8 degrees plus or minus 0.2 degrees and 24.6 degrees plus or minus 0.2 degrees. Related solvents in a preparation process of the crystal form F are cheap, the conditions are mild, the operation is simple, good controllability and reproducibility are realized, further, the prepared crystal form has great stability, the HPLC (high performance liquid chromatography) purity is higher than 99%, and the phenomenon of crystal transformation can be avoided; besides, the solubility is high, the dissolubility is good, and the bioavailability is high.

The invention discloses a method for preparing ibrutinib, and relates to an intermediate compound used for preparing the ibrutinib, wherein the intermediate compound has a structural formula shown in a formula II. The invention also discloses a method for preparing an intermediate, which is characterized in that a compound in a formula III and an acyl chloride derivative are subjected to a reaction, and then the ibrutinib is obtained through a further reaction. The impurity content of the ibrutinib prepared by the method is obviously reduced.

The invention discloses a preparation method for ibrutinib and belongs to the technical field of drug synthesis. The preparation method specifically includes the steps that 3-amino-4-cyano pyrazol and formamidine acetate serve as initial raw materials, and ibrutinib is obtained through a cyclization reaction, a halogenating reaction, a nucleophilic substitution reaction, a Mitsunobu reaction and an amidation reaction. According to the method, the raw materials are easy to obtain, conditions are mild, the process operability and controllability are high, cost is low, the yield is high, fewer side products are generated, purification is easy, and the high-quality product is obtained.

The invention provides a eutectic complex composed of resveratrol and a protein kinase inhibitor, and a composition comprising the eutectic complex. The eutectic complex is characterized in that the protein kinase inhibitor is selected from one of imatinib, gefitinib, erlotinib, sunitinib, sorafenib, dasatinib, lapatinib, nilotinib, pazopanib, afatinib, crizotinib, axitinib, regorafenib, ibrutinib, lenvatinib, palbociclib, osimertinib and alectinib or pharmaceutically acceptable salt thereof. The eutectic complex provided by the invention can produce synergistic effects of inhibiting histamine release.

The invention discloses a method for synthesizing an important intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib. The method comprises the following steps: step one, condensing malononitrile and triethyl orthoformate and then carrying out a one-pot reaction with hydrazine hydrate to obtain 5-amino-4-cyano-pyrazole; step two, condensing the 5-amino-4-cyano-pyrazole with formamide to prepare a compound of formula (II) 4-amino-1H-pyrazolo[3,4-d]pyrimidine; step three, carrying out a bromination reaction of the compound of formula (II) and brominating agent to obtain a compound of formula (III) 4-amino-3-bromine-1H-pyrazolo[3,4-d]pyrimidine; step four, carrying out a Stille reaction on the compound of formula (III) and trimethyl p-phenoxy phenyltin under the catalyst effect of metal palladium to prepare a compound of formula (I) 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine. According to the method for synthesizing the important intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib provided by the invention, raw materials are low in price and easily obtained, the reaction conditions are moderate, the operation is simple and convenient, the method is suitable for industrial production, and a new way is provided for preparing Ibrutinib and intermediate.

The invention relates to ibrutinib and a liquid-phase separation test method of a corresponding isomer impurity of ibrutinib and belongs to the technical field of separation testing. The test method comprises the steps of taking a CHIRALPAK AD-H, 4.6mm*250mm, 5-micrometer chiral chromatographic column as a separation chromatographic column, and taking a mixed solvent of an alkene solvent and an alcohol solvent at a volume ratio of 35:65 as a mobile phase. The method can effectively separate and test ibrutinib and the corresponding isomer impurity of ibrutinib, and be used for production, and a separation degree can reach above 5.

The invention discloses a preparation method of an Ibrutinib intermediate shown as a formula 4. The method comprises the following steps: in a organic solvent, under effect of an acid-binding agent, a compound shown as a formula 2 and a compound shown as a formula 3 are subjected to a nucleophilic substitution reaction, and the Ibrutinib intermediate shown as the formula 4 is prepared. The acid-binding agent is one or more of sodium carbonate, potash and sodium hydride; wherein, Y is C1-C6 alkyl, phenyl or C1-C6 alkyl-substituted phenyl; and Z is halogen, or 4-phenoxyl-phenyl. The preparation method has the advantages of simple operation, low cost, less reagent amount, less three wastes, environmental pollution, simple post-treatment, high yield, and high optical purity, and is suitable for industrial production.

Described herein are methods for treating and preventing graft versus host disease using ACK inhibitors. The methods include administering to an individual in need thereof an ACK inhibitor such as ibrutinib for treating and preventing graft versus host disease.

The invention discloses a separation and purification method of an ibrutinib intermediate-(3R)-4-amino-3-(4-phenoxyphenyl)-1-(1-tert-butoxycarbonylpiperidine-3-group)-1-1H-pyrazole [3, 4-d] pyrimidine. The separation and purification method includes: after Mitsunobu reaction for preparing the intermediate stops, adding magnesium chloride into a mixture; cooling after back-flowing; filtering to remove compound precipitate of magnesium chloride and triphenyl phosphine oxide to obtain the intermediate high in purity. Column chromatography is omitted in the process, so that the separation and purification method is high in efficiency and low in cost.

The invention belongs to the field of pharmaceutical synthesis, and relates to an impurity in the bulk pharmaceutical chemical production process and a preparation method of the impurity, in particular to a process impurity of Ibrutinib 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazole [3,4-d]pyrimidine-1-yl]-1-piperidyl]-2-propylene-1-ketone and a preparation method of the process impurity.

The invention discloses a high-efficiency preparation method for ibrutinib, which belongs to the technical field of organic synthesis. A concrete synthetic route is shown in a specification. The method has the advantages of mild reaction condition, simple operation, low cost, convenient purifying, friendly environment, and high product optical purity, and is suitable for industrial production.

The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of deuterated ibrutinib. The preparation method of the deuterated ibrutinib provided by the invention comprises the following step of: synthesizing the positioned deuterated ibrutinib from the raw material ibrutinib under the illumination condition under the catalysis of a photosensitizer. The method provided by the invention has the characteristics of simple operation, mild conditions, high yield, good selectivity, environmental protection and the like, and the synthesized deuterated ibrutinib significantly increases the absorption degree of the drug, thereby providing a new process route for the synthesis of selective deuterated ibrutinib.

The invention relates to a synthesis and purification process of ibrutinib intermediates, in particular to a process to obtain ibrutinib intermediates with the purity being greater than 97 percent by performing Mitsunobu reaction and Boc removal processes on 3-(4-phenoxyl phenyl)-1H-pyrazole[3,4-d]pyridine-4-amine and (s)-1-t-butyloxycarboryl-3-hydroxypiperidine, triphenylphosphine and DIAD to obtain intermediate mixing samples, using solvents for crystallization to obtain intermediate coarse products, and then recrystallizing the coarse products by a mixed solvent method. According to the process, a one-pot method is used for obtaining the ibrutinib intermediates; the reaction process is simple; the yield is high; meanwhile, an efficient refining method is also provided.