159 results about "Palbociclib" patented technology

The invention belongs to the technical field of medicine, and relates to a palbociclib gastric-floating tablet and a preparation method thereof. The palbociclib gastric-floating tablet comprises, by mass, 10%-30% of palbociclib, 20%-50% of hydroxypropyl methylcellulose, 20%-40% of bleaching auxiliaries, 2%-10% of foaming agents, 0%-25% of microcrystalline cellulose and 0.5%-3% of magnesium stearate. A dry granulating technology or a wet granulating technology can be used as the preparation technology. The palbociclib gastric-floating tablet is high in bioavailability, has a slow release tendency, and effectively lowers the total dosage. The palbociclib gastric-floating tablet and the preparation method thereof have the unique advantages that two different mechanisms are used for preparing the gastric-floating tablet, and accordingly the prepared tablet can keep floating in gastric juice by more than 10 hours and continuously release drugs in the hydrochloric acid solution with the pH being 1.2; the problem that the bioavailability is low due to the fact that drugs are extremely difficult to dissolve after the pH is higher than four is effectively solved; the medicine taking frequency is reduced; toxic and side effects are lightened; and the complaisance of a patient is effectively improved.

The invention belongs to the field of medicine preparations, and relates to a pharmaceutical composition prepared by a dry granulation technology. With palbociclib or a pharmaceutical salt thereof as an effective component, proper auxiliary materials such as a filler, a disintegrant, a flow aid and a lubricant are added; and the pharmaceutical composition is prepared by tabletting or capsule filling after dry granulation. The preparation provided by the invention is designed aiming at the properties and characteristics of the palbociclib or the pharmaceutical salt thereof; the palbociclib can be rapidly released; and meanwhile, various requirements such as clinical medication, patient compliance and industrial large-scale production can be met.

The invention belongs to the field of pharmacy and particularly relates to a medicinal preparation of palbociclib and a preparing method thereof. The medicinal preparation comprises palbociclib, an acidic adjuvant and an optional hydrophily high-molecular material. Compared with a conventional preparation, the medicinal preparation has more excellent solubility and in-vitro dissolution property, and can be used for enhancing in-vivo adsorption and bioavailability of palbociclib.

The invention relates to a method for preparing compound palbociclib (shown as the formula I). A compound D (shown as the formula II) serves as a raw material, and a compound E (shown as the formula III) is obtained through a rearrangement reaction of alkenyl ether; then the compound E is subjected to t-butyloxycarboryl protection group removal under the acidic condition, and target product palbociclib is obtained; an R group in a compound D is selected from any one of a C1-C6 alkyl group, a C1-C6 halogenate alkyl group, C1-C6 hydroxyalkyl and a C1-C6 naphthenic base. The process procedure and operation steps are easy and convenient, prepared palbociclib is high in purity, and good popularization prospects are achieved.

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 present invention is a palbociclib preparation method, a solid A is obtained by substitution reaction of 2, 4-dichloro pyrimidine and cyclopentyl amine, a solid B is obtained by dehydration reaction of 2,2-diacetyl-acetic acid and the solid A, a solid C is obtained by cyclization reaction of the solid B, a solid D is obtained by reaction of the solid C and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester, and palbociclib is obtained by salt-forming reaction of the solid D and ethylenehydrinsulfonic acid, the palbociclib preparation method comprises five steps, compared with the prior art, the steps are less, and comprise no step restricting enlargement of the process, the raw material is cheap, the use of expensive palladium reagents is avoided, manufacturing cost is lower; at the same time, use of bromine causing greater environmental pollution impact is avoided, and the preparation method meets the requirements of green and sustainable development.

The invention belongs to the field of pharmaceutical and chemical engineering, and particularly relates to a preparation method of palbociclib. 2-acetyl-2-butenoic acid methyl ester, malononitrile and a guanidino compound III are reacted together according to an ultrasonic-microwave assisted synthesis method, and a compound IV is rapidly obtained with a high yield; then, sodium nitrite and hypophosphorous acid are subjected to a deamination reduction reaction to generate a compound V; then, the compound V and cyclopentane halide are subjected to a coupled reaction under the action of a catalyst to generate a compound VI; finally, a dehydrogenation reaction is conducted under the action of a catalyst TPND to obtain the palbociclib. The method has the advantages that reaction conditions are mild, the technological process is simple and reasonable, reaction time is short, aftertreatment is easy, product quality is high, and the yield is high.

The invention discloses a palbociclib pharmaceutical composition, comprising palbociclib or its medicinal salt and a pharmaceutically acceptable auxiliary material, wherein the palbociclib or its medicinal salt is 50-150 Mum, and the medicinal salt includes isethionates, hydrochlorides, sulfates or benzene sulfonates.Direct mixing and capsuling process of raw and auxiliary materials is used for the pharmaceutical composition provided herein, the biological availability is high, product quality stability is good, the technical process is easy to control, inter-batch reproducibility is good, and the composition is easy to industrialize.

The invention relates to a capsule containing palbociclib and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. This product can be used in combination with letrozole for patients with advanced breast cancer. The capsule contains palbociclib, diluent, disintegrant and lubricant, wherein the mass ratio of palbociclib is 10% to 40%, and the mass ratio of diluent is 30% to 80%, The mass proportion of the disintegrating agent is 1%-10%, and the consumption amount of the lubricant is 0.5-5%. In addition, the present invention also discloses a method for preparing palbociclib capsules. The palbociclib capsules prepared by the method of the present invention have simple process and operation, and are particularly suitable for industrial production. The prepared The palbociclib capsule has good stability and good dissolution rate.

The invention belongs to the field of chemical medicine synthesis technology, and more specifically relates to a preparation method of Palbociclib isethionate. The method comprises four steps and is used for preparing Palbociclib, that is 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-one isethionate. The method has the advantages of mild process conditions, simple post-treatment, high purity, low reaction cost, and easy industrial production.

The invention relates to a preparation method of palbociclib. The method comprises the following steps: carrying out N-acetoacetylation reaction by using cyclopentylamine and an acetoacetylation agent to obtain N,N-di(acetoacetyl) cyclopentylamine (II), carrying out intramolecular condensation on N,N-di(acetoacetyl) cyclopentylamine (II) in the presence of an alkaline reagent to obtain N-cyclopentyl-3-acetyl-4-methyl-6-hydroxy-2-pyridone (III), enabling N-cyclopentyl-3-acetyl-4-methyl-6-hydroxy-2-pyridone (III) to react with a formylation reagent to prepare N-cyclopentyl-3-acetyl-4-methyl-5-formyl-6-chlorine-2-pyridone (IV), carrying out pyrimidine ring reaction by using N-cyclopentyl-3-acetyl-4-methyl-5-formyl-6-chlorine-2-pyridone (IV) and N-(5-(4-tert-butoxy carbonyl-1-hexahydropyrazinyl)-2-pyridyl) guanidine sulfate (V), and then hydrolyzing under the alkaline condition to prepare palbociclib. The preparation method of palbociclib is easily available in raw materials, short in process, simple and convenient to operate and safe and environmentally friendly in process.

The invention relates to a preparation method of high-purity palbociclib. The method comprises using acetoacetate for reflux dehydration in the function of an acid catalyst to prepare 2-acetyl-3-methyl-2-diethyl (methyl) glutaconate (III), condensing the compound (III) and trimethyl orthoformate for methanol removal to obtain 2-acetyl-3-methyl-4-methoxymethylene-2-diethyl (methyl) glutaconate (IV), cyclizing the compound (IV) and N-(5-(4-tertbutoxycarbonyl-1-hexahydropiperazinyl)-2-pyridyl) guanidine (V) with pyrimidine to obtain 2-acetyl-3-[[5-(4-tertbutoxycarbonylpiperazinyl-1-yl) pyridine-2-yl] amino]-3H-4-one-dihydropiperazinyl-2-ethyl (methyl) butenyl ester (VI), and finally cyclizing the compound (VI) and cyclopentylamine to remove Boc protecting groups, thereby obtaining palbociclib. The preparation method is cheap and available in raw materials, short in technical process, simple and convenient to operate, good in reaction selectivity, and high in product yield and purity and is green and eco-friendly.

The invention relates to the field of medicine synthesis, and discloses a preparation method of a Palbociclib intermediate. In the preparation process, 5-bromine-2,4-dichloropyrimidine is used as a starting raw material; through ammoniation substitution reaction, green solvent PEG (polyethylene glycol) promotion palladium catalysis coupled reaction, BTC (triphosgene) promotion cyclization reactionand NBS (N-bromosuccinimide) bromination reaction, a target compound V is finally obtained; through aftertreatment improvement, the HPLC purity of the final product can reach 99 percent or higher. Compared with a traditional process, the preparation method has the main beneficial effects that the reaction conditions are mild; the operation is simple and convenient; the palladium catalyst consumption is low; the yield is high; the cost is low; the three-waste quantity is small; the industrialization is easy; high implementation values and socioeconomic benefits are realized.

The invention provides a novel synthetic method of Palbociclib, comprising the following steps: 1) under the action of alkali and a solvent, an intermediate V and an intermediate B1 undergo a condensation reaction to obtain a compound VI; 2) the compound VI undergoes exchange with a Grignard reagent, and then the exchange reaction product reacts with an acylation reagent to obtain a compound VII; when X is acetyl, the compound VI is the compound VII; 3) the compound VII undergoes deprotection reaction under the action of hydroxyethanesulphonic acid and finally salification is conducted so as to obtain the finished product Palbociclib X. the synthetic method has a simple process route, is low-cost, and is suitable for industrial production. The synthetic route is as shown in the specification.

The invention relates to a palbociclib pharmaceutical composition and a preparation method thereof and belongs to the technical field of medicines. The pharmaceutical composition is prepared from the following components in percentage by mass: 27.00 percent to 28.50 percent of palbociclib, 21.00 percent to 22.5 percent of lactose, 42.50 percent to 44.00 percent of microcrystalline cellulose, 4.5 percent to 5.5 percent of sodium carboxymethyl starch, 0.5 percent to 0.8 percent of silicon dioxide and 1.2 percent to 2.0 percent of magnesium stearate. In the pharmaceutical composition, the palbociclib is used as an active component, the lactose and the microcrystalline cellulose are used as a filling agent, the sodium carboxymethyl starch is used as an efficient disintegrating agent, the silicon dioxide is used as a flow aid and the magnesium stearate is used as a lubricant; main and auxiliary materials have good compatibility and the medicine has good stability; all the components are matched with one another and have a coordinating effect; the obtained pharmaceutical composition has a good dissolution effect and a high dissolution degree, and can be sufficiently absorbed so that the curative effect is improved.

The present invention relates to solid dosage forms of palbociclib comprising a water-soluble acid. The dosage forms described herein have desirable pharmacokinetic characteristics.

The invention provides a novel preparation method for a selective kinases inhibitor Palbociclib for cyclin-dependent kinases CDK4 and CDK6, and belongs to the technical field of medicament preparation. The preparation method comprises taking 4-amino-5-bromo-2-chloropyrimidine as an initial raw material, performing acetylation with N-methoxy-N-methylacetamide to obtain an intermediate 2, performing Friedlaender reaction on the intermediate and a raw material ethyl acetoacetate to obtain an intermediate 3, and performing amino substitution on the intermediate 3 and a halogenated cyclopentane to obtain an intermediate 4; performing substitution reaction on a raw material 5-bromo-2-nitropyridine and a raw material tert-butyl 1-piperazinecarboxylate to obtain an intermediate 5, and reducing the intermediate 5 to obtain an intermediate 6; performing substitution reaction on the intermediate 4 and the intermediate 6, and performing deprotection to obtain the target product 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]-8H-pyrido[2,3-d]pyrimidin-7-one with the yield of 45% or more. A brand-new route is employed, the reaction raw materials are cheap and easy to obtain, reaction conditions are mild, noble metal catalysts are avoided, and the preparation method is suitable for industrialized production.

The invention relates to a preparation method for Palbociclib. The method comprises the following steps: taking 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridino[2,3-d]pyridine-2-yl-amino)-pyridine-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a starting raw material; performing Heck reaction, rearrangement, deprotection and neutral reaction to obtain the Palbociclib, wherein the total yield is 70 to 80 percent. According to the preparation method disclosed by the invention, non-Pd-catalyzed heck reaction is investigated, such that a phosphorus-containing ligand which is high in cost and needs harsh reaction conditions is avoided, and the production cost and the technological operation risk are reduced; acetylchloride is used for rearrangement and deprotection reaction to obtain Palbociclib hydrochloride, and the Palbociclib hydrochloride is alkalized to obtain the high-purity Palbociclib.

This invention reveals the method for preparing Palbociclib (I). The preparation includes: produce the 6-acetyl-5-methyl-2-substituent-pyrido[2,3-d]pyrimidin-7(8H)-one (IV) through the ring-closure reaction by using accessible raw materials of 1-(4-amino-2-substituent-5-pyrimidinyl) ethanone (II) and acetylacetic ester (III); produce the 6-acetyl-8-cyclopentyl-5-methyl-2-substituent-pyrido[2,3-d]pyrimidin-7(8H)-one (VI) through the substitution reaction between the intermediate (IV) and the cyclopentane halide (V); prepare the Palbociclib (I) through the condensation and hydrolysis reactions between the intermediate (VI) and 4-(6-amino-3-pyridinyl)-1-piperazinecarboxylic acid 1,1-dimethylethyl ester (VII). This method for preparing Palbociclib (I) is characterized by easily available raw materials, concise process and economy and environmental protection, and it is suitable for industrialized production.

The invention belongs to the field of pharmaceutical and chemical engineering, and particularly relates to a preparation method of palbociclib. 2-acetyl-2-butenoic acid methyl ester, malononitrile and a guanidino compound III are reacted together according to an ultrasonic-microwave assisted synthesis method, and a compound IV is rapidly obtained with a high yield; then, sodium nitrite and hypophosphorous acid are subjected to a deamination reduction reaction to generate a compound V; then, the compound V and cyclopentane halide are subjected to a coupled reaction under the action of a catalyst to generate a compound VI; finally, a dehydrogenation reaction is conducted under the action of a catalyst TPND to obtain the palbociclib. The method has the advantages that reaction conditions are mild, the technological process is simple and reasonable, reaction time is short, aftertreatment is easy, product quality is high, and the yield is high.

The invention relates to an analysis and detection method of palbociclib intermediates and impurities in the palbociclib intermediates, in particular to a mass analysis method of the palbociclib intermediates. The method comprises the step of conducting mass analysis on the palbociclib intermediates by the adoption of an efficient liquid chromatography. According to the method, an adopted chromatographic column is a chromatographic column C18, and the column temperature is 28-45 DEG C. According to the method, by the adoption of the liquid chromatography, the palbociclib intermediates and the impurities in the palbociclib intermediates are effectively separated under certain chromatographic conditions, and the content of the impurities in the palbociclib intermediates can be accurately determined by the method.

The invention relates to a medicinal composition containing an amorphous palbociclib solid dispersion. The medicinal composition contains a solid dispersion formed by palbociclib and an organic carrier, and at least one pharmaceutically acceptable auxiliary material, the palbociclib accounts for 20-80% of the total weight of the solid dispersion, and the auxiliary material accounts for 0.1-80% of the weight of the solid dispersion, wherein the palbociclib is an amorphous form, the background peaks of the organic carrier and the pharmaceutically acceptable auxiliary material exist in the X-ray powder diffracted spectrum of the composition, and the characteristic peak of palbociclib crystals does not exist in the spectrum. The invention also relates to a preparation method of the medicinal composition of amorphous palbociclib. The medicinal composition of the palbociclib has good stability and dispersibility, increases the dissolvability of the palbociclib, is in favor of improving the bioavailability of a medicinal preparation and the medicine absorption of bodies, and keeps good physical stability and chemical stability under accelerated test conditions. The preparation method of the amorphous composition has the advantages of simplicity in operation, low cost, good reappearance, easiness in realization, and suitableness for industrial production.

The invention discloses a preparation method of palbociclib. The preparation method comprises the following steps: 1) dissolving 4-(6-aminopyridine-3-yl)-piperazine-1-tertiary butyl carboxylate into asolvent A, adding an alkali reagent, activating at 0-20 DEG C, adding 6-bromine-2-chlorine-8-cyclopentyl-5-methyl-pyridino-[2,3-D]-pyrimidine-7(8H)-ketone, adjusting the solution to acid after a reaction is completed, cooling and filtering, taking filter cakes, and drying the filter cakes to obtain an intermediate I; 2) in the presence of an inert atmosphere, dissolving the intermediate I and butyl vinyl ether into a solvent B, catalyzing with a catalyst at 95-105 DEG C, cooling and separating a crystal after the reaction is completed, filtering, and taking the filter cakes, and drying the filter cakes to obtain an intermediate II; 3) dissolving the intermediate II into a solvent C, adding an acid, adjusting the solution to acid after the reaction is completed, filtering, and taking and centrifuging filtrate to obtain a target product, namely palbociclib. By adjusting reaction parameters and optimizing preparation process procedures, the preparation method is high in product yield, good in purity, simple and mild in process conditions and applicable to industrial large-scale production.

The invention discloses a method for preparing a palbociclib intermediate. The method comprises the following steps: (1) enabling a compound N-cyclopentyl-5-methyl-2-chloro-6-bromine pyridino[2,3-d]pyrimidine-7(8H)-ketone as shown in a formula (I) to react with trimethyl silicon alkyl acetylene to form a compound N-cyclopentyl-5-methyl-2-chloro-6-acetenyl pyridino[2,3-d]pyrimidine-7(8H)-ketone as shown in a formula (II) under the existence of cuprous bromide and potassium tert-butoxide; (2) hydrolyzing the compound N-cyclopentyl-5-methyl-2-chloro-6-acetenyl pyridino[2,3-d]pyrimidine-7(8H)-ketone which is obtained in step (1) and as shown in the formula (II) in an acidic aqueous solution, thus obtaining the palbociclib intermediate N-cyclopentyl-5-methyl-2-chloro-6-acetyl pyridino[2,3-d]pyrimidine-7(8H)-ketone; the formula (I) and the formula (II) are shown in the description. According to the method disclosed by the invention, a new path is developed for preparing the palbociclib intermediate, the conditions are gentle, and the yield is high.

The invention relates to the field of pharmaceutical preparations, and particularly discloses a palbociclib pharmaceutical composition and a method for preparing the same. The palbociclib pharmaceutical composition comprises, by weight, 20%-30% of palbociclib, 30%-40% of pregelatinized starch, 20%-30% of lactitol, 3%-5% of starch sodium glycollate, 4%-6% of hydroxyethyl methyl celluloses, 3%-5% ofhydroxyethyl celluloses and 1%-3% of citric acid fatty glyceride. The palbociclib pharmaceutical composition and the method have the advantages that excellent dissolution effects can be realized by the palbociclib pharmaceutical composition, the contents of related substances can be obviously reduced, the stability can be obviously enhanced, and clinical medicines can be advantageously safely used and can be advantageously stored for a long term; the particle sizes of raw auxiliary materials are controlled, accordingly, the palbociclib pharmaceutical composition is good in mixing property andflowability as discovered via experiments, and capsules can be directly filled with the palbociclib pharmaceutical composition by means of mixing.

Solid state forms of Palbociclib dimesylate, processes for preparation thereof and use thereof for preparation of Palbociclib are disclosed.

The invention discloses a method for synthesizing palbociclib. The method comprises the following steps: (1) carrying out substitution reaction between a compound of a formula VI and a compound of a formula VII, so as to obtain a compound of a formula VIII; (2) carrying out acylation reaction between the compound of the formula VIII and a compound of a formula III, so as to obtain a compound of aformula IX; (3) carrying out self-coupling on the compound of the formula IX in the presence of a metal catalyst, so as to obtain a compound of a formula X; and (4) carrying out deprotection on the compound of the formula X, so as to obtain a compound of a formula XI, namely the palbociclib. Compared with the prior art, the method has the advantages that a noble metal catalyst or a toxic dehydrogenation reagent or the like is not used, the reaction conditions are mild, the reaction selectivity is good, the total yield is relatively high, the total yield is relatively high, the liquid-phase purity of the product is high, the production cost is substantially lowered, and the method is relatively suitable for industrial production.

The invention discloses a palbociclib intermediate synthesizing method. According to the method, 2,4-dichloro-5-bromopyrimidine is utilized as a starting raw material; firstly, 5-position bromine is replaced by Grignard reaction; then, the starting material reacts with a boryl replacing reagent to generate aryl boric acid; then, the starting raw material couples with methyl 3-iodo crotonate through Suzuki reaction; then, pyrimidine ring subjects substitution reaction with cyclopentylamine under existence of organic alkali; finally, flupirtine exchange ring formation is performed to obtain palbociclib intermediate 2-chloro-8-cyclopentyl-5methyl-8H-pyrido(2,3-d)pyrimidine-7-one. Noble metal palladium on carbon in the palbociclib intermediate synthesizing method disclosed by the invention isfiltered while being heat to be recycled. The palbociclib intermediate synthesizing method has the advantages of simpleness in operation, easiness in obtaining raw materials, high product yield and suitability for industrial production.

The invention provides a preparation method of a palbociclib crystal form A. The preparation method is simple and easy to perform. The used reagents are all common reagents. The preparation method is suitable for industrial massive production. The product purity is high and meets requirements of pharmaceutical crystal form.