30 results about "Pralatrexate" patented technology

The invention discloses a pralatrexate (I) preparation method, which comprises the following preparation steps: performing cyclization reaction on dialkyl N-[4-(1-(2-propinyl)-3,4-dioxo-n-butyl)benzoyl]-L-glutamate (II) and 2,4,5,6-tetraminopyrimidine (III) under oximation conditions to generate an intermediate compound alkyl N-[4-[1-(2,4-diamino-6-pteridine)methyl-3-butynyl]benzoyl]-L-glutamate (IV); and performing hydrolysis reaction on the intermediate compound (IV) to prepare pralatrexate (I). The preparation method is accessible in raw materials, simple in process, economic, environment-friendly and suitable for industrial production.

The present invention discloses a practical synthesis process of a new anticancer drug pralatrexate. According to the present invention, 10-propargyl-10-methoxycarbonyl-4-deoxy-4-amino-10-deaza pteroic acid methyl ester is adopted as a starting raw material, a saponification reaction is performed to obtain 4-(2-carboxy-1-(2,4-diaminopteridine-6-yl)pent-4-yn-2-yl)benzoic acid, the 4-(2-carboxy-1-(2,4-diaminopteridine-6-yl)pent-4-yn-2-yl)benzoic acid is subjected to decarboxylation to obtain 4-(1-(2,4-diaminopteridine-6-yl)pent-4-yn-2-yl)benzoic acid, the 4-(1-(2,4-diaminopteridine-6-yl)pent-4-yn-2-yl)benzoic acid reacts with L-diethyl glutamate to obtain 10-propargyl-10-deaza aminopterin diethyl ester, and finally a saponification reaction is performed to obtain the target product pralatrexate, wherein the green, high yield and convenient synthesis of the pralatrexate is completed, the final product can achieve the level from several grams to tens of grams, the purity is more than or equal to 90%, and the good industrial application prospects are provided.

The invention discloses a novel medical compound 4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate (I) and a preparation method thereof. The preparation method comprises the following steps of carrying out an addition reaction on 4-carbalkoxy benzaldehyde (II) and 3-propargyl bromide (III) to generate 4-(1-hydroxyl-3-butyne) benzoate (IV); and carrying out a coupled reaction on an intermediate (IV) and pyruvaldehyde dialkyl acetal (V) after being subjected to enolization under the action of a metal catalyst to form the 4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate (I). According to the intermediate (I) and the preparation method thereof, a novel preparation way for the antineoplastic pralatrexate is provided and the economic and technological development of the pralatrexate is promoted.

The invention specifically relates to a preparation method for high-purity pralatrexate intermediate, belonging to the technical field of medicine. The preparation method is based on preparation of PLQS-3 and comprises the following steps: preparing crude PLQS-3 by using a crystallization solvent; then heating and washing the crude PLQS-3 with a single solvent, and carrying out filtering while the crude PLQS-3 is still hot so as to obtain high-purity PLQS-3; subjecting the PLQS-3 to hydrolysis with an appropriate amount of inorganic alkali liquor at a certain temperature; adding excess hydrochloric acid into a hydrolysis solution to obtain a hydrochloride; and refining the hydrochloride with a solvent such as anhydrous ethanol to obtain high-purity PLQS-4 hydrochloride. According to the invention, the purity of PLQS-4 is improved through refining of the crude PLQS-3; and the preparation method can be well used in the production of pralatrexate.

The invention relates to a pralatrexate degradation impurity and a preparation method thereof. Specifically, the formula (I) of the pralatrexate degradation impurity is N-[4-1- [(2-amino-4-hydrox-6-pteridine) methyl]-3-butine-1-group] benzoyl]-L-glutamate. An N-[4-1- [(2-amino-4-diamido-6-pteridine) methyl]-3-butine-1-group] benzoic acid compound is subjected to substitution, condensation and hydrolysis, and a target compound is obtained, so that the pralatrexate degradation impurity is synthesized. According to the method, the compound of the formula (I) is chemically synthesized for the first time, and the obtained target compound can be separated efficiently and rapidly.

The invention discloses a small-molecule inhibitor of influenza virus. The small-molecule inhibitor is pralatrexate, the structural formula of the pralatrexate is shown as a formula I, and the small-molecule inhibitor can inhibit influenza viruses, specifically influenza A viruses such as H1N1, H5N1 or H5N6 subtype influenza viruses. The research finds that the small-molecule inhibitor has a remarkable inhibition effect on H1N1, H5N6 and H5N1 subtype influenza viruses, and the compound shown in the formula I has broad-spectrum anti-influenza A virus potential preliminarily; meanwhile, the toxicity of the small-molecule inhibitor to cells is small, the CC50 of the small-molecule inhibitor to MDCK cells is larger than 200 mu M, the CC50 / EC50 ratio (namely the selectivity index SI) is larger than 200, and the small-molecule inhibitor can be used as a safe and effective anti-influenza virus medicine.

The invention discloses a preparation process for a high-purity pralatrexate intermediate. A purification tank is used in the process; a driving chamber is arranged in the purification tank, and the purification tank is internally provided with a driving mechanism for powering the operation of a device used in the process; a dissolution chamber and a crystallization chamber are also arranged in the purification tank; the lower end walls of the dissolution chamber and the crystallization chamber are both internally provided with filtering mechanisms; an air inlet mechanism is arranged in the right end wall of the crystallization chamber; the driving chamber is internally provided with a control mechanism for controlling the operation of the filtering mechanism and the air inlet mechanism. When the device is used for purification of a pralatrexate intermediate, the cooling of a dissolved solution is accelerated in the manners of rotary stirring, bubble stirring and acceleration of gas flow in the crystallization chamber, so the precipitation of crystals in the dissolved solution is accelerated, which thus accelerates purification efficiency; the device carries out both dissolving andcrystallization, so the degree of automation is increased; and dissolving is accelerated by mechanical transmission.

The invention provides a pralatrexate crystal form and a preparation method thereof, and concretely relates to a pralatrexate E crystal form, a preparation method thereof, a crystallized composition containing the pralatrexate E crystal form, and a medicinal composition containing the pralatrexate E crystal form. The pralatrexate E crystal form prepared in the invention has the advantages of high purity, high degree of crystallization, and good stability; and the preparation method of the pralatrexate E crystal form has the advantages of simplicity, cheap and easily available solvent, mild crystallization conditions, and suitableness for industrial production.

The invention relates to a pralatrexate degradation impurity and a preparation method thereof. Specifically, the formula (I) of the pralatrexate degradation impurity is N-[4-1- [(2-amino-4-hydrox-6-pteridine) methyl]-3-butine-1-group] benzoyl]-L-glutamate. An N-[4-1- [(2-amino-4-diamido-6-pteridine) methyl]-3-butine-1-group] benzoic acid compound is subjected to substitution, condensation and hydrolysis, and a target compound is obtained, so that the pralatrexate degradation impurity is synthesized. According to the method, the compound of the formula (I) is chemically synthesized for the first time, and the obtained target compound can be separated efficiently and rapidly.

The invention belongs to the technical field of medicine and particularly relates to a refining method of a pralatrexate intermediate. The method comprises the following steps: adding a crude productof an intermediate 10-propargyl-10-deazaaminopterin dimethyl ester (PLQS-6) to a refining solvent to be heated and dissolved; performing activated carbon decoloration and hot filtration; cooling, stirring and crystallizing the filtrate; and washing the filter cake with the refining solvent so as to obtain a high-purity pralatrexate intermediate PLQS-6. The used refining solvent is a low-boiling-point solvent, so that the problem of excessive solvent residues such as DMF (dimethyl formamide) and DMSO (dimethyl sulfoxide) is avoided, the refining solvent can also be recycled, and the cost is saved. The method provided by the invention has the advantages that application of column chromatography separation is avoided, the yield is improved, the whole technological operation is simplified, theoperation method is simple, the yield and the purity of the obtained pralatrexate intermediate are higher, and the method is suitable for industrial production.

The disclosure relates generally to alpha polyglutamated pralatrexate, formulations containing liposomes filled with alpha polyglutamated pralatrexate, methods of making the alpha polyglutamated pralatrexate and liposome containing formulations, and methods of using polyglutamated alpha polyglutamated pralatrexate and liposome containing formulations to treat hyperproliferative disorders (e.g., cancer) and disorders of the immune system (e.g., an autoimmune disease such as rheumatoid arthritis).

The invention discloses a crystal form of pralatrexate, a pharmaceutical composition containing the pralatrexate, and a preparation method and an application of the pralatrexate. According to the crystal form, in an X-ray powder diffraction pattern using a radiation source as Cu-Kalpha, characteristic absorption peaks are formed at the diffraction angles 2theta of 8.29 degrees, 15.73 degrees, 16.72 degrees, 17.21 degrees, 18.46 degrees, 19.01 degrees, 21.38 degrees, 25.25 degrees and 25.56 degrees; and the error range of 2theta is + / -0.2 degrees. The preparation method of the crystal form disclosed by the invention comprises the following steps: heating and dissolving pralatrexate into a good solvent; and dropwise adding an anti-solvent until turbidity is achieved, naturally cooling, and devitrifying, so as to obtain the crystal form. The crystal form of the pralatrexate disclosed by the invention has the advantages of high purity, good stability and the like.

The invention provides a high-purity Pralatrexate solid and its preparation method. The high-purity Pralatrexate solid provided by the invention is prepared by recrystallization of an aqueous solution of lower alkyl ketone and has advantages of high purity, low individual impurity content, good stability, high safety and the like. Meanwhile, the preparation method of the high-purity Pralatrexate solid provided by the invention can be adopted to effectively remove IN0222(2,4-diamido-6-chloromethylpteridine) or its analogue and raise safety of medicine. In addition, the preparation method of the high-purity Pralatrexate solid is simple, a solvent is cheap and easily available, and crystallization condition is mild. The preparation method is suitable for industrial production.

The invention belongs to the technical field of medicine, and in particular relates to a preparation method of a pralatrexate intermediate. The invention provides a method for preparing an intermediate α-propargyl-(4-methyl formate)-methyl phenylacetate with simpler operation and lower impurity content, especially the proportion of bispropargyl impurities generated in the product Obviously reduce, the yield of the target product α-propargyl-(4-methyl formate)-methyl phenylacetate of generation obviously increases, and the purity of product improves greatly, can be applied to large-scale production of pralatrexate bulk drug and The preparation of its intermediates.

The present invention relates to compositions and methods for treating lymphoma in a subject in need thereof, said methods comprising administering to the patient in need thereof a therapeutically effective amount of a combination of belinostat and pralatrexate, wherein said therapeutically effective amount results in a synergistic antiproliferative effect on cancer cell growth.

The invention discloses a medical intermediate N-[4-(1-(2-propinyl)-3, 4-dioxo-n-butyl) benzoyl]-L-glutamic dialkyl ester (I) and a preparation method thereof. The preparation method comprises the following steps of carrying out a condensation reaction on 4-(1-hydroxyl-3-butyne) benzoic acid (II) and L-glutamic dialkyl ester (III) to generate N-[4-(1-hydroxyl-3-butyne) benzoyl]-L-glutamic dialkyl ester (IV); and carrying out a coupled reaction on the intermediate (IV) and methylglyoxal dimethylacetal subjected to enolization to generate the N-[4-(1-(2-propinyl)-3, 4-dioxo-n-butyl) benzoyl]-L-glutamic dialkyl ester (I). According to the intermediate (I) and the preparation method thereof, a novel preparation way for the antineoplastic pralatrexate is provided and the economic and technological development of the pralatrexate is promoted.

The present invention relates to compositions and methods for treating lymphoma in a subject in need thereof, said methods comprising administering to the patient in need thereof a therapeutically effective amount of a combination of belinostat and pralatrexate, wherein said therapeutically effective amount results in a synergistic antiproliferative effect on cancer cell growth.

The invention specifically relates to a preparation method for a pralatrexate intermediate, belonging to the technical field of medicine. According to the preparation method for the intermediate alpha-propargyl-(4-methylformate)-methylphenyl acetate, operation is more convenient and the content of impurities is lower; and in particular, the ratio of dithropropyl impurities in the produced intermediate is obviously reduced, the yield of the target product alpha-propargyl-(4-methylformate)-methylphenyl acetate is significantly increased, and product purity is greatly improved. The preparation method can be applied to large-scale production of pralatrexate bulk drugs and preparation of pralatrexate intermediates.

The invention discloses a preparation method of Pralatrexate (I). The preparation method comprises the following steps of: hydrolyzing N-[4-(1-(2-propinyl)-3,4-dioxo n-butyl)benzoyl]-L-glutamic acid dialkyl ester (II) to generate an intermediate N-[4-(1-(2-propinyl)-3,4-dioxo n-butyl)benzoyl]-L-glutamic acid (IV); and performign cyclization reaction on the intermediate (IV) and 2,4,5,6-tetra-aminopyrimidine (III) under the condition of oxime formation to prepare the Pralatrexate (I). The raw materials are easily available, the process is simple, and the preparation method is economical, environmentally-friendly and suitable for industrial production.

The invention discloses a crystal form of pralatrexate, a pharmaceutical composition containing the pralatrexate, and a preparation method and an application of the pralatrexate. According to the crystal form, in an X-ray powder diffraction pattern using a radiation source as Cu-Kalpha, characteristic absorption peaks are formed at the diffraction angles 2theta of 8.29 degrees, 15.73 degrees, 16.72 degrees, 17.21 degrees, 18.46 degrees, 19.01 degrees, 21.38 degrees, 25.25 degrees and 25.56 degrees; and the error range of 2theta is + / -0.2 degrees. The preparation method of the crystal form disclosed by the invention comprises the following steps: heating and dissolving pralatrexate into a good solvent; and dropwise adding an anti-solvent until turbidity is achieved, naturally cooling, and devitrifying, so as to obtain the crystal form. The crystal form of the pralatrexate disclosed by the invention has the advantages of high purity, good stability and the like.

The invention discloses a pralatrexate (I) preparation method, which comprises the following preparation steps: performing cyclization reaction on dialkyl N-[4-(1-(2-propinyl)-3,4-dioxo-n-butyl)benzoyl]-L-glutamate (II) and 2,4,5,6-tetraminopyrimidine (III) under oximation conditions to generate an intermediate compound alkyl N-[4-[1-(2,4-diamino-6-pteridine)methyl-3-butynyl]benzoyl]-L-glutamate (IV); and performing hydrolysis reaction on the intermediate compound (IV) to prepare pralatrexate (I). The preparation method is accessible in raw materials, simple in process, economic, environment-friendly and suitable for industrial production.

The invention belongs to the technical field of medicine and particularly relates to a preparation method of pralatrexate finished products. The method comprises the following steps: by taking PLQS-6as a raw material and respectively taking acetone, methyl ethyl ketone, butanone, dioxane and the like as solvents, performing temperature control, and dropwise adding inorganic base in batches to control the generation of impurities; after the reaction is completed, dropwise adding a crystallization solvent to enable pralatrexate to be crystallized; collecting pralatrexate crystallized solids; adding the solids to purified water to be dissolved; performing washing with dichloromethane; and then, adjusting the pH value with acetic acid to obtain pralatrexate solids. The synthetic method provided by the invention is simple and easy to operate, the impurities are easy to remove, the yield and the purity of the prepared pralatrexate are higher, and the method is suitable for industrial production.

The invention belongs to the technical field of medicine, and in particular relates to a method for refining a pralatrexate intermediate. The method comprises the steps of: adding the crude product of the intermediate 10-propargyl-10-desazaaminopterin dimethyl ester (PLQS-6) into a refined solvent, heating and dissolving, decolorizing activated carbon, hot filtering, cooling the filtrate and stirring for crystallization, The filter cake is washed with a refined solvent to obtain a high-purity pralatrexate intermediate PLQS‑6. The refined solvents used are all low-boiling solvents, which not only avoids the problem of excessive dissolved residues of DMF and DMSO, but also facilitates the recycling of refined solvents and saves costs. The application of column chromatographic separation is avoided, the yield is improved, the entire process operation is simplified, the operation method is simple, the yield and purity are high, and the method is suitable for industrial production.

The invention relates to the technical field of medicinal chemistry, in particular to the synthesis of anticancer drug 10-Propargyl-10-deazaaminopterin Pralatrexate and its intermediates. The present invention provides a method with simpler operation, lower product-related impurity content, easier purification of intermediates, avoiding the purification method of column chromatography, and can be applied to the preparation of large-scale production of pralatrexate raw materials and its important intermediates and purification methods.

The invention relates to a pralatrexate composition, and especially relates to a stable pralatrexate injection as well as a preparation method and application thereof. The pralatrexate injection comprises pralatrexate, a pH regulator, an isotonic agent and water for injection, and optionally further comprises a stabilizer, wherein the pH value of the pralatrexate injection is 6.5-7.3. The pralatrexate injection prepared by the invention has the advantages of simple process, low cost, safety, reliability, good stability, convenience in clinical use, suitability for industrial production and thelike.

The disclosure relates generally to gamma polyglutamated pralatrexate compositions, including delivery vehicles such as liposomes containing the gamma polyglutamated pralatrexate, and methods of making and using the gamma polyglutamated pralatrexate compositions to treat hyperproliferative disorders (e.g., cancer) and disorders of the immune system (e.g., inflammation and autoimmune diseases such as rheumatoid arthritis).