93 results about "Pemetrexed disodium" patented technology

A crystal form of folic acid antagonistic N-(4-(2-(2-amino-4,7-methyl-4-oxo-1H-pyrrolo(2,3-d)pyrimidine-5-radical)ethyl)benzoyl)-L-glutamic acid disodium salt and its production are disclosed.

The invention relates to a pemetrexed disodium lyophilized powder injection, which consists of pemetrexed disodium, mannitol and sodium sulfite in the following weight portions: 50 portions of the pemetrexed disodium, 10 to 50 portions of mannitol, and 0.1 to 1 portions of sodium sulfite; and the pH value of the pemetrexed disodium lyophilized powder injection is between 7.0 and 8.0. The process for preparing the pemetrexed disodium lyophilized powder injection comprises the following steps: placing the mannitol in a sterile chamber; adding 80 percent of water for injection into the sterile chamber to dissolve the mannitol; adding the sodium sulfite to the mixture after the water for injection is cooled to a temperature of between 15 and 25 DEG C, and evenly stirring the solution for dissolving the sodium sulfite; then, adding the pemetrexed disodium into the solution, and stirring the solution to completely dissolve the pemetrexed disodium and evenly mixing the pemetrexed disodium, and adjusting the pH value of the solution to between 7.0 and 8.0; decarbidizing; after an intermediate compound passes examination, carrying out volume fixing, filtering, filling, partially stopping, traying, lyophilizing, nitrogen aerating, stopping and unboxing, sealing by a plastic-aluminum combined cap, and packaging after passes quality inspection to obtain the pemetrexed disodium lyophilized powder injection. The invention has the advantages of simple preparation process, convenience and practicality, good repeatability and low production cost, and can realize industrial large-scale production easily.

The invention belongs to the technical field of medication, and in particular relates to a pemetrexed disodium freeze-dried powder injection and a preparation method thereof. The pemetrexed disodium freeze-dried powder injection consists of pemetrexed disodium and mannitol, wherein the mass ratio of the mannitol to the pemetrexed disodium is (0.6-2.0):1. The preparation method comprises the following steps: adding injecting water into a liquid preparation tank; adding the pemetrexed disodium weighted according to the formula; stirring until the pemetrexed disodium completely dissolved; adding the mannitol; regulating the pH by utilizing a hydrochloric acid solution or a sodium hydroxide solution; adding activated carbon for decoloration; filtering to remove the carbon; finely filtering with a filter membrane; subpackaging; and freezing and drying. The pemetrexed disodium freeze-dried powder injection has excellent moldability; the appearance of the solution before freezing is clear; the frozen and dry product has good re-dissolubility; and the re-dissolved product has the advantages of good clarity, low impurity content, low moisture content, good stability and controllable quality.

The invention provides a method for purifying high-purity pemetrexed disodium. The method is realized by combining a salting-out method with an organic solvent / water mixed solvent crystallization method. The method provided by the invention is carried out at normal temperature; and by using the method, the quantities and contents of organic impurities and inorganic impurities in the purified products can be effectively controlled, the content of the organic impurities satisfies requirements on identification thresholds of the impurities of bulk drugs in China, and the quantity of the organic impurities is obviously reduced.

The invention relates to a freeze-dried pharmaceutical composition of pemetrexed disodium and a preparation method thereof. The invention provides a pemetrexed disodium freeze-dried composition containing pemetrexed disodium, trehalose and freeze-dried excipients, the parts by mass are 110 parts of pemetrexed disodium, 60-60 parts of trehalose 105 parts, 0-40 parts of freeze-dried excipients. The preparation process is: dissolving pemetrexed disodium, trehalose and lyophilized excipients in water, stirring until the solution is clear, adjusting the pH to 7.5-8.0 with sodium hydroxide or hydrochloric acid solution, and removing the pyrogen from the above clear solution and filter to sterilize, freeze-dry to make a sterile powdery solid pharmaceutical composition, seal the container under nitrogen protection, and pack to obtain a finished product. The pharmaceutical composition of the present invention can obviously improve local stimulation effects such as discomfort, pain and even inflammatory reaction during pemetrexed disodium infusion, and improve patient compliance.

The invention provides a preparation method of pemetrexed disodium for injection, which comprises the following steps: (1) cleaning rubber plugs, and sterilizing; (2) cleaning and sterilizing vials; (3) disinfecting aluminum-plastic caps; (4) preparing solution; (5) filling medicinal solution passing tests into the vials, and half capping; (6) vacuum freeze drying; (7) pressing the rubber plugs, boxing, rolling the caps, and carrying out visual inspection; and (8) packaging, inspecting finished products, and storing after finished product inspection is passed.

The invention provides an industrialized production method of high-purity pemetrexed disodium, comprising the following steps of: (1) adding crude pemetrexed disodium into a reactor, adding water and stirring to dissolve at a temperature of 10-30 DEG C; (2) adding tetrahydrofuran or acetonitrile serving as a dissolvent into the reaction solution of the step (1), dissolving out a part of solids, adding kieselguhr or silica gel and stirring for 5-30 minutes; and (3) filtering the reaction solution of the step (2), adding dissolvent same as the dissolvent added in the step (2) into filtrate, crystallizing for 0.5-10 hours at a temperature of 10-30 DEG C, isolating solids, and drying for 0.5-10 hours at a temperature of 20-40 DEG C to obtain the high-purity pemetrexed disodium. By means of the production method, the shortcomings that in the prior art column chromatography, purification and heating are needed, the product purity is low, the operation is cumbersome and the industrialized production is difficult to realize are overcome; the production method is simple and convenient for operation, is easy to realize the industrialized production and has the advantages of few consumption of dissolvent, energy saving, environmental protection and low labor intensity; and the products have the advantages of white color, high purity, less than 0.05% of impurities in a single product and good stability.

The invention discloses pemetrexed disodium liposome injection which is mainly made of pemetrexed disodium and a preparation method thereof, distearoyl phosphatidyl glycerol, dipalmitoyl phosphatidyl choline, PEG600, cholesterol and mannitol. The liposome injection has the advantages that the particle size of liposome is small, the liposome is uniformly distributed, the encapsulation efficiency is high, the leakage rate is low, the stability is good, the solubility of the pemetrexed disodium and the quality of injection products are improved, the toxic and side effect is reduced, and the curative effect is improved.

The invention discloses an amorphous polymorph for pemetrexed disodium and a preparation method thereof. An X-ray powder diffraction pattern of the amorphous polymorph does not contain an identifiable diffraction peak form. For not containing crystal water, the amorphous polymorph for the pemetrexed disodium is simple to dry on production, does not need special equipment, has low production cost, and is suitable for industrial production.

The present invention relates to new compound diethyl 4-(4-oxobutyl) benzoyl-L-glutamate and its preparation process and application. The compound diethyl 4-(4-oxobutyl) benzoyl-L-glutamate in the chemical expression as shown is prepared through the reaction of compound diethyl 4-bromo benzoyl-L-glutamate and 3-butene-1-alcohol inside Nú¼N-dimethyl formamide solvent under the action of palladium acetate catalyst, weak alkali reagent, lithium halide and phase transfer catalyst in the protection of inert gas at 50-70 deg.c. The compound diethyl 4-(4-oxobutyl) benzoyl-L-glutamate is used in synthesizing diethyl 4-[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate as the intermediate of Pemetrexed disodium. The present invention results in shortened Pemetrexed disodium synthesizing path and lowered production cost.

The invention provides a preparation method of pemetrexed disodium, which comprises the steps of performing hydrolysis reaction of 4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] methyl benzoate in sodium hydroxide to generate acid, then condensing with L-glutamic acid diethyl ester to obtain N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester toluenesulfonate, obtaining the crude pemetrexed disodium through saponification under the action of sodium hydroxide, and finally crystallizing in a mixed solvent at room temperature to obtain the end product. With the adoption of the technical scheme, the purification and purification of the crude pemetrexed disodium can be directly performed, so that the cost can be effectively lowered. As the steps are carried out at room temperature, the oxidation of the pemetrexed disodium caused by high temperature can be effectively avoided. The purity of the end product is high and meets the national requirement on purity of chemicals.

The invention provides a method for preparing a pemetrexed disodium 2.5 water crystal. The method comprises the following steps of: (1) dissolving a raw material, namely pemetrexed disodium in water; (2) dropwise adding the aqueous solution of the pemetrexed disodium into an organic solvent which can be miscible with the water, and crystallizing; and (3) filtering, collecting a filter cake, and drying to obtain a target product. The preparation method is high in controllability, easy and convenient to operate, high in repeatability, high in production yield, and stable in crystal form and industrial production is easy to implement, and special equipment is not required.

The invention discloses a pemetrexed disodium freeze-dried powder injection for injection and a preparation method thereof. The pemetrexed disodium freeze-dried powder injection contains disodium hydrogen phosphate and dipotassium hydrogen phosphate buffer salt, wherein the weight ratio of disodium hydrogen phosphate to dipotassium hydrogen phosphate is (8-10):1, and the pH value of liquid medicine is 6.5-7.5 before freeze-drying. The pemetrexed disodium freeze-dried powder injection disclosed by the invention enhances the pharmaceutical stability, has the advantages of less auxiliary material variety and usage amount, more safety and reliability and simple preparation process, and meets the requirement for mass production.

The invention belongs to the field of pharmaceutical preparations and the technical field of breast cancers, and discloses a preparation method and application of a soluble nano drug delivery system inhibiting multidrug resistance breast cancer growth. According to the preparation method and application, water-soluble super-molecular organic framework (SOF) nano particles server as carriers for the first time, the system is obtained through self-assembly of tetrahedral molecules obtained through tetraphenylmethane derivatization and CB[8] in a water phase, and chemotherapy drugs such as neutral drug doxorubicin and anionic drug pemetrexed disodium, folate derivatives, targeted integrin specific ligands such as RDG peptide derivatives and infrared probe molecules such as IR-820 can be loaded simultaneously; the SOF nano-drug carrier has the release characteristic of pH dependence, is accumulated in tumor tissue at high concentration, has a specific growth inhibiting effect on tumor cells with drug resistance in the tumor tissue due to P-glycoprotein overexpression and can obviously increase the retention volume of a chemotherapy drug in multidrug resistance breast cancer tissue, effectively inhibit the multidrug resistance breast cancer growth and significantly improve the curative effect on a multidrug resistance breast cancer.

The invention relates to an injection composition, and in particular relates to an injection composition of pemetrexed disodium and a preparation method of the injection composition. The injection composition is prepared from pemetrexed disodium, mannitol and beta-cyclodextrin. The injection composition of pemetrexed disodium is simple in preparation process and effectively reduces the preparation cost. The pemetrexed disodium freeze-dried powder prepared by the invention has the advantages of excellent dissolvability, few impurity content, low moisture content and good stability.

The invention relates to a disodium salt key point intermediate 1-nitro -2-(2, 6-diamino -4-(3H) oxo-metadiazine -5-group)-4 - (4-carboxyl phenyl)-1-butagas in the field of chemistry and medicine. It also discloses a method for preparing for the compound and the method for using the intermediate to synthesize the disodium salt.

The invention discloses related substances F and G of pemetrexed disodium as well as preparation and detection researches on the two substances. Remarkable economic and technical benefits can be made for improvement of the quality and the safety of medicines of pemetrexed disodium. The chemical formulae of the two substances are as shown in the specification.

A stable ready-to-use pharmaceutical composition comprising pemetrexed or pharmaceutically acceptable salts thereof, wherein the composition is free from antioxidants, amino acids and chelating agents. Also provided is a process for preparing a stable ready-to-use pharmaceutical composition comprising the steps: i) purging inert gas into a parenterally acceptable aqueous solvent until the dissolved oxygen content of the solvent comes to less than 7 mg / L, preferably less than 3 mg / L; ii) adding pemetrexed disodium under stirring; iii) adjusting the pH of the resulting solution to between 4 to 9; iv) optionally adding additional aqueous solvent; wherein the composition is purged with inert gas throughout the entire process.

The invention relates to a method for analyzing and detecting a pemetrexed disodium intermediate. The method is used for quality control of the pemetrexed disodium intermediate. According to the method, octadecylsilane chemically bonded silica serves as a chromatographic column of packing (C18, 4.6*250mm, 5 micrometers), a monopotassium phosphate solution and acetonitrile serve as a mobile phase, the detection wavelength is 249-259nm, and high performance liquid chromatography is performed for analysis and detection. According to the analysis and detection method, the pemetrexed disodium intermediate can be effectively separated from impurities thereof, and the method has the advantages of high separation degree, good linear relation, simple operation, high repeatability and durability and stable and reliable result.

The invention discloses application of pemetrexed disodium or pharmaceutically-acceptable salt thereof in preparing medicine for treating or preventing herpes virus infection. According to the application, pemetrexed disodium of a completely non-cytotoxic concentration is selected and used for conducting a herpes virus resisting experiment, the result shows that the compound has significant herpes virus resisting activity in dose dependency, and pemetrexed disodium performs the herpes virus resisting effect by inhibiting virus reproduction. Detection of herpes viruses of different subtypes shows that pemetrexed disodium has broad-spectrum herpes virus resisting activity, is high in selection index, can be developed into medicine for treating or preventing herpes virus infection and has broad application prospects.

The invention discloses pemetrexed disodium for injection. The pemetrexed disodium for injection comprises the components in part by weight as follows: 50-60 parts of a pemetrexed disodium compound, 20-40 parts of mannitol and 2-4 parts of arginine. Besides, the invention further provides the pemetrexed disodium compound, the stability of the pemetrexed disodium compound is improved remarkably, the organic solvent residual volume is low, the quality can be controlled, and the pemetrexed disodium compound can be placed for a long time and cannot change easily, so that the medication safety for a patient is improved greatly.

The invention relates to the technical field of medicine, and specifically provides a preparation process for synthesizing high-purity Pemedolac. The invention solves the problem that the original process has very low enlarging yield by preparing a stable and high-purity intermediate sodium 3-(4-methoxycarbonyl)phenyl-1-hdyroxypropylsulphonate, establishes a fundamental base for preparing the high-purity Pemedolac at the same time, and further effectively controls the production of key impurities by using weak alkali salts of Pemedolac in a final purification stage; thus, the yield of the production process is high, and the quality of the product is extremely good; and the method is more convenient to prepare a high-purity anticancer drug pemetrexed disodium. At the same time, the preparation process provided by the invention has mild process conditions; the solvent is convenient to be recycled and applied mechanically; the preparation process provided by the invention is more energy-saving and environment-friendly. The structure of the Pemedolac is shown in the specification.

A preparation method of pemetrexed disodium is disclosed. The preparation method comprises the following steps: (1) dissolving 30-35 parts of 2-(3-(trifluoromethyl)phenyl) malonate and 15-20 parts ofN-(pyridin-5-yl methyl) pyridine-2-amine in a solvent, adding a catalyst, and carrying out a sealed stirring reaction under a microwave condition to obtain a crude product; and (2) removing the solvent from the crude product under reduced pressure, adding ethyl acetate, uniformly stirring, and carrying out silica gel column chromatography to obtain the pemetrexed disodium. According to the method,the 2-(3-(trifluoromethyl)phenyl) malonate and the N-(pyridin-5-yl methyl) pyridine-2-amine directly react under the conditions of the catalyst and microwaves, the reaction process is only one step,the reaction process is greatly shortened, and the yield of pemetrexed disodium is increased.

The invention relates to a preparation method of a pemetrexed disodium key intermediate, more specifically to a high-yield preparation method of the pemetrexed disodium key intermediate. The preparation method comprises the following steps: (a) with a compound of a formula (I) as a raw material, carrying out a Heck reaction with allyl alcohol to obtain a compound of a formula (III); (b) removing one molecule of water by utilizing a dehydrating agent after condensing the compound of the formula (III) with nitromethane to obtain a compound of a formula (IV); (c) carrying out a Michael addition reaction on the compound of the formula (IV) to generate a compound of a formula (V); and (d) carrying out a Nef reaction on the compound of the formula (V) to obtain a compound of a formula (I). The preparation method of the pemetrexed disodium key intermediate has the advantages of having a short reaction process, not existing harsh reaction conditions, shortening the reaction time and being capable of remarkably improving the yield of products.

The invention belongs to the pharmaceutical chemistry field and relates to a crystal form of a key intermediate of the folic acid inhibitor medicine pemetrexed disodium and a preparation method of the intermediate. The pemetrexed methyl ester p-toluenesulfanate provided by the invention has stable crystal form and high purity, thus the purity of pemetrexed methyl ester can be effectively increased, the problem of the complicated extraction of pemetrexed methyl ester can be solved, the pemetrexed methyl ester p-toluenesulfanate has positive influence on the increase of the quality of the subsequent product pemetrexed disodium and industrial production can be performed easily.

The invention discloses a preparation method of pemetrexed disodium, which can directly hydrolyzing into salt after an organic solvent is removed, rather than salifying together with p-toluenesulfonic acid and / or purifying a product by adopting a crystallization method during the preparation process, thus omitting the step of salifying together with p-toluenesulfonic acid and / or crystallization through ethanol, effectively improving the total yield of drugs to 68-75%; in the preparation process, a peptide condensing agent is firstly prepared and is fully reacted with pemedolac in the organic solvent into transient-state acid ester, so that the generation of N-methylation impurities can be effectively inhibited in the reaction together with L-glutamic acid diethyl ester hydrochloride, the defect that the content of N-methylation impurities during the one-pot preparation process in the prior art exceeds 0.1% can be avoided, the advantages for opening up Europe and America markets can be brought, the defect that the raw materials are not reacted thoroughly to cause high cost can also be overcome; the HPLC (High Performance Liquid Chromatograph) of the finished pemetrexed disodium obtained by adopting the method is more than or equal to 99.8%, and the content of single impurities is less than 0.1%.

The invention discloses a synthesis method for an intermediate of an impurity A of pemetrexed disodium and belongs to the field of drug synthesis. (4-(2-(2-amino-1-methyl-4,7-dihydro-4-oxo-1H-pyrrolo(2,3-d)pyrimidine-5-yl)ethyl)benzoyl)-L-glutamic acid is an impurity A of pemetrexed disodium, and 4-(2-(2-amino-1-methyl-4,7-dihydro-4-oxo-1H-pyrrolo(2,3-d)pyrimidine-5-yl)ethyl)methyl benzoate is an important intermediate required for synthesis of the impurity A. The synthesis method of the intermediate comprises the following steps: carrying out a reaction on a compound I 1-methylguanidine and a compound II ethyl cyanoacetate to obtain a compound III 2,6-diamino-4-carbonyl-1-methylpyrimidine, and carrying out a reaction on a compound IV 4-(4-carbonyl-3 brombutyl)methyl benzoate and the compound III to obtain a compound V 4-(2-(2-amino-1-methyl-4,7-dihydro-4-oxo-1H-pyrrolo(2,3-d)pyrimidine-5-yl)ethyl)methyl benzoate.