62 results about "Dexmedetomidine Hydrochloride" patented technology

The invention provides a new method for preparing dexmedetomidine hydrochloride. According to the method, Lewis acid is used as a catalyst, and racemized medetomidine is prepared by a Friedel-Crafts reaction; and the racemized medetomidine is resolved by (+)-di-p-toluoyl-tartaric acid [(+)-DDTA] to obtain dexmedetomidine. The dexmedetomidine is salified in hydrochloric acid to obtain dexmedetomidine hydrochloride.

The invention belongs to the technical field of drug preparation, and particularly relates to dexmedetomidine hydrochloride injection and a preparation process thereof. The dexmedetomidine hydrochloride injection comprises main materials and water for injection. The main materials comprise an active component and auxiliary materials. The auxiliary materials comprise an osmotic pressure modifier and a metal ion complexing agent. Dexmedetomidine hydrochloride serves as the active component. Sodium chloride serves as the osmotic pressure modifier. Compared with the prior art, the dexmedetomidine hydrochloride injection has the advantages that pH, content and related substance results of all embodiments are still qualified after the dexmedetomidine hydrochloride injection is subjected to high temperature, illumination and acceleration for 6 months and 24 months, and it is proved that the whole product is stable in quality. In addition, the dexmedetomidine hydrochloride injection is simple in preparation process, low in cost and beneficial to industrial production.

The invention relates to a preparation method of dexmedetomidine hydrochloride key intermediate, an [alpha]2 receptor agonist, namely 1-(2,3-dimethyl)-1-(1H-imidazole-4-yl)ethanol (I). The preparation method is characterized in that reformastsky reaction is adopted, 4-iodoimidazol (II) can be reacted with 2,3-dimethyl acetophenone (III) fast at No.1 position without the need of protection to result in target product; the preparation method has the advantages of easy control of reaction conditions, simple operation, high quality and yield of the product and great availability of raw materials, and ensures the quality of the final synthetic product, namely dexmedetomidine hydrochloride.

The invention discloses a type of 2-(2,3-dimethyl phenyl) diester malonate, a preparation method thereof, and an application thereof in an intermediate 1-(2,3-dimethyl phenyl) ethanol used for synthesizing dexmedetomidine hydrochloride. According to the invention, 2,3-dimethylbenzoic acid is adopted as an initial raw material. The initial raw material is chlorized into 2,3-dimethylbenzoyl chloride. 2,3-dimethylbenzoyl chloride is subject to a reaction with diester malonate under the existences of triethanolamine and magnesium chloride anhydrous, such that 2-(2,3-dimethyl phenyl) diester malonate is obtained. 2-(2,3-dimethyl phenyl) diester malonate is hydrolyzed with sulfuric acid, such that 1-(2,3-dimethyl phenyl)ethanone is obtained. 1-(2,3-dimethyl phenyl)ethanone is then reduced by a reducing agent, such that 1-(2,3-dimethyl phenyl)ethanol is obtained. The operation of the method is simple and convenient; the raw materials of the method are cheap and are easy to obtain; the reaction conditions are mild; and the purity of the finished products is high. With the method provided by the invention, special separating and purifying are not required. The method is suitable to be applied in large-scale productions.

The invention discloses a preparation method of a pre-filled dexmedetomidine hydrochloride injection. The preparation method of the pre-filled dexmedetomidine hydrochloride injection comprises the following steps of: A, preparing 80% of prescribed dose of water for injection, adding the prescribed dose of dexmedetomidine hydrochloride, stirring to dissolve for 5-8 minutes, then adding the water for injection to full dose, carrying out convection, and stirring and dissolving for 8-10 minutes; B, filtering a solution obtained by step A by virtue of a filter, and detecting an intermediate; and C, carrying out nitrogen filling, prefilling, encapsulation and sterilization on a solution obtained by step B, thus the pre-filled dexmedetomidine hydrochloride injection is obtained. The preparation method of the pre-filled hydrochloric acid dexmedetomidine injection has the advantages that concept is skilful, operation is simple, the problem that the dexmedetomidine hydrochloride injection is polluted in clinical application and inconvenient to use can be effectively solved, and rapidity and safety of an operation process can be guaranteed.

The invention provides nasal drops used for anesthesia. The nasal drops are characterized in that dexmedetomidine hydrochloride injection and ketamine hydrochloride are adopted as the raw materials, an osmotic pressure regulator, a bacteriostatic agent, an antioxidant, a cosolvent and a pH value regulator with certain amount are added, the steps including concentrated preparation, diluted preparation, filling, sterilizing and externally packaging are carried out, and thus the nasal drops are obtained. For the nasal drops used for anesthesia, a special administration channel does not need to beestablished, so that no pain exists during the medication process of a patient, the compliance is good, the stability is good during the storage process of the product, deterioration due to crystallization does not exists, within the period of validity, the pH of the solution basically has no change, the microbial limit is qualified, the validity period of the product is as long as 24 months or alonger time, the increased amount of impurities during the preparation process is small, the increased amount of impurities during the whole preparation process is only 0.01%, the preparation processis simple and feasible, and the nasal drops are worthy of market promotion.

The invention provides a method of measuring the content of related substance in dexmedetomidine hydrochloride active ingredient. The method comprises the following steps: analyzing the dexmedetomidine hydrochloride active ingredient by means of liquid chromatography to obtain a chromatogram conveniently; and determining the content of related substance in the dexmedetomidine hydrochloride active ingredient based on the chromatogram. The method can effectively measure impurities, initial materials and intermediates probably introduced in a synthetic process of dexmedetomidine hydrochloride and effectively control the quality of a dexmedetomidine hydrochloride drug. The method has the characteristics of effectiveness, sensitivity, specificity and accuracy.

The invention discloses a high-purity intermediate crystal of dexmedetomidine, a preparation method of the high-purity intermediate crystal, a high-purity dexmedetomidine hydrochloride crystal prepared from the high-purity intermediate crystal and a method for preparing the high-purity dexmedetomidine hydrochloride crystal from the high-purity intermediate crystal. The prepared intermediate crystal is dextro-4[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-L-(-) malate which has the purity of 99.9%, the total related substance impurity content of less than 0.10%, the single impurity content of less than 0.05%, the optical purity of 100.0% and the elemental analysis and theoretical value difference of less than 0.3% and is stable in property and easy to store; and the high-purity dexmedetomidine hydrochloride crystal, namely, 4-[1-2,3-dimethylphenyl)ethyl]-1H-imidazole hydrochloride, prepared from the intermediate crystal prepared by using the method, has the purity of 99.9%, the total related substance impurity content of less than 0.10%, the single impurity content of less than 0.05%, the optical purity of 100.0% and the elemental analysis and theoretical value difference of less than 0.3% and is stable in property and easy to store.

The invention discloses an invisible nasal sticker preparation for pediatric anesthesia preoperative sedation and a preparation method for the invisible nasal sticker preparation. Such a nasal sticker comprises an elastic biocolloid prepared from a biological skeleton material and a medicinal beta-cyclodextrin inclusion complex and a transparent back sticker. According to the nasal sticker, a high polymer biological material is adopted as a carrier, so that the nasal sticker has the advantages of stable and remarkable efficacy, small and invisible structure, convenience and comfort for use, capability of targeted delivery at an acupoint, fast action and the like. The nasal sticker has the remarkable effects that the nasal sticker preparation is applied to the Yingxiang acupoint or the nasal cavity of a child patient to be operated to make a sedative dexmedetomidine hydrochloride in the nasal sticker preparation rapidly absorbed by the nasal mucosa, so that the aim of sedation before anesthesia without influence on breathing is fulfilled, and the adverse psychological effects of muscular injection or intravenous injection on the child patient are avoided.

The invention provides a method for preparing a dexmedetomidine hydrochloride key intermediate 4-(2,3-dimethyl benzoyl)-1-triphenylmethyl imidazole. The method is characterized in that 1-triphenylmethyl-4-(N-methyl-N-methoxy) imidazole formamide is used as a raw material and reacted with a Grignard reagent of 2,3-dimethyl halogenobenzene to obtain the 4-(2,3-dimethyl benzoyl)-1-triphenylmethyl imidazole. The steps of the method are simple, the reaction can well remain on 'ketone', the yield is high, and the raw materials are rich and convenient, so the method can be effectively used for industrial large-scale production.

Disclosed is a dry powder inhalant for anesthesia. The dry powder inhalant for the anesthesia is prepared by the following steps that dexmedetomidine hydrochloride injection and ketamine hydrochloride are used as raw materials, a certain amount of carriers, active protective agents, lubricating agents and pH adjusting agents are added, and pretreatment, mixing, drying, total mixing and injected packing are conducted. According to the dry powder inhalant for the anesthesia, special medicine feeding channels do not need to be established, in the medicine taking process, patients are painless, the compliance is good, the stability in the product storing process is good, pH changing and impurity increment in the storing process are low, the impurity increment within the expiry date is only 0.06%, the expiry date of products reaches above 36 months, the flowability of the powder is good, the angle of repose is less than 42 degrees, the content uniformity is good, the content RSD of a plurality of points is less than 1%, the preparing process is simple and easy to operate, and the dry powder inhalant for the anesthesia is worthy of market promotion.

The present disclosure relates to the treatment of agitation or signs of agitation in certain human subjects, including subjects with a neurodegenerative, neuropsychiatric or opioid withdrawal disorder, by administering dexmedetomidine hydrochloride by the intravenous route.

The invention discloses an industrial preparation method of dexmedetomidine hydrochloride, and belongs to the field of medicines. The method comprises the following steps: directly carrying out a Friedel-Crafts alkylation reaction on initial raw materials comprising 1-(2,3-dimethylphenyl)ethanol not subjected to a chlorination (thionyl chloride) reaction and protected imidazole under the catalysis of a Lewis acid to obtain racemic dexmedetomidine, carrying out pre-resolution purification on the racemic dexmedetomidine through a chiral acid, carrying out chiral acid resolution and alkali dissociation, and adding a hydrochloric acid organic solvent to form a salt in order to obtain the dexmedetomidine hydrochloride. The method avoids use of the toxic and corrosive regent thionyl chloride, allows the above product with high chiral and chemical purity to be obtained and the yield to be high, and is suitable for industrial production.

The present invention provides a dexmedetomidine hydrochloride synthesis process, and relates to the technical field of drug synthesis, the dexmedetomidine hydrochloride synthesis process uses 1-(1-chloroethyl)-2,3-xylene and trimethylsilylimidazole as starting materials, and alkylation, resolution, dissociation and salification reactions are performed to synthesize the dexmedetomidine hydrochloride. According to the method, L-tartaric acid is used as a resolving agent, and the resolving efficiency is improved by controlling the proportion of the resolving agent and the number of resolving times; a one-step method is adopted for free salification, intermediate quality control and purification steps are not needed, the purity of the prepared finished product is larger than 99.8%, the isomeris not larger than 0.2%, through process optimization, the efficiency of the synthesis process is remarkably improved, and the obtained finished product directly meets the commercial production requirements of raw material medicines.

The invention relates to a dexmedetomidine hydrochloride lyophilized powder injection and a preparation method, and belongs to the field of pharmaceutical preparations. The dexmedetomidine hydrochloride lyophilized powder injection comprises, by weight, 1 part of dexmedetomidine hydrochloride and 2-20 parts of middle molecular weight dextran. The method comprises the steps that the dextran is dissolved by adding part of injection water, and stirring and filtering are conducted; the dexmedetomidine hydrochloride is taken, after the dexmedetomidine hydrochloride is dissolved by adding in citricacid-sodium citrate buffering liquid, the dexmedetomidine hydrochloride is added to a decarburized solution, and the injection water is additionally added to the full amount; the PH value is adjustedto 5.0-6.0, microfiltration is conducted, and the injection is obtained after freezing drying is conducted. The injection has the advantages of being good in resolubility, and high in stability and safety.

The invention discloses a method for preparing 2,3-dimethyl benzaldehyde. The method includes the steps that firstly, under the protection of nitrogen, a Grignard reagent is prepared from 2,3-dimethyl benzene halide; secondly, the Grignard reagent and N,N-dimethyl formamide are reacted; finally, the 2,3-dimethyl benzaldehyde is prepared through hydrolyzing, purifying and separating. The method is reasonable in design, mild in reaction condition, simple in technology and easy and convenient to operate; the obtained 2,3-dimethyl benzaldehyde is a key intermediate for synthesizing dexmedetomidine hydrochloride, the sources of the raw materials are rich, and industrial applicability is achieved.

The invention discloses a method for preparing dexmedetomidine hydrochloride for anesthesia and sedation during an operation. The method comprises the following steps: (a) stirring and reacting 2,3-dimethyl styrene and imidazole in ionic liquid to obtain 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole in the presence of an iron salt; (b) reacting the 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole with L-(+)-tartaric acid, and performing suction filtering to obtain dexmedetomidine tartrate; (c) stirring the dexmedetomidine tartrate in an aqueous solution of sodium hydroxide, performing dichloromethane extraction and concentration, and stirring in a saturated hydrochloric acid methanol solution to obtain the dexmedetomidine hydrochloride. According to the method, the ionic liquid is used for alkylation reaction of the imidazole under catalysis of the iron salt, so that the reaction time is effectively shortened, and high yield is achieved; fewer steps are required, and the cost is lower; conditions in each step are mild, use of a large amount of lewis acid is avoided, and easiness for industrial production is achieved.

The invention relates to a method for detecting bacterial endotoxin in dexmedetomidine hydrochloride by a gel process. The method comprises the following steps of: preparing a dexmedetomidine hydrochloride solution by using dimethyl sulfoxide as a solvent, and diluting the prepared dexmedetomidine hydrochloride solution by using dimethyl sulfoxide and/or a diluent I and bacterial endotoxin inspection water until a concentration not lower than a minimum effective active concentration to prepare a test solution; and carrying out bacterial endotoxin detection by adopting a gel process. By adopting the detection method, the interference effect of dexmedetomidine hydrochloride on bacterial endotoxin can be eliminated, the dilution multiple is small, the detection result is accurate and reliable, the operation is simple and convenient, the detection cost is low, and compared with photometric detection, the operation is convenient and simple.

The invention discloses a preparation process of dexmedetomidine hydrochloride for ICU (intensive care unit) sedation and analgesia. The preparation process includes the steps: first, stirring and reacting 1-(1-halogenated ethyl)-2, 3-dimethyl benzene and imidazole in ionic liquid under catalysis of ferric trichloride to obtain 4-[1-(2, 3-dimethyl phenyl) ethyl]-1H-imidazole; second, refluxing the 4-[1-(2, 3-dimethyl phenyl) ethyl]-1H-imidazole obtained in the first step and L-(+)-tartaric acid in absolute ethyl alcohol, and performing standing, cooling and suction filtration to obtain dexmedetomidine tartrate; third, stirring the dexmedetomidine tartrate in sodium hydroxide aqueous solution, extracting methylene dichloride, concentrating the solution, stirring the solution in saturated hydrochloric acid methanol solution to obtain the dexmedetomidine hydrochloride. The method is short in reaction time, high in yield, milder in condition and suitable for industrial popularization.

The invention discloses a preparation method of dexmedetomidine hydrochloride. The preparation method comprises the following steps: in a reaction solvent dichloromethane, carrying out a Friedel-Crafts reaction on 1-(1-chloroethyl)-2,3-dimethylbenzene and N-TMS imidazole under the action of lewis acid titanium tetrachloride to generate medetomidine; in a reaction solvent ethanol, resolving medetomidine by using L-(+)-tartaric acid to obtain medetomidine with a dextrorotation configuration; in a reaction solvent ethyl acetate, salifying dexmedetomidine in a hydrochloric acid solution to obtaina crude dexmedetomidine hydrochloride product; and finally, carrying out refining in a recrystallization mode to obtain a finished dexmedetomidine hydrochloride product. The preparation method has fewsteps, is simple and convenient to operate and is suitable for industrial production.

The invention discloses a method for synthesizing a dexmedetomidine hydrochloride intermediate. The synthesis method comprises the step that 1-(1-trifluoromethanesulfonate)ethyl-2,3-dimethylbenzene and imidazole are subjected to stirring reacting in ionic liquid in the presence of alkali and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride to obtain the dexmedetomidine hydrochloride intermediate 4-[1-(2,3-dimethylbenzene)ethyl]-1H-imidazole. The method is short in reacting time and high in product production efficiency and yield and has the good selectivity on a target (S)-isomer.