30 results about "Cisatracurium Besylate" patented technology

The invention discloses a method for separating and purifying cis-benzene sulfonic acid atracurium through preparative liquid chromatography, which is to use a mobile phase to dissolve benzene sulfonic acid atracurium, load the benzene sulfonic acid atracurium on a preparative liquid-phase chromatographic silica gel column, perform normal-phase or opposite-phase liquid-phase chromatographic separation under the elution of the mobile phase, and reclaim the cis-benzene sulfonic acid atracuriums, wherein immobile-phase silica gel is modified bonded silica gel, and the particle diameter of the immobile-phase silica gel is between 1 and 200 micrometers; the load ratio of the immobile-phase silica gel to atracurium is not more than 1,000; and the pressure of the silica gel column is between 250 and 400 psi. The cis-benzene sulfonic acid atracurium obtained by the method has high purity, high yield and low cost; the amount of an organic solvent used is low; the pollution is light; and the maneuverability is strong. The treatment time of the method is shortened by approximately 10 times compared with the prior art, and simultaneously the method can feed samples continuously, realize automatic operation and the like.

The present invention provides novel isoquinolinium compounds, methods of producing the isoquinolinium compounds, and methods for converting them into cisatracurium, e.g., cisatracurium besylate. The isoquinolinium compounds of the present invention can be obtained in the form of solids, which can be purified using simple techniques and can be used to afford pure cisatracurium besylate without HPLC purification

The invention discloses a preparation method of cisatracurium besylate. The method comprises the following steps: carrying out weal base dissociation on a R-tetrahydropapaverine-N-acetyl-L-leucine salt having a chiral purity of above 99.5% as a starting material so as to obtain R-tetrahydropapaverine; then carrying out a reaction on R-tetrahydropapaverine and 1,5-pentyl glycol diacrylate so as toobtain (1R,1'R)-2,2'-(3,11-dioxo-4,10-dioxa-1,13-subtridecyl) di[1,2,3,4-tetralin-6,7-dimethoxy-1-(3,4-dimethoxyl)benzyl]isoquinoline; after carrying out oxalate refinement and weal base dissociation, carrying out a reaction on (1R,1'R)-2,2'-(3,11-dioxo-4,10-dioxa-1,13-subtridecyl) di[1,2,3,4-tetralin-6,7-dimethoxy-1-(3,4-dimethoxyl)benzyl]isoquinoline and methyl benzenesulfonate so as to prepare1R,1'R-atracurium besilate; and finally, carrying out column chromatography separation on 1R,1'R-atracurium besilate so as to obtain cisatracurium besylate. By using the preparation method, the yieldof cisatracurium besylate can reach 30%, the purity of the product reaches above 98.6%, and single impurity content is below 0.3; and the process is brief, the yield is stable, and the product quality is good, thus the preparation method disclosed by the invention has an industrial application prospect.

The present invention provides R,R′-atracurium salts processes for producing and purifying such salts, and methods of using such salts to produce highly pure cisatracurium besylate.

The present invention provides a process of producing cisatracurium compounds, e.g., cisatracurium besylate, from isoquinolinium salts of the structural formula (VIIA) wherein X− is an anion and R is H or a C1-C6 alkyl, or an activated form of the carboxylic acid with 1,5-pentanediol to form a cisatracurium salt, optionally via an intermediate compound (VIII). The cisatracurium compounds can be purified using simple techniques to afford pure cisatracurium besylate without the need for HPLC purification.

The invention relates to a Cisatracurium besylate lyophilized preparation composition stable at room temperature and a preparation method thereof. The lyophilized preparation contains benzene sulfonic acid Cisatracurium besylate and a lyophilization excipient, a weight ratio of the lyophilization excipient to the benzene sulfonic acid Cisatracurium besylate (W / W) is 1:1-5:1. The lyophilized preparation overcomes the defect of cryopreservation of an existing lyophilized preparation, and is convenient for hospitals and patients for storage. The lyophilized preparation is used for muscle relaxation for operation patients.

The invention relates to the drug synthesis field and particularly relates to a preparation method of high-purity cisatracurium besylate. The preparation method comprises the steps of reacting by virtue of a compound of a formula (III) and benzenesulfonic acid, carrying out substitution reaction on an obtained compound of a formula (IV) so as to generate a compound of a formula (V), and reacting by virtue of the compound of the formula (V) with 1,5-dichloropentane so as to generate cisatracurium besylate. An intermediate and sodium hydroxide or sodium hydrogen carbonate form sodium salt in a preparation process, namely that the intermediate is purified, so that reaction conditions of a laboratory and the production are easily met and controlled, the production efficiency is high, side reaction is little, the product purity is high, and sodium hydroxide or sodium hydrogen carbonate is easily available and relatively low in price.

The invention discloses an industrial purification and preparation method for cisatracurium besylate. According to the preparation method, the refining operation process is simplified, and firstly, under the circumstance of not changing a base, high-purity cisatracurium besylate is obtained in a non-column chromatography preparation mode. By adopting the preparation method disclosed by the invention, the production cycle is shortened greatly, productivity is improved, the yield reaches 40% or above, the content of cisatracurium besylate in a product is not less than 98%, the total content of impurities is less than or equal to 2%, the content of mono-quaternaries is less than or equal to 0.5%, the content of other single maximum impurity is less than or equal to 0.5%, and the content of all isomers is less than or equal to 0.1%.

The invention relates to an industrial preparation method of cisatracurium besylate. The preparation method simplifies the refinement operation process, and obtains the high-purity cisatracurium besylate in a non-chromatographic column chromatography preparation mode under the condition of not changing the salt base for the first time. The preparation method can greatly shorten the production cycle, enhance the productivity and increase the yield to 45% above. In the product, the content of cisatracurium besylate is not lower than 98%, the content of total impurities does not exceed 2%, the content of mono quaternary ammonium salts does not exceed 0.2%, the content of other maximum individual impurities does not exceed 0.3%, and the content of isomers does not exceed 0.1%.

The invention discloses a preparation method of cisatracurium besylate. The method comprises the following steps: carrying out weal base dissociation on a R-tetrahydropapaverine-N-acetyl-L-leucine salt having a chiral purity of above 99.5% as a starting material so as to obtain R-tetrahydropapaverine; then carrying out a reaction on R-tetrahydropapaverine and 1,5-pentyl glycol diacrylate so as toobtain (1R,1'R)-2,2'-(3,11-dioxo-4,10-dioxa-1,13-subtridecyl) di[1,2,3,4-tetralin-6,7-dimethoxy-1-(3,4-dimethoxyl)benzyl]isoquinoline; after carrying out oxalate refinement and weal base dissociation, carrying out a reaction on (1R,1'R)-2,2'-(3,11-dioxo-4,10-dioxa-1,13-subtridecyl) di[1,2,3,4-tetralin-6,7-dimethoxy-1-(3,4-dimethoxyl)benzyl]isoquinoline and methyl benzenesulfonate so as to prepare1R,1'R-atracurium besilate; and finally, carrying out column chromatography separation on 1R,1'R-atracurium besilate so as to obtain cisatracurium besylate. By using the preparation method, the yieldof cisatracurium besylate can reach 30%, the purity of the product reaches above 98.6%, and single impurity content is below 0.3; and the process is brief, the yield is stable, and the product quality is good, thus the preparation method disclosed by the invention has an industrial application prospect.

The invention relates to an industrial preparation method of cisatracurium besylate. The preparation method simplifies the refinement operation process, and obtains the high-purity cisatracurium besylate in a non-chromatographic column chromatography preparation mode under the condition of not changing the salt base for the first time. The preparation method can greatly shorten the production cycle, enhance the productivity and increase the yield to 45% above. In the product, the content of cisatracurium besylate is not lower than 98%, the content of total impurities does not exceed 2%, the content of mono quaternary ammonium salts does not exceed 0.2%, the content of other maximum individual impurities does not exceed 0.3%, and the content of isomers does not exceed 0.1%.

The invention relates to injection cisatracurium besylate for storage and transportation at 25 DEG C and a preparation and freeze-drying production process of the injection cisatracurium besylate. The specific formula of the injection cisatracurium besylate includes 10 mg to 20 mg of cisatracurium besilate, 20 mg to 50 mg of dextran, 50 mg of mannitol and 2000 ml to 3000 ml of water for injection, wherein the PH of a solution containing 20% benzenesulfonic acid is properly adjusted. The freeze-drying production process includes pre-freezing, sublimation drying, re-drying, tamponade and cover rolling. By the adoption of the freeze-drying production process, the chemical stability of the medicine is improved, the cisatracurium besylate can be stored, transported and used at the temperature below 25 DEG C, product quality is guaranteed, storage and transportation conditions of a finished product are reduced, product quality is improved, and the cisatracurium besylate has the important significance in the medical application field.

The invention discloses a preparation method of an impurity W in cisatracurium besylate, and belongs to the technical field of synthesis of chemical substances. The preparation method includes the following steps: A, taking and reacting 1,5-pentanediol, glacial acetic acid and a catalyst to obtain a reaction solution; B, adding water and n-hexane to the reaction solution, performing stirring and liquid separation, and collecting the obtained aqueous layer solution; C, washing the aqueous layer solution with n-hexane, and collecting the washed aqueous layer solution; D, extracting the aqueous layer solution with dichloromethane, and collecting the dichloromethane layer solution; E, adding a drying agent to the dichloromethane layer solution, and filtering and concentrating the obtained solution to obtain 1,5-pentanediol monoacetate; and F, reacting the 1,5-pentanediol monoacetate with the impurity A in cisatracurium besylate, adding a solvent, stirring and filtering the obtained solution to obtain impurity W crystals, and drying the impurity W crystals to obtain the final product impurity W. The impurity of the prepared cisatracurium besylate is high, the preparation method is simple, and the prepared impurity W can be directly used in the quantitative detection process of the impurity W in the cisatracurium besylate as a standard.

The invention discloses cisatracurium besylate injection and a preparation method thereof. The cisatracurium besylate injection can be subjected to constant-temptation fluid preparation and storage, also can be applied in a clinical compatibility way, is high in safety, is high in medicine compliance and provides a new choice for clinical application. The injection consists of cisatracurium besylate, citric acid and ethyl alcohol, is safe and stable, and has the advantages of a moderate fluid preparation technology and storage condition and good clinical compliance.

The present invention belongs to the technical field of medicine, and particularly relates to a cisatracurium besylate composition for injection, wherein the cisatracurium besylate composition comprises 2.0 mg / mL of cisatracurium besylate, 0.8-1.5 mg / mL of methionine, 1.0-2.0 mg / mL of vitamin C, an appropriate amount of a pH value adjusting agent, and 1000 mL of water for injection. According to the present invention, vitamin C provides the anti-oxidation effect, and methionine can increase the glutathione content in vivo so as to activate acetylcholinesterase, reduce the concentration of acetylcholine, and promote the combination between cisatracurium besylate and cholinergic receptors, such that the prepared pharmaceutical composition has advantages of good stability and excellent efficacy.

The invention discloses a method for determining content of cisatracurium besylate of raw materials by an HPLC (High Performance Liquid Chromatography). New chromatographic conditions for determining the content of the cisatracurium besylate by the HPLC are established; an isocratic elution manner is adopted so that the preparation of a mobile phase is changed to one portion from two portions and the method is relatively convenient and saves time; and meanwhile, the isocratic elution is good for prolonging the service life of an instrument and a chromatographic column. According to the method, time consumed by single-needle sample feeding is 25 minutes and the checking efficiency is improved; and the consumption of the mobile phase is reduced so that the checking cost is reduced.

The invention discloses cisatracurium besylate with a new crystal form and a purifying method thereof. The purifying method comprises the following steps: (A) adding amorphous cisatracurium besylate into a polar solvent with the volume being 20-40 times of that of the amorphous cisatracurium besylate, and stirring till being completely dissolved; (B) filtering the obtained solution by a microporous filtering membrane, then putting filtrate at the temperature of 22+ / -5 DEG C, stirring for 5-30 hours; and (C) filtering to obtain filtering cakes, carrying out vacuum drying for 2-14 hours at the temperature of 30-40 DEG C to obtain white powder. The cisatracurium besylate and the purifying method disclosed by the invention have the advantages that 2theta in an X-ray diffraction pattern has main characteristic diffraction peaks at 7.0+ / -0.2, 8.6+ / -0.2, 11.2+ / -0.2, 12.8+ / -0.2, 17.4+ / -0.2, 18.5+ / -0.2, 19.4+ / -0.2, 20.8+ / -0.2 and 23.9+ / -0.2; the stability is better, and the storage and transportation of crude drugs are convenient; and the purifying method is simple and is suitable for industrial production.

The present invention provides R,R′-atracurium salts, processes for producing and purifying such salts, and methods of using such salts to produce highly pure cisatracurium besylate.

The present invention provides novel isoquinolinium compounds, methods of producing the isoquinolinium compounds, and methods for converting them into cisatracurium, e.g., cisatracurium besylate. The isoquinolinium compounds of the present invention can be obtained in the form of solids, which can be purified using simple techniques and can be used to afford pure cisatracurium besylate without HPLC purification.

The invention discloses a method for preparing impurity W in cisatracurium besylate, belonging to the technical field of chemical substance synthesis, including A. Take 1,5-pentanediol, glacial acetic acid, and a catalyst to react to obtain a reaction solution; B. Add water and n-hexane to the reaction solution, stir and separate the liquid, and collect the aqueous layer solution; C. Washing the aqueous layer solution with n-hexane, collecting the washed aqueous layer solution; D. Extract the aqueous layer solution with dichloromethane, and collect the dichloromethane layer solution; E. Add a desiccant to the dichloromethane layer solution, filter, and concentrate to obtain 1,5-pentanediol acetate monoester; F. 1,5-pentanediol acetic acid monoester reacts with impurity A in cisatracurium besylate, adds a solvent, stirs, and filters to obtain impurity W crystallization, and dry to obtain final product impurity W. The cisatracurium besylate impurity W prepared by the present invention has high purity, and the preparation method is simple, and the prepared impurity W can be directly used as a standard for the quantitative detection process of the impurity W in the cisatracurium besylate.

The present invention belongs to the technical field of medicine, and particularly relates to a cisatracurium besylate composition for injection, wherein the cisatracurium besylate composition comprises 2.0 mg / mL of cisatracurium besylate, 0.8-1.5 mg / mL of methionine, 1.0-2.0 mg / mL of vitamin C, an appropriate amount of a pH value adjusting agent, and 1000 mL of water for injection. According to the present invention, vitamin C provides the anti-oxidation effect, and methionine can increase the glutathione content in vivo so as to activate acetylcholinesterase, reduce the concentration of acetylcholine, and promote the combination between cisatracurium besylate and cholinergic receptors, such that the prepared pharmaceutical composition has advantages of good stability and excellent efficacy.

The invention provides a preparation method and application of cisatracurium besylate, and the preparation method comprises the following steps: (1) dissolving R-tetrahydropapaverine-N-acetyl-L-leucine salt, adjusting the pH value with an alkaline solution, and then mixing with methyl 3-bromopropionate and alkali for reaction to obtain an intermediate A; (2) mixing and reacting the intermediate A obtained in the step (1) with alkali to obtain an intermediate B; (3) mixing and reacting the intermediate B obtained in the step (2) with a methylation reagent to obtain an intermediate C; and (4) mixing and reacting the intermediate C obtained in the step (3), a catalyst and a dehydrating agent to obtain cisatracurium besylate. The preparation method provided by the invention is safe in production process, high in yield, few in isomer and low in maximum single impurity.

The invention relates to a preparation method of a tetrahydrobenzyl isoquinoline compound, which is characterized in that the method comprises the step of adding a specific chiral organic acid into a mixture containing a compound shown as a formula (I) to form a salt, and the chemical purity and optical purity of the prepared product of the compound shown as the formula (I) are greatly improved while the high yield is ensured. The method is favorable for improving the total yield and controlling the product quality in the synthesis process of the mivacurium chloride or cisatracurium besylate finished product, provides a powerful guarantee for improving the safety and effectiveness of the finished product medicine, and is suitable for industrial production.

The invention relates to a preparation method of a cisatracurium besylate impurity O. The preparation method comprises the following steps: S1, taking (1R)-1-[(3, 4-dimethoxyphenyl)-methyl]-1, 2, 3, 4-tetrahydro-6, 7-dimethoxy-2-methoxycarbonyl ethyl-isoquinoline, methyl benzenesulfonate, acetonitrile and a catalyst to react, so as to obtain a cisatracurium besylate impurity D; s2, taking the impurity D, 1, 5-pentanediol, dichloromethane and a catalyst to react to obtain an impurity F; s3, taking the impurity F, acryloyl chloride, dichloromethane and a catalyst to react to obtain an impurity O crude product; and S4, preparing a purified impurity O pure product through a liquid phase. According to the method, the defect that an effective method for preparing the cisatracurium besylate impurity O is lacked in the prior art is overcome, the purity of the prepared impurity O is high, the preparation method is simple, the used reagent is low in price and easy to obtain, the yield is high, and the impurities D and F can be prepared in the synthesis route.

The invention discloses a preparation method of a cisatracurium besylate intermediate. The method is as follows: compound III is freed by adding alkali, reacts with tert-butyl acrylate under the catalysis of acetic acid, and then adds oxalic acid to form a salt to obtain the compound of formula VI; compound of formula VI is freed by adding alkali, and then firstly becomes salt, and then hydrolyze the tert-butyl ester in it into carboxylic acid under heating to obtain the compound of formula VII, and then carry out esterification reaction with 1,5-pentanediol in situ to generate an esterified product, after washing the excess compound of formula VII with water, add Alkali alkalization, and then salify with oxalic acid to obtain the intermediate of formula IV. The product of the present invention has high yield and high purity, can be directly put into the cisatracurium besylate for the last step reaction without refining to finally obtain the cisatracurium besylate, and has simple aftertreatment and is easy for industrialized production.

The invention relates to novel crystal form cisatracurium besylate and a crystallization method thereof. The crystallization method comprises the following steps of: dissolving amorphous cisatracurium besylate with acetone, adding the obtained solution into an ethyl acetate solvent, and crystallizing to obtain a cisatracurium besylate crystal. The crystallization method only relates to two organic solvents, namely acetone and ethyl acetate, the dosage is relatively small, the crystallization time is short, and the crystallization method is more suitable for industrial production from the angle of amplification. Meanwhile, the prepared novel crystal form cisatracurium besylate is very high in quality, the purity can reach 99.89%, the yield can reach 99.12%, and a very good crystallization condition and purification method for cisatracurium besylate are provided.