- Development and validation of a chiral LC-MS method for the enantiomeric resolution of (+) and (?)-medetomidine in equine plasma by using polysaccharide-based chiral stationary phases
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The detection and separation of medetomidine enantiomers from the complex biological matrices poses a great analytical challenge, especially in the field of forensic toxicology and pharmacology. Couple of researchers reported resolution of medetomidine using protein-based chiral columns, but the reported method is quiet challenging and tedious to be employed for routine analysis. This research paper reported a method that enables the enantio-separation of medetomidine by using polysaccharide cellulose chiral column. The use of chiralcel OJ-3R column was found to have the highest potential for successful chiral resolution. Ammonium hydrogen carbonate was the ideal buffer salt for chiral liquid chromatography (LC) with electrospray ionization (ESI)+ mass spectrometry (MS) detection for the successful separation and detection of racemic compound. The method was linear over the range of 0 to 20 ng/mL in equine plasma and the inter-day precisions of levomedetomidine, dexmedetomidine were 1.36% and 1.89%, respectively. The accuracy of levomedetomidine was in the range of 99.25% to 101.57% and that for dexmedetomidine was 99.17% to 100.99%. The limits of quantification for both isomers were 0.2 ng/mL. Recovery and matrix effect on the analytes were also evaluated. Under the optimized conditions, the validated method can be adapted for the identification and resolution of the medetomidine enantiomers in different matrices used for drug testing and analysis.
- Karakka Kal, Abdul Khader,Nalakath, Jahfar,Kunhamu Karatt, Tajudheen,Perwad, Zubair,Mathew, Binoy,Subhahar, Michael
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- Efficient synthesis of (S)-4(5)-[1-(2,3-dimethylphenyl) ethyl]imidazole tartrate, the potent α2 adrenoceptor agonist dexmedetomidine
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(S,R)-4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole 5 is prepared in 41% yield, by a new reliable method from readily available starting materials. The separation of the enantiomers proceeds through the selective crystallisation of the (+)-tartrate of the (S) enantiomer 6 in the presence of the (R) enantiomer free base.
- Cordi, Alex A.,Persigand, Thierry,Lecouve, Jean-Pierre
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Read Online
- Synthesis method of dexmedetomidine
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The invention discloses a synthesis method of dexmedetomidine, which comprises the following steps: by taking (2,3-dimethylphenyl)(1H-imidazol-5-yl)methanone (I) as a starting material, conducting reacting with ethyl chloroformate to obtain 4-(2,3-dimethylbenzoyl)-1H-imidazol-1-ethyl formate (II), reacting with formaldehyde to obtain ethyl 4-(1-(2, 3-dimethylbenzoyl)-1H-imidazole-1-formate (II), and conducting reacting with formaldehyde to obtain ethyl 4-(1-(2,3-dimethylphenyl)vinyl)-1H-imidazol-1-formate (III), conducting chiral catalytic reduction to obtain ethyl (S)-4-(1-(2,3-dimethylphenyl)ethyl)-1H-imidazol-1-formate (III), and conducting deprotection to obtain dexmedetomidine. The synthetic method is short in synthetic route, easy to operate and high in yield.
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Paragraph 0041; 0045; 0046; 0050; 0051; 0055; 0056; 0060
(2021/06/22)
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- METHOD FOR PREPARING DEXMEDETOMIDINE
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The present invention relates to a method for preparing dexmedetomidine having the following formula (I): or a pharmaceutically acceptable salt and/or solvate thereof, comprising the following successive steps: a) asymmetric hydrogenation of a methylene derivative of the following formula (II): in order to obtain dexmedetomidine, and b) optionally salifying and/or solvating dexmedetomidine in order to obtain a pharmaceutically acceptable salt and/or solvate of dexmedetomidine, wherein the methylene derivative of formula (II) is prepared from a halide of the following formula (V), in which Hal2 represents a halogen atom such as Br, and a cyanoimidazole of the following formula (VI):. The present invention relates also to methods for preparing synthesis intermediates of dexmedetomidine from the halide of formula (V) and the cyanoimidazole of formula (VI), these synthesis intermediates being the methylene derivative of formula (II), an alcohol of the following formula (III), and a ketone of the following formula (IV):.
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Page/Page column 19; 22-23
(2021/05/15)
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- METHOD FOR PRODUCING IMIDAZOLE DERIVATIVE
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PROBLEM TO BE SOLVED: To provide a novel method for producing an optically active imidazole compound useful as a pharmaceutical. SOLUTION: A production method includes the steps for making a compound represented by formula (3) react with hydrogen gas in the presence of an optically active metal complex catalyst, to obtain a compound represented by formula (4) with high yield and high selectivity (in the formula, R1 is an amino protecting group, and * is an asymmetric carbon atom). SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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- Intermediate for preparing medetomidine and its preparation method and use
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The invention provides an intermediate for preparing medetomidine. The intermediate is a compound shown in the formula (I). The invention also provides a preparation method of the intermediate, and ause of the intermediate in the preparation of medetomidine. The compound shown in the formula (I) is used for preparation of medetomidine so that the raw material is cheap and easy to obtain, synthesis processes are simple, the reaction cycle is short, the environmental pollution is avoided, operation is simple, the harsh reaction conditions are avoided, the operation and post-treatment are simple, the yield and the product purity are high, the intermediate in each step is a solid and is easy to purify, a production cost is low, and the intermediate is suitable for industrial large-scale production and conforms to the principle of green chemistry.
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- Method for synthesizing dexmedetomidine hydrochloride intermediate
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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.
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Paragraph 0028; 0029; 0030; 0031; 0032; 0033; 0034-0044
(2017/08/28)
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- Preparation process of dexmedetomidine hydrochloride for ICU (intensive care unit) sedation and analgesia
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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.
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Paragraph 0038; 0039; 0040; 0041; 0042; 0043; 0044-0064
(2017/08/28)
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- Synthetic method of dexmedetomidine hydrochloride intermediate
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The invention discloses a synthetic method of a dexmedetomidine hydrochloride intermediate. The synthetic method comprises the following step: carrying out contact reaction on 1-(1-haloethyl)-2,3-dimethylbenzene and imidazole in ionic liquid in the presence of alkali and [1,1'-bis(diphenylphosphino) ferrocene] palladium dichloride to obtain the dexmedetomidine hydrochloride intermediate 4-[1-(2,3-dimethyl phenyl) ethyl]-1H-imidazole. The method is short in reaction time and high in yield, and has good selectivity for a target (S)-isomer.
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Paragraph 0033; 0034; 0035; 0036; 0037; 0038; 0039; 0040-005
(2017/08/28)
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- A hydrochloride right tablet the onamot decides intermediate preparation process (by machine translation)
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The invention discloses a right hydrochloride tablet the onamot decides intermediate preparation process, the preparation process includes: will be 1 - (1 - halogenated ethyl) - 2, 3 - dimethylphenyl and imidazole and alkali and NiCl2 (Dppf) added to the organic solvent in the obtained by stirring reaction the temperature of the hydrochloric acid right tablet the onamot decides intermediate 4 - [1 - (2, 3 - dimethyl phenyl) ethyl] - 1H - imidazole. According to the present invention to provide a preparation process of a hydrochloric acid preparation of the right tablet the onamot decides intermediate 4 - [1 - (2, 3 - dimethyl phenyl) ethyl] - 1H - imidazole high yield and the target (S)- isomer has good selectivity. (by machine translation)
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Paragraph 0022; 0023; 0024; 0025; 0026; 0027; 0028-0050
(2017/08/28)
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- A method of splitting the US holds the onamot ding (by machine translation)
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The invention provides a method for splitting the US holds the onamot ding method, comprises the following steps: step (1): adding medetomidine in organic solvent, acid and catalyst in order to produce the medetomidine amide; step (2): in order to enzyme Novozym 435 for resolving agent, in the United States under the condition of a weak acid to amide holds the onamot ding asymmetric hydrolysis, and use the extractant right US holds the onamot ding. In the present invention, can avoid the use of camphor sulfonic acid as the chiral reagent, and puts forward a new split holds the onamot dingright US holds the onamot ding United States in order to prepare the method, this method has the advantages of easy operation, mild condition, high yield, good optical activity of the product and the like. (by machine translation)
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Paragraph 0046; 0047
(2017/08/29)
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- Dexmedetomidine hydrochloride intermediate resolution method
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The invention discloses a dexmedetomidine hydrochloride intermediate resolution method. The resolution method includes: (1) subjecting salt racemized 4-[1-(2,3-dimethyl phenyl)ethyl]-1H-imidazole to sulfonation reaction with a sulfonating agent; (2) subjecting a product obtained in the step (1) to stirring salt-forming reaction with lysine ethyl ester in absolute ethyl alcohol, standing, and performing suction filtration to obtain (S)-salt; (3) allowing reaction of the (S)-salt obtained in the step (2) in sodium hydroxide aqueous solution to obtain (S)-4-[1-(2,3-dimethyl phenyl)ethyl]-1H-imidazole. According to the resolution method, sulfonation is performed prior to adoption of chiral compound lysine ethyl ester for resolution, high resolution efficiency and resolution yield can be achieved. By providing of the dexmedetomidine hydrochloride intermediate resolution method, a beneficial raw material supply guarantee can be provided for dexmedetomidine hydrochloride, and great market potential is realized.
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Paragraph 0047-0049
(2017/07/06)
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- Method for preparing dexmedetomidine
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The invention provides a method for preparing dexmedetomidine, and particularly provides a method for preparing medetomidine midbody 1-(2,3-dimethyl phenyl)-1-(1-trityl-1H-imidazole-4-base) ethyl alcohol. The compound medetomidine midbody as shown in formula I is synthesized through Grignard reaction. The invention further provides a method for preparing dexmedetomidine hydrochloride. The technology has the advantages that the number of steps is small, yield is high, operation is easy, and product purity is high and is quite suitable for industrial production.
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- Method for preparing dexmedetomidine hydrochloride key intermediate
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The invention discloses a method for preparing a dexmedetomidine hydrochloride key intermediate. The method comprises the following steps: by taking 1-(1-chloroethyl)-2,3-dimethyl benzene and N-Boc-imidazole as raw materials, carrying out a low-temperature reaction in an aprotic organic solvent in the presence of Lewis acid, thereby obtaining a compound of a formula (III). According to the method disclosed by the invention, the starting materials refer to industrialized popular commodities and are stable in properties and easy to preserve, the defect that the raw materials are unstable in the process of preparing the conventional dexmedetomidine hydrochloride intermediate is overcome, and the method is high in reaction yield, suitable for industrial production and has high application value. The structural formula is as shown in the specification.
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Paragraph 0037; 0038; 0039
(2016/11/24)
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- PROCESS FOR THE RESOLUTION OF MEDETOMIDINE AND RECOVERY OF THE UNWANTED ENANTIOMER
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A new and efficient process to obtain Medetomidine enantiomers, a selective and potent α2-receptor agonist, is presented. Such process comprises a resolution step and a racemisation reaction, to be able to recover the unwanted enantiomer which can be recycled as starting material.
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Paragraph 0035
(2013/09/12)
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- PROCESS FOR THE PREPARATION OF DEXMEDETOMIDINE
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The invention discloses a novel process for preparation of dexmedetomidine in higher yield and with enantiomeric purity more than 99%.
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Page/Page column 7
(2013/05/23)
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