CN113800999A - Dexmedetomidine hydrochloride impurity and synthesis method and application thereof - Google Patents
Dexmedetomidine hydrochloride impurity and synthesis method and application thereof Download PDFInfo
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- C07C22/02—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings
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- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
- C07C45/73—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with hydrogenation
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
- G01N2001/2893—Preparing calibration standards
Abstract
The invention discloses dexmedetomidine hydrochloride impurity and a synthesis method and application thereof, belonging to the technical field of pharmaceutical chemistry; the inventionThe dexmedetomidine hydrochloride impurity has a structural formula shown as a formula I; wherein R is1And R2Selected from hydroxy, chloro or imidazolyl; the impurities provided by the technical scheme of the invention are not in the existing dexmedetomidine hydrochloride impurity mass spectrum, so that the impurities provided by the technical scheme of the invention can expand the dexmedetomidine hydrochloride impurity mass spectrum, provide a standard substance for the research on the impurities of dexmedetomidine hydrochloride, and further improve the quality standard of dexmedetomidine hydrochloride; meanwhile, the synthesis method of the impurities provided by the technical scheme of the invention has the advantages of high reaction selectivity, simple operation and high purity of the obtained product.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a dexmedetomidine hydrochloride impurity as well as a synthesis method and application thereof.
Background
Dexmedetomidine hydrochloride is a novel alpha 2-adrenoceptor agonist with sympatholytic, sedative and analgesic effects for sedation of both endotracheal intubation and mechanical ventilation of surgically operated patients under general anesthesia. Dexmedetomidine hydrochloride was first marketed in the united states (trade name Precedex) 3 months in 2000 and subsequently approved for marketing in a number of countries. Although dexmedetomidine hydrochloride is on the market for many years, the number of impurities reported by pharmacopoeia is large, but due to the difference of synthetic routes and the complexity of synthetic reaction, a plurality of unknown impurities still exist, and how to obtain the impurities has high technical difficulty; the research on impurities is an important content of drug research and development, and comprises the steps of selecting a proper analysis method, accurately distinguishing and determining the content of the impurities, and determining the reasonable limit of the impurities by integrating the results of pharmaceutical, toxicological and clinical researches, wherein the research runs through the whole process of drug research and development; the research on impurities is separated, purified and identified, and finally the synthesis of the impurities is particularly important in the process of the research on the impurities.
The dexmedetomidine hydrochloride has multiple synthetic routes, wherein 2, 3-dimethyl bromobenzene can be used as an initial material, 1- (2, 3-dimethyl phenyl) -ethanol is obtained by Grignard reaction and acetaldehyde reaction, the 1- (2, 3-dimethyl phenyl) -ethanol is chloridized and then reacts with trimethylsilylimidazole to generate the medetomidine, and the medetomidine hydrochloride is obtained by splitting and salifying, and the synthetic route is shown as the following reaction formula; in this route, it was found that a larger unknown impurity was newly formed in the preparation of 1- (2, 3-dimethylphenyl) -ethanol, and that, upon continuing the subsequent synthesis, it was found by monitoring that the amount of the unknown impurity formed in the preparation of 1- (2, 3-dimethylphenyl) -ethanol was reduced and a new unknown impurity was formed.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a method for synthesizing dexmedetomidine hydrochloride impurities and impurities, so that the impurity spectrum of dexmedetomidine hydrochloride is expanded, and a standard substance is provided for impurity research of dexmedetomidine hydrochloride.
In order to achieve the purpose, the invention adopts the technical scheme that: dexmedetomidine hydrochloride impurity has a structural formula shown in formula I,
wherein R is1And R2Selected from hydroxy, chloro or imidazolyl.
As a preferred embodiment of the dexmedetomidine hydrochloride impurity, the structural formula of the impurity is shown as Ia-Ie;
according to the technical scheme, 2, 3-dimethyl bromobenzene is used as an initial material, 1- (2, 3-dimethyl phenyl) -ethanol is obtained through Grignard reaction and acetaldehyde reaction, and then the initial material is chloridized and reacts with trimethyl silicamidazole to generate medetomidine, and the new impurity generated in the synthesis route of the medetomidine hydrochloride is obtained through splitting and salifying is subjected to structure identification, so that the chemical structural formula of the impurity newly generated in the synthesis route is determined, wherein the impurity Ia is generated during synthesis of the 1- (2, 3-dimethyl phenyl) -ethanol, the mechanism of generation of the impurity Ia is that 3-hydroxy butyraldehyde generated by acetaldehyde polymerization participates in Grignard reaction to generate the impurity Ia, and the subsequent impurity Ia further reacts with a reaction reagent to generate the impurity Ib-Ie; the impurities Ia-Ie provided by the technical scheme of the invention are not in the existing dexmedetomidine hydrochloride hybrid mass spectrum, so that the impurities Ia-Ie provided by the technical scheme of the invention can expand the dexmedetomidine hydrochloride hybrid mass spectrum, provide a standard for the impurity research of dexmedetomidine hydrochloride, and further improve the quality standard of dexmedetomidine hydrochloride.
In addition, the invention also provides a synthetic method of the impurity, which comprises the following steps:
(1) the 2 ', 3' -dimethyl acetophenone and acetaldehyde are subjected to aldol condensation under the catalysis of a catalyst to generate 1- (2, 3-dimethylphenyl) -3-hydroxy-1-butanone;
(2) reacting the 1- (2, 3-dimethylphenyl) -3-hydroxy-1-butanone obtained in the step (1) with a reducing agent to obtain an impurity Ia;
(3) performing chlorination reaction on the impurity Ia obtained in the step (2) to obtain an impurity Ib;
(4) and (4) reacting the impurity Ib and trimethylsilylimidazole in the step (3), and hydrolyzing to obtain an impurity Ic, an impurity Id and an impurity Ie.
As a preferred embodiment of the synthesis method of the present invention, in the step (1), the molar ratio of 2 ', 3' -dimethylacetophenone to acetaldehyde is 1: (0.5-0.8).
As a preferable embodiment of the synthesis method of the present invention, in the step (1), the reaction solvent for aldol condensation includes tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetone, dichloromethane or chloroform.
As a preferred embodiment of the synthesis method of the present invention, in the step (1), the reaction temperature of aldol condensation is 20 to 45 ℃.
As a preferred embodiment of the synthesis method of the present invention, in the step (1), the catalyst is a basic catalyst; the basic catalyst comprises a basic compound, an organic amine compound or an anion exchange resin; the basic compounds include oxides, hydroxides, bicarbonates, carbonates and carboxylates of alkali or alkaline earth metals.
As a preferred embodiment of the synthesis method of the present invention, in the step (1), the catalyst comprises an alkali metal hydroxide.
As a preferred embodiment of the synthesis method of the present invention, in the step (1), the catalyst comprises sodium hydroxide, potassium hydroxide, lithium hydroxide or calcium hydroxide; when the catalyst is used, the catalyst is prepared into an aqueous solution and is added into a reaction system for catalysis.
As a preferred embodiment of the synthesis method of the present invention, in the step (2), the reducing agent includes sodium borohydride, potassium borohydride or lithium aluminum hydride.
As a preferred embodiment of the synthesis method of the present invention, in the step (2), the molar ratio of the reducing agent to the 1- (2, 3-dimethylphenyl) -3-hydroxy-1-butanone is (1-2): 1, the reaction temperature is 0-10 ℃.
As a preferred embodiment of the synthesis method of the present invention, in the step (3), the chlorination reagent for the chlorination reaction includes thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or lucas reagent.
As a preferred embodiment of the synthesis method of the present invention, in the step (3), the molar ratio of the chlorinating agent to the impurity Ia is (1.5 to 5.5): 1, the reaction temperature is 20-40 ℃.
In addition, the invention also provides application of the impurity in research of dexmedetomidine hydrochloride impurities.
Compared with the prior art, the invention has the beneficial effects that:
(1) the impurities Ia-Ie provided by the technical scheme of the invention are not in the existing dexmedetomidine hydrochloride hybrid mass spectrum, so that the impurities Ia-Ie provided by the technical scheme of the invention can expand the dexmedetomidine hydrochloride hybrid mass spectrum, provide a standard for the impurity research of dexmedetomidine hydrochloride, and further improve the quality standard of dexmedetomidine hydrochloride;
(2) the synthesis method of the impurities Ia-Ie provided by the technical scheme of the invention has the advantages of high reaction selectivity, simple operation and high purity of the obtained product.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
The synthetic routes for dexmedetomidine hydrochloride impurities Ia-Ie are shown in the above reaction schemes, and the compounds in the reactions are all obtained by conventional commercial routes, except where otherwise indicated.
The polarity of the impurities Id and Ie is close, so that a high-purity substance is difficult to obtain through common liquid phase separation, and meanwhile, the impurities Id and Ie can be combined and controlled in the actual production process of dexmedetomidine hydrochloride; therefore, the two are not further separated in the examples of the present invention, but the preparation method and the hydrogen spectrum data are given as a mixture of the two.
Examples
Synthesizing dexmedetomidine hydrochloride impurities Ia-Ie in the embodiment of the invention; the specific synthesis method comprises the following steps:
(1) synthesis of 1- (2, 3-dimethylphenyl) -3-hydroxy-1-butanone:
adding 15g (0.10mol) of 2 ', 3' -dimethylacetophenone and 60mL of tetrahydrofuran and acetaldehyde into a 250mL three-necked flask, adding 60mL of 10% sodium hydroxide solution, heating to 35-45 ℃, reacting for 3 hours, removing tetrahydrofuran under reduced pressure, adding ethyl acetate to extract a concentrated solution, drying an organic layer obtained by extraction with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a viscous liquid, quickly preparing a liquid phase, separating to obtain 11.27g of a colorless transparent liquid, and detecting that the target product 1- (2, 3-dimethylphenyl) -3-hydroxy-1-butanone is obtained, wherein the yield is 58.30%.
Nuclear magnetic characterization:1H NMR(500MHz,CDCl3):7.41～7.48(1H,m),7.14～7.21(2H,m),4.24～4.31(1H,m),2.78～3.13(1H,br),2.34(3H,s),2.27(3H,s),1.82～1.89(2H,m),1.24(3H,d,J＝6.3)。
(2) synthesis of impurity Ia:
dissolving 11.27g (0.059mol) of 1- (2, 3-dimethylphenyl) -3-hydroxy-1-butanone synthesized in the step (1) by using 100mL of methanol, adding 2.38g (0.063mol) of sodium borohydride at the temperature of 5 ℃ in an ice-water bath, reacting at room temperature for 1h, then carrying out extraction and quenching reaction by using 5% hydrochloric acid, carrying out reduced pressure concentration to remove the methanol, extracting by using ethyl acetate, drying an organic layer obtained by extraction by using anhydrous sodium sulfate, then filtering, carrying out reduced pressure concentration to obtain viscous liquid, rapidly preparing a liquid phase, separating to obtain 9.35g of colorless transparent liquid, and detecting that the target product impurity Ia (1- (2, 3-dimethylphenyl) -1, 3-butanediol) has the yield of 82.96%.
Nuclear magnetic characterization:1H NMR(500MHz,CDCl3):7.35～7.40(1H,m),7.06～7.16(2H,m),5.20(1H,dd,J＝2.85,9.8),4.12～4.21(1H,m),2.56～3.5(2H,br),2.28(3H,s),2.21(3H,s),1.76～1.83(2H,m),1.22(3H,d,J＝6.2)。
(3) synthesis of impurity Ib:
dissolving 9.35g (0.051mol) of 1- (2, 3-dimethylphenyl) -1, 3-butanediol in 100mL of dichloromethane, adding 28.7g (0.24mol) of thionyl chloride, heating up, refluxing for reaction for 2h, cooling, adding 100mL of ice water, stirring for layering, concentrating an organic layer, quickly preparing a liquid phase, separating to obtain 8.42g of colorless transparent liquid, and detecting to obtain an impurity Ib (1- (2, 3-dimethylphenyl) -1, 3-dichlorobutane) serving as a target product, wherein the yield is 76.00%.
Nuclear magnetic characterization:1H NMR(500MHz,CDCl3):7.37～7.42(1H,m),7.16～7.24(2H,m),4.41～4.49(1H,m),3.48～3.55(1H,m),2.27(3H,s),2.21(3H,s),1.94～2.03(2H,m),1.47(3H,d,J＝6.2)。
(4) synthesis of impurity Ic:
adding 20mL of dichloromethane and 9.90g (0.052mol) of titanium tetrachloride into a 250mL three-neck flask, dropwise adding a mixed solution of 14.60g (0.10mol) of trimethylsilylimidazole and 30mL of dichloromethane at the temperature of 10 ℃, continuously reacting for 1h, continuously dropwise adding 1- (2, 3-dimethylphenyl) -1, 3-dichlorobutane 4.00g (0.018mol) and 20mL of dichloromethane solution at the temperature of 10 ℃ or below, reacting for 1h at room temperature, transferring to the room temperature for reacting for 20h, dropwise adding 70mL of purified water at the temperature of 10 ℃ or below, stirring and hydrolyzing for 2h, separating out an aqueous phase, adjusting the pH value to 9-10 with 30% sodium hydroxide, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating by using fast preparative liquid chromatography to obtain 1.67g of a white-like solid, and detecting as an object product impurity Ic (4,4' - (1- (2, 3-dimethylphenyl) butane-1, 3-diyl) bis (1H-imidazole)), yield 32.62%.
Nuclear magnetic characterization:1H NMR(500MHz,CDCl3):11.42(2H,br),7.63～7.69(2H,m),7.42～7.47(2H,m),7.21～7.34(3H,m),4.12～4.18(1H,m),2.72～2.81(1H,m),2.28(3H,s),2.21(3H,s),1.77～1.85(2H,m),1.21(3H,d,J＝6.0)。
(5) synthesis of impurities Id and Ie:
adding 4.50g (0.024mol) of 20mL of dichloromethane and titanium tetrachloride into a 250mL three-necked flask, dropwise adding a mixed solution of 7.30g (0.052mol) of trimethylsilylimidazole and 30mL of dichloromethane at the temperature of 10 ℃, continuously reacting for 1h, continuously dropwise adding 1- (2, 3-dimethylphenyl) -1, 3-dichlorobutane at the temperature of below 10 ℃, continuously reacting for 1h with 20mL of dichloromethane solution, reacting at room temperature for 1h, transferring to room temperature for reacting for 20h, dropwise adding 70mL of purified water at the temperature of below 10 ℃, stirring and hydrolyzing for 2h, separating out an aqueous phase, adjusting the pH value to 9-10 by using 30% sodium hydroxide, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, separating by using fast preparative liquid chromatography to obtain 3.27g of light yellow liquid, and obtaining the yield of 76.94%.
Nuclear magnetic characterization:1H NMR(500MHz,CDCl3):7.58～7.63(1H,m),7.47～7.52(1H,m),7.14～7.27(3H,m),5.48～5.80(2H,br),4.22～4.28(1H,m),2.63～2.70(1H,m),2.29(3H,s),2.18(3H,s),1.84～1.93(2H,m),1.23(3H,d,J＝6.3)。
finally, it should be noted that the above embodiments are intended to illustrate the technical solutions of the present invention and not to limit the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. The dexmedetomidine hydrochloride impurity is characterized in that the structural formula is shown as a formula I,
wherein R is1And R2Selected from hydroxy, chloro or imidazolyl.
2. Dexmedetomidine hydrochloride impurity according to claim 1, characterized in that the structural formula of the impurity is Ia-Ie;
3. the method for synthesizing impurities according to claim 1, comprising the steps of:
(1) the 2 ', 3' -dimethyl acetophenone and acetaldehyde are subjected to aldol condensation under the catalysis of a catalyst to generate 1- (2, 3-dimethylphenyl) -3-hydroxy-1-butanone;
(2) reacting the 1- (2, 3-dimethylphenyl) -3-hydroxy-1-butanone obtained in the step (1) with a reducing agent to obtain an impurity Ia;
(3) performing chlorination reaction on the impurity Ia obtained in the step (2) to obtain an impurity Ib;
(4) and (4) reacting the impurity Ib and trimethylsilylimidazole in the step (3), and hydrolyzing to obtain an impurity Ic, an impurity Id and an impurity Ie.
4. The synthesis method according to claim 3, wherein in the step (1), the molar ratio of 2 ', 3' -dimethylacetophenone to acetaldehyde is 1: (0.5-0.8).
5. The method according to claim 3, wherein in the step (1), the reaction solvent for aldol condensation comprises tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetone, dichloromethane or chloroform; the reaction temperature of the aldol condensation is 20-45 ℃.
6. The synthesis method according to claim 3, wherein in the step (1), the catalyst is a basic catalyst;
the basic catalyst comprises a basic compound, an organic amine compound or an anion exchange resin;
the basic compounds include oxides, hydroxides, bicarbonates, carbonates and carboxylates of alkali or alkaline earth metals.
7. The synthesis method according to claim 3, wherein in the step (2), the reducing agent comprises sodium borohydride, potassium borohydride or lithium aluminum hydride;
wherein the molar ratio of the reducing agent to the 1- (2, 3-dimethylphenyl) -3-hydroxy-1-butanone is (1-2): 1.
8. the synthesis method as claimed in claim 3, wherein in the step (3), the chlorination reagent for chlorination reaction includes thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride or Lucas reagent.
9. The synthesis method according to claim 8, wherein in the step (3), the molar ratio of the chlorinating reagent to the impurity Ia is (1.5-5.5): 1, the reaction temperature is 20-40 ℃.
10. Use of the impurity of claim 1 or 2 in studies of dexmedetomidine hydrochloride impurities.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106588779A (en) * | 2016-12-15 | 2017-04-26 | 青岛辰达生物科技有限公司 | Method for synthesizing dexmedetomidine hydrochloride intermediate |
| CN111548308A (en) * | 2020-03-18 | 2020-08-18 | 遂成药业股份有限公司 | Synthesis process of dexmedetomidine hydrochloride |
| CN113321619A (en) * | 2020-09-01 | 2021-08-31 | 南京恒正药物研究院有限公司 | Novel dexmedetomidine hydrochloride impurity and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106588779A (en) * | 2016-12-15 | 2017-04-26 | 青岛辰达生物科技有限公司 | Method for synthesizing dexmedetomidine hydrochloride intermediate |
| CN111548308A (en) * | 2020-03-18 | 2020-08-18 | 遂成药业股份有限公司 | Synthesis process of dexmedetomidine hydrochloride |
| CN113321619A (en) * | 2020-09-01 | 2021-08-31 | 南京恒正药物研究院有限公司 | Novel dexmedetomidine hydrochloride impurity and preparation method thereof |
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