CN113321619A - Novel dexmedetomidine hydrochloride impurity and preparation method thereof - Google Patents
Novel dexmedetomidine hydrochloride impurity and preparation method thereof Download PDFInfo
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- CN113321619A CN113321619A CN202010904891.9A CN202010904891A CN113321619A CN 113321619 A CN113321619 A CN 113321619A CN 202010904891 A CN202010904891 A CN 202010904891A CN 113321619 A CN113321619 A CN 113321619A
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- dexmedetomidine hydrochloride
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- 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
- C07D233/56—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
Abstract
The invention relates to a new dexmedetomidine hydrochloride impurity, namely 2, 4-bis [1- (2, 3-dimethylphenyl) ethyl ] -1H-imidazole, and a preparation and purification method thereof; the preparation method is obtained by reacting 1- (1-chloroethyl) -2, 3-dimethylbenzene with N-trimethylsilylimidazole under the condition of Lewis acid and purifying. The impurity has a novel structure, is reported for the first time, has great influence on the medication safety and effectiveness of dexmedetomidine hydrochloride injection products, and has great significance on the quality control of dexmedetomidine hydrochloride raw material medicines and preparations, and the dexmedetomidine hydrochloride injection products are difficult to completely remove. The preparation method provided by the invention has the characteristics of simple method, convenience in operation, high product purity and the like, and can be applied to the research of impurity reference substances of dexmedetomidine hydrochloride. The purification method provided by the invention has the characteristics of simple method, convenient operation, good refining effect, high yield, low cost, industrial scale-up production and the like, and has great significance for the research of the production process of the raw material medicine of dexmedetomidine hydrochloride.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a novel dexmedetomidine hydrochloride impurity and a preparation method and a purification removal method thereof.
Background
Dexmedetomidine hydrochloride injection is an alpha 2-adrenoceptor agonist developed by the cooperation of Orion Pharma (Finland) and Abott (USA) and is first marketed in the United states 3 months in 2000. The product is dextroisomer of alpha 2-adrenergic receptor stimulant medetomidine, and compared with medetomidine, the product has stronger selectivity on central alpha 2-adrenergic receptor stimulation, short half-life and small dosage. Sedation of surgical patients undergoing general anesthesia during endotracheal intubation and mechanical ventilation.
Dexmedetomidine hydrochloride is used as an injection, the impurity content of the dexmedetomidine hydrochloride is strictly controlled, and deeper research is carried out, and especially, the research on unknown impurities has great significance on the safety and the effectiveness of the dexmedetomidine hydrochloride.
The structural formula of dexmedetomidine hydrochloride is as follows:
related impurities of dexmedetomidine hydrochloride reported in the literature and data at present mainly include: USP impurities A-E have the following structural formulas:
USP impurity a, chemical name: 1- (2, 3-dimethylphenyl) -1- (1H-imidazol-5-yl) ethanol; structural formula (xvi):
USP impurity B, chemical name: 1- (1-phenyl-1H-imidazole-5-) -1- (2, 3-dimethylphenyl l) ethanol; structural formula (xvi):
USP impurity C, chemical name: 5- [1- (2, 3-dimethylphenyl) ethyl ] -1-ethyl-1H-imidazole; structural formula (xvi):
USP impurity D, chemical name: 1-benzyl-5- (1- (2, 3-dimethylphenyl) ethyl) -1H-imidazole; structural formula (xvi):
USP impurity E, chemical name: 1-benzyl-5- [1- (2, 3-dimethylphenyl) ethenyl ] -1H-imidazole; structural formula (xvi):
the synthesis of the dexmedetomidine hydrochloride bulk drug can generate various side reaction impurities in a multi-step chemical reaction process, partial impurities are easy to generate and are not easy to completely remove in the existing production process, and the impurities are remained in the dexmedetomidine hydrochloride bulk drug and further introduced into the dexmedetomidine hydrochloride preparation to become unknown impurities. The new impurities proposed by the invention are easy to generate in the dexmedetomidine hydrochloride key intermediate medetomidine production process, are easy to grow in the storage process of the crude medetomidine product, and are difficult to be completely removed in the process after the separation. Unknown new impurities have great influence on the safety, effectiveness and the like of medicines, particularly injections, so that research on new impurities of dexmedetomidine hydrochloride is urgent.
The research on the impurities is beneficial to the quality research of the dexmedetomidine hydrochloride raw material medicine and the preparation, improves the quality standard of the dexmedetomidine hydrochloride raw material medicine and the preparation, and improves the medication safety of the dexmedetomidine hydrochloride preparation.
Disclosure of Invention
The invention provides a new impurity of dexmedetomidine hydrochloride, and the code number is YM-Imp38 for convenience of management in the research process. The details are as follows:
YM-Imp38, chemical name: 2, 4-bis [1- (2, 3-dimethylphenyl) ethyl ] -1H-imidazole. The structural formula is as follows:
the invention also provides a method for preparing the novel dexmedetomidine hydrochloride impurity shown as the formula YM-Imp 38.
The preparation method of YM-Imp38 comprises the following steps: the compound is prepared by reacting 1- (1-chloroethyl) -2, 3-dimethylbenzene with N-trimethylsilylimidazole under the condition of Lewis acid and purifying by column chromatography. The reaction equation for the method of synthesizing YM-Imp38 is as follows:
the purification and removal method of YM-Imp38 comprises the following steps: recrystallizing the medetomidine crude product by using an organic solvent to obtain a medetomidine refined product. The recrystallization solvent is selected from ethyl acetate, isopropyl acetate, methyl acetate, ethanol, methanol, isopropanol, acetone, and toluene. All the above can achieve the purpose of completely removing YM-Imp 38.
The invention reports a new impurity of dexmedetomidine hydrochloride for the first time, and provides a preparation method and a purification removal method of the group of impurities. The impurity has important significance on the quality research of the dexmedetomidine hydrochloride bulk drug and the preparation, and the inventor also requests to protect that the compound shown as the formula YM-Imp38 and the related substances thereof (including but not limited to salifying compounds, chiral isomers, salts thereof and the like of the impurity) are used as impurity reference substances for the content analysis and the quality control of the dexmedetomidine hydrochloride bulk drug and the preparation.
Description of the drawings:
FIG. 1 is a typical liquid chromatogram of a crude medetomidine (impurity retention time 68.669min, content 3.28%).
FIG. 2 is a typical liquid chromatogram of the pure product of the new impurity (retention time of the impurity 28.818min, content 90.95%).
FIG. 3 is a liquid chromatogram (impurity retention time 66.208 min) of the pure medetomidine product, as positioned in the medetomidine detection method.
FIG. 4 is a typical liquid chromatogram of a refined medetomidine product (no impurities detected, detection limit < 0.01%).
FIG. 5 is a nuclear magnetic hydrogen spectrum of the new impurity.
Fig. 6 is a typical mass spectrum of the new impurity.
Detailed Description
The invention is described in further detail below with reference to specific examples, which are provided only for the purpose of further illustrating the invention, but are not to be construed as limiting the invention in any way.
Example 1: preparation of YM-Imp38
Adding 1- (1-chloroethyl) -2, 3-dimethylbenzene (4 kg), N-trimethylsilylimidazole (8 g) and dichloromethane (50L) into a 100L glass reaction kettle, starting stirring, adding ferric trichloride (12 kg), heating to reflux, continuously stirring for reacting overnight, cooling to room temperature, slowly dripping water (50L), filtering, adding alkali liquor into a water phase obtained by layering a filtrate to adjust the pH value to 11-12, extracting with dichloromethane (33L 3), combining organic phases, concentrating to dryness, and obtaining a medetomidine crude product (4.2 kg, the impurity content of 3.28%).
Taking 100g of the medetomidine crude product, and treating the medetomidine crude product with n-hexane: ethyl acetate =20:1 column chromatography gave YM-Imp38 (1.8 g, HPLC purity 90.95%).
Example 2: preparation of YM-Imp38
Adding 1- (1-chloroethyl) -2, 3-xylene (10 g), N-trimethylsilylimidazole (26 g) and dichloromethane (100 ml) into a 500ml three-neck round-bottom flask, starting stirring, adding zinc dichloride (20 g), heating to reflux, continuously stirring for reacting overnight, cooling to room temperature, slowly dripping water (100 ml), filtering, adding alkali liquor into a water phase obtained by layering a filtrate to adjust the pH value to 11-12, extracting with dichloromethane (100 ml × 2), combining organic phases, concentrating until the organic phases are dried to obtain a medetomidine crude product (the impurity content is 3.10%).
The medetomidine crude product is prepared by the steps of n-hexane: ethyl acetate =20:1 column chromatography gave YM-Imp38 (0.5 g, 88.90% HPLC purity).
Example 3: preparation of YM-Imp38
Adding 1- (1-chloroethyl) -2, 3-xylene (10 g), N-trimethylsilylimidazole (26 g) and dichloromethane (100 ml) into a 500ml three-neck round-bottom flask, starting stirring, adding titanium tetrachloride (28 g), heating to reflux, continuously stirring for reacting overnight, cooling to room temperature, slowly dripping water (100 ml), filtering, adding alkali liquor into a water phase obtained by separating filtrate into layers to adjust the pH value to 11-12, extracting with dichloromethane (100 ml × 2), combining organic phases, concentrating until the organic phases are dry, and obtaining a medetomidine crude product (the impurity content is 2.40%).
The medetomidine crude product is prepared by the steps of n-hexane: ethyl acetate =20:1 column chromatography gave YM-Imp38 (0.9 g, 90.18% HPLC purity).
Example 4: preparation of YM-Imp38
Adding 1- (1-chloroethyl) -2, 3-xylene (10 g), N-trimethylsilylimidazole (26 g) and dichloromethane (100 ml) into a 500ml three-neck round-bottom flask, starting stirring, adding aluminum trichloride (20 g), heating to reflux, continuously stirring for reacting overnight, cooling to room temperature, slowly dripping water (100 ml), filtering, adding alkali liquor into a water phase obtained by layering filtrate to adjust the pH value to 11-12, extracting with dichloromethane (100 ml × 2), combining organic phases, concentrating to dryness to obtain a medetomidine crude product (the impurity content is 2.90%).
The medetomidine crude product is prepared by the steps of n-hexane: ethyl acetate =20:1 column chromatography gave YM-Imp38 (1.0 g, HPLC purity 87.10%).
Example 5: removal of YM-Imp38 (purification of medetomidine)
The medetomidine crude product (100 g) obtained in example 1 and dichloromethane (400 ml) were added to a 500ml round bottom flask, stirred, heated to reflux for 30min, cooled to-20 ℃, stirred overnight, filtered to obtain a refined medetomidine product (49 g, yield 49%, no detectable impurities by HPLC).
Example 6: removal of YM-Imp38 (purification of medetomidine)
The crude medetomidine (100 g) obtained in example 1 and toluene (1000 ml) were added to a 2000ml round bottom flask and stirred, heated to reflux for 30min, cooled to-20 ℃, stirred overnight, filtered to obtain 1 refined medetomidine toluene (86 g, yield 86%, impurity content 0.02% by HPLC).
Refining for 1 time according to the above process to obtain refined medetomidine toluene for 2 times (77 g, yield 90%, total yield 77.4%, and no impurity detected by HPLC).
Example 7: removal of YM-Imp38 (purification of medetomidine)
The medetomidine crude product (100 g) obtained in example 1 and ethyl acetate (800 ml) were added to a 2000ml round bottom flask, stirred, heated to reflux for 30min, cooled to-20 ℃, stirred overnight, filtered to obtain a refined medetomidine product (88 g, yield 88%, no impurity detected by HPLC).
Example 8: removal of YM-Imp38 (purification of medetomidine)
The medetomidine crude product (100 g) obtained in example 1 and absolute ethyl alcohol (600 ml) are added into a 1000ml round bottom flask, stirring is started, heating is carried out until reflux is kept for 30min, the temperature is reduced to-10 ℃, stirring is continued overnight, and filtration is carried out to obtain a medetomidine refined product (58 g, yield 58%, and impurity is not detected by HPLC).
Claims (9)
1. A new dexmedetomidine hydrochloride impurity, chemical name: 2, 4-bis [1- (2, 3-dimethylphenyl) ethyl ] -1H-imidazole, of the formula:
2. a new dexmedetomidine hydrochloride impurity according to claim 1 including its related salt former compounds and its chiral isomers.
3. The dexmedetomidine hydrochloride impurity of claim 1 can be used as an impurity reference for content analysis and quality control of dexmedetomidine hydrochloride bulk drug and formulation.
4. The method for preparing dexmedetomidine hydrochloride neoimpurity (YM-Imp 38) according to claim 1 comprises the steps of:
1) reacting 1- (1-chloroethyl) -2, 3-xylene with N-trimethylsilylimidazole under the condition of Lewis acid;
2) quenching, extracting, concentrating and the like the reaction liquid to obtain a medetomidine crude product;
3) and (3) carrying out column chromatography separation on the medetomidine crude product obtained by the treatment of the reaction liquid to obtain an impurity pure product.
5. The Lewis acid according to claim 4 selected from the group consisting of: aluminum trichloride, zinc dichloride, ferric trichloride and titanium tetrachloride, and preferably ferric trichloride.
6. Dexmedetomidine hydrochloride new impurity according to claim 1 cannot be completely removed by recrystallization or multiple resolution directly after resolution by the subsequent steps of the dexmedetomidine hydrochloride production process.
7. The method for refining dexmedetomidine hydrochloride as claimed in claim 6, wherein the method comprises the step of recrystallizing a crude product of medetomidine and refining the product for subsequent production.
8. Crude medetomidine recrystallization solvent according to claim 6 is selected from the group consisting of ethyl acetate, isopropyl acetate, methyl acetate, ethanol, methanol, isopropanol, acetone, toluene, preferably ethyl acetate.
9. The novel dexmedetomidine hydrochloride impurity according to claims 1-8 is used for content analysis and quality control of dexmedetomidine hydrochloride bulk drug and formulation.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113800999A (en) * | 2021-10-18 | 2021-12-17 | 广东嘉博制药有限公司 | Dexmedetomidine hydrochloride impurity and synthesis method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103694175A (en) * | 2013-12-18 | 2014-04-02 | 北京华禧联合科技发展有限公司 | New method for preparing dexmedetomidine hydrochloride |
| CN105175340A (en) * | 2015-10-26 | 2015-12-23 | 海南通用康力制药有限公司 | Method for preparing high-purity dexmedetomidine hydrochloride crystal from high-purity intermediate crystal |
| CN106749027A (en) * | 2016-11-21 | 2017-05-31 | 石药银湖制药有限公司 | A kind of synthesis technique of dexmedetomidine hydrochloride intermediate |
| CN111253316A (en) * | 2020-03-31 | 2020-06-09 | 陕西博森生物制药股份集团有限公司 | Preparation method of dexmedetomidine hydrochloride |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103694175A (en) * | 2013-12-18 | 2014-04-02 | 北京华禧联合科技发展有限公司 | New method for preparing dexmedetomidine hydrochloride |
| CN105175340A (en) * | 2015-10-26 | 2015-12-23 | 海南通用康力制药有限公司 | Method for preparing high-purity dexmedetomidine hydrochloride crystal from high-purity intermediate crystal |
| CN106749027A (en) * | 2016-11-21 | 2017-05-31 | 石药银湖制药有限公司 | A kind of synthesis technique of dexmedetomidine hydrochloride intermediate |
| CN111253316A (en) * | 2020-03-31 | 2020-06-09 | 陕西博森生物制药股份集团有限公司 | Preparation method of dexmedetomidine hydrochloride |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113800999A (en) * | 2021-10-18 | 2021-12-17 | 广东嘉博制药有限公司 | Dexmedetomidine hydrochloride impurity and synthesis method and application thereof |
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Application publication date: 20210831 |