New dexmedetomidine hydrochloride impurity and preparation method thereof

Abstract

The invention provides a dexmedetomidine hydrochloride new impurity and a preparation method thereof. The impurity is 2, 4-bis (2, 3-dimethylphenyl) diethyl ether and comprises but not limited to a salifying form, a chiral isomer and a salt thereof, and the preparation method of the novel impurity comprises the following steps: mixing 1-(1-chloroethyl)-2, 3-dimethylbenzene and 1-(2, 3-dimethylphenyl)-ethanol in an aqueous solution of sodium hydroxide, heating and stirring, standing for layering, drying and filtering to obtain the 2, 4-bis (2, 3-dimethylphenyl) diethyl ether. And distilling at normal pressure to obtain the 2, 4-bis (2, 3-dimethyl phenyl) diethyl ether. The new impurity provided by the invention is crucial to deep research on the quality of dexmedetomidine hydrochloride bulk drugs and preparations, provides a new reference standard for content analysis and quality control, and also promotes establishment of a stricter quality standard. By protecting the application of the compounds as impurity reference substances, the invention aims to enhance the safety and effectiveness of dexmedetomidine hydrochloride preparations and ensure the medicine quality, thereby generating positive influence on medicine research and development and clinical application.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemistry, and in particular to a new impurity of dexmedetomidine hydrochloride and a preparation method thereof. Background Art

[0002] Dexmedetomidine hydrochloride injection is an α2-adrenergic receptor agonist developed by Orion Pharma (Finland) and Abott (USA). It was first launched in the United States in March 2000. This product is the dextrorotatory isomer of the α2-adrenergic receptor agonist medetomidine. Compared with medetomidine, this product has stronger selectivity for central α2-adrenergic receptor stimulation, a short half-life, and a very small dosage. It is used for sedation during endotracheal intubation and mechanical ventilation in surgical patients undergoing general anesthesia. As an injection, the impurity content of dexmedetomidine hydrochloride should be strictly controlled and further studied, especially the study of unknown impurities is of great significance to its safety and effectiveness. The structural formula of dexmedetomidine hydrochloride is as follows:

[0003]

[0004] During the synthesis of dexmedetomidine hydrochloride, the starting material 1-(1-chloroethyl)-2,3-xylene reacts with N-trimethylsilyl imidazole under Lewis acid conditions to generate dexmedetomidine, which is then followed by a multi-step chemical transformation. This process is not only complex but also prone to produce a variety of side reaction impurities, especially new impurities derived from key starting materials, which may increase in content during storage and are difficult to completely remove through existing processes, and eventually remain in the raw materials and preparations. Given the significant impact of these unknown impurities on drug safety and efficacy, in-depth research on them is crucial to improving the quality standards and drug safety of dexmedetomidine hydrochloride.

[0005] Therefore, research on these new impurities is particularly urgent, which will help improve the quality control system and ensure the safety and efficacy of dexmedetomidine hydrochloride preparations. Summary of the invention

[0006] In view of this, the present invention proposes a new impurity of dexmedetomidine hydrochloride and a preparation method thereof. The new impurity proposed in the present invention is an important impurity in 1-(1-chloroethyl)-2,3-xylene, a key starting material of dexmedetomidine hydrochloride, which is also easy to grow during the storage of crude dexmedetomidine and is difficult to be completely removed in the process after splitting.

[0007] In the first aspect, the present invention provides a new impurity of dexmedetomidine hydrochloride, the chemical name of the impurity is: 2,4-bis(2,3-dimethylphenyl)ethyl ether, and the structure is shown in formula (I):

[0008]

[0009] On the basis of the above technical scheme, preferably, the salt-forming compound related to formula (I) and its chiral isomers are included.

[0010] On the basis of the above technical scheme, preferably, the dexmedetomidine hydrochloride impurity is used as an impurity reference substance for content analysis and quality control of dexmedetomidine hydrochloride raw materials and preparations.

[0011] In a second aspect, the present invention relates to a method for preparing the above-mentioned new impurity, comprising the following steps:

[0012] In an aqueous solution of sodium hydroxide, 1-(1-chloroethyl)-2,3-dimethylbenzene and 1-(2,3-dimethylphenyl)-ethanol are mixed, heated and stirred, allowed to stand for stratification, dried, filtered, and distilled at normal pressure to obtain 2,4-bis(2,3-dimethylphenyl)ethyl ether.

[0013] On the basis of the above technical solution, preferably, the heating temperature is 90-100° C. and the stirring time is 3-5 h.

[0014] On the basis of the above technical solution, preferably, after the stratification, the organic phase is dried, and the desiccant is selected from anhydrous calcium chloride and / or anhydrous sodium sulfate.

[0015] On the basis of the above technical solution, preferably, the 2,4-bis(2,3-dimethylphenyl)ethyl ether is a fraction at 100-110° C. under atmospheric distillation.

[0016] The new impurity of dexmedetomidine hydrochloride and the preparation method thereof provided by the present invention have the following beneficial effects compared with the prior art:

[0017] The present invention discloses for the first time a new impurity present in dexmedetomidine hydrochloride, and provides a method for preparing the impurity and its related compounds (including but not limited to its salified form and chiral isomers and salts thereof). This discovery is crucial for in-depth research on the quality of dexmedetomidine hydrochloride bulk drug and preparations, not only providing new reference standards for content analysis and quality control, but also promoting the establishment of more stringent quality standards. By protecting the application of these compounds as impurity reference substances, the present invention aims to enhance the safety and effectiveness of dexmedetomidine hydrochloride preparations, ensure drug quality, and thus have a positive impact on drug development and clinical application. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0019] Figure 1 A synthetic route diagram of 1-(1-chloroethyl)-2,3-xylene provided by the present invention;

[0020] Figure 2 A synthetic route map for the new impurity proposed in the present invention;

[0021] Figure 3 is a typical gas chromatogram of the starting material 1-(1-chloroethyl)-2,3-dimethylbenzene;

[0022] Figure 4 A process map for the preparation of dexmedetomidine hydrochloride provided by the present invention;

[0023] Figure 5 This is the H NMR spectrum of impurity 1 in the spiked experiment of the present invention;

[0024] Figure 6 This is the NMR carbon spectrum of impurity 1 in the spiked experiment of the present invention;

[0025] Figure 7 This is the two-dimensional NMR HSQC spectrum of impurity 1 in the spiked experiment of the present invention;

[0026] Figure 8 This is the two-dimensional nuclear magnetic HMBC spectrum of impurity 1 in the spiked experiment of the present invention;

[0027] Fig. 9 This is the nuclear magnetic hydrogen spectrum of impurity 2 in the spiked experiment of the present invention;

[0028] Fig.10 This is the NMR carbon spectrum of impurity 2 in the spiked experiment of the present invention;

[0029] Fig.11 This is the two-dimensional NMR HSQC spectrum of impurity 2 in the spiked experiment of the present invention;

[0030] Fig.12 This is the two-dimensional nuclear magnetic HMBC spectrum of impurity 2 in the spiked experiment of the present invention. DETAILED DESCRIPTION

[0031] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] like Figure 1 As shown in FIG. 1 , the synthetic route of 1-(1-chloroethyl)-2,3-xylene, the key starting material of dexmedetomidine hydrochloride, is as follows: diazotization reaction is carried out in hydrobromic acid, and 2,3-dimethylbromobenzene is obtained after extraction, drying and distillation. 2,3-dimethylbromobenzene is subjected to Grignard reaction by adding magnesium strips to tetrahydrofuran, and then condensed with carbon dioxide, extracted, concentrated and dried to obtain 2,3-dimethylbenzoic acid. 2,3-Dimethylbenzoic acid reacts with thionyl chloride to obtain acyl chloride, which is then condensed with diethyl malonate, and then hydrolyzed and decarboxylated with sulfuric acid, and then extracted and distilled under reduced pressure to obtain 2,3-dimethylacetophenone. 2,3-Dimethylacetophenone is reduced with sodium borohydride in methanol, and then chlorinated with hydrochloric acid, extracted and concentrated to obtain 1-(1-chloroethyl)-2,3-dimethylbenzene.

[0033] In the above route, when preparing 1-(1-chloroethyl)-2,3-dimethylbenzene, a large unknown impurity was found to be newly generated. The structure was confirmed to be the impurity 2,4-bis(2,3-dimethylphenyl)ethyl ether. The reaction mechanism is speculated to be: 1-(1-chloroethyl)-2,3-dimethylbenzene reacts with its hydrolysis impurity III to obtain the product. The structure has two chiral centers, but its own structure is a mirror-symmetric structure, so it has only two diastereoisomers, namely impurity 1 and impurity 2, such as Figure 2 shown.

[0034] The product 1-(1-chloroethyl)-2,3-dimethylbenzene was detected by high performance gas chromatography to obtain Figure 3 Chromatogram shown.

[0035] Figure 3 In the analysis, the peak positions corresponding to the retention times of 54.7min and 55.5min are the two diastereomers mentioned above.

[0036] To avoid contingency, the inventor purchased multiple batches of starting materials from the market to prepare 1-(1-chloroethyl)-2,3-dimethylbenzene for testing. The test results are shown in Table 1.

[0037] Table 1 Test results of multiple batches of 1-(1-chloroethyl)-2,3-dimethylbenzene

[0038]

[0039] The following are specific embodiments of the present invention.

[0040] Example 1

[0041] This embodiment provides a method for preparing the impurity, comprising the following steps:

[0042] Put 20g of sodium hydroxide and 100mL of water into a three-necked flask, add 150g (1mol) of 1-(2,3-dimethylphenyl)-ethanol and 168.6g (1mol) of 1-(1-chloroethyl)-2,3-dimethylbenzene after fully dissolving, heat and reflux and stir for 4h. Layer, dry the organic phase with anhydrous CaCl2, filter, evaporate the filtrate to remove the solvent, distill at atmospheric pressure, collect the fraction at 100-110°C, and obtain 2,4-bis(2,3-dimethylphenyl)ethyl ether (14.2g, yield 8.42%).

[0043] Example 2

[0044] This embodiment provides a method for preparing the impurity, comprising the following steps:

[0045] Put 30g of sodium hydroxide and 100mL of water into a three-necked flask, add 150g (1mol) of 1-(2,3-dimethylphenyl)-ethanol and 185.5g (1.1mol) of 1-(1-chloroethyl)-2,3-dimethylbenzene after fully dissolving, heat and reflux and stir for 4h. Layer, extract the organic phase with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, evaporate the filtrate to remove the solvent, distill at atmospheric pressure, collect the 100-110°C fraction, and obtain the above impurity (16.2g, yield 9.61%).

[0046] In order to study the influence of the above impurities in the subsequent preparation of dexmedetomidine hydrochloride, a spiked experiment was carried out. The experiment included: taking chlorinated sample 1 at random, adding impurity 1 (1.7%) and impurity 2 (1.8%) thereto; taking chlorinated sample 2 from the same batch, adding impurity 1 (1.3%) and impurity 2 (1.3%) thereto, and using the above samples as follows: Figure 4 The process synthesis route is used to prepare rotatory dexmedetomidine. According to the removal rate of impurities in the preparation process, the internal control standards of impurities 1 and 2 in the starting material 1-(1-chloroethyl)-2,3-xylene are formulated to ensure that the impurities do not affect subsequent production. The specific results are shown in Table 2 below:

[0047] Table 2 Results of the spiked experiment with 1-(1-chloroethyl)-2,3-dimethylbenzene

[0048]

[0049]

[0050] As shown in Table 2, according to the results of the spiked experiment, the limits of impurity 1 and impurity 2 are no more than 1.5%, which can meet the subsequent process requirements.

[0051] The inventors further tested the samples by hydrogen spectrum, carbon spectrum and HSQC. The test results are as follows: Figures 5 to 12 shown.

[0052] It can be confirmed from the hydrogen spectrum, carbon spectrum and HSQC that the sample contains 3 groups of CH3 hydrogen and 4 groups of CH3 hydrogen, 3 groups of CH3 carbon signals, 4 groups of CH3 carbon signals and 3 groups of quaternary carbon signals. According to the range of chemical shift, it can be judged that 3 of the 4 groups of CH3 hydrogen are aromatic protons, and 3 of the 4 groups of CH3 carbon are aromatic carbons, which matches the structural characteristics of the new impurity of the present invention.

[0053] In HMBC, H-4 / C-5, H-4 / C-2, H-1 / C-3, H-1 / C-8, H-9 / C-2, H-9 / C-7, and H-10 / C-8 are correlated, and the substitution positions of the groups on the benzene ring can be determined; the chemical shift of C-9 is 71.80 ppm, indicating that H-9 is connected to the O atom, and the structural fragment A can be determined:

[0054]

[0055] In HMBC, H-9 / C-9 are correlated, indicating that there are two identical fragments A connected by O atoms, and the structure can be determined as

[0056]

[0057] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A new impurity of dexmedetomidine hydrochloride, characterized in that The chemical name of the impurity is: 2,4-bis(2,3-dimethylphenyl)ethyl ether, and its structure is shown in formula (I):

2. The dexmedetomidine hydrochloride new impurity according to claim 1, characterized in that It also includes salt-forming compounds related to formula (I) and chiral isomers thereof.

3. The new impurity of dexmedetomidine hydrochloride according to claim 2, characterized in that The dexmedetomidine hydrochloride impurity is used as an impurity reference substance for content analysis and quality control of dexmedetomidine hydrochloride raw materials and preparations.

4. A method for preparing the new impurity of dexmedetomidine hydrochloride according to any one of claims 1 to 3, characterized in that: The method comprises the following steps: In an aqueous solution of sodium hydroxide, 1-(1-chloroethyl)-2,3-dimethylbenzene and 1-(2,3-dimethylphenyl)-ethanol are mixed, heated and stirred, allowed to stand for stratification, dried, filtered, and distilled at normal pressure to obtain 2,4-bis(2,3-dimethylphenyl)ethyl ether.

5. The method for preparing the new impurity of dexmedetomidine hydrochloride as claimed in claim 4, characterized in that, The molar ratio of the 1-(1-chloroethyl)-2,3-dimethylbenzene to the 1-(2,3-dimethylphenyl)-ethanol is 1:1.2, and the concentration of the sodium hydroxide aqueous solution is 5 to 7.5 mol / L.

6. The method for preparing the new impurity of dexmedetomidine hydrochloride as claimed in claim 5, characterized in that: The heating temperature is 90-100° C., and the stirring time is 3-5 hours.

7. The method for preparing the new impurity of dexmedetomidine hydrochloride according to claim 6, characterized in that: After the separation, the organic phase is dried, and the desiccant is selected from anhydrous calcium chloride and / or anhydrous sodium sulfate.

8. The method for preparing the new impurity of dexmedetomidine hydrochloride according to claim 7, characterized in that: The 2,4-bis(2,3-dimethylphenyl)ethyl ether is a fraction at 100-110° C. under normal pressure distillation.

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