Dexmedetomidine derivative, application thereof and dexmedetomidine transdermal patch preparation quality control or detection method

Abstract

The invention discloses a dexmedetomidine derivative, application of the dexmedetomidine derivative and a quality control or detection method of a dexmedetomidine transdermal patch preparation, the dexmedetomidine derivative can be used as a standard substance for quality control of the dexmedetomidine transdermal patch preparation, and meanwhile, the invention provides a preparation method of the dexmedetomidine derivative.

Description

Technical Field

[0001] This article relates to drug quality control technology, in particular to a dexmedetomidine derivative and its use and a quality control or detection method for a dexmedetomidine transdermal patch preparation. Background Art

[0002] Dexmedetomidine is a highly selective α2-adrenaline receptor agonist. It is the dextrorotatory isomer of medetomidine and has a stronger selectivity for central α2-adrenaline receptor stimulation than medetomidine. It has sedative, hypnotic, analgesic, and sympathetic nerve blocking effects.

[0003] More than five years of clinical experience in the United States has shown that dexmedetomidine hydrochloride can produce stable sedation and awakening effects, has a unique synergistic effect on the physiological and psychological needs of critically ill patients, and can significantly reduce the amount of anesthetics required to induce anesthesia.

[0004] Although existing methods and literature have classified some known impurities, there are still many impurities that are unknown impurities. So far, there have been no reports of new impurities in dexmedetomidine high-molecular-weight long-chain copolymers in dexmedetomidine transdermal patches, nor have there been reports on dexmedetomidine derivatives. Summary of the invention

[0005] The following is an overview of the subject matter described in detail herein. This overview is not intended to limit the scope of protection of this application.

[0006] The present application provides a dexmedetomidine derivative and a quality control and detection method for a dexmedetomidine transdermal patch preparation. The dexmedetomidine derivative can be used as a standard for quality control of a dexmedetomidine transdermal patch preparation. A preparation method of the dexmedetomidine derivative is also provided.

[0007] In one aspect, the present application provides a dexmedetomidine derivative, wherein the dexmedetomidine derivative is a dexmedetomidine derivative A, or a stereoisomer thereof, or an acid salt thereof as shown in the following formula:

[0008]

[0009] In one embodiment, the dexmedetomidine derivative is a dexmedetomidine derivative B, or a stereoisomer thereof, or an acid salt thereof as shown in the following formula:

[0010]

[0011] In one embodiment, the dexmedetomidine derivative is a conjugate of dexmedetomidine and an acrylate polymer, or a stereoisomer thereof, or an acid salt thereof, wherein the conjugate includes one or two of the following monomers:

[0012]

[0013] In the above monomer, R1 is hydrogen or methyl; and the molecular weight of the conjugate is 500 to 1 million.

[0014] In a second aspect, the present application provides a use of a dexmedetomidine derivative in quality control or content detection of a dexmedetomidine transdermal patch preparation, wherein the dexmedetomidine derivative is a dexmedetomidine derivative A, or a stereoisomer thereof, or an acid salt thereof as shown in the following formula:

[0015]

[0016] The dexmedetomidine transdermal patch preparation comprises a pressure-sensitive adhesive layer, wherein the pressure-sensitive adhesive layer comprises dexmedetomidine or a salt thereof and an acrylate pressure-sensitive adhesive;

[0017] In some embodiments, the use optionally includes detecting the content of dexmedetomidine or its acid salt, dexmedetomidine derivative A, or dexmedetomidine or its acid salt and dexmedetomidine derivative A.

[0018] In one embodiment, the use of the dexmedetomidine derivative in the quality control or content detection of a dexmedetomidine transdermal patch preparation, wherein the dexmedetomidine derivative is a dexmedetomidine derivative B, or a stereoisomer thereof, or an acid salt thereof as shown in the following formula:

[0019]

[0020] In some embodiments, the use optionally includes detecting the content of dexmedetomidine or its acid salt, dexmedetomidine derivative B, or dexmedetomidine or its acid salt and dexmedetomidine derivative B.

[0021] In one embodiment, the use of the dexmedetomidine derivative in the quality control or content detection of a dexmedetomidine transdermal patch preparation, wherein the dexmedetomidine derivative is a conjugate of dexmedetomidine and an acrylate polymer, or a stereoisomer thereof, or an acid salt thereof, wherein the conjugate includes one or two of the following monomers:

[0022]

[0023] In the above monomer, R1 is hydrogen or methyl; and the molecular weight of the conjugate is 500 to 1 million;

[0024] In some embodiments, the use optionally comprises degrading the conjugate and detecting the content of dexmedetomidine or its acid salt, dexmedetomidine derivative A, or dexmedetomidine or its acid salt and dexmedetomidine derivative A, dexmedetomidine or its acid salt and dexmedetomidine derivative B, or dexmedetomidine or its acid salt and dexmedetomidine derivative A and dexmedetomidine derivative B.

[0025] In a third aspect, the present application provides a method for preparing a dexmedetomidine derivative, wherein the dexmedetomidine derivative is a dexmedetomidine derivative A or a dexmedetomidine derivative B; the preparation method comprises reacting dexmedetomidine with a C1-C20 carboxylic acid glycidyl ester or an acrylate pressure-sensitive adhesive in the presence of a polar organic solvent, and after the reaction is completed, separating to obtain a dexmedetomidine derivative A, a dexmedetomidine derivative B, or a dexmedetomidine derivative A and a dexmedetomidine derivative B.

[0026] In another aspect of the third aspect, the present application provides a method for preparing a dexmedetomidine derivative, wherein the dexmedetomidine derivative is a dexmedetomidine derivative A, a dexmedetomidine derivative B, or a dexmedetomidine derivative A and a dexmedetomidine derivative B; the preparation method comprises reacting dexmedetomidine with an acrylate pressure-sensitive adhesive in the presence of a polar organic solvent, and after the reaction is completed, separating to obtain a dexmedetomidine derivative A, a dexmedetomidine derivative B, or a dexmedetomidine derivative A and a dexmedetomidine derivative B.

[0027] In some embodiments of the third aspect, the C1-C20 carboxylic acid glycidyl ester is glycidyl butyrate.

[0028] In some embodiments of the third aspect, the acrylic pressure-sensitive adhesive includes but is not limited to DURO-TAK 87-900A, DURO-TAK 87-9301, DURO-TAK 87-4098, DURO-TAK 87-2510, DURO-TAK 87-2287, DURO-TAK 87-4287, DURO-TAK 87-2516, DURO-TAK 87-2074, DURO-TAK 87-235A, DURO-TAK87-2353, DURO-TAK 87-2852, DURO-TAK 87-2051, DURO-TAK 87-2052, DURO-TAK 87-2054, DURO-TAK 87-2194, DURO-TAK 87-2196, GELVA GMS 3083, GELVA GMS 788 or GELVA GMS9073.

[0029] In some embodiments of the third aspect, the polar organic solvent is a C1-C6 alkanol, optionally, methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol.

[0030] In some embodiments of the third aspect, when dexmedetomidine reacts with the acrylate pressure-sensitive adhesive, it is carried out in the presence of the polar organic solvent and a base.

[0031] In some embodiments of the third aspect, the base is an inorganic base or an organic base. Optionally, the inorganic base is sodium hydroxide or potassium hydroxide, etc.; the organic base is a sodium salt or potassium salt of a lower alkanol such as sodium methoxide, sodium ethoxide or potassium tert-butoxide, etc.

[0032] In some embodiments of the third aspect, the reaction of dexmedetomidine and C1-C20 carboxylic acid glycidyl ester may further include being carried out in the presence of a polyol and a water-soluble polymer; optionally, the polyol is glycerol or propylene glycol; the water-soluble polymer is polyethylene glycol such as PEG200 to PEG2000, or povidone such as povidone K30, povidone K90 or copovidone.

[0033] In some embodiments of the third aspect, the separation method after the reaction is completed includes but is not limited to chromatography.

[0034] In an exemplary embodiment of the third aspect, the preparation method comprises the following steps:

[0035] (1) Anhydrous ethanol and povidone K90 are thoroughly mixed after magnetic stirring to prepare a povidone K90 solution;

[0036] (2) Accurately weigh dexmedetomidine, glycidyl butyrate, propylene glycol, povidone K90 solution, and anhydrous ethanol;

[0037] (3) Collect the impurity solution using a preparative liquid chromatograph.

[0038] Furthermore, the conditions for preparing the liquid phase in step (3) are:

[0039] The mixed solution was diluted with 0.1% trifluoroacetic acid aqueous solution according to the proportion, and the column was chromatographically analyzed using Technologies XinC 20*250mm 100A10μm, with a flow rate of 25mL / min, gradient elution, and a wavelength of 214nm;

[0040] The collection time of impurity 1 is 6.50-7.20 min, and the collection time of impurity 2 is 7.20-8.40 min.

[0041] Furthermore, the gradient elution conditions are:

[0042] Time (min) Acetonitrile (%) 0.1% trifluoroacetic acid aqueous solution (%) 0 20 80 10 40 60 10.1 100 0 13 100 0 13.1 20 80 17 20 80 .

[0043] In an exemplary embodiment, the dexmedetomidine derivative A and the dexmedetomidine derivative B obtained by the preparation method are analyzed by one or more methods selected from ultraviolet-visible absorption chromatography, electrospray ionization, LC-HRMS, and nuclear magnetic resonance spectrometer to determine the structures of the dexmedetomidine derivative A and the dexmedetomidine derivative B.

[0044] In a fourth aspect, the present application provides a quality control method for a dexmedetomidine transdermal patch preparation, the quality control method comprising controlling the dexmedetomidine derivative A, dexmedetomidine derivative B, or dexmedetomidine derivative A and dexmedetomidine derivative B in the dexmedetomidine transdermal patch preparation to be no more than 20 mol % of the dexmedetomidine in the dexmedetomidine transdermal patch preparation; in another embodiment, the content of the dexmedetomidine derivative A, dexmedetomidine derivative B, or dexmedetomidine derivative A and dexmedetomidine derivative B is no more than 14 mol %, 13 mol %, 12 mol %, 11 mol % or 10 mol % of the total content of dexmedetomidine in the transdermal patch preparation.

[0045] In some embodiments of the fourth aspect, the dexmedetomidine transdermal patch preparation is placed for a long time. In an exemplary embodiment, the dexmedetomidine transdermal patch preparation is placed at a temperature not lower than -20°C ± 2°C, and a humidity of 60% RH ± 20% RH. In a specific exemplary embodiment, the dexmedetomidine transdermal patch preparation is placed at a temperature of 25°C ± 2°C, and a humidity of 60% RH ± 5% RH.

[0046] In an exemplary embodiment, the dexmetodine transdermal patch preparation is placed at room temperature for at least 3 months, 6 months, at least 12 months, at least 18 months, or at least 28 months. In another embodiment, it is placed at room temperature for at least 28 months.

[0047] In some embodiments of the fourth aspect, the quality control method comprises degrading the conjugate of dexmedetomidine and an acrylate polymer, and detecting the content of dexmedetomidine or its acid salt, dexmedetomidine derivative A, dexmedetomidine derivative B, dexmedetomidine or its acid salt and dexmedetomidine derivative A, dexmedetomidine or its acid salt and dexmedetomidine derivative B, or dexmedetomidine or its acid salt and dexmedetomidine derivative A and dexmedetomidine derivative B.

[0048] In a fifth aspect, the present application provides a method for detecting dexmedetomidine in a dexmedetomidine transdermal patch preparation, the detection method comprising degrading the conjugate of dexmedetomidine and an acrylate polymer, and detecting the content of dexmedetomidine or its acid salt, dexmedetomidine derivative A, dexmedetomidine derivative B, dexmedetomidine or its acid salt and dexmedetomidine derivative A, dexmedetomidine or its acid salt and dexmedetomidine derivative B, or dexmedetomidine or its acid salt and dexmedetomidine derivative A and dexmedetomidine derivative B.

[0049] In some embodiments of the fifth aspect, the degradation step includes being carried out under alcohol, alkali and heating conditions, optionally, the alcohol is a C1-C6 alkanol, optionally, methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; the alkali is an inorganic base or an organic base, optionally, the inorganic base is sodium hydroxide or potassium hydroxide, etc.; the organic base is a sodium salt or potassium salt of a lower alkanol such as sodium methoxide, sodium ethoxide or potassium tert-butoxide, etc.; the heating temperature is 10°C-90°C, preferably 70°C.

[0050] In an exemplary embodiment, the reaction time of the degradation is not less than 1 hour. In an exemplary embodiment, the alkali concentration is at least 0.8M, and the reaction time is not less than 1 hour. In an exemplary embodiment, the alkali concentration is at least 0.8M, and the reaction time is not less than 2 hours. In an exemplary embodiment, the alkali concentration is at least 0.8M, and the reaction time is not less than 4 hours. In an exemplary embodiment, the alkali concentration is at least 0.8M, and the reaction time is not less than 6 hours. In an exemplary embodiment, the alkali concentration is at least 1M, and the reaction time is not less than 1 hour. In an exemplary embodiment, the alkali concentration is at least 1M, and the reaction time is not less than 2 hours. In an exemplary embodiment, the alkali concentration is at least 1M, and the reaction time is not less than 4 hours. In an exemplary embodiment, the alkali concentration is at least 1M, and the reaction time is not less than 6 hours.

[0051] In some embodiments of the fifth aspect, the detection method further comprises detecting by high performance liquid chromatography, and the chromatographic conditions of the detection are as follows:

[0052] Chromatographic column: octadecylsilane bonded silica gel as filler;

[0053] Mobile phase: component A is potassium dihydrogen phosphate solution, component B is acetonitrile.

[0054] In an exemplary embodiment, the pH of component A is 2-4, preferably pH 3;

[0055] The concentration of component A is 0.01-0.1 mol / L, preferably 0.05 mol / L;

[0056] The volume ratio of the component A to the component B is 70:30-80:20, preferably 75:25.

[0057] In an exemplary embodiment, the chromatographic conditions further include:

[0058] Detection wavelength: 214nm;

[0059] Column temperature: 25-35°C;

[0060] Flow rate: 0.1-1.5mL / min.

[0061] In an exemplary embodiment, the detection wavelength is 214 nm, the column temperature is 30° C., and the flow rate is 1.0 mL / min.

[0062] In an exemplary embodiment, the detection method comprises the following steps:

[0063] 1) Prepare solution

[0064] Take the dexmedetomidine transdermal patch and add isopropyl alcohol and sodium hydroxide to dissolve it;

[0065] 2) Detection

[0066] Pipetting the dexmedetomidine test solution in the solution in the above step and injecting it into a high performance liquid chromatograph for detection, and recording a chromatogram;

[0067] 3) Analyze the chromatogram

[0068] According to the chromatograms of the test solution and the reference solution, calculate the total amount of dexmedetomidine derivative A and dexmedetomidine derivative B in the test sample.

[0069] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0070] The present invention fills the gap of effective detection method for new impurities of dexmedetomidine high molecular weight long chain copolymers in dexmedetomidine transdermal patches and dexmedetomidine derivatives, which are degradation products of the dexmedetomidine transdermal patches. The detection method can accurately and quantitatively detect the content of dexmedetomidine and related substances in dexmedetomidine transdermal patches, and can be used for quality control of dexmedetomidine transdermal patches. At the same time, a preparation method of dexmedetomidine derivatives is provided.

[0071] Other features and advantages of the present application will be described in the following description, and partly become apparent from the description, or be understood by implementing the present application. Other advantages of the present application can be realized and obtained by the schemes described in the description and the drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] The accompanying drawings are used to provide an understanding of the technical solution of the present application and constitute a part of the specification. Together with the embodiments of the present application, they are used to explain the technical solution of the present application and do not constitute a limitation on the technical solution of the present application.

[0073] Figure 1 Dexmedetomidine chromatographic peak and derivative chromatographic peak in the chromatogram;

[0074] Figure 2 Dexmedetomidine chromatographic peak and derivative chromatographic peak in the chromatogram;

[0075] Figure 3 Dexmedetomidine chromatographic peak and derivative chromatographic peak in the chromatogram;

[0076] Figure 4 Comparison chart of dexmedetomidine derivatives generated at room temperature for 20 days;

[0077] Figure 5 This is the LC-HRMS test spectrum;

[0078] Figure 6 is the H NMR spectrum;

[0079] Figure 7 This is the carbon nuclear magnetic resonance spectrum. DETAILED DESCRIPTION

[0080] The present invention discloses a method for preparing a dexmedetomidine polymer long-chain copolymer impurity and a derivative thereof. In order to make the purpose, technical scheme and advantages of the present application clearer, the embodiments of the present invention will be described in detail below. It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other arbitrarily.

[0081] Instruments: SQP electronic balance, ME3002T electronic balance, vacuum freeze dryer (Ningbo Xinzhi), preparative liquid chromatograph, Bruker AVANCE NEO 600 nuclear magnetic resonance spectrometer (TI-0052), mass spectrometer, electrospray ionization (HESI), KQ-500VDE ultrasonic cleaning machine, XMTD-204 constant temperature magnetic stirrer, Memmert stability test box.

[0082] Example 1 Long-term test of dexmedetomidine transdermal patch

[0083] During the stability study of the dexmedetomidine transdermal patch, the stability study data were tested under the conditions of 25°C ± 2°C and 60% RH ± 5% RH.

[0084] Take this product, remove the back protective layer, stick the patch on a gauze of appropriate size, quantitatively add 50mL of 30% acetonitrile, place at room temperature for at least 2 hours, after ultrasonication, take out and cool, shake well, filter, and take the filtrate as the test solution. Take an appropriate amount of dexmedetomidine reference substance, accurately weigh it, dissolve it in 30% acetonitrile and quantitatively dilute it to make a solution containing about 32μg of dexmedetomidine per 1mL as the reference substance solution. Accurately measure 20μg of the reference substance solution and the test solution respectively, and inject them into the liquid chromatograph in turn, using octadecylsilane bonded silica gel as the filler and potassium dihydrogen phosphate-acetonitrile as the mobile phase. Record the chromatogram and obtain the average content of 10 patches.

[0085] As shown in Table 1 below, the level of total impurity increase does not match the level of dexmedetomidine content decrease. After the dexmedetomidine transdermal patch was placed for 12 months, the impurity content increased to 0.33% (an increase of 0.18%), and the dexmedetomidine content decreased to 92.4% (a decrease of 3.9%); after 24 months, the impurity content increased to 0.84% ​​(an increase of 0.69%), and the dexmedetomidine content decreased to 91.6% (a decrease of 4.7%). There is obvious material non-conservation in the increase in impurities and the decrease in dexmedetomidine. 3.72% of unknown impurities were generated at 12 months, and 4.01% of unknown impurities were generated at 24 months.

[0086] Table 1 Long-term study of dexmedetomidine transdermal patch

[0087]

[0088] Example 2 Presence of Dexmedetomidine High Molecular Impurities

[0089] The dexmedetomidine transdermal patch was tested by high performance liquid chromatography according to the quality standards and inspection operating procedures. The specific detection conditions were: a chromatographic column with octadecylsilane bonded silica gel as a filler; the mobile phase component A was 0.05 mol / L potassium dihydrogen phosphate solution, component B was acetonitrile, the volume ratio of component A to the component B was 70:30-80:20, preferably 75:25, pH was 3, the detection wavelength was 214 nm, the column temperature was 30° C., and the flow rate was 1.0 mL / min.

[0090] The degradation process and products are shown in the following table:

[0091] Table 2 Dexmedetomidine test solution detection

[0092]

[0093] The original dexmedetomidine transdermal patch contains API, acrylic pressure-sensitive adhesive and related excipients. After extraction, the transdermal patch theoretically does not contain API, that is, dexmedetomidine. The above controlled variable test solution was centrifuged (10000rpm / min) to take the supernatant, and tested, and the solution was left to stand overnight to investigate the stability. Figure 1 The chromatographic peaks of dexmedetomidine and impurities (later confirmed to be dexmedetomidine derivatives) in the chromatogram. From Group 1 and Group 2, it can be seen that the group containing only API did not generate dexmedetomidine derivatives after heating to 70°C with alcohol and alkali, while the transdermal patch group containing acrylic pressure-sensitive adhesive generated dexmedetomidine derivatives. From Group 2 and Group 3, it can be seen that after content extraction, the transdermal patch theoretically containing no API was heated to 70°C with alcohol. Under alkaline conditions, dexmedetomidine and its derivatives were generated in the patch without dexmedetomidine in Group 2, and dexmedetomidine and its derivatives were not obtained in Group 3.

[0094] Table 3 Dexmedetomidine test solution detection

[0095]

[0096] The formation conditions of the degradation product dexmedetomidine derivatives were further explored. Under the chromatographic conditions, the dexmedetomidine derivatives had an absorption peak near 3.5-4.0. As shown in Table 3, isopropanol and the heating temperature of 70°C were the same: no dexmedetomidine derivatives were generated after heating 0.1M and 0.5M bases for 5.5 hours, and dexmedetomidine derivatives were generated after heating 1M base for 5.5 hours. It can be seen that no dexmedetomidine derivatives were generated under alkaline conditions below 0.5M. The heating temperature of 0.2M acid was 70°C, and no dexmedetomidine derivatives were generated under the conditions of 4 hours. The heating temperature of neutral conditions was 70°C, and no dexmedetomidine derivatives were generated under the conditions of 5.5 hours. It can be seen that no dexmedetomidine derivatives were generated under acidic or neutral conditions for a long time. The experimental results are as follows Figure 2 .

[0097] Further investigation of the effect of heating time showed that dexmedetomidine derivatives were generated when 1M base was heated for 2h, 4h, and 5.5h, among which only a small amount of dexmedetomidine derivatives were generated when alcohol and 1M base were heated for 2h. The peak areas of the derivatives were basically the same at 4h and 5.5h, that is, the amount of the derivatives generated was basically the same. The experimental results are shown in Figure 3 .

[0098] It was determined that the dexmedetomidine polymer copolymer can stably produce dexmedetomidine derivatives after heating with alcohol and alkali, and can be stably detected. At the same time, the relative peak area ratio of the dexmedetomidine derivative is about 5%, which is basically consistent with the reduced content of dexmedetomidine (6%). There is no such derivative impurity when heating with API alcohol and alkali, which shows that the impurity is not produced by the degradation of a single dexmedetomidine, but is extracted from the patch.

[0099] Example 3 Preparation of Dexmedetomidine Derivatives

[0100] Accurately weigh 17.07 g of anhydrous ethanol, add 3.00 g of povidone K90, stir magnetically for 30 min, and mix thoroughly to prepare a povidone K90 solution;

[0101] Dexmedetomidine, glycidyl butyrate, propylene glycol, povidone K90 solution, and anhydrous ethanol were accurately weighed. The specific weighing values ​​are shown in the following table (unit: g);

[0102] Table 5 Preparation of dexmedetomidine derivatives

[0103] prescription Dexmedetomidine Glycidyl Butyrate Propylene glycol K90 solution Anhydrous ethanol 0% Glycidyl Butyrate Medicated Prescription 0.10962 0.00 1.84 1.28 8.63 2% Glycidyl Butyrate Blank Prescription 0.00000 0.19 1.88 1.21 8.30 2% glycidyl butyrate medicated prescription 0.53912 0.32 2.22 6.09 43.08

[0104] Example 4 Enrichment of Dexmedetomidine Derivatives

[0105] The mixed solution in Example 3 was diluted with 100 mL of 0.1% trifluoroacetic acid aqueous solution according to the concentration gradient, and the diluted solution was injected into the preparative liquid chromatograph.

[0106] The chromatographic conditions were as follows:

[0107] Chromatographic column: Technologies XinC 20*250mm 100A 10μm

[0108] Flow rate: 25mL / min

[0109] The gradient table is as follows:

[0110] Time (min) Acetonitrile (%) 0.1% trifluoroacetic acid aqueous solution (%) 0 20 80 10 40 60 10.1 100 0 13 100 0 13.1 20 80 17 20 80

[0111] Collection time: Impurity 1 (6.50-7.20min)

[0112] Wavelength: 214nm

[0113] The impurity solution was collected by a preparative liquid chromatograph; the impurity solution collected in a 2% glycidyl butyrate drug-containing solution was placed in a glass dish and freeze-dried in a freeze dryer.

[0114] Example 5 Relationship between consumption of dexmedetomidine and glycidyl butyrate

[0115] A gradient concentration of glycidyl butyrate + dexmedetomidine + excipients (propylene glycol, anhydrous ethanol, povidone K90) was designed, placed at room temperature, and tested on days 0, 4, 7, 12, and 20. As the amount of glycidyl butyrate added increased, the dexmedetomidine content decreased faster, as shown in Table 6 below.

[0116] Table 6 Compatibility data of raw materials and auxiliary materials

[0117]

[0118] The consumption and consumption rate of dexmedetomidine are positively correlated with the dosage of glycidyl butyrate. In the glycidyl butyrate substitution experiment, after the content of glycidyl butyrate decreased, a large dexmedetomidine derivative impurity peak was generated, such as Figure 4 This is a comparison between the "prescription containing 2% glycidyl butyrate" and the "prescription containing 0% glycidyl butyrate" after being placed at room temperature for 20 days.

[0119] Example 6 Structural confirmation of target impurity

[0120] Take a dexmedetomidine derivative, add dimethyl sulfoxide to dissolve it, dilute it with acetonitrile, and then inject and test it as follows:

[0121] Table 4 LC-MS

[0122]

[0123]

[0124] Electrospray ionization (HESI) was used for mass spectrometry analysis, and a full-scale MS scan was performed in the positive ion mode to obtain the quasi-molecular ion peak [M+H] + The m / z is 275.17493, and the molecular formula calculated by high-resolution mass spectrometry is C 16 H 22 N2O2 (its [M+H] + Theoretical value: m / z 275.17540, relative mass deviation 1.71ppm). [M+H] + Ion m / z 275.17493 by ddMS 2 The fragment ions obtained by secondary MS analysis in 2-mode included m / z 95.06071, m / z 169.09703, etc. Figure 5 . Molecular formula: C8H 13 N2O2 + The mass is 169.09715, C5H7N2 + The mass is 95.06037.

[0125] Example 7 Structural confirmation of target impurity

[0126] Take an appropriate amount of dexmedetomidine derivative and dissolve it in dimethyl sulfoxide-d6. Use Bruker AVANCE NEO 600 NMR spectrometer (TI-0052) for detection. See the attached test spectrum. Figure 6 and Figure 7 .

[0127] In the 1H-1H COSY, δH 6.57 (d, J = 7.6 Hz, 1H, H-1), δH 6.99 (t, J = 7.6 Hz, 1H, H-2), and δH7.05 (overlap, 1H, H-3) are correlated in sequence, and δH 4.51 (overlap, 1H, H-9) is correlated with δH 1.48 (d, J = 7.0 Hz, 3H, H-10); combined with the HMBC spectrum, δH 4.51 (overlap, 1H, H-9) is correlated, δH 2.27 (s, 3H, H-7), and δH2.30 (s, 3H, H-8) are correlated, and the fragment on the trisubstituted benzene ring is determined.

[0128] In 1H-1H COSY, δH[3.72(overlap,1H),3.68(overlap,1H),H-16], δH 3.72(overlap,1H,H-17), δH[3.42(overlap,1H),3.18(dd,J=10.9,6.3Hz,1H),H-18] are correlated in turn; combined with the HMBC spectrum of structure a, δH[3.72(overlap,1H),3.68(overlap,1H),H-16], the substitution on the imidazole ring and its connection mode with the trisubstituted benzene ring are determined, combined with the molecular formula C 16 H 22 N2O2, dexmedetomidine derivative A was speculated and verified.

[0129] In the HMBC spectrum of structure b, δH [4.27 (dd, J = 13.7, 2.7 Hz, 1H), 4.06 (dd, J = 13.8, 8.0 Hz, 1H), H-16'] is correlated, and δH 7.46 (s, 1H, H-12') is correlated to determine the substitution on the imidazole ring and its connection mode with the trisubstituted benzene ring. Combined with the molecular formula C 16 H 22 N2O2, dexmedetomidine derivative B was speculated and verified.

[0130] The present application describes multiple embodiments, but the description is exemplary rather than restrictive, and it is obvious to a person skilled in the art that there may be more embodiments and implementations within the scope of the embodiments described in the present application.

Claims

1. A dexmedetomidine derivative, which is a dexmedetomidine derivative A as shown in the following formula, or a stereoisomer thereof, or an acid salt thereof; 2. A dexmedetomidine derivative, which is a dexmedetomidine derivative B, or a stereoisomer thereof, or an acid salt thereof as shown in the following formula:

3. A dexmedetomidine derivative, which is a conjugate of dexmedetomidine and an acrylate polymer, or a stereoisomer thereof, or an acid salt thereof, wherein: The conjugate includes one or two of the following monomers: In the above monomer, R1 is hydrogen or methyl; and the molecular weight of the conjugate is 500 to 1 million.

4. Use of the dexmedetomidine derivative according to any one of claims 1 to 3 in quality control or content detection of a dexmedetomidine transdermal patch preparation, wherein: The dexmedetomidine transdermal patch preparation comprises a pressure-sensitive adhesive layer, and the pressure-sensitive adhesive layer contains dexmedetomidine or its salt and an acrylate pressure-sensitive adhesive.

5. The method for preparing the dexmedetomidine derivative according to claim 1 or 2, comprising reacting dexmedetomidine with a C1-C20 carboxylic acid glycidyl ester or an acrylate pressure-sensitive adhesive in the presence of a polar organic solvent, and separating to obtain a dexmedetomidine derivative A, a dexmedetomidine derivative B, or a dexmedetomidine derivative A and a dexmedetomidine derivative B after the reaction is completed; Optionally, when dexmedetomidine reacts with the acrylate pressure-sensitive adhesive, it is carried out in the presence of the polar organic solvent and a base.

6. The preparation method according to claim 5, wherein: The C1-C20 carboxylic acid glycidyl ester is glycidyl butyrate; and / or The acrylic pressure-sensitive adhesive includes but is not limited to DURO-TAK 87-900A, DURO-TAK 87-9301, DURO-TAK87-4098, DURO-TAK 87-2510, DURO-TAK 87-2287, DURO-TAK 87-4287, DURO-TAK 87-2516, DURO-TAK 87-2074, DURO-TAK 87-235A, DURO-TAK 87-2353, DURO-TAK 87-2852, DURO-TAK87-2051, DURO-TAK 87-2052, DURO-TAK 87-2054, DURO-TAK 87-2194, DURO-TAK 87-2196, GELVA GMS 3083, GELVA GMS 788 or GELVA GMS 9073; and / or The polar organic solvent is a C1-C6 alkanol, optionally, methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; and / or The base is an inorganic base or an organic base, and optionally, the inorganic base is sodium hydroxide or potassium hydroxide, etc.; the organic base is a sodium salt or potassium salt of a lower alkanol such as sodium methoxide, sodium ethoxide or potassium tert-butoxide, etc.; and / or The separation method after the reaction is completed includes, but is not limited to, chromatography.

7. A quality control method for a dexmedetomidine transdermal patch preparation, comprising controlling the dexmedetomidine derivative A, dexmedetomidine derivative B, or dexmedetomidine derivative A and dexmedetomidine derivative B in the dexmedetomidine transdermal patch preparation to be no more than 20 mol % of the dexmedetomidine in the dexmedetomidine transdermal patch preparation; optionally, the dexmedetomidine derivative A, dexmedetomidine derivative B, or dexmedetomidine derivative A and dexmedetomidine derivative B content is no more than 14 mol %, 13 mol %, 12 mol %, 11 mol % or 10 mol % of the total dexmedetomidine content in the transdermal patch preparation; Here, the dexmedetomidine transdermal patch preparation includes a pressure-sensitive adhesive layer, and the pressure-sensitive adhesive layer contains dexmedetomidine or its salt and an acrylate pressure-sensitive adhesive; here, the dexmedetomidine derivative A is as claimed in claim 1; and the dexmedetomidine derivative B is as claimed in claim 2.

8. The quality control method according to claim 7, wherein: The dexmedetomidine transdermal patch preparation is tested for long-term storage; optionally, the dexmedetomidine transdermal patch preparation is stored at a temperature not lower than -20°C ± 2°C, and a humidity of 60% RH ± 20% RH; or, the dexmedetomidine transdermal patch preparation is stored at a temperature of 25°C ± 2°C, and a humidity of 60% RH ± 5% RH; and / or The dexmetodine transdermal patch preparation is placed at room temperature for at least 3 months, 6 months, at least 12 months, at least 18 months, or at least 28 months; or, is placed at room temperature for at least 28 months.

9. The quality control method according to claim 7 or 8, wherein: The quality control method comprises degrading a conjugate of dexmedetomidine and an acrylate polymer, and detecting the content of dexmedetomidine or its acid salt, dexmedetomidine derivative A, dexmedetomidine derivative B, dexmedetomidine or its acid salt and dexmedetomidine derivative A, dexmedetomidine or its acid salt and dexmedetomidine derivative B, or dexmedetomidine or its acid salt and dexmedetomidine derivative A and dexmedetomidine derivative B; the conjugate of dexmedetomidine and an acrylate polymer is as claimed in claim 3.

10. A method for detecting dexmedetomidine in a dexmedetomidine transdermal patch preparation, the method comprising degrading a conjugate of dexmedetomidine and an acrylate polymer, and detecting the content of dexmedetomidine or its acid salt, dexmedetomidine derivative A, dexmedetomidine derivative B, dexmedetomidine or its acid salt and dexmedetomidine derivative A, dexmedetomidine or its acid salt and dexmedetomidine derivative B, or dexmedetomidine or its acid salt and dexmedetomidine derivative A and dexmedetomidine derivative B; wherein: The dexmedetomidine derivative A is as claimed in claim 1; the dexmedetomidine derivative B is as claimed in claim 2; and the conjugate of dexmedetomidine and acrylate polymer is as claimed in claim 3.

11. The detection method according to claim 10, wherein: The degradation step includes being carried out under alcohol, alkali and heating conditions; Optionally, the alcohol is a C1-C6 alkanol, optionally, methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; and / or The base is an inorganic base or an organic base, and optionally, the inorganic base is sodium hydroxide or potassium hydroxide, etc.; the organic base is a sodium salt or potassium salt of a lower alkanol such as sodium methoxide, sodium ethoxide or potassium tert-butoxide, etc.; and / or The heating temperature is 10°C-90°C, preferably 70°C; and / or The degradation reaction time is no less than 1 hour; and the alkali concentration is at least 0.8M.

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