Synthesis process of low catalytic consumption and high optical purity dexmedetomidine hydrochloride and low irritation injection

Abstract

The application discloses a synthesis process of low-catalyst-consumption high-optical-purity dexmedetomidine hydrochloride and a low-irritation injection, and belongs to the technical field of medical chemical engineering and pharmaceutical preparations. The synthesis process takes 2,3-dimethylacetophenone as raw material, and a unique vinyl imidazole intermediate is synthesized through palladium catalytic coupling of a p-toluenesulfonyl hydrazone intermediate; then, asymmetric catalytic hydrogenation is carried out in the presence of potassium iodide by using an (R)-BINAP-Rh catalytic system; and finally, dexmedetomidine hydrochloride is obtained through salification and purification. The process significantly inhibits the poisoning effect of an imidazole ring on a catalyst, high-optical-purity products can be obtained under a lower hydrogen pressure, chiral resolution is not needed, and the total yield is high. The low-irritation injection is prepared by using a specific process of full low-temperature and low-oxygen on the basis of the high-purity raw medicine. The synthesis process provided by the application has the advantages of mild process conditions, low catalyst consumption and suitability for industrial production; and the prepared injection has the advantages of excellent stability, low irritation and important clinical application value.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical and pharmaceutical preparation technology, specifically relating to a synthesis process for dexmedetomidine hydrochloride with low catalytic consumption and high optical purity, and a low-irritation injection solution. Background Technology

[0002] Dexmedetomidine hydrochloride is a highly selective α2-adrenergic receptor agonist widely used for sedation and analgesia in intensive care units (ICUs) and surgical anesthesia. Its molecule contains a chiral center, and only the (S)-configuration possesses pharmacological activity. In the prior art, patents such as CN115108993A (Zhejiang Arthur Pharmaceuticals, 2022-09-27) disclose a route for preparing dexmedetomidine hydrochloride using 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazole as an intermediate via low-pressure hydrogenation via R-BINAP-Rh.

[0003] However, existing synthetic processes still have room for optimization. For example, CN115108993A (Zhejiang Arthur Pharmaceuticals, 2022-09-27) discloses a route for preparing dexmedetomidine hydrochloride by hydrogenation at 1.5 MPa using 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazole as an intermediate via R-BINAP combined with a metal catalyst (Example 4, yield 82.0%, ee 99.95%). However, this document does not reveal the mechanism by which iodide ions (KI) act as a co-catalyst to inhibit the poisoning of the Rh center by the nitrogen atom of imidazole, nor does it provide a comprehensive optimization of KI dosage within a 0.5-2.0 times window for low-pressure (1.5-2.5 MPa) stability and industrial catalytic consumption. Secondly, there are challenges related to formulation stability and safety. Dexmedetomidine injection is prone to oxidative degradation during storage, generating impurities; and it is often accompanied by vascular irritation during clinical use, which is related to trace amounts of optical isomers remaining in the active pharmaceutical ingredient and oxidative stress during the formulation process.

[0004] Existing technologies typically optimize synthesis or formulation processes in isolation, lacking a synergistic control scheme across the entire chain from "high-purity raw material source" to "low-irritant formulation end product". Summary of the Invention

[0005] The core of this invention lies in providing a low-pressure, high-efficiency, and highly selective full-chain preparation process. By optimizing the hydrazone-olefination reaction conditions in step S1 and introducing potassium iodide (KI) as a co-catalyst for chiral hydrogenation in step S3 (asymmetric hydrogenation), high optical purity active pharmaceutical ingredient can be prepared under low pressure without the need for subsequent chiral resolution steps. Furthermore, combined with a low-temperature and low-oxygen formulation process, a highly stable injection solution can be obtained.

[0006] To achieve the above objectives, the present invention provides the following specific technical solutions:

[0007] In a first aspect, the present invention provides a process for synthesizing dexmedetomidine hydrochloride with low catalytic consumption and high optical purity, comprising the following steps:

[0008] S1. Preparation of p-toluenesulfonylhydrazone intermediate: 2,3-dimethylacetophenone and p-toluenesulfonylhydrazine were reacted in an organic solvent in the presence of an acidic catalyst, and the p-toluenesulfonylhydrazone intermediate was obtained after post-treatment.

[0009] S2. Preparation of 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium intermediate: Under an inert atmosphere and in the presence of a palladium catalyst, the p-toluenesulfonylhydrazone intermediate obtained in step S1 is subjected to a palladium-catalyzed coupling reaction with 4-bromo-1H-imidazolium in an organic solvent and in the presence of a base, and the vinylimidazolium intermediate is obtained after post-treatment.

[0010] S3. Asymmetric catalytic hydrogenation: The vinylimidazole intermediate obtained in step S2 is dissolved in a solvent, and a chiral bisphosphine ligand, a transition metal precursor and potassium iodide are added. An asymmetric catalytic hydrogenation reaction is carried out under a hydrogen atmosphere to obtain dexmedetomidine free base.

[0011] S4. Salt formation and purification: The free base of dexmedetomidine obtained in step S3 is reacted with hydrochloric acid to form a salt, which is then crystallized and purified to obtain dexmedetomidine hydrochloride.

[0012] Preferably, in step S1, the acidic catalyst is p-toluenesulfonic acid, and the amount used is 0.5%-5% of the molar amount of 2,3-dimethylacetophenone; the organic solvent is anhydrous ethanol, the reaction temperature is 55-65℃, and the reaction time is 3-6 hours.

[0013] Preferably, in step S2, the palladium catalyst is Pd(dppf)Cl2, the base is cesium carbonate, and the organic solvent is anhydrous tetrahydrofuran; the reaction temperature is 75-85℃, the reaction is carried out in a sealed reactor under autogenous pressure, and the reaction time is 5-8 hours.

[0014] Preferably, in step S3, the chiral bisphosphine ligand is (R)-BINAP, the transition metal precursor is [Rh(COD)Cl]2, and the molar ratio of (R)-BINAP to [Rh(COD)Cl]2 is 1.8:1 to 3:1; the molar ratio of potassium iodide to [Rh(COD)Cl]2 is 100:1 to 500:1.

[0015] Preferably, in step S3, the amount of potassium iodide used is 0.5 to 2.0 times the molar amount of the vinylimidazole intermediate.

[0016] Preferably, in step S3, the pressure of the asymmetric catalytic hydrogenation reaction is 1.5-2.5 MPa, the temperature is 45-55℃, and the time is 10-15 hours.

[0017] As a further preferred embodiment, a synthesis process for dexmedetomidine hydrochloride with low catalytic consumption and high optical purity specifically includes the following steps:

[0018] S1. Preparation of p-toluenesulfonylhydrazone intermediate: 1.0-1.5 kg of 2,3-dimethylacetophenone and 1.36-2.03 kg of p-toluenesulfonylhydrazine were added to anhydrous ethanol, wherein the molar ratio of p-toluenesulfonylhydrazine to 2,3-dimethylacetophenone was controlled between 1.05:1 and 1.10:1 (i.e., p-toluenesulfonylhydrazine was always in excess by 5%-10%). The amount of p-toluenesulfonic acid catalyst was 0.5%-5% of the molar amount of 2,3-dimethylacetophenone. The solution was dissolved in 5-10 L of anhydrous ethanol and refluxed at 55-65 °C for 3-6 hours. After the reaction was completed, the solution was cooled to 0-5 °C to crystallize, filtered, washed with ethanol, and dried under vacuum to obtain a white solid p-toluenesulfonylhydrazone intermediate. The purpose of this step is to convert the ketone group into a highly reactive hydrazone group through hydrazone reaction, providing a high-purity and stable precursor for the palladium-catalyzed coupling in step S2, and avoiding the side reactions caused by direct olefination.

[0019] S2. Preparation of 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium intermediate (C-vinylimidazolium intermediate): The p-toluenesulfonylhydrazone intermediate (1.0-1.5 kg) obtained in S1, 4-bromo-1H-imidazolium (0.45-0.80 kg, based on a molar ratio of 1.05-1.10:1 to hydrazone), cesium carbonate (1.5-2.5 kg) and Pd(dppf)Cl2 (0.015-0.030 kg) are added to anhydrous tetrahydrofuran (5-15 L), placed in a sealed pressure-resistant reactor, and stirred at 75-85 °C for 5-8 hours under nitrogen protection. During the reaction, the pressure inside the reactor is maintained by the autogenous vapor pressure generated by the solvent tetrahydrofuran at the reaction temperature. After the reaction was complete, the mixture was cooled and filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from n-heptane to give a white to off-white solid, 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium intermediate. This step converts the hydrazone intermediate into the crucial C-vinylimidazolium intermediate via a palladium-catalyzed coupling reaction (the hydrazone intermediate undergoes in-situ denitrogenation under the action of a base and palladium to generate an alkenylpalladium active intermediate, which then undergoes C-C coupling with 4-bromo-1H-imidazolium). This structure significantly improves the induction efficiency of subsequent chiral hydrogenation. It should be noted that in the 4-bromo-1H-imidazolium molecule used in this step, the bromine atom is located at the C-4 position of the imidazolium. In the Pd(dppf)Cl2 / Cs2CO3 / THF system, oxidative addition preferentially occurs at the C-Br bond; the imidazolium NH is partially deprotonated in the presence of cesium carbonate, but this species does not directly undergo oxidative addition with Pd(0), and the coupling transfer occurs at the C-4 position. However, since the C4 and C5 positions of the 1H-imidazolium ring can be rapidly interchanged via NH tautomerism, 4-substituted and 5-substituted-1H-imidazolium are in the same tautomerism system. To maintain consistency with the intermediate nomenclature of the existing process (CN115108993A) cited in the background art for direct comparison, and referring to the nomenclature of the final product dexmedetomidine hydrochloride, this application uniformly adopts a 5-digit number, namely 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium. This process has no N-alkenylation byproducts. Excess 4-bromo-1H-imidazole is removed by recrystallization from n-heptane, eliminating the need for chromatographic purification; the process is simple and efficient.

[0020] S3, Low-pressure asymmetric catalytic hydrogenation: The vinylimidazole intermediate (0.5-1.5 kg, about 2.5-7.5 mol) obtained in S2 is dissolved in methanol (5-10 L), and potassium iodide (0.5-2.0 times the molar amount of the vinylimidazole intermediate), [Rh(COD)Cl]2 (3-8 g) and (R)-BINAP (10-20 g) are added sequentially; the reaction system is replaced with hydrogen three times, and the reaction is stirred at a hydrogen pressure of 1.5-2.5 MPa and a temperature of 45-55℃ for 10-15 hours; after the reaction is completed, the catalyst is recovered by filtration, and the filtrate is concentrated to dryness under reduced pressure to obtain dexmedetomidine free base.

[0021] S4. Salt formation and purification: Add 5 times the amount of anhydrous ethanol to the free base of dexmedetomidine obtained in step S3, and adjust the pH to 2.0-2.5 by adding concentrated hydrochloric acid dropwise while stirring. Stir and crystallize at 0-5℃ for 4 hours, filter, recrystallize the filter cake once with anhydrous ethanol, and dry under vacuum at 60℃ to obtain dexmedetomidine hydrochloride raw material. In this step, potassium iodide acts as a co-catalyst in synergy with the (R)-BINAP-Rh catalytic system, where the molar ratio of potassium iodide to rhodium is approximately 100:1 to 500:1 (KI is calculated as 0.5 to 2.0 times the molar amount of the intermediate, and Rh is calculated as [Rh(COD)Cl]2). The inventors hypothesize that the coordination of the excess iodide ions with the rhodium center is in a reversible dynamic equilibrium. This coordination does not lead to permanent deactivation of the catalyst, but rather effectively weakens the irreversible coordination poisoning effect of the imidazole nitrogen atoms in the substrate on the metal center by adjusting the electron density of the rhodium center. This significantly improves the stereoselectivity under low pressure and greatly reduces the consumption of noble metal catalysts.

[0022] Preferably, in step S1, 2,3-dimethylacetophenone (1.0 kg), p-toluenesulfonyl hydrazine (1.36 kg), p-toluenesulfonic acid catalyst (0.5% mol) and anhydrous ethanol (5 L) are added to a 5 L reactor, and the mixture is heated to 55 °C and refluxed for 3 h. After the reaction is completed, the mixture is cooled to 0 °C to crystallize, filtered, washed with ethanol, and dried under vacuum to obtain a white solid.

[0023] Preferably, in step S2, 1.0 kg (3.16 mol) of hydrazone, 0.50 kg (3.42 mol, 1.08 equivalent) of 4-bromo-1H-imidazole, 1.50 kg (4.60 mol) of Cs2CO3, and 0.015 kg of Pd(dppf)Cl2 are added to anhydrous tetrahydrofuran (8 L). Under nitrogen protection, the mixture is stirred at 75 °C for 5 h, cooled and filtered, the filtrate is concentrated under reduced pressure, and the residue is recrystallized from n-heptane to obtain approximately 0.580 kg (yield 92.6%) of a white to off-white solid 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazole intermediate.

[0024] Preferably, in step S3, 0.580 kg of the vinylimidazole intermediate obtained in S2 is dissolved in 5 L of methanol, and 1.452 mol (0.5 times) of KI, 3 g of [Rh(COD)Cl]2, and 10 g of (R)-BINAP are added. Hydrogen gas is replaced three times, and the mixture is stirred at 1.5 MPa and 45 °C for 10 h. The catalyst is recovered by filtration, and the filtrate is concentrated to dryness under reduced pressure to obtain dexmedetomidine free base.

[0025] Preferably: In step S4, 5 times the amount of anhydrous ethanol is added to the dexmedetomidine free base obtained in step S3, and concentrated hydrochloric acid is added dropwise under stirring to adjust the pH to 2.0-2.5. The mixture is stirred at 0-5℃ for 4 hours to crystallize, filtered, and the filter cake is recrystallized once with anhydrous ethanol and dried under vacuum at 60℃ to obtain 0.618 kg of dexmedetomidine hydrochloride raw material (the combined yield of S3 and S4 is 89.3% based on intermediates, and the total yield based on 2,3-dimethylacetophenone is 78.2%).

[0026] Secondly, the present invention provides a dexmedetomidine hydrochloride injection, using high-purity dexmedetomidine hydrochloride obtained by the above-described synthesis process as the active pharmaceutical ingredient, and prepared by a method including the following steps:

[0027] S5. Under inert gas protection, dissolve sodium chloride and the dexmedetomidine hydrochloride raw material in water for injection at a temperature not exceeding 35°C, adjust the temperature of the solution to below 30°C, and adjust the pH to 4.5-5.5 with dilute hydrochloric acid to obtain the drug solution; then sterilize the drug solution by sterilization filtration, nitrogen filling and sealing, and sterilization to obtain the final product.

[0028] As a further preferred embodiment, a dexmedetomidine hydrochloride injection is prepared using high-purity dexmedetomidine hydrochloride as the active pharmaceutical ingredient, and by a method including the following steps:

[0029] S5. Low-temperature and low-oxygen preparation and sterilization of the injection solution: In a nitrogen-protected preparation system, dissolve 10-20g of dexmedetomidine hydrochloride raw material (prepared in S3) and 700-900g of sodium chloride in 80-90L of water for injection, controlling the dissolution temperature to be no higher than 35℃ and the dissolved oxygen content to be ≤1.0 mg / L, stirring until completely dissolved; then cool the solution to below 30℃, adjust the pH to 4.5-5.5 with dilute hydrochloric acid, and add water for injection to 100L to obtain the solution; filter the solution through a 0.22 μm microporous membrane for sterilization, and fill it into ampoules (2 mL / ampoule) under nitrogen protection, controlling the headspace residual oxygen content to be ≤7.0% (the headspace residual oxygen content is controlled by the nitrogen filling process and confirmed by online or offline detection using a residual oxygen analyzer), immediately seal, and finally autoclave at 121-123℃ for 12-15 minutes. Dexmedetomidine hydrochloride injection was prepared within minutes. This step employed a stepped temperature control strategy of "medium-temperature dissolution (≤35℃) + low-temperature preparation (≤30℃)" to balance the dissolution efficiency and heat sensitivity of the active pharmaceutical ingredient. Combined with nitrogen purging protection (headspace residual oxygen ≤7.0%) and standard moist heat sterilization procedures, it effectively inhibited oxidative degradation of the drug during liquid preparation and storage while ensuring aseptic level, significantly reducing the content of related substances and vascular irritation. The resulting injection solution had an osmolality of 285~295 mOsmol / kg (freezing point depression method) and a measured pH of 4.8~5.2.

[0030] Preferably: In step S5, 10g of the active pharmaceutical ingredient and 700g of sodium chloride are dissolved in 80L of water for injection (≤35℃), cooled to below 30℃, the pH is adjusted to 4.5-5.5 with dilute hydrochloric acid, and water is added to 100L to obtain the drug solution; the drug solution is sterilized by filtration through a 0.22μm filter membrane, nitrogen-filled (2mL / vial, headspace residual oxygen ≤7.0%), and autoclaved at 121℃ for 12 min.

[0031] Advantages of this invention:

[0032] It should be noted that the inventors speculated that iodide ions ( It can coordinate with the Rh center to regulate its electron density and weaken the coordination poisoning effect of the imidazole nitrogen atom on the metal center. This mechanism inference does not constitute a limitation on the scope of protection of the claims, but is only used to explain the source of the synergistic effect.

[0033] 1. This invention, through the design of a unique p-toluenesulfonylhydrazone-vinylimidazole synthetic route, ingeniously constructs a "precursor" intermediate that is not prone to poisoning of noble metal catalysts, thereby avoiding the technical problem of catalyst deactivation caused by the imidazole ring in the traditional route from the source, and creating conditions for low-pressure and high-selectivity hydrogenation.

[0034] 2. In the asymmetric hydrogenation step, this invention innovatively introduces potassium iodide as an additive, which works synergistically with a specific (R)-BINAP-Rh catalytic system. This overcomes the shortcomings of existing technologies (such as CN115108993A) that may require high-load noble metal catalysts to combat imidazole poisoning. Under conditions of significantly reduced reaction pressure (approximately 2.0 MPa) and extremely low catalyst dosage (e.g., Rh to substrate molar ratio as low as 0.4%), highly enantioselective hydrogenation of vinyl groups is effectively achieved. The optical purity of the product (enantiomer excess value (ee)) can stably reach 99.8% or higher (maximum single impurity ≤0.03%, R-isomer ≤0.02%, total impurities ≤0.10%). No subsequent chiral resolution step is required, simplifying the process and improving atom economy.

[0035] 3. Based on the above-mentioned raw materials with high optical and chemical purity, the present invention further optimizes the preparation process of the injection solution. Through strict low temperature and low oxygen (nitrogen protection) control throughout the process, it was unexpectedly discovered that the oxidative degradation of the drug in the solution can be greatly inhibited, resulting in a leapfrog improvement in the long-term stability of the formulation, while effectively reducing vascular irritation during injection.

[0036] 4. The synthesis process provided by this invention has a high overall yield, low catalyst consumption, and mild and safe reaction conditions, making it suitable for industrial-scale production. The prepared injection solution has stable quality and good safety, and has significant economic and social benefits. Attached Figure Description

[0037] Figure 1 This is a comparison chart of enantiomeric excess (ee) values ​​and total yield of the drug substance under different catalytic conditions.

[0038] Figure 2 A chart comparing the increase in related substances over 6 months in accelerated testing of the injection solution.

[0039] Figure 3 Comparison of histopathological scores for irritation of the marginal ear veins in rabbits. Detailed Implementation

[0040] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention. It should be noted that, unless otherwise specified, the following embodiments and features described therein can be combined with each other.

[0041] Unless otherwise specified, all reagents and instruments used in the following examples and comparative examples were commercially available. 2,3-Dimethylacetophenone, p-toluenesulfonylhydrazine, 4-bromo-1H-imidazole, and cesium carbonate were purchased from Sinopharm Chemical Reagent Co., Ltd.; (R)-BINAP was purchased from Bid Pharmaceuticals; and [Rh(COD)Cl]2 was purchased from Alfa Esa (China) Chemical Co., Ltd.

[0042] Example 1

[0043] S1. Preparation of p-toluenesulfonylhydrazone intermediate: 2,3-Dimethylacetophenone (1.0 kg), p-toluenesulfonylhydrazine (1.36 kg, approximately 1.08 equivalents), p-toluenesulfonic acid catalyst (0.5% mol), and anhydrous ethanol (5 L) were added to a 5 L reactor. The mixture was heated to 55 °C and refluxed for 3 h. After the reaction was complete, the mixture was cooled to 0 °C to crystallize, filtered, washed with ethanol, and dried under vacuum to obtain approximately 2.02 kg of white solid p-toluenesulfonylhydrazone intermediate, with a yield of approximately 94.6%. The purpose of this step is to convert the ketone group into a highly reactive hydrazone group through hydrazoneization, providing a high-purity and stable precursor for the palladium-catalyzed coupling in step S2, and avoiding the side reactions caused by direct olefination.

[0044] S2. Preparation of 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium intermediate (C-vinylimidazolium intermediate): 1.0 kg (3.16 mol) of hydrazone, 0.50 kg (3.42 mol, 1.08 equivalent) of 4-bromo-1H-imidazolium, 1.50 kg (4.60 mol) of Cs₂CO₃, and 0.015 kg of Pd(dppf)Cl₂ were added to anhydrous tetrahydrofuran (water content ≤0.1%, dried by molecular sieve; 8 L). The mixture was placed in a sealed reactor and stirred at 75 °C for 5 h under nitrogen protection, with the reaction proceeding under autogenous pressure. The mixture was cooled and filtered, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from n-heptane to give about 0.580 kg of a white to off-white solid 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazole intermediate (3.16 mol hydrazone, theoretical 0.626 kg, yield 92.6%). (Structural confirmation: ¹H NMR (400MHz, DMSO-d6) δ 12.5(s, 1H, NH), 7.6~7.2(m, 5H, ArH+imidazolium ring H), 6.8(dd, 1H, =CH), 5.4(dd, 1H, =CH), 2.3(s, 3H, CH3), 2.2(s, 3H, CH3); HRMS(ESI+) calcd for C13H14N2 [M+H]+ 199.1235, found 199.1232), This step converts the hydrazone intermediate into the key C-vinylimidazolium intermediate via palladium-catalyzed coupling reaction. This structure can significantly improve the induction efficiency of subsequent chiral hydrogenation. It should be noted that in the 4-bromo-1H-imidazolium molecule used in this step, the bromine atom is located at the C-4 position of the imidazolium. In the Pd(dppf)Cl2 / Cs2CO3 / THF system, oxidative addition preferentially occurs at the C-Br bond. The imidazolium NH is partially deprotonated in the presence of cesium carbonate, but this species does not directly undergo oxidative addition with Pd(0), and the coupling transfer occurs at the C-4 position. Therefore, the product is 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium. It should be noted that the C4 and C5 positions of the 1H-imidazolium ring can be rapidly interchanged via NH tautomerism, and 4-substituted and 5-substituted-1H-imidazolium are in the same tautomerism system. For comparison with existing technologies and in accordance with pharmacopoeia nomenclature, this application uniformly adopts a 5-position number, namely 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium. No N-alkenylation byproducts are produced. After the reaction is complete, excess unreacted 4-bromo-1H-imidazole can be easily removed by recrystallization from n-heptane without the need for chromatographic purification, making the process simple and efficient.

[0045] S3, Asymmetric Catalytic Hydrogenation: 0.580 kg (2.925 mol) of the vinylimidazole intermediate obtained in S2 was dissolved in 5 L of methanol, and 1.452 mol (0.241 kg, i.e., 0.5 times the molar amount of the intermediate) of KI, 3 g of [Rh(COD)Cl]2, and 10 g of (R)-BINAP were added. Hydrogen gas was purged three times, and the reaction was stirred at 1.5 MPa and 45 °C for 10 h. The catalyst was recovered by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain the free base of dexmedetomidine.

[0046] S4. Salt formation and purification: Add 5 times the amount of anhydrous ethanol to the free base of dexmedetomidine obtained in step S3, and adjust the pH to 2.2 by adding concentrated hydrochloric acid dropwise while stirring. Stir and crystallize at 3°C ​​for 4 hours, filter, recrystallize the filter cake once with anhydrous ethanol, and dry under vacuum at 60°C to obtain 0.618 kg of dexmedetomidine hydrochloride raw material (combined yield of S3 and S4: 89.3%, total yield based on ketones: 78.2%).

[0047] S5. Low-temperature and low-oxygen preparation and sterilization of the injection solution: Dissolve 10 g of the active pharmaceutical ingredient and 700 g of sodium chloride in 80 L of water for injection (≤35 ℃), cool to below 30 ℃, adjust the pH to 4.9~5.1 with dilute hydrochloric acid (actual value 4.95), and add water to 100 L. Filter sterilely through a 0.22 μm filter membrane, fill with nitrogen (2 mL / vial, headspace residual oxygen ≤7.0%), and autoclave at 121 ℃ for 12 min. This step employs a stepped temperature control strategy of "medium-temperature dissolution (≤35℃) + low-temperature preparation (≤30℃)" to balance the dissolution efficiency and heat sensitivity of the active pharmaceutical ingredient. Combined with nitrogen purging protection (headspace residual oxygen ≤7.0%) and standard moist heat sterilization procedures, it effectively inhibits oxidative degradation of the drug during liquid preparation and storage while ensuring aseptic assurance levels, significantly reducing the content of related substances and vascular irritation. The resulting injection solution has an osmotic pressure of 286 mOsmol / kg and a measured pH of 4.95.

[0048] Example 2

[0049] S1. Preparation of p-toluenesulfonylhydrazone intermediate: 2,3-Dimethylacetophenone (1.2 kg), p-toluenesulfonylhydrazine (1.63 kg, based on a molar ratio of 1.08:1), p-toluenesulfonic acid catalyst (2.0% mol, based on 2,3-dimethylacetophenone), and anhydrous ethanol (6 L) were added to a 6 L reactor. The mixture was heated to 58 °C and refluxed for 4 h. After the reaction was complete, the mixture was cooled to 2 °C to crystallize, filtered, washed with ethanol, and dried under vacuum to obtain approximately 2.44 kg of white solid p-toluenesulfonylhydrazone intermediate, with a yield of approximately 95.2%. The purpose of this step is to convert the ketone group into a highly reactive hydrazone group through hydrazoneization, providing a high-purity and stable precursor for the palladium-catalyzed coupling in step S2, and avoiding the side reactions caused by direct olefination.

[0050] S2. Preparation of 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium intermediate: The above-mentioned hydrazone intermediate (1.2 kg, about 3.79 mol), 4-bromo-1H-imidazolium (0.59 kg, about 4.04 mol, 1.07 equivalents), cesium carbonate (1.77 kg, about 5.43 mol, 1.44 equivalents), and Pd(dppf)Cl2 (0.017 kg, about 23.2 mmol, loading 0.61 mol%) were added to anhydrous tetrahydrofuran (water content ≤0.1%, dried by molecular sieve; 9 L). The mixture was placed in a sealed reactor and reacted at 78 °C for 6 h under nitrogen protection with stirring. The reaction was carried out under autogenous pressure within the reactor. The mixture was cooled and filtered, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from n-heptane to give approximately 0.703 kg (93.6%) of a white to off-white solid 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium intermediate. (Structural confirmation: ¹H NMR (400MHz, DMSO-d6) δ 12.5(s, 1H, NH), 7.6~7.2(m, 5H, ArH+imidazolium ring H), 6.8(dd, 1H, =CH), 5.4(dd, 1H, =CH), 2.3(s, 3H, CH3), 2.2(s, 3H, CH3); HRMS (ESI+) calcd for C13H14N2 [M+H]+ 199.1235, found 199.1231). This structure significantly improves the induction efficiency of subsequent chiral hydrogenation. It should be noted that in the 4-bromo-1H-imidazolium molecule used in this step, the bromine atom is located at the C-4 position of the imidazolium. In the Pd(dppf)Cl2 / Cs2CO3 / THF system, oxidative addition preferentially occurs at the C-Br bond; the imidazolium NH is partially deprotonated in the presence of cesium carbonate, but this species does not directly undergo oxidative addition with Pd(0), and the coupling transfer occurs at the C-4 position, so the product is 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium. It should also be noted that the C4 and C5 positions of the 1H-imidazolium ring can be rapidly interchanged via NH tautomerism, and 4-substituted and 5-substituted-1H-imidazolium belong to the same tautomerism system; for comparison with existing technologies and in accordance with pharmacopoeia nomenclature, this application uniformly adopts a 5-position number, i.e., 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium. No N-alkenylation byproducts are produced. After the reaction is complete, excess unreacted 4-bromo-1H-imidazole can be easily removed by recrystallization from n-heptane without the need for chromatographic purification, making the process simple and efficient.

[0051] S3, Low-pressure asymmetric catalytic hydrogenation: The vinylimidazole intermediate (0.703 kg) obtained in S2 was dissolved in methanol (6 L), and 3.546 mol KI (0.589 kg, i.e., 1.0 times the amount of the intermediate 3.546 mol), [Rh(COD)Cl]2 (4.0 g), and (R)-BINAP (13 g) were added sequentially. Hydrogen was purged three times, and the reaction was stirred at 1.8 MPa and 50 °C for 11 h. The catalyst was recovered by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain dexmedetomidine free base.

[0052] S4. Salt formation and purification: Add 5 times the amount of anhydrous ethanol to the free base of dexmedetomidine obtained in step S3, and adjust the pH to 2.3 by adding concentrated hydrochloric acid dropwise while stirring. Stir and crystallize at 1°C for 4 hours, filter, recrystallize the filter cake once with anhydrous ethanol, and dry under vacuum at 60°C to obtain about 0.775 kg of dexmedetomidine hydrochloride raw material (the combined yield of S3 and S4 is 92.4%, and the total yield based on 2,3-dimethylacetophenone is 82.3%).

[0053] S5. Low-temperature and low-oxygen preparation and sterilization of the injection solution: Dissolve 13g of dexmedetomidine hydrochloride raw material obtained in S3 and 750g of sodium chloride in 84L of water for injection (≤35℃), stir until completely dissolved, cool to below 30℃, adjust the pH to 4.9~5.1 with dilute hydrochloric acid (actual value 5.05), add water for injection to a final volume of 100L, and stir evenly. Filter sterilely through a 0.22μm filter membrane, fill into ampoules (2mL / ampoule) under nitrogen purging, control the headspace residual oxygen content to ≤7.0%, seal immediately, and finally autoclave at 121.5℃ for 13 minutes to obtain dexmedetomidine hydrochloride injection solution. This step employs a stepped temperature control strategy of "medium-temperature dissolution (≤35℃) + low-temperature preparation (≤30℃)" to balance the dissolution efficiency and heat sensitivity of the active pharmaceutical ingredient. Combined with nitrogen purging protection (headspace residual oxygen ≤7.0%) and standard moist heat sterilization procedures, it effectively inhibits oxidative degradation of the drug during liquid preparation and storage while ensuring aseptic assurance levels, significantly reducing the content of related substances and vascular irritation. The resulting injection solution has an osmotic pressure of 288 mOsmol / kg and a measured pH of 5.05.

[0054] Example 3

[0055] S1. Preparation of p-Toluenesulfonylhydrazone intermediate: 2,3-Dimethylacetophenone (1.4 kg), p-toluenesulfonylhydrazine (1.90 kg, based on a molar ratio of 1.08:1), p-toluenesulfonic acid catalyst (3.5% mol, based on 2,3-dimethylacetophenone), and anhydrous ethanol (8 L) were added to an 8 L reactor. The mixture was heated to 62 °C and refluxed for 5 h. After the reaction was complete, the mixture was cooled to 3 °C to crystallize, filtered, washed with ethanol, and dried under vacuum to obtain approximately 2.84 kg of white solid p-toluenesulfonylhydrazone intermediate, with a yield of approximately 95.0%. The purpose of this step is to convert the starting ketone into a highly crystalline hydrazone derivative, utilizing its excellent crystallization properties to achieve efficient purification and provide a high-purity precursor for subsequent coupling reactions.

[0056] S2. Preparation of 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium intermediate: The above-mentioned hydrazone intermediate (1.4 kg, about 4.42 mol), 4-bromo-1H-imidazolium (0.68 kg, about 4.73 mol, 1.07 equivalents), cesium carbonate (2.06 kg, about 6.32 mol, 1.43 equivalents), and Pd(dppf)Cl2 (0.020 kg, about 27.5 mmol, loading 0.62 mol%) were added to anhydrous tetrahydrofuran (water content ≤0.1%, dried by molecular sieve; 11 L). The mixture was placed in a sealed reactor and stirred at 82 °C for 7 h under nitrogen protection, with the reaction proceeding under autogenous pressure. The mixture was cooled and filtered, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from n-heptane to give approximately 0.806 kg (92.0%) of a white to off-white solid 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium intermediate. (Structural confirmation: ¹H NMR (400MHz, DMSO-d6) δ 12.5(s, 1H, NH), 7.6~7.2(m, 5H, ArH+imidazolium ring H), 6.8(dd, 1H, =CH), 5.4(dd, 1H, =CH), 2.3(s, 3H, CH3), 2.2(s, 3H, CH3); HRMS (ESI+) calcd for C13H14N2 [M+H]+ 199.1235, found 199.1233). This structure significantly improves the induction efficiency of subsequent chiral hydrogenation. It should be noted that in the 4-bromo-1H-imidazolium molecule used in this step, the bromine atom is located at the C-4 position of the imidazolium. In the Pd(dppf)Cl2 / Cs2CO3 / THF system, oxidative addition preferentially occurs at the C-Br bond; the imidazolium NH is partially deprotonated in the presence of cesium carbonate, but this species does not directly undergo oxidative addition with Pd(0), and the coupling transfer occurs at the C-4 position, so the product is 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium. It should also be noted that the C4 and C5 positions of the 1H-imidazolium ring can be rapidly interchanged via NH tautomerism, and 4-substituted and 5-substituted-1H-imidazolium belong to the same tautomerism system; for comparison with existing technologies and in accordance with pharmacopoeia nomenclature, this application uniformly adopts a 5-position number, i.e., 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium. No N-alkenylation byproducts are produced. After the reaction is complete, excess unreacted 4-bromo-1H-imidazole can be easily removed by recrystallization from n-heptane without the need for chromatographic purification, making the process simple and efficient.

[0057] S3, Low-pressure asymmetric catalytic hydrogenation: The vinylimidazole intermediate (0.806 kg) obtained in S2 was dissolved in methanol (8 L), and 6.099 mol KI (1.014 kg, i.e., 1.5 times the amount of the 4.066 mol intermediate), 6.5 g [Rh(COD)Cl]2, and 17 g (R)-BINAP were added sequentially. Hydrogen was purged three times, and the reaction was stirred at 2.2 MPa and 52 °C for 13 h. The catalyst was recovered by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain dexmedetomidine free base.

[0058] S4. Salt formation and purification: Add 5 times the amount of anhydrous ethanol to the free base of dexmedetomidine obtained in step S3, and adjust the pH to 2.1 by adding concentrated hydrochloric acid dropwise while stirring. Stir and crystallize at 4°C for 4 hours, filter, recrystallize the filter cake once with anhydrous ethanol, and dry under vacuum at 60°C to obtain about 0.888 kg of dexmedetomidine hydrochloride raw material (the combined yield of S3 and S4 is 92.3%, and the total yield based on 2,3-dimethylacetophenone is 80.7%).

[0059] S5. Low-temperature and low-oxygen preparation and sterilization of the injection solution: Dissolve 17g of dexmedetomidine hydrochloride raw material obtained in S3 and 850g of sodium chloride in 85L of water for injection (≤35℃), stir until completely dissolved, cool to below 30℃, adjust the pH to 4.9~5.1 with dilute hydrochloric acid (actual value 5.02), add water for injection to a final volume of 100L, and stir evenly. Filter sterilely through a 0.22μm filter membrane, fill into ampoules (2mL / ampoule) under nitrogen purging, control the headspace residual oxygen content to ≤7.0%, seal immediately, and finally autoclave at 122.5℃ for 14 minutes to obtain dexmedetomidine hydrochloride injection solution. This step employs a stepped temperature control strategy of "medium-temperature dissolution (≤35℃) + low-temperature preparation (≤30℃)" to balance the dissolution efficiency and heat sensitivity of the active pharmaceutical ingredient. Combined with nitrogen purging protection (headspace residual oxygen ≤7.0%) and standard moist heat sterilization procedures, it effectively inhibits oxidative degradation of the drug during liquid preparation and storage while ensuring aseptic assurance levels, significantly reducing the content of related substances and vascular irritation. The resulting injection solution has an osmotic pressure of 291 mOsmol / kg and a measured pH of 5.02.

[0060] Example 4

[0061] S1. Preparation of p-toluenesulfonylhydrazone intermediate: 2,3-dimethylacetophenone (1.5 kg), p-toluenesulfonylhydrazine (2.03 kg, based on a molar ratio of 1.08:1), p-toluenesulfonic acid catalyst (5.0% mol, based on 2,3-dimethylacetophenone), and anhydrous ethanol (10 L) were added to a 10 L reactor. The mixture was heated to 65 °C and refluxed for 6 h. After the reaction was complete, the mixture was cooled to 5 °C to crystallize, filtered, washed with ethanol, and dried under vacuum to obtain approximately 3.05 kg of white solid p-toluenesulfonylhydrazone intermediate, with a yield of approximately 95.2%. The purpose of this step is to convert the ketone group into a highly reactive hydrazone group through hydrazoneization, providing a high-purity and stable precursor for the palladium-catalyzed coupling in step S2, and avoiding the side reactions caused by direct olefination.

[0062] S2. Preparation of 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium intermediate: The above-mentioned hydrazone intermediate (1.5 kg, about 4.71 mol), 4-bromo-1H-imidazolium (0.76 kg, about 5.19 mol, 1.10 equivalents), cesium carbonate (2.36 kg, about 7.29 mol, 1.54 equivalents), and Pd(dppf)Cl2 (0.022 kg, about 30.1 mmol, loading 0.64 mol%) were added to anhydrous tetrahydrofuran (water content ≤0.1%, dried by molecular sieve; 13 L). The mixture was placed in a sealed reactor and stirred at 85 °C for 8 h under nitrogen protection, with the reaction proceeding under autogenous pressure. The mixture was cooled and filtered, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from n-heptane to give approximately 0.870 kg (92.6%) of a white to off-white solid 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium intermediate. (Structural confirmation: ¹H NMR (400MHz, DMSO-d6) δ 12.5(s, 1H, NH), 7.6~7.2(m, 5H, ArH+imidazolium ring H), 6.8(dd, 1H, =CH), 5.4(dd, 1H, =CH), 2.3(s, 3H, CH3), 2.2(s, 3H, CH3); HRMS (ESI+) calcd for C13H14N2 [M+H]+ 199.1235, found 199.1229). This structure significantly improves the induction efficiency of subsequent chiral hydrogenation. It should be noted that in the 4-bromo-1H-imidazolium molecule used in this step, the bromine atom is located at the C-4 position of the imidazolium. In the Pd(dppf)Cl2 / Cs2CO3 / THF system, oxidative addition preferentially occurs at the C-Br bond; the imidazolium NH is partially deprotonated in the presence of cesium carbonate, but this species does not directly undergo oxidative addition with Pd(0), and the coupling transfer occurs at the C-4 position, so the product is 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium. It should also be noted that the C4 and C5 positions of the 1H-imidazolium ring can be rapidly interchanged via NH tautomerism, and 4-substituted and 5-substituted-1H-imidazolium belong to the same tautomerism system; for comparison with existing technologies and in accordance with pharmacopoeia nomenclature, this application uniformly adopts a 5-position number, i.e., 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium. No N-alkenylation byproducts are produced. After the reaction is complete, excess unreacted 4-bromo-1H-imidazole can be easily removed by recrystallization from n-heptane without the need for chromatographic purification, making the process simple and efficient.

[0063] S3, Low-pressure asymmetric catalytic hydrogenation: The vinylimidazole intermediate (0.870 kg) obtained in S2 was dissolved in methanol (10 L), and 8.778 mol KI (1.459 kg, i.e., 2.0 times the amount of the intermediate 4.389 mol), [Rh(COD)Cl]2 (9.0 g), and (R)-BINAP (21 g) were added sequentially. Hydrogen was purged three times, and the reaction was stirred at 2.5 MPa and 55 °C for 15 h. The catalyst was recovered by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain dexmedetomidine free base.

[0064] S4. Salt formation and purification: Add 5 times the amount of anhydrous ethanol to the free base of dexmedetomidine obtained in step S3, and adjust the pH to 2.4 by adding concentrated hydrochloric acid dropwise while stirring. Stir and crystallize at 2°C for 4 hours, filter, recrystallize the filter cake once with anhydrous ethanol, and dry under vacuum at 60°C to obtain about 0.940 kg of dexmedetomidine hydrochloride raw material (the combined yield of S3 and S4 is 90.5%, and the total yield based on 2,3-dimethylacetophenone is 79.8%).

[0065] S5. Low-temperature and low-oxygen preparation and sterilization of the injection solution: Dissolve 20g of dexmedetomidine hydrochloride raw material obtained in S3 and 900g of sodium chloride in 90L of water for injection (≤35℃), stir until completely dissolved, cool to below 30℃, adjust the pH to 4.9~5.1 with dilute hydrochloric acid (actual value 4.98), add water for injection to a final volume of 100L, and stir evenly. Filter sterilely through a 0.22μm filter membrane, fill into ampoules (2mL / ampoule) under nitrogen purging, control the headspace residual oxygen content to ≤7.0%, seal immediately, and finally autoclave at 123℃ for 15 minutes to obtain dexmedetomidine hydrochloride injection solution. This step employs a stepped temperature control strategy of "medium-temperature dissolution (≤35℃) + low-temperature preparation (≤30℃)" to balance the dissolution efficiency and heat sensitivity of the active pharmaceutical ingredient. Combined with nitrogen purging protection (headspace residual oxygen ≤7.0%) and standard moist heat sterilization procedures, it effectively inhibits oxidative degradation of the drug during liquid preparation and storage while ensuring aseptic assurance levels, significantly reducing the content of related substances and vascular irritation. The resulting injection solution has an osmotic pressure of 294 mOsmol / kg and a measured pH of 4.98.

[0066] Comparative Example 1: Except for step S3, in which potassium iodide is not added, the remaining steps are the same as in Example 1. This comparative example is used to verify the phenomenon that the yield and optical purity of the conventional (R)-BINAP-Rh system are drastically reduced due to imidazole nitrogen poisoning under low pressure in the absence of iodide ion inhibition poisoning, thus demonstrating from the opposite perspective the indispensability of adding KI in this invention.

[0067] Comparative Example 2: Except for step S3, in which potassium iodide is replaced with an equimolar amount of sodium chloride, the other steps are the same as in Example 1.

[0068] Comparative Example 3: Except for step S5, which is prepared in an environment with high residual oxygen (insufficient nitrogen filling, headspace residual oxygen content of about 12%), the other steps are the same as in Example 1.

[0069] Comparative Example 4: Except for step S3, in which potassium iodide is replaced with an equimolar amount of sodium bromide (NaBr), the other steps are the same as in Example 1.

[0070] Comparative Example 5: Except for step S5, in which the active pharmaceutical ingredient (API) was replaced with a specific low optical purity product, the remaining steps were the same as in Example 1. The specific low optical purity product was simulated by artificially adding purified levometric hydrochloride to the high-purity API (ee value approximately 99.96%) obtained in Example 1 until the R-isomer content was approximately 10.75% (corresponding to an ee value of approximately 78.50%). This was done to eliminate interference from other chemical impurities and to examine solely the effect of high R-isomer content in the API on formulation stability and vascular irritation.

[0071] Comparative Example 6: Except for step S5, nitrogen protection was not performed (the headspace was air, with a residual oxygen content of about 21%), and the dissolution temperature was controlled in the same way as in Example 1 (≤35°C).

[0072] S5. Preparation of Injection Solution (Comparative Example 6): Dissolve 10g of the active pharmaceutical ingredient and 700g of sodium chloride in 80L of water for injection (≤35℃), cool to below 30℃, adjust the pH to 4.9~5.1 with dilute hydrochloric acid (actual value 4.95), and add water to 100L. Filter sterilely through a 0.22μm filter membrane, fill into ampoules (2mL / ampoule, headspace residual oxygen about 21%) under air, seal immediately, and autoclave at 121℃ for 12min.

[0073] Comparative Example 7: Except for step S5, in which nitrogen protection is provided but the dissolution temperature is controlled at 40°C (the ≤35°C medium-temperature dissolution step is not performed), the other steps are the same as in Example 1.

[0074] S5. Preparation of Injection Solution (Comparative Example 7): Dissolve 10g of the active pharmaceutical ingredient and 700g of sodium chloride in 80L of water for injection (dissolution temperature 40℃). Cool to below 30℃, adjust the pH to 4.9~5.1 with dilute hydrochloric acid (actual value 4.95), and add water to 100L. Filter sterilely through a 0.22μm filter membrane, fill into ampoules (2mL / ampoule, control headspace residual oxygen ≤7.0%) under nitrogen purging, seal immediately, and autoclave at 121℃ for 12min.

[0075] Test methods and instrument descriptions

[0076] 1. Determination of chemical purity and impurities of active pharmaceutical ingredients (HPLC)

[0077] Following the relevant methods in the Chinese Pharmacopoeia, a C18 column was used with gradient elution in acetonitrile-phosphate buffer (pH 3.0) at a detection wavelength of 220 nm. This was used to determine the HPLC purity, total impurities, and maximum single impurity of the active pharmaceutical ingredient. Since enantiomers co-elute with the main peak on a non-chiral column, the "total impurities" figure does not include R-isomers.

[0078] 2. Determination of optical purity of active pharmaceutical ingredient

[0079] The enantiomeric excess value (ee) was determined by chiral high-performance liquid chromatography (Chiralpak AD-H column, n-hexane / methanol / diethylamine = 90 / 10 / 0.1), which is suitable for solid drug substances.

[0080] 3. Determination of related substances in injection solutions (non-chiral)

[0081] Referring to the C18 column conditions described in section 1 above, the total impurities, maximum single impurity, and known oxidizing impurities (dexmedetomidine-N-oxide, relative retention time approximately 0.73) of the injection sample were determined. Similarly, this "total impurities" does not include R-isomers.

[0082] 4. Determination of R-isomers in injection solutions (chiral reverse-phase method)

[0083] A reversed-phase chiral column, Chiral-AGP (4.0 mm × 150 mm, 5 μm), was used. The mobile phase was 0.03 mol / L dipotassium hydrogen phosphate buffer (pH 7.0)-acetonitrile (82.5:17.5). The flow rate was 0.5 mL / min, and the detection wavelength was 214 nm. Injection solutions were directly injected for analysis. This method is suitable for aqueous injection matrices, avoiding solvent compatibility issues caused by hexane systems.

[0084] 5. Measurement of osmolality

[0085] The freezing point depression method was used for determination.

[0086] I. Core Performance Verification of Asymmetric Catalytic Synthesis Process

[0087] 1.1 Test Objective

[0088] This invention verifies the core advantage of the "vinylimidazolium intermediate + potassium iodide + (R)-BINAP-Rh" synergistic catalytic system in achieving high yield and high optical purity synthesis under low pressure.

[0089] 1.2 Test Samples

[0090] Examples 1-4, Comparative Examples 1, 2, and 4.

[0091] 1.3 Test Methods

[0092] Overall yield: Calculated using 2,3-dimethylacetophenone as the starting base material, according to the formula:

[0093] The overall yield (%) is calculated as follows: S1 hydrazone reaction yield × S2 yield × combined yield of S3 and S4 (including asymmetric hydrogenation, salt formation, and recrystallization) × 100%; where S2 yield = actual mass of vinylimidazole intermediate / (amount of hydrazone fed × 198.26 / 316.4), where 198.26 is the molecular weight of the intermediate and 316.4 is the molecular weight of the hydrazone; since the free base obtained in step S3 is directly purified by salt formation in S4 without separate separation, the combined yield of S3 and S4 = actual mass of dexmedetomidine hydrochloride / (mass of intermediate fed × 236.74 / 198.26). The overall yield data for each example are consistent with those in Table 1.

[0094] HPLC purity and ee value determination of active pharmaceutical ingredient: Perform according to items 1 and 2 of the "Test Methods and Instrument Instructions" above.

[0095] Table 1 Comparison of core performance of active pharmaceutical ingredient synthesis processes

[0096] *Note: Overall yield (%) = Actual yield of S1 hydrazone × S2 yield × S3 × Combined yield of S3 and S4 × 100%. Comparative Example 2 used NaCl as the additive, and Comparative Example 4 used NaBr as the additive. The amounts used were the same as in Example 1, which was 0.5 times the molar amount of the substrate. The S2 yields of Comparative Examples 1, 2, and 4 were the same as in Example 1, calculated as 92.6%.

[0097] Table 1 compares the core performance of the active pharmaceutical ingredient synthesis process. Figure 1 The table and graph show a comparison of enantiomeric excess (ee) values ​​and overall yields of the active pharmaceutical ingredient under different catalytic conditions. As can be seen from the table and graph, under the same low-pressure hydrogenation conditions (1.5 MPa), the core additive potassium iodide (KI) is far superior to other halides or no additive. Comparative Example 1 (without additive) had an enantiomeric excess (ee) value of only 78.5% and a low yield, proving that the additive is indispensable. Although Comparative Examples 2 (NaCl) and 4 (NaBr) showed some improvement, their enantiomeric excess (ee) values ​​(89.8%, 91.5%) and yields were still significantly lower than those of Example 1 (KI, ee value 99.96%, yield 78.2%). This indicates that iodide ions (I⁻) have a specific promoting effect on the low-pressure, high-selectivity hydrogenation of the specific catalytic system “vinylimidazolium intermediate-(R)-BINAP-Rh”, an effect that cannot be predicted by those skilled in the art through conventional halide substitution. Examples 2-4 further demonstrate that, in the presence of KI, the process of the present invention can stably produce products with high optical purity (enantiomeric excess (ee) value > 99.8%) and high chemical purity within a wide pressure range of 1.5-2.5 MPa.

[0098] II. Verification of the long-term chemical stability of the injection solution

[0099] 2.1 Test Objective

[0100] To verify the key effect of the synergistic effect of "high optical purity active pharmaceutical ingredient" and "low temperature and low oxygen nitrogen filling process" on inhibiting drug oxidative degradation and improving the long-term stability of the formulation.

[0101] 2.2 Test Samples

[0102] Examples 1, 3, 5, 6 and 7.

[0103] 2.3 Test Methods

[0104] Accelerated test: The injection solution was placed in a constant temperature and humidity chamber at 40℃±2℃ and relative humidity of 75%±5% for 6 months of accelerated testing.

[0105] Related substances determination: Samples were taken at the end of 0 and 6 months, and the total impurities, maximum single impurities, known oxidized impurities and R-isomers were determined according to items 3 and 4 of the "Test Methods and Instrument Instructions" above.

[0106] The increase in related substances = total impurity content over 6 months - total impurity content over 0 months.

[0107] Table 2 Comparison of accelerated stability of the injection solution (40℃, 6 months)

[0108] *Note: 1. The known oxidizing impurity is dexmedetomidine nitrogen oxide (dexmedetomidine-N-oxide), located at a relative retention time of approximately 0.73. 2. Total impurities (%), maximum single impurity (%), and known oxidizing impurities (%) were all determined using a non-chiral C18 column, excluding R-isomers (R-isomers co-elute with the main peak on non-chiral columns); R-isomers (%) were determined separately using a reversed-phase chiral column Chiral-AGP, with specific chromatographic conditions described in section 2.3. This is a separate method from the Chiralpak AD-H normal-phase method used for determining the ee value of the active pharmaceutical ingredient in Table 1, applicable to both aqueous injection samples and pure active pharmaceutical ingredient samples, respectively. 3. "—" indicates that impurities were not separately measured before sterilization at this time point. 4. Comparative Example 5 was a low-optical-purity sample of the high-purity active pharmaceutical ingredient from Example 1, artificially incorporating an R-isomer (lemedetomidine hydrochloride). The R-isomer content was approximately 10.75% (corresponding to an ee value of approximately 78.50%), used to simulate the effect of low-optical-purity raw materials on the formulation. The determination of this high-concentration R-isomer was performed using the same Chiral-AGP method as in Example 1. Method validation showed good linearity (r>0.999) within the concentration range of 0.02%–12%, with recoveries of 98.0%–101.5%, indicating that this method is suitable for accurate quantification of R-isomers over a wide concentration range. 5. Comparative Example 6 was an aerobic process sample without nitrogen purging and with the same dissolution temperature control as Example 1 (≤35℃); Comparative Example 7 was a nitrogen-protected sample with the dissolution temperature controlled at 40℃ (excluding the ≤35℃ medium-temperature dissolution step), otherwise identical to Example 1.

[0109] Table 2 shows the accelerated stability comparison of the injection solution (40℃, 6 months). Figure 2 A comparison chart of the increase in related substances over 6 months in the accelerated testing of the injectable solution. Table 2 and Figure 2The data clearly show that the total impurities in each example and comparative example before sterilization were slightly lower than the total impurities after 0 months (after sterilization). The difference mainly stemmed from the trace degradation introduced during the moist heat sterilization process, but the increase was ≤0.02%~0.03%. Example 1 (ee 99.96% + ≤35℃ dissolution + nitrogen headspace residual oxygen ≤7.0%) had only 0.06% total impurities before sterilization, 0.08% after sterilization, and 0.25% after 6 months of accelerated sterilization, an increase of 0.17%. The maximum single impurity (0.09%) and the known oxidized impurity (0.05%) were both far below the ICH identification limit, and the R-isomer (0.02%) remained stable, demonstrating the comprehensive control capability of the entire process chain of this invention over various impurities. The total impurity increase (0.57%) of Comparative Example 3 (high-purity raw material + conventional nitrogen purging, headspace residual oxygen approximately 12%) over 6 months was 3.4 times that of Example 1. The largest single impurity (0.28%) exceeded the identification limit, and the known oxidized impurities (0.22%) increased significantly, indicating that strictly controlling the headspace residual oxygen to ≤7.0% is crucial for suppressing the formation of oxidized impurities. The total impurities of Comparative Example 7 (high-purity raw material + nitrogen purging protection but dissolution temperature 40°C) before sterilization (0.08%) and after 0 months (0.11%) were both slightly higher than those of Example 1. After 6 months, the total impurity increase reached 0.47%, with the largest single impurity (0.20%) and the known oxidized impurities (0.16%) significantly higher than those of Example 1. The results indicate that although nitrogen purging can partially inhibit oxidation, increasing the dissolution temperature to 40°C still accelerates trace degradation during drug preparation, leading to an increase in initial impurity levels, which are further amplified during subsequent storage. This demonstrates the necessity of the "≤35°C medium-temperature dissolution" step in this invention for controlling initial impurity levels. Comparative Example 5 (low-purity raw material + optimized process) showed a 6-month total impurity increase of up to 0.90%, with accelerated oxidation impurities (0.38%) significantly higher than other groups, proving that the impurity profile of low-optical-purity raw materials is complex, and even optimized formulation processes cannot compensate for raw material defects. Comparative Example 6 (high-purity raw material + aerobic temperature-controlled process) showed the highest 6-month total impurity increase (1.47%), with the largest single impurity (0.82%) and oxidation impurities (0.72%) being the highest among all groups, providing direct evidence that the aerobic high-temperature environment leads to severe drug oxidation. In summary, only through the synergistic control of the entire chain—"high optical purity raw material (ee≥99.8%) + low-temperature dissolution (≤35℃) + nitrogen-filled low-oxygen filling (headspace residual oxygen ≤7.0%)"—can the increase in various impurities during long-term storage of the injection solution be kept within safe limits. Any omission or deviation of parameters in any step (such as excessive residual oxygen in Comparative Example 3, excessively high dissolution temperature in Comparative Example 7, or unqualified raw material in Comparative Example 5) will lead to a significant increase in impurity levels, fully demonstrating the synergistic and complementary relationship between the various process features of this invention.

[0110] III. Verification of the safety (vascular irritation) of the injection solution

[0111] 3.1 Test Objective

[0112] To verify the decisive role of high optical purity active pharmaceutical ingredients in reducing vascular irritation of injection solutions, and to investigate the impact of the process on safety.

[0113] 3.2 Test Samples

[0114] Example 1, Comparative Example 5, and Comparative Example 6.

[0115] 3.3 Test Methods

[0116] Animal model: In accordance with the "Technical Guidelines for Drug Irritation, Allergy and Hemolysis Studies", a rabbit ear vein injection model (New Zealand white rabbits, n=6 / group) was used, with the drug administered once daily for 3 consecutive days.

[0117] Histopathological scoring: 48 hours after the last administration, blood vessels and surrounding tissues at the injection site were collected for HE staining, observed under a microscope, and scored on a scale of 0-4 (0 points: no change; 4 points: severe necrosis / embolism).

[0118] Table 3 Comparison of Vascular Irritation of Injection Solutions

[0119] Group API ee / % Mean histopathological score Irritation determination Example 1 99.96 0.4 ± 0.2 Non-irritating Comparative Example 5 78.50 2.2 ± 0.3 moderate stimulation Comparative Example 6 99.96 1.8 ± 0.4 Mild stimulation

[0120] Note: The scoring criteria are based on a 0-4 point scale (0 points indicates no change, 4 points indicates severe necrosis).

[0121] Table 3 is a comparison table of the vascular irritation of the injection solution. Figure 3 Comparison of histopathological scores for vascular irritation of the marginal ear veins in rabbits. Table 3 and... Figure 3 The results showed that Example 1 (high-purity raw materials + superior process) had an average score of only 0.4, which was judged as "non-irritating" and had the best safety profile. Comparative Example 5 (low-purity raw materials + superior process) scored as high as 2.2, which was "moderately irritating," directly confirming that the R-isomer and related impurities introduced by low optical purity raw materials are the main endogenous factors causing vascular irritation. Comparative Example 6 (high-purity raw materials + aerobic process) scored 1.8, which was "mildly irritating," indicating that the oxidative degradation products generated under inferior processes can also become new sources of irritation. This set of data further confirms from the perspective of drug safety that the value of this invention lies in eliminating the material basis causing irritation from both the source and the process through the whole-chain control of "high-purity synthesis" and "low-temperature hypoxia preparation."

[0122] Three sets of performance tests comprehensively and progressively demonstrated the inventiveness and technological advancement of the present invention from three dimensions: synthesis process efficiency, formulation chemical stability, and clinical drug safety. The data clearly show that the specific intermediate structure, the synergistic effect of the potassium iodide additive, and the chiral Rh catalyst are key to the high-yield, high-optical-purity synthesis; and that using this high-purity raw material as a basis, combined with a low-temperature, low-oxygen formulation process, ensures the acquisition of a highly stable, low-irritation injection. The comparative data and the examples present a stark contrast, fully satisfying the patent law's requirements for demonstrating inventiveness.

[0123] The above-described embodiments are merely illustrative of specific implementations of the present invention, and while the descriptions are detailed, they should not be construed as limiting the scope of protection of the present invention. It should be noted that for those skilled in the art, any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention should be considered equivalent substitutions and are included within the scope of protection of the present invention.

Claims

1. A process for synthesizing dexmedetomidine hydrochloride with low catalytic consumption and high optical purity, characterized in that, Includes the following steps: S1. Preparation of p-toluenesulfonylhydrazone intermediate: 2,3-dimethylacetophenone and p-toluenesulfonylhydrazine were reacted in an organic solvent in the presence of an acidic catalyst, and the p-toluenesulfonylhydrazone intermediate was obtained after post-treatment. S2. Preparation of 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium intermediate: Under an inert atmosphere and in the presence of a palladium catalyst, the p-toluenesulfonylhydrazone intermediate obtained in step S1 is subjected to a palladium-catalyzed coupling reaction with 4-bromo-1H-imidazolium in an organic solvent and in the presence of a base. After post-treatment, 5-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazolium intermediate is obtained. S3. Asymmetric catalytic hydrogenation: The vinylimidazole intermediate obtained in step S2 is dissolved in a solvent, and a chiral bisphosphine ligand, a transition metal precursor and potassium iodide are added. An asymmetric catalytic hydrogenation reaction is carried out under a hydrogen atmosphere to obtain dexmedetomidine free base. S4. Salt formation and purification: The free base of dexmedetomidine obtained in step S3 is reacted with hydrochloric acid to form a salt, which is then crystallized and purified to obtain dexmedetomidine hydrochloride.

2. The synthesis process according to claim 1, characterized in that, In step S1, the acidic catalyst is p-toluenesulfonic acid, and the amount used is equal to the molar amount of 2,3-dimethylacetophenone. The organic solvent is anhydrous ethanol, and the reaction temperature is... The reaction time is Hour.

3. The synthesis process according to claim 1, characterized in that, In step S2, the palladium catalyst is Pd(dppf)Cl2, the base is cesium carbonate, and the organic solvent is anhydrous tetrahydrofuran; the reaction temperature is 75-85℃, the reaction is carried out in a sealed reactor under autogenous pressure, and the reaction time is 5-8 hours.

4. The synthesis process according to claim 1, characterized in that, In step S3, the chiral bisphosphine ligand is (R)-BINAP, the transition metal precursor is [Rh(COD)Cl]2, and the molar ratio of (R)-BINAP to [Rh(COD)Cl]2 is 1.8:1 to 3:1; the molar ratio of potassium iodide to [Rh(COD)Cl]2 is 100:1 to 500:

1.

5. The synthesis process according to claim 4, characterized in that, In step S3, the amount of potassium iodide used is 0.5 to 2.0 times the molar amount of the vinylimidazole intermediate.

6. The synthesis process according to claim 1, characterized in that, In step S3, the pressure of the asymmetric catalytic hydrogenation reaction is 1.5-2.5 MPa, the temperature is 45-55℃, and the time is 10-15 hours.

7. A dexmedetomidine hydrochloride injection, characterized in that, High-purity dexmedetomidine hydrochloride obtained by the synthesis process described in any one of claims 1-6 is used as the active pharmaceutical ingredient, and is prepared by a method including the following steps: S5. Under inert gas protection, dissolve sodium chloride and the dexmedetomidine hydrochloride raw material in water for injection at a temperature not exceeding 35°C, adjust the temperature of the solution to below 30°C, and adjust the pH to 4.5-5.5 with dilute hydrochloric acid to obtain the drug solution; then sterilize the drug solution by sterilization filtration, nitrogen filling and sealing, and sterilization to obtain the final product.

8. The injection solution according to claim 7, characterized in that, In step S5, the inert gas is nitrogen, and the preparation process is carried out in an environment with a dissolved oxygen content ≤1.0 mg / L.

9. The injection solution according to claim 7, characterized in that, In step S5, the residual oxygen content in the headspace of the container is controlled to be ≤7.0% during filling.

10. The injection solution according to claim 7, characterized in that, In step S5, the sterilization is performed by moist heat sterilization at 121-123 ℃ for 12-15 minutes.

Images