Dexmedetomidine hydrochloride raw material and injection preparation method

Abstract

The invention discloses a preparation method of an injection, and particularly relates to a dexmedetomidine hydrochloride raw material and a preparation method of an injection of the dexmedetomidine hydrochloride raw material. According to the method, cheap 2, 3-dimethylbenzoic acid is taken as a starting raw material, and a target compound dexmedetomidine hydrochloride is obtained through substitution of TMSI, Grignard reaction of carbonyl, dehydration of hydroxyl, hydrogenation reduction of olefin, raceme resolution, dissociation and salt forming reaction, so that the reaction process is shortened, the loss of intermediate separation is avoided, the reaction yield is increased, and the method is suitable for industrial production. And the production cost is reduced.

Description

Technical Field

[0001] The invention belongs to the medical field and mainly relates to an injection, in particular to a dexmedetomidine hydrochloride raw material and an injection preparation method. Background Art

[0002] Dexmedetomidine hydrochloride, molecular formula is C 13 H 17 ClN2 is an α2-adrenergic receptor agonist with analgesic and sedative activity. Dexmedetomidine hydrochloride injection is an α2-adrenergic receptor agonist developed by Orion Pharma (Finland) and Abott (USA). It was first launched in the United States in March 2000 and in Japan in January 2004. This product is the dextrorotatory isomer of the α2-adrenergic receptor agonist medetomidine. Compared with medetomidine, this product has stronger selectivity for central α2-adrenergic receptor stimulation, a short half-life, and a small dosage. It is clinically suitable for sedation of patients who are intubated and using ventilators during intensive care treatment. Dexmedetomidine is the active dextrorotatory isomer of medetomidine, which has antisympathetic, sedative and analgesic effects. Compared with medetomidine, this product has stronger selectivity for central α2-adrenergic receptor stimulation, and is 8 times more selective than clonidine for α2-adrenergic receptors. 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 for inducing anesthesia; preoperative administration of this product can reduce the amount of opioids or non-opioid analgesics before and after surgery. This feature is of great significance for anesthesia and intensive care; it can also promote the stability of catecholamine hemodynamics, effectively reduce tracheal intubation, surgical stress, and anesthesia and early recovery hemodynamic response. Summary of the invention

[0003] In view of this, the present invention uses cheap 2,3-dimethylbenzoic acid as a raw material, protects the 1H position, and uses ammonium formate as a hydrogen donor to prepare dexmedetomidine hydrochloride with high medical value through a series of synthetic methods.

[0004] In a first aspect, the present invention provides a method for preparing a dexmedetomidine hydrochloride raw material, comprising the following steps:

[0005] S1, the starting material is 2,3-dimethylbenzoic acid; 15L of anhydrous dichloromethane is added to a 25L reactor, 1.5kg of 2,3-dimethylbenzoic acid (10mol, 1.0eq) is added at room temperature, then the temperature is cooled to 0-5°C in an ice-water bath, and 1.02L of oxalyl chloride (12mol, 1.2eq) is added dropwise to the reactor while maintaining the temperature at 0-5°C. After the addition is completed, 0.5-1ml of N,N-dimethylformamide is added, the temperature is slowly raised to room temperature, and the mixture is stirred overnight. When the raw material disappears (sampling is performed by high performance liquid chromatography to confirm the reaction is complete), the reaction is completed, and the product 2,3-dimethylbenzoyl chloride (the structural formula of 2,3-dimethylbenzoyl chloride is );

[0006] S2. Add 2-2.5 L of 0.2 mol / L Lewis acid to a 20 L reactor, and dropwise add 0.1 mol / L TMSI under an ice bath. 2800-3400ml and dichloromethane 600-1000ml, after continuous stirring for 30min, slowly add the 2,3-dimethylbenzoyl chloride obtained in step S1 into the reactor, the concentration of 2,3-dimethylbenzoyl chloride is 0.1-0.2mol / L, the amount of addition is 2.1-2.8L, the external bath temperature is controlled at 0-5°C and continuous stirring is performed for 1h, and then stirred at room temperature for 15h to obtain product 1 (the structural formula of product 1 is ), then stirred at room temperature for 15 hours to obtain product 1, product 1 is then reacted with 3 to 4 L of 2 to 4 mol / L methyl magnesium bromide tetrahydrofuran solution, after the reaction is completed, 5-10 L of 5% ammonium chloride aqueous solution is slowly added to the reaction solution, stirred for 30 minutes and then allowed to stand for stratification, the aqueous phase is extracted once with 1 to 3 L of ethyl acetate, then the organic phases are combined and concentrated to dryness under reduced pressure, the residue is passed through a silica gel column and eluted with PE:EA=10:1 to 1:1, after elution, the solvent is concentrated to dryness under reduced pressure, the residue is recrystallized with n-heptane:ethyl acetate 10:1, filtered, and dried to obtain compound 2 (the structural formula of compound 2 is );

[0007] S3, add 5L of deionized water to a 10L reactor, then slowly drop 500-600ml of concentrated sulfuric acid, stir for 1h after the dropwise addition, add 1.5-2.3Kg of compound 2 obtained in step S2 and 2.5-3L of toluene, then heat to 85-95°C and keep stirring for 3-4h, after the reaction is completed, let stand until the temperature of the reaction solution drops to 40-50°C to obtain a stratified solution, retain the water layer and extract with 2L of toluene, remove the toluene extraction layer to obtain the water layer, which is compound 3 (the structural formula of compound 3 is ), which was directly used in the synthesis of compound 4;

[0008] S4, adding the water layer (compound 3) obtained in the step S3 to a 5L reaction container, and then adding 0.6-0.8Kg of ammonium formate, after the temperature of the reaction solution rises to 45-55°C, adding Pd / C catalyst in batches, maintaining the temperature and stirring for 3-6h, after the reaction is completed, the reaction solution is cooled to 15-25°C, 50% NaOH aqueous solution is slowly added dropwise to adjust the pH to 11-12, 1-1.5L of dichloromethane is added, and the filtrate is collected after suction filtration, the filter cake is washed with 500ml of dichloromethane, and the filtrate is combined after washing. The filtrate is allowed to stand for stratification, and the water layer is extracted with dichloromethane. After the extraction is completed, the organic layers are combined, and then the combined organic layers are washed with 1-2L of 15% NaCl aqueous solution and concentrated under reduced pressure to dryness, and the evaporated solid is dissolved in 1-2L of anhydrous ethanol for suction filtration, and inorganic salts are filtered out by suction filtration to obtain compound 4 (also called the racemic form of medetomidine);

[0009] S5, adding the ethanol solution of compound 4 obtained in step S3 to a 5L reactor, adding 800-1000ml of anhydrous ethanol, 800-1000ml of anhydrous methanol and 0.4 equivalent of L-(+)-tartaric acid as a substrate, heating to 65-75°C while stirring, maintaining the temperature for reaction until the reaction solution is clear, lowering the temperature to room temperature, stirring overnight, filtering after the reaction is completed, washing the filter cake with 400-500ml of a mixed solution of anhydrous ethanol and anhydrous methanol (anhydrous ethanol and anhydrous methanol are mixed in a volume ratio of 4:1), and then washing with 90% ethanol solution. Repeat the above operation, and split after multiple recrystallization to obtain compound 5 (also called tartrate of dexmedetomidine) with qualified optical purity (ee%>99.7%);

[0010] S6, adding the compound 5 obtained in the step 5 to a 5L reactor, then adding 400-500ml of deionized water and 1-1.5L of dichloromethane, stirring for 10-20min, slowly adding 300-400ml of 2-3mol / L NaOH aqueous solution, and then stirring for 30min, ending the stirring, standing and stratifying to collect the dichloromethane layer, the water layer is washed twice with 500-1000ml of dichloromethane, and the dichloromethane is removed by rotary evaporation. The evaporated solid is dissolved in 200-250ml of anhydrous ethanol and placed in a 1L reaction container, cooled to 0-5°C, and then 280-300ml of 4-8mol / L hydrogen chloride ethanol solution is slowly added dropwise. After the addition is completed, the reaction is stirred for 30min, and the ethanol is removed by rotary evaporation. The remaining solid is dissolved in 350ml of anhydrous ethanol, filtered with a 0.22μm filter membrane, and the filtrate is collected in a 5L reaction container, and 1.5-3L 12.5%wt of methyl tert-butyl ether was added dropwise, stirred at room temperature overnight, then cooled to 10-15°C and stirred for 1h. After the reaction was completed, the filter cake was washed with 200ml of 1%wt of methyl tert-butyl ether, and then the methyl tert-butyl ether was removed by rotary evaporation to obtain the final product, dexmedetomidine hydrochloride 6 (the structural formula of dexmedetomidine hydrochloride 6 is );

[0011] Preferably, the Lewis acid used in step S2 is BF3OEt2.

[0012] Preferably, the catalyst used in step S4 is Pd / C, wherein the Pd content is 10%.

[0013] Preferably, in step S4, the catalyst Pd / C should be added in batches, and the specific method is: add 100-130g Pd / C catalyst in the first batch, keep stirring at the temperature for 1-2h, add 120g Pd / C catalyst in the second batch, keep stirring at the temperature for 1-2h, and add 70-80g Pd / C catalyst in the third batch, keep stirring at the temperature for 1-2h.

[0014] Preferably, in step S5, the first recrystallization of the compound 5 salified with L-(+)-tartaric acid is carried out with ethanol:methanol=5:1, and the second and subsequent recrystallization solvents are ethanol:water=10:1.

[0015] In a second aspect, the present invention provides a method for preparing dexmedetomidine hydrochloride injection, wherein the dexmedetomidine hydrochloride prepared by the above-mentioned dexmedetomidine hydrochloride raw material preparation method is dissolved in a 0.9% sodium chloride solution to prepare a 100ug / ml dexmedetomidine hydrochloride injection, and the pH of the prepared injection is tested, and after the pH value is qualified, the injection is filled and sealed in a sterile environment.

[0016] The beneficial effects of the present invention are:

[0017] 1. The raw material used in the present invention is 2,3-dimethylbenzoic acid, which is cheap.

[0018] 2. The present invention shortens the reaction process and avoids the loss of intermediate separation, thereby improving the reaction yield and reducing production costs.

[0019] 3. The synthesis of compound 3 of the present invention is carried out simultaneously with the dehydration of the deprotecting group, and after the reaction is completed, the product is dissolved in the water layer with sulfuric acid to form a salt, and water can be used as a solvent to directly carry out the next step of hydrogenation reduction reaction, which can avoid separating the product and reduce its loss.

[0020] 4. The present invention uses ammonium formate as a donor instead of hydrogen because when hydrogen is used as a hydrogen donor, the entire hydrogen system and hydrogenation reactor are difficult to verify. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0022] Figure 1 This is a diagram of the synthesis process of dexmetomidine hydrochloride.

[0023] Figure 2 It is a comparison chart of the yields of Example 1 and Comparative Examples 1-3.

[0024] Figure 3 It is a comparison chart of the yields of Example 2 and Comparative Examples 4 and 5.

[0025] Figure 4 It is a comparison chart of the chemical purity of Examples 1-3 and Comparative Example 6. DETAILED DESCRIPTION

[0026] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the content of the present invention and are not used to limit the present invention.

[0027] Embodiment 1:

[0028] This embodiment provides a method for preparing a dexmedetomidine hydrochloride raw material. The synthetic route is as follows: Figure 1 As shown, it includes the following steps:

[0029] S1, the starting material is 2,3-dimethylbenzoic acid; 15L of anhydrous dichloromethane is added to a 25L reactor, 1.5kg of 2,3-dimethylbenzoic acid (10mol, 1.0eq) is added at room temperature, then the temperature is cooled to 3°C in an ice-water bath, and the temperature is maintained at 3°C, 1.02L of oxalyl chloride (12mol, 1.2eq) is added dropwise to the reactor, after the addition is completed, 1ml of N,N-dimethylformamide is added, the temperature is slowly raised to room temperature, stirred overnight, the reaction is terminated after the disappearance of the raw materials, and the product 2,3-dimethylbenzoyl chloride is obtained by concentration under reduced pressure;

[0030] S2, in a 20L reactor, add 2L of 0.2mol / L Lewis acid, add 2800ml of 0.1mol / L TMSI and 1000ml of dichloromethane dropwise in an ice bath, continue stirring for 30min, slowly add the 2,3-dimethylbenzoyl chloride obtained in step S1 into the reactor, the concentration of 2,3-dimethylbenzoyl chloride is 0.2mol / L, the amount added is 2.1L, control the external bath temperature at 3°C, continue stirring for 1h, then stir at room temperature for 15h to obtain product 1, then stir at room temperature for 15h to obtain Product 1, product 1 is reacted with 3L of 2mol / L methylmagnesium bromide tetrahydrofuran solution, after the reaction is completed, 5L of 5% ammonium chloride aqueous solution is slowly added to the reaction solution, stirred for 30min and then allowed to stand for stratification, the aqueous phase is extracted once with 2L of ethyl acetate, then the organic phases are combined and concentrated to dryness under reduced pressure, the residue is passed through a silica gel column and eluted with PE:EA=10:1, after elution, the solvent is concentrated to dryness under reduced pressure, the residue is recrystallized with n-heptane:ethyl acetate 10:1, filtered, and dried to obtain compound 2; wherein the Lewis acid is BF3OEt2;

[0031] S3, add 5L of deionized water to a 10L reactor, then slowly add 600ml of concentrated sulfuric acid, stir for 1h after the addition is completed, add 2.3Kg of compound 2 obtained in step S2 and 3L of toluene, then heat to 95°C and keep stirring for 4h, after the reaction is completed, let stand until the temperature of the reaction solution drops to 50°C to obtain a stratified solution, retain the water layer and extract with 2L of toluene, remove the toluene extraction layer to obtain the water layer, which is compound 3, which is directly used in the synthesis of compound 4;

[0032] S4, the water layer obtained in step S3 was added to a 5L reaction vessel, and then 0.8Kg of ammonium formate was added. After the temperature of the reaction solution rose to 55°C, 130g of Pd / C catalyst was added, the temperature was maintained and stirred for 2h, and then 120g of Pd / C catalyst was added, the temperature was maintained and stirred for 2h, and then 80g of Pd / C catalyst, keep stirring at the temperature for 2h. After the reaction is completed, the reaction liquid is cooled to 25°C, 50% NaOH aqueous solution is slowly added dropwise to adjust the pH to 12, 1.5L of dichloromethane is added, and the filtrate is collected after suction filtration. The filter cake is washed with 500ml of dichloromethane, and the filtrate is combined after washing. The filtrate is allowed to stand for stratification, and the water layer is extracted with dichloromethane. After the extraction is completed, the organic layers are combined, and then the combined organic layers are washed with 2L of 15% NaCl aqueous solution and concentrated to dryness under reduced pressure. The evaporated solid is dissolved in 2L of anhydrous ethanol and suction filtered. The inorganic salt is filtered out by suction to obtain an ethanol solution of compound 4; wherein the Pd content in the catalyst Pd / C is 10%;

[0033] S5, adding the ethanol solution of compound 4 obtained in step S3 to a 5L reactor, adding 1000ml of anhydrous ethanol, 1000ml of anhydrous methanol and 0.4 equivalents of L-(+)-tartaric acid as a substrate, heating to 75°C while stirring, maintaining the temperature for reaction until the reaction solution is clear, lowering the temperature to room temperature, stirring overnight, filtering after the reaction is completed, washing the filter cake with 500ml of a mixed solution of anhydrous ethanol and anhydrous methanol (anhydrous ethanol and anhydrous methanol are mixed in a volume ratio of 4:1), and then washing with 90% ethanol solution, repeating the above operation, and resolving after multiple recrystallizations to obtain compound 5 with qualified optical purity (ee%>99.7%); wherein the first recrystallization solvent is ethanol:methanol=5:1, and the second and subsequent recrystallization solvents are ethanol:water=10:1;

[0034] S6, the compound 5 obtained in the step 5 is added to a 5L reactor, and then 500ml of deionized water and 1.5L of dichloromethane are added, and then 400ml of 3mol / L NaOH aqueous solution is slowly added, and then stirred for 30min, and the stirring is terminated. The dichloromethane layer is collected by standing and stratification, and the water layer is washed twice with 1000ml of dichloromethane, and the dichloromethane is removed by rotary evaporation. The solid after evaporation is dissolved in 200ml of anhydrous ethanol and placed in a 1L reaction container, and the temperature is lowered to 2°C, and then 280ml of 5mol / L hydrogen chloride ethanol solution is slowly added dropwise. After the addition is completed, the reaction is stirred for 30min, and the ethanol is removed by rotary evaporation. The remaining solid is dissolved in 350ml of anhydrous ethanol, and filtered with a 0.22um filter membrane. The filtrate is collected in a 5L reaction container, and 3L 12.5%wt of methyl tert-butyl ether was added dropwise, stirred at room temperature overnight, then cooled to 15°C and stirred for 1h. After the reaction was completed, the mixture was filtered and the filter cake was washed with 200ml of 1%wt of methyl tert-butyl ether, and then the methyl tert-butyl ether was removed by rotary evaporation to obtain the final product, dexmedetomidine hydrochloride 6;

[0035] S7. Dissolve the prepared dexmedetomidine hydrochloride in 0.9% sodium chloride solution to prepare a 100 μg / ml dexmedetomidine hydrochloride injection, test the pH of the prepared injection, and fill and seal under a sterile environment if the pH is qualified.

[0036] Comparative Example 1: Except that the Lewis acid (BF3OEt2) in step S2 is replaced by AlCl3, the rest is the same as Example 1.

[0037] Comparative Example 2: Except for adding 10% Pd / C in step S4 at one time, the rest is the same as Example 1.

[0038] Comparative Example 3: Except that the hydrogen donor ammonium formate in step S4 is directly replaced by hydrogen, the rest is the same as Example 1.

[0039] The yield can be analyzed by high performance liquid chromatography test. The final product dexmedetomidine hydrochloride obtained by S6 in Example 1 and Comparative Examples 1-3 is tested and analyzed. The yield of dexmedetomidine hydrochloride is as follows: Figure 2 shown.

[0040] according to Figure 2 It can be seen that the decrease in the yield of product 6 after replacing Lewis acid with AlCl3 may be due to the decrease in the yield of intermediate 1 under the action of AlCl3. The present invention adds the catalyst 10% Pd / C three times, effectively improves the utilization rate of hydrogen donor ammonium formate, and reduces the amount of catalyst used, thereby achieving a higher yield.

[0041] Embodiment 2:

[0042] This embodiment provides a method for preparing a dexmedetomidine hydrochloride raw material. The synthetic route is as follows: Figure 1 As shown, it includes the following steps:

[0043] S1, the starting material is 2,3-dimethylbenzoic acid; 15L of anhydrous dichloromethane is added to a 25L reactor, 1.5kg of 2,3-dimethylbenzoic acid (10mol, 1.0eq) is added at room temperature, then the temperature is cooled to 2°C in an ice-water bath, and the temperature is maintained at 2°C, 1.02L of oxalyl chloride (12mol, 1.2eq) is added dropwise to the reactor, after the addition is completed, 0.5ml of N,N-dimethylformamide is added, the temperature is slowly raised to room temperature, stirred overnight, the reaction is terminated after the disappearance of the raw materials, and the product 2,3-dimethylbenzoyl chloride is obtained by concentrating under reduced pressure;

[0044] S2, in a 20L reactor, add 2L of 0.2mol / L Lewis acid, add 2900ml of 0.1mol / L TMSI and 600ml of dichloromethane dropwise in an ice bath, continue stirring for 30min, slowly add the 2,3-dimethylbenzoyl chloride obtained in step S1 into the reactor, the concentration of 2,3-dimethylbenzoyl chloride is 0.1mol / L, the amount added is 2.7L, control the external bath temperature at 2°C, continue stirring for 1h, then stir at room temperature for 15h to obtain product 1, then stir at room temperature for 15h to obtain product 1, the product 1 is reacted with 3.5L of 2.7mol / L methylmagnesium bromide tetrahydrofuran solution, and after the reaction is completed, 7L of 5% ammonium chloride aqueous solution is slowly added to the reaction solution, stirred for 30min and then allowed to stand for stratification, the aqueous phase is extracted once with 2L of ethyl acetate, and then the organic phases are combined and concentrated to dryness under reduced pressure, the residue is passed through a silica gel column and eluted with PE:EA=5:1, and the solvent is concentrated to dryness under reduced pressure after elution, and the residue is recrystallized with n-heptane:ethyl acetate 10:1, filtered, and dried to obtain compound 2; wherein the Lewis acid is BF3OEt2;

[0045] S3, add 5L of deionized water to a 10L reactor, then slowly add 500ml of concentrated sulfuric acid, stir for 1h after the addition is completed, add 1.5Kg of compound 2 obtained in step S2 and 2.5L of toluene, then heat to 85°C and keep stirring for 3h, after the reaction is completed, let stand until the temperature of the reaction solution drops to 40°C to obtain a stratified solution, retain the water layer and extract with 2L of toluene, remove the toluene extraction layer to obtain the water layer, which is compound 3, which is directly used in the synthesis of compound 4;

[0046] S4, the water layer obtained in step S3 was added to a 5L reaction vessel, and then 0.6Kg of ammonium formate was added. After the temperature of the reaction solution rose to 45°C, 100g of Pd / C catalyst was added, the temperature was maintained and stirred for 1.5h, and then 120g of Pd / C catalyst was added, the temperature was maintained and stirred for 1h, and then 70g of Pd / C catalyst, keep stirring at the temperature for 2h. After the reaction is completed, the reaction solution is cooled to 15°C, 50% NaOH aqueous solution is slowly added dropwise to adjust the pH to 11, 1L of dichloromethane is added, the filtrate is collected after suction filtration, the filter cake is washed with 500ml of dichloromethane, the filtrate is combined after washing, the filtrate is allowed to stand for stratification, the water layer is extracted with dichloromethane, the organic layers are combined after the extraction is completed, and the combined organic layers are washed with 1L of 15% NaCl aqueous solution and concentrated to dryness under reduced pressure, the evaporated solid is dissolved in 1L of anhydrous ethanol and suction filtered, and the inorganic salt is filtered out by suction filtration to obtain compound 4; wherein the Pd content in the catalyst Pd / C is 10%;

[0047] S5, adding the ethanol solution of compound 4 obtained in step S3 to a 5L reactor, adding 800ml of anhydrous ethanol, 800ml of anhydrous methanol and 0.4 equivalent of L-(+)-tartaric acid as a substrate, heating to 65°C while stirring, maintaining the temperature for reaction until the reaction solution is clear, lowering the temperature to room temperature, stirring overnight, filtering after the reaction, washing the filter cake with 400ml of a mixed solution of anhydrous ethanol and anhydrous methanol (anhydrous ethanol and anhydrous methanol are mixed in a volume ratio of 4:1), and then washing with 90% ethanol aqueous solution, repeating the above operation, and resolving after multiple recrystallizations to obtain compound 5 with qualified optical purity (ee%>99.7%); wherein the first recrystallization solvent is ethanol:methanol=5:1, and the second and subsequent recrystallization solvents are ethanol:water=10:1;

[0048] S6, the compound 5 obtained in the step 5 is added to a 5L reactor, and then 400ml of deionized water and 1L of dichloromethane are added, and then 300ml of 2mol / L NaOH aqueous solution is slowly added, and then stirred for 30min, and the stirring is terminated. The dichloromethane layer is collected by standing and stratification, and the water layer is washed twice with 500ml of dichloromethane, and the dichloromethane is removed by rotary evaporation. The evaporated solid is dissolved in 250ml of anhydrous ethanol and placed in a 1L reaction container, cooled to 3°C, and then 7300ml of 7mol / L hydrogen chloride ethanol solution is slowly added dropwise. After the addition is completed, the reaction is stirred for 30min, and the ethanol is removed by rotary evaporation. The remaining solid is dissolved in 350ml of anhydrous ethanol, and filtered with a 0.22μm filter membrane. The filtrate is collected in a 5L reaction container, and 1.5L 12.5%wt of methyl tert-butyl ether was added dropwise and stirred at room temperature overnight, then cooled to 10°C and stirred for 1h. After the reaction was completed, the mixture was filtered and the filter cake was washed with 200ml of 1%wt of methyl tert-butyl ether, and then the methyl tert-butyl ether was removed by rotary evaporation to obtain the final product, dexmedetomidine hydrochloride 6;

[0049] S7. Dissolve the prepared dexmedetomidine hydrochloride in 0.9% sodium chloride solution to prepare 100 ug / ml dexmedetomidine hydrochloride injection, test the pH of the prepared injection, and fill and seal under a sterile environment if the pH is qualified.

[0050] Comparative Example 4: Except that the first recrystallization solvent in step S5 is ethanol, and the second and subsequent recrystallization solvents are water, the rest is the same as Example 2.

[0051] Comparative Example 5: Except that the first recrystallization solvent in step S5 is methanol, and the second and subsequent recrystallization solvents are ethanol, the rest is the same as Example 2.

[0052] The yield can be analyzed by high performance liquid chromatography test. The final product dexmedetomidine hydrochloride obtained by S6 in Example 2 and Comparative Examples 4-5 was tested and analyzed. The yield of dexmedetomidine hydrochloride is as follows: Figure 3 shown.

[0053] Depend on Figure 3 It can be seen that changing the recrystallization solvent will change the degree of precipitation of the substance in the reaction system, resulting in a decrease in yield.

[0054] Embodiment 3:

[0055] S1, the starting material is 2,3-dimethylbenzoic acid; 15L of anhydrous dichloromethane is added to a 25L reactor, 1.5kg of 2,3-dimethylbenzoic acid (10mol, 1.0eq) is added at room temperature, then the temperature is cooled to 1°C in an ice-water bath, and the temperature is maintained at 1°C, 1.02L of oxalyl chloride (12mol, 1.2eq) is added dropwise to the reactor, after the addition is completed, 0.75ml of N,N-dimethylformamide is added, the temperature is slowly raised to room temperature, stirred overnight, the reaction is terminated after the disappearance of the raw materials, and the product 2,3-dimethylbenzoyl chloride is obtained by concentration under reduced pressure;

[0056] S2. In a 20L reactor, add 2.25L of 0.2mol / L Lewis acid, and add 0.1mol / L TMSI dropwise in an ice bath. 3000ml and 800ml of dichloromethane, after continuous stirring for 30min, slowly add the 2,3-dimethylbenzoyl chloride obtained in the step S1 into the reactor, the concentration of 2,3-dimethylbenzoyl chloride is 0.15mol / L, the amount of addition is 2.6L, the external bath temperature is controlled to be continuously stirred at 1°C for 1h, and then stirred at room temperature for 15h to obtain product 1, and then stirred at room temperature for 15h to obtain product 1, product 1 is then reacted with 3.8L of 3mol / L methylmagnesium bromide tetrahydrofuran solution, after the reaction is completed, 10L of 5% ammonium chloride aqueous solution is slowly added to the reaction solution, stirred for 30min and then allowed to stand for stratification, the aqueous phase is extracted once with 3L of ethyl acetate, then the organic phases are combined and concentrated to dryness under reduced pressure, the residue is passed through a silica gel column and eluted with PE:EA=1:1, the solvent is concentrated to dryness under reduced pressure after elution, the residue is recrystallized with n-heptane:ethyl acetate 10:1, filtered, and dried to obtain compound 2; wherein the Lewis acid is BF3OEt2;

[0057] S3, add 5L of deionized water to a 10L reactor, then slowly add 550ml of concentrated sulfuric acid, stir for 1h after the addition is complete, add 2Kg of compound 2 obtained in step S2 and 2.8L of toluene, then heat to 90°C and keep stirring for 3.5h, after the reaction is complete, let stand until the temperature of the reaction solution drops to 35°C to obtain a stratified solution, retain the water layer and extract with 2L of toluene, the obtained water layer is compound 3, which is directly used in the synthesis of compound 4;

[0058] S4, the water layer obtained in step S3 was added to a 5L reaction vessel, and then 0.7Kg of ammonium formate was added. After the temperature of the reaction solution rose to 50°C, 120g of Pd / C catalyst was added, the temperature was maintained and stirred for 1h, and then 120g of Pd / C catalyst was added, the temperature was maintained and stirred for 1h, and then 75g of Pd / C catalyst, keep stirring at the temperature for 1h. After the reaction is completed, the reaction liquid is cooled to 20°C, 50% NaOH aqueous solution is slowly added dropwise to adjust the pH to 12, 1.3L of dichloromethane is added, and the filtrate is collected after suction filtration. The filter cake is washed with 500ml of dichloromethane, and the filtrate is combined after washing, and the stratification is allowed to stand. The water layer is extracted with dichloromethane again. After the extraction is completed, the organic layers are combined, and then washed with 1.5L of 15% NaCl aqueous solution and concentrated to dryness under reduced pressure. The evaporated solid is dissolved in 1.5L of anhydrous ethanol and suction filtered. The inorganic salt is filtered out by suction to obtain compound 4; wherein the Pd content in the catalyst Pd / C is 10%;

[0059] S5, adding the ethanol solution of compound 4 obtained in step S3 to a 5L reactor, adding 900ml of anhydrous ethanol, 900ml of anhydrous methanol and 0.4 equivalent of L-(+)-tartaric acid as a substrate, heating to 70°C while stirring, maintaining the temperature for reaction until the reaction solution is clear, lowering the temperature to room temperature, stirring overnight, filtering after the reaction, washing the filter cake with 450ml of a mixed solution of anhydrous ethanol and anhydrous methanol (anhydrous ethanol and anhydrous methanol are mixed in a volume ratio of 4:1), and then washing with 90% ethanol aqueous solution, repeating the above operation, and resolving after multiple recrystallizations to obtain compound 5 with qualified optical purity (ee%>99.7%); wherein the first recrystallization solvent is ethanol:methanol=5:1, and the second and subsequent recrystallization solvents are ethanol:water=10:1;

[0060] S6, the compound 5 obtained in the step 5 is added to a 5L reactor, and then 450ml of deionized water and 1.3L of dichloromethane are added, and then 360ml of 2.5mol / L NaOH aqueous solution is slowly added, and then stirred for 30min, and the stirring is terminated. The dichloromethane layer is collected by standing and stratification, and the water layer is washed twice with 900ml of dichloromethane, and the dichloromethane is removed by rotary evaporation. The evaporated solid is dissolved in 230ml of anhydrous ethanol and placed in a 1L reaction container, cooled to 3°C, and then 290ml of 4.8mol / L hydrogen chloride ethanol solution is slowly added dropwise. After the addition is completed, the reaction is stirred for 30min, and the ethanol is removed by rotary evaporation. The remaining solid is dissolved in 350ml of anhydrous ethanol, and filtered with a 0.22um filter membrane. The filtrate is collected in a 5L reaction container, and 3L of 12.5%wt of methyl tert-butyl ether was added dropwise and stirred at room temperature overnight, then cooled to 10°C and stirred for 1h. After the reaction was completed, the mixture was filtered and the filter cake was washed with 200ml of 1%wt of methyl tert-butyl ether, and then the methyl tert-butyl ether was removed by rotary evaporation to obtain the final product, dexmedetomidine hydrochloride 6;

[0061] S7. Dissolve the prepared dexmedetomidine hydrochloride in 0.9% sodium chloride solution to prepare 100 ug / ml dexmedetomidine hydrochloride injection, test the pH of the prepared injection, and fill and seal under a sterile environment if the pH is qualified.

[0062] Comparative Example 6: Except for replacing L-(+)-tartaric acid with camphor yellow acid in step S5, the rest is the same as Example 3.

[0063] The chemical purity of dexmedetomidine hydrochloride was analyzed after high performance liquid chromatography testing. According to the test results, the purity of dexmedetomidine hydrochloride was calculated using the formula: purity of dexmedetomidine hydrochloride = content of dexmedetomidine hydrochloride ÷ total amount of mixture × 100%. The chemical purity of dexmedetomidine hydrochloride was determined by measuring the final product dexmedetomidine hydrochloride obtained by S6 in Examples 1-3 and Comparative Example 6. The results are as follows: Figure 4 shown.

[0064] Depend on Figure 4 It can be seen that the chemical purity of dexmedetomidine hydrochloride in samples 1-3 is basically the same and the purity is all above 90%, indicating that L-(+)-tartaric acid has specificity for the resolution of product 5.

[0065] The above-mentioned embodiments only express the specific implementation of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for preparing a dexmedetomidine hydrochloride raw material, characterized in that: The following steps are included: S1, the starting material is 2,3-dimethylbenzoic acid; add 15L of anhydrous dichloromethane to a 25L reactor, add 1.5kg of 2,3-dimethylbenzoic acid at room temperature, then cool to 0-5°C in an ice-water bath, maintain the temperature at 0-5°C, drop 1.02L of oxalyl chloride into the reactor, after the dropwise addition is complete, add 0.5-1ml of N,N-dimethylformamide, slowly warm to room temperature, stir overnight, confirm that the raw material disappears and the reaction is over, and concentrate under reduced pressure to obtain the product 2,3-dimethylbenzoyl chloride; S2, in a 20L reactor, add 2-2.5L of 0.2mol / L Lewis acid, add 2800-3400ml of 0.1mol / L TMSI and 600-1000ml of dichloromethane dropwise in an ice bath, continue stirring for 30min, slowly add the 2,3-dimethylbenzoyl chloride obtained in step S1 into the reactor, the concentration of 2,3-dimethylbenzoyl chloride is 0.1-0.2mol / L, the amount added is 2.1-2.8L, control the external bath temperature at 0-5°C, continue stirring for 1h, and then stir at room temperature for 15h to obtain product 1, and then mix product 1 with 3-4L of 2-4mol / L The mixture was reacted with a tetrahydrofuran solution of methyl magnesium bromide, and after the reaction, 5-10 L of a 5% aqueous solution of ammonium chloride was slowly added to the reaction solution, and the mixture was stirred for 30 min and allowed to stand for stratification. The aqueous phase was extracted once with 1-3 L of ethyl acetate, and then the organic phases were combined and concentrated to dryness under reduced pressure. The residue was passed through a silica gel column and eluted with PE:EA=10:1 to 1:

1. After elution, the solvent was concentrated to dryness under reduced pressure, and the residue was recrystallized with n-heptane:ethyl acetate 10:1, filtered, and dried to obtain compound 2; S3, add 5L of deionized water to a 10L reactor, then slowly drop 500-600ml of concentrated sulfuric acid, stir for 1h after the dropwise addition, add 1.5-2.3kg of compound 2 obtained in step S2 and 2.5-3L of toluene, then heat to 85-95°C and keep stirring for 3-4h, after the reaction is completed, let stand until the temperature of the reaction solution drops to 40-50°C to obtain a stratified solution, retain the water layer and extract with 2L of toluene, remove the toluene extraction layer to obtain the water layer, i.e., compound 3, which is directly used in the synthesis of compound 4; S4, adding the compound 3 obtained in the step S3 to a 5L reaction container, and then adding 0.6-0.8kg of ammonium formate, after the temperature of the reaction solution rises to 45-55°C, adding Pd / C catalyst in batches, maintaining the temperature and stirring for 3-6h, after the reaction is completed, the reaction solution is cooled to 15-25°C, 50% NaOH aqueous solution is slowly added dropwise to adjust the pH to 11-12, 1-1.5L of dichloromethane is added, and the filtrate is collected after suction filtration, the filter cake is washed with 500ml of dichloromethane, and the filtrate is combined after washing. The filtrate is allowed to stand for stratification, and the aqueous layer is extracted with dichloromethane. After the extraction is completed, the organic layers are combined, and then the combined organic layers are washed with 1-2L of 15% NaCl aqueous solution and concentrated under reduced pressure to dryness, and the evaporated solid is dissolved in 1-2L of anhydrous ethanol and suction filtered, and the inorganic salt is filtered out by suction filtration, and the filtrate is collected to obtain an ethanol solution of compound 4; S5, adding the ethanol solution of compound 4 obtained in step S4 to a 5L reactor, adding 800-1000ml of anhydrous ethanol, 800-1000ml of anhydrous methanol and 0.4 equivalents of L-(+)-tartaric acid as a substrate, heating to 65-75°C while stirring, maintaining the temperature for reaction until the reaction solution is clear, lowering the temperature to room temperature, stirring overnight, and filtering after the reaction is completed. The filter cake is washed with 400-500ml of a mixed solution of anhydrous ethanol and anhydrous methanol, and then washed with 90% ethanol solution, and the above operation is repeated. After collecting the filter cake, it is separated by recrystallization for multiple times to obtain compound 5 with qualified optical purity; S6, adding the compound 5 obtained in the step 5 to a 5L reactor, then adding 400-500ml of deionized water and 1-1.5L of dichloromethane, stirring for 10-20min, slowly adding 300-400ml of 2-3mol / L NaOH aqueous solution, and then stirring for 30min, ending the stirring, standing for stratification to collect the dichloromethane layer, and then washing it once with 15% NaCl, rotary evaporation to remove dichloromethane, the evaporated solid is dissolved in 200-250ml of anhydrous ethanol and placed in a 1L reaction container, cooled to 0-5°C, and then slowly adding 280-300ml of 4-8mol / L hydrogen chloride ethanol solution, stirring the reaction for 30min after the addition is completed, rotary evaporation to remove ethanol, the remaining solid is dissolved in 350ml of anhydrous ethanol, filtered through a 0.22μmol filter membrane, the filtrate is collected in a 5L reaction container, and 1.5-3L 12.5%wt of methyl tert-butyl ether was added dropwise and stirred at room temperature overnight, then cooled to 10-15°C and stirred for 1h. After the reaction was completed, the mixture was filtered and the filter cake was washed with 200ml of 1%wt of methyl tert-butyl ether. The filter cake was evaporated to remove methyl tert-butyl ether to obtain the final product, dexmedetomidine hydrochloride 6.

2. A method for preparing a dexmedetomidine hydrochloride raw material according to claim 1, characterized in that: The Lewis acid used in step S2 is BF3OEt2.

3. A method for preparing a dexmedetomidine hydrochloride raw material and injection according to claim 1, characterized in that: The catalyst used in step S4 is Pd / C, wherein the Pd content is 10%.

4. A method for preparing a dexmedetomidine hydrochloride raw material according to claim 1, characterized in that: In step S4, the catalyst Pd / C should be added in batches, and the specific method is: add 100-130g Pd / C catalyst in the first batch, keep stirring at the temperature for 1-2h, add 120g Pd / C catalyst in the second batch, keep stirring at the temperature for 1-2h, and add 70-80g Pd / C catalyst in the third batch, keep stirring at the temperature for 1-2h.

5. A method for preparing a dexmedetomidine hydrochloride raw material according to claim 1, characterized in that: In step S5, the first recrystallization solvent of compound 5 salified with L-(+)-tartaric acid is ethanol:methanol=5:1, and the second and subsequent recrystallization solvents are ethanol:water=10:

1.

6. A method for preparing dexmedetomidine hydrochloride injection, characterized in that: The dexmedetomidine hydrochloride prepared by the method for preparing a dexmedetomidine hydrochloride raw material according to any one of claims 1 to 5 is dissolved in a 0.9% sodium chloride solution to prepare a 100 ug / ml dexmedetomidine hydrochloride injection, and the pH of the prepared injection is tested. After the pH value is qualified, the injection is filled and sealed in a sterile environment.

Images