Preparation method of medetomidine

Abstract

The invention provides a medetomidine preparation method, which comprises: S1, taking 2, 3-dimethyl benzaldehyde as an initial raw material, and carrying out a reaction on the 2, 3-dimethyl benzaldehyde and methylmagnesium chloride to generate 1-(2, 3-dimethyl phenyl) ethanol; s2, excessive silyl group protected imidazole is added into a reaction system in the step S1, and an activated [1-(2, 3-dimethylphenyl) ethyoxyl] silyl ether intermediate is obtained; taking trimethylsilyl trifluoromethanesulfonate as a catalyst, carrying out a Friedel-Crafts reaction with silyl-protected imidazole, and after the reaction is finished, carrying out post-treatment on the reaction liquid to obtain a medetomidine crude product. 2, 3-dimethyl benzaldehyde is adopted as a starting raw material, medetomidine is prepared through a one-pot method, raw materials are cheap, reaction steps are short, the production cost is greatly reduced, TMSOTf is adopted as a catalyst in the Friedel-Crafts reaction, the reaction is efficient, it can be effectively avoided that in the aftertreatment process of a traditional catalyst titanium tetrachloride, a large number of titanic acid colloidal solid insoluble substances are formed, and the yield of medetomidine is increased. The problem that post-treatment layering is difficult is solved, and the yield is increased.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a preparation method of medetomidine. Background Art

[0002] Dexmedetomidine, chemically known as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, is a novel α- 2 -Adrenergic receptor agonist, developed by Orion Pharma (Finland), its hydrochloride was first launched in the United States by Abott (USA) on December 27, 1999 as a sedative hypnotic, with the trade name "Precedex". It is currently approved by the FDA for sedation treatment in the United States, especially for ICU patients. In 2009, the FDA approved it for sedation during endotracheal intubation and mechanical ventilation in surgical patients under general anesthesia. Medetomidine has antisympathetic, sedative and analgesic effects. Its α 2 / α 1 The selectivity is as high as 45000, which is a highly efficient α 2 -Adrenergic receptor agonist, with an affinity for adrenergic receptors 8 times higher than that of clonidine, a short half-life and a small effective dose, suitable for sedation of patients who are intubated and on ventilators during intensive care treatment.

[0003] At present, there are many reports on the synthesis of medetomidine:

[0004] The first method was reported by Alex A. Cordi et al., using 4-(1-triphenylmethyl)imidazole aldehyde as the starting material, and obtaining medetomidine through multiple steps including two-step Grignard reaction, oxidation and hydrogenation reduction; however, this route has many steps, the raw materials are expensive, the cost is high and they are difficult to obtain.

[0005] The second method is to use 2,3-dimethylphenylmagnesium bromide as the starting material, 4-(acyloxymethyl)imidazole in tetrahydrofuran for Friedel-Crafts reaction, and then hydrogenate reduction to obtain medetomidine, such as patent US4910214. The starting material in this reaction route is in short supply and difficult to obtain.

[0006] The third method is to use imidazole as the starting material, iodine, trityl protection, and then Grignard reaction with 2,3-dimethylbenzaldehyde, and then oxidation, methylation, dehydration reaction, hydrogenation to obtain medetomidine, such as patent EP1918282. This synthetic route has many steps and consumes a large amount of iodine.

[0007] The fourth method is to prepare 1-(2,3-dimethylphenyl)ethanol by reducing 2,3-dimethylacetophenone, and then chlorinate to obtain 1-(2,3-dimethylphenyl)-1-chloroethane and react with N-(trimethylsilyl)imidazole to obtain medetomidine, such as patents CN103694175 A and CN112979552A. However, this route requires halogen substitution of 1-(2,3-dimethylphenyl)ethanol, which causes great environmental pollution and low overall process yield. In addition, titanium tetrachloride is used as a catalyst in the Friedel-Crafts reaction, and post-treatment stratification is difficult, resulting in a large amount of wastewater. Summary of the invention

[0008] The purpose of the present invention is to provide a method for preparing medetomidine, which can at least solve some of the defects existing in the prior art.

[0009] To achieve the above object, the present invention adopts the following technical solution:

[0010] A method for preparing medetomidine comprises the following steps:

[0011] S1, using 2,3-dimethylbenzaldehyde as a starting material, reacting with methylmagnesium chloride to produce 1-(2,3-dimethylphenyl)ethanol;

[0012] S2. Add an excess of silyl-protected imidazole to the reaction system of step S1 to obtain an activated [1-(2,3-dimethylphenyl)ethoxy]silyl ether intermediate; and use trimethylsilyl trifluoromethanesulfonate as a catalyst to carry out a Friedel-Crafts reaction with the silyl-protected imidazole. After the reaction, post-treat the reaction solution to obtain a crude product of medetomidine.

[0013] Furthermore, the preparation method of medetomidine further comprises step S3, refining the crude medetomidine product of step S2, and the specific process is as follows:

[0014] S31, adding the crude medetomidine to ethyl acetate, introducing hydrogen chloride gas to form salt, crystallizing and filtering to obtain medetomidine hydrochloride;

[0015] S32. Add medetomidine hydrochloride into water, adjust the pH to alkaline, and filter to obtain high-purity medetomidine.

[0016] Furthermore, in step S1, the molar ratio of 2,3-dimethylbenzaldehyde to methylmagnesium chloride is 1:1 to 1.5; the reaction temperature is -20 to 66° C., and the reaction time is 1 to 6 hours.

[0017] Furthermore, in step S2, the silyl-protected imidazole is trimethylsilyl imidazole or tert-butyldimethylsilyl imidazole, and the amount of the silyl-protected imidazole is 2 to 8 times the molar amount of 2,3-dimethylbenzaldehyde.

[0018] Furthermore, in step S2, the amount of trimethylsilyl trifluoromethanesulfonate used is 2 to 5 times the molar amount of 2,3-dimethylbenzaldehyde.

[0019] Furthermore, in step S2, the temperature of the Friedel-Crafts reaction is -10 to 66°C, and the reaction time is 2 to 12 hours.

[0020] Furthermore, in step S2, the reaction solution is post-treated by adding the reaction solution into an alkaline aqueous solution, extracting with an organic solvent, and concentrating to obtain a crude product of medetomidine.

[0021] Furthermore, the alkaline aqueous solution is a sodium hydroxide solution or a sodium carbonate solution, and the organic solvent is dichloromethane or ethyl acetate.

[0022] Furthermore, in the step S31, the temperature of the hydrogen chloride gas introduced during salt formation is -20 to 30°C until the pH value of the solution is 1 to 3; the crystallization temperature is -10 to 30°C, and the crystallization time is 1 to 8 hours; and the HPLC purity of the obtained medetomidine hydrochloride is ≥98%.

[0023] Furthermore, in step S32, the pH is adjusted to 10-11 using a sodium carbonate aqueous solution or a sodium hydroxide aqueous solution with a mass concentration of 5-10%.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] (1) The preparation method of medetomidine provided by the present invention uses 2,3-dimethylbenzaldehyde as a starting material, which is cheap and greatly reduces the production cost. In addition, the reaction steps are short and the one-pot operation is convenient.

[0026] (2) In the preparation process of 1-(2,3-dimethylphenyl)ethanol provided by the present invention, methylmagnesium chloride is used as a Grignard reagent. The reagent is commercially available and cheap, and the process is mature. After the reaction, no separation and purification treatment is required, and the next step reaction can be directly carried out, which has no effect on the subsequent reaction, reduces the amount of solvent used, avoids the generation of post-treatment wastewater, and effectively improves the yield.

[0027] (3) In the preparation method of medetomidine provided by the present invention, after adding silyl-protected imidazole, the hydroxyl group of 1-(2,3-dimethylphenyl)ethanol will be activated by the silyl group to form a silyl ether, which can be directly used for Friedel-Crafts reaction, avoiding the conventional process of first halogenation and then Friedel-Crafts reaction, reducing the reaction steps, avoiding environmental pollution, and improving the yield; and using trimethylsilyl trifluoromethanesulfonate as a catalyst, the reaction is efficient, and the problem of forming a large amount of titanic acid colloidal solid insoluble matter during the post-treatment of the traditional catalyst titanium tetrachloride, which leads to difficulty in post-treatment stratification, can be effectively avoided. At the same time, the problem of difficulty in effective and complete extraction during the extraction of medetomidine hydrochloride with dichloromethane is avoided, thereby improving the yield.

[0028] (4) The purity of the product obtained by the method for preparing medetomidine provided by the present invention is ≥98.5%, and the total yield is ≥75%. DETAILED DESCRIPTION

[0029] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] The present invention provides a method for preparing medetomidine, and its synthetic route is as follows:

[0031]

[0032] The specific steps include:

[0033] S1. 2,3-dimethylbenzaldehyde is used as a starting material and reacted with methylmagnesium chloride to generate 1-(2,3-dimethylphenyl)ethanol.

[0034] Specifically, the molar ratio of 2,3-dimethylbenzaldehyde to methylmagnesium chloride is 1:1-1.5, preferably 1:1.05-1.1; the reaction temperature is -20-66°C, preferably 10-30°C, and the reaction time is 1-6h, preferably 2-4h; the reaction is carried out under nitrogen or argon protection throughout the process, and the solvent of the reaction system is one or more of tetrahydrofuran, ether, dichloromethane, and acetonitrile, and the water content of the solvent is ≤0.1%.

[0035] After the reaction is completed, no separation or purification is required and the next step reaction can be carried out directly, which has no effect on subsequent reactions. In addition, the solvent in the reaction system can be used for subsequent reactions, reducing the amount of solvent used, which is conducive to the one-pot synthesis of medetomidine.

[0036] S2. Add an excess of silyl-protected imidazole to the reaction system of step S1 to obtain an activated [1-(2,3-dimethylphenyl)ethoxy]silyl ether intermediate; and use trimethylsilyl trifluoromethanesulfonate (TMSOTf) as a catalyst to carry out Friedel-Crafts reaction with the silyl-protected imidazole. After the reaction, post-treat the reaction solution to obtain a crude product of medetomidine.

[0037] Specifically, the silyl-protected imidazole is trimethylsilyl imidazole or tert-butyl dimethylsilyl imidazole, and the amount of the silyl-protected imidazole is 2 to 8 times the molar amount of 2,3-dimethylbenzaldehyde. The obtained [1-(2,3-dimethylphenyl)ethoxy]silyl ether intermediate has the following structural formula:

[0038] Wherein, R = trimethyl or tert-butyl dimethyl.

[0039] Optionally, the silyl-protected imidazole is trimethylsilyl imidazole, and its preparation process is as follows: add imidazole, hexamethyldisilazane and concentrated sulfuric acid in sequence, and heat in an oil bath at 120-128°C for reaction; after the reaction is completed, cool to below 100°C, remove unreacted hexamethyldisilazane by reduced pressure distillation, and collect the boiling range 80-95°C / 10mmHg fraction to obtain trimethylsilyl imidazole.

[0040] Specifically, the amount of trimethylsilyl trifluoromethanesulfonate is 2 to 5 times the molar amount of 2,3-dimethylbenzaldehyde; the temperature of the Friedel-Crafts reaction is -10 to 66°C, preferably 10 to 30°C, and the reaction time is 2 to 12 hours, preferably 4 to 8 hours.

[0041] After the Friedel-Crafts reaction is completed, the reaction liquid in the reaction system is post-treated, specifically, the reaction liquid is added to an alkaline aqueous solution, extracted with an organic solvent, and concentrated to obtain a crude medetomidine product; wherein the alkaline aqueous solution can be selected from but not limited to a sodium hydroxide solution or a sodium carbonate solution with a mass concentration of 5-10%, the organic solvent used for extraction can be selected from but not limited to dichloromethane or ethyl acetate, and the extraction can be performed multiple times, and 2-3 extractions are used in the present invention.

[0042] Further, in order to obtain high-purity medetomidine, the crude medetomidine obtained above is subjected to a refining treatment, and the specific process is as follows:

[0043] (1) adding the crude medetomidine obtained above to ethyl acetate, introducing hydrogen chloride gas to form salt, crystallizing and filtering to obtain medetomidine hydrochloride. Wherein, when ethyl acetate is selected as the organic solvent for extraction in the above post-treatment process, the extraction does not need to be concentrated, and hydrogen chloride gas is directly introduced to crystallize and filter to obtain medetomidine hydrochloride.

[0044] Specifically, during salt formation, the temperature of hydrogen chloride gas introduced is -20 to 30°C, preferably 0 to 10°C, until the pH value of the solution is 1 to 3, preferably 2 to 3; the crystallization temperature is -10 to 30°C, preferably 0 to 10°C, and the crystallization time is 1 to 8 hours, preferably 2 to 3 hours; the HPLC purity of the obtained medetomidine hydrochloride is ≥98%.

[0045] (2) Add medetomidine hydrochloride to water, adjust the pH to alkaline, and filter to obtain high-purity medetomidine.

[0046] Specifically, in this process, the pH can be adjusted by, but not limited to, a sodium carbonate aqueous solution or a sodium hydroxide aqueous solution with a mass concentration of 5 to 10%, and the pH is adjusted to 10 to 11.

[0047] By adopting the preparation method of medetomidine of the present invention, the purity of the prepared medetomidine free base is ≥98.5%, and the total yield can reach more than 75% based on 2,3-dimethylbenzaldehyde.

[0048] The preparation process and effects of medetomidine of the present invention are described below by means of specific examples.

[0049] Embodiment 1:

[0050] This embodiment provides a method for preparing medetomidine, and the specific process is as follows:

[0051] (1) Preparation of 1-(2,3-dimethylphenyl)ethanol

[0052] Under nitrogen protection, add 260 mL of 3 mol / L methylmagnesium chloride tetrahydrofuran solution (i.e. 0.78 mol of methylmagnesium chloride) to a 1000 mL reaction bottle, wherein 200 mL of tetrahydrofuran (THF) and a water content of ≤0.01% are added; then 2,3-dimethylbenzaldehyde (100 g, 0.74 mol) is slowly added dropwise, and the dropping temperature is controlled not to be higher than 30°C. After the addition is completed, react at 20°C for 4 hours.

[0053] (2) Preparation of N-(trimethylsilyl)imidazole

[0054] In a 2000mL single-mouth bottle, imidazole (220g, 3.23mol), hexamethyldisilazane (400g, 2.48mol) and concentrated sulfuric acid (1.5g, 0.015mol) were added in sequence, and heated in an oil bath at 120-128°C for 4h. After the reaction, the temperature was lowered to below 100°C, and the unreacted hexamethyldisilazane was removed by vacuum distillation. The boiling range of 80-95°C / 10mmHg was collected, about 350g, with a yield of 77.3%.

[0055] (3) Preparation of crude medetomidine

[0056] Under ice bath, add N-(trimethylsilyl)imidazole (311 g, 2.22 mol) to the reaction bottle (1), and stir at room temperature for 1-2 h; cool to 0-10°C, add trimethylsilyl trifluoromethanesulfonate (411 g, 1.85 mol) dropwise, control the temperature not to exceed 20°C, and heat to 30°C for 4 h, until the reaction is complete.

[0057] The reaction mixture was slowly added into an icy 10% sodium hydroxide solution (1000 mL), the aqueous phase was extracted with dichloromethane (2×500 mL), the organic phases were combined and concentrated to obtain crude medetomidine as an oil.

[0058] (4) Purification of crude medetomidine

[0059] The crude medetomidine was added to ethyl acetate (500 mL), hydrogen chloride gas was introduced, and the temperature was controlled between 0 and 10° C. until the pH of the solution was 2 to 3; then crystallization was carried out at 0 to 10° C. for 3 h, and medetomidine hydrochloride was obtained by filtration.

[0060] Medetomidine hydrochloride was dissolved in water (1000 mL), and the pH was adjusted to 11 with 5% sodium hydroxide solution to precipitate a white solid, which was filtered to obtain medetomidine.

[0061] The results showed that 124 g of medetomidine was obtained through purification with a purity of 98.6%. The yield was 83.7% based on 2,3-dimethylbenzaldehyde.

[0062] Embodiment 2:

[0063] This embodiment provides a method for preparing medetomidine, and the specific process is as follows:

[0064] (1) Preparation of 1-(2,3-dimethylphenyl)ethanol

[0065] Under nitrogen protection, add 400 mL of 2 mol / L methylmagnesium chloride tetrahydrofuran solution (i.e. 0.8 mol of methylmagnesium chloride) to a 1000 mL reaction bottle; then slowly add 2,3-dimethylbenzaldehyde (100 g, 0.74 mol) dropwise, and control the dropping temperature not higher than 30°C. After the addition is completed, react at 30°C for 2 h.

[0066] (2) Preparation of N-(trimethylsilyl)imidazole

[0067] In a 2000mL single-mouth bottle, imidazole (220g, 3.23mol), hexamethyldisilazane (400g, 2.48mol) and concentrated sulfuric acid (1.5g, 0.015mol) were added in sequence, and the mixture was heated in an oil bath at 120-128°C for 5h. After the reaction, the temperature was lowered to below 100°C, and the unreacted hexamethyldisilazane was removed by vacuum distillation with a water pump. The internal temperature was raised to 120-130°C, and an oil pump was used to continue distillation. The 80-95°C fraction was collected, about 355g, with a yield of 78.4%.

[0068] (3) Preparation of crude medetomidine

[0069] Under ice bath, add N-(trimethylsilyl)imidazole (350 g, 2.5 mol) to the reaction bottle (1), and stir at room temperature for 1-2 h; cool to 0-10°C, add trimethylsilyl trifluoromethanesulfonate (329 g, 1.48 mol) dropwise, control the temperature not to exceed 20°C, and heat to 20°C for 8 h until the reaction is complete.

[0070] The reaction mixture was slowly added into an icy 10% sodium carbonate solution (600 mL), the aqueous phase was extracted with ethyl acetate (3×500 mL), and the organic phases were combined to obtain an ethyl acetate extract of crude medetomidine.

[0071] (4) Purification of crude medetomidine

[0072] Hydrogen chloride gas was introduced into the ethyl acetate extract of the crude medetomidine, and the temperature was controlled between 0 and 10° C. until the pH value of the solution was 2 to 3; then, crystallization was carried out at 0 to 10° C. for 2 h, and medetomidine hydrochloride was obtained by filtration.

[0073] Medetomidine hydrochloride was dissolved in water (1000 mL), and the pH was adjusted to 10 with 5% sodium hydroxide solution to precipitate a white solid, which was filtered to obtain medetomidine.

[0074] The results showed that 116 g of medetomidine was obtained through purification, with a purity of 99.4% and a yield of 78.3% based on 2,3-dimethylbenzaldehyde.

[0075] Comparative Example 1:

[0076] This comparative example provides a method for preparing medetomidine, and its specific process is substantially the same as that of the above-mentioned Example 1, except that trimethylsilyl trifluoromethanesulfonate in the step of preparing crude medetomidine in Example 1 is replaced by a traditional catalyst titanium tetrachloride.

[0077] The medetomidine prepared in this comparative example was measured, and its purity was 97.6%, and its yield was 57.8% based on 2,3-dimethylbenzaldehyde. According to analysis, in the preparation process of medetomidine, a large amount of colloidal solid insolubles of titanate will be formed during the post-treatment process using the traditional catalyst titanium tetrachloride, which leads to the problem of difficulty in post-treatment stratification, thereby greatly reducing the purity and yield of the product; while the use of trimethylsilyl trifluoromethanesulfonate as a catalyst in the present invention effectively avoids this problem caused by titanium tetrachloride, and also avoids the problem that it is difficult to effectively extract and completely extract medetomidine hydrochloride in the process of dichloromethane extraction, so the purity and yield of the product are greatly improved.

[0078] The above examples are merely illustrative of the present invention and do not constitute a limitation on the protection scope of the present invention. All designs that are the same or similar to the present invention fall within the protection scope of the present invention.

Claims

1. A method for preparing medetomidine, characterized in that: The steps include: S1, using 2,3-dimethylbenzaldehyde as a starting material, reacting with methylmagnesium chloride to produce 1-(2,3-dimethylphenyl)ethanol; S2. Add an excess of silyl-protected imidazole to the reaction system of step S1 to obtain an activated [1-(2,3-dimethylphenyl)ethoxy]silyl ether intermediate; and use trimethylsilyl trifluoromethanesulfonate as a catalyst to carry out a Friedel-Crafts reaction with the silyl-protected imidazole. After the reaction, post-treat the reaction solution to obtain a crude product of medetomidine.

2. The method for preparing medetomidine according to claim 1, characterized in that, The step S3 is also included, wherein the crude medetomidine product of step S2 is subjected to a refining treatment, and the specific process is as follows: S31, adding the crude medetomidine to ethyl acetate, introducing hydrogen chloride gas to form salt, crystallizing and filtering to obtain medetomidine hydrochloride; S32. Add medetomidine hydrochloride into water, adjust the pH to alkaline, and filter to obtain high-purity medetomidine.

3. The method for preparing medetomidine according to claim 1 or 2, characterized in that: In the step S1, the molar ratio of 2,3-dimethylbenzaldehyde to methylmagnesium chloride is 1:1 to 1.5; the reaction temperature is -20 to 66° C., and the reaction time is 1 to 6 hours.

4. The method for preparing medetomidine according to claim 1 or 2, characterized in that: In the step S2, the silyl-protected imidazole is trimethylsilyl imidazole or tert-butyldimethylsilyl imidazole, and the amount of the silyl-protected imidazole is 2 to 8 times the molar amount of 2,3-dimethylbenzaldehyde.

5. The method for preparing medetomidine according to claim 1 or 2, characterized in that: In the step S2, the amount of trimethylsilyl trifluoromethanesulfonate used is 2 to 5 times the molar amount of 2,3-dimethylbenzaldehyde.

6. The method for preparing medetomidine according to claim 1 or 2, characterized in that: In step S2, the temperature of the Friedel-Crafts reaction is -10 to 66°C, and the reaction time is 2 to 12 hours.

7. The method for preparing medetomidine according to claim 1 or 2, characterized in that: In the step S2, the reaction solution is post-treated by adding the reaction solution into an alkaline aqueous solution, extracting with an organic solvent, and concentrating to obtain a crude medetomidine product.

8. The method for preparing medetomidine according to claim 7, characterized in that: The alkaline aqueous solution is a sodium hydroxide solution or a sodium carbonate solution, and the organic solvent is dichloromethane or ethyl acetate.

9. The method for preparing medetomidine according to claim 2, characterized in that: In the step S31, the temperature of hydrogen chloride gas introduced during salt formation is -20 to 30°C until the pH value of the solution is 1 to 3; the crystallization temperature is -10 to 30°C, and the crystallization time is 1 to 8 hours; and the HPLC purity of the obtained medetomidine hydrochloride is ≥98%.

10. The method for preparing medetomidine according to claim 2, characterized in that: In the step S32, the pH is adjusted to 10-11 by using a sodium carbonate aqueous solution or a sodium hydroxide aqueous solution with a mass concentration of 5-10%.

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