Synthesis method of morphonidazole key intermediate
By reacting anhydrous aluminum trichloride with epoxypropane in ethyl acetate to form an aqueous solution of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole hydrochloride salt in ethyl acetate, and combining the ring under the action of sodium hydroxide, the problems of high operation risk, difficulty in obtaining raw materials and insoluble aluminum salt by-products in the prior art were solved, and the preparation of a key intermediate of morpholinidazole was achieved with efficient and simplified preparation of morpholinidazole.
Patent Information
- Application Number
- CN202410082495.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-01-19
- Publication Date
- 2025-07-22
AI Technical Summary
In the prior art, when preparing the key intermediate morpholinenirazone 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole, there are problems such as high operating risk, difficulty in obtaining raw materials, difficulty in post-reaction treatment, and the generation of large amounts of insoluble aluminum salt by-products.
Anhydrous aluminum trichloride and epoxypropane were used to react in ethyl acetate to form an aqueous solution of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole hydrochloride salt, and then the ring was combined under the action of sodium hydroxide, and the next reaction was directly carried out, and the solubility of the aluminum salt by-products was improved by using the acidic aqueous solution, and the operation was simplified by the "one-pot method".
The acquisition of high-quality target products has been achieved, the production process has been simplified, the production cost has been reduced, and the total yield has been increased to more than 90%, solving the problems of post-treatment difficulties and waste solids.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to a method for synthesizing a key intermediate of morinidazole. Background Art
[0002] Morinidazole, belonging to the third-generation nitroimidazole antibacterial drug, was approved for marketing in China in February 2014, and it is also the first nitroimidazole anti-infective drug developed by Chinese people with independent intellectual property rights. This drug has low toxicity and good activity, and is mainly used for surgical infections and gynecological infections caused by anaerobic bacteria clinically.
[0003] 1-(2,3-Epoxypropyl)-2-methyl-5-nitroimidazole (Formula I) is a key intermediate for the preparation of morinidazole.
[0004]
[0005] The example of Chinese Patent CN100344626 discloses that the compound of Formula I is prepared by reacting 2-methyl-5-nitroimidazole with epifluorohydrin under strong acidic conditions.
[0006]
[0007] Although this preparation method can obtain the compound of Formula I through only one-step reaction, this method uses formic acid as the reaction solvent and concentrated sulfuric acid as the catalyst, with high operation risks and high requirements for reaction equipment. Moreover, the market supply of epifluorohydrin is extremely small and it is not easy to obtain. Therefore, this preparation method urgently needs a new optimized process to replace it in actual production.
[0008] Dhanaraju Mandalapu et al. disclosed another preparation method of the compound of Formula I in an article published in European Journal of Medicinal Chemistry in 2016. The route is as follows:
[0009]
[0010] This method uses more readily available epichlorohydrin (Formula III) as the starting material, reacts under the catalysis of aluminum trichloride, and obtains 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole (Formula IV) through column chromatography purification. Then, it reacts in a mixed solvent of dichloromethane and sodium hydroxide solution to close the ring to obtain Compound I. The literature reports that the total yield of the two steps is only 72%.
[0011] The inventor team repeated this synthesis route according to the method disclosed in the literature. In the actual production operation process, there is a phenomenon of a large amount of aluminum salt colloid by-products generated in the reaction, the post-treatment operation of the reaction is difficult, and a large amount of solid waste residue is generated.
[0012] Chinese Patent CN110922362 also prepares the compound using the synthetic route reported by Dhanaraju Mandalapu et al. The macroporous resin after activation and drying is swollen with an organic solvent and then mixed with anhydrous aluminum trichloride for reaction, aiming to solve the impact of a large amount of insoluble aluminum salt colloid generated by using aluminum trichloride on the post-treatment of the reaction. However, the aluminum trichloride macroporous resin catalyst involved in this technology needs to be prepared in advance, and macromolecular resin is introduced in the production process of the active pharmaceutical ingredient, bringing new problems to the quality control of drugs. There is no method in the prior art to solve the insoluble aluminum salt generated in the preparation of the key intermediate of morinidazole (Formula I) through simple technical means. Summary of the Invention
[0013] The object of the present invention is to overcome the deficiencies in the prior art for preparing 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole, and to provide a method for preparing the key intermediate 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole of morinidazole.
[0014] The present invention provides a method for preparing the key intermediate 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole of morinidazole, comprising the following steps:
[0015]
[0016] a) 2-Methyl-5-nitroimidazole shown in Formula II undergoes a substitution reaction with epichlorohydrin shown in Formula III in ethyl acetate under the action of anhydrous aluminum trichloride. After acid-water extraction treatment, an aqueous hydrochloric acid solution of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole shown in Formula IV is obtained;
[0017] b) A polar solvent is directly added to dilute the above aqueous solution, and a ring-closure reaction occurs under the action of sodium hydroxide to obtain a reaction solution of 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole shown in Formula I. After extraction with a good solvent, washing with water, concentrating the organic phase, adding a poor solvent, crystallizing in a mixed solvent system, filtering, and drying, the finished product of 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole shown in Formula I is finally obtained.
[0018] Among them, in the above preparation process step (a), the molar ratio of the anhydrous aluminum trichloride to the compound of Formula II is 1.0 - 1.5:1; the acid water is dilute hydrochloric acid, and the molar ratio of hydrochloric acid to the compound of Formula II is 2.0 - 4.0:1.
[0019] In the above preparation process step (b), the polar solvent is selected from acetonitrile, tetrahydrofuran, acetone; preferably acetonitrile;
[0020] In the above preparation process step (b), the molar ratio of the base to the compound of formula II is 3.0 to 5.0:1; the good solvent is ethyl acetate, dichloromethane, toluene; preferably ethyl acetate;
[0021] The poor solvent is methyl tert-butyl ether, n-heptane, cyclohexane; preferably n-heptane;
[0022] In the mixed solvent system, the volume ratio of the good solvent to the poor solvent is 1:2 to 5.
[0023] Compared with the prior art, the present invention has the following beneficial effects:
[0024] (1) By using an acidic aqueous solution system, the solubility of the poorly soluble aluminum salt by-product is increased in this method, and by utilizing the characteristic that 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole (formula IV) can form a salt with an acid and dissolve in water, the aqueous solution containing the product 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole (formula IV) and the aluminum salt by-product can directly undergo the next reaction without separation, solving the technical problems of difficult post-treatment and generation of a large amount of waste solids faced when using aluminum trichloride currently; high-quality target products can be obtained;
[0025] (2) This method uses a "one-pot" reaction, which is simple, reduces the transfer of materials, and shortens the production cycle;
[0026] (3) The raw materials, reagents, and solvents used are cheap and easily available, and the production cost is low;
[0027] (4) The total yield of the process route of the present invention is more than 90%, and the total yield is significantly improved compared with the prior art. Description of the Drawings
[0028] Figure 1 It is the 1H NMR spectrum of the key intermediate 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole prepared in Example 1 of the present invention. Detailed Description of the Invention
[0029] The present invention will be further described in detail below through examples. These examples are only used to illustrate the present invention and do not limit the scope of the present invention.
[0030] Example 1
[0031] Under stirring, ethyl acetate (200 ml) and 2-methyl-5-nitroimidazole (20 g, 157.4 mmol) were successively added to the reaction flask. The temperature was lowered to 5 - 10 °C, and then anhydrous aluminum trichloride (17.9 g, 157.4 mmol) and epichlorohydrin (16.0 g, 173.1 mmol) were successively added. The temperature was raised to reflux for reaction, and TLC was used to monitor the complete reaction of 2-methyl-5-nitroimidazole. After the reaction was completed, the reaction solution was cooled to room temperature, 200 ml of water and concentrated hydrochloric acid (62.1 g, 629.6 mmol) were successively added, stirred for 15 - 30 min, and then left to stand for liquid separation to separate out the aqueous phase.
[0032] Acetonitrile (200 ml) was added to the aqueous phase and stirred for dilution, and then an alkali solution prepared by adding sodium hydroxide (31.5 g, 787 mmol) and water (250 ml) was added. The reaction was stirred at 20 - 30 °C, and TLC was used to monitor the complete reaction of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole. The reaction solution was extracted with ethyl acetate (200 ml), and the organic phase was separated out. The organic phase was concentrated under reduced pressure until 20 ml remained. Methyl tert-butyl ether (40 ml) was added to the concentrated residue, stirred to precipitate a solid, cooled to 0 - 5 °C and filtered. The filter cake was washed with methyl tert-butyl ether (20 ml), and after drying, 26.5 g of a white powdery solid (Compound of Formula I) was obtained, with a yield of 87.92% and a purity of 99.5%. Mp: 110 - 112 °C. 1 H NMR (400 MHz, DMSO-d6): 7.94 (s, 1H), 4.91 - 4.87 (dd, 1H), 4.23 - 4.18 (dd, 1H), 3.39, 3.38 (d, 1H), 2.90 - 2.88 (t, 1H), 2.54, 2.53 (d, 1H), 2.51 (s, 3H).
[0033] Example 2
[0034] Under stirring, ethyl acetate (200 ml) and 2-methyl-5-nitroimidazole (20 g, 157.4 mmol) were successively added to the reaction flask. The temperature was lowered to 5 - 10 °C, and then anhydrous aluminum trichloride (24.8 g, 188.9 mmol) and epichlorohydrin (16.0 g, 173.1 mmol) were successively added. The temperature was raised to reflux for reaction, and TLC was used to monitor the complete reaction of 2-methyl-5-nitroimidazole. After the reaction was completed, the reaction solution was cooled to room temperature, 200 ml of water and concentrated hydrochloric acid (46.6 g, 472.2 mmol) were successively added, stirred for 15 - 30 min, and then left to stand for liquid separation to separate out the aqueous phase.
[0035] Add tetrahydrofuran (200 ml) to the aqueous phase and stir to dilute it. Then add the alkaline solution prepared by adding sodium hydroxide (25.2 g, 629.6 mmol) and water (250 ml). Stir and react at 20 - 30 °C, and monitor the reaction of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole by TLC until the reaction is complete. Extract the reaction solution with dichloromethane (200 ml), separate the organic phase, concentrate the organic phase under reduced pressure until 20 ml remains. Add n-heptane (80 ml) to the concentrated residue, stir to precipitate a solid, cool to 0 - 5 °C and filter. Wash the filter cake with n-heptane (20 ml). After drying the filter cake, 25.9 g of a white powdery solid (Compound of Formula I) is obtained, with a yield of 90% and a purity of 99.1%.
[0036] Example 3
[0037] Add ethyl acetate (200 ml) and 2-methyl-5-nitroimidazole (20 g, 157.4 mmol) to the reaction flask in sequence under stirring. Cool to 5 - 10 °C, then add anhydrous aluminum trichloride (31.0 g, 236.1 mmol) and epichlorohydrin (16.0 g, 173.1 mmol) in sequence. Heat to reflux for reaction, and monitor the reaction of 2-methyl-5-nitroimidazole by TLC until the reaction is complete. After the reaction is completed, cool the reaction solution to room temperature, add 200 ml of water and concentrated hydrochloric acid (31.0 g, 314.8 mmol) in sequence. Stir for 15 - 30 min and then let it stand for liquid separation to separate the aqueous phase.
[0038] Add acetone (200 ml) to the aqueous phase and stir to dilute it. Then add the alkaline solution prepared by adding sodium hydroxide (18.8 g, 472.2 mmol) and water (250 ml). Stir and react at 20 - 30 °C, and monitor the reaction of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole by TLC until the reaction is complete. Extract the reaction solution with toluene (200 ml), separate the organic phase, concentrate the organic phase under reduced pressure until 20 ml remains. Add cyclohexane (100 ml) to the concentrated residue, stir to precipitate a solid, cool to 0 - 5 °C and filter. Wash the filter cake with cyclohexane (20 ml). After drying the filter cake, 26.3 g of a white powdery solid (Compound of Formula I) is obtained, with a yield of 91% and a purity of 99.2%.
[0039] Example 4
[0040] With stirring, ethyl acetate (5 L) and 2-methyl-5-nitroimidazole (500 g, 3.93 mol) were successively added to the reaction flask. The temperature was lowered to 5 - 10 °C, and then anhydrous aluminum trichloride (628.8 g, 4.72 mol) and epichlorohydrin (400.0 g, 4.32 mol) were successively added. The temperature was raised to reflux for reaction, and TLC was used to monitor the complete reaction of 2-methyl-5-nitroimidazole. After the reaction was completed, the reaction solution was cooled to room temperature, water (5 L) and concentrated hydrochloric acid (1163.0 g, 11.8 mol) were successively added, stirred for 15 - 30 min, then left to stand for liquid separation, and the aqueous phase was separated out.
[0041] Acetonitrile (5 L) was added to the aqueous phase and stirred for dilution, and then an alkali solution prepared by adding sodium hydroxide (628.8 g, 15.7 mol) and water (6 L) was added. The reaction was stirred at 20 - 30 °C, and TLC was used to monitor the complete reaction of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole. The reaction solution was extracted with ethyl acetate (5 L), the organic phase was separated out, and the organic phase was concentrated under reduced pressure until 500 ml remained. n-Heptane (2.5 L) was added to the concentrated residue, stirred to precipitate a solid, cooled to 0 - 5 °C and filtered, and the filter cake was washed with n-heptane (500 ml). After the filter cake was dried, 677.3 g of a white powdery solid (compound of formula I) was obtained, with a yield of 94% and a purity of 99.7%.
[0042] The applicant declares that the present invention illustrates the detailed method of the present invention through the above-mentioned examples, but the present invention is not limited to the above-mentioned detailed method, that is, it does not mean that the present invention must rely on the above-mentioned detailed method to be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent substitution of each raw material of the product of the present invention, the addition of auxiliary components, and the selection of specific methods, etc., all fall within the protection scope and the disclosure scope of the present invention.
[0043] Comparative Example 1
[0044] With stirring, ethyl acetate (200 ml) and 2-methyl-5-nitroimidazole (20 g, 157.4 mmol) were successively added to the reaction flask. The temperature was lowered to 5 - 10 °C, and then anhydrous aluminum trichloride (42.0 g, 314.8 mmol) and epichlorohydrin (16.0 g, 173.1 mmol) were successively added. The temperature was raised to reflux for reaction, and TLC was used to monitor the complete reaction of 2-methyl-5-nitroimidazole. After the reaction was completed, the reaction solution was cooled to room temperature, 200 ml of water and concentrated hydrochloric acid (23.3 g, 236.1 mmol) were successively added, stirred for 15 - 30 min, then left to stand for liquid separation, and it was difficult to layer, and the aqueous phase was separated out.
[0045] Acetonitrile (200 ml) was added to the aqueous phase and stirred for dilution. Then, an alkaline solution prepared by adding sodium hydroxide (12.6 g, 314.8 mmol) and water (250 ml) was added. The reaction was stirred at 20 - 30 °C, and TLC was used to monitor the reaction. It was found that there was still a large amount of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole remaining and it could not be completely consumed. The reaction solution was extracted with ethyl acetate (200 ml), and the organic phase was separated. The organic phase was concentrated under reduced pressure until 20 ml remained. Methyl tert-butyl ether (150 ml) was added to the concentrated residue, and an oily substance was precipitated by stirring. Then, the oily substance gradually solidified into a solid. The temperature was lowered to 0 - 5 °C and filtered. The filter cake was washed with methyl tert-butyl ether (20 ml). After drying the filter cake, 14.6 g of a pale yellow powdery solid (compound of formula I) was obtained, with a yield of 51% and a purity of 85.4%.
[0046] Comparative Example 2
[0047] Ethyl acetate (200 ml) and 2-methyl-5-nitroimidazole (20 g, 157.4 mmol) were successively added to the reaction flask under stirring. The temperature was lowered to 5 - 10 °C, and then anhydrous aluminum trichloride (52.5 g, 393.5 mmol) and epichlorohydrin (16.0 g, 173.1 mmol) were successively added. The reaction was heated to reflux, and TLC was used to monitor the reaction until 2-methyl-5-nitroimidazole was completely reacted. After the reaction was completed, the reaction solution was cooled to room temperature, 200 ml of water and concentrated hydrochloric acid (77.6 g, 787.0 mmol) were successively added. After stirring for 15 - 30 min, the mixture was allowed to stand for liquid separation, and the aqueous phase was separated out.
[0048] Tetrahydrofuran (200 ml) was added to the aqueous phase and stirred for dilution. Then, an alkaline solution prepared by adding sodium hydroxide (37.8 g, 944.4 mmol) and water (250 ml) was added. The reaction was stirred at 20 - 30 °C, and TLC was used to monitor the reaction until 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole was completely reacted. The reaction solution was extracted with ethyl acetate (200 ml), and the organic phase was separated. The organic phase was concentrated under reduced pressure until 20 ml remained. n-Heptane (40 ml) was added to the concentrated residue, and an oily substance was precipitated by stirring. Then, the oily substance gradually solidified into a solid. The temperature was lowered to 0 - 5 °C and filtered. The filter cake was washed with n-heptane (20 ml). After drying the filter cake, 14.6 g of an off-white powdery solid (compound of formula I) was obtained, with a yield of 42% and a purity of 90.1%.
Claims
1. A process for preparing the key intermediate of morinidazole, 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole, characterized in that The process described is a "one-pot method" and includes the following steps: a) 2-Methyl-5-nitroimidazole shown in Formula II undergoes a substitution reaction with epichlorohydrin shown in Formula III in ethyl acetate under the action of anhydrous aluminum trichloride. After acid-water extraction treatment, an aqueous hydrochloric acid solution of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole shown in Formula IV is obtained; b) A polar solvent is directly added to dilute the aqueous solution obtained in the previous step, and a ring-closure reaction occurs under the action of sodium hydroxide to obtain a reaction solution of 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole shown in Formula I. After extraction with a good solvent, washing with water, concentrating the organic phase, adding a poor solvent, crystallization in a mixed solvent system, filtration, and drying, finally, the finished product of 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole shown in Formula I is obtained.
2. The process for preparing the key intermediate of morinidazole, 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole, according to claim 1, is characterized in that In reaction step (a), the molar ratio of the anhydrous aluminum trichloride to the compound of Formula II is 1.0 - 1.5:
1.
3. The process for preparing the key intermediate of morinidazole, 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole, according to claim 1, is characterized in that In reaction step (a), the acid water is dilute hydrochloric acid, and the molar ratio of hydrochloric acid to the compound of Formula II is 2.0 - 4.0:
1.
4. The process for preparing the key intermediate of morinidazole, 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole, according to claim 1, is characterized in that In reaction step (b), the polar solvent is selected from acetonitrile, tetrahydrofuran, and acetone; preferably acetonitrile.
5. A process for preparing the key intermediate of morinidazole, 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole, according to claim 1, characterized in that In reaction step (b), the molar ratio of the base to the compound of Formula II is 3.0 - 5.0:
1.
6. The process for preparing the key intermediate of morinidazole, 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole, according to claim 1, is characterized in that In reaction step (b), the good solvent is selected from ethyl acetate, dichloromethane, and toluene; preferably ethyl acetate.
7. A process for preparing the key intermediate of morinidazole, 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole, according to claim 1, characterized in that In reaction step (b), the poor solvent is selected from methyl tert-butyl ether, n-heptane, and cyclohexane; preferably n-heptane.
8. The process for preparing the key intermediate of morinidazole, 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole, according to claim 1, is characterized in that In reaction step (b), the volume ratio of the good solvent to the poor solvent in the mixed solvent system is 1:2 - 5.