Preparation method of high-purity moroxydine

Abstract

The application relates to a preparation method of high-purity moricizine, specifically, 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole and morpholine are used as raw materials, reaction is carried out under alkaline conditions, and then recrystallization is carried out to obtain moricizine, the reaction conditions, especially the crystallization mode, are optimized, the yield of the moricizine crude product can reach more than 90%, the total yield after refining can reach more than 85%, the purity can reach 100%, and the 30kg-level pilot test verification is carried out, the process has good reproducibility, and is suitable for large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing high-purity morpholinidazole. Background Technology

[0002] Anaerobic bacteria are abundant in all cavities of the human body, especially in the intestines, mouth, and vagina, where they, along with aerobic bacteria, constitute the normal flora of these organs. When our physical condition changes, they can cause infections in different parts of the body, including appendicitis, cholecystitis, otitis media, oral infections, endometritis, and salpingitis. In recent years, with unbalanced work-rest schedules and changes in dietary habits, the number of people suffering from these diseases has been increasing. Nitroimidazole drugs can treat these diseases caused by anaerobic bacteria, and therefore, these drugs are widely used in clinical practice and have attracted much attention. Currently, the main nitroimidazole drugs available domestically and internationally include metronidazole, tinidazole, ornidazole, and morpholinidazole. Morolinidazole has higher anti-anaerobic activity than metronidazole, tinidazole, and ornidazole, and has better safety and lower toxicity.

[0003] Moroxydazole (compound I) is a third-generation 5-nitroimidazole antibacterial drug, approved for marketing in 2014. It is a Class 1.1 new drug developed in my country with independent intellectual property rights. Current reports indicate that the synthesis of moroxydazole suffers from drawbacks such as difficult intermediate preparation, challenging separation processes preventing industrial-scale production, low yield, and low purity. Therefore, improving the synthetic method is currently a pressing need.

[0004] The structure of morpholinidazole is shown below:

[0005]

[0006] Existing reported processes and their advantages and disadvantages:

[0007] Patent CN100427094 reports a ring-opening reaction of 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole with morpholine to obtain morpholinidazole. While this reported synthetic route is simple, it easily generates the isomer impurity 3-(2-methyl-5-nitro-1H-imidazol-1-yl)-2-morpholinylpropanol, making the product difficult to separate, resulting in decreased yield and purity, and making it unsuitable for industrial production. This isomer impurity can affect the quality of the drug and increase the risk to patients. The specific route is as follows:

[0008]

[0009] Patents CN104829541A, CN1995036B, and CN1850086A report methods for obtaining morpholinidazole from 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole via ring-opening, salt formation, release, and recrystallization with morpholine. The ring-opening process using halides is relatively vigorous and dangerous, and the raw materials are expensive, making it unsuitable for industrial production. The specific route is as follows:

[0010]

[0011] Patent WO2020119212A1 reports the preparation of morpholinidazole from 2-(chloromethyl)ethylene oxide and 2-methyl-5-nitro-1H-imidazolium via ring-opening and nucleophilic substitution reactions. This process is relatively cumbersome. The first step uses concentrated sulfuric acid, which is highly corrosive and dangerous. Separating the products in the first and second steps is difficult, resulting in a low yield of only 44.5%, making it unsuitable for industrial production. The specific route is as follows:

[0012]

[0013] Therefore, there is a need to invent a route with high yield, high purity, and that is more suitable for industrial production. Summary of the Invention

[0014] The purpose of this invention is to overcome the defects in the prior art and provide a method for preparing high-purity morpholinidazole with high yield.

[0015] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0016] This invention provides a method for preparing high-purity morpholinidazole:

[0017]

[0018] S1 nucleophilic substitution: 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole (compound II) was reacted with morpholine and potassium carbonate in anhydrous ethanol at 60-80°C for 4-6 h, cooled to 50-60°C, filtered, and the filtrate was cooled to 10-20°C. The pH was adjusted to 2-4 with acid, crystallized, filtered, and the filter cake was added to water. The pH was adjusted to 8-9 with alkali, and the mixture was stirred at this temperature for 0.2-1 h. After filtration and drying, crude compound I was obtained.

[0019] S2 recrystallization: Add the crude compound obtained in step S1 to purified water, heat to 70-75℃, add pharmaceutical charcoal, keep warm and stir for 0.5-1h, filter, heat to 70-75℃ again, then slowly cool to 60-65℃, keep warm and stir for 0.5-1h when the solid precipitates, slowly cool to 10-20℃, keep warm and stir for 1.5-2.5h, centrifuge, and dry.

[0020] As some preferred embodiments of the present invention, the molar ratio of compound II, morpholine, and potassium carbonate in step S1 is 1:1.1-2.5:0.5-1.5.

[0021] As some preferred embodiments of the present invention, the molar ratio of compound II, morpholine, and potassium carbonate in step S1 is 1:1.6:0.6.

[0022] In some preferred embodiments of the present invention, the mass ratio of compound II to anhydrous ethanol in step S1 is 1:12 to 20.

[0023] As some preferred embodiments of the present invention, the acid in step S1 is selected from any one of hydrochloric acid, sulfuric acid, nitric acid, and glacial acetic acid.

[0024] As some preferred embodiments of the present invention, the alkali in step S1 is selected from any one of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and ammonium carbonate.

[0025] As some preferred embodiments of the present invention, in step S1, the pH is adjusted to 3 with acid, and in step S1, the pH is adjusted to 8.5 with alkali.

[0026] As some preferred embodiments of the present invention, the mass ratio of crude product to purified water in step S2 is 1:4 to 7.

[0027] As some preferred embodiments of the present invention, in step S2, the temperature is slowly lowered to 60-65°C at 0.3°C / min, and the solid is stirred at this temperature for 0.5-1h while it is being precipitated, and then the temperature is slowly lowered to 10-20°C at 0.5°C / min.

[0028] The beneficial effects of adopting the above technical solution are as follows:

[0029] 1. The method provided by this invention prepares morpholine nitrazole in one step, which is shorter and simpler, and can also effectively avoid the generation of isomers of morpholine nitrazole, thus ensuring the safety of medication.

[0030] 2. This invention uses 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole as a raw material and optimizes the reaction conditions, especially the crystallization method, to obtain a crude morpholinidazole product with a yield of over 90% and a total yield of over 85% after purification, which is higher than the level of the original reference formulation.

[0031] 3. In this invention, the salt formation step is followed by the esterification reaction step and then processed using a method of heating dissolution and gradient crystallization. The resulting product has a purity of over 99.9% and a yield of up to 90%.

[0032] 4. In the existing technology, the yield of crude morpholinidazole is only about 75%, and the purity is difficult to reach 99.9% or above of the original formulation. The recrystallization step provided by this invention enables the purified morpholinidazole to reach 100% purity. It has been verified by a 30kg-level pilot test, and the process has good reproducibility and is suitable for large-scale production. Attached Figure Description

[0033] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0034] Figure 1 This is the hydrogen spectrum of morpholinidazole prepared in Example 1;

[0035] Figure 2 This is the carbon spectrum of morpholinidazole prepared in Example 1;

[0036] Figure 3 This is the HPLC chromatogram of morpholinidazole prepared in Example 1. Detailed Implementation

[0037] To make the objectives, technical solutions, and advantages of the present invention clearer, the invention will be described clearly and completely below in conjunction with specific embodiments.

[0038] Example 1

[0039] S1 Substitution: Add 460.0 kg of anhydrous ethanol to the reactor, start stirring, add 30.0 kg of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole, 11.4 kg of fine potassium carbonate powder, and 19.2 kg of morpholine. After rinsing the container and reactor walls with 15.0 kg of anhydrous ethanol, add the ethanol to the reactor. Heat to 70°C, maintain the temperature and stir for 5 hours. After the reaction is complete, cool to 55°C, filter, and wash the filter cake with 30.0 kg of anhydrous ethanol. Cool the filtrate to 15°C, adjust the pH to 3 with 6 mol / L hydrochloric acid, crystallize for 0.5 hours, filter, and wash the filter cake with 60.00 kg of anhydrous ethanol.

[0040] 54.0 kg of purified water and the above filter cake were added to the reaction vessel under stirring. The mixture was cooled to 15°C, and 1.5 kg of activated carbon was added and stirred for 0.5 h. After filtration, the reaction vessel and filter cake were washed with 12.0 kg of purified water. The filtrates were combined, cooled to 10°C, and ammonia was slowly added at 15°C to adjust the pH to 8.5. The mixture was kept at this temperature and stirred for 0.5 h. After filtration, the filter cake was washed with 60.0 kg of purified water and dried under vacuum at 45°C for 5 h to obtain crude compound I, with a yield of 92.1%.

[0041] Step 2: Recrystallization:

[0042] 132.0 kg of purified water was added to the reactor, and stirring was started. 24.0 kg of crude compound I was added, and the temperature was raised to 80°C. The mixture was stirred for 20 min, and 1.2 kg of pharmaceutical charcoal was added. The mixture was kept at this temperature and stirred for 0.5 h. The mixture was filtered while hot, and the filter cake was washed with 12.0 kg of purified water. The filtrates were combined, and the temperature of the filtrate was raised to 75°C and stirred for 1 h. The temperature was then slowly lowered to 65°C at a rate of 0.3°C / min, and stirred for 1 h. The temperature was then lowered to 15°C at a rate of 0.5°C / min, and stirred for 2 h. The mixture was centrifuged and dried under vacuum at 45°C for 2 h to obtain compound I, with a yield of 93.3%. 1 H-NMR, 400MHz, MeOD-d4)δ: 2.489-2.564 (9H), 3.708-3.724 (4H), 4.090-4.116 (1H), 4.120-4.169 (1H), 4.610 (1H), 4.733-4.892 (1H), 7.958 (1H), spectrum is as follows Figure 1 ;( 13 C-NMR, 400MHz, DMSO-d4) δ: 13.13, 47.91, 50.60, 53.96, 62.28, 66.50, 67.07, 131.19, 138.75, 152.01, spectral values ​​are as follows Figure 2 High-performance liquid chromatography (HPLC) purity 100%, chromatogram as follows: Figure 3 .

[0043] Example 2

[0044] S1 Substitution: Add 4.6 kg of anhydrous ethanol to the reactor, start stirring, add 300.0 g of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole, 114.0 g of finely powdered potassium carbonate, and 192.0 g of morpholine. Heat to 70°C and maintain the temperature with stirring for 5 h. After the reaction is complete, cool to 55°C, filter, and wash the filter cake with 300.0 g of anhydrous ethanol. Cool the filtrate to 15°C, adjust the pH to 3 with hydrochloric acid, allow crystallization for 0.5 h, filter, and wash the filter cake with 600.0 g of anhydrous ethanol.

[0045] 540.0 g of purified water and the above filter cake were added to the reaction flask with stirring. The mixture was cooled to 15°C, and 15.0 g of activated carbon was added and stirred for 0.5 h. After filtration, the filter cake was washed with 120.0 g of purified water. The filtrates were combined, cooled to 10°C, and ammonia was slowly added at 15°C to adjust the pH to 8.5. The mixture was kept at this temperature and stirred for 0.5 h. After filtration, the filter cake was washed with 600.0 g of purified water and dried under vacuum at 45°C for 5 h to obtain crude compound I, with a yield of 92.3%.

[0046] Step 2: Recrystallization:

[0047] 960.0 g of purified water was added to the reaction flask, and stirring was started. 240.0 g of crude compound I was added, and the temperature was raised to 80 °C. The mixture was stirred for 20 min, and 12.0 g of pharmaceutical charcoal was added. The mixture was kept warm and stirred for 0.5 h, and then filtered while hot. The filter cake was washed with 120.0 g of purified water, and the filtrates were combined. The filtrate was heated to 75 °C and stirred for 1 h. The temperature was then slowly lowered to 65 °C at 0.3 °C / min and stirred for 1 h. The temperature was then lowered to 15 °C at 0.5 °C / min and stirred for 2 h. The mixture was filtered, and then dried under vacuum at 45 °C for 2 h to obtain compound I with a yield of 94.5% and a purity of 99.9%.

[0048] Example 3

[0049] S1 Substitution: Add 4.6 kg of anhydrous ethanol to the reactor, start stirring, add 300.0 g of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole, 114.0 g of finely powdered potassium carbonate, and 192.0 g of morpholine. Heat to 70°C and maintain the temperature with stirring for 5 h. After the reaction is complete, cool to 55°C, filter, and wash the filter cake with 300.0 g of anhydrous ethanol. Cool the filtrate to 15°C, adjust the pH to 3 with hydrochloric acid, allow crystallization for 0.5 h, filter, and wash the filter cake with 600.0 g of anhydrous ethanol.

[0050] 540.0 g of purified water and the above filter cake were added to the reaction flask with stirring. The mixture was cooled to 15°C, and 15.0 g of activated carbon was added and stirred for 0.5 h. After filtration, the filter cake was washed with 120.0 g of purified water. The filtrates were combined, cooled to 10°C, and ammonia was slowly added at 15°C to adjust the pH to 8.5. The mixture was kept at this temperature and stirred for 0.5 h. After filtration, the filter cake was washed with 600.0 g of purified water and dried under vacuum at 45°C for 5 h to obtain crude compound I, with a yield of 92.0%.

[0051] Step 2: Recrystallization:

[0052] 1.7 kg of purified water was added to the reactor, and stirring was started. 240.0 g of crude compound I was added, and the temperature was raised to 80 °C. The mixture was stirred for 20 min, and 12.0 g of pharmaceutical charcoal was added. The mixture was kept warm and stirred for 0.5 h, and then filtered while hot. The filter cake was washed with 120.0 g of purified water, and the filtrates were combined. The filtrate was heated to 75 °C and stirred for 1 h. The temperature was then slowly lowered to 65 °C at 0.3 °C / min and stirred for 1 h. The temperature was then lowered to 15 °C at 0.35 °C / min and stirred for 2 h. The mixture was filtered, and then dried under vacuum at 45 °C for 2 h to obtain compound I with a yield of 92.2% and a purity of 99.9%.

[0053] Example 4

[0054] S1 Substitution: Add 2.3 kg of anhydrous ethanol to the reactor, start stirring, add 150.0 g of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole, 47.0 g of finely powdered potassium carbonate, and 66.0 g of morpholine. Heat to 60°C and maintain the temperature with stirring for 6 hours. After the reaction is complete, cool to 50°C, filter, and wash the filter cake with 150.0 g of anhydrous ethanol. Cool the filtrate to 15°C, adjust the pH to 2 with hydrochloric acid, allow crystallization for 0.5 hours, filter, and wash the filter cake with 300.0 g of anhydrous ethanol.

[0055] 270.0 g of purified water and the above filter cake were added to the reaction flask with stirring. The mixture was cooled to 15°C, and 7.5 g of activated carbon was added and stirred for 0.5 h. After filtration, the filter cake was washed with 60.0 g of purified water. The filtrates were combined, cooled to 15°C, and ammonia was slowly added at 15°C to adjust the pH to 8. The mixture was kept at this temperature and stirred for 0.5 h. After filtration, the filter cake was washed with 300.0 g of purified water and dried under vacuum at 45°C for 5 h to obtain crude compound I, with a yield of 90.8%.

[0056] Step 2: Recrystallization:

[0057] Add 660.0 g of purified water to the reaction flask, start stirring, add 120.0 g of crude compound I, heat to 75 °C, stir for 20 min, add 6.0 g of pharmaceutical charcoal, keep warm and stir for 0.5 h, filter while hot, wash the filter cake with 60.0 g of purified water, combine the filtrates, heat the filtrate to 75 °C and keep warm and stir for 1 h, slowly cool to 60 °C at 0.3 °C / min, keep warm and stir for 1 h, then cool to 15 °C at 0.5 °C / min, keep warm and stir for 2 h, filter, and vacuum dry at 45 °C for 2 h to obtain compound I with a yield of 92.9% and a purity of 99.8%.

[0058] Example 5

[0059] S1 Substitution: Add 2.3 kg of anhydrous ethanol to the reactor, start stirring, add 150.0 g of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole, 141.5 g of finely powdered potassium carbonate, and 149.0 g of morpholine. Heat to 80°C and maintain the temperature with stirring for 4 hours. After the reaction is complete, cool to 60°C, filter, and wash the filter cake with 150.0 g of anhydrous ethanol. Cool the filtrate to 15°C, adjust the pH to 4 with hydrochloric acid, allow crystallization for 0.5 hours, filter, and wash the filter cake with 300.0 g of anhydrous ethanol.

[0060] 270.0 g of purified water and the above filter cake were added to the reaction flask with stirring. The mixture was cooled to 15°C, and 7.5 g of activated carbon was added and stirred for 0.5 h. After filtration, the filter cake was washed with 60.0 g of purified water. The filtrates were combined, cooled to 15°C, and ammonia was slowly added at 15°C to adjust the pH to 9. The mixture was kept at this temperature and stirred for 0.5 h. After filtration, the filter cake was washed with 300.0 g of purified water and dried under vacuum at 45°C for 5 h to obtain crude compound I, with a yield of 92.8%.

[0061] Step 2: Recrystallization: Add 660.0g of purified water to the reaction flask, start stirring, add 120.0g of crude compound I, heat to 75℃, stir for 20min, add 6.0g of pharmaceutical charcoal, keep warm and stir for 0.5h, filter while hot, wash the filter cake with 60.0g of purified water, combine the filtrates, heat the filtrate to 75℃ and keep warm and stir for 1h, slowly cool to 65℃ at 0.3℃ / min, keep warm and stir for 1h, then cool to 15℃ at 0.5℃ / min, keep warm and stir for 2h, filter, and vacuum dry at 45℃ for 2h to obtain compound I, with a yield of 92.8% and a purity of 99.8%.

[0062] Comparative Example 1

[0063] S1 Substitution: Add 1.53 kg of anhydrous ethanol to the reactor, start stirring, add 100.0 g of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole, 38.0 g of finely powdered potassium carbonate, and 64.0 g of morpholine. Heat to 70°C and maintain the temperature with stirring for 5 hours. After the reaction is complete, cool to 55°C, filter, and wash the filter cake with 100.0 g of anhydrous ethanol. Cool the filtrate to 15°C, adjust the pH to 3 with hydrochloric acid, allow crystallization for 0.5 hours, filter, and wash the filter cake with 200.0 g of anhydrous ethanol.

[0064] 180.0 g of purified water and the above filter cake were added to the reaction flask with stirring. The mixture was cooled to 15°C, and 5.0 g of activated carbon was added and stirred for 0.5 h. After filtration, the filter cake was washed with 40.0 g of purified water. The filtrates were combined, cooled to 10°C, and ammonia was slowly added at 15°C to adjust the pH to 8.5. The mixture was kept at this temperature and stirred for 0.5 h. After filtration, the filter cake was washed with 200.0 g of purified water and dried under vacuum at 45°C for 5 h to obtain crude compound I, with a yield of 92.1%.

[0065] Step 2: Recrystallization:

[0066] 440.0 g of purified water was added to the reaction flask, and stirring was started. 80.0 g of crude compound I was added, and the temperature was raised to 80 °C. The mixture was stirred for 20 min, and 4.0 g of pharmaceutical charcoal was added. The mixture was kept warm and stirred for 0.5 h. While still hot, the mixture was filtered at 0.3 °C / min and slowly cooled to 65 °C. The mixture was kept warm and stirred for 1 h, and then cooled to 15 °C at 0.5 °C / min. The mixture was kept warm and stirred for 2 h, filtered, and dried under vacuum at 45 °C for 2 h to obtain compound I with a yield of 91.8% and a purity of 99.0%.

[0067] Comparative Example 2

[0068] S1 Substitution: Add 1.53 kg of anhydrous ethanol to the reactor, start stirring, add 300.0 g of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole, 38.0 g of finely powdered potassium carbonate, and 64.0 g of morpholine. Heat to 70°C and maintain the temperature with stirring for 5 hours. After the reaction is complete, cool to 55°C, filter, and wash the filter cake with 100.0 g of anhydrous ethanol. Cool the filtrate to 15°C, adjust the pH to 3 with hydrochloric acid, allow crystallization for 0.5 hours, filter, and wash the filter cake with 200.0 g of anhydrous ethanol.

[0069] 180.0 g of purified water and the above filter cake were added to the reaction flask with stirring. The mixture was cooled to 15°C, and 5.0 g of activated carbon was added and stirred for 0.5 h. After filtration, the filter cake was washed with 40.0 g of purified water. The filtrates were combined, cooled to 10°C, and ammonia was slowly added at 15°C to adjust the pH to 8.5. The mixture was kept at this temperature and stirred for 0.5 h. After filtration, the filter cake was washed with 200.0 g of purified water and dried under vacuum at 45°C for 5 h to obtain crude compound I, with a yield of 92.0%.

[0070] Step 2: Recrystallization:

[0071] 440.0 g of purified water was added to the reaction flask, and stirring was started. 80.0 g of crude compound I was added, and the temperature was raised to 80 °C. The mixture was stirred for 20 min, and 4.0 g of pharmaceutical charcoal was added. The mixture was kept warm and stirred for 0.5 h, and then filtered while hot. The filter cake was washed with 40.0 g of purified water, and the filtrates were combined. The filtrate was slowly cooled to 15 °C at a rate of 0.3 °C / min, and stirred for 2 h. The mixture was then filtered, and dried under vacuum at 45 °C for 2 h to obtain compound I with a yield of 92.5% and a purity of 99.1%.

[0072] Comparative Example 3

[0073] S1 Substitution: Add 766.7g of methanol to the reaction vessel, start stirring, add 50.0g of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole, 19.0g of finely powdered potassium carbonate, and 32.0g of morpholine. Heat to 70℃ and maintain the temperature with stirring for 5 hours. After the reaction is complete, cool to 55℃, filter, and wash the filter cake with 50.0g of methanol. Cool the filtrate to 15℃, adjust the pH to 3 with hydrochloric acid, allow crystallization for 0.5 hours, filter, and wash the filter cake with 100.0g of methanol.

[0074] Add 90.0 g of purified water and the above filter cake to the reaction flask with stirring. Cool to 15°C, add 2.5 g of activated carbon and stir for 0.5 h. Filter, and wash the filter cake with 20.0 g of purified water. Combine the filtrates, cool the filtrate to 10°C, and slowly add ammonia water at 15°C to adjust the pH to 8.5. Maintain the temperature and stir for 0.5 h. Filter, wash the filter cake with 100.0 g of purified water, and dry the filter cake under vacuum at 45°C for 5 h to obtain crude compound I, with a yield of 89.6%.

[0075] Step 2: Recrystallization:

[0076] 220.0 g of purified water was added to the reaction flask, and stirring was started. 40.0 g of crude compound I was added, and the temperature was raised to 80 °C. The mixture was stirred for 20 min, and 2.0 g of pharmaceutical charcoal was added. The mixture was kept warm and stirred for 0.5 h, and then filtered while hot. The filter cake was washed with 20.0 g of purified water, and the filtrates were combined. The filtrate was heated to 75 °C and stirred for 1 h. The temperature was then slowly lowered to 65 °C at 0.3 °C / min and stirred for 1 h. The temperature was then lowered to 15 °C at 0.5 °C / min and stirred for 2 h. The mixture was filtered, and then dried under vacuum at 45 °C for 2 h to obtain compound I with a yield of 93.0% and a purity of 99.9%.

[0077] Comparative Example 4

[0078] S1 Substitution: Add 766.7 g of anhydrous ethanol to the reaction flask, start stirring, add 50.0 g of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole, 14.5 g of sodium carbonate, and 32.0 g of morpholine. Heat to 70°C and stir for 5 h. After the reaction is complete, cool to 55°C, filter, and wash the filter cake with 50.0 g of anhydrous ethanol. Cool the filtrate to 15°C, adjust the pH to 3 with hydrochloric acid, crystallize for 0.5 h, filter, and wash the filter cake with 100.0 g of anhydrous ethanol.

[0079] Add 90.0 g of purified water and the above filter cake to the reaction flask with stirring. Cool to 15°C, add 2.5 g of activated carbon and stir for 0.5 h. Filter, and wash the filter cake with 20.0 g of purified water. Combine the filtrates, cool the filtrate to 10°C, and slowly add ammonia water at 15°C to adjust the pH to 8.5. Maintain the temperature and stir for 0.5 h. Filter, wash the filter cake with 100.0 g of purified water, and dry the filter cake under vacuum at 45°C for 5 h to obtain crude compound I, with a yield of 89.5%.

[0080] Step 2: Recrystallization:

[0081] 220.0 g of purified water was added to the reaction flask, and stirring was started. 40.0 g of crude compound I was added, and the temperature was raised to 80 °C. The mixture was stirred for 20 min, and 2.0 g of pharmaceutical charcoal was added. The mixture was kept warm and stirred for 0.5 h, and then filtered while hot. The filter cake was washed with 20.0 g of purified water, and the filtrates were combined. The filtrate was heated to 75 °C and stirred for 1 h. The temperature was then slowly lowered to 65 °C at 0.3 °C / min and stirred for 1 h. The temperature was then lowered to 15 °C at 0.5 °C / min and stirred for 2 h. The mixture was filtered, and then dried under vacuum at 45 °C for 2 h to obtain compound I with a yield of 93.2% and a purity of 100.0%.

[0082] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing high-purity moricizine, characterized in that, S1 nucleophilic substitution: 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole is reacted with morpholine and potassium carbonate in anhydrous ethanol at 60-80℃ for 4-6h, the temperature is lowered to 50-60℃, filtration is performed, the filtrate is cooled to 10-20℃, the pH is adjusted to 2-4 with an acid, crystallization is performed, filtration is performed, the filter cake is added to water, the pH is adjusted to 8-9 with a base, and the mixture is stirred for 0.2-1h, filtration is performed, and drying is performed to obtain crude compound I; S2 recrystallization: crude compound I obtained in step S1 is added to purified water, the temperature is raised to 70-75℃, medicinal charcoal is added, the mixture is stirred for 0.5-1h, filtration is performed, the temperature is raised to 70-75℃ again, and the temperature is slowly lowered to 60-65℃ at a rate of 0.3℃ / min, the mixture is stirred for 0.5-1h when the solid is precipitated, the temperature is slowly lowered to 10-20℃ at a rate of 0.5℃ / min, the mixture is stirred for 1.5-2.5h, centrifugation is performed, and drying is performed; the molar ratio of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole, morpholine and potassium carbonate in step S1 is 1:1.6:0.

6.

2. The method for preparing high-purity morpholinidazole according to claim 1, characterized in that, the mass ratio of 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole to anhydrous ethanol in step S1 is 1:12-20.

3. The method for preparing high-purity morpholinidazole according to claim 1, characterized in that, the acid in step S1 is selected from any one of hydrochloric acid, sulfuric acid, nitric acid and glacial acetic acid.

4. The method for preparing high-purity morpholinidazole according to claim 1, characterized in that, the base in step S1 is selected from any one of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and ammonium carbonate.

5. The method for preparing high-purity morpholinidazole according to claim 1, characterized in that, the pH is adjusted to 3 with an acid in step S1, and the pH is adjusted to 8.5 with a base in step S1.

6. The method for preparing high-purity morpholinidazole according to claim 1, characterized in that, the mass ratio of crude product to purified water in step S2 is 1:4-7.

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