Preparation method of molinidazole

Abstract

The invention relates to a preparation method of morphonidazole, which adopts safe, environment-friendly and economical water as a reaction solvent, so that the reaction has higher reaction safety, excellent reactivity and regioselectivity without adding a catalyst, and the generation of morphonidazole isomers and other impurities can be obviously reduced or even eliminated in the reaction process. The reaction rate is accelerated, and the reaction conversion rate is improved, so that the purity of the morphonidazole is improved, the subsequent purification difficulty is further reduced, and the process cost is reduced; and meanwhile, the purification process of the crude product of the morphonidazole is also improved, and the purity of the morphonidazole is effectively improved by changing the type of a recrystallization solvent and simplifying recrystallization steps. In conclusion, the production process of the morphonidazole is effectively simplified, the developed process is safe, environmentally friendly, simple, efficient and high in stability, the production cost of the morphonidazole can be remarkably reduced, and the commercial production requirement is met; furthermore, the morphonidazole prepared by the method is high in purity and stable in quality, and meets the medicinal standard.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and particularly to a preparation method of morinidazole. Background Art

[0002] Nitroimidazole antibacterial drugs are a class of synthetic antibacterial drugs, which have the advantages of a broad anaerobic antibacterial spectrum, low price, and good efficacy. They are widely combined with other antibacterial drugs for the mixed infections of anaerobic bacteria and aerobic bacteria in various clinical systems. Common nitroimidazole drugs mainly include metronidazole, tinidazole, ornidazole, morinidazole, etc.

[0003] Among them, morinidazole sodium chloride injection is a third-generation nitroimidazole drug developed by Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Due to its strong antibacterial effect against anaerobic bacteria, low toxicity, and high safety, it has been widely used in clinical practice. Morinidazole is mainly used for the infections of adults caused by sensitive bacteria, and its indications include pelvic inflammatory disease in gynecology, combined surgical treatment of suppurative appendicitis, gangrenous appendicitis, etc. Research shows that its medicinal mechanism may be that the nitro group in the molecule is reduced to an amino group or forms free radicals in an anaerobic environment, and then interacts with cell components, thereby causing the death of microorganisms. The structural formula of morinidazole is shown as follows:

[0004]

[0005] Traditional preparation methods of morinidazole mainly include the following several: (1) Using halides such as chlorides, bromides or iodides of alkali metals as catalysts, 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole and morpholine as raw materials, heating and reacting in organic solvents such as acetonitrile, tetrahydrofuran, acetone, etc., and then cooling and crystallizing to obtain the crude product of morinidazole, and then obtaining morinidazole through acid addition for salting, decolorization with activated carbon, alkali addition for liberation, and recrystallization; (2) Dissolving 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole and 4-hydroxypiperidine in acetonitrile, adding morpholine, refluxing for 2 h, recovering acetonitrile under reduced pressure, and obtaining morinidazole through recrystallization; (3) Reacting 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole with morpholine and potassium carbonate in absolute ethanol at 60 °C to 80 °C for 4 h to 6 h, cooling to 50 °C to 60 °C, filtering, cooling the filtrate to 10 °C to 20 °C, adjusting the pH to 2 to 4 with acid, crystallizing, filtering, adding the filter cake to water, adjusting the pH to 8 to 9 with alkali, keeping warm and stirring for 0.2 h to 1 h, filtering, drying to obtain the crude product, and then obtaining morinidazole through stirring with medicinal charcoal, multi-step temperature-controlled recrystallization, and drying; (4) Adding acetic acid and concentrated sulfuric acid, stirring for 1 hour, then adding 2-(chloromethyl)oxirane and 2-methyl-5-nitro-1H-imidazole, at 10 o C~20 oReact for two hours, and 1-chloro-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol is obtained by column chromatography; 1-chloro-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol, potassium carbonate and morpholine are added to ethanol, reflux for 6 hours, cool the reaction solution, spin off ethanol and purify by column chromatography to obtain ornidazole morpholine.

[0006] It can be seen that most of the traditional preparation methods of ornidazole morpholine have the following problems: metal halides, acids, and bases need to be used as catalysts and a large amount of organic solvents in the reaction process, resulting in high production costs, environmental unfriendliness, and low reaction safety; at the same time, the reaction regioselectivity cannot be well controlled, resulting in an increase in the formation of ornidazole morpholine isomers and other impurities, and the purity of the crude ornidazole morpholine is not high, further increasing the difficulty of subsequent purification. Summary of the Invention

[0007] Based on this, it is necessary to provide a preparation method of ornidazole morpholine. By changing the solvent type to water, this preparation method reduces the production cost investment and is environmentally friendly. Using a specific solvent enables the reaction to have excellent reactivity and regioselectivity without adding catalysts such as metal halides, acids, and bases, and can significantly reduce or even eliminate the formation of ornidazole morpholine isomers and other impurities.

[0008] The present invention provides a preparation method of ornidazole morpholine, including the following steps:

[0009] Mix epoxidized ornidazole, morpholine and water for reaction to prepare ornidazole morpholine.

[0010] In some embodiments, stage temperature control is adopted during the reaction process, and the stage temperature control includes:

[0011] The first stage: heat up to 30°C - 70°C, keep warm and stir for 3h - 7h;

[0012] The second stage: cool down to 0°C - 20°C, keep warm and stir for 1h - 2h.

[0013] In some embodiments, the molar ratio of epoxidized ornidazole to morpholine is 1:(1.0 - 2.0).

[0014] In some embodiments, the volume of water is 3 - 7 times the mass of epoxidized ornidazole.

[0015] In some embodiments, after the reaction, a purification step is further included, and the purification step includes the first recrystallization and the second recrystallization.

[0016] In some embodiments, the solvent used in the first recrystallization is water; the solvent used in the second recrystallization includes one or more of methanol, ethanol, and isopropanol.

[0017] In some of these embodiments, the step of the first recrystallization includes:

[0018] Filter and dry the obtained reaction system to obtain crude ornidazole morpholine I. Mix the crude ornidazole morpholine I with water, heat the obtained mixture to 60°C to 100°C, and keep stirring for 1 h to 2 h;

[0019] Then cool down to 0°C to 20°C, keep stirring for 1 h to 2 h, filter and dry to obtain crude ornidazole morpholine II.

[0020] In some of these embodiments, in the first recrystallization, the volume of the water is 3 to 7 times the mass of the crude ornidazole morpholine I.

[0021] In some of these embodiments, the step of the second recrystallization includes:

[0022] Mix the crude ornidazole morpholine II with the solvent used in the second recrystallization, heat the obtained mixture to 50°C to 100°C, and keep stirring for 1 h to 2 h;

[0023] Then cool down to 0°C to 20°C, keep stirring for 1 h to 2 h, filter and dry to obtain ornidazole morpholine.

[0024] In some of these embodiments, in the second recrystallization, the volume of the solvent used in the second recrystallization is 3 to 7 times the mass of the crude ornidazole morpholine II.

[0025] Compared with the prior art, the present application has the following beneficial effects:

[0026] The present application uses epoxidized ornidazole and morpholine as raw materials to prepare ornidazole morpholine. By using water, which is safe, environmentally friendly and economical, as the reaction solvent, the reaction has high reaction safety, excellent reactivity and regioselectivity without adding catalysts such as metal halides, acids, and bases. During the reaction process, the generation of ornidazole morpholine isomers and other impurities can be significantly reduced or even eliminated, the reaction rate can be accelerated, the reaction conversion rate can be increased, thereby improving the purity of the crude ornidazole morpholine, further reducing the subsequent purification difficulty, and lowering the process cost.

[0027] Furthermore, the present application uses an alcohol solvent with low cost and strong volatility as the recrystallization solvent to refine the crude ornidazole morpholine, which can effectively improve the purity of ornidazole morpholine. At the same time, the purification step of the crude ornidazole morpholine is simplified to two-step recrystallization. While ensuring the product quality, the production process is simplified as much as possible, and relatively cumbersome operation steps are avoided.

[0028] In summary, the production process of morinidazole is effectively simplified by the present application. The developed process is safe, environmentally friendly, simple, efficient, and highly stable, which can significantly reduce the production cost of morinidazole and meet the requirements of commercial production. Further, the morinidazole prepared by the present invention has high purity, stable quality, and meets the pharmaceutical standards. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present application. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0030] Figure 1 It is the HPLC diagram of the morinidazole prepared in Example 1. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0031] The preparation method of morinidazole of the present invention will be further described in detail below with reference to specific embodiments. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosed content of the present invention more thorough and comprehensive. Those skilled in the art can make similar improvements without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs. The terms used in the description of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0033] Unless otherwise stated or there is a contradiction, the terms or phrases used herein have the following meanings:

[0034] As used herein, "one or more" means any one, any two, or any two or more of the listed items.

[0035] As used herein, the optional scope of "and / or", "or / and", "and / or" includes any one of two or more related listed items, and also includes any and all combinations of the related listed items. The said any and all combinations include any two related listed items, any more related listed items, or the combination of all related listed items.

[0036] As used herein, "further", "even further", "especially", etc. are used for descriptive purposes and indicate differences in content, but should not be construed as limiting the protection scope of the present invention.

[0037] In this text, the meaning of "a plurality of" is at least two, such as two, three, etc., unless otherwise specifically defined. In the description of the present invention, the meaning of "several" is at least one, such as one, two, etc., unless otherwise specifically defined.

[0038] In the present invention, regarding numerical ranges, unless otherwise specified, the above numerical ranges are considered continuous and include the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when the range refers to integers, it includes each integer between the minimum and maximum values of the range. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0039] In the present invention, the percentage content involved, unless otherwise specified, refers to the mass percentage for solid-liquid mixtures and solid-solid mixtures, and refers to the volume percentage for liquid-liquid mixtures.

[0040] In the present invention, the percentage concentration involved, unless otherwise specified, refers to the final concentration. The final concentration refers to the proportion of the added component in the system after adding the component.

[0041] The temperature parameters in the present invention, unless otherwise specifically limited, allow both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuation within a range such as ±5°C, ±2°C, ±1°C, ±0.5°C, ±0.4°C, ±0.3°C, ±0.2°C, ±0.1°C is allowed. Normal temperature in the present invention refers to no temperature control operation, generally referring to 4°C to 35°C, preferably 20 ± 5°C.

[0042] In the present invention, among the technical features described in an open-ended manner, it includes a closed technical solution composed of the listed features, as well as an open technical solution including the listed features.

[0043] In the process of preparing morinidazole using epoxidized ornidazole and morpholine as raw materials, it is necessary to first undergo a ring-opening reaction of the epoxide to generate morinidazole; and the raw material epoxidized ornidazole has two ring-opening reaction sites. The main reaction generates morinidazole, and the side reaction generates impurities mainly composed of isomers of morinidazole. The reaction mechanisms and corresponding structures of the product and by-products are as shown below:

[0044]

[0045] It can be seen that how to avoid the formation of morpholinonidazole isomers is a key issue for further improving the purity of the prepared morpholinonidazole. The technicians of this application unexpectedly found during the experiment that in the process of preparing morpholinonidazole from epoxidized ornidazole and morpholine as raw materials, the reaction effect has a great relationship with the type of reaction solvent. When using a specific solvent, it helps to accelerate the reaction rate, improve the reaction conversion rate and reaction regioselectivity. Further, when the selected solvent is safe and environmentally friendly water, no morpholinonidazole isomer impurities are detected in the reaction solution, and the reaction effect is better. It is speculated that this may be because water provides protons in the reaction system, accelerates the reaction process, and improves the reaction conversion rate, enabling the reaction to ensure excellent regioselectivity without adding metal halides. At the same time, the use of water makes the process of morpholinonidazole have lower production costs.

[0046] The present invention provides a method for preparing morpholinonidazole, which includes the following steps:

[0047] Mix epoxidized ornidazole, morpholine and water and carry out a reaction to prepare morpholinonidazole.

[0048] In one specific example, stage temperature control is adopted during the reaction, and the stage temperature control includes:

[0049] The first stage: heat up to 30°C - 70°C and keep warm and stir for 3h - 7h;

[0050] The second stage: cool down to 0°C - 20°C and keep warm and stir for 1h - 2h.

[0051] It can be understood that the temperature in the first stage includes but is not limited to: 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C; the stirring time in the first stage includes but is not limited to: 3h, 4h, 5h, 6h, 7h. The temperature in the second stage includes but is not limited to: 0 o °C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C; the stirring time in the second stage includes but is not limited to: 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h.

[0052] Further, in the first stage, the reaction system is in a clear solution state for 10min - 30min during the reaction process, and then morpholinonidazole will gradually precipitate. The obtained crude product I has a high purity, low impurity content, and no morpholinonidazole isomer impurities are detected, which is beneficial to subsequent further purification.

[0053] In one specific example, the molar ratio of epoxidized ornidazole to morpholine is 1:(1.0 - 2.0). It can be understood that the molar ratio of epoxidized ornidazole to morpholine includes but is not limited to: 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0.

[0054] In one specific example, the volume of water is 3 - 7 times the mass of epoxidized ornidazole. It can be understood that the volume of water includes but is not limited to 3 times, 4 times, 5 times, 6 times, and 7 times the mass of epoxidized ornidazole.

[0055] In one specific example, after the reaction ends, a purification step is further included.

[0056] In one specific example, the purification step includes a first recrystallization and a second recrystallization.

[0057] In one specific example, the solvent used in the first recrystallization is water.

[0058] In one specific example, the solvent used in the second recrystallization includes one or more of methanol, ethanol, and isopropanol.

[0059] The traditional purification method for crude ornidazole still has the following problems: when purifying crude ornidazole, the operation is relatively cumbersome, requiring a large amount of organic solvents, acids, and bases, with a high process cost and being environmentally unfriendly, unable to meet the requirements of commercial production. This application improves the purification process of crude ornidazole, simplifies it to two-step recrystallization, changes the type of recrystallization solvent and simplifies the recrystallization steps, uses an alcohol solvent with a low cost and strong volatility as the recrystallization solvent to refine crude ornidazole, and effectively improves the purity of ornidazole. Specifically, the alcohol solvent has good decolorization ability and impurity removal ability for the product, has a strong ability to remove impurities, can reduce process risks. At the same time, the alcohol solvent has a low cost and strong volatility, which is beneficial for sample drying, with less solvent residue, and effectively reduces production costs.

[0060] In one specific example, the steps of the first recrystallization include:

[0061] Filter and dry the obtained reaction system to obtain crude ornidazole I, mix the crude ornidazole I with water, heat the obtained mixture to 60°C - 100°C, and keep it warm and stir for 1h - 2h;

[0062] Then cool it to 0°C - 20°C, keep it warm and stir for 1h - 2h, filter and dry to obtain crude ornidazole II.

[0063] Understandably, in the step of the first recrystallization, the elevated temperature includes but is not limited to: 60 o °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C, 100 °C; the time for holding and stirring after heating includes but is not limited to: 1 h, 1.1 h, 1.2 h, 1.3 h, 1.4 h, 1.5 h, 1.6 h, 1.7 h, 1.8 h, 1.9 h, 2 h. The reduced temperature includes but is not limited to: 0 o °C, 1 o °C, 2 o °C, 3 o °C, 4 o °C, 5 o °C, 6 o °C, 7 o °C, 8 o °C, 9 o °C, 10 o °C, 11 o °C, 12 o °C, 13 o °C, 14 o °C, 15 o °C, 16 o °C, 17 o °C, 18 o °C, 19 o °C, 20 o °C; the time for holding and stirring after cooling includes but is not limited to: 1 h, 1.1 h, 1.2 h, 1.3 h, 1.4 h, 1.5 h, 1.6 h, 1.7 h, 1.8 h, 1.9 h, 2 h.

[0064] In one specific example, in the first recrystallization, the volume of water is 3 to 7 times the mass of the crude product I of moxnidazole. Understandably, in the first recrystallization, the volume of water includes but is not limited to 3 times, 4 times, 5 times, 6 times, and 7 times the mass of the crude product I of moxnidazole.

[0065] In one specific example, the steps of the second recrystallization include:

[0066] Mix the crude product II of moxnidazole with the solvent used in the second recrystallization, heat the resulting mixture to 50 °C to 100 °C, add activated carbon, hold and stir for 1 h to 2 h, and filter;

[0067] Then cool to 0 °C to 20 °C, hold and stir for 1 h to 2 h, filter and dry to obtain moxnidazole.

[0068] Understandably, in the step of the second recrystallization, the elevated temperature includes but is not limited to: 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C; the time for holding and stirring after the temperature rise includes but is not limited to: 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h. The reduced temperature includes but is not limited to: 0 o °C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C; the time for holding and stirring after the temperature drop includes but is not limited to: 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h.

[0069] In one specific example, in the step of the second recrystallization, the volume of the solvent used in the second recrystallization is 3 to 7 times the mass of the crude ornidazole II. Understandably, the volume of the solvent used in the second recrystallization includes but is not limited to 3 times, 4 times, 5 times, 6 times, and 7 times the mass of the crude ornidazole II.

[0070] In the preparation process of ornidazole, in addition to the main impurity of ornidazole isomers, there may also be impurity A and impurity B. Among them, impurity A is a process impurity generated during the preparation of epoxidized ornidazole, and impurity B is a derivative impurity of the ornidazole process intermediate, and the structures are as shown below. And the technicians of this application found through a large number of experiments that when water is selected as the reaction solvent to prepare ornidazole, no ornidazole isomers are detected in the crude ornidazole; and after two recrystallizations, neither impurity A, impurity B nor ornidazole isomers are detected in the ornidazole, and the purity of the prepared ornidazole can be as high as 100%.

[0071]

[0072] The following is further described in combination with specific examples. For the raw materials involved in the following specific examples, unless otherwise specified, they can all be obtained commercially; for the instruments used, unless otherwise specified, they can all be obtained commercially; for the processes involved, unless otherwise specified, they are all conventional selections of those skilled in the art.

[0073] The preparation process of ornidazole in the examples is summarized as follows:

[0074]

[0075] Example 1

[0076] Add 200 mL of water, 40.02 g of ornidazole epoxide, and 22.89 g of morpholine to a 500 mL reaction bottle and heat to 70 o C, stir for 3 h, and then cool to 20 o C, stir at this temperature for 2 h, filter and dry to obtain an orange-yellow solid, which is crude morpholinidazole I, 46.65 g in total, with HPLC purity of 99.7%, no morpholinidazole isomers detected, the proportion of epoxidized ornidazole was 0.16%, the proportion of impurity A was 0.14%, and impurity B was not detected.

[0077] Add 136 mL of water and 45.05 g of crude morpholinonitrile I to a 500 mL reaction flask and heat to 90 o C, stir for 2 h, and then cool to 20 o C, keep warm and stir for 2 h, filter and dry to obtain a dark yellow solid, i.e. crude morpholiniazole II, 38.25 g in total.

[0078] Add 150 mL of methanol and 30.01 g of crude morpholinonitrile II to a 250 mL reaction flask and heat to 70 o C, add 1.50 g of activated carbon, stir for 1 h, filter, and cool to 20 o C, keep warm and stir for 2h, filter and dry to obtain a light yellow solid, i.e. 25.81g of morpholinonitrile, with HPLC purity of 100.0%. The analysis results of the obtained morpholinonitrile are as follows: Figure 1 shown.

[0079] Example 2

[0080] Add 120 mL of water and 40.03 g of ornidazole epoxide to a 500 mL reaction bottle, start stirring, add 22.91 g of morpholine, and heat to 45 o C, keep stirring for 6 h, then cool to 20 o C, stir at this temperature for 1.5 h, filter and dry to obtain an orange-yellow solid, which is 46.06 g of crude morpholinidazole I, with an HPLC purity of 99.6%, no morpholinidazole isomers detected, the proportion of epoxidized ornidazole was 0.28%, the proportion of impurity A was 0.09%, and impurity B was not detected.

[0081] Add 225 mL of water and 45.01 g of crude morpholinonitrile I to a 500 mL reaction flask and heat to 80 o C, stir for 1 h, and cool to 0 o C, keep warm and stir for 1 h, filter and dry to obtain a dark yellow solid, which is 38.25 g of crude morpholiniazole II.

[0082] Add 150 mL of a mixed solvent (volume ratio of methanol to ethanol is 1:1) and 30.02 g of crude ornidazole II to a 250 mL reaction flask. Heat the mixture to 70 o °C, add 1.50 g of activated carbon, stir for 2 h while maintaining the temperature, filter, and then cool to 20 o °C. Stir for 2 h while maintaining the temperature, filter, and dry to obtain a pale yellow solid, which is 24.32 g of ornidazole with an HPLC purity of 100.0%.

[0083] The following investigation examples examine the effects of the recrystallization solvent and the number of recrystallization times on the removal of impurities and the quality of the prepared ornidazole, as follows:

[0084] Investigation Example 1

[0085] Add 200 mL of water and 40.03 g of epoxidized ornidazole to a 500 mL reaction flask. Start stirring, add 22.95 g of morpholine, heat to 60 °C, stir for 4 h while maintaining the temperature, cool to 20 °C, stir for 1 h while maintaining the temperature, filter, and dry to obtain an orange-yellow solid, which is 46.92 g of crude ornidazole I with an HPLC purity of 99.8%. The proportion of epoxidized ornidazole is 0.11%, the ornidazole isomer is not detected, the proportion of impurity A is 0.09%, and impurity B is not detected.

[0086] Add 180 mL of methanol and 45.06 g of crude ornidazole I (with impurities added to make the content of impurity A 0.39% and the content of impurity B 0.90%) to a 500 mL reaction flask. Heat to 60 °C, add 2.26 g of activated carbon, stir for 2 h while maintaining the temperature, cool to 20 °C, stir for 1.5 h while maintaining the temperature, filter, and dry to obtain a pale yellow solid, which is 38.03 g of ornidazole with an HPLC purity of 99.95%. Impurity A is not detected, and the proportion of impurity B is 0.05%.

[0087] Investigation Example 2

[0088] Add 200 mL of water and 40.00 g of epoxidized ornidazole to a 500 mL reaction flask. Start stirring, add 22.95 g of morpholine, heat to 60 °C, stir for 3 h while maintaining the temperature, cool to 20 °C, stir for 2 h while maintaining the temperature, filter, and dry to obtain an orange-yellow solid, which is 46.76 g of crude ornidazole I with an HPLC purity of 99.7%. The proportion of epoxidized ornidazole is 0.19%, the ornidazole isomer is not detected, the proportion of impurity A is 0.11%, and impurity B is not detected.

[0089] Add 180 mL of water and 45.01 g of crude ornidazole I (contaminated with impurities, with impurity A content of 0.37% and impurity B content of 0.92%) to a 500 mL reaction flask. Heat up to 95 °C, add 2.25 g of activated carbon, stir while maintaining the temperature for 1 h and then filter. Cool down to 20 °C, stir while maintaining the temperature for 1 h, filter, and dry to obtain a dark yellow solid, i.e., 38.41 g of ornidazole with an HPLC purity of 99.14%. Impurity A was not detected, and the proportion of impurity B was 0.86%.

[0090] It can be seen that when using the doped ornidazole sample as the raw material and selecting an alcohol solvent as the recrystallization solvent, due to the good decolorization ability and impurity removal ability of the alcohol solvent for the product, the contents of impurity A and impurity B in ornidazole are significantly reduced, especially impurity A can be completely removed; when using the doped ornidazole sample as the raw material and selecting water as the recrystallization solvent, impurity A can also be removed, but the ability to remove impurity B is significantly inferior to that of the alcohol solvent.

[0091] Comparative Example 1

[0092] The preparation method of Comparative Example 1 is basically the same as that of Example 1, except that: methanol is used to replace water as the reaction solvent in equal volume. Specifically:

[0093] Add 100 mL of methanol and 20.06 g of epoxy ornidazole to a 250 mL reaction flask, start stirring, add 11.43 g of morpholine, heat up to 45 o °C, stir while maintaining the temperature for 7 h, cool down to 20 o °C, stir while maintaining the temperature for 2 h, filter, and dry to obtain an orange-yellow solid, which is 21.78 g of crude ornidazole I with an HPLC purity of 99.4%. The ornidazole isomer was not detected, the proportion of epoxy ornidazole was 0.49%, the proportion of impurity A was 0.13%, and impurity B was not detected.

[0094] Add 140 mL of water and 20.05 g of crude ornidazole I to a 500 mL reaction flask, heat up to 100 o °C, stir while maintaining the temperature for 2 h, cool down to 10 o °C, stir while maintaining the temperature for 2 h, filter, and dry to obtain a dark yellow solid, which is 16.61 g of crude ornidazole II.

[0095] Add 105 mL of methanol and 15.07 g of crude ornidazole II to a 250 mL reaction flask, heat up to 50 o °C, add 1.50 g of activated carbon, stir while maintaining the temperature for 1 h, filter, cool down to 20 o °C, stir while maintaining the temperature for 1 h, filter, and dry to obtain a light yellow solid, which is 12.31 g of ornidazole with an HPLC purity of 100.0%.

[0096] Comparative Example 2

[0097] The preparation method of Comparative Example 2 was basically the same as that of Example 1, except that: acetonitrile was used to replace water as the reaction solvent in equal volume. Specifically:

[0098] Add 100 mL of acetonitrile and 20.06 g of epoxidized ornidazole to a 250 mL reaction flask, start stirring, add 11.45 g of morpholine, and heat up to 70 o °C, keep stirring at this temperature for 3 h, cool down to 20 o °C, keep stirring at this temperature for 1.2 h, filter, and dry to obtain an orange-yellow solid, which is 21.75 g of crude morpholine nitrazole I, with an HPLC purity of 97.3%. Morpholine nitrazole isomers were not detected, the proportion of epoxidized ornidazole was 2.02%, the proportion of impurity A was 0.24%, and impurity B was not detected.

[0099] Add 140 mL of water and 20.03 g of crude morpholine nitrazole I to a 500 mL reaction flask, heat up to 92 o °C, keep stirring at this temperature for 2 h, cool down to 10 o °C, keep stirring at this temperature for 2 h, filter, and dry to obtain a dark yellow solid, which is 16.61 g of crude morpholine nitrazole II.

[0100] Add 75 mL of methanol and 15.04 g of crude morpholine nitrazole II to a 250 mL reaction flask, heat up to 65 o °C, add 0.76 g of activated carbon, keep stirring at this temperature for 2 h, filter, cool down to 0 o °C, keep stirring at this temperature for 2 h, filter, and dry to obtain a pale yellow solid, which is 12.31 g of morpholine nitrazole, with an HPLC purity of 100.0%.

[0101] Comparative Example 3

[0102] The preparation method of Comparative Example 3 was basically the same as that of Example 1, except that: ethanol was used to replace water as the reaction solvent in equal volume. Specifically:

[0103] Add 200 mL of ethanol and 40.00 g of epoxidized ornidazole to a 500 mL reaction flask, add 22.91 g of morpholine, heat up to 70 o °C, keep stirring at this temperature for 3 h, cool down to 20 o °C, keep stirring at this temperature for 2 h, filter, and dry to obtain an orange-yellow solid, which is 46.01 g of crude morpholine nitrazole I, with an HPLC purity of 99.4%. Morpholine nitrazole isomers were not detected, the proportion of epoxidized ornidazole was 0.24%, the proportion of impurity A was 0.26%, and impurity B was not detected.

[0104] Add 136 mL of water and 45.00 g of crude ornidazole morpholine I into a 500 mL reaction flask, heat up to 80 o °C, keep warm and stir for 2 h, then cool down to 10 o °C, keep warm and stir for 2 h, filter, and dry to obtain a dark yellow solid, which is crude ornidazole morpholine II, with a total of 37.95 g.

[0105] Add 150 mL of methanol and 30.00 g of crude ornidazole morpholine II into a 250 mL reaction flask, heat up to 70 o °C, add 1.52 g of activated carbon, keep warm and stir for 1 h, filter, then cool down to 20 o °C, keep warm and stir for 2 h, filter, and dry to obtain a pale yellow solid, which is 24.81 g of ornidazole morpholine, with an HPLC purity of 100.0%.

[0106] From the experimental results of each example, it can be seen that in this application, epoxidized ornidazole and morpholine are used as raw materials to prepare ornidazole morpholine. By using water, which is safe, environmentally friendly and economical, as the solvent, the reaction has high reaction safety, excellent reactivity and regioselectivity without adding catalysts such as metal halides, acids, and bases. During the reaction process, the generation of ornidazole morpholine isomers and other impurities can be significantly reduced or even eliminated, the reaction rate can be accelerated, the reaction conversion rate can be increased, thereby improving the purity of ornidazole morpholine, further reducing the subsequent purification difficulty, and lowering the process cost. Further, in this application, an alcohol solvent with a low cost and strong volatility is used as the recrystallization solvent to refine the crude ornidazole morpholine, which can effectively improve the purity of ornidazole morpholine. At the same time, the purification step of the crude ornidazole morpholine is simplified to two-step recrystallization, avoiding relatively cumbersome operation steps.

[0107] In summary, this application effectively simplifies the production process of ornidazole morpholine. The developed process is safe, environmentally friendly, simple, efficient and stable, can significantly reduce the production cost of ornidazole morpholine, and meet the requirements of commercial production. Further, the ornidazole morpholine prepared by the present invention has high purity, stable quality and meets the pharmaceutical standards.

[0108] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of concise description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope recorded in this specification.

[0109] The above-described embodiments merely represent several implementation manners of the present invention. The description thereof is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all fall within the protection scope of the present invention. Therefore, the protection scope of the present invention patent shall be subject to the appended claims, and the specification and drawings can be used to explain the content of the claims.

Claims

1. A preparation method of morinidazole, characterized in that, it comprises the following steps: Epoxidized ornidazole, morpholine and water are mixed for reaction to prepare morinidazole.

2. The preparation method of morinidazole according to claim 1, characterized in that, stage temperature control is adopted during the reaction, and the stage temperature control includes: The first stage: heating to 30°C - 70°C and keeping warm and stirring for 3h - 7h; The second stage: cooling to 0°C - 20°C and keeping warm and stirring for 1h - 2h.

3. The preparation method of morinidazole according to claim 1, characterized in that, the molar ratio of epoxidized ornidazole to morpholine is 1:(1.0 - 2.0).

4. The preparation method of morinidazole according to claim 1, characterized in that, the volume of water is 3 - 7 times the mass of epoxidized ornidazole.

5. The preparation method of morinidazole according to any one of claims 1 - 4, characterized in that, after the reaction, a purification step is further included, and the purification step includes the first recrystallization and the second recrystallization.

6. The preparation method of morinidazole according to claim 5, characterized in that, the solvent used in the first recrystallization is water; the solvent used in the second recrystallization includes one or more of methanol, ethanol and isopropanol.

7. The preparation method of morinidazole according to claim 5 or 6, characterized in that, the steps of the first recrystallization include: filtering and drying the obtained reaction system to obtain crude morinidazole I, mixing the crude morinidazole I with water, heating the obtained mixture to 60°C - 100°C, and keeping warm and stirring for 1h - 2h; then cooling to 0°C - 20°C, keeping warm and stirring for 1h - 2h, filtering and drying to obtain crude morinidazole II.

8. The preparation method of morinidazole according to claim 7, characterized in that, in the first recrystallization, the volume of water is 3 - 7 times the mass of crude morinidazole I.

9. The preparation method of morinidazole according to claim 5 or 6, characterized in that, the steps of the second recrystallization include: mixing the crude morinidazole II with the solvent used in the second recrystallization, heating the obtained mixture to 50°C - 100°C, and keeping warm and stirring for 1h - 2h; then cooling to 0°C - 20°C, keeping warm and stirring for 1h - 2h, filtering and drying to obtain morinidazole.

10. The preparation method of morinidazole according to claim 9, characterized in that, in the second recrystallization, the volume of the solvent used in the second recrystallization is 3 - 7 times the mass of crude morinidazole II.

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