A method for synthesizing morinidazole

Abstract

The present invention relates to the technical field of pharmaceutical synthesis, and specifically discloses a method for synthesizing morinidazole. First, the present invention performs a substitution reaction between morpholine and epichlorohydrin to obtain the intermediate 4-(2,3-epoxypropyl)morpholine; then, 4-(2,3-epoxypropyl)morpholine is subjected to a condensation reaction with 2-methyl-5-nitroimidazole to obtain a material system containing morinidazole; and then, through salification and liberation, morinidazole is obtained. Using morpholine, epichlorohydrin, and 2-methyl-5-nitroimidazole as raw materials, the raw materials are all bulk chemicals, the product quality is stable, and the price is low. The synthesis method of the present invention has a simple operation process, relatively mild reaction conditions, and low preparation cost. The purity of the prepared morinidazole can reach more than 99.9%, and the total yield can reach more than 73%, which is suitable for large-scale industrial production and has good industrial prospects and social benefits.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a method for synthesizing morinidazole. Background Art

[0002] Morinidazole, with the chemical name of 1-[3-(4-morpholinyl)-2-hydroxypropyl]-2-methyl-5-nitro-1H-imidazole, has the molecular formula of C 11 H 18 N4O4, and its structural formula is shown as Formula I. As a third-generation nitroimidazole derivative, morinidazole is used to treat anaerobic infectious diseases such as pelvic inflammatory disease and appendicitis. Compared with the previous generations of nitroimidazole drugs, morinidazole has strong anti-anaerobic activity, rapid onset, good tolerance, and high safety. Its antibacterial activity against Bacteroides fragilis, Veillonella, and Clostridium perfringens is equivalent to that of ornidazole, and is 2-8 times stronger than that of metronidazole and tinidazole; its antibacterial activity against Bacteroides distasonis and Bacteroides ovatus is equivalent to that of ornidazole, and is 2-4 times stronger than that of metronidazole and tinidazole.

[0003]

[0004] Currently, the preparation method of morinidazole uses 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole as the raw material, and obtains it through ring-opening, salting, free, and recrystallization with morpholine. Its specific reaction route is shown as Formula 1. However, this synthesis method requires the use of halide as a catalyst for ring-opening, the reaction is relatively violent and dangerous, the raw material price is relatively expensive, and it is not suitable for industrial production. In addition, the prior art also reports that using ornidazole as the raw material, 1-(2,3-epoxypropyl)-2-methyl-5-nitroimidazole is first prepared under alkaline conditions, and then morinidazole is obtained through ring-opening and recrystallization with morpholine. Its specific reaction route is shown as Formula 2. However, the inventor repeated the above reaction route of morinidazole and found that the total yield of the prepared morinidazole was about 69%, and the purity was poor, only about 98.5%, which could not meet the requirements of the raw drug. At the same time, the price of its raw materials was relatively expensive, the product cost was high, and it was also not suitable for industrial production.

[0005]

[0006] In view of the good market prospect of morinidazole, there are many by-products under the existing synthesis reaction conditions, resulting in low yield, poor quality of morinidazole, high production cost, and certain danger. At present, there is an urgent need to develop a synthetic process route that is green and environmentally friendly, low in cost, stable in product quality, and suitable for industrial production. Summary of the Invention

[0007] In view of the above problems, the present invention provides a method for synthesizing morinidazole, which has mild reaction conditions, significantly improves the yield and purity of morinidazole, has low production costs, a short route, and is suitable for industrial production.

[0008] To solve the above technical problems, the present invention adopts the following technical solutions:

[0009] A method for synthesizing morinidazole, comprising the following steps:

[0010] S1, adding morpholine and epichlorohydrin to a first solvent, mixing evenly, and carrying out a substitution reaction at -10 to 15 °C to obtain 4-(2,3-epoxypropyl)morpholine;

[0011] S2, adding the 4-(2,3-epoxypropyl)morpholine and 2-methyl-5-nitroimidazole to a second solvent and carrying out a condensation reaction; after the reaction ends, adjusting the pH value of the reaction system to strongly acidic, and performing solid-liquid separation to obtain the morinidazole salt;

[0012] S3, adding the morinidazole salt to water, adjusting the pH value of the system to weakly basic, and performing solid-liquid separation to obtain morinidazole.

[0013] The reaction formula for synthesizing morinidazole is as shown in Formula 3.

[0014]

[0015] Compared with the prior art, the method for synthesizing morinidazole provided by the present invention first undergoes a substitution reaction between morpholine and epichlorohydrin to obtain the intermediate 4-(2,3-epoxypropyl)morpholine; then, 4-(2,3-epoxypropyl)morpholine and 2-methyl-5-nitroimidazole are subjected to a condensation reaction to obtain a material system containing morinidazole; and finally, morinidazole is obtained through salification and liberation. The present invention uses morpholine, epichlorohydrin, and 2-methyl-5-nitroimidazole as raw materials, which are all bulk chemicals, with stable product quality and low prices. The synthesis method of the present invention has a simple operation process, mild reaction conditions, and low preparation costs.

[0016] The inventors found through a large number of experiments that if the temperature of the substitution reaction exceeds the above range, a large number of side reactions will occur, which will adversely affect the yield and purity of the final product morinidazole. The results of the examples show that the method for synthesizing morinidazole provided by the present invention has a purity of more than 99.9%, the single impurity is less than 0.1%, and the total impurity is less than 0.1%; the total product yield reaches more than 73%, is suitable for large-scale industrial production, and has good industrial prospects and social benefits.

[0017] Preferably, in step S1, the molar ratio of the morpholine to the epichlorohydrin is 1:(1 to 1.5).

[0018] Preferably, in step S1, the first solvent is at least one of water, chloroform, acetone, tetrahydrofuran, ether, ethyl acetate, or dichloromethane.

[0019] Preferably, in step S1, the mass ratio of morpholine to the first solvent is 1:(0.1 - 10), more preferably 1:(0.5 - 5), and even more preferably 1:(0.8 - 1).

[0020] In the present invention, both morpholine and epichlorohydrin are in liquid state and can react without a solvent. However, through a large number of experiments, the inventor found that morpholine, epichlorohydrin, and the first solvent can be miscible. Under the condition of using the first solvent as a medium, the substitution reaction between morpholine and epichlorohydrin proceeds more thoroughly and fully, and the yield and purity of 4-(2,3-epoxypropyl)morpholine are higher.

[0021] Preferably, in step S1, the temperature of the substitution reaction is 0 - 5°C, and the reaction time is 3 - 10 h.

[0022] More preferably, in step S1, after the substitution reaction, it further includes a post-treatment step:

[0023] When the first solvent is water, the post-treatment includes extraction, washing, and concentration;

[0024] When the first solvent is chloroform, the post-treatment includes phase separation, washing, and concentration;

[0025] When the first solvent is acetone, tetrahydrofuran, ether, ethyl acetate, or dichloromethane, the post-treatment includes concentration, extraction, washing, and concentration.

[0026] In step S1 of the present invention, when the first solvent is water, after the substitution reaction, the reaction system does not separate into layers. An extraction solvent needs to be used to extract the reaction system, separate the phases, wash the acid and impurities in the organic phase, and then concentrate to remove the extraction solvent to obtain 4-(2,3-epoxypropyl)morpholine; when the first solvent is chloroform, after the substitution reaction, the reaction system can be separated into layers after standing, and the acid and impurities in the organic phase can be directly washed, and then the first solvent (chloroform) is concentrated to obtain 4-(2,3-epoxypropyl)morpholine; when the first solvent (acetone, tetrahydrofuran, ether, ethyl acetate, or dichloromethane) is dissolved in water, after the substitution reaction, the reaction system does not separate into layers. The first solvent needs to be concentrated and removed first, and then an extraction solvent is used to extract the concentrated system, separate the phases, wash the acid and impurities in the organic phase, and then concentrate again to remove the extraction solvent to obtain 4-(2,3-epoxypropyl)morpholine.

[0027] More preferably, in step S1, the extraction solvent used for extraction is at least one of dichloromethane, ethyl acetate, dichloroethane, ethyl formate, methyl formate or chloroform.

[0028] More preferably, in step S1, the ratio of the total mass of the morpholine and the epichlorohydrin to the volume of the extraction solvent is 1 g:(0.5 - 1.5) mL.

[0029] More preferably, in step S1, the number of extraction times is 1 - 2 times.

[0030] More preferably, in step S1, the organic phase is washed successively with an alkaline solution and saturated brine.

[0031] In the present invention, the acidic substances in the organic phase can be washed out by the alkaline solution, and the remaining alkali in the organic phase can be washed out by the saturated brine.

[0032] More preferably, in step S1, the alkaline solution is a 1 - 10 mol / L sodium hydroxide solution, potassium hydroxide solution or lithium hydroxide solution.

[0033] Exemplarily, in step S1, after washing with the alkaline solution, it is left to stand for phase separation first, and then the organic phase is washed with saturated brine.

[0034] Exemplarily, in step S1, after washing, it further includes: drying the washed organic phase with anhydrous sodium sulfate, filtering out the anhydrous sodium sulfate, concentrating the obtained filtrate to obtain 4-(2,3-epoxypropyl)morpholine.

[0035] In the present invention, the purification and separation operation of 4-(2,3-epoxypropyl)morpholine is simple and easy to perform, the yield can reach more than 90%, and the purity can reach more than 96%. In addition, the selection of the first solvent and the extraction solvent used in the present invention is relatively single, can be recycled and reused, reduce the generation of waste liquid, and reduce the environmental burden.

[0036] Preferably, in step S2, the molar ratio of the 4-(2,3-epoxypropyl)morpholine to the 2-methyl-5-nitroimidazole is (1 - 1.5):1.

[0037] Preferably, in step S2, the second solvent is at least one of isopropanol, ethanol, tert-butanol, n-butanol or methyl ethyl ketone.

[0038] Preferably, in step S2, the ratio of the total mass of the 4-(2,3-epoxypropyl)morpholine and the 2-methyl-5-nitroimidazole to the volume of the second solvent is 1 g:(3 - 18) mL, and more preferably 1 g:

[0039] (5 - 10) mL.

[0040] The selection of the second solvent used in the present invention is relatively single, which can be recycled and reused, reducing the generation of waste liquid and alleviating the environmental burden.

[0041] Preferably, in step S2, the condensation reaction is carried out in a reflux manner, and the reaction time is 6 to 20 h, more preferably 8 to 15 h.

[0042] Preferably, in step S2, an inorganic acid is used to adjust the pH value of the reaction system, and the inorganic acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid or nitric acid.

[0043] Preferably, in step S2, the strong acidity means that pH = 1 to 3.

[0044] The present invention does not limit the concentration of the inorganic acid. In order to reduce the added volume of the inorganic acid, a high-concentration inorganic acid can be selected.

[0045] The present invention does not require the added amount of water in step S3, and it is only necessary to dissolve clearly. The inventor found through a large number of experiments that, under the same conditions, compared with other solvent types, using water as the solvent of morpholinonidazole salt has a better separation effect on morpholinonidazole.

[0046] Preferably, in step S3, at least one of sodium hydroxide solution, potassium hydroxide solution, lithium hydroxide solution, sodium carbonate solution, potassium carbonate solution or ammonia water is used to adjust the pH value of the system.

[0047] Preferably, in step S3, the weak alkalinity means that pH = 8 to 9.

[0048] Exemplarily, after solid-liquid separation in step S3, it further includes: washing the obtained solid with water and drying. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 It is the HPLC detection chart of 4-(2,3-epoxypropyl)morpholine obtained in Example 1 of the present invention;

[0050] Figure 2 It is the HPLC detection chart of morpholinonidazole obtained in Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0051] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0052] In order to better illustrate the present invention, further illustrative examples are given below through embodiments.

[0053] Example 1

[0054] This embodiment provides a method for synthesizing morinidazole, which comprises the following steps:

[0055] S1, Add 261 g (3.0 mol) of morpholine to 250 g of water, slowly add 300.5 g (3.2 mol) of epichlorohydrin at 2 °C, and carry out a substitution reaction for 4 h; after the reaction is completed, extract the reaction system with 300 mL×2 (indicating 2 extractions, with a dosage of 300 mL each time) of dichloromethane, separate the phases, and combine the organic phases; add 830 mL of 4 mol / L NaOH solution to the organic phase for washing, let it stand to separate the phases, and then wash the organic phase with saturated brine, with a dosage of 300 mL each time, until it is neutral; dry the washed organic phase with 30 g of anhydrous sodium sulfate, filter, and concentrate the obtained filtrate (remove dichloromethane) to obtain 403.2 g (2.8 mol) of 4-(2,3-epoxypropyl)morpholine, with a yield of 94.0% and an HPLC purity of 99.8% (see Figure 1 ).

[0056] S2, Take the above 4-(2,3-epoxypropyl)morpholine and 355.2 g (2.8 mol) of 2-methyl-5-nitroimidazole and add them to 5 L of isopropanol, heat up to reflux, and carry out a condensation reaction for 10 h; then cool to room temperature, add concentrated hydrochloric acid dropwise to the reaction system to adjust the pH of the system to 2, filter, and obtain morinidazole hydrochloride.

[0057] S3, Add the above morinidazole hydrochloride to 5 L of water to dissolve it clearly, adjust the pH of the system to 8.5 with ammonia water, filter, wash the obtained solid with water, and dry it to obtain 653.4 g (2.4 mol) of morinidazole, with a yield of 85.8% and an HPLC purity of 100% (see Figure 2 ). After calculation, the total yield is 80.7%.

[0058] Example 2

[0059] This embodiment provides a method for synthesizing morinidazole, which comprises the following steps:

[0060] S1, add 261g (3.0mol) of morpholine to 130g of chloroform, slowly add 278g (3.0mol) of epichlorohydrin at -10°C, and carry out substitution reaction for 3h; after the reaction, stand for phase separation, add 1000mL of 1mol / L KOH solution to the organic phase for washing, stand for phase separation, and then wash the organic phase with saturated brine, each time using 300mL, until neutral; dry the washed organic phase with 30g of anhydrous sodium sulfate, filter, and concentrate the filtrate (to remove chloroform) to obtain 386.8g (2.7mol) of 4-(2,3-epoxypropyl)morpholine, with a yield of 90.2% and an HPLC purity of 96.2%.

[0061] S2, take the above 4-(2,3-epoxypropyl)morpholine and 312.2g (2.5mol) of 2-methyl-5-nitroimidazole, add them into 3.5L of ethanol, raise the temperature to reflux, and carry out condensation reaction for 6.5h; then cool to room temperature, add concentrated sulfuric acid dropwise to the reaction system, adjust the pH of the system to 1, filter, and obtain morpholine nitroazole hydrochloride.

[0062] S3, add the above morpholiniazole hydrochloride to 5L water, dissolve it, adjust the pH of the system to 8 with KOH solution, filter, wash the obtained solid with water, and dry it to obtain 593.7g (2.2mol) morpholiniazole, the yield is 81.3%, and the HPLC purity is 99.96%. After calculation, the total yield is 73.3%.

[0063] Example 3

[0064] This embodiment provides a method for synthesizing morpholiniazole, comprising the following steps:

[0065] S1, add 261g (3.0mol) of morpholine to 180g of acetone, slowly add 333g (3.6mol) of epichlorohydrin at 0℃, and carry out substitution reaction for 4h; after the reaction, concentrate to remove acetone, extract the concentrated system with 300mL×2 dichloroethane, separate the phases, and combine the organic phases; add 800mL of 6mol / L LiOH solution to the organic phase for washing, let stand for phase separation, and then wash the organic phase with saturated brine, each time using 300mL, until neutral; dry the washed organic phase with 30g of anhydrous sodium sulfate, filter, and concentrate the filtrate (to remove dichloroethane) to obtain 409.1g (2.9mol) of 4-(2,3-epoxypropyl)morpholine, with a yield of 95.4% and a HPLC purity of 99.3%.

[0066] S2. Take the above-mentioned 4-(2,3-epoxypropyl)morpholine and 202.6 g (2.4 mol) of 2-methyl-5-nitroimidazole and add them to 5.5 L of tert-butanol. Heat up to reflux and carry out the condensation reaction for 10 h. Then cool down to room temperature, add concentrated phosphoric acid dropwise to the reaction system to adjust the pH of the system to 1.5, filter to obtain morinidazole hydrochloride.

[0067] S3. Add the above-mentioned morinidazole hydrochloride to 5 L of water to dissolve it clearly. Use LiOH solution to adjust the pH of the system to 8.5, filter, wash the obtained solid with water, and dry it to obtain 666.5 g (2.5 mol) of morinidazole, with a yield of 86.3% and an HPLC purity of 100%. After calculation, the total yield is 82.3%.

[0068] Example 4

[0069] This example provides a method for synthesizing morinidazole, which includes the following steps:

[0070] S1. Add 261 g (3.0 mol) of morpholine to 400 g of tetrahydrofuran, slowly add 360 g (3.9 mol) of epichlorohydrin at 5°C, and carry out the substitution reaction for 6 h. After the reaction is completed, concentrate to remove tetrahydrofuran, extract the concentrated system with 300 mL × 2 of methyl formate, separate the phases, and combine the organic phases. Add 500 mL of 10 mol / L NaOH solution to the organic phase for washing, let it stand to separate the phases, and then wash the organic phase with saturated brine, with each amount being 300 mL, until it is washed to neutral. Dry the washed organic phase with 30 g of anhydrous sodium sulfate, filter, and concentrate the obtained filtrate (remove methyl formate) to obtain 402.4 g (2.8 mol) of 4-(2,3-epoxypropyl)morpholine, with a yield of 93.8% and an HPLC purity of 98.7%.

[0071] S2. Take the above-mentioned 4-(2,3-epoxypropyl)morpholine and 264.6 g (2.1 mol) of 2-methyl-5-nitroimidazole and add them to 6.5 L of n-butanol. Heat up to reflux and carry out the condensation reaction for 15 h. Then cool down to room temperature, add perchloric acid dropwise to the reaction system to adjust the pH of the system to 2.5, filter to obtain morinidazole hydrochloride.

[0072] S3. Add the above-mentioned morinidazole hydrochloride to 5 L of water to dissolve it clearly. Use NaOH solution to adjust the pH of the system to 9, filter, wash the obtained solid with water, and dry it to obtain 644.9 g (2.4 mol) of morinidazole, with a yield of 84.9% and an HPLC purity of 100%. After calculation, the total yield is 79.6%.

[0073] Example 5

[0074] This embodiment provides a method for synthesizing morinidazole, which includes the following steps:

[0075] S1. Add 261 g (3.0 mol) of morpholine to 500 g of diethyl ether, and slowly add 415 g (4.5 mol) of epichlorohydrin at 14 °C, and carry out a substitution reaction for 10 h; after the reaction is completed, concentrate to remove diethyl ether, and extract the concentrated system with 300 mL×2 of chloroform, separate the phases, and combine the organic phases; add 830 mL of 4 mol / L KOH solution to the organic phase for washing, let it stand to separate the phases, and then wash the organic phase with saturated brine, with a dosage of 300 mL each time, until it is neutral; dry the washed organic phase with 30 g of anhydrous sodium sulfate, filter, and concentrate the obtained filtrate (remove chloroform) to obtain 397.7 g (2.8 mol) of 4-(2,3-epoxypropyl)morpholine, with a yield of 92.7% and an HPLC purity of 98.8%.

[0076] S2. Take the above 4-(2,3-epoxypropyl)morpholine and 238.5 g (1.9 mol) of 2-methyl-5-nitroimidazole and add them to 5 L of methyl ethyl ketone, heat up to reflux, and carry out a condensation reaction for 18 h; then cool to room temperature, add concentrated nitric acid dropwise to the reaction system, adjust the pH of the system to 3, filter, and obtain morinidazole hydrochloride.

[0077] S3. Add the above morinidazole hydrochloride to 5 L of water to dissolve it clearly, adjust the pH of the system to 8.5 with Na2CO3 solution, filter, wash the obtained solid with water, and dry it to obtain 625.4 g (2.3 mol) of morinidazole, with a yield of 83.3% and an HPLC purity of 99.98%. After calculation, the total yield is 77.2%.

[0078] Comparative Example 1

[0079] This comparative example provides a method for synthesizing 4-(2,3-epoxypropyl)morpholine, which is similar to Example 1, except that: no water is added in the substitution reaction in step S1, and the remaining operations are the same as those in Example 1. The specific steps are as follows:

[0080] Add 261 g (3.0 mol) of morpholine to a 2 L reaction flask, slowly add 300.5 g (3.2 mol) of epichlorohydrin at 2 °C, and carry out a substitution reaction for 4 h; after the reaction is completed, add 600 mL of dichloromethane, add 830 mL of 4 mol / L NaOH solution to the reaction solution for washing, let it stand for phase separation, and then wash the organic phase with saturated brine, with a dosage of 300 mL each time, until it is washed to neutral; dry the washed organic phase with 30 g of anhydrous sodium sulfate, filter, concentrate the obtained filtrate, and obtain 281.1 g (2.0 mol) of 4-(2,3-epoxypropyl)morpholine, with a yield of 65.5% and an HPLC purity of 87.5%.

[0081] Comparative Example 2

[0082] This comparative example provides a method for synthesizing 4-(2,3-epoxypropyl)morpholine, which is similar to Example 1, except that: the temperature of the substitution reaction in step S1 is 20 °C, and the remaining operations are the same as those in Example 1 and will not be elaborated. Finally, 315.3 g (2.2 mol) of 4-(2,3-epoxypropyl)morpholine is obtained, with a yield of 73.5% and an HPLC purity of 89.3%.

[0083] Comparative Example 3

[0084] This comparative example provides a method for synthesizing 4-(2,3-epoxypropyl)morpholine, which is similar to Example 1, except that: the temperature of the substitution reaction in step S1 is -15 °C, and the remaining operations are the same as those in Example 1 and will not be elaborated. Finally, 163.5 g (1.1 mol) of 4-(2,3-epoxypropyl)morpholine is obtained, with a yield of 38.1% and an HPLC purity of 58.9%.

[0085] Comparative Example 4

[0086] This comparative example provides a method for synthesizing morinidazole, which is similar to Example 1, except that: in step S3, water is replaced with ethanol of the same mass, and the remaining operations are the same as those in Example 1, specifically including the following steps:

[0087] S1, the same as Example 1 and will not be elaborated, to obtain 405.3 g (2.8 mol) of 4-(2,3-epoxypropyl)morpholine, with a yield of 94.5% and an HPLC purity of 99.7%.

[0088] S2, the same as Example 1 and will not be elaborated.

[0089] S3. Add the above-mentioned morinidazole hydrochloride into 5 L of ethanol, stir evenly, adjust the pH of the system to 8.5 with ammonia water, filter, wash the obtained solid with water, and dry it to obtain 482.3 g (1.8 mol) of morinidazole with a yield of 63.0% and an HPLC purity of 98.7%. After calculation, the total yield is 59.6%.

[0090] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, or improvements made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A synthesis method of morinidazole, characterized in that, It includes the following steps: S1. Add morpholine and epichlorohydrin to the first solvent, mix evenly, and carry out a substitution reaction at -10 to 15 °C to obtain 4-(2,3-epoxypropyl)morpholine; S2. Add the obtained 4-(2,3-epoxypropyl)morpholine and 2-methyl-5-nitroimidazole to the second solvent to carry out a condensation reaction; after the reaction ends, adjust the pH value of the reaction system to strong acidity, carry out solid-liquid separation to obtain morpholine nitrozole salt; S3. Add the obtained morpholine nitrozole salt to water, adjust the pH value of the system to weak alkalinity, carry out solid-liquid separation to obtain morpholine nitrozole.

2. The synthesis method of morinidazole according to claim 1, characterized in that, In step S1, the molar ratio of the morpholine to the epichlorohydrin is 1:(1 - 1.5); In step S2, the molar ratio of the 4-(2,3-epoxypropyl)morpholine to the 2-methyl-5-nitroimidazole is (1 - 1.5):

1.

3. The synthesis method of morinidazole according to claim 1, characterized in that, In step S1, the temperature of the substitution reaction is 0 to 5 °C, and the reaction time is 3 to 10 h; In step S2, the condensation reaction is carried out in a reflux manner, and the reaction time is 6 to 20 h.

4. The synthesis method of morinidazole according to claim 1, characterized in that, In step S1, the first solvent is at least one of water, chloroform, acetone, tetrahydrofuran, ether, ethyl acetate or dichloromethane; the mass ratio of the morpholine to the first solvent is 1:(0.1 - 10).

5. The synthesis method of morinidazole according to claim 4, characterized in that, In step S1, after the substitution reaction ends, it further includes a post-treatment step: When the first solvent is water, the post-treatment includes extraction, washing and concentration; When the first solvent is acetone, tetrahydrofuran, ether, ethyl acetate or dichloromethane, the post-treatment includes concentration, extraction, washing and concentration; The extraction solvent used for the extraction is at least one of dichloromethane, ethyl acetate, dichloroethane, ethyl formate, methyl formate or chloroform.

6. The synthesis method of morinidazole according to claim 5, characterized in that, In step S1, the volume ratio of the total mass of the morpholine and the epichlorohydrin to the extraction solvent is 1 g:(0.5 - 1.5) mL.

7. The synthesis method of morinidazole according to claim 5, characterized in that, In step S1, the organic phase is washed successively with an alkaline solution and saturated brine; The alkaline solution is a 1 - 10 mol / L sodium hydroxide solution, potassium hydroxide solution or lithium hydroxide solution.

8. The synthesis method of morinidazole according to claim 1, characterized in that, In step S2, the second solvent is at least one of isopropanol, ethanol, tert-butanol, n-butanol or methyl ethyl ketone.

9. The synthesis method of morinidazole according to claim 1 or 8, characterized in that, In step S2, the volume ratio of the total mass of the 4-(2,3-epoxypropyl)morpholine and the 2-methyl-5-nitroimidazole to the second solvent is 1 g:(3 - 18) mL.

10. The synthesis method of morinidazole according to claim 1, characterized in that, In step S2, the strong acidity means pH = 1 - 3; In step S3, the weak alkalinity means pH = 8 - 9.

Images