Preparation method of morniflufen-ethyl

Abstract

The invention belongs to the technical field of anti-inflammatory and analgesic drugs, and discloses a preparation method of morniflufen, which comprises the following steps: adding purified water and a cosolvent into chloroethyl morpholine hydrochloride, and fully dissolving to obtain a first mixture; adding an acid-binding agent and fluniic acid into the first mixture to obtain a second mixture; heating the second mixture at 50-100 DEG C to react for 4-8 hours, and removing impurities to obtain a third mixture; cooling the third mixture to 25-35 DEG C, and slowly adding purified water to obtain a fourth mixture; and cooling and crystallizing the fourth mixture, and drying to obtain the morniflufen. According to the present invention, the water-soluble chloroethyl morpholine hydrochloride is adopted to replace hydroxyethyl morpholine to synthesize the moraniflurane, and the alcohol solvent is adopted to replace the solvent acetone so as to easily crystallize, such that the high-quality and high-yield moraniflurane with the impurities conforming to the safety standard can be produced at the low cost under the mild reaction condition.

Description

Technical Field

[0001] The present invention relates to the technical field of production of anti-inflammatory and analgesic drugs, in particular to a method for preparing morphiflumate. Background Art

[0002] Morniflumate, a nonsteroidal anti-inflammatory drug, has a well-established anti-inflammatory effect and is widely used in the treatment and research of inflammatory diseases. It can be used to relieve the joint pain and inflammation of osteoarthritis, the pain of musculoskeletal diseases, and soft tissue inflammation such as bursitis and tenosynovitis. Currently, the synthesis of morniflumate primarily uses hydroxyethylmorpholine and flunilic acid as raw materials, with alkali metal carbonates as acid binders, in acetone solvent at a reaction temperature of approximately 60°C. However, this method has numerous drawbacks: the product yield is low, typically only around 80%; the content of morpholine genotoxic impurities in the product is as high as several hundred parts per million (PPM), far from meeting the export drug (ICHQ7M) requirement of less than 1 PPM; crystallization is difficult, resulting in a sticky finished product; and high solvent consumption leads to high synthesis costs. Summary of the Invention

[0003] The object of the present invention is to provide a method for preparing morphiflumate, which can produce high-quality, high-yield morphiflumate with impurities that meet safety standards at a low cost and under mild reaction conditions.

[0004] A method for preparing morphiflumate, comprising:

[0005] S1, adding purified water and a cosolvent to chloroethylmorpholine hydrochloride to fully dissolve to obtain a first mixture;

[0006] S2, adding an acid binding agent and flunic acid to the first mixture to obtain a second mixture;

[0007] S3, heating the second mixture at 50° C. to 100° C. for 4 to 8 hours to obtain a third mixture after removing impurities;

[0008] S4, cooling the third mixture to 25° C. to 35° C., adding purified water to obtain a fourth mixture;

[0009] S5, cooling the fourth mixture for crystallization, and drying to obtain the morphiflumate.

[0010] Preferably, the molar ratio of chloroethylmorpholine hydrochloride:flunilic acid:cosolvent and acid binding agent is 1:1-3:3-6:0.5-1.5.

[0011] Preferably, in S3, the impurity removal includes refining, decolorization and filtration.

[0012] Preferably, in S3, the molar ratio of chloroethylmorpholine hydrochloride to purified water is 1:0.2-0.4.

[0013] Preferably, in S5, the temperature of the cooling crystallization of the fourth mixture is 0°C to 10°C.

[0014] Preferably, the drying process of the fourth mixture is:

[0015] 5.1, under nitrogen protection, filter the fourth mixture at high speed to separate the solid and liquid;

[0016] 5.2. Wash the solid separated in 5.1 with purified water and spin dry to obtain wet product of morphiflunomide;

[0017] 5.3, heating and drying the wet product of morphiflumate;

[0018] 5.4. Control the loss on drying of morphiflunomide to ≤ 0.1%, and cool the mixture until the temperature drops below 30° C. to obtain a dry morphiflunomide product.

[0019] Preferably, the cosolvent is an alcohol cosolvent;

[0020] The alcohol cosolvent is selected from any one or more of isopropanol, ethanol, and methanol.

[0021] Preferably, the acid binding agent is an alkali metal carbonate;

[0022] The alkali metal carbonate is selected from any one or more of potassium carbonate, sodium carbonate, magnesium carbonate and calcium carbonate.

[0023] Compared with the prior art, the present invention has the following advantages:

[0024] The present invention adopts chloroethylmorpholine hydrochloride as raw material, utilizes the characteristic that it is very soluble in water, dissolves it in purified water, makes the reaction more fully proceed, then adds alkali metal carbonate (such as sodium carbonate / potassium), neutralizes the hydrochloric acid in chloroethylmorpholine hydrochloride, then quickly adds flunilic acid, makes the chloroethyl in chloroethylmorpholine hydrochloride and flunilic acid undergo substitution reaction, and generates morphifluanid; and before crystallization, adds purified water so that residual morpholine impurities cannot be precipitated, makes the morpholine content of genotoxin impurities in the final product controlled below 1PPM, improves the quality of the product, and meets the requirements of drug index. The present invention replaces acetone solvent with alcohol solvent with relatively high boiling point, has smaller recovery loss, thereby reducing the cost of synthesis, and has high product crystallization rate and improved yield. That is, the present application uses chloroethylmorpholine hydrochloride that is very soluble in water to replace hydroxyethylmorpholine, has low synthesis cost and low reaction temperature; uses alcohol solvent to replace solvent acetone for easy crystallization, and produces morphifluanid with high quality, high yield and impurities meeting safety standards at low cost and mild reaction conditions.

[0025] In this application, the use of highly water-soluble chloroethylmorpholine hydrochloride allows for a more complete reaction, increasing the product yield by approximately 10%. Alcoholic cosolvents increase the solubility of the raw materials, improving the mass transfer efficiency of the reaction system and enabling a more uniform and efficient reaction. Alkali metal carbonates, an acid-binding agent, neutralize the hydrochloric acid generated, maintaining the pH of the reaction system and promoting the reaction toward product formation. The molar ratio of chloroethylmorpholine hydrochloride: flunilic acid: cosolvent to acid-binding agent is 1:1-3:3-6:0.5-1.5. The water-soluble cosolvent is 0.1-0.3 times the weight of the chloroethylmorpholine hydrochloride, and the alcoholic cosolvent is 3-6 times the weight of the alcohol. Excess alcohol is used as the solvent, achieving dissolution and filtration, and facilitates crystallization after decolorization. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a schematic diagram of the reaction flow of a method for preparing morphiflumate according to the present application;

[0027] Figure 2 This is a structural diagram of a morphiflumate product prepared using a method for preparing morphiflumate of the present application;

[0028] Figure 3 is the mass spectrum of standard morphiflumate;

[0029] Figure 4 The mass spectrum of the morphiflumate product prepared by the preparation method of morphiflumate of the present application is shown in FIG.

[0030] Figure 5 is the infrared spectrum of standard morphiflumate;

[0031] Figure 6 This is an infrared spectrum of a morphiflumate product prepared by a method for preparing morphiflumate of the present application;

[0032] Figure 7 This is the standard morphiflumate H NMR spectrum;

[0033] Figure 8 The following is a hydrogen nuclear magnetic spectrum of a morphiflumate product prepared by a method for preparing morphiflumate of the present application. DETAILED DESCRIPTION

[0034] A preparation process of morphiflumate is specifically as follows:

[0035] S1, adding purified water and a cosolvent to chloroethylmorpholine hydrochloride, stirring and dissolving the mixture to obtain a uniform first mixture.

[0036] S2, after the first mixture is completely dissolved, an acid binding agent is added to the first mixture, and flunic acid is quickly added and stirred to obtain a second mixture.

[0037] S3, heating the second mixture to 50° C. to 100° C. and reacting for 4 to 8 hours to allow the reaction to proceed fully. After the reaction is completed, performing purification, decolorization, filtration and other impurity removal operations in sequence to obtain a third mixture.

[0038] S4, cooling the third mixture to 25° C. to 35° C., slowly adding purified water, and stirring uniformly to obtain a fourth mixture.

[0039] S5, cooling the fourth mixture to 0°C to 10°C for crystallization, and then treating it according to a specific drying process to finally obtain the morphiflumate product.

[0040] It should be noted that:

[0041] In the present application, in S1, purified water and chloroethylmorpholine hydrochloride are pressed into a reaction tank under pressure and stirred and dissolved, wherein the pressure is 0.1 MPa to 0.5 MPa;

[0042] In S1, purified water is used as a polar solvent to dissolve chloroethylmorpholine hydrochloride (possibly a water-soluble salt) and ensure its complete dissociation into an active form; an alcohol solvent is introduced as a cosolvent or reaction medium to adjust the polarity of the system, promote the mixing and dissolution of subsequent non-polar reactants (such as fluonic acid), and may also reduce the polarity of water to reduce side reactions (such as hydrolysis).

[0043] In S2, an alkali metal carbonate (such as sodium carbonate / potassium carbonate) is added to neutralize the hydrochloric acid (HCl) in chloroethylmorpholine hydrochloride to generate sodium chloride, potassium chloride and carbon dioxide, thereby adjusting the system to a weakly alkaline environment and promoting the subsequent nucleophilic substitution reaction. Flunic acid is added all at once to avoid local overacidity or side reactions (such as decomposition of chloroethylmorpholine). The fluoride ion (or fluorine-containing group) in flunic acid acts as a nucleophilic reagent and attacks the chlorine atom of chloroethylmorpholine under alkaline conditions, causing a substitution reaction to generate the target product morpholine ester. Subsequently, heating to increase the reaction temperature can accelerate the reaction kinetics, shorten the reaction time, and may also promote the nucleophilicity of the fluoride ion.

[0044] In S3, unreacted raw materials, by-products and colored impurities (such as tar-like substances) are removed through a refining process to improve the purity of the product; decolorization is performed, such as by using activated carbon to adsorb pigment impurities, to improve the appearance of the product (such as avoiding yellow or brown); insoluble impurities (such as unreacted salts, activated carbon, etc.) are removed by filtration to obtain a clarified third mixture.

[0045] In S4, the solubility of the system is reduced by cooling, providing supersaturated conditions for the subsequent crystallization step. Purified water is then added to change the polarity of the solvent (e.g., from an alcohol-water mixed solvent to a higher water content), further reducing the solubility of the product and promoting crystallization.

[0046] In S5, the cooling rate is controlled (e.g., gradient cooling) to allow morphiflumate to slowly precipitate in the form of crystals, thereby reducing impurity inclusion and improving crystal purity. The crystals are collected by filtration or centrifugation to remove residual solvent and soluble impurities in the mother liquor. Residual water and solvent are removed by reduced pressure drying or vacuum drying to ensure that the product achieves the desired purity and stability.

[0047] Finally, morphifluanid with high yield and high crystal purity was prepared.

[0048] In the present application, the cosolvent is an alcohol cosolvent, which can be selected from any one or more of isopropanol, ethanol, and methanol, preferably ethanol; the alcohol cosolvent can not only improve the solubility of the raw materials and promote the reaction, but also has a relatively high boiling point and smaller recovery loss, which helps to reduce the synthesis cost.

[0049] In the present application, the acid-binding agent is an alkali metal carbonate, which can be selected from any one or more of potassium carbonate, sodium carbonate, magnesium carbonate, and calcium carbonate, preferably sodium carbonate or potassium carbonate. These alkali metal carbonates can effectively neutralize the acid generated in the reaction, promote the reaction to proceed in the forward direction, and have a positive effect on product quality and control of reaction conditions.

[0050] In the present application, the molar ratio of chloroethylmorpholine hydrochloride, flunilic acid, cosolvent and acid binding agent is controlled in the range of 1:1-3:3-6:0.5-1.5, and the molar ratio of chloroethylmorpholine hydrochloride:flunilic acid and alkali metal carbonate is preferably 1:1-2:0.5-1.

[0051] The molar ratio of chloroethylmorpholine hydrochloride to purified water is: 1:0.2~0.4.

[0052] Within this ratio range, the reaction proceeds more favorably, which can effectively improve product yield and quality.

[0053] In this application, the impurity removal process in S3 specifically includes three key steps: refining, decolorization, and filtration. Refining removes byproducts and excess impurities generated during the reaction; decolorization using a decolorizing agent such as activated carbon improves the purity and appearance of the product; and finally, filtration thoroughly separates solid impurities to ensure the purity of the third mixture.

[0054] The heating temperature of the second mixture in S3 is set to 50°C to 100°C, and the heating time is 4h to 8h. Within this temperature and time range, the reaction can proceed fully while avoiding impurity generation and product decomposition caused by excessive reaction, thereby ensuring a high product yield and quality.

[0055] The molar ratio of chloroethylmorpholine hydrochloride to purified water in S3 is 1:0.2-0.4. This ratio can not only ensure the full dissolution of chloroethylmorpholine hydrochloride, providing good conditions for subsequent reactions, but also play a role in regulating the concentration of the reaction system and promoting the reaction during the reaction.

[0056] The cooling crystallization temperature of the fourth mixture in S5 is controlled at 0° C. to 10° C. Within this temperature range, morphiflumate can be rapidly crystallized and the crystallization effect is good, which is beneficial to improving the purity and yield of the product.

[0057] The drying process of the fourth mixture in S5 is as follows:

[0058] 5.1, solid-liquid separation: Under nitrogen protection, the fourth mixture is subjected to high-speed rejection filtration to achieve effective solid-liquid separation and reduce impurity residues;

[0059] 5.2. Solid washing: Wash the separated solid with purified water to further remove impurities adsorbed on the surface, and then spin dry to obtain a wet product of morphifluanid;

[0060] 5.3. Heating and drying: heat and dry the wet morphiflumate;

[0061] 5.4. Drying endpoint control: strictly control the drying loss of morphiflunomide to ≤0.1%. After the drying loss reaches the standard, cool to below 30°C to obtain the dry morphiflunomide product to ensure stable product quality.

[0062] To make the technical solution of the present invention clearer and easier to understand, the present invention is described in detail below with reference to specific embodiments and accompanying drawings. However, it should be understood that the embodiments described are only some of the embodiments of the present invention, not all of them. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0063] Example 1

[0064] 10 g of purified water, 30 g of chloroethylmorpholine hydrochloride, 120 mL of isopropyl alcohol, 20 g of sodium carbonate, and 40 g of fluonic acid were added to a reaction flask. The reaction was carried out at 70° C. for 5 hours under nitrogen protection. After the reaction, the mixture was filtered and then cooled for crystallization. At 35° C., 120 mL of purified water was added dropwise at a constant flow rate of 4 mL / min for 30 minutes using a peristaltic pump under stirring. The mixture was further cooled to 5° C. and filtered to obtain 59.3 g of the product with a yield of 93.0% (based on chloroethylmorpholine hydrochloride). The product was tested and no morpholine genotoxin impurities were detected.

[0065] Example 2

[0066] 10 g of purified water, 30 g of chloroethylmorpholine hydrochloride, 120 mL of anhydrous ethanol, 20 g of sodium carbonate, and 40 g of fluonic acid were added to a reaction flask, and the reaction was carried out at 70° C. for 5 hours under nitrogen protection. After the reaction, the mixture was filtered and then cooled for crystallization. At 35° C., 120 mL of purified water was added dropwise at a constant flow rate of 4 mL / min using a peristaltic pump for 30 minutes under stirring. The mixture was further cooled to 5° C. and filtered to obtain 57.6 g of the product with a yield of 90.4% (based on chloroethylmorpholine hydrochloride). After testing, no morpholine genotoxin impurities were detected in the product.

[0067] Example 3

[0068] 10 g of purified water, 30 g of chloroethylmorpholine hydrochloride, 120 mL of isopropanol, 26 g of potassium carbonate, and 40 g of fluonic acid were added to a reaction flask. Under nitrogen protection, the reaction was carried out at 70° C. for 5 hours. After the reaction, the reaction was filtered and then cooled for crystallization. At 35° C., 120 mL of purified water was added dropwise at a constant flow rate of 4 mL / min for 30 minutes using a peristaltic pump under stirring. The product was continued to be cooled to 5° C. and filtered to obtain 55.3 g of the product with a yield of 86.8% (based on chloroethylmorpholine hydrochloride). The product test results showed that no morpholine genotoxins were detected.

[0069] Example 4

[0070] 10 g of purified water, 30 g of chloroethylmorpholine hydrochloride, 120 mL of isopropanol, 20 g of sodium carbonate, and 40 g of fluonic acid were added to a reaction flask. Under nitrogen protection, the reaction was carried out at 50° C. for 5 hours. After the reaction, the reaction was filtered and then cooled for crystallization. 120 mL of purified water was added at 35° C., and the mixture was further cooled to 5° C. and filtered to obtain 57.3 g of the product with a yield of 89.9% (based on chloroethylmorpholine hydrochloride). No morpholine genotoxin impurities were detected.

[0071] Example 5

[0072] 50 g of purified water, 30 g of chloroethylmorpholine hydrochloride, 20 g of sodium carbonate, and 40 g of fluonic acid were added to a reaction flask and reacted at 100° C. for 5 hours under nitrogen protection. After the reaction, 120 mL of isopropanol was added and filtered at 70° C., then cooled and crystallized. 120 mL of purified water was added at 35° C., and the mixture was further cooled to 5° C. and filtered to obtain 57.9 g of the product with a yield of 90.8% (based on chloroethylmorpholine hydrochloride). No morpholine genotoxin impurities were detected.

[0073] Example 6 (different reaction times)

[0074] 10 g of purified water, 30 g of chloroethylmorpholine hydrochloride, 120 mL of isopropanol, 20 g of sodium carbonate, and 40 g of fluonic acid were added to a reaction flask. Under nitrogen protection, the reaction was carried out at 70° C. for 4 hours. After the reaction, the reaction was filtered and then cooled for crystallization. 120 mL of purified water was added at 35° C., and the mixture was further cooled to 5° C. and filtered to obtain 56.6 g of the product with a yield of 88.8% (based on chloroethylmorpholine hydrochloride). No morpholine genotoxin impurities were detected.

[0075] Example 7 (different reaction times)

[0076] 10 g of purified water, 30 g of chloroethylmorpholine hydrochloride, 120 mL of isopropyl alcohol, 20 g of sodium carbonate, and 40 g of flunilic acid were added to a reaction flask and reacted at 70°C under nitrogen for 8 hours. After the reaction, the mixture was filtered and cooled to crystallize. 120 mL of purified water was added at 35°C, and the mixture was further cooled to 5°C and filtered to obtain 58.1 g of the product, with a yield of 91.2% (based on chloroethylmorpholine hydrochloride). No morpholine genotoxin impurities were detected.

[0077] In the above embodiments 1 to 7, the drying process of the fourth mixture is specifically as follows:

[0078] Specifically:

[0079] 5.1. Open the nitrogen protection device and put the fourth mixture into the centrifuge. Run it at low speed first to evenly distribute the mixture. When the centrifuge is full, close the discharge valve and adjust the centrifuge to high speed. Perform high-speed filtration for 5 minutes to achieve solid-liquid separation.

[0080] 5.2. Wash the separated solid with purified water for 5 minutes, and then spin-dry for 5 minutes to obtain a wet product of morphifluanid.

[0081] 5.3. Place the wet product of morphifluanid into a boiling dryer for drying.

[0082] 5.4. Drying Endpoint Control: When the outlet air temperature of the boiling dryer rises to 55°C-65°C, sample and test the drying loss, strictly controlling the drying loss to ≤0.1%. When the drying loss test passes, stop heating and cool the temperature to below 30°C by cold blowing. Stir and vibrate for 3 minutes before discharging the product to obtain the dried morphine fluocinolone product.

[0083] like Figure 2 Shown is a schematic structural diagram of morphifluanid prepared by a method for preparing morphifluanid described in this application; Figure 2As can be seen, the molecular structure contains: a pyridine ring (a nitrogen-containing heterocycle), an amide bond (-CONH-), a morpholine ring (a six-membered heterocycle containing nitrogen and oxygen), and a trifluoromethylbenzene structure (a benzene ring containing -CF3). The trifluoromethyl group is a strong electron-withdrawing group that changes the electron cloud density of the benzene ring, affecting the molecule's hydrophobicity and metabolic stability. It is used in drug design to optimize drug efficacy and pharmacokinetic properties. This shows that it meets the molecular structural characteristics of morphine.

[0084] Figure 3 and Figure 4 They are respectively the mass spectra of the standard product (i.e., standard morphiflumate) and the prepared sample (i.e., the morphiflumate product prepared by the present application), Figure 3 and Figure 4 It can be seen that in the mass spectrum of the prepared sample, the strong molecular ion peak m / z 394 corresponds to the MH negative ion, indicating a partial molecular weight of 395. Therefore, it can be concluded that the mass spectrum of the prepared sample is consistent with the mass spectrum of the standard; the data obtained from the mass spectrum show that the molecular weight of the sample is comparable to that of morphine.

[0085] Figure 5 and Figure 6 They are infrared spectra of the standard product (i.e., standard morphiflunomide) and the prepared product (i.e., the morphiflunomide product prepared by the present application). Figure 5 and Figure 6 The peak values ​​of each group are shown in Table 1:

[0086] Table 1 Group peaks of infrared spectra of standard products and prepared samples

[0087] No. <![CDATA[Standard product / cm -1 > <![CDATA[Preparation of product / cm -1 > deviation 1 3280.36 3280.45 ﹤1 2 2965.52 2965.50 ﹤1 3 2850.86 2850.89 ﹤1 4 2792.40 2792.37 ﹤1 5 1696.79 1696.83 ﹤1 6 1613.75 1613.74 ﹤1 7 1581.10 1581.23 ﹤1 8 1530.33 1530.39 ﹤1 9 1492.07 1492.05 ﹤1 10 1460.73 1460.65 ﹤1 11 1397.26 1397.28 ﹤1 12 1328.20 1328.21 ﹤1 13 1288.61 1288.61 ﹤1 14 1256.11 1256.11 ﹤1 15 1193.21 1193.25 ﹤1 16 1148.61 1148.55 ﹤1 17 1129.98 1130.15 ﹤1 18 1091.62 1091.73 ﹤1 19 1068.40 1068.48 ﹤1 20 1052.09 1052.19 ﹤1 21 1009.67 1009.72 ﹤1 22 963.21 963.28 ﹤1 23 937.15 937.21 ﹤1 24 871.75 871.65 ﹤1 25 792.81 792.86 ﹤1 26 773.61 773.69 ﹤1 27 694.53 694.62 ﹤1 28 661.87 662.16 ﹤1

[0088] As can be seen from Table 1, the infrared spectra of the standard product and the prepared product show obvious vibration absorption peaks of pyridine, morpholine, amine, carboxylic acid hydroxyl, carbonyl, aromatic ring, carbon-nitrogen bond and carbon-oxygen bond, indicating that the morphiflumate product prepared by the method described in this application contains pyridine, morpholine, amine, carboxylic acid hydroxyl, carbonyl, aromatic ring, carbon-nitrogen bond, carbon-oxygen bond and other groups;

[0089] exist Figure 5 and Figure 6 In the IR spectra of the standard and the prepared sample, the IR spectra are completely consistent. Figure 5 and Figure 6 The wavenumber position of the characteristic peaks (such as carbonyl, aromatic ring, heterocyclic ring, etc.), the wavenumber of the key peaks in the two figures (such as 1700cm -1 Nearby ester carbonyl, 1600cm -1 The fingerprint region (1500cm) is basically the same as that of the standard, indicating that the functional group type and chemical bond vibration mode of the sample are consistent with those of the standard. -1 ~500cm-1 ) The peak shape matches well, with no obvious extra or missing peaks, indicating that the molecular structure of the sample is highly consistent with that of the standard. Figure 5 and Figure 6 The coincidence is good, the deviation is <1, and there is no significant difference. It can be concluded that the structure of the morphiflumate product prepared in this application is consistent with that of the standard morphiflumate; Figure 6 It can be seen that the morphiflumate product prepared in this application has no abnormal absorption peaks, indicating that no obvious impurities were detected in the product under the test conditions. Therefore, it can be concluded that the chemical structure of the morphiflumate sample prepared by the method described in this application is consistent with that of the morphiflumate standard, and that qualified morphiflumate was prepared.

[0090] Figure 7 and Figure 8 The 1H-NMR spectra of the standard product (i.e., standard morphiflumate) and the prepared product (i.e., the morphiflumate product prepared using the method described in this application) are shown in Table 2:

[0091] Table 2 1H-NMR (hydrogen nuclear magnetic resonance) data of standard products and prepared products

[0092]

[0093] As can be seen from Table 2, the difference in chemical shift δ (ppm) between the standard and the prepared product is extremely small, ranging from 0.01ppm to 0.03ppm, indicating that the chemical environments of hydrogen atoms in the prepared product and the standard are highly similar, preliminarily proving that the structures of the standard and the prepared product are consistent.

[0094] At the same time Figure 7 and Figure 8 The characteristic peak positions of the two spectra (such as peaks around 10ppm, 7ppm~8ppm aromatic region, 3ppm~4ppm, etc.) are basically coincident, indicating that the chemical environment of hydrogen atoms in the prepared product and the standard are consistent, and the characteristic peak positions of the two spectra echo the data in Table 2, and there is no obvious distortion in the peak shape. It can be concluded that the prepared product and the standard are highly matched in the chemical environment of hydrogen atoms, the molecular structure is basically the same, the product purity / structure is in line with expectations, and from Figure 7 and Figure 8 There are 13 proton signals in the structures observed in the two spectra. The 1H-NMR spectrum data confirms that the molecular structure of the sample is consistent with that of morphine, and the prepared product is consistent with the standard.

[0095] In summary, the method for preparing morphiflumate described in this application produces a standard morphiflumate product.

[0096] The following is a comparison of the product yield and impurities of morphiflumate prepared by the prior art and the method for preparing morphiflumate described in this application.

[0097] Comparative Example (Morniflumate prepared using existing technology)

[0098] According to existing technology, 30g of hydroxyethylmorpholine and 40g of flunilic acid were used as raw materials, and 20g of sodium carbonate was used as an acid-binding agent. The reaction was carried out in 120mL of acetone at 60°C for 5 hours. After completion of the reaction, filtration and crystallization were performed to obtain 48g of the product with an 80% yield (based on the hydroxyethylmorpholine). The product was tested and the morpholine genotoxin impurity content was 300 parts per million (PPM).

[0099] The parameters of the morpholine impurities in Examples 1 to 7 and the comparative example were detected by LC-MS / MS, and the parameters are shown in Table 3:

[0100] Table 3

[0101]

[0102]

[0103] The product yields and impurities of morphiflumate prepared by the preparation method of the comparative example and the preparation methods of Examples 1 to 7 of the present application are shown in Table 4:

[0104] Table 4 Comparison of product yield and impurities between the preparation methods of the comparative examples and the present application examples 1 to 7

[0105]

[0106] As shown in Table 3, when hydroxyethylmorpholine and flunilic acid are reacted in the existing method, the product yield is only 80%, and the morpholine genotoxin impurity is as high as 200 ppm to 500 ppm (cited from literature or experimental data), far exceeding the ICHQ3D limit (≤1 ppm). However, the present application adjusts the molar ratio of chloroethylmorpholine hydrochloride, flunilic acid, and acid-binding agent (1:1 to 3:0.5 to 1.5), combined with the gradient addition of purified water, to prevent the precipitation of morpholine impurities in the reaction system, and the impurity content of the final product is less than 1 ppm. Ethanol or isopropanol (boiling point 78° C. to 82° C.) is used instead of acetone (boiling point 56° C.), reducing volatilization losses and improving the solvent recovery rate to over 90%.

Claims

1. A method for preparing morphiflumate, characterized in that: The preparation method of morphiflumate comprises: S1, adding purified water and a cosolvent to chloroethylmorpholine hydrochloride to fully dissolve to obtain a first mixture; S2, adding an acid binding agent and flunic acid to the first mixture to obtain a second mixture; S3, heating the second mixture at 50° C. to 100° C. for 4 to 8 hours to obtain a third mixture after removing impurities; S4, cooling the third mixture to 25° C. to 35° C., adding purified water to obtain a fourth mixture; S5, cooling the fourth mixture for crystallization, and drying to obtain the morphiflumate.

2. The method for preparing morphiflumate according to claim 1, wherein The molar ratio of chloroethylmorpholine hydrochloride:flunilic acid:cosolvent and acid binding agent is 1:1-3:3-6:0.5-1.

5.

3. The method for preparing morphiflumate according to claim 1, wherein In S3, impurity removal includes refining, decolorization and filtration.

4. The method for preparing morphiflumate according to claim 1, wherein In S3, the molar ratio of chloroethylmorpholine hydrochloride to purified water is 1:0.2-0.

4.

5. The method for preparing morphiflumate according to claim 1, wherein In S5, the temperature of the cooling crystallization of the fourth mixture is 0°C to 10°C.

6. The method for preparing morphiflumate according to claim 1, wherein: The drying process of the fourth mixture is: 5.1, under nitrogen protection, filter the fourth mixture at high speed to separate the solid and liquid; 5.

2. Wash the solid separated in 5.1 with purified water and spin dry to obtain wet product of morphiflunomide; 5.3, heating and drying the wet product of morphiflumate; 5.

4. Control the loss on drying of morphiflunomide to ≤ 0.1%, and cool the mixture until the temperature drops below 30° C. to obtain a dry morphiflunomide product.

7. The method for preparing morphiflumate according to claim 1, wherein: The cosolvent is an alcohol cosolvent; The alcohol cosolvent is selected from any one or more of isopropanol, ethanol, and methanol.

8. The method for preparing morphiflumate according to claim 1, wherein: The acid binding agent is an alkali metal carbonate; The alkali metal carbonate is selected from any one or more of potassium carbonate, sodium carbonate, magnesium carbonate and calcium carbonate.

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