Preparation method of teriflunomide and intermediate thereof

Abstract

The invention discloses a preparation method of teriflunomide and an intermediate thereof in the technical field of medicine preparation. The preparation method comprises the following steps: step 1, mixing and stirring cyanoacetic acid, p-trifluoromethylaniline and an ethyl acetate solvent; 2, putting the mixture into microwave reaction equipment, and carrying out condensation reaction by utilizing the microwave reaction equipment to generate a key intermediate; step 3, after the condensation reaction is finished, carrying out condensation post-treatment, and drying the key intermediate by using microwave reaction equipment to obtain a purified intermediate; and 4, mixing the purified intermediate with acetyl chloride and sodium methoxide in a proper solvent to generate teriflunomide. According to the invention, the biocatalyst is adopted to replace the traditional metal catalyst, the reaction conditions are optimized, the post-treatment steps are simplified, the operation difficulty and cost are reduced, and the environmental pollution is reduced while the yield is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and specifically is a method for preparing teriflunomide and its intermediates. Background Art

[0002] Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system, which can cause neuritis, retrobulbar optic neuritis, ophthalmoplegia, limb paralysis, pyramidal tract signs and psychiatric symptoms, seriously affecting the quality of life of patients. Ophthalmoplegia can lead to limited eye movement of patients, which in turn affects the ability of visual tracking and focusing, making it difficult for patients to read, write or perform other activities that require fine visual function. When the optic nerve is affected by inflammation, patients may experience decreased vision, visual field defects or even blindness, which causes great damage to the patient's visual function. Because the transmission of nerve signals in the damaged myelin sheath is blocked, the muscles cannot receive normal nerve innervation. Limb paralysis not only limits the patient's ability to move, but may also lead to complications such as muscle atrophy and joint stiffness.

[0003] Teriflunomide, chemically known as (Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide, is a hydroorotate dehydrogenase inhibitor developed by Sanofi. It mainly inhibits dihydroorotate dehydrogenase to prevent the synthesis of pyrimidines in lymphocytes. While significantly alleviating central nervous system diseases, it can also reduce the relapse rate. Compared with other similar drugs on the market, teriflunomide is easy to use, has good efficacy, few side effects, delays the natural course of the disease and improves patient prognosis. Therefore, it is an ideal drug for the treatment of relapsing multiple sclerosis with strong competitiveness and good clinical application prospects.

[0004] The existing preparation methods of teriflunomide and its intermediates usually require multiple reaction steps, which often involve complex chemical reactions and separation and purification processes, resulting in a long preparation cycle. Due to the harsh reaction conditions, such as high temperature and high pressure, these conditions consume a lot of energy. Long reaction times not only increase production costs, but may also affect the quality and stability of the product. Therefore, it is necessary to propose a preparation method of teriflunomide and its intermediates with high operational safety. Summary of the invention

[0005] In order to solve the problem that the traditional method for preparing teriflunomide has many steps and leads to a long preparation cycle, the purpose of the present invention is to provide a method for preparing teriflunomide and its intermediates, which uses a biocatalyst to replace the traditional metal catalyst, optimizes the reaction conditions, simplifies the post-processing steps, reduces the difficulty and cost of operation, and achieves the goal of reducing environmental pollution while improving the yield.

[0006] In order to achieve the above object, the technical scheme of the present invention is as follows: A method for preparing teriflunomide and its intermediates comprises the following steps:

[0007] Step 1: Mix cyanoacetic acid and p-trifluoromethylaniline with ethyl acetate solvent and stir;

[0008] Step 2: placing the mixture in a microwave reaction device, and using the microwave reaction device to perform a condensation reaction to generate a key intermediate;

[0009] Step 3: After the condensation reaction is completed, post-condensation treatment is performed, and the key intermediate is dried using a microwave reaction device to obtain a purified intermediate;

[0010] Step 4: mixing the purified intermediate with acetyl chloride and sodium methoxide in tetrahydrofuran solvent, and allowing the intermediate to undergo acetylation reaction with acetyl chloride under the action of sodium methoxide to generate teriflunomide;

[0011] Step 5: After the acetylation reaction is completed, acetylation post-treatment is performed, and teriflunomide is dried using a microwave reaction device to obtain the purified target product teriflunomide.

[0012] Furthermore, in step 1, the molar ratio of cyanoacetic acid to p-trifluoromethylaniline is cyanoacetic acid: p-trifluoromethylaniline=4:1.

[0013] Furthermore, in step 2, the condensation agent of the condensation reaction is EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride) solution, the microwave reaction temperature is 50-55° C., and the condensation reaction is carried out for 5 hours.

[0014] Furthermore, in step three, the post-condensation treatment includes washing with an aqueous sodium bicarbonate solution, an aqueous hydrochloric acid solution and an aqueous sodium chloride solution, respectively. After washing, anhydrous sodium sulfate is added and dried for 1 hour.

[0015] Furthermore, in step three, the post-condensation treatment also includes performing a suction filtration operation, concentrating the filtrate under reduced pressure, adding 100 mL of isopropanol to the concentrate for washing, and beating at a temperature of -2 to 5°C for 1.5 hours.

[0016] Further, in step three, the microwave reaction equipment is used for drying at 45-55° C. to obtain a purified intermediate.

[0017] Furthermore, in step 4, the molar ratio of the purified intermediate to the amount of acetyl chloride and the amount of sodium methoxide is purified intermediate: acetyl chloride: sodium methoxide = 1:5.45:4, and the acetylation reaction time is 1 to 2 hours.

[0018] Furthermore, in step five, the acetylation post-treatment includes concentrating the reaction system under reduced pressure, adding 75 ml of water to the concentrate, and stirring and mixing for 1 hour.

[0019] Furthermore, in step five, the acetylation post-treatment also includes performing suction filtration to separate the solid product, adding 300 ml of anhydrous ethanol, stirring at 50-60° C. for 2.5 hours, cooling to 0-8° C., filtering again, and washing with anhydrous ethanol.

[0020] Furthermore, in step five, a microwave reaction device is used for drying at 45-65° C. to obtain the purified target product teriflunomide.

[0021] The basic scheme has the following beneficial effects: 1. The present invention compares and investigates the reaction by directly adding the condensing agent at one time, and finds that the yield of adding the condensing agent at one time is higher than that of adding the condensing agent in a dropwise manner, which can significantly improve the yield of the product. Compared with the traditional post-treatment method, the use of EDC for condensation does not require cumbersome filtering operations, but can directly remove by-products and impurities by washing with sodium bicarbonate aqueous solution and hydrochloric acid aqueous solution. This discovery greatly simplifies the post-treatment steps and reduces the difficulty and cost of operation. The post-treatment of this method is simple, and while improving the yield, it avoids the use of chlorination reagents. Chlorination reagents are widely used in chemical synthesis, but the waste generated by them is often difficult to handle and causes certain pollution to the environment. By optimizing the addition method of the condensing agent and the post-treatment steps, this method achieves the improvement of yield while reducing environmental pollution, and has significant green environmental protection advantages.

[0022] 2. In the traditional teriflunomide synthesis process, sodium hydride, as a commonly used alkali, shows good activity in chemical reactions, but has a high risk factor. The instability of sodium hydride in the air, the high reactivity with water, and the heat and hydrogen that may be generated during the operation all increase the safety risks in industrial production. In the synthesis process of teriflunomide, the present invention systematically optimizes the type of alkali, the type of solvent, the reaction time and the material ratio. This optimization strategy not only significantly improves the safety of industrial production, but also improves the efficiency of synthesis and the yield of the product. The present invention uses sodium methoxide as a substitute. Compared with sodium hydride, sodium methoxide is more stable in chemical properties, and the heat and hydrogen generated by the reaction with water are also less, thereby greatly reducing the safety risks in the operation process. At the same time, sodium methoxide shows good activity in the reaction and can effectively promote the reaction.

[0023] Under the same conditions, the reaction is carried out, and sodium methoxide does not need a solvent to dissolve and drip to feed, and the solid can be directly added to the reaction solution for feeding. This feeding method is not only easy to operate, but also reduces cumbersome dissolving and dripping steps, reduces the difficulty and cost of operation, improves the stability of production, and avoids the problems of reaction heterogeneity and increased by-products that may be caused by batch feeding. And post-processing is carried out by direct quenching. This method can quickly terminate the reaction, reduce the temperature of the reaction system, and separate the product from impurities by simple operation, further improving the purity and yield of the product.

[0024] 3. The present invention is deeply optimized in terms of reaction conditions and post-processing steps. In terms of the optimization of reaction conditions, key parameters such as the temperature, pressure and reaction time of the reaction are precisely controlled to ensure that the reaction is carried out under optimal conditions. This not only improves the efficiency of the reaction and the yield of the product, but also reduces the generation of by-products, providing a better basis for subsequent purification steps. An efficient and environmentally friendly treatment method is adopted to effectively separate the product from impurities through simple operations. This treatment method not only simplifies the post-processing process, reduces the difficulty and cost of operation, but also ensures the high purity of the product. The impurities and by-products generated during the reaction are successfully removed to obtain the high-purity target product teriflunomide. The strict requirements of drug synthesis on the purity of raw materials are met, and reliable raw material guarantees are provided for subsequent drug research and development and production. This not only improves the efficiency and economic benefits of production, but also makes the synthesis method of the present invention easier to promote and apply in industrial production.

[0025] 4. The present invention adopts the auxiliary synthesis technology of microwave reaction equipment to improve the reaction rate and yield. Microwaves can provide specific energy. Under the action of microwaves, the reactant molecules can be more easily activated, thereby reducing the activation energy of the reaction and improving the conversion rate and yield. This energy transfer method is direct and efficient, which significantly accelerates the reaction rate and greatly shortens the synthesis cycle. At the same time, microwave heating is more uniform than traditional heating. Traditional heating methods often have temperature gradients, resulting in uneven heating of various parts in the reaction system, affecting the reaction effect and the quality of the product. Microwave heating can ensure that the entire reaction system is heated evenly, making the reaction more stable and controllable. This is not only conducive to improving the purity and quality of the product, but also helps to reduce the generation of by-products, further improving the efficiency and economic benefits of the reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is an axonometric diagram of a microwave reaction device according to an embodiment of the present invention.

[0027] Figure 2 It is a front cross-sectional view of a microwave reaction device according to an embodiment of the present invention.

[0028] Figure 3It is a top cross-sectional view of a microwave reaction device according to an embodiment of the present invention. DETAILED DESCRIPTION

[0029] The following is further described in detail through specific implementation methods:

[0030] The reference numerals in the drawings of the specification include: main body 1, rotating motor 2, rotating shaft 3, stirring blade 4, top cover 5, waveguide 6, magnetron 7, controller 8, temperature sensor 9, and fan 10.

[0031] The embodiment is basically as shown in the attached Figure 1 -Attached Figure 3 As shown: A method for preparing teriflunomide and its intermediates, comprising the following steps:

[0032] Step 1: Mix cyanoacetic acid, p-trifluoromethylaniline and ethyl acetate and stir, wherein the molar ratio of cyanoacetic acid to p-trifluoromethylaniline is cyanoacetic acid: p-trifluoromethylaniline = 4:1;

[0033] Step 2: placing the mixture in a microwave reaction device, adding a condensation agent EDC (1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride) solution, and using the microwave reaction device to perform a condensation reaction at a microwave reaction temperature of 50-55° C. for 5 hours to generate a key intermediate;

[0034] Step 3: After the condensation reaction is completed, post-condensation treatment is performed, and sodium bicarbonate aqueous solution, hydrochloric acid aqueous solution and sodium chloride aqueous solution are used for washing respectively. After washing, anhydrous sodium sulfate is added to dry for 1 hour, and suction filtration is performed. The filtrate is concentrated under reduced pressure, 100 mL of isopropanol is added to the concentrate for washing, and pulping is performed at a temperature of -2 to 5°C for 1.5 hours, and drying is performed at 45 to 55°C using a microwave reaction device to obtain a purified intermediate;

[0035] Step 4: Mix the purified intermediate with acetyl chloride and sodium methoxide in tetrahydrofuran solvent, the molar ratio of the intermediate to acetyl chloride and sodium methoxide is intermediate: acetyl chloride: sodium methoxide = 1:5.45:4, and allow the intermediate and acetyl chloride to undergo acetylation reaction under the action of sodium methoxide for 1 to 2 hours to generate teriflunomide;

[0036] Step 5: After the acetylation reaction is completed, the acetylation post-treatment is carried out, the reaction system is concentrated under reduced pressure, 75 ml of water is added to the concentrate, and the mixture is stirred and slurried for 1 hour, and the solid product is separated by filtration. 300 ml of anhydrous ethanol is added, and the temperature is controlled at 50-60° C. and stirred for 2.5 hours, and then the temperature is lowered to 0-8° C., and the product is filtered again. The product is washed with anhydrous ethanol and dried at 45-65° C. using a microwave reaction device to obtain the purified target product teriflunomide.

[0037] The microwave reaction device structure preferably includes a main body 1, a rotating motor 2 is fixedly connected to the bottom of the main body 1 with bolts, and the model of the rotating motor 2 is preferably MDS-4A220V, the output shaft of the rotating motor 2 is coaxially bolted and fixedly connected to a rotating shaft 3, the rotating shaft 3 extends from the bottom of the main body 1 to the inside of the main body 1, and a plurality of stirring blades 4 are fixedly bolted to the rotating shaft 3, a top cover 5 is detachably connected to the top of the main body 1, a plurality of waveguides 6 are arranged in the side wall of the main body 1, and the input end of the waveguide 6 is connected to a magnetron 7, the magnetron 7 is fixedly bolted to the outside of the main body 1, and the magnetron 7 is electrically connected to a transformer The transformer is electrically connected to the external power supply, the magnetron 7 is signal-connected to the controller 8, and the controller model is preferably GH91-WBFY-201. A temperature sensor 9 is fixedly connected to the inside of the main body 1 by bolts, and the temperature sensor 9 model is preferably hy-c129-100k3950. The temperature sensor 9 is signal-connected to the controller 8. A fan 10 is fixedly connected to the end of the outer side of the main body 1 away from the magnetron 7 by bolts, and the fan 10 model is preferably SL12038HA2BL. The input end of the fan 10 is connected to the inside of the main body 1, and the fan 10 is signal-connected to the controller 8.

[0038] The specific implementation process is as follows: first, when microwave reaction is required, open the top cover 5, add the reaction materials into the main body 1, close the top cover 5, set the corresponding temperature and time through the controller 8, and adjust according to the characteristics and needs of the reaction materials; transmit microwaves to the waveguide 6 through the magnetron 7, and the waveguide 6 transmits the microwaves to the inside of the main body 1, and the microwaves vibrate rapidly through the fluctuation of the microwave electric field. This vibration causes friction between molecules to generate heat, thereby heating the reactants. The rotation of the stirring blade 4 can not only mix the reactants, but also evenly distribute the heat in the reactants.

[0039] When the temperature in the main body 1 exceeds the preset value of the controller 8, the temperature sensor 9 transmits a signal to the controller 8, and turns off the magnetron 7, so that the waveguide 6 stops heating the reactants, and vice versa, so that the temperature in the reaction device is always maintained at around the preset value. When the reaction time is over, the reaction device stops heating through the controller 8 and issues a reminder. Microwave heating directly acts on the molecules, with fast heating speed and high efficiency. The reactants are heated evenly by the cooperation of the stirring blades 4 to avoid local overheating or overcooling. And the temperature and time of the reaction are precisely controlled to ensure the quality of the reaction. The equipment has a high degree of automation, reduces manual operation, and can further improve safety and reliability.

[0040] Experiments and Results

[0041] 1. Materials and Methods

[0042] 1.1 Experimental Group 1

[0043] Patients with multiple sclerosis (MS) were given teriflunomide 14 mg + normal saline 500 ml intravenous drip once a day. Baseline safety indicators were monitored once a week for 6 consecutive weeks. The end of medication was when the patient stopped taking the medication or the study observation ended.

[0044] 1.2 Experimental Group 2

[0045] Patients were given teriflunomide 7 mg + normal saline 500 ml intravenous drip once a day. Baseline safety indicators were monitored once a week for 6 consecutive weeks. The end of medication was when the patient stopped taking the medication or the study observation ended.

[0046] 1.3 Control group

[0047] The patient was given 500 ml of normal saline intravenously once a day. The baseline safety indicators were monitored once a week thereafter for 6 consecutive weeks.

[0048] 2. Criteria

[0049] The three groups were compared in terms of treatment effects, adverse reactions, hospital stay, neurological function before and after treatment, and inflammatory factor levels. Efficacy criteria: markedly effective: MS patients' neurological function was normal, and symptoms and signs basically disappeared; effective: MS patients' neurological function improved by >50%; ineffective: MS patients' neurological function basically did not improve. Total effective rate = (markedly effective + effective) / total number of cases × 100.00%.

[0050] 3. Results

[0051] 3.1 Validity

[0052] There were significant differences in the treatment effects among experimental group 1, experimental group 2 and the control group. The total effectiveness of experimental group 1 and experimental group 2 was significantly higher than that of the control group, and the difference was statistically significant (P < 0.05), as shown in Table 1. In experimental group 1, 60% of the patients had significant effects and 30% had effective effects; in experimental group 2, 50% had significant effects and 35% had effective effects, and the control group had an effective effect of 10%. Both experimental group 1 and experimental group 2 used teriflunomide for treatment, and the total effective rates of the two groups were high, 90% and 85% respectively. This shows that teriflunomide shows good efficacy in the treatment of multiple sclerosis and can significantly improve the symptoms or condition of patients.

[0053] Table 1 Comparison of treatment effects among three groups

[0054]

[0056] Note: Compared with the control group, P<0.05

[0057] 3.2 Security

[0058] The adverse reactions in experimental group 1, experimental group 2 and control group were generally similar, as shown in Table 2. The three groups were similar in the incidence of adverse reactions, with the combined adverse reaction rates of experimental group 1 and control group being 15%, while that of experimental group 2 was slightly lower at 10%. Among them, headache, diarrhea and other types of adverse reactions occurred in all groups, but no serious adverse reactions were observed. Hair loss was reported in only one case in experimental group 2. In terms of safety assessment, the three groups were similar in the incidence of headache, diarrhea, hair loss and other types of adverse reactions, and the overall incidence of adverse reactions was low. There was no significant difference in the incidence of adverse reactions between experimental group 1 and experimental group 2 (both using teriflunomide) and the control group (using placebo) (P>0.05), which means that from a statistical point of view, teriflunomide did not increase the risk of adverse reactions in treatment. It is worth noting that although some patients experienced adverse reactions, overall, these reactions were mild and tolerable, and no serious adverse reactions were reported. This further confirms the good safety of teriflunomide in treatment.

[0059] Table 2 Comparison of adverse reactions among the three groups

[0060] Group Number of cases Headache diarrhea Hair loss other total Experimental Group 1 20 1 1 0 1 3 Experimental Group 2 20 0 1 1 0 2 Control group 20 1 1 0 1 3

[0061] Note: Compared with the control group, P>0.05

[0062] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0063] The above is only an embodiment of the present invention. The common sense such as the known specific structure and characteristics in the scheme is not described in detail here. The ordinary technicians in the relevant field know all the common technical knowledge in the technical field of the invention before the application date or priority date, can obtain all the existing technologies in the field, and have the ability to apply the conventional experimental means before that date. The ordinary technicians in the relevant field can improve and implement this scheme in combination with their own abilities under the enlightenment given by this application. Some typical known structures or known methods should not become obstacles for ordinary technicians in the relevant field to implement this application. It should be pointed out that for those skilled in the art, without departing from the structure of the present invention, several deformations and improvements can be made, which should also be regarded as the protection scope of the present invention, which will not affect the effect of the implementation of the present invention and the practicality of the patent. The protection scope required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A method for preparing teriflunomide and its intermediates, characterized in that: The following steps are involved: Step 1: Mix cyanoacetic acid and p-trifluoromethylaniline with ethyl acetate solvent and stir; Step 2: placing the mixture in a microwave reaction device, and using the microwave reaction device to perform a condensation reaction to generate a key intermediate; Step 3: After the condensation reaction is completed, post-condensation treatment is performed, and the key intermediate is dried using a microwave reaction device to obtain a purified intermediate; Step 4: mixing the purified intermediate with acetyl chloride and sodium methoxide in tetrahydrofuran solvent, and allowing the intermediate to undergo acetylation reaction with acetyl chloride under the action of sodium methoxide to generate teriflunomide; Step 5: After the acetylation reaction is completed, acetylation post-treatment is performed, and teriflunomide is dried using a microwave reaction device to obtain the purified target product teriflunomide.

2. The method for preparing teriflunomide and its intermediates according to claim 1, characterized in that: In step 1, the molar ratio of cyanoacetic acid to p-trifluoromethylaniline is cyanoacetic acid: p-trifluoromethylaniline=4:

1.

3. The method for preparing teriflunomide and its intermediates according to claim 2, characterized in that: In step 2, the condensation agent for the condensation reaction is EDC solution, the microwave reaction temperature is 50-55° C., and the condensation reaction is carried out for 5 hours.

4. The method for preparing teriflunomide and its intermediates according to claim 3, characterized in that: In step 3, the post-condensation treatment includes washing with aqueous sodium bicarbonate solution, aqueous hydrochloric acid solution and aqueous sodium chloride solution respectively. After washing, anhydrous sodium sulfate is added to dry for 1 hour.

5. The method for preparing teriflunomide and its intermediates according to claim 4, characterized in that: In step three, the post-condensation treatment also includes performing a suction filtration operation, concentrating the filtrate under reduced pressure, adding 100 mL of isopropanol to the concentrate for washing, and beating at a temperature of -2 to 5°C for 1.5 hours.

6. The method for preparing teriflunomide and its intermediates according to claim 5, characterized in that: In step three, a microwave reaction device is used for drying at 45-55° C. to obtain a purified intermediate.

7. The method for preparing teriflunomide and its intermediates according to claim 6, characterized in that: In step 4, the molar ratio of the purified intermediate to the amount of acetyl chloride and the amount of sodium methoxide is purified intermediate: acetyl chloride: sodium methoxide = 1:5.45:4, and the acetylation reaction time is 1 to 2 hours.

8. The method for preparing teriflunomide and its intermediates according to claim 7, characterized in that: In step 5, the acetylation post-treatment includes concentrating the reaction system under reduced pressure, adding 75 ml of water to the concentrate, and stirring and mixing for 1 hour.

9. The method for preparing teriflunomide and its intermediates according to claim 8, characterized in that: In step 5, the acetylation post-treatment also includes performing suction filtration to separate the solid product, adding 300 ml of anhydrous ethanol, stirring at 50-60° C. for 2.5 hours, cooling to 0-8° C., filtering again, and washing with anhydrous ethanol.

10. The method for preparing teriflunomide and its intermediates according to claim 9, characterized in that: In step 5, the microwave reaction equipment is used for drying at 45-65° C. to obtain the purified target product teriflunomide.

Images