A simple method for preparing trimetazidine

Abstract

The application provides a method for preparing raw medicine trimetazidine in an environment-friendly manner. 2,3,4-trimethoxybenzaldehyde and piperazine are used as raw materials, water is used as a solvent, and trimetazidine is prepared through reduction amination catalyzed by an iridium, manganese or rhenium catalyst. The synthesis method provided by the application has the advantages of mild reaction conditions, simple steps, simple operation, environmental protection, high synthesis efficiency, convenient separation and purification, and industrial application prospect, and has a positive role in the fields of organic synthesis, medicine production and fine chemical industry.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and a starting material is 2,3,4-trimethoxybenzaldehyde and piperazine, and trimetazidine is prepared by catalytic reduction amination in one step. BACKGROUND

[0002] Trimetazidine (also known as trimetazidine) is a widely used and commercially available drug, with the English name of Trimetazidine and the chemical name of 1-(2,3,4-trimethoxybenzyl) piperazine (CAS registration number 5011-34-7), which is used for treating angina pectoris, acute myocardial infarction and other heart diseases, and has the effects of improving myocardial blood supply, protecting myocardial cells and improving cardiac function.

[0003] The literature reported synthesis methods of trimetazidine mainly include:

[0004] (1) using 2,3,4-trimethoxybenzyl chloride as an alkylating agent

[0005]

[0006] As shown in Reaction Formula 1A, Wang Wen-hao et al. used 2,3,4-trimethoxybenzyl chloride as an alkylating agent to directly alkylate piperazine in the presence of inorganic or organic bases. However, since the activity of 2,3,4-trimethoxybenzyl chloride is too high, both nitrogen atoms of piperazine can be simultaneously alkylated, so there are many by-products, and the yield is 44.2% (Wang Wen-hao, Zhang Xin, Xu Ping, Chinese Journal of Medicinal Chemistry, 2003, 13, 218-221).

[0007] As shown in Reaction Formula 1B, the U.S. patent (Servier, J. 1966, US3262852) uses 2,3,4-trimethoxybenzyl chloride and N-formyl piperazine as raw materials to first condense to prepare a monoalkylated intermediate, N-formyl trimetazidine, and then through de-formylation under alkaline conditions, acidification and other steps, trimetazidine is successfully prepared. Trurong et al. prepared 2,3,4-trimethoxybenzyl chloride by chloromethylation of 1,2,3-trimethoxybenzene, and then synthesized trimetazidine by this method (Trurong, P. et al, Tap Chi Duoc Hoc. 2010, 50, 49-53).

[0008] As shown in Reaction Formula 1C, the Chinese patent (Zhang Le-bo, Sun Shou-fei, Zhang Bai-kun, Li Zhong-jing, Jiang Rui-ling. Invention patent application. 2018, CN 201811650286.2) uses N-Boc-protected piperazine as a raw material to prepare trimetazidine.

[0009] As shown in Reaction Formula 1D, French patent (Gilbert R. 1982, FR2493316) uses 2,3,4-trimethoxybenzyl chloride and 2-piperazinone as raw materials, and through two steps of alkylation and LiAlH4 reduction, trimetazidine is obtained. The method is complex, and the raw material 2-piperazinone is expensive.

[0010] In the above method, due to the presence of three methoxy groups, the stability of 2,3,4-trimethoxybenzyl chloride is poor, which is not convenient for storage, and needs to be prepared from the corresponding 1,2,3-trimethoxybenzene, 2,3,4-trimethoxybenzyl alcohol or 2,3,4-trimethoxybenzaldehyde.

[0011] (2) Using 2,3,4-trimethoxybenzyl alcohol as an alkylating agent

[0012] As shown in Reaction Formula 2, Beller and Jagadeesh et al. use 2,3,4-trimethoxybenzyl alcohol and piperazine as raw materials, and under the catalysis of Co nanoparticles, trimetazidine is prepared in one step, and the yield is 81% determined by gas chromatography. In this method, strong base (potassium tert-butoxide), high temperature, and anhydrous harsh reaction conditions are required, and the preparation route of Co nanoparticles is complex, so the cost of this method is large, and it is not suitable for large-scale industrialization (Ma, Z.; Zhou, B.; Li, X.; Kadam, R. G.; Gawande, M. B.; Petr, M.; Zboˇril, R.; Beller, M.; Jagadeesh, R. V. Chem. Sci. 2022, 13, 111-117).

[0013]

[0014] (3) Reductive amination of 2,3,4-trimethoxybenzaldehyde

[0015] As shown in Reaction Formula 3E, Chinese patents published in 2009 and 2011 (Qi Chenze, Yao XianDong, Sun Xudong, Zeng Mingfeng, Shen YongMao, Xiao Huiquan. 2009, Invention patent application, CN 200910099518.4; Yan WenGue, Qi XinGuo, Li Xinhao, Zhao Shuming, Liu Nian. 2010, Invention patent application, CN 201010106200.7) respectively use 2,3,4-trimethoxybenzaldehyde and piperazine as raw materials, and realize the synthesis of trimetazidine by using noble metal palladium or nickel catalytic hydrogenation. However, high-pressure hydrogen is used in the catalytic process, which has a high risk index.

[0016]

[0017] As shown in reaction formula 3F, US Patents (Jean-Claude, S. 1992, US5142053) use LiAlH4 or NaBH4 as reducing agents, achieving high yields. However, the use of LiAlH4 and NaBH4 limits large-scale industrial production.

[0018] As shown in Reaction Scheme 3G, He Maoqun et al. directly used formic acid as a reducing agent to obtain trimetazidine in 83–92% yield. However, when no catalyst was added, the reaction temperature was high (85–110°C), and the amount of piperazine added was 6–10 times that of the aldehyde, making product separation difficult and unfavorable for large-scale production (He Maoqun, Miao Dezu, Wang Longke, Huang Wentao, Cao Guangwei, Liu Yang, Zhang Peng. 2012, invention patent application, CN 201210379589). Liu Yiwen et al. prepared trimetazidine using a complex of pyridineamide and iridium as a catalyst and formic acid as a reducing agent (Liu Yiwen, Chen Duopeng, Mao Yefu, Zhan Xiang, Liu Qixing, Zhou Haifeng. 2022, invention patent application, CN 202210026936).

[0019] As shown in Reaction Scheme 4, Zhou Haifeng et al. used 2,3,4-trimethoxybenzaldehyde and N-Boc piperazine as raw materials and [Ir(cod)Cl]2-PPh3 as a catalyst under high-pressure hydrogen to synthesize N-Boc-protected trimetazidine, which was then deprotected with HCl to obtain the target product. This method has a high yield, but the process uses a large amount of expensive transition metal catalysts and high-pressure hydrogen, and requires post-treatment deprotection, making the steps more complicated (Zhou Haifeng, Chen Duopeng, Liu Yiwen, Liu Qixing. 2022, invention patent application, CN2022115488949). The reaction can also occur via reductive amination using sodium triacetoxyborohydride (NaBH(OAc)3) (Long, H. et al. J. Med. Chem. 2021, 64, 12089–12108).

[0020]

[0021] (4) Other synthesis methods

[0022] As shown in Reaction Scheme 5, Liu Yude et al. used methylpiperazine as a precursor and added a halogen (preferably chlorine) to generate halomethylpiperazine at low temperature. Trimethoxybenzene was then added, and a zinc catalyst was added in batches to obtain trimetazidine. This method is time-consuming and complex, and the halogen is dangerous and highly toxic, making it unsuitable for industrial production (Liu Yude and Song Jia. 2014, Invention Patent Application, 201410722190.8).

[0023]

[0024] To address the above issues, the present invention aims to provide a simple, efficient, and environmentally friendly method for synthesizing trimetazidine. This method uses inexpensive, commercially available 2,3,4-trimethoxybenzaldehyde and piperazine as starting materials, water as the solvent, and the catalysis of a highly efficient iridium, manganese, or rhenium catalyst to prepare trimetazidine. This method offers high overall yields, a short number of steps, environmentally friendly and mild reaction conditions, and simple post-processing. Summary of the Invention

[0025] The technical solutions of the present invention are as follows:

[0026] As shown in Reaction Formula 6, 2,3,4-trimethoxybenzaldehyde (Formula 1) and piperazine (Formula 2) are used as raw materials, formic acid is used as a reducing agent, and in the presence of the catalyst represented by C1 to C18, the reaction is carried out at 80° C. for 1 to 6 hours to obtain trimetazidine.

[0027]

[0028] In the above reaction formula:

[0029] 1. The catalyst used is a mixture of one or more of C1 to C18, preferably C1, C2, C3, C8, C11, C13, C14, and C17, with C2, C8, and C14 being most preferred.

[0030] 2. The amount of piperazine (Formula 2) used is 1 to 5 molar equivalents relative to 2,3,4-trimethoxybenzaldehyde (Formula 1).

[0031] 3. The molar amount of the catalyst is in the range of 0.001% to 10% relative to 2,3,4-trimethoxybenzaldehyde (Formula 1).

[0032] 4. The reaction temperature is 0-100°C, with the preferred temperature being 80°C.

[0033] 5. The solvent is usually water. The reaction can also occur by adding one or more organic solvents miscible with water (methanol, ethanol, propanol, isopropanol, acetone, ethylene glycol, tetrahydrofuran, 1,4-dioxane).

[0034] 6. Formic acid is used as a reducing agent in the reaction; the reaction can also occur when a mixture of formate (sodium formate, lithium formate, potassium formate, magnesium formate, or ammonium formate) and sulfuric acid is used as a reducing agent.

[0035] Advantages and positive effects of the present invention:

[0036] The present invention provides a simple method for preparing the raw material drug trimetazidine. This method will have positive impacts in the fields of organic synthesis, pharmaceuticals, and fine chemicals. Compared with previous methods, the synthesis method provided by the present invention is simple to operate, has mild reaction conditions, is environmentally friendly, and has high synthesis efficiency, showing promising industrial applications.

[0037] Reaction Formula

[0038] Figure 1 The nuclear magnetic resonance hydrogen spectrum (400 MHz, CDC13) of trimetazidine.

[0039] Figure 2 The nuclear magnetic resonance carbon spectrum (101 MHz, CDC13) of trimetazidine. DETAILED DESCRIPTION

[0040] The following further illustrates the application by taking C2 catalyst as an example, but the application is not limited in the scope of the example.

[0041] In a 50 mL round-bottom flask equipped with a magnetic stirrer, 2,3,4-trimethoxybenzaldehyde (1.96 g, 10 mmol, 1 mol equivalent), piperazine (1.09 g, 12 mmol, 1.2 mol equivalent), ethanol (6 mL), deionized water (15 mL), HCO2H (0.75 mL, 20 mmol, 2 mol equivalent) were added in sequence. Catalyst C2 (0.57 mg, 0.01 mol%) was added to the above system, and the reaction was carried out at 80°C for 6 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography was used for separation to obtain the trimetazidine product.

[0042] Orange-red oily liquid, 2.51 g, yield 95%, R f = 0.30 (dichloromethane / methanol = 15:1, v / v).

[0043] 1 H NMR (400 MHz, Chloroform-d) δ 6.93 (d, J = 8.5 Hz, 1H), 6.58 (d, J = 8.5 Hz, 1H), 3.86-3.77 (m, 9H), 3.40 (s, 2H), 2.82 (t, J = 4.8 Hz, 4H), 2.55 (s, 1H), 2.38 (s, 4H).

[0044] 13 C NMR (101 MHz, Chloroform-d) δ 152.8, 152.6, 142.2, 125.1, 123.8, 106.8, 61.1, 60.7, 57.0, 55.9, 54.1, 45.9.

[0045] The same product can also be obtained when other catalysts are used by using the same operation steps. The specific yield and catalyst dosage are shown in the following table.

[0046]

[0047]

Claims

1. A method for preparing trimetazidine simply, characterized in that: Trimetazidine is prepared in one step using 2,3,4-trimethoxybenzaldehyde (Formula 1) and piperazine (Formula 2) as raw materials, structures shown in C1 to C6 as catalysts, and formic acid as a reducing agent; the solvent is water and ethanol, and the temperature is 80°C.

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