Simple method for preparing trimetazidine

Abstract

The invention provides an environment-friendly method for preparing a raw material medicine trimetazidine. 2, 3, 4-trimethoxybenzaldehyde and piperazine are used as raw materials, water is used as a solvent, and the trimetazidine is prepared in one step through reductive amination catalyzed by an iridium, manganese or rhenium catalyst. The synthesis method provided by the invention is mild in reaction condition, simple in step, simple to operate, green and environment-friendly, high in synthesis efficiency and convenient to separate and purify, has an industrial application prospect, and plays a positive role in the fields of organic synthesis, medicine production, fine chemical engineering and the like.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and uses 2,3,4-trimethoxybenzaldehyde and piperazine as starting materials to prepare trimetazidine in one step through catalytic reduction amination. Background Art

[0002] Trimetazidine (also known as trimetazidine) is a widely used commercial drug. Its English name is Trimetazidine and its chemical name is 1-(2,3,4-trimethoxybenzyl)piperazine (CAS registration number 5011-34-7). It is used to treat heart diseases such as angina pectoris and acute myocardial infarction. It has the effects of improving myocardial blood supply, protecting myocardial cells and improving heart function.

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

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

[0005]

[0006] As shown in reaction formula 1A, Wang Wenhao et al. used 2,3,4-trimethoxybenzyl chloride as an alkylating agent to directly alkylate piperazine in the presence of an inorganic or organic base. However, due to the high activity of 2,3,4-trimethoxybenzyl chloride, both nitrogen atoms of piperazine can be alkylated at the same time, resulting in a large number of byproducts with a yield of 44.2%. (Wang Wenhao, Zhang Xin, Xu Ping, Chinese Journal of Medicinal Chemistry, 2003, 13, 218–221).

[0007] As shown in reaction formula 1B, the US patent (Servier, J. 1966, US3262852) uses 2,3,4-trimethoxybenzyl chloride and N-formylpiperazine as raw materials, first condenses to prepare a monoalkylated intermediate, N-formyl trimetazidine, and then successfully prepares trimetazidine through steps such as deformylation and acidification under alkaline conditions. Trurong et al. prepared 2,3,4-trimethoxybenzyl chloride by chloromethylation of 1,2,3-trimethoxybenzene, and then used this method to synthesize trimetazidine (Trurong, P. et al, TapChi Duoc Hoc. 2010, 50, 49–53).

[0008] As shown in reaction formula 1C, the Chinese patent (Zhang Lebo, Sun Shoufei, Zhang Baikun, Li Zhongjing, Jiang Ruiling. 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, in a French patent (Gilbert R.1982, FR2493316), 2,3,4-trimethoxybenzyl chloride and 2-piperazinone are used as raw materials, and trimetazidine is obtained through two steps of alkylation and LiAlH4 reduction. The process of this method is complicated, and the raw material 2-piperazinone is expensive.

[0010] In the above method, due to the presence of three methoxy groups, 2,3,4-trimethoxybenzyl chloride has poor stability and is inconvenient to store, 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 the alkylating agent

[0012] As shown in reaction formula 2, Beller and Jagadeesh et al. used 2,3,4-trimethoxybenzyl alcohol and piperazine as raw materials, and prepared trimetazidine in one step under the catalysis of Co nanoparticles, and the yield was 81% as determined by gas chromatography. This method requires harsh reaction conditions such as strong base (potassium tert-butoxide), high temperature, and anhydrous, and the preparation route of Co nanoparticles is complicated. Therefore, this method is costly and not suitable for large-scale industrial production (Ma, Z.; Zhou, B.; Li, X.; Kadam, RG; Gawande, MB; Petr, M.; Zboˇril, R.; Beller, M.; Jagadeesh, RV Chem. Sci. 2022, 13, 111–117).

[0013]

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

[0015] As shown in reaction formula 3E, the Chinese patents published in 2009 and 2011 (Qi Chenze, Yao Xiandong, Sun Xudong, Zeng Minfeng, Shen Yongmiao, Xiao Huiquan. 2009, invention patent application, CN 200910099518.4; Yan Wenge, Qi Xinguo, Li Xinhao, Zhao Shuming, Liu Nian. 2010, invention patent application, CN 201010106200.7) used 2,3,4-trimethoxybenzaldehyde and piperazine as raw materials, respectively, and used precious metal palladium or nickel for catalytic hydrogenation to achieve the synthesis of trimetazidine. 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 Pat. No. 5,142,053 (Jean-Claude, S. 1992) uses LiAlH4 or NaBH4 as a reducing agent with a high yield, but the use of LiAlH4 and NaHB4 limits large-scale industrial production.

[0018] As shown in reaction formula 3G, He Maoqun et al. directly used formic acid as a reducing agent to obtain trimetazidine with a yield of 83-92%. However, when no catalyst is added, the reaction temperature is high (85-110°C), and the amount of piperazine added is 6-10 times that of aldehyde, making it difficult to separate the product, which is not conducive to 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. used a complex of pyridine amide and metal iridium as a catalyst and formic acid as a reducing agent to prepare trimetazidine (Liu Yiwen, Chen Duopeng, Mao Yefu, Zhan Xiang, Liu Qixing, Zhou Haifeng. 2022, invention patent application, CN 202210026936).

[0019] As shown in reaction formula 4, Zhou Haifeng et al. used 2,3,4-trimethoxybenzaldehyde and N-Boc piperazine as raw materials, [Ir(cod)Cl]2-PPh3 as catalyst, and synthesized N-Boc-protected trimetazidine under high-pressure hydrogen, and then deprotected it with HCl to obtain the target product. This method has a high yield, but more expensive transition metal catalysts and high-pressure hydrogen are used in the process, and post-treatment deprotection is required, and the steps are cumbersome (Zhou Haifeng, Chen Duopeng, Liu Yiwen, Liu Qixing. 2022, invention patent application, CN2022115488949). The reaction can also occur by 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 formula 5, Liu Yude et al. used methyl piperazine as a precursor, added a halogen element (preferably chlorine), generated halomethyl piperazine at low temperature, then added trimethoxybenzene, and added zinc catalyst in batches to obtain trimetazidine. This method is time-consuming, complicated to operate, and halogen is dangerous and toxic, which is not conducive to industrial production (Liu Yude, Song Jia. 2014, invention patent application, 201410722190.8).

[0023]

[0024] In view of the above problems, the present invention aims to provide a simple, efficient, green and environmentally friendly method for synthesizing trimetazidine. The method uses cheap commercially available 2,3,4-trimethoxybenzaldehyde and piperazine as starting materials, uses water as solvent, and prepares trimetazidine under the catalysis of an efficient iridium, manganese or rhenium catalyst. The method has a high overall yield, short steps, green and mild reaction conditions, and simple post-treatment. Summary of the invention

[0025] The technical solution of the present invention is 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 a catalyst shown 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, C17, and most preferably C2, C8, and C14.

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

[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 when one or more organic solvents miscible with water (methanol, ethanol, propanol, isopropanol, acetone, ethylene glycol, tetrahydrofuran, 1,4-dioxane) are added.

[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 method for simply preparing the raw material drug trimetazidine. The present invention will have a positive effect in the fields of organic synthesis, medicine and fine chemicals. Compared with the previous methods, the synthesis method provided by the present invention is simple to operate, has mild reaction conditions, is green and environmentally friendly, has high synthesis efficiency, and has industrial application prospects.

[0037] Attached reaction formula

[0038] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of trimetazidine (400 MHz, CDCl3).

[0039] Figure 2 This is the carbon NMR spectrum of trimetazidine (101 MHz, CDCl3). DETAILED DESCRIPTION

[0040] The present invention is further illustrated below by taking C2 catalyst as an example, but the present invention is not limited to the scope of the example.

[0041] 2,3,4-trimethoxybenzaldehyde (1.96 g, 10 mmol, 1 molar equivalent), piperazine (1.09 g, 12 mmol, 1.2 molar equivalent), ethanol (6 mL), deionized water (15 mL), HCO2H (0.75 mL, 20 mmol, 2 molar equivalent) were added to a 50 mL round-bottom flask equipped with a magnetic rod. Catalyst C2 (0.57 mg, 0.01 mol%) was added to the above system and reacted 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 × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The trimetazidine product was obtained by column chromatography.

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

[0043] 1 H NMR(400MHz,Chloroform-d)δ6.93(d,J=8.5Hz,1H),6.58(d,J=8.5Hz,1H),3. 86–3.77(m,9H),3.40(s,2H),2.82(t,J=4.8Hz,4H),2.55(s,1H),2.38(s,4H).

[0044] 13 C NMR (101MHz, Chloroform-d) δ152.8,152.6,142.2,125.1,123.8,106.8,61.1,60.7,57.0,55.9,54.1,45.9.

[0045] The same product can be obtained by using the same operation steps and other catalysts. 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: Using 2,3,4-trimethoxybenzaldehyde (Formula 1) and piperazine (Formula 2) as raw materials, using the structure shown in C1 to C18 as a catalyst, and using formic acid as a reducing agent, trimetazidine is prepared in one step.

2. The method according to claim 1, characterized in that The catalyst used is selected from a mixture of one or more of C1 to C18.

3. The method according to claim 1, characterized in that The reducing agent used is a mixture of formic acid or a formate salt (sodium formate, lithium formate, potassium formate, magnesium formate, or ammonium formate) and sulfuric acid.

4. The method according to claim 1, characterized in that: The solvent used is water, methanol, ethanol, propanol, isopropanol, acetone, ethylene glycol, tetrahydrofuran, 1,4-dioxane or a mixture thereof.

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