A method for preparing the active pharmaceutical ingredient butylphthalide

Abstract

This invention provides an environmentally friendly method for preparing the active pharmaceutical ingredient butylphthalide. Using butylphthalide as a raw material and water as a solvent, the active pharmaceutical ingredient butylphthalide is prepared in a simple, environmentally friendly one-pot process via hydrolysis with sodium hydroxide solution, acidification with sulfuric acid solution, and reductive lactone formation catalyzed by an iridium catalyst. After simple extraction, drying, and concentration, a product with a purity greater than 99% according to 1H NMR spectroscopy and a yield greater than 90% is obtained. The synthetic method provided by this invention features concise reaction conditions and steps, simple operation, is environmentally friendly, has high synthesis efficiency, and facilitates separation and purification. It has promising industrial applications and plays a positive role in organic synthesis, pharmaceutical production, and fine chemicals.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis. Using butenylphthalide as the starting material, it prepares the active pharmaceutical ingredient butylphthalide in an environmentally friendly manner through a one-pot process. Background Technology

[0002] Butylphthalide, chemically named (±)-3-butyl-1(H)-isobenzofuranone (CAS Registry No. 6066-49-5), also known as apigenin, can be extracted from celery seeds or synthesized artificially (Xiong, M. and Li, Z. Curr. Org. Chem. 2007, 11, 833-844.; Karmakar, R.; Pahari, P.; Mal, D. Chem. Rev. 2014, 114, 6213-6284.; Marco-Contelles J.; Zhang, YJ Med. Chem. 2020, 63, 12485-12510.). Butylphthalide is a Class I new drug with independent intellectual property rights in my country. It has various pharmacological activities, such as increasing the number of capillaries in ischemic areas, promoting the establishment of collateral circulation, enhancing cerebral blood flow, protecting mitochondria, improving cerebral energy metabolism, reducing infarct area, and alleviating the degree of neurological damage, etc. (Zhao, Q.; Zhang, C.; Wang, X.; Chen, L.; Ji, H.; Zhang, Y. Neurochem.) Int, 2012, 60, 134-144. Lu, XL; Luo, D.; Yao, XL; Wang, GL; Liu, ZY; Li, ZX; Huang,RX;Pei,Z.;Ou,JSJCardiovasc.Pharmacol.,2012,59,352-362.Li,J.;Li,Y.;Ogle,M.;Zhou,X.;Song,M.;Yu,SP;Wei,L.Brain Res,2010,1359,216-226.Huai,Y.;Dong,Y.;Xu,J.;Meng,N.;Song,C.;Li,W.;Lv,P.Neural Regen Res, 2013, 8, 1733-1742. Wo, X.;Han, J.;Wang, J.;Wang, X.;Liu, X.;Wang, Z. Pak J Med Sci, 2020, 36, 615-620.). Currently, commercially available butylphthalide is used to treat mild to moderate acute ischemic stroke.

[0003] The main synthetic methods using 3-butenylphthalide as a raw material include:

[0004] (1) Direct hydrogenation method. Li Shaobai et al. of Lanzhou University disclosed a method using diethyl ether as solvent and Pd / C as catalyst to obtain butylphthalide by column chromatography with a yield of 95% (Li Shaobai, Zhang Shaoming, Li Yulin. Synthesis of (±)-apigenin. Journal of Lanzhou University - Natural Science Edition, 1990, 26, 118-119). Recently published patent applications include: (Sun Xiaobo, Tian Yu, Sun Xiao. A hydroxypentylbenzoic acid diester compound and its preparation method and pharmaceutical application. Invention patent application. CN114315585; Tang Lei, Fan Lingling, Liu Jian, Chen Wenzhang, Zhu Tao. Ligustrazine-butylphthalide composite compounds and their preparation methods and applications in drugs. Invention patent application. CN106928155; Zheng Ligang, Zhang Bingzhu, Liu Xiaopeng, Zhang Yong, Wei Yonghao. Preparation method of butylphthalide. Invention patent application. CN115093385; Niu Feng, Qi Juncai, Zhao Shoupo, Jiao Kuiliang, Zhao Nan. A high-content butylphthalide composition and...) Its preparation method. Invention patent application. CN105968077; Niu Feng, Shi Mutian, Lu Shengjie, Qi Juncai, Jiao Kuiliang. A new pretreatment method for butylphthalide. Invention patent application. CN105418564; Niu Feng, Qi Juncai, Zhao Nan, Jiao Kuiliang, Han Chunjing. Invention patent application. CN105130934; Liu, H.; Deng, X.; Huang, X.; Ji, N.; He, W. Org. Biomol. Chem. 2020, 18, 3654-3658; He, X.; Xue, F. Tetrahedron Lett. 2014, 55, 1956-1958) also all adopt the catalytic hydrogenation method based on Pd catalyst. Duan Xiaofeng, Xiu Liwei, and others used Ni-series catalysts to replace Pd-series catalysts (Duan Xiaofeng, Xiu Liwei, Zhang Xianmei, Tan Dunchao, Zou Dechao, Chen Xianhong, Wang Ke. A method for preparing high-purity butylphthalide. Invention patent application. CN107235943; Xiu Liwei, Duan Xiaofeng, Zhang Xianmei, Tan Dunchao, Zou Dechao, Chen Xianhong, Wang Ke. A method for preparing butylphthalide. Invention patent application CN107216298). These methods require high-pressure hydrogen and specialized reaction equipment, posing certain risks. The use of diethyl ether under high-temperature conditions and the adoption of column chromatography separation in the purification process limit industrial application.

[0005]

[0006] (2) Three-step hydrolysis-reduction-esterification method (Zhang Lijun, Xu Jingren, Cai Wei, Qian Bin, Wen Shaopeng, Zhu Jing, Bao Meiling, Chen Fengqin, Shi Ying, Dong Zhikui. A method for preparing butylphthalide. Invention patent application. CN111943921; Chen Yong, Niu Po, Hu Heping, Ding Zhao. Invention patent application. CN114685410). Butenephthalide is hydrolyzed with an alkaline solution to obtain 2-pentanoylbenzoate, which is then reduced with sodium borohydride and acidified to obtain butylphthalide. This three-step method involves cumbersome reaction steps and is costly, making it unsuitable for large-scale preparation.

[0007]

[0008] To address the above problems, this invention aims to provide a simple, efficient, and environmentally friendly method for synthesizing butylphthalide. This method uses inexpensive, commercially available butene phthalide as the starting material and prepares racemic butylphthalide in a one-pot process under the catalysis of a highly efficient iridium catalyst. This method features high overall yield, short steps, mild and environmentally friendly reaction conditions, and simple post-processing. Summary of the Invention

[0009] The technical solution of the present invention is as follows:

[0010] As shown in the following reaction formula, 2-pentanoylbenzoic acid intermediate is obtained by hydrolysis with sodium hydroxide and acidification with sulfuric acid using butene phthalide (Formula 1) as raw material; without separation, iridium catalysts shown in C1 to C6 are directly added to the reaction flask, and the reaction is carried out in an aqueous phase in a one-pot process to prepare the active pharmaceutical ingredient butene phthalide (Formula 2).

[0011]

[0012] In the above reaction formula:

[0013] In the first step of the reaction, the amount of sodium hydroxide used is 1-20 molar equivalents, and the amount of sulfuric acid used is 2-20 molar equivalents, compared to butenephthalide (Formula 1).

[0014] In the second step of the reaction, the catalyst used is one of C1 to C6, with C1, C2, and C3 being preferred catalysts, and C2 being the most preferred.

[0015] In the second step of the reaction, the molar amount of the catalyst relative to butene phthalide (Formula 1) ranges from 0.001% to 10%.

[0016] In the first step of the reaction, the reaction temperature is 0–100℃;

[0017] In the second step of the reaction, the reaction temperature is 0 to 100°C, with the preferred temperature being 80°C.

[0018] In the second step of the reaction, the solvent is usually water, but the reaction can also occur if methanol, ethanol, propanol, isopropanol, or acetone are added.

[0019] In the second step of the reaction, formic acid is used as the hydrogen source; 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 the hydrogen source.

[0020] In the second step of the reaction, the amount of formic acid or formate salt relative to butenephthalide (Formula 1) is 1 to 100 molar equivalents. Advantages and positive effects of the present invention:

[0021] This invention provides a convenient method for preparing the active pharmaceutical ingredient butylphthalide. This invention will have positive applications in the fields of biology, medicine, and fine chemicals. Compared to previous methods, the synthesis method provided by this invention is simple to operate, environmentally friendly, and highly efficient, making it very promising for industrial applications. Attached Figure Description

[0022] Figure 1 The 1H NMR spectrum (400MHz, CDCl3) of the active pharmaceutical ingredient butylphthalide.

[0023] Figure 2 The image shows the carbon NMR spectrum (101 MHz, CDCl3) of the active pharmaceutical ingredient butylphthalide.

[0024] Figure 3 This is the gas chromatogram of the active pharmaceutical ingredient butylphthalide.

[0025] Figure 4 This is the EI (Electron Ionization) source mass spectrum of the active pharmaceutical ingredient butylphthalide. Detailed Implementation

[0026] The present invention is further illustrated below using a C2 catalyst as an example, but this does not limit the scope of the invention to the examples described.

[0027] first step:

[0028] Add 9.40 g (50 mmol) of n-butenyl phthalate (Formula 1) and 20 mL of sodium hydroxide aqueous solution (11 wt%) to a 100 mL three-necked flask equipped with a condenser and a dropping funnel. Stir at 100 °C for 1 hour. After the solution cools to room temperature, add dilute sulfuric acid (2 mol / L) to the flask to adjust the pH to 6-7.

[0029] Step Two:

[0030] Catalyst C2 (5.7 mg, 0.02 mol%) was dissolved in 10 mL of deionized water and added to the above system. After preheating at 80 °C for 3 minutes, anhydrous formic acid (15 mL, 0.4 mol, 8 equiv) was added dropwise to the reaction system through a dropping funnel, and the reaction was carried out at 80 °C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain butylphthalide as shown in Formula 2.

[0031] Yellow oily liquid, yield 9.10g, 95% yield. f =0.60 (petroleum ether / ethyl acetate = 5:1, v / v).

[0032] 1 H NMR (400MHz, CDCl3): δ7.87(d,J=7.7Hz,1H),7.65(td,J=7.6,0.9Hz,1H),7.50(t,J=7.5Hz,1H),7.43(d,J=7.6Hz,1H),5.46(dd,J=7.9,4 .1Hz,1H),2.03(dddd,J=14.2,10.0,5.9,4.2Hz,1H),1.74(dddd,J=14.5,10.0,7.9,4.9Hz,1H),1.52–1.31(m,4H),0.88(t,J=7.1Hz,3H).

[0033] 13 C NMR (101MHz, CDCl3): δ170.8,150.2,134.0,129.1,126.2,125.7,121.8,81.5,34.5,27.0,22.5,13.9.

[0034] GC-MS(EI)[M]:calcd 190.10,found:190.20.

[0035] Using the same operating procedures and other catalysts, the same products can be obtained. Specific yields and catalyst dosages are shown in the table below.

[0036] catalyst Catalyst dosage (mg) Catalyst equivalent (mol%) Separation yield (%) C1 5.9 0.02 92 C2 5.7 0.02 95 C3 5.7 0.02 94 C4 5.7 0.02 93 C5 5.4 0.02 91 C6 5.8 0.02 90

Claims

1. A process for the preparation of a bulk drug of dl-bufonin, characterized in that, The method comprises two steps: in the first step, butenolide is used as raw material, sodium hydroxide aqueous solution is added for hydrolysis, and then sulfuric acid is added for acidification; in the second step, a C1-C6 catalyst, formic acid or formate salt is directly added into the reaction system of the first step to generate racemic butenafine of formula 2 by one-pot method 。

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