Preparation method of benvimod

Abstract

According to the preparation method of the benvimod, the trans-cinnamyl aldehyde is used as a raw material, reaction conditions are mild, used reagents are low in toxicity and high in safety, the production process is easy and convenient to operate, the product yield is high, and the preparation method is suitable for large-scale industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine and chemical industry, and relates to a preparation method of binimetinib. BACKGROUND

[0002] The binimetinib cream is researched and developed by Beijing Wenfeng Tianji Pharmaceutical Technology Co., Ltd., and is approved for marketing by the State Drug Administration in May 2019, and the trade name is Xinbik. The binimetinib is approved for marketing by the FDA on May 23, 2022, and the trade name is Vtama, which is used for treating adult plaque psoriasis externally. All psoriasis patients, regardless of severity, are included. The binimetinib is the first nonsteroidal new molecular entity for treating psoriasis approved in the United States in the past 25 years. The binimetinib is a stilbene compound, which belongs to a nonsteroidal anti-inflammatory / immune and anti-cell proliferation small molecule drug, can significantly inhibit the expression of factors such as interleukin-2, interleukin-13, interleukin-17 and tumor necrosis factor, and can also inhibit the activation and migration of T cells, and can be used for treating various major autoimmune, inflammatory and cell proliferation diseases. The structure of the binimetinib is as follows:

[0003]

[0004] Patent CN103172497A discloses a synthesis method of the binimetinib. Methyl 3,5-dimethoxybenzoate is used as raw material, and (E)-3,5-dihydroxy-4-isopropyl stilbene is prepared through the steps of isopropylization, reduction, chlorination, phosphate esterification, condensation and demethylation. Concentrated sulfuric acid is used in step one, potassium borohydride and boron trifluoride ether are used in step two, and thionyl chloride is used in step three. The production process is highly dangerous and pollutes the environment. Pyridine hydrochloride is used in step five, and the reaction temperature is 180-190 DEG C. The production equipment has high requirements. The specific synthesis route is as follows:

[0005]

[0006] Patent CN105884581A discloses a synthesis method of the binimetinib. 4-Isopropylbenzaldehyde is used as raw material, and (E)-3,5-dihydroxy-4-isopropyl stilbene is prepared through the steps of bromination, methoxylation, demethylation, esterification and condensation. Liquid bromine is used in step one, sodium methoxide is used in step two, and pyridine is used in step three. The reagents used in the production process are highly toxic and inconvenient to operate. Moreover, many by-products are generated in the synthesis process. The specific synthesis route is as follows:

[0007] SUMMARY

[0008] The application aims to provide a preparation method of binidolol based on the prior art, which uses trans-cinnamaldehyde as raw material, has mild reaction conditions, uses reagents with low toxicity and high safety, is easy to operate, has high product yield, and is suitable for large-scale industrial production.

[0009] The technical scheme of the application is as follows.

[0010] A preparation method of binidolol comprises the following steps.

[0011] (1) compound I is subjected to condensation reaction with 4-methyl-2-pentanone in the presence of a base to prepare compound II;

[0012] (2) compound II is subjected to chemical reaction with diethyl malonate in the presence of triethylamine and lithium bromide to prepare compound III;

[0013] (3) compound III is subjected to cyclization reaction in the presence of potassium tert-butoxide to prepare compound IV;

[0014] (4) compound IV is subjected to hydrolysis reaction in the presence of a base, acidification after adding an acid, and decarboxylation reaction to prepare compound V;

[0015] (5) compound V is subjected to bromination reaction in the presence of a brominating agent to prepare compound VI;

[0016] (6) compound VI is subjected to chemical reaction in the presence of a catalyst to prepare compound VII; the specific synthesis route is as follows:

[0017]

[0018]

[0019] For the application, in step (1), the base is sodium hydroxide or potassium hydroxide. The molar ratio of compound I to the base is 1:1.2-1.8, preferably 1:1.4-1.6, and more preferably 1:1.5; and the molar ratio of compound I to 4-methyl-2-pentanone is 1:2.5-4.0, preferably 1:3.0-3.4, and more preferably 1:3.2.

[0020] In step (1), the reaction temperature is -15-5 ℃, preferably -10-0 ℃; the reaction time is 2-10 hours, preferably 4 hours; and the reaction solvent is one or more selected from the group consisting of methanol, ethanol and isopropanol.

[0021] For the present application, in step (2), the molar ratio of compound I to diethyl malonate is 1:1.2-1.8, preferably 1:1.4-1.6, more preferably 1:1.5; the molar ratio of compound I to triethylamine is 1:1.2-1.8, preferably 1:1.4-1.6, more preferably 1:1.5; the molar ratio of compound I to lithium bromide is 1:0.1-0.5, preferably 1:0.15-0.25, more preferably 1:0.2.

[0022] In step (2), the reaction temperature is 20-50℃; preferably 25-35℃ or 35-45℃; the reaction time is 8-20 hours, preferably 10-14 hours; and the reaction solvent is selected from toluene or ethylbenzene.

[0023] For the present application, in step (3), the molar ratio of compound III to potassium tert-butoxide is 1:1.2-1.8, preferably 1:1.3-1.5, more preferably 1:1.4; and the reaction solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dimethyl sulfoxide or N,N-dimethylformamide.

[0024] For the present application, in step (4), the base is sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide; wherein the molar ratio of compound IV to base is 1:2.5-4.5, preferably 1:3.2-3.8, more preferably 1:3.4-3.6; and the reaction solvent is one or more of methanol, ethanol or toluene.

[0025] In step (4), during the hydrolysis reaction, the temperature is 15-35℃, preferably 20-30℃; the reaction time is 2-8 hours, preferably 4 hours; during the decarboxylation reaction, the reaction temperature is 45-65℃, preferably 50-60℃; and the reaction time is 0.5-2.5 hours, preferably 1 hour.

[0026] For the present application, in step (5), the brominating agent is selected from 1,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide or benzyltrimethylammonium tribromide, preferably 1,3-dibromo-5,5-dimethylhydantoin or N-bromosuccinimide; wherein the molar ratio of compound V to brominating agent is 1:0.2-2.0, preferably 1:0.4-1.5, more preferably 1:0.5-1.2; the reaction temperature is 35-55℃, preferably 40-50℃; the reaction time is 10-20 hours, preferably 14-16 hours; and the reaction solvent is selected from one or more of methanol, ethanol or isopropanol.

[0027] For the present application, in step (6), the catalyst is selected from one or more of tetrabutylammonium iodide, tetrabutylammonium bromide or tetrabutylammonium chloride, preferably tetrabutylammonium chloride or tetrabutylammonium iodide; wherein the molar ratio of compound VI to catalyst is 1:0.1-0.5, preferably 1:0.15-0.25, more preferably 1:0.2; the reaction temperature is 65-85°C, preferably 70-80°C; the reaction time is 2-8 hours, preferably 4 hours; and the reaction solvent is one or more of methanol, ethanol or acetonitrile.

[0028] The technical solution of the present application has the following advantages:

[0029] The present application provides a preparation method of binidolol, which uses trans-cinnamaldehyde as a raw material, has mild reaction conditions, uses reagents with low toxicity and high safety, is simple to operate, has high product yield, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 is the HPLC spectrum of the target product binidolol in Example 1;

[0031] Figure 2 is the HPLC spectrum of the target product binidolol in Example 2. DETAILED DESCRIPTION

[0032] The present application can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the content described in the examples is only used to illustrate the present application, and should not and will not limit the present application described in detail in the claims.

[0033] Example 1

[0034] A preparation method of binidolol includes the following steps:

[0035] (1) Preparation of compound II ((5E,7E)-2-methyl-8-phenyl octa-5,7-dien-4-one), the synthesis route is as follows:

[0036]

[0037] To a reaction flask was added compound I (trans-cinnamaldehyde, 20.00 g, 0.151 mol) and 4-methyl-2-pentanone (48.50 g, 0.484 mol), stirring was started, and sodium hydroxide-methanol solution (sodium hydroxide (9.08 g, 0.227 mol) dissolved in 100 ml of methanol) was added dropwise. After the dropwise addition was completed, the reaction was stirred for 4 hours at -10 to 0 °C. The resulting reaction solution was added to 200 ml of toluene and 100 ml of drinking water, and the mixture was separated. The organic phase was washed with 100 ml of drinking water and 100 ml of saturated brine, respectively. The organic phase was concentrated under reduced pressure, and distilled with 100 ml of toluene. After the concentration was completed, compound II ((5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one) was obtained as a yellowish liquid in a yield of 97.0%.

[0038] (2) Preparation of compound III ((E)-2-(7-methyl-5-oxo-l-phenyloct-l-en-3-yl)malonic acid diethyl ester) according to the following synthetic scheme:

[0039]

[0040] To a reaction flask was added compound II ((5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one, 30.00 g, 0.140 mol), 180 ml of toluene, malonic acid diethyl ester (33.63 g, 0.210 mol), triethylamine (21.25 g, 0.210 mol), and lithium bromide (2.43 g, 0.028 mol), stirring was started, and the reaction was stirred for 10 hours at 35 to 45 °C. The resulting reaction solution was cooled and separated. The organic phase was washed with 240 ml of drinking water, and then concentrated under reduced pressure. After the concentration was completed, compound III ((E)-2-(7-methyl-5-oxo-l-phenyloct-l-en-3-yl)malonic acid diethyl ester) was obtained as a yellowish liquid in a yield of 94.1%.

[0041] (3) Preparation of compound IV ((E)-3-isopropyl-2,4-dioxo-6-phenylstyrylcyclohexane-l-carboxylic acid ethyl ester) according to the following synthetic scheme:

[0042]

[0043] Into a reaction flask was placed compound III ((E)-2-(7-methyl-5-oxo-l- phenylhept-l-en-3-yl)malonic acid diethyl ester, 15.00 g, 0.040 mol) and 60 ml of toluene, and stirring was started. A solution of potassium tert-butoxide in 2-methyltetrahydrofuran (potassium tert-butoxide, 6.29 g, 0.056 mol, dissolved in 30 ml of 2-methyltetrahydrofuran) was added dropwise at a temperature of -5 to 5 °C. After the dropwise addition was completed, the reaction was stirred at 20 to 30 °C for 5 hours. The resulting reaction solution was added to 1 N hydrochloric acid solution, 60 ml, and the organic phase was separated. The organic phase was washed with 60 ml of drinking water and saturated 60 ml of brine, respectively, and then concentrated under reduced pressure. To the concentrate was added 40 ml of toluene, and the solution was stirred at a temperature of 20 to 30 °C until it became clear. Then, 150 ml of methylcyclohexane was added dropwise, and the mixture was allowed to crystallize for 2 hours. The mixture was filtered, and the filter cake was dried under vacuum at 30 to 40 °C for 16 hours to obtain compound IV ((E)-3-isopropyl-2,4-dioxo-6-styrylcyclohexane-l-carboxylic acid ethyl ester) as a white solid in a yield of 92.8%.

[0044] (4) Preparation of compound V ((E)-2-isopropyl-5-styrylcyclohexane-l,3-dione) according to the following synthetic scheme:

[0045]

[0046] Into a reaction flask was placed compound III ((E)-2-(7-methyl-5-oxo-l- phenylhept-l-en-3-yl)malonic acid diethyl ester, 15.00 g, 0.040 mol) and 60 ml of toluene, and stirring was started. A solution of potassium tert-butoxide in 2-methyltetrahydrofuran (potassium tert-butoxide, 6.29 g, 0.056 mol, dissolved in 30 ml of 2-methyltetrahydrofuran) was added dropwise at a temperature of -5 to 5 °C. After the dropwise addition was completed, the reaction was stirred at 20 to 30 °C for 5 hours. The resulting reaction solution was added to 1 N hydrochloric acid solution, 60 ml, and the organic phase was separated. The organic phase was washed with 60 ml of drinking water and saturated 60 ml of brine, respectively, and then concentrated under reduced pressure. To the concentrate was added 40 ml of toluene, and the solution was stirred at a temperature of 20 to 30 °C until it became clear. Then, 150 ml of methylcyclohexane was added dropwise, and the mixture was allowed to crystallize for 2 hours. The mixture was filtered, and the filter cake was dried under vacuum at 30 to 40 °C for 16 hours to obtain compound IV ((E)-3-isopropyl-2,4-dioxo-6-styrylcyclohexane-l-carboxylic acid ethyl ester) as a white solid in a yield of 92.8%.

[0047] (5) Preparation of compound VI ((E)-2-bromo-2-isopropyl-5-styrylcyclohexane-l,3- dione) according to the following synthetic scheme:

[0048]

[0049] Into a reaction flask was placed compound V ((E)-2-isopropyl-5-styrylcyclohexane-1,3-dione, 8.00 g, 0.031 mol) and 64 ml of methanol, stirring was started, 1,3-dibromo-5,5-dimethylhydantoin (4.92 g, 0.017 mol) was added, the reaction was stirred at 40-50 °C for 1 hour, the resulting reaction solution was added dropwise with 48 ml of drinking water, the temperature was lowered to 20-30 °C, and crystallization was carried out for 2 hours, the filter cake was vacuum dried at 40-50 °C for 16 hours to obtain compound VI ((E)-2-bromo-2-isopropyl-5-styrylcyclohexane-1,3-dione) in the form of a white solid with a yield of 92.0%.

[0050] (6) Preparation of compound VII ((E)-3,5-dihydroxy-4-isopropylstilbene), the synthetic route is as follows:

[0051]

[0052] Into a reaction flask was placed compound VI ((E)-2-bromo-2-isopropyl-5-styrylcyclohexane-1,3-dione, 9.00 g, 0.269 mol), tetrabutylammonium chloride (14.94 g, 0.054 mol) and 27 ml of acetonitrile, stirring was started, the reaction was stirred at 70-80 °C for 4 hours, the resulting reaction solution was added with 27 ml of methyl tert-butyl ether and 45 ml of drinking water, the liquid was separated, the organic phase was washed with 45 ml of drinking water, 45 ml of n-heptane was added dropwise, crystallization was carried out for 2 hours, the filter cake was vacuum dried at 75-85 °C for 24 hours to obtain the target product, i.e. compound VII ((E)-3,5-dihydroxy-4-isopropylstilbene), with a yield of 90.0% and a HPLC purity of 99.958%.

[0053] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 2H, OH), 7.57 (d, 2H, J = 7.52 Hz), 7.36 (t, 2H, J = 7.48 Hz), 7.25 (t, 1H, J = 7.24 Hz), 7.01 (d, 1H, J = 16.36 Hz), 6.88 (d, 1H, J = 16.32 Hz), 6.48 (s, 2H), 3.34 (s, 1H), 1.24 (d, 6H, J = 7.04 Hz).

[0054] Example 2

[0055] (1) Preparation of compound II ((5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one), the synthetic route is as follows:

[0056]

[0057] To a reaction flask was added compound I (trans-cinnamaldehyde, 20.00 g, 0.151 mol) and 4-methyl-2-pentanone (48.50 g, 0.484 mol), stirring was started, and a potassium hydroxide-methanol solution (potassium hydroxide (12.74 g, 0.227 mol) dissolved in 100 ml of methanol) was added dropwise. After the dropwise addition was completed, the reaction was stirred for 4 hours at -10 to 0 °C. The resulting reaction solution was added to 200 ml of toluene and 100 ml of drinking water, and the mixture was separated. The organic phase was washed with 100 ml of drinking water and 100 ml of saturated brine, respectively, and then concentrated under reduced pressure. The resulting compound II ((5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one) was obtained as a yellowish liquid in a yield of 96.2%.

[0058] (2) Preparation of compound III ((E)-2-(7-methyl-5-oxo-l-phenyloct-l-en-3-yl)malonic acid diethyl ester) was prepared according to the following synthetic scheme:

[0059]

[0060] To a reaction flask was added compound II ((5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one, 25.00 g, 0.117 mol), 150 ml of toluene, malonic acid diethyl ester (28.03 g, 0.175 mol), triethylamine (17.71 g, 0.175 mol), and lithium bromide (2.01 g, 0.023 mol), stirring was started, and the reaction was stirred for 14 hours at 25 to 35 °C. The resulting reaction solution was separated into layers at a low temperature, and the organic phase was washed with 200 ml of drinking water. The organic phase was concentrated under reduced pressure, and the resulting compound III ((E)-2-(7-methyl-5-oxo-l-phenyloct-l-en-3-yl)malonic acid diethyl ester) was obtained as a yellowish liquid in a yield of 92.8%.

[0061] (3) Preparation of compound IV ((E)-3-isopropyl-2,4-dioxo-6-phenylstyrylcyclohexane-l-carboxylic acid ethyl ester) was prepared according to the following synthetic scheme:

[0062]

[0063] To a reaction flask was added compound III ((E)-2-(7-methyl-5-oxo-l-phenyl- oct-l-en-3-yl)malonic acid diethyl ester, 12.00 g, 0.032 mol) and 48 ml of toluene, and stirring was started. A solution of potassium tert-butoxide-dimethylsulfoxide (potassium tert-butoxide (5.03 g, 0.045 mol) dissolved in 24 ml of dimethylsulfoxide) was added dropwise at a temperature of -5 to 5 °C. After the dropwise addition was completed, the reaction was stirred at 20 to 30 °C for 6 hours. The resulting reaction solution was added to 1 N 48 ml of hydrochloric acid solution, and the organic phase was separated and washed with 48 ml of drinking water and 48 ml of saturated brine, respectively. The organic phase was then concentrated under reduced pressure. To the concentrate was added 32 ml of toluene, and the solution was stirred at a temperature of 20 to 30 °C until it became clear. Then, 120 ml of n-heptane was added dropwise. After the dropwise addition was completed, the solution was allowed to crystallize for 2 hours. The resulting product was filtered, and the filter cake was dried at 30 to 40 °C under reduced pressure for 16 hours to obtain compound IV ((E)-3-isopropyl-2,4-dioxo-6-phenylstyrylcyclohexane-l-carboxylic acid ethyl ester) as a white solid in a yield of 92.5%.

[0064] (4) Preparation of compound V ((E)-2-isopropyl-5-phenylstyrylcyclohexane-l,3-dione) according to the following synthetic scheme:

[0065]

[0066] To a reaction flask was added compound III ((E)-2-(7-methyl-5-oxo-l-phenyl- oct-l-en-3-yl)malonic acid diethyl ester, 12.00 g, 0.032 mol) and 48 ml of toluene, and stirring was started. A solution of potassium tert-butoxide-dimethylsulfoxide (potassium tert-butoxide (5.03 g, 0.045 mol) dissolved in 24 ml of dimethylsulfoxide) was added dropwise at a temperature of -5 to 5 °C. After the dropwise addition was completed, the reaction was stirred at 20 to 30 °C for 6 hours. The resulting reaction solution was added to 1 N 48 ml of hydrochloric acid solution, and the organic phase was separated and washed with 48 ml of drinking water and 48 ml of saturated brine, respectively. The organic phase was then concentrated under reduced pressure. To the concentrate was added 32 ml of toluene, and the solution was stirred at a temperature of 20 to 30 °C until it became clear. Then, 120 ml of n-heptane was added dropwise. After the dropwise addition was completed, the solution was allowed to crystallize for 2 hours. The resulting product was filtered, and the filter cake was dried at 30 to 40 °C under reduced pressure for 16 hours to obtain compound IV ((E)-3-isopropyl-2,4-dioxo-6-phenylstyrylcyclohexane-l-carboxylic acid ethyl ester) as a white solid in a yield of 92.5%.

[0067] (5) Preparation of compound VI ((E)-2-bromo-2-isopropyl-5-phenylstyrylcyclohexane-l,3-dione) according to the following synthetic scheme:

[0068]

[0069] Into a reaction flask was added compound V ((E)-2-isopropyl-5-styrylcyclohexane-1,3-dione, 10.00 g, 0.039 mol) and 80 ml of methanol, stirring was started, N-bromosuccinimide (7.64 g, 0.043 mol) was added, the reaction was stirred at 40-50 °C for 1 hour, the resulting reaction solution was added dropwise with 60 ml of drinking water, cooled to 20-30 °C, crystallized for 2 hours, suction filtered, the filter cake was vacuum dried at 40-50 °C for 14 hours to obtain compound VI ((E)-2-bromo-2-isopropyl-5-styrylcyclohexane-1,3-dione) as a white solid with a yield of 92.8%.

[0070] (6) Preparation of compound VII ((E)-3,5-dihydroxy-4-isopropylstilbene), the synthetic route is as follows:

[0071]

[0072] Into a reaction flask was added compound VI ((E)-2-bromo-2-isopropyl-5-styrylcyclohexane-1,3-dione, 12.00 g, 0.359 mol), tetrabutylammonium iodide (26.47 g, 0.072 mol) and 36 ml of acetonitrile, stirring was started, the reaction was stirred at 70-80 °C for 4 hours, the resulting reaction solution was added with 36 ml of methyl tert-butyl ether and 60 ml of drinking water, liquid-liquid separation was performed, the organic phase was washed with 60 ml of drinking water, 60 ml of n-heptane was added dropwise, crystallized for 3 hours, suction filtered, the filter cake was vacuum dried at 75-85 °C for 24 hours to obtain the target product, i.e., compound VII ((E)-3,5-dihydroxy-4-isopropylstilbene), with a yield of 91.6% and a HPLC purity of 99.969%.

[0073] Comparative Example 1

[0074] Preparation of compound II ((5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one), the synthetic route is as follows:

[0075]

[0076] Into a reaction flask was added compound I (trans-cinnamaldehyde, 20.00 g, 0.151 mol) and 4-methyl-2-pentanone (48.50 g, 0.484 mol), stirring was started, and sodium hydroxide-methanol solution (sodium hydroxide (9.08 g, 0.227 mol) dissolved in 100 ml of methanol) was added dropwise. After the dropwise addition was completed, the reaction was stirred at 10-20 °C for 4 hours. The resulting reaction solution was added to 200 ml of toluene and 100 ml of drinking water, and the mixture was separated. The organic phase was washed with 100 ml of drinking water and 100 ml of saturated brine, respectively. The organic phase was concentrated under reduced pressure, and distilled with 100 ml of toluene. After the concentration was completed, compound II ((5E, 7E)-2-methyl-8-phenylocta-5, 7-dien-4-one) was obtained as a yellowish liquid in a yield of 42.7%.

[0077] Comparative Example 2

[0078] Compound III ((E)-2-(7-methyl-5-oxo-l-phenyloct-l-en-3-yl)malonic acid diethyl ester) was prepared according to the following synthetic route:

[0079]

[0080] Into a reaction flask was added compound II ((5E, 7E)-2-methyl-8-phenylocta-5, 7-dien-4-one, 20.00 g, 0.094 mol), 120 ml of toluene, malonic acid diethyl ester (22.42 g, 0.140 mol), triethylamine (14.17 g, 0.140 mol), and lithium bromide (1.61 g, 0.018 mol), stirring was started, and the reaction was stirred at 55-65 °C for 15 hours. The resulting reaction solution was cooled and separated. The organic phase was washed with 160 ml of drinking water, and then concentrated under reduced pressure. After the concentration was completed, compound III ((E)-2-(7-methyl-5-oxo-l-phenyloct-l-en-3-yl)malonic acid diethyl ester) was obtained as a yellowish liquid in a yield of 62.8%.

[0081] The above examples are only used to illustrate the technical solutions of the present application, but not to limit the present application; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that they can still modify the technical solutions described in the foregoing examples, or make equivalent replacements for some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A process for the preparation of binidolide, characterized in that, The method comprises the following steps: (1) condensation reaction of compound I with 4-methyl-2-pentanone in the presence of a base to prepare compound II; (2) chemical reaction of compound II with diethyl malonate in the presence of triethylamine and lithium bromide to prepare compound III; (3) cyclization reaction of compound III in the presence of potassium tert-butoxide to prepare compound IV; (4) hydrolysis reaction of compound IV in the presence of a base, acidification after adding an acid, and decarboxylation reaction to prepare compound V; (5) bromination reaction of compound V in the presence of a brominating agent to prepare compound VI; (6) chemical reaction of compound VI in the presence of a catalyst to prepare compound VII; The specific synthesis route is as follows:

2. The process for the preparation of binidolide according to claim 1, characterized in that, In step (1), the base is sodium hydroxide or potassium hydroxide; the molar ratio of compound I to the base is 1:1.2-1.8, preferably 1:1.4-1.6, and more preferably 1:1.5; and the molar ratio of compound I to 4-methyl-2-pentanone is 1:2.5-4.0, preferably 1:3.0-3.4, and more preferably 1:3.

2.

3. The process for preparing benveimod according to claim 1, characterized in that, In step (1), the reaction temperature is -15-5°C, preferably -10-0°C; the reaction time is 2-10 hours, preferably 4 hours; and the reaction solvent is one or more of methanol, ethanol, or isopropanol.

4. The process for preparing benveimod according to claim 1, characterized in that, In step (2), the molar ratio of compound I to diethyl malonate is 1:1.2-1.8, preferably 1:1.4-1.6, and more preferably 1:1.5; the molar ratio of compound I to triethylamine is 1:1.2-1.8, preferably 1:1.4-1.6, and more preferably 1:1.5; and the molar ratio of compound I to lithium bromide is 1:0.1-0.5, preferably 1:0.15-0.25, and more preferably 1:0.

2.

5. The process for preparing binidolide according to claim 1, characterized in that, In step (2), the reaction temperature is 20-50°C, preferably 25-35°C or 35-45°C; the reaction time is 8-20 hours, preferably 10-14 hours; and the reaction solvent is toluene or ethylbenzene.

6. The process for preparing benveimod according to claim 1, characterized in that, In step (3), the molar ratio of compound III to potassium tert-butoxide is 1:1.2-1.8, preferably 1:1.3-1.5, and more preferably 1:1.4; and the reaction solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dimethyl sulfoxide, or N,N-dimethylformamide.

7. The process for preparing benveimod according to claim 1, characterized in that, In step (4), the base is sodium hydroxide, potassium hydroxide, or lithium hydroxide, preferably sodium hydroxide; the molar ratio of compound IV to the base is 1:2.5-4.5, preferably 1:3.2-3.8, and more preferably 1:3.4-3.6; and the reaction solvent is one or more of methanol, ethanol, or toluene.

8. The process for preparing benveimod according to claim 1, characterized in that, In step (4), in the hydrolysis reaction, the temperature is 15-35°C, preferably 20-30°C; the reaction time is 2-8 hours, preferably 4 hours; in the decarboxylation reaction, the reaction temperature is 45-65°C, preferably 50-60°C; and the reaction time is 0.5-2.5 hours, preferably 1 hour.

9. The process for preparing benveimod according to claim 1, characterized in that, In step (5), the brominating agent is selected from 1,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide or benzyltrimethylammonium tribromide, preferably 1,3-dibromo-5,5-dimethylhydantoin or N-bromosuccinimide; the molar ratio of the compound V to the brominating agent is 1:0.2-2.0, preferably 1:0.4-1.5, more preferably 1:0.5-1.2; the reaction temperature is 35-55°C, preferably 40-50°C; the reaction time is 10-20 hours, preferably 14-16 hours; and the reaction solvent is one or more of methanol, ethanol or isopropanol.

10. The process for preparing binidolide according to claim 1, characterized in that, In step (6), the catalyst is selected from one or more of tetrabutylammonium iodide, tetrabutylammonium bromide or tetrabutylammonium chloride, preferably tetrabutylammonium chloride or tetrabutylammonium iodide; the molar ratio of the compound VI to the catalyst is 1:0.1-0.5, preferably 1:0.15-0.25, more preferably 1:0.2; the reaction temperature is 65-85°C, preferably 70-80°C; the reaction time is 2-8 hours, preferably 4 hours; and the reaction solvent is one or more of methanol, ethanol or acetonitrile.

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