Preparation method of benvimod

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of benvimod. The preparation method provided by the invention comprises the following steps: mixing 3, 5-dimethoxy-4-isopropyl benzyl alcohol, 2-iodoxybenzoic acid and a first organic solvent, and carrying out oxidation reaction to obtain 3, 5-dimethoxy-4-isopropyl benzaldehyde; mixing the 3, 5-dimethoxy-4-isopropyl benzaldehyde, diethyl benzyl phosphate, a base catalyst and a second organic solvent, and carrying out a condensation reaction, so as to obtain 3, 5-dimethoxy-4-isopropyl stilbene; and mixing the 3, 5-dimethoxy-4-isopropyl stilbene, aluminum trichloride, an organic alkali and a third organic solvent, and carrying out a demethylation reaction, so as to obtain the benvimod. The preparation method provided by the invention has the advantages of cheap and easily available raw materials, simple and efficient process, no need of complex post-treatment, high yield and suitability for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of benvimod. Background Art

[0002] Benvitimod, also known as benvitimod, is mainly used for the topical treatment of mild to moderate stable psoriasis vulgaris (mainly plaque psoriasis) in adults. Currently, the synthesis routes of benvitimod mainly include the following.

[0003] The related art discloses route 1 (Formula 1) with a total yield of 39.1%. In the first step of the route, the isopropyl group is prone to di- or tri-substituted products, because the alkyl group is an induced electron-donating group, and it is difficult to control the mono-substitution; compound 3 to compound 4 uses thionyl chloride, which is highly toxic and dangerous, and industrial production requires high equipment and operation; the demethylation conditions in the last step are difficult to control and the pyridine has a strong odor, which is inconvenient for industrial production.

[0004]

[0005] Route 2 (Formula 2) has a total yield of 56.5%. In this route, the bromination reaction of compound 8 to compound 9 is prone to produce monosubstituted or polysubstituted byproducts; compound 10 to compound 11 has a strong pyridine odor and requires a high temperature reaction of 150°C, which places high requirements on the reaction equipment.

[0006]

[0007] Route 3 (Formula 3) has a total yield of 39.0%. Lithium aluminum tetrahydride, boron tribromide and butyl lithium in this route are very likely to cause explosion and fire, and the industrial production risk factor is extremely high; PCC contains heavy metal chromium, and it is necessary to check the chromium residue in the drug. The industrial production risk factor of this route is extremely high.

[0008]

[0009] The total yield of route 4 (Formula 4) is 48.2%. The raw materials of this route are uncommon reagents and are relatively expensive.

[0010]

[0011] It can be seen that the current synthesis route of Benvimod has high requirements on equipment or raw materials, and there is an urgent need to provide a simpler and more efficient preparation process. Summary of the invention

[0012] The object of the present invention is to provide a method for preparing benvimod. The preparation method provided by the present invention is simple and efficient, and the raw materials are cheap and easily available.

[0013] In order to achieve the above object, the present invention provides the following technical solutions:

[0014] The present invention provides a method for preparing benvimod, comprising the following steps:

[0015] Mixing 3,5-dimethoxy-4-isopropylbenzyl alcohol, 2-iodoacylbenzoic acid and a first organic solvent, and performing an oxidation reaction to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde;

[0016] The 3,5-dimethoxy-4-isopropylbenzaldehyde, diethyl benzyl phosphate, a base catalyst and a second organic solvent are mixed to carry out a condensation reaction to obtain 3,5-dimethoxy-4-isopropylstilbene;

[0017] The 3,5-dimethoxy-4-isopropylstilbene, aluminum chloride, an organic base and a third organic solvent are mixed and subjected to a demethylation reaction to obtain the benvimod.

[0018] Preferably, the mass ratio of the 3,5-dimethoxy-4-isopropylbenzyl alcohol to 2-iodoacylbenzoic acid is 1:1.4-1.8;

[0019] The temperature of the oxidation reaction is 20-30° C. and the time is 2-3 hours.

[0020] Preferably, the mass ratio of 3,5-dimethoxy-4-isopropylbenzaldehyde to diethyl benzyl phosphate is 1:1 to 1.2;

[0021] The condensation reaction temperature is 47-53° C. and the reaction time is 2-3 hours.

[0022] Preferably, the mass ratio of 3,5-dimethoxy-4-isopropylstilbene to aluminum chloride is 1:2.5-3;

[0023] The temperature of the demethylation reaction is 107-113° C. and the time is 2-4 hours.

[0024] Preferably, the first organic solvent is dimethyl sulfoxide;

[0025] The second organic solvent is tetrahydrofuran;

[0026] The third organic solvent is toluene.

[0027] Preferably, the preparation method of 3,5-dimethoxy-4-isopropylbenzyl alcohol comprises the following steps:

[0028] Mixing 3,5-dihydroxybenzoic acid, dimethyl sulfate, potassium carbonate and a fourth organic solvent to carry out a methylation reaction to obtain methyl 3,5-dimethoxybenzoate;

[0029] The methyl 3,5-dimethoxybenzoate, isopropanol, chlorosulfonic acid and sulfuric acid are mixed and subjected to an alkylation reaction to obtain 3,5-dimethoxy-4-isopropylbenzoic acid;

[0030] The 3,5-dimethoxy-4-isopropylbenzoic acid, borohydride salt, boron trifluoride solution and the fifth organic solvent are mixed and subjected to a reduction reaction to obtain the 3,5-dimethoxy-4-isopropylbenzyl alcohol.

[0031] Preferably, the mass ratio of 3,5-dihydroxybenzoic acid to dimethyl sulfate is 2:4-7;

[0032] The temperature of the methylation reaction is 62-68° C. and the time is 20-30 hours.

[0033] Preferably, the mass ratio of methyl 3,5-dimethoxybenzoate to isopropanol is 10:4-5;

[0034] The temperature of the alkylation reaction is 57-63° C. and the time is 20-24 hours.

[0035] Preferably, the mass ratio of the 3,5-dimethoxy-4-isopropylbenzoic acid to the borohydride salt is 4:3-4;

[0036] The temperature of the reduction reaction is room temperature and the time is 4 to 5 hours.

[0037] Preferably, the demethylation reaction further comprises extraction, concentration of the organic phase and recrystallization performed in sequence.

[0038] The present invention provides a preparation method of Benvimod, comprising the following steps: 3,5-dimethoxy-4-isopropylbenzyl alcohol, 2-iodoacylbenzoic acid and a first organic solvent are mixed, and an oxidation reaction is performed to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde; the 3,5-dimethoxy-4-isopropylbenzaldehyde, diethyl benzyl phosphate, a base catalyst and a second organic solvent are mixed, and a condensation reaction is performed to obtain 3,5-dimethoxy-4-isopropyl diphenylethylene; the 3,5-dimethoxy-4-isopropyl diphenylethylene, aluminum chloride, an organic base and a third organic solvent are mixed, and a demethylation reaction is performed to obtain the Benvimod. The raw materials used in the preparation method provided by the present invention are cheap and easy to obtain, the process is simple and efficient, no complicated post-processing is required, the yield is high, and it is suitable for industrial production. DETAILED DESCRIPTION

[0039] The present invention provides a method for preparing benvimod, comprising the following steps:

[0040] Mixing 3,5-dimethoxy-4-isopropylbenzyl alcohol, 2-iodoacylbenzoic acid and a first organic solvent, and performing an oxidation reaction to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde;

[0041] The 3,5-dimethoxy-4-isopropylbenzaldehyde, diethyl benzyl phosphate, a base catalyst and a second organic solvent are mixed to carry out a condensation reaction to obtain 3,5-dimethoxy-4-isopropylstilbene;

[0042] The 3,5-dimethoxy-4-isopropylstilbene, aluminum chloride, an organic base and a third organic solvent are mixed and subjected to a demethylation reaction to obtain the benvimod.

[0043] In the present invention, unless otherwise specified, all raw material components are commercially available products well known to those skilled in the art.

[0044] The invention mixes 3,5-dimethoxy-4-isopropylbenzyl alcohol, 2-iodoacylbenzoic acid and a first organic solvent, and performs an oxidation reaction to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde.

[0045] In the present invention, the mass ratio of the 3,5-dimethoxy-4-isopropylbenzyl alcohol to 2-iodoacylbenzoic acid is preferably 1:1.4-1.8, more preferably 1:1.4-1.6; the first organic solvent is preferably dimethyl sulfoxide; the mass ratio of the 3,5-dimethoxy-4-isopropylbenzyl alcohol to the volume ratio of the first organic solvent is preferably 1 g:13-16 mL, more preferably 1 g:14.5 mL.

[0046] In the present invention, the mixing method is preferably stirring.

[0047] In the present invention, the temperature of the oxidation reaction is preferably 20-30° C., more preferably 25° C., and the time is preferably 2-3 h, more preferably 2.5 h.

[0048] In the present invention, the oxidation reaction preferably also includes a first crystallization, a first filtration, a first washing, a second filtration, concentration, dissolution, a second crystallization, a second washing and drying; the reagent for the first crystallization is preferably water; the reagent for the first washing is preferably ethyl acetate; the solvent for the dissolution is preferably methanol; the reagent for the second crystallization is preferably water; the second crystallization is preferably cooling and stirring crystallization; the temperature of the cooling and stirring crystallization is preferably -5°C, and the time is preferably 1 to 2h, more preferably 1.5h; the reagent for the second washing is preferably water; the drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 47 to 53°C, more preferably 50°C, and the time is preferably 8h.

[0049] The invention uses 2-iodoacylbenzyl alcohol to oxidize 3,5-dimethoxy-4-isopropylbenzyl alcohol to generate aldehyde. The post-treatment method comprises the following steps: adding water to wash out the solid, filtering to remove the solvent dimethyl sulfoxide, and beating the filter cake with ethyl acetate. 2-iodoacylbenzyl acid is insoluble in ethyl acetate, while the product is soluble in ethyl acetate. The product can be purified with simple characteristics and high efficiency. The post-treatment of the reaction is simple, and the product can be obtained with high yield.

[0050] After obtaining the 3,5-dimethoxy-4-isopropylbenzaldehyde, the present invention mixes the 3,5-dimethoxy-4-isopropylbenzaldehyde, diethyl benzyl phosphate, a base catalyst and a second organic solvent to carry out a condensation reaction to obtain 3,5-dimethoxy-4-isopropylstilbene.

[0051] In the present invention, the mass ratio of the 3,5-dimethoxy-4-isopropylbenzaldehyde and benzyl diethyl phosphate is preferably 1:1-1.2, more preferably 1:1.1; the base catalyst includes tert-butoxide or n-butyl lithium; the tert-butoxide preferably includes one or more of potassium tert-butoxide, sodium tert-butoxide and lithium tert-butoxide; the base catalyst is an alkaline catalyst solution; the concentration of the alkaline catalyst solution is preferably 0.08-0.1 g / mL, more preferably 0.089 g / mL; the solvent is preferably tetrahydrofuran; the mass ratio of the 3,5-dimethoxy-4-isopropylbenzaldehyde to the volume ratio of the alkaline catalyst solution is preferably 13.01 g:80±10 mL, more preferably 13.01 g:80 mL; the second organic solvent is preferably tetrahydrofuran; the mass ratio of the 3,5-dimethoxy-4-isopropylbenzaldehyde to the volume ratio of the second organic solvent is preferably 1 g:6-9 mL, more preferably 1 g:7.5 mL.

[0052] In the present invention, the mixing order of feeding is preferably to dissolve the 3,5-dimethoxy-4-isopropylbenzaldehyde and diethyl benzyl phosphate in the second organic solvent and then add the base catalyst.

[0053] In the present invention, the temperature of the condensation reaction is preferably 47-53° C., more preferably 50° C., and the time is preferably 2-3 h, more preferably 1.5 h; the condensation reaction is preferably carried out in a nitrogen atmosphere.

[0054] In the present invention, the condensation reaction preferably also includes rotary evaporation, first dissolution, extraction, first washing, first drying, concentration, cooling, second dissolution, crystallization, filtration, second washing and second drying in sequence; the first dissolving reagent is preferably water; the extracting reagent is preferably ethyl acetate, and the number of times is preferably 3 times; the first washing preferably includes water washing and saturated sodium chloride washing in sequence; the first drying reagent is preferably anhydrous sodium sulfate; the second dissolving reagent is preferably methanol; the second crystallization reagent is preferably water; the second crystallization is preferably cooling and stirring crystallization; the temperature of the cooling and stirring crystallization is preferably -5°C, and the time is preferably 2 to 3h; the second washing reagent is preferably water; the second drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 27 to 33°C, more preferably 30°C, and the time is preferably 4 to 5h, more preferably 4.5h.

[0055] After obtaining the 3,5-dimethoxy-4-isopropylbenzylbenzene, the present invention mixes the 3,5-dimethoxy-4-isopropylbenzylbenzene, aluminum chloride, an organic base and a third organic solvent, and performs a demethylation reaction to obtain the benvimod.

[0056] In the present invention, the mass ratio of the 3,5-dimethoxy-4-isopropylstilbene and aluminum chloride is preferably 1:2.5-3, more preferably 1:2.7; the organic base preferably includes triethylamine and / or diethylamine; the mass ratio of the 3,5-dimethoxy-4-isopropylstilbene and the organic base is preferably 2:3-5, more preferably 1:2; the third organic solvent is preferably toluene; the mass ratio of the 3,5-dimethoxy-4-isopropylstilbene and the volume ratio of the third organic solvent is preferably 1g:5-7mL, more preferably 1g:6mL.

[0057] In the present invention, the feeding order of the demethylation reaction is preferably to first dissolve 3,5-dimethoxy-4-isopropylstilbene in toluene, and then add triethylamine and aluminum trichloride in sequence; the aluminum trichloride is preferably added in batches.

[0058] In the present invention, the temperature of the demethylation reaction is preferably 107-113° C., more preferably 110° C., and the time is preferably 2-4 h, more preferably 3 h; the demethylation reaction is carried out under acidic conditions.

[0059] In the present invention, the demethylation reaction preferably further comprises extraction, concentration of organic phase and recrystallization in sequence; the extraction preferably further comprises quenching; the extraction preferably further comprises backwashing and first drying; the recrystallization preferably comprises dissolution, precipitation, suction filtration, washing and second drying; the quenching reagent is preferably hydrochloric acid; the concentration of the hydrochloric acid is 10-15% and the amount of the hydrochloric acid is preferably adjusted to pH 1-2; the extraction reagent is preferably ethyl acetate; the number of extractions is preferably 3 times, and the amount of the reagent used for each time is preferably 30-40 mL; the backwashing reagent is preferably water; the number of backwashings is preferably 10-15%. The number of times is preferably 2 times, and the amount of reagent used in a single time is preferably 20 mL; the first dried reagent is preferably anhydrous sodium sulfate; the amount of the first dried reagent is preferably 10-20 g; the dissolved reagent is preferably toluene; the amount of toluene is preferably 10-15 mL; the dissolving temperature is preferably 60±3°C; the precipitated reagent is preferably petroleum ether; the amount of petroleum ether is preferably 20-25 mL; the precipitation temperature is preferably -5°C, and the time is preferably 1-2 h; the washed reagent is preferably petroleum ether; the second drying temperature is preferably 50±3°C, and the time is preferably 6-10 h.

[0060] In the present invention, 3,5-dimethoxy-4-isopropylstilbene can be demethylated under acidic conditions. The present invention also uses aluminum trichloride. In the experiment, aluminum trichloride alone is difficult to dissolve in the reaction solution, so the reaction proceeds very slowly. After adding triethylamine and then aluminum trichloride, aluminum trichloride can be dissolved in the reaction solution, which greatly promotes the reaction efficiency.

[0061] In the present invention, the preparation method of 3,5-dimethoxy-4-isopropylbenzyl alcohol comprises the following steps:

[0062] Mixing 3,5-dihydroxybenzoic acid, dimethyl sulfate, potassium carbonate and a fourth organic solvent to carry out a methylation reaction to obtain methyl 3,5-dimethoxybenzoate;

[0063] The methyl 3,5-dimethoxybenzoate, isopropanol, chlorosulfonic acid and sulfuric acid are mixed and subjected to an alkylation reaction to obtain 3,5-dimethoxy-4-isopropylbenzoic acid;

[0064] The 3,5-dimethoxy-4-isopropylbenzoic acid, borohydride salt, boron trifluoride solution and the fifth organic solvent are mixed and subjected to a reduction reaction to obtain the 3,5-dimethoxy-4-isopropylbenzyl alcohol.

[0065] The present invention mixes 3,5-dihydroxybenzoic acid, dimethyl sulfate, potassium carbonate and a fourth organic solvent, and performs a methylation reaction to obtain methyl 3,5-dimethoxybenzoate.

[0066] In the present invention, the mass ratio of the 3,5-dihydroxybenzoic acid to dimethyl sulfate is preferably 2:4-7, more preferably 2:5.5; the mass ratio of the 3,5-dihydroxybenzoic acid to potassium carbonate is preferably 1:2-4, more preferably 1:3; the fourth organic solvent is preferably acetone; the mass ratio of the 3,5-dihydroxybenzoic acid to the volume ratio of the fourth organic solvent is preferably 1 g:2-4 mL, more preferably 1 g:3 mL.

[0067] In the present invention, the mixing order of feeding is to dissolve 3,5-dimethoxy-4-isopropylbenzoic acid in the fourth organic solvent, and then sequentially add potassium carbonate and dimethyl sulfate; the dimethyl sulfate is preferably added dropwise.

[0068] In the present invention, the temperature of the methylation reaction is preferably 62-68° C., more preferably 65° C., and the time is preferably 20-30 h, more preferably 25 h.

[0069] In the present invention, the methylation reaction preferably further includes dissolution, crystallization, filtration and drying in sequence; the dissolving solvent is water; the crystallization is preferably cooling and stirring crystallization; the temperature of the cooling and stirring crystallization is preferably -5°C, and the time is preferably 3 to 4 hours, more preferably 3.5 hours; the filtration is preferably reduced pressure filtration; the drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 30°C, and the time is preferably more than 5 hours, more preferably 5 hours.

[0070] After obtaining the methyl 3,5-dimethoxybenzoate, the present invention mixes the methyl 3,5-dimethoxybenzoate, isopropanol, chlorosulfonic acid and sulfuric acid to carry out an alkylation reaction to obtain 3,5-dimethoxy-4-isopropylbenzoic acid.

[0071] In the present invention, the mass volume ratio of the methyl 3,5-dimethoxybenzoate and isopropanol is preferably 1 g: 2 to 4 mL, more preferably 1 g: 3 mL; the mass ratio of the methyl 3,5-dimethoxybenzoate and chlorosulfonic acid is preferably 8 to 17: 1, more preferably 13: 1; the mass fraction of the sulfuric acid is preferably 60% to 80%, more preferably 70%; the mass fraction of the methyl 3,5-dimethoxybenzoate and sulfuric acid is preferably 19.4: 3.8 to 4.2, more preferably 19.4: 4.

[0072] In the present invention, the mixing order of adding materials is preferably to add methyl 3,5-dimethoxybenzoate, isopropanol, sulfuric acid and chlorosulfonic acid in sequence; the chlorosulfonic acid is preferably added dropwise.

[0073] In the present invention, the temperature of the alkylation reaction is preferably 57-63° C., more preferably 60° C., and the time is preferably 20-24 h, more preferably 22 h.

[0074] In the present invention, the alkylation reaction preferably further comprises a first crystallization, a first filtration, a first washing, a first drying, a dissolving, a second crystallization, a second filtration, a second washing and a second drying performed in sequence; the reagent for the first crystallization is preferably water; the temperature of the water is preferably 70-75°C, more preferably 73°C; the reagent for the first washing is preferably water; the temperature of the water is preferably 70-75°C, more preferably 73°C; the first drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 57-63°C, more preferably 60°C, and the time is preferably 8-10h, more preferably 9h; the solvent for the dissolution is preferably toluene; the second crystallization is preferably crystallization by cooling and stirring; the temperature of the crystallization by cooling and stirring is preferably -5°C, and the time is preferably 4h; the reagent for the second washing is preferably toluene; the toluene is cold toluene; the second drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 57-63°C, more preferably 60°C, and the time is preferably 8-10h, more preferably 9h.

[0075] The Friedel-Crafts alkylation reaction of the present invention is an important step reaction in the preparation process of Benvimod. By reducing the concentration of sulfuric acid, the post-processing pressure is reduced. The improvement of the yield and the weakening of the toxicity treatment have very important application value for the industrial production of Benvimod. In addition, the present invention provides a reasonable mechanism explanation, which is conducive to the intermediate monitoring reaction during industrial production.

[0076] After obtaining the 3,5-dimethoxy-4-isopropylbenzoic acid, the present invention mixes the 3,5-dimethoxy-4-isopropylbenzoic acid, a borohydride salt, a boron trifluoride solution and a fifth organic solvent, and performs a reduction reaction to obtain the 3,5-dimethoxy-4-isopropylbenzyl alcohol.

[0077] In the present invention, the borohydride salt preferably includes potassium borohydride and / or sodium borohydride; the mass ratio of the 3,5-dimethoxy-4-isopropyl benzoic acid to the borohydride salt is preferably 10:7-10, more preferably 10:7-8; the concentration of boron trifluoride in the boron trifluoride solution is preferably 46%-48%, more preferably 47%; the solvent is preferably diethyl ether; the mass ratio of the 3,5-dimethoxy-4-isopropyl benzoic acid to the boron trifluoride solution is preferably 2-4:4, more preferably 3:4; the fifth organic solvent is preferably tetrahydrofuran; the mass ratio of the 3,5-dimethoxy-4-isopropyl benzoic acid to the volume ratio of the fifth organic solvent is preferably 1g:6-7mL, more preferably 15.36g:100mL.

[0078] In the present invention, the mixing order of feeding is preferably to dissolve 3,5-dimethoxy-4-isopropylbenzoic acid in the fifth organic solvent, and then sequentially add the borohydride salt and the boron trifluoride solution; the adding temperature of the borohydride salt is preferably 0°C; the addition of the borohydride salt also preferably includes stirring; after adding the borohydride salt, it is also preferably included to stir for 10 to 15 minutes, more preferably 10 minutes; the boron trifluoride solution is preferably added dropwise.

[0079] In the present invention, the temperature of the reduction reaction is preferably room temperature, more preferably 15 to 25° C., and the time is preferably 4 to 5 hours, more preferably 4 hours.

[0080] In the present invention, the reduction reaction preferably further includes quenching, stirring, first filtration, first washing, first drying, concentration, dissolution, crystallization, second filtration, second washing and second drying in sequence; the quenching reagent is preferably water; the water is preferably added dropwise; the stirring time is preferably 10 minutes; the first washing reagent is preferably tetrahydrofuran; the first drying reagent is preferably anhydrous sodium sulfate; the dissolving solvent is preferably methanol; the crystallization is preferably crystallization by cooling and stirring; the temperature of the crystallization by cooling and stirring is preferably -5°C, and the time is preferably 1 to 2 hours, more preferably 1.5 hours; the second washing reagent is preferably water, more preferably cold water; the second drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 50°C, and the time is preferably 8 hours.

[0081] In the preparation method provided by the present invention, 3,5-dimethoxy-4-isopropyl diphenylethylene can be demethylated under acidic conditions, HBr easily causes double bond addition to be unavailable, aluminum trichloride is used in the present invention, but aluminum trichloride is not easily soluble in toluene, so an organic base is added to increase the dissolution of aluminum trichloride, which greatly promotes the reaction efficiency. The raw materials used in the preparation method are cheap and easy to obtain, the process is simple and efficient, no complicated post-processing is required, the yield is high, and it is suitable for industrial production.

[0082] In order to further illustrate the present invention, the preparation method of Benvimod provided by the present invention is described in detail below in combination with examples, but they should not be construed as limiting the scope of protection of the present invention.

[0083] Example 1

[0084] The chemical reaction formula of the preparation method provided in this embodiment is shown in Formula 5, which specifically includes the following steps:

[0085]

[0086] Preparation of compound (1): 15.4 g (0.10 mol) of white solid 3,5-dihydroxybenzoic acid and 50 mL of acetone were added to a 250 mL round-bottom flask, and 48.4 g (0.35 mol) of potassium carbonate was added after stirring at room temperature to dissolve. 41.6 g (0.33 mol) of dimethyl sulfate was slowly added dropwise while stirring thoroughly. The temperature was controlled to 65±3°C and refluxed for 20 h. After the reaction was completed as detected by TLC, the reaction was stopped. 150 mL of water was added and stirred to dissolve the solid, and then the mixture was transferred to a cold bath at -5°C and cooled and stirred for crystallization for 3 h. The mixture was filtered under reduced pressure, and the filter cake was washed with cold water. The filter cake was collected and dried in a vacuum drying oven at 30°C for 5 h to obtain 19.4 g of white solid compound (1) with a yield of 99%.

[0087] Preparation of compound (2): 19.4g of compound (1), 60mL of isopropanol, and 3.8g of 60%-80% sulfuric acid were added to a 250mL round-bottom flask, and 1.17g (0.01mol) of chlorosulfonic acid was added dropwise after stirring and dissolving, and the temperature was raised to 60±3°C and stirred for reaction for 20h. After TLC detection, 300mL of 70°C hot water was added, stirred for 5min, filtered, and the filter cake was washed with 20mL of hot water, collected, crushed, and vacuum dried at 60°C for 8h. After the crude product and 60mL of toluene were heated and dissolved, they were transferred to a cold bath at -5°C and stirred for crystallization for 4h, filtered, and rinsed with cold toluene. The filter cake was collected, crushed, and vacuum dried at 60°C for 8h to obtain 15.36g of gray-green solid, with a yield of 80%.

[0088] Preparation of compound (3): 15.36 g of intermediate (2) was added to a 250 mL round-bottom flask, 100 mL of tetrahydrofuran was added to dissolve, 11.24 g of potassium borohydride was slowly added under stirring at 0°C, the gas release rate was controlled, and the addition was stirred for 10 min, 20 g of 47% boron trifluoride ether solution was added dropwise, and the mixture was stirred at room temperature for 4 h after the addition was completed. After TLC was checked to be complete, water was slowly added dropwise under ice-water cooling to quench the reaction until no gas was released, and the mixture was stirred at room temperature for 10 min. The mixture was filtered through diatomaceous earth, rinsed with 15 mL of tetrahydrofuran, the filtrate was collected, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid. Add 50 mL of methanol to dissolve, stir to dissolve, then add 100 mL of water to precipitate solid, stir at -5°C for 1 hour to fully crystallize, filter the filter cake and rinse with 20 mL of cold water, and dry the filter cake in a vacuum oven at 50°C for 8 hours to obtain 13.68 g of light yellow solid with a yield of 95%.

[0089] Preparation of compound (10): Add 13.68 g of compound (3), 20.01 g of 2-iodoacylbenzoic acid and 200 mL of dimethyl sulfoxide into a 250 mL single-mouth bottle, stir to dissolve, and react at room temperature for 2 h. After checking by TLC, add 50 mL of water, stir for 10 min, filter, collect the solid, add 50 mL of ethyl acetate for washing, filter, and concentrate the filtrate to obtain a solid. Add 50 mL of methanol to dissolve, add 50 mL of water dropwise to crystallize, stir at -5°C for 1 h, filter, rinse the filter cake with water, and dry the filter cake in a vacuum drying oven at 50±3°C for 8 h to obtain 13.01 g of off-white solid, with a yield of 96%.

[0090] Preparation of compound (25): 13.01 g of compound (10) and 14.31 g of benzyl diethyl phosphate were dissolved in 100 mL of tetrahydrofuran, and after stirring and dissolving, a solution prepared by 7.15 g of potassium tert-butoxide and 80 mL of tetrahydrofuran was slowly added, and the temperature was controlled not to exceed 50 ± 3 ° C. Under nitrogen protection, the reaction was carried out at room temperature for 2 h. After the reaction was detected by TLC, the solvent was removed by rotary evaporation, 50 mL of water was added and stirred for 5 min, and then 30 mL of ethyl acetate was used for extraction 3 times each time, the organic phases were combined, backwashed once with water, backwashed once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to obtain an oily liquid, and cooled to form a solid. After dissolving in 50 mL of methanol, 10 mL of water was added dropwise to precipitate crystals, stirred in a -5 ° C cold bath for 2 h, filtered, the filter cake was rinsed with water, and the filter cake was dried in a vacuum drying oven at 30 ° C for 4-5 h to obtain 16.93 g of solid, with a yield of 96%.

[0091] Preparation of compound (7): 16.93 g of compound (25) was dissolved in 100 mL of toluene, and 36.41 g of triethylamine was added under ice-water bath cooling, and 47.41 g of aluminum chloride was slowly added in batches, and the temperature was raised to 110 ± 3 ° C, and the reaction was continued for 2 h, and then the temperature was lowered to room temperature, and 10% hydrochloric acid was added dropwise to adjust the pH value to 1, and the mixture was stirred for 10 min, and the mixture was extracted with ethyl acetate (30 mL × 3), backwashed with water (20 mL × 2), dried with anhydrous sodium sulfate (10 g), filtered and concentrated, and the organic phase was cooled to obtain a gray solid. 10 mL of toluene was added, the temperature was raised to 60 ± 3 ° C, 20 mL of petroleum ether was added dropwise to precipitate a solid, and the mixture was fully cooled at -5 ° C for 1 h, and the filter cake was rinsed with petroleum ether and dried at 50 ° C for 6 h to obtain Benvimod. The total yield of Benvimod obtained in this example was 52.0%.

[0092] The following is the hydrogen spectrum data of the product obtained in Example 1.

[0093] 1H NMR (600MHz, DMSO-d, 25℃) δ9.06(s,1H),7.56(d,J=7.56Hz,2H),7.35(t,J=7.56Hz,2H),7.24(t,J=7.56Hz,1H), 7.00(d,J=16.32Hz,1H),6.88(d,J=16.32Hz,1H),6.47(s,1H)3.43(hept,J=7.08Hz,1H),1.24(d,J=7.08Hz,6H).

[0094] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing benvimod, characterized in that: The following steps are involved: Mixing 3,5-dimethoxy-4-isopropylbenzyl alcohol, 2-iodoacylbenzoic acid and a first organic solvent, and performing an oxidation reaction to obtain 3,5-dimethoxy-4-isopropylbenzaldehyde; The 3,5-dimethoxy-4-isopropylbenzaldehyde, diethyl benzyl phosphate, a base catalyst and a second organic solvent are mixed to carry out a condensation reaction to obtain 3,5-dimethoxy-4-isopropylstilbene; The 3,5-dimethoxy-4-isopropylstilbene, aluminum chloride, an organic base and a third organic solvent are mixed and subjected to a demethylation reaction to obtain the benvimod.

2. The preparation method according to claim 1, characterized in that: The mass ratio of the 3,5-dimethoxy-4-isopropylbenzyl alcohol to 2-iodoacylbenzoic acid is 1:1.4-1.8; The temperature of the oxidation reaction is 20-30° C. and the time is 2-3 hours.

3. The preparation method according to claim 1, characterized in that: The mass ratio of 3,5-dimethoxy-4-isopropylbenzaldehyde to diethyl benzyl phosphate is 1:1-1.2; The condensation reaction temperature is 47-53° C. and the reaction time is 2-3 hours.

4. The preparation method according to claim 1, characterized in that: The mass ratio of 3,5-dimethoxy-4-isopropylstilbene to aluminum chloride is 1:2.5-3; The temperature of the demethylation reaction is 107-113° C. and the time is 2-4 hours.

5. The preparation method according to claim 1, characterized in that: The first organic solvent is dimethyl sulfoxide; The second organic solvent is tetrahydrofuran; The third organic solvent is toluene.

6. The preparation method according to claim 1, characterized in that: The preparation method of 3,5-dimethoxy-4-isopropylbenzyl alcohol comprises the following steps: Mixing 3,5-dihydroxybenzoic acid, dimethyl sulfate, potassium carbonate and a fourth organic solvent to carry out a methylation reaction to obtain methyl 3,5-dimethoxybenzoate; The methyl 3,5-dimethoxybenzoate, isopropanol, chlorosulfonic acid and sulfuric acid are mixed and subjected to an alkylation reaction to obtain 3,5-dimethoxy-4-isopropylbenzoic acid; The 3,5-dimethoxy-4-isopropylbenzoic acid, borohydride salt, boron trifluoride solution and the fifth organic solvent are mixed and subjected to a reduction reaction to obtain the 3,5-dimethoxy-4-isopropylbenzyl alcohol.

7. The preparation method according to claim 6, characterized in that: The mass ratio of 3,5-dihydroxybenzoic acid to dimethyl sulfate is 2:4-7; The temperature of the methylation reaction is 62-68° C. and the time is 20-30 hours.

8. The preparation method according to claim 6, characterized in that: The mass ratio of methyl 3,5-dimethoxybenzoate to isopropanol is 10:4-5; The temperature of the alkylation reaction is 57-63° C. and the time is 20-24 hours.

9. The preparation method according to claim 6, characterized in that: The mass ratio of the 3,5-dimethoxy-4-isopropylbenzoic acid to the borohydride salt is 4:3-4; The reduction reaction time is 4 to 5 hours.

10. The preparation method according to claim 1, characterized in that: The demethylation reaction further includes extraction, concentration of organic phase and recrystallization.

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