A continuous flow process for the preparation of benzenesulfofide, hydrogenated benzenesulfofide and analogues thereof

Abstract

The application discloses a continuous flow preparation method of benzenesulfoxylenimide, hydrogenated benzenesulfoxylenimide and analogues thereof, and adopts the continuous flow preparation method to react a solution of compound I with a hydrobromic acid solution in a micro-channel reactor under suitable reaction temperature and reaction pressure conditions for a period of time to obtain corresponding compound II. The application adopts the micro-channel reactor, stably controls the temperature through the temperature control all-in-one machine, controls the feeding flow rate and molar ratio through two four-fluorine feeding pumps, and then precisely controls the reaction process; in addition, the reactant material realizes uniform mixing of the material and rapid heat transfer in the micro-channel, improves the selectivity of the product, and can reduce the content of the tar by-product in the SiC / four-fluorine micro-channel reactor small holdup container, and the crude product yield is improved by 8-9%; the product property is obviously improved; and the continuous flow process is adopted, the influence of the strong corrosiveness of the hydrobromic acid on the equipment, personnel and environment is reduced, the continuous operation can be continuously carried out without interruption, and the application is suitable for industrialized production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a continuous flow preparation method of benvitimod, hydrogenated benvitimod and analogues thereof. BACKGROUND

[0002] Stilbenes are a well known class of compounds with a variety of activities, which are widely distributed in nature. 3,5,4'-trihydroxystilbene, also known as piceatannol, has a series of physiological activities, including anti-inflammatory and chemoprevention of cancer (Jang, et al. 1997, Science, 275, 218, US6,008,260). Some patents and literatures (WO / 92 / 16486, WO99 / 40056, WO01 / 95859 and Cushman M. et. al., 1992, J. Med. Chern., 35: 2293-2306) disclose some compounds derived from 3,4,5-trimethoxystilbene, which show certain anti-tumor activity and certain degree of cytokine regulation activity.

[0003] Recently, a group of uniquely substituted stilbene derivatives has been reported in the literature, in which two hydroxyl groups are at 3 and 5 positions, and there is also a substituent at 4 position between the two hydroxyl groups (Patents: US7868047; US321,050; CA2393297; EP1490374; WO2004 / 031117; WO2002 / 057219 and WO01 / 42231), these compounds have inhibitory activity on kinases, anti-infective activity, influence on T lymphocytes, macrophages, neutrophils and mast cells, and can regulate various immune and inflammatory activities. Representative examples include benvitimod and hydrogenated benvitimod.

[0004] Benvitimod is the first aromatic hydrocarbon receptor agonist drug on the market, as a new generation of anti-inflammatory drug, it has skin anti-infective, tyrosinase inhibition, repair of stratum corneum, regulation of skin immune function, and can be used for treating various major autoimmune diseases, such as psoriasis, eczema, atopic dermatitis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, chronic kidney disease, ankylosing spondylitis, Sjogren's syndrome, polymyositis, vasculitis, polymyalgia rheumatica, immune thrombocytopenia, dry eye syndrome, type 1 diabetes and arthritis, etc., and is also widely used in the field of cosmetics or pharmaceutical reagents.

[0005] The drug structure of fumaderm is E-3,5-dihydroxy-4-isopropyl-stilbene, and the precursor methylation is E-3,5-dimethoxy-4-isopropyl-stilbene. There are many literatures and patents reported on the demethylation method of benzyl ether, and the commonly used reaction systems include: ① strong acid, hydrogen halide acid method; ② boron halide and aluminum halide method; ③ magnesium iodide and lithium iodide method; ④ selective oxidation reagent method. Among the demethylation reagents, anhydrous aluminum chloride has moderate demethylation ability, and the single demethylation product is mainly obtained; boron tribromide needs low temperature operation and needs inert atmosphere, which is not suitable for industrial production; the demethylation reaction of hydrobromic acid needs to be heated to reflux temperature, the reaction time is long, and the corrosion is strong.

[0006] In the chemical synthesis route of fumaderm (Li Jianxiong, 2020, Chinese patent CN112661611A), the demethylation reaction of the methylated precursor compound thereof is described. A process is disclosed in Chinese patent CN111217681A, which also involves a demethylation reaction of a similar structure, as follows: 1 kg of 3,5-dimethoxy-4-isopropyl-stilbene, 3 kg of pyridine hydrochloride, nitrogen replacement for three times in the reaction kettle, heating to 185℃ under nitrogen protection, reaction for 6h, cooling to 100℃, adding 4 kg of 1M hydrochloric acid to the reaction kettle, 3.2 kg of ethyl acetate, stirring until the solid is completely dissolved, cooling to room temperature, standing and separating, washing the organic phase with 2 kg of water, concentrating the organic phase to dryness, adding 800 g of dimethylbenzene to the residue, heating to 100℃, stirring until the solid is completely dissolved, cooling to 0℃, keeping for 2h, filtering, washing the filter cake with a small amount of dimethylbenzene, and drying at 60℃ under vacuum to obtain 734g of white solid product with a yield of 84%. The process requires inert atmosphere protection, and the reaction needs to be carried out at high temperature for a long time, which leads to the generation of a large amount of tar by-products, not only increasing the treatment pressure of the decolorization process (such as the increase of activated carbon dosage and the increase of decolorization times), but also indirectly reducing the yield due to incomplete separation of impurities and target product; at the same time, pyridine hydrochloride is easy to sublimate under high temperature conditions, which will cause pipeline blockage in scale-up production, and frequent intermittent shutdown is needed for dredging, which seriously affects the production continuity and efficiency. In addition, the process from reaction completion to obtaining the crude product is long, involving multiple transfers, extractions, washings, dryings, and concentratings, which not only consumes time and effort, but also may cause material loss due to complicated steps, further affecting the final yield and production efficiency; it is not suitable for industrial production. SUMMARY

[0007] The technical problem to be solved by the present application is to provide a continuous flow preparation method of fumaderm, hydrogenated fumaderm and its analogues with high efficiency, less by-products, precise control of reaction progress and suitability for industrialization.

[0008] The technical solution of the present application is:

[0009] A continuous flow method for preparing benfotiamine, hydrobenfotiamine and analogues thereof, comprising the following steps:

[0010] Using the continuous flow method, a solution of compound I is reacted with a hydrobromic acid solution in a microchannel reactor at a suitable reaction temperature and reaction pressure for a period of time to obtain the corresponding compound II;

[0011] wherein the compound I has the following structural formula:

[0012] ;

[0013] The compound II has the following structural formula:

[0014] ;

[0015] wherein in the compound I and the compound II, R represents a substituted or unsubstituted alkyl group, branched alkyl group and corresponding alkoxy group having a carbon number of 1-7;

[0016] wherein the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopentyl, n-hexyl or cyclohexyl.

[0017] Further, the compound I is selected from 3,5-dimethoxy-4-isopropyl stilbene, 3,5-dimethoxy-4-isopropyl stilbene or 3,5-dimethoxy-4-ethyl stilbene and 3,5-dimethoxy-4-ethyl stilbene, and the compound II is selected from 3,5-dihydroxy-4-isopropyl stilbene, phenethyl-4-isopropyl-3,5-resorcinol or 3,5-dihydroxy-4-ethyl stilbene and 3,5-dimethoxy-4-ethyl stilbene.

[0018] Further, the continuous flow method specifically comprises the following steps:

[0019] (1) Preparation of material in tank A, add solvent to tank A, then add compound I to tank A, control the temperature at 25-50℃, stir and dissolve for standby, to obtain the material in tank A;

[0020] (2) Preparation of material in tank B, add hydrobromic acid solution to tank B, control the temperature to 0-30℃, to obtain the material in tank B;

[0021] (3) The demethylation in the silicon carbide micro-channel reactor, the first tetrafluoro feeding pump is used to transport the material in the storage tank A obtained in the step (1) to the micro-channel reactor, at the same time, the second tetrafluoro feeding pump is used to transport the material in the storage tank B obtained in the step (2) to the micro-channel reactor, the micro-channel reactor is controlled to the reaction temperature, the reaction material is completed in the demethylation reaction in the micro-channel reactor under the reaction pressure, the effluent directly enters the cold water quenching device, the system temperature is instantaneously reduced by being rapidly mixed with the cold water, the reaction process is terminated, the subsequent side reaction is avoided, and the primary product after quenching is obtained;

[0022] (4) The primary product after quenching in the step (3) is subjected to suction filtration or pressure filtration, and the filter cake is collected; subsequently, the filter cake is washed with purified water for multiple times, the water amount for each time is 0.5-2 times of the mass of the filter cake, until the washing liquid is detected to be slightly acidic or neutral, so that the water-soluble impurities such as residual hydrobromic acid, acetic acid and salts are removed, and the intermediate after washing is obtained; after drying, the activated carbon is used for decolorization, the crude product is concentrated, and the white solid product is obtained through recrystallization.

[0023] Further, the solvent is selected from glacial acetic acid in the step (1), and the mass ratio of the solvent to the compound I is (3-10):1.

[0024] Further, the hydrobromic acid solution is 20wt.%-50wt.%, and the solvent is water, acetic acid or any proportion mixture of water and acetic acid.

[0025] Further, the hydrobromic acid solution is 48% aqueous solution or 33wt.% hydrobromic acid acetic acid solution.

[0026] Further, the volume flow rate ratio of the first tetrafluoro feeding pump to the second tetrafluoro feeding pump is controlled to be 0.2-2 in the step (3).

[0027] Further, the micro-channel reactor is provided with a heat exchange layer outside the micro-channel in the step (3), the heat exchange layer is filled with circulating heat conduction oil, the heat conduction oil is circulated and heated by the temperature control all-in-one machine, the heat conduction oil can be selected from circulating silicon oil or other heat conduction oils, and the reaction temperature in the micro-channel reactor is controlled to be 144-156 DEG C by the temperature control all-in-one machine.

[0028] Further, the micro-channel reactor is provided with a pressure control structure at the discharge end in the step (3), so as to control the reaction pressure, and the reaction pressure is 6.5-8.5 bar.

[0029] The present application has the advantages that:

[0030] The application adopts a micro-channel reactor, especially a SiC / tetrafluoro micro-channel reactor, to perform continuous flow process preparation of benofloxacin and its analogs, temperature control all-in-one machine is used to stably control the temperature in the reactor, and two tetrafluoro feeding pumps are used to control the feeding flow rate and molar ratio, so as to realize the purpose of precisely controlling the reaction process; in addition, the reactant is uniformly mixed in the micro-channel, and the heat is rapidly transferred, so that the selectivity of the demethylated product is improved; and the micro-channel reactor is performed in a small liquid holdup container, the uniform mixing of the material in the micro-channel reactor and the short residence time significantly reduce the generation of tar polymers in the reaction process, and the content of tar by-products is reduced; due to the significant reduction of the tar and other by-products, the yield of the crude product is directly increased by more than 8%; at the same time, due to the reduction of the impurity content, the operation frequency of the activated carbon decolorization process is reduced, and the white solid properties (such as purity, crystal form regularity) of the final product are obviously improved; and the continuous flow process is adopted, the residence time of the reaction is short, the influence of the strong corrosive hydrogen bromide on the equipment, personnel and environment is reduced, the safety risk is low, the continuous operation can be continuously performed without interruption, and the application is suitable for industrial production. DETAILED DESCRIPTION

[0031] The specific embodiments of the application will be further described below. It should be noted that the description of these embodiments is used to help understand the application, but does not constitute a limitation on the application. In addition, the technical features involved in each embodiment of the application described below can be combined with each other as long as they do not conflict with each other.

[0032] A continuous flow preparation method of benofloxacin, hydrogenated benofloxacin and its analogs, comprising the following steps:

[0033] Using the continuous flow preparation method, under suitable reaction temperature and reaction pressure conditions, the solution of compound I is reacted with the hydrogen bromide solution in the micro-channel reactor for a period of time to obtain the corresponding compound II;

[0034] The structural formula of compound I is as follows:

[0035] ;

[0036] The structural formula of compound II is as follows:

[0037] ;

[0038] In compound I and compound II, R represents a substituted or unsubstituted alkyl group, a branched alkyl group and a corresponding alkoxy group with a carbon number of 1-7;

[0039] The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopentyl, n-hexyl or cyclohexyl.

[0040] wherein compound I is selected from 3,5-dimethoxy-4-isopropylstilbene, 3,5-dimethoxy-4-isopropylstilbene or 3,5-dimethoxy-4-ethylstilbene and 3,5-dimethoxy-4-ethylstilbene, and compound II is selected from 3,5-dihydroxy-4-isopropylstilbene, 4-isopropyl-benzeneethanol-3,5-dihydroxybenzene or 3,5-dihydroxy-4-ethylstilbene and 3,5-dimethoxy-4-ethylstilbene, respectively.

[0041] The specific steps of the continuous flow preparation method are as follows:

[0042] (1) Preparation of materials in tank A, add solvent to tank A, then add compound I to tank A, control the temperature at 25-50°C, stir and dissolve for standby, to obtain the material in tank A, the solvent can be glacial acetic acid, and the mass ratio of the solvent to compound I is (3-10): 1.

[0043] (2) Preparation of materials in tank B, add hydrobromic acid solution to tank B, control the temperature to 0-30°C, to obtain the material in tank B, the hydrobromic acid solution is 30wt.%-50wt.% optimal, the solvent can be water, acetic acid or any proportion mixture of water and acetic acid, in the preferred scheme, the hydrobromic acid solution is 48% aqueous solution or 33wt.% hydrobromic acid acetic acid solution.

[0044] (3) Demethylation in the silicon carbide micro-channel reactor, use the first tetrafluoro feeding pump to transport the material in tank A obtained in step (1) to the micro-channel reactor, at the same time, use the second tetrafluoro feeding pump to transport the material in tank B obtained in step (2) to the micro-channel reactor, control the volume flow rate ratio of the first tetrafluoro feeding pump to the second tetrafluoro feeding pump at 0.2-2, control the micro-channel reactor to the reaction temperature, after the reactant material completes the demethylation reaction in the micro-channel reactor under the reaction pressure, the effluent directly enters the cold water quenching device (or quenching channel), through rapid mixing with cold water (the temperature can be controlled at 5-45°C), the system temperature is instantaneously reduced, the reaction process is terminated, and the occurrence of subsequent side reactions (such as tar generation, product decomposition, etc.) is avoided, to obtain the initial product after quenching;

[0045] (4) The initial product after quenching in step (3) is subjected to suction filtration (or pressure filtration), and the filter cake is collected; then the filter cake is washed with purified water (the temperature can be controlled at 0-45°C) for multiple times, until the washing liquid is neutral or close to neutral through detection (such as pH test paper or conductivity instrument), to remove residual hydrobromic acid, acetic acid and salts and other water-soluble impurities, to obtain the intermediate after washing; after drying, activated carbon is used for decolorization, and the crude product is concentrated to obtain a white solid product.

[0046] About the temperature control of the micro-channel reactor in step (3): a heat exchange layer is arranged axially outside the micro-channel, and a circulating heat-conducting oil is filled in the heat exchange layer. The heat-conducting oil is heated by a temperature control all-in-one machine, and the heat-conducting oil can be selected from a circulating silicon oil or other heat-conducting oils. The reaction temperature in the micro-channel reactor is controlled by the temperature control all-in-one machine to be 144-156°C.

[0047] About the pressure control of the micro-channel reactor in step (3): a pressure control structure is arranged at the outlet end of the micro-channel reactor to control the reaction pressure. The reaction pressure is 6.5-8.5 bar.

[0048] Example 1

[0049] Example 1 provides a preparation method of benfotiamine, which comprises the following steps:

[0050] Into the liquid storage tank A, 30 L of glacial acetic acid is added, and the temperature is controlled to 30-35°C. Then, 5 kg of 3,5-dimethoxy-4-isopropyl stilbene is added into the liquid storage tank A, and stirred and dissolved for 1 h to obtain the material of the liquid storage tank A;

[0051] Into the liquid storage tank B, 53 kg of 33 wt.% hydrobromic acid in acetic acid solution is added, and the temperature is controlled to 16.5-8.5°C to obtain the material of the liquid storage tank B;

[0052] The temperature of the SiC / tetrafluoro micro-channel reactor is controlled by the temperature control all-in-one machine to be 149-151°C, and the pressure of the SiC / tetrafluoro micro-channel reactor is controlled by the pressure control structure to be 7-7.5 bar. Then, the material of the liquid storage tank A obtained in step (1) is delivered to the SiC / tetrafluoro micro-channel reactor by using a first tetrafluoro feeding pump, and the material of the liquid storage tank B obtained in step (2) is delivered to the SiC / tetrafluoro micro-channel reactor by using a second tetrafluoro feeding pump. The volume flow rate of the first tetrafluoro feeding pump is controlled to be 200 mL / min, and the volume flow rate of the second tetrafluoro feeding pump is controlled to be 300 mL / min. After the reaction system stays in the micro-channel for 10 min, the quenched primary product is obtained by cooling, flowing through the pressure control structure, and mixing with cooling water (the temperature can be controlled to be 5-45°C).

[0053] The quenched primary product is subjected to suction filtration (or pressure filtration), and the filter cake is collected. Then, the filter cake is washed with purified water (the temperature can be controlled to be 0-45°C) for multiple times. The amount of water used for each washing is 0.5-2 times the mass of the filter cake, until the washing liquid is neutral (determined by pH test paper or conductivity meter) to remove the residual hydrobromic acid, acetic acid and salts and other water-soluble impurities, to obtain the washed intermediate. After drying, the activated carbon is used for decolorization, and the crude product is concentrated to obtain 4.10 kg of white solid product, which is 3,5-dihydroxy-4-isopropyl stilbene (benfotiamine), and the yield is 90.7%.

[0054] Example 2

[0055] Example 2 provides a preparation method of hydrophenytoin, comprising the following steps:

[0056] Into the storage tank A, add glacial acetic acid 50L, control the temperature to 35-40℃, then add 3,5-dimethoxy-4-isopropyl diphenyl ethane 5kg into the storage tank A, stir and dissolve for 0.5h, to obtain the storage tank A material;

[0057] Into the storage tank B, add 48% hydrobromic acid aqueous solution 45kg, control the temperature to 20-25℃, to obtain the storage tank B material;

[0058] Control the temperature of SiC / tetrafluoro micro-channel reactor at 154-156℃ by temperature control all-in-one machine, control the pressure of SiC / tetrafluoro micro-channel reactor at 8-8.5bar by pressure control structure, then use the first tetrafluoro feed pump to deliver the storage tank A material obtained in step (1) to the SiC / tetrafluoro micro-channel reactor, at the same time, use the second tetrafluoro feed pump to deliver the storage tank B material obtained in step (2) to the SiC / tetrafluoro micro-channel reactor, control the volume flow rate of the first tetrafluoro feed pump at 340mL / min, control the volume flow rate of the second tetrafluoro feed pump at 280mL / min. After the reaction system stays in the micro-channel for 8min, quench the initial product by cooling, mix with cooling water after flowing through the pressure control structure (the temperature can be controlled at 5-45℃), to obtain the quenched initial product;

[0059] After quenching, the initial product is subjected to suction filtration (or pressure filtration), and the filter cake is collected; then the filter cake is washed with purified water (the temperature can be controlled at 0-45℃) for multiple times, and the amount of water used for each washing is 0.5-2 times the mass of the filter cake, until the washing liquid is neutral (determined by pH test paper or conductivity meter), to remove residual hydrobromic acid, acetic acid and salts and other water-soluble impurities, to obtain the washed intermediate. After drying, decolorization with activated carbon, and concentration, the crude product is obtained, and the crude product is recrystallized with methyl tert-butyl ether and n-heptane to obtain 3.88kg of white solid product, which is phenylethyl-4-isopropyl-3,5-resorcinol (hydrophenytoin), with a yield of 86.1%.

[0060] Example 3

[0061] Example 3 provides a preparation method of phenytoin analog, comprising the following steps:

[0062] Into the storage tank A, add glacial acetic acid 40L, control the temperature to 25-30℃, then add 3,5-dimethoxy-4-cyclohexyl diphenyl ethane 5kg into the storage tank A, stir and dissolve for 0.5h, to obtain the storage tank A material;

[0063] To the tank B, add hydrobromic acid 33wt.% acetic acid solution 38kg, control the temperature to 10-15℃, get the tank B material;

[0064] The temperature of SiC / tetrafluoro micro-channel reactor is controlled by temperature control all-in-one machine at 144-146℃, the pressure of SiC / tetrafluoro micro-channel reactor is controlled by pressure control structure at 6.5-7bar, then the tank A material obtained in step (1) is transported to SiC / tetrafluoro micro-channel reactor by using the first tetrafluoro feeding pump, at the same time, the tank B material obtained in step (2) is transported to SiC / tetrafluoro micro-channel reactor by using the second tetrafluoro feeding pump, the volume flow rate of the first tetrafluoro feeding pump is controlled at 230mL / min, the volume flow rate of the second tetrafluoro feeding pump is controlled at 190mL / min. After the reaction system stays in the micro-channel for 12min, it is cooled, mixed with cooling water (the temperature can be controlled at 5-45℃) after flowing through the pressure control structure, to obtain the quenched primary product;

[0065] The quenched primary product is subjected to suction filtration (or pressure filtration), and the filter cake is collected; then the filter cake is washed with purified water (the temperature can be controlled at 0-45℃) for multiple times, and the amount of water used for each washing is 0.5-2 times the mass of the filter cake, until the washing liquid is neutral (determined by pH test paper or conductivity meter) to remove residual hydrobromic acid, acetic acid and salts and other water-soluble impurities, to obtain the washed intermediate. After drying, decolorization with activated carbon, and concentration, the crude product is obtained, and the crude product is recrystallized from methyl tert-butyl ether and n-heptane to obtain 4.05kg of white solid product, which is 3,5-dihydroxy-4-cyclohexyldiphenyl ethylene (a phenothibene analogue), with a yield of 88.6%.

[0066] Comparative Example 1

[0067] The comparative example provides a preparation method of phenothibene, comprising the following steps:

[0068] Install a reflux condenser, a thermometer and a feeding funnel on a 5L three-port round bottom flask, add 3,5-dimethoxy-4-isopropyl stilbene 100g and 1500mL glacial acetic acid as a solvent into the flask, heat to 70℃, stir to dissolve, add demethylation reagent 48% aqueous hydrogen bromide solution 1kg, heat to 110℃ (oil bath), stir to reflux for 8h, the reaction is completed, and the temperature is reduced to room temperature. Pour the reaction solution into ice water, and perform suction filtration (or pressure filtration) on the initial product, collect the filter cake; then wash the filter cake with purified water (the temperature can be controlled at 0-45℃) for multiple times, and the amount of water used in each washing is 0.5-2 times the mass of the filter cake, until the washing liquid is neutral (determined by pH test paper or conductivity meter) to remove residual hydrogen bromide, acetic acid and salts and other water-soluble impurities, to obtain the washed intermediate. After drying, decolorization with activated carbon, and concentration, a crude product is obtained, which is recrystallized from methyl tert-butyl ether and n-heptane to obtain a white solid 75.9g (benfenotate), with a yield of 84.3%.

[0069] Comparative Example 2

[0070] The comparative example provides a preparation method of benfenotate, which comprises the following steps:

[0071] Into a 50L reaction kettle, pyridine hydrochloride 18kg is added, and under the protection of nitrogen, the temperature is raised to 90℃, 3,5-dimethoxy-4-isopropyl stilbene 5kg is added, heated to above 180℃, and stirred to react for about 2.5h, then cooled to 90℃, 25L of toluene is added, stirred and cooled, and the precipitated pyridine hydrochloride solid is filtered. The filtrate is washed with dilute hydrochloric acid, decolorized with activated carbon, filtered, concentrated, and recrystallized to obtain 3.80kg of white solid product 3,5-dihydroxy-4-isopropyl stilbene (benfenotate), with a yield of 85.0%.

[0072] It can be seen that, in the method for preparing benfenotate and its analogs provided by the application, the reaction time is greatly shortened by the high mass transfer and heat transfer capacity of the silicon carbide micro-channel reactor, the temperature control is more accurate, the generation of demethylated intermediates and by-products is reduced, and the yield of the demethylated product is obviously improved; the aggregation of a large amount of materials in the kettle process is avoided, the safety risk of the reaction is reduced, and the influence of the hydrogen bromide reactant on personnel and the environment is reduced; the process of the application can precisely control the reaction progress, has high synthesis efficiency, is simple to operate, and is easy to industrialize.

[0073] The application has the following advantages:

[0074] (1) Continuous flow production, suitable for industrial production;

[0075] (2) Short exposure time of hydrogen bromide, obvious reduction of corrosion in the process, small holdup of the reaction, and reduction of safety risk;

[0076] (3) the reaction speed is fast, the residence time is not more than 15 min, much shorter than more than 6 h of the prior art, which avoids potential decomposition of the product or occurrence of side reactions, especially with less tar and lighter color of the crude product;

[0077] (4) the reaction selectivity is high, and there are few side reaction products, mainly the product of removing dimethyl;

[0078] (5) the reaction yield is high, and the yield can reach more than 88%, and the yield of some compounds can reach more than 90%.

[0079] The embodiments of the present application are described in detail above, but the present application is not limited to the described embodiments. For those skilled in the art, various changes, modifications, replacements and variations of the embodiments can be made without departing from the principles and spirits of the present application, and still fall within the protection scope of the present application.

Claims

1. A continuous flow process for the preparation of feno- fene, hydrofeno fene and analogues thereof, characterized in that, The method comprises the following steps: (1) material preparation in tank A: add solvent glacial acetic acid into tank A, then add compound I into tank A, control the temperature at 25-50℃, stir and dissolve for standby, to obtain the material in tank A; the mass ratio of the solvent to compound I is (3-10):1; (2) material preparation in tank B: add hydrobromic acid solution into tank B, control the temperature at 0-30℃, to obtain the material in tank B; the hydrobromic acid solution is 20wt.%-50wt.%, and the solvent is water, acetic acid or any proportion mixture of water and acetic acid; (3) demethylation in the silicon carbide micro-channel reactor: use the first tetrafluoro feeding pump to deliver the material in tank A obtained in step (1) into the silicon carbide micro-channel reactor, at the same time, use the second tetrafluoro feeding pump to deliver the material in tank B obtained in step (2) into the silicon carbide micro-channel reactor; the volume flow rate ratio of the first tetrafluoro feeding pump to the second tetrafluoro feeding pump is controlled at 0.2-2; control the reaction temperature in the silicon carbide micro-channel reactor at 144-156℃, and the reaction pressure is 6.5-8.5 bar; after the demethylation reaction of the reactant material is completed in the silicon carbide micro-channel reactor, the effluent directly enters the cold water or ice water quenching device, the system temperature is instantly reduced by rapid mixing with cold water, the reaction process is terminated, and the occurrence of subsequent side reactions is avoided, to obtain the quenched primary product; (4) filter the quenched primary product in step (3) by suction filtration or pressure filtration, and collect the filter cake; then wash the filter cake with purified water for multiple times until the washing liquid is neutral by detection, to remove the residual hydrobromic acid, acetic acid and salts, to obtain the washed intermediate; after drying, decolorization and concentration, the crude product is obtained, and the crude product is recrystallized to obtain the white solid product; The structural formula of compound I is as follows: ； The structural formula of compound II is as follows: ； Wherein, R represents unsubstituted methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopentyl, n-hexyl or cyclohexyl.

2. The continuous flow process for the preparation of fencolmod, hydrofencolmod and analogues thereof according to claim 1, characterized by: Compound I is selected from 3,5-dimethoxy-4-isopropyl stilbene, 3,5-dimethoxy-4-isopropyl stilbene or 3,5-dimethoxy-4-ethyl stilbene, and correspondingly, compound II is selected from 3,5-dihydroxy-4-isopropyl stilbene, phenethyl-4-isopropyl-3,5-resorcinol or 3,5-dihydroxy-4-ethyl stilbene.

3. The continuous flow process for the preparation of fencolmod, hydrofencolmod and analogues thereof according to claim 1, characterized by the fact that: The hydrobromic acid solution is a 48wt.% aqueous solution or a 33wt.% hydrobromic acid acetic acid solution.

4. The continuous flow process for the preparation of fencolmod, hydrofencolmod and analogues thereof according to claim 1, characterized in that: In step (3), a heat exchange layer is arranged axially outside the micro-channel of the micro-channel reactor, and circulating heat conduction oil is filled in the heat exchange layer, the heat conduction oil is circulated and heated by the temperature control all-in-one machine, and the reaction temperature in the micro-channel reactor is controlled by the temperature control all-in-one machine.

5. The continuous flow process for the preparation of fencolmod, hydrofencolmod and analogues thereof according to claim 1, characterized by the fact that: In step (3), a pressure control structure is arranged at the discharge end of the micro-channel reactor to control the reaction pressure.

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