Preparation method of hydrogenated benvitimod and analogue thereof

Abstract

The invention discloses a preparation method of hydrogenated benvitimod and analogues thereof, and belongs to the technical field of organic synthesis. The method comprises the following steps: S1, mixing a compound I and palladium carbon in a solvent to obtain slurry; s2, under the protection of nitrogen, preheating the silicon carbide microchannel reactor to 20-70 DEG C, and then introducing hydrogen and the slurry in the step S1; the reaction temperature is 20-70 DEG C, the reaction pressure is 1-10 kg, and the retention time of the slurry is 1-20 min; and S3, carrying out solid-liquid separation, concentration, recrystallization and drying on the reaction liquid in the step S2 to obtain a compound II. The method adopts continuous flow production and is suitable for industrial production; the reaction speed is high, and the residence time does not exceed 20 min and is much shorter than overnight time in the prior art; the reaction yield is high and can reach 95% or above, and the yield of part of compounds can reach 99% or above; the catalyst dosage is small, and the reaction cost is greatly reduced.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing hydrogenated benzene modifier and its analogs, which is a new continuous flow production process. Background Art

[0002] Diphenylethane compounds have been successfully used in medicine, and sargrelide hydrochloride is a good example. Sargrelide hydrochloride has a specific antagonistic effect on the 5-HT2 receptors of platelets and smooth muscles. It has the effects of inhibiting platelet aggregation and anti-thrombotic effects, and is widely used to improve ischemic symptoms such as ulcers, pain and coldness caused by chronic arterial occlusive disease. Diphenylethane compounds are the reduction or metabolites of stilbene compounds.

[0003] A diphenylethane compound is disclosed in the Chinese patent CN101062043B. The compound is compared with stilbene compounds and their anticancer activity is discovered for the first time. 3,4,5,4'-tetramethoxy-diphenylethane-3'-o-phosphate disodium salt (abbreviated as: ECB1P) is one of the diphenylethane compounds. Although it has a similar structure and a similar parent nucleus to stilbene compounds and diphenylethylene compounds Combretastatin A-4 (CA-4), diphenylethane avoids the double bond of diphenylethylene compounds and does not have cis-trans isomerism. Among diphenylethylene compounds (such as CA-4), the cis configuration is the most effective in destroying tumor blood vessels, while the trans configuration of this compound has no inhibitory effect on tumors and even brings certain toxic side effects, which increases the process requirements for separation and purification and increases the difficulty of preparation. At the same time, diphenylethylene compounds are very easy to isomerize to trans structures under ultraviolet light, so they need to be stored at low temperature and away from light, which brings great difficulties to the storage and practical application of diphenylethylene compounds. The diphenylethane compound ECB1P is a methoxydiphenylethane salt with 4'-methoxy and 3'-hydroxy structures. It does not have cis-trans isomerism, which can greatly improve the stability of the drug. It has good water solubility and stable physical and chemical properties. Drug activity tests and toxicity tests have proved that the diphenylethane compound has good anti-tumor activity and tumor vascular targeted toxicity. Stilbene compounds are a well-known compound with multiple activities and are widely distributed in nature. 3,5,4'-Trihydroxystilbene, also known as resveratrol, has a series of physiological activities, including anti-inflammatory treatment and chemoprevention of cancer (Jang, et al. 1997, Science, 275, 218, US6,008,260). Some patents and documents (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 all show certain anti-tumor activity and certain degree of cytokine regulation activity. Similarly, the substitution of the two benzene rings of diphenylethane will lead to a large number of derivatives.

[0004] Recently, a group of uniquely substituted stilbene derivatives have been reported in the literature. In this group of derivatives, two hydroxyl groups are at the 3 and 5 positions, and there is also a substituent at the 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 against kinases, anti-infective activity, effects on T lymphocytes, macrophages, neutrophils and mast cells, and can also regulate a variety of immune and inflammatory activities.

[0005] Benvitimod is the first aryl hydrocarbon receptor agonist drug to be marketed. As a new generation of anti-inflammatory drugs, it has the effects of skin anti-infection, tyrosinase inhibition, stratum corneum repair, and skin immune regulation. It can be used to treat a variety of 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, Sjögren's syndrome, polymyositis, vasculitis, polymyalgia rheumatica, immune thrombocytopenia, dry eye, type 1 diabetes and arthritis, etc. It is also widely used in the field of cosmetics or pharmaceutical reagents.

[0006] The reduction hydrogenation of the drug generates a new diphenylethane drug (Li Jianxiong, 2013, Chinese patent CN103483158B). This type of reduction can be a reaction of diphenylethylene with hydrogen under a palladium-carbon catalyst to produce a reduction reaction of the carbon-carbon double bond. The process is as follows: 1-(3,5-dimethoxy-4-isopropylphenyl)-2-phenylethylene (0.3 g) was dissolved in 50 ml of ethanol, Pd / C (25 mg, 10% W / W) was added, and the mixture was placed in a hydrogenation reactor. Hydrogen was introduced into the reaction solution at room temperature. After the reaction was completed, the pressure was reduced, the hydrogenation reactor was opened, the reaction solution was filtered through Celite, and 1-(3,5-dimethoxy-4-isopropylphenyl)-2-phenylethane was obtained by evaporation. The amount of catalyst used was relatively high, reaching 10%.

[0007] A process is disclosed in Chinese patent publication CN111217681A, in which a hydrogenation process with a similar structure is also designed, as follows: 1kg 3,5-dihydroxy-4-isopropylbenzene was dissolved in 5kg anhydrous ethanol, 50g wet palladium carbon was added, hydrogen (1atm) was passed, and the mixture was stirred overnight at room temperature. The palladium carbon was filtered to remove the palladium carbon, and the ethanol was concentrated to remove the ethanol. The solid was recrystallized from xylene to obtain 957g of solid product (phenylethyl-4-isopropyl-3,5-resorcinol) with a yield of 95%. The reaction was carried out under normal pressure and required a long time to react overnight to obtain the reduced product. In addition, the amount of palladium carbon catalyst used was too much (5wt% of the reactant), which was not conducive to industrial production. Summary of the invention

[0008] The present invention provides a continuous flow production process for hydrogenated benzene modifier and its analogs. The scheme is as follows: The embodiment of the present invention provides a method for preparing hydrogenated benzene mod and its analogs, the method comprising: in a solvent, compound I and hydrogen react under the catalysis of palladium carbon to obtain compound II; the reaction is carried out in a silicon carbide microchannel reactor, and the reaction conditions are: the amount of palladium carbon is 0.1-2% by weight of compound I, the temperature is 20-70°C, the residence time is 1-20min, and the reaction pressure is 1-10 kg.

[0009] This new flow chemistry process unexpectedly greatly shortens the reaction time and reduces the amount of catalyst used, providing a new, low-cost and safe method for the synthesis of this type of compound, which is particularly suitable for large-scale industrial production.

[0010] Wherein, the structural formula of compound I is as follows: ; The structural formula of compound II is as follows: .

[0011] Among them, in compound Ⅰ and compound Ⅱ, R 1 Selected from phenolic hydroxyl group -OH or methoxy group -OMe, etc., R 2 The alkyl group is selected from substituted or unsubstituted alkyl groups with 1 to 7 carbon atoms, branched alkyl groups and their corresponding alkoxy groups, etc. The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopentyl, n-hexyl or cyclohexyl, etc.

[0012] The solvent in the embodiment of the present invention is selected from ethyl acetate, tetrahydrofuran, methanol, anhydrous ethanol or isopropanol, etc. Preferably, it is ethyl acetate, anhydrous ethanol or tetrahydrofuran.

[0013] Specifically, the compound I in the embodiment of the present invention is selected from 3,5-dihydroxy-4-isopropylbenzylbenzene, 3,5-dimethoxy-4-isopropylbenzylbenzene or 3,5-dihydroxy-4-ethylbenzylbenzene; correspondingly, the compound II is selected from phenethyl-4-isopropyl-3,5-resorcinol, 2-isopropyl-1,3-dimethoxy-5-phenethylbenzene or phenethyl-4-ethyl-3,5-resorcinol.

[0014] Specifically, the preparation method of hydrogenated benzophenone and its analogs in the embodiment of the present invention comprises: S1: Dissolve compound I in a solvent and add palladium-carbon catalyst to obtain a slurry.

[0015] S2: Under nitrogen protection, preheat the silicon carbide microchannel reactor to 20-70°C, and then introduce hydrogen and the slurry of step S1; the reaction temperature is 20-70°C, the reaction pressure is 1-10 kg, and the residence time of the slurry is 1-20 min.

[0016] S3: The reaction solution of step S2 is subjected to solid-liquid separation, concentration, recrystallization and drying to obtain compound II.

[0017] Wherein, in step S1, the mass ratio of solvent, compound I and palladium carbon is 1-40:1:0.001-0.02. Preferably, the mass ratio of solvent, compound I and palladium carbon is 5-40:1:0.005-0.02.

[0018] Wherein, in step S2, the flow rate of hydrogen is 100-5000sccm; the flow rate of slurry is 20-500mL / min. Preferably, the flow rate of hydrogen is 200-2000sccm; the flow rate of slurry is 50-200mL / min.

[0019] Wherein, in step S2, the reaction temperature is preferably 40-70°C, the reaction pressure is preferably 2-8 kg, and the residence time of the slurry is preferably 3-10 min.

[0020] Wherein, in step S3, the recrystallization solvent is selected from one or more of methanol, ethanol, benzene, toluene, petroleum ether, n-hexane, n-heptane and cyclohexane, etc., preferably methanol.

[0021] The slurry is delivered to the silicon carbide microchannel reactor through a diaphragm pump (to control the flow rate), and the hydrogen is delivered to the silicon carbide microchannel reactor through a pipeline with a flow controller (to control the flow rate). The silicon carbide microchannel reactor is heated by heat transfer oil, which is selected from silicone oil or other heat transfer oils. A gas-liquid separator is provided at the discharge end of the silicon carbide microchannel reactor for gas-liquid separation; a pressure control structure is provided on the gas-liquid separator to control the reaction pressure.

[0022] More specifically, the method for preparing hydrogenated benzophenone and its analogs in the embodiment of the present invention comprises: S1: Dissolve 3,5-dihydroxy-4-isopropylbenzylbenzene in ethyl acetate, and add palladium-carbon catalyst to obtain a slurry (which can be filtered to remove large particles that affect the operation of the silicon carbide microchannel reactor). The mass ratio of ethyl acetate, 3,5-dihydroxy-4-isopropylbenzylbenzene and palladium-carbon is 5-40:1:0.001-0.02.

[0023] S2: Under nitrogen protection, preheat the silicon carbide microchannel reactor to 40-60°C, and then introduce hydrogen and the slurry of step S1. The reaction temperature is 40-60°C, the reaction pressure is 1-5 kg, the residence time of the slurry is 3-10 min, the flow rate of hydrogen is 50-600 sccm, and the flow rate of the slurry is 20-100 mL / min.

[0024] S3: The reaction solution of step S2 is subjected to solid-liquid separation, concentration, recrystallization and drying to obtain phenethyl-4-isopropyl-3,5-resorcinol.

[0025] More specifically, the method for preparing hydrogenated benzophenone and its analogs in the embodiment of the present invention comprises: S1: Dissolve 3,5-dihydroxy-4-ethylbenzylbenzene in tetrahydrofuran, and add palladium-carbon catalyst to obtain slurry (which can be filtered to remove large particles that affect the operation of the silicon carbide microchannel reactor). The mass ratio of tetrahydrofuran, 3,5-dihydroxy-4-ethylbenzylbenzene and palladium-carbon is 5-40:1:0.001-0.02.

[0026] S2: Under nitrogen protection, preheat the silicon carbide microchannel reactor to 50-70°C, and then introduce hydrogen and the slurry of step S1. The reaction temperature is 50-70°C, the reaction pressure is 5-10 kg, the residence time of the slurry is 1-8 min, the flow rate of hydrogen is 500-1000 sccm, and the flow rate of the slurry is 50-200 mL / min.

[0027] S3: The reaction solution of step S2 is subjected to solid-liquid separation, concentration, recrystallization and drying to obtain phenethyl-4-ethyl-3,5-resorcinol.

[0028] The present invention has the following advantages: (1) Continuous flow production, suitable for industrial production.

[0029] (2) Less hydrogen is used, reducing safety risks.

[0030] (3) The reaction speed is fast, and the residence time does not exceed 20 minutes, which is much shorter than the overnight reaction in the prior art.

[0031] (4) The reaction yield is high, the yield can reach more than 95%, and the yield of some compounds can reach more than 99%; the purity reaches 99%, and the purity of some compounds is 99.9%.

[0032] (5) The amount of catalyst used is small (no more than 2%), which greatly reduces the reaction cost. DETAILED DESCRIPTION

[0033] The invention is further described below through specific examples, but it should be noted that these examples are merely illustrative and do not limit the scope of the invention.

[0034] Example 1 Example 1 provides a method for preparing hydrogenated styrene glycol (phenethyl-4-isopropyl-3,5-resorcinol), comprising the following steps: Step 1: Dissolve 1 kg of 3,5-dihydroxy-4-isopropylstilbene (phenylene glycol) completely with 5 kg of ethyl acetate, add 5 g of wet palladium-carbon catalyst, and obtain a reaction slurry.

[0035] Step 2: The silicon carbide microchannel reactor is pressurized to 3 kg, and after preheating to 50°C, the reaction slurry obtained in step 1 is injected into the silicon carbide microchannel reactor at a flow rate of 50 mL / min and hydrogen at a flow rate of 500 sccm to carry out a mixed reaction. The residence time of the reaction liquid in the silicon carbide microchannel is about 8 minutes. The gas-liquid separator at the tail end of the silicon carbide microchannel reactor realizes gas-liquid separation, the tail gas is connected to the tail gas absorption treatment device, and the liquid is released through the lower ball valve to obtain a crude product solution.

[0036] Step 3: The reaction solution was filtered to remove the palladium carbon catalyst, concentrated to remove the solvent ethyl acetate, added with methanol 3 times the mass of the liquid, cooled to 0-5°C, crystallized to obtain a solid, and vacuum dried at 60°C for 4 hours to obtain 958 g of a white solid product (phenethyl-4-isopropyl-3,5-resorcinol), with a yield of 95.0% and an HPLC purity of 99.32%.

[0037] Example 2 Example 2 provides a method for preparing a hydrogenated benzene analog (2-isopropyl-1,3-dimethoxy-5-phenylethylbenzene), comprising the following steps: Step 1: Add 30 kg of anhydrous ethanol to completely dissolve 1 kg of 3,5-dimethoxy-4-isopropylphenylethylene, and add 12 g of wet palladium-carbon catalyst to obtain a reaction slurry.

[0038] Step 2: The silicon carbide microchannel reactor is pressurized to 6 kg, and after preheating to 60°C, the reaction slurry obtained in step 1 is injected into the silicon carbide microchannel reactor at a flow rate of 180 mL / min and hydrogen at a flow rate of 1000 sccm to carry out a mixed reaction. The residence time of the reaction liquid in the silicon carbide microchannel is about 6 minutes. The gas-liquid separator at the tail end of the silicon carbide microchannel reactor realizes gas-liquid separation, the tail gas is connected to the tail gas absorption treatment device, and the liquid is released through the lower ball valve to obtain a crude product solution.

[0039] Step 3: The reaction solution was filtered, concentrated, recrystallized and vacuum dried to obtain 972 g of a white solid product (2-isopropyl-1,3-dimethoxy-5-phenylethylbenzene) with a yield of 96.5% and an HPLC purity of 99.58%.

[0040] Example 3 Example 3 provides a method for preparing a hydrogenated styrene analog (phenethyl-4-ethyl-3,5-resorcinol), comprising the following steps: Step 1: Add 16 kg of tetrahydrofuran to 1 kg of 3,5-dihydroxy-4-ethylstilbene and dissolve completely, add 18 g of wet palladium carbon, and filter to obtain a reaction slurry.

[0041] Step 2: The silicon carbide microchannel reactor is pressurized to 8 kg, and after preheating to 65°C, the reaction slurry obtained in step 1 is injected into the silicon carbide microchannel reactor at a flow rate of 100 mL / min and hydrogen at a flow rate of 800 sccm for mixed reaction. The residence time of the reaction liquid in the silicon carbide microchannel is about 3 minutes. The gas-liquid separator at the tail end of the silicon carbide microchannel reactor realizes gas-liquid separation, the tail gas is connected to the tail gas absorption treatment device, and the liquid is released through the lower ball valve to obtain the initial product solution.

[0042] Step 4: The reaction solution was filtered, concentrated, recrystallized and vacuum dried to obtain 998 g of a white solid product (phenethyl-4-ethyl-3,5-resorcinol) with a yield of 99.1% and a HPLC purity of 99.92%.

[0043] Comparative Example 1 Comparative Example 1 provides a method for preparing hydrogenated styrene glycol, comprising the following steps: Step 1: Put 100g 3,5-dihydroxy-4-isopropylstilbene, 1kg anhydrous ethanol, and 10g wet palladium carbon catalyst into a 3L reactor, stir, and replace the air in the reactor with nitrogen three times.

[0044] Step 2: Raise the temperature to 40°C, continue to introduce hydrogen (1 atm), and stir at room temperature overnight to obtain a crude product solution.

[0045] Step 3: After the reaction, 95.7 g of white solid product (phenethyl-4-isopropyl-3,5-resorcinol) was obtained after post-treatment such as filtration, concentration, recrystallization and drying. The yield was 95.0% and the HPLC purity was 96.8%.

[0046] Comparative Example 2 The process of Comparative Example 2 is consistent with that of Example 1, with a residence time of about 8 min. The difference is that a glass microchannel reactor is used. The yield of the product is 92.9%, and the HPLC purity is 98.84%.

[0047] Comparative Example 3 The process of Comparative Example 3 is consistent with that of Example 1, except that a glass microchannel reactor is used with a residence time of about 20 min; the yield of the product is 94.1% and the HPLC purity is 99.21%.

[0048] It can be seen that in the preparation method of the present invention, the efficient mass transfer and heat transfer capabilities of the silicon carbide microchannel reactor are used to achieve the equivalent reaction of hydrogenation reduction and the rapid removal of reaction heat, shorten the reaction time, reduce the residence time of the reactants in the silicon carbide microchannel reactor, reduce the amount of catalyst used, and have a higher product yield.

[0049] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing hydrogenated benzophenone and its analogs, the method comprising: In a solvent, compound I and hydrogen react under the catalysis of palladium carbon to obtain compound II; characterized in that the reaction is carried out in a silicon carbide microchannel reactor, and the reaction conditions are: temperature is 20-70°C, the amount of palladium carbon is 0.1-2% of the weight of compound I, the residence time is 1-20 minutes, and the reaction pressure is 1-10 kg; Wherein, the structural formula of compound I is as follows: ； The structural formula of compound II is as follows: ； Among them, R1 is selected from phenolic hydroxyl -OH or methoxy -OMe, R2 is selected from substituted or unsubstituted alkyl with a carbon number of 1-7, branched alkyl and its corresponding alkoxy, and the alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopentyl, n-hexyl or cyclohexyl.

2. The method for preparing hydrogenated benzophenone and its analogs according to claim 1, characterized in that: The solvent is selected from ethyl acetate, tetrahydrofuran, methanol, anhydrous ethanol or isopropanol.

3. The method for preparing hydrogenated benzophenone and its analogs according to claim 1, characterized in that: The compound I is selected from 3,5-dihydroxy-4-isopropylbenzylbenzene, 3,5-dimethoxy-4-isopropylbenzylbenzene or 3,5-dihydroxy-4-ethylbenzylbenzene; correspondingly, the compound II is selected from phenethyl-4-isopropyl-3,5-resorcinol, 2-isopropyl-1,3-dimethoxy-5-phenethylbenzene or phenethyl-4-ethyl-3,5-resorcinol.

4. The method for preparing hydrogenated benzophenone and its analogues according to claim 1 or 3, characterized in that: The method comprises: S1: dissolving compound I in a solvent, and adding palladium-carbon catalyst to obtain a slurry; S2: Under nitrogen protection, preheat the silicon carbide microchannel reactor to 20-70°C, and then introduce hydrogen and the slurry of step S1; the reaction temperature is 20-70°C, the reaction pressure is 1-10 kg, and the residence time of the slurry is 1-20 min; S3: The reaction solution of step S2 is subjected to solid-liquid separation, concentration, recrystallization and drying to obtain compound II.

5. The method for preparing hydrogenated benzophenone and its analogs according to claim 4, characterized in that: In step S1, the mass ratio of the solvent, compound I and palladium carbon is 1-40:1:0.001-0.

02.

6. The method for preparing hydrogenated benzophenone and its analogs according to claim 4, characterized in that: In step S2, the flow rate of hydrogen is 100-5000 sccm; the flow rate of slurry is 20-500 mL / min.

7. The method for preparing hydrogenated benzophenone and its analogs according to claim 4, characterized in that: In step S3, the recrystallization solvent is selected from one or more of methanol, ethanol, benzene, toluene, petroleum ether, n-hexane, n-heptane and cyclohexane.

8. The method for preparing hydrogenated benzophenone and its analogs according to claim 4, characterized in that: The slurry is delivered to the silicon carbide microchannel reactor through a diaphragm pump, and hydrogen is delivered to the silicon carbide microchannel reactor through a pipeline with a flow controller; the silicon carbide microchannel reactor is heated by heat transfer oil, and a gas-liquid separator is provided at its discharge end; a pressure control structure is provided on the gas-liquid separator to control the reaction pressure.

9. The method for preparing hydrogenated benzophenone and its analogs according to claim 4, characterized in that: The method comprises: S1: dissolving 3,5-dihydroxy-4-isopropylstilbene in ethyl acetate, and adding palladium-carbon catalyst to obtain a slurry; wherein the mass ratio of ethyl acetate, 3,5-dihydroxy-4-isopropylstilbene and palladium-carbon is 5-40:1:0.001-0.02; S2: Under nitrogen protection, preheat the silicon carbide microchannel reactor to 40-60°C, and then introduce hydrogen and the slurry of step S1; the reaction temperature is 40-60°C, the reaction pressure is 1-5 kg, the residence time of the slurry is 3-10min; the flow rate of hydrogen is 50-600sccm; the flow rate of the slurry is 20-100mL / min; S3: The reaction solution of step S2 is subjected to solid-liquid separation, concentration, recrystallization and drying to obtain phenethyl-4-isopropyl-3,5-resorcinol.

10. The method for preparing hydrogenated benzophenone and its analogs according to claim 4, characterized in that: The method comprises: S1: dissolving 3,5-dihydroxy-4-ethylstilbene in tetrahydrofuran, and adding palladium-carbon catalyst to obtain a slurry; wherein the mass ratio of tetrahydrofuran, 3,5-dihydroxy-4-ethylstilbene and palladium-carbon is 5-40:1:0.001-0.02; S2: Under nitrogen protection, preheat the silicon carbide microchannel reactor to 50-70°C, and then introduce hydrogen and the slurry of step S1; the reaction temperature is 50-70°C, the reaction pressure is 5-10 kg, the residence time of the slurry is 1-8 min; the flow rate of hydrogen is 500-1000 sccm; the flow rate of the slurry is 50-200 mL / min; S3: The reaction solution of step S2 is subjected to solid-liquid separation, concentration, recrystallization and drying to obtain phenethyl-4-ethyl-3,5-resorcinol.

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