Continuous preparation method and continuous preparation system of rilmenidine

Abstract

The invention discloses a continuous preparation method and continuous preparation system of rilmenidine, the method comprising: passing a hydrogen-ammonia gas mixture and a feed liquid A containing dicyclopropyl ketone into a fixed-bed reactor I to carry out an oximation hydrogenation reaction; separating the system after the reaction by gas-liquid separation, drying, and degassing to obtain a degassed system; nitrogen, the degassed system and a feed liquid B containing 2-oxazolidinone, a reaction aid, and a cosolvent are input into a fixed-bed reactor II to carry out a substitution dehydrogenation reaction; washing the system after the reaction, phase separation, drying, filtering, evaporating, and recrystallizing to obtain rilmenidine. The present invention prepares rilmenidine by continuously reacting dicyclopropyl ketone with 2-oxazolidinone after oximation hydrogenation, and the total conversion rate of the reaction can be stabilized at 90.7% after continuous operation for 200h, with the characteristics of higher production efficiency and better product stability.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a continuous preparation method and a continuous preparation system of rilmenidine. Background Art

[0002] Preventing and treating hypertension is crucial for reducing organ damage and complications. The number of drugs used to treat cardiovascular disease is increasing.

[0003] Rilmenidine, developed by Servier, a French company, is a representative second-generation centrally acting antihypertensive drug. Because it selectively targets the II-imidazoline receptors in the ventrolateral nucleus of the medulla oblongata, it is also known as an imidazoline receptor antagonist (N-(dicyclopropylmethyl)-4,5-dihydro-2-oxazolamide). Rilmenidine has a weak effect on α-2 adrenergic receptors and lacks significant central sedative effects. It exerts its antihypertensive effects by binding to imidazoline receptors, with a stable and reliable antihypertensive effect. Clinically, it exhibits advantages such as good tolerability, minimal side effects, good safety, and significant efficacy.

[0004] There are two main routes for the synthesis of rilmenidine reported so far, both of which are step-by-step preparation processes. One involves the cyclization of 2-chloroethyl isocyanate and dicyclopropylmethylamine by heating in the presence of potassium fluoride supported on aluminum oxide (Biooranic & Medicinal Chemistry Letters 1994, 4, 2317-22). The other involves the reaction of chloroisocyanate with dicyclopropylmethylamine in two consecutive steps (DE2362754). However, the raw materials for both methods are difficult to obtain, and the preparation of these two raw materials requires multiple chemical reactions, resulting in a complex process and high cost. CN1629144A discloses a method for preparing rilmenidine by condensing 2-alkoxyoxazoline and dicyclopropylmethylamine, which simplifies the previously complex production process to a certain extent. However, the raw material dicyclopropylmethylamine still adopts a step-by-step synthesis method in which dicyclopropyl ketone is used to generate an oxime followed by hydrogenation reduction. The total yield of the entire synthetic route is less than 70%. Qiang Yongkang reported a nickel-catalyzed one-pot hydrogenation of dicyclopropyl ketone with ammonia to directly obtain dicyclopropyl methylamine, a key intermediate. Boron trifluoride etherate and hydrochloropropane were then used with 2-oxazolidinone to produce another key intermediate, 2-ethoxyoxazoline. These two intermediates were then combined to yield rilmenidine. The overall yield of this synthetic route reached 80%, significantly improving the traditional process's raw material scarcity and high cost.

[0005] However, the reaction conditions of the above routes are still relatively harsh, there are many reaction steps, the post-processing is cumbersome, the overall reaction yield is not high, and the cost is expensive. From the perspective of industrial production, there is still a lot of room for optimization. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to address the deficiencies of the above-mentioned prior art and provide a continuous preparation method and system for rilmenidine. The present invention provides a method for continuously preparing rilmenidine by performing an oximation and hydrogenation reaction of dicyclopropyl ketone followed by substitution and dehydration with 2-oxazolidinone to continuously prepare rilmenidine. The total conversion rate of the reaction can be stabilized at a maximum of 90.7% after 200 hours of continuous operation, thus achieving higher production efficiency and better product stability.

[0007] In order to solve the above technical problems, the technical solution adopted by the present invention is: a continuous preparation method of rilmenidine, characterized in that the synthesis route of the method is as follows:

[0008]

[0009] The above-mentioned continuous preparation method of rilmenidine is characterized by comprising:

[0010] Step 1: mixing dicyclopropyl ketone with an organic solvent to obtain a feed solution A;

[0011] Step 2, preheating the hydrogen-ammonia mixture to 30-80°C and then passing it into a fixed bed reactor I equipped with a heterogeneous catalyst, until the pressure in the fixed bed reactor I equipped with a heterogeneous catalyst is 0.1-2 MPa.G and maintained, setting the temperature of the fixed bed reactor I equipped with a heterogeneous catalyst to 30-80°C and maintaining it, preheating the feed liquid A to 30-80°C and then passing it into the fixed bed reactor I equipped with a heterogeneous catalyst at a flow rate of 0.1 mL / min-5 mL / min for oximation hydrogenation reaction;

[0012] Step 3: performing gas-liquid separation on the system after the reaction in step 2 to obtain a liquid phase system;

[0013] Step 4: drying and degassing the liquid phase system to obtain a degassed system;

[0014] Step 5: mixing 2-oxazolidinone, the reaction aid solution and the cosolvent to obtain a feed solution B;

[0015] Step 6, preheating nitrogen to 50-100 ° C and then passing it into a fixed bed reactor II containing a heterogeneous catalyst, until the pressure in the fixed bed reactor II containing the heterogeneous catalyst is 1 atm and maintained, setting the temperature of the fixed bed reactor II containing the heterogeneous catalyst to 50-100 ° C and maintaining it, mixing the degassed system in step 4 and the feed liquid B in step 5 in a volume ratio of 1: (1-1.2) to obtain a mixture, preheating the mixture to 50-100 ° C and inputting it into the fixed bed reactor II containing the heterogeneous catalyst at a flow rate of 0.1 mL / min to 5 mL / min for substitution dehydrogenation reaction;

[0016] Step 7: Wash the reaction system in step 6, separate the phases to obtain an organic phase, dry the organic phase, filter, and evaporate to dryness to obtain a crude product;

[0017] Step 8: Recrystallize the crude product to obtain rilmenidine.

[0018] The above-mentioned continuous preparation method of rilmenidine is characterized in that, in step 1, the organic solvent is one or more of alcohols, ethers, nitriles, esters, alkanes, halogenated hydrocarbons and aromatic hydrocarbons; the alcohol organic solvent is methanol, anhydrous ethanol, isopropanol or tert-butanol; the ether organic solvent is diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; the nitrile organic solvent is acetonitrile or propionitrile; the ester organic solvent is methyl acetate, Ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, dimethyl carbonate, diethyl carbonate or ethyl methyl carbonate; the alkane organic solvent is n-pentane, n-heptane, n-hexane, cyclohexane or petroleum ether; the halogenated hydrocarbon organic solvent is dichloromethane or 1,2-dichloroethane; the aromatic hydrocarbon organic solvent is benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene or p-dichlorobenzene.

[0019] The above-mentioned continuous preparation method of rilmenidine is characterized in that, in step 1, the concentration of dicyclopropyl ketone in the feed solution A is 5 to 50 g / L.

[0020] The above-mentioned continuous preparation method of rilmenidine is characterized in that, in step 2, the average residence time of liquid A in the fixed bed reactor I containing a heterogeneous catalyst is 3 to 5 h, and the volume ratio of hydrogen and ammonia in the hydrogen-ammonia mixture is (1 to 10): 1; in step 2, the flow rate of the hydrogen-ammonia mixture is 1 to 50 mL / min; in step 2, the mass of the heterogeneous catalyst is 1 to 50 g; in step 2, the heterogeneous catalyst is a metal-supported heterogeneous catalyst, and the mass percentage of the metal in the metal-supported heterogeneous catalyst is 0.5% to 15%; in step 2, the heterogeneous catalyst morphology is spherical or cylindrical, with a particle size range of 0.5 mm to 4 mm, and the heterogeneous catalyst is one or two of a rhodium-based heterogeneous support catalyst, a ruthenium-based heterogeneous support catalyst, a palladium-based heterogeneous support catalyst, and a platinum-based heterogeneous support catalyst.

[0021] The above-mentioned continuous preparation method of rilmenidine is characterized in that, in step 5, the reaction aid solution is a reaction aid solution obtained by dissolving the reaction aid in ether, and the reaction aid is boron trifluoride or tetrafluoroboric acid; in step 5, the concentration of 2-oxazolidinone in the feed solution B is 4 to 40 g / L, and the molar ratio of 2-oxazolidinone to the reaction aid is 1: (1 to 5).

[0022] The above-mentioned continuous preparation method of rilmenidine is characterized in that, in step 5, the cosolvent is one or more of alcohols, ethers, nitriles, esters, alkanes, halogenated hydrocarbons and aromatic hydrocarbons; the alcohol cosolvent is methanol, anhydrous ethanol, isopropanol or tert-butanol; the ether cosolvent is diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; the nitrile cosolvent is acetonitrile or propionitrile; the ester cosolvent is methyl acetate, ethyl acetate The cosolvents are ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, dimethyl carbonate, diethyl carbonate or ethyl methyl carbonate; the alkane cosolvent is n-pentane, n-heptane, n-hexane, cyclohexane or petroleum ether; the halogenated hydrocarbon cosolvent is dichloromethane or 1,2-dichloroethane; the aromatic hydrocarbon cosolvent is benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene or p-dichlorobenzene.

[0023] The above-mentioned continuous preparation method of rilmenidine is characterized in that, in step six, the average residence time of the mixture in the fixed bed reactor II containing a heterogeneous catalyst is 4 to 10 hours; in step six, the mass of the heterogeneous catalyst is 2g to 100g; in step six, the heterogeneous catalyst is a metal-supported heterogeneous catalyst, and the mass percentage of the metal in the metal-supported heterogeneous catalyst is 0.1% to 10%; in step six, the heterogeneous catalyst morphology is spherical or cylindrical, with a particle size range of 0.2mm to 4mm, and the heterogeneous catalyst is one or two of a rhodium-based heterogeneous support catalyst, a ruthenium-based heterogeneous support catalyst, a palladium-based heterogeneous support catalyst and a platinum-based heterogeneous support catalyst.

[0024] The above-mentioned continuous preparation method of rilmenidine is characterized in that, in step six, the heterogeneous catalyst is one or two of a rhodium-based heterogeneous support catalyst, a palladium-based heterogeneous support catalyst and a platinum-based heterogeneous support catalyst.

[0025] In addition, the present invention also provides a continuous preparation system of rilmenidine, characterized in that the system includes a fixed bed reactor I for carrying out an oximation hydrogenation reaction and a fixed bed reactor II for carrying out a substitution dehydrogenation reaction, and the fixed bed reactor I is connected to the fixed bed reactor II.

[0026] Compared with the prior art, the present invention has the following advantages:

[0027] 1. The method of the present invention for continuously preparing rilmenidine comprises the following steps: performing an oximation and hydrogenation reaction of dicyclopropyl ketone followed by substitution and dehydration with 2-oxazolidinone to continuously prepare rilmenidine. The total conversion rate of the reaction can be stabilized at a maximum of 90.7% after continuous operation for 200 hours, thus having the characteristics of higher production efficiency and better product stability.

[0028] 2. The system for continuously preparing rilmenidine of the present invention connects two fixed-bed reactors in series to realize the two-step reaction in the synthesis process. The cascade reaction process assisted by drying and degassing has the characteristics of high reaction efficiency and few by-products, which can effectively reduce the impact of large-scale post-processing steps such as extraction, evaporation, filtration and purification in traditional processes on the product.

[0029] 3. The method for continuously preparing rilmenidine of the present invention greatly shortens the length of the original process route. The hydrogenation and dehydrogenation reactions are carried out in sequence through catalytic reactions, which greatly simplifies the complex oximation and substitution reactions in the previous process route. The total yield of the route can reach 85.8%, and the purity of the target product can reach 99.1%. It has the characteristics of high conversion rate, mild reaction process, easy control of the reaction process, few by-products, and low energy consumption.

[0030] 4. The raw and auxiliary materials of the method for continuously preparing rilmenidine of the present invention are all commercially available and inexpensive, thus avoiding the use of expensive and highly toxic isocyanate compounds.

[0031] The technical solution of the present invention is further described in detail below with reference to the accompanying drawings and embodiments.

[0032] Figures in the specification

[0033] Figure 1 This is a schematic structural diagram of the system for continuously preparing rilmenidine in Example 16 of the present invention. DETAILED DESCRIPTION

[0034] The following is a detailed description of the specific embodiments of the present invention. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention and are not intended to limit the present invention.

[0035] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0036] The present invention will be described in detail below through examples. In the following examples, unless otherwise specified, the raw materials used are all commercially available industrial grade products.

[0037] The present invention provides a continuous preparation method of rilmenidine, and the process route is:

[0038]

[0039] The continuous preparation method of rilmenidine of the present invention comprises: continuously feeding a liquid A obtained by mixing dicyclopropyl ketone and an organic solvent into a fixed bed reactor I filled with a hydrogen-ammonia mixed gas to carry out an oximation hydrogenation reaction; subjecting the system after the oximation hydrogenation reaction to gas-liquid separation and drying and degassing to obtain a degassed system; continuously feeding the degassed system and a liquid B containing 2-oxazolidinone into a fixed bed reactor II to carry out a substitution dehydrogenation reaction; and washing, phase separation, and recrystallization of the system after the substitution dehydrogenation reaction to obtain rilmenidine. Specifically, the method comprises:

[0040] Step 1, mixing dicyclopropyl ketone with an organic solvent to obtain a feed liquid A; the organic solvent can be one or more of alcohols, ethers, nitriles, esters, alkanes, halogenated hydrocarbons and aromatic hydrocarbons, the alcohol organic solvent can be methanol, anhydrous ethanol, isopropanol or tert-butanol, the ether organic solvent can be ether, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; the nitrile organic solvent can be acetonitrile or propionitrile, the ester organic solvent can be methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, dimethyl carbonate, diethyl carbonate or carbonyl carbonate. The alkane organic solvent may be n-pentane, n-heptane, n-hexane, cyclohexane or petroleum ether, the halogenated hydrocarbon organic solvent may be dichloromethane or 1,2-dichloroethane, and the aromatic hydrocarbon organic solvent may be benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene or p-dichlorobenzene. For example, the organic solvent may be anhydrous ethanol, tetrahydrofuran, methyl acetate, n-heptane, dichloromethane, toluene or m-dichlorobenzene, or a mixture of any one or more of the above organic solvents. The concentration of dicyclopropyl ketone in the feed liquid A is 5 to 50 g / L, and the concentration may be, for example, 5 g / L, 50 g / L or 20 g / L.

[0041] Step 2: Preheat the hydrogen-ammonia mixture to 30-80°C and then pass it into the fixed bed reactor I equipped with a heterogeneous catalyst, until the pressure in the fixed bed reactor I equipped with a heterogeneous catalyst is 0.1-2 MPa.G and maintained, set the temperature of the fixed bed reactor I equipped with a heterogeneous catalyst to 30-80°C and maintain, preheat the feed liquid A to 30-80°C and then pass it into the fixed bed reactor equipped with a heterogeneous catalyst at a flow rate of 0.1 mL / min-5 mL / min. An oximation hydrogenation reaction is carried out in a fixed-bed reactor I; the average residence time of the feed liquid A in the fixed-bed reactor I containing a heterogeneous catalyst is 3 to 5 hours, for example, 3 hours, 4 hours, or 5 hours; the volume ratio of hydrogen to ammonia in the hydrogen-ammonia mixture is (1 to 10):1, for example, 1:1, 2:1, or 10:1, and the flow rate of the hydrogen-ammonia mixture is 1 to 50 mL / min, for example, 1 mL / min, 30 mL / min, or 50 mL / min;

[0042] The mass of the heterogeneous catalyst is 1 to 50 g, for example, 1 g, 10 g or 50 g;

[0043] The heterogeneous catalyst is a metal-supported heterogeneous catalyst, and the mass percentage of the metal in the metal-supported heterogeneous catalyst is 0.5% to 15%, for example, 0.5%, 10% or 15%;

[0044] The metal-supported heterogeneous catalyst has a spherical or cylindrical morphology and a particle size range of 0.5 mm to 4 mm;

[0045] The preheating temperature of the hydrogen-ammonia mixture, the reactor setting temperature and the preheating temperature of the feed liquid A are equal and are all 30-80°C, for example, 30°C, 50°C or 80°C;

[0046] The metal-supported heterogeneous catalyst may be one or two of a rhodium-based heterogeneous support catalyst, a ruthenium-based heterogeneous support catalyst, a palladium-based heterogeneous support catalyst, and a platinum-based heterogeneous support catalyst, for example, a rhodium-based heterogeneous support catalyst, a ruthenium-based heterogeneous support catalyst, a palladium-based heterogeneous support catalyst, or a platinum-based heterogeneous support catalyst, or a combination of two of the above catalysts; the metal form in the metal-supported heterogeneous catalyst may be one or more of a simple substance, an oxide, a chloride, a hydroxide, a sulfate, a carbonate, a nitrate, a phosphate, a borate, a carboxylate, and a sulfonate, and the carrier may be activated carbon, or one or more of aluminum oxide, silicon oxide, zirconium oxide, and magnesium oxide, or a combination of aluminum oxide and one or more of silicon oxide, zirconium oxide, and magnesium oxide;

[0047] The preparation method of the metal-supported heterogeneous catalyst can be an impregnation method commonly used in the art, or other preparation methods. The impregnation method, for example, is as follows: impregnating a metal-soluble salt solution with the support for 12 hours, followed by drying and reducing at 80-150° C. to obtain the catalyst; the drying temperature can be, for example, 80° C., 120° C., or 150° C., and the drying time can be 6 hours, 10 hours, or 20 hours; the reduction can be carried out in an N2 and / or H2 atmosphere;

[0048] The metal-supported heterogeneous catalyst may further comprise an auxiliary agent, which may be, for example, one or two of NaCl, Mn(NO3)2, Ni(NO3)2·6H2O, CuCl2, Mg(NO3)2·3H2O, and Zn(NO3)2·6H2O, or a combination of NaCl and Mn(NO3)2, Ni(NO3)2·6H2O, CuCl2, Mg(NO3)2·3H2O, or Zn(NO3)2·6H2O;

[0049] Step 3: performing gas-liquid separation on the system after the reaction in step 2 to obtain a liquid phase system;

[0050] Step 4: drying and degassing the liquid phase system to obtain a degassed system;

[0051] Step 5: mixing 2-oxazolidinone and a reaction aid solution with a cosolvent to obtain a feed solution B; the reaction aid solution is a reaction aid solution obtained by dissolving a reaction aid in ether, and the reaction aid is boron trifluoride or tetrafluoroboric acid;

[0052] In the feed solution B, the concentration of 2-oxazolidinone is 4 to 40 g / L, for example, 4 g / L, 20 g / L or 40 g / L; the molar ratio of 2-oxazolidinone to the reaction aid is 1:(1 to 5), for example, 1:1, 1:2 or 1:5;

[0053] The cosolvent can be one or more of alcohols, ethers, nitriles, esters, alkanes, halogenated hydrocarbons and aromatic hydrocarbons. The alcohol cosolvent can be methanol, anhydrous ethanol, isopropyl alcohol or tert-butyl alcohol. The ether cosolvent can be ethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether. The nitrile cosolvent can be acetonitrile or propionitrile. The ester cosolvent can be methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isoamyl acetate, methyl propionate Ester, ethyl propionate, propyl propionate, dimethyl carbonate, diethyl carbonate or ethyl methyl carbonate, the alkane cosolvent may be n-pentane, n-heptane, n-hexane, cyclohexane or petroleum ether, the halogenated hydrocarbon cosolvent may be dichloromethane or 1,2-dichloroethane, the aromatic hydrocarbon cosolvent may be benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene or p-dichlorobenzene, for example, the cosolvent may be the same as in step 1, or a mixture of any one or more of the above cosolvents;

[0054] Step 6. Preheat nitrogen to 50-100 ° C and then pass it into the fixed bed reactor II containing a heterogeneous catalyst until the pressure in the fixed bed reactor II containing the heterogeneous catalyst is 1 atm and maintained, set the temperature of the fixed bed reactor II containing the heterogeneous catalyst to 50-100 ° C and maintain it, and mix the degassed system in step 4 and the feed liquid B in step 5 in a volume ratio of 1: (1-1.2) to obtain a mixture. After preheating the mixture to 50-100 ° C, the mixture was heated at 0.1 mL / min~5 mL / min. min is input into a fixed bed reactor II containing a heterogeneous catalyst for substitution dehydrogenation reaction; the volume ratio can be, for example, 1:1.05, 1:1.2 or 1:1.1; the preheating temperature can be, for example, 50°C, 80°C or 100°C, and the flow rate can be, for example, 0.1 mL / min, 2 mL / min or 5 mL / min; the average residence time of the mixture in the fixed bed reactor II containing the heterogeneous catalyst is 4 to 10 hours, and the average residence time can be, for example, 4 hours, 8 hours or 10 hours;

[0055] The mass of the heterogeneous catalyst is 2 g to 100 g, for example, 2 g, 10 g or 100 g; the heterogeneous catalyst is a metal-supported heterogeneous catalyst; the mass percentage of the metal in the metal-supported heterogeneous catalyst is 0.1% to 10%, for example, 0.1%, 5% or 10%; the metal-supported heterogeneous catalyst has a spherical or cylindrical morphology, and a particle size range of 0.2 mm to 4 mm;

[0056] The metal-supported heterogeneous catalyst can be one or two of a rhodium-based heterogeneous carrier catalyst, a ruthenium-based heterogeneous carrier catalyst, a palladium-based heterogeneous carrier catalyst and a platinum-based heterogeneous carrier catalyst, for example, a rhodium-based heterogeneous carrier catalyst, a ruthenium-based heterogeneous carrier catalyst, a palladium-based heterogeneous carrier catalyst or a platinum-based heterogeneous carrier catalyst, or a combination of two of the above catalysts; the metal form in the metal-supported heterogeneous catalyst can be one or more of a simple substance, oxide, chloride, hydroxide, sulfate, carbonate, nitrate, phosphate, borate, carboxylate and sulfonate, and the carrier is one or more of graphite, talc, activated carbon, SiO2, Al2O3 and diatomaceous earth; preferably, ... The catalyst is one or two of a rhodium-based heterogeneous support catalyst, a palladium-based heterogeneous support catalyst and a platinum-based heterogeneous support catalyst; further preferably, when the metal-supported heterogeneous catalyst in step six is ​​a rhodium-based heterogeneous support catalyst, the metal-supported heterogeneous catalyst in step two is one or two of a ruthenium-based heterogeneous support catalyst, a palladium-based heterogeneous support catalyst and a platinum-based heterogeneous support catalyst, when the metal-supported heterogeneous catalyst in step six is ​​a palladium-based heterogeneous support catalyst and / or a platinum-based heterogeneous support catalyst, the metal-supported heterogeneous catalyst in step two is one or two of a rhodium-based heterogeneous support catalyst, a ruthenium-based heterogeneous support catalyst, a palladium-based heterogeneous support catalyst and a platinum-based heterogeneous support catalyst;

[0057] The preparation method of the metal-supported heterogeneous catalyst can be the same as step 2;

[0058] Step 7: Wash the reaction system in step 6 with saturated brine, separate the phases to obtain an organic phase, dry the organic phase, filter, and evaporate to dryness to obtain a crude product; the drying step is drying with anhydrous sodium sulfate;

[0059] Step eight, recrystallizing the crude product to obtain rilmenidine; the solvent for the recrystallization is ethyl acetate or n-hexane; the melting point of the recrystallization is 105-107°C.

[0060] Example 1

[0061] This embodiment provides a continuous preparation method of rilmenidine, which specifically comprises:

[0062] Step 1, mixing dicyclopropyl ketone with an organic solvent to obtain a feed liquid A; the organic solvent is anhydrous ethanol; the concentration of dicyclopropyl ketone in the feed liquid A is 5g / L;

[0063] Step 2, the hydrogen-ammonia mixture is preheated to 40 ° C and passed into a fixed bed reactor I equipped with a palladium-based heterogeneous catalyst, and the pressure in the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst is maintained at 0.5 MPa.G, and the temperature of the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst is set to 40 ° and maintained, and the feed liquid A is preheated to 40 ° C and passed into the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst at a flow rate of 1 mL / min for oximation hydrogenation reaction; the average residence time of the feed liquid A in the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst is 3h; the hydrogen-ammonia mixture The volume ratio of hydrogen to ammonia is 1:1, the mass of the palladium-based heterogeneous catalyst is 10 g, the palladium-based heterogeneous catalyst is a palladium-based heterogeneous catalyst with activated carbon as a carrier supporting palladium, the mass percentage of palladium in the palladium-based heterogeneous catalyst is 1%, and the mass percentage of palladium = metallic palladium / the palladium-based heterogeneous catalyst; the palladium-based heterogeneous catalyst has a spherical morphology and a particle size range of 0.5 mm to 4 mm; the palladium-based heterogeneous catalyst may also have a columnar morphology; the hydrogen-ammonia mixed gas flow rate introduced into the fixed bed reactor I containing the palladium-based heterogeneous catalyst is maintained at a pressure of 30 mL / min;

[0064] Step 3: Perform gas-liquid separation on the system after the reaction in step 2 to obtain a liquid phase system; the gas-liquid separation can separate hydrogen and ammonia for recycling;

[0065] Step 4: drying and degassing the liquid phase system to obtain a degassed system; the drying is performed using 4A molecular sieves; the degassing is performed by bubbling degassing, the degassing is performed using nitrogen, the nitrogen flow rate is 100 mL / min, and the degassing time is 2 h;

[0066] Step 5, mixing 2-oxazolidinone and a reaction aid solution with a cosolvent to obtain a feed liquid B; the reaction aid solution is a boron trifluoride etherate solution, the reaction aid is boron trifluoride, the cosolvent is tetrahydrofuran, the mass percentage of the boron trifluoride etherate solution is 47%, the concentration of 2-oxazolidinone in the feed liquid B is 4 g / L, and the molar ratio of 2-oxazolidinone to boron trifluoride is 1:2; 2-oxazolidinone and a reaction aid solution are mixed with a cosolvent to obtain a feed liquid B; the reaction aid solution is a boron trifluoride etherate solution, the reaction aid is boron trifluoride, the cosolvent is tetrahydrofuran, the mass percentage of the boron trifluoride etherate solution is 47%, the concentration of 2-oxazolidinone in the feed liquid B is 4 g / L, and the molar ratio of 2-oxazolidinone to boron trifluoride is 1:2;

[0067] Step six, preheating nitrogen to 80 ° C and passing it into a fixed bed reactor II equipped with a platinum-based heterogeneous catalyst, until the pressure in the fixed bed reactor II equipped with a platinum-based heterogeneous catalyst is 1atm and maintained, setting the temperature of the fixed bed reactor II equipped with a platinum-based heterogeneous catalyst to 80 ° C and maintaining it, and mixing the degassed system in step four and the step five feed liquid B in a volume ratio of 1: 1.1 to obtain a mixture, preheating the mixture to 80 ° C and inputting it into a fixed bed reactor II equipped with a platinum-based heterogeneous catalyst at a flow rate of 2 mL / min for substitution dehydrogenation reaction; the mixture is heated in a fixed bed reactor equipped with a platinum-based heterogeneous catalyst. The average residence time in the fixed bed reactor II is 4 hours; the mass of the platinum-based heterogeneous catalyst is 10 g, the platinum-based heterogeneous catalyst is a catalyst in which platinum is supported on Al2O3, the mass percentage of platinum in the platinum-based heterogeneous catalyst is 1%, the morphology of the platinum-based heterogeneous catalyst is spherical, and the particle size range is 0.2 mm to 4 mm; the morphology of the platinum-based heterogeneous catalyst can also be columnar; after stable operation for a predetermined time, sampling is performed at the discharge port, and the residual raw material and product content before and after the two steps are analyzed to obtain the total raw material conversion rate, and the results are listed in Table 1 below; the predetermined time is 50 hours, 100 hours, or 200 hours;

[0068] Step 7: Wash the reaction system in step 6 with saturated brine, separate the phases to obtain an organic phase, dry the organic phase, filter, and evaporate to dryness to obtain a crude product; the drying step is drying with anhydrous sodium sulfate;

[0069] Step eight, recrystallizing the crude product to obtain rilmenidine; the recrystallization solvent is ethyl acetate, and the recrystallization solvent can also be n-hexane; the melting point of the recrystallization is 105-107°C;

[0070] In this embodiment, the purity of pure rilmenidine is shown in Table 1, and the nuclear magnetic resonance and mass spectra are as follows:

[0071] 1 HNMR (CDCl3, 400M): δ (ppm) 3.90 (m, 2H), 3.72 (m, 2H), 2.35 (m, 1H), 1.10 (m, 2H), 0.42 (m, 8H).

[0072] MS: m / z = 180.43 [M+H] +

[0073] Example 2

[0074] This embodiment provides a continuous preparation method of rilmenidine, which specifically comprises:

[0075] Step 1, mixing dicyclopropyl ketone with an organic solvent to obtain a feed liquid A; the organic solvent is ethylene glycol dimethyl ether; the concentration of dicyclopropyl ketone in the feed liquid A is 10g / L;

[0076] Step 2: Preheat the hydrogen-ammonia mixture to 60°C and pass it into a fixed bed reactor I equipped with a palladium-based heterogeneous catalyst, until the pressure in the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst is 1.0 MPa.G and maintained, set the temperature of the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst to 60°C and maintain it, preheat the feed liquid A to 60°C and pass it into the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst at a flow rate of 5 mL / min for oximation hydrogenation reaction; the average residence time of the feed liquid A in the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst is 200 nm. The reaction time is 3h; the volume ratio of hydrogen to ammonia in the hydrogen-ammonia mixture is 2:1, the mass of the palladium-based heterogeneous catalyst is 20g, the palladium-based heterogeneous catalyst is a palladium-based heterogeneous catalyst in which palladium is supported on activated carbon as a carrier, the mass percentage of palladium in the palladium-based heterogeneous catalyst is 2%, the palladium-based heterogeneous catalyst has a spherical morphology and a particle size range of 0.5mm to 4mm; the palladium-based heterogeneous catalyst may also have a columnar morphology; the hydrogen-ammonia mixture gas flow rate introduced into the fixed-bed reactor I containing the palladium-based heterogeneous catalyst is maintained at a pressure of 30mL / min;

[0077] Step 3: Perform gas-liquid separation on the system after the reaction in step 2 to obtain a liquid phase system; the gas-liquid separation can separate hydrogen and ammonia for recycling;

[0078] Step 4: drying and degassing the liquid phase system to obtain a degassed system; the drying is performed using 4A molecular sieves; the degassing is performed by bubbling degassing, the degassing is performed using nitrogen, the nitrogen flow rate is 100 mL / min, and the degassing time is 2 h;

[0079] Step 5, mixing 2-oxazolidinone and a reaction aid solution with a cosolvent to obtain a feed solution B; the reaction aid solution is a boron trifluoride ether solution, the reaction aid is boron trifluoride, the cosolvent is dichloromethane, the mass percentage of the boron trifluoride ether solution is 47%, the concentration of 2-oxazolidinone in the feed solution B is 8 g / L, and the molar ratio of 2-oxazolidinone to boron trifluoride is 1:2.5;

[0080] Step six, the nitrogen is preheated to 70 ° C and then passed into a fixed bed reactor II equipped with a platinum heterogeneous catalyst, and the pressure in the fixed bed reactor II equipped with a platinum heterogeneous catalyst is 1atm and maintained, the temperature of the fixed bed reactor II equipped with a platinum heterogeneous catalyst is set to 70 ° C and maintained, the degassed system in step four and the step five liquid B are mixed according to a volume ratio of 1:1.05 to obtain a mixture, and the mixture is preheated to 70 ° C and input into a fixed bed reactor II equipped with a platinum heterogeneous catalyst at a flow rate of 4 mL / min for substitution dehydrogenation reaction; the mixture is in a fixed bed reactor II equipped with a platinum heterogeneous catalyst The average residence time is 4h; the mass of the platinum-based heterogeneous catalyst is 20g, the platinum-based heterogeneous catalyst is a catalyst with Al2O3 as a carrier supporting platinum, the mass percentage of platinum in the platinum-based heterogeneous catalyst is 0.5%, the morphology of the platinum-based heterogeneous catalyst is spherical, and the particle size range is 0.2mm~4mm; the morphology of the platinum-based heterogeneous catalyst can also be columnar; after stable operation for a predetermined time, sampling is performed at the discharge port, and the residual raw materials and product contents before and after the two steps are analyzed to obtain the total conversion rate of the raw materials. The results are listed in Table 1 below; the predetermined time is 50h, 100h or 200h; the hydrogen-ammonia mixture is the same as in step 2;

[0081] Step 7: Wash the reaction system in step 6 with saturated brine, separate the phases to obtain an organic phase, dry the organic phase, filter, and evaporate to dryness to obtain a crude product; the drying step is drying with anhydrous sodium sulfate;

[0082] Step eight, recrystallizing the crude product to obtain rilmenidine; the solvent for the recrystallization is ethyl acetate, or n-hexane; the melting point of the recrystallization is 105-107°C.

[0083] The nuclear magnetic resonance and mass spectrum of rilmenidine in this example are basically the same as those in Example 1.

[0084] Example 3

[0085] This embodiment provides a continuous preparation method of rilmenidine, which specifically comprises:

[0086] Step 1, mixing dicyclopropyl ketone with an organic solvent to obtain a feed liquid A; the organic solvent is toluene; the concentration of dicyclopropyl ketone in the feed liquid A is 20 g / L;

[0087] Step 2: Preheat the hydrogen-ammonia mixture to 80°C and pass it into a fixed bed reactor I equipped with a palladium-based heterogeneous catalyst, until the pressure in the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst is 2.0 MPa.G and maintained, set the temperature of the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst to 80°C and maintain it, preheat the feed liquid A to 80°C and pass it into the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst at a flow rate of 5 mL / min for oximation hydrogenation reaction; the average residence time of the feed liquid A in the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst is 2.0 MPa.G. The reaction time is 4h; the volume ratio of hydrogen to ammonia in the hydrogen-ammonia mixture is 5:1, the mass of the palladium-based heterogeneous catalyst is 20g, the palladium-based heterogeneous catalyst is a palladium-based heterogeneous catalyst in which palladium is supported on activated carbon as a carrier, the mass percentage of palladium in the palladium-based heterogeneous catalyst is 5%, the palladium-based heterogeneous catalyst has a spherical morphology and a particle size range of 0.5mm to 4mm; the palladium-based heterogeneous catalyst may also have a columnar morphology; the hydrogen-ammonia mixture gas flow rate introduced into the fixed-bed reactor I containing the palladium-based heterogeneous catalyst is maintained at 30mL / min;

[0088] Step 3: Perform gas-liquid separation on the system after the reaction in step 2 to obtain a liquid phase system; the gas-liquid separation can separate hydrogen and ammonia for recycling;

[0089] Step 4: drying and degassing the liquid phase system to obtain a degassed system; the drying is performed using 4A molecular sieves; the degassing is performed by bubbling degassing, the degassing is performed using nitrogen, the nitrogen flow rate is 100 mL / min, and the degassing time is 2 h;

[0090] Step 5, mixing 2-oxazolidinone and a reaction aid solution with a cosolvent to obtain a feed solution B; the reaction aid solution is a tetrafluoroboric acid ether solution, the reaction aid is tetrafluoroboric acid, the cosolvent is anhydrous ethanol, the mass percentage of the tetrafluoroboric acid ether solution is 55%, the concentration of 2-oxazolidinone in the feed solution B is 8 g / L, and the molar ratio of 2-oxazolidinone to tetrafluoroboric acid is 1:4;

[0091] Step six, preheating nitrogen to 100 ° C and passing it into a fixed bed reactor II equipped with a platinum-based heterogeneous catalyst, until the pressure in the fixed bed reactor II equipped with a platinum-based heterogeneous catalyst is 1atm and maintained, setting the temperature of the fixed bed reactor II equipped with a platinum-based heterogeneous catalyst to 100 ° C and maintaining, and mixing the degassed system in step four and the feed liquid B in step five in a volume ratio of 1:1.05 to obtain a mixture, preheating the mixture to 100 ° C and inputting it into a fixed bed reactor II equipped with a platinum-based heterogeneous catalyst at a flow rate of 5 mL / min for substitution dehydrogenation reaction; the mixture is heated in a fixed bed reactor equipped with a platinum-based heterogeneous catalyst. The average residence time in the device II is 6 hours; the mass of the platinum-based heterogeneous catalyst is 20 g, the platinum-based heterogeneous catalyst is a catalyst loaded with platinum on an Al2O3 carrier, the mass percentage of platinum in the platinum-based heterogeneous catalyst is 2%, the morphology of the platinum-based heterogeneous catalyst is spherical, and the particle size range is 0.2 mm to 4 mm; the morphology of the platinum-based heterogeneous catalyst can also be columnar; after stable operation for a predetermined time, sampling is performed at the discharge port, and the residual raw materials and product contents before and after the two steps are analyzed to obtain the total conversion rate of the raw materials. The results are listed in Table 1 below; the predetermined time is 50 hours, 100 hours or 200 hours; the hydrogen-ammonia mixture is the same as in step 2;

[0092] Step 7: Wash the reaction system in step 6 with saturated brine, separate the phases to obtain an organic phase, dry the organic phase, filter, and evaporate to dryness to obtain a crude product; the drying step is drying with anhydrous sodium sulfate;

[0093] Step eight, recrystallizing the crude product to obtain rilmenidine; the solvent for the recrystallization is ethyl acetate, or n-hexane; the melting point of the recrystallization is 105-107°C.

[0094] The nuclear magnetic resonance and mass spectrum of rilmenidine in this example are basically the same as those in Example 1.

[0095] Example 4

[0096] This embodiment provides a continuous preparation method of rilmenidine, which specifically comprises:

[0097] Step 1, mixing dicyclopropyl ketone with an organic solvent to obtain a feed liquid A; the organic solvent is cyclohexane; the concentration of dicyclopropyl ketone in the feed liquid A is 30 g / L;

[0098] Step 2: preheat the hydrogen-ammonia mixture to 30°C and pass it into a fixed bed reactor I equipped with a palladium-based heterogeneous catalyst, until the pressure in the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst is 1.5 MPa.G and maintained, the temperature of the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst is set to 30°C and maintained, and the feed liquid A is preheated to 30°C and passed into the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst at a flow rate of 0.5 mL / min for oximation hydrogenation reaction; the average residence time of the feed liquid A in the fixed bed reactor I equipped with a palladium-based heterogeneous catalyst is The reaction time is 5h; the volume ratio of hydrogen to ammonia in the hydrogen-ammonia mixture is 10:1, the mass of the palladium-based heterogeneous catalyst is 40g, the palladium-based heterogeneous catalyst is a palladium-based heterogeneous catalyst in which palladium is supported on activated carbon as a carrier, the mass percentage of palladium in the palladium-based heterogeneous catalyst is 15%, the palladium-based heterogeneous catalyst has a spherical morphology and a particle size range of 0.5mm to 4mm; the palladium-based heterogeneous catalyst may also have a columnar morphology; the hydrogen-ammonia mixture gas flow rate introduced into the fixed-bed reactor I containing the palladium-based heterogeneous catalyst is maintained at a pressure of 30mL / min;

[0099] Step 3: Perform gas-liquid separation on the system after the reaction in step 2 to obtain a liquid phase system; the gas-liquid separation can separate hydrogen and ammonia for recycling;

[0100] Step 4: drying and degassing the liquid phase system to obtain a degassed system; the drying is performed using 4A molecular sieves; the degassing is performed by bubbling degassing, the degassing is performed using nitrogen, the nitrogen flow rate is 100 mL / min, and the degassing time is 2 h;

[0101] Step 5, mixing 2-oxazolidinone and a reaction aid solution with a cosolvent to obtain a feed solution B; the reaction aid solution is a tetrafluoroboric acid ether solution, the reaction aid is tetrafluoroboric acid, the cosolvent is ethyl acetate, the mass percentage of the tetrafluoroboric acid ether solution is 55%, the concentration of 2-oxazolidinone in the feed solution B is 24 g / L, and the molar ratio of 2-oxazolidinone to tetrafluoroboric acid is 1:5;

[0102] Step six, preheating nitrogen to 60 ° C and passing it into a fixed bed reactor II equipped with a platinum-based heterogeneous catalyst, until the pressure in the fixed bed reactor II equipped with a platinum-based heterogeneous catalyst is 1atm and maintained, setting the temperature of the fixed bed reactor II equipped with a platinum-based heterogeneous catalyst to 60 ° C and maintaining it, and mixing the degassed system in step four and the feed liquid B in step five in a volume ratio of 1:1.2 to obtain a mixture, and preheating the mixture to 60 ° C and inputting it into a fixed bed reactor II equipped with a platinum-based heterogeneous catalyst at a flow rate of 1 mL / min for substitution dehydrogenation reaction; the mixture is in a fixed bed reactor II equipped with a platinum-based heterogeneous catalyst. The average residence time in the reaction mixture is 6 hours; the mass of the platinum-based heterogeneous catalyst is 60 g, the platinum-based heterogeneous catalyst is a catalyst containing platinum on an Al2O3 carrier, the mass percentage of platinum in the platinum-based heterogeneous catalyst is 5%, the morphology of the platinum-based heterogeneous catalyst is spherical, and the particle size range is 0.2 mm to 4 mm; the morphology of the platinum-based heterogeneous catalyst can also be columnar; after stable operation for a predetermined time, sampling is performed at the discharge port, and the residual raw materials and product contents before and after the two steps are analyzed to obtain the total conversion rate of the raw materials. The results are listed in Table 1 below; the predetermined time is 50 hours, 100 hours or 200 hours; the hydrogen-ammonia mixture is the same as that in step 2;

[0103] Step 7: Wash the reaction system in step 6 with saturated brine, separate the phases to obtain an organic phase, dry the organic phase, filter, and evaporate to dryness to obtain a crude product; the drying step is drying with anhydrous sodium sulfate;

[0104] Step eight, recrystallizing the crude product to obtain rilmenidine; the solvent for the recrystallization is ethyl acetate, or n-hexane; the melting point of the recrystallization is 105-107°C.

[0105] The nuclear magnetic resonance and mass spectrum of rilmenidine in this example are basically the same as those in Example 1.

[0106] Example 5

[0107] This embodiment is the same as embodiment 1, except that in step 2, the fixed bed reactor uses a platinum-based heterogeneous catalyst under the same conditions.

[0108] Example 6

[0109] This embodiment is the same as embodiment 2, except that, in step 2, the fixed bed reactor uses a ruthenium-based heterogeneous catalyst under the same conditions.

[0110] Example 7

[0111] This embodiment is the same as embodiment 3, except that, in step 2, the fixed bed reactor uses a rhodium-based heterogeneous catalyst under the same conditions.

[0112] Example 8

[0113] This embodiment is the same as embodiment 1, except that in step 6, the fixed bed reactor uses a palladium-based heterogeneous catalyst under the same conditions.

[0114] Example 9

[0115] This embodiment is the same as embodiment 2, except that in step 6, the fixed bed reactor uses a ruthenium-based heterogeneous catalyst under the same conditions.

[0116] Example 10

[0117] This embodiment is the same as embodiment 3, except that in step 6, the fixed bed reactor uses a rhodium-based heterogeneous catalyst under the same conditions.

[0118] Example 11

[0119] This embodiment is the same as embodiment 1, except that in step 2, the fixed bed reactor uses a platinum-based heterogeneous catalyst under the same conditions, and in step 6, the fixed bed reactor uses a palladium-based heterogeneous catalyst under the same conditions.

[0120] Example 12

[0121] This embodiment is the same as embodiment 2, except that in step 2, the fixed bed reactor uses a rhodium-based heterogeneous catalyst under the same conditions, and in step 6, the fixed bed reactor uses a ruthenium-based heterogeneous catalyst under the same conditions.

[0122] Example 13

[0123] This embodiment is the same as embodiment 3, except that in step 2, the fixed bed reactor uses a ruthenium-based heterogeneous catalyst under the same conditions, and in step 6, the fixed bed reactor uses a rhodium-based heterogeneous catalyst under the same conditions.

[0124] Example 14

[0125] This embodiment provides a continuous preparation method of rilmenidine, which specifically comprises:

[0126] Step 1, mixing dicyclopropyl ketone with an organic solvent to obtain a feed liquid A; the organic solvent is anhydrous ethanol and acetonitrile in a volume ratio of 1:2; the concentration of dicyclopropyl ketone in the feed liquid A is 10g / L;

[0127] Step 2: preheating the hydrogen-ammonia mixture to 30°C and then passing it into a fixed bed reactor I equipped with a first metal-supported heterogeneous catalyst, until the pressure in the fixed bed reactor I equipped with the first metal-supported heterogeneous catalyst is 0.1 MPa.G and maintained, setting the temperature of the fixed bed reactor I equipped with the first metal-supported heterogeneous catalyst to 30°C and maintaining it, preheating the feed liquid A to 30°C and then passing it into the fixed bed reactor I equipped with the first metal-supported heterogeneous catalyst at a flow rate of 0.1 mL / min for oximation hydrogenation reaction; the average residence time of the feed liquid A in the fixed bed reactor I equipped with the first metal-supported heterogeneous catalyst is 3h; The volume ratio of hydrogen and ammonia in the hydrogen-ammonia mixture is 10:1, the mass of the first metal-supported heterogeneous catalyst is 50 g, the first metal-supported heterogeneous catalyst is a first metal-supported heterogeneous catalyst with aluminum oxide as a carrier to support the metal, the first metal-supported heterogeneous catalyst is a palladium-supported catalyst and a rhodium-supported catalyst in a mass ratio of 2:1, the mass percentage of palladium and rhodium are 0.5% respectively, the first metal-supported heterogeneous catalyst has a spherical morphology, and the particle size range is 0.5 mm to 4 mm; the hydrogen-ammonia mixture gas flow rate introduced into the fixed bed reactor I containing the first metal-supported heterogeneous catalyst is maintained at a pressure of 1 mL / min;

[0128] Step 3: Perform gas-liquid separation on the system after the reaction in step 2 to obtain a liquid phase system; the gas-liquid separation can separate hydrogen and ammonia for recycling;

[0129] Step 4: drying and degassing the liquid phase system to obtain a degassed system; the drying is performed using 4A molecular sieves; the degassing is performed by bubbling degassing, the degassing is performed using nitrogen, the nitrogen flow rate is 100 mL / min, and the degassing time is 2 h;

[0130] Step 5, mixing 2-oxazolidinone and a reaction aid solution with a cosolvent to obtain a feed solution B; the reaction aid solution is a boron trifluoride ether solution, the reaction aid is boron trifluoride, the cosolvent is m-dichlorobenzene, the mass percentage of the boron trifluoride ether solution is 47%, the concentration of 2-oxazolidinone in the feed solution B is 8 g / L, and the molar ratio of 2-oxazolidinone to boron trifluoride is 1:1;

[0131] Step six, preheating nitrogen to 50 ° C and then passing it into a fixed bed reactor II equipped with a second metal-supported heterogeneous catalyst, until the pressure in the fixed bed reactor II equipped with the second metal-supported heterogeneous catalyst is 1atm and maintained, setting the temperature of the fixed bed reactor II equipped with the second metal-supported heterogeneous catalyst to 50 ° C and maintaining, and mixing the degassed system in step four and the feed liquid B in step five in a volume ratio of 1: 1 to obtain a mixture, and preheating the mixture to 50 ° C at a flow rate of 0.1 mL / min to input it into the fixed bed reactor II equipped with the second metal-supported heterogeneous catalyst for substitution dehydrogenation reaction; the average stop of the mixture in the fixed bed reactor II equipped with the second metal-supported heterogeneous catalyst is 200 ℃. The residence time is 10h; the mass of the second metal-supported heterogeneous catalyst is 100g, the second metal-supported heterogeneous catalyst is a catalyst with Al2O3 as a carrier metal, the second metal-supported heterogeneous catalyst is a palladium-supported catalyst and a platinum-supported catalyst with a mass ratio of 1:1, the mass percentage of palladium and platinum are 0.1% respectively, the morphology of the second metal-supported heterogeneous catalyst is spherical, and the particle size range is 0.2mm~4mm; after stable operation for the predetermined time, sampling is performed at the discharge port, and the residual raw materials and product content before and after the two steps are analyzed to obtain the total conversion rate of the raw materials, and the results are listed in Table 1 below; the predetermined time is 50h, 100h or 200h; the hydrogen-ammonia mixture is the same as in step 2;

[0132] Step 7: Wash the reaction system in step 6 with saturated brine, separate the phases to obtain an organic phase, dry the organic phase, filter, and evaporate to dryness to obtain a crude product; the drying step is drying with anhydrous sodium sulfate;

[0133] Step eight, recrystallizing the crude product to obtain rilmenidine; the solvent for the recrystallization is ethyl acetate, or n-hexane; the melting point of the recrystallization is 105-107°C.

[0134] The nuclear magnetic resonance and mass spectrum of rilmenidine in this example are basically the same as those in Example 1.

[0135] Example 15

[0136] This embodiment provides a continuous preparation method of rilmenidine, which specifically comprises:

[0137] Step 1: mixing dicyclopropyl ketone with an organic solvent to obtain a feed liquid A; the organic solvent is n-pentane, toluene and n-heptane in a volume ratio of 2:1:1; the concentration of dicyclopropyl ketone in the feed liquid A is 50 g / L;

[0138] Step 2: preheating the hydrogen-ammonia mixture to 60° C. and then passing it into a fixed bed reactor I containing a first metal-supported heterogeneous catalyst, until the pressure in the fixed bed reactor I containing the first metal-supported heterogeneous catalyst is 2.0 MPa.G and maintained, setting the temperature of the fixed bed reactor I containing the first metal-supported heterogeneous catalyst to 60° C. and maintaining it, preheating the feed liquid A to 60° C. and then passing it into the fixed bed reactor I containing the first metal-supported heterogeneous catalyst at a flow rate of 5 mL / min for oximation hydrogenation reaction; the average residence time of the feed liquid A in the fixed bed reactor I containing the first metal-supported heterogeneous catalyst is 3 h; The volume ratio of hydrogen and ammonia in the hydrogen-ammonia mixture is 1:1, the mass of the first metal-supported heterogeneous catalyst is 1 g, the first metal-supported heterogeneous catalyst is a first metal-supported heterogeneous catalyst in which a metal is supported on a silicon oxide carrier, the first metal-supported heterogeneous catalyst is a palladium-supported catalyst and a platinum-supported catalyst in a mass ratio of 1:1, and the mass percentages of palladium and platinum are 10% respectively; the first metal-supported heterogeneous catalyst has a spherical morphology and a particle size range of 0.5 mm to 4 mm; the hydrogen-ammonia mixture gas flow rate introduced into the fixed-bed reactor I containing the first metal-supported heterogeneous catalyst is maintained at 50 mL / min;

[0139] Step 3: Perform gas-liquid separation on the system after the reaction in step 2 to obtain a liquid phase system; the gas-liquid separation can separate hydrogen and ammonia for recycling;

[0140] Step 4: drying and degassing the liquid phase system to obtain a degassed system; the drying is performed using 4A molecular sieves; the degassing is performed by bubbling degassing, the degassing is performed using nitrogen, the nitrogen flow rate is 100 mL / min, and the degassing time is 2 h;

[0141] Step 5, mixing 2-oxazolidinone and a reaction aid solution with a cosolvent to obtain a feed solution B; the reaction aid solution is a boron trifluoride ether solution, the reaction aid is boron trifluoride, the cosolvent is xylene, the mass percentage of the boron trifluoride ether solution is 47%, the concentration of 2-oxazolidinone in the feed solution B is 40 g / L, and the molar ratio of 2-oxazolidinone to boron trifluoride is 1:3;

[0142] Step six, preheating nitrogen to 70 ° C and then passing it into a fixed bed reactor II containing a second metal-supported heterogeneous catalyst, until the pressure in the fixed bed reactor II containing the second metal-supported heterogeneous catalyst is 1atm and maintained, setting the temperature of the fixed bed reactor II containing the second metal-supported heterogeneous catalyst to 70 ° C and maintaining it, mixing the degassed system in step four and the feed liquid B in step five in a volume ratio of 1:1.15 to obtain a mixture, preheating the mixture to 70 ° C and inputting it into the fixed bed reactor II containing the second metal-supported heterogeneous catalyst at a flow rate of 4 mL / min for substitution dehydrogenation reaction; the mixture is in the fixed bed reactor II containing the second metal-supported heterogeneous catalyst The average residence time is 8h; the mass of the second metal-supported heterogeneous catalyst is 2g, the second metal-supported heterogeneous catalyst is a catalyst with Al2O3 as a carrier metal, the second metal-supported heterogeneous catalyst is a palladium-supported catalyst and a platinum-supported catalyst with a mass ratio of 2:1, the mass percentage of palladium and platinum are 10% respectively, the morphology of the second metal-supported heterogeneous catalyst is spherical, and the particle size range is 0.2mm~4mm; after stable operation for the predetermined time, sampling is performed at the discharge port, and the residual raw materials and product content before and after the two steps are analyzed to obtain the total raw material conversion rate, and the results are listed in Table 1 below; the predetermined time is 50h, 100h or 200h; the hydrogen-ammonia mixture is the same as in step 2;

[0143] Step 7: Wash the reaction system in step 6 with saturated brine, separate the phases to obtain an organic phase, dry the organic phase, filter, and evaporate to dryness to obtain a crude product; the drying step is drying with anhydrous sodium sulfate;

[0144] Step eight, recrystallizing the crude product to obtain rilmenidine; the solvent for the recrystallization is ethyl acetate, or n-hexane; the melting point of the recrystallization is 105-107°C.

[0145] The nuclear magnetic resonance and mass spectrum of rilmenidine in this example are basically the same as those in Example 1.

[0146] Example 16

[0147] This embodiment provides a continuous preparation system of rilmenidine, such as Figure 1 As shown, it includes a first material tank 1, a fixed bed reactor I3 for carrying out oximation hydrogenation reaction, a gas-liquid separation tank 5 and a degassing tower 7, which are connected in sequence, and a fixed bed reactor II4 for carrying out substitution dehydrogenation reaction connected to the discharge port of the degassing tower 7, and the feed port of the fixed bed reactor II4 is also connected to the second material tank 2;

[0148] The fixed bed reactor I3 is provided with a first catalyst bed layer, and the fixed bed reactor II4 is provided with a second catalyst bed layer.

[0149] The fixed bed reactor I3 and the fixed bed reactor II4 are both variable diameter reactors. Variable diameter reactors are commonly used in the art and each comprises a straight section and two variable diameter sections, the two variable diameter sections being connected to the two ends of the diameter section, respectively. In the present invention, the height-to-diameter ratio of the straight section of the variable diameter reactor used is 5 to 50, preferably 10 to 40, and more preferably 10 to 30. The height-to-diameter ratio of the straight section is the ratio of the distance between the lowest cross section and the highest cross section of the straight section to the inner diameter of the straight section. The ratio of the length of the straight section to the total length of the variable diameter section is (30 to 40):1.

[0150] The first catalyst bed and the second catalyst bed are both bed structures formed by stacking corresponding catalysts; in the present invention, the height of the first catalyst bed and the second catalyst bed are both 10 cm to 80 cm; the catalysts in the first catalyst bed and the second catalyst bed include one or more of rhodium-based heterogeneous support catalysts, ruthenium-based heterogeneous support catalysts, palladium-based heterogeneous support catalysts and platinum-based heterogeneous support catalysts.

[0151] Comparative Example 1

[0152] This comparative example provides a discontinuous preparation method of rilmenidine, which uses a stirred tank reactor instead of a fixed bed reactor, specifically comprising:

[0153] Step 1: Under nitrogen protection, liquid A and a palladium-based heterogeneous catalyst were added to a stirred tank reactor; the liquid A was the same as that in step 1 of Example 1; the palladium-based heterogeneous supported catalyst was the same as that in step 2 of Example 1, the only difference being that the catalyst was in powder form;

[0154] Step 2: Replace the nitrogen in the stirred tank reactor with hydrogen three times, empty it, and then charge it with a hydrogen-ammonia mixture. Keep the pressure and temperature of the stirred tank reactor the same as in Example 1, and react for 3 hours. The flow rate and amount of the hydrogen-ammonia mixture charged are the same as in Example 1.

[0155] Step 3: drying and degassing the system after the reaction in step 2 to obtain a degassed system;

[0156] Step 4: Under nitrogen protection, the degassed system of step 3 and feed liquid B were added to a stirred tank reactor at a volume ratio of 1:1.1, and a platinum-based heterogeneous catalyst was placed; the feed liquid B was the same as the feed liquid B in step 5 of Example 1; the platinum-based heterogeneous catalyst was the same as that in Example 1, except that the morphology was powder;

[0157] Step 5: The nitrogen pressure and temperature of the stirred tank reactor were maintained consistent with those in Step 6 of Example 1, and the reaction was continued for 4 hours. After the reaction was completed, samples were taken and the remaining raw materials and product contents before and after the reaction were analyzed to obtain the total conversion rate of the raw materials. The results are listed in Table 1 below.

[0158] Step 6: Wash the reaction system with saturated brine, separate the phases to obtain an organic phase, dry the organic phase, filter, and evaporate to dryness to obtain a crude product;

[0159] Step 7: Recrystallize the crude product to obtain rilmenidine; calculate the product yield and detect the purity of the product after recrystallization. The results are listed in Table 1 below.

[0160] Comparative Example 2

[0161] This comparative example is the same as comparative example 1, except that the catalysts used in step 1 and step 4 are the catalysts recovered from the reaction in comparative example 1.

[0162] Comparative Example 3

[0163] This comparative example is the same as comparative example 1, except that the catalysts used in step 1 and step 4 are the catalysts recovered from the reaction in comparative example 2.

[0164] Comparative Example 4

[0165] This comparative example is the same as comparative example 1, except that the catalysts used in step 1 and step 4 are the catalysts recovered from the reaction in comparative example 3.

[0166] Comparative Example 5

[0167] This comparative example is the same as comparative example 1, except that the catalysts used in step 1 and step 4 are the catalysts recovered from the reaction in comparative example 4.

[0168] Comparative Example 6

[0169] This comparative example is the same as comparative example 1, except that the amount of raw materials and parameters are the same as those of Example 13 instead of Example 1.

[0170] Comparative Example 7

[0171] This comparative example is the same as comparative example 6, except that the catalysts used in step 1 and step 4 are the catalysts recovered from the reaction in comparative example 6.

[0172] Comparative Example 8

[0173] This comparative example is the same as comparative example 6, except that the catalysts used in step 1 and step 4 are the catalysts recovered from the reaction in comparative example 7.

[0174] Comparative Example 9

[0175] This comparative example is the same as comparative example 6, except that the catalysts used in step 1 and step 4 are the catalysts recovered from the reaction in comparative example 8.

[0176] Comparative Example 10

[0177] This comparative example is the same as comparative example 6, except that the catalysts used in step 1 and step 4 are the catalysts recovered from the reaction in comparative example 9.

[0178] Performance evaluation

[0179] Table 1 Reaction results of continuous preparation of rilmenidine

[0180]

[0181]

[0182] The conversion rate and yield in Table 1 are the yield and conversion rate of liquid A converted into the product when the equipment is in stable operation and continues to operate for a preset time. The purity is the purity of the corresponding recrystallized product.

[0183] As shown in Table 1, the present invention continuously prepares rilmenidine by hydrogenating dicyclopropyl ketone with 2-oxazolidinone followed by substitution and dehydration. The total conversion rate can be stabilized at a maximum of 90.7% after 200 hours of continuous operation. Combining Example 1, Example 13, Comparative Example 1, and Comparative Example 6, it can be seen that the continuous preparation of rilmenidine using the dual fixed-bed reactor system of the present invention achieves substantially the same yield and selectivity as the preparation of rilmenidine using the autoclave reaction in the comparative example, indicating that the novel process using the dual fixed-bed reactor system of the present invention has no effect on the yield and conversion of the synthesis of rilmenidine.

[0184] In addition, based on Examples 1 to 13, the present invention further found that not all precious metal heterogeneous catalysts are suitable for the method of continuously preparing rilmenidine according to the present invention. For example, when the heterogeneous catalyst in step six of the process is Ru, the reaction yield and conversion rate are significantly reduced. On this basis, when the heterogeneous catalyst in the reaction of step two is Rh, the effect of the continuous reaction will be further affected.

[0185] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent structural change made to the above embodiment based on the technical essence of the invention shall still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A continuous preparation method of rilmenidine, characterized in that, The synthetic route of the method is as follows: ； The following steps are involved: Step 1: mixing dicyclopropyl ketone with an organic solvent to obtain a feed solution A; Step 2, preheating the hydrogen-ammonia mixture to 30-80°C and then passing it into a fixed bed reactor I equipped with a heterogeneous catalyst, until the pressure in the fixed bed reactor I equipped with a heterogeneous catalyst is 0.1-2 MPa.G and maintained, setting the temperature of the fixed bed reactor I equipped with a heterogeneous catalyst to 30-80°C and maintaining it, preheating the feed liquid A to 30-80°C and then passing it into the fixed bed reactor I equipped with a heterogeneous catalyst at a flow rate of 0.1 mL / min-5 mL / min for oximation hydrogenation reaction; the average residence time of the feed liquid A in the fixed bed reactor I equipped with a heterogeneous catalyst is 3-5 h, the volume ratio of hydrogen and ammonia in the hydrogen-ammonia mixture is (1-10):1; the flow rate of the hydrogen-ammonia mixture is 1-50 mL / min; the mass of the heterogeneous catalyst is 1~50g; the heterogeneous catalyst is a metal-supported heterogeneous catalyst, and the mass percentage of the metal in the metal-supported heterogeneous catalyst is 0.5%~15%; the heterogeneous catalyst morphology is spherical or cylindrical, the particle size range is 0.5mm~4mm, and the heterogeneous catalyst is one or two of a rhodium-based heterogeneous support catalyst, a ruthenium-based heterogeneous support catalyst, a palladium-based heterogeneous support catalyst and a platinum-based heterogeneous support catalyst; Step 3: performing gas-liquid separation on the system after the reaction in step 2 to obtain a liquid phase system; Step 4: drying and degassing the liquid phase system to obtain a degassed system; Step 5: mixing 2-oxazolidinone, the reaction aid solution and the cosolvent to obtain a feed solution B; Step 6. Preheat nitrogen to 50-100 ° C and then pass it into a fixed bed reactor II containing a heterogeneous catalyst, until the pressure in the fixed bed reactor II containing a heterogeneous catalyst is 1 atm and maintained, set the temperature of the fixed bed reactor II containing a heterogeneous catalyst to 50-100 ° C and maintain it, mix the degassed system in step 4 and the feed liquid B in step 5 in a volume ratio of 1: (1-1.2) to obtain a mixture, preheat the mixture to 50-100 ° C and input it into the fixed bed reactor II containing a heterogeneous catalyst at a flow rate of 0.1 mL / min-5 mL / min for substitution. Dehydrogenation reaction; the average residence time of the mixture in the fixed bed reactor II containing a heterogeneous catalyst is 4 to 10 hours; the mass of the heterogeneous catalyst is 2 g to 100 g; the heterogeneous catalyst is a metal-supported heterogeneous catalyst, and the mass percentage of the metal in the metal-supported heterogeneous catalyst is 0.1% to 10%; the heterogeneous catalyst has a spherical or cylindrical morphology and a particle size range of 0.2 mm to 4 mm, and the heterogeneous catalyst is one or two of a rhodium-based heterogeneous support catalyst, a ruthenium-based heterogeneous support catalyst, a palladium-based heterogeneous support catalyst, and a platinum-based heterogeneous support catalyst; Step 7: Wash the reaction system in step 6, separate the phases to obtain an organic phase, dry the organic phase, filter, and evaporate to dryness to obtain a crude product; Step 8: Recrystallize the crude product to obtain rilmenidine.

2. The continuous preparation method of rilmenidine according to claim 1, characterized in that In step 1, the organic solvent is one or more of alcohols, ethers, nitriles, esters, alkanes, halogenated hydrocarbons and aromatic hydrocarbons; the alcohol organic solvent is methanol, anhydrous ethanol, isopropanol or tert-butanol; the ether organic solvent is diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; the nitrile organic solvent is acetonitrile or propionitrile; the ester organic solvent is methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, dimethyl carbonate, diethyl carbonate or ethyl methyl carbonate; the alkane organic solvent is n-pentane, n-heptane, n-hexane, cyclohexane or petroleum ether; the halogenated hydrocarbon organic solvent is dichloromethane or 1,2-dichloroethane; the aromatic hydrocarbon organic solvent is benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene or p-dichlorobenzene.

3. The continuous preparation method of rilmenidine according to claim 1, characterized in that, In step 1, the concentration of dicyclopropyl ketone in the feed solution A is 5~50g / L.

4. The continuous preparation method of rilmenidine according to claim 1, characterized in that In step 5, the reaction aid solution is a reaction aid solution obtained by dissolving a reaction aid in ether, and the reaction aid is boron trifluoride or tetrafluoroboric acid; in step 5, the concentration of 2-oxazolidinone in the feed solution B is 4~40 g / L, and the molar ratio of 2-oxazolidinone to the reaction aid is 1:(1~5).

5. The continuous preparation method of rilmenidine according to claim 1, characterized in that, In step 5, the cosolvent is one or more of alcohols, ethers, nitriles, esters, alkanes, halogenated hydrocarbons and aromatic hydrocarbons; the alcohol cosolvent is methanol, anhydrous ethanol, isopropanol or tert-butanol; the ether cosolvent is ether, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; the nitrile cosolvent is acetonitrile or propionitrile; the ester cosolvent is methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isoamyl acetate, methyl propionate, ethyl propionate, propyl propionate, dimethyl carbonate, diethyl carbonate or ethyl methyl carbonate; the alkane cosolvent is n-pentane, n-heptane, n-hexane, cyclohexane or petroleum ether; the halogenated hydrocarbon cosolvent is dichloromethane or 1,2-dichloroethane; the aromatic hydrocarbon cosolvent is benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene or p-dichlorobenzene.

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