A continuous flow preparation method for agomelatine intermediate

Abstract

The present invention belongs to the technical field of pharmaceutical chemical synthesis, and the present invention provides a continuous flow preparation method of agomelatine intermediate. The preparation method comprises the following steps: mixing material one, material two and material three and reacting to obtain agomelatine intermediate; the material one comprises (7-methoxy-1-naphthyl)acetonitrile, acid binding agent and solvent; the material two comprises hydrogen; the material three comprises a carrier catalyst. The present invention adds all materials to a continuous micro-reaction hydrogenation reactor, flows through a catalyst bed layer for hydrogenation reaction, and continuously flows under suitable conditions to hydrogenate agomelatine intermediate. The preparation method has the characteristics of short reaction time, mild reaction conditions and high yield of product.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical synthesis, and in particular to a continuous flow preparation method of an agomelatine intermediate. Background Art

[0002] With the increasing requirements and supervision of the state on safe production, the pharmaceutical and fine chemical industries are facing more and more safety challenges in using traditional intermittent autoclaves for hydrogenation reduction reactions. Therefore, the pharmaceutical and fine chemical industries urgently need to replace the original intermittent hydrogenation reduction process with a continuous hydrogenation reduction process.

[0003] Agomelatine, Chinese name: N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, the structural formula is as follows:

[0004]

[0005] Agomelatine is a 5-HT2C antagonist, MTNR1A agonist and MTNR1B agonist developed by Servier Pharmaceuticals in France. It is used to treat major depressive disorder. It was approved for marketing by the European Medicines Agency (EMA) in February 2009 under the trade name Thymanax. In April 2011, the State Food and Drug Administration approved the import application under the trade name Dimension New. Agomelatine mainly restores the patient's disordered biological rhythm to normal through the synergistic effect of stimulating melatonin receptors MT1 and MT2 and antagonizing 5-HT2C, thereby exerting an antidepressant effect. The suprachiasmatic nucleus (SCN) is the regulatory center of the biological rhythm system, with abundant MT1, MT2 and 5-HT2C receptors. Agomelatine increases the secretion of melatonin through the stimulating effect on melatonin receptors, stimulates MT1 and MT2 receptors, and regulates biological rhythms through the action of the post-melatonin receptor signaling pathway, which can restore the disordered biological rhythm to normal. Agomelatine binds to 5-HT2C receptors in the hippocampus, amygdala and prefrontal cortex of the brain. Antagonism to 5-HT2C receptors can prevent light stimulation from inhibiting melatonin synthesis, increase the DA level in the prefrontal cortex, accelerate the secretion of adrenaline in the locus coeruleus, promote nerve regeneration, and make the pituitary gland secrete more calming hormones, effectively playing an antidepressant role. Therefore, the research on the new synthesis route of agomelatine has great application value.

[0006] European Patent EP0447285B1 and US Patent US5194614A reported a method for preparing agomelatine: 7-methoxytetralone (IV) and ethyl bromoacetate were subjected to Reformatsky reaction and sulfur dehydrogenation aromatization to obtain ethyl (7-methoxy-1-naphthyl)acetate (VI), which was then subjected to hydrolysis, chlorination, amination, dehydration elimination, and reduction to obtain intermediate (III), and finally acetylated to obtain agomelatine (I). As shown in the following formula:

[0007]

[0008] Another preparation method for synthesizing agomelatine is reported in the foreign patent EP1564202B1 / US20050182276A1: a new synthesis method using 7-methoxy-1-naphtholone (IV) as the starting material, that is, 7-methoxy-1-naphtholone (IV) is directly condensed with cyanoacetic acid in the presence of benzylamine and heptanoic acid to obtain (7-methoxy-3,4-dihydro-1-naphthyl)acetonitrile (X), and then refluxed dehydrogenation reaction in toluene with allyl methacrylate as a hydrogen acceptor and 5% palladium carbon as a catalyst to obtain (7-methoxy-1-naphthyl)acetonitrile (II); then hydrogenation reduction reaction at 40°C in an ammonia-containing ethanol medium and in the presence of Raney nickel, and reaction with hydrochloric acid in an ethyl acetate solution to obtain hydrochloride, namely (7-methoxy-1-naphthyl)ethylamine hydrochloride (III); finally, acetylation reaction is performed under the action of sodium acetate and acetic anhydride to obtain agomelatine (I). As shown in the following formula:

[0009]

[0010] Another preparation method for synthesizing agomelatine is reported in the foreign patent WO2011 / 006387A1: 7-methoxy-1-naphtholone (Ⅳ) and acetonitrile are cyanated with n-butyl lithium to obtain 2-(1,2,3,4-tetrahydro-1-hydroxy-7-methoxy-1-naphthyl)acetonitrile (VI); then, DDQ is used to perform an aromatization dehydrogenation reaction at room temperature to generate 2-(3,4-dihydro-1-hydroxy-7-methoxy-1-naphthyl)acetonitrile (XII); then, the reaction is refluxed in an acidic medium (TSOH) to obtain (7-methoxy-1-naphthyl)acetonitrile (II); finally, tetrahydrofuran is used as the reaction solvent, and Raney nickel is first used for hydrogenation reduction to obtain (7-methoxy-1-naphthyl)ethylamine (III), which is then acylated with acetic anhydride to obtain agomelatine (I). As shown in the following formula:

[0011]

[0012] Another preparation method for synthesizing agomelatine is reported in Chinese patent CN101638376B: 7-methoxy-1-naphthylethanol (XIII) is used as a starting material, and sulfonylated with benzenesulfonyl chloride in an aprotic solvent and alkaline conditions to obtain 7-methoxy-1-naphthylethylbenzenesulfonate (XIV); then, it is refluxed with potassium salt of phthalimide in a polar aprotic solvent (DMF, acetonitrile) to obtain N-[2-(7-methoxy-1-naphthyl)-ethylphthalimide (XV); then, it is refluxed and hydrolyzed in the presence of a base, and then salted with hydrogen chloride ethyl acetate solution to obtain (7-methoxy-1-naphthyl)ethylamine hydrochloride (III); finally, acetylation reaction is performed to obtain agomelatine (I).

[0013]

[0014] However, the above existing methods all have shortcomings, for example, they require high temperature and high pressure reaction conditions, expensive equipment, and low reaction yield, which is not conducive to large-scale industrial production.

[0015] Therefore, how to provide a method for synthesizing agomelatine intermediates with short reaction time, high product yield and high reactant conversion rate has become a problem that needs to be solved urgently by those skilled in the art. Summary of the invention

[0016] In view of this, the present invention provides a continuous flow preparation method of agomelatine intermediates, which aims to solve the technical problems of harsh reaction conditions and low product yield in the existing agomelatine intermediate synthesis methods.

[0017] In order to achieve the above object, the present invention adopts the following technical solution:

[0018] The present invention provides a continuous flow preparation method of agomelatine intermediate, comprising the following steps:

[0019] The material one, the material two and the material three are mixed and reacted to obtain the agomelatine intermediate;

[0020] The material 1 includes (7-methoxy-1-naphthyl)acetonitrile, an acid-binding agent and a solvent; the material 2 includes hydrogen; and the material 3 includes a carrier catalyst;

[0021] The reaction is a continuous flow reaction.

[0022] Furthermore, the agomelatine intermediate is 2-(7-methoxynaphthalen-1-yl)ethylamine, and its structural formula is as follows:

[0023]

[0024] Furthermore, the reaction temperature is 50-120° C., the reaction time is 60-1800 s, and the reaction pressure is 10-60 bar.

[0025] Furthermore, in the supported catalyst, the catalyst accounts for 10 to 85% of the total mass of the supported catalyst.

[0026] Furthermore, the catalyst includes one or more of palladium, platinum, ruthenium, rhodium, cobalt and nickel; and the carrier includes alumina, activated carbon or silicon oxide.

[0027] Furthermore, the acid binding agent includes one or more of triethylamine, ammonia water and pyridine; the solvent includes one or more of methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, toluene and water.

[0028] Furthermore, the mass ratio of the (7-methoxy-1-naphthyl)acetonitrile, the acid binding agent and the solvent is 1:0.5-5:1-30.

[0029] Furthermore, the mass ratio of the (7-methoxy-1-naphthyl)acetonitrile to the catalyst is 1:0.05-1.

[0030] Furthermore, the flow rate of material one is 0.5-100 mL / min, and the flow rate of material two is ≤8 L / min.

[0031] It can be seen from the above technical solution that compared with the prior art, the beneficial effects of the present invention are as follows:

[0032] A complete gas-liquid-solid (catalyst) three-phase reaction system is constructed by using a continuous flow hydrogenation reaction device. The required device occupies a small area, has a large output per unit space, and has an increased safety factor, which reduces the potential safety hazards of the hydrogenation reaction. The process has a short reaction time (shortened from 5 to 48 hours in an intermittent pressure hydrogenation reactor to 60 to 1800 seconds), a small reaction liquid holding volume, and no amplification effect, which essentially changes the safety of the reaction; the purity of the product in the reaction liquid is above 90%; the molar yield of the target product obtained by the reaction liquid through post-treatment steps such as catalyst separation, concentration, acidification, organic solvent washing and extraction, alkalization, organic solvent extraction, acidification crystallization, filtration and drying is above 90%, and the product purity is above 99.0%, which is suitable for industrial production.

[0033] The present invention utilizes the high mixing efficiency and excellent mass transfer and heat transfer performance of the microreactor, strengthens the interphase mass transfer and heat transfer capacity during the reaction process, can significantly reduce the reactor volume, improve the reaction yield, and improve production efficiency and safety. The method can solve the problems of low production efficiency, poor reaction purity, and high device danger in the intermittent pressure hydrogenation reactor process, can realize continuous automated operation of the process, and has the advantages of high yield and good safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The figure is a simplified process flow diagram of the continuous flow preparation method of agomelatine intermediate. DETAILED DESCRIPTION

[0035] The present invention provides a continuous flow preparation method of agomelatine intermediate, comprising the following steps:

[0036] The material one, the material two and the material three are mixed and reacted to obtain the agomelatine intermediate;

[0037] The material 1 includes (7-methoxy-1-naphthyl)acetonitrile, an acid-binding agent and a solvent; the material 2 includes hydrogen; and the material 3 includes a carrier catalyst;

[0038] The reaction is a continuous flow reaction.

[0039] In the present invention, the continuous flow reaction is carried out in a fixed bed continuous hydrogenation reactor, which includes a gas circuit control system, a feed pump, a liquid circuit control system, a gas-liquid distributor, a reaction system and a data acquisition control system; the gas circuit control system includes a gas circuit inlet, a hydrogen mass flow meter, a pressure regulating valve and a pressure transmitter; the liquid circuit control system includes a liquid circuit inlet, a preheater, a condenser, a buffer tank, a gas-liquid separator, an automatic regulating valve, a back pressure valve, a pressure transmitter, a pressure differential transmitter and a temperature sensor; the reaction system includes a reaction column, and a catalyst bed is arranged in the reaction column; the gas-liquid distributor is provided with a gas circuit inlet and a liquid circuit inlet, and material one and material two enter the gas-liquid distributor through the gas circuit inlet and the liquid circuit inlet provided on the gas-liquid distributor respectively, and then enter the catalyst bed in the reaction column for reaction after mixing, and the gas-liquid distributor and the reaction column are directly connected to avoid gas-liquid dispersion; the data acquisition control system includes a PLC main control, an explosion-proof cabinet, a hydrogen alarm instrument control and display system, supporting industrial control software, computer control software and a power module.

[0040] In the present invention, the flow rate of material 1 in the fixed bed continuous hydrogenation reactor is 0.5-100 mL / min, preferably 10-80 mL / min; the flow rate of material 2 in the fixed bed continuous hydrogenation reactor is ≤8 L / min, preferably ≤6 L / min, and more preferably ≤4 L / min.

[0041] In the present invention, the agomelatine intermediate is 2-(7-methoxynaphthalen-1-yl)ethylamine, and its structural formula is as follows:

[0042]

[0043] In the present invention, the structural formula of the (7-methoxy-1-naphthyl)acetonitrile is as follows:

[0044]

[0045] The synthetic route of the intermediate of agomelatine synthesized from (7-methoxy-1-naphthyl)acetonitrile is as follows:

[0046]

[0047] In the present invention, the reaction temperature is 50-120°C, preferably 70-110°C, and more preferably 80-90°C; the reaction time is 60-1800s, preferably 100-1500s, and more preferably 300-1000s; the reaction pressure is 10-60bar, preferably 20-50bar, and more preferably 30-40bar.

[0048] In the present invention, in the supported catalyst, the catalyst accounts for 10 to 85% of the total mass of the supported catalyst, preferably 30 to 70%, and more preferably 50 to 55%.

[0049] In the present invention, the catalyst includes one or more of palladium, platinum, ruthenium, rhodium, cobalt and nickel, preferably one or more of palladium, platinum, rhodium, cobalt and nickel, and more preferably one or more of palladium, platinum and nickel; the carrier includes aluminum oxide, activated carbon or silicon oxide, preferably activated carbon or silicon oxide, and more preferably activated carbon.

[0050] In the present invention, the acid binding agent includes one or more of triethylamine, ammonia water and pyridine, preferably triethylamine and / or ammonia water, and more preferably ammonia water; the solvent includes one or more of methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, toluene and water, preferably one or more of methanol, ethanol, isopropanol, toluene and water, and more preferably ethanol and water; the mass ratio of ethanol to water is preferably 1:0.1-2, more preferably 1:0.4-1.6, and even more preferably 1:0.8-1.2.

[0051] In the present invention, the mass ratio of the (7-methoxy-1-naphthyl)acetonitrile, the acid binding agent and the solvent is 1:0.5-5:1-30, preferably 1:1-4:5-25, and more preferably 1:2-3:10-20.

[0052] In the present invention, the mass ratio of (7-methoxy-1-naphthyl)acetonitrile to the catalyst is 1:0.05-1, preferably 1:0.1-0.8, and more preferably 1:0.3-0.6.

[0053] In the present invention, after the reaction is completed, the reaction solution is extracted and crystallized to obtain agomelatine intermediate, and the solvent used for extraction is one or more of toluene, ethyl acetate, dichloromethane and chloroform, preferably toluene and / or ethyl acetate, more preferably toluene; the mass ratio of (7-methoxy-1-naphthyl)acetonitrile to the solvent is 1:1-6, preferably 1:2-4, more preferably 1:3;

[0054] The solvent used for crystallization is one or more of toluene, ethyl acetate, dichloromethane and chloroform, preferably toluene and / or ethyl acetate, and more preferably toluene; the mass ratio of (7-methoxy-1-naphthyl)acetonitrile to the solvent is 1:5-20, preferably 1:8-16, and more preferably 1:10-12.

[0055] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0056] Example 1

[0057] A fixed bed continuous hydrogenation reactor MXC-GH1000-S was used, which was purchased from Yangzhou Boklai Biopharmaceutical Technology Co., Ltd.

[0058] Material 1: 50.0 g (7-methoxy-1-naphthyl)acetonitrile, 100 g ammonia water with a mass concentration of 30% and 975 g ethanol were mixed and stirred until a clear liquid was dissolved. The mixture was pumped into the microchannel reactor and the flow rate was set to 60 mL / min through the metering module.

[0059] Material 2: Hydrogen, through the gas circuit controller, set the gas flow rate to 4L / min.

[0060] Material 3: Silica-supported nickel catalyst, 85 g of silica and 15 g of nickel, were added to the reaction column.

[0061] The reaction pressure was set to 40 bar, the system was set to a circulating temperature of 80 ° C, and the reaction was carried out for 300 s by a continuous flow reactor reaction column (3L volume), and the reaction solution was collected. The purity of 2-(7-methoxynaphthalene-1-yl)ethylamine in the reaction solution was 98.23%. A small amount of loaded nickel and mechanical impurities in the reaction solution were removed by filtration, transferred to an eggplant-shaped single-mouth bottle, and concentrated under reduced pressure until no fraction flowed out, then an appropriate amount of water was added, hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 1.5, 150g of toluene was added for extraction, and the reaction was allowed to stand for stratification. Liquid alkali was added to the water layer to adjust the pH to 12.5, 750g of dichloromethane was added, hydrochloric acid was added dropwise for acidification, the temperature was lowered for crystallization, filtered, rinsed with dichloromethane, and dried to obtain 2-(7-methoxynaphthalene-1-yl)ethylamine hydrochloride. The liquid chromatography purity was 99.78%, the maximum single impurity was 0.019%, and the molar yield was 94.86%.

[0062] Example 2

[0063] A fixed bed continuous hydrogenation reactor MXC-GH1000-S was used, which was purchased from Yangzhou Boklai Biopharmaceutical Technology Co., Ltd.

[0064] Material 1: 50.0 g (7-methoxy-1-naphthyl)acetonitrile, 100 g ammonia water with a mass concentration of 25% and 975 g ethanol were mixed and stirred until a clear liquid was dissolved. The mixture was pumped into the microchannel reactor and the flow rate was set to 60 mL / min through the metering module.

[0065] Material 2: Hydrogen, through the gas circuit controller, set the gas flow rate to 4L / min.

[0066] Material 3: Silica-supported nickel catalyst, 85 g of silica and 15 g of nickel, were added to the reaction column.

[0067] The reaction pressure was set to 40 bar, the system was set to a circulating temperature of 100 ° C, and the reaction was carried out for 300 s by a continuous flow reactor reaction column (3L volume), and the reaction solution was collected. The purity of 2-(7-methoxynaphthalene-1-yl)ethylamine in the reaction solution was 97.93%. A small amount of loaded nickel and mechanical impurities in the reaction solution were removed by filtration, transferred to an eggplant-shaped single-mouth bottle, and concentrated under reduced pressure until no fraction flowed out, then an appropriate amount of water was added, hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 1.0, 150g of toluene was added for extraction, and the reaction was allowed to stand for stratification. Liquid alkali was added to the water layer to adjust the pH to 12.0, 750g of dichloromethane was added, hydrochloric acid was added dropwise for acidification, the temperature was lowered for crystallization, filtered, rinsed with dichloromethane, and dried to obtain 2-(7-methoxynaphthalene-1-yl)ethylamine hydrochloride. The liquid chromatography purity was 99.66%, the maximum single impurity was 0.036%, and the molar yield was 93.06%.

[0068] Comparative Example

[0069] A high-pressure hydrogenation reactor was used. 50.0 g (7-methoxy-1-naphthyl) acetonitrile, 100 g ammonia water with a mass concentration of 25%, 975 g ethanol and a silicon oxide-supported nickel catalyst (85 g silicon oxide, 15 g nickel) were placed in a high-pressure hydrogenation reactor, and nitrogen and hydrogen replacement were performed, and stirring was performed. Hydrogen was introduced intermittently to maintain the hydrogen pressure of the system at 8.0 MPa. After stirring the reaction at 80 ° C for 8 hours, the reaction liquid was collected. The purity of 2-(7-methoxynaphthalene-1-yl) ethylamine in the reaction liquid was 92.45%. The reaction solution was filtered to remove nickel and mechanical impurities, transferred to an eggplant-shaped single-mouth bottle, and concentrated under reduced pressure until no fraction flowed out, then an appropriate amount of water was added, hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 1.5, 150g of toluene was added for extraction, and the reaction was allowed to stand for stratification, and liquid alkali was added to the aqueous layer to adjust the pH to 12.5, 750g of dichloromethane was added, hydrochloric acid was added dropwise for acidification, the temperature was lowered for crystallization, filtered, rinsed with dichloromethane, and dried to obtain 2-(7-methoxynaphthalen-1-yl)ethylamine hydrochloride. The liquid chromatography purity was 99.73%, the maximum single impurity was 0.038%, and the molar yield was 90.06%.

[0070] It can be seen from Examples 1 to 2 and the comparative example that the molar yield of the product of the example is above 90%, and the product purity is above 99.0%, both of which are higher than the intermittent reaction of the comparative example, and the reaction time is greatly shortened; while the intermittent pressure hydrogenation reactor reacts for 8 hours, and its molar yield is relatively low, and is only 21.42% when the intermittent reaction is 1 hour. This shows that the technical solution of the present invention greatly shortens the reaction time and also improves the yield and purity of agomelatine intermediates.

[0071] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A continuous flow preparation method for agomelatine intermediates, characterized in that: The following steps are involved: The material one, the material two and the material three are mixed and reacted to obtain the agomelatine intermediate; The material 1 includes (7-methoxy-1-naphthyl)acetonitrile, an acid-binding agent and a solvent; the material 2 includes hydrogen; and the material 3 includes a carrier catalyst; The reaction is a continuous flow reaction; The reaction temperature is 50-120°C, the reaction time is 60-1800s, and the reaction pressure is 10-60bar; The catalyst comprises one or more of palladium, platinum, ruthenium, rhodium, cobalt and nickel; the carrier comprises alumina, activated carbon or silicon oxide; The flow rate of material one is 0.5-100 mL / min, and the flow rate of material two is ≤8 L / min.

2. The continuous flow preparation method according to claim 1, characterized in that: The agomelatine intermediate is 2-(7-methoxynaphthalen-1-yl)ethylamine, and its structural formula is as follows:

3. The continuous flow preparation method according to claim 1 or 2, characterized in that: In the supported catalyst, the catalyst accounts for 10 to 85% of the total mass of the supported catalyst.

4. The continuous flow preparation method according to claim 1 or 2, characterized in that: The acid binding agent includes one or more of triethylamine, ammonia water and pyridine; the solvent includes one or more of methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, toluene and water.

5. The continuous flow preparation method according to claim 4, characterized in that: The mass ratio of the (7-methoxy-1-naphthyl)acetonitrile, the acid binding agent and the solvent is 1:0.5-5:1-30.

6. The continuous flow preparation method according to claim 1 or 5, characterized in that: The mass ratio of the (7-methoxy-1-naphthyl)acetonitrile to the catalyst is 1:0.05-1.

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