A method for the synthesis of agomelatine

Abstract

The application provides a synthesis method of agomelatine. The starting material I is reacted with SOCl2 to obtain acyl chloride under the action of a solvent A, and then reacted with NH4OH to obtain intermediate I; the intermediate I is reacted with (CF3CO)2O under the action of a solvent B and triethylamine to obtain intermediate II through dehydration; the intermediate II is subjected to catalytic hydrogenation reaction with Raney Ni and H2 under the action of a solvent C to obtain intermediate III; the intermediate III is reacted with HCl under the action of a solvent D to obtain intermediate IV; and the intermediate IV is condensed with CH3COCl under the action of a solvent E and Cs2CO3 to obtain agomelatine. The method is simple in operation, mild in reaction condition, high in yield, low in cost, friendly to the environment, and suitable for industrial large-scale production of agomelatine.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and specifically relates to a method for synthesizing agomelatine. Background Technology

[0002] Agomelatine, chemically named N-[2-(7-methoxynaphthyl-1-yl)ethyl]acetamide, and marketed as Valdoxan, is a bioisosteric (electron) analog of melatonin developed by the French company Servier. It replaces the indole ring with a naphthalene ring, making it more metabolically stable than melatonin. Agomelatine was approved for marketing in the European Union in February 2009 for the treatment of adult depression, representing a breakthrough in the field. Its innovation lies in its unique mechanism of action; it is the world's first melatonin (MT1, MT2) receptor agonist and also a 5-HT2C receptor antagonist.

[0003] European patent EP0447285 reports a method for obtaining 7-methoxy-1-naphthylacetonitrile from 7-methoxy-1-naphthylacetonitrile via condensation with ethyl bromoacetate, aromatization, ester hydrolysis, acylation, amination, and dehydration. Agomelatine is then obtained via cyano reduction and acetylation. The route is as follows:

[0004] This route involves many reaction steps, is time-consuming, and uses a lot of solvents, which is not conducive to the determination of residual solvents in the finished product. It is also costly, generates a lot of waste, and does not meet the requirements of industrial production. Summary of the Invention

[0005] The present invention aims to provide a simple, mild, high-yield, low-cost, and environmentally friendly method for synthesizing agomelatine.

[0006] To achieve the above-mentioned objectives, the present invention provides a method for synthesizing agomelatine, the specific implementation of which is as follows: The synthetic route of the agomelatine method described in this invention is as follows: .

[0007] The present invention discloses a method for synthesizing agomelatine, the steps of which are as follows: (1) Starting material I: (7-methoxy-1-naphthyl)acetic acid reacts with SOCl2 in solvent A to obtain acyl chloride, and then reacts with NH4OH to obtain intermediate I (7-methoxy-1-naphthyl)acetamide; (2) Intermediate I was dehydrated by reacting with (CF3CO)2O in solvent B and triethylamine to give intermediate II (7-methoxy-1-naphthyl)acetonitrile; (3) Intermediate II undergoes catalytic hydrogenation with Raney Ni and H2 in solvent C to obtain intermediate III (7-methoxy-1-naphthyl)ethylamine; (4) Intermediate III reacts with HCl in solvent D to give intermediate IV (7-methoxy-1-naphthyl) ethylamine hydrochloride; (5) Intermediate IV condenses with CH3COCl in solvent E and Cs2CO3 to obtain agomelatine.

[0008] The method for synthesizing agomelatine according to the present invention, wherein solvent A used in step (1) is one or more of diethyl ether, chloroform, dichloromethane, tetrahydrofuran, toluene, and anhydrous ethanol; the molar ratio of the starting material I to SOCl2 is 1:1.1 to 1:1.5, and the molar ratio of the starting material I to NH4OH is 1:2 to 1:4; the system is heated to 40℃ to 80℃ under stirring; and the reaction time is 2 to 6 h.

[0009] The method for synthesizing agomelatine according to the present invention includes a solvent B used in step (2) which is one or more of dichloromethane, tetrahydrofuran, toluene, isopropyl ether, and triethylamine; the molar ratio of intermediate I to (CF3CO)2O is 1:1.5 to 1:3, and the molar ratio of intermediate I to triethylamine is 1:2 to 1:3; the system is heated to 20℃ to 40℃ under stirring; and the reaction time is 4 to 8 hours.

[0010] The method for synthesizing agomelatine according to the present invention includes a solvent C used in step (3) that is one or more of tetrahydrofuran, anhydrous ethanol, and toluene; the mass ratio of intermediate II to Raney Ni is 8:1 to 15:1; the system is heated to 30°C to 90°C under stirring; and the reaction time is 2 to 6 hours.

[0011] The method for synthesizing agomelatine according to the present invention, wherein the solvent D used in step (4) is one or more of dichloromethane, tetrahydrofuran, ethanol, methanol, ethyl acetate, toluene, and dioxane; the mass-volume ratio of intermediate III to HCl is 10:0.9 to 10:1.1; the system is heated to 20°C to 30°C under stirring; and the reaction time is 1 to 3 hours.

[0012] The method for synthesizing agomelatine according to the present invention, wherein the solvent E used in step (5) is one or more of dichloromethane, tetrahydrofuran, anhydrous ethanol, methanol, toluene, n-hexane, and dioxane; the molar ratio of intermediate IV to Cs2CO3 is 1:1.5~1:3, and the molar ratio of intermediate IV to CH3COCl is 1:1.05~1:1.2; the system is heated to -5℃~70℃ under stirring; the reaction time is 3~8h.

[0013] The present invention discloses a method for synthesizing agomelatine, wherein solvent A used in step (1) is dichloromethane; the molar ratio of starting material I to SOCl2 is 1:1.8, and the molar ratio of starting material I to NH4OH is 1:4; the system is heated to 50°C under stirring; the reaction time is 2-3 h, wherein the mass ratio of starting material I to dichloromethane is 1:2.

[0014] The present invention discloses a method for synthesizing agomelatine, wherein solvent B used in step (2) is dichloromethane; the molar ratio of intermediate I to (CF3CO)2O is 1:2.5, and the molar ratio of intermediate I to triethylamine is 1:2.5; the system is heated to -20℃ to 20℃ under stirring; the reaction time is 2 to 4 h. Specifically, the mass ratio of intermediate I to dichloromethane is 1:4; during the purification of crude intermediate II, the crystallization temperature is -5℃ to 5℃, the crystallization time is 5 to 8 h, and the mass ratio of crude intermediate II to isopropyl ether is 1:5.

[0015] The method for synthesizing agomelatine according to the present invention, wherein solvent C used in step (3) is tetrahydrofuran; the mass ratio of intermediate II to Raney Ni is 10:1; the system is pressurized to 4~5MPa by hydrogen gas and heated to 70℃~90℃ under stirring; the reaction time is 4~5h, wherein the mass ratio of intermediate II to tetrahydrofuran is 1:2.

[0016] The method for synthesizing agomelatine according to the present invention includes a solvent D in step (4) of which is ethyl acetate; the mass-volume ratio of intermediate III to HCl is 10:1; the system is stirred and crystallized at 10℃~20℃; the crystallization time is 5~6h, wherein the mass ratio of intermediate III to ethyl acetate is 1:1.5.

[0017] The method for synthesizing agomelatine according to the present invention, wherein the solvent E used in step (5) is toluene; the molar ratio of intermediate IV to Cs2CO3 is 1:2.5, and the molar ratio of intermediate IV to CH3COCl is 1:1.1; the system is heated to -5℃~70℃ under stirring; the reaction time is 7~8h, wherein the mass ratio of intermediate IV to toluene is 1:20; when purifying crude agomelatine, the crystallization temperature is 0℃~15℃, the crystallization time is 2~22h, the mass ratio of crude agomelatine to toluene is 1:3, the mass ratio of crude agomelatine to n-hexane is 1:1, the mass ratio of crude agomelatine to anhydrous ethanol is 1:5, and the mass ratio of crude agomelatine to purified water is 1:8.

[0018] Beneficial effects of this invention: The present invention provides an improved method for the synthesis of agomelatine, overcoming the shortcomings of existing methods and technologies. Following the atom-economic synthesis principles of green chemistry, this method offers an improved approach to agomelatine preparation. Using starting material I as raw material, the method shortens the reaction steps, reduces material loss, increases yield, lowers costs, and reduces environmental pollution, achieving the goal of green synthesis and making it suitable for large-scale industrial production of agomelatine.

[0019] The synthetic route of agomelatine in this invention is as follows: intermediate I reacts with (CF3CO)2O to dehydrate and obtain intermediate II; intermediate II undergoes catalytic hydrogenation reaction with Raney Ni and H2 to obtain intermediate III; intermediate III reacts with HCl to obtain intermediate IV; intermediate IV is condensed with CH3COCl in solvent E and Cs2CO3 to obtain agomelatine.

[0020] The innovation in the step of condensing intermediate IV with CH3COCl to obtain agomelatine lies in the use of toluene as the solvent and Cs2CO3 as the base reagent. Existing agomelatine synthesis processes mostly use dichloromethane as the solvent and Na2CO3, K2CO3, NaOH, or triethylamine as the base reagent. These base reagents are immiscible with dichloromethane, which is detrimental to the reaction, and dichloromethane is volatile. Toluene is an excellent organic solvent with a high boiling point, low volatility, and good stability, and is widely used in chemical production. The numerous properties exhibited by Cs2CO3 in organic synthesis stem from the relatively soft Lewis acidity of cesium ions, allowing it to dissolve in organic solvents such as alcohols, DMF, toluene, and diethyl ether. This good solubility in organic solvents allows Cs2CO3 to participate as an effective inorganic base in palladium-catalyzed chemical reactions such as the Heck, Suzuki, and Sonogashira reactions. For example, the Suzuki cross-coupling reaction can achieve a yield of 86% with the support of Cs2CO3, while the same reaction only yields 29% and 50% with the participation of sodium carbonate or triethylamine, respectively.

[0021] Similarly, in the Heck reaction of methacrylates with chlorobenzene, Cs₂CO₃ exhibits a significant advantage over other bases such as potassium carbonate, sodium acetate, triethylamine, and potassium phosphate. Cs₂CO₃ also has important applications in the O-alkylation of phenolic compounds. Furthermore, Cs₂CO₃ has important uses in the synthesis of natural products. In addition, due to its good solubility in organic solvents, cesium carbonate also has important applications in solid-supported organic reactions.

[0022] Therefore, toluene was chosen as the solvent and Cs₂CO₃ as the base reagent, as the two are miscible, which is beneficial to the reaction and thus improves the yield of agomelatine in this invention. Under these process conditions, toluene has very low volatility and can be redistilled and recycled, saving reagents and costs, and causing less environmental pollution. Detailed Implementation

[0023] The following examples are only for further illustration of the present invention and do not limit the scope of the present invention in any way. Example

[0024] Step 1: Add starting material I (30.00 g, 138.73 mmol) and 60.00 g dichloromethane to a 250 mL three-necked flask, heat and stir, and raise the temperature to 40 °C. After dissolving completely, slowly add SOCl2 (29.71 g, 249.72 mmol) dropwise while maintaining reflux. After the addition is complete, reflux the reaction for 2 h. Monitor the reaction by TLC until it is complete, then evaporate the reaction solution to dryness under reduced pressure to obtain a brown oily substance.

[0025] The obtained oily substance was dissolved in 60.00g of anhydrous ethanol. Under ice-salt water cooling, 30.00g of concentrated ammonia was slowly added while stirring continuously, and a pale yellow solid precipitated. After filtration and drying, intermediate I was obtained in the amount of 29.80g, with a yield of 99.79% and a purity of 95.66%.

[0026] Step 2: Intermediate I (25.00 g, 116.14 mmol), 100.00 g dichloromethane, and triethylamine (29.38 g, 290.36 mmol) were added to a 500 mL three-necked flask and stirred to dissolve. Under ice-salt water cooling, (CF3CO)2O (60.98 g, 290.36 mmol) was slowly added dropwise. After the addition was complete, stirring was continued for 1 h, followed by stirring at room temperature for 2 h. The reaction was monitored by TLC until complete, and the reaction solution was evaporated to dryness under reduced pressure.

[0027] 125.00 g of water was added to the evaporated product, and the mixture was stirred for 0.5 h. After filtration and drying, 33.00 g of crude intermediate II was obtained. 175.00 g of isopropyl ether and 2.50 g of activated carbon were added to the crude intermediate II for decolorization, and the product was recrystallized to obtain 20.07 g of purified intermediate II, with a yield of 87.33% and a purity of 98.02%.

[0028] Step 3: Intermediate II (18.00 g, 91.26 mmol) and 36.00 g tetrahydrofuran were added to a 250 mL three-necked flask. 1.80 g Raney Ni was added with stirring, and hydrogen gas was bubbled through the flask to pressurize it to 4-5 MPa. The temperature was raised to 80 °C, and the reaction was stirred for 5 h. The reaction was monitored by TLC until complete. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain 17.55 g of intermediate III, with a yield of 95.53% and a purity of 98.85%.

[0029] Step 4: Intermediate III (15.50 g, 77.01 mmol) and 23.25 g of ethyl acetate were added to a 100 mL three-necked flask and stirred at room temperature to dissolve. Then, 1.60 mL of concentrated hydrochloric acid was added to the solution, causing a white solid to precipitate. The temperature was lowered to 10-20 °C, and the mixture was stirred for 6 hours to allow crystallization. After the reaction was complete, the mixture was filtered and dried to obtain 17.96 g of intermediate IV, with a yield of 98.12% and a purity of 97.94%.

[0030] Step 5: Add intermediate IV (15.00 g, 63.10 mmol), 300.00 g toluene, and Cs2CO3 (51.40 g, 157.74 mmol) to a 500 mL three-necked flask, stir at room temperature for 0.5 h, cool to -5 °C to 5 °C, slowly add CH3COCl (5.45 g, 69.42 mmol) dropwise, controlling the temperature at 0 °C to 5 °C during the dropwise addition, continue stirring for 0.5 h after the dropwise addition is complete, raise the temperature to 40 °C to 50 °C, and continue stirring the reaction for 6 to 8 h.

[0031] TLC monitoring until the reaction was basically complete was performed. 140.00 g of water was added to the reaction solution with stirring. The mixture was stirred for 50 min, allowed to stand for 15 min, separated, and the aqueous phase was discarded. The organic phase was retained and washed twice with 140.00 g of saturated NaCl solution. The organic phase was concentrated under reduced pressure to obtain 15.20 g of crude agomelatine.

[0032] Purification: 15.20g crude agomelatine, 50.00g toluene, and 1.50g activated carbon were added to a 100mL three-necked flask. The mixture was stirred and heated to 75℃~80℃, and kept at this temperature for 1 hour. The mixture was filtered while hot, and the filtrate was transferred to a 250mL three-necked flask. 16.00g n-hexane was added while stirring, and the mixture was heated to 85℃ to dissolve the solid. The temperature was then slowly lowered to 0℃~15℃, and crystallization was allowed to occur for 22 hours. The crystals were filtered and dried to obtain 14.83g of a white solid powder.

[0033] The obtained 14.83 g white solid powder, 76.90 g anhydrous ethanol, and 120.84 g water were added to a 500 mL three-necked flask. The mixture was stirred and heated to 75℃~80℃. After dissolving completely, the mixture was stirred for 10 min, then gradually cooled to 0℃~5℃ and kept at this temperature for 2~3 h to allow crystals to crystallize. After centrifugation and drying, 14.29 g of purified agomelatine was obtained, with a yield of 93.07% and a purity of 99.43%. Example

[0034] Step 1: Add starting material I (30.00 g, 138.73 mmol) and 60.00 g dichloromethane to a 250 mL three-necked flask, heat and stir, and raise the temperature to 40 °C. After dissolving completely, slowly add SOCl2 (29.71 g, 249.72 mmol) dropwise while maintaining reflux. After the addition is complete, reflux the reaction for 2 h. Monitor the reaction by TLC until it is complete, then evaporate the reaction solution to dryness under reduced pressure to obtain a brown oily substance.

[0035] The obtained oily substance was dissolved in 60.00g of anhydrous ethanol. Under ice-salt water cooling, 30.00g of concentrated ammonia was slowly added while stirring continuously. A pale yellow solid precipitated out. After filtration and drying, intermediate I was obtained in the amount of 29.83g, with a yield of 99.89% and a purity of 95.79%.

[0036] Step 2: Intermediate I (25.00 g, 116.14 mmol), 100.00 g dichloromethane, and triethylamine (29.38 g, 290.36 mmol) were added to a 500 mL three-necked flask and stirred to dissolve. Under ice-salt water cooling, (CF3CO)2O (60.98 g, 290.36 mmol) was slowly added dropwise. After the addition was complete, stirring was continued for 1 h, followed by stirring at room temperature for 2 h. The reaction was monitored by TLC until complete, and the reaction solution was evaporated to dryness under reduced pressure.

[0037] 125.00 g of water was added to the evaporated product, and the mixture was stirred for 0.5 h. After filtration and drying, 32.89 g of crude intermediate II was obtained. 175.00 g of isopropyl ether and 2.50 g of activated carbon were added to the crude intermediate II for decolorization, and the product was recrystallized to obtain 20.04 g of purified intermediate II, with a yield of 87.20% and a purity of 98.11%.

[0038] Step 3: Intermediate II (18.00 g, 91.26 mmol) and 36.00 g tetrahydrofuran were added to a 250 mL three-necked flask. 1.80 g Raney Ni was added with stirring, and hydrogen gas was bubbled through the flask to pressurize it to 4-5 MPa. The temperature was raised to 80 °C, and the reaction was stirred for 5 h. The reaction was monitored by TLC until complete. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain 17.55 g of intermediate III, with yields of 95.91% and 98.78%.

[0039] Step 4: Intermediate III (15.50 g, 77.01 mmol) and 23.25 g of ethyl acetate were added to a 100 mL three-necked flask and stirred at room temperature to dissolve. Then, 1.60 mL of concentrated hydrochloric acid was added to the solution, causing a white solid to precipitate. The temperature was lowered to 10℃~20℃, and the mixture was stirred for 6 hours to allow crystallization. After the reaction was complete, the mixture was filtered and dried to obtain 17.92 g of intermediate IV, with a yield of 97.89% and a purity of 97.77%.

[0040] Step 5: Add intermediate IV (15.00 g, 63.10 mmol), 400.00 g dichloromethane, and triethylamine (14.10 g, 139.34 mmol) to a 500 mL three-necked flask, stir at room temperature for 0.5 h, cool to -5 °C to 5 °C, slowly add CH3COCl (5.40 g, 68.79 mmol) dropwise, controlling the temperature at 0 °C to 5 °C during the dropwise addition, continue stirring for 0.5 h after the dropwise addition is complete, raise the temperature to 30 °C to 40 °C, and continue stirring for 8 h.

[0041] TLC monitoring until the reaction was basically complete was performed. 140.00 g of water was added to the reaction solution with stirring. The mixture was stirred for 50 min, allowed to stand for 15 min, separated, and the aqueous phase was discarded. The organic phase was retained and washed twice with 140.00 g of saturated NaCl solution. The organic phase was concentrated under reduced pressure to obtain 14.30 g of crude agomelatine.

[0042] Purification: 14.30 g crude agomelatine, 43.00 g toluene, and 1.43 g activated carbon were added to a 100 mL three-necked flask. The mixture was stirred and heated to 75℃~80℃, and kept at this temperature for 1 h. The mixture was filtered while hot, and the filtrate was transferred to a 250 mL three-necked flask. 15.00 g n-hexane was added while stirring, and the mixture was heated to 85℃ to dissolve the solid. The temperature was then slowly lowered to 0℃~15℃, and crystallization was allowed to occur for 22 h. The crystals were filtered and dried to obtain 13.11 g of a white solid powder.

[0043] The obtained 13.11 g white solid powder, 68.00 g anhydrous ethanol, and 106.82 g water were added to a 500 mL three-necked flask. The mixture was stirred and heated to 75℃~80℃. After dissolving completely, the mixture was stirred for 10 min, then gradually cooled to 0℃~5℃ and kept at this temperature for 2~3 h to allow crystals to crystallize. After centrifugation and drying, 11.23 g of purified agomelatine was obtained, with a yield of 73.15% and a purity of 98.92%. Example

[0044] Step 1: Add starting material I (30.00 g, 138.73 mmol) and 60.00 g dichloromethane to a 250 mL three-necked flask, heat and stir, and raise the temperature to 40 °C. After dissolving completely, slowly add SOCl2 (29.71 g, 249.72 mmol) dropwise while maintaining reflux. After the addition is complete, reflux the reaction for 2 h. Monitor the reaction by TLC until it is complete, then evaporate the reaction solution to dryness under reduced pressure to obtain a brown oily substance.

[0045] The obtained oily substance was dissolved in 60.00g of anhydrous ethanol. Under ice-salt water cooling, 30.00g of concentrated ammonia was slowly added while stirring continuously, and a pale yellow solid precipitated. After filtration and drying, intermediate I was obtained in the amount of 29.85g, with a yield of 99.96% and a purity of 95.70%.

[0046] Step 2: Intermediate I (25.00 g, 116.14 mmol), 100.00 g dichloromethane, and triethylamine (29.38 g, 290.36 mmol) were added to a 500 mL three-necked flask and stirred to dissolve. Under ice-salt water cooling, (CF3CO)2O (60.98 g, 290.36 mmol) was slowly added dropwise. After the addition was complete, stirring was continued for 1 h, followed by stirring at room temperature for 2 h. The reaction was monitored by TLC until complete, and the reaction solution was evaporated to dryness under reduced pressure.

[0047] 125.00 g of water was added to the evaporated product, and the mixture was stirred for 0.5 h. After filtration and drying, 33.06 g of crude intermediate II was obtained. 175.00 g of isopropyl ether and 2.50 g of activated carbon were added to the crude intermediate II for decolorization, and the product was recrystallized to obtain 20.08 g of purified intermediate II, with a yield of 87.37% and a purity of 98.00%.

[0048] Step 3: Intermediate II (18.00 g, 91.26 mmol) and 36.00 g tetrahydrofuran were added to a 250 mL three-necked flask. 1.80 g Raney Ni was added with stirring, and hydrogen gas was bubbled through the flask to pressurize it to 4-5 MPa. The temperature was raised to 80 °C, and the reaction was stirred for 5 h. The reaction was monitored by TLC until complete. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain 17.51 ​​g of intermediate III, with a yield of 95.69% and a purity of 98.83%.

[0049] Step 4: Intermediate III (15.50 g, 77.01 mmol) and 23.25 g of ethyl acetate were added to a 100 mL three-necked flask and stirred at room temperature to dissolve. Then, 1.60 mL of concentrated hydrochloric acid was added to the solution, causing a white solid to precipitate. The temperature was lowered to 10-20 °C, and the mixture was stirred for 6 hours to allow crystallization. After the reaction was complete, the mixture was filtered and dried to obtain 18.04 g of intermediate IV, with a yield of 98.56% and a purity of 97.81%.

[0050] Step 5: Add intermediate IV (15.00 g, 63.10 mmol), 400.00 g dichloromethane, and K2CO3 (21.80 g, 157.74 mmol) to a 500 mL three-necked flask, stir at room temperature for 0.5 h, cool to -5 °C to 5 °C, slowly add CH3COCl (5.45 g, 69.42 mmol) dropwise, controlling the temperature at 0 °C to 5 °C during the dropwise addition, continue stirring for 0.5 h after the dropwise addition is complete, raise the temperature to 40 °C to 50 °C, and continue stirring the reaction for 6 to 8 h.

[0051] TLC monitoring until the reaction was basically complete was performed. 140.00 g of water was added to the reaction solution with stirring, and the mixture was stirred for 50 min. After standing for 15 min, the aqueous phase was separated and discarded, while the organic phase was retained. The organic phase was washed twice with 140.00 g of saturated NaCl solution. The organic phase was concentrated under reduced pressure to obtain 14.96 g of crude agomelatine.

[0052] Purification: 14.96 g of crude agomelatine, 45.00 g of toluene, and 1.45 g of activated carbon were added to a 100 mL three-necked flask. The mixture was stirred and heated to 75℃~80℃, and kept at this temperature for 1 h. The mixture was filtered while hot, and the filtrate was transferred to a 250 mL three-necked flask. 16.00 g of n-hexane was added while stirring, and the mixture was heated to 85℃ to dissolve the solid. The temperature was then slowly lowered to 0℃~15℃, and crystallization was allowed to occur for 22 h. The crystals were filtered and dried to obtain 13.34 g of a white solid powder.

[0053] The obtained 13.34 g white solid powder, 69.17 g anhydrous ethanol, and 108.70 g water were added to a 500 mL three-necked flask. The mixture was stirred and heated to 75℃~80℃. After dissolving completely, the mixture was stirred for 10 min, then gradually cooled to 0℃~5℃ and kept at this temperature for 2~3 h to allow crystals to crystallize. After centrifugation and drying, 12.86 g of purified agomelatine was obtained, with a yield of 83.79% and a purity of 99.11%.

[0054] contrast:

[0055] Comparative experiments showed that the purity, yield, and overall yield of the agomelatine purified product prepared using this invention were all improved. The solvent in this invention can be recycled, saving reagents and costs, and causing less environmental pollution.

Claims

1. A method for synthesizing agomelatine, characterized in that, The synthetic route is as follows: 。 2. The method for synthesizing agomelatine according to claim 1, characterized in that, The steps of the synthesis method are as follows: (1) Starting material I: (7-methoxy-1-naphthyl)acetic acid reacts with SOCl2 in solvent A to obtain acyl chloride, and then reacts with NH4OH to obtain intermediate I (7-methoxy-1-naphthyl)acetamide; (2) Intermediate I was dehydrated by reacting with (CF3CO)2O in solvent B and triethylamine to give intermediate II (7-methoxy-1-naphthyl)acetonitrile; (3) Intermediate II undergoes catalytic hydrogenation with Raney Ni and H2 in solvent C to obtain intermediate III (7-methoxy-1-naphthyl)ethylamine; (4) Intermediate III reacts with HCl in solvent D to give intermediate IV (7-methoxy-1-naphthyl) ethylamine hydrochloride; (5) Intermediate IV condenses with CH3COCl in solvent E and Cs2CO3 to obtain agomelatine.

3. The method for synthesizing agomelatine according to claim 2, characterized in that, The solvent A used in step (1) is one or more of diethyl ether, chloroform, dichloromethane, tetrahydrofuran, toluene, and anhydrous ethanol; the molar ratio of the starting material I to SOCl2 is 1:1.1 to 1:1.5, and the molar ratio of the starting material I to NH4OH is 1:2 to 1:4; the system is heated to 40℃ to 80℃ under stirring; the reaction time is 2 to 6 hours.

4. The method for synthesizing agomelatine according to claim 2, characterized in that, The solvent B used in step (2) is one or more of dichloromethane, tetrahydrofuran, toluene, isopropyl ether, and triethylamine; the molar ratio of intermediate I to (CF3CO)2O is 1:1.5 to 1:3, and the molar ratio of intermediate I to triethylamine is 1:2 to 1:3; the system is heated to 20℃ to 40℃ under stirring; the reaction time is 4 to 8 hours.

5. The method for synthesizing agomelatine according to claim 2, characterized in that, The solvent C used in step (3) is one or more of tetrahydrofuran, anhydrous ethanol, and toluene; the mass ratio of intermediate II to Raney Ni is 8:1 to 15:1; the system is heated to 30°C to 90°C under stirring; and the reaction time is 2 to 6 hours.

6. The method for synthesizing agomelatine according to claim 2, characterized in that, The solvent D used in step (4) is one or more of dichloromethane, tetrahydrofuran, ethanol, methanol, ethyl acetate, toluene, and dioxane; the mass-volume ratio of intermediate III to HCl is 10:0.9 to 10:1.1; the system is heated to 20°C to 30°C under stirring; the reaction time is 1 to 3 hours.

7. The method for synthesizing agomelatine according to claim 2, characterized in that, The solvent E used in step (5) is one or more of dichloromethane, tetrahydrofuran, anhydrous ethanol, methanol, toluene, n-hexane, and dioxane; the molar ratio of intermediate IV to Cs2CO3 is 1:1.5~1:3, and the molar ratio of intermediate IV to CH3COCl is 1:1.05~1:1.2; the system is heated to -5℃~70℃ under stirring; the reaction time is 3~8h.

8. The method for synthesizing agomelatine according to claim 3, characterized in that, The solvent A used in step (1) is dichloromethane; the molar ratio of the starting material I to SOCl2 is 1:1.8, and the molar ratio of the starting material I to NH4OH is 1:4; the system is heated to 50°C under stirring; the reaction time is 2~3h, wherein the mass ratio of the starting material I to dichloromethane is 1:

2.

9. The method for synthesizing agomelatine according to claim 4, characterized in that, Solvent B used in step (2) is dichloromethane; the molar ratio of intermediate I to (CF3CO)2O is 1:2.5, and the molar ratio of intermediate I to triethylamine is 1:2.5; the system is heated to -20℃~20℃ under stirring; the reaction time is 2~4h. The mass ratio of intermediate I to dichloromethane is 1:4; during the purification of crude intermediate II, the crystallization temperature is -5℃~5℃, the crystallization time is 5~8h, and the mass ratio of crude intermediate II to isopropyl ether is 1:

5.

10. The method for synthesizing agomelatine according to claim 5, characterized in that, The solvent C used in step (3) is tetrahydrofuran; the mass ratio of intermediate II to Raney Ni is 10:1; the system is pressurized to 4~5MPa by hydrogen gas and heated to 70℃~90℃ under stirring; the reaction time is 4~5h, wherein the mass ratio of intermediate II to tetrahydrofuran is 1:

2.

11. The method for synthesizing agomelatine according to claim 6, characterized in that, The solvent D used in step (4) is ethyl acetate; the mass-to-volume ratio of intermediate III to HCl is 10:1; the system is stirred and crystallized at 10℃~20℃; the crystallization time is 5~6h, wherein the mass ratio of intermediate III to ethyl acetate is 1:1.

5.

12. The method for synthesizing agomelatine according to claim 7, characterized in that, The solvent E used in step (5) is toluene; the molar ratio of intermediate IV to Cs2CO3 is 1:2.5, and the molar ratio of intermediate IV to CH3COCl is 1:1.1; the system is heated to -5℃~70℃ under stirring; the reaction time is 7~8h, wherein the mass ratio of intermediate IV to toluene is 1:20, the crystallization temperature of crude agomelatine is 0℃~15℃, the crystallization time is 2~22h, the mass ratio of crude agomelatine to toluene is 1:3, the mass ratio of crude agomelatine to n-hexane is 1:1, the mass ratio of crude agomelatine to anhydrous ethanol is 1:5, and the mass ratio of crude agomelatine to purified water is 1:8.

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