A preparation method of agomelatine

Abstract

The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of agomelatine. In the present invention, a compound with the structure shown in Formula 1, an organic solvent, a first base reagent, nitromethane and silica gel are mixed for a condensation reaction to obtain a compound with the structure shown in Formula 2; an ammonia methanol solution, the compound with the structure shown in Formula 2, cyclohexene and a palladium catalyst are mixed for an aromatization reaction, and the obtained aromatization reaction solution is subjected to a reduction reaction in a hydrogen atmosphere to obtain a compound with the structure shown in Formula 3; the compound with the structure shown in Formula 3, an organic solvent, a second base reagent and an amidation reagent are mixed for an acetylation reaction to obtain the agomelatine. The present invention adopts a one-step method for aromatization and reduction, simplifies the operation, improves the reaction yield, reduces the three wastes, and at the same time avoids the dimer impurities generated during the reduction of the cyano group. The obtained agomelatine product has high purity and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of agomelatine. Background Art

[0002] Agomelatine, chemically named N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide and commercially named Valdoxan, is a bio(electronic) isostere analogue of melatonin developed by Servier, France. It replaces the indole ring with a naphthalene nucleus, 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 new breakthrough in the field of depression treatment. 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. The structure of agomelatine is as follows:

[0003]

[0004] European Patent EP0447285 reported that starting from 7-methoxy-1-tetralone, through condensation with ethyl bromoacetate, aromatization, ester hydrolysis, acyl chlorination, ammoniation, and dehydration, 7-methoxy-1-naphthaleneacetonitrile was obtained, and then agomelatine was obtained through cyanide reduction and acetylation. The route is as follows:

[0005]

[0006] This route has many reaction steps, takes a long time, uses a lot of solvents throughout the route, is not conducive to the determination of residual solvents in the finished product, has a high cost, and does not meet the industrial requirements.

[0007] Chinese Patent CN200880101738 reported that starting from 7-methoxy-1-naphthoic acid, through borane reduction, chlorination, and cyanation, the key intermediate 7-methoxy-1-naphthaleneacetonitrile was obtained. The route is as follows:

[0008]

[0009] This method simplifies the preparation process of the key intermediate of agomelatine, but the route uses highly toxic borane and potassium cyanide, which is not conducive to industrial production.

[0010] "Synthesis of Agomelatine" (Tang Jiadeng, Cen Junda., Journal of Chinese Pharmaceutical Industry, 2008,

[0011] 39(3), 161 - 162) reported that starting from 7 - methoxy - 1 - tetralone, agomelatine was obtained through condensation with cyanoacetic acid, DDQ aromatization, and reduction and acetylation of the cyano group. The route is as follows:

[0012]

[0013] Although this method does not require the use of highly toxic borane and potassium cyanide, it is necessary to first perform aromatization and then carry out cyano reduction and amidation. Moreover, cyano reduction and amidation are carried out in a "one - pot" manner, inevitably generating dimer impurities and dimer amidation impurities, resulting in low purity of agomelatine and bringing pressure and risks to the quality of the bulk drug product. Summary of the Invention

[0014] The purpose of the present invention is to provide a preparation method of agomelatine. The preparation method provided by the present invention simplifies the operation steps, improves the reaction yield and the purity of the agomelatine product, reduces the emission of three wastes at the same time, avoids the dimer impurities generated during cyano reduction, and is suitable for industrial production.

[0015] In order to achieve the above purpose, the present invention provides the following technical solutions:

[0016] The present invention provides a preparation method of agomelatine, comprising the following steps:

[0017] Mix the compound with the structure shown in formula 1, an organic solvent, a first base reagent, nitromethane, and silica gel to carry out a condensation reaction to obtain a compound with the structure shown in formula 2;

[0018]

[0019] Mix the ammonia - methanol solution, the compound with the structure shown in formula 2, an aromatization aid, and a palladium catalyst to carry out an aromatization reaction, and carry out a reduction reaction on the obtained aromatization reaction solution in a hydrogen atmosphere to obtain

[0020] a compound with the structure shown in formula 3;

[0021]

[0022] Mix the compound with the structure shown in formula 3, an organic solvent, a second base reagent, and an amidation reagent to carry out an acetylation reaction to obtain the agomelatine.

[0023] Preferably, the first base reagent includes one or more of n - hexylamine, ammonium formate, and ammonium acetate.

[0024] Preferably, the mass ratio of the compound with the structure shown in formula 1 to the first base reagent is 1:0.03 - 0.1;

[0025] The mass ratio of the compound with the structure shown in Formula 1 to nitromethane is 1:0.2 to 1;

[0026] The mass ratio of the compound with the structure shown in Formula 1 to silica gel is 1:0.05 to 1.5.

[0027] Preferably, the temperature of the condensation reaction is 50 to 110 °C.

[0028] Preferably, an oily product is obtained after the reduction reaction; the oily product is mixed with an alcohol solvent, and the pH value is adjusted to ≤2 to obtain an acidic solution; the acidic solution is cooled to ≤5 °C for crystallization, and after solid-liquid separation, a salt of the compound with the structure shown in Formula 3 is obtained.

[0029] Preferably, the palladium catalyst is palladium on carbon, and the mass percentage content of palladium in the palladium on carbon is 5%;

[0030] The aromatization assistant includes cyclohexene and / or ethylene;

[0031] The mass ratio of the compound with the structure shown in Formula 2 to the aromatization assistant is 1:0.4 to 1.0;

[0032] The mass ratio of the compound with the structure shown in Formula 2 to the palladium catalyst is 1:0.05 to 0.15.

[0033] Preferably, the temperatures of the aromatization reaction and the reduction reaction are independently 40 to 100 °C, the hydrogen pressure of the reduction reaction is 0.5 to 3 Mpa, and the time of the aromatization reaction is 5 to 24 h.

[0034] Preferably, the second base reagent includes one or more of triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, and potassium bicarbonate;

[0035] The amidation reagent includes acetic anhydride and / or acetyl chloride.

[0036] Preferably, the molar ratio of the compound with the structure shown in Formula 3 to the second base reagent is 1.0:0.8 to 3.0;

[0037] The molar ratio of the compound with the structure shown in Formula 3 to the amidation reagent is 1.0:0.8 to 1.5.

[0038] Preferably, the temperature of the acetylation reaction is -20 to 30 °C.

[0039] The present invention provides a preparation method of agomelatine, comprising the following steps: mixing a compound with the structure shown in Formula 1, an organic solvent, a first base reagent, nitromethane and silica gel for a condensation reaction to obtain a compound with the structure shown in Formula 2; mixing an ammonia methanol solution, the compound with the structure shown in Formula 2, an aromatization auxiliary and a palladium catalyst for an aromatization reaction, and carrying out a reduction reaction on the obtained aromatization reaction solution in a hydrogen atmosphere to obtain a compound with the structure shown in Formula 3; mixing the compound with the structure shown in Formula 3, an organic solvent, a second base reagent and an amidation reagent for an acetylation reaction to obtain the agomelatine. The preparation method provided by the present invention uses the compound with the structure shown in Formula 1 as the starting material for the reaction, and successively carries out a condensation reaction, an aromatization reaction and an acetylation reaction. In particular, the aromatization and reduction are carried out in one step, which simplifies the operation, improves the reaction yield, reduces the three wastes, and at the same time avoids the dimer impurities generated during the reduction of the cyano group. The obtained agomelatine product has high purity and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 It is the mass spectrum of the compound with the structure shown in Formula 2 prepared in Example 1;

[0041] Figure 2 It is the nuclear magnetic resonance spectrum of the compound with the structure shown in Formula 3 prepared in Example 1;

[0042] Figure 3 It is the nuclear magnetic resonance spectrum of the agomelatine compound prepared in Example 1;

[0043] Figure 4 It is the liquid phase spectrum of the agomelatine prepared in Example 1;

[0044] Figure 5 It is the preparation flow chart of the agomelatine provided by the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0045] The present invention provides a preparation method of agomelatine, comprising the following steps:

[0046] Mixing a compound with the structure shown in Formula 1, an organic solvent, a first base reagent, nitromethane and silica gel for a condensation reaction to obtain a compound with the structure shown in Formula 2;

[0047]

[0048] Mixing an ammonia methanol solution, the compound with the structure shown in Formula 2, an aromatization auxiliary and a palladium catalyst for an aromatization reaction, and carrying out a reduction reaction on the obtained aromatization reaction solution in a hydrogen atmosphere to obtain

[0049] a compound with the structure shown in Formula 3;

[0050]

[0051] Mix the compound of the structure shown in Formula 3, an organic solvent, a second base reagent and an amidating reagent, and carry out an acetylation reaction to obtain the agomelatine.

[0052] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well-known to those skilled in the art.

[0053] In the present invention, the compound of the structure shown in Formula 1, an organic solvent (denoted as the first organic solvent), a first base reagent, nitromethane and silica gel are mixed to carry out a condensation reaction to obtain the compound of the structure shown in Formula 2;

[0054]

[0055] In the present invention, the first organic solvent is specifically preferably toluene. The first base reagent preferably includes one or more of n-hexylamine, ammonium formate and ammonium acetate, and more preferably n-hexylamine. In the present invention, the role of the silica gel is the catalyst for the condensation reaction.

[0056] In the present invention, the mass ratio of the compound of the structure shown in Formula 1 to the first base reagent is preferably 1:0.03 - 0.1, more preferably 1:0.04 - 0.07, and still more preferably 1:0.05 - 0.06. The mass ratio of the compound of the structure shown in Formula 1 to nitromethane is preferably 1:0.2 - 1, more preferably 1:0.25 - 0.8, and further preferably 1:0.3 - 0.5. The mass ratio of the compound of the structure shown in Formula 1 to silica gel is preferably 1:0.05 - 1.5, more preferably 1:0.08 - 1, and further preferably 1:0.09 - 0.5. The present invention has no special requirements for the dosage of the first solvent, and it is only necessary to ensure the smooth progress of the condensation reaction.

[0057] In the present invention, the temperature of the condensation reaction is preferably 50 - 110 °C, more preferably 80 - 100 °C; the heat preservation time is preferably 12 - 15 h. In the present invention, the condensation reaction preferably uses TLC to detect the reaction process. The developing agent used for the TLC detection is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 4:1; during the TLC detection, when the spot of the compound of the structure shown in Formula 1 disappears, the condensation reaction ends.

[0058] In the present invention, after the condensation reaction ends, a condensation reaction solution is obtained. The present invention preferably cools the condensation reaction solution to room temperature and then performs solid-liquid separation. After the obtained liquid product is washed with water, an organic phase is obtained; the organic phase is concentrated under reduced pressure, and the obtained concentrate contains the compound of the structure shown in Formula 2. The present invention preferably directly performs the subsequent aromatization reaction on the concentrate.

[0059] After obtaining the compound with the structure shown in Formula 2 (the above-mentioned concentrate), an ammonia methanol solution, the compound with the structure shown in Formula 2, cyclohexene and a palladium catalyst are mixed to carry out an aromatization reaction, and the obtained aromatization reaction solution is subjected to a reduction reaction in a hydrogen atmosphere to obtain the compound with the structure shown in Formula 3;

[0060]

[0061] In the present invention, the ammonia methanol solution is preferably a saturated ammonia methanol solution. The palladium catalyst is preferably palladium on carbon, and the mass percentage content of the palladium on carbon is preferably 5%.

[0062] In the present invention, the mass ratio of the compound with the structure shown in Formula 2 to cyclohexene is preferably 1:0.4 - 1.0, more preferably 1:0.45 - 0.8. The mass ratio of the compound with the structure shown in Formula 2 to the palladium catalyst is preferably 1:0.05 - 0.15, more preferably 1:0.08 - 0.12. The mass ratio of the compound with the structure shown in Formula 2 to the volume of the ammonia methanol solution is preferably 1 g:0.01 - 0.03 L.

[0063] In the present invention, the aromatization reaction and the reduction reaction are carried out in a high-pressure hydrogenation reactor. In the present invention, the temperature of the aromatization reaction is preferably 40 - 100 °C, more preferably 50 - 90 °C, and further preferably 60 - 80 °C; the heat preservation time is preferably 5 - 24 h, more preferably 10 - 15 h. After the aromatization reaction, in the present invention, hydrogen is preferably charged into the reaction vessel to make the obtained aromatization reaction solution carry out a reduction reaction in a hydrogen atmosphere. In the present invention, the reduction reaction is a reaction for hydrogenating the aliphatic double bond and nitro group of the compound with the structure shown in Formula 2. In the present invention, the temperature of the reduction reaction is preferably 40 - 100 °C, more preferably 50 - 90 °C, and further preferably 60 - 80 °C; the heat preservation time is preferably 1 - 5 h, more preferably 4 h. The hydrogen pressure of the reduction reaction is preferably 0.5 Mpa - 3 Mpa, more preferably 0.8 - 2 MPa, and further preferably 0.9 - 1.5 MPa.

[0064] In the present invention, after the reduction reaction is completed, a reduction reaction solution is obtained. In the present invention, it is preferably to cool the reduction reaction solution to room temperature and then carry out solid-liquid separation, concentrate the obtained liquid-phase product to obtain an oily product. In the present invention, the solid-liquid separation is preferably filtration, and the concentration is preferably vacuum concentration. The oily product is obtained by vacuum concentrating to dryness.

[0065] In the present invention, after the reduction reaction to obtain an oily product; the present invention preferably mixes the oily product with an alcohol solvent, adjusts the pH value to ≤2 to obtain an acidic solution; cools the acidic solution to ≤5 °C for crystallization, and after solid-liquid separation, a salt of the compound of the structure shown in Formula 3 is obtained. In the present invention, the alcohol solvent is preferably ethanol, the temperature of the mixed solution obtained by mixing the oily product and the alcohol solvent is preferably ≤30 °C, the present invention preferably uses an acid solution to adjust the pH value of the mixed solution to ≤2, preferably 1-2; the acid solution is preferably sulfuric acid, phosphoric acid, tartaric acid or hydrochloric acid, more preferably hydrochloric acid, and the mass percentage content of the hydrochloric acid is preferably 35-37%. The present invention preferably uses hydrochloric acid to adjust the pH value of the mixed solution, which is beneficial to obtaining the hydrochloride of the compound of the structure shown in Formula 3 with high purity by recrystallization. The end temperature of cooling the acidic solution is preferably ≤5 °C, more preferably 5 °C; the present invention preferably keeps the temperature at ≤5 °C for 1-5 h, more preferably 5 h for crystallization. The solid-liquid separation is preferably suction filtration, and the present invention preferably dries the solid product obtained by solid-liquid separation to obtain the compound of the structure shown in Formula 3.

[0066] In the present invention, when the acid solution is preferably hydrochloric acid, the obtained product is the hydrochloride of the compound of the structure shown in Formula 3, and the structure of the hydrochloride of the compound of the structure shown in Formula 3 is:

[0067]

[0068] The present invention preferably uses the hydrochloride of the compound of the structure shown in Formula 3 for the subsequent acetylation reaction.

[0069] After obtaining the compound of the structure shown in Formula 3, the present invention mixes the compound of the structure shown in Formula 3, an organic solvent (denoted as the second organic solvent), a second base reagent and an amidation reagent to carry out an acetylation reaction to obtain the agomelatine.

[0070] In the present invention, the second organic solvent is preferably dichloromethane. The second base reagent preferably includes one or more of triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium bicarbonate, more preferably triethylamine. The amidation reagent preferably includes acetic anhydride and / or acetyl chloride, more preferably acetic anhydride.

[0071] In the present invention, the molar ratio of the compound of the structure shown in Formula 3 to the second base reagent is preferably 1.0:0.8 to 3.0, more preferably 1.0:1.0 to 2.0, and most preferably 1.0:1.5 to 2.0. The molar ratio of the compound of the structure shown in Formula 3 to the amidation reagent is preferably 1.0:0.8 to 1.5, more preferably 1.0:0.9 to 1.4, and further preferably 1.0:1 to 1.3. There is no special requirement for the dosage of the second organic solvent in the present invention, as long as the acetylation reaction can proceed smoothly.

[0072] In the present invention, the step of mixing the compound of the structure shown in Formula 3, the second organic solvent, the second base reagent and the amidation reagent is preferably as follows: dissolving the compound of the structure shown in Formula 3 in the second organic solvent to obtain a solution of the compound of the structure shown in Formula 3; cooling the solution of the compound of the structure shown in Formula 3 to 0-5°C, and dropping the second base reagent and the amidation reagent. In the present invention, the temperature of the acetylation reaction is preferably -20 to 30°C, more preferably -10 to 10°C, and further preferably 0 to 5°C. The present invention preferably conducts the acetylation reaction under the condition of 0-5°C. Compared with conducting the acetylation reaction at high temperature, it is beneficial to inhibit the generation of side reactions and improve the purity of the target product agomelatine.

[0073] In the present invention, the acetylation reaction preferably uses TLC to detect the reaction process. The developing agent used for the TLC detection is preferably dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is preferably 10:1; during the TLC detection, when the spot of the compound of the structure shown in Formula 3 disappears, the acetylation reaction ends.

[0074] In the present invention, after the acetylation reaction ends, an acetylation reaction solution is obtained. The present invention preferably washes the acetylation reaction solution to obtain an organic phase; dries the organic phase and concentrates it to dryness, stirs and mixes the obtained concentrate with n-hexane and then performs solid-liquid separation, and dries the obtained solid product to obtain the agomelatine. In the present invention, the washing is preferably carried out in sequence: washing with water, washing with saturated sodium bicarbonate aqueous solution and washing with saturated brine. The reagent used for drying is preferably anhydrous sodium sulfate. The concentration is preferably concentration under reduced pressure. The temperature of the stirring and mixing is preferably room temperature, and the time is preferably 1 h. The solid-liquid separation is preferably suction filtration.

[0075] The above preparation method provided by the present invention adopts a one-step method for aromatization and reduction reactions; it avoids the dimer impurities generated by the reduction of cyanide groups; simplifies the operation process, has less three wastes, the yield of each step is greater than 90%, and the obtained agomelatine product has high purity, which is suitable for industrial production.

[0076] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below in conjunction with embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0077] The embodiments provided by the present invention are carried out according to the Figure 5 preparation process shown, where Figure 5 SM-1 in represents the compound of the structure shown in Formula 1, AG-1 represents the compound of the structure shown in Formula 2, and AG-2 represents the compound of the structure shown in Formula 3.

[0078] Example 1

[0079] Add 150 g of SM-1 (7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde), 600 mL of toluene into a 1000 mL reaction flask. While stirring, add 8 g of n-hexylamine, 57.8 g of nitromethane, and 15 g of silica gel. Heat to 100 °C and keep the reaction for 12 hours. After detecting by TLC (developing agent volume ratio: petroleum ether: ethyl acetate = 4:1) until the reaction is complete (the spot of 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde disappears), cool down to room temperature, filter. Wash the filtrate once with 100 mL of water, and concentrate the organic layer under reduced pressure to dryness to obtain 165.5 g of an oily substance AG-1, which is directly used for the next reaction with a yield of 90%.

[0080] The mass spectrum of AG-1 is as shown in Figure 1 : 234.1 [M+H] + .

[0081] Add 3 L of saturated ammonia methanol solution, 100 g of AG-1, 50 g of cyclohexene, and 10 g of 5% palladium carbon into a 5 L high-pressure hydrogenation reactor. React at 70 °C for 12 hours, then charge hydrogen and keep the pressure at 1.0 Mpa for 4 hours. Cool down to room temperature, filter to remove the catalyst, and concentrate the filtrate under reduced pressure to dryness to obtain an oily substance;

[0082] Add the above-mentioned oily substance and 200 mL of ethanol into a 500 mL reaction flask. Control the temperature at 30 °C, adjust the pH value to 2 with concentrated hydrochloric acid, cool down to 5 °C for crystallization for 5 hours, filter by suction, and dry at 55 °C to obtain 96.7 g of AG-2 solid with a yield of 95.1%.

[0083] The nuclear magnetic resonance spectrum of the AG-2 product is as shown in Figure 2 Therefore, the nuclear magnetic data is as follows: 1H-NMR (500 MHz, DMSO-d6) δ: 8.42 (3H, s), 7.87 (1H, m), 7.77 (1H, d), 7.49 (1H, s), 7.39 (1H, d), 7.31 (1H, m), 7.21 (1H, m), 3.96 (3H, s), 3.43 (2H, m), 3.09 (2H, m).

[0084] Add 50 g of AG-2 and 500 mL of dichloromethane to a 1000 mL reaction flask. Cool the temperature to 0 °C, control the temperature at 2.5 ± 2.5 °C, and dropwise add 32 g of triethylamine (the molar ratio of AG-2 to triethylamine is 1.5) and 25.8 g of acetic anhydride (the molar ratio of AG-2 to acetic anhydride is 1.2). Keep the temperature for reaction for 2 hours. Detect by TLC (developing agent volume ratio: dichloromethane: methanol = 10:1) until the reaction is complete (the spot of AG-2 disappears). Wash once with 100 mL of water, once with 100 mL of saturated sodium bicarbonate aqueous solution, and once with 100 mL of saturated brine. Dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to dryness, add 100 mL of n-hexane, stir at room temperature for 1 hour, filter by suction, and dry at 55 °C to obtain 50 g of white solid. The yield of agomelatine is 97.5%.

[0085] The NMR spectrum of the agomelatine product is as Figure 3 Therefore, the NMR data are as follows: 1H-NMR (500 MHz, DMSO-d6) δ: 8.11 (1H, s), 7.84 (1H, d), 7.72 (1H, d), 7.62 (1H, s), 7.33 (2H, m), 7.19 (1H, m), 3.95 (3H, s), 3.38 (2H, m), 3.15 (2H, m), 1.84 (3H, s).

[0086] The purity detection spectrum of agomelatine is as Figure 4 , and the data are shown in Table 1. The liquid phase purity is 99.96%.

[0087] Table 1 Chromatographic data of agomelatine

[0088] RT Area %Area Height USP Plate Count USP Resolution USP Tailing 1 7.320 497.603 0.01 90.969 38805.825 0.941 2 7.890 3900717.591 99.96 628292.770 35125.599 3.603 1.124 3 8.926 947.761 0.02 121.218 25835.708 5.485 0.849

[0089] The advantages of the invention are that the aromatization and reduction are carried out by a one-step method, which simplifies the operation, improves the reaction yield, reduces the three wastes, and at the same time avoids the dimer impurities generated during the reduction of the cyano group, and is suitable for industrial production.

[0090] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, not all embodiments. Other embodiments can be obtained according to these embodiments without creative work, and these embodiments all belong to the protection scope of the present invention.

Claims

1. A preparation method of agomelatine, characterized in that, it comprises the following steps: Mixing a compound with the structure shown in Formula 1, an organic solvent, a first base reagent, nitromethane and silica gel for condensation reaction to obtain a compound with the structure shown in Formula 2; Mixing an ammonia methanol solution, a compound with the structure shown in Formula 2, an aromatization auxiliary and a palladium catalyst for aromatization reaction, the palladium catalyst being palladium on carbon, and the aromatization auxiliary being cyclohexene and / or ethylene, and carrying out a reduction reaction on the obtained aromatization reaction solution in a hydrogen atmosphere to obtain a compound with the structure shown in Formula 3; Mixing a compound with the structure shown in Formula 3, an organic solvent, a second base reagent and an amidation reagent for acetylation reaction to obtain the agomelatine.

2. The preparation method according to claim 1, characterized in that, the first base reagent includes one or more of n-hexylamine, ammonium formate and ammonium acetate.

3. The preparation method according to claim 1, characterized in that, the mass ratio of the compound with the structure shown in Formula 1 to the first base reagent is 1:0.03 - 0.1; the mass ratio of the compound with the structure shown in Formula 1 to nitromethane is 1:0.2 - 1; the mass ratio of the compound with the structure shown in Formula 1 to silica gel is 1:0.05 - 1.

5.

4. The preparation method according to any one of claims 1 to 3, characterized in that, the temperature of the condensation reaction is 50 - 110 °C.

5. The preparation method according to claim 1, characterized in that, an oily product is obtained after the reduction reaction; mixing the oily product and an alcohol solvent, adjusting the pH value ≤ 2 to obtain an acidic solution; cooling the acidic solution to ≤ 5 °C for crystallization, and separating the solid and liquid to obtain a salt of the compound with the structure shown in Formula 3.

6. The preparation method according to claim 1 or 5, characterized in that, the mass percentage of palladium in the palladium on carbon is 5%; the mass ratio of the compound with the structure shown in Formula 2 to the aromatization auxiliary is 1:0.4 - 1.0; the mass ratio of the compound with the structure shown in Formula 2 to the palladium catalyst is 1:0.05 - 0.

15.

7. The preparation method according to claim 1, characterized in that, the temperature of the aromatization reaction and the reduction reaction is independently 40 - 100 °C, the hydrogen pressure of the reduction reaction is 0.5 - 3 Mpa, and the time of the aromatization reaction is 5 - 24 h.

8. The preparation method according to claim 1, characterized in that, the second base reagent includes one or more of triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium bicarbonate; the amidation reagent includes acetic anhydride and / or acetyl chloride.

9. The preparation method according to claim 1 or 8, characterized in that, the mass ratio of the compound with the structure shown in Formula 3 to the second base reagent is 1.0:0.8 - 3.0; the mass ratio of the compound with the structure shown in Formula 3 to the amidation reagent is 1.0:0.8 - 1.

5.

10. The preparation method according to claim 1, characterized in that, the temperature of the acetylation reaction is -20 - 30 °C.

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