A method for synthesizing agomelatine

Abstract

The present invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing agomelatine. In the present invention, a compound having the structure shown in Formula 1 and a compound having the structure shown in Formula 2 are mixed for a condensation reaction, and the organic solution of the compound having the structure shown in Formula 3 obtained by solid-liquid separation is mixed with an acid solution for a decarboxylation reaction to obtain a compound having the structure shown in Formula 4; an ammonia methanol solution, the compound having the structure shown in Formula 4, an aromatization auxiliary agent, a palladium catalyst and a nickel catalyst are mixed for an aromatization reaction, and the obtained aromatization reaction solution is continued to carry out a reduction reaction in a hydrogen atmosphere to obtain a compound having the structure shown in Formula 5; the compound having the structure shown in Formula 5, an organic solvent, a second base reagent and an amidation reagent are mixed for an acetylation reaction to obtain the agomelatine. The present invention simplifies the operation, improves the yield and purity of the reaction target product, reduces the three wastes, 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 method for synthesizing agomelatine. Background Art

[0002] Agomelatine, chemically named N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide, with the trade name Valdoxan, is a bio(electronic) isostere analogue of melatonin developed by Servier Company in 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 and represents 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 cyano 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. Summary of the Invention

[0007] The purpose of the present invention is to provide a method for synthesizing agomelatine. The synthesis method provided by the present invention has simple steps, less three wastes, high product yield and purity, and is suitable for industrial production.

[0008] To achieve the above purpose, the present invention provides the following technical solutions:

[0009] The present invention provides a method for synthesizing agomelatine, comprising the following steps:

[0010] Mix the compound of the structure shown in Formula 1, an organic solvent, a first base reagent, and the compound of the structure shown in Formula 2 for a condensation reaction, and perform solid-liquid separation to obtain an organic solution of the compound of the structure shown in Formula 3;

[0011]

[0012] In Formula 1, X is a halogen, and in Formula 2, R is a C1-C6 alkyl group;

[0013] Mix the organic solution of the compound with the structure shown in Formula 3 and an acid solution to carry out a decarboxylation reaction to obtain a compound with the structure shown in Formula 4;

[0014]

[0015] Mix an ammonia methanol solution, the compound with the structure shown in Formula 4, an aromatization assistant, a palladium catalyst, and a nickel 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 a compound with the structure shown in Formula 5;

[0016]

[0017] Mix the compound with the structure shown in Formula 5, an organic solvent, a second base reagent, and an amidation reagent to carry out an acetylation reaction to obtain the agomelatine.

[0018] Preferably, in Formula 1, X is chlorine, bromine or iodine, and in Formula 2, R is methyl or ethyl;

[0019] The first base reagent is potassium carbonate;

[0020] The molar ratio of the compound with the structure shown in Formula 1 to the compound with the structure shown in Formula 2 is 1:0.8 - 1.5;

[0021] The molar ratio of the compound with the structure shown in Formula 1 to the first base reagent is 1:0.5 - 2.0.

[0022] Preferably, the temperature of the condensation reaction is 50 - 150 °C.

[0023] Preferably, the acid solution is a hydrochloric acid solution, and the mass percentage content of the hydrochloric acid solution is 35 - 37%;

[0024] The molar ratio of the compound with the structure shown in Formula 3 to the acid in the acid solution is 1:1 - 10.

[0025] Preferably, the temperature of the decarboxylation reaction is 50 - 150 °C.

[0026] Preferably, the palladium catalyst is palladium on carbon, and the mass percentage content of palladium in the palladium on carbon is 5%;

[0027] The nickel catalyst is Raney nickel;

[0028] The aromatization assistant includes cyclohexene and / or ethylene.

[0029] Preferably, the mass ratio of the compound with the structure shown in Formula 4 to the aromatization assistant is 1:0.4 - 1.0;

[0030] The mass ratio of the compound of the structure shown in Formula 4 to the palladium catalyst is 1:0.05 - 0.15;

[0031] The mass ratio of the compound of the structure shown in Formula 4 to the nickel catalyst is 1:0.05 - 0.15.

[0032] Preferably, 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 - 5 Mpa, and the time of the reduction reaction is 5 - 24 h.

[0033] 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;

[0034] The amidating reagent includes acetic anhydride and / or acetyl chloride;

[0035] The molar ratio of the compound of the structure shown in Formula 5 to the second base reagent is 1.0:0.8 - 3.0;

[0036] The molar ratio of the compound of the structure shown in Formula 5 to the amidating reagent is 1.0:0.8 - 1.5.

[0037] Preferably, the temperature of the acetylation reaction is -20 - 30 °C.

[0038] The present invention provides a method for synthesizing agomelatine, which includes the following steps: mixing the compound of the structure shown in Formula 1, an organic solvent, a first base reagent, and the compound of the structure shown in Formula 2 for a condensation reaction, and performing solid-liquid separation to obtain an organic solution of the compound of the structure shown in Formula 3; X in Formula 1 is a halogen, and R in Formula 2 is a C1 - 6 alkyl group; mixing the organic solution of the compound of the structure shown in Formula 3 and an acid solution for a decarboxylation reaction to obtain the compound of the structure shown in Formula 4; mixing an ammonia methanol solution, the compound of the structure shown in Formula 4, an aromatization aid, a palladium catalyst, and a nickel catalyst for an aromatization reaction, and performing a reduction reaction on the obtained aromatization reaction solution in a hydrogen atmosphere to obtain the compound of the structure shown in Formula 5; mixing the compound of the structure shown in Formula 5, an organic solvent, a second base reagent, and an amidating reagent for an acetylation reaction to obtain the agomelatine. The preparation method provided by the present invention uses the compound of the structure shown in Formula 1 and the compound of the structure shown in Formula 2 as the starting reaction materials, and successively undergoes a condensation reaction, a decarboxylation 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 yield and purity of the reaction target product, reduces the three wastes, and is suitable for industrial production. Description of the Drawings

[0039] Figure 1 It is the mass spectrum of the compound of the structure shown in Formula 4 prepared in Example 1;

[0040] Figure 2 The NMR spectrum of the compound with the structure shown in Formula 5 prepared in Example 1;

[0041] Figure 3 The NMR spectrum of the agomelatine compound prepared in Example 1;

[0042] Figure 4 The HPLC spectrum of the agomelatine prepared in Example 1;

[0043] Figure 5 The preparation flow chart of the agomelatine provided by the present invention. Detailed implementation manners

[0044] The present invention provides a method for synthesizing agomelatine, comprising the following steps:

[0045] Mix the compound with the structure shown in Formula 1, an organic solvent, a first base reagent, and the compound with the structure shown in Formula 2 for a condensation reaction, and perform solid-liquid separation to obtain an organic solution of the compound with the structure shown in Formula 3;

[0046]

[0047] X in Formula 1 is a halogen, and R in Formula 2 is a C1-C6 alkyl group;

[0048] Mix the organic solution of the compound with the structure shown in Formula 3 and an acid solution for a decarboxylation reaction to obtain the compound with the structure shown in Formula 4;

[0049]

[0050] Mix an ammonia methanol solution, the compound with the structure shown in Formula 4, an aromatization assistant, a palladium catalyst, and a nickel catalyst for an aromatization reaction, and perform a reduction reaction on the obtained aromatization reaction solution in a hydrogen atmosphere to obtain the compound with the structure shown in Formula 5;

[0051]

[0052] Mix the compound with the structure shown in Formula 5, an organic solvent, a second base reagent, and an amidation reagent for an acetylation reaction to obtain the agomelatine.

[0053] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well-known to those skilled in the art.

[0054] The present invention mixes the compound with the structure shown in Formula 1, an organic solvent (denoted as the first organic solvent), a first base reagent, and the compound with the structure shown in Formula 2 for a condensation reaction, and performs solid-liquid separation to obtain an organic solution of the compound with the structure shown in Formula 3;

[0055]

[0056] X in Formula 1 is a halogen, and R in Formula 2 is a C1-C6 alkyl group.

[0057] In the present invention, X in Formula 1 is preferably fluorine, chlorine, bromine or iodine, more preferably chlorine, bromine or iodine, and R in Formula 2 is preferably a C1-C4 alkyl group, more preferably a C1-C3 alkyl group, and further preferably methyl or ethyl. In the present invention, the first base reagent is preferably potassium carbonate. The first organic solvent is preferably N,N-dimethylformamide (DMF).

[0058] In the present invention, the molar ratio of the compound of the structure shown in Formula 1 to the compound of the structure shown in Formula 2 is preferably 1:0.8 - 1.5, more preferably 1:0.9 - 1.2. The molar ratio of the compound of the structure shown in Formula 1 to the first base reagent is preferably 1:0.5 - 2.0, more preferably 1:0.6 - 1.8, and further preferably 1:0.8 - 1.5. The present invention has no special requirements for the dosage of the first organic solvent, as long as the condensation reaction can proceed smoothly.

[0059] In the present invention, the step of mixing the compound of the structure shown in Formula 1, the first organic solvent, the first base reagent, and the compound of the structure shown in Formula 2 is preferably: dissolving the compound of the structure shown in Formula 1 in the first organic solvent, and then dropwise adding the first base reagent and the compound of the structure shown in Formula 2 under stirring conditions. In the present invention, the temperature of the condensation reaction is preferably 50 - 150°C, more preferably 80 - 120°C; the heat preservation time is preferably 4 - 8 h. In the present invention, the condensation reaction preferably uses TLC to detect the reaction process, and 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; when the spot of the compound of the structure shown in Formula 1 disappears during the TLC detection, the condensation reaction ends.

[0060] 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 to obtain an organic solution of the compound of the structure shown in Formula 3. The present invention preferably directly performs the subsequent decarboxylation reaction on the organic solution of the compound of the structure shown in Formula 3. In the present invention, the solvent in the organic solution of the compound of the structure shown in Formula 3 is the first organic solvent. The solid-liquid separation is preferably filtration.

[0061] After obtaining the organic solution of the compound of the structure shown in Formula 3, the present invention mixes the organic solution of the compound of the structure shown in Formula 3 and an acid solution to perform a decarboxylation reaction to obtain a compound of the structure shown in Formula 4;

[0062]

[0063] In the present invention, the acid solution is preferably a hydrochloric acid solution, and the mass percentage content of the hydrochloric acid solution is 35-37%.

[0064] In the present invention, the molar ratio of the compound of the structure shown in Formula 3 to the acid in the acid solution is preferably 1:1-10, more preferably 1:1.5-9.

[0065] In the present invention, the step of mixing the organic solution of the compound of the structure shown in Formula 3 and the acid solution is preferably: dropping the acid solution into the organic solution of the compound of the structure shown in Formula 3. The dropping is carried out under stirring conditions. In the present invention, the temperature of the decarboxylation reaction is preferably 50-150 °C, more preferably 60-120 °C; the heat preservation time is preferably 1-3 h, more preferably 2 h. In the present invention, the decarboxylation reaction preferably uses TLC to detect the reaction process, and 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 3 disappears, the condensation reaction ends.

[0066] In the present invention, after the decarboxylation reaction is completed, a decarboxylation reaction solution is obtained. In the present invention, it is preferred to cool the decarboxylation reaction solution to room temperature and then mix it with water to obtain a mixed reaction solution; extract the mixed reaction solution with dichloromethane to obtain an extracted organic phase; concentrate the extracted organic phase under reduced pressure to dryness, and the obtained oily concentrate contains the compound of the structure shown in Formula 4. In the present invention, it is preferred to directly carry out the subsequent aromatization reaction on the oily concentrate. In the present invention, the number of extractions is preferably 2 times, and the extracted organic phases are combined to obtain the extracted organic phase.

[0067] After the compound of the structure shown in Formula 4 (the above-mentioned oily concentrate), in the present invention, an ammonia methanol solution, the compound of the structure shown in Formula 4, an aromatization assistant, a palladium catalyst and a nickel 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 of the structure shown in Formula 5;

[0068]

[0069] 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 palladium in the palladium on carbon is preferably 5%. The nickel catalyst is preferably Raney nickel. The aromatization assistant preferably includes cyclohexene and / or ethylene, more preferably cyclohexene.

[0070] In the present invention, the mass ratio of the compound of the structure shown in Formula 4 to the aromatization assistant is preferably 1:0.4 to 1.0, more preferably 1:0.45 to 0.8, and further preferably 1:0.5 to 0.6. The mass ratio of the compound of the structure shown in Formula 4 to the palladium catalyst is preferably 1:0.05 to 0.15, more preferably 1:0.06 to 0.12. The mass ratio of the compound of the structure shown in Formula 4 to the nickel catalyst is preferably 1:0.05 to 0.15, more preferably 1:0.06 to 0.12.

[0071] 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 to 100 °C, more preferably 50 to 90 °C, and further preferably 60 to 80 °C; the heat preservation time is preferably 1 to 5 h, more preferably 3 h. After the aromatization reaction, in the present invention, hydrogen is preferably charged into the reaction vessel so that the obtained aromatization reaction solution undergoes a reduction reaction in a hydrogen atmosphere. In the present invention, the reduction reaction is a reaction for reducing the cyano group of the compound of the structure shown in Formula 4 with hydrogen. In the present invention, the temperature of the reduction reaction is preferably 40 to 100 °C, more preferably 50 to 90 °C, and further preferably 60 to 80 °C; the heat preservation time is preferably 5 to 24 h, more preferably 10 to 12 h. The hydrogen pressure of the reduction reaction is preferably 0.5 to 5 Mpa, more preferably 0.8 to 4 MPa, and further preferably 0.9 to 3 MPa.

[0072] In the present invention, after the reduction reaction is completed, a reduction reaction solution is obtained. In the present invention, it is preferred to cool the reduction reaction solution to room temperature and then perform solid-liquid separation, and the obtained liquid-phase product is concentrated 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.

[0073] In the present invention, an oily product is obtained after the reduction reaction. After obtaining the 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 obtains the salt of the compound shown in Formula 5 after solid-liquid separation. 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, and 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 shown in Formula 5 with high purity by crystallization. The end temperature of cooling the acidic solution is preferably ≤5 °C, more preferably 5 °C; the present invention preferably performs the heat preservation for crystallization for 1-5 h, more preferably 5 h under the condition that the temperature is preferably ≤5 °C. 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 salt of the compound shown in Formula 5.

[0074] In the present invention, when the acid solution is preferably hydrochloric acid, the obtained product is the hydrochloride of the compound shown in Formula 5, and the structure of the hydrochloride of the compound shown in Formula 5 is:

[0075]

[0076] The present invention preferably uses the hydrochloride of the compound shown in Formula 5 for the subsequent acetylation reaction.

[0077] After obtaining the compound shown in Formula 5 (the hydrochloride of the compound shown in Formula 5 above), the present invention mixes the compound shown in Formula 5 (hydrochloride), 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.

[0078] 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.

[0079] In the present invention, the molar ratio of the compound of the structure shown in Formula 5 to the second base reagent is preferably 1.0:0.8 to 3.0, more preferably 1.0:1.0 to 2.5, and further preferably 1.0:1.2 to 2. The mass ratio of the compound of the structure shown in Formula 5 to the amidation reagent is preferably 1.0:0.8 to 1.5, more preferably 1.0:1.0 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.

[0080] In the present invention, the step of mixing the compound of the structure shown in Formula 5, 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 5 in the second organic solvent to obtain a compound solution of the structure shown in Formula 5; cooling the compound solution of the structure shown in Formula 5 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.

[0081] 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 5 disappears, the acetylation reaction ends.

[0082] 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 vacuum concentration. 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.

[0083] The above - mentioned synthesis method provided by the present invention can synthesize the compound of the structure shown in Formula 4 from the compound of the structure shown in Formula 1 and the compound of the structure shown in Formula 2 by continuous reaction, improving the utilization rate of the reaction equipment, the yield and purity of the target product; at the same time, the present invention adopts a one - step method for aromatization and reduction reactions, simplifies the operation process, has less three - wastes, high yields in each step, and the obtained agomelatine product has high purity, being suitable for industrial production.

[0084] 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 protection scope of the present invention.

[0085] The embodiments provided by the present invention are prepared according to the Figure 5 synthesis process shown, where Figure 5 SM-1 in is a compound with the structure shown in Formula 1, SM-2 is a compound with the structure shown in Formula 2, AG-1 is a compound with the structure shown in Formula 3, AG-2 is a compound with the structure shown in Formula 4, and AG-3 is a compound with the structure shown in Formula 5.

[0086] Example 1

[0087] Add 100 g of SM-1 (1-chloro-7-methoxy-1,2,3,4-tetrahydronaphthalene) and 300 mL of DMF to a 1000 mL reaction flask. While stirring, add 105 g of potassium carbonate and 56 g of SM-2 (methyl cyanoacetate). Heat to 100 °C and keep the reaction at this temperature for 5 hours. After TLC detection (developing agent volume ratio: petroleum ether: ethyl acetate = 4:1), react until complete (the spot of 1-chloro-7-methoxy-1,2,3,4-tetrahydronaphthalene disappears). Cool to room temperature and filter. The filtrate is the DMF solution of AG-1, which is directly used for the next reaction.

[0088] Add the above DMF solution of AG-1 to a 1000 mL reaction flask. While stirring, dropwise add 150 mL of concentrated hydrochloric acid (mass percentage content is 37%). The molar ratio of AG-1 to HCl in hydrochloric acid is 1:3.4. Heat to 95 °C and react, keep the reaction at this temperature for 2 hours. After TLC detection (developing agent volume ratio: petroleum ether: ethyl acetate = 4:1), react until complete (the spot of AG-1 disappears). Cool to room temperature and pour the reaction solution into 600 mL of ice water. Extract twice with dichloromethane, 300 mL each time. Concentrate the dichloromethane layer under reduced pressure to dryness to obtain 105.3 g of an oily substance, AG-2, which is directly used for the next reaction. The overall yield of the two steps is 96.0%.

[0089] The mass spectrum of AG-2 is as Figure 1 : 202.1 [M+H]+.

[0090] Add 3 L of saturated ammonia methanol solution, 100 g of AG-2, 57 g of cyclohexene, 10 g of 5% palladium carbon, and 10 g of Raney nickel to a 5 L high-pressure hydrogenation reactor. React at 70 °C for 3 hours, then react at a hydrogen pressure of 3.0 Mpa for 12 hours. Cool to room temperature, filter to remove the catalyst, and concentrate the filtrate under reduced pressure to dryness to obtain an oily substance;

[0091] Add the above-mentioned oily substance and 200 mL of ethanol to a 500-mL reaction flask. Control the temperature at 30 °C, adjust the pH to 2 with concentrated hydrochloric acid (mass percentage content is 37%), cool down to 5 °C for crystallization for 5 hours, perform suction filtration, and dry to obtain 99.2 g of AG-3 solid with a yield of 90.0%.

[0092] The NMR spectrum of the AG-3 product is as Figure 2 shown, and the NMR data are as follows: 1 H-NMR(500MHz,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).

[0093] Add 50 g of AG-3 and 500 mL of dichloromethane to a 1000-mL reaction flask. Cool down to 0 °C, control the temperature not exceeding 5 °C, add dropwise 32 g of triethylamine and 25.8 g of acetic anhydride, keep the temperature for reaction for 2 hours, perform TLC detection (developer volume ratio: dichloromethane: methanol = 10:1) until the reaction is complete (the spot of AG-3 disappears), wash once with 100 mL of water, wash once with 100 mL of saturated sodium bicarbonate aqueous solution, wash 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 and stir at room temperature for 1 hour, perform suction filtration, and dry to obtain 50 g of white solid agomelatine with a yield of 97.5%.

[0094] The NMR spectrum of the agomelatine product is as Figure 3 shown, and the NMR data are as follows: 1 H-NMR(500MHz,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).

[0095] The purity detection spectrum of agomelatine is as Figure 4 , and the data information is shown in Table 1, with the liquid phase purity of 99.918%.

[0096] Table 1 Purity Detection Data of Agomelatine

[0097] Detector A 275 nm

[0098] Peak No. Retention Time Compound Name Area Height Theoretical Plate Number Tailing Factor Resolution Area % Label 1 6.005 293 26 6324 1.083 -- 0.003 2 6.917 110 16 25404 1.281 3.834 0.001 3 7.203 1401 132 10936 1.627 1.273 0.016 4 7.916 981 81 8834 1.175 2.330 0.011 5 10.192 8671224 457771 6283 2.511 5.348 99.918 6 13.757 547 34 14307 1.211 7.316 0.006 7 16.489 2121 120 18856 0.997 5.811 0.024 8 18.641 1324 73 24105 1.088 4.481 0.015 9 26.965 352 20 52765 1.044 17.528 0.004 Total 8678353 458273 100.000

[0099] The synthesis method provided by the present invention enables continuous production of AG-2, improves the equipment utilization rate. The aromatization and reduction are carried out by a one-step method, which simplifies the operation, increases the reaction yield, reduces the three wastes, and is suitable for industrial production.

[0100] Example 2

[0101] The preparation method is basically the same as that of Example 1, except that 1-chloro-7-methoxy-1,2,3,4-tetrahydronaphthalene is replaced by 1-bromo-7-methoxy-1,2,3,4-tetrahydronaphthalene.

[0102] Example 3

[0103] The preparation method is basically the same as that of Example 1, except that 1-chloro-7-methoxy-1,2,3,4-tetrahydronaphthalene is replaced by 1-iodo-7-methoxy-1,2,3,4-tetrahydronaphthalene.

[0104] Example 4

[0105] The preparation method is basically the same as that of Example 1, except that methyl cyanoacetate is replaced by ethyl cyanoacetate.

[0106] 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 of them. Other embodiments can be obtained based on these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for synthesizing agomelatine, characterized in that, It includes the following steps: Mix the compound of the structure shown in Formula 1, an organic solvent, a first base reagent, and the compound of the structure shown in Formula 2 for a condensation reaction, and perform solid-liquid separation to obtain an organic solution of the compound of the structure shown in Formula 3; X in Formula 1 is a halogen, and R in Formula 2 is a C1-C6 alkyl group; Mix the organic solution of the compound of the structure shown in Formula 3 and an acid solution for a decarboxylation reaction to obtain the compound of the structure shown in Formula 4; Mix an ammonia methanol solution, the compound of the structure shown in Formula 4, an aromatization assistant, a palladium catalyst, and a nickel catalyst for an aromatization reaction, and perform a reduction reaction on the obtained aromatization reaction solution in a hydrogen atmosphere to obtain the compound of the structure shown in Formula 5. The palladium catalyst is palladium on carbon, the nickel catalyst is Raney nickel, and the aromatization assistant is cyclohexene and / or ethylene; Mix the compound of the structure shown in Formula 5, an organic solvent, a second base reagent, and an amidation reagent for an acetylation reaction to obtain the agomelatine.

2. The synthesis method according to claim 1, characterized in that, X in Formula 1 is chlorine, bromine or iodine, and R in Formula 2 is methyl or ethyl; The first base reagent is potassium carbonate; The molar ratio of the compound of the structure shown in Formula 1 to the compound of the structure shown in Formula 2 is 1:0.8 - 1.5; The molar ratio of the compound of the structure shown in Formula 1 to the first base reagent is 1:0.5 - 2.

0.

3. The synthesis method according to claim 1 or 2, characterized in that, The temperature of the condensation reaction is 50 - 150 °C.

4. The synthesis method according to claim 1, characterized in that, The acid solution is a hydrochloric acid solution, and the mass percentage content of the hydrochloric acid solution is 35 - 37%; The molar ratio of the compound of the structure shown in Formula 3 to the acid in the acid solution is 1:1 - 10.

5. The synthesis method according to claim 1 or 4, characterized in that, The temperature of the decarboxylation reaction is 50 - 150 °C.

6. The synthesis method according to claim 1, characterized in that, The mass percentage content of palladium in the palladium on carbon is 5%.

7. The synthesis method according to claim 1 or 6, characterized in that, The mass ratio of the compound of the structure shown in Formula 4 to the aromatization assistant is 1:0.4 - 1.0; The mass ratio of the compound of the structure shown in Formula 4 to the palladium catalyst is 1:0.05 - 0.15; The mass ratio of the compound of the structure shown in Formula 4 to the nickel catalyst is 1:0.05 - 0.

15.

8. The synthesis 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 - 5 Mpa, and the time of the reduction reaction is 5 - 24 h.

9. The synthesis method according to claim 1, wherein, 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; The molar ratio of the compound of the structure shown in Formula 5 to the second base reagent is 1.0:0.8 - 3.0; The molar ratio of the compound of the structure shown in Formula 5 to the amidation reagent is 1.0:0.8 - 1.

5.

10. The synthesis method according to claim 1 or 9, characterized in that, The temperature of the acetylation reaction is -20 - 30 °C.

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