A method for preparing agomelatine

Abstract

This invention relates to a method for preparing agomelatine, belonging to the field of pharmaceutical synthesis technology. To address the problems of long, unsafe, and low-yield existing routes, this invention provides a method for preparing agomelatine, comprising: reacting a compound of formula 8 with acetic anhydride to obtain the final product, compound 1 (agomelatine); further comprising reacting a compound of formula 4 with dimethyl sulfate in a mixed solvent of alcohol and water in the presence of an alkali metal hydroxide to obtain compound 5; subjecting compound 5 to hydrogenation reduction under the catalysis of borohydride to obtain compound 6; reacting compound 6 with benzylamine under the action of potassium tert-butoxide to obtain compound 7; and subjecting compound 7 to catalytic hydrogenation reduction under the catalysis of a palladium-containing catalyst to obtain compound 8. This invention features simple post-processing, easier recovery of the palladium catalyst, and high product yield, effectively improving reaction efficiency and safety.

Description

Technical Field

[0001] This invention relates to a method for preparing agomelatine, belonging to the field of pharmaceutical synthesis technology. Background Technology

[0002] Agomelatine, chemically named N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide, is a novel hypnotic drug. Its main mechanism of action is to stimulate the pineal gland to secrete melatonin while inhibiting the inhibitory effect of serotonin on the brain. This allows it to both promote sleep and combat depression, with fewer side effects and good drug tolerance. Clinically, it is primarily used to treat adult depression. Its structural formula is as follows:

[0003]

[0004] The representative synthetic routes for agomelatine disclosed in existing literature mainly include the following: One route reported in existing literature uses 7-methoxy-1-naphthone as the starting material, undergoes a condensation reaction with ethyl 2-bromoacetate, followed by sulfur dehydrogenation aromatization, saponification, acylation, amination, and dehydration to obtain the key intermediate 7-methoxy-1-naphthylacetonitrile, which is then reduced with Raney nickel to obtain the intermediate 7-methoxy-1-naphthylethylamine, and finally acetylated to obtain the final product agomelatine. This synthetic route is as follows:

[0005]

[0006] However, this route involves many reaction steps and has a low overall reaction yield. In addition, the aromatization reaction in the process requires high temperature, and the cyano reduction requires Raney Ni catalyst, which has high safety requirements and is not conducive to industrial production.

[0007] For example, European patent application (publication number EP2562151A) reports a synthesis using inexpensive β-naphthol as a starting material. The process involves acetylation, α-chloroacetylation, ketone carbonyl reduction, phenolic hydroxyl methylation, reaction with potassium phthalimide, and then reaction with hydrazine hydrate to obtain the intermediate 7-methoxy-1-naphthylethylamine. Finally, acetylation yields the final product agomelatine. The reaction route for this synthesis is as follows:

[0008]

[0009] Although the use of β-naphthol as the starting material in this synthesis route has the advantage of readily available raw materials, the route employs highly toxic hydrazine hydrate and a highly corrosive and irritating catalytic system of titanium tetrachloride and triethylsilane during the synthesis process. This results in high safety requirements and makes it unsuitable for industrial production. Summary of the Invention

[0010] To address the problems existing in the prior art, this invention provides a method for preparing agomelatine, which solves the problem of how to provide a new route that is safer and has a higher product yield.

[0011] The objective of this invention is achieved through the following technical solution: a method for preparing agomelatine, which includes reacting a compound of formula 8 with acetic anhydride to obtain the final product, compound of formula 1, agomelatine.

[0012]

[0013] The method is characterized by further comprising the following steps:

[0014] A. In the presence of alkali metal hydroxides, compound 4 is reacted with dimethyl sulfate in a mixed solvent of alcohol solvent 1 and water to obtain compound 5.

[0015]

[0016] B. The compound of formula 5 is subjected to a catalytic reduction reaction under the catalysis of borohydride to obtain the compound of formula 6;

[0017]

[0018] C. Under the action of potassium tert-butoxide, the compound of formula 6 is reacted with benzylamine to obtain the compound of formula 7;

[0019]

[0020] D. Under the catalytic action of a palladium-containing catalyst, compound 7 undergoes a catalytic hydrogenation reduction reaction to obtain compound 8;

[0021]

[0022] This invention improves the synthetic route by first reacting the ester group in compound 4 with dimethyl sulfate in the presence of a base to form the corresponding methoxy group. This avoids the drawback of requiring a highly corrosive catalytic system such as titanium tetrachloride for carbonyl reduction in this step. Using the improved route, only hydrogenation reduction with borohydride is needed to reduce the carbonyl group in the corresponding compound 5 to a hydroxyl group to form compound 6. After reacting this hydroxyl group with benzylamine to obtain an intermediate, the double bond and benzyl group in compound 7 can be reduced in one step using a palladium-containing catalyst to obtain agomaline. The key intermediate of latine is compound 8 or its acid salt, such as hydrochloride. The use of palladium on carbon offers advantages such as mild reaction conditions, simple post-processing, and easier recovery of the palladium catalyst. It not only has the advantages of high product yield but also low cost. At the same time, due to the improvement of the reaction route, the intermediate compound 7 is formed during the reaction, which effectively avoids the use of dichlorocyanobenzene with aromatizing reagents and eliminates the need for hydrogenation reduction of cyano groups using Raney nickel, which has strict safety requirements. This more effectively improves the efficiency and safety of the reaction and provides a new synthetic route while ensuring the yield and quality of intermediates and products.

[0023] In the above-described method for preparing agomelatine, preferably, the alkali metal hydroxide in step A is selected from one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide; the alcohol solvent is selected from C1-C4 lower alcohol solvents. The reaction is more efficient under the action of the alkali metal hydroxide, allowing the ester group in compound 4 to react with dimethyl sulfate to form a methoxy group, and resulting in a high yield of the intermediate product. The use of a mixed system of alcohol solvent and water allows for a gentler reaction. The lower alcohol solvent can be methanol, ethanol, propanol, butanol, or isopropanol, etc.

[0024] In the reaction process of step A above, after the reaction is completed, post-treatment can be performed as needed to remove solvents, etc., to obtain the corresponding intermediate compound of formula 5. As a further preferred embodiment, after the reaction in step A is completed, an acid (such as hydrochloric acid or dilute sulfuric acid, an inorganic acid solution) is added to the reaction solution to adjust the pH of the system to neutral, and then the alcohol solvent is removed by vacuum concentration. Then, an insoluble solvent is added to the residue for extraction. After the organic layer is washed with water, the solvent is removed by distillation to dryness to obtain the corresponding intermediate compound of formula 5. The insoluble solvent mentioned above is preferably dichloromethane or ethyl acetate, etc.

[0025] In step A above, the amounts of raw materials used can be adjusted appropriately to ensure a more complete reaction and reduce waste. More preferably, the molar ratio of the compound of formula 4 to dimethyl sulfate in step A is 1:1.2–1.5, which improves the conversion rate of the raw materials, increases the yield and quality of the intermediate product, and further reduces waste. The alcohol solvent used in the reaction can be any amount generally required in the art. More specifically, the molar ratio of the compound of formula 4 to the alkali metal hydroxide is preferably 1:1.1–1.3.

[0026] In the above-described method for preparing agomelatine, preferably, the borohydride in step B is selected from one or more of potassium borohydride, sodium borohydride, and lithium borohydride. Because this invention first reacts the ester bond to form a methoxy group, the hydrogenation reduction of the carbonyl group is easier to perform. Only the catalytic hydrogenation reduction using borohydride is needed to convert the carbonyl group to hydrogen to form the corresponding hydroxyl group, and the reaction conversion rate is high. It also avoids the use of highly corrosive catalysts such as titanium tetrachloride for reduction, which is beneficial for safe production. As a further preferred embodiment, the molar ratio of the compound of formula 5 to the borohydride in step B is 1:1.1 to 1.5.

[0027] In the above-described method for preparing agomelatine, the reaction in step B is generally carried out in an organic solvent, which allows for a gentler reaction. The amount of organic solvent used can be any amount commonly used in the art. As a further preferred embodiment, the reaction in step B is carried out in an ether solvent selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane (1,4-dioxane), and the temperature of the catalytic reduction reaction is 40°C to 60°C.

[0028] As a further preferred option, after the reaction described in step B is completed, acid is added to the reaction solution for quenching, followed by distillation to remove the solvent. Then, a mixture of a non-water-soluble organic solvent and water is added for extraction. The resulting organic phase is then distilled to remove the solvent, yielding the intermediate compound of formula 6. Quenching with acid, such as hydrochloric acid or dilute sulfuric acid solution, helps to better ensure the quality of the intermediate product and reduce the generation of other impurities. The aforementioned non-water-soluble organic solvent, such as ethyl acetate, dichloromethane, or chloroform, can be used for extraction. Extraction treatment can better remove soluble impurities and improve the purity and quality of the intermediate product.

[0029] In the above-described method for preparing agomelatine, preferably, the palladium-containing catalyst in step D is selected from palladium hydroxide catalyst or palladium-carbon catalyst containing 5% to 10% palladium by mass. Because the reaction of compound 6 with benzylamine followed by a reduction reaction allows for a more efficient reaction, eliminating the need for catalysts such as Raney nickel, and more importantly, this invention, through catalytic hydrogenation using a palladium-containing catalyst, can directly reduce and remove the double bond and corresponding benzyl group in compound 7 to obtain the corresponding compound 8. This method offers advantages such as mild reaction conditions, high yield of intermediate products, simple post-processing, and the ability to recycle and reuse the palladium-containing catalyst, resulting in less waste and making it more suitable for industrial production.

[0030] In the above-described method for preparing agomelatine, preferably, the catalytic hydrogenation reduction reaction in step D is carried out in alcohol solvent two, wherein alcohol solvent two is selected from one or more of methanol, ethanol, propanol, and isopropanol. Carrying the catalytic hydrogenation reaction in alcohol solvent two allows for a gentler hydrogenation process. The terms alcohol solvent one and alcohol solvent two are used merely for better description and clarity of context, and are not intended to limit the description of alcohol solvents.

[0031] In the catalytic hydrogenation reaction in step D above, it is best to introduce hydrogen gas and control the reaction pressure at 0.5 MPa to 0.6 MPa to make the hydrogenation more efficient and improve the product yield. This also allows the compound of formula 8 to form its corresponding acid salt form, such as the hydrochloride salt of formula 8. More preferably, after the catalytic hydrogenation reaction in step D is completed, the alcohol solvent in the reaction solution is concentrated to remove it, and then an organic solvent capable of dissolving the compound of formula 8 is added. Hydrochloric acid solution is then added to carry out a salt-forming reaction to obtain the corresponding hydrochloride salt of formula 8. The organic solvent capable of dissolving the compound of formula 8 can be selected from dichloromethane, chloroform, and ethyl acetate, but is not limited to those listed above. Dissolving the compound of formula 8 in this way is to better facilitate its reaction with acids such as hydrochloric acid to form an acid salt. Furthermore, it is best to control the temperature of the above salt-forming reaction at 0 to 10°C.

[0032] In the above-described method for preparing agomelatine, preferably, the reaction temperature in step C is 20°C to 40°C. The reaction between compound 6 and benzylamine proceeds gently under the action of potassium tert-butoxide, and the reaction temperature is easily controlled, which is beneficial for production operations. More preferably, the molar ratio of compound 6:potassium tert-butoxide:benzylamine in step C is 1:1.1–1.3:1.1–1.6.

[0033] In the above-described method for preparing agomelatine, preferably, the reaction in step C is carried out in an ether solvent such as THF. Other ether solvents may include 2-methyltetrahydrofuran, dioxane, etc. It is best to carry out the reaction under an inert gas atmosphere, such as nitrogen. More preferably, after the reaction is complete, the organic solvent is removed by distillation, and then a non-water-soluble organic solvent such as ethyl acetate, dichloromethane, chloroform, or toluene is added to the residue for extraction. After standing and separating the layers, the organic layer is collected, and the solvent is removed by distillation to obtain the corresponding intermediate product.

[0034] In the above-mentioned method for preparing agomelatine, preferably, the reaction temperature in step A is 0℃~10℃; and the temperature of the catalytic hydrogenation reduction reaction in step D is 20℃~30℃.

[0035] In the above-described method for preparing agomelatine, preferably, the compound of formula 4 described in step A is synthesized through the following steps:

[0036] The compound of formula 4 described in step A is synthesized through the following steps:

[0037] a. In the presence of an alkaline reagent, β-naphthol of Formula 2 is esterified with acetic anhydride in a non-water-soluble organic solvent to obtain compound 3.

[0038]

[0039] b. Under the catalysis of Lewis acid, the compound of formula 3 is reacted with chloroacetyl chloride to obtain the compound of formula 4;

[0040]

[0041] In the above-described method for preparing agomelatine, preferably, the alkaline reagent is selected from one or more of triethylamine, sodium carbonate, and potassium carbonate; the non-water-soluble organic solvent is selected from one or more of dichloromethane, chloroform, and ethyl acetate; and the Lewis acid is selected from aluminum trichloride.

[0042] As a further preferred embodiment, it is preferable that the molar ratio of the compound of formula 2 to acetic anhydride is 1:1.1 to 1.3, and the molar ratio of the compound of formula 2 to the basic reagent is 1:1.1 to 1.3. Further preferably, the temperature of the esterification reaction is controlled at 20°C to 30°C.

[0043] As a further preferred embodiment, the molar ratio of the compound of formula 3: chloroacetyl chloride: Lewis acid is 1:1.1–1.3:1.3–1.5. By appropriately controlling the amount of each raw material, the utilization rate of the raw materials can be better improved, the conversion rate can be increased, and unnecessary impurities can be avoided, thus ensuring the quality of the product. It is best to control the reaction temperature between -30℃ and -10℃.

[0044] In the above-mentioned method for preparing agomelatine, as a preferred embodiment, the specific method for synthesizing agomelatine by reacting the hydrochloride salt of the compound of formula 8 with acetic anhydride is as follows:

[0045] In the presence of an acid-binding agent, the hydrochloride salt of compound 8 is reacted with acetic anhydride in an organic solvent to give compound 1, agomelatine. The reaction is preferably carried out at temperatures between 0°C and 10°C.

[0046] The preparation route of agomelatine in this invention can be represented by the following reaction equation:

[0047]

[0048] In summary, compared with the prior art, the present invention has the following advantages:

[0049] 1. By improving the synthetic route, the ester bond group in compound 4 is first reacted with dimethyl sulfate in the presence of a base to form the corresponding methoxy group. This avoids the defect of requiring a strongly corrosive catalytic system for carbonyl reduction in this step, effectively avoiding the use of titanium tetrachloride, etc. With the action of a palladium-containing catalyst, the double bond and benzyl group in compound 7 can be reduced together to obtain compound 8, the key intermediate of agomelatine, or its acid salt such as hydrochloride. Moreover, the use of palladium-containing catalysts such as palladium on carbon makes the reaction conditions mild, and the post-processing is simple and easier to recover the palladium catalyst. It not only has the advantages of high product yield but also low cost.

[0050] 2. This invention effectively avoids the use of dichlorocyanobenzene with aromatizing reagents, and also eliminates the need for methods such as hydrogenation reduction of cyano groups using Raney nickel, which has high safety requirements. This more effectively improves the efficiency and safety of the reaction, and provides a new synthetic route while ensuring the yield and quality of intermediates and products. Detailed Implementation

[0051] The technical solution of the present invention will be further described in detail below through specific embodiments, but the present invention is not limited to these embodiments.

[0052] Example 1

[0053] Synthesis of compound 3:

[0054]

[0055] 100 g (0.69 mol) of β-naphthol, 77.20 g (0.76 mol) of triethylamine, and 450 g of dichloromethane were added to a 1 L clean reaction flask. The mixture was stirred at 20 °C–25 °C for 30 min, then cooled to 0–5 °C. Acetic anhydride 78.30 g (0.76 mol) was slowly added dropwise to the reaction vessel while controlling the temperature. The addition was carried out over approximately 1.5 h. After the addition was completed, the reaction was stirred at 0–5 °C for another 1 h. Then the reaction temperature was increased. The mixture was stirred at 20℃~25℃ for another 1 hour. After the reaction was complete, 300g of water was added to the reaction solution, and the mixture was stirred at 20℃~25℃ for 15 minutes. The mixture was allowed to stand and separate into layers. The collected organic layer was washed successively with 300g of 5% sodium carbonate aqueous solution and 300g of water. The collected organic layer was concentrated under reduced pressure to dryness to obtain 124.2g of pale yellow intermediate product, which is the corresponding compound of formula 3, with a yield of 96.16% and a purity of 99.34%.

[0056] Example 2

[0057] Synthesis of compound 4:

[0058]

[0059] 120 g (0.64 mol) of compound 3 and 1200 g of dichloromethane were added to a 2 L reaction flask and stirred at 20 °C–25 °C for 20 min. The mixture was then cooled to 0 °C–5 °C. 125 g (0.94 mol) of aluminum trichloride was added in portions to the reaction solution, and the mixture was stirred for 20 min. The mixture was then cooled to -25 °C–-20 °C, and 87 g (0.77 mol) of chloroacetyl chloride was slowly added dropwise over 1.5 h. The mixture was kept at -25 °C–-20 °C for 4 h. Samples were taken for analysis. After the reaction was complete, 500 g of 5% hydrochloric acid solution was slowly added dropwise over approximately 1 h. The mixture was stirred after the addition was complete. After 5 minutes of settling, the organic layer was allowed to separate into layers. The collected organic layer was washed successively with 500 g of water, 300 g of saturated sodium bicarbonate aqueous solution, and 300 g of water. The organic layer was then concentrated to dryness. 960 g of methanol was added to the residue, and the mixture was heated to 60℃~65℃ and stirred until the solution became clear. The mixture was kept at this temperature and stirred for 1 hour, then slowly cooled to 10℃~15℃ and stirred for 2 hours to allow crystallization. The solution was filtered, washed with 100 g of methanol, and the resulting solid wet product was dried under vacuum to obtain 98.5 g of the dry pale yellow intermediate product, compound 4, with a yield of 58.19% and a purity of 98.59%.

[0060] Example 3

[0061] Synthesis of Compound Formula 5

[0062]

[0063] 80 g (0.31 mol) of compound 4, 14 g (0.35 mol) of sodium hydroxide, 300 g of methanol, and 100 g of water were added to a 1 L reaction flask. The mixture was stirred at room temperature for 4 h, then cooled to 0 °C–5 °C. 50 g (0.4 mol) of dimethyl sulfate was slowly added dropwise over approximately 1 h. After the addition was complete, the temperature was maintained at 0 °C–5 °C for 2 h. After the reaction was complete, the pH was adjusted to neutral with 5% hydrochloric acid solution, and then concentrated under reduced pressure to remove most of the methanol solvent. Then, 200 g of dichloromethane (DCM) was added at room temperature, and the mixture was stirred for 20 min. The mixture was allowed to stand and separate into layers. The collected organic layer was washed twice with 150 g of water each time. The organic layer was then concentrated to dryness to remove the solvent, yielding 65.20 g of a pale yellow oily substance, namely compound 5, with a yield of 91.23% and a purity of 97.54%.

[0064] Example 4

[0065] Synthesis of Compound Formula 6

[0066]

[0067] 50 g (0.21 mol) of compound 5 and 250 g of THF were added to a 0.5 L reaction flask and stirred at room temperature for 20 min until homogeneous. Then, 9.53 g (0.25 mol) of sodium borohydride was added, and the temperature was raised to 50℃~55℃ and maintained for 2 h. After the reaction was complete, 47.5 g (0.25 mol) of 5% hydrochloric acid aqueous solution was added to the reaction solution to quench the reaction. Then, THF was removed by vacuum distillation to obtain crude residue. 150 g of ethyl acetate and 150 g of water were added to the residue, and the mixture was stirred for 20 min. After standing and separating the layers, the organic layer was washed once with 150 g of water. The organic layer was then distilled under vacuum to remove the organic solvent, yielding 47.5 g of a pale yellow oily substance, which is compound 6, with a yield of 94.19% and a purity of 98.25%.

[0068] Example 5

[0069] Synthesis of Compound Formula 7

[0070]

[0071] 35.40 g (0.15 mol) of compound 6, 20.20 g (0.18 mol) of potassium tert-butoxide, 18.50 g (0.17 mol) of benzylamine, and 140 g of THF were added to a 0.5 L reaction flask. The mixture was purged with nitrogen three times and kept at 20 °C–25 °C for 1 h. Then, 100 g of water was added, and the organic solvent was removed by vacuum distillation. 100 g of ethyl acetate was added to the residue, and the mixture was stirred for 10 min. The mixture was allowed to stand and separate into layers. The collected organic layer was washed once with 100 g of water, and the organic solvent was removed by vacuum distillation, yielding 46.89 g of a pale yellow liquid. The liquid was allowed to stand overnight, and white crystals precipitated. The liquid was filtered, and the filter cake was collected and dried under vacuum to obtain 36.8 g of white granular crystals, which is compound 7. The yield was 85.03% and the purity was 98.32%.

[0072] Example 6

[0073] Synthesis of Compound Formula 8 Hydrochloride (2-(7-ethoxynaphthyl)ethylamine Hydrochloride)

[0074]

[0075] 20 g (0.07 mol) of compound 7 (Formula 7), 2.0 g of 5% Pd-C catalyst, and 70 g of methanol were added to a stainless steel autoclave. Air was replaced with nitrogen, followed by hydrogen to replace the nitrogen. The catalytic hydrogenation reaction was carried out at 20°C–25°C with the hydrogen pressure controlled at 0.5–0.6 MPa for 16 hours. After passing the intermediate control, the mixture was filtered, washed with 20 g of methanol to recover the Pd-C catalyst, and the filtrate was concentrated under reduced pressure to remove the solvent until dry. 70 g of dichloromethane and 7.2 g of concentrated hydrochloric acid were added to the residue, and the mixture was stirred at 0–5°C for 1 hour. The mixture was filtered, the filter cake was washed with dichloromethane, and dried under vacuum to obtain 15.56 g of the hydrochloride salt of compound 8 (2-(7-ethoxynaphthyl)ethylamine hydrochloride), a light yellow to off-white powder with a purity of 98.55% and a yield of 94.70%.

[0076] Example 7

[0077] Synthesis of agomelatine

[0078]

[0079] 15 g (0.063 mol) of 2-(7-methoxy-1-catechyl)ethylamine hydrochloride, 100 g of dichloromethane, and 10.5 g (0.07 mol) of anhydrous potassium carbonate were added to a reaction flask. The mixture was stirred and cooled to 0–5 °C. 4.0 g (0.067 mol) of acetic anhydride was slowly added dropwise, maintaining the temperature at 0–5 °C. After the addition was complete, the temperature was maintained at 0–5 °C for 1 hour. After the reaction was deemed satisfactory, 60 g of water was added dropwise to the reaction solution, and the mixture was stirred for 10 minutes. The mixture separated into layers, and the collected organic layer was washed three times with 60 g of water. The organic layer was then concentrated to dryness. 50 g of toluene and 0.3 g of activated carbon were added to the residue, and the mixture was heated to 60–65 °C and maintained for 30 minutes. Then, the mixture was slowly cooled to -10 °C to -5 °C and maintained for 2 hours. The mixture was filtered and dried to obtain 13.54 g of agomelatine, a white solid powder with a yield of 88.20% and a purity of 99.5%.

[0080] Example 8

[0081] Synthesis of Compound Formula 5

[0082] 80 g (0.31 mol) of compound 4, 16 g (0.4 mol) of sodium hydroxide, 350 g of ethanol, and 130 g of water were added to a 1 L reaction flask. The mixture was stirred at room temperature for 4 h, then cooled to 0 °C–5 °C. 58.6 g (0.47 mol) of dimethyl sulfate was slowly added dropwise over approximately 1.5 h. After the addition was complete, the temperature was maintained at 0 °C–5 °C for 2 h. After the reaction was complete, the pH was adjusted to neutral with 5% hydrochloric acid solution, and then concentrated under reduced pressure to remove most of the ethanol solvent. Then, 200 g of dichloromethane (DCM) was added at room temperature, and the mixture was stirred for 20 min. The mixture was allowed to stand and separate into layers. The collected organic layer was washed twice with 150 g of water each time. The organic layer was then concentrated to dryness to remove the solvent, yielding 65.96 g of a pale yellow oily substance, the corresponding compound 5, with a yield of 92.3% and a purity of 97.8%.

[0083] Example 9

[0084] Synthesis of Compound Formula 6

[0085] 50 g (0.21 mol) of compound 5 and 250 g of THF were added to a 0.5 L reaction flask and stirred at room temperature for 20 min until homogeneous. Then, 12.2 g (0.32 mol) of sodium borohydride was added, and the temperature was raised to 50℃~55℃ and maintained for 2 h. After the reaction was complete, 49 g of 5% hydrochloric acid aqueous solution was added to the reaction solution to quench the reaction. Then, THF was removed by vacuum distillation to obtain crude residue. 150 g of ethyl acetate and 150 g of water were added to the residue, and the mixture was stirred for 20 min. After standing and separating the layers, the collected organic layer was washed once with 150 g of water. The organic layer was then distilled under reduced pressure to remove the organic solvent, yielding 47.3 g of a pale yellow oily substance, which is compound 6, with a yield of 93.8% and a purity of 98.1%.

[0086] Example 10

[0087] Synthesis of Compound Formula 7

[0088] 35.40 g (0.15 mol) of compound 6, 22.44 g (0.18 mol) of potassium tert-butoxide, 26.12 g (0.24 mol) of benzylamine, and 140 g of THF were added to a 0.5 L reaction flask. The mixture was purged with nitrogen three times and kept at 20 °C–25 °C for 1 h. Then, 100 g of water was added, and the organic solvent was removed by vacuum distillation. 100 g of ethyl acetate was added to the residue, and the mixture was stirred for 10 min. The mixture was allowed to stand and separate into layers. The collected organic layer was washed once with 100 g of water, and the organic solvent was removed by vacuum distillation to obtain a pale yellow liquid. The liquid was allowed to stand overnight, and white crystals precipitated. The liquid was filtered, and the filter cake was collected and dried under vacuum to obtain 37.35 g of white granular crystals of compound 7, with a yield of 86.3% and a purity of 98.43%.

[0089] Example 11

[0090] Synthesis of Compound Formula 8 Hydrochloride (2-(7-ethoxynaphthyl)ethylamine Hydrochloride)

[0091] 20 g (0.07 mol) of compound 7 (Formula 7), 2.2 g of 5% Pd-C catalyst, and 70 g of methanol were added to a stainless steel autoclave. Air was replaced with nitrogen, followed by hydrogen to replace the nitrogen. The catalytic hydrogenation reaction was carried out at 20°C–25°C with the hydrogen pressure controlled at 0.5–0.6 MPa for 16 hours. After passing the intermediate control, the mixture was filtered, washed with 20 g of methanol to recover the Pd-C catalyst, and the filtrate was concentrated under reduced pressure to remove the solvent until dry. 70 g of dichloromethane and 8.0 g of concentrated hydrochloric acid were added to the residue, and the mixture was stirred at 0–5°C for 1 hour. The mixture was filtered, the filter cake was washed with dichloromethane, and dried under vacuum to obtain 15.64 g of the hydrochloride salt of compound 8 (2-(7-ethoxynaphthyl)ethylamine hydrochloride), a light yellow to off-white powder with a purity of 98.6% and a yield of 95.2%.

[0092] Example 12

[0093] Synthesis of agomelatine

[0094] 15 g (0.063 mol) of 2-(7-methoxy-1-catechyl)ethylamine hydrochloride, 100 g of dichloromethane, and 12 g of anhydrous potassium carbonate were added to a reaction flask. The mixture was stirred and cooled to 0–5 °C. 4.5 g (0.075 mol) of acetic anhydride was slowly added dropwise, maintaining the temperature at 0–5 °C. After the addition was complete, the reaction was maintained at 0–5 °C for 1 hour. After the reaction was deemed satisfactory, 70 g of water was added dropwise to the reaction solution, and the mixture was stirred for 10 minutes. The mixture separated into layers, and the collected organic layer was washed three times with 60 g of water. The organic layer was then concentrated to dryness. 50 g of toluene and 0.5 g of activated carbon were added to the residue, and the mixture was heated to 60–65 °C and maintained for 30 minutes. Then, the mixture was slowly cooled to -10 °C to -5 °C and maintained for 2 hours. The mixture was filtered and dried to obtain 13.45 g of agomelatine, a white solid powder with a yield of 87.6% and a purity of 99.6%.

[0095] Example 13

[0096] Synthesis of compound 3:

[0097] 100 g (0.69 mol) of β-naphthol, 79 g of triethylamine, and 500 g of dichloromethane were added to a 1 L clean reaction flask and stirred at 20 °C–25 °C for 30 min. The mixture was then cooled to 0–5 °C, and 91.8 g (0.9 mol) of acetic anhydride was slowly added dropwise over approximately 2.0 h. After the addition was complete, the reaction was stirred at 0–5 °C for 1 h. The temperature was then increased to 20 °C–25 °C, and stirring was continued at this temperature for another 1 h. After the reaction was complete, 300 g of water was added to the reaction mixture, and the mixture was stirred at 20 °C–25 °C for 15 min. The mixture was allowed to stand and separate into layers. The collected organic layer was washed successively with 300 g of 5% sodium carbonate aqueous solution and 300 g of water. The collected organic layer was concentrated under reduced pressure to dryness to obtain 123.7 g of a pale yellow intermediate product, the corresponding compound of formula 3, with a yield of 95.8% and a purity of 99.5%.

[0098] 120 g (0.64 mol) of compound 3 and 1200 g of dichloromethane were added to a 2 L reaction flask and stirred at 20 °C–25 °C for 20 min. The mixture was then cooled to 0 °C–5 °C. 111 g (0.83 mol) of aluminum trichloride was added in portions to the reaction solution, and the mixture was stirred for 20 min. The mixture was then cooled to -22 °C–-20 °C, and 93.7 g (0.83 mol) of chloroacetyl chloride was slowly added dropwise over 1.5 h. The mixture was kept at -22 °C–-20 °C for 3.5 h. Samples were taken for analysis. After the reaction was complete, 480 g of 5% hydrochloric acid solution was slowly added dropwise over approximately 1 h. Stir for 15 minutes, allow to stand and separate into layers. Wash the collected organic layer successively with 500g of water, 300g of saturated sodium bicarbonate aqueous solution, and 300g of water. Concentrate the organic layer to dryness. Add 960g of methanol to the residue, then heat to 60℃~65℃ and stir until the solution is clear. Maintain the temperature and stir for 1 hour, then slowly cool to 10℃~15℃ and stir for 2 hours to allow crystallization. Filter and wash with 100g of methanol. Dry the obtained solid wet product under vacuum to obtain 100g of the dry pale yellow intermediate product, compound 4, with a yield of 59.1% and a purity of 98.45%.

[0099] The specific embodiments described in this invention are merely illustrative of the spirit of the invention. Those skilled in the art to which this invention pertains can make various modifications or additions to the described specific embodiments or use similar methods to replace them, without departing from the spirit of the invention or exceeding the scope defined by the appended claims.

[0100] Although the present invention has been described in detail and specific embodiments have been cited, it will be apparent to those skilled in the art that various changes or modifications can be made without departing from the spirit and scope of the invention.

Claims

1. A method for preparing agomelatine, the method comprising reacting a compound of formula 8 with acetic anhydride to obtain the final product, compound of formula 1, agomelatine; Its features are, The method also includes the following steps: A. In the presence of alkali metal hydroxides, compound 4 is reacted with dimethyl sulfate in a mixed solvent of alcohol solvent 1 and water to obtain compound 5. B. The compound of formula 5 is subjected to a catalytic reduction reaction under the catalysis of borohydride to obtain the compound of formula 6. C. Under the action of potassium tert-butoxide, the compound of formula 6 is reacted with benzylamine to obtain the compound of formula 7; D. Under the catalytic action of a palladium-containing catalyst, the compound of formula 7 undergoes a catalytic hydrogenation reduction reaction to obtain the compound of formula 8; the palladium-containing catalyst is selected from palladium hydroxide catalyst or palladium-carbon catalyst containing 5% to 10% palladium by mass. 。 2. The method for preparing agomelatine according to claim 1, characterized in that, The alkali metal hydroxide mentioned in step A is selected from one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide; the alcohol solvent is selected from lower alcohol solvents of C1 to C4.

3. The method for preparing agomelatine according to claim 1, characterized in that, The borohydride mentioned in step B is selected from one or more of potassium borohydride, sodium borohydride, and lithium borohydride.

4. The method for preparing agomelatine according to claim 1, characterized in that, The reaction described in step B is carried out in an ether solvent, which is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran and dioxane, and the temperature of the catalytic reduction reaction is 40℃~60℃.

5. The method for preparing agomelatine according to any one of claims 1-4, characterized in that, The catalytic hydrogenation reduction reaction described in step D is carried out in alcohol solvent two, which is selected from one or more of methanol, ethanol, propanol, and isopropanol.

6. The method for preparing agomelatine according to any one of claims 1-4, characterized in that, The reaction temperature in step C is 20℃~40℃.

7. The method for preparing agomelatine according to any one of claims 1-4, characterized in that, The temperature of the reaction in step A is 0℃~10℃; the temperature of the catalytic hydrogenation reduction reaction in step D is 20℃~30℃.

8. The method for preparing agomelatine according to any one of claims 1-4, characterized in that, The compound of formula 4 described in step A is synthesized through the following steps: a. In the presence of an alkaline reagent, β-naphthol of Formula 2 is esterified with acetic anhydride in a non-water-soluble organic solvent to obtain compound 3. b. Under the catalysis of Lewis acid, the compound of formula 3 is reacted with chloroacetyl chloride to obtain the compound of formula 4; 。 9. The method for preparing agomelatine according to claim 8, characterized in that, The alkaline reagent is selected from one or more of triethylamine, sodium carbonate, and potassium carbonate; the non-water-soluble organic solvent is selected from one or more of dichloromethane, chloroform, and ethyl acetate; and the Lewis acid is selected from aluminum trichloride.

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