CN117964510A - Preparation method of agomelatine - Google Patents

Abstract

The invention relates to a preparation method of agomelatine, and belongs to the technical field of drug synthesis. In order to solve the problems of longer route, unsafe and low yield of the existing route, the preparation method of agomelatine is provided, which comprises the steps of reacting a compound shown in a formula 8 with acetic anhydride to obtain an end product, namely the agomelatine shown in a formula 1; further comprises reacting a compound of formula 4 with dimethyl sulfate in a mixed solvent of an alcohol solvent I and water in the presence of an alkali metal hydroxide to obtain a compound of formula 5; carrying out hydrogenation reduction reaction on the compound of the formula 5 under the catalysis of borohydride to obtain a compound 6; reacting a compound shown in a formula 6 with benzylamine under the action of potassium tert-butoxide to obtain a compound shown in a formula 7; and (3) carrying out catalytic hydrogenation reduction reaction on the compound of the formula 7 under the catalysis of a palladium-containing catalyst to obtain the compound of the formula 8. The invention has the advantages of simple post-treatment, easy recovery of palladium catalyst, high product yield and effective improvement of reaction efficiency and safety.

Description

Preparation method of agomelatine

Technical Field

The invention relates to a preparation method of agomelatine, and belongs to the technical field of drug synthesis.

Background

Agomelatine (Agomelat ine), the chemical name N- [2- (7-methoxynaphthalene-1-yl) ethyl ] acetamide, is a novel hypnotic, has the main action mechanism of stimulating the secretion of melatonin from pine cone bodies and simultaneously inhibiting the brain inhibition effect of serotonin, thereby not only promoting sleep, but also resisting depression, and has fewer side effects and good drug resistance, and is mainly used for clinically treating adult depression. The structural formula is as follows:

The synthesis of agomelatine disclosed in the prior literature mainly comprises the following steps of taking 7-methoxy-1-tetralone as a starting material, carrying out condensation reaction with 2-bromoacetic acid ethyl ester, then carrying out dehydrogenation aromatization by sulfur, carrying out saponification, acyl chlorination, ammoniation and dehydration to obtain a key intermediate 7-methoxy-1-naphthylacetonitrile, then carrying out Raney nickel reduction to obtain an intermediate 7-methoxy-1-naphthylethylamine, and finally carrying out acetylation to obtain the final product agomelatine, wherein the synthesis route is as follows:

However, the route has the advantages of more reaction steps, low overall reaction yield, high temperature required for aromatization reaction in the reaction process, raney Ni catalyst required for cyano reduction, high safety requirement and no contribution to industrial production.

As reported in European patent application (publication No. EP 2562151A), beta-naphthol with low price is used as a starting material, and is subjected to acetylation, alpha-chloracetylation, ketocarbonyl reduction, phenolic hydroxyl methylation, reaction with phthalimide potassium salt, reaction with hydrazine hydrate to obtain an intermediate 7-methoxy-1-naphthylethylamine, and final acetylation to obtain an end product agomelatine, wherein the synthetic reaction route is as follows:

in the synthesis of the route, although the starting raw material adopts beta-naphthol, which has the advantage of easily available raw material, the synthesis route adopts hydrazine hydrate with high toxicity, and a catalytic system of titanium tetrachloride and triethylsilicon hydride with strong corrosiveness and strong irritation is adopted in the synthesis process, so that the safety requirement is high, and the method is not suitable for industrial production.

Disclosure of Invention

The invention aims at the problems existing in the prior art, and provides a preparation method of agomelatine, which solves the problems of providing a new route, along with safer reaction route and high product yield.

The invention aims at realizing the following technical scheme, namely a preparation method of agomelatine, which comprises the steps of reacting a compound shown in a formula 8 with acetic anhydride to obtain an end product, namely the agomelatine shown in the formula 1;

Characterized in that the method further comprises the steps of:

A. Reacting a compound of formula 4 with dimethyl sulfate in a mixed solvent of an alcohol solvent I and water in the presence of an alkali metal hydroxide to obtain a compound of formula 5;

B. Carrying out catalytic reduction reaction on the compound of the formula 5 under the catalysis of borohydride to obtain a compound of the formula 6;

C. reacting a compound shown in a formula 6 with benzylamine under the action of potassium tert-butoxide to obtain a compound shown in a formula 7;

D. Under the catalysis of a palladium-containing catalyst, carrying out catalytic hydrogenation reduction reaction on the compound shown in the formula 7 to obtain a compound shown in the formula 8;

According to the invention, the synthetic route is improved, ester bond groups in the compound of the formula 4 are firstly subjected to formation of corresponding methoxy groups with dimethyl sulfate in the presence of alkali, the defect that a strong corrosion catalytic system such as titanium tetrachloride is needed for carbonyl reduction in the reaction is avoided, the carbonyl in the corresponding compound of the formula 5 can be reduced to hydroxyl to form a compound 6 by adopting the route after the improvement of the invention only through adopting borohydride for hydrogenation reduction, and after the hydroxyl is reacted with benzylamine to obtain an intermediate, the double bond in the compound of the formula 7 and benzyl can be reduced by adopting a one-step method under the action of a palladium-containing catalyst to obtain a key intermediate compound of agomelatine or an acid salt thereof such as hydrochloride; meanwhile, due to the improvement of the reaction route, the structure of the intermediate compound of the formula 7 is formed in the reaction process, the adoption of dichloro dicyanobenzene matched aromatization reagent is effectively avoided, the hydrogenation reduction of cyano and other modes by Raney nickel with strict safety operation requirements are not needed, the reaction efficiency and safety are more effectively improved, and the provision of a new synthesis route can be realized while the yield and quality of the intermediate and the product are ensured.

In the above process for preparing agomelatine, preferably, the hydroxide of an alkali metal in the step a is one or more selected from sodium hydroxide, potassium hydroxide and lithium hydroxide; the alcohol solvent is a lower alcohol solvent selected from C ₁～C₄. The ester bond group in the compound shown in the formula 4 reacts with dimethyl sulfate to form methoxy group under the action of alkali metal hydroxide, and the intermediate product has the advantage of high yield; the above-mentioned mixed system using an alcohol solvent and water enables the reaction to proceed more gently, and the above-mentioned lower alcohol solvents may be methanol, ethanol, propanol, butanol, isopropanol, etc.

In the reaction in the above step A, after the completion of the reaction, a post-treatment may be performed as needed to remove the solvent or the like to obtain the corresponding compound of formula 5. As a further preferred embodiment, after the completion of the reaction in step A, an acid (which may be an inorganic acid solution such as hydrochloric acid or dilute sulfuric acid) is added to the reaction mixture to adjust the pH of the mixture to neutral, the mixture is concentrated under reduced pressure to remove the first alcohol solvent, and then a water-insoluble solvent, which may be dichloromethane or ethyl acetate, is added to the residue to extract the mixture, and the organic layer is washed with water and then distilled to remove the solvent to dryness to give the corresponding compound of formula 5.

The raw materials in the reaction in the step A can be properly adjusted according to the dosage of each raw material, so that the reaction can be more complete, and the waste of the raw materials is reduced. As a still further preferred aspect, the molar ratio of the compound of formula 4 to dimethyl sulfate in step A is preferably 1:1.2 to 1.5, which is beneficial to improving the conversion rate of raw materials, improving the yield and quality of intermediate products and reducing the waste of raw materials. The alcohol solvent used in the reaction may be any alcohol solvent according to the general dosage requirements in the art. Further, it is preferable to make the molar ratio of the compound of formula 4 to the alkali metal hydroxide be 1:1.1 to 1.3.

In the above process for preparing agomelatine, preferably, the borohydride in the step B is one or more selected from potassium borohydride, sodium borohydride and lithium borohydride. The method firstly reacts the ester bond to form the methoxy group, so that the hydrogenation reduction of the carbonyl is easier to carry out, the carbonyl can be converted and hydrogenated to form the corresponding hydroxyl by adopting the borohydride for catalytic hydrogenation reduction, the reaction conversion rate is high, the reduction by adopting strong corrosive catalysts such as titanium tetrachloride and the like is avoided, and the method is favorable for safe production. As a still further preferred aspect, the molar ratio of compound of formula 5 to borohydride in step B is 1:1.1 to 1.5.

In the above-mentioned process for preparing agomelatine, the reaction in step B is generally carried out in an organic solvent, so that the reaction can be carried out more gently. The amount of the organic solvent may be any amount according to the general use in the art. As a further preferred feature, 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 catalytic reduction reaction is carried out at a temperature of 40 ℃ to 60 ℃.

As a further preferred embodiment, after the completion of the reaction in the step B, the reaction mixture is quenched by adding an acid thereto, the solvent is distilled off, and then a mixture of a water-insoluble organic solvent and water is added thereto for extraction, and the obtained organic phase is distilled off to obtain the compound of the formula 6 as an intermediate. The acid can be hydrochloric acid solution or dilute sulfuric acid solution for quenching, which is favorable for better ensuring the quality of intermediate products and reducing the generation of other impurities, and the water-insoluble organic solvent can be ethyl acetate, dichloromethane or chloroform and other solvents for extraction, so that the soluble impurities can be better removed through extraction treatment, and the purity quality of the intermediate products is improved.

In the above process for preparing agomelatine, preferably, the palladium-containing catalyst in the step D is selected from palladium hydroxide catalyst or palladium-carbon catalyst containing 5 to 10% by mass of palladium. The method can effectively carry out the reaction by carrying out the reduction reaction after the reaction of the compound 6 and the benzylamine, does not need to adopt catalysts such as Raney nickel and the like, and more importantly, the method can directly reduce double bonds in the compound of the formula 7 and corresponding benzyl groups together and remove the benzyl groups by adopting the palladium-containing catalyst for catalytic hydrogenation to obtain the corresponding compound of the formula 8, and has the advantages of mild reaction conditions and high yield of intermediate products, simple post-treatment, recycling and reusing the palladium-containing catalyst, less three wastes and more suitability for industrial production.

In the above process for preparing agomelatine, it is preferable that the catalytic hydrogenation reduction reaction in the step D is performed in an alcohol solvent two selected from one or more of methanol, ethanol, propanol and isopropanol. The catalytic hydrogenation reaction is carried out in the alcohol solvent II, so that the hydrogenation can be carried out more mildly. The above alcohol solvent one and alcohol solvent two are for better description only, and the context will be clear, not for limiting description of the alcohol solvents.

In the catalytic hydrogenation reaction in the step D, the hydrogen is preferably introduced and the reaction pressure is controlled to be 0.5-0.6 MPa, so that the hydrogenation is more effectively performed, and the improvement of the product yield of the reaction is facilitated. The compounds of formula 8 may also be formed into the corresponding acid salt forms, such as the hydrochloride salt of the compounds of formula 8, and the like. Still more preferably, after the catalytic hydrogenation reaction in the step D is completed, the alcohol solvent in the reaction solution is removed by concentration, then the organic solvent capable of dissolving the compound of formula 8 is added, and the hydrochloric acid solution is added to perform the salification reaction, so as to obtain the hydrochloride of the corresponding compound of formula 8. The above-mentioned organic solvent capable of dissolving the compound of formula 8 may be selected from organic solvents such as methylene chloride, chloroform and ethyl acetate, but is not limited to the above list, so that the compound of formula 8 is dissolved for better reaction with an acid such as hydrochloric acid to form an acid salt. Further, the temperature of the salt-forming reaction is preferably controlled to 0 to 10 ℃.

In the above process for the preparation of agomelatine, the reaction in step C is preferably carried out at a temperature of 20℃to 40 ℃. The compound of formula 6 and the benzylamine can be mildly carried out under the action of potassium tert-butoxide, and the reaction temperature is easy to control, thereby being beneficial to production operation. As a still further preference, the compound of formula 6 in step C: potassium tert-butoxide: the molar ratio of the benzylamine is 1:1.1 to 1.3:1.1 to 1.6.

In the above process for producing agomelatine, it is preferable that the reaction in step C is carried out in an ether solvent such as THF. The ether solvent may be 2-methyltetrahydrofuran, dioxane, etc. Preferably, the reaction is carried out under an inert gas atmosphere, such as under nitrogen. As a further preferred aspect, the reaction is completed and then the organic solvent is distilled off, then a water-insoluble organic solvent such as ethyl acetate, methylene chloride, chloroform, toluene and the like is added to the residue for extraction, and after standing for delamination, the organic layer is collected and distilled off to obtain the corresponding intermediate product.

In the above process for preparing agomelatine, preferably, the temperature of the reaction in step a is from 0 ℃ to 10 ℃; the temperature of the catalytic hydrogenation reduction reaction in the step D is 20-30 ℃.

In the above process for the preparation of agomelatine, preferably, the compound of formula 4 in step a is synthesized by:

the compound of formula 4 described in step a is synthesized by the steps of:

a. In the presence of an alkaline reagent, carrying out esterification reaction on beta-naphthol of a compound shown in a formula 2 and acetic anhydride in a water-insoluble organic solvent to obtain a compound shown in a formula 3;

b. reacting a compound shown in a formula 3 with chloroacetyl chloride under the catalysis of Lewis acid to obtain a compound shown in the formula 4;

In the above preparation method of agomelatine, preferably, the alkaline agent is one or more selected from triethylamine, sodium carbonate and potassium carbonate; the water-insoluble organic solvent is selected from one or more of dichloromethane, chloroform and ethyl acetate; the lewis acid is selected from aluminum trichloride.

As a further preferred aspect, the molar ratio of the compound of formula 2 to acetic anhydride is preferably 1:1.1 to 1.3, wherein the compound of formula 2 is as follows: the molar ratio of the alkaline reagent is 1:1.1 to 1.3, and further preferably, the temperature of the esterification reaction is controlled to 20 to 30 ℃.

As a still further preference, the compound of formula 3: chloroacetyl chloride: the molar ratio of Lewis acid is 1:1.1 to 1.3:1.3 to 1.5. Through carrying out appropriate control to the quantity of each raw materials, the utilization ratio of raw materials can be better improved, conversion rate is improved, unnecessary impurities can be avoided more advantageously, and the quality of products is ensured. The reaction temperature is preferably controlled to-30℃to-10 ℃.

In the above preparation method of agomelatine, preferably, the specific method for synthesizing agomelatine by reacting the hydrochloride of the compound of formula 8 with acetic anhydride (acetic anhydride) is as follows:

Reacting the hydrochloride of the compound of formula 8 with acetic anhydride in an organic solvent in the presence of an acid binding agent to obtain the agomelatine of the compound of formula 1. The reaction is preferably carried out at a temperature of 0℃to 10 ℃.

The route of the process for the preparation of agomelatine according to the invention can be represented by the following reaction equation:

in summary, compared with the prior art, the invention has the following advantages:

1. By improving the synthetic route, the ester bond group in the compound of the formula 4 is firstly subjected to formation of the corresponding methoxy group with dimethyl sulfate in the presence of alkali, so that the defect that a strong corrosion catalytic system is needed for carbonyl reduction in the reaction is avoided, titanium tetrachloride and the like are effectively avoided, double bonds in the compound of the formula 7 and benzyl groups can be reduced together under the action of a palladium-containing catalyst to obtain a key intermediate compound of the agomelatine of the formula 8 or an acid salt thereof, such as hydrochloride, and the palladium-containing catalyst, such as palladium carbon and the like, is adopted to make the reaction condition mild, the post-treatment is simple, the palladium catalyst is easier to recycle, and the product yield is high and the cost is low.

2. The invention can effectively avoid the adoption of dichloro dicyanobenzene aromatization reagent, does not need the hydrogenation reduction of cyano and other modes by Raney nickel with higher safety requirement, more effectively improves the efficiency and safety of the reaction, and can ensure the yield and quality of intermediates and products while providing a new synthetic route.

Detailed Description

The technical scheme of the present invention will be further specifically described by means of specific examples, but the present invention is not limited to these examples.

Example 1

Synthesis of compounds of formula 3:

Adding 100g (0.69 mol) of beta-naphthol, 77.20g (0.76 mol) of triethylamine and 450g of methylene dichloride into a 1L clean reaction bottle, stirring for 30min at 20-25 ℃, cooling to 0-5 ℃, slowly dropwise adding 78.30g (0.76 mol) of acetic anhydride into the reaction kettle, dropwise adding for about 1.5h, after the dropwise adding, controlling the reaction to continue stirring at 0-5 ℃ for 1h, then raising the temperature of the reaction to 20-25 ℃, continuing to stir at the temperature for 1h, adding 300g of water into the reaction solution after the reaction is finished, stirring for 15min at 20-25 ℃, standing for layering, washing the collected organic layer with 300g of 5% sodium carbonate aqueous solution and 300g of water in sequence, concentrating the collected organic layer under reduced pressure until the organic layer is dried to obtain 124.2g of a pale yellow intermediate product, namely the corresponding compound of the formula 3, wherein the yield is 96.16%, and the purity is 99.34%.

Example 2

Synthesis of compounds of formula 4:

120g (0.64 mol) of compound shown in formula 3 and 1200g of methylene dichloride are put into a 2L reaction bottle, stirred for 20min at 20-25 ℃, then cooled to 0-5 ℃, 125g (0.94 mol) of aluminum trichloride is put into the reaction liquid in batches, stirred for 20min, cooled to-25-20 ℃, 87g (0.77 mol) of chloroacetyl chloride is slowly added dropwise, the reaction is carried out for 4h at-25-20 ℃, sampling detection is carried out, 500g of 5% hydrochloric acid solution is slowly added dropwise after the reaction is finished, about 1h is carried out, stirring is carried out for 15min after the dropwise, standing and layering are carried out, the collected organic layer is sequentially washed with 500g of water, 300g of saturated sodium bicarbonate and 300g of water, then the organic layer is concentrated to dryness, 960g of methanol is added into the remainder, then the remainder is heated to 60-65 ℃ and stirred to clarify the solution, the temperature is kept for 1h, the temperature is kept for 10-15 ℃ and the time, the crystallization is fully carried out for 2h, filtration is carried out, 100g of methanol is used for leaching, the obtained solid is dried under the condition of wet condition, and the purity of the intermediate is 19.98.98%, and the dry product is obtained, and the purity of the dry product is 19.98%.

Example 3

Synthesis of Compound of formula 5

80G (0.31 mol) of the compound of formula 4, 14g (0.35 mol) of sodium hydroxide, 300g of methanol and 100g of water are added into a 1L reaction bottle, stirred at room temperature for 4 hours, cooled to 0-5 ℃,50 g (0.4 mol) of dimethyl sulfate is slowly added dropwise, about 1 hour is added dropwise, the temperature is controlled to be 0-5 ℃ after the completion of the dropwise addition, the reaction is carried out for 2 hours at a temperature of between 0 and 5 ℃, the pH value is adjusted to be neutral by using a 5% hydrochloric acid aqueous solution, then the reaction is carried out for reduced pressure concentration to remove most of methanol solvent, then 200g of Dichloromethane (DCM) is added at room temperature, stirred for 20 minutes, the reaction is kept stand for layering, the collected organic layer is washed with 150g of water for 2 times each time, and then the organic layer is concentrated to be dried to remove the solvent, so that 65.20g of light yellow oily matter is obtained, and the yield is 91.23% and the purity is 97.54%.

Example 4

Synthesis of Compound of formula 6

50G (0.21 mol) of the compound shown in formula 5 and 250g of THF are put into a 0.5L reaction bottle, stirred at room temperature for 20min until uniformity, 9.53g (0.25 mol) of sodium borohydride is added, the temperature is raised to 50-55 ℃, the reaction is carried out for 2h under heat preservation, after the reaction is completed, 47.5g (0.25 mol) of 5% hydrochloric acid aqueous solution is added into the reaction liquid for quenching reaction, then the reduced pressure distillation is carried out to remove THF, thus obtaining crude residues, 150g of ethyl acetate and 150g of water are added into the residues, stirring is carried out for 20min, standing and layering are carried out, the collected organic layer is washed for 1 time by 150g of water, and then the organic solvent is distilled out under reduced pressure to obtain 47.5g of light yellow oily matter, namely the compound shown in formula 6, and the purity is 98.25%.

Example 5

Synthesis of Compound of formula 7

35.40G (0.15 mol) of the compound of formula 6, 20.20g (0.18 mol) of potassium tert-butoxide, 18.50g (0.17 mol) of benzylamine and 140g of THF are put into a 0.5L reaction flask, nitrogen is replaced 3 times, the flask is incubated at 20-25 ℃ for 1h, water is added for 100g, then the organic solvent is removed by reduced pressure distillation, 100g of ethyl acetate is added to the remainder, stirring is carried out for 10min, standing and layering are carried out, the collected organic layer is washed with 100g of water for 1 time, the organic layer is distilled off under reduced pressure to obtain 46.89g of light yellow liquid, standing overnight, white crystals are precipitated, filtered, filter cakes are collected, 36.8g of white granular crystals are obtained, namely the compound of formula 7, the yield is 85.03%, and the purity is 98.32%.

Example 6

Synthesis of Compound hydrochloride of formula 8 (2- (7-ethoxynaphthyl) ethylamine hydrochloride)

Adding 20g (0.07 mo 1)) of a compound of formula 7, 2.0g of a 5% Pd-C catalyst and 70g of methanol into a stainless steel autoclave, replacing air with nitrogen, then introducing hydrogen to replace nitrogen, carrying out catalytic hydrogenation reaction for 16 hours at 20-25 ℃ under the condition that the pressure of the hydrogen is controlled to be 0.5-0.6 Mpa, filtering after the medium control is qualified, eluting with 20g of methanol, recovering the Pd-C catalyst, concentrating the obtained filtrate under reduced pressure to remove the solvent until the solvent is dry, adding 70g of dichloromethane and 7.2g of concentrated hydrochloric acid into the residue, stirring for 1 hour at 0-5 ℃, filtering, eluting the filter cake with dichloromethane, and drying under the vacuum condition to obtain the hydrochloride (2- (7-ethoxynaphthyl) ethylamine hydrochloride) of the compound of formula 8, wherein the light yellow is 15.56g of white-like powder, and the purity is 98.55%, and the yield is 94.70%.

Example 7

Synthesis of agomelatine

15G (0.063 mol) of 2- (7-methoxy-1-Cai Ji) ethylamine hydrochloride, 100g of dichloromethane and 10.5g (0.07 mol) of anhydrous potassium carbonate are added into a reaction bottle, stirred, cooled to 0-5 ℃, 4.0g (0.067 mol) of acetic anhydride is slowly added dropwise, the temperature is controlled to be 0-5 ℃, the reaction is carried out for 1 hour at the temperature of 0-5 ℃ after the dropwise addition, 60g of water is dropwise added into the reaction liquid after the completion of the central control, stirred for 10 minutes, layering is carried out, the collected organic layer is washed by 60g of water and washed for 3 times, the organic layer is concentrated to dryness, 50g of toluene and 0.3g of active carbon are added into the remainder, heated to 60-65 ℃ and kept for 30 minutes, then slowly cooled to-10-5 ℃, kept for 2 hours, filtered and dried, and the product agomelatine 13.54g, white solid powder with the yield of 88.20% and the purity of 99.5% is obtained.

Example 8

Synthesis of Compound of formula 5

80G (0.31 mol) of the compound of formula 4, 16g (0.4 mol) of sodium hydroxide, 350g of ethanol and 130g of water are added into a 1L reaction bottle, stirred at room temperature for 4 hours, cooled to 0-5 ℃, 58.6g (0.47 mol) of dimethyl sulfate is slowly added dropwise, about 1.5 hours is added dropwise, the temperature is controlled to be 0-5 ℃ after the completion of the dropwise, the reaction is carried out for 2 hours at the temperature, after the completion of the reaction, the pH is regulated to be neutral by using a 5% hydrochloric acid aqueous solution, then the reaction is concentrated under reduced pressure to remove most of ethanol solvent, then 200g of Dichloromethane (DCM) is added at room temperature, stirred for 20 minutes, the mixture is left to stand for delamination, the collected organic layer is washed with 150g of water for 2 times each time, then the organic layer is concentrated to dry to remove the solvent, and 65.96g of light yellow oily matter is obtained, and the corresponding compound of formula 5 is 92.3% in yield and 97.8%.

Example 9

Synthesis of Compound of formula 6

50G (0.21 mol) of the compound shown in formula 5 and 250g of THF are put into a 0.5L reaction bottle, stirred at room temperature for 20min until uniformity, then 12.2g (0.32 mol) of sodium borohydride is added, the temperature is raised to 50-55 ℃, the reaction is carried out for 2h under heat preservation, after the reaction is completed, 49g of 5% hydrochloric acid aqueous solution is added into the reaction solution for quenching reaction, then reduced pressure distillation is carried out to remove THF, thus obtaining a crude residue, 150g of ethyl acetate and 150g of water are added into the residue, stirring is carried out for 20min, standing and layering are carried out, the collected organic layer is washed for 1 time by 150g of water, and then the organic layer is distilled out under reduced pressure to obtain 47.3g of light yellow oily matter, namely the compound shown in formula 6, the yield is 93.8%, and the purity is 98.1%.

Example 10

Synthesis of Compound of formula 7

35.40G (0.15 mol) of the compound of formula 6, 22.44g (0.18 mol) of potassium tert-butoxide, 26.12g (0.24 mol) of benzylamine and 140g of THF are put into a 0.5L reaction bottle, nitrogen is replaced for 3 times, the temperature is kept at 20-25 ℃ for 1h, water is added for 100g, then the organic solvent is removed by reduced pressure distillation, 100g of ethyl acetate is added to the residue, stirring is carried out for 10min, standing and layering are carried out, the collected organic layer is washed with 100g of water for 1 time, the organic layer is distilled off under reduced pressure to obtain light yellow liquid, standing is carried out overnight, white crystals are separated out, filtration is carried out, a filter cake is collected, and 37.35g of white granular crystal form 7 compound is obtained, the yield is 86.3% and the purity is 98.43% under vacuum condition.

Example 11

Synthesis of Compound hydrochloride of formula 8 (2- (7-ethoxynaphthyl) ethylamine hydrochloride)

Adding 20g (0.07 mo 1)) of a compound of formula 7, 2.2g of 5% Pd-C catalyst and 70g of methanol into a stainless steel autoclave, replacing air with nitrogen, then introducing hydrogen to replace nitrogen, carrying out catalytic hydrogenation reaction for 16 hours at 20-25 ℃ under the condition that the pressure of the hydrogen is controlled to be 0.5-0.6 Mpa, filtering after the medium control is qualified, eluting with 20g of methanol, recovering the Pd-C catalyst, concentrating the obtained filtrate under reduced pressure to remove the solvent until the solvent is dry, adding 70g of dichloromethane and 8.0g of concentrated hydrochloric acid into the residue, stirring for 1 hour at 0-5 ℃, filtering, eluting the filter cake with dichloromethane, and drying under the vacuum condition to obtain the hydrochloride (2- (7-ethoxynaphthyl) ethylamine hydrochloride) of the compound of formula 8, wherein the light yellow is similar to white powder 15.64g, the purity is 98.6%, and the yield is 95.2%.

Example 12

Synthesis of agomelatine

15G (0.063 mol) of 2- (7-methoxy-1-Cai Ji) ethylamine hydrochloride, 100g of dichloromethane and 12g of anhydrous potassium carbonate are added into a reaction bottle, stirring is carried out, cooling is carried out to 0-5 ℃, 4.5g (0.075 mol) of acetic anhydride is slowly added dropwise, the temperature is controlled to be 0-5 ℃ after the dripping is finished, the reaction is carried out for 1 hour under the heat preservation, 70g of water is dropwise added into the reaction liquid after the central control is finished, stirring is carried out for 10 minutes, layering is carried out, the collected organic layer is washed by 60g of water for 3 times, the organic layer is concentrated to be dry, 50g of toluene and 0.5g of active carbon are added into the residue, heating is carried out to 60-65 ℃, then the temperature is slowly cooled to-10 ℃ to-5 ℃, the temperature is kept for 2 hours, filtering and drying are carried out, and the product agomelatine 13.45g, white solid powder is obtained, and the yield is 87.6%, and the purity is 99.6%.

Example 13

Synthesis of compounds of formula 3:

adding 100g (0.69 mol) of beta-naphthol, 79g of triethylamine and 500g of methylene dichloride into a 1L clean reaction bottle, stirring for 30min at 20-25 ℃, cooling to 0-5 ℃, controlling the temperature, slowly dropwise adding 91.8g (0.9 mol) of acetic anhydride into the reaction kettle, dropwise adding about 2.0h, controlling the reaction to continue stirring at 0-5 ℃ for reaction for 1h, then raising the temperature of the reaction to 20-25 ℃, continuing to control the temperature, stirring for 1h, adding 300g of water into the reaction liquid after the reaction is finished, stirring for 15min at 20-25 ℃, standing for layering, washing the collected organic layer sequentially with 300g of 5% sodium carbonate aqueous solution and 300g of water, concentrating the collected organic layer under reduced pressure until the organic layer is dried to obtain 123.7g of a pale yellow intermediate product, wherein the corresponding compound of formula 3 has the yield of 95.8% and the purity of 99.5%.

120G (0.64 mol) of the compound shown in the formula 3 and 1200g of methylene dichloride are put into a 2L reaction bottle, stirred for 20min at 20-25 ℃, then cooled to 0-5 ℃, 111g (0.83 mol) of aluminum trichloride is put into the reaction liquid in batches, stirred for 20min, cooled to-22-20 ℃, 93.7g (0.83 mol) of chloroacetyl chloride is slowly added dropwise, the mixture is subjected to heat preservation reaction for 3.5h at-22-20 ℃, sampling detection is carried out, 480g of 5% hydrochloric acid solution is slowly added dropwise after the reaction is finished, about 1h is added dropwise, stirring is carried out for 15min after the dripping, standing and layering are carried out, the collected organic layer is sequentially washed with 500g of water, 300g of saturated sodium bicarbonate solution and 300g of water, then the organic layer is concentrated to dryness, 960g of methanol is added into the residue, then the solution is heated to 60-65 ℃ and stirred to the temperature, the solution is stirred for 1h at the temperature of 10-15 ℃, the temperature is slowly stirred for 2 h, crystallization is fully carried out, 100g of methanol is leached and 100g is used for leaching, the dry product is obtained under the condition that the dry product is in a vacuum state, the purity of a dry product is 100.45%, and the dry product is a light yellow solid product is obtained under the condition of which is in a vacuum condition of 4.45%.

The specific embodiments described herein are offered by way of illustration only. Those skilled in the art may make various modifications or additions to the described embodiments or substitutions thereof without departing from the spirit of the invention or exceeding the scope of the invention as defined in the accompanying claims.

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims (10)

1. A preparation method of agomelatine, which comprises the steps of reacting a compound shown in a formula 8 with acetic anhydride to obtain an end product, namely the agomelatine shown in a formula 1;

Characterized in that the method further comprises the steps of:

A. Reacting a compound of formula 4 with dimethyl sulfate in a mixed solvent of an alcohol solvent I and water in the presence of an alkali metal hydroxide to obtain a compound of formula 5;

B. Carrying out catalytic reduction reaction on the compound of the formula 5 under the catalysis of borohydride to obtain a compound of the formula 6;

C. reacting a compound shown in a formula 6 with benzylamine under the action of potassium tert-butoxide to obtain a compound shown in a formula 7;

D. Under the catalysis of a palladium-containing catalyst, carrying out catalytic hydrogenation reduction reaction on the compound shown in the formula 7 to obtain a compound shown in the formula 8;

2. The preparation method of agomelatine according to claim 1, wherein the hydroxide of alkali metal in step a is selected from one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the alcohol solvent is a lower alcohol solvent selected from C ₁～C₄.

3. The preparation method of agomelatine according to claim 1, wherein said borohydride in step B is selected from one or more of potassium borohydride, sodium borohydride and lithium borohydride.

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

5. The preparation method of agomelatine according to claim 1, wherein the palladium-containing catalyst in step D is selected from palladium hydroxide catalyst or palladium-carbon catalyst containing 5 to 10% by mass of palladium.

6. The process for the preparation of agomelatine according to any one of claims 1 to 5, characterised in that in step D the catalytic hydrogenation reduction is carried out in an alcoholic solvent two selected from one or more of methanol, ethanol, propanol, isopropanol.

7. Process for the preparation of agomelatine according to any one of claims 1 to 5, characterised in that the temperature of the reaction in step C is between 20 ℃ and 40 ℃.

8. The process for the preparation of agomelatine according to any one of claims 1 to 5, characterised in that the temperature of the reaction in step a is between 0 ℃ and 10 ℃; the temperature of the catalytic hydrogenation reduction reaction in the step D is 20-30 ℃.

9. Process for the preparation of agomelatine according to any one of claims 1 to 5, characterised in that in step a the compound of formula 4 is synthesised by the following steps:

a. In the presence of an alkaline reagent, carrying out esterification reaction on beta-naphthol of a compound shown in a formula 2 and acetic anhydride in a water-insoluble organic solvent to obtain a compound shown in a formula 3;

b. reacting a compound shown in a formula 3 with chloroacetyl chloride under the catalysis of Lewis acid to obtain a compound shown in the formula 4;

10. The preparation method of agomelatine according to claim 9, wherein said alkaline reagent is selected from one or more of triethylamine, sodium carbonate and potassium carbonate; the water-insoluble organic solvent is selected from one or more of dichloromethane, chloroform and ethyl acetate; the lewis acid is selected from aluminum trichloride.