Preparation method of dapoxetine hydrochloride

Abstract

The invention relates to the technical field of drug synthesis, and discloses a dapoxetine hydrochloride preparation method, which comprises: a catalytic reaction step: providing 3-chloropropiophenone and naphthol as reactants, and carrying out a condensation reaction by using a catalyst to generate a reaction intermediate; a reduction step: carrying out a reduction reaction on the reaction intermediate and a reducing agent to form a reduction precursor; methylation: carrying out methylation reaction on the reduction precursor and a methylation reagent to introduce a methyl group; and a hydrochloric acid acidification step: carrying out a hydrochloric acid acidification reaction on the methylation product and hydrogen chloride to generate dapoxetine hydrochloride. By adopting the supercritical carbon dioxide, the lipase or the metal organic framework catalyst, hydrogen reduction and the process of dropwise adding the methylation reagent, the reaction efficiency, the selectivity and the product purity are improved, the generation of by-products is reduced, the reaction conditions are optimized, and the environmental pollution is reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and specifically to a preparation method of dapoxetine hydrochloride. Background Art

[0002] With the improvement of living standards, people's requirements for health and quality of life are getting higher and higher. As a common drug, dapoxetine hydrochloride is widely used in the treatment of sexual dysfunction problems such as premature ejaculation, and has important market demand.

[0003] At present, the preparation technology of dapoxetine hydrochloride mainly relies on traditional catalytic reactions, reduction, methylation and other steps. The solvents used in conventional catalytic reactions are usually organic solvents, which can effectively dissolve reactants and promote the smooth progress of the reaction. The catalysts used, such as traditional metal catalysts or anhydrous metal salts, can effectively accelerate chemical reactions and improve the conversion rate of reactions under certain conditions. Through these methods, the production process can achieve stability and repeatability to meet the needs of large-scale production.

[0004] However, there are still some deficiencies in the existing technology; firstly, although conventional solvents can dissolve reactants, they have strong volatility, are difficult to recycle, and the pollution problem cannot be ignored; secondly, although traditional catalysts can effectively catalyze reactions under conventional conditions, their catalytic efficiency is low, and they require high temperature and long reaction time, which are prone to the generation of by-products and it is difficult to ensure the high purity of the product. More importantly, the existing reduction steps often rely on highly reactive reducing agents such as borohydrides. Such reducing agents react violently and are prone to generate by-products, and strict control is required during use; in addition, the reagent usage amount and addition method in the methylation process are also difficult to accurately control, and problems such as over-methylation or incomplete methylation are likely to occur, affecting the purity of the product. Summary of the Invention

[0005] Aiming at the deficiencies of the existing technology, the present invention provides a preparation method of dapoxetine hydrochloride, which solves the problems of solvent pollution, low catalytic efficiency, difficult control of reducing agents and incomplete methylation in the existing technology.

[0006] To achieve the above objectives, the present invention is realized through the following technical solutions: A preparation method of dapoxetine hydrochloride, comprising the following steps: Catalytic reaction step: 3-chloropropiophenone and naphthol are provided as reactants, and a catalyst is used for the condensation reaction to generate reaction intermediates. The essence of the catalytic reaction is to condense 3-chloropropiophenone and naphthol through a nucleophilic attack reaction. First, the active center of the catalyst (whether it is the active site of the enzyme or the metal center of the MOF) can stimulate the activity of the reactant molecules. In particular, the hydroxyl group in naphthol is prone to form a negative charge and attacks the carbonyl group of 3-chloropropiophenone with the help of the catalyst. This attack process generates a reaction intermediate. Specifically, the carbonyl group of 3-chloropropiophenone and the hydroxyl group of naphthol undergo a nucleophilic attack to form an ether bond, and the generated intermediate will provide a key basis for the subsequent reduction reaction; Reduction step: The reaction intermediate is subjected to a reduction reaction with a reducing agent to form a reduction precursor. The reduction reaction mainly reduces the carbonyl group or other oxygen-containing groups of the reaction intermediate through electron transfer. When a borohydride is used as the reducing agent, it can provide hydrogen atoms and then reduce the carbonyl group or other unsaturated groups (such as alkenes or nitriles) in the intermediate. The borohydride breaks the double bond by transferring hydrogen to the target position of the reactant to obtain a saturated organic compound; Methylation step: The reduction precursor is subjected to a methylation reaction with a methylation reagent to introduce a methyl group. The mechanism of the methylation reaction is usually through a nucleophilic substitution reaction. The methyl group in the methylation reagent (such as methyl iodide) reacts with the nucleophilic site (such as a nitrogen atom) in the reduction precursor by the detachment of the iodide ion to form a new carbon-nitrogen bond. The key to methylation lies in the selection of the methylation reagent. It must be able to provide a stable methyl group and undergo a nucleophilic substitution with the active site in the reduction precursor under the reaction conditions. Dropwise addition of the methylation reagent can avoid excessive reaction, ensure the control of the reaction process, and promote the smooth progress of the reaction by selecting an appropriate solvent system (such as dichloromethane or acetonitrile); Hydrochlorination step: The methylation product is subjected to a hydrochlorination reaction with hydrogen chloride to generate dapoxetine hydrochloride. The mechanism of hydrochlorination is that the chloride ion in the hydrogen chloride gas reacts with the nitrogen atom in the methylation product to form a nitrogen-chloride salt. This reaction is an acid-base reaction. Hydrogen chloride provides a proton and releases a chloride ion. In this process, the chloride ion combines with the nitrogen atom to form dapoxetine hydrochloride salt. The key to this step is the addition method of hydrogen chloride and the control of the reaction time to ensure that hydrogen chloride can react completely and avoid the generation of by-products; Purification and crystallization step: The dapoxetine hydrochloride is subjected to purification and crystallization treatment to obtain the final product. Purification and crystallization is a physical separation process based on the difference in solubility of different compounds in solvents. The solubility of crude dapoxetine hydrochloride in the solvent is relatively high, while the solubility of impurities is relatively low. Therefore, through recrystallization, the impurities can be separated from the target product.

[0007] Preferably, the catalytic reaction step includes: Mix 3-chloropropiophenone and naphthol in a weight ratio of 1:1.2 to 1:1.5, and connect 3-chloropropiophenone and naphthol through a nucleophilic attack reaction to generate a reaction intermediate. As a nucleophile, the hydroxyl group (-OH) in the naphthol molecule can form a negative charge under the action of a catalyst, and then conduct a nucleophilic attack on the carbonyl group of 3-chloropropiophenone. In this process, the aromatic ring of naphthol attacks the carbonyl group of 3-chloropropiophenone through its hydroxyl group, and after removing the chloride ion, a new chemical bond (i.e., C-O bond) is formed, thus forming an intermediate with an ether structure; Use a lipase or a metal-organic framework catalyst, and its dosage is 0.5 to 3 of the total mass of the reactants. When using lipase as a catalyst, through its unique enzyme active sites and structure, it optimizes the contact and reactivity of the reactants at the molecular level and enhances the nucleophilic attack ability of naphthol on 3-chloropropiophenone. The selectivity of lipase can effectively reduce the occurrence of side reactions and accelerate the condensation reaction at the same time; if a metal-organic framework catalyst (MOF) is used, its catalytic action comes from the metal center and pore structure of the MOF. The metal center in the MOF can enhance the electrophilicity of the reactants through the electronic effect, making 3-chloropropiophenone more vulnerable to nucleophilic attack. The MOF also provides an ordered reaction space, which can control the selectivity of the reaction and improve the yield of the target product; React in a green solvent, and the green solvent is supercritical carbon dioxide. The reaction temperature is controlled at 30 to 80 degrees Celsius, and the reaction time is controlled at 2 to 6 hours. Selecting green solvents such as ethanol, tetrahydrofuran or supercritical carbon dioxide not only conforms to the principles of green chemistry, but also can optimize the solvent environment of the reaction. Ethanol and tetrahydrofuran can effectively dissolve the reactants to ensure that the reactants are fully contacted and participate in the reaction; while supercritical carbon dioxide, as a green solvent, can increase the solubility of the reactants and can be recovered after the reaction, without causing a burden on the environment.

[0008] Preferably, the reduction step includes: Dissolve the reaction intermediate generated in the catalytic reaction step in an organic solvent. When borohydride is used as a reducing agent, it will provide hydrogen atoms. Borohydride will react with the carbonyl group or other unsaturated groups (such as olefins or nitriles) in the intermediate during the reaction, thereby reducing it to the corresponding alkyl compound. Its reaction mechanism is usually that the hydrogen atoms in the borohydride reduce the carbonyl carbon in the reactant to a saturated carbon and release borate at the same time. This reaction is a typical nucleophilic reduction reaction; A reducing agent is added to the above solution. The reducing agent is borohydride or hydrogen, and its usage amount is 1 to 3 times the mass of the intermediate. If hydrogen is selected as the reducing agent, the hydrogenation reaction needs to be carried out with the help of a catalyst. Hydrogen molecules are first adsorbed and dissociated into hydrogen atoms on the catalyst surface, and then the hydrogen atoms enter the reactants and react with them. In this process, the hydrogen atoms will directly undergo an addition reaction with the unsaturated bonds in the intermediate to complete the reduction process. The hydrogen reduction reaction usually requires a metal catalyst (such as palladium, platinum, nickel, etc.) to accelerate the dissociation of hydrogen and the reduction reaction.

[0009] Preferably, the methylation step includes: The precursor obtained from the reduction step is dissolved in an organic solvent. The organic solvent is selected from dichloromethane or acetonitrile and is carried out under nitrogen protection. The methyl group in methyl iodide or trimethylsilylmethane (TMS) reacts with the nucleophilic site in the reduction precursor through the departure of the iodide ion or silyl group. The reduction precursor molecule may contain nucleophilic centers (such as nitrogen atoms, oxygen atoms, etc.), and these positions can undergo nucleophilic substitution reactions with the methyl groups in the methylation reagent. The result of the reaction is that an active site (usually a nitrogen atom) in the precursor molecule is substituted by a methyl group, forming a new carbon-nitrogen bond. Methyl iodide is a common methylation reagent, which reacts with the nucleophilic center in the reduction precursor by providing a methyl group. Trimethylsilylmethane, on the other hand, carries out the methylation reaction by providing a trimethylsilyl group, and this reagent may be more efficient for some molecules with strong nucleophilicity; A methylation reagent is added to the above solution. The methylation reagent is selected from methyl iodide or trimethylsilylmethane, and its addition method is by dropwise addition. The usage amount is 1 to 3 times the mass of the precursor. The dropwise addition method is to avoid excessive reaction and ensure the controllability of the reaction, and to avoid the generation of by-products due to excessive reaction of the methylation reagent with the precursor. The use of nitrogen protection is to avoid adverse reactions of some oxidation-sensitive intermediates or reagents in the reaction with oxygen in the air, thus affecting the smooth progress of the reaction.

[0010] Preferably, the methylation step further includes: React at a reaction temperature of 0 to 25 °C. The control of the temperature is to ensure the mildness of the methylation reaction and avoid the decomposition of the methylation reagent or other side reactions caused by too high a temperature. When the temperature is controlled at 0 to 25 °C, the reaction rate is moderate, which can not only ensure the effective progress of the methylation reaction but also avoid side reactions caused by overheating. Too high a temperature may make the reaction too violent, resulting in excessive methylation or the decomposition of the reactants into other unwanted by-products. Therefore, through low-temperature control, the methyl group in the reaction can be accurately introduced into the target position; The reaction time is controlled within 4 to 6 hours. Controlling the reaction time (4 to 6 hours) helps ensure the completeness of the reaction. If the reaction time is too short, the reaction will end before the methylation group is fully introduced, resulting in an incomplete reaction. Therefore, controlling the reaction time within 4 to 6 hours ensures the full progress of the methylation reaction, avoids side reactions, and at the same time guarantees the purity of the target product.

[0011] Preferably, the hydrochlorination step includes: Dissolve the product obtained from the methylation step in a suitable organic solvent, and the organic solvent is selected from ethyl acetate. In this step, through the acid-base reaction of the chloride ion in hydrogen chloride gas with the nitrogen atom in the methylation product, a hydrochloride is formed. In this process, the nitrogen atom in the methylation product is the nucleophilic center and can combine with the chloride ion in hydrogen chloride to form a nitrogen-chlorine bond, thereby generating dapoxetine hydrochloride; Introduce hydrogen chloride gas into the above solution. Hydrogen chloride (HCl), as a strong acid, can provide hydrogen ions. These hydrogen ions form hydrogen bonds with the nitrogen atom in the methylation product, activating the nitrogen atom and making it more nucleophilic, and then it can combine with the chloride ion to form the hydrochloride of nitrogen chloride. This process is a typical acid-base reaction, where hydrogen chloride provides protons and the chloride ion combines with the nitrogen atom to form a stable hydrochloride; React at room temperature, and control the reaction time within 1 to 2 hours. During the reaction process, the introduction of hydrogen chloride is gradual to ensure its appropriate concentration and avoid the reaction being too violent or generating side reactions. The introduced hydrogen chloride gas will continue to react until the reaction reaches equilibrium. Therefore, a reaction time of 1 to 2 hours is the ideal time to ensure the completion of the reaction and obtain a pure product.

[0012] Preferably, the purification and crystallization step includes: Dissolve the crude product obtained from the hydrochlorination step in an organic solvent, and the organic solvent is selected from ethyl acetate. The basic principle of purification and crystallization is to separate the target product and impurities through solubility differences; Adopt the recrystallization method to purify the crude product using isopropyl alcohol or ethyl acetate. During the recrystallization process, ethyl acetate and isopropyl alcohol play important roles as solvents. Ethyl acetate has good solubility and can dissolve dapoxetine hydrochloride and impurities when heated; Perform crystallization treatment at room temperature to fifty degrees Celsius to obtain the product. When the solution cools from room temperature to 50 °C, the solubility of dapoxetine hydrochloride decreases significantly, and thus crystals precipitate. The addition of isopropyl alcohol can further improve the solubility difference, thereby helping dapoxetine hydrochloride to crystallize out better.

[0013] Preferably, the green solvent includes supercritical carbon dioxide, and the reaction conditions include: The reaction temperature is 100 to 120 degrees Celsius; The reaction pressure is 10 to 15 MPa. The density and solubility of supercritical carbon dioxide are closely related to the reaction temperature and pressure. By adjusting the reaction temperature to 100 to 120 °C and the reaction pressure to 10 to 15 MPa, supercritical carbon dioxide can be made to work within the boundary region between liquid and gas, thereby obtaining better solubility and reactivity. In addition, appropriate temperature and pressure also contribute to the selectivity of the reaction and the high yield of the target product; The reaction time is 2 to 4 hours. In the supercritical carbon dioxide environment, the solubility of the reactants and the activity of the catalyst are significantly enhanced. Therefore, the reaction time can be controlled between 2 and 4 hours. This time period is sufficient to ensure the full progress of the reaction while avoiding side reactions or unnecessary solvent consumption caused by too long a time.

[0014] Preferably, when the catalyst is lipase, its usage amount is 0.5 to 2 of the total mass of the reactants; when it is a metal-organic framework catalyst, its usage amount is 1 to 3 of the total mass of the reactants. As a catalyst, lipase mainly promotes the reaction through its enzyme active sites. Lipase usually has high selectivity. Therefore, even with a small usage amount (0.5 to 2), it can efficiently catalyze the reaction and reduce the generation of by-products; the catalytic action of MOF mainly depends on its metal centers, and these metal ions can interact with the electron clouds in the reactants, thereby enhancing the electrophilicity of the reactants and making them more prone to reaction. The usage amount of MOF is usually higher (1 to 3), mainly because its catalytic efficiency is affected by its surface area and pore structure.

[0015] The present invention provides a method for preparing dapoxetine hydrochloride. It has the following beneficial effects: 1. The present invention uses supercritical carbon dioxide as a solvent, which not only improves the reaction efficiency but also reduces environmental pollution. Compared with traditional organic solvents, supercritical carbon dioxide has higher solubility and diffusivity, can significantly accelerate the reaction process, and is easy to recycle after the reaction, completely solving the problems of solvent pollution and difficult recycling.

[0016] 2. By using lipase or metal-organic framework catalyst (MOF), the present invention has optimized the catalytic efficiency and selectivity. The enzyme catalysis and the high specific surface area of MOF make the reaction milder and faster, reducing the generation of by-products. Compared with traditional catalysts, this catalytic system has a higher reaction rate and can complete the reaction at a lower temperature, reducing energy consumption.

[0017] 3. The present invention adopts the method of dropping the methylation reagent in the methylation step, precisely controlling the reaction process and avoiding the by-products of excessive methylation. Compared with the traditional direct addition method, this dropping method effectively improves the purity of the product and the controllability of the reaction, ensuring the efficient and stable production of the product.

[0018] 4. The present invention combines the advantages of supercritical carbon dioxide and green solvents, not only enhancing the solubility of reactants but also optimizing the efficiency of purification and crystallization. Compared with traditional solvents, the use of supercritical carbon dioxide accelerates the crystallization process of the target product and significantly improves the product purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is a flowchart of the method of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0020] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the drawings in the specification of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts belong to the scope of protection of the present invention.

[0021] Please refer to the attached Figure 1 : Example 1: Preparation method using supercritical carbon dioxide and lipase catalyst Catalytic reaction step: Reactants: 3-chloropropiophenone and naphthol are mixed in a mass ratio of 1:1.2.

[0022] Catalyst: Lipase is used as the catalyst, and the dosage of lipase is 1% of the total mass of the reactants.

[0023] Solvent: Supercritical carbon dioxide is used, the temperature is set at 80 °C, the pressure is 12 MPa, and the reaction time is 4 hours.

[0024] Reduction step: The intermediate generated in the catalytic reaction is dissolved in tetrahydrofuran (50 ml).

[0025] Borohydride is added to the solution, the reaction time is controlled at 3 hours, and the usage amount is 1.5 times the mass of the intermediate.

[0026] Methylation step: The reduction precursor is dissolved in dichloromethane (40 ml) and protected with nitrogen.

[0027] Methyl iodide is added dropwise, and the usage amount is 2 times the mass of the precursor. The reaction is carried out at room temperature for 5 hours.

[0028] Hydrochlorination step: The methylation product is dissolved in ethyl acetate (100 ml).

[0029] Hydrogen chloride gas is introduced into the solution, and the reaction is carried out at room temperature for 1.5 hours.

[0030] Purification and crystallization step: The crude product of the hydrochlorination reaction is dissolved in ethyl acetate (80 mL).

[0031] Recrystallization is carried out using isopropanol, with the crystallization temperature controlled at 30 °C and the crystallization time of 4 hours.

[0032] Example 2: Preparation method using supercritical carbon dioxide and metal-organic framework catalyst Catalytic reaction step: Reactants: 3-chloropropiophenone and naphthol are mixed in a mass ratio of 1:1.3.

[0033] Catalyst: A metal-organic framework catalyst (MOF) is used, and its dosage is 2% of the total mass of the reactants.

[0034] Solvent: Supercritical carbon dioxide is adopted, with the temperature set at 100 °C, the reaction pressure of 13 MPa, and the reaction time of 3 hours.

[0035] Reduction step: The intermediate generated from the catalytic reaction is dissolved in acetonitrile (50 mL).

[0036] Hydrogen (10 L) is added, and the hydrogenation reaction is carried out at room temperature. The amount of hydrogen used is 2 times the mass of the intermediate, and the reaction time is 2 hours.

[0037] Methylation step: The reduction precursor is dissolved in dichloromethane (50 mL) under nitrogen protection.

[0038] Trimethylsilylmethane is added to the solution, with the usage amount being 2 times the mass of the precursor, and it is added dropwise. The reaction temperature is set at 20 °C, and the reaction time is 4 hours.

[0039] Hydrochlorination step: The methylation product is dissolved in ethyl acetate (100 mL).

[0040] Hydrogen chloride gas is introduced, and the reaction is carried out at room temperature for 1 hour.

[0041] Purification and crystallization step: The hydrochlorination crude product is dissolved in ethyl acetate (80 mL).

[0042] Purification is carried out by recrystallization using ethyl acetate, with the crystallization temperature controlled at 40 °C and the crystallization time of 4 hours.

[0043] Example 3: Comparative example of traditional solvent method Catalytic reaction step: Reactants: 3-chloropropiophenone and naphthol are mixed in a mass ratio of 1:1.3.

[0044] Catalyst: Anhydrous CuSO4 is used as the catalyst, and the dosage of the catalyst is 5% of the total mass of the reactants.

[0045] Solvent: Acetonitrile (60 mL) is used as the solvent, the reaction temperature is set at 100 °C, and the reaction time is 5 hours.

[0046] Reduction step: Dissolve the intermediate in dichloromethane (50 mL).

[0047] Add borohydride to the solution, and the usage amount is 1.5 times the mass of the intermediate, and the reaction time is controlled within 3 hours.

[0048] Methylation step: Dissolve the reduction precursor in dichloromethane (50 mL) and protect it with nitrogen.

[0049] Add methyl iodide, and the usage amount is 2 times the mass of the precursor. The reaction is carried out at room temperature, and the reaction time is 6 hours.

[0050] Hydrochlorination step: Dissolve the methylation product in ethyl acetate (80 mL).

[0051] Pass hydrogen chloride gas into the solution, the reaction is carried out at room temperature, and the reaction time is 2 hours.

[0052] Purification and crystallization step: Dissolve the crude hydrochlorinated product in ethyl acetate (100 mL).

[0053] Purify by recrystallization using ethyl acetate, the crystallization temperature is 45 °C, and the crystallization time is 5 hours.

[0054] Comparative example 1: Use a traditional solvent to replace supercritical carbon dioxide Comparative example process: Catalytic reaction step: Reactants: Mix 3-chloropropiophenone and naphthol in a mass ratio of 1:1.2.

[0055] Catalyst: Use lipase as the catalyst, and the dosage of the lipase is 1% of the total mass of the reactants.

[0056] Solvent: Replace supercritical carbon dioxide, use ethanol (50 mL) as the solvent, the reaction temperature is set at 80 °C, and the reaction time is 4 hours.

[0057] Reduction step: Dissolve the intermediate generated by the catalytic reaction in tetrahydrofuran (50 mL).

[0058] Add borohydride to the solution, control the reaction time at 3 hours, and the dosage is 1.5 times the mass of the intermediate.

[0059] Methylation step: Dissolve the reduction precursor in dichloromethane (40 mL) and protect it with nitrogen.

[0060] Add methyl iodide dropwise, and the dosage is 2 times the mass of the precursor. The reaction is carried out at room temperature for 5 hours.

[0061] Hydrochlorination step: Dissolve the methylation product in ethyl acetate (100 mL).

[0062] Pass hydrogen chloride gas into the solution. The reaction is carried out at room temperature for 1.5 hours.

[0063] Purification and crystallization step: Dissolve the crude hydrochlorination reaction product in ethyl acetate (80 mL).

[0064] Recrystallize with isopropanol, control the crystallization temperature at 30 °C, and the crystallization time is 4 hours.

[0065] Comparative Example 2: Use hydrogen reduction instead of borohydride Comparative example process: Catalytic reaction step: Reactants: Mix 3-chloropropiophenone and naphthol in a mass ratio of 1:1.2.

[0066] Catalyst: Use lipase as the catalyst, and the dosage of lipase is 1% of the total mass of the reactants.

[0067] Solvent: Use supercritical carbon dioxide, set the temperature at 80 °C, the reaction pressure is 12 MPa, and the reaction time is 4 hours.

[0068] Reduction step: Dissolve the intermediate generated by the catalytic reaction in tetrahydrofuran (50 mL).

[0069] Add hydrogen (10 L) to the solution, carry out the hydrogenation reaction at room temperature, the amount of hydrogen used is 2 times the mass of the intermediate, and the reaction time is 3 hours.

[0070] Methylation step: Dissolve the reduction precursor in dichloromethane (40 mL) and protect it with nitrogen.

[0071] Add methyl iodide dropwise, and the dosage is 2 times the mass of the precursor. The reaction is carried out at room temperature for 5 hours.

[0072] Hydrochlorination step: The methylation product is dissolved in ethyl acetate (100 mL).

[0073] Hydrogen chloride gas is introduced into the solution, and the reaction is carried out at room temperature for 1.5 hours.

[0074] Purification and crystallization step: The crude product of the hydrochlorination reaction is dissolved in ethyl acetate (80 mL).

[0075] Recrystallization is carried out using isopropanol, with the crystallization temperature controlled at 30 °C and the crystallization time being 4 hours.

[0076] Comparative Example 3: Lower dosage of methylation reagent Comparative example process: Catalytic reaction step: Reactants: 3-chloropropiophenone and naphthol are mixed in a mass ratio of 1:1.3.

[0077] Catalyst: Lipase is used as the catalyst, and the dosage of lipase is 1% of the total mass of the reactants.

[0078] Solvent: Supercritical carbon dioxide is used, the temperature is set at 80 °C, the reaction pressure is 12 MPa, and the reaction time is 4 hours.

[0079] Reduction step: The intermediate generated from the catalytic reaction is dissolved in tetrahydrofuran (50 mL).

[0080] Borohydride is added to the solution, the reaction time is controlled at 3 hours, and the dosage is 1.5 times the mass of the intermediate.

[0081] Methylation step: The reduction precursor is dissolved in dichloromethane (40 mL) under nitrogen protection.

[0082] Methyl iodide is added dropwise, and the dosage is 1.5 times the mass of the precursor. The reaction is carried out at room temperature for 5 hours.

[0083] Hydrochlorination step: The methylation product is dissolved in ethyl acetate (100 mL).

[0084] Hydrogen chloride gas is introduced into the solution, and the reaction is carried out at room temperature for 1.5 hours.

[0085] Purification and crystallization step: The crude product of the hydrochlorination reaction is dissolved in ethyl acetate (80 mL).

[0086] Recrystallization was carried out using isopropanol, with the crystallization temperature controlled at 30 °C and the crystallization time being 4 hours.

[0087] Comparative Example 4: Using a higher concentration of hydrogen chloride Comparative example procedure: Catalytic reaction step: Reactants: 3-chloropropiophenone and naphthol were mixed in a mass ratio of 1:1.2.

[0088] Catalyst: Lipase was used as the catalyst, and the amount of lipase was 1% of the total mass of the reactants.

[0089] Solvent: Supercritical carbon dioxide was used, the temperature was set at 80 °C, the reaction pressure was 12 MPa, and the reaction time was 4 hours.

[0090] Reduction step: The intermediate generated from the catalytic reaction was dissolved in tetrahydrofuran (50 mL).

[0091] Borohydride was added to the solution, the reaction time was controlled at 3 hours, and the amount used was 1.5 times the mass of the intermediate.

[0092] Methylation step: The reduction precursor was dissolved in dichloromethane (40 mL) under nitrogen protection.

[0093] Methyl iodide was added dropwise, and the amount used was 2 times the mass of the precursor. The reaction was carried out at room temperature for 5 hours.

[0094] Hydrochlorination step: The methylation product was dissolved in ethyl acetate (100 mL).

[0095] High-concentration hydrogen chloride gas (concentration 80%) was introduced into the solution, the reaction was carried out at room temperature for 1 hour.

[0096] Purification and crystallization step: The crude product of the hydrochlorination reaction was dissolved in ethyl acetate (80 mL).

[0097] Recrystallization was carried out using isopropanol, with the crystallization temperature controlled at 30 °C and the crystallization time being 4 hours.

[0098] Comparative experiment: Experimental purpose: This experiment aims to compare 3 examples and 4 comparative examples. By strictly controlling a single variable, analyze the effects of various factors on the product purity, yield, and by-product formation, and verify the advantages of the present invention in process optimization, selectivity control, and environmental friendliness.

[0099] Experimental materials: Examples 1 - 3; Comparative Examples 1-4; Experimental procedures: Catalytic reaction: Mix 3-chloropropiophenone and naphthol in a specified ratio.

[0100] Add a catalyst (lipase / MOF / anhydrous CuSO4) and a solvent (supercritical carbon dioxide or a traditional organic solvent).

[0101] Set the reaction temperature and time (30 - 120 °C, 2 - 6 hours).

[0102] After the reaction is completed, cool to room temperature and separate the target product by liquid-liquid extraction.

[0103] Reduction reaction: Take the intermediate obtained from the catalytic reaction and dissolve it in tetrahydrofuran or acetonitrile.

[0104] Add a reducing agent (borohydride or hydrogen), control the temperature (0 - 25 °C), and stir for 2 - 4 hours.

[0105] After the reaction is completed, recover the solvent by vacuum distillation and extract the target product.

[0106] Methylation reaction: Take the reduction product, dissolve it in dichloromethane, and stir under nitrogen protection.

[0107] Dropwise add a methylation reagent (methyl iodide or trimethylsilylmethane) to the reaction solution.

[0108] Control the temperature (0 - 25 °C) and stir for 4 - 6 hours.

[0109] After the reaction is completed, perform extraction and purification.

[0110] Hydrochlorination reaction: Dissolve the methylation product in ethyl acetate and pass hydrogen chloride gas through it.

[0111] Set the reaction temperature to room temperature and continue to pass the gas for 1 - 2 hours.

[0112] Filter and dry to obtain the crude product of dapoxetine hydrochloride.

[0113] Purification and crystallization: Dissolve the crude product in ethyl acetate and purify it by recrystallization.

[0114] Use isopropanol or ethyl acetate as the recrystallization solvent and control the temperature from room temperature to 50 °C.

[0115] Filter and dry to obtain the final high-purity dapoxetine hydrochloride.

[0116] Effects of different experimental conditions on the yield and purity of dapoxetine hydrochloride Summary: The reaction solvent plays a crucial role in the catalytic efficiency. Using supercritical carbon dioxide not only provides higher solubility but also enhances the reaction activity of the catalyst, resulting in both a higher yield and purity compared to the traditional organic solvent ethanol (Examples and Comparative Example 1). This advantage mainly stems from the high diffusivity of supercritical CO2, which allows reactants to more easily access the catalytic sites and increases the catalytic conversion rate. Additionally, during the reaction, supercritical CO2 can rapidly escape from the system, avoiding solvent residues and improving the product purity.

[0117] The selectivity of the reduction step has a profound impact on the quality of the final product. When using hydrogen as the reducing agent (Example 3), although the reaction is mild and there are fewer by-products, the yield is slightly higher compared to borohydride (Example 1). Under the action of a metal catalyst, hydrogen can selectively hydrogenate, avoiding unnecessary side reactions. However, when the solvent environment is poor or the catalyst activity is low, the reduction reaction may be inhibited, leading to a decrease in yield (Comparative Example 2).

[0118] Different hydrochlorination conditions directly affect the purity of the final product and the content of by-products. High-concentration hydrogen chloride (Comparative Example 4) leads to over-hydrochlorination, significantly increasing the content of by-products, while under standard concentration conditions (Examples 1, 2, and 3), the reaction is stable, ensuring the purity of the product. This is because at higher acidity, side reactions such as over-protonation or by-product rearrangement may occur, resulting in a decrease in the final purity. Therefore, controlling the concentration of hydrogen chloride is crucial for optimizing the reaction.

[0119] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing dapoxetine hydrochloride, characterized in that, It includes the following steps: Catalytic reaction step: Provide 3-chloropropiophenone and naphthol as reactants, and use a catalyst to carry out a condensation reaction to generate a reaction intermediate; Reduction step: Carry out a reduction reaction on the reaction intermediate with a reducing agent to form a reduction precursor; Methylation step: Carry out a methylation reaction on the reduction precursor with a methylation reagent to introduce a methyl group; Hydrochlorination step: Carry out a hydrochlorination reaction on the methylation product with hydrogen chloride to generate dapoxetine hydrochloride; Purification and crystallization step: Carry out purification and crystallization treatment on the dapoxetine hydrochloride to obtain the final product.

2. The preparation method of dapoxetine hydrochloride according to claim 1, wherein, The catalytic reaction step includes: Mix 3-chloropropiophenone and naphthol at a weight ratio of 1:1.2 to 1:1.5; Use a lipase or a metal-organic framework catalyst, and its dosage is 0.5 to 3 of the total mass of the reactants, to carry out a condensation reaction; React in a green solvent, and the green solvent is supercritical carbon dioxide. The reaction temperature is controlled at 30 to 80 °C, and the reaction time is controlled at 2 to 6 hours.

3. The preparation method of dapoxetine hydrochloride according to claim 1, wherein The reduction step includes: Dissolve the reaction intermediate generated in the catalytic reaction step in an organic solvent; Add a reducing agent to the above solution. The reducing agent is borohydride or hydrogen, and its dosage is 1 to 3 of the mass of the intermediate.

4. The preparation method of dapoxetine hydrochloride according to claim 1, characterized in that, The methylation step includes: Dissolve the precursor obtained in the reduction step in an organic solvent. The organic solvent is selected from dichloromethane or acetonitrile, and it is carried out under nitrogen protection; Add a methylation reagent to the above solution. The methylation reagent is selected from methyl iodide or trimethylsilylmethane, and its addition method is by dropwise addition, and its dosage is 1 to 3 of the mass of the precursor.

5. The preparation method of dapoxetine hydrochloride according to claim 4, characterized in that, The methylation step further includes: React at a reaction temperature of 0 to 25 °C; The reaction time is controlled at 4 to 6 hours.

6. The preparation method of dapoxetine hydrochloride according to claim 1, characterized in that, The hydrochlorination step includes: Dissolve the product obtained in the methylation step in a suitable organic solvent. The organic solvent is selected from ethyl acetate; Introduce hydrogen chloride gas into the above solution; React at room temperature, and the reaction time is controlled at 1 to 2 hours.

7. A method for preparing dapoxetine hydrochloride according to claim 1, characterized in that, The purification and crystallization step includes: Dissolve the crude product obtained in the hydrochlorination step in an organic solvent. The organic solvent is selected from ethyl acetate; Adopt a recrystallization method to purify the crude product with isopropyl alcohol or ethyl acetate; Carry out crystallization treatment at room temperature to 50 °C to obtain the product.

8. A method for preparing dapoxetine hydrochloride according to claim 2, characterized in that, The green solvent includes supercritical carbon dioxide, and the reaction conditions include: The reaction temperature is 100 to 120 °C; The reaction pressure is 10 to 15 MPa; The reaction time is 2 to 4 hours.

9. The preparation method of dapoxetine hydrochloride according to claim 2, characterized in that, When the catalyst is lipase, its dosage is 0.5 to 2 of the total mass of the reactants. When the catalyst is a metal-organic framework catalyst, its dosage is 1 to 3 of the total mass of the reactants.

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