Preparation method of dapoxetine hydrochloride

Abstract

The invention discloses a preparation method of dapoxetine hydrochloride, which adopts acetonitrile as a reaction solvent, is easy to recycle and reuse, and avoids the generation of a large amount of nitrogen-containing wastewater; sodium hydroxide or potassium hydroxide is used as an acid-binding agent which is cheap and easy to obtain; isopropyl ether is adopted as a crystallization solvent, heating is carried out until reflux is achieved, filtering is carried out while the solution is hot, insoluble impurities with large polarity can be filtered out, filtrate is cooled to-10-10 DEG C for crystallization, solid-liquid separation is carried out, impurities with small polarity can be removed, and the obtained dapoxetine base is good in crystallization performance. And the defect that the hydrochloride is prepared by introducing hydrogen chloride gas in the prior art is avoided. According to the dapoxetine hydrochloride, methylbenzene is adopted as a reaction solvent, concentrated hydrochloric acid is adopted as acid, after charging is completed, heating is conducted till backflow and water separation are conducted, after water separation is completed, a large amount of white crystalline solid dapoxetine hydrochloride can be separated out, and the dapoxetine hydrochloride prepared through the method and the intermediate of the dapoxetine hydrochloride are high in yield and purity.

Description

Technical Field

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

[0002] Dapoxetine (trade name Priligy) is a new type of fast-acting selective serotonin reuptake inhibitor (SSRI), which is applicable to the treatment of premature ejaculation in men aged 18 - 64. It can take effect after the first dose, has a short half-life, and there is no need to worry about drug accumulation in the body. It has been launched in China, Finland, Sweden, Portugal, Austria, Italy, Spain, Germany, etc., and has good market prospects.

[0003] Journal Document 1 reported a safe and inexpensive method for introducing asymmetric reduction of ketones. The production cost of (R)-(+)-3-chloro-1-phenyl-1-propanol has been significantly reduced. As an intermediate for the preparation of dapoxetine hydrochloride, this route has the defect that the elimination side reaction is relatively serious during the dimethylamino substitution reaction, resulting in low yield and complex product purification process.

[0004] Patent Document 1 reported that using (R)-(+)-3-chloro-1-phenyl-1-propanol (2) and 1-naphthol (3) as starting materials, sodium hydride as the base, DMF as the solvent, reacting overnight at room temperature, pouring the reactant into water, extracting with ethyl acetate, combining the organic phases, washing with water, washing with 1N sodium hydroxide aqueous solution, drying with anhydrous sodium sulfate, evaporating the solvent to obtain the crude product of compound 4 (yield 92%); recrystallizing with n-hexane / ethyl acetate to obtain compound 4 R-3-(1-naphthyloxy)-1-phenyl-1-propanol (yield 54%); compound 4 reacts with triethylamine, 4-dimethylaminopyridine (DMAP), and methanesulfonyl chloride (MsCl) to obtain the active intermediate 5. Without separation, dimethylamine is added and the reaction is closed at room temperature for 40 hours. The reaction solution is poured into water, and the pH is adjusted to 12.95 with 5N sodium hydroxide aqueous solution, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and the solvent is evaporated to obtain dapoxetine base (6) (yield 94%); the obtained dapoxetine base is dissolved in dry ethyl acetate, insoluble substances are removed by suction filtration, and a solution of hydrogen chloride in ethyl acetate is added to the filtrate, and the precipitate is collected by filtration to obtain dapoxetine hydrochloride (yield 69%). The process route diagram is as follows:

[0005]

[0006] This process uses sodium hydride, and the reaction operation process is dangerous; using n-hexane / ethyl acetate for recrystallization has a low yield; using a solution of hydrogen chloride in ethyl acetate has a high production cost; the purity of the dapoxetine base obtained by this process is relatively low; the yield of the step of forming dapoxetine hydrochloride is relatively low.

[0007] Patent Document 2 reported that using 3-chloropropiophenone (7) and 1-naphthol (3) as starting materials, under nitrogen protection, using potassium carbonate, sodium hydroxide or potassium hydroxide as the base, and N,N-dimethylformamide (DMF) as the reaction solvent, reacting at 15 - 50 °C for 15 - 40 hours. After the reaction was completed, it was poured into water, and the insoluble matter was collected to obtain the etherified product (8) (yield 64% - 74%); the etherified product (8) was subjected to asymmetric reduction to obtain compound 4 (yield 72% - 92%); compound 4 reacted with triethylamine, DMAP, and MsCl for a period of time, then dimethylamine hydrochloride was added and reacted at 15 - 40 °C for 25 - 80 h, then added to water, the pH value was adjusted to 13 with NaOH solution, extracted and layered with ethyl acetate, the organic layer was dried with anhydrous sodium sulfate, then filtered and distilled to an oily substance, then cooled and crystallized by filtration to obtain the solid of dapoxetine free base. The solid of dapoxetine free base was dissolved in isopropanol (IPA), and then the isopropanol solution of hydrogen chloride was added for crystallization to obtain dapoxetine hydrochloride (yield 90% - 94%).

[0008]

[0009] In this process, DMF was used as the solvent for the etherification reaction, and a large amount of nitrogen-containing wastewater would be generated during the post-treatment process; when preparing compound 1 from compound 4 in this process, dimethylamine hydrochloride was used as the reaction material, and the hydrochloride form of dimethylamine reduced the nucleophilicity of dimethylamine, which would cause the reaction to be difficult to proceed completely, and thus the repeatability of this process was poor.

[0010] Journal Document 2 reported that compound 4 was stirred at room temperature for 12 h under the action of triethylamine, DMAP, and methylsulfonyl chloride. Then, the temperature was lowered to 0 °C, dimethylamine hydrochloride was added, and then an excessive amount of triethylamine was added, and the reaction was continued to stir at room temperature for 24 h. After the reaction was completed, it was extracted with ethyl acetate, dried with anhydrous sodium sulfate, the solvent was evaporated to obtain the crude product of dapoxetine base. Finally, it was purified by silica gel column chromatography, and the eluent was dichloromethane / methanol (9:1) to obtain the oily substance of dapoxetine base (yield 70%).

[0011]

[0012] This process uses triethylamine to free dimethylamine hydrochloride to in-situ obtain dimethylamine, overcoming the disadvantage of insufficient nucleophilicity of dimethylamine hydrochloride. However, the purification of dapoxetine base by silica gel column chromatography has a cumbersome operation process and does not have the prospect of industrial application. The melting point of dapoxetine base is 48 - 49 °C. Although the literature uses silica gel column chromatography for the purification of dapoxetine base, the obtained dapoxetine base is an oily substance, indicating that the crystallization performance of dapoxetine base is poor.

[0013] Patent Document 3 reported that when preparing dapoxetine hydrochloride, excessive hydrochloric acid gas would cause the precipitated dapoxetine hydrochloride product to dissolve or turn into an oily substance, making it difficult for separation and purification. Excessive hydrochloric acid gas was likely to overflow, requiring high requirements for operators and equipment. This patent reported that the dapoxetine base was salted out and dissolved clearly under the action of an alcohol solvent / hydrogen chloride gas, and then an ether solvent was added dropwise for crystallization, and the crystals were collected to obtain dapoxetine hydrochloride (yield 75%-79%). However, the yield of the salting-out step in this process was low. Using a mixed solvent for recrystallization was difficult to recycle and reuse, resulting in high production costs.

[0014] Journal Document 3 reported that when preparing the dapoxetine base from Compound 5, a tetrahydrofuran solution of dimethylamine was used, stirred at 25 °C for 15 h, the solvent was evaporated, water and dichloromethane were added to the residue, the organic phase was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oily substance 6 (yield 74.2%); 6 was dissolved in ethyl acetate, cooled to 0-5 °C, dry hydrogen chloride gas was introduced until the pH reached 1.0, stirred for crystallization, and filtered to obtain white solid dapoxetine hydrochloride (yield 98%). The tetrahydrofuran solution of dimethylamine used in this process was expensive, and the obtained dapoxetine was a brown oily substance containing a large amount of impurities; obtaining dapoxetine hydrochloride by introducing dry hydrogen chloride gas and controlling the pH had poor process controllability. Once excessive hydrogen chloride gas was introduced, the precipitated solid dapoxetine hydrochloride in the reaction system was likely to dissolve. If the amount of hydrogen chloride gas introduced was insufficient, the yield would be reduced.

[0015] Journal Document 1: Org. Process Res. Dev. 2012, 16, 710-713;

[0016] Journal Document 2: Tetrahedron Letters, 2013, 54(45), 5991–5993;

[0017] Journal Document 3: China Pharmacy, 2020, (31), 7: 816-819;

[0018] Patent Document 1: US5292962;

[0019] Patent Document 2: CN107382751;

[0020] Patent Document 3: CN113880721.

[0021] In summary, providing a synthesis process with low production cost, high product purity, and high reactant yield is still an urgent technical problem to be solved in the field of dapoxetine synthesis. Summary of the Invention

[0022] In view of the deficiencies of the prior art, the present invention provides a preparation method of dapoxetine hydrochloride with high yield and high product purity.

[0023] The present invention provides a preparation method of dapoxetine hydrochloride, comprising the following steps:

[0024]

[0025] S1, Preparation of R-3-(1-naphthyloxy)-1-phenyl-1-propanol:

[0026] Add (R)-(+)-3-chloro-1-phenyl-1-propanol, 1-naphthol, an acid-binding agent, and a solvent into a reaction vessel respectively, heat up to reflux, maintain reflux and stir for reaction, distill off the solvent under reduced pressure, add deionized water, heat up to 85°C - 95°C, then cool down to 25°C - 30°C to precipitate a solid product, filter by suction, and dry under vacuum to obtain an off-white solid.

[0027] Preferably, in step S1, the acid-binding agent is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, triethylamine, etc. Considering cost factors, sodium hydroxide or potassium hydroxide is preferred, and the alkalinity of potassium hydroxide / sodium hydroxide is strong, and the catalytic effect is better than that of triethylamine and potassium carbonate.

[0028] Preferably, in step S1, the solvent is acetonitrile. Commonly used polar aprotic solvents, such as DMF, require a method of extruding the product by adding water during post-treatment, which will produce nitrogen-containing wastewater and is not easy to recycle. Therefore, the present invention uses acetonitrile as the solvent.

[0029] Preferably, in step S1, the reflux stirring reaction time is 7 - 10 h, preferably 8 h.

[0030] Preferably, in step S1, the molar ratio of (R)-(+)-3-chloro-1-phenyl-1-propanol to 1-naphthol is 1:1.05 - 1.3, preferably 1:1.1. A slight excess of 1-naphthol can ensure the complete reaction of (R)-(+)-3-chloro-1-phenyl-1-propanol and improve the conversion rate of the more expensive material.

[0031] Preferably, in step S1, the molar ratio of (R)-(+)-3-chloro-1-phenyl-1-propanol to potassium hydroxide is 1:1.1 - 1.5, preferably 1:1.2.

[0032] S2, Preparation of dapoxetine:

[0033] Compound 4, tetrahydrofuran, triethylamine, and DMAP were added to a reaction vessel. Under nitrogen protection, the temperature was lowered to -5°C - 10°C. While maintaining the temperature at -5°C - 10°C, methanesulfonyl chloride was added dropwise. After the addition was complete, the mixture was stirred at -5°C - 10°C for 1 - 2 h. Dimethylamine hydrochloride was added, followed by triethylamine. The mixture was stirred and reacted for 7 - 10 h, preferably 8 h. The solvent was removed by distillation under reduced pressure. Deionized water and dichloromethane were added for extraction. The organic phase was separated, washed with deionized water, and the solvent was removed by distillation under reduced pressure to obtain a brown oil, which was the crude product of dapoxetine.

[0034] Preferably, in step S2, the molar ratio of compound 4 to the first added triethylamine, methanesulfonyl chloride, DMAP, dimethylamine hydrochloride, and the second added triethylamine is 1:1.1 - 2:1.1 - 2:0.01 - 0.1:3 - 5:3 - 5, preferably 1:1.5:1.3:0.05:4:4.

[0035] Compound 4 to compound 6 underwent two reactions:

[0036]

[0037] The first added triethylamine served as an acid-binding agent for compound 4 and methanesulfonyl chloride (1 equivalent of HCl is generated during the reaction of the alcohol hydroxyl group in compound 4 with methanesulfonyl chloride); the second added triethylamine was used to convert dimethylamine hydrochloride into dimethylamine (the basicity of triethylamine is stronger than that of dimethylamine), enhancing the nucleophilicity of dimethylamine.

[0038] Preferably, in step S2, it also includes heating the brown oil obtained in the above operation steps to reflux in an ether solvent, filtering while hot to remove insoluble impurities, cooling to -10°C - 10°C, stirring for crystallization, filtering by suction, and drying in vacuo to obtain an off-white solid, which is the refined product of dapoxetine; the ether solvent is selected from at least one of isopropyl ether, methyl tert-butyl ether, and ethyl tert-butyl ether; more preferably isopropyl ether.

[0039] S3. Preparation of dapoxetine hydrochloride:

[0040] Dapoxetine and a solvent were added to a reaction vessel, concentrated hydrochloric acid was added, and the mixture was stirred at 20°C - 30°C for 1 ± 0.5 h, then heated to reflux for 3 ± 0.5 h to separate water. The temperature was lowered to 35°C - 45°C, and filtered by suction. The filter cake was dried in vacuo at 65°C - 75°C to obtain a white crystalline solid.

[0041] Preferably, in step S3, the solvent is toluene or n-heptane.

[0042] Both of these two solvents are immiscible with water, and the water-separation method can be used to remove the water in the salification system to improve the yield. Alcohols such as isopropanol and ethanol are miscible with water, and the water-separation method cannot be used to remove the water in the system. Moreover, alcohols have a high solubility in dapoxetine hydrochloride, resulting in a low yield.

[0043] Preferably, in step S3, the molar ratio of dapoxetine to concentrated hydrochloric acid in the feed is 1:1.0 - 1.2, preferably 1:1.05; the mass-to-volume ratio of dapoxetine to toluene is 1:3 - 10, preferably 1:5.

[0044] Compared with the prior art, the technical solution provided by this application has the following beneficial effects:

[0045] (1) This application provides a method for efficiently preparing R-3-(1-naphthyloxy)-1-phenyl-1-propanol. Using acetonitrile as the reaction solvent, it is easy to recycle and avoid the generation of a large amount of nitrogen-containing wastewater. Using sodium hydroxide or potassium hydroxide as the acid-binding agent, it is inexpensive and easily available. The purity of the obtained R-3-(1-naphthyloxy)-1-phenyl-1-propanol reaches over 98%, and the yield reaches over 90%.

[0046] (2) This application provides a crystallization purification method for preparing high-purity dapoxetine base, eliminating the silica gel column chromatography purification method. Different from the prior art scheme of dissolving the prepared dapoxetine base oil in an ester and then introducing hydrogen chloride gas directly to prepare dapoxetine hydrochloride, this application first crystallizes and purifies the dapoxetine base in the oil, and explores the most suitable solvent type. Further combined with heating under reflux and hot filtration to remove the relatively polar insoluble impurities, and then cooling and crystallization to remove the relatively non-polar impurities, so that the purity of the obtained dapoxetine base reaches over 99.5%, improving the crystallization performance. Subsequently, preparing dapoxetine hydrochloride not only improves the yield but also makes the purity of dapoxetine hydrochloride reach over 99.5%.

[0047] (3) This application provides a method for efficiently preparing dapoxetine hydrochloride. Using toluene as the reaction solvent and concentrated hydrochloric acid as the acid for salification, it overcomes the defect in the prior art that the precipitated dapoxetine hydrochloride product dissolves due to introducing a slightly excessive amount of hydrogen chloride gas, resulting in unstable yield, improves the yield of the product, and reduces the production cost. The salification step is combined with the crystallization scheme of dapoxetine base, further improving the product purity. Under the combined action of the two, the yield reaches over 95%, and the purity reaches over 99.5%.

[0048] (4) The preparation method provided by this application has a short reaction time, shortening the production cycle and improving the production efficiency. Description of the Drawings

[0049] The accompanying drawings forming a part of this invention are used to provide a further understanding of the invention. The schematic embodiments and descriptions thereof of the invention are used to explain the invention and do not constitute an improper limitation of the invention. Description of the Drawings:

[0051] Figure 1 It is the HPLC chromatogram of the crude dapoxetine in Step 2;

[0052] Figure 2 It is the HPLC chromatogram of the refined dapoxetine in Step 2;

[0053] Figure 3 It is the HPLC chromatogram of the insoluble impurities in Step 2;

[0054] Figure 4 It is the HPLC chromatogram of the refined mother liquor in Step 2;

[0055] Figure 5 It is the HPLC chromatogram of dapoxetine hydrochloride in Step 3;

[0056] Figure 6 It is the DSC chromatogram of dapoxetine hydrochloride in Step 3. Detailed Description of the Invention

[0057] It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which this invention belongs.

[0058] HPLC Purity Detection Method:

[0059] Instruments and Chromatographic Conditions: High Performance Liquid Chromatograph; Chromatographic Column Model: Agilent ZORBAX Extend-C18 3.5μm, 150*4.6mm; Mobile Phase: 0.04% Diethylamine - 10mmol / L Sodium Bicarbonate Aqueous Solution as Mobile Phase A, Acetonitrile as Mobile Phase B, gradient elution is carried out according to Table 1; Detection Wavelength: 210nm; Injection Volume: 10μl; Flow Rate: 1.0mL / min; Column Temperature: 35°C; Running Time: 62min.

[0060] Table 1 Gradient Elution Program

[0061]

[0062] Example 1,

[0063] 1. Preparation of R-3-(1-Naphthyloxy)-1-phenyl-1-propanol (4)

[0064]

[0065] The reaction route is as above. (R)-(+)-3-chloro-1-phenyl-1-propanol (170.6 g, 1.0 mol), 1-naphthol (158.6 g, 1.1 mol), potassium hydroxide (67.3 g, 1.2 mol), and acetonitrile (500 mL) were respectively added to the reaction flask. The temperature was raised to reflux, and the reaction was stirred under reflux for 8 h. The solvent was removed by distillation under reduced pressure. Deionized water (500 mL) was added, and the temperature was raised to 90 °C. Then, the temperature was lowered to 25 - 30 °C, and filtration was carried out. Vacuum drying was performed at 50 °C for 8 h to obtain 266.1 g of an off-white solid with a yield of 95.6% and an HPLC purity of 98.5%. When the temperature reached 90 °C, R-3-(1-naphthyloxy)-1-phenyl-1-propanol was in a molten state. The main effect achieved by this method was to remove impurities such as potassium 1-naphtholate and potassium chloride.

[0066] 2. Preparation of dapoxetine

[0067]

[0068] Compound 4 (266.1 g, 0.956 mol), tetrahydrofuran (1600 mL), triethylamine (145.1 g, 1.434 mol), and DMAP (5.8 g, 0.0478 mol) were added to the reaction flask. Under nitrogen protection, the temperature was lowered to -5 °C, and the temperature was maintained at -5 °C - 10 °C. Methanesulfonyl chloride (142.4 g, 1.243 mol) was added dropwise. After the addition was complete, the reaction was stirred at 0 °C for 2 h. Dimethylamine hydrochloride (311.8 g, 3.824 mol) was added, and then triethylamine (387.0 g, 3.824 mol) was added. The mixture was stirred and reacted for 8 h. The solvent was removed by distillation under reduced pressure. Deionized water (1500 mL) and dichloromethane (1500 mL) were added for extraction. The organic phase was separated, and the organic phase was washed with deionized water (500 mL). The solvent was removed by distillation under reduced pressure to obtain a brown oil, which was the crude product of dapoxetine. The HPLC purity was 97.0%.

[0069] In the present invention, triethylamine can liberate dimethylamine with strong nucleophilicity. Compared with the method of directly adding dimethylamine gas, the feeding is convenient and the cost is low. The present invention preferably uses triethylamine. After the reaction is completed, it is washed with water, evaporated to dryness, and then refined with isopropyl ether. Different from other methods of forming salts and washing by first adding acid and then adjusting the pH with an alkaline solution, the product obtained by the method provided by the present invention has high purity, good properties, and strong controllability.

[0070] The brown oil obtained in the above operation steps and isopropyl ether (550 mL) were added to the reaction flask. The temperature was raised to reflux, and hot filtration was carried out to remove insoluble impurities. The temperature was lowered to -10 °C, and crystallization was carried out with stirring for 1 h. Filtration was carried out, and vacuum drying was performed at 30 °C for 8 h to obtain an off-white solid, which was the fine product of dapoxetine, with a weight of 267.2 g, a yield of 91.5%, and an HPLC purity of 99.9%.

[0071] One innovative point of the present invention is to first add triethylamine as an acid-binding agent, and then add triethylamine again to convert dimethylamine hydrochloride into dimethylamine, enhancing the nucleophilicity, and then using isopropyl ether for refining to obtain a relatively high-purity dapoxetine base.

[0072] Another innovative point of the present invention is to remove the moisture in the system (water has a certain solubility in dapoxetine hydrochloride, and the presence of water can reduce the yield) by refluxing and separating water through a toluene / concentrated hydrochloric acid system for the relatively high-purity base, and prepare high-purity dapoxetine hydrochloride (above 99.5%) with a high yield (above 95%). At the same time, combining these two innovative points has a better effect. If the dapoxetine base is not refined, then the toluene / concentrated hydrochloric acid system method cannot obtain high-purity dapoxetine hydrochloride.

[0073] The HPLC chromatograms of crude dapoxetine, the HPLC chromatograms of high-quality dapoxetine, the HPLC pictures of insoluble impurities, and the HPLC chromatograms of the refining mother liquor (the filtrate after suction filtration) are as Figures 1 to 4 shown.

[0074] 3. Preparation of Dapoxetine Hydrochloride

[0075]

[0076] Add dapoxetine (267.2 g, 0.875 mol) and toluene (1336 mL) to a reaction flask. At 25 °C, add concentrated hydrochloric acid (76.6 mL, 0.919 mol), maintain stirring and reaction at 25 °C for 1 h, heat up to reflux, separate water for 3 h, cool down to 40 °C, carry out suction filtration, and dry the filter cake in vacuo at 70 °C to obtain 296.1 g of a white crystalline solid. The yield is 99.0% and the HPLC purity is 100%. The HPLC chromatograms and DSC chromatograms of dapoxetine hydrochloride are as Figures 5 to 6 shown.

[0077] Example 2

[0078] 1. Preparation of R-3-(1-naphthyloxy)-1-phenyl-1-propanol (4)

[0079] (R)-(+)-3-chloro-1-phenyl-1-propanol (170.6 g, 1.0 mol), 1-naphthol (151.4 g, 1.05 mol), potassium hydroxide (61.7 g, 1.1 mol), and acetonitrile (400 mL, the recycled acetonitrile obtained in Example 1 was used in this example) were respectively added to a reaction flask. The temperature was raised to reflux, and the reaction was stirred under reflux for 7 h. The solvent was removed by distillation under reduced pressure. Deionized water (500 mL) was added, and the temperature was raised to 90 °C. Then, the temperature was lowered to 25 - 30 °C, and filtration was carried out. Vacuum drying was performed at 50 °C for 8 h to obtain 254.7 g of an off-white solid with a yield of 91.5% and an HPLC purity of 98.1%.

[0080] 2. Preparation of dapoxetine

[0081] Compound 4 (254.7 g, 0.915 mol), tetrahydrofuran (1600 mL), triethylamine (101.9 g, 1.007 mol), and DMAP (1.1 g, 0.00915 mol) were added to a reaction flask. Under nitrogen protection, the temperature was lowered to -5 °C, and the temperature was maintained at -5 °C - 10 °C. Methanesulfonyl chloride (115.4 g, 1.007 mol) was added dropwise. After the addition was complete, the reaction was stirred at 0 °C for 2 h. Dimethylamine hydrochloride (223.8 g, 2.745 mol) was added, and then triethylamine (277.8 g, 2.745 mol) was added. The mixture was stirred and reacted for 8 h. The solvent was removed by distillation under reduced pressure. Deionized water (1500 mL) and dichloromethane (1500 mL) were added for extraction. The organic phase was separated, and the organic phase was washed with deionized water (500 mL). The solvent was removed by distillation under reduced pressure to obtain a brown oil.

[0082] The brown oil obtained in the above operation steps and methyl tert-butyl ether (550 mL) were added to a reaction flask. The temperature was raised to reflux, and filtration was carried out while it was hot to remove insoluble impurities. The temperature was lowered to 0 °C, and crystallization was carried out with stirring for 1 h. Filtration was carried out, and vacuum drying was performed at 30 °C for 8 h to obtain 253.5 g of an off-white solid with a yield of 90.7% and an HPLC purity of 99.9%.

[0083] 3. Preparation of dapoxetine hydrochloride

[0084] Dapoxetine (253.5 g, 0.830 mol) and toluene (760.5 mL) were added to a reaction flask. At 25 °C, concentrated hydrochloric acid (69.2 mL, 0.830 mol) was added, and the reaction was stirred at 25 °C for 1 h. The temperature was raised to reflux, and water was separated for 3 h. The temperature was lowered to 40 °C, and filtration was carried out. The filter cake was vacuum dried at 70 °C to obtain 280.3 g of a white crystalline solid. The yield was 98.8%, and the HPLC purity was 100%.

[0085] As can be seen from this example, using recycled acetonitrile for the preparation of R-3-(1-naphthyloxy)-1-phenyl-1-propanol has no obvious effect on the yields and purities of this reaction and subsequent reactions.

[0086] Example 3

[0087] 1. Preparation of R-3-(1-naphthyloxy)-1-phenyl-1-propanol (4)

[0088] Add (R)-(+)-3-chloro-1-phenyl-1-propanol (170.6 g, 1.0 mol), 1-naphthol (187.4 g, 1.3 mol), potassium hydroxide (84.2 g, 1.5 mol), and acetonitrile (500 mL) into a reaction flask respectively. Heat up to reflux, maintain reflux and stir for 10 h. Distill off the solvent under reduced pressure. Add deionized water (500 mL), heat up to 90 °C, then cool down to 25 - 30 °C, filter by suction, and dry in vacuum at 50 °C for 8 h to obtain 256.9 g of off-white solid, with a yield of 92.3% and an HPLC purity of 98.3%.

[0089] 2. Preparation of dapoxetine

[0090] Add compound 4 (256.9 g, 0.923 mol), tetrahydrofuran (1600 mL), triethylamine (186.8 g, 1.846 mol), and DMAP (11.3 g, 0.0923 mol) into a reaction flask. Under nitrogen protection, cool down to -5 °C, maintain the temperature at -5 °C - 10 °C, and dropwise add methanesulfonyl chloride (211.5 g, 1.846 mol). After dropping, stir at 0 °C for 2 h. Add dimethylamine hydrochloride (376.3 g, 4.615 mol), then add triethylamine (467.0 g, 4.615 mol). Stir the mixture for 8 h. Distill off the solvent under reduced pressure. Add deionized water (1500 mL) and dichloromethane (1500 mL) for extraction. Separate the organic phase, wash the organic phase with deionized water (500 mL), and distill off the solvent under reduced pressure to obtain a brown oily substance.

[0091] Add the brown oily substance obtained in the above operation steps and ethyl tert-butyl ether (550 mL) into a reaction flask. Heat up to reflux, filter while hot to remove insoluble impurities. Cool down to 10 °C, stir for crystallization for 1 h, filter by suction, and dry in vacuum at 30 °C for 8 h to obtain 254.4 g of off-white solid, with a yield of 90.3% and an HPLC purity of 99.8%.

[0092] 3. Preparation of dapoxetine hydrochloride

[0093] Dapoxetine (254.4 g, 0.833 mol) and n-heptane (2554 mL) were added to a reaction flask. At 25 °C, concentrated hydrochloric acid (83.3 mL, 0.100 mol) was added, and the mixture was stirred at 25 °C for 1 h. Then the temperature was raised to reflux, and water was separated for 3 h. The temperature was then lowered to 40 °C, and filtration was performed by suction. The filter cake was dried in vacuo at 70 °C to obtain 279.0 g of a white crystalline solid. The yield was 97.9%, and the HPLC purity was 99.9%.

[0094] Comparative Example 1

[0095] Purification of dapoxetine (investigating the purification solvent of dapoxetine)

[0096] According to the operation steps of Example 1, the obtained brown oil (50 g) and the purification solvent (150 mL) were added to a reaction flask. The temperature was raised to reflux, and hot filtration was carried out. The temperature was lowered to -10 °C, and crystallization was carried out with stirring for 1 h. Filtration was performed by suction. The yield, purity, and properties of the obtained product are shown in the following table:

[0097] Name of refined solvent Dry weight of obtained dapoxetine Yield of obtained dapoxetine Purity of obtained product Color of product Ethanol 39.1g 78.1％ 98.1 Yellow Isopropanol 41.7g 83.4％ 97.6 Yellow

[0098] It can be seen that when other alcohol solvents are used for the purification of dapoxetine, the yield of dapoxetine is relatively low, the purity of the obtained product is low, and the yield and purity are inferior to those of isopropyl ether.

[0099] Comparative Example 2

[0100] Purification of dapoxetine (investigating the purification temperature of dapoxetine)

[0101] According to the operation steps of Example 1, the obtained brown oil (50 g) and the purification solvent (150 mL) were added to a reaction flask. The temperature was raised to reflux, and hot filtration was carried out. The temperature was lowered to a certain temperature, and crystallization was carried out with stirring for 1 h. Filtration was performed by suction. The yield, purity, and properties of the obtained product are shown in the following table:

[0102] Crystallization temperature Dry weight of obtained dapoxetine Yield of obtained dapoxetine Purity of obtained product Color of product -20℃ 47.7g 95.3％ 98.7％ Yellow 20℃ 42.4g 84.8％ 99.8％ Off-white 30℃ 37.8g 75.6％ 99.9％ Off-white

[0103] It can be seen that if the crystallization temperature is higher than 10 °C, the yield will decrease, and if it is lower than -10 °C, it is not easy to achieve industrial production and the energy consumption is relatively high.

[0104] Comparative Example 3

[0105] Preparation of dapoxetine hydrochloride

[0106] According to the operation steps of Example 1, the obtained brown oil (50 g) was directly salted out using the concentrated hydrochloric acid / toluene system without purification according to the operation steps of Example 1. The purity of the obtained product was 96.4%, and the yield was 98.6%.

[0107] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A preparation method of dapoxetine hydrochloride, characterized in that, It includes the following steps: S1, Preparation of R-3-(1-naphthyloxy)-1-phenyl-1-propanol: Add (R)-(+)-3-chloro-1-phenyl-1-propanol, 1-naphthol, an acid-binding agent, and a solvent into a reaction vessel respectively, heat up to reflux, maintain reflux and stir the reaction, distill off the solvent under reduced pressure, add deionized water, heat up to 85 °C - 95 °C and then cool down to 25 - 30 °C to precipitate a solid product, filter by suction, and dry under vacuum to obtain an off-white solid, which is R-3-(1-naphthyloxy)-1-phenyl-1-propanol; S2, Preparation of dapoxetine: Add R-3-(1-naphthyloxy)-1-phenyl-1-propanol, tetrahydrofuran, triethylamine, and 4-dimethylaminopyridine into a reaction vessel. Under nitrogen protection, cool down to -5 °C - 10 °C, maintain the temperature, dropwise add methanesulfonyl chloride. After the addition is complete, stir the reaction at -10 °C - 0 °C, add dimethylamine hydrochloride, then add triethylamine, stir the mixture for reaction, distill off the solvent under reduced pressure, add deionized water and dichloromethane for extraction, separate the organic phase, wash the organic phase with deionized water, distill off the solvent under reduced pressure to obtain a brown oil, which is the crude product of dapoxetine; S3, Preparation of dapoxetine hydrochloride: Add dapoxetine and a solvent into a reaction vessel, add concentrated hydrochloric acid, stir the reaction, heat up to reflux for water separation, cool down, filter by suction, and dry the filter cake under vacuum to obtain a white crystalline solid.

2. The preparation method of dapoxetine hydrochloride according to claim 1, wherein In step S1, the acid-binding agent is selected from one or a combination of several of sodium hydroxide, potassium hydroxide, potassium carbonate, and triethylamine.

3. The preparation method of dapoxetine hydrochloride according to claim 1, characterized in that, In step S1, the solvent is acetonitrile.

4. The preparation method of dapoxetine hydrochloride according to claim 1, wherein, In step S1, the molar dosage ratio of (R)-(+)-3-chloro-1-phenyl-1-propanol to 1-naphthol is 1:1.05 - 1.3, preferably 1:1.

1.

5. The preparation method of dapoxetine hydrochloride according to claim 1, characterized in that, In step S1, the molar dosage ratio of (R)-(+)-3-chloro-1-phenyl-1-propanol to potassium hydroxide is 1:1.1 - 1.5, preferably 1:1.

2.

6. The preparation method of dapoxetine hydrochloride according to claim 1, characterized in that, In step S2, the molar dosage ratio of R-3-(1-naphthyloxy)-1-phenyl-1-propanol to the first added triethylamine, methanesulfonyl chloride, 4-dimethylaminopyridine, dimethylamine hydrochloride, and the second added triethylamine is 1:1.1 - 2:1.1 - 2:0.01 - 0.1:3 - 5:3 - 5.

7. The preparation method of dapoxetine hydrochloride according to claim 1, wherein, In step S2, it also includes heating the obtained brown oil to reflux in an ether solvent, filtering while hot to remove insoluble impurities, cooling down to -10 °C - 10 °C, stirring for crystallization, filtering by suction, and drying under vacuum to obtain an off-white solid, which is the refined product of dapoxetine; the ether solvent is selected from at least one of isopropyl ether, methyl tert-butyl ether, and ethyl tert-butyl ether; more preferably isopropyl ether.

8. The preparation method of dapoxetine hydrochloride according to claim 1, characterized in that, In step S3, the solvent is toluene or n-heptane.

9. The preparation method of dapoxetine hydrochloride according to claim 1, characterized in that, In step S3, the molar feeding ratio of dapoxetine to concentrated hydrochloric acid is 1:1.0 - 1.2, preferably 1:1.05; when the solvent is toluene, the mass-volume ratio of dapoxetine to toluene is 1:3 - 10, preferably 1:

5.

10. The preparation method of dapoxetine hydrochloride according to claim 1, wherein, In step S3, the reaction temperature is 20 °C - 30 °C, cool down to 35 °C - 45 °C after water separation, and dry the filter cake under vacuum at 65 °C - 75 °C.

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