Asymmetric preparation method of dapoxetine hydrochloride

Abstract

According to the asymmetric preparation method of dapoxetine hydrochloride, provided by the invention, the dapoxetine hydrochloride is obtained by taking 3-halogenated propiophenone as a raw material and carrying out asymmetric reduction, coupling etherification, amination and salification, a chiral center is prepared by adopting asymmetric reduction, a subsequent resolution process is avoided, the route economy is improved, and the method is suitable for industrial production. The method is of great significance to cost reduction of enterprises.

Description

Technical Field

[0001] The present invention belongs to the technical fields of medicine and chemical engineering, and particularly relates to an asymmetric preparation method of dapoxetine hydrochloride. Background Art

[0002] Dapoxetine hydrochloride has a similar pharmacological effect to other SSRIs. Initially, dapoxetine was studied as an antidepressant drug. However, different from other SSRIs, the pharmacokinetics of dapoxetine shows that it has rapid oral absorption, a short half-life, and rapid excretion, making it a drug suitable for on-demand treatment of premature ejaculation.

[0003] Dapoxetine hydrochloride, English name: (S)-N,N-Dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine hydrochloride, has the following structural formula:

[0004]

[0005] Currently, the methods for synthesizing dapoxetine hydrochloride are divided into chiral synthesis and achiral synthesis. The achiral synthesis method includes a resolution step, which is far lower than chiral synthesis in terms of yield and economy. The background route is as follows:

[0006] Route 1: Using 3-chloropropiophenone as the starting material, chlorosulfonyl isocyanate as the chiral catalyst, and the highly stereoselective amination reaction of chiral benzyl ether as the key step to synthesize dapoxetine. This reaction route has the advantages of easy operation and high optical purity of the product, but it has a long reaction route, a low yield, the chiral catalyst chlorosulfonyl isocyanate is not easily obtained, and toxic substances such as toluene and palladium metal are used in the reaction. The route is as follows:

[0007]

[0008] Route 2: This route uses benzaldehyde as the starting material, and through a chiral auxiliary-mediated acetic aldehyde aldol condensation reaction, an aldol adduct is obtained. Then, the functional groups of the obtained product are transformed to finally synthesize dapoxetine. This route has the advantages of high total yield and easy recovery of the chiral auxiliary, but racemic compounds are easily generated during the reaction, resulting in a decrease in the optical purity of the product, and the highly toxic substance methanesulfonyl chloride is used in the reaction. The route is as follows:

[0009]

[0010] Route 3: This route uses chiral raw material D-phenylglycine as the starting material and synthesizes dapoxetine through eight steps of reactions such as reduction, Eschweiler-Clark methylation, and Williamson etherification. This reaction route has advantages such as high yield and simple operation. However, its raw material D-phenylglycine has a high price, highly toxic substance NaCN is used in the reaction, and the reaction route is relatively long. The route is as follows:

[0011]

[0012] Route 4: This route uses 3-chloropropiophenone as the starting material and finally obtains dapoxetine hydrochloride through reactions such as reduction, etherification, methylation, resolution, liberation, and salification. This reaction route has advantages such as simple operation and easy reaction control. However, this route adopts a resolution process, which reduces the overall yield of the process. The route is as follows:

[0013] Summary of the Invention

[0014] The present invention provides a new process for preparing dapoxetine hydrochloride with high yield and high economy.

[0015] The present invention provides a method for preparing dapoxetine (Compound 5), comprising the following steps:

[0016]

[0017] Wherein, X is selected from halogen, such as Cl, Br or I;

[0018] (1) Compound 1 undergoes an asymmetric reduction reaction to obtain Compound 2;

[0019] (2) Compound 2 and Compound 3 undergo a coupling etherification reaction to obtain Compound 4;

[0020] (3) Compound 4 and dimethylamine undergo an amination reaction to obtain Compound 5.

[0021] According to an embodiment of the present invention, in step (1), the reaction is carried out in the presence of N,N-diethylaniline borane and diphenylprolinol .

[0022] According to an embodiment of the present invention, in step (1), the molar ratio of Compound 1, N,N-diethylaniline borane and diphenylprolinol is selected from 1:(0.1-5):(0.005-0.5), such as 1:(0.5-2):(0.01-0.1).

[0023] According to an embodiment of the present invention, in step (1), the reaction can be carried out in the presence of an organic solvent, such as at least one of tetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, tert-butanol, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl acetate, toluene or acetone.

[0024] According to an embodiment of the present invention, in step (1), the temperature of the reaction can be 0 - 50 °C, for example 20 - 50 °C, such as 20 - 30 °C.

[0025] According to an embodiment of the present invention, in step (1), the reaction time can be 0.1 - 12 h, for example 0.5 - 6 h, such as 1 h, 2 h, 3 h, 4 h, 5 h.

[0026] According to an embodiment of the present invention, in step (2), the reaction can be carried out under the action of a base, and the base can be an inorganic base, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate or potassium phosphate.

[0027] According to an embodiment of the present invention, in step (2), the reaction can be carried out in the presence of an organic solvent, such as at least one of tetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, tert-butanol, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl acetate, toluene or acetone.

[0028] According to an embodiment of the present invention, in step (2), the molar ratio of compound 2 to compound 3 is selected from 1:(0.5 - 5), for example 1:(0.8 - 3).

[0029] According to an embodiment of the present invention, in step (2), the temperature of the reaction can be 20 - 100 °C, for example 30 - 80 °C, such as 50 °C, 60 °C, 70 °C.

[0030] According to an embodiment of the present invention, in step (2), the reaction time can be 0.1 - 12 h, for example 0.5 - 6 h, such as 1 h, 2 h, 3 h, 4 h, 5 h.

[0031] According to an embodiment of the present invention, in step (3), the dimethylamine can be aqueous dimethylamine solution, dimethylamine alcohol solution or dimethylamine gas, and preferably dimethylamine gas.

[0032] According to an embodiment of the present invention, in step (3), the reaction can be carried out under the action of a base, and the base can be an organic base, such as triethylamine, pyridine, DMAP, DIPEA.

[0033] According to an embodiment of the present invention, in step (3), the reaction can be carried out in the presence of a sulfonylation reagent, and the sulfonylation reagent can be selected from methanesulfonyl chloride, nitrobenzoyl chloride, p-nitrobenzoyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride.

[0034] According to an embodiment of the present invention, in step (3), the reaction can be carried out in the presence of an organic solvent, and the organic solvent can be at least one of tetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, tert-butanol, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl acetate, toluene or acetone.

[0035] According to an embodiment of the present invention, in step (3), the molar ratio of the compound 4, the sulfonylation reagent and the base is selected from 1:(0.2-5):(0.5-8), such as 1:(0.8-2):(1-3).

[0036] According to an embodiment of the present invention, in step (3), the temperature of the reaction can be 0-50 °C, such as 10-30 °C, such as 20 °C, 25 °C, 30 °C.

[0037] According to an embodiment of the present invention, in step (3), the reaction time can be 0.1-12 h, such as 0.5-6 h, such as 1 h, 2 h, 3 h, 4 h, 5 h.

[0038] According to an embodiment of the present invention, the compound 5 can be further reacted with an HCl solution to obtain the compound 6, namely dapoxetine hydrochloride.

[0039]

[0040] According to an embodiment of the present invention, the HCl solution is a solution formed by dissolving HCl in water or an organic solvent, and the organic solvent can be selected from at least one of methanol, ethanol, isopropanol, dioxane, ethyl acetate; for example, an isopropanol solution of HCl.

[0041] According to an embodiment of the present invention, the concentration of the HCl solution is 10-50%, such as 20%-30%, such as 24%.

[0042] According to an embodiment of the present invention, the reaction can be carried out in the presence of an organic solvent, such as at least one of tetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, tert-butanol, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl acetate, toluene or acetone.

[0043] Beneficial effects

[0044] An asymmetric preparation method of dapoxetine hydrochloride provided by the present invention uses asymmetric reduction to prepare chiral centers, avoids subsequent separation processes, improves the route economy, can be industrially produced, and is of great significance for enterprises to reduce costs. Specific embodiments

[0045] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are only illustrative and explanatory of the present disclosure, and should not be construed as limiting the protection scope of the present disclosure. All technologies implemented based on the above content of the present disclosure are covered within the scope intended to be protected by the present disclosure.

[0046] Unless otherwise specified, the raw materials and reagents used in the following embodiments are commercially available products or can be prepared by known methods.

[0047] Example 1

[0048] 1. Asymmetric reduction:

[0049] Put 80 g of dichloromethane and 25 g of 3-chloropropiophenone into a clean and dry 250 ml three-necked flask, heat up to 25 ± 5 °C, add 15 g of N,N-diethylaniline borane and 3.3 g of diphenylprolinol, and keep the reaction at 25 ± 5 °C for 1 hour. Then add 10 g of acetone, continue the reaction for 1 hour, dropwise add 20 g of purified water, separate the liquid, evaporate the organic phase to dryness, and obtain the reduction product compound 2 with a yield of 92%.

[0050]

[0051] 2. Coupling etherification

[0052] Add 22 g of the reduction product to 80 g of tetrahydrofuran, stir to dissolve, add 4 g of sodium hydroxide and 20 g of 1-naphthol, heat up to 50 - 60 °C and react for 3 hours; cool down to 25 °C, add 200 g of purified water and 200 g of ethyl acetate, stir and extract, concentrate the organic phase to half of its volume, and filter to obtain the etherification product compound 4 with a yield of 90%.

[0053]

[0054] 3. Amination

[0055] Add 20 g of the etherification product to 50 g of tetrahydrofuran, then add 11 g of methylsulfonyl chloride and 15 g of triethylamine. React at 20°C - 30°C for 1 hour, then introduce dimethylamine gas for 10 hours. After the reaction is completed, add 200 g of purified water and 150 g of ethyl acetate, stir to dissolve, extract, separate the organic phase, dry it, and then evaporate to dryness to obtain the amination product compound 5 with a yield of 87%.

[0056]

[0057] 4. Salt formation

[0058] Add 10 g of the amination product to 100 g of isopropanol, stir to dissolve, then add 200 g of 24% hydrogen chloride isopropanol solution. Keep the temperature at 0 - 5°C and react for 2 hours. After the reaction is completed, concentrate to a volume of 180 ml, filter to obtain dapoxetine hydrochloride with a yield of 90%.

[0059]

[0060] The results are summarized in Table 1.

[0061] Example 2

[0062] 1. Asymmetric reduction:

[0063] Put 100 g of ethylene glycol dimethyl ether and 25 g of 3-chloropropiophenone into a clean and dry 250 ml three-necked flask, heat up to 25 ± 5°C, add 15 g of N,N-diethylaniline borane and 3.3 g of diphenylprolinol, and keep reacting at 25 ± 5°C for 1 hour. Then add 10 g of acetone, continue to react for 1 hour, and then dropwise add 20 g of purified water. Separate the liquid, evaporate the organic phase to dryness to obtain the reduction product compound 2 with a yield of 98%.

[0064] 2. Coupling etherification

[0065] Add 20 g of the reduction product to 80 g of tetrahydrofuran, stir to dissolve, then add 3.8 g of sodium hydroxide and 18 g of 1-naphthol, heat up to 50 - 60°C and react for 3 hours; cool down to 25°C, add 200 g of purified water and 200 g of ethyl acetate, stir and extract, concentrate the organic phase to half of its volume, filter to obtain the etherification product compound 4 with a yield of 88%.

[0066] 3. Amination

[0067] 18 g of the etherification product was added to 40 g of tetrahydrofuran, 9 g of methylsulfonyl chloride and 11 g of triethylamine were added, and the reaction was carried out at 20 °C to 30 °C for 1 hour. Dimethylamine gas was introduced for 10 hours. After the reaction was completed, 180 g of purified water and 130 g of ethyl acetate were added, stirred and dissolved, extracted, and the organic phase was separated. After drying, it was evaporated to dryness to obtain the amination product compound 5 with a yield of 85%.

[0068] 4. Salt formation

[0069] 10 g of the amination product was added to 100 g of isopropanol, stirred and dissolved, 200 g of 24% hydrochloric acid isopropanol solution was added, and the temperature was maintained at 0 - 5 °C for 2 hours. After the reaction was completed, it was concentrated to a volume of 180 ml, filtered to obtain dapoxetine hydrochloride with a yield of 88%.

[0070] The results are summarized in Table 1.

[0071] Example 3

[0072] 1. Asymmetric reduction:

[0073] 24 kg of dichloromethane and 9 kg of 3-chloropropiophenone were added to a clean and dry 200-liter reaction kettle, the temperature was raised to 25 ± 5 °C, 7.9 kg of N,N-diethylaniline borane and 0.7 kg of diphenylprolinol were added, and the reaction was carried out at 25 ± 5 °C for 1 - 2 hours. Then 7.2 kg of acetone was added, and after continuing the reaction for 1 hour, 40 kg of purified water was added dropwise. After liquid separation, the organic phase was separated and evaporated to dryness to obtain the reduction product compound 2 with a yield of 93%.

[0074] 2. Coupling etherification

[0075] 33 kg of tetrahydrofuran was added to a 100-liter glass reaction kettle, 6.2 kg of the reduction product was added, stirred and dissolved, 1.74 kg of sodium hydroxide and 5.1 kg of 1-naphthol were added, and the temperature was raised to 50 - 60 °C for 3 hours; the temperature was lowered to 25 °C, 30 kg of purified water and 20 kg of ethyl acetate were added, stirred and extracted, the organic phase was concentrated to half of the volume, and filtered to obtain the etherification product compound 4 with a yield of 90%.

[0076] 3. Amination

[0077] 6 kg of the etherification product was added to a 100-liter reaction kettle and added to 50 kg of tetrahydrofuran, 3.7 kg of methylsulfonyl chloride and 4.2 kg of triethylamine were added, and the reaction was carried out at 20 °C to 30 °C for 1 hour. Dimethylamine gas was introduced for 10 hours. After the reaction was completed, the reaction solution was transferred to a 200-liter enamel reaction kettle for treatment, 50 kg of purified water and 30 kg of ethyl acetate were added, stirred and dissolved, extracted, the organic phase was separated, dried, and evaporated to dryness to obtain the amination product compound 5 with a yield of 87%.

[0078] 4. Salt formation

[0079] In a 50-L glass reactor, 5.4 kg of the aminated product was added, 30 kg of isopropanol was added, and the mixture was stirred until dissolved. Then 10 kg of a 24% hydrochloric acid isopropanol solution was added, and the temperature was maintained at 0 - 5 °C for 2 hours. After the reaction was completed, filtration was carried out to obtain dapoxetine hydrochloride with a yield of 90%. The results are summarized in Table 1.

[0080] Example 4

[0081] 1. Asymmetric reduction

[0082] Into a clean and dry 200-L reactor, 24 kg of ethylene glycol dimethyl ether and 9 kg of 3-chloropropiophenone were charged. The temperature was raised to 25 ± 5 °C, 8.8 kg of N,N-diethylaniline borane and 1.12 kg of diphenylprolinol were added, and the reaction was carried out at 25 ± 5 °C for 1 - 2 hours. Then 7.2 kg of acetone was added, and after continuing the reaction for 1 hour, 40 kg of purified water was added dropwise. After liquid separation, the organic phase was evaporated to dryness to obtain the reduction product, compound 2, with a yield of 95%.

[0083] 2. Coupling etherification

[0084] Into a 100-L glass reactor, 30 kg of tetrahydrofuran was added, and 6.0 kg of the reduction product was added. After stirring until dissolved, 1.66 kg of sodium hydroxide and 4.9 kg of 1-naphthol were added, and the temperature was raised to 50 - 60 °C for 3 hours. After cooling to 25 °C, 30 kg of purified water and 20 kg of ethyl acetate were added, and stirring extraction was carried out. The organic phase was concentrated to half of its volume, and then filtration was carried out to obtain the etherification product, compound 4, with a yield of 89%.

[0085] 3. Amination

[0086] Into a 100-L reactor, 5.5 kg of the etherification product was added to 45 kg of tetrahydrofuran, 3.2 kg of methylsulfonyl chloride and 3.8 kg of triethylamine were added, and the reaction was carried out at 20 °C - 30 °C for 1 hour. Dimethylamine gas was introduced for 10 hours. After the reaction was completed, the reaction solution was transferred to a 200-L enamel reactor for treatment. 48 kg of purified water and 27 kg of ethyl acetate were added, and after stirring until dissolved, extraction was carried out. The organic phase was separated, dried, and then evaporated to dryness to obtain the aminated product, compound 5, with a yield of 88%.

[0087] 4. Salt formation

[0088] In a 50-L glass reactor, 5 kg of the aminated product was added, 28 kg of isopropanol was added, and the mixture was stirred until dissolved. Then 9.5 kg of a 24% hydrochloric acid isopropanol solution was added, and the temperature was maintained at 0 - 5 °C for 2 hours. After the reaction was completed, filtration was carried out to obtain dapoxetine hydrochloride with a yield of 92%. The results are summarized in Table 1.

[0089] Example 5

[0090] 1. Asymmetric reduction

[0091] Into a clean and dry 200-liter reactor, 24 kg of ethylene glycol dimethyl ether and 9 kg of 3-chloropropiophenone were charged. The temperature was raised to 25 ± 5 °C, and 13.2 kg of N,N-diethylaniline borane and 0.93 kg of diphenylprolinol were added. The reaction was carried out at 25 ± 5 °C for 1 - 2 hours. Then 7.2 kg of acetone was added, and after continuing the reaction for 1 hour, 40 kg of purified water was added dropwise. After liquid separation, the organic phase was evaporated to dryness to obtain the reduction product, compound 2, with a yield of 94%.

[0092] 2. Coupling etherification

[0093] Into a 100-liter glass reactor, 30 kg of tetrahydrofuran was added, and 6.1 kg of the reduction product was added. After stirring and dissolving, 1.71 kg of sodium hydroxide and 5.0 kg of 1-naphthol were added. The temperature was raised to 50 - 60 °C and the reaction was carried out for 3 hours; the temperature was lowered to 25 °C, 31 kg of purified water and 22 kg of ethyl acetate were added, and after stirring and extraction, the organic phase was concentrated to half of its volume and filtered to obtain the etherification product, compound 4, with a yield of 88%.

[0094] 3. Amination

[0095] Into a 100-liter reactor, 5.5 kg of the etherification product was added to 45 kg of tetrahydrofuran, 3.2 kg of methylsulfonyl chloride and 3.8 kg of triethylamine were added, and the reaction was carried out at 20 °C - 30 °C for 1 hour. Dimethylamine gas was introduced for 10 hours. After the reaction was completed, the reaction solution was transferred to a 200-liter enamel reactor for treatment. 48 kg of purified water and 27 kg of ethyl acetate were added, and after stirring and dissolving, extraction was carried out. The organic phase was separated, dried, and then evaporated to dryness to obtain the amination product, compound 5, with a yield of 89%.

[0096] 4. Salt formation

[0097] In a 50-liter glass reactor, 5.1 kg of the amination product was added, 29 kg of isopropanol was added, and after stirring and dissolving, 9.8 kg of 24% hydrogen chloride isopropanol solution was added. The temperature was maintained at 0 - 5 °C and the reaction was carried out for 2 hours. After the reaction was completed, filtration was carried out to obtain dapoxetine hydrochloride, with a yield of 90%. The results are summarized in Table 1.

[0098] Table 1 Finished product standards of examples

[0099]

[0100] As can be seen from the above table, the total yield of the present invention is relatively high, with good economic efficiency for enterprises, and it can be prepared on a large scale, suitable for industrial production.

[0101] Comparative example 1

[0102]

[0103] 1. Reduction

[0104] Add 3-chloropropiophenone (10 g) and 100 mL of methanol to a 250 mL three-necked flask, and stir to dissolve. Cool down to 5 °C, and slowly add dropwise a methanol solution of sodium borohydride (1.79 g) (add 30 mL of methanol and 1 mL of 5% sodium hydroxide solution to sodium borohydride), and react at low temperature for 2 h. Add hydrochloric acid dropwise to adjust the pH to 3 - 4, and rotary evaporate to remove methanol; extract with ethyl acetate 3 times; wash with sodium bicarbonate solution 2 times, wash with water 2 times, and wash with saturated brine 1 time; dry over anhydrous sodium sulfate, filter by suction, and concentrate to obtain 10.02 g of compound a. Yield: 99.0%, Purity: 97.7%.

[0105] 2. Coupling Etherification

[0106] Add compound a (10.00 g), 1-naphthol (9.29 g), and 100 mL of N,N-dimethylformamide to a 250 mL three-necked flask, and stir to dissolve. Control the temperature at about 5 °C, add sodium hydroxide (2.34 g), react at 5 °C for 30 min, then slowly raise the temperature to 50 °C, and react for 8 h. Cool the reaction system to about 10 °C, add 300 mL of ice water to the reaction system; extract with toluene 3 times, wash with water 1 time; wash with 1% sodium hydroxide solution until the aqueous phase is colorless; wash with water until the aqueous phase is neutral; wash with saturated brine 1 time; dry over anhydrous sodium sulfate; filter by suction; concentrate to obtain 15.94 g of compound b. Yield: 97.7%, Purity: 98.5%.

[0107] 3. Amination

[0108] Add compound b (10.00 g), triethylamine (7.27 g), and 100 mL of tetrahydrofuran to a 250 mL four-necked flask, protect with nitrogen, stir to dissolve, cool down to 5 °C - 10 °C, control the temperature and add dropwise a mixed solution of methanesulfonyl chloride (4.94 g) and tetrahydrofuran (20 mL), stir at low temperature for 2 h, add dimethylamine (24.30 g), slowly raise the temperature to 25 °C, and react for 16 h. Add 80 mL of water to the reaction system, adjust the pH to 12 with 5% sodium hydroxide solution, and extract with toluene 2 times; combine the organic phases, wash with water 1 time; wash with saturated brine 1 time; dry over anhydrous sodium sulfate; filter by suction; concentrate to obtain 10.60 g of compound c. Yield: 96.6%, Purity: 97.3%.

[0109] 4. Resolution and Salt Formation

[0110] Compound c (10.00 g) and 50 mL of dichloromethane were added to a reaction flask and stirred to dissolve at 15 °C. D-(+)-di-p-toluoyl tartaric acid (12.65 g) was added and stirred for 0.5 h. Then 50 mL of ethyl acetate was added and stirring was continued for 1 h. Filtration was carried out by suction, and the filter cake was washed with a mixed solvent of dichloromethane and ethyl acetate in a ratio of 1:1. The solid was dried to obtain 10.42 g of crude compound d. Yield: 46%, Purity: 98.6%.

[0111] Recrystallization: Crude compound d (10 g) and 100 mL of dichloromethane were added to a reaction flask and heated to reflux until the sample dissolved. Then 150 mL of ethyl acetate was added, and the temperature was naturally lowered to 15 °C and stirring was carried out for 2 h for crystallization. Filtration was carried out by suction, and the filter cake was washed 3 times with a dichloromethane-ethyl acetate (2:3) mixture. The product was dried in a blast dryer at 40 °C for 12 h to obtain 9.33 g of compound d. Yield: 93.3%, Purity: 99.8%.

[0112] 5. Freeing

[0113] Compound d (10 g), 50 mL of dichloromethane and 50 mL of water were added to a reaction flask and stirred to dissolve at room temperature. 10% sodium hydroxide solution was added to adjust the pH to 10, and stirring was continued for 1 h. It was left to stand for layering, and the aqueous layer was extracted 2 times with dichloromethane. The organic phases were combined. The combined organic phase was washed 2 times with water, once with saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and concentrated to obtain 4.26 g of compound 5. Yield: 96.5%

[0114] 6. Salt formation

[0115] Compound 5 (4 g) and 24 mL of ethyl acetate were added to a reaction flask and stirred to dissolve at room temperature. The temperature was controlled at 0 - 5 °C, and 4.8 mL of 3.5 mol / L hydrogen chloride in ethyl acetate solution was added dropwise. Stirring was carried out at 2 °C for 1 h. Filtration was carried out by suction, and the filter cake was washed 2 times with ethyl acetate. The solid was dried at 40 °C for 4 h to obtain 4.27 g of crude compound 6. Yield: 95.4%, Purity: 99.87%.

[0116] Recrystallization: Crude compound 6 (4 g) and 20 mL of isopropanol were added to a reaction flask and heated to reflux until the sample dissolved. The temperature was slowly lowered to 8 °C and stirring was carried out for 2 h for crystallization. Filtration was carried out by suction, and the filter cake was washed 2 times with ethyl acetate. The product was dried in vacuo at 40 °C for 12 h to obtain 3.79 g of dapoxetine hydrochloride (compound 6). Yield: 94.8%, Purity: 99.98%.

[0117] mp 182 - 184 °C, [α]D25 = +129.3° (C = 1%, methanol);

[0118] 11H-NMR (400 MHz, CDCl3): 2.334 - 2.418 [s, 6H, N(CH3)2], 2.691 - 2.775 (m, 2H, CHCH2CH2O), 3.697 - 3.733 (t, J = 7.0 Hz, 1H, Ph C-H), 3.978 - 4.035 (m, 1H, OCH2), 4.135 - 4.188 (m, 1H, OCH2), 6.734 - 6.753 (d, J = 7.6 Hz, 1H, ArH), 7.281 - 7.609 (m, 9H, Ar H), 7.885 - 7.908 (d, J = 9.2 Hz, 1H, Ar H), 8.411 - 8.433 (d, J = 8.8 Hz, 1H, Ar H). MS m / z: 306 [M+H]+.

[0119]

[0120] Compared with the route of Comparative Example 1, the purity of the related substances of the obtained finished product is basically the same, both greater than 99.9%. However, from the perspective of the economy of the process development route, the overall yield of the route of Comparative Example 1 is only 35%, which is much lower than the overall yield of the process route of the present invention. Therefore, the process route of the present invention has high economy and market competitiveness.

[0121] The above has given an exemplary description of the implementation manners of the technical solutions of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above implementation manners. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included within the protection scope of the claims of this application.

Claims

1. A method for preparing compound 5, comprising the following steps: Wherein, X is selected from halogen, such as Cl, Br or I; (1) Compound 1 undergoes an asymmetric reduction reaction to obtain compound 2; (2) Compound 2 and compound 3 undergo a coupling etherification reaction to obtain compound 4; (3) Compound 4 and dimethylamine undergo an amination reaction to obtain compound 5; Preferably, in step (1), the reaction can be carried out in the presence of N,N - diethylaniline borane and diphenylprolinol .

2. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of compound 1, N,N - diethylaniline borane and diphenylprolinol is selected from 1:(0.1 - 5):(0.005 - 0.5), such as 1:(0.5 - 2):(0.01 - 0.1).

3. The preparation method according to claim 1 or 2, characterized in that, In step (2), the reaction can be carried out under the action of a base, and the base can be an inorganic base, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate or potassium phosphate.

4. The preparation method according to any one of claims 1-3, characterized in that, In step (2), the molar ratio of compound 2 and compound 3 is selected from 1:(0.5 - 5), such as 1:(0.8 - 3).

5. The preparation method according to any one of claims 1-4, characterized in that, In step (3), the dimethylamine can be aqueous dimethylamine solution, dimethylamine alcohol solution or dimethylamine gas, preferably dimethylamine gas.

6. The preparation method according to any one of claims 1-5, characterized in that, In step (3), the reaction can be carried out under the action of a base, and the base can be an organic base, such as triethylamine, pyridine, DMAP, DIPEA.

7. The preparation method according to any one of claims 1-6, characterized in that, In step (3), the reaction can be carried out in the presence of a sulfonylation reagent, and the sulfonylation reagent can be selected from methanesulfonyl chloride, nitrobenzoyl chloride, p - nitrobenzoyl chloride, benzenesulfonyl chloride, p - toluenesulfonyl chloride.

8. The preparation method according to any one of claims 1-7, characterized in that, In step (3), the molar ratio of compound 4, sulfonylation reagent and base is selected from 1:(0.2 - 5):(0.5 - 8), such as 1:(0.8 - 2):(1 - 3).

9. The preparation method according to any one of claims 1-8, characterized in that, Compound 5 can further react with HCl solution to obtain compound 6, namely dapoxetine hydrochloride.

10. The preparation method according to claim 9, wherein The HCl solution is a solution formed by dissolving HCl in water or an organic solvent, and the organic solvent can be selected from at least one of methanol, ethanol, isopropanol, dioxane, ethyl acetate; such as isopropanol solution of HCl; Preferably, the concentration of the HCl solution is 10 - 50%, such as 20% - 30%.

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