A process for the preparation of paroxetine hydrochloride

Abstract

The application relates to the technical field of medicine synthesis, in particular to a preparation method of paroxetine hydrochloride, which has a synthesis route as shown in the figure; the whole preparation process of the application is simple in process, the synthesis route has higher yield, the final product has higher purity, the post-treatment is simple, compared with the existing synthesis technology, the production cost is lower, the application meets the needs of industrialized large-scale production.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, specifically to a method for preparing paroxetine hydrochloride. Background Technology

[0002] Paroxetine hydrochloride is a phenylpiperidine compound used to treat depression. It is a potent, highly effective, and selective central nervous system 5-HT reuptake inhibitor. It works by inhibiting active 5-HT transport, increasing 5-HT concentration in the synaptic cleft, and enhancing 5-HTergic neurotransmission. It has minimal effect on norepinephrine and dopamine reuptake. Its antidepressant potency is similar to that of tricyclic antidepressants (TCAs), but its side effects are significantly fewer, classifying it as a third-generation antidepressant. Furthermore, experimental results show that paroxetine hydrochloride has almost no affinity for muscarinic receptors, α-adrenergic receptors, β-adrenergic receptors, dopamine D2 receptors, histamine H1 receptors, and 5-HT2 receptors; therefore, it has fewer adverse reactions in the central and autonomic nervous systems. Paroxetine hydrochloride was developed by GlaxoSmithKline and approved for marketing by the U.S. Food and Drug Administration (FDA) in 1991. It can be used to treat various types of depression, phobia disorders with or without agoraphobia, and obsessive-compulsive disorder. It is characterized by rapid onset of action and good tolerability.

[0003] Currently, although several methods for preparing paroxetine hydrochloride have been reported in the prior art, such as CN104447714A and CN102718756A, all of which use N-methylparoxetine as a raw material, this raw material is expensive and unsuitable as a starting material for the production of paroxetine hydrochloride. Furthermore, the preparation methods for paroxetine hydrochloride in the aforementioned patents are complex, have low production efficiency, and generate large amounts of waste liquid due to the extensive use of solvents, which is detrimental to environmental protection requirements. Summary of the Invention

[0004] In order to solve the problems existing in the above-mentioned technologies, the purpose of this invention is to provide a method for preparing paroxetine hydrochloride that has mild reaction conditions, simple operation, high yield and purity, safe production and is suitable for large-scale industrial production.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] A method for preparing paroxetine hydrochloride, the synthetic route of which is as follows:

[0007]

[0008] Specifically, the following steps are included:

[0009] (1) In the presence of aluminum chloride, compound 11 and compound 10 undergo a Friedel-Crafts reaction to give compound 9;

[0010] (2) In the presence of anhydrous cerium chloride, compound 9 reacts with vinyl magnesium bromide to give compound 8;

[0011] (3) Compound 8 was dehydrated to obtain compound 7;

[0012] (4) In the presence of a base and a catalyst, compound 7 reacts with compound 6 to give compound 5;

[0013] (5) In the presence of a Lewis acid, compound 5 reacts with compound 4 to give compound 3;

[0014] (6) In the presence of palladium on carbon catalyst, compound 3 undergoes a reduction reaction with hydrogen to obtain compound 2;

[0015] (7) Compound 1 was prepared by reacting compound 2 with concentrated hydrochloric acid to form a salt.

[0016] Preferably, in step (2), the molar ratio of compound 9, vinyl magnesium bromide, and anhydrous cerium chloride is 1:(1-2.5):(1-2.5).

[0017] Preferably, in step (3), the reaction temperature is 80–120°C.

[0018] Preferably, in step (4), the alkali is one of sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, or potassium carbonate.

[0019] Preferably, in step (4), the catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, or 18-crown ether-6.

[0020] Preferably, in step (4), the solvent is one of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane, or methyltetrahydrofuran.

[0021] Preferably, in step (4), the molar ratio of compound 6, catalyst, and base is 1:(0.01~0.1):

[0022] (1~10).

[0023] Preferably, in step (5), the Lewis acid is one of aluminum chloride, copper chloride, ferric chloride, magnesium chloride, magnesium bromide, magnesium iodide, tin chloride, titanium tetrachloride, zinc chloride, zinc bromide, zinc iodide, or boron trifluoride.

[0024] Preferably, in step (5), the solvent is one of dichloromethane, toluene, chloroform, pyridine, diethyl ether, N,N-dimethylformamide, triethylamine, diisopropylethylamine, or water.

[0025] Preferably, in step (5), the molar ratio of compound 4, compound 5, and Lewis acid is 1:(1-3):

[0026] (0.2~2).

[0027] Preferably, in step (5), the reaction temperature is -10 to 80°C.

[0028] Preferably, in step (6), the palladium-carbon catalyst contains 10% palladium by mass.

[0029] Preferably, in step (6), the amount of palladium catalyst added is 2 to 10% of the mass of compound 3.

[0030] Preferably, in step (6), the reaction temperature is 20–60°C.

[0031] Furthermore, in this invention, compound 3 can also be synthesized using the following route:

[0032]

[0033] Specifically, the following steps are included:

[0034] (a1) In the presence of a Lewis acid, compound 7 was reacted with compound 4 to obtain compound 12;

[0035] (a2) In the presence of a base and a catalyst, compound 12 was reacted with compound 6 to give compound 3.

[0036] Preferably, in step (a1), the Lewis acid is one of aluminum chloride, copper chloride, ferric chloride, magnesium chloride, magnesium bromide, magnesium iodide, tin chloride, titanium tetrachloride, zinc chloride, zinc bromide, zinc iodide, or boron trifluoride.

[0037] Preferably, in step (a1), the solvent is one of dichloromethane, toluene, chloroform, pyridine, diethyl ether, N,N-dimethylformamide, triethylamine, diisopropylethylamine, or water.

[0038] Preferably, in step (1), the molar ratio of compound 4, compound 7, and Lewis acid is 1:(1-3):(0.2-2).

[0039] Preferably, in step (a1), the reaction temperature is -10 to 80°C.

[0040] Preferably, in step (a2), the alkali is one of sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, or potassium carbonate.

[0041] Preferably, in step (a2), the catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, or 18-crown ether-6.

[0042] Preferably, in step (a2), the solvent is one of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane, or methyltetrahydrofuran.

[0043] Preferably, in step (a2), the molar ratio of compound 6, catalyst, and base is 1:(0.01-0.1):(1-10).

[0044] Furthermore, in this invention, compound 2 can also be synthesized using the following route:

[0045]

[0046] Specifically, the following steps are included:

[0047] (b1) In the presence of a palladium on carbon catalyst, compound 12 was reduced with hydrogen to obtain compound 13;

[0048] (b2) In the presence of a base and a catalyst, compound 13 was reacted with compound 6 to obtain compound 2.

[0049] Preferably, in step (b1), the palladium-on-carbon catalyst contains 10% palladium by mass.

[0050] Preferably, in step (b1), the amount of palladium catalyst added is 2 to 10% of the mass of compound 12.

[0051] Preferably, in step (b1), the reaction temperature is 20–60°C.

[0052] Preferably, in step (b2), the alkali is one of sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, or potassium carbonate.

[0053] Preferably, in step (b2), the catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, or 18-crown ether-6.

[0054] Preferably, in step (b2), the solvent is one of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane, or methyltetrahydrofuran.

[0055] Preferably, in step (b2), the molar ratio of compound 6, catalyst, and base is 1:(0.01-0.1):(1-10).

[0056] Compared with the prior art, the beneficial effects of the present invention are:

[0057] This invention provides a novel method for preparing paroxetine hydrochloride, in order to... and The target compound, paroxetine hydrochloride, was obtained from the starting material through a multi-step reaction. The entire preparation process is simple, and experiments have shown that this synthetic route has a high yield, high purity of the final product, and simple post-processing. Compared with existing synthetic technologies, the production cost is low, which meets the needs of large-scale industrial production. Detailed Implementation

[0058] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0059] Example 1

[0060]

[0061] (1) Synthesis of compound 9

[0062] 40 mmol of compound 11, 42 mmol of aluminum chloride, and 30 mL of dichloromethane were added to a reactor. Then, 45 mmol of compound 10 was slowly added at 20 °C. After the addition was complete, the mixture was heated to reflux, and the reaction was monitored by TLC until the starting material was fully reacted. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was slowly poured into ice water while stirring. The solution was extracted three times with diethyl ether, and the ether layer was washed three times with saturated brine. After drying with anhydrous magnesium sulfate, the solvent was evaporated to dryness using a rotary evaporator to obtain a yellow solid. Recrystallization from petroleum ether yielded compound 9, with a yield of 94.5% and a purity of 99.3%.

[0063] (2) Synthesis of compound 8

[0064] Under nitrogen protection, 11 mmol of anhydrous cerium chloride and 20 mL of tetrahydrofuran were added to a round-bottom flask, and the suspension was stirred at room temperature (20–30 °C) for 2 hours. The flask was then placed in an ethanol dry ice bath at -78 °C for 30 minutes. 11 mmol of vinyl magnesium bromide was added to the reaction mixture via syringe, and the reaction mixture was stirred at -78 °C for 45 minutes. 5.5 mmol of a solution of compound 9 (dissolved in 25 mL of tetrahydrofuran) was slowly added via syringe, and the reaction temperature was maintained at -78 °C. The reaction mixture was monitored by TLC to ensure complete reaction of the starting material. The reaction mixture was quenched with saturated NaHCO3. After separation, the aqueous layer was extracted with diethyl ether. The combined organic layers were washed successively with saturated NaHCO3, water, and brine, dried over Na2SO4, concentrated under reduced pressure, and purified by rapid column chromatography (hexane / ethyl acetate = 95:5) to give compound 8 in 92.8% yield and 99.1% purity.

[0065] (3) Synthesis of compound 7

[0066] 50 mmol of compound 8 and 100 mL of concentrated hydrochloric acid were added to a four-necked flask equipped with a reflux condenser, thermometer, and stirrer. The mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by vacuum distillation. The residue was recrystallized from n-octane to give compound 7, with a yield of 86.3% and a purity of 98.7%.

[0067] (4) Synthesis of compound 5

[0068] 250 mL of dichloromethane, 0.01 mol of tetrabutylammonium bromide, 1.19 mol of potassium hydroxide, 0.13 mol of compound 6, and 0.19 mol of compound 7 were added to a reaction flask, and the mixture was heated to reflux. After the reaction was complete, the reaction solution was slowly added to 200 mL of ice water, stirred for 15 min, and then allowed to stand for separation. The lower organic phase was washed with 200 mL of water, stirred for 15 min, and then allowed to stand for separation. The lower organic phase was desoluble until almost no fraction remained, yielding compound 5 with a yield of 91.8% and a purity of 99.3%.

[0069] (5) Synthesis of compound 3

[0070] 0.2 mol of compound 4 and 300 mL of dichloromethane were added to a reaction flask and stirred to dissolve. Then, 0.3 mol of compound 5 and 0.2 mol of magnesium iodide were added, and the reaction mixture was reacted at 20 °C. After the reaction was complete, the mixture was concentrated under vacuum, and the residue was dissolved in 150 mL of diethyl ether, washed with NaHCO3 solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Compound 3 was purified by rapid chromatography (hexane-EtOAc, 98:2) to give compound 3 in 93.6% yield and 99.2% purity.

[0071] (6) Synthesis of Compound 2

[0072] 40 g of compound 3, 100 mL of anhydrous ethanol, and 3.2 g of 10% palladium on carbon were added to an autoclave. The mixture was purged with nitrogen three times and hydrogen three times. Hydrogen was added at 2–3 MPa, and the reaction was carried out at 40 °C. The reaction was monitored by TLC until the reactants were fully reacted. After the reaction was complete, the mixture was cooled and filtered. The filtrate was desolvated to obtain compound 2 with a yield of 96.8% and a purity of 99.4%.

[0073] (7) Synthesis of Compound 1

[0074] 0.2 mol of compound 2, 0.2 mol of concentrated hydrochloric acid, and 200 mL of toluene were added to a reaction flask, and the reaction mixture was reacted at 25 °C. After the reaction was completed, the mixture was filtered, washed with 200 mL of toluene and 200 mL of water, recrystallized from 2-propanol, and dried to give compound 1, with a yield of 98.2% and a purity of 99.5%.

[0075] Example 2

[0076]

[0077] (1) Synthesis of compound 9

[0078] 40 mmol of compound 11, 42 mmol of aluminum chloride, and 30 mL of dichloromethane were added to a reactor. Then, 45 mmol of compound 10 was slowly added at 20 °C. After the addition was complete, the mixture was heated to reflux, and the reaction was monitored by TLC until the starting material was fully reacted. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was slowly poured into ice water while stirring. The solution was extracted three times with diethyl ether, and the ether layer was washed three times with saturated brine. After drying with anhydrous magnesium sulfate, the solvent was evaporated to dryness using a rotary evaporator to obtain a yellow solid. Recrystallization from petroleum ether yielded compound 9, with a yield of 94.5% and a purity of 99.3%.

[0079] (2) Synthesis of compound 8

[0080] Under nitrogen protection, 6.6 mmol of anhydrous cerium chloride and 20 mL of tetrahydrofuran were added to a round-bottom flask, and the suspension was stirred at room temperature (20–30 °C) for 2 hours. The flask was then placed in an ethanol dry ice bath at -78 °C for 30 minutes. 6.6 mmol of vinyl magnesium bromide was added to the reaction mixture via syringe, and the reaction mixture was stirred at -78 °C for 45 minutes. 5.5 mmol of a solution of compound 9 (dissolved in 25 mL of tetrahydrofuran) was slowly added via syringe, and the reaction temperature was maintained at -78 °C. The reaction mixture was monitored by TLC until the starting material was completely reacted. The reaction mixture was quenched with saturated NaHCO3. After separation, the aqueous layer was extracted with diethyl ether. The combined organic layers were washed successively with saturated NaHCO3, water, and brine, dried over Na2SO4, concentrated under reduced pressure, and purified by rapid column chromatography (hexane / ethyl acetate = 95:5) to give compound 8, with a yield of 88.6% and a purity of 98.7%.

[0081] (3) Synthesis of compound 7

[0082] 50 mmol of compound 8 and 100 mL of concentrated hydrochloric acid were added to a four-necked flask equipped with a reflux condenser, thermometer, and stirrer. The mixture was stirred at 80 °C. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by vacuum distillation. The residue was recrystallized from n-octane to give compound 7, with a yield of 83.8% and a purity of 98.4%.

[0083] (4) Synthesis of compound 5

[0084] 250 mL of tetrahydrofuran, 0.006 mol of tetrabutylammonium chloride, 0.9 mol of sodium tert-butoxide, 0.13 mol of compound 6, and 0.19 mol of compound 7 were added to a reaction flask, and the mixture was heated to reflux. After the reaction was complete, the reaction solution was slowly added to 200 mL of ice water, stirred for 15 min, and then allowed to stand for separation. The lower organic phase was washed with 200 mL of water, stirred for 15 min, and then allowed to stand for separation. The lower organic phase was desoluble until there were almost no fractions left, yielding compound 5 with a yield of 83.7% and a purity of 98.4%.

[0085] (5) Synthesis of compound 3

[0086] 0.2 mol of compound 4 and 300 mL of toluene were added to a reaction flask and stirred to dissolve. Then, 0.5 mol of compound 5 and 0.05 mol of titanium tetrachloride were added, and the reaction mixture was reacted at 60 °C. After the reaction was complete, the mixture was concentrated under vacuum, and the residue was dissolved in 150 mL of diethyl ether, washed with NaHCO3 solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Compound 3 was purified by rapid chromatography (hexane-EtOAc, 98:2) to give compound 3 in 90.4% yield and 99.1% purity.

[0087] (6) Synthesis of Compound 2

[0088] 40 g of compound 3, 100 mL of anhydrous ethanol, and 1.6 g of 10% palladium on carbon were added to an autoclave. The mixture was purged with nitrogen three times and hydrogen three times. Hydrogen was added at 2–3 MPa, and the reaction was carried out at 60 °C. The reaction was monitored by TLC until the reactants were fully reacted. After the reaction was complete, the mixture was cooled and filtered. The filtrate was desolvated to obtain compound 2, with a yield of 92.1% and a purity of 99.2%.

[0089] (7) Synthesis of Compound 1

[0090] 0.2 mol of compound 2, 0.2 mol of concentrated hydrochloric acid, and 200 mL of toluene were added to a reaction flask, and the reaction mixture was reacted at 50 °C. After the reaction was completed, the mixture was filtered, washed with 200 mL of toluene and 200 mL of water, recrystallized from 2-propanol, and dried to give compound 1, with a yield of 97.6% and a purity of 99.4%.

[0091] Example 3

[0092]

[0093] (1) Synthesis of compound 12

[0094] 0.2 mol of compound 4 and 300 mL of pyridine were added to a reaction flask and stirred to dissolve. Then, 0.24 mol of compound 7 and 0.36 mol of zinc chloride were added, and the reaction mixture was reacted at 80 °C. After the reaction was complete, the mixture was concentrated under vacuum, and the residue was dissolved in 150 mL of diethyl ether, washed with NaHCO3 solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Compound 12 was purified by rapid chromatography (hexane-EtOAc, 98:2) to give compound 12 in 91.3% yield and 98.7% purity.

[0095] (2) Synthesis of compound 3

[0096] 250 mL of dichloromethane, 0.009 mol of tetrabutylammonium bromide, 0.39 mol of potassium tert-butoxide, 0.13 mol of compound 6, and 0.19 mol of compound 12 were added to a reaction flask, and the mixture was heated to reflux. After the reaction was complete, the reaction solution was slowly added to 200 mL of ice water, stirred for 15 min, and then allowed to stand for separation. The lower organic phase was washed with 200 mL of water, stirred for 15 min, and then allowed to stand for separation. The lower organic phase was desoluble until almost no fraction remained, yielding compound 3 with a yield of 89.6% and a purity of 99.1%.

[0097] Example 4

[0098]

[0099] (1) Synthesis of compound 12

[0100] 0.2 mol of compound 4 and 300 mL of triethylamine were added to a reaction flask and stirred until dissolved. Then, 0.56 mol of compound 7 and 0.1 mol of aluminum chloride were added, and the reaction mixture was reacted at -10 °C. After the reaction was complete, the mixture was concentrated under vacuum, and the residue was dissolved in 150 mL of diethyl ether, washed with NaHCO3 solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Compound 12 was purified by rapid chromatography (hexane-EtOAc, 98:2) to give compound 12 in 87.5% yield and 98.5% purity.

[0101] (2) Synthesis of compound 3

[0102] 250 mL of toluene, 0.004 mol of 18-crown ether-6, 0.65 mol of potassium carbonate, 0.13 mol of compound 6, and 0.19 mol of compound 12 were added to a reaction flask, and the mixture was heated to reflux. After the reaction was complete, the reaction solution was slowly added to 200 mL of ice water, stirred for 15 min, and then allowed to stand for separation. The lower organic phase was washed with 200 mL of water, stirred for 15 min, and then allowed to stand for separation. The lower organic phase was desoluble until almost no fraction remained, yielding compound 3 with a yield of 84.7% and a purity of 98.7%.

[0103] Example 5

[0104]

[0105] (1) Synthesis of compound 13

[0106] 40 g of compound 12, 100 mL of anhydrous ethanol, and 4 g of 10% palladium on carbon were added to an autoclave. The mixture was purged with nitrogen three times and hydrogen three times. Hydrogen was added at 2–3 MPa, and the reaction was carried out at 20 °C. The reaction was monitored by TLC until the reactants were fully reacted. After the reaction was complete, the mixture was cooled and filtered. The filtrate was desolvated to obtain compound 13, with a yield of 94.6% and a purity of 99.3%.

[0107] (2) Synthesis of Compound 2

[0108] 250 mL of methyl tert-butyl ether, 0.013 mol of tetrabutylammonium bromide, 0.26 mol of potassium hydroxide, 0.13 mol of compound 6, and 0.19 mol of compound 13 were added to a reaction flask, and the mixture was heated to reflux. After the reaction was complete, the reaction solution was slowly added to 200 mL of ice water, stirred for 15 min, and then allowed to stand for separation. The lower organic phase was washed with 200 mL of water, stirred for 15 min, and then allowed to stand for separation. The lower organic phase was desoluble until almost no fraction remained, yielding compound 2 with a yield of 87.8% and a purity of 98.9%.

[0109] Example 6

[0110]

[0111] (1) Synthesis of compound 13

[0112] 40 g of compound 12, 100 mL of anhydrous ethanol, and 0.8 g of 10% palladium on carbon were added to an autoclave. The mixture was purged with nitrogen three times and hydrogen three times. Hydrogen was added at 2–3 MPa, and the reaction was carried out at 60 °C. The reaction was monitored by TLC until the reactants were fully reacted. After the reaction was complete, the mixture was cooled and filtered. The filtrate was desolvated to obtain compound 13, with a yield of 91.6% and a purity of 99.1%.

[0113] (2) Synthesis of Compound 2

[0114] 250 mL of tetrahydrofuran, 0.002 mol of tetrabutylammonium chloride, 1.1 mol of potassium tert-butoxide, 0.13 mol of compound 6, and 0.19 mol of compound 13 were added to a reaction flask, and the mixture was heated to reflux. After the reaction was complete, the reaction solution was slowly added to 200 mL of ice water, stirred for 15 min, and then allowed to stand for separation. The lower organic phase was washed with 200 mL of water, stirred for 15 min, and then allowed to stand for separation. The lower organic phase was desoluble until there were almost no fractions left, yielding compound 2 with a yield of 82.6% and a purity of 98.2%.

[0115] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing paroxetine hydrochloride, characterized in that, The synthesis route is as follows: Specifically, the following steps are included: (1) In the presence of aluminum chloride, compound 11 and compound 10 undergo a Friedel-Crafts reaction to give compound 9; (2) In the presence of anhydrous cerium chloride, compound 9 reacts with vinyl magnesium bromide to give compound 8; (3) Compound 8 was dehydrated to obtain compound 7; (4) In the presence of a base and a catalyst, compound 7 reacts with compound 6 to give compound 5; (5) In the presence of a Lewis acid, compound 5 reacts with compound 4 to give compound 3; (6) In the presence of palladium on carbon catalyst, compound 3 undergoes a reduction reaction with hydrogen to obtain compound 2; (7) Compound 1 was prepared by reacting compound 2 with concentrated hydrochloric acid to form a salt.

2. The method for preparing paroxetine hydrochloride according to claim 1, characterized in that: In step (2), the molar ratio of compound 9, vinyl magnesium bromide, and anhydrous cerium chloride is 1:(1-2.5):(1-2.5).

3. The method for preparing paroxetine hydrochloride according to claim 1, characterized in that: In step (3), the reaction temperature is 80–120°C.

4. The method for preparing paroxetine hydrochloride according to claim 1, characterized in that: In step (4), one or more of the following conditions may be selected: a. The base is one of sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, or potassium carbonate; b. The catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, or 18-crown ether-6; c. The solvent is one of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane, or methyltetrahydrofuran; d. The molar ratio of compound 6, catalyst, and base is 1:(0.01~0.1):(1~10).

5. The method for preparing paroxetine hydrochloride according to claim 1, characterized in that: In step (5), one or more of the following conditions may be selected: a. The Lewis acid is one of aluminum chloride, copper chloride, ferric chloride, magnesium chloride, magnesium bromide, magnesium iodide, tin chloride, titanium tetrachloride, zinc chloride, zinc bromide, zinc iodide, or boron trifluoride; b. The solvent is one of dichloromethane, toluene, chloroform, pyridine, diethyl ether, N,N-dimethylformamide, triethylamine, diisopropylethylamine, or water; c. The molar ratio of compound 4, compound 5, and Lewis acid is 1:(1-3):(0.2-2); d. The reaction temperature is -10 to 80℃.

6. The method for preparing paroxetine hydrochloride according to claim 1, characterized in that: In step (6), one or more of the following conditions may be selected: a. The palladium content in the palladium-on-carbon catalyst is 10% by mass; b. The amount of the palladium catalyst on carbon added is 2-10% of the mass of compound 3; c. The reaction temperature is 20–60℃.

7. A method for preparing paroxetine hydrochloride, characterized in that, The synthesis route is as follows: Specifically, the following steps are included: (1) In the presence of aluminum chloride, compound 11 and compound 10 undergo a Friedel-Crafts reaction to give compound 9; (2) In the presence of anhydrous cerium chloride, compound 9 reacts with vinyl magnesium bromide to give compound 8; (3) Compound 8 was dehydrated to obtain compound 7; (4) In the presence of Lewis acid, compound 7 reacts with compound 4 to give compound 12; (5) In the presence of a base and a catalyst, compound 12 reacts with compound 6 to give compound 3; (6) In the presence of palladium on carbon catalyst, compound 3 undergoes a reduction reaction with hydrogen to obtain compound 2; (7) Compound 1 was prepared by reacting compound 2 with concentrated hydrochloric acid to form a salt.

8. The method for preparing paroxetine hydrochloride according to claim 7, characterized in that: In step (4), one or more of the following conditions may be selected: a. The Lewis acid is one of aluminum chloride, copper chloride, ferric chloride, magnesium chloride, magnesium bromide, magnesium iodide, tin chloride, titanium tetrachloride, zinc chloride, zinc bromide, zinc iodide, or boron trifluoride; b. The solvent is one of dichloromethane, toluene, chloroform, pyridine, diethyl ether, N,N-dimethylformamide, triethylamine, diisopropylethylamine, or water; c. The molar ratio of compound 4, compound 7, and Lewis acid is 1:(1-3):(0.2-2); d. The reaction temperature is -10 to 80℃; In step (5), one or more of the following conditions may be selected: a. The base is one of sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, or potassium carbonate; b. The catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, or 18-crown ether-6; c. The solvent is one of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane, or methyltetrahydrofuran; d. The molar ratio of compound 6, catalyst, and base is 1:(0.01~0.1):(1~10).

9. A method for preparing paroxetine hydrochloride, characterized in that, The synthesis route is as follows: Specifically, the following steps are included: (1) In the presence of aluminum chloride, compound 11 and compound 10 undergo a Friedel-Crafts reaction to give compound 9; (2) In the presence of anhydrous cerium chloride, compound 9 reacts with vinyl magnesium bromide to give compound 8; (3) Compound 8 was dehydrated to obtain compound 7; (4) In the presence of Lewis acid, compound 7 reacts with compound 4 to give compound 12; (5) In the presence of palladium on carbon catalyst, compound 12 was reduced with hydrogen to obtain compound 13; (6) In the presence of a base and a catalyst, compound 13 was reacted with compound 6 to obtain compound 2; (7) Compound 1 was prepared by reacting compound 2 with concentrated hydrochloric acid to form a salt.

10. The method for preparing paroxetine hydrochloride according to claim 9, characterized in that: In step (5), one or more of the following conditions may be selected: a. The palladium content in the palladium-on-carbon catalyst is 10% by mass; b. The amount of the palladium catalyst on carbon added is 2-10% of the mass of compound 12; c. The reaction temperature is 20–60°C; In step (6), one or more of the following conditions may be selected: a. The base is one of sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, or potassium carbonate; b. The catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride, or 18-crown ether-6; c. The solvent is one of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane, or methyltetrahydrofuran; d. The molar ratio of compound 6, catalyst, and base is 1:(0.01~0.1):(1~10).

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