CN117447454A - Preparation method of paroxetine hydrochloride - Google Patents

Preparation method of paroxetine hydrochloride Download PDF

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Publication number
CN117447454A
CN117447454A CN202311285388.XA CN202311285388A CN117447454A CN 117447454 A CN117447454 A CN 117447454A CN 202311285388 A CN202311285388 A CN 202311285388A CN 117447454 A CN117447454 A CN 117447454A
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compound
chloride
catalyst
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reaction
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戚陈陈
兰国新
魏海玉
焦腊梅
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Chongqing Puyou Biomedical Co ltd
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Chongqing Puyou Biomedical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of paroxetine hydrochloride, which comprises the following synthetic route:

Description

Preparation method of paroxetine hydrochloride
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of paroxetine hydrochloride.
Background
Paroxetine hydrochloride is a phenylpiperidine compound, is a powerful and efficient selective central nervous 5-HT reuptake inhibitor for treating depression, acts by inhibiting active transport of 5-HT, increasing synaptic cleft 5-HT concentration and enhancing 5-HT energy nerve conduction, has little influence on reuptake of norepinephrine and dopamine, has similar antidepressant effect intensity as tricyclic antidepressants (TCAs), has obviously smaller side effect than tricyclic antidepressants (TCAs), and belongs to a third-generation antidepressant new medicine. In addition, the experimental results show that paroxetine hydrochloride has little affinity with muscarinic receptors, alpha-adrenergic receptors, beta-adrenergic receptors, dopamine D2 receptors, histamine H1 receptors, 5-HT2 receptors, and thus, fewer adverse reactions of the central and autonomic nervous systems. Paroxetine hydrochloride was developed by the company Gelanin Smith and approved by the United states Food and Drug Administration (FDA) for sale in 1991, can be used for treating various types of depression, fear disorders with or without fear of squares, obsessive compulsive disorder, and has the characteristics of quick response and good tolerance.
At present, although various methods for preparing paroxetine hydrochloride have been reported in the prior art, such as CN104447714a and CN102718756a, which all use N-methyl paroxetine as a raw material, the raw materials are expensive and are not suitable as a starting material for producing paroxetine hydrochloride. In addition, the preparation method of paroxetine hydrochloride in the patent has complex procedures, low production efficiency and large amount of waste liquid generated by using a large amount of solvents, thereby being not beneficial to the requirement of environmental protection.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to provide a preparation method of paroxetine hydrochloride, which has the advantages of mild reaction conditions, simple operation, high yield and purity, safe production and suitability for industrial mass production.
In order to achieve the above purpose, the present invention provides the following technical solutions:
the preparation method of paroxetine hydrochloride comprises the following synthetic routes:
the method specifically comprises the following steps:
(1) Performing Friedel-crafts reaction on a compound 11 and a compound 10 in the presence of aluminum chloride to obtain a compound 9;
(2) Reacting the compound 9 with vinyl magnesium bromide in the presence of anhydrous cerium chloride to obtain a compound 8;
(3) Carrying out dehydration reaction on the compound 8 to obtain a compound 7;
(4) Reacting the compound 7 with the compound 6 in the presence of a base and a catalyst to obtain a compound 5;
(5) Reacting compound 5 with compound 4 in the presence of a lewis acid to give compound 3;
(6) In the presence of a palladium-carbon catalyst, carrying out reduction reaction on the compound 3 and hydrogen to obtain a compound 2;
(7) Compound 2 is salified with concentrated hydrochloric acid to prepare compound 1.
Preferably, in the step (2), the molar ratio of the compound 9, the vinyl magnesium bromide and the anhydrous cerium chloride is 1 (1-2.5): 1-2.5.
Preferably, in step (3), the reaction temperature is 80 to 120 ℃.
Preferably, in the step (4), the base is one of sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide or potassium carbonate.
Preferably, in step (4), the catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride or 18-crown-6.
Preferably, in the step (4), the solvent is one of tetrahydrofuran, toluene, methyl tert-butyl ether, dichloromethane or methyl tetrahydrofuran.
Preferably, in the step (4), the molar ratio of the compound 6, the catalyst and the base is 1 (0.01-0.1):
(1～10)。
preferably, in the step (5), the lewis acid is one of aluminum chloride, copper chloride, ferric chloride, magnesium bromide, magnesium iodide, tin chloride, titanium tetrachloride, zinc chloride, zinc bromide, zinc iodide, or boron trifluoride.
Preferably, in the step (5), the solvent is one of dichloromethane, toluene, chloroform, pyridine, diethyl ether, N-dimethylformamide, triethylamine, diisopropylethylamine or water.
Preferably, in the step (5), the molar ratio of the compound 4, the compound 5 and the lewis acid is 1 (1-3):
(0.2～2)。
preferably, in step (5), the reaction temperature is from-10 to 80 ℃.
Preferably, in the step (6), the mass percentage of palladium in the palladium-carbon catalyst is 10%.
Preferably, in the step (6), the palladium carbon catalyst is added in an amount of 2 to 10% by mass of the compound 3.
Preferably, in step (6), the reaction temperature is 20 to 60 ℃.
Further, in the present invention, compound 3 can also be synthesized as follows:
the method specifically comprises the following steps:
(a1) Reacting compound 7 with compound 4 in the presence of a lewis acid to give compound 12;
(a2) Compound 12 is reacted with compound 6 in the presence of a base and a catalyst to give compound 3.
Preferably, in step (a 1), the lewis acid is one of aluminum chloride, copper chloride, iron chloride, magnesium bromide, magnesium iodide, tin chloride, titanium tetrachloride, zinc chloride, zinc bromide, zinc iodide, or boron trifluoride.
Preferably, in step (a 1), the solvent is one of dichloromethane, toluene, chloroform, pyridine, diethyl ether, N-dimethylformamide, triethylamine, diisopropylethylamine or water.
Preferably, in the step (1), the molar ratio of the compound 4 to the compound 7 to the Lewis acid is 1 (1-3): 0.2-2.
Preferably, in step (a 1), the reaction temperature is from-10 to 80 ℃.
Preferably, in step (a 2), the base is one of sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide or potassium carbonate.
Preferably, in step (a 2), the catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride or 18-crown-6.
Preferably, in step (a 2), the solvent is one of tetrahydrofuran, toluene, methyl tert-butyl ether, methylene chloride or methyltetrahydrofuran.
Preferably, in the step (a 2), the molar ratio of the compound 6, the catalyst and the alkali is 1 (0.01-0.1): 1-10.
Further, in the present invention, compound 2 can also be synthesized as follows:
the method specifically comprises the following steps:
(b1) In the presence of a palladium-carbon catalyst, carrying out reduction reaction on the compound 12 and hydrogen to obtain a compound 13;
(b2) Compound 13 is reacted with compound 6 in the presence of a base and a catalyst to give compound 2.
Preferably, in the step (b 1), the mass percentage of palladium in the palladium-carbon catalyst is 10%.
Preferably, in the step (b 1), the palladium carbon catalyst is added in an amount of 2 to 10% by mass of the compound 12.
Preferably, in step (b 1), the reaction temperature is 20 to 60 ℃.
Preferably, in step (b 2), the base is one of sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide or potassium carbonate.
Preferably, in step (b 2), the catalyst is one of tetrabutylammonium bromide, tetrabutylammonium chloride or 18-crown-6.
Preferably, in step (b 2), the solvent is one of tetrahydrofuran, toluene, methyl tert-butyl ether, methylene chloride or methyltetrahydrofuran.
Preferably, in the step (b 2), the molar ratio of the compound 6, the catalyst and the alkali is 1 (0.01-0.1): 1-10.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a brand new preparation method of paroxetine hydrochloride, which aims atAnd->The target compound, namely paroxetine hydrochloride, is obtained by multi-step reaction of the raw materials. The whole preparation process is simple in process, the yield of the synthetic route is high through experiments, the purity of the final product is high, the post-treatment is simple, and compared with the existing synthetic technology, the preparation method is low in production cost and meets the requirement of industrial mass production.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
(1) Synthesis of Compound 9
To the reactor were added 40mmol of compound 11, 42mmol of aluminum chloride and 30mL of methylene chloride, 45mmol of compound 10 was slowly added at 20℃and after the addition was completed, the reaction was heated to reflux and TLC monitored for completion of the starting material reaction. After the reaction was completed, the reaction mixture was cooled to room temperature, and the reaction mixture was slowly poured into ice water while stirring. Extracting with diethyl ether for 3 times, washing diethyl ether layer with saturated salt water for 3 times, drying with anhydrous magnesium sulfate, evaporating solvent with rotary evaporator to obtain yellow solid, and recrystallizing with petroleum ether to obtain compound 9 with yield of 94.5% and purity of 99.3%.
(2) Synthesis of Compound 8
Under nitrogen protection, 11mmol of anhydrous cerium chloride and 20mL of tetrahydrofuran were added to the round-bottomed flask, and the suspension was stirred at room temperature (20 to 30 ℃ C.) for 2 hours. The flask was placed in an ethanol dry ice bath at-78 ℃ for an additional 30 minutes. 11mmol of vinylmagnesium bromide was added to the reaction mixture by syringe at-78 ℃The reaction mixture was stirred for 45 minutes. 5.5mmol of compound 9 (dissolved in 25mL of tetrahydrofuran) was slowly added via syringe, the reaction temperature was maintained at-78deg.C, and TLC monitored the completion of the starting material reaction. With saturated NaHCO 3 The reaction mixture was quenched. After separation, the aqueous layer was extracted with diethyl ether. Sequentially with saturated NaHCO 3 The combined organic layers were washed with water and brine, and dried over Na 2 SO 4 The product was purified by flash column chromatography (hexane/ethyl acetate=95:5) to give compound 8 in 92.8% yield and 99.1% purity.
(3) Synthesis of Compound 7
Into a four-necked flask equipped with a reflux condenser, a thermometer and a stirrer, 50mmol of Compound 8 and 100mL of concentrated hydrochloric acid were charged, and the reaction was stirred at 100 ℃. After the reaction, the mixture was cooled to room temperature, the solvent was removed by distillation under reduced pressure, and the residue was recrystallized from n-octane to give compound 7 in a yield of 86.3% and a purity of 98.7%.
(4) Synthesis of Compound 5
250mL of methylene chloride, 0.01mol of tetrabutylammonium bromide, 1.19mol of potassium hydroxide, 0.13mol of Compound 6 and 0.19mol of Compound 7 were charged into a reaction flask, and the mixture was refluxed at a temperature. After the reaction is finished, slowly adding the reaction solution into 200mL of ice water, stirring for 15min, standing for separating, washing the lower organic phase with 200mL of water, stirring for 15min, standing for separating, and desolventizing the lower organic phase until no fraction is basically generated, thereby obtaining the compound 5 with the yield of 91.8% and the purity of 99.3%.
(5) Synthesis of Compound 3
To the reaction flask, 0.2mol of Compound 4 and 300mL of methylene chloride were added, and the mixture was dissolved by stirring, and then 0.3mol of Compound 5 and 0.2mol of magnesium iodide were added to react at 20 ℃. After the reaction was completed, the mixture was concentrated in vacuo, and the residue was dissolved in 150mL of diethyl ether with NaHCO 3 The solution was washed, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification by flash chromatography (hexane-EtOAc, 98:2) afforded compound 3 in 93.6% yield and 99.2% purity.
(6) Synthesis of Compound 2
40g of compound 3, 100mL of absolute ethyl alcohol and 3.2g of 10% palladium carbon are added into an autoclave, nitrogen is replaced for three times, hydrogen is replaced for three times, hydrogenation is carried out for 2-3 MPa, the temperature is controlled to be 40 ℃, and TLC monitors that the raw materials are completely reacted. After the reaction is finished, the temperature is reduced, the filter is pressed and filtered, and the filtrate is desolventized to obtain the compound 2 with the yield of 96.8% and the purity of 99.4%.
(7) Synthesis of Compound 1
To the reaction flask were added 0.2mol of Compound 2, 0.2mol of concentrated hydrochloric acid and 200mL of toluene, and the reaction mixture was reacted at 25 ℃. After the reaction was completed, the mixture was filtered, washed with 200mL of toluene and 200mL of water, recrystallized from 2-propanol and dried to give compound 1 in a yield of 98.2% and a purity of 99.5%.
Example 2
(1) Synthesis of Compound 9
To the reactor were added 40mmol of compound 11, 42mmol of aluminum chloride and 30mL of methylene chloride, 45mmol of compound 10 was slowly added at 20℃and after the addition was completed, the reaction was heated to reflux and TLC monitored for completion of the starting material reaction. After the reaction was completed, the reaction mixture was cooled to room temperature, and the reaction mixture was slowly poured into ice water while stirring. Extracting with diethyl ether for 3 times, washing diethyl ether layer with saturated salt water for 3 times, drying with anhydrous magnesium sulfate, evaporating solvent with rotary evaporator to obtain yellow solid, and recrystallizing with petroleum ether to obtain compound 9 with yield of 94.5% and purity of 99.3%.
(2) Synthesis of Compound 8
6.6mmol of anhydrous cerium chloride and 20mL of tetrahydrofuran were added to the round bottom flask under nitrogen and the suspension was stirred at room temperature (20-30 ℃ C.) for 2 hours. The flask was placed in an ethanol dry ice bath at-78 ℃ for an additional 30 minutes. 6.6mmol of vinylmagnesium bromide was added to the reaction mixture by syringe, and the reaction mixture was stirred at-78℃for 45 minutes. 5.5mmol of compound 9 (dissolved in 25mL of tetrahydrofuran) was slowly added via syringe, the reaction temperature was maintained at-78deg.C, and TLC monitored the completion of the starting material reaction. With saturated NaHCO 3 The reaction mixture was quenched. After separation, the aqueous layer was extracted with diethyl ether. Ei-yiSaturated NaHCO for secondary use 3 The combined organic layers were washed with water and brine, and dried over Na 2 SO 4 The product was purified by flash column chromatography (hexane/ethyl acetate=95:5) to give compound 8 in 88.6% yield and 98.7% purity.
(3) Synthesis of Compound 7
Into a four-necked flask equipped with a reflux condenser, a thermometer and a stirrer, 50mmol of Compound 8 and 100mL of concentrated hydrochloric acid were charged, and the reaction was stirred at 80 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was recrystallized from n-octane to give compound 7 in a yield of 83.8% and a purity of 98.4%.
(4) Synthesis of Compound 5
Into the reaction flask, 250mL of tetrahydrofuran, 0.006mol of tetrabutylammonium chloride, 0.9mol of sodium t-butoxide, 0.13mol of Compound 6 and 0.19mol of Compound 7 were charged, and the mixture was refluxed at elevated temperature. After the reaction is finished, slowly adding the reaction solution into 200mL of ice water, stirring for 15min, standing for separating, washing the lower organic phase with 200mL of water, stirring for 15min, standing for separating, and desolventizing the lower organic phase until no fraction is basically generated, thereby obtaining the compound 5 with the yield of 83.7% and the purity of 98.4%.
(5) Synthesis of Compound 3
To the reaction flask, 0.2mol of Compound 4 and 300mL of toluene were added, and the mixture was stirred and dissolved, and then 0.5mol of Compound 5 and 0.05mol of titanium tetrachloride were added, whereby the reaction mixture was reacted at 60 ℃. After the reaction was completed, the mixture was concentrated in vacuo, and the residue was dissolved in 150mL of diethyl ether with NaHCO 3 The solution was washed, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification by flash chromatography (hexane-EtOAc, 98:2) afforded compound 3 in 90.4% yield and 99.1% purity.
(6) Synthesis of Compound 2
40g of compound 3, 100mL of absolute ethyl alcohol and 1.6g of 10% palladium carbon are added into an autoclave, nitrogen is replaced for three times, hydrogen is replaced for three times, hydrogenation is carried out for 2-3 MPa, the temperature is controlled to be 60 ℃, and TLC monitors that the raw materials are completely reacted. After the reaction is finished, the temperature is reduced, the filter is pressed and filtered, and the filtrate is desolventized to obtain the compound 2, the yield is 92.1%, and the purity is 99.2%.
(7) Synthesis of Compound 1
To the reaction flask were added 0.2mol of Compound 2, 0.2mol of concentrated hydrochloric acid and 200mL of toluene, and the reaction mixture was reacted at 50 ℃. After the reaction, the mixture was filtered, washed with 200mL of toluene and 200mL of water, recrystallized from 2-propanol and dried to give compound 1 in 97.6% yield and 99.4% purity.
Example 3
(1) Synthesis of Compound 12
To the reaction flask, 0.2mol of Compound 4 and 300mL of pyridine were added, and the mixture was stirred and dissolved, and then 0.24mol of Compound 7 and 0.36mol of zinc chloride were added, and the reaction mixture was reacted at 80 ℃. After the reaction was completed, the mixture was concentrated in vacuo, and the residue was dissolved in 150mL of diethyl ether with NaHCO 3 The solution was washed, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification by flash chromatography (hexane-EtOAc, 98:2) afforded compound 12 in 91.3% yield and 98.7% purity.
(2) Synthesis of Compound 3
Into the reaction flask were charged 250mL of methylene chloride, 0.009mol of tetrabutylammonium bromide, 0.39mol of potassium t-butoxide, 0.13mol of Compound 6 and 0.19mol of Compound 12, and the mixture was refluxed at elevated temperature. After the reaction is finished, slowly adding the reaction solution into 200mL of ice water, stirring for 15min, standing for separating, washing the lower organic phase with 200mL of water, stirring for 15min, standing for separating, and desolventizing the lower organic phase until no fraction is basically generated, thereby obtaining the compound 3, wherein the yield is 89.6%, and the purity is 99.1%.
Example 4
(1) Synthesis of Compound 12
Into a reaction flask, 0.2mol of Compound 4 and 300mL of triethylamine were added, and the mixture was dissolved by stirring, and then 0.56mol of Compound 7 and 0.1mol of aluminum chloride were added to the mixture at-10 ℃The reaction is carried out. After the reaction was completed, the mixture was concentrated in vacuo, and the residue was dissolved in 150mL of diethyl ether with NaHCO 3 The solution was washed, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification by flash chromatography (hexane-EtOAc, 98:2) afforded compound 12 in 87.5% yield and 98.5% purity.
(2) Synthesis of Compound 3
Into the reaction flask, 250mL of toluene, 0.004mol of 18-crown-6, 0.65mol of potassium carbonate, 0.13mol of Compound 6 and 0.19mol of Compound 12 were charged, and the mixture was heated to reflux. After the reaction is finished, slowly adding the reaction solution into 200mL of ice water, stirring for 15min, standing for separating, washing the lower organic phase with 200mL of water, stirring for 15min, standing for separating, and desolventizing the lower organic phase until no fraction is basically generated, thereby obtaining the compound 3 with the yield of 84.7% and the purity of 98.7%.
Example 5
(1) Synthesis of Compound 13
40g of compound 12, 100mL of absolute ethyl alcohol and 4g of 10% palladium carbon are added into an autoclave, nitrogen is replaced for three times, hydrogen is replaced for three times, hydrogenation is carried out for 2-3 MPa, the temperature is controlled to be 20 ℃, and TLC monitors that the raw materials are reacted completely. After the reaction is finished, the temperature is reduced, the filter is pressed and filtered, and the filtrate is desolventized to obtain the compound 13, the yield is 94.6%, and the purity is 99.3%.
(2) Synthesis of Compound 2
Into the reaction flask were charged 250mL of methyl t-butyl ether, 0.013mol of tetrabutylammonium bromide, 0.26mol of potassium hydroxide, 0.13mol of Compound 6 and 0.19mol of Compound 13, and the mixture was refluxed at elevated temperature. After the reaction is finished, slowly adding the reaction solution into 200mL of ice water, stirring for 15min, standing for separating, washing the lower organic phase with 200mL of water, stirring for 15min, standing for separating, and desolventizing the lower organic phase until no fraction is basically generated, thereby obtaining the compound 2 with the yield of 87.8% and the purity of 98.9%.
Example 6
(1) Synthesis of Compound 13
40g of compound 12, 100mL of absolute ethyl alcohol and 0.8g of 10% palladium carbon are added into an autoclave, nitrogen is replaced for three times, hydrogen is replaced for three times, hydrogenation is carried out for 2-3 MPa, the temperature is controlled to be 60 ℃, and TLC monitors that the raw materials are completely reacted. After the reaction is finished, the temperature is reduced, the filter is pressed and filtered, and the filtrate is desolventized to obtain the compound 13 with the yield of 91.6% and the purity of 99.1%.
(2) Synthesis of Compound 2
Into the reaction flask, 250mL of tetrahydrofuran, 0.002mol of tetrabutylammonium chloride, 1.1mol of potassium t-butoxide, 0.13mol of Compound 6 and 0.19mol of Compound 13 were charged, and the mixture was refluxed at elevated temperature. After the reaction is finished, slowly adding the reaction solution into 200mL of ice water, stirring for 15min, standing for separating, washing the lower organic phase with 200mL of water, stirring for 15min, standing for separating, and desolventizing the lower organic phase until no fraction is basically generated, thereby obtaining the compound 2 with the yield of 82.6% and the purity of 98.2%.
Although embodiments of the present 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 therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (10)

1. The preparation method of paroxetine hydrochloride is characterized by comprising the following synthetic route:
the method specifically comprises the following steps:
(1) Performing Friedel-crafts reaction on a compound 11 and a compound 10 in the presence of aluminum chloride to obtain a compound 9;
(2) Reacting the compound 9 with vinyl magnesium bromide in the presence of anhydrous cerium chloride to obtain a compound 8;
(3) Carrying out dehydration reaction on the compound 8 to obtain a compound 7;
(4) Reacting the compound 7 with the compound 6 in the presence of a base and a catalyst to obtain a compound 5;
(5) Reacting compound 5 with compound 4 in the presence of a lewis acid to give compound 3;
(6) In the presence of a palladium-carbon catalyst, carrying out reduction reaction on the compound 3 and hydrogen to obtain a compound 2;
(7) Compound 2 is salified with concentrated hydrochloric acid to prepare compound 1.
2. The process for the preparation of paroxetine hcl according to claim 1, wherein: in the step (2), the molar ratio of the compound 9 to the vinyl magnesium bromide to the anhydrous cerium chloride is 1 (1-2.5) to 1-2.5.
3. The process for the preparation of paroxetine hcl according to claim 1, wherein: in the step (3), the reaction temperature is 80-120 ℃.
4. The process for the preparation of paroxetine hcl according to claim 1, wherein: in the step (4), one or more of the following conditions are optional:
a. the alkali 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 tertiary butyl ether, methylene dichloride or methyl tetrahydrofuran;
d. the mol ratio of the compound 6 to the catalyst to the alkali is 1 (0.01-0.1) to 1-10.
5. The process for the preparation of paroxetine hcl according to claim 1, wherein: in the step (5), one or more of the following conditions are optional:
a. the Lewis acid is one of aluminum chloride, copper chloride, ferric chloride, magnesium bromide, magnesium iodide, stannic 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-dimethylformamide, triethylamine, diisopropylethylamine or water;
c. the molar ratio of the compound 4 to the compound 5 to the Lewis acid is 1 (1-3) (0.2-2);
d. the reaction temperature is-10 to 80 ℃.
6. The process for the preparation of paroxetine hcl according to claim 1, wherein: in the step (6), one or more of the following conditions are optional:
a. the mass percentage of palladium in the palladium-carbon catalyst is 10%;
b. the addition amount of the palladium-carbon catalyst is 2-10% of the mass of the compound 3;
c. the reaction temperature is 20-60 ℃.
7. The process for the preparation of paroxetine hcl according to claim 1, wherein: the compound 3 can also be synthesized by the following synthetic route:
the method specifically comprises the following steps:
(a1) Reacting compound 7 with compound 4 in the presence of a lewis acid to give compound 12;
(a2) Compound 12 is reacted with compound 6 in the presence of a base and a catalyst to give compound 3.
8. The process for the preparation of paroxetine hcl according to claim 7, wherein: in said step (a 1), optionally one or more of the following conditions:
a. the Lewis acid is one of aluminum chloride, copper chloride, ferric chloride, magnesium bromide, magnesium iodide, stannic 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-dimethylformamide, triethylamine, diisopropylethylamine or water;
c. the molar ratio of the compound 4 to the compound 7 to the Lewis acid is 1 (1-3) (0.2-2);
d. the reaction temperature is-10 to 80 ℃;
in said step (a 2), optionally one or more of the following conditions:
a. the alkali 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 tertiary butyl ether, methylene dichloride or methyl tetrahydrofuran;
d. the mol ratio of the compound 6 to the catalyst to the alkali is 1 (0.01-0.1) to 1-10.
9. The process for the preparation of paroxetine hcl according to claim 1, wherein: the compound 2 can also be synthesized by the following synthetic route:
the method specifically comprises the following steps:
(b1) In the presence of a palladium-carbon catalyst, carrying out reduction reaction on the compound 12 and hydrogen to obtain a compound 13;
(b2) Compound 13 is reacted with compound 6 in the presence of a base and a catalyst to give compound 2.
10. The process for the preparation of paroxetine hcl according to claim 9, wherein: in said step (b 1), optionally one or more of the following conditions:
a. the mass percentage of palladium in the palladium-carbon catalyst is 10%;
b. the addition amount of the palladium-carbon catalyst is 2-10% of the mass of the compound 12;
c. the reaction temperature is 20-60 ℃;
in said step (b 2), optionally one or more of the following conditions:
a. the alkali 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 tertiary butyl ether, methylene dichloride or methyl tetrahydrofuran;
d. the mol ratio of the compound 6 to the catalyst to the alkali is 1 (0.01-0.1) to 1-10.
CN202311285388.XA 2023-10-07 2023-10-07 Preparation method of paroxetine hydrochloride Pending CN117447454A (en)

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