Process for the synthesis of venlafaxine hydrochloride

Abstract

This invention discloses a method for synthesizing venlafaxine hydrochloride, comprising the following steps: reacting a Grignard reagent obtained from the reaction of bromocyclohexane with metallic magnesium with acrolein to obtain compound-1; reacting compound-1 with methanesulfonyl chloride to obtain compound-2; reacting compound-2 with triethylamine to obtain compound-3; reacting compound-3 with hydrogen peroxide and acetic anhydride in the presence of sodium hydroxide to obtain compound-4; oxidizing compound-4 with ozone and then reducing it with sodium borohydride to obtain compound-5; reacting compound-5 with methanesulfonyl chloride and then with dimethylamine to obtain compound-6; reacting a Grignard reagent obtained from the reaction of p-bromoanisole with metallic magnesium with compound-6 to obtain compound-7; and reacting compound-7 with hydrogen chloride to form a salt to obtain venlafaxine hydrochloride. The raw materials used in this invention are inexpensive and readily available, with a total molar yield of 67.98%, and the produced venlafaxine hydrochloride has a purity of over 99.5%. The product has high yield, low cost, and good quality, making it suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for synthesizing venlafaxine hydrochloride. Background Technology

[0002] Venlafaxine hydrochloride, chemically named (±)-1-[2-(dimethylamino)-1-(4-(methoxyphenyl)ethyl]cyclohexanol hydrochloride, traded as Effexor, is a new-generation antidepressant developed by Wyeth-Ayerst. Unlike other antidepressants, it possesses a unique chemical structure and neuropharmacological action. It exerts its antidepressant effect by inhibiting the reuptake of serotonin and norepinephrine, without inhibiting monoamine oxidase, histamine, or α1-NA receptors, and has few adverse reactions. Clinically, it is used to treat various types of depression. Clinical trials have shown that venlafaxine hydrochloride has a rapid onset of action, few side effects, and similar efficacy in treating geriatric depression as in younger patients. Long-term use is safe and effective.

[0003] The synthetic process reported in J.Med.Chem.1990,33(10):2899-2905 uses p-methoxyphenylacetonitrile and cyclohexanone as starting materials, and obtains venlafaxine hydrochloride through condensation, reduction and methylation reactions with a yield of 37.8%. This method has harsh reaction conditions, high equipment requirements and low yield.

[0004]

[0005] The synthesis process disclosed in European patent EP00945958 uses 4-methoxyphenylacetic acid as the starting material, and proceeds through esterification, Claisen condensation, amination, catalytic hydrogenation, and Grignard reaction to obtain venlafaxine hydrochloride with a yield of 38%. This method requires a high-pressure reactor for catalytic hydrogenation, resulting in high equipment investment and low yield, making it unsuitable for industrial production.

[0006]

[0007] In addition, US Patent 4535186 and the document "An Improved and Impurity-Free Large-Scale Synthesis of Venlafaxine Hydrochloride," Org. Process Res. Dev. 2011, 15, 1392, both disclose methods for synthesizing venlafaxine hydrochloride from methoxyphenylacetonitrile and cyclohexanone. However, these methods have high production costs, and the hydrogenation reduction of the cyano group uses a high-pressure hydrogenation reactor, which carries a high risk.

[0008] In summary, all publicly available synthetic methods suffer from low yields and high costs, and many processes involve high-risk reactions such as high-pressure hydrogenation. Therefore, it is of great significance to develop a synthetic route for venlafaxine hydrochloride that uses inexpensive and readily available starting materials, achieves high reaction yields, has lower costs, and is suitable for large-scale industrial production.

[0009] The information disclosed in this background section is intended only to enhance the understanding of the overall background of the invention and should not be construed as an admission or in any way implying that the information constitutes prior art known to those skilled in the art. Summary of the Invention

[0010] The purpose of this invention is to provide a method for synthesizing venlafaxine hydrochloride with inexpensive and readily available starting materials, high reaction yield, low cost, and suitability for large-scale industrial production.

[0011] To achieve the above objectives, embodiments of the present invention provide a method for synthesizing venlafaxine, comprising the following steps: Step (a): cyclohexane bromide reacts with magnesium metal to obtain a first Grignard reagent, which is then reacted with acrolein in the presence of cuprous iodide to obtain compound-1; Step (b): compound-1 reacts with methanesulfonyl chloride in the presence of triethylamine to obtain compound-2; compound-2 reacts with triethylamine to obtain compound-3; compound-3 reacts with hydrogen peroxide and acetic anhydride in the presence of sodium hydroxide to obtain compound-4; compound-4 is first oxidized with ozone and then reduced with sodium borohydride to obtain compound-5; Step (c): compound-5 reacts with methanesulfonyl chloride in the presence of triethylamine and then with dimethylamine to obtain compound-6; Step (d): p-bromoanisole reacts with magnesium metal to obtain a second Grignard reagent, which is then reacted with compound-6 in the presence of cuprous iodide to obtain compound-7; compound-7 reacts with hydrogen chloride to form a salt to obtain venlafaxine hydrochloride.

[0012] In one or more embodiments of the present invention, in the synthesis of compound-1 in step (a), the reaction is carried out in a first solvent, which is an immiscible diethyl ether or methyl tert-butyl ether, preferably methyl tert-butyl ether; the molar ratio of bromocyclohexane to magnesium is 1.0:(1.0 to 1.06); the reaction temperature of bromocyclohexane with magnesium to form the first Grignard reagent is reflux; the amount of cuprous iodide is 5% to 15% of bromocyclohexane, molar percentage; the molar ratio of bromocyclohexane to acrolein is 1.0:(1.0 to 1.1); the reaction temperature of the first Grignard reagent with acrolein is initially -20 to -10°C, and then increased to 20 to 30°C.

[0013] In one or more embodiments of the present invention, in the synthesis of compound-2 in step (b), the molar ratio of compound-1 to triethylamine and methanesulfonyl chloride is 1.0:(1.0-1.1):(1.0-1.1); the reaction solvent is one of dichloromethane, trichloromethane or 1,2-dichloroethane, preferably dichloromethane; and the reaction temperature is 0-5°C.

[0014] In one or more embodiments of the present invention, in the synthesis of compound-3 in step (b), the molar ratio of triethylamine to compound-1 is (1.0 to 1.1):1.0; and the reaction temperature is 20 to 30°C.

[0015] In one or more embodiments of the present invention, in the synthesis of compound-4 in step (b), the molar ratio of sodium hydroxide to compound-1 is 1.0:1.0; the hydrogen peroxide is 50% hydrogen peroxide, and the molar ratio of 50% hydrogen peroxide, acetic anhydride and compound-1 is (1.1-1.2):(0.55-0.6):1.0; the reaction temperature is 0-5°C.

[0016] In one or more embodiments of the present invention, in the synthesis of compound-5 in step (b), methanol solvent is added to the ozone oxidation reaction, and the weight of methanol is 0.8 to 1.2 times that of compound-1; the temperature of the ozone oxidation reaction is -60 to -50°C; the molar ratio of sodium borohydride to compound-1 in the reduction reaction is (1.3 to 1.7):1.0, and the temperature of the reduction reaction is initially -60 to -50°C, and then increased to -15 to -10°C.

[0017] In one or more embodiments of the present invention, in the synthesis of compound-6 in step (c), the molar ratio of compound-5 to triethylamine and methanesulfonyl chloride is 1.0:(1.0-1.1):(1.0-1.1); the reaction is carried out in a first reaction solvent, which is one of dichloromethane, trichloromethane, or 1,2-dichloroethane, preferably dichloromethane; the reaction temperature is 0-5°C; a 40% aqueous solution of dimethylamine is used for the reaction with dimethylamine, and the molar ratio of dimethylamine to compound-5 is (2.5-3.5):1.0; the reaction temperature with dimethylamine is initially 0-5°C, and then increased to 20-30°C.

[0018] In one or more embodiments of the present invention, in step (d) the synthesis of compound-7, the reaction is carried out in a second reaction solvent, which is an immiscible diethyl ether or methyl tert-butyl ether, preferably methyl tert-butyl ether; the molar ratio of compound-6 to p-bromoanisole and magnesium is 1.0:(1.1-1.3):(1.4-1.6); the reaction temperature of p-bromoanisole and magnesium to form the second Grignard reagent is reflux; the amount of cuprous iodide is 5%-15% of compound-6, molar percentage; the reaction temperature of the second Grignard reagent with compound-6 is -40 to -30°C.

[0019] In one or more embodiments of the present invention, in the synthesis of venlafaxine hydrochloride in step (d), the reaction is carried out in a third reaction solvent, which is one of dichloromethane, trichloromethane or 1,2-dichloroethane, preferably dichloromethane; dry hydrogen chloride gas is introduced to maintain the pH of the reaction solution between 4.0 and 5.0; and the reaction temperature is 20 to 30°C.

[0020] In one or more embodiments of the present invention, in the synthesis of compound-4 in step (b), the sodium hydroxide is spherical sodium hydroxide.

[0021] Beneficial effects:

[0022] Current methods for synthesizing venlafaxine hydrochloride suffer from low yields and high costs, and many processes involve high-pressure hydrogenation, a highly hazardous reaction. The synthetic route provided by this invention utilizes inexpensive and readily available starting materials, offers high reaction yields, and has lower costs, making it suitable for large-scale industrial production. Detailed Implementation

[0023] The specific embodiments of the present invention will be described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments.

[0024] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0025] More specifically, to solve the above-mentioned technical problems, the present invention provides a method for synthesizing venlafaxine hydrochloride, which may include the following steps:

[0026] Step (a): Bromocyclohexane reacts with metallic magnesium to give the first Grignard reagent, which then reacts with acrolein in the presence of cuprous iodide to give compound 1. The reaction equation is as follows:

[0027]

[0028] Step (b): Compound-1 reacts with methanesulfonyl chloride in the presence of triethylamine to give compound-2; compound-2 reacts with triethylamine to give compound-3; compound-3 reacts with hydrogen peroxide and acetic anhydride in the presence of sodium hydroxide to give compound-4; compound-4 is first oxidized with ozone and then reduced with sodium borohydride to give compound-5. The reaction equation is:

[0029]

[0030] Step (c): Compound-5 reacts first with methanesulfonyl chloride in the presence of triethylamine, then with dimethylamine, to give compound-6. The reaction equation is as follows:

[0031]

[0032] Step (d): Bromoanisole reacts with metallic magnesium to give a second Grignard reagent, which then reacts with compound-6 in the presence of cuprous iodide to give compound-7. Compound-7 then forms a salt with hydrogen chloride to give venlafaxine hydrochloride. The reaction equation is:

[0033]

[0034] Example 1: Preparation of Compound-1

[0035] Install a mechanical stirrer, thermometer, constant-pressure dropping funnel, and spherical condenser in a dry 3000 ml four-necked flask. Purge the reaction apparatus three times with nitrogen. Add magnesium filings (12.52 g, 0.515 mol) and dry methyl tert-butyl ether (163.06 g) to the four-necked flask. Add a solution of methyl tert-butyl ether (489.18 g) containing bromocyclohexane (81.53 g, 0.5 mol) to the constant-pressure dropping funnel. Connect the constant-pressure dropping funnel to a nitrogen cylinder via a flexible tube. Adjust the flow rate using the pressure reducing valve on the nitrogen cylinder to gently purge nitrogen into the reaction apparatus, which then exits through the spherical condenser. Turn on the mechanical stirrer and heat to reflux. Using a constant-pressure dropping funnel, first add approximately 10% of a methyl tert-butyl ether solution of bromocyclohexane, initiating vigorous reflux. Then, add the remaining methyl tert-butyl ether solution of bromocyclohexane over approximately 2 hours. After the addition is complete, continue reflux for another 2 hours. Purge the reaction apparatus with nitrogen gas and cool to -20 to -10°C. Add cuprous iodide (9.52 g, 0.05 mol) and stir for 10 minutes. In another constant-pressure dropping funnel, add acrolein (29.43 g, 0.525 mol) of methyl tert-butyl ether (652.24 g) solution. Quickly replace the constant-pressure dropping funnel used for adding the methyl tert-butyl ether solution of bromocyclohexane with this new constant-pressure dropping funnel. After assembly, connect the new constant-pressure dropping funnel to a nitrogen cylinder via a flexible hose. Adjust the flow rate using the pressure reducing valve on the nitrogen cylinder to gently purge nitrogen gas into the reaction apparatus, which then exits through the spherical condenser. Control the temperature to -20 to -10°C, and add acrolein methyl tert-butyl ether solution dropwise over approximately 2 hours. After the addition is complete, slowly raise the temperature to room temperature (20–30°C) over approximately 1 hour, and continue stirring at 20–30°C for 30 minutes. Prepare a 12% hydrochloric acid aqueous solution (326.12 g) in a beaker. Transfer the hydrochloric acid solution to an empty constant-pressure dropping funnel, remove the nitrogen protection, and add the 12% hydrochloric acid aqueous solution dropwise at 20–30°C over approximately 1 hour. After the addition is complete, continue stirring for 30 minutes, then let it stand for 30 minutes to separate the layers. Collect the upper organic layer. Add a 5% sodium carbonate aqueous solution to the organic layer to adjust the pH to 6.0–8.0. After adjusting the pH, let it stand for 30 minutes to separate the layers, and collect the upper organic layer. Add 10% sodium chloride solution (326.12g) to the organic layer, stir for 30 minutes, let stand for another 30 minutes, separate the layers, and take the upper organic layer.Anhydrous magnesium sulfate (8.15 g) was added to the organic layer and stirred for 30 minutes. Then activated carbon (8.15 g) was added and stirred for 30 minutes. The mixture was filtered, and the filter cake was washed with 81.53 g of methyl tert-butyl ether. The filtrate and washings were combined. The solvent methyl tert-butyl ether was first distilled at atmospheric pressure, and the temperature was gradually increased to 60 °C until no solvent distilled out. At 60 °C, the residual methyl tert-butyl ether was distilled under reduced pressure using a water pump (vacuum degree of -0.09 to -0.1 MPa). After no liquid distilled out, the mixture was degassed under reduced pressure for 15 minutes to obtain compound-1 (a pale yellow oily liquid). A sample was taken for GC analysis, and the purity was 98.21%, the weight was 67.35 g, and the molar yield was 96.06%.

[0036] Example 2: Preparation of Compound-5

[0037] Equip a 1000ml four-necked flask with a mechanical stirrer, thermometer, and constant-pressure dropping funnel. Add compound-1 (70.11g, 0.5mol), dichloromethane (350.55g), and triethylamine (53.12g, 0.525mol) to the flask, stir, and cool to 0–5°C. Add methanesulfonyl chloride (60.14g, 0.525mol) to the constant-pressure dropping funnel, maintaining the temperature at 0–5°C, for approximately 1 hour. After addition, stir at 0–5°C for 20 minutes, take a sample for GC analysis; compound-2 residue is less than 1%, indicating the reaction is complete. Heat the mixture to 20–30°C and add triethylamine (53.12 g, 0.525 mol) to another constant-pressure dropping funnel. Add the triethylamine dropwise while maintaining the temperature at 20–30°C for about 1 hour. After the addition is complete, stir the mixture at 20–30°C for 3 hours. Take a sample for GC analysis. The residue of compound-2 is less than 1%. The reaction is complete.

[0038] Add 350.55 g of 10% sodium chloride aqueous solution, stir for 30 minutes, let stand for 30 minutes, separate into layers, take the lower organic layer containing compound-3, and transfer it to a 1000 ml four-necked flask. Attach a mechanical stirrer, thermometer, and constant-pressure dropping funnel, and stir while cooling to 0–5 °C. Add 20.0 g (0.5 mol) of spherical sodium hydroxide and 39.11 g (0.575 mol) of 50% hydrogen peroxide to the four-necked flask. Add acetic anhydride (29.35 g (0.2875 mol) to the constant-pressure dropping funnel, and add acetic anhydride dropwise while maintaining the temperature at 0–5 °C for approximately 1 hour. After addition, stir for 3 hours while maintaining the temperature at 0–5 °C. Take a sample for GC analysis; the residue of compound-3 is less than 1%, indicating the reaction is complete. Add water (350.55g) pre-cooled to 0-5℃, stir for 10 minutes, let stand for 30 minutes, separate into layers, remove the lower organic layer, heat to 20-30℃, add 5% sodium carbonate aqueous solution to the organic layer, adjust the pH to 6.0-8.0, after the pH is reached, add 5% sodium sulfite aqueous solution (70.11g), stir for 30 minutes, let stand for 30 minutes, separate into layers, remove the lower organic layer, add 10% sodium chloride aqueous solution (70.11g), stir for 30 minutes, let stand for 30 minutes, separate into layers, remove the lower organic layer, add anhydrous magnesium sulfate (7.011g), stir for 30 minutes, filter, wash the filter cake with dichloromethane (70.11g), combine the filtrate and washings to obtain a dichloromethane solution containing compound-4.

[0039] Transfer the dichloromethane solution containing compound 4 to a 1000ml four-necked flask. Install a mechanical stirrer and a thermometer. Insert glass tubes into two of the four necks of the flask, with the inlet glass tube below the liquid level and the outlet glass tube above the liquid level. Add methanol (70.11g) to the flask and cool it to -60 to -50°C using liquid nitrogen. Prepare ozone using an ozone generator. At -60 to -50°C, introduce ozone into the reaction solution through the inlet glass tube until the reaction solution turns deep blue. Stop introducing ozone and stir for 30 minutes. Use a nitrogen cylinder to supply nitrogen. At -60 to -50°C, introduce nitrogen into the reaction solution through the inlet glass tube to remove the ozone. Detect the tail gas in the outlet glass tube with water-moistened starch-potassium iodide test paper. When the color does not change, continue introducing nitrogen for 5 minutes. After 5 minutes, stop introducing nitrogen. Sodium borohydride (28.37 g, 0.75 mol) was added in batches at -60 to -50 °C over approximately 30 minutes. After the addition was complete, the mixture was stirred at -60 to -50 °C for 30 minutes. The temperature was then slowly increased to -15 to -10 °C over approximately 1 hour. The mixture was then stirred at -15 to -10 °C for another hour. A sample was taken for GC analysis, and the residue of compound -4 was less than 1%. The reaction was then complete.

[0040] Add 10% sodium chloride aqueous solution (210.33g), stir for 15 minutes, let stand for 30 minutes, separate the layers, and separate the upper water layer (water layer-①) and the lower organic layer (organic layer-①).

[0041] Add dichloromethane (70.11g) to water layer ①, stir for 15 minutes, let stand for 30 minutes, separate the layers, and separate the upper water layer (water layer ②) and the lower organic layer (organic layer ②).

[0042] Add dichloromethane (70.11g) to water layer ②, stir for 15 minutes, let stand for 30 minutes, separate the layers, separate the lower organic layer (organic layer ③), and discard the water layer.

[0043] Combine the organic layers -①+②+③, add anhydrous magnesium sulfate (14.02 g), stir for 30 minutes, then add activated carbon (14.02 g), stir for 30 minutes, filter, and wash the filter cake with dichloromethane (140.22 g). Combine the filtrate and washings to obtain a dichloromethane solution containing compound -5.

[0044] First, distill the solvent dichloromethane at atmospheric pressure, gradually raising the temperature to 50°C until no solvent distilled off. Then, at 50°C, distill the remaining dichloromethane under reduced pressure (vacuum degree -0.09 to -0.1 MPa) using a water pump. After no liquid distilled off, continue degassing under reduced pressure for 15 minutes to obtain compound-5 (a pale yellow oily liquid). A sample was taken for GC analysis, and the purity was 97.69%, the weight was 65.80 g, and the molar yield was 92.55%.

[0045] Example 3: Preparation of Compound-6

[0046] Equip a 1000ml four-necked flask with a mechanical stirrer, thermometer, and constant-pressure dropping funnel. Add compound-5 (71.1g, 0.5mol), dichloromethane (355.5g), and triethylamine (53.12g, 0.525mol) to the flask, stir, and cool to 0–5°C. Add methanesulfonyl chloride (60.14g, 0.525mol) to the constant-pressure dropping funnel, maintaining the temperature at 0–5°C for approximately 1 hour. After addition, stir at 0–5°C for 20 minutes, and perform GC analysis. The residue of compound-5 is less than 1%, indicating the reaction is complete. Add 10% sodium chloride aqueous solution (355.5g), stir for 30 minutes, and let stand for 30 minutes. The mixture separates into layers; discard the upper aqueous layer and collect the lower organic layer. Transfer the organic layer to a 1000ml four-necked flask, equip it with a mechanical stirrer, thermometer, and constant-pressure dropping funnel, and stir while cooling to 0–5°C. Add 169.07 g (1.5 mol) of 40% dimethylamine aqueous solution to a constant pressure dropping funnel. Add the 40% dimethylamine aqueous solution dropwise at 0-5℃ for about 1 hour. After the addition is complete, raise the temperature to 20-30℃ for about 2 hours. Stir the reaction at 20-30℃ for 10 hours. The mixture separates into layers. Discard the upper aqueous layer and take the lower organic layer. Add 355.5 g (10% sodium chloride aqueous solution) to the organic layer and stir for 30 minutes. Let it stand for 30 minutes. The mixture separates into layers again. Discard the upper aqueous layer and take the lower organic layer. Add 7.11 g (anhydrous magnesium sulfate) to the organic layer and stir for 30 minutes. Then add 7.11 g (activated carbon) and stir for 30 minutes. Filter the mixture and wash the filter cake with dichloromethane (71.1 g). Combine the filtrate and washings to obtain a dichloromethane solution containing compound-6. First, dichloromethane was distilled at atmospheric pressure. The temperature was gradually increased to 50°C until no more solvent distilled off. Then, at 50°C, the residual dichloromethane was distilled off under reduced pressure (vacuum degree of -0.09 to -0.1 MPa) using a water pump. After no more liquid distilled off, degassing was continued under reduced pressure for 15 minutes to obtain compound-6 (brownish-yellow oily liquid). A sample was taken for GC analysis, and the purity was 95.39%, the weight was 81.79 g, and the molar yield was 96.64%.

[0047] Example 4: Preparation of venlafaxine hydrochloride

[0048] Install a mechanical stirrer, thermometer, constant-pressure dropping funnel, and spherical condenser in a dry 3000 ml four-necked flask. Purge the reaction apparatus three times with nitrogen. Add magnesium filings (18.23 g, 0.75 mol) and dry methyl tert-butyl ether (169.26 g) to the four-necked flask. Add a solution of p-bromoanisole (112.22 g, 0.6 mol) in methyl tert-butyl ether (507.78 g) to the constant-pressure dropping funnel. Connect the constant-pressure dropping funnel to a nitrogen cylinder via a flexible tube. Adjust the flow rate using the pressure reducing valve on the nitrogen cylinder to gently purge nitrogen into the reaction apparatus, which then exits through the spherical condenser. Turn on the mechanical stirrer and heat to reflux. Using a constant-pressure dropping funnel, first add approximately 10% of a methyl tert-butyl ether solution of p-bromoanisole, initiating vigorous reflux. Then, add the remaining methyl tert-butyl ether solution of p-bromoanisole over approximately 2 hours. After the addition is complete, continue reflux for another 2 hours. Purge the reaction apparatus with nitrogen gas, cool to 20–30°C, add cuprous iodide (9.52 g, 0.05 mol), stir for 30 minutes, and then cool to -40 to -30°C. Add a solution of methyl tert-butyl ether (677.04 g) of compound-6 (84.63 g, 0.5 mol) to another constant-pressure dropping funnel. Quickly replace the constant-pressure dropping funnel used for adding the methyl tert-butyl ether solution of p-bromoanisole with this new constant-pressure dropping funnel. After assembly, connect the new constant-pressure dropping funnel to a nitrogen cylinder via a hose. Adjust the flow rate using the pressure reducing valve on the nitrogen cylinder to gently purge nitrogen into the reaction apparatus, which then exits through the spherical condenser. Maintain the temperature at -40 to -30°C and add the methyl tert-butyl ether solution of compound-6 dropwise over approximately 4 hours. After the addition is complete, maintain the temperature at -40 to -30°C and stir the reaction for 10 hours. Take a sample; GC analysis shows that compound-6 is less than 1%, indicating the reaction is complete.

[0049] Remove the nitrogen protection, control the temperature to no more than 30°C, add 10% hydrochloric acid solution dropwise, adjust the pH value to 3.0-3.5, after the pH value is in place, control the temperature to 20-30°C, continue stirring for 1 hour, then let it stand for 30 minutes to separate the layers, remove the water layer, and discard the organic layer.

[0050] At room temperature, add dichloromethane (677.04g) to the water layer, stir for 5 minutes, add 20% ammonia water dropwise to adjust the pH value to 8.0-9.0. After the pH value is reached, continue stirring for 1 hour, then let it stand for 30 minutes to separate the layers. Remove the organic layer and discard the water layer.

[0051] Anhydrous magnesium sulfate (8.46 g) was added to the organic layer, stirred for 30 minutes, filtered, and the filter cake was washed with dichloromethane (84.63 g). The filtrate and washings were combined to obtain a dichloromethane solution containing compound-7. The dichloromethane solvent was distilled at atmospheric pressure, and the temperature was gradually increased to 50°C until no more solvent distilled off. The temperature was then lowered to 20–30°C, and dichloromethane (677.04 g) was added, followed by activated carbon (8.46 g). The mixture was stirred for 30 minutes, filtered, and the filter cake was washed with dichloromethane (84.63 g). The filtrate and washings were combined, and dry hydrogen chloride gas was slowly introduced at 20–30°C until the pH of the reaction solution was between 4.0 and 5.0. After the pH was reached, stirring was continued for 1.5 hours. The sample was filtered, and the filter cake was washed with dichloromethane (84.63 g) to obtain venlafaxine hydrochloride wet product. It was dried under vacuum at 40-45 °C for 4-5 hours to obtain 124.16 g of white solid, with a molar yield of 79.12% and an HPLC purity of 99.77%.

[0052] The foregoing description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A method for synthesizing venlafaxine hydrochloride, characterized in that, Includes the following steps: Step (a): bromocyclohexane reacts with metallic magnesium to give the first Grignard reagent, which then reacts with acrolein in the presence of cuprous iodide to give compound-1; Step (b): Compound-1 reacts with methanesulfonyl chloride in the presence of triethylamine to give compound-2; compound-2 reacts with triethylamine to give compound-3; compound-3 reacts with hydrogen peroxide and acetic anhydride in the presence of sodium hydroxide to give compound-4; compound-4 is first oxidized with ozone and then reduced with sodium borohydride to give compound-5. Step (c): Compound-5 is first reacted with methanesulfonyl chloride in the presence of triethylamine, and then with dimethylamine to give compound-6; Step (d): Bromoanisole reacts with metallic magnesium to give a second Grignard reagent, which then reacts with compound-6 in the presence of cuprous iodide to give compound-7. Compound-7 then forms a salt with hydrogen chloride to give venlafaxine hydrochloride.

2. The method for synthesizing venlafaxine hydrochloride according to claim 1, characterized in that, In the synthesis of compound-1 in step (a), the reaction is carried out in a first solvent, which is an immiscible diethyl ether or methyl tert-butyl ether; the molar ratio of bromocyclohexane to magnesium is 1.0:(1.0 to 1.06); the reaction temperature of bromocyclohexane with magnesium to form the first Grignard reagent is reflux; the amount of cuprous iodide is 5% to 15% of bromocyclohexane, molar percentage; the molar ratio of bromocyclohexane to acrolein is 1.0:(1.0 to 1.1); the reaction temperature of the first Grignard reagent with acrolein is initially -20 to -10 °C, and then increased to 20 to 30 °C.

3. The method for synthesizing venlafaxine hydrochloride according to claim 1, characterized in that, In the synthesis of compound-2 in step (b), the molar ratio of compound-1 to triethylamine and methanesulfonyl chloride is 1.0:(1.0-1.1):(1.0-1.1); the reaction solvent is one of dichloromethane, trichloromethane or 1,2-dichloroethane; and the reaction temperature is 0-5°C.

4. The method for synthesizing venlafaxine hydrochloride according to claim 1, characterized in that, In the synthesis of compound-3 in step (b), the molar ratio of triethylamine to compound-1 is (1.0–1.1):1.0; the reaction temperature is 20–30 °C.

5. The method for synthesizing venlafaxine hydrochloride according to claim 1, characterized in that, In step (b) the synthesis of compound-4, the molar ratio of sodium hydroxide to compound-1 is 1.0:1.0; the hydrogen peroxide is 50% hydrogen peroxide, and the molar ratio of 50% hydrogen peroxide, acetic anhydride and compound-1 is (1.1~1.2):(0.55~0.6):1.0; the reaction temperature is 0~5℃.

6. The method for synthesizing venlafaxine hydrochloride according to claim 1, characterized in that, In the synthesis of compound-5 in step (b), methanol is added as a solvent in the ozone oxidation reaction. The weight of methanol is 0.8 to 1.2 times that of compound-1. The temperature of the ozone oxidation reaction is -60 to -50°C. In the reduction reaction, the molar ratio of sodium borohydride to compound-1 is (1.3 to 1.7):1.

0. The temperature of the reduction reaction is initially -60 to -50°C, and then increased to -15 to -10°C.

7. The method for synthesizing venlafaxine hydrochloride according to claim 1, characterized in that, In step (c) the synthesis of compound-6, the molar ratio of compound-5 to triethylamine and methanesulfonyl chloride is 1.0:(1.0–1.1):(1.0–1.1); the reaction is carried out in a first reaction solvent, which is one of dichloromethane, trichloromethane, or 1,2-dichloroethane; the reaction temperature is 0–5 °C; a 40% aqueous solution of dimethylamine is used for the reaction with dimethylamine, and the molar ratio of dimethylamine to compound-5 is (2.5–3.5):1.0; the reaction temperature with dimethylamine is initially 0–5 °C, and then increased to 20–30 °C.

8. The method for synthesizing venlafaxine hydrochloride according to claim 1, characterized in that, In step (d) the synthesis of compound-7, the reaction is carried out in a second reaction solvent, which is an immiscible diethyl ether or methyl tert-butyl ether; the molar ratio of compound-6 to p-bromoanisole and magnesium is 1.0:(1.1–1.3):(1.4–1.6); the reaction temperature of p-bromoanisole with magnesium to form the second Grignard reagent is reflux; the amount of cuprous iodide is 5%–15% of compound-6, in molar percentage; the reaction temperature of the second Grignard reagent with compound-6 is -40 to -30 °C.

9. The method for synthesizing venlafaxine hydrochloride according to claim 1, characterized in that, In step (d) the synthesis of venlafaxine hydrochloride, the reaction is carried out in a third reaction solvent, which is one of dichloromethane, trichloromethane or 1,2-dichloroethane; dry hydrogen chloride gas is introduced to maintain the pH of the reaction solution between 4.0 and 5.0; and the reaction temperature is 20 to 30°C.

10. The method for synthesizing venlafaxine hydrochloride according to claim 1, characterized in that, In the synthesis of compound-4 in step (b), the sodium hydroxide is spherical sodium hydroxide.

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