A method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor

Abstract

This invention discloses a method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor, comprising: weighing 2-methyltetrahydrofuran according to a predetermined ratio in a pre-dried reaction vessel; adding magnesium (1.1 to 1.3 equivalents) and an initiator to the 2-methyltetrahydrofuran; adding 1-chloro-4-methoxybutane (1.0 equivalents) dropwise; maintaining the reaction temperature at 30-60°C; and keeping the temperature constant for two hours after the addition is complete to obtain a 4-methoxybutylmagnesium chloride solution, which is raw material A solution; and dissolving 4-trifluoromethylbenzonitrile (0.9-0.95 equivalents) in 2-methyltetrahydrofuran. This invention can improve reaction yield, reduce side reactions, enhance mass transfer efficiency, solve the production safety hazards caused by violent exothermic reactions, overcome the safety risks of traditional batch reactor technology, use microreactors for safe and efficient post-processing, and use continuous distillation to purify the product, finally obtaining 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone in a yield of over 92%.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis and production technology, and more specifically, to a method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor. Background Technology

[0002] 5-Methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone is an important intermediate of fluvoxamine maleate. Fluvoxamine maleate is used to treat depression, obsessive-compulsive disorder, and anxiety disorders, which cause anxiety and insomnia.

[0003] Chinese patent CN101654419A discloses a method for preparing fluvoxamine maleate. The method uses p-trifluoromethylbenzoic acid as a raw material, first synthesizes N-methyl-N-methoxy-p-trifluoromethylbenzamide (Weinreb amide) in an amidation system, and then reacts it with 4-methoxybutylmagnesium halide to prepare 5-methoxy-1-(4-trifluoromethylphenyl)pentanone. The acylation reagent P(NMeOMe)3 is used, and a large amount of heat is released during the reaction with Grignard reagent.

[0004] Chinese patent CN 101602658 A uses p-trifluoromethylbenzonitrile as a raw material, reacting it with a Grignard reagent to generate 5-methoxy-1-(4-trifluoromethylphenyl)pentanone, cleverly avoiding the use of phosphorus-containing reagents. However, In the synthesis of 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone, the reaction is directly carried out with p-trifluoromethylbenzonitrile using Grignard reagent. However, the temperature and dropping rate are difficult to control during the reaction, which can easily lead to incomplete reaction and low product yield.

[0005] Therefore, how to control the reaction rate and reduce the overall risk during the reaction process is an urgent problem to be solved. Summary of the Invention

[0006] This invention proposes a method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor, which can overcome the safety risks of traditional batch reactor technology and can greatly shorten the reaction time and improve the product yield.

[0007] The technical solution of this invention is implemented as follows: A method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor, comprising: In a pre-dried reaction vessel, 2-methyltetrahydrofuran was weighed according to the formula. Magnesium (1.1 to 1.3 equivalents) and an initiator were added to the 2-methyltetrahydrofuran. 1-chloro-4-methoxybutane (1.0 equivalent) was added dropwise. The reaction temperature was maintained at 30-60℃. After the addition was completed, the temperature was kept warm for two hours to obtain a 4-methoxybutylmagnesium chloride solution, which is the raw material A solution. 4-Trifluoromethylbenzonitrile (0.9-0.95 equivalents) was dissolved in 2-methyltetrahydrofuran and mixed thoroughly to prepare raw material B solution. Raw material A solution and raw material B solution were fed into a microchannel continuous flow system at a volume ratio of 1:1.1 for reaction. The reaction was carried out at a pressure of 0.1-3.0 MPa and a temperature of 30-60°C for 5-100 s to obtain a reaction solution. After quenching and distillation, 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone was obtained. This was an exothermic reaction.

[0008] Weigh 2-methyltetrahydrofuran according to the ratio and put it into a pre-dried reaction vessel. After adding magnesium and initiator, add 1-chloro-4-methoxybutane dropwise. Keep the reaction at 30-60℃ for two hours to obtain 4-methoxybutylmagnesium chloride solution, which is raw material A solution. 4-Trifluoromethylbenzonitrile was dissolved in 2-methyltetrahydrofuran and mixed thoroughly to obtain raw material B solution; Raw material A solution and raw material B solution are pumped into a microchannel reactor in a certain proportion; the reaction is carried out at a reaction temperature of 30-60℃ and a pressure of 0.1-3.0MPa for 5-100s to obtain a reaction solution, which is then processed and purified to obtain 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone.

[0009] Preferably, the initiator comprises bromoethane and 1,2-dibromoethane reagent, wherein the weight ratio of bromoethane to 1,2-dibromoethane reagent is 1-5:1.

[0010] Preferably, the weight ratio of the 1-chloro-4-methoxybutane, the initiator, and the 2-methyltetrahydrofuran is 1:0.005-0.02:1.1-1.3.

[0011] Preferably, the weight ratio of the 4-trifluoromethylbenzonitrile to the 2-methyltetrahydrofuran is 1:0.9-1.

[0012] Preferably, the volume ratio of the raw material A solution to the raw material B solution pumped into the microchannel reactor is 1:1.1.

[0013] Preferably, the raw material A solution and the raw material B solution are slurry feeds, and the slurry flow rate is the ratio of the reactor liquid holding capacity V to the reaction residence time t; wherein, the reaction residence time t is 5~100s, and the reactor liquid holding capacity V is 5~2500mL.

[0014] Preferably, the microchannel reactor is a continuous flow microchannel reactor; the continuous flow microchannel reactor is composed of 1 to 20 microchannel reactor modules connected together; the internal channel depth of the continuous flow microchannel reactor is 100 μm to 10 mm.

[0015] Preferably, the modular structure of the microchannel reactor is one of the following: microtubular structure, trough structure, T-shaped structure, spherical structure, teardrop structure, umbrella structure, or heart-shaped structure; the material of the microchannel reactor is one of the following: special glass, silicon carbide, sapphire, corrosion-resistant alloy, or fluoropolymer.

[0016] Preferably, the post-processing includes continuous quenching and extraction to separate the organic and inorganic phases; the reaction module of the microchannel reactor is a two-inlet single-outlet module, and the structure of the two-inlet single-outlet module is a T-shaped structure, a spherical baffle, a teardrop-shaped structure or a heart-shaped structure, with a channel hydraulic diameter of 0.5mm-10mm.

[0017] Preferably, the refining process includes continuous distillation, atmospheric distillation, vacuum distillation, recrystallization, sublimation, and column chromatography separation and purification methods.

[0018] Beneficial effects: The present invention uses a microchannel reactor, which enables rapid mixing between material molecules at the millisecond level, increases mass transfer rate, avoids heat accumulation, results in low mixing reaction temperature, reduces by-product content, and improves product yield and selectivity. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0020] Figure 1 This is a process flow diagram of a method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor according to an embodiment of the present invention. Detailed Implementation

[0021] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention are within the scope of protection of the present invention.

[0022] According to embodiments of the present invention, a method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor is provided.

[0023] like Figure 1 As shown, in this optional embodiment, the method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor according to embodiments of the present invention includes: Step S101: Weigh 2-methyltetrahydrofuran according to the ratio and put it into a pre-dried reaction vessel. After adding magnesium and initiator, add 1-chloro-4-methoxybutane dropwise. Keep the reaction at 30-60℃ for two hours to obtain 4-methoxybutylmagnesium chloride solution, which is raw material A solution. Step S103: Dissolve 4-trifluoromethylbenzonitrile in 2-methyltetrahydrofuran and mix thoroughly to obtain raw material B solution; In step S105, raw material solution A and raw material solution B are pumped into a microchannel reactor in proportion; the reaction is carried out at a reaction temperature of 30-60℃ and a pressure of 0.1-3.0MPa for 5-100s to obtain a reaction solution, which is then processed and purified to obtain 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone.

[0024] In this optional embodiment, the initiator comprises bromoethane and 1,2-dibromoethane reagent, wherein the weight ratio of bromoethane to 1,2-dibromoethane reagent is 1-5:1.

[0025] In this optional embodiment, the weight ratio of the 1-chloro-4-methoxybutane, the initiator, and the 2-methyltetrahydrofuran is 1:0.005-0.02:1.1-1.3.

[0026] In this optional embodiment, the weight ratio between the 4-trifluoromethylbenzonitrile and the 2-methyltetrahydrofuran is 1:0.9-1.

[0027] In this optional embodiment, the volume ratio of the raw material A solution to the raw material B solution pumped into the microchannel reactor is 1:1.1.

[0028] In this optional embodiment, the raw material A solution and the raw material B solution are slurry feeds, and the slurry flow rate is the ratio of the reactor liquid holding capacity V to the reaction residence time t; wherein, the reaction residence time t is 5~100s, and the reactor liquid holding capacity V is 5~2500mL.

[0029] In this optional embodiment, the microchannel reactor is a continuous flow microchannel reactor; the continuous flow microchannel reactor is composed of 1 to 20 microchannel reactor modules connected together; the internal channel depth of the continuous flow microchannel reactor is 100um to 10mm.

[0030] In this optional embodiment, the module structure of the microchannel reactor is one of the following: microtubular structure, trough structure, T-shaped structure, spherical structure, teardrop structure, umbrella structure, or heart-shaped structure; the material of the microchannel reactor is one of the following: special glass, silicon carbide, sapphire, corrosion-resistant alloy, or fluoropolymer.

[0031] In this optional embodiment, the post-processing includes continuous quenching and extraction to separate the organic and inorganic phases; the reaction module of the microchannel reactor is a two-inlet single-outlet module, and the structure of the two-inlet single-outlet module is a T-shaped structure, a spherical baffle, a teardrop-shaped structure or a heart-shaped structure, with a channel hydraulic diameter of 0.5mm-10mm.

[0032] In this optional embodiment, the refining process includes continuous distillation, atmospheric distillation, vacuum distillation, recrystallization, sublimation, and column chromatography separation and purification methods.

[0033] To facilitate understanding of the above technical solutions of the present invention, the following detailed embodiments will further illustrate the above technical solutions of the present invention.

[0034] Example 1 In practical applications, the process for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor can be described as follows: A 1-liter four-necked flask was dried at 130℃ for 1 hour and then cooled by purging with nitrogen. 150.0 g of 2-methyltetrahydrofuran, 29.0 g of magnesium (1.2 equivalents), and an initiator were added, followed by the dropwise addition of 122.5 g (1.0 equivalent) of 1-chloro-4-methoxybutane. The temperature was controlled below 30-60℃, and after the addition was completed, the flask was kept at 45℃ for two hours to obtain raw material A solution. The initiator contained 1.0 g of bromoethane and dibromoethane in a weight ratio of 2:1. A mixture of 150.0 g of p-trifluoromethylbenzonitrile and 2-methyltetrahydrofuran forms a raw material B solution of 162.5 g (0.95 equivalents). Open the valve at the bottom of the raw material tanks and feed solutions A and B separately using the feed pump. Set the flow rate of raw material tank A (containing raw material A) to 10 ml / min and the flow rate of raw material tank B (containing raw material B) to 11 ml / min using the counting pump. Preheat both raw material solutions A and B by setting the heat exchanger temperature to 40°C and maintaining the reaction time in the channel for 30 seconds. The reaction product flows out of the reactor in a highly dispersed, continuous flow after passing through a cooling pan and ice-water bath. After the reaction is complete, feed a 10 wt% hydrochloric acid solution (pH ≤ 1, no white solid) using the feed pump, followed by two washes with 200 mL of pure water. Purify the compound by continuous distillation to obtain 227.4 g of compound, with a yield of 92%.

[0035] Example 2 In practical applications, the process for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor can be described as follows: A 1-liter four-necked flask was dried at 130℃ for 1 hour and then cooled by purging with nitrogen. 300.0 g of 2-methyltetrahydrofuran, 60.0 g of magnesium (1.23 equivalents), and an initiator were added. 245.0 g of 1-chloro-4-methoxybutane (1.0 equivalent) was added dropwise. The temperature was controlled below 30-60℃. After the addition was complete, the flask was kept at 45℃ for two hours to obtain raw material A solution. The initiator contained 2.0 g of bromoethane and dibromoethane in a weight ratio of 4:1. A mixture of 325.0 g of p-trifluoromethylbenzonitrile and 325.0 g of 2-methyltetrahydrofuran forms a 325.0 g (0.95 equivalent) solution of raw material B. Open the valve at the bottom of the raw material tanks and feed solutions A and B separately using the feed pump. Using a counting pump, adjust the flow rate of raw material tank A (containing raw material A) to 20 ml / min and the flow rate of raw material tank B (containing raw material B) to 22 ml / min. Then, preheat the raw material solutions A and B by setting the heat exchanger temperature to 45°C and maintaining the reaction time in the channel for 15 seconds. The reaction product flows out of the reactor in a highly dispersed, continuous flow after passing through a cooling pan and ice-water bath. After the reaction is complete, feed a 10 wt% hydrochloric acid solution (pH ≤ 1, no white solid) using the feed pump, followed by two washes with a total of 400 mL of pure water. After purification by continuous distillation, 494.0 g of the compound is obtained, with a yield of 94%.

[0036] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor, characterized in that, include: Weigh 2-methyltetrahydrofuran according to the ratio and put it into a pre-dried reaction vessel. After adding magnesium and initiator, add 1-chloro-4-methoxybutane dropwise. Keep the reaction at 30-60℃ for two hours to obtain 4-methoxybutylmagnesium chloride solution, which is raw material A solution. 4-Trifluoromethylbenzonitrile was dissolved in 2-methyltetrahydrofuran and mixed thoroughly to obtain raw material B solution; Raw material A solution and raw material B solution are pumped into a microchannel reactor in a certain proportion; the reaction is carried out at a reaction temperature of 30-60℃ and a pressure of 0.1-3.0MPa for 5-100s to obtain a reaction solution, which is then processed and purified to obtain 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone.

2. The method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor according to claim 1, characterized in that, The initiator comprises bromoethane and 1,2-dibromoethane reagent, wherein the weight ratio of bromoethane to 1,2-dibromoethane reagent is 1-5:

1.

3. The method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor according to claim 1, characterized in that, The weight ratio of the 1-chloro-4-methoxybutane, the initiator, and the 2-methyltetrahydrofuran is 1:0.005-0.02:1.1-1.

3.

4. The method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor according to claim 1, characterized in that, The weight ratio of 4-trifluoromethylbenzonitrile to 2-methyltetrahydrofuran is 1:0.9-1.

5. The method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor according to claim 1, characterized in that, The volume ratio of raw material A solution to raw material B solution pumped into the microchannel reactor is 1:1.

1.

6. The method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor according to claim 1, characterized in that, The raw material solution A and the raw material solution B are slurry feeds, and the slurry flow rate is the ratio of the reactor liquid holding capacity V to the reaction residence time t; wherein, the reaction residence time t is 5~100s, and the reactor liquid holding capacity V is 5~2500mL.

7. The method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor according to claim 1, characterized in that, The microchannel reactor is a continuous flow microchannel reactor; the continuous flow microchannel reactor is composed of 1 to 20 microchannel reactor modules connected together; the internal channel depth of the continuous flow microchannel reactor is 100um to 10mm.

8. The method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor according to claim 7, characterized in that, The modular structure of the microchannel reactor is one of the following: microtubular structure, trough structure, T-shaped structure, spherical structure, teardrop structure, umbrella structure, or heart-shaped structure; the material of the microchannel reactor is one of the following: special glass, silicon carbide, sapphire, corrosion-resistant alloy, or fluoropolymer.

9. The method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor according to claim 1, characterized in that, The post-processing includes continuous quenching and extraction to separate the organic and inorganic phases; the reaction module of the microchannel reactor is a two-inlet single-outlet module, and the structure of the two-inlet single-outlet module is a T-shaped structure, a spherical baffle, a teardrop-shaped structure or a heart-shaped structure, with a channel hydraulic diameter of 0.5mm-10mm.

10. The method for preparing 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone using a microchannel reactor according to claim 1, characterized in that, The refining process includes continuous distillation, atmospheric distillation, vacuum distillation, recrystallization, sublimation, and column chromatography separation and purification methods.

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