Method for preparing 4-cyanobenzyl bromide through continuous flow photocatalysis
The preparation of 4-cyanobenzyl bromide under closed conditions using a continuous flow photocatalytic reactor solves the problems of complex operation and safety hazards associated with traditional batch reactors, achieving efficient, safe, and high-purity preparation suitable for both laboratory and industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ANHUI UNIV
- Filing Date
- 2026-02-02
- Publication Date
- 2026-05-12
AI Technical Summary
Traditional batch reactors are complex to operate, labor-intensive, and pose safety hazards, making it difficult to achieve efficient and safe preparation of 4-cyanobenzyl bromide.
A continuous flow photocatalytic reactor was used for the photocatalytic reaction. The reaction was carried out in a closed feed, reaction and discharge process using a 365 nm-480 nm light source at 10-50 °C for 1-20 min. The reaction was then quenched, extracted and purified to obtain high-purity 4-cyanobenzyl bromide.
It improves the yield of the target compound, reduces the incidence of side reactions, and is suitable for small-scale laboratory production and large-scale industrial production, meeting the requirements for efficient and high-purity preparation.
Smart Images
Figure CN122010775A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for the preparation of 4-cyanobenzyl bromide by continuous flow photocatalysis. Background Technology
[0002] 4-Cyanobenzyl bromide is an important intermediate in organic synthesis, its molecular structure consisting of a benzene ring, a cyano group, and a bromomethyl group. This compound has wide applications in organic chemistry and materials science. In organic synthesis, 4-cyanobenzyl bromide is often used as an alkylating agent due to its high reactivity. The bromine atom, as a good leaving group, can undergo substitution reactions with nucleophiles to introduce the cyanobenzyl structure into the target molecule, enabling the construction of complex cyano-containing compounds. Furthermore, the cyano group can be reduced to an amino group or hydrolyzed to a carboxylic acid, further expanding its application potential in drug synthesis, such as as a precursor for antitumor or antibacterial drugs. Traditional batch reactors are complex to operate, require high levels of physical exertion for operators, and involve easy contact with hazardous reagents. Summary of the Invention
[0003] To overcome the shortcomings of the prior art, this invention provides a safer continuous-flow photocatalytic method for preparing 4-cyanobenzyl bromide. By synthesizing the target compound through a continuous photocatalytic reaction, the yield of the target compound is significantly improved while reducing the incidence of side reactions.
[0004] To achieve its objectives, the present invention employs the following technical solution:
[0005] The present invention provides a continuous flow photocatalytic method for preparing 4-cyanobenzyl bromide, comprising the following steps:
[0006] Step 1: Raw material preparation: Add p-toluenenitrile and organic solvent to the reaction vessel, stir well and set as solution a for later use; place hydrogen peroxide in a container as solution b for later use; place hydrobromic acid in a container as solution c for later use;
[0007] Step 2: Bromination reaction: Using water cooling and turning on the photocatalytic reactor, pump the solutions a, b and c into the continuous flow photocatalytic reactor, control the temperature at 10-40℃, and react for 1-20 min to obtain the reaction solution;
[0008] Step 3: Quenching: Add a quenching agent to the reaction solution obtained in Step 2, extract with an organic solvent to obtain the extract, and wash with brine;
[0009] Step 4: Purification: The extract obtained in Step 3 is subjected to vacuum distillation to obtain 4-cyanobenzyl bromide;
[0010] The reaction route is shown below:
[0011] .
[0012] In step 1, the organic solvent is one or a combination of several of dimethyl sulfoxide, n-heptane, methanol, and cyclohexane.
[0013] In step 1, the concentration of p-toluenenitrile in solution a is 1.7-17 mol / L; the mass concentration of H2O2 in solution b is 10%-50%; and the mass concentration of HBr in solution c is 10%-50%.
[0014] Furthermore, the molar ratio of H2O2 to p-toluenenitrile is 1.2-2:1; the molar ratio of HBr to p-toluenenitrile is 1.0-1.5:1.
[0015] In step 2, the wavelength of light in the continuous flow photocatalytic reactor is 365 nm-480 nm; the reaction time is 1-20 min; and the reaction temperature is 10-50℃.
[0016] Furthermore, the wavelength of light in the continuous flow photocatalytic reactor is 365-395 nm; the reaction time is 5-15 min; and the reaction temperature is 20-40℃.
[0017] In step 3, the quenching agent is one or a combination of several of the following: water, saturated sodium bicarbonate solution, and saturated sodium hydroxide solution.
[0018] Compared with existing technologies, the beneficial effects of this invention are reflected in:
[0019] Core technological innovation: Continuous flow photocatalysis replaces the traditional batch reaction, which is the most core innovation of the patent and changes the synthesis mode of this substance.
[0020] Upgraded reaction system: Abandoning the traditional open / semi-open batch reactor, a continuous flow photocatalytic reactor is adopted. Through a closed continuous feeding, reaction and discharge process, the problems of uneven material mixing and difficult control of reaction conditions in the traditional process are solved.
[0021] The reaction conditions of this invention are mild: the excellent mass and heat transfer capabilities of the continuous flow help suppress side reactions, ensuring the stability and controllability of the reaction.
[0022] The present invention features a short reaction time: due to the high intensity of the photocatalytic light source, the reaction time is shorter, reducing the formation of polybrominated byproducts.
[0023] The method of this invention is not only suitable for small-scale laboratory synthesis, but also meets the needs of large-scale industrial production. It is of great significance for the efficient and high-purity preparation of 4-cyanobenzyl bromide. Attached Figure Description
[0024] Figure 1 This is a flowchart of the reaction process of the method of the present invention.
[0025] Figure 2 This is the 1H NMR spectrum of the raw material p-toluenenitrile.
[0026] Figure 3 The image shows the 1H NMR spectrum of the product 4-cyanobenzyl bromide. Detailed Implementation
[0027] The technical solution of the present invention is further illustrated below through specific embodiments. These embodiments are only for illustrative purposes and are not intended to limit the scope of the invention.
[0028] Example 1:
[0029] The method for preparing 4-cyanobenzyl bromide by continuous flow photocatalysis in this embodiment includes the following steps:
[0030] 1. Prepare solution a by mixing p-toluenenitrile (4.5 mol, 528.1 g), n-heptane (1100 ml), and dimethyl sulfoxide (550 ml); prepare 30% hydrogen peroxide (6.75 mol, 1.5 eq) as solution b; prepare 40% hydrobromic acid solution (4.5 mol, 1 eq) as solution c.
[0031] 2. Turn on the cooling system to stabilize the temperature of the continuous flow photocatalytic reactor at 30℃. The wavelength of the photocatalytic lamp is 365nm. Introduce solutions a, b, and c into the continuous flow photocatalytic reactor to maintain the temperature at approximately 30℃ (±3℃). Control the reaction time to 10 minutes until the raw material solution is completely discharged.
[0032] 3. The reaction liquid flowing out of the continuous flow photocatalytic reactor was quenched with saturated sodium hydroxide aqueous solution. The aqueous phase was discarded, the organic phase was washed once with water, dried with anhydrous sodium sulfate, and finally evaporated under reduced pressure to obtain 1006.5 g of 4-cyanobenzyl bromide, with a yield of 90% and an HPLC purity of 97%.
[0033] Example 2:
[0034] The method for preparing 4-cyanobenzyl bromide by continuous flow photocatalysis in this embodiment includes the following steps:
[0035] 1. Prepare solution a by mixing p-toluenenitrile (9 mol, 1055.1 g), n-heptane (2200 ml), and dimethyl sulfoxide (1100 ml); prepare 30% hydrogen peroxide (12.6 mol, 1.4 eq) as solution b; prepare 40% hydrobromic acid solution (9 mol, 1 eq) as solution c.
[0036] 2. Turn on the cooling system to stabilize the temperature of the continuous flow photocatalytic reactor at 30℃. The wavelength of the photocatalytic lamp is 365nm. Introduce solutions a, b, and c into the continuous flow photocatalytic reactor to maintain the temperature at approximately 30℃ (±3℃). Control the reaction time to 15 minutes until the raw material solution has completely passed through.
[0037] 3. The reaction liquid flowing out of the continuous flow photocatalytic reactor was quenched with saturated sodium hydroxide aqueous solution. The aqueous phase was discarded, the organic phase was washed once with water, dried with anhydrous sodium sulfate, and finally evaporated under reduced pressure to obtain 1499.4 g of 4-cyanobenzyl bromide, with a yield of 85% and an HPLC purity of 94%.
[0038] Example 3:
[0039] The method for preparing 4-cyanobenzyl bromide by continuous flow photocatalysis in this embodiment includes the following steps:
[0040] 1. Prepare solution a by mixing p-toluenenitrile (2.25 mol, 264.0 g), n-heptane (550 ml), and dimethyl sulfoxide (275 ml). Prepare 30% hydrogen peroxide (3.6 mol, 1.6 eq) as solution b. Prepare 40% hydrobromic acid solution (2.45 mol, 1.1 eq) as solution c.
[0041] 2. Turn on the cooling system to stabilize the temperature of the continuous flow photocatalytic reactor at 30℃. The wavelength of the photocatalytic lamp is 365nm. Introduce solutions a, b, and c into the continuous flow photocatalytic reactor to maintain the temperature at approximately 30℃ (±3℃). Control the reaction time to 8 minutes until the raw material solution is completely discharged.
[0042] 3. The reaction liquid flowing out of the continuous flow photocatalytic reactor was quenched with saturated sodium hydroxide aqueous solution. The aqueous phase was discarded, the organic phase was washed once with water, dried with anhydrous sodium sulfate, and finally evaporated under reduced pressure to obtain 383.7 g of 4-cyanobenzyl bromide, with a yield of 87% and an HPLC purity of 95%.
[0043] Example 4:
[0044] The method for preparing 4-cyanobenzyl bromide by continuous flow photocatalysis in this embodiment includes the following steps:
[0045] 1. Prepare solution a by mixing p-toluenenitrile (3 mol, 352.4 g), n-heptane (800 ml), and dimethyl sulfoxide (400 ml); prepare 30% hydrogen peroxide (4.5 mol, 1.5 eq) as solution b; prepare 40% hydrobromic acid solution (3 mol, 1 eq) as solution c.
[0046] 2. Turn on the cooling system to stabilize the temperature of the continuous flow photocatalytic reactor at 30℃. The wavelength of the photocatalytic lamp is 395nm. Introduce solutions a, b, and c into the continuous flow photocatalytic reactor to maintain the temperature at approximately 30℃ (±3℃). Control the reaction time to 10 minutes until the raw material solution has completely passed through.
[0047] 3. The reaction liquid flowing out of the continuous flow photocatalytic reactor was quenched with saturated sodium hydroxide aqueous solution. The aqueous phase was discarded, the organic phase was washed once with water, dried with anhydrous sodium sulfate, and finally evaporated under reduced pressure to obtain 470.4 g of 4-cyanobenzyl bromide, with a yield of 80% and an HPLC purity of 94%.
[0048] Example 5:
[0049] The method for preparing 4-cyanobenzyl bromide by continuous flow photocatalysis in this embodiment includes the following steps:
[0050] 1. Prepare solution a by mixing p-toluenenitrile (6 mol, 704.8 g), methanol (800 ml), and cyclohexane (400 ml); prepare 40% hydrogen peroxide (9 mol, 1.5 eq) as solution b; prepare 30% hydrobromic acid solution (6.6 mol, 1.1 eq) as solution c.
[0051] 2. Turn on the cooling system to stabilize the temperature of the continuous flow photocatalytic reactor at 25℃. The wavelength of the photocatalytic lamp is 365nm. Introduce solutions a, b, and c into the continuous flow photocatalytic reactor to maintain the temperature at approximately 25℃ (±3℃). Control the reaction time to 12 minutes until the feed liquid is completely discharged.
[0052] 3. The reaction liquid flowing out of the continuous flow photocatalytic reactor was quenched with saturated sodium bicarbonate aqueous solution. The aqueous phase was discarded, the organic phase was washed once with brine, dried with anhydrous magnesium sulfate, and finally evaporated under reduced pressure to obtain 1123.5 g of 4-cyanobenzyl bromide, with a yield of 88% and an HPLC purity of 96%.
[0053] Example 6:
[0054] The method for preparing 4-cyanobenzyl bromide by continuous flow photocatalysis in this embodiment includes the following steps:
[0055] 1. Prepare solution a by mixing p-toluenenitrile (1.5 mol, 176.2 g), dimethyl sulfoxide (300 ml), and methanol (150 ml); prepare 20% hydrogen peroxide (2.4 mol, 1.6 eq) as solution b; prepare 50% hydrobromic acid solution (1.8 mol, 1.2 eq) as solution c.
[0056] 2. Turn on the cooling system to stabilize the temperature of the continuous flow photocatalytic reactor at 35℃. The wavelength of the photocatalytic lamp is 380nm. Introduce solutions a, b, and c into the continuous flow photocatalytic reactor to maintain the temperature at approximately 35℃ (±3℃). Control the reaction time to 14 minutes until the raw material solution is completely discharged.
[0057] 3. Quench the reaction liquid flowing out of the continuous flow photocatalytic reactor by adding a mixed solution of saturated sodium bicarbonate and saturated sodium hydroxide (volume ratio 1:1), discard the aqueous phase, wash the organic phase once with brine, dry it with anhydrous sodium sulfate, and finally evaporate it under reduced pressure to obtain 254.5 g of 4-cyanobenzyl bromide, with a yield of 83% and an HPLC purity of 95%.
[0058] Based on the above Examples 1-6, the following conclusions can be drawn: When the wavelength of light in the continuous flow photocatalytic reactor is 365 nm, the yield and purity of the product obtained are better than those of other methods. Different retention times and temperatures will affect the purity and yield of the product. Example 1 is the preferred method.
[0059] This invention relates to a highly efficient method for preparing high-purity continuous-flow photocatalytic 4-cyanobenzyl bromide via a photocatalytic continuous-flow reaction. Using p-toluenenitrile as a raw material, p-toluenenitrile is dissolved in an organic solvent, followed by photocatalytic radical bromination to obtain 4-cyanobenzyl bromide. The catalytic reaction process is mild, simple to operate, produces few byproducts, and yields a product with high purity and stable performance. This method addresses the shortcomings of traditional synthesis processes, eliminating complex operational steps and ensuring a high degree of airtightness throughout the process, minimizing exposure to air. It meets the needs of large-scale industrial production and has broad application prospects.
[0060] The above description represents the preferred embodiment of the invention. Those skilled in the art can still make certain improvements to the invention, but these improvements still fall within the scope of protection of the invention.
Claims
1. A method for the continuous flow photocatalytic preparation of 4-cyanobenzyl bromide, characterized in that... Includes the following steps: Step 1: Raw material preparation: Add p-toluenenitrile and organic solvent to the reaction vessel, stir well and set as solution a for later use; place hydrogen peroxide in a container as solution b for later use; place hydrobromic acid in a container as solution c for later use; Step 2: Bromination reaction: Using water cooling and turning on the photocatalytic reactor, pump the solutions a, b and c into the continuous flow photocatalytic reactor, control the temperature at 10-40℃, and react for 1-20 min to obtain the reaction solution; Step 3: Quenching: Add a quenching agent to the reaction solution obtained in Step 2, extract with an organic solvent to obtain the extract, and wash with brine; Step 4: Purification: The extract obtained in Step 3 is subjected to vacuum distillation to obtain 4-cyanobenzyl bromide; The reaction route is shown below: 。 2. The method according to claim 1, characterized in that: In step 1, the organic solvent is one or a combination of several of dimethyl sulfoxide, methanol, and cyclohexane.
3. The method according to claim 1, characterized in that: In step 1, the concentration of p-toluenenitrile in solution a is 1.7-17 mol / L; the mass concentration of H2O2 in solution b is 10%-50%; and the mass concentration of HBr in solution c is 10%-50%.
4. The method according to claim 3, characterized in that: In step 1, the molar ratio of H2O2 to p-toluenenitrile is 1.2-2:1; the molar ratio of HBr to p-toluenenitrile is 1.0-1.5:
1.
5. The method according to claim 1, characterized in that: In step 2, the wavelength of light in the continuous flow photocatalytic reactor is 365 nm-480 nm; the reaction time is 1-20 min; and the reaction temperature is 10-50℃.
6. The method according to claim 5, characterized in that: In step 2, the wavelength of light in the continuous flow photocatalytic reactor is 365-395 nm; the reaction time is 5-15 min; and the reaction temperature is 20-40℃.
7. The method according to claim 1, characterized in that: In step 3, the quenching agent is one or a combination of several of the following: water, saturated sodium bicarbonate solution, and saturated sodium hydroxide solution.