Synthetic method of p-methylthio benzaldehyde
Through microchannel reaction technology and nano-Au support solid catalysts for ammonium salts, the problems of high-temperature reaction, waste acid generation and environmental pollution in the existing p-sulfone benzaldehyde synthesis methods are solved, and high efficiency, environmental protection and high product harvesting are achieved synthesis of p-methylthiobenzaldehyde.
Patent Information
- Application Number
- CN202411625955.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-14
- Publication Date
- 2025-02-18
AI Technical Summary
The existing synthesis methods of p-methylsulfone benzaldehyde have problems such as high temperature reaction, waste acid production, increased organic impurities, high safety risks, low product yields and environmental pollution.
Using microchannel reaction technology, p-chlorobenzaldehyde and sodium methylthiolate were mixed in an alcohol aqueous solvent, and a solid catalyst supported by a nano-Au support was used to react to achieve the efficient synthesis of p-methylthiobenzaldehyde.
Achieved high product yield (up to 92%) and high purity (up to 99%) p-methylthiobenzaldehyde synthesis, avoiding the generation of foul-odor gases and environmental pollution in solid-liquid reactions, simplifying operations and shortening Reaction time.
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Abstract
Description
Technical Field
[0001] The invention relates to a method for synthesizing p-methylthiobenzaldehyde, and belongs to the technical field of pharmaceutical intermediate synthesis. Background Art
[0002] Florfenicol (also known as fluorofen and fluorosulfamic acid) is a white or off-white crystalline powder, odorless and bitter. It is a new chloramphenicol-based broad-spectrum antibacterial drug for veterinary use that was successfully developed in the late 1980s. In the process of synthesizing florfenicol, D-p-methylsulfonylphenylserine ethyl ester (commonly known as D-ethyl ester) is a key intermediate, and the synthesis of this key intermediate is based on p-methylsulfonylbenzaldehyde as a raw material. Therefore, the synthesis of this raw material is also very important. Among them, the CAS No. 5398-77-6 of the p-methylsulfonylbenzaldehyde has the following structural formula:
[0003]
[0004] There are two synthetic routes for p-methylsulfonylbenzaldehyde in the existing literature:
[0005] One of them uses p-methylsulfonyltoluene as the starting material, reacts with bromine at high temperature to produce p-methylsulfonyldibromomethylbenzene, which is then hydrolyzed to produce p-methylsulfonylbenzaldehyde;
[0006] Another synthetic route is to use p-chlorobenzaldehyde as a starting material, react it with sodium methyl mercaptan to generate 4-(methylmercapto)benzaldehyde, and then use hydrogen peroxide to catalyze oxidation to synthesize p-methylsulfonylbenzaldehyde.
[0007] However, in the above-mentioned synthetic route, bromine is used in the first synthetic route, hydrobromic acid will be produced in the reaction process, resulting in a large amount of waste acid, and the reaction is a high temperature reaction, a large amount of organic impurities will be produced in the production process, and the difficulty of wastewater treatment is increased. At the same time, bromine has certain safety risks in the production and transportation process, which is not easy to produce safely and operate, and the overall product yield is only about 85%, and the cost is relatively high; although the reaction conditions are relatively mild in the second synthetic route, and the overall yield can also reach the scope of 88-92%, but the synthesis is one of the main raw materials, sodium methyl mercaptide, which is easily hydrolyzed to release stench and the methyl mercaptan gas with extremely low threshold value, will inevitably produce stench and toxic pollutants in the process of using kettle reaction, which has a large impact on the environment and poor operating conditions. And due to solid-liquid reaction, the reaction time is long, which greatly increases the difficulty of reaction. Therefore, the current research tendency is to find a continuous production method that can overcome the inconvenience of operation caused by the raw material sodium methyl mercaptide in the second reaction method. Summary of the invention
[0008] The present invention aims at the defects existing in the above prior art and provides a method for synthesizing p-methylthiobenzaldehyde, which solves the problem of how to achieve continuous synthesis with environmental friendliness and high product yield.
[0009] The objective of the present invention is achieved by the following technical scheme: a method for synthesizing p-methylthiobenzaldehyde, characterized in that the method comprises the following steps:
[0010] A. dissolving the raw material p-chlorobenzaldehyde in an alcohol solvent to form an alcohol solution of p-chlorobenzaldehyde;
[0011] B. The alcohol solution of p-chlorobenzaldehyde and the aqueous solution of sodium methyl mercaptan are respectively transported into the microchannel of the microchannel reactor, mixed and reacted with a solid catalyst fixed in the catalytic zone to obtain the corresponding product p-methylthiobenzaldehyde; the solid catalyst is supported by nano Au and loaded with a phase transfer catalyst ammonium salt.
[0012] By adopting the microchannel reaction mode, the solid catalyst fixed in the catalytic zone in the microchannel is supported by nano Au and loaded with a phase transfer catalyst ammonium salt, so that the reaction liquid passing through the catalytic zone can effectively realize the reaction under the action of the fixed catalyst to generate p-methylthiobenzaldehyde, and by improving the system of reaction raw materials, the sodium methyl mercaptan is directly prepared in the form of an aqueous solution and the p-chlorobenzaldehyde is prepared in the form of an alcohol solution, so that the existing kettle reaction adopts a solid-liquid reaction system, and the alcohol-water miscible property in the raw material system of the present invention can be utilized, so that the two raw materials are fully contacted in the form of a solution and flow through the area of the fixed solid catalyst, and under the joint action of the solid catalyst supported by nano Au and the loaded phase transfer catalyst ammonium salt, the p-methylthiobenzaldehyde can be efficiently and quickly converted into the product, and the product has the effects of high yield and high purity. In addition, after adopting the microchannel reaction, the reaction system of the present invention adopts an alcohol-water reaction solvent system, and the characteristic of the generated product being an oily substance is utilized, so that subsequent separation can be quickly realized, unnecessary impurity products can be more effectively avoided, and continuous reaction can be better realized, which greatly shortens the reaction time; the problem that sodium methyl mercaptan is easily hydrolyzed to release malodorous gas in the existing system adopting solid-liquid reaction is effectively avoided, and the system has the advantages of being environmentally friendly and easy to operate.
[0013] In the above-mentioned synthesis method of p-methylthiobenzaldehyde, preferably, the phase transfer catalyst ammonium salt in step B is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltriethylammonium chloride and tetrabutylammonium hydrogen sulfate. The above-mentioned ammonium salt can be more effectively adsorbed on the nano Au carrier, and can also effectively promote the reaction in the positive direction, with high reaction conversion rate, and short reaction time of the whole process, that is, the residence time of the raw materials after mixing and flowing through the catalytic zone in the microchannel reactor is short, the reaction efficiency is high, and it is more conducive to industrial production.
[0014] In the above-mentioned synthesis method of p-methylthiobenzaldehyde, preferably, the molar ratio of nano Au to phase transfer catalyst ammonium salt in the solid catalyst is 1: 0.2-0.4. Due to the use of a system using nano Au as a carrier and loaded with ammonium salt, only a small amount of ammonium salt is needed to effectively catalyze the reaction, and the above-mentioned catalyst has good stability. The catalyst of the above-mentioned dosage ratio is fixed in the catalytic zone of the microchannel reaction, which can achieve the effect of repeated use, and the reuse rate is high. As further preferred, the addition amount of the solid catalyst is 1.1%-1.8% of the mass of the raw material p-chlorobenzaldehyde.
[0015] In the above-mentioned synthesis method of p-methylthiobenzaldehyde, preferably, the reaction temperature in step B is 50°C to 100°C. The microchannel reaction has the effect of stable reaction, and can better achieve the effect of high purity and high yield of the product. It also has efficient heat and mass transfer characteristics, so that at the above-mentioned reaction temperature, the effect of rapid reaction conversion to generate the corresponding product can be achieved, the advantage of efficient reaction is achieved, the reaction time is greatly shortened, and the synthesis of the present invention has the effect of short reaction time. As a further preference, the reaction temperature in step B is 55°C to 80°C.
[0016] In the above-mentioned synthesis method of p-methylthiobenzaldehyde, preferably, the solid catalyst in step B is prepared by the following method:
[0017] HAuCl4 is added to water, then carbonate is added, and an aqueous solution of sodium borohydride is added under stirring to react to obtain a nano-Au sol;
[0018] Add ammonium salt as a phase transfer catalyst to the obtained nano Au sol, mix them, and control the temperature to be 50° C. to 80° C. for drying to obtain the solid catalyst.
[0019] By using HAuCl4 as raw material, forming Au sol under the action of carbonate and sodium borohydride, and then mixing with phase transfer catalyst ammonium salt, the formed nano Au is mixed with ammonium salt in the form of sol, and the ammonium salt can be effectively fully and evenly adsorbed on the surface of Au carrier, with good dispersibility, and a catalyst with Au as carrier and loaded ammonium salt is obtained, which has good catalytic activity and high reusability. As further preferred, the carbonate is selected from sodium carbonate and / or potassium carbonate. Raw materials are easy to obtain and low in cost, which is more conducive to the needs of industrial production.
[0020] In the above-mentioned synthesis method of p-methylthiobenzaldehyde, preferably, the alcohol solvent in step A is selected from one or more of methanol, ethanol, propanol and isopropanol.
[0021] In the above-mentioned method for synthesizing p-methylthiobenzaldehyde, preferably, the residence time of the reaction in step B in the catalytic zone is 1 min to 3 min.
[0022] In the above-mentioned method for synthesizing p-methylthiobenzaldehyde, preferably, the molar ratio of p-chlorobenzaldehyde to sodium methylthiolate is 1:1.0-1.5.
[0023] In summary, compared with the prior art, the present invention has the following advantages:
[0024] 1. The present invention can effectively avoid the existing kettle reaction using a solid-liquid reaction system, utilizes the property that alcohol and water in the raw material system of the present invention are miscible, makes the two raw materials fully contact in the form of solution and flow through the area of the fixed solid catalyst, can efficiently and quickly convert into the product p-methylthiobenzaldehyde, has the effect of high product yield and high purity, the yield reaches more than 92%, and the purity reaches more than 99%.
[0025] 2. After adopting the microchannel reaction, the reaction system of the present invention adopts an alcohol-water reaction solvent system, and the subsequent separation can be quickly realized by utilizing the characteristic that the generated product is an oily substance, and the continuous reaction can be better realized, which greatly shortens the reaction time; the problem that sodium methyl mercaptan is easily hydrolyzed and releases malodorous gas under the existing system adopting solid-liquid reaction is effectively avoided, and the environment is friendly. DETAILED DESCRIPTION
[0026] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.
[0027] Example 1
[0028] Synthesis of solid catalyst
[0029] HAuCl4 was added to deionized water, and then an aqueous solution of potassium carbonate was added, and a freshly prepared aqueous solution of sodium borohydride was added under stirring to react until the color of the solution changed from blue-purple to orange-red. The reaction was completed to obtain a nano-Au sol.
[0030] Then, a phase transfer catalyst tetrabutylammonium chloride is added to the obtained nano Au sol for thorough mixing, and then ultrasonic treatment is performed for 1 hour, and then stirring is performed for 12 hours. After the stirring is completed, the temperature is controlled at 70°C to 80°C for drying. After the drying is completed, the obtained crude product is cleaned with a mixed solution of ethanol and deionized water for 3-5 times to obtain a solid catalyst, which uses Au as a cross-section and carries tetrabutylammonium chloride. The amount of raw materials added is controlled so that the molar ratio of nano Au to tetrabutylammonium chloride in the obtained solid catalyst is 1:0.4.
[0031] Example 2
[0032] Synthesis of solid catalyst
[0033] HAuCl4 was added to deionized water, and then an aqueous solution of sodium carbonate was added, and a freshly prepared aqueous solution of sodium borohydride was added under stirring to react until the color of the solution changed from blue-purple to orange-red. The reaction was completed to obtain a nano-Au sol.
[0034] Then, a phase transfer catalyst benzyltriethylammonium chloride is added to the obtained nano Au sol for thorough mixing, and then ultrasonic treatment is performed for 1 hour, and then stirring is performed for 10 hours. After the stirring is completed, the temperature is controlled at 70°C to 80°C for drying. After the drying is completed, the obtained crude product is cleaned with a mixed solution of ethanol and deionized water for 3-5 times to obtain a solid catalyst, which uses Au as a cross-section and loads benzyltriethylammonium chloride. The amount of raw materials added is controlled so that the molar ratio of nano Au to benzyltriethylammonium chloride in the obtained solid catalyst is 1:0.25.
[0035] Example 3
[0036] Synthesis of solid catalyst
[0037] HAuCl4 was added to deionized water, and then an aqueous solution of sodium carbonate was added, and a freshly prepared aqueous solution of sodium borohydride was added under stirring to react until the color of the solution changed from blue-purple to orange-red. The reaction was completed to obtain a nano-Au sol.
[0038] Then, a phase transfer catalyst tetrabutylammonium hydrogen sulfate is added to the obtained nano Au sol for thorough mixing, and then ultrasonic treatment is performed for 1 hour, and then stirring is performed for 10 hours. After the stirring is completed, the temperature is controlled at 75°C for drying. After the drying is completed, the obtained crude product is cleaned with a mixed solution of ethanol and deionized water for 4 times to obtain a solid catalyst, which uses Au as a cross-section and carries tetrabutylammonium hydrogen sulfate. The amount of raw materials added is controlled so that the molar ratio of nano Au to tetrabutylammonium hydrogen sulfate in the obtained solid catalyst is 1:0.2.
[0039] Example 4
[0040] Weigh 14.2 g (0.1 mol) of p-chlorobenzaldehyde as a raw material and dissolve it in 130 ml of ethanol to obtain an alcohol solution of p-chlorobenzaldehyde;
[0041] Add 16.5 g (0.11 mol) of sodium methyl mercaptan to 60 ml of water to prepare a sodium methyl mercaptan aqueous solution;
[0042] The alcohol solution of p-chlorobenzaldehyde and the aqueous solution of sodium methyl mercaptan prepared as above were respectively conveyed into the inlet of the microchannel reactor by pumps, mixed in the microchannel reactor to form a mixed liquid and continuously conveyed to react with the solid catalyst fixed in the catalytic zone in the channel. The solid catalyst fixed in the catalytic zone was a nanoscale solid catalyst obtained by the method of Example 1. The fixed amount of the nanoscale solid catalyst was 0.21 g. The reaction temperature was controlled at 50°C to 60°C, and the time for conveying the reaction mixed liquid through the catalytic zone was 3 minutes. After the reaction was completed, the reaction liquid obtained after the reaction was allowed to stand for oil-water separation, and the aqueous phase was removed by layers to obtain 13.2 g of the corresponding oily p-methylthiobenzaldehyde with a purity of 99.3%.
[0043] Example 5
[0044] Weigh 14.2 g (0.1 mol) of p-chlorobenzaldehyde as a raw material and dissolve it in 140 ml of methanol to obtain an alcohol solution of p-chlorobenzaldehyde;
[0045] Add 18 g (0.12 mol) of sodium methyl mercaptan to 60 ml of water to prepare a sodium methyl mercaptan aqueous solution;
[0046] The alcohol solution of p-chlorobenzaldehyde and the aqueous solution of sodium methyl mercaptan prepared as above were respectively conveyed into the inlet of the microchannel reactor by pumps, mixed in the microchannel reactor to form a mixed liquid and continuously conveyed to react with the solid catalyst fixed in the catalytic zone in the channel. The solid catalyst fixed in the catalytic zone was a nanoscale solid catalyst obtained by the method of Example 2. The fixed amount of the nanoscale solid catalyst was 0.26 g. The reaction temperature was controlled at 55°C to 60°C, and the time for conveying the reaction mixed liquid through the catalytic zone was 3 minutes. After the reaction was completed, the reaction liquid obtained after the reaction was allowed to stand for oil-water separation, and the aqueous phase was removed by layers to obtain 12.8 g of the corresponding oily p-methylthiobenzaldehyde with a purity of 99.2%.
[0047] Example 6
[0048] Weigh 14.2 g (0.1 mol) of p-chlorobenzaldehyde as a raw material and dissolve it in 150 ml of ethanol to obtain an alcohol solution of p-chlorobenzaldehyde;
[0049] Add 19.5 g (0.13 mol) of sodium methyl mercaptan to 80 ml of water to prepare a sodium methyl mercaptan aqueous solution;
[0050] The alcohol solution of p-chlorobenzaldehyde and the aqueous solution of sodium methyl mercaptan prepared as above were respectively conveyed into the inlet of the microchannel reactor by pumps, mixed in the microchannel reactor to form a mixed liquid and continuously conveyed to react with the solid catalyst fixed in the catalytic zone in the channel. The solid catalyst fixed in the catalytic zone was a nanoscale solid catalyst obtained by the method of Example 3. The fixed amount of the nanoscale solid catalyst was 0.16 g. The reaction temperature was controlled at 65°C to 70°C, and the time for conveying the reaction mixed liquid through the catalytic zone was 2 minutes. After the reaction was completed, the reaction liquid obtained after the reaction was allowed to stand for oil-water separation, and the aqueous phase was removed by layers to obtain 12.6 g of the corresponding oily p-methylthiobenzaldehyde with a purity of 99.1%.
[0051] Example 7
[0052] Weigh 14.2 g (0.1 mol) of p-chlorobenzaldehyde as a raw material and dissolve it in 160 ml of propanol to obtain an alcohol solution of p-chlorobenzaldehyde;
[0053] Weigh 18 g (0.12 mol) of raw material sodium methyl mercaptan and add it to 60 ml of water to prepare a sodium methyl mercaptan aqueous solution;
[0054] The alcohol solution of p-chlorobenzaldehyde and the aqueous solution of sodium methyl mercaptan prepared as above were respectively conveyed into the inlet of the microchannel reactor by pumps, mixed in the microchannel reactor to form a mixed liquid and continuously conveyed to react with the solid catalyst fixed in the catalytic zone in the channel. The solid catalyst fixed in the catalytic zone was a nanoscale solid catalyst obtained by the method of Example 2. The fixed amount of the nanoscale solid catalyst was 0.23 g. The reaction temperature was controlled at 95°C to 100°C, and the time for conveying the reaction mixed liquid through the catalytic zone was 1 min. After the reaction was completed, the reaction liquid obtained after the reaction was allowed to stand for oil-water separation, and the aqueous phase was removed by layers to obtain 12.7 g of the corresponding oily p-methylthiobenzaldehyde with a purity of 99.3%.
[0055] The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.
[0056] Although the present invention has been described in detail and some specific embodiments have been cited, it is obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention.
Claims
1. A method for synthesizing p-methylthiobenzaldehyde, characterized in that: The method comprises the following steps: A. dissolving the raw material p-chlorobenzaldehyde in an alcohol solvent to form an alcohol solution of p-chlorobenzaldehyde; B. The alcohol solution of p-chlorobenzaldehyde and the aqueous solution of sodium methyl mercaptan are respectively transported into the microchannel of the microchannel reactor, mixed and reacted with a solid catalyst fixed in the catalytic zone to obtain the corresponding product p-methylthiobenzaldehyde; the solid catalyst is supported by nano Au and loaded with a phase transfer catalyst ammonium salt.
2. The synthetic method of p-methylthiobenzaldehyde according to claim 1, characterized in that: The phase transfer catalyst ammonium salt in step B is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltriethylammonium chloride and tetrabutylammonium hydrogen sulfate.
3. The synthetic method of p-methylthiobenzaldehyde according to claim 1, characterized in that: The molar ratio of nano-Au to the ammonium salt of the phase transfer catalyst in the solid catalyst is 1:0.2-0.
4.
4. The synthetic method of p-methylthiobenzaldehyde according to claim 1, 2 or 3, characterized in that: The reaction temperature in step B is 50°C to 100°C.
5. The method for synthesizing p-methylthiobenzaldehyde according to claim 1, 2 or 3, characterized in that: The solid catalyst in step B is prepared by the following method: HAuCl4 is added to water, then carbonate is added, and an aqueous solution of sodium borohydride is added under stirring to react to obtain a nano-Au sol; Add ammonium salt as a phase transfer catalyst to the obtained nano Au sol, mix them, and control the temperature to be 50° C. to 80° C. for drying to obtain the solid catalyst.
6. The method for synthesizing p-methylthiobenzaldehyde according to claim 5, characterized in that: The carbonate is selected from sodium carbonate and / or potassium carbonate.
7. The method for synthesizing p-methylthiobenzaldehyde according to claim 1, 2 or 3, characterized in that: The alcohol solvent in step A is selected from one or more of methanol, ethanol, propanol and isopropanol.
8. The method for synthesizing p-methylthiobenzaldehyde according to claim 1, 2 or 3, characterized in that: The residence time of the reaction in step B in the catalytic zone is 1 min to 3 min.
9. The method for synthesizing p-methylthiobenzaldehyde according to claim 1, 2 or 3, characterized in that: The molar ratio of p-chlorobenzaldehyde to sodium methyl mercaptan is 1:1.0-1.5.