A method for synthesizing 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine by a continuous flow photo-thermal integrated method
The synthesis of N-substituted ortho-phenylthio aromatic amines via a continuous flow photothermal method solves the problems of high cost and uncontrollable reaction in existing technologies, achieving efficient, safe, and controllable compound synthesis and providing a green synthesis method for large-scale industrialization.
Patent Information
- Application Number
- CN202310138518.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-02-20
- Publication Date
- 2026-02-24
- Estimated Expiration
- 2043-02-20
AI Technical Summary
Existing technologies for synthesizing N-substituted ortho-phenylthio aromatic amine compounds suffer from problems such as high cost, scale-up effect, uncontrollable reaction, and flammability and explosiveness, making it difficult to achieve large-scale industrialization.
The synthesis was carried out using a continuous flow photothermal method with N-benzyl-2-naphthylamine and 2,2',4,4'-tetramethyldiphenyl disulfide as raw materials, sodium iodide as catalyst, and acetonitrile as solvent. The reaction was conducted through a continuous flow reaction instrument system with integrated photothermal gas-liquid mixing. The reaction conditions were mild and no transition metal catalysis was required.
It improves reaction efficiency and safety, enables controllable and green synthesis of compounds, and is suitable for large-scale industrial production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine using a continuous flow photothermal integrated method. Background Technology
[0002] N-substituted-ortho-phenylthio aromatic amines are not only important precursors for the synthesis of benzothiazoles and benzothiazides, but their skeletal structures are also widely present in drug molecules. Many small organic molecules containing this structure can serve as important intermediates in drug synthesis; for example, the antidepressant vortioxetine and the psychotropic drug quetiapine both contain this structure (Synlett, 2021, 32, 940). In the past, scientists have devoted considerable effort to constructing the core structures of N-substituted-ortho-phenylthio aromatic amines, primarily using transition metal catalysis, requiring high temperatures, or utilizing poorly obtained substrates as reactants ((a) Adv. Synth. Catal., 2019, 361, 3331; (b) J. Am. Chem. Soc., 2015, 137, 14071). However, due to factors such as high cost and scale-up effects, the large-scale industrialization of these methods remains quite limited. Therefore, there is an urgent need to design a green, sustainable synthetic route without scale-up effects to construct N-substituted ortho-phenylthio aromatic amine compounds.
[0003] Currently, in terms of synthesis technology, pharmaceutical and chemical companies mainly use batch reactors for large-scale production, which suffers from problems such as high temperatures, scale-up effects, uncontrollable reactions, and flammability and explosiveness. Photocatalysis, used under milder conditions, is less common. With the continuous development of chemical technology, we previously invented a system for scaled-up synthesis reactions, "A Photothermal Integrated Gas-Liquid Mixing Series Continuous Flow Reaction Instrument System" (Chinese invention patent application number 2022109247697, under substantive examination). Based on this, this invention uses N-benzyl-2-naphthylamine and 2,2',4,4'-tetramethyldiphenyl disulfide as raw materials, sodium iodide as a catalyst, and acetonitrile as a solvent, and successfully achieved the synthesis of 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine, a compound containing the N-substituted-ortho-phenylthio aromatic amine skeleton, using the invented photothermal integrated gas-liquid mixing series continuous flow reaction instrument system. This invention utilizes a continuous-flow photothermal integrated reaction technology to synthesize 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine, significantly improving reaction efficiency, shortening reaction time, enhancing reaction safety and controllability, and overcoming the scale-up effect of conventional reactions. It provides a bottleneck-free, scale-up reaction technology for the synthesis of this compound. This invention not only offers a green, efficient, safe, and controllable synthetic method for the scale-up synthesis of N-substituted ortho-phenylthio aromatic amine skeleton compounds, but also provides a valuable practical example of the unlimited-scale industrial synthesis of intermediates such as drug molecules and functional materials using a "photothermal integrated gas-liquid mixing series continuous flow reaction system." Summary of the Invention
[0004] The purpose of this invention is to address the shortcomings and deficiencies of existing technologies by providing a continuous-flow photothermal integrated method for the synthesis of 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine. This invention develops a scale-up synthesis method for 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine using N-benzyl-2-naphthylamine and 2,2',4,4'-tetramethyldiphenyl disulfide as raw materials, sodium iodide as a catalyst, and acetonitrile as a solvent, utilizing a photothermal integrated gas-liquid mixing series continuous-flow reaction instrument system. This method features readily available and simple substrates, requires no transition metal catalysis, has mild reaction conditions, and high atom economy. The reaction method offers advantages such as high efficiency, safety, controllability, environmental friendliness, and unlimited scale-up, providing a very practical method for the synthesis of 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine with excellent application prospects.
[0005] The objective of this invention is achieved through the following technical solution.
[0006] A method for synthesizing 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine using a continuous flow photothermal integrated method comprises the following steps:
[0007] (1) Add N-benzyl-2-naphthylamine, 2,2',4,4'-tetramethyldiphenyl disulfide as raw materials, catalyst and solvent to a storage bottle, and introduce oxygen or air into the reaction solution; (2) Set and turn on the flow rate, wavelength and power of light and reaction temperature of the mobile pump of the photothermal integrated gas-liquid mixing continuous flow reaction instrument system, and pump the reaction solution into the microchannel reaction device with the reaction conditions set according to the set flow rate. Collect the effluent and monitor the reaction process by thin-film chromatography. If the reaction is not complete, when the primary flow is complete, introduce oxygen or air into the effluent, switch the reaction flow direction, and then carry out the secondary flow to continue the reaction. Repeat this until the reaction is complete. After separation and purification, 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine as shown in Formula III is obtained.
[0008] Furthermore, the chemical reaction equations for the synthesis process are shown below:
[0009]
[0010] In the formula, the catalyst is sodium iodide, the solvent is acetonitrile, the oxidant is oxygen, and the reaction heating temperature is 25~80℃; the molar ratio of the compound shown in structural formula I and the compound shown in structural formula II to the catalyst is 1:0.5~3:0.05~0.20; the concentration of the compound shown in formula (I) in the reaction solution is 0.05~0.30mol / L; the flow rate of the introduced oxygen or air is adjusted according to the flow rate set by the mobile pump to achieve optimal gas-liquid mixing.
[0011] Furthermore, in step (2), the wavelength of the blue light in the reaction is 436~490nm, and the intensity of the light source is 16~100W.
[0012] Furthermore, in step (2), the flow rate of the reaction solution pumped into the microchannel reaction device is 0.50 to 6 mL / min.
[0013] Furthermore, in step (2), the microchannel has an inner diameter of 1-3 mm and is made of polytetrafluoroethylene.
[0014] Furthermore, the reaction apparatus is a photothermal integrated gas-liquid mixing continuous flow reaction system, specifically comprising: at least three heated magnetic stirrers, one integrated peristaltic pump, at least one photocatalytic / thermochemical continuous flow reaction system, two storage bottles, and a sample introduction system; the photocatalytic / thermochemical continuous flow reaction systems are connected in series; the two storage bottles contain the reaction liquid and the effluent, respectively; the heated magnetic stirrers are used to stir the liquid in the storage bottles to promote gas-liquid mixing, and also utilize the heating and liquid stirring of the photocatalytic / thermochemical continuous flow reaction system (see simplified diagram of this reaction system). Figure 7 (As shown).
[0015] Furthermore, a representative reaction instrument for the synthesis process is a photothermal integrated gas-liquid mixing continuous flow reaction instrument system, which consists of four heated magnetic stirrers, one integrated peristaltic pump, two photocatalytic / thermochemical continuous flow reaction systems, two storage bottles, and a sample introduction system; the two photocatalytic / thermochemical continuous flow reaction systems are connected in series; the two storage bottles contain the reaction liquid and the effluent, respectively; the heated magnetic stirrers are used to stir the liquid in the storage bottles to promote gas-liquid mixing, and also use the heating and liquid stirring of the photocatalytic / thermochemical continuous flow reaction system.
[0016] Further, in step (2), the separation and purification operation is as follows: the reaction solution is added to ethyl acetate, washed and extracted twice with saturated NaCl solution, the upper organic phase solution is taken, dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and then separated and purified by column chromatography to obtain the 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine.
[0017] This invention utilizes N-benzyl-2-naphthylamine and 2,2',4,4'-tetramethyldiphenyl disulfide as raw materials, sodium iodide as catalyst, and acetonitrile as solvent to achieve the scaled-up synthesis of 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine using a photothermal integrated gas-liquid mixing continuous flow reaction instrument system.
[0018] Compared with existing technologies, the present invention has the following advantages and beneficial effects: the substrate of the present invention is simple and easy to obtain, does not require transition metal catalysis, has mild reaction conditions, high atom economy, and the reaction method has the advantages of high efficiency, safety, controllability, greenness and unlimited scale-up, making it easy to carry out actual industrial production. Attached Figure Description
[0019] Figure 1 The image shows the hydrogen spectrum of the target product, 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine.
[0020] Figure 2 This is the carbon spectrum of the target product 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine.
[0021] Figure 3 This is the high-resolution mass spectrum of the target product 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine.
[0022] Figure 4 This is a physical image of the photothermal integrated gas-liquid mixing continuous flow reaction instrument system of Example 1.
[0023] Figure 5 This is a physical image of the photothermal integrated gas-liquid mixing continuous flow reaction instrument system of Example 2.
[0024] Figure 6 This is a physical image of the photothermal integrated gas-liquid mixing continuous flow reaction instrument system of Example 3.
[0025] Figure 7 This is a simplified diagram of a photothermal integrated gas-liquid mixing continuous flow reaction instrument system. Specific implementation methods
[0026] The technical solution of the present invention will be further described in detail below with reference to specific embodiments and accompanying drawings, but the scope of protection and implementation of the present invention are not limited thereto.
[0027] Example 1
[0028] The integrated photothermal gas-liquid mixing continuous flow reaction system consists of four heated magnetic stirrers, one integrated peristaltic pump, two photocatalytic / thermochemical continuous flow reaction systems, two storage bottles, and a sample introduction system, as shown in the simplified diagram above. N-benzyl-2-naphthylamine (10 mmol), 2,2',4,4'-tetramethyldiphenyl disulfide (5.5 mmol), sodium iodide (10 mol%, 1 mmol), and acetonitrile (100 mL) were added to the left storage bottle. Oxygen was bubbled through, and stirring was started to ensure thorough gas-liquid mixing. The temperature was set to 60℃, the wavelength to 455 nm (16×6 w), and the flow direction was adjusted from left to right at a flow rate of 3 mL / min for one continuous flow reaction. After approximately one hour, all the liquid in the left storage bottle flowed into the right storage bottle. Thin-layer chromatography (TLC) was used to detect the reaction, and the reactants were found to be incompletely reacted. Open the oxygen flow valve and magnetic stirrer on the right-hand reservoir, switch the peristaltic pump flow direction to flow from right to left, and conduct two continuous flow reactions. Repeat this continuous flow reaction four times, taking approximately 4 hours. Thin-layer chromatography (TLC) monitoring showed that the reaction was complete. Wash the extraction reaction solution twice with saturated NaCl solution, and collect the upper organic phase solution. Dry the organic phase with anhydrous magnesium sulfate and concentrate under reduced pressure to obtain the crude product. Separate and purify the crude product by column chromatography, dry, weigh, characterize, and calculate the yield. Analysis of nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) revealed that the product was 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine, with a yield of 72%.
[0029] Based on the above data, the structure of the target product is inferred as follows:
[0030] 1 H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.26-7.17 (m, 6H), 7.02(d, J = 9.0 Hz, 1H), 6.98 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 8.0 Hz,1H), 5.96 (s, 1H), 4.48 (s, 2H), 2.49 (s, 3H), 2.20 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 148.99, 139.21, 136.89, 134.95, 134.39, 132.00, 131.75, 131.06,128.56, 128.31, 127.70, 127.64, 127.24, 127.07, 126.84,.124.65, 124.23,122.08, 113.66, 104.26, 47.61, 20.67, 19.92. HRMS (ESI) m / z calcd for C 25 H 24 NS + (M+H) + 370.1624, found 370.1630.
[0031] Based on the above data, the structure of the target product is inferred as follows:
[0032] .
[0033] Example 2
[0034] The photothermal integrated gas-liquid mixing continuous flow reaction system consists of four heated magnetic stirrers, one integrated peristaltic pump, two photocatalytic / thermochemical continuous flow reaction systems, two storage bottles, and a sample introduction system, as shown in the simplified diagram above. N-benzyl-2-naphthylamine (10 mmol), 2,2',4,4'-tetramethyldiphenyl disulfide (5.5 mmol), sodium iodide (10 mol%, 1 mmol), and acetonitrile (100 mL) were added to the left storage bottle. Oxygen was bubbled through, and stirring was started to ensure thorough gas-liquid mixing. The temperature was set to 60℃, the wavelength to 455 nm (16×6 w), and the flow direction was adjusted from left to right at a flow rate of 0.5 mL / min. After approximately 6 hours, one continuous flow reaction was completed, and all the liquid in the left storage bottle flowed into the right storage bottle. Thin-layer chromatography (TLC) was used to detect the reaction, revealing that a small amount of raw material remained unreacted. The reaction mixture was washed twice with saturated NaCl solution, and the upper organic phase solution was collected. The organic phase was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography, dried, weighed, characterized, and the yield was calculated. Analysis of the nuclear magnetic resonance (NMR) spectrum and high-resolution mass spectrum revealed the product to be 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine, with a yield of 60%.
[0035] Based on the above data, the structure of the target product is inferred as follows:
[0036] 1 H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.26-7.17 (m, 6H), 7.02(d, J = 9.0 Hz, 1H), 6.98 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 8.0 Hz,1H), 5.96 (s, 1H), 4.48 (s, 2H), 2.49 (s, 3H), 2.20 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ148.99, 139.21, 136.89, 134.95, 134.39, 132.00, 131.75, 131.06,128.56, 128.31, 127.70, 127.64, 127.24, 127.07, 126.84,.124.65, 124.23,122.08, 113.66, 104.26, 47.61, 20.67, 19.92. HRMS (ESI) m / z calcd for C 25 H 24 NS + (M+H) + 370.1624, found 370.1630.
[0037] Based on the above data, the structure of the target product is inferred as follows:
[0038] .
[0039] Example 3
[0040] The integrated photothermal gas-liquid mixing continuous flow reaction system consisted of three heated magnetic stirrers, one integrated peristaltic pump, one photocatalytic / thermochemical continuous flow reaction system, two storage bottles, and a sample introduction system. N-benzyl-2-naphthylamine (10 mmol), 2,2',4,4'-tetramethyldiphenyl disulfide (5.5 mmol), sodium iodide (10 mol%, 1 mmol), and acetonitrile (100 mL) were added to the left storage bottle. Oxygen was bubbled through, and stirring was started to ensure thorough gas-liquid mixing. The temperature was set to 60℃, the wavelength to 455 nm (16×6 w), and the flow direction was adjusted from left to right at a flow rate of 3 mL / min for one continuous flow reaction. After approximately 50 minutes, all the liquid in the left storage bottle flowed into the right storage bottle. Thin-layer chromatography (TLC) was used to detect the reaction, indicating that the reactants were not completely reacted. Open the oxygen flow valve and magnetic stirrer on the right-hand reservoir, switch the peristaltic pump flow direction to flow from right to left, and conduct two continuous flow reactions. Repeat this continuous flow reaction 11 times, taking approximately 9 hours. Thin-layer chromatography (TLC) monitoring showed that the reaction was complete. Wash the extraction reaction solution twice with saturated NaCl solution, and collect the upper organic phase solution. Dry the organic phase with anhydrous magnesium sulfate and concentrate under reduced pressure to obtain the crude product. Separate and purify the crude product by column chromatography, dry, weigh, characterize, and calculate the yield. Analysis of nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) revealed that the product was 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine, with a yield of 71%.
[0041] Based on the above data, the structure of the target product is inferred as follows:
[0042] 1 H NMR (500 MHz, CDCl3) δ 8.200 (d, J = 8.5 Hz, 1H), 7.729 (d, J = 9.0 Hz, 1H), 7.660 (d, J = 8.0 Hz, 1H), 7.376 (t, J = 7.8 Hz, 1H), 7.255-7.171 (m, 6H),7.016 (d, J = 9.0 Hz, 1H), 6.977 (s, 1H), 6.663 (d, J = 8.0 Hz, 1H), 6.353 (d, J =8.0 Hz, 1H), 5.963 (s, 1H), 4.478 (s, 2H), 2.493 (s, 3H), 2.202 (s, 3H). 13 CNMR (126 MHz, CDCl3) δ 148.991, 139.212, 136.885, 134.949, 134.387, 132.002,131.750, 131.058, 128.561, 128.314, 127.698, 127.641, 127.237, 127.073,126.836,.124.650, 124.226, 122.077, 113.656, 104.257, 47.614, 20.674, 19.924.HRMS (ESI) m / z calcd for C 25 H 24 NS + (M+H) + 370.1624, found 370.1630.
[0043] Based on the above data, the structure of the target product is inferred as follows:
[0044] .
Claims
1. A method for synthesizing 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine using a continuous flow photothermal integrated method, characterized in that, Includes the following steps: ； (1) Dissolve N-benzyl-2-naphthylamine as shown in Formula I, 2,2',4,4'-tetramethyldiphenyl disulfide as shown in Formula II and a catalyst in a solvent to obtain a reaction solution, and then introduce oxygen or air into the reaction solution. (2) The reaction solution is pumped into a microchannel reaction device equipped with a light source of a certain wavelength and power and a set heating temperature at a set flow rate. The effluent is collected and the reaction progress is monitored by thin-layer chromatography. If the reaction is not complete, oxygen or air is introduced into the effluent when the primary flow is complete, the reaction flow rate is switched, and the secondary flow is carried out to continue the reaction. This process is repeated until the reaction is complete. After separation and purification, 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine as shown in Formula III is obtained. In step (1), the catalyst is sodium iodide; the solvent is acetonitrile; and the oxidant is oxygen. In step (2), the reaction heating temperature is 25~80℃.
2. The method according to claim 1, characterized in that, In step (1), the molar ratio of the compound shown in Formula I and the compound shown in Formula II to the catalyst is 1:0.5 to 3:0.05 to 0.20; the concentration of the compound shown in Formula (I) in the reaction solution is 0.05 to 0.30 mol / L.
3. The method according to claim 1, characterized in that, The flow rate of oxygen or air introduced is adjusted according to the flow rate set on the peristaltic pump to ensure optimal gas-liquid mixing.
4. The method according to claim 1, characterized in that, In step (2), the wavelength of the blue light source in the reaction is 436~490nm and the power of the light is 16~100W.
5. The method according to claim 1, characterized in that, In step (2), the flow rate of the reaction solution pumped into the microchannel reaction device is 0.50 to 6 mL / min.
6. The method according to claim 1, characterized in that, In step (2), the microchannel has an inner diameter of 1-3 mm and is made of polytetrafluoroethylene.
7. The method according to claim 1, characterized in that, In step (2), the separation and purification operation is as follows: the reaction solution is added to ethyl acetate, washed and extracted twice with saturated NaCl solution, the upper organic phase solution is taken, dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and then separated and purified by column chromatography to obtain the 1-(2,4-dimethylphenyl)thio-N-benzyl-2-naphthylamine.
8. The method according to claim 1, characterized in that, The reaction instrument is a photothermal integrated gas-liquid mixing continuous flow reaction system, specifically consisting of at least 3 heating magnetic stirrers, 1 integrated peristaltic pump, at least 1 photocatalytic / thermochemical continuous flow reaction system, two liquid storage bottles, and a sample injection system.
9. The method according to claim 8, characterized in that, In the aforementioned photothermal integrated gas-liquid mixing continuous flow reaction system, the photocatalytic / thermochemical continuous flow reaction systems are connected in series; the two storage bottles contain the reaction liquid and the effluent, respectively; the heated magnetic stirrer is used to stir the liquid in the storage bottle to promote gas-liquid mixing, and is also used for heating and stirring the liquid in the photocatalytic / thermochemical continuous flow reaction system.
10. The method according to claim 9, characterized in that, The photothermal integrated gas-liquid mixing continuous flow reaction instrument system consists of four heated magnetic stirrers, one integrated peristaltic pump, two photocatalytic / thermochemical continuous flow reaction systems, two storage bottles, and a sample introduction system. The two photocatalytic / thermochemical continuous flow reaction systems are connected in series. The two storage bottles contain the reaction liquid and the effluent, respectively. The heated magnetic stirrers are used to stir the liquid in the storage bottles to promote gas-liquid mixing, and also for heating and stirring the liquid in the photocatalytic / thermochemical continuous flow reaction systems.