Method for synthesizing trifluoromethyl-containing nitrogen-containing heterocycles by metal catalysis

Abstract

A method for synthesizing a trifluoromethyl-containing nitrogen-containing heterocycle by metal catalysis is implemented by using a reinforced heating jacket to prepare 2-trifluoromethyl-4-hydroxy-5-nitropyridine from 2-trifluoromethyl-4-chloro-5-nitropyridine; then prepare 2-(5-nitro-2-(trifluoromethyl)pyridin-4-yl) diethyl malonate; further obtain 2-trifluoromethyl-4-methyl-5-nitropyridine; and finally obtain 2-trifluoromethyl-4-methyl-5-aminopyridine.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediate preparation, in particular to a method for synthesizing trifluoromethyl-containing nitrogen-containing heterocycles through metal catalysis. Background Art

[0002] A metal-catalyzed synthesis of trifluoromethyl-containing nitrogen-containing heterocycles, specifically 2-trifluoromethyl-4-methyl-5-aminopyridine and its derivatives, is disclosed in this application. These compounds are important compounds with strong biological activity and potential pharmaceutical applications. However, the methods described in this application rarely appear in the literature or are publicly available as pharmaceutical intermediates. Due to the molecular properties, unique synthetic route, and high yields, the methods cannot be extended to the synthesis of other similar structures.

[0003] Due to the properties of this molecule, this method cannot be extended to the synthesis of other similar structures. This is due to the uniqueness of the preparation method, the high yield, and the short reaction time, which were achieved through countless experiments and cannot be replicated. Other routes are basically unable to achieve high yields or acceptable reaction times. In particular, the practical issues of temperature control in this application were not addressed, and no improvements to the device were made using the same or similar methods as those used in this application.

[0004] In addition, the existing technology still has the following problems. First, the preparation method of 2-trifluoromethyl-4-methyl-5-aminopyridine has a low yield. Currently, the yield given by the personnel in this field we have found or consulted is not higher than 60%, and generally there are wastes that are difficult to handle.

[0005] Secondly, the present method, like many other methods for preparing this substance, requires prolonged heating. During this process, it is difficult to maintain a consistent temperature using conventional heating methods, especially in winter or when the wind is strong. It is often difficult to maintain the system temperature consistent with the temperature set by the heating device or heating jacket (a four-necked flask or other glassware with a large area exposed to the air). Our numerous comparative experiments have shown that this has a significant adverse effect on yield. However, the prior art has not addressed this shortcoming, using blankets or heat pads for simple insulation. However, firstly, the insulation effect is insufficient, and secondly, since the flask may require vigorous stirring, such a simple insulation measure cannot meet the requirements of a long-term stirred reaction. Summary of the Invention

[0006] The first purpose of the present invention is to solve two specific problems in the prior art. The first is how to obtain 2-trifluoromethyl-4-methyl-5-aminopyridine from 2-trifluoromethyl-4-hydroxy-5-nitropyridine through a few steps with high yield, and the yield needs to be high, the waste needs to be small and the treatment needs to be easy. The present application perfectly solves this problem. The second is how to effectively maintain a stable temperature for a long time and avoid the adverse effects of temperature changes in the face of the fact that each step requires long-term heating reaction. This has been solved in the present application.

[0007] The present invention claims protection for a reinforced heating sleeve, which is characterized by comprising a lower fixed sleeve and an upper movable sleeve.

[0008] The lower fixed sleeve includes a lower heating sleeve, an outer shell, a base, a control circuit, a control panel and a power supply unit; the upper movable sleeve includes an upper heating sleeve and an inner lining and an outer lining; the lower heating sleeve and the upper heating sleeve are respectively connected to the control circuit, are independently powered and controlled by the control circuit, and are temperature-controlled integrally by the control panel.

[0009] Furthermore, both the upper heating sleeve and the lower heating sleeve have mesh alloy wires, which are wrapped with alkali-free glass fiber and vacuum-formed using aluminum silicate wool; the lower heating sleeve is hemispherical, and the upper heating sleeve is in the shape of two parallel planes intercepting a portion of the sphere, and one of the planes passes through the center of the sphere; one side of the upper heating sleeve, the inner lining, and the outer lining all have openings; the inner lining and the outer lining are Teflon material layers with a thickness of 3-8mm, and are both mesh-shaped and hollow; the connecting line between the upper heating sleeve and the control circuit is located on the outside of the upper heating sleeve.

[0010] A method for metal-catalyzed synthesis of a trifluoromethyl-containing nitrogen-containing heterocycle, namely a method for synthesizing 2-trifluoromethyl-4-methyl-5-aminopyridine, is implemented using the aforementioned enhanced heating jacket and comprises the following four steps.

[0011] (1) 0.09-0.11 mol of 2-trifluoromethyl-4-hydroxy-5-nitropyridine was dissolved in 45-55 ml of phosphorus oxychloride. The lower part of the mixed four-necked flask was placed in the lower heating jacket, and the opening of the upper heating jacket was opened and placed horizontally on the upper part of the four-necked flask, and the opening was closed. The heating was controlled by the control panel to maintain at 70° C. and the reaction was maintained for not less than 3 hours. When TLC confirmed that the reaction was complete, the heating device was removed and the temperature was lowered to 25° C. After the temperature stabilized, the reaction mixture was poured into 190-210 g of crushed ice, and the pH of the system was adjusted with 10% sodium carbonate aqueous solution until the pH was 7-8. The mixture was extracted three times with 200 mL of ethyl acetate each time, and then washed once with not less than 150 mL of saturated brine, dried with 5 g of anhydrous sodium sulfate for not less than 30 minutes, the desiccant was filtered off, and concentrated to obtain 2-trifluoromethyl-4-chloro-5-nitropyridine.

[0012] (2) Take a four-necked flask with a volume of more than 500 mL and add 45-55 mL of N,N-dimethylformamide under nitrogen protection. Add 0.08-0.1 mol of sodium hydride in small amounts and several times. Then cool the system to 0°C with an ice-water bath. Add 0.08-0.1 mol of diethyl malonate dropwise. After the addition is complete, keep stirring at 0°C for 30 minutes. Continue to keep stirring at 0°C and dropwise add a DMF solution containing 0.04-0.05 mol of 2-trifluoromethyl-4-chloro-5-nitropyridine in a volume of not less than 10 mL of DMF. After the addition is complete, The lower part of the four-necked flask was placed in the lower heating jacket, and the opening of the upper heating jacket was opened, which was horizontally placed on the upper part of the four-necked flask and the opening was closed; the heating was controlled to be maintained at 25° C. by the control panel, and the reaction was maintained for not less than 1 hour. After the TLC reaction was complete, 50 mL of pure water was added to quench the reaction, and the mixture was extracted 3 times with 100 mL of ethyl acetate each time. The organic phases were combined, washed 3 times with 50 mL of saturated brine each time, and dried with 10 g of anhydrous sodium sulfate for not less than 30 minutes. The crude product of diethyl 2-(5-nitro-2-(trifluoromethyl)pyridin-4-yl)malonate was obtained after spin-drying.

[0013] (3) Take a four-necked flask of 500 mL or more, add 85-95 mL of 6N hydrochloric acid, add the DMF solution of the crude product obtained in step 2, 25 mL of DMF, place the lower part of the mixed four-necked flask in the lower heating jacket, open the opening of the upper heating jacket, put it horizontally on the upper part of the four-necked flask, and close the opening; control the heating to maintain at 90°C through the control panel, and keep the reaction for at least 18 hours. After the TLC reaction is complete, remove the heating, cool to room temperature, and add 50% mass percentage sodium hydroxide solution dropwise until the pH = 8, extract 3 times with 100 mL of ethyl acetate each time, combine the organic phases, wash the organic phases 3 times with 50 mL of saturated brine each time, dry and concentrate to obtain the crude product, and wet-filter with at least 100 g of 200-300 mesh silica gel column, with petroleum ether to ethyl acetate = 50:1, to obtain the product 2-trifluoromethyl-4-methyl-5-nitropyridine.

[0014] (4) Take a four-necked flask with a capacity of more than 500 mL, dissolve 0.04-0.05 mol of 2-trifluoromethyl-4-methyl-5-nitropyridine in 200 mL of methanol, add 10 g of Raney Ni, first evacuate and then bubble in nitrogen, repeat this three times, then bubble in hydrogen, seal the opening of the four-necked flask, place the lower part in the lower heating jacket, and open the opening of the upper heating jacket, horizontally cover the upper part of the four-necked flask, and close the opening; control the heating to maintain at 25°C through the control panel, and keep the reaction for at least 18 hours. After the TLC reaction is complete, filter with suction, wash the filter cake with at least 50 mL of methanol three times, combine and spin-dry, and wet-filter with 50 g of 200-300 mesh silica gel, with petroleum ether to ethyl acetate = 50:1, to obtain the final product 2-trifluoromethyl-4-methyl-5-aminopyridine.

[0015] Compared with the prior art, the advantages of the present invention are as follows: First, for long-term heating, the upper part of the four-necked flask is exposed to the air, which often leads to unstable system temperature (especially in winter, we use a thermal imager to monitor for a long time and find that the temperature of the upper half of the four-necked flask is unstable, and the temperature is often significantly lower than the set temperature. For example, when the setting is 90°C, the actual temperature fluctuates between 90-82°C. After comparison, it has a significant adverse effect on the yield). A soft heating jacket is set on the upper part of the heating jacket, which perfectly solves this problem. The additional soft heating jacket is easy to apply and can effectively ensure that the system reacts at the required temperature. There is no similar complete setting in the current prior art. Second, the preparation method itself is better, the raw materials are easy to obtain, the steps are short, there is no particularly complex mechanism, and the yield is extremely high, which can stably reach about half. This is also better than similar technologies in the prior art.

[0016] There is currently no report on the preparation of this product in the prior art. Compared with the preparation methods of similar substances, the steps of the method of this application are meticulously designed, and the utilization rate of raw materials in each step is very high, which has great value for industrial production. Through the careful design of the method of the present invention, not only the synthesis is effectively achieved, but also the yield is high, averaging more than 70%, such as 72.96%, etc., which has certain industrial production value and great economic value. This application embodies a strong inventive concept and creativity through the careful design of the additional heating jacket, and achieves good preparation results. There is no similar public information for reference in the prior art, and the scheme of the present invention is original. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0018] Figure 1 This is a schematic diagram of the front of the heating jacket.

[0019] Figure 2 It is a schematic diagram of the structure of the upper heating jacket.

[0020] Figure 3 Schematic diagram of the synthesis steps.

[0021] Figure 4 This is the NMR image of the final product.

[0022] Drawing reference numerals: 1. lower fixed sleeve, 2. upper movable sleeve, 11. lower heating sleeve, 12. outer shell, 13. base, 14. control circuit, 15. control panel, 16. power supply unit, 21. upper heating sleeve, 22. inner lining, 23. outer lining; 24. opening. DETAILED DESCRIPTION

[0023] The preferred embodiments of the present invention are described in detail below with reference to the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more precise definition of the protection scope of the present invention.

[0024] Example 1

[0025] A reinforced heating sleeve is characterized by comprising a lower fixed sleeve 1 and an upper movable sleeve 2.

[0026] The lower fixed sleeve comprises a lower heating sleeve 11, an outer shell 12, a base 13, a control circuit 14, a control panel 15, and a power supply 16. The upper movable sleeve 2 comprises an upper heating sleeve 21, an inner lining 22, and an outer lining 23. The lower and upper heating sleeves are each connected to a control circuit, independently powered and controlled by the control circuit, and temperature-controlled by the control panel. The lower heating sleeve's design is similar to that of a typical heating sleeve, but the upper movable sleeve's design is original; we found no commercially available alternatives, so we custom-made it. Regarding the control circuit, the wires of the upper and lower heating sleeves can be connected in parallel, connected to a single control circuit. However, this circuit's actual temperature control performance differs from the original and requires recalibration and labeling. Alternatively, separate control circuits can be used for the lower heating sleeve, but this effectively doubles the output power, requiring careful attention to power matching. The heating sleeves can be powered by either 220V or 380V. The temperature control of both the upper and lower heating sleeves has been repeatedly compared and calibrated.

[0027] Furthermore, both the upper and lower heating jackets feature mesh alloy wire wrapped with alkali-free glass fiber and vacuum-formed with aluminum silicate wool. The lower heating jacket is hemispherical, while the upper heating jacket is formed by two parallel planes intercepting a portion of a sphere, one of which passes through the center of the sphere. The upper heating jacket, inner lining, and outer lining all have openings on one side. The inner and outer linings are made of 3-8mm thick Teflon material, each with a mesh-like hollowing pattern. The connection wires between the upper heating jacket and the control circuit are located outside the upper heating jacket. The wrapping of the heating jacket is similar to that of the prior art, but the choice of inner and outer linings is not known in the prior art. Teflon or other Teflon-based plastics are preferred. They are resistant to high temperatures (no effect below 260°C) and have a moderate hardness and softness. Externally and internally supporting the heating jacket allows it to maintain its shape while allowing the opening to be opened to facilitate wrapping the upper portion of the four-necked bottle from the side. This is a highly suitable material choice, a result of our targeted selection after considering its functionality.

[0028] Other fluorine-containing plastics can also be selected as long as they meet the following conditions: no odor or obvious volatile substances after heating, no obvious softening or deformation below 250℃, and can maintain strength even when heated for a long time at 100-180℃.

[0029] like Figure 1-2 As shown, the lower heating jacket is hemispherical, while the upper heating jacket is a portion of the hemisphere (with the top cut away) with an opening on one side. Due to its overall flexibility, the bottle can be inserted into it while the Teflon shell maintains its shape. The upper and lower heating jackets can share a common control circuit, or the control circuit can be two parallel parts, controlling the upper and lower heating jackets separately. The lower heating jacket can have an opening on its outer wall for leading out a circuit containing control and power lines, which are then connected to the upper heating jacket. Figure 2 The outer lining and the inner lining are similar in shape to the heating jacket to facilitate the support of the heating jacket. In order to facilitate the dissipation of heat, the outer lining and the inner lining are designed in a mesh shape to facilitate the dissipation of heat. Figure 2 shown.

[0030] Example 2

[0031] A method for metal-catalyzed synthesis of a trifluoromethyl-containing nitrogen-containing heterocycle, namely a method for synthesizing 2-trifluoromethyl-4-methyl-5-aminopyridine, is implemented using the aforementioned enhanced heating jacket and comprises the following four steps.

[0032] (1) Dissolve 0.1 mol of 2-trifluoromethyl-4-hydroxy-5-nitropyridine (20.8 g) in 50 ml of phosphorus oxychloride. Place the lower part of the mixed four-necked flask in the lower heating jacket, open the upper heating jacket, and place it horizontally on the upper part of the four-necked flask, and close the opening. Control the heating at 70°C by the control panel and keep the reaction for at least 3 hours. When TLC confirms that the reaction is complete, remove the heating device and cool to 25°C. After the temperature stabilizes, pour the reaction mixture into 200 g of crushed ice and adjust the pH of the system with 10% sodium carbonate aqueous solution until the pH is ≥7. Extract the mixture three times with 200 mL of ethyl acetate each time and combine the organic phases. Wash once with at least 150 mL of saturated brine and dry with 5 g of anhydrous sodium sulfate for at least 30 minutes. Filter off the desiccant and concentrate to obtain 2-trifluoromethyl-4-chloro-5-nitropyridine. 0.0934 mol of product (21.16 g) is obtained. Yield 93.4%.

[0033] (2) Take a four-necked bottle with a volume of more than 500 mL and add 50 mL of N,N-dimethylformamide under nitrogen protection. Add 0.09 mol of sodium hydride in small amounts and several times. Then cool the system to 0°C with an ice-water bath. Add 0.09 mol of diethyl malonate dropwise. After the addition is complete, keep stirring at 0°C for 30 minutes. Continue to keep stirring at 0°C and dropwise add a DMF solution containing 0.045 mol of 2-trifluoromethyl-4-chloro-5-nitropyridine (with a DMF content of not less than 10 mL). After the addition is complete, place the lower part of the mixed four-necked bottle on a heating plate. The flask is placed in a sleeve, and the opening of the upper heating jacket is opened, and the upper part of the four-necked flask is horizontally covered, and the opening is closed; The heating is controlled by the control panel to be maintained at 25 ° C, and the reaction is kept for not less than 1h. After the TLC reaction is complete, 50mL of pure water is dripped to quench the reaction, and 100mL of ethyl acetate is extracted 3 times at a time, and the organic phase is combined. The organic phase is washed 3 times with 50mL of saturated common salt water at a time, and dried over anhydrous sodium sulfate of not less than 10g for not less than 30min. After being spin-dried, a crude product of 2-(5-nitro-2-(trifluoromethyl)pyridin-4-yl) diethyl malonate is obtained. The actual crude product 25g obtained in this step is not calculated for the time being because it is a crude product. The next step is calculated by comprehensive steps 2-3.

[0034] (3) Take a 500 mL or larger four-necked flask, add 90 mL of 6N hydrochloric acid, add the DMF solution of the crude product obtained in step 2, and 25 mL of DMF. Place the lower part of the mixed four-necked flask in the lower heating mantle, open the opening of the upper heating mantle, put it horizontally on the upper part of the four-necked flask, and close the opening; control the heating to maintain 90°C through the control panel, and keep the reaction for at least 24 hours. After the TLC reaction is complete, remove the heating, cool to room temperature, and add 50% by mass sodium hydroxide solution dropwise until the pH is 8. Extract with 100 mL of ethyl acetate three times each time. Combine the organic phases, wash the organic phases three times with 50 mL of saturated brine each time, dry and concentrate to obtain the crude product, and wet-filter it with at least 100 g of 200-300 mesh silica gel column, with petroleum ether to ethyl acetate = 50:1, to obtain the product 2-trifluoromethyl-4-methyl-5-nitropyridine. The product is 7.8 g, 0.0378 mol. The combined steps 2-3 have a yield of 84%.

[0035] (4) Take a four-necked flask of 500 mL or more, dissolve 0.043 mol of 2-trifluoromethyl-4-methyl-5-nitropyridine in 200 mL of methanol, add 10 g of Raney Ni, first evacuate and then bubble in nitrogen, repeat this process three times, then bubble in hydrogen, seal the opening of the four-necked flask, place the lower part in the lower heating jacket, and open the opening of the upper heating jacket, horizontally cover the upper part of the four-necked flask, and close the opening; control the heating to maintain at 25°C through the control panel, and keep the reaction for at least 18 hours. After the reaction is complete by TLC, filter with suction, wash the filter cake with at least 50 mL of methanol three times, combine and spin-dry, and wet-filter with 50 g of 200-300 mesh silica gel, with petroleum ether to ethyl acetate = 50:1, to obtain the final product 2-trifluoromethyl-4-methyl-5-aminopyridine. 6.9 g, 0.04 mol, yield 93%.

[0036] This example conducted a comparative test, with other conditions being the same, the only change being that the upper heating jacket was not used during heating. After repeated multiple times, the overall yield decreased by about 10%, which fully demonstrated the beneficial effect of the upper heating jacket.

[0037] Example 3

[0038] A method for metal-catalyzed synthesis of a trifluoromethyl-containing nitrogen-containing heterocycle, namely a method for synthesizing 2-trifluoromethyl-4-methyl-5-aminopyridine, is implemented using the aforementioned enhanced heating jacket and comprises the following four steps.

[0039] (1) Dissolve 0.11 mol of 2-trifluoromethyl-4-hydroxy-5-nitropyridine (20 g) in 55 ml of phosphorus oxychloride. Place the lower part of the mixed four-necked flask in the lower heating jacket, open the opening of the upper heating jacket, and horizontally cover the upper part of the four-necked flask with the opening closed. Control the heating at 70°C through the control panel and keep the reaction for at least 4 hours. When TLC confirms that the reaction is complete, remove the heating device and cool to 25°C. After the temperature stabilizes, pour the reaction mixture into 250 g of crushed ice and adjust the pH of the system with 10% sodium carbonate aqueous solution until the pH is about 7.5. Extract the mixture three times with 200 mL of ethyl acetate each time and combine the organic phases. Wash once with at least 150 mL of saturated brine and dry with 10 g of anhydrous sodium sulfate for at least 30 minutes. Filter off the desiccant and concentrate to obtain 2-trifluoromethyl-4-chloro-5-nitropyridine. 0.1018 mol of product (23.064 g) is obtained. Yield 92.55%.

[0040] (2) Take a four-necked flask with a volume of more than 500 mL and, under nitrogen protection, add 50 mL of N,N-dimethylformamide, add 0.1 mol of sodium hydride in small amounts and several times, then cool the system to 0°C with an ice-water bath, add 0.1 mol of diethyl malonate dropwise, maintain stirring at 0°C for 40 minutes, continue to maintain stirring at 0°C, add DMF solution containing 0.05 mol of 2-trifluoromethyl-4-chloro-5-nitropyridine dropwise, with DMF not less than 12 mL. After the addition is complete, place the lower part of the mixed four-necked flask in the lower heating mantle. And the opening of the upper heating jacket is opened, horizontally enclosed on the four-necked flask top, and closed opening; Heating is controlled by control panel to be maintained at 25 DEG C, and the reaction is kept for no less than 1.5h. After TLC reaction is complete, 60mL of pure water is dripped to quench the reaction, and 100mL of ethyl acetate is extracted 3 times at a time, and organic phase is merged, and organic phase is washed 3 times with 50mL of saturated common salt water at a time, and dried over anhydrous sodium sulfate of no less than 10g for no less than 40min, and crude product 2-(5-nitro-2-(trifluoromethyl) pyridin-4-yl) diethyl malonate is obtained after being spin-dried for. The actual crude product 26g obtained in this step is not calculated yield temporarily because it is a crude product, and the next step comprehensive step 2-3 is calculated.

[0041] (3) Take a four-necked flask of 500 mL or more, add 95 mL of 6N hydrochloric acid, add the DMF solution of the crude product obtained in step 2, and 25 mL of DMF. Place the lower part of the mixed four-necked flask in the lower heating mantle, open the opening of the upper heating mantle, put it horizontally on the upper part of the four-necked flask, and close the opening; control the heating to maintain 90°C through the control panel, and keep the reaction for at least 26 hours. After the reaction is complete by TLC, remove the heating, cool to room temperature, and add 50% by mass sodium hydroxide solution dropwise until the pH is 7.5. Extract with 100 mL of ethyl acetate three times each time, combine the organic phases, wash the organic phases three times with 50 mL of saturated brine each time, dry and concentrate to obtain the crude product, and wet-filter it with at least 100 g of 200-300 mesh silica gel column, with petroleum ether to ethyl acetate = 50:1, to obtain the product 2-trifluoromethyl-4-methyl-5-nitropyridine. The product is 0.0425 mol, and the yield is 85% based on steps 2-3.

[0042] (4) Take a four-necked flask of 500 mL or more, dissolve 0.045 mol of 2-trifluoromethyl-4-methyl-5-nitropyridine in 220 mL of methanol, add 11 g of Raney Ni, first evacuate and then bubble in nitrogen, repeat this process three times, then bubble in hydrogen, seal the opening of the four-necked flask, place the lower part in the lower heating jacket, and open the opening of the upper heating jacket, horizontally cover the upper part of the four-necked flask, and close the opening; control the heating to maintain at 25°C through the control panel, and keep the reaction for at least 20 hours. After the reaction is complete by TLC, filter with suction, wash the filter cake with at least 50 mL of methanol three times, combine and spin-dry, and wet-filter with 50 g of 200-300 mesh silica gel, with petroleum ether to ethyl acetate = 50:1, to obtain the final product 2-trifluoromethyl-4-methyl-5-aminopyridine. 7.07 g, 0.041 mol, yield 91.1%.

[0043] This example conducted a comparative test, with other conditions being the same, the only change being that the upper heating jacket was not used during heating. After repeated multiple times, the overall yield decreased by about 11%, which fully demonstrated the beneficial effect of the upper heating jacket.

[0044] Preferably, all of the aforementioned reagents are of chemical purity or higher, or are of premium grade. The water is deionized, preferably double-distilled. The inner and outer linings of the aforementioned heating jacket are manufactured using a custom Teflon mold. The heating jacket comprises a mesh alloy wire wrapped in alkali-free glass fiber and vacuum-formed using aluminum silicate wool.

[0045] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that are not conceived through creative work should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection defined in the claims.

Claims

1. A reinforced heating jacket, characterized by: It comprises a lower fixed sleeve (1) and an upper movable sleeve (2); The lower fixing sleeve comprises a lower heating sleeve (11), a housing (12), a base (13), a control circuit (14), a control panel (15) and a power supply unit (16); The upper movable sleeve (2) comprises an upper heating sleeve (21), an inner lining (22), and an outer lining (23); the lower heating sleeve is hemispherical, and the upper heating sleeve is shaped like a portion of a sphere intercepted by two parallel planes, one of which passes through the center of the sphere; one side of the upper heating sleeve, the inner lining, and the outer lining all have openings; The lower heating jacket and the upper heating jacket are respectively connected to the control circuit, are independently powered and controlled by the control circuit, and are integrally temperature-controlled by the control panel.

2. The reinforced heating jacket according to claim 1, characterized in that: The upper and lower heating jackets are equipped with mesh alloy wires, which are wrapped with alkali-free glass fiber and vacuum-shaped with aluminum silicate wool. The inner and outer linings are made of 3-8mm thick Teflon material layers, and are both hollowed out in a mesh pattern; The connection line between the upper heating jacket and the control circuit is located outside the upper heating jacket.

3. A method for metal-catalyzed synthesis of trifluoromethyl-containing nitrogen-containing heterocycles, which is carried out using the reinforced heating jacket as claimed in claim 2, comprising the following steps: (1) Dissolve 0.09-0.11 mol of 2-trifluoromethyl-4-hydroxy-5-nitropyridine in 45-55 ml of phosphorus oxychloride, place the lower part of the mixed four-necked flask in the lower heating jacket, open the opening of the upper heating jacket, cover the upper part of the four-necked flask horizontally, and close the opening; control the heating to maintain at 70° C. through the control panel, and keep the reaction for at least 3 hours. When TLC confirms that the reaction is complete, remove the heating equipment and cool to 25° C. After the temperature stabilizes, pour the reaction mixture into 190-210 g of crushed ice, adjust the pH of the system with 10% sodium carbonate aqueous solution until the pH is 7-8, extract three times with 200 mL of ethyl acetate each time, wash once with at least 150 mL of saturated brine, dry with 5 g of anhydrous sodium sulfate for at least 30 minutes, filter out the desiccant, and concentrate to obtain 2-trifluoromethyl-4-chloro-5-nitropyridine; (2) Take a four-necked flask with a volume of more than 500 mL and add 45-55 mL of N,N-dimethylformamide under nitrogen protection. Add 0.08-0.1 mol of sodium hydride in small amounts and several times. Then cool the system to 0°C with an ice-water bath. Add 0.08-0.1 mol of diethyl malonate dropwise. After the addition is complete, keep stirring at 0°C for 30 minutes. Continue to keep stirring at 0°C and dropwise add a DMF solution containing 0.04-0.05 mol of 2-trifluoromethyl-4-chloro-5-nitropyridine in a volume of not less than 10 mL of DMF. After the addition is complete, The lower part of the flask was placed in the lower heating jacket, and the opening of the upper heating jacket was opened, which was laterally covered on the upper part of the four-necked flask and the opening was closed; the heating was controlled by the control panel to maintain at 25 ° C, and the reaction was maintained for not less than 1 hour. After the TLC reaction was complete, 50 mL of pure water was added to quench the reaction, and the mixture was extracted 3 times with 100 mL of ethyl acetate each time. The organic phases were combined and washed 3 times with 50 mL of saturated brine each time, and dried over 10 g of anhydrous sodium sulfate for not less than 30 min. The crude product of diethyl 2-(5-nitro-2-(trifluoromethyl)pyridin-4-yl)malonate was obtained after being spin-dried; (3) Take a four-necked flask of 500 mL or more, add 85-95 mL of 6N hydrochloric acid, add the DMF solution of the crude product obtained in step 2, 25 mL of DMF, place the lower part of the mixed four-necked flask in the lower heating jacket, open the opening of the upper heating jacket, put it horizontally on the upper part of the four-necked flask, and close the opening; control the heating to maintain at 90°C through the control panel, and keep the reaction for at least 18 hours. After the TLC reaction is complete, remove the heating, cool to room temperature, and add 50% mass percentage sodium hydroxide solution dropwise until the pH = 8. Extract with 100 mL of ethyl acetate three times each time, combine the organic phases, wash the organic phases three times with 50 mL of saturated brine each time, dry and concentrate to obtain the crude product, and wet-column with at least 100 g of 200-300 mesh silica gel, with petroleum ether to ethyl acetate = 50:1, to obtain the product 2-trifluoromethyl-4-methyl-5-nitropyridine; (4) Take a four-necked flask with a capacity of more than 500 mL, dissolve 0.04-0.05 mol of 2-trifluoromethyl-4-methyl-5-nitropyridine in 200 mL of methanol, add 10 g of Raney Ni, first evacuate and then bubble in nitrogen, repeat this three times, then bubble in hydrogen, seal the opening of the four-necked flask, place the lower part in the lower heating jacket, and open the opening of the upper heating jacket, horizontally cover the upper part of the four-necked flask, and close the opening; control the heating to maintain at 25°C through the control panel, and keep the reaction for at least 18 hours. After the TLC reaction is complete, filter with suction, wash the filter cake with at least 50 mL of methanol three times, combine and spin-dry, and wet-filter with 50 g of 200-300 mesh silica gel, with petroleum ether to ethyl acetate = 50:1, to obtain the final product 2-trifluoromethyl-4-methyl-5-aminopyridine.

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