A method for synthesizing trifluoromethyl-substituted fluorine-containing heterocyclic carboxylic acid

Abstract

A method for synthesizing a trifluoromethyl-substituted fluorine-containing heterocyclic carboxylic acid is carried out using a heating auxiliary device, characterized in that the method comprises the following steps: 2-bromo-5-fluoropyridine is dissolved in trifluoroacetic acid, hydrogen peroxide is slowly added dropwise, and the mixture is stirred at 70°C to obtain 2-bromo-5-fluoropyridine-1-oxide; 3-hydroxy-6-(trifluoromethyl)pyridine-2-carboxylic acid is obtained through five steps as the final product; wherein the heating reaction is all carried out using a heating auxiliary device, including a preparation step, a left and right straight portion installation step, and a left and right half portion installation step. The heating auxiliary device comprises a heating jacket (1) and an upper heat-insulating cover (2).

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of pharmaceutical intermediates, and in particular to a method for synthesizing trifluoromethyl-substituted fluorine-containing heterocyclic carboxylic acid. Background Art

[0002] 6-(Trifluoromethyl)pyridine and its derivatives are an important class of compounds with strong biological activity and are widely used in the fields of medicine and pesticides. Therefore, the synthesis of its derivatives has received widespread attention, especially in pharmaceutical intermediates. However, the 3-hydroxy-6-(trifluoromethyl)pyridine-2-carboxylic acid mentioned in this application rarely appears as a pharmaceutical intermediate, or there is any literature or information disclosed. Due to the characteristics of this molecule, the unique synthetic route, and the unique high yield problem, this method 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 this preparation method, the high yield, and the short reaction time, which have been obtained through countless experiments, and the irreproducibility of other routes.

[0004] In addition, the prior art also has the problem that the temperature cannot be guaranteed. Generally, a four-necked flask is used for small-scale preparation. We found that if the reaction temperature is strictly controlled, the yield can be guaranteed to a certain extent, but it is difficult to guarantee in reality. Due to toxicity considerations, the preparation of this application usually requires ventilation, and it is more appropriate to operate in a fume hood, which means that the environmental heating method is not very useful. However, without insulation measures, the temperature of the upper part of the four-necked flask cannot be guaranteed, especially when the ventilation is turned on. When ventilation is to be ensured, the heating temperature of the upper part of the four-necked flask often cannot be guaranteed, and it is often 2-5°C lower, which has a great adverse effect on the reaction yield.

[0005] Such a problem exists in the preparation of 3-hydroxy-6-(trifluoromethyl)pyridine-2-carboxylic acid in the present application. Because the solvent is toxic, ventilation is necessary. Ventilation will cause the temperature of the upper part of the four-necked flask to be insufficient. If a thermal insulation blanket is simply applied, firstly, it is not fixed well, and secondly, the thermal insulation effect cannot be guaranteed. 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 3-hydroxy-6-(trifluoromethyl)pyridine-2-carboxylic acid from 2-bromo-5-fluoropyridine through a few steps with high yield. The present application perfectly solves this problem. The second is the need to maintain ventilation, and how to maintain stable heat preservation during ventilation. Both problems are solved in this application.

[0007] The present invention claims protection for a heating auxiliary device, which is characterized in that: the heating auxiliary device includes a heating sleeve and an upper thermal insulation cover; the heating sleeve includes an outer shell, a heating component, a heating outer lining, and a connecting line; the upper thermal insulation cover includes a left straight part, a right straight part, a left half, and a right half.

[0008] The heating component is formed by folding a heating tube coil and forming a concave hemispherical shell shape. The heating outer lining is asbestos cloth or aluminum silicate wool covering the upper surface of the heating component.

[0009] Furthermore, the left straight portion and the right straight portion are both in the shape of a semi-cylindrical shell, and the lower edges of the left straight portion and the right straight portion have a groove that is stuck in the outer edge of the upper portion of the shell, the front vertical edge of the left straight portion has a concave portion that is adapted to the convex portion of the front vertical edge of the right straight portion, and the rear vertical edge of the left straight portion has a convex portion that is adapted to the concave portion of the rear vertical edge of the right straight portion.

[0010] The left and right halves are both made of a polyurethane layer below and a blanket layer above, and there are several pairs of male and female Velcro adjacent to the left and right halves; the outer edges of the left and right halves are respectively attached to the female Velcro layers on the outside of the upper edges of the left straight part and the right straight part with Velcro.

[0011] Furthermore, the left straight part and the right straight part are made of transparent or translucent PPSU or polycarbonate, and the material of the blanket layer is one of the following: insulating foam glass, polyurethane thermal insulation material, aluminum silicate needle-punched blanket, silver-plated aluminum film, rock wool, and tinfoil; one of the left half or the right half has a "ρ"-shaped opening for inserting the fourth mouth of a four-necked bottle, and has at least a pair of Velcro at the tail of the "ρ" shape.

[0012] A method for preparing 3-hydroxy-6-(trifluoromethyl)pyridine-2-carboxylic acid, which is implemented using the above-mentioned heating auxiliary device, is characterized in that it comprises the following steps: (1) in a four-necked flask, 1.0eq, 44-52g of 2-bromo-5-fluoropyridine is dissolved in 80-160mL of trifluoroacetic acid at room temperature, and then 1.2eq of hydrogen peroxide dissolved in water at a concentration of 30% is slowly added dropwise, wrapped with a heating auxiliary device, heated to 70°C, stirred for reaction for 16 hours, and the heating auxiliary device is removed. After the reaction is completed, 1.16 eq of Na2SO3 is added to the mixture while maintaining the temperature at 0°C, stirred for 10 minutes, and diluted with 20 mL of water to obtain a crude product. The crude product is extracted three times with 50 mL of dichloromethane each time, and the pH value is adjusted to 7 by adding sodium carbonate. The organic phase is washed with 30 mL of saturated concentrated brine and dried over anhydrous sodium sulfate for 30 minutes. The crude product is wet-filtered with 120 g of 200-300 mesh silica gel (petroleum ether / ethyl acetate = 5:1-2:1) to obtain intermediate 1 as a white solid.

[0013] (2) In a four-necked flask, under nitrogen protection, 38-44 g of intermediate product 1, 1.0 eq was dissolved in 150-250 mL of acetonitrile, and then 5.0 eq of triethylamine and 5.0 eq of trimethylsilyl cyanide were added. The mixture was wrapped with a heating auxiliary device and stirred at 100 ° C for 48 hours. The heating auxiliary device was removed to obtain a crude product. The crude product was wet-filtered with 60 g of 200-300 mesh silica gel, and petroleum ether / ethyl acetate = 10:1 to obtain intermediate product 2 as a white solid.

[0014] (3) In a four-necked flask, under nitrogen protection, 1.0 eq of 17-20 g of intermediate product 2 was dissolved in 80-120 mL of methanol solution, and then 1.3 eq of sodium methoxide dissolved in methanol at a mass fraction of 25% was slowly added. The mixture was wrapped with a heating auxiliary device and stirred at 75°C for not less than 1 hour. The heating auxiliary device was removed, and the reaction mixture was cooled to room temperature. It was diluted with 40 mL of water and 40 mL of dichloromethane in sequence, and then extracted three times with 40 mL of dichloromethane each time. The organic phase was washed three times with 40 mL of saturated brine each time, and then dried with sufficient anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was wet-coated with not less than 30 g of 200-300 mesh silica gel, and petroleum ether / ethyl acetate = 5:1 to obtain intermediate product 3 as a white solid.

[0015] (4) In a four-necked flask, under nitrogen protection, 1.0 eq of 14-17 g of intermediate product 3 was dissolved in 180-220 mL of N,N-dimethylformamide, and then 1.5 eq of trifluoromethyl 2,2-difluoro-2-(fluorosulfonyl)acetate and 1.5 eq of cuprous iodide were added. The mixture was wrapped with a heating auxiliary device and stirred at 80°C for not less than 16 hours. The heating auxiliary device was removed, and the mixture was cooled to room temperature. It was diluted with 100 mL of ethyl acetate and 50 mL of water in sequence, and then extracted with ethyl acetate three times, each time with 40 mL. The organic phase was washed three times with 20 mL of saturated brine each time, dried over sufficient anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was wet-coated with not less than 120 g of 200-300 mesh silica gel, and petroleum ether / ethyl acetate = 10:1-2:1 to obtain intermediate product 4 as a yellow solid.

[0016] (5) In a four-necked flask, 1.0 eq (10-12 g) of intermediate product 4 was dissolved in 50-70 mL of ethanol and 15-25 mL of water at room temperature, 10.0 eq of potassium hydroxide was added, and the mixture was covered with a heating auxiliary device and stirred at 80°C for not less than 2 hours. The heating auxiliary device was removed, and the pH value of the mixture was adjusted to 7-8 with 1 M hydrochloric acid, and then the pH value was adjusted to 1 with 1 M potassium bisulfate. The mixture was extracted three times with a 10:1 dichloromethane / methanol mixture, 20 mL each time, and the organic phase was washed three times with 10 mL of saturated brine each time, dried over sufficient anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was wet-filtered with at least 15 g of 200-300 mesh silica gel column, petroleum ether / ethyl acetate = 10:1, to obtain intermediate product 5 as a yellow solid.

[0017] (6) In a four-necked flask, 1.0 eq of 2.5-3.5 g of the intermediate product 5 was dissolved in 15-25 mL of pyridine at room temperature, and then 3.0 eq of magnesium chloride was slowly added. The mixture was covered with a heating auxiliary device, heated to 100°C and stirred for not less than 5 hours. The heating auxiliary device was removed, and the pH value of the reaction mixture was first adjusted to 7-8 with 1 M hydrochloric acid, and then adjusted to 1 with 1 M potassium bisulfate. The mixture was extracted three times with 20 mL of a 10:1 dichloromethane / methanol mixture each time. The organic phase was washed with 10 mL of saturated brine and dried over sufficient anhydrous sodium sulfate to obtain a crude product. The crude product was wet-coated with not less than 25 g of 200-300 mesh silica gel in a mixture of acetonitrile:water = 10:1-20:1 to obtain 3-hydroxy-6-(trifluoromethyl)pyridine-2-carboxylic acid as a white solid.

[0018] The steps of wrapping with a heating auxiliary device in the above (1)-(6) are specifically as follows:

[0019] (A) Preparation step: keep the four-necked bottle in a clamped state, and support its bottom with the heated outer liner (13);

[0020] (B) Installation steps of the left and right straight parts: align the left and right straight parts and install them, and clamp the grooves of their lower edges on the outer edge of the upper part of the shell (11), insert the convex part of the front side of the right straight part into the concave part of the front side of the left straight part to fix it, and insert the convex part of the rear side of the left straight part into the concave part of the rear side of the right straight part to fix it;

[0021] (C) Steps for installing the left and right halves: Attach the outer edges of the left and right halves to the female Velcro layers outside the upper edges of the left and right straight parts respectively, and make sure that the several pairs of male and female Velcros adjacent to the left and right halves are attached to each other.

[0022] Compared with the existing technology, the advantages of the present invention are: First, the device is improved. The device perfectly solves two problems: how to ensure the heating effect while ensuring ventilation, so that the four-necked flask, especially the upper part, can maintain the reaction temperature instead of being 2-5°C lower. In addition, if a heating blanket is simply covered, it is difficult to fix. Many specialized heating equipment not only takes up a lot of space but is also difficult to disassemble. The device of the present application is simple to operate, has good effect, and is easy to disassemble.

[0023] Currently, there are no reports of the production of this product in the prior art. Compared with similar methods for preparing substances, the method of this application is meticulously designed, with very high raw material utilization rates in each step, making it extremely valuable for industrial production. Through the meticulous design of the method of the present invention, not only is synthesis achieved efficiently, but the yield is also high, with an overall yield of 15-20%, which has certain industrial production value and great economic value. Through the careful design of the heating assistance, this application embodies a strong inventive concept and creativity, achieving good preparation results. There is no similar public information in the prior art to draw on, and the solution of the present invention is original. In contrast, if the heating assistance device of this application is not used, and other conditions remain unchanged, the overall yield does not exceed 15%, which is at least 5% lower than that of the method of this application. It can be seen that the negative effects of not keeping warm are very obvious. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] 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.

[0025] Figure 1 It is a forward schematic diagram of the entire device.

[0026] Figure 2 It is a schematic diagram of the decomposition of the upper insulation cover structure.

[0027] Figure 3 It is a schematic diagram of the main reaction flow of this application.

[0028] Figure 4 This is the NMR image of the final product.

[0029] Reference numerals: heating sleeve 1 , upper heat-insulating cover 2 , outer shell 11 , heating component 12 , heating outer lining 13 , connecting line 14 , left straight portion 21 , right straight portion 22 , left half 23 , right half 24 , grooves 211 , 221 . DETAILED DESCRIPTION

[0030] 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.

[0031] Example 1

[0032] A heating assist device, characterized in that: the heating assist device comprises a heating jacket 1 and an upper thermal insulation cover 2; the heating jacket comprises an outer shell 11, a heating element 12, a heating lining 13, and a connecting line 14; the upper thermal insulation cover comprises a left straight portion 21, a right straight portion 22, a left half 23, and a right half 24. The heating element is connected to an external power source via a power cord.

[0033] The heating element 12 is formed by coiling a heating tube into a concave hemispherical shell. The heating lining is made of asbestos cloth or aluminum silicate wool covering the upper surface of the heating element. The heating jacket can be ordered as a whole or assembled from ordered components. The heating tube is powered by 220V and the outer shell is made of stainless steel or aluminum alloy.

[0034] Furthermore, both the left and right straight portions are semi-cylindrical and fit into a 2000-500 mL four-necked bottle. The lower edges of the left and right straight portions each have grooves 211 and 221 that snap onto the upper outer edge of the housing 11. The front vertical edge of the left straight portion has a recess that fits with the convex portion of the front vertical edge of the right straight portion, and the rear vertical edge of the left straight portion has a convex portion that fits with the concave portion of the rear vertical edge of the right straight portion. The convex portion is, for example, a rectangular parallelepiped, and the concave portion is, for example, a rectangular parallelepiped groove.

[0035] Both the left and right halves are constructed by laminating a polyurethane layer below and a carpet layer above. The left and right halves have pairs of male and female Velcro strips located adjacent to each other. The outer edges of the left and right halves are attached to the female Velcro strips located outside the upper edges of the left and right straight sections, respectively. The Velcro strips can be replaced with other similar strips or fastening methods.

[0036] Furthermore, the left and right straight portions are made of transparent or translucent PPSU or polycarbonate, preferably transparent for easier viewing. The blanket layer is made of one of the following: insulating foam glass, polyurethane insulation material, aluminum silicate needle-punched blanket, silver-coated aluminum film, rock wool, or tin foil. Either the left or right half has a "r"-shaped opening for inserting the fourth mouth of a four-necked bottle, and at least one pair of Velcro strips at the end of the "r" shape. The r-shaped opening is suitable for inserting the fourth mouth of a four-necked bottle, substantially enclosing it beneath the left or right half, with the rest of the opening essentially uncovered.

[0037] A method for preparing 3-hydroxy-6-(trifluoromethyl)pyridine-2-carboxylic acid, which is implemented by using the above-mentioned heating auxiliary device, is characterized in that it comprises the following steps: (1) in a four-necked bottle, 1.0eq, 48g of 2-bromo-5-fluoropyridine is dissolved in 100mL of trifluoroacetic acid at room temperature, and then 1.2eq of hydrogen peroxide dissolved in water at a concentration of 30% is slowly added dropwise, wrapped with a heating auxiliary device, heated to 70°C, stirred for reaction for 16 hours, removed the heating auxiliary device, and after the reaction is completed, kept at To the mixture, 1.16 eq of Na₂SO₃ was added at 0°C, stirred for 10 minutes, and diluted with 20 mL of water to obtain the crude product. The crude product was extracted three times with 50 mL of dichloromethane each time. The pH was adjusted to 7 with sodium carbonate. The organic phase was washed with 30 mL of saturated brine and dried over anhydrous sodium sulfate for 30 minutes. The crude product was then wet-coated with 120 g of 200-300 mesh silica gel in a 4:1 ratio of petroleum ether to ethyl acetate to obtain the intermediate product, 1,2-bromo-5-fluoropyridine-1-oxide, as a white solid in an 88.3% yield.

[0038] 1 HNMR (400MHz, CDCl3): δ8.33 (dd, J=4.1, 2.6Hz, 1H), 7.62 (dd, J=9.1, 6.6Hz, 1H), 7.02–6.91 (m, 1H). LCMS: 192.0, 193.9 ([M+H] + ).

[0039] (2) In a four-necked flask, under nitrogen protection, 41.0 g of the intermediate product 1,2-bromo-5-fluoropyridine-1-oxide and 1.0 eq were dissolved in 200 mL of acetonitrile. 5.0 eq of triethylamine and 5.0 eq of trimethylsilyl cyanide were then added. The mixture was covered with a heating auxiliary device and stirred at 100°C for 48 hours. The heating auxiliary device was removed to obtain a crude product. The product was wet-filtered with 60 g of 200-300 mesh silica gel in a column with petroleum ether / ethyl acetate = 10:1 to obtain the intermediate product 2,6-bromo-3-fluoro-2-cyanopyridine as a white solid. The yield was 55.4%.

[0040] 1 HNMR (400MHz, CDCl3): δ7.74 (dd, J=8.9, 3.8Hz, 1H), 7.55–7.46 (m, 1H).

[0041] (3) In a four-necked flask, under nitrogen protection, 1.0 eq (18.3 g) of the intermediate product 2,6-bromo-3-fluoro-2-cyanopyridine was dissolved in 100 mL of methanol solution, and then 1.3 eq of sodium methoxide dissolved in methanol at a mass fraction of 25% was slowly added. The mixture was covered with a heating auxiliary device and stirred at 75°C for 1 hour. The heating auxiliary device was removed, and the reaction mixture was cooled to room temperature. It was diluted with 40 mL of water and 40 mL of dichloromethane in sequence, and then extracted three times with 40 mL of dichloromethane each time. The organic phase was washed three times with 40 mL of saturated brine each time, and then dried with sufficient anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was wet-filtered with 30 g of 200-300 mesh silica gel column, and petroleum ether / ethyl acetate = 5:1 to obtain the intermediate product 3,6-bromo-3-methoxy-2-cyanopyridine as a white solid. The yield was 88.5%.

[0042] 1 HNMR (400MHz, CDCl3): δ7.62 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 3.2 Hz, 1H), 3.96 (s, 3H). LCMS:213.0,215.0([M+H] + ).

[0043] (4) In a four-necked flask, under nitrogen protection, 1.0 eq (15.8 g) of intermediate product 3 was dissolved in 200 mL of N,N-dimethylformamide, followed by the addition of 1.5 eq of trifluoromethyl 2,2-difluoro-2-(fluorosulfonyl)acetate and 1.5 eq of cuprous iodide. The mixture was covered with a heating auxiliary device and stirred at 80°C for 16 hours. The heating auxiliary device was removed, and the mixture was cooled to room temperature. The mixture was diluted with 100 mL of ethyl acetate and 50 mL of water in sequence, and then extracted with ethyl acetate three times, each time with 40 mL. The organic phase was washed three times with 20 mL of saturated brine, dried over sufficient anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was wet-filtered with 120 g of 200-300 mesh silica gel column (petroleum ether / ethyl acetate = 8:1) to obtain the intermediate product 4,3-methoxy-6-(trifluoromethyl)-2-cyanopyridine as a yellow solid. The yield was 82.0%.

[0044] 1 HNMR (400MHz, CDCl3): δ7.86 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 4.06 (s, 3H). LCMS:203.1([M+H] + ).

[0045] (5) In a four-necked flask, 1.0 eq (10.6 g) of the intermediate product 4,3-methoxy-6-(trifluoromethyl)-2-cyanopyridine was dissolved in 60 mL of ethanol and 20 mL of water at room temperature. 10.0 eq of potassium hydroxide was added, and the mixture was covered with a heating device and stirred at 80°C for 2 hours. The heating device was removed, and the mixture was adjusted to pH 7.5 with 1 M hydrochloric acid and then to pH 1 with 1 M potassium bisulfate. The mixture was extracted three times with 20 mL of a 10:1 dichloromethane / methanol mixture. The organic phase was washed three times with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was wet-coated with 15 g of 200-300 mesh silica gel in a 10:1 ratio of petroleum ether to ethyl acetate to obtain the intermediate product 5,3-methoxy-6-(trifluoromethyl)pyridine-2-carboxylic acid as a yellow solid. The yield was 60.1%.

[0046] 1 H NMR (400MHz, DMSO-d6): δ 8.01 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H). LCMS:222.0([M+H] + ).

[0047] (6) In a four-necked flask, 1.0 eq (2.9 g) of the intermediate product 5,3-methoxy-6-(trifluoromethyl)pyridine-2-carboxylic acid was dissolved in 20 mL of pyridine at room temperature. 3.0 eq of magnesium chloride was slowly added, the mixture was heated to 100°C and stirred for 5 hours, and the heating device was removed. The pH of the reaction mixture was first adjusted to 7.5 with 1 M hydrochloric acid and then to 1 with 1 M potassium bisulfate. The mixture was extracted three times with 20 mL of a 10:1 dichloromethane / methanol mixture. The organic phase was washed with 10 mL of saturated brine and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was wet-coated with 25 g of 200-300 mesh silica gel in a ratio of acetonitrile to water of 15:1 to obtain 3-hydroxy-6-(trifluoromethyl)pyridine-2-carboxylic acid as a white solid. The yield was 87.0%. The total yield was 18.56%.

[0048] 1 H NMR (400MHz, DMSO-d6): δ12.40 (s, 2H), 7.93 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H). LCMS:208.0([M+H] + ).

[0049] The steps of wrapping with a heating auxiliary device in the above (1)-(6) are specifically as follows:

[0050] (A) Preparation step: keep the four-necked bottle in a clamped state, and support its bottom with the heated outer lining (13);

[0051] (B) Installation steps of the left and right straight parts: align the left and right straight parts and install them, and clamp the grooves of their lower edges on the outer edge of the upper part of the shell (11), insert the convex part of the front side of the right straight part into the concave part of the front side of the left straight part to fix it, and insert the convex part of the rear side of the left straight part into the concave part of the rear side of the right straight part to fix it;

[0052] (C) Steps for installing the left and right halves: Attach the outer edges of the left and right halves to the female Velcro layers outside the upper edges of the left and right straight parts respectively, and make sure that the several pairs of male and female Velcros adjacent to the left and right halves are attached to each other.

[0053] Example 2

[0054] This Example 2 is a comparative example of Example 1, in which the heating auxiliary device is not used. The total yield is repeated many times and none of them exceeds 15%. It can be seen that the effect of the heating auxiliary device is very obvious and outstanding.

[0055] Example 3

[0056] A heating assist device, characterized in that: the heating assist device comprises a heating jacket 1 and an upper thermal insulation cover 2; the heating jacket comprises an outer shell 11, a heating element 12, a heating lining 13, and a connecting line 14; the upper thermal insulation cover comprises a left straight portion 21, a right straight portion 22, a left half 23, and a right half 24. The heating element is connected to an external power source via a power cord.

[0057] The heating element 12 is formed by coiling a heating tube into a concave hemispherical shell. The heating lining is made of asbestos cloth or aluminum silicate wool covering the upper surface of the heating element. The heating jacket can be ordered as a whole or assembled from ordered components. The heating tube is connected to a 220V or 380V power supply, and the outer shell is made of stainless steel or aluminum alloy.

[0058] Furthermore, both the left and right straight portions are semi-cylindrical and compatible with 2000, 1000, and 500 mL four-necked bottles. The lower edges of the left and right straight portions each have grooves 211 and 221 that snap onto the upper outer edge of the housing 11. The front vertical edge of the left straight portion has a recess that mates with the convex portion of the front vertical edge of the right straight portion, and the rear vertical edge of the left straight portion has a convex portion that mates with the concave portion of the rear vertical edge of the right straight portion. The convex portion is, for example, a rectangular parallelepiped, and the concave portion is, for example, a rectangular parallelepiped groove.

[0059] Both the left and right halves are constructed by laminating a polyurethane layer below and a carpet layer above. The left and right halves have pairs of male and female Velcro strips located adjacent to each other. The outer edges of the left and right halves are attached to the female Velcro strips located outside the upper edges of the left and right straight sections, respectively. The Velcro strips can be replaced with other similar strips or fastening methods.

[0060] Furthermore, the left and right straight portions are made of transparent or translucent PPSU or polycarbonate, preferably transparent for easier viewing. The blanket layer is made of one of the following: insulating foam glass, polyurethane insulation material, aluminum silicate needle-punched blanket, silver-coated aluminum film, rock wool, or tin foil. Either the left or right half has a "r"-shaped opening for inserting the fourth mouth of a four-necked bottle, and at least one pair of Velcro strips at the end of the "r" shape. The r-shaped opening is suitable for inserting the fourth mouth of a four-necked bottle, substantially enclosing it beneath the left or right half, with the rest of the opening essentially uncovered.

[0061] A method for preparing 3-hydroxy-6-(trifluoromethyl)pyridine-2-carboxylic acid, which is implemented by using the above-mentioned heating auxiliary device, is characterized in that it comprises the following steps: (1) in a four-necked bottle, 1.0eq, 50g of 2-bromo-5-fluoropyridine is dissolved in 110mL of trifluoroacetic acid at room temperature, and then 1.2eq of hydrogen peroxide dissolved in water at a concentration of 30% is slowly added dropwise, wrapped with a heating auxiliary device, heated to 70°C, stirred for reaction for 17 hours, removed the heating auxiliary device, and after the reaction is completed, kept at To the mixture, 1.16 eq of Na₂SO₃ was added at 0°C, stirred for 15 minutes, and diluted with 30 mL of water to obtain the crude product. The crude product was extracted three times with 60 mL of dichloromethane each time. The pH was adjusted to 7 with sodium carbonate. The organic phase was washed with 40 mL of saturated brine and dried over anhydrous sodium sulfate for 40 minutes. The crude product was then wet-coated with 150 g of 200-300 mesh silica gel in a 3:1 ratio of petroleum ether to ethyl acetate to obtain the intermediate product, 1,2-bromo-5-fluoropyridine-1-oxide, as a white solid in an 89.4% yield.

[0062] 1 HNMR (400MHz, CDCl3): δ8.33 (dd, J=4.1, 2.6Hz, 1H), 7.62 (dd, J=9.1, 6.6Hz, 1H), 7.02–6.91 (m, 1H). LCMS: 192.0, 193.9 ([M+H] + ).

[0063] (2) In a four-necked flask, under nitrogen protection, 42.0 g of the intermediate product 1,2-bromo-5-fluoropyridine-1-oxide and 1.0 eq were dissolved in 250 mL of acetonitrile. 5.0 eq of triethylamine and 5.0 eq of trimethylsilyl cyanide were then added. The mixture was covered with a heating auxiliary device and stirred at 100°C for 50 hours. The heating auxiliary device was removed to obtain a crude product. The product was wet-filtered with 70 g of 200-300 mesh silica gel using a column column with petroleum ether / ethyl acetate = 5:1 to obtain the intermediate product 2,6-bromo-3-fluoro-2-cyanopyridine as a white solid. The yield was 55.9%.

[0064] 1 HNMR (400MHz, CDCl3): δ7.74 (dd, J=8.9, 3.8Hz, 1H), 7.55–7.46 (m, 1H).

[0065] (3) In a four-necked flask, under nitrogen protection, 1.0 eq (19 g) of the intermediate product 2,6-bromo-3-fluoro-2-cyanopyridine was dissolved in 110 mL of methanol solution, and then 1.3 eq of sodium methoxide dissolved in methanol at a mass fraction of 25% was slowly added. The mixture was covered with a heating auxiliary device and stirred at 75°C for 2 hours. The heating auxiliary device was removed, and the reaction mixture was cooled to room temperature. It was diluted with 50 mL of water and 50 mL of dichloromethane in sequence, and extracted three times with 50 mL of dichloromethane each time. The organic phase was washed three times with 50 mL of saturated brine each time, and then dried over sufficient anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was wet-filtered with 40 g of 200-300 mesh silica gel column, and petroleum ether / ethyl acetate = 7:1 to obtain the intermediate product 3,6-bromo-3-methoxy-2-cyanopyridine as a white solid. The yield was 89.7%.

[0066] 1 HNMR (400MHz, CDCl3): δ7.62 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 3.2 Hz, 1H), 3.96 (s, 3H). LCMS:213.0,215.0([M+H] + ).

[0067] (4) In a four-necked flask, under nitrogen protection, 1.0 eq of 17 g of intermediate product 3 was dissolved in 250 mL of N,N-dimethylformamide, followed by the addition of 1.5 eq of trifluoromethyl 2,2-difluoro-2-(fluorosulfonyl)acetate and 1.5 eq of cuprous iodide. The mixture was covered with a heating auxiliary device and stirred at 80°C for 18 hours. The heating auxiliary device was removed, and the mixture was cooled to room temperature. The mixture was diluted with 120 mL of ethyl acetate and 60 mL of water in sequence, and then extracted with ethyl acetate three times, each time with 50 mL. The organic phase was washed three times with 30 mL of saturated brine, dried over sufficient anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was wet-coated with 130 g of 00-300 mesh silica gel in a ratio of petroleum ether to ethyl acetate of 5:1 to obtain the intermediate product 4,3-methoxy-6-(trifluoromethyl)-2-cyanopyridine as a yellow solid. The yield was 83.0%.

[0068] 1 HNMR (400MHz, CDCl3): δ7.86 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 4.06 (s, 3H). LCMS:203.1([M+H] + ).

[0069] (5) In a four-necked flask, 1.0 eq (11 g) of the intermediate product 4,3-methoxy-6-(trifluoromethyl)-2-cyanopyridine was dissolved in 70 mL of ethanol and 30 mL of water at room temperature. 10.0 eq of potassium hydroxide was added, and the mixture was covered with a heating auxiliary device and stirred at 80°C for 2.5 hours. The heating auxiliary device was removed, and the mixture was adjusted to pH 7.6-7.8 with 1 M hydrochloric acid, and then to pH 1 with 1 M potassium bisulfate. The mixture was extracted three times with a 10:1 dichloromethane / methanol mixture, each time 30 mL. The organic phase was washed three times with 20 mL of saturated brine each time, dried over sufficient anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was wet-coated with 20 g of 200-300 mesh silica gel in a petroleum ether / ethyl acetate ratio of 8:1 to obtain the intermediate product 5,3-methoxy-6-(trifluoromethyl)pyridine-2-carboxylic acid as a yellow solid. The yield was 62.4%.

[0070] 1 H NMR (400MHz, DMSO-d6): δ 8.01 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 3.94 (s, 3H). LCMS:222.0([M+H] + ).

[0071] (6) In a four-necked flask, 1.0 eq (3 g) of the intermediate product 5,3-methoxy-6-(trifluoromethyl)pyridine-2-carboxylic acid was dissolved in 30 mL of pyridine at room temperature. 3.0 eq of magnesium chloride was slowly added, the mixture was heated to 100°C and stirred for 6 hours, and the heating device was removed. The pH of the reaction mixture was first adjusted to 7.6-7.8 with 1 M hydrochloric acid, and then to 1 with 1 M potassium bisulfate. The mixture was extracted three times with 30 mL of a 10:1 dichloromethane / methanol mixture. The organic phase was washed with 20 mL of saturated brine and dried over sufficient anhydrous sodium sulfate to obtain a crude product. The crude product was wet-coated with 30 g of 200-300 mesh silica gel in a 10:1 ratio of acetonitrile to water to obtain 3-hydroxy-6-(trifluoromethyl)pyridine-2-carboxylic acid as a white solid. The yield was 88.2%. The total yield was 20.48%.

[0072] 1 H NMR (400MHz, DMSO-d6): δ12.40 (s, 2H), 7.93 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H). LCMS:208.0([M+H] + ).

[0073] The steps of wrapping with a heating auxiliary device in the above (1)-(6) are specifically as follows:

[0074] (A) Preparation step: keep the four-necked bottle in a clamped state, and support its bottom with the heated outer lining (13);

[0075] (B) Installation steps of the left and right straight parts: align the left and right straight parts and install them, and clamp the grooves of their lower edges on the outer edge of the upper part of the shell (11), insert the convex part of the front side of the right straight part into the concave part of the front side of the left straight part to fix it, and insert the convex part of the rear side of the left straight part into the concave part of the rear side of the right straight part to fix it;

[0076] (C) Steps for installing the left and right halves: fit the outer edges of the left and right halves onto the female Velcro layers outside the upper edges of the left and right straight parts respectively, and make the several pairs of male and female Velcros at the adjacent parts of the left and right halves fit together. The p-shaped opening is suitable for placing the fourth mouth of a four-mouth bottle and making it basically wrapped under the left half or the right half.

[0077] Example 4

[0078] This example is a comparative example of Example 3, in which no heating auxiliary device is used. The total yield is repeated multiple times and none of them is higher than 15%.

[0079] Preferably, all the above reagents are of chemical purity or higher, or are of premium purity. The water is deionized water, preferably double distilled water.

[0080] 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 method for synthesizing a trifluoromethyl-substituted fluorine-containing heterocyclic carboxylic acid, which is implemented using a heating auxiliary device, characterized in that: The heating auxiliary device comprises a heating jacket (1) and an upper heat-insulating cover (2); The heating sleeve comprises a shell (11), a heating component (12), a heating outer lining (13), and a connecting line (14); The upper heat-insulating cover comprises a left straight portion (21), a right straight portion (22), a left half portion (23), and a right half portion (24); The heating element (12) is formed by folding a heating tube into a concave hemispherical shell shape, and the heating outer lining is asbestos cloth or aluminum silicate wool covering the upper surface of the heating element; The left straight portion and the right straight portion are both in the shape of a semi-cylindrical shell, and the lower edges of the left straight portion and the right straight portion are each provided with a groove that is clamped on the outer edge of the upper portion of the shell (11), the front vertical edge of the left straight portion is provided with a concave portion that matches the convex portion of the front vertical edge of the right straight portion, and the rear vertical edge of the left straight portion is provided with a convex portion that matches the concave portion of the rear vertical edge of the right straight portion; The left and right halves are both made of a polyurethane layer below and a carpet layer above, and there are several pairs of male and female Velcro strips adjacent to the left and right halves. The outer edges of the left and right halves are respectively attached to the female Velcro strips on the outer sides of the upper edges of the left and right straight parts with Velcro strips. The left and right straight parts are made of transparent or translucent PPSU or polycarbonate, and the blanket layer is made of one of the following: insulating foam glass, polyurethane insulation material, aluminum silicate needle-punched blanket, silver-coated aluminum film, rock wool, or tinfoil; One of the left or right halves has a "ρ"-shaped opening for receiving the fourth mouth of a four-mouth bottle, and has at least one pair of Velcro fasteners at the end of the "ρ" shape; The synthesis method of the trifluoromethyl-substituted fluorine-containing heterocyclic carboxylic acid comprises the following steps: (1) In a four-necked flask, 1.0 eq, 44-52 g of 2-bromo-5-fluoropyridine was dissolved in 80-160 mL of trifluoroacetic acid at room temperature, and then 1.2 eq of hydrogen peroxide dissolved in water at a concentration of 30% was slowly added dropwise. The four-necked flask was wrapped with a heating auxiliary device, and the temperature was raised to 70°C. The mixture was stirred for 16 hours, and the heating auxiliary device was removed. After the reaction was completed, 1.16 eq of Na2SO3 was added to the mixture while maintaining the temperature at 0°C. The mixture was stirred for 10 minutes and diluted with 20 mL of water to obtain a crude product. The crude product was extracted three times with 50 mL of dichloromethane each time, and the pH value was adjusted to 7 by adding sodium carbonate. The organic phase was washed with 30 mL of saturated concentrated brine and dried with sufficient anhydrous sodium sulfate for 30 minutes. The crude product was wet-columnized with 120 g of 200-300 mesh silica gel, and petroleum ether / ethyl acetate = 5:1-2:1 to obtain the intermediate product 1 as a white solid. (2) In a four-necked flask, under nitrogen protection, 38-44 g of intermediate product 1, 1.0 eq was dissolved in 150-250 mL of acetonitrile, and then 5.0 eq of triethylamine and 5.0 eq of trimethylsilyl cyanide were added. The four-necked flask was wrapped with a heating auxiliary device, and the mixture was stirred at 100 ° C for 48 hours. The heating auxiliary device was removed to obtain a crude product, which was wet-filtered with 60 g of 200-300 mesh silica gel column, petroleum ether / ethyl acetate = 10:1, to obtain a white solid intermediate product 2; (3) In a four-necked flask, under nitrogen protection, 1.0 eq of 17-20 g of intermediate product 2 was dissolved in 80-120 mL of methanol solution, and then 1.3 eq of sodium methoxide dissolved in methanol at a mass fraction of 25% was slowly added. The four-necked flask was wrapped with a heating auxiliary device and stirred at 75 ° C for not less than 1 hour. The heating auxiliary device was removed, and the reaction mixture was cooled to room temperature. It was diluted with 40 mL of water and 40 mL of dichloromethane in sequence, and then extracted three times with 40 mL of dichloromethane each time. The organic phase was washed three times with 40 mL of saturated brine each time, and then dried with sufficient anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was wet-filtered with not less than 30 g of 200-300 mesh silica gel and petroleum ether / ethyl acetate = 5:1 to obtain a white solid intermediate product 3; (4) In a four-necked flask, under nitrogen protection, 1.0 eq of 14-17 g of intermediate product 3 was dissolved in 180-220 mL of N,N-dimethylformamide, and then 1.5 eq of 2,2-difluoro-2-(fluorosulfonyl)acetic acid trifluoromethyl ester and 1.5 eq of cuprous iodide were added. The four-necked flask was wrapped with a heating auxiliary device and stirred at 80°C for not less than 16 hours. The heating auxiliary device was removed and the mixture was cooled to room temperature. It was diluted with 100 mL of ethyl acetate and 50 mL of water in sequence, and then extracted with ethyl acetate three times, each time with 40 mL. The organic phase was washed three times with 20 mL of saturated brine each time, dried with sufficient anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was wet-filtered with not less than 120 g of 200-300 mesh silica gel column, petroleum ether / ethyl acetate = 10:1-2:1, to obtain intermediate product 4 as a yellow solid; (5) In a four-necked flask, 1.0 eq (10-12 g) of intermediate product 4 was dissolved in 50-70 mL of ethanol and 15-25 mL of water at room temperature, 10.0 eq of potassium hydroxide was added, the four-necked flask was covered with a heating auxiliary device, and the mixture was stirred at 80°C for not less than 2 hours. The heating auxiliary device was removed, and the pH value of the mixture was adjusted to 7-8 with 1 M hydrochloric acid, and then the pH value was adjusted to 1 with 1 M potassium bisulfate. The mixture was extracted three times with a 10:1 dichloromethane / methanol mixture, 20 mL each time, and the organic phase was washed three times with 10 mL of saturated brine each time, dried over sufficient anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was wet-filtered with at least 15 g of 200-300 mesh silica gel column, petroleum ether / ethyl acetate = 10:1, to obtain intermediate product 5 as a yellow solid; (6) In a four-necked flask, 1.0 eq of 2.5-3.5 g of the intermediate product 5 was dissolved in 15-25 mL of pyridine at room temperature, and then 3.0 eq of magnesium chloride was slowly added. The four-necked flask was wrapped with a heating auxiliary device, and the temperature was raised to 100° C. and stirred for not less than 5 hours. The heating auxiliary device was removed, and the pH value of the reaction mixture was first adjusted to 7-8 with 1 M hydrochloric acid, and then adjusted to 1 with 1 M potassium bisulfate. The mixture was extracted three times with 20 mL of a 10:1 dichloromethane / methanol mixture each time. The organic phase was washed with 10 mL of saturated brine and dried over sufficient anhydrous sodium sulfate to obtain a crude product. The crude product was wet-coated with not less than 25 g of 200-300 mesh silica gel, and acetonitrile:water = 10:1-20:1 to obtain 3-hydroxy-6-(trifluoromethyl)pyridine-2-carboxylic acid as a white solid. The steps (1) to (6) of wrapping the four-necked bottle with the heating auxiliary device are as follows: (A) Preparation step: keep the four-necked bottle in a clamped state, and support its bottom with the heated outer liner (13); (B) Installation steps of the left and right straight parts: align the left and right straight parts and install them, and clamp the grooves of their lower edges on the outer edge of the upper part of the shell (11), insert the convex part of the front side of the right straight part into the concave part of the front side of the left straight part to fix it, and insert the convex part of the rear side of the left straight part into the concave part of the rear side of the right straight part to fix it; (C) Steps for installing the left and right halves: Attach the outer edges of the left and right halves to the female Velcro layers outside the upper edges of the left and right straight parts respectively, and make sure that the several pairs of male and female Velcros adjacent to the left and right halves are attached to each other.

Images