Synthesis method of halogen-substituted thienopyridine compounds

Abstract

A method for synthesizing a halogen-substituted thienopyridine compound, namely, a method for synthesizing 3-chlorothieno[2,3-c]pyridine-2-carboxylic acid, is implemented by using a reinforced heating jacket to prepare 3-aminothieno[2,3-B]pyridine-2-carboxylic acid ethyl ester by reacting 3-chloro-4-cyanopyridine, ethyl mercaptoacetate, and sodium methoxide; then preparing 3-chlorothieno[2,3-c]pyridine-2-carboxylic acid ethyl ester; and finally obtaining the final product, 3-chlorothieno[2,3-c]pyridine-2-carboxylic acid.

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 a halogen-substituted thienopyridine compound. Background Art

[0002] 3-Chlorothieno[2,3-c]pyridine-2-carboxylic acid and its derivatives are an important class of compounds with strong biological activity and potential pharmaceutical applications. However, the method described in this application has rarely been used as a pharmaceutical intermediate, nor has any literature or documentation been published. Due to the molecular properties, unique synthetic route, and high yields, the 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 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 3-chlorothieno[2,3-c]pyridine-2-carboxylic acid has a low yield. Currently, the yield given by the personnel in this field we have found or consulted is not higher than 40%, and generally there is waste that is difficult to handle.

[0005] Secondly, the present method, like many other methods for preparing this substance, requires heating or maintaining a specific temperature for a long time. During this process, it is difficult to ensure 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 (four-necked flasks or other glassware with large areas exposed to the air). After multiple comparative experiments, we found that this actually has a significant adverse effect on the yield. However, the existing technology does not pay attention to this defect. At most, blankets or insulation pads are used for simple insulation. However, firstly, the insulation effect is insufficient, and secondly, since the bottle may need to be vigorously stirred, such a simple insulation measure cannot meet the needs of the bottle during long-term stirring 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 3-chlorothieno[2,3-c]pyridine-2-carboxylic acid from ethyl mercaptoacetate 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 to avoid the adverse effects of temperature changes in each step requiring long-term heating reaction. Both of these problems are 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 1 and an upper movable sleeve 2.

[0008] The lower fixing sleeve includes a lower heating sleeve 11 , a housing 12 , a base 13 , a control circuit 14 , a control panel 15 and a power supply 16 .

[0009] The upper movable sleeve 2 includes 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, inner lining, and outer lining are all truncated cones with a small top and a large bottom, and the upper edges have inner edges extending horizontally inward, and one side of the upper heating sleeve, inner lining, and outer lining has a vertical opening.

[0010] 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.

[0011] Furthermore, both the upper heating sleeve and the lower heating sleeve are equipped with mesh alloy wires, which are wrapped with alkali-free glass fiber and vacuum-formed using aluminum silicate wool; the inner and outer linings are 3-8mm thick Teflon material layers, and are both mesh-shaped and hollow; the connecting wire between the upper heating sleeve and the control circuit is located on the outside of the upper heating sleeve.

[0012] A method for synthesizing a halogen-substituted thienopyridine compound is implemented using a reinforced heating jacket, comprising the following steps: (1) dissolving 150-152 mmol of ethyl mercaptoacetate in 300 mL of N,N-dimethylformamide in a four-necked flask, slowly adding 300-305 mmol of sodium methoxide, cooling the flask to 0°C after the addition is complete, stirring and reacting for at least 30 minutes, then adding 110-120 mmol of 3-chloro-4-cyanopyridine, placing the lower portion of the four-necked flask in a lower heating jacket, and opening the upper heating jacket so as to be laterally mounted on the four-necked flask. The upper part of the flask was added and the opening was closed; the heating was controlled to be maintained at 120°C by the control panel, and the reaction was maintained for at least 2 hours. When TLC determined that the reaction was complete, the heating equipment was removed and the reaction mixture was cooled to room temperature to obtain a crude product, which was diluted with at least 600 mL of water and extracted with 300 mL of ethyl acetate for at least three times. The organic phases were combined and washed three times with 200 mL of saturated brine each time, dried over 20 g of anhydrous sodium sulfate for 30 minutes, filtered and concentrated to obtain a yellow solid containing ethyl 3-aminothieno[2,3-B]pyridine-2-carboxylate, which was called mixture A.

[0013] (2) Dissolve mixture A containing 4.5-5.5 g of ethyl 3-aminothieno[2,3-B]pyridine-2-carboxylate in 30 mL of 12N hydrochloric acid. Place sufficient icy ether in an outer wide-mouthed glass container, cool the system to -30°C, dropwise add 25 mL of an aqueous solution containing 1.6-1.75 g of sodium nitrite, and allow to stand for at least 10 minutes. Place the lower part of the four-necked flask in the lower heating mantle, and open the opening of the upper heating mantle. Put it horizontally on the upper part of a 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 1 hour, extract three times with 50 mL of dichloromethane each time, combine the organic phases, wash with sodium bicarbonate solution, filter and concentrate the crude product, and wet-filter it with at least 30 g of 200-300 mesh silica gel through a column with petroleum ether / ethyl acetate = 2:1 to obtain product B: 3-chlorothieno[2,3-c]pyridine-2-carboxylic acid ethyl ester as a white solid.

[0014] (3) Take a four-necked flask with a capacity of 500 mL or more, add no less than 30 mL of tetrahydrofuran, add 2.6-2.8 g of product B under stirring, and after all the addition, slowly add 10 mL of 1N lithium hydroxide solution, place the lower part of the four-necked flask in the lower heating jacket, and 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 25°C through the control panel, and keep the reaction for no less than 3 hours, dissolve the reaction mixture with sufficient water, spin dry to remove tetrahydrofuran, extract three times with 50 mL of dichloromethane each time, adjust the aqueous phase to pH 3 with 1N hydrochloric acid, filter, and dry to obtain 3-chlorothieno[2,3-c]pyridine-2-carboxylic acid as a white solid.

[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, if it is set at 90°C, the actual temperature fluctuates between 90-82°C, or even lower. 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 to perfectly solve 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 raw material utilization rate 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 50%, such as 52%, 53%, 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 includes 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 includes 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, inner lining, and outer lining are all truncated cones with a smaller top and a larger bottom. The upper edges of the upper heating sleeve have inner edges that extend horizontally inward, and one side of the upper heating sleeve, inner lining, and outer lining has a vertical opening.

[0027] The lower and upper heating jackets are connected to separate control circuits, independently powered and controlled by the control circuits, with integrated temperature control from the control panel. The lower heating jacket's setup is similar to a standard heating jacket, but the upper removable jacket's design is original; we couldn't find a commercially available alternative, so we custom-made it. Regarding the control circuit, the wires of the upper and lower heating jackets can be connected in parallel, connected to a single control circuit. However, this circuit's actual temperature control will differ from the original and require recalibration and labeling. Alternatively, separate control circuits can be used for the lower heating jacket, but this effectively doubles the output power, so ensure proper power matching between the power supplies. The heating jackets can be powered by either 220V or 380V. The temperature control of both the upper and lower heating jackets has been repeatedly compared and calibrated.

[0028] 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 inner and outer linings are 3-8mm thick Teflon layers, each with a mesh-like hollowing pattern. The connection between the upper heating jacket and the control circuit is located on the outside of the upper heating jacket. The wrapping of the heating jacket is similar to that of the prior art, but the choice of the inner and outer linings is not known in the prior art. Teflon or other Teflon-based plastics are preferred, as 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 a specific shape while allowing the opening to be opened, making it convenient for wrapping the upper portion of the four-necked bottle from the side. This is a targeted material selection made after we first considered the functionality.

[0029] 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℃.

[0030] like Figure 1-2 As shown, the lower heating jacket is hemispherical, while the upper heating jacket is a section of a truncated cone (with the top of the cone cut off) 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.

[0031] Example 2

[0032] A method for synthesizing a halogen-substituted thienopyridine compound, specifically for synthesizing 3-chlorothieno[2,3-c]pyridine-2-carboxylic acid, is implemented using a reinforced heating mantle, and comprises the following steps: (1) dissolving 150.8 mmol, 25.93 g of ethyl mercaptoacetate in 300 mL of N,N-dimethylformamide in a four-necked flask, slowly adding 23.31 g, 301.6 mmol of sodium methoxide, cooling to 0°C after the addition, stirring and reacting for at least 30 minutes, then adding 23 g, 116 mmol of 3-chloro-4-cyanopyridine, and placing the lower part of the four-necked flask in the lower heating mantle. The opening of the upper heating jacket was opened and placed horizontally over the top of the four-necked flask, and the opening was closed. The heating was maintained at 120°C using the control panel, and the reaction was continued for at least 2 hours. When TLC confirmed the reaction was complete, the heating device was removed and the reaction mixture was cooled to room temperature to obtain a crude product. The crude product was diluted with at least 600 mL of water and extracted at least three times with 300 mL of ethyl acetate each time. The organic phases were combined and washed three times with 200 mL of saturated brine each time. The product was dried over 20 g of anhydrous sodium sulfate for 30 minutes, filtered, and concentrated to obtain a yellow solid containing ethyl 3-aminothieno[2,3-B]pyridine-2-carboxylate, referred to as mixture A. The mixture may contain methyl acrylate and ethyl acrylate, of which 28.2 g, calculated as ethyl 3-aminothieno[2,3-B]pyridine-2-carboxylate, was present, for a yield of 75.9% in this step.

[0033] The product nuclear magnetic data are as follows: 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.55 (d, J = 5.5 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 5.92 (s, 2H), 4.39 (q, J = 7.1 Hz, 0.8H), 3.93 (s, 1.8H), 1.41 (t, J = 7.1 Hz, 1.2H). MS: (M+H) + :m / z=209.1and223.1.

[0034] (2) Dissolve mixture A containing 5 g, 23.256 mmol of ethyl 3-aminothieno[2,3-B]pyridine-2-carboxylate in 30 mL of 12N hydrochloric acid. Place sufficient icy ether in the outer wide-mouthed glass container, cool the system to -30°C, dropwise add 25 mL of an aqueous solution containing 1.68 g, 24.419 mmol of sodium nitrite, and keep the mixture warm for at least 10 minutes (temperature below 0°C). Place the lower part of the four-necked flask in the lower heating mantle and The upper heating mantle was opened and placed horizontally over the top of the four-necked flask, and the opening was closed. Heating was maintained at 25°C using the control panel, and the reaction was continued for at least 1 hour. Extraction was performed three times with 50 mL of dichloromethane each time. The organic phases were combined and washed with sodium bicarbonate solution. The crude product was filtered and concentrated, and then wet-filtered through a column using at least 30 g of 200-300 mesh silica gel (petroleum ether / ethyl acetate = 2:1) to obtain product B: ethyl 3-chlorothieno[2,3-c]pyridine-2-carboxylate as a white solid. 4.1 g of product B was obtained, for a yield of 77.8%.

[0035] The product NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ9.19 (s, 1H), 8.68 (s, 1H), 7.86 (d, J=5.4Hz, 1H), 4.47 (q, J=7.1Hz, 2H), 1.45 (t, J=7.1Hz, 3H).MS: (M+H) + :m / z=242.1.

[0036] (3) Take a four-necked flask of 500 mL or more, add no less than 30 mL of tetrahydrofuran, add 2.7 g (11.203 mmol) of product B under stirring, and after all the addition, slowly add 10 mL of 1N lithium hydroxide solution. Place the lower part of the 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 25°C through the control panel, and keep the reaction for no less than 3 hours. Dissolve the reaction mixture with sufficient water, spin dry to remove tetrahydrofuran, extract three times with 50 mL of dichloromethane each time, adjust the aqueous phase to pH 3 with 1N hydrochloric acid, filter, and dry to obtain 3-chlorothieno[2,3-c]pyridine-2-carboxylic acid as a white solid. Yield: 88%. Total yield: 51.96%.

[0037] The product NMR data are as follows: 1 H NMR (400MHz, DMSO) δ14.34 (s, 1H), 9.41 (s, 1H), 8.67 (d, J=5.6Hz 1H), 7.90–7.88 (m, 1H).MS: (M+H) + :m / z=214.0.

[0038] 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% to only about 41%, which fully demonstrated the beneficial effect of the upper heating jacket.

[0039] Example 3

[0040] A method for synthesizing a halogen-substituted thienopyridine compound, specifically for synthesizing 3-chlorothieno[2,3-c]pyridine-2-carboxylic acid, is implemented using a reinforced heating jacket, and comprises the following steps: (1) dissolving 151 mmol of ethyl mercaptoacetate in 300 mL of N,N-dimethylformamide in a four-necked flask, slowly adding 302 mmol of sodium methoxide, cooling to 0°C after the addition, stirring the reaction for at least 30 minutes, then adding 117 mmol of 3-chloro-4-cyanopyridine, placing the lower part of the four-necked flask in a lower heating jacket, and opening the upper heating jacket. , placed horizontally on the top of a four-necked flask and closed; heating was controlled by the control panel to maintain at 120°C, and the reaction was continued for at least 2 hours. When TLC confirmed the reaction was complete, the heating device was removed and the reaction mixture was cooled to room temperature to obtain a crude product, which was diluted with at least 600 mL of water and extracted with 300 mL of ethyl acetate at least three times. The organic phases were combined and washed three times with 200 mL of saturated brine each time, dried over 20 g of anhydrous sodium sulfate for 30 minutes, filtered and concentrated to obtain a yellow solid containing ethyl 3-aminothieno[2,3-B]pyridine-2-carboxylate, referred to as mixture A. The mixture may contain methyl acrylate and ethyl acrylate, of which 28.4 g was calculated as ethyl 3-aminothieno[2,3-B]pyridine-2-carboxylate, for a yield of 76.34% in this step.

[0041] The product nuclear magnetic data are as follows: 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 8.55 (d, J = 5.5 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 5.92 (s, 2H), 4.39 (q, J = 7.1 Hz, 0.8H), 3.93 (s, 1.8H), 1.41 (t, J = 7.1 Hz, 1.2H). MS: (M+H) + :m / z=209.1and223.1.

[0042] (2) Mixture A containing 5.1 g of ethyl 3-aminothieno[2,3-B]pyridine-2-carboxylate was dissolved in 30 mL of 12N hydrochloric acid. Sufficient icy ether was placed in an outer wide-mouthed glass container, the system temperature was cooled to -30°C, and the mixture containing was added dropwise. 715g of sodium nitrite in 25mL of aqueous solution was insulated and allowed to stand for at least 20 minutes (temperature below 0°C). The lower portion of a four-necked flask was placed in a lower heating mantle, and the upper heating mantle, opened and placed horizontally over the upper portion of the four-necked flask, was closed. Heating was controlled to maintain 25°C using a control panel, and the reaction was continued for at least 2 hours. Extraction was performed three times with 60mL of dichloromethane each time. The organic phases were combined and washed with sodium bicarbonate solution. The crude product was filtered and concentrated, and then wet-filtered with at least 50g of 200-300 mesh silica gel in a 2:1 ratio of petroleum ether to ethyl acetate to obtain product B: ethyl 3-chlorothieno[2,3-c]pyridine-2-carboxylate as a white solid. 4.2g of product B was obtained, with a yield of 78.13%.

[0043] The product NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ9.19 (s, 1H), 8.68 (s, 1H), 7.86 (d, J=5.4Hz, 1H), 4.47 (q, J=7.1Hz, 2H), 1.45 (t, J=7.1Hz, 3H).MS: (M+H) + :m / z=242.1.

[0044] (3) Take a four-necked flask of 500 mL or more, add no less than 40 mL of tetrahydrofuran, add 2.8 g of product B under stirring, and after all the addition, slowly add 11 mL of 1N lithium hydroxide solution. Place the lower part of the 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 25°C through the control panel, and keep the reaction for no less than 3.5 hours. Dissolve the reaction mixture with sufficient water, spin dry to remove tetrahydrofuran, extract three times with 50 mL of dichloromethane each time, adjust the aqueous phase to pH 3 with 1N hydrochloric acid, filter, and dry to obtain 3-chlorothieno[2,3-c]pyridine-2-carboxylic acid as a white solid. Yield 89%. Total yield 53.08%.

[0045] The product NMR data are as follows: 1 H NMR (400MHz, DMSO) δ14.34 (s, 1H), 9.41 (s, 1H), 8.67 (d, J=5.6Hz 1H), 7.90–7.88 (m, 1H).MS: (M+H) + :m / z=214.0.

[0046] 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% to only about 40%, which fully demonstrated the beneficial effect of the upper heating jacket.

[0047] 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.

[0048] 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 halogen-substituted thienopyridine compound, which is carried out using a reinforced heating mantle, wherein: The reinforced heating sleeve 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) includes 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, the inner lining, and the outer lining are all truncated cone-shaped with a small top and a large bottom, and the upper edges all have inner edges extending horizontally inwards, and one side of the upper heating sleeve, the inner lining, and the outer lining all have vertical openings; The lower heating jacket and the upper heating jacket are connected to the control circuit respectively, and are independently powered and controlled by the control circuit, and the temperature is controlled integrally by the control panel; 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; The synthesis method of a halogen-substituted thienopyridine compound comprises the following specific steps: (1) Dissolve 150-152 mmol of ethyl mercaptoacetate in 300 mL of N,N-dimethylformamide and place it in a four-necked flask. Slowly add 300-305 mmol of sodium methoxide. After the addition is complete, cool to 0°C and stir to react for at least 30 minutes. Then add 110-120 mmol of 3-chloro-4-cyanopyridine. Place the lower part of the 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 by the control panel. The heat was maintained at 120°C and the reaction was continued for at least 2 hours. When TLC confirmed that the reaction was complete, the heating equipment was removed and the reaction mixture was cooled to room temperature to obtain a crude product, which was diluted with at least 600 mL of water and extracted with 300 mL of ethyl acetate at least three times. The organic phases were combined and washed three times with 200 mL of saturated brine each time, dried over 20 g of anhydrous sodium sulfate for 30 minutes, filtered and concentrated to obtain a yellow solid containing ethyl 3-aminothieno[2,3-B]pyridine-2-carboxylate, referred to as mixture A. (2) Dissolve mixture A containing 4.5-5.5 g of ethyl 3-aminothieno[2,3-B]pyridine-2-carboxylate in 30 mL of 12N hydrochloric acid. Place sufficient icy ether in an outer wide-mouthed glass container, cool the system to -30°C, dropwise add 25 mL of an aqueous solution containing 1.6-1.75 g of sodium nitrite, and allow to stand for at least 10 minutes. Place the lower part of the four-necked flask in the lower heating mantle, and open the opening of the upper heating mantle. Place the mixture horizontally on the top of a four-necked flask and close the opening; control the heating to maintain at 25°C via the control panel and maintain the reaction for at least 1 hour. Extract the mixture three times with 50 mL of dichloromethane each time. Combine the organic phases and wash with sodium bicarbonate solution. Filter and concentrate the crude product, and wet-filter it with at least 30 g of 200-300 mesh silica gel using a column chromatography method with petroleum ether / ethyl acetate = 2:1 to obtain product B: ethyl 3-chlorothieno[2,3-c]pyridine-2-carboxylate as a white solid. (3) Take a four-necked flask with a capacity of 500 mL or more, add no less than 30 mL of tetrahydrofuran, add 2.6-2.8 g of product B under stirring, and after all the addition, slowly add 10 mL of 1N lithium hydroxide solution, place the lower part of the four-necked flask in the lower heating jacket, and 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 25°C through the control panel, and keep the reaction for no less than 3 hours, dissolve the reaction mixture with sufficient water, spin dry to remove tetrahydrofuran, extract three times with 50 mL of dichloromethane each time, adjust the aqueous phase to pH 3 with 1N hydrochloric acid, filter, and dry to obtain 3-chlorothieno[2,3-c]pyridine-2-carboxylic acid as a white solid.

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