A method for synthesizing 1-chlorobenzo[4,5]thieno[2,3-c]pyridine

Abstract

The application discloses a synthesis method of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine, and relates to the technical field of preparation of heterocyclic organic compounds containing thiophene and pyridine; the application comprises the following steps: taking 5-bromo-2-chloropyridine and phenylboronic acid as raw materials, and preparing 2-chloro-5-phenylpyridine intermediate product through Suzuki coupling; adding sulfur as a cyclization thiophene raw material; under electrocatalysis conditions, sulfur is solidified through nucleophilic addition, sulfur free radicals are generated through single electron transfer, and the cyclization thiophene synthesis under mild conditions is completed; 1-chlorobenzo[4,5]thieno[2,3-c]pyridine is obtained by separating the crude product; the raw materials are cheap and easy to obtain, the cost is low, the reaction process is simple and easy to operate, the reaction period is simplified, the reaction condition is mild, the three wastes are less, the product yield is good, and the method is suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of preparation of thienyl, pyridyl containing heterocyclic organic compounds, in particular to a synthesis method of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine. BACKGROUND

[0002] OLED (Organic Light Emitting Diode) is known as the flat panel technology of the 21st century due to its low driving voltage, high luminance, fast response, high efficiency, ultra-thin and flexible foldable advantages. As a new display technology, OLED is currently in the early stage of industrial explosion. According to the development history of display technology, the next decade will be an era in which OLED gradually dominates. 1-chlorobenzo[4,5]thieno[2,3-c]pyridine is a key intermediate for synthesizing OLED green light doping materials, which has attracted more and more attention in recent years. Therefore, how to efficiently prepare it has always been a research hotspot in the OLED industry.

[0003] The invention patent application with publication number CN115190879A and the name of new compounds and organic light emitting devices containing the same discloses the prior art based on the construction of thienyl ring by means of sulfur-methyl oxidation ring closing, and then the synthesis of target molecules. The synthesis route can be represented as follows:

[0004]

[0005] The above synthesis route has the following disadvantages: the pyridine derivative of the first step Suzuki coupling: 3-bromo-6-chloro-2-(methylthio)pyridine is expensive and needs to be synthesized in advance, which increases the reaction preparation period. The sulfur-methyl group can further poison the Pd catalyst, which requires a relatively large amount of expensive catalyst, further increasing the reaction cost, which is not conducive to industrial production. The second step requires the use of oxidant hydrogen peroxide, which has poor operability and high risk coefficient. In the second and third steps, a large amount of water is needed for solid extraction in the post-processing stage, which produces a lot of waste and has low flux and poor operability. The whole synthesis route is long and complicated, which is not conducive to large-scale production and application. In summary, there is an urgent need for a synthesis method of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine to solve these problems. SUMMARY

[0006] The present application relates to the technical field of preparation of thienyl, pyridyl containing heterocyclic organic compounds, in particular to a synthesis method of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine.

[0007] In order to achieve the above object, the present application provides the following technical scheme: a synthesis method of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine, comprising the following specific contents: 5-bromo-2-chloropyridine and phenylboronic acid are used as raw materials, 2-chloro-5-phenylpyridine intermediate product is prepared by Suzuki coupling, sulfur is added as a cyclization thienation raw material, under electrocatalytic conditions, sulfur is solidified by nucleophilic addition, sulfur radical is generated by single electron transfer, cyclization thienation synthesis under mild conditions is completed, and 1-chlorobenzo[4,5]thieno[2,3-c]pyridine is obtained by separating a crude product.

[0008] Preferably, in the raw materials, the molar ratio of 5-bromo-2-chloropyridine, phenylboronic acid and sulfur is 1:1.05:(0.2-0.3).

[0009] Preferably, in the Suzuki coupling, the dosage of the palladium catalyst is 0.05% of the molar amount of 5-bromo-2-chloropyridine, and the catalyst is Pd-132.

[0010] Preferably, in the Suzuki coupling, the dosage of the base is twice of the molar amount of 5-bromo-2-chloropyridine, and the base is selected from potassium carbonate, sodium carbonate and potassium hydroxide.

[0011] Preferably, in the Suzuki coupling, the ratio of the volume of the organic phase in the solvent to the molar amount of 5-bromo-2-chloropyridine is 100ml:0.05mol, and the solvent is selected from xylene-ethanol-water in a volume ratio of 7:3:3, tetrahydrofuran-water in a volume ratio of 10:1 and DMF-water in a volume ratio of 10:1.

[0012] Preferably, the electrocatalytic conditions are specifically as follows: an acidic additive is added, an electrode is inserted, and a current is adjusted.

[0013] Preferably, the acidic additive is selected from p-toluenesulfonic acid monohydrate, trifluoroacetic acid and hydrochloric acid, and the dosage of the acidic additive is half of the molar amount of 5-bromo-2-chloropyridine.

[0014] Preferably, the electrode is Pt(-)|C(+), Pb(-)|Pt(+) or Ni(-)|C(+).

[0015] Preferably, the current is 15mA.

[0016] Preferably, under the electrocatalytic conditions, the reaction is carried out at room temperature for 6-10 hours.

[0017] Compared with the prior art, the present application has the following beneficial effects:

[0018] 1. The synthesis method of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine, first, 2-chloro-5-phenylpyridine is obtained by classic Suzuki coupling of cheap 5-bromo-2-chloropyridine and phenylboronic acid, the raw material is widely available and low in cost, avoiding complex and expensive substrates in the existing process, greatly simplifying the reaction route and cycle, and improving the competitiveness of the production process; then, cheap sulfur is used as a raw material for electrocatalytic coupling, sulfur is solidified by nucleophilic addition, and then single electron transfer is used to generate S free radicals, so that the synthesis of cyclization thiophene is realized under mild conditions, the synthesis method is two steps in one pot, simple and reasonable to operate, the conditions are mild, the coupling process can be realized at room temperature, the corresponding electrochemical conversion can be realized without adding electrolyte, the cost is low, the three wastes are low, a little control can obtain high yield, and it is suitable for large-scale production.

[0019] 2. The synthesis method of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine, electrocatalysis is selected instead of traditional oxidative coupling, avoiding the need for equivalent oxidants in traditional CDC coupling, which can further reduce the amount of three wastes and meet the essence of green chemistry.

[0020] 3. The synthesis method of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine, cheap and readily available sulfur is used as the thiophene parent sulfur source, avoiding the cumbersome steps of pre-synthesizing mercaptan derivatives and avoiding the odor during the synthesis of mercaptan derivatives, which is highly operable and economical in steps, and more green and environmentally friendly. DETAILED DESCRIPTION

[0021] A synthesis method of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine, comprising the following specific contents: 5-bromo-2-chloropyridine and phenylboronic acid are used as raw materials, 2-chloro-5-phenylpyridine intermediate is prepared by Suzuki coupling, sulfur is added as a cyclization thiophene raw material, under electrocatalytic conditions, sulfur is solidified by nucleophilic addition, and the generation of sulfur free radicals is realized by single electron transfer, the synthesis of cyclization thiophene is completed under mild conditions, 1-chlorobenzo[4,5]thieno[2,3-c]pyridine is obtained by separating the crude product, the method for separating the crude product can adopt common organic separation methods in the field of organic chemistry, such as recrystallization, vacuum distillation, etc., and column chromatography is preferably adopted.

[0022] In a more preferred embodiment, the molar ratio of the above three raw materials, 5-bromo-2-chloropyridine, phenylboronic acid and sulfur, can be further optimized to 1:1.05:(0.2-0.3).

[0023] The Suzuki coupling is generally carried out under an inert atmosphere, such as nitrogen atmosphere, in an organic solvent by adding a base, a palladium catalyst and raw materials and heating for reaction, but studies have shown that oxygen or air atmosphere can also be normal reaction, and even can speed up the reaction rate, therefore, the present application does not limit this, as long as the 2-chloro-5-phenylpyridine is prepared by using the Suzuki coupling; for reference, the amount of the palladium catalyst can be set to 0.05% of the molar amount of 5-bromo-2-chloropyridine, and the catalyst is preferably Pd-132, which has a faster reaction speed and is beneficial to efficient conversion, and other palladium catalysts such as Pd(PPh3)4 and Pd2(dba)3 can also be selected; the amount of the base can be set to 2 times of the molar amount of 5-bromo-2-chloropyridine, and the base can be selected from potassium carbonate, sodium carbonate, potassium hydroxide and other commonly used bases for Suzuki coupling; the ratio of the volume of the organic phase in the solvent to the molar amount of 5-bromo-2-chloropyridine can be set to 100 ml:0.05 mol, and the solvent can be selected from xylene-ethanol-water in a volume ratio of 7:3:3, tetrahydrofuran-water in a volume ratio of 10:1, DMF-water in a volume ratio of 10:1, and the like;

[0024] In addition, specifically, the above-mentioned electrocatalytic conditions include adding an acidic additive, inserting an electrode, and adjusting the current; for reference, the acidic additive can be selected from p-toluenesulfonic acid monohydrate, trifluoroacetic acid, and hydrochloric acid, which serves to activate the pyridine ring and further realize Minisic nucleophilic addition, and acidic substances such as acetic acid and phosphoric acid can also be used, and it should be noted that the strength of the acidity in the reaction solution system can affect the yield of the final product, and the amount of the acidic additive is preferably half of the molar amount of 5-bromo-2-chloropyridine, and the electrode can be Pt(-)|C(+), Pb(-)|Pt(+) or Ni(-)|C(+), and other commonly used electrocatalytic electrodes can also be used, and the current for electrocatalysis can be set to 15 mA, and the reaction is generally complete under electrocatalytic conditions at room temperature for 6-10 hours.

[0025] Example 1

[0026] Under a nitrogen atmosphere, 9.62 g of 5-bromo-2-chloropyridine (Mr=192.44, 99%, 0.05 mol), 6.40 g of phenylboronic acid (Mr=121.93, 99%, 0.0525 mol), 17.75 mg of Pd-132 (Mr=710.1, 99.9%, 0.000025 mol), 13.82 g of potassium carbonate (Mr=138.21, 99%, 0.1 mol) were added into a 250 ml four-necked flask, 100 ml of tetrahydrofuran and 10 ml of water were added, and after the feeding was completed, the temperature was raised to reflux, and after 6 hours, thin layer chromatography (TLC) analysis was performed, and after the reaction was completed, the temperature was reduced to room temperature;

[0027] 4.31 g of p-toluenesulfonic acid monohydrate (Mr = 172.2, 99%, 0.025 mol) and 2.56 g of sulfur (Mr = 256.52, 99.9%, 0.01 mol) were added, and a platinum electrode and a carbon electrode were inserted below the liquid surface to serve as the cathode and anode. The current was adjusted to 15 mA, and the reaction was carried out at room temperature for 8 h. Thin layer chromatography (TLC) was used for monitoring. After the reaction was completed, the mixture was filtered, and water (100 mL) and ethyl acetate (100 mL) were added for extraction. The organic layer was desolvated and then column chromatography was performed to obtain 9.23 g of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine in a yield of 84.3%.

[0028] Example 2

[0029] Under a nitrogen atmosphere, 9.62 g of 5-bromo-2-chloropyridine (Mr = 192.44, 99%, 0.05 mol), 6.40 g of phenylboric acid (Mr = 121.93, 99%, 0.0525 mol), 17.75 mg of Pd-132 (Mr = 710.1, 99.9%, 0.000025 mol), and 13.82 g of potassium carbonate (Mr = 138.21, 99%, 0.1 mol) were added to a 250 mL four-necked flask. 70 mL of xylene, 30 mL of ethanol, and 30 mL of water were added. After the addition of the materials, the temperature was raised to reflux. After 6 h, thin layer chromatography (TLC) was used for monitoring. After the reaction was completed, the temperature was lowered to room temperature.

[0030] 2.85 g of trifluoroacetic acid (Mr = 114.02, 99%, 0.025 mol) and 2.56 g of sulfur (Mr = 256.52, 99.9%, 0.01 mol) were added, and a lead electrode and a platinum electrode were inserted below the liquid surface to serve as the cathode and anode. The current was adjusted to 15 mA, and the reaction was carried out at room temperature for 10 h. Thin layer chromatography (TLC) was used for monitoring. After the reaction was completed, the mixture was filtered, and water (100 mL) and ethyl acetate (100 mL) were added for extraction. The organic layer was desolvated and column chromatography was performed to obtain 5.50 g of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine in a yield of 50.3%.

[0031] Example 3

[0032] In a 250 mL four-necked flask, under nitrogen atmosphere, 9.62 g of 5-bromo-2-chloropyridine (Mr = 192.44, 99%, 0.05 mol), 6.40 g of phenylboronic acid (Mr = 121.93, 99%, 0.0525 mol), 17.75 mg of Pd-132 (Mr = 710.1, 99.9%, 0.000025 mol), 13.82 g of potassium carbonate (Mr = 138.21, 99%, 0.1 mol) were added, 100 mL of DMF and 10 mL of water were added, after the addition of the reagents, the temperature was raised to reflux, after 6 h, the reaction was monitored by thin layer chromatography (TLC), after the end of the reaction, the temperature was lowered to room temperature;

[0033] 4.31 g of p-toluenesulfonic acid monohydrate (Mr = 172.2, 99%, 0.025 mol), 3.08 g of sulfur (Mr = 256.52, 99.9%, 0.012 mol) were added, platinum and carbon electrodes were inserted below the liquid level, acting as cathode and anode, the current was adjusted to 15 mA, the reaction was carried out at room temperature for 10 h, it was monitored by thin layer chromatography (TLC), after the end of the reaction, it was filtered, water (100 mL) and ethyl acetate (100 mL) were added and extracted, after the removal of the organic layer, column chromatography gave 10.36 g of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine with a yield of 94.6%.

[0034] Example 4

[0035] In a 250 mL four-necked flask, under nitrogen atmosphere, 9.62 g of 5-bromo-2-chloropyridine (Mr = 192.44, 99%, 0.05 mol), 6.40 g of phenylboronic acid (Mr = 121.93, 99%, 0.0525 mol), 17.75 mg of Pd-132 (Mr = 710.1, 99.9%, 0.000025 mol), 13.82 g of potassium carbonate (Mr = 138.21, 99%, 0.1 mol) were added, 100 mL of DMF and 10 mL of water were added, after the addition of the reagents, the temperature was raised to reflux, after 6 h, the reaction was monitored by thin layer chromatography (TLC), after the end of the reaction, the temperature was lowered to room temperature;

[0036] 0.86 g of hydrochloric acid (Mr = 34.36, 99%, 0.025 mol), 3.84 g of sulfur (Mr = 256.52, 99.9%, 0.015 mol) were added, nickel and carbon electrodes were inserted below the liquid level, acting as cathode and anode, the current was adjusted to 15 mA, the reaction was carried out at room temperature for 10 h, it was monitored by thin layer chromatography (TLC), after the end of the reaction, it was filtered, water (100 mL) and ethyl acetate (100 mL) were added and extracted, after the removal of the organic layer, column chromatography gave 2.69 g of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine with a yield of 24.6%.

[0037] Example 5

[0038] Into a 250 mL four-necked flask, 9.62 g of 5-bromo-2-chloropyridine (Mr = 192.44, 99%, 0.05 mol), 6.40 g of phenylboronic acid (Mr = 121.93, 99%, 0.0525 mol), 17.75 mg of Pd-132 (Mr = 710.1, 99.9%, 0.000025 mol), 13.82 g of potassium carbonate (Mr = 138.21, 99%, 0.1 mol), 100 mL of DMF and 10 mL of water were added, and after the addition was completed, the temperature was raised to reflux, and after 6 h, thin layer chromatography (TLC) was used for monitoring, and after the reaction was completed, the temperature was reduced to room temperature;

[0039] 4.31 g of p-toluenesulfonic acid monohydrate (Mr = 172.2, 99%, 0.025 mol), 3.84 g of sulfur (Mr = 256.52, 99.9%, 0.015 mol) were added, a nickel electrode and a carbon electrode were inserted below the liquid level to serve as a cathode and an anode, the current was adjusted to 15 mA, and the reaction was carried out at room temperature for 8 h, thin layer chromatography (TLC) was used for monitoring, and after the reaction was completed, filtration was performed, water (100 mL) and ethyl acetate (100 mL) were added for extraction, and after the organic layer was separated, column chromatography was performed to obtain 9.67 g of 1-chlorobenzo[4,5]thieno[2,3-c]pyridine, with a yield of 88.3%.

[0040] The following is a brief supplement to the effect on the yield:

[0041] In the above examples, the purpose of using thin layer chromatography (TLC) for monitoring in the Suzuki coupling reaction is to ensure the yield of the first step, so as not to affect the yield of the second step;

[0042] In the above examples, the yield of the final 1-chlorobenzo[4,5]thieno[2,3-c]pyridine product can reach about 95%, and the reason for the lower yield in Examples 2 and 4 is mainly due to the selection of the acidic additive, among which hydrochloric acid and trifluoroacetic acid are weaker in their respective acidities than p-toluenesulfonic acid monohydrate in the respective systems, so the completion yield is lower with respect to the sulfur curing process, and then the overall yield is reduced, and trifluoroacetic acid is an organic acid, which has better solubility in organic phase than hydrochloric acid, so the corresponding yield is better than that of hydrochloric acid.

[0043] The above is only a preferred embodiment of the present application, but the protection scope of the present application is not limited thereto, and any changes or replacements easily thought of by those skilled in the art within the technical scope disclosed by the present application should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be defined by the protection scope defined by the claims.

[0044] The details not described in the present application are well-known to those skilled in the art.

Claims

1. A method for synthesizing 1-chlorobenzo[4,5]thieno[2,3-c]pyridine, characterized in that: include: Using 5-bromo-2-chloropyridine and phenylboronic acid as raw materials, a base, a palladium catalyst and the raw materials are added to an organic solvent under a nitrogen atmosphere, and a 2-chloro-5-phenylpyridine intermediate is prepared by Suzuki coupling. Sulfur is added as a cyclothiophenation raw material, and under electrocatalytic conditions, the sulfur is solidified through nucleophilic addition, and sulfhydryl radicals are generated through single electron transfer, thereby completing the cyclothiophenation synthesis under mild conditions. The crude product is separated to obtain 1-chlorobenzo[4,5]thieno[2,3-c]pyridine. The electrocatalytic conditions are: adding an acidic additive, inserting an electrode, and adjusting the current. The acidic additive is p-toluenesulfonic acid monohydrate, trifluoroacetic acid, or hydrochloric acid.

2. The method for synthesizing 1-chlorobenzo[4,5]thieno[2,3-c]pyridine according to claim 1, characterized in that: The molar ratio of 5-bromo-2-chloropyridine, phenylboric acid and sulfur is 1:1.05:(0.2-0.3).

3. The method for synthesizing 1-chlorobenzo[4,5]thieno[2,3-c]pyridine according to claim 1, characterized in that: In the Suzuki coupling, the amount of palladium catalyst used is 0.05% of the molar amount of 5-bromo-2-chloropyridine, and the catalyst is Pd-132.

4. The method for synthesizing 1-chlorobenzo[4,5]thieno[2,3-c]pyridine according to claim 1, characterized in that: In the Suzuki coupling, the amount of the base used is twice the molar amount of 5-bromo-2-chloropyridine, and the base is selected from potassium carbonate, sodium carbonate or potassium hydroxide.

5. The method for synthesizing 1-chlorobenzo[4,5]thieno[2,3-c]pyridine according to claim 1, characterized in that: In the Suzuki coupling, the ratio of the volume of the organic phase in the solvent to the molar amount of 5-bromo-2-chloropyridine is 100 ml:0.05 mol, and the solvent is selected from xylene-ethanol-water with a volume ratio of 7:3:3, tetrahydrofuran-water with a volume ratio of 10:1, or DMF-water with a volume ratio of 10:

1.

6. The method for synthesizing 1-chlorobenzo[4,5]thieno[2,3-c]pyridine according to claim 1, characterized in that: The amount of the acidic additive used is half the molar amount of 5-bromo-2-chloropyridine.

7. The method for synthesizing 1-chlorobenzo[4,5]thieno[2,3-c]pyridine according to claim 1, characterized in that: The electrodes are Pt(-)|C(+), Pb(-)|Pt(+) or Ni(-)|C(+).

8. The method for synthesizing 1-chlorobenzo[4,5]thieno[2,3-c]pyridine according to claim 1, characterized in that: The current was 15 mA.

9. The method for synthesizing 1-chlorobenzo[4,5]thieno[2,3-c]pyridine according to claim 1, characterized in that: Under the electrocatalytic conditions, the reaction is carried out at room temperature for 6-10 hours.

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