A new preparation method and application method of quinoline-2-boronic acid ester

Abstract

This invention discloses a novel method for preparing and applying quinoline-2-boron ester. A one-pot method is used with a hexane solution of 2-bromoquinoline and n-butyllithium as raw materials, and tetrahydrofuran as solvent. At -70 to -90°C, 2-lithiumquinoline is formed, which is then captured by triisopropyl borate to generate isopropyl-quinoline-2-boron ester lithium salt. Without separation, the formed isopropyl-quinoline-2-boron ester lithium salt is directly reacted with N-phenyldiethanolamine to generate a novel quinoline-2-boron acid N-phenyldiethanolamine ester. The entire reaction process is simple and easy to operate, and the resulting product is easily separated and purified, with a yield of over 80%. The preparation cost is significantly reduced, the experiment has good reproducibility, and it has significant commercial application potential.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to a novel method for preparing and applying quinoline-2-boronate. Background Technology

[0002] Quinoline compounds are not only important bioactive molecules, but also important intermediates in organic synthesis and drug synthesis.

[0003] In recent years, due to the rapid development of the OLED industry, more and more research results have shown that the excellent performance of quinoline compounds in the field of organic electroluminescence cannot be ignored.

[0004] However, while there is a large body of literature on the other active sites of quinoline besides the 2-position, there are few reports on methods for constructing a series of fused-ring heterocycles using the 2-position of quinoline. This shows that the introduction of the active group at the 2-position of quinoline has always been a challenge in the laboratory.

[0005] The Suzuki reaction used in the existing literature for the synthesis of quinoline compounds all uses quinoline-2-boronic acid and conventional quinoline-2-boron ester.

[0006] From the limited existing literature, it can be seen that quinoline-2-boronic acid and conventional quinoline-2-boronic ester are the mainstream intermediates used. However, quinoline-2-boronic acid is difficult to prepare, with a reaction yield of less than 30% in the laboratory, resulting in excessively high costs and limited commercial application. Although there are literatures supporting the preparation methods of quinoline-2-boronic ester, the reproducibility of the methods in the laboratory is poor, with almost no product formation. Furthermore, quinoline-2-boronic ester is less reactive than boric acid, limiting its application range. For most Suzuki reactions that require high reactivity, it cannot be successfully coupled.

[0007] Therefore, researching and developing a novel method for preparing quinoline-2-boronate has great market potential, and this quinoline-2-boronate can be applied in the Suzuki coupling reaction. Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of the prior art and provide a new method for preparing and applying quinoline-2-boronate.

[0009] To solve the technical problem, the technical solution of the present invention is: a novel method for preparing quinoline-2-boronate, comprising the following steps:

[0010] Step 1: Using 2-bromoquinoline, triisopropyl borate, and n-butyllithium as raw materials, an isopropyl-quinoline-2-boron ester lithium salt solution is generated, wherein the equivalent ratio of 2-bromoquinoline, triisopropyl borate, and n-butyllithium is 1:1.1~2:1.1~2; Step 2: N-phenyldiethanolamine is added to the isopropyl-quinoline-2-boron ester lithium salt solution generated in Step 1, and the reaction is carried out to generate quinoline-2-boron N-phenyldiethanolamine ester, wherein the equivalent ratio of isopropyl-quinoline-2-boron ester lithium salt to N-phenyldiethanolamine is 1:1~2.

[0011] Preferably, step 1 specifically involves: under inert gas protection, dissolving 2-bromoquinoline and triisopropyl borate in tetrahydrofuran, adding them to a reactor vessel, and cooling the vessel to -70 to -90°C while stirring, and controlling the temperature below -70°C. A hexane solution of n-butyllithium is then added dropwise to the system. After the addition is complete, the system is naturally heated to room temperature and stirred for 16 to 24 hours to ensure complete reaction. The ratio of 2-bromoquinoline to tetrahydrofuran is 1 g: 5 to 10 mL.

[0012] Preferably, step 2 specifically involves: dissolving N-phenyldiethanolamine in tetrahydrofuran, adding it to the system of step 1, then heating the reaction to reflux and stirring for 4-8 hours to generate a quinoline-2-boronic acid N-phenyldiethanolamine ester system, wherein the ratio of N-phenyldiethanolamine to tetrahydrofuran is 1 g: 1-3 mL.

[0013] Preferably, the post-treatment of the quinoline-2-boronic acid N-phenyldiethanolamine ester system is as follows: the solvents tetrahydrofuran and n-hexane in the distillation system are replaced with isopropanol. After the replacement is completed, the system is cooled to room temperature and stirred for 12-24 hours. The product will precipitate in solid form. It is directly filtered, washed with isopropanol, and then dried at normal pressure to obtain the desired product, quinoline-2-boronic acid N-phenyldiethanolamine ester.

[0014] Preferably, the equivalence ratio of 2-bromoquinoline, triisopropyl borate, and n-butyllithium is 1:1.5:1.5, and the equivalence ratio of isopropyl-quinoline-2-boron ester lithium salt to N-phenyldiethanolamine is 1:1.5.

[0015] Preferably, a novel method for applying quinoline-2-boronic acid ester involves adding N-phenyldiethanolamine quinoline-2-boronic acid ester and substrate A with halogenated or sulfonate active groups to a reactor vessel under inert gas protection. A base, palladium catalyst, cuprous iodide, and triphenylphosphine are then added, followed by solvent. Stirring is initiated, and the system is heated to 60–120°C and maintained at this temperature for 12–24 hours until the reaction is complete. The system is then cooled to room temperature, concentrated to remove the original solvent, and toluene and water are added to extract the product. The toluene phase is then silicated. After removing the catalyst using a gel column, product B was obtained by crystallization with ethanol. The equivalence ratio of quinoline-2-boronic acid N-phenyldiethanolamine ester to substrate A was 1–2:1. The equivalence ratio of quinoline-2-boronic acid N-phenyldiethanolamine ester, base, palladium catalyst, cuprous iodide, and triphenylphosphine was 1–2:1.5–2:0.01–0.05:0.2–0.4:0.04–0.2. The volume ratio of quinoline-2-boronic acid N-phenyldiethanolamine ester to solvent was 1 g:5–10 mL. The structural formula of substrate A is [insert structural formula here]. Where X is selected from -Cl, -Br, -I, -Otf, and R is selected from -H, -NO2, -CN, -CHO, -Ar, -Me, -OMe; the structural formula of product B is Where R is one of -H, -NO2, -CN, -CHO, -Ar, -Me, -OMe.

[0016] Preferably, the alkali is selected from potassium carbonate, cesium carbonate, and potassium phosphate; the palladium catalyst is selected from tetraphenylphosphine palladium, palladium acetate, and diphenylphosphine palladium dichloride; and the solvent is selected from tetrahydrofuran, dioxane, and N,N-dimethylformamide.

[0017] Preferably, the equivalent ratio of the quinoline-2-borate N-phenyldiethanolamine ester to substrate A with halogen or sulfonate active groups is 1.1:1.

[0018] Preferably, the ratio of toluene to water is 1:1.

[0019] Compared with the prior art, the advantages of the present invention are as follows:

[0020] (1) This invention discloses a method for preparing quinoline-2-boron ester. The method uses a one-pot process with a hexane solution of 2-bromoquinoline and n-butyllithium as raw materials and tetrahydrofuran as solvent to form 2-lithiumquinoline at -70 to -90°C. Then, it is captured by triisopropyl borate to generate isopropyl-quinoline-2-boron ester lithium salt. Without separation, the formed isopropyl-quinoline-2-boron ester lithium salt is directly reacted with N-phenyldiethanolamine to generate a new quinoline-2-boron N-phenyldiethanolamine ester. The whole reaction process is simple and easy to operate. After the reaction, it is easy to separate and purify. The yield can be as high as 80% or more. The preparation cost is greatly reduced. The experiment has good reproducibility and is of great significance for commercial application.

[0021] (2) The quinoline-2-boronic acid N-phenyldiethanolamine ester prepared by this invention has the same activity as quinoline-2-boronic acid, and is more stable in the Suzuki reaction process. It has improved tolerance to reaction conditions and can withstand more stringent reaction conditions, which can ensure the smooth progress of the coupling reaction and facilitate the construction of quinoline-based fused-ring heterocyclic compounds.

[0022] (3) The preparation method of quinoline-2-boronic acid N-phenyldiethanolamine ester of the present invention is simple, easy to operate, simple to post-process, has a high yield, can greatly reduce the preparation cost, has great commercial practical significance, and retains the high activity equivalent to boric acid.

[0023] (4) After the preparation of quinoline-2-boronic acid N-phenyldiethanolamine ester of the present invention is completed, isopropanol is used for solvent replacement to precipitate the product in high yield;

[0024] (5) The electron-donating macrocycle used to protect quinoline-2-boronic acid in this invention is provided by N-phenyldiethanolamine, which has the advantage of making the borate ester more stable and having good tolerance and reactivity in the subsequent Suzuki reaction.

[0025] (6) The base, palladium catalyst, cuprous iodide and triphenylphosphine used in this invention are all materials that are widely available on the market and are cheaper than similar compounds. Furthermore, using such a combination can significantly improve catalytic efficiency, shorten reaction time, and has a clear advantage in controlling reaction energy consumption. Attached Figure Description

[0026] Figure 1 The hydrogen NMR spectrum of the product in Example 1 of this invention;

[0027] Figure 2 The hydrogen NMR spectrum of the product in Example 4 of this invention;

[0028] Figure 3 The hydrogen NMR spectrum of the product in Example 5 of this invention;

[0029] Figure 4 The hydrogen NMR spectrum of the product in Example 6 of this invention. Detailed Implementation

[0030] The present invention will be described below with reference to specific embodiments. The raw materials, solvents and catalysts used are all conventional commercial products. The following embodiments are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0031] This invention discloses a novel method for preparing quinoline-2-boronate, comprising the following steps:

[0032] Step 1: Using 2-bromoquinoline, triisopropyl borate, and n-butyllithium as raw materials, an isopropyl-quinoline-2-boron ester lithium salt solution is generated, wherein the equivalent ratio of 2-bromoquinoline, triisopropyl borate, and n-butyllithium is 1:1.1~2:1.1~2; Step 2: N-phenyldiethanolamine is added to the isopropyl-quinoline-2-boron ester lithium salt solution generated in Step 1, and the reaction is carried out to generate quinoline-2-boron N-phenyldiethanolamine ester, wherein the equivalent ratio of isopropyl-quinoline-2-boron ester lithium salt to N-phenyldiethanolamine is 1:1~2.

[0033] Preferably, step 1 specifically involves: under inert gas protection, dissolving 2-bromoquinoline and triisopropyl borate in tetrahydrofuran, adding them to a reactor vessel, and cooling the vessel to -70 to -90°C while stirring, and controlling the temperature below -70°C. A hexane solution of n-butyllithium is then added dropwise to the system. After the addition is complete, the system is naturally heated to room temperature and stirred for 16 to 24 hours to ensure complete reaction. The ratio of 2-bromoquinoline to tetrahydrofuran is 1 g: 5 to 10 mL.

[0034] Preferably, step 2 specifically involves: dissolving N-phenyldiethanolamine in tetrahydrofuran, adding it to the system of step 1, then heating the reaction to reflux and stirring for 4-8 hours to generate a quinoline-2-boronic acid N-phenyldiethanolamine ester system, wherein the ratio of N-phenyldiethanolamine to tetrahydrofuran is 1 g: 1-3 mL.

[0035] Preferably, the post-treatment of the quinoline-2-boronic acid N-phenyldiethanolamine ester system is as follows: the solvents tetrahydrofuran and n-hexane in the distillation system are replaced with isopropanol. After the replacement is completed, the system is cooled to room temperature and stirred for 12-24 hours. The product will precipitate in solid form. It is directly filtered, washed with isopropanol, and then dried at normal pressure to obtain the desired product, quinoline-2-boronic acid N-phenyldiethanolamine ester.

[0036] Preferably, the equivalent ratio of 2-bromoquinoline, triisopropyl borate, and n-butyllithium is 1:1.5:1.5, and the equivalent ratio of isopropyl-quinoline-2-boron ester lithium salt and N-phenyldiethanolamine is 1:1.5.

[0037] Preferably, a novel method for applying quinoline-2-boronic acid ester involves adding N-phenyldiethanolamine quinoline-2-boronic acid ester and substrate A with halogenated or sulfonate active groups to a reactor vessel under inert gas protection. A base, palladium catalyst, cuprous iodide, and triphenylphosphine are then added, followed by solvent. Stirring is initiated, and the system is heated to 60–120°C and maintained at this temperature for 12–24 hours until the reaction is complete. The system is then cooled to room temperature, concentrated to remove the original solvent, and toluene and water are added to extract the product. The toluene phase is then silicated. After removing the catalyst using a gel column, product B was obtained by crystallization with ethanol. The equivalence ratio of quinoline-2-boronic acid N-phenyldiethanolamine ester to substrate A was 1–2:1. The equivalence ratio of quinoline-2-boronic acid N-phenyldiethanolamine ester, base, palladium catalyst, cuprous iodide, and triphenylphosphine was 1–2:1.5–2:0.01–0.05:0.2–0.4:0.04–0.2. The volume ratio of quinoline-2-boronic acid N-phenyldiethanolamine ester to solvent was 1 g:5–10 mL. The structural formula of substrate A is [insert structural formula here]. Where X is selected from -Cl, -Br, -I, -Otf, and R is selected from -H, -NO2, -CN, -CHO, -Ar, -Me, -OMe; the structural formula of product B is Where R is one of -H, -NO2, -CN, -CHO, -Ar, -Me, -OMe.

[0038] Preferably, the alkali is selected from potassium carbonate, cesium carbonate, and potassium phosphate; the palladium catalyst is selected from tetraphenylphosphine palladium, palladium acetate, and diphenylphosphine palladium dichloride; and the solvent is selected from tetrahydrofuran, dioxane, and N,N-dimethylformamide.

[0039] Preferably, the equivalent ratio of the quinoline-2-borate N-phenyldiethanolamine ester to substrate A with halogen or sulfonate active groups is 1.1:1.

[0040] Preferably, the ratio of toluene to water is 1:1.

[0041] The preparation process of the quinoline-2-boronic acid N-phenyldiethanolamine ester:

[0042] Under an inert gas atmosphere, 1 eq of 2-bromoquinoline and 1.1 eq–2.0 eq of triisopropyl borate were dissolved in tetrahydrofuran and added to a reactor vessel. While stirring, the mixture was cooled to -70 to -90 °C and maintained below -70 °C. A hexane solution of 1.1 eq–2.0 eq of n-butyllithium was added dropwise to the system. After the addition was complete, the mixture was allowed to warm naturally to room temperature and stirred for 16–24 h to ensure complete reaction. Then, 1 eq–2.0 eq of N-phenyl Diethanolamine is dissolved in tetrahydrofuran and added to the system. The reaction is then heated to reflux and stirred for 4-8 hours. After the reaction is complete, the solvents tetrahydrofuran and n-hexane in the system are distilled off to replace them with isopropanol. After the replacement is complete, the system is cooled to room temperature and stirred for 12-24 hours. The product will precipitate as a solid. It is then filtered directly, washed with isopropanol, and dried under normal pressure to obtain the desired product, quinoline-2-boronic acid N-phenyldiethanolamine ester, with a yield of up to 80%.

[0043] The preparation process of the 2-phenylquinoline:

[0044] Under an inert gas atmosphere, 1 eq–2 eq of N-phenyldiethanolamine quinoline-2-borate and 1 eq of substrate A with active groups such as halogen (-Cl, -Br, -I) or sulfonate (-Otf) were added to a reactor vessel. Then, 1.5 eq–2 eq of base (potassium carbonate, cesium carbonate, potassium phosphate), 0.01 eq–0.05 eq of palladium catalyst (tetraphenylphosphine palladium, palladium acetate, diphenylphosphine palladium dichloride), 0.2 eq–0.4 eq of cuprous iodide, and 0.04 eq–0.2 eq of triphenylphosphine were added. Finally, solvent (tetrahydrofuran, dioxane, N,N-dimethylformamide) was added. Stirring was started, and the system was heated to 60–120 °C. After holding at this temperature for 12–24 h until the reaction was complete, the system was cooled to room temperature. The original solvent was removed by concentration, and the product was extracted with toluene and water. The toluene phase was passed through a silica gel column to remove the catalyst, and then crystallized with ethanol to obtain product B, with a yield of 60–90%.

[0045] Example 1

[0046] Under an inert gas atmosphere, 20.8 g of 2-bromoquinoline (1 eq) and 28.2 g of triisopropyl borate (1.5 eq) were dissolved in 120 mL of tetrahydrofuran and added to a 500 mL three-necked flask. The mixture was cooled to -70 to -90 °C with stirring, and the temperature was controlled below -70 °C. 60 mL of 2.5 M n-butyllithium in n-hexane solution (1.5 eq) was added dropwise to the system. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 18 h to allow the reaction to proceed completely. Then, 27.2 g of N-phenyldiethanolamine (1.5 eq) was dissolved in 55 mL of tetrahydrofuran and added to the system. The reaction mixture was then heated to reflux and stirred for 6 h. After the reaction was complete, the solvents tetrahydrofuran and n-hexane in the system were distilled off and replaced with isopropanol. After the replacement was completed, the system was cooled to room temperature and stirred for 16 hours. The product precipitated out as a solid. It was directly filtered, washed with isopropanol, and dried at normal pressure to obtain 26.2 g of quinoline-2-boronic acid N-phenyldiethanolamine ester, with a yield of 82%.

[0047] like Figure 1 The image shown is the 1H-NMR spectrum of the quinoline-2-boronic acid N-phenyldiethanolamine ester synthesized in this embodiment.

[0048] Example 2

[0049] Under an inert gas atmosphere, 20.8 g of 2-bromoquinoline (1 eq) and 20.7 g of triisopropyl borate (1.1 eq) were dissolved in 120 mL of tetrahydrofuran and added to a 500 mL three-necked flask. The mixture was cooled to -70 to -90 °C with stirring, and the temperature was controlled below -70 °C. 44 mL of 2.5 M n-butyllithium in n-hexane solution (1.1 eq) was added dropwise to the system. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 24 h to allow the reaction to proceed completely. Then, 19.9 g of N-phenyldiethanolamine (1.1 eq) was dissolved in 40 mL of tetrahydrofuran and added to the system. The reaction mixture was then heated to reflux and stirred for 8 h. After the reaction was complete, the solvents tetrahydrofuran and n-hexane in the system were distilled off to replace them with isopropanol. After the replacement was completed, the system was cooled to room temperature and stirred for 20 hours. The product precipitated out as a solid. It was directly filtered, washed with isopropanol, and dried at normal pressure to obtain 25.4 g of quinoline-2-boronic acid N-phenyldiethanolamine ester, with a yield of 80%.

[0050] Example 3

[0051] Under an inert gas atmosphere, 20.8 g of 2-bromoquinoline (1 eq) and 37.6 g of triisopropyl borate (2.0 eq) were dissolved in 120 mL of tetrahydrofuran and added to a 500 mL three-necked flask. The mixture was cooled to -70 to -90 °C with stirring, and the temperature was controlled below -70 °C. 80 mL of 2.5 M n-butyllithium in n-hexane solution (2.0 eq) was added dropwise to the system. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 16 h to allow the reaction to proceed completely. Then, 36.2 g of N-phenyldiethanolamine (2.0 eq) was dissolved in 70 mL of tetrahydrofuran and added to the system. The reaction mixture was then heated to reflux and stirred for 4 h. After the reaction was complete, the solvents tetrahydrofuran and n-hexane in the system were distilled off and replaced with isopropanol. After the replacement was completed, the system was cooled to room temperature and stirred for 12 hours. The product precipitated out as a solid. It was directly filtered, washed with isopropanol, and dried at normal pressure to obtain 25.8 g of quinoline-2-boronic acid N-phenyldiethanolamine ester, with a yield of 81%.

[0052] Example 4

[0053] Under argon protection, 15.7 g of bromobenzene (1.0 eq) and 35.0 g of N-phenyldiethanolamine quinoline-2-boronic acid (1.1 eq) were weighed into a 500 mL three-necked flask. 27.6 g of potassium carbonate (2.0 eq), 1.15 g of tetraphenylphosphine palladium (0.01 eq), 3.80 g of cuprous iodide (0.2 eq), and 2.62 g of triphenylphosphine (0.1 eq) were added. Finally, 150 mL of tetrahydrofuran was added. Magnetic stirring was started, and the system was heated to 66 °C. After stirring at this temperature for 16 h, a sample was taken to check for complete reaction. The system was cooled to 20 °C and concentrated to remove tetrahydrofuran. 150 mL of toluene and 150 mL of water were added, and the product was extracted by stirring thoroughly. The aqueous phase was discarded after standing and separation. The organic phase was purified by passing the solvent through a silica gel column to remove the catalyst. The purified solvent was concentrated to dryness to obtain a crude solid. The crude solid was recrystallized from ethanol to obtain 18 g of a white solid with a purity of 99%, yielding 88%.

[0054] like Figure 2 The image shown is the 1H-NMR spectrum of the synthesized product in this embodiment.

[0055] Example 5

[0056] Under inert gas protection, 47.8 g of N-phenyldiethanolamine quinoline-2-borate (1.5 eq) and 13.7 g of 4-chlorobenzonitrile (1.0 eq) were added to a 250 mL single-necked flask, followed by 48.9 g of cesium carbonate (1.5 eq), 1.4 g of palladium dichloride dichloride (0.02 eq), 5.7 g of cuprous iodide (0.3 eq), 5.24 g of triphenylphosphine (0.2 eq), and finally 140 mL of dioxane. The mixture was stirred and heated to 102 °C. After 20 h, the reaction was complete. The mixture was cooled to room temperature, concentrated to remove the original solvent, and then the product was extracted with toluene and water. The toluene phase was passed through a silica gel column to remove the catalyst, and then crystallized with ethanol to obtain 18.4 g of a white solid product, with a yield of 80%.

[0057] like Figure 3 The image shown is the 1H-NMR spectrum of the synthesized product in this embodiment.

[0058] Example 6

[0059] Under inert gas protection, 63.8 g of N-phenyldiethanolamine quinoline-2-borate (2.0 eq) and 24 g of 3-methylphenyltrifluoromethanesulfonate (1.0 eq) were added to a 500 mL three-necked flask, followed by 31.8 g of potassium phosphate (1.5 eq), 225 mg of palladium acetate (0.01 eq), 3.8 g of cuprous iodide (0.2 eq), and 1.3 g of triphenylphosphine (0.05 eq). Finally, 200 mL of N,N-dimethylformamide was added, and the mixture was stirred. The system was heated to 120 °C and kept at this temperature for 16 h until the reaction was complete. After cooling the system to room temperature, toluene and water were added to extract the product. The toluene phase was passed through a silica gel column to remove the catalyst, and then crystallized with ethanol to obtain 17.1 g of a white solid product, with a yield of 78%.

[0060] like Figure 4 The image shown is the 1H-NMR spectrum of the synthesized product in this embodiment.

[0061] The reaction principle of this invention is as follows:

[0062]

[0063] This invention discloses a method for preparing quinoline-2-boronate, specifically a method for preparing quinoline-2-boronate N-phenyldiethanolamine ester. A one-pot method is used with a hexane solution of 2-bromoquinoline and n-butyllithium as raw materials, and tetrahydrofuran as solvent. At -70 to -90°C, 2-lithiumquinoline is formed, which is then captured by triisopropyl borate to generate isopropyl-quinoline-2-boronate lithium salt. Without separation, the formed isopropyl-quinoline-2-boronate lithium salt is directly reacted with N-phenyldiethanolamine to generate a new quinoline-2-boronate N-phenyldiethanolamine ester. This invention provides a method for protecting the boric acid at the 2-position of quinoline with an electron-donating macrocycle to form a new quinoline-2-boronate ester, which is simpler, more readily available, and has a higher reaction yield. This invention also provides a method for using quinoline-2-boronate N-phenyldiethanolamine ester in the subsequent Suzuki coupling reaction process, enabling the coupling reaction to proceed smoothly and thus facilitating the construction of fused-ring heterocyclic compounds.

[0064] The entire reaction process of this invention is simple and easy to operate, and the product is easy to separate and purify after completion. The yield can be as high as 80% or more, the preparation cost is greatly reduced, the experiment has good reproducibility, and it has great significance for commercial application.

[0065] The quinoline-2-boronic acid N-phenyldiethanolamine ester prepared by this invention has the same activity as quinoline-2-boronic acid, and is more stable in the Suzuki reaction process. It has improved tolerance to reaction conditions and can withstand more stringent reaction conditions, ensuring the smooth progress of coupling reactions and facilitating the construction of quinoline-based fused-ring heterocyclic compounds.

[0066] The method for preparing quinoline-2-boronic acid N-phenyldiethanolamine ester of the present invention is simple, easy to operate, simple to post-process, has a high yield, can greatly reduce the preparation cost, has great commercial practical significance, and retains the high activity equivalent to boric acid.

[0067] After the preparation of quinoline-2-boronic acid N-phenyldiethanolamine ester in this invention is completed, isopropanol is used for solvent replacement to precipitate the product in high yield.

[0068] The electron-donating macrocycle used in the protection of quinoline-2-boronic acid in this invention is provided by N-phenyldiethanolamine, which has the advantage of giving the borate ester higher stability and good tolerance and reactivity in the subsequent Suzuki reaction.

[0069] The base, palladium catalyst, cuprous iodide, and triphenylphosphine used in this invention are all readily available materials on the market and are inexpensive compared to similar compounds. Furthermore, using this combination can significantly improve catalytic efficiency, shorten reaction time, and has a clear advantage in controlling reaction energy consumption.

[0070] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

[0071] Many other changes and modifications can be made without departing from the concept and scope of this invention. It should be understood that this invention is not limited to the specific embodiments, and the scope of this invention is defined by the appended claims.

Claims

1. A novel process for the preparation of quinoline-2-boronic acid esters, characterized in that, The method comprises the following steps: Step 1: isopropyl-quinoline-2-boronate lithium salt solution is generated from 2-bromoquinoline, triisopropyl borate and n-butyllithium, and the equivalent ratio of the 2-bromoquinoline, triisopropyl borate and n-butyllithium is 1:1.1-2:1.1-2; The step 1 is specifically: under the protection of inert gas, 2-bromoquinoline and triisopropyl borate are dissolved in tetrahydrofuran, and then are added into a reactor, and then are cooled to-70--90 DEG C under stirring, and the temperature is controlled below-70 DEG C, and then n-butyllithium solution in n-hexane is added dropwise into the system, and then the system is naturally warmed to room temperature after the dropwise addition is completed, and then is stirred for 16-24 hours to make the reaction complete, and the amount ratio of the 2-bromoquinoline to tetrahydrofuran is 1g:5-10 mL; Step 2: N-phenyldiethanolamine is added into the isopropyl-quinoline-2-boronate lithium salt solution generated in step 1, and then quinoline-2-boronate N-phenyldiethanolamine ester is generated by reaction, and the equivalent ratio of the isopropyl-quinoline-2-boronate lithium salt and the N-phenyldiethanolamine is 1:1-2; The step 2 is specifically: the N-phenyldiethanolamine is dissolved in tetrahydrofuran, and then is added into the system in step 1, and then the reaction is warmed to reflux state, and then is kept warm and stirred for 4-8 hours, and then quinoline-2-boronate N-phenyldiethanolamine ester system is generated by reaction, and the amount ratio of the N-phenyldiethanolamine to tetrahydrofuran is 1g:1-3 mL.

2. The method for preparing a novel quinoline-2-boronate ester according to claim 1, characterized in that, The post-treatment of the quinoline-2-boronate N-phenyldiethanolamine ester system is: the solvents tetrahydrofuran and n-hexane in the system are distilled, and then are replaced by isopropyl alcohol, and then the system is cooled to room temperature after the replacement is completed, and then is kept warm and stirred for 12-24 hours, and then the product is precipitated in the form of solid, and then is directly filtered, and then is washed with isopropyl alcohol, and then is dried under normal pressure to obtain the required product quinoline-2-boronate N-phenyldiethanolamine ester.

3. The method for preparing a novel quinoline-2-boronate ester according to claim 1, characterized in that, The equivalent ratio of the 2-bromoquinoline, triisopropyl borate and n-butyllithium is 1:1.5:1.5, and the equivalent ratio of the isopropyl-quinoline-2-boronate lithium salt and the N-phenyldiethanolamine is 1:1.

5.

4. A method of using a novel quinoline-2-boronic acid ester, characterized by: The quinoline-2-boronic acid N-phenyl diethanolamine ester prepared by the method of claim 1-3 and the substrate A with halogen or sulfonate active group are added into a reactor under inert gas protection, the base, palladium catalyst, cuprous iodide and triphenylphosphine are added, and finally the solvent is added, the stirring is started, the system is heated to 60-120℃, and after 12-24h, the reaction is completed, the system is cooled to room temperature, the original solvent is removed by concentration, and then the product is extracted by adding toluene and water, the toluene phase is passed through a silica gel column to remove the catalyst, and then the product B is obtained by crystallization with ethanol, the equivalent ratio of the quinoline-2-boronic acid N-phenyl diethanolamine ester and the substrate A is 1-2:1, the equivalent ratio of the quinoline-2-boronic acid N-phenyl diethanolamine ester, the base, the palladium catalyst, the cuprous iodide and the triphenylphosphine is 1-2:1.5-2:0.01-0.05:0.2-0.4:0.04-0.2, and the dosage ratio of the quinoline-2-boronic acid N-phenyl diethanolamine ester and the solvent is 1g:5-10mL, and the structural formula of the substrate A is wherein X is selected from one of -Cl, -Br, -I, -Otf, and R is selected from one of -H, -NO2, -CN, -CHO, -Ar, -Me, -OMe; and the structural formula of the product B is wherein R is one of -H, -NO2, -CN, -CHO, -Ar, -Me, -OMe.

5. A method of using a new quinoline-2-boronic acid ester according to claim 4, characterized by: The base is selected from one of potassium carbonate, cesium carbonate and potassium phosphate, the palladium catalyst is selected from one of tetrakis triphenylphosphine palladium, palladium acetate and dichlorobis(triphenylphosphine)palladium, and the solvent is selected from one of tetrahydrofuran, dioxane and N,N-dimethylformamide.

6. A method of using a new quinoline-2-boronic acid ester according to claim 4, characterized by: The equivalent ratio of the quinoline-2-boronate N-phenyldiethanolamine ester and the substrate A with halogen or sulfonate active group is 1.1:

1.

7. A method of using a new quinoline-2-boronic acid ester according to claim 4, characterized by: The amount ratio of the toluene to water is 1:1.

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