CN117756832A - Synthesis method of quinoline-2-boronic acid pinacol ester - Google Patents
Synthesis method of quinoline-2-boronic acid pinacol ester Download PDFInfo
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- CN117756832A CN117756832A CN202311822694.2A CN202311822694A CN117756832A CN 117756832 A CN117756832 A CN 117756832A CN 202311822694 A CN202311822694 A CN 202311822694A CN 117756832 A CN117756832 A CN 117756832A
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- quinoline
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Abstract
The invention belongs to the technical field of compound synthesis, and particularly discloses a synthesis method of quinoline-2-boronic acid pinacol ester. The synthesis method of quinoline-2-boric acid pinacol ester provided by the invention prepares a quinoline-2-boric acid pinacol ester product by reacting quinoline with trimethyl oxonium tetrafluoroborate, 4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxacyclopentaborane and cesium fluoride. The synthesis method of the quinoline-2-boronic acid pinacol ester provided by the invention is simple to operate, raw materials are easy to obtain, and industrial production is easy to realize.
Description
Technical Field
The invention relates to the technical field of compound synthesis, in particular to a method for synthesizing quinoline-2-boric acid pinacol ester.
Background
Quinoline-2-boronic acid pinacol ester is an important organic compound, can be used as a drug intermediate, is also more and more concerned in the preparation of luminescent materials, and is in continuous increase in demand.
There are many reports on the synthesis of pinacol borate. For example, patent application publication No. CN113372369A discloses a method for preparing pinacol phenylborate, which uses carboxylic ester as a substrate and isonicotinic acid ester as a catalyst to prepare a target product. The patent application publication No. CN110964046A discloses a method for synthesizing 2-nitrobenzoic acid pinacol ester, in which nitrobenzene is used as catalyst B (C 6 F 5 ) 3 Under catalysis, the catalyst reacts with boron trihalide in an ortho-position guiding way, and then pinacol and organic alkali are added into a mixed system to perform an ester forming reaction, so that 2-nitrobenzoic acid pinacol ester is generated. The synthesis of a quinolone antibiotic intermediate is disclosed in the publication No. CN107304198AThe process relates to the synthesis of pinacol borate, which takes pyridine bromide as a raw material and carries out Miyaura reaction with pinacol diboron to prepare the pinacol borate compound.
In view of the year by year increase in demand for pinacol borate compounds, synthesis of pinacol borate compounds has been sought in recent years. The invention aims to provide a novel method for synthesizing quinoline-2-pinacol borate, which is expected to provide more selectivity for synthesizing pinacol borate compounds, and has important significance.
Disclosure of Invention
The invention mainly solves the technical problem of providing a synthesis method of quinoline-2-boric acid pinacol ester, which has simple reaction operation and is expected to realize industrial production.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for synthesizing quinoline-2-boronic acid pinacol ester, the method comprising the steps of:
(1) Quinoline is added into an organic solvent, then the temperature is reduced to-5-0 ℃, trimethyloxonium tetrafluoroborate is added, and the mixture is stirred and reacts for 1-4 hours at-5-0 ℃ to obtain a reaction solution 1;
(2) Adding 4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxacyclopentaborane (a compound shown in formula (1)) into the reaction liquid 1, and then heating to 20-40 ℃ for reaction for 0.5-2 hours to obtain a reaction liquid 2;
(3) And cooling the reaction liquid 2 to-5-0 ℃, adding cesium fluoride, reacting for 3-8 hours at-5-0 ℃, then heating to 20-40 ℃, and continuing to react for 5-15 hours to prepare the quinoline-2-boric acid pinacol ester.
The reaction formula of the synthesis method of quinoline-2-boronic acid pinacol ester provided by the invention is as follows:
as one embodiment of the present invention, all of the steps (1) to (3) are performed under the protection of an inert gas, preferably, the inert gas is nitrogen.
In step (1), as an embodiment of the present invention, the organic solvent is DMF (N, N-dimethylformamide), preferably anhydrous DMF is used.
As one embodiment of the present invention, the molar ratio of the trimethyloxonium tetrafluoroborate to the quinoline is (1.0-1.5): 1, preferably (1.1-1.3): 1.
As one embodiment of the present invention, the molar ratio of the 4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxaborolan to the quinoline is (1.0-2.0): 1, preferably (1.3-1.6): 1.
As one embodiment of the present invention, the molar ratio of cesium fluoride (CsF) to quinoline is (1.5-3.0): 1, preferably (1.8-2.2): 1. The cesium fluoride is preferably anhydrous cesium fluoride.
As a further preferred embodiment of the present invention, the molar ratio of said trimethyloxonium tetrafluoroborate to said quinoline is 1.2:1; and/or the molar ratio of the 4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxaborolan to the quinoline is 1.5:1; and/or the molar ratio of cesium fluoride to quinoline is 2.0:1.
As a specific embodiment of the invention, the synthesis method of the quinoline-2-boronic acid pinacol ester comprises the following steps:
(1) Under the protection of nitrogen, quinoline is added into anhydrous DMF, stirred and cooled to 0 ℃, trimethyloxonium tetrafluoroborate is added, and stirred and reacted for 1-4 hours at 0 ℃ to obtain reaction liquid 1;
(2) Adding 4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxaborolan into the reaction liquid 1, then heating to room temperature (about 25 ℃) and reacting for 0.5-2 hours to obtain a reaction liquid 2;
(3) And cooling the reaction liquid 2 to 0 ℃, adding anhydrous cesium fluoride, controlling the temperature of the reaction liquid to be not more than 0 ℃ in the process of adding the anhydrous cesium fluoride, reacting for 3-8 hours at the temperature of 0 ℃ after the addition, then heating to room temperature (about 25 ℃) and continuously reacting for 5-15 hours to prepare the quinoline-2-boric acid pinacol ester.
The synthesis method of quinoline-2-boronic acid pinacol ester provided by the invention has the advantages of simple reaction operation, easily obtained raw materials and prospect for industrial production.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of a quinoline-2-boronic acid pinacol ester product obtained in example 1 of the present invention.
Detailed Description
The following describes the technical scheme of the present invention in detail by examples.
The raw materials used in the following examples, not specifically described, were all obtained by purchase.
Example 1
The embodiment provides a synthesis method of quinoline-2-boronic acid pinacol ester, which comprises the following preparation steps:
quinoline (12.9 g,0.1 mol) was added to 350mL of anhydrous DMF under nitrogen protection, stirred and cooled to 0 ℃, then trimethyloxonium tetrafluoroborate (17.8 g,0.12 mol) was added in portions, and the mixture was stirred and reacted at 0 ℃ for 2 hours to obtain a reaction solution 1;
4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxaborolan (30.0 g,0.15 mol) was added to the reaction solution 1, and then naturally warmed to room temperature (about 25 ℃ C.) to react for 1 hour to obtain a reaction solution 2;
the reaction solution 2 was cooled to 0℃and then anhydrous cesium fluoride (30.4 g,0.2 mol) was added in portions, the temperature of the reaction solution was controlled to be not higher than 0℃during the addition of anhydrous cesium fluoride, the reaction was carried out at 0℃for 5 hours after the addition, and then the reaction was continued for 10 hours after naturally warming to room temperature (about 25 ℃). The reaction was complete as detected by TLC.
600mL of ethyl acetate and 300mL of water are added into the reaction solution, the mixture is stirred and mixed, then the solution is separated, an oil phase is collected, the oil phase is dried by sodium sulfate, then the solvent is distilled off under reduced pressure, and then the mixture is purified by column chromatography, so that the quinoline-2-pinacol borate with the purity of 96% is obtained, wherein the total amount of the quinoline-2-pinacol borate is 18.9 g. The nuclear magnetic resonance hydrogen spectrum of the target compound quinoline-2-boronic acid pinacol ester is shown in figure 1.
Example 2
The embodiment provides a synthesis method of quinoline-2-boronic acid pinacol ester, which comprises the following preparation steps:
quinoline (12.9 g,0.1 mol) was added to 350mL of anhydrous DMF under nitrogen protection, stirred and cooled to 0 ℃, then trimethyloxonium tetrafluoroborate (16.3 g,0.11 mol) was added in portions, and the mixture was stirred and reacted at 0 ℃ for 2 hours to obtain a reaction solution 1;
4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxaborolan (30.0 g,0.15 mol) was added to the reaction solution 1, and then naturally warmed to room temperature (about 25 ℃ C.) to react for 1 hour to obtain a reaction solution 2;
the reaction solution 2 was cooled to 0℃and then anhydrous cesium fluoride (30.4 g,0.2 mol) was added in portions, the temperature of the reaction solution was controlled to be not higher than 0℃during the addition of anhydrous cesium fluoride, the reaction was carried out at 0℃for 5 hours after the addition, and then the reaction was continued for 10 hours after naturally warming to room temperature (about 25 ℃). The reaction was complete as detected by TLC.
600mL of ethyl acetate and 300mL of water are added into the reaction solution, the mixture is stirred and mixed, then the mixture is separated, an oil phase is collected, the oil phase is dried by sodium sulfate, then the solvent is distilled off under reduced pressure, and then the mixture is purified by column chromatography, so that 17.9g of quinoline-2-pinacol borate with the purity of 95% is obtained.
Example 3
The embodiment provides a synthesis method of quinoline-2-boronic acid pinacol ester, which comprises the following preparation steps:
quinoline (12.9 g,0.1 mol) was added to 350mL of anhydrous DMF under nitrogen protection, stirred and cooled to 0 ℃, then trimethyloxonium tetrafluoroborate (17.8 g,0.12 mol) was added in portions, and the mixture was stirred and reacted at 0 ℃ for 2 hours to obtain a reaction solution 1;
4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxaborolan (24.0 g,0.12 mol) was added to the reaction solution 1, and then naturally warmed to room temperature (about 25 ℃ C.) to react for 1 hour to obtain a reaction solution 2;
the reaction solution 2 was cooled to 0℃and then anhydrous cesium fluoride (30.4 g,0.2 mol) was added in portions, the temperature of the reaction solution was controlled to be not higher than 0℃during the addition of anhydrous cesium fluoride, the reaction was carried out at 0℃for 5 hours after the addition, and then the reaction was continued for 10 hours after naturally warming to room temperature (about 25 ℃). The reaction was complete as detected by TLC.
600mL of ethyl acetate and 300mL of water are added into the reaction solution, the mixture is stirred and mixed, then the mixture is separated, an oil phase is collected, the oil phase is dried by sodium sulfate, then the solvent is distilled off under reduced pressure, and then the mixture is purified by column chromatography, so that 17.2g of quinoline-2-pinacol borate with the purity of 97% is obtained.
Example 4
The embodiment provides a synthesis method of quinoline-2-boronic acid pinacol ester, which comprises the following preparation steps:
quinoline (12.9 g,0.1 mol) was added to 350mL of anhydrous DMF under nitrogen protection, stirred and cooled to 0 ℃, then trimethyloxonium tetrafluoroborate (17.8 g,0.12 mol) was added in portions, and the mixture was stirred and reacted at 0 ℃ for 2 hours to obtain a reaction solution 1;
4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxaborolan (30.0 g,0.15 mol) was added to the reaction solution 1, and then naturally warmed to room temperature (about 25 ℃ C.) to react for 1 hour to obtain a reaction solution 2;
the reaction solution 2 was cooled to 0℃and then anhydrous cesium fluoride (22.8 g,0.15 mol) was added in portions, the temperature of the reaction solution was controlled to be not higher than 0℃during the addition of anhydrous cesium fluoride, the reaction was carried out at 0℃for 5 hours after the addition, and then the reaction was continued for 10 hours after naturally warming to room temperature (about 25 ℃). The reaction was complete as detected by TLC.
600mL of ethyl acetate and 300mL of water are added into the reaction solution, the mixture is stirred and mixed, then the solution is separated, an oil phase is collected, the oil phase is dried by sodium sulfate, then the solvent is distilled off under reduced pressure, and then the mixture is purified by column chromatography, so that the quinoline-2-pinacol borate with the purity of 96% is obtained, wherein the total amount of 17.4 g.
Example 5
The embodiment provides a synthesis method of quinoline-2-boronic acid pinacol ester, which comprises the following preparation steps:
quinoline (129 g,1 mol) was added to 2.5L of anhydrous DMF under nitrogen protection, stirred and cooled to 0 ℃, followed by addition of trimethyloxonium tetrafluoroborate (178 g,1.2 mol) in portions, and stirred at 0 ℃ for 3 hours to give reaction solution 1;
4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxaborolan (300 g,1.5 mol) was added to the reaction solution 1, and then naturally warmed to room temperature (about 25 ℃ C.) to react for 2 hours to obtain a reaction solution 2;
the reaction solution 2 was cooled to 0℃and anhydrous cesium fluoride (304 g,2 mol) was added in portions, the temperature of the reaction solution was controlled to be not higher than 0℃during the addition of anhydrous cesium fluoride, the reaction was carried out at 0℃for 5 hours after the addition, and then the reaction was continued for 12 hours after naturally raising the temperature to room temperature (about 25 ℃). The reaction was complete as detected by TLC.
Ethyl acetate 4L and water 2L were added to the reaction solution, and the mixture was stirred and mixed, followed by separation, oil phase collection, drying of the oil phase over sodium sulfate, and subsequent evaporation of the solvent under reduced pressure, yielding a total of 217g of quinoline-2-boronic acid pinacol ester with a purity of 86%.
The foregoing description is only illustrative of the present invention and is not intended to limit the scope of the invention, and all equivalent modifications made by the teachings of the present invention, or direct or indirect application in other related arts, are included in the scope of the present invention.
Claims (7)
1. A method for synthesizing quinoline-2-boronic acid pinacol ester, which is characterized by comprising the following steps:
(1) Quinoline is added into an organic solvent, then the temperature is reduced to-5-0 ℃, trimethyloxonium tetrafluoroborate is added, and the mixture is stirred and reacts for 1-4 hours at-5-0 ℃ to obtain a reaction solution 1;
(2) Adding 4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxacyclopentaborane into the reaction liquid 1, heating to 20-40 ℃, and reacting for 0.5-2 hours to obtain a reaction liquid 2;
(3) And cooling the reaction liquid 2 to-5-0 ℃, adding cesium fluoride, reacting for 3-8 hours at-5-0 ℃, then heating to 20-40 ℃, and continuing to react for 5-15 hours to prepare the quinoline-2-boric acid pinacol ester.
2. The method according to claim 1, wherein step (1), step (2) and step (3) are all carried out under the protection of an inert gas, preferably nitrogen.
3. The method according to claim 1 or 2, wherein in step (1), the organic solvent is DMF.
4. A method according to any of claims 1-3, characterized in that the molar ratio of the trimethyloxonium tetrafluoroborate to the quinoline is (1.0-1.5): 1, preferably the molar ratio is (1.1-1.3): 1.
5. The method according to claim 4, wherein the molar ratio of 4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxolan borane to quinoline is (1.0-2.0): 1, preferably the molar ratio is (1.3-1.6): 1.
6. The method according to claim 5, characterized in that the molar ratio of cesium fluoride to quinoline is (1.5-3.0): 1, preferably the molar ratio is (1.8-2.2): 1.
7. The method according to any one of claims 1 to 6, wherein the molar ratio of the trimethyloxonium tetrafluoroborate to the quinoline is 1.2:1; and/or the molar ratio of the 4, 5-tetramethyl-2-trimethylsilyl- [1,3,2] dioxaborolan to the quinoline is 1.5:1; and/or the molar ratio of cesium fluoride to quinoline is 2.0:1.
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