CN103804403A - Method for preparing 2-hydroxybenzeneboronic acid - Google Patents
Method for preparing 2-hydroxybenzeneboronic acid Download PDFInfo
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- CN103804403A CN103804403A CN201410063438.4A CN201410063438A CN103804403A CN 103804403 A CN103804403 A CN 103804403A CN 201410063438 A CN201410063438 A CN 201410063438A CN 103804403 A CN103804403 A CN 103804403A
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Abstract
The invention provides a method for preparing 2-hydroxybenzeneboronic acid, which relates to the technical field of industrial production for 2-hydroxybenzeneboronic acid. The method is characterized by comprising the following steps of: selecting raw material phenol which is already commercialized in the market as an initial raw material, in a normal-temperature condition, protecting hydroxyl at first, and then directly dripping n-butyllithium in the mixture of protected hydroxyl intermediate and borate compounds without separating crude products, and after the reaction is finished, hydrolyzing to prepare 2-hydroxybenzeneboronic acid. The method is easily-available in raw materials, high in both the purity and yield of the reaction product, stable in process conditions, simple to operate and suitable for large-scale production, and provides novel thinking and method for preparing 2-hydroxybenzeneboronic acid.
Description
Technical field
The present invention relates to 2-hydroxybenzene boric acid industrial production technology field, be specifically related to a kind of method of the 2-of preparation hydroxybenzene boric acid.
Background technology
2-hydroxybenzene boric acid is the important molecule fragment of preparing novel therapeutic diabetes medicament, is also important organic synthesis medicine, pesticide intermediate simultaneously, is widely used in Suzuki cross-coupling reaction, is the key intermediate of preparation 2-hydroxyl biphenyl compound.Therefore, develop a kind of high benefit, 2-hydroxybenzene boric acid synthesis technique is significant cheaply.
Present stage, the method for preparing 2-hydroxybenzene boric acid mainly contains following several:
1, take 2-hydroxybenzene pinacol borate as raw material [Tetrahedron Letters, Vol.45,2004, p6657-6660] is 2-hydroxybenzene boric acid with hydrochloric acid hydrolysis in acetonitrile solvent.Although the method bibliographical information molar yield is up to 95%, raw material 2-hydroxybenzene pinacol borate is difficult for obtaining and is expensive, is not suitable for suitability for industrialized production.
2, [the Tetrahedron Letters take 2-bromophenol as raw material, Vol.51,2010, p2335-2338.Journal of Medicinal Chemistry, Vol.56,2013, p6626-6637], in ether or tetrahydrofuran solvent, add boric acid ester compound and n-Butyl Lithium reaction, hydrolysis afterwards generates 2-hydroxybenzene boric acid.The method is prepared the 2-hydroxybenzene boric acid of 1 mole, at least needs to consume the n-Butyl Lithium of 2 moles, and production cost is significantly raise, and raw material 2-bromophenol price is higher, is not suitable for large-scale industrial production 2-hydroxybenzene boric acid.
Summary of the invention
The object of the present invention is to provide a kind of method of the 2-of preparation hydroxybenzene boric acid; it is initial feed that the method is selected business-like raw material phenol on market; raw material is easy to get; product yield is higher; with low cost, stable process conditions, simple to operate; be applicable to large-scale production, for preparation 2-hydroxybenzene boric acid provides a kind of new thinking and method.
Technical problem to be solved by this invention realizes by the following technical solutions:
A kind of method of preparing 2-hydroxybenzene boric acid, it is characterized in that, selecting raw material phenol is initial feed, under the condition of normal temperature, first protect hydroxyl, then crude product, without separation, directly splashes into n-Butyl Lithium in the hydroxy intermediate of protection and the mixture of boric acid ester compound, is prepared into 2-hydroxybenzene boric acid after completion of the reaction through hydrolysis;
The concrete preparation process of reaction process is as follows:
(1) protection hydroxyl: add raw material phenol and hydroxy-protecting agent in reactor, start stirring, add catalyzer to start reaction, the weight ratio scope of phenol and hydroxy-protecting agent is 0.5 to 2.0, and the weight ratio scope of catalyzer and phenol is 0.1% to 5%;
(2) boration: after protection hydroxyl reaction, low-boiling-point substance in reactor is distilled and removed under negative pressure, add ether solvent and boric acid ester compound, system is cooled to-80 to-60 ℃, and in-80 to-60 ℃, drip the hexane solution of n-Butyl Lithium, drip and finish, insulation reaction in-80 to-30 ℃; Wherein the mol ratio of boric acid ester compound and phenol is 1.0 to 1.5, and the mol ratio of n-Butyl Lithium and phenol is 1.0 to 2.0, and soaking time is 2 to 8 hours;
(3) termination reaction: drip water and sour termination reaction at-30 to 0 ℃, pH value scope is 1-3, then system is warming up to 15 to 30 ℃ of reaction 1-3 hour;
(4) aftertreatment: acid adjustment is finished, and low-boiling-point substance in reactor is distilled and removed under negative pressure, and residuum is thick product, adds water, and backflow 1-3 hour, is cooled to 0 to 10 ℃, suction filtration, in 50 to 80 ℃ of oven dry, obtain product sterling.
Further, in step (1), hydroxy-protecting agent used is dihydropyrane, and catalyzer is pyridine toluenesulfonate; In step (2), ether solvent comprises ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran and methyl tertiary butyl ether, and boric acid ester compound comprises trimethyl borate, triisopropyl borate ester and tributyl borate; In step (3), acid comprises acetic acid, hydrochloric acid and sulfuric acid.
Further, step (1) hydroxy-protecting agent used is dihydropyrane, and catalyzer is pyridine toluenesulfonate, and the weight ratio of phenol and hydroxy-protecting agent is 1.0, and the weight ratio of catalyzer and phenol is 1%; In step (2), ether solvent comprises tetrahydrofuran (THF) or 2-methyltetrahydrofuran, and boric acid ester compound comprises trimethyl borate or triisopropyl borate ester, and wherein the mol ratio of boric acid ester compound and phenol is 1.2, and the mol ratio of n-Butyl Lithium and phenol is 1.2; In step (3), acid comprises hydrochloric acid or sulfuric acid.
Further, step (1) hydroxy-protecting agent used is dihydropyrane, and catalyzer is pyridine toluenesulfonate, and the weight ratio of phenol and hydroxy-protecting agent is 1.0, and the weight ratio of catalyzer and phenol is 1%; In step (2), ether solvent is tetrahydrofuran (THF), and boric acid ester compound is trimethyl borate, and wherein the mol ratio of boric acid ester compound and phenol is 1.2, and the mol ratio of n-Butyl Lithium and phenol is 1.2; In step (3), acid is hydrochloric acid.
The invention has the beneficial effects as follows:
1, the present invention adopts raw material cheap and easy to get, has significantly reduced production cost, can meet the needs of large-scale production;
2, hydroxyl protection of the present invention reaction is reacted two steps and is combined into a step (one kettle way) with boration, has saved intermediate purification step, meets the theory of Green Chemistry, has reduced the harm of environmental pollution, and has saved production cost;
3, the 2-hydroxybenzene boric acid yield that prepared by the method for the invention is higher, with low cost, and stable process conditions is simple to operate, facilitates enterprise's scale operation.
Embodiment
For technique means, creation characteristic that the present invention is realized, reach object and effect is easy to understand, below in conjunction with specific embodiment, further set forth the present invention, but following embodiment is only the preferred embodiments of the present invention, not all.Based on the embodiment in embodiment, those skilled in the art are other embodiment that obtains under the prerequisite of not making creative work, all belongs to protection scope of the present invention.
Embodiment 1:
10 liters of glass reactors are joined mechanical stirring, thermometer, constant pressure funnel, under nitrogen protection, add raw material phenol 940g, dihydropyrane 940g, adds catalyzer pyridine toluenesulfonate 94g under stirring, react 8 hours, 60 ℃ of underpressure distillation, remove low-boiling-point substance in system, in reaction flask, add 3000g tetrahydrofuran (THF) afterwards, with respect to the triisopropyl borate ester of phenol 1.2 equivalents, be cooled to-80 ℃, drip the n-Butyl Lithium with respect to phenol 1.5 equivalents, drip Bi Jixu-80 ℃ of reactions 8 hours, reaction solution is slowly warming up to-30 ℃, in system, add 2000g water, with hydrochloric acid adjust pH to 1, 30 ℃ of reactions 2 hours, 60 ℃ of underpressure distillation, remove system internal solvent, 3000g adds water, reflux 2 hours, be cooled to 5 ℃, suction filtration, obtain white product wet product, obtain product in 80 ℃ of oven dry, molar yield (in phenol) 73%.
Embodiment 2:
10 liters of glass reactors are joined mechanical stirring, thermometer, constant pressure funnel, under nitrogen protection, add raw material phenol 940g, dihydropyrane 940g, adds catalyzer pyridine tosilate 94g under stirring, react 8 hours, 60 ℃ of underpressure distillation, remove low-boiling-point substance in system; In reaction flask, add 3000g tetrahydrofuran (THF) afterwards, with respect to the trimethyl borate of phenol 1.2 equivalents, be cooled to-80 ℃, drip the n-Butyl Lithium with respect to phenol 1.5 equivalents, drip Bi Jixu-80 ℃ of reactions 8 hours, reaction solution is slowly warming up to-30 ℃, in system, add 2000g water, with hydrochloric acid adjust pH to 1,30 ℃ of reactions 2 hours, 60 ℃ of underpressure distillation, remove system internal solvent, the 3000g that adds water, refluxes 2 hours, is cooled to 5 ℃, suction filtration, obtain white product wet product, obtain product in 80 ℃ of oven dry, molar yield (in phenol) 81%.
Embodiment 3:
10 liters of glass reactors are joined mechanical stirring, thermometer, constant pressure funnel; under nitrogen protection, add raw material phenol 940g, dihydropyrane 940g, adds catalyzer pyridine tosilate 94g under stirring; react 8 hours, 60 ℃ of underpressure distillation, remove low-boiling-point substance in system.In reaction flask, add 3000g tetrahydrofuran (THF) afterwards, with respect to the trimethyl borate of phenol 1.2 equivalents, be cooled to-80 ℃, drip the n-Butyl Lithium with respect to phenol 1.2 equivalents, drip Bi Jixu-80 ℃ of reactions 8 hours, reaction solution is slowly warming up to-30 ℃, in system, add 2000g water, with hydrochloric acid adjust pH to 1,30 ℃ of reactions 2 hours, 60 ℃ of underpressure distillation, remove system internal solvent, the 3000g that adds water, refluxes 2 hours, is cooled to 5 ℃, suction filtration, obtain white product wet product, obtain product in 80 ℃ of oven dry, molar yield (in phenol) 83%.
As can be seen here, in the present invention, the method for the disclosed 2-of preparation hydroxybenzene boric acid can obtain the target product of high yield, and synthetic method raw material is easy to get; with low cost, stable process conditions, simple to operate; be applicable to large-scale production, for preparation 2-hydroxybenzene boric acid provides a kind of new thinking and method.
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what in above-described embodiment and specification sheets, describe is only preference of the present invention; be not used for limiting the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (4)
1. prepare the method for 2-hydroxybenzene boric acid for one kind, it is characterized in that, selecting raw material phenol is initial feed, under the condition of normal temperature, first protect hydroxyl, then crude product, without separation, directly splashes into n-Butyl Lithium in the hydroxy intermediate of protection and the mixture of boric acid ester compound, is prepared into 2-hydroxybenzene boric acid after completion of the reaction through hydrolysis;
The concrete preparation process of reaction process is as follows:
(1) protection hydroxyl: add raw material phenol and hydroxy-protecting agent in reactor, start stirring, add catalyzer to start reaction, the weight ratio scope of phenol and hydroxy-protecting agent is 0.5 to 2.0, and the weight ratio scope of catalyzer and phenol is 0.1% to 5%;
(2) boration: after protection hydroxyl reaction, low-boiling-point substance in reactor is distilled and removed under negative pressure, add ether solvent and boric acid ester compound, system is cooled to-80 to-60 ℃, and in-80 to-60 ℃, drip the hexane solution of n-Butyl Lithium, drip and finish, insulation reaction in-80 to-30 ℃; Wherein the mol ratio of boric acid ester compound and phenol is 1.0 to 1.5, and the mol ratio of n-Butyl Lithium and phenol is 1.0 to 2.0, and soaking time is 2 to 8 hours;
(3) termination reaction: drip water and sour termination reaction at-30 to 0 ℃, pH value scope is 1-3, then system is warming up to 15 to 30 ℃ of reaction 1-3 hour;
(4) aftertreatment: acid adjustment is finished, and low-boiling-point substance in reactor is distilled and removed under negative pressure, and residuum is thick product, adds water, and backflow 1-3 hour, is cooled to 0 to 10 ℃, suction filtration, in 50 to 80 ℃ of oven dry, obtain product sterling.
2. the method for preparing 2-hydroxybenzene boric acid according to claim 1, is characterized in that: in step (1), hydroxy-protecting agent used is dihydropyrane, and catalyzer is pyridine toluenesulfonate; In step (2), ether solvent comprises ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran and methyl tertiary butyl ether, and boric acid ester compound comprises trimethyl borate, triisopropyl borate ester and tributyl borate; In step (3), acid comprises acetic acid, hydrochloric acid and sulfuric acid.
3. the method for preparing 2-hydroxybenzene boric acid according to claim 1, it is characterized in that: step (1) hydroxy-protecting agent used is dihydropyrane, catalyzer is pyridine toluenesulfonate, and the weight ratio of phenol and hydroxy-protecting agent is 1.0, and the weight ratio of catalyzer and phenol is 1%; In step (2), ether solvent comprises tetrahydrofuran (THF) or 2-methyltetrahydrofuran, and boric acid ester compound comprises trimethyl borate or triisopropyl borate ester, and wherein the mol ratio of boric acid ester compound and phenol is 1.2, and the mol ratio of n-Butyl Lithium and phenol is 1.2; In step (3), acid comprises hydrochloric acid or sulfuric acid.
4. the method for preparing 2-hydroxybenzene boric acid according to claim 1, it is characterized in that, step (1) hydroxy-protecting agent used is dihydropyrane, and catalyzer is pyridine toluenesulfonate, the weight ratio of phenol and hydroxy-protecting agent is 1.0, and the weight ratio of catalyzer and phenol is 1%; In step (2), ether solvent is tetrahydrofuran (THF), and boric acid ester compound is trimethyl borate, and wherein the mol ratio of boric acid ester compound and phenol is 1.2, and the mol ratio of n-Butyl Lithium and phenol is 1.2; In step (3), acid is hydrochloric acid.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896974A (en) * | 2014-04-11 | 2014-07-02 | 北京乐威泰克医药技术有限公司 | Method for preparing 2-hydroxyphenylboronic acid |
| CN104788483A (en) * | 2015-01-23 | 2015-07-22 | 沧州普瑞东方科技有限公司 | A method of preparing phenylboronic acid ortho- meta- and para-substituted with hydroxy and mercapto |
| CN107011368A (en) * | 2016-08-29 | 2017-08-04 | 苏州健雄职业技术学院 | A kind of preparation method of the hydroxyl phenyl boric acid of 3 methoxyl group 2 |
| CN111072698A (en) * | 2019-12-28 | 2020-04-28 | 沧州普瑞东方科技有限公司 | Preparation method of hydroxyphenylboronic acid |
| CN112174993A (en) * | 2020-11-27 | 2021-01-05 | 郑州萃智医药科技有限公司 | Preparation method of 2, 6-dimethylpyridine-3-boric acid |
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| CN1151117A (en) * | 1994-04-29 | 1997-06-04 | 得克萨斯生物技术公司 | Binding of E-selectin, P-selectin or L-selectin to sialyl-Lewis(x) or sialyl-lewis(a) |
| WO2000009512A2 (en) * | 1998-08-17 | 2000-02-24 | Eukarion, Inc. | Bipyridine manganese complexes |
| WO2003091262A1 (en) * | 2002-04-24 | 2003-11-06 | Symyx Technologies, Inc. | Bridged bi-aromatic ligands, complexes, catalysts and processes for polymerizing and poymers therefrom |
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Patent Citations (3)
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| CN1151117A (en) * | 1994-04-29 | 1997-06-04 | 得克萨斯生物技术公司 | Binding of E-selectin, P-selectin or L-selectin to sialyl-Lewis(x) or sialyl-lewis(a) |
| WO2000009512A2 (en) * | 1998-08-17 | 2000-02-24 | Eukarion, Inc. | Bipyridine manganese complexes |
| WO2003091262A1 (en) * | 2002-04-24 | 2003-11-06 | Symyx Technologies, Inc. | Bridged bi-aromatic ligands, complexes, catalysts and processes for polymerizing and poymers therefrom |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896974A (en) * | 2014-04-11 | 2014-07-02 | 北京乐威泰克医药技术有限公司 | Method for preparing 2-hydroxyphenylboronic acid |
| CN104788483A (en) * | 2015-01-23 | 2015-07-22 | 沧州普瑞东方科技有限公司 | A method of preparing phenylboronic acid ortho- meta- and para-substituted with hydroxy and mercapto |
| CN107011368A (en) * | 2016-08-29 | 2017-08-04 | 苏州健雄职业技术学院 | A kind of preparation method of the hydroxyl phenyl boric acid of 3 methoxyl group 2 |
| CN111072698A (en) * | 2019-12-28 | 2020-04-28 | 沧州普瑞东方科技有限公司 | Preparation method of hydroxyphenylboronic acid |
| CN112174993A (en) * | 2020-11-27 | 2021-01-05 | 郑州萃智医药科技有限公司 | Preparation method of 2, 6-dimethylpyridine-3-boric acid |
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| CN103804403B (en) | 2016-05-18 |
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Denomination of invention: Method for preparing 2-hydroxybenzeneboronic acid Effective date of registration: 20170728 Granted publication date: 20160518 Pledgee: Bengbu financing guarantee Group Co., Ltd. Pledgor: China Synchem Technology Co., Ltd. Registration number: 2017340000130 |
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Denomination of invention: Method for preparing 2-hydroxybenzeneboronic acid Effective date of registration: 20180904 Granted publication date: 20160518 Pledgee: CITIC Bank Limited by Share Ltd Bengbu branch Pledgor: China Synchem Technology Co., Ltd. Registration number: 2018340000450 |