CN112174993A - Preparation method of 2, 6-dimethylpyridine-3-boric acid - Google Patents
Preparation method of 2, 6-dimethylpyridine-3-boric acid Download PDFInfo
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- CN112174993A CN112174993A CN202011363877.9A CN202011363877A CN112174993A CN 112174993 A CN112174993 A CN 112174993A CN 202011363877 A CN202011363877 A CN 202011363877A CN 112174993 A CN112174993 A CN 112174993A
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Abstract
The invention discloses a preparation method of 2, 6-dimethylpyridine-3-boric acid, which comprises the following steps: adding 2, 6-dimethyl-3-bromopyridine, a catalyst I and an alkali II into an organic solvent III, and stirring for 6-12h at 80-120 ℃ under uniform stirring to prepare an intermediate 2, 6-dimethyl-3-pyridine boronic acid pinacol ester; adding acid IV into a reaction system without purification treatment, and stirring for 6-12h at 80-120 ℃ to realize hydrolysis of the boric acid ester and purification treatment to obtain a solid product 2, 6-dimethylpyridine-3-boric acid. The method simplifies the production operation process, and adopts a safe and easily-operated one-pot method to efficiently prepare the product 2, 6-dimethylpyridine-3-boric acid. The method is simple and easy to operate, reduces the requirements of production equipment, controls the cost and is more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of synthesis of drug intermediates, and particularly relates to a preparation method of 2, 6-dimethylpyridine-3-boric acid.
Background
2, 6-dimethyl pyridine-3-boric acid is used as an intermediate module of a medicine and a photoelectric material, the preparation is extremely difficult, the price is higher, and the conventional route 2, 6-dimethyl-3-bromopyridine adopts a low-temperature method using butyl lithium, but the method cannot well obtain a product and has low product yield.
Disclosure of Invention
The invention aims to provide a method for efficiently preparing a product 2, 6-dimethylpyridine-3-boric acid by a one-pot method. The method is simple and easy to operate, reduces the requirements of production equipment, controls the cost and is more suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme: a preparation method of 2, 6-dimethylpyridine-3-boric acid is characterized by comprising the following steps:
(1) preparation of intermediate 2, 6-dimethyl-3-pyridineboronic acid pinacol ester: adding 2, 6-dimethyl-3-bromopyridine, diboronic acid pinacol ester, a catalyst I (1-3 percent), a catalyst I and a base II into an organic solvent III, uniformly stirring for 6-12h at 80-120 ℃, and obtaining an intermediate 2, 6-dimethyl-3-pyridineboronic acid pinacol ester after the raw materials are completely reacted by high performance liquid chromatography or TLC plate detection; the molar ratio of the 2, 6-dimethyl-3-bromopyridine to the diboron acid pinacol ester to the catalyst I to the alkali II is 1: 1.0-1.5: (0.01-0.05) to (2-5);
(2) adding acid IV into the reaction system in the step (1) without purification treatment, stirring for 6-12h at 80-120 ℃, stopping stirring, and performing post-treatment to obtain a solid product 2, 6-dimethylpyridine-3-boric acid.
Furthermore, in the step (2), the molar ratio of the 2, 6-dimethyl-3-bromopyridine to the acid IV is 1: 6.0-20.
Further, the post-processing method in the step (2) comprises the following steps: and (3) carrying out suction filtration, washing a filter cake by using ethyl acetate, collecting filtrate, carrying out desolventizing concentration, adding water and sodium bicarbonate to neutralize until a large amount of solid is separated out, filtering and washing to obtain a solid product 2, 6-dimethylpyridine-3-boric acid.
Further, the catalyst I is one or more of palladium acetate, 1' -bis (diphenylphosphino) ferrocene palladium dichloride (II), tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride (II) and palladium chloride.
Further, the alkali II is one or more of triethylamine, sodium carbonate, potassium carbonate, sodium acetate and potassium acetate.
Further, the organic solvent III is one or more of tetrahydrofuran, dioxane, toluene and N, N-dimethylformamide.
Further, the acid IV is an inorganic acid or an organic acid.
Further, the acid IV is an inorganic acid, and the acid IV is one of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. Preferably, hydrochloric acid is used, and the molar ratio of the hydrochloric acid to the 2, 6-dimethyl-3-bromopyridine is (6.0-20) to 1.
Further, the acid IV is an organic acid, and the acid IV is one of acetic acid, p-toluenesulfonic acid, formic acid, sulfonic acid and trifluoroacetic acid.
Compared with the prior art, the invention has the beneficial effects that: the invention discloses a preparation method of 2, 6-dimethylpyridine-3-boric acid, which comprises the following steps: adding 2, 6-dimethyl-3-bromopyridine, a catalyst I and an alkali II into an organic solvent III, and stirring for 6-12h at 80-120 ℃ under uniform stirring to prepare an intermediate 2, 6-dimethyl-3-pyridine boronic acid pinacol ester; adding acid IV into a reaction system without purification treatment, and stirring for 6-12h at 80-120 ℃ to realize hydrolysis of the boric acid ester and purification treatment to obtain a solid product 2, 6-dimethylpyridine-3-boric acid. The method simplifies the production operation process, adopts the one-pot method to efficiently prepare the product 2, 6-dimethylpyridine-3-boric acid, has the advantages of simple method and easy operation, effectively reduces the requirements of production equipment, controls the cost, and is more suitable for industrial production.
Drawings
FIG. 1 shows the NMR spectrum of 2, 6-lutidine-3-boronic acid, a product of the present invention.
Detailed Description
In order that those skilled in the art will better understand the present invention, the following description will be made in conjunction with specific embodiments thereof:
example 1
A preparation method of 2, 6-dimethylpyridine-3-boric acid is characterized by comprising the following steps:
(1) preparation of intermediate 2, 6-dimethyl-3-pyridineboronic acid pinacol ester: adding 2, 6-dimethyl-3-bromopyridine, diboronic acid pinacol ester, a catalyst I (1-3 percent), a catalyst I and a base II into an organic solvent III, uniformly stirring for 6-12h at 80-120 ℃, and obtaining an intermediate 2, 6-dimethyl-3-pyridineboronic acid pinacol ester after the raw materials are completely reacted by high performance liquid chromatography or TLC plate detection; the molar ratio of the 2, 6-dimethyl-3-bromopyridine to the diboron acid pinacol ester to the catalyst I to the alkali II is 1: 1.0-1.5: (0.01-0.05) to (2-5);
(2) adding acid IV into the reaction system in the step (1) without purification treatment, stirring for 6-12h at 80-120 ℃, stopping stirring, and performing post-treatment to obtain a solid product 2, 6-dimethylpyridine-3-boric acid. The post-processing method comprises the following steps: and (3) carrying out suction filtration, washing a filter cake by using ethyl acetate, collecting filtrate, carrying out desolventizing concentration, adding water and sodium bicarbonate to neutralize until a large amount of solid is separated out, filtering and washing to obtain a solid product 2, 6-dimethylpyridine-3-boric acid.
The synthetic route of the invention is as follows:
。
specifically, 2, 6-dimethyl-3-bromopyridine (186.05 g, 1.0 mol), pinacol diboride (304.80 g, 1.2mol, 1.2eq), anhydrous potassium acetate (196.30 g, 2.0mol, 2.0eq), and palladium acetate (2.25g, 0.01mol, 0.01eq) were dissolved in dioxane (70 ml) under a nitrogen atmosphere. The reaction was heated to 120 ℃ for 6 hours. TLC monitoring indicated complete reaction, 200ml of concentrated HCl was added and the reaction was heated to 100 ℃ for an additional 6 hours. The reaction solution is cooled to room temperature, filtered, the filter cake is washed by dioxane, the filtrate is collected, desolventized and concentrated, 300ml of water is added, sodium bicarbonate is neutralized until a large amount of solid is separated out, and the white solid product 101.3g (yield: 67%) is obtained after filtration and washing.
1H NMR (400 MHz,DMSO-d6+D2O) : 7.46-7.48 (d, 1H), 6.56-6.58 (d, IH), 1.93 (s, IH),1.80(s, IH)。
Example 2
2, 6-dimethyl-3-bromopyridine (186.05 g, 1.0 mol), pinacol diboride (304.80 g, 1.2mol, 1.2eq), sodium carbonate (212.00g, 2.0mol, 2.0eq) and tetrakis (triphenylphosphine) palladium (11.56g, 0.01mol, 0.01eq) were added to N, N-dimethylformamide (1000ml) under a nitrogen atmosphere, and heated to 120 ℃ for 6 hours. TLC monitoring indicated complete reaction, 600ml of concentrated HCl was added and the reaction was heated to 100 ℃ for an additional 6 hours. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate, the filtrate was collected, desolventized and concentrated, 500ml of water was added, and sodium bicarbonate was neutralized to precipitate a large amount of solid, which was filtered and washed to obtain 95.2g (yield: 63%) of a white-like solid product.
1H NMR (400 MHz,DMSO-d6+D2O) : 7.46-7.48 (d, 1H), 6.56-6.58 (d, IH), 1.93 (s, IH),1.80(s, IH)。
Example 3
2, 6-dimethyl-3-bromopyridine (186.05 g, 1.0 mol), pinacol diboride (304.80 g, 1.2mol, 1.2eq), sodium carbonate (212.00g, 2.0mol, 2.0eq) and PdCl2(dppf), DCM (24.51g, 0.03mol, 0.03eq) were added to dioxane (1000ml) under nitrogen atmosphere and heated to 120 ℃ for 6 hours. TLC monitoring indicated complete reaction, 600ml of concentrated HCl was added and the reaction was heated to 100 ℃ for an additional 6 hours. The reaction solution is cooled to room temperature, filtered, the filter cake is washed by dioxane, the filtrate is collected, desolventized and concentrated, 500ml of water is added, sodium bicarbonate is neutralized until a large amount of solid is separated out, and the white solid product 86.20g (yield: 57%) is obtained after filtration and washing.
1H NMR (400 MHz,DMSO-d6+D2O) : 7.46-7.48 (d, 1H), 6.56-6.58 (d, IH), 1.93 (s, IH),1.80(s, IH)。
Example 4
2, 6-dimethyl-3-bromopyridine (186.05 g, 1.0 mol), pinacol diboride (304.80 g, 1.2mol, 1.2eq), potassium carbonate (276.42g, 2.0mol, 2.0eq) and PdCl2(dppf), DCM (24.51g, 0.03mol, 0.03eq) were added to toluene (1000ml) under a nitrogen atmosphere and heated to 120 ℃ for 6 hours. TLC monitoring indicated complete reaction, 600ml of concentrated HCl was added and the reaction was heated to 100 ℃ for an additional 6 hours. The reaction solution is cooled to room temperature, filtered, the filter cake is washed by dioxane, the filtrate is collected, desolventized and concentrated, 500ml of water is added, sodium bicarbonate is neutralized until a large amount of solid is separated out, and the white solid product 107.3g (yield: 71%) is obtained after filtration and washing.
1H NMR (400 MHz,DMSO-d6+D2O) : 7.46-7.48 (d, 1H), 6.56-6.58 (d, IH), 1.93 (s, IH),1.80(s, IH)。
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (9)
1. A preparation method of 2, 6-dimethylpyridine-3-boric acid is characterized by comprising the following steps:
(1) preparation of intermediate 2, 6-dimethyl-3-pyridineboronic acid pinacol ester: adding 2, 6-dimethyl-3-bromopyridine, diboronic acid pinacol ester, a catalyst I and an alkali II into an organic solvent III, uniformly stirring for 6-12h at 80-120 ℃, and obtaining an intermediate 2, 6-dimethyl-3-pyridineboronic acid pinacol ester after the raw materials are completely reacted by high performance liquid chromatography or TLC plate detection; the molar ratio of the 2, 6-dimethyl-3-bromopyridine to the diboron acid pinacol ester to the catalyst I to the alkali II is 1: 1.0-1.5: (0.01-0.05) to (2-5);
(2) adding acid IV into the reaction system in the step (1) without purification treatment, stirring for 6-12h at 80-120 ℃, stopping stirring, and performing post-treatment to obtain a solid product 2, 6-dimethylpyridine-3-boric acid.
2. The method for producing 2, 6-lutidine-3-boronic acid according to claim 1, wherein: in the step (2), the molar ratio of the 2, 6-dimethyl-3-bromopyridine to the acid IV is 1: 6.0-20.
3. The method for producing 2, 6-lutidine-3-boronic acid according to claim 2, wherein: the post-processing method in the step (2) comprises the following steps: and (3) carrying out suction filtration, washing a filter cake by using ethyl acetate, collecting filtrate, carrying out desolventizing concentration, adding water and sodium bicarbonate to neutralize until a large amount of solid is separated out, filtering and washing to obtain a solid product 2, 6-dimethylpyridine-3-boric acid.
4. The method for producing 2, 6-lutidine-3-boronic acid according to claim 3, wherein: the catalyst I is one or more of palladium acetate, 1' -bis (diphenylphosphino) ferrocene palladium dichloride (II), tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride (II) and palladium chloride.
5. The method for producing 2, 6-lutidine-3-boronic acid according to claim 3, wherein: the alkali II is one or more of triethylamine, sodium carbonate, potassium carbonate, sodium acetate and potassium acetate.
6. The method for producing 2, 6-lutidine-3-boronic acid according to claim 3, wherein: the organic solvent III is one or more of tetrahydrofuran, dioxane, toluene and N, N-dimethylformamide.
7. The method for producing 2, 6-lutidine-3-boronic acid according to claim 3, wherein: the acid IV is inorganic acid or organic acid.
8. The method of producing 2, 6-lutidine-3-boronic acid according to claim 7, wherein: the acid IV is inorganic acid, and the acid IV is one of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
9. The method of producing 2, 6-lutidine-3-boronic acid according to claim 7, wherein: the acid IV is organic acid, and the acid IV is one of acetic acid, p-toluenesulfonic acid, formic acid, sulfonic acid and trifluoroacetic acid.
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Citations (7)
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| GB814647A (en) * | 1955-06-28 | 1959-06-10 | Shell Res Ltd | A process for the manufacture of organoboron compounds |
| CN102532109A (en) * | 2010-12-27 | 2012-07-04 | 浙江海正药业股份有限公司 | Synthetic method of lapatinib and salt of lapatinib |
| CN103204868A (en) * | 2012-01-14 | 2013-07-17 | 成都爱群科技有限公司 | One-pot method for synthesizing chiral amino boronate intermediate |
| CN103804403A (en) * | 2014-02-24 | 2014-05-21 | 蚌埠中实化学技术有限公司 | Method for preparing 2-hydroxybenzeneboronic acid |
| CN104478917A (en) * | 2014-12-31 | 2015-04-01 | 大连联化化学有限公司 | Synthesis method for 1-substitution-1H-pyrazol-4-boric acid pinacol ester |
| CN106946915A (en) * | 2017-03-16 | 2017-07-14 | 安徽至善新材料有限公司 | A kind of high-purity, method to chlorophenylboronic acid is prepared in high yield |
| CN109790166A (en) * | 2016-06-20 | 2019-05-21 | 诺华股份有限公司 | Imidazopyridine is used for treating cancer |
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2020
- 2020-11-27 CN CN202011363877.9A patent/CN112174993A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB814647A (en) * | 1955-06-28 | 1959-06-10 | Shell Res Ltd | A process for the manufacture of organoboron compounds |
| CN102532109A (en) * | 2010-12-27 | 2012-07-04 | 浙江海正药业股份有限公司 | Synthetic method of lapatinib and salt of lapatinib |
| CN103204868A (en) * | 2012-01-14 | 2013-07-17 | 成都爱群科技有限公司 | One-pot method for synthesizing chiral amino boronate intermediate |
| CN103804403A (en) * | 2014-02-24 | 2014-05-21 | 蚌埠中实化学技术有限公司 | Method for preparing 2-hydroxybenzeneboronic acid |
| CN104478917A (en) * | 2014-12-31 | 2015-04-01 | 大连联化化学有限公司 | Synthesis method for 1-substitution-1H-pyrazol-4-boric acid pinacol ester |
| CN109790166A (en) * | 2016-06-20 | 2019-05-21 | 诺华股份有限公司 | Imidazopyridine is used for treating cancer |
| CN106946915A (en) * | 2017-03-16 | 2017-07-14 | 安徽至善新材料有限公司 | A kind of high-purity, method to chlorophenylboronic acid is prepared in high yield |
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