3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxo boron pentane-2-yl) acrylate

Abstract

The invention discloses a preparation method of 3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxo boron pentane-2-yl) acrylate, and belongs to the technical field of preparation of medical intermediates. According to the invention, bis [(pinacol) boryl] methane and glyoxylate are used as raw materials, and under an alkali condition, 3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxo boron pentane-2-yl) acrylate is synthesized by a one-step method. According to the method, all the raw materials can be conveniently purchased on the market, and the mixed alkali of 2, 2, 6, 6-tetramethylpiperidine lithium and lithium tert-butoxide is adopted, so that the alkali consumption is reduced, the reaction is carried out at a relatively easily reached temperature, meanwhile, the yield is increased, the production cost is reduced, and industrial production is easy.

Description

Technical Field

[0001] The invention relates to a method for preparing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) acrylate, belonging to the technical field of pharmaceutical intermediate preparation. Background Art

[0002] 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) acrylate is an important organic intermediate with a wide range of applications. Acrylate units are widely used in coatings, adhesives, plastics and other fields. Boric acid pinacol ester functional groups can introduce acrylate structural units into various compounds such as medicines, fragrances, pesticides and materials to construct new uses.

[0003] For this product, after searching the literature on the prior art, there are relatively few synthesis methods. Patents and literature [WO2018140876A; WO2023173121A; WO202158416A; New Journal of Chemistry, 2018, 42, 17346; Synthesis, 2024, 56, 1498; Organic and Biomolecular Chemistry, 2015, 13, 7136] report that propiolate and pinacol diboron are reacted with copper catalyst and strong base to generate 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl) acrylate, and the reaction formula is as follows:

[0004]

[0005] Since the method for synthesizing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate is relatively single, it is necessary to conduct in-depth research on the synthesis route of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate to provide a better and more economical process route to meet the growing market demand. Summary of the invention

[0006] In order to overcome the above technical defects, the present invention provides a method for preparing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate. Using bis[(pinacol)boryl]methane and glyoxylate as raw materials, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate is synthesized in one step under alkaline conditions. Wherein: the general structure of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate is as follows:

[0007]

[0008] Wherein, R is selected from methyl, ethyl or tert-butyl.

[0009] The objective of the present invention is achieved through the following technical solutions, and the reaction equation is expressed as follows:

[0010]

[0011] The method comprises the following steps: mixing bis[(pinacol)boryl]methane and a base in a solvent, adding glyoxylate to generate 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)acrylate.

[0012] Preferably, in the above steps, the base is selected from one or both of 2,2,6,6-tetramethylpiperidinium lithium and lithium tert-butoxide. The best condition is a mixed base of 2,2,6,6-tetramethylpiperidinium lithium and lithium tert-butoxide.

[0013] Preferably, in the above steps, the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or cyclopentyl methyl ether.

[0014] Preferably, in the above steps, the glyoxylic acid ester is selected from methyl glyoxylate, ethyl glyoxylate or tert-butyl glyoxylate.

[0015] Preferably, in the above steps, the molar ratio of the glyoxylate, bis[(pinacol)boryl]methane and the base is 1:1-1.6:1-2.

[0016] Preferably, in the above steps, the reaction is carried out under the protection of an inert gas (nitrogen or argon).

[0017] Beneficial effects of the present invention:

[0018] A. The present invention develops a simple and practical synthetic route, all raw materials are cheap and easily available, and the yield is high.

[0019] B. Using glyoxylate and bis[(pinacol)boryl]methane as raw materials, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolpentane-2-yl)acrylate was directly synthesized in one step. The design was reasonable and provided a new route for the synthesis of such compounds.

[0020] C. Using a mixed base of 2,2,6,6-tetramethylpiperidinium lithium and lithium tert-butoxide reduces the amount of base used, allowing the reaction to proceed at a temperature that is easier to reach, while also increasing the yield and reducing production costs. Specific embodiments

[0021] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily think of changes or substitutions within the technical scope disclosed by the present invention, and these shall be within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be subject to the scope of protection described in the claims.

[0022] Example 1

[0023]

[0024] Under argon protection, 2,2,6,6-tetramethylpiperidinium lithium (16.2 g, 0.11 mol) was added to 110 mL of tetrahydrofuran solvent, cooled to 0°C, and a solution of bis[(pinacol)boryl]methane (29.5 g, 0.11 mol) and 220 mL of tetrahydrofuran was slowly added dropwise. After the addition was complete, the system temperature was maintained at 0°C and stirred for 30 minutes. The mixture was then cooled to -78°C, and a solution of methyl glyoxylate (10.6 g, 0.1 mol) and 20 mL of tetrahydrofuran was slowly added dropwise. After the addition was complete, The temperature was slowly raised to room temperature, reacted for 2 hours, quenched by adding 100 mL of saturated aqueous ammonium chloride solution, then 100 mL of water was added, and then extracted twice with 300 mL of ethyl acetate. The organic layers were combined and concentrated. The crude product was purified by column chromatography with an eluent of ethyl acetate / petroleum ether (v / v=1 / 15-20) to give 12.9 g of methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate with a yield of 61% (calculated based on bis[(pinacol)boryl]methane raw material), GC 99.1%. 1 HNMR (400MHz, CDCl3): 6.76 (d, 1H), 6.62 (d, 1H), 3.76 (s, 3H), 1.27 (s, 12H).

[0025] Example 2

[0026]

[0027] Under argon protection, 2,2,6,6-tetramethylpiperidinium lithium (16.2 g, 0.11 mol) was added to 110 mL of tetrahydrofuran solvent, cooled to 0 ° C, and a solution of bis[(pinacol)boryl]methane (29.5 g, 0.11 mol) and 220 mL of tetrahydrofuran was slowly added dropwise. After the addition was complete, the system temperature was maintained at 0 ° C and stirred for 30 minutes, then cooled to -78 ° C, and a solution of tert-butyl glyoxylate (13 g, 0.1 mol) and 20 mL of tetrahydrofuran was slowly added dropwise. After the addition was complete, the system temperature was maintained at 0 ° C and stirred for 30 minutes. Then the temperature was lowered to -78 ° C, and tert-butyl glyoxylate (13 g, 0.1 mol) and 20 mL of tetrahydrofuran were slowly added dropwise. After the addition was complete, the mixture was slowly stirred. The temperature was slowly raised to room temperature, and the reaction was carried out for 4 hours. 100 mL of saturated aqueous ammonium chloride solution was added to quench the mixture, and then 100 mL of water was added. The mixture was then extracted twice with 300 mL of ethyl acetate. The organic layers were combined and concentrated. The crude product was purified by column chromatography with an eluent of ethyl acetate / petroleum ether (v / v=1 / 15-20) to give 17.8 g of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate with a yield of 70% (calculated based on bis[(pinacol)boryl]methane raw material), and GC 99.2%. 1 HNMR (400MHz, CDCl3): 6.69 (d, 1H), 6.58 (d, 1H), 1.48 (s, 9H), 1.27 (s, 12H).

[0028] Example 3

[0029]

[0030] Under argon protection, 2,2,6,6-tetramethylpiperidinium lithium (16.2 g, 0.11 mol) was added to 110 mL of tetrahydrofuran solvent, cooled to 0°C, and a solution of bis[(pinacol)boryl]methane (29.5 g, 0.11 mol) and 220 mL of tetrahydrofuran was slowly added dropwise. After the addition was complete, the system temperature was maintained at 0°C and stirred for 30 minutes. The temperature was then cooled to -78°C, and a solution of ethyl glyoxylate (10.2 g, 0.1 mol) and 20 mL of tetrahydrofuran was slowly added dropwise. After the addition was complete, the temperature was slowly raised. The mixture was warmed to room temperature and reacted for 2 hours. 100 mL of saturated aqueous ammonium chloride solution was added to quench the mixture. 100 mL of water was then added. The mixture was extracted twice with 300 mL of ethyl acetate. The organic layers were combined and concentrated. The crude product was purified by column chromatography with an eluent of ethyl acetate / petroleum ether (v / v=1 / 15-20) to give 14.5 g of ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate with a yield of 64% (calculated based on bis[(pinacol)boryl]methane starting material) and a GC of 99.6%. 1 HNMR (400MHz, CDCl3): 6.74(d,1H), 6.61(d,1H), 4.19(m,2H), 1.25(s,12H), 1.20(m,3H).

[0031] Example 4

[0032]

[0033] Under argon protection, lithium tert-butoxide (13.2 g, 0.165 mol) was added to a solution of bis[(pinacol)boryl]methane (29.5 g, 0.11 mol) and 220 mL of tetrahydrofuran, the temperature was raised to 50° C., stirred for 30 minutes, then cooled to room temperature, a solution of tert-butyl glyoxylate (13 g, 0.1 mol) and 20 mL of tetrahydrofuran was added dropwise, the addition was complete, the reaction was continued for 6 hours, 100 mL of water was added, and then extracted twice with 200 mL of ethyl acetate, the organic layers were combined, concentrated, and the crude product was purified by column chromatography, eluent ethyl acetate / petroleum ether (v / v=1 / 15-20) to obtain 17.8 g of product tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolpentane-2-yl)acrylate, with a yield of 70% (calculated as tert-butyl glyoxylate), GC99%.

[0034] Example 5

[0035]

[0036] Under argon protection, 2,2,6,6-tetramethylpiperidinium lithium (1.5 g, 0.01 mol) and lithium tert-butoxide (8 g, 0.1 mol) were added to 110 mL of tetrahydrofuran solvent, cooled to 0 ° C, and a solution of bis[(pinacol)boryl]methane (29.5 g, 0.11 mol) and 220 mL of tetrahydrofuran was slowly added dropwise. After the addition was completed, the system temperature was maintained at 0 ° C. and stirred for 30 minutes. Then, a solution of tert-butyl glyoxylate (13 g, 0.1 mol) and 20 mL of tetrahydrofuran was slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature, the reaction was carried out for 4 hours, 100 mL of saturated aqueous ammonium chloride solution was added to quench, 100 mL of water was added, and then extracted twice with 300 mL of ethyl acetate. The organic layers were combined and concentrated. The crude product was purified by column chromatography with an eluent of ethyl acetate / petroleum ether (v / v=1 / 15-20) to obtain 20.6 g of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate with a yield of 81% (calculated as tert-butyl glyoxylate) and a GC of 99.1%.

[0037] The operation of Example 5 was adopted, 13 g (0.1 mol) of tert-butyl glyoxylate and bis[(pinacol)boryl]methane (32.2 g, 0.11 mol) were added, and the temperature and the amount of the base were adjusted. The reaction results were as follows:

[0038]

[0039] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate, characterized in that: The method comprises the following steps: mixing bis[(pinacol)boryl]methane and a base in an organic solvent, adding glyoxylate to generate 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane-2-yl)acrylate.

2. The method for preparing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate according to claim 1, characterized in that: The base is selected from one or both of 2,2,6,6-tetramethylpiperidinium lithium and lithium tert-butoxide.

3. The method for preparing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate according to claim 1, characterized in that: The solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or cyclopentyl methyl ether.

4. The method for preparing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate according to claim 1, characterized in that: The glyoxylic acid ester is selected from methyl glyoxylate, ethyl glyoxylate or tert-butyl glyoxylate.

5. The method for preparing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate according to claim 1, characterized in that: The molar ratio of the glyoxylate, bis[(pinacol)boryl]methane and the base is 1:1-1.6:1-2.

6. The method for preparing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate according to claim 1, characterized in that: The reaction was carried out under inert gas protection.

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