A kind of preparation method of diethylmethoxyborane

Abstract

The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing diethylmethoxyborane, comprising the following steps: (1) adding ethylmagnesium bromide solution dropwise to trimethyl borate solution under nitrogen protection, controlling the temperature of the reaction system at 5 to 0°C, and reacting for 2 to 5 hours, and preparing the feed solution after the reaction is completed; wherein the molar ratio of trimethyl borate to ethylmagnesium bromide is 1:1.98 to 2.02; (2) adding ammonium salt suspension dropwise to the feed solution in step (1) under nitrogen protection, controlling the reaction temperature at 25°C, and reacting for 3 to 6 hours, and separating by rectification after the reaction is completed, so as to obtain diethylmethoxyborane. The process is simple and greatly improves the yield and purity of the target product.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing diethylmethoxyborane. Background Art

[0002] Diethylmethoxyborane is often used as a chiral catalyst, asymmetric reducing agent, and free radical reaction initiator in the synthesis of compounds with unique structures. In industry, the synthesis of raw materials such as avastatin, rosuvastatin, fluvastatin, and abiraterone is also inseparable from it. Compared with triethylborane and diethylmethoxyborane, which have similar uses, diethylmethoxyborane is more favored by scientific researchers and industrial production due to its good stability and easy separation, placement, transportation, and use.

[0003] At present, there are many documents and patents reporting the synthesis method of diethylmethoxyborane. Leng Yanguo et al. reported a synthesis process of diethylalkoxyborane in a patent: ethyl Grignard reagent is added dropwise to trimethyl borate solution at ultra-low temperature, then acidic aqueous solution or alkaline aqueous solution is added to quench the unreacted Grignard reagent, the organic phase is extracted and separated, washed with saturated brine and dried over anhydrous magnesium sulfate to obtain diethylboric acid, alcohols and n-heptane are added to reflux, and finally distilled and separated. This process uses aqueous solution to quench the Grignard reagent, and the reaction is violent and rapid to generate a large amount of flammable ethane accompanied by heat release, which is very dangerous. In addition, the product yield is only about 70%. Qin Duwei et al. reported a synthesis process of diethylalkoxyborane in a patent: an ether solution of boron trifluoride reacts with an ethyl Grignard reagent to obtain triethylborane, and then an ether solution of methanol is added dropwise to complete the conversion, and then a stabilizer organic amine compound is added. After the stirring reaction is completed, the solution is separated from the solid to obtain an ether solution of methoxydiethylborane. After low-temperature freezing, solid impurities are precipitated in a white corrugated shape and filtered out. This method uses boron trifluoride as a raw material, which is costly and dangerous. Xie Xianqing et al. reported a synthesis process: ethylmagnesium bromide is synthesized using bromoethane and magnesium with ether as a solvent, and then added dropwise to trimethyl borate at low temperature. The crude steaming fraction is added with methanol and carboxylic acid and heated to reflux for methoxylation reaction, and finally distilled and separated. The crude steaming step of this method requires a sufficiently long time to completely dissociate the complex of methoxymagnesium bromide, diethylmethoxyborane and triethylboron before the boron series can be steamed out, which is time-consuming and energy-intensive. Therefore, in view of the above technical problems, the present invention has developed a preparation method for diethylmethoxyborane. Summary of the invention

[0004] The technical problem to be solved by the present invention is: in view of the deficiencies in the prior art, a method for preparing diethylmethoxyborane is provided. The preparation method has fewer steps and lower energy consumption, and greatly improves the yield of diethylmethoxyborane.

[0005] In order to solve the above technical problems, the technical solution of the present invention is:

[0006] A method for preparing diethylmethoxyborane, comprising the following steps:

[0007] (1) under nitrogen protection, ethylmagnesium bromide solution is added dropwise to trimethyl borate solution, the temperature of the reaction system is controlled at -5 to 0°C, the reaction time is 2 to 5 hours, and the obtained feed solution is used for standby after the reaction is completed; wherein the molar ratio of trimethyl borate to ethylmagnesium bromide is 1:1.98-2.02;

[0008] (2) Under nitrogen protection, the ammonium salt suspension is added dropwise to the feed liquid in step (1), the reaction temperature is controlled at 25° C., the reaction time is 3-6 hours, and after the reaction is completed, diethylmethoxyborane is obtained by distillation and separation.

[0009] As an improved technical solution, the solvent in the trimethyl borate solution and the ethyl magnesium bromide solution in step (1) is an ether solvent or 1,4-dioxane.

[0010] As an improved technical solution, the ether solvent is isobutyl ether, phenethyl ether, diethylene glycol dimethyl ether, isophenyl dimethyl ether, butyl glycidyl ether or n-butyl ether.

[0011] As a preferred technical solution, the ammonium salt in the ammonium salt suspension in step (2) is ammonium chloride, ammonium bromide, ammonium iodide, ammonium acetate, ammonium nitrate or ammonium sulfate.

[0012] As an improved technical solution, the solvent in the ammonium salt suspension in step (2) is isobutyl ether, phenethyl ether, diethylene glycol dimethyl ether, isophenyl dimethyl ether, butyl glycidyl ether, n-butyl ether or 1,4-dioxane.

[0013] As a preferred technical solution, the molar ratio of the ammonium salt in the ammonium salt suspension in step (2) to the trimethyl borate in step (1) is 1.2-1.8:1.

[0014] The reaction equation involved in the present invention is:

[0015] Step (1)

[0016]

[0017] Step (2)

[0018]

[0019] After adopting the above technical solution, the beneficial effects of the present invention are:

[0020] The present invention uses ammonium salt to treat the complex after the ethylation reaction of trimethyl borate and ethyl Grignard reagent, and the ammonia ligand replaces the methoxy magnesium halide ligand. At the same time, the generated methanol also reacts with the triethyl boron byproduct generated by over-substitution to obtain diethyl methoxy borane. The system can directly distill to obtain high-purity diethyl methoxy borane. The process method is simple and greatly improves the yield and purity of the target product. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the nuclear magnetic resonance detection spectrum of diethylmethoxyborane in Example 4 of the present invention. DETAILED DESCRIPTION

[0022] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention. Example 1

[0023] Under nitrogen protection, weigh 20g of trimethyl borate, dilute it with 40mL of isobutyl ether and place it in a -1℃ cold bath for magnetic stirring. Take 190mL of 2.0M ethyl magnesium bromide isobutyl ether solution and slowly drop it into the trimethyl borate solution in a -1℃ cold bath under nitrogen protection. Continue stirring for 2h after the addition to obtain a snow-white paste-like turbid liquid. Weigh 22.6g of ammonium bromide and beat it with 80mL of isobutyl ether to obtain a suspension. Under nitrogen positive pressure protection, add the ammonium bromide suspension dropwise to the above snow-white paste system. After stirring for 3h, use a double-headed needle to transfer the reaction system to the bottom reaction bottle of the distillation tower protected by nitrogen. Distill and separate to obtain 17.90g of diethyl methoxy borane. The product is characterized by only the peak of diethyl methoxy borane using the nuclear magnetic resonance boron spectrum, with a gas phase purity of 99.20% and a yield of 93.48%. Example 2

[0024] Under nitrogen protection, weigh 30g of trimethyl borate, dilute it with 60mL of 1,4-dioxane and place it in a -2℃ cold bath for magnetic stirring. Take 285mL of 2.0M ethyl magnesium iodide in 1,4-dioxane solution and slowly drop it into the trimethyl borate solution in a -2℃ cold bath under nitrogen protection. Continue stirring for 2.5h after the addition to obtain a snow-white viscous turbid liquid. Weigh 54.40g of ammonium iodide and beat it with 90mL of 1,4-dioxane to obtain a suspension. Under nitrogen positive pressure protection, drop the ammonium iodide suspension into the above snow-white viscous turbid liquid. After stirring for 3.5h, use a double-ended needle to transfer the reaction system into the bottom reaction bottle of the distillation tower protected by nitrogen, and separate and obtain 26.77g of diethylmethoxyborane as the product. The product was characterized by only the peak of diethylmethoxyborane using the boron nuclear magnetic resonance spectrum, with a gas phase purity of 99.35% and a yield of 93.35%. Example 3

[0025] Under nitrogen protection, weigh 100g of trimethyl borate, dilute it with 200mL of phenethyl ether and place it in a -3℃ cold bath for magnetic stirring. Take 1900mL of 1.0M ethyl magnesium iodide phenethyl ether solution and slowly drop it into the trimethyl borate solution in a -3℃ cold bath under nitrogen protection. Continue stirring for 3h after the addition to obtain a snow-white viscous turbid liquid. Weigh 72.0g of ammonium chloride and beat it with 300mL of phenethyl ether to prepare a suspension. Under nitrogen positive pressure protection, add the ammonium chloride suspension dropwise to the above-mentioned snow-white viscous turbid liquid. After stirring for 4h, use a double-headed needle to transfer the reaction system to the bottom reaction bottle of the distillation tower protected by nitrogen, and separate and obtain 89.9204g of diethyl methoxy borane by distillation. The product is characterized by only the peak of diethyl methoxy borane using the nuclear magnetic resonance boron spectrum, with a gas phase purity of 99.51% and a yield of 94.22%. Example 4

[0026] Under nitrogen protection, weigh 416g of trimethyl borate, dilute it with 800mL of diethylene glycol dimethyl ether and place it in a 0℃ cold bath for magnetic stirring. Take 8000mL of 1.0M diethylene glycol dimethyl ether solution of ethyl magnesium iodide and slowly drop it into the trimethyl borate solution in a 0℃ cold bath under nitrogen protection. Continue stirring for 3.5h after the addition to obtain a snow-white viscous turbid liquid. Weigh 445g of ammonium acetate and beat it with 1000mL of diethylene glycol dimethyl ether to obtain a suspension. Under nitrogen positive pressure protection, add the ammonium acetate suspension dropwise to the above-mentioned snow-white viscous turbid liquid. After stirring for 4.5h, use a double-ended needle to transfer the reaction system to the bottom reaction bottle of the distillation tower protected by nitrogen, and separate and obtain 386.68g of diethylmethoxyborane as the product by distillation. The product was characterized by only the peak of diethylmethoxyborane using the boron nuclear magnetic resonance spectrum, with a gas phase purity of 99.80% and a yield of 96.51%. Example 5

[0027] Under nitrogen protection, weigh 41.6g trimethyl borate, dilute it with 80mL of isophenyl dimethyl ether and place it in a -4℃ cold bath for magnetic stirring. Take 400mL of 2.0M isophenyl dimethyl ether solution of ethyl magnesium iodide and slowly drop it into the trimethyl borate solution in a -4℃ cold bath under nitrogen protection. After the addition, continue stirring for 4h to obtain a snow-white viscous turbid liquid. Weigh 49.30g of ammonium nitrate and beat it with 160mL of isophenyl dimethyl ether to obtain a suspension. Under nitrogen positive pressure protection, add the ammonium nitrate suspension dropwise to the above snow-white viscous turbid liquid. After stirring for 5h, use a double-headed needle to transfer the reaction system to the bottom reaction bottle of the distillation tower protected by nitrogen, and separate and obtain 37.79g of diethyl methoxy borane. The product is characterized by the nuclear magnetic resonance boron spectrum only for the peak of diethyl methoxy borane, with a gas phase purity of 99.04% and a yield of 93.60%. Example 6

[0028] Under nitrogen protection, weigh 20g of trimethyl borate, dilute it with 60 mL of butyl glycidyl ether and place it in a -5℃ cold bath for magnetic stirring. Take 200mL of 2.0M ethyl magnesium iodide butyl glycidyl ether solution and slowly drop it into the trimethyl borate solution in a -5℃ cold bath under nitrogen protection. After the addition, continue stirring for 4.5h to obtain a snow-white viscous turbid liquid. Weigh 43.24g of ammonium sulfate and beat it with 80mL of butyl glycidyl ether to prepare a suspension. Under nitrogen positive pressure protection, add the ammonium sulfate suspension dropwise to the above snow-white viscous turbid liquid. After stirring for 5.5h, use a double-headed needle to transfer the reaction system to the bottom reaction bottle of the distillation tower protected by nitrogen, and separate and obtain 18.56g of diethyl methoxy borane. The product is characterized by the nuclear magnetic resonance boron spectrum only for the peak of diethyl methoxy borane, with a gas phase purity of 99.00% and a yield of 91.90%. Example 7

[0029] Under nitrogen protection, weigh 40g of trimethyl borate, dilute it with 80mL of n-butyl ether and place it in a 0℃ cold bath for magnetic stirring. Take 152mL of 2.5M n-butyl ether solution of ethyl magnesium iodide and slowly drop it into the trimethyl borate solution in a 0℃ cold bath under nitrogen protection. Continue stirring for 5h after the addition to obtain a snow-white viscous turbid liquid. Weigh 67.86g of ammonium bromide and beat it with 120mL of n-butyl ether to obtain a suspension. Under nitrogen positive pressure protection, add the ammonium bromide suspension dropwise to the above snow-white viscous turbid liquid. After stirring for 6h, use a double-headed needle to transfer the reaction system to the bottom reaction bottle of the distillation tower protected by nitrogen, and separate the product diethyl methoxy borane 35.25g. The product is characterized by the nuclear magnetic resonance boron spectrum only for the peak of diethyl methoxy borane, with a gas phase purity of 99.71% and a yield of 91.33%.

[0030] In order to better prove that the process of the present invention can improve the yield and purity of diethylmethoxyborane, 6 comparative examples are given with reference to Example 4, and the details are shown in the following.

[0031] Comparative Example 1

[0032] The difference from Example 4 is that the reaction temperature of step (1) is -10°C, and the other operations are the same; 36.11 g of diethylmethoxyborane is obtained by distillation separation. The product is characterized by the peaks of diethylmethoxyborane and ethyldimethoxyborane by NMR boron spectrum, with a gas phase purity of 96.85% and a yield of 90.88%.

[0033] Comparative Example 2

[0034] The difference from Example 4 is that the reaction temperature of step (1) is 10°C, and the other operations are the same; 35.02 g of diethylmethoxyborane is obtained by distillation separation. The product is characterized by only the peak of diethylmethoxyborane by NMR boron spectrum, with a gas phase purity of 99.74% and a yield of 90.77%.

[0035] Comparative Example 3

[0036] The difference from Example 4 is that the reaction time of step (2) is 2.5 h, and the other operations are the same. The product diethylmethoxyborane 35.88 g is obtained by distillation separation. The product has peaks of diethylmethoxyborane and ethyldimethoxyborane in the NMR boron spectrum, with a gas phase purity of 97.38% and a yield of 90.80%.

[0037] Comparative Example 4

[0038] The difference from Example 4 is that the reaction time of step (2) is 6.5 h, and the other operations are the same. The product diethylmethoxyborane 36.32 g is obtained by distillation separation. The product is characterized by only the peak of diethylmethoxyborane by NMR boron spectrum, with a gas phase purity of 99.78% and a yield of 94.17%.

[0039] Comparative Example 5

[0040] The difference from Example 4 is that the molar ratio of trimethyl borate to ethylmagnesium bromide in step (1) is 1:1.8, and the other operations are the same; 36.17 g of diethylmethoxyborane is obtained by distillation separation. The peaks of diethylmethoxyborane and ethyldimethoxyborane in the product nuclear magnetic resonance boron spectrum are 89.54% in gas phase purity and 84.16% in yield.

[0041] Comparative Example 6

[0042] The difference from Example 4 is that the molar ratio of trimethyl borate to ethylmagnesium bromide in step (1) is 1:2.1, and the other operations are the same; 34.69 g of diethylmethoxyborane is obtained by distillation separation. The product is characterized by only the peak of diethylmethoxyborane by NMR boron spectrum, with a gas phase purity of 99.66% and a yield of 89.84%.

[0043] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing diethylmethoxyborane, characterized in that: The preparation method comprises the following steps: (1) under nitrogen protection, ethyl magnesium bromide solution is added dropwise to trimethyl borate solution, the temperature of the reaction system is controlled at -5 to 0°C, the reaction time is 2 to 5 hours, and the feed solution obtained after the reaction is completed is used for standby; wherein the molar ratio of trimethyl borate to ethyl magnesium bromide is 1:1.98-2.02; the solvent in the trimethyl borate solution and ethyl magnesium bromide solution is isobutyl ether; or the solvent in the trimethyl borate solution and ethyl magnesium bromide solution is 1,4-dioxane; or the solvent in the trimethyl borate solution and ethyl magnesium bromide solution is phenethyl ether; or the solvent in the trimethyl borate solution and ethyl magnesium bromide solution is diethylene glycol dimethyl ether; or the solvent in the trimethyl borate solution and ethyl magnesium bromide solution is isophenyl dimethyl ether; or the solvent in the trimethyl borate solution and ethyl magnesium bromide solution is butyl glycidol; (2) under nitrogen protection, the ammonium salt suspension is added dropwise to the feed liquid in step (1), the reaction temperature is controlled at 25°C, the reaction time is 3-6h, and after the reaction is completed, diethylmethoxyborane is obtained by distillation separation; when the solvent in the trimethyl borate solution and the ethyl magnesium bromide solution is isobutyl ether, the ammonium salt suspension is a suspension obtained by pulping ammonium bromide and isobutyl ether; when the solvent in the trimethyl borate solution and the ethyl magnesium bromide solution is 1,4-dioxane, the ammonium salt suspension is a suspension obtained by pulping ammonium iodide and 1,4-dioxane; when the trimethyl borate solution and the ethyl magnesium bromide solution are When the solvent in the trimethyl borate solution and the ethyl magnesium bromide solution is phenethyl ether, the ammonium salt suspension is a suspension obtained by pulping ammonium chloride and phenethyl ether; when the solvent in the trimethyl borate solution and the ethyl magnesium bromide solution is diethylene glycol dimethyl ether, the ammonium salt suspension is a suspension obtained by pulping ammonium acetate and diethylene glycol dimethyl ether; or when the solvent in the trimethyl borate solution and the ethyl magnesium bromide solution is isophenyl dimethyl ether, the ammonium salt suspension is a suspension obtained by pulping ammonium nitrate and isophenyl dimethyl ether; when the solvent in the trimethyl borate solution and the ethyl magnesium bromide solution is butyl glycidol, the ammonium salt suspension is a suspension obtained by pulping ammonium sulfate and butyl glycidyl ether.

2. The method for preparing diethylmethoxyborane according to claim 1, characterized in that: The molar ratio of the ammonium salt in the ammonium salt suspension in step (2) to the trimethyl borate in step (1) is 1.2-1.8:1.

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