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Method for preparing phenylboronic acid-2-methyl formate

A technology of methyl benzoate and methyl formate, which is applied in the field of preparing methyl phenylboronic acid-2-formate, and achieves the effects of stable process conditions, simple operation and high yield

Active Publication Date: 2009-09-02
JILIN ASYMCHEM LAB CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The traditional organolithium reagent method is to replace methyl o-bromobenzoate with lithium-bromine exchange reaction with alkyllithium to obtain substituted lithium benzene, then react with borate compounds, and hydrolyze to obtain corresponding substituted phenylboronic acid, but it will Simultaneously, the side reaction of n-butyllithium attacking the functional group of methyl o-bromobenzoate

Method used

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  • Method for preparing phenylboronic acid-2-methyl formate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] In the 72L reaction flask, add 19.9kg tetrahydrofuran (1g / 7ml), 3.2kg methyl o-bromobenzoate (1.0eq) and 3.36kg isopropyl borate (1.2eq) at one time, after the addition is complete, start stirring, and the system Cool down to -88~-82°C, and add 4.6kg (1.1eq) of 2.5M n-butyllithium dropwise at -88~-82°C. After the drop is complete, the system is kept at -88~-82°C for 3 hours. The response is complete. The system was terminated with acetic acid. After the termination, the system was warmed up to -35~-30°C, and the pH of the system was adjusted to 1~2 with 18% dilute hydrochloric acid, and then the pH was adjusted to 5~6 with saturated sodium bicarbonate solution. Separate the liquid, extract the aqueous phase with isopropyl acetate, combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to a certain extent, add petroleum ether to the system, and then cool down the system for -2 to 2 ℃, stirred and crystallized...

Embodiment 2

[0029] In a 20L reaction flask, add 8.17kg methyl tert-butyl ether (1g / 5ml), add 2.15kg methyl o-bromobenzoate (1.0eq) and 1.90kg triethyl borate (1.3eq) at one time, and the addition is complete , the system was cooled to -88~-82°C, and 2.5M n-butyllithium 3.36kg (1.2eq) was added dropwise at -88~-82°C. After the addition was complete, the reaction was complete after 2 hours. After completion, return the system to -35~-30℃, adjust the pH of the system to 1~2 with dilute hydrochloric acid, then adjust the pH of the system to 5~6 with saturated sodium bicarbonate solution, let stand to separate the liquids, and wash the organic phase with brine , dried over anhydrous sodium sulfate, filtered, concentrated, cooled to crystallize, filtered with suction, dried at 40-45°C to obtain 0.94kg of the product. Yield 52.2%, liquid chromatography purity (HPLC): 98.0%.

Embodiment 3

[0031] Into the 350L reactor, pump 101.48kg of 2-methyltetrahydrofuran (1g / 10ml) into the system at one time, add 11.8kg of methyl o-bromobenzoate (1.0eq) and 5.7kg of trimethyl borate (1.0eq) After the addition, start stirring, cool down the system to -88~-82°C, and add 16.2kg (1.05eq) of 2.5M n-butyllithium dropwise at -88~-82°C. (3h), terminate the reaction with citric acid, after the termination, return the system to -35~-30°C, adjust the pH of the system to 1~2 with dilute hydrochloric acid, and then continue to adjust the pH of the system to 5~5 with saturated sodium bicarbonate solution 6. Stand still for liquid separation, wash the organic phase with brine, dry over anhydrous sodium sulfate, filter, concentrate, cool down to crystallize, filter with suction, and dry at 40-45°C to obtain 5.76kg of the product. Yield 58.2%, liquid chromatography purity (HPLC): 99.1%.

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Abstract

The invention relates to a method for preparing phenylboronic acid-2-methyl formate. A starting material is a commercial raw material on the market or easy-to-prepare bromobenzoic acid methyl ester; and under a condition of low temperature, n-butyl lithium is dripped into a mixture of the main raw material of bromobenzoic acid methyl ester and a boric acid ester compound to form the phenylboronic acid-2-methyl formate through hydrolysis. The method has the advantages of readily available raw materials, high reaction purity and yield, stable process conditions, simple operation and suitability for large-scale production and provides a new thought and means for preparing the phenylboronic acid-2-methyl formate.

Description

(1) Technical field: [0001] The invention relates to a method for preparing methyl phenylboronic acid-2-formate. (two) background technology: [0002] Phenylboronic acid-2-methyl carboxylate is an important intermediate for the preparation of new antihypertensive drugs and the drug Losartan for the treatment of diabetic nephropathy; it is also an important organic synthesis intermediate and pharmaceutical and pesticide intermediates, widely used in Suzuki cross-coupling Reactions, asymmetric synthesis of amino acids, amino compound catalysts, etc., are also widely used in the synthesis of drugs and asymmetric catalysts, and also have very important applications in sugar sensors, substance separation and purification, and drug controlled release systems. Therefore, it is of great significance to develop a high-efficiency, low-cost synthesis process of phenylboronic acid-2-methyl carboxylate. [0003] At present, the methods for preparing phenylboronic acid compounds mainly c...

Claims

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Application Information

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IPC IPC(8): C07F5/04
Inventor 洪浩韦建王美娟
Owner JILIN ASYMCHEM LAB CO LTD
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