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Synthesis method for 1-substitution-1H-pyrazol-4-boric acid pinacol ester

A technology of pinacol ester and synthesis method, which is applied in the field of preparation of 1-substituted-1H-pyrazole-4-boronic acid pinacol ester, can solve problems such as difficult operation, expensive cost of pinacol borane and catalyst, etc. problem, to achieve the effect of low cost and simple reaction operation

Inactive Publication Date: 2015-04-01
DALIAN NETCHEM CHIRAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The shortcoming of this method is that pinacol borane and catalyzer are relatively expensive and costly, and difficult to operate

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] A method for preparing 1-substituted-1H-pyrazole-4-boronic acid pinacol ester, taking 1,3-dimethylpyrazole-4-boronic acid pinacol ester as an example:

[0027] 1,3-Dimethyl-4-bromopyrazole (50g, 0.286mol), tetrahydrofuran (420g) and triisopropyl borate (64.5g, 0.343mol) were placed in a four-necked flask, and the temperature was controlled at -65 o C to -80 o C, add n-hexyllithium (195ml, 0.429mol) dropwise, GC central control, after the reaction of the raw material 1,3-dimethyl-4-bromopyrazole, add pinacol (50.6g, 0.429mol), naturally Warm up to 25 o C, stirred for 2.5 hours, quenched with water, cooled to -30 o C, add glacial acetic acid to acidify and stir for 3 hours, add solid sodium carbonate to adjust the pH to 7. Extracted 3 times with 100ml of ethyl acetate, washed the combined oil phase with 100ml of water 3 times, dried with anhydrous magnesium sulfate, suction filtered, and rotary evaporated to obtain off-white solid, which was beaten with n-heptane and s...

Embodiment 2

[0029] A method for preparing 1-substituted-1H-pyrazole-4-boronic acid pinacol ester, 1,3-dimethylpyrazole-4-boronic acid pinacol ester is an example:

[0030] 1,3-Dimethyl-4-bromopyrazole (50g, 0.286mol), tetrahydrofuran (420g) and trimethyl borate (35.6g, 0.343mol) were placed in a four-necked flask, and the temperature was controlled at -70 o C to -80 o C, add n-hexyllithium (169ml, 0.372mol) dropwise, GC central control, after the reaction of the raw material 1,3-dimethyl-4-bromopyrazole is completed, add pinacol (43.8g, 0.372mol), naturally Warm up to 25 o C, stirred for 2.5 hours, quenched with water, cooled to -30 o C, add glacial acetic acid to acidify and stir for 3 hours, add solid sodium carbonate to adjust the pH to 7. Extracted 3 times with 100ml of ethyl acetate, washed the combined oil phase with 100ml of water 3 times, dried with anhydrous magnesium sulfate, suction filtered, and rotary evaporated to obtain off-white solid, which was beaten with n-heptane an...

Embodiment 3

[0032] A method for preparing 1-substituted-1H-pyrazole-4-boronic acid pinacol ester, 1-isopropylpyrazole-4-boronic acid pinacol ester is an example:

[0033] Put 1-isopropyl-4-bromopyrazole (54.1g, 0.286mol), tetrahydrofuran (420g) and triisopropyl borate (64.5g, 0.343mol) in a four-necked flask, and control the temperature at -70 o C to -80 o C, add n-hexyllithium (195ml, 0.429mol) dropwise, and control in GC. After the reaction of the raw material 1-isopropyl-4-bromopyrazole is completed, add pinacol (50.6g, 0.429mol), and naturally heat up to 25 o C, stirred for 3 hours, quenched by adding 50ml of water, cooled to -30 o C, add glacial acetic acid to acidify and stir for 3 hours, add solid sodium carbonate to adjust the pH to 7. Extract 3 times with 100ml of ethyl acetate, wash the combined oil phase with 100ml of water 3 times, dry with anhydrous magnesium sulfate, filter with suction, and rotary evaporate to obtain off-white solid, beat with n-heptane and filter with s...

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Abstract

The invention discloses a synthesis method for 1-substitution-1H-pyrazol-4-boric acid pinacol ester. According to the method, 1-substitution-4-bromopyrazole, boric acid ester and n-hexylithium serving raw materials have an reaction and are boronized with a one-pot method, so 1-substitution-1H-pyrazol-4-boric acid ester and lithium hydrate are generated, then pinacol is used for exchange to generate 1-substitution-1H-pyrazol-4-boric acid pinacol ester and lithium hydrate, finally lithium hydrate is hydrolyzed by acetic acid, and 1-substitution-1H-pyrazol-4-boric acid pinacol ester is obtained. The raw materials used in the method are easy to obtain, and the method is easy and convenient to conduct, and is suitable for preparing 1-substitution-1H-pyrazol-4-boric acid pinacol ester compounds.

Description

technical field [0001] The invention relates to a preparation method of 1-substituted-1H-pyrazole-4-boronic acid pinacol ester, belonging to the technical field of synthesis and preparation of organic chemicals. Background technique [0002] 1-Substituted-1H-pyrazole-4-boronic acid pinacol ester is a relatively new class of compounds and important pharmaceutical intermediates with broad application prospects, such as crizotinib intermediate 1-(1-tert Butoxycarbonylpiperidin-4-yl)pyrazole-4-boronic acid pinacol ester. At present, there are four kinds of synthetic methods about this type of compound reported in the literature. Method one: use 1-substituted-4-bromopyrazole as the starting material, and use n-butyllithium at -90 o C reaction for 1 hour, warming up to -70 o C, adding trimethyl borate, reacting for 0.5 hours, quenching with ammonium chloride aqueous solution, separating the oil phase, and concentrating to obtain 1-ethylpyrazole-4-boronic acid (Ref: Journal of He...

Claims

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Application Information

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IPC IPC(8): C07F5/04
CPCC07F5/04
Inventor 王宪学郑鹏
Owner DALIAN NETCHEM CHIRAL TECH
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