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A kind of synthetic method of 3-cyclopropylphenylboronic acid

A technology of cyclopropylphenylboronic acid and cyclopropylboronic acid, which is applied in the field of synthesis of 3-cyclopropylphenylboronic acid, can solve the problems of potential safety hazards, lithiation reagent n-butyllithium is afraid of water and flammability, etc., and meets the equipment requirements Low cost, low cost, and mild reaction conditions

Active Publication Date: 2021-11-26
蚌埠产品质量监督检验研究院 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the harsh reaction conditions that require liquid nitrogen or dry ice to cool down, the lithiated reagent n-butyllithium used is afraid of water and is flammable, which poses a safety hazard.

Method used

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  • A kind of synthetic method of 3-cyclopropylphenylboronic acid
  • A kind of synthetic method of 3-cyclopropylphenylboronic acid
  • A kind of synthetic method of 3-cyclopropylphenylboronic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] This embodiment includes the following steps:

[0029] Step 1: 250mL three-neck bottle, equipped with a thermometer and a condenser tube, under nitrogen protection, put 9.57g (0.05mol) of 3-chlorobromobenzene, 70mL of 1,4-dioxane and 15mL of water, start stirring, and pour into Add potassium phosphate 31.84g (0.15mol), PdCl 2 (dppf) 1.83g (0.0025mol) and cyclopropylboronic acid 6.44g (0.075mol). After the feeding is completed, the nitrogen is replaced three times, and the heating is turned on to react at 80°C for 4.0h. Sample delivery, gas phase detection of 3-chlorobromobenzene raw material remains unchanged, stop the reaction, add ethyl acetate for extraction, filter the organic layer with diatomaceous earth, evaporate the solvent to dryness, then heat up and distill under reduced pressure to obtain 3-cyclopropylchlorobenzene 6.94 g (0.045mol), the yield is 91.0%, 1 H NMR (CDCl 3 ,400MHz):δ7.21-7.12(m,2H),7.07(s,1H),6.97(d,J=7.5Hz,1H),1.92-1.86(m,1H),1.03-0.98(m,2...

Embodiment 2

[0032] This embodiment includes the following steps:

[0033] Step 1: 250mL three-neck bottle, equipped with a thermometer and a condenser, under nitrogen protection, put 9.57g (0.05mol) of 3-chlorobromobenzene, 64mL of tetrahydrofuran and 16mL of water, start stirring, and add 20.7g of potassium carbonate to the reaction bottle in turn (0.15mol), PdCl 2 (dppf) 1.10 g (0.0015 mol) and cyclopropylboronic acid 6.44 g (0.075 mol). After the feeding is completed, the nitrogen is replaced three times, and the heating is turned on to react at 60°C for 4.0h. Sample delivery, gas phase detection of 3-chlorobromobenzene raw material remains unchanged, stop the reaction, add ethyl acetate to extract, filter the organic layer with diatomaceous earth, evaporate the solvent to dryness, then heat up and distill under reduced pressure to obtain 3-chlorocyclopropylbenzene 6.71 g (0.043mol), the yield is 88.0%;

[0034] The second step: 250mL three-necked bottle, equipped with a thermometer...

Embodiment 3

[0036] This embodiment includes the following steps:

[0037] Step 1: 250mL three-necked bottle, equipped with a thermometer and a condenser, under nitrogen protection, put 9.57g (0.05mol) of 3-chlorobromobenzene, 65mL of DMF and 15mL of water, start stirring, and add 10.60g of sodium carbonate to the reaction bottle in turn (0.10mol), PdCl 2(dppf) 0.37g (0.0005mol) and cyclopropylboronic acid 4.72g (0.055mol). After the feeding is completed, the nitrogen is replaced three times, and the heating is turned on to react at 120°C for 8.0h. Sample delivery, gas phase detection of 3-chlorobromobenzene raw material remains unchanged, stop the reaction, add ethyl acetate for extraction, filter the organic layer with diatomaceous earth, evaporate the solvent to dryness, then heat up and distill under reduced pressure to obtain 3-chlorocyclopropylbenzene 6.52 g (0.042mol), the yield is 85.5%;

[0038] Step 2: 250mL three-necked bottle, equipped with a thermometer and a condenser, und...

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Abstract

The invention discloses a synthesis method of 3-cyclopropylphenylboronic acid, which belongs to the technical field of organic synthesis. The method uses 3-chlorobromobenzene and cyclopropyl boronic acid as starting materials through palladium-catalyzed coupling, or uses 3-chlorobromobenzene and cyclopropyl Grignard reagent as starting materials to generate 3- Cyclopropylchlorobenzene is then reacted with tetrahydroxydiboron under nickel catalysis to obtain 3-cyclopropylphenylboronic acid. After purification with alcohol and water, the product purity is as high as 99.8%. According to the activity difference of bromine and chlorine, the present invention adopts different metal relays or couples in the presence of cheap metal nickel, has mild reaction conditions and high product purity, and can be used as a potential industrial scale-up route.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 3-cyclopropylphenylboronic acid. Background technique [0002] Because the special chemical structure of the cyclopropyl ring can enhance metabolic stability, it is often used as a molecular building block in drug design, some of which have been approved by the FDA, such as Resina for the treatment of hyperuricemia and gout Germany. Its molecular structure is as follows: [0003] [0004] 3-Cyclopropylphenylboronic acid is a commonly used intermediate in the synthesis of cyclopropyl-substituted aryl drug candidate molecules. At present, it has been reported in the literature that this type of boronic acid is mainly synthesized by cyclopropyl-substituted aryl bromide and n-butyllithium at -70 ° C. Lithiation occurs under ultra-low temperature conditions, followed by borate reaction preparation under borate conditions. Due to the harsh reac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02
CPCC07F5/025
Inventor 刘雪艳徐剑霄汤庆文高永慧张坤刘洪强魏佳玉
Owner 蚌埠产品质量监督检验研究院
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