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Preparation method of N-substituted-tetrahydropyridine-3/4-boric acid/ester

A technology of tetrahydropyridine and boric acid, which is applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as the lack of obvious advantages in the cost of the synthesis process, the small number of suppliers in the raw material market, and the troublesome hydrolysis of pinacol esters. High competitiveness and high reaction selectivity

Active Publication Date: 2020-04-14
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method needs to pass through coupling reaction, uses expensive palladium catalyst coupling, and raw material market supplier quantity is less
[0009] Although the above methods can realize the synthesis of such products to a certain extent, the methods lack versatility, and most of them need to be coupled with expensive metal palladium catalysts. The cost advantage of the synthesis process is not obvious, and they are all limited to boric acid For pinacol ester products, if you need to obtain the corresponding boric acid, it is relatively troublesome to hydrolyze the pinacol ester

Method used

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  • Preparation method of N-substituted-tetrahydropyridine-3/4-boric acid/ester
  • Preparation method of N-substituted-tetrahydropyridine-3/4-boric acid/ester
  • Preparation method of N-substituted-tetrahydropyridine-3/4-boric acid/ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025]

[0026] In a 500mL three-necked flask, add pyridine-4-boronic acid pinacol ester (20.5g, 0.1mol), benzyl chloride (12.6g, 0.1mol) and chlorobenzene (110mL) in turn, stir evenly, then heat up to reflux for reaction 5 hours, the reaction of the raw materials was detected to be completed. After the solvent was evaporated to dryness under reduced pressure, 33.2 g of light yellow solid quaternary salt was obtained. The solid was added to 180 mL of tetrahydrofuran to form a suspension, cooled to -10 °C, and sodium borohydride (4.2 g, 0.11 mol) was added in batches. During the addition, obvious bubbles were generated, and the heat was violently exothermic, which was maintained during each addition. The temperature does not exceed 0°C. After the addition was completed, the mixture was naturally returned to room temperature and continued to be stirred for 2 hours, and the reaction was detected by TLC. The saturated ammonium chloride solution was carefully quenched, extract...

Embodiment 2

[0028]

[0029] In a 500mL three-necked flask, add pyridine-3-boronic acid pinacol ester (20.5g, 0.1mol), benzyl chloride (12.6g, 0.1mol) and chlorobenzene (110mL) in turn, stir evenly, heat up to reflux reaction 5 hours, the reaction of the raw materials was detected to be completed. After the solvent was evaporated to dryness under reduced pressure, 33.5 g of light yellow solid quaternary salt was obtained. The solid was added to 180 mL of tetrahydrofuran to form a suspension, cooled to -10 °C, and sodium borohydride (4.2 g, 0.11 mol) was added in batches. During the addition, obvious bubbles were generated, and the heat was violently exothermic, which was maintained during each addition. The temperature does not exceed 0°C. After the addition was completed, the mixture was naturally returned to room temperature and continued to be stirred for 3 hours, and the reaction was detected by TLC. The saturated ammonium chloride solution was carefully quenched, extracted with e...

Embodiment 3

[0031]

[0032] In a 500mL three-necked flask, add pyridine-3-boronic acid pinacol ester (20.5g, 0.1mol) and 120mL of dichloromethane in turn, stir evenly, cool down to 0°C, and start adding MeI (14.9g, 0.105mol) dropwise , the dropwise addition was completed, the reaction was continued for 1 hour, then the temperature was raised to reflux for 5 hours, and the reaction of the raw materials was detected. After the solvent was evaporated to dryness under reduced pressure, 34.9 g of a light pink solid quaternary salt was obtained. The solid was added to 240 mL of acetonitrile to form a suspension, cooled to -10 °C, and sodium borohydride (4.2 g, 0.11 mol) was added in batches. During the addition, obvious bubbles were generated, and the heat was violently exothermic, which was maintained during each addition. The temperature does not exceed 0°C. After the addition was completed, the mixture was naturally returned to room temperature and continued to be stirred for 5 hours, an...

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Abstract

The invention discloses a preparation method of N-substituted tetrahydropyridine-3 / 4-boric acid / ester, and belongs to the technical field of organic boric acid chemistry. The method comprises the following steps: carrying out a reaction on pyridine-3 / 4-boric acid / ester and a halide to form a quaternary salt, and reducing the quaternary salt with sodium / potassium borohydride in an aprotic solvent to generate N-substituted-tetrahydropyridine-3 / 4-boric acid / ester. According to the method, easily-synthesized pyridine-3 / 4-boric acid / ester is used as a raw material, the product can be obtained through two continuous steps, and the reaction selectivity is high, so that the defect that palladium-catalyzed coupling or ultralow temperature is needed when substituted piperidone is adopted as a raw material is overcome, the method is verified on the hectogram scale, and a concise and efficient synthesis path is provided for preparation of the compound.

Description

technical field [0001] The invention relates to a preparation method of N-substituted tetrahydropyridine-3 / 4-boronic acid / ester, and belongs to the field of pharmaceutical intermediate synthesis. Background technique [0002] In the field of new drug research and development, the use of piperidine structural unit drugs is increasing, and there are many drugs in different clinical stages. For example, V-116517 targeting TRPV1 is in the second clinical phase for the treatment of chronic pain. , Postherpetic neuralgia, acute pain. (Refer to J.Med.Chem.2014, 57, 6781-6794 and US8575199B2.) [0003] Regarding the synthesis of aza six-membered cycloalkenyl boronate esters in such structural drugs, there are mainly the following methods: [0004] In the literature method, N-substituted-4-piperidone was used as raw material, and LiHMDS or LDA and PhNTf were combined with LiHMDS or LDA at ultra-low temperature. 2 The reaction produces alkenyl triflate, which is separated by column...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/04C07F5/02
CPCC07F5/04C07F5/025Y02P20/55
Inventor 刘宗伦申海兵田利国王栋召王建凯
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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