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A method for synthesizing n-substituted-1,2,3,6-tetrahydropyridine-5-boronate

A technology of tetrahydropyridine and boronate ester, applied in the field of pharmaceutical intermediate synthesis, can solve the problems of application limitation, poor selectivity, inability to carry out effective separation, etc., and achieve the effect of avoiding column chromatography

Active Publication Date: 2017-05-31
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The biggest disadvantage of the above-mentioned method is: the selectivity is very poor when the raw material becomes alkenyl triflate through alkali, and the isomer ratio usually obtained is nearly 2:1-3:1, and the separation of the intermediate requires a column Chromatography, and the separation yield is usually 24-50%. After the intermediate is directly coupled, an inseparable mixture is usually obtained, and even the method of column chromatography cannot be effectively separated, which further restricts the development of this type of compound. Amplified synthesis, application is limited

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Synthesis of N-methyl-1,2,3,6-tetrahydropyridine-5-boronic acid pinacol ester:

[0023] In a 250mL reaction flask, add 16.9g (0.1mol) of ethyl N-methyl-1,2,3,6-tetrahydropyridine-5-carboxylate and 110mL of dichloromethane, and add 16.0g of bromine dropwise at room temperature (0.1 mol). After the addition is complete, first stir the reaction at room temperature for 30 minutes. After the reaction is detected by TLC, add 20 mL of sulfolane to dissolve, raise the temperature to 50-60°C, and start to add 2M KOH (0.3mol) dropwise. Bubbles come out during the dropwise addition. The escape speed of the bubbles controls the drop rate. After the dropwise addition, when the bubbles no longer escape, raise the temperature to 80-90°C for 2-3 hours, and rectify under reduced pressure to obtain 11.6g of colorless liquid N-methyl-1 , 2,3,6-tetrahydropyridine-5-bromo, yield 66%.

[0024] Under nitrogen protection, add 90 mL of dioxane, N-methyl-1,2,3,6-tetrahydropyridine-5-bromo (11....

Embodiment 2

[0026] Synthesis of N-ethyl-1,2,3,6-tetrahydropyridine-5-boronic acid pinacol ester:

[0027] In a 250mL reaction flask, add 15.5g (0.1mol) of N-ethyl-1,2,3,6-tetrahydropyridine-5-carboxylic acid and 110mL tetrahydrofuran, and add 16.6g (0.1mol) of bromine dropwise at room temperature . After the addition is complete, first stir the reaction at room temperature for 30 minutes. After the raw material cannot be detected by TLC (ninhydrin), add 20 mL of sulfolane to dissolve, raise the temperature to 50-60°C, and start to add 30.4 g of DBU (0.2 mol) dropwise. Bubbles come out during the addition process, and the dropping speed is controlled according to the speed of the bubbles escaping. After the addition is completed, when the bubbles no longer escape, the temperature is raised to 80-90°C for 2-3 hours, and 14.1g is obtained by vacuum distillation Colorless liquid N-ethyl-1,2,3,6-tetrahydropyridine-5-bromide, yield 74%.

[0028] Under nitrogen protection, add 90 mL of dioxane...

Embodiment 3

[0030] Synthesis of N-benzyl-1,2,3,6-tetrahydropyridine-5-boronic acid pinacol ester:

[0031] In a 250mL reaction flask, add 15.5g (0.1mol) of N-benzyl-1,2,3,6-tetrahydropyridine-5-carboxylic acid and 110mL of dichloromethane, and add 25.4g (0.1mol) of iodine at room temperature . After the addition is complete, first stir at room temperature for 30 minutes, TLC (ninhydrin color development) detects that the raw material does not change, add 40 mL of sulfolane to dissolve, heat up to 50-60 ° C, start to drop 37.2 g of DBN (0.3 mol), Bubbles emerge during the dropwise addition, and the rate of addition is controlled according to the escape speed of the bubbles. After the dropwise addition, when the bubbles no longer escape, the temperature is raised to 90-100°C for 2-3 hours, and vacuum distillation yields 15.8 g Pale yellow liquid N-benzyl-1,2,3,6-tetrahydropyridine-5-iodine, yield 53%.

[0032] Under nitrogen protection, add 90mL DMSO, N-benzyl-1,2,3,6-tetrahydropyridine-5...

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PUM

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Abstract

The invention discloses a method for synthesizing N-substitute-1, 2, 3, 6-tetrahydropyridine-5-boric acid ester. According to the method, N-substitute-1, 2, 3, 6-tetrahydropyridine-5-carboxylic acid (ester) serves as the raw material, conducts addition with halogen and then is subjected to alkaline condition elimination to form alkenyl halide and then subjected to coupling with al boron ester under the condition of metal palladium catalyzation, and the N-substitute-1, 2, 3, 6-tetrahydropyridine-5-boric acid ester is obtained. According to the method, the obtained midbody alkenyl halide does not contain isomer, separation is easy to conduct, purity of an obtained product is high, and the method provides a simple way for synthesis of compounds of the type.

Description

technical field [0001] The invention relates to a method for synthesizing N-substituted-1,2,3,6-tetrahydropyridine-5-boronate, belonging to the field of synthesis of pharmaceutical intermediates. Background technique [0002] As an important structural unit, N-substituted-1,2,3,6-tetrahydropyridine-5-boronate is widely used in the synthesis of various active drugs after Suzuki coupling. Most of the available materials directly use this type of compound as a raw material, and only a few documents and patents report the synthesis method. [0003] The existing synthetic methods mainly include: starting from N-substituted piperidone, converting carbonyl into alkenyl trifluoromethanesulfonate through HMDSLi or LDA and N,N-bistrifluoromethanesulfonanilide at ultra-low temperature, The product was subsequently obtained after Suzuki coupling. [0004] The biggest disadvantage of the above-mentioned method is: the selectivity is very poor when the raw material becomes alkenyl trifl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02
CPCC07F5/02
Inventor 冷延国于伟东张进
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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