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Synthesis method of N-methyl-1, 2, 5, 6-tetrahydropyridine-4-boronic acid pinacol ester

A technology of tetrahydropyridine and pinacol esters, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of high price, low molar yield, and the need for low temperature, so as to inhibit the formation of quaternary ammonium salts, and the post-reaction treatment is simple and post-reaction Easy to handle effects

Active Publication Date: 2020-03-27
安徽英特美科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses reagents with high risk factors such as triphenyl phosphite and isopropylmagnesium chloride. The reaction process requires low temperature and the cost of raw materials is high, which limits the scale-up production.
[0004] 2. WO2018067512, using N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester as raw material, formaldehyde as methylation reagent, palladium carbon as catalyst for hydrogenation reduction, low molar yield at 75%
This process requires low temperature conditions and uses expensive metal palladium as a catalyst, which is not suitable for large-scale production

Method used

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  • Synthesis method of N-methyl-1, 2, 5, 6-tetrahydropyridine-4-boronic acid pinacol ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Add N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (154.6g, 0.5mol) and hydrogen chloride / methanol solution (2.0mol / L, 0.5L) into a 1.0L reaction flask , 20 ℃ stirring for 1.0h. Check the completion of the reaction, adjust the pH to neutral with triethylamine, desolventize the methanol solution, and vacuum-dry to obtain the crude product, which can be directly carried out to the next step without purification.

[0024] Add paraformaldehyde (18.0 g, 0.6 mol), formic acid (368.2 g, 8.0 mol), and HOBt (81.1 g, 0.6 mol) into the reaction flask of the crude product from the previous step. After feeding, heat to 60°C and stir for 5.0h. After the reaction was completed, the pH was adjusted to 8-9 with triethylamine, and the solvent was removed under reduced pressure. Add 2500mL of n-heptane to the system, raise the temperature to 50°C and stir thoroughly, filter with diatomaceous earth while it is hot, evaporate the filtrate to dryness, add 20:1 cyclohexane:et...

Embodiment 2

[0026] N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (154.6g, 0.5mol) and trifluoroacetic acid / dichloromethane solution (2.0mol / L, 0.5L) were added 1.0L reaction bottle, keep warm at 20°C and stir for 1.0h. The pH was adjusted to neutral with triethylamine, the methanol solution was desolvated, and vacuum-dried to obtain the crude product, which was directly carried to the next step without purification.

[0027] Put paraformaldehyde (30.0 g, 1.0 mol), formic acid (460.3 g, 10.0 mol), and HOBt (81.1 g, 0.6 mol) into the reaction flask of the crude product from the previous step. After feeding, heat to 60°C and stir for 5.0h. Adjust the pH to 8-9 with triethylamine, and remove the solvent. Add 2500mL of n-heptane to the system, raise the temperature to 50°C and stir thoroughly, filter with diatomaceous earth while it is hot, evaporate the filtrate to dryness, add 20:1 cyclohexane:ethyl acetate mixed solvent and freeze to -20°C for recrystallization to obtain o...

Embodiment 3

[0029] Add N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (154.6g, 0.5mol) and hydrogen chloride / ethanol solution (2.0mol / L, 0.75L) into a 1.0L reaction flask , keep warm at 20°C and stir for 1.0h. The pH was adjusted to neutral with triethylamine, the methanol solution was desolvated, and vacuum-dried to obtain the crude product, which was directly carried to the next step without purification.

[0030] Add paraformaldehyde (30.0 g, 1.0 mol), formic acid (460.0 g, 10.0 mol), and HOBt (135.2 g, 1.0 mol) into the reaction flask of the crude product from the previous step. After feeding, heat to 50°C and stir for 5.0h. After the reaction was completed, the pH was adjusted to 8-9 with triethylamine, and the solvent was removed. Add 2500mL of n-hexane to the system, raise the temperature to 40°C and stir thoroughly, filter with diatomaceous earth while it is hot, evaporate the filtrate to dryness, add a 50:1 mixed solvent of cyclohexane:ethyl acetate and freeze to...

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Abstract

The invention belongs to the field of synthesis of medical intermediates, and particularly relates to a synthesis method of N-methyl-1, 2, 5, 6-tetrahydropyridine-4-boronic acid pinacol ester. According to the method, N-Boc-1, 2, 5, 6-tetrahydropyridine-4-boronic acid pinacol ester is selected as a raw material, Boc protection is removed under an acidic condition, paraformaldehyde, a reducing reagent and HOBt are added for an N-methylation reaction, the method can effectively inhibit the occurrence of quaternary ammonium salt side reactions, the post-treatment is simple, and the method is suitable for industrial production. The crude product is recrystallized to obtain the N-methyl-1, 2, 5, 6-tetrahydropyridine-4-boronic acid pinacol ester product with the purity of more than 98.0%, and the two-step molar yield is more than 90%.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of N-methyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. Background technique [0002] N-methyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester is an important pharmaceutical intermediate, widely used in anti-tumor, cardiovascular and other drugs. Among them, the Btk inhibitor synthesized by coupling reaction is mainly used for the treatment of B cell lymphoma. Protein kinase inhibitors can inhibit the growth of tumors and are used to treat cardiovascular disorders, diseases caused by viral infections such as malaria and AIDS, and can also be used for autoimmune diseases. There are many routes for the synthesis of N-methyl-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, and the disclosed synthetic methods are as follows: [0003] 1. CN105566367A, using N-methyl-4-piperidone as raw material, thro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02
CPCC07F5/025Y02P20/55
Inventor 徐剑霄刘洪强赵士民魏佳玉朱克明
Owner 安徽英特美科技有限公司