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A kind of synthesis technique of pyridine-4-boronic acid

A synthesis process, the technology of bromopyridine hydrochloride, which is applied in the field of synthesis process of pyridine-4-boronic acid, can solve the problems of cumbersome post-processing, poor solubility, and difficult removal of inorganic salts, etc.

Active Publication Date: 2019-08-23
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above technical scheme, due to the amphoteric characteristics of 4-pyridine boric acid itself, it is inevitable to add hydrochloric acid to hydrolyze the boric acid ester into boric acid in the post-treatment process. Neutral, repeated solvent extraction, resulting in cumbersome post-treatment, while generating a lot of waste water
Pyridine-4-boronic acid has poor solubility in common solvents such as ethyl acetate and tetrahydrofuran. Once the product is precipitated, the trapped inorganic salt is difficult to remove

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] In the reaction flask, add 4-bromopyridine hydrochloride (23.9 g, 0.1 mol) and 80 mL of diethoxymethane under temperature control from -10°C to -5°C, and dropwise add 30% aqueous sodium hydroxide solution (about 1.5-1.6 eq), the system is gradually layered under stirring, after HPLC detects that the water layer is completely free, let it stand for layering, add solid sodium hydroxide to the diethoxymethane layer and dry it, take the supernatant and set aside for use, and the external standard is calibrated 4- Bromopyridine content 96.8%.

[0020] Cool the diethoxymethane layer to -20°C to -10°C, start to drop Bu3MgLi (0.042mol) generated by mixing 2.5M BuLi and 2M BuMgCl Grignard reagent at a molar ratio of 2:1, and continue stirring after the dropwise addition is complete After reacting for 1-2 hours, take a sample and add D2O, then send it for HNMR detection (the ratio of deuterated pyridine to pyridine is 97:3), and the exchange is completed. Start to add BrB(NMe 2...

Embodiment 2

[0023] In the reaction flask, add 4-bromopyridine hydrochloride (23.9g, 0.1mol) and 70mL cyclopentyl methyl ether under temperature control from -10°C to -5°C, and dropwise add 40% potassium hydroxide aqueous solution (approximately 1.3- 1.5eq), the system was gradually layered under stirring, after HPLC detected that the water layer was completely free, it was allowed to stand for layering, and the cyclopentyl methyl ether layer was dried by adding solid potassium hydroxide, and the supernatant was extracted for later use, and the external standard was calibrated The content of 4-bromopyridine is 95.5%.

[0024] The cyclopentyl methyl ether layer was cooled to -20°C to -10°C, and i-PrBu generated by mixing 2.5M BuLi and 2M i-PrMgCl Grignard reagent at a molar ratio of 2:1 was started dropwise. 2 MgLi (0.035mol), after the dropwise addition is complete, continue to stir and react for 1-2 hours, take a sample and add D2O and send it for HNMR detection (the ratio of deuterated p...

Embodiment 3

[0027] In the reaction kettle, add 4-bromopyridine hydrochloride (2.39Kg, 10mol) and 12L toluene under temperature control from -10°C to -5°C, and slowly add 40% aqueous sodium hydroxide solution (12mol, 1.2eq) dropwise under stirring , the temperature during the dropping process does not exceed 0°C, the system is gradually layered under stirring, and after HPLC detects that the water layer is completely free, it is allowed to stand for layering, and the toluene layer is added to solid sodium hydroxide to dry, and the supernatant is extracted for later use. The standard 4-bromopyridine content is 96.8%.

[0028] Cool the toluene layer to -20°C to -10°C, start to drop Bu3MgLi (4.2mol) generated by mixing 2.5M BuLi and 2M BuMgCl Grignard reagent in a molar ratio of 2:1, after the dropwise addition is completed, continue to stir for 3 hours, After taking a sample and adding D2O, it was sent for HNMR detection (the ratio of deuterated pyridine to pyridine was 97.5:2.5), and the ex...

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Abstract

The invention discloses a synthetic process for pyridine-4-boronic acid. The synthetic process comprises the following steps: with 4-bromopyridine hydrochloride as a raw material, carrying out dissociation under an alkaline condition so as to obtain 4-bromopyridine; adding alkyl magnesiumlithium and a haloboron reagent at a low temperature, and carrying out distillation so as to obtain a pyridine-4-boron amine intermediate; and carrying out exchanging and hydrolysis so as to obtain pyridine-4-boronic acid. The method overcomes the problem that free 4-bromopyridine is prone to polymerization, avoids the influence of the characteristic that pyridine-4-boronic acid has zwitterions, and realizes maximum product precipitation. The process has been verified on a scale of kilograms.

Description

technical field [0001] The invention relates to a synthesis process of pyridine-4-boronic acid, which belongs to the field of synthesis of pharmaceutical intermediates. Background technique [0002] Pyridine-4-boronic acid is used as an advanced pharmaceutical intermediate, for example, after coupling and reduction, it is used as a piperidinyl structural unit to synthesize the marketed drug Ceritinib for the treatment of ALK-positive metastatic non-small cell lung cancer. [0003] Existing synthesis methods mainly include two categories: 1) As early as 1965, 4-bromopyridine was exchanged with butyllithium, then reacted with trimethyl borate, added acetic acid to reflux to quench the reaction, and the separation yield was 20% . The low yield is mainly due to the fact that pyridine-4-boronic acid itself has certain hydrophilicity, which makes separation and purification difficult; meanwhile, under different pH conditions, pyridine-4-boronic acid has different degrees of ampho...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02
Inventor 冷延国张进申海兵
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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