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Synthesis process of 2,6-dichloropyridine-4-boracic acid pinacol ester

A kind of technology of dichloropyridine and synthesis process, applied in the field of pharmaceutical intermediate synthesis, can solve problems such as expensive metal iridium catalyst, and achieve the effects of easy recycling and short operation steps

Active Publication Date: 2018-05-04
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The existing synthetic methods are all based on 2,6-dichloropyridine as a raw material, and under the aid of microwaves, 3mol% [Ir(OMe)cod] 2 and dtbyp are combined with biboronic acid pinacol ester or pinacol at 80°C. Alcohol borane reaction obtains 2,6-dichloropyridine-4-boronic acid pinacol ester, above two kinds of synthetic methods are all relatively direct, but because metal iridium catalyst is relatively expensive, it is relatively easier to become the technical scheme adopted by academia, in Before becoming an effective scale-up process, a more suitable synthesis process still needs to be found

Method used

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  • Synthesis process of 2,6-dichloropyridine-4-boracic acid pinacol ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Under the protection of nitrogen, 120 ml of anhydrous tetrahydrofuran and 2,2,6,6-tetramethylpiperidine (33.9 g, 0.24 mol) were added to the reaction flask equipped with a dropping device, cooled to -70 ° C to - At 80°C, 96 ml (0.24 mol) of 2.5M n-butyllithium solution was added dropwise. After completion of the dropwise addition, keep stirring for 1 hour. Dissolve 2,6-dichloropyridine (29.6 g, 0.20 mol) in 150 ml of anhydrous tetrahydrofuran, mix well, transfer to the above-mentioned dropping funnel, start adding the mixed solution dropwise, and keep the reaction temperature during the dropping at -70°C to -60°C.

[0019] After the dropwise addition is completed, continue to stir and react for 1-2 hours. After sampling and adding D2O for derivatization, it is confirmed that the conversion rate is greater than 95% (position selectivity 4-position / 3-position 35:1). Then, a mixed solution of BrB(C4H8N)2 (48.5 g, 0.21 mol) dissolved in 180 ml of anhydrous tetrahydrofuran...

Embodiment 2

[0022] Under the protection of nitrogen, 120 ml of anhydrous 2-methyltetrahydrofuran and 2,2,6,6-tetramethylpiperidine (33.9 g, 0.24 mol) were added to the reaction flask equipped with a dropping device, cooled to - From 70°C to -80°C, 96 ml (0.24 mol) of 2.5M n-butyllithium solution was added dropwise. After completion of the dropwise addition, keep stirring for 1 hour. Dissolve 2,6-dichloropyridine (29.6 g, 0.20 mol) in 130 ml of anhydrous 2-methyltetrahydrofuran, mix well and transfer it into the above-mentioned dropping funnel, start adding the mixed solution dropwise, during the dropping process , keep the reaction temperature at -70°C to -60°C.

[0023] After the dropwise addition, continue to stir the reaction for 1-2 hours, take a sample and add D2O to derivatize and confirm that the conversion rate is greater than 95% (position selectivity 4-position / 3-position 33:1). Then in the dropping funnel, add ClB(NMe2) 2 (95% purity, 33.9 grams, 0.24 mole) is dissolved in th...

Embodiment 3

[0026] Under the protection of nitrogen, 120 ml of anhydrous diethoxymethane and 2,2,6,6-tetramethylpiperidine (33.9 g, 0.24 mol) were added to the reaction flask equipped with a dropping device, cooled to - From 70°C to -80°C, 115ml (2M, 0.23mol) of isopropylmagnesium chloride solution was started to be added dropwise. After completion of the dropwise addition, keep stirring for 1 hour. Dissolve 2,6-dichloropyridine (29.6 g, 0.20 mol) in 180 ml of anhydrous diethoxymethane, mix well and transfer it into the above-mentioned dropping funnel, start adding the mixed solution dropwise, during the dropping process , keep the reaction temperature at -70°C to -60°C.

[0027] After the dropwise addition is completed, continue to stir and react for 1-2 hours. After sampling and adding D2O for derivatization, it is confirmed that the conversion rate is greater than 92% (position selectivity 4-position / 3-position 28:1). Then add BrB (NiPr2) 2 (58.2 grams, 0.20 moles) in the dropping fu...

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Abstract

The invention discloses a synthesis process of 2,6-dichloropyridine-4-boracic acid pinacol ester. 2,6-dichloropyridine is used as raw materials; under the existence of 2,2,6,6-lithium tetramethylpiperidide or Grignard reagents, protons are selectively removed at low temperature; a boron halide reagent is added; then, pinacol is added for treatment to obtain the 2,6-dichloropyridine-4-boracic acidpinacol ester. The method has the advantages that the operation steps are short; 2,2,6,6-tetramethylpiperidide can be easily recovered and utilized; 4-site products can be obtained at high selectivity; potential practical values are realized.

Description

technical field [0001] The invention relates to a synthesis process of 2,6-dichloropyridine-4-boronic acid pinacol ester, belonging to the field of synthesis of pharmaceutical intermediates. Background technique [0002] 2,6-Dichloropyridine-4-boronic acid pinacol ester, English name 2,6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine , CAS: 408492-27-3, used for the synthesis of advanced pharmaceutical intermediates after Suzuki coupling. [0003] The existing synthetic methods are all based on 2,6-dichloropyridine as a raw material, and under the aid of microwaves, 3mol% [Ir(OMe)cod] 2 and dtbyp are combined with biboronic acid pinacol ester or pinacol at 80°C. Alcohol borane reaction obtains 2,6-dichloropyridine-4-boronic acid pinacol ester, above two kinds of synthetic methods are all relatively direct, but because metal iridium catalyst is relatively expensive, it is relatively easier to become the technical scheme adopted by academia, in Before becom...

Claims

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Application Information

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IPC IPC(8): C07F5/02C07F5/04
CPCC07F5/025C07F5/04
Inventor 冷延国张进田利国
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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