Synthesis method of 3, 5-dichloro-2-cyanopyridine

A synthetic method, the technology of cyanopyridine, applied in the chemical field, can solve the problems of high production cost and large dosage, and achieve the effects of reducing the generation of waste water, high yield and high content

Pending Publication Date: 2019-11-26
CHONGQING MEDICAL & PHARMA COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the amount of triethylamine and trimethylsilyl cyanide is relatively large (according to the amount of substance, raw material: triethylamine: trimethylsilyl cyanide = 1:2:3), and the production cost is relatively high

Method used

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  • Synthesis method of 3, 5-dichloro-2-cyanopyridine
  • Synthesis method of 3, 5-dichloro-2-cyanopyridine
  • Synthesis method of 3, 5-dichloro-2-cyanopyridine

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Embodiment 1

[0042] The synthetic method of the present embodiment comprises the steps:

[0043] (1) Synthesis of 3,5-dichloro-2-fluoropyridine

[0044] Add 2,3,5-trichloropyridine 93.1g (mass fraction 98%, 0.50mol), 300mL sulfolane, powdered potassium fluoride 32.2g (mass fraction 99%, 0.55mol), heated to a temperature of 155-160°C and kept for 8h, sampling analysis, at this time, the content of 2,3,5-trichloropyridine is less than 1.0%, stop the reaction, cool to room temperature, filter, use sulfolane for solid Wash three times (10 mL each), and combine the filtrate and washings.

[0045] (2) Synthesis of 3,5-dichloro-2-cyanopyridine

[0046]Add 1.0g catalyst tetrabutylammonium bromide, 35.5g powdery solid potassium cyanide (massfraction 99%, 0.55mol) in the 3,5-dichloro-2-fluoropyridine solution of step (1) gained, heat To 120-125 ℃ for cyanation reaction. During the reaction, take samples to detect the content changes of intermediates and products, keep warm until the content of i...

Embodiment 2

[0048] The synthetic method of the present embodiment comprises the steps:

[0049] (1) Synthesis of 3,5-dichloro-2-fluoropyridine

[0050] Add 2,3,5-trichloropyridine 93.1g (mass fraction 98%, 0.50mol), 300mL dimethyl sulfoxide, powdered sodium fluoride 23.3 g (mass fraction 99%, 0.55mol), heated to reflux state and maintained for 8h, sampling analysis, at this time, the content of 2,3,5-trichloropyridine was less than 1.0%, stopped the reaction, cooled to room temperature, filtered, and the solid was washed with dichloropyridine Methyl sulfoxide was washed three times (10 mL each), and the filtrate and washings were combined.

[0051] (2) Synthesis of 3,5-dichloro-2-cyanopyridine

[0052] Add 1.0g catalyst benzyltriethylammonium chloride, 27.2g powdered solid sodium cyanide (mass fraction 99%, 0.55mol) to the 3,5-dichloro-2-fluoropyridine solution obtained in step (1) , heated to 125-130 ° C for cyanation reaction. During the reaction, take a sample to detect the change ...

Embodiment 3

[0054] The synthetic method of the present embodiment comprises the steps:

[0055] (1) Synthesis of 3,5-dichloro-2-fluoropyridine

[0056] Add 2,3,5-trichloropyridine 93.1g (mass fraction 98%, 0.50mol), 300mLN,N-dimethylformamide, powdered fluorine Potassium chloride 32.2g (mass fraction 99%, 0.55mol), heated to reflux and kept for 8h, sampling analysis, at this time, the content of 2,3,5-trichloropyridine is less than 1.0%, stop the reaction, cool to room temperature, filter, solid Wash with N,N-dimethylformamide three times (10 mL each time), and combine the filtrate and washings.

[0057] (2) Synthesis of 3,5-dichloro-2-cyanopyridine

[0058] Add 1.0g catalyst tetrabutylammonium bromide, 27.2g powdery solid sodium cyanide (mass fraction 99%, 0.55mol) in the 3,5-dichloro-2-fluoropyridine solution of step (1) gained, heat To reflux for cyanation reaction. During the reaction process, take samples to detect the content changes of intermediates and products, keep warm unti...

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Abstract

The invention provides a synthesis method of 3, 5-dichloro-2-cyanopyridine. The method includes the steps of: 1) in the presence of a solvent, mixing 2, 3, 5-trichloropyridine with a fluoride for reaction to obtain 3, 5-dichloro-2-fluoropyridine; and 2) mixing the 3, 5-dichloro-2-fluoropyridine prepared in step 1) with a catalyst and a cyanide salt for reaction to obtain 3, 5-dichloro-2-cyanopyridine. The method provided by the invention uses sodium cyanide, potassium cyanide or other cheap and easily available cyanide salts as the cyaniding reagent with a dosage far lower than that of the existing method, and can acquire the target product with high yield and high content, thereby greatly reducing the production cost, also greatly reducing the production of wastewater in the three wastes,and being an efficient and environment-friendly production method of 3, 5-dichloro-2-cyanopyridine.

Description

technical field [0001] The invention relates to the field of chemistry, in particular to a method for synthesizing a pharmaceutical intermediate 3,5-dichloro-2-cyanopyridine. Background technique [0002] 3,5-dichloro-2-cyanopyridine ( figure 1 ) is an important intermediate in the synthesis of prolyl hydroxylase inhibitors. Prolyl hydroxylase inhibitors are clinically used in the prevention and treatment of peripheral vascular disease (PVD), coronary artery disease (CAD), heart failure, ischemia and anemia. [0003] [0004] Document J.Heterocycl.Chem.1996, 33,1815-1821 reported a method of 3,5-dichloro-2-cyanopyridine: 2,3,5-trichloropyridine as raw material, polyethylene glycol Dimethyl ether is used as a solvent, potassium iodide and tetraphenylphosphine bromide are used as catalysts, cuprous cyanide is used as a cyanidation reagent, and the reaction is heated under reflux for 89 hours to obtain the product. The disadvantages of this method are high reaction temper...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/84
CPCC07D213/84
Inventor 丁永良韩丹王丽娟张稳稳程家蓉
Owner CHONGQING MEDICAL & PHARMA COLLEGE
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