Method for the synthesis of 3,5-dichloro-2-cyanopyridine

Abstract

The application provides a synthesis method of 3,5-dichloro-2-cyanopyridine, comprising the following steps: 1) mixing 2,3,5-trichloropyridine with fluoride in the presence of a solvent to obtain 3,5-dichloro-2-fluoropyridine; 2) mixing the 3,5-dichloro-2-fluoropyridine obtained in step 1) with a catalyst and a cyanide salt to obtain 3,5-dichloro-2-cyanopyridine. The application uses cheap and readily available cyanide salt such as sodium cyanide or potassium cyanide as a cyanation reagent, and the cyanide salt consumption is much lower than that of the prior art, so that the target product with high yield and high content can be obtained, thereby greatly reducing the production cost and greatly reducing the generation of wastewater in the three wastes, and the application is an efficient and environmentally friendly 3,5-dichloro-2-cyanopyridine production method.

Description

Technical Field

[0001] This invention relates to the field of chemistry, and in particular to a method for synthesizing the pharmaceutical intermediate 3,5-dichloro-2-cyanopyridine. Background Technology

[0002] 3,5-Dichloro-2-cyanopyridine is an important intermediate in the synthesis of prolyl hydroxylase inhibitors. Prolyl hydroxylase inhibitors are clinically used to prevent and treat peripheral vascular disease (PVD), coronary artery disease (CAD), heart failure, ischemia, and anemia.

[0003]

[0004] The literature J. Heterocycl. Chem. 1996, 33, 1815-1821 reports a method for producing 3,5-dichloro-2-cyanopyridine: using 2,3,5-trichloropyridine as a raw material, polyethylene glycol dimethyl ether as a solvent, potassium iodide and tetraphenylphosphine bromide as catalysts, and cuprous cyanide as a cyaniding agent, the reaction is carried out under reflux for 89 hours to obtain the product. The disadvantages of this method are high reaction temperature, long reaction time, and low yield (40%). Furthermore, the amount of cuprous cyanide used is enormous (by molar amount, 2,3,5-trichloropyridine:cuprous cyanide = 1:6.4), resulting in high production costs and difficulties in waste treatment. The chemical reaction formula is as follows:

[0005]

[0006] Chinese patent CN109020882A optimized the process: using 2,3,5-trichloropyridine as the starting material, it reacts with bromide in the presence of organic acid to prepare the intermediate 3,5-dichloro-2-bromopyridine; then, in the presence of organic solvent and catalyst, it reacts with cuprous cyanide to obtain 2,5-dichloro-2-cyanopyridine, and recrystallization yields a product with a purity greater than 99%. The chemical reaction formula is as follows:

[0007]

[0008] However, the reaction process is complex, hydrogen bromide is volatile, and the yield is still not high (the overall yield is about 65%).

[0009] US Patent US2003 / 0232842 A1 reports another synthetic method: using 3,5-dichloropyridine-N-oxide as a starting material, dimethylaminoformyl chloride as a catalyst, and trimethylsilylcyanide as a cyaniding agent for direct cyanidation, 3,5-dichloro-2-cyanopyridine is obtained in a yield of 40.2%. The chemical reaction formula is as follows:

[0010]

[0011] US Patent 6046207 reports a similar synthetic method: using 3,5-dichloropyridine-N-oxide as a starting material, triethylamine as a catalyst, and trimethylsilylcyanide as a cyaniding agent for direct cyanidation, the product yield is as high as 97%. However, the amounts of triethylamine and trimethylsilylcyanide used are relatively large (by molar weight, the ratio of starting material to triethylamine to trimethylsilylcyanide is 1:2:3), resulting in higher production costs. The chemical reaction formula is as follows:

[0012] Summary of the Invention

[0013] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide a method for synthesizing 3,5-dichloro-2-cyanopyridine, which solves the problems of high synthesis cost and low yield of 3,5-dichloro-2-cyanopyridine in the prior art.

[0014] To achieve the above and other related objectives, the present invention provides a method for synthesizing 3,5-dichloro-2-cyanopyridine, comprising the following steps:

[0015] 1) 2,3,5-trichloropyridine was reacted with a fluoride in the presence of a solvent to give 3,5-dichloro-2-fluoropyridine;

[0016] 2) Take the 3,5-dichloro-2-fluoropyridine obtained in step 1) and react it with a catalyst and cyanide to obtain 3,5-dichloro-2-cyanopyridine.

[0017] Optionally, in step 1), the fluoride is selected from at least one of potassium fluoride, sodium fluoride, and cesium fluoride.

[0018] Optionally, in step 1), the reaction is carried out under heating conditions, and the temperature of the reaction solution is heated to 150-200°C.

[0019] Optionally, in step 1), the solvent is selected from dipole aprotic solvents.

[0020] Optionally, in step 1), the dipolar aprotic solvent is selected from at least one of DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), and sulfolane. The above solvents are only a partial list, and other similar solvents are also within the scope of protection of this invention.

[0021] Optionally, in step 1), chloride is removed by solid-liquid separation, and the resulting solid is 3,5-dichloro-2-fluoropyridine.

[0022] Optionally, in step 1), the molar ratio of the fluoride to the 2,3,5-trichloropyridine is 1:(1.0-1.2), preferably 1:(1.05-1.1), and specifically can be 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, 1:1.10, 1:1.11, 1:1.12, 1:1.13, 1:1.14, 1:1.15, 1:1.16, 1:1.17, 1:1.18, 1:1.19, 1:1.20, etc.

[0023] Optionally, in step 2), the catalyst is selected from quaternary ammonium salt phase transfer catalysts.

[0024] Optionally, in step 2), the quaternary ammonium salt phase transfer catalyst is selected from at least one of tetrabutylammonium bromide, benzyltriethylammonium chloride, trioctylmethylammonium chloride, tetramethylammonium bromide, tetrapropylammonium chloride, tetrabutylammonium iodide, triethylbenzylammonium bromide, triethylhexylammonium bromide, and triethyloctylammonium bromide. The above catalysts are only a partial list, and other similar catalysts are also within the protection scope of this invention.

[0025] Optionally, in step 2), the cyanide salt is selected from at least one of potassium cyanide and sodium cyanide, preferably potassium cyanide.

[0026] Optionally, in step 2), the molar ratio of the cyanide salt to the 2,3,5-trichloropyridine is (1.0-1.2):1, specifically 1.0:1, 1.01:1, 1.02:1, 1.03:1, 1.04:1, 1.05:1, 1.06:1, 1.07:1, 1.08:1, 1.09:1, 1.10:1, 1.11:1, 1.12:1, 1.13:1, 1.14:1, 1.15:1, 1.16:1, 1.17:1, 1.18:1, 1.19:1, 1.2:1, etc.

[0027] Optionally, in step 2), the reaction is carried out under heating conditions, and the temperature of the reaction solution is heated to 120-150°C.

[0028] Optionally, in step 2), after the reaction is complete, the resulting solution is cooled and then the solid and liquid are separated. The solid obtained is an inorganic salt, and the liquid is a solution of 3,5-dichloro-2-cyanopyridine. The main purpose of solid-liquid separation is to remove salt.

[0029] Optionally, in step 2), the resulting solution is cooled to room temperature.

[0030] Optionally, the method further includes step 3) concentrating the 3,5-dichloro-2-cyanopyridine obtained in step 2) under reduced pressure, mixing the resulting residue with an organic solvent, washing with water, concentrating and crystallizing to obtain the product.

[0031] Optionally, the organic solvent is selected from at least one of alkanes and cycloalkanes.

[0032] Optionally, the organic solvent has a boiling point >60°C, which can reduce solvent loss due to evaporation.

[0033] The present invention also provides 3,5-dichloro-2-cyanopyridine synthesized according to the above method.

[0034] The solid-liquid separation methods mentioned in the above steps can be decantation, filtration, centrifugation, etc., with filtration being the preferred method.

[0035] As described above, the synthesis method of 3,5-dichloro-2-cyanopyridine of the present invention has the following beneficial effects: The present invention uses inexpensive and readily available cyanide salts such as sodium cyanide or potassium cyanide as cyaniding reagents, and the amount of cyanide salt used is much lower than that of existing methods, which can obtain the target product with high yield and high content, thereby greatly reducing production costs and significantly reducing the generation of wastewater in the three wastes. It is a highly efficient and environmentally friendly method for producing 3,5-dichloro-2-cyanopyridine. Attached Figure Description

[0036] Figure 1 The diagram shown is a production process flow chart according to an embodiment of the present invention. Detailed Implementation

[0037] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0038] The production process involved in the following embodiments is as follows: Figure 1 As shown.

[0039] The reagent information in the following examples is shown below:

[0040] 2,3,5-Trichloropyridine: Hubei Zhonglong Kang Sheng Fine Chemical Co., Ltd.; CP, Sulfolane: Liaoning Huarun Chemical Co., Ltd.; CP, Potassium Fluoride: Hubei Chushengwei Chemical Co., Ltd.; CP, Sodium Fluoride: Hubei Chushengwei Chemical Co., Ltd.; CP, Tetrabutylammonium Bromide: Chengdu Kelong Chemical Reagent Factory; AR, Sodium Cyanide: Hebei Chengxin Co., Ltd.; CP, Potassium Cyanide: Hebei Chengxin Co., Ltd.; CP, Benzyltriethylammonium Chloride: Chengdu Kelong Chemical Reagent Factory; AR, Dimethyl Sulfoxide: Chengdu Kelong Chemical Reagent Factory; AR, N,N-Dimethylformamide: Chengdu Kelong Chemical Reagent Factory; AR, n-Hexane: Chengdu Kelong Chemical Reagent Factory; AR, Cyclohexane: Chengdu Kelong Chemical Reagent Factory; AR.

[0041] Example 1

[0042] The synthesis method in this embodiment includes the following steps:

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

[0044] Add 93.1 g (98% by mass, 0.50 mol) of 2,3,5-trichloropyridine, 300 mL of sulfolane, and 32.2 g (99% by mass, 0.55 mol) of powdered potassium fluoride to a four-necked flask equipped with a thermometer, reflux condenser, and stirrer. Heat to 155-160 °C and maintain for 8 h. Take a sample for analysis. At this point, the content of 2,3,5-trichloropyridine is less than 1.0%. Stop the reaction, cool to room temperature, filter, and wash the solid three times with sulfolane (10 mL each time). Combine the filtrate and washings.

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

[0046] Add 1.0 g of tetrabutylammonium bromide catalyst and 35.5 g of powdered solid potassium cyanide (99% by mass, 0.55 mol) to the 3,5-dichloro-2-fluoropyridine solution obtained in step (1), and heat to 120-125 °C to carry out the cyanation reaction. During the reaction, samples were taken to monitor changes in the content of intermediates and products. The reaction was stopped when the intermediate content was less than 2.0% (approximately 10 hours), cooled to room temperature, and filtered. The resulting solid was washed three times with sulfolane (10 mL each time). The filtrates and washings were combined and concentrated under reduced pressure (temperature less than 150°C, vacuum greater than -0.095 MPa) to recover the solvent sulfolane. 500 mL of cyclohexane was added to the residue, and the mixture was heated to 40-45°C. The residue was washed with water and the phases were separated. The organic phase was cooled to 0-5°C to crystallize. The mixture was filtered (using rapid filter paper with a pore size of 80-120 micrometers) and dried under reduced pressure (temperature less than 60°C) to obtain 75.5 g of product (product content 98.6%, moisture less than 0.1%), with a yield of 86.1% (based on 2,3,5-trichloropyridine).

[0047] Example 2

[0048] The synthesis method in this embodiment includes the following steps:

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

[0050] Add 93.1 g (98% by mass, 0.50 mol) of 2,3,5-trichloropyridine, 300 mL of dimethyl sulfoxide, and 23.3 g (99% by mass, 0.55 mol) of powdered sodium fluoride to a four-necked flask equipped with a thermometer, reflux condenser, and stirrer. Heat to reflux and maintain for 8 h. Take a sample for analysis. At this point, the content of 2,3,5-trichloropyridine is less than 1.0%. Stop the reaction, cool to room temperature, filter, and wash the solid three times with dimethyl sulfoxide (10 mL each time). Combine the filtrate and washings.

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

[0052] Add 1.0 g of catalyst benzyltriethylammonium chloride and 27.2 g of powdered solid sodium cyanide (99% by mass, 0.55 mol) to the 3,5-dichloro-2-fluoropyridine solution obtained in step (1), and heat to 125-130 °C to carry out the cyanation reaction. During the reaction, samples were taken to monitor changes in the content of intermediates and products. The reaction was stopped when the intermediate content was less than 2.0% (approximately 10 hours), cooled to room temperature, and filtered. The resulting solid was washed three times with dimethyl sulfoxide (10 mL each time). The filtrates and washings were combined and concentrated under reduced pressure (temperature less than 150°C, vacuum greater than -0.095 MPa) to recover the solvent sulfolane. 500 mL of n-hexane was added to the residue, and the mixture was heated to 40-45°C. The residue was washed with water and the phases were separated. The organic phase was cooled to 0-5°C to crystallize. The mixture was filtered (using rapid filter paper with a pore size of 80-120 micrometers) and dried under reduced pressure (temperature less than 60°C) to obtain 73.7 g of product (product content 98.5%, moisture less than 0.1%), with a yield of 83.9% (based on 2,3,5-trichloropyridine).

[0053] Example 3

[0054] The synthesis method in this embodiment includes the following steps:

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

[0056] Add 93.1 g (98% by mass, 0.50 mol) of 2,3,5-trichloropyridine, 300 mL of N,N-dimethylformamide, and 32.2 g (99% by mass, 0.55 mol) of powdered potassium fluoride to a four-necked flask equipped with a thermometer, reflux condenser, and stirrer. Heat to reflux and maintain for 8 h. Take a sample for analysis. At this time, the content of 2,3,5-trichloropyridine is less than 1.0%. Stop the reaction, cool to room temperature, filter, and wash the solid three times with N,N-dimethylformamide (10 mL each time). Combine the filtrate and washings.

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

[0058] Add 1.0 g of tetrabutylammonium bromide catalyst and 27.2 g of powdered solid sodium cyanide (99% by mass, 0.55 mol) to the 3,5-dichloro-2-fluoropyridine solution obtained in step (1), and heat to reflux to carry out the cyanidation reaction. During the reaction, samples were taken to monitor changes in the content of intermediates and products. The reaction was stopped when the intermediate content was less than 2.0% (approximately 11 hours), cooled to room temperature, and filtered. The resulting solid was washed three times (10 mL each time) with N,N-dimethylformamide. The filtrates and washings were combined and concentrated under reduced pressure (temperature less than 150°C, vacuum greater than -0.095 MPa) to recover the solvent sulfolane. 500 mL of cyclohexane was added to the residue, and the mixture was heated to 40-45°C. The residue was washed with water and the phases were separated. The organic phase was cooled to 0-5°C to crystallize. The mixture was filtered (using rapid filter paper with a pore size of 80-120 micrometers) and dried under reduced pressure (temperature less than 60°C) to obtain 72.6 g of product (product content 98.0%, moisture less than 0.1%), with a yield of 82.3% (based on 2,3,5-trichloropyridine).

[0059] In summary, this invention uses inexpensive and readily available cyanide salts such as sodium cyanide or potassium cyanide as cyaniding reagents, and the amount of cyanide salt used is much lower than that of existing methods, which can obtain high yield and high content of target product, thereby significantly reducing production costs and greatly reducing the generation of wastewater in the three wastes. It is a highly efficient and environmentally friendly method for producing 3,5-dichloro-2-cyanopyridine.

[0060] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A method for the synthesis of 3,5-dichloro-2-cyanopyridine, characterized in that, Includes the following steps: (1) Synthesis of 3,5-dichloro-2-fluoropyridine Add 93.1 g of 0.50 mol of 98% 2,3,5-trichloropyridine, 300 mL of sulfolane, and 32.2 g of 0.55 mol of 99% powdered potassium fluoride to a four-necked flask equipped with a thermometer, reflux condenser, and stirrer. Heat to 155-160 °C and maintain for 8 h. Take a sample for analysis. At this point, the content of 2,3,5-trichloropyridine is less than 1.0%. Stop the reaction, cool to room temperature, filter, and wash the solid three times with 10 mL of sulfolane each time. Combine the filtrate and washings. (2) Synthesis of 3,5-dichloro-2-cyanopyridine Add 1.0 g of tetrabutylammonium bromide catalyst and 35.5 g of 0.55 mol of 99% potassium cyanide powder to the 3,5-dichloro-2-fluoropyridine solution obtained in step (1). Heat to 120-125℃ for cyanation reaction. During the reaction, take samples to detect the changes in the content of intermediates and products. Keep warm for 10 h until the content of intermediates is less than 2.0%. Stop the reaction, cool to room temperature, filter, and wash the obtained solid three times with sulfolane, 10 mL each time. Combine the filtrate and washing liquid, concentrate under reduced pressure at a temperature less than 150℃ and a vacuum greater than -0.095 MPa, recover the solvent sulfolane, add 500 mL of cyclohexane to the residue, heat to 40-45℃, wash with water, separate the phases, cool the organic phase to 0-5℃ to crystallize, filter with rapid filter paper with a pore size of 80-120 micrometers, and dry under reduced pressure at a temperature less than 60℃ to obtain the product.

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