2, 6-dichloro-3-cyano-4-methylpyridine and preparation method thereof
By optimizing the synthesis method of 2,6-dichloro-3-cyano-4-methylpyridine, using a weak base carbonate catalyst and a dehydrating agent, and combining distillation technology to carry out the reaction at low temperature, the problems of expensive raw materials and numerous side reactions were solved, and high-yield, high-purity product production was achieved.
Patent Information
- Application Number
- CN202510956520.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-11
- Publication Date
- 2025-10-31
AI Technical Summary
Existing methods for synthesizing 2,6-dichloro-3-cyano-4-methylpyridine involve expensive raw materials, numerous side reactions, low yields, and low purity. Furthermore, side reactions are easily triggered under high temperature and high pressure conditions, resulting in high production costs and low efficiency.
Weak base carbonate catalysts are used to control the reaction rate in stages. By distillation is combined to remove byproducts and dehydrating agents. Highly polar solvents are used to react with chlorination catalysts at lower temperatures to optimize reaction conditions and reduce side reactions.
It significantly improved product yield and quality, reduced production costs, reduced environmental pollution, and enhanced production efficiency and product purity.
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Figure CN120865078A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of intermediate preparation technology, and in particular to a 2,6-dichloro-3-cyano-4-methylpyridine and its preparation method. Background Technology
[0002] 2,6-Dichloro-3-cyano-4-methylpyridine, as an important organic intermediate, is widely used in the pharmaceutical field and in the synthesis of novel materials, such as nevirapine, liquid crystal materials, and directional luminescent pigments. Due to its wide application in multiple fields, developing an efficient and economical synthetic method is crucial.
[0003] Currently, there are various methods for synthesizing 2,6-dichloro-3-cyano-4-methylpyridine. The most widely used industrial preparation generally involves two steps: the first step uses ethyl acetoacetate and cyanoacetamide as starting materials to prepare 2,6-dihydroxy-3-cyano-4-methylpyridine via cyclization under strong base catalysis; the second step uses 2,6-dihydroxy-3-cyano-4-methylpyridine and phosphorus oxychloride as main starting materials to prepare the target product 2,6-dichloro-3-cyano-4-methylpyridine under high temperature and high pressure conditions (temperature > 180℃, pressure > 0.6 MPa). However, this method has several problems: First, cyanoacetamide is difficult to obtain and expensive as a starting material, directly increasing raw material costs. Second, the first step involves numerous side reactions, resulting in a final product yield of less than 80%, further increasing production costs and reducing economic efficiency. Finally, the high temperature and pressure environment of the second step easily triggers a series of side reactions. These side reactions not only affect the purity of the product but also limit the yield of the final product, making it difficult to break through the 80% yield barrier. In addition, the solubility of the catalyst in water also makes recycling difficult, increasing the environmental burden and raising production costs.
[0004] Therefore, there is an urgent need to develop an economical, environmentally friendly and efficient synthetic route to improve the production efficiency of 2,6-dichloro-3-cyano-4-methylpyridine. Summary of the Invention
[0005] In view of this, the present invention proposes a high-yield and efficient method for preparing 2,6-dichloro-3-cyano-4-methylpyridine, thereby improving the overall economic efficiency of the process.
[0006] In a first aspect, the present invention provides a method for preparing 2,6-dichloro-3-cyano-4-methylpyridine, comprising the following steps: S1, acetoacetamide and ethyl cyanoacetate were reacted in organic solvent I with carbonate as catalyst to condense the byproduct ethanol, and then a dehydrating agent was added for cyclization to obtain 2,6-dihydroxy-3-cyano-4-methylpyridine. S2. The 2,6-dihydroxy-3-cyano-4-methylpyridine obtained in step S1 is subjected to chlorination in organic solvent II under the action of 4-dimethylaminopyridine (DMAP) and phosphorus pentachloride to obtain 2,6-dichloro-3-cyano-4-methylpyridine.
[0007] In one or more possible embodiments, in step S1, the carbonate is selected from potassium carbonate or cesium carbonate; the molar ratio of the acetylacetamide, the ethyl cyanoacetate and the carbonate is 1:1:(1.1~1.3).
[0008] In one or more possible embodiments, in step S1, the organic solvent I is selected from one or more of toluene, xylene, N,N-dimethylformamide, or dimethyl sulfoxide.
[0009] In one or more possible embodiments, the mass ratio of the acetylacetamide to the organic solvent I is 1:(2.5~4).
[0010] In one or more possible embodiments, in step S1, the absorbent is selected from calcium chloride, magnesium sulfate, or sodium sulfate.
[0011] In one or more possible embodiments, the mass ratio of the absorbent to the acetylacetamide is (0.25~0.35):1.
[0012] In one or more possible embodiments, in step S1, the condensation temperature is 80~85℃; the cyclization temperature is 68~70℃; and the cyclization time is 5~6h.
[0013] In one or more possible embodiments, in step S2, the organic solvent II is selected from one or more of dichlorobenzene, nitrobenzene, or N,N-dimethylaniline.
[0014] In one or more possible embodiments, in step S2, the molar ratio of 2,6-dihydroxy-3-cyano-4-methylpyridine, 4-dimethylaminopyridine and phosphorus pentachloride is (0.192~0.2):(0.0008~0.0025):(0.15~0.2).
[0015] In one or more possible embodiments, the chlorination reaction is carried out at a temperature of 120-150°C for a time of 12-16 hours.
[0016] Secondly, the present invention relates to 2,6-dichloro-3-cyano-4-methylpyridine prepared by the above preparation method, wherein the purity of the product is not less than 99.0% and the total molar yield of the two steps is greater than 95%.
[0017] The 2,6-dichloro-3-cyano-4-methylpyridine and its preparation method provided by this invention have the following advantages over the prior art: The method for preparing 2,6-dichloro-3-cyano-4-methylpyridine provided by this invention significantly improves product yield and quality through optimized reaction conditions. The use of a weak base carbonate catalysis and staged rate control, combined with distillation to remove byproducts and the application of a desiccant, effectively reduces side reactions. Furthermore, the use of a highly polar solvent and a chlorination catalyst at a lower temperature avoids the side reaction problems caused by high temperature and high pressure. Both the solvent and catalyst used in the entire process can be recycled and reused, reducing production costs and environmental pollution. This preparation method is not only environmentally friendly and economical but also significantly improves production efficiency and product quality. Attached Figure Description
[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0019] Figure 1 The reaction equation for the preparation of 2,6-dichloro-3-cyano-4-methylpyridine provided by the present invention.
[0020] Figure 2 The nuclear magnetic resonance spectrum of 2,6-dichloro-3-cyano-4-methylpyridine prepared in Example 1 of this invention. Detailed Implementation
[0021] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.
[0022] The present invention will be further explained below with reference to specific implementation methods. Unless otherwise specified, the main materials involved in the embodiments are all commercially available conventional products.
[0023] Example 1 like Figure 1As shown, the 2,6-dichloro-3-cyano-4-methylpyridine of this embodiment is prepared by the following steps: S1. Mix 20.2 g (0.2 mol, 1 eq) acetylacetamide, 22.6 g (0.2 mol, 1 eq) ethyl cyanoacetate, 50 g toluene, and 0.22 mol potassium carbonate in a four-necked flask equipped with a distillation column and apparatus. Stir and gradually heat under normal pressure, distilling off the ethanol byproduct until the internal temperature reaches 85°C and no further fractions are obtained. Cool to 68°C, add 5 g calcium chloride to the four-necked flask, and maintain the reaction temperature for 5 hours. When the content of intermediate II is <0.5% as determined by HPLC, stop the reaction. Filter the solid while hot (it can be reused after activation). Cool the filtrate to 5°C with stirring, filter, and dry to obtain 2,6-dihydroxy-3-cyano-4-methylpyridine. The solvent can be recovered and reused after simple distillation.
[0024] According to calculations, the molar yield of 2,6-dihydroxy-3-cyano-4-methylpyridine prepared in step S1 of this embodiment is greater than 96%, and the content detected by liquid chromatography-HPLC is >99.0%.
[0025] S2. To the 2,6-dihydroxy-3-cyano-4-methylpyridine obtained in S1, add 0.1 g DMAP, 0.15 mol phosphorus pentachloride, and 60 g dichlorobenzene sequentially. Stir and gradually heat to 120°C for 12 hours. When the 2,6-dihydroxy-3-cyano-4-methylpyridine content is <0.5% as detected by liquid chromatography-HPLC, stop the reaction. Cool to 40°C and add the reaction mixture dropwise to 150 mL of ice water under stirring, completing the addition over approximately 1 hour. After the addition is complete, stir at 40°C for 1 hour, then cool to 20°C, filter, wash with water, and dry to obtain the product 2,6-dichloro-3-cyano-4-methylpyridine. The filtered mother liquor can be neutralized to pH 7 with alkali, and the solvent used can be separated, recovered by high-vacuum distillation, and directly reused.
[0026] The mass of the 2,6-dichloro-3-cyano-4-methylpyridine product prepared in this example was determined to be approximately 35.4 g. The content was >99.0% as determined by liquid chromatography-HPLC, and the nuclear magnetic resonance spectrum is as follows. Figure 2 As shown.
[0027] Calculations show that the total molar yield of the two steps in this embodiment is >95%.
[0028] Example 2 The 2,6-dichloro-3-cyano-4-methylpyridine of this embodiment was prepared by the following steps: S1. Mix 20.2 g (0.2 mol, 1 eq) acetylacetamide, 22.6 g (0.2 mol, 1 eq) ethyl cyanoacetate, 60 g xylene, and 0.22 mol cesium carbonate in a four-necked flask equipped with a distillation column and apparatus. Stir and gradually heat under normal pressure, distilling off the ethanol byproduct until the internal temperature reaches 85°C and no further fractions are obtained. Cool to 70°C, add 5 g sodium sulfate to the four-necked flask, and maintain the reaction temperature for 5 hours. Stop the reaction when the content of intermediate II is <0.5% as determined by HPLC. Filter the solid while hot (it can be reused after activation). Cool the filtrate to 5°C with stirring, filter, and dry to obtain 2,6-dihydroxy-3-cyano-4-methylpyridine. The solvent can be recovered and reused after simple distillation.
[0029] According to calculations, the molar yield of 2,6-dihydroxy-3-cyano-4-methylpyridine prepared in step S1 of this embodiment is greater than 96%, and the content detected by liquid chromatography-HPLC is >99.0%.
[0030] S2. Add 0.2 g DMAP, 0.18 mol phosphorus pentachloride, and 80 g nitrobenzene sequentially to the 2,6-dihydroxy-3-cyano-4-methylpyridine obtained in S1. While stirring, gradually raise the temperature to 130℃ and react for 14 hours. When the content of 2,6-dihydroxy-3-cyano-4-methylpyridine is <0.5% as detected by liquid chromatography-HPLC, stop the reaction. After cooling to 45℃, add the reaction mixture dropwise to 160 ml of ice water under stirring, completing the addition over approximately 1.5 hours. After the addition is complete, stir at 45℃ for 2 hours, then cool to 25℃, filter, wash with water, and dry to obtain the product 2,6-dichloro-3-cyano-4-methylpyridine. The filtered mother liquor can be neutralized to pH 8 with alkali, and the solvent used can be separated by high-vacuum distillation and directly reused.
[0031] The product weight of 2,6-dichloro-3-cyano-4-methylpyridine was determined to be approximately 35.5g, and the content was >99.0% as detected by liquid chromatography-HPLC.
[0032] Calculations show that the total molar yield of the two steps in this embodiment is >95%.
[0033] Example 3 The 2,6-dichloro-3-cyano-4-methylpyridine of this embodiment was prepared by the following steps: S1. Mix 20.2 g (0.2 mol, 1 eq) acetylacetamide, 22.6 g (0.2 mol, 1 eq) ethyl cyanoacetate, 60 g DMSO (dimethyl sulfoxide), and 0.24 mol potassium carbonate in a four-necked flask equipped with a distillation column and apparatus. Stir and gradually heat under normal pressure, distilling off the ethanol byproduct until the internal temperature reaches 85°C and no further fractions are obtained. Cool to 70°C, add 6 g magnesium sulfate to the four-necked flask, and maintain the reaction temperature for 6 hours. Stop the reaction when the content of intermediate II is <0.5% as determined by HPLC. Filter the solid while hot (it can be reused after activation). Cool the filtrate to 10°C with stirring, filter, and dry to obtain 2,6-dihydroxy-3-cyano-4-methylpyridine. The solvent can be recovered and reused after simple distillation.
[0034] According to calculations, the molar yield of 2,6-dihydroxy-3-cyano-4-methylpyridine prepared in step S1 of this embodiment is greater than 96%, and the content detected by liquid chromatography-HPLC is >99.0%.
[0035] S2. Add 0.3 g DMAP, 0.2 mol phosphorus pentachloride, and 100 g N,N-dimethylaniline sequentially to the 2,6-dihydroxy-3-cyano-4-methylpyridine obtained in S1. While stirring, gradually raise the temperature to 150 °C and react for 16 hours. When the content of 2,6-dihydroxy-3-cyano-4-methylpyridine is <0.5% as detected by liquid chromatography-HPLC, stop the reaction. After cooling to 40 °C, add the reaction mixture dropwise to 200 ml of ice water under stirring, completing the addition over approximately 2 hours. After the addition is complete, stir at 45 °C for 2 hours, then cool to 25 °C, filter, wash with water, and dry to obtain the product 2,6-dichloro-3-cyano-4-methylpyridine. The filtered mother liquor can be neutralized to pH 7 with alkali, and the solvent used can be separated by high-vacuum distillation and recovered for direct reuse.
[0036] The product weight of 2,6-dichloro-3-cyano-4-methylpyridine was determined to be approximately 35.8g, and the content was >99.0% as determined by liquid chromatography-HPLC.
[0037] Calculations show that the total molar yield of the two steps in this embodiment is >95%.
[0038] Comparative Example 1 The difference from Example 1 is that no absorbent was added, while the rest of the steps remained the same.
[0039] According to calculations, the molar yield of 2,6-dihydroxy-3-cyano-4-methylpyridine obtained in step S1 of the comparative example is about 80%, and the content detected by liquid chromatography-HPLC is about 96%.
[0040] The reason for this may be that the water generated by the cyclization reaction not only affects the reaction equilibrium process, but also promotes unnecessary side reactions, such as the hydrolysis of cyano groups, thereby reducing the yield and purity of the first step product.
[0041] Comparative Example 2 The difference from Example 1 is that in step S1, the amount of carbonate used is 0.21 mol, while the other steps remain unchanged.
[0042] According to calculations, the molar yield of 2,6-dihydroxy-3-cyano-4-methylpyridine obtained in step S1 of the comparative example is about 85%, and the content detected by liquid chromatography-HPLC is about 95%.
[0043] The possible reason is that when the amount of carbonate is insufficient, the alkalinity of the reaction system cannot reach the required level, the reactants may not be fully activated, the expected chemical reaction cannot proceed efficiently, and the carbonate remains in the reaction mixture, which reduces the yield of the target product and affects the purity of the product.
[0044] Comparative Example 3 The difference from Example 1 is that in step S1, a distillation column was not installed to remove the byproduct ethanol, while the other steps remain unchanged.
[0045] According to calculations, the molar yield of 2,6-dihydroxy-3-cyano-4-methylpyridine obtained in step S1 of the comparative example is about 90%, and the content is 92% as detected by liquid chromatography-HPLC.
[0046] The possible reasons are: byproduct ethanol hinders the reaction equilibrium process, and the raw materials are not completely converted.
[0047] Comparative Example 4 The difference from Example 1 is that in step S2, 0.2 mol of phosphorus trichloride or phosphorus oxychloride is used, while the other steps remain unchanged.
[0048] The product weight of 2,6-dichloro-3-cyano-4-methylpyridine was determined to be approximately 25g, and the content was approximately 92% as determined by liquid chromatography-HPLC.
[0049] Calculations show that the total molar yield of the two steps in this embodiment is <70%.
[0050] The possible reason is that phosphorus trichloride or phosphorus oxychloride has a low boiling point, making it impossible to heat up to the predetermined reaction temperature, thus preventing complete conversion.
[0051] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A method for preparing 2,6-dichloro-3-cyano-4-methylpyridine, characterized in that, Includes the following steps: S1, acetoacetamide and ethyl cyanoacetate were reacted in organic solvent I with carbonate as catalyst to condense the byproduct ethanol, and then a dehydrating agent was added for cyclization to obtain 2,6-dihydroxy-3-cyano-4-methylpyridine. S2. The 2,6-dihydroxy-3-cyano-4-methylpyridine obtained in step S1 is subjected to chlorination in organic solvent II under the action of 4-dimethylaminopyridine and phosphorus pentachloride to obtain 2,6-dichloro-3-cyano-4-methylpyridine.
2. The method for preparing 2,6-dichloro-3-cyano-4-methylpyridine as described in claim 1, characterized in that, In step S1, the carbonate is selected from potassium carbonate or cesium carbonate; The molar ratio of the acetoacetamide, the ethyl cyanoacetate, and the carbonate is 1:1:(1.1~1.3).
3. The method for preparing 2,6-dichloro-3-cyano-4-methylpyridine as described in claim 1, characterized in that, In step S1, the organic solvent I is selected from toluene, xylene, N,N-dimethylformamide, or dimethyl sulfoxide.
4. The method for preparing 2,6-dichloro-3-cyano-4-methylpyridine as described in claim 1, characterized in that, In step S1, the absorbent is selected from calcium chloride, magnesium sulfate, or sodium sulfate.
5. The method for preparing 2,6-dichloro-3-cyano-4-methylpyridine as described in claim 4, characterized in that, The mass ratio of the absorbent to the acetylacetamide is (0.25~0.35):
1.
6. The method for preparing 2,6-dichloro-3-cyano-4-methylpyridine as described in claim 1, characterized in that, In step S1, the condensation temperature is 80~85℃; the cyclization temperature is 68~70℃; and the cyclization time is 5~6h.
7. The method for preparing 2,6-dichloro-3-cyano-4-methylpyridine as described in claim 1, characterized in that, In step S2, the organic solvent II is selected from dichlorobenzene, nitrobenzene, or N,N-dimethylaniline.
8. The method for preparing 2,6-dichloro-3-cyano-4-methylpyridine as described in claim 7, characterized in that, In step S2, the molar ratio of 2,6-dihydroxy-3-cyano-4-methylpyridine, 4-dimethylaminopyridine and phosphorus pentachloride is (0.192~0.2):(0.0008~0.0025):(0.15~0.2).
9. The method for preparing 2,6-dichloro-3-cyano-4-methylpyridine as described in claim 7, characterized in that, The chlorination reaction is carried out at a temperature of 120-150°C for 12-16 hours.
10. A 2,6-dichloro-3-cyano-4-methylpyridine prepared by the preparation method according to any one of claims 1 to 9, characterized in that, The purity of the 2,6-dichloro-3-cyano-4-methylpyridine is not less than 99.0%, and the total molar yield of the two steps is greater than 95%.