CN113292489B - Preparation method of dichlorodialkyl nicotinonitrile - Google Patents
Preparation method of dichlorodialkyl nicotinonitrile Download PDFInfo
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- CN113292489B CN113292489B CN202110667044.XA CN202110667044A CN113292489B CN 113292489 B CN113292489 B CN 113292489B CN 202110667044 A CN202110667044 A CN 202110667044A CN 113292489 B CN113292489 B CN 113292489B
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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Abstract
The invention provides a preparation method of dichlorodialkyl nicotinonitrile, belonging to the technical field of chemical synthesis and comprising the following steps: performing chlorination reaction by using a compound I as a raw material and chlorine or N-chlorosuccinimide as a chlorination reagent to generate a compound II; carrying out condensation reaction on the compound II and cyanoacetamide under the action of alkali to generate a compound III; and carrying out chlorination reaction on the compound III and phosphorus oxychloride to generate the dichlorodialkyl nicotinonitrile. The preparation method of the invention avoids using sulfuryl chloride as a chlorinating agent, thereby avoiding the generation of sulfur dioxide tail gas and avoiding the corrosion of the generated acidic waste gas to equipment and the like.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of dichlorodialkyl nicotinonitrile.
Background
The oligoprocone (opiane) is a drug developed by Portugal Bial-Portella pharmaceutical company, is a novel small chemical molecular entity, is a novel potent and selective catechol-O-methyltransferase inhibitor (COMT inhibitor), and can be clinically used for treating adult Parkinson's disease and patients with terminal symptom fluctuation by combining levodopa and a dopa decarboxylase inhibitor.
The key intermediate in the synthesis of oppicapone is 2, 5-dichloro-4, 6-dimethylnicotinonitrile, and the prior art (WO 2013/089573 a1) discloses a synthetic route for 2, 5-dichloro-4, 6-dimethylnicotinonitrile:
the method is characterized in that cyanoacetamide and acetylacetone are used as raw materials to carry out condensation reaction, and then chlorination reaction is carried out twice, wherein chlorination of C-H bonds is carried out by taking sulfonyl chloride as a chlorination reagent, and chlorination of C ═ O bonds is carried out by taking phosphorus oxychloride as a chlorination reagent.
In the process of implementing the invention, the inventors found that the above synthetic route has at least the following defects:
when C-H is chlorinated by taking sulfuryl chloride as a chlorinating agent, a large amount of sulfur dioxide and hydrogen chloride gas can be generated, and the generated sulfur dioxide gas cannot be effectively absorbed and utilized, so that waste gas pollution is caused.
Disclosure of Invention
Based on the background problems, the invention aims to provide a preparation method of dichlorodialkyl nicotinonitrile, which avoids using sulfuryl chloride as a chlorinating reagent, thereby reducing the production difficulty and reducing the output of acid waste gas.
In order to achieve the above object, the embodiment of the present invention provides a technical solution:
a method for preparing dichlorodialkyl nicotinonitrile comprises the following steps:
step I: performing chlorination reaction by using a compound I shown in a formula I as a raw material and using chlorine or N-chlorosuccinimide as a chlorination reagent to generate a compound II shown in a formula II;
step II: carrying out condensation reaction on the compound II and cyanoacetamide under the action of alkali to generate a compound III shown in a formula III;
step III: performing chlorination reaction on the compound III and phosphorus oxychloride to generate dichlorodialkyl nicotinonitrile shown as a formula IV;
wherein the content of the first and second substances,
the formula I is:
formula II is
Formula III is
Formula IV is
Further, the R group is selected from one of methyl, ethyl, propyl, isopropyl and sec-butyl.
Further, in the step I, the mol ratio of the compound I to the chlorine gas/N-chlorosuccinimide is controlled to be 1: 1-1.1.
Furthermore, in the step I, when the chlorine is used as a chlorinating reagent to synthesize the compound II, the reaction temperature of the compound I and the chlorine is controlled to be 5-50 ℃, the reaction pressure is 1-2atm, and the reaction time is 3-5 h.
Further, in the step II, when the compound II reacts with cyanoacetamide, alcohol is used as a solvent; controlling the molar ratio of the cyanoacetamide to the compound II to be 1:1-1.1, and controlling the molar ratio of the base to the cyanoacetamide to be 0.04-0.06: 1.
Furthermore, in the step II, the reaction temperature of the compound II and the cyanoacetamide is controlled to be 50-75 ℃, and the reaction time is controlled to be 24-48 h.
Further, in the step III, the molar ratio of the compound III to the phosphorus oxychloride is controlled to be 1: 3.5-5.5.
Furthermore, the reaction temperature of the compound III and the phosphorus oxychloride is controlled to be 80-100 ℃, and the reaction time is 1.5-3.5 h.
Further, in the step III, when the compound III reacts with phosphorus oxychloride, a phase transfer catalyst is added, and the molar ratio of the phase transfer catalyst to the compound III is 0.45-0.55: 1.
Further, in the step III, after the reaction is finished, distilling the reaction liquid under reduced pressure until a solid I is separated out, and then dissolving the separated solid I in an organic solvent I to form a feed liquid;
and adding the feed liquid into water, stirring, standing, layering, washing the lower layer with water, distilling to separate out a solid II, adding the separated out solid II into an organic solvent II for dissolving, cooling, separating out the material, filtering, and leaching to obtain the dichlorodialkyl nicotinonitrile.
Compared with the prior art, the invention has the following effects:
1. the method takes the compound I as a raw material, takes chlorine or N-chlorosuccinimide (NCS) as a chlorination reagent to react to generate the compound II, and then carries out condensation reaction with cyanoacetamide to generate the compound III, thereby avoiding using sulfuryl chloride as a chlorination reagent, avoiding generating sulfur dioxide tail gas and avoiding corrosion of generated acid waste gas to equipment and the like.
2. When chlorine is used as a chlorination reagent, the excess unreacted chlorine can be completely absorbed by the alkaline solution and converted into sodium hypochlorite as a byproduct, so that the economic benefit is improved.
3. The invention controls the reaction temperature of the compound I and chlorine to regulate and control the reaction pressure, and when the temperature is higher than 50 ℃ and the pressure is higher than 2atm, polychlorinated impurities can be generated.
4. According to the invention, when the compound II reacts with cyanoacetamide, the excessive compound II is controlled, so that the reaction can be completely ensured.
5. When the compound III reacts with phosphorus oxychloride, the phosphorus oxychloride is used as a solvent, so that the molar ratio of the phosphorus oxychloride can be up to 5.5 times of that of the compound III, the phosphorus oxychloride after the reaction can be recycled, the reaction temperature of the compound III and the phosphorus oxychloride is controlled to be 80-100 ℃, and when the temperature is lower than 80 ℃, the reaction materials are difficult to completely dissolve.
Detailed Description
In order to solve the defect that a large amount of sulfur dioxide gas generated in the existing 2, 5-dichloro-4, 6-dimethylnicotinonitrile synthesis process is difficult to recycle, the embodiment of the invention provides a preparation method of dichlorodialkylnicotinonitrile, which takes a compound I as a raw material, takes chlorine or N-chlorosuccinimide (NCS) as a chlorination reagent to react to generate a compound II, and then carries out condensation reaction with cyanoacetamide to generate a compound III.
The invention will be elucidated by means of specific embodiments.
Example 1
The preparation method of the 2, 5-dichloro-4, 6-dimethylnicotinonitrile comprises the following steps:
step I: adding 1kg of acetylacetone (9.988mol, 1.0eq) into a 2L pressure reaction kettle, controlling the temperature of a reaction system to be 5 ℃ under the stirring condition, closing other valves of the reaction kettle, slowly introducing 708g of chlorine (9.988mol, 1.0eq) from a feed inlet, closing all the valves, heating, slowly increasing the pressure in the kettle along with the temperature rise, controlling the temperature to keep the pressure in the reaction kettle at 1atm, and reacting for 5 hours to generate 3-chloro-acetylacetone; the reaction is shown in equation (I):
monitoring the sampling gas phase, and after the reaction is finished, discharging the residual chlorine gas into a sodium hydroxide aqueous solution for absorption to obtain a sodium hypochlorite byproduct; the reaction yielded 1.249kg of product, reaction yield: 91.2%, gas phase purity: 98.1 percent.
The reaction product is sampled and subjected to nuclear magnetic hydrogen spectrum test, and the result is as follows: 1 HNMR:. delta.2.5 (6H, s), 4.6(1H, s), from which it was found that the reaction product was indeed 3-chloro-acetylacetone.
Step II: in a 1L glass four-necked flask, 100g (1.189mol, 1.0eq) of cyanoacetamide, 160g (1.189mol, 1.0eq) of 3-chloro-acetylacetone, morpholine: 4.4g (0.05mol, 0.04eq) and 850g (26.53mol, 22.3eq) of methanol were stirred and heated, and the reaction was maintained at 50 ℃ for 48 hours, as shown in equation (II):
the liquid phase monitoring reaction is completed, the temperature is reduced to 10-15 ℃ after the reaction is finished, the filtration is carried out, and the methanol is leached to obtain 5-chloro-4, 6-dimethyl-3-cyanopyridone; and (5) drying to obtain a dry product: 200.5g, yield: 91.3%, liquid phase purity: 98.9 percent.
The reaction product is sampled and subjected to nuclear magnetic hydrogen spectrum test, and the result is as follows: 1HNMR 2.36 (. delta.2H, s),. 2.41(3H, s),. 3.31(1H, brs) and the reaction product was indeed 5-chloro-4, 6-dimethyl-3-cyanopyridone.
Step III: in a 2L glass four-neck flask, 1675g of phosphorus oxychloride (10.924mol, 3.5eq) was added, and 5-chloro-4, 6-dimethyl-3-cyanopyridone was added with stirring: 570g (3.121mol, 1.0eq), tetramethylammonium chloride: 154g (1.40mol, 0.45eq), heated to 80 ℃ and reacted for 3.5h as shown in equation (III):
the thin layer shows that the raw material disappears, the raw material is distilled under reduced pressure, phosphorus oxychloride is evaporated until solid I is precipitated, the temperature is reduced, then 2500mL of dichloromethane is added, the mixture is stirred until the solid I is completely dissolved, and dichloromethane feed liquid is obtained, wherein in other embodiments, trichloromethane and dichloroethane can be used for replacing dichloromethane;
adding 1000ml of water into a 5L glass bottle, slowly pouring the dichloromethane feed liquid into the water while stirring, controlling the temperature to be 15-35 ℃, stirring and layering after all the dichloromethane feed liquid is added, washing the lower dichloromethane feed liquid with 200ml of water twice, then distilling and concentrating, and distilling under reduced pressure in the later period until a solid II is separated out;
adding the solid II into 2300g of isopropanol to dissolve, wherein in other embodiments, the isopropanol can be replaced by methanol, ethanol, petroleum ether and n-heptane, cooling and separating the materials after complete dissolution, filtering at 0-5 ℃, leaching by precooled isopropanol to obtain a reaction product, and drying to obtain a product: 597g, yield: 94.5%, purity: 99.3 percent.
The reaction product is sampled and subjected to nuclear magnetic hydrogen spectrum test, and the result is as follows: 1 HNMR:. delta.263 (3H, s), 2.68(3H, s), from which it was found that the reaction product was indeed 2, 5-dichloro-4, 6-dimethylnicotinonitrile.
Example 2
The preparation method of the 2, 5-dichloro-4, 6-dimethylnicotinonitrile comprises the following steps:
step I: adding 1kg of acetylacetone (9.988mol, 1.0eq) into a 2L pressure reaction kettle, controlling the temperature of a reaction system to be 10 ℃ under the stirring condition, closing other valves of the reaction kettle, slowly introducing 720g of chlorine (10.154mol, 1.02eq) from a feed inlet, closing all the valves, heating, slowly increasing the pressure in the kettle along with the temperature rise, controlling the temperature to keep the pressure in the reaction kettle at 1atm, and reacting for 5 hours to generate 3-chloro-acetylacetone;
sampling and monitoring gas phase, after the reaction is finished, discharging the residual chlorine into a sodium hydroxide aqueous solution for absorption to obtain a sodium hypochlorite byproduct; after the reaction, 1.263kg of 3-chloro-acetylacetone was obtained, and the reaction yield was: 92.1%, gas phase purity: 98.0 percent.
Step II: in a 1L glass four-necked flask, 100g of cyanoacetamide (1.189mol, 1.0eq), 172g of 3-chloro-acetylacetone (1.278mol, 1.07eq), morpholine: 5.2g (0.06mol, 0.05eq) of ethanol 1221.3g (26.51mol, 22.3eq) are stirred, heated and reacted for 48 hours at 50 ℃;
after the liquid phase monitoring reaction is finished, cooling to 10-15 ℃ after the reaction is finished, filtering, and leaching with methanol to obtain 5-chloro-4, 6-dimethyl-3-cyanopyridone; and (5) drying to obtain a dry product: 204.9g, yield: 93.1%, liquid phase purity: 98.7 percent.
Step III: in a 2L glass four-necked flask, 1800g of phosphorus oxychloride (11.739mol, 3.8eq) was added and 5-chloro-4, 6-dimethyl-3-cyanopyridone: 570g (3.121mol, 1.0eq), tetramethylammonium chloride: 171g (1.56mol, 0.5eq), heating to 85 ℃ and reacting for 3 h;
the post-treatment procedure after the end of the reaction was the same as in example 1, and 601.6g of the product was obtained after the end of the treatment, the product yield: 95.1%, product purity: 99.2 percent.
Example 3
The preparation method of the 2, 5-dichloro-4, 6-dimethylnicotinonitrile comprises the following steps:
step I: adding 1kg of acetylacetone (9.988mol, 1.0eq) into a 2L pressure reaction kettle, controlling the temperature of a reaction system to be 25 ℃ under the stirring condition, closing other valves of the reaction kettle, slowly introducing 720g of chlorine (10.154mol, 1.02eq) from a feed inlet, closing all the valves, heating, slowly increasing the pressure in the kettle along with the temperature rise, controlling the temperature to keep the pressure in the reaction kettle at 2atm, and reacting for 3h to generate 3-chloro-acetylacetone;
monitoring the sampling gas phase, and after the reaction is finished, discharging the residual chlorine gas into a sodium hydroxide aqueous solution for absorption to obtain a sodium hypochlorite byproduct; the reaction yielded 1.268kg of 3-chloro-acetylacetone, and the reaction yield was: 91.7%, gas phase purity: 97.2 percent.
Step II: in a 1L glass four-necked flask, 100g (1.189mol, 1.0eq) of cyanoacetamide, 172g (1.278mol, 1.07eq) of compound I, sodium hydroxide: 2.4g (0.06mol, 0.05eq), 850g (26.51mol, 22.3eq) of methanol, stirring and heating, and keeping the temperature at 65 ℃ for reaction for 36 hours;
the liquid phase monitoring reaction is completed, the temperature is reduced to 10-15 ℃ after the reaction is finished, the filtration is carried out, and the methanol is leached to obtain 5-chloro-4, 6-dimethyl-3-cyanopyridone; drying to obtain a dry product 207g, yield: 93.6%, liquid phase purity: 98.2 percent.
Step III: in a 2L glass four-necked flask, 1800g of phosphorus oxychloride (11.739mol, 3.8eq) was added and 5-chloro-4, 6-dimethyl-3-cyanopyridone: 570g (3.121mol, 1.0eq), tetrabutylammonium bromide: 503g (1.56mol, 0.5eq), heating to 90 ℃ and reacting for 2.5 h;
the post-treatment procedure after the completion of the reaction was the same as in example 1, and 596.5g of a product was obtained after the completion of the treatment, the product yield: 94.2%, product purity: 99.1 percent.
Example 4
The preparation method of the 2, 5-dichloro-4, 6-dimethylnicotinonitrile comprises the following steps:
step I: adding 1kg of acetylacetone (9.988mol, 1.0eq) into a 2L pressure reaction kettle, controlling the temperature of a reaction system to be 15 ℃ under the stirring condition, closing other valves of the reaction kettle, slowly introducing 779g of chlorine (10.987mol, 1.1eq) from a feed inlet, closing all the valves, heating, slowly increasing the pressure in the kettle along with the temperature rise, controlling the temperature to keep the pressure in the reaction kettle at 1atm, and reacting for 5 hours to generate 3-chloro-acetylacetone;
sampling and monitoring gas phase, after the reaction is finished, discharging the residual chlorine into a sodium hydroxide aqueous solution for absorption to obtain a sodium hypochlorite byproduct; after the reaction, 1.266kg of 3-chloro-acetylacetone was obtained, and the reaction yield was: 91.2%, gas phase purity: 96.8 percent.
Step II: in a 1L glass four-necked flask, 100g (1.189mol, 1.0eq) of cyanoacetamide, 176g (1.308mol, 1.1eq) of compound I, pyridine: 5.5g (0.07mol, 0.06eq) and 850g (26.51mol, 22.3eq) of methanol, stirring and heating, and keeping the temperature at 75 ℃ for reaction for 24 hours;
the liquid phase monitoring reaction is completed, the temperature is reduced to 10-15 ℃ after the reaction is finished, the filtration is carried out, and the methanol is leached to obtain 5-chloro-4, 6-dimethyl-3-cyanopyridone; and (5) drying to obtain a dry product: 204.6g, yield: 92.6%, liquid phase purity: 98.3 percent.
Step III: in a 2L glass four-neck flask, 1914g (12.484mol, 4eq) of phosphorus oxychloride is added, and 5-chloro-4, 6-dimethyl-3-cyanopyridone: 570g (3.121mol, 1.0eq), tetramethylammonium chloride: 188g (1.716mol, 0.55eq), heating to 100 ℃, and reacting for 1.5 h;
the post-treatment procedure after the completion of the reaction was the same as in example 1, and 590.2g of a product was obtained after the completion of the treatment, the product yield: 93.3%, product purity: 99.2 percent.
Example 5
The preparation method of 2, 5-dichloro-4, 6-dimethylnicotinonitrile is different from the embodiment 2 in that N-chlorosuccinimide is taken as a chlorinating reagent, and the specific step I is as follows:
step I: in a 2L reaction flask, 150kg of acetylacetone (1.498mol, 1.0eq) were added and, with stirring, N-chlorosuccinimide: 204g (1.528mol, 1.02eq), and finally chloroform: 950ml, heating and refluxing for 5 hours, cooling to 0-5 ℃, filtering out succinimide, adding 500ml of water into the system, extracting and washing, layering, and concentrating and drying an organic phase to obtain a compound I: 177.4g, reaction yield: 88%, gas phase purity: 97.4 percent.
The rest of the reaction process is the same as example 2.
Example 6
The preparation method of 2, 5-dichloro-4, 6-diethyl nicotinonitrile comprises the following steps:
step I: adding 1kg of 3, 5-heptanedione (7.812mol, 1.0eq) into a 2L pressure reaction kettle, controlling the temperature of a reaction system to be 10 ℃ under the condition of stirring, closing other valves of the reaction kettle, slowly introducing 565g of chlorine (7.968mol, 1.02eq) from a feed inlet, closing all the valves, heating, slowly increasing the pressure in the kettle along with the temperature rise, controlling the temperature to keep the pressure in the reaction kettle at 1atm, and reacting for 5 hours to generate 4-chloro-3, 5-heptanedione;
and (5) sampling gas phase monitoring, and after the reaction is finished, discharging the residual chlorine gas into a sodium hydroxide aqueous solution for absorption to obtain a sodium hypochlorite byproduct.
Step II: in a 1L glass four-necked flask, 100g (1.189mol, 1.0eq) of cyanoacetamide, 207.6g (1.278mol, 1.07eq) of 4-chloro-3, 5-heptanedione, morpholine: 5.2g (0.06mol, 0.05eq) of ethanol 1221.3g (26.51mol, 22.3eq) are stirred, heated and reacted for 48 hours at 50 ℃;
the liquid phase monitoring reaction is completed, the temperature is reduced to 10-15 ℃ after the reaction is finished, the filtration is carried out, and the methanol is leached to obtain 5-chloro-4, 6-diethyl-3-cyanopyridone; and drying to obtain a dry product.
Step III: in a 2L glass four-necked flask, 1800g of phosphorus oxychloride (11.739mol, 3.8eq) was added and 5-chloro-4, 6-diethyl-3-cyanopyridinone was added with stirring: 657.39g (3.121mol, 1.0eq), tetramethylammonium chloride: 171g (1.56mol, 0.5eq), heating to 85 ℃ and reacting for 3 h; the post-treatment process after the reaction is the same as the method for preparing 2, 5-dichloro-4, 6-dimethylnicotinonitrile.
Example 7
The preparation method of the 2, 5-dichloro-4, 6-diisopropyl nicotinonitrile comprises the following steps:
step I: adding 1kg of 2, 6-dimethyl-3, 5-heptanedione (6.4mol, 1.0eq) into a 2L pressure reaction kettle, controlling the temperature of a reaction system to be 10 ℃ under the stirring condition, closing other valves of the reaction kettle, slowly introducing 463g of chlorine (6.528mol, 1.02eq) from a feed inlet, closing all the valves, heating, slowly increasing the pressure in the kettle along with the temperature rise, controlling the temperature to keep the pressure in the reaction kettle at 1atm, and reacting for 5 hours to generate 4-chloro-2, 6-dimethyl-3, 5-heptanedione;
and (5) sampling gas phase monitoring, and after the reaction is finished, discharging the residual chlorine gas into a sodium hydroxide aqueous solution for absorption to obtain a sodium hypochlorite byproduct.
Step II: in a 1L glass four-necked flask, 100g (1.189mol, 1.0eq) of cyanoacetamide, 243.7g (1.278mol, 1.07eq) of 4-chloro-2, 6-dimethyl-3, 5-heptanedione, morpholine: 5.2g (0.06mol, 0.05eq) of ethanol 1221.3g (26.51mol, 22.3eq) are stirred, heated and reacted for 48 hours at 50 ℃;
the liquid phase monitoring reaction is completed, the temperature is reduced to 10-15 ℃ after the reaction is finished, the filtration is carried out, and the methanol is leached to obtain 5-chloro-4, 6-diethyl-3-cyanopyridone; and drying to obtain a dry product.
Step III: in a 2L glass four-necked flask, 1800g of phosphorus oxychloride (11.739mol, 3.8eq) was added and 5-chloro-4, 6-diisopropyl-3-cyanopyridone was added with stirring: 744.78g (3.121mol, 1.0eq), tetramethylammonium chloride: 171g (1.56mol, 0.5eq), heating to 85 ℃ and reacting for 3 h; the post-treatment process after the reaction is finished is the same as the method for preparing the 2, 5-dichloro-4, 6-dimethylnicotinonitrile.
Example 8
The preparation method of the 2, 5-dichloro-4, 6-di-sec-butyl nicotinonitrile comprises the following steps:
step I: adding 1kg of 3, 7-dimethyl-4, 6-nonanedione (5.4mol, 1.0eq) into a 2L pressure reaction kettle, controlling the temperature of a reaction system to be 10 ℃ under the stirring condition, closing other valves of the reaction kettle, slowly introducing 393g of chlorine (5.54mol, 1.02eq) from a feed inlet, closing all the valves, heating, slowly increasing the pressure in the kettle along with the temperature rise, controlling the temperature to keep the pressure in the reaction kettle at 1atm, and reacting for 5 hours to generate 5-chloro-3, 7-dimethyl-4, 6-nonanedione;
and (5) sampling gas phase monitoring, and after the reaction is finished, discharging the residual chlorine gas into a sodium hydroxide aqueous solution for absorption to obtain a sodium hypochlorite byproduct.
Step II: in a 1L glass four-necked flask, 100g of cyanoacetamide (1.189mol, 1.0eq), 279.5g of 5-chloro-3, 7-dimethyl-4, 6-nonanedione (1.278mol, 1.07eq), morpholine: 5.2g (0.06mol, 0.05eq) of ethanol 1221.3g (26.51mol, 22.3eq) are stirred, heated and reacted for 48 hours at 50 ℃;
after the liquid phase monitoring reaction is finished, cooling to 10-15 ℃ after the reaction is finished, filtering, and leaching with methanol to obtain 5-chloro-4, 6-di-sec-butyl-3-cyanopyridone; and drying to obtain a dry product.
Step III: into a 2L glass four-necked flask, 1800g (11.739mol, 3.8eq) of phosphorus oxychloride was charged, and 832g (3.121mol, 1.0eq) of 5-chloro-4, 6-di-sec-butyl-3-cyanopyridinone was added under stirring: 171g (1.56mol, 0.5eq), heating to 85 ℃ and reacting for 3 h; the post-treatment process after the reaction is the same as the method for preparing 2, 5-dichloro-4, 6-dimethylnicotinonitrile.
It should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications belong to the protection scope of the present invention.
Claims (5)
1. The preparation method of dichlorodialkyl nicotinonitrile is characterized by comprising the following steps:
step I: performing chlorination reaction by using a compound I shown in a formula I as a raw material and using chlorine or N-chlorosuccinimide as a chlorination reagent to generate a compound II shown in a formula II, wherein the mol ratio of the compound I to the chlorine/the N-chlorosuccinimide is controlled to be 1: 1-1.1; when chlorine is used as a chlorinating reagent to synthesize the compound II, the reaction temperature of the compound I and the chlorine is controlled to be 5-25 ℃, the reaction pressure is 1-2atm, and the reaction time is 3-5 h;
step II: carrying out condensation reaction on the compound II and cyanoacetamide under the action of alkali to generate a compound III shown in a formula III; when the compound II reacts with cyanoacetamide, alcohol is used as a solvent; controlling the molar ratio of cyanoacetamide to compound II to be 1:1-1.1, and the molar ratio of the base to cyanoacetamide to be 0.04-0.06: 1; controlling the reaction temperature of the compound II and cyanoacetamide to be 50-75 ℃ and the reaction time to be 24-48 h;
step III: performing chlorination reaction on the compound III and phosphorus oxychloride to generate dichlorodialkyl nicotinonitrile shown as a formula IV;
wherein, the first and the second end of the pipe are connected with each other,
formula I is:
formula II is
Formula III is
Formula IV is
The R group is selected from one of methyl, ethyl, propyl, isopropyl and sec-butyl.
2. The method for preparing dichlorodialkylnicotinonitrile according to claim 1, wherein in the step III, the molar ratio of the compound III to the phosphorus oxychloride is controlled to be 1:3.5 to 5.5.
3. The method according to claim 2, wherein the reaction temperature of the compound III with phosphorus oxychloride is controlled to 80 to 100 ℃ and the reaction time is controlled to 1.5 to 3.5 hours.
4. The method for preparing dichlorodialkylnicotinonitrile according to claim 1, wherein in the step III, a phase transfer catalyst is added when the compound III reacts with phosphorus oxychloride, and the molar ratio of the phase transfer catalyst to the compound III is 0.45-0.55: 1.
5. The method according to claim 1, wherein in step III, after the reaction is completed, the reaction solution is distilled under reduced pressure to precipitate a solid I, and the precipitated solid I is dissolved in an organic solvent I to form a feed solution;
and adding the feed liquid into water, stirring, standing, layering, taking the lower layer, washing with water, distilling until a solid II is separated out, adding the separated solid II into an organic solvent II for dissolving, cooling, separating out the material, filtering, and leaching to obtain the dichlorodialkyl nicotinonitrile.
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