Preparation method of 2-chloro-N, N-dimethyl nicotinamide

Abstract

The invention relates to a preparation method of 2-chloro-N, N-dimethyl nicotinamide, and belongs to the technical field of pesticides. The preparation method comprises the following steps: taking N, N-dimethyl cyanoacetamide, 1, 1, 3, 3-tetramethoxypropane and a compound shown as a formula II as raw materials, carrying out one-pot reaction to obtain a compound shown as a formula I, and then carrying out cyclization reaction on the compound shown as the formula I and hydrogen chloride gas to obtain 2-chloro-N, N-dimethyl nicotinamide; the reaction formula is as follows: # imgabs0 #; wherein R1 and R2 are the same or different and are independently selected from methyl, ethyl, n-propyl or phenyl. The method is mild in reaction condition, simple in process, low in cost, high in yield, few in three wastes, high in safety during reaction, high in production efficiency, green, environmentally friendly and suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticides, and particularly relates to a preparation method of 2-chloro-N,N-dimethylnicotinamide. Background Art

[0002] Nicosulfuron is an important post-emergence herbicide for corn. The compound 2-chloro-N,N-dimethylnicotinamide is an important intermediate for the production of nicosulfuron. The process stability, safety, three wastes, environmental protection, cost and other factors of the manufacture of 2-chloro-N,N-dimethylnicotinamide seriously affect the economic benefits of nicosulfuron herbicide.

[0003] The structure of 2-chloro-N,N-dimethylnicotinamide is as follows: ; There are several methods for the synthesis route of 2-chloro-N,N-dimethylnicotinamide as follows: Method 1: Japanese Patent JP59-144759 discloses a process for preparing 2-chloronicotinic acid by oxidation and chlorination of 3-cyanopyridine. The reaction route is as follows: ; This method uses 3-cyanopyridine as the starting material, oxidizes it with an aqueous hydrogen peroxide solution to obtain the N-oxide of nicotinamide, then undergoes a chlorination reaction to obtain 2-chloro-3-cyanopyridine. This intermediate undergoes a hydrolysis reaction with an aqueous strong base solution to obtain 2-chloronicotinic acid, which reacts with thionyl chloride to form 2-chloronicotinoyl chloride and then reacts with dimethylamine to obtain 2-chloro-N,N-dimethylnicotinamide. In this process route, the explosive precursor hydrogen peroxide is used, and the oxidation process is one of the 18 key supervised hazardous chemical processes. The chlorination reagent phosphorus oxychloride used in the chlorination process belongs to a highly toxic chemical, the reaction is violent, there are relatively large potential safety hazards, and a large amount of phosphorus-containing wastewater is difficult to treat, resulting in serious environmental pollution.

[0004] Method 2: Patent CN101693687A reports a preparation method of obtaining 2-chloro-N,N-dimethylnicotinamide by hydrolysis reaction of 2-chloro-3-trichloromethylpyridine with an aqueous solution of dimethylamine. The reaction route is as follows: ; This method avoids the use of thionyl chloride, but the raw material 2-chloro-3-trichloromethylpyridine is not easily available, has a high market price, and has relatively high requirements for reaction pH control, resulting in a relatively large amount of wastewater generated, and is not suitable for industrial production.

[0005] Method 3: Patent CN115260092 reported that 3-chloropropenal and N,N-dimethylcyanoacetamide underwent Knoevenagel reaction in a solvent catalyzed by an organic amine hydrochloride, and a composite catalyst was added to the system to form a ring to obtain 2-chloro-N,N-dimethylnicotinamide. The reaction route is as follows: ; In this method, the raw material 3-chloropropenal is not easily available and has a high price.

[0006] Method 4: In the literature "New Synthesis Method of 2-Chloro-N,N-Dimethylnicotinamide" by Hu Fei et al., Modern Agrochemicals, Vol. 12, No. 3, pp. 18-21, it was reported that using propargyl alcohol and di-n-propylamine as starting materials, first catalytic oxidation was carried out to generate 3-di-n-propylaminopropenal, then it underwent Knoevenagel reaction with N,N-dimethylcyanoacetamide, and then cyclization with HCl gas to obtain 2-chloro-N,N-dimethylnicotinamide. The reaction route is as follows: ; The raw materials of this method are easily available, the operation is simple, the reaction conditions are mild, and the three wastes are less. However, the propargyl alcohol used in this process is a highly toxic chemical, and the synthesis of 3-di-n-propylaminopropenal requires pressurized air oxidation in a high-pressure autoclave with a silicon-manganese composite catalyst, the reaction heat release is large, there are safety risks, and 3-di-n-propylaminopropenal is unstable and easily continues to react with di-n-propylamine to generate bis-di-n-propylamine impurities. The structure is as follows: ; Bis-di-n-propylamine impurities cannot be used in the next step of the reaction. They enter the aqueous phase during the post-treatment process, resulting in high wastewater COD and other indicators, poor environmental protection of the process, and the yield of preparing 3-di-n-propylaminopropenal is only 88%, the yield is on the low side, and the total yield of this method is only about 60% - 65%. Patent CN112812059 also reported a similar synthesis method.

[0007] Therefore, it is very urgent and necessary to develop a simple, green, safe, economical and effective synthesis method and synthesis process for 2-chloro-N,N-dimethylnicotinamide. Summary of the Invention

[0008] Aiming at the problems of dangerous reaction raw materials and reaction processes, and difficult availability of reaction raw materials in the existing methods for preparing 2-chloro-N,N-dimethylnicotinamide, the present invention provides a preparation method of 2-chloro-N,N-dimethylnicotinamide to solve the above problems. The present invention uses easily available raw materials N,N-dimethylcyanoacetamide, 1,1,3,3-tetramethoxypropane and disubstituted imine, and 2-chloro-N,N-dimethylnicotinamide can be obtained through two-step reactions. The reaction conditions are simple, and the raw materials are easily available and have low toxicity.

[0009] The technical solution of the present invention is as follows: The present invention provides a method for preparing 2-chloro-N,N-dimethylnicotinamide. Using N,N-dimethylcyanoacetamide, 1,1,3,3-tetramethoxypropane and a compound of formula II (disubstituted imine) as raw materials, the compound of formula I (2-cyano-5-disubstituted-N,N-dimethyl-2,4-pentadienamide) is obtained by a one-pot reaction, and then cyclized with hydrogen chloride gas to obtain 2-chloro-N,N-dimethylnicotinamide. The reaction formula is as follows: ; Wherein, R1 and R2 are the same or different and are each independently selected from methyl, ethyl, n-propyl or phenyl. For example, dimethylamine, diethylamine, di-n-propylamine, N-methylaniline, N-ethylaniline, etc. can be selected.

[0010] Further, the steps of the one-pot reaction are: after mixing N,N-dimethylcyanoacetamide and 1,1,3,3-tetramethoxypropane, the temperature is raised and reacted for a period of time, and then cooled to 20-30 °C; then the compound of formula II is added to the reaction system and reacted continuously, and the reaction solution is concentrated to obtain the compound of formula I.

[0011] Further, the molar ratio of N,N-dimethylcyanoacetamide to 1,1,3,3-tetramethoxypropane is 1:1-2, preferably 1:2.

[0012] Further, the molar ratio of N,N-dimethylcyanoacetamide to the compound of formula II is 1:1-3, preferably 1:1.05.

[0013] Further, when carrying out the one-pot reaction, a catalyst is added when N,N-dimethylcyanoacetamide and 1,1,3,3-tetramethoxypropane are mixed. The catalyst is one of 98% sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, preferably 98% sulfuric acid.

[0014] Further, the molar ratio of N,N-dimethylcyanoacetamide to the catalyst is 1:0.01-0.05; preferably 1:0.01.

[0015] Further, the reaction temperature of N,N-dimethylcyanoacetamide and 1,1,3,3-tetramethoxypropane is 120 °C-150 °C, preferably 130 °C-135 °C.

[0016] Further, the compound of formula II added to the reaction system is diluted with a solvent. The solvent used is one of methanol, ethanol, tetrahydrofuran, toluene, dichloromethane or 1,2-dichloroethane, preferably 1,2-dichloroethane.

[0017] Further, the temperature of the compound of formula II added to the reaction system is 20 to 30 °C.

[0018] Further, the pressure of the cyclization reaction of the compound of formula I with hydrogen chloride gas is 0.1 to 0.5 MPa, preferably 0.3 MPa.

[0019] Further, the reaction solvent used in the cyclization reaction of the compound of formula I with hydrogen chloride gas is at least one of toluene, xylene, dichloromethane, 1,2-dichloroethane, 1,4-dioxane, preferably 1,2-dichloroethane.

[0020] Further, the reaction temperature of the cyclization reaction of the compound of formula I with hydrogen chloride gas is 20 to 30 °C.

[0021] The beneficial effects of the present invention are as follows: The present invention provides a preparation method for synthesizing 2-chloro-N,N-dimethylnicotinamide from inexpensive and easily available N,N-dimethylcyanoacetamide, 1,1,3,3-tetramethoxypropane, disubstituted amine, and hydrogen chloride. The reaction conditions of the present invention are mild, the process is simple, the cost is low, the yield is high, the three wastes are less, the safety during the reaction is high, the production efficiency is high and it is green and environmentally friendly, and it is suitable for large-scale industrial production. Detailed implementation manners

[0022] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts shall fall within the protection scope of the present invention.

[0023] Example 1 (1) Synthesis of 2-cyano-5-di-n-propylamino-N,N-dimethyl-2,4-pentadienamide

[0024] To a 500 mL three-necked flask containing a magnetic stir bar, 98% sulfuric acid (98 mg, 1.0 mmol, 0.01 eq), 1,1,3,3-tetramethoxypropane (32.84 g, 0.20 mol, 2.00 eq), and N,N-dimethylcyanoacetamide (11.2 g, 0.10 mol, 1.00 eq) were added successively. The mixture was stirred at 25 °C until homogeneous, then placed in an oil bath and heated to 130 °C - 135 °C. After maintaining the temperature and stirring for 50 minutes, the reaction solution was cooled to 25 °C. A mixture of di-n-propylamine (10.62 g, 105 mmol, 1.05 eq) and 1,2-dichloroethane (20 g) was slowly added dropwise to the above solution. During the addition, the temperature increased slightly, and the temperature rise was controlled to not exceed 5 °C. After the addition was complete, stirring was continued at 30 °C for 30 minutes. 15 g of the above reaction solution was taken, and the solvent 1,2-dichloroethane was removed by rotary evaporation under reduced pressure to obtain a crude product. 5 g of ethyl acetate was added to it for recrystallization, followed by washing with water and suction filtration to obtain 4.34 g of a yellow solid. Purity: 96.3% (HPLC), Yield: 85.5% (calculated based on N,N-dimethylcyanoacetamide). The remaining reaction solution was directly used for the next cyclization reaction. The NMR data is as follows: 1 HNMR (500 MHz, CDCl3) δ: 7.76 (d, J= 12.4 Hz, 1H), 7.00 (d, J=12.4Hz, 1H), 5.59 (t, J=12.4 Hz, 1H), 3.21 (t, J=6.0 Hz, 4H), 3.11 (s, 6H),1.64 (m, 4H), 0.96 - 0.92 (m, 6H).

[0025] (2) Synthesis of 2-chloro-N,N-dimethylnicotinamide

[0026] Take 40 g of the 1,2-dichloroethane solution of 2-cyano-5-dipropylamino-N,N-dimethyl-2,4-pentadienamide synthesized in step (1), put it into a high-pressure reactor, introduce hydrogen chloride gas, and keep the pressure at 0.3 MPa. Stir and react at 27 - 30 °C for 6 hours. Take a sample for TLC plate monitoring until the raw materials are completely converted. Release the pressure, and blow in air to drive away the excess hydrogen chloride gas in the reactor. Absorb the tail gas (30% sodium hydroxide solution). Adjust the pH value of the reaction solution to 7 - 8 with 30% sodium hydroxide solution, let it stand and separate layers. Adjust the pH value of the aqueous phase to 12 - 13, separate layers to recover dipropylamine. Rotate and evaporate the solvent from the organic phase to obtain the crude product, and recrystallize it with 10 g of tert-butyl methyl ether to obtain 6.68 g of pale yellow solid 2-chloro-N,N-dimethylnicotinamide, purity: 97.1% (HPLC), two-step yield: 81.8% (calculated based on N,N-dimethylcyanoacetamide). The NMR data is as follows: 1 HNMR (500 MHz, CDCl3) δ: 8.46 - 8.44 (m, 1H), 7.69 - 7.67 (m, 1H), 7.34 - 7.31 (m, 1H), 3.17 (s, 3H), 2.91 (s, 3H).

[0027] Example 2 (1) Synthesis of 2-cyano-5-dipropylamino-N,N-dimethyl-2,4-pentadienamide

[0028] Add 98% concentrated sulfuric acid (98 mg, 1.0 mmol, 0.01 eq), 1,1,3,3-tetramethoxypropane (32.84 g, 0.20 mol, 2.00 eq) and N,N-dimethylcyanoacetamide (11.2 g, 0.10 mol, 1.00 eq) to a 500 mL three-necked flask equipped with a magnetic stirrer in sequence. Stir and mix evenly at 26 °C, place it in an oil bath and heat to 130 - 135 °C, stir and react for 50 minutes. Then cool the reaction solution to 30 °C. Slowly dropwise add the mixed solution of dipropylamine (10.62 g, 105 mmol, 1.05 eq) and methanol (25 g) to the above solution. There is a slight temperature rise during the dropping process, control the temperature rise amplitude not exceeding 5 °C. After the dropping is completed, continue to stir at 30 °C for 20 minutes. Rotate and evaporate the solvent methanol under reduced pressure to obtain the crude product, and add 30.0 g of dichloromethane solvent to dissolve it for the next cyclization use.

[0029] (2) Synthesis of 2-chloro-N,N-dimethylnicotinamide

[0030] Take the dichloromethane solution of 2-cyano-5-di-n-propylamino-N,N-dimethyl-2,4-pentadienamide synthesized in step (1), put it into a high-pressure reactor, introduce hydrogen chloride gas, and keep the pressure at 0.3 MPa. Stir and react at 26 - 29 °C for 7 hours. Take a sample for TLC plate monitoring until the raw materials are completely converted. Release the pressure, blow in air to drive away the excess hydrogen chloride gas in the reactor, absorb the tail gas (30% sodium hydroxide solution), adjust the pH value of the reaction solution to 7 - 8 with 30% sodium hydroxide solution, let it stand for liquid separation, adjust the pH value of the aqueous phase to 12 - 13, separate and recover di-n-propylamine. Rotate and evaporate the solvent from the organic phase to obtain the crude product, and recrystallize it with 20 g of ether to obtain 14.25 g of pale yellow solid 2-chloro-N,N-dimethylnicotinamide, purity: 96.4% (HPLC), two-step yield: 80.1% (calculated based on N,N-dimethylcyanoacetamide).

[0031] Example 3 (1) Synthesis of 2-cyano-5-di-n-propylamino-N,N-dimethyl-2,4-pentadienamide

[0032] Add methanesulfonic acid (144.15 mg, 1.5 mmol, 0.03 eq), 1,1,3,3-tetramethoxypropane (18.43 g, 74.85 mmol, 1.5 eq) and N,N-dimethylcyanoacetamide (5.6 g, 49.9 mmol, 1.00 eq) successively into a 500 mL three-necked flask equipped with a magnetic stirrer. Stir and mix evenly at 30 °C, place it in an oil bath and heat it to 130 - 135 °C and stir and react for 2 hours. Then cool the reaction solution to 28 °C, and slowly dropwise add a mixture of di-n-propylamine (5.30 g, 52.4 mmol, 1.05 eq) and tetrahydrofuran (45 g) into the above solution. There is a slight temperature rise during the dropping process, control the temperature rise amplitude not exceeding 5 °C. After the dropping is completed, continue to stir at 30 °C for 20 minutes. Rotate and evaporate the solvent under reduced pressure to obtain the crude product, and add 35.0 g of toluene solvent to dissolve it for the next cyclization use.

[0033] (2) Synthesis of 2-chloro-N,N-dimethylnicotinamide

[0034] Put the toluene solution of 2-cyano-5-di-n-propylamino-N,N-dimethyl-2,4-pentadienamide synthesized in step (1) into a high-pressure reactor, introduce hydrogen chloride gas, and keep stirring and reacting at 28 - 30 °C under a pressure of 0.5 MPa for 5 hours. Take a sample for TLC plate monitoring until the raw materials are completely converted. Release the pressure, blow in air to drive away the excess hydrogen chloride gas in the reactor, absorb the tail gas (30% sodium hydroxide solution), adjust the pH value of the reaction solution to 7 - 8 with 30% sodium hydroxide solution, let it stand for layering, adjust the pH value of the aqueous phase to 12 - 13, layer and recover di-n-propylamine. The organic phase is rotary evaporated to remove the solvent to obtain 7.46 g of crude product. The content is measured to be 68.8% by HPLC external standard method. The two-step yield is 55.7% (calculated based on N,N-dimethylcyanoacetamide).

[0035] Example 4 (1) Synthesis of 2-cyano-5-di-n-propylamino-N,N-dimethyl-2,4-pentadienamide

[0036] Add p-toluenesulfonic acid monohydrate (475.5 mg, 2.50 mmol, 0.05 eq), 1,1,3,3-tetramethoxypropane (9.83 g, 59.88 mmol, 1.2 eq) and N,N-dimethylcyanoacetamide (5.6 g, 49.9 mmol, 1.00 eq) into a 500 mL three-necked flask equipped with a magnetic stirrer in sequence. Stir and mix evenly at 25 °C, place it in an oil bath and heat it to 140 - 145 °C and stir and react for 5 hours. Then cool the reaction solution to 28 °C. Slowly dropwise add the mixed solution of di-n-propylamine (6.56 g, 64.87 mmol, 1.3 eq) and 28 g of absolute ethanol to the above solution. There is a slight temperature rise during the dropping process. Control the temperature rise range not to exceed 5 °C. After the dropping is completed, continue to stir at 29 °C for 80 minutes. Rotate evaporate under reduced pressure to remove the solvent ethanol to obtain a crude product. Add 25.0 g of 1,2-dichloroethane to dissolve it for the next cyclization use.

[0037] (2) Synthesis of 2-chloro-N,N-dimethylnicotinamide

[0038] Put the toluene solution of 2-cyano-5-di-n-propylamino-N,N-dimethyl-2,4-pentadienamide synthesized in step (1) into a high-pressure reactor, introduce hydrogen chloride gas, and keep the pressure at 0.4 MPa. Stir and react at 26 - 28 °C for 4 hours. Take a sample for TLC plate monitoring until the raw materials are completely converted. Release the pressure, blow in air to drive away the excess hydrogen chloride gas in the reactor, absorb the tail gas (with 30% sodium hydroxide solution), adjust the pH value of the reaction solution to 7 - 8 with 30% sodium hydroxide solution, let it stand for liquid separation. Adjust the pH value of the aqueous phase to 12 - 13, separate and recover di-n-propylamine. Rotate and evaporate the organic phase to remove the solvent to obtain 5.76 g of crude product. The content is measured to be 72.5% by HPLC external standard method. The two-step yield is 45.3% (calculated based on N,N-dimethylcyanoacetamide).

[0039] Example 5 (1) Synthesis of 2-cyano-5-dimethylamino-N,N-dimethyl-2,4-pentadienamide

[0040] Add 98% concentrated sulfuric acid (98 mg, 1.0 mmol, 0.01 eq), 1,1,3,3-tetramethoxypropane (32.84 g, 0.20 mol, 2.00 eq) and N,N-dimethylcyanoacetamide (11.2 g, 0.10 mol, 1.00 eq) to a 500 mL three-necked flask equipped with a magnetic stirrer in sequence. Stir and mix evenly at 23 °C, place it in an oil bath and heat to 130 - 135 °C, stir and react for 50 minutes. Then cool the reaction solution to 25 °C. Slowly add 30% dimethylamine methanol solution (48.08 g, 0.3 mol, 3.0 eq) dropwise to the above solution. There is a slight temperature rise during the dropping process, control the temperature rise amplitude not exceeding 5 °C. After the dropping is completed, continue to stir at 25 °C for 30 minutes. Rotate and evaporate under reduced pressure to remove the solvent and excess methylamine to obtain the crude product. Take a sample for NMR analysis. Dissolve the crude product with 25.0 g of 1,2-dichloroethane for the next cyclization use. The NMR data is as follows: 1 HNMR (400 MHz, CDCl3) δ: 7.76 (d, J= 12.4 Hz, 1H), 7.01 (d, J=12.4Hz, 1H), 5.54 (t, J=12.4 Hz, 1H), 3.10 - 2.95 (m, 12H).

[0041] (2) Synthesis of 2-chloro-N,N-dimethylnicotinamide

[0042] Put the toluene solution of 2-cyano-5-dimethylamino-N,N-dimethyl-2,4-pentadienamide synthesized in step (1) into a high-pressure reactor, introduce hydrogen chloride gas, and keep stirring and reacting at 25 - 26 °C for 2.5 hours under a pressure of 0.3 MPa. Take a sample for TLC plate monitoring until the raw materials are completely converted. Release the pressure, blow in air to drive away the excess hydrogen chloride gas in the reactor, absorb the tail gas (30% sodium hydroxide solution), adjust the pH value of the reaction solution to 7 - 8 with 30% sodium hydroxide solution, let it stand for liquid separation, and rotary evaporate the organic phase to remove the solvent to obtain 15.48 g of crude product. The content is measured to be 92.5% by HPLC external standard method. The two-step yield is 77.5% (calculated based on N,N-dimethylcyanoacetamide).

[0043] Example 6 (1) Synthesis of 2-cyano-5-di-n-propylamino-N,N-dimethyl-2,4-pentadienamide

[0044] Add 98% concentrated sulfuric acid (98 mg, 1.0 mmol, 0.01 eq), 1,1,3,3-tetramethoxypropane (18.06 g, 0.11 mol, 1.1 eq), and N,N-dimethylcyanoacetamide (11.2 g, 0.10 mol, 1.00 eq) into a 500 mL three-necked flask equipped with a magnetic stirrer in sequence. Stir and mix evenly at 30 °C, heat it in an oil bath to 130 - 135 °C and stir and react for 50 minutes. Then cool the reaction solution to 30 °C. Slowly dropwise add the mixed solution of di-n-propylamine (12.14 g, 0.12 mol, 1.2 eq) and 1,2-dichloroethane (30 g) into the above solution. There is a slight temperature rise during the dropping process, and control the temperature rise amplitude not to exceed 5 °C. After the dropping is completed, continue to stir at 25 °C for 45 minutes, and directly use it for the next cyclization reaction.

[0045] (2) Synthesis of 2-chloro-N,N-dimethylnicotinamide

[0046] Put the 1,2-dichloroethane solution of 2-cyano-5-dipropylamino-N,N-dimethyl-2,4-pentadienamide synthesized in step (1) into a high-pressure reactor, introduce hydrogen chloride gas, and keep stirring and reacting at 22 - 25 °C for 6 hours under a pressure of 0.3 MPa. Take a sample for TLC plate monitoring until the raw materials are completely converted. Release the pressure, and blast air to drive away the excess hydrogen chloride gas in the reactor. Absorb the tail gas (30% sodium hydroxide solution). Adjust the pH value of the reaction solution to 7 - 8 with 30% sodium hydroxide solution, let it stand for liquid separation. Adjust the pH value of the aqueous phase to 12 - 13, separate and recover dipropylamine. Rotate and evaporate the organic phase to remove the solvent to obtain the crude product. The crude product obtained by rotating and evaporating the organic phase to remove the solvent is 14.10 g, and its content measured by HPLC external standard method is 96.1%. The overall yield of the two steps is 73.4% (calculated based on N,N-dimethylcyanoacetamide). Example 7 (1) Synthesis of 2-cyano-5-dipropylamino-N,N-dimethyl-2,4-pentadienamide

[0047] Add 98% concentrated sulfuric acid (490 mg, 1.0 mmol, 0.05 eq), 1,1,3,3-tetramethoxypropane (32.84 g, 0.20 mol, 2.00 eq) and N,N-dimethylcyanoacetamide (11.2 g, 0.10 mol, 1.00 eq) into a 500 mL three-necked flask equipped with a magnetic stirrer in sequence. Stir and mix evenly at 25 °C, place it in an oil bath and heat it to 130 - 135 °C and stir and react for 50 minutes. Then cool the reaction solution to 21 °C. Slowly add a mixture of dipropylamine (12.14 g, 0.12 mol, 1.2 eq) and 30.0 g of 1,2-dichloroethane to the above solution. There is a slight temperature rise during the dropping process, and control the temperature rise amplitude not to exceed 5 °C. After the dropping is completed, continue to stir at 25 °C for 45 minutes, and directly use it for the next cyclization reaction.

[0048] (2) Synthesis of 2-chloro-N,N-dimethylnicotinamide

[0049] The 1,2-dichloroethane solution of 2-cyano-5-di-n-propylamino-N,N-dimethyl-2,4-pentadienamide synthesized in step (1) was put into a high-pressure reactor, and hydrogen chloride gas was introduced. While maintaining a pressure of 0.3 MPa, the reaction was stirred at 20 - 23 °C for 6 hours. Samples were taken for TLC plate monitoring until the raw materials were completely converted. Then, the pressure was released, and air was bubbled in to remove the excess hydrogen chloride gas in the reactor. The tail gas was absorbed (with 30% sodium hydroxide solution). The pH value of the reaction solution was adjusted to 7 - 8 with 30% sodium hydroxide solution, and then allowed to stand for liquid separation. The pH value of the aqueous phase was adjusted to 12 - 13, and di-n-propylamine was recovered by liquid separation. The organic phase was rotary evaporated to remove the solvent to obtain 14.92 g of crude product. The content was measured to be 97.0% by HPLC external standard method. The two-step yield was 78.3% (calculated based on N,N-dimethylcyanoacetamide). Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, those of ordinary skill in the art can make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions should all fall within the scope of the present invention. / Any person skilled in the art within the technical scope disclosed by the present invention can easily think of changes or substitutions, which should all be covered by the protection scope of the present invention.

Claims

1. A method for preparing 2-chloro-N,N-dimethylnicotinamide, characterized in that: Using N,N-dimethylcyanoacetamide, 1,1,3,3-tetramethoxypropane and the compound of formula II as raw materials, a one-pot reaction is performed to obtain the compound of formula I, which is then subjected to a cyclization reaction with hydrogen chloride gas to obtain 2-chloro-N,N-dimethylnicotinamide; the reaction formula is as follows: ； Wherein, R1 and R2 are the same or different and are independently selected from methyl, ethyl, n-propyl or phenyl.

2. The method for preparing 2-chloro-N,N-dimethylnicotinamide according to claim 1, characterized in that: The one-pot reaction steps are as follows: N,N-dimethylcyanoacetamide and 1,1,3,3-tetramethoxypropane are mixed, the temperature is raised for reaction for a period of time, and then the temperature is lowered to 20-30°C; then the compound of formula II is added to the reaction system to continue the reaction, and the reaction solution is concentrated to obtain the compound of formula I.

3. The method for preparing 2-chloro-N,N-dimethylnicotinamide according to claim 2, characterized in that: The molar ratio of the N,N-dimethylacetamide to 1,1,3,3-tetramethoxypropane is 1:1 to 2.

4. The method for preparing 2-chloro-N,N-dimethylnicotinamide according to claim 2, characterized in that: The molar ratio of the N,N-dimethylacetamide to the compound of formula II is 1:1 to 3.

5. The method for preparing 2-chloro-N,N-dimethylnicotinamide according to claim 2, characterized in that: In the one-pot reaction, a catalyst is added when N,N-dimethylacetamide cyanoacetamide and 1,1,3,3-tetramethoxypropane are mixed, and the catalyst is one of 98% sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid.

6. The method for preparing 2-chloro-N,N-dimethylnicotinamide according to claim 5, characterized in that: The molar ratio of the N,N-dimethylacetamide cyanide to the catalyst is 1:0.01 to 0.

05.

7. The method for preparing 2-chloro-N,N-dimethylnicotinamide according to claim 2, characterized in that: The reaction temperature of N,N-dimethylacetamide cyanide and 1,1,3,3-tetramethoxypropane is 120 ℃ ~ 150 ℃.

8. The method for preparing 2-chloro-N,N-dimethylnicotinamide according to claim 2, characterized in that: The compound of formula II added to the reaction system is diluted with a solvent, and the solvent used is one of methanol, ethanol, tetrahydrofuran, toluene, dichloromethane or 1,2-dichloroethane.

9. The method for preparing 2-chloro-N,N-dimethylnicotinamide according to claim 1, characterized in that: The pressure of the cyclization reaction of the compound of formula I and hydrogen chloride gas is 0.1 to 0.5 MPa.

10. The method for preparing 2-chloro-N,N-dimethylnicotinamide according to claim 9, characterized in that: The reaction solvent used in the cyclization reaction of the compound of formula I with hydrogen chloride gas is at least one of toluene, xylene, dichloromethane, 1,2-dichloroethane and 1,4-dioxane.

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