Two-step continuous preparation method of 2-chloro-N, N-dimethyl nicotinamide

Abstract

The invention provides a two-step continuous preparation method of 2-chloro-N, N-dimethyl nicotinamide, which comprises the following steps: mixing 2-chloronicotinic acid with a solvent and thionyl chloride in proportion to prepare a solution A; continuously adding the solution A into the first section of the tubular reactor at a certain flow through a metering pump, and controlling the reaction temperature and the retention time to prepare a solution B; and continuously feeding the solution B into a tubular reactor II, continuously adding dimethylamine into the tubular reactor II, controlling the pressure, the temperature and the retention time, carrying out an amide reaction in the tubular reactor, and carrying out solid-liquid separation by using a centrifugal machine after the reaction is completed to obtain a liquid which is a 2-chloro-N, N-nicotinamide solution. According to the technical scheme, the compatible organic matter is used for replacing a large amount of thionyl chloride to serve as the reaction solvent, two-step continuous reaction is achieved, the procedure of distilling excessive reactants after acyl chloride is prepared is omitted, and the technological process is simplified.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis and specifically relates to a method for continuously preparing 2-chloro- N,N -Dimethylnicotinamide method. Background Art

[0002] Nicosulfuron, also known as Yunongle and Nicosulfuron, has a molecular formula of C 15 H 18 N6O6S, chemical name 2-(4,6-dimethoxypyrimidine-2-pyrimidinylcarbamoylaminosulfonyl)- N,N -Dimethylnicotinamide is a sulfonylurea herbicide used for weeding in corn fields. It is widely used because of its advantages such as high efficiency, low toxicity and high selectivity.

[0003] 2-Chloro- N,N -Dimethylnicotinamide is an important intermediate for the synthesis of the original drug nicosulfuron. There are four reported synthesis methods. The first is the amidation of nicotinic acid by hydrogen peroxide oxidation, chlorination with thionyl chloride or phosphorus oxychloride, and dimethylamine. The reaction formula is as follows:

[0004] The second method uses 2-chloronicotinic acid as the starting material, and synthesizes the product through the amide reaction of dichlorothionyl and dimethylamine. The reaction formula is as follows:

[0005] The third is the reaction of 2-chloro-3-trichloromethylpyridine with dimethylamine aqueous solution, the reaction formula is as follows;

[0006] The fourth method is to react aminoacrolein with cyanoacetamide to undergo Konevenagel condensation and pass hydrogen chloride to close the ring. The reaction formula is as follows:

[0007] The above four methods each have their own shortcomings: the first method has side reactions during the chlorination process, resulting in a complex system, difficult separation, and low yield. The second method uses an excess of thionyl chloride, which needs to be distilled before the amidation reaction, and the process is relatively complicated; during the amidation reaction, local heat release is serious, heating is uneven, and inaccurate temperature control and overheating bring safety hazards. The third method has high raw material costs and is difficult to obtain. The fourth method has low raw material costs, but the hydrogen chloride ring closure takes up to 30 hours and the amount of hydrogen chloride used is large. Summary of the invention

[0008] The present invention aims to simplify the process flow, shorten the reaction time and reduce the safety risk of the reaction based on the existing process.

[0009] To achieve the above objectives, the present invention provides a method for continuously preparing 2-chloro- N,N -dimethylnicotinamide method, the method comprising the following steps: (1) 2-Chloronicotinic acid is mixed with a solvent and thionyl chloride in a certain proportion to prepare solution A; (2) Solution A is continuously added to a first section of a tubular reactor at an appropriate flow rate through a metering pump, and the reaction temperature and retention time are controlled to prepare solution B; (3) Solution B is continuously fed into the second tubular reactor, and dimethylamine is continuously added to the second tubular reactor. The pressure, temperature, flow rate and retention time are controlled, and an amide reaction is carried out in the tubular reactor. The solid-liquid separation is carried out by a centrifuge, and the liquid is 2-chloro- N,N -Niacinamide solution.

[0010] The tubular reactor used in the present invention is a customized product, the inner pipe is made of 316L material, the jacket is made of 304 material, the tube is filled with special-shaped 316L parts, and the pressure resistance is 4Mpa. The materials can be fully mixed when flowing through the inner tube, the heat transfer oil in the jacket can quickly exchange heat, and the pressure in the tube can be adjusted by the back pressure valve. This customized equipment has the advantages of acid and alkali tolerance, adjustable back pressure, fast heat exchange speed and uniform mixing.

[0011] Preferably, in step (1), the mass ratio of 2-chloronicotinic acid to solvent and thionyl chloride is 1:3-7:0.76-0.85; Preferably, in step (1), the solvent is one of 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dichlorobenzene and 1-chlorobutane.

[0012] The solvent of the invention significantly increases the dissolution effect of 2-chloronicotinic acid, increases the reaction fluidity of 2-chloronicotinic acid and thionyl chloride, increases the contact area between molecules, and accelerates the reaction rate.

[0013] Preferably, in step (2), the flow rate of solution A is 31-35 L / h.

[0014] Preferably, in step (2), the reaction temperature is 90-95° C., the pressure is controlled at 0.7-1 MPa, and the retention time is controlled at 3-5 minutes.

[0015] Preferably, in step (3), the flow rate of dimethylamine is 4-5 L / h.

[0016] Preferably, in step (3), the pressure is controlled at 0.7-1 MPa, the temperature is controlled at 10-20° C., and the retention time is 0.1-1 minute.

[0017] The temperature, pressure and time parameters of the present invention are verified through multiple experiments, and the basis for determining the parameters is the result of the experimental conversion rate.

[0018] The reaction formula of the technical solution of the present invention is as follows:

[0019] Technical Effects Compared with the effects of the prior art, the beneficial effects of the present invention include: (1) a large amount of dichlorothionyl is replaced by a compatible organic matter as a reaction solvent, thereby realizing a two-step continuous reaction, omitting the step of distilling excess reactants after preparing the acyl chloride, and simplifying the process flow; (2) compared with preparing 2-chloronicotinoyl chloride by reflux at room temperature, the substance is prepared more rapidly under high temperature and high pressure, shortening the reaction time; (3) the volume of the reaction liquid in the tubular reactor is less than 50 L, which is less than the reaction liquid in the industrial thousand-liter kettle device, and the heat exchange is rapid, with low safety risks. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is a schematic diagram of the reaction process of the present invention. DETAILED DESCRIPTION

[0021] In order to make the technical solution of the present invention clearer, the present invention is further described in detail in combination with reaction equations, process mode diagrams and embodiments.

[0022] The conversion rates in the following cases were all measured by the high performance liquid chromatography area normalization method, and the detection conditions were as follows: the detector was a high performance liquid chromatography UV-visible detector with a detection wavelength of 255 nm; the chromatographic column was C18 5 μm 4.6×150 mm; the mobile phase A was chromatographic acetonitrile, and the mobile phase B was a 4 mg / mL formic acid aqueous solution, and the flow rates of the mobile phases A and B were both 0.5 mL / min.

[0023] Example 1 1 kg of 2-chloronicotinic acid was mixed with 3 kg of 2-methyltetrahydrofuran and 0.76 kg of thionyl chloride to prepare solution A; solution A was continuously added to the first section of the tubular reactor at a flow rate of 35 L / h through a metering pump, and the reaction temperature was controlled at 90°C and the retention time was 3.2 minutes to prepare solution B; the pressure was controlled at 0.7 MPa, the temperature was 15°C, and dimethylamine was continuously added to the second section of the tubular reactor at a flow rate of 4.2 L / h, and an amide reaction was carried out in the second section of the tubular reactor and retained for 10 seconds. The reaction product was separated into solid and liquid by a centrifuge, and the liquid was a 2-chloro-N,N-nicotinamide solution. The conversion rate was measured by high performance liquid chromatography, and the conversion rate was 86.4% based on 2-chloronicotinic acid.

[0024] Example 2 1 kg of 2-chloronicotinic acid, 3 kg of 1,4-dioxane and 0.76 kg of thionyl chloride were mixed to prepare solution A; solution A was continuously added to the first stage of the tubular reactor at a flow rate of 35 L / h through a metering pump, and the reaction temperature was controlled at 90°C and the retention time was 3.2 minutes to prepare solution B; dimethylamine was continuously added to the second stage of the tubular reactor at a flow rate of 4.2 L / h under the pressure of 0.7 MPa and the temperature of 15°C, and an amide reaction was carried out in the tubular reactor and retained for 10 seconds. The reaction product was separated into solid and liquid by a centrifuge, and the liquid was 2-chloro- N,N -Nicotinamide solution, the conversion rate was measured by high performance liquid chromatography, and the conversion rate was 89.6% based on 2-chloronicotinic acid.

[0025] Example 3 1 kg of 2-chloronicotinic acid, 3 kg of 1-chlorobutane and 0.76 kg of thionyl chloride were mixed to prepare solution A; solution A was continuously added to the first stage of the tubular reactor at a flow rate of 35 L / h through a metering pump, and the reaction temperature was controlled at 90°C and the retention time was 3.2 minutes to prepare solution B; dimethylamine was continuously added to the second stage of the tubular reactor at a flow rate of 4.2 L / h under the pressure of 0.7 MPa and the temperature of 15°C, and an amide reaction was carried out in the tubular reactor and retained for 10 seconds. The reaction product was separated into solid and liquid by a centrifuge, and the liquid was 2-chloro- N,N -Nicotinamide solution, the conversion rate was measured by high performance liquid chromatography, and the conversion rate was 88.2% based on 2-chloronicotinic acid.

[0026] Example 4 1 kg of 2-chloronicotinic acid was mixed with 3 kg of 1,2-dichlorobenzene and 0.76 kg of thionyl chloride to prepare solution A; solution A was continuously added to the first stage of the tubular reactor at a flow rate of 35 L / h through a metering pump, and the reaction temperature was controlled at 90°C and the retention time was 3.2 minutes to prepare solution B; the pressure was controlled at 0.7 MPa and the temperature was 15°C, and dimethylamine was continuously added to the second stage of the tubular reactor at a flow rate of 4.2 L / h, and an amide reaction was carried out in the tubular reactor and retained for 10 seconds. The reaction product was separated into solid and liquid by a centrifuge, and the liquid was 2-chloro- N,N -Nicotinamide solution, the conversion rate was measured by high performance liquid chromatography, and the conversion rate was 92.3% based on 2-chloronicotinic acid.

[0027] Comparative Example Keeping the dosage, temperature, pressure and process conditions unchanged with those in Example 1, other ethers, chlorinated hydrocarbons and aromatic solvents were screened. The results are shown in the following table:

[0028] Example 5 1 kg of 2-chloronicotinic acid was mixed with 3 kg of 1,2-dichlorobenzene and 0.76 kg of thionyl chloride to prepare solution A; solution A was continuously added to the first stage of the tubular reactor at a flow rate of 35 L / h through a metering pump, and the reaction temperature was controlled at 95°C and the retention time was 3.2 minutes to prepare solution B; the pressure was controlled at 0.7 MPa and the temperature was 15°C, and dimethylamine was continuously added to the second stage of the tubular reactor at a flow rate of 4.2 L / h, and an amide reaction was carried out in the tubular reactor and retained for 10 seconds. The reaction product was separated into solid and liquid by a centrifuge, and the liquid was 2-chloro- N,N -Nicotinamide solution, the conversion rate was measured by high performance liquid chromatography, and the conversion rate was 94.4% based on 2-chloronicotinic acid.

[0029] Example 6 1 kg of 2-chloronicotinic acid was mixed with 3 kg of 1,2-dichlorobenzene and 0.76 kg of thionyl chloride to prepare solution A; solution A was continuously added to the first stage of the tubular reactor at a flow rate of 32 L / h through a metering pump, and the reaction temperature was controlled at 95°C and the retention time was 4 minutes to prepare solution B; the pressure was controlled at 0.9 MPa and the temperature was 15°C, and dimethylamine was continuously added to the second stage of the tubular reactor at a flow rate of 4.6 L / h, and an amide reaction was carried out in the tubular reactor and retained for 30 seconds. The reaction product was separated into solid and liquid by a centrifuge, and the liquid was 2-chloro- N,N -Nicotinamide solution, the conversion rate was measured by high performance liquid chromatography, and the conversion rate was 96.1% based on 2-chloronicotinic acid.

[0030] Example 7 1 kg of 2-chloronicotinic acid was mixed with 4 kg of 1,2-dichlorobenzene and 0.8 kg of thionyl chloride to prepare solution A; solution A was continuously added to the first stage of the tubular reactor at a flow rate of 32 L / h through a metering pump, and the reaction temperature was controlled at 95°C and the retention time was 4 minutes to prepare solution B; the pressure was controlled at 0.9 MPa and the temperature was 15°C, and dimethylamine was continuously added to the second stage of the tubular reactor at a flow rate of 4.6 L / h, and an amide reaction was carried out in the tubular reactor and retained for 30 seconds. The reaction product was separated into solid and liquid by a centrifuge, and the liquid was 2-chloro- N,N -Nicotinamide solution, the conversion rate was measured by high performance liquid chromatography, and the conversion rate was 97.4% based on 2-chloronicotinic acid.

[0031] Example 8 1 kg of 2-chloronicotinic acid was mixed with 4 kg of 1,2-dichlorobenzene and 0.8 kg of thionyl chloride to prepare solution A; solution A was continuously added to the first stage of the tubular reactor at a flow rate of 32 L / h through a metering pump, and the reaction temperature was controlled at 95°C and the retention time was 4 minutes to prepare solution B; the pressure was controlled at 0.9 MPa and the temperature was 18°C, and dimethylamine was continuously added to the second stage of the tubular reactor at a flow rate of 4.6 L / h, and an amide reaction was carried out in the tubular reactor and retained for 30 seconds. The reaction product was separated into solid and liquid by a centrifuge, and the liquid was 2-chloro- N,N-Nicotinamide solution, the conversion rate was measured by high performance liquid chromatography, and the conversion rate was 98.5% based on 2-chloronicotinic acid.

[0032] Example 9 1 kg of 2-chloronicotinic acid was mixed with 4 kg of 1,2-dichlorobenzene and 0.8 kg of thionyl chloride to prepare solution A; solution A was continuously added to the first stage of the tubular reactor at a flow rate of 32 L / h through a metering pump, and the reaction temperature was controlled at 95°C and the retention time was 4 minutes to prepare solution B; the pressure was controlled at 0.9 MPa and the temperature was 20°C, and dimethylamine was continuously added to the second stage of the tubular reactor at a flow rate of 4.2 L / h, and an amide reaction was carried out in the tubular reactor and retained for 40 seconds. The reaction product was separated into solid and liquid by a centrifuge, and the liquid was 2-chloro- N,N -Nicotinamide solution, the conversion rate was measured by high performance liquid chromatography, and the conversion rate was 98.7% based on 2-chloronicotinic acid.

[0033] Comparative Example 7 0.5kg 2-chloronicotinic acid and 2 kg thionyl chloride were stirred and refluxed in a 5L jacketed glass reactor. Samples were taken for HPLC analysis after 0.5h, and the conversion rate was 70%; samples were taken for HPLC analysis after 1.5 hours, and the conversion rate reached 99.5%. Then the mixture was concentrated to dryness under reduced pressure, and 3kg dichloromethane was added to the concentrate to dissolve. The temperature was controlled at about 0°C, and dimethylamine gas was introduced under stirring. The introduction speed was strictly controlled during ventilation. If the flow rate was too fast, the temperature of the reaction liquid would rise rapidly and dimethylamine gas would overflow. When the solution was detected to be 9 with pH test paper, the dimethylamine was stopped, and the ammonia introduction time was 1 hour. After the temperature was raised to room temperature and stirring was continued for 1 hour, the conversion rate of the reaction liquid was 95.6% by HPLC, and the reaction was stopped. Filter, and the filtrate obtained was 2-chloro- N,N -Niacinamide solution.

[0034] The present invention is not limited to the above-mentioned embodiments, and any other changes, combinations, substitutions, modifications made without departing from the principles of the present invention shall be regarded as equivalent replacement modes and included in the protection scope of the present invention.

Claims

1. A two-step continuous preparation of 2-chloro- N,N -dimethylnicotinamide method, characterized in that The following steps are involved: (1) 2-Chloronicotinic acid is mixed with a solvent and thionyl chloride in a certain proportion to prepare solution A; (2) Solution A is continuously added to a section of a tubular reactor at a certain flow rate through a metering pump, and the reaction temperature and retention time are controlled to prepare solution B; (3) Solution B is continuously fed into the second tubular reactor, and dimethylamine is continuously added to the second tubular reactor. The pressure, temperature and retention time are controlled, and an amide reaction is carried out in the tubular reactor. After the reaction is completed, the solid and liquid are separated by a centrifuge, and the liquid is 2-chloro- N,N -Niacinamide solution.

2. The two-step continuous preparation of 2-chloro- N,N -dimethylnicotinamide method, characterized in that In the step (1), the mass ratio of 2-chloronicotinic acid to solvent and dichlorothionyl is 1:3-7:0.76-0.

85.

3. The continuous preparation of 2-chloro- N,N -dimethylnicotinamide method, characterized in that In the step (1), the solvent is selected from any one of 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dichlorobenzene, and 1-chlorobutane.

4. The two-step continuous preparation of 2-chloro- N,N -dimethylnicotinamide method, characterized in that In the step (2), the flow rate of solution A is 31-35 L / h; the reaction temperature is 90-95° C., the pressure is controlled at 0.7-1 MPa; and the retention time is controlled at 3-5 minutes.

5. The two-step continuous preparation of 2-chloro- N,N -dimethylnicotinamide method, characterized in that In the step (3), the flow rate of dimethylamine is 4-5 L / h, the pressure is controlled at 0.7-1 MPa, the temperature is controlled at 10-20° C., and the retention time is 0.1-1 minute.

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