A kind of preparation method of 2-pyridinecarboxaldehyde

Abstract

The present invention relates to the technical field of organic chemistry, and discloses a preparation method of 2-pyridinecarboxaldehyde, wherein the preparation method comprises the following steps: using 2-halopyridine as a raw material, reacting with a Grignard reagent or an organic lithium under the condition of -10 to 0°C to generate an active metal compound intermediate, and then reacting with N,N-dimethylformamide at room temperature to generate 2-pyridinecarboxaldehyde. The present invention adopts cheap and easily available 2-halopyridine and a Grignard reagent or an organic reagent to generate an active intermediate, and then reacts with N,N-dimethylformamide to synthesize 2-pyridinecarboxaldehyde in one step, and the reaction is mild, waste is small, and it is easy to handle, the production cost is low, the product conversion rate is high, the one-step synthesis cycle is short, and it has good production convenience.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemistry, and in particular to a method for preparing 2-pyridinecarboxaldehyde. Background Art

[0002] As an important pharmaceutical intermediate and fine chemical raw material, 2-pyridinecarboxaldehyde has a wide range of applications and broad market prospects. In medicine, as an important pharmaceutical intermediate, 2-pyridinecarboxaldehyde can be used to synthesize the laxative bisacopyr, and is also the raw material for synthesizing the organophosphate antidote pralidoxime. Recently, it has been reported that 2-pyridinecarboxaldehyde can also be used as a raw material for synthesizing anti-HIV protease inhibitors; in agriculture, 2-pyridinecarboxaldehyde is an essential intermediate for synthesizing some acaricides; in the photosensitive industry, 2-pyridinecarboxaldehyde can be used to synthesize nitrogen-containing heterocyclic color photographic materials.

[0003] There are many synthetic routes for 2-pyridinecarboxaldehyde reported in the literature, but they can be summarized into two routes with different starting materials.

[0004] One is to use 2-pyridinecarboxylic acid as the starting material, and obtain 2-pyridinecarboxaldehyde through esterification, hydrazinolysis, and reoxidation (Huang Shengtang, Huang Wenlong, Zhang Huibin. Improvement of the synthesis process of 2-pyridinecarboxaldehyde [J]. Chemical Reagents, 2005, 27(1): 58).

[0005] The second method is to use 2-methylpyridine as a raw material, and then N-oxidize, rearrange, hydrolyze and then oxidize to prepare 2-pyridinecarboxaldehyde (Shan Shiming, Yu Shuqin, Liao Hong, etc. Synthesis of 2-pyridinecarboxaldehyde [J]. Chinese Journal of Pharmaceutical Industry, 1997, 28 (8): 377-378); or N-oxidize, nitrosate and hydrolyze to prepare 2-pyridinecarboxaldehyde (CN200910212467, CN201410531499); or chlorinate and hydrolyze to 2-pyridinemethanol, and then oxidize to synthesize 2-pyridinecarboxaldehyde (CN200910143970). The oxidants used in the oxidation reaction, such as selenium dioxide or lead tetraacetate, are highly toxic, easily cause environmental pollution, and have a low yield.

[0006] In the process of implementing the present invention, the inventors found that there are at least the following problems in the prior art that have not been solved:

[0007] The oxidation of alcohols to aldehydes is a very important reaction in organic synthesis. However, since aldehydes are substances in an intermediate oxidation state between alcohols and carboxylic acids, they can easily be over-oxidized to form 2-pyridinecarboxylic acid during the reaction. The production of carboxylic acids will reduce the yield of the reaction and the purity of the product.

[0008] In addition, the existing technologies all have the disadvantages of large post-processing pollution, high production difficulty, expensive and highly toxic oxidizing agents, etc. In particular, the chlorination technology of dimethylbenzene often requires the use of more active chlorides such as thionyl chloride, so the production process has high pollution waste, is highly corrosive to equipment, and is difficult to produce. Summary of the invention

[0009] The object of the present invention is to provide a method for preparing 2-pyridinecarboxaldehyde, so as to solve the problems of high energy consumption, large pollution, high cost and difficult operation in the production process of 2-pyridinecarboxaldehyde proposed in the background technology.

[0010] To achieve the above object, the present invention provides the following technical solution: a method for preparing 2-pyridinecarboxaldehyde, the preparation method comprising the following steps:

[0011] Take 2-halopyridine as raw material, react with Grignard reagent or organic lithium at -10~0℃ to generate active metal compound intermediate, and then react with N,N-dimethylformamide (DMF) at room temperature to generate 2-pyridinecarboxaldehyde. The reaction equation is as follows:

[0012]

[0013] Where:

[0014] RM is organic lithium;

[0015] RMX is a Grignard reagent;

[0016] X is a halogen;

[0017] M is metal;

[0018] R is a hydrocarbon group.

[0019] As a preferred embodiment of the present invention, 2-halopyridine is used as a raw material, and reacts with a Grignard reagent at -10 to 0°C to generate an active metal compound intermediate. The specific process is as follows: 2-halopyridine is placed in a reaction bottle, and 2-bromopyridine and 100 ml of tetrahydrofuran are added. At this time, the reaction bottle releases heat, and a cooling medium is placed outside the reaction bottle. The cooling medium is used to limit the internal temperature of the reaction bottle when it releases heat, and the inside of the reaction bottle is cooled. When the inside of the reaction bottle is cooled to 0 to 5°C, an isopropyl magnesium chloride solution is added dropwise, and the reaction is kept warm for 1 hour after the addition is completed to obtain an active metal compound intermediate; wherein, 2-bromopyridine is 31.6 g, 0.20 mol, and the isopropyl magnesium chloride solution is 0.20 mol.

[0020] As a preferred embodiment of the present invention, the specific process of reacting with N,N-dimethylformamide to generate 2-pyridinecarboxaldehyde is as follows: N,N-dimethylformamide (29.2 g, 0.40 mol) is added dropwise to the active metal compound intermediate, and the temperature is raised to room temperature for reaction for 2 hours after the addition, and then thin layer chromatography tracking analysis is performed. After the reaction is complete, 100 ml of saturated brine is added dropwise, and the layers are allowed to stand for stratification. The organic phase is concentrated to remove the solvent tetrahydrofuran, and the concentrated solution is distilled under reduced pressure to obtain 20.3 g of 2-pyridinecarboxaldehyde, wherein the yield of 2-pyridinecarboxaldehyde is 94.9%, and GC (gas chromatography): 99.2%.

[0021] Compared with the prior art, the present invention provides a method for preparing 2-pyridinecarboxaldehyde, which has the following characteristics:

[0022] Beneficial effects:

[0023] The invention discloses a method for preparing 2-pyridinecarboxaldehyde. The invention adopts cheap and readily available 2-halopyridine and Grignard reagent or organic reagent to react to generate an active intermediate, and then reacts with N,N-dimethylformamide to synthesize 2-pyridinecarboxaldehyde in one step. In the preparation process, the reaction temperature of the whole process is room temperature or close to room temperature, there is no very low or very high temperature, the reaction is mild, the product conversion rate is high, the waste is small, the production cost is low, the one-step synthesis cycle is short, and the method has good production convenience. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Other features, objects and advantages of the present invention will become more apparent from the detailed description of non-limiting embodiments made with reference to the following drawings:

[0025] Figure 1 The present invention is a schematic flow diagram of a method for preparing 2-pyridinecarboxaldehyde;

[0026] Figure 2 It is a schematic diagram for comparing data of the embodiments of the present invention and the comparative examples. DETAILED DESCRIPTION

[0027] In order to better understand the purpose, structure and function of the present invention, the preparation method of 2-pyridinecarboxaldehyde of the present invention is further described in detail below in conjunction with the accompanying drawings.

[0028] Example 1

[0029] like Figure 1 As shown, the present invention provides a technical solution: a method for preparing 2-pyridinecarboxaldehyde, the preparation method comprising the following steps:

[0030] Take 2-halopyridine as raw material, react with Grignard reagent at -10℃ to generate active metal compound intermediate, and then react with N,N-dimethylformamide (DMF) at room temperature to generate 2-pyridinecarboxaldehyde. The reaction equation is as follows:

[0031]

[0032] Where:

[0033] RM is organic lithium;

[0034] RMX is a Grignard reagent;

[0035] X is a halogen;

[0036] M is metal;

[0037] R is a hydrocarbon group.

[0038] In this embodiment, 2-halopyridine is used as a raw material, and reacts with a Grignard reagent at -10°C to generate an active metal compound intermediate. The specific process is as follows: 2-bromopyridine and 100 ml of tetrahydrofuran are added to a reaction flask, and the reaction flask releases heat. At the same time, a cooling medium is placed outside the reaction flask, and the cooling medium is dry ice. The cooling medium is used to limit the internal temperature of the reaction flask when it releases heat, and at the same time, the inside of the reaction flask is cooled. When the inside of the reaction flask is cooled to -10°C, an isopropyl magnesium bromide solution is added dropwise, and the reaction is kept warm for 1 hour after the addition is completed to obtain an active metal compound intermediate; wherein, 2-bromopyridine is 31.6 g, 0.20 mol, and the isopropyl magnesium bromide solution is 0.20 mol.

[0039] In this embodiment, the specific process of reacting with N,N-dimethylformamide to generate 2-pyridinecarboxaldehyde is as follows: N,N-dimethylformamide (29.2 g, 0.40 mol) is added dropwise to the active metal compound intermediate, and the temperature is raised to room temperature for reaction for 2 hours after the addition is completed, and then thin layer chromatography tracking analysis is performed. After the reaction is complete, 100 ml of saturated brine is added dropwise, and the layers are allowed to stand for stratification. The organic phase is concentrated to remove the solvent tetrahydrofuran, and the concentrated solution is distilled under reduced pressure to obtain 20.3 g of 2-pyridinecarboxaldehyde, wherein the yield of 2-pyridinecarboxaldehyde is 94.9%, and GC (gas chromatography): 99.2%.

[0040] Example 2

[0041] like Figure 1 As shown, the present invention provides a technical solution: a method for preparing 2-pyridinecarboxaldehyde, the preparation method comprising the following steps:

[0042] Take 2-halopyridine as raw material, react with Grignard reagent at 0℃ to generate active metal compound intermediate, and then react with N,N-dimethylformamide (DMF) at room temperature to generate 2-pyridinecarboxaldehyde. The reaction equation is as follows:

[0043]

[0044] Where:

[0045] RM is organic lithium;

[0046] RMX is a format reagent;

[0047] X is a halogen;

[0048] M is metal;

[0049] R is a hydrocarbon group.

[0050] In this embodiment, 2-halopyridine is used as a raw material, and reacts with a Grignard reagent at 0°C to generate an active metal compound intermediate. The specific process is as follows: 2-bromopyridine and 100 ml of tetrahydrofuran are added to a reaction flask, and the reaction flask releases heat. At the same time, a cooling medium is placed outside the reaction flask, and the cooling medium is dry ice. The cooling medium is used to limit the internal temperature of the reaction flask when it releases heat, and at the same time, the inside of the reaction flask is cooled. When the inside of the reaction flask is cooled to 0°C, an isopropyl magnesium bromide solution is added dropwise, and the reaction is kept warm for 1 hour after the addition is completed to obtain an active metal compound intermediate; wherein, 2-bromopyridine is 31.6 g, 0.20 mol, and the isopropyl magnesium bromide solution is 0.20 mol.

[0051] In this embodiment, the specific process of generating 2-pyridinecarboxaldehyde with N,N-dimethylformamide is as follows: N,N-dimethylformamide (29.2 g, 0.40 mol) is added dropwise to the active metal compound intermediate, and the temperature is raised to room temperature for reaction for 2 hours after the addition is completed, and then thin layer chromatography tracking analysis is performed. After the reaction is complete, 100 ml of saturated brine is added dropwise, and the layers are allowed to stand for stratification. The organic phase is concentrated to remove the solvent tetrahydrofuran, and the concentrated solution is distilled under reduced pressure to obtain 20.3 g of 2-pyridinecarboxaldehyde, wherein the yield of 2-pyridinecarboxaldehyde is 94.9%, and GC (gas chromatography): 99.2%.

[0052] Example 3

[0053] like Figure 1 As shown, a method for preparing 2-pyridinecarboxaldehyde comprises the following steps:

[0054] Take 2-halopyridine as raw material, react with organic lithium at -10℃ to generate active metal compound intermediate, and then react with N,N-dimethylformamide (DMF) at room temperature to generate 2-pyridinecarboxaldehyde. The reaction equation is as follows:

[0055]

[0056] Where:

[0057] RM is organic lithium;

[0058] RMX is a Grignard reagent;

[0059] X is a halogen;

[0060] M is metal;

[0061] R is a hydrocarbon group.

[0062] In this embodiment, the 2-halopyridine is used as a raw material, and reacts with organic lithium at -10°C to generate an active metal compound intermediate. The specific process is as follows: 2-iodine pyridine (41.0 g, 0.20 mol) and 100 ml of n-hexane are added to a reaction flask. At this time, the reaction flask releases heat, and a cooling medium is placed outside the reaction flask. The cooling medium is dry ice. The cooling medium is used to limit the internal temperature of the reaction flask when it releases heat, and at the same time, the inside of the reaction flask is cooled. When the inside of the reaction flask is cooled to -10°C, n-butyl lithium n-hexane solution (0.25 mol) is added dropwise, and the reaction is kept warm for 1 hour after the addition is completed to obtain an active metal compound intermediate.

[0063] In this embodiment, the specific process of reacting with N,N-dimethylformamide to generate 2-pyridinecarboxaldehyde is as follows: N,N-dimethylformamide (29.2 g, 0.40 mol) is added dropwise to the active metal compound intermediate, and the temperature is raised to room temperature for reaction for 2 hours after the addition is completed. Thin layer chromatography tracking analysis is performed. After the reaction is complete, 100 ml of saturated brine is added dropwise, and the mixture is allowed to stand for stratification. The aqueous phase is extracted with 30 ml of n-hexane, the organic phases are combined, and washed with 100 ml of saturated brine. The organic phase is concentrated to remove the solvent n-hexane, and the concentrate is distilled under reduced pressure to obtain 20.6 g of 2-pyridinecarboxaldehyde, with a yield of 96.3%, and GC (gas chromatography): 99.5%.

[0064] Example 4

[0065] like Figure 1 As shown, a method for preparing 2-pyridinecarboxaldehyde comprises the following steps:

[0066] Take 2-halopyridine as raw material, react with organic lithium at 0℃ to generate active metal compound intermediate, and then react with N,N-dimethylformamide (DMF) at room temperature to generate 2-pyridinecarboxaldehyde. The reaction equation is as follows:

[0067]

[0068] Where:

[0069] RM is organic lithium;

[0070] RMX is a format reagent;

[0071] X is a halogen;

[0072] M is metal;

[0073] R is a hydrocarbon group.

[0074] In this embodiment, the 2-halopyridine is used as a raw material, and reacts with organic lithium at 0°C to generate an active metal compound intermediate. The specific process is as follows: 2-iodine pyridine (41.0 g, 0.20 mol) and 100 ml of n-hexane are added to the reaction, and the reaction bottle releases heat. At the same time, a cooling medium is placed outside the reaction bottle, and the cooling medium is dry ice. The cooling medium is used to limit the internal temperature of the reaction bottle when it releases heat, and at the same time, the inside of the reaction bottle is cooled. When the inside of the reaction bottle is cooled to 0°C, n-butyl lithium n-hexane solution (0.25 mol) is added dropwise, and the reaction is kept warm for 1 hour after the addition is completed to obtain an active metal compound intermediate.

[0075] In this embodiment, the specific process of reacting with N,N-dimethylformamide to generate 2-pyridinecarboxaldehyde is as follows: N,N-dimethylformamide (29.2 g, 0.40 mol) is added dropwise to the active metal compound intermediate, and the temperature is raised to room temperature for reaction for 2 h after the addition is complete. Thin layer chromatography tracking analysis is performed. After the reaction is complete, 100 ml of saturated brine is added dropwise, and the mixture is allowed to stand for stratification. The aqueous phase is extracted with 30 ml of n-hexane, the organic phases are combined, and washed with 100 ml of saturated brine. The organic phase is concentrated to remove the solvent n-hexane, and the concentrate is distilled under reduced pressure to obtain 20.5 g of 2-pyridinecarboxaldehyde, with a yield of 96.0%, and GC (gas chromatography): 99.4%.

[0076] Comparative Example 1

[0077] In this comparative example, 2-pyridinecarboxylic acid is used as the starting material, and 2-pyridinecarboxaldehyde is obtained through esterification, hydrazinolysis and reoxidation.

[0078] Comparative Example 2

[0079] In this comparative example, 2-methylpyridine is used as a raw material, and 2-pyridinecarboxaldehyde is prepared by N-oxidation, rearrangement, hydrolysis and then oxidation.

[0080] The present invention adopts the methods of Examples 1 to 4 and Comparative Examples 1 and 2 to prepare 2-pyridinecarboxaldehyde, which can effectively prove that: the present invention adopts cheap and readily available 2-halopyridine and Grignard reagent or organic reagent to react to generate an active intermediate, and then reacts with N,N-dimethylformamide to synthesize 2-pyridinecarboxaldehyde in one step. During the preparation process, the reaction temperature of the whole process is room temperature or close to room temperature, there is no very low or very high temperature, the reaction is mild, and the product conversion rate is high, the waste is small, the one-step synthesis cycle is short, and the production convenience is very good.

[0081] It is to be understood that the present invention is described by some embodiments, and it is known to those skilled in the art that various changes or equivalent substitutions may be made to these features and embodiments without departing from the spirit and scope of the present invention. In addition, under the teachings of the present invention, these features and embodiments may be modified to adapt to specific circumstances and materials without departing from the spirit and scope of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed herein, and all embodiments falling within the scope of the claims of this application are within the scope of protection of the present invention.

Claims

1. A method for preparing 2-pyridinecarboxaldehyde, characterized in that: Add 2-bromopyridine and 100 ml of tetrahydrofuran into the reaction flask. The reaction flask releases heat. A cooling medium is placed outside the reaction flask. The cooling medium is dry ice. The cooling medium is used to limit the internal temperature of the reaction flask when it releases heat. At the same time, the temperature inside the reaction flask is lowered. When the temperature inside the reaction flask is lowered to -10°C, add isopropylmagnesium bromide solution dropwise. After the addition is completed, keep the temperature for 1 hour to obtain an active metal compound intermediate. Among them, 2-bromopyridine is 31.6g, 0.20mol, and isopropylmagnesium bromide solution is 0.20mol; Add 29.2 g, 0.40 mol of N,N-dimethylformamide to the active metal compound intermediate, warm to room temperature and react for 2 hours, then perform thin layer chromatography tracking analysis. After the reaction is complete, add 100 ml of saturated brine, let stand to separate the layers, subtract and concentrate the organic phase to remove the solvent tetrahydrofuran, and distill the concentrate under reduced pressure to obtain 2-pyridinecarboxaldehyde.

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