Process for the preparation of 2-(methylsulfonyl)nicotinaldehyde

Abstract

This invention relates to a method for preparing 2-(methylsulfonyl)nicotinaldehyde, belonging to the field of organic synthesis technology. The invention includes the following steps: Under a protective atmosphere, 2-mercaptonicotinic acid and potassium carbonate are dissolved in an organic solvent, and iodomethane is added to react, yielding a white solid methyl 2-methylthionicotinic acid ester; the obtained methyl 2-methylthionicotinic acid ester is dissolved in acetic acid with sodium tungstate hydrate, and an oxidizing agent is added at -5℃ to 5℃, the reaction is carried out at room temperature, and the product is collected to obtain a white solid methyl 2-(methylsulfonyl)nicotinic acid ester; Under a protective atmosphere, the obtained methyl 2-(methylsulfonyl)nicotinic acid ester is dissolved in tetrahydrofuran, and a reducing agent is added and stirred to react at -83℃ to -73℃, after the reaction is completed, the product is collected to obtain 2-(methylsulfonyl)nicotinaldehyde. The purity of the 2-(methylsulfonyl)nicotinaldehyde obtained by this invention is 97%-99%, and the overall yield is above 70%.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing 2-(methylsulfonyl)nicotinaldehyde. Background Technology

[0002] 2-(Methylsulfonyl)nicotinaldehyde is an important chemical raw material and organic building block. It is an important intermediate in the synthesis of nicotinamide and nicotinic acid esters. Studies have shown that nicotinamide compounds play an important role in anti-skin aging and are used as additives in skin care products. In addition, 2-(methylsulfonyl)nicotinaldehyde is also a necessary structural unit for the synthesis of some novel antihypertensive drugs. Therefore, exploring how to prepare 2-(methylsulfonyl)nicotinaldehyde with high efficiency, high yield and low cost is a topic with important application value.

[0003] In existing technologies, the raw material for preparing methyl 2-(methylsulfonyl)nicotinic acid is mostly 2-methylthionicotinic acid. This method suffers from high starting material costs and cumbersome post-reaction processing. Although some literature (Heterocycles 2010, 81, 413; Journal of the Korean Chemical Society 2021, 65, 166) uses 2-mercaptonicotinic acid as the starting material and sulfuric acid as a catalyst to reflux in methanol to obtain methyl 2-methylthionicotinic acid, this method suffers from low yield, long reaction time, and involves the use and post-treatment of sulfuric acid, placing higher demands on the production environment. The reaction route is as follows:

[0004]

[0005] Therefore, the existing technology for preparing methyl 2-(methylsulfonyl)nicotinic acid has drawbacks such as high starting material costs, low reaction conversion rates, and long reaction times. Furthermore, there are no reports on the synthesis of 2-(methylsulfonyl)nicotinic acid aldehyde from methyl 2-(methylsulfonyl)nicotinic acid in the current technology. Therefore, there is an urgent need to provide a method for preparing 2-(methylsulfonyl)nicotinic acid aldehyde with high yield and low cost. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a method for preparing 2-(methanesulfonyl)nicotinaldehyde. In this invention, 2-(methanesulfonyl)nicotinaldehyde possesses a more reactive aldehyde group, which can be readily applied in various chemical reactions and derived into various structural units. Based on these reasons, this invention provides a high-yield, low-cost method for preparing 2-(methanesulfonyl)nicotinaldehyde.

[0007] This invention is achieved through the following steps:

[0008] The purpose of this invention is to provide a method for preparing 2-(methylsulfonyl)nicotinaldehyde, comprising the following steps:

[0009] (1) Under a protective atmosphere, 2-mercaptonicotinic acid and an alkaline agent are dissolved in an organic solvent, and iodomethane is added to react and 2-methylthionicotinic acid methyl ester is obtained.

[0010] (2) The 2-methylthionicotinic acid methyl ester obtained in step (1) is reacted with the catalytic system in an organic solvent to obtain 2-(methylsulfonyl)nicotinic acid methyl ester;

[0011] (3) Under a protective atmosphere, the methyl 2-(methylsulfonyl)nicotinic acid obtained in step (2) is dissolved in an organic solvent, and a reducing agent is added and stirred to react, thereby obtaining the 2-(methylsulfonyl)nicotinic acid aldehyde.

[0012] In one embodiment of the present invention, the organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, acetic acid, N,N-dimethylformamide and N,N-dimethylacetamide.

[0013] In one embodiment of the present invention, in step (1), the molar ratio of 2-mercaptonicotinic acid, iodomethane and alkali is 1:2:2.5 to 1:4:5.

[0014] In one embodiment of the present invention, in step (1), the reaction time is 4h to 8h.

[0015] In one embodiment of the present invention, the alkaline agent is selected from one or more of potassium carbonate, potassium bicarbonate, dipotassium hydrogen phosphate, triethylamine, and N,N-diisopropylethylamine.

[0016] In one embodiment of the present invention, in step (2), the catalytic system is sodium tungstate / hydrogen peroxide, sodium periodate / rhodium chloride, cyanuric acid / sodium hypochlorite, or mCPBA.

[0017] In one embodiment of the present invention, the molar ratio of methyl 2-methylthionicotinic acid ester to hydrogen peroxide and sodium tungstate in the catalytic system is 1:2:0.05 to 1:2.5:0.1.

[0018] In one embodiment of the present invention, in step (2), the reaction time is 8h to 12h.

[0019] In one embodiment of the present invention, in step (3), the molar ratio of methyl 2-(methylsulfonyl)nicotinic acid to the reducing agent is 1:1 to 1:1.2.

[0020] In one embodiment of the present invention, in step (3), the reducing agent is diisobutylaluminum hydride and / or red aluminum.

[0021] In one embodiment of the present invention, in step (3), the reaction conditions are: -83℃ to -73℃ for 3h to 6h.

[0022] In one embodiment of the present invention, step (3) further includes recrystallizing 2-(methylsulfonyl)nicotinaldehyde.

[0023] In one embodiment of the present invention, the recrystallization process is as follows: ethyl acetate is added to crude 2-(methylsulfonyl)nicotinaldehyde, stirred and heated, with the temperature controlled at 45°C to 50°C, insoluble matter is removed by filtration, n-hexane is added to the filtrate, the temperature is controlled at around 45°C, and after stirring for a period of time, the heating is removed, the temperature is lowered until the solid precipitates, and the product is obtained by filtration.

[0024] In one embodiment of the present invention, the synthetic route for 2-(methylsulfonyl)nicotinaldehyde is as follows:

[0025]

[0026] The technical solution of the present invention has the following advantages compared with the prior art:

[0027] (1) This invention uses 2-mercaptonicotinic acid as the starting material and synthesizes the target product 2-(methylsulfonyl)nicotinic acid in high yield and high purity through three steps: methylation, oxidation and reduction. The raw materials are cheap and readily available, the reaction is easy to operate and the post-processing is relatively simple, which effectively reduces the synthesis cost. At the same time, it can stably obtain high purity and has a good prospect for industrial production.

[0028] (2) The synthesis product of the present invention was determined by nuclear magnetic resonance hydrogen spectrum, which showed that the final product synthesized by the present invention was 2-(methylsulfonyl)nicotinaldehyde with a purity of 97%-99% and a total yield of over 70%. Attached Figure Description

[0029] To make the content of this invention easier to understand, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings, wherein...

[0030] Figure 1 This is the 1H NMR spectrum of 2-(methylsulfonyl)nicotinaldehyde in this invention. Detailed Implementation

[0031] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.

[0032] Example 1

[0033] (1) Synthesis of methyl 2-methylthionicotinic acid ester

[0034] Under a nitrogen atmosphere, 15.5 g (0.1 mol) of 2-mercaptonicotinic acid, 34.6 g (0.25 mol) of potassium carbonate, and 75 mL of DMF were added to a 500 mL three-necked flask, and the temperature was slowly lowered to 0 ± 5 °C. Iodomethane (28.4 g, 0.2 mol) was slowly added dropwise (ensuring the temperature did not exceed 5 °C), and the mixture was allowed to return to room temperature for 4 hours after the addition was complete. Then, 1 M dilute hydrochloric acid was added to adjust the pH to approximately 2–3, at which point a solid precipitated. Approximately 300 mL of water was slowly added, and the mixture was stirred at 0 °C for 0.5 hours. The mixture was filtered, and the solid was washed with cold water to obtain 16.7 g of a white solid, methyl 2-methylthionicotinic acid, with a yield of 91.2%.

[0035] (2) Synthesis of methyl 2-(methylsulfonyl)nicotinic acid

[0036] In a 250 mL three-necked flask, methyl 2-methylthionicotinic acid (9.15 g, 50 mmol), sodium tungstate hydrate (0.82 g, 2.5 mmol), and acetic acid (50 mL) were added to a 500 mL three-necked flask. The mixture was cooled to 0 ± 5 °C, and 30 wt% hydrogen peroxide (11.3 g, 100 mmol) was slowly added. After the addition was complete, the mixture was allowed to return to room temperature for 8 h. After the reaction was complete, 200 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phase was washed successively with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 10.0 g of white solid methyl 2-(methylsulfonyl)nicotinic acid, with a yield of 93.6%.

[0037] (3) Synthesis of 2-(methylsulfonyl)nicotinaldehyde

[0038] Under a nitrogen atmosphere, methyl 2-(methylsulfonyl)nicotinate (8.6 g, 40 mmol) and tetrahydrofuran (100 mL) were added to a 500 mL three-necked flask, and the temperature was slowly lowered to -78 ± 5 °C. DIBAL (40 mL, 40 mmol, 1 M in n-hexane) was slowly added dropwise. The reaction was stirred at -78 ± 5 °C for 3 h. After the reaction was complete, 1.6 mL of water, 1.6 mL of 15% NaOH solution, and 4 mL of water were added sequentially to quench the reaction. Anhydrous sodium sulfate was then added, and the mixture was stirred for 0.5 h. The mixture was filtered, and the organic phase was concentrated to dryness to obtain the crude product. Ethyl acetate was added to the crude 2-(methylsulfonyl)nicotinaldehyde, and the mixture was stirred and heated at 45℃–50℃. Insoluble matter was removed by filtration. Hexane was added to the filtrate, and the temperature was maintained at approximately 45℃. After stirring for a period of time, the heating was removed, and the mixture was cooled until a solid precipitated. Filtering yielded 6.1 g of white solid 2-(methylsulfonyl)nicotinaldehyde, with a yield of 82.7%. The overall yield of the final product was 70.6%.

[0039] The products were characterized by nuclear magnetic resonance (NMR), such as Figure 1 As shown.

[0040] Example 2

[0041] (1) Synthesis of methyl 2-methylthionicotinic acid ester

[0042] Under a nitrogen atmosphere, 15.5 g (0.1 mol) of 2-mercaptonicotinic acid, 34.6 g (0.25 mol) of potassium carbonate, and 100 mL of acetonitrile were added to a 500 mL three-necked flask, and the temperature was slowly lowered to 0 ± 5 °C. Iodomethane (28.4 g, 0.2 mol) was slowly added dropwise (ensuring the temperature did not exceed 5 °C), and the mixture was allowed to return to room temperature for 4 hours after the addition was complete. Then, 1 M dilute hydrochloric acid was added to adjust the pH to approximately 2–3, at which point a solid precipitated. Approximately 300 mL of water was slowly added, and the mixture was stirred at 0 °C for 0.5 hours. The mixture was filtered, and the solid was washed with cold water to obtain 15.3 g of a white solid, methyl 2-methylthionicotinic acid, with a yield of 83.6%.

[0043] (2) Synthesis of methyl 2-(methylsulfonyl)nicotinic acid

[0044] In a 250 mL three-necked flask, methyl 2-methylthionicotinic acid (9.15 g, 50 mmol), sodium tungstate hydrate (0.82 g, 2.5 mmol), and acetic acid (50 mL) were added to a 500 mL three-necked flask. The mixture was cooled to 0 ± 5 °C, and 30 wt% hydrogen peroxide (11.3 g, 100 mmol) was slowly added. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 12 h. After the reaction was complete, 200 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phase was washed successively with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 9.6 g of white solid methyl 2-(methylsulfonyl)nicotinic acid, with a yield of 89.8%.

[0045] (3) Synthesis of 2-(methylsulfonyl)nicotinaldehyde

[0046] Under a nitrogen atmosphere, methyl 2-(methylsulfonyl)nicotinate (8.6 g, 40 mmol) and tetrahydrofuran (100 mL) were added to a 500 mL three-necked flask, and the temperature was slowly lowered to -78 ± 5 °C. Dibaal (40 mL, 40 mmol, 1 M dibaal dissolved in n-hexane) was slowly added dropwise. The reaction was stirred at -78 ± 5 °C for 6 h. After the reaction was complete, 1.6 mL of water, 1.6 mL of 15% NaOH solution, and 4 mL of water were added sequentially to quench the reaction. Anhydrous sodium sulfate was then added, and the mixture was stirred for 0.5 h. The mixture was filtered, and the organic phase was concentrated to dryness to obtain the crude product. Ethyl acetate was added to the crude 2-(methylsulfonyl)nicotinaldehyde, and the mixture was stirred and heated at 45℃–50℃. Insoluble matter was removed by filtration. Hexane was added to the filtrate, and the temperature was maintained at approximately 45℃. After stirring for a period of time, the heating was removed, and the mixture was cooled until a solid precipitated. Filtering yielded 6.3 g of white solid 2-(methylsulfonyl)nicotinaldehyde, with a yield of 85.4%. The final product yield was 64.1%.

[0047] Example 3

[0048] (1) Synthesis of methyl 2-methylthionicotinic acid ester

[0049] Under a nitrogen atmosphere, 2-mercaptonicotinic acid (62.1 g, 0.4 mol), potassium carbonate (276 g, 2 mol), and DMF (300 mL) were added to a 2 L three-necked flask, and the temperature was lowered to 0 ± 5 °C. Iodomethane (125.2 g, 1.6 mol) was slowly added dropwise (ensuring the temperature did not exceed 5 °C), and the reaction was allowed to proceed at room temperature for 8 h after the addition was complete. Then, 1 M dilute hydrochloric acid was added to adjust the pH to approximately 2–3, at which point a solid precipitated. Approximately 1.2 L of water was slowly added, and the mixture was stirred at 0 °C for 0.5 h. After filtration, the solid was washed with cold water to obtain 67.8 g of a white solid, methyl 2-methylthionicotinic acid, with a yield of 92.6%.

[0050] (2) Synthesis of methyl 2-(methylsulfonyl)nicotinic acid

[0051] In a 250 mL three-necked flask, methyl 2-methylthionicotinic acid (45.8 g, 0.25 mol), sodium tungstate hydrate (6 g, 0.02 mol), and acetic acid (200 mL) were added to a 2 L three-necked flask. The mixture was cooled to 0 ± 5 °C, and 30 wt% hydrogen peroxide (56.5 g, 0.55 mol) was slowly added. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 8 h. After the reaction was complete, 800 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (250 mL * 3). The organic phase was washed successively with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 9.9 g of white solid methyl 2-(methylsulfonyl)nicotinic acid, with a yield of 92.9%.

[0052] (3) Synthesis of 2-(methylsulfonyl)nicotinaldehyde

[0053] Under a nitrogen atmosphere, methyl 2-(methylsulfonyl)nicotinic acid (43 g, 0.2 mmol) and tetrahydrofuran (500 mL) were added to a 2 L three-necked flask, and the temperature was slowly lowered to -78 ± 5 °C. Dibaal (240 mL, 0.24 mol, 1 M dibaal dissolved in n-hexane) was slowly added dropwise. The reaction was stirred at -78 ± 5 °C for 3 h. After the reaction was complete, 9.6 mL of water, 9.6 mL of 15% NaOH solution, and 24 mL of water were added sequentially to quench the reaction. Anhydrous sodium sulfate was added, and the mixture was stirred for 0.5 h. The mixture was filtered, and the organic phase was concentrated to dryness to obtain the crude product. Recrystallization from ethyl acetate / n-hexane yielded 32.7 g of a white solid, 2-(methylsulfonyl)nicotinic acid, with a yield of 88.6%. The overall yield of the final product was 76.2%.

[0054] Comparative Example 1

[0055] This comparative example provides a method for synthesizing methyl 2-methylthionicotinic acid, the specific steps of which are as follows:

[0056] Under a nitrogen atmosphere, 62.1 g (0.4 mol) of 2-mercaptonicotinic acid, 10 mL (98%), and 1 L of methanol were added to a 2 L three-necked flask. After the addition was complete, the mixture was refluxed for 24 h. The reaction was then quenched with sodium carbonate solution, extracted with ethyl acetate (200 mL x 3), dried over anhydrous sodium sulfate, and separated by rapid column chromatography (silica gel) with hexane / ethyl acetate (20:1, v / v) as the eluent, yielding 32.4 g of a white solid, methyl 2-methylthionicotinic acid, in a yield of 44.3%.

[0057] Comparative Example 2

[0058] The preparation method of 2-(methylsulfonyl)nicotinaldehyde in this comparative example is similar to that in Example 1, except that:

[0059] The reducing agent used in step (3) was LiAlH4; the yield of the final white solid was 32.4%.

[0060] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for preparing 2-(methylsulfonyl)nicotinaldehyde, characterized in that, Includes the following steps: (1) Under a protective atmosphere, 2-mercaptonicotinic acid and an alkaline agent are dissolved in an organic solvent, and iodomethane is added to react and 2-methylthionicotinic acid methyl ester is obtained; (2) The 2-methylthionicotinic acid methyl ester obtained in step (1) is reacted with the catalytic system in an organic solvent to obtain 2-(methylsulfonyl)nicotinic acid methyl ester; (3) Under a protective atmosphere, the methyl 2-(methylsulfonyl)nicotinic acid obtained in step (2) is dissolved in an organic solvent, and a reducing agent is added and stirred to react, thereby obtaining the 2-(methylsulfonyl)nicotinic acid aldehyde; In step (3), the molar ratio of methyl 2-(methylsulfonyl)nicotinic acid to the reducing agent is 1:1 to 1:1.2; In step (3), the reducing agent is diisobutylaluminum hydride and / or red aluminum.

2. The preparation method according to claim 1, characterized in that: The organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, acetic acid, N,N-dimethylformamide and N,N-dimethylacetamide.

3. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of 2-mercaptonicotinic acid, iodomethane and alkali is 1:2:2.5 to 1:4:

5.

4. The preparation method according to claim 1, characterized in that: In step (1), the alkali agent is selected from one or more of potassium carbonate, potassium bicarbonate, dipotassium hydrogen phosphate, triethylamine and N,N-diisopropylethylamine.

5. The preparation method according to claim 1, characterized in that: In step (2), the catalytic system is sodium tungstate / hydrogen peroxide, sodium periodate / rhodium chloride, cyanuric acid / sodium hypochlorite, or mCPBA.

6. The preparation method according to claim 1, characterized in that: In step (2), the reaction time is 8 h to 12 h.

7. The preparation method according to claim 1, characterized in that: In step (3), the reaction conditions are: -83℃ to -73℃ for 3 h to 6 h.

8. The preparation method according to claim 1, characterized in that: Step (3) also includes recrystallization of 2-(methylsulfonyl)nicotinaldehyde.

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