Synthesis method of 5-difluoromethoxy-2-pyridylaldehyde
Through a new synthesis route, the reaction of 5-hydroxy-2-picolinic acid and sulfoxide chloride is used to combine the effects of DMF and alkali metal carbonate, and then combined with sodium difluorochloroacetate and DIBAL-H, a one-step synthesis method is realized, solving the problem of low synthesis efficiency of 5-difluoromethoxy-2-picolinaldehyde in the prior art, and improving the conversion rate and economic benefits.
Patent Information
- Application Number
- CN202411697351.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-26
- Publication Date
- 2025-02-28
AI Technical Summary
The lack of effective synthesis methods for 5-difluoromethoxy-2-pyridine formaldehyde in the prior art has resulted in low conversion rate and many synthesis steps, making it difficult to amplify production and improve economic benefits.
A new synthesis route was adopted, and 5-hydroxy-2-picolinic acid was used as the starting material, and the reaction of sulfoxide chloride was carried out. Then, under the combined action of alkali metal carbonate and sodium difluorochloroacetate in DMF, after multiple steps, the one-step synthesis method was finally achieved using the combination of DIBAL-H and morpholine, and 5-difluoromethoxy-2-picolinaldehyde was obtained directly.
The conversion rate of 5-difluoromethoxy-2-pyridine formaldehyde is improved, the synthesis steps are simplified, production can be amplified, and economic benefits are improved.
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Abstract
Description
Technical Field
[0001] The invention relates to the field of preparation of pyridine derivatives, in particular to a method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde. Background Art
[0002] 5-Difluoromethoxy-2-pyridinecarboxaldehyde is an important pharmaceutical intermediate. Currently, there is no literature reporting its synthesis process. It has an inhibitory effect on mPGES-1 and is a useful pyridine derivative as an active ingredient for the prevention or treatment of inflammation, pain, rheumatism and other diseases. This article provides a synthetic route for 5-difluoromethoxy-2-pyridinecarboxaldehyde, aiming to improve the conversion rate of 5-difluoromethoxy-2-pyridinecarboxaldehyde, simplify the synthesis steps, scale up production, and improve economic benefits. Summary of the invention
[0003] The object of the present invention is to provide a method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde to solve the above technical problems.
[0004] In order to solve the above technical problems, the present invention adopts the following technical solutions:
[0005] A method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde, wherein the structural formula of 5-difluoromethoxy-2-pyridinecarboxaldehyde is as follows:
[0006]
[0007] The synthetic route is as follows:
[0008]
[0009] The synthesis steps are as follows:
[0010] 1) 5-hydroxy-2-pyridinecarboxylic acid was dissolved in methanol as the starting material, chloride was added at 15°C, the reaction was carried out at 45°C for 12 hours, and the reaction solution was concentrated to obtain 5-hydroxy-2-methylpyridine carboxylate hydrochloride;
[0011] 2) dissolving 5-hydroxy-2-methyl pyridine carboxylate hydrochloride in DMF, adding alkali metal carbonate and stirring, then adding sodium difluorochloroacetate, reacting at 85° C. for 3 h, adding water after the reaction temperature drops to 25° C. and extracting twice with methyl tert-butyl ether, combining the organic phases, and drying to obtain a crude product, which is purified by column to obtain 5-(difluoromethoxy)picolinic acid methyl ester;
[0012] 3) Add morpholine to tetrahydrofuran, protect with nitrogen, cool to 0°C, add DIBAL-H (1.5M) dropwise, control the temperature at 0-5°C, react for 30 minutes after addition, dissolve 5-(difluoromethoxy)picolinic acid methyl ester in tetrahydrofuran and add dropwise to the reaction solution, control the temperature at 0-5°C, react for 30 minutes after addition, add water and stir for 30 minutes, remove tetrahydrofuran under reduced pressure, extract with chloromethane, combine the organic phases, add saturated aqueous sodium bisulfite solution, filter, rinse the filter cake with dichloromethane, add sodium bicarbonate solution to the filter cake and add formaldehyde dropwise until the reaction solution is completely dissolved, separate the layers, and dry the organic phase to obtain 5-difluoromethoxy-2-pyridinecarboxaldehyde.
[0013] Preferably, in step 1), the chloride is thionyl chloride.
[0014] Preferably, in step 2), the alkali metal carbonate is potassium carbonate or cesium carbonate.
[0015] The beneficial effects of the present invention are:
[0016] The present invention provides a novel synthetic route for 5-difluoromethoxy-2-pyridinecarboxaldehyde, filling the blank in the synthesis of the molecule. In addition, a novel synthetic method is adopted for directly reducing the methyl ester to the aldehyde group, and a one-step synthesis method is realized by using a combination of DLBAI-H and morpholine. Compared with the traditional synthetic method of first reducing to an alcohol and then oxidizing to an aldehyde, the method has the advantages of high conversion rate, fewer synthetic steps, and the ability to scale up production. DETAILED DESCRIPTION
[0017] In order to facilitate the understanding of the present invention, the present invention is described more fully below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.
[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.
[0019] Specific embodiments of the present invention are described below.
[0020] Example 1
[0021] In this embodiment, a method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde is proposed, and the synthetic route of the method is as follows:
[0022]
[0023] The synthesis method is as follows:
[0024] 1) Synthesizing compound (2), dissolving 10 g of 5-hydroxy-2-picolinic acid in 100 ml of methanol, adding 10 ml of thionyl chloride dropwise at 15° C., reacting at 45° C. for 12 h, concentrating the reaction solution to obtain 13 g of a crude product, which is 5-hydroxy-2-methylformate pyridine hydrochloride, with a yield of 100%;
[0025] 2) Synthesizing compound (3), dissolving 13 g of 5-hydroxy-2-methylformate pyridine hydrochloride in 100 ml of DMF, adding 28 g of potassium carbonate and stirring for 30 min, adding 16 g of sodium difluorochloroacetate, reacting at 85° C. for 3 h, cooling the reaction solution to 25° C., adding 300 ml of water and extracting twice with 200 ml of methyl tert-butyl ether, combining the organic phases, and drying to obtain a crude product, which was purified by column to obtain 8.7 g of a white solid, with a yield of 60%;
[0026] 3) Synthesis of compound (i), add 14g of morpholine to 60ml of tetrahydrofuran, protect with nitrogen, cool to 0°C, add 104ml of DIBAL-H (1.5M) dropwise, control the temperature at 0-5°C, react for 30min after addition, dissolve 8g of 5-(difluoromethoxy)picolinic acid methyl ester in 20ml of tetrahydrofuran and add dropwise to the reaction solution, control the temperature at 0-5°C, react for 30min after addition, add 50ml of water and stir for 30min, remove tetrahydrofuran under reduced pressure, extract with 50ml*2 dichloromethane, combine the organic phases, add saturated sodium bisulfite aqueous solution, filter, and rinse the filter cake with dichloromethane. Add 7% sodium bicarbonate aqueous solution to the filter cake and add formaldehyde dropwise until the reaction solution is completely dissolved, separate, and dry the organic phase to obtain 4.1g of yellow liquid, with a yield of 60%.
[0027] Example 2
[0028] In this embodiment, a method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde is proposed, and the synthetic route of the method is as follows:
[0029]
[0030] The synthesis method is as follows:
[0031] 1) Synthesizing compound (2), dissolving 10 g of 5-hydroxy-2-picolinic acid in 100 ml of methanol, adding 10 ml of thionyl chloride dropwise at 15° C., reacting at 45° C. for 12 h, concentrating the reaction solution to obtain a crude product, and directly carrying out the next step of the reaction, the crude product is 5-hydroxy-2-methylformate pyridine hydrochloride, the yield is 100%, and the crude product is 13 g;
[0032] 2) Synthesizing compound (3), dissolving 10 g of 5-hydroxy-2-methylformate pyridine hydrochloride in 100 ml of DMF, adding 50 g of cesium carbonate and stirring for 30 min, adding 13 g of sodium difluorochloroacetate, reacting at 85° C. for 3 h, cooling the reaction solution to 25° C., adding 230 ml of water and extracting twice with 150 ml of methyl tert-butyl ether, combining the organic phases, and drying to obtain a crude product, which was purified by column to obtain 7.8 g of a white solid with a yield of 70%;
[0033] 3) Synthesis of compound (i): 7.4 g of morpholine was added to 60 ml of tetrahydrofuran, nitrogen was protected, the temperature was lowered to 0°C, 55 ml of DIBAL-H (1.5 M) was added dropwise, the temperature was controlled at 0-5°C, and the reaction was continued for 30 min after the addition was completed. 5.6 g of methyl 5-(difluoromethoxy)picolinate was dissolved in 15 ml of tetrahydrofuran and added dropwise to the reaction solution, the temperature was controlled at 0-5°C, and the reaction was continued for 30 min after the addition was completed. 35 ml of water was added and stirred for 30 min, tetrahydrofuran was removed under reduced pressure, and 35 ml*2 of dichloromethane was used for extraction. The organic phases were combined and dried to obtain a crude product, which was purified by column to obtain 2.1 g of a yellow liquid with a yield of 45%.
[0034] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.
[0035] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.
Claims
The synthesis method of 1.5-difluoromethoxy-2-pyridinecarboxaldehyde is characterized in that ,5-difluoromethoxy-2-pyridinecarboxaldehyde has the following structural formula: The synthetic route is as follows: The synthesis steps are as follows: 1) 5-hydroxy-2-pyridinecarboxylic acid was dissolved in methanol as the starting material, chloride was added at 15°C, the reaction was carried out at 45°C for 12 hours, and the reaction solution was concentrated to obtain 5-hydroxy-2-methylpyridine carboxylate hydrochloride; 2) dissolving 5-hydroxy-2-methyl pyridine carboxylate hydrochloride in DMF, adding alkali metal carbonate and stirring, then adding sodium difluorochloroacetate, reacting at 85° C. for 3 h, adding water after the reaction temperature drops to 25° C. and extracting twice with methyl tert-butyl ether, combining the organic phases, and drying to obtain a crude product, which is purified by column to obtain 5-(difluoromethoxy)picolinic acid methyl ester; 3) Add morpholine to tetrahydrofuran, protect with nitrogen, cool to 0°C, add DIBAL-H (1.5M) dropwise, control the temperature at 0-5°C, react for 30 minutes after addition, dissolve 5-(difluoromethoxy)picolinic acid methyl ester in tetrahydrofuran and add dropwise to the reaction solution, control the temperature at 0-5°C, react for 30 minutes after addition, add water and stir for 30 minutes, remove tetrahydrofuran under reduced pressure, extract with chloromethane, combine the organic phases, add saturated aqueous sodium bisulfite solution, filter, rinse the filter cake with dichloromethane, add sodium bicarbonate solution to the filter cake and add formaldehyde dropwise until the reaction solution is completely dissolved, separate the layers, and dry the organic phase to obtain 5-difluoromethoxy-2-pyridinecarboxaldehyde.
2. The method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde according to claim 1, characterized in that: In step 1), the chloride is thionyl chloride.
3. The method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde according to claim 1, characterized in that: In step 2), the alkali metal carbonate is potassium carbonate or cesium carbonate.