Synthesis method of 5-difluoromethoxy-2-pyridylaldehyde
Through a new synthesis route, including multi-step reaction and purification steps, the conversion rate and economic benefits of 5-difluoromethoxy-2-pyridine formaldehyde were successfully improved, and the complexity and efficiency of synthesis of this compound in the prior art was solved. Low problem.
Patent Information
- Application Number
- CN202411697350.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-26
- Publication Date
- 2025-02-18
AI Technical Summary
At present, there is a lack of effective synthesis process for 5-difluoromethoxy-2-pyridine formaldehyde, which leads to its low conversion rate and complex synthesis steps, making it difficult to produce on a large scale and improve economic benefits.
A new synthetic route is adopted, including reacting 5-hydroxy-2-picolinic acid with sulfoxide chloride to produce 5-hydroxy-2-formate methylpyridine hydrochloride, followed by alkali metal carbonate in DMF and The sodium difluorochloroacetate reaction was performed, and the methyl 5-(difluoromethoxy)pylinylate was obtained by extraction and column purification, and finally 5-difluoromethoxy-2-pylinylcarboxydehyde was obtained by reducing and oxidation steps.
The conversion rate of 5-difluoromethoxy-2-pyridine formaldehyde is improved, the synthesis steps are simplified, the production costs are reduced, and the economic benefits are improved. The reducing agents and oxidants used are cheap and easy to obtain.
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Abstract
Description
Technical Field
[0001] The invention relates to the field of preparation of pyridine derivatives, and in particular to a method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde. Background Art
[0002] 5-Difluoromethoxy-2-pyridinecarboxaldehyde is a pyridine derivative and an important pharmaceutical intermediate. Currently, there is no literature reporting on its production and synthesis process. This paper provides a synthetic route for 5-difluoromethoxy-2-pyridinecarboxaldehyde, aiming to improve the conversion rate of 5-difluoromethoxy-2-pyridinecarboxaldehyde, simplify the synthetic 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, thionyl chloride was added at 15°C, the reaction was carried out at 60°C for 16 hours, and the reaction solution was concentrated to obtain 5-hydroxy-2-methylformate pyridine hydrochloride;
[0011] 2) dissolving 5-hydroxy-2-methyl pyridine carboxylate hydrochloride in DMF, adding alkali metal carbonate and stirring, adding sodium difluorochloroacetate, reacting at 85° C. for 1.5-3 h, adding water after the reaction temperature drops to 25° C., 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) adding methyl 5-(difluoromethoxy)picolinate to an organic solvent, protecting with nitrogen, cooling to 0°C, adding a reducing agent in batches, controlling the temperature to less than 45°C, and keeping the temperature for reaction for 1-3 hours after the addition, followed by post-treatment of the reducing agent;
[0013] 4) subjecting 5-(difluoromethoxy)-2-hydroxymethylpyridine to an oxidation reaction with an oxidant, and performing post-treatment and purification after the reaction to obtain 5-hydroxy-2-methylformate pyridine hydrochloride.
[0014] Preferably, in step 2), the alkali metal carbonate is any one of potassium carbonate or cesium carbonate.
[0015] Preferably, the organic solvent in step 3) is any one of methanol or tetrahydrofuran.
[0016] Preferably, in step 3), the reducing agent is any one of sodium borohydride, lithium aluminum tetrahydride and red aluminum solution.
[0017] Preferably, in step 4), the oxidant is any one of 2,2,6,6-tetramethylpiperidinyl oxide or Dess-Martin periodinane.
[0018] The beneficial effects of the present invention are:
[0019] The invention provides a novel synthesis route of 5-difluoromethoxy-2-pyridinecarboxaldehyde, filling the synthesis blank of the molecule, wherein cheap and readily available sodium borohydride is used to reduce the ester group to alcohol, and then TEMPO is used to oxidize it to aldehyde, which is more economical and has a higher yield. DETAILED DESCRIPTION
[0020] 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.
[0021] 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.
[0022] Specific embodiments of the present invention are described below.
[0023] Example 1
[0024] In this embodiment, a method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde is proposed, and the synthetic route of the method is as follows:
[0025]
[0026] The synthesis method is as follows:
[0027] 1) Synthesizing compound (2), dissolving 135 g of compound (1), i.e. 5-hydroxy-2-picolinic acid in 950 ml of methanol, adding 223 g of thionyl chloride dropwise at 15° C., reacting at 60° C. for 16 h, and concentrating the reaction solution to obtain 5-hydroxy-2-methylformate pyridine hydrochloride, with a yield of 100%, 184 g;
[0028] 2) Synthesizing compound (3), dissolving 184 g of 5-hydroxy-2-methyl pyridine hydrochloride in 1.84 L DMF, adding 402 g of potassium carbonate in batches and stirring for 30 min, heating the reaction solution to 80° C., adding 225 g of sodium difluorochloroacetate in batches, reacting at 85° C. for 1.5 h after the addition, cooling the reaction solution to 25° C., adding 1.4 L of water and extracting twice with 450 ml of methyl tert-butyl ether, combining the organic phases, and drying to obtain a crude product, which was purified by column to obtain 100 g of 5-(difluoromethoxy)picolinic acid methyl ester, with a yield of 66%;
[0029] 3) Synthesizing compound (4), adding 100 g of 5-(difluoromethoxy)picolinic acid methyl ester to 850 ml of methanol, protecting with nitrogen, cooling to 0°C, adding 56 g of sodium borohydride in batches, controlling the temperature to less than 45°C, keeping the temperature for reaction for 3 h after the addition, cooling the reaction solution to below 15°C, adding 150 ml of saturated ammonium chloride aqueous solution dropwise and stirring for 30 min, concentrating under reduced pressure to remove methanol, extracting the residue with 150 ml*3 ethyl acetate, combining the organic phases and concentrating to obtain 84 g of 5-(difluoromethoxy)-2-hydroxymethylpyridine, with a yield of 98%;
[0030] 4) Synthesizing compound (i), 84 g of 5-(difluoromethoxy)-2-hydroxymethylpyridine, 3.8 g of 2,2,6,6-tetramethylpiperidinium oxide, and 24.6 g of sodium bromide were added to 670 ml of dichloromethane, and then 670 g of 7% sodium bicarbonate aqueous solution was added, the temperature was lowered to 10° C., 500 g of 10% sodium hypochlorite aqueous solution was added dropwise, and the temperature was controlled to be less than 10° C. After the addition was completed, the reaction was kept warm for 2 h, the reaction solution was allowed to stand for stratification, the aqueous phase was extracted once with 400 ml of dichloromethane, the organic phases were combined, spin-dried and purified by column to obtain 71 g of 5-difluoromethoxy-2-pyridinecarboxaldehyde, with a yield of 85%.
[0031] Example 2
[0032] In this embodiment, a method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde is proposed, and the synthetic route of the method is as follows:
[0033]
[0034] The synthesis method is as follows:
[0035] 1) Synthesizing compound (2), dissolving 135 g of compound (1), i.e. 5-hydroxy-2-picolinic acid in 950 ml of methanol, adding 223 g of thionyl chloride dropwise at 15° C., reacting at 60° C. for 16 h, and concentrating the reaction solution to obtain 5-hydroxy-2-methylformate pyridine hydrochloride, with a yield of 100%, 184 g;
[0036] 2) To synthesize compound (3), 10 g of 5-hydroxy-2-methylformate pyridine hydrochloride was dissolved in 100 ml of DMF, 50 g of cesium carbonate was added and stirred for 30 min, 13 g of sodium difluorochloroacetate was added, and the mixture was reacted at 85° C. for 3 h. The reaction solution was cooled to 25° C., 230 ml of water was added, and the mixture was extracted twice with 150 ml of methyl tert-butyl ether. The organic phases were combined and dried to obtain a crude product, which was purified by column to obtain 7.8 g of a white solid with a yield of 70%.
[0037] 3) Synthesizing compound (4), adding 7.8 g of methyl 5-(difluoromethoxy)picolinate to 78 ml of tetrahydrofuran, protecting with nitrogen, cooling to 0°C, adding 1.48 g of lithium aluminum tetrahydride in batches, controlling the temperature to less than 10°C, keeping the temperature for reaction for 1 hour after the addition, dropping 1.48 g of water, then dropping 1.48 g of 15% sodium hydroxide aqueous solution, then dropping 1.48 g of water and stirring for 15 min, controlling the temperature to 10-15°C, filtering, rinsing the filter cake with 7.8 ml of tetrahydrofuran, combining the filtrate, and concentrating under reduced pressure to obtain a crude product, which was purified by column to obtain 6.24 g of 5-(difluoromethoxy)-2-hydroxymethylpyridine, with a yield of 93%;
[0038] (4) To synthesize compound (i), 6.24 g of 5-(difluoromethoxy)-2-hydroxymethylpyridine was added to 62.5 ml of dichloromethane, and the temperature was cooled to 0° C. under nitrogen protection. Then 18 g of Dess-Martin periodinane was added, and the temperature was naturally raised to 25° C. for reaction for 2 hours. The reaction solution was cooled to 0° C., and 62.5 ml of a saturated aqueous solution of sodium carbonate and sodium thiosulfate in a ratio of 1:1 was added dropwise to quench the reaction. The organic phase was separated, and the organic phase was spin-dried and purified by column to obtain 4.06 g of 5-difluoromethoxy-2-pyridinecarboxaldehyde, with a yield of 64%.
[0039] Example 3
[0040] In this embodiment, a method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde is proposed, and the synthetic route of the method is as follows:
[0041]
[0042] The synthesis method is as follows:
[0043] 1) Synthesizing compound (2), dissolving 135 g of compound (1), i.e. 5-hydroxy-2-picolinic acid in 950 ml of methanol, adding 223 g of thionyl chloride dropwise at 15° C., reacting at 60° C. for 16 h, and concentrating the reaction solution to obtain 5-hydroxy-2-methylformate pyridine hydrochloride, with a yield of 100%, 184 g;
[0044] 2) To synthesize compound (3), 10 g of 5-hydroxy-2-methylformate pyridine hydrochloride was dissolved in 100 ml of DMF, 50 g of cesium carbonate was added and stirred for 30 min, 13 g of sodium difluorochloroacetate was added, and the mixture was reacted at 85° C. for 3 h. The reaction solution was cooled to 25° C., 230 ml of water was added, and the mixture was extracted twice with 150 ml of methyl tert-butyl ether. The organic phases were combined and dried to obtain a crude product, which was purified by column to obtain 7.8 g of a white solid with a yield of 70%.
[0045] 3) Synthesizing compound (4), adding 7.8 g of methyl 5-(difluoromethoxy)picolinate to 78 ml of tetrahydrofuran, protecting with nitrogen, cooling to 0°C, adding dropwise 13.3 g of red aluminum solution, controlling the temperature to less than 10°C, keeping the temperature for reaction for 1 hour after the addition, adding dropwise 15.6 ml of saturated aqueous ammonium chloride solution and stirring for 30 min, controlling the temperature to 10-15°C, extracting with 30 ml*3 ethyl acetate, combining the organic phases, concentrating to obtain a crude product, and subjecting the crude product to column purification to obtain 5.46 g of 5-(difluoromethoxy)-2-hydroxymethylpyridine, with a yield of 82%;
[0046] (4) To synthesize compound (i), 5.46 g of 5-(difluoromethoxy)-2-hydroxymethylpyridine was added to 54.7 ml of dichloromethane, and the temperature was cooled to 0° C. under nitrogen protection. Then 15.7 g of Dess-Martin periodinane was added, and the temperature was naturally raised to 25° C. for reaction for 2 hours. The reaction solution was cooled to 0° C., and 54.9 ml of a saturated aqueous solution of sodium carbonate and sodium thiosulfate in a ratio of 1:1 was added dropwise to quench the reaction. The organic phase was separated, and the organic phase was spin-dried and purified by column to obtain 3.55 g of 5-difluoromethoxy-2-pyridinecarboxaldehyde, with a yield of 64%.
[0047] 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.
[0048] 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
1. A method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde, 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, thionyl chloride was added at 15°C, the reaction was carried out at 60°C for 16 hours, and the reaction solution was concentrated to obtain 5-hydroxy-2-methylformate pyridine hydrochloride; 2) dissolving 5-hydroxy-2-methyl pyridine carboxylate hydrochloride in DMF, adding alkali metal carbonate and stirring, adding sodium difluorochloroacetate, reacting at 85° C. for 1.5-3 h, adding water after the reaction temperature drops to 25° C., 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) adding methyl 5-(difluoromethoxy)picolinate to an organic solvent, protecting with nitrogen, cooling to 0°C, adding a reducing agent in batches, controlling the temperature to less than 45°C, and keeping the temperature for reaction for 1-3 hours after the addition, followed by post-treatment of the reducing agent; 4) subjecting 5-(difluoromethoxy)-2-hydroxymethylpyridine to an oxidation reaction with an oxidant, and performing post-treatment and purification after the reaction to obtain 5-hydroxy-2-methylformate pyridine hydrochloride.
2. A method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde according to claim 1, characterized in that: In step 2), the alkali metal carbonate is any one of potassium carbonate or cesium carbonate.
3. A method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde according to claim 1, characterized in that: In step 3), the organic solvent is any one of methanol or tetrahydrofuran.
4. A method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde according to claim 1, characterized in that: In step 3), the reducing agent is any one of sodium borohydride, lithium aluminum tetrahydride and red aluminum solution.
5. A method for synthesizing 5-difluoromethoxy-2-pyridinecarboxaldehyde according to claim 1, characterized in that: In step 4), the oxidant is any one of 2,2,6,6-tetramethylpiperidinoxide or Dess-Martin periodinane.