Industrial preparation method of 2-hydroxy-6-(trifluoromethyl) pyridine

Abstract

The invention relates to an industrial preparation method of 2-hydroxy-6-(trifluoromethyl) pyridine, which comprises the following steps: in an inert solvent, taking 2-chloro-6-(trifluoromethyl) pyridine as a raw material, and carrying out C-O bond coupling reaction on the 2-chloro-6-(trifluoromethyl) pyridine and alkali under the action of a catalyst to prepare the 2-hydroxy-6-(trifluoromethyl) pyridine. Compared with the prior art, the method has the advantages of cheap raw materials, simplicity in operation, capability of reacting under normal pressure, relatively mild conditions, safety, environment friendliness, easiness in industrial production and the like.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical preparation technology, and relates to an industrial preparation method of 2-hydroxy-6-(trifluoromethyl)pyridine. Background Technology

[0002] 2-Hydroxy-6-(trifluoromethyl)pyridine is a common organic synthesis intermediate, often participating in subsequent transformations in its tautomer ketone form. In the pharmaceutical field, it serves as a key intermediate in the synthesis of fluorinated drugs, such as antiviral drugs (e.g., HIV protease inhibitors), anticancer drugs (kinase inhibitors), or anti-inflammatory drugs. In the pesticide and agrochemical fields, the trifluoromethyl group can enhance the lipophilicity and metabolic stability of molecules. The combination of hydroxyl and trifluoromethyl groups may interfere with the enzyme systems of pathogens, thus exhibiting antibacterial or antifungal activity, and is widely used in agrochemicals (e.g., the methacrylate fungicide azoxystrobin). In the field of polymer materials, 2-hydroxy-6-(trifluoromethyl)pyridine can be used to produce polyvinyl alcohol resins and synthetic fibers. It can also be copolymerized with other monomers to prepare adhesives for various applications, creating polymeric synthetic materials with different properties.

[0003] Currently, there are two main routes reported for the synthesis of 2-hydroxy-6-(trifluoromethyl)pyridine both domestically and internationally: Route 1: The routes reported in CN110467567 and US5973159 require high temperature (150°C) and high pressure (100 psi), which are harsh conditions, result in low yields, and lead to high costs. Route 2: The route reported by CN113185455 is long, has high raw material costs, and a low overall yield, resulting in high costs. Therefore, there is an urgent need in this field to develop a method for preparing 2-hydroxy-6-(trifluoromethyl)pyridine that uses inexpensive raw materials, is simple to operate, can react under normal pressure, has relatively mild conditions, is safe and environmentally friendly, and is easy to produce industrially. Summary of the Invention

[0004] The purpose of this invention is to provide an industrial preparation method for 2-hydroxy-6-(trifluoromethyl)pyridine, which is economical, efficient, safe and environmentally friendly, with relatively mild reaction conditions and easy to industrialize.

[0005] The objective of this invention can be achieved through the following technical solutions: An industrial method for preparing 2-hydroxy-6-(trifluoromethyl)pyridine includes the following steps: 2-hydroxy-6-trifluoromethylpyridine was prepared by reacting 2-chloro-6-(trifluoromethyl)pyridine with a base in an inert solvent under the action of a catalyst via a CO bond coupling reaction.

[0006] Furthermore, the catalyst is a combination of a copper-based active ingredient and a ligand. Even further, the copper-based active ingredient is one or more of Cu powder, CuI, CuBr, CuCl, CuTc, CuCN, CuSCN, Cu2O, Cu(OAc)2, CuSO4, Cu2CO3, Cu(NO3)2, CuBr2, CuCl2, CuO, Cu(AcAc)2, and 8-hydroxyquinoline copper, preferably CuBr or Cu2O.

[0007] Furthermore, the ligand is any one or a combination of compounds having the following structures: or , Among them, R a It is an optionally substituted C6-C14 aryl, or an optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O and S, or an optionally substituted 5-7 membered heterocyclic alkyl containing 1-3 ring atoms independently selected from C, N, O and S. R b It is an optionally substituted C6-C14 aryl group, or an optionally substituted 5-6 membered heteroaryl group containing 1-3 independently selected ring atoms from C, N, O and S; R c It is an optionally substituted C6-C14 aryl, or an optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O and S, or an optionally substituted 5-7 membered heterocyclic alkyl containing 1-3 ring atoms independently selected from C, N, O and S. R d It is an optionally substituted C6-C14 aryl group, or an optionally substituted 5-6 membered heteroaryl group containing 1-3 ring atoms independently selected from C, N, O and S.

[0008] Furthermore, the ligand is selected from one or more of the following L1 to L12: , , , , , , , , , , , .

[0009] More preferably, the ligand is any one or a combination of the following: , , , .

[0010] Furthermore, the amount of the copper-based active ingredient is 0.1 to 10% of the molar amount of 2-chloro-6-(trifluoromethyl)pyridine, for example, it can be 1%, 2%, 5%, etc.

[0011] Furthermore, the amount of the ligand used is 0.1 to 10% of the molar amount of 2-chloro-6-(trifluoromethyl)pyridine, for example, it can be 1%, 2%, 5%, etc.

[0012] Furthermore, the alkali is one or a combination of several of the following: sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, and tetrabutylammonium hydroxide. Sodium hydroxide and potassium hydroxide are preferred.

[0013] Furthermore, the amount of alkali used is 1 to 10 times the molar amount of 2-chloro-6-(trifluoromethyl)pyridine, for example, it can be 2 times, 3 times, 5 times, etc.

[0014] Furthermore, the inert solvent is one or more of the following: water, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, and ester solvents.

[0015] Furthermore, the ether solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, anisole, and diphenyl ether; The ketone solvent is one or more of acetone, butanone, and methyl isobutyl ketone; The alcohol solvent is one or more selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol. The ester solvent is one or both of isopropyl acetate and isobutyl acetate.

[0016] Furthermore, the coupling reaction temperature is 80~110℃, preferably 90~100℃, and the time is 2~24h, preferably 10~16h.

[0017] Compared with the prior art, the present invention has the following advantages: (1) The method does not involve dangerous reactions and does not involve experiments under high temperature and high pressure, thus avoiding significant safety risks.

[0018] (2) The raw materials are cheap and the operation is simple. No precious metal catalysts are used, which gives it a significant cost advantage.

[0019] (3) The catalyst dosage is small, the catalytic efficiency is high, the reaction yield is high, and the product purity is good.

[0020] (4) This invention is carried out under normal pressure, and the reaction conditions are relatively mild, making it suitable for industrial production. Detailed Implementation

[0021] The present invention will now be described in detail with reference to specific embodiments. These embodiments are based on the technical solution of the present invention and provide detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following embodiments.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0023] As used herein, the terms "and / or," "or / and," and "and / or" encompass any one of two or more of the related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected using at least two conjunctions selected from "and / or," "or / and," and "and / or," it should be understood that, in this application, the technical solution undoubtedly includes solutions connected by "logical AND," and also undoubtedly includes solutions connected by "logical OR."

[0024] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0025] In this application, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0026] This document only specifically discloses some numerical ranges. However, any lower limit can be combined with any upper limit to form an unspecified range; and any lower limit can be combined with other lower limits to form an unspecified range, just as any upper limit can be combined with any other upper limit to form an unspecified range. Furthermore, each individually disclosed point or single value can itself serve as a lower or upper limit and be combined with any other point or single value or with other lower or upper limits to form an unspecified range.

[0027] Unless otherwise specified, the temperature parameters in this application may be either constant temperature processing or processing within a certain temperature range. The constant temperature processing allows temperature fluctuations within the precision range controlled by the instrument, such as ±5°C, ±4°C, ±3°C, ±2°C, or ±1°C.

[0028] In this document, the term "suitable" as used in phrases such as "suitable combination," "suitable method," and "any suitable method" refers to the ability to implement the technical solution of this application, solve the technical problem of this application, and achieve the expected technical effect of this application.

[0029] In this application, terms such as "further," "even more," and "particularly" are used for descriptive purposes and to indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0030] In this application, "optionally," "optionally," and "optional" mean that something is optional, that is, it means that it is selected from either "with" or "without." If there are multiple "optional" entries in a technical solution, unless otherwise specified, and there are no contradictions or mutual constraints, each "optional" entry shall be independent.

[0031] In the description of the application, "multiple" means at least two, such as two, three, etc., unless otherwise explicitly specified.

[0032] Unless otherwise specified, all preparations and tests described herein took place at 25°C.

[0033] The terms “comprising,” “including,” “containing,” “having,” “comprising,” or other variations thereof are intended to cover non-closed inclusion, and no distinction is made between these terms. The term “comprising” means that other steps and ingredients may be added without affecting the final result. The compositions and methods / processes of the present invention comprise, consist of, and substantially consist of the essential elements and limitations described herein, as well as any additional or optional ingredients, components, steps, or limitations described herein. No distinction is made between the terms “efficacy,” “performance,” “effect,” and “potency” herein.

[0034] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions. Unless otherwise specified, all technical features and optional technical features of this application can be combined to form new technical solutions.

[0035] Unless otherwise specified, all steps in this application may be performed sequentially or randomly, but sequentially is preferred.

[0036] Example 1: 100 g of 2-chloro-6-(trifluoromethyl)pyridine, 66.1 g of sodium hydroxide, 322 g of tert-amyl alcohol, 1.58 g of cuprous bromide, and 3.46 g of ligand L1 were added to a 1 L reaction flask. The mixture was purged with nitrogen three times, heated to 110 °C, and stirred for 12 h. The reaction was confirmed to be complete by HPLC. After filtration and concentration, 500 g of process water was added. The pH of the aqueous phase was adjusted to 1-2 with dilute hydrochloric acid. The mixture was then filtered and dried to obtain 85.35 g of the product with a purity of 99.8%. 1 HNMR (DMSO-d6): δ6.95 (d, J=8.4Hz, 1H), 6.95 (d, J=7.2Hz, 1H), 7.88 (t, J=8.0Hz, 1H), 11.70 (s, 1H) Example 2: 100 g of 2-chloro-6-(trifluoromethyl)pyridine, 66.1 g of sodium hydroxide, 322 g of tert-amyl alcohol, 2.00 g of cuprous oxide, and 3.46 g of ligand L1 were added to a 1 L reaction flask. The mixture was purged with nitrogen three times, heated to 110 °C, and stirred for 12 h. The reaction was confirmed to be complete by HPLC. After filtration and concentration, 500 g of process water was added. The pH of the aqueous phase was adjusted to 1-2 with dilute hydrochloric acid. The mixture was then filtered and dried to obtain 76.36 g of the product with a purity of 99.1%. 1 HNMR (DMSO-d6): δ6.95 (d, J=8.4Hz, 1H), 6.95 (d, J=7.2Hz, 1H), 7.88 (t, J=8.0Hz, 1H), 11.70 (s, 1H) Example 3: 100 g of 2-chloro-6-(trifluoromethyl)pyridine, 66.1 g of sodium hydroxide, 400 g of water, 1.58 g of cuprous bromide, and 3.46 g of ligand L1 were added to a 1 L reaction flask. The mixture was purged with nitrogen three times, heated to 110 °C, and stirred for 12 h. The reaction was confirmed to be complete by HPLC. The mixture was filtered, and the pH of the aqueous phase was adjusted to 1-2 with dilute hydrochloric acid. After filtration and drying, 67.38 g of the product was obtained with a purity of 98.3%. 1 HNMR (DMSO-d6): δ6.95 (d, J=8.4Hz, 1H), 6.95 (d, J=7.2Hz, 1H), 7.88 (t, J=8.0Hz, 1H), 11.70 (s, 1H) Example 4: 100 g of 2-chloro-6-(trifluoromethyl)pyridine, 96 g of sodium hydroxide, 400 g of water, 1.58 g of cuprous bromide, and 3.46 g of ligand L1 were added to a 1 L reaction flask. The mixture was purged with nitrogen three times, heated to 110 °C, and stirred for 12 h. The reaction was confirmed to be complete by HPLC. The mixture was filtered, and the pH of the aqueous phase was adjusted to 1-2 with dilute hydrochloric acid. After filtration and drying, 78.16 g of the product with a purity of 99.1% was obtained. 1 HNMR (DMSO-d6): δ6.95 (d, J=8.4Hz, 1H), 6.95 (d, J=7.2Hz, 1H), 7.88 (t, J=8.0Hz, 1H), 11.70 (s, 1H) Example 5: 100 g of 2-chloro-6-(trifluoromethyl)pyridine, 93 g of potassium hydroxide, 400 g of water, 1.58 g of cuprous bromide, and 3.46 g of ligand L1 were added to a 1 L reaction flask. The mixture was purged with nitrogen three times, heated to 110 °C, and stirred for 12 h. The reaction was confirmed to be complete by HPLC. The mixture was filtered, and the pH of the aqueous phase was adjusted to 1-2 with dilute hydrochloric acid. After filtration and drying, 71.8 g of the product with a purity of 98.9% was obtained. 1 HNMR (DMSO-d6): δ6.95 (d, J=8.4Hz, 1H), 6.95 (d, J=7.2Hz, 1H), 7.88 (t, J=8.0Hz, 1H), 11.70 (s, 1H) Example 6: 100 g of 2-chloro-6-(trifluoromethyl)pyridine, 66.1 g of sodium hydroxide, 322 g of tert-amyl alcohol, 1.58 g of cuprous bromide, and 3.61 g of ligand L2 were added to a 1 L reaction flask. The mixture was purged with nitrogen three times, heated to 110 °C, and stirred for 12 h. The reaction was confirmed to be complete by HPLC. After filtration and concentration, 500 g of process water was added. The pH of the aqueous phase was adjusted to 1-2 with dilute hydrochloric acid. The mixture was then filtered and dried to obtain 61.09 g of the product with a purity of 98.4%. 1 HNMR (DMSO-d6): δ6.95 (d, J=8.4Hz, 1H), 6.95 (d, J=7.2Hz, 1H), 7.88 (t, J=8.0Hz, 1H), 11.70 (s, 1H) Example 7: 100 g of 2-chloro-6-(trifluoromethyl)pyridine, 66.1 g of sodium hydroxide, 322 g of tert-amyl alcohol, 1.58 g of cuprous bromide, and 3.34 g of ligand L4 were added to a 1 L reaction flask. The mixture was purged with nitrogen three times, heated to 110 °C, and stirred for 12 h. The reaction was confirmed to be complete by HPLC. After filtration and concentration, 500 g of process water was added. The pH of the aqueous phase was adjusted to 1-2 with dilute hydrochloric acid. The mixture was then filtered and dried to obtain 73.67 g of the product with a purity of 99.1%.1 HNMR (DMSO-d6): δ6.95 (d, J=8.4Hz, 1H), 6.95 (d, J=7.2Hz, 1H), 7.88 (t, J=8.0Hz, 1H), 11.70 (s, 1H) Example 8: 100 g of 2-chloro-6-(trifluoromethyl)pyridine, 66.1 g of sodium hydroxide, 322 g of tert-amyl alcohol, 1.58 g of cuprous bromide, and 2.67 g of ligand L10 were added to a 1 L reaction flask. The mixture was purged with nitrogen three times, heated to 110 °C, and stirred for 12 h. The reaction was confirmed to be complete by HPLC. After filtration and concentration, 500 g of process water was added. The pH of the aqueous phase was adjusted to 1-2 with dilute hydrochloric acid. The mixture was then filtered and dried to obtain 53.90 g of the product with a purity of 98.0%. 1 HNMR (DMSO-d6): δ6.95 (d, J=8.4Hz, 1H), 6.95 (d, J=7.2Hz, 1H), 7.88 (t, J=8.0Hz, 1H), 11.70 (s, 1H) The catalysts and ligands were adjusted according to the aforementioned Example 1, and the results are shown in the table below.

[0037] Table 1 Furthermore, this invention has found that when only copper-based active components are used (e.g., copper salts, copper powder, or a combination of copper salts and copper powder (or different copper salts)), i.e., without the addition of ligands to the catalyst, the entire reaction cannot proceed even under the same conditions as in Example 1, such as reflux reaction. This reflects the safety and operability of the reaction of this invention. In addition, compared to existing technologies (which require high temperature and high pressure to achieve good conversion rates), the catalyst has high catalytic efficiency, can be used for experiments at atmospheric pressure, and the reaction conditions are relatively mild, avoiding significant production safety risks.

[0038] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. An industrial method for preparing 2-hydroxy-6-(trifluoromethyl)pyridine, characterized in that, Includes the following steps: 2-hydroxy-6-trifluoromethylpyridine was prepared by reacting 2-chloro-6-(trifluoromethyl)pyridine with a base in an inert solvent under the action of a catalyst via a CO bond coupling reaction.

2. The industrial preparation method of 2-hydroxy-6-(trifluoromethyl)pyridine according to claim 1, characterized in that, The catalyst is a combination of copper-based active ingredients and ligands, wherein the copper-based active ingredients are one or more of Cu powder, CuI, CuBr, CuCl, CuTc, CuCN, CuSCN, Cu2O, Cu(OAc)2, CuSO4, Cu2CO3, Cu(NO3)2, CuBr2, CuCl2, CuO, Cu(AcAc)2, and 8-hydroxyquinoline copper. The ligand is any one or a combination of compounds having the following structures: or , Among them, R a It is an optionally substituted C6-C14 aryl, or an optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O and S, or an optionally substituted 5-7 membered heterocyclic alkyl containing 1-3 ring atoms independently selected from C, N, O and S. R b It is an optionally substituted C6-C14 aryl group, or an optionally substituted 5-6 membered heteroaryl group containing 1-3 independently selected ring atoms from C, N, O and S; R c It is an optionally substituted C6-C14 aryl, or an optionally substituted 5-6 membered heteroaryl containing 1-3 ring atoms independently selected from C, N, O and S, or an optionally substituted 5-7 membered heterocyclic alkyl containing 1-3 ring atoms independently selected from C, N, O and S. R d It is an optionally substituted C6-C14 aryl group, or an optionally substituted 5-6 membered heteroaryl group containing 1-3 ring atoms independently selected from C, N, O and S.

3. The industrial preparation method of 2-hydroxy-6-(trifluoromethyl)pyridine according to claim 2, characterized in that, The ligand is selected from one or more of the following L1 to L12: 、 、 、 、 、 、 、 、 、 、 、 。 4. The industrial preparation method of 2-hydroxy-6-(trifluoromethyl)pyridine according to claim 2, characterized in that, The amount of the copper-based active ingredient is 0.1 to 10% of the molar amount of 2-chloro-6-(trifluoromethyl)pyridine.

5. The industrial preparation method of 2-hydroxy-6-(trifluoromethyl)pyridine according to claim 2, characterized in that, The amount of the ligand used is 0.1 to 10% of the molar amount of 2-chloro-6-(trifluoromethyl)pyridine.

6. The industrial preparation method of 2-hydroxy-6-(trifluoromethyl)pyridine according to claim 1, characterized in that, The alkali is one or a combination of several of the following: sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, and tetrabutylammonium hydroxide.

7. The industrial preparation method of 2-hydroxy-6-(trifluoromethyl)pyridine according to claim 1, characterized in that, The amount of alkali used is 1 to 10 times the molar amount of 2-chloro-6-(trifluoromethyl)pyridine.

8. The industrial preparation method of 2-hydroxy-6-(trifluoromethyl)pyridine according to claim 1, characterized in that, The inert solvent is one or more of the following: water, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, and ester solvents.

9. The industrial preparation method of 2-hydroxy-6-(trifluoromethyl)pyridine according to claim 8, characterized in that, The ether solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, anisole, and diphenyl ether; The ketone solvent is one or more of acetone, butanone, and methyl isobutyl ketone; The alcohol solvent is one or more selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol. The ester solvent is one or both of isopropyl acetate and isobutyl acetate.

10. The industrial preparation method of 2-hydroxy-6-(trifluoromethyl)pyridine according to claim 1, characterized in that, The coupling reaction is carried out at a temperature of 80~110℃ for 2~24h.

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