Preparation method of 2-propylpyridine-4 (1H)-ketone acetate
By using a palladium catalyst to treat 2-cyclopropylpyridin-4-ol and acetic acid in a hydrogen atmosphere, the high yield and high purity 2-propylpyridin-4(1H)-one acetate was successfully prepared, which solved the synthesis problem in the prior art and was suitable for industrial production.
Patent Information
- Application Number
- CN202510545710.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-28
- Publication Date
- 2025-08-01
AI Technical Summary
In the prior art, there are very few reports on the synthesis of 2-propylpyridine-4(1H)-one acetate, and there is a lack of high yield and high purity preparation methods.
Using 2-cyclopropylpyridin-4-ol as the raw material, a palladium catalyst and acetic acid are used to react in a hydrogen atmosphere. The specific steps include adding palladium carbon or palladium carbon hydroxide to the alcohol solvent, controlling the reaction temperature and pressure, and carrying out the hydrogenation reaction.
The preparation of 2-propylpyridine-4(1H)-one acetate with high yield and high purity is achieved. The reaction conditions are mild, the catalyst dosage is low, and the side reactions are few, making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pharmaceutical synthesis, and particularly to a method for preparing 2-propylpyridin-4(1H)-one acetate. Background Art
[0002] 4-Hydroxypyridine compounds and their derivatives are a class of important organic compounds and important raw materials for synthesizing various drugs. For example, they can be used to synthesize pyridine sulfonamide diuretics such as Torasemide, and such drugs are widely used clinically for treating cardiovascular diseases such as heart failure and hypertension. In addition, 4-hydroxypyridine can also be used as a raw material for synthesizing other drug intermediates such as 4-mercaptopyridine, further expanding its application scope in the field of drug synthesis.
[0003] Among them, 2-propylpyridin-4(1H)-one acetate is an important pharmaceutical intermediate, and there are few reports on its synthesis at present. Given the wide application value of 2-propylpyridin-4(1H)-one acetate, it is of great significance to develop a process route for 2-propylpyridin-4(1H)-one acetate with high yield and high purity.
[0004] 2-Propylpyridin-4(1H)-one acetate
[0005] Therefore, the present invention aims to develop a new method for preparing 2-propylpyridin-4(1H)-one acetate. Summary of the Invention
[0006] The main technical problem to be solved by the present invention is to provide a method for preparing 2-propylpyridin-4(1H)-one acetate.
[0007] To solve the above technical problem, the technical solution adopted by the present invention is: a method for preparing 2-propylpyridin-4(1H)-one acetate, using 2-cyclopropylpyridin-4-ol as a raw material (shown in formula (I)), reacting in a hydrogen atmosphere in the presence of a palladium catalyst and acetic acid to prepare 2-propylpyridin-4(1H)-one acetate (shown in formula (II)).
[0008] The method for preparing 2-propylpyridin-4(1H)-one acetate provided by the present invention involves the following reaction formula:
[0009]
[0010] As an embodiment of the present invention, the palladium catalyst is palladium on carbon and / or palladium hydroxide on carbon. Using palladium on carbon and / or palladium hydroxide on carbon as the palladium catalyst can effectively improve the reaction efficiency and the selectivity of the product.
[0011] As an embodiment of the present invention, the reaction is carried out in an alcohol solvent, and the alcohol solvent is selected from at least one of methanol, ethanol, and isopropanol.
[0012] As an embodiment of the present invention, the feeding mass ratio of the 2-cyclopropylpyridin-4-ol to the palladium catalyst is 1:(0.05 - 0.1).
[0013] As an embodiment of the present invention, the feeding molar ratio of the 2-cyclopropylpyridin-4-ol to the acetic acid is 1:(1.5 - 3).
[0014] As an embodiment of the present invention, the reaction temperature of the reaction is 30 - 70 °C.
[0015] As an embodiment of the present invention, the reaction time of the reaction is 6 - 15 h.
[0016] As a preferred embodiment of the present invention, the reaction temperature of the reaction is 45 - 55 °C.
[0017] As a preferred embodiment of the present invention, the reaction time of the reaction is 9 - 11 h.
[0018] As an embodiment of the present invention, the reaction is carried out under pressure conditions, and the hydrogen pressure in the reaction system is 2 - 4 MPa.
[0019] Specifically, the feeding mass ratio of the 2-cyclopropylpyridin-4-ol to the palladium catalyst can be 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1 or any other value within the range of 1:(0.05 - 0.1). It should be noted that when using palladium on carbon as the palladium catalyst, the feeding mass of the palladium catalyst refers to the actual mass of the palladium on carbon input, not the mass of the active substance contained in the palladium on carbon.
[0020] Specifically, the feeding molar ratio of the 2-cyclopropylpyridin-4-ol to the acetic acid can be 1:1.5, 1:1.8, 1:2.0, 1:2.2, 1:2.5, 1:3.0 or any other value within the range of 1:(1.5 - 3).
[0021] The preparation method of 2-propylpyridin-4(1H)-one acetate provided by the present invention has the advantages of mild reaction conditions, low catalyst dosage, simple operation, few side reactions, and high yield, and can be used for the industrial production of 2-propylpyridin-4(1H)-one acetate.
[0022] The preparation method of 2-propylpyridin-4(1H)-one acetate provided by the present invention can obtain a high-purity 2-propylpyridin-4(1H)-one acetate product after simple post-treatment of the reactants after the reaction is completed. BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Figure 1 The 2-propylpyridin-4(1H)-one acetate prepared in Example 1 of the present invention is 1 H-NMR spectrum. DETAILED DESCRIPTION
[0024] The following examples are intended to further illustrate the present invention, but are not intended to limit the scope of protection of the present invention.
[0025] In the following examples, unless otherwise specified, all the drugs used were commercially available products.
[0026] Example 1
[0027] This embodiment provides a method for preparing 2-propylpyridin-4(1H)-one acetate, and the reaction formula is:
[0028]
[0029] A 1L three-necked flask was used as a reaction vessel, 50 g of 2-cyclopropylpyridin-4-ol (shown in formula (I), 370 mmol) was added to 500 mL of methanol, and then 44.4 g of acetic acid (740 mmol) was added. Then, 5 g of palladium carbon (purchased, with an effective substance content of 10%) was added to the three-necked flask under a nitrogen atmosphere. The material on the wall of the reaction flask was rinsed with 50 mL of methanol, and then hydrogen was replaced, maintaining the hydrogen pressure at 2 to 4 MPa. The reaction was stirred at 50 ° C for 10 h. The reaction was complete by TLC detection.
[0030] The reaction system was filtered, and the filtrate was concentrated to obtain a solid. The obtained solid was washed with n-hexane and dried to obtain 68.6 g of 2-propylpyridin-4(1H)-one acetate (represented by formula (II), 348 mmol) with a yield of 94%.
[0031] Example 2
[0032] This example provides a method for preparing 2-propylpyridin-4(1H)-one acetate. The reaction formula is the same as that shown in Example 1. Take a 1L three-necked flask as the reaction vessel, add 50 g of 2-cyclopropylpyridin-4-ol (370 mmol) to 500 mL of methanol, then add 44.4 g of acetic acid (740 mmol). Then, under a nitrogen atmosphere, add 2.5 g of palladium on carbon (purchased, the content of the active substance is 10%) to the three-necked flask, rinse the materials on the wall of the reaction flask with 50 mL of methanol, and then displace the hydrogen, maintaining the hydrogen pressure at 2-4 MPa. Stir and react at 50 °C for 10 h, and detect that the reaction is complete by TLC.
[0033] Filter the reaction system, concentrate the filtrate to obtain a solid, wash the obtained solid with n-hexane, and after drying, obtain 65.8 g (334 mmol) of 2-propylpyridin-4(1H)-one acetate, with a yield of 90%.
[0034] Example 3
[0035] This example provides a method for preparing 2-propylpyridin-4(1H)-one acetate. The reaction formula is the same as that shown in Example 1. Take a 1L three-necked flask as the reaction vessel, add 50 g of 2-cyclopropylpyridin-4-ol (370 mmol) to 500 mL of methanol, then add 44.4 g of acetic acid (740 mmol). Then, under a nitrogen atmosphere, add 5 g of palladium hydroxide on carbon (purchased, the content of the active substance is 15%) to the three-necked flask, rinse the materials on the wall of the reaction flask with 50 mL of methanol, and then displace the hydrogen, maintaining the hydrogen pressure at 2-4 MPa. Stir and react at 50 °C for 10 h, detect that there is raw material remaining by TLC, continue to stir and react for 5 h, and detect that the reaction is complete by TLC.
[0036] Filter the reaction system, concentrate the filtrate to obtain a solid, wash the obtained solid with n-hexane, and after drying, obtain 65.0 g (330 mmol) of 2-propylpyridin-4(1H)-one acetate, with a yield of 89%.
[0037] Example 4
[0038] This example provides a method for preparing 2-propylpyridin-4(1H)-one acetate. The reaction formula is the same as that shown in Example 1. Take a 1L three-necked flask as the reaction vessel, add 50 g of 2-cyclopropylpyridin-4-ol (370 mmol) to 500 mL of methanol, then add 44.4 g of acetic acid (740 mmol), and then add 2.5 g of palladium on carbon (purchased, the content of the active substance is 15%) to the three-necked flask under a nitrogen atmosphere. Rinse the materials on the wall of the reaction flask with 50 mL of methanol, then displace with hydrogen, maintain the hydrogen pressure at 2 - 4 MPa, and stir and react at 50 °C for 10 h. TLC detection shows that there is raw material remaining. Continue to stir and react for 5 h. TLC detection still shows that there is raw material remaining, and the reaction ends.
[0039] Filter the reaction system, concentrate the filtrate to obtain a solid, wash the obtained solid with n-hexane, and after drying, obtain 54.6 g (277 mmol) of 2-propylpyridin-4(1H)-one acetate, with a yield of 75%.
[0040] Example 5
[0041] This example provides a method for preparing 2-propylpyridin-4(1H)-one acetate. The reaction formula is the same as that shown in Example 1. Take a 1L three-necked flask as the reaction vessel, add 50 g of 2-cyclopropylpyridin-4-ol (370 mmol) to 500 mL of ethanol, then add 44.4 g of acetic acid (740 mmol), and then add 5 g of palladium on carbon (the content of the active substance is 10%) to the three-necked flask under a nitrogen atmosphere. Rinse the materials on the wall of the reaction flask with 50 mL of ethanol, then displace with hydrogen, maintain the hydrogen pressure at 2 - 4 MPa, and stir and react at 50 °C for 15 h. TLC detection shows that the reaction is complete.
[0042] Filter the reaction system, concentrate the filtrate to obtain a solid, wash the obtained solid with n-hexane, and after drying, obtain 62.6 g (318 mmol) of 2-propylpyridin-4(1H)-one acetate, with a yield of 86%.
[0043] Example 6
[0044] This example provides a method for preparing 2-propylpyridin-4(1H)-one acetate. The reaction formula is the same as that shown in Example 1. Take a 1L three-necked flask as the reaction vessel, add 50 g of 2-cyclopropylpyridin-4-ol (370 mmol) to 500 mL of isopropanol, then add 44.4 g of acetic acid (740 mmol), and then add 5 g of palladium on carbon (the content of the active substance is 10%) to the three-necked flask under a nitrogen atmosphere. Rinse the materials on the wall of the reaction flask with 50 mL of isopropanol, then displace with hydrogen, maintain the hydrogen pressure at 2 - 4 MPa, and stir and react at 50 °C for 15 h. TLC detection shows that the reaction is complete.
[0045] The reaction system was filtered, and the filtrate was concentrated to obtain a solid. The obtained solid was washed with n-hexane and dried to obtain 60.5 g (307 mmol) of 2-propylpyridin-4(1H)-one acetate, with a yield of 83%.
[0046] Example 7
[0047] This example provides a method for preparing 2-propylpyridin-4(1H)-one acetate. The reaction formula is the same as that shown in Example 1. A 1 L three-necked flask was used as the reaction vessel. 50 g of 2-cyclopropylpyridin-4-ol (370 mmol) was added to 500 mL of methanol, and then 44.4 g of acetic acid (740 mmol) was added. Then, 5 g of palladium-carbon (with an active substance content of 10%) was added to the three-necked flask under a nitrogen atmosphere. The materials on the reaction flask wall were rinsed with 50 mL of methanol, and then hydrogen was displaced. The hydrogen pressure was maintained at 2 - 4 MPa, and the reaction was stirred at 30 °C for 15 h. The reaction was detected to be complete by TLC.
[0048] The reaction system was filtered, and the filtrate was concentrated to obtain a solid. The obtained solid was washed with n-hexane and dried to obtain 58.3 g (296 mmol) of 2-propylpyridin-4(1H)-one acetate, with a yield of 80%.
[0049] Example 8
[0050] This example provides a method for preparing 2-propylpyridin-4(1H)-one acetate. The reaction formula is the same as that shown in Example 1. A 1 L three-necked flask was used as the reaction vessel. 50 g of 2-cyclopropylpyridin-4-ol (370 mmol) was added to 500 mL of methanol, and then 44.4 g of acetic acid (740 mmol) was added. Then, 5 g of palladium-carbon (with an active substance content of 10%) was added to the three-necked flask under a nitrogen atmosphere. The materials on the reaction flask wall were rinsed with 50 mL of methanol, and then hydrogen was displaced. The hydrogen pressure was maintained at 2 - 4 MPa, and the reaction was stirred at 70 °C for 10 h. The reaction was detected to be complete by TLC.
[0051] The reaction system was filtered, and the filtrate was concentrated to obtain a solid. The obtained solid was washed with n-hexane and dried to obtain 51.8 g (263 mmol) of 2-propylpyridin-4(1H)-one acetate, with a yield of 71%.
[0052] The 2-propylpyridin-4(1H)-one acetate prepared in Example 1 was taken for nuclear magnetic resonance analysis, and the obtained nuclear magnetic resonance 1 1H-NMR spectrum is as Figure 1 shown. From Figure 1 this, it can be seen that the target product 2-propylpyridin-4(1H)-one acetate was successfully prepared in this invention.
[0053] The purities (the purity test was carried out by liquid chromatography) of the 2-propylpyridin-4(1H)-one acetates prepared in Examples 1 to 8 were analyzed respectively. The results are shown in Table 1.
[0054] Table 1
[0055]
[0056]
[0057] From Figure 1 the data in Table 1, it can be seen that for the preparation method of 2-propylpyridin-4(1H)-one acetate provided by the present invention, using 2-cyclopropylpyridin-4-ol as the starting material, a palladium catalyst, reacting with hydrogen to open the ring in the presence of acetic acid, the 2-propylpyridin-4(1H)-one acetate product can be prepared, and the product has a high yield and high purity.
[0058] The above are only the embodiments of the present invention, and do not limit the patent scope of the present invention. Any equivalent transformation made by using the content of the specification of the present invention, directly or indirectly applied in other related technical fields, shall be included in the patent protection scope of the present invention.
Claims
1. A method for preparing 2-propylpyridin-4(1H)-one acetate, characterized in that, Using 2-cyclopropylpyridin-4-ol as a raw material, reacting in a hydrogen atmosphere in the presence of a palladium catalyst and acetic acid to obtain 2-propylpyridin-4(1H)-one acetate.
2. The preparation method according to claim 1, characterized in that, The palladium catalyst is palladium on carbon and / or palladium hydroxide on carbon.
3. The preparation method according to claim 1, characterized in that, The reaction is carried out in an alcohol solvent, and the alcohol solvent is selected from at least one of methanol, ethanol, and isopropyl alcohol.
4. The preparation method according to claim 1, characterized in that, The feeding mass ratio of the 2-cyclopropylpyridin-4-ol to the palladium catalyst is 1:(0.05 - 0.1).
5. The preparation method according to claim 1, wherein, The feeding molar ratio of the 2-cyclopropylpyridin-4-ol to the acetic acid is 1:(1.5 - 3).
6. The preparation method according to any one of claims 1-5, characterized in that, The reaction temperature of the reaction is 30 - 70 °C.
7. The preparation method according to claim 6, characterized in that, The reaction time of the reaction is 6 - 15 h.
8. The preparation method according to claim 6, characterized in that, The reaction temperature of the reaction is 45 - 55 °C.
9. The preparation method according to claim 7, characterized in that, The reaction time of the reaction is 9 - 11 h.
10. The preparation method according to claim 1, wherein The reaction is carried out under pressure conditions, and the hydrogen pressure in the reaction system is 2 - 4 MPa.