A method for preparing 3-isochromone
3-Isochromone was directly synthesized via a one-step carbonylation reaction. The preparation of 3-isochromone using a palladium catalyst and iodomethane as an auxiliary agent under a carbon monoxide atmosphere solved the problems of high cost and high pollution in existing technologies, and achieved a highly efficient and environmentally friendly synthesis process.
Patent Information
- Application Number
- CN202310502961.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-05-06
- Publication Date
- 2025-10-28
- Estimated Expiration
- 2043-05-06
AI Technical Summary
Existing industrial manufacturing methods for 3-isochromone suffer from high production costs, severe pollution, and strong corrosiveness.
3-Isochromone was synthesized directly from o-diphenylmethanol using a one-step carbonylation reaction with palladium catalysts such as tetraphenylphosphine palladium and catalytic aids such as iodomethane, under a carbon monoxide atmosphere.
It simplifies the synthetic route, reduces costs, minimizes pollution, achieves mild reaction conditions, and improves synthetic efficiency.
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Abstract
Description
Technical Field
[0001] This invention relates to a method for synthesizing 3-isochromone. Background Technology
[0002] 3-Isochromone and its alternative derivatives are important intermediates in the industrial production of pharmaceuticals and agrochemicals, especially in the synthesis of strobilurins, fungicides. Strobilurins inhibit mitochondrial respiration in fungi and are characterized by high efficiency, broad spectrum, and environmental friendliness, making them a widely used drug prodrug.
[0003] Current industrial methods for manufacturing 3-isochromone suffer from drawbacks such as high production costs, high pollution, and high corrosivity. To address these issues, we explored using o-benzyl alcohol as a raw material to directly synthesize 3-isochromone via a one-step carbonylation reaction, significantly shortening the synthetic route.
[0004] In summary, this paper describes a novel palladium-catalyzed carbonylation method for the preparation of o-diphenylmethanol. Summary of the Invention
[0005] The purpose of this invention is to provide a method for synthesizing 3-isochromone.
[0006]
[0007] Reaction Equation 1: Synthesis of 3-Isochromone
[0008] The specific operating steps are as follows (reaction equation 1):
[0009] The reaction was carried out in a 300 mL high-pressure reactor. The catalyst, catalyst promoter, and ligand were weighed and injected into the solvent under a nitrogen atmosphere. The reaction was then carried out in a carbon monoxide atmosphere at 70-150 °C, preferably 110-130 °C. The reaction time was 10-36 hours, preferably 18-24 hours. After the reaction was completed, 3-isochromone 2 was obtained by separation.
[0010] The catalyst is one or more of tetraphenylphosphine palladium, palladium chloride, palladium acetylacetonate, and diphenylphosphine dichloride palladium, preferably tetraphenylphosphine palladium.
[0011] The ligand is one or more of the following: triphenylphosphine, 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl, 9,9-dimethyl-4,5-bis(dicyclohexylphosphine)-9H-oxanthracene, and 2-diphenylphosphine-2',4',6'-triisopropylbiphenyl, preferably 9,9-dimethyl-4,5-bis(dicyclohexylphosphine)-9H-oxanthracene;
[0012] The catalyst additive is one or more of iodomethane, sodium iodide, potassium iodide, lithium iodide, and iodine, preferably iodomethane.
[0013] The solvent is one or more of tetrahydrofuran, dichloromethane, toluene, DMF, and DMSO, preferably tetrahydrofuran.
[0014] The pressure of carbon monoxide is 1-30 atmospheres, preferably 1-10 atmospheres.
[0015] The present invention has the following advantages:
[0016] First, the one-step method replaces the traditional multi-step reaction, eliminating cumbersome steps, reducing costs, and greatly improving synthesis efficiency. Second, the reaction is mild and non-corrosive. Third, it uses gaseous CO as the carbonyl source, which is inexpensive and readily available.
[0017] This invention uses gaseous CO as the carbonyl source and, with the aid of a catalytic amount of palladium catalyst, efficiently and directly obtains the 3-isochromone product in one step. Detailed Implementation
[0018] To better understand the present invention, the following embodiments are provided:
[0019]
[0020] Example 1
[0021] The reaction was carried out in a 300 mL high-pressure reactor. First, 0.2 mmol of o-benzyl alcohol, 0.015 mmol of tetraphenylphosphine palladium, 0.015 mmol of 9,9-dimethyl-4,5-bis(dicyclohexylphosphino)-9H-oxanthracene, and 0.02 mmol of iodomethane were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 1.5 mL of tetrahydrofuran was added as a solvent. The vial was then tightly capped with a rubber cap. A syringe was then injected... One end of the needle tip was inserted through the bottle cap into the vial, allowing the vial to communicate with the outside world through the needle. The vial was then placed in a high-pressure reactor, and the reactor was purged with carbon monoxide at 5 atmospheres. At this point, the carbon monoxide inside the reactor was connected to the inside of the vial through the needle. The reactor was then placed at 120°C for 22.0 hours to react. After the reaction was completed, 3-isochromone 2 was obtained by column chromatography with a yield of 95%. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.
[0022] The test data is as follows:
[0023] 3-Isochromone 2: 1H NMR (400MHz, CDCl3) δ7.39–7.30(m,2H),7.28–7.22(m,2H),5.33(s,2H),3.73(s,2H).
[0024] 13 C NMR (100MHz, CDCl3) δ170.7,131.5,130.9,128.8,127.3,127.0,124.6,70.1,36.2.
[0025] Example 2
[0026] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the catalyst for the reaction is replaced with an equimolar amount of triphenylphosphine, and the yield of the target product 3-isochromone will be 23%.
[0027] Example 3
[0028] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the reaction temperature is reduced to 100 degrees Celsius, and the yield of the target product 3-isochromone is reduced to 56%.
[0029] Example 4
[0030] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the amount of iodomethane in the reaction is reduced to 1% mol, and the yield of the target product 3-isochromone is reduced to 26%.
[0031] Example 5
[0032] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the catalyst for the reaction is changed to an equimolar amount of palladium dichloride, and the yield of the target product 3-isochromone is reduced to 69%.
[0033] Example 6
[0034] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the carbon monoxide pressure of the reaction is reduced to 1 bar, and the yield of the target product 3-isochromone is 55%.
[0035] Comparative Example 1
[0036] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the reaction temperature is reduced to 60 degrees Celsius, the yield of the target product 3-isochromone is reduced to 5%, and there is a large surplus of raw materials.
[0037] Comparative Example 2
[0038] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the catalyst for the reaction is changed to an equimolar amount of palladium acetate, the yield of the target product 3-isochromone is reduced to 0%, and the raw materials are largely left over.
[0039] Comparative Example 3
[0040] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the co-catalyst for the reaction is replaced with an equimolar amount of sodium iodide, and the yield of the target product 3-isochromone is reduced to 12%.
[0041] Comparative Example 4
[0042] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the iodomethane in the reaction is removed, the yield of the target product 3-isochromone is reduced to 0%, and the raw materials are largely left over.
[0043] Comparative Example 5
[0044] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the catalyst for the reaction is removed, the yield of the target product 3-isochromone is reduced to 0%, and the raw materials are largely left over.
Claims
1. A method for preparing 3-isochromone, characterized in that: 3-Isochromone 2 was prepared from o-benzyl alcohol 1 and carbon monoxide under palladium catalysis, as shown in the following reaction formula: ； The specific operating steps are as follows: The reaction was carried out in a high-pressure reactor by mixing the catalyst, o-benzyl alcohol 1, ligand and catalyst promoter to obtain a mixture. The solvent was injected into the mixture under a nitrogen atmosphere, and the gas atmosphere in the reactor was replaced with carbon monoxide gas. The reaction was carried out at 120°C for 22 hours. After the reaction was completed, 3-isochromone was obtained by separation. The palladium catalyst is tetraphenylphosphine palladium; The ligand is 9,9-dimethyl-4,5-bis(dicyclohexylphosphino)-9H-oxanthracene; The catalyst additive is iodomethane; The pressure of carbon monoxide in the high-pressure reactor is 5 atmospheres.
2. The preparation method according to claim 1, characterized in that: The molar ratio of o-benzyl alcohol 1 to catalyst and ligand is 0.2:0.015:0.
015.
3. The preparation method according to claim 1, characterized in that: The molar ratio of o-benzyl alcohol 1 to the catalyst promoter is 10:
1.
4. The preparation method according to claim 1, characterized in that: The solvent is tetrahydrofuran; The amount of the above solvent used is 1.5 mL for every 0.2 mmol of o-diphenylethanol.
5. The preparation method according to claim 1, characterized in that: The total volume of the reaction substrate o-benzyl alcohol, catalyst, co-catalyst, ligand, and solvent in the high-pressure reactor shall not exceed 50% of the reactor's volume.