A method for preparing a diaryl ether compound

Abstract

The application provides a preparation method of a diaryl ether compound with higher yield, and belongs to the field of organic synthesis. The preparation method of the diaryl ether compound provided by the application has the following reaction formula: the method comprises the following steps: mixing and reacting a compound 1 or a salt thereof, a compound 2, a solvent and a base reagent, and then the diaryl ether compound is obtained. In the application, at least one of sodium carbonate, cesium carbonate or potassium carbonate is used as the base reagent, so that the target compound can be prepared with higher yield. In the application, the cesium salt is used as a reaction catalyst, so that the reaction time can be effectively shortened, and the reaction yield is further improved.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and specifically to a method for preparing a diaryl ether compound. Background Technology

[0002] According to multiple patent reports, including WO2007059257A1, WO201179274A1, WO2022003575A1, and WO2022006386A1, compound 3 is an important molecular building block that can be used to prepare a variety of drugs.

[0003]

[0004] In the prior art, compound 3 is usually prepared by linear synthesis. For example, according to WO2022006386A, the synthetic route of compound 3a is as follows:

[0005]

[0006] However, the yields of the multi-step reactions in this route are all low, which limits the yield of compound 3. Summary of the Invention

[0007] This invention addresses the aforementioned problems and aims to provide a method for preparing diaryl ether compounds with higher yields. The method for preparing diaryl ether compounds provided by this invention includes at least the following reactions:

[0008]

[0009] Preferably, the reaction includes the following convergent synthesis:

[0010]

[0011] In the above formula, X is any one of F, Cl, Br, or I.

[0012] D1, D2, and D3 are mutually independent of each other and can be either N or CR3.

[0013] R1, R2, and R3 are independently any one of hydrogen, cyano, nitro, azide, alkyl, alkenyl, alkoxy, aryloxy, and haloalkyl.

[0014] R4 is either nitro or nitroso.

[0015] Specifically, the present invention provides the following two methods for preparing diaryl ether compounds.

[0016] Method 1:

[0017] Method 1 provides a method for preparing diaryl ether compounds, characterized by the following reaction formula:

[0018]

[0019] In the above formula, X is any one of F, Cl, Br, or I.

[0020] D1, D2, and D3 are mutually independent of each other and can be either N or CR3.

[0021] R1, R2, and R3 are independently any one of hydrogen, cyano, nitro, azide, alkyl, alkenyl, alkoxy, aryloxy, and haloalkyl.

[0022] Includes the following steps:

[0023] The product is obtained by reacting compound 1 or its salt, compound 2, solvent, and base reagent.

[0024] The solvent is N,N-dimethylacetamide.

[0025] The method for preparing diaryl ether compounds provided in Method 1 may also have the following characteristic: wherein compound 1 is... R1 is any one of hydrogen, C1-C10 alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl.

[0026] The method for preparing diaryl ether compounds provided in Method 1 may also have the following characteristic: wherein compound 2 is... X is any one of F, Cl, Br or I.

[0027] The method for preparing diaryl ether compounds provided in Method 1 may also have the following feature: wherein the base reagent is any one or more of potassium carbonate, sodium carbonate, or cesium carbonate.

[0028] The method for preparing diaryl ether compounds provided in Method 1 may also have the following feature: wherein the mass-volume ratio of compound 2 to solvent is 1 g: (2.5-8) mL.

[0029] The method for preparing diaryl ether compounds provided in Method 1 may also have the following characteristics: wherein the molar ratio of compound 1 to compound 2 is (1.2-1.5):1, and the molar ratio of the base reagent to compound 2 is (1.5-2.5):1.

[0030] The method for preparing diaryl ether compounds provided in Method 1 may also have the following characteristic: the reaction temperature is 120℃-160℃.

[0031] The method for preparing diaryl ether compounds provided in Method 1 may also include the following steps:

[0032] Add (1.2-1.5) parts of compound 1, 1 part of compound 2, and (1.5-2.5) parts of alkaline reagent (by molar) to the solvent. Under an inert atmosphere, heat to 120℃-160℃ and react for 6-48 hours. After post-treatment, compound 3 is obtained.

[0033] The method for preparing diaryl ether compounds provided in Method 1 may also have the following characteristic: the post-processing includes the following steps:

[0034] Cool the reaction solution to 10℃-20℃, add water, extract with an organic solvent, take the organic phase, and perform column chromatography, recrystallization, or crystallization to obtain the final product.

[0035] Method 2:

[0036] Method 2 provides a method for preparing diaryl ether compounds, characterized by the following reaction formula:

[0037]

[0038] In the above formula, X is any one of F, Cl, Br, or I.

[0039] D1, D2, and D3 are mutually independent of each other and can be either N or CR3.

[0040] R1, R2, and R3 are independently any one of hydrogen, cyano, nitro, azide, alkyl, alkenyl, alkoxy, aryloxy, and haloalkyl.

[0041] Includes the following steps:

[0042] The product is obtained by mixing and reacting compound 1 or its salt, compound 2, solvent, base reagent, and catalyst.

[0043] The catalyst is a cesium salt.

[0044] The method for preparing diaryl ether compounds provided in Method 2 may also have the following characteristic: wherein compound 1 is... R1 is any one of hydrogen, C1-C10 alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl.

[0045] The method for preparing the diaryl ether compound provided in Method 2 may also have the following characteristic: wherein, compound 2 is... X is any one of F, Cl, Br or I.

[0046] The method for preparing diaryl ether compounds provided in Method 2 may also have the following feature: wherein the base reagent is any one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, or potassium tert-butoxide.

[0047] The method for preparing the diaryl ether compound provided in Method 2 may also have the following characteristic: wherein the cesium salt is any one or more of cesium carbonate, cesium fluoride, cesium sulfate, cesium nitrate, cesium chloride, cesium iodide, cesium bromide, cesium iodide, cesium formate, cesium bicarbonate, and cesium acetate.

[0048] The method for preparing the diaryl ether compound provided in Method 2 may also have the following feature: wherein the molar ratio of the catalyst to compound 2 is (0.02-0.3):1.

[0049] The method for preparing diaryl ether compounds provided in Method 2 may also have the following characteristic: wherein the solvent is any one or more of N,N-dimethylacetamide, N,N-dimethylformamide, or N-methylpyrrolidone.

[0050] The method for preparing diaryl ether compounds provided in Method 2 may also have the following feature: wherein the mass-volume ratio of compound 2 to solvent is 1 g: (2.5-8) mL.

[0051] The method for preparing diaryl ether compounds provided in Method 2 may also have the following characteristics: the molar ratio of compound 1 to compound 2 is (1.2-1.5):1, and the molar ratio of the base reagent to compound 2 is (1.5-2.5):1.

[0052] The method for preparing diaryl ether compounds provided in Method 2 may also have the following characteristic: the reaction temperature is 120℃-160℃.

[0053] The method for preparing diaryl ether compounds provided in Method 2 may also include the following steps:

[0054] Add (1.2-1.5) parts of compound 1, 1 part of compound 2, (1.5-2.5) parts of alkaline reagent and (0.02-0.3) parts of catalyst (by molar weight) to the solvent, and react at 120℃-160℃ for 6-48 hours under an inert atmosphere. After post-treatment, compound 3 is obtained.

[0055] The method for preparing diaryl ether compounds provided in Method 2 may also have the following characteristic: the post-processing includes the following steps:

[0056] Cool the reaction solution to 10℃-20℃, add water, extract with an organic solvent, take the organic phase, and perform column chromatography, recrystallization, or crystallization to obtain the final product.

[0057] The role and effect of invention

[0058] According to the method for preparing diaryl ether compounds of the present invention, since N,N-dimethylacetamide is used as the reaction solvent, the present invention can obtain the target compound in a high yield.

[0059] According to the method for preparing diaryl ether compounds of the present invention, because cesium salt is used as a catalyst for the reaction, not only can the reaction time be effectively shortened, but the reaction yield is further improved. Detailed Implementation

[0060] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments.

[0061] In the following examples, unless otherwise stated, all chemical reagents are commercially available products.

[0062] In the following examples, DMAc is N,N-dimethylacetamide, DMSO is dimethyl sulfoxide, DMF is N,N-dimethylformamide, NMP is N-methylpyrrolidone, and DMF-DMA is N,N-dimethylformamide dimethyl acetal.

[0063] <Example 1>

[0064] Preparation of compound 1a

[0065] This embodiment provides a method for preparing compound 2a, and the reaction formula is as follows:

[0066]

[0067] Includes the following steps:

[0068] 1 L of 3 wt% sodium hydroxide aqueous solution and 100 g of compound 4 (0.729 mol, 1.0 eq) were added to the reaction vessel. The temperature was lowered to 0-5 °C, and 68.9 g of hydrazine hydrate (85 wt%, 1.17 mol, 1.6 eq) was added dropwise. The reaction was stirred at 0-5 °C for 16 h. The mixture was filtered, the filter cake was washed with water and dried to obtain 62.9 g of compound 1a, a black solid, with a yield of 70.1% and a liquid phase purity of 99.6%.

[0069] <Example 2>

[0070] Preparation of compound 6

[0071] This embodiment provides a method for preparing compound 6, and the reaction formula is as follows:

[0072]

[0073] Includes the following steps:

[0074] Under nitrogen protection, 25 g of compound 5 (194 mmol, 1.0 eq) was added to 75 mL of ethanol, and the temperature was maintained at 25 °C. Then, 27.8 g of DMF-DMA (233 mmol, 1.2 eq) was added, the temperature was raised to 65 °C, and the mixture was stirred for 4 h. The temperature was then lowered to 25 °C, and 16.2 g of hydroxylamine hydrochloride (233 mmol, 1.2 eq) was added. The mixture was kept at this temperature for 1 h. The reaction solution was then quenched by adding it to 175 mL of 8 wt% sodium bicarbonate aqueous solution. The mixture was filtered, the solid was collected, washed once with water, and dried to give 32.1 g of compound 6, with a yield of 96.1% and a purity of 99.2%.

[0075] <Example 3>

[0076] Preparation of compound 2a

[0077] This embodiment provides a method for preparing compound 2a, and the reaction formula is as follows:

[0078]

[0079] Includes the following steps:

[0080] 70 g of compound 6 (408 mmol, 1.0 eq) was added to 500 mL of toluene, heated to 45 °C, and 116 g of trifluoroacetic anhydride (551 mmol, 1.35 eq) was added. The mixture was stirred and kept at this temperature for 5 h. The solvent was removed by vacuum distillation, and the mixture was cooled to 10 °C. 200 mL of water and 200 mL of dichloromethane were added, and the mixture was extracted. The organic phase was collected, washed once with saturated sodium chloride aqueous solution, concentrated under reduced pressure, and recrystallized from ethanol to give 40.9 g of compound 2a, with a yield of 65.3% and a purity of 98.5%.

[0081] <Example 4>

[0082] Preparation of compound 3a

[0083] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:

[0084]

[0085] Includes the following steps:

[0086] 20 g of compound 2a (130 mmol, 1.0 eq), 20.8 g of compound 1a (169 mol, 1.3 eq), and 45 g of potassium carbonate (326 mmol, 2.5 eq) were added to 60 mL of DMAc. Under nitrogen protection, the mixture was heated to 150 °C and stirred for 16 h. The temperature was then lowered to 15 °C, 400 g of water was added, and the mixture was stirred at 15 °C for 30 min. A solid precipitated out. The solid was filtered, washed once with water, and dried at 60 °C for 12 h to obtain 25.7 g of compound 3a, with a yield of 82.3%.

[0087] <Example 5>

[0088] Screening of reaction conditions

[0089] This embodiment further refines the reaction conditions based on Example 4, including the following steps:

[0090] 20 g of compound 2a (130 mmol, 1.0 eq), 20.8 g of compound 1a (169 mol, 1.3 eq), and 2.5 eq of base reagent were added to the reaction solvent. Under nitrogen protection, the mixture was heated to the reaction temperature and stirred for 16 h. The temperature was then lowered to 15 °C, 400 g of water was added, and the mixture was stirred at 15 °C for 30 min. A solid precipitated out. The solid was filtered, washed once with water, and dried at 60 °C for 12 h.

[0091] The screening results are shown in Table 1.

[0092] Table 1 Screening of reaction conditions

[0093] Serial Number Alkali reagent reaction solvent reaction temperature yield 1 Potassium carbonate 60mLDMF 150℃ 70.1％ 2 Potassium carbonate 60mL DMAc 130℃ 81.2％ 3 Potassium carbonate 60mL DMSO 150℃ 12.8％ 4 Potassium carbonate 60mL NMP 150℃ 22.0％ <![CDATA[5 * ]]> Potassium carbonate 60mL DMAc 150℃ 46.1％ 6 Potassium carbonate 140mL DMAc 150℃ 87.1％ 7 Sodium hydroxide 60mL DMAc 150℃ 47.9％ 8 Potassium tert-butoxide 60mL DMAc 150℃ 41.9％

[0094] * The reaction time is 10 hours.

[0095] Table 1 shows that when potassium carbonate is used as the base, the reaction yield is higher than when sodium hydroxide or potassium tert-butoxide are used as the base. When DMF or DMAc is used as the reaction solvent, the reaction yield is significantly higher than when DMSO or NMP is used. High reaction yields can be obtained at reaction temperatures between 130℃ and 150℃, with a slightly higher yield at 150℃. Furthermore, based on condition 5 in Table 1 and Example 4, it is known that under the above conditions, the reaction requires approximately 16 hours to complete.

[0096] <Example 6>

[0097] Preparation of compound 3a

[0098] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:

[0099]

[0100] Includes the following steps:

[0101] 20 g of compound 2a (130 mmol, 1.0 eq), 20.8 g of compound 1a (169 mol, 1.3 eq), 45 g of potassium carbonate (326 mmol, 2.5 eq), and 21 g of cesium carbonate (64 mmol, 0.05 eq) were added to 60 mL of DMAc. Under nitrogen protection, the mixture was heated to 150 °C and stirred for 10 h. The temperature was then lowered to 15 °C, 400 g of water was added, and the mixture was stirred at 15 °C for 30 min. A solid precipitated out. The solid was filtered, washed once with water, and dried at 60 °C for 12 h to obtain 28.4 g of compound 3a, with a yield of 91.0%.

[0102] <Example 7>

[0103] Screening of reaction conditions

[0104] This embodiment refines the reaction conditions based on Example 6, including the following steps:

[0105] 20 g of compound 2a (130 mmol, 1.0 eq), 20.8 g of compound 1a (169 mol, 1.3 eq), 2.5 eq of base reagent and catalyst were added to 60 mL of DMAc. Under nitrogen protection, the mixture was heated to 150 °C and stirred for 10 h. The mixture was then cooled to 15 °C, 400 g of water was added, and the mixture was stirred at 15 °C for 30 min. A solid precipitated out. The solid was filtered, washed once with water, and dried at 60 °C for 12 h.

[0106] The screening results are shown in Table 2.

[0107] Table 2 Screening of reaction conditions

[0108] Serial Number Alkali reagent catalyst yield 1 cesium carbonate - 94.5％ 2 Potassium carbonate 0.2 eq cesium carbonate 92.5％ 3 Potassium carbonate 0.2 eq potassium iodide 57.4％ 4 Potassium carbonate 0.2 eq cuprous iodide 11.2％ 5 Potassium carbonate 0.2eq copper powder 15.6％ 6 Potassium carbonate 0.2eq cesium fluoride 86.2％ 7 Sodium hydroxide 0.2 eq cesium carbonate 83.6％ 8 Potassium carbonate 0.1 eq cesium carbonate 92.3％

[0109] Table 2 shows that when cesium salts are used as the base reagent or catalyst, the reaction yield is significantly higher compared to cuprous and potassium salts. Combining conditions 5 in Table 1 and 4-5 in Table 2, it can be found that when copper or cuprous salts are used as catalysts, they not only fail to promote the reaction but also inhibit it, leading to a decrease in the reaction yield. Furthermore, as shown in Example 6, using 0.05 eq to 0.2 eq of cesium carbonate as a catalyst not only achieves a high product yield but also shortens the reaction time.

[0110] The role and effect of the embodiments

[0111] According to the preparation method of the diaryl ether compound involved in the above embodiments, because N,N-dimethylacetamide is used as the reaction solvent, the present invention can obtain the target compound in a high yield.

[0112] According to the preparation method of the diaryl ether compound involved in the above embodiments, because cesium salt is used as the catalyst for the reaction, it can not only effectively shorten the reaction time, but also further improve the reaction yield.

[0113] Furthermore, the reaction yield was significantly improved because DMAc was used as the reaction solvent.

[0114] Furthermore, because cesium salts are used as catalysts, not only is the reaction time effectively shortened, but the reaction yield is also significantly improved.

[0115] Furthermore, since the catalytic reaction requires only 0.05 eq of cesium salt, the reaction cost can be effectively reduced.

[0116] The above embodiments are preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention.

Claims

1. A method for preparing a diaryl ether compound, characterized in that, The reaction formula is as follows: In the above formula, compound 1 is R1 is a C1-C10 alkyl group. The compound 2 is X is Cl or Br. Includes the following steps: 1.2-1.5 parts (molar amount) of compound 1, 1 part of compound 2, 1.5-2.5 parts (molar amount) of base reagent, and 0.02-0.3 parts (molar amount) of catalyst were added to the solvent. The mixture was reacted at 150℃-160℃ for 10-48 hours under an inert atmosphere. After post-treatment, compound 3 was obtained. The catalyst is a cesium salt; the solvent is DMAc. The alkaline reagent is any one or more of sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide.

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