A di-tert-butyl compound, a preparation method and application thereof in organic synthesis

Abstract

The application discloses a di-tert-butyl ester compound, a preparation method and application thereof in organic synthesis, and belongs to the field of organic synthesis. A new synthesis route is provided, wherein compound 1 (salicylic acid or a derivative substituted on a benzene ring thereof) and compound 2 are directly used as starting materials, a carboxyl group does not need to be additionally protected, and the di-tert-butyl ester compound can be efficiently and quickly prepared in one step.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a di-tert-butyl ester compound, its preparation method, and its application in organic synthesis. Background Technology

[0002] Literature such as US2005 / 0004162A1 and "Virtual screening-driven discovery of dual 5-HT6 / 5-HT2A receptor ligands with pro cognitive properties" (European Journal of Medicinal Chemistry, 185, 2020, 111857) reports that benzofuran-3(2H)-one compounds can serve as intermediates for a class of antidepressants. These studies also provide routes for preparing benzofuran-3(2H)-one compounds using compound A as an intermediate; this route is also a commonly used one for preparing benzofuran-3(2H)-one compounds.

[0003]

[0004] However, in the existing technology, the steps for preparing compound A are mostly lengthy and time-consuming, requiring the protection of the carboxyl group before subsequent reactions, which leads to low product yield. Summary of the Invention

[0005] To address the aforementioned issues, this invention proposes a novel synthetic route that directly uses salicylic acid or its substituted benzene ring derivatives as starting materials. This route eliminates the need for additional protection of the carboxyl group and allows for the efficient and rapid preparation of di-tert-butyl ester compounds in a single step.

[0006] This invention provides a method for preparing di-tert-butyl ester, the reaction formula of which is as follows:

[0007]

[0008] In the above formula, each R is independently Cl, Br, I, F or C1-C6 alkyl.

[0009] n is the number of substituent groups R on the benzene ring, selected from 0, 1, 2, 3, 4.

[0010] Whether each R is the same or different,

[0011] X is Cl, Br, or I.

[0012] Includes the following steps:

[0013] In the presence of an organic solvent and a basic reagent, compound 1 reacts with compound 2 to give compound 3.

[0014] In one embodiment of the present invention, the reactants consist of the organic solvent, the basic reagent, compound 1, and compound 2.

[0015] In one embodiment of the present invention, compound 1 may specifically be...

[0016] In one embodiment of the present invention, compound 2 may specifically be...

[0017] In one embodiment of the present invention, the organic solvent is selected from any one or more of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), and 2-methyltetrahydrofuran.

[0018] In one embodiment of the present invention, the alkaline reagent is selected from alkali metal carbonates and / or alkali metal hydroxides; wherein the alkali metal carbonate may be potassium carbonate and / or sodium carbonate, and the alkali metal hydroxide may be potassium hydroxide and / or sodium hydroxide.

[0019] In one embodiment of the present invention, the molar ratio of compound 1 to compound 2 is 1:(2.0-3.0). Specifically, 1:2.5 is optional.

[0020] In one embodiment of the present invention, the molar ratio of compound 1 to the basic reagent is 1:(2.0-3.0). Specifically, 1:2.5 may be selected.

[0021] In one embodiment of the present invention, the concentration of compound 1 relative to the organic solvent is 30-80 mg / mL. Specifically, 50 mg / mL may be selected.

[0022] In one embodiment of the present invention, the reaction temperature is 50-80°C and the time is 2-3 hours.

[0023] The present invention also provides a di-tert-butyl ester compound with the following structural formula:

[0024]

[0025] Each R is independently Cl, Br, I, F or C1-C6 alkyl.

[0026] n is 0, 1, 2, 3, 4.

[0027] Each R may be the same or different.

[0028] This invention also provides the application of the above-mentioned di-tert-butyl ester compound in organic synthesis, the application involving the following reaction process:

[0029]

[0030] In the above formula, each R is independently Cl, Br, I, F or C1-C6 alkyl.

[0031] n is 0, 1, 2, 3, 4.

[0032] Whether each R is the same or different,

[0033] Includes the following steps:

[0034] Compound 3 is converted into compound 4 under the action of a base.

[0035] In one embodiment of the present invention, the alkali may be an alkali metal hydroxide; preferably lithium hydroxide.

[0036] In one embodiment of the present invention, the molar ratio of compound 3 to the base is 1:(0.1-3). More preferably, it is 1:(0.1-0.2).

[0037] In one embodiment of the present invention, the reaction process is carried out in a solvent environment, wherein the solvent is selected from any one or more of the following: methanol, ethanol, tert-butanol, and water.

[0038] In one embodiment of the present invention, the concentration of compound 3 relative to the solvent is 0.2-0.5 g / mL.

[0039] In one embodiment of the present invention, the reaction process involves dissolving compound 3 in a solvent, then adding an aqueous solution of alkali, and mixing the mixture at -10 to 5°C.

[0040] In one embodiment of the present invention, the concentration of the alkali in the aqueous solution is 1-5 mol / L. Specifically, 2 mol / L is optional.

[0041] In one embodiment of the present invention, the mixing reaction is carried out at a temperature of 0°C for 1 hour.

[0042] The role and effect of invention

[0043] According to the di-tert-butyl ester compound and its preparation method of the present invention, since salicylic acid or its derivatives substituted on the benzene ring can be used directly as starting materials without additional protection of the carboxyl group, the present invention can efficiently and quickly prepare the di-tert-butyl ester compound in only one step.

[0044] According to the application of the di-tert-butyl ester compound of the present invention in organic synthesis, under alkaline conditions, the ester group undergoes hydrolysis while the ether bond does not react, thus efficiently preparing the corresponding dicarboxylic acid compounds. Attached Figure Description

[0045] Figure 1 This is the proton spectrum of compound 3a in Example 1 of the present invention. Detailed Implementation

[0046] 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 and accompanying drawings.

[0047] In the following embodiments, unless otherwise stated, all raw materials are commercially available products.

[0048] <Example 1>

[0049] Preparation of compound 3a

[0050] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:

[0051]

[0052] The reaction steps are as follows:

[0053] 500 mg of compound 1a (3.2 mmol, 1.0 eq) and 1.56 g of compound 2a (8.0 mmol, 2.5 eq) were dissolved in 10 mL of LDM, and 1.1 g of potassium carbonate (8.0 mmol, 2.5 eq) was added. Under nitrogen protection, the mixture was heated to 60 °C and stirred for 2 h. 20 mL of water and 20 mL of ethyl acetate were added to the reaction solution, and the mixture was extracted. The organic phase was collected, washed once with saturated brine, and subjected to column chromatography to give 1.02 g of compound 3a, a colorless liquid, with a yield of 82.9%.

[0054] The proton NMR spectrum of compound 3a (deuterated reagent is DMSO-d6) is as follows: Figure 1 As shown.

[0055] <Comparative Example 1>

[0056] Preparation of diethyl ester compounds

[0057] This comparative example attempts to prepare a diethyl ester compound, and the reaction formula is as follows:

[0058]

[0059] The reaction steps are as follows:

[0060] 500 mg of compound 1a (3.2 mmol, 1.0 eq) and 1.33 g of compound 2b (8.0 mmol, 2.5 eq) were dissolved in 10 mL of LDM, and 1.1 g of potassium carbonate (8.0 mmol, 2.5 eq) was added. The mixture was heated to 60 °C and stirred for 2 h under nitrogen protection. Samples were taken and analyzed by LCMS. The reaction system contained 25% compound 1a, 46% compound 3c, and 16% compound 3b.

[0061] <Comparative Example 2>

[0062] Preparation of diethyl ester compounds

[0063] This comparative example attempts to prepare a diethyl ester compound, and the reaction formula is as follows:

[0064]

[0065] The reaction steps are as follows:

[0066] 500 mg of compound 1a (3.2 mmol, 1.0 eq) and 1.33 g of compound 2b (8.0 mmol, 2.5 eq) were dissolved in 10 mL of LMF. 1.1 g of potassium carbonate (8.0 mmol, 2.5 eq) and 206 mg of tetrabutylammonium bromide (0.64 mmol, 0.2 eq) were added. The mixture was heated to 60 °C and stirred for 2 h under nitrogen protection. The reaction mixture was sampled and analyzed by LCMS. The reaction system contained 68% compound 1a, 20% compound 3c, and 8% compound 3b.

[0067] <Comparative Example 3>

[0068] Preparation of diethyl ester compounds

[0069] This comparative example attempts to prepare a diethyl ester compound. The reaction steps are as follows:

[0070] 500 mg of compound 1a (3.2 mmol, 1.0 eq) and 1.33 g of compound 2b (8.0 mmol, 2.5 eq) were dissolved in 10 mL of THF, and 0.97 g of DBU (6.4 mmol, 2.0 eq) was added. The mixture was stirred at room temperature for 2 h under nitrogen protection. LCMS analysis showed that the mixture was all from the starting materials and no reaction occurred.

[0071] <Example 2>

[0072] Preparation of compound 4

[0073] This embodiment provides a method for preparing compound 4, and the reaction formula is as follows:

[0074]

[0075] Includes the following steps:

[0076] 1.23 g of compound 3a (3.2 mmol) was dissolved in 5 mL of methanol, and 0.26 mL of 2 mol / L lithium hydroxide aqueous solution was added. The mixture was cooled to 0 °C and stirred for 1 h. Methanol was removed under reduced pressure, and the pH was adjusted to 1 with 1 mol / L HCl aqueous solution. The mixture was filtered, and the solid was collected and washed with water to obtain 0.637 g of compound 4, with a yield of 92.8%.

[0077] The role and effect of the embodiments

[0078] According to the di-tert-butyl ester compound and its preparation method involved in the above embodiments, since 5-fluorosalicylic acid can be used directly as the starting material without the need for additional protection of the carboxyl group, the present invention can efficiently and quickly prepare the di-tert-butyl ester compound in only one step.

[0079] Furthermore, by using tert-butyl bromoacetate as a starting material, the applicant unexpectedly discovered that compared to ethyl bromoacetate, tert-butyl bromoacetate could complete the reaction in a shorter time and at a higher yield, significantly shortening the reaction time and improving production efficiency.

[0080] Based on the application of the di-tert-butyl ester compound in organic synthesis as described in the above embodiments, under alkaline conditions, the ester group undergoes hydrolysis while the ether bond does not react, thus efficiently preparing the corresponding dicarboxylic acid compounds.

[0081] Furthermore, the applicant unexpectedly discovered that only a small amount of aqueous lithium hydroxide solution was needed as the base reagent to achieve the hydrolysis reaction, thus the reaction could achieve excellent yields under very mild conditions.

[0082] 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 di-tert-butyl ester compound, characterized in that, The reaction formula is as follows: In the above formula, each R is independently Cl, Br, I, F or C1-C6 alkyl. n is 0, 1, 2, 3, 4, Whether each R is the same or different, X is Br. Includes the following steps: In the presence of an organic solvent and a basic reagent, compound 1 reacts with compound 2 to give compound 3; The organic solvent is N,N-dimethylformamide; The alkaline reagent is potassium carbonate; The reaction is carried out at a temperature of 50-80℃ for 2-3 hours.

2. The method for preparing the di-tert-butyl ester compound according to claim 1, characterized in that: in, Compound 1 is .

3. The method for preparing the di-tert-butyl ester compound according to claim 1, characterized in that, in, The molar ratio of compound 1 to compound 2 is 1:(2.0-3.0).

4. The method for preparing the di-tert-butyl ester compound according to claim 1, characterized in that, in, The molar ratio of compound 1 to compound 2 is 1:2.

5.

5. The method for preparing the di-tert-butyl ester compound according to claim 1, characterized in that, The molar ratio of compound 1 to the basic reagent is 1:(2.0-3.0).

6. The method for preparing the di-tert-butyl ester compound according to claim 1, characterized in that, The molar ratio of compound 1 to the basic reagent is 1:2.

5.

7. The method for preparing the di-tert-butyl ester compound according to claim 1, characterized in that, The concentration of compound 1 relative to the organic solvent is 30-80 mg / mL.

8. The method for preparing the di-tert-butyl ester compound according to claim 1, characterized in that, The concentration of compound 1 relative to the organic solvent is 50 mg / mL.

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