Process for the preparation of boronic esters and their use

Abstract

The application provides a preparation method of borate and application thereof, and belongs to the field of organic synthesis. The preparation method of the borate provided by the application comprises the following steps: mixing compound 1, compound 2, a solvent, a base and a catalyst, reacting under an inert atmosphere at 80-100 DEG C, post-treatment and purification, and thus compound 3 is obtained, wherein the catalyst is dichloro[1,1'-bis(tert-butylphosphine)]dichloroferrocenepalladium, and the molar ratio of compound 1 to the catalyst is 500:(0.01-2.2). The application surprisingly finds that the target compound can be efficiently prepared without other side reactions by reducing the amount of the catalyst.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to a preparation method of borate ester and application thereof. BACKGROUND

[0002] In the prior art, it is a common choice to use aryl bromide compound to react with pinacol diboronic acid under the catalysis of palladium catalyst to prepare aryl borate ester. For example, patent WO2018014802 discloses in its specification that 5-bromo-3-fluoro-2-methoxypyridine can react with pinacol diboronic acid under the catalysis of chloropalladium triphenylphosphine to obtain the corresponding borate ester compound.

[0003] However, patent WO2018127800 discloses on page 149 of its specification that 5-bromo-2-fluoro-3-methoxypyridine can only obtain the corresponding aryl boronic acid under the conventional reaction condition and cannot obtain aryl borate ester compound. SUMMARY

[0004] The present application is carried out to solve the above problems, and aims to provide a preparation method for preparing the borate ester compound with high yield and application thereof as a pharmaceutical intermediate.

[0005] The present application provides a borate ester compound, which has the following structural formula:

[0006]

[0007] The present application also provides a preparation method of borate ester compound, which has the following reaction formula:

[0008]

[0009] The preparation method comprises the following steps:

[0010] The compound 1, the compound 2, the solvent, the base and the catalyst are mixed, and then reacted under an inert atmosphere at 80-100°C, followed by post-treatment and purification to obtain the compound 3, wherein the catalyst is dichloro[1,1'-bis(tert-butylphosphine)]ferrocenepalladium, and the molar ratio of the compound 1 to the catalyst is 500:(0.01-2.2).

[0011] In the preparation method of the borate ester compound provided by the present application, the solvent can also have the following characteristics: the solvent is 1,4-dioxane.

[0012] In the preparation method of the borate ester compound provided by the present application, the base can also have the following characteristics: the base is any one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium acetate and sodium acetate.

[0013] In the preparation method of the borate compound provided by the application, the molar ratio of the compound 1 to the compound 2 can be 1:(1-3).

[0014] In the preparation method of the borate compound provided by the application, the molar ratio of the compound 1 to the base can be 1:(1-3).

[0015] In the preparation method of the borate compound provided by the application, the mass-volume ratio of the compound 1 to the solvent can be 1g:(10-40)mL.

[0016] In the preparation method of the borate compound provided by the application, the mass ratio of the compound 1 to the catalyst can be 1:(0.0001-0.015). Preferably, the mass ratio of the compound 1 to the catalyst can be 1:(0.0008-0.015).

[0017] In the preparation method of the borate compound provided by the application, the post-treatment can comprise the following steps:

[0018] The mixed solvent of water and ethyl acetate is added to the reaction solution, and extraction is performed. The organic phase is obtained. Preferably, the volume ratio of water to ethyl acetate in the mixed solvent is (1-3):(1-3).

[0019] In the preparation method of the borate compound provided by the application, the post-treatment can comprise the following steps:

[0020] The compound 1, the compound 2, the solvent, the base and the catalyst are mixed, and the reaction is performed under an inert atmosphere at 80-100°C to obtain a reaction solution. The mixed solvent of water and ethyl acetate is added to the reaction solution, and extraction is performed 1-3 times. The organic phase is obtained. Preferably, the volume ratio of the reaction solution to the mixed solvent is (1-3):(1-3). The organic phase is concentrated under reduced pressure, and column chromatography is performed to obtain the compound 3.

[0021] The application further provides a borate compound and a method for preparing aryl alcohol from the borate compound, and the reaction formula is as follows:

[0022]

[0023] The reaction comprises the following steps:

[0024] The compound 3, the solvent and hydrogen peroxide are mixed and stirred for 1-20h. Post-treatment and purification are performed to obtain the compound 4. Preferably, the solvent is any one or more of dichloromethane, acetonitrile or tetrahydrofuran, and the molar ratio of the compound 3 to hydrogen peroxide is 1:(1-3).

[0025] In the application of the borate compound provided by the present application, it can also have the feature that it comprises the following reaction steps:

[0026] The compound 3, solvent, hydrogen peroxide are mixed and stirred for 1-20 hours, sodium sulfite or sodium thiosulfate is added to quench the reaction, organic solvent is extracted, the organic phase is taken, dried, concentrated under reduced pressure, and column chromatography is performed to obtain the compound 4.

[0027] Effects of the application

[0028] According to the preparation method of the borate compound involved in the present application, the applicant unexpectedly found that the compound 3 can be efficiently prepared without other side reactions by reducing the amount of catalyst.

[0029] According to the application of the borate compound involved in the present application, the applicant unexpectedly found that the corresponding aryl alcohol can be prepared in a higher yield under the same reaction conditions by using the borate compound such as compound 3 compared with the corresponding boronic acid compound. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 is the hydrogen spectrum of the compound 3 prepared in Example 1 of the present application;

[0031] Figure 2 is the liquid phase diagram of the compound 3 prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0032] In order to make the technical means, creative features, purposes and effects achieved by the present application easy to understand, the present application is specifically described below in combination with examples and drawings.

[0033] In the following examples, each chemical reagent is commercially available unless otherwise specified.

[0034] <Example 1>

[0035] Preparation of compound 3

[0036] The present example provides a preparation method of compound 3, and the reaction formula is as follows:

[0037]

[0038] comprises the following reaction steps:

[0039] Into a reaction vessel, 150 mL of 1,4-dioxane, 10 g of compound 1 (48.5 mmol, 1.0 eq), 18.5 g of pinacol diboronic acid (i.e. compound 2, 72.75 mmol, 1.5 eq), 7.14 g of potassium acetate (72.75 mmol, 1.5 eq) and 0.1 g of dichloro[l, l'-bis(tert-butylphosphine)] palladium(II) dicyclohexylphosphine) (i.e. Pd(dppf)Cl2, 0.137 mmol) were sequentially added, the reaction vessel was replaced with nitrogen, the reaction vessel was heated to 90 °C, and the reaction was allowed to proceed for 8 h. The reaction system was naturally cooled to room temperature, filtered, and the solid was removed. 50 mL of water and 50 mL of ethyl acetate were added, and the mixture was extracted twice. The organic phase was collected and concentrated under reduced pressure. Column chromatography was performed to obtain 9.5 g of compound 3, which was a yellowish solid, with a yield of 77.3% and a liquid-phase purity of 96.2%.

[0040] The hydrogen spectrum of compound 3 is shown in Figure 1 The liquid-phase spectrum of compound 3 is shown in Figure 2

[0041] <Example 2>

[0042] Screening of catalysts and their amounts

[0043] In this example, the catalysts and their amounts were screened based on Example 1. Except for the conditions listed in the table below, the other reaction conditions were the same as in Example 1.

[0044] The screening results are shown in Table 1.

[0045] Table 1 Screening of catalysts and their amounts

[0046] Serial number Catalyst Catalyst amount Compound 3 yield 1 [Pd(dppf)Cl2] 1g - 2 [Pd(dppf)Cl2] 0.15g 68.0％ 3 [Pd(dppf)Cl2] 0.008g 55.3％ 4 [Pd(dppf)Cl2] 0.001g 28.5％ 5 [Pd2(dba)3] 0.1g -

[0047] As can be seen from Table 1, when Pd(dppf)Cl2 is used as the catalyst and the amount is between 0.001 g and 0.15 g, compound 3 can be obtained in a relatively good yield. However, when the amount of Pd(dppf)Cl2 is 1 g, compound 3 cannot be obtained, and the main product of the reaction is In addition, when Pd2(dba)3 is used as the catalyst, compound 3 cannot be obtained, and the main product of the reaction is also

[0048] <Example 3>

[0049] Screening of reaction conditions

[0050] In this example, the reaction conditions were screened based on Example 1. The specific reaction steps are as follows:

[0051] ​Into a reaction vessel, 150 mL of N,N-dimethylformamide, 10 g of compound 1 (48.5 mmol, 1.0 eq), 18.5 g of pinacol diborane (i.e. compound 2, 72.75 mmol, 1.5 eq), 7.14 g of potassium acetate (72.75 mmol, 1.5 eq) and 0.1 g of dichloro[l, l'-bis(tert-butylphosphine)] palladium ferrocene (i.e. Pd(dppf)Cl2, 0.137 mmol) were sequentially added. The reaction vessel was replaced with nitrogen gas to make the reaction vessel in a nitrogen atmosphere, and the reaction vessel was warmed to 90°C. The reaction was allowed to proceed for 8 h, and the reaction system was naturally cooled to room temperature. Sampling was performed, and LC-MS detection was performed. Compound 3 was not observed. According to the LC-MS spectrum, it was inferred that the main product prepared in this example was

[0052] Example 4

[0053] Screening of reaction conditions

[0054] Into a reaction vessel, 150 mL of anhydrous tetrahydrofuran, 10 g of compound 1 (48.5 mmol, 1.0 eq) were sequentially added. The reaction vessel was cooled to -20°C, and 48.5 mL of isopropyl lithium chloride magnesium chloride complex (1.3 mol / L tetrahydrofuran solution, 63.05 mmol, 1.3 eq) was added. The reaction was stirred at -20°C for 4 h, and 12.4 g of isopropyl pinacol borate (72.75 mmol, 1.5 eq) was added. The reaction was warmed to 75°C and reacted for 4 h. Sampling was performed, and LC-MS detection was performed. Compound 3 was not observed. The main product was an unknown compound.

[0055] Example 5

[0056] Screening of reaction conditions

[0057] Into a reaction vessel, 150 mL of anhydrous tetrahydrofuran, 10 g of compound 1 (48.5 mmol, 1.0 eq) were sequentially added. The reaction vessel was cooled to -20°C, and 48.5 mL of isopropyl lithium chloride magnesium chloride complex (1.3 mol / L tetrahydrofuran solution, 63.05 mmol, 1.3 eq) was added. The reaction was stirred at -20°C for 4 h, and 12.4 g of isopropyl pinacol borate (72.75 mmol, 1.5 eq) was added. The reaction was warmed to 75°C and reacted for 4 h. Sampling was performed, and LC-MS detection was performed. Compound 3 was not observed. The main product was an unknown compound.

[0058] Example 6

[0059] A method for preparing an aryl alcohol

[0060] This example provides a method for preparing an aryl alcohol, and the reaction formula is as follows:

[0061]

[0062] The method comprises the following reaction steps:

[0063] Dissolve 5 g of compound 3 (19.76 mmol, 1.0 eq) in 50 mL of acetonitrile, add 5.6 g of 30 wt% hydrogen peroxide (49.4 mmol, 2.5 eq), stir the reaction at room temperature for 5 h, quench the reaction by adding 30 mL of saturated aqueous sodium sulfite solution, extract with 30 mL of ethyl acetate and 30 mL of water, take the organic phase, concentrate under reduced pressure, and column chromatography to obtain 2.40 g of compound 4 with a yield of 84.8% and a purity of 98.5%.

[0064] According to the report of Chinese patent application CN 112189008A, the aryl alcohol such as compound 4 can be used as an intermediate for preparing a drug for preventing and / or treating neurodegenerative diseases, cerebral leukodystrophy, cancer, inflammatory diseases, musculoskeletal diseases, or metabolic diseases.

[0065] <Embodiment 7>

[0066] A method for preparing an aryl alcohol

[0067] The embodiment provides a method for preparing an aryl alcohol, and the reaction formula is as follows:

[0068]

[0069] The method comprises the following reaction steps:

[0070] Dissolve 5 g of compound 5 (29.2 mmol, 1.0 eq) in 50 mL of acetonitrile, add 8.3 g of 30 wt% hydrogen peroxide (73 mmol, 2.5 eq), stir the reaction at room temperature for 5 h, quench the reaction by adding 40 mL of saturated aqueous sodium sulfite solution, extract with 30 mL of ethyl acetate and 30 mL of water, take the organic phase, concentrate under reduced pressure, and column chromatography to obtain 2.37 g of compound 4 with a yield of 56.7% and a purity of 98.0%.

[0071] Effects of the embodiment

[0072] According to the method for preparing the borate compound involved in the above embodiment, the applicant unexpectedly found that compound 3 can be efficiently prepared without other side reactions by reducing the amount of catalyst.

[0073] According to the application of the borate compound involved in the above embodiment, the applicant unexpectedly found that the borate compound such as compound 3 can be used to prepare the corresponding aryl alcohol with a higher yield under the same reaction conditions than the borate compound of compound 5.

[0074] The above embodiments are preferred cases of the present application and are not used to limit the protection scope of the present application.

Claims

1. A method for preparing a borate ester compound, characterized in that, The reaction formula is as follows: Includes the following steps: Compound 1, compound 2, solvent, base, and catalyst are mixed and reacted under an inert atmosphere at 80℃-100℃ to obtain a reaction solution. Add a mixed solvent of water and ethyl acetate to the reaction solution, extract 1-3 times, and collect the organic phase; The organic phase was concentrated under reduced pressure and subjected to column chromatography to obtain compound 3. The catalyst is dichloro[1,1'-bis(tert-butylphosphine)]ferrocene palladium. The solvent is 1,4-dioxane. The alkali is any one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium acetate, and sodium acetate. The mass ratio of compound 1 to the catalyst is 1:(0.0008~0.015).

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

3. The method for preparing the borate ester compound according to claim 1, characterized in that, in, The molar ratio of compound 1 to the base is 1:(1-3).

4. The method for preparing the borate ester compound according to claim 1, characterized in that, in, The mass-to-volume ratio of compound 1 to the solvent is 1 g:(10-40) mL.

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