The invention discloses a method for preparing 1, 1apos through self-coupling of boric acid catalyzed by copper. -difluoro-2, 2apos, and-difluoro-2, 2apos; process for the preparation of-binaphthalene

Abstract

The invention belongs to the technical field of synthesis of pharmaceutical and chemical intermediates, and particularly relates to a method for preparing 1, 1 '-difluoro-2, 2'-binaphthalene through self-coupling of boric acid catalyzed by copper. According to the method provided by the invention, (1-fluoro-2-naphthyl) boric acid is used as an initial raw material, simple and cheap cuprous oxide is used as a catalyst, an organic weak base compound is further matched, and a self-coupling reaction is carried out at room temperature, so that the 1, 1 '-difluoro-2, 2'-binaphthalene is prepared. The preparation method is low in cost, mild in reaction condition, simple to operate, green, environment-friendly, safe and efficient, the high-purity 1, 1 '-difluoro-2, 2'-binaphthalene product can be obtained with high yield only through simple preparation and purification steps, the high-temperature and ultralow-temperature reaction conditions of an existing preparation process are avoided, and the yield of the 1, 1 '-difluoro-2, 2'-binaphthalene product is increased. And the problems of difficult reaction operation, high risk and high production cost of the existing preparation process are effectively solved, and the method is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of the synthesis of pharmaceutical and chemical intermediates, and particularly relates to a method for the copper-catalyzed self-coupling of boronic acid to prepare 1,1'-difluoro-2,2'-binaphthalene. Background Art

[0002] The difluorobinaphthalene structure is an important structural unit of natural products, drugs, pesticides, and functional materials. In particular, the organic π-conjugated materials (Compound 3) synthesized by oxidizing difluorobinaphthalene compounds such as 1,1'-difluoro-2,2'-binaphthalene (Compound 2) have excellent optical and charge properties and are widely used in organic light-emitting diodes (OLEDs), organic field-effect transistors (OFETs), and organic photovoltaic power generation (OPV), etc.

[0003]

[0004] Currently, for the chemical synthesis of difluorobinaphthalene compounds, the coupling reaction of aromatic C-C bonds is an important synthesis method. The coupling reaction is divided into Suzuki-Type cross-coupling reaction and Ullmann-Type self-coupling reaction, which are used to prepare asymmetric biphenyl compounds and symmetric biphenyl compounds respectively. In recent years, due to the characteristics of arylboronic acids such as being more stable and less toxic than organometallic reagents, they have been widely used as arene coupling reagents to prepare biphenyl compounds. However, most of the current arylboronic acid self-coupling reactions are catalyzed by precious metal Pd, and recently there have also been studies using precious metals such as Au, Rh, and Ni as catalysts, but these metals are expensive as catalysts, and some even require the use of some ligands and oxidants that are difficult to synthesize.

[0005] For example, the synthesis method of 1,1'-difluoro-2,2'-binaphthalene reported in the patent document with the publication number CN117603174A (paragraph 0020 of the specification) is as follows: using 1-fluoronaphthalene, B-(1-fluoro-2-naphthyl)boronic acid, cesium carbonate, dichlorobenzene (diphenylphosphine)palladium (Pd(PPh 3 )Cl 2 ) as raw materials and carrying out the synthesis reaction at 85°C. However, this reaction uses a palladium catalyst, which is expensive and requires a high-temperature reaction.

[0006] The synthesis method of 1,1'-difluoro-2,2'-binaphthalene reported in the existing literature (Leroux, F.; Mangano, G.; Schlosser, M. Eur. J. Org. Chem., 2005, 5049) is as follows: using 1-fluoronaphthalene as the initial raw material and reacting with tert-butyllithium, copper(I) bromide, nitrobenzene, and alumina to obtain the product. However, this reaction needs to be operated at an ultra-low temperature of -75°C, which is not conducive to industrial scale-up production, and tert-butyllithium also has the danger of being flammable.

[0007] Based on the above research status, how to provide a preparation method of 1,1'-difluoro-2,2'-binaphthalene with low cost, mild conditions, simple operation, environmental friendliness, and high safety and efficiency, so as to solve the problems of high-temperature or ultra-low-temperature reaction conditions and high production costs in the above processes, has become a technical problem that needs to be solved urgently in the present invention. Summary of the Invention

[0008] In view of the above problems, one of the objectives of the present invention is to provide a method for preparing 1,1'-difluoro-2,2'-binaphthalene by copper-catalyzed boric acid self-coupling. The preparation process not only has low cost, but also has mild reaction conditions, simple operation, environmental friendliness, high safety and efficiency. Through simple preparation and purification steps, 1,1'-difluoro-2,2'-binaphthalene with high purity can be obtained in high yield, avoiding the harsh reaction conditions of high temperature or ultra-low temperature in the existing processes, and also solving the problems of difficult reaction operation, high danger and high production cost, which is beneficial to industrial production.

[0009] To achieve the above objective, the technical solution adopted by the present invention is:

[0010] A method for preparing 1,1'-difluoro-2,2'-binaphthalene by copper-catalyzed boric acid self-coupling, comprising the following steps:

[0011] (1) Stirring and reacting (1-fluoro-2-naphthyl)boronic acid, cuprous oxide, and an organic weak base compound in a solvent to obtain a reaction product;

[0012] (2) Filtering the reaction product, then extracting and concentrating to obtain a crude product;

[0013] (3) Performing low-temperature crystallization treatment on the crude product to obtain the product 1,1'-difluoro-2,2'-binaphthalene;

[0014] Wherein, the molar ratio of (1-fluoro-2-naphthyl)boronic acid, cuprous oxide, and the organic weak base compound is (1-2):(0.1-0.2):(2-4).

[0015] As a preferred solution, in step (1), the organic weak base compound is pyridine or piperidine, and more preferably pyridine.

[0016] As a preferred solution, in step (1), the solvent is one or more of acetonitrile, toluene, dioxane, and tetrahydrofuran, and more preferably acetonitrile.

[0017] In order to improve the reaction efficiency and product selectivity, as a preferred solution, in step (1), the molar ratio of (1-fluoro-2-naphthyl)boronic acid, cuprous oxide, and the organic weak base compound is 1:0.1:2.

[0018] As a preferred embodiment, in step (1), the temperature of the stirring reaction is 15 - 40 °C, and the time is 12 - 18 h. Further preferably, the temperature of the stirring reaction is 20 - 30 °C, and the time is 15 h.

[0019] As a preferred embodiment, in step (1), the dosage ratio of (1-fluoro-2-naphthyl)boronic acid to the solvent is 1 g∶(5 - 20) mL, more preferably 1 g∶10 mL.

[0020] As a preferred embodiment, in step (2), the extractant used for extraction is ethyl acetate.

[0021] As a preferred embodiment, in step (3), the temperature of the low-temperature crystallization treatment is 5 - 15 °C, more preferably 10 °C.

[0022] As a further preferred embodiment, the process of the low-temperature crystallization treatment is: dissolving the crude product in a crystallization solvent, then crystallizing at a temperature of 5 - 15 °C, and filtering to obtain the product 1,1'-difluoro-2,2'-binaphthalene.

[0023] As a further preferred embodiment, the crystallization solvent is ethanol or methanol, more preferably ethanol. Further, the dosage ratio of the crude product to the crystallization solvent is 1 g∶(1 - 5) mL.

[0024] The technical solution of the present invention has the following advantages and beneficial effects:

[0025] The method for preparing 1,1'-difluoro-2,2'-binaphthalene by copper-catalyzed boric acid self-coupling provided by the present invention uses (1-fluoro-2-naphthyl)boronic acid as the starting material, and for the first time uses simple and inexpensive cuprous oxide as a catalyst, further in combination with an organic weak base compound, to carry out a self-coupling reaction at room temperature, and then through filtration, extraction, and crystallization, thereby effectively preparing the 1,1'-difluoro-2,2'-binaphthalene product.

[0026] The above preparation method of the present invention not only has low cost, but also has mild reaction conditions, simple operation, green environmental protection, safety and high efficiency. Through simple preparation and purification steps, a high-purity 1,1'-difluoro-2,2'-binaphthalene product can be obtained in high yield. The above preparation strategy of the present invention not only avoids the high-temperature and ultra-low-temperature reaction conditions of the existing preparation process, but also effectively solves the problems of difficult reaction operation, high danger, and high production cost in the preparation of 1,1'-difluoro-2,2'-binaphthalene, which is beneficial to industrial production and has broad application prospects in the field of the preparation of 1,1'-difluoro-2,2'-binaphthalene. Description of the Drawings

[0027] Figure 11H NMR spectrum of 1,1′-difluoro-2,2′-binaphthalene prepared in Example 1 of the present invention 1 1H NMR spectrum Specific embodiments

[0028] To make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be described clearly and completely below in conjunction with specific embodiments. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without making creative efforts shall fall within the protection scope of the present invention.

[0029] Among them, in the embodiments of the present invention, all solvents used are commercially available chemically pure or analytically pure. In the present invention, "room temperature" has the meaning commonly understood in the art, that is, 25 ± 5°C. In the embodiments of the present invention, the structure of the compound is determined by nuclear magnetic resonance (NMR) technology.

[0030] The method for preparing 1,1′-difluoro-2,2′-binaphthalene by copper-catalyzed boric acid self-coupling provided in the following embodiments of the present invention has a process route as shown in the following formula:

[0031]

[0032] When preparing 1,1′-difluoro-2,2′-binaphthalene (Compound 2), (1-fluoro-2-naphthyl)boronic acid (i.e., Compound 1) is used as the starting material, cuprous oxide is used as the catalyst, and further combined with an organic weak base compound. The self-coupling reaction is carried out at room temperature, and then through filtration, extraction, and crystallization, the 1,1′-difluoro-2,2′-binaphthalene product can be effectively prepared.

[0033] Example 1

[0034] This example provides a method for preparing 1,1′-difluoro-2,2′-binaphthalene by copper-catalyzed boric acid self-coupling, including the following steps:

[0035] Dissolve 50 g of (1-fluoro-2-naphthyl)boronic acid in 500 mL of acetonitrile, then successively add 1.9 g of cuprous oxide (0.1 eq) and 20.5 g of pyridine and mix them. Stir and react at room temperature for 15 h. Detect that the reaction is complete by TLC. Then filter the product obtained from the reaction, add ethyl acetate and water for extraction. Dry the organic phase with anhydrous sodium sulfate, concentrate it to obtain the crude product of the reactant. Then add the crude product of the reactant to ethanol (250 mL), heat it to 55 °C and stir. After complete dissolution, cool it to 10 °C, and then filter to obtain 35.9 g of white solid product, which is the product 1,1'-difluoro-2,2'-binaphthalene, with a yield of 94%. Among them, in this example, the molar ratio of (1-fluoro-2-naphthyl)boronic acid, cuprous oxide, and pyridine is 1:0.1:2.

[0036] Example 2

[0037] This example provides a method for the copper-catalyzed self-coupling of boronic acid to prepare 1,1'-difluoro-2,2'-binaphthalene, which includes the following steps:

[0038] Dissolve 50 g of (1-fluoro-2-naphthyl)boronic acid in 500 mL of acetonitrile, then successively add 3.8 g of cuprous oxide (0.2 eq) and 20.5 g of pyridine and mix them. Stir and react at room temperature for 15 h. Detect that there is a small amount of raw material remaining by TLC. Continue to extend the reaction time by 15 h and there is still no change. Then filter the product obtained from the reaction, add ethyl acetate and water for extraction. Dry the organic phase with anhydrous sodium sulfate, concentrate it to obtain the crude product of the reactant. Then add the crude product of the reactant to ethanol (250 mL), heat it to 55 °C and stir. After complete dissolution, cool it to 10 °C, and then filter to obtain 30.18 g of white solid product, which is the product 1,1'-difluoro-2,2'-binaphthalene, with a yield of 79%. Among them, in this example, the molar ratio of (1-fluoro-2-naphthyl)boronic acid, cuprous oxide, and pyridine is 1:0.2:2.

[0039] Example 3

[0040] This example provides a method for the copper-catalyzed self-coupling of boronic acid to prepare 1,1'-difluoro-2,2'-binaphthalene, which includes the following steps:

[0041] Dissolve 50 g of (1-fluoro-2-naphthyl)boronic acid in 500 mL of acetonitrile, then successively add 1.9 g of cuprous oxide (0.1 eq) and 30.7 g of pyridine, and stir and react at room temperature for 15 h. Detect the completion of the reaction by TLC. Then filter the product obtained from the reaction, add ethyl acetate and water for extraction, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain the crude product of the reactant. Then add the crude product of the reactant to ethanol (250 mL), heat to 55 °C and stir. After complete dissolution, cool to 10 °C, and then filter to obtain 33.2 g of a white solid product, which is the product 1,1'-difluoro-2,2'-binaphthalene, with a yield of 87%. Among them, in this example, the molar ratio of (1-fluoro-2-naphthyl)boronic acid, cuprous oxide, and pyridine is 1:0.1:3.

[0042] Example 4

[0043] This example provides a method for the copper-catalyzed self-coupling of boronic acid to prepare 1,1'-difluoro-2,2'-binaphthalene, which includes the following steps:

[0044] Dissolve 50 g of (1-fluoro-2-naphthyl)boronic acid in 500 mL of acetonitrile, then successively add 3.8 g of cuprous oxide (0.2 eq) and 30.7 g of pyridine, and stir and react at room temperature for 15 h. Detect the completion of the reaction by TLC. Then filter the product obtained from the reaction, add ethyl acetate and water for extraction, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain the crude product of the reactant. Then add the crude product of the reactant to ethanol (250 mL), heat to 55 °C and stir. After complete dissolution, cool to 10 °C, and then filter to obtain 30.9 g of a white solid product, which is the product 1,1'-difluoro-2,2'-binaphthalene, with a yield of 81%. Among them, in this example, the molar ratio of (1-fluoro-2-naphthyl)boronic acid, cuprous oxide, and pyridine is 1:0.2:3.

[0045] Experimental example

[0046] Take the 1,1'-difluoro-2,2'-binaphthalene product prepared in Example 1 for nuclear magnetic resonance analysis, and the obtained nuclear magnetic 1 HNMR spectrum is as Figure 1 shown. It can be Figure 1 seen that the target product 1,1'-difluoro-2,2'-binaphthalene was successfully prepared in this invention. In addition, the nuclear magnetic resonance analysis results of the 1,1'-difluoro-2,2'-binaphthalene products prepared in Examples 2 to 4 are the same as those in Example 1, and this invention will not elaborate further.

[0047] Further, the yields of the 1,1'-difluoro-2,2'-binaphthalene products prepared in Examples 1 to 4 were statistically analyzed, and then the purity of the products was detected by HPLC. The results are shown in Table 1.

[0048] Table 1. Yield and purity results of 1,1′-difluoro-2,2′-binaphthalene products prepared in Examples 1-4

[0049] Grouping Color and Morphology Yield (%) Purity (%) Example 1 White Solid 94％ 99.2％ Example 2 White Solid 79％ 99.4％ Example 3 White Solid 87％ 99.5％ Example 4 White Solid 81％ 99.1％

[0050] As can be seen from the data in Table 1, the method for preparing 1,1′-difluoro-2,2′-binaphthalene by copper-catalyzed boric acid self-coupling provided by the present invention uses (1-fluoro-2-naphthyl) boric acid as the starting material, uses cuprous oxide as the catalyst in combination with an organic weak base compound, and undergoes a self-coupling reaction at room temperature. After filtration, extraction, and crystallization, 1,1′-difluoro-2,2′-binaphthalene products with high purity (>99%) and high yield (>79%) can be effectively prepared, effectively solving the problems of difficult reaction operation, high danger, and high production cost in the existing method for preparing 1,1′-difluoro-2,2′-binaphthalene, which is beneficial to industrial production.

[0051] Although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing 1,1'-difluoro-2,2'-binaphthyl by copper-catalyzed boric acid self-coupling, characterized in that: The following steps are involved: (1) stirring (1-fluoro-2-naphthyl)boric acid, cuprous oxide, and an organic weak base compound in a solvent to react to obtain a reactant; (2) filtering the reactant, extracting and concentrating to obtain a crude product; (3) subjecting the crude product to low-temperature crystallization to obtain the product 1,1'-difluoro-2,2'-binaphthalene; The molar ratio of the (1-fluoro-2-naphthyl)boric acid, cuprous oxide and organic weak base compound is (1-2): (0.1-0.2): (2-4).

2. The method for preparing 1,1'-difluoro-2,2'-binaphthyl by copper-catalyzed boric acid self-coupling according to claim 1, characterized in that: In step (1), the organic weak base compound is pyridine or piperidine.

3. The method for preparing 1,1'-difluoro-2,2'-binaphthyl by copper-catalyzed boric acid self-coupling according to claim 1, characterized in that: In step (1), the solvent is one or more of acetonitrile, toluene, dioxane, and tetrahydrofuran.

4. The method for preparing 1,1'-difluoro-2,2'-binaphthyl by copper-catalyzed boric acid self-coupling according to claim 1, characterized in that: In step (1), the molar ratio of the (1-fluoro-2-naphthyl)boric acid, cuprous oxide and organic weak base compound is 1:0.1:

2.

5. The method for preparing 1,1'-difluoro-2,2'-binaphthyl by copper-catalyzed boric acid self-coupling according to claim 1, characterized in that: In step (1), the stirring reaction is carried out at a temperature of 15 to 40° C. and for a time of 12 to 18 hours.

6. The method for preparing 1,1'-difluoro-2,2'-binaphthyl by copper-catalyzed boric acid self-coupling according to claim 1, characterized in that: In step (1), the amount ratio of the (1-fluoro-2-naphthyl)boric acid to the solvent is 1 g: (5-20) mL.

7. The method for preparing 1,1'-difluoro-2,2'-binaphthyl by copper-catalyzed boric acid self-coupling according to any one of claims 1 to 6, characterized in that: In step (2), the extraction agent used in the extraction is ethyl acetate.

8. The method for preparing 1,1'-difluoro-2,2'-binaphthyl by copper-catalyzed boric acid self-coupling according to any one of claims 1 to 6, characterized in that: In step (3), the temperature of the low-temperature crystallization treatment is 5 to 15°C.

9. The method for preparing 1,1'-difluoro-2,2'-binaphthyl by copper-catalyzed boric acid self-coupling according to claim 8, characterized in that: The process of low-temperature crystallization treatment is: dissolving the crude product in a crystallization solvent, then placing it at a temperature of 5 to 15° C. for crystallization, and filtering to obtain the product 1,1'-difluoro-2,2'-binaphthalene.

10. The method for preparing 1,1'-difluoro-2,2'-binaphthyl by copper-catalyzed boric acid self-coupling according to claim 9, characterized in that: The crystallization solvent is ethanol or methanol; the usage ratio of the crude product to the crystallization solvent is 1g: (1-5)mL.

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