Preparation method of 4-phenoxyphenylboronic acid

Abstract

The invention discloses a preparation method of 4-phenoxyphenylboronic acid, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: by taking diphenyl ether as a raw material, reacting with fuming nitric acid under the action of tris (pentafluorophenyl) boron, so as to generate a 4-nitrodiphenyl ether intermediate; generating 4-aminodiphenyl ether from the 4-nitrodiphenyl ether intermediate under the action of tetrahydroxy diboron and a catalyst, and then generating 4-phenoxyphenylboronic acid from the 4-aminodiphenyl ether and excessive tetrahydroxy diboron under the action of tert-butyl nitrite. In the first step of the route, the positioning selectivity of 4-position nitro is increased through specific Lewis acid, in the second step, nitro reduction and boronation are carried out through a continuous one-pot method, and the synthesis method of the compound is enriched.

Description

Technical Field

[0001] The invention relates to a preparation method of 4-phenoxyphenylboronic acid, and belongs to the technical field of organic synthesis. Background Art

[0002] The main use of 4-phenoxyphenylboronic acid is as an important intermediate in organic synthesis. It is often used as a chemical intermediate, liquid crystal intermediate, etc., and is used as the main raw material in the synthesis of the targeted anticancer drug ibrutinib.

[0003] In the field of chemistry and materials science, 4-phenoxyphenylboronic acid has good thermal and chemical stability and is easily soluble in organic solvents such as dichloromethane and tetrahydrofuran, which makes it easy to operate and handle in chemical reactions. It can react with a variety of compounds, such as aldehydes, ketones, carboxylic acids, etc., through nucleophilic substitution, addition or reduction, thereby preparing a variety of organic compounds with specific structures and functions. In addition, it can also be copolymerized or cross-linked with other compounds to prepare polymer materials with special properties, such as excellent mechanical properties, thermal stability or electrical properties, so it has potential application prospects in engineering, aerospace and automotive fields.

[0004] In large-scale industrial production, 4-phenoxyphenylboronic acid is also widely used in various chemical reactions, especially in the field of organic synthesis. Since its structure contains both a benzene ring and a boronic acid group, it can undergo cross-coupling reactions with aromatic halides under the catalysis of transition metals. This reaction has a wide range of uses in drug synthesis, polymer chemistry and other fields.

[0005] There are many methods for synthesizing 4-phenoxyphenylboronic acid, among which [Organic Process Research and Development, 2018, 22, 741; Chemistry-A European Journal, 2000, 6, 3821; Angewandte Chemie-International Edition, 2008, 47, 1115; Journal of Materials Chemistry C, 2016, 4, 6016; CN106146511; US2002156081; CN105820184] and other reports use 4-bromodiphenyl ether and triester of borate as raw materials, and react under the action of lithium reagent or Grignard reagent to obtain the chemical reaction equation as follows:

[0006]

[0007] The literature [Journal of Organic Chemistry, 2020, 85, 10966] reported that 4-bromodiphenyl ether and tetrahydroxydiboron were reacted under the action of potassium tert-butoxide to obtain 4-phenoxyphenylboronic acid. The chemical reaction equation is as follows:

[0008]

[0009] Previous synthesis methods all involved 4-bromodiphenyl ether. However, when using the diphenyl ether bromination method, it is difficult to control the monobrominated product and separation is relatively difficult. In view of the importance of the 4-phenoxyphenylboronic acid product, it is still necessary to develop other synthesis processes starting from diphenyl ether. Summary of the invention

[0010] In order to overcome the above technical defects, the present invention provides a method for preparing 4-phenoxyphenylboronic acid. Diphenyl ether is used as a raw material and reacted with fuming nitric acid under the action of tri(pentafluorophenyl)borane to generate a 4-nitrodiphenyl ether intermediate; the 4-nitrodiphenyl ether intermediate generates 4-aminodiphenyl ether under the action of tetrahydroxydiborane and a catalyst, and then generates 4-phenoxyphenylboronic acid with an excess of tetrahydroxydiborane under the action of tert-butyl nitrite. In the first step of the route of the present invention, the selectivity of the nitro group at the 4th position is increased by a specific Lewis acid, and in the second step, the nitro group reduction and borylation are carried out by a continuous one-pot method, which enriches the synthesis method of this type of compound.

[0011] The preparation method of 4-phenoxyphenylboronic acid described in the present invention is represented by the following reaction equation:

[0012]

[0013] The steps include:

[0014] A. Mix diphenyl ether, tri(pentafluorophenyl)boron and fuming nitric acid in acetic acid and react to generate 4-nitrodiphenyl ether under low temperature conditions;

[0015] B. 4-nitrodiphenyl ether, tetrahydroxydiboron and a base catalyst are mixed in an alcohol solvent, and then tert-butyl nitrite and acetonitrile are added, and the temperature is raised to react to obtain 4-phenoxyphenylboronic acid.

[0016] Furthermore, in the above technical solution, in step A, the molar ratio of diphenyl ether, tri(pentafluorophenyl)boron and fuming nitric acid is 1:0.02-0.05:1-1.3.

[0017] Furthermore, in the above technical solution, in step A, the low temperature is 0-20°C.

[0018] Furthermore, in the above technical solution, in step B, the base catalyst is selected from DMAP, DBU, 2,2'-bipyridine or 4,4'-bipyridine, preferably 4,4'-bipyridine.

[0019] Furthermore, in the above technical solution, in step B, the molar ratio of 4-nitrodiphenyl ether, tetrahydroxydiborane, base catalyst and tert-butyl nitrite is 1:3-5:0.15-0.25:1.5-2.

[0020] Furthermore, in the above technical solution, in step B, the alcohol solvent is selected from methanol, ethanol, isopropanol or n-butanol.

[0021] Furthermore, in the above technical solution, in step A, the temperature of the temperature-raising reaction is selected from 40-60°C.

[0022] The present invention has the following beneficial effects:

[0023] A. The present invention uses diphenyl ether as a raw material, which is cheap and readily available. The nitration reaction of diphenyl ether under the catalysis of a specific Lewis acid improves the position selectivity of 4-nitrodiphenyl ether.

[0024] B. In the second step of the present invention, tetrahydroxyboric acid is used as both a reducing agent and a boric acid reaction raw material to prepare 4-phenoxyboric acid from 4-nitrodiphenyl ether using a one-step method. The route is novel and the operation steps are reduced. Specific embodiments

[0025] The present invention will be further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0026] Example 1

[0027]

[0028] Under nitrogen protection, at 0-5°C, 17 g (0.1 mol) of diphenyl ether, 1.5 g (0.003 mol) of tri(pentafluorophenyl)boron and 7.6 g (0.12 mol) of fuming nitric acid were mixed in 250 mL of acetic acid, heated to room temperature, and reacted for 6 hours. The reaction of diphenyl ether was monitored by a plate. 90 mL of dibutyl ether was added for extraction twice, and the organic layer was washed twice with 30 mL of saturated sodium bicarbonate. The organic layer was concentrated and subjected to high vacuum distillation to obtain 15.5 g of 4-nitrodiphenyl ether, which solidified after cooling. The yield was 72% and the chemical purity was 99.5%. 1 HNMR (400MHz, CDCl 3): 8.22(d,2H),7.48-7.44(m,2H),7.28-7.22(m,1H),7.11(d,2H),7.02-7.00(m,2H).

[0029] Example 2

[0030]

[0031] Under nitrogen protection, at 0-5°C, 17 g (0.1 mol) of diphenyl ether, 2.6 g (0.005 mol) of tri(pentafluorophenyl)borane and 6.3 g (0.1 mol) of fuming nitric acid were mixed in 250 mL of acetic acid, heated to room temperature, and reacted for 5 hours. The reaction of diphenyl ether was monitored by a plate. 90 mL of dibutyl ether was added for extraction twice, and the organic layer was washed twice with 30 mL of saturated sodium bicarbonate. The organic layer was concentrated and subjected to high vacuum distillation to obtain 14.8 g of 4-nitrodiphenyl ether, which solidified after cooling. The yield was 69%.

[0032] Example 3

[0033]

[0034] Under nitrogen protection, 21.5 g (0.1 mol) of 4-nitrodiphenyl ether, 35.9 g (0.4 mol) of tetrahydroxydiborane and 3.1 g (0.02 mol) of 4,4'-bipyridine were mixed in 320 mL of ethanol and reacted at room temperature for 6 hours. Subsequently, 15.5 g (0.15 mol) of tert-butyl nitrite and 45 mL of acetonitrile were added, the temperature was raised to 50-55 ° C., the reaction was carried out for 2 hours, the temperature was lowered to room temperature, and then a saturated aqueous sodium carbonate solution was added to adjust the pH to 8-9, 150 mL of ethyl acetate was added to extract twice, the aqueous layer was adjusted to pH 2-3 with hydrochloric acid (3 M), and then 100 mL of ethyl acetate was added to extract 3 times, the ethyl acetate layers were combined and concentrated to obtain a crude product, and then ethyl acetate / n-heptane (v / v=1:11) was used for slurrying to obtain 17.7 g of 4-phenoxyphenylboronic acid, with a yield of 83%, and HPLC99.2%. 1 HNMR (400 MHz, DMSO-d 6 ):7.92(m,1H),7.88(t,1H),7.81(d,1H),7.43(m,2H),7.14(m,1H),6.92-7.07(m,5H).

[0035] Example 4

[0036]

[0037] Under nitrogen protection, 21.5 g (0.1 mol) of 4-nitrodiphenyl ether, 26.9 g (0.3 mol) of tetrahydroxydiboron and 2.3 g (0.015 mol) of 2,2'-bipyridine were mixed in 320 mL of ethanol and reacted at room temperature for 8 hours. Subsequently, 20.6 g (0.2 mol) of tert-butyl nitrite and 45 mL of acetonitrile were added, the temperature was raised to 50-55 ° C., the reaction was carried out for 1.5 hours, the temperature was lowered to room temperature, and then a saturated aqueous sodium carbonate solution was added to adjust the pH to 8-9, 150 mL of ethyl acetate was added to extract twice, the aqueous layer was adjusted to pH 2-3 with hydrochloric acid (3 M), and then 100 mL of ethyl acetate was added to extract 3 times, the ethyl acetate layers were combined and concentrated to obtain a crude product, and then ethyl acetate / n-heptane (v / v=1:11) was used for slurrying to obtain 16.7 g of 4-phenoxyphenylboronic acid, with a yield of 78%, and HPLC99.1%.

[0038] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 4-phenoxyphenylboronic acid, characterized in that: The steps include: A. Mix diphenyl ether, tri(pentafluorophenyl)boron and fuming nitric acid in acetic acid and react to generate 4-nitrodiphenyl ether under low temperature conditions; B. 4-nitrodiphenyl ether, tetrahydroxydiboron and a base catalyst are mixed in an alcohol solvent, and then tert-butyl nitrite and acetonitrile are added, and the temperature is raised to react to obtain 4-phenoxyphenylboronic acid.

2. The method for preparing 2,6-dihydroxytoluene according to claim 1, characterized in that: In step A, the molar ratio of diphenyl ether, tris(pentafluorophenyl)boron and fuming nitric acid is 1:0.02-0.05:1-1.

3.

3. The method for preparing 2,6-dihydroxytoluene according to claim 1, characterized in that: In step A, the low temperature is 0-20°C.

4. The method for preparing 4-phenoxyphenylboronic acid according to claim 1, characterized in that: In step B, the base catalyst is selected from DMAP, DBU, 2,2'-bipyridine or 4,4'-bipyridine.

5. The method for preparing 4-phenoxyphenylboronic acid according to claim 3, characterized in that: In step B, the base catalyst is 4,4'-bipyridine.

6. The method for preparing 4-phenoxyphenylboronic acid according to claim 1, characterized in that: In step B, the molar ratio of 4-nitrodiphenyl ether, tetrahydroxydiboron, base catalyst and tert-butyl nitrite is 1:3-5:0.15-0.25:1.5-2.

7. The method for preparing 4-phenoxyphenylboronic acid according to claim 1, characterized in that: In step B, the alcohol solvent is selected from methanol, ethanol, isopropanol or n-butanol.

8. The method for preparing 2,6-dihydroxytoluene according to claim 1, characterized in that: In step B, the temperature of the reaction is selected from 40-60°C.

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