A preparation method of 2-fluoro-4-pyridineboronic acid

Abstract

The present invention discloses a preparation method of 2-fluoro-4-pyridineboronic acid, belonging to the technical field of organic synthesis. Using 2-fluoropyridine as a raw material, it is oxidized with hydrogen peroxide and acetic acid to obtain 2-fluoropyridine N-oxide, and then undergoes a nitration reaction with a nitrating reagent to obtain 2-fluoro-4-nitropyridine N-oxide. Subsequently, it reacts with acetyl bromide or an acetic acid solution of hydrogen bromide to obtain 4-bromo-2-fluoropyridine N-oxide, and then is coupled with tetrahydroxy diboron under the catalysis of 1,3-bis(diphenylphosphinopropane) nickel dichloride to obtain 2-fluoro-4-pyridineboronic acid. The process of the present invention has a high yield, avoids the formation of isomers, ensures the product quality, and is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to a preparation method of 2-fluoropyridin-4-ylboronic acid, belonging to the technical field of organic synthesis. Background Art

[0002] 2-fluoropyridin-4-ylboronic acid, with the English name 2-fluoropyridin-4-ylboronic acid and CAS: 401815-98-3. Many alkaloids contain a pyridine ring system, and most of them have biological activities. Pyridine and its derivatives are widely used in the fields of medicine, pesticides, rubber, dyes, etc. Fluoropyridine and its derivatives introduce strongly electron-withdrawing fluorine atoms into the pyridine ring. The electronegativity of the nitrogen atom in the pyridine ring itself is relatively strong, so that fluoropyridine compounds have special biological activities and functions. 2-fluoropyridin-4-ylboronic acid is an organic building block, which can be coupled with boric acid to form various compounds. Its fluoropyridine has special physiological activities and has great potential in the fields of medicine, natural medicines, pesticides, etc.

[0003] At present, most patents and literatures use 4-bromo-2-fluoropyridine or 4-iodo-2-fluoropyridine as raw materials and synthesize them by the method of deep-cooling n-butyllithium boration. Among them, [Tetrahedron, 2002, vol. 58, #22, p. 4369-4373] uses 4-bromo-2-fluoropyridine as a raw material, adds a stabilizer TMEDA, removes bromine with n-butyllithium at -60 °C, and then borates with triisopropyl borate, and then quenches to obtain the target product. When using ultra-low temperature n-butyllithium boration reaction, the requirements for post-treatment are high, and the product is prone to deterioration and other reasons, and the yield is 64%. The reaction equation is as follows:

[0004]

[0005] In the post-treatment of the existing literature, the requirements for acidification of 2-fluoropyridin-4-ylboronic acid are high, and the stability during the product concentration process is poor. To solve the above problems, the present invention adopts a simple process, easily available raw materials, stable process, and each intermediate can be sold, which is suitable for large-scale production in factories, so as to meet the growing market demand. Summary of the Invention

[0006] In order to overcome the above technical defects, the present invention uses 2-fluoropyridine as a raw material, undergoes N-oxidation with hydrogen peroxide and acetic acid to obtain 2-fluoropyridine N-oxide, then undergoes nitration reaction with a nitrating reagent to obtain 2-fluoro-4-nitropyridine N-oxide, then reacts with acetyl bromide or acetic acid solution of hydrogen bromide to obtain 4-bromo-2-fluoropyridine N-oxide, and then couples with tetrahydroxy diboron under the catalysis of 1,3-bis(diphenylphosphinopropane)nickel dichloride to obtain 2-fluoropyridin-4-ylboronic acid. This process has a high yield, avoids the formation of isomers, ensures the product quality, and is suitable for large-scale production.

[0007] The preparation method of 2-fluoro-4-pyridineboronic acid according to the present invention comprises the following steps:

[0008]

[0009] Oxidation reaction: Mix 2-fluoropyridine, acetic acid and concentrated sulfuric acid, add hydrogen peroxide, and heat up to obtain 2-fluoropyridine N-oxide;

[0010] Nitration reaction: Add a nitrating reagent and a catalyst to 2-fluoropyridine N-oxide, and heat up for nitration to obtain 2-fluoro-4-nitropyridine N-oxide;

[0011] Bromination reaction: Mix 2-fluoro-4-nitropyridine N-oxide with an acetic acid solution containing acetyl bromide or an acetic acid solution containing hydrogen bromide, and heat up for reaction to obtain 4-bromo-2-fluoropyridine N-oxide;

[0012] Coupling reaction: Mix 4-bromo-2-fluoropyridine N-oxide, 1,3-bis(diphenylphosphinopropane)nickel dichloride, tetrahydroxy diboron and ethanol, add triethylamine, and heat up for reaction to obtain 2-fluoro-4-pyridineboronic acid.

[0013] Further, in the above technical solution, in the oxidation reaction, the hydrogen peroxide is selected from 25-30% hydrogen peroxide.

[0014] Further, in the above technical solution, in the oxidation reaction, the molar ratio of 2-fluoropyridine, acetic acid, concentrated sulfuric acid to 30% hydrogen peroxide is 1:1.45-1.55:0.8-1.0:1.5-2.0.

[0015] Further, in the above technical solution, in the nitration reaction, the nitrating reagent is selected from the combination of concentrated sulfuric acid / fuming nitric acid or fuming sulfuric acid / potassium nitrate.

[0016] Further, in the above technical solution, in the oxidation reaction and the nitration reaction, the concentrated sulfuric acid is selected from 98% concentrated sulfuric acid.

[0017] Further, in the above technical solution, in the nitration reaction, the molar ratio of 2-fluoro-4-nitropyridine N-oxide, fuming nitric acid or potassium nitrate is 1:1.3-1.8.

[0018] Further, in the above technical solution, in the bromination reaction, the molar ratio of 2-fluoro-4-nitropyridine N-oxide to acetyl bromide or hydrogen bromide is 1:6.5-8.5.

[0019] Further, in the above technical solution, in the coupling reaction, the molar ratio of 4-bromo-2-fluoropyridine N-oxide, 1,3-bis(diphenylphosphinopropane)nickel dichloride, tetrahydroxy diboron to triethylamine is 1:0.05-0.10:2.2-3.0:3.0.

[0020] The present invention has the following beneficial effects:

[0021] 1. First, 2-fluoropyridine is N-oxidized to activate the para-position of the pyridine. When nitrated, the C4 position is substituted, and there are no isomers, ensuring that there are no isomer residues in the product. Using fuming sulfuric acid and potassium nitrate makes the first two steps of the reaction continuous and the operation convenient.

[0022] 2. Through coupling with an excessive amount of tetrahydroxy diboron, while coupling, nitrogen oxides are consumed, and finally 2-fluoro-4-pyridineboronic acid is obtained. This process is stable, safe, and the yield is as high as over 90%. Specific embodiments

[0023] The present invention will be further described below through specific examples. These examples should be understood as only for illustrating the present invention and not for limiting the protection scope of the present invention. After reading the content recorded in the present invention, those skilled in the art can 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.

[0024] Example 1

[0025]

[0026] Add 97.1 g (1 mol) of 2-fluoropyridine, 90.1 g (1.5 mol) of acetic acid, and 100 g of concentrated sulfuric acid into the reaction flask. Heat up to 35 - 40 °C and dropwise add 181.4 g (1.6 mol) of 30% hydrogen peroxide solution. React at 65 - 70 °C for 6 hours. Concentrate under reduced pressure to distill off acetic acid. Add it into ice water and extract with dichloromethane. Wash the organic phase with saturated sodium bicarbonate aqueous solution. Concentrate the organic phase until it stops flowing to obtain 106.9 g of 2-fluoropyridine N-oxide, with a yield of 94.5% and an HPLC of 96.3%. 1 HNMR(400MHz,CDCl3)δ:8.38 - 8.36(m,1H),7.55 - 7.52(m,1H),7.26 - 7.20(m,2H).

[0027] Example 2

[0028]

[0029] Add 100 g of concentrated sulfuric acid into the reaction flask, cool down the temperature to 5 - 10 °C, add 22.6 g (0.2 mol) of 2-fluoropyridine N-oxide and 2.2 g of triphenylborane in batches, slowly warm up to room temperature, dropwise add 18.9 g (0.3 mol) of fuming nitric acid at room temperature, warm up to 45 - 50 °C and react for 3 hours, cool down to 5 - 10 °C, pour it into the reaction kettle filled with ice water, filter, dissolve the filter cake with 300 mL of dichloromethane, wash the organic phase with saturated sodium carbonate aqueous solution and water respectively, concentrate the organic phase until no liquid flows out to obtain 25.5 g of 2-fluoro-4-nitropyridine N-oxide, with a yield of 80.6% and HPLC of 97.7%. 1 HNMR(400MHz,DMSO-d6)δ:8.40-8.36(m,2H),7.93-7.91(m,1H).

[0030] Example 3

[0031]

[0032] Add 48.5 g (0.5 mol) of 2-fluoropyridine, 45 g (0.75 mol) of acetic acid and 50 g of concentrated sulfuric acid into the reaction flask, warm up to 35 - 40 °C and dropwise add 90.7 g (0.8 mol) of 30% hydrogen peroxide, react at 65 - 70 °C for 6 hours, then cool down to 5 - 10 °C, add 80 g of 10% oleum and 3.0 g of triphenylborane, slowly warm up to room temperature, add 91 g (0.9 mol) of potassium nitrate in batches, warm up to 50 - 60 °C and react for 5 hours, cool down to 5 - 10 °C, pour it into the reaction kettle filled with ice water, filter, wash the filter cake with water, dissolve it with 500 mL of dichloromethane, wash the organic phase with saturated sodium bicarbonate aqueous solution and water respectively, concentrate the organic phase until no liquid flows out to obtain 67.1 g of 2-fluoro-4-nitropyridine N-oxide, with a yield of 84.9% and HPLC of 98.4%.

[0033] Example 4

[0034]

[0035] Add 31.6 g (0.2 mol) of 2-fluoro-4-nitropyridine N-oxide and 170 mL of acetic acid into the reaction flask, dropwise add 158.1 g (1.4 mol) of acetyl bromide, warm up to reflux and react for 7 hours, cool down to 50 °C, concentrate under reduced pressure until no liquid flows out, cool down to room temperature, add 100 mL of ice water, extract with 200 mL of dichloromethane, then wash once with saturated sodium bicarbonate aqueous solution and water, concentrate the organic phase under reduced pressure, add n-heptane for pulping, filter, dry to obtain 34 g of 4-bromo-2-fluoropyridine N-oxide, with a yield of 88.6% and HPLC: 99.3%. 1HNMR(400MHz,CDCl3)δ:8.12 - 8.10(m,1H),7.69 - 7.67(m,1H),7.36 - 7.32(m,1H).

[0036] Example 5

[0037]

[0038] Add 31.6 g (0.2 mol) of 2 - fluoro - 4 - nitropyridine N - oxide and 440 g of 33% hydrobromic acid acetic acid solution into a reaction flask equipped with an acid gas absorption device. Heat up to 95 °C and react for 3 hours. Cool down to 40 °C, concentrate under reduced pressure until no more liquid flows, cool down to room temperature, add 100 mL of ice water, extract with 200 mL of dichloromethane, then wash once with saturated sodium bicarbonate aqueous solution and water. Concentrate the organic phase under reduced pressure, add n - heptane for pulping, filter, and dry to obtain 35.1 g of 4 - bromo - 2 - fluoropyridine N - oxide, with a yield of 91.3% and HPLC of 99.4%.

[0039] Example 6

[0040]

[0041] Under nitrogen protection, add 28.8 g (0.15 mol) of 4 - bromo - 2 - fluoropyridine N - oxide, 5.4 g (0.01 mol) of 1,3 - bis(diphenylphosphinopropane)nickel dichloride, 32.3 g (0.36 mol) of tetra - hydroxy diboron, and 250 mL of ethanol into a reaction flask. Dropwise add 45.5 g (0.45 mol) of triethylamine, heat up to 80 °C and react for 8 hours. Cool down to room temperature, filter through diatomaceous earth, concentrate the filtrate under reduced pressure until 2 volumes remain, replace with 250 mL of methyl tert - butyl ether, then add another 250 mL of methyl tert - butyl ether. Add 5 g of silica gel and 1 g of activated carbon, heat up to 30 - 35 °C and stir for 1 hour. Cool down to room temperature and filter. Concentrate the filtrate under reduced pressure, add n - heptane for pulping, filter, and dry to obtain 18.5 g of 2 - fluoro - 4 - pyridineboronic acid, with a yield of 87.7% and HPLC: 99.3%. 1 HNMR(400MHz,DMSO - d 6 +H 2 O)δ:8.38 - 8.36(m,1H),7.69(s,1H),7.62 - 7.60(m,1H).

[0042] As described above, the above are only the preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes, should be covered within the protection scope of the present invention.

Claims

1. A preparation method of 2-fluoro-4-pyridineboronic acid, characterized in that, it comprises the following steps: Oxidation reaction: Mix 2-fluoropyridine, acetic acid and concentrated sulfuric acid, add hydrogen peroxide, and heat up to obtain 2-fluoropyridine N-oxide; Nitration reaction: Add a nitrating agent and a catalyst to 2-fluoropyridine N-oxide, and heat up for nitration to obtain 2-fluoro-4-nitropyridine N-oxide; Bromination reaction: Mix 2-fluoro-4-nitropyridine N-oxide with an acetic acid solution containing acetyl bromide or an acetic acid solution containing hydrogen bromide, and heat up for reaction to obtain 4-bromo-2-fluoropyridine N-oxide; Coupling reaction: Mix 4-bromo-2-fluoropyridine N-oxide, 1,3-bis(diphenylphosphinopropane)nickel dichloride, tetrahydroxy diboron and ethanol, add triethylamine, and heat up for reaction to obtain 2-fluoro-4-pyridineboronic acid.

2. The preparation method of 2-fluoro-4-pyridineboronic acid according to claim 1, characterized in that: In the oxidation reaction, the hydrogen peroxide is selected from 25-30% hydrogen peroxide.

3. The preparation method of 2-fluoro-4-pyridineboronic acid according to claim 1, characterized in that: In the oxidation reaction, the molar ratio of 2-fluoropyridine, acetic acid, concentrated sulfuric acid to hydrogen peroxide is 1: 1.45-1.55: 0.8-1.0: 1.5-2.

0.

4. The preparation method of 2-fluoro-4-pyridineboronic acid according to claim 1, characterized in that: In the nitration reaction, the nitrating agent is selected from the combination of concentrated sulfuric acid / fuming nitric acid or fuming sulfuric acid / potassium nitrate.

5. The preparation method of 2-fluoro-4-pyridineboronic acid according to claim 4, characterized in that: In the oxidation reaction and the nitration reaction, the concentrated sulfuric acid is selected from 98% concentrated sulfuric acid.

6. The preparation method of 2-fluoro-4-pyridineboronic acid according to claim 4, characterized in that: In the nitration reaction, the molar ratio of 2-fluoro-4-nitropyridine N-oxide, fuming nitric acid or potassium nitrate is 1: 1.3-1.

8.

7. The preparation method of 2-fluoro-4-pyridineboronic acid according to claim 1, characterized in that: In the bromination reaction, the molar ratio of 2-fluoro-4-nitropyridine N-oxide to acetyl bromide or hydrogen bromide is 1: 6.5-8.

5.

8. The preparation method of 2-fluoro-4-pyridineboronic acid according to claim 1, characterized in that: In the coupling reaction, the molar ratio of 4-bromo-2-fluoropyridine N-oxide, 1,3-bis(diphenylphosphinopropane)nickel dichloride, tetrahydroxy diboron to triethylamine is 1:0.05-0.10: 2.2-3.0: 3.0.

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