Overview
5-Fluoro-2-hydroxyacetophenone, also known as 2-acetyl-4-fluorophenol, is an important pharmaceutical intermediate that can be used as a synthetic intermediate for a variety of β-blockers and has broad applications. market expectation.
Synthesis【1】【2】
The currently reported general preparation method is to use p-fluorophenol as raw material, undergo hydroxyl acylation, and then use Fries rearrangement to synthesize it. Using this method to synthesize raw materials is expensive, especially the fluorine atom on the aromatic ring is a strong electron-withdrawing group, which may have a greater impact on the acylation and rearrangement yields.
1. Using p-aminophenol as raw material, double esterification of amino group and phenolic hydroxyl group is carried out in one step, Fries rearrangement is carried out under aluminum trichloride/sodium chloride conditions, and the hydrolyzate is fluorinated and heated to obtain 5- Fluoro-2-hydroxyacetophenone finished product
Reaction principle:
The reaction equation is as follows:
Experimental steps:
(1). Preparation of 4-acetamidophenol acetate (1)
Put p-aminophenol (32.7 g, 0.3 mol) and acetic anhydride (76.5 g, 0.75 mol) into 250 mL benzene, stir and heat, and reflux at 80°C for 3 hours. After the reaction is completed, recover the solvent by distillation under reduced pressure to dryness, cool it, add 300 L of water, and precipitate the solid. Filter and dry it to obtain 55.0 g of off-white solid, with a yield of 93.0%. It can be used directly in the next reaction without purification.
(2). Preparation of 2-acetyl-4-acetamidophenol (2)
Put 1 (38.6 g, 0.2 mol), anhydrous aluminum trichloride (80 g, 0.6 mol) and sodium chloride (40 g, 0.68 mol) into the reaction flask, stir and heat to 120°C, react The mixture is in the form of a thin paste, accompanied by the release of a large amount of acidic gas; keep the reaction for 3 hours. When no more gas is released, cool the reaction mixture to 60°C, slowly add 160 mL of water to the mixture, stir vigorously, freeze, and After suction filtration and drying, 36.3 g of light yellow solid was obtained, with a yield of 94.0%.
(3). Preparation of 2-acetyl-4-aminophenol (3)
Add 2 (38.6 g, 0.2 mol) and hydrochloric acid (400 mL, 6 mol/L) into a 500 mL round-bottomed flask and maintain reflux for 6 hours. After refluxing, cool, adjust the pH value to 6-7, precipitate the solid, dry and weigh to obtain 18.9 g of solid, with a yield of 75.6%.
(4). Preparation of 5-fluoro-2-hydroxyacetophenone (4)
Add 3 (30.2 g, 0.2 mol) to excess hydrogen fluoride (11.4 g, 0.6 mol), lower the temperature to -5°C, and gradually add solid sodium nitrite (17.3 g, 0.2 mol). The reaction temperature is 0 -5℃, after the addition, keep the reaction for 5 hours; then gradually raise the temperature to 40℃ for thermal decomposition; after complete decomposition, adjust the pH value to 6-7, and steam distillate to obtain 25.1 g of white crystal product, yield 82 %.
Discussion Analysis
(1). Selection of acetylation reagents in the preparation of intermediate 1
Using glacial acetic acid as the acetylation reagent takes a long reaction time and the yield is not high; using acetyl chloride as the acetylation reagent has a higher yield, but acetyl chloride is not easy to store and can easily cause the container interface to sinter; choose acetic anhydride As an acetylation reagent, it is ideal. When using acetyl chloride and acetic anhydride, the time consumption is equivalent, and the yield is also equivalent, but acetic anhydride is more convenient to store and use.
(2). Selection of co-solvent in the preparation of intermediate 2
The Fries rearrangement of phenol acetate is a key step in the entire reaction. Sodium chloride is a more suitable co-solvent, which lowers the reaction temperature, and the product has a better color. Because of its good water solubility, it is easy to remove, and the yield is high. During the reaction process, it was also found that the dryness of intermediate product 2 and the moisture content in sodium chloride have a greater impact on the Fries rearrangement. 2 needs to be relatively dry and the moisture content of sodium chloride should be as low as possible.
You can dry it properly before the reaction. The yield is better when the reaction temperature is 120°C.
(3). Selection of hydrolysis conditions in the preparation of intermediate 3
In the process of preparing intermediate 3, you can choose to hydrolyze under alkaline or acidic conditions. Hydrolysis of intermediate product 3 under acidic conditions has a higher yield, and the optimized conditions are n (2):n (hydrochloric acid) = 1:12, and the reaction time is 6 h.
This route synthesizes 5-fluoro-2-hydroxyacetophenone. The raw materials are cheap and have stronger acylation ability than those reported in the literature. The high double esterification yield makes the reaction proceed smoothly and the amino group is protected at the same time. The yield can reach 93.0 %; Fries rearrangement uses sodium chloride as co-solvent, the reaction is easy, the crystal form is good, and the yield can reach 94.0%; Hydrolysis reaction under acidic conditions for 6 hours, the yield is 75.6%; Fluorine diazotization yield is 82.0%; Total yield The rate is 54.5%. The raw materials of the entire synthesis process are cheap, the reaction conditions are relatively mild, and the yield is high, so it has industrial production and application value.
2. One-pot synthesis is a green chemical method that is easy to operate and can be conveniently used in large-scale chemical production
Stir the mixture of 4.6 g (50mmol) p-fluorophenol and 45g (56mmol) chlorinated ethylene at room temperature for 0.5h, and quickly add anhydrous AlCl3 to the mixture at 120 degrees. Stirring was continued for 2-3 hours, and the final product of the reaction was determined by thin layer chromatography, after which the reaction product was cooled to room temperature. After injecting ice water into the final product, filter out the yellow precipitate, rinse with cold water until neutral, air-dry and weigh the yield to 88.9%. The optimal molar ratio of p-fluorophenol to AlCl3 is about 1.00:1.86. The excess catalyst AlCl3 and p-fluorophenol complex hinders the rearrangement reaction, resulting in a reduction in yield.
This method is very useful for the synthesis of 5-fluoro-2-hydroxy-acetophenone.Improvements were made to combine the original two-step reaction into one step, eliminating the cumbersome separation and purification of the intermediate product ester, greatly shortening the reaction time, making the operation simple and suitable for industrial production.
References
[1] Yu Weiguo, Shi Haibo, Zhao Xiangkui, Preparation of 5-fluoro-2-hydroxyacetophenone, Fine Chemical Intermediates, 2009.04, page 45
[2] Sheng Ruilong, Yang Yunxu, Zhang Junping, Yu Anguang, Wang Wuwei, Wang Naixing, Zhao Jia, “One-pot method” synthesis of 5-fluoro-2-hydroxy-acetophenone, Synthetic Chemistry, 2005.01, page 87
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