Preparation method of 2,4-ditertbutyl-5-aminophenol

A technology of di-tert-butyl and aminophenol is applied in the preparation of amino hydroxy compounds, the preparation of organic compounds, the preparation of carboxylic acid amides, etc. Good economy, good application prospects, simple reaction conditions and raw materials

Active Publication Date: 2016-08-24
SHANGHAI FAMO BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the yield of the first step of bromination reaction is not ideal, about 66%, and it needs to be separated and purified by column chromatography; in addition, the last step of hydroge...

Method used

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  • Preparation method of 2,4-ditertbutyl-5-aminophenol
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  • Preparation method of 2,4-ditertbutyl-5-aminophenol

Examples

Experimental program
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Embodiment 1

[0038] The preparation of embodiment 1 N-(3-hydroxyphenyl) acetamide (1)

[0039] Mix 0.1mol m-aminophenol (10.9g) with 60mL acetic acid, stir at 60°C; draw 0.12mol acetic anhydride (12.2g, 11.34mL) with a needle, and add acetic anhydride dropwise within 15min while stirring at 60°C in the mixture.

[0040] After reacting for 2 hours, the reaction solution was cooled to room temperature, poured into 300 mL of water while stirring, and continued to stir after pouring, and a white solid appeared. Stir overnight (8-12 hr), filter with suction, and dry to obtain 13.8 g of white solid with a yield of 91%.

[0041] 1 H NMR(400MHz,DMSO-d6):δ2.01(s,3H),6.42(m,1H),6.92(m,1H),7.04(m,1H),7.18(m,1H),9.33(s ,1H),9.78(s,1H).ESI-MS(m / z)152.2[M+H] + .

Embodiment 2

[0042] Example 2 Preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)acetamide (1)

[0043] Weigh N-(3-hydroxyphenyl)acetamide (12.5g, 0.083mol) prepared in Example 1 and place it in an eggplant-shaped flask, add 300mL toluene, stir and dissolve; then add tert-butanol (23.1mL, 17.9 g, 0.25mol), and 99.8wt% concentrated sulfuric acid (16.3g, 9.0mL, 0.166mmol) was added dropwise within 10min with stirring.

[0044] Stirring was continued at room temperature (10-30°C) for 12 hours, and an off-white solid was generated, which was filtered by suction. Add this solid to 200 mL of water, add saturated NaHCO 3 The pH of the solution was adjusted to 6, suction filtered, washed with water until neutral (pH=6.8-7.2), and a white solid was obtained, which was dried to obtain 17.0 g of the solid, with a yield of 78%.

[0045] 1H NMR(400MHz,DMSO-d6):δ1.25(s,9H),1.33(s,9H),1.99(s,3H),6.45(s,1H),7.11(s,1H),9.00(s ,1H),9.16(s,1H).ESI-MS(m / z)264.3[M+H] + ,527.4[2M+H] + ,549.4[2M+Na] + ...

Embodiment 3

[0046] Example 3 Preparation of 2,4-di-tert-butyl-5-aminophenol (1)

[0047] Add 0.038mol N-(2,4-di-tert-butyl-5-hydroxyphenyl)acetamide (10.0g) into ethanol-water solution (150mL) with a volume concentration of 80%, stir, and add 9.7 mol / L hydrochloric acid 20.6mL (0.2mol), and then reflux for 12h. Part of the solvent (about 80 mL) was distilled off under reduced pressure, and the remaining reactant was poured into 100 mL of ice water and stirred to form an off-white solid, which was suction filtered and dried. The solid was mixed with 80mL of water, stirred, and 20% sodium hydroxide was added to adjust the pH to 6 to form an off-white solid, which was suction filtered and dried. The crude product was recrystallized and purified with 70 mL of ethyl acetate / petroleum ether mixture (volume ratio of ethyl acetate to petroleum ether: 1:1) to obtain 7.4 g of a white solid product with a yield of 88%.

[0048] 1 H NMR (400MHz, DMSO-d 6 ): δ1.32(s,9H),1.34(s,9H),6.79(s,1H),7...

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Abstract

The invention relates to the technical field of organic synthesis and bulk pharmaceutical chemical intermediate preparation, in particular to a preparation method of cystic fibrosis treatment new drug ivacaftor key intermediate 2,4-ditertbutyl-5-aminophenol. The method comprises the steps of 1, acetylation, wherein (A) m-aminophenol or (B) acetic anhydride or acetyl chloride is used as a raw material, and a reaction is carried out to prepare N-(3-hydroxyphenyl)acetamide; 2, tertiary butyl substituting, wherein N-(3-hydroxyphenyl) acetamide and tert butyl alcohol are catalyzed by concentrated sulfuric acid to prepare N-(2,4-ditertbutyl-5-hydroxy phenyl)acetamide; 3, deacetylation, wherein the N-(2,4-ditertbutyl-5-hydroxy phenyl)acetamide is hydrolyzed by acid or alkali to obtain 2,4-ditertbutyl-5-aminophenol. According to the synthesis process, raw materials are easy to obtain, reaction conditions are mold, postprocessing is easy and convenient, amplified preparation is promoted, and the yield is high.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and the preparation of raw material drug intermediates, in particular to the preparation of a key intermediate of 2,4-di-tert-butyl-5-aminophenol, a new drug for the treatment of cystic fibrosis, ivacaftor. Preparation. Background technique [0002] Ivacaftor (ivacaftor) is a drug developed by Vertex of the United States for the treatment of rare cystic fibrosis. It was approved by the US Food and Drug Administration (FDA) on January 31, 2012. The trade name is Kalydeco . The drug is used to treat a rare form of cystic fibrosis (CF) caused by the G551D mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and is suitable for patients aged 6 years and above. Its chemical name structure is as shown in formula I: [0003] [0004] 2,4-di-tert-butyl-5-aminophenol is the key intermediate raw material for the preparation of ivacaftor, and its chemical structure...

Claims

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Application Information

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IPC IPC(8): C07C215/76C07C213/02
CPCC07C213/02C07C231/02C07C231/12C07C215/76C07C233/25
Inventor 江锣斌茆勇军朱春平朱国庆陈天昀王晗
Owner SHANGHAI FAMO BIOTECH CO LTD
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