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Preparation method of 4-hydroxyquinoline-3-carboxylic acid

A technology of hydroxyquinoline and o-nitrobenzoic acid, applied in the direction of organic chemistry, can solve the problems of high production cost and environmental pollution of 4-hydroxyquinoline-3-carboxylic acid, achieve good application prospects, reduce costs, avoid Effect of poorly soluble impurities

Active Publication Date: 2016-12-07
SHANGHAI UNIV OF ENG SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the production cost of 4-hydroxyquinoline-3-carboxylic acid is high by high temperature ring method, and there is an environmental pollution problem.

Method used

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  • Preparation method of 4-hydroxyquinoline-3-carboxylic acid
  • Preparation method of 4-hydroxyquinoline-3-carboxylic acid
  • Preparation method of 4-hydroxyquinoline-3-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1 Preparation of 3-(2-nitrophenyl)-3-oxopropionic acid ethyl ester (1)

[0036] A: Mix o-nitrobenzoic acid (3.0 g, 18 mmol) and 30 mL of acetonitrile, stir at 20° C., add N,N-carbonyldiimidazole (3.2 g, 19.8 mmol) in batches, and react for 4 hours. The solution is yellowish and clear.

[0037] B: Take a three-necked flask and add monoethyl malonate potassium salt (15.3 g, 90 mmol) into 60 mL of acetonitrile, and stir. Install the thermometer, use about 15min to MgCl 2 (1.85 g, 19.44 mmol) was added in portions. The temperature of the reaction solution rose slightly. After the addition, it was stirred at 35°C for 30min, then cooled to 25°C, and triethylamine (5.46g, 54mmol, 7.52mL) was slowly added dropwise under stirring. With the addition of triethylamine, the reaction solution became thicker and appeared White lumps. Stir for 30 min after addition.

[0038] C: Add the reaction solution in A to B, and the temperature rises slightly. Then it was stirred a...

Embodiment 2

[0041] Example 2 Preparation of ethyl 3-(2-aminophenyl)-3-oxopropionate (1)

[0042] Dissolve ethyl 3-(2-nitrophenyl)-3-oxopropionate (2.4 g, 0.01 mol) in methanol (50 mL), and add 0.5 g of catalyst Raney nickel; The reaction was stirred at 20°C for 8 hours, the catalyst was filtered out through diatomaceous earth, and concentrated to obtain 2.0 g of ethyl 3-(2-aminophenyl)-3-oxopropionate with a yield of 96% as a brown liquid.

[0043] 1 H NMR (400MHz, CDCl 3 ):δ=1.31(t,J=7.2Hz,3H),3.44(s,2H),4.24(q,J=7.2Hz,2H),6.68(m,2H),7.30(m,1H),7.86 (m,1H),8.77(brs,2H).MS(ESI):m / z=207.0[M–H] – .

Embodiment 3

[0044] The preparation of embodiment 3 4-hydroxyquinoline-3-formic acid ethyl ester (1)

[0045] 3-(2-aminophenyl)-3-oxopropanoic acid ethyl ester (1.8g, 0.0087mol) was dissolved in toluene (30mL), and N,N-dimethylformamide dimethyl acetal was added thereto (2.9g, 0.025mol), reacted at reflux temperature for 8h; the reaction solution was cooled to 20°C, the precipitated solid was filtered and washed with a mixture of equal volumes of ethanol and water (2mLx2 times), dried at 50°C, washed with 15mL ethyl acetate Recrystallize and purify the mixed liquid with an equal volume of petroleum ether to obtain 1.3 g of ethyl 4-hydroxyquinoline-3-carboxylate, with a yield of 70%, as an off-white solid.

[0046] 1 H NMR (400MHz, DMSO-d 6 ):δ=1.29(t,J=7.2Hz,3H),4.22(q,J=7.2Hz,2H),7.42(m,1H),7.62(m,1H),7.71(m,1H),8.16 (m,1H),8.55(s,1H),12.31(s,1H).MS(ESI):m / z=218.2[M+H] + .

[0047] HPLC: Column: InertSustain C18 (250mm×4.6mm×5μm); Detection wavelength: 220nm; Flow rate: 0.8mL / min; Co...

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Abstract

The invention relates to the technical field of organic synthesis and bulk drug intermediates, and concretely relates to a preparation method of a key intermediate 4-hydroxyquinoline-3-carboxylic acid of a new medicine ivacaftor for treating cystic fibrosis. The preparation method comprises the following steps: 1, carrying out a condensation reaction: reacting o-nitrobenzoic acid, potassium monoethyl malonate and N,N-carbonyldiimidazole to prepare ethyl 3-(2-nitrophenyl)-3-oxopropanoate; 2, carrying out a reduction reaction: carrying out catalytic hydrogenation reduction on ethyl 3-(2-nitrophenyl)-3-oxopropanoate to prepare ethyl 3-(2-aminophenyl)-3-oxopropanoate; 3, carrying out a cyclization reaction: carrying out nucleophilic addition and cyclization reaction on ethyl 3-(2-aminophenyl)-3-oxopropanoate and N,N-dimethyl formamide dimethyl acctel to obtain ethyl 4-hydroxyquinoline-3-carboxylate; and 4, carrying out a hydrolysis reaction: carrying out the hydrolysis reaction on ethyl 4-hydroxyquinoline-3-carboxylate to obtain 4-hydroxyquinoline-3-carboxylic acid. The preparation method has the advantages of easily available raw materials, mild reaction conditions, simplicity and convenience in post-treatment, suitableness for amplified preparation, and high yield.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and preparation of bulk drug intermediates, in particular to a method for preparing a key intermediate 4-hydroxyquinoline-3-carboxylic acid of ivacaftor, a new drug for treating cystic fibrosis. 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 ivacaftor chemical name structure is shown in formula 1: [0003] [0004] 4-Hydroxyquinoline-3-carboxylic acid is a key intermediate raw material for the preparation of ivacaftor, and its chemical structure is shown in for...

Claims

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Application Information

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IPC IPC(8): C07D215/56
CPCC07D215/56
Inventor 张建超茆勇军王娇江锣斌朱国庆王晗
Owner SHANGHAI UNIV OF ENG SCI
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