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Novel preparation method of 4-alkoxy nicotinic acid compound

A technology for hydrocarbyloxynicotinic acid and hydrocarbyloxynicotinamide, which is applied in the field of preparation of 4-hydrocarboxynicotinic acid compounds, can solve the problems of polychlorinated waste water, expensive and harsh starting materials, etc. The raw materials are simple and easy to obtain, the operation process is easy to control, and the effect of less chlorine-containing waste

Inactive Publication Date: 2020-03-13
NANJING AGRICULTURAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In view of this, it is of great significance and necessity to prepare nicotinic acid compounds quickly and efficiently. The synthesis of 4-alkoxy nicotinic acid compounds generally uses 4-halogenated nicotinic acid as the starting material, and is catalyzed by copper under high temperature conditions. Ullman reaction or strong base-mediated nucleophilic substitution reaction to prepare, the conditions used in this route are relatively harsh, the starting materials are expensive (such as the price of analytically pure 4-chloronicotinic acid is more than 10 times higher than that of nicotinic acid), in addition, it will produce More chlorine-containing wastewater or waste

Method used

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  • Novel preparation method of 4-alkoxy nicotinic acid compound
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  • Novel preparation method of 4-alkoxy nicotinic acid compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Synthesis of Niacinamide Compound C

[0038]

[0039] Weigh nicotinic acid A (1mmol), o-(4,5-dihydro-2-oxazolyl) aniline intermediate B (1mmol), and 4-dimethylaminopyridine DMAP (0.2mmol) in a 50mL eggplant-shaped bottle , dissolved in 5mL of dichloromethane (DCM), added the condensing agent EDCI (1.2mmol) under ice-cooling, stirred at room temperature, tracked and monitored the reaction progress by thin-layer chromatography (TLC), and post-treated for about 6h. Add 10 mL of water to quench the reaction, extract with dichloromethane (15 mL×3) after separation, combine the dichloromethane phases and wash with water (10 mL×2) and saturated sodium chloride solution (10 mL×2) After drying over sodium, the solvent was evaporated under reduced pressure, and after silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1), the nicotinamide compound C was obtained with a yield of 74%. LC-MS (ESI+) m / z: Calcd.for [M+H: C 15 h 14 N 3 o 2 ]:...

Embodiment 2

[0040] Example 2: Synthesis of 4-alkoxynicotinamide compound D

[0041]

[0042] Weigh nicotinamide compound C (1mmol), sodium carbonate (2mmol) and copper acetate (0.5mmol) into the reaction flask in turn, add DMSO (5mL) to it, and then add 3-methylphenol (3mmol), React at 80°C for 8 hours, cool to room temperature, add ethyl acetate (EtOAc, 20mL) to dilute, then add (28%-30%) ammonium hydroxide solution (NH 3 ·H 2 (20, 8 mL) into the reaction system, continue stirring for 20 min, extract with ethyl acetate (EtOAc, 20 mL×3), combine the organic phases and wash with saturated sodium bicarbonate solution (NaHCO 3 , 10mL×3), washed with water (10mL×3), washed with saturated sodium chloride (NaCl, 10mL×3) solution, and washed the organic phase with anhydrous sodium sulfate (NaCl 2 SO 4 ) drying, after concentration, carry out column chromatography (V 石油醚 :V 乙酸乙酯 =12:1), a white solid D was obtained with a yield of 83%.

[0043] LC-MS (ESI+) m / z: Calcd.for [M+H: C 22 h ...

Embodiment 3

[0046] Example 3: Synthesis of 4-alkoxynicotinic acid compound E

[0047]

[0048] Weigh 2-(3-trifluoromethyl)phenoxynicotinamide compound D (1mmol) and sodium hydroxide (40mmol) into a reaction flask, add 5mL of ethanol, and react at 80°C for 6h. After the reaction is complete, The organic solvent was evaporated to dryness, water was added, and extracted with ethyl acetate (EtOAc) (15mL×3), the organic phases were combined and dried by adding anhydrous sodium sulfate, concentrated and then column chromatographed (eluent: V 石油醚 :V 乙酸乙酯 =20:1), and 125 mg of o-(4,5-dihydro-2-oxazolyl)aniline intermediate B was recovered with a yield of 77.6%. Add 1M hydrochloric acid (HCl) solution to the aqueous phase, adjust the pH to 4, extract with ethyl acetate (EtOAc) (15mL×3), add anhydrous sodium sulfate to dry, concentrate and column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =2:1) ​​to obtain 4-(3-methyl)-phenoxynicotinic acid E with a yield of 77%.

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Abstract

The invention discloses a preparation method of a 4-alkoxy nicotinic acid compound represented by the following formula (I). The preparation method comprises the following steps: forming nicotinamideby using a nicotinic acid compound as an initial raw material, preparing a 4-alkoxy nicotinic acid compound by using carbon-hydrogen bond regioselective etherification as a key technology, and finallycompleting the preparation of the 4-alkoxy nicotinic acid compound through hydrolysis. The preparation method has the advantages of simple and easily available raw materials, mild process reaction conditions, convenient operation, recyclable guide group, low cost, and good industrialization prospect.

Description

technical field [0001] The invention belongs to the fields of organic synthesis and chemical industry; specifically, it refers to a preparation method of 4-alkoxynicotinic acid compounds. Background technique [0002] Niacin, also known as nicotinic acid and vitamin B3, is one of the 13 vitamins necessary for the human body, and it also includes its derivative nicotinamide or nicotinamide in the human body. Nicotinic acid and nicotinamide are components of coenzyme I and coenzyme II, involved in lipid metabolism in vivo, oxidation process of tissue respiration and carbohydrate decomposition process. Niacin has been approved by the FDA as a blood lipid-lowering drug for more than 50 years (Atherosclerosis, 2010, 210, 353-361.). Niacin and its derivatives also exhibit remarkable and diverse biological activities and pharmacological properties, such as lowering blood lipids, anti-oxidation, anti-aging, promoting detoxification metabolism, repairing DNA and food additives, etc....

Claims

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Application Information

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IPC IPC(8): C07D213/80C07D213/803C07D413/12
CPCC07D213/80C07D213/803C07D413/12
Inventor 李圣坤宋泽华王国通李伟王侠
Owner NANJING AGRICULTURAL UNIVERSITY
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