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A kind of synthesis method of (rs)-2-(10-hydrogen-9-oxa-1-azanthracen-6-yl) propionic acid degradation impurity

A technology of ethyl and nicotinic acid, which is applied in the direction of organic chemistry, can solve the problems of cumbersome synthesis process and difficulty in obtaining it, and achieve the effects of high yield, stable quality and mild reaction conditions

Active Publication Date: 2016-01-06
WUHAN LEADPHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] This route obtains 7-ethyl-5-oxo- 5H-[1]benzopyrano[2,3-b]pyridine, however, the reaction yield was only 3%; the starting material 2-amino-6-ethyl-4-oxochroman-3- Formaldehyde has no market supply, and the synthesis process is cumbersome and difficult to obtain

Method used

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  • A kind of synthesis method of (rs)-2-(10-hydrogen-9-oxa-1-azanthracen-6-yl) propionic acid degradation impurity
  • A kind of synthesis method of (rs)-2-(10-hydrogen-9-oxa-1-azanthracen-6-yl) propionic acid degradation impurity
  • A kind of synthesis method of (rs)-2-(10-hydrogen-9-oxa-1-azanthracen-6-yl) propionic acid degradation impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1. Preparation of 2-(4-ethylphenoxy)nicotinic acid

[0033] In a dry 100mL round-bottomed flask, add 30mL of anhydrous methanol and 6.1g of sodium methoxide, add 24g of p-ethylphenol under stirring at room temperature, continue stirring for 5min after addition, then add 8.8g of 2-chloronicotinic acid, and reflux reaction 1h; distill methanol off, raise the temperature to 180-190°C to continue the reaction for 1h, stop heating, and when the temperature of the reaction solution drops to 100°C, pour it into 60mL of ice water, extract with ethyl acetate, and wash the water layer with concentrated hydrochloric acid (37wt %, the same as in the following examples) Adjust the pH value to 2, a large amount of white solid precipitated out, filtered with suction, washed the filter cake with a small amount of water, and dried to obtain 8.2 g of white solid, with a yield of 60%. 1 H-NMR(d-DMSO,400MHz)δ(ppm):1.19(m,3H);2.1(m,2H);6.99(d,2H,J=8.4Hz);7.21(m,3H);8.24( m,2H); 13.21(s,1H)...

Embodiment 2

[0037] 1. Preparation of 2-(4-ethylphenoxy)nicotinic acid

[0038] In a 100mL round bottom flask, add 30mL of methanol and 4.5g of sodium hydroxide, add 24g of p-ethylphenol under stirring at room temperature, continue stirring for 5min after addition, then add 8.8g of 2-chloronicotinic acid, and reflux for 1h; Remove methanol, raise the temperature to 180-190°C to continue the reaction for 1 hour, stop heating, and when the temperature of the reaction solution drops to 100°C, pour it into 60mL of ice water, extract with ethyl acetate, and adjust the pH value of the water layer to 2 with concentrated hydrochloric acid. , a large amount of white solid was precipitated, suction filtered, the filter cake was washed with a small amount of water, and dried to obtain 7.1 g of white solid, with a yield of 52%, and its structural formula was confirmed by H NMR spectrum.

[0039] 2. Preparation of 7-ethyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine

[0040] In a dry 250mL round bottom flas...

Embodiment 3

[0042] 1. Preparation of 2-(4-ethylphenoxy)nicotinic acid

[0043] In a dry 1L round-bottomed flask, add 300mL of anhydrous methanol and 60g of sodium methoxide, add 240g of p-ethylphenol under stirring at room temperature, continue stirring for 5min after addition, then add 90g of 2-chloronicotinic acid, and reflux for 1h. Distill methanol off, raise the temperature to 180-190°C and continue the reaction for 1 hour, stop heating, and when the temperature of the reaction solution drops to 100°C, pour it into 600mL of ice water, extract with ethyl acetate, and adjust the pH value of the water layer with concentrated hydrochloric acid to 2. A large amount of white solid was precipitated, filtered with suction, the filter cake was washed with a small amount of water, and dried to obtain 87 g of white solid, with a yield of 64%. Its structural formula was confirmed by H NMR spectrum.

[0044] 2. Preparation of 7-ethyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine

[0045] In a dry 3L ro...

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Abstract

The invention relates to the technical field of organic compounds and particularly discloses a synthesis method for 7-ethyl-5-oxo-5H-[1]-benzopyran [2,3-b] pyridine which is an (RS)-2-(10-hydrogen-9-oxa-1-acridine-6-group) propionic acid degradation impurity. According to the method, the 7-ethyl-5-oxo-5H-[1]-benzopyran [2,3-b] pyridine is prepared by taking paraethyl phenol, 2-chloronicotinic acid and the like as raw materials through a Williamson reaction, a cyclization reaction and the like. The synthesis method disclosed by the invention has the advantages that the synthesis route is short, the raw materials can be simply and easily obtained, reaction conditions are mild, high temperature, high pressure or a special catalyst is not needed, the operation is simple, the yield is high, and the quality is stable. The synthesis method is suitable for volume production.

Description

technical field [0001] The invention relates to the technical field of synthesis of organic compounds, in particular to a (RS)-2-(10-hydrogen-9-oxa-1-azanthracene-6-yl) propionic acid degradation impurity 7-ethyl-5- Synthetic method of oxo-5H-[1]benzopyrano[2,3-b]pyridine. Background technique [0002] (RS)-2-(10-hydrogen-9-oxa-1-azanthracen-6-yl)propionic acid is a non-steroidal anti-inflammatory analgesic drug developed by Welfide Company (formerly Gifford Pharmaceutical Co., Ltd., now Mitsubishi Pharmaceuticals). Senshou Pharmaceutical Co., Ltd. developed it as eye drops and launched it in Japan in 1988. It has significant analgesic, anti-inflammatory, antipyretic and anti-rheumatic effects. Its effect is stronger than aspirin, indomethacin, and ibuprofen, and its mechanism of action is to inhibit prostaglandin synthase, thereby blocking the effect of inflammatory mediators. The structure is as follows: [0003] [0004] It has been reported in the literature that ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/052
Inventor 张茂王革陈蔚江
Owner WUHAN LEADPHARM TECH CO LTD