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Preparation method of hydronidone

A technology of oxynidone and pyridone, which is applied in the field of preparation of oxynidone, can solve the problems of cumbersome sewage and waste treatment, easy formation of highly toxic gas, expensive reagents, etc., and achieves suitable for large-scale production, high yield, The effect of short reaction times

Inactive Publication Date: 2020-04-14
BEIJING CONTINENT PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Chinese patent application CN2003000968 discloses a synthetic method of the compound of formula I, using 2-amino-5-methylpyridine as the starting material, the method uses Me as the phenolic hydroxyl protecting group, the reagents used for its deprotection are expensive, and the reaction process It is easy to form highly toxic gas in the medium, and the sewage waste treatment is cumbersome, the operation is cumbersome, and the yield is low (40%)
[0006] In addition, most of the methods for preparing oxynidone in the prior art involve the protection of the hydroxyl group of p-bromophenol, which needs to increase tedious reaction procedures in the industrial process, has low efficiency, low yield, and is not environmentally friendly.

Method used

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  • Preparation method of hydronidone
  • Preparation method of hydronidone

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Reaction equation:

[0032]

[0033] Feed amount and feed ratio

[0034] Feeding amount and charging ratio of table 2 embodiment 1

[0035]

[0036] 1. Preparation of crude compound of formula I

[0037] 1.1 get the sulfate compound of formula I

[0038] Put 22 kg of N-(4-methoxyphenyl)-5-methyl-2-pyridone (compound of formula II) into the reactor, then add 180 kg of 65% sulfuric acid under stirring, and start to heat up to strong reflux after heating , the external temperature is controlled at 165°C, and the internal temperature is controlled at 148°C-150°C. After about 4 hours, there is no raw material point in the spot plate test, and the raw material content is lower than 6% in the LC test. Stop heating, cool to about 60°C, and add drinking water 100 kg, continue to cool, crystallize at 5°C to 10°C for 2 hours, filter, wash the filter cake three times with 15 kg of ethyl acetate (three equal parts), put the filter cake in an evaporating dish and dry it to...

Embodiment 2

[0047] Feed amount and feed ratio

[0048] Feeding amount and charging ratio of table 3 embodiment 2

[0049]

[0050]

[0051] 2.1 Preparation of crude compound of formula I

[0052] Put 11 kilograms of N-(4-methoxyphenyl)-5-methyl-2-pyridone (compound of formula II) into the reactor, then add 180 kilograms of 50% sulfuric acid under stirring, and start to heat up to strong Reflux, the reaction temperature is controlled at 120°C to 125°C, after about 24 hours, there is no raw material point in the TLC test, and the raw material content is less than 6% in the LC test, stop heating, cool to about 60°C, add 20 kg of water, continue cooling, 5°C Crystallize at ~10°C for 2 hours, filter, wash the filter cake three times with 7.5 kg of ethyl acetate, and put the filter cake in an evaporating dish to dry. Get about 11 kilograms of the sulfate compound of formula I.

[0053]Post-treatment (neutralization and crystallization, beating and refining, refining decolorization) i...

Embodiment 3

[0055] Feed amount and feed ratio

[0056] Feeding amount and charging ratio of table 4 embodiment 3

[0057]

[0058] 3.1 Preparation of crude compound of formula I

[0059] Put 11 kilograms of N-(4-methoxyphenyl)-5-methyl-2-pyridone (compound of formula II) into the reactor, then add 62.5 kilograms of 80% sulfuric acid under stirring, and start to heat up to strong after heating. Reflux, the reaction temperature is controlled at 165°C to 170°C. After about 2 hours, there is no raw material point in the TLC test, and the raw material content is less than 6% in the LC test. Stop heating, cool to about 60°C, add 60 kg of water, continue to cool, 5°C Crystallize at ~10°C for 2 hours, filter, wash the filter cake three times with 7.5 kg of ethyl acetate, and put the filter cake in an evaporating dish to dry. Get about 10 kilograms of the sulfate compound of formula I.

[0060] Post-treatment (neutralization and crystallization, beating and refining, refining decolorizatio...

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Abstract

The invention discloses a preparation method of hydronidone. The method comprises the following steps: carrying out a heating reflux reaction on N-(4-methoxyphenyl)-5-methyl-2-pyridone and sulfuric acid to obtain a compound hydronidone shown as a formula I; and the method is simple and convenient to operate, mild in reaction condition, short in reaction time, high in yield and low in reaction rawmaterial toxicity.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a method for preparing oxynidone without toxic gas generation. Background technique [0002] Liver fibrosis is the common pathological basis in the progress of chronic liver diseases. Various chronic injuries cause liver cell degeneration and necrosis, abnormal proliferation and excessive deposition of fibrous connective tissue, wrapping regenerated liver cells, forming "pseudolobules" and destroying the original liver tissue In the end, the liver will become nodular and harden, and the liver function will be damaged or even disappear completely, forming cirrhosis. [0003] A variety of chronic diseases can cause liver fibrosis, such as chronic viral hepatitis, chronic alcoholism, cholestasis, metabolic disorders caused by congenital enzyme defects, long-term exposure to poisons and drugs, etc. Liver fibrosis and cirrhosis are one of the main reasons that affect the quality o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/64
CPCC07D213/64
Inventor 罗楹马松江陈建麒
Owner BEIJING CONTINENT PHARM CO LTD
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