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CN112225689A - Preparation method of 3-amino-2-hydroxypyridine - Google Patents

Preparation method of 3-amino-2-hydroxypyridine Download PDF

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Publication number
CN112225689A
CN112225689A CN202011290175.2A CN202011290175A CN112225689A CN 112225689 A CN112225689 A CN 112225689A CN 202011290175 A CN202011290175 A CN 202011290175A CN 112225689 A CN112225689 A CN 112225689A
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Prior art keywords
solution
hydroxypyridine
reaction
solid
mixing
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CN202011290175.2A
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Chinese (zh)
Inventor
廖明
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Nanjing Mairuimi Biotechnology Co ltd
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Nanjing Mairuimi Biotechnology Co ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72Nitrogen atoms
    • C07D213/73Unsubstituted amino or imino radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention discloses a preparation method of 3-amino-2-hydroxypyridine, which comprises the following steps: mixing 2-chloropyridine with an alcohol solution, adding an alkaline alcohol solution, and reacting to obtain a solution I; adjusting the solution I to obtain a solution II; carrying out mixed reaction on the solution II and a hydrobromic acid solution to obtain 2-hydroxypyridine; mixing 2-hydroxypyridine with concentrated sulfuric acid, adding fuming nitric acid at the temperature of 0 ℃, reacting for a period of time, and filtering to obtain a solid I; the preparation method of the 3-amino-2-hydroxypyridine has the advantages of simple synthesis process, few steps, remarkably improved product yield and mild reaction conditions, thereby saving production cost and having higher industrial applicable value.

Description

Preparation method of 3-amino-2-hydroxypyridine
Technical Field
The invention relates to the technical field of compound preparation, in particular to a preparation method of 3-amino-2-hydroxypyridine.
Background art:
pyridine is a six-membered heterocyclic compound containing one nitrogen atom, i.e., one carbon of the benzene molecule is substituted with nitrogen, and it has many specific pharmacological and structural properties. Pyridine derivatives are widely present in nature, and many of them have specific pharmacological effects. The molecular formula of the 3-amino-2-hydroxypyridine is C5H6N2O, molecular weight 110.11, melting point 170-. The 3-amino-2-hydroxypyridine is an irritant substance, can be used in the pharmaceutical industry, and can be used as an intermediate of anti-AIDS drugs. The traditional 3-amino-2-hydroxypyridine synthesis method has the disadvantages of expensive raw materials, high production cost, complex synthesis process and high temperature in the synthesis process, and is easy to cause danger.
Disclosure of Invention
The invention aims to provide a preparation method of 3-amino-2-hydroxypyridine, which aims to overcome the defects of complex process and high temperature which are easy to cause danger in the prior art.
A process for the preparation of 3-amino-2-hydroxypyridine, comprising the steps of:
mixing 2-chloropyridine with an alcohol solution, adding an alkaline alcohol solution, and reacting to obtain a solution I;
adjusting the solution I to obtain a solution II;
carrying out mixed reaction on the solution II and a hydrobromic acid solution to obtain 2-hydroxypyridine;
mixing 2-hydroxypyridine with concentrated sulfuric acid, adding fuming nitric acid at the temperature of 0 ℃, reacting for a period of time, and filtering to obtain a solid I;
and mixing the solid I with DMF, heating to 60-70 ℃, adding a catalyst and hydrogen for continuous reaction, and washing by diethyl ether to obtain a solid II, namely the 3-amino-2-hydroxypyridine.
Further, the method for obtaining the solution I by mixing 2-chloropyridine with an alcohol solution and adding an alkaline alcohol solution to react comprises the following steps:
mixing a proper amount of 2-chloropyridine with an alcohol solution;
after mixing evenly, adding an alkaline alcohol solution, adjusting the temperature to 65-75 ℃, and reacting for 10-15 hours;
wherein the molar ratio of the 2-chloropyridine to the alkaline alcoholic solution is 1: 2-20.
Further, the method for obtaining the second solution after the first solution is subjected to the adjustment treatment comprises the following steps:
filtering the obtained solution I to remove the solvent to obtain a residue;
water was added to the residue to dissolve, and an acidic substance was added to adjust the pH to 4-7.
Further, the method for obtaining the 2-hydroxypyridine by mixing and reacting the solution II with the hydrobromic acid solution comprises the following steps:
mixing the solution II with hydrobromic acid with the concentration of 70-90 ℃, and stirring for 7-15 hours;
after the reaction is finished, cooling and filtering out solid to obtain 2-hydroxypyridine;
wherein the concentration of hydrobromic acid is 30-40 v/v%.
Further, the method for mixing 2-hydroxypyridine with concentrated sulfuric acid, adding fuming nitric acid at 0 ℃, reacting for a period of time, and filtering to obtain a solid I comprises the following steps:
adding 2-hydroxypyridine into a single-mouth bottle, adding concentrated sulfuric acid, stirring for dissolving, and cooling to 0 ℃ in an ice salt bath;
after the temperature reaches, slowly dropwise adding fuming nitric acid, and stirring for half an hour after the adding;
and slowly pouring the reaction liquid into ice, stirring, separating out solids, filtering, washing and drying to obtain a first solid.
Further, the method for preparing the solid II, namely the 3-amino-2-hydroxypyridine comprises the following steps of mixing the solid I with DMF, heating to 60-70 ℃, adding a catalyst and hydrogen for continuous reaction, and washing with diethyl ether to obtain the solid II:
adding the prepared solid I into a single-mouth bottle, adding DMF oil bath, heating to the external temperature of 60-70 ℃, and dissolving under stirring;
adding a catalyst under the protection of nitrogen; blowing hydrogen into the hydrogen balloon, pumping out other gases by the three-way pumping head to form a hydrogen atmosphere, keeping the temperature at 60-70 ℃, and stirring for reacting for 5-10 hours;
after the reaction is finished, washing the obtained product by diethyl ether, separating out solid and filtering to obtain the target product 3-amino-2-hydroxypyridine.
Further, the alcohol solution comprises one or more of methanol, ethanol, propanol and tert-butanol.
Further, the acidic substance comprises one or more of acetic acid, formic acid, propionic acid, dilute sulfuric acid, hydrochloric acid and phosphoric acid.
Further, the basic alcohol solution includes an alcohol solution of sodium tert-butoxide or a methanol solution of sodium methoxide.
Further, the catalyst was 10% Pd/C.
The invention has the advantages that: according to the preparation method of the 3-amino-2-hydroxypyridine, 2-chloropyridine is used as a starting material, the synthesis process is simple, the number of steps is small, the yield of the product is remarkably improved, the reaction conditions are mild, the production cost is saved, and the industrial applicable value is higher.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.
A process for the preparation of 3-amino-2-hydroxypyridine, comprising the steps of:
the method comprises the following steps: mixing 2-chloropyridine with an alcohol solution, adding an alkaline alcohol solution, and reacting to obtain a solution I;
mixing a proper amount of 2-chloropyridine with an alcohol solution;
after mixing evenly, adding an alkaline alcohol solution, adjusting the temperature to 65-75 ℃, and reacting for 10-15 hours;
wherein the molar ratio of the 2-chloropyridine to the alkaline alcoholic solution is 1: 2-20.
The alcohol solution comprises one or more of methanol, ethanol, propanol and tert-butanol.
The alkaline alcohol solution comprises an alcohol solution of sodium tert-butoxide or a methanol solution of sodium methoxide.
Step two: adjusting the solution I to obtain a solution II;
filtering the obtained solution I to remove the solvent to obtain a residue;
water was added to the residue to dissolve, and an acidic substance was added to adjust the pH to 4-7.
The acidic substance comprises one or more of acetic acid, formic acid, propionic acid, dilute sulfuric acid, hydrochloric acid and phosphoric acid.
Step three: carrying out mixed reaction on the solution II and a hydrobromic acid solution to obtain 2-hydroxypyridine;
mixing the solution II with hydrobromic acid with the concentration of 70-90 ℃, and stirring for 7-15 hours;
after the reaction is finished, cooling and filtering out solid to obtain 2-hydroxypyridine;
wherein the concentration of hydrobromic acid is 30-40 v/v%.
Step four: mixing 2-hydroxypyridine with concentrated sulfuric acid, adding fuming nitric acid at the temperature of 0 ℃, reacting for a period of time, and filtering to obtain a solid I;
adding 2-hydroxypyridine into a single-mouth bottle, adding concentrated sulfuric acid, stirring for dissolving, and cooling to 0 ℃ in an ice salt bath;
after the temperature reaches, slowly dropwise adding fuming nitric acid, and stirring for half an hour after the adding;
and slowly pouring the reaction liquid into ice, stirring, separating out solids, filtering, washing and drying to obtain a first solid.
Step five: and mixing the solid I with DMF, heating to 60-70 ℃, adding a catalyst and hydrogen for continuous reaction, and washing by diethyl ether to obtain a solid II, namely the 3-amino-2-hydroxypyridine.
Adding the prepared solid I into a single-mouth bottle, adding DMF oil bath, heating to the external temperature of 60-70 ℃, and dissolving under stirring;
adding a catalyst under the protection of nitrogen; blowing hydrogen into the hydrogen balloon, pumping out other gases by the three-way pumping head to form a hydrogen atmosphere, keeping the temperature at 60-70 ℃, and stirring for reacting for 5-10 hours;
after the reaction is finished, washing the obtained product by diethyl ether, separating out solid and filtering to obtain a target product 3-amino-2-hydroxypyridine; wherein the catalyst is 10% Pd/C.
The technical scheme of the invention is specifically illustrated by the following embodiments:
example 1
Mixing 1mol of 2-chloropyridine with methanol, adding 2mol of sodium tert-butoxide alcoholic solution, adjusting the temperature to 65 ℃, and reacting for 10 hours; after the reaction is finished, filtering to remove the solvent to obtain a residue, adding water into the residue for dissolving, adding hydrochloric acid to adjust the pH to 4, adding 30 v/v% hydrobromic acid for mixing, keeping the reaction temperature at 70 ℃, and stirring for 7 hours; after the reaction is finished, cooling and filtering out a solid, adding concentrated sulfuric acid into the solid, stirring and dissolving, cooling to 0 ℃ in an ice salt bath, slowly dropwise adding fuming nitric acid, and stirring for half an hour after the addition is finished;
slowly pouring the reaction solution into ice, stirring, separating out a solid, filtering, washing, drying to obtain a first solid, adding the prepared first solid into a single-mouth bottle, adding DMF oil bath, heating to an external temperature of 60 ℃, and dissolving under stirring; adding 10% Pd/C under the protection of nitrogen; hydrogen is pumped into the hydrogen balloon, other gases are pumped out by the three-way pumping head to form a hydrogen atmosphere, the temperature is kept at 60 ℃, and the stirring reaction is carried out for 5 hours;
after the reaction is finished, washing the obtained product by diethyl ether, separating out solid and filtering to obtain the target product 3-amino-2-hydroxypyridine.
Example 2
Mixing 1mol of 2-chloropyridine with ethanol, adding 2mol of sodium tert-butoxide ethanol solution, adjusting the temperature to 70 ℃, and reacting for 10 hours; after the reaction is finished, filtering to remove the solvent to obtain a residue, adding water into the residue for dissolving, adding dilute sulfuric acid to adjust the pH to 5, adding 35 v/v% hydrobromic acid for mixing, keeping the reaction temperature at 80 ℃, and stirring for 10 hours; after the reaction is finished, cooling and filtering out a solid, adding concentrated sulfuric acid into the solid, stirring and dissolving, cooling to 0 ℃ in an ice salt bath, slowly dropwise adding fuming nitric acid, and stirring for half an hour after the addition is finished;
slowly pouring the reaction solution into ice, stirring, separating out a solid, filtering, washing, drying to obtain a first solid, adding the prepared first solid into a single-mouth bottle, adding DMF oil bath, heating to the external temperature of 65 ℃, and dissolving under stirring; adding 10% Pd/C under the protection of nitrogen; hydrogen is pumped into the hydrogen balloon, other gases are pumped out by the three-way pumping head to form a hydrogen atmosphere, the temperature is kept at 65 ℃, and the stirring reaction is carried out for 8 hours;
after the reaction is finished, washing the obtained product by diethyl ether, separating out solid and filtering to obtain the target product 3-amino-2-hydroxypyridine.
Example 3
Mixing 1mol of 2-chloropyridine with ethanol, adding 2mol of sodium methoxide alcohol solution, adjusting the temperature to 75 ℃, and reacting for 10 hours; after the reaction is finished, filtering to remove the solvent to obtain a residue, adding water into the residue for dissolving, adding dilute sulfuric acid to adjust the pH to 5, adding 40 v/v% hydrobromic acid for mixing, keeping the reaction temperature at 90 ℃, and stirring for 15 hours; after the reaction is finished, cooling and filtering out a solid, adding concentrated sulfuric acid into the solid, stirring and dissolving, cooling to 0 ℃ in an ice salt bath, slowly dropwise adding fuming nitric acid, and stirring for half an hour after the addition is finished;
slowly pouring the reaction solution into ice, stirring, separating out a solid, filtering, washing, drying to obtain a first solid, adding the prepared first solid into a single-mouth bottle, adding DMF oil bath, heating to an external temperature of 70 ℃, and dissolving under stirring; adding 10% Pd/C under the protection of nitrogen; hydrogen is pumped into the hydrogen balloon, other gases are pumped out by the three-way pumping head to form a hydrogen atmosphere, the temperature is kept at 70 ℃, and the stirring reaction is carried out for 10 hours;
after the reaction is finished, washing the obtained product by diethyl ether, separating out solid and filtering to obtain the target product 3-amino-2-hydroxypyridine.
It will be appreciated by those skilled in the art that the invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The embodiments disclosed above are therefore to be considered in all respects as illustrative and not restrictive. All within the scope of or equivalent to the present invention.

Claims (10)

1. A method for preparing 3-amino-2-hydroxypyridine, comprising the steps of:
mixing 2-chloropyridine with an alcohol solution, adding an alkaline alcohol solution, and reacting to obtain a solution I;
adjusting the solution I to obtain a solution II;
carrying out mixed reaction on the solution II and a hydrobromic acid solution to obtain 2-hydroxypyridine;
mixing 2-hydroxypyridine with concentrated sulfuric acid, adding fuming nitric acid at the temperature of 0 ℃, reacting for a period of time, and filtering to obtain a solid I;
and mixing the solid I with DMF, heating to 60-70 ℃, adding a catalyst and hydrogen for continuous reaction, and washing by diethyl ether to obtain a solid II, namely the 3-amino-2-hydroxypyridine.
2. The process according to claim 1, wherein the reaction is carried out in the presence of a 3-amino-2-hydroxypyridine: the method for preparing the solution I by mixing 2-chloropyridine with an alcohol solution and then adding an alkaline alcohol solution into the mixture to react comprises the following steps:
mixing a proper amount of 2-chloropyridine with an alcohol solution;
after mixing evenly, adding an alkaline alcohol solution, adjusting the temperature to 65-75 ℃, and reacting for 10-15 hours;
wherein the molar ratio of the 2-chloropyridine to the alkaline alcoholic solution is 1: 2-20.
3. The process according to claim 2, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: the method for obtaining the second solution after the first solution is subjected to the adjustment treatment comprises the following steps:
filtering the obtained solution I to remove the solvent to obtain a residue;
water was added to the residue to dissolve, and an acidic substance was added to adjust the pH to 4-7.
4. A process for preparing 3-amino-2-hydroxypyridine according to claim 3, wherein: the method for obtaining the 2-hydroxypyridine by carrying out mixed reaction on the solution II and the hydrobromic acid solution comprises the following steps:
mixing the solution II with hydrobromic acid with the concentration of 70-90 ℃, and stirring for 7-15 hours;
after the reaction is finished, cooling and filtering out solid to obtain 2-hydroxypyridine;
wherein the concentration of hydrobromic acid is 30-40 v/v%.
5. The process according to claim 4, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: the method for mixing 2-hydroxypyridine with concentrated sulfuric acid, adding fuming nitric acid at the temperature of 0 ℃, reacting for a period of time, and filtering to obtain a solid I comprises the following steps:
adding 2-hydroxypyridine into a single-mouth bottle, adding concentrated sulfuric acid, stirring for dissolving, and cooling to 0 ℃ in an ice salt bath;
after the temperature reaches, slowly dropwise adding fuming nitric acid, and stirring for half an hour after the adding;
and slowly pouring the reaction liquid into ice, stirring, separating out solids, filtering, washing and drying to obtain a first solid.
6. The process according to claim 5, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: mixing the solid I with DMF, heating to 60-70 ℃, adding a catalyst and hydrogen for continuous reaction, and washing by diethyl ether to obtain a solid II, namely the 3-amino-2-hydroxypyridine, comprising the following steps:
adding the prepared solid I into a single-mouth bottle, adding DMF oil bath, heating to the external temperature of 60-70 ℃, and dissolving under stirring;
adding a catalyst under the protection of nitrogen; blowing hydrogen into the hydrogen balloon, pumping out other gases by the three-way pumping head to form a hydrogen atmosphere, keeping the temperature at 60-70 ℃, and stirring for reacting for 5-10 hours;
after the reaction is finished, washing the obtained product by diethyl ether, separating out solid and filtering to obtain the target product 3-amino-2-hydroxypyridine.
7. The process for producing 3-amino-2-hydroxypyridine according to any one of claims 2 to 6, wherein: the alcohol solution comprises one or more of methanol, ethanol, propanol and tert-butanol.
8. The process for producing 3-amino-2-hydroxypyridine according to any one of claims 3 to 6, wherein: the acidic substance comprises one or more of acetic acid, formic acid, propionic acid, dilute sulfuric acid, hydrochloric acid and phosphoric acid.
9. The process according to claim 7, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: the alkaline alcohol solution comprises an alcohol solution of sodium tert-butoxide or a methanol solution of sodium methoxide.
10. The process according to claim 6, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of: the catalyst was 10% Pd/C.
CN202011290175.2A 2020-11-17 2020-11-17 Preparation method of 3-amino-2-hydroxypyridine Withdrawn CN112225689A (en)

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