CN107857725A - A kind of synthetic method of the methanol of 2 aminopyridine 4 - Google Patents
A kind of synthetic method of the methanol of 2 aminopyridine 4 Download PDFInfo
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- CN107857725A CN107857725A CN201711370476.4A CN201711370476A CN107857725A CN 107857725 A CN107857725 A CN 107857725A CN 201711370476 A CN201711370476 A CN 201711370476A CN 107857725 A CN107857725 A CN 107857725A
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- methanol
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- added dropwise
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- IOOFPEBRBXNMKX-UHFFFAOYSA-N Cc(c(CO)c1)cnc1C(N)=O Chemical compound Cc(c(CO)c1)cnc1C(N)=O IOOFPEBRBXNMKX-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic 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
- C07D213/02—Heterocyclic 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
- C07D213/04—Heterocyclic 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
- C07D213/60—Heterocyclic 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
Abstract
The invention discloses a kind of synthetic method of the methanol of 2 aminopyridine 4, comprise the following steps：Compound 2 is made in 4 pyridinemethanols and formamide reactant aqueous solution；Compound 2 and NaOH solution are mixed, it is placed in reactor, it is 5 10 DEG C to control temperature, and NaBrO solution is added dropwise thereto, after being added dropwise to complete, the 2h of sustained response 1 at such a temperature, after being warming up to 50 60 DEG C of sustained response 1h afterwards, it is down to room temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the methanol of 2 aminopyridine 4 is made.The synthetic method of the application is simple to operate, and mild condition, accessory substance is less, and product purity is high, and product yield is higher.
Description
Technical field
The present invention relates to organic synthesis field, more particularly to a kind of synthetic method of PA -4- methanol.
Background technology
The noval chemical compound that phenyl ring is replaced by pyridine and is prepared has higher bioactivity and lower toxicity, Huo Zhegeng
High absorbability and selectivity, therefore pyridines intermediate has obtained news and developed fastly.Pyridine can be used for synthesizing medical industry
Sulfanilamide (SN), cortisone, close toxin, vitamin A and the medicine for treating blood vessel dilatation, reducing blood lipid and local anaesthesia；Also can be in agricultural chemicals
It is used to produce diquat dibromide, herbicide and agrochemical in industry.Wherein aminopyridines are that one kind has heterocycle knot
The ring ammoniacal substance of structure, equally also had a wide range of applications in many fields of organic chemical industry.PA -4- methanol is a variety of
Enzyme, polypeptide, the new inhibitor of hormone receptor, antagonist, the raw material of conditioning agent, have in medicine intermediate field quite important
Status.
The preparation method of existing research report aminopyridines has following several：1st, pyridine and Sodamide are direct
Aminating reaction is carried out, but this method reaction condition is more harsh, reaction reagent is difficult to obtain, and accessory substance is more, product
Yield is relatively low；2nd, ammonolysis reaction is carried out under the catalyst such as mantoquita or palladium carbon by haloperidid, this method uses catalyst
Cost is higher, and the requirement to equipment is more strict, operating difficulties；3rd, pyridine is nitrified through hydrogen peroxide oxidation, fuming nitric aicd
After nitrification pyridine is made, then through reducing obtained aminopyridine, this method step is more, and pollution is more serious, and composition is high, it is difficult to work
Industry metaplasia is produced；4th, using cyanopyridine as raw material, aminopyridine is made by catalyzing hydrolysis, Hofmann degradation, this method raw material is honest and clean
Valency is easy to get, and yield is higher, but its catalyst obtains complex, and is only capable of preparing 4-aminopyridine, use range by
Limitation.Therefore, a kind of operation of research and development is relatively simple, and the preparation methods of the higher aminopyridines of yield has important
Practical value.
Chinese patent CN201310680246.3 discloses a kind of preparation method of PA -4- methanol, wraps successively
Include following steps：Using 2- chloroisonicotinic acids as raw material, under thionyl chloride effect with small molecular alcohol carrying out esterification, to obtain 2- chlorine different
Nicotinate, 2- chloroisonicotinic acids ester are reduced into 2- chloropyridine -4- methanol under reducing agent effect, last 2- chloropyridines -4- methanol and
Ammoniacal liquor carries out aminating reaction under copper class catalyst and obtains PA -4- methanol.2- amino is prepared using the invention
Pyridine -4- methanol technics routes are short, avoid the generation of a large amount of waste liquids and waste residue, reduce the pollution to environment, and product
High income, copper class catalyst can be recycled in aminating reaction, reduce production cost, suitable industrialized production.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of PA -4- methanol, the synthetic method is simple to operate,
Mild condition, accessory substance is less, and product purity is high, and product yield is higher.
To achieve the above object, the present invention uses following technical scheme：
A kind of synthetic method of PA -4- methanol, comprises the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, adds the concentrated sulfuric acid, be heated to 70-80 DEG C, afterwards
After addition formyl amine aqueous solution is well mixed thereto, hydrogen peroxide, after being added dropwise to complete, keeping temperature back flow reaction 45- is added dropwise
60min, it is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 3-5 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 5-10 DEG C to control temperature, thereto
NaBrO solution is added dropwise, after being added dropwise to complete, sustained response 1-2h, is warming up to 50-60 DEG C of sustained response 1h afterwards at such a temperature
Afterwards, room temperature is down to, is repeatedly extracted using ethyl acetate, merges organic phase, is evaporated under reduced pressure and removes ethyl acetate, is made described
PA -4- methanol；
Preferably, the mass concentration of the concentrated sulfuric acid is 80-85% in the step (1).
Preferably, the mass concentration of formyl amine aqueous solution is 75-82% in the step (1).
Preferably, the usage amount mol ratio of 4- pyridinemethanols and formamide is 4 in the step (1):5-7.
Preferably, the usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1 in the step (1):1.2-1.5.
Preferably, the mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 15- in the step (2)
25%.
Preferably, compound 2 and NaBrO usage amounts mol ratio are 1 in the step (2):1.2-1.5.
The invention has the advantages that hydrogen peroxide is used as initiator so that 4- pyridinemethanols enter with formamide
Row reaction, the course of reaction is selectively strong, and accessory substance is less, and reaction rate is fast, improves reaction efficiency.By further
Abjection carbonyl reaction, prepare target product, course of reaction condition is more gentle, simple to operate, and final product extract
Easily, the product obtained has higher purity and yield, is very suitable for large-scale industrial production.
Embodiment
In order to be better understood from the present invention, below by embodiment, the present invention is further described, and embodiment is served only for solving
The present invention is released, any restriction will not be formed to the present invention.
Embodiment 1
A kind of synthetic method of PA -4- methanol, comprises the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, adds the concentrated sulfuric acid, be heated to 70 DEG C, it is backward
After wherein addition formyl amine aqueous solution is well mixed, hydrogen peroxide is added dropwise, after being added dropwise to complete, keeping temperature back flow reaction 45min,
It is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 3 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 5 DEG C to control temperature, is dripped thereto
Add NaBrO solution, after being added dropwise to complete, sustained response 1h, after being warming up to 50 DEG C of sustained response 1h afterwards, is down to room at such a temperature
Temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the 2- amino pyrrole is made
Pyridine -4- methanol；
The mass concentration of the concentrated sulfuric acid is 80-85% in the step (1)；The mass concentration of formyl amine aqueous solution is 75%；
The usage amount mol ratio of 4- pyridinemethanols and formamide is 4:5；The usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1:
1.2。
The mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 15% in the step (2), chemical combination
Thing 2 is 1 with NaBrO usage amounts mol ratio:1.2.
The purity of the PA -4- methanol of preparation is 99.5%, yield 94.6%.
Embodiment 2
A kind of synthetic method of PA -4- methanol, comprises the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, adds the concentrated sulfuric acid, be heated to 80 DEG C, it is backward
After wherein addition formyl amine aqueous solution is well mixed, hydrogen peroxide is added dropwise, after being added dropwise to complete, keeping temperature back flow reaction 60min,
It is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 5 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 10 DEG C to control temperature, is dripped thereto
Add NaBrO solution, after being added dropwise to complete, sustained response 2h, after being warming up to 60 DEG C of sustained response 1h afterwards, is down to room at such a temperature
Temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the 2- amino pyrrole is made
Pyridine -4- methanol.
The mass concentration of the concentrated sulfuric acid is 85% in the step (1)；The mass concentration of formyl amine aqueous solution is 82%；4- pyrroles
The usage amount mol ratio of pyridine methanol and formamide is 4:7；The usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1:1.5.
The mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 25% in the step (2), chemical combination
Thing 2 is 1 with NaBrO usage amounts mol ratio:1.5.
The purity of the PA -4- methanol of preparation is 99.6%, yield 95.2%.
Embodiment 3
A kind of synthetic method of PA -4- methanol, comprises the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, adds the concentrated sulfuric acid, be heated to 70 DEG C, it is backward
After wherein addition formyl amine aqueous solution is well mixed, hydrogen peroxide is added dropwise, after being added dropwise to complete, keeping temperature back flow reaction 60min,
It is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 3 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 10 DEG C to control temperature, is dripped thereto
Add NaBrO solution, after being added dropwise to complete, sustained response 1h, after being warming up to 60 DEG C of sustained response 1h afterwards, is down to room at such a temperature
Temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the 2- amino pyrrole is made
Pyridine -4- methanol.
The mass concentration of the concentrated sulfuric acid is 80% in the step (1)；The mass concentration of formyl amine aqueous solution is 82%；4- pyrroles
The usage amount mol ratio of pyridine methanol and formamide is 4:5；The usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1:1.5.
The mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 15% in the step (2), chemical combination
Thing 2 is 1 with NaBrO usage amounts mol ratio:1.5.
The purity of the PA -4- methanol of preparation is 99.5%, yield 95.9%.
Embodiment 4
A kind of synthetic method of PA -4- methanol, comprises the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, adds the concentrated sulfuric acid, be heated to 80 DEG C, it is backward
After wherein addition formyl amine aqueous solution is well mixed, hydrogen peroxide is added dropwise, after being added dropwise to complete, keeping temperature back flow reaction 45min,
It is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 5 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 5 DEG C to control temperature, is dripped thereto
Add NaBrO solution, after being added dropwise to complete, sustained response 2h, after being warming up to 50 DEG C of sustained response 1h afterwards, is down to room at such a temperature
Temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the 2- amino pyrrole is made
Pyridine -4- methanol.
The mass concentration of the concentrated sulfuric acid is 85% in the step (1)；The mass concentration of formyl amine aqueous solution is 75%；4- pyrroles
The usage amount mol ratio of pyridine methanol and formamide is 4:7；The usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1:1.2.
The mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 25% in the step (2), chemical combination
Thing 2 is 1 with NaBrO usage amounts mol ratio:1.2.
The purity of the PA -4- methanol of preparation is 99.4%, yield 95.5%.
Embodiment 5
A kind of synthetic method of PA -4- methanol, comprises the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, adds the concentrated sulfuric acid, be heated to 75 DEG C, it is backward
After wherein addition formyl amine aqueous solution is well mixed, hydrogen peroxide is added dropwise, after being added dropwise to complete, keeping temperature back flow reaction 50min,
It is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 4 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 10 DEG C to control temperature, is dripped thereto
Add NaBrO solution, after being added dropwise to complete, sustained response 1h, after being warming up to 55 DEG C of sustained response 1h afterwards, is down to room at such a temperature
Temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the 2- amino pyrrole is made
Pyridine -4- methanol.
The mass concentration of the concentrated sulfuric acid is 82% in the step (1)；The mass concentration of formyl amine aqueous solution is 80%；4- pyrroles
The usage amount mol ratio of pyridine methanol and formamide is 4:6；The usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1:1.4.
The mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 18% in the step (2), chemical combination
Thing 2 is 1 with NaBrO usage amounts mol ratio:1.3.
The purity of the PA -4- methanol of preparation is 99.6%, yield 94.9%.
Claims (7)
1. a kind of synthetic method of PA -4- methanol, it is characterised in that comprise the following steps：
(1) 4- pyridinemethanols are mixed in a kettle with tetrahydrofuran, add the concentrated sulfuric acid, be heated to 70-80 DEG C, it is backward its
After middle addition formyl amine aqueous solution is well mixed, hydrogen peroxide, after being added dropwise to complete, keeping temperature back flow reaction 45- is added dropwise
60min, it is evaporated under reduced pressure afterwards, after the solid filtering of precipitation, is cleaned 3-5 times with water, compound 2 is made after drying；
(2) obtained compound 2 and NaOH solution are mixed, are placed in reactor, it is 5-10 DEG C to control temperature, is added dropwise thereto
NaBrO solution, after being added dropwise to complete, sustained response 1-2h, after being warming up to 50-60 DEG C of sustained response 1h afterwards, drops at such a temperature
To room temperature, repeatedly extracted using ethyl acetate, merge organic phase, be evaporated under reduced pressure and remove ethyl acetate, the 2- ammonia is made
Yl pyridines -4- methanol；
2. the synthetic method of PA -4- methanol according to claim 1, it is characterised in that：In the step (1)
The mass concentration of the concentrated sulfuric acid is 80-85%.
3. the synthetic method of PA -4- methanol according to claim 1, it is characterised in that：In the step (1)
The mass concentration of formyl amine aqueous solution is 75-82%.
4. the synthetic method of PA -4- methanol according to claim 1, it is characterised in that：In the step (1)
The usage amount mol ratio of 4- pyridinemethanols and formamide is 4:5-7.
5. the synthetic method of PA -4- methanol according to claim 1, it is characterised in that：In the step (1)
The usage amount mol ratio of 4- pyridinemethanols and hydrogen peroxide is 1:1.2-1.5.
6. the synthetic method of PA -4- methanol according to claim 1, it is characterised in that：In the step (2)
The mass concentration of NaOH solution is that the mass concentration of 40%, NaBrO solution is 15-25%.
7. the synthetic method of PA -4- methanol according to claim 1, it is characterised in that：In the step (2)
Compound 2 is 1 with NaBrO usage amounts mol ratio:1.2-1.5.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711370476.4A CN107857725A (en) | 2017-12-19 | 2017-12-19 | A kind of synthetic method of the methanol of 2 aminopyridine 4 |
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| CN201711370476.4A CN107857725A (en) | 2017-12-19 | 2017-12-19 | A kind of synthetic method of the methanol of 2 aminopyridine 4 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1627874B1 (en) * | 2004-08-17 | 2008-04-02 | Lanxess Deutschland GmbH | Preparation of fluorinated 1,3-benzodioxanes |
| CN101302193A (en) * | 2008-05-27 | 2008-11-12 | 上海瑞恒生物技术有限公司 | Entironment-friendly preparation of sorafenib intermediate |
| CN102459246A (en) * | 2009-04-07 | 2012-05-16 | 阿斯利康(瑞典)有限公司 | Method and apparatus for producing heat energy and carbon dioxide |
-
2017
- 2017-12-19 CN CN201711370476.4A patent/CN107857725A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1627874B1 (en) * | 2004-08-17 | 2008-04-02 | Lanxess Deutschland GmbH | Preparation of fluorinated 1,3-benzodioxanes |
| CN101302193A (en) * | 2008-05-27 | 2008-11-12 | 上海瑞恒生物技术有限公司 | Entironment-friendly preparation of sorafenib intermediate |
| CN102459246A (en) * | 2009-04-07 | 2012-05-16 | 阿斯利康(瑞典)有限公司 | Method and apparatus for producing heat energy and carbon dioxide |
Non-Patent Citations (1)
| Title |
|---|
| 王清龙等: "Ｍｉｎｉｓｃｉ自由基取代反应最新研究进展", 《河南师范大学学报（自然科学版）》 * |
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Application publication date: 20180330 |