CN108003122A - A kind of synthetic method of 4- amino tetrahydro pyrans - Google Patents
A kind of synthetic method of 4- amino tetrahydro pyrans Download PDFInfo
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- CN108003122A CN108003122A CN201711380597.7A CN201711380597A CN108003122A CN 108003122 A CN108003122 A CN 108003122A CN 201711380597 A CN201711380597 A CN 201711380597A CN 108003122 A CN108003122 A CN 108003122A
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- Prior art keywords
- oxinane
- synthetic method
- added dropwise
- amino tetrahydro
- tetrahydro pyrans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D309/14—Nitrogen atoms not forming part of a nitro radical
Abstract
The invention discloses a kind of synthetic method of 4 amino tetrahydro pyran, comprise the following steps：4 formic acid of oxinane is soluble in water, is heated to temperature as 60 70 DEG C, ammonium hydroxide is added dropwise under stirring condition thereto, after being added dropwise to complete, continues stirring 1 2h of reaction, after reaction, is down to room temperature, 4 formamide oxinane mixed solutions are made；4 formamide oxinane mixed solutions of preparation are cooled to temperature as 5 10 DEG C, NaOH solution is added, after stirring evenly, NaBrO solution is added dropwise thereto, after being added dropwise to complete, 1 2h of sustained response at such a temperature, after being warming up to 50 60 DEG C of sustained response 1h afterwards, is down to room temperature, extracted using dichloromethane, merge organic phase, after vacuum distillation removes dichloromethane, recrystallize and 4 amino tetrahydro pyrans are made.The synthetic method of the application is easy 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 4- amino tetrahydro pyrans.
Background technology
Pyrans is a kind of oxygen-containing hexa-member heterocycle system for the carbon atom that oxygen atom is replaced in hexatomic ring, be it is a kind of very
Important heterocyclic compound.Pyran compounds have extensive bioactivity, and the synthesis of such compound has important meaning
Justice.It is the important feature kernel of the natural products such as many carbohydrate, polyether antibiotic, ocean toxin, pheromones, it is given birth to
Thing activity plays very important effect.Oxinane is also the important synthetic intermediate for building other heterocyclic compounds, such
Heterocyclic compound proves there is anticancer, antianaphylaxis, anti-aging, suppression cancer cell and anticytotoxin activity according to existing report
Etc. there is good effect.Therefore, the synthetic method of oxinane class compound receives the extensive concern of researcher,
Have become the research hotspot of organic synthesis.
According to current report, the preparation method of 4- amino tetrahydro pyrans is mainly the following：(1) with oxinane-
4- ketone and ammonium acetate are raw material, are reacted in ethanol by adding molecular sieve powder and sodium cyanoborohydride, so as to make
It is standby to obtain 4- amino tetrahydro pyrans；(2) under the catalysis of Raney's nickel, by the way that Tetrahydro-pyran-4-one is contacted with ammonia and hydrogen
Method target product is prepared；(3) it is Tetrahydro-pyran-4-one is molten in the mixing of water, N,N-dimethylformamide and formic acid
Heating is so as to obtained 4- amino tetrahydro pyrans in liquid；(4) by 4- chloros oxinane and ammonia in a kettle at a certain temperature
Reacted, 4- amino tetrahydro pyrans are made.Above method still suffers from the defects of certain and deficiency, and product yield is subject to larger
Limitation, is not particularly suited for large-scale industrial production.Therefore, research is a kind of operates relatively simple, the higher preparation side of yield
Method has important practical value.
Chinese patent CN201210520592.0 discloses a kind of one pot process technique of 4- amino tetrahydro pyrans, with 4-
Cyano group oxinane, sodium hydroxide solution (or potassium hydroxide solution) they are Material synthesis 4- formamide oxinanes, then toward 4- first
Liquor natrii hypochloritis's (or sodium hypobromite solution) is slowly added in acid amides oxinane, is then heated to reflux, decarboxylation life
Into product 4- amino tetrahydro pyrans.All reaction raw materials are placed in one pot and are reacted, by selecting suitable reaction condition, synthesis
4- amino tetrahydro pyrans, high selectivity, impurity is few, and intermediate product does not have to separation, high income, practical value height.
The content of the invention
The object of the present invention is to provide a kind of synthetic method of 4- amino tetrahydro pyrans, the synthetic method is easy to operate, bar
Part is gentle, and 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 4- amino tetrahydro pyrans, comprises the following steps：
(1) oxinane -4- formic acid is soluble in water, and it is 60-70 DEG C to be heated to temperature, and ammonia is added dropwise thereto under stirring condition
Water, after being added dropwise to complete, continues stirring reaction 1-2h, after reaction, is down to room temperature, it is molten that the mixing of 4- formamides oxinane is made
Liquid；
(2) 4- formamide oxinane mixed solutions prepared by step 1 are cooled to temperature as 5-10 DEG C, it is molten adds NaOH
Liquid, after stirring evenly, is added dropwise NaBrO solution, after being added dropwise to complete, sustained response 1-2h, heats up afterwards at such a temperature thereto
To 50-60 DEG C of sustained response 1h, room temperature is down to, is extracted using dichloromethane, merge organic phase, vacuum distillation removes two
After chloromethanes, recrystallize and 4- amino tetrahydro pyrans are made.
Preferably, the usage amount molal volume ratio of oxinane -4- formic acid and water is 3-5mol/L in the step (1).
Preferably, the concentration of ammonium hydroxide is 13mol/L in the step (1).
Preferably, the usage amount molal volume ratio of oxinane -4- formic acid and ammonium hydroxide is 10 in the step (1):
1mol/L。
Preferably, the mass concentration of NaOH solution is 40%, 4- formamide oxinane mixed solutions in the step (2)
Usage amount volume ratio with NaOH solution is 7:1.
Preferably, NaBrO concentration of polymer solution is 15-25% in the step (2).
Preferably, the usage amount molar ratio of the oxinane -4- formic acid and NaBrO is 1:1.2-1.5.
The invention has the advantages that oxinane -4- formic acid is used now to be reacted itself and ammonium hydroxide for raw material
After 4- formamide oxinanes are made, the reaction for carrying out abjection carbonyl prepares 4- amino tetrahydro pyrans.The preparation method of the application
With good selectivity, accessory substance is less in preparation process, and the product purity prepared is higher.Also, during the reaction
Easy to operate without intermediate purification step, product yield is higher, 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 4- amino tetrahydro pyrans, comprises the following steps：
(1) oxinane -4- formic acid is soluble in water, is heated to temperature as 60 DEG C, ammonium hydroxide is added dropwise under stirring condition thereto,
After being added dropwise to complete, continue stirring reaction 1h, after reaction, be down to room temperature, 4- formamide oxinane mixed solutions are made；
(2) 4- formamide oxinane mixed solutions prepared by step 1 are cooled to temperature as 5 DEG C, add NaOH solution,
After stirring evenly, NaBrO solution is added dropwise thereto, after being added dropwise to complete, sustained response 1h, is warming up to 50 DEG C afterwards at such a temperature
After sustained response 1h, room temperature is down to, is extracted using dichloromethane, merges organic phase, after vacuum distillation removes dichloromethane,
4- amino tetrahydro pyrans are made in recrystallization.
Preferably, the usage amount molal volume ratio of oxinane -4- formic acid and water is 3mol/L in the step (1).
The concentration of ammonium hydroxide is 13mol/L in step (1)；The usage amount of oxinane -4- formic acid and ammonium hydroxide in step (1)
Molal volume ratio is 10:1mol/L.
The mass concentration of NaOH solution is 40%, 4- formamide oxinane mixed solutions and NaOH solution in step (2)
Usage amount volume ratio be 7:1；NaBrO concentration of polymer solution is 15% in step (2).Oxinane -4- formic acid and NaBrO's
Usage amount molar ratio is 1:1.2.
Obtained 4- amino tetrahydro pyrans purity is 99.2%, product yield 90.4%.
Embodiment 2
A kind of synthetic method of 4- amino tetrahydro pyrans, comprises the following steps：
(1) oxinane -4- formic acid is soluble in water, is heated to temperature as 70 DEG C, ammonium hydroxide is added dropwise under stirring condition thereto,
After being added dropwise to complete, continue stirring reaction 2h, after reaction, be down to room temperature, 4- formamide oxinane mixed solutions are made；
(2) 4- formamide oxinane mixed solutions prepared by step 1 are cooled to temperature as 10 DEG C, it is molten adds NaOH
Liquid, after stirring evenly, is added dropwise NaBrO solution, after being added dropwise to complete, sustained response 2h, is warming up to afterwards at such a temperature thereto
After 60 DEG C of sustained response 1h, room temperature is down to, is extracted using dichloromethane, merge organic phase, vacuum distillation removes dichloromethane
After alkane, recrystallize and 4- amino tetrahydro pyrans are made.
Preferably, the usage amount molal volume ratio of oxinane -4- formic acid and water is 5mol/L in the step (1).
The concentration of ammonium hydroxide is 13mol/L in step (1)；The usage amount of oxinane -4- formic acid and ammonium hydroxide in step (1)
Molal volume ratio is 10:1mol/L.
The mass concentration of NaOH solution is 40%, 4- formamide oxinane mixed solutions and NaOH solution in step (2)
Usage amount volume ratio be 7:1；NaBrO concentration of polymer solution is 25% in step (2).Oxinane -4- formic acid and NaBrO's
Usage amount molar ratio is 1:1.5.
Obtained 4- amino tetrahydro pyrans purity is 99.3%, product yield 91.2%.
Embodiment 3
A kind of synthetic method of 4- amino tetrahydro pyrans, comprises the following steps：
(1) oxinane -4- formic acid is soluble in water, is heated to temperature as 60 DEG C, ammonium hydroxide is added dropwise under stirring condition thereto,
After being added dropwise to complete, continue stirring reaction 2h, after reaction, be down to room temperature, 4- formamide oxinane mixed solutions are made；
(2) 4- formamide oxinane mixed solutions prepared by step 1 are cooled to temperature as 5 DEG C, add NaOH solution,
After stirring evenly, NaBrO solution is added dropwise thereto, after being added dropwise to complete, sustained response 2h, is warming up to 50 DEG C afterwards at such a temperature
After sustained response 1h, room temperature is down to, is extracted using dichloromethane, merges organic phase, after vacuum distillation removes dichloromethane,
4- amino tetrahydro pyrans are made in recrystallization.
Preferably, the usage amount molal volume ratio of oxinane -4- formic acid and water is 5mol/L in the step (1).
The concentration of ammonium hydroxide is 13mol/L in step (1)；The usage amount of oxinane -4- formic acid and ammonium hydroxide in step (1)
Molal volume ratio is 10:1mol/L.
The mass concentration of NaOH solution is 40%, 4- formamide oxinane mixed solutions and NaOH solution in step (2)
Usage amount volume ratio be 7:1；NaBrO concentration of polymer solution is 15% in step (2).Oxinane -4- formic acid and NaBrO's
Usage amount molar ratio is 1:1.5.
Obtained 4- amino tetrahydro pyrans purity is 99.2%, product yield 91.8%.
Embodiment 4
A kind of synthetic method of 4- amino tetrahydro pyrans, comprises the following steps：
(1) oxinane -4- formic acid is soluble in water, is heated to temperature as 70 DEG C, ammonium hydroxide is added dropwise under stirring condition thereto,
After being added dropwise to complete, continue stirring reaction 1h, after reaction, be down to room temperature, 4- formamide oxinane mixed solutions are made；
(2) 4- formamide oxinane mixed solutions prepared by step 1 are cooled to temperature as 10 DEG C, it is molten adds NaOH
Liquid, after stirring evenly, is added dropwise NaBrO solution, after being added dropwise to complete, sustained response 1h, is warming up to afterwards at such a temperature thereto
After 60 DEG C of sustained response 1h, room temperature is down to, is extracted using dichloromethane, merge organic phase, vacuum distillation removes dichloromethane
After alkane, recrystallize and 4- amino tetrahydro pyrans are made.
Preferably, the usage amount molal volume ratio of oxinane -4- formic acid and water is 3mol/L in the step (1).
The concentration of ammonium hydroxide is 13mol/L in step (1)；The usage amount of oxinane -4- formic acid and ammonium hydroxide in step (1)
Molal volume ratio is 10:1mol/L.
The mass concentration of NaOH solution is 40%, 4- formamide oxinane mixed solutions and NaOH solution in step (2)
Usage amount volume ratio be 7:1；NaBrO concentration of polymer solution is 25% in step (2).Oxinane -4- formic acid and NaBrO's
Usage amount molar ratio is 1:1.2.
Obtained 4- amino tetrahydro pyrans purity is 99.3%, product yield 90.8%.
Embodiment 5
A kind of synthetic method of 4- amino tetrahydro pyrans, comprises the following steps：
(1) oxinane -4- formic acid is soluble in water, is heated to temperature as 60 DEG C, ammonium hydroxide is added dropwise under stirring condition thereto,
After being added dropwise to complete, continue stirring reaction 1h, after reaction, be down to room temperature, 4- formamide oxinane mixed solutions are made；
(2) 4- formamide oxinane mixed solutions prepared by step 1 are cooled to temperature as 10 DEG C, it is molten adds NaOH
Liquid, after stirring evenly, is added dropwise NaBrO solution, after being added dropwise to complete, sustained response 2h, is warming up to afterwards at such a temperature thereto
After 60 DEG C of sustained response 1h, room temperature is down to, is extracted using dichloromethane, merge organic phase, vacuum distillation removes dichloromethane
After alkane, recrystallize and 4- amino tetrahydro pyrans are made.
Preferably, the usage amount molal volume ratio of oxinane -4- formic acid and water is 4mol/L in the step (1).
The concentration of ammonium hydroxide is 13mol/L in step (1)；The usage amount of oxinane -4- formic acid and ammonium hydroxide in step (1)
Molal volume ratio is 10:1mol/L.
The mass concentration of NaOH solution is 40%, 4- formamide oxinane mixed solutions and NaOH solution in step (2)
Usage amount volume ratio be 7:1；NaBrO concentration of polymer solution is 18% in step (2).Oxinane -4- formic acid and NaBrO's
Usage amount molar ratio is 1:1.4.
Obtained 4- amino tetrahydro pyrans purity is 99.3%, product yield 90.3%.
Claims (7)
1. a kind of synthetic method of 4- amino tetrahydro pyrans, it is characterised in that comprise the following steps：
(1) oxinane -4- formic acid is soluble in water, and it is 60-70 DEG C to be heated to temperature, and ammonium hydroxide is added dropwise thereto under stirring condition,
After being added dropwise to complete, continue stirring reaction 1-2h, after reaction, be down to room temperature, 4- formamide oxinane mixed solutions are made；
(2) 4- formamide oxinane mixed solutions prepared by step 1 are cooled to temperature as 5-10 DEG C, add NaOH solution,
After stirring evenly, NaBrO solution is added dropwise thereto, after being added dropwise to complete, sustained response 1-2h, is warming up to afterwards at such a temperature
After 50-60 DEG C of sustained response 1h, room temperature is down to, is extracted using dichloromethane, merge organic phase, vacuum distillation removes dichloro
After methane, recrystallize and 4- amino tetrahydro pyrans are made.
2. the synthetic method of 4- amino tetrahydro pyrans according to claim 1, it is characterised in that：Four in the step (1)
The usage amount molal volume ratio of hydrogen pyrans -4- formic acid and water is 3-5mol/L.
3. the synthetic method of 4- amino tetrahydro pyrans according to claim 1, it is characterised in that：Ammonia in the step (1)
The concentration of water is 13mol/L.
4. the synthetic method of 4- amino tetrahydro pyrans according to claim 3, it is characterised in that：Four in the step (1)
The usage amount molal volume ratio of hydrogen pyrans -4- formic acid and ammonium hydroxide is 10:1mol/L.
5. the synthetic method of 4- amino tetrahydro pyrans according to claim 1, it is characterised in that：In the step (2)
The mass concentration of NaOH solution is that the usage amount volume ratio of 40%, 4- formamide oxinane mixed solutions and NaOH solution is 7:
1。
6. the synthetic method of 4- amino tetrahydro pyrans according to claim 1, it is characterised in that：In the step (2)
NaBrO concentration of polymer solution is 15-25%.
7. the synthetic method of 4- amino tetrahydro pyrans according to claim 1, it is characterised in that：Oxinane-the 4-
The usage amount molar ratio of formic acid and NaBrO are 1:1.2-1.5.
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| CN201711380597.7A CN108003122A (en) | 2017-12-20 | 2017-12-20 | A kind of synthetic method of 4- amino tetrahydro pyrans |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014145029A2 (en) * | 2013-03-15 | 2014-09-18 | Deciphera Pharmaceuticals, Llc | N-acyl-n'-(pyridin-2-yl) ureas and analogs exhibiting anti-cancer and anti-proliferative activities |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014145029A2 (en) * | 2013-03-15 | 2014-09-18 | Deciphera Pharmaceuticals, Llc | N-acyl-n'-(pyridin-2-yl) ureas and analogs exhibiting anti-cancer and anti-proliferative activities |
Non-Patent Citations (2)
| Title |
|---|
| 何敬文: "《药物合成》", 30 September 2013 * |
| 李正化: "《药物化学（第二版）》", 30 November 1979 * |
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Application publication date: 20180508 |