CN108084083A - A kind of synthetic method of N- substituent groups -1,2,3,6- tetrahydropyridines - Google Patents
A kind of synthetic method of N- substituent groups -1,2,3,6- tetrahydropyridines Download PDFInfo
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- CN108084083A CN108084083A CN201711419204.9A CN201711419204A CN108084083A CN 108084083 A CN108084083 A CN 108084083A CN 201711419204 A CN201711419204 A CN 201711419204A CN 108084083 A CN108084083 A CN 108084083A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a kind of synthetic method of 1,2,3,6 tetrahydropyridine of N substituent groups of technical field of chemical synthesis, which is as follows：S1：It weighs 2 10~15g of piperidones to be put into the three-neck flask of 500ml, then adds in 200~300ml of anhydrous tetrahydrofuran solution and dissolved, and be subsequently charged with nitrogen with vacuum cycle pumping vacuum and protect；S2：40~60ml n-BuLis are added in, stir 30~50min, 20~40ml of benzyl chloroformate solution is then added dropwise and participates in 1~2h of reaction；S3：After the reaction was complete, with organic solvent 60~80ml dilute reaction solutions, then reaction solution is warmed to room temperature, mixed liquor is extracted with ethyl acetate, the organic phase of extraction is dried with anhydrous cupric sulfate；S4：Then by silica gel column purification, vacuum drains rear finished product, and preparation process of the present invention is simple and easily controllable, and target product yield is high, and entire synthesis technology and social performance are notable, and there is the good marketization to use and go prospect.
Description
Technical field
The invention discloses a kind of N- substituent groups -1,2, the synthetic method of 3,6- tetrahydropyridines is specially chemical industry synthesis skill
Art field.
Background technology
All kinds of 5,6-tetrahydropyridine derivatives can be manufactured various pharmaceutical compositions using it as active ingredient, treat a variety of human bodies
Disease.The 5,6-tetrahydropyridine derivative of existing synthesis have 1- methyl 4-phenyls tetrahydropyridine, 4- aryl tetrahydropyridine, 5- aryl four
Bis- pyridinium hydroxide, 6- aryl -4,5- formamido tetrahydropyridines, at present, alkyl, phenyl and ethoxycarbonyl on tetrahydro pyridine ring
The yield of the synthetic method of radical derivative is not high, and purity is relatively low, and building-up process is cumbersome, and production efficiency is low.For this purpose, we carry
A kind of N- substituent groups -1,2 are gone out, the synthetic method of 3,6- tetrahydropyridines comes into operation, to solve the above problems.
The content of the invention
It is an object of the invention to provide a kind of N- substituent groups -1,2, the synthetic methods of 3,6- tetrahydropyridines, in solution
State the problem of being proposed in background technology.
To achieve the above object, the present invention provides following technical solution：A kind of N- substituent groups -1,2,3,6- tetrahydropyridines
Synthetic method, the synthetic method are as follows：
S1：It weighs 10~15g of 2- piperidones to be put into the three-neck flask of 500ml, then adds in anhydrous tetrahydrofuran solution
200~300ml is dissolved, and is subsequently reduced to low-temp reaction, and is subsequently charged with nitrogen with vacuum cycle pumping vacuum and protects；
S2：40~60ml n-BuLis are added in, 30~50min is stirred, 20~40ml of benzyl chloroformate solution is then added dropwise
Participate in 1~2h of reaction；
S3：After the reaction was complete, with organic solvent 60~80ml dilute reaction solutions, then reaction solution is warmed to room temperature, uses second
Acetoacetic ester extracts mixed liquor, and the organic phase of extraction is dried with anhydrous cupric sulfate；
S4：Then by silica gel column purification, vacuum drains rear finished product.
Preferably, in the step S1, -60~-50 DEG C is cooled to using dry ice acetone bath, keeps 3~5h of low-temp reaction.
Preferably, in the step S2, benzyl chloroformate solution is dissolved in tetrahydrofuran solution for benzyl chloroformate and makes
, and be added dropwise in 3~5min.
Preferably, in the step S2, contact plate monitoring is carried out using TLC plates in reaction process, is specifically drawn with dropper
A small amount of reaction solution is simultaneously instilled in centrifuge tube, then instills methanol dilution, is drawn dilution contact plate with capillary, is then being unfolded
It carries out climbing plate in agent, the absorption intensity of the UV absorption point of observing response object under visible ultraviolet lamp, to determine reaction progress
Degree.
Preferably, the solvent is petroleum ether and the mixture of ethyl acetate, wherein petroleum ether：Ethyl acetate=1:
0.8。
Preferably, in the step S3, organic solvent is fine according to 1 by methanol and second:1 ratio mixes.
Compared with prior art, the beneficial effects of the invention are as follows：Preparation process of the present invention is simple and easily controllable, target
Product yield is high, and entire synthesis technology and social performance are notable, and there is the good marketization to use and go prospect.
Description of the drawings
Fig. 1 is synthetic method flow chart of the present invention.
Specific embodiment
Below in conjunction with the attached drawing in the embodiment of the present invention, the technical solution in the embodiment of the present invention is carried out clear, complete
Site preparation describes, it is clear that described embodiment is only part of the embodiment of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, those of ordinary skill in the art are obtained every other without making creative work
Embodiment belongs to the scope of protection of the invention.
Embodiment one
A kind of N- substituent groups -1,2, the synthetic method of 3,6- tetrahydropyridines, the synthetic method are as follows：
S1：It weighs 2- piperidones 10g to be put into the three-neck flask of 500ml, then adds in anhydrous tetrahydrofuran solution 200ml
It is dissolved, is subsequently reduced to low-temp reaction, and be subsequently charged with nitrogen with vacuum cycle pumping vacuum and protect, using dry ice acetone bath
- 60 DEG C are cooled to, keeps low-temp reaction 3h；
S2：40ml n-BuLis are added in, stir 30min, benzyl chloroformate solution 20ml is then added dropwise and participates in reaction 1h, chlorine
Benzyl formate solution is dissolved in tetrahydrofuran solution for benzyl chloroformate and is made, and is added dropwise in 3min, reaction process
It is middle to carry out contact plate monitoring using TLC plates, specifically a small amount of reaction solution is drawn with dropper and instilled in centrifuge tube, then instill first
Alcohol dilutes, and dilution contact plate is drawn with capillary, then carries out climbing plate in solvent, the solvent is petroleum ether and acetic acid
The mixture of ethyl ester, wherein petroleum ether：Ethyl acetate=1:0.8, the UV absorption point of observing response object under visible ultraviolet lamp
Absorption intensity, come determine reaction carry out degree；
S3：After the reaction was complete, with organic solvent 60ml dilute reaction solutions, then reaction solution is warmed to room temperature, with acetic acid second
Ester extracts mixed liquor, and the organic phase of extraction is dried with anhydrous cupric sulfate, and organic solvent is fine according to 1 by methanol and second:1 ratio is mixed
It closes；
S4：Then by silica gel column purification, vacuum drains rear finished product.
Embodiment two
A kind of N- substituent groups -1,2, the synthetic method of 3,6- tetrahydropyridines, the synthetic method are as follows：
S1：It weighs 2- piperidones 15g to be put into the three-neck flask of 500ml, then adds in anhydrous tetrahydrofuran solution 300ml
It is dissolved, is subsequently reduced to low-temp reaction, and be subsequently charged with nitrogen with vacuum cycle pumping vacuum and protect, using dry ice acetone bath
- 50 DEG C are cooled to, keeps low-temp reaction 5h；
S2：60ml n-BuLis are added in, stir 50min, benzyl chloroformate solution 40ml is then added dropwise and participates in reaction 2h, chlorine
Benzyl formate solution is dissolved in tetrahydrofuran solution for benzyl chloroformate and is made, and is added dropwise in 5min, reaction process
It is middle to carry out contact plate monitoring using TLC plates, specifically a small amount of reaction solution is drawn with dropper and instilled in centrifuge tube, then instill first
Alcohol dilutes, and dilution contact plate is drawn with capillary, then carries out climbing plate in solvent, the solvent is petroleum ether and acetic acid
The mixture of ethyl ester, wherein petroleum ether：Ethyl acetate=1:0.8, the UV absorption point of observing response object under visible ultraviolet lamp
Absorption intensity, come determine reaction carry out degree；
S3：After the reaction was complete, with organic solvent 80ml dilute reaction solutions, then reaction solution is warmed to room temperature, with acetic acid second
Ester extracts mixed liquor, and the organic phase of extraction is dried with anhydrous cupric sulfate, and organic solvent is fine according to 1 by methanol and second:1 ratio is mixed
It closes；
S4：Then by silica gel column purification, vacuum drains rear finished product.
Embodiment three
A kind of N- substituent groups -1,2, the synthetic method of 3,6- tetrahydropyridines, the synthetic method are as follows：
S1：It weighs 2- piperidones 12g to be put into the three-neck flask of 500ml, then adds in anhydrous tetrahydrofuran solution 260ml
It is dissolved, is subsequently reduced to low-temp reaction, and be subsequently charged with nitrogen with vacuum cycle pumping vacuum and protect, using dry ice acetone bath
- 55 DEG C are cooled to, keeps low-temp reaction 4h；
S2：50ml n-BuLis are added in, stir 40min, benzyl chloroformate solution 30ml is then added dropwise and participates in reaction 1h, chlorine
Benzyl formate solution is dissolved in tetrahydrofuran solution for benzyl chloroformate and is made, and is added dropwise in 4min, reaction process
It is middle to carry out contact plate monitoring using TLC plates, specifically a small amount of reaction solution is drawn with dropper and instilled in centrifuge tube, then instill first
Alcohol dilutes, and dilution contact plate is drawn with capillary, then carries out climbing plate in solvent, the solvent is petroleum ether and acetic acid
The mixture of ethyl ester, wherein petroleum ether：Ethyl acetate=1:0.8, the UV absorption point of observing response object under visible ultraviolet lamp
Absorption intensity, come determine reaction carry out degree；
S3：After the reaction was complete, with organic solvent 70ml dilute reaction solutions, then reaction solution is warmed to room temperature, with acetic acid second
Ester extracts mixed liquor, and the organic phase of extraction is dried with anhydrous cupric sulfate, and organic solvent is fine according to 1 by methanol and second:1 ratio is mixed
It closes；
S4：Then by silica gel column purification, vacuum drains rear finished product.
In summary described in embodiment, highly preferred embodiment of the present invention is embodiment three, and preparation process of the present invention is simply simultaneously
And it is easily controllable, target product yield is high, and entire synthesis technology and social performance are notable, and there is the good marketization to use
Go prospect.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
Understanding without departing from the principles and spirit of the present invention can carry out these embodiments a variety of variations, modification, replace
And modification, the scope of the present invention is defined by the appended.
Claims (6)
1. a kind of N- substituent groups -1,2, the synthetic method of 3,6- tetrahydropyridines, it is characterised in that：The specific steps of the synthetic method
It is as follows：
S1：10~15g of 2- piperidones is weighed to be put into the three-neck flask of 500ml, subsequent addition anhydrous tetrahydrofuran solution 200~
300ml is dissolved, and is subsequently reduced to low-temp reaction, and is subsequently charged with nitrogen with vacuum cycle pumping vacuum and protects；
S2：40~60ml n-BuLis are added in, stir 30~50min, 20~40ml of benzyl chloroformate solution is then added dropwise and participates in
React 1~2h；
S3：After the reaction was complete, with organic solvent 60~80ml dilute reaction solutions, then reaction solution is warmed to room temperature, with acetic acid second
Ester extracts mixed liquor, and the organic phase of extraction is dried with anhydrous cupric sulfate；
S4：Then by silica gel column purification, vacuum drains rear finished product.
2. a kind of N- substituent groups -1,2 according to claim 1, the synthetic method of 3,6- tetrahydropyridines, it is characterised in that：
In the step S1, -60~-50 DEG C are cooled to using dry ice acetone bath, keeps 3~5h of low-temp reaction.
3. a kind of N- substituent groups -1,2 according to claim 1, the synthetic method of 3,6- tetrahydropyridines, it is characterised in that：
In the step S2, benzyl chloroformate solution is dissolved in tetrahydrofuran solution for benzyl chloroformate and is made, and in 3~5min
It is added dropwise.
4. a kind of N- substituent groups -1,2 according to claim 1, the synthetic method of 3,6- tetrahydropyridines, it is characterised in that：
In the step S2, contact plate monitoring is carried out using TLC plates in reaction process, specifically draws a small amount of reaction solution and drop with dropper
Enter in centrifuge tube, then instill methanol dilution, draw dilution contact plate with capillary, then carry out climbing plate in solvent,
It can be seen that under ultraviolet lamp the UV absorption point of observing response object absorption intensity, come determine reaction carry out degree.
5. a kind of N- substituent groups -1,2 according to claim 4, the synthetic method of 3,6- tetrahydropyridines, it is characterised in that：
The solvent is petroleum ether and the mixture of ethyl acetate, wherein petroleum ether：Ethyl acetate=1:0.8.
6. a kind of N- substituent groups -1,2 according to claim 1, the synthetic method of 3,6- tetrahydropyridines, it is characterised in that：
In the step S3, organic solvent is fine according to 1 by methanol and second:1 ratio mixes.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101696187A (en) * | 2009-09-30 | 2010-04-21 | 徐州工业职业技术学院 | Synthesizing method of N-substituent-1,2,3,6-tetrahydropyridine |
| CN103073472A (en) * | 2013-01-15 | 2013-05-01 | 武汉药明康德新药开发有限公司 | Preparation method of 2-trifluoromethyl-1-carbobenzoxy-1-aza-cyclane |
-
2017
- 2017-12-25 CN CN201711419204.9A patent/CN108084083A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101696187A (en) * | 2009-09-30 | 2010-04-21 | 徐州工业职业技术学院 | Synthesizing method of N-substituent-1,2,3,6-tetrahydropyridine |
| CN103073472A (en) * | 2013-01-15 | 2013-05-01 | 武汉药明康德新药开发有限公司 | Preparation method of 2-trifluoromethyl-1-carbobenzoxy-1-aza-cyclane |
Non-Patent Citations (4)
| Title |
|---|
| ARIANNA GIOVANNINI等: "Organometallic ring-opening reactions of N-acyl and N-alkoxycarbonyl lactams. Synthesis of cyclic imines", 《J. ORG. CHEM.》 * |
| FILIPPO DE SIMONE等: "Catalytic Selective Cyclizations of Aminocyclopropanes: Formal Synthesis of Aspidospermidine and Total Synthesis of Goniomitine", 《ANGEW. CHEM. INT. ED.》 * |
| FILIPPO DE SIMONE等: "Formal Homo-Nazarov and Other Cyclization Reactions of Activated Cyclopropanes", 《CHEM. EUR. J.》 * |
| 古奇（GUTSCHE，C.D.）等: "《有机化学基础 下》", 31 July 1986, 高等教育出版社 * |
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