CN106316952A - Preparation method for synthesizing medical intermediate 6,7-dihydro-5H-cyclopentaneopyridine through ionic liquid method - Google Patents
Preparation method for synthesizing medical intermediate 6,7-dihydro-5H-cyclopentaneopyridine through ionic liquid method Download PDFInfo
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- CN106316952A CN106316952A CN201610701513.4A CN201610701513A CN106316952A CN 106316952 A CN106316952 A CN 106316952A CN 201610701513 A CN201610701513 A CN 201610701513A CN 106316952 A CN106316952 A CN 106316952A
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- C07—ORGANIC CHEMISTRY
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- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
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Abstract
The invention relates to preparation of medical intermediates and particularly relates to a preparation method for synthesizing a medical intermediate 6,7-dihydro-5H-cyclopentaneopyridine through an ionic liquid method. The preparation method comprises the following steps: (1) preparing an ionic liquid anchored catalyst BMImZnCl3; and (2) by taking cyclopentanone and propargylamine as raw materials, performing microwave heating to synthesize the medical intermediate 6,7-dihydro-5H-cyclopentaneopyridine in a BMImBF4/BMImZnCl3 catalytic system, extracting, drying and distilling the reaction solution by using an organic solvent after the reaction is ended, thereby obtaining the product with the content over 99.0%, wherein the yield of the product is 70-75%. The method disclosed by the invention is capable of synthesizing 6,7-dihydro-5H-cyclopentaneopyridine through microwaves in the ionic liquid, is mild in reaction conditions, short in reaction time, high in reaction selectivity and yield, adopts the recyclable ionic liquid catalyst and simple operation and after-treatment, and is a high-efficiency and environmental-friendly synthetic method.
Description
Technical field
The invention belongs to the preparing technical field of medicine intermediate, be specifically related in the middle of a kind of ionic liquid synthesis medicine
The preparation method of body 6,7-dihydro-5H-Pentamethylene. also (b) pyridine.
Background technology
6,7-dihydro-5H-Pentamethylene. also (b) pyridine is the important of synthesis forth generation cephalosporins new drug cefpirome
Intermediate, has antiulcer, the important physiologically active such as anticancer.
6,7-dihydro-5H-Pentamethylene. also (b) pyridine synthesized still in the experimental stage, and primary synthetic methods has thermal rearrangement anti-
Answer, catalytic dehydration dehydrogenation reaction, Friedlander condensation reaction, Grignard reagent ring-closure reaction, Diels-Alder react
With 1,5-dicarbonyl compound cyclization etc..
The synthetic method of most study is the catalytic addition cyclization method with Ketocyclopentane and propargylamine at present, and Abbiati etc. adopts
With expensive sodium chloraurate catalyst；Wei Fuxiang, Liu Baoyou etc. use ionic liquid copper-loaded catalyst BMImBF4/
BMImCuCl3；Duan Weiya master thesis is catalyzed with iron chloride functionalized ion liquid；Chen Rener, Zhou Xiaohua etc. use
In autoclave, Cu-lyt. catalyzes and synthesizes.
Being a step condensation method with the catalytic addition cyclization method of Ketocyclopentane and propargylamine, reactions steps is short, is synthesis 6,7-bis-
The study hotspot of hydrogen-5H-Pentamethylene. also (b) pyridine, but differ farther out from industrial operation.
It is thus desirable to one is efficient, economy, product impurity are few, simple to operate, low cost, oligosaprobic 6,7-dihydro-5H-
The preparation method of Pentamethylene. also (b) pyridine.
Ionic liquid is as a kind of novel green solvent, the most volatile, solvability strong, polarity controllable, easily reclaim
Huge profit use, has the advantages that conventional organic solvents is incomparable, receives significant attention；Ionic liquid is as all kinds of catalyst
Carrier has been successfully applied in multiple organic synthesis, the advantage of ionic liquid carried catalyst: 1. easy and reactant or product
Separate, it is simple to recovery；2. there is preferable mechanical performance, it is to avoid the decomposition of catalyst is run off；3. it is easily achieved homogeneous
Catalysis, improves the activity and selectivity of catalyst.Ionic liquid carried catalyst opens brand-new catalysis new way, illustrates wide
Wealthy application prospect.
Summary of the invention
It is an object of the invention to provide a kind of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also
The preparation method of (b) pyridine, with Ketocyclopentane and propargylamine as raw material, uses ionic liquid carried catalyst, and microwave synthesizes.
This invention takes following technical scheme:
Ionic liquid carried catalyst BMImZnCl3, with Ketocyclopentane and propargylamine as raw material, urge at microwave reaction kettle and ionic liquid
Catalyzing and synthesizing medicine intermediate 6,7-dihydro-5H-Pentamethylene. also [b] pyridine in change system, reaction terminates reactant liquor with organic molten
Agent is extracted, and is dried, and distillation obtains content product more than 99.0%.
Medicine intermediate 6, in the preparation method of 7-dihydro-5H-Pentamethylene. also (b) pyridine, the throwing that Ketocyclopentane and propine are pressed
The amount ratio of material material is for 1:1.2 ~ 1.8；Ionic liquid BMImBF4Consumption is Ketocyclopentane 3 ~ 5 times；Catalyst BMImZnCl3For
The 5 ~ 15% of BMImBF4 consumption.Microwave reaction temperature is 60 ~ 100 DEG C；It is acetic acid second that reaction terminate reactant liquor to extract organic solvent
Ester, ethanol, dichloromethane, toluene etc.；Post processing is reactant liquor organic solvent extraction, is dried, distillation.Ionic liquid-catalyzed body
System is recovered as: collect lower floor's filtrate ionic liquid and catalyst, removes Organic substances for 3 times with organic solvent washing, then 70 DEG C true
The empty 2h that is dried, set is for lower batch reaction.
Reaction condition of the present invention is gentle, and the response time is short, and reaction selectivity and yield are high, and ionic-liquid catalyst is capable of circulation
Using, operation and post processing are simple, are a kind of synthetic methods efficient, eco-friendly.
Detailed description of the invention
Below by way of specific embodiment, technical scheme is described in further detail, but the protection model of the present invention
Enclose and be not limited thereto.
Embodiment 1
A kind of preparation method of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also (b) pyridine
Specifically comprise the following steps that
Ionic liquid carried catalyst BMImZnCl3Synthesis:
34.9gBMIm(1-butyl-3-methylimidazolium chloride is added in 500mL reaction bulb), add 100mL hexamethylene,
27.2g zinc chloride, back flow reaction 5h, reduce pressure distilling off solvent, obtains 62g ionic liquid and carries zinc chloride catalyst BMImZnCl3。
6,7-dihydro-5H-Pentamethylene. also (b) pyridine synthesizes:
In sealed microwave reactor, put into Ketocyclopentane 42g(0.5mol successively), propargylamine 35.7g(0.65mol), BMImBF4/
BMImZnCl3Catalyst system 181g(catalyst 13.4g, accounts for 8%), stirring reaction 5h under the conditions of 70 DEG C of microwave radiations.Reaction
Complete, it is cooled to room temperature, extracts by ethyl acetate 150mL, merge upper organic layer, anhydrous magnesium sulfate is dried；Filtering, filtrate subtracts
Pressure distillation, recycling design, then rise high-temperature rectification, collect fraction, obtain content 99.2% 6,7-dihydro-5H-Pentamethylene. is also
(b) pyridine product 41.8g, yield 70%.
Ionic liquid catalyst systems reclaims:
Collect lower floor's filtrate ionic liquid and catalyst, wash 3 times with dichloromethane and remove Organic substance, then 70 DEG C of vacuum drying
2h.Set is for lower batch reaction.
Embodiment 2
A kind of preparation method of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also (b) pyridine
Specifically comprise the following steps that
6,7-dihydro-5H-Pentamethylene. also (b) pyridine synthesizes:
In sealed microwave reactor, put into Ketocyclopentane 42g(0.5mol successively), propargylamine 35.7g(0.65mol), BMImBF4/
BMImZnCl3Catalyst system 181g(catalyst 18g, accounts for 10%), stirring reaction 5h under the conditions of 70 DEG C of microwave radiations.Reaction
Complete, it is cooled to room temperature, extracts by ethyl acetate 150mL, merge upper organic layer, anhydrous magnesium sulfate is dried；Filtering, filtrate subtracts
Pressure distillation, recycling design, then rise high-temperature rectification, collect fraction, obtain content 99.2% 6,7-dihydro-5H-Pentamethylene. is also
(b) pyridine product 44g, yield 74%.
Ionic liquid catalyst systems reclaims:
Collect lower floor's filtrate ionic liquid and catalyst, wash 3 times with dichloromethane and remove Organic substance, then 70 DEG C of vacuum drying
2h.Set is for lower batch reaction.
Embodiment 3
A kind of preparation method of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also (b) pyridine
Specifically comprise the following steps that
6,7-dihydro-5H-Pentamethylene. also (b) pyridine synthesizes:
In sealed microwave reactor, put into Ketocyclopentane 42g(0.5mol successively), propargylamine 35.7g(0.65mol), BMImBF4/
BMImZnCl3Catalyst system 181g(catalyst 13.4g, accounts for 8%), stirring reaction 4h under the conditions of 80 DEG C of microwave radiations.Reaction
Complete, it is cooled to room temperature, extracts by ethyl acetate 150mL, merge upper organic layer, anhydrous magnesium sulfate is dried；Filtering, filtrate subtracts
Pressure distillation, recycling design, then rise high-temperature rectification, collect fraction, obtain content 99.2% 6,7-dihydro-5H-Pentamethylene. is also
(b) pyridine product 43g, yield 72%.
Ionic liquid catalyst systems reclaims:
Collect lower floor's filtrate ionic liquid and catalyst, wash 3 times with dichloromethane and remove Organic substance, then 70 DEG C of vacuum drying
2h.Set is for lower batch reaction.
Embodiment 4
A kind of preparation method of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also (b) pyridine
Specifically comprise the following steps that
6,7-dihydro-5H-Pentamethylene. also (b) pyridine synthesizes:
In sealed microwave reactor, put into Ketocyclopentane 42g(0.5mol successively), propargylamine 35.7g(0.65mol), BMImBF4/
BMImZnCl3Catalyst system 181g(catalyst 18g, accounts for 10%), stirring reaction 1h under the conditions of 80 DEG C of microwave radiations.Reaction
Complete, it is cooled to room temperature, extracts with toluene 150mL, merge upper organic layer, anhydrous magnesium sulfate is dried；Filtering, filtrate decompression is steamed
Evaporate, recycling design, then rise high-temperature rectification, collect fraction, obtain content 99.2% 6,7-dihydro-5H-Pentamethylene. also (b)
Pyridine product 43.6g, yield 73%.
Ionic liquid catalyst systems reclaims:
Collect lower floor's filtrate ionic liquid and catalyst, wash 3 times with dichloromethane and remove Organic substance, then 70 DEG C of vacuum drying
2h.Set is for lower batch reaction.
Claims (9)
1. an ionic liquid synthesis medicine intermediate 6, the preparation method of 7-dihydro-5H-Pentamethylene. also (b) pyridine, its system
Preparation Method includes: (1) ionic liquid carried catalyst BMImZnCl3Preparation, (2) with Ketocyclopentane and propargylamine as raw material,
BMImBF4/BMImZnCl3Under catalyst system and catalyzing, microwave heating synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. (b) pyridine, instead
Reactant liquor organic solvent extraction should be terminated, be dried, distillation, obtain content product more than 99.0%, yield reaches 70% ~ 75%.
2. a kind of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also (b) pyrrole as claimed in claim 1
The preparation method of pyridine, it is characterised in that first prepare ionic liquid carried catalyst BMImZnCl3。
3. a kind of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also (b) pyrrole as claimed in claim 1
The preparation method of pyridine, it is characterised in that the ratio of the amount of the material of reaction raw materials Ketocyclopentane and propargylamine is 1:1.2 ~ 1.8.
4. a kind of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also (b) pyrrole as claimed in claim 1
The preparation method of pyridine, it is characterised in that ionic liquid BMImBF4Consumption is Ketocyclopentane 3 ~ 5 times.
5. a kind of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also (b) pyrrole as claimed in claim 1
The preparation method of pyridine, it is characterised in that catalyst BMImZnCl3For BMImBF4The 5% ~ 15% of consumption.
6. a kind of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also (b) pyrrole as claimed in claim 1
The preparation method of pyridine, it is characterised in that microwave reaction temperature is 60 ~ 100 DEG C.
7. a kind of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also (b) pyrrole as claimed in claim 1
The preparation method of pyridine, it is characterised in that it is ethyl acetate, ethanol, dichloromethane, first that reaction terminate reactant liquor to extract organic solvent
Benzene etc..
8. a kind of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also (b) pyrrole as claimed in claim 1
The preparation method of pyridine, it is characterised in that described post processing is reactant liquor organic solvent extraction, is dried, and distillation obtains content
Product more than 99.0%.
9. a kind of ionic liquid synthesis medicine intermediate 6,7-dihydro-5H-Pentamethylene. also (b) pyrrole as claimed in claim 1
The preparation method of pyridine, it is characterised in that ionic liquid catalyst systems is recovered as: collect lower floor's filtrate ionic liquid and catalyst, uses
Organic solvent washing removes Organic substance, then 70 DEG C of vacuum drying 2h for 3 times, and set is for lower batch reaction.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112778306A (en) * | 2021-03-08 | 2021-05-11 | 吉林化工学院 | Synthetic method of 1, 8-naphthyridine derivative |
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2016
- 2016-08-23 CN CN201610701513.4A patent/CN106316952A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103509590A (en) * | 2012-06-21 | 2014-01-15 | 中国石油天然气股份有限公司 | Oxidative desulfurization method based on Lewis acidic ionic liquid |
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| 凌杰 等: "酸性离子液体及其在催化酯化反应中的应用研究进展", 《化学工程与装备》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112778306A (en) * | 2021-03-08 | 2021-05-11 | 吉林化工学院 | Synthetic method of 1, 8-naphthyridine derivative |
| CN112778306B (en) * | 2021-03-08 | 2024-01-26 | 吉林化工学院 | Synthesis method of 1, 8-naphthyridine derivative |
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Application publication date: 20170111 |