CN108530370A - A kind of method of one pot process cycleanine - Google Patents
A kind of method of one pot process cycleanine Download PDFInfo
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- CN108530370A CN108530370A CN201810593472.0A CN201810593472A CN108530370A CN 108530370 A CN108530370 A CN 108530370A CN 201810593472 A CN201810593472 A CN 201810593472A CN 108530370 A CN108530370 A CN 108530370A
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- Prior art keywords
- cycleanine
- pot process
- reaction
- sulfate
- cyclization
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of methods of one pot process cycleanine; it is related to organic intermediate synthesis technical field; using diethylenetriamine and diethanol amine as reaction raw materials; in the presence of acid binding agent intermediate is generated through cyclization with protective agent benzene sulfonyl chloride; intermediate obtains cycleanine sulfate through concentrated sulfuric acid Deprotection, and the neutralized reaction in toluene of cycleanine sulfate generates cycleanine.The present invention simplifies the generation for reducing a large amount of brine wastes, waste residue while operating process, reduces cost, to be suitable for industrialization large-scale production cycleanine to having reported that synthetic method is improved.
Description
Technical field：
The present invention relates to Manufacturing Technologies of Organic Intermediates fields, and in particular to a kind of side of one pot process cycleanine
Method.
Background technology：
Cycleanine is mainly as synthetic intermediate, it can also be used to developer intermediate.Industrialized production uses at present
Richman-Atkins synthetic methods, using diethylenetriamine and diethanol amine as raw material, respectively with paratoluensulfonyl chloride to each ammonia
Base and hydroxyl are protected, and are obtained two protection products and are condensed, cyclization, then Deprotection, and final alkalization is free to be taken turns
Ring rattan is peaceful.Its synthetic route：
The synthetic method and its cumbersome, obtained 3 purity of intermediate is not also high, and huge using quantity of solvent, cost pole
Uneconomical, environmental protection pressure is also huge.In addition cycleanine product is obtained from 3 Deprotection of intermediate to be deprotected through persulfuric acid
Base, hydrochloric acid replace sulfate, then alkali neutralization, and acidic and alkaline waste water and brine waste amount are huge, and the pressure for facing environmental protection is very huge,
It currently emphasizes under environmental-friendly form, the production technology is on the verge of being replaced.
Invention content：
Technical problem to be solved by the present invention lies in provide a kind of to substantially reduce cost, simplify operation and reduce useless
Water, waste residue yield one pot process cycleanine method.
The technical problems to be solved by the invention are realized using technical solution below：
A kind of method of one pot process cycleanine is being tied up using diethylenetriamine and diethanol amine as reaction raw materials
Intermediate is generated through cyclization with protective agent benzene sulfonyl chloride in the presence of sour agent, intermediate obtains torus through concentrated sulfuric acid Deprotection
The peaceful sulfate of rattan, the neutralized reaction in toluene of cycleanine sulfate generate cycleanine.
The cyclization is using N,N-dimethylformamide as reaction dissolvent.
The acid binding agent is potassium carbonate.
The neutralization reaction is using sodium hydroxide solution as neutralization reagent.
The beneficial effects of the invention are as follows：
(1) present invention is by one-step synthesis method intermediate, without detach diethylenetriamine and diethanol amine respectively with protection
The product (intermediate 1 and intermediate 2) of agent reaction reduces solvent dosage and waste residue yield, most while greatly simplifying operation
Final decline low cost；
(2) intermediate is made through one-step method as protective agent in the present invention benzene sulfonyl chloride smaller and more economical using molecular weight,
Protectant a large amount of uses are avoided while reducing cost and increase wastewater treatment difficulty；
(3) although the present invention still sloughs the protecting group on intermediate structure using concentrated sulfuric acid classical approach, neutralization is simplified
Free operation replaces sulfate without using hydrochloric acid, but directly cycleanine sulfate is placed in toluene, using in liquid caustic soda
With the product cycleanine that dissociates；This process simplify operating process, and reduce the generation of a large amount of brine wastes, waste residue, from
And it is suitable for industrialization large-scale production cycleanine.
Specific implementation mode：
In order to make the technical means, the creative features, the aims and the efficiencies achieved by the present invention be easy to understand, tie below
Specific embodiment is closed, the present invention is further explained.
Embodiment 1
The synthesis of intermediate：
In dry reaction kettle, input DMF 1600kg, diethylenetriamine 100kg, diethanol amine 100.2kg, potassium carbonate
After 1382kg, 20-25 DEG C of stirring 30min, start that benzene sulfonyl chloride is added dropwise, 20-25 DEG C, 3h drips off 1070kg, is warming up to 30 DEG C instead
3h should be stirred, 110-115 DEG C of insulation reaction 12h is continuously heating to, DMF solvent is recovered under reduced pressure to dry, the addition heat in reaction kettle
After water 2800kg, 80 DEG C of stirring 2h, filter while hot, filter cake is washed with water to neutrality, and drying obtains in canescence or faint yellow solid
Mesosome 650kg, yield 91% (diethylenetriamine calculating).
Embodiment 2
The synthesis of intermediate：
In dry reaction kettle, input DMF 1000kg, diethylenetriamine 100kg, diethanol amine 100.2kg, triethylamine
After 850kg, 20-25 DEG C of stirring 30min, start that benzene sulfonyl chloride is added dropwise, 20-25 DEG C, 3h drips off 1070kg, is warming up to 30 DEG C of reactions
3h is stirred, 100-105 DEG C of insulation reaction 12h is continuously heating to, DMF solvent is recovered under reduced pressure to dry, the addition hot water in reaction kettle
After 1800kg, 50 DEG C of stirring 30min, filter while hot, filter cake is washed with water to neutrality, dries intermediate 641kg, yield 89.7%.
Embodiment 3
The synthesis of cycleanine：
Intermediate 650kg, concentrated sulfuric acid 3250kg are put into dry reaction kettle, are warming up to 90 DEG C, react 60h, heat preservation knot
Beam is cooled to 20 DEG C, starts that 3000kg absolute ethyl alcohols are added dropwise, a large amount of pale solids, a small amount of absolute ethyl alcohol rinsing is precipitated in stirring
Afterwards, in reaction kettle of the filter cake input equipped with 2000kg toluene, it is multiple that 30% liquid caustic soda of dropwise addition is adjusted to feed liquid water layer pH >=11,30min
After survey pH >=11 are constant, it is filtered to remove solid, then liquid lower layer water phase point is gone, starts to concentrate toluene feed liquid to 1/4, freeze
To -2 DEG C, solid crystal is filtered out, drying obtains cycleanine product 104kg, yield 73%.
The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (4)
1. a kind of method of one pot process cycleanine, it is characterised in that：Using diethylenetriamine and diethanol amine as reaction
Raw material generates intermediate with protective agent benzene sulfonyl chloride in the presence of acid binding agent through cyclization, and intermediate is deprotected through the concentrated sulfuric acid
Base obtains cycleanine sulfate, and the neutralized reaction in toluene of cycleanine sulfate generates cycleanine.
2. the method for one pot process cycleanine according to claim 1, it is characterised in that：The cyclization with N,
Dinethylformamide is as reaction dissolvent.
3. the method for one pot process cycleanine according to claim 1, it is characterised in that：The acid binding agent is carbonic acid
Potassium.
4. the method for one pot process cycleanine according to claim 1, it is characterised in that：The neutralization reaction is with hydrogen
Sodium hydroxide solution is as neutralization reagent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810593472.0A CN108530370A (en) | 2018-06-08 | 2018-06-08 | A kind of method of one pot process cycleanine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810593472.0A CN108530370A (en) | 2018-06-08 | 2018-06-08 | A kind of method of one pot process cycleanine |
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| CN108530370A true CN108530370A (en) | 2018-09-14 |
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| CN201810593472.0A Pending CN108530370A (en) | 2018-06-08 | 2018-06-08 | A kind of method of one pot process cycleanine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110922365A (en) * | 2019-12-13 | 2020-03-27 | 山东铂源药业有限公司 | Preparation method of high-purity cycleanine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827150A (en) * | 2012-09-06 | 2012-12-19 | 中国工程物理研究院核物理与化学研究所 | Fullerene single-large-ring polyamine derivative and preparation method thereof |
| US9062009B2 (en) * | 2012-12-31 | 2015-06-23 | National Yang Ming University | Macrocyclic compounds and metal complexes for bioimaging and biomedical applications |
-
2018
- 2018-06-08 CN CN201810593472.0A patent/CN108530370A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827150A (en) * | 2012-09-06 | 2012-12-19 | 中国工程物理研究院核物理与化学研究所 | Fullerene single-large-ring polyamine derivative and preparation method thereof |
| US9062009B2 (en) * | 2012-12-31 | 2015-06-23 | National Yang Ming University | Macrocyclic compounds and metal complexes for bioimaging and biomedical applications |
Non-Patent Citations (1)
| Title |
|---|
| TAKUMI YASUDA，ET AL.: "Estradiol linked to hetermacrocycles – Part 1： Estradiol-DO3A hybrid", 《ORIGINAL COMMUNICATION》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110922365A (en) * | 2019-12-13 | 2020-03-27 | 山东铂源药业有限公司 | Preparation method of high-purity cycleanine |
| CN110922365B (en) * | 2019-12-13 | 2021-04-27 | 山东铂源药业有限公司 | Preparation method of high-purity cycleanine |
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Application publication date: 20180914 |
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