CN106977463A - A kind of synthetic method of biphenyl substituted piperazine derivatives - Google Patents
A kind of synthetic method of biphenyl substituted piperazine derivatives Download PDFInfo
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- CN106977463A CN106977463A CN201710401796.5A CN201710401796A CN106977463A CN 106977463 A CN106977463 A CN 106977463A CN 201710401796 A CN201710401796 A CN 201710401796A CN 106977463 A CN106977463 A CN 106977463A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a kind of synthetic method of biphenyl substituted piperazine derivatives 4 (base of N Boc piperazines 3) biphenyl; using 4 acetyl biphenyls as initiation material; target product is obtained through peroxidating, cyclization, upper Boc, the compound is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of biphenyl substituted piperazine derivatives
A kind of synthesis technique of 4- (N-Boc- piperazine -3- bases) biphenyl.
Technical background
Biphenyl substituted piperazine derivatives 4- (N-Boc- piperazine -3- bases) biphenyl, structural formula is：
Antimicrobial agents are a current clinical practice relatively wide, class medicines of large usage quantity, in control and treatment disease side
Face is played an important role.The antimicrobial agents kind of current Clinical practice is numerous, but a large amount of with antimicrobial agents
And widely use, irrational use particularly clinically, or even abuse, finally result in multidrug resistant.Therefore, how to overcome
Multidrug resistant turns into the important topic of antimicrobial agents research both at home and abroad at present.The method for solving drug resistance is numerous, wherein newly
The research and development of type structure antimicrobial agents are to solve one of important channel of drug resistance, it has also become current pharmaceutical chemistry is very active
Field.
Piperazine ring is the class basic group commonly used in pharmaceutical chemistry research, its small toxicity, easily formed multiple hydrogen bonds or from
Sub-key, often can the effectively lipid of regulating drug and acid-base balance constant.Molecule is introduced into, can effectively be increased
The alkaline and water solubility of molecule, so as to strengthen the activity of molecule.Therefore, to a certain extent, piperazine group is a synergy base
Group, often introduces in the design and exploitation of many medicines.Research shows that the compound replaced containing piperazine and N- is often shown extensively
Bioactivity, such as antimicrobial, anti-hypertension, anticancer, anti-inflammatory and analgesic, especially as antimicrobial agents, it is studied
Enliven and quickly grow, show the development potentiality of broadness.
Class bridged piperazine derivatives intermediate of the present invention plays an important roll for new drug development.
The content of the invention
The invention discloses a kind of synthetic method of biphenyl substituted piperazine derivatives 4- (N-Boc- piperazine -3- bases) biphenyl,
Using 4- acetyl biphenyls as initiation material, target product is obtained through peroxidating, cyclization, upper Boc, synthesis step is as follows：
(1) using 4- acetyl biphenyls as initiation material, oxidized reaction obtains 2；
(2) occur ring-closure reaction with ethylenediamine 3, obtain 3；
(3) 3 and Boc2O reactions obtain 4；
In a preferred embodiment, the oxidising agent used in described oxidation reaction prepare compound 2 is selected from dioxy
Change selenium；Reducing agent used in described ring-closure reaction prepare compound 3 is selected from sodium borohydride；Described amido protecting reaction is used
Alkali be selected from sodium acid carbonate.
In a preferred embodiment, the solvent used in described oxidation reaction prepare compound 2 is selected from tetrahydrofuran；
Solvent used in described ring-closure reaction prepare compound 3 is selected from ethanol；Described amido protecting reaction solvent used is selected from
Dichloromethane.
In a preferred embodiment, the reaction temperature used in described oxidation reaction prepare compound 2 is solvent
Reflux temperature；Temperature used in described ring-closure reaction prepare compound 3 is the reflux temperature of solvent；Described amido protecting is anti-
Temperature that should be used is room temperature.
The present invention relates to the synthesis technique of biphenyl substituted piperazine derivatives 4- (N-Boc- piperazine -3- bases) biphenyl, do not have at present
There is other Patents documents report.
The present invention is further described by the following embodiment, and these descriptions are not present invention to be made into one
The restriction of step.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 4- (two glyoxals) biphenyl
20g 4- acetyl biphenyls are added in 150ml tetrahydrofurans, 45g selenium dioxide, heating stirring backflow is added
12 hours, room temperature is cooled to, is filtered, is added water and ethyl acetate is extracted, point liquid, drying, concentration obtain crude product two
Glyoxal is recrystallized to give 11g 4- (two glyoxals) biphenyl to bromobenzene.
(2) synthesis of 4- piperazines biphenyl
10g 4- (two glyoxals) biphenyl is added in 130ml ethanol, 8.5g ethylenediamines is added, is heated to reflux 6
Hour, room temperature is cooled to, 3.8g sodium borohydrides are added portionwise, is stirred at room temperature 4 hours, 1N hydrochloric acid is added, adds ethyl acetate,
Extraction point liquid, collects organic phase, point liquid, drying, concentration, and silica gel post separation obtains 9.5g 4- piperazine biphenyl on residue.
(3) synthesis of 4- (N-Boc- piperazine -3- bases) biphenyl
9g 4- piperazine biphenyl is added in 100ml dichloromethane, 9.8g di-tert-butyl dicarbonates, the second of 3ml tri- is added
Amine, is stirred at room temperature 24 hours, adds water, and extraction point liquid collects organic phase, point liquid, drying, concentration, silicagel column point on residue
From 12.4g 4- (N-Boc- piperazine -3- bases) biphenyl.
Claims (6)
1. a kind of synthetic method of biphenyl substituted piperazine derivatives 4- (N-Boc- piperazine -3- bases) biphenyl, it is characterized in that with 4- second
Acyl group biphenyl is initiation material, obtains target product 4 through peroxidating, cyclization, upper Boc, synthetic route is as follows：
2. method according to claim 1, it is characterized in that described 3 steps reaction is,
(1) using 4- acetyl biphenyls as initiation material, oxidized reaction obtains 2；
(2) occur ring-closure reaction with ethylenediamine 3, obtain 3；
(3) 3 and Boc2O reactions obtain 4；
3. method according to claim 1, it is characterised in that the oxidising agent used in described oxidation reaction prepare compound 2
One or more of mixtures in manganese dioxide, selenium dioxide, pyridine chlorochromate, pyridinium dichromate, chromium trioxide；
Reducing agent used in described ring-closure reaction prepare compound 3 be selected from lithium borohydride, sodium borohydride, potassium borohydride, Lithium Aluminium Hydride,
One or more of mixtures in sodium cyanoborohydride, sodium triacetoxy borohydride；Described amido protecting reaction is used
Alkali be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, triethylamine, sodium acid carbonate, pyridine, three isopropyls
One or more of mixtures in base amine, saleratus.
4. method according to claim 1, it is characterised in that the solvent used in described oxidation reaction prepare compound 2 is selected from
Methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- dimethyl methyls
One or more of mixtures in acid amides, DMAC N,N' dimethyl acetamide；It is molten used in described ring-closure reaction prepare compound 3
Agent is selected from methanol, ethanol, isopropanol, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, toluene, tetrahydrofuran, first
One or more in benzene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide
Mixture；Described amido protecting reaction solvent used is selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, two
Chloromethanes, chloroform, ethyl acetate, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N,
One or more of mixtures in N- dimethyl acetamides.
5. method according to claim 1, it is characterised in that the reaction temperature used in described oxidation reaction prepare compound 2
It is the reflux temperature of 0 DEG C~solvent；Temperature used in described ring-closure reaction prepare compound 3 is the backflow temperature of 0 DEG C-solvent
Degree；Described amido protecting reaction temperature used is the reflux temperature of 0 DEG C-solvent.
6. method according to claim 1, it is characterised in that the reaction temperature used in described oxidation reaction prepare compound 2
It is room temperature；Temperature used in described ring-closure reaction prepare compound 3 is the reflux temperature of solvent；Described amido protecting reaction
Temperature used is room temperature.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710401796.5A CN106977463A (en) | 2017-05-31 | 2017-05-31 | A kind of synthetic method of biphenyl substituted piperazine derivatives |
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| CN201710401796.5A CN106977463A (en) | 2017-05-31 | 2017-05-31 | A kind of synthetic method of biphenyl substituted piperazine derivatives |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106854189A (en) * | 2015-12-08 | 2017-06-16 | 湖南华腾制药有限公司 | A kind of synthetic method of diethylenediamine compound |
Citations (4)
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|---|---|---|---|---|
| CN101115717A (en) * | 2005-02-10 | 2008-01-30 | 安万特药物公司 | Substituted bis aryl and heteroaryl compounds as selective 5ht2a antagonists |
| WO2015055698A1 (en) * | 2013-10-16 | 2015-04-23 | Boehringer Ingelheim International Gmbh | Piperazine derivatives and the use thereof as medicament |
| CN106854189A (en) * | 2015-12-08 | 2017-06-16 | 湖南华腾制药有限公司 | A kind of synthetic method of diethylenediamine compound |
| CN107778257A (en) * | 2016-08-29 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of synthetic method of bridged piperazine derivatives |
-
2017
- 2017-05-31 CN CN201710401796.5A patent/CN106977463A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101115717A (en) * | 2005-02-10 | 2008-01-30 | 安万特药物公司 | Substituted bis aryl and heteroaryl compounds as selective 5ht2a antagonists |
| WO2015055698A1 (en) * | 2013-10-16 | 2015-04-23 | Boehringer Ingelheim International Gmbh | Piperazine derivatives and the use thereof as medicament |
| CN106854189A (en) * | 2015-12-08 | 2017-06-16 | 湖南华腾制药有限公司 | A kind of synthetic method of diethylenediamine compound |
| CN107778257A (en) * | 2016-08-29 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of synthetic method of bridged piperazine derivatives |
Non-Patent Citations (1)
| Title |
|---|
| YONG LI ET AL: ""Asymmetric Hydrogenation of 2-Aryl-5,6-dihydropyrazine Derivatives with Chiral Cationic Ruthenium Diamine Catalysts"", 《CHINESE JOURNAL OF CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106854189A (en) * | 2015-12-08 | 2017-06-16 | 湖南华腾制药有限公司 | A kind of synthetic method of diethylenediamine compound |
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