CN107778257A - A kind of synthetic method of bridged piperazine derivatives - Google Patents
A kind of synthetic method of bridged piperazine derivatives Download PDFInfo
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- CN107778257A CN107778257A CN201610769728.XA CN201610769728A CN107778257A CN 107778257 A CN107778257 A CN 107778257A CN 201610769728 A CN201610769728 A CN 201610769728A CN 107778257 A CN107778257 A CN 107778257A
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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
Abstract
The invention discloses a kind of synthetic method of the carboxylic acid tert-butyl ester of bridged piperazine derivatives 3 (3 nitrobenzophenone) piperazine 1, using 1 (3 nitrobenzophenone) ethyl ketone 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 bridged piperazine derivatives 3- (3- nitre
Base phenyl) piperazine -1- carboxylic acid tert-butyl esters a kind of synthesis technique.
Technical background
Bridged piperazine derivatives 3- (3- nitrobenzophenones) piperazine -1- carboxylic acid tert-butyl esters, structural formula are：
Antimicrobial agents are the current clinical practice a kind of medicines larger compared with wide, dosage, in control and treatment disease side
Face plays an important role.The antimicrobial agents kind of Clinical practice is numerous at present, 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 one of important channels for solving drug resistance, it has also become current pharmaceutical chemistry is very active
Field.
Piperazine ring be in pharmaceutical chemistry research commonly use a kind of basic group, 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
Molecule it is alkaline and water-soluble, 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 substituted 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
Actively and quickly grow, show the development potentiality of broadness.
A kind of 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 bridged piperazine derivatives 3- (3- nitrobenzophenones) piperazine -1- carboxylic acid tert-butyl esters,
Using 1- (3- nitrobenzophenones) ethyl ketone as initiation material, target product is obtained through peroxidating, cyclization, upper Boc, synthesis step is as follows：
(1) using 1- (3- nitrobenzophenones) ethyl ketone as initiation material, oxidized reaction obtains 2；
(2) ring-closure reaction is occurred for 3 and ethylenediamine, obtains 3；
(3) 3 and Boc2O reacts to obtain 4；
In a preferred embodiment, the oxidising agent used in the described benzene of oxidation reaction prepare compound 2 is selected from two
Selenium oxide；Reducing agent used in described ring-closure reaction prepare compound 3 is selected from sodium borohydride；Described amido protecting reaction institute
Alkali is selected from sodium acid carbonate.
In a preferred embodiment, the solvent used in the described benzene of oxidation reaction prepare compound 2 is selected from tetrahydrochysene furan
Mutter；Solvent used in described ring-closure reaction prepare compound 3 is selected from ethanol；Described amido protecting reaction solvent choosing used
From dichloromethane.
In a preferred embodiment, the reaction temperature used in the described benzene of 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
Reaction temperature used is room temperature.
The present invention relates to the synthesis technique of bridged piperazine derivatives 3- (3- nitrobenzophenones) piperazine -1- carboxylic acid tert-butyl esters, 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 compound 2
20g parabromoacetophenones are added in 150ml tetrahydrofurans, add 45g selenium dioxide, heating stirring backflow 12 is small
When, room temperature is cooled to, is filtered, is added water and ethyl acetate is extracted, liquid separation, drying, concentration obtain crude product diethyl two
Aldehyde is recrystallized to give 11g compounds 2 to bromobenzene.
(2) synthesis of compound 3
The glyoxals of 10g bis- are added in 130ml ethanol to bromobenzene, add 8.5g ethylenediamines, are heated to reflux 6 hours,
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, is extracted
Liquid separation, organic phase is collected, liquid separation, drying, concentration, silica gel post separation obtains 9.5g compounds 3 on residue.
(3) synthesis of 3- (4- bromophenyls) piperazine -1- carboxylic acid tert-butyl esters
9g 2- (4- bromophenyls) piperazine is added in 100ml dichloromethane, add 9.8g di-tert-butyl dicarbonates,
3ml triethylamines, it is stirred at room temperature 24 hours, addition water, extraction liquid separation, collection organic phase, liquid separation, drying, concentration, silicon on residue
Glue post separation obtains 12.4g 3- (4- bromophenyls) piperazine -1- carboxylic acid tert-butyl esters.
Claims (6)
- A kind of 1. synthetic method of bridged piperazine derivatives 3- (3- nitrobenzophenones) piperazine -1- carboxylic acid tert-butyl esters, it is characterized in that with 1- (3- Nitrobenzophenone) ethyl ketone is initiation material, target product 4 is obtained 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 1- (3- nitrobenzophenones) ethyl ketone as initiation material, oxidized reaction obtains 2；(2) ring-closure reaction is occurred for 3 and ethylenediamine, obtains 3；(3) 3 and Boc2O reacts to obtain 4；
- 3. method according to claim 1, it is characterised in that the oxidation examination used in the described benzene of oxidation reaction prepare compound 2 One or more of mixing of the agent in manganese dioxide, selenium dioxide, pyridine chlorochromate, pyridinium dichromate, chromium trioxide Thing；Reducing agent used in described ring-closure reaction prepare compound 3 is selected from lithium borohydride, sodium borohydride, potassium borohydride, tetrahydrochysene aluminium One or more of mixtures in lithium, sodium cyanoborohydride, sodium triacetoxy borohydride；Described amido protecting reaction institute Alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, triethylamine, sodium acid carbonate, pyridine, three different One or more of mixtures in propyl group amine, saleratus.
- 4. method according to claim 1, it is characterised in that the solvent choosing used in the described benzene of oxidation reaction prepare compound 2 From methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- dimethyl One or more of mixtures in formamide, DMAC N,N' dimethyl acetamide；Used in described ring-closure reaction prepare compound 3 Solvent 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 the described benzene of oxidation reaction prepare compound 2 Degree 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 the described benzene of oxidation reaction prepare compound 2 Degree is room 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.
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| CN201610769728.XA CN107778257A (en) | 2016-08-29 | 2016-08-29 | A kind of synthetic method of bridged piperazine derivatives |
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| CN201610769728.XA CN107778257A (en) | 2016-08-29 | 2016-08-29 | A kind of synthetic method of bridged piperazine derivatives |
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Cited By (2)
| 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 |
| CN106977463A (en) * | 2017-05-31 | 2017-07-25 | 湖南华腾制药有限公司 | A kind of synthetic method of biphenyl substituted piperazine derivatives |
Citations (2)
| 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 |
| CN105636961A (en) * | 2013-10-16 | 2016-06-01 | 勃林格殷格翰国际有限公司 | Piperazine derivatives and the use thereof as medicament |
-
2016
- 2016-08-29 CN CN201610769728.XA patent/CN107778257A/en not_active Withdrawn
Patent Citations (2)
| 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 |
| CN105636961A (en) * | 2013-10-16 | 2016-06-01 | 勃林格殷格翰国际有限公司 | Piperazine derivatives and the use thereof as medicament |
Non-Patent Citations (1)
| Title |
|---|
| YONG LI等: "Asymmetric hrdrogenation of 2-aryl-5,6-dihydropyrazine derivatives with chiral cationic ruthenium diamine catalysts", 《CHINESE JOURNAL OF CHEMISTRY》 * |
Cited By (2)
| 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 |
| CN106977463A (en) * | 2017-05-31 | 2017-07-25 | 湖南华腾制药有限公司 | A kind of synthetic method of biphenyl substituted piperazine derivatives |
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Application publication date: 20180309 |