CN104817515A - Preparation method of benzene substituent oxadiazole compound - Google Patents
Preparation method of benzene substituent oxadiazole compound Download PDFInfo
- Publication number
- CN104817515A CN104817515A CN201510193918.7A CN201510193918A CN104817515A CN 104817515 A CN104817515 A CN 104817515A CN 201510193918 A CN201510193918 A CN 201510193918A CN 104817515 A CN104817515 A CN 104817515A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- xylol
- solvent
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- WHMALKKSNDMZAB-UHFFFAOYSA-N CCNCc1nc(-c(cc(cc2)OC)c2Br)n[o]1 Chemical compound CCNCc1nc(-c(cc(cc2)OC)c2Br)n[o]1 WHMALKKSNDMZAB-UHFFFAOYSA-N 0.000 description 1
- HVHQHSLJAQURBJ-UHFFFAOYSA-N COc(cc1C=N)ccc1Br Chemical compound COc(cc1C=N)ccc1Br HVHQHSLJAQURBJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a preparation method of a benzene substituent oxadiazole compound N-((3-(2-bromine-5-methoxy phenyl)-1, 2, 4-oxadiazole-5-radical) methyl) ethylamine. 4-bromoanisole serves as a starting material and is subjected to aldehydes, oximate, elimination, addition, cyclization and substitution reaction to obtain a target product 7. The product serving as a template micro-molecule for synthesizing diversified compound libraries.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, oxadiazole compound N-((3-(the bromo-5-p-methoxy-phenyl of 2-)-1 is replaced in particular to a kind of benzene, 2,4-oxadiazoles-5-base) methyl) preparation method of ethamine.
Technical background
Compound N-((3-(the bromo-5-p-methoxy-phenyl of 2-)-1,2,4-oxadiazoles-5-bases) methyl) ethamine, structural formula is:
This compound N-((3-(2-bromo-5-p-methoxy-phenyl)-1,2,4-oxadiazoles-5-bases) methyl) ethamine and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current N-((3-(2-bromo-5-p-methoxy-phenyl)-1,2,4-oxadiazoles-5-bases) methyl) ethamine is comparatively difficult.Therefore, need exploitation raw material to be easy to get, easy to operate, reaction is easy to control, the synthetic method that overall yield is suitable.
Summary of the invention
The invention discloses a kind of benzene and replace oxadiazole compound N-((3-(the bromo-5-p-methoxy-phenyl of 2-)-1,2,4-oxadiazoles-5-base) methyl) preparation method of ethamine, with 4-bromoanisole for starting raw material, obtain target product 7 through aldehyde radical, oximate, elimination, addition, Guan Huan, substitution reaction, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with 4-bromoanisole for starting raw material, be obtained by reacting 2 through aldehyde radical,
(2) carry out oximation reaction 2, obtain 3,
(3) carry out eliminative reaction 3 and obtain 4,
(4) carry out addition reaction 4 and obtain 5,
(5) carry out ring closure reaction 5 and obtain 6,
(6) carry out substitution reaction 6 and obtain 7;
One preferred embodiment in, the reagent that described aldehyde glycosylation reaction prepares compound 2 used is selected from DMF; The reagent that described oximation reaction prepares compound 3 used is selected from oxammonium hydrochloride; The reagent that described eliminative reaction prepares compound 4 used is selected from phosphorus oxychloride; The reagent that described addition reaction prepares compound 5 used is selected from oxammonium hydrochloride; The reagent that described pass cyclization prepares compound 6 used is selected from chloroacetyl chloride; The alkali that described substitution reaction prepares compound 7 used is selected from salt of wormwood.
One preferred embodiment in, the solvent that described aldehyde glycosylation reaction prepares compound 2 used is selected from tetrahydrofuran (THF); Described oximation reaction prepares compound 3 solvent selected from ethanol used; The solvent that described eliminative reaction prepares compound 4 used is selected from tetrahydrofuran (THF); The mixture of compound 5 solvent selected from methanol used and water is prepared in described addition reaction; The solvent that described pass cyclization prepares compound 6 used is selected from methylene dichloride; The solvent that described substitution reaction prepares compound 7 used is selected from DMF.
One preferred embodiment in, it is-78 DEG C ~ room temperature that described aldehyde glycosylation reaction prepares compound 2 temperature of reaction used; Described oximation reaction prepares the reflux temperature that compound 3 temperature used is solvent; Described eliminative reaction prepares the reflux temperature that compound 4 temperature used is solvent; It is room temperature that compound 5 temperature used is prepared in described addition reaction; It is room temperature that described pass cyclization prepares compound 6 temperature used; It is 100 DEG C that compound 7 temperature used is prepared in described substitution reaction.
The present invention relates to the preparation method that a kind of benzene replaces oxadiazole compound N-((3-(the bromo-5-p-methoxy-phenyl of 2-)-1,2,4-oxadiazoles-5-bases) methyl) ethamine, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound N-((3-(the bromo-5-p-methoxy-phenyl of 2-)-1,2,4-oxadiazoles-5-bases) methyl) ethamine.
The present invention is further described by the following embodiment, and these descriptions are not be further limited content of the present invention.One skilled in the art will understand that the equivalent replacement that technical characteristic of the present invention is done, or improve accordingly, still belong within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of the bromo-5-methoxybenzaldehyde of 2-
20g 4-bromoanisole is joined in 230ml tetrahydrofuran (THF), is cooled to-78 DEG C, add the n-Butyl Lithium of 130ml 2.5M, stirring reaction 2 hours, then add DMF, naturally stirred overnight at room temperature is warming up to, add 1N hydrochloric acid, add ethyl acetate, extraction separatory, collect organic phase, drying, concentrated, obtain the bromo-5-methoxybenzaldehyde of 17g 2-.
(2) synthesis of 2-bromo-5-methoxybenzaldehyde oxime
Bromo-for 17g 2-5-methoxybenzaldehyde is joined in 210ml ethanol, adds 14g oxammonium hydrochloride, reflux 4 hours, add water and extraction into ethyl acetate separatory, collect organic phase, dry, concentrate and obtain 15g 2-bromo-5-methoxybenzaldehyde oxime.
(3) synthesis of the bromo-5-HOMOVERATRONITRILE of 2-
Bromo-for 15g 2-5-methoxybenzaldehyde oxime is joined in 150ml tetrahydrofuran (THF), adds 40g trifluoroacetic anhydride, then add 20ml triethylamine, concentrated, add water and extraction into ethyl acetate separatory, collect organic phase, drying, concentrated, on residuum, silicagel column is separated to obtain the bromo-5-HOMOVERATRONITRILE of 11g 2-.
(4) synthesis of 2-bromo-N'-hydroxy-5-methyl oxygen base benzenyl amidine
Bromo-for 11g 2-5-HOMOVERATRONITRILE is joined in the mixed solvent of 200ml methyl alcohol and 100ml water, add 9g oxammonium hydrochloride and 12g sodium acetate, anhydrous again, reflux stirring reaction 12 hours, add water and ethyl acetate, extraction separatory, collects organic phase, dry, concentrated, on residuum, silicagel column is separated and obtains 9g 2-bromo-N'-hydroxy-5-methyl oxygen base benzenyl amidine.
(5) synthesis of 3-(the bromo-5-p-methoxy-phenyl of 2-)-5-(chloromethyl)-1,2,4-oxadiazoles
Bromo-for 8g 2-N'-hydroxy-5-methyl oxygen base benzenyl amidine is joined in 180ml methylene dichloride, adds 7g triethylamine, add 10g chloroacetyl chloride, stirring at room temperature 4 hours, filters, concentrated, residuum joins in 150ml toluene, and heated overnight at reflux adds water and ethyl acetate, extraction separatory, collect organic phase, dry, concentrate and obtain 6g 3-(the bromo-5-p-methoxy-phenyl of 2-)-5-(chloromethyl)-1,2,4-oxadiazoles.
(6) synthesis of N-((3-(the bromo-5-p-methoxy-phenyl of 2-)-1,2,4-oxadiazoles-5-bases) methyl) ethamine
5g 3-(the bromo-5-p-methoxy-phenyl of 2-)-5-(chloromethyl)-1,2,4-oxadiazoles joins 120ml N, in dinethylformamide, add 4g salt of wormwood and 3.6g ethylamine hydrochloride again, be heated to 100 DEG C, stir 3 hours, add water and ethyl acetate, extraction separatory, collect organic phase, drying, concentrated, residuum silicagel column is separated and obtains 3g N-((3-(the bromo-5-p-methoxy-phenyl of 2-)-1,2,4-oxadiazoles-5-base) methyl) ethamine.
Claims (5)
1. a benzene replaces oxadiazole compound N-((3-(the bromo-5-p-methoxy-phenyl of 2-)-1,2,4-oxadiazoles-5-base) methyl) preparation method of ethamine, with 4-bromoanisole for starting raw material, obtain target product 7 through aldehyde radical, oximate, elimination, addition, Guan Huan, substitution reaction, synthetic route is as follows:
2. method according to claim 1, it is characterized by 6 described step reactions is,
(1) with 4-bromoanisole for starting raw material, be obtained by reacting 2 through aldehyde radical,
(2) carry out oximation reaction 2, obtain 3,
(3) carry out eliminative reaction 3 and obtain 4,
(4) carry out addition reaction 4 and obtain 5,
(5) carry out ring closure reaction 5 and obtain 6,
(6) carry out substitution reaction 6 and obtain 7;
3. according to the method for claim 1-2, it is characterized in that, the reagent that described aldehyde glycosylation reaction prepares compound 2 used is selected from DMF; The reagent that described oximation reaction prepares compound 3 used is selected from oxammonium hydrochloride; Described eliminative reaction is prepared compound 4 reagent used and is selected from the mixture of one or more in phosphorus oxychloride, the vitriol oil, trifluoroacetic anhydride; The reagent that described addition reaction prepares compound 5 used is selected from oxammonium hydrochloride; The reagent that described pass cyclization prepares compound 6 used is selected from chloroacetyl chloride; Described substitution reaction is prepared compound 7 alkali used and is selected from the mixture of one or more in sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, triethylamine, pyridine.
4. according to the method for claim 1-2, it is characterized in that, described aldehyde glycosylation reaction prepares compound 2 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, triethylamine, pyridine, acetonitrile, acetic acid, trimethyl orthoformate; Described oximation reaction prepares compound 3 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile, ammoniacal liquor; Described eliminative reaction prepares compound 4 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetic acid, water; Compound 5 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, acetonitrile, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, toluene, o-Xylol, p-Xylol, m-xylene, N are prepared in described addition reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetic acid, water; Described pass cyclization prepares compound 6 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile, ammoniacal liquor; Compound 7 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, toluene, o-Xylol, p-Xylol, m-xylene, N are prepared in described substitution reaction, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetonitrile.
5. according to the method for claim 1-2, it is characterized in that, described aldehyde glycosylation reaction prepares the reflux temperature that compound 2 temperature of reaction used is-78 DEG C ~ solvent; Described oximation reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; Described eliminative reaction prepares the reflux temperature that compound 4 temperature used is room temperature ~ solvent; The reflux temperature that compound 5 temperature used is room temperature ~ solvent is prepared in described addition reaction; It is 0 DEG C ~ room temperature that described pass cyclization prepares compound 6 temperature used; The reflux temperature that compound 7 temperature used is room temperature ~ solvent is prepared in described substitution reaction.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510193918.7A CN104817515A (en) | 2015-04-22 | 2015-04-22 | Preparation method of benzene substituent oxadiazole compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510193918.7A CN104817515A (en) | 2015-04-22 | 2015-04-22 | Preparation method of benzene substituent oxadiazole compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104817515A true CN104817515A (en) | 2015-08-05 |
Family
ID=53728016
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510193918.7A Pending CN104817515A (en) | 2015-04-22 | 2015-04-22 | Preparation method of benzene substituent oxadiazole compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104817515A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107400099A (en) * | 2016-05-19 | 2017-11-28 | 湖南华腾制药有限公司 | The preparation method of Yi Zhong oxadiazole compounds |
| CN107698535A (en) * | 2016-08-08 | 2018-02-16 | 湖南华腾制药有限公司 | A kind of preparation method of benzene substitution oxadiazole compound |
| CN107778264A (en) * | 2016-08-29 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of preparation method of the substitution oxadiazole compound containing fluorobenzene |
| CN108129415A (en) * | 2016-12-01 | 2018-06-08 | 湖南华腾制药有限公司 | A kind of synthetic method of fluorobenzene substitution oxadiazole compound |
| CN108299333A (en) * | 2017-01-12 | 2018-07-20 | 湖南华腾制药有限公司 | One kind 3,5- bis- replaces the preparation method of oxadiazole compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012129564A2 (en) * | 2011-03-24 | 2012-09-27 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Proteasome chymotrypsin-like inhibition using pi-1833 analogs |
| CN103261132A (en) * | 2010-12-21 | 2013-08-21 | 捷恩智株式会社 | Compound containing dihydrophenanthrene, liquid crystal composition and liquid crystal display |
-
2015
- 2015-04-22 CN CN201510193918.7A patent/CN104817515A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103261132A (en) * | 2010-12-21 | 2013-08-21 | 捷恩智株式会社 | Compound containing dihydrophenanthrene, liquid crystal composition and liquid crystal display |
| WO2012129564A2 (en) * | 2011-03-24 | 2012-09-27 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Proteasome chymotrypsin-like inhibition using pi-1833 analogs |
Non-Patent Citations (2)
| Title |
|---|
| SERGEY A. MALASHIKHIN ET AL.: "Efficient Discovery of Fluorescent Chemosensors Based on a Biarylpyridine Scaffold", 《ORGANIC LETTERS》 * |
| SEVIL OZCAN ET AL.: "Oxadiazole-isopropylamides as Potent and Noncovalent Proteasome Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107400099A (en) * | 2016-05-19 | 2017-11-28 | 湖南华腾制药有限公司 | The preparation method of Yi Zhong oxadiazole compounds |
| CN107698535A (en) * | 2016-08-08 | 2018-02-16 | 湖南华腾制药有限公司 | A kind of preparation method of benzene substitution oxadiazole compound |
| CN107778264A (en) * | 2016-08-29 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of preparation method of the substitution oxadiazole compound containing fluorobenzene |
| CN108129415A (en) * | 2016-12-01 | 2018-06-08 | 湖南华腾制药有限公司 | A kind of synthetic method of fluorobenzene substitution oxadiazole compound |
| CN108299333A (en) * | 2017-01-12 | 2018-07-20 | 湖南华腾制药有限公司 | One kind 3,5- bis- replaces the preparation method of oxadiazole compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104817515A (en) | Preparation method of benzene substituent oxadiazole compound | |
| CN104844528A (en) | Preparation method of triazole derivative | |
| CN104926775A (en) | Preparation method of fluorine-containing pyran derivative | |
| CN104230853B (en) | A kind of preparation method of (p-methylphenyl) methylamine-N-ethylmorpholine hydrochloride | |
| CN104829581A (en) | Preparation method of 6-bromo pyran derivative | |
| CN104829574A (en) | 8-bromo pyran derivative preparation method | |
| CN104829547A (en) | Substituted triazole compound preparation method | |
| CN104860910A (en) | Preparation method of 8-fluoropyran derivative | |
| CN104844549A (en) | Preparation method of 7 - bromine pyran derivatives | |
| CN104387367A (en) | Method for preparing disubstituted benzimidazole derivative | |
| CN104829575A (en) | Preparation method of 6-fluoropyran derivative | |
| CN104829576A (en) | Preparation method of 7-fluoropyran derivatives | |
| CN105001117A (en) | Method for synthesizing chlorine-containing azide compound | |
| CN105017066A (en) | Chlorinated azide preparation method | |
| CN105001118A (en) | Method for preparing iodine-containing azido compound | |
| CN104402880A (en) | Preparation method of imidazopyridine derivative | |
| CN104326977A (en) | Preparation method of 6,7-diethyl-4-hydroxyquinoline | |
| CN105061253A (en) | Preparation method of bromine-containing azide | |
| CN104788399A (en) | Preparation method of fluorine-containing oxadiazole compound | |
| CN104876918A (en) | Preparation method of pyrazinyl substituted oxadiazole compound | |
| CN105130841A (en) | Preparation method of 3-iodophenyl azide compound | |
| CN104292180A (en) | Preparation method of oxadiazole derivative | |
| CN104327029A (en) | Preparation method of oxygen-containing heterocyclic compound | |
| CN104725331A (en) | Method for preparing 5-fluorobenzo[d]oxazole-2-nitrile | |
| CN108129415A (en) | A kind of synthetic method of fluorobenzene substitution oxadiazole compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150805 |
|
| WD01 | Invention patent application deemed withdrawn after publication |