CN104292180A - Preparation method of oxadiazole derivative - Google Patents
Preparation method of oxadiazole derivative Download PDFInfo
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- CN104292180A CN104292180A CN201410534535.7A CN201410534535A CN104292180A CN 104292180 A CN104292180 A CN 104292180A CN 201410534535 A CN201410534535 A CN 201410534535A CN 104292180 A CN104292180 A CN 104292180A
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- reaction
- compound
- ester
- temperature
- xylol
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- YUZYEEJHPAKHJA-UHFFFAOYSA-N CCc1nc(-c2cccc(C(N)=O)c2)n[o]1 Chemical compound CCc1nc(-c2cccc(C(N)=O)c2)n[o]1 YUZYEEJHPAKHJA-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
Abstract
The invention discloses a preparation method of an oxadiazole derivative 3-(5-ethyl-1,2,4-oxadiazole-3-yl) benzamide. Methyl 3-cyanobenzoate is taken as a starting raw material, addition, cyclization and ester ammonolysis reaction are carried out for obtaining a target product, and the oxadiazole derivative is an important medical intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, particularly the preparation method of a kind of oxadiazoles derivative 3-(5-ethyl-1,2,4-oxadiazoles-3-base) benzamide.
Technical background
Compound 3-(5-ethyl-1,2,4-oxadiazoles-3-base) benzamide, structural formula is:
This compound 3-(5-ethyl-1,2,4-oxadiazoles-3-base) benzamide and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 3-(5-ethyl-1,2,4-oxadiazoles-3-base) benzamide 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 one and prepare 3-(5-ethyl-1,2,4-oxadiazoles-3-base) method of benzamide, with 3-cyano-benzoic acid methyl ester for starting raw material, ammonolysis reaction through addition, Guan Huan, ester obtains target product 4, and synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with 3-cyano-benzoic acid methyl ester for starting raw material, obtain 2 through addition reaction;
(2) carry out ring closure reaction 2, obtain 3;
(3) the ammonia solution protective reaction that 3 carry out ester is obtained 4;
One preferred embodiment in, the alkali that described addition reaction prepares compound 2 used is selected from triethylamine; The reagent that described ring closure reaction prepares compound 3 used is selected from propionyl chloride; The alkali that the ammonolysis reaction of described ester prepares compound 4 used is selected from sodium carbonate.
One preferred embodiment in, compound 2 solvent selected from ethanol used is prepared in described addition reaction; The solvent that described ring closure reaction prepares compound 3 used is selected from methylene dichloride; The solvent that the ammonolysis reaction of described ester prepares compound 4 used is selected from tetrahydrofuran (THF).
One preferred embodiment in, described ring closure reaction prepares the reflux temperature that compound 2 temperature of reaction used is solvent; It is 0 DEG C ~ room temperature that described ring closure reaction prepares compound 3 temperature used; It is room temperature that the ammonolysis reaction of described ester prepares compound 4 temperature used.
The present invention relates to the preparation method of a kind of 3-(5-ethyl-1,2,4-oxadiazoles-3-base) benzamide, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound 3-(5-ethyl-1,2,4-oxadiazoles-3-base) benzamide.
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 (Z)-methyl-3-(N'-hydroxyl amidino groups) methyl benzoate
19g 3-cyano-benzoic acid methyl ester is joined in 200ml dehydrated alcohol, add 8g oxammonium hydrochloride and 5g triethylamine, return stirring 15 hours, concentrated, add hydrochloric acid, add ethyl acetate again, separatory, then add ammoniacal liquor tune pH>8, aqueous phase is extracted with ethyl acetate, dry, concentrated, 11.8g (Z)-methyl-3-(N'-hydroxyl amidino groups) methyl benzoate.
(2) synthesis of 3-methyl (5-ethyl-1,2,4-oxadiazoles-3-base) methyl benzoate
11g (Z)-methyl-3-(N'-hydroxyl amidino groups) methyl benzoate is joined in 150ml methylene dichloride, is cooled to 0 DEG C, slowly adds 6g propionyl chloride, after adding, at 0 DEG C, add 4g triethylamine, naturally rise to room temperature, stirring is spent the night, add water, extraction separatory, adds extraction into ethyl acetate, separatory, drying, concentrated, on residuum, silicagel column is separated to obtain 8g 3-methyl (5-ethyl-1,2,4-oxadiazoles-3-base) methyl benzoate.
(3) synthesis of 3-(5-ethyl-1,2,4-oxadiazoles-3-base) benzamide
8g 3-methyl (5-ethyl-1,2,4-oxadiazoles-3-base) methyl benzoate joins in 100ml tetrahydrofuran (THF), then adds 100ml ammoniacal liquor and 13g sodium carbonate, stirring at room temperature 10 hours, add ethyl acetate and water, extraction separatory, dry, concentrated, on residuum, silicagel column is separated to obtain 6g 3-(5-ethyl-1,2,4-oxadiazoles-3-base) benzamide.
Claims (6)
1. prepare oxadiazoles derivative 3-(5-ethyl-1 for one kind, 2,4-oxadiazoles-3-base) preparation method of benzamide, with 3-cyano-benzoic acid methyl ester for starting raw material, ammonolysis reaction through addition, Guan Huan, ester obtains target product 4, and synthetic route is as follows.
2. method according to claim 1, it is characterized by 3 described step reactions is,
(1) with 3-cyano-benzoic acid methyl ester for starting raw material, obtain 2 through addition reaction;
(2) carry out ring closure reaction 2, obtain 3;
(3) the ammonia solution protective reaction that 3 carry out ester is obtained 4;
3. according to the method for claim 1-2, it is characterized in that, described addition reaction is prepared compound 2 alkali used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus; The reagent that described ring closure reaction prepares compound 3 used is selected from propionyl chloride; The ammonolysis reaction of described ester is prepared compound 4 alkali used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus.
4. according to the method for claim 1-2, it is characterized in that, compound 2 solvent selected from methanol used, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, 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; Described ring closure 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, water; The ammonolysis reaction of described ester prepares compound 4 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.
5. according to the method for claim 1-2, it is characterized in that, the reflux temperature that compound 2 temperature of reaction used is 0 DEG C ~ solvent is prepared in described addition reaction; It is 0 DEG C ~ room temperature that described ring closure reaction prepares compound 3 temperature used; The ammonolysis reaction of described ester prepare compound 4 used be 0 DEG C ~ room temperature.
6. according to the method for claim 1-2, it is characterized in that, described ring closure reaction prepares the reflux temperature that compound 2 temperature of reaction used is solvent; It is 0 DEG C ~ room temperature that described ring closure reaction prepares compound 3 temperature used; It is room temperature that the ammonolysis reaction of described ester prepares compound 4 temperature used.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410534535.7A CN104292180A (en) | 2014-10-12 | 2014-10-12 | Preparation method of oxadiazole derivative |
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| CN201410534535.7A CN104292180A (en) | 2014-10-12 | 2014-10-12 | Preparation method of oxadiazole derivative |
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| CN104292180A true CN104292180A (en) | 2015-01-21 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104876918A (en) * | 2015-04-23 | 2015-09-02 | 湖南华腾制药有限公司 | Preparation method of pyrazinyl substituted oxadiazole compound |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000006566A1 (en) * | 1998-07-30 | 2000-02-10 | Syngenta Limited | Benzazoles: benzoxazole, benzthiazole and benzimidazole derivatives |
| WO2002092588A2 (en) * | 2001-05-11 | 2002-11-21 | Pharmacia Corporation | Aromatic sulfone hydroxamates and their use as protease inhibitors |
| CN1387514A (en) * | 1999-05-14 | 2002-12-25 | G·D·瑟尔公司 | Aromatic sulfone hydroxamic acid metalloprotease inhibitor |
| CN104056278A (en) * | 2003-04-11 | 2014-09-24 | Ptc治疗公司 | 1,2,4-oxadiazole benzoic acid compounds |
-
2014
- 2014-10-12 CN CN201410534535.7A patent/CN104292180A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000006566A1 (en) * | 1998-07-30 | 2000-02-10 | Syngenta Limited | Benzazoles: benzoxazole, benzthiazole and benzimidazole derivatives |
| CN1387514A (en) * | 1999-05-14 | 2002-12-25 | G·D·瑟尔公司 | Aromatic sulfone hydroxamic acid metalloprotease inhibitor |
| WO2002092588A2 (en) * | 2001-05-11 | 2002-11-21 | Pharmacia Corporation | Aromatic sulfone hydroxamates and their use as protease inhibitors |
| CN1764655A (en) * | 2001-05-11 | 2006-04-26 | 法马西亚公司 | Aromatic sulfone hydroxamates and their use as protease inhibitors |
| CN104056278A (en) * | 2003-04-11 | 2014-09-24 | Ptc治疗公司 | 1,2,4-oxadiazole benzoic acid compounds |
Non-Patent Citations (1)
| Title |
|---|
| DOUGLAS S. AULD ET AL.: "Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124", 《PNAS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104876918A (en) * | 2015-04-23 | 2015-09-02 | 湖南华腾制药有限公司 | Preparation method of pyrazinyl substituted oxadiazole compound |
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Application publication date: 20150121 |