CN104876919A - Preparation method of oxadiazole compound - Google Patents
Preparation method of oxadiazole compound Download PDFInfo
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- CN104876919A CN104876919A CN201510221109.2A CN201510221109A CN104876919A CN 104876919 A CN104876919 A CN 104876919A CN 201510221109 A CN201510221109 A CN 201510221109A CN 104876919 A CN104876919 A CN 104876919A
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
The invention discloses a preparation method of a oxadiazole compound (6-(4-(5-(chloromethyl)-1,2,4-oxadiazole-3-yl) aryl) pyrimidine-4-yl) methylamine. By taking 4-bromoxynil as an initial raw material, the preparation method comprises the following step of carrying out addition reaction, esterifying reaction, ring closing reaction, coupling reaction, amidation reaction and reduction reaction to obtain a target product 7. The product obtained by the preparation method disclosed by the invention serves as template small molecules for synthesizing a variety of compound libraries.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, in particular to a kind of oxadiazole compound (6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-yl) preparation method of methylamine.
Technical background
Compound (6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-yl) methylamine, structural formula is:
This compound (6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-yl) methylamine and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of (6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-yl) methylamine is comparatively difficult at present.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 oxadiazole compound (6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-yl) preparation method of methylamine, with 4-bromoxynil for starting raw material, obtain target product 7 through addition, esterification, Guan Huan, coupling, amidation, reduction reaction, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with 4-bromoxynil for starting raw material, obtain 2 through addition reaction,
(2) carry out esterification 2, obtain 3,
(3) carry out ring closure reaction 3 and obtain 4,
(4) carry out linked reaction 4 and obtain 5,
(5) carry out amidate action 5 and obtain 6,
(6) carry out reduction reaction 6 and obtain 7;
One preferred embodiment in, the alkali that described addition reaction prepares compound 2 used is selected from sodium hydroxide; The alkali that described acylation reaction prepares compound 3 used is selected from triethylamine; The alkali that described ring closure reaction prepares compound 4 used is selected from salt of wormwood; Described linked reaction is prepared compound 5 reagent used and is selected from 6-(ethoxycarbonyl) pyrimidine-4-yl boric acid; The reagent that described amidate action prepares compound 6 used is selected from ammoniacal liquor; The reductive agent that described reduction reaction prepares compound 7 used is selected from Lithium Aluminium Hydride.
One preferred embodiment in, compound 2 solvent selected from ethanol used is prepared in described addition reaction; The solvent that described acylation reaction prepares compound 3 used is selected from methylene dichloride; The solvent that described ring closure reaction prepares compound 4 used is selected from toluene; The solvent that described linked reaction prepares compound 5 used is selected from DMF; The solvent that described amidate action prepares compound 6 used is selected from ammoniacal liquor; The solvent that described reduction reaction prepares compound 7 used is selected from tetrahydrofuran (THF).
One preferred embodiment in, the reflux temperature that compound 2 temperature of reaction used is solvent is prepared in described addition reaction; It is room temperature that described acylation reaction prepares compound 3 temperature used; Described ring closure reaction prepares the reflux temperature that compound 4 temperature used is solvent; It is 100 DEG C that described linked reaction prepares compound 5 temperature used; It is room temperature that described amidate action prepares compound 6 temperature used; Described reduction reaction prepares the reflux temperature that compound 7 temperature used is solvent.
The present invention relates to the preparation method of a kind of oxadiazole compound (6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-yl) methylamine, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound (6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-yl) methylamine.
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 4-bromo-N'-hydroxybenzylamine
16g 4-bromoxynil is joined in 170ml ethanol, adds 14g oxammonium hydrochloride, then add 1N sodium hydroxide, reflux stirs 2 hours, cooling, adds 3N hydrochloric acid, adds ethyl acetate, extraction separatory, collect organic phase, dry, concentrated, obtain 12g 4-bromo-N'-hydroxybenzylamine.
(2) synthesis of 4-bromo-N'-hydroxybenzylamine chloracetate
12g 4-bromo-N'-hydroxybenzylamine is joined in 200ml methylene dichloride, more slowly drips 9.8g chloroacetyl chloride, add triethylamine 7ml, stirring at room temperature 8 hours, adds water extraction separatory, collects organic phase, drying, concentrates and obtains 10g 4-bromo-N'-hydroxybenzylamine chloracetate.
(3) synthesis of 3-(4-bromophenyl)-5-(chloromethyl)-1,2,4-oxadiazoles
10g 4-bromo-N'-hydroxybenzylamine chloracetate is joined in 130ml toluene, add 12g salt of wormwood, reflux stirs 6 hours, cooling, filters, and collects filtrate, concentrated, on residuum, silicagel column is separated to obtain 7g 3-(4-bromophenyl)-5-(chloromethyl)-1,2,4-oxadiazoles.
(4) synthesis of ethyl-6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-carboxylic acid, ethyl ester
7g 3-(4-bromophenyl)-5-(chloromethyl)-1,2,4-oxadiazoles joins 100ml N, in dinethylformamide, add 11g 6-(ethoxycarbonyl) pyrimidine-4-yl boric acid and 12g Anhydrous potassium carbonate again, be heated to 100 DEG C, stirring reaction 6 hours, adds water and ethyl acetate, extraction separatory, collect organic phase, drying, concentrated, on residuum, silicagel column is separated and obtains 8.6g ethyl-6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-carboxylic acid, ethyl ester.
(5) synthesis of 6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-methane amide
8g ethyl-6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-carboxylic acid, ethyl ester joins in 200ml ammoniacal liquor, and stirring at room temperature 12 hours, adds ethyl acetate, extraction separatory, collect organic phase, dry, concentrate and obtain 5.6g 6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-methane amide.
(6) synthesis of (6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-yl) methylamine
5g 6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-methane amide joins in 180ml dry tetrahydrofuran, slowly add 3.4g Lithium Aluminium Hydride again, reflux stirs 2 hours, add aqueous sodium hydroxide solution, filter, then add ethyl acetate, extraction separatory, collect organic phase, drying, concentrated, residuum silicagel column is separated and obtains 3.2g (6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-yl) methylamine.
Claims (5)
1. an oxadiazole compound (6-(4-(5-(chloromethyl)-1,2,4-oxadiazoles-3-base) phenyl) pyrimidine-4-yl) preparation method of methylamine, with 4-bromoxynil for starting raw material, obtain target product 7 through addition, esterification, Guan Huan, coupling, amidation, reduction reaction, synthetic route is as follows:
2. method according to claim 1, it is characterized by 6 described step reactions is,
(1) with 4-bromoxynil for starting raw material, obtain 2 through addition reaction,
(2) carry out esterification 2, obtain 3,
(3) carry out ring closure reaction 3 and obtain 4,
(4) carry out linked reaction 4 and obtain 5,
(5) carry out amidate action 5 and obtain 6,
(6) carry out reduction reaction 6 and obtain 7;
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, salt of wormwood, sodium carbonate, sodium bicarbonate; Described acylation reaction is prepared compound 3 alkali used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, sodium bicarbonate, ammoniacal liquor, triethylamine, pyridine; Described ring closure reaction is prepared compound 4 alkali used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate, sodium bicarbonate, ammoniacal liquor, triethylamine, pyridine; Described linked reaction is prepared compound 5 reagent used and is selected from 6-(ethoxycarbonyl) pyrimidine-4-yl boric acid; Described amidate action is prepared compound 6 reagent used and is selected from one or both mixture in ammoniacal liquor, ammonia; Described reduction reaction is prepared compound 7 reductive agent used and is selected from the mixture of one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, Lithium Aluminium Hydride.
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, triethylamine, pyridine, acetonitrile, acetic acid, trimethyl orthoformate; Described acylation 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 ring closure 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; Described linked reaction prepares 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, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, acetic acid, water; Described amidate action 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; Described reduction reaction prepares 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, 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, the reflux temperature that compound 2 temperature of reaction used is 0 DEG C ~ solvent is prepared in described addition reaction; Described acylation reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; Described ring closure reaction prepares the reflux temperature that compound 4 temperature used is 0 DEG C ~ solvent; Described linked reaction prepares the reflux temperature that compound 5 temperature used is 0 DEG C ~ solvent; Described amidate action prepares the reflux temperature that compound 6 temperature used is 0 DEG C ~ solvent; Described reduction reaction prepares the reflux temperature that compound 7 temperature used is 0 DEG C ~ solvent.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311544A (en) * | 2014-09-22 | 2015-01-28 | 湖南华腾制药有限公司 | Preparation method of benzoxazole derivative |
| CN104387331A (en) * | 2014-10-27 | 2015-03-04 | 湖南华腾制药有限公司 | Preparation method of pyrazine derivative |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311544A (en) * | 2014-09-22 | 2015-01-28 | 湖南华腾制药有限公司 | Preparation method of benzoxazole derivative |
| CN104387331A (en) * | 2014-10-27 | 2015-03-04 | 湖南华腾制药有限公司 | Preparation method of pyrazine derivative |
Non-Patent Citations (1)
| Title |
|---|
| YASAR DÜRÜST，ET AL.: ""Synthesis and anti-protozoal activity of novel dihydropyrrolo[3,4-d][1,2,3]triazoles"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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Application publication date: 20150902 |