CN104628721A - Preparation method of imidazo [1, 2-a] pyridine derivative - Google Patents
Preparation method of imidazo [1, 2-a] pyridine derivative Download PDFInfo
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- CN104628721A CN104628721A CN201510033306.1A CN201510033306A CN104628721A CN 104628721 A CN104628721 A CN 104628721A CN 201510033306 A CN201510033306 A CN 201510033306A CN 104628721 A CN104628721 A CN 104628721A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses a preparation method of an imidazo [1, 2-a] pyridine derivative 3-(chloromethyl)2,7-dimethyl imidazole [1, 2-a] pyridine. With ethyl acetoacetate as an initial raw material, a target product is obtained by chlorination, cyclization, reduction and chlorination; and the compound 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 imidazo [1,2-a] pyridine derivate 3-(chloromethyl)-2,7-dimethyl-imidazo [1,2-a] pyridine.
Technical background
Compound 3-(chloromethyl)-2,7-dimethyl-imidazo [1,2-a] pyridine, structural formula is:
This compound 3-(chloromethyl)-2,7-dimethyl-imidazo [1,2-a] pyridine and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 3-(chloromethyl)-2,7-dimethyl-imidazo [1,2-a] pyridine 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 imidazo [1,2-a] pyridine derivate 3-(chloromethyl)-2,7-dimethyl-imidazo [1,2-a] preparation method of pyridine, take methyl aceto acetate as starting raw material, obtain target product 5 through superchlorination, Guan Huan, reduction, chlorination reaction, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) be starting raw material with methyl aceto acetate, obtain 2 through chlorination reaction;
(2) carry out ring closure reaction 2, obtain 3;
(3) carry out reduction reaction 3 and obtain 4;
(4) carry out chlorination reaction 4 and obtain 5;
One preferred embodiment in, the reagent that described chlorination reaction prepares compound 2 used is selected from chlorine; The reagent that described ring closure reaction prepares compound 3 used is selected from 2-AMINO-4-PICOLINE; The reagent that described reduction reaction prepares compound 4 used is selected from sodium borohydride; The reagent that described chlorination reaction prepares compound 5 used is selected from sulfur oxychloride.
One preferred embodiment in, the solvent that described chlorination reaction prepares compound 2 used is selected from acetic acid; Described ring closure reaction prepares compound 3 solvent selected from ethanol used; Described reduction reaction prepares compound 4 solvent selected from methanol used; The solvent that described chlorination reaction prepares compound 5 used is selected from toluene.
One preferred embodiment in, described chlorination reaction prepares the reflux temperature that compound 2 temperature of reaction used is solvent; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is solvent; Described reduction reaction prepares the room temperature that compound 4 temperature used is solvent; Described chlorination reaction prepares the reflux temperature that compound 5 temperature used is solvent.
The present invention relates to the preparation method of a kind of imidazo [1,2-a] pyridine derivate 3-(chloromethyl)-2,7-dimethyl-imidazo [1,2-a] pyridine, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound thing 3-(chloromethyl)-2,7-dimethyl-imidazo [1,2-a] pyridine.
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 2-chloroacetyl acetacetic ester
34g methyl aceto acetate is joined in 400ml acetic acid, and pass into chlorine to saturated, reflux stirs 2 hours, cooling, concentrated, add water and ethyl acetate, then add saturated sodium bicarbonate, extraction separatory, collect organic phase, dry, concentrated, obtain 27g 2-chloroacetyl acetacetic ester.
The synthesis of (2) 2,7-dimethyl-imidazo [1,2-a] Nicotinicum Acidum ethyl esters
27g 2-chloroacetyl acetacetic ester is joined in 250ml dehydrated alcohol, and reflux stirs spends the night, and cooling is concentrated, add water and ethyl acetate, extraction separatory, collects organic phase, dry, concentrated, cross post separation and obtain 39g 2,7-dimethyl-imidazo [1,2-a] Nicotinicum Acidum ethyl ester.
(3) synthesis of (2,7-dimethyl-imidazo [1,2-a] pyridin-3-yl) methyl alcohol
39g 2,7-dimethyl-imidazo [1,2-a] Nicotinicum Acidum ethyl ester is joined in 500ml methyl alcohol, add 50g sodium borohydride, stirring at room temperature 12 hours, adds dilute hydrochloric acid, concentrated removing methyl alcohol, adds ethyl acetate, extraction separatory, collect organic phase, drying, concentrated, on residuum, silicagel column is separated to obtain 31g (2,7-dimethyl-imidazo [1,2-a] pyridin-3-yl) methyl alcohol.
(4) synthesis of 3-(chloromethyl)-2,7-dimethyl-imidazo [1,2-a] pyridine
31g (2,7-dimethyl-imidazo [1,2-a] pyridin-3-yl) methyl alcohol is joined in 200ml toluene, add 70ml sulfur oxychloride, reflux stirs 5 hours, concentrated, add water and ethyl acetate, extraction separatory, collects organic phase, dry, concentrated, on residuum, silicagel column is separated to obtain 7g 3-(chloromethyl)-2,7-dimethyl-imidazo [1,2-a] pyridine.
Claims (6)
1. imidazo [1,2-a] pyridine derivate 3-(chloromethyl)-2, a 7-dimethyl-imidazo [1,2-a] preparation method of pyridine, take methyl aceto acetate as starting raw material, obtain target product 5 through superchlorination, Guan Huan, reduction, chlorination reaction, synthetic route is as follows
2. method according to claim 1, it is characterized by 4 described step reactions is,
(1) be starting raw material with methyl aceto acetate, obtain 2 through chlorination reaction;
(2) carry out ring closure reaction 2, obtain 3;
(3) carry out reduction reaction 3 and obtain 4;
(4) carry out chlorination reaction 4 and obtain 5;
3. according to the method for claim 1-2, it is characterized in that, described chlorination reaction is prepared compound 2 reagent used and is selected from the mixture of one or more in chlorine, hydrogenchloride, phosphorus oxychloride, sulfur oxychloride; The reagent that described ring closure reaction prepares compound 3 used is selected from 2-AMINO-4-PICOLINE; Described reduction reaction is prepared compound 4 reagent used and is selected from the mixture of one or more in lithium borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, sodium triacetoxy borohydride, Lithium Aluminium Hydride; Described chlorination reaction is prepared compound 5 reagent used and is selected from the mixture of one or more in chlorine, hydrogenchloride, phosphorus oxychloride, sulfur oxychloride.
4. according to the method for claim 1-2, it is characterized in that, described chlorination 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; 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, acetonitrile, water; Described reduction reaction prepares compound 4 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, phosphorus oxychloride; Described chlorination reaction prepares compound 5 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, acetic acid, water.
5. according to the method for claim 1-2, it is characterized in that, described chlorination reaction prepares the reflux temperature that compound 2 temperature of reaction used is 0 DEG C ~ solvent; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is room temperature ~ solvent; Described reduction reaction prepares the reflux temperature that compound 4 temperature used is room temperature ~ solvent; Described chlorination reaction prepares the reflux temperature that compound 5 temperature used is 0 DEG C ~ solvent.
6. according to the method for claim 1-2, it is characterized in that, described chlorination reaction prepares the reflux temperature that compound 2 temperature of reaction used is solvent; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is solvent; Described reduction reaction prepares the room temperature that compound 4 temperature used is solvent; Described chlorination reaction prepares the reflux temperature that compound 5 temperature used is solvent.
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Cited By (3)
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| CN106946875A (en) * | 2017-02-16 | 2017-07-14 | 杭州师范大学 | A kind of preparation method of the imidazole heterocyclic compounds of 3 oxygen substitutions of C |
| CN107286154A (en) * | 2016-04-05 | 2017-10-24 | 湖南华腾制药有限公司 | A kind of preparation method of fluorine-containing imidazopyridine derivatives |
| CN107400127A (en) * | 2016-05-20 | 2017-11-28 | 湖南华腾制药有限公司 | A kind of preparation method of fluorine-containing imidazopyridine derivatives |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107286154A (en) * | 2016-04-05 | 2017-10-24 | 湖南华腾制药有限公司 | A kind of preparation method of fluorine-containing imidazopyridine derivatives |
| CN107400127A (en) * | 2016-05-20 | 2017-11-28 | 湖南华腾制药有限公司 | A kind of preparation method of fluorine-containing imidazopyridine derivatives |
| CN106946875A (en) * | 2017-02-16 | 2017-07-14 | 杭州师范大学 | A kind of preparation method of the imidazole heterocyclic compounds of 3 oxygen substitutions of C |
| CN106946875B (en) * | 2017-02-16 | 2019-05-17 | 杭州师范大学 | A kind of preparation method for the imidazole heterocyclic compounds that C-3 oxygen replaces |
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