CN104277042A - Preparation method of imidazopyridine derivative - Google Patents
Preparation method of imidazopyridine derivative Download PDFInfo
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- CN104277042A CN104277042A CN201410542903.2A CN201410542903A CN104277042A CN 104277042 A CN104277042 A CN 104277042A CN 201410542903 A CN201410542903 A CN 201410542903A CN 104277042 A CN104277042 A CN 104277042A
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- AVYYNZWWGNNXRW-UHFFFAOYSA-N CCOC(c1c[n](ccc(C)c2)c2n1)=O Chemical compound CCOC(c1c[n](ccc(C)c2)c2n1)=O AVYYNZWWGNNXRW-UHFFFAOYSA-N 0.000 description 1
- VNNCXDKQWHXZMU-UHFFFAOYSA-N Cc1cc2nc(CO)c[n]2cc1 Chemical compound Cc1cc2nc(CO)c[n]2cc1 VNNCXDKQWHXZMU-UHFFFAOYSA-N 0.000 description 1
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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
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- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a preparation method of imidazopyridine derivative 2-(chloromethyl)-7-methyl-imidazo-[1,2-a] pyridine. A target product is obtained through ring closing, reduction and chlorination based on 2-amido-4-methylpyridine as an initial raw material. 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 imidazopyridine derivatives 2-(chloromethyl)-7-methyl-imidazoles also [1,2-a] pyridine.
Technical background
Compound 2-(chloromethyl)-7-methyl-imidazoles also [1,2-a] pyridine, structural formula is:
This compound 2-(chloromethyl)-7-methyl-imidazoles also [1,2-a] pyridine and relevant derivative has widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 2-(chloromethyl)-7-methyl-imidazoles also [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 the method that one prepares 2-(chloromethyl)-7-methyl-imidazoles also [1,2-a] pyridine, 2-AMINO-4-PICOLINE is starting raw material, and obtain target product 4 through the ring that reaches a standard, reduction, chlorination, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) be starting raw material with 2-AMINO-4-PICOLINE, obtain 2 through ring closure reaction;
(2) carry out reduction reaction 2, obtain 3;
(3) carry out chlorination reaction 3 and obtain 4;
One preferred embodiment in, described ring closure reaction is prepared compound 2 reagent used and is selected from 3-BrPA ethyl ester; The reductive agent that described reduction reaction prepares compound 3 used is selected from sodium borohydride; The chlorizating agent that described chlorination reaction prepares compound 4 used is selected from sulfur oxychloride.
One preferred embodiment in, the solvent that described ring closure reaction prepares compound 2 used is selected from glycol dimethyl ether; Described reduction reaction prepares compound 3 solvent selected from methanol used; The solvent that described chlorination reaction prepares compound 4 used is selected from toluene.
One preferred embodiment in, described ring closure reaction prepares the room temperature that compound 2 temperature of reaction used is solvent; It is room temperature that described reduction reaction prepares compound 3 temperature used; Described chlorination reaction prepare compound 4 used be the reflux temperature of solvent.
The present invention relates to the preparation method of a kind of 2-(chloromethyl)-7-methyl-imidazoles also [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 2-(chloromethyl)-7-methyl-imidazoles also [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 7-methyl-imidazoles also [1,2-a] pyridine-2-ethyl formate
25g2-amino-4-methylpyridine is joined in 200ml glycol dimethyl ether, add 54g3-ethyl bromide acetone, stirred overnight at room temperature, concentrate and add ethyl acetate and water again, separatory, drying, concentrated, residuum upper prop is separated and obtains 28g7-methyl-imidazoles also [1,2-a] pyridine-2-ethyl formate.
(2) synthesis of (7-methyl-imidazoles is [1,2-a] pyridine-2-base also) methyl alcohol
26g7-methyl-imidazoles also [1,2-a] pyridine-2-ethyl formate joins in 280ml anhydrous methanol, add 17g sodium borohydride again, stirring at room temperature 2 hours, add saturated ammonium chloride, then add ethyl acetate and water, extract separatory, drying, concentrate, on residuum, silicagel column is separated to obtain 18g (7-methyl-imidazoles is [1,2-a] pyridine-2-base also) methyl alcohol.
(3) synthesis of 2-(chloromethyl)-7-methyl-imidazoles also [1,2-a] pyridine
16g (7-methyl-imidazoles also [1,2-a] pyridine-2-base) methyl alcohol joins in 190ml toluene, add 52g sulfur oxychloride again, reflux stirs 3 hours, concentrated, adds ethyl acetate and saturated sodium bicarbonate aqueous solution, extraction separatory, dry, concentrated, on residuum, silicagel column is separated to obtain 12g2-(chloromethyl)-7-methyl-imidazoles also [1,2-a] pyridine.
Claims (6)
1. the preparation method of imidazopyridine derivatives 2-(chloromethyl)-7-methyl-imidazoles also [1,2-a] pyridine, take 2-AMINO-4-PICOLINE as starting raw material, obtain target product 4 through the ring that reaches a standard, reduction, chlorination, synthetic route is as follows.
2. method according to claim 1, it is characterized by 3 described step reactions is,
(1) be starting raw material with 2-AMINO-4-PICOLINE, obtain 2 through ring closure reaction;
(2) carry out reduction reaction 2, obtain 3;
(3) carry out chlorination reaction 3 and obtain 4;
3. according to the method for claim 1-2, it is characterized in that, described ring closure reaction is prepared compound 2 reagent used and is selected from 3-BrPA ethyl ester; Described reduction reaction is prepared compound 3 reductive agent used and is selected from the mixture of one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine; Described chlorination reaction is prepared compound 4 chlorizating agent used and is selected from the mixture of one or more in chlorine, hydrogenchloride, sulfur oxychloride, phosphorus trichloride, phosphorus oxychloride.
4. according to the method for claim 1-2, it is characterized in that, described ring closure 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, glycol dimethyl ether; Described reduction 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; Described chlorination reaction 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, described ring closure reaction prepares the reflux temperature that compound 2 temperature of reaction used is 0 DEG C ~ solvent; Described reduction reaction prepares the reflux temperature that compound 3 temperature used is 0 DEG C ~ solvent; Described chlorination reaction prepare compound 4 used be the reflux temperature of 0 DEG C ~ solvent.
6. according to the method for claim 1-2, it is characterized in that, it is room temperature that described ring closure reaction prepares compound 2 temperature of reaction used; It is room temperature that described reduction reaction prepares compound 3 temperature used; Described chlorination reaction prepare compound 4 used be the reflux temperature of solvent.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557926A (en) * | 2015-01-30 | 2015-04-29 | 何思伟 | Synthesis method of 3-substituted imidazopyridine compound as medical intermediate |
| CN104628721A (en) * | 2015-01-22 | 2015-05-20 | 湖南华腾制药有限公司 | Preparation method of imidazo [1, 2-a] pyridine derivative |
| 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 |
| CN107698583A (en) * | 2016-08-08 | 2018-02-16 | 湖南华腾制药有限公司 | A kind of preparation method of imidazopyridine derivatives |
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| WO2007056220A2 (en) * | 2005-11-04 | 2007-05-18 | Amira Pharmaceuticals, Inc. | 5-lipoxygenase-activating protein (flap) inhibitors |
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| CN101006078A (en) * | 2004-06-17 | 2007-07-25 | 惠氏公司 | Gonadotropin releasing hormone receptor antagonists |
| WO2007056220A2 (en) * | 2005-11-04 | 2007-05-18 | Amira Pharmaceuticals, Inc. | 5-lipoxygenase-activating protein (flap) inhibitors |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628721A (en) * | 2015-01-22 | 2015-05-20 | 湖南华腾制药有限公司 | Preparation method of imidazo [1, 2-a] pyridine derivative |
| CN104557926A (en) * | 2015-01-30 | 2015-04-29 | 何思伟 | Synthesis method of 3-substituted imidazopyridine compound as medical intermediate |
| CN104557926B (en) * | 2015-01-30 | 2016-06-22 | 深圳市祥根生物科技有限公司 | A kind of synthetic method of medicine intermediate 3-substituted imidazole pyridine compounds and their |
| 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 |
| CN107698583A (en) * | 2016-08-08 | 2018-02-16 | 湖南华腾制药有限公司 | A kind of preparation method of imidazopyridine derivatives |
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