CN104387367A - Method for preparing disubstituted benzimidazole derivative - Google Patents
Method for preparing disubstituted benzimidazole derivative Download PDFInfo
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- CN104387367A CN104387367A CN201410605725.3A CN201410605725A CN104387367A CN 104387367 A CN104387367 A CN 104387367A CN 201410605725 A CN201410605725 A CN 201410605725A CN 104387367 A CN104387367 A CN 104387367A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a method for preparing a disubstituted benzimidazole derivative which is 5-methyl-2-(4-methyl-piperidin-1-yl)-1H-benzo[d]imidazole. The target product is prepared by taking 5-methyl-2-nitroaniline as a starting raw material through procedures of reducing, cyclizing, chloridizing and nucleophilic reaction. The compound functions as an important pharmaceutical intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, particularly a kind of preparation method of 2 substituted benzimidazole derivative 5-methyl-2-(4-methyl piperidine-1-base)-1H-benzo [d] imidazoles.
Technical background
Compound 5-methyl-2-(4-methyl piperidine-1-base)-1H-benzo [d] imidazoles, structural formula is:
This compound 5-methyl-2-(4-methyl piperidine-1-base)-1H-benzo [d] imidazoles and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of current 5-methyl-2-(4-methyl piperidine-1-base)-1H-benzo [d] imidazoles 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 preparation method of 2 substituted benzimidazole derivative 5-methyl-2-(4-methyl piperidine-1-base)-1H-benzo [d] imidazoles, with 5-methyl-2-N-methyl-p-nitroaniline for starting raw material, obtain target product 5 through reduction, Guan Huan, chlorination, nucleophilic reaction, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with 5-methyl-2-N-methyl-p-nitroaniline for starting raw material, obtain 2 through reduction reaction;
(2) carry out ring closure reaction 2, obtain 3;
(3) carry out chlorination reaction 3 and obtain 4;
(4) carry out nucleophilic reaction 4 and obtain 5;
One preferred embodiment in, the reductive agent that described reduction reaction prepares compound 2 used is selected from hydrogen; The reagent that described ring closure reaction prepares compound 3 used is selected from DMAP; The reagent that described chlorination reaction prepares compound 4 used is selected from phosphorus oxychloride; The alkali that described nucleophilic reaction prepares compound 5 used is selected from salt of wormwood.
One preferred embodiment in, described reduction reaction prepares compound 2 solvent selected from methanol used; The solvent that described ring closure reaction prepares compound 3 used is selected from acetonitrile; The solvent that described chlorination reaction prepares compound 4 used is selected from phosphorus oxychloride; The solvent that described nucleophilic reaction prepares compound 5 used is selected from DMF.
One preferred embodiment in, it is room temperature that described reduction reaction prepares compound 2 temperature of reaction used; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is solvent; Described chlorination reaction prepares the reflux temperature that compound 4 temperature used is solvent; Described hydrolysis reaction prepares the reflux temperature that compound 5 temperature used is solvent.
The present invention relates to a kind of preparation method of 2 substituted benzimidazole derivative 5-methyl-2-(4-methyl piperidine-1-base)-1H-benzo [d] imidazoles, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of compound thing 5-methyl-2-(4-methyl piperidine-1-base)-1H-benzo [d] imidazoles.
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) 4-methyl isophthalic acid, the synthesis of 2-pentanoic
32g 5-methyl-2-N-methyl-p-nitroaniline is joined in 350ml methyl alcohol, and add 3.2g 10% palladium carbon, pass into hydrogen, stirring is spent the night, and filters, and collects filtrate, concentrated, obtains 24g 4-methyl isophthalic acid, 2-pentanoic.
(2) synthesis of 5-methyl-2-oxo-1,3-bis-tertbutyloxycarbonyl-2H-benzo [d] imidazoles
41g tert-Butyl dicarbonate is joined in 400ml acetonitrile, adds 0.4g DMAP, stirring at room temperature 40min, add 23g 4-methyl isophthalic acid again, 2-pentanoic, reflux stirs 16 hours, cooling, concentrated, add water and extraction into ethyl acetate separatory, collect organic phase, dry, concentrated, obtain 17g 5-methyl-2-oxo-1,3-bis-tertbutyloxycarbonyl-2H-benzo [d] imidazoles.
(3) synthesis of 2-chloro-5-methyl isophthalic acid H-benzo [d] imidazoles
16g 5-methyl-2-oxo-1,3-bis-tertbutyloxycarbonyl-2H-benzo [d] imidazoles joins in 180ml phosphorus oxychloride, reflux stirs 3 hours, reaction solution is slowly poured in frozen water, adds ethyl acetate, extraction separatory, collect organic phase, drying, concentrated, on residuum, silicagel column is separated to obtain 11g 2-chloro-5-methyl isophthalic acid H-benzo [d] imidazoles.
(4) synthesis of 5-methyl-2-(4-methyl piperidine-1-base)-1H-benzo [d] imidazoles
Chloro-for 10g 2-5-methyl isophthalic acid H-benzo [d] imidazoles is joined 130ml N, in dinethylformamide, add 15g Anhydrous potassium carbonate and 9g 4-methyl piperidine, reflux stirs 2 hours, and cooling, adds water and extraction into ethyl acetate, separatory, collect organic phase, concentrated, on residuum, silicagel column is separated and obtains 7g 5-methyl-2-(4-methyl piperidine-1-base)-1H-benzo [d] imidazoles.
Claims (6)
1. prepare the preparation method of 2 substituted benzimidazole derivative 5-methyl-2-(4-methyl piperidine-1-base)-1H-benzo [d] imidazoles for one kind, with 5-methyl-2-N-methyl-p-nitroaniline for starting raw material, obtain target product 5 through reduction, Guan Huan, chlorination, nucleophilic reaction, synthetic route is as follows.
2. method according to claim 1, it is characterized by 4 described step reactions is,
(1) with 5-methyl-2-N-methyl-p-nitroaniline for starting raw material, obtain 2 through reduction reaction;
(2) carry out ring closure reaction 2, obtain 3;
(3) carry out chlorination reaction 3 and obtain 4;
(4) carry out nucleophilic reaction 4 and obtain 5;
3. according to the method for claim 1-2, it is characterized in that, described reduction reaction is prepared compound 2 reductive agent used and is selected from the mixture of one or more in iron powder, zinc powder, hydrogen, sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine; The reagent that described ring closure reaction prepares compound 3 used is selected from DMAP; Described chlorination reaction is prepared compound 4 reagent used and is selected from the mixture of one or more in sulfur oxychloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, chlorine; Described nucleophilic reaction prepares the mixture of one or more in the mixture of one or more that compound 5 alkali used is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus, sodium methylate, sodium ethylate, sodium tert-butoxide.
4. according to the method for claim 1-2, it is characterized in that, described reduction 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; 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 chlorination 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 nucleophilic 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 reduction 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 0 DEG C ~ solvent; Described chlorination reaction prepares the reflux temperature that compound 4 temperature used is 0 DEG C ~ solvent; Described nucleophilic 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, it is room temperature that described reduction reaction prepares compound 2 temperature of reaction used; Described ring closure reaction prepares the reflux temperature that compound 3 temperature used is solvent; Described chlorination reaction prepares the reflux temperature that compound 4 temperature used is solvent; Described hydrolysis reaction prepares the reflux temperature that compound 5 temperature used is solvent.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432108A (en) * | 2016-07-28 | 2017-02-22 | 浙江工业大学 | Hydrazone compound containing methyl quinoxaline structure, preparation method and application thereof |
| CN107176952A (en) * | 2016-03-09 | 2017-09-19 | 湖南华腾制药有限公司 | A kind of synthetic method of imidazole derivative |
| CN107501236A (en) * | 2017-08-22 | 2017-12-22 | 长沙深橙生物科技有限公司 | A kind of preparation method of 2 substituted benzimidazole derivatives |
| CN107778252A (en) * | 2016-08-30 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of preparation method of benzimidazoles compound |
| CN109796349A (en) * | 2019-03-01 | 2019-05-24 | 西南石油大学 | A method of it going back original aromatic nitro compound and prepares aromatic amine compounds |
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| WO2002048152A2 (en) * | 2000-12-12 | 2002-06-20 | Neurogen Corporation | Spiro[isobenzofuran-1,4'-piperidin]-3-ones and 3h-spiroisobenzofuran-1,4'-piperidines |
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2014
- 2014-11-02 CN CN201410605725.3A patent/CN104387367A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2002048152A2 (en) * | 2000-12-12 | 2002-06-20 | Neurogen Corporation | Spiro[isobenzofuran-1,4'-piperidin]-3-ones and 3h-spiroisobenzofuran-1,4'-piperidines |
Non-Patent Citations (1)
| Title |
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| YOCHAI BASEL, ET AL.: "Di-tert-butyl Dicarbonate and 4-(Dimethylamino)pyridine Revisited. Their Reactions with Amines and Alcohols", 《J. ORG. CHEM.》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107176952A (en) * | 2016-03-09 | 2017-09-19 | 湖南华腾制药有限公司 | A kind of synthetic method of imidazole derivative |
| CN106432108A (en) * | 2016-07-28 | 2017-02-22 | 浙江工业大学 | Hydrazone compound containing methyl quinoxaline structure, preparation method and application thereof |
| CN106432108B (en) * | 2016-07-28 | 2019-02-22 | 浙江工业大学 | A kind of hydrazone compounds and the preparation method and application thereof of the structure of benzopyrazines containing methyl |
| CN107778252A (en) * | 2016-08-30 | 2018-03-09 | 湖南华腾制药有限公司 | A kind of preparation method of benzimidazoles compound |
| CN107501236A (en) * | 2017-08-22 | 2017-12-22 | 长沙深橙生物科技有限公司 | A kind of preparation method of 2 substituted benzimidazole derivatives |
| CN109796349A (en) * | 2019-03-01 | 2019-05-24 | 西南石油大学 | A method of it going back original aromatic nitro compound and prepares aromatic amine compounds |
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Application publication date: 20150304 |