CN107501236A - A kind of preparation method of 2 substituted benzimidazole derivatives - Google Patents
A kind of preparation method of 2 substituted benzimidazole derivatives Download PDFInfo
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- CN107501236A CN107501236A CN201710726685.1A CN201710726685A CN107501236A CN 107501236 A CN107501236 A CN 107501236A CN 201710726685 A CN201710726685 A CN 201710726685A CN 107501236 A CN107501236 A CN 107501236A
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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 kind of preparation method of 2 carboxylic acids of substituted benzimidazole derivative 1 (base of 5 methyl 1H benzos [d] imidazoles 2) piperidines 4, using the nitroaniline of 5 methyl 2 as initiation material, target product is obtained by reduction, cyclization, chlorination, necleophilic reaction, the compound is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of 2 substituted benzimidazoles spread out
The preparation method of biological 1- (5- methyl isophthalic acid H- benzos [d] imidazoles -2- bases) piperidines -4- carboxylic acids.
Technical background
Compound 1- (5- methyl isophthalic acid H- benzos [d] imidazoles -2- bases) piperidines -4- carboxylic acids, structural formula are：
This compound 1- (5- methyl isophthalic acid H- benzos [d] imidazoles -2- bases) piperidines -4- carboxylic acids and the derivative of correlation are in medicine
There is extensive use in chemistry and organic synthesis.1- (5- methyl isophthalic acid H- benzos [d] imidazoles -2- bases) piperidines -4- carboxylic acids at present
Synthesis is more difficult.Therefore it is easy to get, it is necessary to develop a raw material, easy to operate, reaction is easily controllable, and overall yield is suitably closed
Into method.
The content of the invention
The invention discloses a kind of 2 substituted benzimidazole derivative 1- (5- methyl isophthalic acid H- benzos [d] imidazoles -2- bases) piperazines
The preparation method of pyridine -4- carboxylic acids, using 5- methyl -2- nitroanilines as initiation material, by reduction, cyclization, chlorination, necleophilic reaction
Target product 5 is obtained, synthesis step is as follows：
(1) using 5- methyl -2- nitroanilines as initiation material, 2 are obtained by reduction reaction；
(2) ring closure reaction is carried out 2, obtains 3；
(3) 3 progress chlorination reactions are obtained 4；
(4) 4 progress necleophilic reactions are obtained 5；
In a preferred embodiment, the reducing agent used in described reduction reaction prepare compound 2 is selected from hydrogen；Institute
The reagent used in ring closure reaction prepare compound 3 stated is selected from DMAP；Described chlorination reaction prepare compound 4
Reagent used is selected from POCl3；Alkali used in described necleophilic reaction prepare compound 5 is selected from potassium carbonate.
In a preferred embodiment, the solvent used in described reduction reaction prepare compound 2 is selected from methanol；It is described
Ring closure reaction prepare compound 3 used in solvent be selected from acetonitrile；Solvent choosing used in described chlorination reaction prepare compound 4
From POCl3；Solvent used in described necleophilic reaction prepare compound 5 is selected from N,N-dimethylformamide.
In a preferred embodiment, the reaction temperature used in described reduction reaction prepare compound 2 is room temperature；Institute
The temperature used in ring closure reaction prepare compound 3 stated is the reflux temperature of solvent；The described institute of chlorination reaction prepare compound 4
Temperature is the reflux temperature of solvent；Temperature used in described hydrolysis prepare compound 5 is the reflux temperature of solvent.
The present invention relates to a kind of 2 substituted benzimidazole derivative 1- (5- methyl isophthalic acid H- benzos [d] imidazoles -2- bases) piperazines
The preparation method of pyridine -4- carboxylic acids, reported currently without other Patents documents.
The present invention is further described by the following embodiment, and these descriptions are not present invention to be made into one
The restriction of step.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) 4- methyl isophthalic acids, the synthesis of 2- diphenylamines
32g 5- methyl -2- nitroanilines are added in 350ml methanol, the palladium carbons of 3.2g 10% is added, is passed through hydrogen,
It is stirred overnight, filters, collects filtrate, concentration, obtain 24g 4- methyl isophthalic acids, 2- diphenylamines.
(2) synthesis of 5- methyl -2- oxos -1,3- two tertbutyloxycarbonyl -2H- benzos [d] imidazoles
41g di-tert-butyl dicarbonates are added in 400ml acetonitriles, 0.4g DMAPs is added, is stirred at room temperature
40min, 23g 4- methyl isophthalic acids are added, 2- diphenylamines, are heated to reflux stirring 16 hours, are cooled down, concentration, add water and acetic acid second
Ester extracts liquid separation, collects organic phase, dries, and concentration, obtains the tertbutyloxycarbonyl -2H- benzene of 17g 5- methyl -2- oxos -1,3- bis-
And [d] imidazoles.
(3) synthesis of chloro- 5- methyl isophthalic acids H- benzos [d] imidazoles of 2-
Tertbutyloxycarbonyl -2H- benzos [d] imidazoles of 16g 5- methyl -2- oxos -1,3- two is added to 180ml trichlorine oxygen
In phosphorus, stirring 3 hours is heated to reflux, reaction solution is poured slowly into frozen water, add ethyl acetate, extract liquid separation, collected organic
Phase, dry, concentration, silica gel post separation obtains chloro- 5- methyl isophthalic acids H- benzos [d] imidazoles of 11g 2- on residue.
(4) synthesis of 1- (5- methyl isophthalic acid H- benzos [d] imidazoles -2- bases) piperidines -4- carboxylic acids
Chloro- 5- methyl isophthalic acids H- benzos [d] imidazoles of 10g 2- is added in 130ml DMFs, added
15g Anhydrous potassium carbonates and 9g piperidines -4- formic acid, stirring 2 hours is heated to reflux, cooling, adds water and ethyl acetate extraction, point
Liquid, organic phase is collected, concentrated, the isolated 7g 1- of silicagel column (5- methyl isophthalic acid H- benzos [d] imidazoles -2- bases) piperazine on residue
Pyridine -4- carboxylic acids.
Claims (6)
1. one kind prepares 2 substituted benzimidazole derivative 1- (5- methyl isophthalic acid H- benzos [d] imidazoles -2- bases) piperidines -4- carboxylic acids
Preparation method, using 5- methyl -2- nitroanilines as initiation material, target is obtained by reduction, cyclization, chlorination, necleophilic reaction
Product 5, synthetic route is as follows.
2. method according to claim 1, it is characterized in that described 4 steps reaction is,
(1) using 5- methyl -2- nitroanilines as initiation material, 2 are obtained by reduction reaction；
(2) ring closure reaction is carried out 2, obtains 3；
(3) 3 progress chlorination reactions are obtained 4；
(4) 4 progress necleophilic reactions are obtained 5；
3. method according to claim 1, it is characterised in that the reducing agent choosing used in described reduction reaction prepare compound 2
One from iron powder, zinc powder, hydrogen, sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine
Kind or several mixtures；Reagent used in described ring closure reaction prepare compound 3 is selected from DMAP；Described
Reagent used in chlorination reaction prepare compound 4 is in thionyl chloride, POCl3, phosphorus trichloride, phosphorus pentachloride, chlorine
One or more of mixtures；Alkali used in described necleophilic reaction prepare compound 5 is selected from sodium hydroxide, potassium hydroxide, hydrogen
Lithia, sodium carbonate, potassium carbonate, triethylamine, sodium acid carbonate, pyridine, triisopropylamine, saleratus, sodium methoxide, caustic alcohol,
One or more of mixtures in one or more of mixtures in sodium tert-butoxide.
4. method according to claim 1, it is characterised in that the solvent used in described reduction reaction prepare compound 2 is selected from
Methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,
One or more of mixtures in dinethylformamide, DMAC N,N' dimethyl acetamide, triethylamine, pyridine, acetonitrile；Described
Solvent used in ring closure reaction prepare compound 3 is selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, first
One in benzene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, water
Kind or several mixtures；Solvent used in described chlorination reaction prepare compound 4 is selected from methanol, ethanol, normal propyl alcohol, isopropyl
Alcohol, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- bis-
One or more of mixtures in NMF, DMAC N,N' dimethyl acetamide, acetonitrile, POCl3；Described nucleophilic is anti-
The solvent used in prepare compound 5 is answered to be selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dioxane, dichloromethane
Alkane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N- dimethylacetamides
One or more of mixtures in amine, acetic acid, water.
5. method according to claim 1, it is characterised in that the reaction temperature used in described reduction reaction prepare compound 2
It is the reflux temperature of 0 DEG C~solvent；Temperature used in described ring closure reaction prepare compound 3 is the backflow temperature of 0 DEG C~solvent
Degree；Temperature used in described chlorination reaction prepare compound 4 is the reflux temperature of 0 DEG C~solvent；Described necleophilic reaction system
Temperature used in standby compound 5 is the reflux temperature of 0 DEG C~solvent.
6. method according to claim 1, it is characterised in that the reaction temperature used in described reduction reaction prepare compound 2
It is room temperature；Temperature used in described ring closure reaction prepare compound 3 is the reflux temperature of solvent；It is prepared by described chlorination reaction
Temperature used in compound 4 is the reflux temperature of solvent；Temperature used in described hydrolysis prepare compound 5 is solvent
Reflux temperature.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104387367A (en) * | 2014-11-02 | 2015-03-04 | 湖南华腾制药有限公司 | Method for preparing disubstituted benzimidazole derivative |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104387367A (en) * | 2014-11-02 | 2015-03-04 | 湖南华腾制药有限公司 | Method for preparing disubstituted benzimidazole derivative |
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Application publication date: 20171222 |
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