CN104311491A - Preparation method of benzimidazole derivative - Google Patents
Preparation method of benzimidazole derivative Download PDFInfo
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- CN104311491A CN104311491A CN201410468482.3A CN201410468482A CN104311491A CN 104311491 A CN104311491 A CN 104311491A CN 201410468482 A CN201410468482 A CN 201410468482A CN 104311491 A CN104311491 A CN 104311491A
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- compound
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- xylol
- temperature
- ring closure
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- RKRXTVLCZDPERO-UHFFFAOYSA-N Cc1nc(ccc([N+]([O-])=O)c2)c2[nH]1 Chemical compound Cc1nc(ccc([N+]([O-])=O)c2)c2[nH]1 RKRXTVLCZDPERO-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of t-butyl-2-methyl-3H-benzo[d]imidazole-5-yl-carbamic acid which is a benzimidazole derivative. The benzimidazole derivative is prepared from 4-nitrobenzene-1,2-diamine as an initial raw material by ring closure, reduction and tertbutyloxycarbonyl protection and is an important medicine 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 the benzimidizole derivatives tertiary butyl-2-methyl-3H-benzo [d] imidazoles-5-aminocarbamic acid.
Technical background
The compound tertiary butyl-2-methyl-3H-benzo [d] imidazoles-5-aminocarbamic acid, structural formula is:
This compound tertiary butyl-2-methyl-3H-benzo [d] imidazoles-5-aminocarbamic acid and relevant derivative have widespread use in pharmaceutical chemistry and organic synthesis.The synthesis of the current tertiary butyl-2-methyl-3H-benzo [d] imidazoles-5-aminocarbamic acid 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 the tertiary butyl-2-methyl-3H-benzo [d] imidazoles-5-aminocarbamic acid; with 4-oil of mirbane-1; 2-diamines is starting raw material, and obtain target product 4 through the ring that reaches a standard, reduction, tertbutyloxycarbonyl protection, synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) with 4-oil of mirbane-1,2-diamines for starting raw material, obtain 2 through ring closure reaction;
(2) carry out reduction reaction 2, obtain 3;
(3) carry out tertbutyloxycarbonyl protective reaction 3 and obtain 4;
One preferred embodiment in, the reagent that described ring closure reaction prepares compound 2 used is selected from acetic acid; The reductive agent that described reduction reaction prepares compound 3 used is selected from lithium aluminium hydride; The alkali that described tertbutyloxycarbonyl protective reaction prepares compound 4 used is selected from triethylamine.
One preferred embodiment in, the solvent that described ring closure reaction prepares compound 2 used is selected from toluene; The solvent that described reduction reaction prepares compound 3 used is selected from tetrahydrofuran (THF); The solvent that described tertbutyloxycarbonyl protective reaction prepares compound 4 used is selected from methylene dichloride.
One preferred embodiment in, described ring closure reaction prepares the reflux temperature that compound 2 temperature of reaction used is solvent; It is 0 DEG C ~ room temperature that described reduction reaction prepares compound 3 temperature used; Described tertbutyloxycarbonyl protective reaction prepare compound 4 used be room temperature.
The present invention relates to a kind of preparation method of the tertiary butyl-2-methyl-3H-benzo [d] imidazoles-5-aminocarbamic acid, there is no other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of the compound tertiary butyl-2-methyl-3H-benzo [d] imidazoles-5-aminocarbamic acid.
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-methyl-6-nitro-1H-benzo [d] imidazoles
15g4-oil of mirbane-1,2-diamines is joined in 120ml toluene, adds 50g acetic acid, return stirring 6 hours, concentrated add ethyl acetate and water again, separatory, drying, concentrated, residuum upper prop is separated and obtains 19g2-methyl-6-nitro-1H-benzo [d] imidazoles.
(2) synthesis of 2-methyl-3H-benzo [d] imidazoles-5-amine
18g2-methyl-6-nitro-1H-benzo [d] imidazoles is joined in 260ml anhydrous tetrahydro furan, be cooled to 0 DEG C, slowly add 8g Lithium Aluminium Hydride, after adding, naturally room temperature is risen to, stir 2 hours, then be cooled to 0 DEG C, slowly add aqueous sodium hydroxide solution, filter, add extraction into ethyl acetate, separatory, drying, concentrated, on residuum, silicagel column is separated to obtain 12g2-methyl-3H-benzo [d] imidazoles-5-amine.
(3) synthesis of the tertiary butyl-2-methyl-3H-benzo [d] imidazoles-5-aminocarbamic acid
10g2-methyl-3H-benzo [d] imidazoles-5-amine is joined in 140ml methylene dichloride, add 3ml triethylamine again, drip 8g tert-Butyl dicarbonate, stirring at room temperature 6 hours, add water, extraction separatory, dry, concentrated, on residuum, silicagel column is separated to obtain the 13g tertiary butyl-2-methyl-3H-benzo [d] imidazoles-5-aminocarbamic acid.
Claims (5)
1. prepare the method for the benzimidizole derivatives tertiary butyl-2-methyl-3H-benzo [d] imidazoles-5-aminocarbamic acid for one kind; with 4-oil of mirbane-1; 2-diamines is starting raw material, and obtain target product 4 through the ring that reaches a standard, reduction, tertbutyloxycarbonyl protection, synthetic route is as follows.
2. method according to claim 1, it is characterized by 3 described step reactions is,
(1) with 4-oil of mirbane-1,2-diamines for starting raw material, obtain 2 through ring closure reaction;
(2) carry out reduction reaction 2, obtain 3;
(3) carry out tertbutyloxycarbonyl protective reaction 3 and obtain 4;
3. according to the method for claim 1-2, it is characterized in that, the reagent that described ring closure reaction prepares compound 2 used is selected from acetic acid; 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, palladium carbon-hydrogen; Described tertbutyloxycarbonyl protective reaction is prepared compound 4 alkali used and is selected from the mixture of one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus.
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; 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; Compound 4 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 tertbutyloxycarbonyl protective reaction; 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; It is 0 DEG C ~ room temperature that described reduction reaction prepares compound 3 temperature used; Described tertbutyloxycarbonyl protective reaction prepare compound 4 used be 0 DEG C ~ room temperature.
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 solvent; It is 0 DEG C ~ room temperature that described reduction reaction prepares compound 3 temperature used; Described tertbutyloxycarbonyl protective reaction prepare compound 4 used be room temperature.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410468482.3A CN104311491A (en) | 2014-09-15 | 2014-09-15 | Preparation method of benzimidazole derivative |
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| CN201410468482.3A CN104311491A (en) | 2014-09-15 | 2014-09-15 | Preparation method of benzimidazole derivative |
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| CN104311491A true CN104311491A (en) | 2015-01-28 |
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| CN201410468482.3A Pending CN104311491A (en) | 2014-09-15 | 2014-09-15 | Preparation method of benzimidazole derivative |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020065307A1 (en) * | 1994-08-04 | 2002-05-30 | Synaptic Pharmaceutical Corporation | Novel benzimidazole derivatives |
| WO2009090548A2 (en) * | 2008-01-17 | 2009-07-23 | Glenmark Pharmaceuticals, S.A. | 3-azabicyclo [3.1.0] hexane derivatives as vanilloid receptor ligands |
-
2014
- 2014-09-15 CN CN201410468482.3A patent/CN104311491A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020065307A1 (en) * | 1994-08-04 | 2002-05-30 | Synaptic Pharmaceutical Corporation | Novel benzimidazole derivatives |
| WO2009090548A2 (en) * | 2008-01-17 | 2009-07-23 | Glenmark Pharmaceuticals, S.A. | 3-azabicyclo [3.1.0] hexane derivatives as vanilloid receptor ligands |
Non-Patent Citations (1)
| Title |
|---|
| KUNAL KUMAR，等: "Benzimidazole-based antibacterial agents against Francisella tularensis", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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Application publication date: 20150128 |