CN107337645A - A kind of preparation method of 1 substituted benzimidazole derivative - Google Patents
A kind of preparation method of 1 substituted benzimidazole derivative Download PDFInfo
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- CN107337645A CN107337645A CN201710726507.9A CN201710726507A CN107337645A CN 107337645 A CN107337645 A CN 107337645A CN 201710726507 A CN201710726507 A CN 201710726507A CN 107337645 A CN107337645 A CN 107337645A
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- prepare compound
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- xylene
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- DNMFAFVMNIVSKG-UHFFFAOYSA-N CC(C)COc(cc(cc1)C(OC)=O)c1F Chemical compound CC(C)COc(cc(cc1)C(OC)=O)c1F DNMFAFVMNIVSKG-UHFFFAOYSA-N 0.000 description 1
- WNXJFWXLMKXFNM-UHFFFAOYSA-N COc(cc(CN)cc1)c1-[n]1c2ccccc2nc1 Chemical compound COc(cc(CN)cc1)c1-[n]1c2ccccc2nc1 WNXJFWXLMKXFNM-UHFFFAOYSA-N 0.000 description 1
- LWGCZCMLPRMKIZ-UHFFFAOYSA-N COc(cc(cc1)C(O)=O)c1F Chemical compound COc(cc(cc1)C(O)=O)c1F LWGCZCMLPRMKIZ-UHFFFAOYSA-N 0.000 description 1
- 0 Cc1ccccc1N=CNc(ccc(*)c1)c1OC Chemical compound Cc1ccccc1N=CNc(ccc(*)c1)c1OC 0.000 description 1
Classifications
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of preparation method of 1 substituted benzimidazole derivative (4 (base of 1H benzos [d] imidazoles 1) 3 methoxyphenyls) methylamine, using the methoxy benzoic acid of 4 fluorine 3 as initiation material, target product is obtained through over-churning, condensation, amidatioon, reduction 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 1 substituted benzimidazole spreads out
The preparation method of biological (4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyls) methylamine.
Technical background
Compound (4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyls) methylamine, structural formula are：
This compound (4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyls) methylamine and the derivative of correlation are in medicine
There is extensive use in thing chemistry and organic synthesis.(4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyls) methylamine at present
Synthesis it 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 suitable
Synthetic method.
The content of the invention
The invention discloses a kind of 1 substituted benzimidazole derivative (4- (1H- benzos [d] imidazoles -1- bases) -3- methoxy
Base phenyl) methylamine preparation method, using the fluoro- 3- methoxy benzoic acids of 4- as initiation material, through over-churning, condensation, amidatioon, also
Original reaction obtains target product 5, and synthesis step is as follows：
(1) using the fluoro- 3- methoxy benzoic acids of 4- as initiation material, 2 are obtained by esterification；
(2) condensation reaction is carried out 2, obtains 3；
(3) 3 progress amidation process are obtained 4；
(4) 4 progress reduction reactions are obtained 5；
In a preferred embodiment, the reagent used in described esterification prepare compound 2 is selected from thionyl chloride；
Alkali used in described condensation reaction prepare compound 3 is selected from potassium carbonate；Used in described amidation process prepare compound 4
Reagent is selected from ammoniacal liquor；Reducing agent used in described reduction reaction prepare compound 5 is selected from lithium aluminium hydride reduction.
In a preferred embodiment, the solvent used in described esterification prepare compound 2 is selected from methanol；It is described
Condensation reaction prepare compound 3 used in solvent be selected from N,N-dimethylformamide；Described amidation process prepares chemical combination
Solvent used in thing 4 is selected from ammoniacal liquor；Solvent used in described reduction reaction prepare compound 5 is selected from tetrahydrofuran.
In a preferred embodiment, the reaction temperature used in described esterification prepare compound 2 is room temperature；Institute
The temperature used in condensation reaction prepare compound 3 stated is the reflux temperature of solvent；Described amidation process prepare compound 4
Temperature used is the reflux temperature of solvent；Temperature used in described reduction reaction prepare compound 5 is room temperature.
The present invention relates to a kind of 1 substituted benzimidazole derivative (4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyl group
Phenyl) methylamine preparation method, currently without other Patents documents report.
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) synthesis of the fluoro- 3- methoxyl methyl benzoates of 4-
The fluoro- 3- methoxy benzoic acids of 26g 4- are added in 200ml methanol, 50ml thionyl chlorides is added, is stirred overnight,
Concentration, obtains the fluoro- 3- methoxyl methyl benzoates of 29g 4-.
(2) (the synthesis of 4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyl methyl formates
The fluoro- 3- methoxyl methyl benzoates of 28g 4- are added in 320ml DMFs, add 19g carbon
Sour potassium and 36g benzimidazoles, stirring 5 hours is heated to reflux, cooled down, concentration adds water and ethyl acetate extraction liquid separation, and collection has
Machine phase, dry, concentration, obtain 36g (4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyl methyl formates.
(3) (the synthesis of 4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyl formamides
35g (4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyl methyl formates are added in 200ml ammoniacal liquor,
Stirring 3 hours is heated to reflux, cooling, adds ethyl acetate, liquid separation is extracted, collection organic phase, dries, concentration, silicon on residue
Glue post separation obtains 21g (4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyl formamides.
(4) synthesis of (4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyls) methylamine
20g, (4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyl formamides are added to the anhydrous tetrahydrochysene furans of 150ml
In muttering, 7g Lithium Aluminium Hydrides are added, are stirred at room temperature 3 hours, added frozen water and ethyl acetate extraction, liquid separation, collect organic phase, it is dense
Contract, the isolated 11g of silicagel column (4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyls) methylamine on residue.
Claims (5)
1. one kind prepares 1 substituted benzimidazole derivative (4- (1H- benzos [d] imidazoles -1- bases) -3- methoxyphenyls) methylamine
Preparation method, using the fluoro- 3- methoxy benzoic acids of 4- as initiation material, obtained through over-churning, condensation, amidatioon, reduction reaction
Target product 5, synthetic route is as follows
2. method according to claim 1, it is characterised in that the reagent used in described esterification prepare compound 2 is selected from
Hydrogen chloride, sulfuric acid, p-methyl benzenesulfonic acid, thionyl chloride, dicyclohexylcarbodiimide, one kind in 4- dimethylamino pyridines or several
The mixture of kind；Alkali used in described condensation reaction prepare compound 3 is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, carbon
In sour sodium, potassium carbonate, triethylamine, sodium acid carbonate, pyridine, triisopropylamine, saleratus, sodium methoxide, caustic alcohol, sodium tert-butoxide
One or more of mixtures in one or more of mixtures；Used in described amidation process prepare compound 4
One or more of mixtures of the reagent in thionyl chloride, ammoniacal liquor, ammonia, N, N'- carbonyl dimidazoles；Described reduction is anti-
The reducing agent used in prepare compound 5 is answered to be selected from iron powder, zinc powder, hydrogen, sodium borohydride, potassium borohydride, lithium borohydride, cyano group boron
One or more of mixtures in sodium hydride, lithium aluminium hydride, borine.
3. method according to claim 1, it is characterised in that the solvent used in described esterification 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 condensation 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 amidation process prepare compound 4 is selected from methanol, ethanol, normal propyl alcohol, different
Propyl alcohol, tetrahydrofuran, dioxane, dichloromethane, chloroform, toluene, ortho-xylene, paraxylene, meta-xylene, N, N-
One or more of mixtures in dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, POCl3；Described reduction
React the solvent used in prepare compound 5 and 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.
4. method according to claim 1, it is characterised in that the reaction temperature used in described esterification prepare compound 2
It is the reflux temperature of 0 DEG C~solvent；Temperature used in described condensation reaction prepare compound 3 is the backflow temperature of 0 DEG C~solvent
Degree；Temperature used in described amidation process prepare compound 4 is the reflux temperature of 0 DEG C~solvent；Described reduction reaction
Temperature used in prepare compound 5 is the reflux temperature of 0 DEG C~solvent.
5. method according to claim 1, it is characterised in that the reaction temperature used in described esterification prepare compound 2
It is room temperature；Temperature used in described condensation reaction prepare compound 3 is the reflux temperature of solvent；Described amidation process system
Temperature used in standby compound 4 is room temperature；Temperature used in described reduction reaction prepare compound 5 is the backflow temperature of solvent
Degree.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710726507.9A CN107337645A (en) | 2017-08-22 | 2017-08-22 | A kind of preparation method of 1 substituted benzimidazole derivative |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710726507.9A CN107337645A (en) | 2017-08-22 | 2017-08-22 | A kind of preparation method of 1 substituted benzimidazole derivative |
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| Publication Number | Publication Date |
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| CN107337645A true CN107337645A (en) | 2017-11-10 |
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| CN201710726507.9A Withdrawn CN107337645A (en) | 2017-08-22 | 2017-08-22 | A kind of preparation method of 1 substituted benzimidazole derivative |
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2017
- 2017-08-22 CN CN201710726507.9A patent/CN107337645A/en not_active Withdrawn
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Application publication date: 20171110 |