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
  • C07D235/08—Radicals containing only hydrogen and carbon atoms
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• the invention belongs to the technical field of organic synthesis, and relates to a benzimidazole compound and a preparation method thereof.
• the benzimidazole ring system is one of the most ubiquitous core structures used for drug discovery and has been found in many biologically active compounds.
• Raf kinase inhibitor
• LCK lymphocyte-specific kinase inhibitor, etc.
• serotonin receptor phosphodiesterase IV antihistamine Astemizole4 and anti-ulcer omeprazole.
• o-fluoronitrobenzene compound 8 is another precursor which produces compound 3 by three-step synthesis, the fluorine group of compound 8 is substituted by a primary amine (SN2), the nitro group is reduced to an amine, and then Cyclization with formic acid produces the target compound.
• SN2 primary amine
• the present invention provides a benzimidazole compound according to the above-mentioned deficiencies in the prior art, and provides a preparation method thereof, and synthesizes various substituted benzimidazole compounds by SN2 and cyclization reaction, that is, through one-pot reaction.
• the product is formed by cyclization of the corresponding fluoroaryl-N,N-dimethylformamidine and primary amine via an amine followed by cyclization of the dimethylamine.
• R 1 is -H, -Cl, alkyl
• R 2 is -NO 2 , -F, -Cl, Br, -CF 3 , -CN, -CO 2 CH 3 , -CO 2 CH 3 CH 2 ;
• R 3 is -H, alkyl, -CN, -CF 3 ;
• R 4 is -H, -Cl, alkyl, cycloalkyl, -CN;
• R 5 is -H, alkyl, fluoroalkyl, cycloalkyl, arylcyclo, heteroaryl ring;
• Y is -CH, -CH 2 , -N, -NH, -NH 2 , cycloalkyl.
• the preparation method of the benzimidazole compound of the invention comprises the following steps:
• the molar ratio of the compound of the formula (II) to the compound of the formula (III) is 1:1 to 12.
• R 2 is an electron withdrawing group, and R 2 is preferably -NO 2 , -CF 3 or -CN.
• the compound of the formula (III) is a primary amine, preferably a primary aliphatic amine, a primary aromatic amine or a primary amine containing a heterocyclic ring.
• the solvent is DMF, DMA, DMSO, HMPA, THF or dioxane.
• the reaction temperature is 80 to 220 ° C, and the time is 0.2 to 5 h.
• the invention has the beneficial effects of synthesizing various substituted benzimidazoles by SN2 and cyclization reaction, that is, by one-pot reaction from the corresponding o-fluoroaryl-N,N-dimethylformamidine and primary amine. Substitution of the fluorine atom by an amine then eliminates the cyclization of dimethylamine to form a product. Compared with the traditional method, the substitution and the ring closure are completed in one pot, the reaction process does not require the use of metal catalysts and/or toxic reagents, the synthesis method has specific selectivity, the reaction product has no isomers, and the process flow is simple and the yield is simple. high.
• the room temperature is 25 ° C;
• the stirring method defined by the number of revolutions is a conventional stirring method, and the number of revolutions is 500 to 1000 rpm.
• reaction mixture was cooled to room temperature, and the reaction mixture was placed in a 50 atmosphere. In a 250 mL separatory funnel of mL water. The mixture was extracted with 3 ⁇ 30 mL of ethyl acetate. Ethyl acetate in the organic phase was removed by rotary distillation, and the mixture was purified by silica gel column chromatography to give the product 1-cyclobutyl-5-nitro-1H-benzo[d]imidazole [1-cyclobutyl-5-nitro- 1H-benzo[d]imidazole] 0.117 g, yield 54%.
• reaction mixture was poured into a 250 mL separatory funnel containing 50 mL of water. The mixture was extracted with 3 ⁇ 30 mL of ethyl acetate. Ethyl acetate in the organic phase was removed by rotary distillation, and the mixture was purified by silica gel column chromatography to give the product 5-nitro-1-((tetrahydrofuran-2)methyl)-1H-benzo[d]imidazole [5- Nitro-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole] 0.192 g, yield 78%.
• reaction mixture was poured into a 250 mL separatory funnel containing 50 mL of water. The mixture was extracted with 3 ⁇ 30 mL of ethyl acetate. Ethyl acetate in the organic phase was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography to give the product 5-nitro-1-((tetrahydrofuran-2)methyl)-1H-benzo[d]imidazole [4- (3-(5-nitro-1H-benzo[d]imidazol-1-yl)propyl)morpholine] 0.246 g, yield 85%.
• reaction mixture was poured into a 250 mL separatory funnel containing 50 mL of water. The mixture was extracted with 3 ⁇ 30 mL of ethyl acetate. Ethyl acetate in the organic phase was removed by rotary distillation, and the mixture was purified by silica gel column chromatography to afford 4-(3-(6-methyl-5-nitro-1H-benzo[d]imidazole-1). 4-(3-(6-methyl-5-nitro-1H-benzo[d]imidazol-1-yl)propyl)morpholine] 0.216 g, 71% yield.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

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• 2017
  • 2017-07-19 CN CN201710589775.0A patent/CN107445899A/zh active Pending
  • 2017-09-28 US US16/485,457 patent/US10787420B2/en not_active Expired - Fee Related
  • 2017-09-28 WO PCT/CN2017/103942 patent/WO2019015112A1/zh not_active Ceased
  • 2017-09-28 JP JP2020509138A patent/JP6944682B2/ja not_active Expired - Fee Related

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