CN108250149B - A kind of chemical synthesis process of double-benzimidazoles compound - Google Patents
A kind of chemical synthesis process of double-benzimidazoles compound Download PDFInfo
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- CN108250149B CN108250149B CN201810206547.5A CN201810206547A CN108250149B CN 108250149 B CN108250149 B CN 108250149B CN 201810206547 A CN201810206547 A CN 201810206547A CN 108250149 B CN108250149 B CN 108250149B
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- 150000001875 compounds Chemical class 0.000 claims description 42
- 239000012043 crude product Substances 0.000 claims description 40
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 238000003756 stirring Methods 0.000 claims description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
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- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000007474 system interaction Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 102000009310 vitamin D receptors Human genes 0.000 description 1
- 108050000156 vitamin D receptors Proteins 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
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl 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
- C07D403/14—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 three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to field of medicaments, and in particular to a kind of chemical synthesis process of double-benzimidazoles compound.The double-benzimidazoles compound uses 4 bromine benzimidazoles for starting material, is obtained by two step Friedel-Crafts reactions, reduction reaction, diazo-reaction, Sang Demaier reactions and Huffman alkylated reaction.This method raw material is cheap and easy to get, simple for process, and reaction process is easily operated, high income, is suitble to industrial mass production.
Description
This application be on November 24th, 2017, a kind of entitled double-benzimidazoles compound and its use the applying date
Way and chemical synthesis process, application No. is the divisional applications of 2017111954464 earlier application.
Technical field
The invention belongs to field of medicaments, and in particular to a kind of chemical synthesis process of double-benzimidazoles compound.
Background technology
Psoriasis（Psoriasis）It is a kind of scales of skin that peel off papule dermatoses with features such as keratinocyte abnormality proliferations,
It is a kind of chronic, autoimmune disease for easily recurring, the definite cause of disease and pathogenesis are unclear.The disease is in cold district
For illness rate compared with torrid areas height, Northern Europe white people are higher than Asia yellow's illness rate.The illness rate of Norway is 1. 4%, and men and women suffers from
Sick rate is close.The illness rate of Denmark is up to 2. 9%, and Spain is 1.17~1. 43%.Britain is 1. 5%~2. 8%.China,
The illness rate of the Asian countries such as Japan psoriasis is relatively low.China showed that illness rate is in epidemiological survey in 1984
0. 123%.North city illness rate is that Shelter in South China Cities is 0. 153%, northern country 0. 176%, Southern Rural Area 0. 078%（
Build the epidemiology of middle psoriasis and risk factor practicality hospital clinical magazines, 2013,10（1）:4-6）.
Research thinks that psoriasis is inherent immunity system and adaptive immune system interaction under multiple-factor inheritance
Result.Onset of psoriasis is related to T cell, Dendritic Cells, keratinocyte, mast cell and macrophage function
Change.These cells and relevant cell factor, chemotactic factor (CF) interaction have mediated the relevant epidermal proliferation of psoriasis, angling not
Entirely, the external symptom such as acanthosis..In recent years, the major target class of psoriasis new drug development be vitamin D receptor stimulating agent, it is thin
26 enzyme inhibitor of born of the same parents' pigment P, p 38 alpha mitogen activating protein kinase inhibitor, inhibitors of protein kinase C, tumour are bad
Necrosis factor alpha inhibitor, phosphodiesterase 4 inhibitors, Janus kinase inhibitors, interleukin and its acceptor inhibitor, cutin are formed
Cytostatics, sphingosine-1-phosphate receptor antagonists etc.（Chen Ming, Zhong Jiemin, Liu Guanping wait Journal of Chinese Hospital Pharmacy,
2015,35（9）：846-849.）.
Benzimidazole is the presence of a kind of chemical constitution in most drugs, is a kind of important pharmaceutical intermediate.Antibacterial
Agent such as carbendazim and bacterium spirit；Antiparasitic agent such as albendazole；Gastric acid secretion inhibiting drug such as Omeprazole；Anti-atherogenic is hard
Chemical drug object such as BMS-212122；Anticancer drug such as PPTMB（What meet be full of the Chongqing benzimidazoles residues antitumor progress doctor
It learns, 2011,40 (27):2796-2798）Deng containing benzimidazole structure, but its action target spot and structure-activity relationship are deposited
In significant difference.
In terms of psoriasis small molecule therapeutic, Liarozole has benzimidazole structure, and in addition there are one individually for tool
There is benzothiazole structure, anti-psoriasis effect to be better than Liarozole by phenyl ring and imidazole ring, Ta Laluo azoles and R116010.Li A
Azoles, Ta Laluo azoles, the structural formula of R116010 are as follows：
By above structure as it can be seen that Liarozole, Ta Laluo azoles, R11601 all have a benzo nitrogen azoles structure, in benzo nitrogen
There are one phenyl ring and a five-ring heterocycles for one end connection of azoles structure, wherein and phenyl ring and five-ring heterocycles itself are in that branch-like is arranged
Though row or phenyl ring and five yuan miscellaneous for linear array but intermediate add larger alkyl substituent；Liarozole, Ta Laluo azoles,
The equal non-linearity structures of R11601, but be in larger branched structure.These similar structure features are often based on structure-activity relationship
The result of design.Such as according to the structural analysis of small molecule and target spot enzyme acceptor binding pocket.Wherein Ta Laluo azoles, R11601 pairs
The therapeutic effect of psoriasis is better than Liarozole.
Although the drug for having some treatment psoriasis at present enters clinical application, its therapeutic effect is still limited.Still
It needs to research and develop new, better efficacy curing psoriasis drug.
Invention content
For the existing existing above problem, an object of the present invention is to provide a kind of novel double-benzimidazoles
Compound.To achieve the above object, technical scheme is as follows：
A kind of double-benzimidazoles compound has structure shown in following general formula：
Wherein X is the amino-substituent containing only a nitrogen-atoms, and X is total by the carbon atoms on a benzene ring of nitrogen-atoms and benzimidazole
Valence connects；R is methyl.
Preferably, the X is one kind in alkyl amino, dialkyl amido or pyrrolidinyl.
Preferably, the X is one kind in isopropylamino, diethylamino, 3- methylpyrrole alkyl.
Preferably, the X is isopropylamino.
Preferably, the X is diethylamino.
Preferably, the X is 3- methylpyrrole alkyl.
Another aspect provides above-mentioned double-benzimidazoles compounds in preparing curing psoriasis drug
Purposes.
It is yet another aspect of the present invention to provide the chemical synthesis process of above-mentioned double-benzimidazoles compound, including walk as follows
Suddenly：
The first step, compound 1 occur Friedel-Crafts alkylation with compound 2 under the action of lewis acid and obtain compound
3；
Second step, compound 3 occur Friedel-Crafts alkylation with compound 4 under the action of lewis acid and obtain compound
5；
Third walks, and compound 5 is under the catalytic action of Pd/C plus hydrogen occurs reduction reaction and obtains compound 6；
4th step, compound 6 react to obtain compound 7 by diazo-reaction, Sang Demaier；
5th step, compound 7 obtain target product 8 with amine by Huffman alkylated reaction in the presence of alkali.
Preferably, the above-mentioned first step, second step reaction described in lewis acid be ZnCl2、AlCl3、FeCl3、SnCl4、
NbCl5Any one of；The cuprous salt of the reactions of Sang Demaier described in four-step reaction is any one of CuBr, CuCl；The
In the reaction of five steps, alkali used in the Huffman alkylated reaction is NaOH, Na2CO3、NaHCO3、KOH、K2CO3、KHCO3、CsOH
Any one of；In the reaction of 5th step, the amine is one kind in isopropylamine, diethylamide, 3- crassitudes.
The chemical synthesis process of double-benzimidazoles compound described in when X is isopropylamino includes the following steps：
The first step, alchlor are dissolved in nitrobenzene, 0oCompound 2, stirring are added under C；Compound 1 is dissolved in nitro
Benzene is added in the case of stirring in above-mentioned solution, is reacted 100oIt is stirred overnight under C；After the completion of reaction, 0oUnder C with
NaOH solution neutralizes；Dichloromethane extracts, and collects organic phase, saturated common salt washing, anhydrous magnesium sulfate drying；Filtering, filtrate subtract
Pressure distillation obtains crude product；Crude product filters through silica gel, recrystallizes to obtain compound 3 in ethyl acetate.
Second step, alchlor are dissolved in nitrobenzene, 0oCompound 3, stirring are added under C；Compound 4 is dissolved in nitro
Benzene is added in the case of stirring in above-mentioned reaction solution, is reacted 120oIt is stirred overnight under C；After the completion of reaction, 0oUnder C with
NaOH solution neutralizes；Dichloromethane extracts, and collects organic phase, saturated common salt washing, anhydrous magnesium sulfate drying；Filtering, filtrate subtract
Pressure distillation obtains crude product；Crude product purifies to obtain compound 5 through column chromatography.
Third walks, and compound 5 is dissolved in absolute ethyl alcohol, 5% Pd/C is added, at room temperature H2Compressive reaction is stayed overnight；Reaction stops
Afterwards, diatomite removes Pd/C, collects filtrate, solvent is removed under reduced pressure and obtains crude product；Crude product purifies to obtain compound 6 through column chromatography.
4th step, compound 6 are dissolved in hydrochloric acid solution, and ice-water bath is cooled to -5oC, sodium nitrite is soluble in water, is slowly added dropwise
Into above-mentioned solution, stirring forms reaction solution 1；Cuprous bromide, concentrated hydrochloric acid and dichloromethane mixing, are cooled to 10 ~ 15 DEG C,
Form reaction solution 2；Reaction solution 1 is slowly added dropwise into reaction solution 2,10 ~ 15 DEG C are stirred 4 hours；After completion of the reaction, dichloromethane
Extraction merges organic layer, saturated common salt washing, anhydrous magnesium sulfate drying；Filtering, filtrate decompression distill to obtain crude product, crude product warp
It is recrystallized to give compound 7.
5th step, potassium carbonate are dissolved in DMF, and isopropylamine is added, is vigorously stirred；Compound 7 is dissolved in DMF, is protected in nitrogen
Above-mentioned solution is added dropwise under conditions of shield, after charging, is heated to reflux 4 hours；After reaction stops, reaction solution is cooled to room
4% sodium hydroxide solution and ethyl acetate are added after temperature, extraction merges organic layer, saturated common salt washing, and anhydrous magnesium sulfate is done
It is dry；Filtering, filtrate decompression are distilled off to obtain crude product；Crude product purifies to obtain compound 8 through column chromatography.
When X is 3- methylpyrrole alkyl, the chemical synthesis process of the double-benzimidazoles compound includes as follows
Step：
The first step, alchlor are dissolved in nitrobenzene, 0oCompound 2, stirring are added under C；Compound 1 is dissolved in nitro
Benzene is added in the case of stirring in above-mentioned solution, is reacted 100oIt is stirred overnight under C；After the completion of reaction, 0oUnder C with
NaOH solution neutralizes；Dichloromethane extracts, and collects organic phase, saturated common salt washing, anhydrous magnesium sulfate drying；Filtering, filtrate subtract
Pressure distillation obtains crude product；Crude product filters through silica gel, recrystallizes to obtain compound 3 in ethyl acetate.
Second step, alchlor are dissolved in nitro, 0oCompound 3, stirring are added under C；Compound 4 is dissolved in nitrobenzene,
It is added in above-mentioned reaction solution, is reacted 120 in the case of stirringoIt is stirred overnight under C；After the completion of reaction, 0oUnder C with
NaOH solution neutralizes；Dichloromethane extracts, and collects organic phase, saturated common salt washing, anhydrous magnesium sulfate drying；Filtering, filtrate subtract
Pressure distillation obtains crude product；Crude product purifies to obtain compound 5 through column chromatography.
Third walks, and compound 5 is dissolved in absolute ethyl alcohol, 5% Pd/C is added, at room temperature H2Compressive reaction is stayed overnight；Reaction stops
Afterwards, diatomite removes Pd/C, collects filtrate, solvent is removed under reduced pressure and obtains crude product；Crude product purifies to obtain compound 6 through column chromatography.
4th step, compound 6 are dissolved in hydrochloric acid solution, and ice-water bath is cooled to -5oC, sodium nitrite is soluble in water, is slowly added dropwise
Into above-mentioned solution, stirring forms reaction solution 1；Cuprous bromide, concentrated hydrochloric acid and dichloromethane mixing, are cooled to 10 ~ 15 DEG C,
Form reaction solution 2；Reaction solution 1 is slowly added dropwise into reaction solution 2,10 ~ 15 DEG C are stirred 4 hours；After completion of the reaction, dichloromethane
Extraction merges organic layer, saturated common salt washing, anhydrous magnesium sulfate drying；Filtering, filtrate decompression distill to obtain crude product, crude product warp
It is recrystallized to give compound 7.
5th step, potassium hydroxide are dissolved in DMF, and 3- crassitudes are added, are vigorously stirred.Compound 7 is dissolved in DMF,
Above-mentioned solution, after charging, heated overnight at reflux are added dropwise under conditions of nitrogen protection.After reaction stops, reaction solution
4% sodium hydroxide solution and ethyl acetate are added after being cooled to room temperature, extraction merges organic layer, and saturated common salt washing is anhydrous
Magnesium sulfate is dried.Filtering, filtrate decompression are distilled off to obtain crude product.Crude product purifies to obtain compound 8 through column chromatography.
The DMF described in technical solution of the present invention described in technical solution of the present invention is dimethylformamide, is chemical synthesis
Common reagent.
Compared with the existing technology, the present invention has designed and synthesized novel double-benzimidazoles compound for the first time, and for the first time
It is found that therapeutic activity of the double-benzimidazoles compound to psoriasis.The conjunction for the double-benzimidazoles compound invented
Cheap and easy to get at method starting material, synthesis step is succinct, and synthesis condition is mild, and building-up process is easily controllable, and yield is high, is suitable for
Industrialized production.
Specific implementation mode
Below with reference to the specific embodiment detailed explanation present invention, the embodiment only for technical scheme of the present invention into
Row illustrates, and the present invention is not limited to following embodiments.
1 2- of embodiment（4- methoxyphenyls）Benzimidazole（Compound 3）Synthesis
Weigh alchlor（40g）It is added in three-necked flask, nitrobenzene 500ml is added, stirring is cooled to 0oC, then
Weigh anisole（10.8g）It is added in reaction solution, stirs.Weigh the bromo- 1H- benzimidazoles of 2-（19.7g）It is dissolved in nitrobenzene
（20ml）, it is added in the case of stirring in above-mentioned reaction solution, after charging, reaction solution is increased to 100oC is stirred
Night, thin-layered chromatography detect reaction process.After the completion of reaction, reaction is cooled to 0oC is slowly added into 1mol/lNaOH solution
300ml is neutralized.Organic phase is detached, water layer is extracted with dichloromethane（100ml×3）, merge organic phase, saturated common salt washing
（200ml×1）, anhydrous magnesium sulfate drying.Filtering, collects filtrate, and vacuum distillation obtains brown solid substance.Again by the substance
It is dissolved in ethyl acetate 50ml, is filtered by 200-300 mesh silica gel, collect filtrate, vacuum distillation obtains light yellow solid object
Matter.By the solid matter 50oIt is dissolved under conditions of C in 20ml ethyl acetate, is then cooled to 0oIt is placed 2 hours under C,
There are a large amount of solid matters to be precipitated, solid is collected in filtering, and vacuum drying obtains target product 2-（4- methoxyphenyls）Benzo miaow
Azoles 15.8g, yield 70.5%.
1HNMR(400Hz, DMSO): δ 7.642-7.613(m,2H), 7.411-7.359(m, 2H), 7.119-
7.102(m, 2H), 6.904-6.891(m, 2H), 4.733(br, 1H), 3.476(s, 3H).
MS(EI): 225.1(MH+)
2 2- of embodiment（4- methoxyphenyls）-6（5- nitros -1H- benzimidazolyl-2 radicals-base）- 1H- benzimidazoles（Chemical combination
Object 5）Synthesis
Weigh alchlor（26.7g）It is added in three-necked flask, nitrobenzene 300ml is then added, stirring is cooled to
0oThen C weighs 2-（4- methoxyphenyls）- 1H- benzimidazoles（14.2g）Solution nitrobenzene 20ml is added in reaction solution,
Stirring.Weigh the bromo- 5 nitro -1H- benzimidazoles of 2-（16.9g）It is dissolved in nitrobenzene（20ml）, it is added in the case of stirring
It states in reaction solution, after charging, reaction solution is increased to 120oC is stirred overnight, and thin-layered chromatography detects reaction process.Reaction
After the completion, reaction is cooled to 0oC is slowly added into 1mol/lNaOH solution 200ml and neutralizes.Detach organic phase, water layer dichloro
Methane extracts（100ml×3）, merge organic phase, saturated common salt washing（200ml×1）, anhydrous magnesium sulfate drying.Filtering is collected
Filtrate, vacuum distillation obtain red brown solid substance.The solid matter is purified through column chromatography（200-300 mesh silica gel, acetic acid second
Ester：N-hexane=2:1 is used as elutriant）Obtain target product 2-（4- methoxyphenyls）-6（5- nitro -1H- benzimidazolyl-2 radicals -
Base）- 1H- benzimidazole 11.5g, yield 47.2%.
1HNMR(400Hz, DMSO): δ 8.427(s, 1H), 8.074-8.061(m, 1H), 7.964-7.915
(m, 2H), 7.638(s, 1H), 7.419-7.352(m, 3H), 6.873-6.797(m, 2H), 5.274(s, 1H),
4.629(br, 1H), 3.419(s, 3H).
MS(EI): 386.1(MH+)
3 2- of embodiment（4- methoxyphenyls）-6（5- amino -1H- benzimidazolyl-2 radicals-base）- 1H- benzimidazoles（Chemical combination
Object 6）Synthesis
By 2-（4- methoxyphenyls）-6（5- nitros -1H- benzimidazolyl-2 radicals-base）- 1H- benzimidazoles（10.2g,）It is dissolved in
In 100ml absolute ethyl alcohols, 5% Pd/C is then added（1.2g）, reaction is placed in H at room temperature2Pressurization (20 ~ 60psi) was reacted
Night.After reaction stops, diatomite is filtered to remove Pd/C, collects filtrate, solvent is removed under reduced pressure and obtains yellow oil.The yellow oil
Shape substance is purified through column chromatography（200-300 mesh silica gel, dichloromethane：Methanol=1:1 is used as elutriant）Obtain target product 2-
（4- methoxyphenyls）-6（5- amino -1H- benzimidazolyl-2 radicals-base）- 1H- benzimidazole 8.4g, yield 89.3%.
1HNMR(400Hz, DMSO): δ 7.924(m, 1H), 7.611-7.596(d, J=6.0Hz, 1H),
7.485-7.446(m, 2H), 7.324-7.295(m, 2H), 6.912-6.845(m, 3H), 6.574-6.523(m,
1H), 5.023(br, 1H), 4.862-4.851(s, 2H), 4.554-4.542(s, 1H), 3.358(s, 3H).
MS(EI): 356.2(MH+)
4 2- of embodiment（4- methoxyphenyls）-6（The bromo- 1H- benzimidazolyl-2 radicals-bases of 5-）- 1H- benzimidazoles（Compound
7）Synthesis
Weigh 2-（4- methoxyphenyls）-6（5- amino -1H- benzimidazolyl-2 radicals-base）- 1H- benzimidazoles（8.0g）It is added
Into reaction bulb, 3mol/l hydrochloric acid solutions are then added into reaction bulb（24ml）, stirring makes 2-（4- methoxyphenyls）-6（5-
Amino -1H- benzimidazolyl-2 radicals-base）- 1H- benzimidazoles are completely dissolved in hydrochloric acid solution, are cooled to -5oC, then by nitrous
Sour sodium（1.6g）It is dissolved in 5ml water, forms solution, be slowly dropped in above-mentioned reaction bulb, control temperature is slowly dripped at 0 ~ 5 DEG C
After adding, maintains temperature to be 0 ~ 5 DEG C and react 1 hour.Cuprous bromide is added in another take in a reaction bulb（0.65g）, concentrated hydrochloric acid
（10ml）And dichloromethane（50ml）, it is cooled to 10 ~ 15 DEG C in the case of stirring, then above-mentioned reaction solution is slowly added dropwise
Into the reaction bulb, after being added dropwise, 10 ~ 15 DEG C of controlling reaction temperature stirs 4 hours, and thin-layer chromatography tracking reaction has been reacted
Bi Hou, detaches organic layer, and water layer is extracted with dichloromethane（50ml×2）, merge organic layer, saturated common salt washing（50ml×1）,
Anhydrous magnesium sulfate is dried.Filtering, collects filtrate, and vacuum distillation removes solvent, yellow solid matter obtained, by the yellow solid
Matter is recrystallized with methanol, obtains target product 2-（4- methoxyphenyls）-6（The bromo- 1H- benzimidazolyl-2 radicals-bases of 5-）-1H-
Benzimidazole 7.8g, yield 82.6%.
1HNMR(400Hz, DMSO): δ 7.934(s, 1H), 7.842-7.834(d, J=Hz, 1H), 7.643-
7.675(m, 1H), 7.512-7.437(m, 3H), 7.369-7.308(m, 2H), 6.825-6.799(m, 2H),
5.269(br, 1H), 4.697(br, 1H), 3.469(s, 3H).
MS(EI): 419.4(MH+)
5 2- of embodiment（4- methoxyphenyls）- 6- [5- (isopropylaminos）- 1H- benzimidazolyl-2 radicals-yl] -1H- benzos
Imidazoles（Compound 8a）Synthesis
Weigh potassium carbonate（0.6g）It is dissolved in DMF（20ml）In, stirring makes solid matter dissolve in 5 minutes, is added at room temperature different
Propylamine（4.5g）, it is vigorously stirred 10 minutes.Weigh 2-（4- methoxyphenyls）-6（The bromo- 1H- benzimidazolyl-2 radicals-bases of 5-）- 1H- benzene
And imidazoles（1.6g）It is dissolved in DMF（5ml）In, it is added dropwise under conditions of nitrogen protection in above-mentioned solution, after charging,
It is heated to reflux 4 hours, thin-layered chromatography detects reaction process.After reaction stops, reaction solution being cooled to room temperature, then to reaction
4% sodium hydroxide solution is added in liquid（100ml）And ethyl acetate（100ml）, stir 5 minutes, detach organic layer, water layer
It is extracted with ethyl acetate（50ml×2）, merge organic layer, saturated common salt washing（50ml×1）, anhydrous magnesium sulfate drying.Filtering,
Filtrate is collected, vacuum distillation removes solvent and obtains yellow solid matter.The yellow solid matter is purified through column chromatography（Neutral alumina
Aluminium, dichloromethane：Methanol=6:1 is used as elutriant）Obtain target product 2-（4- methoxyphenyls）- 6- [5- (2- Methylethyls
Amino）- 1H- benzimidazolyl-2 radicals-yl] -1H- benzimidazole 1.1g, yield 72.5%.
1HNMR(400Hz, DMSO): δ 7.919(s, 1H), 7.643-7.675(m, 1H), 7.453-7.367
(m, 4H), 6.911-6.794(m, 3H), 6.436-6.411(m, 1H), 5.647(s, 1H), 4.589(br, 1H),
4.235(s, 1H), 3.394(s, 3H), 3.094-3.011(m, 1H), 0.987-0.968(d, J=7.6Hz, 6H).
13C NMR(400Hz, DMSO):162.382, 156.161, 155.829, 143.557, 140.473,
139.892, 138.716, 130.843, 129.076, 126.455, 125.968, 122.781, 119.687,
117.552, 117.494, 115.083, 114.961, 105.679, 58.436, 36.592, 19.855.
MS(EI): 398.1(MH+)
6 2- of embodiment（4- methoxyphenyls）- 6 [5- (diethylaminos）- 1H- benzimidazolyl-2 radicals-yl] -1H- benzos
Imidazoles（Compound 8b）Synthesis
Weigh cesium hydroxide（0.75g）It is dissolved in DMF（20ml）In, stirring makes solid matter dissolve in 5 minutes, is added at room temperature
Diethylamide（7.3g）, it is vigorously stirred 10 minutes.Weigh 2-（4- methoxyphenyls）-6（The bromo- 1H- benzimidazolyl-2 radicals-bases of 5-）-
1H- benzimidazoles（2.1g）It is dissolved in DMF（5ml）In, it is added dropwise in above-mentioned solution, has fed under conditions of nitrogen protection
Bi Hou, heated overnight at reflux, thin-layered chromatography detect reaction process.Reaction stop after, reaction solution is cooled to room temperature, then to
4% sodium hydroxide solution is added in reaction solution（100ml）And ethyl acetate（100ml）, it stirs 5 minutes, detaches organic layer,
Water layer is extracted with ethyl acetate（50ml×2）, merge organic layer, saturated common salt washing（50ml×1）, anhydrous magnesium sulfate drying.
Filtering, collects filtrate, and vacuum distillation removes solvent and obtains yellow solid matter.The yellow solid matter is purified through column chromatography（In
Property aluminium oxide, dichloromethane：Methanol=7:1 is used as elutriant）Obtain target product 2-（4- methoxyphenyls）- 6 [5- (diethyl
Amino）- 1H- benzimidazolyl-2 radicals-yl] -1H- benzimidazole 1.3g, yield 63.1%.
1HNMR(400Hz, DMSO): δ 8.016(s, 1H), 7.714-7.011(m, 1H), 7.598-7.585
(m, 1H), 7.502-7.489(m, 1H), 7.369-7.314(m, 2H), 7.005-6.856(m, 3H), 6.548-
6.529(m, 1H), 5.335(br, 1H), 4.589(br, 1H), 3.891(s, 3H), 3.058-3.037(m, 4H),
1.057-1.015(t, J=8.8Hz, 6H).
13C NMR(400Hz, DMSO): 160.847, 155.963, 154.231, 148.726, 140.082,
139.819, 138.924, 129.859, 128.634, 125.149, 123.248, 122.291, 118.198,
118.074, 116.248, 113.586, 112.894, 106.316, 59.447, 39.282, 20.831.
MS(EI): 412.2(MH+)
7 2- of embodiment（4- methoxyphenyls）- 6 [5- (3- methylpyrrole alkyl）- 1H- benzimidazolyl-2 radicals-yl] -1H-
Benzimidazole（Compound 8c）Synthesis
Weigh potassium hydroxide（0.3g）It is dissolved in DMF（20ml）In, stirring makes solid matter dissolve in 5 minutes, is added at room temperature
3- crassitudes（10.2g）, it is vigorously stirred 10 minutes.Weigh 2-（4- methoxyphenyls）-6（The bromo- 1H- benzimidazolyl-2 radicals-of 5-
Base）- 1H- benzimidazoles（2.2g）It is dissolved in DMF（5ml）In, it is added dropwise in above-mentioned solution, adds under conditions of nitrogen protection
After material, heated overnight at reflux, thin-layered chromatography detects reaction process.After reaction stops, reaction solution being cooled to room temperature, so
4% sodium hydroxide solution is added in backward reaction solution（100ml）And ethyl acetate（100ml）, stir 5 minutes, separation has
Machine layer, water layer are extracted with ethyl acetate（50ml×2）, merge organic layer, saturated common salt washing（50ml×1）, anhydrous magnesium sulfate
It is dry.Filtering, collects filtrate, and vacuum distillation removes solvent and obtains yellow solid matter.The yellow solid matter is pure through column chromatography
Change（Neutral alumina, dichloromethane：Methanol=15:2 are used as elutriant）Obtain target product 2-（4- methoxyphenyls）-6[5-
(3- methylpyrrole alkyl）- 1H- benzimidazolyl-2 radicals-yl] -1H- benzimidazole 0.92g, yield 41.3%.
1HNMR(400Hz, DMSO): δ 7.947-7.930(m, 1H), 7.695-7.602(m, 1H), 7.517-
7.499(m, 1H), 7.481(s, 1H), 7.334-7.291(m, 2H), 7.004-6.842(m, 3H), 6.647-
6.601(m, 1H), 5.042(br, 1H), 4.862(s, 1H), 3.737(s, 3H), 3.082-2.919(m, 4H),
1.591-1.484(m, 2H), 1.336-1.299(m, 1H), 0.887-0.865(d, J=8.8Hz, 3H).
13C NMR(400Hz, DMSO): 161.316, 156.442, 155.947, 150.583, 141.369,
140.916, 140.023, 129.716, 128.055, 125.996, 125.023, 124.276, 119.158,
118.731, 116.043, 115.619, 114.887, 106.994, 62.691, 60.004, 48.639, 37.868,
35.186, 17.561.
MS(EI): 424.3(MH+)
8 compound of embodiment treats the pharmacodynamic experiment of psoriasis
One, drug
1. positive control medicine：
1.1Hoechst 33258：Hoechst 33258 is a kind of bisbenzimidazole compound, molecular weight 533.88,
No. CAS：23491-45-4, be it is a kind of can be relatively low to cytotoxicity with the substance of penetration cell film.It is commonly used for thin
Karyon coloring material.The compound is similar to the compound of the present invention structure, therefore as positive control.Hoechst 33258
Purchased from abundant bio tech ltd of upper Hisense.
1.2 liarozole hydrochloride：English name Liarozole hydrochloride, No. CAS：115575-11-6 is a kind of
Tretinoin analogies containing single benzimidazole structure can block the metabolism of Tretinoin, increase endogenous Tretinoin in blood and tissue,
Clinical test proves that it has therapeutic effect to chronic plaque psoriasis.The compound all has benzene with the compound of the present invention
And glyoxaline structure, and belong to antipsoriatic object, therefore as positive control.Liarozole hydrochloride surpasses purchased from Shanghai grinds biotechnology
Co., Ltd.
Experimental drug
Compound 8a, 8b, 8c of embodiment 5-7 is respectively as experimental drug.
Two, experimental animal model and grouping and administration
1. the foundation of experimental animal model
SPF grades of BALB/c mouse, male, weight 18 to 22g tie up the limited public affairs of tonneau China's experimental animal technology purchased from Beijing
Department.Animal adaptability in SPF environment, which is raised one week, is used as quarantine.
After quarantine, back part of animal is lost hair or feathers using 10% sodium sulfide solution, and depilation area is 2x2 square centimeters.
Single cage is raised 24 hours after mouse picric acid marker number after losing hair or feathers.After single cage is raised 24 hours, each mouse is with miaow quinoline
Not special emulsifiable paste（Hubei KeYi Pharmacentic Co., Ltd., 3g:0.15g/ branch）Uniformly it is applied to back hair removal section skin, coating area
2x2 square centimeters, 1 times/day, 50 mg emulsifiable pastes every time, continuous 14 days.Using PASI indexes (Psoriasis area and
Severity index, psoriasis area and severity index) to the erythema, the scales of skin that peel off, leaching in rat model back modeling region
Three symptoms of profit degree score, and three, which scores to be added, obtains PASI overall scores.Erythema, the scales of skin that peel off, infiltration degree use 0-4 respectively
Divide evaluation：0=nothing；1=slight；2=moderate；3=severe；4=pole severe.Three every mouse erythema, the scales of skin that peel off, infiltration degree indexs
Scoring of the summation of scoring as the mouse severity of psoriasis, i.e., the severity of psoriasis scoring of every mouse for 0 to
12 points.
Grouping and administration
The successful mouse of modeling is randomly divided into 5 groups, every group 6.Respectively Hoechst is smeared in back modeling region
33258, the alcohol dispersion liquid of liarozole hydrochloride, compound 8a, compound 8b or compound 8c.Wherein Hoechst 33258, salt
Sour Liarozole, compound 8a, compound 8b, compound 8c dosage be daily 1mg, successive administration 14 days.
Three, pharmacodynamic evaluations indexs and experimental result
Use PASI exponent pair each group mouse psoriasis within 24 hours before first administration and after the last administration after modeling
Severity scale is evaluated and is recorded, and the severity of psoriasis scoring of each group mouse is indicated with the mean value of this group of mouse.
As a result it see the table below.
a:The P compared with before administration<0.05; b:The P compared with liarozole hydrochloride group<0.01; c:With liarozole hydrochloride group phase
Compare P<0.05.
By the above results as it can be seen that each group mouse severity of psoriasis PASI scores without significant difference before administration, illustrate each
The severity of psoriasis of group before administration is comparable.
The PASI scorings with administration of 33258 groups of mouse of Hoechst are preceding without significant difference after administration, illustrate Hoechst
33258 pairs of psoriasis are without therapeutic effect.The PASI of mouse after liarozole hydrochloride, compound 8a, compound 8b, compound 8c administrations
Before scoring is substantially less than administration, illustrate that these compounds have therapeutic effect to psoriasis.Wherein compound 8a, compound 8b, change
The PASI scorings for closing mouse after object 8c is administered are substantially less than liarozole hydrochloride group, illustrate compound 8a, compound 8b, compound 8c
Liarozole hydrochloride group is better than to the therapeutic effect of psoriasis.PASI after wherein compound 8a, compound 8b, the administration of compound 8c groups
Scoring is followed successively by from low to high：Compound 8a, compound 8b, compound 8c illustrate compound 8a, compound 8b, compound 8c
The therapeutic effect of psoriasis is reduced successively.The closed loop N substituent groups of visual compounds 8c may influence medicine to a certain extent
Effect.
Claims (4)
1. a kind of chemical synthesis process of double-benzimidazoles compound, which is characterized in that the double-benzimidazoles compound
Structure with following general formula：
Wherein X is one kind in isopropylamino, 3- methylpyrrole alkyl, and X is former by the phenyl ring carbon of nitrogen-atoms and benzimidazole
Son is covalently attached；R is methyl；
The chemical synthesis process of the double-benzimidazoles compound includes the following steps：
The first step, compound 1 occur Friedel-Crafts alkylation with compound 2 under the action of lewis acid and obtain compound 3；
Second step, compound 3 occur Friedel-Crafts alkylation with compound 4 under the action of lewis acid and obtain compound 5；
Third walks, and compound 5 is under the catalytic action of Pd/C plus hydrogen occurs reduction reaction and obtains compound 6；
4th step, compound 6 react to obtain compound 7 by diazo-reaction, Sang Demaier；
5th step, compound 7 obtain target product 8 with amine by Huffman alkylated reaction in the presence of alkali.
2. the chemical synthesis process of double-benzimidazoles compound according to claim 1, which is characterized in that the first step,
Lewis acid described in second step reaction is ZnCl2、AlCl3、FeCl3、SnCl4、NbCl5Any one of；In four-step reaction
The cuprous salt of the Sang Demaier reactions is any one of CuBr, CuCl；In the reaction of 5th step, the Huffman alkylation is anti-
It is NaOH, Na to answer alkali used2CO3、NaHCO3、KOH、K2CO3、KHCO3, any one of CsOH；In the reaction of 5th step, the amine
For one kind in isopropylamine, 3- crassitudes.
3. the chemical synthesis process of double-benzimidazoles compound according to claim 1, which is characterized in that the X is
The chemical synthesis process of isopropylamino, the double-benzimidazoles compound includes the following steps：
The first step, alchlor are dissolved in nitrobenzene, 0oCompound 2, stirring are added under C；Compound 1 is dissolved in nitrobenzene, is being stirred
It is added in above-mentioned solution, is reacted 100 in the case of mixingoIt is stirred overnight under C；After the completion of reaction, 0oWith NaOH solution under C
It neutralizes；Dichloromethane extracts, and collects organic phase, saturated common salt washing, anhydrous magnesium sulfate drying；Filtering, filtrate decompression are distilled
To crude product；Crude product filters through silica gel, recrystallizes to obtain compound 3 in ethyl acetate；
Second step, alchlor are dissolved in nitrobenzene, 0oCompound 3, stirring are added under C；Compound 4 is dissolved in nitrobenzene, is being stirred
It is added in above-mentioned reaction solution, is reacted 120 in the case of mixingoIt is stirred overnight under C；After the completion of reaction, 0oIt is molten with NaOH under C
Liquid neutralizes；Dichloromethane extracts, and collects organic phase, saturated common salt washing, anhydrous magnesium sulfate drying；Filtering, filtrate decompression distillation
Obtain crude product；Crude product purifies to obtain compound 5 through column chromatography；
Third walks, and compound 5 is dissolved in absolute ethyl alcohol, 5% Pd/C is added, at room temperature H2Compressive reaction is stayed overnight；After reaction stops, silicon
Diatomaceous earth removes Pd/C, collects filtrate, solvent is removed under reduced pressure and obtains crude product；Crude product purifies to obtain compound 6 through column chromatography；
4th step, compound 6 are dissolved in hydrochloric acid solution, and ice-water bath is cooled to -5oC, sodium nitrite is soluble in water, is slowly dropped to
It states in solution, stirs, form reaction solution 1；Cuprous bromide, concentrated hydrochloric acid and dichloromethane mixing, are cooled to 10 ~ 15 DEG C, are formed
Reaction solution 2；Reaction solution 1 is slowly added dropwise into reaction solution 2,10 ~ 15 DEG C are stirred 4 hours；After completion of the reaction, dichloromethane extracts
It takes, merges organic layer, saturated common salt washing, anhydrous magnesium sulfate drying；Filtering, filtrate decompression distill to obtain crude product, and crude product is through weight
Crystallization obtains compound 7；
5th step, potassium carbonate are dissolved in DMF, and isopropylamine is added, is vigorously stirred；Compound 7 is dissolved in DMF, in nitrogen protection
Under the conditions of above-mentioned solution is added dropwise, after charging, be heated to reflux 4 hours；After reaction stops, after reaction solution is cooled to room temperature
4% sodium hydroxide solution and ethyl acetate is added, extraction merges organic layer, saturated common salt washing, anhydrous magnesium sulfate drying；
Filtering, filtrate decompression are distilled off solvent and obtain crude product；Crude product purifies to obtain compound 8 through column chromatography.
4. the chemical synthesis process of double-benzimidazoles compound according to claim 1, which is characterized in that the X is
3- methylpyrrole alkyl, the chemical synthesis process of the double-benzimidazoles compound include the following steps：
The first step, alchlor are dissolved in nitrobenzene, 0oCompound 2, stirring are added under C；Compound 1 is dissolved in nitrobenzene, is being stirred
It is added in above-mentioned solution, is reacted 100 in the case of mixingoIt is stirred overnight under C；After the completion of reaction, 0oWith NaOH solution under C
It neutralizes；Dichloromethane extracts, and collects organic phase, saturated common salt washing, anhydrous magnesium sulfate drying；Filtering, filtrate decompression are distilled
To crude product；Crude product filters through silica gel, recrystallizes to obtain compound 3 in ethyl acetate；
Second step, alchlor are dissolved in nitrobenzene, 0oCompound 3, stirring are added under C；Compound 4 is dissolved in nitrobenzene, is being stirred
It is added in above-mentioned reaction solution, is reacted 120 in the case of mixingoIt is stirred overnight under C；After the completion of reaction, 0oIt is molten with NaOH under C
Liquid neutralizes；Dichloromethane extracts, and collects organic phase, saturated common salt washing, anhydrous magnesium sulfate drying；Filtering, filtrate decompression distillation
Obtain crude product；Crude product purifies to obtain compound 5 through column chromatography；
Third walks, and compound 5 is dissolved in absolute ethyl alcohol, 5% Pd/C is added, at room temperature H2Compressive reaction is stayed overnight；After reaction stops, silicon
Diatomaceous earth removes Pd/C, collects filtrate, solvent is removed under reduced pressure and obtains crude product；Crude product purifies to obtain compound 6 through column chromatography；
4th step, compound 6 are dissolved in hydrochloric acid solution, and ice-water bath is cooled to -5oC, sodium nitrite is soluble in water, is slowly dropped to
It states in solution, stirs, form reaction solution 1；Cuprous bromide, concentrated hydrochloric acid and dichloromethane mixing, are cooled to 10 ~ 15 DEG C, are formed
Reaction solution 2；Reaction solution 1 is slowly added dropwise into reaction solution 2,10 ~ 15 DEG C are stirred 4 hours；After completion of the reaction, dichloromethane extracts
It takes, merges organic layer, saturated common salt washing, anhydrous magnesium sulfate drying；Filtering, filtrate decompression distill to obtain crude product, and crude product is through weight
Crystallization obtains compound 7；
5th step, potassium hydroxide are dissolved in DMF, and 3- crassitudes are added, are vigorously stirred；Compound 7 is dissolved in DMF, in nitrogen
Above-mentioned solution, after charging, heated overnight at reflux are added dropwise under conditions of gas shielded；After reaction stops, reaction solution cooling
4% sodium hydroxide solution and ethyl acetate are added after to room temperature, extraction merges organic layer, saturated common salt washing, anhydrous slufuric acid
Magnesium is dried；Filtering, filtrate decompression are distilled off solvent and obtain crude product；Crude product purifies to obtain compound 8 through column chromatography.
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