CN109320458B - Diaryl imidazole-containing compound, preparation method and medical application thereof - Google Patents

Diaryl imidazole-containing compound, preparation method and medical application thereof Download PDF

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CN109320458B
CN109320458B CN201811189972.4A CN201811189972A CN109320458B CN 109320458 B CN109320458 B CN 109320458B CN 201811189972 A CN201811189972 A CN 201811189972A CN 109320458 B CN109320458 B CN 109320458B
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孙昊鹏
卢鑫
李琦
杨鸿瑜
陈瑶
李启航
冯锋
曲玮
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Abstract

The invention discloses diaryl imidazole compounds shown as a formula (I). The invention also discloses application of the diaryl imidazole compound in preparing a medicament for preventing or treating Alzheimer's disease. The inventors evaluated the activity of diarylimidazole compounds in treating alzheimer's disease using screening of inhibitory activities of butyrylcholinesterase and IDO1 as vectors, and found that diarylimidazole compounds have excellent in vitro activity and can be used as a precursor substance for further development to exert an anti-alzheimer's disease effect by inhibiting cholinesterase activity.
Figure DDA0001827249070000011

Description

Diaryl imidazole-containing compound, preparation method and medical application thereof
Technical Field
The invention belongs to the field of medicines, and relates to diaryl imidazole compounds, a preparation method thereof, and application of the compounds in preparation of medicines for treating Alzheimer's disease.
Background
Alzheimer's Disease (AD) is a neurodegenerative disease. The clinical manifestations are degenerative loss of memory and cognitive function. According to the Alzheimer's disease Association, AD is one of the ten leading causes of death for which there is no way to prevent, cure or delay progression in the United states. By 2016, there are approximately 4700 million dementia patients worldwide, and by 2050 this figure will exceed 1.31 billion. These numbers may still be lower than the actual patient population, since this does not include those patients in the earliest clinical stages of the disease. AD patients require long-term care, with costs of treatment reaching $ 818 billion in 2015 in the united states for AD and other dementias, and are predicted to be a disease with costs of trillion in 2018.
China is the world with the highest general population growth trend for older people, and is expected to increase from around 2 billion in 2015 to 4.9 billion in 2050 (united nations 2016). The aging trend is increased, and China faces a severe test on the aspect of treating AD, which is not only a challenge of the medical industry, but also a problem to be solved in the economic development. According to the ' report of world alzheimer's disease in 2015 ', 950 million people in china are estimated to have dementia, accounting for 20% of the total number of dementia in the world, and by 2030, chinese AD patients are expected to increase to 1600 more than ten thousand. The treatment cost of AD far exceeds the treatment cost of diabetes, apoplexy and other diseases. The medical level of AD in China is still in the first stage, and the development of diagnosis, prevention and treatment is imminent. The long-term course of AD causes significant emotional and economic burdens on the patients, their families, and the whole society. Therefore, the search for effective drugs and treatment strategies for AD treatment has become a critical issue to be solved urgently in the medical field of the whole world.
The pathogenesis of AD is extremely complex and involves multiple aspects. The exact cause of AD is currently not yet definitively determined by scientists. Its main pathological features include the following aspects 1) beta-amyloid peptide fragments: extracellular, self-aggregating, cytotoxic a β oligomers and fibrils; 2) excessive phosphorylation of Tau protein aggregates intracellularly to form neurofibrillary tangles (NFTs); 3) cholinergic conduction disorder caused by damage to cholinergic nerves; 4) loss of a neurosynaptic; 5) neuroinflammation and too high a concentration of metal ions within cells; 6) oxidative stress and mitochondrial dysfunction. Scientists have proposed a number of treatment strategies for the pathological characteristics of AD.
Although a number of potential strategies for treating AD have been proposed, they are in the basic research phase. Currently, clinically effective drugs mainly comprise cholinesterase inhibitors. The cholinergic system is mainly composed of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and hydrolyzes the neurotransmitter acetylcholine (Ach), which plays an important role in cholinergic neurotransmission. As the course of AD progresses, levels of AChE in the brain gradually decrease, while BuChE remains unchanged and even increases to 165% of normal levels. In the advanced stages of AD, BuChE is responsible for the hydrolysis of acetylcholine in the brain instead of AChE. BuChE is an enzyme closely related to AChE, and performs the regulation of cholinergic neurotransmitters by hydrolyzing acetylcholine. Although BuChE is thought to play a minor role in regulating brain ACh levels, it has been reported to be associated with drug metabolism and detoxification. Some evidence also suggests that increased BuChE activity plays an important role in a β aggregation at the early stage of age spot formation. The potential importance of BuChE has been demonstrated by AChE knockout mice in a model where BuChE compensates for AChE deficiency, maintaining the normal cholinergic pathway in AChE-null animals. Currently, AChE inhibitors are widely used to restore ACh levels, but administration of "classical" AChE inhibitors to patients may produce side effects such as nausea and vomiting, with these concomitant undesirable results primarily due to inhibition of peripheral AChE. Selective BuChE inhibitors may circumvent classical cholinergic toxicity. This suggests that inhibition of the effects of BuChE may be more effective than selective AChE, especially against mid-late AD.
Indoleamine 2,3-dioxygenase (IDO), widely expressed in mammalian tissues or cells, especially lymphoid tissues and placenta, is the rate-limiting enzyme of the Tryptophan (TRP) catabolic Kynurenine Pathway (KP). IDO plays an important role in the immune system, and high-expression IDO is involved in immune escape of tumors. At the same time, there is increasing evidence that IDO is associated with the pathogenesis of AD. Perturbation in KP is strongly correlated with AD. The L-kynurenine (L-KYN)/TRP ratio in blood and cerebrospinal fluid of AD patients is increased compared to healthy individuals, consistent with an increase in brain IDO levels and 3-hydroxykynurenine in serum, and this increase in ratio is positively correlated with cognitive impairment. The immunoreactivity of IDO and quinolinic acid (QUIN) was observed in microglia, astrocytes and neurons of hippocampal tissues of AD patients, and the highest signal was observed in the periphery of senile plaques. Both are found in neurofibrillary tangles, and QUIN is present in intracellular aggregates of particles in cortical neurons. Abeta (beta)42Induces expression of IDO1 and increases QUIN production in human macrophages and microglia. Studies of human neuronal and mouse models indicate that Abeta42The elevation of (c) is consistent with the induction of KP by pro-inflammatory cytokines that induce IDO, TDO and Kynurenine-3-monooxygenase (KMO) activity. Furthermore, treatment of human neurons with QUIN resulted in up-regulation of genes involved in tau protein phosphorylation, which may provide a mechanism for AD to form neurofibrillary tangles. In addition, key enzymes in KP such as IDO and KMO and well-known AD markers of A beta deposition and Tau protein excessPhosphorylation is at the same location in the brain.
The molecular effect of a single target point is limited, the defects of a 'one molecule-one target point' strategy emerge gradually, and a new drug design strategy is produced and favored by more scientific researchers. The principle of the multi-target strategy (MTDL) is that one molecule can act on two or more related targets simultaneously, and the combination of multiple effects is beneficial for the treatment of multifactorial related pathological diseases such as AD. A large number of multi-target molecules emerge, and new vitality is injected for the research of treating AD. Although no MTDL drug has yet entered clinical studies, this new design strategy still has great potential.
The above studies fully demonstrate that designing synthetic BuChE/IDO1 dual-target inhibitors would have advantages over single-target therapy in the treatment of AD. The discovery, design and analysis of the BuChE/IDO1 double-target inhibitor for generating the biological mechanism of AD treatment not only have extremely important basic research value, but also have wide application prospect.
Disclosure of Invention
The invention aims to provide diaryl imidazole compounds with an anti-Alzheimer disease effect.
The purpose of the invention is realized by the following technical scheme:
diaryl imidazole compounds shown as a formula (I) or pharmaceutically acceptable salts thereof,
Figure BDA0001827249050000031
wherein A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aromatic condensed ring; the substituent of the phenyl group being halogen, -NO2、-CN、Cl～C6Alkyl, halogen substituted C1～C4Alkyl radical, C1～C3Alkoxy, naphthyl substituents being halogen, -NO2、-CN、-OH、Cl～C6Alkyl, heterocyclic substituents being halogen, -NO2CN, -OH, halogen-substituted C1～C4Alkyl radical, C1～C4Alkyl radical, C1～C3An alkoxy group; l is selected from-O-, -S-or-C (O) O-; n is 1,2, 3.
Preferably, A is selected from substituted or unsubstituted phenyl, unsubstituted naphthyl, unsubstituted aromatic heterocycle, unsubstituted hybrid aromatic condensed ring, and the substituent of phenyl is selected from hydrogen, fluorine, chlorine, bromine, halogen substituted C1～C4Alkyl radical, C1～C4Alkyl radical, C1～C3An alkoxy group; l is selected from-O-, -C (O) O-; n is 1,2, 3.
Further preferably, A is selected from the group consisting of substituted or unsubstituted phenyl, unsubstituted naphthyl, thiophene, benzo [ d][1,3]Dioxoles, phenyl substituents selected from hydrogen, fluorine, chlorine, bromine substituted C1～C4Alkyl radical, C1～C4Alkyl, or C1～C3An alkoxy group; l is selected from-O-, -C (O) O; n is 1,2, 3. In certain embodiments of the present invention, the phenyl substituent is ortho, meta, para, di, or tri substituted.
Still more preferably, when L ═ O-, n ═ 1; a is substituted or unsubstituted phenyl, unsubstituted naphthyl, thiophene, benzo [ d ] [1,3] dioxole, wherein the substituent of the phenyl is selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy and tert-butyl; when L ═ C (O) O, n ═ 1,2,3, A is taken from 3, 4-difluorophenyl.
When the phenyl group is substituted with other than hydrogen, it is preferably a halogen mono-, di-or tri-substituted at the 2,3, 4, 5-positions, and more preferably fluorine or chlorine di-or tri-substituted at the 2,3, 4, 5-positions.
The diaryl imidazole compounds are selected from the following compounds, and the structures of the compounds are shown in a table 1:
TABLE 1
Figure BDA0001827249050000041
Figure BDA0001827249050000051
Figure BDA0001827249050000061
Figure BDA0001827249050000071
It is another object of the present invention to provide a method for preparing a diarylimidazole compound, comprising:
substituted aryl ethanone is used as a raw material, alpha-bromo aryl ethanone is obtained by bromine bromination, and the alpha-bromo aryl ethanone is obtained by alkylation with imidazole N
Figure BDA0001827249050000072
Then reacting with sodium borohydride to obtain
Figure BDA0001827249050000073
And finally reacting with 3-methoxybenzyl chloride or aryl carboxylic acid with different chain lengths to prepare the diaryl imidazole compound shown in the formula (I).
The preparation method of the invention preferably comprises the following steps:
step (1), substituting aryl ethanone, using trichloromethane as reaction solvent in Br2Stirring for 1h at room temperature under the action of the solvent, quenching the reaction by saturated sodium sulfite after the reaction is finished, washing an organic phase by saturated sodium bicarbonate and saturated salt solution, drying by anhydrous sodium sulfate, and removing the solvent in vacuum to obtain a crude product; the substituted arylethanone and Br2The molar ratio of (A) to (B) is 1: 1-1.5;
and (2) dissolving alpha-bromoarylethanone and imidazole in tetrahydrofuran, adding potassium carbonate, stirring at room temperature for 3 hours, removing the reaction liquid in vacuum, adding water, and extracting with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, spun-dried, and separated by silica gel column chromatography. Wherein, the eluent of the silica gel column chromatography is dichloromethane and methanol which are 100:1 v/v; the molar ratio of the alpha-bromoarylethanone to the imidazole to the potassium carbonate is (1: 2: 2) - (1): 3: 3;
step (3) of mixing
Figure BDA0001827249050000081
Dissolving in absolute methanol, adding sodium borohydride under ice-bath condition, stirring for 1 hour under the ice-bath condition, and heating and refluxing. Adding water to quench reaction, extracting with ethyl acetate, mixing organic phases, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, spin drying, and separating with silica gel column chromatography to obtain
Figure BDA0001827249050000082
Wherein, the eluent is DCM, MeOH is 30:1 v/v; said
Figure BDA0001827249050000083
The molar ratio of the sodium borohydride to the sodium borohydride is 1: 2-1: 3;
step (4) when L is-O-, the operation is that
Figure BDA0001827249050000084
Dissolving in DMF, adding sodium hydride under ice bath, reacting at room temperature for 1 hour, adding 3-methoxybenzyl chloride under ice bath, and reacting at room temperature for 1 hour. Quenching with water, extracting with ethyl acetate, washing the organic phase with saturated salt solution sequentially, drying with anhydrous sodium sulfate, spin drying, and separating with silica gel column chromatography to obtain compound with structure shown in formula (I); said
Figure BDA0001827249050000085
The molar ratio of the NaH to the 3-methoxy benzyl chloride is 1:1.2: 1.2-1: 1.2: 1.3; eluent is DCM, MeOH ═ 30:1 v/v. When L is-C (O) O, it is operated to
Figure BDA00018272490500000810
Dissolved in DCM, dicyclohexylcarbodiimide and p-dimethylaminopyridine were added under ice-bath and reacted at room temperature for 2 hours. The reaction solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography to obtain a compound having the structure represented by formula (I). Said
Figure BDA0001827249050000088
And with
Figure BDA0001827249050000089
The molar ratio of dicyclohexylcarbodiimide to dimethylaminopyridine is 1:1:1: 0.1-1: 1.3:1.3: 0.1; eluent is DCM, MeOH ═ 30:1 v/v.
The synthetic route of the diaryl imidazole compound is as follows:
Figure BDA0001827249050000091
the diaryl imidazole compound can inhibit butyrylcholine esterase and indoleamine 2,3-dioxygenase simultaneously, has good selectivity on acetylcholinesterase, and can be used as a precursor substance which is further developed to play a role in resisting Alzheimer's disease by inhibiting the activities of butyrylcholine esterase and indoleamine 2, 3-dioxygenase.
Therefore, the invention also aims to provide the application of the diaryl imidazole compound or the pharmaceutically acceptable salt thereof in preparing the medicines for preventing or treating the Alzheimer disease.
The medicament is prepared by taking the diaryl imidazole compound or the pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient and a pharmaceutically acceptable carrier; the dosage form of the medicine is capsule, pill, tablet, granule or injection.
The composition takes the diaryl imidazole compound or the pharmaceutically acceptable salt thereof as an effective component or a main effective component, and a pharmaceutically acceptable carrier.
Has the advantages that:
the diaryl imidazole compound has certain inhibitory activity on butyrylcholinesterase and indoleamine 2, 3-dioxygenase-1, and has good selectivity on acetylcholinesterase. In addition, the compound of the invention has no obvious toxicity to PC-12 and SH-5YSY cell strains under the dosage of 50 mu M in MTT experiments, and part of the compound has slight protective effect on cells. In the water maze experiment for mouse behavior research, the compounds 8 and 13 are shown to effectively reverse the mouse cognitive disorder caused by the scopolamine at both the doses of 10mg/kg and 30mg/kg, and the compound 13(10mg/kg) is optimal and equivalent to the control group. In addition, in the acute hepatotoxicity evaluation experiment of mice, the two doses of 10mg/kg and 30mg/kg of the compounds 8 and 13 have no significant influence on alanine aminotransferase and aspartate aminotransferase, do not cause adverse morphological change of liver, and show preliminary safety. In the early stage of Alzheimer's disease, 80% of acetylcholine is hydrolyzed by acetylcholinesterase, butyrylcholinesterase has almost no effect, the level of acetylcholinesterase is reduced and the function is almost lost with the aggravation of the disease course, at the moment, the level and the function of butyrylcholinesterase are relatively improved, and the substituted acetylcholinesterase becomes the main metabolic enzyme of acetylcholine. Therefore, the inhibitory activity of butyrylcholinesterase is particularly important for the treatment of severe alzheimer's disease. The L-kynurenine (L-KYN)/TRP ratio in blood and cerebrospinal fluid of AD patients is increased compared to healthy individuals, consistent with an increase in IDO1 levels in brain and 3-HK in serum, and this increase in ratio is positively correlated with cognitive impairment. Inhibition of IDO1 has been demonstrated in animal models to alleviate cognitive disorders. The diaryl imidazole compound has good inhibitory activity on butyrylcholinesterase and IDO1, and is expected to provide better treatment effect on Alzheimer's disease than a single target inhibitor.
Drawings
FIG. 1 time of arrival of mouse at missing platform location
FIG. 2 representative trajectory of a mouse to a missing platform location
FIG. 3 Effect of Compounds of the examples on survival of PC12 cells
FIG. 4 Effect of the Compounds of the examples on SH-SY5Y cell survival
FIG. 5 is the alanine aminotransferase levels of seven groups of mice at three time points; in the figure, ns indicates that the model group has no significant difference from the control group.
FIG. 6 shows aspartate transaminase levels in seven groups of mice at three time points; in the figure, ns indicates that the model group has no significant difference from the control group.
FIG. 7 is a histopathological section of mouse liver; wherein, (A) the liver section of the control group mouse; (B) liver sections of model mice 36 hours after dosing; (C) liver sections of mice in the tacrine group 36 hours after administration; (D) compound 8(10mg/kg) treated group mouse liver sections 36 hours after administration; (E) compound 8(30mg/kg) treated group mouse liver sections 36 hours after administration; (F) compound 13(10mg/kg) treatment group mouse liver sections 36 hours after administration; (G) compound 13(30mg/kg) treated mouse liver sections 36 hours after dosing.
Detailed Description
The technical solutions of the present invention are further described below by way of examples, but it should not be construed that the scope of the present invention is limited to the following examples. According to the technical scheme of the invention, other modifications, substitutions and alterations can be made according to common technical knowledge and conventional means in the field without departing from the technical idea of the invention, and the technology realized based on the technical scheme of the invention is within the scope of the invention.
The structure of the compound was determined by Nuclear Magnetic Resonance (NMR). The apparatus is a Bruker AVANCE-300 nuclear magnetic resonance apparatus, and the determination solvent is CDCl3Internal standard TMS, chemical shift 10-6ppm。
Example 1
(1) Synthesis of 2-bromo-1- (4-fluorophenyl) ethan-1-one
Taking 4-fluoro acetophenone (1.38g,10mmol), trichloromethane as a reaction solvent, and adding Br2(1.91g,12mmol) was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.1g of crude product.
(2) Synthesis of 1- (4-fluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (4-fluorophenyl) ethan-1-one (2.1g,9.67mmol) and imidazole (1.31g,19.35mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.67g,19.35mmol) was added, and after stirring at room temperature for 3h, the reaction solution was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.4g of a yellow solid in 64.5% yield.
(3) Synthesis of 1- (4-fluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (4-fluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.02g, 5mmol) was dissolved in 50ml of anhydrous methanol, and sodium borohydride (378mg,10mmol) was added under ice bath, stirred for one hour and then refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The product was obtained as a pale yellow solid 880mg by spin-drying, without additional purification, in 86.7% yield.
(4) Synthesis of 1- (2- (4-fluorophenyl) -2- ((3-methoxybenzyl) oxy) ethyl) -1H-imidazole
1- (4-fluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (206mg,1mmol) was dissolved in 2ml DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 141mg (compound 6) as a colorless oil, in 43.1% yield. TLC detected as a dot, with fluorescence under UV 254 nm.1H NMR(300MHz,CDCl3)δ7.44(s,1H),7.28(d,J＝4.5Hz,1H),7.24(s,1H),7.23(s,1H),7.09(t,J＝8.5Hz,2H),7.04(s,1H),6.90(s,1H),6.84(d,J＝7.4Hz,1H),6.74(d,J＝7.2Hz,2H),4.55(dd,J1＝7.3,J2＝4.3Hz,1H),4.47(d,J＝11.8Hz,1H),4.21(d,J＝11.8Hz,1H),4.16(d,J＝7.4Hz,1H),4.09(dd,J1＝14.3Hz,J2＝4.2Hz,1H),3.80(s,3H).ESI:m/z[M+H]+,calcd.for C19H19FN2O2:327.1431；found 327.1503.
Example 2
(1) Synthesis of 2-bromo-1- (2, 4-difluorophenyl) ethan-1-one
2, 4-difluoroacetophenone (1.56g,10mmol) was dissolved in 100ml of chloroform and slowly added dropwise in ice bathBr2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.3g of crude product.
(2) Synthesis of 1- (2, 4-difluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (2, 4-difluorophenyl) ethan-1-one (2.3g,9.78mmol) and imidazole (1.33g,19.57mmol) were dissolved in 50ml tetrahydrofuran, potassium carbonate (2.7g,19.57mmol) was added, and after stirring at room temperature for 3h, the reaction was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.6g of a yellow solid in 72.7% yield.
(3) Synthesis of 1- (2, 4-difluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (2, 4-difluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.1g, 5mmol) was dissolved in 50ml of anhydrous methanol, sodium borohydride (378mg,10mmol) was added under ice bath, stirred for one hour and then refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry to give 920mg of a pale yellow solid, i.e., the product, without additional purification, 83.7% yield.
(4) Synthesis of 1- (2- (2, 4-difluorophenyl) -2- ((3-methoxybenzyl) oxy) ethyl) -1H-imidazole
1- (2, 4-difluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (222mg,1mmol) was dissolved in 2ml of DMF, and after 1 hour reaction at room temperature by addition of 60% sodium hydride (48mg,1.2mmol) in ice bath, 3-methoxybenzyl chloride (180mg,1.2mmol) in ice bath was added, and the reaction was continued for 1 hour at room temperature. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 145mg (compound 7) of a colorless oil, with a yield of 42.1%. TLC detection is one point, and the ultraviolet lamp has fluorescence under 254 nm.1H NMR(300MHz,CDCl3)δ7.55(s,1H),7.44(s,1H),7.24(t,J＝8.0Hz,1H),7.15(d,J＝8.3Hz,2H),7.04(s,1H),6.90(s,1H),6.84(d,J＝7.3Hz,1H),6.73(d,J＝7.6Hz,2H),4.53(dd,J1＝7.2,J2＝4.3Hz,1H),4.48(d,J＝11.9Hz,1H),4.21(d,J＝11.9Hz,1H),4.15(d,J＝7.2Hz,1H),4.09(dd,J1＝14.3Hz,J2＝4.4Hz,1H),3.80(s,3H).ESI:m/z[M+H]+,calcd.for C19H18F2N2O2:345.1336；found.345.1409.
Example 3
(1) Synthesis of 2-bromo-1- (3, 4-difluorophenyl) ethan-1-one
3, 4-difluoroacetophenone (1.56g,10mmol) was dissolved in 100ml of chloroform, and Br was slowly added dropwise in ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.3g of crude product.
(2) Synthesis of 1- (3, 4-difluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (3, 4-difluorophenyl) ethan-1-one (2.3g,9.78mmol) and imidazole (1.33g,19.57mmol) were dissolved in 50ml tetrahydrofuran, potassium carbonate (2.7g,19.57mmol) was added, and after stirring at room temperature for 3h, the reaction was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.6g of a yellow solid in 72.7% yield.
(3) Synthesis of 1- (3, 4-difluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (3, 4-difluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.1g, 5mmol) was dissolved in 50ml of anhydrous methanol, sodium borohydride (378mg,10mmol) was added under ice bath, stirred for one hour and then refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry to give 920mg of a pale yellow solid, i.e., the product, without additional purification, 83.7% yield.
(4) Synthesis of 1- (2- (3, 4-difluorophenyl) -2- ((3-methoxybenzyl) oxy) ethyl) -1H-imidazole
1- (2, 4-difluorophenyl) -2- (1H-imidazole-1-yl) ethan-1-ol (222mg,1mmol) was dissolved in 2ml DMF, 60% sodium hydride (48mg,1.2mmol) was added under ice bath, and after 1 hour of reaction at room temperature, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice bath, and further 1 hour of reaction at room temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, and spin-dried, and separated by silica gel column chromatography (DCM: MeOH: 30:1v/v) to give 170mg (compound 8) as a colorless oil, in 48.5% yield. TLC detection is one point, and the ultraviolet lamp has fluorescence under 254 nm.1H NMR(300MHz,CDCl3)δ7.43(s,1H),7.29–7.24(m,1H),7.23–7.17(m,1H),7.15–7.09(m,1H),7.04(s,1H),7.01–6.94(m,1H),6.89(s,1H),6.87–6.82(m,1H),6.76–6.70(m,2H),4.55–4.52(m,1H),4.49(d,J＝11.7Hz,1H),4.22(d,J＝11.9Hz,1H),4.14(d,J＝7.2Hz,1H),4.08(dd,J1＝14.3Hz,J2＝4.4Hz,1H),3.80(s,3H).ESI:m/z[M+H]+,calcd.for C19H18F2N2O2:345.1336；found.345.1421
Example 4
(1) Synthesis of 2-bromo-1- (4-chlorophenyl) ethan-1-one
4-Chloroacetophenone (1.54g,10mmol) was dissolved in 100ml of chloroform, and Br was slowly added dropwise under ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.3g of crude product.
(2) Synthesis of 1- (4-chlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (4-chlorophenyl) ethan-1-one (2.3g,9.87mmol) and imidazole (1.34g,19.7mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.7g,19.7mmol) was added, and after stirring at room temperature for 3 hours, the reaction solution was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.6g of a yellow solid in 72.7% yield.
(3) Synthesis of 1- (4-chlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (4-chlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.1g, 5mmol) was dissolved in 50ml of anhydrous methanol, and sodium borohydride (378mg,10mmol) was added under ice bath, stirred for one hour and then refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-drying to obtain 980mg of light yellow solid, namely the product, without additional purification, with the yield of 89.1%.
(4) Synthesis of 1- (2- (4-chlorophenyl) -2- ((3-methoxybenzyl) oxy) ethyl) -1H-imidazole
1- (4-chlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (222mg,1mmol) was dissolved in 2ml of DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 160mg (compound 9) of a colorless oil, with a yield of 47.8%. TLC detected as a dot, with fluorescence under UV 254 nm.1H NMR(300MHz,CDCl3)δ7.45(s,1H),7.38(d,J＝8.1Hz,2H),7.26(d,J＝8.4Hz,1H),7.21(d,J＝8.1Hz,2H),7.04(s,1H),6.90(s,1H),6.84(d,J＝8.6Hz,1H),6.73(d,J＝7.4Hz,2H),4.54(dd,J1＝7.0Hz,J2＝4.5Hz,1H),4.47(d,J＝11.8Hz,1H),4.21(d,J＝12.0Hz,1H),4.15(d,J＝7.4Hz,1H),4.09(dd,J1＝14.3Hz,J2＝4.2Hz,1H),3.80(s,3H).ESI:m/z[M+H]+,calcd.for C19H19ClN2O2:343.1135；found.343.1218
Example 5
(1) Synthesis of 2-bromo-1- (3-chlorophenyl) ethan-1-one
Dissolving 3-chloroacetophenone (1.54g,10mmol) in 100ml of chloroform, and slowly adding Br dropwise under ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.3g of crude product.
(2) Synthesis of 1- (3-chlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (3-chlorophenyl) ethan-1-one (2.3g,9.87mmol) and imidazole (1.34g,19.7mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.7g,19.7mmol) was added, and after stirring at room temperature for 3 hours, the reaction solution was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.6g of a yellow solid in 72.7% yield.
(3) Synthesis of 1- (3-chlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (3-chlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.1g, 5mmol) was dissolved in 50ml of anhydrous methanol, and sodium borohydride (378mg,10mmol) was added under ice bath, stirred for one hour and then refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-drying to obtain 980mg of light yellow solid, namely the product, without additional purification, with the yield of 89.1%.
(4) Synthesis of 1- (2- (3-chlorophenyl) -2- ((3-methoxybenzyl) oxy) ethyl) -1H-imidazole
1- (3-chlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (222mg,1mmol) was dissolved in 2ml of DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice bath to conduct reaction at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice bath to conduct reaction at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 199mg (compound 10) of a colorless oil, in 58.1% yield. TLC detection is one point, and the ultraviolet lamp has fluorescence under 254 nm.1H NMR(300MHz,CDCl3)δ7.47(s,1H),7.36(d,J＝2.0Hz,1H),7.35–7.30(m,2H),7.24(t,J＝8.1Hz,1H),7.15(ddd,J1＝3.7Hz,J2＝2.8Hz,J3＝1.5Hz,1H),7.05(s,1H),6.92(t,J＝1.1Hz,1H),6.87–6.81(m,1H),6.73(t,J＝4.1Hz,2H),4.56–4.53(m,1H),4.50(d,J＝11.7Hz,1H),4.23(d,J＝11.9Hz,1H),4.16(d,J＝7.6Hz,1H),4.09(dd,J1＝14.3Hz,J2＝4.1Hz,1H).ESI:m/z[M+H]+,calcd.for C19H19ClN2O2:343.1135；found.343.1206
Example 6
(1) Synthesis of 2-bromo-1- (2-chlorophenyl) ethan-1-one
2-Chloroacetophenone (1.54g,10mmol) was dissolved in 100ml of chloroform, and Br was slowly added dropwise under ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.3g of crude product.
(2) Synthesis of 1- (2-chlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (2-chlorophenyl) ethan-1-one (2.3g,9.87mmol) and imidazole (1.34g,19.7mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.7g,19.7mmol) was added, and after stirring at room temperature for 3 hours, the reaction solution was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.6g of a yellow solid in 72.7% yield.
(3) Synthesis of 1- (2-chlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (2-chlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.1g, 5mmol) was dissolved in 50ml of anhydrous methanol, and sodium borohydride (378mg,10mmol) was added under ice bath, stirred for one hour and then refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-drying to obtain 980mg of light yellow solid, namely the product, without additional purification, with the yield of 89.1%.
(4) Synthesis of 1- (2- (2-chlorophenyl) -2- ((3-methoxybenzyl) oxy) ethyl) -1H-imidazole
1- (2-chlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (222mg,1mmol) was dissolved in 2ml of DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour. Quenching with water, extracting with ethyl acetate, sequentially washing the organic phase with saturated salt solution, drying with anhydrous sodium sulfate, spinning, and separating with silica gel column chromatography (DCM: MeOH: 30:1v/v) to obtain colorless oilSubstance 130mg (compound 11), yield 38.1%. TLC detected as a dot, with fluorescence under UV 254 nm.1H NMR(300MHz,CDCl3)δ7.51(s,1H),7.48–7.41(m,2H),7.35–7.33(m,1H),7.31(dd,J＝3.4,1.7Hz,1H),7.28(s,1H),5.06(dd,J＝7.8,2.8Hz,1H),4.49(d,J＝11.6Hz,1H),4.26(d,J＝3.9Hz,1H),4.24–4.20(m,1H),4.08(dd,J＝14.4,7.8Hz,1H),3.81(s,3H).ESI:m/z[M+H]+,calcd.for C19H19ClN2O2:343.1135；found.343.1202
Example 7
(1) Synthesis of 2-bromo-1- (3, 4-dichlorophenyl) ethan-1-one
3, 4-Dichloroacetophenone (1.89g,10mmol) was dissolved in 100ml of chloroform, and Br was slowly added dropwise in ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.5g of crude product.
(2) Synthesis of 1- (3, 4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (3, 4-dichlorophenyl) ethan-1-one (2.5g,9.36mmol) and imidazole (1.27g,18.7mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.58g,18.7mmol) was added, and after stirring at room temperature for 3 hours, the reaction solution was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.4g of a yellow solid in 54.7% yield.
(3) Synthesis of 1- (3, 4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (3, 4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.29g, 5mmol) was dissolved in 50ml of anhydrous methanol, sodium borohydride (378mg,10mmol) was added under ice bath, and after stirring for one hour, it was refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry to obtain 900mg of a pale yellow solid, i.e., the product, without additional purification, 69.7% yield.
(4) Synthesis of 1- (2- (3, 4-dichlorophenyl) -2- ((3-methoxybenzyl) oxy) ethyl) -1H-imidazole
1- (3, 4-dichlorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (257mg,1mmol) was dissolved in 2ml DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice bath to react at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice bath to react at room temperature for 1 hour. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, and spin-dried, and separated by silica gel column chromatography (DCM: MeOH: 30:1v/v) to give 160mg (compound 12) as a colorless oil, in 42.4% yield. TLC detection is one point, and the ultraviolet lamp has fluorescence under 254 nm.1H NMR(300MHz,CDCl3)δ7.47(d,J＝8.1Hz,1H),7.41(d,J＝2.0Hz,1H),7.25(t,J＝7.9Hz,1H),7.09(dd,J＝8.3,2.0Hz,1H),7.06(s,1H),6.90(s,1H),6.88–6.82(m,1H),6.72(d,J＝7.1Hz,1H),4.55–4.51(m,1H),4.49(d,J＝8.7Hz,1H),4.22(d,J＝14.0Hz,1H),4.14(d,J＝7.3Hz,1H),4.09(dd,J1＝14.4Hz,J2＝4.3Hz,1H),3.80(s,2H).ESI:m/z[M+H]+,calcd.for C19H18Cl2N2O2:377.0745；found.377.0822
Example 8
(1) Synthesis of 2-bromo-1- (2, 4-dichloro, 5-fluorophenyl) ethan-1-one
Dissolving 2, 4-dichloro, 5-fluoro acetophenone (2.07g,10mmol) in 100ml of chloroform, and slowly adding Br dropwise under ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.85g of crude product.
(2) Synthesis of 1- (2, 4-dichloro, 5-fluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one
Crude 2-bromo-1- (2, 4-dichloro, 5-fluorophenyl) ethan-1-one (2.85g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3h, the reaction was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry, silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.8g of a yellow solid in 65.9% yield.
(3) Synthesis of 1- (2, 4-dichloro, 5-fluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (2, 4-dichloro, 5-fluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.37g, 5mmol) was dissolved in 50ml of anhydrous methanol, sodium borohydride (378mg,10mmol) was added under ice bath, stirred for one hour and refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry to give 1.27mg of a pale yellow solid, which is the product, with no additional purification, 92.7% yield.
(4) Synthesis of 1- (2- (2, 4-dichloro, 5-fluorophenyl) -2- ((3-methoxybenzyl) oxy) ethyl) -1H-imidazole
1- (2, 4-dichloro, 5-fluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (275mg,1mmol) was dissolved in 2ml DMF, 60% sodium hydride (48mg,1.2mmol) was added under ice bath, and after 1 hour at room temperature, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice bath, and further 1 hour at room temperature. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 120mg (compound 13) of a colorless oil, with a yield of 30.3%. TLC detected as a dot, with fluorescence under UV 254 nm.1H NMR(300MHz,CDCl3)δ7.50(d,J＝6.4Hz,1H),7.28(d,J＝2.5Hz,1H),7.26–7.22(m,1H),7.06(s,1H),6.93(s,1H),6.86(dd,J＝8.3,2.5Hz,1H),6.74(t,J＝5.4Hz,1H),4.95(dd,J1＝7.5Hz,J2＝2.4Hz,1H),4.49(d,J＝11.6Hz,1H),4.25(d,J＝11.8Hz,1H),4.20(dd,J1＝14.6Hz,J2＝2.9Hz,1H),4.05(dd,J1＝14.5Hz,J2＝7.6Hz,1H),3.81(s,2H).ESI:m/z[M+H]+,calcd.for C19H17Cl2FN2O2:395.0651；found.395.0721
Example 9
(1) Synthesis of 2-bromo-1- (4-bromophenyl) ethan-1-one
4-bromoacetophenone (1.99g,10mmol) was dissolved in 100ml of chloroform, and Br was slowly added dropwise under ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour and saturated after completion of the reactionThe reaction was quenched with sodium sulfite and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.78g of crude product.
(2) Synthesis of 1- (4-bromophenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (4-bromophenyl) ethan-1-one (2.78g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3 hours, the reaction solution was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 2.0g of a yellow solid in 74.9% yield.
(3) Synthesis of 1- (4-bromophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (4-bromophenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.36g, 5mmol) was dissolved in 50ml of anhydrous methanol, and sodium borohydride (378mg,10mmol) was added under ice bath, followed by stirring for one hour and refluxing for another 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry to give 1.27g of a pale yellow solid, which is the product, without additional purification, 92.7% yield.
(4) Synthesis of 1- (2- (4-bromophenyl) -2- ((3-methoxybenzyl) oxy) ethyl) -1H-imidazole
1- (4-bromophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (267mg,1mmol) was dissolved in 2ml DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice bath to react at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice bath to react at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 170mg (compound 14) as a colorless oil in 43.9% yield. TLC detection is one point, and the ultraviolet lamp has fluorescence under 254 nm.1H NMR(300MHz,CDCl3)δ7.47(s,1H),7.31(d,J＝6.6Hz,1H),7.29(s,1H),7.24(d,J＝7.6Hz,1H),7.04(s,1H),6.94(d,J＝7.5Hz,2H),6.87(s,1H),6.84(s,1H),4.92(dd,J1＝6.7Hz,J2＝4.1Hz,1H),4.48(d,J＝11.7Hz,1H),4.26(d,J＝11.7Hz,1H),4.20(d,J＝10.6Hz,1H),4.14(dd,J1＝13.8Hz,J2＝6.5Hz,2H),3.81(s,3H).ESI:m/z[M+H]+,calcd.for C19H19BrN2O2:389.0630；found.389.0691
Example 10
(1) Synthesis of 2-bromo-1- (3-bromophenyl) ethan-1-one
3-bromoacetophenone (1.99g,10mmol) was dissolved in 100ml of chloroform, and Br was slowly added dropwise under ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.78g of crude product.
(2) Synthesis of 1- (3-bromophenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (3-bromophenyl) ethan-1-one (2.78g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3h, the reaction solution was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.6g of a yellow solid in 61.5% yield.
(3) Synthesis of 1- (3-bromophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (3-bromophenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.36g, 5mmol) was dissolved in 50ml of anhydrous methanol, and sodium borohydride (378mg,10mmol) was added under ice bath, followed by stirring for one hour and refluxing for another 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry to give 1.2g of pale yellow solid, i.e. product, without additional purification, 88.2% yield.
(4) Synthesis of 1- (2- (3-bromophenyl) -2- ((3-methoxybenzyl) oxy) ethyl) -1H-imidazole
1- (3-bromophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (267mg,1mmol) was dissolved in 2ml DMF, 60% sodium hydride (48mg,1.2mmol) was added under ice bath, and after 1 hour reaction at room temperature, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice bath, and then at room temperatureThe reaction was carried out for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 150mg (compound 15) as a colorless oil in 38.9% yield.1H NMR(300MHz,CDCl3)δ7.54–7.50(m,1H),7.48(t,J＝1.7Hz,1H),7.46(s,1H),7.29–7.23(m,2H),7.19(dt,J1＝7.7Hz,J2＝1.2Hz,1H),7.05(s,1H),6.91(t,J＝1.2Hz,1H),6.88–6.82(m,1H),6.73(t,J＝4.1Hz,2H),4.55–4.51(m,1H),4.49(d,J＝7.6Hz,1H),4.23(d,J＝11.9Hz,1H),4.17(t,J＝7.2Hz,1H),4.09(dd,J1＝14.3Hz,J2＝4.1Hz,1H),3.80(s,3H).ESI:m/z[M+H]+,calcd.for C19H19BrN2O2:387.0630；found.387.0698
Example 11
(1) Synthesis of 2-bromo-1- (4-tert-butylphenyl) ethan-1-one
4-tert-butyl acetophenone (1.76g,10mmol) was dissolved in 100ml of chloroform, and Br was slowly added dropwise under ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.55g of crude product.
(2) Synthesis of 1- (4-tert-butylphenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (4-tert-butylphenyl) ethan-1-one (2.55g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3 hours, the reaction mixture was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.5g of a white solid in 62.0% yield.
(3) Synthesis of 1- (4-tert-butylphenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (4-tert-butylphenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.21g, 5mmol) was dissolved in 50ml of anhydrous methanol, and sodium borohydride (378mg,10mmol) was added under ice-bath, followed by stirring for one hour and refluxing for another 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry to give 1.0g of a pale yellow solid, which is the product, with no additional purification, 83.3% yield.
(4) Synthesis of 1- (2- ((3-methoxybenzyl) oxy) -2- (4-tert-butylphenyl) ethyl) -1H-imidazole
1- (3-bromophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (244mg,1mmol) was dissolved in 2ml DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 199mg (compound 16) of a colorless oil, with a yield of 54.4%.1H NMR(300MHz,CDCl3)δ7.48(s,1H),7.43(d,J＝8.3Hz,2H),7.27(d,J＝10.3Hz,2H),7.24–7.22(m,2H),7.05(s,1H),6.96(s,1H),6.83(dd,J1＝9.0Hz,J2＝1.7Hz,1H),6.77–6.72(m,3H),4.54(dd,J1＝8.1Hz,J2＝3.8Hz,1H),4.49(d,J＝11.9Hz,1H),4.22(d,J＝8.2Hz,1H),4.20–4.15(m,1H),4.08(dd,J1＝14.3Hz,J2＝3.8Hz,1H),3.79(s,3H),1.36(s,9H).ESI:m/z[M+H]+,calcd.for C23H28N2O2:365.2151；found.365.2227
Example 12
(1) Synthesis of 2-bromo-1- (4-methoxyphenyl) ethan-1-one
Dissolving 4-methoxyacetophenone (1.5g,10mmol) in 100ml chloroform, and slowly adding Br dropwise under ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.29g of crude product.
(2) Synthesis of 1- (4-methoxyphenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (4-methoxyphenyl) ethan-1-one (2.29g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3h, the reaction solution was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.9g of a white solid in 87.9% yield.
(3) Synthesis of 1- (4-methoxyphenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (4-methoxyphenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.09g, 5mmol) was dissolved in 50ml of anhydrous methanol, sodium borohydride (378mg,10mmol) was added under ice bath, stirred for one hour and then refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry to give 1.1g of a pale yellow solid, which is the product, with no additional purification and 90.2% yield.
(4) Synthesis of 1- (2- ((3-methoxybenzyl) oxy) -2- (4-methoxyphenyl) ethyl) -1H-imidazole
1- (4-methoxyphenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (218mg,1mmol) was dissolved in 2ml DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice bath to react at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice bath to react at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 210mg (compound 17) of a colorless oil in 62.1% yield.1H NMR(300MHz,CDCl3)δ7.24(d,J＝7.9Hz,1H),7.21–7.17(m,2H),6.91(d,J＝2.0Hz,2H),6.89–6.80(m,2H),6.75–6.71(m,2H),6.70–6.67(m,1H),4.51(dd,J1＝7.6Hz,J2＝4.2Hz,1H),4.46(d,J＝11.9Hz,1H),4.21(t,J＝3.7Hz,1H),4.17(d,J＝7.8Hz,1H),4.08(dd,J1＝14.2Hz,J2＝4.2Hz,1H),3.83(s,2H),3.78(s,3H).ESI:m/z[M+H]+,calcd.for C20H22N2O3:339.1630；found.339.1707
Example 13
(1) Synthesis of 2-bromo-1- (4-trifluoromethylphenyl) ethan-1-one
Taking 4-trifluoromethyl acetophenone (1.88g,10mmol) was dissolved in 100ml of chloroform and Br was slowly added dropwise under ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.67g of crude product.
(2) Synthesis of 1- (4-trifluoromethylphenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (4-trifluoromethylphenyl) ethan-1-one (2.67g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3h, the reaction solution was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.7g of a white solid in 66.9% yield.
(3) Synthesis of 1- (4-trifluoromethylphenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (4-trifluoromethylphenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.27g, 5mmol) was dissolved in 50ml of anhydrous methanol, and sodium borohydride (378mg,10mmol) was added under ice bath, followed by stirring for one hour and refluxing for another 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry to obtain 1.08g of a pale yellow solid, which is the product, without additional purification, with a yield of 85.0%.
(4) Synthesis of 1- (2- ((3-methoxybenzyl) oxy) -2- (4-trifluoromethylphenyl) ethyl) -1H-imidazole
1- (4-trifluoromethylphenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (256mg,1mmol) was dissolved in 2ml of DMF, and 60% sodium hydride (48mg,1.2mmol) was added thereto under ice-cooling, and after 1 hour at room temperature, 3-methoxybenzyl chloride (180mg,1.2mmol) was added thereto under ice-cooling, and the mixture was reacted for another 1 hour at room temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 221mg (compound 18) of a colorless oil, in 58.9% yield.1H NMR(300MHz,CDCl3)δ7.66(d,J＝8.1Hz,1H),7.42(d,J＝5.3Hz,1H),7.39(s,1H),7.29–7.21(m,1H),7.04(s,1H),6.90(s,1H),6.87–6.82(m,1H),6.76–6.71(m,1H),4.64(dd,J1＝7.0Hz,J2＝4.4Hz,1H),4.49(d,J＝11.8Hz,1H),4.24(d,J＝11.8Hz,1H),4.17(d,J＝7.3Hz,1H),4.12(dd,J1＝14.4Hz,J2＝4.5Hz,1H),3.79(s,3H).ESI:m/z[M+H]+,calcd.for C20H19F3N2O2:377.1399；found 377.1468
Example 14
(1) Synthesis of 2-bromo-1- (4-methylphenyl) ethan-1-one
4-methylacetophenone (1.34g,10mmol) was dissolved in 100ml of chloroform and Br was slowly added dropwise in an ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.13g of crude product.
(2) Synthesis of 1- (4-methylphenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (4-methylphenyl) ethan-1-one (2.13g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3h, the reaction solution was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and column chromatography on silica gel (DCM: MeOH ═ 100:1v/v) afforded 1.5g of a white solid in 75.1% yield.
(3) Synthesis of 1- (4-methylphenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (4-methylphenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.0g, 5mmol) was dissolved in 50ml of anhydrous methanol, sodium borohydride (378mg,10mmol) was added under ice-bath, stirred for one hour and then refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-drying to obtain 900mg of light yellow solid, namely the product, without additional purification, with the yield of 90.0%.
(4) Synthesis of 1- (2- ((3-methoxybenzyl) oxy) -2- (4-methylphenyl) ethyl) -1H-imidazole
1- (4-methylphenyl)) -2- (1H-imidazol-1-yl) ethan-1-ol (202mg,1mmol) was dissolved in 2ml DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice bath to react at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice bath to react at room temperature for 1 hour. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, and spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 120mg (compound 19) of a colorless oil, in 37.1% yield.1H NMR(300MHz,CDCl3)δ7.45(s,1H),7.24(s,1H),7.21(s,2H),7.18(d,J＝8.2Hz,2H),7.04(s,1H),6.94(s,1H),6.83(d,J＝7.5Hz,1H),6.74(d,J＝6.8Hz,2H),4.53(dd,J1＝7.8Hz,J2＝4.0Hz,1H),4.48(d,J＝11.9Hz,1H),4.22(d,J＝6.1Hz,1H),4.18(d,J＝8.0Hz,1H),4.08(dd,J1＝14.2Hz,J2＝4.1Hz,1H),3.80(s,3H),2.40(s,3H).ESI:m/z[M+H]+,calcd.for C20H122N2O2:323.1681；found.323.1753.
Example 15
(1) Synthesis of 2-bromo-1- (2-methylphenyl) ethan-1-one
3-methylacetophenone (1.34g,10mmol) was dissolved in 100ml of chloroform and Br was slowly added dropwise in an ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.13g of crude product.
(2) Synthesis of 1- (3-methylphenyl) -2- (1H-imidazol-1-yl) ethan-1-one
The crude 2-bromo-1- (3-methylphenyl) ethan-1-one (2.13g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3h, the reaction solution was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and column chromatography on silica gel (DCM: MeOH ═ 100:1v/v) afforded 1.5g of a white solid in 75.1% yield.
(3) Synthesis of 1- (3-methylphenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (4-methylphenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.0g, 5mmol) was dissolved in 50ml of anhydrous methanol, sodium borohydride (378mg,10mmol) was added under ice-bath, stirred for one hour and then refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The product was obtained as a pale yellow solid 880mg by spin-drying, without additional purification, in 88.0% yield.
(4) Synthesis of 1- (2- ((3-methoxybenzyl) oxy) -2- (3-methylphenyl) ethyl) -1H-imidazole
1- (3-methylphenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (202mg,1mmol) was dissolved in 2ml of DMF, and 60% sodium hydride (48mg,1.2mmol) was added thereto under ice-cooling, and after 1 hour at room temperature, 3-methoxybenzyl chloride (180mg,1.2mmol) was added thereto under ice-cooling, and the mixture was reacted for another 1 hour at room temperature. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 134mg (compound 20) of a colorless oil, with a yield of 41.4%.1H NMR(300MHz,CDCl3)δ7.46(s,1H),7.29(s,2H),7.20(s,1H),7.11(s,2H),7.04(s,1H),6.92(s,1H),6.85(s,1H),6.75(s,2H),4.50(d,J＝12.3Hz,2H),4.25(s,1H),4.19(d,J＝13.8Hz,1H),4.11(s,1H),3.80(s,3H),2.39(s,3H).ESI:m/z[M+H]+,calcd.for C20H22N2O2:323.1681；found.323.1753
Example 16
(1) Synthesis of 2-bromo-1- (2, 5-dimethylphenyl) ethan-1-one
Dissolving 2, 5-dimethylacetophenone (1.48g,10mmol) in 100ml of chloroform, and slowly adding Br dropwise under ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.28g of crude product.
(2) Synthesis of 1- (2, 5-dimethylphenyl) -2- (1H-imidazol-1-yl) ethan-1-one
Crude 2-bromo-1- (2, 5-dimethylphenyl) ethan-1-one (2.28g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3h, the reaction was removed in vacuo, water was added, and extraction was performed with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.55g of a white solid in 72.4% yield.
(3) Synthesis of 1- (2, 5-dimethylphenyl) -2- (1H-imidazol-1-yl) ethan-1-ol
1- (2, 5-dimethylphenyl) -2- (1H-imidazol-1-yl) ethan-1-one (1.08g, 5mmol) was dissolved in 50ml of anhydrous methanol, sodium borohydride (378mg,10mmol) was added under ice bath, stirred for one hour and then refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The product was obtained in 870g of white solid by spin drying, without additional purification, in 80.6% yield.
(4) Synthesis of 1- (2- (2, 5-dimethylphenyl) -2- ((3-methoxybenzyl) oxy) ethyl) -1H-imidazole
1- (2, 5-dimethylphenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (216mg,1mmol) was dissolved in 2ml of DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, and spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 220mg (compound 21) of a colorless oil, in 65.3% yield.1H NMR(300MHz,CDCl3)δ7.50(s,1H),7.28–7.20(m,2H),7.09(s,2H),7.05(s,1H),6.93(s,1H),6.84(d,J＝7.8Hz,1H),6.73(d,J＝6.3Hz,2H),4.77(dd,J1＝8.2Hz,J2＝3.6Hz,1H),4.49(d,J＝11.7Hz,1H),4.18(d,J＝11.6Hz,1H),4.13(d,J＝8.1Hz,1H),4.02(dd,J1＝14.3Hz,J2＝3.5Hz,1H),3.79(s,3H),2.36(s,3H),2.20(s,3H).ESI:m/z[M+H]+,calcd.for C21H24N2O2:337.1838；found.337.1911
Example 17
(1) Synthesis of 2-bromo-1-phenylethyl-1-one
Acetophenone (1.2g,10mmol) was dissolved in 100ml chloroform and slowly cooled in ice bathDropwise adding Br2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.00g of crude product.
(2) Synthesis of 2- (1H-imidazol-1-yl) -1-phenylethyl-1-one
Crude 2-bromo-1-phenylethyl-1-one (2.00g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3 hours, the reaction solution was removed in vacuo, water was added, and extraction was carried out with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.5g of a white solid in 75.1% yield.
(3) Synthesis of 2- (1H-imidazol-1-yl) -1-phenylethyl-1-ol
2- (1H-imidazol-1-yl) -1-phenylethyl-1-one (1.0g, 5mmol) was dissolved in 50ml of anhydrous methanol, and sodium borohydride (378mg,10mmol) was added under ice bath, stirred for one hour and refluxed for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-drying to obtain 900mg of light yellow solid, namely the product, without additional purification, with the yield of 90.0%.
(4) Synthesis of 1- (2- ((3-methoxybenzyl) oxy) -2-phenylethyl) -1H-imidazole
1- (4-methylphenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (188mg,1mmol) was dissolved in 2ml DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 120mg (compound 22) of a colorless oil, with a yield of 38.9%.1H NMR(300MHz,CDCl3)δ7.49(s,1H),7.43–7.37(m,3H),7.31(d,J＝2.4Hz,1H),7.28(s,1H),7.24(t,J＝8.1Hz,1H),7.05(s,1H),6.93(s,1H),6.87–6.82(m,1H),6.77–6.72(m,2H),4.57(dd,J1＝7.7,J2＝4.0Hz,1H),4.49(d,J＝11.9Hz,1H),4.25(s,1H),4.21–4.16(m,1H),4.11(dd,J1＝14.3,J2＝4.1Hz,1H),3.80(s,3H).ESI:m/z[M+H]+,calcd.for C19H20N2O2:309.1525；found.309.1597
Example 18
(1) Synthesis of 2-bromo-1- (naphthalen-2-yl) ethan-1-one
Dissolving 2-acetonaphthone (1.7g,10mmol) in 100ml chloroform, and slowly adding Br dropwise under ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.49g of crude product.
(2) Synthesis of 2- (1H-imidazol-1-yl) -1- (naphthalen-2-yl) ethyl-1-one
2-bromo-1- (naphthalen-2-yl) eth-1-one crude (2.49g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3h, the reaction was removed in vacuo, water was added, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.5g of a white solid in 75.1% yield.
(3) Synthesis of 2- (1H-imidazol-1-yl) -1- (naphthalen-2-yl) ethyl-1-ol
2- (1H-imidazol-1-yl) -1-phenylethyl-1-one (1.18g, 5mmol) was dissolved in 50ml of anhydrous methanol, and sodium borohydride (378mg,10mmol) was added under ice bath, followed by stirring for one hour and refluxing for another 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The product was obtained as a pale yellow solid 948mg by spin-drying, without additional purification, in 80.3% yield.
(4) Synthesis of 1- (2- ((3-methoxy) oxy) -2- (naphthalen-2-yl) ethyl) -1H-imidazole
2- (1H-imidazol-1-yl) -1- (naphthalen-2-yl) ethyl-1-ol (238mg,1mmol) was dissolved in 2ml DMF, 60% sodium hydride (48mg,1.2mmol) was added under ice bath, reaction was carried out at room temperature for 1 hour, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice bath, and further reaction was carried outThe reaction was carried out at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 190mg of a white solid (compound 23) with a yield of 52.9%.1H NMR(300MHz,CDCl3)δ7.88(ddd,J1＝11.2Hz,J2＝7.4Hz J3＝4.4Hz,1H),7.76(s,1H),7.57(t,J＝3.4Hz,1H),7.54(d,J＝3.3Hz,1H),7.50(s,1H),7.43(dd,J1＝8.5Hz,J2＝1.7Hz,1H),7.28(d,J＝2.7Hz,1H),7.24(d,J＝8.1Hz,1H),7.06(s,1H),6.95(s,1H),6.85(dd,J1＝8.3Hz,J2＝1.5Hz,1H),6.76(dd,J1＝4.2Hz,J2＝2.6Hz,1H),4.74(dd,J1＝7.8Hz,J2＝4.0Hz,1H),4.54(d,J＝11.9Hz,1H),4.32(dd,J1＝11.4Hz,J2＝4.8Hz,1H),4.27(d,J＝6.0Hz,1H),4.22(d,J＝4.0Hz,1H).ESI:m/z[M+H]+,calcd.for C23H22N2O2:359.1681；found.359.1755
Example 19
(1) Synthesis of 2-bromo-1- (thien-2-yl) ethan-1-one
2-acetylthiophene (1.26g,10mmol) was dissolved in 100ml of chloroform, and Br was slowly added dropwise under ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.05g of crude product.
(2) Synthesis of 2- (1H-imidazol-1-yl) -1- (thiophen-2-yl) ethyl-1-one
2-bromo-1- (thien-2-yl) ethan-1-one crude product (2.05g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml of tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3h, the reaction solution was removed in vacuo, water was added and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and column chromatography on silica gel (DCM: MeOH ═ 100:1v/v) afforded 1.3g of a white solid in 67.7% yield.
(3) Synthesis of 2- (1H-imidazol-1-yl) -1- (naphthalen-2-yl) ethyl-1-ol
2- (1H-imidazol-1-yl) -1- (thiophen-2-yl) ethyl-1-one (960mg, 5mmol) was dissolved in 50ml of anhydrous methanol, and sodium borohydride (378mg,10mmol) was added under ice bath, followed by stirring for one hour and refluxing for another 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry to give 840mg of a pale yellow solid, i.e. the product, without additional purification, 87.5% yield.
(4) Synthesis of 1- (2- ((3-methoxy) oxy) -2- (thiophen-2-yl) ethyl) -1H-imidazole
2- (1H-imidazol-1-yl) -1- (thiophen-2-yl) ethyl-1-ol (194mg,1mmol) was dissolved in 2ml of DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, and then spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 186mg of a brown oil (compound 24) in 59.2% yield.1H NMR(300MHz,CDCl3)δ7.48(s,1H),7.40–7.35(m,1H),7.27–7.20(m,1H),7.04(dd,J1＝5.1Hz,J2＝3.5Hz,2H),6.99–6.94(m,2H),6.88–6.80(m,1H),6.75(t,J＝4.1Hz,2H),4.82(dd,J1＝7.8Hz,J2＝4.2Hz,1H),4.57(d,J＝11.8Hz,1H),4.35–4.30(m,1H),4.28(d,J＝8.0Hz,1H),4.18(dd,J1＝14.2Hz,J2＝4.2Hz 1H),3.80(s,3H).ESI:m/z[M+H]+,calcd.for C17H18N2O2S:315.1089；found.315.1155
Example 20
(1) Synthesis of 1- (benzo [ d ] [1,3] dioxol-5-yl) -2-bromo-1-one
Taking 1- (benzo [ d ]][1,3]Dioxolen-5-yl) ethan-1-one (1.64g,10mmol) was dissolved in 100ml of chloroform and Br was slowly added dropwise in ice bath2(1.91g,12mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour, after completion of the reaction, the reaction was quenched with saturated sodium sulfite, and the organic phase was washed with saturated sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to give 2.43g of crude product.
(2) Synthesis of 1- (benzo [ d ] [1,3] dioxol-5-yl) -2- (1H-imidazol-1-yl) ethyl-1-one
Crude 1- (benzo [ d ] [1,3] dioxol-5-yl) -2-bromo-1-one (2.43g,10mmol) and imidazole (1.36g,20mmol) were dissolved in 50ml tetrahydrofuran, potassium carbonate (2.76g,20mmol) was added, and after stirring at room temperature for 3h, the reaction solution was removed in vacuo, water was added, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Spin-dry and silica gel column chromatography (DCM: MeOH ═ 100:1v/v) afforded 1.4g of a white solid in 60.8% yield.
(3) Synthesis of 1- (benzo [ d ] [1,3] dioxol-5-yl) -2- (1H-imidazol-1-yl) ethyl-1-ol
1- (benzo [ d ] [1,3] dioxol-5-yl) -2- (1H-imidazol-1-yl) ethyl-1-one (1.15g, 5mmol) was dissolved in 50ml of anhydrous methanol, and sodium borohydride (378mg,10mmol) was added under ice bath, followed by stirring for one hour and refluxing for 2 hours. After the reaction, water was added to quench, extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The product was obtained as a pale yellow solid, 960mg, without additional purification, 83.5% yield.
(4) Synthesis of 1- (2-benzo [ d ] [1,3] dioxol-5-yl) -2- ((3-methoxybenzyl) oxy) ethyl) -1H-imidazole
2- (1H-imidazol-1-yl) -1- (thiophen-2-yl) ethyl-1-ol (232mg,1mmol) was dissolved in 2ml of DMF, and 60% sodium hydride (48mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour, and after that, 3-methoxybenzyl chloride (180mg,1.2mmol) was added under ice-bath to react at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (DCM: MeOH ═ 30:1v/v) to give 110mg (compound 25) of a colorless oil, with a yield of 31.2%.1H NMR(300MHz,CDCl3)δ7.49(s,1H),7.28(s,1H),7.05(s,1H),6.92(s,1H),6.80(s,4H),6.74(s,2H),6.00(s,2H),4.49(d,J＝8.8Hz,2H),4.23(d,J＝10.9Hz,2H),4.17(s,1H),4.08(d,J＝13.8Hz,1H),3.80(s,3H).ESI:m/z[M+H]+,calcd.for C20H20N2O2:353.1423；found.353.1487
Example 21
The same procedures as in steps (1), (2) and (3) of example 3 were carried out
(4) Synthesis of 1- (3, 4-difluorophenyl) -2- (1H-imidazol-1-yl) ethyl 2- (3-methoxyphenyl) acetate
1- (2, 4-difluorophenyl) -2- (1H-imidazol-1-yl) ethan-1-ol (112mg,0.5mmol) and 3-methoxyphenylacetic acid (83mg,0.5mmol) were dissolved in 5ml DCM, dicyclohexylcarbodiimide (103mg,0.5mmol) and p-dimethylaminopyridine (6mg,0.05mmol) were added under ice bath and stirring was continued for 0.5H. The reaction mixture was allowed to cool to room temperature for 2 hours. The reaction mixture was washed with water and brine in this order. Dried over anhydrous sodium sulfate, dried and chromatographed on silica gel (DCM: MeOH ═ 30:1v/v) to give 130mg (compound 26) as a colorless oil in 69.9% yield.
1H NMR(300MHz,CDCl3)δ7.29(d,J＝1.8Hz,1H),7.21(s,1H),7.11(dt,J1＝9.9,J2＝8.2Hz,1H),6.99(s,1H),6.96–6.91(m,1H),6.87(d,J＝8.7Hz,1H),6.85–6.80(m,2H),6.79–6.76(m,1H),6.65(s,1H),5.89(t,J＝5.6Hz,1H),4.21(s,1H),4.19(s,1H),3.82(s,3H),3.65(s,2H).ESI:m/z[M+H]+,calcd.for C20H18F2N2O3:373.1285；found.353.1357
Example 22
Referring to the procedure of example 21, 3-methoxyphenylacetic acid was replaced with 3- (3-methoxyphenyl) propionic acid to give 150mg of a colorless oil in a yield of 77.7% (compound 27). Was identified as 1- (3, 4-difluorophenyl) -2- (1H-imidazol-1-yl) ethyl 3- (3-methoxyphenyl) propionate.1H NMR(300MHz,CDCl3)δ7.28(s,1H),7.21(t,J＝7.9Hz,1H),7.12(dt,J1＝10.0,J2＝8.2Hz,1H),7.03(s,1H),7.00–6.91(m,1H),6.89–6.82(m,1H),6.80–6.74(m,2H),6.71(d,J＝1.9Hz,1H),6.02–5.71(m,1H),4.27–4.12(m,1H),3.79(s,2H),2.92(t,J＝7.5Hz,1H),2.71(t,J＝7.2Hz,1H).ESI:m/z[M+H]+,calcd.for C21H20N2O2:387.1442；found.387.1525
Example 23
Referring to the procedure of example 21, 3-methoxyphenylacetic acid was replaced with 4- (3-methoxyphenyl) butyric acid to give 160mg of a colorless oil in 80.0% yield (compound 28). Was identified as 4- (4-methoxyphenyl) butanoic acid 1- (3, 4-difluorophenyl) -2- (1H-imidazol-1-yl) ethyl ester.
1H NMR(300MHz,CDCl3)δ7.34(s,1H),7.19(ddd,J1＝11.3,J2＝10.0,J3＝4.9Hz,2H),7.12–7.05(m,1H),7.04(s,1H),6.97–6.91(m,1H),6.82(t,J＝1.2Hz,1H),6.79–6.73(m,2H),6.71(d,J＝2.0Hz,1H),5.95–5.87(m,1H),4.27(dd,J1＝13.5,J2＝5.5,1H),4.21(dd,J1＝13.5,J2＝4.2Hz,1H),3.81(s,3H),2.60(t,J＝7.5Hz,2H),2.38(t,J＝7.5Hz,2H),1.94(p,J＝7.5Hz,2H).ESI:m/z[M+H]+,calcd.for C22H22F2N2O3:401.1598；found.401.1685
EXAMPLE 24 determination of cholinesterase inhibitory Activity
Drugs and reagents: the compounds prepared in examples 6-28, AChE (e.c.3.1.1.7, Type VI-S, selected from eels), BuChE (e.c.3.1.1.8, selected from horse serum), 5' -dithiobis (2-nitrobenzoic acid) (DTNB), Acetylthiocholine (ATC) iodide and Butyrylthiocholine (BTC) iodide were purchased from sigma; tacrine was synthesized by the laboratory (purity > 95%).
The instrument comprises: THERMO Varioskan Flash full-wavelength multifunctional microplate reader.
The experimental method comprises the following steps:
(1) preparing a buffer solution: 13.6g of potassium dihydrogen phosphate are dissolved in 1L of water and the pH is adjusted to 8. + -. 0.1 with potassium hydroxide. The solution was stored at 4 ℃ until use.
(2) Preparing a 0.01M DTNB solution: 0.396g of DTNB and 0.15g of sodium bicarbonate were dissolved in 100mL of water to prepare a 0.01M DTNB solution, which was stored at-20 ℃ for further use.
(3) Preparing 0.075M ATC and BTC solution: 0.217g ATC is dissolved in 10mL water to prepare 0.075M ATC and BTC solution, and the solution is stored at the temperature of minus 20 ℃ for standby; 0.237g BTC was dissolved in 10mL water to make a 0.075M BTC solution, which was stored at-20 ℃ until use.
(4) Preparing AChE and BuChE solutions: dissolving 5000 units of AChE in 1mL of 1% gel solution, diluting with water to 100mL to obtain AChE solution with concentration of 5 units/mL, and storing at-20 deg.C; 5000 units of BuChE was dissolved in 1mL of 1% gel solution, and then diluted to 100mL with water to prepare a BuChE solution having a concentration of 5 units/mL, which was stored at-30 ℃ for use.
(5) Preparing a test solution: test compound was dissolved in ethanol to give a concentration of 10-3M (ethanol did not affect the test results), and then diluted with water to give concentrations of 10-4、10-5、10-6、10-7、10-8、10-9A solution of M.
Before the experiment was started, all solutions were warmed to room temperature and the AChE, BuChE solution was diluted one-fold with water to make an enzyme solution with a concentration of 2.5 units/mL. Background UV absorbance was measured with blank buffer (3 mL). Adding 100 mu L of tested compound solution, 100 mu L of DTNB solution and 100 mu L of enzyme solution into 3mL of buffer solution, adding 20 mu L of ATC or BTC solution to trigger reaction, immediately timing and simultaneously quickly mixing the test solution uniformly, and measuring the ultraviolet absorbance at the wavelength of 412nM after 2 min. The blank control was measured using an equal volume of water instead of the test solution. All tests were run in parallel three times. The absorbance (OD value) of the test compound at each concentration was recorded with the UV absorption value of the blank control group as 100%, and the obtained result was calculated by using GraphPad prism (GraphPad Software, San Diego, Calif., USA) Software in a non-linear regression analysis mode (non-linear regression analysis model) to obtain the corresponding IC50Values, as shown in table 2.
And (4) analyzing results: 14 Compounds have inhibitory Activity on BuChE (IC)501.9-126 μ M), with compounds 8, 13, 27 and 28 having the best activity and the absence of AChE inhibitory activity, indicating that they are very selective BuChE inhibitors.
TABLE 2 test results of the compounds on AChE, BuChE and IDO1
Figure BDA0001827249050000301
Figure BDA0001827249050000311
Note: data are expressed as mean ± SEM (n ═ 3), NA for no active, and nd for not determined.
EXAMPLE 25 determination of indoleamine 2, 3-dioxygenase-1 inhibitory Activity
Drugs and reagents: examples 6-28 Compounds, rhIDO-1 enzyme (expressed in this group), ascorbic acid, catalase, subunit blue, L-tryptophan, p-dimethylaminobenzaldehyde, trichloroacetic acid were all purchased from Aladdin.
The instrument comprises: THERMO Varioskan Flash full-wavelength multifunctional microplate reader.
The experimental method comprises the following steps:
(1) preparing a buffer solution: 13.6g of potassium dihydrogen phosphate are dissolved in 1L of water and the pH is adjusted to 6.5. + -. 0.1 with hydrochloric acid. The solution was stored at 4 ℃ until use.
(2) Preparing a substrate mixed solution: a)0.4M PBS with 80mmol/L ascorbic acid, b) PBS with 400ug/mL catalase, 40umol/L methylene blue, 800 umol/LL-tryptophan, c) equal volume mixing a), b), the component concentration as follows: 40mmol/L ascorbic acid, 200ug/mL catalase, 20umol/L methylene blue, 400umol/L L-tryptophan.
(3) Preparing 2% acetic acid solution of p-dimethylaminobenzaldehyde: 149mg of p-dimethylaminobenzaldehyde are dissolved in 7.45ml of acetic acid.
(4) Preparing a test solution: dissolving the test compound in dimethyl sulfoxide (<0.1%) to obtain a concentration of 10-3M (dimethyl sulfoxide did not affect the test results), and then diluted with water to give concentrations of 10-4、10-5、10-6、10-7、10-8、10-9A solution of M.
In a 500uL reaction system, 50mmol/LPBS buffer solution (pH6.5), 40mmol/L ascorbic acid, 200ug/mL catalase, 20umol/L methylene blue, substrate L-tryptophan and a sample to be detected are mixed, the mixed solution is preheated for 5 minutes at 37 ℃, then 0.05umol/L rhIDO1 enzyme is added, the reaction is carried out for 30 minutes at 37 ℃, 30% trichloroacetic acid 2 is added after the enzymatic reactionThe reaction was terminated at 00uL, the reaction solution was heated at 65 ℃ for 15 minutes, centrifuged at 12000rpm for 5 minutes, 100uL of the supernatant was taken and mixed with an equal volume of 2% p-dimethylaminobenzaldehyde in acetic acid, and the yellow color produced by the reaction of kynurenine with it was observed at 480nm using a microplate reader. All tests were run in parallel in triplicate. The absorbance (OD value) of the test compound at each concentration was recorded with the UV absorption value of the blank control group as 100%, and the obtained result was calculated by using GraphPad Prism6(GraphPad Software, San Diego, Calif., USA) Software in a non-linear regression analysis mode (non-linear regression analysis model) to obtain the corresponding IC50The results are shown in table 2.
And (4) analyzing results: the compounds have inhibitory activity against IDO1, IC of 13 compounds50<100 μ M. Compounds 6 and 15 are most preferably IC5016.6. mu.M and 15.2. mu.M, respectively. Combining the two targets, compounds 8 and 13 both had comparable inhibitory activity against BuChE and IDO 1.
Example 26 Water maze experiment
Drugs and reagents: the compound of example 8, 13, scopolamine hydrobromide was purchased from alatin reagent (S107418, shanghai), tacrine (purity > 95%).
The instrument comprises the following steps: panlab SMART 3.0 behavioural video analyzer
Animals: adult male ICR mice (8-10 weeks, 20-25 grams in body weight) were purchased from Yangzhou university medical center
The experimental method comprises the following steps: the 56 mice were randomly divided into 7 subgroups (8 mice per group) (i) vehicle as blank control group, (ii) scopolamine as model group, (iii) tacrine plus scopolamine as positive control, and (iv) compound 8(10mg/kg) plus scopolamine as test group, (v) compound 8(30mg/kg) plus scopolamine as test group, (vi) compound 13(100mg/kg) plus scopolamine as test group, (vii) compound 13(30mg/kg) plus scopolamine as test group. Mice in the model group, tacrine group, compound 8 group (10mg/kg), compound 8 group (30mg/kg), compound 13 group (10mg/kg) and compound 13 group (30mg/kg) were injected intraperitoneally with scopolamine (1mg/kg), and the blank control group was injected with saline. After 30 minutes, the tacrine group, the compound 8 group (10mg/kg), the compound 8 group (30mg/kg), the compound 13 group (10mg/kg) and the compound 13 group (30mg/kg) were intraperitoneally injected with scopolamine, and the control group was injected with physiological saline.
An escape platform (diameter 10 cm) is fixed in a circular pool (diameter 120 cm and height 60 cm), and fresh water (kept at 25 ℃) with the depth of 40 cm is filled to form a water maze. Placed in a bright room. After 5 days of learning and memory training, probe tests were performed on day 6. To assess cognitive function, each mouse was trained on a visible platform (marked with a flag, 5cm high) alone for 2 days, and on the water maze on a hidden platform (placed 1cm below the water surface) from day 3 to day 5. All mice were subjected to 2 training trials per day, each trial lasting 90 seconds. The time each mouse found the platform (successful escape) was recorded. If the mouse fails to reach the platform within 90 seconds, the test is terminated and the mouse is carefully placed by hand onto the platform. Each mouse will remain on the platform for 30 seconds, whether successful or not. On the last day (day 6), the platform was removed from the pool and the mice were tested, allowing each mouse 90 seconds to search for the platform. The time and trajectory of the mouse to the missing platform position was recorded. The experimental results are shown in Table 3 and FIG. 1
And (4) analyzing results: as can be seen by combining the table 3 and the figure 1, compared with the control group, the average time of the model group mice reaching the platform is significantly different, which indicates that scopolamine can cause memory deficiency of the mice, and indicates that the molding is successful. The time and distance spent by tacrine groups was significantly reduced relative to the model group, indicating that tacrine significantly improved memory and cognitive function in mice. The average time and distance to the platform of the mice in the compound 8 and 13 treatment groups were lower than those in the model group, indicating that the compounds 8 and 13 have an improving effect on the memory and cognitive functions of the mice. The effect of the compound 13 treatment group under two doses is better than that of the compound 8 treatment group, and the effect of the compound 13(10mg/kg) treatment group is equivalent to that of the control group, which shows that the compound 13 can well reverse scopolamine to cause memory deficiency of mice. FIG. 2 is a graph of representative trajectories for groups of mice, the trajectories for model group mice being significantly longer and more chaotic than for the blank group; the performance of the mice in the tacrine group is obviously improved compared with that of the model group, which shows that tacrine has obvious improvement on the memory and cognitive functions of the mice; the trajectories of the compound 8-treated group and the compound 13-treated group were also improved relative to the model group, and the compound 8(10mg/kg), the compound 13(10mg/kg) and the compound 13(30mg/kg) were superior to the tacrine group, indicating that the mouse memory and cognitive function improving effects were superior to tacrine.
TABLE 3 time at which the mouse reached the platform
Figure BDA0001827249050000331
Data are presented as mean ± SEM (n-8; ns-no significant difference, p <0.05, p <0.01, p <0.001vs model group).
Example 27 MTT assay
Drugs and reagents: 3- (4, 5-Dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) (available from Aladdin)
The instrument comprises the following steps: THERMO Varioskan Flash full-wavelength multifunctional microplate reader.
The experimental method comprises the following steps: target cells (5X 10)3Volume 0.1ml) were placed in a 96-well flat-bottom culture plate and cells were allowed to adhere to the bottom of the plate overnight at 37 ℃. Cells were treated with various concentrations of the compounds for 24 hours. MTT reagent was added to the wells and the plates were incubated at 37 ℃ for 4 hours. Cells were disrupted by adding 0.1ml lysis buffer to the wells. After incubation they were kept at 37 ℃ for a further 24 hours and the colour reaction was measured at 570nm using a microplate reader. All groups were performed 3 times in parallel. The experimental results are shown in table 4, fig. 3 and fig. 4.
And (4) analyzing results: all compounds were not significantly toxic to PC12 and SH-SY5Y cells at a concentration of 50 μ M, only compound 13 was slightly toxic to PC12 cells. Most compounds have slight protective effect on SH-SY5Y nerve cells. The above data indicate the preliminary safety of the compounds. Most compounds were less cytotoxic than the positive control tacrine, indicating the potential safety of the compound.
TABLE 4 survival rates of PC12 and SH-SY5Y cells
Figure BDA0001827249050000341
Figure BDA0001827249050000351
Experimental example 27 acute hepatotoxicity study
Animals: adult male ICR mice (8-10 weeks, 20-25 grams in weight) were purchased from the university of Yangzhou medical center.
The instrument comprises the following steps: biochemical analyzers (HITACHI 7020, japan); ultra-thin semi-automatic microtomes (Leica RM2245, germany).
Grouping: 42 mice were randomly divided into 7 groups (6 mice per group): control, model, tacrine, compound 12 treated, compound 15 treated.
The experimental method comprises the following steps: tacrine (30mg/kg), compound 8 two doses (10mg/kg and 30mg/kg), and compound 13 two doses (10mg/kg and 30mg/kg) were dissolved in CMC-Na solution (0.5g CMC-Na, 100mL distilled water), respectively, and administered by gavage. The control mice were gavaged with normal saline, and the model mice were injected with scopolamine (1mg/kg) intraperitoneally. Heparinized sera were obtained from the retrobulbar plexus at 8 hours, 22 hours and 36 hours after administration, respectively. By a commercially available assay kit: two liver injury indexes of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) are determined by mouse alanine aminotransferase kit (EF551, EF550) and AST detection kit (EH027, EF 548). Mice were sacrificed 1 hour after the last collection of pellet blood, livers were removed and morphologically studied by immunohistochemistry. Two 3mm sections from the liver gate to the left outer lobe margin were separated using an ultra-thin semi-automatic microtome, immediately placed in 10% formaldehyde buffer, fixed for two days, embedded with paraffin to prepare 5 μm paraffin sections, deparaffinized, and histopathological examination was performed with hematoxylin and eosin staining. The results of the experiments are shown in tables 5, 6 and 5 to 7.
And (4) analyzing results: the ALT and AST levels of the compound 8(10mg/kg), the compound 8(30mg/kg), the compound 13(10mg/kg) and the compound 13(30mg/kg) were comparable to those of the control group and the model group at three time points, and there was no significant difference, indicating that the compounds have preliminary safety. In addition, histopathology showed that compound 8 (fig. 7D and 7E) and compound 13 (fig. 7F and 7G) did not cause adverse morphological changes in the liver compared to the control group (fig. 7A), and these results indicate the safety of the compounds, suggesting that these compounds have good clinical application prospects.
TABLE 5 mouse alanine transaminase levels at three time points
Figure BDA0001827249050000361
TABLE 6 mouse aspartate transaminase levels at three time points
Figure BDA0001827249050000362

Claims (6)

1. Diaryl imidazole compounds shown as a formula (I) or pharmaceutically acceptable salts thereof,
Figure FDA0003600417730000011
the diaryl imidazole compound is as follows:
Figure FDA0003600417730000012
2. a process for preparing diarylimidazoles as claimed in claim 1, comprising: substituted aryl ethanone is used as a raw material, alpha-bromo aryl ethanone is obtained by bromine bromination, and the alpha-bromo aryl ethanone is obtained by alkylation with imidazole N
Figure FDA0003600417730000013
Then reacting with sodium borohydride to obtain
Figure FDA0003600417730000014
And finally reacting with 3-methoxybenzyl chloride or aryl carboxylic acid with different chain lengths to prepare the diaryl imidazole compound shown in the formula (I).
3. The method for preparing diarylimidazoles according to claim 2, characterized by comprising the steps of:
step (1) of substituting aryl ethanone, using trichloromethane as a reaction solvent, in Br2Under the action of the reaction, stirring for 1-1.5 h at 25-30 ℃, after the reaction is finished, quenching the reaction by saturated sodium sulfite, washing an organic phase by saturated sodium bicarbonate and saturated salt water, drying anhydrous sodium sulfate, and removing the solvent in vacuum to obtain a crude product of the alpha-bromoarylethanone; the substituted aryl ethyl ketone and Br2The molar ratio of (A) to (B) is 1: 1-1.5;
dissolving alpha-bromoarylethanone and imidazole in tetrahydrofuran, adding potassium carbonate, stirring at room temperature for 2-3 h, removing the reaction liquid in vacuum, adding water, and extracting with ethyl acetate; washing the organic phase with water and saturated brine, drying with anhydrous sodium sulfate, spin-drying, and separating with silica gel column chromatography to obtain
Figure FDA0003600417730000021
Wherein, the eluent of the silica gel column chromatography is dichloromethane-methanol 100:1 v/v; the molar ratio of the alpha-bromoarylethanone to the imidazole to the potassium carbonate is 1:2: 2-1: 3: 3;
step (3) is to
Figure FDA0003600417730000022
Dissolving in anhydrous methanol, adding sodium borohydride under an ice bath condition, stirring for 1-1.5 hours at the temperature, heating and refluxing for 2-3 hours, adding water to quench the reaction, extracting with ethyl acetate, combining organic phases, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, spin-drying, and separating by silica gel column chromatography to obtain the compound; wherein, the eluentIs DCM: MeOH ═ 30:1 v/v; said
Figure FDA0003600417730000023
The molar ratio of the sodium borohydride to the sodium borohydride is 1: 2-1: 3;
step (4) when L is-O-, the operation is that
Figure FDA0003600417730000024
Dissolving in DMF, adding sodium hydride in ice bath, reacting for 1-1.5 hours at room temperature, adding 3-methoxybenzyl chloride in ice bath, reacting for 1-1.5 hours at room temperature, quenching with water, extracting with ethyl acetate, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, spin-drying, and separating by silica gel column chromatography to obtain a structural compound shown in formula (I); said
Figure FDA0003600417730000025
The molar ratio of the NaH to the 3-methoxy benzyl chloride is 1:1.2: 1.2-1: 1.2: 1.3; eluent is DCM, MeOH is 30:1 v/v; when L is-C (O) O-, the operation is
Figure FDA0003600417730000026
Dissolving the mixture and corresponding carboxylic acid in DCM, adding dicyclohexylcarbodiimide and p-dimethylaminopyridine under ice bath, and reacting for 2-3 hours at room temperature; washing the reaction solution with water and saturated saline solution, drying by anhydrous sodium sulfate, spin-drying, and separating by silica gel column chromatography to obtain a compound with a structure shown in formula (I); said
Figure FDA0003600417730000027
The molar ratio of the carboxylic acid to the dicyclohexylcarbodiimide to the dimethylaminopyridine is 1:1:1: 0.1-1: 1.3:1.3: 0.1; eluent is DCM, MeOH ═ 30:1 v/v.
4. The use of a diarylimidazole compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for the prevention or treatment of alzheimer's disease.
5. The use according to claim 4, wherein the medicament is prepared from the diarylimidazole compounds or pharmaceutically acceptable salts thereof as an active ingredient or a main active ingredient, and a pharmaceutically acceptable carrier; the dosage form of the medicine is capsule, pill, tablet, granule or injection.
6. A pharmaceutical composition comprising the diarylimidazole compounds or pharmaceutically acceptable salts thereof according to claim 1.
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