CN101759686A - Synthesizing method and application of 2-substituted aryl-1-substituted benzyl benzimidazole compound - Google Patents

Abstract

The invention discloses a synthesizing method of a 2-substituted aryl-1-substituted benzyl benzimidazole compound, comprising the following steps of: adding an o-phenylenediamine compound to a reactor; adding a water-alcohol mixed solvent with 30-100 times by weight of the o-phenylenediamine compound under the stirring; then adding aromatic aldehyde, wherein the mole ratio of the o-phenylenediamine compound to the aromatic aldehyde is 1 to 2.0-2.5; then heating, refluxing and then adding a weed acid catalyst after relfuxing; continuously relfuxing and reacting for 30-90 minutes, finishing reaction; and then pouring a reaction mixture into ice water to sequentially perform stirring, pumping filtration, washing and alcohol recrystallization so as to obtain the 2-substituted aryl-1-substituted benzyl benzimidazole compound. The synthesizing method has short synthetic route, high yield coefficient, simple and moderate reaction condition, easy operation, high atom utility ratio, easy recycling of a reaction solvent in a water-alcohol system, low cost and easy obtaining of the catalyst; the whole reaction process reflects a green synthetic chemistry idea; and in addition, the obtained 2-substituted aryl-1-substituted benzyl benzimidazole compound has higher inhibitor for a thioformamide peptidase.

Description

Synthetic method and application of 2-substituted aryl-1-substituted benzylbenzimidazole compound

technical field

The invention belongs to the technical field of benzazine heterocyclic compounds, and in particular relates to benzimidazole compounds and derivatives thereof.

Background technique

Benzimidazole compounds have good biological activity, and many benzimidazole derivatives have shown good antibacterial, antihypertensive and anticancer activities in clinical treatment. Benzimidazole derivatives can also be used to simulate the active site of natural superoxide dismutase to study biological activity. Among the benzimidazole compounds, some compounds have been found to have good pharmacological activity, such as omeprazole and lansoprazole, which can be used as proton pump inhibitors.

Benzimidazole compounds containing different substituents should have different biological activities. By screening the biological activities of these compounds, we hope to find better antibacterial and antiviral drugs or proton pump inhibitors with high efficiency and low toxicity. Therefore, the synthesis and application research of this kind of compound has always attracted the attention of medicinal chemists.

Contents of the invention

The purpose of the present invention is to provide a synthesis method of 2-substituted aryl-1-substituted benzylbenzimidazole compounds, and the application of such compounds as inhibitors of methylthioamidopeptidase.

In order to achieve the above object, the technical means adopted in the present invention are: the synthetic method of this 2-substituted aryl-1-substituted benzylbenzimidazole compound is:

Add the o-phenylenediamine compound to the reactor, add a water-alcohol mixed solvent with a weight of 30-100 times the weight of the o-phenylenediamine compound under stirring, and then add the aromatic aldehyde, and the molar ratio of the o-phenylenediamine compound to the aromatic aldehyde is 1: 2.0-2.5; then heat, add a weak acid catalyst after reflux; continue the reflux reaction for 30-90 minutes, and end the reaction; then perform TLC to track the reaction process, pour the reaction mixture into ice water for stirring, suction filtration, water washing, Recrystallized from ethanol to obtain 2-substituted aryl-1-substituted benzylbenzimidazole compound.

Further, the weak acid catalyst of the present invention is oxalic acid, or a mixture of oxalate and acid.

Further, the water-alcohol mixed solvent of the present invention is a mixed solution of ethanol and water.

The 2-substituted aryl-1-substituted benzylbenzimidazole compound obtained by the above synthetic method of the present invention has a general structural formula as shown in formula (I)

Wherein, R, R ¹ , R ² groups are -NO ₂ , -N(CH ₃ ) ₂ , -OH, -OCH ₃ , H, 3,4-OCH ₂ O-, -Br, -Cl, F, Any of -COOH, an alkyl group with 1-6 carbons, and a cycloalkyl group with 3-7 carbons. R, R ¹ and R ² may be the same or different.

The use of the 2-substituted aryl-1-substituted benzylbenzimidazole compound of the present invention is that the compound is used as an inhibitor of methylthioamidopeptidase.

The invention measures the inhibitory rate of the compound to yeast methionine peptidase (ScMetAP1). Methionine peptidase is an essential protease that widely exists in prokaryotes (such as Escherichia coli) and eukaryotes (such as yeast, mammals) and other biological systems. Its physiological function is mainly to participate in the synthesis of new proteins. The cleavage of N-terminal methionine plays an important role in maintaining the biological activity of proteins in organisms, correct intracellular positioning and physiological degradation. The results show that the 2-substituted aryl-1-substituted benzylbenzimidazole compound of the present invention has a higher inhibition rate on methionine peptidase (ScMetAP1).

The present invention takes ortho-phenylenediamine as the method for the synthesis of 2-substituted aryl-1-substituted benzylbenzimidazole compound as a raw material and has the following advantages:

(1) The synthetic route is short and the yield is high;

(2) The reaction conditions are simple and mild, and easy to operate;

(3) The atom utilization rate is high; the reaction solvent is a water-alcohol system, which is easy to recycle; a cheap and easy-to-obtain catalyst is used, and the whole process embodies the concept of green synthetic chemistry.

Detailed ways

1. Synthesis Example

Reagents and instruments used in the present invention are: X-4 type microscopic melting point measuring instrument (temperature is not corrected); Avatar370 FT-TR (Nicolet infrared spectrometer (KBr tablet); Bruker 400 UltraShield ^TM (400MHz) nuclear magnetic resonance instrument; deuterated DMSO is the solvent, TMS is the internal standard. The reagents used are commercially available analytical grade.

Embodiment one:

Add o-phenylenediamine (2mmol, 0.21g) and ethanol-water mixed solvent (6mL, about 6g) into the reactor in sequence, and stir to dissolve. To this solution was added benzaldehyde (4 mmol). Heat to raise the temperature, add oxalic acid (0.2 mmol) after reflux, continue to reflux until the reaction is complete, pour the reaction mixture into 80 mL of ice water, stir for 30 min, filter with suction, wash with water, and recrystallize with ethanol. 2-Phenyl-1-benzylbenzimidazole was obtained. White solid; Yield 86%; mp131-132°C; IR (KBr): 3060 (v=CH), 2926 (vCH), 1489 (vC=N), 726, 699 (δ=CH), 1598 (benzene skeleton); ¹ H-NMR (DMSO): δ: 5.57 (s, 2H), 10: R = 4-OH6.98 (d, 2H), 7.21-7.28 (m, 5H), 7.50-7.53 (m, 4H), 7.69-7.74 (m, 3H).

Embodiment two:

Add o-phenylenediamine (2mmol, 0.21g) and ethanol-water mixed solvent (10mL, about 10g) into the reactor in sequence, and stir to dissolve. To this solution was added p-hydroxybenzaldehyde (4.5 mmol). Heat to raise the temperature, add sodium oxalate (0.2mmol) and HCl (0.1M, 2mL) after reflux, continue to reflux until the end of the reaction, pour the reaction mixture into 80mL of ice water, stir for 30min, filter with suction, wash with water, and recrystallize with ethanol. 2-(4-hydroxy)phenyl-1-(4-hydroxy)benzylbenzimidazole was obtained. White powder; Yield 76%; mp223-224°C; IR(KBr): 3259(vOH), 3024(v=CH), 2803(vCH), 1443(vC=N), 839,815(δ=CH) , 1611 (benzene ring skeleton). ¹ H-NMR (DMSO): δ: 5.41 (s, 2H), 9.39 (s, 1H), 9.95 (s, 1H), 6.64-6.66 (d, 2H), 6.81- 6.83(d, 2H), 6.88-6.90(d, 2H), 7.18-7.22(m, 2H), 7.40-7.42(d, 1H), 7.54-7.56(d, 2H), 7.64-7.65(d, 1H ).

Embodiment three:

Add o-phenylenediamine (2mmol, 0.21g) and ethanol-water mixed solvent (8mL, about 8g) into the reactor in turn, and stir to dissolve. To this solution was added 2-hydroxybenzaldehyde (4.1 mmol). Heat to raise the temperature, add sodium oxalate (0.25mmol) and H ₂ SO ₄ (0.05M, 2mL) after reflux, continue to reflux until the end of the reaction, pour the reaction mixture into 80mL ice water, stir for 30min, filter with suction, wash with water, ethanol recrystallization. 2-(2-hydroxy)phenyl-1-(2-hydroxy)benzylbenzimidazole was obtained. Pale yellow powder; yield 84%; mp209-210°C; IR (KBr): 3296 (vOH), 3049 (v=CH), 2947 (vCH), 1452 (vC=N), 753 (δ=CH), 1593 (benzene ring skeleton). ¹ H-NMR (DMSO): δ: 5.39 (s, 2H), 6.38-6.39 (d, 1H), 6.57-6.61 (t, 1H), 6.81-6.83 (d, 1H) , 6.88-6.92(t, 1H), 7.03-7.04(d, 2H), 7.19-7.27(m, 2H), 7.34-7.43(m, 3H), 7.70-7.72(d, 1H), 10.86(2H, brs).

Embodiment four:

Add o-phenylenediamine (2mmol, 0.21g) and ethanol-water mixed solvent (15mL, about 15g) into the reactor in sequence, and stir to dissolve. To this solution was added 4-methoxybenzaldehyde (4 mmol). Heat to raise the temperature, add sodium oxalate (0.2mmol) and p-toluenesulfonic acid (0.2mmol) after reflux, continue to reflux until the end of the reaction, pour the reaction mixture into 80mL of ice water, stir for 60min, filter with suction, wash with water, recrystallize with ethanol . 2-(4-methoxy)phenyl-1-(4-methoxy)benzylbenzimidazole was obtained. White powder; yield 77%; mp127-128°C; IR (KBr): 3055 (v=CH), 2912 (vCH), 1512 (vC=N), 829 (δ=CH), 1611 (benzene ring skeleton) . ¹ H-NMR (DMSO) δ: 6.84-7.85 (m, 12H), 5.39 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H).

Embodiment five:

Add o-phenylenediamine (2mmol, 0.21g) and ethanol-water mixed solvent (20mL, about 20g) into the reactor in sequence, and stir to dissolve. To this solution was added 3,4-acetalbenzaldehyde (5 mmol). Heat to raise the temperature, add oxalic acid (0.2 mmol) after reflux, continue to reflux until the reaction is complete, pour the reaction mixture into 80 mL of ice water, stir for 90 min, filter with suction, wash with water, and recrystallize with ethanol. 2-(3,4-acetal)phenyl-1-(3,4-acetal)benzylbenzimidazole was obtained. White powder; yield 81%; mp171-173 ° C; IR (KBr): 3019 (v=CH), 2900 (vCH), 1483 (vC=N), 816,740 (δ=CH), 1607 (benzene skeleton), 1249 (vCO); ¹ H-NMR (DMSO): δ: 5.46 (s, 2H), 5.96 (s, 2H), 6.12 (s, 2H), 6.43-6.45 (d, 1H), 6.59 ( s, 1H), 6.79-6.81 (d, 1H), 7.06-7.08 (d, 1H), 7.22-7.26 (m, 4H), 7.45-7.47 (t, 1H), 7.67-7.69 (t, 1H).

2. Activity test implementation

The invention measures the inhibitory rate of the compound to yeast methionine peptidase (ScMetAP1).

Purpose:

Methionine peptidase (MetAP) is an essential protease that widely exists in prokaryotes (such as Escherichia coli) and eukaryotes (such as yeast, mammals) and other biological systems. The cleavage of the N-terminal methionine of the synthetic protein plays an important role in maintaining the biological activity of the protein in the organism, the correct positioning in the cell and the physiological degradation.

experimental method:

ScMetAP1 can hydrolyze the thioester bond of the synthetic substrate Met-S-C-Phe, and the product Met-SH is rapidly combined with excess DTNB

The reaction produces 3-hydroxy-4-nitrothiophenolate with absorption at 412nm, and the enzyme activity is determined by detecting the change of light absorption at 412nm.

Experimental results:

The inhibition rate of 2-substituted aryl-1-substituted benzylbenzimidazole compounds to methionine peptidase is shown in Table 1:

The inhibitory rate of table 1 compound to methionine peptidase

Claims (4)

1. a kind of synthetic method of 2-substituted aryl-1-substituted benzylbenzimidazole compound is characterized in that: in reactor, add o-phenylenediamine compound, add weight is o-phenylenediamine compound 30- 100 times of water-alcohol mixed solvent, then add aromatic aldehyde, the molar ratio of o-phenylenediamine compound and aromatic aldehyde is 1:2.0-2.5; then heat, add weak acid catalyst after reflux; continue reflux reaction for 30-90min , to end the reaction; then pour the reaction mixture into ice water for stirring, suction filtration, washing with water, and ethanol recrystallization in order to obtain 2-substituted aryl-1-substituted benzyl benzimidazole compound. 2. The synthetic method according to claim 1, characterized in that: the weak acid catalyst is oxalic acid, or a mixture of oxalate and acid. 3. The synthetic method according to claim 1, characterized in that: the water-alcohol mixed solvent is a mixed solution of ethanol and water. 4. The use of the 2-substituted aryl-1-substituted benzylbenzimidazole compound according to claim 1, characterized in that the compound is used as an inhibitor of methionine peptidase.