CN111875591B - Method for catalytic synthesis of drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative - Google Patents
Method for catalytic synthesis of drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative Download PDFInfo
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Abstract
The invention discloses a catalytic synthesis drug intermediate 3-benzo [ d]Imidazole benzolsA method for preparing pyrone derivatives, belonging to the technical field of organic synthesis. The method takes substituted benzaldehyde, 2-cyanomethyl benzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione as reaction raw materials to prepare 3-benzo [ d ] under the catalysis of an alkaline ionic liquid catalyst]Of imidazole benzopyrone derivatives; the structural formula of the basic ionic liquid catalyst is as follows:
by adopting the technical scheme of the invention, the problems that the catalyst cannot be recycled and the using amount is large in the preparation process can be effectively solved, the types and the content of byproducts are reduced, the product purification process is simplified, the reaction cost is greatly saved, and the pollution degree to the environment is reduced.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for catalytically synthesizing a drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative.
Background
Benzopyrone is a basic skeleton of a natural organic compound, and many benzopyrone compounds have wide biological activity and photochromic effect and are widely applied to the fields of medicines, pesticides, dyes, cosmetics and the like. The medicine with benzimidazolone skeleton is widely applied to clinical practice, and has good application prospect, such as sodium rabeprazole serving as an anti-ulcer medicine, azilsartan serving as an antihypertensive medicine, bilastine serving as a receptor antagonist, bentinib serving as an anti-tumor medicine, and bemacillin serving as an anti-cancer medicine. The 3-benzo [ d ] imidazole benzopyrone derivative containing both benzimidazole structure and benzopyrone structure has strong effect on inhibiting Rho kinase activity. Therefore, the synthesis of 3-benzo [ d ] imidazole benzopyrone derivatives has received much attention.
Traditionally, a multistep synthesis method is adopted for synthesizing the 3-benzo [ d ] imidazole benzopyrone derivative, the synthesis route is long, and the reaction conditions are harsh, so that the yield is low in the whole synthesis process, the environmental pollution is serious, and the industrial large-scale production is difficult to realize. The multi-component one-pot method can greatly reduce the usage amount of reaction solvent, the complexity of intermediate product purification and the pollution degree to the environment, and has higher atom economy. Based on the method, ethanol is used as a reaction solvent, organic base pyridine is used as a catalyst, aromatic aldehyde, 2-cyanomethyl benzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione are catalyzed by Wang Xiang and the like, three components of the 3-benzo [ d ] imidazole benzopyrone derivative are synthesized by a one-pot method, and the yield is 48-89%. The method has the advantages of mild reaction conditions, simple and convenient post-treatment and the like (three-component one-pot synthesis of the 3-benzo [ d ] imidazole chromene derivative [ J ], organic chemistry, 2019, 39: 3299-3303, preparation method of the 3-benzimidazole chromene derivative [ P ], application number: 201910141572.4). However, this method also has several disadvantages: 1. pyridine is less catalytically active, resulting in larger amounts (10 mol%); 2. the catalyst pyridine and the reaction solvent ethanol cannot be recycled, so that the environmental pollution is serious and the economic benefit is poor; 3. the selectivity of the catalyst is poor, the side reaction is more, and the product yield is lower; 4. the reaction time is longer.
Based on the defects of the prior art, the invention of a new method for synthesizing a drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative is needed.
Disclosure of Invention
1. Problems to be solved
The invention aims to overcome the defects that a catalyst cannot be recycled and the using amount is large in the process of synthesizing a drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative by adopting a catalytic one-pot method in the prior art, and provides a method for catalytically synthesizing the drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative. The technical scheme of the invention can effectively solve the problems, reduce the types and the contents of byproducts, simplify the purification process of the products, greatly save the reaction cost and reduce the pollution degree to the environment.
2. Technical scheme
In order to solve the problems, the technical scheme adopted by the invention is as follows:
the invention relates to a method for catalytically synthesizing a drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative, which takes substituted benzaldehyde, 2-cyanomethyl benzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione as reaction raw materials to react under the catalytic action of an alkaline ionic liquid catalyst to prepare the 3-benzo [ d ] imidazole benzopyrone derivative; the structural formula of the basic ionic liquid catalyst is as follows:
the preparation method of the basic ionic liquid catalyst used in the present invention is described in the related literature (Dual basic ionic liquid a catalyst for synthesis of (2-amino-3-cyano-4H-chromen-4-yl) phosphoric acid dimethyl ester and its molecular linking reactant [ J ], Research on Chemical Intermediates, 2020, 46: 621-637).
Further, the preparation reaction uses an isopropanol aqueous solution as a reaction solvent.
Furthermore, the volume percentage of the isopropanol in the isopropanol aqueous solution in the total volume of the isopropanol aqueous solution is 84-91%.
Furthermore, the volume of the isopropanol aqueous solution in milliliters is 4 to 7 times of the amount of the substituted benzaldehyde substance in millimoles.
Furthermore, the amount of the added substance of the basic ionic liquid catalyst is 4-6% of the amount of the substituted benzaldehyde substance.
Furthermore, the method specifically comprises the following steps:
step 1: firstly, adding an isopropanol aqueous solution into a reaction vessel, then adding substituted benzaldehyde, 2-cyanomethyl benzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione, stirring at room temperature, uniformly mixing, and finally adding an alkaline ionic liquid catalyst;
step 2: heating to reflux the solvent, keeping the temperature until the raw material point disappears (TLC detection), and stopping stirring after the reaction is finished;
and step 3: cooling the reaction liquid to room temperature, grinding the precipitated solid, standing, and performing suction filtration to obtain filter residue;
and 4, step 4: washing the filter residue with an isopropanol aqueous solution washing solution, and drying in vacuum to obtain a 3-benzo [ d ] imidazole benzopyrone derivative;
and 5: supplementing a washing solution to the filtrate after suction filtration, then adding reaction raw materials to replace benzaldehyde, 2-cyanomethyl benzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione, and carrying out the next round of circulating reaction according to the steps 1 to 4.
The chemical reaction formula involved in the synthesis of the drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative by the method is as follows:
furthermore, the reaction vessel in the step 1 is a three-neck flask with a magnetic stirring bar, a thermometer and a spherical condenser; the mass ratio of the substituted benzaldehyde, 2-cyanomethyl benzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione is 1: 1: (1.0-1.3).
Furthermore, in the step 2, the solvent is heated in an oil bath manner and uniformly heated until the solvent is refluxed, and the solvent vapor is kept not to exceed the second ball of the spherical condenser pipe in the refluxing process; the reflux reaction time is 26-48 min.
Furthermore, in the step 4, the washing solution of the aqueous isopropanol solution adopts the aqueous isopropanol solution with the same concentration in the step 1; washing for 3-4 times, vacuum drying at 85-88 ℃, and vacuum drying for 22-24 hours; the number of times of the cyclic reaction in the step 5 is 1-4.
Further, the substituted benzaldehyde includes any one of p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-methoxybenzaldehyde, m-nitrobenzaldehyde, 2, 3-dichlorobenzaldehyde, 2, 4-dichlorobenzaldehyde and 3, 4-dichlorobenzaldehyde.
3. Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
(1) according to the method for catalytically synthesizing the drug intermediate 3-benzo [ d ] imidazolone derivative, in the preparation process of the drug intermediate, the basic ionic liquid simultaneously containing a Bronsted basic site and a Lewis basic site is used as a catalyst, and the catalyst has high catalytic activity on the reaction of synthesizing the 3-benzo [ d ] imidazolone derivative by substituted benzaldehyde, 2-cyanomethyl benzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione, so that the reaction time can be effectively shortened compared with an organic or inorganic base catalyst in the existing preparation method of the 3-benzo [ d ] imidazolone derivative under the condition of ensuring the product yield. On the other hand, the method of the invention can greatly reduce the usage amount of the catalyst: in the prior art, the usage amount of the catalyst is 10% of the amount of the substituted benzaldehyde substance as a reaction raw material, and the catalyst is only 4-6% of the amount of the substituted benzaldehyde substance in the reaction.
(2) The method for catalytically synthesizing the drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative adopts the basic ionic liquid which is difficult to volatilize and has a stable structure as the catalyst, so that the catalyst can be recycled, the production cost is reduced, and the pollution to the environment is reduced.
(3) The method for catalytically synthesizing the drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative has lower types and contents of byproducts in the reaction due to higher reaction selectivity of the basic ionic liquid. In addition, the isopropanol aqueous solution with specific concentration has the function of both a reaction solvent and a recrystallization solvent in the reaction, so that a catalytic system consisting of the alkaline ionic liquid catalyst and the isopropanol aqueous solution can be reused without any treatment, the utilization rate of reaction raw materials is improved, the discharge amount of waste liquid is reduced, the pollution to the environment is reduced, and the economic benefit and the environmental benefit are high.
(4) The method for catalytically synthesizing the drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative utilizes the alkaline ionic liquid catalyst and the isopropanol aqueous solution with specific concentration to form a catalytic system, adopts the isopropanol aqueous solution containing a certain amount of moisture, and can better exert the strong polarity and strong basicity of the alkaline ionic liquid catalyst compared with absolute ethyl alcohol, thereby more effectively improving the catalytic reaction efficiency.
(5) According to the method for catalytically synthesizing the drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative, on one hand, the catalytic activity and the use effect of the basic ionic liquid catalyst can be fully ensured by optimally designing the selection, the proportion and the dosage of specific reaction raw materials, so that the yield and the purity of the product are effectively improved; on the other hand, the process parameters are optimized, so that the product purification process is simplified, the reaction cost is greatly saved, and the pollution degree to the environment is reduced.
Drawings
FIG. 1 is a graphical representation of the effect of the number of times the catalytic system is used on the purity and yield of the product 2-amino-3- (1H-benzo [ d ] imidazole) -4- (2, 3-dichlorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one in example 1 of the present invention;
FIG. 2 is a graphical representation of the effect of the number of times the catalytic system was used on the purity and yield of the product 2-amino-3- (1H-benzo [ d ] imidazole) -4- (2, 3-dichlorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one in example 7 of the present invention.
Detailed Description
The present invention is further described in the following examples so that those skilled in the art can better understand the present invention and can practice the present invention, but the examples are not intended to limit the present invention, and those skilled in the art can make insubstantial modifications and adaptations to the present invention without departing from the scope of the present invention.
In the following examples, the reaction product 3-benzo [ d ] imidazole benzopyrone derivative was characterized by NMR using an AVANCE 400MHz NMR spectrometer from Bruker, Germany; infrared Spectrometry measurements characterisation was performed using an EQUINOX 55 Infrared spectrometer (KBr pellet) from Bruker, Germany; the high performance liquid chromatography purity measurement adopts a high performance liquid chromatograph of 1260Infinity II of Agilent company in America; the melting point of the reaction product was determined using an XR4A micro melting point apparatus from Shanghai optical instruments. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
To a 50ml three-necked flask containing 5ml of an aqueous isopropanol solution (volume of isopropanol is 86% based on the total volume of the aqueous isopropanol solution) and equipped with a spherical condenser, a thermometer and a magnetic stirrer were added 1.0mmol of p-fluorobenzaldehyde, 1.0mmol of 2-cyanomethylbenzimidazole and 1.2mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.05mmol of a basic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 43min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow solid is separated out, the solid is crushed, the reaction liquid is kept still for 18 hours, vacuum filtration is carried out, filter residues are washed by an isopropanol water solution washing liquid (the volume of isopropanol accounts for 86 percent of the total volume of the isopropanol water solution) (5ml is multiplied by 3), vacuum drying is carried out at the temperature of 85 ℃ for 24 hours, 0.35g of 2-amino-3- (1H-benzo [ d ] imidazole) -4- (4-fluorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one is obtained, the purity is 98.2 percent by high performance liquid chromatography, and the yield is 84 percent by calculation. After 5ml of the filtrate is supplemented by the washing liquid, p-fluorobenzaldehyde, 2-cyanomethylbenzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added, and the next cycle reaction is carried out according to the reaction conditions and the operation steps.
The characterization data for the product 2-amino-3- (1H-benzo [ d ] imidazole) -4- (4-fluorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one obtained in this example are as follows:
a yellow solid; m.p.235-237; IR (KBr): nu 3445, 3292, 1687, 1640, 1619, 1534, 1510, 1386, 1359, 1281, 1226cm-1；1H NMR(400MHz，DMSO-d6)：δ＝0.84(s，3H)，1.02(s，3H)，2.16(d，J＝15.8Hz，1H)，2.31(d，J＝16.2Hz，1H)，2.43(d，J＝18.0Hz，1H)，2.57(d，J＝15.8Hz，1H)，4.96(s，1H)，6.93～6.99(m，4H)，7.25(d，J＝6.4Hz，1H)，7.34～7.39(m，3H)，7.81(s，2H)，11.69(s，1H)。
Example 2
A50 ml three-neck flask containing 6ml of an aqueous isopropanol solution (the volume of isopropanol accounts for 87 percent of the total volume of the aqueous isopropanol solution) and provided with a spherical condenser, a thermometer and a magnetic stirrer was charged with 1.0mmol of p-chlorobenzaldehyde, 1.0mmol of 2-cyanomethylbenzimidazole and 1.1mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly and then 0.05mmol of a basic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 33min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow solid is separated out, the solid is crushed, the reaction liquid is kept still for 18 hours, vacuum filtration is carried out, filter residues are washed by isopropanol water solution washing liquid (the volume of isopropanol accounts for 87 percent of the total volume of the isopropanol water solution), vacuum drying is carried out at 85 ℃ for 24 hours, 0.37g of 2-amino-3- (1H-benzo [ d ] imidazole) -4- (4-chlorphenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one is obtained, the purity is 98.9 percent by high performance liquid chromatography, and the yield is 88 percent by calculation. After 6ml of the filtrate is filled with the washing liquid, p-chlorobenzaldehyde, 2-cyanomethylbenzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added into the filtrate, and the next circulation reaction is carried out according to the reaction conditions and the operation steps.
The characterization data for the product 2-amino-3- (1H-benzo [ d ] imidazole) -4- (4-chlorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one obtained in this example are as follows:
a yellow solid; m.p. 226-228; IR (KBr): nu 3441, 3211, 1679, 1642, 1524, 1473, 1450, 1373, 1271, 1249cm-1；1H NMR(400MHz，DMSO-d6)：δ＝0.85(s，3H)，1.04(s，3H)，2.13(d，J＝15.8Hz，1H)，2.32(d，J＝15.8Hz，1H)，2.42(d，J＝17.6Hz，1H)，2.53(d，J＝17.6Hz，1H)，4.98(s，1H)，6.97～7.03(m，2H)，7.22(d，J＝7.0Hz，2H)，7.29(d，J＝6.6Hz，1H)，7.41～7.43(m，3H)，7.84(s，2H)，11.76(s，1H)。
Example 3
A50 ml three-neck flask containing 6ml of an aqueous isopropanol solution (the volume of isopropanol accounts for 87 percent of the total volume of the aqueous isopropanol solution) and provided with a spherical condenser, a thermometer and a magnetic stirrer was charged with 1.0mmol of p-bromobenzaldehyde, 1.0mmol of 2-cyanomethylbenzimidazole and 1.0mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly and then charged with 0.05mmol of a basic ionic liquid catalyst. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 31min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow solid is separated out, the solid is crushed, the reaction liquid is kept stand for 18 hours, vacuum filtration is carried out, filter residues are washed by isopropanol water solution washing liquid (the volume of isopropanol accounts for 87 percent of the total volume of the isopropanol water solution), vacuum drying is carried out at 85 ℃ for 24 hours, 0.43g of 2-amino-3- (1H-benzo [ d ] imidazole) -4- (4-bromophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one is obtained, the purity is 98.0 percent through high performance liquid chromatography, and the yield is 91 percent through calculation. After 6ml of the filtrate is filled with the washing liquid, p-bromobenzaldehyde, 2-cyanomethylbenzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added, and the next circulation reaction is carried out according to the reaction conditions and the operation steps.
The characterization data for the product 2-amino-3- (1H-benzo [ d ] imidazole) -4- (4-bromophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-chromen-5-one obtained in this example are as follows:
a yellow solid; m.p.227～229；IR(KBr)：ν＝3443，3214，1676，1641，1528，1479，1452，1376，1273，1224cm-1；1H NMR(400MHz，DMSO-d6)：δ＝0.87(s，3H)，1.02(s，3H)，2.09(d，J＝16.2Hz，1H)，2.26～7.41(m，2H)，2.55(d，J＝17.8Hz，1H)，4.93(s，1H)，6.98～7.02(m，2H)，7.26(d，J＝7.0Hz，1H)，7.31～7.39(m，5H)，7.85(s，2H)，11.77(s，1H)。
Example 4
A50 ml three-necked flask containing 7ml of an aqueous isopropanol solution (the volume of isopropanol accounts for 91% of the total volume of the aqueous isopropanol solution) and equipped with a spherical condenser, a thermometer and a magnetic stirrer was charged with 1.0mmol of p-methoxybenzaldehyde, 1.0mmol of 2-cyanomethylbenzimidazole and 1.3mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.06mmol of a basic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 48min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow solid is separated out, the solid is crushed, the reaction liquid is kept still for 18 hours, vacuum filtration is carried out, filter residues are washed by an isopropanol water solution washing liquid (the volume of isopropanol accounts for 91 percent of the total volume of the isopropanol water solution) (5ml is multiplied by 3), vacuum drying is carried out at the temperature of 85 ℃ for 24 hours, 0.31g of 2-amino-3- (1H-benzo [ d ] imidazole) -4- (4-methoxyphenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one is obtained, the purity is 98.7 percent by high performance liquid chromatography, and the yield is 73 percent by calculation. After 7ml of the filtrate is supplemented with the washing liquid, p-methoxybenzaldehyde, 2-cyanomethylbenzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added, and the next cycle reaction is carried out according to the above reaction conditions and operation steps.
The characterization data for the product 2-amino-3- (1H-benzo [ d ] imidazole) -4- (4-methoxyphenyl) -7, 7-dimethyl-7, 8-dihydro-4H-chromen-5-one obtained in this example are as follows:
a yellow solid; m.p.207-209; IR (KBr): nu 3446, 3279, 1676, 1677, 1631, 1614, 1539, 1506, 1452, 1374, 1252, 1220cm-1；1H NMR(400MHz，DMSO-d6)：δ＝0.91(s，3H)，1.08(s，3H)，2.13(d，J＝16.0Hz，1H)，2.29(d，J＝16.0Hz，1H)，2.43(d，J＝17.4Hz，1H)，2.54(d，J＝17.4Hz，1H)，3.65(s，3H)，4.97(s，1H)，6.71(d，J＝8.0Hz，2H)，6.98～7.02(m，2H)，7.29～7.32(m，3H)，7.44(d，J＝7.2Hz，1H)，7.75(s，2H)，11.71(s，1H)。
Example 5
To a 50ml three-necked flask containing 4ml of an aqueous isopropanol solution (the volume of isopropanol is 84% of the total volume of the aqueous isopropanol solution), equipped with a spherical condenser, a thermometer and a magnetic stirrer, were added 1.0mmol of m-nitrobenzaldehyde, 1.0mmol of 2-cyanomethylbenzimidazole and 1.0mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed well, and then 0.04mmol of an alkaline ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 26min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow solid is separated out, the solid is crushed, the reaction liquid is kept stand for 18 hours, vacuum filtration is carried out, filter residues are washed by an isopropanol water solution washing liquid (the volume of isopropanol accounts for 84 percent of the total volume of the isopropanol water solution) (5ml is multiplied by 3), vacuum drying is carried out at 88 ℃ for 22 hours, 0.42g of 2-amino-3- (1H-benzo [ d ] imidazole) -7, 7-dimethyl-4- (3-nitrophenyl) -7, 8-dihydro-4H-benzopyran-5-one is obtained, the purity is 98.4 percent through high performance liquid chromatography, and the yield is 95 percent through calculation. After 4ml of washing liquid is filled up, m-nitrobenzaldehyde, 2-cyanomethylbenzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added into the filtrate, and the next circulation reaction is carried out according to the reaction conditions and the operation steps.
The characterization data for the product 2-amino-3- (1H-benzo [ d ] imidazole) -7, 7-dimethyl-4- (3-nitrophenyl) -7, 8-dihydro-4H-chromen-5-one obtained in this example are as follows:
a yellow solid; m.p.245-247; IR (KBr): v 3428, 3349, 1672, 1640, 1518, 1473, 1371, 1344, 1270 and 1223cm-1；1H NMR(400MHz，DMSO-d6)：δ＝0.88(s，3H)，1.07(s，3H)，2.17(d，J＝16.0Hz，1H)，2.32(d，J＝16.0Hz，1H)，2.49(d，J＝16.2Hz，1H)，2.59(d，J＝17.6Hz，1H)，5.16(s，3H)，6.99～7.03(m，2H)，7.26(d，J＝7.0Hz，2H)，7.40(d，J＝7.0Hz，1H)，7.49(d，J＝8.0Hz，1H)，7.81(d，J＝7.8Hz，1H)，7.97～8.03(m，2H)，8.33(s，1H)，11.25(s，1H)。
Example 6
To a 50ml three-necked flask containing 6ml of an aqueous isopropanol solution (the volume of isopropanol is 89% based on the total volume of the aqueous isopropanol solution), equipped with a spherical condenser, a thermometer and a magnetic stirrer, were added 1.0mmol of 3, 4-dichlorobenzaldehyde, 1.0mmol of 2-cyanomethylbenzimidazole and 1.2mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed well, and then 0.06mmol of a basic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 43min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow solid is separated out, the solid is crushed, the reaction liquid is kept stand for 18H, vacuum filtration is carried out, filter residue is washed by isopropanol water solution washing liquid (the volume of isopropanol accounts for 89 percent of the total volume of the isopropanol water solution) (5ml multiplied by 3), vacuum drying is carried out at the temperature of 87 ℃ for 23H, then 0.35g of 2-amino-3- (1H-benzo [ d ] imidazole) -4- (3, 4-dichlorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one is obtained, the purity is 98.1 percent through high performance liquid chromatography, and the yield is 76 percent through calculation. After 6ml of the filtrate is filled with the washing liquid, 3, 4-dichlorobenzaldehyde, 2-cyanomethyl benzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added, and the next circulation reaction is carried out according to the reaction conditions and the operation steps.
The product obtained in this example, 2-amino-3- (1H-benzo [ d ] imidazole) -4- (3, 4-dichlorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one, was characterized as follows:
a yellow solid; m.p.221-223; IR (KBr): nu 3447, 3224, 1681, 1649, 1582, 1460, 1383, 1275, 1224, 1170cm-1；1H NMR(400MHz，DMSO-d6)：δ＝0.86(s，3H)，1.02(s，3H)，2.11(d，J＝16.2Hz，1H)，2.28～2.48(m，2H)，2.61(d，J＝17.6Hz，1H)，5.00(s，1H)，7.06～7.10(m，2H)，7.27(d，J＝8.2Hz，2H)，7.39(d，J＝6.6Hz，1H)，7.46(d，J＝8.2Hz，1H)，7.66(s，1H)，8.01(s，2H)，11.82(s，1H)。
Example 7
A50 ml three-necked flask containing 6ml of an aqueous isopropanol solution (the volume of isopropanol accounts for 88% of the total volume of the aqueous isopropanol solution) and equipped with a spherical condenser, a thermometer and a magnetic stirrer was charged with 1.0mmol of 2, 3-dichlorobenzaldehyde, 1.0mmol of 2-cyanomethylbenzimidazole and 1.1mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.05mmol of an alkaline ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 37min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow solid is separated out, the solid is crushed, the reaction liquid is kept stand for 18H, vacuum filtration is carried out, filter residue is washed by isopropanol water solution washing liquid (the volume of isopropanol accounts for 88 percent of the total volume of the isopropanol water solution) (5ml multiplied by 4), vacuum drying is carried out at 85 ℃ for 24H, then 0.40g of 2-amino-3- (1H-benzo [ d ] imidazole) -4- (2, 3-dichlorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one is obtained, the purity is 98.8 percent through high performance liquid chromatography, and the yield is 87 percent through calculation. After 6ml of the filtrate is filled with the washing liquid, 2, 3-dichlorobenzaldehyde, 2-cyanomethylbenzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added, and the next circulation reaction is carried out according to the reaction conditions and the operation steps.
The product obtained in this example, 2-amino-3- (1H-benzo [ d ] imidazole) -4- (2, 3-dichlorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one, was characterized as follows:
a yellow solid; m.p.242 to 244; IR (KBr): nu 3453, 3334, 1691, 1639, 1528, 1454, 1431, 1383, 1282, 1258cm-1；1H NMR(400MHz，DMSO-d6)：δ＝0.93(s，3H)，1.05(s，3H)，2.14(d，J＝16.0Hz，1H)，2.36(d，J＝15.8Hz，1H)，2.51(d，J＝17.8Hz，1H)，2.67(d，J＝17.4Hz，1H)，5.38(s，1H)，7.03～7.09(m，2H)，7.28～7.45(m，4H)，7.87(s，2H)，7.91(d，J＝8.4Hz，1H)，11.50(s，1H)。
Example 8
A50 ml three-necked flask containing 6ml of an aqueous isopropanol solution (the volume of isopropanol accounts for 88% of the total volume of the aqueous isopropanol solution) and equipped with a spherical condenser, a thermometer and a magnetic stirrer was charged with 1.0mmol of 2, 4-dichlorobenzaldehyde, 1.0mmol of 2-cyanomethylbenzimidazole and 1.1mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.05mmol of an alkaline ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the refluxes for 41min, detecting by TLC (thin-plate chromatography), and ending the reaction when the raw material point disappears. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow solid is separated out, the solid is crushed, the reaction liquid is kept stand for 18H, vacuum filtration is carried out, filter residue is washed by isopropanol water solution washing liquid (the volume of isopropanol accounts for 88 percent of the total volume of the isopropanol water solution) (5ml multiplied by 3), vacuum drying is carried out at 85 ℃ for 24H, then 0.39g of 2-amino-3- (1H-benzo [ d ] imidazole) -4- (2, 4-dichlorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one is obtained, the purity is 98.3 percent through high performance liquid chromatography, and the yield is 84 percent through calculation. After 6ml of the filtrate is filled with the washing liquid, 2, 4-dichlorobenzaldehyde, 2-cyanomethylbenzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added, and the next circulation reaction is carried out according to the reaction conditions and the operation steps.
The product obtained in this example, 2-amino-3- (1H-benzo [ d ] imidazole) -4- (2, 4-dichlorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one, was characterized as follows:
a yellow solid; m.p.219-221; IR (KBr): nu 3429, 3318, 1678, 1635, 1554, 1542, 1524, 1461, 1450, 1402, 1269cm-1；1H NMR(400MHz，DMSO-d6)：δ＝0.97(s，3H)，1.08(s，3H)，2.12(d，J＝16.4Hz，1H)，2.34～2.54(m，2H)，2.71(d，J＝17.8Hz，1H)，5.29(s，1H)，7.07～7.12(m，2H)，7.35～7.39(m，3H)，7.43(d，J＝6.4Hz，1H)，7.86(s，2H)，7.98(d，J＝6.8Hz，1H)，11.57(s，1H)。
Comparative example 1
A50 ml three-necked flask containing 6ml of isopropyl alcohol and equipped with a spherical condenser, a thermometer and a magnetic stirrer was charged with 1.0mmol of 2, 4-dichlorobenzaldehyde, 1.0mmol of 2-cyanomethylbenzimidazole and 1.1mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed well, and then 0.05mmol of an alkaline ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser), maintaining the reflux for 41min, and detecting by TLC (thin-plate chromatography) until the raw material point does not completely disappear. And (3) stopping heating and stirring, naturally cooling the reaction liquid to room temperature, not precipitating any solid, carrying out rotary evaporation on isopropanol to obtain a small amount of solid, and measuring the purity of the product 2-amino-3- (1H-benzo [ d ] imidazole) -4- (2, 4-dichlorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one in the solid by using high performance liquid chromatography to be 54.3% and calculating the yield to be 67%.
Comparative example 2
A50 ml three-necked flask containing 6ml of distilled water and equipped with a bulb condenser, a thermometer and a magnetic stirrer was charged with 1.0mmol of 2, 4-dichlorobenzaldehyde, 1.0mmol of 2-cyanomethylbenzimidazole and 1.1mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature to form a suspension, and then 0.05mmol of an alkaline ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping refluxing for 41min, closing heating and stirring, naturally cooling the reaction liquid to room temperature, carrying out a large amount of solid, grinding the solid, standing for 18H, carrying out vacuum filtration, washing filter residues with distilled water (5ml multiplied by 3), and carrying out vacuum drying at 85 ℃ to obtain a light yellow solid, wherein the purity of a product 2-amino-3- (1H-benzo [ d ] imidazole) -4- (2, 4-dichlorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one in the solid is 11.7% by high performance liquid chromatography, and the calculated yield is 8%.
The results of examining the effect of the number of times of using the catalyst system composed of aqueous isopropanol and basic ionic liquid on the purity and yield of the product 2-amino-3- (1H-benzo [ d ] imidazole) -4- (4-fluorophenyl) -7, 7-dimethyl-7, 8-dihydro-4H-benzopyran-5-one by the methods of example 1 and example 7 are shown in fig. 1 and fig. 2, respectively. As can be seen from fig. 1 and 2, as the number of times of use of the catalyst system increases, both the yield and purity of the product decrease, but the decrease is small, and considering the decrease of the yield and purity of the product, the economic efficiency is the highest when the number of times of recycle of the catalyst system is 4.
As can be seen from the data of fig. 1-2 and comparative examples 1-2, when the aqueous isopropanol solution is used as the reaction solvent, and the volume of isopropanol in the aqueous isopropanol solution is optimally designed to be the percentage of the total volume of the aqueous isopropanol solution (ranging from 84% to 91%), the purity and yield of the obtained product can be effectively ensured.
Claims (7)
1. A method for catalytically synthesizing a drug intermediate 3-benzo [ d ] imidazole benzopyrone derivative is characterized by comprising the following steps: the method takes substituted benzaldehyde, 2-cyanomethyl benzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione as reaction raw materials to react under the catalysis of an alkaline ionic liquid catalyst to prepare the 3-benzo [ d ] imidazole benzopyrone derivative; the structural formula of the basic ionic liquid catalyst is as follows:
the preparation reaction takes isopropanol water solution as a reaction solvent.
2. The method for the catalytic synthesis of 3-benzo [ d ] imidazolone derivatives as pharmaceutical intermediates of claim 1, wherein: the volume of the isopropanol in the isopropanol aqueous solution accounts for 84-91% of the total volume of the isopropanol aqueous solution.
3. The method for the catalytic synthesis of 3-benzo [ d ] imidazolone derivatives as pharmaceutical intermediates of claim 1, wherein: the volume of the isopropanol aqueous solution in milliliters is 4-7 times of the amount of the substituted benzaldehyde substance in millimoles.
4. A process for the catalytic synthesis of a pharmaceutical intermediate, 3-benzo [ d ] imidazolone derivative, according to any one of claims 1-3, characterized in that: the amount of the added basic ionic liquid catalyst is 4-6% of the amount of the substituted benzaldehyde substance.
5. The method for the catalytic synthesis of a pharmaceutical intermediate, 3-benzo [ d ] imidazolone derivative, according to any one of claims 1-3, comprising in particular the steps of:
step 1: firstly, adding an isopropanol aqueous solution into a reaction vessel, then adding substituted benzaldehyde, 2-cyanomethyl benzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione, stirring at room temperature, uniformly mixing, and finally adding an alkaline ionic liquid catalyst;
step 2: heating to reflux the solvent, keeping the temperature until the reaction is finished, and turning off the stirring;
and step 3: cooling the reaction liquid to room temperature, grinding the precipitated solid, standing, and performing suction filtration to obtain filter residue;
and 4, step 4: washing the filter residue with an isopropanol aqueous solution washing solution, and drying in vacuum to obtain a 3-benzo [ d ] imidazole benzopyrone derivative;
and 5: supplementing a washing solution to the filtrate after suction filtration, then adding reaction raw materials to replace benzaldehyde, 2-cyanomethyl benzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione, and carrying out the next round of circulating reaction according to the steps 1 to 4;
the reaction vessel is a three-mouth flask with a magnetic stirring bar, a thermometer and a spherical condenser pipe; the mass ratio of the substituted benzaldehyde, 2-cyanomethyl benzimidazole and 5, 5-dimethyl-1, 3-cyclohexanedione is 1: 1: (1.0-1.3);
the substituted benzaldehyde is selected from any one of p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-methoxybenzaldehyde, m-nitrobenzaldehyde, 2, 3-dichlorobenzaldehyde, 2, 4-dichlorobenzaldehyde and 3, 4-dichlorobenzaldehyde.
6. The method for the catalytic synthesis of 3-benzo [ d ] imidazolone derivatives as pharmaceutical intermediates of claim 5, wherein: in the step 2, heating in an oil bath mode and uniformly heating until the solvent flows back, wherein the solvent vapor is kept not to exceed a second ball of the spherical condenser pipe in the reflux process; the reflux reaction time is 26-48 min.
7. The method for the catalytic synthesis of 3-benzo [ d ] imidazolone derivatives as pharmaceutical intermediates of claim 5, wherein: in the step 4, the isopropanol aqueous solution washing solution adopts the isopropanol aqueous solution with the same concentration in the step 1; washing for 3-4 times, vacuum drying at 85-88 ℃, and vacuum drying for 22-24 hours; the number of times of the cyclic reaction in the step 5 is 1-4.
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