Preparation method of drug intermediate benzimidazole quinazolinone derivative

Abstract

The invention belongs to the technical field of preparation of drug intermediates, and particularly relates to a preparation method of a drug intermediate benzimidazole quinazolinone derivative. Aromatic aldehyde, 5, 5-dimethyl-1, 3-cyclohexanedione and 2-aminobenzimidazole are used as reaction raw materials, the acidic eutectic solvent composed of betaine and lactic acid is selected as the catalyst, the catalytic activity of the catalyst is high, and therefore the yield of the benzimidazoquinazolinone derivative is increased within a short time; the catalyst has high reaction selectivity and few side reactions and byproducts, so that the purity of the crude product is high, complex operations such as recrystallization or column chromatography are not needed, and the method is environment-friendly and efficient; the catalyst can be recycled without any treatment, and the yield and the purity of the product obtained in the recycling process are reduced slightly; and the catalyst which is recycled for multiple times can be regenerated in a simple washing manner, so that industrial continuous production is facilitated.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical intermediates, and particularly relates to a preparation method of a pharmaceutical intermediate, a benzimidazole quinazolinone derivative. BACKGROUND

[0002] Heterocyclic compounds are ubiquitous in nature and widely distributed, and the number of which accounts for about half of the known organic compounds. Many important substances and some natural and synthetic drugs with significant therapeutic effect for clinical application contain the structure of heterocyclic compounds. As a kind of nitrogen-containing heterocyclic compounds, quinazolinone compounds have good biological activity and pharmacological activity, and show excellent activity in terms of sterilization, anti-inflammatory, pain relief, fungicidal, anti-convulsion, anti-hypertension, anti-cancer and the like, and have been a research hotspot for pharmacologists. In addition, the benzimidazole structure is an important pharmacophore, and derivatives containing such structure have good biological activity and reactivity, and have a wide range of applications in terms of antibacterial, anticancer, anti-diabetes, anti-ulcer and the like. Therefore, benzimidazoloquinazolinone derivatives having both benzimidazole and quinazolinone structures have more extensive applications in the preparation of drugs.

[0003] Up to now, the preparation of benzimidazoloquinazolinone derivatives often adopts a multi-step synthesis method, which brings about problems such as low product yield, complex preparation process, and serious environmental pollution. In order to solve these problems, a three-component one-pot method for preparing benzimidazoloquinazolinone derivatives from aldehyde, 1,3-cyclohexanedione derivative and 2-aminobenzimidazole has appeared in the laboratory. For example, in 2008, M. M. Heravi et al. used heteropolyacid H6P2W 18 O 62 as a catalyst, and aromatic aldehyde, 5,5-dimethyl-1,3-cyclohexanedione and 2-aminobenzimidazole were reacted in a boiling acetonitrile solution to obtain a series of benzimidazoloquinazolinone derivatives; in 2010, Liu Chenjiang et al. prepared benzimidazoloquinazolinone derivatives under ultrasonic irradiation from aromatic aldehyde, 1,3-cyclohexanedione and 2-aminobenzimidazole in ionic liquid [bmim]Br medium; in 2013, R. G. Puligoundla et al. prepared benzimidazoloquinazolinone derivatives from aromatic aldehyde, 1,3-cyclohexanedione and 2-aminobenzimidazole in the presence of catalyst H6P2W 18 O 62• 18H2O was replaced by molecular iodine. In the same year, G. Krishnamurthy et al. realized the preparation of benzimidazoquinazolinone derivatives under microwave assistance and silica gel promotion; in 2014, M. R. Mousavi et al. prepared benzimidazoquinazolinone derivatives from aromatic aldehyde, 5,5-dimethyl-1,3-cyclohexanedione and 2-aminobenzimidazole in acetonitrile solution under the condition of heating with p-toluenesulfonic acid as catalyst. However, the above methods still have the following shortcomings if they are large-scale industrialized production: 1. Considering that the catalyst cannot be recycled or regenerated, the production cost is high; 2. The product needs to be set up a separate purification process, and the process is relatively complex; 3. It is not easy to realize continuous production; 4. The environmental pollution is more serious.

[0004] Deep eutectic solvent refers to a combination of a certain molar ratio of hydrogen bond donor and hydrogen bond acceptor, the melting point is much lower than that of each component, and it is in liquid state at room temperature. The hydrogen bond donor mainly includes alcohol, acid, amine and other compounds, such as urea, p-toluenesulfonic acid, etc., and the hydrogen bond acceptor is generally a quaternary ammonium salt, among which the most common one is choline chloride. The diversity combination of hydrogen bond donor and hydrogen bond acceptor can design deep eutectic solvents with different structures and properties. Because deep eutectic solvents have the advantages of simple preparation process, low cost, biodegradability, non-toxicity and non-volatility, they can be applied in many fields, such as extraction, separation, catalysis, etc.

[0005] Therefore, the inventors expect to design a preparation method for catalytically preparing benzimidazoquinazolinone derivatives by using acidic deep eutectic solvent as catalyst and reaction solvent, and aromatic aldehyde, 5,5-dimethyl-1,3-cyclohexanedione and 2-aminobenzimidazole as raw materials, so as to make the catalyst realize recycling and regeneration, thereby achieving the purpose of efficiently, economically, environmentally and continuously preparing pharmaceutical intermediates benzimidazoquinazolinone derivatives, and the application has very wide market potential and application prospect. SUMMARY

[0006] In view of the problems in the prior art, the purpose of the present application is to overcome the deficiencies in the existing preparation process of benzimidazoquinazolinone derivatives, and a new preparation method of pharmaceutical intermediates benzimidazoquinazolinone derivatives is provided. By selecting a specific acidic deep eutectic solvent as catalyst and reaction solvent, the three-component one-pot reaction of aromatic aldehyde, 5,5-dimethyl-1,3-cyclohexanedione and 2-aminobenzimidazole is catalyzed to prepare benzimidazoquinazolinone derivatives under the condition of heating, so as to realize the recycling and regeneration of the catalytic system, and the purposes of short reaction time, high product yield, environmental protection and continuous large-scale production, etc.

[0007] In order to achieve the above technical purpose and achieve the above technical effect, the present application is realized by the following technical scheme:

[0008] The present application provides a preparation method of a pharmaceutical intermediate benzimidazole quinazolinone derivative, characterized in that the method comprises the following steps:

[0009] Under the conditions of heating and acidic eutectic solvent as catalyst and reaction solvent, the preset reaction raw materials are reacted as follows:

[0010]

[0011] The preset reaction raw materials are aromatic aldehyde, 5, 5-dimethyl-1, 3-cyclohexanedione and 2-amino benzimidazole.

[0012] Further, the acidic eutectic solvent is composed of betaine and lactic acid, and the molar ratio of betaine to lactic acid is 1:4.

[0013] Further, the molar ratio of the aromatic aldehyde, 5, 5-dimethyl-1, 3-cyclohexanedione and 2-amino benzimidazole is 1:1-1.2:1.

[0014] Further, the volume of the acidic eutectic solvent used is 5-8 times of the aromatic aldehyde in millimoles.

[0015] Further, the aromatic aldehyde is selected from any one of benzaldehyde, o-chlorobenzaldehyde, o-nitrobenzaldehyde, m-chlorobenzaldehyde, m-bromobenzaldehyde, m-nitrobenzaldehyde, m-hydroxybenzaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-nitrobenzaldehyde, p-hydroxybenzaldehyde, p-methoxybenzaldehyde, 2, 4-dichlorobenzaldehyde.

[0016] Further, the preset reaction raw materials need to be heated in the acidic eutectic solvent, then cooled and crystallized, filtered, washed and dried to obtain the benzimidazole quinazolinone derivative;

[0017] The heating reaction is to add the acidic eutectic solvent and the reaction raw materials into a reaction container in sequence, heat to 40-65℃ for reaction, and the reaction time is controlled to be 11-27 min;

[0018] The cooling and crystallization is to naturally cool to room temperature after the reaction is completed, and a large amount of crystals is precipitated;

[0019] The filtration is to crush the crystals precipitated after standing, stand for 2 h, and then perform filtration to obtain filter residue and filtrate;

[0020] The washing and drying is to wash the filter residue with acetone and vacuum dry to obtain the benzimidazole quinazolinone derivative.

[0021] Further, the filtrate after filtration mainly comprises the acidic eutectic solvent, a small amount of unreacted raw materials and generated by-products; the filtrate after filtration can be directly recycled without any treatment.

[0022] Further, the specific operation steps of recycling the filtrate are as follows: directly adding aromatic aldehyde, 5,5-dimethyl-1,3-cyclohexanedione and 2-aminobenzimidazole into the filtrate for the next round of reaction, and recycling for several times; in view of the requirement of purity of the drug intermediate and the economic consideration of production, when the high performance liquid chromatography purity of the product benzimidazoquinazolinone derivative is lower than 98% or the yield is reduced by more than 5% compared with the initial use of the acidic eutectic solvent, the recycling of the filtrate is stopped.

[0023] Further, the filtrate stopped from recycling can be subjected to regeneration treatment for removing unreacted raw materials and by-products, and the specific operation steps of the regeneration treatment are as follows: adding petroleum ether with a preset milliliter amount into the filtrate stopped from recycling, stirring magnetically for 10 min, then separating by a separatory funnel, then adding petroleum ether with the same milliliter amount into the lower liquid in the separatory funnel, stirring magnetically for 10 min, then separating by the separatory funnel, then adding petroleum ether with the same milliliter amount into the lower liquid in the separatory funnel, stirring magnetically for 10 min, then separating by the separatory funnel, and then adding petroleum ether with the same milliliter amount into the lower liquid in the separatory funnel, a total of 3 times, distilling the lower liquid in the separatory funnel obtained in the third time under reduced pressure at 75 DEG C until the weight is constant, and then vacuum drying at 85 DEG C for 12 h to obtain the regenerated acidic eutectic solvent.

[0024] The regenerated acidic eutectic solvent can be used again by making up the milliliter amount of the acidic eutectic solvent lost in the recycling and regeneration processes.

[0025] Further, the volume of the petroleum ether used is 1.5-2.0 times the volume of the acidic eutectic solvent used; and the boiling range of the petroleum ether is 60-90 DEG C.

[0026] The beneficial effects of the present application are as follows:

[0027] 1. The preparation method of the drug intermediate benzimidazoquinazolinone derivative of the present application uses aromatic aldehyde, 5,5-dimethyl-1,3-cyclohexanedione and 2-aminobenzimidazole as the reaction raw materials, and uses the acidic eutectic solvent composed of betaine and lactic acid as the catalyst, so that the catalytic activity of the catalyst is higher, thereby improving the yield of the benzimidazoquinazolinone derivative in a shorter time.

[0028] 2. The preparation method of the drug intermediate benzimidazoquinazolinone derivative of the present application has higher reaction selectivity of the catalyst, less side reactions and by-products, and higher purity of the crude product, so that complex operations such as recrystallization or column chromatography are not needed, and the method is environmentally friendly and efficient.

[0029] 3. The preparation method of the pharmaceutical intermediate benzimidazoquinazolinone derivative according to the present application has mild reaction conditions and less by-products, so that the catalyst can be recycled without any treatment, and the yield and purity of the product obtained during the recycling process decrease less.

[0030] 4. The preparation method of the pharmaceutical intermediate benzimidazoquinazolinone derivative according to the present application can regenerate the catalyst after recycling for several times by simple washing, which is convenient for industrial continuous production.

[0031] Of course, implementing any product of the present application does not necessarily need to achieve all the above advantages at the same time. BRIEF DESCRIPTION OF DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed for the embodiment description will be briefly introduced as follows. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor.

[0033] Figure 1 Preparation of 3,3-dimethyl-12-(2,4-dichlorophenyl)-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one for Example 11 1 H NMR;

[0034] Figure 2 Preparation of 3,3-dimethyl-12-(2,4-dichlorophenyl)-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one for Example 11 1 H NMR. DETAILED DESCRIPTION

[0035] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only some embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0036] The hydrogen nuclear magnetic resonance characterization of the reaction products of the benzimidazoloquinazolinone derivatives in the following examples was performed using an AVANCE II 500 MHz nuclear magnetic resonance instrument from Bruker, Germany; the high performance liquid chromatography purity was determined using a UFLC-2010PLUS fast high performance liquid chromatograph from Shimadzu, Japan; and the melting point was determined using an X-4 micro melting point analyzer from Gongyi Kerui Instrument Co., Ltd.

[0037] The acidic deep eutectic solvent catalyst used in this example was prepared according to the following literature:

[0038] Comprehensive evaluation of deep eutectic solvents in extraction of bioactive natural products[J],ACS Sustainable Chemistry Engineering,2016,4:2405~2411,other reagents or instruments used without indicating the manufacturer are conventional products that can be purchased from the market.

[0039] The present invention will be further described below with reference to specific embodiments.

[0040] Example 1

[0041] Preparation of 3,3-dimethyl-12-phenyl-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one

[0042]

[0043] Into a 50 mL four-necked flask with stirring bar, condenser and thermometer containing 7 mL acidic deep eutectic solvent, 1.0 mmol of benzaldehyde, 1.1 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 1.0 mmol of 2-aminobenzimidazole were added respectively, and the mixture was stirred magnetically at room temperature until homogeneous. The temperature was raised to 51 °C by heating uniformly with a silicone oil bath, and the timer was started at this temperature until the TLC (thin layer chromatography, V(ethyl acetate):V(n-hexane)=3:1) test showed the disappearance of the starting material, which took 22 min. The stirring and heating were stopped immediately, and the natural cooling to room temperature led to the precipitation of a large amount of white solid, which was crushed and left to stand for 2 h before being filtered under suction. The filter residue was washed with acetone (5 mL x 3) and dried under vacuum at a temperature of 75 °C for 5 h to give 0.31 g of white solid. The structure of the product was confirmed by 1H NMR and IR spectroscopy as 3,3-dimethyl-12-phenyl-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one. The purity of the product was determined by HPLC to be 99.2%, and the yield was calculated to be 90%.

[0044] The 3,3-dimethyl-12-phenyl-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one obtained in this example was a white solid; m.p. 361-363 °C; 1 1H NMR (500 MHz, DMSO-d6): δH= 10.18 (s, 1H), 7.37 (q, J=8.0 Hz, 3H), 7.33 (d, J=8.0 Hz, 3H), 7.24 (t, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.95 (t, J=8.0 Hz, 1H), 6.41 (s, 1H), 2.58 (d, J=16.0 Hz, 1H), 2.45 (d, J=16.0 Hz, 1H), 2.26 (d, J=16.0 Hz, 1H), 2.05 (d, J=16.0 Hz, 1H), 1.05 (s, 3H), 0.92 (s, 3H).

[0045] Example 2

[0046] Recycling of acidic deep eutectic solvent

[0047] To the filtrate produced in Example 1, 1.0 mmol of benzaldehyde, 1.1 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 1.0 mmol of 2-aminobenzimidazole were directly added, and the acid eutectic solvent was recycled according to the reaction conditions and operation steps of Example 1. The product 3,3-dimethyl-12-phenyl-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one was used for 6 times, and the changes of the yield and purity of the product are shown in Table 1:

[0048] Table 1

[0049]

[0050]

[0051] From the data in Table 1, it can be seen that with the increase of the number of times of using the acid eutectic solvent, the purity and yield of the product both show a decreasing trend, which may be related to the amount of by-products and the loss of the acid eutectic solvent during use. Considering the economic benefits and the purity requirements of drug intermediates, if the high performance liquid chromatography purity of the product 3,3-dimethyl-12-phenyl-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one is 98.5% or the yield reduction is limited to 5%, the acid eutectic solvent can be used for 5 times without any treatment.

[0052] Example 3

[0053] Regeneration of the acid eutectic solvent that cannot be recycled

[0054] To the acid eutectic solvent used for 6 times in Example 2, 12 mL of petroleum ether (boiling range 60-90°C) was added, and after magnetic stirring for 10 min, the liquid was separated by a separatory funnel. Then 12 mL of petroleum ether (boiling range 60-90°C) was added to the lower layer liquid in the separatory funnel, and after magnetic stirring for 10 min, the liquid was separated by a separatory funnel. Then 12 mL of petroleum ether (boiling range 60-90°C) was added to the lower layer liquid in the separatory funnel, and after magnetic stirring for 10 min, the liquid was separated by a separatory funnel. The lower layer liquid in the separatory funnel obtained in the third time was distilled to constant weight at 75°C under reduced pressure, and then vacuum dried at 85°C for 12 h to obtain the regenerated acid eutectic solvent, the volume of which was measured to be 6.6 mL, and the recovery rate was 94%.

[0055] Example 4

[0056] Use of the regenerated acid eutectic solvent

[0057] To the regenerated acidic deep eutectic solvent of Example 3, fresh prepared acidic deep eutectic solvent was added to make the volume reach 7 mL, then 1.0 mmol of benzaldehyde, 1.1 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 1.0 mmol of 2-aminobenzimidazole were added, then the reaction was carried out according to the reaction conditions and operation steps of Example 1, and finally 0.31 g of white solid was obtained. Nuclear magnetic resonance hydrogen spectrum and infrared spectrum structure analysis showed that it was 3,3-dimethyl-12-phenyl-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one; high performance liquid chromatography showed that the purity was 99.0%, and the yield was 88% by calculation.

[0058] Example 5

[0059] Cyclic use of regenerated acidic deep eutectic solvent

[0060] To the filtrate produced in Example 4, 1.0 mmol of benzaldehyde, 1.1 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 1.0 mmol of 2-aminobenzimidazole were directly added, and the cyclic use of regenerated acidic deep eutectic solvent was carried out according to the reaction conditions and operation steps of Example 1. The regenerated acidic deep eutectic solvent was used for a total of 4 times, and the yield and purity of the product 3,3-dimethyl-12-phenyl-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one were changed as shown in Table 2:

[0061] Table 2

[0062]

[0063] From the data in Table 2, it can be seen that with the increase of the number of times of using the regenerated acidic deep eutectic solvent, the purity and yield of the product still show a decreasing trend, which is also related to the accumulation of by-products and the loss of the acidic deep eutectic solvent in use. Considering the economic benefits and the purity requirements of drug intermediates, if the high performance liquid chromatography purity of the product 3,3-dimethyl-12-phenyl-1,2,3,4,5,12-hexahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one is 98.5% or the yield reduction is 5%, the regenerated acidic deep eutectic solvent can be used for 3 times without any treatment.

[0064] Example 6

[0065] Preparation of 12-(2-chlorophenyl)-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one

[0066]

[0067] Into a 50 mL four-necked flask with stir bar, condenser and thermometer containing 7 mL acidic deep eutectic solvent, 1.0 mmol of 2-chlorobenzaldehyde, 1.2 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 1.0 mmol of 2-aminobenzimidazole were added respectively, and the mixture was stirred magnetically at room temperature until homogeneous. The temperature was raised to 59 °C by heating uniformly with a silicone oil bath, and the timer was started at this temperature until the TLC (thin plate chromatography, V(ethyl acetate):V(n-hexane)=3:1) test showed that the starting material spot disappeared, which took 25 min. The stirring and heating were stopped immediately, and the natural cooling to room temperature resulted in the precipitation of a large amount of white solid, which was crushed and left to stand for 2 h before being suction filtered. The filter residue was washed with acetone (5 mL x 3) and dried under vacuum at a temperature of 75 °C for 5 h to obtain 0.33 g of white solid. The structure of 12-(2-chlorophenyl)-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one was analyzed by nuclear magnetic resonance hydrogen spectrum and infrared spectrum, and its purity was determined by high performance liquid chromatography to be 99.4%, and the yield was calculated to be 87%.

[0068] The 12-(2-chlorophenyl)-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one obtained in this example was a white solid; m.p. 367-369 °C; 1 H NMR (500 MHz, DMSO-d6): δ H = 11.15 (s, 1H), 6.90-7.50 (m, 8H), 6.66 (s, 1H), 2.53-2.64 (m, 2H), 2.23 (d, J = 16.6 Hz, 1H), 2.03 (d, J = 16.2 Hz, 1H), 1.06 (s, 3H), 0.96 (s, 3H).

[0069] Example 7

[0070] Preparation of 12-(4-chlorophenyl)-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one

[0071]

[0072] To a 50 mL four-necked flask equipped with a stirrer, condenser, and thermometer, 6 mL of an acidic deep eutectic solvent was added 1.0 mmol of p-chlorobenzaldehyde, 1.0 mmol of 5,5-dimethyl-1,3-cyclohexanedione, and 1.0 mmol of 2-aminobenzimidazole. Mix thoroughly at room temperature with magnetic stirring. Heat uniformly in a methyl silicone oil bath to 45°C, maintaining this temperature and counting until the starting material spot disappears as determined by TLC (thin plate chromatography, V (ethyl acetate): V (n-hexane) = 3:1), which takes 18 minutes. Stirring and heating were immediately discontinued, and the mixture was allowed to cool naturally to room temperature. A large amount of white solid precipitated, which was crushed, allowed to stand for 2 hours, and then filtered. The residue was washed with acetone (5 mL x 3) and dried under vacuum at 75°C for 5 hours to yield 0.35 g of a white solid. The structural analysis of H NMR and IR spectroscopy showed that the compound was 12-(4-chlorophenyl)-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one. The purity was determined to be 99.4% by HPLC, and the yield was calculated to be 92%.

[0073] 12-(4-chlorophenyl)-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one obtained in this example: white solid; mp 384~386℃; 1 H NMR (500 MHz, DMSO-d6): δ H =11.12 (s, 1H), 6.97~7.41 (m, 8H), 6.46 (s, 1H), 2.56~2.68 (m, 2H), 2.24 (d, J=16.1Hz, 1H), 2.05 (d, J=16.3Hz, 1H), 1.08 (s, 3H), 0.94 (s, 3H).

[0074] Example 8

[0075] Preparation of 3,3-dimethyl-12-(4-nitrophenyl)-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one

[0076]

[0077] Into a 50 mL four-necked flask with stir bar, condenser and thermometer containing 5 mL acidic deep eutectic solvent, 1.0 mmol of 4-nitrobenzaldehyde, 1.0 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 1.0 mmol of 2-aminobenzimidazole were added respectively, and the mixture was stirred magnetically at room temperature until homogeneous. The temperature was raised to 40 °C by heating uniformly with a silicone oil bath, and the timer was started at this temperature until the TLC (thin plate chromatography, V(ethyl acetate):V(n-hexane) = 3:1) test showed that the starting material spot had disappeared, which took 11 min. The stirring and heating were stopped immediately, and the natural cooling to room temperature resulted in the precipitation of a large amount of white solid. After crushing and standing for 2 h, the product was filtered off, and the residue was washed with acetone (5 mL x 3) and dried under vacuum at 75 °C for 5 h to obtain 0.38 g of white solid. The structure of 3,3-dimethyl-12-(4-nitrophenyl)-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one was analyzed by 1H nuclear magnetic resonance spectroscopy and infrared spectroscopy. The purity of the product was 99.1% as determined by high-performance liquid chromatography, and the yield was 96% as calculated.

[0078] The 3,3-dimethyl-12-(4-nitrophenyl)-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one obtained in this example was a white solid with a melting point of 360-362 °C. 1 H NMR (500 MHz, DMSO-d6): δ H = 11.29 (s, 1H), 6.94-8.12 (m, 8H), 6.59 (s, 1H), 2.53-2.66 (m, 2H), 2.26 (d, J = 16.2 Hz, 1H), 2.06 (d, J = 16.3 Hz, 1H), 1.06 (s, 3H), 0.91 (s, 3H).

[0079] Example 9

[0080] Preparation of 12-(4-hydroxyphenyl)-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one

[0081]

[0082] Into a 50 mL four-necked flask with stirring bar, condenser and thermometer containing 8 mL acidic deep eutectic solvent, 1.0 mmol of 4-hydroxybenzaldehyde, 1.2 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 1.0 mmol of 2-aminobenzimidazole were added respectively, and the mixture was stirred magnetically at room temperature until homogeneous. The temperature was raised to 65 °C by heating uniformly with a silicone oil bath, and the timer was started at this temperature until the disappearance of the starting material point was detected by TLC (thin plate chromatography, V(ethyl acetate):V(n-hexane) = 3:1), which took 27 min. The stirring and heating were stopped immediately, and the natural cooling to room temperature resulted in the precipitation of a large amount of white solid, which was crushed and left to stand for 2 h before being filtered under suction. The filter residue was washed with acetone (5 mL x 3) and dried under vacuum at a temperature of 75 °C for 5 h to give 0.33 g of white solid. Nuclear magnetic resonance hydrogen spectrum and infrared spectrum structure analysis showed that it was 12-(4-hydroxyphenyl)-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one; high performance liquid chromatography showed that its purity was 99.5%, and the yield was 90% by calculation.

[0083] The 12-(4-hydroxyphenyl)-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one obtained in this example was a white solid; m.p. 312-314 °C; 1 H NMR (500 MHz, DMSO-d6): δ H = 11.04 (s, 1H), 9.38 (s, 1H), 6.60-7.36 (m, 8H), 6.28 (s, 1H), 2.50-2.73 (m, 2H), 2.24 (d, J = 16.1 Hz, 1H), 2.05 (d, J = 16.1 Hz, 1H), 1.05 (s, 3H), 0.94 (s, 3H).

[0084] Example 10

[0085] Preparation of 12-(4-methoxyphenyl)-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one

[0086]

[0087] Into a 50 mL four-necked flask with stirring bar, condenser and thermometer containing 8 mL acidic deep eutectic solvent, 1.0 mmol of 4-methoxybenzaldehyde, 1.2 mmol of 5,5-dimethyl-1,3-cyclohexanedione and 1.0 mmol of 2-aminobenzimidazole were added respectively, and the mixture was stirred magnetically at room temperature until homogeneous. The temperature was raised to 63 °C by heating uniformly with a silicone oil bath, and the timer was started at this temperature until the disappearance of the starting material point was detected by TLC (thin plate chromatography, V(ethyl acetate):V(n-hexane)=3:1), which took 22 min. The stirring and heating were stopped immediately, and the natural cooling to room temperature resulted in the precipitation of a large amount of white solid, which was crushed and left to stand for 2 h before being filtered under suction. The filter residue was washed with acetone (5 mL x 3) and dried under vacuum at a temperature of 75 °C for 5 h to give 0.34 g of white solid. The structure of the product was confirmed by 1H nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy as 12-(4-methoxyphenyl)-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one. The purity of the product was determined by high-performance liquid chromatography (HPLC) to be 99.2%, and the yield was calculated to be 91%.

[0088] The 12-(4-methoxyphenyl)-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one obtained in this example was a white solid; m.p. 373-375 °C; 1 H NMR (500 MHz, DMSO-d6): δ H = 11.02 (s, 1H), 6.79-7.33 (m, 8H), 6.34 (s, 1H), 3.63 (s, 3H), 2.51-2.62 (m, 2H), 2.24 (d, J = 16.1 Hz, 1H), 2.02 (d, J = 16.1 Hz, 1H), 1.02 (s, 3H), 0.91 (s, 3H).

[0089] Example 11

[0090] Preparation of 3,3-dimethyl-12-(2,4-dichlorophenyl)-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one

[0091]

[0092] Into a 50 mL four-necked flask with stirring bar, condenser and thermometer, containing 8 mL acidic deep eutectic solvent, 1.0 mmol 2,4-dichlorobenzaldehyde, 1.2 mmol 5,5-dimethyl-1,3-cyclohexanedione and 1.0 mmol 2-aminobenzimidazole were added respectively, and the mixture was stirred magnetically at room temperature. The temperature was raised to 63 °C by heating with a silicone oil bath, and the temperature was kept constant. The time was recorded when the starting material disappeared by TLC (thin plate layer chromatography, V(acetic ether):V(n-hexane)=3:1), which took 24 min. The stirring and heating were stopped immediately, and the mixture was allowed to cool to room temperature. A large amount of white solid was precipitated, which was crushed and allowed to stand for 2 h before being filtered. The residue was washed with acetone (5 mL x 3) and dried at 75 °C under vacuum for 5 h to give 0.39 g of white solid. The structure of the product was confirmed by 1H NMR and IR spectroscopy. The purity of the product was 99.1% by HPLC, and the yield was 93% by calculation.

[0093] The 3,3-dimethyl-12-(2,4-dichlorophenyl)-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one obtained in this example was a white solid with a melting point of 314-316 °C. 1H NMR (500 MHz, DMSO-d6): δH= 11.25 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.08-7.12 (m, 1H), 7.03 (s, 1H), 6.96 (t, J=8.0 Hz, 1H), 6.65 (s, 1H), 2.33 (d, J=16.0 Hz, 1H), 2.29 (d, J=12.0 Hz, 1H), 2.24 (d, J=16.0 Hz, 1H), 2.04 (d, J=16.0 Hz, 1H), 1.06 (s, 3H), 0.95 (s, 3H).

[0094] The preferred embodiments of the present application disclosed above are only used to illustrate the present application. The preferred embodiments do not describe all the details and limit the present application to the specific embodiments. Obviously, many modifications and variations can be made according to the content of the present specification. The present specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present application, so that those skilled in the art can well understand and utilize the present application. The present application is limited only by the claims and their full scope and equivalents.

Claims

1. A method for preparing a pharmaceutical intermediate benzimidazole quinazolinone derivative, characterized in that: The method comprises the following steps: Under the conditions of heating and an acidic deep eutectic solvent as a catalyst and reaction solvent, the preset reaction raw materials are subjected to the following reaction: The preset reaction raw materials are aromatic aldehyde, 5,5-dimethyl-1,3-cyclohexanedione and 2-aminobenzimidazole.

2. The preparation method according to claim 1, characterized in that The acidic deep eutectic solvent consists of betaine and lactic acid, wherein the molar ratio of betaine to lactic acid is 1:

4.

3. The preparation method according to claim 1, characterized in that The molar ratio of the aromatic aldehyde, 5,5-dimethyl-1,3-cyclohexanedione and 2-aminobenzimidazole is 1:1 to 1.2:

1.

4. The preparation method according to claim 1, characterized in that The volume of the acidic deep eutectic solvent used in milliliters is 5 to 8 times the amount of the aromatic aldehyde in millimoles.

5. The preparation method according to claim 1, characterized in that The aromatic aldehyde is selected from any one of benzaldehyde, o-chlorobenzaldehyde, o-nitrobenzaldehyde, m-chlorobenzaldehyde, m-bromobenzaldehyde, m-nitrobenzaldehyde, m-hydroxybenzaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-nitrobenzaldehyde, p-hydroxybenzaldehyde, p-methoxybenzaldehyde and 2,4-dichlorobenzaldehyde.

6. The preparation method according to claim 1, characterized in that The preset reaction raw materials need to be heated in an acidic deep eutectic solvent, then cooled and crystallized, filtered, washed, and dried before the benzimidazole-quinazolinone derivatives can be obtained. The heating reaction is to add the acidic deep eutectic solvent and the reaction raw materials into the reaction container in sequence, heat to 40-65°C for reaction, and control the reaction time to be 11-27 minutes; The cooling crystallization is to naturally cool the reaction to room temperature after completion to precipitate a large amount of crystals; The suction filtration is to crush the crystals precipitated after standing, stand for 2 hours and then filter to obtain filter residue and filtrate; The washing and drying process is to wash the filter residue with acetone and vacuum dry it to obtain the benzimidazole quinazolinone derivative.

7. The preparation method according to claim 6, characterized in that The filtrate after filtration mainly includes the acidic low eutectic solvent, a very small amount of unreacted raw materials and generated by-products; the filtrate after filtration can be directly recycled without any treatment.

8. The preparation method according to claim 7, characterized in that The specific operation steps of recycling the filtrate are: directly adding aromatic aldehyde, 5,5-dimethyl-1,3-cyclohexanedione and 2-aminobenzimidazole to the filtrate for the next round of reaction, and recycling it several times; considering the purity requirements of the pharmaceutical intermediate and production economic considerations, when the high performance liquid chromatography purity of the product benzimidazole quinazolinone derivative is lower than 98% or the yield is reduced by more than 5% compared with the initial use of the acidic deep eutectic solvent, the filtrate recycling is stopped.

9. The preparation method according to claim 8, characterized in that The filtrate that has stopped recycling can be regenerated to remove unreacted raw materials and by-products. The specific steps of the regeneration treatment are: adding a preset milliliter of petroleum ether to the filtrate that has stopped recycling, magnetically stirring for 10 minutes, and then separating the liquid with a separatory funnel, and then adding the same milliliter of petroleum ether to the lower layer of the separatory funnel. After magnetic stirring for 10 minutes, separate the liquid with a separatory funnel, and then add the same milliliter of petroleum ether to the lower layer of the separatory funnel. This is performed three times in total, and the lower layer of the separatory funnel obtained in the third time is distilled under reduced pressure at 75°C to constant weight, and then vacuum dried at 85°C for 12 hours to obtain a regenerated acidic low eutectic solvent; The regenerated acidic deep eutectic solvent can be reused by making up for the milliliters of the acidic deep eutectic solvent lost during the circulation and regeneration process.

10. The preparation method according to claim 9, characterized in that The volume usage of the petroleum ether is 1.5 to 2.0 times that of the acidic deep eutectic solvent; and the boiling range of the petroleum ether is 60 to 90°C.

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