CN113999216B - Method for preparing medical intermediate 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative - Google Patents
Method for preparing medical intermediate 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative Download PDFInfo
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Abstract
The invention discloses a method for preparing a medical intermediate 3- (1H-indolyl-3-carbonyl) -2H-chromene-2-one derivative, belonging to the field of pharmaceutical chemicals. The invention relates to 3-cyanoacetylindole derivatives and salicylaldehyde derivativesThe 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative is prepared by using the following catalyst as a reaction raw material:
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of a pharmaceutical intermediate 3- (1H-indolyl-3-carbonyl) -2H-chromene-2-one derivative.
Background
The chromene-2-ketone derivative is an important heterocyclic compound which is widely existed in nature, has obvious biological activities of resisting coagulation, resisting cancer, resisting HIV and the like, and has wide application in the field of medicine. In recent years, in order to further improve the application range and value of chromen-2-one derivatives, various structural modifications have been made. In addition, the compounds containing indole rings also have biological or medicinal values and have very important functions in the aspects of antibiosis, anticancer, antitumor and the like. Therefore, the 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivatives containing both indole ring and chromen-2-one structure have wider application, and the preparation thereof draws wide attention of drug synthesizers.
The preparation of the 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative usually adopts a multi-step method, and the synthesis route is long and the reaction conditions are harsh, so that the product synthesis yield is low, the environmental pollution is serious, and the industrial large-scale production is difficult to realize. Based on this, the use of the one-step method not only greatly reduces the use amount of the reaction solvent and the complexity of the purification of the intermediate product, but also reduces the pollution degree to the environment in the production process, and has higher economical efficiency. However, few reports have been made up to this point on the one-step preparation of 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivatives. For example, khadharNavaz Umar Basha et al, use sodium carbonate as a catalyst to prepare a series of 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivatives by reacting a 3-cyanoacetylindole derivative with a salicylaldehyde derivative in an aqueous methanol solution (Synthesis, antioxidant, and antimicrobial activity of 3- (1H-indole-3-carbonyl) -2H-chromen-2-ones [ J ], journal of Heterocyclic Chemistry,2021, 58 to 2008.
However, the preparation method has many disadvantages in the industrial large-scale application process, for example, the catalyst and the reaction solvent cannot be recycled, and a large amount of waste liquid generated can pollute the environment; the catalyst system consisting of the catalyst and the reaction solvent cannot be recycled, so that the utilization rate of reaction raw materials is low, the atom economy is poor, and the production continuity of the whole preparation process is poor.
Disclosure of Invention
1. Problems to be solved
The invention aims to solve the problems of low yield and purity and easy environmental pollution of the existing preparation process of the 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative, and provides a method for preparing a medical intermediate 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative by one-step catalysis.
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 preparing a medical intermediate 3- (1H-indolyl-3-carbonyl) -2H-chromene-2-ketone derivative, which takes a 3-cyanoacetylindole derivative and a salicylaldehyde derivative as reaction raw materials to prepare the 3- (1H-indolyl-3-carbonyl) -2H-chromene-2-ketone derivative under the catalysis of the following catalyst:
aiming at the problems existing in the existing preparation process of the 3- (1H-indolyl-3-carbonyl) -2H-chromene-2-one derivative, the invention optimizes the type of the catalyst, and the catalyst is selected to be high in efficiency and selectivity for preparing the 3- (1H-indolyl-3-carbonyl) -2H-chromene-2-one derivative under catalysis, so that the reaction efficiency can be effectively improved, the generation of byproducts can be effectively inhibited, the yield and purity of the obtained 3- (1H-indolyl-3-carbonyl) -2H-chromene-2-one derivative are further ensured, and the reaction time is favorably shortened. The reaction equation of the present invention is as follows:
furthermore, the preparation method specifically comprises the following steps:
the method comprises the following steps: adding a pre-prepared mixed solvent into a reaction container, then adding a salicylaldehyde derivative, a 3-cyanoacetylindole derivative and a catalyst, and magnetically stirring at room temperature to form a reaction solution;
step two: uniformly heating the reaction solution to 40-57 ℃, keeping the temperature under magnetic stirring until the raw material point disappears, and then stopping stirring and heating;
step three: naturally cooling the reaction liquid in the step two to room temperature, grinding the precipitated solid, standing, and carrying out suction filtration;
step four: washing and vacuum drying the filter residue obtained by suction filtration to obtain a 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative;
step five: and adding reaction raw materials, namely salicylaldehyde derivatives and 3-cyanoacetylindole derivatives into the filtrate after suction filtration in proportion, and carrying out the next reaction according to the steps.
Further, the reaction is carried out with ethanol, [ Bmim ]]BF 4 And distilled water as a reaction solvent. By optimizing the composition and the dosage of the reaction solvent and the mass ratio of each component in the reaction solvent, the occurrence of side reactions can be further reduced, and the catalytic activity of the catalyst can be best exerted. Meanwhile, the mixed solvent not only serves as a reaction solvent, but also has the function of a recrystallization solvent, so that the purification process of the product is simpler. Specifically, ethanol, [ Bmim ] contained in the mixed solvent]BF 4 And distilled water in a volume ratio of 8: (1-2): 5, the volume amount of the mixed solvent in ml is 6 to 8 times the molar amount of the 3-cyanoacetylindole derivative in mmol.
Furthermore, the catalytic system of the invention can be reused without any treatment, so that the utilization rate of reaction raw materials is further improved, and the economic and environmental benefits are higher. Meanwhile, the method is favorable for realizing the industrial large-scale continuous production of the 3- (1H-indolyl-3-carbonyl) -2H-chromene-2-one derivative. In addition, the catalytic system consisting of the mixed solvent and the catalyst which is recycled for many times is subjected to reduced pressure distillation, and then the residual liquid is washed for 3 to 5 times by using petroleum ether (the boiling range is 60 to 90 ℃), so that the regeneration of the catalytic system can be realized.
Further, the ratio of the amount of the salicylaldehyde derivative to the amount of the 3-cyanoacetylindole derivative is (1 to 1.3): 1, the molar weight of the catalyst is 4-7% of the 3-cyanoacetylindole derivative.
Furthermore, in the fourth step, the vacuum drying temperature is 80 ℃, and the drying time is 6 hours; in the second step, the reaction time is 86-123 min.
Furthermore, the salicylaldehyde derivative is any one of salicylaldehyde, 3-ethoxy salicylaldehyde, 5-bromo salicylaldehyde and 3, 5-dichloro salicylaldehyde.
Further, the 3-cyanoacetylindole derivative is 3-cyanoacetylindole or 3-cyanoacetyl-2-methylindole.
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. The hydrogen nuclear magnetic resonance characterization of the reaction product in the following examples adopts a nuclear magnetic resonance instrument with the model of AVANCE 400MHz of Germany Bruker company; the Fourier infrared spectrum characterization adopts an infrared spectrometer of Nicolet 6700 model number of Nicolet corporation of Nigaku USA; the HPLC purity measurement is performed by using a HPLC of ESSENTIA LC-15C, manufactured by Shimadzu corporation of Japan; the melting point of the reaction product is determined by using an SGW X-4B micro melting point apparatus.
Example 1
Preparation of 6-bromo-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one:
to a solution containing 6mL of a mixed solvent (ethanol, [ Bmim ]]BF 4 And distilled water in a volume ratio of 8:1.5: 5) A50 mL single-neck flask with a spherical condenser tube and a magnetic stirrer is added with 1.1mmol of 5-bromosalicylaldehyde and 1.0mmol of 3-cyanoacetylindole, stirred at room temperature, mixed uniformly, and then added with 0.05mmol of catalyst. Heating in oil bath, uniformly heating to 49 deg.C, keeping the temperature, reacting for 104min, detecting by TLC (thin-plate chromatography), removing raw material spot, and finishing the reaction. Heating and stirring are stopped, the reaction liquid is cooled to room temperature, a large amount of yellow solid is separated out, the solid is crushed, the mixture is kept stand for 4 hours and filtered, filter residue is washed by methanol (5 mL multiplied by 3) and dried in vacuum at the temperature of 80 ℃ for 6 hours, and then 0.31g of 6-bromo-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one is obtained, and the reaction equation is as follows:
the purity of the resulting 6-bromo-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one was 98.9% as determined by high performance liquid chromatography, with a yield of 83% by calculation. And (3) directly adding 5-bromosalicylaldehyde and 3-cyanoacetylindole into the filtrate, and carrying out the next cycle reaction according to the reaction conditions and the operation steps.
The performance parameters of the 6-bromo-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one obtained in this example are as follows: a yellow solid; m.p.209-211 ℃; IR (KBr) v: 3264 3040, 1737, 1649, 1591, 1475, 1285, 1083, 954, 816, 772cm -1 ； 1 H NMR(400MHz，DMSO-d6)：δ＝6.92(t，J＝8.2Hz，1H)，7.13(m，3H)，7.42(m，3H)，8.01(m，2H)，12.22(s，1H)。
The catalyst system of this example was distilled under reduced pressure from the filtrate obtained after 5 times of use to remove ethanol and water, the remaining liquid was washed 3 times with 6mL of petroleum ether (boiling range 60-90 ℃), dried under vacuum at 85 ℃ for 2H, the distilled ethanol and water were added to the washed remaining liquid, 5-bromosalicylaldehyde and 3-cyanoacetylindole were added after mixing well, according to the reaction conditions of this example, 0.31g of 6-bromo-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one was finally obtained, the purity was 98.7% by HPLC, and the yield was 82% by calculation.
Example 2
Preparation of 6-bromo-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one:
to a solution containing 7mL of a mixed solvent (ethanol, [ Bmim ]]BF 4 And distilled water in a volume ratio of 8:1: 5) 1.0mmol of 5-bromosalicylaldehyde and 1.0mmol of 3-cyanoacetyl-2-methylindole are added into a 50mL single-neck flask with a spherical condenser tube and a magnetic stirrer, stirred at room temperature, mixed uniformly, and then added with 0.04mmol of alkaline ionic liquid catalyst. Heating in oil bath, uniformly heating to 40 ℃, carrying out heat preservation reaction for 86min, detecting by TLC (thin-plate chromatography), and finishing the reaction when the raw material point disappears. Turning off heating and stirring, cooling the reaction liquid to room temperature, precipitating a large amount of orange solid, grinding the solid, standing for 4H, performing suction filtration, washing filter residues by methanol (5 mL multiplied by 4), and drying the filter residues in vacuum at 80 ℃ for 6H to obtain 0.34g of 6-bromo-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one, wherein the reaction equation of the reaction is as follows:
the purity of the obtained 6-bromo-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one was 99.1% as determined by high performance liquid chromatography, and the yield was 89% by calculation. Directly adding 5-bromosalicylaldehyde and 3-cyanoacetyl-2-methylindole into the filtrate, and carrying out the next cycle reaction according to the reaction conditions and the operation steps.
The performance parameters of 6-bromo-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one obtained in this example are as follows: an orange solid; m.p.181-183 ℃; IR (KBr) v: 3313 3168, 1747, 1663, 1564, 1480, 1152, 1072, 940, 839, 778cm -1 ； 1 H NMR(400MHz，DMSO-d6)：δ＝2.47(s，3H)，6.96(d，J＝8.8Hz，1H)，7.15(m，3H)，7.44(m，2H)，7.70(s，1H)，8.08(m，1H)，12.15(s，1H)。
The catalyst system of this example was distilled under reduced pressure using 6 times the filtrate to remove ethanol and water, the remaining liquid was washed 5 times with 6mL of petroleum ether (boiling range 60-90 ℃), dried under vacuum at 85 ℃ for 2H, the distilled ethanol and water were added, after mixing well, 5-bromosalicylaldehyde and 3-cyanoacetyl-2-methylindole were added, according to the reaction conditions of this example, 0.34g of 6-bromo-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one was finally obtained, purity was 99.0% by HPLC, and yield was 87% by calculation.
Effect of catalytic system usage times on product purity and yield:
the influence of the use times of the catalyst system composed of the mixed solvent and the basic ionic liquid in example 1 and example 2 on the purity and yield of the product is examined, and the results are shown in tables 1 and 2 respectively.
TABLE 1 Effect of the number of uses of the catalytic System on the purity and yield of the product 6-bromo-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one
| Number of uses of the catalytic System | Purity/%) | Yield/% |
| 1 | 98.9 | 83 |
| 2 | 98.8 | 83 |
| 3 | 98.6 | 81 |
| 4 | 98.5 | 81 |
| 5 | 98.1 | 81 |
TABLE 2 Effect of the number of times of use of the catalytic System on the purity and yield of the product 6-bromo-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one
| Number of uses of the catalytic System | Purity/%) | Yield/% |
| 1 | 99.1 | 89 |
| 2 | 99.0 | 89 |
| 3 | 98.8 | 89 |
| 4 | 98.6 | 89 |
| 5 | 98.5 | 86 |
| 6 | 98.2 | 84 |
As can be seen from the data in the table: the catalytic system disclosed by the invention has the advantages that the catalytic preparation efficiency of the 3- (1H-indolyl-3-carbonyl) -2H-chromene-2-one is higher, the yield and the purity of the obtained product are higher, the recycling performance is better, and the stability of the yield and the purity of the obtained product can be ensured simultaneously in the recycling process.
Example 3
Preparation of 6, 8-dichloro-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one:
to a solution containing 8mL of a mixed solvent (ethanol, [ Bmim ]]BF 4 And distilled water in a volume ratio of 8:1.8: 5) A50 mL single-neck flask with a spherical condenser tube and a magnetic stirrer is added with 1.3mmol of 3, 5-dichlorosalicylaldehyde and 1.0mmol of 3-cyanoacetylindole, stirred at room temperature, mixed uniformly and then added with 0.06mmol of basic ionic liquid catalyst. Heating in oil bath, uniformly heating to 52 deg.C, holding temperature, reacting for 114min, detecting by TLC (thin plate chromatography), removing raw material spot, and finishing reaction. Heating and stirring are stopped, the reaction liquid is cooled to room temperature, a large amount of white solid is separated out, the solid is crushed, the mixture is kept stand for 4 hours and filtered, filter residues are washed by methanol (5 mL multiplied by 5), and vacuum drying is carried out at the temperature of 80 ℃ for 6 hours, so as to obtain 0.31g of 6, 8-dichloro-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-ketone, and the reaction equation of the reaction is as follows:
the purity of the obtained 6, 8-dichloro-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one was 99.3% as determined by high performance liquid chromatography, and the yield was 86% by calculation. 3, 5-dichlorosalicylaldehyde and 3-cyanoacetylindole are directly added into the filtrate, and the next cycle reaction is carried out according to the reaction conditions and the operation steps.
The performance parameters of 6, 8-dichloro-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one obtained in this example are as follows: a white solid; m.p.160-162 ℃; IR (KBr) v: 3279 3148, 1712, 1643, 1514, 1435, 1283, 1095, 972, 864, 786cm -1 ； 1 H NMR(400MHz，DMSO-d6)：δ＝7.23(m，2H)，7.49(m，1H)，7.70(m，2H)，8.21(m，2H)，8.50(d，J＝3.4Hz，1H)，12.23(s，1H)。
Example 4
Preparation of 6, 8-dichloro-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one:
to a solution containing 8mL of a mixed solvent (ethanol, [ Bmim ]]BF 4 And distilled water in a volume ratio of 8:2: 5) A50 mL single-neck flask with a spherical condenser and a magnetic stirrer was charged with 1.3mmol of 3, 5-dichlorosalicylaldehyde and 1.0mmol of 3-cyanoacetyl-2-methylindole, stirred at room temperature, mixed well, and then 0.07mmol of an alkaline ionic liquid catalyst was added. Heating in oil bath, uniformly heating to 57 ℃, carrying out heat preservation reaction for 123min, detecting by TLC (thin plate chromatography), and finishing the reaction when the raw material point disappears. Heating and stirring are turned off, the reaction liquid is cooled to room temperature, a large amount of white solid is separated out, the solid is crushed, the mixture is kept stand for 4 hours and filtered, filter residue is washed by methanol (5 mL multiplied by 5), vacuum drying is carried out at the temperature of 80 ℃ for 6 hours, and then 0.29g of 6, 8-dichloro-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one is obtained, and the reaction equation of the reaction is as follows:
the purity of the obtained 6, 8-dichloro-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one was 99.1% as determined by high performance liquid chromatography, and the yield was 78% by calculation. 3, 5-dichlorosalicylaldehyde and 3-cyanoacetyl-2-methylindole are directly added into the filtrate, and the next cycle reaction is carried out according to the reaction conditions and the operation steps.
The performance parameters of 6, 8-dichloro-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one obtained in this example are as follows: a white solid; m.p.224-226 ℃; IR (KBr) v: 3306 3127, 1735, 1612, 1586, 1484, 1096, 974, 869, 776cm -1 ； 1 H NMR(400MHz，DMSO-d6)：δ＝2.47(s，3H)，7.11(t，J＝8.4Hz，3H)，7.44(m，2H)，7.72(m，2H)，12.12(s，1H)。
Example 5
Preparation of 8-ethoxy-3- (1H-indole-3-carbonyl) -2H-chromen-2-one:
to a solution containing 8mL of a mixed solvent (ethanol, [ Bmim ]]BF 4 And distilled water in a volume ratio of 8:1.1: 5) 1.1mmol of 3-ethoxysalicylaldehyde and 1.0mmol of 3-cyanoacetylindole are added into a 50mL single-neck flask with a spherical condenser tube and a magnetic stirrer, stirred at room temperature, mixed uniformly, and then added with 0.05mmol of basic ionic liquid catalyst. Heating in oil bath, uniformly heating to 43 deg.C, holding temperature, reacting for 97min, detecting by TLC (thin plate chromatography), removing raw material spot, and finishing reaction. Heating and stirring are stopped, the reaction liquid is cooled to room temperature, a large amount of brown solid is separated out, the solid is crushed, the mixture is kept stand for 4 hours and filtered, filter residues are washed by methanol (5 mL multiplied by 5), and vacuum drying is carried out at the temperature of 80 ℃ for 6 hours, so as to obtain 0.30g of 8-ethoxy-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one, and the reaction equation of the reaction is as follows:
the purity of the resulting 8-ethoxy-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one, as determined by high performance liquid chromatography, was 99.2%, which was calculated to give a yield of 89%. 3-ethoxy salicylaldehyde and 3-cyanoacetyl indole are directly added into the filtrate, and the next cycle reaction is carried out according to the reaction conditions and the operation steps.
The performance parameters of the 8-ethoxy-3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one obtained in this example are as follows: a brown solid; m.p.240-242 ℃; IR (KBr) v: 3157 3106, 1725, 1653, 1519, 1457, 1284, 1115, 1098, 937, 889, 742cm -1 ； 1 H NMR(400MHz，DMSO-d6)：δ＝1.40(s，3H)，4.16(q，J＝5.0Hz，2H)，6.91(m，5H)，7.49(m，2H)，8.17(m，2H)，12.24(s，1H)。
Example 6
Preparation of 8-ethoxy-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one:
to a solution containing 8mL of a mixed solvent (ethanol, [ Bmim ]]BF 4 And distilled water in a volume ratio of 8:1: 5) 1.0mmol of 3-ethoxysalicylaldehyde and 1.0mmol of 3-cyanoacetyl-2-methylindole are added into a 50mL single-neck flask with a spherical condenser tube and a magnetic stirrer, stirred at room temperature, mixed uniformly, and then added with 0.04mmol of alkaline ionic liquid catalyst. Heating in oil bath, uniformly heating to 41 deg.C, holding temperature, reacting for 89min, detecting by TLC (thin plate chromatography), removing raw material spot, and finishing reaction. Turning off heating and stirring, cooling the reaction liquid to room temperature, precipitating a large amount of white solid, grinding the solid, standing for 4H, performing suction filtration, washing filter residues by methanol (5 mL multiplied by 5), and performing vacuum drying at 80 ℃ for 6H to obtain 0.32g of 8-ethoxy-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one, wherein the reaction equation of the reaction is as follows:
the purity of the obtained 8-ethoxy-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one was 99.4% as determined by high performance liquid chromatography, and the yield was 92% by calculation. 3-ethoxy salicylaldehyde and 3-cyanoacetyl-2-methylindole are directly added into the filtrate, and the next cycle reaction is carried out according to the reaction conditions and the operation steps.
The performance parameters of the 8-ethoxy-3- (2-methyl-1H-indolyl-3-carbonyl) -2H-chromen-2-one obtained in this example are as follows: a white solid; m.p.168-170 ℃; IR (KBr) v: 3274 3172, 1638, 1593, 1459, 1274, 1140, 1086, 942, 887, 744cm -1 ； 1 H NMR(400MHz，DMSO-d6)：δ＝1.43(s，3H)，2.48(s，3H)，4.22(s，2H)，6.93(s，3H)，7.09(s，2H)，7.74(m，2H)，8.24(m，1H)，12.07(s，1H)。
Claims (5)
1. A method for preparing a medical intermediate 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative is characterized in that the method takes a 3-cyanoacetylindole derivative and a salicylaldehyde derivative as reaction raw materials, and ethanol and [ Bmim ]]BF 4 And distilled water as a reaction solvent, under the catalysis of the following catalysts, preparing the 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative:
the salicylaldehyde derivative is any one of 3-ethoxysalicylaldehyde, 5-bromosalicylaldehyde and 3, 5-dichlorosalicylaldehyde, the 3-cyanoacetylindole derivative is 3-cyanoacetylindole or 3-cyanoacetyl-2-methylindole, and the method specifically comprises the following steps:
the method comprises the following steps: adding a pre-prepared mixed solvent into a reaction container, then adding a salicylaldehyde derivative, a 3-cyanoacetylindole derivative and a catalyst, and magnetically stirring at room temperature to form a reaction solution;
step two: uniformly heating the reaction solution to 40-57 ℃, keeping the temperature until the raw material point disappears under magnetic stirring, and then stopping stirring and heating, wherein the reaction time is 86-123 min;
step three: naturally cooling the reaction liquid in the step two to room temperature, grinding the precipitated solid, standing, and carrying out suction filtration;
step four: washing and vacuum drying filter residue obtained by suction filtration to obtain a 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative;
step five: and adding reaction raw materials, namely salicylaldehyde derivatives and 3-cyanoacetylindole derivatives into the filtrate after suction filtration in proportion, and carrying out the next reaction according to the steps.
2. The preparation method of 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative as a pharmaceutical intermediate according to claim 1A method of biology, characterized by: ethanol, [ Bmim ] contained in the mixed solvent]BF 4 And distilled water in a volume ratio of 8: (1-2): 5, the volume amount of the mixed solvent in ml is 6 to 8 times the molar amount of the 3-cyanoacetylindole derivative in mmol.
3. The method for preparing a pharmaceutical intermediate 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative according to claim 1, wherein: and (3) carrying out reduced pressure distillation on the catalyst system consisting of the mixed solvent and the catalyst after being recycled for many times, washing the residual liquid for 3-5 times by using petroleum ether, and then adding the distilled ethanol and distilled water into the washed residual liquid again to form a new catalyst system for reaction.
4. The method for preparing a pharmaceutical intermediate 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative according to claim 1, wherein: the ratio of the amounts of the salicylaldehyde derivative and the 3-cyanoacetylindole derivative is (1-1.3): 1, the molar weight of the catalyst is 4-7% of that of the 3-cyanoacetylindole derivative used.
5. The method for preparing a pharmaceutical intermediate 3- (1H-indolyl-3-carbonyl) -2H-chromen-2-one derivative according to claim 1, wherein: in the fourth step, the vacuum drying temperature is 80 ℃, and the drying time is 6 hours.
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