Preparation and synthesis method of amino-substituted nitrogen-containing heterocyclic ring

Abstract

The invention relates to a preparation and synthesis method of an amino-substituted nitrogen-containing heterocyclic ring, which is carried out by using an ice bath auxiliary device, and is characterized by comprising the following steps: adding p-aminobenzaldehyde into a toluene solution of aminoacetaldehyde dimethyl acetal, heating to reflux to obtain (Z)-N-(4-acetamido-benzylidene)-2, 2-dimethoxyethylamine, and reacting for 2-4 hours to obtain the N-(4-acetamido-benzylidene)-2, 2-dimethoxyethylamine. And carrying out three steps to obtain the 6-aminoisoquinoline. Wherein the reaction liquid is poured into the crushed ice, an ice bath auxiliary device is used for implementing, and the ice bath auxiliary device comprises an ice crusher (1), a carrying table (2), a heating plate array (3) and a tray (4).

Description

Technical Field

[0001] The invention relates to the technical field of preparation of pharmaceutical intermediates, and in particular to a preparation and synthesis method of an amino-substituted nitrogen-containing heterocycle. Background Art

[0002] 6-aminoisoquinoline and its derivatives are an important class of compounds with strong biological activity and are widely used in the fields of medicine, pesticides, etc. Therefore, their synthesis has received widespread attention, especially among pharmaceutical intermediates. However, the synthesis of 3-hydroxy-5-bromoisoquinoline mentioned in this application rarely appears as a pharmaceutical intermediate, or there are few documents or materials disclosed. Due to the characteristics of the molecule, the unique synthesis route, and the unique high yield problem, this method cannot be extended to the synthesis of other similar structures.

[0003] Due to the characteristics of this molecule, this method cannot be extended to the synthesis of other similar structures. This is determined by the originality of the preparation method obtained through countless experiments, the high yield and the non-replicability of the short reaction time. Other routes basically cannot have a high yield or an acceptable reaction time.

[0004] In addition, the prior art also has the following problem, that is, the product is mixed with ice after post-treatment, and the solid is precipitated after treatment. This is not easy to operate in practice. There are several difficulties: after mixing with ice, the amount of ice is usually large to effectively ensure the low temperature, but the ice is difficult to melt at this time. Ice that is not easy to melt may retain the product, resulting in a significant reduction in the reaction product. Furthermore, after mixing with ice, even if the ice melts, the volume of the mixture becomes huge. How to effectively transfer it to the filtration / extraction device is a problem. If a small volume measuring tool is used for multiple transfers, first, it is easy to spill, and second, the measuring tool itself is easy to retain the product, which is not easy to transfer all of it to the filtration / extraction result. In short, there is no suitable matching device for the ice bath, resulting in a large amount of product loss, and the ice bath and the final transfer filtration / extraction process are particularly difficult to operate.

[0005] Such a problem exists in the preparation of 6-aminoisoquinoline of the present application, especially in step 1, which requires mixing with a large amount of ice, but without special equipment, firstly, it is difficult to operate and highly dangerous, which may easily lead to the spillage of reactants and reaction failure, and secondly, the operation and measuring tools are cumbersome and the reaction product may be easily lost. Summary of the invention

[0006] The first purpose of the present invention is to solve two specific problems in the prior art. The first problem is how to obtain 6-aminoisoquinoline from easily available aminoacetaldehyde dimethyl acetal through a few steps with high yield. The present application perfectly solves this problem. The second problem is that there is no suitable matching equipment for ice bath, which results in a large amount of product loss and is particularly difficult to operate. Both problems are solved in the present application.

[0007] The present invention claims protection for an ice bath auxiliary device, which is characterized in that the ice bath auxiliary device comprises an ice crusher (1), a carrier (2), a heating plate array (3), and a tray (4).

[0008] The upper surface of the carrier is flat and has a square groove (21) which can accommodate the heating plate array.

[0009] The tray is made of metal, rectangular in shape when viewed from above, with an open top surface and side walls no less than 10 cm in height.

[0010] Furthermore, the carrier is made of wood or engineering plastic, and one corner of the square groove has a through groove (22) for leading out the power line of the heating plate array.

[0011] The blade teeth on the ice crusher drum are diamond-shaped flat nails, and the length and width of the upper surface of the carrier are correspondingly longer than the length and width of the tray; the volume of the tray is not less than 2800mL.

[0012] The heating sheet array is formed by embedding m*n array-arranged PET heating sheets into an array frame for fixing, where m and n are both positive integers and are both ≥2; the depth of the square groove is 0.3-3mm greater than the thickness of the heating sheet array.

[0013] A sharp protrusion (41) is provided in the middle of the narrow side or at a corner of the narrow side of the tray.

[0014] The platform is formed by a plate-shaped platform board (23) supported on a platform frame (24) having a plurality of legs, and a handle (231) is provided on one narrow side of the platform board.

[0015] A preparation and synthesis method of an amino-substituted nitrogen-containing heterocycle is implemented using the above ice bath auxiliary device and is characterized in that it includes the following steps.

[0016] 1) At room temperature, add 1.23-1.25 mol of aminoacetaldehyde dimethyl acetal dissolved in 2000 mL of toluene to a three-necked flask or a four-necked flask, add 1.22-1.24 mol of p-aminobenzaldehyde in batches while stirring, and after all the addition, heat the system to reflux temperature, add water to a water separator and keep the temperature for not less than 5 hours, stop heating and cool to room temperature, remove the reaction mixture and spin dry, rinse the spin-dried solid matter with not less than 100 mL of n-heptane for not less than 2 times to obtain the product of step 1 (Z)-N-(4-acetylamino-benzylidene)-2,2-dimethoxyethylamine.

[0017] 2) At room temperature, 0.19-0.21 mol of the product of step 1 is dissolved in 150 mL of methanol, hydrogen is continuously introduced and the hydrogen atmosphere is maintained, and the mixture is stirred in an autoclave, and 4.9-5.1 g of 10% palladium carbon is added in batches, and the hydrogen is replaced at least twice. The autoclave is sealed and pressurized to 45 Psi, and the reaction is stirred for at least 4 hours. The reaction mixture is removed, and the solvent is removed by vacuum to obtain the product of step 2, N-(4-acetylaminobenzyl)-2,2-dimethoxyethylamine.

[0018] 3) Take a four-necked bottle, add 200 mL of concentrated sulfuric acid, add 49-51 g of phosphorus pentoxide thereto in batches, control the temperature at 45-50° C., dissolve 49-51 g of the product of step 2 in 150 mL of dichloromethane to form a solution, and add it dropwise to the system. After the addition is complete, heat the system to 80° C., keep stirring and react for at least 1 hour, and then cool the system to room temperature.

[0019] Using an ice bath auxiliary device, prepare not less than 2 kg of crushed ice in a tray, pour all the reaction mixture into the crushed ice and mix, adjust the pH to 9-10 with a 2N sodium hydroxide solution cooled to 4-5°C, and after the ice is completely melted, pour the mixture in the tray into an extraction container for extraction 4 times, adding not less than 500 mL of ethyl acetate each time, and after extraction, combine the organic phases, wash with not less than 300 mL of saturated brine, and dry with not less than 20 g of anhydrous sodium sulfate. Remove the solvent to obtain a solid crude product, prepare an eluent in a ratio of petroleum ether: ethyl acetate = 10:1 to 5:1, add 0.5% volume of triethylamine based on the total volume of the eluent, and obtain the product of step 3, 6-acetylaminoisoquinoline.

[0020] 4) Take a four-necked bottle, add 200 mL of anhydrous methanol, add 15 g of KOH in batches while stirring, keep stirring after adding, add 24-26 g of the product of step 3 in batches, keep stirring and heat to reflux temperature after adding, keep stirring and heating under reflux for at least 2 hours, remove the heating of the system, cool to room temperature, vacuum remove the solvent, pour all the residues of the system into not less than 100 mL of water in a wide-mouth container, adjust the pH value to 10-11 with 3N hydrochloric acid, keep stirring and cool to 5-10°C, keep warm and stir for not less than 2 hours, until no solid is precipitated, rinse 2-4 times with 20 mL of deionized water each time to obtain the final product, 6-aminoisoquinoline.

[0021] In step (3), the crushed ice is prepared by an ice crusher, and when the ice is completely melted, it is heated by a heating plate array. The extraction is poured into the extraction container four times by repeatedly lifting the handle of the carrier plate by 3-20 cm, so that the liquid mixture in the tray is poured into the extraction device four times from the sharp protruding part for extraction.

[0022] Compared with the prior art, the advantages of the present invention are: 1. Improvement in the device. The device perfectly solves two problems: how to make the entire operation convenient and practical under the premise of adding a large amount of ice to the reaction mixture. The device of the present application can mix a large amount of ice, and after the reaction, there is special heating, and the excess ice can be quickly converted into water. And there is another problem, that is, how to transfer it to the filtration / extraction problem. For a large amount of water / reaction mixture, a medium-volume measuring tool is generally used for transfer, but this will cause a part of the effective substance to be retained, which is difficult to transfer to the final product. The device of the present application directly solves the problem of how to transfer it to the filtration / extraction device by setting a pointed mouth and a handle, and the tray can be lifted at one end. The device of the present application is simple to operate, effective, and easy to disassemble.

[0023] There is no report on the preparation of this product in the prior art. Compared with the preparation methods of similar substances, the steps of the method of this application are meticulously studied, and the utilization rate of raw materials in each step is very high, which is of great value for industrial production. Through the meticulous design of the method of the present invention, not only the synthesis is effectively achieved, but also the yield is high. The total yield exceeds 55% in most cases, which has a certain industrial production value and a large economic value. The application embodies a strong inventive concept and creativity through the careful design of ice bath assistance, and achieves a good preparation effect. There is no similar public information available for reference in the prior art, and the scheme of the present invention is original. In contrast, if the ice bath auxiliary device of the present application is not used, other conditions remain unchanged, and the total yield does not exceed 40%, the yield is at least reduced by 15% compared with the method of the present application. It can be seen that the negative effects of not cooperating with special devices are very obvious. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0025] Figure 1 is a schematic diagram of the ice bath auxiliary device.

[0026] Figure 2 Schematic diagram of the main reaction flow of this application.

[0027] Figure 3 This is the NMR image of the final product.

[0028] Figure numerals: 1. ice crusher, 2. carrier, 3. heating plate array, 4. tray, 21. square groove, 22. through groove, sharp protrusion, 23. carrier plate, 24. carrier frame, 231 handle. DETAILED DESCRIPTION

[0029] The preferred embodiments of the present invention are described in detail below in conjunction with the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0030] Example 1

[0031] An ice bath auxiliary device, characterized in that the ice bath auxiliary device comprises an ice crusher 1, a carrier 2, a heating plate array 3, and a tray 4. The ice crusher is a commercially available product, but the degree of crushing of the crushed ice needs to be ensured, for example, the maximum size of the crushed ice particles is not greater than 0.5-1 cm. The carrier is made of wood or engineering plastics.

[0032] The upper surface of the carrier is flat and has a square groove 21, which can accommodate the heating plate array. The square groove is a blind groove.

[0033] The tray is made of metal, and is rectangular when viewed from above, with an open upper surface and a side wall height of not less than 10 cm. For example, it is made of stainless steel, aluminum alloy, or magnesium-aluminum alloy. The tray is placed on the upper surface of the carrier, and the square groove is used to place the heating plate array.

[0034] Furthermore, the carrier is made of wood or engineering plastic, or wood inside and engineering plastic outside, or metal inside and engineering plastic outside, and one corner of the square groove has a through groove 22 for leading out the power line of the heating sheet array. In this way, the wires of the heating sheet array can be led out separately. The heating sheet array is adapted to an integral transformer and adjusted to 110V or 220V voltage.

[0035] The blade teeth on the ice crusher drum are diamond-shaped flat nails, and the length and width of the upper surface of the carrier are correspondingly longer than the length and width of the tray; the volume of the tray is not less than 2800mL.

[0036] The heating sheet array is formed by m*n array-arranged PET heating sheets embedded in an array frame, where m and n are both positive integers and ≥ 2; the depth of the square groove is 0.3-3 mm greater than the thickness of the heating sheet array. M*n is, for example, 4*3 or 6*2. The heating sheet is, for example, a circular disc, and the thickness is, for example, between 0.4 and 2 cm. The array frame is, for example, a metal product.

[0037] The narrow side center or narrow side corner of the tray has a pointed protrusion 41. This pointed protrusion, its maximum inclination angle is for example 45 °. It is used to pour the tray mixture into the suction filtration device.

[0038] The stage is formed by a plate-shaped stage board 23 supported on a stage frame 24 having a plurality of legs, and a handle 231 is provided on one narrow side of the stage board.

[0039] Example 2

[0040] A preparation and synthesis method of an amino-substituted nitrogen-containing heterocycle is implemented using the above ice bath auxiliary device and is characterized in that it includes the following steps.

[0041] 1) At room temperature, add 1.24 mol of aminoacetaldehyde dimethyl acetal dissolved in 2000 mL of toluene to a three-necked flask or a four-necked flask, add 1.23 mol of p-aminobenzaldehyde in batches while stirring, and after all are added, heat the system to reflux temperature, add water to a water separator and keep the temperature for 5 hours, stop heating and cool to room temperature, remove the reaction mixture and spin dry, rinse the spin-dried solid material with 120 mL of n-heptane twice, and obtain the product of step 1 (Z)-N-(4-acetylamino-benzylidene)-2,2-dimethoxyethylamine. 74 g, 96.8% yield.

[0042] 2) At room temperature, 0.2 mol of the product of step 1 was dissolved in 150 mL of methanol, hydrogen was continuously introduced and maintained in a hydrogen atmosphere, and stirred in an autoclave, 5 g of 10% palladium carbon was added in batches, and the hydrogen was replaced twice. The autoclave was sealed and pressurized to 45 Psi, and the reaction was stirred for 4 hours. The reaction mixture was removed and the solvent was removed by vacuum to obtain the product of step 2, N-(4-acetylaminobenzyl)-2,2-dimethoxyethylamine. 48 g, 95.2% yield.

[0043] 3) Take a four-necked bottle, add 200 mL of concentrated sulfuric acid, add 50 g of phosphorus pentoxide thereto in batches, control the temperature at 45-48 ° C, dissolve 50 g of the product of step 2 in 150 mL of dichloromethane to form a solution, and add it dropwise to the system. After the addition is completed, heat the system to 80 ° C, keep stirring and react for 1.5 hours, and then cool the system to room temperature.

[0044] Using an ice bath auxiliary device, prepare no less than 2 kg of crushed ice in a tray, pour all the reaction mixture into the crushed ice and mix, adjust the pH to 9-10 with a 2N sodium hydroxide solution cooled to 4°C, and after the ice is completely melted, pour the mixture in the tray into an extraction container for extraction 4 times, add 510 mL of ethyl acetate each time, combine the organic phases after extraction, wash with 310 mL of saturated brine, dry with 22 g of anhydrous sodium sulfate, remove the solvent to obtain a solid crude product, prepare an eluent in a ratio of petroleum ether: ethyl acetate = 10:1, add 0.5% volume of triethylamine based on the total volume of the eluent, and obtain the product of step 3, 6-acetylaminoisoquinoline. 26.4 g, 71.3%.

[0045] 4) Take a four-necked bottle, add 200mL of anhydrous methanol, add 15g of KOH in batches while stirring, keep stirring after adding, add 25g of the product of step 3 in batches, keep stirring and heat to reflux temperature after adding, keep stirring and heating under reflux for 2.5h, remove the heating of the system, cool to room temperature, vacuum to remove the solvent, pour all the residues of the system into 120mL of water in a wide-mouth container, adjust the pH value to 10-11 with 3N hydrochloric acid, keep stirring and cool to 5-10°C, keep warm and stir for 2.5h until no solid precipitates, rinse 3 times with 20mL of deionized water each time to obtain the final product, 6-aminoisoquinoline. 16.3g, 84.1% yield. Total yield 55.26%.

[0046] In step (3), the crushed ice is prepared by an ice crusher, and when the ice is completely melted, it is heated by a heating plate array. The extraction is poured into the extraction container four times by repeatedly lifting the handle of the carrier plate by 5 cm, so that the liquid mixture in the tray is poured into the extraction device four times from the protruding part of the sharp corner for extraction.

[0047] Example 3

[0048] A preparation and synthesis method of an amino-substituted nitrogen-containing heterocycle is implemented using the above ice bath auxiliary device and is characterized in that it includes the following steps.

[0049] 1) At room temperature, add 1.25 mol of aminoacetaldehyde dimethyl acetal dissolved in 2000 mL of toluene to a three-necked flask or a four-necked flask, add 1.24 mol of p-aminobenzaldehyde in batches while stirring, and after all are added, heat the system to reflux temperature, add water to a water separator and keep the temperature for 5.5 hours, stop heating and cool to room temperature, remove the reaction mixture and spin dry, rinse the spin-dried solid material with 130 mL of n-heptane for 3 times, and obtain the product of step 1 (Z)-N-(4-acetylamino-benzylidene)-2,2-dimethoxyethylamine. 97.10% yield.

[0050] 2) At room temperature, 0.205 mol of the product of step 1 was dissolved in 150 mL of methanol, hydrogen was continuously introduced and maintained in a hydrogen atmosphere, and stirred in an autoclave, 5.1 g of 10% palladium carbon was added in batches, and the hydrogen was replaced 3 times. The autoclave was sealed and pressurized to 45 Psi, and the reaction was stirred for 5 hours. The reaction mixture was removed and the solvent was removed by vacuum to obtain the product of step 2, N-(4-acetylaminobenzyl)-2,2-dimethoxyethylamine. The yield was 95.74%.

[0051] 3) Take a four-necked bottle, add 205 mL of concentrated sulfuric acid, add 51 g of phosphorus pentoxide thereto in batches, control the temperature at 46-50° C., dissolve 51 g of the product of step 2 in 150 mL of dichloromethane to form a solution, and add it dropwise to the system. After the addition is complete, heat the system to 80° C., keep stirring and react for 2 hours, and then cool the system to room temperature.

[0052] Using an ice bath auxiliary device, prepare no less than 2 kg of crushed ice in a tray, pour all the reaction mixture into the crushed ice and mix, adjust the pH to 9-10 with a 2N sodium hydroxide solution cooled to 5°C, and after the ice is completely melted, pour the mixture in the tray into an extraction container for extraction 4 times, add 520 mL of ethyl acetate each time, combine the organic phases after extraction, wash with 320 mL of saturated brine, dry with 24 g of anhydrous sodium sulfate, remove the solvent to obtain a solid crude product, prepare an eluent in a ratio of petroleum ether: ethyl acetate = 8:1, add 0.5% volume of triethylamine based on the total volume of the eluent, and obtain the product 6-acetylaminoisoquinoline in step 3. 71.67%.

[0053] 4) Take a four-necked bottle, add 200 mL of anhydrous methanol, add 15.6 g of KOH in batches while stirring, keep stirring after adding, add 26 g of the product of step 3 in batches, keep stirring and heat to reflux temperature after adding, keep stirring and heating under reflux for 3 hours, remove the heating of the system, cool to room temperature, vacuum to remove the solvent, pour all the residues of the system into 130 mL of water in a wide-mouth container, adjust the pH value to 10-11 with 3N hydrochloric acid, keep stirring and cool to 5-10°C, keep warm and stir for 3 hours, stop the reaction until no solid precipitates, rinse 4 times with 25 mL of deionized water each time, and obtain the final product, 6-aminoisoquinoline. 84.57% yield. Total yield 56.35%.

[0054] In step (3), the crushed ice is prepared by an ice crusher, and when the ice is completely melted, it is heated by a heating plate array. The extraction is poured into the extraction container four times by repeatedly lifting the handle of the carrier plate by 8 cm, so that the liquid mixture in the tray is poured into the extraction device four times from the protruding part of the sharp corner for extraction.

[0055] Example 4

[0056] This example is a comparative example of Example 3, in which no ice bath auxiliary device was used. Due to the loss of a large amount of product during transfer, the total yield was repeated many times and none was higher than 40%.

[0057] Preferably, all the above reagents are of chemical purity or higher, or are of superior purity. The water is deionized water, preferably double distilled water.

[0058] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that are not conceived through creative work should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope defined in the claims.

Claims

1. An ice bath auxiliary device, characterized in that: The ice bath auxiliary device comprises an ice crusher (1), a carrier (2), a heating plate array (3), and a tray (4); The upper surface of the carrier is flat and has a square groove (21) in which the heating plate array can be placed; The tray is made of metal, rectangular in shape when viewed from above, with an open top surface and side walls no less than 10 cm in height.

2. A heating auxiliary device according to claim 1, characterized in that: The carrier is made of wood or engineering plastics, and one corner of the square groove has a through groove (22) for leading out the power line of the heating plate array; The teeth on the ice crusher drum are diamond-shaped flat nails, and the length and width of the upper surface of the carrier are correspondingly longer than the length and width of the tray; the volume of the tray is not less than 2800mL; The heating sheet array is formed by embedding m*n array-arranged PET heating sheets into an array frame, where m and n are both positive integers and are both ≥ 2; the depth of the square groove is 0.3-3 mm greater than the thickness of the heating sheet array; A sharp protrusion (41) is provided in the middle of the narrow side or at a corner of the narrow side of the tray; The platform is formed by a plate-shaped platform board (23) supported on a platform frame (24) having a plurality of legs, and a handle (231) is provided on one narrow side of the platform board.

3. A method for preparing and synthesizing an amino-substituted nitrogen-containing heterocycle, which is implemented using an ice bath auxiliary device as claimed in any one of claims 1-2, characterized in that: The following steps are involved: 1) at room temperature, add 1.23-1.25 mol of aminoacetaldehyde dimethyl acetal dissolved in 2000 mL of toluene to a three-necked flask or a four-necked flask, add 1.22-1.24 mol of p-aminobenzaldehyde in batches while stirring, and after all the addition, heat the system to reflux temperature, add water to a water separator and keep the temperature for not less than 5 hours, stop heating and cool to room temperature, remove the reaction mixture and spin dry, rinse the spin-dried solid with not less than 100 mL of n-heptane for not less than 2 times to obtain the product of step 1 (Z)-N-(4-acetylamino-benzylidene)-2,2-dimethoxyethylamine; 2) At room temperature, 0.19-0.21 mol of the product of step 1 was dissolved in 150 mL of methanol, hydrogen was continuously introduced and the hydrogen atmosphere was maintained, and the mixture was stirred in an autoclave, and 4.9-5.1 g of 10% palladium carbon was added in batches, and the hydrogen was replaced at least twice. The autoclave was sealed and pressurized to 45 Psi, and the reaction was stirred for at least 4 hours. The reaction mixture was removed, and the solvent was removed by vacuum to obtain the product of step 2, N-(4-acetylaminobenzyl)-2,2-dimethoxyethylamine; 3) Take a four-necked bottle, add 200 mL of concentrated sulfuric acid, add 49-51 g of phosphorus pentoxide thereto in batches, control the temperature at 45-50° C., dissolve 49-51 g of the product of step 2 in 150 mL of dichloromethane to form a solution, and add it dropwise to the system. After the addition is complete, heat the system to 80° C., keep stirring and react for at least 1 hour, and then cool the system to room temperature; Using an ice bath auxiliary device, prepare not less than 2 kg of crushed ice in a tray, pour all the reaction mixture into the crushed ice and mix, adjust the pH to 9-10 with a 2N sodium hydroxide solution cooled to 4-5°C, and after all the ice melts, pour the mixture in the tray into an extraction container for extraction 4 times, adding not less than 500 mL of ethyl acetate each time, combine the organic phases after extraction, wash with not less than 300 mL of saturated brine, and dry with not less than 20 g of anhydrous sodium sulfate, remove the solvent to obtain a solid crude product, prepare an eluent in a ratio of petroleum ether: ethyl acetate = 10:1 to 5:1, add 0.5% volume of triethylamine based on the total volume of the eluent, and obtain the product 6-acetylaminoisoquinoline in step 3; 4) Take a four-necked bottle, add 200 mL of anhydrous methanol, add 15 g of KOH in batches while stirring, keep stirring after adding, add 24-26 g of the product of step 3 in batches, keep stirring and heat to reflux temperature after adding, keep stirring and heating under reflux for at least 2 hours, remove the heating of the system, cool to room temperature, vacuum remove the solvent, pour all the residues of the system into not less than 100 mL of water in a wide-mouth container, adjust the pH value to 10-11 with 3N hydrochloric acid, keep stirring and cool to 5-10°C, keep warm and stir for not less than 2 hours, until no solid is precipitated, rinse 2-4 times with 20 mL of deionized water each time to obtain the final product, 6-aminoisoquinoline. In the step (3), the crushed ice is prepared by an ice crusher, and when the ice is completely melted, it is heated by a heating plate array. The extraction is poured into the extraction container four times by repeatedly lifting the handle of the carrier plate by 3-20 cm, so that the liquid mixture in the tray is poured into the extraction device four times from the sharp protruding part for extraction.

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