CN112121463B - Preparation method of polysubstituted benzo nitrogen-containing heterocyclic methylamine - Google Patents

Abstract

A preparation method of polysubstituted benzo nitrogen-containing heterocyclic methylamine is carried out by utilizing an ultrasonic extraction device and is characterized by comprising the following steps: preparing N- (2-bromophenyl) -1, 1-dimethoxypropane-2-imine from acetone aldehyde dimethyl acetal and o-bromobenzylamine; then the red viscous oily substance 3-methylisoquinoline-8-methylamine is prepared through four steps, and is a final product; the extraction is implemented by using an ultrasonic extraction device, and comprises a preparation step, a covering step, a vibration and shaking step, a repeating step and a receiving step. The ultrasonic extraction device comprises an extraction part (1), a shell part (2), an ultrasonic part (3), a cross rod part (4), a left support part (5), a right support part (6), a glass device (7) and a demulsification component (8).

Description

Preparation method of polysubstituted benzo nitrogen-containing heterocyclic methylamine

Technical Field

The invention relates to the technical field of preparation of a drug intermediate, in particular to a preparation method of polysubstituted benzo nitrogen-containing heterocyclic methylamine.

Background

Isoquinoline and derivatives thereof are important compounds, have strong biological activity, and are widely applied to the fields of medicines, pesticides and the like, so that the synthesis of pyrazole derivatives is concerned widely, and particularly the isoquinoline and derivatives thereof are widely applied to medical intermediates. CN2016100987718 discloses a preparation method of 8-nitro-1, 2,3, 4-tetrahydroisoquinoline, CN201610042580.X provides a synthesis method of 4-hydroxy-8-bromoisoquinoline, and CN201210340505.3 provides a preparation method of 7-bromoisoquinoline, which are examples of application and synthesis of isoquinoline derivatives, but the 3-methylisoquinoline 8-methylamine mentioned in the application rarely appears as a pharmaceutical intermediate, or documents or data are disclosed. Due to the characteristics of the molecule, a unique synthetic route and a unique higher yield problem, the method cannot be popularized to the synthesis of other similar structures.

Due to the nature of the molecule, this method cannot be generalized to the synthesis of other similar structures. This is determined by the originality of the preparation, the higher yields and the irreproducibility of the shorter reaction times obtained in numerous trials, other routes having substantially no higher yields or acceptable reaction times.

In addition, the prior art has the problem that the existing extraction devices have the disadvantages that the reaction dosage of the application far exceeds the dosage which is generally simple and qualitative, under the dosage, a simple extraction instrument is not applied, if a common liquid separation extraction device is used, only a maximum of 300ml can be extracted each time, one extraction needs to be separated for a plurality of times, the separation and combination are needed for a plurality of times, and time, labor and energy are wasted, and a great deal of time and energy are used for the synthesis personnel for the link, so that the application is not worth. Also there are some companies at present to order great extraction equipment, but only do extraction equipment greatly, can not solve the problem, because the extraction equipment is because the problem of dissolved matter nature, generally must be glass equipment just can be durable, but too big glass equipment rocks, it is all difficult to move, though can once take up a large amount of liquid mixture, nevertheless be difficult to grip in the extraction operation, it is inconvenient to rock the vibrations, it breaks easily to fall into, the degree of difficulty has been increased for actual operation again, do not have means among the prior art and solve both problems simultaneously, extraction device volume undersize that is the undersize, and the inconvenient problem of too big extraction device vibration operation, it is strong to provide a maneuverability, can once carry out the device of big hydrops extraction again.

The preparation of 3-methyl isoquinoline 8-methylamine of the application has the problems that the once extraction of the optical solvent is 500ml, small equipment can not be loaded and is very troublesome for several times, large equipment often uses a glass ware which is not movable and dares to shake, the whole experiment is scrapped when the equipment fails once, and the equipment is wasted and dangerous.

Disclosure of Invention

The first purpose of the invention is to solve two specific problems in the prior art, namely, the problem of how to obtain 3-methylisoquinoline 8-methylamine through few and high-yield steps from the acetone aldehyde dimethyl acetal, the scheme of the invention perfectly solves the problem, and the problems of high implementation difficulty of an extraction link, small volume of an extraction device and inconvenient vibration operation of an overlarge extraction device are solved in the invention.

The invention claims an ultrasonic extraction device, which is characterized in that: comprises an extraction part 1, a shell part 2, an ultrasonic part 3, a cross rod part 4, a left support part 5, a right support part 6, a glass device 7 and a demulsification component 8.

The extraction part 1 comprises a cylindrical part 11, an upper opening 12, an upper cover 13, a cone part 14, a liquid stop plug group 15 and a liquid outlet 16. The main part of extraction portion 1 is formed by last opening 12, cylinder portion 11, the concatenation of cone portion 14 from top to bottom, cylinder portion 11 is hollow cylinder type, the big-end-up of upper opening 12 and medial surface are dull polish portion 121, the outer fringe of upper cover 13 and dull polish portion 121 adaptation is the dull polish face, upper cover 13 top center has handle portion 131, cone portion 14 is hollow circular cone type, end liquid bolt group 15 has between cone portion 14 and liquid outlet 16, end liquid bolt group 15 has a end liquid chamber 153, end the horizontal through-hole that has one and liquid route looks vertically in the liquid chamber 153, wherein fill in and end liquid bolt 151, end liquid bolt handle 152 has on one side.

The outer shell 2 includes a concave ring 21, a main shell 22, an observation groove 23, a peripheral edge 24, a support portion 25 and a vibration head groove 27, the concave ring 21 is attached to the uppermost portion of the cone portion 14, the main shell 22 is attached to the cylindrical portion 11, the observation groove 23 is a plurality of vertical rectangular through grooves symmetrically formed in the main shell 22 in the circumferential direction, the peripheral edge 24 is a peripheral protruding edge of the lower portion of the support portion 25, and the inner side of the support portion 25 supports the upper opening 12. The main shell 22 has a concave recess matching the left side of the vibration head groove 27, and the vibration head groove 27 has a downward groove matching the vibration head 31.

The ultrasonic device 3 comprises a vibration head 31, a transducer 32, a generator 33, a power supply 34 and a reinforced cable 35, wherein the vibration head 31 and the transducer 32 are connected through the reinforced cable 35, a connecting line of the vibration head 31 and the transducer 32 is wrapped in the reinforced cable 35, the transducer 32 is connected with the generator 33, and the generator 33 is powered by the power supply 34. The vibrating head 31 is inserted into the groove and fixed by a groove screw 36.

The middle of the cross rod part 4 is provided with a circular ring part 42, the inner diameter of the circular ring part is matched with the outer diameter of the main shell 22, the periphery 24 can be supported by the upper part of the circular ring part 42, and the left and the right of the circular ring part 42 are respectively connected with a left cylindrical cross rod 41 and a right cylindrical cross rod 43 integrally.

The left support part 5 comprises a left rod 51, a left base 52, a left upper ring 53, a left hinge part 54, a left lower ring 55, a left flange 56 and a left bearing 57, the left support part 5 is positioned on the left side of the extraction part 1, the left base 52 is a cylindrical base with a screw hole in the middle, the lower end of the left rod 51 is screwed into the screw hole and fixed, the upper end of the left rod 51 is connected with the left lower ring 55 in a welding mode, the left lower ring 55 is buckled with the left upper ring 53 which is in a semi-annular shape, the left sides of the left lower ring 55 and the left upper ring 53 are hinged through the left hinge part 54, the right side of the left lower ring 55 and the left upper ring 53 is provided with a pair of left flanges 56 which are matched, the left flanges 56 are fixed through bolt groups, the left bearing 57 is fixed in the buckled left lower ring 55 and the left upper ring 53, and the inner hole of the left bearing 57 is inserted into the left cross rod 41.

Right support portion 6 includes right pole 61, right base 62, right upper ring 63, right articulated portion 64, right lower ring 65, right flange 66, right bearing 67, right support portion 6 is located extraction portion 1 right-hand, right base 62 is the cylindrical base that the centre has a screw, right pole 61 lower extreme is fixed to screwing in to this screw, right pole 61 upper end welded connection right lower ring 65, right lower ring 65 and the same semicircular right upper ring 63 lock that is in the top, right lower ring 65 and right upper ring 63 right side are articulated through right articulated portion 64, the left side has a pair of right flange 66 of looks adaptation, right flange 66 is fixed by bolt group, the right lower ring 65 and the right upper ring 63 internal fixation of lock have right bearing 67, right bearing 67 hole inserts right horizontal pole 43.

The glass unit 7 is located below the liquid outlet 16.

The demulsification assembly 8 includes a ball portion 81, a sheet portion 82 and a cone portion 83.

Preferably, the extraction part is made of glass. Vaseline is coated in the horizontal through holes.

The shell part is made of nylon PA66, polytetrafluoroethylene or engineering plastic.

The vibration head groove 27 is fixed on the main casing 22 by winding a plurality of turns of electrical tape.

The working power of the vibration head is between 60 and 100W, the working frequency is between 15KHZ and 100KHZ, and the head part of the vibration head is in a horn shape and is provided with an extended straight column.

The cross rod part 4, the left support part 5 and the right support part 6 are made of stainless steel.

The left bearing and the right bearing are ball bearings. The left bearing and the right bearing can be internally and externally provided with rubber gaskets.

The glass 7 is a combination of a large-volume wide-mouth container or a large-caliber funnel and other glassware.

The demulsification component 8 is made of polytetrafluoroethylene.

A method for preparing polysubstituted benzo nitrogen-containing heterocyclic methylamine, which is carried out by using an ultrasonic extraction device as described above due to the large amount of extraction agent required, is characterized by comprising the following steps.

(1) Dissolving 64-68g of acetone aldehyde dimethyl acetal in 2100ml of toluene, adding 105-115g of o-bromobenzylamine while stirring, heating to about 120 ℃, reacting until water separation is finished, confirming complete reaction through LCMS detection, and concentrating to obtain light yellow liquid N- (2-bromophenyl) -1, 1-dimethoxypropane-2-imine.

(2) Dissolving 165-175g of N- (2-bromophenyl) -1, 1-dimethoxypropane-2-imine in 1600-1800ml of ethanol, controlling the temperature to be below 30-35 ℃, slowly adding 55-59g of sodium borohydride in batches, continuously keeping the temperature of 30-35 ℃ for reaction for 8-16h after the addition is finished, confirming the reaction is complete through LCMS detection, dropwise adding 300ml of water, concentrating to remove the ethanol, adding at least 1L of water for dissolving, selecting 500ml of ethyl acetate for extraction for three times each time, washing an organic phase for 1-3 times by using 300ml of saturated saline solution, and concentrating to obtain a light yellow viscous liquid N- (2-bromophenyl) -1, 1-dimethoxypropane-2-amine.

(3) 206-210g of phosphorus pentoxide are added in portions to 500ml of concentrated sulfuric acid, the temperature is kept not too high. After the addition, heating to 70 ℃, dropwise adding a solution obtained by dissolving 135-145g of N- (2-bromophenyl) -1, 1-dimethoxypropane-2-amine with 300ml of dichloromethane, keeping the temperature at 70 ℃ for reaction for 1h after the dropwise addition is finished, cooling to room temperature, pouring the mixture into ice water, keeping the temperature below 25 ℃ under the premise of continuously cooling the mixture with the ice water outside, adjusting the pH value of the mixture to 9 with sodium hydroxide, selecting a solvent as 500ml of ethyl acetate for extraction for three times each time, concentrating, mixing the sample and passing through a column; this gave 8-bromo-3-methylisoquinoline as a yellow solid.

(4) 45-55g of 8-bromo-3-methylisoquinoline are dissolved in 500ml of N, N-dimethylformamide, adding 30-34g of zinc cyanide and 15-17g of PdCl2(dppf) in sequence, replacing nitrogen for three times, heating the mixture to 140 ℃, reacting for 8-16h, and (3) confirming the reaction is complete through LCMS detection, cooling the system to room temperature, adding 1L of ethyl acetate and 1.5L of water for dilution, paving sufficient diatomite, performing suction filtration, washing the solid of the mixture twice with 500mL of ethyl acetate, separating the mother liquor, combining organic phases, washing the organic phase 1 time with 100mL of water, washing the organic phase 2-3 times with 100mL of saturated saline solution, drying the organic phase with anhydrous sodium sulfate, concentrating the dried organic phase, and purifying the organic phase by using a 100-sand 200-mesh silica gel column under the premise that the PE/EA is 3:1 to obtain the white solid 3-methyl-8-cyanoisoquinoline.

(5) 27-33g of 3-methyl-8-cyanoisoquinoline is dissolved in 500ml of methanol, 9.5-10.5g of raney nickel is added to replace hydrogen for three times, 500ml of 7M NH3 methanol solution is added, the reaction is confirmed to be complete by LCMS detection after the mixture returns to the room temperature, the reaction is filtered, the mother solution is concentrated, and dichloromethane/methanol is 20:1, and then the mixture is purified by a 100-mesh silica gel column to obtain a red viscous oily substance 3-methylisoquinoline-8-methylamine which is the final product.

The extraction in the above (1) to (5) is carried out by using the ultrasonic extraction device of claim 2, and comprises the following specific steps:

(A) the preparation method comprises the following steps: the extraction portion is cleaned and aired, the extraction portion is completely sleeved into the outer shell portion to be fixed, the outer shell portion is sleeved into the circular ring portion, so that the periphery (24) can be supported by the upper portion of the circular ring portion (42), the left side of the vibration head groove (27) is pushed into a concave pit on the main shell (22), and the vibration head groove is wound for multiple circles at high temperature by using electrical adhesive tapes and is fixed on the main shell (22).

(B) Covering: the cover (13) is opened, the mixture to be extracted and the solvent are poured in, the demulsifying component is placed so that the ball part is outside the upper opening and the cone part is inward, and the cover is carefully closed.

(C) A vibration shaking step: pushing the shell part to enable the shell part to shake forwards and backwards for 10-20 times in a pendulum manner, enabling the manual idle straight shell part to be approximately static, starting the ultrasonic device and enabling the vibration head to vibrate for 1-2min at a frequency of more than 20KHz, and standing for 2-4 min.

(D) Repeating the steps: and C3-5 times of repetition.

(E) A receiving step: stopping extraction, opening the upper cover, taking out the demulsification component, respectively taking out the mixture of different phases below the liquid outlet by using different glassware, and pouring out the last phase of the extraction part from the upper opening.

Preferably, all of the foregoing reagents are chemically pure or purer. The water is deionized water, preferably double distilled water.

Compared with the prior art, the invention has the advantages that: the improvement on the device perfectly solves two problems; the problems that the implementation difficulty of an extraction link is high, the volume of an undersized extraction device is undersized, and the vibration operation of an oversized extraction device is inconvenient are solved; moreover, the ultrasonic device of this application combines the mode unique characteristic, if fixed in advance, then can't put into, and this kind of recess adds the mode of sticky tape, and fixed intensity is enough, easily dismantles again, and the fixed problem of large-scale glassware has been solved to the shape of shell 2. The problem of liquid level observation after fixing has been solved to the observation tank, can see through its degree of separation of observing the organic phase, and is very convenient, and is bulky more in addition, has the emulsion breaking difficult problem more, and the emulsion breaking subassembly that the polytetrafluoroethylene was done is cut with monoblock polytetrafluoroethylene, can solve the emulsion breaking problem effectively. And when the bearing pressure of the lower concave ring is high, the lower concave ring can be used for assisting in fixing the metal ring with the radian outside, and the lower concave ring can be detached when not used.

At present, no report of the preparation of the product exists in the prior art, compared with a preparation method of similar substances, the method disclosed by the invention has the advantages that the steps are delicate, the utilization rate of raw materials in each step is very high, the method has great value for realizing industrial production, the synthesis is effectively realized through the fine design of the method disclosed by the invention, the yield is high, 16g of red viscous oily 3-methylisoquinoline-8-methylamine can be obtained through acetone aldehyde dimethyl acetal (66g), the method has certain industrial production value and great economic value, the method disclosed by the invention embodies extremely strong invention conception and creativity through the unique design of an extraction link, a good preparation effect is obtained, similar public information can not be used for reference in the prior art, and the scheme disclosed by the invention has originality. In contrast, the preparation by the traditional extraction method wastes at least one time in the extraction link, so that the method has no practical value. The traditional extraction equipment has insufficient volume, is difficult to extract under the condition of a large amount of solvents, is difficult to transfer materials, most of the materials are lost during each transfer, mixing and separation, and a large amount of substances are adhered to each neck of a glass container for many times when the materials are few, so that the yield is seriously influenced.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.

Fig. 1 is an overall schematic view of the apparatus.

Fig. 2 is a schematic side structure diagram of the left and right support parts.

Fig. 3 is a schematic top view of a cross bar portion of the present invention.

Figure 4 is a view of an ultrasound device of the present invention.

FIG. 5 is a schematic view of the composition of the extraction section.

Figure 6 is a schematic view of the housing portion composition.

FIG. 7 is a schematic lateral and forward view of the demulsification assembly.

FIG. 8 is a nuclear magnetic diagram of 3-methylisoquinoline-8-methylamine.

FIG. 9 is a scheme of synthesis of 3-methylisoquinoline-8-methylamine.

Reference numerals: the extraction part 1, the cylindrical part 11, the upper opening 12, the frosted part 121, the upper cover 13, the handle part 131, the cone part 14, the liquid stop bolt group 15, the liquid stop bolt 151, the liquid stop bolt handle 152, the liquid stop cavity 153, the liquid outlet 16, the outer shell part 2, the lower concave ring 21, the main shell 22, the observation groove 23, the peripheral edge 24, the bearing part 25, the vibration head groove 27, the ultrasonic part 3, the vibration head 31, the transducer 32, the generator 33, the power supply 34, the reinforcing cable 35, the groove screw 36, the cross rod part 4, the left cross rod 41, the circular ring part 42, the right cross rod 43, the left support part 5, the left rod 51, the left base 52, the left upper ring 53, the left hinge part 54, the left lower ring 55, the left flange 56, the left bearing 57, the right support part 6, the right rod 61, the right base 62, the right upper ring 63, the right hinge part 64, the right lower ring 65, the right flange 66, the right bearing 67, the glass ware 7, the cone component 8, the ball part 81, the sheet part 82 and the emulsion breaking 83.

Detailed Description

The preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, and the scope of the present invention will be more clearly and clearly defined.

Example 1

An ultrasonic extraction device is characterized in that: comprises an extraction part 1, a shell part 2, an ultrasonic part 3, a cross rod part 4, a left support part 5, a right support part 6, a glass device 7 and a demulsification component 8. The extraction device can be divided into a plurality of specifications, for example, the volume of the extraction part can be 1L, 2L, 3L, 4L and 5L to meet different requirements.

The extraction part 1 comprises a cylindrical part 11, an upper opening 12, an upper cover 13, a cone part 14, a liquid stop plug group 15 and a liquid outlet 16. The main part of extraction portion 1 is formed by last opening 12, cylinder portion 11, the concatenation of cone portion 14 from top to bottom, cylinder portion 11 is hollow cylinder type, the big-end-up of upper opening 12 and medial surface are dull polish portion 121, the outer fringe of upper cover 13 and dull polish portion 121 adaptation is the dull polish face, upper cover 13 top center has handle portion 131, cone portion 14 is hollow circular cone type, end liquid bolt group 15 has between cone portion 14 and liquid outlet 16, end liquid bolt group 15 has a end liquid chamber 153, end the horizontal through-hole that has one and liquid route looks vertically in the liquid chamber 153, wherein fill in and end liquid bolt 151, end liquid bolt handle 152 has on one side. To prevent the liquid from being ejected by excessive pressure, the liquid stop can be fitted with a rubber band or a special rubber retainer that is placed prior to the addition of liquid to retain the liquid stop stem 152 against ejection by excessive pressure.

The outer shell 2 includes a concave ring 21, a main shell 22, an observation groove 23, a peripheral edge 24, a support portion 25 and a vibration head groove 27, the concave ring 21 is attached to the uppermost portion of the cone portion 14, the main shell 22 is attached to the cylindrical portion 11, the observation groove 23 is a plurality of vertical rectangular through grooves symmetrically formed in the main shell 22 in the circumferential direction, the peripheral edge 24 is a peripheral protruding edge of the lower portion of the support portion 25, and the inner side of the support portion 25 supports the upper opening 12. The main shell 22 has a concave recess matching the left side of the vibration head groove 27, and the vibration head groove 27 has a downward groove matching the vibration head 31. The lower concave ring 21, the main shell 22, the observation groove 23, the periphery 24 and the bearing part 25 are integrally formed, and for the heavier situation, in order to prevent the lower concave ring 21 from deforming to cause the extraction part to slide out and break, a metal fixing belt can be arranged outside the lower concave ring 21, the lower concave ring can be made of aluminum alloy and is tightly fixed by a flange and a bolt, and the radian of the metal fixing belt is tightly attached to the outside of the lower concave ring.

The ultrasonic device 3 comprises a vibration head 31, a transducer 32, a generator 33, a power supply 34 and a reinforced cable 35, wherein the vibration head 31 and the transducer 32 are connected through the reinforced cable 35, a connecting line of the vibration head 31 and the transducer 32 is wrapped in the reinforced cable 35, the transducer 32 is connected with the generator 33, and the generator 33 is powered by the power supply 34. The vibrating head 31 is inserted into the groove and fixed by a groove screw 36. The power of the vibration head is between 60 and 100W, the frequency is an integer between 15KHZ and 100KHZ, a certain section of the vibration head is in a horn shape and is provided with an extended straight column, the groove is matched with the same type of the vibration head, and the groove is further provided with at least two symmetrical through holes for the groove screw 36 to penetrate through and penetrate through the screw hole on the vibration head for fixation.

The middle of the cross rod part 4 is provided with a circular ring part 42, the inner diameter of the circular ring part is matched with the outer diameter of the main shell 22, the periphery 24 can be supported by the upper part of the circular ring part 42, and the left and the right of the circular ring part 42 are respectively connected with a left cylindrical cross rod 41 and a right cylindrical cross rod 43 integrally. The circular ring portion 42, the left cross bar 41 and the right cross bar 43 may be formed by integrally molding stainless steel or by welding.

The left support part 5 comprises a left rod 51, a left base 52, a left upper ring 53, a left hinge part 54, a left lower ring 55, a left flange 56 and a left bearing 57, the left support part 5 is positioned on the left side of the extraction part 1, the left base 52 is a cylindrical base with a screw hole in the middle, the lower end of the left rod 51 is screwed into the screw hole and fixed, the upper end of the left rod 51 is connected with the left lower ring 55 in a welding mode, the left lower ring 55 is buckled with the left upper ring 53 which is in a semi-annular shape, the left sides of the left lower ring 55 and the left upper ring 53 are hinged through the left hinge part 54, the right side of the left lower ring 55 and the left upper ring 53 is provided with a pair of left flanges 56 which are matched, the left flanges 56 are fixed through bolt groups, the left bearing 57 is fixed in the buckled left lower ring 55 and the left upper ring 53, and the inner hole of the left bearing 57 is inserted into the left cross rod 41. The left bearing is a ball bearing, and a circle of balls are arranged between the inner ring and the outer ring.

Right support portion 6 includes right pole 61, right base 62, right upper ring 63, right articulated portion 64, right lower ring 65, right flange 66, right bearing 67, right support portion 6 is located extraction portion 1 right-hand, right base 62 is the cylindrical base that the centre has a screw, right pole 61 lower extreme is fixed to screwing in to this screw, right pole 61 upper end welded connection right lower ring 65, right lower ring 65 and the same semicircular right upper ring 63 lock that is in the top, right lower ring 65 and right upper ring 63 right side are articulated through right articulated portion 64, the left side has a pair of right flange 66 of looks adaptation, right flange 66 is fixed by bolt group, the right lower ring 65 and the right upper ring 63 internal fixation of lock have right bearing 67, right bearing 67 hole inserts right horizontal pole 43. The left bearing is a ball bearing, and a circle of balls are arranged between the inner ring and the outer ring.

The glass unit 7 is located below the liquid outlet 16. The demulsification assembly 8 includes a ball portion 81, a sheet portion 82 and a cone portion 83. The demulsification assembly made of polytetrafluoroethylene is cut into polytetrafluoroethylene in one piece, the ball part is used for dropping the whole assembly, the piece part is very thin, the cone part is very thin, and the tip is needle-shaped. The demulsification assembly may in practice be arranged in a plurality of different cone heights.

Preferably, the extraction part is made of glass. Vaseline is coated in the horizontal through holes. The shell part is made of nylon PA66, polytetrafluoroethylene or engineering plastic. The vibration head groove 27 is fixed on the main casing 22 by winding a plurality of turns of electrical tape. The working power of the vibration head is between 60 and 100W, the working frequency is between 15KHZ and 100KHZ, and the head part of the vibration head is in a horn shape and is provided with an extended straight column. The cross rod part 4, the left support part 5 and the right support part 6 are made of stainless steel. The left bearing and the right bearing are ball bearings. The left bearing and the right bearing can be internally and externally provided with rubber gaskets. The glass 7 is a large volume wide mouth container or a combination of a large bore funnel and other glassware, such as a large beaker, or a jar. The demulsification component 8 is made of polytetrafluoroethylene.

Example 2

A method for preparing polysubstituted benzo nitrogen-containing heterocyclic methylamine, which is carried out by using an ultrasonic extraction device as described above due to the large amount of extraction agent required, is characterized by comprising the following steps.

(1) Dissolving 64-68g of acetone aldehyde dimethyl acetal in 2100ml of toluene, adding 105-115g of o-bromobenzylamine while stirring, heating to about 120 ℃, reacting until water separation is finished, confirming complete reaction through LCMS detection, and concentrating to obtain light yellow liquid N- (2-bromophenyl) -1, 1-dimethoxypropane-2-imine.

(2) Dissolving 165-175g of N- (2-bromophenyl) -1, 1-dimethoxypropane-2-imine in 1600-1800ml of ethanol, controlling the temperature to be below 30-35 ℃, slowly adding 55-59g of sodium borohydride in batches, continuously keeping the temperature of 30-35 ℃ for reaction for 8-16h after the addition is finished, confirming the reaction is complete through LCMS detection, dropwise adding 300ml of water, concentrating to remove the ethanol, adding at least 1L of water for dissolving, selecting 500ml of ethyl acetate for extraction for three times each time, washing an organic phase for 1-3 times by using 300ml of saturated saline solution, and concentrating to obtain a light yellow viscous liquid N- (2-bromophenyl) -1, 1-dimethoxypropane-2-amine.

(3) 206-210g of phosphorus pentoxide are added in portions to 500ml of concentrated sulfuric acid, the temperature is kept not too high. After the addition, heating to 70 ℃, dropwise adding a solution obtained by dissolving 135-145g of N- (2-bromophenyl) -1, 1-dimethoxypropane-2-amine with 300ml of dichloromethane, keeping the temperature at 70 ℃ for reaction for 1h after the dropwise addition is finished, cooling to room temperature, pouring the mixture into ice water, keeping the temperature below 25 ℃ under the premise of continuously cooling the mixture with the ice water outside, adjusting the pH value of the mixture to 9 with sodium hydroxide, selecting a solvent as 500ml of ethyl acetate for extraction for three times each time, concentrating, mixing the sample and passing through a column; this gave 8-bromo-3-methylisoquinoline as a yellow solid.

(4) 45-55g of 8-bromo-3-methylisoquinoline are dissolved in 500ml of N, N-dimethylformamide, adding 30-34g of zinc cyanide and 15-17g of PdCl2(dppf) in sequence, replacing nitrogen for three times, heating the mixture to 140 ℃, reacting for 8-16h, and (3) confirming the reaction is complete through LCMS detection, cooling the system to room temperature, adding 1L of ethyl acetate and 1.5L of water for dilution, paving sufficient diatomite, performing suction filtration, washing the solid of the mixture twice with 500mL of ethyl acetate, separating the mother liquor, combining organic phases, washing the organic phase 1 time with 100mL of water, washing the organic phase 2-3 times with 100mL of saturated saline solution, drying the organic phase with anhydrous sodium sulfate, concentrating the dried organic phase, and purifying the organic phase by using a 100-sand 200-mesh silica gel column under the premise that the PE/EA is 3:1 to obtain the white solid 3-methyl-8-cyanoisoquinoline.

(5) 27-33g of 3-methyl-8-cyanoisoquinoline is dissolved in 500ml of methanol, 9.5-10.5g of raney nickel is added to replace hydrogen for three times, 500ml of 7M NH3 methanol solution is added, the reaction is confirmed to be complete by LCMS detection after the mixture returns to the room temperature, the reaction is filtered, the mother solution is concentrated, and dichloromethane/methanol is 20:1, and then the mixture is purified by a 100-mesh silica gel column to obtain a red viscous oily substance 3-methylisoquinoline-8-methylamine which is the final product.

Example 3

A method for preparing polysubstituted benzo nitrogen-containing heterocyclic methylamine, which is carried out by using an ultrasonic extraction device as described above due to the large amount of extraction agent required, is characterized by comprising the following steps.

(1) Dissolving 68g of pyruvic aldehyde dimethyl acetal in 2100ml of toluene, adding 113.33g of o-bromobenzylamine while stirring, heating to about 120 ℃, reacting until water separation is finished, confirming complete reaction through LCMS detection, and concentrating to obtain light yellow liquid N- (2-bromophenyl) -1, 1-dimethoxypropane-2-imine. The yield thereof was found to be 100%.

(2) Dissolving 175g of N- (2-bromophenyl) -1, 1-dimethoxypropane-2-imine in 1800ml of ethanol, controlling the temperature to be below 32 ℃, slowly adding 59g of sodium borohydride in batches, continuously keeping the temperature at 32 ℃ after the addition is finished, reacting for 10 hours, confirming the reaction completion through LCMS detection, dropwise adding 300ml of water, concentrating to remove ethanol, dissolving in at least 1L of water, selecting a solvent as 500ml of ethyl acetate for extraction three times each time, washing the organic phase with 300ml of saturated common salt for 1 time, and concentrating to obtain a light yellow viscous liquid N- (2-bromophenyl) -1, 1-dimethoxypropane-2-amine. The yield thereof was found to be 83.4%.

(3) 210g of phosphorus pentoxide were added in portions to 500ml of concentrated sulfuric acid, the temperature being kept at not too high. After the addition, heating to 70 ℃, dropwise adding 145g of a solution obtained by dissolving N- (2-bromophenyl) -1, 1-dimethoxypropane-2-amine with 300ml of dichloromethane, reacting at 70 ℃ for 1h after the dropwise addition is finished, cooling to room temperature, pouring the mixture into ice water, keeping the temperature below 25 ℃ under the premise of continuously cooling the mixture with the ice water outside, adjusting the pH value of the mixture to 9 with sodium hydroxide, selecting a solvent as 500ml of ethyl acetate for extraction three times each time, concentrating, mixing the mixture with a sample, and passing the mixture through a column; this gave 8-bromo-3-methylisoquinoline as a yellow solid. The yield thereof was found to be 47.9%.

(4) Dissolving 55g of 8-bromo-3-methylisoquinoline in 500mL of N, N-dimethylformamide, sequentially adding 34g of zinc cyanide and 17g of PdCl2(dppf), replacing nitrogen for three times, heating the mixture to 140 ℃, reacting for 10h, confirming complete reaction through LCMS detection, cooling the system to room temperature, adding 1L of ethyl acetate and 1.5L of water for dilution, paving sufficient diatomite, performing suction filtration, washing the solid of the mixture twice with 500mL of ethyl acetate, separating mother liquor, combining organic phases, washing the organic phases with 100mL of water for 1 time and 100mL of saturated saline for 2 times, drying the organic phases with anhydrous sodium sulfate, concentrating, and purifying by using a 100-mesh 200-mesh silica gel column under the premise that PE/EA is 3:1 to obtain the white solid 3-methyl-8-cyanoisoquinoline. The yield thereof was found to be 84.1%.

(5) Dissolving 33g of 3-methyl-8-cyanoisoquinoline in 500ml of methanol, adding 10.5g of raney nickel, replacing hydrogen for three times, adding 500ml of 7M NH3 methanol solution, reacting for 24 hours, confirming the completion of the reaction by LCMS detection, performing suction filtration, concentrating the mother liquor, and purifying by using a 100-mesh and 200-mesh silica gel column under the premise that dichloromethane/methanol is 20:1 to obtain a red viscous oily substance, namely 3-methylisoquinoline-8-methylamine, which is a final product. The yield thereof was found to be 52.8%. The total yield is 17.7%.

Meanwhile, under the condition of completely identical conditions, a control test is carried out in a mode that a common extraction vessel is used for extraction, separation is carried out, and combination is carried out, and the yield is 14.29%. Significantly lower than data with a dedicated device.

Example 4

A method for preparing polysubstituted benzo nitrogen-containing heterocyclic methylamine, which is carried out by using an ultrasonic extraction device as described above due to the large amount of extraction agent required, is characterized by comprising the following steps.

(1) Dissolving 66g of acetoaldehyde dimethyl acetal in 2000ml of toluene, adding 110g of o-bromobenzylamine while stirring, heating to about 120 ℃, reacting until water separation is finished, confirming complete reaction through LCMS detection, and concentrating to obtain light yellow liquid N- (2-bromophenyl) -1, 1-dimethoxypropane-2-imine. The yield thereof was found to be 100%.

(2) Dissolving 170g of N- (2-bromophenyl) -1, 1-dimethoxypropane-2-imine in 1700ml of ethanol, controlling the temperature to be below 33 ℃, slowly adding 57g of sodium borohydride in batches, continuously keeping the temperature at 33 ℃ after the addition is finished, reacting for 12h, confirming the reaction completion through LCMS detection, dropwise adding 300ml of water, concentrating to remove ethanol, dissolving in at least 1L of water, selecting a solvent which is 500ml of ethyl acetate for extraction three times each time, washing the organic phase with 300ml of saturated common salt for 2 times, and concentrating to obtain a light yellow viscous liquid N- (2-bromophenyl) -1, 1-dimethoxypropane-2-amine. Yield: 82.3 percent.

(3) 208g of phosphorus pentoxide were added in portions to 500ml of concentrated sulfuric acid, the temperature being kept not too high. After the addition, heating to 70 ℃, dropwise adding 140g of a solution obtained by dissolving N- (2-bromophenyl) -1, 1-dimethoxypropane-2-amine with 300ml of dichloromethane, reacting at 70 ℃ for 1h after the dropwise addition is finished, cooling to room temperature, pouring the mixture into ice water, keeping the temperature below 25 ℃ under the premise of continuously cooling the mixture with the ice water outside, adjusting the pH value of the mixture to 9 with sodium hydroxide, selecting a solvent as 500ml of ethyl acetate for extraction three times each time, concentrating, mixing the mixture with a sample, and passing the mixture through a column; this gave 8-bromo-3-methylisoquinoline as a yellow solid. Yield: 46.3 percent.

(4) Dissolving 50g of 8-bromo-3-methylisoquinoline in 500mL of N, N-dimethylformamide, sequentially adding 32g of zinc cyanide and 16g of PdCl2(dppf), replacing nitrogen for three times, heating the mixture to 140 ℃, reacting for 12h, confirming complete reaction through LCMS detection, cooling the system to room temperature, adding 1L of ethyl acetate and 1.5L of water for dilution, paving sufficient diatomite, performing suction filtration, washing the solid of the mixture twice with 500mL of ethyl acetate, separating mother liquor, combining organic phases, washing the organic phases with 100mL of water for 1 time and 100mL of saturated saline for 3 times, drying the organic phases with anhydrous sodium sulfate, concentrating, and purifying by using a 100-mesh 200-mesh silica gel column under the premise that PE/EA is 3:1 to obtain the white solid 3-methyl-8-cyanoisoquinoline. Yield: 82.0 percent.

(5) Dissolving 30g of 3-methyl-8-cyanoisoquinoline in 500ml of methanol, adding 10g of raney nickel, replacing hydrogen for three times, adding 500ml of 7M NH3 methanol solution, reacting for 24 hours, confirming the reaction is complete by LCMS detection, performing suction filtration, concentrating the mother liquor, and purifying by using 100-mesh and 200-mesh silica gel column under the premise that dichloromethane/methanol is 20:1 to obtain 16g of red viscous oily 3-methylisoquinoline-8-methylamine, which is a final product. Yield: 52.1 percent. The total yield is 16.28%.

Meanwhile, under the condition of completely identical conditions, a control test is carried out in a mode that a common extraction vessel is used for extraction, and separation and combination are carried out, and the yield is 13.44%. Significantly lower than data with a dedicated device.

Example 5

The extraction in the above (1) to (5) is carried out by using the ultrasonic extraction device, and the specific steps are as follows.

(A) The preparation method comprises the following steps: the extraction portion is cleaned and aired, the extraction portion is completely sleeved into the outer shell portion to be fixed, the outer shell portion is sleeved into the circular ring portion, so that the periphery (24) can be supported by the upper portion of the circular ring portion (42), the left side of the vibration head groove (27) is pushed into a concave pit on the main shell (22), and the vibration head groove is wound for multiple circles at high temperature by using electrical adhesive tapes and is fixed on the main shell (22). The degree of depth of this pit can be 5mm, and this pit can be hugged closely the adaptation with the groove left side of shaking, inserts and can tentatively fix, alleviates the fixed pressure of adhesive tape, should shake the groove left side can further have with the pit in specific convex part complex concave part to reinforcing fixed effect. Electrician's adhesive tape can be replaced by a belt of making things convenient for the dismouting, and the dismouting is easier, and fixed effect is better.

(B) Covering: the cover (13) is opened, the mixture to be extracted and the solvent are poured in, the demulsifying component is placed so that the ball part is outside the upper opening and the cone part is inward, and the cover is carefully closed. The upper cover can be additionally provided with an air vent which is provided with an air release valve, and the air release valve can allow air to pass through when being lifted to a certain degree and is used for adjusting the internal and external air pressure. The demulsification assembly can be provided with a plurality of cones with different heights.

(C) A vibration shaking step: and pushing the shell part to enable the shell part to swing back and forth 16 times, enabling the manual idle straight shell part to be approximately static, starting the ultrasonic device and enabling the vibration head to vibrate for 2min at the frequency of 30KHz, and standing for 2 min.

(D) Repeating the steps: repeat step C4 times. Substantially stable stratification can be confirmed via the observation tank before the start of each iteration.

(E) A receiving step: stopping extraction, opening the upper cover, taking out the demulsification component, respectively taking out the mixture of different phases below the liquid outlet by using different glassware, and pouring out the last phase of the extraction part from the upper opening.

Example 6

The specific steps of the extraction in the above (1) to (5) are as follows.

(A) The preparation method comprises the following steps: the extraction portion is cleaned and aired, the extraction portion is completely sleeved into the outer shell portion to be fixed, the outer shell portion is sleeved into the circular ring portion, so that the periphery (24) can be supported by the upper portion of the circular ring portion (42), the left side of the vibration head groove (27) is pushed into a concave pit on the main shell (22), and the vibration head groove is wound for multiple circles at high temperature by using electrical adhesive tapes and is fixed on the main shell (22). The degree of depth of this pit can be 7mm, and this pit can be hugged closely the adaptation with the groove left side of shaking, inserts and can tentatively fix, alleviates the fixed pressure of adhesive tape, should shake the groove left side can further have with the pit in specific convex part complex concave part to reinforcing fixed effect. Electrician's adhesive tape can be replaced by a belt of making things convenient for the dismouting, and the dismouting is easier, and fixed effect is better.

(B) Covering: the cover (13) is opened, the mixture to be extracted and the solvent are poured in, the demulsifying component is placed so that the ball part is outside the upper opening and the cone part is inward, and the cover is carefully closed. The upper cover can be additionally provided with an air vent which is provided with an air release valve, and the air release valve can allow air to pass through when being lifted to a certain degree and is used for adjusting the internal and external air pressure. The demulsification assembly can be provided with a plurality of cones with different heights.

(C) A vibration shaking step: and pushing the shell part to enable the shell part to shake 20 times back and forth in a pendulum manner, enabling the manual idle straight shell part to be approximately static, starting the ultrasonic device and enabling the vibration head to vibrate for 2min at the frequency of 45KHz, and standing for 4 min.

(D) Repeating the steps: repeat step C5 times. Substantially stable stratification can be confirmed via the observation tank before the start of each iteration.

(E) A receiving step: stopping extraction, opening the upper cover, taking out the demulsification component, respectively taking out the mixture of different phases below the liquid outlet by using different glassware, and pouring out the last phase of the extraction part from the upper opening.

Preferably, all of the foregoing reagents are chemically pure or purer. The water is deionized water, preferably double distilled water. The dosage proportion selection is data prepared in an initial laboratory, in actual preparation, in order to achieve large dosage and good preparation, the dosage is generally calculated by at least multiplying 10 times, and at the moment, common extraction equipment is not used, special extraction equipment is needed, and large dosage extraction is dealt with.

The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that are not thought of through the inventive work should be included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope defined by the claims.

Claims (1)

1. A method for preparing polysubstituted benzo nitrogen-containing heterocyclic methylamine is carried out by utilizing an ultrasonic extraction device, and is characterized in that:

the ultrasonic extraction device comprises an extraction part (1), a shell part (2), an ultrasonic part (3), a cross rod part (4), a left support part (5), a right support part (6), a glass device (7) and a demulsification component (8);

the extraction part (1) comprises a cylindrical part (11), an upper opening (12), an upper cover (13), a conical part (14), a liquid stop plug group (15) and a liquid outlet (16); the main body part of the extraction part (1) is formed by splicing an upper opening (12), a cylindrical part (11) and a cone part (14) from top to bottom, the cylindrical part (11) is in a hollow cylinder shape, the upper opening (12) is large in size and small in size, the inner side face of the upper opening (12) is a frosted part (121), the outer edge of an upper cover (13) matched with the frosted part (121) is a frosted face, the center of the upper part of the upper cover (13) is provided with a handle part (131), the cone part (14) is in a hollow cone shape, a liquid stopping bolt group (15) is arranged between the cone part (14) and a liquid outlet (16), the liquid stopping bolt group (15) is provided with a liquid stopping cavity (153), a horizontal through hole vertical to a liquid passage is formed in the liquid stopping cavity (153), a liquid stopping bolt (151) is plugged in the liquid stopping cavity, and a liquid stopping bolt handle (152) is arranged on one side of the liquid stopping bolt;

the outer shell part (2) comprises a concave ring (21), a main shell (22), an observation groove (23), a peripheral edge (24), a bearing part (25) and a vibration head groove (27), the concave ring (21) is attached to the uppermost part of the cone part (14), the main shell (22) is attached to the cylindrical part (11), the observation groove (23) is a plurality of vertical rectangular through grooves which are circumferentially and symmetrically formed in the main shell (22), the peripheral edge (24) is a circumferential protruding edge of the lower part of the bearing part (25), and the inner side of the bearing part (25) bears the upper opening (12); the main shell (22) is provided with a concave pit matched with the left side of the vibration head groove (27), and the vibration head groove (27) is provided with a downward groove matched with the vibration head (31);

the ultrasonic part (3) comprises a vibration head (31), a transducer (32), a generator (33), a power supply (34) and a reinforced cable (35), the vibration head (31) is connected with the transducer (32) through the reinforced cable (35), a connecting line of the vibration head (31) and the transducer (32) is wrapped in the reinforced cable (35), the transducer (32) is connected with the generator (33), and the generator (33) is powered by the power supply (34); the vibration head (31) is inserted into the groove and is fixed by a groove screw (36);

the middle of the cross rod part (4) is provided with a circular ring part (42), the inner diameter of the circular ring part is matched with the outer diameter of the main shell (22), the periphery (24) is supported by the upper part of the circular ring part (42), and the left and the right of the circular ring part (42) are respectively connected with a left cylindrical cross rod (41) and a right cylindrical cross rod (43) integrally;

the left support part (5) comprises a left rod (51), a left base (52), a left upper ring (53), a left hinge part (54), a left lower ring (55), a left flange (56) and a left bearing (57), the left support part (5) is positioned on the left side of the extraction part (1), the left base (52) is a cylindrical base with a screw hole in the middle, the lower end of the left rod (51) is screwed into the screw hole for fixation, the upper end of the left rod (51) is welded with the left lower ring (55), the left lower ring (55) is buckled with the left upper ring (53) which is semi-annular in the upper part, the left sides of the left lower ring (55) and the left upper ring (53) are hinged through the left hinge part (54), and the right side is provided with a pair of matched left flanges (56), the left flange (56) is fixed by a bolt group, a left bearing (57) is fixed in the buckled left lower ring (55) and the left upper ring (53), and an inner hole of the left bearing (57) is inserted into the left cross rod (41);

the right support part (6) comprises a right rod (61), a right base (62), a right upper ring (63), a right hinge part (64), a right lower ring (65), a right flange (66) and a right bearing (67), the right support part (6) is positioned at the right side of the extraction part (1), the right base (62) is a cylindrical base with a screw hole in the middle, the lower end of the right rod (61) is screwed into the screw hole for fixation, the upper end of the right rod (61) is welded and connected with the right lower ring (65), the right lower ring (65) is buckled with the right upper ring (63) which is semi-annular at the upper part, the right lower ring (65) is hinged with the right upper ring (63) through the right hinge part (64), and the left side is provided with a pair of right flanges (66) which are matched, the right flange (66) is fixed by a bolt group, a right bearing (67) is fixed in the buckled right lower ring (65) and the right upper ring (63), and an inner hole of the right bearing (67) is inserted into the right cross rod (43);

the glass device (7) is positioned below the liquid outlet (16);

the demulsification assembly (8) comprises a ball part (81), a sheet part (82) and a cone part (83);

the extraction part is made of glass; vaseline is coated in the horizontal through hole;

the shell part is any one of nylon PA66 and polytetrafluoroethylene;

the head vibration groove (27) is wound and fixed on the main shell (22) by using electrical tape for multiple circles;

the working power of the vibration head is between 60 and 100W, the working frequency is between 15KHZ and 100KHZ, and the head part of the vibration head is in a horn shape and is provided with an extended straight column;

the cross rod part (4), the left support part (5) and the right support part (6) are made of stainless steel;

the left bearing and the right bearing are ball bearings; the left bearing and the right bearing can be internally and externally provided with rubber gaskets;

the glass device (7) is a combination of a large-volume wide-mouth container or a large-caliber funnel and other glass vessels;

the demulsification component (8) is made of polytetrafluoroethylene;

the preparation method of the polysubstituted benzo nitrogen-containing heterocyclic methylamine comprises the following steps:

(1) dissolving 64-68g of acetone aldehyde dimethyl acetal in 1900-2100ml of toluene, adding 105-115g of o-bromobenzylamine while stirring, heating to 120 ℃, reacting until water separation is finished, confirming complete reaction through LCMS detection, and concentrating to obtain light yellow liquid N- (2-bromophenyl) -1, 1-dimethoxypropane-2-imine;

(2) dissolving 165-175g of N- (2-bromophenyl) -1, 1-dimethoxypropane-2-imine in 1600-1800ml of ethanol, controlling the temperature to be below 30-35 ℃, slowly adding 55-59g of sodium borohydride in batches, continuously keeping the temperature of 30-35 ℃ for reaction for 8-16h after the addition is finished, confirming the reaction is complete through LCMS detection, dropwise adding 300ml of water, concentrating to remove ethanol, adding at least 1L of water for dissolving, selecting 500ml of ethyl acetate for extraction for three times each time, washing an organic phase for 1-3 times by using 300ml of saturated saline solution, and concentrating to obtain a light yellow viscous liquid N- (2-bromophenyl) -1, 1-dimethoxypropane-2-amine;

(3) adding 206-210g of phosphorus pentoxide into 500ml of concentrated sulfuric acid in batches, and keeping the temperature not too high; after the addition, heating to 70 ℃, dropwise adding a solution obtained by dissolving 135-145g of N- (2-bromophenyl) -1, 1-dimethoxypropane-2-amine with 300ml of dichloromethane, keeping the temperature at 70 ℃ for reaction for 1h after the dropwise addition is finished, cooling to room temperature, pouring the mixture into ice water, keeping the temperature below 25 ℃ under the premise of continuously cooling the mixture with the ice water outside, adjusting the pH value of the mixture to 9 with sodium hydroxide, selecting a solvent as 500ml of ethyl acetate for extraction for three times each time, concentrating, mixing the sample and passing through a column; obtaining yellow solid 8-bromo-3-methylisoquinoline;

(4) 45-55g of 8-bromo-3-methylisoquinoline are dissolved in 500ml of N, N-dimethylformamide, and 30-34g of zinc cyanide and 15-17g of PdCl are added in this order₂(dppf), replacing nitrogen for three times, heating the mixture to 140 ℃, reacting for 8-16h, determining that the reaction is complete through LCMS detection, cooling the system to room temperature, adding 1L of ethyl acetate and 1.5L of water for dilution, paving sufficient diatomite, performing suction filtration, washing the solid of the mixture twice with 500mL of ethyl acetate, separating mother liquor, combining organic phases, washing the organic phases for 1 time with 100mL of water, washing for 2-3 times with 100mL of saturated saline, drying with anhydrous sodium sulfate, concentrating, and purifying with 100-phase 200-mesh silica gel column on the premise that PE/EA is 3:1 to obtain a white solid 3-methyl-8-cyanoisoquinoline;

(5) dissolving 27-33g of 3-methyl-8-cyanoisoquinoline in 500ml of methanol, adding 9.5-10.5g of Raney nickel, displacing hydrogen three times, adding 500ml of 7M NH₃A methanol solution, wherein the reaction is completed after 24 hours of reaction from the return of the mixture to room temperature through LCMS detection, suction filtration, mother liquor concentration, and purification by using a 100-sand 200-mesh silica gel column under the premise that dichloromethane/methanol is 20:1 to obtain a red viscous oily substance 3-methylisoquinoline-8-methylamine which is a final product;

the extraction is implemented by using the ultrasonic extraction device, and the specific steps are as follows:

(A) the preparation method comprises the following steps: cleaning and airing the extraction part, completely sleeving the extraction part into the shell part for fixation, sleeving the shell part into the circular ring part so that the periphery (24) can be supported by the upper part of the circular ring part (42), pushing the left side of the vibration head groove (27) into a pit on the main shell (22), winding the vibration head groove for multiple circles at high temperature by using an electrical adhesive tape, and fixing the vibration head groove on the main shell (22);

(B) covering: opening the upper cover (13), pouring the mixture to be extracted and the solvent, placing the demulsification component to enable the ball part to be outside the upper opening and the cone part to be inward, and carefully covering the upper cover;

(C) a vibration shaking step: pushing the shell part to enable the shell part to shake forwards and backwards for 10-20 times in a pendulum manner, enabling the manual idle straight shell part to be approximately static, starting the ultrasonic part and enabling the vibration head to vibrate for 1-2min at a frequency of more than 20KHz, and standing for 2-4 min;

(D) repeating the steps: repeating the step C3-5 times;

(E) a receiving step: stopping extraction, opening the upper cover, taking out the demulsification component, respectively taking out the mixture of different phases below the liquid outlet by using different glassware, and pouring out the last phase of the extraction part from the upper opening.

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