A method for preparing a cyclopropyl-substituted nitrogen-containing six-membered heterocyclic compound

Abstract

A method for preparing a cyclopropyl-substituted nitrogen-containing six-membered heterocyclic compound is carried out using a synthesis device. The synthesis device comprises: a four-necked flask (1), a stepped trough (2), an isothermal bath (3), a gas pipe (4), a gas source (5), and a water bath (6). Starting from 6-fluoroisoquinoline, the synthesis device is used to obtain 5-cyclopropyl-6-fluoroisoquinoline through four steps and post-treatment.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediate preparation, and in particular to a method for preparing a cyclopropyl-substituted nitrogen-containing six-membered heterocyclic compound. Background Art

[0002] Fluoroisoquinoline and its derivatives are an important class of compounds with strong biological activity and potential pharmaceutical applications. However, the method described in this application has rarely been used as a pharmaceutical intermediate, nor has any literature or documentation been published. Due to the molecular properties, unique synthetic route, and high yields, this method cannot be extended to the synthesis of other similar structures.

[0003] For 5-cyclopropyl-6-fluoroisoquinoline, those skilled in the art can obtain it through a series of adjustments and changes in the preparation methods. However, the preparation is not the most difficult problem. The yield and the presence of impurities are more important issues. The core issue of the application of this substance as an intermediate is the preparation cost, but the existing technology does not provide sufficient technical inspiration for this.

[0004] The preparation of 5-cyclopropyl-6-fluoroisoquinoline revealed the importance of temperature control. The step for obtaining 6-fluoro-5-nitroisoquinoline involves using an ice-water bath for insulation. However, repeated reactions in practice resulted in unstable yields. This instability, according to reaction experiments, was primarily due to temperature fluctuations caused by the reaction itself. External regulation of the ice-water bath often lacked sufficient response, leading to internal temperature fluctuations. We attempted to improve the repeatability of the reaction by introducing nitrogen, but this improvement still fell short of expectations. This adverse effect also introduced a new variable: the nitrogen temperature. Although the system was an ice-water bath, the nitrogen introduced was at room temperature. To ensure that the introduction of nitrogen did not affect the reaction, the nitrogen needed to be cooled to or near the system temperature. This required additional cooling measures, and using an ice-water bath to cool the nitrogen was difficult to implement. A long nitrogen line had to be buried in the ice-water bath. However, the thin line was easily damaged, posing a significant risk of affecting the reaction.

[0005] Due to the properties of this molecule, this method cannot be extended to the synthesis of other similar structures. This is due to the uniqueness of the preparation method, the high yield, and the short reaction time, which were achieved through countless experiments and cannot be replicated. Other routes are basically unable to achieve high yields or acceptable reaction times. In particular, the practical issues of temperature control in this application were not addressed, and no improvements to the device were made using the same or similar methods as those used in this application. Summary of the Invention

[0006] The first object of the present invention is to solve two specific problems in the prior art. One is the problem that the reaction itself changes temperature, affecting the effect of the ice-water bath. Introducing nitrogen can make it stable, and the solution of the present application perfectly solves this problem. The other is that the introduced nitrogen also needs to be cooled to 0° or -5 - 0°, but the cooling in the usual operation mode is not reliable, which is solved in the present application. We have solved this problem by designing a water bath part that can兼顾 cool the incoming gas, and the actual effect is better.

[0007] The present invention claims to protect a synthesis device, which is characterized in that it includes: a four-neck flask, a stepped groove, a constant-temperature groove, a gas transmission pipe, a gas source, and a water bath part.

[0008] The stepped groove is divided into an upper top groove and a lower bottom groove. The cross-sections of the top groove and the bottom groove are both rectangular, and the cross-sectional area of the top groove is at least 50 square centimeters larger than that of the bottom groove; the bottom groove of the stepped groove is completely immersed in the liquid level in the water bath part.

[0009] The constant-temperature groove is "冂"-shaped when viewed from above and can be placed inside the top groove; the constant-temperature groove is composed of an upper cover and a lower groove. The edge of the upper cover is fastened to the outer side of the upper part of the lower groove. The upper cover has air inlets and air outlets near both ends. The air inlets and air outlets are both cylindrical through holes. The upper surface of the upper cover has several pairs of counterweight protrusions, and each counterweight protrusion has a slender rectangular counterweight block clamped inside.

[0010] The gas source includes two parts, a gas cylinder and a flow meter. The gas transmission pipe includes a first gas transmission pipe, a second gas transmission pipe, and a third gas transmission pipe; the first gas transmission pipe connects the outlet of the gas cylinder and the air inlet and passes through the flow meter; the second gas transmission pipe connects the air outlet and the gas inlet of the four-neck flask; the third gas transmission pipe leads the gas out from the gas outlet of the four-neck flask.

[0011] Furthermore, the gas inlet and gas outlet of the four-neck flask are equipped with perforated rubber stoppers; the lower grooves of the stepped groove and the constant-temperature groove are made of glass, and the upper cover is made of polytetrafluoroethylene; the cross-sections of the top groove and the bottom groove are both square, and there are at least three pairs of counterweight protrusions. The counterweight blocks are hollow or solid stainless steel products, and the longitudinal section is square; the lower surface of the upper cover has multiple vertically extending baffles, and all the baffles together form a baffle group; adjacent baffles alternately extend from one side or the other side of the upper cover; a polyurethane thin layer for sealing is pasted on the inner sides of the air inlets and air outlets; the gas cylinder is filled with high-pressure nitrogen, and the effective gas delivery flow rate of the flow meter includes 0.3 - 5 L / min; the cross-section of the water-containing part of the water bath part is larger than the cross-sectional area of the bottom groove but smaller than the cross-sectional area of the top groove.

[0012] A method for preparing 5-cyclopropyl-6-fluoroisoquinoline is carried out using the aforementioned synthesis device, characterized in that it comprises the following steps: (1) taking a clean 2L four-necked flask, adding 440-460mL of concentrated sulfuric acid, clamping the flask and immersing the bottom of the flask in water in a stepped trough, immersing the isothermal trough in the stepped trough, and immersing the lower part of the stepped trough in a water bath; maintaining the temperature of the water bath at 0°C, connecting the isothermal trough, gas cylinder, flow meter, and three gas pipes, and introducing nitrogen gas through the flow meter at a rate of 1-3L / min, adding 45g of 6-fluoroisoquinoline in batches, and then adding 33-35g of potassium nitrate in batches within 1-1.5 hours. After the addition is complete, the temperature is maintained at 0°C and the reaction is continued until TLC shows that the reaction is complete. Post-treatment: The reaction mixture was poured into 2 kg of crushed ice, and the pH value was first adjusted to between 2 and 3 with a 20% by mass aqueous solution of NaOH, and then the pH value was adjusted to 8-9 with solid sodium carbonate. After complete precipitation, the precipitated solid was filtered and washed 2-3 times with 300 mL of purified water each time, dried, and slurried with 200 mL of a 20:1 ratio of n-heptane and ethyl acetate to obtain 6-fluoro-5-nitroisoquinoline.

[0013] (2) First, heat 390-410 mL of glacial acetic acid to 60°C, add 53-55 g of 6-fluoro-5-nitroisoquinoline, and stir until completely dissolved. Then, add 390-410 mL of water, maintaining the system at 60°C. Add 43-45 g of iron powder in small batches over 2 hours, and maintain the system at 60-70°C for at least 2 hours, until TLC shows that the reaction is complete.

[0014] Post-treatment: The reaction mixture was cooled and poured into 500 mL of water. The pH value was adjusted to between 8 and 10 with a 25% by mass aqueous solution of NaOH. After precipitation was complete, the precipitated solid was filtered, heated and dissolved with an appropriate amount of ethyl acetate several times, dried and spun dry, and then extracted with water several times, spun dry and combined to obtain a crude product; the crude product was dissolved in sufficient methanol, decolorized with an appropriate amount of activated carbon, spun dry, and purified with PE:EA = 20:1 to obtain 6-fluoro-5-aminoisoquinoline.

[0015] (3) Take a clean 2L four-necked bottle, set up a stirrer, clamp it and immerse the bottom of the bottle in the water of the stepped tank, immerse the isothermal tank in the stepped tank, and immerse the lower part of the stepped tank in the water bath; the water bath adopts an ice salt bath to maintain the system at -5-0°C, connect the isothermal tank, gas cylinder, flow meter, and three gas pipes, and let nitrogen flow into the flow meter at a rate of 1-3L / min, add 70-80mL of 48% by mass hydrobromic acid, and add 29-30g of 6-fluoro-5-ammonia in batches. 1. Add 12-13g of copper bromide to the mixture, stir and react for at least 10min, dissolve 24-26g of sodium nitrite in 52mL of deionized water, and add it dropwise to the four-necked flask within 5min, keep warm and stir for more than 30min, then add sodium bromide / copper sulfate mixed solution dropwise, with a ratio of 31g of sodium bromide, 55-56g of copper sulfate, and 250mL of water. After adding, replace the ice salt bath with room temperature water, and keep the water bath at a constant temperature of 20-25℃ for reaction overnight.

[0016] Post-treatment: The reaction mixture was adjusted to pH 7.5-8.5 with aqueous ammonia, extracted multiple times with appropriate amounts of ethyl acetate, and the combined products were dried and concentrated to obtain a red oil. Column chromatography was performed using n-heptane:ethyl acetate = 20:1 to 10:1 to obtain 6-fluoro-5-bromoisoquinoline.

[0017] (4) Take a clean 2L four-necked flask, add 9.5-10.5g of 6-fluoro-5-bromoisoquinoline to 100mL of dioxane, then add 3eq equivalent of triethylamine to 6-fluoro-5-bromoisoquinoline and 0.15eq equivalent of cuprous iodide to 6-fluoro-5-bromoisoquinoline, evacuate the system to a vacuum degree of less than 0.1mPa, then add high-purity nitrogen to about 1 atmosphere, pass nitrogen gas at 1-3L / min below the liquid level of the system for at least 10min, add 0.025eq equivalent of xphos Pd G2 catalyst to 6-fluoro-5-bromoisoquinoline, and then evacuate the system with high-purity nitrogen at least once, put a heating jacket on the system, heat the system to 100℃, react for at least 10 hours, or until TLC shows that the reaction is complete, and then cool the system.

[0018] Post-treatment: The system was filtered, and the filter cake was washed multiple times with 100 mL of ethyl acetate each time. The system was concentrated to dryness and separated by column chromatography using 200-300 mesh silica gel and an eluent of n-heptane:ethyl acetate = 20:1 to 10:1 to obtain the product 5-cyclopropyl-6-fluoroisoquinoline.

[0019] Compared with the prior art, the advantages of the present invention are: we have obtained the reaction conditions, especially the reaction conditions of step one and step three, by repeated comparisons, but after repeated repetitions, the reaction yield is unstable. We carry out some auxiliary cooling on the upper part of the four-necked flask, such as packing ice cubes, packing cooling patches, etc., and find that the yield is improved and the reaction repeatability is also improved, but this method is not safe to implement, there are operational risks, and nitrogen must be introduced, and the complexity of the device is too high. Second, it is not necessary to introduce nitrogen into the reaction of this application, but it is found in practice that introducing nitrogen takes out some heat and assists in maintaining a specific stability of the system, which has a good effect on the yield of the reaction, but the premise is that the nitrogen introduced should be the temperature desired by the system, such as 0°C. However, how to cool the nitrogen introduced is a big problem, and additional cooling measures are required. It is difficult to operate with an ice-water bath to cool the nitrogen, and a large length of nitrogen pipe must be buried in an ice-water bath, but because the pipeline is thin, it is easy to break, which affects the risk of reaction. The main advantages of this application are: 1. By introducing nitrogen gas to reduce the temperature, the problem of unstable reaction temperature and unstable yield is properly solved. This application, especially steps 1 and 3, are extremely sensitive to temperature. If they cannot be stably maintained at the required specific temperature, the reaction yield will have a significant adverse effect. 2. The problem of how to cool down the nitrogen gas is properly solved, and there is no extra energy waste. The method is more active and safer than directly placing the nitrogen tube in an ice-water bath. From the results, the yield is improved, and the repeatability of the reaction is improved, and the data of multiple experiments are relatively stable. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. 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 any creative work.

[0021] Figure 1 It is a schematic diagram of the front and top view of the device.

[0022] Figure 2 This is a schematic diagram of the upper cover and lower tank structure of the isothermal bath.

[0023] Figure 3 This is a schematic diagram of the isothermal bath cover and the counterweight.

[0024] Figure 4 This is a schematic diagram of the gas flow path including the isothermal bath.

[0025] Figure 5 It is a schematic diagram of the main preparation route.

[0026] Figure 6This is the NMR image of the final product.

[0027] Figure numerals: four-necked bottle 1, stepped trough 2, top trough 21, bottom trough 22, isothermal bath 3, upper cover 31, lower trough 32, air inlet 311, air outlet 312, counterweight protrusion 313, counterweight block 314, baffle group 315, gas pipe 4, first gas pipe 41, second gas pipe 42, third gas pipe 43, gas source 5, gas cylinder 51, flow meter 52. DETAILED DESCRIPTION

[0028] The preferred embodiments of the present invention are 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, thereby making a clearer and more precise definition of the protection scope of the present invention.

[0029] Example 1

[0030] A synthesis device, characterized in that it includes: a four-necked bottle 1, a stepped trough 2, an isothermal bath 3, a gas pipe 4, a gas source 5, and a water bath 6. The inlet and outlet of the four-necked bottle are placed on both sides for easy wiring and processing, and the nitrogen line is commercially available. It is equipped with a sealed rubber stopper, or other more corrosion-resistant stoppers to isolate the air, such as polytetrafluoroethylene stoppers. For safety reasons, the speed of nitrogen introduction cannot be greater than 10L / min, and a reasonable value is, for example, between 0.3-3L / min, or a specific value. The speeds of the inlet and outlet gases are basically the same.

[0031] The stepped trough 2 consists of a top trough 21 and a bottom trough 22. Both have rectangular cross-sections, with the top trough's cross-sectional area at least 50 square centimeters larger than the bottom's. The bottom trough is completely submerged in the liquid surface within the water bath. The stepped trough is made of quartz glass, or other commercially available glass for chemical containers. The rectangular shape, for example, is square, and the bottom trough's cross-sectional area is at least 30 square centimeters larger than the cross-sectional area of ​​a four-necked flask.

[0032] The top view of the isothermal bath 3 is in an inverted U shape and can be placed inside the top bath; the isothermal bath is assembled by an upper cover 31 and a lower bath 32. The edge of the upper cover is fastened to the outer side of the upper part of the lower bath. The upper cover has air inlets 311 and air outlets 312 near both ends. Both the air inlet and the air outlet are cylindrical through-holes. The upper surface of the upper cover has several pairs of counterweight protrusions, and each counterweight protrusion is provided with a slender rectangular counterweight block. With the setting of the isothermal bath, nitrogen gas is introduced through the air inlet and exits through the air outlet, and is affected and cooled therein. The setting of the baffle group makes the air flow flow tortuously inside, with as long a flow time as possible and as sufficient cooling as possible. The lower bath is made of the same material as the stepped bath, and the upper cover is made of polytetrafluoroethylene. The inner side of the outer edge of the upper cover can be made into a rough surface for easy sealing. After being wetted with a part of water, the sealing effect is good. Here, there is a problem that the isothermal bath will float, that is, the inside is gas. To ensure that it does not float, it is squeezed by polytetrafluoroethylene gaskets on three sides. For example, the upper side of the gasket is slightly thicker, so that the isothermal bath is always immersed in water.

[0033] The gas source includes two parts: a gas cylinder 51 and a flow meter 52. The gas pipeline 4 includes a first gas pipeline 41, a second gas pipeline 42, and a third gas pipeline 43; the first gas pipeline connects the outlet of the gas cylinder and the air inlet and passes through the flow meter; the second gas pipeline connects the air outlet and the gas inlet of the four-neck flask; the third gas pipeline exports the gas from the gas outlet of the four-neck flask. The gas cylinder and the flow meter are both commercially available products. The gas pipeline is also a commercially available product, and it is preferably to choose the one with a relatively thick wall.

[0034] Furthermore, the gas inlet and the gas outlet of the four-neck flask are equipped with perforated rubber stoppers; the stepped bath and the lower bath of the isothermal bath are made of glass, and the upper cover is made of polytetrafluoroethylene; the cross-sections of the top bath and the bottom bath are both square. There are at least three pairs of counterweight protrusions, and the counterweight blocks are hollow or solid stainless steel products with a square longitudinal section; the lower surface of the upper cover has multiple vertically downward extending baffles 3151, and all the baffles together form a baffle group 315; adjacent baffles alternately extend from one side or the other side of the upper cover; polyurethane thin layers for sealing are pasted on the inner sides of the air inlet and the air outlet; the gas cylinder is filled with high-pressure nitrogen gas, and the effective gas delivery flow rate of the flow meter includes 0.3 - 5 L / min; the cross-section of the water-containing part of the water bath part is larger than the cross-sectional area of the bottom bath but smaller than the cross-sectional area of the top bath. For the convenience of manufacturing, the counterweight protrusions are, for example, integrally formed with the upper cover itself, or can be separately formed and glued on the flat surface of the upper cover. The slender rectangular counterweight block is, for example, a cuboid of a*b*c, where b = c and a is much larger than b and c. For example, it is more than 10 times. After the upper cover is buckled, the baffle 3151 basically reaches the bottom of the lower bath to ensure the tortuosity of the gas path.

[0035] Example 2

[0036] A preparation method of 5-cyclopropyl-6-fluoroisoquinoline is carried out using the aforementioned synthesis device, and includes the following steps:

[0037] (1) Take a clean 2L four-necked flask, add 450mL of concentrated sulfuric acid, clamp it and immerse the bottom of the flask in the water of the stepped trough, immerse the isothermal bath in the stepped trough, and immerse the lower part of the stepped trough in the water bath; maintain the temperature of the water bath at 0℃, connect the isothermal bath, gas cylinder, flow meter, and three gas pipes, and feed nitrogen at a rate of 2L / min through the flow meter and maintain it. Add 45g of 6-fluoroisoquinoline in batches, and then add 34g of potassium nitrate in batches within 1 hour. After complete addition, maintain the temperature at 0℃ and continue the reaction until TLC shows that the reaction is complete.

[0038] Post-treatment: The reaction mixture was poured into 2 kg of crushed ice. The pH was first adjusted to 2.5 with a 20% by mass aqueous solution of NaOH, then to 8.5 with solid sodium carbonate. After complete precipitation, the precipitated solid was filtered and washed twice with 300 mL of purified water each time, dried, and slurried with 200 mL of a 20:1 ratio of n-heptane to ethyl acetate to obtain 54 g of 6-fluoro-5-nitroisoquinoline. Yield: 92.7%.

[0039] (2) First, heat 400 mL of glacial acetic acid to 60°C, add 54 g of 6-fluoro-5-nitroisoquinoline, stir until completely dissolved, add 400 mL of water, maintain the system at 60°C, add 44 g of iron powder in small batches over 2 hours, and maintain the system at 60-70°C for at least 2 hours, until TLC shows that the reaction is complete.

[0040] Post-treatment: The reaction mixture was cooled and poured into 500 mL of water. The pH was adjusted to 9 with a 25% by mass aqueous solution of NaOH. After precipitation was complete, the precipitated solid was filtered and dissolved several times with an appropriate amount of ethyl acetate. The mixture was dried and then extracted with water several times. The mixture was then dried and combined to obtain a crude product. The crude product was dissolved in sufficient methanol, decolorized with an appropriate amount of activated carbon, and purified with PE:EA (20:1) to obtain 40 g of 6-fluoro-5-aminoisoquinoline. HPLC results were 92% at 214 nm and >95% at 254 nm. NMR purity was 88.0%.

[0041] (3) Take a clean 2L four-necked bottle, set up a stirrer, clamp it and immerse the bottom of the bottle in the water of the stepped trough, immerse the isothermal bath in the stepped trough, and immerse the lower part of the stepped trough in the water bath; the water bath adopts an ice salt bath to keep the system at -3°C to -2°C, connect the isothermal bath, gas cylinder, flow meter, and three gas pipes, and feed nitrogen into the flow meter at a rate of 2L / min and maintain it, add 72mL of 48% by mass hydrobromic acid, and add 29.3g of 6- Fluoro-5-aminoisoquinoline, then add 12.5g of copper bromide, stir and react for at least 10 minutes, dissolve 25g of sodium nitrite in 52mL of deionized water, and add it dropwise to the four-necked flask within 5 minutes, keep warm and stir for 35 minutes, then add sodium bromide / copper sulfate mixed solution dropwise, with a ratio of 31g of sodium bromide, 55.8g of copper sulfate, and 250mL of water. After the addition is complete, replace the ice salt bath with room temperature water, and keep the water bath at 25℃ for overnight reaction.

[0042] Post-treatment: The reaction mixture was adjusted to pH 8 with aqueous ammonia and extracted three times with appropriate amounts of ethyl acetate. The combined products were dried and concentrated to obtain a red oil. Column chromatography was performed using n-heptane:ethyl acetate in a ratio of 20:1 to 10:1 to obtain 22 g of 6-fluoro-5-bromoisoquinoline (54.7%).

[0043] (4) Take a clean 2L four-necked flask, add 10g of 6-fluoro-5-bromoisoquinoline to 100mL of dioxane, then add 3eq equivalent of triethylamine to 6-fluoro-5-bromoisoquinoline and 0.15eq equivalent of cuprous iodide to 6-fluoro-5-bromoisoquinoline, evacuate the system to a vacuum degree of less than 0.08mPa, then replenish high-purity nitrogen to about 1 atmosphere, pass nitrogen gas at 2L / min below the liquid level of the system for 20min, add 0.025eq equivalent of xphos Pd G2 catalyst to 6-fluoro-5-bromoisoquinoline, and then evacuate the system with high-purity nitrogen at least once. Put a heating jacket on the system, heat the system to 100℃, react for at least 12 hours, or until TLC shows that the reaction is complete, and then cool the system.

[0044] Post-treatment: The system was filtered, and the filter cake was washed multiple times with 100 mL of ethyl acetate each time. The system was concentrated to dryness and separated by column chromatography using 200-300 mesh silica gel and an eluent of n-heptane:ethyl acetate = 20:1 to 10:1 to obtain 6.6 g of the product 5-cyclopropyl-6-fluoroisoquinoline. 85.7%. The total yield was 38.24%. A comparison showed that without the use of the device of the present application and without nitrogen flow, the maximum reaction yield was only 31%. After the introduction of nitrogen, the reaction yield increased and stabilized, but the maximum was around 34%. Only after the use of the device of the present application did the yield reach or even exceed 38%.

[0045] Example 3

[0046] A method for preparing 5-cyclopropyl-6-fluoroisoquinoline, using the aforementioned synthesis device, comprises the following steps:

[0047] (1) Take a clean 2L four-necked flask, add 450mL of concentrated sulfuric acid, clamp it and immerse the bottom of the flask in the water of the stepped trough, immerse the isothermal bath in the stepped trough, and immerse the lower part of the stepped trough in the water bath; maintain the temperature of the water bath at 0℃, connect the isothermal bath, gas cylinder, flow meter, and three gas pipes, and feed nitrogen at a rate of 2L / min through the flow meter and maintain it. Add 45g of 6-fluoroisoquinoline in batches, and then add 34.5g of potassium nitrate in batches within 1 hour. After complete addition, maintain the temperature at 0℃ and continue the reaction until TLC shows that the reaction is complete.

[0048] Post-treatment: The reaction mixture was poured into 2 kg of crushed ice, and the pH value was first adjusted to 2.3 with a 20% mass percentage NaOH aqueous solution, and then the pH value was adjusted to 8.3 with solid sodium carbonate. After complete precipitation, the precipitated solid was filtered and washed twice with 300 mL of purified water each time, dried, and slurried with 200 mL of 20:1 n-heptane and ethyl acetate to obtain 54.7 g of 6-fluoro-5-nitroisoquinoline. In this step, before nitrogen was passed and the device of the present application was used, the yield was relatively low and the value was unstable. The 6-fluoro-5-nitroisoquinoline obtained was 44.1 g, 45.2 g, 40.9 g, 46.8 g, and 39.2 g, which was not suitable for practical preparation. After nitrogen was passed, the product obtained by the reaction was about 50 g, but it was also unstable. After using the device of the present application, the product was generally above 53.5 g, and the yield was stable, basically between 53.5 g and 55 g.

[0049] (2) First, heat 405 mL of glacial acetic acid to 60°C, add 54.5 g of 6-fluoro-5-nitroisoquinoline, and stir until completely dissolved. Then, add 400 mL of water, maintaining the system at 60°C. Add 43.6 g of iron powder in small batches over 2 hours, and maintain the system at 65-68°C for at least 3 hours, until TLC shows that the reaction is complete.

[0050] Post-treatment: The reaction mixture was cooled and poured into 500 mL of water. The pH value was adjusted to 9 with a 25% mass percentage of NaOH aqueous solution. After precipitation was completed, the precipitated solid was filtered, heated and dissolved with an appropriate amount of ethyl acetate several times, dried and spun dry, and then extracted with water several times, spun dry and combined to obtain a crude product; the crude product was dissolved in sufficient methanol, decolorized with an appropriate amount of activated carbon, spun dry, and purified with PE:EA=20:1 to obtain 41.2 g of 6-fluoro-5-aminoisoquinoline.

[0051] (3) Take a clean 2L four-necked bottle, set up a stirrer, clamp it and immerse the bottom of the bottle in the water of the stepped trough, immerse the isothermal bath in the stepped trough, and immerse the lower part of the stepped trough in the water bath; the water bath adopts an ice salt bath to maintain the system at -2°C (±0.5), connect the isothermal bath, gas cylinder, flow meter, and three gas pipes, and introduce nitrogen at a rate of 2.2L / min and maintain it, add 75mL of 48% by mass hydrobromic acid, and add 29.6g of 6 -fluoro-5-aminoisoquinoline, then add 12.7g of copper bromide, stir and react for at least 10 minutes, dissolve 25.5g of sodium nitrite in 52mL of deionized water, and add it dropwise into the four-necked flask within 5 minutes, keep warm and stir for 35 minutes, and then add sodium bromide / copper sulfate mixed solution dropwise, with a ratio of 31g of sodium bromide, 55.8g of copper sulfate, and 250mL of water. After the addition is completed, replace the ice salt bath with room temperature water, and keep the water bath at 25℃ for overnight reaction.

[0052] Post-treatment: The reaction mixture was adjusted to pH 8.2-8.4 with aqueous ammonia, extracted three times with an appropriate amount of ethyl acetate, and the combined mixture was dried and concentrated to obtain a red oil. Column chromatography was performed using n-heptane:ethyl acetate in a ratio of 20:1 to 10:1 to obtain 22.3 g of 6-fluoro-5-bromoisoquinoline. In this step, without nitrogen purging and without the use of the apparatus of the present application, the yield was relatively low and unstable. The yields of 6-fluoro-5-bromoisoquinoline obtained were 16.1 g, 16.8 g, 17.9 g, 18.1 g, and 15.3 g, respectively, making them unsuitable for practical preparation. After nitrogen purging, the product obtained in the reaction was consistently around 20 g, but this was also unstable. After using the apparatus of the present application, the product was generally above 22 g, and the yield was stable, generally ranging from 22 g to 24 g.

[0053] (4) Take a clean 2L four-necked flask, add 9.8g of 6-fluoro-5-bromoisoquinoline to 100mL of dioxane, then add 29.5g of triethylamine and 2.7g of cuprous iodide to 6-fluoro-5-bromoisoquinoline, evacuate the system to a vacuum degree of less than 0.09mPa, then replenish high-purity nitrogen to about 1 atmosphere, pass nitrogen gas at 2.1L / min below the liquid level for 20min, add 0.027eq of xphos Pd G2 catalyst to 6-fluoro-5-bromoisoquinoline, and then evacuate the system with high-purity nitrogen at least once. Put a heating jacket on the system, heat the system to 100℃, and react for at least 14 hours until TLC shows that the reaction is complete, then cool the system.

[0054] Post-treatment: The system was filtered, and the filter cake was washed multiple times with 100 mL of ethyl acetate each time. The system was concentrated to dryness and separated by column chromatography using 200-300 mesh silica gel and an eluent of n-heptane:ethyl acetate = 20:1 to 10:1 to obtain 6.73 g of the product 5-cyclopropyl-6-fluoroisoquinoline.

[0055] Preferably, all the above reagents are of chemical purity or higher, or are of premium purity. The water is deionized water, preferably double distilled water.

[0056] There are currently no reports of the production of this product in the prior art. Compared with similar methods for preparing substances, the steps of the present invention are meticulously designed, and the raw material utilization rate 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 is the synthesis effectively achieved, but the yield is also high, which has certain industrial production value and great economic value. The present application embodies a strong inventive concept and creativity through the careful design of how to effectively cool the nitrogen protection without consuming additional energy, and achieves good preparation results. There is no similar public information available for reference in the prior art, and the present invention scheme is original. The present invention's device is original and innovatively solves the problem of insufficient temperature maintenance capacity of relying solely on the lower ice-water bath. The applicant used traditional equipment, and compared with the present invention's method, the yield was reduced by at least 15%, and there was a considerable risk that steps one and three would not be performed correctly.

[0057] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that are not conceived through creative work should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection defined in the claims.

Claims

1. A synthesis device, characterized in that: Comprising: Four-neck flask (1), stepped groove (2), constant-temperature bath (3), gas transmission pipe (4), gas source (5), water bath part (6); The stepped groove (2) is divided into an upper top groove (21) and a lower bottom groove (22). The cross-sections of both the top groove and the bottom groove are rectangular, and the cross-sectional area of the top groove is at least 50 square centimeters larger than that of the bottom groove; the bottom groove of the stepped groove is completely immersed in the liquid level inside the water bath part; The constant-temperature bath (3) looks like a "冂" shape when viewed from above and can be placed inside the top groove; the constant-temperature bath is assembled by an upper cover (31) and a lower groove (32). The edge of the upper cover is fastened to the outer side of the upper part of the lower groove. The upper cover has air inlets (311) and air outlets (312) near two ends. Both the air inlets and air outlets are cylindrical through holes. The upper surface of the upper cover has several pairs of counterweight protrusions, and each counterweight protrusion houses a slender cuboid counterweight block; The gas source includes two parts, a gas cylinder (51) and a flowmeter (52). The gas transmission pipe (4) includes a first gas transmission pipe (41), a second gas transmission pipe (42), and a third gas transmission pipe (43); the first gas transmission pipe connects the outlet of the gas cylinder and the air inlet and passes through the flowmeter; the second gas transmission pipe connects the air outlet and the gas inlet of the four-neck flask; the third gas transmission pipe exports the gas from the gas outlet of the four-neck flask.

2. A synthesis device according to claim 1, characterized in that: The gas inlet and gas outlet of the four-neck flask are equipped with perforated rubber stoppers; The lower grooves of the stepped groove and the constant-temperature bath are made of glass, and the upper cover is made of polytetrafluoroethylene; The cross-sections of the top groove and the bottom groove are both square. There are at least three pairs of counterweight protrusions, and the counterweight blocks are hollow or solid stainless steel products with a square longitudinal section; The lower surface of the upper cover has a plurality of baffles (3151) extending vertically downward, and all the baffles together form a baffle group (315); adjacent baffles alternately extend from one side or the other side of the upper cover; A polyurethane thin layer for sealing is pasted inside the air inlets and air outlets; The gas cylinder is filled with high-pressure nitrogen, and the effective gas delivery flow rate of the flowmeter includes 0.3 - 5 L / min; The cross-section of the water-containing part of the water bath part is larger than the cross-sectional area of the bottom groove but smaller than the cross-sectional area of the top groove.

3. A method for preparing 5-cyclopropyl-6-fluoroisoquinoline, using a synthesis device as claimed in claim 2, characterized in that: Including the following steps: (1) Take a clean 2L four-neck flask, add 440 - 460 mL of concentrated sulfuric acid. After clamping it well, immerse the bottom in the water of the stepped groove, immerse the constant-temperature bath in the stepped groove, and immerse the lower part of the stepped groove in the water bath part; keep the temperature of the water bath part at 0 °C. Connect the constant-temperature bath, the gas cylinder, the flowmeter, and the three gas transmission pipes. Pass nitrogen into the flowmeter at a speed of 1 - 3 L / min. Add 45 g of 6-fluoroisoquinoline in batches, and then add 33 - 35 g of potassium nitrate in batches within 1 - 1.5 hours. After complete addition, keep the temperature at 0 °C and continue the reaction until TLC shows that the reaction is complete; Post-treatment: Pour the reaction mixture into 2 kg of crushed ice. First, adjust the pH value to between 2 and 3 with a 20% mass percentage of NaOH aqueous solution, and then adjust the pH value to 8 - 9 with solid sodium carbonate. After complete precipitation, filter the precipitated solid by suction, and wash it 每次用300mL纯净水洗2 - 3次 with 300 mL of pure water 2 - 3 times each time, dry it, and slurry it with 200 mL of a 20:1 mixture of n-heptane and ethyl acetate to obtain 6-fluoro-5-nitroisoquinoline; (2) First, heat 390-410 mL of glacial acetic acid to 60°C, add 53-55 g of 6-fluoro-5-nitroisoquinoline, stir until completely dissolved, add 390-410 mL of water, maintain the system at 60°C, add 43-45 g of iron powder in small batches over 2 hours, maintain the system at 60-70°C, and react for at least 2 hours, until TLC shows that the reaction is complete; Post-treatment: The reaction mixture was cooled and poured into 500 mL of water. The pH value was adjusted to between 8 and 10 with a 25% by mass aqueous solution of NaOH. After precipitation was complete, the precipitated solid was filtered, heated and dissolved several times with an appropriate amount of ethyl acetate, dried and spun dry, and then extracted with water several times, spun dry and combined to obtain a crude product; the crude product was dissolved in sufficient methanol, decolorized with an appropriate amount of activated carbon, spun dry, and purified with PE:EA = 20:1 to obtain 6-fluoro-5-aminoisoquinoline; (3) Take a clean 2L four-necked bottle, set up a stirrer, clamp it and immerse the bottom of the bottle in the water of the stepped tank, immerse the isothermal tank in the stepped tank, and immerse the lower part of the stepped tank in the water bath; the water bath adopts an ice salt bath to maintain the system at -5-0°C, connect the isothermal tank, gas cylinder, flow meter, and three gas pipes, and let nitrogen flow into the flow meter at a rate of 1-3L / min, add 70-80mL of 48% by mass hydrobromic acid, and add 29-30g of 6-fluoro-5-ammonia in batches.

1. Add 12-13g of copper bromide to the mixture and stir for at least 10 minutes. Dissolve 24-26g of sodium nitrite in 52mL of deionized water and add it dropwise to the four-necked flask within 5 minutes. Keep warm and stir for more than 30 minutes. Then, add a sodium bromide / copper sulfate mixed solution dropwise with a ratio of 31g of sodium bromide, 55-56g of copper sulfate, and 250mL of water. After the addition is complete, replace the ice salt bath with room temperature water and keep the water bath at a constant temperature of 20-25°C for overnight reaction. Post-treatment: The reaction mixture was adjusted to pH 7.5-8.5 with aqueous ammonia, extracted several times with appropriate amounts of ethyl acetate, and the combined products were dried and concentrated to obtain a red oil. Column chromatography was performed using n-heptane:ethyl acetate = 20:1 to 10:1 to obtain 6-fluoro-5-bromoisoquinoline; (4) Take a clean 2L four-necked flask, add 9.5-10.5g of 6-fluoro-5-bromoisoquinoline to 100mL of dioxane, then add 3eq equivalent of triethylamine to 6-fluoro-5-bromoisoquinoline, 0.15eq equivalent of cuprous iodide to 6-fluoro-5-bromoisoquinoline, evacuate the system to a vacuum degree of less than 0.1mPa, then add high-purity nitrogen to about 1 atmosphere, pass nitrogen gas at 1-3L / min below the liquid level for at least 10min, add 0.025eq equivalent of xphos Pd G2 catalyst to 6-fluoro-5-bromoisoquinoline, and then evacuate and fill with high-purity nitrogen at least once, put a heating jacket on the system, heat the system to 100℃, react for at least 10 hours, or until TLC shows that the reaction is complete, and then cool the system; Post-treatment: The system was filtered, and the filter cake was washed multiple times with 100 mL of ethyl acetate each time. The system was concentrated to dryness and separated by column chromatography using 200-300 mesh silica gel and an eluent of n-heptane:ethyl acetate = 20:1 to 10:1 to obtain the product 5-cyclopropyl-6-fluoroisoquinoline.

4. The method for preparing 5-cyclopropyl-6-fluoroisoquinoline according to claim 3, wherein The following steps are involved: (1) Take a clean 2L four-necked bottle, add 450mL of concentrated sulfuric acid, clamp it and immerse the bottom of the bottle in the water of the stepped tank, immerse the isothermal tank in the stepped tank, and immerse the lower part of the stepped tank in the water bath; the water bath is kept at a temperature of 0°C, connect the isothermal tank, gas cylinder, flow meter, and three gas pipes, and feed nitrogen at a rate of 2L / min through the flow meter and maintain it. Add 45g of 6-fluoroisoquinoline in batches, and then add 34g of potassium nitrate in batches within 1 hour. After the addition is complete, keep the temperature at 0°C and continue the reaction until TLC shows that the reaction is complete; Post-treatment: The reaction mixture was poured into 2 kg of crushed ice, and the pH value was first adjusted to 2.5 with a 20% by mass aqueous solution of NaOH, and then adjusted to 8.5 with solid sodium carbonate. After precipitation was complete, the precipitated solid was filtered and washed twice with 300 mL of purified water each time, dried, and slurried with 200 mL of a 20:1 ratio of n-heptane and ethyl acetate to obtain 6-fluoro-5-nitroisoquinoline; (2) First, heat 400 mL of glacial acetic acid to 60°C, add 54 g of 6-fluoro-5-nitroisoquinoline, stir until completely dissolved, add 400 mL of water, maintain the system at 60°C, add 44 g of iron powder in small batches over 2 hours, and maintain the system at 60-70°C for at least 2 hours, until TLC shows that the reaction is complete; Post-treatment: The reaction mixture was cooled and poured into 500 mL of water. The pH value was adjusted to 9 with a 25% by mass aqueous solution of NaOH. After precipitation was complete, the precipitated solid was filtered, heated and dissolved with an appropriate amount of ethyl acetate several times, dried and spun dry, and then extracted with water several times, spun dry and combined to obtain a crude product; the crude product was dissolved in sufficient methanol, decolorized with an appropriate amount of activated carbon, spun dry, and purified with PE:EA = 20:1 to obtain 6-fluoro-5-aminoisoquinoline; (3) Take a clean 2L four-necked bottle, set up a stirrer, clamp it and immerse the bottom of the bottle in the water of the stepped trough, immerse the isothermal bath in the stepped trough, and immerse the lower part of the stepped trough in the water bath; the water bath adopts an ice salt bath to keep the system at -3°C to -2°C, connect the isothermal bath, gas cylinder, flow meter, and three gas pipes, and feed nitrogen into the flow meter at a rate of 2L / min and maintain it, add 72mL of 48% by mass hydrobromic acid, and add 29.3g of 6- Fluoro-5-aminoisoquinoline, then add 12.5g of copper bromide, stir and react for at least 10 minutes, dissolve 25g of sodium nitrite in 52mL of deionized water, add it dropwise to the four-necked flask within 5 minutes, keep warm and stir for 35 minutes, then add a sodium bromide / copper sulfate mixed solution dropwise with a ratio of 31g of sodium bromide, 55.8g of copper sulfate, and 250mL of water. After the addition is complete, replace the ice salt bath with room temperature water and keep the water bath at 25℃ for overnight reaction; Post-treatment: The reaction mixture was adjusted to pH 8 with aqueous ammonia, extracted three times with an appropriate amount of ethyl acetate, and the combined products were dried and concentrated to obtain a red oil. Column chromatography was performed using n-heptane:ethyl acetate = 20:1 to 10:1 to obtain 6-fluoro-5-bromoisoquinoline; (4) Take a clean 2L four-necked flask, add 10g of 6-fluoro-5-bromoisoquinoline to 100mL of dioxane, then add 3eq equivalent of triethylamine to 6-fluoro-5-bromoisoquinoline, 0.15eq equivalent of cuprous iodide to 6-fluoro-5-bromoisoquinoline, evacuate the system to a vacuum degree of less than 0.08mPa, then add high-purity nitrogen to about 1 atmosphere, pass 2L / min nitrogen below the liquid level of the system for 20min, add 0.025eq equivalent of xphos Pd G2 catalyst to 6-fluoro-5-bromoisoquinoline, and then evacuate and fill with high-purity nitrogen at least once, put a heating jacket on the system, heat the system to 100℃, react for at least 12 hours, or until TLC shows that the reaction is complete, and then cool the system; Post-treatment: The system was filtered, and the filter cake was washed multiple times with 100 mL of ethyl acetate each time. The system was concentrated to dryness and separated by column chromatography using 200-300 mesh silica gel and an eluent of n-heptane:ethyl acetate = 20:1 to 10:1 to obtain the product 5-cyclopropyl-6-fluoroisoquinoline.

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