Preparation method of 2-hydroxy-4-amino-5-methylpyridine

Abstract

The invention relates to a preparation method of 2-hydroxy-4-amino-5-methylpyridine, and the preparation method comprises the following steps of: preparing 2-hydroxy-4-amino-5-methylpyridine; and by adopting a fixed bed and continuous flow technology, the reaction safety is greatly improved, the yield can be maintained while mass production can be realized, the production cost is reduced, the safety is improved, and the method is suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical intermediate synthesis, and in particular to a method for preparing 2-hydroxy-4-amino-5-methylpyridine. Background Art

[0002] 2-Hydroxy-4-amino-5-methylpyridine (compound of formula I) is an important fragment in drug design. Its derivatives have high biological activity and are widely used in the fields of chemistry, chemical industry and medicine. For example, in the synthesis of proton pump inhibitor omeprazole (a), non-steroidal selective mineralocorticoid receptor antagonist finerenone (b), etc., 2-hydroxy-4-amino-5-methylpyridine is a very important intermediate. Gastric ulcer is one of the common and frequently-occurring diseases in the Chinese population. Although its incidence rate has begun to show a downward trend in recent years, it is still one of the most common diseases in digestive system diseases. The occurrence of gastric ulcer is mainly related to the imbalance between the damage factors of the gastroduodenal mucosa and the self-defense and repair factors of the mucosa. Helicobacter pylori infection, non-steroidal anti-inflammatory drugs (NSAID, such as aspirin), and abnormal gastric acid secretion are common causes of ulcers. Typical ulcer pain is characterized by long-term, periodic and rhythmic nature. Omeprazole (a) is an effective proton pump inhibitor that can inhibit gastric acid secretion. The mineralocorticoid receptor (MR) is a member of the steroid receptor family. It regulates blood pressure by regulating the effects of aldosterone (Aldo) on renal sodium handling. Clinical trial data have shown that MR antagonists also have beneficial effects in the treatment of renal diseases (including diabetic nephropathy) (Kidney International 2011, 79, 1051). In July 2021, based on the positive results of the FIDELIO-DKD Phase III clinical study in adult patients with chronic kidney disease and type 2 diabetes, the US FDA approved finerenone (b) On the market, in December 2021, the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended approval of the marketing application for the non-steroidal selective mineralocorticoid receptor antagonist finerenone (b), and recommended finerenone (10 mg or 20 mg) for the treatment of adult patients with chronic kidney disease (stages 3 and 4 with albuminuria) and type 2 diabetes. In recent years, connecting 2-hydroxy-4-amino-5-methylpyridine (compound of formula I) to a specific structure to seek some active screening drugs has become one of the hot spots in the drug discovery stage. Therefore, 2-hydroxy-4-amino-5-methylpyridine (compound of formula I) is a very promising drug intermediate.

[0003]

[0004]

[0005] The currently disclosed synthesis methods of 2-hydroxy-4-amino-5-methylpyridine (such as CN114656400A, CN115340492 A, CN 113474332A) are mostly carried out in a reaction kettle, which is difficult to post-process, and the reaction is difficult to scale up, making it difficult to carry out industrial mass production. It can be seen that it is of great significance to develop a simple, safe, easy to scale up and low-cost synthesis process of 2-hydroxy-4-amino-5-methylpyridine. Summary of the invention

[0006] Purpose of the invention: The purpose of the present invention is to solve the problems of high cost, low safety and unsuitability for industrial production in the process of preparing 2-hydroxy-4-amino-5-methylpyridine (Formula I compound) in the prior art, and to provide an improved preparation method for preparing 2-hydroxy-4-amino-5-methylpyridine (Formula I compound). Steps 1 and 3 of the method adopt fixed bed technology, which effectively improves the product yield, high reaction purity, stable and controllable continuous reaction, greatly improves safety, and has a long catalyst life, which is suitable for large-scale amplification; in step 3, the reduction of halogen-containing nitropyridine compounds is commonly used in iron powder-acid process, but the production capacity of this process is limited, and with the increase of amplification scale, the heat of reaction is also greatly increased, and it cannot be amplified on a large scale, and more waste metal salts are generated in the production process, and the production cost is difficult to reduce. After adopting the continuous process, the reaction process is continuously controllable, the safety risk is reduced, and the catalyst is recyclable, and no solid waste is generated, which greatly reduces the cost of the reaction. Steps 2 and 4 adopt flow chemistry, and the reaction end point is accurately controlled by continuous flow technology, the yield is improved and stabilized, the amount of three wastes is reduced, and the production cost is reduced, which is suitable for industrial production.

[0007] The present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0008]

[0009] Step 1: The compound of formula II is dissolved in an organic solvent 1, and reacts with hydrogen peroxide in a fixed bed reactor under the action of a catalyst 1 to generate a compound of formula III;

[0010] Step 2: The compound of formula III is dissolved in an acidic solvent and reacted with an acidic reagent in a continuous reactor to generate a compound of formula IV;

[0011] Step 3: The compound of formula IV is dissolved in an organic solvent 2, and reacts with a reducing agent in the presence of a catalyst 2 in a fixed bed reactor to generate a compound of formula V;

[0012] Step 4: The compound of formula V is dissolved in an organic solvent 3, and reacted with an alkaline reagent in a continuous reactor to generate a compound of formula I.

[0013] Preferably, the catalyst 1 in step 1 is TS-1, which is spherical or strip-shaped;

[0014] More preferably, the catalyst 1 in step 1 is strip TS-1, the reaction temperature is 75-80° C., and the reaction time is 0.1-60 mins.

[0015] Preferably, the organic solvent 1 in step 1 is selected from methanol or acetonitrile.

[0016] Preferably, the molar ratio of the compound of formula II to hydrogen peroxide in step 1 is 1:2-3.

[0017] Preferably, the acidic solvent in step 2 is selected from concentrated sulfuric acid, and the acidic reagent is selected from concentrated sulfuric acid + fuming nitric acid; the amount of the acidic solvent is 1.5 to 8.5 times the volume of the compound of formula III; the amount of concentrated sulfuric acid in the acidic reagent is 1 to 7 times the volume of the compound of formula III; the molar mass ratio of the compound of formula III to the fuming nitric acid is 1:4.5 to 9; the reaction temperature is 85 to 110° C.; the reaction pressure is 0.6 to 0.8 MPa; and the reaction time is 0.5 to 1 h;

[0018] More preferably, the acidic solvent in step 2 is selected from concentrated sulfuric acid, and the acidic reagent is selected from concentrated sulfuric acid + fuming nitric acid; the amount of the acidic solvent is 1.5 to 2 times the volume of the compound of formula III; the amount of concentrated sulfuric acid in the acidic reagent is 1 to 2 times the volume of the compound of formula III; the molar mass ratio of the compound of formula III to fuming nitric acid is 1:4.5 to 6; the reaction temperature is 100 to 105° C.; the reaction pressure is 0.7 to 0.8 MPa; and the reaction time is 0.5 to 1 h.

[0019] Preferably, the reducing agent in step 3 is hydrogen, and the catalyst 2 is 2% Pt-C.

[0020] Preferably, the organic solvent 2 in step 3 is selected from one or more of THF, methanol or ethanol;

[0021] Preferably, the reaction temperature in step 3 is 60-100° C., and the reaction time is 0.1-60 mins;

[0022] More preferably, the organic solvent 2 in step 3 is a mixed solvent of THF+methanol, the mass ratio of THF to methanol is 3-4:1; the reaction temperature is 70-85°C; and the reaction time is 0.1-60 mins.

[0023] Preferably, the organic solvent 3 in step 4 is selected from one or more of THF, methanol or water;

[0024] Preferably, the alkaline agent in step 4 is selected from 10-20% potassium hydroxide solution, and the molar mass ratio of the compound of formula V to the potassium hydroxide solution is 1:5-18;

[0025] Preferably, in step 4, the reaction temperature is 200-240° C.; the reaction pressure is 3-5 MPa;

[0026] More preferably, the organic solvent 3 described in step 4 is THF, and the amount used is 6 times the volume of the compound of formula V; the alkaline reagent described in step 4 is 10% potassium hydroxide solution, and the molar mass ratio of the compound of formula V to the potassium hydroxide solution is 1:5; the reaction temperature in step 4 is 220-230° C.; and the reaction pressure is 4.5-5.0 MPa.

[0027] The abbreviations of some reaction reagents involved in the present invention are as follows:

[0028] THF: Tetrahydrofuran

[0029] TS-1: Titanium silicate molecular sieve (CAS No.: 12173-28-3)

[0030] Beneficial Effects

[0031] The present invention provides a method for preparing 2-hydroxy-4-amino-5-methylpyridine (compound of formula I), using 2-chloro-5-methylpyridine (compound of formula II) as a raw material, adopting a fixed bed process, reacting with an oxidant under the action of a catalyst to generate a compound of formula III; the compound of formula III is reacted with a reducing agent under the action of an acidic reagent, adopting a flow chemistry technique to generate a compound of formula IV; the compound of formula IV reacts with a reducing agent under the action of a catalyst, adopting a fixed bed process to generate a compound of formula V; the compound of formula V reacts with an alkaline reagent to generate a compound of formula I. Compared with the existing synthesis process, the new process uses advanced fixed bed technology and flow chemistry technology, with high reaction purity, stable continuous reaction, and continuous controllability, which solves the problem that the original synthesis route process is limited in capacity, high in danger, and has many wastes, and the production cost is difficult to reduce. It can maintain a high yield and improve safety during large-scale industrial production. In summary, the technical solution provided by the present invention has a good economic effect, reduces production costs, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings in the following description are some embodiments of the present invention.

[0033] Figure 1 For the final product of Example 1 of the present invention 1 H-NMR spectrum (400 MHz, DMSO-d6);

[0034] Figure 2 It is the HPLC spectrum of the final product of Example 1 of the present invention. DETAILED DESCRIPTION

[0035] The present invention is further illustrated below in conjunction with specific embodiments. The embodiments are implemented based on the technical solutions of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0036] Example 1

[0037]

[0038] Preparation of compound of formula III:

[0039] Weigh TS-1 catalyst (10L) and slowly pour it into the reaction tube. Plug cotton at the reactor outlet and pad the nickel mesh, then tighten the ferrules at both ends of the reactor. Fill the reactor with nitrogen and back pressure to 0.5MPa, and check the air tightness of the system. Add formula II compound (3.0kg, 20.891mol, 1eq.) and acetonitrile (49.01kg) into the pneumatic stirring tank, stir until dissolved, then slowly add 30% hydrogen peroxide (7.99kg) and continue to stir evenly, and put it into the raw material tank for use. Fill the pump; turn on the reactor's hot and cold all-in-one machine to 60℃, turn on the preheater's hot and cold all-in-one machine to 50℃; turn on the feed pump and set it to 3000mL / min to enter the preheater; after the temperature is over, set the reactor's hot and cold all-in-one machine to 80℃, the preheater temperature to 70℃, and when the specified temperature is reached, set the liquid feed rate to 5000mL / min. After GC detection is complete, cut into the product tank; transfer the reaction solution to a clean reactor, start stirring, cool to 0-10°C, add sodium thiosulfate solution dropwise, control the temperature in the reactor not higher than 25°C, take a sample for testing with starch potassium iodide test paper, and after the test paper does not change color, concentrate at 30-40°C, cool to 15-25°C, add chloroform (3V), stir, separate, collect the organic phase, add chloroform (3V) to the aqueous phase, stir, stand, separate, combine the organic phases, add water (3V), stir, stand, separate, concentrate, add n-heptane (5V), concentrate, stir at 0-10°C for 2h, filter, wash the filter cake with n-heptane (1V), and dry at 30-40°C for 5-10h to obtain the title compound (3.043kg, yield 86.58%).

[0040] Preparation of compounds of formula IV:

[0041] Take a four-necked bottle (5L), first add H2SO4 (3.19kg, 1.58V), turn on the stirring ice-water bath to cool below 10°C, add the compound of formula III (1.1kg, 7.66mol, 1.0eq.) in batches, control the temperature below 40°C, stir and dissolve, filter using a sand core funnel, transfer the filtrate into a 5L beaker, and use it as Solution A; take another four-necked bottle (5L), first add H2SO4 (2.01kg, 1.0V), turn on the stirring ice-water bath to cool below 10°C, add fuming nitric acid (2.41kg, 38.3mol, 5eq.) dropwise, control the temperature below 30°C, stir and dissolve, and use it as Solution B.

[0042] Build equipment pipelines. Solution A and Solution B use precise feed pumps for feeding. The discharge pipeline is directly connected to the mixer and connected to a continuous flow tubular or plate reactor (300 mL). The discharge port is connected to a diaphragm back pressure valve with a back pressure of 0.7-0.8 MPa. The back pressure valve is directly connected to a white bucket (10 L) filled with ice. The reactor is heated by a high and low temperature all-in-one machine, and the temperature of the all-in-one machine is controlled at 100-105 °C.

[0043] Two feed pumps simultaneously pump Solution A and Solution B at a flow rate of 5 mL / min. After the two solutions are mixed in the mixer, they enter the pre-heated continuous flow tubular or plate reactor (300 mL) with a residence time of 30 min. After passing through the back pressure valve, a large amount of gas is released from the reaction liquid at the outlet. The reaction liquid flows into a white barrel (10 L) for quenching, and a light yellow gas is generated, which is absorbed by an external alkali solution.

[0044] LC detection showed that the reaction was basically complete. The reaction liquid was collected and poured into a reactor (50L) for post-treatment. The reaction liquid was cooled to 0-10°C, and sodium carbonate was added in batches. The temperature was controlled below 30°C to release gas and heat significantly. The addition was completed in 1h. After the addition was completed, the pH test paper detected pH = 3-4, and then water (4kg) was added. Stir at 20-30°C for 1h. Filter by suction, put the obtained filter cake into a beaker (5L), add water (3kg), use mechanical stirring to beat for 0.5h, filter again, beat the filter cake again and repeat the above operation, filter, drain, rinse the filter cake twice with water (500mL*2), and place the obtained filter cake in a forced air drying oven at 60-70°C for 10-12h to obtain the product formula IV compound (1.22kg, yield 80.2%).

[0045] Preparation of compounds of formula V

[0046] Weigh 2% Pt-C catalyst (10L), slowly pour it into the reaction tube, plug the reactor outlet with cotton and then pad the nickel mesh, then tighten the ferrules at both ends of the reactor; fill the reactor with nitrogen and back pressure to 3.5MPa, check the air tightness of the system; put the compound of formula IV (3.13kg, 16.596mol, 1eq.) and THF (47.56kg) / MeOH (11.89kg) into the pneumatic stirring tank and stir until dissolved, and put it into the raw material tank for standby. Fill the pump, turn on the reactor's cooling and heating integrated machine to 60℃, turn on the preheater's cooling and heating integrated machine to 60℃; adjust the reaction system pressure to 3.0Mpa, turn on hydrogen, set the air intake to 200L / min, turn on the feed pump, set 2000mL / min to enter the preheater; after the temperature is over, set the reactor's cooling and heating integrated machine to 90℃, the preheater temperature to 70℃, and when the temperature reaches the specified temperature, set the liquid feed volume to 3000mL / min. After LC detection shows that the reaction is basically complete, the product tank is cut into; the reaction solution is transferred to a clean reactor, slowly stirred, activated carbon is added, stirred for 2 hours, the reaction solution is filtered through diatomaceous earth, the filter cake is washed with methanol, the filtrate is combined, concentrated, MTBE (2V) is added, concentrated, MTBE (2V) is added, concentrated again, MTBE (2V) and n-heptane (2V) are added, the temperature is lowered to 0-5°C and stirred for 2 hours, filtered, the filter cake is rinsed with n-heptane (1V), and dried at 40-50°C for 5-10 hours to obtain the product formula V compound (2.213 kg, yield 79.39%).

[0047] Preparation of compounds of formula I

[0048] Take a single-necked bottle (250 mL), first add the compound of formula V (20.00 g, 0.140 mol, 1.0 eq.), then add tetrahydrofuran (120.0 mL, 6 v / w), stir at room temperature about 20-25°C to dissolve, and use as solution A; take another single-necked bottle (1 L), first add KOH (40.00 g, 0.713 mol, 5.09 eq.), then add water (360.0 g, 20.00 mol, 142.8 eq.), stir at room temperature 20-25°C to dissolve, prepare a 10% KOH aqueous solution, and use as solution B.

[0049] A continuous flow reaction system was built. Solution A and solution B were accurately fed using a feed pump. The two raw material liquids were preheated in a preheater and then connected to a mixer. They were then connected to a continuous flow tubular or plate reactor (150 mL). The reactor outlet was connected to a back pressure valve. The back pressure of the reaction system was 4.5-5.0 MPa. The back pressure valve outlet pipe was directly connected to a receiving tank (2 L). The reactor temperature was controlled at 220-230 °C.

[0050] Two feed pumps simultaneously pump solution A and solution B at flow rates of 0.62 mL / min and 1.88 mL / min respectively. The two solutions flow through the preheater and then flow through the mixer to mix, and then enter the preheated continuous flow tubular or plate reactor (150 mL). The residence time is 1 hour, and the material is discharged after the back pressure valve, and the feed liquid flows into the receiving bottle.

[0051] After HPLC detection showed that the reaction was complete, hydrochloric acid was added to adjust the pH to 6-7, and the mixture was concentrated under reduced pressure. Anhydrous ethanol (500 mL) was distilled twice to replace the reaction solvent, and insoluble salts were removed by filtration. The filtrate was collected and concentrated under reduced pressure at 40° C. to 0.5 v / w, filtered, and dried at 40-50° C. to obtain the product compound of formula I (12.72 g, yield 75%-95%).

[0052] Comparative Experiment Example 1

[0053]

[0054] The above reaction route is an exploration of condition optimization based on the synthesis method of 2-hydroxy-4-amino-5-methylpyridine (compound of formula I) disclosed in patents such as CN 114656400 A, CN 103193704 A, CN 115340492 A, and CN113474332 A. The results are shown in the data in the table.

[0055] Table 1 Catalyst shape and fixed bed feeding method screening conditions for step 1

[0056]

[0057]

[0058] Table 2 Catalyst life verification in step 1

[0059]

[0060] Table 3 Optimization screening of solvent selection in step 1

[0061]

[0062]

[0063] During the optimization and screening process of the conditions, it was first discovered that there was a small amount of breakage in the spherical catalyst particles, which accumulated at the outlet of the reactor, causing fluctuations in the outlet pipe resistance. Therefore, the TS-1 with a strip molding process was selected for the reaction, and no reactor blockage occurred. Therefore, the corrosion resistance of this catalyst (strip TS-1 catalyst) met the process requirements. Subsequently, the catalyst life was tested, and it was found that the remaining raw materials were basically stable after 260 hours of operation, and the product purity could still be maintained at around 99%, indicating that the catalyst life was relatively long. After that, the reaction solvents were screened, and it was found that the reaction purity when methanol was used as the solvent and hydrogen peroxide (2.5 eq.) was slightly lower than that when acetonitrile was used as the solvent and hydrogen peroxide (3.0 eq.), but the overall purity was still above 99%. Moreover, the results of the large-scale experiment were basically the same as those of the small test, which is suitable for large-scale expansion.

[0064] Table 4 Optimization screening of reagent dosage and flow chemistry reaction conditions in step 2

[0065]

[0066]

[0067] Among them, No. 1 to 4 are traditional batch modes, referring to the experimental operation in CN103193704B. Based on a series of attempts on the dosage of concentrated sulfuric acid and fuming nitric acid, the optimal dosage of the two was determined, and the reaction temperature, pressure, and time were explored to ensure the safety of the reaction while maintaining a high yield.

[0068] Table 5 Step 3 Catalyst Selection and Reaction Conditions Screening

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075] The side reaction that usually occurs in the reduction of 2-chloro-substituted pyridine derivatives is that the chlorine atoms are simultaneously reduced to hydrogen. The reduction of halogen-containing nitropyridine compounds reported at present usually uses an iron powder-acid process, but this process has limited production capacity, there are potential safety hazards, it cannot be scaled up on a large scale, and more waste metal salts are produced during the production process, and it is difficult to reduce production costs. In the present invention, a variety of catalysts are tried, and it is found that the catalyst activity is too strong or the reaction temperature is too high, which may lead to the generation of dechlorination impurities. Finally, 2% Pt-C is selected as the optimal condition, which can be selectively reduced and retain the halogen atoms on the pyridine ring. A large number of experiments are subsequently carried out to further explore the reaction solvent and catalyst life, and the effect of the amplification experiment to find the optimal industrial production conditions.

[0076] Table 6 Lifetime study of step 3 catalyst (2% Pt-C) (reaction solvent is 5wt% THF-MeOH (mass ratio 3:1))

[0077]

[0078] Table 7 Step 3 scale-up process condition trial and optimization screening (catalyst is 2% Pt-C, reaction solvent is 5wt% THF-MeOH (mass ratio 4:1))

[0079]

[0080] The reduction of halogen-containing nitropyridine compounds usually uses the iron powder-acid process, but this process has limited production capacity, and as the scale increases, the reaction heat also increases greatly, which cannot be scaled up on a large scale. In addition, a large amount of waste metal salts are generated during the production process, and it is difficult to reduce production costs. After adopting the continuous process, the reaction process is continuously controllable, reducing safety risks, and the catalyst is recyclable, and no solid waste is generated, which greatly reduces the cost of the reaction.

[0081] Table 8 Optimization screening of reagent dosage and flow chemistry reaction conditions in step 4

[0082]

[0083]

[0084]

[0085] Based on a series of screening of the reaction system, the optimal dosage of material concentration was determined, and the reaction retention time, pressure, reaction temperature, etc. were explored.

[0086] Although the above describes the specific implementation methods of the present invention, it is not intended to limit the scope of protection of the present invention. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing a compound of formula I, characterized in that The following steps are included: Step 1: The compound of formula II is dissolved in an organic solvent 1, and reacts with hydrogen peroxide in a fixed bed reactor under the action of a catalyst 1 to generate a compound of formula III; Step 2: The compound of formula III is dissolved in an acidic solvent and reacted with an acidic reagent in a continuous reactor to generate a compound of formula IV; Step 3: The compound of formula IV is dissolved in an organic solvent 2, and reacts with a reducing agent in the presence of a catalyst 2 in a fixed bed reactor to generate a compound of formula V; Step 4: The compound of formula V is dissolved in an organic solvent 3, and reacted with an alkaline reagent in a continuous reactor to generate a compound of formula I.

2. The preparation method according to claim 1, characterized in that: The catalyst 1 in step 1 is TS-1, which is spherical or strip-shaped.

3. The preparation method according to claim 1, characterized in that: The catalyst 1 in step 1 is TS-1, which is in the shape of strips, and the reaction temperature is 75-80°C.

4. The preparation method according to claim 1, characterized in that: In step 1, the organic solvent 1 is selected from methanol or acetonitrile.

5. The preparation method according to claim 1 or claim 3, characterized in that: The molar ratio of the compound of formula II to hydrogen peroxide in step 1 is 1:2-3.

6. The preparation method according to claim 1, characterized in that: The acidic solvent in step 2 is selected from concentrated sulfuric acid, and the acidic reagent is selected from concentrated sulfuric acid + fuming nitric acid; the amount of the acidic solvent is 1.5 to 8.5 times the volume of the compound of formula III; the amount of concentrated sulfuric acid in the acidic reagent is 1 to 7 times the volume of the compound of formula III; the molar mass ratio of the compound of formula III to the fuming nitric acid is 1:4.5 to 9; the reaction temperature is 85 to 110° C.; the reaction pressure is 0.6 to 0.8 MPa; and the reaction time is 0.5 to 1 h.

7. The preparation method according to claim 1, characterized in that: The acidic solvent in step 2 is selected from concentrated sulfuric acid, and the acidic reagent is selected from concentrated sulfuric acid + fuming nitric acid; the amount of the acidic solvent is 1.5 to 2 times the volume of the compound of formula III; the amount of concentrated sulfuric acid in the acidic reagent is 1 to 2 times the volume of the compound of formula III; the molar mass ratio of the compound of formula III to the fuming nitric acid is 1:4.5 to 6; the reaction temperature is 100 to 105° C.; the reaction pressure is 0.7 to 0.8 MPa; and the reaction time is 0.5 to 1 h.

8. The preparation method according to claim 1, characterized in that: The reducing agent in step 3 is hydrogen, and the catalyst 2 is 2% Pt-C.

9. The preparation method according to claim 1, characterized in that: The organic solvent 2 described in step 3 is selected from one or more of THF, methanol or ethanol.

10. The preparation method according to claim 1, characterized in that: The reaction temperature in step 3 is 60-100°C.

11. The preparation method according to claim 1, characterized in that: The organic solvent 2 described in step 3 is a mixed solvent of THF+methanol, and the mass ratio of THF to methanol is 3-4:1; the reaction temperature is 70-85°C.

12. The preparation method according to claim 1, characterized in that: The organic solvent 3 described in step 4 is selected from one or more of THF, methanol or water.

13. The preparation method according to claim 1, characterized in that: The alkaline reagent described in step 4 is selected from 10-20% potassium hydroxide solution, and the molar mass ratio of the compound of formula V to the potassium hydroxide solution is 1:5-18.

14. The preparation method according to claim 1, characterized in that: In step 4, the reaction temperature is 200-240° C.; the reaction pressure is 3-5 MPa.

15. The preparation method according to claim 1, characterized in that: The organic solvent 3 described in step 4 is THF, and the amount used is 6 times the volume of the compound of formula V; the alkaline reagent described in step 4 is 10% potassium hydroxide solution, and the molar mass ratio of the compound of formula V to the potassium hydroxide solution is 1:5; the reaction temperature in step 4 is 220-230° C.; and the reaction pressure is 4.5-5.0 MPa.

Images