A process for the preparation of 2,5-bis(aminomethyl)tetrahydrofuran

Abstract

The present application relates to a kind of preparation method of compound IV, reaction as follows: including the following steps: step (1): compound I, in benzylamine is reacted to obtain compound II;Step (2): compound II, in the presence of reducing agent is reduced, and is reacted with hydrochloric acid reagent to obtain compound III step (3): compound III, in the presence of metal catalyst and hydrogen source is reacted to obtain compound IV.The process route of the present application can effectively inhibit amine group activity in the synthesis process by selecting dihydrochloride, avoid intermolecular polymerization reaction caused by amine group, so that the yield of reaction system is improved, and the properties of intermediate are stable, reproducibility is good, preparation method is simple to operate, yield is high, product quality is good, easy to realize industrial production.

Description

Technical Field

[0001] The 2,5-bis(aminomethyl)tetrahydrofuran involved in this invention belongs to the field of biomass conversion for the preparation of energy chemicals. Background Technology

[0002] Diamines can be used to prepare polyamides and polyurethanes. Polyamides and polyurethanes have long been the preferred materials in engineering plastics. If a method for efficiently converting biomass into diamines can be developed, it will be possible to achieve biomass-based production of polyamides and polyurethanes. 2,5-Bis(aminomethyl)tetrahydrofuran (BAMTHF) is an important biomass-based monomer that can be used as a monomer for bio-based polyamides or polyurethanes, and its structure is shown below:

[0003]

[0004] Patent CN105377971B discloses a method for preparing 2,5-bis(aminomethyl)tetrahydrofuran from 5-hydroxymethylfurfural as a starting material through reduction, esterification, substitution, and reduction; the overall yield is 71% in four steps. However, this method requires two hydrogenation reductions and uses highly toxic methanesulfonyl chloride and highly explosive and toxic sodium azide. The metal catalyst is expensive and dangerous, making this method unsuitable for industrial scale-up. The preparation method is as follows:

[0005]

[0006] Patent CN108129425B discloses a method using furan-2,5-dicarboxaldehyde dioxime as a raw material, achieving a conversion rate of over 90%. However, this method requires a catalytic hydrogenation temperature of 130℃, making the reaction conditions quite harsh and unsuitable for industrial scale-up. The preparation method is as follows:

[0007]

[0008] Patent CN117263886A discloses a method for preparing 2,5-bis(aminomethyl)tetrahydrofuran from 2,5-tetrahydrofuran dimethyl alcohol as a starting material through esterification, substitution, and hydrolysis. The second step of this method requires substitution at 150°C, a relatively high temperature, which is not conducive to industrial scale-up. The preparation method is as follows:

[0009]

[0010] Patent CN110325520A discloses a preparation method using 2,5-tetrahydrofurandimethyl alcohol as a starting material, and outlines three routes as follows:

[0011] Route 1:

[0012]

[0013] Route 2:

[0014]

[0015] Route 3:

[0016]

[0017] Route 1 involves a three-step reaction to prepare 2,5-bis(aminomethyl)tetrahydrofuran. This method requires two hydrogenation reactions and the use of hydrazine hydrate, a potentially explosive reagent. The metal catalyst is relatively expensive, which is not conducive to industrial scale-up. Route 2 uses dioxime as a starting material and catalytically hydrogenates it with 5% Pd / C to obtain 2,5-bis(aminomethyl)tetrahydrofuran, producing 5% polymerization byproducts. Route 3 is reported to use dioxime as a starting material and catalytically hydrogenate it with Raney nickel to obtain 2,5-bis(aminomethyl)tetrahydrofuran, producing approximately 12% polymerization byproducts. Summary of the Invention

[0018] To address the shortcomings of existing technologies, such as low yield or demanding conditions, this invention provides a method for preparing 2,5-bis(aminomethyl)tetrahydrofuran. This method is simple, efficient, and yields high results, significantly reducing costs and facilitating large-scale commercial production.

[0019] To achieve the above technical objectives, the present invention adopts the following technical solution:

[0020] The first aspect of this invention provides a method for preparing compound IV, the reaction formula of which is shown below:

[0021]

[0022] Includes the following steps:

[0023] Step (1): Compound I reacts with benzylamine to give compound II;

[0024] Step (2): Compound II undergoes a reduction reaction in the presence of a reducing agent, and reacts with hydrochloric acid reagent to obtain compound III;

[0025] Step (3): Compound III reacts in the presence of a metal catalyst and a hydrogen source to give compound IV.

[0026] As a further improvement of the present invention, including but not limited to, step (1) reaction includes: reacting compound I with benzylamine in an organic solvent to obtain compound II;

[0027] As a further improvement of the present invention, the molar ratio of compound I to benzylamine in step (1) is 1:(2.05-3.5), preferably 1:(2.08-2.5);

[0028] As a further improvement of the present invention, including but not limited to, the organic solvent in step (1) is selected from one or a combination of ether solvents, haloalkane solvents, ketone solvents, aromatic hydrocarbon solvents, nitrile solvents, ester solvents, alcohol solvents, sulfone solvents, and amide solvents, preferably an alcohol solvent; the ether solvent is selected from one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, or dioxane; the haloalkane solvent is selected from one or a combination of dichloromethane, dichloroethane, or chloroform; the ketone solvent is preferably acetone; the aromatic hydrocarbon solvent is selected from one or a combination of toluene or xylene; the nitrile solvent is preferably acetonitrile; the ester solvent is selected from one or a combination of ethyl acetate, ethyl formate, or isopropyl acetate; the alcohol solvent is selected from one or a combination of methanol, ethanol, or isopropanol; the sulfone solvent is preferably dimethyl sulfoxide; and the amide solvent is selected from one or a combination of N,N-dimethylformamide or N,N-dimethylacetamide.

[0029] As a further improvement of the present invention, including but not limited to, the organic solvent in step (1) is selected from one or a combination of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methanol, ethanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane, and dimethyl sulfoxide, preferably methanol;

[0030] As a further improvement of the present invention, including but not limited to, the volume of organic solvent used in step (1) is 5 to 20 times the mass of compound I (g), preferably 6 to 10 times;

[0031] As a further improvement of the present invention, including but not limited to, the reaction temperature of step (1) is 10 to 30°C;

[0032] As a further improvement of the present invention, including but not limited to, the reaction time of step (1) is 0.5 to 5 hours, preferably 0.5 to 2 hours.

[0033] As a further improvement of the present invention, including but not limited to, step (2) includes: compound II undergoes a reduction reaction with a reducing agent in an organic solvent, and reacts with hydrochloric acid reagent to obtain compound III;

[0034] As a further improvement of the present invention, the reduction reaction time in step (2) is 0.5 to 8 hours, preferably 1.5 to 4.5 hours;

[0035] As a further improvement of the present invention, in step (2), the reaction time of the reaction with hydrochloric acid reagent is 0.5 to 3 hours, preferably 0.5 to 2 hours.

[0036] As a further improvement of the present invention, including but not limited to, the hydrochloric acid reagent in step (2) is selected from one or a combination of concentrated hydrochloric acid, dilute hydrochloric acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / ethanol solution, and hydrochloric acid / methanol solution, preferably hydrochloric acid / ethyl acetate solution;

[0037] As a further improvement of the present invention, including but not limited to, the molar ratio of compound II to hydrochloric acid reagent in step (2) is 1:(2-5), preferably 1:(2.01-3);

[0038] As a further improvement of the present invention, including but not limited to, the reducing agent in step (2) is selected from one or a combination of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, and aluminum borohydride, preferably sodium borohydride;

[0039] As a further improvement of the present invention, including but not limited to, the molar ratio of compound II to reducing agent in step (2) is 1:(2-5), preferably 1:(2.01-3);

[0040] As a further improvement of the present invention, including but not limited to, the organic solvent in step (2) is selected from one or a combination of methanol, ethanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform, acetone, acetonitrile, ethyl acetate, ethyl formate, and isopropyl acetate, preferably ethanol or ethyl acetate;

[0041] As a further improvement of the present invention, including but not limited to, the volume of the organic solvent in step (2) is 3 to 15 times the mass of compound II in g, preferably 5 to 12 times;

[0042] As a further improvement of the present invention, including but not limited to, the reaction temperature of step (2) is 10 to 45°C, preferably 15 to 35°C.

[0043] As a further improvement of the present invention, including but not limited to, step (2) includes the following reaction: after reduction reaction, quenching, filtration, and concentration; adding ethyl acetate for extraction and separation, adding hydrochloric acid / ethyl acetate solution dropwise to the organic phase and stirring to form a salt; filtration, washing the filter cake with ethyl acetate, filtration, and obtaining solid compound III.

[0044] As a further improvement of the present invention, including but not limited to, step (2) of the present invention cleverly uses a one-pot method, first reducing and then reacting directly in the organic phase to form salt, reducing manpower and material resources and saving costs.

[0045] As a further improvement of the present invention, including but not limited to, step (3) reaction includes: reacting compound III in an organic solvent in the presence of a metal catalyst and a hydrogen source to obtain compound IV;

[0046] As a further improvement of the present invention, including but not limited to, the reaction hydrogen pressure in step (3) is selected from 0.5 to 10 MPa, preferably 4 to 6 MPa;

[0047] As a further improvement of the present invention, including but not limited to, the metal catalyst in step (3) is selected from one or a combination of palladium on carbon (Pd / C), palladium hydroxide (Pd(OH)2), platinum on carbon (Pt / C), and rhodium-alumina (Rh / Al2O3), preferably palladium on carbon (Pd / C);

[0048] As a further improvement of the present invention, including but not limited to, the metal catalyst in step (3) is selected from Pd / C, preferably 5% Pd / C or 10% Pd / C, and more preferably 10% Pd / C;

[0049] As a further improvement of the present invention, including but not limited to, the mass g ratio of compound III to the metal catalyst in step (3) is 1:(0.01 to 0.1), preferably 1:(0.03 to 0.06); for example, 1:0.05;

[0050] As a further improvement of the present invention, including but not limited to, the organic solvent in step (3) is selected from one or a combination of methanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform, acetone, toluene, acetonitrile, and ethyl acetate, preferably methanol;

[0051] As a further improvement of the present invention, including but not limited to, the volume of organic solvent used in step (3) is 5 to 20 times, preferably 6 to 12 times, for example 10 times, of the mass of compound III in g;

[0052] As a further improvement of the present invention, including but not limited to, the reaction temperature of step (3) is 35 to 100°C, preferably 55 to 85°C;

[0053] As a further improvement of the present invention, including but not limited to, the reaction time of step (3) is 3 to 20 hours, preferably 5 to 12 hours;

[0054] As a further improvement of the present invention, including but not limited to, the post-reaction treatment method for the preparation of compound IV in step (3) includes filtering after the reaction is complete; or selectively using an organic solvent for evaporation, preferably using ethanol for evaporation 1 to 6 times or 1 to 4 times, such as 1 time, 2 times, 3 times, 4 times, 5 times or 6 times; recrystallizing with ethanol and drying in a forced-air environment at 25 to 50°C to obtain solid compound IV.

[0055] As a further improvement of the present invention, including but not limited to, the present invention uses the free base of compound III for the reaction, and found that the reaction is more complicated and has more byproducts. However, when the dihydrochloride is used for the reaction, the reaction yield can reach 85%, and the dihydrochloride can effectively inhibit the activity of the amine group and avoid the intermolecular polymerization reaction caused by the amine group. The prior art CN110325520A uses Raney nickel to prepare 2,5-bis(aminomethyl)tetrahydrofuran, which produces about 12% polymerization byproducts. The process route of the present invention can solve the problem of intermolecular polymerization byproducts.

[0056] A second aspect of this invention provides a method for preparing compound IV, the reaction formula of which is shown below:

[0057]

[0058] The preparation methods for steps (2) to (3) in this scheme are as described in the first aspect of the present invention.

[0059] Includes the following steps:

[0060] Step (2): Compound II undergoes a reduction reaction in the presence of a reducing agent, and reacts with hydrochloric acid reagent to obtain compound III;

[0061] Step (3): Compound III reacts in the presence of a metal catalyst and a hydrogen source to give compound IV.

[0062] A third aspect of the present invention provides a compound III with the following structure:

[0063]

[0064] A fourth aspect of the present invention also provides a method for preparing compound V, comprising preparing compound IV by the method for preparing compound IV according to the first or second aspect of the present invention, and further preparing compound V from compound IV; the reaction formula is shown below:

[0065]

[0066] Beneficial technical effects of the present invention:

[0067] 1) This invention uses 2,5-dicarboxyfuran as the starting material and prepares compound IV through substitution, reduction and catalytic hydrogenation. It avoids the use of toxic reagents, explosive reagents and high temperature conditions in the prior art. The operation is simple, the yield is high and the post-processing is simple. The product can be obtained by purifying by pulping, which is easy to realize industrial production.

[0068] 2) The inventors, repeating the reduction conditions of prior art CN110325520A, found that dioxime had poor solubility, making the reduction reaction difficult and resulting in no product being obtained. This invention improves the solubility of the intermediate by replacing hydroxylamine with benzylamine, allowing subsequent reduction to proceed smoothly.

[0069] 3) The inventors selected the free base of compound III for the reaction and found that the reaction was relatively messy with many byproducts. However, when the dihydrochloride was used for the reaction, the reaction yield could reach 85% and the purity could reach 98%. Moreover, the dihydrochloride can effectively inhibit the activity of the amine group and avoid the intermolecular polymerization reaction caused by the amine group. The existing technology CN110325520A uses Raney nickel to prepare 2,5-bis(aminomethyl)tetrahydrofuran, which produces about 12% polymerization byproducts. The process route of the present invention can solve the problem of intermolecular polymerization byproducts. The intermediate is stable, reproducible, and the preparation method is simple to operate. The product quality is good and it is easy to realize industrial production.

[0070] 4) The process route of the present invention is short, the conditions are mild, the operation is simple, the yield is high, and the post-processing is simple. The product can be obtained simply by purifying by pulping, which reduces the "three wastes" and is suitable for industrial production. Attached Figure Description

[0071] Figure 1 The HPLC spectrum of the product obtained in Example 2.1 of this invention;

[0072] Figure 2 The product obtained in Embodiment 2.1 of the present invention 1 H-NMR spectrum;

[0073] Figure 3 The product obtained in Embodiment 4.1 of the present invention 1 H-NMR spectrum;

[0074] Figure 4 This is the GC spectrum of the product obtained in Comparative Example 3 of the present invention. Detailed Implementation

[0075] The preparation method of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0076] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0077] Example 1.1:

[0078]

[0079] 2,5-Diformylfuran (185 g, 1.49 mol) was added to a 2 L three-necked flask, followed by 1.2 L of methanol. Stirring was started, and benzylamine (335.5 g, 3.13 mol) was added dropwise at room temperature with stirring for 1 h. The reaction progress was monitored by HPLC. A large amount of solid was produced. After the reaction was complete, the mixture was filtered, and the filter cake was washed twice with 185 mL of methanol. The wet product was dried in a forced-air environment at 35–45 °C for 16 h to give a yellow solid compound II (389 g, yield 86.4%).

[0080] Examples 1.2–1.5 follow the procedure of Example 1.1, but with variations in the amount of benzylamine used to prepare product compound II, as detailed in Table 1 below.

[0081] Table 1

[0082]

[0083] Examples 1.5–1.8 follow the procedure of Example 1.1, but with variations in solvent volume to prepare compound I, as detailed in Table 2 below.

[0084] Table 2

[0085]

[0086] Through creative work, the inventors ultimately determined the suitable equivalent of benzylamine, solvent, and solvent volume. For example, as shown in Tables 1 (Examples 1.1-1.4), the yield is best when the molar equivalent of compound I to benzylamine is between 2.1 and 2.35. Using molar equivalents outside this range leads to incomplete reaction of the raw materials and difficulty in purifying the product in the reaction solution. For example, as shown in Tables 2 (Examples 1.5-1.8), when methanol is used as the solvent, the reaction effect is best when the ratio of compound I mass (g) to methanol volume (mL) is 7.5, with a controlled product content of 95%. When ethanol is used as the solvent, although the controlled product content can also reach 93%, the volume of the solvent is about 1.5 times that of methanol. From an economic and environmental perspective, methanol is chosen as the solvent, and the best effect is achieved when the molar equivalent of compound I to benzylamine is between 2.1 and 2.35. This method has the advantages of simple post-processing, good reproducibility, and high conversion rate, making it suitable for industrial production.

[0087] Example 2.1:

[0088]

[0089] Compound II (370 g, 1.22 mol) was added to a 5 L three-necked flask, along with 3.7 L of ethanol. Stirring was started and the temperature was lowered to 15 °C. Sodium borohydride (108.8 g, 2.93 mol) was added and stirred for 2–4 h. HPLC monitoring was performed to ensure the reaction was complete. The temperature was maintained below 30 °C. 2.5 L of 1 mol / L dilute hydrochloric acid was slowly added dropwise, followed by 1.6 L of saturated sodium carbonate solution. The mixture was filtered and concentrated. Then, 1.5 L of ethyl acetate was added for extraction and separation. 629 mL of 4 mol / L HCl / EA solution was added dropwise to the organic phase and stirred for 1 h to form a salt. The mixture was filtered, and the filter cake was washed with ethyl acetate. The wet product was dried at 40–50 °C for 10 h to obtain a white solid, compound III (418 g, HPLC purity 98.1%, Rt = 9.172 min, yield 90%). The HPLC chromatogram is shown below. Figure 1 As shown, 1 H-NMR spectrum as shown Figure 2 As shown.

[0090] Example 3.1:

[0091]

[0092] Compound III (250 g, 0.66 mol) was added to a 5 L three-necked flask, along with 2.5 L of methanol, and stirring was started. A 10% palladium-on-carbon catalyst (12.5 g) was added, and the temperature was raised to 60 °C. Hydrogen was then added to 5 MPa, and the mixture was maintained at 80 °C for 6 h. After the reaction was complete, the mixture was filtered, and the organic phase was concentrated under reduced pressure and distilled with ethanol. The solution was then recrystallized from ethanol. The wet product was dried under blast heat at 35–40 °C for 12 h to give a white solid, compound IV (113.8 g, yield 85%, purity 98%).

[0093] Example 3.2 Following the procedure of Example 3.1, the solvent was changed to prepare product compound IV, as shown in Table 3 below:

[0094] Table 3

[0095] Example solvent Results and Discussion Example 3.1 methanol After 6 hours of reaction, the reactants were completely converted, with a yield of 85%. Example 3.2 ethanol After 12 hours of reaction, there was virtually no reaction.

[0096] Through creative work, the inventors finally determined the suitable solvent. For example, as can be seen from Examples 3.1 to 3.2 in Table 3, when ethanol is used as a solvent, even if the reaction time is extended, the raw materials will not react at all. Therefore, methanol is the best solvent, with a yield of up to 85%. It also has the advantages of simple post-processing and good reproducibility, making it suitable for industrial production.

[0097] Example 4.1:

[0098]

[0099] Compound IV (100 g, 0.66 mol) was added to a 3 L three-necked flask, along with 500 mL of ethanol. Stirring was started. NaOH solution (39.9 g, dissolved in 40 mL of water) was added, and the mixture was allowed to react at room temperature for 0.5 h. After the reaction was complete, the mixture was filtered, and the filter cake was washed twice with ethanol to purify the product, yielding a colorless oily compound V (62.7 g, 98.3% yield). 1 H-NMR spectrum as shown Figure 3 As shown.

[0100] Comparative Example 1:

[0101]

[0102] Compound I (30g) was added to a 500mL three-necked flask, followed by 210mL of ethanol. Hydroxylamine hydrochloride was then dissolved in 90mL of water and added dropwise to the system at a controlled temperature of 25–35℃. After the addition was complete, the mixture was stirred for 20 minutes, and TLC showed that the reaction was complete. The mixture was then cooled to 20℃ and filtered. The filter cake was washed twice with water. 81.4g of a pale yellow wet solid was obtained and dried at 50℃ for 18 hours.

[0103] Comparative Example 2:

[0104]

[0105] Raney nickel (100 mg) was added to the reaction flask, and dioxane (6 mL) and compound II-1 (500 mg) were added to replace the hydrogen gas. The mixture was heated to 120 °C and stirred for 3 h under a pressure of 4 MPa. No new spots were generated during TLC monitoring.

[0106] Comparative Examples 2.1 to 2.3 followed the same procedure as Comparative Example 2, but with variations in catalyst, solvent, and pressure to prepare the product, as detailed in Table 4 below.

[0107] Table 4

[0108]

[0109] Comparative Example 3:

[0110]

[0111] Compound III-2 (250 mg, 0.82 mmol) was added to a 100 mL three-necked flask, along with 25 mL of methanol, and stirring was started. A 10% palladium-on-carbon catalyst (75 mg) was added, and the temperature was raised to 60 °C. Hydrogen was then added to 5 MPa, and the mixture was maintained at 80 °C for 6 h. GC monitoring showed a mixed reaction with low purity. The GC spectrum is shown below. Figure 4 As shown.

Claims

1. A method for preparing compound IV, the reaction formula is as follows: comprising the following steps: Step (1): compound I is reacted with benzylamine to obtain compound II; Step (2): compound II is subjected to a reduction reaction in the presence of a reducing agent, and is reacted with a hydrochloric acid reagent to obtain compound III; Step (3): compound III is reacted in the presence of a metal catalyst and a hydrogen source to obtain compound IV; the reducing agent in step (2) is selected from one or a combination of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride and aluminum borohydride; the metal catalyst in step (3) is selected from one or a combination of Pd / C, Pd(OH)2, Pt / C and Rh / Al2O3; the hydrogen source in step (3) is hydrogen.

2. A method for preparing compound IV, the reaction formula is as follows: comprising the following steps: Step (2): compound II is subjected to a reduction reaction in the presence of a reducing agent, and is reacted with a hydrochloric acid reagent to obtain compound III; Step (3): compound III is reacted in the presence of a metal catalyst and a hydrogen source to obtain compound IV; the reducing agent in step (2) is selected from one or a combination of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride and aluminum borohydride; the metal catalyst in step (3) is selected from one or a combination of Pd / C, Pd(OH)2, Pt / C and Rh / Al2O3; the hydrogen source in step (3) is hydrogen.

3. The method of claim 1, wherein: The step (1) comprises: compound I is reacted with benzylamine in an organic solvent to obtain compound II.

4. The method of claim 3, wherein: The step (1) further satisfies one or more of the following conditions: a) the molar ratio of compound I to benzylamine is 1: (2.05-3.5); b) the organic solvent is selected from one or a combination of an ether solvent, a halogenated alkane solvent, a ketone solvent, an aromatic hydrocarbon solvent, a nitrile solvent, an ester solvent, an alcohol solvent, a sulfone solvent and an amide solvent; the ether solvent is selected from one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran or dioxane; the halogenated alkane solvent is selected from one or a combination of dichloromethane, dichloroethane or chloroform; the ketone solvent is acetone; the aromatic hydrocarbon solvent is selected from one or a combination of toluene or xylene; the nitrile solvent is acetonitrile; the ester solvent is selected from one or a combination of ethyl acetate, ethyl formate or isopropyl acetate; the alcohol solvent is selected from one or a combination of methanol, ethanol or isopropanol; the sulfone solvent is dimethyl sulfoxide; and the amide solvent is selected from one or a combination of N,N-dimethylformamide and N,N-dimethylacetamide; c) the volume of the organic solvent is 5-20 times the mass of compound I; d) the reaction temperature is 10-30°C; e) the reaction time is 0.5-5h.

5. The method of claim 4, wherein: The step (1) further satisfies one or more of the following conditions: a) the molar ratio of compound I to benzylamine is 1: (2.08-2.5); b) the organic solvent is selected from one or a combination of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methanol, ethanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane, dimethyl sulfoxide; c) the volume of the organic solvent mL is 6-10 times the mass of compound I g; d) the reaction time is 0.5-2 h.

6. The method of claim 5, wherein: The organic solvent of the step (1) is selected from methanol.

7. The production method according to claim 1 or 2, characterized by: The step (2) comprises: compound II is reduced with a reducing agent in an organic solvent, and reacted with a hydrochloric acid reagent to obtain compound III.

8. The method of claim 7, wherein: The step (2) further satisfies one or more of the following conditions: a) the hydrochloric acid reagent is selected from one or a combination of concentrated hydrochloric acid, dilute hydrochloric acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / ethanol solution, and hydrochloric acid / methanol solution; b) the molar ratio of compound II to the hydrochloric acid reagent is 1: (2-5) ; c) the volume of the organic solvent mL is 3-15 times the mass of compound II g; d) the organic solvent is selected from one or a combination of methanol, ethanol, propanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform, acetone, acetonitrile, ethyl acetate, ethyl formate, and isopropyl acetate; e) the reducing agent is sodium borohydride; f) the molar ratio of compound II to the reducing agent is 1: (2-5) ; g) the reaction temperature is 10-45℃.

9. The method of claim 8, wherein: The step (2) further satisfies one or more of the following conditions: a) the hydrochloric acid reagent is selected from hydrochloric acid / ethyl acetate solution; b) the molar ratio of compound II to the hydrochloric acid reagent is 1: (2.01-3) ; c) the volume of the organic solvent mL is 5-12 times the mass of compound II g; d) the organic solvent is selected from ethanol or ethyl acetate; e) the molar ratio of compound II to the reducing agent is 1: (2.01-3) ; f) the reaction temperature is 15-35℃.

10. The method of claim 7, wherein: The step (2) further satisfies one or more of the following conditions: a) the reduction reaction time is 0.5-8 h; b) the reaction time for the reaction with the hydrochloric acid reagent is 0.5-3 h.

11. The method of claim 10, wherein: The step (2) further satisfies one or more of the following conditions: a) the reduction reaction time is 1.5-4.5 h; b) the reaction time for the reaction with the hydrochloric acid reagent is 0.5-2 h.

12. The method of making according to claim 1 or 2, wherein: The step (2) reaction comprises: after the reduction reaction, quenching, filtering, and concentrating; adding ethyl acetate to extract and separate, and adding hydrochloric acid / ethyl acetate solution dropwise to the organic phase to stir to form a salt; filtering, washing the filter cake with ethyl acetate, filtering, and obtaining solid compound III.

13. The method of making according to claim 1 or 2, wherein: The step (3) comprises: compound III is reacted in an organic solvent in the presence of a metal catalyst and hydrogen to obtain compound IV.

14. The method of claim 13, wherein: The step (3) further satisfies one or more of the following conditions: a) the reaction hydrogen pressure is selected from 0.5-10 MPa; b) the metal catalyst is selected from Pd / C; c) the mass ratio of compound III to metal catalyst is 1: (0.01~0.1) g; d) the organic solvent is selected from one or combination of methanol, propanol, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform, acetone, toluene, acetonitrile, ethyl acetate; e) the volume of the organic solvent is 5~20 times of the mass of compound III; f) the reaction temperature is 35~100℃; g) the reaction time is 3~20h.

15. The method of claim 14, wherein: The step (3) further satisfies one or more of the following conditions: a) the reaction hydrogen pressure is selected from 4~6MPa; b) the metal catalyst is selected from 5%Pd / C or 10%Pd / C; c) the mass ratio of compound III to metal catalyst is 1: (0.03~0.06) g; d) the organic solvent is selected from methanol; e) the volume of the organic solvent is 6~12 times of the mass of compound III; f) the reaction temperature is 55~85℃; g) the reaction time is 5~12h.

16. The method of making according to claim 1 or 2, wherein: The post-treatment method of the reaction of step (3) for preparing compound IV includes filtering after the reaction; using organic solvent to distill, recrystallizing with ethanol, and drying at 25~50℃ with air blast to obtain solid compound IV.

17. The method of claim 16, wherein: The post-treatment method of the reaction of step (3) for preparing compound IV includes filtering after the reaction; using ethanol to distill 1~6 times, recrystallizing with ethanol, and drying at 25~50℃ with air blast to obtain solid compound IV.

18. A method for preparing compound V, comprising preparing compound IV by the method of any one of claims 1~17, and further reacting compound IV to prepare compound V, the reaction formula being shown as follows: 。

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