Preparation method of lorenstat and intermediate thereof

Abstract

The invention discloses a preparation method of lorenstat and an intermediate thereof, and relates to the technical field of compound preparation. The structural formula of the intermediate for synthesizing lorenstat is shown in the specification. When the intermediate is used for preparing lorenstat, the intermediate can directly react with a piperazine side chain by utilizing the activity of sulfydryl in molecules of the intermediate, so that the synthesis steps are simplified, and expensive or complex reagents are prevented from being used. A synthetic route constructed based on the intermediate is short and efficient, reaction conditions are mild, and the yield of a final product is greatly increased. The process route provided by the invention has the advantages of simplicity and convenience in operation, low cost, high yield and the like, and a feasible technical scheme is provided for realizing large-scale and economic production of lorenstat.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of compound preparation, in particular to a preparation method of lorundrostat and intermediates thereof. BACKGROUND

[0002] Lorundrostat is a selective and highly active dipeptidyl peptidase-4 (DPP-4) inhibitor, which is usually used as an oral hypoglycemic drug for the treatment of type 2 diabetes. The core of the molecular structure usually contains a specific heterocyclic system connected to a functionalized piperazine side chain through complex chemical bonds, finally forming an active drug molecule, the structure of which is as follows: .

[0003] This specific structure makes it exhibit targeted biological activity. However, its complex molecular skeleton also brings significant challenges to synthesis. Traditional synthetic routes often rely on multi-step protection and deprotection strategies, use of expensive or sensitive reagents (such as certain organometallic reagents or special oxidizing agents), or require additional functional group activation reactions on key intermediates. These methods not only have long steps, low atom economy, but also have high raw material costs and safety risks in the process, making it difficult to achieve efficient, economical and large-scale production. Therefore, developing a synthetic route based on cheap and readily available raw materials, with simple reaction steps, mild reaction conditions and suitable for industrial amplification, is a key technical requirement for promoting the production of this drug.

[0004] In view of this, the present application is proposed. SUMMARY

[0005] The purpose of the present application is to provide a preparation method of lorundrostat and intermediates thereof.

[0006] The present application is realized as follows: In a first aspect, the present application provides an intermediate compound for synthesizing lorundrostat, which is 5-(4-methylphenyl)-1,2,4-triazine-3-thiol, and its structural formula is shown as formula I: .

[0007] In a second aspect, the present application provides a preparation method of an intermediate compound for synthesizing lorundrostat, comprising the following steps: subjecting aminothiourea to a cyclization reaction with p-toluylformic acid under the action of an alkaline reagent.

[0008] In some preferred embodiments, the alkaline reagent is selected from at least one of sodium hydroxide, potassium hydroxide or potassium carbonate, and the cyclization reaction is carried out in an alcohol solvent or an alcohol-water mixed solvent.

[0009] In a third aspect, the present application provides a preparation method of lorenzanol, comprising the following steps: reacting the intermediate compound or salt thereof described above with an amine compound containing a piperazine or substituted piperazine structure to obtain lorenzanol.

[0010] In some preferred embodiments, the amine compound containing a piperazine or substituted piperazine structure has a structural formula as shown in Formula II:

[0011] wherein R1 represents an optionally substituted alkyl group, an amino protecting group, or a group having a structural formula as shown below:

[0012] wherein R2 and R3 each independently represent hydrogen, acetyl or an amino protecting group.

[0013] In some preferred embodiments, the amine compound containing a piperazine or substituted piperazine structure is selected from piperazine, N-Boc-piperazine, N-Cbz-piperazine or N-[(1R,4R)-4-{[2-(piperazin-1-yl)acetyl]amino}cyclohexyl]acetamide.

[0014] In some preferred embodiments, the reaction is carried out in a C1-C5 alcohol or amide solvent.

[0015] In some preferred embodiments, the catalyst for the reaction is selected from a tertiary amine of a linear, cyclic or branched C1-C20 alkyl group.

[0016] In some preferred embodiments, the tertiary amine is selected from triethylamine, diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, tetramethyl-1,8-naphthalene diamine or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0017] In some preferred embodiments, when the piperazine amino group of the amine compound containing a piperazine or substituted piperazine structure is protected, the preparation method further comprises: performing a deprotection reaction to obtain an intermediate containing a free piperazine group; performing an alkylation reaction on the obtained intermediate containing a free piperazine group to obtain an acid intermediate; and performing a condensation reaction on the acid intermediate to obtain lorenzanol, and the reaction formula is as follows: .

[0018] The present application has the following beneficial effects: The present application provides a new intermediate for synthesizing lorcaserin, introduces a highly reactive sulfhydryl group, utilizes the direct reactivity of the sulfhydryl group, avoids the functional group pre-activation step (such as hydroxyl chlorination) required in the traditional process and the use of expensive or sensitive reagents, thereby greatly reducing the cost of raw materials and reagents. Secondly, the synthesis path is simplified and the reaction steps are reduced, which not only improves the overall atomic economy of the reaction, but also reduces the consumption of solvents and the generation of three wastes, making the process more green and environmentally friendly. In addition, the reaction conditions of the route are mild and easy to operate, effectively improving the yield and purity of the reaction, and enhancing the stability and reproducibility of the process. BRIEF DESCRIPTION OF DRAWINGS

[0019] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following will briefly introduce the drawings needed to be used in the embodiments. It should be understood that the following drawings only show some embodiments of the present application, and therefore should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can also be obtained without creative labor on the basis of these drawings.

[0020] Figure 1 The synthesis route of lorcaserin prepared in the embodiments of the present application is shown in the figure. DETAILED DESCRIPTION

[0021] In order to make the purpose, technical solutions and advantages of the embodiments of the present application more clear, the technical solutions in the embodiments of the present application will be described clearly and completely. The specific conditions are not specified in the embodiments, and are carried out according to conventional conditions or manufacturer's recommended conditions. The reagents or instruments used are not specified by the manufacturer, and are all conventional products that can be purchased on the market.

[0022] The preparation method of lorcaserin and its intermediate provided in the present application will be described in detail below.

[0023] In the first aspect, the present application provides an intermediate compound for synthesizing lorcaserin, which is 5-(4-methylphenyl)-1,2,4-triazine-3-sulfhydryl, and its structural formula is shown as formula I: .

[0024] The inventors introduce a highly reactive sulfhydryl group in the intermediate, utilize the direct reactivity of the sulfhydryl group, avoid the functional group pre-activation step (such as hydroxyl chlorination) required in the traditional process and the use of expensive or sensitive reagents, thereby greatly reducing the cost of raw materials and reagents. Secondly, the synthesis path is simplified and the reaction steps are reduced, which not only improves the overall atomic economy of the reaction, but also reduces the consumption of solvents and the generation of three wastes, making the process more green and environmentally friendly.

[0025] In a second aspect, the present application provides a preparation method of an intermediate compound for synthesizing lorenzanol, comprising the following steps: subjecting aminothiourea to a cyclization reaction with p-tolyl formic acid under the action of an alkaline reagent selected from at least one of sodium hydroxide, potassium hydroxide or potassium carbonate, and the cyclization reaction is carried out in an alcohol solvent or an alcohol-water mixed solvent. The synthesis is carried out with reference to the following synthesis path: .

[0026] In the process of synthesizing the key intermediate of lorenzanol, the present application adopts a preparation strategy with simple steps and mild conditions. The step directly cyclizes aminothiourea, which is easily available and low in price on the market, with p-tolyl formic acid under alkaline conditions. The solvent required for the reaction is low in cost, high in safety and easy to recover and process. The entire reaction system does not need to use noble metal catalyst, anhydrous and anaerobic harsh conditions or special protection measures, and the operation is simple and the conditions are mild, which not only significantly reduces the raw material and process cost, but also improves the stability and scalability of the reaction.

[0027] In a third aspect, the present application provides a preparation method of lorenzanol, comprising the following steps: using an intermediate compound or a salt thereof and an amine compound containing a piperazine or substituted piperazine structure to react to obtain lorenzanol.

[0028] Further, the reaction is carried out in a C1-C5 alcohol or amide solvent, and the catalyst for the reaction is selected from a tertiary amine of a linear, cyclic or branched C1-C20 alkyl.

[0029] In some preferred embodiments, the tertiary amine is selected from triethylamine, diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, tetramethyl-1,8-naphthalene diamine or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0030] In some preferred embodiments, the amine compound containing a piperazine or substituted piperazine structure has a structural formula as shown in Formula II:

[0031] In some preferred embodiments, the amine compound containing a piperazine or substituted piperazine structure has a structural formula as shown in Formula II:

[0032] In some preferred embodiments, the amine compound containing a piperazine or substituted piperazine structure has a structural formula as shown in Formula II:

[0033] The amine compound containing piperazine or substituted piperazine structure is selected from piperazine, N-Boc-piperazine, N-Cbz-piperazine or N-[(1R, 4R)-4-{[2-(piperazin-1-yl)acetyl]amino}cyclohexyl]acetamide, and the structural formula is shown as follows: 、 、 and .

[0034] Specifically, when the amine compound containing piperazine or substituted piperazine structure is N-[(1R, 4R)-4-{[2-(piperazin-1-yl)acetyl]amino}cyclohexyl]acetamide, the amine compound containing piperazine or substituted piperazine structure and the intermediate compound are directly reacted to prepare lometrexol, and the synthesis is carried out according to the following synthesis path: .

[0035] In some preferred embodiments, when the piperazine amino group of the amine compound containing piperazine or substituted piperazine structure is protected, the preparation method further comprises: performing a deprotection reaction to obtain an intermediate containing a free piperazine group; performing an alkylation reaction on the obtained intermediate containing a free piperazine group to obtain an acid intermediate; and performing a condensation reaction on the acid intermediate to obtain lometrexol.

[0036] Specifically, when the amine compound containing piperazine or substituted piperazine structure is N-Boc-piperazine, a deprotection reaction, an alkylation reaction and a condensation reaction are further required.

[0037] Further, the deprotection is carried out under acidic conditions, and the acid is selected from trifluoroacetic acid or hydrochloric acid, and the synthesis is carried out according to the following synthesis path: .

[0038] In some preferred embodiments, the alkylation reaction is a reaction of the intermediate containing a free piperazine group with ethyl bromoacetate under alkaline conditions, and the base is selected from at least one of potassium carbonate, cesium carbonate or triethylamine, and the synthesis is carried out according to the following synthesis path: .

[0039] In some preferred embodiments, the condensation reaction is a reaction of the ester intermediate with trans-4-acetamidocyclohexylamine in a polar aprotic solvent, and the solvent is selected from at least one of N, N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone or acetonitrile, and the synthesis is carried out according to the following synthesis path: .

[0040] The features and properties of the present application are further described in detail below in combination with examples.

[0041] Example 1 This embodiment presents a method for preparing lorenstat, including the following steps, and the synthesis flowchart is shown below. Figure 1 As shown: S1. Synthesis of the intermediate: 51.05 g of p-methylacetophenone (0.373 mol, 1.0 eq) was added to a 1000 mL three-necked flask, followed by 500 mL of 1,4-dioxane, and stirred until dissolved. Then, 76.65 g of selenium dioxide (0.671 mol, 1.8 eq) was weighed and dissolved in 100 mL of purified water. The selenium dioxide aqueous solution was added dropwise to the reaction flask at 25–30 °C. After the addition was complete, the temperature was raised to 80–90 °C and the reaction was carried out for 7 hours. The heating was turned off, and the mixture was cooled to room temperature and filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure at 45 °C until a solid precipitated. 500 mL of saturated sodium thiosulfate solution and 500 mL of ethyl acetate were added, and the mixture was stirred for 0.5 hours. The mixture was separated, and the aqueous phase was extracted twice with 250 mL of ethyl acetate each time. The combined organic phases were filtered again, and the filtrate was concentrated under reduced pressure at 40–45 °C to obtain an oily substance, which then spontaneously and slowly crystallized. Add 300 mL of n-heptane to the concentrated residue, stir for 1–2 hours, filter, and wash the filter cake with 50 mL of n-heptane. Then dry under reduced pressure at 45 °C to obtain 46.31 g of solid a-1. The mass spectrometry results are as follows: 1H NMR (400 MHz, Chloroform-d) δ 9.53 (s, 1H), 7.87 – 7.81 (m, 3H), 7.38 (dq, J = 8.1, 0.8 Hz, 3H), 2.31 (s, 3H). Mass spectrum m / z 149.1 [M+H]+.

[0042] 20.0 g (0.122 mol, 1.0 eq, hydrate) of solid a-1 was dissolved in 200 mL of methanol and cooled to 0–10 °C. 12.30 g (0.135 mol, 1.1 eq) of aminothiourea was added, and the mixture was purged with nitrogen. The mixture was stirred at 0–10 °C for 3–4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure at 40 °C to remove most of the methanol. 100 mL of ethyl acetate was added, and the mixture was stirred for about 1 hour before filtration. The filter cake was collected and dried under reduced pressure at 40 °C.

[0043] The filter cake was added to a 500 mL reaction flask, followed by 400 mL of 1 mol / L NaOH solution. The mixture was heated to 90–95 °C and reacted for 1–2 hours. After the reaction was complete, the mixture was cooled to room temperature, and impurities were extracted twice with ethyl acetate (200 mL each time). The organic phase was then discarded. Acetic acid was added to the aqueous phase to adjust the pH to 6–8. The organic phase was extracted with ethyl acetate, collected, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure at 40 °C to obtain 15.02 g of an orange-yellow solid, i.e., the intermediate compound. The mass spectrometry results were as follows: ¹H NMR (400 MHz, Chloroform-d) δ 9.02 (s, 1H), 7.83 (s, 1H), 7.81–7.75 (m, 2H), 7.28–7.22 (m, 2H). Mass spectrum m / z 204.1 [M+H]+.

[0044] S2, Substitution Reaction: 0.50 g (2.46 mmol, 1.0 eq) of compound b-2 and 1.10 g (9.8 mmol, 4.0 eq) of triethylenediamine (DABCO) were dissolved in 10 mL of n-butanol, and then 0.92 g (4.94 mmol, 2 eq) of 1-Boc-piperazine was added. The mixture was heated to 110 °C and reacted for 5–6 hours. The mixture was extracted with 20 mL of water and 20 mL of ethyl acetate. The aqueous phase was extracted again with 20 mL of ethyl acetate. The organic phases were combined and washed with 20 mL of saturated sodium chloride solution. After separation, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45 °C to obtain an oil. 5 mL of 18% hydrochloric acid was added to the oil, and the mixture was heated to 50–60 °C and stirred for 3–4 hours. After cooling to 0-10℃ and stirring to induce crystallization for 1 hour, the mixture was filtered and dried under reduced pressure at 45℃ to obtain 533 mg of solid a-5. Its mass spectrometry results were as follows: 1H NMR (400 MHz, Chloroform-d) δ 7.80 – 7.74 (m, 1H), 7.28 – 7.21 (m, 1H), 3.71 (dd, J = 5.3, 4.6 Hz, 2H), 3.05 (td, J = 4.9, 3.3 Hz, 2H), 2.15 (p, J = 3.3 Hz, 0H). Mass spectrum m / z 256.2 [M+H]+.

[0045] S3, Alkylation reaction: 500 mg of compound a-5 (1.96 mmol, 1.0 eq) and 327 mg (1.96 mmol, 1.0 eq) of ethyl bromoacetate were dissolved in 5 mL of THF, and 380 mg (2.94 mmol, 1.5 eq) of diisopropylethylamine was added. The reaction was heated to 35 °C for 2 h. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and concentrated to dryness under reduced pressure at 40 °C. Add 3 mL of 2 mol / L NaOH aqueous solution to the concentrated residue, stir and hydrolyze at room temperature. After the reaction is complete, adjust the pH to 6-8 with hydrochloric acid, precipitate the solid, filter and dry under reduced pressure to obtain b-7. Its mass spectrometry results are as follows: 1H NMR (400 MHz, Chloroform-d) δ 9.38 (s, 1H), 9.06 (s, 1H), 7.80 – 7.74 (m, 2H), 7.27 – 7.22 (m, 2H), 3.82 – 3.76 (m, 4H), 3.43 (s, 2H), 2.92 – 2.86 (m, 4H), 2.36 (s, 2H). Mass spectrum m / z 314.2 [M+H]+.

[0046] S4. Dissolve 100.0 g (0.876 mol, 1 eq) of trans-1,4-diaminocyclohexane in 1800 mL of acetonitrile. Add dropwise 95.5 g (0.438 mol, 0.5 eq) of a 200 mL solution of di-tert-butyl dicarbonate in acetonitrile at temperatures below 30°C. After the addition is complete, maintain the temperature at 20-30°C with stirring for 3 hours. Concentrate the reaction solution under reduced pressure at 35°C until no fraction remains. Add 1800 mL of water and stir for 1 hour. Then add 1 L of DCM and 20 mL of acetic acid and stir. Separate the solutions and collect the aqueous phase. Add potassium carbonate to adjust the pH to 7-8. The solid precipitates, and the mixture is stirred for 2 hours. The solid was collected by filtration and dried under reduced pressure at 40 °C to obtain 70.02 g a-11. Its mass spectrometry results were as follows: ¹H NMR (400 MHz, Chloroform-d) δ 4.57 (d, J = 8.2 Hz, 1H), 3.52 (dtt, J = 8.2, 6.0, 3.5 Hz, 1H), 3.00 (dqt, J = 9.3, 6.2, 2.9 Hz, 1H), 1.69 – 1.61 (m, 1H), 1.65 – 1.60 (m, 1H), 1.63 – 1.56 (m, 2H), 1.54 – 1.41 (m, 4H), 1.35 (d, J = 6.4 Hz, 2H). Mass spectrum m / z 215.2 [M+H]+.

[0047] Add 1.8 L of dichloromethane to 70.0 g (0.312 mol, 1.0 eq) of compound a-11 obtained above, stir, and add 50.4 mL (0.537 mol, 1.7 eq) of acetic anhydride and 10.2 mL (0.073 mol, 0.23 eq) of triethylamine at 20-30 °C. Stir the reaction for 2-3 hours. After the reaction is complete, wash with 1.8 L of water. Separate the layers, extract the aqueous phase once with 500 mL of dichloromethane, combine the organic phases, wash once with saturated sodium bicarbonate solution, separate the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure at 40 °C. After concentrating to no fraction, add a small amount of methanol twice with distillation. Dissolve the concentrated residue in 400 mL of methanol. Add another 450 mL of methanol to a 2 L reaction flask, cool to 0-10 °C, and add 149 g (1.898 mol, 6.1 eq) of acetyl chloride, keeping the temperature below 10 °C during the dropwise addition. Then, the methanol solution of the concentrated residue was added to the reaction flask, and the mixture was stirred at 20-30°C for 16 hours. After the reaction was complete, the sample was concentrated under reduced pressure at 40 °C and distilled once with 300 mL of methyl tert-butyl ether to obtain 46.50 g of solid a-6. The mass spectrometry results were as follows: ¹H NMR (400 MHz, Chloroform-d) δ 6.22 (d, J = 8.8 Hz, 1H), 3.43 (dtt, J = 8.9, 6.0, 3.2 Hz, 1H), 3.00 (dqt, J = 9.3, 6.2, 2.9 Hz, 1H), 1.96 (s, 2H), 1.70 – 1.64 (m, 1H), 1.67 – 1.59 (m, 3H), 1.59 – 1.42 (m, 4H), 1.35 (d, J = 6.4 Hz, 2H). (m / z mass spectrometry) 157.1[M+H]+.

[0048] S5. Condensation reaction: Add 5 mL of DMF to 450 mg (1.44 mmol, 1.0 eq) of compound b-7 solid, then add 270 mg of compound a-6 (1.73 mmol, 1.2 eq), stir and add 467 mg of CDI (2.88 mmol, 2.0 eq). After reacting for 16 hours, extract with water and dichloromethane. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure at 40 °C to obtain a solid. Add 5 mL of methanol and slurry. The sample was filtered and washed with methanol. The filter cake was collected and dried to obtain 390 mg of yellow solid a-8. The mass spectrometry results were as follows: 1H NMR (400 MHz, DMSO-d6) δ 7.81 – 7.73 (m, 1H), 7.24 – 7.17 (m, 1H), 3.74 – 3.66 (m, 2H), 3.40 – 3.27 (m, 1H), 2.96 – 2.88 (m, 2H), 2.36 – 2.31 (m, 1H), 1.85 (s, 1H), 1.69 – 1.48 (m, 3H). Mass spectrum m / z 452.3 [M+H]+.

[0049] S6. Add 4.50 g (9.98 mmol, 1.0 eq) of α-8 to a 250 mL three-necked reaction flask, along with 10 mL of purified water and 40 mL of methanol. Stir at 20–30 °C. Then add 1.67 g (10.0 mmol, 1.01 eq) of 48% hydrogen bromide solution. After dissolving, concentrate under reduced pressure at 40 °C to remove methanol. After stopping concentration, raise the temperature to 90 °C and stir at this temperature for 2–3 hours. Slowly cool to room temperature and stir for 10–20 hours. Filter, wash the filter cake with 20 mL of purified water, collect the filter cake, and dry under reduced pressure at 40 °C to obtain 3.263 g of yellow solid API.

[0050] Example 2 This embodiment proposes a method for preparing lorensta, including the following steps: 0.50 g (2.46 mmol, 1.0 eq) of compound b-2 was dissolved in 10 mL of N-methylpyrrolidone, and then 1.39 g (4.92 mmol, 2 eq) of N-[(1R,4R)-4-{[2-(piperazin-1-yl)acetyl]amino}cyclohexyl]acetamide was added. The mixture was heated to 140 °C and reacted for 5–6 hours. The temperature was then lowered to 20–30 °C, 20 mL of water was added, and the mixture was further cooled to 0–10 °C. After stirring and crystallization for 1 hour, the mixture was filtered and dried under reduced pressure at 45 °C to obtain 0.65 g of yellow solid a-8. 1H NMR (400 MHz, Chloroform-d) δ 7.80 – 7.74 (m,1H), 7.28 – 7.21 (m, 1H), 3.71 (dd, J = 5.3, 4.6 Hz, 2H), 3.05 (td, J = 4.9,3.3 Hz, 2H), 2.15 (p, J = 3.3 Hz, 0H). Mass spectrum m / z 452.3[M+H]+.

[0051] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. An intermediate compound for the synthesis of lorensta, characterized in that, The compound is 5-(4-methylphenyl)-1,2,4-triazine-3-thiophenol, and its structural formula is shown in Formula I: 。 2. A method for preparing the intermediate compound as described in claim 1, characterized in that, Includes the following steps: The aminothiourea and p-methylbenzoylcarboxylic acid undergo a cyclization reaction under the action of an alkaline reagent.

3. The preparation method according to claim 2, characterized in that, The alkaline reagent is selected from at least one of sodium hydroxide, potassium hydroxide, or potassium carbonate, and the cyclization reaction is carried out in an alcohol solvent or an alcohol-water mixed solvent.

4. A method for preparing lorenstat, characterized in that, Includes the following steps: Lorenzat is obtained by reacting the intermediate compound as described in claim 1 or its salt with an amine compound containing a piperazine or a substituted piperazine structure.

5. The method for preparing lorenstat according to claim 4, characterized in that, The structural formula of the amine compound containing piperazine or substituted piperazine is shown in Formula II: Where R1 represents an optionally substituted alkyl group, an amino protecting group, or a group with the following structural formula: R2 and R3 each independently represent hydrogen, acetyl, or amino protecting groups.

6. The method for preparing lorenstat according to claim 5, characterized in that, The amine compounds containing piperazine or substituted piperazine structures are selected from piperazine, N-Boc-piperazine, N-Cbz-piperazine, or N-[(1R,4R)-4-{[2-(piperazin-1-yl)acetyl]amino}cyclohexyl]acetamide.

7. The method for preparing lorenstat according to claim 5, characterized in that, The reaction is carried out in C1-C5 alcohol or amide solvents.

8. The method for preparing lorenstat according to claim 5, characterized in that, The catalyst for the reaction is selected from straight-chain, cyclic, or branched C1-C20 alkyl tertiary amines.

9. A method for preparing lorenstat according to claim 8, characterized in that, The tertiary amine is selected from triethylamine, diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, tetramethyl-1,8-naphthyldiamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene.

10. A method for preparing lorenstat according to claim 4, characterized in that, When the piperazine amino group of the amine compound containing piperazine or a substituted piperazine structure is protected, the preparation method further includes: performing a deprotection reaction to obtain an intermediate containing a free piperazine group; subjecting the obtained intermediate containing a free piperazine group to an alkylation reaction to obtain an acid intermediate; and subjecting the acid intermediate to a condensation reaction to obtain lorensta, as shown in the following reaction formula: 。

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