A process for the preparation of 4-(2-aminoethyl)piperazine-2,6-dione derivatives
By carrying out substitution and cyclization reactions in the presence of an acid-binding agent, combined with sodium hydroxide deprotection, the problems of harsh conditions and low yield in traditional methods are solved, and a mild method for the efficient preparation of 4-(2-aminoethyl)piperazine-2,6-dione derivatives is realized.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- KANGHUA SHANGHAI DRUG RES DEV CO LTD
- Filing Date
- 2023-07-21
- Publication Date
- 2026-05-01
AI Technical Summary
Traditional methods for preparing 4-(2-aminoethyl)piperazine-2,6-dione compounds require stringent conditions, are difficult to adapt to the synthesis of compounds with protecting groups, and result in low yields.
A 4-(2-aminoethyl)piperazine-2,6-dione derivative was prepared by reacting compound e with chloroacetamide in the presence of an acid-binding agent, followed by a reaction with methyl chloroacetate, and finally cyclization and deprotection with sodium hydroxide.
A high-efficiency preparation of 4-(2-aminoethyl)piperazine-2,6-dione derivatives under mild conditions was achieved, with high yield, suitable for the synthesis of compounds with protecting groups.
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Abstract
Description
A method for preparing 4-(2-aminoethyl)piperazine-2,6-dione derivatives Technical Field
[0001] This invention belongs to the field of organic synthesis, and specifically relates to a method for preparing 4-(2-aminoethyl)piperazine-2,6-dione derivatives. Background Technology
[0002] Traditional methods for preparing 4-(2-aminoethyl)piperazine-2,6-dione, its hydrochloride, and analogues involve reacting an amino starting material with two parts of tert-butyl bromoacetate to generate a tert-butyl N,N-diacetate substituted product, followed by acidolysis to remove the tert-butyl ester and obtain N,N-diacetate. This diacetate is then cyclized with formamide under high temperature and pressure (150-160°C, 22.5 atm) to yield piperazine-2,6-dione analogues. This method is demanding and not ideal for the synthesis of many analogues with protecting groups. Summary of the Invention
[0003] The purpose of this invention is to provide a method for preparing 4-(2-aminoethyl)piperazine-2,6-dione derivatives that is mild, easy to operate, has high yield, and is highly efficient.
[0004] Specifically, the present invention provides a method for preparing compound of formula c, comprising the steps of:
[0005] (1) In the first solvent, in the presence of an acid-binding agent, compound e undergoes a substitution reaction with chloroacetamide to give compound a;
[0006]
[0007] (2) In the second solvent, in the presence of an acid-binding agent, compound a undergoes a substitution reaction with methyl chloroacetate to give compound b;
[0008]
[0009] (3) In a third solvent, under the action of sodium hydroxide, compound b undergoes cyclization to give compound c.
[0010]
[0011] PG is an amino protecting group.
[0012] In one or more embodiments, in step (1), the molar ratio of compound e to the amount of the acid-binding agent is 1:1-2.
[0013] In one or more embodiments, in step (1), the molar ratio of compound e to chloroacetamide is 1:1-2;
[0014] In one or more embodiments, in step (2), the molar ratio of the compound of formula a to the amount of the acid-binding agent is 1:1-2.
[0015] In one or more embodiments, in step (2), the molar ratio of compound a to methyl chloroacetate is 1:1-2.
[0016] In one or more embodiments, in step (3), the molar ratio of compound b to sodium hydroxide is 1:0.5-2;
[0017] The present invention also provides a method for preparing a compound of formula d, the method comprising the aforementioned steps (1) to (3), and further comprising the step of:
[0018] (4) In the fourth solvent, under the action of an acidic reagent, compound c is deprotected to give compound d;
[0019]
[0020] PG is an amino protecting group.
[0021] In one or more embodiments, in steps (1) and (2), the acid-binding agent is independently selected from one or more of triethylamine, sodium carbonate, morpholine, N,N-diisopropylethylamine, pyridine, piperidine, imidazole and potassium carbonate; preferably, the acid-binding agent is selected from one or two of triethylamine and sodium carbonate.
[0022] In one or more embodiments, in step (4), the acidic reagent is a protic acid or a mixture of a protic acid and an inert solvent; the protic acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid; the inert solvent is selected from one or more of dioxane, dichloromethane and ethyl acetate; preferably, the acidic reagent is a mixture of hydrochloric acid and dioxane.
[0023] In one or more embodiments, in step (4), the proton concentration of the acidic reagent is 5-10 mol / L.
[0024] In one or more embodiments, the amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl, or p-toluenesulfonyl; preferably, the amino protecting group is tert-butoxycarbonyl.
[0025] In one or more embodiments, in step (1), the first solvent is selected from one or more of dichloromethane, N,N-dimethylacetamide, tetrahydrofuran and dioxane, preferably dichloromethane.
[0026] In one or more embodiments, in step (1), the reaction is carried out at -20 to 40°C.
[0027] In one or more embodiments, in step (1), the reaction proceeds for 5-48 hours.
[0028] In one or more embodiments, in step (2), the second solvent is selected from one or more of N,N-dimethylformamide, dichloromethane, tetrahydrofuran and dioxane, preferably N,N-dimethylformamide.
[0029] In one or more embodiments, in step (2), the reaction is carried out at -20 to 40°C.
[0030] In one or more embodiments, in step (2), the reaction proceeds for 5-48 hours.
[0031] In one or more embodiments, in step (3), the third solvent is selected from one or more of ethanol, N,N-dimethylacetamide and tetrahydrofuran, preferably ethanol.
[0032] In one or more embodiments, in step (3), the reaction is carried out at -20 to 40°C.
[0033] In one or more embodiments, in step (3), the reaction proceeds for 5-48 hours.
[0034] In one or more embodiments, in step (4), the fourth solvent is selected from one or more of dichloromethane, dioxane, and ethyl acetate, preferably dichloromethane.
[0035] In one or more embodiments, in step (4), the reaction is carried out at -20 to 40°C.
[0036] In one or more embodiments, in step (4), the reaction proceeds for 0.5-10 hours. Attached Figure Description
[0037] Figure 1 is the 1H NMR spectrum of 4-(2-aminoethyl)piperazine-2,6-dione hydrochloride prepared in Example 1.
[0038] Figure 2 is the mass spectrum of compound a in Example 1.
[0039] Figure 3 is the mass spectrum of compound c in Example 1. Detailed Implementation
[0040] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as embodiments) can be combined with each other to form preferred technical solutions.
[0041] Through extensive and in-depth research, the inventors unexpectedly discovered for the first time that by selecting a suitable intermediate, the yield of the cyclization step in the preparation of 4-(2-aminoethyl)piperazine-2,6-dione derivatives can be significantly improved. Specifically, this invention first involves a substitution reaction between monoprotected ethylenediamine and chloroacetamide to obtain a monoacetamide-substituted product, which is then substituted with methyl chloroacetate. Following cyclization and optional deprotection, the 4-(2-aminoethyl)piperazine-2,6-dione derivative is prepared. This invention is based on this discovery.
[0042] The method for preparing the 4-(2-aminoethyl)piperazine-2,6-dione derivative of the present invention includes the following steps:
[0043] (1) In the first solvent, in the presence of an acid-binding agent, compound e undergoes a substitution reaction with chloroacetamide to give compound a;
[0044]
[0045] (2) In the second solvent, in the presence of an acid-binding agent, compound a undergoes a substitution reaction with methyl chloroacetate to give compound b;
[0046]
[0047] (3) In a third solvent, under the action of sodium hydroxide, compound b undergoes cyclization to give compound c.
[0048]
[0049] PG is an amino protecting group.
[0050] In some embodiments, the method for preparing the 4-(2-aminoethyl)piperazine-2,6-dione derivative of the present invention further includes the following steps:
[0051] (4) In the fourth solvent, under the action of an acidic reagent, compound c is deprotected to give compound d;
[0052]
[0053] PG is an amino protecting group.
[0054] In step (1), the acid-binding agent may be selected from one or more of triethylamine, sodium carbonate, morpholine, N,N-diisopropylethylamine, pyridine, piperidine, imidazole, and potassium carbonate. Preferably, the acid-binding agent in step (1) is triethylamine.
[0055] In step (1), the molar ratio of compound e to the acid-binding agent can be 1:1-2. Preferably, the molar ratio of compound e to the acid-binding agent is 1:1-1.5.
[0056] In step (1), the molar ratio of compound e to chloroacetamide can be 1:1-2. Preferably, the molar ratio of compound e to chloroacetamide is 1:1-1.3.
[0057] In some embodiments, in step (1), chloroacetamide is slowly added dropwise to increase the yield of the monoacetamide-substituted product and reduce the formation of disubstituted byproducts.
[0058] In step (1), the first solvent can be selected from common organic solutions, as long as it does not adversely affect the reaction. Available first solvents include, but are not limited to, one or more of dichloromethane, N,N-dimethylacetamide, tetrahydrofuran, and dioxane. Preferably, the first solvent is dichloromethane.
[0059] The reaction in step (1) can be carried out at -20 to 40°C, preferably at -20 to 30°C. In some embodiments, the reaction in step (1) can be carried out at room temperature without additional heating or cooling. Preferably, the reaction in step (1) can be carried out at 0 to 20°C. The reaction in step (1) can be carried out for 5 to 48 hours, for example, 10 hours, 15 hours, or 20 hours.
[0060] In this invention, the amino protecting group can be tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or p-toluenesulfonyl (Ts). Preferably, the amino protecting group is Boc.
[0061] In step (1), the reaction can be carried out in air or under the protection of an inert gas, preferably under the protection of an inert gas. The inert gas can be nitrogen or argon, preferably nitrogen.
[0062] In step (2), the second solvent can be selected from common organic solutions, as long as it does not adversely affect the reaction. Available second solvents include, but are not limited to, one or more of N,N-dimethylformamide, dichloromethane, tetrahydrofuran, and dioxane. Preferably, the second solvent is N,N-dimethylformamide.
[0063] The reaction in step (2) can be carried out at -20 to 40°C, preferably at -20 to 30°C. In some embodiments, the reaction in step (2) does not require additional heating or cooling and is carried out at room temperature. Preferably, the reaction in step (2) can be carried out at 0 to 20°C. The reaction in step (2) can be carried out for 5 to 48 hours, for example, 10 hours, 15 hours, or 20 hours.
[0064] In step (2), the reaction can be carried out in air or under the protection of an inert gas, preferably under the protection of an inert gas. The inert gas can be nitrogen or argon, preferably nitrogen.
[0065] In step (2), the available acid-binding agents include, but are not limited to, triethylamine, sodium carbonate, morpholine, N,N-diisopropylethylamine, pyridine, piperidine, imidazole, and potassium carbonate. The acid-binding agent used in step (2) may be the same as or different from the acid-binding agent used in step (1). Preferably, in step (2), the acid-binding agent is sodium carbonate.
[0066] In step (2), the molar ratio of compound a to the acid-binding agent can be 1:1-2. Preferably, the molar ratio of compound a to the acid-binding agent is 1:1-1.5.
[0067] In step (2), the molar ratio of compound a to methyl chloroacetate can be 1:1-2. Preferably, the molar ratio of compound a to methyl chloroacetate is 1:1-1.3.
[0068] In some implementations, in step (2), methyl chloroacetate is slowly added dropwise; preferably, the temperature of the reaction system is controlled at 0°C during the dropwise addition of methyl chloroacetate.
[0069] In a preferred embodiment, in step (3), sodium hydroxide is ground into powder before being used in the reaction; preferably, sodium hydroxide is ground into powder under an infrared lamp. Grinding sodium hydroxide into powder facilitates the ring-closing reaction.
[0070] In step (3), the molar ratio of compound b to sodium hydroxide can be 1:0.5-2. Preferably, the molar ratio of compound b to sodium hydroxide is 1:0.8-1.3.
[0071] In step (3), the third solvent can be selected from common organic solutions, as long as it does not adversely affect the reaction. Available third solvents include, but are not limited to, one or more of ethanol, N,N-dimethylacetamide, and tetrahydrofuran. Preferably, the third solvent is ethanol.
[0072] The reaction in step (3) can be carried out at -20 to 40°C, preferably at -20 to 30°C. In some embodiments, the reaction in step (3) does not require additional heating or cooling and can be carried out at room temperature. Preferably, the reaction in step (3) can be carried out at 0 to 20°C. The reaction in step (3) can be carried out for 5 to 48 hours, for example, 10 hours, 15 hours, or 20 hours.
[0073] In step (4), the acidic reagent can be a protic acid or a mixture of a protic acid and an inert solvent. Available protic acids include one or more selected from hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. Available inert solvents include one or more selected from dioxane, dichloromethane, and ethyl acetate. Preferably, the acidic reagent is a mixture of hydrochloric acid and dioxane.
[0074] The proton concentration of the acidic reagent used in step (4) can be 5-10 mol / L, preferably 7-9 mol / L.
[0075] In step (4), the fourth solvent can be selected from common organic solutions, as long as it does not adversely affect the reaction. Available fourth solvents include, but are not limited to, one or more of dichloromethane, dioxane, and ethyl acetate. Preferably, the fourth solvent is dichloromethane.
[0076] The reaction in step (4) can be carried out at -20 to 40°C, for example, 0°C, 10°C, or 25°C. In some embodiments, the reaction in step (4) does not require additional heating or cooling and can proceed at room temperature. Preferably, the reaction in step (4) can be carried out at 0 to 20°C. The reaction in step (4) can proceed for 0.5 to 10 hours, for example, 3 hours, 4 hours, 6 hours, or 8 hours. Preferably, it can proceed for 1 to 5 hours.
[0077] The advantages of this invention include:
[0078] (1) The method of the present invention is mild and easy to operate, does not require high temperature and high pressure, and does not require the use of strong base, which is more conducive to the synthesis of piperazine-2,6-dione derivatives with protecting groups;
[0079] (2) The method of the present invention has a high yield and high efficiency in obtaining the target compound.
[0080] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
[0081] Example 1: Preparation of 4-(2-aminoethyl)piperazine-2,6-dione hydrochloride
[0082]
[0083] (1) Preparation of Boc-2-(2-amino-2-oxoethyl)ethylenediamine (compound a):
[0084] Weigh 50 g of mono-Boc-ethylenediamine and place it in a 1000 mL three-necked reaction flask. Add 500 mL of dichloromethane. Add 37.9 g of triethylamine, and under nitrogen protection, slowly add 32 g of chloroacetamide dropwise at room temperature. After the addition is complete, stir the mixture overnight at room temperature. Reduce the solvent to dryness, add 200 mL of water, and extract five times with ethyl acetate. Combine the extracts and dry them with anhydrous sodium sulfate. Filter and concentrate the filtrate to obtain 67 g of Boc-2-(2-amino-2-oxoethyl)ethylenediamine, with a yield of 98.9%. Its mass spectrum is shown in Figure 2.
[0085] (2) Preparation of methyl 2-((2-amino-2-oxoethyl)(2-(Boc-amino)ethyl)amino)acetate (compound b):
[0086] 60 g of Boc-2-(2-amino-2-oxoethyl)ethylenediamine was placed in a 250 mL three-necked flask, and 150 mL of N'N-dimethylformamide and 35 g of sodium carbonate were added. Under nitrogen protection, the mixture was cooled to 0 °C, and 33 g of methyl chloroacetate was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction solution was poured into 300 mL of water and extracted five times with ethyl acetate. The extracts were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated and passed through a normal-phase silica gel column (100-200 mesh) under petroleum ether:ethyl acetate ratio of 10:1-1:1 to obtain 45 g of methyl 2-((2-amino-2-oxoethyl)(2-(Boc-amino)ethyl)amino)acetate, with a yield of 56.5%.
[0087] (3) Preparation of Boc-4-(2-aminoethyl)piperazine-2,6-dione (compound c):
[0088] Weigh 45 g of methyl 2-((2-amino-2-oxoethyl)(2-(Boc-amino)ethyl)amino)acetate and place it in a 500 mL single-necked reaction flask. Dissolve it in 250 mL of ethanol, then add 6.2 g of ground sodium hydroxide powder and stir overnight at room temperature. Quench the reaction solution in 10% glacial citric acid aqueous solution, adjust the pH to 7-8 with sodium hydroxide, and evaporate the ethanol to dryness. Extract the remaining solution three times with ethyl acetate, combine the filtrates, dry them with anhydrous sodium sulfate, and evaporate to dryness. Pass the crude product through a normal-phase silica gel column (100-200 mesh) under the elution conditions of petroleum ether:ethyl acetate = 10:1-1:1 to obtain 26 g of Boc-4-(2-aminoethyl)piperazine-2,6-dione, with a yield of 64.1%. Its mass spectrum is shown in Figure 3.
[0089] (4) Preparation of 4-(2-aminoethyl)piperazine-2,6-dione hydrochloride (compound d):
[0090] 26 g of the intermediate Boc-4-(2-aminoethyl)piperazine-2,6-dione was dissolved in 100 mL of dichloromethane, and 50 mL of dioxane hydrochloride solution with a proton concentration of 8 mol / L was added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the solution was slurried twice with 20 mL of petroleum ether / dichloromethane (1:1) to obtain 18 g of 4-(2-aminoethyl)piperazine-2,6-dione hydrochloride, with a yield of 90%. Its 1H NMR spectrum is shown in Figure 1.
[0091] Comparative Example 1
[0092] The ring-closing method involves adding two ethyl carboxylate groups at once, followed by aminolysis. This method requires tube sealing and high temperature conditions, and the yield is very low (~5%).
[0093]
[0094] (1) Preparation of ethyl acetate 2,2'-(2-(Boc–amino)ethylimino)diethyl acetate (compound of formula a'):
[0095] Weigh 10 g of mono-Boc-ethylenediamine (compound e) and place it in a 250 mL three-necked flask. Add 50 mL of dichloromethane. Add 18.9 g of triethylamine, and under nitrogen protection, slowly add 23.0 g of ethyl bromodiphenyl ether dropwise at room temperature. After the addition is complete, stir the mixture overnight at room temperature. Reduce the solvent to dryness, add 200 mL of water, and extract five times with ethyl acetate. Combine the extracts and dry them with anhydrous sodium sulfate. Filter and concentrate the filtrate to obtain 23 g of ethyl 2,2'-(2-(Boc–amino)ethylimino)diethyl acetate, 100% yield.
[0096] (2) Preparation of Boc-4-(2-aminoethyl)piperazine-2,6-dione (compound c):
[0097] Weigh 10 g of ethyl 2,2'-(2-(Boc–amino)ethylimino)diethyl acetate and place it in a 100 mL sealed tube. Add 60 mL of ammonia-methanol solution (7 mol / L) to dissolve the product, then seal and heat to 100 °C overnight. TLC spotting revealed very little product, with the main impurities being diamide byproducts.
[0098] Comparative Example 2
[0099] Repeat the method of step (1) in Example 1, but replace chloroacetamide with methyl chloroacetate.
[0100]
[0101] (1) Preparation of methyl 2-(2-(Boc–amino)ethylamino)acetate (compound of formula a”):
[0102] Weigh 5 g of mono-Boc-ethylenediamine (compound e) and place it in a 100 mL three-necked flask. Add 30 mL of dichloromethane. Add 3.8 g of triethylamine, and under nitrogen protection, slowly add 4.6 g of methyl chloroacetate dropwise at room temperature. After the addition is complete, stir the mixture overnight at room temperature. TLC analysis revealed that the product is mainly a disubstituted product, with a significant amount of unreacted starting material.
[0103] Comparative Example 3
[0104]
[0105] (1) Preparation of 2-((2-amino-2-oxoethyl)(2-(Boc-amino)ethyl)amino)acetic acid isopropyl ester (compound of formula b', R = Ipr):
[0106] 6 g of Boc-2-(2-amino-2-oxoethyl)ethylenediamine (compound a) was placed in a 100 mL three-necked flask, and 15 mL of N'N-dimethylformamide and 3.5 g of sodium carbonate were added. Under nitrogen protection, the mixture was cooled to 0 °C, and 3.7 g of isopropyl chloroacetate was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction solution was poured into 30 mL of water and extracted five times with ethyl acetate. The extracts were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated after filtration and column chromatography to obtain 4.9 g of 2-((2-amino-2-oxoethyl)(2-(Boc-amino)ethyl)amino)acetic acid isopropyl ester.
[0107] (2) Preparation of Boc-4-(2-aminoethyl)piperazine-2,6-dione (compound c):
[0108] Weigh 4.9 g of isopropyl 2-((2-amino-2-oxoethyl)(2-(Boc-amino)ethyl)amino)acetate and place it in a 100 mL single-necked reaction flask. Dissolve it in 25 mL of ethanol, then add 0.62 g of sodium hydroxide powder (before or after grinding) or an equivalent amount of LDA. Stir the mixture at room temperature overnight. No product was observed on TLC, and some of the starting material was saponified.
[0109] Comparative Example 4
[0110]
[0111] (1) Preparation of ethyl acetate 2-((2-amino-2-oxoethyl)(2-(Boc-amino)ethyl)amino) (compound of formula b', R = Et):
[0112] 6 g of Boc-2-(2-amino-2-oxoethyl)ethylenediamine (compound a) was placed in a 100 mL three-necked flask, and 15 mL of N'N-dimethylformamide and 3.5 g of sodium carbonate were added. Under nitrogen protection, the mixture was cooled to 0 °C, and 3.5 g of ethyl chloroacetate was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction solution was poured into 30 mL of water and extracted five times with ethyl acetate. The extracts were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated after filtration and column chromatography to obtain 4.7 g of ethyl 2-((2-amino-2-oxoethyl)(2-(Boc-amino)ethyl)amino)acetate.
[0113] (2) Preparation of Boc-4-(2-aminoethyl)piperazine-2,6-dione (compound c):
[0114] Weigh 4.7 g of ethyl 2-((2-amino-2-oxoethyl)(2-(Boc-amino)ethyl)amino)acetate and place it in a 100 mL single-necked reaction flask. Dissolve it in 25 mL of ethanol, then add 0.62 g of sodium hydroxide powder (before or after grinding) or an equivalent amount of LDA. Stir the mixture at room temperature overnight. No product was observed on TLC, and some of the starting material was saponified.
[0115] Comparative Example 5
[0116] In step (3) of Example 1, sodium hydroxide can achieve a better ring-closing effect, but strong bases such as sodium methoxide and LDA cannot be used to obtain the product.
[0117]
[0118] (1) Preparation of Boc-4-(2-aminoethyl)piperazine-2,6-dione (compound c):
[0119] Weigh 2 g of methyl 2-((2-amino-2-oxoethyl)(2-(Boc-amino)ethyl)amino)acetate (compound b) and place it in a 100 mL single-necked reaction flask. Add 10 mL of ethanol to dissolve it, then add 6.5 mmol of LDA or sodium methoxide and stir overnight at room temperature. No product was observed on TLC, and some of the starting material was saponified.
Claims
1. A method for preparing compound of formula c, characterized in that, The steps include: (1) in a first solvent, in the presence of an acid-binding agent, compound e undergoes a substitution reaction with chloroacetamide to obtain compound a; (2) In the second solvent, in the presence of an acid-binding agent, compound a undergoes a substitution reaction with methyl chloroacetate to give compound b; (3) In a third solvent, under the action of sodium hydroxide, compound b undergoes cyclization to give compound c; PG is an amino protecting group.
2. The method as described in claim 1, characterized in that, In step (1), the molar ratio of compound e to the amount of the acid-binding agent is 1:1-2.
3. The method as described in claim 1, characterized in that, In step (1), the molar ratio of compound e to chloroacetamide is 1:1-2.
4. The method as described in claim 1, characterized in that, In step (2), the molar ratio of compound a to the amount of the acid-binding agent is 1:1-2.
5. The method as described in claim 1, characterized in that, In step (2), the molar ratio of compound a to methyl chloroacetate is 1:1-2.
6. The method as described in claim 1, characterized in that, In step (3), the molar ratio of compound b to sodium hydroxide is 1:0.5-2.
7. The method as described in claim 1, characterized in that, In steps (1) and (2), the acid-binding agents are each independently selected from one or more of triethylamine, sodium carbonate, morpholine, N,N-diisopropylethylamine, pyridine, piperidine, imidazole and potassium carbonate.
8. The method as described in claim 1, characterized in that, In steps (1) and (2), the acid-binding agent is selected from one or both of triethylamine and sodium carbonate.
9. The method as described in claim 1, characterized in that, The amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl, or p-toluenesulfonyl.
10. The method as described in claim 1, characterized in that, The amino protecting group is tert-butyloxycarbonyl.
11. The method as described in claim 1, characterized in that, In step (1), the first solvent is selected from one or more of dichloromethane, N,N-dimethylacetamide, tetrahydrofuran and dioxane, and the reaction is carried out at -20~40°C for 5-48 hours.
12. The method as described in claim 1, characterized in that, In step (1), the first solvent is dichloromethane.
13. The method as described in claim 1, characterized in that, In step (2), the second solvent is selected from one or more of N,N-dimethylformamide, dichloromethane, tetrahydrofuran and dioxane, and the reaction is carried out at -20~40°C for 5-48 hours.
14. The method as described in claim 1, characterized in that, In step (2), the second solvent is N,N-dimethylformamide.
15. The method as described in claim 1, characterized in that, In step (3), the third solvent is selected from one or more of ethanol, N,N-dimethylacetamide and tetrahydrofuran, and the reaction is carried out at -20~40°C for 5-48 hours.
16. The method as described in claim 1, characterized in that, In step (3), the third solvent is ethanol.
17. A method for preparing a compound of formula d, characterized in that, The method includes steps (1) to (3) of the method according to any one of claims 1-8 and 11-16, and further includes the step: (4) in a fourth solvent, under the action of an acidic reagent, deprotecting compound c to obtain compound d; Wherein, the anion of the compound of formula d is Cl. - The acidic reagent is a protic acid or a mixture of a protic acid and an inert solvent; the protic acid is hydrochloric acid.
18. The method as described in claim 17, characterized in that, The inert solvent is selected from one or more of dioxane, dichloromethane, and ethyl acetate.
19. The method as described in claim 17, characterized in that, The acidic reagent is a mixture of hydrochloric acid and dioxane.
20. The method as described in claim 17, characterized in that, The proton concentration of the acidic reagent is 5-10 mol / L.
21. The method as described in claim 17, characterized in that, In step (4), the fourth solvent is selected from one or more of dichloromethane, dioxane and ethyl acetate, and the reaction is carried out at -20~40℃ for 0.5-10 hours.
22. The method as described in claim 17, characterized in that, In step (4), the fourth solvent is dichloromethane.
23. The method as described in claim 17, characterized in that, The amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl, or p-toluenesulfonyl.
24. The method as described in claim 17, characterized in that, The amino protecting group is tert-butyloxycarbonyl.