Preparation method of 4-oxa-7-azaspiro [2.5] octane-6-ketone

Abstract

The invention relates to a preparation method of 4-oxa-7-azaspiro [2.5] octane-6-ketone, and belongs to the field of chemical synthesis of medicines. Hydrochloride of glycine ester is used as a starting material, and 4-oxa-7-azaspiro [2.5] octane-6-ketone is obtained through five steps of protecting group introduction, cyclization, condensation, protecting group removal and intramolecular cyclization reaction and serves as the starting material of the anti-influenza virus medicine and analogues of the anti-influenza virus medicine. The synthesis route is ingenious in design, the use of a palladium catalyst and a harmful reagent chloroacetyl chloride in the prior art is reduced or avoided, and the material cost and the production cost of the whole route are reduced by 70% or above compared with those of the prior art by improving the yield of the two key reactions of condensation and cyclization and simplifying the operation steps. The method is suitable for industrial application.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of synthetic chemistry of drugs, and relates to a preparation method of 4-oxa-7-azaspiro[2.5]octan-6-one. BACKGROUND

[0002] 4-oxa-7-azaspiro[2.5]octan-6-one is an important starting material for synthesis of anti-influenza virus drugs and analogs thereof, and has a chemical structure as shown in formula I: .

[0003] Patent CN119101009A describes a preparation method of 4-oxa-7-azaspiro[2.5]octan-6-one, and a reaction route thereof is as shown in the following figure:

[0004] The preparation method has the following problems: (1) the step of preparing the compound of formula V from the compound of formula IV needs to use a large amount of expensive palladium metal catalyst (0.2 w / w), and the catalyst is difficult to recover, which greatly increases the material cost; (2) the preparation of the compound of formula VI needs to use chloroacetyl chloride, and the reagent has strong irritation, which increases the human safety risk in the production process; (3) the exposed hydroxyl group in the compound of formula V competitively affects the condensation of the amino group and chloroacetyl chloride, and more by-products are generated; (4) the intramolecular cyclization reaction of the compound of formula VI to prepare the compound of formula VII (4-oxa-7-azaspiro[2.5]octan-6-one) has poor reactivity due to the steric hindrance of the tertiary alcohol structure, and harsh reaction conditions are needed, and the reaction conversion rate is low, and then the reaction yield is low; (5) in the work-up stage of the fifth step reaction, the purification process of 4-oxa-7-azaspiro[2.5]octan-6-one is complex, and needs to go through multiple purification means such as acidification, low-temperature beating, column chromatography, which will cause serious loss of the target product, and greatly increase the production time and economic cost. SUMMARY

[0005] Therefore, the purpose of the application is to provide a preparation method of 4-oxa-7-azaspiro[2.5]octan-6-one, which is more environmentally friendly, has a clever synthetic route, simple work-up and purification steps, obviously improved overall route yield, and reduced production cost, and is more suitable for industrial production.

[0006] To achieve the above purpose, the application provides the following technical scheme. 1. A preparation method of 4-oxa-7-azaspiro[2.5]octan-6-one, characterized in that the preparation is performed according to the following route: .

[0007] The specific experimental steps are as follows: (1) Compound II is reacted under the condition of a basic reagent to introduce a protecting group through a protecting group precursor, to obtain compound III; Preferably, the compound II is glycine ester hydrochloride, which is selected from one of glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride; the basic reagent is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide; the protecting group precursor is selected from one of benzyl bromide, benzyl chloride, 4-methoxybenzyl bromide or 4-methoxybenzyl chloride; and the reaction solvent is selected from one of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide or dichloromethane. Preferably, the molar ratio of the compound II, the protecting group precursor and the basic reagent is 1:2:2.5~1:2.2:4, and the reaction temperature is 20~40℃.

[0008] (2) Compound III is reacted under the action of titanium isopropylate and ethyl magnesium bromide to obtain compound IV; Preferably, the reaction solvent is selected from one of tetrahydrofuran or diethyl ether, the molar ratio of compound III, titanium isopropylate and ethyl magnesium bromide is 1:0.25:2~1:1:4, and the reaction temperature is -25~25℃.

[0009] (3) Compound IV is subjected to a tertiary alcohol substitution reaction with a haloacetic ester under the condition of a basic reagent, to obtain compound V; Preferably, the haloacetic ester is selected from one of methyl bromoacetate, methyl chloroacetate, ethyl bromoacetate, ethyl chloroacetate, isopropyl bromoacetate, isopropyl chloroacetate, tert-butyl bromoacetate or tert-butyl chloroacetate; the basic reagent is selected from one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium carbonate, sodium hydroxide or sodium hydride; and the reaction solvent is selected from one of 1,4-dioxane, isopropyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, tetrahydrofuran or N-methyl pyrrolidone. Preferably, the molar ratio of compound IV, the haloacetic ester and the basic reagent is 1:1:1~1:2:2, and the reaction temperature is 10~50℃.

[0010] (4) Compound V is removed of the protecting group under the condition of a palladium metal catalyst or an acidic reagent, to obtain compound VI; Preferably, the catalyst is selected from one of Pd(OH)2 / C or Pd / C; the acidic reagent is selected from one of trifluoroacetic acid, hydrobromic acid or hydrochloric acid; and the reaction solvent is selected from one of methanol, ethanol, dichloromethane or tetrahydrofuran. Preferably, the mass ratio of compound V and the catalyst is 1:0.05~1:0.2, and the reaction temperature is 30~65℃.

[0011] (5) intramolecular cyclization of intermediate Ⅵ under basic or acidic reagent conditions to obtain compound Ⅰ; Preferably, the basic reagent is selected from one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide or sodium bicarbonate; the acidic reagent is selected from one of acetic acid, hydrochloric acid or sulfuric acid; and the reaction solvent is selected from one of methanol, ethanol or tetrahydrofuran. Preferably, the molar ratio of compound Ⅵ to the basic reagent or the acidic reagent is 1:1 to 1:3, and the reaction temperature ranges from 20 to 60℃.

[0012] 2. 4-Oxa-7-azaspiro[2.5]octan-6-one prepared according to the above preparation method.

[0013] The present application has the following advantages: Compared with the prior art (patent CN119101009A), the preparation method of the present application has improved in terms of atomic economy, process safety, simple operation and production cost, and the core advantages are reflected in the following three aspects: (1) Innovative design of key steps: replacing the high-risk and low-efficiency acylation step with a mild and efficient condensation reaction In the third step of the present application, halogenated acetic ester is used as an alkylating agent to replace the chloroacetyl chloride used in the fourth step of the prior art, successfully introducing the key methylene and carbonyl structural units in the six-membered ring of 4-oxa-7-azaspiro[2.5]octan-6-one. Chloroacetyl chloride is a reactive acylating agent with irritant and corrosive properties, increasing the risk of operation and safety. In addition, the acylation step in the prior art has low yield and poor atomic economy. By using the relatively mild halogenated acetic ester, the present application improves the yield of this step and ensures its process safety, thereby reducing the operational risk in the production process.

[0014] (2) Comprehensive benefits of removing benzyl group: low cost, high quality and environmental protection Compared with the prior art, the debenzylization step in the fourth step of the present application is adjusted after the hydroxyl alkylation step, avoiding the possibility of chelation of the naked hydroxyl group with the palladium catalyst. Therefore, only a small amount of catalyst (0.05 w / w) is required to obtain a high yield and high purity of the target product, thereby reducing the potential risk of metal residues to product quality and the surrounding environment, and also providing feasibility for the recovery of the subsequent catalyst, laying the foundation for the entire route to be green, high quality and low cost.

[0015] (3) Clever optimization of cyclization strategy: replacing intramolecular cyclization under the action of strong base with small steric hindrance cyclization In the key ring-forming reaction of the fifth step of the application, due to the reasonable design of the third step, the ring-forming mode is changed from the condensation reaction of the existing technology of the tertiary alcohol with large steric hindrance and weak nucleophilicity to the reaction of the primary amine and the ester; the ring-forming step of the application has strong thermodynamic driving force, low requirement for acid-base environment, and can be efficiently completed by heating in alcohol only with weak base or acid; the method not only avoids the use of strong base (such as t-BuOK), simplifies the feeding and post-processing operation, but also improves the final yield, thereby greatly reducing the production cost, and highlighting the application potential of the method in industrialization.

[0016] In summary, the preparation method of the application reduces or avoids the use of palladium catalyst in the existing process, avoids the use of hazardous reagent chloroacetyl chloride, and is more safe and environmentally friendly; by improving the yield of the condensation and ring-forming two key reactions, the total yield of the entire synthesis route is 64.20%, which is nearly doubled compared with the existing process; the operation steps are further simplified, so that the material cost and production cost of the entire route are reduced by more than 70% compared with the prior art, thereby providing a more advantageous green and efficient synthesis path for the preparation of 4-oxa-7-azaspiro[2.5]octan-6-one.

[0017] Other advantages, objects, and features of the application will be set forth in part in the following specification, and in part will become apparent to those skilled in the art from a consideration of the following specification, or can be learned from practice of the application. The objects and other advantages of the application can be realized and attained by the methods and instrumentalities set forth in the following specification. DETAILED DESCRIPTION

[0018] The embodiments of the application are illustrated by specific concrete examples below, and those skilled in the art can easily understand other advantages and effects of the application from the disclosure of the specification. The application can also be implemented or applied by different specific embodiments, and the details in the specification can be modified or changed based on different views and applications without departing from the spirit of the application. It should be noted that the diagrams provided in the following examples only illustrate the basic concept of the application in a schematic manner, and the following examples and features in the examples can be combined with each other without conflict.

[0019] Example 1 Preparation of 4-oxa-7-azaspiro[2.5]octan-6-one (compound of formula I) The specific preparation steps are as follows: (1) Preparation of compound of formula III

[0020] The compound of formula II (31.13 g, 0.22 mol, 1.0 eq) and acetonitrile (311 mL, 10 V) were added to the reaction bottle, then potassium carbonate (77.06 g, 0.55 mol, 2.5 eq) was added, stirred at room temperature for 0.5 h, then benzyl bromide (76.29 g, 0.44 mol, 2.0 eq) was slowly added dropwise into the reaction bottle, followed by reaction at room temperature for 6 h; thin layer chromatography (TLC) detection showed that the raw material disappeared and the reaction was complete; ethyl acetate (311 mL, 10 V) was added to the reaction liquid, after stirring, the organic layer was washed twice with purified water (each time 156 mL, 5 V), dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain the compound of formula III as a white solid, 58.96 g, yield 93.3%.

[0021] The 1H NMR hydrogen spectrum information of compound III is: 1H NMR (600 MHz, CDCl3) δ 7.42-7.37 (m, 4H), 7.35-7.29 (m, 4H), 7.27-7.24 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.83 (s, 4H), 3.29 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H).

[0022] The mass spectrum information of compound III is: [M+H] + = m / z 284.16.

[0023] (2) Preparation of compound IV

[0024] The compound of formula III (20.00 g, 0.071 mol, 1.0 eq), tetrahydrofuran (200 mL, 10 V) and titanium isopropylate (6.02 g, 0.3 eq) were added to the reaction bottle, cooled to -5°C, then 1M ethyl magnesium bromide in tetrahydrofuran solution (105.9 mL, 0.21 mol, 3.0 eq) was slowly added dropwise, after the addition was completed, the temperature was raised to 10°C and reacted for 4 h; TLC detection showed that the raw material disappeared and the reaction was complete; the temperature was controlled below 10°C, and saturated ammonium chloride aqueous solution (20 mL, 1 V) was slowly added dropwise to quench the reaction; after the addition was completed, it was filtered, the filtrate was rotary evaporated, the residue was dissolved in n-hexane (100 mL, 5 V), and then filtered, the filtrate was rotary evaporated to obtain the compound of formula IV as a light yellow oil, the product was 15.90 g (0.059 mol), the yield was 88.7%.

[0025] The 1H NMR hydrogen spectrum information of compound IV is: 1H NMR (600 MHz, CDCl3) δ 7.35-7.33 (m, 4H), 7.33-7.31 (m, 4H), 7.27-7.24 (m, 2H), 3.72 (s, 4H), 2.63 (s, 2H), 0.80-0.75 (m, 2H), 0.40-0.35 (m, 2H).

[0026] The mass spectrum information of compound IV is: [M+H] + = m / z 268.17.

[0027] (3) Preparation of compound V

[0028] Compound IV (4.09 g, 0.015 mol, 1.0 eq) and tetrahydrofuran (61 mL, 15V) were added to the reaction bottle, stirred and dissolved, then methyl bromoacetate (2.75 g, 0.018 mol, 1.2 eq) was added, stirred at room temperature for 15 min, sodium ethoxide (1.25 g, 0.018 mol, 1.2 eq) was added, then the temperature was raised to 50°C for 1 h; TLC detection showed that the raw material disappeared and the reaction was complete, ethyl acetate (61 mL, 15V) was added to the reaction liquid, stirred and then the organic layer was washed once with purified water (61 mL, 15V), and twice with saturated brine (61 mL, 15V each time), dried over anhydrous sodium sulfate, filtered and the filtrate was rotary evaporated to obtain compound V as a yellow oil, 4.88 g, yield 95.7%.

[0029] The 1H NMR hydrogen spectrum information of compound V is: 1H NMR (600 MHz, CDCl3) δ 7.39-7.35 (m, 4H), 7.32-7.28 (m, 4H), 7.25-7.20 (m, 2H), 4.07 (s, 2H), 3.75 (s, 3H), 3.67 (s, 4H), 2.63 (s, 2H), 0.92-0.86 (m, 2H), 0.49-0.44 (m, 2H).

[0030] The mass spectrum information of compound V is: [M+H] + = m / z 340.19.

[0031] (4) Preparation of compound VI

[0032] The compound of formula V (5.00 g, 0.015 mol, 1.0 w / w) and anhydrous methanol (50 mL, 10 V) were added to a three-necked flask, then 10% palladium-carbon (0.25 g, 0.05 w / w) was added, after three times of hydrogen replacement, the temperature was raised to 45°C, and the reaction was carried out under hydrogen atmosphere for 8 h; TLC detection showed that the raw material disappeared and the reaction was complete. The reaction liquid was naturally reduced to room temperature, filtered, and the filtrate was rotary evaporated to obtain the compound of formula VI as a yellowish oil, 2.26 g, yield 96.2%.

[0033] The mass spectrum information of the compound of formula VI is: [M+H] + = m / z 160.09.

[0034] (5) Preparation of the compound of formula I

[0035] The compound of formula VI (1.60 g, 0.01 mol, 1.0 eq) and anhydrous ethanol (51 mL, 30 V) were added to a reaction flask, and potassium carbonate (2.76 g, 0.020 mol, 2.0 eq) was added under stirring at room temperature, then the temperature was raised to 60°C and the reaction was carried out for 16 h; TLC detection showed that the raw material disappeared and the reaction was complete; the reaction liquid was naturally reduced to room temperature, filtered, and the filtrate was rotary evaporated, the residue was dissolved in methyl tert-butyl ether (8.5 mL, 5 V), stirred at room temperature, and n-heptane (25.5 mL, 15 V) was slowly added dropwise to precipitate a large amount of solid. After filtration, the filter cake was washed with n-heptane (5 mL) and dried under reduced pressure at 40°C to obtain the compound of formula I as a yellowish brown solid, 1.11 g, yield 84.3%.

[0036] The 1H NMR hydrogen spectrum information of the compound I is: 1H NMR (600 MHz, CDCl3) δ 7.16 (s, 1H), 4.16 (s, 2H), 3.40 (d, J = 2.3 Hz, 2H), 1.01-0.96 (m, 2H), 0.70-0.64 (m, 2H).

[0037] The mass spectrum information of the compound of formula I is: [M+H] + = m / z 128.07.

[0038] Example 2 Synthesis of 4-oxa-7-azaspiro[2.5]octan-6-one (compound of formula I) The specific synthesis steps are as follows: (1) Preparation of the compound of formula III

[0039] The compound of formula II (12.55 g, 0.10 mol, 1.0 eq) and acetonitrile (125 mL, 10 V) were added to the reaction bottle, then potassium carbonate (77.06 g, 0.55 mol, 2.5 eq) was added, stirred at room temperature for 0.5 h, then 4-methoxybenzyl chloride (31.32 g, 0.20 mol, 2.0 eq) was slowly added dropwise into the reaction bottle, followed by reaction at room temperature for 6 h; TLC detection showed that the raw material disappeared and the reaction was complete, acetic ether (125 mL, 10 V) was added to the reaction liquid, stirred and then the organic layer was washed twice with purified water (63 mL each time, 5 V), dried over anhydrous sodium sulfate, filtered and then the filtrate was rotary evaporated to obtain the compound of formula III as a white solid, product 31.3 g, yield 95.0%.

[0040] The 1H NMR hydrogen spectrum information of the compound of formula III is: 1H NMR (600 MHz, CDCl3) δ 7.30-7.26 (m, 4H), 6.87-6.83 (m, 4H), 3.79 (s, 6H), 3.72 (s, 4H), 3.67 (s, 3H), 3.26 (s, 2H).

[0041] The mass spectrum information of the compound of formula III is: [M+H] + = m / z 330.17.

[0042] (2) Preparation of the compound of formula IV

[0043] The compound of formula III (20.00 g, 0.061 mol, 1.0 eq), tetrahydrofuran (200 mL, 10 V) and tetraisopropyl titanate (5.16 g, 0.018 mol, 0.3 eq) were added to the reaction bottle, cooled to -5°C, then 1 M ethyl magnesium bromide in tetrahydrofuran solution (90.8 mL, 0.18 mol, 3.0 eq) was slowly added dropwise, after the dropwise addition was completed, the temperature was increased to 10°C and reacted for 4 h; TLC detection showed that the raw material disappeared and the reaction was complete, the temperature was controlled below 10°C, and saturated ammonium chloride aqueous solution (20 mL, 1V) was slowly added dropwise to quench the reaction; after the dropwise addition was completed, filtration was performed, the filtrate was rotary evaporated, the residue was dissolved in n-hexane (100 mL, 5V), and then filtration was performed again, the filtrate was rotary evaporated to obtain the compound of formula IV as a light yellow oil, product 18.68 g, yield 94%.

[0044] The mass spectrum information of the compound of formula IV is: [M+H] + = m / z 328.19.

[0045] (3) Preparation of the compound of formula V

[0046] Compound of formula IV (9.81 g, 0.03 mol, 1.0 eq) and tetrahydrofuran (147 mL, 15 V) were added into a reaction flask, stirred and dissolved, then methyl bromoacetate (5.51 g, 0.036 mol, 1.2 eq) was added, stirred at room temperature for 15 min, sodium ethoxide (2.50 g, 0.036 mol, 1.2 eq) was added, then the temperature was raised to 50°C for 1 h; TLC detection showed that the raw material disappeared and the reaction was complete. Ethyl acetate (147 mL, 15 V) was added to the reaction liquid, stirred and then the organic layer was washed once with purified water (147 mL, 15 V) and twice with saturated brine (147 mL, 15 V each time), dried over anhydrous sodium sulfate, filtered and the filtrate was rotary evaporated to obtain a compound of formula V as a yellow oil, 11.63 g, yield 97.2%.

[0047] The nuclear magnetic resonance hydrogen spectrum information of the compound of formula V is:1H NMR (600 MHz, CDCl3) δ 7.26-7.23 (m, 4H), 6.86-6.82 (m, 4H), 4.07 (s, 2H), 3.79 (s, 6H), 3.75 (s, 3H), 3.58 (s, 4H), 2.60 (s, 2H), 0.89-0.87 (m, 2H), 0.46-0.43 (m, 2H).

[0048] The mass spectrum information of the compound of formula V is: [M+H] + = m / z 400.21.

[0049] (4) Preparation of compound of formula VI

[0050] Compound of formula V (10.00 g) was added into a three-necked flask, then trifluoroacetic acid (50 mL) was added, the temperature was raised to 65°C and stirred overnight; TLC detection showed that the raw material disappeared and the reaction was complete. The reaction liquid was reduced to room temperature and rotary evaporated under reduced pressure to obtain a compound of formula VI as a brown oil, 4.0 g, yield 100%.

[0051] The mass spectrum information of the compound of formula VI is: [M+H] + = m / z 160.09.

[0052] (5) Preparation of compound of formula I

[0053] The compound of formula VI (3.18 g, 0.02 mol, 1.0 eq) and anhydrous ethanol (32 mL, 10 V) were added to a reaction bottle, sodium hydroxide (2.4 g, 0.06 mol, 3.0 eq) was added under stirring at room temperature, and then the temperature was raised to 60°C for 16 h; TLC detection showed that the raw material disappeared and the reaction was complete; the reaction liquid was reduced to room temperature, filtered, and the filtrate was rotary evaporated; the residue was dissolved in methyl tert-butyl ether (16 mL, 5 V), stirred at room temperature, and slowly added with n-heptane (48 mL, 15 V) to precipitate a large amount of solid; the filter cake was washed with n-heptane (7 mL) and dried at 40°C under reduced pressure to obtain the compound of formula I as a yellow-brown solid, 2.19 g, yield 86.3%.

[0054] The 1H NMR hydrogen spectrum information of the compound of formula I is 1H NMR (600 MHz, CDCl3) δ 7.16 (s, 1H), 4.16 (s, 2H), 3.40 (d, J = 2.3 Hz, 2H), 1.01-0.96 (m, 2H), 0.70-0.64 (m, 2H).

[0055] The mass spectrum information of the compound of formula I is: [M+H] + = m / z 128.07.

[0056] In summary, the preparation method of the present application reduces or avoids the use of palladium catalyst in the prior art, avoids the use of hazardous reagent chloroacetyl chloride, and is more safe and environmentally friendly; by improving the yield of the two key reactions of condensation and ring formation, the total yield of the entire synthesis route is 64.20%, which is nearly doubled compared to the prior art; further simplifying the operation steps, the material cost and production cost of the entire route are reduced by more than 70% compared to the prior process, providing a more advantageous green and efficient synthesis path for the preparation of 4-oxa-7-azaspiro[2.5]octan-6-one.

[0057] Finally, it should be pointed out that the above examples are only used to illustrate the technical solutions of the present application and are not limiting, although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced equivalently without departing from the purpose and scope of the technical solutions, which should be covered in the scope of the claims of the present application.

Claims

1. A method for preparing 4-oxa-7-azaspiro[2.5]octane-6-one, characterized in that, Prepared via the following route: 。 2. The preparation method according to claim 1, characterized in that, Compound II, under alkaline conditions, is introduced with a protecting group via a protecting group precursor reaction to yield compound III. Compound II is glycine ester hydrochloride, selected from glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride. The alkaline reagent is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, or potassium hydroxide. The protecting group precursor is selected from benzyl bromide, benzyl chloride, 4-methoxybenzyl bromide, or 4-methoxybenzyl chloride. The reaction solvent is selected from acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or dichloromethane.

3. The preparation method according to claim 2, characterized in that, The molar ratio of compound II, the protecting precursor, and the basic reagent is 1:2:2.5 to 1:2.2:4, and the reaction temperature is 20 to 40°C.

4. The preparation method according to claim 1, characterized in that, Compound III reacts with tetraisopropyl titanate and ethyl magnesium bromide to give compound IV. The reaction solvent is selected from tetrahydrofuran or diethyl ether. The molar ratio of compound III, tetraisopropyl titanate and ethyl magnesium bromide is 1:0.25:2 to 1:1:

4. The reaction temperature is -25 to 25℃.

5. The preparation method according to claim 1, characterized in that, Compound IV undergoes a tertiary alcohol substitution reaction with a haloacetic acid ester under alkaline conditions to give compound V. The haloacetic acid ester is selected from one of methyl bromoacetate, methyl chloroacetate, ethyl bromoacetate, ethyl chloroacetate, isopropyl bromoacetate, isopropyl chloroacetate, tert-butyl bromoacetate, or tert-butyl chloroacetate. The alkaline reagent is selected from one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium carbonate, sodium hydroxide, or sodium hydride. The reaction solvent is selected from one of 1,4-dioxane, isopropyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, tetrahydrofuran, or N-methylpyrrolidone.

6. The preparation method according to claim 5, characterized in that, The molar ratio of compound IV, haloacetic acid ester, and basic reagent is 1:1:1 to 1:2:2, and the reaction temperature is 10 to 50 °C.

7. The preparation method according to claim 1, characterized in that, Compound V is deprotected under palladium metal catalysis or acidic reagent conditions to obtain compound VI. The catalyst is selected from Pd(OH)2 / C or Pd / C; the acidic reagent is selected from trifluoroacetic acid, hydrobromic acid or hydrochloric acid; and the reaction solvent is selected from methanol, ethanol, dichloromethane or tetrahydrofuran.

8. The preparation method according to claim 7, characterized in that, The mass ratio of compound V to catalyst is 1:0.05 to 1:0.2, and the reaction temperature is 30 to 65°C.

9. The preparation method according to claim 1, characterized in that, Intermediate VI undergoes intramolecular cyclization under alkaline or acidic conditions to yield compound I. The alkaline reagent is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, or sodium bicarbonate; the acidic reagent is selected from acetic acid, hydrochloric acid, or sulfuric acid; the reaction solvent is selected from methanol, ethanol, or tetrahydrofuran; the molar ratio of compound VI to the alkaline or acidic reagent is 1:1 to 1:3; and the reaction temperature range is 20 to 60 °C.

10. The preparation method according to any one of claims 1 to 9 yields 4-oxa-7-azaspiro[2.5]octane-6-one.

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