Preparation method of intermediate for preparing 4-oxa-7-azaspiro [2.5] octane-6-one and intermediate product thereof

Abstract

The invention relates to a preparation method of an intermediate for preparing 4-oxa-7-azaspiro [2.5] octane-6-ketone and an intermediate product of the intermediate, and belongs to the field of pharmaceutical chemical synthesis. Hydrochloride of glycine ester is used as a starting material, an intermediate product 2-(1-(aminomethyl) cyclopropoxy) acetate (VI) is obtained through a protective group introduction reaction, cyclization, condensation and protective group removal, the structural formula of the intermediate product is shown in the specification, and R2 is selected from-CH3,-CH2-CH3,-CH (CH3) 2 and-C (CH3) 3. The intermediate product is subjected to intramolecular cyclization to prepare 4-oxa-7-azaspiro [2.5] octane-6-ketone, and the 4-oxa-7-azaspiro [2.5] octane-6-ketone is used as an initial raw material for synthesizing anti-influenza virus drugs and analogues thereof.

Description

TECHNICAL FIELD

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

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

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

[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 from the compound of formula V needs to use chloroacetyl chloride, which has strong irritation, and increases the human safety risk in the production process; (3) the exposed hydroxyl group in the compound of formula V will competitively affect 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, thereby resulting in a low reaction yield of this step; (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, one of the purposes of the present application is to provide an intermediate product for preparing 4-oxa-7-azaspiro[2.5]octan-6-one, the second purpose of the present application is to provide a preparation method of the intermediate product, and the third purpose of the present application is to provide the application of the intermediate product in the preparation of 4-oxa-7-azaspiro[2.5]octan-6-one.

[0006] To achieve the above purposes, the present application provides the following technical solutions: 1. The present application provides an intermediate product for preparing 4-oxa-7-azaspiro[2.5]octane-6-ketone, which is 2-(1-(aminomethyl)cyclopropoxy)acetate, and the structure of the intermediate product VI is as follows:

[0007] Preferably, R2 is selected from -CH3, -CH2-CH3, -CH(CH3)2, and -C(CH3)3.

[0008] 2. The present application also provides a preparation method of the intermediate product, which is prepared by the following route:

[0009]

[0010] The specific preparation steps are as follows: (1) Compound II is reacted under the condition of a basic reagent to introduce a protecting group precursor, so as to obtain compound III; Preferably, the compound II is glycine ester hydrochloride, which is selected from one of glycine methyl ester hydrochloride and glycine ethyl ester hydrochloride; the basic reagent is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, and lithium hydroxide; the protecting group precursor is selected from one of benzyl bromide, benzyl chloride, 4-methoxybenzyl bromide, and 4-methoxybenzyl chloride; and the reaction solvent is selected from one of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, and dichloromethane.

[0011] 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°C.

[0012] (2) Compound III is reacted under the action of tetraisopropyl titanate and ethyl magnesium bromide to obtain compound IV; Preferably, the reaction solvent is selected from one of tetrahydrofuran and diethyl ether, the molar ratio of compound III, tetraisopropyl titanate, and ethyl magnesium bromide is 1:0.25:2-1:1:4, and the reaction temperature is -25-25°C.

[0013] (3) Compound IV is subjected to a tertiary alcohol substitution reaction with a haloacetic ester under the condition of a basic reagent, so as to obtain compound V; Preferably, the halogenated acetic 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, halogenated acetic ester and basic reagent is 1:1:1~1:2:2, and the reaction temperature is 10~50℃.

[0014] (4) removing the protecting group of compound V under the condition of palladium metal catalysis or acidic reagent to obtain intermediate product VI; Preferably, the catalyst is selected from one of Pd(OH)2 / C or Pd / C; the acid 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 catalyst is 1:0.05~1:0.2, and the reaction temperature is 30~65℃.

[0015] 3. The application also provides the use of the above-mentioned intermediate product in the preparation of 4-oxa-7-azaspiro[2.5]octan-6-one, and the specific preparation method is as follows: .

[0016] The intermediate product VI is intramolecularly cyclized under the condition of basic reagent or acidic reagent to obtain 4-oxa-7-azaspiro[2.5]octan-6-one 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; the reaction solvent is selected from one of methanol, ethanol or tetrahydrofuran; and the molar ratio of intermediate product VI and basic reagent or acidic reagent is 1:1~1:3, and the reaction temperature ranges from 20 to 60℃.

[0017] The application has the following beneficial effects: In summary, the application provides an intermediate product and a preparation method thereof, and the intermediate product is applied to the preparation of 4-oxa-7-azaspiro[2.5]octan-6-one, which is an important starting material for the synthesis of anti-influenza virus drugs and analogs thereof. Compared with the existing method (patent CN119101009A), the preparation method of the application has improved atomic economy, process safety, operation simplicity and production cost, and the core advantages are reflected in the following three aspects: (1) Innovative design of key steps: replacing high-risk and inefficient acylation steps with mild and efficient condensation reactions. In step 3 of this invention, a haloacetate is innovatively used as the alkylating agent, replacing the chloroacetyl chloride used in step 4 of the existing method. This successfully introduces the key methylene and carbonyl structural units into the six-membered ring of 4-oxa-7-azaspiro[2.5]oct-6-one. Chloroacetyl chloride is a reactive acylation agent with irritant and corrosive properties, increasing operational and safety risks. Furthermore, the acylation step in the prior art has low yield and poor atom economy. By applying the relatively mild haloacetate, this invention improves the yield of this step and ensures its process safety, thereby reducing operational risks in the production process.

[0018] (2) Comprehensive benefits of benzyl removal: low cost, high quality, and environmentally friendly Compared to existing methods, this invention adjusts the debenzylation step in step 4 to after the hydroxyalkylation step, thus avoiding the possibility of exposed hydroxyl groups chelating with the palladium catalyst. Therefore, this step only requires a small amount of catalyst (0.05 w / w) to obtain a high-yield, high-purity intermediate product, thereby reducing the potential risks of metal residues to product quality and the surrounding environment. It also provides feasibility for subsequent catalyst recovery, laying the foundation for a green, high-quality, and low-cost route.

[0019] (3) Ingenious optimization of cyclization strategy: replacing intramolecular cyclization under strong base action with sterically hindered cyclization. In the key cyclization reaction for preparing 4-oxa-7-azaspiro[2.5]oct-6-one based on the aforementioned intermediate product, the rational design of the third step transforms the cyclization mechanism from the sterically hindered and weakly nucleophilic tertiary alcohol condensation reaction in existing technologies to a reaction between a primary amine and an ester. The cyclization step of this invention has strong thermodynamic driving force and low requirements for acid and base environments; only a weak base or acid is needed, and cyclization can be efficiently completed by heating in an alcohol. This method not only avoids the use of strong bases (such as t-BuOK), simplifies feeding and post-processing operations, but also improves the final yield, thereby greatly reducing production costs and highlighting the application potential of this method in industrial scale-up.

[0020] In summary, the preparation method provided by this invention reduces or avoids the use of palladium catalysts and the use of hazardous reagent chloroacetyl chloride in existing processes, making the synthetic route safer and more environmentally friendly. By improving the yields of the two key reactions, condensation and cyclization, the overall yield of the synthetic route is 64.20%, which is nearly double that of existing processes. Furthermore, the operation steps are simplified, resulting in a reduction of material costs and production costs of more than 70% compared to previous processes. This provides a more advantageous, green, and efficient synthetic route for the preparation of 4-oxa-7-azaspiro[2.5]octane-6-one.

[0021] Other advantages, objectives, and features of the invention will be set forth in part in the description which follows, and in part will be apparent to those skilled in the art from the following examination, or may be learned from practice of the invention. The objectives and other advantages of the invention can be realized and obtained through the following description. Detailed Implementation

[0022] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0023] Example 1 Preparation of intermediate product VI for the preparation of 4-oxa-7-azaspiro[2.5]octane-6-one, wherein intermediate product VI is methyl 2-(1-(aminomethyl)cyclopropoxy)acetate.

[0024] The specific preparation steps are as follows: (1) Preparation of compound III

[0025] Compound II (31.13 g, 0.22 mol, 1.0 eq) and acetonitrile (311 mL, 10 V) were added to a reaction flask, followed by potassium carbonate (77.06 g, 0.55 mol, 2.5 eq). After stirring at room temperature for 0.5 h, benzyl bromide (76.29 g, 0.44 mol, 2.0 eq) was slowly added dropwise to the reaction flask, and the reaction was allowed to proceed at room temperature for 6 h. Thin-layer chromatography (TLC) showed that the starting material had disappeared and the reaction was complete. Ethyl acetate (311 mL, 10 V) was added to the reaction solution, and after stirring, the organic layer was washed twice with purified water (156 mL each time, 5 V), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound III, a white solid. The product yielded 58.96 g, with a yield of 93.3%.

[0026] The 1H NMR spectrum of compound III is as follows: 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).

[0027] The mass spectrometry information for compound III is: [M+H] + = m / z 284.16.

[0028] (2) Preparation of compound IV

[0029] Compound III (20.00 g, 0.071 mol, 1.0 eq), tetrahydrofuran (200 mL, 10 V), and tetraisopropyl titanate (6.02 g, 0.3 eq) were added to a reaction flask and cooled to -5 °C. Then, a 1 M solution of ethyl magnesium bromide in tetrahydrofuran (105.9 mL, 0.21 mol, 3.0 eq) was slowly added dropwise. After the addition was complete, the temperature was raised to 10 °C and the reaction was carried out for 4 h. TLC showed that the starting material disappeared and the reaction was complete. The temperature was controlled below 10 °C, and a saturated ammonium chloride aqueous solution (20 mL, 1 V) was slowly added dropwise to quench the reaction. After the addition was complete, the mixture was filtered, and the filtrate was evaporated to dryness. The residue was dissolved in n-hexane (100 mL, 5 V), filtered again, and the filtrate was evaporated to dryness to obtain compound IV, a pale yellow oil. The product yielded 15.90 g (0.059 mol), with a yield of 88.7%.

[0030] The 1H NMR spectrum of compound IV is as follows: 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).

[0031] The mass spectrometry information for compound IV is: [M+H] + = m / z 268.17.

[0032] (3) Preparation of compound V

[0033] Compound IV (4.09 g, 0.015 mol, 1.0 eq) and tetrahydrofuran (61 mL, 15 V) were added to a reaction flask and stirred to dissolve. Then, methyl bromoacetate (2.75 g, 0.018 mol, 1.2 eq) was added, and the mixture was stirred at room temperature for 15 min. Sodium ethoxide (1.25 g, 0.018 mol, 1.2 eq) was added, and the mixture was then heated to 50 °C and reacted for 1 h. TLC showed that the starting material disappeared and the reaction was complete. Ethyl acetate (61 mL, 15 V) was added to the reaction mixture, and after stirring, the organic layer was washed once with purified water (61 mL, 15 V) and then twice with saturated brine (61 mL, 15 V each time). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound V, which was a yellow oil. The product yielded 4.88 g, with a yield of 95.7%.

[0034] The 1H NMR spectrum of compound V is as follows: 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).

[0035] The mass spectrometry information for compound V is: [M+H] + = m / z 340.19.

[0036] (4) Preparation of intermediate product VI

[0037] Compound 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, followed by the addition of 10% palladium on carbon (0.25 g, 0.05 w / w). After three purgings with hydrogen, the mixture was heated to 45 °C and reacted under a hydrogen atmosphere for 8 h. TLC analysis showed that the starting material had disappeared and the reaction was complete. The reaction solution was allowed to cool naturally to room temperature, filtered, and the filtrate was evaporated to dryness to obtain the intermediate product methyl 2-(1-(aminomethyl)cyclopropoxy)acetate, which was a pale yellow oil. The product yield was 2.26 g, with a yield of 96.2%.

[0038] The mass spectrometry information for intermediate product VI is: [M+H] + = m / z 160.09.

[0039] Example 2 Based on intermediate product VI obtained in Example 1, 4-oxa-7-azaspiro[2.5]octane-6-one was prepared.

[0040] The specific preparation method is as follows:

[0041] Intermediate product VI (1.60 g, 0.01 mol, 1.0 eq) and anhydrous ethanol (51 mL, 30 V) were added to a reaction flask. Potassium carbonate (2.76 g, 0.020 mol, 2.0 eq) was added with stirring at room temperature, and then the temperature was raised to 60 °C and reacted for 16 h. TLC showed that the starting material disappeared and the reaction was complete. The reaction solution was allowed to cool to room temperature naturally, filtered, and the filtrate was evaporated to dryness. 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. A large amount of solid precipitated. The mixture was filtered again, and the filter cake was washed with n-heptane (5 mL) and dried under reduced pressure at 40 °C to obtain compound I, 4-oxa-7-azaspiro[2.5]octane-6-one, which was a yellowish-brown solid. The product yielded 1.11 g, with a yield of 84.3%.

[0042] The 1H NMR spectrum of compound I is as follows: 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).

[0043] The mass spectrometry information for compound I is: [M+H] + = m / z 128.07.

[0044] Example 3 Preparation of intermediate product VI for the preparation of 4-oxa-7-azaspiro[2.5]octane-6-one, wherein intermediate product VI is methyl 2-(1-(aminomethyl)cyclopropoxy)acetate.

[0045] The specific synthesis steps are as follows: (1) Preparation of compound III

[0046] Compound II (12.55 g, 0.10 mol, 1.0 eq) and acetonitrile (125 mL, 10 V) were added to a reaction flask, followed by potassium carbonate (77.06 g, 0.55 mol, 2.5 eq). After stirring at room temperature for 0.5 h, 4-methoxybenzyl chloride (31.32 g, 0.20 mol, 2.0 eq) was slowly added dropwise to the reaction flask, and the reaction was allowed to proceed at room temperature for 6 h. TLC analysis showed that the starting material had disappeared and the reaction was complete. Ethyl acetate (125 mL, 10 V) was added to the reaction solution, and after stirring, the organic layer was washed twice with purified water (63 mL each time, 5 V), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound III, a white solid. The product yielded 31.3 g, with a yield of 95.0%.

[0047] The proton NMR spectrum of compound III is as follows: 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).

[0048] The mass spectrometry information for compound III is: [M+H] + = m / z 330.17.

[0049] (2) Preparation of compound IV

[0050] Compound 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 a reaction flask and cooled to -5 °C. Then, a 1 M solution of ethyl magnesium bromide in tetrahydrofuran (90.8 mL, 0.18 mol, 3.0 eq) was slowly added dropwise. After the addition was complete, the temperature was raised to 10 °C and the reaction was carried out for 4 h. TLC showed that the starting material disappeared and the reaction was complete. The temperature was controlled below 10 °C, and a saturated ammonium chloride aqueous solution (20 mL, 1 V) was slowly added dropwise to quench the reaction. After the addition was complete, the mixture was filtered, and the filtrate was evaporated to dryness. The residue was dissolved in n-hexane (100 mL, 5 V), filtered again, and the filtrate was evaporated to dryness to obtain compound IV, which was a pale yellow oil. The product was 18.68 g, with a yield of 94%.

[0051] The mass spectrometry information for compound IV is: [M+H] + = m / z 328.19.

[0052] (3) Preparation of compound V

[0053] Compound IV (9.81 g, 0.03 mol, 1.0 eq) and tetrahydrofuran (147 mL, 15 V) were added to a reaction flask and stirred to dissolve. Then, methyl bromoacetate (5.51 g, 0.036 mol, 1.2 eq) was added, and the mixture was stirred at room temperature for 15 min. Sodium ethoxide (2.50 g, 0.036 mol, 1.2 eq) was added, and the mixture was then heated to 50 °C and reacted for 1 h. TLC showed that the starting material disappeared and the reaction was complete. Ethyl acetate (147 mL, 15 V) was added to the reaction solution, and the mixture was stirred. The organic layer was washed once with purified water (147 mL, 15 V) and then twice with saturated brine (147 mL, 15 V each time). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound V, which was a yellow oil. The product yield was 11.63 g, with a yield of 97.2%.

[0054] The 1H NMR spectrum of compound V is as follows: 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).

[0055] The mass spectrometry information for compound V is: [M+H] + = m / z 400.21.

[0056] (4) Preparation of intermediate product VI

[0057] Compound V (10.00 g) was added to a three-necked flask, followed by trifluoroacetic acid (50 mL). The mixture was heated to 65 °C and stirred overnight. TLC showed that the starting material disappeared and the reaction was complete. The reaction solution was cooled to room temperature and evaporated under reduced pressure to obtain the intermediate product methyl 2-(1-(aminomethyl)cyclopropoxy)acetate, which was a brown oil. The product yield was 4.0 g, with a yield of 100%.

[0058] The mass spectrometry information for intermediate product VI is: [M+H] + = m / z 160.09.

[0059] Example 4 Based on intermediate product VI obtained in Example 3, 4-oxa-7-azaspiro[2.5]octane-6-one was prepared.

[0060] The specific preparation method is as follows:

[0061] Intermediate product VI (3.18 g, 0.02 mol, 1.0 eq) and anhydrous ethanol (32 mL, 10 V) were added to a reaction flask. Sodium hydroxide (2.4 g, 0.06 mol, 3.0 eq) was added with stirring at room temperature, and then the temperature was raised to 60 °C and reacted for 16 h. TLC showed that the starting material disappeared and the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in methyl tert-butyl ether (16 mL, 5 V), stirred at room temperature, and n-heptane (48 mL, 15 V) was slowly added dropwise. A large amount of solid precipitated. The mixture was filtered again, and the filter cake was washed with n-heptane (7 mL) and dried under reduced pressure at 40 °C to obtain compound I, 4-oxa-7-azaspiro[2.5]octane-6-one, which was a yellowish-brown solid. The product was 2.19 g, with a yield of 86.3%.

[0062] The proton NMR spectrum of compound I is as follows: 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).

[0063] The mass spectrometry information for compound I is: [M+H] + = m / z 128.07.

[0064] In summary, this invention proposes an intermediate product and its preparation method, which is applied to the preparation of 4-oxa-7-azaspiro[2.5]octane-6-one. The proposed preparation method reduces or avoids the use of palladium catalysts and the use of hazardous reagent chloroacetyl chloride in existing processes, making the synthetic route safer and more environmentally friendly. By improving the yields of the two key reactions, condensation and cyclization, the overall yield of the entire synthetic route is 64.20%, which is nearly double that of existing processes. Furthermore, the operation steps are simplified, reducing the material cost and production cost of the entire route by more than 70% compared to previous processes, providing a more advantageous, green, and efficient synthetic route for the preparation of 4-oxa-7-azaspiro[2.5]octane-6-one.

[0065] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. An intermediate product for preparing 4-oxa-7-azaspiro[2.5]octane-6-one, characterized in that, The intermediate product is 2-(1-(aminomethyl)cyclopropoxy)acetic acid ester, and the structural formula of intermediate product VI is: R2 is selected from -CH3, -CH2-CH3, -CH(CH3)2, and -C(CH3)3.

2. The method for preparing the intermediate product according to claim 1, characterized in that, Prepared via the following route: 。 3. The preparation method according to claim 2, 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 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.

4. The preparation method according to claim 3, 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.

5. The preparation method according to claim 2, 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℃.

6. The preparation method according to claim 2, 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.

7. The preparation method according to claim 6, 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.

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

9. The preparation method according to claim 8, 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.

10. The intermediate product according to claim 1, used in the preparation of 4-oxa-7-azaspiro[2.5]octane-6-one.

11. The application according to claim 10, characterized in that, The preparation method is as follows: 。 12. The application according to claim 11, characterized in that, Intermediate product VI undergoes intramolecular cyclization under alkaline or acidic conditions to yield compound I, 4-oxa-7-azaspiro[2.5]octane-6-one. 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 intermediate product VI to the alkaline or acidic reagent is 1:1 to 1:3; and the reaction temperature range is 20 to 60 °C.

Images