Preparation method of 5-azaspiro [2.4] heptane-1-yl tert-butyl carbamate

Abstract

The invention relates to a preparation method of 5-azaspiro [2.4] heptane-1-yl tert-butyl carbamate, which comprises the following steps: reacting 1-benzyl-3-pyrrolidone with methyl cyanoacetate to obtain an intermediate 1; reacting the intermediate 1 with nitromethane to obtain an intermediate 2; sequentially hydrolyzing the intermediate 2 under the action of an alkaline reagent and an acidic reagent to obtain an intermediate 3; reacting the intermediate 3 with diphenyl azide phosphate to obtain an intermediate 4; reacting the intermediate 4 with tert-butyl alcohol to obtain an intermediate 5; and carrying out hydrogenation reduction reaction on the intermediate 5 to obtain the 5-azaspiro [2.4] heptane-1-yl tert-butyl carbamate. The preparation method provided by the invention has the advantages of cheap and easily available raw materials, simple process operation, safe and controllable production and considerable yield, makes up for the shortage of the existing synthesis method, avoids the amplification danger, and can meet the requirements of large-scale industrialization.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate. Background Art

[0002] 5-Azaspiro[2.4]heptane-1-ylcarbamic acid tert-butyl ester can be used as a drug active molecular fragment for the research and development of various target inhibitors, such as ketohexokinase inhibitors, DNA gyrase or topoisomerase IV inhibitors, peptidylargininedeiminase-4 inhibitors and other types of inhibitors.

[0003] At present, there is a lack of research on the synthesis of tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate, and the synthesis of possible precursor N-protected 5-azaspiro[2.4]heptane-1-carboxylic acid is also very limited. The difficulty lies in the limited means of constructing the spirocyclic three-membered ring. Regarding the construction of the three-membered ring, there is a literature that uses ethyl diazoacetate to form a carbene with a copper or rhodium catalyst, and then undergoes a [1+2] cyclization reaction with an olefin bond. However, ethyl diazoacetate is a highly toxic substance. The reagent will cause decomposition and explosion when heated, and release toxic substances, which brings great danger to industrial production. Patent EP0550025A1 and patent CN106938980A both utilize trimethylsulfoxide iodide to construct the three-membered ring in N-protected 5-azaspiro[2.4]heptane-1-carboxylic acid. The use of this sulfur-containing reagent will generate a large amount of solid and liquid wastes, and will also cause palladium poisoning during the subsequent hydrogenation to cut the benzyl or benzyloxycarbonyl group, thereby causing problems such as incomplete reaction and difficulty in separation and purification.

[0004] In order to make up for the shortage of existing synthesis methods of tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate and avoid the risk of scale-up, a new method with simple operation and green environmental protection is developed to meet the future large-scale and industrial needs. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a method for preparing tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate. The preparation method provided by the present invention has cheap and readily available raw materials, simple process operation, safe and controllable production, and considerable yield, which makes up for the shortcomings of existing synthesis methods, avoids the risk of amplification, and can be applied to the needs of large-scale industrialization.

[0006] To achieve this object, the present invention adopts the following technical solutions:

[0007] The present invention provides a method for preparing tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate, the preparation method comprising the following steps:

[0008] (1) 1-Benzyl-3-pyrrolidone reacts with methyl cyanoacetate to obtain intermediate 1. The reaction formula is as follows:

[0009]

[0010] (2) The intermediate 1 obtained in step (1) reacts with nitromethane to obtain intermediate 2. The reaction formula is as follows:

[0011]

[0012] (3) The intermediate 2 obtained in step (2) is hydrolyzed in the presence of an alkaline agent and an acidic agent in turn to obtain an intermediate 3. The reaction formula is as follows:

[0013]

[0014] (4) The intermediate 3 obtained in step (3) reacts with diphenylphosphoryl azide to obtain intermediate 4. The reaction formula is as follows:

[0015]

[0016] (5) The intermediate 4 obtained in step (4) reacts with tert-butyl alcohol to obtain intermediate 5. The reaction formula is as follows:

[0017]

[0018] (6) The intermediate 5 obtained in step (5) is subjected to a hydrogenation reduction reaction to obtain the tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate, and the reaction formula is as follows:

[0019]

[0020] In the above reaction formula, Me represents a methyl group, and Boc represents a tert-butyloxycarbonyl group.

[0021] The preparation method provided by the present invention starts from 1-benzyl-3-pyrrolidone, first reacts with methyl cyanoacetate through Knoevenage reaction to form an olefin intermediate 1; then uses nitromethane to construct a spiro three-membered ring intermediate 2, and the construction of the three-membered ring avoids the use of ethyl diazoacetate, a dangerous reagent, and also abandons the traditional trimethyl sulfoxide iodide construction method. Instead, nitromethane, a conventional reagent, is used to perform an addition reaction with the olefin bond of the intermediate 1 under alkaline conditions, and the nitro group leaves to form a three-membered ring, thereby overcoming the risk of using ethyl diazoacetate to construct the three-membered ring during amplification and the large amount of solid and liquid waste generated by using trimethyl sulfoxide iodide. In addition, it also avoids palladium poisoning during subsequent hydrogenation, incomplete reaction, and difficulty in separation and purification. Subsequently, it is hydrolyzed to dicarboxylic acid through alkaline hydrolysis and decarboxylated through acidic hydrolysis to obtain monoacid intermediate 3. If only acidic hydrolysis is used for decarboxylation, a rearrangement by-product, a five-membered lactone, is produced. By hydrolyzing twice in stages, the production of by-products can be avoided, and there is no need to post-treat the dicarboxylic acid, thereby improving the reaction efficiency. Then, diphenylphosphoryl azide (DPPA) is used to obtain intermediate 4 through Curtius rearrangement, which is then attacked by nucleophilic attack of tert-butyl alcohol to obtain intermediate 5, and finally hydrogenated and reduced to obtain tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate.

[0022] The preparation method provided by the present invention has cheap and easily available raw materials, simple process operation, safe and controllable production and considerable yield, which makes up for the shortcomings of existing synthesis methods and avoids the risk of scale-up, and can be suitable for large-scale industrial needs.

[0023] Preferably, the molar ratio of 1-benzyl-3-pyrrolidone to methyl cyanoacetate in step (1) is 1:(1.0-1.5), for example, it can be 1:1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0024] Preferably, the reaction in step (1) is carried out in the presence of a catalyst.

[0025] Preferably, the catalyst comprises any one or a combination of at least two of piperidine, ammonium acetate, sodium hydroxide, sodium carbonate, potassium fluoride, aluminum phosphate, diammonium hydrogen phosphate or titanium tetrachloride-pyridine combination.

[0026] Preferably, the molar ratio of 1-benzyl-3-pyrrolidone to the catalyst is 1:(0.1-1.5), for example, it can be 1:0.1, 1:0.2, 1:0.4, 1:0.6, 1:0.8, 1:1, 1:1.2, 1:1.4, 1:1.5, etc.

[0027] Preferably, the reaction in step (1) is carried out in the presence of a solvent.

[0028] Preferably, the solvent is an aprotic solvent.

[0029] Preferably, the aprotic solvent includes any one of benzene, toluene or N,N-dimethylformamide, or a combination of at least two thereof.

[0030] Preferably, the material mixing method of the reaction in step (1) comprises: mixing 1-benzyl-3-pyrrolidone, a solvent and a catalyst to obtain a mixed solution; and dropwise adding methyl cyanoacetate to the mixed solution to obtain a reaction system.

[0031] Preferably, the reaction temperature in step (1) is 0-130°C, for example, 0°C, 20°C, 50°C, 80°C, 110°C, 130°C, etc.

[0032] Preferably, the reaction time of step (1) is 2-16 h, for example, 2 h, 5 h, 10 h, 16 h, etc.

[0033] Preferably, the reaction in step (1) further includes a post-treatment step.

[0034] Preferably, the post-treatment comprises: adding water to the reaction system and stirring, separating the organic phase, washing with a salt solution, washing with water, drying and concentrating to obtain the intermediate 1.

[0035] Preferably, the molar ratio of the intermediate 1 to nitromethane in step (2) is 1:(1-10), for example, it can be 1:1, 1:2, 1:4, 1:6, 1:8, 1:10, etc.

[0036] Preferably, the reaction in step (2) is carried out in the presence of a basic catalyst.

[0037] Preferably, the basic catalyst comprises any one or a combination of at least two of 1,8-diazabicyclo[5.4.0]undec-7-ene, piperidine or triethylamine.

[0038] Preferably, the molar ratio of the intermediate 1 to the alkaline catalyst is 1:(1-2), for example, it can be 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, etc.

[0039] Preferably, the reaction in step (2) is carried out in the presence of a solvent.

[0040] Preferably, the solvent comprises any one of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran, or a combination of at least two thereof.

[0041] Preferably, the material mixing method of the reaction in step (2) comprises: mixing the intermediate 1 and a solvent to obtain a mixed liquid; and dropwise adding nitromethane and a catalyst to the mixed liquid to obtain a reaction system.

[0042] Preferably, the reaction temperature in step (2) is 0-50°C, for example, 0°C, 20°C, 30°C, 50°C, etc.

[0043] Preferably, the reaction time of step (2) is 6-24 h, for example, 6 h, 10 h, 16 h, 24 h, etc.

[0044] Preferably, the reaction in step (2) further comprises a post-treatment step.

[0045] Preferably, the post-treatment comprises: acid washing the reaction system, extracting to obtain an organic phase, and then acid washing again, washing with a salt solution, drying and concentrating to obtain the intermediate 2.

[0046] Preferably, the solvent used for the extraction includes any one of methyl tert-butyl ether, isopropyl ether, ethyl acetate, n-hexane or dichloromethane, or a combination of at least two thereof.

[0047] Preferably, the alkaline reagent in step (3) comprises any one of sodium hydroxide, lithium hydroxide, potassium carbonate, sodium methoxide or sodium tert-butoxide, or a combination of at least two thereof.

[0048] Preferably, the molar ratio of the intermediate 2 to the alkaline reagent in step (3) is 1:(1-10), for example, it can be 1:1, 1:2, 1:4, 1:6, 1:8, 1:10, etc.

[0049] Preferably, the acidic reagent in step (3) comprises any one of hydrochloric acid, sulfuric acid or hydrobromic acid, or a combination of at least two thereof.

[0050] Preferably, in step (3), the acidic reagent is added until the pH value of the system is 1-2, for example, it can be 1, 1.2, 1.4, 1.6, 1.8, 2, etc.

[0051] Preferably, the hydrolysis in step (3) is carried out in the presence of a solvent.

[0052] Preferably, the solvent comprises water.

[0053] Preferably, the temperatures of the hydrolysis in step (3) under the action of an alkaline agent and an acidic agent in sequence are independently 25-100°C, for example, 25°C, 40°C, 60°C, 90°C, 100°C, etc.

[0054] Preferably, the time for hydrolysis in step (3) under the action of alkaline reagent and acidic reagent in sequence is independently 10-20 hours, for example, it can be 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, etc.

[0055] Preferably, the reaction in step (3) further comprises a post-treatment step.

[0056] Preferably, the post-treatment comprises: adding an organic solvent to the reaction system for extraction, separating the organic phase, and obtaining the intermediate 3 after drying, concentrating and beating.

[0057] Preferably, the organic solvent comprises any one of methyl tert-butyl ether, isopropyl ether, petroleum ether, tetrahydrofuran, ethyl acetate or dichloromethane, or a combination of at least two thereof, preferably a combination of methyl tert-butyl ether and tetrahydrofuran.

[0058] Preferably, the molar ratio of the intermediate 3 to diphenylphosphoryl azide in step (4) is 1:(1-3), for example, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, etc.;

[0059] Preferably, the reaction in step (4) is carried out in the presence of an organic base catalyst.

[0060] Preferably, the organic base catalyst includes any one of triethylamine, N,N-diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene or a combination of at least two thereof.

[0061] Preferably, the molar ratio of the intermediate 3 to the organic base catalyst is 1:(1-3), for example, it can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, etc.

[0062] Preferably, the reaction in step (4) is carried out in the presence of a solvent.

[0063] Preferably, the solvent includes any one of toluene, 1,4-dioxane, N,N-dimethylformamide or dimethyl sulfoxide, or a combination of at least two thereof.

[0064] Preferably, the material mixing method of the reaction in step (4) comprises: mixing the intermediate 3 and a solvent to obtain a mixed solution; and adding a catalyst and diphenylphosphoazide to the mixed solution to obtain a reaction system.

[0065] Preferably, the reaction temperature in step (4) is 90-100°C, for example, it can be 90°C, 92°C, 94°C, 96°C, 98°C, 100°C, etc.

[0066] Preferably, the reaction time of step (4) is 1-10 h, for example, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, etc.

[0067] Preferably, the molar ratio of the intermediate 3 in step (4) to the tert-butanol in step (5) is 1:(1-10), for example, it can be 1:1, 1:2, 1:4, 1:6, 1:8, 1:10, etc.

[0068] Preferably, the reaction temperature in step (5) is 90-100°C, for example, 90°C, 92°C, 94°C, 96°C, 98°C, 100°C, etc.

[0069] Preferably, the reaction time of step (5) is 4-24 h, for example, 4 h, 8 h, 16 h, 24 h, etc.

[0070] Preferably, the material mixing method for the reaction in step (5) comprises: adding tert-butanol dropwise to the mixed solution after the reaction in step (4) is completed to obtain a reaction system.

[0071] Preferably, the reaction in step (5) further comprises a post-treatment step.

[0072] Preferably, the post-treatment comprises: washing the reaction system with alkali, extracting to obtain an organic phase, then washing with a salt solution, washing with water, drying, and concentrating to obtain a crude intermediate 5; and then redissolving the crude product, filtering and eluting through a silica gel pad, and concentrating the filtrate to obtain the intermediate 5.

[0073] Preferably, the solvent selected for the extraction includes any one of ethyl acetate, dichloromethane or methyl tert-butyl ether, or a combination of at least two of them.

[0074] Preferably, the solvent selected for the re-dissolution includes any one of n-hexane, n-heptane, petroleum ether or methyl tert-butyl ether, or a combination of at least two thereof.

[0075] Preferably, the hydrogenation reduction reaction in step (6) is carried out in the presence of a catalyst.

[0076] Preferably, the catalyst comprises any one of palladium carbon, platinum carbon, ruthenium carbon or palladium hydroxide, or a combination of at least two thereof.

[0077] Preferably, the mass ratio of the intermediate 5 to the catalyst is 1:(0.05-0.5), for example, it can be 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.5, etc.

[0078] Preferably, the hydrogenation reduction reaction in step (6) is carried out in the presence of a solvent.

[0079] Preferably, the solvent includes any one of methanol, ethanol or isopropanol, or a combination of at least two of them.

[0080] Preferably, the material mixing method for the hydrogenation reduction reaction in step (6) comprises: mixing the intermediate 5, the solvent and the catalyst to obtain a mixed liquid; and replacing the mixed liquid with nitrogen and hydrogen in sequence to obtain a reaction system.

[0081] Preferably, the temperature of the hydrogenation reduction reaction in step (6) is 20-80°C, for example, 20°C, 40°C, 50°C, 60°C, 80°C, etc.

[0082] Preferably, the pressure of the hydrogenation reduction reaction in step (6) is 2-10 MPa, for example, 2 MPa, 3 MPa, 5 MPa, 8 MPa, 10 MPa, etc.

[0083] Preferably, the time of the hydrogenation reduction reaction in step (6) is 4-48 h, for example, 4 h, 8 h, 16 h, 24 h, 36 h, 48 h, etc.

[0084] Preferably, the hydrogenation reduction reaction in step (6) further comprises a post-treatment step.

[0085] Preferably, the post-treatment comprises: filtering and washing the reaction system, and then concentrating the filtrate to obtain a crude product of tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate; re-dissolving the crude product with an organic solvent, and then concentrating to obtain the tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate.

[0086] Preferably, the solvent selected for the re-dissolution includes any one of tetrahydrofuran, acetonitrile or acetone, or a combination of at least two of them.

[0087] Preferably, the preparation method comprises the following steps:

[0088] (1) mixing 1-benzyl-3-pyrrolidone, methyl cyanoacetate, a catalyst and a solvent, reacting at 0-130° C. for 2-16 hours to obtain an intermediate 1; the molar ratio of 1-benzyl-3-pyrrolidone, methyl cyanoacetate and the catalyst is 1:(1.0-1.5):(0.1-1.5);

[0089] (2) mixing the intermediate 1 obtained in step (1), nitromethane, a basic catalyst and a solvent, and reacting at 0-50° C. for 6-24 hours to obtain an intermediate 2; the molar ratio of the intermediate 1, nitromethane and the basic catalyst is 1:(1-10):(1-2);

[0090] (3) mixing the intermediate 2 obtained in step (2) with an aqueous solution of an alkaline reagent, reacting at 25-100° C. for 10-20 hours, then adding an acidic reagent until the pH value of the system is 1-2, and reacting at 25-100° C. for 10-20 hours to obtain an intermediate 3; the molar ratio of the intermediate 2 to the alkaline reagent is 1:(1-10);

[0091] (4) mixing the intermediate 3 obtained in step (3), diphenyl phosphoryl azide, an organic base catalyst and a solvent, and reacting at 90-100° C. for 1-10 hours to obtain an intermediate 4; the molar ratio of the intermediate 3, diphenyl phosphoryl azide and the organic base catalyst is 1:(1-3):(1-3);

[0092] (5) adding tert-butanol dropwise to the mixed solution after the reaction in step (4), reacting at 90-100° C. for 4-24 hours to obtain intermediate 5; the molar ratio of the intermediate 3 in step (4) to the tert-butanol in step (5) is 1:(1-10);

[0093] (6) The intermediate 5 obtained in step (5), a catalyst, a solvent and hydrogen are mixed, and a hydrogenation reduction reaction is carried out at 20-80° C. and 2-10 MPa for 4-48 hours to obtain the tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate; the mass ratio of the intermediate 5 to the catalyst is 1:(0.05-0.5).

[0094] Compared with the prior art, the present invention has at least the following beneficial effects:

[0095] The preparation method provided by the present invention starts from 1-benzyl-3-pyrrolidone, first forms an alkene intermediate 1 with methyl cyanoacetate, then uses nitromethane to construct a spiro three-membered ring intermediate 2, then sequentially performs alkaline hydrolysis and acidic hydrolysis decarboxylation to obtain an acid intermediate 3, then uses diphenylphosphoryl azide (DPPA) to perform Curtius rearrangement to obtain an intermediate 4, which is then attacked by nucleophilic attack of tert-butyl alcohol to obtain an intermediate 5, and finally performs hydrogenation reduction to obtain tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate. The preparation method has cheap and easily available raw materials, simple process operation, safe and controllable production, and considerable yield, which makes up for the shortcomings of existing synthesis methods, avoids the risk of scale-up, and can be applied to large-scale industrialization needs. DETAILED DESCRIPTION

[0096] For the convenience of understanding the present invention, the present invention lists the following embodiments. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0097] Example 1

[0098] A method for preparing tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate comprises the following steps:

[0099] (1) Toluene (10 L, 5 V) was pumped into a reactor equipped with a mechanical stirrer, a heating device, and a water separator, and then 1-benzyl-3-pyrrolidone (2000 g, 11.4 mol, 1.0 eq) was added. After stirring and dissolving, ammonium acetate (176 g, 2.3 mol, 0.2 eq) and acetic acid (523 mL, 9.1 mol, 0.8 eq) were added to the reactor at 25°C, and then methyl cyanoacetate (1108 mL, 12.6 mol, 1.1 eq) was added dropwise. q); the whole reaction system was then heated and refluxed with stirring for 12h, and the water generated during the reaction was separated by a water separator, and the reaction of the raw materials was completed by central control detection; the reaction system was cooled to 25°C, 10L of water was pumped into the reactor and stirred, and then the organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate, each time with 5L, and the organic phases were combined, washed with saturated brine and water in turn, and then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 55°C until there was no droplet, to obtain 2760g of the oily target intermediate 1 product, with a yield of 94.4%;

[0100] (2) A solution of the intermediate 1 (2000 g, 7.8 mol, 1.0 eq) in acetonitrile (30 L, 15 V) was added to a reaction kettle equipped with a mechanical stirrer, and then nitromethane (2093 mL, 39.0 mol, 5.0 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1166 mL, 7.8 mol, 1.0 eq) were added dropwise in sequence under stirring. During the addition of DBU, the reaction solution gradually turned orange-yellow. After the addition was completed, the entire reaction system was stirred at 25 °C. 16h, thin layer chromatography (TLC) detected that there was still a little residual raw material, then 100mL of DBU was added and the reaction was continued to stir for 2h, and the raw material was almost disappeared by central control detection; 20L of methyl tert-butyl ether and 30L of hydrochloric acid (10wt%) were added to the reaction system, stirred for 0.5h and then allowed to stand to separate the organic phase, the separated organic phase was washed twice with 10wt% hydrochloric acid, then washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C until there was no droplet, to obtain 1545g of the target intermediate 2 product, with a yield of 73.2%;

[0101] (3) The intermediate 2 (1500 g, 5.5 mol, 1.0 eq) and 2M sodium hydroxide aqueous solution (13.9 L, 27.7 mol, 5.0 eq) were added to a reactor equipped with a mechanical stirrer and a heating device. The entire reaction system was heated to reflux for 16 h, then cooled to 25 ° C, 10 L of dichloromethane was added to the reactor, and dichloromethane was separated after stirring for a period of time. The aqueous phase was adjusted to pH 1.5 with 50 wt % hydrochloric acid, and then the heating was turned on and refluxed and stirred again for 12 h. The central control detected that the raw material was almost reacted; the reaction system was cooled to 25 ° C, and a mixed solvent of methyl tert-butyl ether and tetrahydrofuran (v / v, 1 / 1) was added to the reactor for extraction twice, each time using 10 L, and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50 ° C, and the residue was purified by pulping with methyl tert-butyl ether to obtain 1086 g of an off-white solid target intermediate 3 product with a yield of 84.6%;

[0102] Structural characterization data of intermediate 3:

[0103] 1 HNMR (400MHz, CDCl3)ppmδ: 0.94-1.26(m,1H),1.65-1.95(m,2H),2.11-2.27(m,1H),2.30-2.86(m,5H),3.72(s,2H),7.13-3.35(m,5H).

[0104] (4) The intermediate 3 (1000 g, 4.3 mol, 1.0 eq) was dissolved in toluene (10 L, 10 V), and then triethylamine (900 mL, 6.5 mol, 1.5 eq) and diphenylphosphoryl azide (DPPA, 14278 g, 5.2 mol, 1.2 eq) were added dropwise to the reaction system. After the addition, the reaction system was heated to 100 °C and reacted for 2 h. This process was exothermic and gaseous, and intermediate 4 was obtained. The next step was carried out directly without treatment.

[0105] (5) The reaction system of step (4) was cooled to 80°C, and tert-butanol (620 mL, 6.5 mol, 1.5 eq, based on intermediate 3) was slowly added dropwise. After the addition, the reaction was continued at 100°C for 12 h. The reaction of the raw materials was almost complete when detected by the central control. The reaction system was cooled to 25°C, and then 10% sodium bicarbonate solution (10 L) and ethyl acetate (5 L) were added. After stirring for a while, the organic phase was separated. The separated organic phase was washed with saturated brine and water, and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 55°C. The residue was dissolved with n-hexane and filtered through a silica gel pad. The eluent was a mixed solvent of n-hexane / ethyl acetate (v / v, 30 / 1). The collected filtrate was concentrated under reduced pressure at 45°C to obtain 960 g of intermediate 5 product with a yield of 73.4%;

[0106] (6) Add the above intermediate 5 (360 g, 1.2 mol, 1.0 eq) and methanol (2700 mL, 7.5 V) to a 5 L hydrogenation kettle, then add 10% palladium carbon (54 g, 15 wt%), replace with nitrogen 3 times, replace with hydrogen 2 times, pressure 3 MPa, start heating to 50 ° C, stir for 18 h, and detect the completion of the reaction of the raw materials during central control; cool the reaction system to 25 ° C, filter the reaction solution twice with diatomaceous earth, wash the filter cake with methanol until no product remains, collect the filtrate and concentrate it under reduced pressure at 50 ° C, and steam the residue with tetrahydrofuran once to obtain 200 g of tert-butyl 5-azaspiro [2.4] heptane-1-ylcarbamate, with a yield of 79.2%;

[0107] Structural characterization data of tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate:

[0108] 1 HNMR(400MHz, CDCl3)ppmδ: 0.89-1.11(m,1H),1.45(s,9H),1.62-1.98(m,2H),2.39 -2.57(m,1H),2.76-2.86(m,1H),3.04-3.38(m,2H),3.42-3.48(m,2H),4.24(s,2H).

[0109] Example 2

[0110] (1) Toluene (10 L, 5 V) was pumped into a reaction kettle equipped with a mechanical stirrer, a heating device, and a water separator, and then 1-benzyl-3-pyrrolidone (2000 g, 11.4 mol, 1.0 eq) was added. After stirring and dissolving, piperidine (194 g, 2.3 mol, 0.2 eq) and acetic acid (131 mL, 2.3 mol, 0.2 eq) were added to the reaction kettle at 25°C, and then methyl cyanoacetate (1007 mL, 11.4 mol, 1.0 eq) was added dropwise. ); the whole reaction system was then heated to reflux and stirred for 16 hours, and the water generated during the reaction was separated by a water separator, and the reaction of the raw materials was completed by central control detection; the reaction system was cooled to 25°C, 10L of water was pumped into the reactor and stirred, and then the organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate, each time with 5L, and the organic phases were combined, washed with saturated brine and water in turn, and then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 55°C until there was no droplet, to obtain 2650g of the oily target intermediate 1 product, with a yield of 89.6%;

[0111] (2) A solution of the intermediate 1 (2000 g, 7.8 mol, 1.0 eq) in acetonitrile (30 L, 15 V) was added to a reaction kettle equipped with a mechanical stirrer, and then nitromethane (1257 mL, 23.4 mol, 3.0 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1516 mL, 10.1 mol, 1.3 eq) were added dropwise in sequence under stirring. During the addition of DBU, the reaction solution gradually became to orange-yellow; after the addition was completed, the entire reaction system was stirred at 35°C for 24h, and the raw material almost disappeared during the central control detection; 20L methyl tert-butyl ether and 30L hydrochloric acid (10wt%) were added to the reaction system, stirred for 0.5h and then allowed to stand to separate the organic phase, the separated organic phase was washed twice with 10wt% hydrochloric acid, then washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C until there was no droplet, to obtain 1620g of the target intermediate 2 product, with a yield of 76.8%;

[0112] (3) The intermediate 2 (1500 g, 5.5 mol, 1.0 eq) and 2M aqueous sodium hydroxide solution (22.2 L, 44.4 mol, 8.0 eq) were added to a reactor equipped with a mechanical stirrer and a heating device. The entire reaction system was heated to reflux for 12 h, then cooled to 25 ° C, 10 L of dichloromethane was added to the reactor, and dichloromethane was separated after stirring for a period of time. The aqueous phase was adjusted to pH 1.5 with 25 wt % sulfuric acid, and then the heating was turned on and refluxed and stirred for 12 h. The central control detected that the raw material was almost reacted; the reaction system was cooled to 25 ° C, and a mixed solvent of methyl tert-butyl ether and tetrahydrofuran (v / v, 1 / 1) was added to the reactor for extraction twice, each time using 10 L, and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50 ° C, and the residue was purified by pulping with methyl tert-butyl ether to obtain 1065 g of an off-white solid target intermediate 3 product with a yield of 83.0%;

[0113] (4) The intermediate 3 (1000 g, 4.3 mol, 1.0 eq) was dissolved in toluene (10 L, 10 V), and then N, N-diisopropylethylamine (1130 mL, 6.5 mol, 1.5 eq) and diphenylphosphoryl azide (DPPA, 14278 g, 5.2 mol, 1.2 eq) were added dropwise to the reaction system. After the addition, the reaction system was heated to 100 ° C and reacted for 2 h. This process was exothermic and gaseous, and intermediate 4 was obtained. The next step was directly carried out without treatment;

[0114] (5) The reaction system of step (4) was cooled to 80°C, and tert-butanol (827 mL, 8.6 mol, 2.0 eq, based on intermediate 3) was slowly added dropwise. After the addition, the reaction was continued at 100°C for 12 h. The reaction of the raw materials was almost complete when detected by the central control. The reaction system was cooled to 25°C, and then 10% sodium bicarbonate solution (10 L) and ethyl acetate (5 L) were added. After stirring for a while, the organic phase was separated. The separated organic phase was washed with saturated brine and water, and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 55°C. The residue was dissolved with n-hexane and filtered through a silica gel pad. The eluent was a mixed solvent of n-hexane / ethyl acetate (v / v, 30 / 1). The collected filtrate was concentrated under reduced pressure at 45°C to obtain 950 g of intermediate 5 product with a yield of 72.7%;

[0115] (6) The above intermediate 5 (423 g, 1.4 mol, 1.0 eq) and methanol (3384 mL, 8.0 V) were added to a 5 L hydrogenation kettle, followed by 10% palladium carbon (85 g, 20 wt%). The atmosphere was replaced with nitrogen three times and hydrogen twice. The pressure was 3 MPa. The temperature was initially raised to 50 ° C. and stirred for 18 h. The reaction of the raw materials was completed after central control detection. The reaction system was cooled to 25 ° C. The reaction solution was filtered twice with diatomaceous earth. The filter cake was washed with methanol until no product remained. The collected filtrate was concentrated under reduced pressure at 50 ° C. The residue was evaporated once with acetone to obtain 240 g of tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate with a yield of 80.8%.

[0116] Example 3

[0117] (1) N,N-dimethylformamide (10 L, 5 V) was pumped into a reaction kettle equipped with a mechanical stirrer, a heating device and a water separator, and then 1-benzyl-3-pyrrolidone (2000 g, 11.4 mol, 1.0 eq) was added. After stirring and dissolving, sodium hydroxide (685 g, 17.1 mol, 1.5 eq) was added to the reaction kettle at 25°C, and then methyl cyanoacetate (1511 mL, 17.1 mol, 1.5 eq) was added dropwise. After the addition, the whole reaction system was heated to 90°C and stirred for 16h. The reaction of the raw materials was almost complete when the central control detected that the reaction was complete. The reaction system was cooled to 25°C, 10L of water and 10L of ethyl acetate were pumped into the reactor and stirred, and then the organic phase was separated. The aqueous phase was extracted once with 5L of ethyl acetate, and the organic phases were combined, washed with saturated brine and water in turn, and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 55°C until there was no droplet, and 2700g of the oily target intermediate 1 product was obtained with a yield of 91.2%;

[0118] (2) A solution of the intermediate 1 (2000 g, 7.8 mol, 1.0 eq) in tetrahydrofuran (30 L, 15 V) was added to a reaction kettle equipped with a mechanical stirrer, and then nitromethane (3351 mL, 62.4 mol, 8.0 eq), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 700 mL, 4.9 mol, 0.6 eq), and triethylamine (1085 mL, 7.8 mol, 1.0 eq) were added dropwise in sequence under stirring; after the addition was completed, the whole The reaction system was stirred at 25°C for 8h. Thin layer chromatography (TLC) showed that the raw material had not reacted completely. The reaction was continued to be stirred for 16h. The raw material almost disappeared during the central control test. 20L of methyl tert-butyl ether and 30L of hydrochloric acid (10wt%) were added to the reaction system. The mixture was stirred for 0.5h and then allowed to stand to separate the organic phase. The separated organic phase was washed twice with 10wt% hydrochloric acid and then with brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50°C until there was no droplet. 1353g of the target intermediate 2 product was obtained with a yield of 64.1%.

[0119] (3) The intermediate 2 (1500 g, 5.5 mol, 1.0 eq) and 4 M aqueous lithium hydroxide solution (13.9 L, 55.5 mol, 10.0 eq) were added to a reactor equipped with a mechanical stirrer and a heating device. The entire reaction system was heated to reflux for 16 h, then cooled to 25 ° C, 10 L of dichloromethane was added to the reactor, and dichloromethane was separated after stirring for a period of time. The aqueous phase was adjusted to pH 1.5 with 50 wt % hydrochloric acid, and then the heating was turned on and refluxed and stirred for 12 h. The central control detected that the raw material was almost reacted; the reaction system was cooled to 25 ° C, and a mixed solvent of methyl tert-butyl ether and tetrahydrofuran (v / v, 1 / 1) was added to the reactor for extraction twice, each time using 10 L, and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50 ° C, and the residue was purified by pulping with methyl tert-butyl ether to obtain 1125 g of an off-white solid target intermediate 3 product with a yield of 87.7%;

[0120] (4) The intermediate 3 (1000 g, 4.3 mol, 1.0 eq) was dissolved in 1,4-dioxane (10 L, 10 V), and then triethylamine (900 mL, 6.5 mol, 1.5 eq) and diphenylphosphoryl azide (DPPA, 14278 g, 5.2 mol, 1.2 eq) were added dropwise to the reaction system. After the addition, the reaction system was heated to 100 °C and reacted for 2 h. This process was exothermic and gaseous, and the intermediate 4 was obtained. The next step was carried out directly without treatment.

[0121] (5) The reaction system of step (4) was cooled to 80°C, and tert-butanol (2068mL, 21.6mol, 5.0eq, based on intermediate 3) was slowly added dropwise. After the addition, the reaction was continued at 100°C for 12h. The reaction of the raw materials was almost complete when detected by the central control. The reaction system was cooled to 25°C, and then 10% sodium bicarbonate solution (10L) and ethyl acetate (5L) were added. After stirring for a while, the organic phase was separated. The separated organic phase was washed with saturated brine and water, and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 55°C. The residue was dissolved with n-hexane and filtered through a silica gel pad. The eluent was a mixed solvent of n-hexane / ethyl acetate (v / v, 30 / 1). The collected filtrate was concentrated under reduced pressure at 45°C to obtain 965g of intermediate 5 product with a yield of 73.8%;

[0122] (6) The intermediate 5 (360 g, 1.2 mol, 1.0 eq) and ethanol (2700 mL, 7.5 V) were added to a 5 L hydrogenation reactor, followed by 20% palladium hydroxide (36 g, 10 wt%). The mixture was replaced with nitrogen three times and hydrogen twice. The pressure was 5 MPa. The temperature was initially raised to 70 ° C. and stirred for 12 h. The reaction of the raw materials was completed after central control. The reaction system was cooled to 25 ° C. The reaction solution was filtered twice with diatomaceous earth. The filter cake was washed with methanol until no product remained. The collected filtrate was concentrated to dryness under reduced pressure at 55 ° C. The residue was then evaporated once with tetrahydrofuran to obtain 190 g of tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate with a yield of 75.2%.

[0123] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate, characterized in that: The preparation method comprises the following steps: (1) 1-Benzyl-3-pyrrolidone reacts with methyl cyanoacetate to obtain intermediate 1. The reaction formula is as follows: (2) The intermediate 1 obtained in step (1) reacts with nitromethane to obtain intermediate 2. The reaction formula is as follows: (3) The intermediate 2 obtained in step (2) is hydrolyzed in the presence of an alkaline agent and an acidic agent in turn to obtain an intermediate 3. The reaction formula is as follows: (4) The intermediate 3 obtained in step (3) reacts with diphenylphosphoryl azide to obtain intermediate 4. The reaction formula is as follows: (5) The intermediate 4 obtained in step (4) reacts with tert-butyl alcohol to obtain intermediate 5. The reaction formula is as follows: (6) The intermediate 5 obtained in step (5) is subjected to a hydrogenation reduction reaction to obtain the tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate, and the reaction formula is as follows:

2. The preparation method according to claim 1, characterized in that: The molar ratio of 1-benzyl-3-pyrrolidone to methyl cyanoacetate in step (1) is 1:(1.0-1.5); Preferably, the reaction in step (1) is carried out in the presence of a catalyst; Preferably, the catalyst comprises any one or a combination of at least two of piperidine, ammonium acetate, sodium hydroxide, sodium carbonate, potassium fluoride, aluminum phosphate, diammonium hydrogen phosphate or titanium tetrachloride-pyridine combination; Preferably, the molar ratio of 1-benzyl-3-pyrrolidone to the catalyst is 1:(0.1-1.5); Preferably, the reaction in step (1) is carried out in the presence of a solvent; Preferably, the solvent is an aprotic solvent; Preferably, the aprotic solvent includes any one of benzene, toluene or N,N-dimethylformamide, or a combination of at least two thereof.

3. The preparation method according to claim 1 or 2, characterized in that: The material mixing method of the reaction in step (1) comprises: mixing 1-benzyl-3-pyrrolidone, a solvent and a catalyst to obtain a mixed solution; adding methyl cyanoacetate dropwise to the mixed solution to obtain a reaction system; Preferably, the reaction temperature in step (1) is 0-130°C; Preferably, the reaction time in step (1) is 2-16 h; Preferably, the reaction in step (1) further includes a post-treatment step; Preferably, the post-treatment comprises: adding water to the reaction system and stirring, separating the organic phase, washing with a salt solution, washing with water, drying and concentrating to obtain the intermediate 1.

4. The preparation method according to any one of claims 1 to 3, characterized in that The molar ratio of the intermediate 1 to nitromethane in step (2) is 1:(1-10); Preferably, the reaction in step (2) is carried out in the presence of a basic catalyst; Preferably, the basic catalyst comprises any one or a combination of at least two of 1,8-diazabicyclo[5.4.0]undec-7-ene, piperidine or triethylamine; Preferably, the molar ratio of the intermediate 1 to the alkaline catalyst is 1:(1-2); Preferably, the reaction in step (2) is carried out in the presence of a solvent; Preferably, the solvent comprises any one of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran, or a combination of at least two thereof.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The material mixing method of the reaction in step (2) comprises: mixing the intermediate 1 and a solvent to obtain a mixed solution; adding nitromethane and a catalyst dropwise to the mixed solution to obtain a reaction system; Preferably, the reaction temperature in step (2) is 0-50°C; Preferably, the reaction time in step (2) is 6-24 h; Preferably, the reaction in step (2) further comprises a post-treatment step; Preferably, the post-treatment comprises: acid washing the reaction system, extracting to obtain an organic phase, and then acid washing again, washing with a salt solution, drying and concentrating to obtain an intermediate 2; Preferably, the solvent used for the extraction includes any one of methyl tert-butyl ether, isopropyl ether, ethyl acetate, n-hexane or dichloromethane, or a combination of at least two thereof.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The alkaline reagent in step (3) includes any one of sodium hydroxide, lithium hydroxide, potassium carbonate, sodium methoxide or sodium tert-butoxide, or a combination of at least two thereof; Preferably, the molar ratio of the intermediate 2 to the alkaline reagent in step (3) is 1:(1-10); Preferably, the acidic reagent in step (3) comprises any one of hydrochloric acid, sulfuric acid or hydrobromic acid, or a combination of at least two thereof; Preferably, in step (3), the acidic reagent is added until the pH value of the system is 1-2; Preferably, the hydrolysis in step (3) is carried out in the presence of a solvent; Preferably, the solvent comprises water; Preferably, the temperature of the hydrolysis in step (3) under the action of the alkaline reagent and the acidic reagent in sequence is independently 25-100°C; Preferably, the time for the hydrolysis in step (3) under the action of an alkaline agent and an acidic agent is independently 10-20 h; Preferably, the reaction in step (3) further comprises a post-treatment step; Preferably, the post-treatment comprises: adding an organic solvent to the reaction system for extraction, separating the organic phase, and drying, concentrating and beating the organic phase to obtain the intermediate 3; Preferably, the organic solvent comprises any one of methyl tert-butyl ether, isopropyl ether, petroleum ether, tetrahydrofuran, ethyl acetate or dichloromethane, or a combination of at least two thereof, preferably a combination of methyl tert-butyl ether and tetrahydrofuran.

7. The preparation method according to any one of claims 1 to 6, characterized in that: In step (4), the molar ratio of the intermediate 3 to diphenylphosphoryl azide is 1:(1-3); Preferably, the reaction in step (4) is carried out in the presence of an organic base catalyst; Preferably, the organic base catalyst comprises any one or a combination of at least two of triethylamine, N,N-diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene; Preferably, the molar ratio of the intermediate 3 to the organic base catalyst is 1:(1-3); Preferably, the reaction in step (4) is carried out in the presence of a solvent; Preferably, the solvent comprises any one of toluene, 1,4-dioxane, N,N-dimethylformamide or dimethyl sulfoxide, or a combination of at least two thereof; Preferably, the material mixing method of the reaction in step (4) comprises: mixing the intermediate 3 and a solvent to obtain a mixed solution; adding a catalyst and diphenylphosphoryl azide to the mixed solution to obtain a reaction system; Preferably, the reaction temperature in step (4) is 90-100°C; Preferably, the reaction time in step (4) is 1-10 h.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The molar ratio of the intermediate 3 in step (4) to the tert-butanol in step (5) is 1:(1-10); Preferably, the reaction temperature in step (5) is 90-100°C; Preferably, the reaction time in step (5) is 4-24 h; Preferably, the material mixing method for the reaction in step (5) comprises: adding tert-butyl alcohol dropwise to the mixed solution after the reaction in step (4) is completed to obtain a reaction system; Preferably, the reaction in step (5) further comprises a post-treatment step; Preferably, the post-treatment comprises: washing the reaction system with alkali, extracting to obtain an organic phase, then washing with a salt solution, washing with water, drying, and concentrating to obtain a crude intermediate 5; then re-dissolving the crude product, filtering and eluting through a silica gel pad, and concentrating the filtrate to obtain an intermediate 5; Preferably, the solvent selected for the extraction includes any one of ethyl acetate, dichloromethane or methyl tert-butyl ether or a combination of at least two thereof; Preferably, the solvent selected for the re-dissolution includes any one of n-hexane, n-heptane, petroleum ether or methyl tert-butyl ether, or a combination of at least two thereof.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The hydrogenation reduction reaction in step (6) is carried out in the presence of a catalyst; Preferably, the catalyst comprises any one or a combination of at least two of palladium carbon, platinum carbon, ruthenium carbon or palladium hydroxide; Preferably, the mass ratio of the intermediate 5 to the catalyst is 1:(0.05-0.5); Preferably, the hydrogenation reduction reaction in step (6) is carried out in the presence of a solvent; Preferably, the solvent comprises any one of methanol, ethanol or isopropanol or a combination of at least two thereof; Preferably, the material mixing method for the hydrogenation reduction reaction in step (6) comprises: mixing the intermediate 5, the solvent and the catalyst to obtain a mixed liquid; replacing the mixed liquid with nitrogen and hydrogen in sequence to obtain a reaction system; Preferably, the temperature of the hydrogenation reduction reaction in step (6) is 20-80°C; Preferably, the pressure of the hydrogenation reduction reaction in step (6) is 2-10 MPa; Preferably, the hydrogenation reduction reaction time in step (6) is 4-48 h; Preferably, the hydrogenation reduction reaction in step (6) further comprises a post-treatment step; Preferably, the post-treatment comprises: filtering and washing the reaction system, and concentrating the filtrate to obtain a crude product of tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate; re-dissolving the crude product with an organic solvent, and then concentrating to obtain the tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate; Preferably, the solvent selected for the re-dissolution includes any one of tetrahydrofuran, acetonitrile or acetone, or a combination of at least two of them.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The preparation method comprises the following steps: (1) mixing 1-benzyl-3-pyrrolidone, methyl cyanoacetate, a catalyst and a solvent, reacting at 0-130° C. for 2-16 h to obtain an intermediate 1; the molar ratio of 1-benzyl-3-pyrrolidone, methyl cyanoacetate and the catalyst is 1:(1.0-1.5):(0.1-1.5); (2) mixing the intermediate 1 obtained in step (1), nitromethane, a basic catalyst and a solvent, and reacting at 0-50° C. for 6-24 hours to obtain an intermediate 2; the molar ratio of the intermediate 1, nitromethane and the basic catalyst is 1:(1-10):(1-2); (3) mixing the intermediate 2 obtained in step (2) with an aqueous solution of an alkaline reagent, reacting at 25-100° C. for 10-20 h, then adding an acidic reagent until the pH value of the system is 1-2, and reacting at 25-100° C. for 10-20 h to obtain an intermediate 3; the molar ratio of the intermediate 2 to the alkaline reagent is 1:(1-10); (4) mixing the intermediate 3 obtained in step (3), diphenyl phosphoryl azide, an organic base catalyst and a solvent, and reacting at 90-100° C. for 1-10 h to obtain an intermediate 4; the molar ratio of the intermediate 3, diphenyl phosphoryl azide and the organic base catalyst is 1:(1-3):(1-3); (5) adding tert-butanol dropwise to the mixed solution after the reaction in step (4), reacting at 90-100° C. for 4-24 hours to obtain intermediate 5; the molar ratio of the intermediate 3 in step (4) to the tert-butanol in step (5) is 1:(1-10); (6) The intermediate 5 obtained in step (5), a catalyst, a solvent and hydrogen are mixed, and a hydrogenation reduction reaction is carried out at 20-80° C. and 2-10 MPa for 4-48 h to obtain the tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate; the mass ratio of the intermediate 5 to the catalyst is 1:(0.05-0.5).

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