Preparation method for tert-butyl 5-azaspiro[2.4]heptan-1-ylcarbamate

Abstract

The present invention relates to a preparation method for tert-butyl 5-azaspiro[2.4]heptan-1-ylcarbamate. The preparation method comprises the following steps: reacting 1-benzyl-3-pyrrolidone with methyl cyanoacetate to obtain intermediate 1; reacting intermediate 1 with nitromethane to obtain intermediate 2; hydrolyzing intermediate 2 under the action of an alkaline reagent and an acidic reagent in sequence to obtain intermediate 3; reacting intermediate 3 with diphenylphosphoryl azide to obtain intermediate 4; reacting intermediate 4 with tert-butyl alcohol to obtain intermediate 5; and subjecting intermediate 5 to a hydrogenation reduction reaction to obtain tert-butyl 5-azaspiro[2.4]heptan-1-ylcarbamate. The preparation method provided by the present invention has the advantages of inexpensive and readily available raw materials, a simple process operation, safe and controllable production and a considerable yield, makes up for the shortages of available synthesis methods, avoids the risks associated with scaled-up production, and can meet the requirements of large-scale industrialization.

Description

A method for preparing tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate Technical Field

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

[0002] 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester, as a drug-active molecular fragment, can be used in the research and development of various target inhibitors, such as ketohexokinase inhibitors, DNA gyrase or topoisomerasr IV inhibitors, peptidylarginine deiminase-4 inhibitors, and other types of inhibitors.

[0003] Currently, research on the synthesis of tert-butyl 5-azaspiro[2,4]heptane-1-ylcarbamate is extremely scarce. The synthesis of the possible precursor, N-protected 5-azaspiro[2,4]heptane-1-carboxylic acid, is also very limited. The difficulty lies in the limited methods for constructing spirocyclic three-membered rings. Regarding the construction of three-membered rings, some literature utilizes ethyl diazonium acetate with copper or rhodium catalysts to form carbenes, which then undergo a [1+2] cyclization reaction with an alkene bond. However, ethyl diazonium acetate is highly toxic; the reagent decomposes and explodes under heating, releasing toxic substances, posing a significant danger to industrial production. Both patents EP0550025A1 and CN106938980A utilize trimethyl sulfoxide 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 result in a large amount of solid and liquid waste, and will also cause palladium poisoning during subsequent hydrogenation of benzyl or benzyloxycarbonyl groups, leading to incomplete reaction and difficulties in separation and purification.

[0004] To address the shortage of existing synthetic methods for 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester, and to avoid the risks of scale-up, a new method that is simple to operate and environmentally friendly has been developed to meet the needs of future large-scale industrialization. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a method for preparing tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate. The preparation method provided by this invention uses inexpensive and readily available raw materials, has a simple process, is safe and controllable in production, and yields considerable results. It compensates for the shortcomings of existing synthetic methods while avoiding the risks of scale-up, making it suitable for large-scale industrial applications.

[0006] To achieve this objective, the present invention adopts the following technical solution:

[0007] This 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 give intermediate 1, as shown in the following reaction formula: ;

[0009] (2) The intermediate 1 obtained in step (1) reacts with nitromethane to obtain intermediate 2, and the reaction formula is as follows: ;

[0010] (3) The intermediate 2 obtained in step (2) is hydrolyzed sequentially under the action of alkaline and acidic reagents to obtain intermediate 3, and the reaction formula is as follows: ;

[0011] (4) The intermediate 3 obtained in step (3) reacts with diphenyl azidophosphate to obtain intermediate 4, and the reaction formula is as follows: ;

[0012] (5) The intermediate 4 obtained in step (4) reacts with tert-butanol to obtain intermediate 5, and the reaction formula is as follows: ;

[0013] (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: .

[0014] In the aforementioned reaction formula, Me represents methyl and Boc represents tert-butyloxycarbonyl.

[0015] The preparation method provided by this invention starts with 1-benzyl-3-pyrrolidone, first reacting it with methyl cyanoacetate via a Knoevenage reaction to form an olefin intermediate 1; then, nitromethane is used to construct a spiro-three-membered ring intermediate 2. The construction of the three-membered ring avoids the use of ethyl diazonium acetate, a hazardous reagent, and also abandons the traditional method of constructing the ring using trimethyl sulfoxide. Instead, it utilizes nitromethane, a conventional reagent, under alkaline conditions, to perform an addition reaction with the olefin bond of intermediate 1, while the nitro group departs to form a three-membered ring. This overcomes the risks associated with scale-up when using ethyl diazonium acetate to construct the three-membered ring and the large amount of solid and liquid waste generated by using trimethyl sulfoxide. In addition, it avoids problems such as palladium poisoning during subsequent hydrogenation, incomplete reaction, and difficulty in separation and purification. Then, it is decarboxylated by alkaline hydrolysis to dicarboxylic acid and then decarboxylated by acidic hydrolysis to obtain monoacid intermediate 3. If decarboxylation is only performed by acidic hydrolysis, a rearrangement byproduct five-membered lactone will be generated. The generation of byproducts can be avoided by two-stage hydrolysis, and there is no need to process dicarboxylic acid afterward, which improves the reaction efficiency. Then, intermediate 4 is obtained by Curtius rearrangement of diphenyl azidophosphate (DPPA), and then nucleophilic attack by tert-butanol to obtain intermediate 5. Finally, hydrogenation reduction is used to obtain tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate.

[0016] The preparation method provided by this invention uses inexpensive and readily available raw materials, has a simple process operation, is safe and controllable in production, and has a considerable yield. It makes up for the shortcomings of existing synthesis methods, avoids the dangers of scale-up, and can be applied to the needs of large-scale industrialization.

[0017] 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.

[0018] Preferably, the reaction in step (1) is carried out in the presence of a catalyst.

[0019] 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 complex.

[0020] 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.

[0021] Preferably, the reaction in step (1) is carried out in the presence of a solvent.

[0022] Preferably, the solvent is an aprotic solvent.

[0023] Preferably, the aprotic solvent includes any one or a combination of at least two of benzene, toluene, or N,N-dimethylformamide.

[0024] Preferably, the material mixing method for the reaction in step (1) includes: mixing 1-benzyl-3-pyrrolidone, solvent and catalyst to obtain a mixture; adding methyl cyanoacetate dropwise to the mixture to obtain a reaction system.

[0025] Preferably, the temperature of the reaction in step (1) is 0-130℃, for example, it can be 0℃, 20℃, 50℃, 80℃, 110℃, 130℃, etc.

[0026] Preferably, the reaction time in step (1) is 2-16 h, for example, 2 h, 5 h, 10 h, 16 h, etc.

[0027] Preferably, the reaction in step (1) is followed by a post-processing step.

[0028] Preferably, the post-processing includes: adding water to the reaction system and stirring to separate the organic phase, washing with salt solution, washing with water, drying and concentrating to obtain intermediate 1.

[0029] Preferably, the molar ratio of intermediate 1 and 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.

[0030] Preferably, the reaction in step (2) is carried out in the presence of an alkaline catalyst.

[0031] Preferably, the alkaline catalyst comprises any one or a combination of at least two of 1,8-diazabicyclo[5.4.0]undec-7-ene, piperidine, or triethylamine.

[0032] Preferably, the molar ratio of intermediate 1 to 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.

[0033] Preferably, the reaction in step (2) is carried out in the presence of a solvent.

[0034] Preferably, the solvent includes any one or a combination of at least two of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran.

[0035] Preferably, the material mixing method for the reaction in step (2) includes: mixing intermediate 1 and solvent to obtain a mixture; adding nitromethane and catalyst dropwise to the mixture to obtain a reaction system.

[0036] Preferably, the temperature of the reaction in step (2) is 0-50℃, for example, it can be 0℃, 20℃, 30℃, 50℃, etc.

[0037] Preferably, the reaction time in step (2) is 6-24 h, for example, 6 h, 10 h, 16 h, 24 h, etc.

[0038] Preferably, the reaction in step (2) further includes a post-processing step.

[0039] Preferably, the post-processing includes: acid washing and extraction of the reaction system to obtain an organic phase, followed by acid washing, salt solution washing, drying and concentration to obtain intermediate 2.

[0040] Preferably, the solvent used for extraction includes any one or a combination of at least two of methyl tert-butyl ether, isopropyl ether, ethyl acetate, n-hexane, or dichloromethane.

[0041] Preferably, the alkaline reagent in step (3) includes any one or a combination of at least two of sodium hydroxide, lithium hydroxide, potassium carbonate, sodium methoxide or sodium tert-butoxide.

[0042] Preferably, the molar ratio of intermediate 2 and 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.

[0043] Preferably, the acidic reagent in step (3) includes any one or a combination of at least two of hydrochloric acid, sulfuric acid, or hydrobromic acid.

[0044] 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.

[0045] Preferably, the hydrolysis in step (3) is carried out in the presence of a solvent.

[0046] Preferably, the solvent includes water.

[0047] Preferably, the hydrolysis temperatures in step (3) under the action of alkaline and acidic reagents are each independently 25-100℃, for example, 25℃, 40℃, 60℃, 90℃, 100℃, etc.

[0048] Preferably, the hydrolysis time in step (3) under the action of alkaline and acidic reagents is 10-20 h each, for example, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, etc.

[0049] Preferably, the reaction in step (3) further includes a post-processing step.

[0050] Preferably, the post-processing includes: adding an organic solvent to the reaction system for extraction, separating the organic phase, and then drying, concentrating and pulping to obtain intermediate 3.

[0051] Preferably, the organic solvent includes any one or a combination of at least two of methyl tert-butyl ether, isopropyl ether, petroleum ether, tetrahydrofuran, ethyl acetate, or dichloromethane, and more preferably a combination of methyl tert-butyl ether and tetrahydrofuran.

[0052] Preferably, the molar ratio of intermediate 3 and diphenyl azidophosphate in step (4) is 1:(1-3), for example, it can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, etc.;

[0053] Preferably, the reaction in step (4) is carried out in the presence of an organic base catalyst.

[0054] Preferably, the organic base catalyst includes any one or a combination of at least two of triethylamine, N,N-diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0055] Preferably, the molar ratio of intermediate 3 to 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.

[0056] Preferably, the reaction in step (4) is carried out in the presence of a solvent.

[0057] Preferably, the solvent comprises any one or a combination of at least two of toluene, 1,4-dioxane, N,N-dimethylformamide, or dimethyl sulfoxide.

[0058] Preferably, the material mixing method for the reaction in step (4) includes: mixing intermediate 3 and solvent to obtain a mixture; adding catalyst and diphenyl azidophosphate dropwise to the mixture to obtain a reaction system.

[0059] Preferably, the reaction temperature in step (4) is 90-100℃, for example, it can be 90℃, 92℃, 94℃, 96℃, 98℃, 100℃, etc.

[0060] Preferably, the reaction time in step (4) is 1-10 h, for example, it can be 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, etc.

[0061] Preferably, the molar ratio of intermediate 3 in step (4) to 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.

[0062] Preferably, the reaction temperature in step (5) is 90-100℃, for example, it can be 90℃, 92℃, 94℃, 96℃, 98℃, 100℃, etc.

[0063] Preferably, the reaction time in step (5) is 4-24 h, for example, it can be 4 h, 8 h, 16 h, 24 h, etc.

[0064] Preferably, the material mixing method for the reaction in step (5) includes: adding tert-butanol dropwise to the mixture after the reaction in step (4) is completed to obtain the reaction system.

[0065] Preferably, the reaction in step (5) further includes a post-processing step.

[0066] Preferably, the post-processing includes: washing the reaction system with alkali and extracting to obtain an organic phase, then washing with salt solution, washing with water, drying, and concentrating to obtain crude intermediate 5; then re-dissolving the crude product, eluting by filtration through a silica gel pad, and concentrating the filtrate to obtain intermediate 5.

[0067] Preferably, the solvent used for extraction includes any one or a combination of at least two of ethyl acetate, dichloromethane, or methyl tert-butyl ether.

[0068] Preferably, the solvent used for the resolution includes any one or a combination of at least two of n-hexane, n-heptane, petroleum ether, or methyl tert-butyl ether.

[0069] Preferably, the hydrogenation reduction reaction in step (6) is carried out in the presence of a catalyst.

[0070] Preferably, the catalyst comprises any one or a combination of at least two of palladium on carbon, platinum on carbon, ruthenium on carbon, or palladium hydroxide.

[0071] 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.

[0072] Preferably, the hydrogenation reduction reaction in step (6) is carried out in the presence of a solvent.

[0073] Preferably, the solvent includes any one or a combination of at least two of methanol, ethanol, or isopropanol.

[0074] Preferably, the material mixing method for the hydrogenation reduction reaction in step (6) includes: mixing intermediate 5, solvent and catalyst to obtain a mixture; and replacing the mixture with nitrogen and hydrogen in sequence to obtain a reaction system.

[0075] Preferably, the temperature of the hydrogenation reduction reaction in step (6) is 20-80℃, for example, it can be 20℃, 40℃, 50℃, 60℃, 80℃, etc.

[0076] Preferably, the pressure of the hydrogenation reduction reaction in step (6) is 2-10 MPa, for example, it can be 2 MPa, 3 MPa, 5 MPa, 8 MPa, 10 MPa, etc.

[0077] Preferably, the hydrogenation reduction reaction in step (6) takes 4-48 hours, for example, 4 hours, 8 hours, 16 hours, 24 hours, 36 hours, 48 ​​hours, etc.

[0078] Preferably, the hydrogenation reduction reaction in step (6) further includes a post-processing step.

[0079] Preferably, the post-processing includes: filtering and washing the reaction system, concentrating the filtrate to obtain crude 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester; redissolving the crude product in an organic solvent, and then concentrating it to obtain the 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester.

[0080] Preferably, the solvent used for the resolution includes any one or a combination of at least two of tetrahydrofuran, acetonitrile, or acetone.

[0081] Preferably, the preparation method includes the following steps:

[0082] (1) Mix 1-benzyl-3-pyrrolidone, methyl cyanoacetate, catalyst and solvent, and react at 0-130℃ for 2-16 h to obtain intermediate 1; the molar ratio of 1-benzyl-3-pyrrolidone, methyl cyanoacetate and catalyst is 1:(1.0-1.5):(0.1-1.5).

[0083] (2) The intermediate 1 obtained in step (1), nitromethane, alkaline catalyst and solvent are mixed and reacted at 0-50℃ for 6-24 h to obtain intermediate 2; the molar ratio of intermediate 1, nitromethane and alkaline catalyst is 1:(1-10):(1-2).

[0084] (3) Mix the intermediate 2 obtained in step (2) with an aqueous solution of an alkaline reagent and react at 25-100℃ for 10-20 h. Then add an acidic reagent until the pH of the system is 1-2 and react at 25-100℃ for 10-20 h to obtain intermediate 3. The molar ratio of intermediate 2 to alkaline reagent is 1:(1-10).

[0085] (4) The intermediate 3 obtained in step (3), diphenyl azidophosphate, organic base catalyst and solvent are mixed and reacted at 90-100℃ for 1-10 h to obtain intermediate 4; the molar ratio of intermediate 3, diphenyl azidophosphate and organic base catalyst is 1:(1-3):(1-3).

[0086] (5) Add tert-butanol dropwise to the mixture after the reaction in step (4) and react at 90-100℃ for 4-24 h to obtain intermediate 5; the molar ratio of intermediate 3 in step (4) and tert-butanol in step (5) is 1:(1-10).

[0087] (6) The intermediate 5 obtained in step (5), the catalyst, the solvent and hydrogen are mixed and subjected to hydrogenation reduction reaction at 20-80℃ and 2-10 MPa for 4-48 h to obtain the 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester; the mass ratio of the intermediate 5 to the catalyst is 1:(0.05-0.5).

[0088] Compared with the prior art, the present invention has at least the following beneficial effects:

[0089] The preparation method provided by this invention starts from 1-benzyl-3-pyrrolidone, first forming an olefin intermediate 1 with methyl cyanoacetate, then constructing a spirotri-ring intermediate 2 with nitromethane, and subsequently obtaining an acid intermediate 3 through alkaline hydrolysis and acidic hydrolysis decarboxylation. Next, intermediate 4 is obtained by Curtius rearrangement of diphenyl azide phosphate (DPPA), and then nucleophilic attack by tert-butanol to obtain intermediate 5. Finally, hydrogenation reduction yields 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester. This preparation method uses inexpensive and readily available raw materials, has a simple process operation, is safe and controllable in production, and has a considerable yield. It makes up for the shortcomings of existing synthesis methods, avoids the danger of scale-up, and can be applied to the needs of large-scale industrialization. Detailed Implementation

[0090] To facilitate understanding of the present invention, the following embodiments are provided. Those skilled in the art should understand that these embodiments are merely illustrative and should not be construed as limiting the scope of the invention.

[0091] Example 1

[0092] A method for preparing tert-butyl 5-azaspiro[2.4]heptane-1-ylcarbamate includes the following steps:

[0093] (1) Toluene (10 L, 5V) was pumped into a reactor equipped with a mechanical stirrer, heating device and water separator. Then 1-benzyl-3-pyrrolidone (2000 g, 11.4 mol, 1.0 eq) was added. After stirring until dissolved, 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. Then methyl cyanoacetate (1108 mL, 12.6 mol, 1.1 eq) was added dropwise. The entire reaction system was then heated and stirred under reflux for 12 h. The water generated during the reaction was separated by the water separator. The reaction was monitored to ensure that the raw materials had reacted completely. The reaction system was cooled to 25°C. 10 L of water was pumped into the reactor and stirred. The organic phase was then separated. The aqueous phase was extracted twice with ethyl acetate, each time using 5g of ethyl acetate. L, combined with organic phases, washed successively with saturated brine and water, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 55°C until no droplets remained, yielding 2760 g of the oily target intermediate 1 product, with a yield of 94.4%.

[0094] (2) An acetonitrile (30 L, 15V) solution containing intermediate 1 (2000 g, 7.8 mol, 1.0 eq) was added to a reaction vessel equipped with a mechanical stirrer. 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 while stirring. During the addition of DBU, the reaction solution gradually turned orange-yellow. After the addition was complete, the entire reaction system was stirred at 25°C for 16 h. Thin-layer chromatography (TLC) showed that a small amount of raw material remained. Then, 100 mL of DBU was added, and the reaction was stirred for another 2 h. The raw material was almost completely eliminated by the control panel. 20 L of methyl tert-butyl ether and 30 L of hydrochloric acid (10 wt%) were added to the reaction system and stirred for 0.5 hours. h was then allowed to stand to separate the organic phase. The separated organic phase was washed twice with 10wt% hydrochloric acid, followed by washing with brine, and then dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50°C until no droplets remained, yielding 1545 g of the target intermediate 2 product, with a yield of 73.2%.

[0095] (3) Add the above intermediate 2 (1500 g, 5.5 mol, 1.0 eq) and 2 M sodium hydroxide aqueous solution (13.9 L, 27.7 mol, 5.0 eq) to a reaction vessel equipped with mechanical stirring and heating device. Heat the entire reaction system under reflux for 16 h, then cool it down to 25 °C. Add 10 L of dichloromethane to the reaction vessel, stir and let it stand, then separate the dichloromethane. Adjust the pH of the aqueous phase to 1.5 with 50 wt% hydrochloric acid. Then turn on the heating and reflux and stir again for 12 h. The raw materials are almost completely reacted according to the control. Cool the reaction system down to 25 °C, add a mixed solvent of methyl tert-butyl ether and tetrahydrofuran (v / v, 1 / 1) to the reaction vessel for extraction twice, each time using 10 L. The combined organic phase is dried with anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure at 50 °C. The residue is purified by slurrying with methyl tert-butyl ether to obtain 1086 g of the off-white solid target intermediate 3 product, with a yield of 84.6%.

[0096] Intermediate 3 structural characterization data:

[0097] 1 HNMR (400MHz, CDCl3) ppm δ: 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).

[0098] (4) Dissolve the above intermediate 3 (1000 g, 4.3 mol, 1.0 eq) in toluene (10 L, 10 V), and then add triethylamine (900 mL, 6.5 mol, 1.5 eq) and diphenyl azidophosphate (DPPA, 14278 g, 5.2 mol, 1.2 eq) dropwise to the reaction system. After the addition is complete, heat the reaction system to 100 °C and react for 2 h. This process is exothermic and gas-releasing, and intermediate 4 is obtained. No further treatment is required to proceed to the next step.

[0099] (5) Cool the reaction system of step (4) to 80°C, and then slowly add tert-butanol (620 mL, 6.5 mol, 1.5 eq, based on intermediate 3). After the addition is complete, continue to react at 100°C for 12 h. The raw materials are almost completely reacted as detected by the central control. Cool the reaction system to 25°C, and then add 10% sodium bicarbonate solution (10 L) and ethyl acetate (5 L). After stirring and standing, separate the organic phase. Wash the separated organic phase with saturated brine and water, dry it with anhydrous sodium sulfate, and filter it. Concentrate the filtrate under reduced pressure at 55°C. Dissolve the residue in hexane and filter it through a silica gel pad. Use a hexane / ethyl acetate mixed solvent (v / v, 30 / 1) as the eluent. Concentrate the collected filtrate under reduced pressure at 45°C to obtain 960 g of intermediate 5 product, with a yield of 73.4%.

[0100] (6) Add the above intermediate 5 (360g, 1.2mol, 1.0eq) and methanol (2700mL, 7.5V) to a 5L hydrogenation reactor, then add 10% palladium on carbon (54g, 15 wt%), purge with nitrogen 3 times, purge with hydrogen 2 times, pressure 3 MPa, start heating to 50℃, stir for 18 h, and monitor the reaction of raw materials until the reaction is complete; cool the reaction system to 25℃, filter the reaction liquid twice with diatomaceous earth, wash the filter cake with methanol until there is no product residue, concentrate the collected filtrate under reduced pressure at 50℃, and evaporate the residue once with tetrahydrofuran to obtain 200g of 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester, yield 79.2%;

[0101] Structural characterization data of 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester:

[0102] 1 HNMR (400MHz, CDCl3) ppm δ: 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).

[0103] Example 2

[0104] (1) Toluene (10 L, 5V) was pumped into a reactor equipped with a mechanical stirrer, heating device and water separator. Then 1-benzyl-3-pyrrolidone (2000 g, 11.4 mol, 1.0 eq) was added. After stirring until dissolved, piperidine (194 g, 2.3 mol, 0.2 eq) and acetic acid (131 mL, 2.3 mol, 0.2 eq) were added to the reactor at 25°C. Then methyl cyanoacetate (1007 mL, 11.4 mol, 1.0 eq) was added dropwise. The entire reaction system was then heated and stirred under reflux for 16 h. The water generated during the reaction was separated by the water separator. The reaction was monitored to ensure that the raw materials had reacted completely. The reaction system was cooled to 25°C. 10 L of water was pumped into the reactor and stirred. The organic phase was then separated. The aqueous phase was extracted twice with ethyl acetate, each time using 5g of ethyl acetate. L, combined organic phases, washed successively with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure at 55°C until no droplets remained, yielding 2650 g of oily target intermediate 1 product, with a yield of 89.6%;

[0105] (2) An acetonitrile (30 L, 15V) solution containing intermediate 1 (2000 g, 7.8 mol, 1.0 eq) was added to a reaction vessel equipped with a mechanical stirrer. 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 while stirring. During the addition of DBU, the reaction solution gradually turned orange-yellow. After the addition was complete, the entire reaction system was stirred at 35°C for 24 h, and the raw materials were almost completely eliminated as detected by the central control. 20 L of methyl tert-butyl ether and 30 L of hydrochloric acid (10 wt%) were added to the reaction system and stirred for 0.5 hours. h was then allowed to stand to separate the organic phase. The separated organic phase was washed twice with 10wt% hydrochloric acid, followed by washing with brine, and then dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50°C until no droplets remained, yielding 1620 g of the target intermediate 2 product, with a yield of 76.8%.

[0106] (3) Add the above intermediate 2 (1500g, 5.5mol, 1.0eq) and 2M sodium hydroxide aqueous solution (22.2 L, 44.4mol, 8.0eq) to a reaction vessel equipped with mechanical stirring and heating device. Heat the entire reaction system under reflux for 12h, then cool it down to 25℃. Add 10 L of dichloromethane to the reaction vessel, stir and let it stand, then separate the dichloromethane. Adjust the pH of the aqueous phase to 1.5 with 25wt% sulfuric acid. Then turn on the heating and reflux and stir again for 12h. The central control detection showed that the raw materials were almost completely reacted. Cool the reaction system down to 25℃, add a mixed solvent of methyl tert-butyl ether and tetrahydrofuran (v / v, 1 / 1) to the reaction vessel for extraction twice, each time using 10 L. The combined organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50℃. The residue was purified by slurrying with methyl tert-butyl ether to obtain 1065 g of the off-white solid target intermediate 3 product, with a yield of 83.0%.

[0107] (4) Dissolve the above intermediate 3 (1000 g, 4.3 mol, 1.0 eq) in toluene (10 L, 10 V), and then add N,N-diisopropylethylamine (1130 mL, 6.5 mol, 1.5 eq) and diphenyl azidophosphate (DPPA, 14278 g, 5.2 mol, 1.2 eq) dropwise to the reaction system. After the addition is complete, heat the reaction system to 100 °C and react for 2 h. This process is exothermic and gas-releasing, and intermediate 4 is obtained. No further treatment is required to proceed to the next step.

[0108] (5) Cool the reaction system of step (4) to 80°C, and then slowly add tert-butanol (827 mL, 8.6 mol, 2.0 eq, based on intermediate 3). After the addition is complete, continue to react at 100°C for 12 h. The reaction of the raw materials is almost complete. Cool the reaction system to 25°C, and then add 10% sodium bicarbonate solution (10 L) and ethyl acetate (5 L). After stirring and standing, separate the organic phase. Wash the separated organic phase with saturated brine and water, dry it with anhydrous sodium sulfate, and filter it. Concentrate the filtrate under reduced pressure at 55°C. Dissolve the residue in hexane and filter it through a silica gel pad. Use a hexane / ethyl acetate mixed solvent (v / v, 30 / 1) as the eluent. Concentrate the collected filtrate under reduced pressure at 45°C to obtain 950 g of intermediate 5 product, with a yield of 72.7%.

[0109] (6) Add the above intermediate 5 (423g, 1.4mol, 1.0eq) and methanol (3384mL, 8.0V) to a 5 L hydrogenation reactor, then add 10% palladium on carbon (85g, 20wt%), purge with nitrogen 3 times, purge with hydrogen 2 times, pressure 3MPa, start heating to 50℃, stir for 18h, and monitor the reaction of raw materials until the reaction is complete; cool the reaction system to 25℃, filter the reaction liquid twice with diatomaceous earth, wash the filter cake with methanol until there is no product residue, concentrate the collected filtrate under reduced pressure at 50℃, and evaporate the residue once with acetone to obtain 240g of 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester, yield 80.8%.

[0110] Example 3

[0111] (1) N,N-dimethylformamide (10 L, 5V) was pumped into a reactor equipped with a mechanical stirrer, heating device and water separator. Then 1-benzyl-3-pyrrolidone (2000 g, 11.4 mol, 1.0 eq) was added. After stirring until dissolved, sodium hydroxide (685 g, 17.1 mol, 1.5 eq) was added to the reactor at 25°C. Then methyl cyanoacetate (1511 mL, 17.1 mol, 1.5 eq) was added dropwise. After the addition was complete, the entire reaction system was heated to 90°C and stirred for 16 h. The reaction was monitored by the central control and the raw materials were almost completely reacted. The reaction system was cooled to 25°C and 10 L of N,N-dimethylformamide (10 L, 5V) was pumped into the reactor. After adding L of water and 10 L of ethyl acetate, the mixture was stirred, and then the organic phase was separated. The aqueous phase was extracted once more with 5 L of ethyl acetate. The organic phases were combined, washed successively with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 55 °C until no droplets remained, yielding 2700 g of the oily target intermediate 1 product, with a yield of 91.2%.

[0112] (2) Add a solution of tetrahydrofuran (30 L, 15 V) containing intermediate 1 (2000 g, 7.8 mol, 1.0 eq) to a reaction vessel equipped with a mechanical stirrer. Then, while stirring, add 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) dropwise. After the addition is complete, stir the entire reaction system at 25 °C for 8 h. Thin-layer chromatography (TLC) shows that the reactants have not reacted completely. Continue stirring for another 16 h, and the reactants are almost completely eliminated. Add 20 L of methyl tert-butyl ether and 30 L of hydrochloric acid (10 wt%) to the reaction system and stir for 0.5 hours. The organic phase was then separated by static filtration. The separated organic phase was washed twice with 10wt% hydrochloric acid, followed by washing with brine, and then dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 50°C until no droplets remained, yielding 1353g of the target intermediate 2 product, with a yield of 64.1%.

[0113] (3) Add the above intermediate 2 (1500 g, 5.5 mol, 1.0 eq) and 4 M lithium hydroxide aqueous solution (13.9 L, 55.5 mol, 10.0 eq) to a reactor equipped with a mechanical stirrer and heating device. Heat the entire reaction system under reflux for 16 h, then cool it down to 25 °C. Add 10 L of dichloromethane to the reactor, stir and let it stand, then separate the dichloromethane. Adjust the pH of the aqueous phase to 1.5 with 50 wt% hydrochloric acid. Then turn on the heating and reflux and stir again for 12 h. The raw materials are almost completely reacted according to the control. Cool the reaction system down to 25 °C, add a mixed solvent of methyl tert-butyl ether and tetrahydrofuran (v / v, 1 / 1) to the reactor and extract twice, each time using 10 L. The combined organic phase is dried with anhydrous sodium sulfate and filtered. The filtrate is concentrated under reduced pressure at 50 °C. The residue is purified by slurrying with methyl tert-butyl ether to obtain 1125 g of the off-white solid target intermediate 3 product, with a yield of 87.7%.

[0114] (4) Dissolve the above intermediate 3 (1000 g, 4.3 mol, 1.0 eq) in 1,4-dioxane (10 L, 10 V), and then add triethylamine (900 mL, 6.5 mol, 1.5 eq) and diphenyl azidophosphate (DPPA, 14278 g, 5.2 mol, 1.2 eq) dropwise to the reaction system. After the addition is complete, heat the reaction system to 100 °C and react for 2 h. This process is exothermic and gas-releasing, and intermediate 4 is obtained. No further treatment is required to proceed to the next step.

[0115] (5) Cool the reaction system of step (4) to 80°C, and then slowly add tert-butanol (2068 mL, 21.6 mol, 5.0 eq, based on intermediate 3). After the addition is complete, continue to react at 100°C for 12 h. The raw materials are almost completely reacted as detected by the central control. Cool the reaction system to 25°C, and then add 10% sodium bicarbonate solution (10 L) and ethyl acetate (5 L). After stirring and standing, separate the organic phase. Wash the separated organic phase with saturated brine and water, dry it with anhydrous sodium sulfate, and filter it. Concentrate the filtrate under reduced pressure at 55°C. Dissolve the residue in hexane and filter it through a silica gel pad. Use a hexane / ethyl acetate mixed solvent (v / v, 30 / 1) as the eluent. Concentrate the collected filtrate under reduced pressure at 45°C to obtain 965 g of intermediate 5 product, with a yield of 73.8%.

[0116] (6) Add the above intermediate 5 (360 g, 1.2 mol, 1.0 eq) and ethanol (2700 mL, 7.5 V) to a 5 L hydrogenation reactor, then add 20% palladium hydroxide (36 g, 10 wt%), purge with nitrogen 3 times, purge with hydrogen 2 times, pressure 5 MPa, start heating to 70 °C, stir for 12 h, and monitor the reaction of raw materials until the reaction is complete; cool the reaction system to 25 °C, filter the reaction liquid twice with diatomaceous earth, wash the filter cake with methanol until there is no product residue, concentrate the collected filtrate under reduced pressure at 55 °C, and evaporate the residue once with tetrahydrofuran to obtain 190 g of 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester, yield 75.2%.

[0117] The applicant declares that the above description is only a specific embodiment 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 conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. A process for the preparation of tert-butyl 5-azaspiro[2.4]heptan-1-ylcarbamate, characterized in that, The preparation method includes the following steps: (1) 1-benzyl-3-pyrrolidinone reacts with methyl cyanoacetate to obtain intermediate 1, and the reaction formula is as follows: ; (2) reacting the intermediate 1 obtained in step (1) with nitromethane to obtain an intermediate 2, as shown in the following reaction formula: ; (3) The intermediate 2 obtained in step (2) is hydrolyzed successively with a basic reagent and an acidic reagent to obtain the intermediate 3, and the reaction formula is as follows: ; (4) The intermediate 3 obtained in step (3) is reacted with diphenyl phosphorazide to obtain the intermediate 4, and the reaction formula is as follows: ; (5) The intermediate 4 obtained in step (4) is reacted with tert-butanol to obtain the intermediate 5, as shown in the following reaction formula: ; (6) The 5-azaspiro[2.4]heptan-1-yl carbamic acid tert-butyl ester is obtained by hydrogenation reduction reaction of the intermediate 5 obtained in step (5), and the reaction formula is as follows: 。 2. The production method according to claim 1, characterized by, In step (1), the molar ratio of 1-benzyl-3-pyrrolidone to methyl cyanoacetate 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 conjugate; 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 or a combination of at least two of benzene, toluene, or N,N-dimethylformamide.

3. The production method according to claim 1 or 2, characterized by, The material mixing method for the reaction in step (1) includes: mixing 1-benzyl-3-pyrrolidone, solvent and catalyst to obtain a mixture; adding methyl cyanoacetate dropwise to the mixture to obtain a reaction system; Preferably, the temperature of the reaction in step (1) is 0-130℃; Preferably, the reaction time in step (1) is 2-16 h; Preferably, the reaction in step (1) further includes a post-processing step; Preferably, the post-processing includes: adding water to the reaction system and stirring to separate the organic phase, washing with salt solution, washing with water, drying and concentrating to obtain intermediate 1.

4. The production process according to any one of claims 1 to 3, characterized in that, In step (2), the molar ratio of intermediate 1 to nitromethane is 1:(1-10). Preferably, the reaction in step (2) is carried out in the presence of an alkaline catalyst; Preferably, the alkaline 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 intermediate 1 to alkaline catalyst is 1:(1-2). Preferably, the reaction in step (2) is carried out in the presence of a solvent; Preferably, the solvent includes any one or a combination of at least two of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran.

5. The production process according to any one of claims 1 to 4, characterized in that, The material mixing method for the reaction in step (2) includes: mixing intermediate 1 and solvent to obtain a mixture; adding nitromethane and catalyst dropwise to the mixture to obtain a reaction system; Preferably, the temperature of the reaction in step (2) is 0-50℃; Preferably, the reaction time in step (2) is 6-24 h; Preferably, the reaction in step (2) further includes a post-processing step; Preferably, the post-processing includes: acid washing and extraction of the reaction system to obtain an organic phase, followed by acid washing, salt solution washing, drying and concentration to obtain intermediate 2; Preferably, the solvent used for extraction includes any one or a combination of at least two of methyl tert-butyl ether, isopropyl ether, ethyl acetate, n-hexane, or dichloromethane.

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

7. The production process according to any one of claims 1 to 6, characterized in that, In step (4), the molar ratio of intermediate 3 and diphenyl azidophosphate 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 intermediate 3 to 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 or a combination of at least two of toluene, 1,4-dioxane, N,N-dimethylformamide, or dimethyl sulfoxide; Preferably, the material mixing method for the reaction in step (4) includes: mixing intermediate 3 and solvent to obtain a mixture; adding catalyst and diphenyl azidophosphate dropwise to the mixture to obtain a reaction system; Preferably, the reaction temperature in step (4) is 90-100℃; Preferably, the reaction time in step (4) is 1-10 h.

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

9. The production process 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 on carbon, platinum on carbon, ruthenium on carbon, or palladium hydroxide; Preferably, the mass ratio of intermediate 5 to 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 includes any one or a combination of at least two of methanol, ethanol, or isopropanol; Preferably, the material mixing method for the hydrogenation reduction reaction in step (6) includes: mixing intermediate 5, solvent and catalyst to obtain a mixture; and replacing the mixture 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℃; Preferably, the pressure of the hydrogenation reduction reaction in step (6) is 2-10 MPa; Preferably, the hydrogenation reduction reaction in step (6) takes 4-48 hours; Preferably, the hydrogenation reduction reaction in step (6) further includes a post-processing step; Preferably, the post-processing includes: filtering and washing the reaction system, concentrating the filtrate to obtain crude 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester; redissolving the crude product in an organic solvent, and then concentrating it to obtain the 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester. Preferably, the solvent used for the resolution includes any one or a combination of at least two of tetrahydrofuran, acetonitrile, or acetone.

10. The production process according to any one of claims 1 to 9, characterized in that, The preparation method includes the following steps: (1) Mix 1-benzyl-3-pyrrolidone, methyl cyanoacetate, catalyst and solvent, and react at 0-130℃ for 2-16 h to obtain intermediate 1; the molar ratio of 1-benzyl-3-pyrrolidone, methyl cyanoacetate and catalyst is 1:(1.0-1.5):(0.1-1.5). (2) The intermediate 1 obtained in step (1), nitromethane, alkaline catalyst and solvent are mixed and reacted at 0-50℃ for 6-24 h to obtain intermediate 2; the molar ratio of intermediate 1, nitromethane and alkaline catalyst is 1:(1-10):(1-2). (3) Mix the intermediate 2 obtained in step (2) with an aqueous solution of an alkaline reagent and react at 25-100℃ for 10-20 h. Then add an acidic reagent until the pH of the system is 1-2 and react at 25-100℃ for 10-20 h to obtain intermediate 3. The molar ratio of intermediate 2 to alkaline reagent is 1:(1-10). (4) The intermediate 3 obtained in step (3), diphenyl azidophosphate, organic base catalyst and solvent are mixed and reacted at 90-100℃ for 1-10 h to obtain intermediate 4; the molar ratio of intermediate 3, diphenyl azidophosphate and organic base catalyst is 1:(1-3):(1-3). (5) Add tert-butanol dropwise to the mixture after the reaction in step (4) and react at 90-100℃ for 4-24 h to obtain intermediate 5; the molar ratio of intermediate 3 in step (4) and tert-butanol in step (5) is 1:(1-10). (6) The intermediate 5 obtained in step (5), the catalyst, the solvent and hydrogen are mixed and subjected to hydrogenation reduction reaction at 20-80℃ and 2-10 MPa for 4-48 h to obtain the 5-azaspiro[2.4]heptane-1-ylcarbamate tert-butyl ester; the mass ratio of the intermediate 5 to the catalyst is 1:(0.05-0.5).

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