Preparation method for tert-butyl (r)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate

Abstract

The present invention relates to a preparation method for tert-butyl (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, comprising the following steps: enabling N-BOC-4-piperidone to undergo a Grignard reaction with allylmagnesium halide to obtain intermediate 1; enabling the intermediate 1 to undergo a substitution reaction with 3-halopropene to obtain intermediate 2; enabling the intermediate 2 to undergo an olefin metathesis reaction under the action of a Grubbs catalyst to obtain intermediate 3; enabling the intermediate 3 to undergo a nitration reaction with nitric acid to obtain intermediate 4; enabling the intermediate 4 to undergo a hydrogenation reduction reaction to obtain racemic intermediate 5; and enabling the intermediate 5 to undergo chiral resolution by means of a resolving agent to obtain a target product. The preparation method provided by the present invention has a short process route, simple operation, and no substantial waste water and waste gas generated, and can achieve relatively high total product yield and chemical and chiral purities.

Description

A method for preparing (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester. Background Technology

[0002] (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester has been shown to be a key fragment in some bioactive drugs, and drugs containing this fragment can be used to treat many diseases, such as MAGL-mediated diseases.

[0003] Pfizer's patent WO2018134695A1 and C4-Therapeutics' patent WO2024119111A2 utilize the raw material tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (Cas 954236-44-3) to further synthesize the target product. The synthesis method of this raw material is reported in patent WO2018026371A1. Pfizer synthesizes the target product by reacting tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate with isopropylamine hydrochloride and pyridoxal 5'-phosphate monohydrate in a buffer solution via Codex-ATA-200 aminotransferase, and further refines it with D-pyroglutamic acid to obtain a target product with high chiral purity. While this method utilizes enzyme technology and achieves high yields, the enzymes used are expensive, and the operation is complex and requires stringent reaction conditions, making it unsuitable for large-scale production. C4-Therapeutics utilizes tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate to form an oxime with hydroxylamine hydrochloride, followed by reduction with Raney nickel to obtain a racemic amine, which is then chemically resolved using D-mandelic acid, finally yielding the target product. Verification of this method revealed that Raney nickel reduction is accompanied by impurities that are difficult to remove, and Raney nickel filtration is also cumbersome.

[0004] Therefore, providing a method for preparing (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester with short synthesis steps, simple operation, low waste, and high overall yield, chemical purity, and chiral purity is an urgent technical problem to be solved in this field. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a method for preparing (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester. The preparation method provided by this invention comprises six process steps: Grignard reaction, substitution reaction, olefin metathesis reaction, nitration reaction, hydrogenation reduction reaction, and chiral resolution. This preparation method features a short process route, simple operation, no large amounts of wastewater or waste gas generated, and can achieve high overall product yield, chemical and chiral purity.

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

[0007] This invention provides a method for preparing (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, the preparation method comprising the following steps:

[0008] (1) N-BOC-4-piperidinone reacts with allyl magnesium halide in a Grignard reaction to give intermediate 1, as shown in the following reaction formula: ;

[0009] X1 is selected from chlorine, bromine, or iodine;

[0010] (2) The intermediate 1 obtained in step (1) undergoes a substitution reaction with 3-halopropene to obtain intermediate 2, and the reaction formula is as follows: ;

[0011] X2 is selected from chlorine, bromine, or iodine;

[0012] (3) The intermediate 2 obtained in step (2) undergoes an olefin metathesis reaction under the action of a Grubb catalyst to obtain intermediate 3, and the reaction formula is as follows: ;

[0013] (4) The intermediate 3 obtained in step (3) undergoes a nitration reaction with nitric acid to obtain intermediate 4, and the reaction formula is as follows: ;

[0014] (5) After the intermediate 4 obtained in step (4) undergoes a hydrogenation reduction reaction, racemic intermediate 5 is obtained, and the reaction formula is as follows: ;

[0015] (6) The intermediate 5 obtained in step (5) was chirally resolved by a resolving agent to obtain the (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, as shown in the following reaction formula: ;

[0016] In the aforementioned reaction formula, Boc represents tert-butyloxycarbonyl.

[0017] The preparation method provided by this invention includes six process steps: Grignard reaction, substitution reaction, olefin metathesis reaction, nitration reaction, hydrogenation reduction reaction, and chiral resolution. This route uses N-BOC-4-piperidinone as the starting material. First, it reacts with allyl magnesium halide through a Grignard reaction to form intermediate 1. Then, it reacts with 3-halopropene through a substitution reaction to obtain intermediate 2. Next, it uses Grubbs catalyst to obtain intermediate 3 through an olefin metathesis reaction. Then, it uses a nitric acid system to carry out a nitration reaction to obtain intermediate 4. Finally, it obtains racemic amine through hydrogenation reduction and obtains the target product through chiral resolution by a resolving agent.

[0018] The preparation method provided by this invention has a short process route, simple operation, no large amount of wastewater and waste gas generated, and can achieve a high total product yield, chemical and chiral purity.

[0019] Preferably, the molar ratio of N-BOC-4-piperidinone to allyl magnesium halide in step (1) is 1:(1~1.5), for example, it can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.5, etc.

[0020] Preferably, the reaction described in step (1) is carried out in the presence of a solvent.

[0021] Preferably, the solvent includes any one or a combination of at least two of tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, or isopropyl ether.

[0022] Preferably, the reaction in step (1) is carried out under nitrogen protection.

[0023] Preferably, after the reaction in step (1) is completed, a quenching agent is added for quenching.

[0024] Preferably, the quenching agent includes any one or a combination of at least two of ammonium chloride, dilute hydrochloric acid, glacial acetic acid, or water.

[0025] Preferably, the material mixing method for the Grignard reaction in step (1) includes: mixing N-BOC-4-piperidinone and a solvent to obtain a mixture; adding a solution of allyl magnesium halide to the mixture to obtain a reaction system, and then carrying out the Grignard reaction.

[0026] Preferably, the temperature at which the drop is added is -5 to 5°C, for example, -5°C, -3°C, 0°C, 3°C, 5°C, etc.

[0027] Preferably, the temperature of the reaction in step (1) is -5~30℃, for example, it can be -5℃, 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, etc.

[0028] Preferably, the reaction time of the format described in step (1) is 4 to 16 hours, for example, it can be 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, etc.

[0029] Preferably, the format reaction in step (1) further includes a post-processing step.

[0030] Preferably, the post-processing includes: separating the reaction system to obtain an organic phase; washing the organic phase with a salt solution, washing with water, drying and concentrating it to obtain a crude product; and distilling the crude product to obtain intermediate 1.

[0031] Preferably, the molar ratio of intermediate 1 and 3-halopropylene in step (2) is 1:(1~2), for example, it can be 1:1, 1:1.1, 1:1.3, 1:1.5, 1:2, etc.

[0032] Preferably, the substitution reaction in step (2) is carried out in the presence of a basic reagent.

[0033] Preferably, the alkaline reagent includes any one or a combination of at least two of sodium tert-butoxide, potassium tert-butoxide, sodium hydride, or sodium bis(trimethylsilyl)amino.

[0034] Preferably, the molar ratio of intermediate 1 to alkaline reagent is 1:(1~2.5), for example, it can be 1:1.2, 1:1.5, 1:1.8, 1:2.0, 1:2.5, etc.

[0035] Preferably, the substitution reaction in step (2) is carried out in the presence of a solvent.

[0036] Preferably, the solvent includes any one or a combination of at least two of tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, or toluene.

[0037] Preferably, the material mixing method for the substitution reaction in step (2) includes: mixing a solvent and an alkaline reagent to obtain a mixture; adding a solution of intermediate 1 and 3-halopropene to the mixture to obtain a reaction system, and then carrying out the substitution reaction.

[0038] Preferably, the temperature at which intermediate 1 and 3-halopropylene are added is independently 10~20℃, for example, 10℃, 12℃, 14℃, 16℃, 18℃, 20℃, etc.

[0039] Preferably, the temperature of the substitution reaction in step (2) is 45~55℃, for example, it can be 45℃, 46℃, 48℃, 50℃, 52℃, 54℃, 55℃, etc.

[0040] Preferably, the substitution reaction in step (2) takes 8 to 24 hours, for example, 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, etc.

[0041] Preferably, the substitution reaction in step (2) further includes a post-processing step.

[0042] Preferably, the post-processing includes: adding water to the reaction system and stirring to separate the organic phase; washing the organic phase with salt solution, washing with water, drying and concentrating to obtain intermediate 2.

[0043] Preferably, the mass ratio of intermediate 2 and Grubb catalyst in step (3) is 1:(0.001~0.05), for example, it can be 1:0.001, 1:0.005, 1:0.01, 1:0.02, 1:0.04, 1:0.05, etc.

[0044] Preferably, the Grubb catalyst comprises any one or a combination of at least two of the first-generation Grubb catalyst, the second-generation Grubb catalyst, or the third-generation Grubb catalyst.

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

[0046] Preferably, the solvent includes any one or a combination of at least two of dichloromethane, ethyl acetate, toluene, or n-heptane.

[0047] Preferably, the temperature of the olefin metathesis reaction in step (3) is 25~100℃, for example, it can be 25℃, 30℃, 40℃, 50℃, 80℃, 100℃, etc.

[0048] Preferably, the time for the olefin metathesis reaction in step (3) is 6 to 24 hours, for example, 6 hours, 8 hours, 12 hours, 16 hours, 24 hours, etc.

[0049] Preferably, the olefin metathesis reaction in step (3) is carried out under nitrogen protection.

[0050] Preferably, the olefin metathesis reaction in step (3) further includes a post-processing step.

[0051] Preferably, the post-processing includes: filtering the reaction system with diatomaceous earth, washing the filter cake, concentrating the filtrate to obtain a crude product; and pulping the crude product to obtain intermediate 3.

[0052] Preferably, the solvent used for washing the filter cake includes any one or a combination of at least two of dichloromethane, ethyl acetate, toluene, or n-heptane.

[0053] Preferably, the solvent used for pulping includes any one or a combination of at least two of methyl tert-butyl ether, petroleum ether, isopropyl ether, n-hexane, or ethyl acetate.

[0054] Preferably, the molar ratio of intermediate 3 and nitric acid in step (4) is 1:(1.5~3.5), for example, it can be 1:1.5, 1:2.0, 1:2.5, 1:3.0, 1:3.5, etc.

[0055] Preferably, the nitration reaction in step (4) is carried out in the presence of a solvent.

[0056] Preferably, the solvent includes any one or a combination of at least two of acetic anhydride, acetic acid, or dichloroethane.

[0057] Preferably, the nitration reaction in step (4) is carried out under nitrogen protection.

[0058] Preferably, the material mixing method for the nitration reaction in step (4) includes: sequentially adding a solution of nitric acid and intermediate 3 to a solvent to obtain a reaction system, and then carrying out the nitration reaction.

[0059] Preferably, the temperature at which nitric acid is added is ≤20℃, for example, it can be 20℃, 15℃, 10℃, 5℃, etc.

[0060] Preferably, the temperature at which the intermediate 3 solution is added is ≤-5℃, for example, it can be -5℃, -6℃, -8℃, -10℃, -12℃, etc.

[0061] Preferably, the temperature of the nitration reaction in step (4) is -25~25℃, for example, it can be -20℃, -10℃, -5℃, 5℃, 10℃, 25℃, etc.

[0062] Preferably, the nitration reaction time in step (4) is 2 to 12 hours, for example, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, etc.

[0063] Preferably, the nitration reaction in step (4) further includes a post-treatment step.

[0064] Preferably, the post-processing includes: washing the reaction system with water and salt solution, extracting the organic phase, drying and concentrating the organic phase to obtain a crude product; redissolving the crude product, adding an alkaline substance, washing with water, acid, alkali and salt solution, separating the organic phase, drying and concentrating the organic phase, filtering with a silica gel pad and concentrating under reduced pressure to obtain intermediate 4.

[0065] Preferably, the solvent used in the extraction includes methyl tert-butyl ether.

[0066] Preferably, the solvent used for the resolution includes dichloromethane.

[0067] Preferably, the alkaline substance includes triethylamine or tetramethylpiperidine.

[0068] Preferably, the hydrogenation reduction reaction in step (5) is carried out in the presence of a catalyst.

[0069] Preferably, the catalyst comprises any one or a combination of at least two of palladium on carbon, platinum on carbon, or ruthenium on carbon.

[0070] Preferably, the mass ratio of intermediate 4 to catalyst is 1:(0.05~0.5), for example, it can be 1:0.05, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.5, etc.

[0071] Preferably, the hydrogenation reduction reaction in step (5) is carried out in the presence of a solvent.

[0072] Preferably, the solvent includes any one or a combination of at least two of ethanol, methanol, or 1,4-dioxane.

[0073] Preferably, the material mixing method for the hydrogenation reduction reaction in step (5) includes: mixing intermediate 4, solvent and catalyst, and replacing them with nitrogen and hydrogen in sequence to obtain the reaction system.

[0074] Preferably, the temperature of the hydrogenation reduction reaction in step (5) is 25~65℃, for example, it can be 25℃, 30℃, 40℃, 50℃, 65℃, etc.

[0075] Preferably, the pressure of the hydrogenation reduction reaction in step (5) is 2~10 MPa, for example, it can be 2 MPa, 3 MPa, 5 MPa, 10 MPa, etc.

[0076] Preferably, the hydrogenation reduction reaction in step (5) takes 8 to 48 hours, for example, 8 hours, 16 hours, 24 hours, 36 hours, 48 ​​hours, etc.

[0077] Preferably, the hydrogenation reduction reaction in step (5) further includes a post-processing step.

[0078] Preferably, the post-processing includes: filtering the reaction system with diatomaceous earth, washing the filter cake, and obtaining a filtrate containing intermediate 5.

[0079] Preferably, the resolving agent in step (6) includes any one or a combination of at least two of D-pyroglutamic acid, D-mandelic acid, or D-tartaric acid.

[0080] Preferably, the molar ratio of intermediate 4 in step (5) to resolving agent in step (6) is 1:(0.75~1.3), for example, it can be 1:0.75, 1:0.85, 1:1.0, 1:1.1, 1:1.2, 1:1.3, etc.

[0081] Preferably, the specific method of the splitting in step (6) includes: adding a splitting agent to the solution system containing intermediate 5 obtained in step (5), heating to dissolve, and then cooling to obtain a solid salt; redissolving the solid salt in water, adding an alkaline reagent to adjust the pH to 10~12 (for example, 10, 10.5, 11, 11.5, 12, etc.) to obtain (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester.

[0082] Preferably, the heating temperature is 60~65℃, for example, it can be 60℃, 61℃, 62℃, 63℃, 64℃, 65℃, etc.

[0083] Preferably, the temperature is reduced to 20~25℃, for example, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, etc.

[0084] Preferably, step (6) splitting further includes a post-processing step.

[0085] Preferably, the post-processing includes: extracting the reaction system to obtain an organic phase, drying, concentrating, and recrystallizing the organic phase to obtain the (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester.

[0086] Preferably, the solvent used in the extraction includes chloroform.

[0087] Preferably, the solvent used for recrystallization includes methyl tert-butyl ether.

[0088] Preferably, the preparation method includes the following steps:

[0089] (1) N-BOC-4-piperidinone and solvent are mixed to obtain a mixture; a solution of allyl magnesium halide is added dropwise to the mixture at -5~5℃ to obtain a reaction system, and then the Grignard reaction is carried out at -5~30℃ for 4~16 h to obtain intermediate 1; the molar ratio of N-BOC-4-piperidinone to allyl magnesium halide is 1:(1~1.5).

[0090] (2) Mix the solvent and the alkaline reagent to obtain a mixture; add the solution of intermediate 1 and 3-halopropene dropwise to the mixture at 10~20℃ to obtain a reaction system, and then carry out a substitution reaction at 45~55℃ for 8~24 h to obtain intermediate 2; the molar ratio of intermediate 1, 3-halopropene and alkaline reagent is 1:(1~2):(1~2.5);

[0091] (3) Mix intermediate 2, Grubb catalyst and solvent, and carry out olefin metathesis reaction at 25~100℃ for 6~24 h to obtain intermediate 3; the mass ratio of intermediate 2 to Grubb catalyst is 1: (0.001~0.05).

[0092] (4) Control the temperature ≤20℃, add nitric acid dropwise to the solvent to obtain a mixture; then control the temperature ≤-5℃, add the solution of intermediate 3 dropwise to the mixture to obtain a reaction system, and then carry out a nitration reaction at -25~25℃ for 2~12 h to obtain intermediate 4; the molar ratio of intermediate 3 to nitric acid is 1:(1.5~3.5).

[0093] (5) Mix intermediate 4, catalyst, solvent and hydrogen, and carry out hydrogenation reduction reaction at 25~65℃ and 2~10 MPa for 8~48 h to obtain intermediate 5; the mass ratio of intermediate 4 to catalyst is 1:(0.05~0.5).

[0094] (6) Add the resolving agent to the solution of intermediate 5, heat to 60~65℃ to dissolve, and then cool to 20~25℃ to obtain a solid salt; redissolve the solid salt in water, add an alkaline reagent to adjust the pH to 10-12, and obtain the (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester; the molar ratio of intermediate 4 in step (5) and the resolving agent in step (6) is 1:(0.75~1.3).

[0095] Compared with the prior art, the present invention has at least the following beneficial effects:

[0096] The preparation method provided by this invention uses N-BOC-4-piperidinone as the starting material and proceeds through six process steps: Grignard reaction, substitution reaction, olefin metathesis reaction, nitration reaction, hydrogenation reduction reaction, and chiral resolution to obtain (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester. This preparation method has a short process route, simple operation, no large amount of wastewater or waste gas generated, and can achieve a high total product yield, chemical and chiral purity, and has high industrial application value. Detailed Implementation Plan

[0097] 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.

[0098] Example 1

[0099] A method for preparing (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester includes the following steps:

[0100] (1) Tetrahydrofuran (20 L, 10V) was added to a reactor equipped with a mechanical stirrer, condenser, and nitrogen protection. Then, N-BOC-4-piperidinone (1992.5 g, 10.0 mol, 1 eq) was added as the starting material. The reaction system was cooled to 0℃. Under nitrogen protection, a 1 M tetrahydrofuran solution of allyl magnesium bromide (11.5 L, 11.5 mol, 1.15 eq) was slowly added dropwise. The temperature of the reaction system was controlled to not exceed 5℃ during the dropwise addition. After the dropwise addition was completed, the reaction system was stirred at 0℃ for 2 h. The reaction system was then naturally raised to 20℃ and stirred. The reaction was monitored by thin-layer chromatography (TLC) to ensure completion. 10 L of ammonium chloride solution was slowly added dropwise to the reactor for quenching, separating the organic phase. 5 L of ammonium chloride solution was then added to the aqueous phase. Extracted once with L-methyl tert-butyl ether, the combined organic phases were washed successively with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated under reduced pressure in a constant temperature water bath at 45°C. The residue was purified by distillation to obtain light brown oily target intermediate 1, product 2025 g, yield 89.1%.

[0101] Structural characterization data of intermediate 1:

[0102] 1 HNMR (400MHz, CDCl3) ppm δ: 1.49 (s, 9H), 1.50-1.88 (m, 4H), 3.10-3.30 (m, 2H), 3.68-3.88 (m, 2H), 5.10 (dd,J=8.4, 1.2Hz, 1H), 5.27 (dd,J=16.4, 1.2 Hz, 1H), 5.94 (dd,J=16.4, 1.2 Hz, 1H).

[0103] (2) THF (12 L, 8 V) was pumped into a reactor equipped with a mechanical stirrer and heating device, followed by sodium tert-butoxide (951 g, 9.9 mol, 1.5 eq). The temperature of the entire reaction system was controlled below 15 °C. Intermediate 1 (1500 g, 6.6 mol, 1.0 eq) was dissolved in 3 L of tetrahydrofuran and slowly added dropwise to the reactor. After the addition was complete, the mixture was stirred for 2 h. Then, 3-bromopropene (958 g, 7.9 mol, 1.2 eq) was added dropwise. The reaction system was then gradually heated to 50 °C and stirred overnight. The reaction of the raw materials was monitored to ensure that the reaction was complete. The reaction system was cooled to 25 °C, and 10 L of water was pumped into the reactor and stirred. The organic phase was then separated, and the aqueous phase was extracted once with 10 L of methyl tert-butyl ether. The organic phases were combined, washed successively with saturated brine and water, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 45 °C until no droplets were observed, yielding target intermediate 2 and product 1652. g, yield 93.6%;

[0104] (3) 15 L of dichloromethane solution of the above intermediate 2 (1550 g, 5.8 mol, 1.0 eq) was pumped into a reaction vessel equipped with a mechanical stirrer and heating device. Under nitrogen protection, Grubbs first-generation catalyst (Cas 172222-30-9, 7.8 g, 5wt‰) was added. The reaction system was then heated to a micro-reflux state and stirred overnight. 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 the reaction liquid was filtered twice with diatomaceous earth. The filter cake was washed with dichloromethane until no product residue was found. The collected filtrate was concentrated under reduced pressure at 45°C and dried. The residue was purified by slurrying with methyl tert-butyl ether to obtain a light yellow solid target intermediate 3. The product was 1150 g, with a yield of 82.9%.

[0105] (4) Add acetic anhydride (3.5 L, 3.5 V) to a reaction vessel equipped with mechanical stirring, condensation device and nitrogen protection, cool the reaction system to -5℃, and then slowly add concentrated nitric acid (450 mL, 10.4 mol, 2.5 eq) dropwise under nitrogen atmosphere, controlling the temperature not to exceed 10℃ during the dropwise addition. After the dropwise addition is completed, cool the reaction system to -20℃. Dissolve the above intermediate 3 (1000 g, 4.2 mmol, 1 eq) in acetic anhydride (about 1.5 L), and then slowly add it dropwise to the reaction vessel under nitrogen atmosphere, controlling the temperature of the reaction system to be below -5℃ during this process. After the dropwise addition is completed, continue stirring the reaction system, and continuously monitor the reaction process until the raw materials are consumed. Slowly put the reaction solution into the prepared ice water (15 L) and stir continuously, then add 10 L of saturated saline solution, and then extract the aqueous phase three times with methyl tert-butyl ether, each time using 10 L of methyl tert-butyl ether. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C. The residue was dissolved in dichloromethane (5 L), and triethylamine (230 mL, 1.7 mol, 0.4 eq) was added at 0°C with stirring. The temperature was then raised to 25°C and stirring was continued for 30 min. The mixture was then further diluted with dichloromethane (25 L), washed sequentially with water, 10 wt% hydrochloric acid, saturated sodium bicarbonate, and brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and then filtered through a silica gel pad. The filtrate was concentrated under reduced pressure at 45°C to obtain target intermediate 4, product 750 g, yield 63.1%.

[0106] (5) Add the above intermediate 4 (625 g, 2.2 mol, 1 eq) and ethanol (3125 mL, 5V) to a 5 L hydrogenation reactor, followed by the addition of 10% palladium on carbon (125 g, 20 wt%). Purify the mixture three times with nitrogen and twice with hydrogen. Maintain a pressure of 3 MPa and start heating to 55 °C. Stir overnight and monitor the reaction to ensure the raw materials have reacted completely, yielding intermediate 5. Cool the reaction system to 25 °C, filter the reaction liquid twice with diatomaceous earth, and wash the filter cake with ethanol (3125 mL, 5V) until no product residue remains. Heat the collected filtrate to 65 °C, and then add D-pyroglutamic acid (241 g, 1.9 mol, 0.85 eq) in batches. After the system is dissolved, continue stirring for 1 h, then cool to 25 °C, filter and collect the solid. Concentrate the filtrate under reduced pressure at 60 °C. Dissolve the residue again with ethanol at 10 times its mass and volume, and heat the system to 65 °C to dissolve completely, then continue stirring for 1 h. h, cool down to 25℃ again, filter and collect the solid; combine the two collected solids and dissolve them in a small amount of water, then adjust the pH to 11 with 5wt% sodium hydroxide, and extract repeatedly with chloroform 3 times, each time using 100mL, the combined organic phase is dried with anhydrous sodium sulfate and filtered, the filtrate is concentrated under reduced pressure at 55℃, the obtained solid is further crystallized with methyl tert-butyl ether and then dried at 50℃ to obtain 185 g of white solid (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, the target product, with a reduction yield of 85.2%, a single configuration resolution yield of 77.1%, and a product ee value of 99.8%. The recovered mother liquor can be re-dissected to obtain more of the target product.

[0107] Structural characterization data of (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester:

[0108] 1 HNMR (400MHz, CDCl3) ppm δ: 1.36-1.50 (m, 13H), 1.52-1.74 (m, 3H), 2.05 (dd,J=10.0, 7.6Hz, 1H), 3.27-3.37 (m, 2H), 3.46-3.65 (m, 4H), 3.93 (dd,J=7.6,5.6 Hz, 1H).

[0109] Example 2

[0110] (1) Ethylene glycol dimethyl ether (20 L, 10V) was added to a reactor equipped with a mechanical stirrer, condenser, and nitrogen protection. Then, N-BOC-4-piperidinone (1992.5 g, 10.0 mol, 1 eq) was added as starting material. The reaction system was cooled to 0℃. Under nitrogen protection, a 1 M solution of allyl magnesium bromide in tetrahydrofuran (12 L, 12.0 mol, 1.2 eq) was slowly added dropwise, controlling the temperature of the reaction system to not exceed 5℃ during the addition process. After the addition was complete, the reaction system was stirred at 0℃ for 4 h. The reaction system was then naturally heated to 25℃ and stirred. The reaction was monitored by thin-layer chromatography (TLC) to ensure completion. 10 L of ammonium chloride solution was slowly added dropwise to the reactor for quenching, followed by the addition of 10 L of... Extracted once with L-methyl tert-butyl ether, the combined organic phases were washed successively with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The organic phases were concentrated under reduced pressure in a constant temperature water bath at 45°C. The residue was purified by distillation to obtain light brown oily target intermediate 1, with a product yield of 1960 g and a yield of 86.2%.

[0111] (2) 1,4-Dioxane (12 L, 8 V) was pumped into a reactor equipped with a mechanical stirrer and heating device, followed by the addition of potassium tert-butoxide (1111 g, 9.9 mol, 1.5 eq). The temperature of the entire reaction system was controlled below 15°C. The above intermediate 1 (1500 g, 6.6 mol, 1.0 eq) was slowly added dropwise to the reactor with 3 L of 1,4-Dioxane. After the addition was completed, the mixture was stirred for 2 h. Then, 3-bromopropene (958 g, 7.9 mol, 1.2 eq) was added dropwise. The reaction system was then gradually heated to 50°C and stirred overnight. The reaction of the raw materials was monitored to ensure that the reaction was complete. The reaction system was cooled to 25°C, and 10 L of water was pumped into the reactor and stirred. The organic phase was then separated, and the aqueous phase was further treated with 10 L of water. Extracted once with L-methyl tert-butyl ether, the organic phases were combined, washed successively with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C until no droplets remained, yielding target intermediate 2, product 1620 g, yield 91.8%;

[0112] (3) 15 L of the above intermediate 2 (1550 g, 5.8 mol, 1.0 eq) in n-heptane solution was pumped into a reaction vessel equipped with mechanical stirring and heating device. Under nitrogen protection, Grubbs first-generation catalyst (Cas 172222-30-9, 4.7 g, 3wt‰) was added. The reaction system was then heated to a micro-reflux state and stirred overnight. 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 the reaction liquid was filtered twice with diatomaceous earth. The filter cake was washed with n-hexane until no product residue was found. The collected filtrate was concentrated under reduced pressure at 45°C and dried. The residue was purified by slurrying with methyl tert-butyl ether to obtain a light yellow solid target intermediate 3. The product was 1127 g, with a yield of 81.2%.

[0113] (4) Add acetic acid (3.5 L, 3.5 V) to a reaction vessel equipped with mechanical stirring, condensation device and nitrogen protection, and cool the reaction system to -5 °C. Then, slowly add concentrated nitric acid (360 mL, 8.4 mol, 2 eq) under nitrogen atmosphere, controlling the temperature not to exceed 10 °C during the addition. After the addition is complete, cool the reaction system to -20 °C. Dissolve the above intermediate 3 (1000 g, 4.2 mmol, 1 eq) in acetic acid (about 1.5 L), and then slowly add it to the reaction vessel under nitrogen atmosphere, controlling the temperature of the reaction system below -5 °C during this process. After the addition is complete, continue stirring the reaction system and continuously monitor the reaction process until the raw materials are almost consumed. Slowly put the reaction solution into the prepared ice water (15 L) and stir continuously. Then add 10 L of saturated saline solution. Then extract the aqueous phase three times with methyl tert-butyl ether, each time using 10 L of methyl tert-butyl ether. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C. The residue was dissolved in dichloromethane (5 L), and triethylamine (230 mL, 1.7 mol, 0.4 eq) was added at 0°C with stirring. The temperature was then raised to 25°C and stirring was continued for 30 min. The mixture was then further diluted with dichloromethane (25 L), washed sequentially with water, 10 wt% hydrochloric acid, saturated sodium bicarbonate, and brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and then filtered through a silica gel pad. The filtrate was concentrated under reduced pressure at 45°C to obtain target intermediate 4, product 708 g, yield 59.6%.

[0114] (5) Add the above intermediate 4 (625 g, 2.2 mol, 1 eq) and methanol (3125 mL, 5V) to a 5 L hydrogenation reactor, followed by the addition of 10% palladium on carbon (94 g, 15 wt%). Purify the mixture three times with nitrogen and twice with hydrogen. Maintain a pressure of 5 MPa and start heating to 45°C. Stir overnight. After monitoring the reaction, the raw materials are basically reacted, and intermediate 5 is obtained. Cool the reaction system to 25°C and filter the reaction liquid twice with diatomaceous earth. Wash the filter cake with methanol (3125 mL, 5V) until no product residue remains. Heat the collected filtrate to a micro-reflux state, and then add D-pyroglutamic acid (284 g, 2.2 mol, 1 eq) in batches. After the system is dissolved, continue stirring for 1 h, then cool to 25°C, filter and collect the solid. Concentrate the filtrate under reduced pressure at 55°C. Dissolve the residue again with 10 times its mass of ethanol. Heat the system to 65°C to dissolve and continue stirring for 1 h. h, cool down to 25℃ again, filter and collect the solid; combine the two collected solids and dissolve them in a small amount of water, then adjust the pH to 11 with 5wt% sodium hydroxide, and extract repeatedly with chloroform 3 times, each time using 200 mL, the combined organic phase is dried with anhydrous sodium sulfate and filtered, the filtrate is concentrated under reduced pressure at 55℃, the obtained solid is further crystallized with methyl tert-butyl ether and then dried at 50℃ to obtain 180 g of white solid (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, the target product, with a reduction yield of 80.2%, a single configuration resolution yield of 79.7%, and a product ee value of 99.7%. The recovered mother liquor can be re-dissected to obtain more of the target product.

[0115] Example 3

[0116] (1) Add tetrahydrofuran (20 L, 10V) to a reactor equipped with mechanical stirring, condensation device and nitrogen protection, followed by N-BOC-4-piperidinone (1992.5 g, 10.0 mol, 1 eq) as starting material. Cool the reaction system to 0℃. Under nitrogen protection, slowly add 1 M tetrahydrofuran solution of allyl magnesium chloride (15 L, 15.0 mol, 1.5 eq), controlling the temperature of the reaction system to not exceed 5℃ during the addition process. After the addition is completed, continue stirring the reaction system at 0℃ for 5 h. Then, naturally raise the reaction system to 25℃ and stir. Monitor the reaction completion by thin-layer chromatography (TLC). Slowly add 10 L of ammonium chloride solution to the reactor for quenching, separate the organic phase, and add 8 L of ammonium chloride solution to the aqueous phase. Extracted once with L-methyl tert-butyl ether, the combined organic phases were washed successively with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The organic phases were concentrated under reduced pressure in a constant temperature water bath at 45°C. The residue was purified by distillation to obtain light brown oily target intermediate 1, product 2005 g, yield 88.2%.

[0117] (2) THF (12 L, 8 V) was pumped into a reactor equipped with a mechanical stirrer and heating device. Then, sodium hydride (343 g, 8.6 mol, 1.3 eq, 60% mineral oil) was added in portions. The temperature of the entire reaction system was controlled below 10 °C. The above intermediate 1 (1500 g, 6.6 mol, 1.0 eq) was dissolved in 3 L of tetrahydrofuran and slowly added dropwise to the reactor. After the addition was completed, the mixture was stirred for 2 h. Then, 3-bromopropene (1038 g, 8.6 mol, 1.3 eq) was added dropwise. The temperature of the reaction system was gradually increased to 40 °C and stirred for 12 h. The reaction was monitored at the control point and the raw materials were almost completely reacted. The reaction system was cooled to 0 °C, and ice water was slowly pumped into the reactor to quench the reaction. The addition was slow and the mixture was stirred continuously. About 15 L of water was added to completely quench the reaction. Then, the organic phase was separated, and the aqueous phase was treated with 10 L of water. L-methyl tert-butyl ether was extracted once, the organic phases were combined, washed successively with saturated brine and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C until no droplets remained, to obtain target intermediate 2, product 1450 g, yield 82.2%;

[0118] (3) 15 L of dichloromethane solution of the above intermediate 2 (1550 g, 5.8 mol, 1.0 eq) was pumped into a reaction vessel equipped with a mechanical stirrer and heating device. Under nitrogen protection, Grubbs second-generation catalyst (Cas 246047-72-3, 2.0 g, 1.3 wt‰) was added. The reaction system was then heated to a micro-reflux state and stirred overnight. 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 the reaction liquid was filtered twice with diatomaceous earth. The filter cake was washed with dichloromethane until no product residue was found. The collected filtrate was concentrated under reduced pressure at 45°C. The residue was purified by slurrying with methyl tert-butyl ether to obtain a light yellow solid target intermediate 3. The product was 1048 g, with a yield of 75.5%.

[0119] (4) Add acetic anhydride (3.5 L, 3.5 V) to a reaction vessel equipped with mechanical stirring, condensation device and nitrogen protection, cool the reaction system to -5℃, and then slowly add concentrated nitric acid (630 mL, 14.6 mol, 3.5 eq) dropwise under nitrogen atmosphere, controlling the temperature not to exceed 10℃ during the dropwise addition. After the dropwise addition is completed, cool the reaction system to -20℃. Dissolve the above intermediate 3 (1000 g, 4.2 mmol, 1 eq) in acetic anhydride (about 1.5 L), and then slowly add it dropwise to the reaction vessel under nitrogen atmosphere, controlling the temperature of the reaction system to be below -5℃ during this process. After the dropwise addition is completed, continue stirring the reaction system, and continuously monitor the reaction process until the raw materials are almost consumed. Slowly put the reaction solution into the prepared ice water (15 L) and stir continuously, then add 10 L of saturated saline solution, and then extract the aqueous phase three times with methyl tert-butyl ether, each time using 10 L of methyl tert-butyl ether. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C. The residue was dissolved in dichloromethane (5 L), and triethylamine (230 mL, 1.7 mol, 0.4 eq) was added at 0°C with stirring. The temperature was then raised to 25°C and stirring was continued for 30 min. The mixture was then further diluted with dichloromethane (25 L), washed sequentially with water, 10 wt% hydrochloric acid, saturated sodium bicarbonate, and brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and then filtered through a silica gel pad. The filtrate was concentrated under reduced pressure at 45°C to obtain target intermediate 4, product 738 g, yield 62.1%.

[0120] (5) Add the above intermediate 4 (625 g, 2.2 mol, 1 eq) and ethanol (3125 mL, 5V) to a 5 L hydrogenation reactor, followed by the addition of 5% ruthenium carbon (100 g, 16 wt%). Purify the mixture three times with nitrogen and twice with hydrogen. The pressure is 3 MPa. The temperature is raised to 55 °C and the mixture is stirred for 36 h. The reaction is monitored to ensure the raw materials have reacted completely, and intermediate 5 is obtained. The reaction system is cooled to 25 °C, and the reaction liquid is filtered twice with diatomaceous earth. The filter cake is washed with ethanol (3125 mL, 5V) until no product residue remains. The collected filtrate is heated to 65 °C, and D-mandelic acid (368 g, 2.4 mol, 1.1 eq) is added in batches. After the system is dissolved, stirring is continued for 1 h. The temperature is then lowered to 25 °C, the solid is filtered and collected. The filtrate is concentrated under reduced pressure at 60 °C. The residue after concentration is dissolved again with ethanol at 10 times its mass and volume. The system is heated to 65 °C and stirred for 1 h. h, cool down to 25℃ again, filter and collect the solid; combine the two collected solids and dissolve them in a small amount of water, then adjust the pH to 11 with 5wt% sodium hydroxide, and extract repeatedly with chloroform 3 times, each time using 150 mL, the combined organic phase is dried with anhydrous sodium sulfate and filtered, the filtrate is concentrated under reduced pressure at 55℃, the obtained solid is further crystallized with methyl tert-butyl ether and then dried at 50℃ to obtain 206 g of white solid (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, the target product, with a reduction yield of 88.7%, a single configuration resolution yield of 82.4%, and a product ee value of 99.6%. The recovered mother liquor can be re-dissected to obtain more of the target product.

[0121] 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 (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8- carboxylic acid tert-butyl ester, characterized in that, The preparation method includes the following steps: (1) N-BOC-4-piperidinone reacts with allyl magnesium halide in a Grignard reaction to give intermediate 1, as shown in the following reaction formula: ; X1 is selected from chlorine, bromine, or iodine; (2) The intermediate 1 obtained in step (1) undergoes a substitution reaction with 3-halopropene to obtain intermediate 2, and the reaction formula is as follows: ; X2 is selected from chlorine, bromine, or iodine; (3) The intermediate 2 obtained in step (2) undergoes an olefin metathesis reaction under the action of a Grubb catalyst to obtain intermediate 3, and the reaction formula is as follows: ; (4) The intermediate 3 obtained in step (3) undergoes a nitration reaction with nitric acid to obtain intermediate 4, and the reaction formula is as follows: ; (5) After the intermediate 4 obtained in step (4) undergoes a hydrogenation reduction reaction, racemic intermediate 5 is obtained, and the reaction formula is as follows: ; (6) The intermediate 5 obtained in step (5) was chirally resolved by a resolving agent to obtain the (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, as shown in the following reaction formula: 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of N-BOC-4-piperidinone to allyl magnesium halide in step (1) is 1:(1~1.5). Preferably, the reaction described in step (1) is carried out in the presence of a solvent; Preferably, the solvent includes any one or a combination of at least two of tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, or isopropyl ether; Preferably, the reaction described in step (1) is carried out under nitrogen protection; Preferably, after the reaction in step (1) is completed, a quenching agent is added for quenching. Preferably, the quenching agent includes any one or a combination of at least two of ammonium chloride, dilute hydrochloric acid, glacial acetic acid, or water.

3. The preparation method according to claim 1 or 2, characterized in that, The material mixing method for the Grignard reaction in step (1) includes: mixing N-BOC-4-piperidinone and a solvent to obtain a mixture; adding a solution of allyl magnesium halide dropwise to the mixture to obtain a reaction system, and then carrying out the Grignard reaction; Preferably, the temperature at which the liquid is added is -5 to 5°C; Preferably, the temperature of the reaction in step (1) is -5~30℃; Preferably, the reaction time of the format described in step (1) is 4 to 16 hours; Preferably, the format reaction in step (1) further includes a post-processing step; Preferably, the post-processing includes: separating the reaction system to obtain an organic phase; washing the organic phase with a salt solution, washing with water, drying and concentrating it to obtain a crude product; and distilling the crude product to obtain intermediate 1.

4. The preparation method according to any one of claims 1-3, characterized in that, In step (2), the molar ratio of intermediate 1 and 3-halopropene is 1:(1~2). Preferably, the substitution reaction in step (2) is carried out in the presence of a basic reagent; Preferably, the alkaline reagent includes any one or a combination of at least two of sodium tert-butoxide, potassium tert-butoxide, sodium hydride, or sodium bis(trimethylsilyl)amino. Preferably, the molar ratio of intermediate 1 to alkaline reagent is 1:(1~2.5). Preferably, the substitution reaction in step (2) is carried out in the presence of a solvent; Preferably, the solvent comprises any one or a combination of at least two of tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane or toluene; Preferably, the material mixing method for the substitution reaction in step (2) includes: mixing a solvent and an alkaline reagent to obtain a mixture; adding a solution of intermediate 1 and 3-halopropene dropwise to the mixture to obtain a reaction system, and then carrying out the substitution reaction; Preferably, the temperatures at which intermediate 1 and 3-halopropylene are added are each independently 10~20°C; Preferably, the temperature of the substitution reaction in step (2) is 45~55℃; Preferably, the substitution reaction in step (2) takes 8 to 24 hours; Preferably, the substitution reaction in step (2) 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 the organic phase with salt solution, washing with water, drying and concentrating to obtain intermediate 2.

5. The preparation method according to any one of claims 1-4, characterized in that, The mass ratio of intermediate 2 and Grubb catalyst in step (3) is 1:(0.001~0.05). Preferably, the Grubb catalyst comprises any one or a combination of at least two of the first-generation Grubb catalyst, the second-generation Grubb catalyst, or the third-generation Grubb catalyst; Preferably, the olefin metathesis reaction in step (3) is carried out in the presence of a solvent; Preferably, the solvent includes any one or a combination of at least two of dichloromethane, ethyl acetate, toluene, or n-heptane; Preferably, the temperature of the olefin metathesis reaction in step (3) is 25~100℃; Preferably, the time for the olefin metathesis reaction in step (3) is 6~24 h; Preferably, the olefin metathesis reaction in step (3) is carried out under nitrogen protection; Preferably, the olefin metathesis reaction in step (3) further includes a post-processing step; Preferably, the post-processing includes: filtering the reaction system with diatomaceous earth, washing the filter cake, concentrating the filtrate to obtain a crude product; and pulping the crude product to obtain intermediate 3. Preferably, the solvent used for washing the filter cake includes any one or a combination of at least two of dichloromethane, ethyl acetate, toluene, or n-heptane; Preferably, the solvent used for pulping includes any one or a combination of at least two of methyl tert-butyl ether, petroleum ether, isopropyl ether, n-hexane, or ethyl acetate.

6. The preparation method according to any one of claims 1-5, characterized in that, In step (4), the molar ratio of intermediate 3 to nitric acid is 1:(1.5~3.5). Preferably, the nitration reaction in step (4) is carried out in the presence of a solvent; Preferably, the solvent includes any one or a combination of at least two of acetic anhydride, acetic acid, or dichloroethane; Preferably, the nitration reaction in step (4) is carried out under nitrogen protection; Preferably, the material mixing method for the nitration reaction in step (4) includes: sequentially adding a solution of nitric acid and intermediate 3 to a solvent to obtain a reaction system, and then carrying out the nitration reaction; Preferably, the temperature at which nitric acid is added is ≤20℃; Preferably, the temperature at which intermediate 3 solution is added is ≤-5℃; Preferably, the temperature of the nitration reaction in step (4) is -25℃ to 25℃; Preferably, the nitration reaction in step (4) takes 2 to 12 hours.

7. The preparation method according to any one of claims 1-6, characterized in that, The nitration reaction in step (4) also includes a post-treatment step; Preferably, the post-processing includes: slowly pouring the reaction system into ice water to quench it, then diluting it with water and / or salt solution, extracting the organic phase, drying and concentrating the organic phase to obtain a crude product; redissolving the crude product, adding an alkaline substance, washing with water, acid, alkali and salt solution, separating the organic phase, drying and concentrating the organic phase, filtering with a silica gel pad and concentrating under reduced pressure to obtain intermediate 4; Preferably, the solvent used in the extraction includes methyl tert-butyl ether; Preferably, the solvent used for the redissolution includes dichloromethane; Preferably, the alkaline substance includes triethylamine or tetramethylpiperidine.

8. The preparation method according to any one of claims 1-7, characterized in that, The hydrogenation reduction reaction in step (5) 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, or ruthenium on carbon; Preferably, the mass ratio of intermediate 4 to catalyst is 1:(0.05~0.5). Preferably, the hydrogenation reduction reaction in step (5) is carried out in the presence of a solvent; Preferably, the solvent includes any one or a combination of at least two of ethanol, methanol, or 1,4-dioxane; Preferably, the material mixing method for the hydrogenation reduction reaction in step (5) includes: mixing intermediate 4, solvent and catalyst, and replacing them with nitrogen and hydrogen in sequence to obtain the reaction system; Preferably, the temperature of the hydrogenation reduction reaction in step (5) is 25~65℃; Preferably, the pressure of the hydrogenation reduction reaction in step (5) is 2~10 MPa; Preferably, the hydrogenation reduction reaction in step (5) takes 8 to 48 hours; Preferably, the hydrogenation reduction reaction in step (5) further includes a post-processing step; Preferably, the post-processing includes: filtering the reaction system with diatomaceous earth, washing the filter cake, and obtaining a filtrate containing intermediate 5.

9. The preparation method according to any one of claims 1-8, characterized in that, The resolving agent in step (6) includes any one or a combination of at least two of D-pyroglutamic acid, D-mandelic acid, or D-tartaric acid; Preferably, the molar ratio of intermediate 4 in step (5) to resolving agent in step (6) is 1:(0.75~1.3). Preferably, the specific method of the splitting in step (6) includes: adding a splitting agent to the solution system containing intermediate 5 obtained in step (5), heating to dissolve, and then cooling to obtain a solid salt; redissolving the solid salt in water, adding an alkaline reagent to adjust the pH to 10-12, and obtaining (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester; Preferably, the heating temperature is 60~65℃; Preferably, the temperature is reduced to 20~25℃; Preferably, step (6) of splitting further includes a post-processing step; Preferably, the post-processing includes: extracting the reaction system to obtain an organic phase, drying, concentrating, and recrystallizing the organic phase to obtain the (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester; Preferably, the solvent used in the extraction includes chloroform; Preferably, the solvent used for recrystallization includes methyl tert-butyl ether.

10. The preparation method according to any one of claims 1-9, characterized in that, The preparation method includes the following steps: (1) N-BOC-4-piperidinone and solvent are mixed to obtain a mixture; a solution of allyl magnesium halide is added dropwise to the mixture at -5~5℃ to obtain a reaction system, and then the Grignard reaction is carried out at -5~30℃ for 4~16 h to obtain intermediate 1; the molar ratio of N-BOC-4-piperidinone to allyl magnesium halide is 1:(1~1.5). (2) Mix the solvent and the alkaline reagent to obtain a mixture; add the solution of intermediate 1 and 3-halopropene dropwise to the mixture at 10~20℃ to obtain a reaction system, and then carry out a substitution reaction at 45~55℃ for 8~24 h to obtain intermediate 2; the molar ratio of intermediate 1, 3-halopropene and alkaline reagent is 1:(1~2):(1~2.5); (3) Mix intermediate 2, Grubb catalyst and solvent, and carry out olefin metathesis reaction at 25~100℃ for 6~24 h to obtain intermediate 3; the mass ratio of intermediate 2 to Grubb catalyst is 1: (0.001~0.05). (4) Control the temperature ≤20℃, add nitric acid dropwise to the solvent to obtain a mixture; then control the temperature ≤-5℃, add the solution of intermediate 3 dropwise to the mixture to obtain a reaction system, and then carry out a nitration reaction at -25~25℃ for 2~12 h to obtain intermediate 4; the molar ratio of intermediate 3 to nitric acid is 1:(1.5~3.5). (5) Mix intermediate 4, catalyst, solvent and hydrogen, and carry out hydrogenation reduction reaction at 25~65℃ and 2~10 MPa for 8~48 h to obtain intermediate 5; the mass ratio of intermediate 4 to catalyst is 1:(0.05~0.5). (6) Add the resolving agent to the solution of intermediate 5, heat to 60~65℃ to dissolve, and then cool to 20~25℃ to obtain a solid salt; redissolve the solid salt in water, add an alkaline reagent to adjust the pH to 10~12, and obtain the (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester; the molar ratio of intermediate 4 in step (5) and the resolving agent in step (6) is 1:(0.75~1.3).

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