Preparation method of (R)-3-amino-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester

Abstract

The invention relates to a preparation method of (R)-3-amino-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester, which comprises the following steps: carrying out Grignard reaction on N-BOC-4-piperidone and allyl magnesium halide to obtain an intermediate 1; carrying out substitution reaction on the intermediate 1 and 3-halogenated propylene to obtain an intermediate 2; performing olefin metathesis reaction on the intermediate 2 under the action of a Grubbs catalyst to obtain an intermediate 3; carrying out nitration reaction on the intermediate 3 and nitric acid to obtain an intermediate 4; carrying out hydrogenation reduction reaction on the intermediate 4 to obtain a racemic intermediate 5; and carrying out chiral resolution on the intermediate 5 by using a resolving agent to obtain a target product. The preparation method provided by the invention is short in process route and simple to operate, does not generate a large amount of waste water and waste gas, and can achieve higher total product yield and chemical and chiral purity.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, 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 Art

[0002] (R)-3-Amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester has been confirmed to be a key fragment of some drugs with good biological activity. 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 use the raw material 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (Cas 954236-44-3) to further synthesize the target product. The synthesis method of this raw material is reported in patent WO2018026371A1. Pfizer uses the raw material 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester with isopropylamine hydrochloride and pyridoxal 5'-phosphate monohydrate in a buffer solution. The target product is synthesized by ATA-200 aminotransferase, and further modified with D-pyroglutamic acid to obtain a target product with high chiral purity. Although the method uses enzyme technology with a high yield, the enzyme used is expensive, the operation is complicated, the reaction conditions are strict, and it is not suitable for large-scale production. C4 Therapeutics uses 3-oxo-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester and hydroxylamine hydrochloride to form an oxime, and then reduces it with Raney nickel to obtain a racemic amine, and then uses D-mandelic acid for chemical splitting, and finally frees the target product. Verification of this method found that Raney nickel reduction is accompanied by impurities and is not easy to remove. Moreover, Raney nickel filtration is more troublesome.

[0004] Therefore, it is a technical problem that is urgently needed to be solved in the art to provide 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, less three wastes, and high overall yield, chemical purity and chiral purity. Summary of the invention

[0005] In order to solve the above technical problems, the present 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 the present invention includes six process steps: Grignard reaction, substitution reaction, olefin metathesis reaction, nitration reaction, hydrogenation reduction reaction and chiral resolution. The preparation method has a short process route, simple operation, no large amount of waste water and waste gas is generated, and a high total product yield, chemical and chiral purity can be achieved.

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

[0007] The present 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-piperidone reacts with allyl magnesium halide to obtain intermediate 1. The reaction formula is as follows:

[0009]

[0010] Wherein, X1 is selected from chlorine, bromine or iodine;

[0011] (2) The intermediate 1 obtained in step (1) undergoes a substitution reaction with 3-halopropylene to obtain intermediate 2. The reaction formula is as follows:

[0012]

[0013] Wherein, X2 is selected from chlorine, bromine or iodine;

[0014] (3) The intermediate 2 obtained in step (2) undergoes olefin metathesis reaction under the action of Grubbs' catalyst to obtain intermediate 3. The reaction formula is as follows:

[0015]

[0016] (4) The intermediate 3 obtained in step (3) undergoes a nitration reaction with nitric acid to obtain an intermediate 4. The reaction formula is as follows:

[0017]

[0018] (5) The intermediate 4 obtained in step (4) is subjected to a hydrogenation reduction reaction to obtain a racemic intermediate 5, and the reaction formula is as follows:

[0019]

[0020] (6) The intermediate 5 obtained in step (5) is subjected to chiral resolution with a resolving agent to obtain the (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, and the reaction formula is as follows:

[0021]

[0022] In the above reaction formula, Boc represents tert-butyloxycarbonyl.

[0023] The preparation method provided by the present invention comprises six process steps: Grignard reaction, substitution reaction, olefin metathesis reaction, nitration reaction, hydrogenation reduction reaction and chiral resolution. The route uses N-BOC-4-piperidone as a starting material, firstly reacts with allyl magnesium halide to form intermediate 1 through Grignard reaction, then reacts with 3-halopropylene through substitution reaction to obtain intermediate 2, then uses Grubbs catalyst to perform olefin metathesis reaction to obtain intermediate 3, then uses nitric acid system to perform nitration reaction to obtain intermediate 4, finally performs hydrogenation reduction to obtain racemic amine, and performs chiral resolution with a resolution agent to obtain the target product through liberation.

[0024] The preparation method provided by the invention has a short process route, is simple to operate, does not generate a large amount of waste water and waste gas, and can achieve a higher total product yield, chemical and chiral purity.

[0025] Preferably, the molar ratio of the N-BOC-4-piperidone to the 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.

[0026] Preferably, the grignard reaction in step (1) is carried out in the presence of a solvent.

[0027] Preferably, the solvent includes any one of tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether or isopropyl ether, or a combination of at least two thereof.

[0028] Preferably, the format reaction in step (1) is carried out under nitrogen protection.

[0029] Preferably, after the format reaction in step (1) is completed, a quencher is added for quenching.

[0030] Preferably, the quenching agent includes any one of ammonium chloride, dilute hydrochloric acid, glacial acetic acid or water, or a combination of at least two of them.

[0031] Preferably, the material mixing method for the Grignard reaction in step (1) comprises: mixing N-BOC-4-piperidone and a solvent to obtain a mixed solution; adding a solution of allyl magnesium halide to the mixed solution to obtain a reaction system, and then performing a Grignard reaction.

[0032] Preferably, the dropping temperature is -5 to 5°C, for example, -5°C, -3°C, 0°C, 3°C, 5°C, etc.

[0033] Preferably, the temperature of the format reaction in step (1) is -5 to 30°C, for example, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, etc.

[0034] Preferably, the reaction time of the format in step (1) is 4 to 16 hours, for example, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, etc.

[0035] Preferably, the format reaction in step (1) further includes a post-processing step.

[0036] Preferably, the post-treatment comprises: separating the reaction system to obtain an organic phase; washing the organic phase with a salt solution, washing with water, drying and concentrating to obtain a crude product; and distilling the crude product to obtain intermediate 1.

[0037] Preferably, the molar ratio of the intermediate 1 to 3-halopropylene in step (2) is 1:(1-2), for example, 1:1, 1:1.1, 1:1.3, 1:1.5, 1:2, etc.

[0038] Preferably, the substitution reaction in step (2) is carried out in the presence of an alkaline reagent.

[0039] Preferably, the alkaline agent includes any one of sodium tert-butoxide, potassium tert-butoxide, sodium hydride, or sodium bis(trimethylsilyl)amide, or a combination of at least two thereof.

[0040] Preferably, the molar ratio of the intermediate 1 to the 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.

[0041] Preferably, the substitution reaction in step (2) is carried out in the presence of a solvent.

[0042] Preferably, the solvent includes any one of tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane or toluene, or a combination of at least two thereof.

[0043] Preferably, the material mixing method for the substitution reaction in step (2) comprises: mixing a solvent and an alkaline reagent to obtain a mixed solution; adding a solution of intermediate 1 and 3-halogenated propene dropwise to the mixed solution to obtain a reaction system, and then performing a substitution reaction.

[0044] Preferably, the temperature when the intermediate 1 and 3-halopropene are added dropwise is independently 10 to 20°C, for example, 10°C, 12°C, 14°C, 16°C, 18°C, 20°C, etc.

[0045] Preferably, the temperature of the substitution reaction in step (2) is 45-55°C, for example, 45°C, 46°C, 48°C, 50°C, 52°C, 54°C, 55°C, etc.

[0046] Preferably, the substitution reaction time in step (2) is 8 to 24 hours, for example, 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, etc.

[0047] Preferably, the substitution reaction in step (2) further comprises a post-treatment step.

[0048] Preferably, the post-treatment comprises: adding water to the reaction system and stirring, separating to obtain an organic phase; washing the organic phase with a salt solution, washing with water, drying and concentrating to obtain the intermediate 2.

[0049] Preferably, the mass ratio of the intermediate 2 to the Grubbs 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.

[0050] Preferably, the Grubbs catalyst includes any one of a first-generation Grubbs catalyst, a second-generation Grubbs catalyst or a third-generation Grubbs catalyst, or a combination of at least two of them.

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

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

[0053] Preferably, the temperature of the olefin metathesis reaction in step (3) is 25-100°C, for example, 25°C, 30°C, 40°C, 50°C, 80°C, 100°C, etc.

[0054] 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.

[0055] Preferably, the olefin metathesis reaction in step (3) is carried out under nitrogen protection.

[0056] Preferably, the olefin metathesis reaction in step (3) further comprises a post-treatment step.

[0057] Preferably, the post-treatment comprises: filtering the reaction system with diatomaceous earth, washing the filter cake, and concentrating the filtrate to obtain a crude product; and slurrying the crude product to obtain intermediate 3.

[0058] Preferably, the solvent used for washing the filter cake includes any one of dichloromethane, ethyl acetate, toluene or n-heptane, or a combination of at least two thereof.

[0059] Preferably, the solvent used for pulping includes any one of methyl tert-butyl ether, petroleum ether, isopropyl ether, n-hexane or ethyl acetate, or a combination of at least two thereof.

[0060] Preferably, the molar ratio of the intermediate 3 to 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.

[0061] Preferably, the nitration reaction in step (4) is carried out in the presence of a solvent.

[0062] Preferably, the solvent includes any one of acetic anhydride, acetic acid or ethylene dichloride, or a combination of at least two of them.

[0063] Preferably, the nitration reaction in step (4) is carried out under nitrogen protection.

[0064] Preferably, the material mixing method for the nitration reaction in step (4) comprises: sequentially adding nitric acid and a solution of the intermediate 3 dropwise to a solvent to obtain a reaction system, and then performing a nitration reaction.

[0065] Preferably, the temperature for adding nitric acid dropwise is ≤20°C, for example, it may be 20°C, 15°C, 10°C, 5°C, etc.

[0066] Preferably, the temperature of the dropwise addition of the intermediate 3 solution is ≤ -5°C, for example, it may be -5°C, -6°C, -8°C, -10°C, -12°C, etc.

[0067] Preferably, the temperature of the nitration reaction in step (4) is -25 to 25°C, for example, -20°C, -10°C, -5°C, 5°C, 10°C, 25°C, etc.

[0068] 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.

[0069] Preferably, the nitration reaction in step (4) further includes a post-treatment step.

[0070] Preferably, the post-treatment comprises: washing the reaction system with water and a salt solution, extracting an 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 washing, alkali washing and salt solution washing, separating the organic phase, drying, concentrating, filtering through a silica gel pad and concentrating under reduced pressure to obtain intermediate 4.

[0071] Preferably, the solvent used in the extraction comprises methyl tert-butyl ether.

[0072] Preferably, the solvent used for the re-dissolution comprises dichloromethane.

[0073] Preferably, the alkaline substance comprises triethylamine or tetramethylpiperidine.

[0074] Preferably, the hydrogenation reduction reaction in step (5) is carried out in the presence of a catalyst.

[0075] Preferably, the catalyst comprises any one of palladium carbon, platinum carbon or ruthenium carbon, or a combination of at least two thereof.

[0076] Preferably, the mass ratio of the intermediate 4 to the 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.

[0077] Preferably, the hydrogenation reduction reaction in step (5) is carried out in the presence of a solvent.

[0078] Preferably, the solvent includes any one of ethanol, methanol, or 1,4-dioxane, or a combination of at least two of them.

[0079] Preferably, the material mixing method for the hydrogenation reduction reaction in step (5) comprises: mixing the intermediate 4, the solvent and the catalyst, and replacing them with nitrogen and hydrogen in sequence to obtain a reaction system.

[0080] Preferably, the temperature of the hydrogenation reduction reaction in step (5) is 25-65°C, for example, 25°C, 30°C, 40°C, 50°C, 65°C, etc.

[0081] Preferably, the pressure of the hydrogenation reduction reaction in step (5) is 2 to 10 MPa, for example, 2 MPa, 3 MPa, 5 MPa, 10 MPa, etc.

[0082] Preferably, the hydrogenation reduction reaction time in step (5) is 8 to 48 hours, for example, 8 hours, 16 hours, 24 hours, 36 hours, 48 ​​hours, etc.;

[0083] Preferably, the hydrogenation reduction reaction in step (5) further comprises a post-treatment step.

[0084] Preferably, the post-treatment comprises: filtering the reaction system with diatomaceous earth, washing the filter cake, and obtaining a filtrate containing the intermediate 5.

[0085] Preferably, the resolving agent in step (6) comprises any one of D-pyroglutamic acid, D-mandelic acid or D-tartaric acid, or a combination of at least two thereof.

[0086] Preferably, the molar ratio of the intermediate 4 in step (5) to the 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.

[0087] Preferably, the specific method of splitting in step (6) comprises: adding a splitting agent to the solution system containing the intermediate 5 obtained in step (5), heating to dissolve, and then cooling to obtain a solid salt; re-dissolving the solid salt in water, adding an alkaline reagent to adjust the pH to 10-12 (for example, it can be 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.

[0088] Preferably, the heating temperature is 60-65°C, for example, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, etc.

[0089] Preferably, the temperature is lowered to 20-25°C, for example, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, etc.

[0090] Preferably, the splitting in step (6) also includes a post-processing step.

[0091] Preferably, the post-treatment comprises: extracting the reaction system to obtain an organic phase, and 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.

[0092] Preferably, the solvent used in the extraction includes chloroform.

[0093] Preferably, the solvent used in the recrystallization comprises methyl tert-butyl ether.

[0094] Preferably, the preparation method comprises the following steps:

[0095] (1) N-BOC-4-piperidone and a solvent are mixed to obtain a mixed solution; a solution of allyl magnesium halide is added dropwise to the mixed solution at -5 to 5°C to obtain a reaction system, and then a Grignard reaction is performed at -5 to 30°C for 4 to 16 hours to obtain an intermediate 1; the molar ratio of the N-BOC-4-piperidone to the allyl magnesium halide is 1:(1 to 1.5);

[0096] (2) mixing a solvent and an alkaline agent to obtain a mixed solution; adding a solution of intermediate 1 and 3-halogenated propene to the mixed solution at 10 to 20° C. to obtain a reaction system, and then performing a substitution reaction at 45 to 55° C. for 8 to 24 hours to obtain intermediate 2; the molar ratio of intermediate 1, 3-halogenated propene and alkaline agent is 1:(1 to 2):(1 to 2.5);

[0097] (3) mixing the intermediate 2, the Grubbs catalyst and the solvent, and performing an olefin metathesis reaction at 25 to 100° C. for 6 to 24 hours to obtain the intermediate 3; the mass ratio of the intermediate 2 to the Grubbs catalyst is 1:(0.001 to 0.05);

[0098] (4) controlling the temperature to ≤20°C, adding nitric acid to the solvent to obtain a mixed solution; then controlling the temperature to ≤-5°C, adding a solution of intermediate 3 to the mixed solution to obtain a reaction system, and then performing a nitration reaction at -25 to 25°C for 2 to 12 hours to obtain intermediate 4; the molar ratio of intermediate 3 to nitric acid is 1:(1.5 to 3.5);

[0099] (5) Mixing the intermediate 4, a catalyst, a solvent and hydrogen, and performing a hydrogenation reduction reaction at 25 to 65° C. and 2 to 10 MPa for 8 to 48 hours to obtain an intermediate 5; the mass ratio of the intermediate 4 to the catalyst is 1:(0.05 to 0.5);

[0100] (6) adding a resolving agent to the solution of the intermediate 5, heating to 60-65° C. to dissolve, and then cooling to 20-25° C. to obtain a solid salt; re-dissolving the solid salt in water, adding an alkaline agent to adjust the pH to 10-12, and obtaining the (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester; the molar ratio of the intermediate 4 in step (5) to the resolving agent in step (6) is 1:(0.75-1.3).

[0101] Compared with the prior art, the present invention has at least the following beneficial effects:

[0102] The preparation method provided by the invention uses N-BOC-4-piperidone as a starting material, and obtains (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester through six process steps including Grignard reaction, substitution reaction, olefin metathesis reaction, nitration reaction, hydrogenation reduction reaction and chiral resolution. The preparation method has a short process route, simple operation, and does not generate a large amount of waste water and waste gas, and can achieve a high total product yield, chemical and chiral purity, and has a high industrial application value. DETAILED DESCRIPTION

[0103] For the convenience of understanding the present invention, the present invention lists the following embodiments. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0104] Example 1

[0105] A method for preparing (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester comprises the following steps:

[0106] (1) Tetrahydrofuran (20 L, 10 V) was added to a reaction kettle equipped with a mechanical stirrer, a condensing device and nitrogen protection, followed by the addition of N-BOC-4-piperidone (1992.5 g, 10.0 mol, 1 eq) as the starting material, and the reaction system was cooled to 0°C. 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 not to exceed 5°C during the addition process. After the addition was completed, the reaction system was continued at 0°C. The mixture was stirred for 2 h, and then the reaction system was naturally heated to 20°C and stirred. The reaction was monitored by TLC. 10 L of ammonium chloride solution was slowly added dropwise to the reactor for quenching. The organic phase was separated, and 5 L of methyl tert-butyl ether was added to the aqueous phase for extraction. The combined organic phase was washed with saturated brine and water in turn, and then 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 a light brown oily target intermediate 1, 2025 g of the product, and a yield of 89.1%;

[0107] Structural characterization data of intermediate 1:

[0108] 1 HNMR (400MHz, CDCl3) ppmδ: 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, 1.2Hz, 1H), 5.94 (dd, J=16.4, 1.2Hz, 1H).

[0109] (2) THF (12 L, 8 V) was pumped into a reaction kettle equipped with a mechanical stirrer and a heating device, and then sodium tert-butoxide (951 g, 9.9 mol, 1.5 eq) was added. The temperature of the entire reaction system was controlled below 15° C. The intermediate 1 (1500 g, 6.6 mol, 1.0 eq) was dissolved in 3 L of tetrahydrofuran and slowly added dropwise to the reaction kettle. After the addition was completed, the mixture was stirred for 2 h, and then 3-bromopropylene (958 g, 7.9 mol, 1 .2eq), then gradually raise the temperature of the reaction system to 50°C and stir overnight, and the reaction of the raw materials is completed when the central control detects; the reaction system is cooled to 25°C, 10L of water is pumped into the reactor and stirred, and then the organic phase is separated, the aqueous phase is extracted once with 10L of methyl tert-butyl ether, the organic phases are combined, washed with saturated brine and water in turn, and then dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure at 45°C until there is no droplet to obtain the target intermediate 2, the product is 1652g, and the yield is 93.6%;

[0110] (3) 15L of the above intermediate 2 (1550g, 5.8mol, 1.0eq) in dichloromethane was drawn into a reactor equipped with a mechanical stirrer and a heating device, and Grubbs first-generation catalyst (Cas172222-30-9, 7.8g, 5wt‰) was added under nitrogen protection, and then the reaction system was heated to a micro-reflux state and stirred overnight. The central control detected that the raw material was almost reacted; the reaction system was cooled to 25°C, the reaction solution was filtered twice with diatomaceous earth, and the filter cake was washed with dichloromethane until no product remained. The collected filtrate was concentrated to dryness under reduced pressure at 45°C, and the residue was purified by pulping with methyl tert-butyl ether to obtain a beige solid target intermediate 3, 1150g of product, and a yield of 82.9%;

[0111] (4) Add acetic anhydride (3.5L, 3.5V) to a reactor equipped with mechanical stirring, condensing device and nitrogen protection, cool the reaction system to -5°C, then slowly add concentrated nitric acid (450mL, 10.4mol, 2.5eq) under nitrogen atmosphere, control the temperature not to exceed 10°C during the addition, and cool the reaction system to -20°C after the addition is completed; dissolve the above intermediate 3 (1000g, 4.2mmol, 1eq) in acetic anhydride (about 1.5L), and then slowly add it to the reactor under nitrogen atmosphere. In this process, control the temperature of the reaction system below -5°C. After the addition is completed, continue to stir the reaction system, and continuously monitor the reaction progress until the raw materials are consumed; slowly put the reaction solution into the ice water prepared in advance (15L) and stirred continuously, then added 10L of saturated brine, then the aqueous phase was extracted with methyl tert-butyl ether 3 times, each time with 10L, the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure at 45°C, the residue was dissolved in dichloromethane (5L), triethylamine (230mL, 1.7mol, 0.4eq) was added at 0°C with stirring, then the temperature was raised to 25°C and continued to stir for 30min, then further diluted with dichloromethane (25L), washed with water, 10wt% hydrochloric acid, saturated sodium bicarbonate and brine in sequence, 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 the target intermediate 4, product 750g, yield 63.1%;

[0112] (5) The above intermediate 4 (625 g, 2.2 mol, 1 eq) and ethanol (3125 mL, 5 V) were added to a 5 L hydrogenation kettle, followed by the addition of 10% palladium carbon (125 g, 20 wt%), nitrogen replacement 3 times, hydrogen replacement 2 times, pressure 3 MPa, and the temperature was raised to 55 ° C. and stirred overnight. The reaction of the raw materials was completed by central control detection to obtain intermediate 5; the reaction system was cooled to 25 ° C. The reaction solution was filtered twice with diatomaceous earth pads, and the filter cake was washed with ethanol (3125 mL, 5 V) until no product remained. The collected filtrate was heated to 65 ° C. and then D-pyroglutamic acid (241 g, 1.9 mol, 0.85 eq) was added in batches. After the system was dissolved, the stirring was continued for 1 h, and then the temperature was lowered to 25 ° C. The solid was filtered and collected. The filtrate was concentrated under reduced pressure at 60 ° C. The residue after concentration was purified by HPLC. The mixture was dissolved again in 10 volumes of ethanol, heated to 65°C until the mixture became clear, and then stirred for 1 hour. The mixture was cooled to 25°C again, filtered and the solid was collected. The solids collected twice were combined and dissolved in a small amount of water. The pH was then adjusted to 11 with 5 wt % sodium hydroxide, and then extracted with chloroform for 3 times, each time with 100 mL of each solution. The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 55°C. The obtained solid was further crystallized with methyl tert-butyl ether and then dried at 50°C to obtain 185 g of the target product (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester as a white solid. The reduction yield was 85.2%, the single configuration resolution yield was 77.1%, and the product ee value was 99.8%. The recovered mother liquor could be re-dissolved to obtain more target products.

[0113] (R)-3-Amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester Structural characterization data:

[0114] 1 HNMR (400MHz, CDCl3) ppmδ: 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=7.6,5.6Hz,1H).

[0115] Example 2

[0116] (1) Add ethylene glycol dimethyl ether (20 L, 10 V) to a reactor equipped with mechanical stirring, a condensing device and nitrogen protection, then add N-BOC-4-piperidone (1992.5 g, 10.0 mol, 1 eq) as the starting material, cool the reaction system to 0°C, and slowly dropwise add 1 M allyl magnesium bromide tetrahydrofuran solution (12 L, 12.0 mol, 1.2 eq) under nitrogen protection. During the dropwise addition, control the temperature of the reaction system to not exceed 5°C. After the dropwise addition is completed, continue to The mixture was stirred at 0°C for 4 hours, and then the reaction system was naturally heated to 25°C and stirred. The reaction was monitored by TLC. 10 L of ammonium chloride solution was slowly added dropwise to the reaction kettle for quenching, and then 10 L of methyl tert-butyl ether was added for extraction. The combined organic phase was washed with saturated brine and water in turn, and then 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 a light brown oily target intermediate 1, 1960 g of the product, and a yield of 86.2%.

[0117] (2) 1,4-dioxane (12 L, 8 V) was pumped into a reaction kettle equipped with a mechanical stirrer and a 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 intermediate 1 (1500 g, 6.6 mol, 1.0 eq) was reacted with 3 L 1,4-dioxane was slowly added dropwise to the reactor, stirred for 2h after addition, and then 3-bromopropylene (958g, 7.9mol, 1.2eq) was added dropwise, and then the reaction system was gradually heated to 50°C and stirred overnight. The reaction of the raw materials was completed during the central control test; the reaction system was cooled to 25°C, 10L of water was pumped into the reactor and stirred, and then the organic phase was separated, and the aqueous phase was extracted once with 10L of methyl tert-butyl ether, the organic phases were combined, washed with saturated brine and water in turn, and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 45°C until there was no droplets to obtain the target intermediate 2, 1620g of product, and the yield was 91.8%;

[0118] (3) 15L of the above intermediate 2 (1550g, 5.8mol, 1.0eq) in n-heptane was drawn into a reactor equipped with a mechanical stirrer and a heating device, and Grubbs first-generation catalyst (Cas172222-30-9, 4.7g, 3wt‰) was added under nitrogen protection, and then the reaction system was heated to a micro-reflux state and stirred overnight. The central control detected that the raw material was almost reacted; the reaction system was cooled to 25°C, the reaction solution was filtered twice with diatomaceous earth, and the filter cake was washed with n-hexane until no product remained. The collected filtrate was concentrated to dryness under reduced pressure at 45°C, and the residue was purified by pulping with methyl tert-butyl ether to obtain a beige solid target intermediate 3, 1127g of product, and a yield of 81.2%;

[0119] (4) Add acetic acid (3.5 L, 3.5 V) to a reactor equipped with mechanical stirring, condensing device and nitrogen protection, cool the reaction system to -5 ° C, and then slowly add concentrated nitric acid (360 mL, 8.4 mol, 2 eq) under nitrogen atmosphere. The temperature is controlled not to exceed 10 ° C during the addition process. After the addition is completed, the reaction system is cooled to -20 ° C; the above intermediate 3 (1000 g, 4.2 mmol, 1 eq) is dissolved in acetic acid (about 1.5 L), and then slowly added to the reactor under nitrogen atmosphere. In this process, the temperature of the reaction system is controlled below -5 ° C. After the addition is completed, the reaction system continues to be stirred, and the central control continuously monitors the reaction progress until the raw materials are almost consumed; the reaction solution is slowly put into the ice water (1 5L) and stirred continuously, then 10L of saturated brine was added, and then the aqueous phase was extracted with methyl tert-butyl ether 3 times, each time with 10L, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C, the residue was dissolved in dichloromethane (5L), triethylamine (230mL, 1.7mol, 0.4eq) was added at 0°C and stirred, then the temperature was raised to 25°C and stirred for 30min, then further diluted with dichloromethane (25L), washed with water, 10wt% hydrochloric acid, saturated sodium bicarbonate and brine in sequence, the organic phase was dried over anhydrous sodium sulfate, filtered, and then filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure at 45°C to obtain the target intermediate 4, 708g of product, and a yield of 59.6%;

[0120] (5) The above intermediate 4 (625 g, 2.2 mol, 1 eq) and methanol (3125 mL, 5 V) were added to a 5 L hydrogenation kettle, followed by the addition of 10% palladium carbon (94 g, 15 wt%), nitrogen replacement 3 times, hydrogen replacement 2 times, pressure 5 MPa, and the temperature was raised to 45 ° C. and stirred overnight. The reaction of the raw materials was basically completed after the central control test, and the intermediate 5 was obtained; the reaction system was cooled to 25 ° C. The reaction solution was filtered twice with diatomaceous earth, and the filter cake was washed with methanol (3125 mL, 5 V) until no product remained. The collected filtrate was heated to a micro-reflux state, and then D-pyroglutamic acid (284 g, 2.2 mol, 1 eq) was added in batches. After the system was dissolved, the stirring was continued for 1 h, and then the temperature was lowered to 25 ° C. The solid was filtered and collected. The filtrate was concentrated under reduced pressure at 55 ° C. The residue after concentration was concentrated with The mixture was dissolved again in 10 volumes of ethanol, heated to 65°C until it became clear and stirred for 1 hour, cooled to 25°C again, filtered and the solid was collected; the solids collected twice were combined and dissolved in a small amount of water, then the pH was adjusted to 11 with 5wt% sodium hydroxide, and then extracted repeatedly with chloroform for 3 times, each time with 200mL of each time; the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure at 55°C; the obtained solid was further crystallized with methyl tert-butyl ether, and then dried at 50°C to obtain 180g of the target product (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester as a white solid, 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-disassembled to obtain more target products.

[0121] Example 3

[0122] (1) Tetrahydrofuran (20 L, 10 V) was added to a reaction kettle equipped with a mechanical stirrer, a condensing device and nitrogen protection, followed by the addition of N-BOC-4-piperidone (1992.5 g, 10.0 mol, 1 eq) as the starting material, and the reaction system was cooled to 0°C. Under nitrogen protection, a 1 M tetrahydrofuran solution of allyl magnesium chloride (15 L, 15.0 mol, 1.5 eq) was slowly added dropwise. The temperature of the reaction system was controlled not to exceed 5°C during the addition process. After the addition was completed, the reaction system was stirred at 0°C. Stir for 5 hours, then the reaction system is naturally heated to 25°C and stirred, and the reaction is completed by monitoring by TLC; 10L of ammonium chloride solution is slowly added dropwise to the reactor for quenching, the organic phase is separated, and the aqueous phase is extracted once by adding 8L of methyl tert-butyl ether, and the combined organic phase is washed with saturated brine and water in turn, and then dried over anhydrous sodium sulfate and filtered, and the organic phase is concentrated under reduced pressure in a constant temperature water bath at 45°C, and the residue is purified by distillation to obtain a light brown oily target intermediate 1, 2005g of the product, and the yield is 88.2%;

[0123] (2) THF (12 L, 8 V) was pumped into a reaction kettle equipped with a mechanical stirrer and a heating device, and then sodium hydride (343 g, 8.6 mol, 1.3 eq, 60% mineral oil) was added portion by portion. The temperature of the entire reaction system was controlled below 10° C. The intermediate 1 (1500 g, 6.6 mol, 1.0 eq) was dissolved in 3 L of tetrahydrofuran and slowly added dropwise to the reaction kettle. After the addition was completed, stirring was performed for 2 h, and then 3-bromopropylene (1038 g, 8.6 mol, 1.3 eq) was added dropwise. The reaction was then heated to 40° C. The system was gradually heated to 40°C and stirred for 12h. The central control detected that the raw materials were almost reacted. The reaction system was cooled to 0°C, and ice water was slowly pumped into the reactor to quench the reaction. In the early stage, it was slowly added and stirred continuously. About 15L of water was added to completely quench the reaction. The organic phase was then separated, and the aqueous phase was extracted once with 10L of methyl tert-butyl ether. The organic phases were combined, washed with saturated brine and water in turn, and then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 45°C until there was no droplet to obtain the target intermediate 2, 1450g of product, and the yield was 82.2%;

[0124] (3) 15L of the above intermediate 2 (1550g, 5.8mol, 1.0eq) in dichloromethane was drawn into a reactor equipped with a mechanical stirrer and a heating device, and Grubbs second-generation catalyst (Cas246047-72-3, 2.0g, 1.3wt‰) was added under nitrogen protection, and then the reaction system was heated to a micro-reflux state and stirred overnight. The central control detected that the raw materials were almost reacted; the reaction system was cooled to 25°C, the reaction solution was filtered twice with diatomaceous earth, the filter cake was washed with dichloromethane until no product remained, the collected filtrate was concentrated to dryness under reduced pressure at 45°C, and the residue was purified by pulping with methyl tert-butyl ether to obtain a beige solid target intermediate 3, 1048g of product, and a yield of 75.5%;

[0125] (4) Add acetic anhydride (3.5 L, 3.5 V) to a reactor equipped with mechanical stirring, condensing device and nitrogen protection, cool the reaction system to -5 ° C, and then slowly add concentrated nitric acid (630 mL, 14.6 mol, 3.5 eq) dropwise under nitrogen atmosphere, and control the temperature not to exceed 10 ° C during the addition process. After the addition is completed, cool the reaction system to -20 ° C; 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 reactor under nitrogen atmosphere. In this process, control the temperature of the reaction system below -5 ° C. After the addition is completed, continue to stir the reaction system, and continuously monitor the reaction progress until the raw materials are almost consumed; slowly put the reaction solution into the ice prepared in advance. Water (15L) and stirred continuously, then 10L of saturated brine was added, and then the aqueous phase was extracted with methyl tert-butyl ether 3 times, each time with 10L, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45°C, the residue was dissolved in dichloromethane (5L), triethylamine (230mL, 1.7mol, 0.4eq) was added at 0°C with stirring, then the temperature was raised to 25°C and continued to stir for 30min, then further diluted with dichloromethane (25L), washed with water, 10wt% hydrochloric acid, saturated sodium bicarbonate and brine in sequence, the organic phase was dried over anhydrous sodium sulfate, filtered, and then filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure at 45°C to obtain the target intermediate 4, 738g of product, and a yield of 62.1%;

[0126] (5) The above intermediate 4 (625 g, 2.2 mol, 1 eq) and ethanol (3125 mL, 5 V) were added to a 5 L hydrogenation reactor, followed by the addition of 5% ruthenium carbon (100 g, 16 wt%), nitrogen replacement 3 times, hydrogen replacement 2 times, pressure 3 MPa, and the temperature was initially raised to 55 ° C. The reaction was stirred for 36 h. The reaction of the raw materials was completed after the central control test to obtain intermediate 5; the reaction system was cooled to 25 ° C. The reaction solution was filtered twice with diatomaceous earth pads, and the filter cake was washed with ethanol (3125 mL, 5 V) until no product remained. The collected filtrate was heated to 65 ° C. D-mandelic acid (368 g, 2.4 mol, 1.1 eq) was then added in batches. After the system was dissolved, the stirring was continued for 1 h, and then the temperature was lowered to 25 ° C. The solid was filtered and collected. The filtrate was concentrated under reduced pressure at 60 ° C. The residue after concentration was purified by HPLC. The mixture was dissolved again in 10 volumes of ethanol, which was 10 times its mass. The system was heated to 65° C. and stirred for 1 h after the mixture was dissolved. The mixture was cooled to 25° C. again, and the solid was filtered and collected. The solids collected twice were combined and dissolved in a small amount of water. The pH was then adjusted to 11 with 5 wt % sodium hydroxide. The mixture was extracted 3 times with chloroform, each time with 150 mL of each. The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 55° C. The obtained solid was further crystallized with methyl tert-butyl ether and then dried at 50° C. to obtain 206 g of the target product (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester as a white solid. The reduction yield was 88.7%, the single configuration resolution yield was 82.4%, and the product ee value was 99.6%. The recovered mother liquor could be re-disassembled to obtain more target products.

[0127] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, characterized in that: The preparation method comprises the following steps: (1) N-BOC-4-piperidone reacts with allyl magnesium halide to obtain intermediate 1. The reaction formula is as follows: Wherein, X1 is selected from chlorine, bromine or iodine; (2) The intermediate 1 obtained in step (1) undergoes a substitution reaction with 3-halopropylene to obtain intermediate 2. The reaction formula is as follows: Wherein, X2 is selected from chlorine, bromine or iodine; (3) The intermediate 2 obtained in step (2) undergoes olefin metathesis reaction under the action of Grubbs' catalyst to obtain intermediate 3. The reaction formula is as follows: (4) The intermediate 3 obtained in step (3) undergoes a nitration reaction with nitric acid to obtain an intermediate 4. The reaction formula is as follows: (5) The intermediate 4 obtained in step (4) is subjected to a hydrogenation reduction reaction to obtain a racemic intermediate 5, and the reaction formula is as follows: (6) The intermediate 5 obtained in step (5) is subjected to chiral resolution with a resolving agent to obtain the (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, and the reaction formula is as follows:

2. The preparation method according to claim 1, characterized in that: The molar ratio of the N-BOC-4-piperidone to the allyl magnesium halide in step (1) is 1:(1-1.5); Preferably, the format reaction in step (1) is carried out in the presence of a solvent; Preferably, the solvent comprises any one or a combination of at least two of tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether or isopropyl ether; Preferably, the format reaction in step (1) is carried out under nitrogen protection; Preferably, after the format reaction in step (1) is completed, a quenching agent is added for quenching; Preferably, the quenching agent includes any one of ammonium chloride, dilute hydrochloric acid, glacial acetic acid or water, or a combination of at least two of them.

3. The preparation method according to claim 1 or 2, characterized in that: The material mixing method of the Grignard reaction in step (1) comprises: mixing N-BOC-4-piperidone and a solvent to obtain a mixed solution; adding a solution of allyl magnesium halide dropwise to the mixed solution to obtain a reaction system, and then performing a Grignard reaction; Preferably, the temperature of the dropping is -5 to 5°C; Preferably, the temperature of the format reaction in step (1) is -5 to 30°C; Preferably, the reaction time of the format in step (1) is 4 to 16 hours; Preferably, the format reaction in step (1) further comprises a post-processing step; Preferably, the post-treatment comprises: separating the reaction system to obtain an organic phase; washing the organic phase with a salt solution, washing with water, drying and concentrating 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 to 3, characterized in that In step (2), the molar ratio of the intermediate 1 to 3-halopropylene is 1:(1-2); Preferably, the substitution reaction in step (2) is carried out in the presence of an alkaline reagent; Preferably, the alkaline agent comprises any one or a combination of at least two of sodium tert-butoxide, potassium tert-butoxide, sodium hydride, or sodium bis(trimethylsilyl)amide; Preferably, the molar ratio of the intermediate 1 to the 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) comprises: mixing a solvent and an alkaline reagent to obtain a mixed solution; adding a solution of the intermediate 1 and 3-halogenated propene dropwise to the mixed solution to obtain a reaction system, and then performing a substitution reaction; Preferably, the temperature when the intermediate 1 and 3-halopropene are added dropwise is independently 10 to 20°C; Preferably, the temperature of the substitution reaction in step (2) is 45-55°C; Preferably, the substitution reaction time in step (2) is 8 to 24 hours; Preferably, the substitution reaction in step (2) further comprises a post-treatment step; Preferably, the post-treatment comprises: adding water to the reaction system and stirring, separating to obtain an organic phase; washing the organic phase with a salt solution, washing with water, drying and concentrating to obtain the intermediate 2.

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

6. The preparation method according to any one of claims 1 to 5, characterized in that: The molar ratio of the intermediate 3 to nitric acid in step (4) 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 comprises any one or a combination of at least two of acetic anhydride, acetic acid or ethylene dichloride; 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) comprises: sequentially adding nitric acid and a solution of the intermediate 3 to a solvent to obtain a reaction system, and then performing a nitration reaction; Preferably, the temperature of adding nitric acid is ≤20°C; Preferably, the temperature of the intermediate 3 solution added dropwise is ≤-5°C; Preferably, the temperature of the nitration reaction in step (4) is -25°C to 25°C; Preferably, the nitration reaction time in step (4) is 2 to 12 hours.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The nitration reaction in step (4) further comprises a post-treatment step; Preferably, the post-treatment comprises: slowly pouring the reaction system into ice water for quenching, then diluting with water and / or salt solution, extracting to obtain an organic phase, drying and concentrating the organic phase to obtain a crude product; re-dissolving the crude product, adding an alkaline substance, washing with water, acid washing, alkali washing and salt solution washing, separating the organic phase, drying, concentrating, 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 re-dissolution includes dichloromethane; Preferably, the alkaline substance comprises triethylamine or tetramethylpiperidine.

8. The preparation method according to any one of claims 1 to 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 carbon, platinum carbon or ruthenium carbon; Preferably, the mass ratio of the intermediate 4 to the 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 comprises any one of ethanol, methanol, or 1,4-dioxane or a combination of at least two thereof; Preferably, the material mixing method for the hydrogenation reduction reaction in step (5) comprises: mixing the intermediate 4, the solvent and the catalyst, and replacing them with nitrogen and hydrogen in sequence to obtain a reaction system; Preferably, the temperature of the hydrogenation reduction reaction in step (5) is 25 to 65° C. Preferably, the pressure of the hydrogenation reduction reaction in step (5) is 2 to 10 MPa; Preferably, the hydrogenation reduction reaction time in step (5) is 8 to 48 hours; Preferably, the hydrogenation reduction reaction in step (5) further comprises a post-treatment step; Preferably, the post-treatment comprises: filtering the reaction system with diatomaceous earth, washing the filter cake, and obtaining a filtrate containing the intermediate 5.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The resolving agent in step (6) comprises any one of D-pyroglutamic acid, D-mandelic acid or D-tartaric acid, or a combination of at least two thereof; Preferably, the molar ratio of the intermediate 4 in step (5) to the resolving agent in step (6) is 1:(0.75-1.3); Preferably, the specific method of splitting in step (6) comprises: adding a splitting agent to the solution system containing the intermediate 5 obtained in step (5), heating to dissolve, and then cooling to obtain a solid salt; re-dissolving the solid salt in water, adding an alkaline agent 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°C; Preferably, the temperature is lowered to 20-25°C; Preferably, the splitting in step (6) further comprises a post-processing step; Preferably, the post-treatment comprises: 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 in the recrystallization comprises methyl tert-butyl ether.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The preparation method comprises the following steps: (1) N-BOC-4-piperidone and a solvent are mixed to obtain a mixed solution; a solution of allyl magnesium halide is added dropwise to the mixed solution at -5 to 5°C to obtain a reaction system, and then a Grignard reaction is performed at -5 to 30°C for 4 to 16 hours to obtain an intermediate 1; the molar ratio of the N-BOC-4-piperidone to the allyl magnesium halide is 1:(1 to 1.5); (2) mixing a solvent and an alkaline agent to obtain a mixed solution; adding a solution of intermediate 1 and 3-halogenated propene to the mixed solution at 10 to 20° C. to obtain a reaction system, and then performing a substitution reaction at 45 to 55° C. for 8 to 24 hours to obtain intermediate 2; the molar ratio of intermediate 1, 3-halogenated propene and alkaline agent is 1:(1 to 2):(1 to 2.5); (3) mixing the intermediate 2, the Grubbs catalyst and the solvent, and performing an olefin metathesis reaction at 25 to 100° C. for 6 to 24 hours to obtain the intermediate 3; the mass ratio of the intermediate 2 to the Grubbs catalyst is 1:(0.001 to 0.05); (4) controlling the temperature to ≤20°C, adding nitric acid to the solvent to obtain a mixed solution; then controlling the temperature to ≤-5°C, adding a solution of intermediate 3 to the mixed solution to obtain a reaction system, and then performing a nitration reaction at -25 to 25°C for 2 to 12 hours to obtain intermediate 4; the molar ratio of intermediate 3 to nitric acid is 1:(1.5 to 3.5); (5) Mixing the intermediate 4, a catalyst, a solvent and hydrogen, and performing a hydrogenation reduction reaction at 25 to 65° C. and 2 to 10 MPa for 8 to 48 hours to obtain an intermediate 5; the mass ratio of the intermediate 4 to the catalyst is 1:(0.05 to 0.5); (6) adding a resolving agent to the solution of the intermediate 5, heating to 60-65° C. to dissolve, and then cooling to 20-25° C. to obtain a solid salt; re-dissolving the solid salt in water, adding an alkaline agent to adjust the pH to 10-12, and obtaining the (R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester; the molar ratio of the intermediate 4 in step (5) to the resolving agent in step (6) is 1:(0.75-1.3).

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