Synthesis method for tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate

Abstract

The present invention provides a synthesis method for tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate. The synthesis method comprises the following steps: N-Boc-4-piperidone and trimethyl phosphonoacetate undergo a witting reaction to obtain an intermediate 1; the intermediate 1 and acetonitrile undergo an addition reaction to obtain an intermediate 2; the intermediate 2 undergoes hydrogenation reduction and aminolysis of esters to obtain an intermediate 3; and the intermediate 3 undergoes a reduction reaction to obtain tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate. The overall method of the present invention features a short route, mild reaction conditions, high product purity, and high yield, and is suitable for industrial production.

Description

A method for synthesizing tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate. Technical Field

[0001] This invention belongs to the field of compound synthesis technology and relates to a method for synthesizing tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate. Background Technology

[0002] 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester has been proven to be a key fragment in some bioactive drugs. Drug molecules containing this fragment can be used to treat CCR8 receptor-related diseases and can also be used as non-peptide glycoprotein antagonists for the prevention of thrombosis. US Patent 6291469 reports a method for synthesizing 3-benzyl-3,9-diazaspirocyclic[5.5]undecane. The method uses N-benzylpiperidin-4-one as the starting material, which reacts with ethyl cyanoacetate in an alcoholic solution of ammonia at low temperature for a long time to generate dicyanocarbodiimide. Then, it is acidically hydrolyzed to obtain a diacid, which is then cyclized with urea at high temperature to obtain an amide, and finally reduced with lithium aluminum hydride to obtain the target product. Patents WO2010108651 and WO2015096035, based on the aforementioned intermediate diacid, involve esterification, reduction, replacing the benzyl group with a Boc protecting group, adding a bis(methanesulfonyl) group (Ms), cyclization with benzylamine, and finally reduction on palladium carbon to remove the benzyl group and obtain the target product. This method is significantly more cumbersome than the previous one. Domestic patent CN101255159 also uses N-benzylpiperidin-4-one and ethyl cyanoacetate as starting materials to synthesize dicyanocarbodiimide, followed by acidic hydrolysis and selective deacidification to obtain carbodiimide. Reduction with lithium aluminum hydride yields a diamine with one benzyl-protected end and one exposed end, which is then protected with Boc and reduced by hydrogenation on palladium carbon to remove the benzyl group and obtain the target product. In the existing reported synthetic methods, the cyclization yield is low, high-temperature conditions are required for the formation of the diimide, and flammable lithium aluminum hydride is used for reduction, all of which pose dangers for large-scale production operations.

[0003] Therefore, in this field, there is a desire to develop a synthetic method that has short synthetic steps, mild reaction conditions, few impurities, high purity and yield, and is conducive to large-scale industrial production. Summary of the Invention

[0004] In view of the shortcomings of the prior art, the purpose of this invention is to provide a method for synthesizing tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0005] To achieve this objective, the present invention adopts the following technical solution:

[0006] On one hand, the present invention provides a method for synthesizing tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, the method comprising the following steps:

[0007] (1) N-Boc-4-piperidinone (SM) reacts with trimethyl phosphonoacetate via a witting reaction to give intermediate 1, as shown in the following reaction formula:

[0008] ;

[0009] (2) Intermediate 1 undergoes an addition reaction with acetonitrile to obtain intermediate 2, as shown in the following reaction formula:

[0010] ;

[0011] (3) Intermediate 2 undergoes hydrogenation reduction and amine transesterification to obtain intermediate 3; the reaction formula is as follows:

[0012] ;

[0013] (4) Intermediate 3 is reduced to obtain tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (abbreviated as TM), and the reaction formula is as follows:

[0014] .

[0015] The present invention has a short synthesis step, mild reaction conditions, few impurities, high purity and yield, which is conducive to large-scale process production.

[0016] Preferably, the molar ratio of N-Boc-4-piperidinone to trimethyl phosphonoacetate in step (1) is 1:1 to 1:2.0, for example, 1:1, 1:1.3, 1:1.5, 1:1.8 or 1:2.0.

[0017] Preferably, the witting reaction in step (1) is carried out in the presence of an alkaline substance.

[0018] Preferably, the alkaline substance is selected from one or a combination of at least two of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, or sodium ethoxide.

[0019] Preferably, the molar ratio of the alkaline substance to N-Boc-4-piperidinone is 1.1:1 to 2.5:1, for example, 1.1:1, 1.3:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.4:1 or 2.5:1.

[0020] Preferably, the witting reaction in step (1) is carried out in an organic solvent selected from any one or a combination of at least two of tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, or N,N-dimethylformamide.

[0021] Preferably, the temperature of the witting reaction in step (1) is 0~25℃, for example 0℃, 5℃, 8℃, 10℃, 13℃, 15℃, 18℃, 20℃, 23℃ or 25℃.

[0022] Preferably, the witting reaction time in step (1) is 6 to 24 hours, for example, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours or 24 hours.

[0023] Preferably, the witting reaction in step (1) is carried out under the protection of a protective gas, preferably nitrogen.

[0024] Preferably, the specific operation of the witting reaction in step (1) is as follows: add an alkaline substance to an organic solvent, add trimethyl phosphonoacetate dropwise under a protective gas atmosphere, keep warm after the addition is complete, and then add N-Boc piperidinone solution dropwise to the system. After the addition is complete, react under stirring to obtain the intermediate 1.

[0025] Preferably, when adding trimethyl phosphonoacetate, the system temperature is controlled to be -5℃ to 0℃, for example -5℃, -3℃, -1℃ or 0℃.

[0026] Preferably, after the addition of trimethyl phosphonoacetate is completed, the mixture is kept at 0~5℃ (e.g., 0℃, 1℃, 3℃ or 5℃) for 1 hour.

[0027] Preferably, the solvent in the N-Boc piperidone solution is selected from tetrahydrofuran.

[0028] Preferably, when adding the N-Boc piperidone solution, the system temperature is controlled at 0~5℃, for example, 0℃, 1℃, 3℃ or 5℃.

[0029] After the N-Boc piperidone solution is added dropwise as described above, the reaction is carried out under stirring, which is the start of the witting reaction. The reaction temperature is controlled at 0~25℃.

[0030] Preferably, the molar ratio of intermediate 1 to acetonitrile in step (2) is 1:1.5 to 1:4.0, for example, 1:1.5, 1:2.0, 1:2.3, 1:2.5, 1:2.8, 1:3.0, 1:3.5 or 1:4.0.

[0031] Preferably, the addition reaction in step (2) is carried out in the presence of a catalyst.

[0032] Preferably, the catalyst is any one of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine (DABCO), or 4-dimethylaminopyridine (DMAP).

[0033] Preferably, the molar ratio of the catalyst to intermediate 1 is 1.1:1 to 2.5:1, for example, 1.1:1, 1.3:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.4:1 or 2.5:1.

[0034] Preferably, the temperature of the addition reaction in step (2) is 20~80℃, for example 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 60℃, 70℃ or 80℃, and the reaction time is 6~24h, for example 6h, 8h, 10h, 13h, 15h, 18h, 20h, 22h or 24h.

[0035] Preferably, in step (3), the hydrogenation reduction to intermediate 2 is reacted with hydrogen under the action of palladium on carbon.

[0036] Preferably, the amount of palladium on carbon is 5% to 50% of the mass of intermediate 2, for example, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%.

[0037] Preferably, the hydrogenation reduction in step (3) is carried out at a pressure of 2 to 5 MPa (e.g., 2 MPa, 3 MPa, 4 MPa or 5 MPa).

[0038] Preferably, the hydrogenation reduction and amine ester exchange in step (3) are carried out at 20-80°C (e.g., 20°C, 22°C, 24°C, 25°C, 26°C, 28°C, 30°C, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C or 80°C).

[0039] Preferably, the hydrogenation reduction and amine ester exchange reaction in step (3) takes 6 to 48 hours, for example, 6 hours, 8 hours, 10 hours, 16 hours, 20 hours, 24 hours, 36 hours or 48 hours.

[0040] In this invention, the hydrogenation reduction and amine-ester exchange reaction are completed in one step.

[0041] Preferably, the reducing agent used in the reduction reaction in step (4) is borane.

[0042] Preferably, the reduction reaction in step (4) is carried out in an organic solvent.

[0043] Preferably, the organic solvent is selected from ether-based organic solvents; more preferably tetrahydrofuran and / or diethyl ether.

[0044] Preferably, the reduction reaction in step (4) is carried out at room temperature (15~65℃, for example 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 55℃ or 65℃), and the reduction reaction takes 6~24h, for example 6h, 8h, 10h, 12h, 15h, 18h, 20h or 24h.

[0045] As a preferred embodiment of the present invention, the synthesis method includes the following steps:

[0046] (1) Under the protection of a protective gas, N-Boc-4-piperidinone and trimethyl phosphonoacetate are reacted in a molar ratio of 1:1 to 1:2.0 in the presence of an alkaline substance to obtain intermediate 1; wherein the alkaline substance is selected from one or a combination of at least two of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide or sodium ethoxide, and the molar ratio of the alkaline substance to N-Boc-4-piperidinone is 1.1:1 to 2.5:1. The witting reaction in step (1) is carried out in an organic solvent, and the organic solvent is selected from any one or a combination of at least two of tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether or N,N-dimethylformamide. The temperature of the witting reaction in step (1) is 0 to 25°C, and the reaction time is 6 to 24 h.

[0047] (2) Intermediate 1 and acetonitrile are reacted in the presence of a catalyst at a molar ratio of 1:1.5 to 1:4.0. The reaction temperature is 20 to 80°C and the reaction time is 6 to 24 h to obtain intermediate 2. The molar ratio of the catalyst to intermediate 1 is 1.1:1 to 2.5:1.

[0048] (3) Intermediate 2 is subjected to hydrogenation reduction and amine-ester exchange reaction with hydrogen under the action of palladium on carbon at 20~80℃ and 2~5MPa for 6~48h to obtain intermediate 3; wherein the amount of palladium on carbon is 5%~50% of the mass of intermediate 2;

[0049] (4) Intermediate 3 is reduced by a reducing agent to obtain tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate. The reducing agent is borane, diisobutylaluminum hydride or lithium aluminum hydride. The reduction is carried out at 15-65°C for 6-24 hours.

[0050] Compared with the prior art, the present invention has the following beneficial effects:

[0051] This invention uses N-Boc-4-piperidinone as the starting material, reacting it with trimethyl phosphonoacetate via a witting reaction to form intermediate 1. This intermediate is then added to acetonitrile to obtain intermediate 2, followed by hydrogenation reduction and a one-step amino-ester exchange reaction under heating to obtain intermediate 3. The carbonyl group of intermediate 3 is then reduced by a reducing agent to obtain the target product. The entire method has a short route, mild reaction conditions, and high product purity and yield, making it suitable for industrial production. Detailed Implementation

[0052] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0053] Example 1

[0054] Preparation of intermediate 1:

[0055] This embodiment provides a method for synthesizing tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, the synthesis method comprising the following steps:

[0056] first step

[0057] Add 1400 mL of tetrahydrofuran to a 3 L reaction flask, followed by potassium tert-butoxide (101.4 g, 0.904 mol, 1.2 eq). After the addition is complete, purge with nitrogen and cool to -5 to 0 °C under nitrogen protection. Slowly add trimethyl phosphoroacetate (165 g, 0.906 mol, 1.2 eq) dropwise through a dropping funnel, keeping the temperature below 0 °C throughout the addition. Incubate at this temperature for 1 hour after the addition is complete. Then, begin adding 400 mL of a tetrahydrofuran solution of N-Boc piperidinone (150 g, 0.753 mol, 1.0 eq) at 0 °C, keeping the temperature below 5 °C throughout the process. After the addition is complete, slowly raise the temperature to 25 °C and stir for 16 hours. Monitor the reaction for completeness using TLC. The reaction solution was slowly poured into 500 mL of 10 wt% hydrochloric acid for quenching, followed by the addition of 700 mL of ethyl acetate and stirring for 10 minutes. After standing and separating the layers, the aqueous phase was extracted once again with 360 mL of ethyl acetate. The combined organic layers were washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure in a constant temperature water bath at 50 °C to obtain 175 g of pale yellow target intermediate 1 solid, with a yield of 91.0%. 1 HNMR (400MHz, CDCl3) ppm δ: 1.51 (s, 9H), 2.28 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 6.8 Hz, 2H), 3.46 - 3.58 (m, 4H), 3.74 (s, 3H), 5.76 (s, 1H).

[0058] Step 2

[0059] Intermediate 1 (100 g, 0.392 mol, 1.0 eq) and DMF (1000 mL, 10V) were added to a 2L reaction flask equipped with a mechanical stirrer and heater. Acetonitrile (40.2 g, 0.978 mol, 2.5 eq) was then added, followed by slow dropwise addition of DBU (71.6 g, 0.470 mol, 1.2 eq) while stirring. After the addition was complete, the reaction system was gradually heated to 60°C and stirred for 16 hours. The starting material was almost completely eliminated by the monitoring system. The reaction system was then cooled to 25°C, and 1L of water and 1L of ethyl acetate were added. After stirring, the organic phase was separated. The aqueous phase was extracted once more with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50 °C until no droplets remained. The residue was purified by washing with silica gel column using an ethyl acetate / n-hexane system at a volume ratio of 1 / 30 to 1 / 20. 80 g of the target intermediate 2 product was obtained, with a yield of 68.9%.

[0060] Step 3

[0061] Intermediate 2 (150 g, 0.506 mol, 1 eq) and methanol (1500 mL, 10V) were added to a 3L hydrogenation reactor, followed by 10% palladium on carbon (30 g, 20wt%). The reactor was purged with nitrogen three times and hydrogen twice. The reaction system pressure was 3 MPa. The temperature was initially raised to 55°C and stirred for 2 days. The reaction mixture was monitored until the reactants had almost completely reacted. The reaction system was then cooled to room temperature. The reaction solution was filtered twice with diatomaceous earth. The filter cake was washed with ethanol until no product residue remained. The collected filtrate was concentrated to dryness under reduced pressure at 50°C. The residue was evaporated once with 300 mL of dichloromethane and then purified by slurrying with methyl tert-butyl ether to obtain 113 g of white solid target intermediate 3, yield: 83.2%.

[0062] Step 4

[0063] Intermediate 3 (100 g, 0.373 mmol, 1 eq) was dissolved in THF (1000 mL, 10V). The reaction system was cooled in an ice bath, and a borane tetrahydrofuran solution (745 mL, 0.745 mmol, 2 eq, 1M tetrahydrofuran solution) was slowly added dropwise under nitrogen protection. After the addition was complete, the reaction system was allowed to rise to room temperature and stirred for 16 h. Then, the temperature was raised to 55 °C and stirred for another 2 h. The reaction was monitored until the reactants were almost completely reacted. The reaction system was cooled to room temperature, and the reaction was quenched with 10 wt% hydrochloric acid. Most of the tetrahydrofuran was removed by concentration under reduced pressure. The remaining aqueous phase was adjusted to alkalinity with saturated sodium bicarbonate, and then extracted repeatedly with ethyl acetate until no product residue remained. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C. The residue was then purified by slurrying with methyl tert-butyl ether and dried under vacuum at 30 °C for 5 h to obtain 75 g of the target product TM as a white solid, with a yield of 79.1%. 1 HNMR (400MHz, CDCl3) ppm δ: 1.41 (brs, 17H), 2.28 (s, 1H), 2.80 (t, J = 5.2 Hz, 4H), 3.36 (t, J = 5.2 Hz, 4H).

[0064] Example 2

[0065] first step

[0066] Add 1400 mL of tetrahydrofuran to a 3 L reaction flask, followed by sodium ethoxide (128.1 g, 1.882 mol, 2.5 eq). After the addition, purge with nitrogen and cool to -5 to 0 °C under nitrogen protection. Slowly add trimethyl phosphoroacetate (205.7 g, 1.129 mol, 1.5 eq) dropwise through a dropping funnel, keeping the temperature below 0 °C throughout the addition. Incubate at this temperature for 1 hour after the addition is complete. Then, begin adding 400 mL of a tetrahydrofuran solution of N-Boc piperidinone (150 g, 0.753 mol, 1.0 eq) at 0 °C, keeping the temperature below 5 °C throughout the process. After the addition is complete, slowly raise the temperature to 25 °C and stir for 20 hours. Monitor the reaction for completeness using TLC. The reaction solution was slowly poured into 500 mL of 15 wt% hydrochloric acid for quenching, followed by the addition of 700 mL of ethyl acetate and stirring for 10 minutes. After standing and separating the layers, the aqueous phase was extracted once again with 360 mL of ethyl acetate. The combined organic layers were washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure in a constant temperature water bath at 50 °C to obtain 155 g of pale yellow target intermediate 1 solid, with a yield of 80.6%.

[0067] Step 2

[0068] Intermediate 1 (100 g, 0.392 mol, 1.0 eq) and DMF (1000 mL, 10V) were added to a 2L reaction flask equipped with a mechanical stirrer and heater. Acetonitrile (56.3 g, 1.371 mol, 3.5 eq) was then added, followed by slow dropwise addition of DBU (89.5 g, 0.588 mol, 1.5 eq) with stirring. After the addition was complete, the reaction system was stirred at 25°C for 16 h. A monitoring test showed that some reactants remained. The temperature was then raised to 50°C and stirring continued for 6 h, after which the reactants were almost completely eliminated. The reaction system was cooled to 25°C, and 1L of water and 1L of ethyl acetate were added. After stirring, the organic phase was separated. The aqueous phase was extracted once more with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50 °C until no droplets remained. The residue was purified by washing with silica gel column using an ethyl acetate / n-hexane system at a volume ratio of 1 / 30 to 1 / 20. 75 g of the target intermediate 2 product was obtained, with a yield of 64.6%.

[0069] Step 3

[0070] Intermediate 2 (150 g, 0.506 mol, 1 eq) and ethanol (1500 mL, 10V) were added to a 3L hydrogenation reactor, followed by 10% palladium on carbon (30 g, 20wt%). The reactor was purged with nitrogen three times and hydrogen twice. The reaction system pressure was 2.5 MPa. The temperature was initially raised to 65℃ and stirred for 36 h. The reaction mixture was monitored until the reactants were almost completely reacted. The reaction system was then cooled to 25℃. The reaction mixture was filtered twice with diatomaceous earth. The filter cake was washed with ethanol until no product residue remained. The collected filtrate was concentrated to dryness under reduced pressure at 50℃. The residue was evaporated once with 300 mL of dichloromethane and then purified by slurrying with methyl tert-butyl ether to obtain 116 g of white solid target intermediate 3, yield: 85.4%.

[0071] Step 4

[0072] Intermediate 3 (100 g, 0.373 mmol, 1 eq) was dissolved in THF (1000 mL, 10 V). The reaction system was cooled in an ice bath, and borane dimethyl sulfide (82 mL, 0.820 mmol, 2.2 eq, 10 M dimethyl sulfide solution) was slowly added dropwise under nitrogen protection. After the addition was complete, the reaction system was allowed to rise naturally to room temperature and stirred for 16 h, followed by reflux and stirring for 1 h. The reaction was monitored until the reactants were almost completely reacted. The reaction system was cooled to room temperature, and the reaction was quenched with 10 wt% hydrochloric acid. The mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. The remaining aqueous phase was adjusted to alkalinity with saturated sodium bicarbonate, and then extracted repeatedly with ethyl acetate until no product residue remained. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C. The residue was then purified by slurrying with methyl tert-butyl ether and dried under vacuum at 30 °C for 5 h to obtain 70 g of the target product TM as a white solid, with a yield of 73.8%.

[0073] Example 3

[0074] first step

[0075] 1200 mL of ethylene glycol dimethyl ether was added to a 3 L reaction flask, followed by sodium tert-butoxide (108.5 g, 1.129 mol, 1.5 eq). After the addition was complete, nitrogen was used to purge the atmosphere, and the temperature was lowered to -5 to 0 °C under nitrogen protection. Trimethyl phosphoroacetate (205.7 g, 1.129 mol, 1.5 eq) was slowly added dropwise through a dropping funnel, with the temperature controlled below 0 °C throughout the addition. The mixture was kept at this temperature for 1 hour after the addition was complete. Then, a 300 mL solution of N-Boc piperidinone (150 g, 0.753 mol, 1.0 eq) in ethylene glycol dimethyl ether was added dropwise at 0 °C, with the temperature controlled below 5 °C throughout the process. After the addition was complete, the temperature was slowly raised to 25 °C and stirred for 16 hours. The reaction was monitored by TLC until complete. The reaction solution was slowly poured into 500 mL of 10 wt% hydrochloric acid for quenching, followed by the addition of 500 mL of water and 800 mL of ethyl acetate. The mixture was stirred for 10 minutes, allowed to stand and separate into layers, and the aqueous phase was extracted once more with 500 mL of ethyl acetate. The combined organic layers were washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure in a constant temperature water bath at 50 °C to obtain 170 g of pale yellow target intermediate 1 solid, with a yield of 88.4%.

[0076] Step 2

[0077] Intermediate 1 (100 g, 0.392 mol, 1.0 eq) and DMF (1000 mL, 10V) were added to a 2L reaction flask equipped with a mechanical stirrer and heater. Acetonitrile (40.2 g, 0.978 mol, 2.5 eq) was then added, followed by slow dropwise addition of DABCO (87.8 g, 0.783 mol, 2.0 eq) while stirring. After the addition was complete, the reaction system was gradually heated to 80℃ and stirred for 16 hours. The starting material was almost completely eliminated by the monitoring system. The reaction system was then cooled to 25℃, and 1L of water and 1L of ethyl acetate were added. After stirring, the organic phase was separated. The aqueous phase was extracted once more with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50 °C until no droplets remained. The residue was purified by washing with silica gel column using an ethyl acetate / n-hexane system at a volume ratio of 1 / 30 to 1 / 20. 62 g of the target intermediate 2 product was obtained, with a yield of 53.4%.

[0078] Step 3

[0079] Intermediate 2 (150 g, 0.506 mol, 1 eq) and methanol (1500 mL, 10V) were added to a 3L hydrogenation reactor, followed by 10% palladium on carbon (75 g, 50wt%). The reactor was purged with nitrogen three times and hydrogen twice. The reaction system pressure was 5 MPa, and the reaction was stirred at 25°C for 14 h. The temperature was then increased to 60°C and the reaction continued for 10 h. The reaction was monitored at the control panel until the reactants had almost completely reacted. The reaction system was cooled to room temperature, and the reaction liquid was filtered twice with diatomaceous earth. The filter cake was washed with methanol until no product residue remained. The collected filtrate was concentrated to dryness under reduced pressure at 50°C. The residue was evaporated once with 300 mL of dichloromethane and then purified by slurrying with methyl tert-butyl ether to obtain 110 g of white solid target intermediate 3, yield: 81.0%.

[0080] Step 4

[0081] Intermediate 3 (100 g, 0.373 mol, 1 eq) was dissolved in THF (1000 mL, 10 V). The reaction system was cooled in an ice bath, and a tetrahydrofuran solution of diisobutylaluminum hydride (745 mL, 0.745 mol, 2 eq, 1 M tetrahydrofuran solution) was slowly added dropwise under nitrogen protection. After the addition was complete, the reaction system was allowed to rise naturally to room temperature and stirred for 24 h. The reaction was monitored at the control point and the raw materials were almost completely reacted. The reaction was quenched with 10 wt% hydrochloric acid. The solid was filtered, and the filtrate was concentrated under reduced pressure to remove most of the tetrahydrofuran. The remaining aqueous phase was adjusted to alkalinity with saturated sodium bicarbonate, and then extracted repeatedly with ethyl acetate until no product residue remained. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50 °C. The residue was then purified by slurrying with methyl tert-butyl ether and dried under vacuum at 30 °C for 5 h to obtain 60 g of the target product TM as a white solid, with a yield of 63.3%.

[0082] Example 4

[0083] The preparation of intermediate 1 includes the following steps:

[0084] Add 1400 mL of tetrahydrofuran to a 3 L reaction flask, followed by potassium tert-butoxide (169 g, 1.506 mol, 2.0 eq). After the addition, purge with nitrogen and cool to -5 to 0 °C under nitrogen protection. Slowly add trimethyl phosphoroacetate (274 g, 1.506 mol, 2.0 eq) dropwise through a dropping funnel, keeping the temperature below 0 °C throughout the addition. Incubate at this temperature for 1 hour after the addition is complete. Then, begin adding a 400 mL solution of N-Boc piperidinone (150 g, 0.753 mol, 1.0 eq) in tetrahydrofuran at 0 °C, maintaining the temperature below 5 °C throughout the process. After the addition is complete, slowly raise the temperature to 25 °C and stir for 16 h. Monitor the reaction for completeness using TLC. The reaction solution was slowly poured into 500 mL of 10 wt% hydrochloric acid for quenching, followed by the addition of 700 mL of ethyl acetate and stirring for 10 minutes. After standing and separating the layers, the aqueous phase was extracted once again with 360 mL of ethyl acetate. The combined organic layers were washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure in a constant temperature water bath at 50 °C to obtain 180 g of pale yellow target intermediate 1 solid, with a yield of 93.7%.

[0085] Example 5

[0086] The preparation of intermediate 2 from intermediate 1 includes the following steps:

[0087] Intermediate 1 (100 g, 0.392 mol, 1.0 eq) and DMF (1000 mL, 10V) were added to a 2 L reaction flask equipped with a mechanical stirrer and heater. Acetonitrile (24.1 g, 0.588 mol, 1.5 eq) was then added, followed by slow dropwise addition of DBU (71.6 g, 0.470 mol, 1.2 eq) while stirring. After the addition was complete, the reaction system was gradually heated to 55 °C and stirred for 16 h. A small amount of reactants remained as detected by the control system. The reaction system was then cooled to 25 °C, and 1 L of water and 1 L of ethyl acetate were added. After stirring, the organic phase was separated. The aqueous phase was extracted once more with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50 °C until no droplets remained. The residue was purified by washing with silica gel column using an ethyl acetate / n-hexane system at a volume ratio of 1 / 30 to 1 / 20. 65 g of the target intermediate 2 product was obtained, with a yield of 56.0%.

[0088] Example 6

[0089] The preparation of intermediate 2 from intermediate 1 includes the following steps:

[0090] Intermediate 1 (100 g, 0.392 mol, 1.0 eq) and DMF (1000 mL, 10V) were added to a 2L reaction flask equipped with a mechanical stirrer and heater. Acetonitrile (64.3 g, 1.567 mol, 4.0 eq) was then added, followed by slow dropwise addition of DBU (71.6 g, 0.470 mol, 1.2 eq) with stirring. After the addition was complete, the reaction system was gradually heated to 65°C and stirred for 16 hours. The starting material was almost completely eliminated by monitoring. The reaction system was then cooled to 25°C, and 1L of water and 1L of ethyl acetate were added. After stirring, the organic phase was separated. The water was extracted once more with 500 ml of ethyl acetate. The organic phases were combined, washed with saturated brine and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50 °C until no droplets remained. The residue was purified by washing with silica gel column. The solvent used was an ethyl acetate / n-hexane system with a volume ratio of 1 / 30 to 1 / 20. 76 g of the target intermediate 2 product was obtained, with a yield of 65.5%.

[0091] The applicant declares that the above embodiments illustrate the synthesis method of the present invention, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for synthesizing tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, characterized in that, The synthesis method includes the following steps: (1) N-Boc-4-piperidinone reacts with trimethyl phosphonoacetate via a witting reaction to give intermediate 1, as shown in the following reaction formula: ; (2) Intermediate 1 undergoes an addition reaction with acetonitrile to obtain intermediate 2, as shown in the following reaction formula: ; (3) Intermediate 2 undergoes hydrogenation reduction and amine transesterification to obtain intermediate 3; the reaction formula is as follows: ; (4) Intermediate 3 was reduced to obtain the tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, as shown in the following reaction formula: 。 2. The synthesis method according to claim 1, characterized in that, The molar ratio of N-Boc-4-piperidinone to trimethyl phosphonoacetate in step (1) is 1:1 to 1:2.0; Preferably, the witting reaction in step (1) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance is selected from one or a combination of at least two of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, or sodium ethoxide. Preferably, the molar ratio of the alkaline substance to N-Boc-4-piperidinone is 1.1:1 to 2.5:1; 3. The synthesis method according to claim 1 or 2, characterized in that, The witting reaction in step (1) is carried out in an organic solvent selected from any one or at least a combination of two of tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether or N,N-dimethylformamide; Preferably, the temperature of the witting reaction in step (1) is 0~25℃; Preferably, the witting reaction time in step (1) is 6~24h; Preferably, the witting reaction in step (1) is carried out under the protection of a protective gas, preferably nitrogen.

4. The synthesis method according to any one of claims 1-3, characterized in that, The specific operation of the witting reaction in step (1) is as follows: add an alkaline substance to an organic solvent, add trimethyl phosphonoacetate dropwise under a protective gas atmosphere, keep warm after the addition is complete, and then add N-Boc piperidinone solution dropwise to the system. After the addition is complete, react under stirring to obtain intermediate 1.

5. The synthesis method according to claim 4, characterized in that, When adding trimethyl phosphonoacetate, the system temperature is controlled to be -5℃ to 0℃; Preferably, after the addition of trimethyl phosphonoacetate is completed, the mixture is kept at 0-5°C for 1-3 hours. Preferably, the solvent in the N-Boc piperidinone solution is selected from tetrahydrofuran; Preferably, the system temperature is controlled at 0~5℃ when the N-Boc piperidone solution is added dropwise.

6. The synthesis method according to claim 1, characterized in that, In step (2), the molar ratio of intermediate 1 to acetonitrile is 1:1.5 to 1:4.0; Preferably, the addition reaction in step (2) is carried out in the presence of a catalyst; Preferably, the catalyst is 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, or 4-dimethylaminopyridine; Preferably, the molar ratio of the catalyst to intermediate 1 is 1.1:1 to 2.5:

1.

7. The synthesis method according to claim 1, characterized in that, The temperature of the addition reaction in step (2) is 20~80℃ and the reaction time is 6~24h.

8. The synthesis method according to claim 1, characterized in that, In step (3), the hydrogenation reduction to intermediate 2 reacts with hydrogen gas under the action of palladium on carbon; Preferably, the amount of palladium on carbon is 5% to 50% of the mass of intermediate 2; Preferably, the hydrogenation reduction in step (3) is carried out at a pressure of 2-5 MPa; Preferably, the amine-ester exchange reaction in step (3) is carried out at a temperature of 20~80℃; Preferably, the hydrogenation reduction and amine ester exchange reaction in step (3) takes 6 to 48 hours.

9. The synthesis method according to claim 1, characterized in that, The reducing agent used in the reduction reaction in step (4) is borane, diisobutylaluminum hydride or lithium aluminum hydride; Preferably, the reduction reaction in step (4) is carried out in an organic solvent; Preferably, the organic solvent is selected from ether-based organic solvents; more preferably, tetrahydrofuran and / or diethyl ether; Preferably, the reduction reaction in step (4) is carried out at 15-65°C for 6-24 hours; 10. The synthesis method according to any one of claims 1-9, characterized in that, The synthesis method includes the following steps: (1) Under the protection of a protective gas, N-Boc-4-piperidinone and trimethyl phosphonoacetate are reacted in a molar ratio of 1:1 to 1:2.0 in the presence of an alkaline substance to obtain intermediate 1; wherein the alkaline substance is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide or sodium ethoxide, and the molar ratio of the alkaline substance to N-Boc-4-piperidinone is 1.1:1 to 2.5:

1. The witting reaction in step (1) is carried out in an organic solvent, and the organic solvent is selected from any one or more of tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether or N,N-dimethylformamide. The temperature of the witting reaction in step (1) is 0 to 25°C, and the reaction time is 6 to 24 h. (2) Intermediate 1 and acetonitrile are reacted in the presence of a catalyst at a molar ratio of 1:1.5 to 1:4.

0. The reaction temperature is 20 to 80 °C and the reaction time is 6 to 24 h to obtain intermediate 2. The molar ratio of the catalyst to intermediate 1 is 1.1:1 to 2.5:

1. (3) Intermediate 2 is subjected to hydrogenation reduction and amine-ester exchange reaction with hydrogen under the action of palladium on carbon at 20~80℃ and 2~5MPa for 6~48h to obtain intermediate 3; wherein the amount of palladium on carbon is 5%~50% of the mass of intermediate 2; (4) Intermediate 3 is reduced by a reducing agent to obtain tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate. The reducing agent is borane, diisobutylaluminum hydride or lithium aluminum hydride. The reduction is carried out at 15-65°C for 6-24 hours.

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