Synthesis method of 3, 9-diazaspiro [5.5] undecane-3-tert-butyl formate

Abstract

The invention provides a synthesis method of 3, 9-diazaspiro [5.5] undecane-3-tert-butyl formate, which comprises the following steps: carrying out witting reaction on N-Boc-4-piperidone and trimethyl phosphonoacetate to obtain an intermediate 1, carrying out addition reaction on the intermediate 1 and acetonitrile to obtain an intermediate 2, and carrying out hydrogenation reduction and amine ester exchange reaction on the intermediate 2 to obtain 3, 9-diazaspiro [5.5] undecane-3-tert-butyl formate. And carrying out a reduction reaction on the intermediate 3 to obtain the 3, 9-diazaspiro [5.5] undecane-3-tert-butyl formate. The whole method is short in route, mild in reaction condition, high in product purity and yield and suitable for industrial production.

Description

Technical Field

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

[0002] 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester has been confirmed to be a key fragment of some drugs with good biological activity. Drug molecules with such fragments can be used to treat diseases related to CCR8 receptors, and can also be used as non-peptide glycoprotein antagonists for the prevention of thrombosis. U.S. Patent No. 6291469 reports a method for synthesizing 3-benzyl-3,9-diazaspiro[5.5]undecane. The method uses N-benzylpiperidin-4-one as a starting material, reacts with ethyl cyanoacetate in an alcohol solution of ammonia under low temperature conditions for a long time to generate dicyanocarbodiimide, and then acid hydrolyzes to obtain the diacid, and the diacid is then cyclized with urea under high temperature conditions to obtain the diimide, and finally reduced by lithium aluminum tetrahydride to obtain the target product. Patent WO2010108651 and patent WO2015096035 are based on the above, using the intermediate diacid reported above as the basis, and then esterification, reduction, changing the benzyl group to a Boc protecting group, adding a bis-methylsulfonyl group (Ms), benzylamine ring closure, and finally palladium carbon reduction and then removing the benzyl group to obtain the target product. This method is obviously more complicated than the above. Domestic patent CN101255159 also uses N-benzylpiperidin-4-one and ethyl cyanoacetate as starting materials to synthesize dicyanocarbodiimide, and then acid hydrolysis selective deacidification to obtain carbodiimide, and then obtains a diamine with one end benzyl protected and the other end exposed by lithium aluminum hydride reduction, and then uses palladium carbon hydrogenation reduction to remove the benzyl group to obtain the target product after Boc protection. In the existing reported synthesis method, the ring closure yield is low, and high temperature conditions are required when forming diimide. In addition, flammable lithium aluminum hydride is used for reduction, which brings dangers during large-scale production operations.

[0003] Therefore, in the art, it is desired to develop a synthesis method with short synthesis steps, mild reaction conditions, few impurities, high purity and yield, and conducive to large-scale process production. Summary of the invention

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

[0005] To achieve this object, the present invention adopts the following technical solutions:

[0006] In one aspect, 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-piperidone (SM) and trimethyl phosphonoacetate are reacted by witting reaction to obtain intermediate 1. The reaction formula is as follows:

[0008]

[0009] (2) Intermediate 1 is subjected to addition reaction with acetonitrile to obtain intermediate 2. The reaction formula is as follows:

[0010]

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

[0012]

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

[0014]

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

[0016] Preferably, the molar ratio of N-Boc-4-piperidone 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 or more 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-piperidone 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, and the organic solvent is selected from any one of tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether or N,N-dimethylformamide, or a combination of at least two thereof.

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

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

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

[0024] Preferably, the specific operation of the witting reaction in step (1) is: adding an alkaline substance to an organic solvent, adding trimethyl phosphonoacetate dropwise thereto under the protection of a protective gas, keeping the temperature after the addition is complete, and then adding N-Boc piperidone solution dropwise to the system, reacting under stirring after the addition is complete to obtain the intermediate 1.

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

[0026] Preferably, after the dropwise addition of trimethyl phosphonoacetate is completed, the mixture is kept at 0-5°C (eg, 0°C, 1°C, 3°C or 5°C) for 1 hour.

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

[0028] Preferably, when the N-Boc piperidone solution is added dropwise, the system temperature is controlled to be 0-5°C, such as 0°C, 1°C, 3°C or 5°C.

[0029] After the N-Boc piperidone solution is added dropwise as described above, the reaction is carried out under stirring, that is, the witting reaction begins, and the reaction temperature is controlled at 0-25°C.

[0030] Preferably, the molar ratio of the 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 the 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°C, for example, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 60°C, 70°C or 80°C, and the reaction time is 6-24h, for example, 6h, 8h, 10h, 13h, 15h, 18h, 20h, 22h or 24h.

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

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

[0037] Preferably, the hydrogenation reduction and amine transesterification reaction in step (3) is carried out at a pressure of 2 to 5 MPa (eg, 2 MPa, 3 MPa, 4 MPa or 5 MPa).

[0038] Preferably, the hydrogenation reduction and amine transesterification reaction in step (3) is 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 time for the hydrogenation reduction and amine ester exchange reaction in step (3) is 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 the present invention, the hydrogenation reduction and amine transesterification 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 organic solvents; preferably tetrahydrofuran and / or diethyl ether.

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

[0045] As a preferred technical solution of the present invention, the synthesis method comprises the following steps:

[0046] (1) Under the protection of protective gas, N-Boc-4-piperidone 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 an 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-piperidone 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 hours.

[0047] (2) intermediate 1 and acetonitrile are subjected to an addition reaction in the presence of a catalyst at a molar ratio of 1:1.5 to 1:4.0, the temperature of the addition reaction is 20 to 80° C., and the reaction time is 6 to 24 hours to obtain intermediate 2; wherein 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 at 20-80° C. and pressure of 2-5 MPa under the action of palladium carbon for 6-48 hours to obtain intermediate 3; wherein the amount of palladium carbon used is 5% to 50% of the mass of intermediate 2;

[0049] (4) The intermediate 3 is reduced with a reducing agent to obtain the tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, wherein the reducing agent is borane, diisobutylaluminum hydride or lithium aluminum tetrahydride, and the reduction is carried out at 15 to 65° C. for a reaction time of 6 to 24 hours.

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

[0051] The present invention uses N-Boc-4-piperidone as a starting material, reacts with trimethyl phosphonoacetate through a witting reaction to form an intermediate 1, then adds acetonitrile to obtain an intermediate 2, and then performs hydrogenation reduction, and performs an amine ester exchange under heating conditions to obtain an intermediate 3 in one step, and then reduces the carbonyl group through a reducing agent to obtain a target product. The entire method has a short route, mild reaction conditions, high product purity and yield, and is suitable for industrial production. DETAILED DESCRIPTION

[0052] The technical solution of the present invention is further described below by specific implementation methods. 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.

[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 method comprising the following steps:

[0056] first step

[0057] Add 1400mL of tetrahydrofuran to a 3-liter reaction bottle, followed by potassium tert-butoxide (101.4g, 0.904mol, 1.2eq), replace with nitrogen, and cool to -5-0°C under nitrogen protection. Slowly add trimethyl phosphoacetate (165g, 0.904mol, 1.2eq) dropwise through a dropping funnel, control the temperature not to exceed 0°C during the addition, and keep warm for 1 hour after the addition. Then, start adding a solution of N-Boc piperidone (150g, 0.753mol, 1.0eq) in tetrahydrofuran (400mL) dropwise at 0°C, control the temperature below 5°C throughout the process, slowly raise the temperature to 25°C and stir for 16h after the addition, and monitor the reaction to be complete by 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. The mixture was allowed to stand for stratification, and the aqueous phase was extracted once with 360 mL of ethyl acetate. The combined organic layers were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure in a constant temperature water bath at 50°C to obtain 175 g of a light yellow solid of the target intermediate 1 in a yield of 91.0%. 1 HNMR (400MHz, CDCl3) ppmδ: 1.51 (s, 9H), 2.28 (t, J = 6.4Hz, 2H), 2.94 (t, J = 6.8Hz, 2H), 3.46-3.58 (m, 4H), 3.74 (s, 3H), 5.76 (s, 1H).

[0058] Step 2

[0059] The above intermediate 1 (100 g, 0.392 mol, 1.0 eq) and DMF (1000 mL, 10 V) were added to a 2 L reaction bottle equipped with a mechanical stirrer and a heating device, followed by acetonitrile (40.2 g, 0.978 mol, 2.5 eq), and DBU (71.6 g, 0.470 mol, 1.2 eq) was slowly added dropwise under stirring. After the addition, the reaction system was gradually heated to 60 ° C and stirred for 16 h. The raw material almost disappeared in the central control test. The reaction system was cooled to 25 ° C, 1 L of water and 1 L of ethyl acetate were added, and the organic phase was separated after stirring. The aqueous phase was extracted once with 500 mL of ethyl acetate, and 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 there were no droplets. The residue was purified by washing with a silica gel column. The solvent used was an ethyl acetate / n-hexane system with a volume ratio of 1 / 30 to 1 / 20 to obtain 80 g of the target intermediate 2 product with a yield of 68.9%.

[0060] Step 3

[0061] Add intermediate 2 (150g, 0.506mol, 1eq) and methanol (1500mL, 10V) to a 3L hydrogenation kettle, then add 10% palladium carbon (30g, 20wt%), replace with nitrogen 3 times, replace with hydrogen 2 times, the reaction system pressure is 3MPa, start heating to 55°C, stir for 2 days, and the raw material is almost reacted after central control detection. The reaction system is cooled to room temperature, the reaction solution is filtered twice with diatomaceous earth, the filter cake is washed with ethanol until there is no product residue, the collected filtrate is concentrated under reduced pressure at 50°C, the residue is evaporated once with 300mL of dichloromethane, and then purified by pulping with methyl tert-butyl ether to obtain 113 grams of white solid target intermediate 3 product, yield: 83.2%.

[0062] Step 4

[0063] The above intermediate 3 (100g, 0.373mmol, 1eq) was dissolved in THF (1000mL, 10V), the reaction system was cooled in an ice bath, and borane tetrahydrofuran solution (745mL, 0.745mmol, 2eq, 1M tetrahydrofuran solution) was slowly added under nitrogen protection. After the addition, the reaction system naturally warmed to room temperature and stirred for 16h, then heated to 55°C and continued to stir for 2h. The central control detected that the raw material was almost reacted. The reaction system was cooled to room temperature, the reaction was quenched with 10wt% hydrochloric acid, and most of the tetrahydrofuran was removed by vacuum concentration. The remaining aqueous phase was adjusted to alkalinity with saturated sodium bicarbonate, and then ethyl acetate was added and repeatedly extracted until no product remained. The combined organic phase was 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 pulping with methyl tert-butyl ether and vacuum dried at 30°C for 5h to obtain 75 grams of the target product TM as a white solid with a yield of 79.1%. 1HNMR (400MHz, CDCl3) ppmδ: 1.41 (brs, 17H), 2.28 (s, 1H), 2.80 (t, J = 5.2Hz, 4H), 3.36 (t, J = 5.2Hz, 4H).

[0064] Example 2

[0065] first step

[0066] Add 1400mL of tetrahydrofuran to a 3-liter reaction bottle, followed by sodium ethoxide (128.1g, 1.882mol, 2.5eq), replace with nitrogen, and cool to -5-0°C under nitrogen protection. Slowly add trimethyl phosphoacetate (205.7g, 1.129mol, 1.5eq) dropwise through a dropping funnel, and control the temperature not to exceed 0°C during the addition process. Keep warm for 1 hour after the addition. Then, start adding a solution of N-Boc piperidone (150g, 0.753mol, 1.0eq) in tetrahydrofuran (400mL) at 0°C, and control the temperature below 5°C during the whole process. After the addition, slowly raise the temperature to 25°C and stir for 20h. The reaction is complete after TLC monitoring. The reaction solution was slowly poured into 500 ml of 15 wt% hydrochloric acid for quenching, and then 700 mL of ethyl acetate was added and stirred for 10 minutes. The mixture was allowed to stand for stratification, and the aqueous phase was extracted once with 360 mL of ethyl acetate. The combined organic layers were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure in a constant temperature water bath at 50°C to obtain 155 g of a light yellow solid of the target intermediate 1 with a yield of 80.6%.

[0067] Step 2

[0068] The above intermediate 1 (100 g, 0.392 mol, 1.0 eq) and DMF (1000 mL, 10 V) were added to a 2L reaction bottle equipped with a mechanical stirrer and a heating device, followed by acetonitrile (56.3 g, 1.371 mol, 3.5 eq), and DBU (89.5 g, 0.588 mol, 1.5 eq) was slowly added dropwise under stirring. After the addition, the reaction system was stirred at 25 ° C for 16 h. The raw material was still remaining when the central control was detected. The temperature was then raised to 50 ° C and stirred for 6 h. The raw material was almost gone when the central control was detected. The reaction system was cooled to 25 ° C, 1 L of water and 1 L of ethyl acetate were added, and the organic phase was separated after stirring. The aqueous phase was extracted once with 500 mL of ethyl acetate, and 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 there were no droplets. The residue was purified by washing with a silica gel column. The solvent used was ethyl acetate / n-hexane system with a volume ratio of 1 / 30 to 1 / 20 to obtain 75 g of the target intermediate 2 product with a yield of 64.6%.

[0069] Step 3

[0070] Add intermediate 2 (150g, 0.506mol, 1eq) and ethanol (1500mL, 10V) to a 3L hydrogenation kettle, then add 10% palladium carbon (30g, 20wt%), replace with nitrogen 3 times, replace with hydrogen 2 times, the reaction system pressure is 2.5MPa, start heating to 65°C, stir for 36h, and the raw material is almost reacted after central control detection. The reaction system is cooled to 25°C, the reaction solution is filtered twice with diatomaceous earth, the filter cake is washed with ethanol until there is no product residue, the collected filtrate is concentrated under reduced pressure at 50°C, the residue is evaporated once with 300mL of dichloromethane, and then purified by pulping with methyl tert-butyl ether to obtain 116 grams of white solid target intermediate 3 product, yield: 85.4%.

[0071] Step 4

[0072] The above intermediate 3 (100g, 0.373mmol, 1eq) was dissolved in THF (1000mL, 10V), the reaction system was cooled in an ice bath, and borane dimethyl sulfide (82mL, 0.820mmol, 2.2eq, 10M dimethyl sulfide solution) was slowly added under nitrogen protection. After the addition, the reaction system naturally rose to room temperature and stirred for 16h, then refluxed and stirred for 1h. The central control detected that the raw material was almost reacted. The reaction system was cooled to room temperature, the reaction was quenched with 10wt% hydrochloric acid, and most of the tetrahydrofuran was removed by vacuum concentration. The remaining aqueous phase was adjusted to alkalinity with saturated sodium bicarbonate, and then ethyl acetate was added and repeatedly extracted until no product remained. The combined organic phase was 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 pulping with methyl tert-butyl ether and vacuum dried at 30°C for 5h to obtain 70 grams of the target product TM as a white solid with a yield of 73.8%.

[0073] Example 3

[0074] first step

[0075] Add 1200mL of ethylene glycol dimethyl ether to a 3-liter reaction bottle, then add sodium tert-butoxide (108.5g, 1.129mol, 1.5eq), replace with nitrogen, and cool down to -5-0°C under nitrogen protection. Slowly add trimethyl phosphoacetate (205.7g, 1.129mol, 1.5eq) dropwise through a dropping funnel, and control the temperature not to exceed 0°C during the addition process. Keep warm for 1 hour after the addition. Then, start to add N-Boc piperidone (150g, 0.753mol, 1.0eq) in ethylene glycol dimethyl ether solution (300mL) at 0°C, and control the temperature below 5°C during the whole process. After the addition, slowly rise to 25°C and stir for 16h. The reaction is complete when monitored by TLC. The reaction solution was slowly poured into 500 ml of 10 wt% hydrochloric acid for quenching, and then 500 mL of water and 800 mL of ethyl acetate were added and stirred for 10 minutes. The mixture was allowed to stand for stratification, and the aqueous phase was extracted once with 500 mL of ethyl acetate. The combined organic layers were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure in a constant temperature water bath at 50°C to obtain 170 g of a light yellow solid of the target intermediate 1 with a yield of 88.4%.

[0076] Step 2

[0077] The above intermediate 1 (100 g, 0.392 mol, 1.0 eq) and DMF (1000 mL, 10 V) were added to a 2 L reaction bottle equipped with a mechanical stirrer and a heating device, followed by acetonitrile (40.2 g, 0.978 mol, 2.5 eq), and DABCO (87.8 g, 0.783 mol, 2.0 eq) was slowly added dropwise under stirring. After the addition, the reaction system was gradually heated to 80 ° C and stirred for 16 h. The raw material almost disappeared in the central control test. The reaction system was cooled to 25 ° C, 1 L of water and 1 L of ethyl acetate were added, and the organic phase was separated after stirring. The aqueous phase was extracted once with 500 mL of ethyl acetate, and 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 there were no droplets. The residue was purified by washing with a silica gel column. The solvent used was ethyl acetate / n-hexane system with a volume ratio of 1 / 30 to 1 / 20 to obtain 62 g of the target intermediate 2 product with a yield of 53.4%.

[0078] Step 3

[0079] Add intermediate 2 (150g, 0.506mol, 1eq) and methanol (1500mL, 10V) to a 3L hydrogenation kettle, then add 10% palladium carbon (75g, 50wt%), replace with nitrogen 3 times, replace with hydrogen 2 times, the reaction system pressure is 5MPa, the reaction system is stirred at 25°C for 14h, then start to heat up to 60°C and continue to react for 10h, the central control detection raw material is almost complete. The reaction system is cooled to room temperature, the reaction solution is filtered twice with diatomaceous earth, the filter cake is washed with methanol until there is no product residue, the collected filtrate is concentrated under reduced pressure at 50°C, the residue is evaporated once with 300mL of dichloromethane, and then purified by pulping with methyl tert-butyl ether to obtain 110 grams of white solid target intermediate 3 product, yield: 81.0%.

[0080] Step 4

[0081] The above intermediate 3 (100g, 0.373mol, 1eq) was dissolved in THF (1000mL, 10V), the reaction system was cooled in an ice bath, and a tetrahydrofuran solution of diisobutylaluminum hydride (745mL, 0.745mol, 2eq, 1M tetrahydrofuran solution) was slowly added dropwise under nitrogen protection. After the addition, the reaction system naturally warmed to room temperature and stirred for 24h. The central control detected that the raw material was almost completely reacted. The reaction was quenched with 10wt% 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 ethyl acetate was added and repeatedly extracted until no product remained. The combined organic phase was 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 pulping with methyl tert-butyl ether and vacuum dried at 30°C for 5h to obtain 60 grams 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 1400mL of tetrahydrofuran to a 3-liter reaction bottle, followed by potassium tert-butoxide (169g, 1.506mol, 2.0eq), replace with nitrogen, and cool to -5-0°C under nitrogen protection. Slowly add trimethyl phosphoacetate (274g, 1.506mol, 2.0eq) dropwise through a dropping funnel, and control the temperature not to exceed 0°C during the addition process. Keep warm for 1 hour after the addition. Then, start adding a solution of N-Boc piperidone (150g, 0.753mol, 1.0eq) in tetrahydrofuran (400mL) dropwise at 0°C, and control the temperature below 5°C during the whole process. After the addition, slowly raise the temperature to 25°C and stir for 16h. The reaction is complete when monitored by TLC. The reaction solution was slowly poured into 500 ml of 10 wt% hydrochloric acid for quenching, and then 700 mL of ethyl acetate was added and stirred for 10 minutes. The mixture was allowed to stand for stratification, and the aqueous phase was extracted once with 360 mL of ethyl acetate. The combined organic layers were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure in a constant temperature water bath at 50°C to obtain 180 g of a light yellow solid of the target intermediate 1 with a yield of 93.7%.

[0085] Example 5

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

[0087] Add the above intermediate 1 (100g, 0.392mol, 1.0eq) and DMF (1000mL, 10V) to a 2L reaction bottle equipped with a mechanical stirrer and a heating device, then add acetonitrile (24.1g, 0.588mol, 1.5eq), slowly add DBU (71.6g, 0.470mol, 1.2eq) dropwise under stirring, gradually heat the reaction system to 55°C and stir for 16h, and the central control detection shows that there is still a little residual raw material. Cool the reaction system to 25°C, add 1L water and 1L ethyl acetate, stir and separate the organic phase. The aqueous phase was extracted once with 500 mL of ethyl acetate, and 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 there were no droplets. The residue was purified by washing with a silica gel column. The solvent used was ethyl acetate / n-hexane system with a volume ratio of 1 / 30 to 1 / 20 to obtain 65 g of the target intermediate 2 product with a yield of 56.0%.

[0088] Example 6

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

[0090] Add the above intermediate 1 (100g, 0.392mol, 1.0eq) and DMF (1000mL, 10V) to a 2L reaction bottle equipped with a mechanical stirrer and a heating device, then add acetonitrile (64.3g, 1.567mol, 4.0eq), slowly add DBU (71.6g, 0.470mol, 1.2eq) under stirring, gradually heat the reaction system to 65°C and stir for 16h, and the raw material almost disappears in the central control test. The reaction system is cooled to 25°C, 1L of water and 1L of ethyl acetate are added, and the organic phase is separated after stirring. The aqueous phase was extracted once with 500 mL of ethyl acetate, and 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 there were no droplets. The residue was purified by washing with a silica gel column. The solvent used was ethyl acetate / n-hexane system with a volume ratio of 1 / 30 to 1 / 20 to obtain 76 g of the target intermediate 2 product with a yield of 65.5%.

[0091] The applicant declares that the present invention illustrates the synthesis method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various 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 comprises the following steps: (1) N-Boc-4-piperidone and trimethyl phosphonoacetate are reacted by witting reaction to obtain intermediate 1. The reaction formula is as follows: (2) Intermediate 1 is subjected to addition reaction with acetonitrile to obtain intermediate 2. The reaction formula is as follows: (3) Intermediate 2 is subjected to hydrogenation reduction and amine ester exchange reaction to obtain intermediate 3; the reaction formula is as follows: (4) Intermediate 3 is subjected to a reduction reaction to obtain the tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, and the reaction formula is as follows:

2. The synthesis method according to claim 1, characterized in that The molar ratio of N-Boc-4-piperidone 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-piperidone 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, wherein the organic solvent is selected from any one of tetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether or N,N-dimethylformamide, or a combination of at least two thereof; Preferably, the temperature of the witting reaction in step (1) is 0 to 25°C; Preferably, the witting reaction time in step (1) is 6 to 24 hours; Preferably, the witting reaction in step (1) is carried out under the protection of a protective gas, and the protective gas is preferably nitrogen.

4. The synthesis method according to any one of claims 1 to 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 thereto under the protection of a protective gas, keep the temperature after the addition is complete, and then add N-Boc piperidone solution dropwise to the system, react under stirring after the addition is complete, and obtain the intermediate 1.

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

6. The synthesis method according to claim 1, characterized in that The molar ratio of the intermediate 1 to acetonitrile in step (2) 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 the 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 to 80° C., and the reaction time is 6 to 24 hours.

8. The synthesis method according to claim 1, characterized in that The hydrogenation reduction in step (3) is to react the intermediate 2 with hydrogen under the action of palladium carbon; Preferably, the amount of palladium carbon is 5% to 50% of the mass of intermediate 2; Preferably, the hydrogenation reduction and amine transesterification reaction in step (3) are carried out at a pressure of 2 to 5 MPa; Preferably, the hydrogenation reduction and amine transesterification reaction in step (3) are carried out at 20-80°C; Preferably, the time for the hydrogenation reduction and amine ester exchange reaction in step (3) is 6 to 48 hours.

9. The synthesis method according to claim 1, characterized in that The reducing agent used in the reduction reaction of step (4) is borane, diisobutylaluminum hydride or lithium aluminum tetrahydride; Preferably, the reduction reaction in step (4) is carried out in an organic solvent; Preferably, the organic solvent is selected from ether organic solvents; preferably tetrahydrofuran and / or diethyl ether; Preferably, the reduction reaction in step (4) is carried out at 15 to 65° C., and the reduction reaction time is 6 to 24 hours.

10. The synthesis method according to any one of claims 1 to 9, characterized in that The synthesis method comprises the following steps: (1) Under the protection of protective gas, N-Boc-4-piperidone and trimethyl phosphonoacetate are subjected to a witting reaction in a molar ratio of 1:1 to 1:2.0 in the presence of an alkaline substance to obtain an 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-piperidone 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 hours. (2) intermediate 1 and acetonitrile are subjected to an addition reaction in the presence of a catalyst at a molar ratio of 1:1.5 to 1:4.0, the temperature of the addition reaction is 20 to 80° C., and the reaction time is 6 to 24 hours to obtain intermediate 2; wherein 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 at 20-80° C. and pressure of 2-5 MPa under the action of palladium carbon for 6-48 hours to obtain intermediate 3; wherein the amount of palladium carbon used is 5% to 50% of the mass of intermediate 2; (4) The intermediate 3 is reduced with a reducing agent to obtain the tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, wherein the reducing agent is borane, diisobutylaluminum hydride or lithium aluminum tetrahydride. The reduction is carried out at 15 to 65° C. and the reaction time is 6 to 24 hours.

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