Synthesis method for 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane

Abstract

Provided in the present invention is a synthesis method for 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane. In the present invention, starting from N-benzyl-2,6-piperidinedione, a dibromide 1 is first formed, followed by formation of a bridged-ring intermediate 2 under alkaline conditions; subsequently, an intermediate 3 is obtained by performing debenzylation, and then two carbonyl groups are reduced to form a free amine 4; then, an amino group is subjected to Boc protection to obtain an intermediate 5, and further debenzylation is performed to form the target product. According to the synthesis method of the present invention, few impurities are produced, and the product is easy to purify and has high purity, so that the overall yield is improved, and the unit cost is effectively reduced, facilitating large-scale industrial production.

Description

A method for synthesizing 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane

[0001] This invention belongs to the field of compound preparation technology and relates to a method for synthesizing 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane. Background Technology

[0002] 6-(tert-Butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane is a key fragment of a drug containing a azirbroming ring. Existing synthetic routes primarily use dimethyl 2,4-dibromoglutarate as the starting material, which reacts with benzylamine to cyclize and generate 1-benzylazirbromobutane-2,4-dicarboxylic acid dimethyl ester. This is then reduced to a diol by sodium borohydride, followed by reduction of the benzyl group with palladium hydroxide and Boc protection of the amine group to obtain 2,4-dihydroxymethyl-1-tert-butoxycarbonylazirbromobutane. Subsequently, the dihydroxy group is Ts-protected, and the cyclization is performed with benzylamine to obtain 3-benzyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester. Finally, it is reduced by hydrogenation on palladium on carbon to obtain the target product. Other reported synthetic routes are based on this with slight modifications. Because the starting material, dimethyl 2,4-dibromoglutarate, exists in both meso and racemic forms in a ratio between 1:2 and 2:3, and the racemic structure is not conducive to ring closure to form the product, these methods result in low overall yields, numerous impurities, and difficult purification, leading to high unit costs. Summary of the Invention

[0003] To address the shortcomings of existing technologies, the present invention aims to provide a method for synthesizing 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane. This method offers advantages such as fewer impurities, easier purification, and higher purity, resulting in increased overall yield and effectively reduced unit cost, thus facilitating large-scale industrial production.

[0004] To achieve this objective, the present invention adopts the following technical solution:

[0005] On one hand, the present invention provides a method for synthesizing 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane, the method comprising the following steps:

[0006] (1) N-benzyl-2,6-piperidinedione reacts with a brominizing agent to give compound 1;

[0007] (2) Compound 1 reacts with benzylamine under alkaline conditions to give compound 2;

[0008] (3) Compound 2 undergoes a debenzylation protection reaction to give compound 3;

[0009] (4) Compound 3 undergoes a carbonyl reduction reaction to give compound 4;

[0010] (5) The amino group in compound 4 was subjected to a Boc protection reaction to obtain compound 5;

[0011] (6) Compound 5 underwent a debenzylation protection reaction to give 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane as shown in TM. The reaction process is as follows:

[0012] .

[0013] In this invention, starting from N-benzyl-2,6-piperidinidone, a dibromo derivative 1 is first formed, followed by the formation of a bridged ring intermediate 2 under basic conditions. Then, the benzyl group is removed to obtain intermediate 3, followed by reduction of the dicarbonyl group to form a free amine 4. The amino group is then subjected to Boc protection to obtain intermediate 5, which is subsequently debenzylated to form the target product. The synthetic method of this invention produces fewer impurities, the product is easy to purify, and has high purity, thereby increasing the overall yield and effectively reducing the unit cost, which is beneficial for large-scale industrial production.

[0014] Preferably, the brominating agent in step (1) is N-bromosuccinimide (NBS), dibromohydantoin, or bromine.

[0015] Preferably, the molar ratio of N-benzyl-2,6-piperidinedione to the brominizing agent in step (1) is 1:3 to 1:5, for example, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5.

[0016] The reaction described in step (1) is carried out in the presence of an initiator.

[0017] Preferably, the initiator is azobisisobutyronitrile (AIBN).

[0018] Preferably, the reaction in step (1) is carried out in a solvent selected from acetonitrile or carbon tetrachloride.

[0019] Preferably, the reaction temperature in step (1) is 20~70℃, for example 20℃, 25℃, 30℃, 40℃, 50℃, 60℃ or 70℃, and the reaction time is 12~48h, for example 12h, 14h, 16h, 18h, 20h, 24h, 28h, 30h, 36h, 40h, 44h or 48h.

[0020] Preferably, after the reaction in step (1) is completed, the reaction system is cooled to 20-25°C (e.g., 20°C, 22°C, 24°C or 25°C), and then further cooled to 0-10°C (e.g., 0°C, 3°C, 5°C, 8°C or 10°C), N,N-diisopropylethylamine and diethyl phosphite are added, and then kept at this temperature for 10-60 min (e.g., 10 min, 20 min, 30 min, 40 min, 50 min or 60 min).

[0021] In the reaction of step (1), a byproduct containing two bromine atoms on the same carbon atom is generated. The addition of N,N-diisopropylethylamine and diethyl phosphite helps to convert all or most of the byproduct on the same carbon atom into the monobromine target product.

[0022] Preferably, the molar ratio of N,N-diisopropylethylamine to N-benzyl-2,6-piperidinedione is 1:1 to 1.2:1, for example, 1:1, 1.05:1, 1.1:1, 1.15:1 or 1.2:1;

[0023] Preferably, the molar ratio of diethyl phosphite to N-benzyl-2,6-piperidinidone is 1:1 to 5:1, for example, 1:1, 1.5:1, 1.8:1, 2:1, 2.5:1, 2.8:1, 3:1, 3.5:1, 4:1, 4.5:1, or 5:1.

[0024] Preferably, the molar ratio of compound 1 to benzylamine in step (2) is 1:1 to 1:3, for example, 1:1, 1:1.5, 1:1.8, 1:2, 1:2.5, 1:2.8 or 1:3.

[0025] Preferably, the alkaline conditions in step (2) are provided by an alkaline substance selected from any one or a combination of at least two of N,N-diisopropylethylamine (DIEA), triethylamine, potassium carbonate, or cesium carbonate.

[0026] Preferably, the reaction in step (2) is carried out under the catalysis of a catalyst.

[0027] Preferably, the catalyst is selected from any one or a combination of at least two of potassium iodide, sodium iodide, or tetrabutylammonium iodide.

[0028] Preferably, the specific operation of the reaction in step (2) is as follows: compound 1 is added to a system containing an alkaline substance and a catalyst, the reaction system is heated, and when the temperature reaches 50°C, benzylamine is added dropwise. During the dropwise addition, the temperature is raised from 50°C to 120°C. After the dropwise addition is completed, the temperature is controlled at 120~125°C and the reaction continues for 1-3 h (e.g., 1 h, 1.5 h, 2 h, 2.5 h or 3 h).

[0029] Preferably, the reaction in step (2) is carried out in a solvent selected from any one or a combination of at least two of DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), or toluene.

[0030] Preferably, the debenzylation protection reaction in step (3) is carried out under a hydrogen atmosphere.

[0031] Preferably, the debenzylation protection reaction in step (3) is carried out at a pressure of 2 to 10 MPa (e.g., 2 MPa, 3 MPa, 5 MPa, 8 MPa or 10 MPa).

[0032] Preferably, the catalyst for the debenzylation protection reaction in step (3) is palladium hydroxide.

[0033] Preferably, the debenzylation protection reaction in step (3) is carried out in a solvent, namely methanol.

[0034] Preferably, the temperature of the debenzylation protection reaction in step (3) is 20~70℃ (e.g., 20℃, 25℃, 30℃, 40℃, 50℃, 60℃ or 70℃), and the reaction time is 12~48h (e.g., 12h, 14h, 16h, 18h, 20h, 24h, 28h, 30h, 36h, 40h, 44h or 48h).

[0035] Preferably, the reducing agent in the reduction reaction of step (4) is borane and / or diisobutylaluminum hydride.

[0036] Preferably, the molar ratio of the reducing agent to compound 3 is 2.5:1 to 5:1, for example, 2.5:1, 2.8:1, 3:1, 3.5:1, 4:1, 4.5:1 or 5:1.

[0037] Preferably, the reduction reaction in step (4) is carried out in a solvent selected from any one or a combination of at least two of tetrahydrofuran, methyl tert-butyl ether or isopropyl ether.

[0038] Preferably, the reduction reaction in step (4) is carried out under nitrogen protection.

[0039] Preferably, the specific operation of the reduction reaction in step (4) is to add the reducing agent dropwise to the reaction system containing compound 3, raise it to room temperature and stir for 6 to 24 hours (e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 22 hours or 24 hours), and then reflux for 1 to 3 hours (1 hour, 1.5 hours, 1.8 hours, 2 hours, 2.5 hours, 2.8 hours or 3 hours) to obtain compound 4.

[0040] Preferably, the Boc protection reaction in step (5) is a reaction between compound 4 and Boc anhydride to obtain compound 5.

[0041] Preferably, the molar ratio of compound 4 to Boc anhydride is 1:1 to 1:1.5, for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5.

[0042] Preferably, the Boc protection reaction in step (5) is carried out in the presence of an alkaline substance.

[0043] Preferably, the alkaline substance is selected from any one or a combination of at least two of triethylamine, N,N-diisopropylethylamine, or sodium bicarbonate.

[0044] Preferably, the Boc protection reaction in step (5) is carried out in a solvent selected from any one or at least a combination of two of dichloromethane, methanol, tetrahydrofuran, acetone or 1,4-dioxane.

[0045] Preferably, the Boc protection reaction in step (5) is carried out at room temperature for a reaction time of 4 to 24 hours, for example, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 22 hours or 24 hours.

[0046] Preferably, the debenzyl protection reaction in step (6) is carried out under a hydrogen atmosphere.

[0047] Preferably, the debenzylation protection reaction in step (6) is carried out at a pressure of 2-10 MPa (e.g., 2 MPa, 3 MPa, 5 MPa, 8 MPa or 10 MPa).

[0048] Preferably, the catalyst for the debenzylation protection reaction in step (6) is palladium hydroxide.

[0049] Preferably, the debenzylation protection reaction in step (6) is carried out in a solvent, namely methanol.

[0050] Preferably, the temperature of the debenzylation protection reaction in step (6) is 20~70℃ (e.g., 20℃, 25℃, 30℃, 40℃, 50℃, 60℃ or 70℃), and the reaction time is 12~48h (e.g., 12h, 14h, 16h, 18h, 20h, 24h, 28h, 30h, 36h, 40h, 44h or 48h).

[0051] Compared with the prior art, the present invention has the following beneficial effects:

[0052] The method for synthesizing 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane of the present invention produces fewer impurities during the reaction process, is easier to purify, and has high purity, thereby increasing the overall yield and effectively reducing the unit cost, which is beneficial for large-scale production. Detailed Implementation

[0053] 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.

[0054] The reaction process for preparing 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane in the following examples is as follows:

[0055] .

[0056] Example 1

[0057] This embodiment provides a method for preparing 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane, comprising the following steps:

[0058] first step:

[0059] SM (50.0 g, 0.246 mol, 1.0 eq) and MeCN (500 mL, 10V) were added to a 1 L reaction flask and stirred until dissolved. NBS (109.5 g, 0.615 mol, 2.5 eq) and AIBN (8.1 g, 0.049 mol, 0.2 eq) were added at room temperature (20–25 °C), followed by three N2 replacements. The temperature was then gradually increased to 50 °C (internal temperature) and the reaction was continued for 16 h. The reaction solution was light yellow, and the control panel detected that there was still some reactant remaining. The system was cooled to room temperature, and NBS (43.8 g, 0.246 mol, 1.0 eq) was added. The temperature was then increased to 50 °C (internal temperature) and the reaction continued for 6 h. The control panel detected that the reactant had almost disappeared. The reaction system was cooled to 20-25°C, then further cooled to 0°C using an ice bath. DIEA (31.8 g, 0.246 mol, 1.0 eq) was added dropwise, followed by diethyl phosphite (34.0 g, 0.246 mol, 1.0 eq), maintaining the system temperature below 10°C during the addition. After the addition was complete, the system was kept at this temperature for 30 min. A saturated sodium bicarbonate solution was then added dropwise to adjust the pH of the reaction solution to approximately 7-8, followed by natural warming to 20-25°C. The reaction solution was subjected to vacuum distillation below 35°C to remove most of the organic solvent. The remaining aqueous phase was repeatedly extracted three times with dichloromethane until no product residue remained. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then slurried with petroleum ether, filtered, and a yellowish-brown solid was obtained. This solid was dried under vacuum at 30°C for 3.5 h to yield 67.2 g of the target product, with a yield of 75.6%.

[0060] Step Two:

[0061] Dibromo intermediate 1 (200 g, 0.554 mol, 1.0 eq) and DMF (1000 mL, 5V) were added to a 2L reaction flask equipped with a mechanical stirrer and heater. Then, DIEA (164.7 g, 1.274 mol, 2.3 eq) and KI (18.5 g, 0.111 mol, 0.2 eq) were added. The reaction system was gradually heated to 120℃ under stirring. During this process, when the temperature reached 50℃, benzylamine (65.3 g, 0.609 mol, 1.1 eq) was added dropwise through a dropping funnel. The addition was controlled so that the benzylamine addition was completed or nearly completed when the temperature reached 120℃. The temperature was then maintained at 120-125℃ for 2 hours, during which the starting material was almost completely eliminated. The reaction system was cooled to room temperature, and 2L of water and 2L of methyl tert-butyl ether were added. The mixture was stirred for 0.5 hours and then allowed to stand for 0.5 hours. The organic phase was then separated by liquid-liquid chromatography. The aqueous phase was extracted once more with 500 mL of methyl tert-butyl ether. The organic phases were combined, washed with 3V saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50°C until no droplets remained, yielding 110 g of the target intermediate 2 product, with a yield of 64.8%.1 HNMR (400MHz, CDCl3) ppmδ: 2.66 - 2.78 (m, 2H), 3.76 - 3.94 (m, 2H), 3.76 (s, 2H), 4.12 - 4.26 (m, 2H), 7.14 - 7.46 (m, 10H).

[0062] Step 3:

[0063] Intermediate 2 (100 g, 0.327 mol, 1 eq) and methanol (500 mL, 5V) were added to a 1L hydrogenation reactor, followed by 20% palladium hydroxide (20 g, 20wt%). The reactor was purged with nitrogen three times and hydrogen twice, with a pressure of 3 MPa. The temperature was initially raised to 50°C and stirred for 12 hours. The reaction mixture was monitored until almost completely reacted. The reaction system was cooled to room temperature, and the reaction liquid was filtered twice using 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 distilled once with 300 mL of dichloromethane and then purified by slurrying with methyl tert-butyl ether to obtain 65 g of the white solid target intermediate 3 product, with a yield of 92.1%.

[0064] Step 4:

[0065] Intermediate 3 (100 g, 0.463 mol, 1 eq) was dissolved in THF (1000 mL, 10V). The reaction system was cooled in an ice bath, and a borane tetrahydrofuran solution (1850 mL, 1.850 mol, 4 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 overnight. Then, it was refluxed and stirred for 2 hours. The reaction was monitored and the starting material was almost completely reacted. The reaction system was cooled to room temperature, and the reaction was quenched with 1N 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 repeatedly extracted with methyl tert-butyl ether until no product residue remained in the aqueous phase. 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 to obtain 75 g of colorless oily intermediate 4 product, yield 86.1%.

[0066] Step 5:

[0067] Intermediate 4 (75 g, 0.398 mol, 1 eq) was dissolved in dichloromethane (525 mL, 7V). Triethylamine (60.5 g, 0.598 mol, 1.5 eq) and Boc anhydride (95.7 g, 0.438 mol, 1.1 eq) were then added to the reaction system. The entire reaction system was stirred overnight at room temperature, and the reaction was monitored until the reactants were almost completely reacted. 500 mL of water was added to the reaction system for dilution and stirring. The organic phase was then separated, and the aqueous phase was extracted once more with 200 mL of dichloromethane. 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 to obtain 100 g of white solid intermediate 5 product, yield 87.0%. 1 HNMR (400MHz, CDCl3) ppmδ: 1.48 (s, 9H), 1.76 (d, J = 8.0 Hz, 1H), 2.38 - 2.45 (m, 1H), 2.74 - 2.82 (m, 2H), 3.04 - 3.30 (m, 2H), 3.74 (s, 2H), 4.06 - 4.18 (m, 2H), 7.24 - 7.38 (m, 5H).

[0068] Step 6:

[0069] Intermediate 5 (100 g, 0.347 mol, 1 eq) and methanol (500 mL, 5V) were added to a 1L hydrogenation reactor, followed by 20% palladium hydroxide (15 g, 15wt%). The reactor was purged with nitrogen three times and hydrogen twice, with a pressure of 3 MPa. The temperature was initially raised to 60°C and stirred for 12 hours. The reaction mixture was monitored until almost completely reacted. The reaction system was cooled to room temperature, and the reaction liquid was filtered twice using 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 purified by slurrying with methyl tert-butyl ether and dried under vacuum at 30°C for 3.5 hours to obtain 60 g of the target product TM as a white solid, with a yield of 87.3%. 1 HNMR (400MHz, DMSO-d6) ppmδ: 1.47 (s, 9H), 1.56 (d, J = 8.0 Hz, 1H), 2.38 - 2.45 (m, 1H), 2.63 - 2.76 (m, 2H), 3.24 - 3.36 (m, 2H), 3.84 - 3.96 (m, 2H).

[0070] Example 2

[0071] first step:

[0072] SM (50.0 g, 0.246 mol, 1.0 eq) and MeCN (500 mL, 10V) were added to a 1 L reaction flask and stirred until dissolved. NBS (131.4 g, 0.738 mol, 3.0 eq) and AIBN (8.1 g, 0.049 mol, 0.2 eq) were added at room temperature (20–25 °C), with N2 purging three times. The temperature was then gradually increased to 60 °C (internal temperature) and reacted for 24 h. The reaction solution was light yellow, and trace amounts of raw materials remained as detected by the control panel. The reaction system was cooled to 20–25 °C, then further cooled to 0 °C using an ice bath. DIEA (47.7 g, 0.369 mol, 1.5 eq) was added dropwise, followed by diethyl phosphite (51.0 g, 0.369 mol, 1.5 eq), maintaining the system temperature below 10 °C during the addition. After the addition was complete, the system was kept at this temperature for 30 min. A saturated sodium bicarbonate solution was added dropwise to the reaction system to adjust the pH to approximately 7-8, and then the temperature was naturally raised to 20-25°C. The reaction solution was distilled under reduced pressure below 35°C to remove most of the organic solvent. The remaining aqueous phase was repeatedly extracted three times with dichloromethane until no product residue remained. The combined organic phases were then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then slurried with petroleum ether, filtered, and a yellowish-brown solid was obtained. This solid was dried under vacuum at 30°C for 3.5 hours to yield 50.5 g of the target product, with a yield of 56.8%.

[0073] Step Two:

[0074] Dibromo intermediate 1 (200 g, 0.554 mol, 1.0 eq) and DMF (1000 mL, 5V) were added to a 2L reaction flask equipped with a mechanical stirrer and heater. Triethylamine (140.1 g, 1.385 mol, 2.5 eq) and KI (27.6 g, 0.166 mol, 0.3 eq) were then added. The reaction system was gradually heated to 120℃ under stirring. During this process, when the temperature reached 50℃, benzylamine (118.7 g, 1.108 mol, 2.0 eq) was added dropwise through a dropping funnel. The addition was controlled so that the benzylamine addition was completed or nearly completed when the temperature reached 120℃. The temperature was then maintained at 120-125℃ for 2 hours, during which the starting material was almost completely eliminated. The reaction system was cooled to room temperature, and 2L of water and 2L of methyl tert-butyl ether were added. The mixture was stirred for 0.5 hours and then allowed to stand for 0.5 hours. The organic phase was then separated by liquid-liquid chromatography. The aqueous phase was extracted once more with 500 mL of methyl tert-butyl ether. The organic phases were combined, washed with 3V saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50°C until no droplets remained, yielding 115 g of the target intermediate 2 product, with a yield of 67.8%.

[0075] Step 3:

[0076] Intermediate 2 (100 g, 0.327 mol, 1 eq) and methanol (500 mL, 5V) were added to a 1L hydrogenation reactor, followed by 15 g (15wt%) of 20% palladium hydroxide. The reactor was purged with nitrogen three times and hydrogen twice, with a pressure of 2 MPa. The temperature was initially raised to 55°C and stirred for 48 h. The reaction mixture was monitored until the reactants were 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 61.8 g of white solid target intermediate 3, yield: 87.5%.

[0077] Step 4:

[0078] Intermediate 3 (100 g, 0.463 mol, 1 eq) was dissolved in THF (1000 mL, 10 V). The reaction system was cooled in an ice bath, and a borane dimethyl sulfide solution (231 mL, 2.313 mol, 5 eq, 10 M borane 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 overnight. Then, it was refluxed and stirred for 2 h. The reaction was monitored and the starting material was almost completely reacted. The reaction system was cooled to room temperature, and the reaction was quenched with 1 N 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 repeatedly extracted with methyl tert-butyl ether until no product residue remained in the aqueous phase. 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 to obtain 72 g of colorless oily intermediate 4 product, yield 82.7%.

[0079] Step 5:

[0080] Intermediate 4 (75 g, 0.398 mol, 1 eq) was dissolved in dichloromethane (525 mL, 7V). Then, N,N-diisopropylethylamine (77.2 g, 0.598 mol, 1.5 eq) and Boc anhydride (130.4 g, 0.598 mol, 1.5 eq) were added to the reaction system. The entire reaction system was stirred overnight at room temperature, and the reaction was monitored until the reactants were almost completely reacted. 500 mL of water was added to the reaction system for dilution and stirring. The organic phase was then separated, and the aqueous phase was extracted once more with 200 mL of dichloromethane. 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 to obtain 105 g of white solid intermediate 5 product, yield 91.4%.

[0081] Step 6:

[0082] Intermediate 5 (100 g, 0.347 mol, 1 eq) and methanol (500 mL, 5V) were added to a 1L hydrogenation reactor, followed by 20% palladium hydroxide (20 g, 20wt%). The reactor was purged with nitrogen three times and hydrogen twice, with a pressure of 5 MPa. The temperature was initially raised to 55°C and stirred for 12 hours. The reaction mixture was monitored until almost completely reacted. The reaction system was cooled to room temperature, and the reaction liquid was filtered twice using 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 purified by slurrying with methyl tert-butyl ether and dried under vacuum at 30°C for 3.5 hours to obtain 61 g of the target product TM as a white solid, with a yield of 88.7%.

[0083] Example 3

[0084] first step:

[0085] SM (50.0 g, 0.246 mol, 1.0 eq) and MeCN (500 mL, 10V) were added to a 1 L reaction flask and stirred until dissolved. NBS (219.0 g, 1.231 mol, 5.0 eq) and AIBN (20.2 g, 0.123 mol, 0.5 eq) were added at room temperature (20–25 °C), with N2 replacement three times. The temperature was then gradually increased to 55 °C (internal temperature) and the reaction was allowed to proceed for 36 h. The reaction solution was light yellow, and the starting material was almost completely eliminated as detected by the control panel. The reaction system was cooled to 20–25 °C, then further cooled to 0 °C using an ice bath. DIEA (127.2 g, 0.984 mol, 4.0 eq) was added dropwise, followed by diethyl phosphite (119.2 g, 0.861 mol, 3.5 eq). The system temperature was kept below 10 °C during the addition. After the addition was complete, the system was kept at this temperature for 30 min. A saturated sodium bicarbonate solution was added dropwise to the reaction system to adjust the pH to approximately 7-8, and then the temperature was allowed to rise naturally to 20-25°C. The reaction solution was distilled under reduced pressure below 35°C to remove most of the organic solvent. The remaining aqueous phase was repeatedly extracted three times with dichloromethane until no product residue remained. The combined organic phases were then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then slurried with petroleum ether, filtered, and a yellowish-brown solid was obtained. This solid was dried under vacuum at 30°C for 3.5 hours to yield 63.5 g of the target product, with a yield of 71.5%.

[0086] Step Two:

[0087] Dibromo intermediate 1 (200 g, 0.554 mol, 1.0 eq) and toluene (1000 mL, 5V) were added to a 2L reaction flask equipped with a mechanical stirrer and heater. Then, potassium carbonate (191.4 g, 1.385 mol, 2.5 eq) and tetrabutylammonium iodide (40.9 g, 0.111 mol, 0.2 eq) were added. Under stirring, the reaction system was gradually heated to 120℃. During this process, when the temperature reached 50℃, benzylamine (178.1 g, 1.662 mol, 3.0 eq) was added dropwise through a dropping funnel. The entire dropping process was controlled so that the benzylamine was added completely or nearly completely when the temperature reached 120℃. Then, the temperature was controlled at 120~125℃ and the reaction was continued for 3 hours. The starting material was almost completely eliminated by the monitoring. The reaction system was cooled to room temperature, and 2 L of water and 2 L of methyl tert-butyl ether were added. The mixture was stirred for 0.5 h and then allowed to stand for 0.5 h. The organic phase was separated by liquid-liquid extraction. The aqueous phase was extracted once more with 500 mL of methyl tert-butyl ether. The organic phases were combined, washed with 3V saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50°C until no droplets remained, yielding 106.3 g of the target intermediate 2 product, with a yield of 62.6%.

[0088] Step 3:

[0089] Intermediate 2 (100 g, 0.327 mol, 1 eq) and methanol (500 mL, 5V) were added to a 1L hydrogenation reactor, followed by 25 g (25 wt%) of 20% palladium hydroxide. The reactor was purged with nitrogen three times and hydrogen twice, with a pressure of 10 MPa. The temperature was initially raised to 35°C and stirred for 12 h. The reaction mixture was monitored until the reactants were 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 distilled once with 300 mL of dichloromethane and then purified by slurrying with methyl tert-butyl ether to obtain 65.5 g of white solid target intermediate 3, yield: 92.8%.

[0090] Step 4:

[0091] Intermediate 3 (100 g, 0.463 mol, 1 eq) was dissolved in THF (1000 mL, 10V). The reaction system was cooled in an ice bath, and a solution of diisobutylaluminum hydride tetrahydrofuran (1388 mL, 1.388 mol, 3 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 overnight. The reaction was monitored until 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 repeatedly extracted with methyl tert-butyl ether 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 to obtain 70.8 g of colorless oily intermediate 4 product, yield 81.3%.

[0092] Step 5:

[0093] Intermediate 4 (75 g, 0.398 mol, 1 eq) was dissolved in tetrahydrofuran (375 mL, 5V). Then, 160 mL of sodium bicarbonate solution (66.9 g, 0.797 mol, 2.0 eq) and Boc anhydride (113.1 g, 0.518 mol, 1.3 eq) were added to the reaction system. The entire reaction system was stirred overnight at room temperature, and the reaction was monitored until the reactants were almost completely reacted. 500 mL of water was added to the reaction system for dilution and stirring. The organic phase was then separated, and the aqueous phase was extracted once with 300 mL of methyl tert-butyl ether. 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 to obtain 98 g of white solid intermediate 5 product, yield 85.3%.

[0094] Step 6:

[0095] Intermediate 5 (100 g, 0.347 mol, 1 eq) and methanol (500 mL, 5V) were added to a 1L hydrogenation reactor, followed by 25 g (25wt%) of 20% palladium hydroxide. The reactor was purged with nitrogen three times and hydrogen twice at a pressure of 10 MPa. The temperature was initially raised to 35°C and stirred for 24 h. The reaction mixture was monitored until almost completely reacted. The reaction system was cooled to room temperature, and the reaction liquid was filtered twice using 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 purified by slurrying with methyl tert-butyl ether and dried under vacuum at 30°C for 3.5 h to obtain 58 g of the target product TM as a white solid, with a yield of 84.4%.

[0096] Comparative Example 1

[0097] A comparative experiment was conducted on the reaction in the first step. The only difference from the first step in Example 1 is that the specific experimental procedure is as follows:

[0098] SM (50.0 g, 0.246 mol, 1.0 eq) and MeCN (500 mL, 10V) were added to a 1 L reaction flask and stirred until dissolved. NBS (109.5 g, 0.615 mol, 2.5 eq) and AIBN (8.1 g, 0.049 mol, 0.2 eq) were added at room temperature (20–25 °C), followed by three N2 replacements. The temperature was then gradually increased to 50 °C (internal temperature) and reacted for 16 h. The reaction solution was light yellow, and the control panel detected residual starting material. The system was cooled to room temperature, and NBS (43.8 g, 0.246 mol, 1.0 eq) was added. The temperature was then increased to 50 °C (internal temperature) and the reaction continued for 6 h. The control panel detected that the starting material had almost disappeared. A saturated sodium bicarbonate solution was added dropwise to adjust the pH of the reaction solution to approximately 7–8, and then the temperature was allowed to rise naturally to 20–25 °C. The reaction solution was distilled under reduced pressure below 35°C to remove most of the organic solvent. The remaining aqueous phase was repeatedly extracted three times with dichloromethane until no product residue remained. The combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was pulped with petroleum ether, filtered, and a yellowish-brown solid was obtained. The solid was dried under vacuum at 30°C for 3.5 h to obtain 20.5 g of the target product, with a yield of 23.1%.

[0099] Comparative Example 2

[0100] A comparative experiment was conducted on the reaction in the second step. The only difference between the second step and the one in Example 1 is that the specific experimental procedure is as follows:

[0101] Dibromo intermediate 1 (200 g, 0.554 mol, 1.0 eq) and DMF (1000 mL, 5V) were added to a 2L reaction flask equipped with a mechanical stirrer and heater. Then, DIEA (164.7 g, 1.274 mol, 2.3 eq) and KI (18.5 g, 0.111 mol, 0.2 eq) were added. The reaction system was gradually heated to 50℃ under stirring. Benzylamine (65.3 g, 0.609 mol, 1.1 eq) was added dropwise through a dropping funnel. After the addition was complete, the temperature was raised to 120℃ and maintained at 120–125℃ for 2 hours. The reaction mixture was monitored until the starting material had almost disappeared. The reaction system was cooled to room temperature, and 2L of water and 2L of methyl tert-butyl ether were added. The mixture was stirred for 0.5 hours and then allowed to stand for another 0.5 hours. The organic phase was then separated by liquid-liquid chromatography. The aqueous phase was extracted once more with 500 mL of methyl tert-butyl ether. The organic phases were combined, washed with 3V saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50°C until no droplets remained, yielding 86.2 g of the target intermediate 2 product, with a yield of 50.8%.

[0102] Comparative Example 3

[0103] A comparative experiment was conducted on the reaction in the second step. The only difference between the second step and the one in Example 1 is that the specific experimental procedure is as follows:

[0104] Dibromo intermediate 1 (200 g, 0.554 mol, 1.0 eq) and DMF (1000 mL, 5V) were added to a 2L reaction flask equipped with a mechanical stirrer and heater. Then, DIEA (164.7 g, 1.274 mol, 2.3 eq) and KI (18.5 g, 0.111 mol, 0.2 eq) were added. Under stirring, benzylamine (65.3 g, 0.609 mol, 1.1 eq) was added dropwise through a dropping funnel at room temperature. After the addition was complete, the reaction system was gradually heated to 120℃, and then the temperature was controlled at 120-125℃ for 2 hours. The reaction mixture was monitored until the starting material was almost completely eliminated. The reaction system was cooled to room temperature, and 2L of water and 2L of methyl tert-butyl ether were added. The mixture was stirred for 0.5 hours and then allowed to stand for another 0.5 hours. The organic phase was then separated by liquid-liquid chromatography. The aqueous phase was extracted once more with 500 mL of methyl tert-butyl ether. The organic phases were combined, washed with 3V saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50°C until no droplets remained, yielding 70.3 g of the target intermediate 2 product, with a yield of 41.4%.

[0105] The applicant declares that this invention illustrates the synthesis method of 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane through the above embodiments, but this invention is not limited to the above embodiments, that is, it does not mean that this invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials for the product of this invention, additions of auxiliary components, and selection of specific methods, all fall within the protection scope and disclosure scope of this invention.

Claims

1. A method for synthesizing 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane, characterized in that, The method includes the following steps: (1) N-benzyl-2,6-piperidinedione SM reacts with a brominizing agent to give compound 1; (2) Compound 1 reacts with benzylamine under alkaline conditions to give compound 2; (3) Compound 2 undergoes a debenzylation protection reaction to give compound 3; (4) Compound 3 undergoes a carbonyl reduction reaction to give compound 4; (5) The amino group in compound 4 was subjected to a Boc protection reaction to obtain compound 5; (6) Compound 5 underwent a debenzylation protection reaction to give 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane as shown in TM. The reaction process is as follows: 。 2. The method according to claim 1, characterized in that, The brominating agent in step (1) is N-bromosuccinimide, dibromohydantoin, or bromine; Preferably, the molar ratio of N-benzyl-2,6-piperidinedione to the brominizing agent in step (1) is 1:3 to 1:

5.

3. The method according to claim 1 or 2, characterized in that, The reaction described in step (1) is carried out in the presence of an initiator; Preferably, the initiator is azobisisobutyronitrile; Preferably, the reaction in step (1) is carried out in a solvent selected from acetonitrile or carbon tetrachloride; Preferably, the temperature of the reaction in step (1) is 20~70℃ and the reaction time is 12~48h; Preferably, after the reaction in step (1) is completed, the reaction system is cooled to 20-25°C, and then further cooled to 0-10°C. N,N-diisopropylethylamine and diethyl phosphite are added, and then kept warm for 10-60 min. Preferably, the molar ratio of N,N-diisopropylethylamine to N-benzyl-2,6-piperidinedione is 1:1 to 1.2:1; Preferably, the molar ratio of diethyl phosphite to N-benzyl-2,6-piperidinide is 1:1 to 5:

1.

4. The method according to any one of claims 1-3, characterized in that, In step (2), the molar ratio of compound 1 to benzylamine is 1:1 to 1:3; Preferably, the alkaline conditions in step (2) are provided by an alkaline substance selected from any one or a combination of at least two of N,N-diisopropylethylamine (DIEA), triethylamine, potassium carbonate, or cesium carbonate; Preferably, the reaction in step (2) is carried out under the catalysis of a catalyst; Preferably, the catalyst is selected from any one or a combination of at least two of potassium iodide, sodium iodide, or tetrabutylammonium iodide.

5. The method according to any one of claims 1-4, characterized in that, The specific operation of the reaction in step (2) is as follows: Compound 1 is added to the system containing alkaline substances and catalysts, the reaction system is heated, and when the temperature reaches 50°C, benzylamine is added dropwise. During the dropwise addition, the temperature is gradually increased from 50°C to 120°C. After the dropwise addition is completed, the temperature is controlled at 120~125°C and the reaction continues for 1~3 hours. Preferably, the reaction in step (2) is carried out in a solvent selected from any one or a combination of at least two of N,N-dimethylformamide, N,N-dimethylacetamide or toluene.

6. The method according to any one of claims 1-5, characterized in that, The debenzylation protection reaction in step (3) is carried out under a hydrogen atmosphere; Preferably, the debenzylation protection reaction in step (3) is carried out under a pressure of 2-10 MPa; Preferably, the catalyst for the debenzylation protection reaction in step (3) is palladium hydroxide; Preferably, the debenzylation protection reaction in step (3) is carried out in a solvent, namely methanol; Preferably, the temperature of the debenzylation protection reaction in step (3) is 20~70℃ and the reaction time is 12~48h.

7. The method according to any one of claims 1-6, characterized in that, In step (4), the reducing agent in the reduction reaction is borane and / or diisobutylaluminum hydride; Preferably, the molar ratio of the reducing agent to compound 3 is 2.5:1 to 5:1; Preferably, the reduction reaction in step (4) is carried out in a solvent, which is selected from any one or a combination of at least two of tetrahydrofuran, methyl tert-butyl ether or isopropyl ether; Preferably, the reduction reaction in step (4) is carried out under nitrogen protection; Preferably, the specific operation of the reduction reaction in step (4) is to add the reducing agent dropwise to the reaction system containing compound 3, raise it to room temperature and stir for 6 to 24 hours, and then reflux for 1 to 3 hours to obtain compound 4.

8. The method according to any one of claims 1-7, characterized in that, The Boc protection reaction in step (5) is the reaction of compound 4 with Boc anhydride to obtain compound 5; Preferably, the molar ratio of compound 4 to Boc anhydride is 1:1 to 1:1.5; Preferably, the Boc protection reaction in step (5) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance is selected from any one or a combination of at least two of triethylamine, N,N-diisopropylethylamine, or sodium bicarbonate; Preferably, the Boc protection reaction in step (5) is carried out in a solvent selected from any one or at least a combination of two of dichloromethane, methanol, tetrahydrofuran, acetone or 1,4-dioxane; Preferably, the Boc protection reaction in step (5) is carried out at room temperature for 4 to 24 hours.

9. The method according to any one of claims 1-8, characterized in that, The benzyl protection reaction in step (6) is carried out under a hydrogen atmosphere; Preferably, the debenzylation protection reaction in step (6) is carried out under a pressure of 2 to 10 MPa.

10. The method according to any one of claims 1-9, characterized in that, The catalyst for the debenzylation protection reaction in step (6) is palladium hydroxide; Preferably, the debenzylation protection reaction in step (6) is carried out in a solvent, namely methanol; Preferably, the temperature of the debenzylation protection reaction in step (6) is 20~70℃ and the reaction time is 12~48h.

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