Synthesis method of 6-(t-butyloxycarboryl)-3, 6-diazabicyclo [3.1. 1] heptane

Abstract

The invention provides a synthesis method of 6-(t-butyloxycarboryl)-3, 6-diazabicyclo [3.1. 1] heptane, which comprises the following steps: starting from N-benzyl-2, 6-piperidinedione, firstly forming a dibromide 1, then forming a bridge ring intermediate 2 under alkaline conditions, then removing benzyl to obtain an intermediate 3, then reducing dicarbonyl to form free amine 4, and finally synthesizing the 6-(t-butyloxycarboryl)-3, 6-diazabicyclo [3.1. 1] heptane. Then performing Boc protection on amino to obtain an intermediate 5, and performing debenzylation to form a target product. According to the synthesis method, few impurities are generated, and the product is easy to purify and high in purity, so that the total yield is increased, the unit cost is effectively reduced, and large-scale industrial production is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of compound preparation and relates to a method for synthesizing 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane. Background Art

[0002] 6-(tert-Butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane is a key fragment of a drug containing an aza-bridged ring. The existing reported methods mainly use 2,4-dibromoglutaric acid dimethyl ester as the starting material, react with benzylamine to cyclize to generate 1-benzylazetidine-2,4-dicarboxylic acid dimethyl ester, and then reduce it to a diol with sodium borohydride, and then reduce the benzyl group with palladium hydroxide and perform Boc protection on the amino group to obtain 2,4-dihydroxymethyl-1-tert-butoxycarbonylazetidine, then perform Ts protection on the dihydroxyl group, and then react with benzylamine to close the ring to obtain 3-benzyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester, and finally perform palladium carbon hydrogenation reduction to obtain the target product. Other reported synthetic routes are also based on this with slight adjustments. Because the starting material 2,4-dibromoglutarate dimethyl ester exists in meso and racemic forms with a ratio of 1:2 to 2:3, and the racemic structure is not conducive to ring closure to form products, these methods result in low overall yields, many impurities, and difficulty in purification, resulting in high unit costs. Summary of the invention

[0003] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a method for synthesizing 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane. The purpose of the present invention is to provide a method for synthesizing 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane, which has few impurities, is easy to purify, and has high purity, thereby improving the total yield, effectively reducing the unit cost, and facilitating large-scale production by process technology.

[0004] To achieve this object, the present invention adopts the following technical solutions:

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

[0006] (1) N-benzyl-2,6-piperidindione reacts with a brominating agent to obtain compound 1;

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

[0008] (3) Compound 2 is subjected to a debenzylation protection reaction to obtain compound 3;

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

[0010] (5) performing a Boc protection reaction on the amino group in compound 4 to obtain compound 5;

[0011] (6) Compound 5 is subjected to a debenzylation reaction to obtain 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane as shown in TM. The reaction process is shown below:

[0012]

[0013] In the present invention, starting from N-benzyl-2,6-piperidindione, a dibromo compound 1 is first formed, and then a bridged ring intermediate 2 is formed under alkaline conditions, and then the benzyl group is removed to obtain an intermediate 3, and then the dicarbonyl group is reduced to form a free amine 4, and then the amino group is Boc protected to obtain an intermediate 5, and then the target product is formed by debenzylation. The synthetic method of the present invention produces less impurities, the product is easy to purify, and the purity is high, so that the total yield is improved, the unit cost is effectively reduced, and it is conducive to large-scale production by process technology.

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

[0015] Preferably, the molar ratio of the N-benzyl-2,6-piperidindione to the brominating 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 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°C, for example 20°C, 25°C, 30°C, 40°C, 50°C, 60°C or 70°C, 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 warm 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 produced. The addition of N,N-diisopropylethylamine and diethyl phosphite helps to convert all or most of the byproduct with the same carbon atom into the monobrominated target product.

[0022] Preferably, the molar ratio of N,N-diisopropylethylamine to N-benzyl-2,6-piperidindione 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-piperidindione 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 condition in step (2) is provided by an alkaline substance, and the alkaline substance is selected from any one of N,N-diisopropylethylamine (DIEA), triethylamine, potassium carbonate or cesium carbonate, or a combination of at least two thereof.

[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 of potassium iodide, sodium iodide or tetrabutylammonium iodide, or a combination of at least two thereof.

[0028] Preferably, the specific operation of the reaction in step (2) is: adding compound 1 to a system containing an alkaline substance and a catalyst, heating the reaction system, and when the temperature rises to 50°C, adding benzylamine dropwise, and raising the temperature from 50°C to 120°C during the addition process. After the addition is completed, the temperature is controlled at 120-125°C and the reaction is continued for 1-3h (e.g., 1h, 1.5h, 2h, 2.5h or 3h).

[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 reaction in step (3) is carried out under a hydrogen atmosphere.

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

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

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

[0034] Preferably, the temperature of the debenzylation protection reaction in step (3) is 20-70°C (e.g., 20°C, 25°C, 30°C, 40°C, 50°C, 60°C or 70°C), 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, and the solvent is selected from any one of tetrahydrofuran, methyl tert-butyl ether or isopropyl ether, or a combination of at least two thereof.

[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 dropwise add the reducing agent into the reaction system containing compound 3, warm to room temperature and stir for 6 to 24 hours (for example, 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 the compound 4.

[0040] Preferably, the Boc protection reaction in step (5) is the reaction of compound 4 with 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 of triethylamine, N,N-diisopropylethylamine or sodium bicarbonate, or a combination of at least two thereof.

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

[0045] Preferably, the Boc protection reaction in step (5) is carried out at room temperature for 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 debenzylation reaction in step (6) is carried out under a hydrogen atmosphere.

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

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

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

[0050] Preferably, the temperature of the debenzylation protection reaction in step (6) is 20-70°C (e.g., 20°C, 25°C, 30°C, 40°C, 50°C, 60°C or 70°C), 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-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane of the present invention has few impurities generated during the reaction, is easy to purify, and has high purity, thereby improving the total yield, effectively reducing the unit cost, and being conducive to technological large-scale production. DETAILED DESCRIPTION

[0053] 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.

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

[0055]

[0056] Example 1

[0057] This embodiment provides a method for preparing 6-(tert-butyloxycarbonyl)-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, 10 V) were added to a 1 L reaction bottle and stirred to dissolve. 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), and N2 was replaced 3 times. Then the temperature was gradually raised to 50 ° C (internal temperature) for 16 hours. The reaction liquid was light yellow. The raw material was still left after the central control test. After the system was cooled to room temperature, NBS (43.8 g, 0.246 mol, 1.0 eq) was added, and then the temperature was raised to 50 ° C (internal temperature) for 6 hours. The raw material almost disappeared after the central control test. The reaction system was cooled to 20-25°C, then the ice bath was changed to continue cooling to 0°C, DIEA (31.8 g, 0.246 mol, 1.0 eq) was added dropwise, and then diethyl phosphite (34.0 g, 0.246 mol, 1.0 eq) was added dropwise. During the addition, the system temperature was kept below 10°C. After the addition was completed, the temperature was kept for 30 min. A saturated sodium bicarbonate solution was added dropwise to the reaction system to adjust the pH value of the reaction solution to about 7-8, and then the temperature was naturally raised to 20-25°C. Most of the organic solvent was removed by vacuum distillation of the reaction solution below 35°C, and the residual aqueous phase was repeatedly extracted three times with dichloromethane until no product remained. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was slurried with petroleum ether and filtered to obtain a yellowish brown solid, which was vacuum dried at 30°C for 3.5h to obtain 67.2 grams of the target product with a yield of 75.6%.

[0060] Step 2:

[0061] Add dibromo intermediate 1 (200g, 0.554mol, 1.0eq) and DMF (1000mL, 5V) to a 2L reaction bottle equipped with a mechanical stirrer and a heating device, then add DIEA (164.7g, 1.274mol, 2.3eq) and KI (18.5g, 0.111mol, 0.2eq), and gradually heat the reaction system to 120°C under stirring. During this process, when the temperature rises to 50°C, benzylamine (65.3g, 0.609mol, 1.1eq) is added dropwise through a dropping funnel. The entire dropping process is controlled to be completed or nearly completed when the temperature rises to 120°C, and then the temperature is controlled at 120-125°C to continue the reaction for 2h. The raw material is almost gone when the central control detects. The reaction system is cooled to room temperature, 2L of water and 2L of methyl tert-butyl ether are added, stirred for 0.5h and then left to stand for 0.5h, and the organic phase is separated. The aqueous phase was extracted once with 500 mL of methyl tert-butyl ether, and the organic phases were combined, washed with 3V saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C until there were no droplets to obtain 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] Add intermediate 2 (100g, 0.327mol, 1eq) and methanol (500mL, 5V) to a 1L hydrogenation reactor, then add 20% palladium hydroxide (20g, 20wt%), replace with nitrogen 3 times, replace with hydrogen 2 times, pressure 3MPa, start heating to 50°C, stir for 12h, and the raw material is almost reacted by 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 methanol until there is no product residue, the collected filtrate is concentrated to dryness 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 65 grams of white solid target intermediate 3 product, yield: 92.1%.

[0064] Step 4:

[0065] The above intermediate 3 (100g, 0.463mol, 1eq) was dissolved in THF (1000mL, 10V), the reaction system was cooled in an ice bath, and a borane tetrahydrofuran solution (1850mL, 1.850mol, 4eq, 1M tetrahydrofuran solution) was slowly added under nitrogen protection. After the addition, the reaction system naturally rose to room temperature and stirred overnight, then refluxed and stirred 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 1N 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 methyl tert-butyl ether was added and repeatedly extracted until there was no product residue in the aqueous phase. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50°C to obtain 75 grams of intermediate 4 product as a colorless oil with a yield of 86.1%.

[0066] Step 5:

[0067] The above intermediate 4 (75g, 0.398mol, 1eq) was dissolved in dichloromethane (525mL, 7V), and then triethylamine (60.5g, 0.598mol, 1.5eq) and Boc anhydride (95.7g, 0.438mol, 1.1eq) were added to the reaction system. The whole reaction system was stirred overnight at room temperature, and the reaction of the raw material in the central control detection was almost complete. 500mL of water was added to the reaction system for dilution and stirring, and then the organic phase was separated, and the aqueous phase was extracted once with 200mL of dichloromethane, and 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 to obtain 100 grams of white solid intermediate 5 product, with a yield of 87.0%. 1 HNMR (400MHz, CDCl3) ppmδ: 1.48 (s, 9H), 1.76 (d, J = 8.0Hz, 1H), 2.38-2.45 (m, 1H), 2.7 4-2.82(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] Add intermediate 5 (100g, 0.347mol, 1eq) and methanol (500mL, 5V) to a 1L hydrogenation reactor, then add 20% palladium hydroxide (15g, 15wt%), replace with nitrogen 3 times, replace with hydrogen 2 times, pressure 3MPa, start heating to 60°C, stir for 12h, and the raw materials are 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 methanol until there is no product residue, the collected filtrate is concentrated under reduced pressure at 50°C, the residue is purified by pulping with methyl tert-butyl ether, and vacuum dried at 30°C for 3.5h to obtain 60g 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 = 8.0Hz, 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, 10 V) were added to a 1 L reaction bottle and stirred to dissolve. 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), and N2 was replaced 3 times. Then the temperature was gradually raised to 60 ° C (internal temperature) for 24 hours. The reaction solution was light yellow, and a trace amount of raw materials remained in the central control detection. The reaction system was cooled to 20-25 ° C, and then the ice bath was changed to continue to cool to 0 ° C, DIEA (47.7 g, 0.369 mol, 1.5 eq) was added dropwise, and then diethyl phosphite (51.0 g, 0.369 mol, 1.5 eq) was added dropwise. During the addition, the system temperature was kept below 10 ° C. After the addition was completed, it was kept warm for 30 minutes. A saturated sodium bicarbonate solution was added dropwise to the reaction system to adjust the pH value of the reaction solution to about 7-8, and then the pH value was naturally raised to 20-25°C. Most of the organic solvent was removed by vacuum distillation of the reaction solution below 35°C, and the residual aqueous phase was repeatedly extracted three times with dichloromethane until no product remained. The combined organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then slurried with petroleum ether and filtered to obtain a yellowish brown solid, which was vacuum dried at 30°C for 3.5h to obtain 50.5g of the target product with a yield of 56.8%.

[0073] Step 2:

[0074] Add dibromo intermediate 1 (200g, 0.554mol, 1.0eq) and DMF (1000mL, 5V) to a 2L reaction bottle equipped with a mechanical stirrer and a heating device, then add triethylamine (140.1g, 1.385mol, 2.5eq) and KI (27.6g, 0.166mol, 0.3eq), and gradually heat the reaction system to 120°C under stirring. During this process, when the temperature rises to 50°C, benzylamine (118.7g, 1.108mol, 2.0eq) is added dropwise through a dropping funnel. The entire dropping process is controlled to be completed or nearly completed when the temperature rises to 120°C, and then the temperature is controlled at 120-125°C to continue the reaction for 2h. The raw material is almost gone when the central control detects. The reaction system is cooled to room temperature, 2L of water and 2L of methyl tert-butyl ether are added, stirred for 0.5h and then left to stand for 0.5h, and the organic phase is separated. The aqueous phase was extracted once with 500 mL of methyl tert-butyl ether, and the organic phases were combined, washed with 3V saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C until there were no droplets to obtain 115 g of the target intermediate 2 product with a yield of 67.8%.

[0075] Step 3:

[0076] Add intermediate 2 (100g, 0.327mol, 1eq) and methanol (500mL, 5V) to a 1L hydrogenation reactor, then add 20% palladium hydroxide (15g, 15wt%), replace with nitrogen 3 times, replace with hydrogen 2 times, pressure 2MPa, start heating to 55°C, stir for 48h, and the raw material is almost reacted by 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 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 61.8 grams of white solid target intermediate 3 product, yield: 87.5%.

[0077] Step 4:

[0078] The above intermediate 3 (100g, 0.463mol, 1eq) was dissolved in THF (1000mL, 10V), the reaction system was cooled in an ice bath, and a borane dimethyl sulfide solution (231mL, 2.313mol, 5eq, 10M borane dimethyl sulfide solution) was slowly added under nitrogen protection, and the reaction system naturally rose to room temperature and stirred overnight, then refluxed and stirred for 2h, and the central control detected that the raw material was almost complete. The reaction system was cooled to room temperature, the reaction was quenched with 1N 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 methyl tert-butyl ether was added and repeatedly extracted until there was no product residue in the aqueous phase. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 50°C to obtain 72 grams of colorless oil intermediate 4 product, with a yield of 82.7%.

[0079] Step 5:

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

[0081] Step 6:

[0082] Add intermediate 5 (100g, 0.347mol, 1eq) and methanol (500mL, 5V) to a 1L hydrogenation reactor, then add 20% palladium hydroxide (20g, 20wt%), replace with nitrogen 3 times, replace with hydrogen 2 times, pressure 5MPa, start heating to 55°C, stir for 12h, and the raw materials are 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 methanol until no product remains, the collected filtrate is concentrated under reduced pressure at 50°C, the residue is purified by pulping with methyl tert-butyl ether, and vacuum dried at 30°C for 3.5h to obtain 61g 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, 10 V) were added to a 1 L reaction bottle and stirred to dissolve. 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), and N2 was replaced 3 times. Then the temperature was gradually raised to 55 ° C (internal temperature) for 36 hours. The reaction solution was light yellow, and the raw material almost disappeared in the central control test. The reaction system dropped to 20-25 ° C, and then the ice bath was changed to continue to cool to 0 ° C, DIEA (127.2 g, 0.984 mol, 4.0 eq) was added dropwise, and then diethyl phosphite (119.2 g, 0.861 mol, 3.5 eq) was added dropwise. During the addition, the system temperature was kept below 10 ° C. After the addition was completed, it was kept warm for 30 minutes. A saturated sodium bicarbonate solution was added dropwise to the reaction system to adjust the pH value of the reaction solution to about 7-8, and then the pH value was naturally raised to 20-25°C. Most of the organic solvent was removed by vacuum distillation of the reaction solution below 35°C, and the residual aqueous phase was repeatedly extracted three times with dichloromethane until no product remained. The combined organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then slurried with petroleum ether and filtered to obtain a yellowish brown solid, which was vacuum dried at 30°C for 3.5h to obtain 63.5g of the target product with a yield of 71.5%.

[0086] Step 2:

[0087] Add dibromo intermediate 1 (200g, 0.554mol, 1.0eq) and toluene (1000mL, 5V) to a 2L reaction bottle equipped with a mechanical stirrer and a heating device, then add potassium carbonate (191.4g, 1.385mol, 2.5eq) and tetrabutylammonium iodide (40.9g, 0.111mol, 0.2eq), and gradually heat the reaction system to 120°C under stirring. During this process, when the temperature rises to 50°C, benzylamine (178.1g, 1.662mol, 3.0eq) is added dropwise through a dropping funnel. The entire dropping process is controlled to be completed or nearly completed when the temperature rises to 120°C, and then the temperature is controlled at 120-125°C to continue the reaction for 3h. The raw material is almost gone when the central control detects that the reaction system is cooled to room temperature, 2L water and 2L methyl tert-butyl ether are added, stirred for 0.5h and then left to stand for 0.5h, and the organic phase is separated. The aqueous phase was extracted once with 500 mL of methyl tert-butyl ether, and the organic phases were combined, washed with 3V saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C until there were no droplets to obtain 106.3 g of the target intermediate 2 product with a yield of 62.6%.

[0088] Step 3:

[0089] Add intermediate 2 (100g, 0.327mol, 1eq) and methanol (500mL, 5V) to a 1L hydrogenation reactor, then add 20% palladium hydroxide (25g, 25wt%), replace with nitrogen 3 times, replace with hydrogen 2 times, pressure 10MPa, start heating to 35°C, stir for 12h, and the raw material is almost reacted by 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 methanol until there is no product residue, the collected filtrate is concentrated to dryness 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 65.5 grams of white solid target intermediate 3 product, yield: 92.8%.

[0090] Step 4:

[0091] The above intermediate 3 (100g, 0.463mol, 1eq) was dissolved in THF (1000mL, 10V), the reaction system was cooled in an ice bath, and diisobutylaluminum hydride tetrahydrofuran solution (1388mL, 1.388mol, 3eq, 1M tetrahydrofuran solution) was slowly added under nitrogen protection, the reaction system naturally rose to room temperature and stirred overnight, and the central control detected that the raw material was almost 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, and the remaining aqueous phase was adjusted to alkalinity with saturated sodium bicarbonate, followed by repeated extraction with methyl tert-butyl ether 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 to obtain 70.8 grams of intermediate 4 product as a colorless oil, with a yield of 81.3%.

[0092] Step 5:

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

[0094] Step 6:

[0095] Add intermediate 5 (100g, 0.347mol, 1eq) and methanol (500mL, 5V) to a 1L hydrogenation reactor, then add 20% palladium hydroxide (25g, 25wt%), replace with nitrogen 3 times, replace with hydrogen 2 times, pressure 10MPa, start heating to 35°C, stir for 24h, 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 methanol until no product remains, the collected filtrate is concentrated under reduced pressure at 50°C, the residue is purified by pulping with methyl tert-butyl ether, and vacuum dried at 30°C for 3.5h to obtain 58g 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 for the reaction in the first step, which was different from the first step in Example 1 only in that the specific experimental operation was as follows:

[0098] SM (50.0g, 0.246mol, 1.0eq) and MeCN (500mL, 10V) were added to a 1L reaction bottle and stirred to dissolve. NBS (109.5g, 0.615mol, 2.5eq) and AIBN (8.1g, 0.049mol, 0.2eq) were added at room temperature (20-25°C), and N2 was replaced 3 times. Then the temperature was gradually raised to 50°C (internal temperature) for 16h. The reaction solution was light yellow. The raw material was still remaining in the central control test. After the system was cooled to room temperature, NBS (43.8g, 0.246mol, 1.0eq) was added, and then the temperature was raised to 50°C (internal temperature) for 6h. The raw material was almost gone in the central control test. The reaction system was cooled to 20-25°C, and a saturated sodium bicarbonate solution was added to the reaction system to adjust the pH value of the reaction solution to about 7-8. The reaction solution was distilled under reduced pressure below 35°C to remove most of the organic solvent, and the residual aqueous phase was repeatedly extracted three times with dichloromethane until no product remained. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was slurried with petroleum ether and filtered to obtain a khaki solid, which was dried in vacuo 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 for the reaction in the second step, which was different from the second step in Example 1 only in that the specific experimental operation was as follows:

[0101] Add dibromo intermediate 1 (200g, 0.554mol, 1.0eq) and DMF (1000mL, 5V) to a 2L reaction bottle equipped with a mechanical stirrer and a heating device, then add DIEA (164.7g, 1.274mol, 2.3eq) and KI (18.5g, 0.111mol, 0.2eq), gradually heat the reaction system to 50°C under stirring, and start to drop benzylamine (65.3g, 0.609mol, 1.1eq) through a dropping funnel. After the addition is complete, raise the temperature to 120°C, control the temperature at 120-125°C and continue the reaction for 2h. The raw material almost disappears when detected by the central control. The reaction system is cooled to room temperature, 2L of water and 2L of methyl tert-butyl ether are added, stirred for 0.5h and then left to stand for 0.5h, and the organic phase is separated. The aqueous phase was extracted once again with 500 mL of methyl tert-butyl ether, and the organic phases were combined, washed with 3V saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C until there were no droplets to obtain 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 for the reaction in the second step, which was different from the second step in Example 1 only in that the specific experimental operation was as follows:

[0104] Add dibromo intermediate 1 (200g, 0.554mol, 1.0eq) and DMF (1000mL, 5V) to a 2L reaction bottle equipped with a mechanical stirrer and a heating device, then add DIEA (164.7g, 1.274mol, 2.3eq) and KI (18.5g, 0.111mol, 0.2eq), and add benzylamine (65.3g, 0.609mol, 1.1eq) through a dropping funnel at room temperature under stirring conditions. After the addition is complete, gradually heat the reaction system to 120°C, and then control the temperature at 120-125°C to continue the reaction for 2h. The raw material almost disappears in the central control test. The reaction system is cooled to room temperature, 2L of water and 2L of methyl tert-butyl ether are added, stirred for 0.5h and then left to stand for 0.5h, and the organic phase is separated. The aqueous phase was extracted once again with 500 mL of methyl tert-butyl ether, and the organic phases were combined, washed with 3V saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 50°C until there were no droplets to obtain 70.3 g of the target intermediate 2 product with a yield of 41.4%.

[0105] The applicant declares that the present invention uses the above-mentioned embodiments to illustrate the synthesis method of 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane of the present invention, 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 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane, characterized in that: The method comprises the following steps: (1) N-benzyl-2,6-piperidindione SM reacts with a bromination reagent to obtain compound 1; (2) Compound 1 reacts with benzylamine under alkaline conditions to obtain compound 2; (3) Compound 2 is subjected to a debenzylation protection reaction to obtain compound 3; (4) Compound 3 undergoes carbonyl reduction reaction to obtain compound 4; (5) performing a Boc protection reaction on the amino group in compound 4 to obtain compound 5; (6) Compound 5 is subjected to a debenzylation reaction to obtain 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane as shown in TM. The reaction process is shown below:

2. The method according to claim 1, characterized in that The bromination reagent in step (1) is N-bromosuccinimide, dibromohydantoin or bromine; Preferably, the molar ratio of the N-benzyl-2,6-piperidindione to the brominating agent in step (1) is 1:3 to 1:

5.

3. The method according to claim 1 or 2, characterized in that: The reaction 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 reaction temperature in step (1) is 20 to 70° C., and the reaction time is 12 to 48 hours; 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 minutes; Preferably, the molar ratio of N,N-diisopropylethylamine to N-benzyl-2,6-piperidindione is 1:1 to 1.2:1; Preferably, the molar ratio of diethyl phosphite to N-benzyl-2,6-piperidindione is 1:1 to 5:

1.

4. The method according to any one of claims 1 to 3, characterized in that In step (2), the molar ratio of compound 1 to benzylamine is 1:1 to 1:3; Preferably, the alkaline condition in step (2) is provided by an alkaline substance, and the alkaline substance is selected from any one or a combination of at least two of N,N-diisopropylethylamine, 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 of potassium iodide, sodium iodide or tetrabutylammonium iodide, or a combination of at least two thereof.

5. The method according to any one of claims 1 to 4, characterized in that The specific operation of the reaction in step (2) is as follows: adding compound 1 to a system containing an alkaline substance and a catalyst, heating the reaction system, and when the temperature rises to 50°C, adding benzylamine dropwise, and gradually raising the temperature from 50°C to 120°C during the addition process. After the addition is completed, controlling the temperature at 120-125°C and continuing the reaction for 1-3h; Preferably, the reaction in step (2) is carried out in a solvent, and the solvent is selected from any one of N,N-dimethylformamide, N,N-dimethylacetamide or toluene, or a combination of at least two thereof.

6. The method according to any one of claims 1 to 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 at a pressure of 2 to 10 MPa; Preferably, the catalyst for the debenzylation reaction in step (3) is palladium hydroxide; Preferably, the debenzylation protection reaction in step (3) is carried out in a solvent, and the solvent is methanol; Preferably, the temperature of the debenzylation protection reaction in step (3) is 20 to 70° C., and the reaction time is 12 to 48 hours.

7. The method according to any one of claims 1 to 6, characterized in that In the reduction reaction of step (4), the reducing agent 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, and the solvent 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 drop the reducing agent into the reaction system containing compound 3, warm 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 to 7, characterized in that The Boc protection reaction in step (5) is a 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, and the solvent is selected from any one or a combination of at least 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 to 8, characterized in that The debenzylation reaction in step (6) is carried out under a hydrogen atmosphere; Preferably, the debenzylation 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 to 9, characterized in that The catalyst for the debenzylation reaction in step (6) is palladium hydroxide; Preferably, the debenzylation protection reaction in step (6) is carried out in a solvent, and the solvent is methanol; Preferably, the temperature of the debenzylation protection reaction in step (6) is 20 to 70° C., and the reaction time is 12 to 48 hours.

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