A process for the preparation of (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane

Abstract

The application discloses a preparation process of (1R, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane, which comprises the following steps: taking 3-methyl-2-butenoic acid ethyl ester as a starting raw material, carrying out an electrophilic addition reaction with bromine in dichloromethane to obtain compound a; taking acetone as a solvent, and performing a removal reaction on the compound a in the presence of anhydrous potassium carbonate to obtain compound b; taking methanol as a solvent, adding sodium methoxide, adding 2-cyanoacetic acid ethyl ester into the system, and performing a nucleophilic addition reaction on the compound b to obtain compound c; taking dimethyl sulfoxide as a solvent, taking lithium chloride as a catalyst, and performing a deesterification reaction on the compound c in the presence of water to obtain compound d; taking methanol as a solvent, taking Raney nickel as a catalyst, adding 7M ammonia / methanol solution, and performing a cyclization reaction on the compound d to obtain compound e; and taking tetrahydrofuran as a solvent, taking lithium aluminum hydride as a catalyst, and reducing the compound e to obtain the product (1R, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane.

Description

Technical Field

[0001] This invention relates to the field of fine chemical synthesis technology, specifically to a preparation process for (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane. Background Technology

[0002] (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane is an important pharmaceutical intermediate that can be further used to prepare (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester, both of which can be used in the synthesis of drugs, such as the hepatitis C virus (HCV) protease inhibitor Boceprevir, and has good market prospects.

[0003] Currently, there are three reported synthetic routes for (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane (patent CN 101384551A, WO 2007075790A1, WO 2009073380A1, US 20100145069A1).

[0004]

[0005] It is evident that all existing synthesis methods use caron anhydride as the starting material.

[0006] Route 1 involves catalytic conversion of an imide to an alkylimide using a catalyst (such as 4-N,N-dimethylaminopyridine or dimethylpyridine) in the presence of a nitrogen source (NH3 or NH4OH, etc.), followed by reduction with lithium aluminum hydride to obtain the target product. Route 2 involves adding an aralkyl / alkenylamine to generate an intermediate alkylimide, then hydrogenating the intermediate with a palladium-on-carbon catalyst under hydrogen-mediated conditions to obtain the imide, and finally reducing it with lithium aluminum hydride. Route 3 simply reverses the last two steps of Route 2, performing reduction followed by hydrogenation.

[0007] However, the starting material, carnelian anhydride, has limited upstream sources and is expensive. Furthermore, the most commonly used synthesis methods among the three are routes 2 and 3, but the hydrogenation process in both routes involves the use of palladium-on-carbon catalysts, further increasing production costs and requiring improvement for industrial production. Summary of the Invention

[0008] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of this invention, the following terms are defined below.

[0009] Those skilled in the art will understand that "about" or "approximately" will vary to some extent in the context in which the term is used. If the use of a term is unclear to those skilled in the art, "about" or "approximately" will mean up to 20% plus or minus the specific term, taking into account the context in which it is used.

[0010] When the term “and / or” is used to connect two or more options, it should be understood to mean any one of the options or any two or more of the options.

[0011] As used herein, the terms “comprising” or “including” mean including the mentioned elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this document, when the terms “comprising” or “including” are used, unless otherwise specified, they also cover situations consisting of the mentioned elements, integers, or steps. For example, when referring to “comprising” or “including” a specific ingredient, it is also intended to cover mixtures consisting of that specific ingredient.

[0012] The phrase "mainly composed of..." as used herein refers to the principal component constituting the mixture. Unless otherwise specified, a component with a weight percentage greater than 50% is generally considered a principal component. A principal component can be a pure substance or a mixture of similar structures or chemical properties that, as those skilled in the art would recognize, can generally be grouped together.

[0013] Any references to temperature ranges, pH ranges, weight (mass) ranges, molecular weight ranges, percentage ranges, etc., in this document, whether expressed using the terms "range" or "various ranges," include the specified endpoints and the points between the two endpoints.

[0014] To address the high production cost issue in the aforementioned method for synthesizing (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane using carronic anhydride as a starting material (and potentially further using palladium as a catalyst), this invention discloses a novel process for preparing (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane. This process uses cheaper starting materials and catalysts, and achieves higher reaction yield and selectivity, resulting in a higher overall yield and reduced production costs.

[0015]

[0016] To achieve the above objectives, the present invention provides the following technical solution:

[0017] In one or more specific embodiments, the present invention provides a process for preparing one or more (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane.

[0018] In one or more specific embodiments, the present invention discloses a process for preparing one or more (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane, comprising the following steps: using ethyl 3-methyl-2-butenoate as a starting material and dichloromethane as a solvent, reacting it with bromine via an electrophilic addition reaction to obtain compound a; using acetone as a solvent, in the presence of anhydrous potassium carbonate, compound a undergoes an elimination reaction to generate compound b; using methanol as a solvent, adding sodium methoxide, and then adding 2... Ethyl cyanoacetate undergoes a nucleophilic addition reaction with compound b to give compound c; in the presence of water, with dimethyl sulfoxide as solvent and lithium chloride as catalyst, compound c undergoes a deesterification reaction to give compound d; with methanol as solvent and Raney nickel as catalyst, and with the addition of 7M ammonia / methanol solution, compound d undergoes a cyclization reaction to give compound e; with tetrahydrofuran as solvent and lithium aluminum hydride as catalyst, compound e is reduced to the product (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane.

[0019] In one or more specific embodiments, the preparation process of (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane includes the following preparation steps:

[0020] S400: (1S,2R)-1-cyano-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid dimethyl ester (compound c) is produced by a defatting reaction to generate methyl (1S,3R)-3-cyano-2,2-dimethylcyclopropane-1-carboxylic acid ester (compound d);

[0021] S500: (1R-5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-one (compound e) is generated by cyclization of methyl (1S,3R)-3-cyano-2,2-dimethylcyclopropane-1-carboxylic acid ester (compound d) as a reactant or intermediate;

[0022] S600: (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane is produced by the reduction reaction of (1R-5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane, which is used as a reactant or intermediate.

[0023] In one or more of these embodiments, the defatting reaction in S400 further includes the following steps:

[0024] (1S,2R)-1-cyano-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid dimethyl ester and lithium chloride were dissolved in a fourth organic solvent (preferably dimethyl sulfoxide), water was added, and the system was heated to 160-170°C for reaction. After the reaction was completed, the system was cooled to room temperature, and excess water was added. After phase separation, extraction, washing, drying, and concentration and purification, methyl (1S,3R)-3-cyano-2,2-dimethylcyclopropane-1-carboxylic acid ester was obtained.

[0025] In one or more specific embodiments, the defatting reaction in S400 further includes the following steps:

[0026] Compound c and lithium chloride were dissolved in a fourth organic solvent, such as dimethyl sulfoxide (DMSO), and water was added. The system was heated to 160–170 °C and reacted for about 30 min. Thin-layer chromatography (TLC) was used for detection. After the reactants had reacted completely, the reaction solution was cooled to room temperature, and about 2 times the volume of water was added. After phase separation, extraction, combining of organic phases, washing and drying, the solution was concentrated under reduced pressure at about 40 °C and purified by column chromatography to obtain compound d.

[0027]

[0028] In one or more of these embodiments, the cyclization reaction in S500 further includes the following steps:

[0029] In a high-pressure reactor, methyl (1S,3R)-3-cyano-2,2-dimethylcyclopropane-1-carboxylic acid ester and Raney nickel are dissolved in a fifth organic solvent (preferably methanol), and ammonia (preferably an ammonia / methanol solution with a molar concentration of about 7M) is added; the high-pressure reactor is purged with an inert atmosphere such as argon and hydrogen respectively, then purged with hydrogen and pressurized, and then heated to react; after the reaction is completed, it is concentrated and purified to obtain (1R-5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-one.

[0030] In one or more specific embodiments, the cyclization reaction in S500 further includes the following steps:

[0031] Compound d and Raney nickel were dissolved in a fifth organic solvent, such as methanol (MeOH), in a high-pressure reactor, and an ammonia / methanol solution with a molar concentration (activity) of approximately 7 M was added. After repeated purging with argon and hydrogen approximately five times, the system was purged with hydrogen and pressurized, then heated to approximately 80 °C and reacted for approximately 16 h. TLC analysis showed that after the reaction was complete, diatomaceous earth-assisted filtration was performed, and the filter cake was washed clean with a fifth organic solvent (e.g., methanol) and concentrated under reduced pressure at approximately 40 °C to obtain compound e.

[0032]

[0033] In one or more of these embodiments, the reduction reaction in S600 further includes the following steps:

[0034] (1R-5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-one was dissolved in a sixth organic solvent (preferably tetrahydrofuran). The system was cooled under an inert atmosphere and lithium aluminum hydride was added to react. The mixture was then heated to reflux. After the reaction was completed, the reaction was quenched by cooling and the product (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane was obtained by concentration and purification.

[0035] In one or more specific embodiments, the reduction reaction in S600 further includes the following steps:

[0036] Compound e was dissolved in a sixth organic solvent, such as tetrahydrofuran (THF). Under an inert atmosphere such as nitrogen or argon, the system was cooled to 0–5 °C, and lithium aluminum hydride was slowly added in batches. The reaction was maintained at this temperature for about 30 min, and then the temperature was raised to about 50 °C and refluxed for about 3 h. After the reaction of the starting materials was completed by TLC, the system was cooled to 0–5 °C to quench the reaction, filtered, and the filter cake was washed clean with an organic solvent (preferably ethyl acetate). After concentration and drying under reduced pressure at about 40 °C, the product (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane was purified by column chromatography.

[0037]

[0038] In one or more of these embodiments, the (1S,2R)-1-cyano-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid dimethyl ester in S400 is prepared from ethyl 3-methyl-2-butenoate via the following preparation steps:

[0039] S100: Dibromo-2,3-methyl-3-butenoate ethyl ester is generated by electrophilic addition reaction of 3-methyl-2-butenoate ethyl ester;

[0040] S200: Ethyl 2-bromo-3,3-dimethylacrylate is generated from ethyl dibromo-2,3-methyl-3-butyrate via an elimination reaction;

[0041] S300: (1S,2R)-1-cyano-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid dimethyl ester is generated by the nucleophilic addition reaction of ethyl 2-bromo-3,3-dimethacrylate.

[0042] In one or more specific embodiments, the electrophilic addition reaction in S100 further includes the following steps:

[0043] Ethyl 3-methyl-2-butenoate is dissolved in a first organic solvent (preferably dichloromethane), cooled, and bromine is added; after the reaction is complete, the solution is concentrated and dried to obtain ethyl dibromo-2,3-methyl-3-butanoate.

[0044] In one or more specific embodiments, the electrophilic addition reaction in S100 further includes the following steps:

[0045] Ethyl 3-methyl-2-butenoate was dissolved in a first organic solvent, such as dichloromethane (DCM), and the system was then cooled to -5 to 5°C. Bromine was slowly added dropwise, and the reaction was maintained at this temperature for about 2 hours. TLC analysis showed that after the reactants had completely reacted, the reaction solution was concentrated under reduced pressure at about 30°C and dried to obtain compound a, which was directly used in the next reaction step.

[0046]

[0047] In one or more of these embodiments, the elimination reaction in S200 further includes the following steps:

[0048] Ethyl dibromo-2,3-methyl-3-butyrate is dissolved in a second organic solvent (preferably acetone), and anhydrous potassium carbonate is added and the mixture is refluxed. After the reaction is complete, the mixture is cooled, filtered, and the filtrate is concentrated and dried to obtain ethyl 2-bromo-3,3-dimethylacrylate.

[0049] In one or more specific embodiments, the elimination reaction in S200 further includes the following steps:

[0050] Compound a was dissolved in a second organic solvent, such as acetone (PA), and anhydrous potassium carbonate was added with stirring. The system was heated to reflux for about 12 hours. After the reactants had reacted completely, the reaction solution was cooled to room temperature and then filtered. The filter cake was washed clean with an organic solvent, such as ethyl acetate. The filtrate was concentrated under reduced pressure at about 40°C and dried to obtain compound b, which was used directly in the next reaction.

[0051]

[0052] In one or more of these embodiments, the nucleophilic addition reaction in S300 further comprises the following steps:

[0053] Sodium methoxide, ethyl 2-bromo-3,3-dimethylacrylate, and ethyl 2-cyanoacetate were added and dissolved in a third organic solvent (preferably methanol) and refluxed. After the reaction was completed, the reaction was quenched by cooling. After phase separation, extraction, washing, drying, and concentration and purification, (1S,2R)-1-cyano-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid dimethyl ester was obtained.

[0054] In one or more specific embodiments, the nucleophilic addition reaction in S300 further includes the following steps:

[0055] Sodium methoxide, compound b, and ethyl 2-cyanoacetate were sequentially added and dissolved in a third organic solvent, such as methanol (MeOH), at 0–10 °C. The system was heated to reflux and reacted for approximately 16 h. TLC analysis was performed. After the reactants had reacted completely, the reaction solution was cooled to room temperature to quench the reaction. The mixture was then separated, extracted, combined, washed, and dried. The solution was concentrated under reduced pressure at approximately 40 °C and purified by column chromatography to obtain compound c.

[0056]

[0057] In one or more of these embodiments, the molar ratio of ethyl 3-methyl-2-butenoate to bromine in S100 is approximately 1:1.

[0058] In one or more of these embodiments, the molar ratio of ethyl dibromo-2,3-methyl-3-butyrate to anhydrous potassium carbonate in S200 is approximately 1:3.

[0059] In one or more of these embodiments, the molar ratio of ethyl 2-bromo-3,3-dimethacrylate to ethyl 2-cyanoacetate to sodium methoxide in S300 is approximately 1:5:2.

[0060] In one or more of these embodiments, the molar ratio of (1S,2R)-1-cyano-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid dimethyl ester to lithium chloride to water in S400 is approximately 1:7:7.

[0061] In one or more of these embodiments, the molar ratio of methyl(1S,3R)-3-cyano-2,2-dimethylcyclopropane-1-carboxylic acid ester to Raney nickel in S500 is approximately 1:0.67.

[0062] In one or more of these embodiments, the ammonia in S500 is an approximately 7M ammonia / methanol solution.

[0063] In one or more of these embodiments, the volume ratio of 7M ammonia / methanol solution to methanol in S500 is approximately 1:3.

[0064] In one or more of these embodiments, the pressure inside the high-pressure reactor in S500 is approximately 2.0 MPa after pressurization.

[0065] In one or more of these embodiments, the molar ratio of (1R-5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-one to lithium aluminum hydride in S600 is approximately 1:1.5.

[0066] In one or more of these embodiments, the reaction quencher in S300 or S600 is preferably a saturated aqueous solution of ammonium chloride.

[0067] In one or more of these embodiments, the reaction in steps S100, S200, S300, S400, S500, and S600 is completed and tracked by TLC. The developing solvent for the TLC is selected from petroleum ether and ethyl acetate, with a volume ratio of petroleum ether to ethyl acetate of approximately 3:1.

[0068] More specifically, the preparation process of one or more (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane provided by the present invention includes the following steps:

[0069] (1) Electrophilic addition reaction

[0070] Ethyl 3-methyl-2-butenoate was dissolved in dichloromethane (DCM) under stirring. The system was then cooled to -5 to 5°C, and bromine was slowly added dropwise. The reaction was maintained at this temperature for about 2 hours. Thin-layer chromatography (TLC) was used for detection. After the reactants had reacted completely, the reaction solution was concentrated under reduced pressure at about 30°C and dried to obtain compound a, which was used directly in the next reaction step.

[0071]

[0072] (2) Elimination reaction

[0073] Compound a was dissolved in acetone, and anhydrous potassium carbonate was added with stirring. The system was heated to reflux for about 12 hours. After the reactants had reacted completely, the reaction solution was cooled to room temperature and then filtered. The filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure at about 40°C and dried to obtain compound b, which was used directly in the next reaction.

[0074]

[0075] (3) Nucleophilic addition reaction

[0076] Sodium methoxide, compound b, and ethyl 2-cyanoacetate were sequentially added to and dissolved in methanol at 0–10 °C. The system was heated to reflux and reacted for approximately 16 h. TLC analysis was performed. After the reactants had completely reacted, the reaction solution was cooled to room temperature to quench the reaction. Phase separation, extraction, combining of organic phases, washing, and drying were performed, followed by vacuum treatment at approximately 40 °C.

[0077]

[0078] The compound was concentrated and purified by column chromatography to obtain compound c.

[0079] (4) Deesterification reaction

[0080] Compound c and lithium chloride were dissolved in dimethyl sulfoxide (DMSO), water was added, and the system was heated to 160–170 °C and reacted for about 30 min. TLC was used for monitoring. After the reactants had reacted completely, the reaction solution was cooled to room temperature, and then about twice the volume of water was added. Phase separation, extraction, combining of the organic phases, washing, and drying were performed, followed by reaction at approximately 40 °C.

[0081]

[0082] The compound d was obtained by concentration under reduced pressure and purification by column chromatography.

[0083] (5) Cycling reaction

[0084] Compound d and Raney nickel were dissolved in methanol in a high-pressure reactor, and approximately 7M ammonia / methanol solution was added. After repeated purging with argon and hydrogen approximately five times, the system was purged with hydrogen and pressurized, then heated to approximately 80°C and reacted for approximately 16 hours. TLC analysis showed that after the reaction was complete, diatomaceous earth-assisted filtration was performed, the filter cake was washed clean with methanol, and concentrated under reduced pressure at approximately 40°C to obtain compound e.

[0085]

[0086] (6) Reduction reaction

[0087] Compound e was dissolved in tetrahydrofuran (THF). Under nitrogen protection, the system was cooled to 0–5°C, and lithium aluminum hydride was slowly added in batches. The reaction was maintained at this temperature for approximately 30 minutes, then the temperature was raised to approximately 50°C and refluxed for approximately 3 hours. TLC analysis was performed. After the reaction was complete, the system was cooled to 0–5°C to quench the reaction, and the mixture was filtered.

[0088]

[0089] The cake was washed with ethyl acetate, concentrated and dried under reduced pressure at about 40°C, and then purified by column chromatography to obtain the product (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane.

[0090] Furthermore, in step (1), the molar ratio of ethyl 3-methyl-2-butenoate to bromine is approximately 1:1.

[0091] Furthermore, in step (2), the molar ratio of compound a to anhydrous potassium carbonate is approximately 1:3.

[0092] Furthermore, in step (3), the molar ratio of compound b to ethyl 2-cyanoacetate to sodium methoxide is approximately 1:5:2.

[0093] Furthermore, in step (4), the molar ratio of compound c to lithium chloride to water is approximately 1:7:7.

[0094] Furthermore, in step (5), the molar ratio of compound d to Raney nickel is approximately 1:0.67.

[0095] Furthermore, in step (5), the volume ratio of 7M ammonia / methanol solution to methanol is approximately 1:3.

[0096] Furthermore, in step (5), the pressure inside the high-pressure reactor after pressurization is approximately 2.0 MPa.

[0097] Furthermore, in step (6), the molar ratio of compound e to lithium aluminum hydride is approximately 1:1.5.

[0098] Furthermore, the reaction quencher in steps (3) and (6) is a saturated ammonium chloride aqueous solution.

[0099] Furthermore, the reaction in steps (1), (2), (3), (4), (5), and (6) is completed by TLC tracking, and the developing solvent for TLC tracking is selected from petroleum ether and ethyl acetate, with a volume ratio of petroleum ether to ethyl acetate of approximately 3:1.

[0100] Compared with the three existing synthetic methods using caron anhydride as a starting material, the present invention has the following advantages and beneficial effects:

[0101] The (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane preparation process provided by this invention completely breaks through previous synthesis techniques. For the starting materials, inexpensive ethyl 3-methyl-2-butenoate and ethyl 2-cyanoacetate were selected (caronic anhydride has a market price 4.7–8.9 times and 28.5–54.0 times that of ethyl 3-methyl-2-butenoate and ethyl 2-cyanoacetate, respectively). In existing technologies, caronic anhydride reacts with aralkyl / alkenylamines to generate alkylimides, which require hydrogenation to obtain imides. However, this invention directly cyclizes to obtain imides, avoiding the use of expensive palladium-on-carbon catalysts during hydrogenation (palladium-on-carbon catalysts have a market price 15.7–74.0 times that of Raney nickel catalysts). The process of this invention significantly reduces production costs and has less environmental pollution, making it more suitable for industrial production. Attached Figure Description

[0102] Figure 1 The H-NMR spectrum of the oily final product obtained from the reaction. Detailed Implementation

[0103] The technical solutions provided by the present invention will be described in detail below with reference to specific embodiments. It should be understood that the following specific embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0104] Example 1

[0105] Electrophilic addition reaction: 100 ml of DCM and 10.0 g (0.078 mol) of ethyl 3-methyl-2-butenoate were added sequentially to a 250 ml reaction flask. The mixture was stirred, and the system was cooled to -5 to 5 °C. 12.5 g (0.078 mol) of bromine was slowly added dropwise while maintaining the system temperature at -5 to 5 °C. The addition process was exothermic. After the addition was complete, the reaction was maintained at this temperature for 2 hours. TLC analysis showed that after the reactants had reacted completely, the reaction solution was directly concentrated and dried under reduced pressure at 30 °C to obtain 22.9 g (0.079 mol) of a red oily substance (compound a), with a yield of 102% (containing a small amount of solvent and bromine). This product was directly used in the next reaction step.

[0106] Example 2

[0107] Elimination reaction: 114.5 ml of acetone and 22.9 g (0.079 mmol) of compound a were added sequentially to a 250 ml reaction flask. 32.9 g (0.239 mmol) of anhydrous potassium carbonate was added with stirring, and the mixture was heated to reflux for 12 h. TLC analysis showed that after the reactants had reacted completely, the reaction solution was cooled to room temperature and then filtered. The filter cake was washed clean with ethyl acetate, and the filtrate was concentrated and dried under reduced pressure at 40 °C to obtain 16.2 g (0.079 mmol) of a pale yellow oil (compound b), with a yield of 100%, which was directly used in the next reaction step.

[0108] Example 3

[0109] Nucleophilic addition reaction: 500 mL of methanol was added to a 1000 mL reaction flask, and the system was cooled to 0–10 °C. 26.0 g (0.482 mol) of sodium methoxide was slowly added in portions. After the addition was complete, the system was kept at 0–10 °C, and 136.5 g (1.205 mol) of ethyl 2-cyanoacetate and 50.0 g (0.241 mol) of compound b were added sequentially. After the addition was complete, the system was heated to reflux for 16 h. TLC analysis showed that after the reactants had reacted completely, the reaction solution was cooled to room temperature, and the reaction was quenched with saturated ammonium chloride aqueous solution. The phases were separated, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 °C, and purified by column chromatography to collect 27.0 g (0.128 mol) of a colorless solid (compound c), with a yield of 53%.

[0110] Example 4

[0111] Deesterification reaction: 270 ml DMSO, 16.1 g (0.896 mol) water, 27.0 g (0.128 mol) compound c, and 37.9 g (0.896 mol) lithium chloride were added sequentially to a 500 ml reaction flask. Heating was initiated, and the system was heated to 160–170 °C for 30 min. TLC analysis was performed. After the reactants had reacted completely, the reaction solution was cooled to room temperature, and twice the volume of water was added. The mixture was extracted four times with ethyl acetate, and the organic phases were combined. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40 °C, and purified by column chromatography to collect 12.7 g (0.083 mol) of a white solid (compound d), with a yield of 65%.

[0112] Example 5

[0113] Cyclization reaction: 150 ml of methanol, 50 ml of 7M ammonia / methanol solution, 10.0 g (0.065 mol) of compound d, and 10.0 g (0.044 mol) of Raney nickel were added to a 500 ml high-pressure reactor. The reactor was purged with argon five times, then with hydrogen five times. The system was then purged with hydrogen and pressurized to 2.0 MPa, and heated to 80 °C for 16 h. TLC analysis showed that after the reactants had reacted completely, the mixture was filtered with diatomaceous earth. The filter cake was washed clean with methanol and concentrated under reduced pressure at 40 °C to obtain 6.87 g (0.055 mol) of a white solid (compound e), with a yield of 84%.

[0114] Example 6

[0115] Reduction reaction: Add 50 ml THF and 5.0 g (0.040 mol) of compound e to a 100 ml reaction flask. Under nitrogen protection, cool the system to 0–5 °C, and slowly add 2.3 g (0.060 mol) of lithium aluminum hydride in batches, controlling the system temperature at 0–5 °C. After the addition is complete, maintain the temperature for 30 min, then reflux at 50 °C for 3 h. TLC detection shows that after the reactants have reacted completely, cool the system to 0–5 °C, add 5 ml of ammonium chloride aqueous solution to quench the reaction, filter, wash the filter cake with ethyl acetate, concentrate under reduced pressure at 40 °C, and then purify by column chromatography to obtain an oily substance (target product (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane) 3.3 g (0.030 mol), yield 75%. The H-NMR spectrum is shown below. Figure 1 .

[0116] The above embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. Any improvements or equivalent substitutions made by those skilled in the art based on the technical solutions of the present invention without departing from the principles of the present invention should be covered within the protection scope of the present invention.

Claims

1. A process for preparing (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane, characterized in that: The preparation process includes the following steps: S400: Methyl(1S,3R)-3-cyano-2,2-dimethylcyclopropane-1,2-dicarboxylic acid ester is generated by the defatting reaction of (1S,2R)-1-cyano-3,3-dimethylcyclopropane-1-carboxylic acid ester. S500: In a high-pressure reactor, methyl (1S,3R)-3-cyano-2,2-dimethylcyclopropane-1-carboxylic acid ester and Raney nickel are dissolved in a fifth organic solvent, and ammonia is added; the high-pressure reactor is purged with hydrogen and pressurized, and then the temperature is increased to react; after the reaction is completed, it is concentrated and purified to obtain (1R-5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-one; S600: (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-one is reduced to (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane.

2. The preparation process of (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane as described in claim 1, characterized in that: (1) The defatting reaction in S400 further includes the following steps: (1S,2R)-1-cyano-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid dimethyl ester and lithium chloride were dissolved in a fourth organic solvent, water was added, and the system was heated to 160-170℃ for reaction. After the reaction was completed, the system was cooled to room temperature, and excess water was added. After phase separation, extraction, washing, drying, and concentration and purification, methyl (1S,3R)-3-cyano-2,2-dimethylcyclopropane-1-carboxylic acid ester was obtained. (2) The reduction reaction in S600 further includes the following steps: (1R-5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-one was dissolved in a sixth organic solvent. The system was cooled under an inert atmosphere and lithium aluminum hydride was added to react. The mixture was then heated to reflux. After the reaction was completed, the reaction was quenched by cooling and the product (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane was obtained by concentration and purification.

3. The preparation process of (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane as described in claim 1 or 2, characterized in that: In S400, (1S,2R)-1-cyano-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid dimethyl ester is prepared from ethyl 3-methyl-2-butenoate via the following preparation steps: S100: Dibromo-2,3-methyl-3-butenoate ethyl ester is generated by electrophilic addition reaction of 3-methyl-2-butenoate ethyl ester; S200: Ethyl 2-bromo-3,3-dimethylacrylate is generated from ethyl dibromo-2,3-methyl-3-butyrate via an elimination reaction; S300: (1S,2R)-1-cyano-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid dimethyl ester is generated by the nucleophilic addition reaction of ethyl 2-bromo-3,3-dimethacrylate.

4. The preparation process of (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane as described in claim 3, characterized in that: (1) The electrophilic addition reaction in S100 further includes the following steps: Ethyl 3-methyl-2-butenoate was dissolved in a first organic solvent, cooled, and bromine was added; after the reaction was completed, the solution was concentrated and dried to obtain ethyl dibromo-2,3-methyl-3-butanoate. (2) The elimination reaction in S200 further includes the following steps: Ethyl dibromo-2,3-methyl-3-butyrate was dissolved in a second organic solvent, and anhydrous potassium carbonate was added and the mixture was refluxed. After the reaction was completed, the mixture was cooled, filtered, and the filtrate was concentrated and dried to obtain ethyl 2-bromo-3,3-dimethylacrylate. (3) The nucleophilic addition reaction in S300 further includes the following steps: Sodium methoxide, ethyl 2-bromo-3,3-dimethylacrylate, and ethyl 2-cyanoacetate were added and dissolved in a third organic solvent and refluxed. After the reaction was completed, the reaction was quenched by cooling. After phase separation, extraction, washing, drying, and concentration and purification, (1S,2R)-1-cyano-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid dimethyl ester was obtained.

5. The preparation process of (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane according to claim 4, characterized in that, The molar ratio of ethyl 3-methyl-2-butenoate to bromine in S100 is 1:

1.

6. The preparation process of (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane according to claim 4, characterized in that, The molar ratio of dibromo-2,3-methyl-3-butyrate ethyl ester to anhydrous potassium carbonate in the S200 is 1:

3.

7. The preparation process of (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane according to claim 4, characterized in that, In the S300, the molar ratio of ethyl 2-bromo-3,3-dimethacrylate to ethyl 2-cyanoacrylate to sodium methoxide is 1:5:

2.

8. The preparation process of (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane according to claim 2, characterized in that, In the S400, the molar ratio of (1S,2R)-1-cyano-3,3-dimethyl-cyclopropane-1,2-dicarboxylic acid dimethyl ester to lithium chloride to water is 1:7:

7.

9. The preparation process of (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane according to claim 2, characterized in that, The molar ratio of methyl(1S,3R)-3-cyano-2,2-dimethylcyclopropane-1-carboxylic acid ester to Raney nickel in the S500 is 1:0.67; the ammonia is a 7M ammonia / methanol solution; and the volume ratio of the 7M ammonia / methanol solution to methanol is 1:

3.

10. The preparation process of (1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane according to claim 2, characterized in that, The molar ratio of (1R-5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-2-one to lithium aluminum hydride in the S600 is 1:1.5.

Images