CN115232059A

CN115232059A - Synthetic method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane

Info

Publication number: CN115232059A
Application number: CN202210919150.7A
Authority: CN
Inventors: 刘晓然; 张少春; 王喜成; 牟新东
Original assignee: Shanghai Suntian Technology Co ltd
Current assignee: Shanghai Suntian Technology Co ltd
Priority date: 2022-08-01
Filing date: 2022-08-01
Publication date: 2022-10-25
Anticipated expiration: 2042-08-01
Also published as: CN115232059B

Abstract

The application discloses a 6, 6-dimethyl-3-azabicyclo [3.1.0]]The synthesis method of the hexane comprises the following steps: (1) Mixing the caronic anhydride and the first solvent evenly, and heating and reacting in hydrogen atmosphere in the presence of the first catalyst to obtain the 6, 6-dimethyl-3-oxabicyclo [3.1.0]]Hexane; and (2) reacting 6, 6-dimethyl-3-oxabicyclo [ 3.1.0%]Hexane and a second solvent are mixed uniformly, and the mixture is heated and reacted in the presence of a second catalyst in the atmosphere of ammonia gas to obtain the 6, 6-dimethyl-3-azabicyclo [3.1.0]]Hexane. The synthesis method has the advantages of few steps, simple process, easy separation, continuous operation, high yield, reduction of three-waste discharge and contribution to industrial production.

Description

Synthetic method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane

The technical field is as follows:

the application belongs to the field of medicinal chemical synthesis, and particularly relates to a synthesis method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.

Background art:

6, 6-dimethyl-3-azabicyclo [3.1.0]The reaction product of hexane,molecular formula C ₇ H ₁₃ N is an important oxygen-containing chemical and an important medical intermediate, and is mainly used for synthesizing a hepatitis C protease inhibitor Boceprevir and a new oral crown medicine PF-07321332:

currently, the synthesis method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane mostly uses imide as a raw material, and uses quantitative reduction reagents such as lithium aluminum hydride, borane or sodium borohydride and the like for reduction (for example, as described in patent documents such as WO2008082508, WO2007075790, WO2009073380, WO2012049688, US7723531 and the like). However, the reduction process has high cost because the reduction reagent has high risk and high cost, and the reduction post-treatment process is complex and has large amount of waste water.

Chinese patent application CN113999160A discloses a method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane by taking dichlorochrysanthemic acid as a raw material, which comprises the steps of carboxyl reduction, hydrolysis, ammoniation, halogenation, hofmann (Hofmann) degradation, cyclization and the like. Although the method reduces the using amount of the reducing reagent (only one carbonyl group needs to be reduced), the reaction step is longer, and a large amount of halogen-containing waste water is generated in the steps of halogenation and Hofmann degradation. In addition, the process requires the use of cis-dichlorochrysanthemic acid as a starting material, which also limits the utility of the process.

In summary, the synthesis process of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane in the prior art all faces the problems of expensive raw materials, the need of using dangerous and expensive reducing reagents, more waste water and solid waste generated in the production process, and the like. Moreover, the preparation processes are all intermittent reactions, the reaction concentration is low, and the production efficiency is generally low.

In view of the problems of the prior art, it is necessary to develop a novel technique for synthesizing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.

The invention content is as follows:

in view of the above-mentioned shortcomings of the prior art, an object of the present application is to provide a method for synthesizing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, wherein the method for synthesizing the product is synthesized by using caronic anhydride as a raw material through hydrogenation and ammoniation steps under the action of a specific catalyst. The synthesis method has the advantages of few steps, simple process, easy separation, continuous operation, high yield, reduction of three-waste discharge and contribution to industrial production.

In order to achieve the above objects, in a first aspect, the present application provides a method for synthesizing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, comprising the steps of:

(1) Mixing the caronic anhydride and a first solvent uniformly, and heating and reacting in a hydrogen atmosphere in the presence of a first catalyst to obtain 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane; and

(2) Uniformly mixing the 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane with a second solvent, and heating to react in an ammonia atmosphere in the presence of a second catalyst to obtain the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.

In one possible embodiment in combination with the first aspect, the first catalyst is a supported metal catalyst comprising a metal active component M and a support S, wherein the metal active component M is at least one element selected from Cu, co, ni, pd, pt and Ru, and the support S is selected from activated carbon, ion exchange resin, γ -Al ₂ O ₃ 、SiO ₂ 、ZrO ₂ 、CeO ₂ 、WO ₃ 、Nb ₂ O ₅ And a zeolitic molecular sieve.

In one possible embodiment in combination with the first aspect, the metal active component M is at least one element selected from Cu, ni, co, and Ru.

Preferably, the metal active component M is at least one element selected from Cu, ni and Ru.

In a possible embodiment in combination with the first aspect, the support S is selected from γ -Al ₂ O ₃ 、SiO ₂ 、Nb ₂ O ₅ And a zeolite molecular sieve.

Preferably, the support S is selected from gamma-Al ₂ O ₃ 、SiO ₂ And a zeolitic molecular sieve.

Further, the zeolite molecular sieve may be an H-ZSM-5, H-ZSM-35, HY or H beta type molecular sieve.

In one possible embodiment in combination with the first aspect, the loading of the metal active component M in the first catalyst is 2wt% to 20wt%.

In one possible embodiment, in combination with the first aspect, the first catalyst is prepared by:

(a) Soaking the carrier S into a water solution of which the precursor concentration is 0.05-0.5 mol/L, stirring for 4-8 h, and filtering; and

(b) Drying the solid obtained by filtering in the step (a) at 120 ℃ for 24 hours, then roasting at 550 ℃ for 6 hours,

wherein the precursor is nitrate or hydrochloride containing the metal active component M.

In a possible embodiment in combination with the first aspect, the reaction temperature of step (1) is 140 ℃ to 350 ℃, preferably 150 ℃ to 250 ℃, and more preferably 150 ℃ to 240 ℃.

In a possible embodiment in combination with the first aspect, the reaction pressure of step (1) is between 0.1MPa and 8MPa, preferably between 2MPa and 6MPa, more preferably between 3MPa and 5MPa.

In one possible embodiment in combination with the first aspect, the first solvent is at least one selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, cyclohexane, n-hexane, and n-heptane.

Preferably, the first solvent is at least one selected from the group consisting of water, methanol, ethanol, isopropanol, tetrahydrofuran, and dioxane.

More preferably, the first solvent is at least one selected from the group consisting of water, tetrahydrofuran and dioxane.

In combination with the first aspect, in one possible embodiment, in the step (1), the mass ratio of the caronic anhydride to the first solvent is 1.

In a possible embodiment in combination with the first aspect, in step (1), the feeding space velocity in terms of caronic anhydride is 0.05h ^-1 ～8h ^-1 Preferably 0.05h ^-1 ～5h ^-1 More preferably 0.05h ^-1 ～3h ^-1 。

In combination with the first aspect, in one possible embodiment, in the step (1), the molar ratio of the caronic anhydride to hydrogen is 1.

With reference to the first aspect, in one possible embodiment, the second catalyst is a supported metal oxide catalyst comprising a metal oxide active component R and a support T, wherein the metal oxide active component R is at least one oxide selected from scandium, yttrium, lanthanum, cerium, ytterbium and lutetium, and the support T is at least one oxide selected from activated carbon, γ -Al ₂ O ₃ 、SiO ₂ 、ZrO ₂ 、WO ₃ 、Nb ₂ O ₅ And a zeolitic molecular sieve.

In one possible embodiment in combination with the first aspect, the metal oxide active component R is at least one selected from oxides of yttrium, lanthanum, cerium, and ytterbium.

Preferably, the metal oxide active component R is at least one selected from oxides of lanthanum, cerium and ytterbium.

In combination with the first aspect,in a possible embodiment, the support T is chosen from gamma-Al ₂ O ₃ 、SiO ₂ 、ZrO ₂ 、Nb ₂ O ₅ And a zeolitic molecular sieve.

Preferably, the support T is selected from gamma-Al ₂ O ₃ 、SiO ₂ And a zeolitic molecular sieve.

Further, the zeolite molecular sieve may be H-ZSM-5, H-ZSM-35, HY or H beta type molecular sieve.

In one possible embodiment in combination with the first aspect, the loading of the metal oxide active component R in the second catalyst is 0.1wt% to 5wt%, preferably 0.1wt% to 3wt%, and more preferably 0.1wt% to 1wt%.

In one possible embodiment, in combination with the first aspect, the second catalyst is prepared by:

(a) Immersing the carrier T into an aqueous solution with the metal precursor concentration of 0.01-0.2 mol/L, stirring for 4h, and filtering; and

(b) The solid obtained by filtration in step (a) was dried at 120 ℃ for 24h, and then calcined at 550 ℃ for 6h.

Further, the metal precursor is nitrate of scandium, yttrium, lanthanum, cerium, ytterbium or lutetium.

In a possible embodiment in combination with the first aspect, the reaction temperature of step (2) is 180 ℃ to 550 ℃, preferably 220 ℃ to 450 ℃, and more preferably 250 ℃ to 450 ℃.

In a possible embodiment in combination with the first aspect, the reaction pressure of step (2) is between 0.1MPa and 5MPa, preferably between 0.1MPa and 2MPa, more preferably between 0.1MPa and 1MPa.

In one possible embodiment in combination with the first aspect, the second solvent is at least one selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, dioxane, cyclohexane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane, and n-dodecane.

Preferably, the second solvent is at least one selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, cyclohexane, n-hexane, and n-heptane.

More preferably, the second solvent is at least one selected from the group consisting of methanol, ethanol, propanol, cyclohexane, n-hexane and n-heptane.

In combination with the first aspect, in one possible embodiment, in the step (2), the volume ratio of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane to the second solvent is 1.

In a possible embodiment in combination with the first aspect, in step (2), the compound is 6, 6-dimethyl-3-oxabicyclo [3.1.0]]The feeding space velocity of the hexane meter is 0.05h ^-1 ～10h ^-1 Preferably 0.05h ^-1 ～5h ^-1 More preferably 0.05h ^-1 ～3h ^-1 。

In combination with the first aspect, in one possible embodiment, in said step (2), the molar ratio of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane to ammonia gas is 1.

In combination with the first aspect, in one possible embodiment, the synthesis method further comprises activating the first catalyst prior to the reaction of step (1): and heating the first catalyst to 200-300 ℃ in a hydrogen atmosphere and keeping the temperature for 1-8 h.

In a possible embodiment in combination with the first aspect, the temperature of activation of the first catalyst is preferably in the range of 200 ℃ to 260 ℃.

In a possible embodiment in combination with the first aspect, the temperature holding time for activation of the first catalyst is preferably 2h to 6h.

Further, in the activation process of the first catalyst, the temperature rise rate was 3 ℃/min.

With reference to the first aspect, in one possible embodiment, the synthesis method further comprises activating the second catalyst prior to the reaction of step (2): and heating the second catalyst to 250-400 ℃ in a nitrogen atmosphere and keeping the temperature for 1-8 h.

In a possible embodiment in combination with the first aspect, the temperature of activation of the second catalyst is preferably in the range of 260 ℃ to 350 ℃.

In a possible embodiment in combination with the first aspect, the temperature holding time for activation of the second catalyst is preferably 2h to 6h.

Further, in the activation process of the second catalyst, the temperature rise rate is 3 ℃/min.

According to the technical scheme provided by the application, compared with the prior art, the method at least comprises the following beneficial effects:

the synthesis method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane according to the application has the advantages of green reaction route, continuous production, high efficiency and simple process operation, the main byproduct is water, the use of dangerous and expensive chemical reduction reagents is avoided, and corrosive wastewater is not generated. Compared with the traditional method, the method is easy to realize industrial production.

Drawings

FIG. 1 is a schematic diagram of a reaction apparatus for the reaction of a caronic anhydride to produce 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane, according to one embodiment of the present application.

FIG. 2 is a schematic diagram of a reaction apparatus for reacting 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane to produce 6,6-dimethyl-3-azabicyclo [3.1.0] hexane according to one embodiment of the application.

Detailed Description

In order that those skilled in the art will be able to more clearly understand the present application, the present application will be described in detail below with reference to examples. Before the description is made, it should be understood that the terms used in the present specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present application on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description proposed herein is just a preferable example for the purpose of illustrations only, not intended to limit the scope of the application, so it should be understood that other equivalents and modifications could be made thereto without departing from the spirit and scope of the application, and the scope of the application as claimed should be determined from the scope of the claims appended hereto. Unless otherwise specified, reagents and equipment used in the following examples are commercially available products.

In a first aspect, the present application provides a method for the synthesis of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane comprising the steps of:

(2) And (3) uniformly mixing the 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane with a second solvent, and heating to react in an ammonia atmosphere in the presence of a second catalyst to obtain the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.

In the application, the 6,6-dimethyl-3-azabicyclo [3.1.0] hexane is synthesized by using the caronic anhydride as a raw material through hydrogenation and ammoniation steps under the action of a specific catalyst. The synthesis method has the advantages of few steps, simple process, easy separation, continuous operation and high yield.

In the present application, the first catalyst is of M/S composition, wherein a metal active component M is supported on a support S. The first catalyst can be used for catalyzing the reduction of the caronic anhydride to remove the carbonyl group to obtain the 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane, and has the advantages of high product selectivity, high yield, continuous production and the like.

In one possible embodiment in combination with the first aspect, the metal active component M is at least one element selected from Cu, ni, co, and Ru. The metal active component M is capable of advantageously catalytically hydrogenating a caronic anhydride to obtain 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane with high selectivity and high yield.

Preferably, the metal active component M is at least one element selected from Cu, ni and Ru. Within the above preferred ranges, the catalytic hydrogenation of the caronic anhydride can be more advantageously carried out.

In a possible embodiment in combination with the first aspect, the support S is selected from γ -Al ₂ O ₃ 、SiO ₂ 、Nb ₂ O ₅ And a zeolitic molecular sieve. The carrier S can provide a large surface area and effectively load the metal active component M.

Further, the zeolite molecular sieve may be H-ZSM-5, H-ZSM-35, HY or H β type molecular sieves available from Tianjin Minn Kanza Co., ltd, for example, but the present application is not particularly limited thereto.

(a) Immersing the carrier S into an aqueous solution of which the concentration of the precursor is 0.05mol/L to 0.5mol/L (for example, 0.05mol/L, 0.06mol/L, 0.07mol/L, 0.08mol/L, 0.1mol/L, 0.15mol/L, 0.2mol/L, 0.25mol/L, 0.3mol/L, 0.35mol/L, 0.4mol/L, 0.45mol/L or 0.5mol/L, or any value in the range), stirring for 4h to 8h, and filtering; and

In a possible embodiment in combination with the first aspect, the reaction temperature of step (1) is 140 ℃ to 350 ℃ (e.g. may be 140 ℃, 150 ℃, 160 ℃, 170 ℃, 180 ℃, 190 ℃, 200 ℃, 210 ℃, 220 ℃, 230 ℃, 240 ℃, 250 ℃, 260 ℃, 270 ℃, 280 ℃, 290 ℃, 300 ℃, 310 ℃, 320 ℃, 340 ℃ or 350 ℃, or any value within said range), and is preferably 150 ℃ to 250 ℃, more preferably 150 ℃ to 240 ℃. At the temperature of the reaction, catalytic hydrogenation of the caronic anhydride can be effectively promoted.

In a possible embodiment in combination with the first aspect, the reaction pressure of step (1) is 0.1 to 8MPa (e.g. may be 0.1 to 0.2, 0.3, 0.5, 0.7 to 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8MPa or any value in the range), and is preferably 2 to 6MPa, more preferably 3 to 5MPa. Under the pressure of the reaction, catalytic hydrogenation of the caronic anhydride can be effectively promoted.

In one possible embodiment in combination with the first aspect, the first solvent is at least one selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, cyclohexane, n-hexane, and n-heptane. In the selection range of the first solvent, the caronic anhydride can be fully dispersed, which is beneficial to the reaction.

In combination with the first aspect, in one possible embodiment, in step (1), the mass ratio of the caronic anhydride to the first solvent is 1. Within the mass ratio range, the caronic anhydride can be favorably dispersed to promote the reaction.

In a possible embodiment in combination with the first aspect, in step (1), the feeding space velocity in terms of caronic anhydride is 0.05h ^-1 ～8h ^-1 (for example, it may be 0.05h ^-1 、0.06h ^-1 、0.07h ^-1 、0.1h ^-1 、0.2h ^-1 、0.5h ^-1 、0.7h ^-1 、1h ^-1 、1.5h ^-1 、2h ^-1 、2.5h ^-1 、3h ^-1 、3.5h ^-1 、4h ^-1 、4.5h ^-1 、5h ^-1 、5.5h ^-1 、6h ^-1 、6.5h ^-1 、7h ^-1 、7.5h ^-1 Or 8h ^-1 Or any value within the stated range), and preferably 0.05h ^-1 ～5h ^-1 More preferably 0.05h ^-1 ～3h ^-1 . Within the stated range of feed space velocities, the reaction can advantageously be promoted to proceed efficiently and continuously.

In combination with the first aspect, in the step (1), the molar ratio of the caronic anhydride to hydrogen is 1. Within the molar ratio range, the highly efficient catalytic reduction of the caronic anhydride to 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane can be advantageously promoted.

In one possible embodiment in combination with the first aspect, the second catalyst is a supported metal oxide catalyst comprising a metal oxide active component R and a support T, wherein the metal oxide is oxygenThe active component R is at least one of oxides selected from scandium, yttrium, lanthanum, cerium, ytterbium and lutetium, and the carrier T is selected from activated carbon and gamma-Al ₂ O ₃ 、SiO ₂ 、ZrO ₂ 、WO ₃ 、Nb ₂ O ₅ And a zeolitic molecular sieve.

In the present application, the second catalyst is of the R/T composition, wherein the support T carries the metal oxide active component R. The second catalyst can be used for catalyzing 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane to be aminated to obtain 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, and has the advantages of high product selectivity, high yield, continuous production and the like.

In one possible embodiment in combination with the first aspect, the metal oxide active component R is at least one selected from oxides of yttrium, lanthanum, cerium, and ytterbium. The metal oxide active component R is capable of advantageously catalytically aminating 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane to obtain 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane with high selectivity and high yield.

Preferably, the metal oxide active component R is at least one selected from oxides of lanthanum, cerium and ytterbium. Within the above preferred range, catalytic amination can be more advantageously performed.

In a possible embodiment in combination with the first aspect, the support T is selected from γ -Al ₂ O ₃ 、SiO ₂ 、ZrO ₂ 、Nb ₂ O ₅ And a zeolitic molecular sieve. The carrier T can provide a large surface area for effectively loading the metal oxide active component R.

Further, the zeolite molecular sieve may be H-ZSM-5, H-ZSM-35, HY or H beta type molecular sieves, for example, those available from Tianjin Minyao catalyst Co., ltd, but the present application is not particularly limited thereto.

In one possible embodiment in combination with the first aspect, the loading of the metal oxide active component R in the second catalyst is 0.1wt% to 5wt% (e.g., may be 0.1wt%, 0.2wt%, 0.3wt%, 0.4wt%, 0.5wt%, 0.6wt%, 0.7wt%, 0.8wt%, 0.9wt%, 1wt%, 1.5wt%, 2wt%, 2.5wt%, 3wt%, 3.5wt%, 4wt%, 4.5wt%, or 5wt%, or any value within the range), and is preferably 0.1wt% to 3wt%, more preferably 0.1wt% to 1wt%. Within the loading amount range, the metal oxide active component R can advantageously exert its catalytic ammoniation property.

(a) Immersing the carrier T in an aqueous solution having a metal precursor concentration of 0.01mol/L to 0.2mol/L (for example, 0.01mol/L, 0.02mol/L, 0.05mol/L, 0.07mol/L, 0.1mol/L, 0.12mol/L, 0.15mol/L, 0.17mol/L, or 0.2mol/L, or any value within the above range), stirring for 4 hours, and filtering; and

(b) Drying the solid obtained by filtering in the step (a) at 120 ℃ for 24h, and then roasting at 550 ℃ for 6h.

In the present application, the second catalyst having high activity and good catalytic amination effect can be obtained by the above-mentioned method for preparing the second catalyst, and the amination of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane into 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane can be favorably promoted.

Further, the metal precursor is nitrate of scandium, yttrium, lanthanum, cerium, ytterbium or lutetium. The metal nitrate is generally good in solubility and readily decomposes to remove nitrate after firing.

In a possible embodiment in combination with the first aspect, the reaction temperature of step (2) is 180 ℃ to 550 ℃ (e.g. 180 ℃, 190 ℃, 200 ℃, 220 ℃, 240 ℃, 260 ℃, 280 ℃, 300 ℃, 320 ℃, 340 ℃, 360 ℃, 380 ℃, 400 ℃, 420 ℃, 440 ℃, 460 ℃, 480 ℃, 500 ℃, 520 ℃, 540 ℃ or 550 ℃, or any value within the range), and preferably 220 ℃ to 450 ℃, more preferably 250 ℃ to 450 ℃. At the temperature of the reaction, the catalytic amination of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane can be promoted effectively.

In a possible embodiment in combination with the first aspect, the reaction pressure of step (2) is 0.1MPa to 5MPa (e.g. may be 0.1MPa, 0.2MPa, 0.3MPa, 0.5MPa, 0.7MPa, 1MPa, 1.5MPa, 2MPa, 2.5MPa, 3MPa, 3.5MPa, 4MPa, 4.5MPa or 5MPa, or any value in the range), and is preferably 0.1MPa to 2MPa, more preferably 0.1MPa to 1MPa. Under the pressure of the reaction, the catalytic ammoniation of the 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane can be effectively promoted.

In one possible embodiment in combination with the first aspect, the second solvent is at least one selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, dioxane, cyclohexane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane, and n-dodecane. Within the selection range of the second solvent, 6-dimethyl-3-oxabicyclo [3.1.0] hexane can be sufficiently dispersed, which is favorable for the reaction.

In combination with the first aspect, in one possible embodiment, in step (2), the volume ratio of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane to the second solvent is 1. Within the above volume ratio range, 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane can be favorably dispersed to promote the reaction. In particular, when the above volume ratio is 1.

In one possible embodiment, in combination with the first aspect, in step (2), the compound is 6, 6-dimethyl-3-oxabicyclo [3.1.0]]The feeding space velocity of the hexane meter is 0.05h ^-1 ～10h ^-1 (for example, it may be 0.05 h) ^-1 、0.07h ^-1 、0.1h ^-1 、0.2h ^-1 、0.5h ^-1 、0.7h ^-1 、1h ^-1 、1.5h ^-1 、2h ^-1 、2.5h ^-1 、3h ^-1 、3.5h ^-1 、4h ^-1 、4.5h ^-1 、5h ^-1 、5.5h ^-1 、6h ^-1 、6.5h ^-1 、7h ^-1 、7.5h ^-1 、8h ^-1 、8.5h ^-1 、9h ^-1 、9.5h ^-1 Or 10h ^-1 Or any value within the stated range), and preferably 0.05h ^-1 ～5h ^-1 More preferably 0.05h ^-1 ～3h ^-1 . Within the stated space velocity range of the feed, the reaction can advantageously be promoted to proceed efficiently and continuously.

In combination with the first aspect, in one possible embodiment, in step (2), the molar ratio of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane to ammonia gas is 1. Within the molar ratio range, the highly efficient catalytic amination of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane to 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane can be favorably promoted.

With reference to the first aspect, in one possible embodiment, the synthesis method further comprises activating the first catalyst prior to the reaction of step (1): the first catalyst is heated to 200 ℃ to 300 ℃ (e.g., may be 200 ℃, 210 ℃, 220 ℃, 230 ℃, 240 ℃, 250 ℃, 260 ℃, 270 ℃, 280 ℃, 290 ℃, or 300 ℃, or any value within the range) in a hydrogen atmosphere and maintained for 1h to 8h (e.g., may be 1h, 2h, 3h, 4h, 5h, 7h, or 8h, or any value within the range).

By activating the first catalyst, the catalyst can be made to exert its catalytic efficacy sufficiently. Moreover, the method is beneficial to the continuous operation of the catalytic reaction. In addition, the activation of the first catalyst is kept for 1-8 h after the temperature is raised to the preset temperature, and the first catalyst can be fully and thoroughly activated through heat preservation, so that the first catalyst is beneficial to comprehensively showing the optimal catalytic state.

Further, in the activation process of the first catalyst, the temperature rise rate is 3 ℃/min. At the temperature rise rate, the structural strength of the carrier is not reduced due to too fast temperature rise, and the activation efficiency is not affected due to too slow temperature rise.

With reference to the first aspect, in one possible embodiment, the synthesis method further comprises activating the second catalyst prior to the reaction of step (2): the second catalyst is heated to 250 ℃ to 400 ℃ (e.g., may be 250 ℃, 260 ℃, 270 ℃, 280 ℃, 290 ℃, 300 ℃, 310 ℃, 320 ℃, 330 ℃, 340 ℃, 350 ℃, 360 ℃, 370 ℃, 380 ℃, 390 ℃, or 400 ℃, or any value within the range) in a nitrogen atmosphere and maintained for 1h to 8h (e.g., may be 1h, 2h, 3h, 4h, 5h, 7h, or 8h, or any value within the range).

By activating the second catalyst, the catalyst can be made to exert its catalytic efficacy sufficiently. Moreover, the continuous catalytic reaction is facilitated. In addition, the activation of the second catalyst is kept for 1-8 h after the temperature is raised to the preset temperature, and the second catalyst can be fully and thoroughly activated through the heat preservation, so that the second catalyst is beneficial to comprehensively showing the optimal catalytic state.

Further, in the activation process of the second catalyst, the temperature rise rate is 3 ℃/min. At the temperature rise rate, the structural strength of the carrier is not reduced due to too fast temperature rise, and the activation efficiency is not affected due to too slow temperature rise.

In addition, in a possible embodiment, after the reaction of the step (1) is completed, the product containing 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane can be condensed and subjected to gas-liquid separation, and then rectified, so that the purified 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane can be collected.

In addition, in a possible embodiment, after the reaction in the step (2) is completed, the product containing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane can be condensed and subjected to gas-liquid separation, and then rectified, so that purified 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane can be collected.

Furthermore, the reaction according to the present application can be carried out, for example, in a fixed bed reactor.

Examples

In the following examples, the caronic anhydride was purchased from rayne reagent, tetrahydrofuran, 1, 4-dioxane, cerium nitrate, lanthanum nitrate, ytterbium nitrate were purchased from national chemical group, ltd; gamma-Al ₂ O ₃ And SiO ₂ Purchased from QingdaoSea wave silica gel desiccant, ltd; the H-ZSM-5 series molecular sieves were purchased from Tianjin Minn Kanzhi catalyst Co., ltd; high-purity nitrogen, high-purity ammonia gas and high-purity hydrogen gas are purchased from great science and technology limited of Qingdao De Hai.

In the synthesis method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane, the caronic anhydride is used as a raw material, and a product containing 6,6-dimethyl-3-azabicyclo [3.1.0] hexane is obtained through hydrogenation and ammoniation reactions under the action of a specific catalyst. The product was first filtered through a 0.22 μm filter and then analyzed by Gas Chromatography (GC) to determine its composition.

Gas chromatography detection conditions: the instrument comprises the following steps: GC2010Plus, column: intercap-FFAP,30m × 0.25mm × 0.25um, vaporization chamber temperature 250 ℃, FID temperature 300 ℃, column oven temperature program: keeping the temperature at 60 ℃ for 1min, and then heating to 230 ℃ at the speed of 15 ℃/min and keeping the temperature for 10min.

The product was analyzed qualitatively by gas chromatography-mass spectrometry (GC-MS). The product was quantified by Shimazu-GC 2010plus gas chromatography and analyzed quantitatively by comparison with standard retention time and peak area size. The correlation calculation formula is as follows:

wherein, the flow unit of the caronic anhydride is g/min, and the unit of the dosage of the catalyst is g.

As shown in fig. 1, which is a schematic view of a reaction apparatus for the reaction of a caronic anhydride to produce 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane according to an embodiment of the present application. Wherein the reaction tube is filled with a first catalyst according to the present application. First, hydrogen gas is introduced into the reaction tube by controlling the flow rate by a mass flow meter to create a hydrogen atmosphere, and then the heating furnace may be heated to activate the first catalyst. Then, while maintaining the temperature of the reaction tube, the caronic anhydride was pumped into the reaction tube by a feed pump, and reacted under a hydrogen atmosphere and catalysis by the first catalyst to produce a product containing 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane. Then, after condensation and gas-liquid separation, purified 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane can be collected and can be used for the next reaction.

As shown in fig. 2, which is a schematic view of a reaction apparatus for reacting 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane to produce 6,6-dimethyl-3-azabicyclo [3.1.0] hexane according to an embodiment of the present application. Wherein the reaction tube is filled with a second catalyst according to the present application. First, nitrogen gas is introduced into the reaction tube by controlling the flow rate through the mass flow meter to create a nitrogen atmosphere, and then the heating furnace may be heated to activate the second catalyst. Then, the temperature of the reaction tube was maintained, nitrogen gas was replaced with ammonia gas, and 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane obtained in the previous reaction was fed into the reaction tube by a feed pump, and reacted in an ammonia gas atmosphere with catalysis of the second catalyst to produce a product containing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane. Then condensing and separating gas and liquid, and collecting the purified final product 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.

Preparation example 1-1: first catalyst Cu/SiO ₂ Preparation of

(a) 20g of SiO ₂ Soaking the mixture into 150mL of aqueous solution of copper nitrate with the concentration of 0.5mol/L, stirring for 4 hours and then filtering; and

(b) Drying the solid obtained by filtering in the step (a) at 120 ℃ for 24 hours, and then roasting at 550 ℃ for 6 hours to obtain the first catalyst Cu/SiO ₂ (Cu loading was 20 wt%).

Preparation examples 1 to 2: first of allCatalyst Ni-Cu/SiO ₂ Preparation of

(a) 20g of SiO ₂ Immersing into 150mL of aqueous solution with copper nitrate concentration of 0.5mol/L and nickel nitrate concentration of 0.5mol/L, stirring for 4h, and filtering; and

(b) Drying the solid obtained by filtering in the step (a) at 120 ℃ for 24h, and then roasting at 550 ℃ for 6h to obtain a first catalyst Ni-Cu/SiO ₂ (the supported amount of Ni was 10wt%, and the supported amount of Cu was 20 wt%).

Preparation examples 1 to 3: first catalyst Co/Al ₂ O ₃ Preparation of

(a) 20g of Al ₂ O ₃ Immersing into 150mL of aqueous solution with the concentration of cobalt nitrate of 0.5mol/L, stirring for 4h, and filtering; and

(b) Drying the solid obtained by filtering in the step (a) at 120 ℃ for 24 hours, and then roasting at 550 ℃ for 6 hours to obtain a first catalyst Co/Al ₂ O ₃ (Co loading 15 wt%).

Preparation examples 1 to 4: first catalyst Pd/Al ₂ O ₃ Preparation of (2)

(a) 20g of Al ₂ O ₃ Soaking the mixture into 50mL of water solution of which the concentration of palladium nitrate is 0.05mol/L, stirring for 8 hours and then filtering; and

(b) Drying the solid obtained by filtering in the step (a) at 120 ℃ for 24 hours, and then roasting at 550 ℃ for 6 hours to obtain a first catalyst Pd/Al ₂ O ₃ (the supported amount of Pd was 3 wt%).

Preparation examples 1 to 5: first catalyst Ru/Al ₂ O ₃ Preparation of

(a) 20g of Al ₂ O ₃ Immersing into 50mL of aqueous solution with ruthenium chloride concentration of 0.05mol/L, stirring for 8h, and filtering; and

(b) Drying the solid obtained by filtering in the step (a) at 120 ℃ for 24 hours, and then roasting at 550 ℃ for 6 hours to obtain a first catalyst Ru/Al ₂ O ₃ (the loading of Ru was 5 wt%).

Preparation example 2-1: second catalyst La ₂ O ₃ Preparation of-ZSM-5

(a) Adding 5g of lanthanum nitrate into a reaction kettle, adding 300mL of water for dissolving, adding 200g of ZSM-5 carrier (spherical and 3mm in diameter), stirring for 4 hours, and evaporating water to dryness; and

(b) Drying the solid obtained in the step (a) at 120 ℃ for 24 hours, and then roasting at 550 ℃ for 6 hours to obtain a second catalyst La ₂ O ₃ -ZSM-5(La ₂ O ₃ The loading was 2.5 wt%).

Preparation examples 2 to 2: second catalyst CeO ₂ Preparation of-ZSM-5

A second catalyst, ceO, was prepared in the same manner as in preparation example 2-1, except that lanthanum nitrate was changed to cerium nitrate in step (a) ₂ -ZSM-5(CeO ₂ The loading was 0.8 wt%).

Preparation examples 2 to 3: second catalyst Yb ₂ O ₃ Preparation of-ZSM-5

A second catalyst Yb was obtained in the same manner as in production example 2-1, except that lanthanum nitrate was changed to ytterbium nitrate in step (a) ₂ O ₃ -ZSM-5(Yb ₂ O ₃ The loading was 4.0 wt%).

Preparation examples 2 to 4: second catalyst CeO ₂ -SiO ₂ Preparation of

A second catalyst, ceO, was prepared in the same preparation method as in preparation example 2-2, except that ZSM-5 was changed to silica in step (a) ₂ -SiO ₂ (CeO ₂ The loading of (b) was 0.8 wt%).

Preparation examples 2 to 5: second catalyst CeO ₂ -γ-Al ₂ O ₃ Preparation of

A second catalyst, ceO, was prepared in the same manner as in preparation example 2-2, except that ZSM-5 was changed to gamma-alumina in step (a) ₂ -γ-Al ₂ O ₃ (CeO ₂ The loading was 0.8 wt%).

Example 1

The catalytic synthesis of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane was carried out using the following method according to the present application:

(1) A fixed bed reactor was charged with 10g of the first catalyst Cu/SiO obtained in preparation example 1-1 ₂ The temperature was raised to 240 ℃ at a rate of 3 ℃/min in a hydrogen atmosphere and maintained for 4 hours to activate the catalyst. After activation, the hydrogen pressure of the system is adjusted to 4MPa, and the hydrogen flow is kept at 150mL/min. Pumping 1, 4-dioxane solution with the concentration of 20wt% of the caronic anhydride into a reactor for reaction, wherein the feeding airspeed is 0.1h based on the caronic anhydride ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain the product.

The product was checked by GC and showed 81% conversion of the caronic anhydride, 81% selectivity to 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane and 15% selectivity to 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one in the product.

(2) A fixed bed reactor was charged with 15g of the second catalyst La obtained in production example 2-1 ₂ O ₃ ZSM-5 (20-40 meshes), and quartz sand is filled in the catalyst up and down. The catalyst was activated by heating to 300 ℃ at a rate of 3 ℃/min under a 100mL/min nitrogen purge and holding for 2 h. After the activation is finished, the nitrogen is switched to ammonia gas, the flow rate of the ammonia gas is 100mL/min, and the reaction pressure is normal pressure. Pumping the product prepared in the step (1) into a catalyst bed layer by using a plunger pump for reaction, wherein the feeding airspeed is 6, 6-dimethyl-3-oxabicyclo [3.1.0]]0.1h calculated as hexane ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain a final product.

The conversion of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane was 89%, the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane in the product was 93%, and the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hex-2-ene was 4%, as determined by GC for the final product.

Example 2

(1) A fixed bed reactor was charged with 10g of the first catalyst Ni-Cu/SiO obtained in preparation example 1-2 ₂ The temperature was raised to 240 ℃ at a rate of 3 ℃/min in a hydrogen atmosphere and maintained for 4 hours to activate the catalyst. After the activation is finished, the hydrogen pressure of the system is adjusted to 4MPa, and the hydrogen flow is kept at 150mL/min. Pumping 1, 4-dioxane solution with the concentration of the caronic anhydride of 20 weight percent into a reactor for reaction, wherein the feeding airspeed is 0.1h based on the caronic anhydride ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain the product.

The product was checked by GC and showed 100% conversion of the caronic anhydride, 89% selectivity to 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane and 9% selectivity to 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one in the product.

(2) A fixed bed reactor was charged with 15g of CeO, a second catalyst obtained in preparation example 2-2 ₂ ZSM-5 (20-40 meshes), and quartz sand is filled in the upper part and the lower part of the catalyst. The catalyst was activated by heating to 300 ℃ at a rate of 3 ℃/min under a 100mL/min nitrogen purge and holding for 2 h. After the activation is finished, the nitrogen is switched to ammonia gas, the flow rate of the ammonia gas is 100mL/min, and the reaction pressure is normal pressure. Pumping the product obtained in the step (1) into a catalyst bed layer by using a plunger pump for reaction, wherein the feeding airspeed is 6, 6-dimethyl-3-oxabicyclo [3.1.0]]0.1h calculated as hexane ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain a final product.

The conversion of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane in the final product was 91%, the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane in the product was 94%, and the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hex-2-ene was 2%, as determined by GC.

Example 3

(1) A fixed bed reactor was charged with 10g of Ru/Al as the first catalyst obtained in preparation examples 1 to 5 ₂ O ₃ The temperature was raised to 240 ℃ at a rate of 3 ℃/min in a hydrogen atmosphere and held for 4h to activate the catalyst. After activation, the hydrogen pressure of the system is adjusted to 4MPa, and the hydrogen flow is kept at 150mL/min. Pumping 1, 4-dioxane solution with the concentration of the caronic anhydride of 20 weight percent into a reactor for reaction, wherein the feeding airspeed is 0.1h based on the caronic anhydride ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain the product.

The product was checked by GC and showed 100% conversion of the caronic anhydride, 91% selectivity to 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane and 3% selectivity to 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one.

(2) A fixed-bed reactor was charged with 15g of the second catalyst Yb prepared in preparation examples 2 to 3 ₂ O ₃ ZSM-5 (20-40 meshes), and quartz sand is filled in the upper part and the lower part of the catalyst. The catalyst was activated by heating to 300 ℃ at a rate of 3 ℃/min under a 100mL/min nitrogen purge and holding for 2 h. After the activation is finished, the nitrogen is switched to ammonia gas, the flow rate of the ammonia gas is 100mL/min, and the reaction pressure is normal pressure. Pumping the product obtained in the step (1) into a catalyst bed layer by using a plunger pump for reaction, wherein the feeding airspeed is 6, 6-dimethyl-3-oxabicyclo [3.1.0]]0.1h calculated as hexane ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain a final product.

The conversion of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane in the final product was 94%, the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane in the product was 89%, and the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hex-2-ene was 6% as determined by GC.

Example 4

(1) A fixed bed reactor was charged with 10g of Co/Al as the first catalyst obtained in preparation examples 1 to 3 ₂ O ₃ The temperature was raised to 240 ℃ at a rate of 3 ℃/min in a hydrogen atmosphere and held for 4h to activate the catalyst. After the activation is finished, the hydrogen pressure of the system is adjusted to 4MPa, and the hydrogen flow is kept at 150mL/min. Pumping 1, 4-dioxane solution with the concentration of the caronic anhydride of 20 weight percent into a reactor for reaction, wherein the feeding airspeed is 0.1h based on the caronic anhydride ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain the product.

The product was checked by GC and showed 100% conversion of the caronic anhydride, 90% selectivity to 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane and 5% selectivity to 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one in the product.

(2) A fixed bed reactor was charged with 15g of CeO, the second catalyst obtained in preparation examples 2 to 4 ₂ -SiO ₂ (20-40 meshes), and quartz sand is filled in the upper part and the lower part of the catalyst. The catalyst was activated by heating to 300 ℃ at a rate of 3 ℃/min under a 100mL/min nitrogen purge and holding for 2 h. After the activation, the nitrogen gas is switched to ammonia gas, the flow rate of the ammonia gas is 100mL/min, and the reaction pressure is normal pressure. Pumping the product obtained in the step (1) into a catalyst bed layer by using a plunger pump for reaction, wherein the feeding airspeed is 6, 6-dimethyl-3-oxabicyclo [3.1.0]]0.1h calculated as hexane ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain a final product.

The conversion of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane in the final product was 94%, the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane in the product was 91%, and the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hex-2-ene in the product was 6% as determined by GC.

Example 5

(1) A fixed bed reactor was charged with 15g of Pd/Al as the first catalyst obtained in preparation examples 1 to 4 ₂ O ₃ The temperature was raised to 240 ℃ at a rate of 3 ℃/min in a hydrogen atmosphere and maintained for 4 hours to activate the catalyst. After activation, the hydrogen pressure of the system is adjusted to 4MPa, and the hydrogen flow is kept at 150mL/min. Pumping 1, 4-dioxane solution with the concentration of the caronic anhydride of 20 weight percent into a reactor for reaction, wherein the feeding airspeed is 0.1h based on the caronic anhydride ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain the product.

The product was checked by GC and showed 100% conversion of the caronic anhydride, 88% selectivity to 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane and 8% selectivity to 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one in the product.

(2) A fixed bed reactor was charged with 15g of CeO, the second catalyst obtained in preparation examples 2 to 5 ₂ -γ-Al ₂ O ₃ (20-40 meshes), and quartz sand is filled in the catalyst up and down. The catalyst was activated by heating to 300 ℃ at a rate of 3 ℃/min under a 100mL/min nitrogen purge and holding for 2 h. After the activation is finished, the nitrogen is switched to ammonia gas, the flow rate of the ammonia gas is 100mL/min, and the reaction pressure is normal pressure. Pumping the product obtained in the step (1) into a catalyst bed layer by using a plunger pump for reaction, wherein the feeding airspeed is 6, 6-dimethyl-3-oxabicyclo [3.1.0]]0.1h calculated as hexane ^-1 Through a condenser andand collecting after a gas-liquid separator to obtain a final product.

The conversion of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane was 94%, the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane in the product was 86%, and the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hex-2-ene was 8%, as determined by GC for the final product.

Example 6

(1) A fixed bed reactor was charged with 10g of Cu/SiO as the first catalyst obtained in production example 1-1 ₂ The temperature was raised to 240 ℃ at a rate of 3 ℃/min in a hydrogen atmosphere and held for 4h to activate the catalyst. After the activation is finished, the hydrogen pressure of the system is adjusted to 4MPa, and the hydrogen flow is kept at 150mL/min. Pumping tetrahydrofuran solution with the concentration of the caronic anhydride of 20wt% into a reactor for reaction, wherein the feeding airspeed is 0.1h in terms of the caronic anhydride ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain the product.

GC detection shows that the conversion rate of the caronic anhydride is 81%, the selectivity of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane in the product is 81%, and the selectivity of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-ketone in the product is 15%.

(2) The catalytic amination of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane was carried out in the same manner as in step (2) of example 5, and the conversion of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane in the final product was 94%, the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane in the product was 86%, and the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hex-2-ene was 8%, as determined by GC.

Comparative example 1

The following procedure was used for the catalytic synthesis of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane:

a fixed bed reactor was charged with 15g of the product obtained in production example 2-2Second catalyst CeO ₂ ZSM-5 (20-40 meshes), and quartz sand is filled in the upper part and the lower part of the catalyst. The catalyst was activated by heating to 300 ℃ at a rate of 3 ℃/min under a 100mL/min nitrogen purge and holding for 2 h. After the activation, the nitrogen gas is switched to ammonia gas, the flow rate of the ammonia gas is 100mL/min, and the reaction pressure is normal pressure. The product obtained in step (1) of example 1 was pumped into a catalyst bed by a plunger pump to react at a feed space velocity of 6, 6-dimethyl-3-oxabicyclo [3.1.0]]Calculated as hexane, 0.03h ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain a final product.

The conversion of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane was 98%, the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane in the product was 44%, and the selectivity for 6, 6-dimethyl-3-azabicyclo [3.1.0] hex-2-ene was 51%, as determined by GC for the final product.

Comparative example 2

The catalytic synthesis of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane was carried out using the following procedure:

15g of H-ZSM-5 (20-40 meshes) is filled into the fixed bed reactor as a catalyst, and quartz sand is filled above and below the catalyst. The catalyst was activated by heating to 350 ℃ at a rate of 3 ℃/min under a 100mL/min nitrogen purge and holding for 2 h. After the activation is finished, the nitrogen is switched to ammonia gas, the flow rate of the ammonia gas is 100mL/min, and the reaction pressure is normal pressure. The product obtained in step (1) of example 1 was pumped into a catalyst bed by a plunger pump to react at a feed space velocity of 6, 6-dimethyl-3-oxabicyclo [3.1.0]]0.1h calculated as hexane ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain a final product.

The conversion of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane in the final product was 49% by GC assay, and the selectivity of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane in the product was 93%.

Comparative example 3

charging 15g of gamma-Al into a fixed bed reactor ₂ O ₃ (20-40 meshes) as a catalyst, and quartz sand is filled in the upper part and the lower part of the catalyst. Purging with nitrogen at 100mL/minThe catalyst was then activated by heating to 350 ℃ at a rate of 3 ℃/min and holding for 2 h. After the activation, the nitrogen gas is switched to ammonia gas, the flow rate of the ammonia gas is 100mL/min, and the reaction pressure is normal pressure. The product obtained in step (1) of example 1 was pumped into a catalyst bed by a plunger pump to react at a feed space velocity of 6, 6-dimethyl-3-oxabicyclo [3.1.0]]0.1h calculated as hexane ^-1 And collecting the product after passing through a condenser and a gas-liquid separator to obtain a final product.

The conversion of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane in the final product was 44% by GC assay, and the selectivity of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane in the product was 89%.

The above-described embodiments of the present application are only preferred embodiments for explaining the present application, and are not limiting to the present application, and those skilled in the art can make modifications without inventive contribution as required after reading the present specification, however, any modifications, equivalents, improvements, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A method for synthesizing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, comprising the steps of:

2. The method of synthesis of claim 1, wherein the first catalyst is a supported metalThe catalyst comprises a metal active component M and a carrier S, wherein the metal active component M is at least one element selected from Cu, co, ni, pd, pt and Ru, and the carrier S is selected from activated carbon, ion exchange resin and gamma-Al ₂ O ₃ 、SiO ₂ 、ZrO ₂ 、CeO ₂ 、WO ₃ 、Nb ₂ O ₅ And a zeolitic molecular sieve,

preferably, the metal active component M is at least one element selected from the group consisting of Cu, ni, co and Ru,

preferably, the metal active component M is at least one element selected from the group consisting of Cu, ni and Ru,

preferably, the support S is selected from gamma-Al ₂ O ₃ 、SiO ₂ 、Nb ₂ O ₅ And a zeolitic molecular sieve,

preferably, the support S is selected from gamma-Al ₂ O ₃ 、SiO ₂ And a zeolitic molecular sieve,

further, the zeolite molecular sieve is H-ZSM-5, H-ZSM-35, HY or H beta type molecular sieve, and

in the first catalyst, the loading amount of the metal active component M is 2-20 wt%.

3. The synthesis method according to claim 2, characterized in that the first catalyst is prepared by the following method:

(a) Soaking the carrier S into a water solution of which the concentration of the precursor is 0.05-0.5 mol/L, stirring for 4-8 h, and filtering; and

4. The method of synthesis according to claim 1,

the reaction temperature in the step (1) is 140-350 ℃, preferably 150-250 ℃, more preferably 150-240 ℃,

the reaction pressure in the step (1) is 0.1 to 8MPa, preferably 2 to 6MPa, more preferably 3 to 5MPa,

in the step (1), the mass ratio of the caronic anhydride to the first solvent is 1,

in the step (1), the feeding airspeed measured by the caronic anhydride is 0.05h ^-1 ～8h ^-1 Preferably 0.05h ^-1 ～5h ^-1 More preferably 0.05h ^-1 ～3h ^-1 ，

In the step (1), the molar ratio of the caronic anhydride to hydrogen is 1.

5. The method of synthesis according to claim 1, wherein the first solvent is at least one selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, cyclohexane, n-hexane and n-heptane,

preferably, the first solvent is at least one selected from the group consisting of water, methanol, ethanol, isopropanol, tetrahydrofuran and dioxane,

more preferably, the first solvent is at least one selected from the group consisting of water, tetrahydrofuran, and dioxane.

6. The synthesis method according to claim 1, characterized in that the second catalyst is a supported metal oxide catalyst comprising a metal oxide active component R and a support T, wherein the metal oxide active component R is at least one oxide selected from scandium, yttrium, lanthanum, cerium, ytterbium and lutetium, and the support T is at least one oxide selected from activated carbon, γ -Al ₂ O ₃ 、SiO ₂ 、ZrO ₂ 、WO ₃ 、Nb ₂ O ₅ And a zeolite molecular sieve, wherein the zeolite molecular sieve is selected from the group consisting of,

preferably, the metal oxide active component R is at least one selected from the group consisting of oxides of yttrium, lanthanum, cerium and ytterbium,

preferably, the metal oxide active component R is at least one selected from oxides of lanthanum, cerium and ytterbium,

preferably, the support T is selected from gamma-Al ₂ O ₃ 、SiO ₂ 、ZrO ₂ 、Nb ₂ O ₅ And a zeolitic molecular sieve,

preferably, the support T is selected from gamma-Al ₂ O ₃ 、SiO ₂ And a zeolitic molecular sieve,

in the second catalyst, the loading amount of the metal oxide active component R is 0.1wt% to 5wt%, preferably 0.1wt% to 3wt%, and more preferably 0.1wt% to 1wt%.

7. The synthesis method according to claim 6, characterized in that the second catalyst is prepared by the following method:

further, the metal precursor is a nitrate of scandium, yttrium, lanthanum, cerium, ytterbium or lutetium.

8. The method of synthesis according to claim 1,

the reaction temperature of the step (2) is 180-550 ℃, preferably 220-450 ℃, more preferably 250-450 ℃,

the reaction pressure in the step (2) is 0.1MPa to 5MPa, preferably 0.1MPa to 2MPa, more preferably 0.1MPa to 1MPa,

in the step (2), the volume ratio of the 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane to the second solvent is 1,

in the step (2), 6-dimethyl-3-oxabicyclo [3.1.0] is used]The feeding space velocity of the hexane meter is 0.05h ^-1 ～10h ^-1 Preferably 0.05h ^-1 ～5h ^-1 More preferably 0.05h ^-1 ～3h ^-1 And an

In the step (2), the molar ratio of 6, 6-dimethyl-3-oxabicyclo [3.1.0] hexane to ammonia gas is 1.

9. The synthesis method according to claim 1, wherein the second solvent is at least one selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, dioxane, cyclohexane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane, and n-dodecane,

preferably, the second solvent is at least one selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, cyclohexane, n-hexane and n-heptane,

10. The synthesis method according to any one of claims 1 to 9,

the synthesis process further comprises activating the first catalyst prior to the reaction of step (1): heating the first catalyst to 200-300 ℃ in hydrogen atmosphere and keeping the temperature for 1-8 h,

preferably, the temperature of activation of the first catalyst is preferably from 200 ℃ to 260 ℃,

preferably, the temperature holding time for activation of the first catalyst is preferably 2 to 6 hours,

further, during the activation of the first catalyst, the temperature rise rate is 3 ℃/min, and/or

The synthesis process further comprises activating the second catalyst prior to the reaction of step (2): heating the second catalyst to 250-400 ℃ in a nitrogen atmosphere, keeping the temperature for 1-8 h,

preferably, the temperature of activation of the second catalyst is preferably in the range of 260 ℃ to 350 ℃,

preferably, the temperature holding time for activation of the second catalyst is preferably 2 to 6 hours,