CN115232056B - Synthesis method of cis-7-azabicyclo [3.3.0] octane - Google Patents

Synthesis method of cis-7-azabicyclo [3.3.0] octane Download PDF

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CN115232056B
CN115232056B CN202210915867.4A CN202210915867A CN115232056B CN 115232056 B CN115232056 B CN 115232056B CN 202210915867 A CN202210915867 A CN 202210915867A CN 115232056 B CN115232056 B CN 115232056B
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CN115232056A (en
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刘晓然
张少春
王喜成
牟新东
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Shanghai Suntian Technology Co ltd
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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Abstract

The invention relates to a synthesis method of cis-7-azabicyclo [3.3.0] octane. The method takes 1, 4-butylene glycol as a raw material, and synthesizes cis-7-azabicyclo [3.3.0] octane through the steps of dehydration reaction, diels-Alder reaction, epoxidation hydration reaction, dehydration reaction (esterification reaction, thermal cracking reaction), ozonization reaction, hydrogenation reaction, ammonification reaction and the like. The method for synthesizing cis-7-azabicyclo [3.3.0] octane has the advantages of simple process, green route, less pollution in the reaction process, continuous operation in multiple steps and high efficiency.

Description

Synthesis method of cis-7-azabicyclo [3.3.0] octane
Technical Field
The invention relates to the field of pharmaceutical chemistry synthesis, in particular to a synthesis method of cis-7-azabicyclo [3.3.0] octane.
Background
Cis-7-azabicyclo [3.3.0] octane is an important intermediate in the field of pharmaceutical synthesis, and can be used for synthesizing gliclazide after nitrosation and zinc powder reduction. Gliclazide is a second-generation sulfonylurea oral hypoglycemic agent, has dual functions of reducing blood sugar and improving blood coagulation, and is registered and sold in more than 130 countries worldwide.
The currently common method for synthesizing cis-7-azabicyclo [3.3.0] octane mainly uses cyclopentane-1, 2-dicarboximide as a raw material, and uses lithium aluminum hydride to reduce two carbonyl groups of the cyclopentane-1, 2-dicarboximide (CN 184096A, WO 2009/140279 A2). The lithium aluminum hydride reagent has high risk, high cost, complex post-reduction treatment process and large wastewater amount, and the cost of the reduction process is always high. In addition, the reduction process (the process improvement of the azabicyclo of the gliclazide intermediate, gu Hu, the process of the preparation of the gliclazide, liu Yongkuan, the article of Zhengzhou university, the new technical research of the preparation of the gliclazide, lin Yuan, the article of Jinan university, and CN 103183632A) can be realized by matching sodium/potassium borohydride with Lewis acid, but the problems of more waste water and high cost still cannot be solved at present. There is also a report (US 8,664,408 B2,US 20120316214A1,CN 1741993A) that cis-7-azabicyclo [3.3.0] octane is obtained by directly hydrogenating cyclopentane-1, 2-dicarboximide by catalytic hydrogenation, but the reaction temperature is generally above 260 ℃, the reaction pressure is above 20MPa, and the danger of the process is greatly increased due to severe reaction conditions, and the requirement on equipment is high.
In addition, the synthesis of the raw material cyclopentane-1, 2-dicarboximide in the process mainly takes cyclohexanone and urea as raw materials to synthesize cyclopentane dicarboxylic acid through multi-step reaction, and the cyclopentane dicarboxylic acid is dehydrated to synthesize cyclopentane dicarboxylic anhydride, and the cyclopentane dicarboxylic anhydride is continuously reacted with ammonia to synthesize the cyclopentane-1, 2-dicarboximide. Bromine is used in the synthesis process, and more halogen-containing wastewater is generated. The process has long route, generates more pollution, and has larger defects under the current severe environment-friendly situation.
There is also a report of obtaining cis-7-azabicyclo [3.3.0] octane by using aza [3.3.0] octane-2-one as a raw material, performing chlorination reaction with phosphorus oxychloride, and then performing zinc powder reduction (The Journal of Organic Chemistry,1977,42,2082-2087). This route does not use lithium aluminum hydride and sodium borohydride, but the raw materials are difficult to prepare, phosphorus oxychloride and zinc powder are needed, and the generation of a large amount of wastes in the production process is unavoidable, so that the economical efficiency and the environmental protection are still challenging.
Synthesis of cis-7-azabicyclo [3.3.0] octane from azacyclo [3.3.0] octan-2-one
In summary, the synthesis process of cis-7-azabicyclo [3.3.0] octane is faced with the problems of high raw material price, the need of using dangerous and expensive reducing reagent, more waste water and solid waste in the production process, and the like. The processes are all intermittent reactions, the reaction concentration is low, and the production efficiency is generally low.
Disclosure of Invention
In order to solve the problems involved in the above-mentioned methods, an object of the present invention is to provide a method for synthesizing cis-7-azabicyclo [3.3.0] octane. The method takes 1, 4-butylene glycol as a raw material, and synthesizes cis-7-azabicyclo [3.3.0] octane through the steps of dehydration reaction, diels-Alder reaction, epoxidation hydration reaction, dehydration reaction (esterification reaction, thermal cracking reaction), ozone oxidation reaction, hydrogenation reaction, ammonification reaction and the like under the action of a catalyst. The method for synthesizing cis-7-azabicyclo [3.3.0] octane has simple process, easy separation, continuous operation in multiple steps, high yield, reduced emission of three wastes and contribution to industrial production.
In order to achieve the above object of the present invention, the following technical solutions are specifically adopted:
the invention provides a synthesis method of cis-7-azabicyclo [3.3.0] octane, which comprises the following steps:
(1) Introducing the compound 1 (1, 4-butylene glycol) into a fixed bed reactor filled with a catalyst for dehydration reaction, condensing a product, separating gas from liquid, and then entering a storage tank, and rectifying the product in the storage tank to obtain a compound 2 (2, 5-dihydrofuran);
(2) Adding a compound 2 and conjugated olefin into a high-pressure reaction kettle, maintaining pressure after replacing air in the kettle with nitrogen to ensure that the reaction kettle is airtight, heating for reaction, cooling after the reaction is finished, decompressing, and rectifying a product to obtain a compound 3;
(3) Mixing the compound 3 with an oxidant, performing epoxidation reaction, adding alkali for hydrolysis, and extracting to obtain a compound 4;
(4) Introducing the compound 4 into a fixed bed reactor filled with a catalyst for dehydration reaction, condensing a product, separating gas from liquid, and then entering a storage tank, and rectifying the product in the storage tank to obtain a compound 5;
or, mixing the compound 4 with acetic anhydride, adding a catalyst, heating for esterification reaction, and distilling to obtain a compound 8; mixing the compound 8 with a solvent, introducing the mixture into a fixed bed reactor for thermal cracking reaction, condensing the product, separating gas from liquid, and then introducing the product into a storage tank, and rectifying the product in the storage tank to obtain a compound 5;
(5) Mixing the compound 5 with a solvent, introducing ozone into the mixture, introducing nitrogen to purge the mixture after the raw materials are completely reacted, and distilling the mixture to obtain a compound 6;
(6) Adding the compound 6 and a catalyst into a high-pressure reaction kettle, replacing air in the kettle with nitrogen, replacing with hydrogen, then filling hydrogen, heating for reaction, continuously supplementing hydrogen into the reaction kettle until the pressure is not reduced continuously, and rectifying after the reaction is finished to obtain a compound 7;
(7) And (3) dissolving the compound 7 in an optional solvent, respectively introducing the solvent and ammonia gas into a fixed bed reactor filled with a catalyst for reaction, condensing the product, separating gas from liquid, and then introducing the product into a storage tank, and rectifying the product in the storage tank to obtain the product cis-7-azabicyclo [3.3.0] octane.
Step (1)
In this step, compound 1 is dehydrated to form a ring by the action of a catalyst, and compound 2 is reacted.
In some embodiments, the catalyst of step (1) is selected from activated carbon, ion exchange resins, gamma-Al 2 O 3 、SiO 2 、ZrO 2 、CeO 2 、WO 3 、Nb 2 O 5 One or more of zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, H. Beta. Manufactured by Tianjin southbound catalyst Co., ltd.);
preferably, the catalyst of step (1) is selected from gamma-Al 2 O 3 、SiO 2 、Nb 2 O 5 Zeolite molecular sieves (e.g. Tianjin southbound catalyst limitedH-ZSM-5, H-ZSM-35, HY, hβ, manufactured by company);
more preferably, the catalyst of step (1) is selected from gamma-Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, H. Beta. Manufactured by Tianjin southbound catalyst Co., ltd.).
In some embodiments, the reaction temperature of step (1) is 100 to 400 ℃, preferably 120 to 300 ℃, more preferably 120 to 280 ℃.
In some embodiments, the compound 1 (1, 4-butenediol) of step (1) has a mass space velocity of from 0.1 to 5 hours -1 Preferably 0.3-3h -1 More preferably 0.5 to 1.5h -1 。
Wherein the mass flow rate of the 1, 4-butylene glycol is g/min, and the mass of the catalyst is g.
Step (2)
In this step, the compound 2 and the conjugated olefin undergo diels-alder reaction to produce the compound 3.
In some embodiments, the molar ratio of the compound 2 (2, 5-dihydrofuran) to conjugated olefin of step (2) is from 1:5 to 5:1, e.g., 1:5, 2:5, 3:5, 4:5, 1:1, 2:1, 3:1, 4:1, 5:1.
In some embodiments, the conjugated olefin of step (2) is selected from one or more of cyclopentadiene and dicyclopentadiene.
In some embodiments, the reaction temperature of step (2) is 140 to 260 ℃, preferably 160 to 220 ℃, more preferably 160 to 200 ℃.
In some embodiments, the reaction time of step (2) is from 10min to 10h, preferably from 30min to 5h, more preferably from 30min to 3h.
Step (3)
In this step, the compound 3 and the oxidizing agent undergo epoxidation reaction to form an epoxy compound, which is hydrolyzed by adding a base to form a compound 4.
In some embodiments, the oxidizing agent of step (3) is selected from one or more of peroxyformic acid, peroxyacetic acid, peroxybenzoic acid, meta-chloroperoxybenzoic acid.
In some embodiments, the molar ratio of compound 1 to oxidant of step (3) is from 1:1.1 to 1:3.
In some embodiments, the epoxidation reaction temperature of step (3) is from-10 to 40 ℃, preferably from 0 to 30 ℃, more preferably from 0 to 20 ℃.
In some embodiments, the epoxidation reaction time of step (3) is 30min to 10h, preferably 30min to 6h, more preferably 30min to 3h.
In some embodiments, in step (3), the compound 3, the organic acid, the hydrogen peroxide and the catalyst are mixed and then subjected to an epoxidation reaction, and the peroxy organic acid is unstable and needs to be prepared in situ. In the step, formic acid, hydrogen peroxide and sulfuric acid are mixed to prepare peroxyformic acid. Sulfuric acid is a catalyst in the preparation of peroxyformic acid.
In some embodiments, the base of step (3) is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
In some embodiments, the hydrolysis temperature of step (3) is 20-70 ℃.
Step (4)
In this step, the process of compound 4 to compound 5 may be one of the following methods:
the method comprises the following steps: the compound 4 is dehydrated under the action of a catalyst.
In some embodiments, the catalyst for the dehydration reaction of step (4) is selected from Al 2 O 3 、SiO 2 、ZrO 2 、CeO 2 、Yb 2 O 3 、Y 2 O 3 、La 2 O 3 、Sc 2 O 3 One or more of the following.
In some embodiments, the dehydration reaction temperature of step (4) is 350-550 ℃.
In some embodiments, the dehydration reaction feed space velocity of step (4) is from 0.05 to 1.0h -1 。
The second method is as follows: the compound 4 and acetic anhydride are subjected to esterification reaction under the action of a catalyst to obtain a compound 8, and then the compound 5 is obtained through thermal cracking.
In some embodiments, the molar ratio of compound 4 to acetic anhydride of step (4) is from 1:2.2 to 1:6.
In some embodiments, the catalyst for the esterification reaction of step (4) is selected from one or more of sulfuric acid, phosphoric acid, hydrochloric acid, amberlyst-15, amberlyst-35.
In some embodiments, the esterification reaction temperature of step (4) is 40-90 ℃.
In some embodiments, the esterification reaction time of step (4) is from 30 minutes to 10 hours.
In some embodiments, the solvent for the thermal cracking reaction of step (4) is selected from one or more of tetrahydrofuran, 1, 4-dioxane, toluene, benzene, xylene, ethyl acetate.
In some embodiments, the thermal cracking reaction temperature of step (4) is 300-600 ℃, preferably 300-550 ℃, more preferably 350-450 ℃.
Step (5)
In this step, the compound 5 and ozone undergo an ozone oxidation reaction to produce the compound 6.
In some embodiments, the solvent of step (5) is selected from one or more of methanol, ethanol, dichloromethane, dichloroethane, water, formic acid, acetic acid.
In some embodiments, the reaction temperature of step (5) is selected from the group consisting of-20 to 30 ℃.
In some embodiments, the mass concentration of said compound 5 of step (5) in the solvent is 10-50wt%, preferably 10-40wt%, more preferably 20-30wt%.
Step (6)
In this step, compound 6 is hydrogenated under the action of a catalyst to produce compound 7.
In some embodiments, the catalyst of step (6) is a supported catalyst M/S, M being a metal active component, S being a support, i.e. the catalyst comprises a support S and a metal active ingredient M supported on the support.
In some embodiments, M is selected from one or more of Cu, ni, co, ru, pd, pt;
preferably, M is selected from one or more of Cu, ni, co, ru;
more preferably, M is selected from one or more of Cu, ni, ru.
In some embodiments, S is selected from activated carbon, ion exchange resins, gamma-Al 2 O 3 、SiO 2 、ZrO 2 、CeO 2 、WO 3 、Nb 2 O 5 One or more of zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, H. Beta. Manufactured by Tianjin southbound catalyst Co., ltd.);
preferably, S is selected from activated carbon, gamma-Al 2 O 3 、SiO 2 、Nb 2 O 5 Zeolite molecular sieves (e.g. TianjinH-ZSM-5, H-ZSM-35, HY, hβ) produced by southbound catalyst limited;
More preferably, S is selected from activated carbon, gamma-Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, H. Beta. Manufactured by Tianjin southbound catalyst Co., ltd.).
In some embodiments, the catalyst of step (6) is added in an amount of 3 to 10t% of compound 6.
In some embodiments, the reaction temperature of step (6) is 100-250 ℃, preferably 120-200 ℃, more preferably 150-200 ℃.
In some embodiments, the reaction pressure of step (6) is from 0.1 to 8MPa, preferably from 2 to 6MPa, more preferably from 3 to 5MPa.
Step (7)
In the step, the compound 7 is subjected to ammonification reaction under the action of a catalyst to generate the cis-7-azabicyclo [3.3.0] octane product.
In some embodiments, the catalyst of step (7) is a supported metal oxide catalyst, i.e., the catalyst comprises a support and a metal oxide supported on the support.
In some embodiments, the metal active component corresponding to the metal oxide is selected from one or more of scandium, yttrium, lanthanum, cerium, ytterbium, lutetium;
preferably, the metal active component corresponding to the metal oxide is selected from one or more of yttrium, lanthanum, cerium and ytterbium;
More preferably, the metal active component corresponding to the metal oxide is selected from one or more of lanthanum, cerium and ytterbium.
In some embodiments, the support is selected from activated carbon, gamma-Al 2 O 3 、SiO 2 、ZrO 2 、WO 3 、Nb 2 O 5 Zeolite molecular sieves (e.g. Tianjin southbound catalystH-ZSM-5, H-ZSM-35, HY, hβ manufactured by the company limited);
preferably, the support is selected from gamma-Al 2 O 3 、SiO 2 、ZrO 2 、Nb 2 O 5 One or more of zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, HY, H. Beta. Manufactured by Tianjin southbound catalyst Co., ltd.);
more preferably, the support is selected from gamma-Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves (e.g., H-ZSM-5, H-ZSM-35, manufactured by Tianjin southbound catalyst Co., ltd.).
In some embodiments, the loading of metal oxide in the supported metal oxide catalyst (precursor solution is evaporated to dryness after impregnation, metal is fully supported on the support surface) is 0.1 to 5wt%, for example 0.1, 0.2, 0.5, 0.6, 0.8, 1, 2, 3, 4, 5%, preferably 0.1 to 3wt%, more preferably 0.1 to 1wt%.
In some embodiments, the reaction temperature of step (7) is 180-550 ℃, preferably 220-450 ℃, more preferably 250-450 ℃.
Step (7) may be performed with or without a solvent.
In some embodiments, the solvent of step (7) is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, dioxane, cyclohexane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane;
preferably, the solvent of step (7) is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, cyclohexane, n-hexane, n-heptane;
more preferably, the solvent of step (7) is selected from one or more of methanol, ethanol, propanol, cyclohexane, n-hexane, n-heptane.
In some embodiments, the volume ratio of said compound 7 to solvent of step (7) is from 1:0.1 to 1:50, preferably from 1:0.5 to 1:20, more preferably from 1:1 to 1:5.
In some implementationsIn an embodiment, the compound 7 of step (7) has a mass space velocity of 0.01 to 10 hours -1 Preferably 0.01-5h -1 More preferably 0.02 to 3 hours -1 。
In some embodiments, the molar ratio of said compound 7 to ammonia of step (7) is from 1:5 to 1:100, preferably from 1:5 to 1:80, more preferably from 1:10 to 1:80.
In some embodiments, the reaction pressure of step (7) is from 0.1 to 3.0MPa, preferably from 0.1 to 2.0MPa, more preferably from 0.1 to 1.0MPa.
The beneficial effects are that:
the invention provides a method for synthesizing cis-7-azabicyclo [3.3.0] octane, which has the advantages of green reaction route, continuous production in multiple steps, high efficiency, simple process operation, water as a main byproduct, avoiding the use of dangerous and expensive chemical reducing agents and no generation of corrosive wastewater. Compared with the traditional method, the method is easy to realize industrial production.
The present invention has been described in detail hereinabove, but the above embodiments are merely exemplary in nature and are not intended to limit the present invention. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or summary or the following examples.
Detailed Description
The invention is further illustrated by the following examples, which are provided for illustrative purposes only and are not to be construed as limiting the scope of the invention as claimed.
Unless otherwise indicated, all materials, reagents, methods and the like used in the examples are those conventionally used in the art.
In the following examples, 1, 4-butenediol, dicyclopentadiene purchased from rohn's reagent, deionized water was self-made, and formic acid, methanol, acetic anhydride, sodium hydroxide, tetrahydrofuran, 1, 4-dioxane, cerium nitrate, lanthanum nitrate, ytterbium oxide, cerium oxide, scandium oxide purchased from the national pharmaceutical chemicals company, inc; gamma-Al 2 O 3 And SiO 2 Purchased from Qingdao sea wave silica gel desiccant Co., ltd; H-ZSM-5 series molecular sieves were purchased from TianjinSouthbound catalyst limited; raney Ni catalyst was purchased from Shanghai Kaiki New Material technologies Co., ltd; high purity nitrogen, high purity ammonia, and high purity hydrogen were purchased from Qingdao de Haiwei technology Co.
In the method for synthesizing cis-7-azabicyclo [3.3.0] octane, 1, 4-butylene glycol is used as a raw material, and cis-7-azabicyclo [3.3.0] octane is synthesized through dehydration reaction, diels-Alder reaction, epoxidation hydration reaction, dehydration reaction (esterification reaction and thermal cracking reaction), ozonization reaction, hydrogenation reaction and ammonification reaction. The product obtained in each step was filtered through a 0.22 μm filter and analyzed by Gas Chromatography (GC). Gas chromatography detection conditions: instrument: island GC2010Plus, chromatographic column: intercap-FFAP,30 mX0.25mm X0.25 μm, vaporization chamber temperature 250 ℃, FID temperature 300 ℃, column oven temperature program: the temperature is kept at 60 ℃ for 1min, and then the temperature is increased to 230 ℃ at a speed of 15 ℃/min for 10min. The products were analyzed qualitatively by gas chromatography-mass spectrometry (GC-MS). The product was quantitatively determined by Shimazu-GC 2010plus gas chromatography. The correlation calculation formula is as follows:
Example 1
1. 20g of gamma-Al was packed in a fixed bed reactor 2 O 3 Catalyst, temperature was raised to 240℃at a nitrogen flow rate of 50ml/min, compound 1 (1, 4-butene diol) was reacted for 0.8h -1 Is pumped into the reactorThe reaction is carried out in the process, the product enters a storage tank after condensation and gas-liquid separation, the product in the storage tank is rectified, the fraction at 62-66 ℃ is taken to obtain the product compound 2, the yield is 77%, the main byproduct is crotonaldehyde, the mass yield is 1%, and the rest of the byproducts are mainly water.
2. 1.0kg of compound 2 and 1.0kg of cyclopentadiene are added into a 5L high-pressure reaction kettle, the air in the kettle is replaced by nitrogen, the pressure is maintained to ensure that the reaction kettle is airtight, the reaction kettle is heated to 180 ℃ for 10 hours, the temperature is reduced after the reaction is finished, the pressure is relieved, 1.79kg of compound 3 is obtained after the product is rectified, and the separation yield is 92%. The remaining by-product was gum.
3. 1890g of formic acid, 349g of 25% hydrogen peroxide and 0.5g of sulfuric acid are added into a flask, and the mixture is stirred at 10 ℃ for 30min to obtain peroxyformic acid. 700g of Compound 3 was slowly added dropwise to the above mixture, and the reaction temperature was controlled to be not more than 20℃during the addition. After the dripping is finished, stirring and reacting for 1h are continued to obtain an intermediate. Then adding saturated sodium hydroxide solution dropwise until the system becomes alkaline, and controlling the internal temperature to be not higher than 30 ℃ in the dropping process. After completion of the dropwise addition, ethyl acetate was added for extraction three times (1000 ml each time), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed to give 810g of compound 4, and the isolated yield was 93%.
4. 20g of Yb was charged into a fixed bed reactor 2 O 3 After the catalyst was activated by heating to 350℃under nitrogen for 2 hours, compound 4 was reacted for 0.1 hour -1 Introducing the space velocity of the mixture into the reactor for reaction, condensing the product, separating gas from liquid, and then entering a storage tankAnd rectifying the product in the storage tank to obtain the compound 5, wherein the separation yield is 83%.
5. 300g of compound 5 and 1200g of methanol are mixed in a 5L flask, ozone is introduced into the mixture, the reaction temperature is controlled to be not higher than minus 10 ℃, after the raw materials are completely reacted, nitrogen is introduced to sweep for 30min, the methanol is distilled off, a fraction at 260 ℃ is taken to obtain 287g of compound 6, and the separation yield is 91%.
6. 250g of Compound 6 and 12.5g of Ru/gamma-Al 2 O 3 Adding (Ru load is 5%) into a 500ml high-pressure reaction kettle, replacing air in the kettle with nitrogen three times, replacing with hydrogen three times, filling 3MPa hydrogen, heating to 180 ℃ for reaction, continuously supplementing hydrogen into the reaction kettle until the pressure is not continuously reduced, rectifying the product after the reaction is finished, taking 145-150 ℃ fractions to obtain 188g of compound 7, and separating the yield to 93%.
7. 150g of Compound 7 and ammonia (150 ml/min) were fed into a fixed bed reactor containing 10g of La-H-ZSM-5, at a reaction temperature of 280℃and a space velocity of 0.08H, respectively -1 Condensing the product, separating gas from liquid, feeding the product into a storage tank, rectifying the product, and obtaining a fraction at 165 ℃ to obtain 135g of cis-7-azabicyclo [3.3.0]Octane, isolation yield was 90%.
Example 2
1. 20g of gamma-Al was packed in a fixed bed reactor 2 O 3 The catalyst was heated to 240℃at a nitrogen flow rate of 50ml/min, compound 1 was heated to 0.8h -1 The product is condensed and separated from gas and liquid, and then enters a storage tank, the product in the storage tank is rectified, and the fraction at 62-66 ℃ is taken to obtain the product compound 2, the yield is 77%, the main byproduct is crotonaldehyde, the mass yield is 1%, and the rest of the byproducts are mainly water.
2. 1.0kg of compound 2 and 1.0kg of cyclopentadiene are added into a 5L high-pressure reaction kettle, the air in the kettle is replaced by nitrogen, the pressure is maintained to ensure that the reaction kettle is airtight, the reaction kettle is heated to 180 ℃ for 10 hours, the temperature is reduced after the reaction is finished, the pressure is relieved, 1.79kg of compound 3 is obtained after the product is rectified, and the separation yield is 92%. The remaining by-product was gum.
3. 1890g of formic acid, 349g of 25% hydrogen peroxide and 0.5g of sulfuric acid are added into a flask, and the mixture is stirred at 10 ℃ for 30min to obtain peroxyformic acid. 700g of Compound 3 was slowly added dropwise to the above mixture, and the reaction temperature was controlled to be not more than 20℃during the addition. After the dripping is finished, stirring and reacting for 1h are continued to obtain an intermediate. Then adding saturated sodium hydroxide solution dropwise until the system becomes alkaline, and controlling the internal temperature to be not higher than 30 ℃ in the dropping process. After completion of the dropwise addition, ethyl acetate was added for extraction three times (1000 ml each time), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed to give 810g of compound 4, and the isolated yield was 93%.
4. 10g of Sc was charged into a fixed bed reactor 2 O 3 The catalyst is heated to 350 ℃ under nitrogen atmosphere, and after 2 hours of catalyst activation, the compound 4 is treated by0.1h -1 Introducing airspeed of (2) into the reactor for reaction, condensing the product, separating gas from liquid, then introducing the product into a storage tank, rectifying the product in the storage tank to obtain the compound 5, and separating the product with 88% of yield.
5. 300g of compound 5 and 1200g of methanol are mixed in a 5L flask, ozone is introduced into the mixture, the reaction temperature is controlled to be not higher than minus 10 ℃, after the raw materials are completely reacted, nitrogen is introduced to sweep for 30min, the methanol is distilled off, a fraction at 260 ℃ is taken to obtain 287g of compound 6, and the separation yield is 91%.
6. 250g of Compound 6 and 12.5g of Ni/gamma-Al 2 O 3 Adding (the loading amount of Ni is 5%) into a 500ml high-pressure reaction kettle, replacing air in the kettle with nitrogen for three times, replacing with hydrogen for three times, then filling 3MPa of hydrogen, heating to 180 ℃ for reaction, continuously supplementing hydrogen into the reaction kettle until the pressure is not continuously reduced, rectifying a product after the reaction is finished, taking 145-150 ℃ fractions to obtain 188g of compound 7, and separating the yield by 92%.
7. 150g of Compound 7 and ammonia (150 ml/min) were fed into a fixed bed reactor containing 10g of La-H-ZSM-5, at a reaction temperature of 280℃and a space velocity of 0.08H, respectively -1 Condensing the product, separating gas from liquid, feeding the product into a storage tank, rectifying the product, and obtaining a fraction at 165 ℃ to obtain 135g of cis-7-azabicyclo [3.3.0 ]]Octane, isolation yield was 90%.
Example 3
1. 20g of gamma-Al was packed in a fixed bed reactor 2 O 3 The catalyst was heated to 240℃at a nitrogen flow rate of 50ml/min, compound 1 was heated to 0.8h -1 The product is condensed and separated from gas and liquid, and then enters a storage tank, the product in the storage tank is rectified, and the fraction at 62-66 ℃ is taken to obtain the product compound 2, the yield is 75%, the main byproduct is crotonaldehyde, the mass yield is 2%, and the rest of the byproducts are mainly water.
2. 1.0kg of compound 2 and 1.0kg of cyclopentadiene are added into a 5L high-pressure reaction kettle, the air in the kettle is replaced by nitrogen, the pressure is maintained to ensure that the reaction kettle is airtight, the reaction kettle is heated to 180 ℃ for 10 hours, the temperature is reduced after the reaction is finished, the pressure is relieved, 1.79kg of compound 3 is obtained after the product is rectified, and the separation yield is 92%. The remaining by-product was gum.
3. 1890g of formic acid, 349g of 25% hydrogen peroxide and 0.5g of sulfuric acid are added into a flask, and the mixture is stirred at 10 ℃ for 30min to obtain peroxyformic acid. 700g of Compound 3 was slowly added dropwise to the above mixture, and the reaction temperature was controlled to be not more than 20℃during the addition. After the dripping is finished, stirring and reacting for 1h are continued to obtain an intermediate. Then adding saturated sodium hydroxide solution dropwise until the system becomes alkaline, and controlling the internal temperature to be not higher than 30 ℃ in the dropping process. After completion of the dropwise addition, ethyl acetate was added for extraction three times (1000 ml each time), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed to give 810g of compound 4, and the isolated yield was 93%.
4. 500g of Compound 4 and 1500g of acetic anhydride were mixed in a 5L flask, 5g of sulfuric acid was added, the mixture was heated to 80℃and reacted for 10 hours, 725g of Compound 8 was obtained by distillation, and the isolation yield was 97%.
700g of compound 8 and 700g of tetrahydrofuran are mixed and then are introduced into a fixed bed reactor heated to 450 ℃, the product is condensed and gas-liquid separated and then enters a storage tank, and 322g of compound 5 is obtained after the product is rectified, and the separation yield is 87%.
5. 300g of compound 5 and 1200g of methanol are mixed in a 5L flask, ozone is introduced into the mixture, the reaction temperature is controlled to be not higher than minus 10 ℃, after the raw materials are completely reacted, nitrogen is introduced to sweep for 30min, the methanol is distilled off, a fraction at 260 ℃ is taken to obtain 287g of compound 6, and the separation yield is 91%.
6. 250g of Compound 6 and 12.5g of Ru/gamma-Al 2 O 3 Adding (Ru load is 5%) into a 500ml high-pressure reaction kettle, replacing air in the kettle with nitrogen three times, replacing with hydrogen three times, filling 3MPa hydrogen, heating to 180 ℃ for reaction, continuously supplementing hydrogen into the reaction kettle until the pressure is not continuously reduced, rectifying the product after the reaction is finished, taking 145-150 ℃ fractions to obtain 188g of compound 7, and separating the yield to 93%.
7. 150g of Compound 7 and ammonia (150 ml/min) were fed into a fixed bed reactor containing 10g of La-H-ZSM-5, at a reaction temperature of 280℃and a space velocity of 0.08H, respectively -1 Condensing the product, separating gas from liquid, feeding the product into a storage tank, rectifying the product, and obtaining a fraction at 165 ℃ to obtain 135g of cis-7-azabicyclo [3.3.0 ]]Octane, isolation yield was 90%.
Example 4
1. A fixed bed reactor was charged with 20g H-ZSM-5 (Si/Al=80) catalyst and the temperature was raised to 240℃at a nitrogen flow rate of 50ml/min to give Compound 1 at 0.8h -1 The product is condensed and separated from gas and liquid, and then enters a storage tank, the product in the storage tank is rectified, and the fraction at 62-66 ℃ is taken to obtain the product compound 2, the yield is 77%, the main byproduct is crotonaldehyde, the mass yield is 1%, and the rest of the byproducts are mainly water.
2. 1.0kg of compound 2 and 1.0kg of cyclopentadiene are added into a 5L high-pressure reaction kettle, air in the kettle is replaced by nitrogen, the pressure is maintained to ensure that the reaction kettle is airtight, the reaction kettle is heated to 200 ℃ for 5 hours, the temperature is reduced after the reaction is finished, the pressure is relieved, the product is rectified to obtain 1.60kg of compound 3, and the separation yield is 82%. The remaining by-product was gum.
3. 1890g of acetic acid, 349g of 25% hydrogen peroxide and 0.5g of sulfuric acid were added into a flask, and the mixture was stirred at 10℃for 30 minutes to obtain peracetic acid. 700g of Compound 3 was slowly added dropwise to the above mixture, and the reaction temperature was controlled to be not more than 20℃during the addition. After the dripping is finished, stirring and reacting for 1h are continued to obtain an intermediate. Then adding saturated sodium hydroxide solution dropwise until the system becomes alkaline, and controlling the internal temperature to be not higher than 30 ℃ in the dropping process. After completion of the dropwise addition, ethyl acetate was added for extraction three times (1000 ml each time), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed to give 800g of compound 4, and the isolation yield was 91%.
4. 500g of Compound 4 was mixed with 1500g of acetic anhydride in a 5L flask, then 5g of Amberlyst-35 was added, the mixture was heated to 80℃and reacted for 10 hours, and 730g of Compound 8 was obtained by distillation, and the isolation yield was 98%.
700g of compound 8 and 700g of tetrahydrofuran are mixed and then are introduced into a fixed bed reactor heated to 400 ℃, products are condensed and gas-liquid separated and then enter a storage tank, and 330g of compound 5 is obtained after the products are rectified, and the separation yield is 89%.
5. 300g of compound 5, 600g of dichloromethane and 600g of methanol are mixed in a 5L flask, ozone is introduced into the mixture, the reaction temperature is controlled to be not higher than-20 ℃, after the raw materials are completely reacted, nitrogen is introduced and purged for 30min, the methanol and the dichloromethane are distilled off, 285g of compound 6 is obtained by taking a fraction at 260 ℃, and the isolation yield is 91%.
6. 250g of compound 6 and 12.5g of Ni/H-ZSM-5 (load of Ru is 5%) are added into a 500ml high-pressure reaction kettle, after the air in the kettle is replaced by nitrogen for three times, the air in the kettle is replaced by hydrogen for three times, then 3MPa hydrogen is filled, the reaction kettle is heated to 200 ℃ for reaction, hydrogen is continuously supplemented into the reaction kettle until the pressure is not reduced any more, after the reaction is finished, a fraction of 145-150 ℃ is distilled from the product to obtain 180g of compound 7, and the separation yield is 90%.
7. 150g of Compound 7 and ammonia (150 ml/min) were respectively introduced into a reactor containing 10g of Ce-gamma-Al 2 O 3 In the fixed bed reactor of (2), the reaction temperature was 280℃and the space velocity was 0.05h -1 The product enters a storage after condensation and gas-liquid separationTank, rectifying the product to obtain 165 deg.c fraction to obtain 130g cis-7-azabicyclo [3.3.0 ]]Octane, isolated yield 87%.
Example 5
1. A fixed bed reactor was charged with 20g of Nb 2 O 3 The catalyst was heated to 240℃at a nitrogen flow rate of 50ml/min, compound 1 was heated to 0.8h -1 The product is condensed and separated from gas and liquid, and then enters a storage tank, the product in the storage tank is rectified, and the fraction at 62-66 ℃ is taken to obtain the product compound 2, the yield is 75%, the main byproduct is crotonaldehyde, the mass yield is 3%, and the rest of the byproducts are mainly water.
2. 1.0kg of compound 2 and 1.0kg of cyclopentadiene are added into a 5L high-pressure reaction kettle, air in the kettle is replaced by nitrogen, the pressure is maintained to ensure that the reaction kettle is airtight, the reaction kettle is heated to 200 ℃ for 5 hours, the temperature is reduced after the reaction is finished, the pressure is relieved, the product is rectified to obtain 1.60kg of compound 3, and the separation yield is 82%. The remaining by-product was gum.
3. 1890g of acetic acid, 349g of 25% hydrogen peroxide and 0.5g of sulfuric acid were added into a flask, and the mixture was stirred at 10℃for 30 minutes to obtain peracetic acid. 700g of Compound 3 was slowly added dropwise to the above mixture, and the reaction temperature was controlled to be not more than 20℃during the addition. After the dripping is finished, stirring and reacting for 1h are continued to obtain an intermediate. Then adding saturated sodium hydroxide solution dropwise until the system becomes alkaline, and controlling the internal temperature to be not higher than 30 ℃ in the dropping process. After completion of the dropwise addition, ethyl acetate was added for extraction three times (1000 ml each time), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed to give 800g of compound 4, and the isolation yield was 91%.
4. 500g of Compound 4 and 1500g of acetic anhydride were mixed in a 5L flask, 5g of sulfuric acid was added, the mixture was heated to 80℃and reacted for 10 hours, 725g of Compound 8 was obtained by distillation, and the isolation yield was 97%.
700g of compound 8 and 700g of 1, 4-dioxane are mixed and then are introduced into a fixed bed reactor heated to 400 ℃, products are condensed and gas-liquid separated and then enter a storage tank, and 328g of compound 5 is obtained after the products are rectified, and the separation yield is 88%.
5. 300g of compound 5 and 1200g of dichloroethane are mixed in a 5L flask, ozone is introduced into the mixture, the reaction temperature is controlled to be not higher than 10 ℃, after the raw materials are completely reacted, nitrogen is introduced to sweep for 30min, the dichloroethane is distilled off, a fraction at 260 ℃ is taken to obtain 282g of compound 6, and the separation yield is 90%.
6. 250g of Compound 6 and 12.5g of Ni/Nb 2 O 3 Adding (Ru load is 5%) into a 500ml high-pressure reaction kettle, replacing air in the kettle with nitrogen three times, replacing with hydrogen three times, filling 3MPa hydrogen, heating to 180 ℃ for reaction, continuously supplementing hydrogen into the reaction kettle until the pressure is not continuously reduced, rectifying the product after the reaction is finished, taking 145-150 ℃ fraction to obtain 176g of compound 7, and separating the yield by 88%.
7. 150g of Compound 7 and ammonia (15)0 ml/min) was charged with 10g of gamma-Al, respectively 2 O 3 In the fixed bed reactor, the reaction temperature was 350℃and the space velocity was 0.05h -1 The product is condensed, separated from gas and liquid and then enters a storage tank, and the product is rectified to obtain a fraction at 165 ℃ to obtain 125g of cis-7-azabicyclo [3.3.0 ]]Octane, isolated yield was 83%.
Example 6
1. A fixed bed reactor was charged with 20g Amberlyst-35 catalyst and the temperature was raised to 120℃at a nitrogen flow rate of 50ml/min to give Compound 1 at a rate of 0.5h -1 The product is condensed and separated from gas and liquid, and then enters a storage tank, the product in the storage tank is rectified, and the fraction at 62-66 ℃ is taken to obtain the compound 2, the yield is 71%, the main byproduct is crotonaldehyde, the mass yield is 5%, and the rest of the byproducts are mainly water.
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2. 1.0kg of compound 2 and 1.0kg of dicyclopentadiene are added into a 5L high-pressure reaction kettle, the air in the kettle is replaced by nitrogen, the pressure is maintained to ensure that the reaction kettle is airtight, the reaction kettle is heated to 200 ℃ for 5 hours, the temperature is reduced and the pressure is relieved after the reaction is finished, 1.60kg of compound 3 is obtained after the product is rectified, and the separation yield is 82%. The remaining by-product was gum.
3. 1890g of acetic acid, 349g of 25% hydrogen peroxide and 0.5g of sulfuric acid were added into a flask, and the mixture was stirred at 10℃for 30 minutes to obtain peracetic acid. 700g of Compound 3 was slowly added dropwise to the above mixture, and the reaction temperature was controlled to be not more than 20℃during the addition. After the dripping is finished, stirring and reacting for 1h are continued to obtain an intermediate. Then adding saturated sodium hydroxide solution dropwise until the system becomes alkaline, and controlling the internal temperature to be not higher than 30 ℃ in the dropping process. After completion of the dropwise addition, ethyl acetate was added for extraction three times (1000 ml each time), and the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed to give 800g of compound 4, and the isolation yield was 91%.
4. 500g of Compound 4 and 1000g of acetic anhydride were mixed in a 5L flask, 5g of sulfuric acid was added, the mixture was heated to 80℃and reacted for 10 hours, and 720g of Compound 8 was obtained by distillation, and the isolation yield was 97%.
700g of compound 8 and 700g of toluene are mixed and then are introduced into a fixed bed reactor heated to 400 ℃, products are condensed and gas-liquid separated and then enter a storage tank, and 330g of compound 5 is obtained after the products are rectified, and the separation yield is 89%.
5. 300g of compound 5 and 1200g of dichloroethane are mixed in a 5L flask, ozone is introduced into the mixture, the reaction temperature is controlled to be not higher than 10 ℃, after the raw materials are completely reacted, nitrogen is introduced to sweep for 30min, the dichloroethane is distilled off, a fraction at 260 ℃ is taken to obtain 282g of compound 6, and the separation yield is 90%.
6. 250g of Compound 6 and 12.5g of Ni/Nb 2 O 3 Adding (Ru load is 5%) into a 500ml high-pressure reaction kettle, replacing air in the kettle with nitrogen three times, replacing with hydrogen three times, filling 3MPa hydrogen, heating to 180 ℃ for reaction, continuously supplementing hydrogen into the reaction kettle until the pressure is not continuously reduced, rectifying the product after the reaction is finished, taking 145-150 ℃ fraction to obtain 176g of compound 7, and separating the yield by 88%.
7. 150g of Compound 7 and ammonia (150 ml/min) were introduced into a fixed bed reactor containing 10g H-ZSM-5, respectively, at a reaction temperature of 350℃and a space velocity of 0.05h -1 The product is condensed, separated from gas and liquid and then enters a storage tank, and the product is rectified to obtain a fraction at 165 ℃ to obtain 131g of cis-7-azabicyclo [3.3.0]]Octane, isolated yield 87%.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limited thereto. Although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some or all of the technical features thereof, without departing from the spirit and scope of the present invention as defined in the claims; and such modifications or substitutions are intended to be within the scope of the present invention as defined by the claims.

Claims (78)

1. A method for synthesizing cis-7-azabicyclo [3.3.0] octane, comprising the steps of:
(1) Introducing the compound 1 into a fixed bed reactor filled with a catalyst for dehydration reaction, condensing a product, separating gas from liquid, and then entering a storage tank, and rectifying the product in the storage tank to obtain a compound 2;
(2) Adding a compound 2 and conjugated olefin into a high-pressure reaction kettle, maintaining pressure after replacing air in the kettle with nitrogen to ensure that the reaction kettle is airtight, heating for reaction, cooling after the reaction is finished, decompressing, and rectifying a product to obtain a compound 3;
(3) Mixing the compound 3 with an oxidant, performing epoxidation reaction, adding alkali for hydrolysis, and extracting to obtain a compound 4;
(4) Introducing the compound 4 into a solid filled with the catalystCarrying out dehydration reaction in a fixed bed reactor, condensing a product, separating gas from liquid, and then entering a storage tank, and rectifying the product in the storage tank to obtain a compound 5; wherein the catalyst for the dehydration reaction of step (4) is selected from Al 2 O 3 、SiO 2 、ZrO 2 、CeO 2 、Yb 2 O 3 、Y 2 O 3 、La 2 O 3 、Sc 2 O 3 One or more of the following; the dehydration reaction temperature of the step (4) is 350-550 ℃;
or,
mixing the compound 4 with acetic anhydride, adding a catalyst, heating for esterification reaction, and distilling to obtain a compound 8; mixing the compound 8 with a solvent, introducing the mixture into a fixed bed reactor for thermal cracking reaction, condensing the product, separating gas from liquid, and then introducing the product into a storage tank, and rectifying the product in the storage tank to obtain a compound 5; wherein the thermal cracking reaction temperature of step (4) is 300-600 ℃;
(5) Mixing the compound 5 with a solvent, introducing ozone into the mixture, introducing nitrogen to purge the mixture after the raw materials are completely reacted, and distilling the mixture to obtain a compound 6; wherein the reaction temperature in the step (5) is-20-30 ℃;
(6) Adding the compound 6 and a catalyst into a high-pressure reaction kettle, replacing air in the kettle with nitrogen, replacing with hydrogen, then filling hydrogen, heating for reaction, continuously supplementing hydrogen into the reaction kettle until the pressure is not reduced continuously, and rectifying after the reaction is finished to obtain a compound 7;
(7) And (3) dissolving the compound 7 in an optional solvent, respectively introducing the solvent and ammonia gas into a fixed bed reactor filled with a catalyst for reaction, condensing the product, separating gas from liquid, and then introducing the product into a storage tank, and rectifying the product in the storage tank to obtain the product cis-7-azabicyclo [3.3.0] octane.
2. The process according to claim 1, wherein the catalyst of step (1) is selected from the group consisting of activated carbon, ion exchange resins, γ -Al 2 O 3 、SiO 2 、ZrO 2 、CeO 2 、WO 3 、Nb 2 O 5 One of zeolite molecular sievesOr a plurality thereof.
3. The process according to claim 2, wherein the catalyst of step (1) is selected from γ -Al 2 O 3 、SiO 2 、Nb 2 O 5 One or more of zeolite molecular sieves.
4. A process according to claim 3, wherein the catalyst of step (1) is selected from γ -Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves.
5. The process of claim 1, wherein the reaction temperature of step (1) is 100-400 ℃.
6. The process of claim 5, wherein the reaction temperature of step (1) is 120-300 ℃.
7. The method of claim 6, wherein the reaction temperature of step (1) is 120-260 ℃.
8. The process according to claim 1, wherein the mass space velocity of the compound 1 of step (1) is 0.1 to 5h -1 。
9. The process according to claim 8, wherein the mass space velocity of the compound 1 of step (1) is 0.3 to 3h -1 。
10. The process according to claim 9, wherein the mass space velocity of the compound 1 of step (1) is 0.5 to 1.5h -1 。
11. The process according to claim 1, wherein the molar ratio of compound 2 to conjugated olefin of step (2) is from 1:5 to 5:1.
12. The process of claim 1, wherein the conjugated olefin of step (2) is selected from one or more of cyclopentadiene and dicyclopentadiene.
13. The process of claim 1, wherein the reaction temperature of step (2) is 140-260 ℃.
14. The method of claim 13, wherein the reaction temperature of step (2) is 160-220 ℃.
15. The method of claim 14, wherein the reaction temperature of step (2) is 160-200 ℃.
16. The method according to claim 1, wherein the reaction time of step (2) is 10min-10h.
17. The method of claim 16, wherein the reaction time of step (2) is 30min to 5h.
18. The method of claim 17, wherein the reaction time of step (2) is 30min-3h.
19. The method of claim 1, wherein the oxidizing agent of step (3) is selected from one or more of peroxyformic acid, peroxyacetic acid, peroxybenzoic acid, meta-chloroperoxybenzoic acid.
20. The method of claim 1, wherein the molar ratio of compound 3 to oxidant of step (3) is from 1:1.1 to 1:3.
21. The process of claim 1, wherein the epoxidation reaction temperature of step (3) is from-10 ℃ to 40 ℃.
22. The process of claim 21, wherein the epoxidation reaction temperature of step (3) is from 0 ℃ to 30 ℃.
23. The process of claim 22, wherein the epoxidation reaction temperature of step (3) is from 0 ℃ to 20 ℃.
24. The process of claim 1, wherein the epoxidation reaction time of step (3) is from 30 minutes to 10 hours.
25. The process of claim 24, wherein the epoxidation reaction time of step (3) is from 30 minutes to 6 hours.
26. The method of claim 25, wherein the epoxidation reaction time of step (3) is from 30 minutes to 3 hours.
27. The method of claim 1, wherein the base of step (3) is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
28. The process according to claim 1, wherein the hydrolysis is carried out at a temperature of 20-70 ℃ with the addition of base in step (3).
29. The process of claim 1, wherein the dehydration reaction feed space velocity of step (4) is from 0.05 to 1.0h -1 。
30. The process according to claim 1, wherein the molar ratio of compound 4 to acetic anhydride of step (4) is from 1:2.2 to 1:6.
31. The process of claim 1, wherein the catalyst for the esterification reaction of step (4) is selected from one or more of sulfuric acid, phosphoric acid, hydrochloric acid, amberlyst-15, amberlyst-35.
32. The process of claim 1, wherein the esterification reaction temperature of step (4) is 40-90 ℃.
33. The process according to claim 1, wherein the esterification reaction time of step (4) is 30min to 10h.
34. The process of claim 1, wherein the solvent for the thermal cracking reaction of step (4) is selected from one or more of tetrahydrofuran, 1, 4-dioxane, toluene, benzene, xylene, ethyl acetate.
35. The process of claim 1, wherein the thermal cracking reaction temperature of step (4) is 300-550 ℃.
36. The process of claim 35, wherein the thermal cracking reaction temperature of step (4) is 350-450 ℃.
37. The method of claim 1, wherein the solvent of step (5) is selected from one or more of methanol, ethanol, methylene chloride, ethylene dichloride, water, formic acid, acetic acid.
38. The method according to claim 1, wherein the mass concentration of the compound 5 of step (5) in the solvent is 10-50wt%.
39. The method according to claim 38, wherein the mass concentration of the compound 5 of step (5) in the solvent is 10-40wt%.
40. The method according to claim 39, wherein the mass concentration of the compound 5 of step (5) in the solvent is 20 to 30wt%.
41. The method according to claim 1, wherein the catalyst of step (6) is a supported catalyst comprising a carrier S and a metal active ingredient M supported on the carrier;
m is selected from one or more of Cu, ni, co, ru, pd, pt;
s is selected from activated carbon, ion exchange resin, gamma-Al 2 O 3 、SiO 2 、ZrO 2 、CeO 2 、WO 3 、Nb 2 O 5 One or more of zeolite molecular sieves.
42. The method of claim 41, wherein M is selected from one or more of Cu, ni, co, ru.
43. The method of claim 42, wherein M is selected from one or more of Cu, ni, ru.
44. The method of claim 41, wherein S is selected from the group consisting of activated carbon, gamma Al 2 O 3 、SiO 2 、Nb 2 O 5 One or more of zeolite molecular sieves.
45. The method of claim 44, wherein S is selected from the group consisting of activated carbon, gamma Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves.
46. The process according to claim 1, wherein the catalyst of step (6) is added in an amount of 3-10wt% of compound 6.
47. The process of claim 1, wherein the reaction temperature of step (6) is 100-250 ℃.
48. The method of claim 47, wherein the reaction temperature of step (6) is 120-200 ℃.
49. The method of claim 48, wherein said reaction temperature of step (6) is 150-200 ℃.
50. The process according to claim 1, wherein the reaction pressure of step (6) is 0.1-8MPa.
51. The method of claim 50, wherein the reaction pressure of step (6) is 2-6MPa.
52. The method of claim 51, wherein the reaction pressure of step (6) is 3-5MPa.
53. The process of claim 1, wherein the catalyst of step (7) is a supported metal oxide catalyst comprising a support and a metal oxide supported on the support;
the carrier is selected from activated carbon, gamma-Al 2 O 3 、SiO 2 、ZrO 2 、WO 3 、Nb 2 O 5 One or more of zeolite molecular sieves;
the metal active component corresponding to the metal oxide is selected from one or more of scandium, yttrium, lanthanum, cerium, ytterbium and lutetium.
54. The method of claim 53, wherein the metal active component corresponding to the metal oxide is selected from one or more of yttrium, lanthanum, cerium, ytterbium.
55. The method of claim 54, wherein the metal active component corresponding to the metal oxide is selected from one or more of lanthanum, cerium, and ytterbium.
56. The method of claim 53, wherein the step ofThe carrier is selected from gamma-Al 2 O 3 、SiO 2 、ZrO 2 、Nb 2 O 5 One or more of zeolite molecular sieves.
57. The method of claim 56, wherein the carrier is selected from the group consisting of gamma-Al 2 O 3 、SiO 2 One or more of zeolite molecular sieves.
58. The method of claim 53, wherein the loading of metal oxide in the supported metal oxide catalyst is from 0.1 to 5wt%.
59. The method of claim 58, wherein the loading of metal oxide in the supported metal oxide catalyst is from 0.1 to 3wt%.
60. The method of claim 59, wherein the loading of metal oxide in the supported metal oxide catalyst is from 0.1 to 1wt%.
61. The method of claim 53, wherein the reaction temperature of step (7) is 180-550 ℃.
62. The method of claim 61, wherein the reaction temperature of step (7) is 220-450 ℃.
63. The method of claim 62, wherein the reaction temperature of step (7) is 250-450 ℃.
64. The process of claim 53 wherein the solvent of step (7) is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, dioxane, cyclohexane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane.
65. The method of claim 64, wherein the solvent of step (7) is selected from one or more of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, cyclohexane, n-hexane, n-heptane.
66. The method of claim 65, wherein the solvent of step (7) is selected from one or more of methanol, ethanol, propanol, cyclohexane, n-hexane, n-heptane.
67. The method of claim 53, wherein the volume ratio of compound 7 to solvent of step (7) is from 1:0.1 to 1:50.
68. The method of claim 67, wherein the volume ratio of said compound 7 to solvent of step (7) is from 1:0.5 to 1:20.
69. The method of claim 68, wherein the volume ratio of said compound 7 to solvent of step (7) is from 1:1 to 1:5.
70. The method of claim 53, wherein said compound 7 of step (7) has a mass space velocity of 0.01 to 10 hours -1 。
71. The process of claim 70 wherein the mass space velocity of said compound 7 of step (7) is from 0.01 to 5 hours -1 。
72. The process of claim 71 wherein said compound 7 of step (7) has a mass space velocity of from 0.02 to 3 hours -1 。
73. The method of claim 53, wherein the molar ratio of compound 7 to ammonia of step (7) is from 1:5 to 1:100.
74. The method of claim 73, wherein the molar ratio of compound 7 to ammonia of step (7) is from 1:5 to 1:80.
75. The method of claim 74, wherein the molar ratio of compound 7 to ammonia of step (7) is from 1:10 to 1:80.
76. The method of claim 53, wherein the reaction pressure of step (7) is 0.1-3.0MPa.
77. The method of claim 76, wherein the reaction pressure of step (7) is from 0.1 MPa to 2.0MPa.
78. The method of claim 77, wherein said reaction pressure of step (7) is 0.1-1.0MPa.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005049568A1 (en) * 2003-11-24 2005-06-02 Potluri Ramesh Babu A process for industrially viable preparation of (s,s,s) phenylmethyl-2-azabicyclo-[3.3.0]-octane-3-carboxylate tosylate
CN112851563A (en) * 2020-12-30 2021-05-28 安徽金鼎医药股份有限公司 Synthesis process of N-amino-3-azabicyclo [3,3,0] octane hydrochloride

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005049568A1 (en) * 2003-11-24 2005-06-02 Potluri Ramesh Babu A process for industrially viable preparation of (s,s,s) phenylmethyl-2-azabicyclo-[3.3.0]-octane-3-carboxylate tosylate
CN112851563A (en) * 2020-12-30 2021-05-28 安徽金鼎医药股份有限公司 Synthesis process of N-amino-3-azabicyclo [3,3,0] octane hydrochloride

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