Synthesis process of trans-p-aminocyclohexanol

Abstract

The invention discloses a synthesis process of trans-p-aminocyclohexanol, and belongs to the technical field of chemical synthesis. The synthesis process of the trans-p-acetamido cyclohexanol comprises the following steps: performing catalytic hydrogenation on p-acetamido phenol, a catalyst A, an additive and a solvent A at a certain pressure and temperature to obtain p-acetamido cyclohexanol, and performing esterification, recrystallization and separation on acetic anhydride and p-acetamido cyclohexanol to obtain trans-p-acetamido cyclohexanol acetate; then, the trans-p-acetamido cyclohexanol acetate is hydrolyzed, and trans-p-aminocyclohexanol is obtained; the trans-p-aminocyclohexanol prepared by the method disclosed by the invention is high in yield and high in purity.

Description

Technical Field

[0001] The invention relates to a synthesis process of trans-p-aminocyclohexanol. Background Art

[0002] As a new type of expectorant, ambroxol has been widely welcomed for its good efficacy and low side effects since it was developed by Boehringer Ingelheim in Germany and launched in Japan in 1984. In the synthesis process of ambroxol, trans-p-aminocyclohexanol is an important intermediate, and the quality of its synthesis process directly affects the quality and cost of the final product.

[0003] At present, the synthesis method of trans-p-aminocyclohexanol is mainly to prepare cis-trans mixed p-acetaminocyclohexanol from p-acetaminophenol through catalytic hydrogenation reaction. Subsequently, in order to obtain the target product of high purity, namely trans-p-aminocyclohexanol, it is usually necessary to separate the cis-trans isomers. This process mainly relies on column chromatography or crystallization in the prior art.

[0004] However, both separation methods have obvious limitations. Although column chromatography can effectively separate cis and trans isomers, its processing capacity per unit time and unit volume is limited and is not suitable for large-scale industrial production. On the other hand, the crystallization method requires repeated crystallization, which not only leads to a large amount of solvent consumption, but also the total yield of the entire process is only 27%, which greatly limits production efficiency and economic benefits.

[0005] Therefore, the present invention provides a synthesis process of trans-p-aminocyclohexanol. Summary of the invention

[0006] The purpose of the present invention is to provide a synthesis process of trans-p-aminocyclohexanol to solve the technical problems mentioned in the above background technology.

[0007] The technical solution for achieving the purpose of the present invention is:

[0008] A synthesis process of trans-p-aminocyclohexanol comprises the following process steps:

[0009] (1) taking acetaminophenol as a reaction raw material, mixing it with solvent A, additives and catalyst A, hydrogenating it under a certain reaction pressure and reaction temperature, filtering it, and crystallizing it to obtain acetaminocyclohexanol;

[0010] (2) esterifying acetylaminocyclohexanol with acetic anhydride, recrystallizing and separating to obtain trans-acetylaminocyclohexanol acetate;

[0011] (3) Separating trans-p-acetylaminocyclohexanol acetate to obtain trans-p-aminocyclohexanol.

[0012] Furthermore, the solvent A is dimethylformamide.

[0013] Furthermore, the additive is a carbonate or sulfate of sodium or potassium.

[0014] Furthermore, the catalyst is a 5% palladium-carbon catalyst.

[0015] Furthermore, in terms of weight fractions, the weight parts of acetaminophenol, solvent A, additives and catalyst A in step (1) are respectively: 250-350 parts by weight of acetaminophenol, 550-650 parts by weight of solvent A, 38-40 parts by weight of additives and 2.5-3 parts by weight of catalyst A.

[0016] Furthermore, the reaction pressure is 1-1.2 MPa; the reaction temperature is 98-102° C.; and the reaction time is controlled at 6.5-7.5 h.

[0017] Furthermore, the hydrogenation reaction in step (1) is carried out under hydrogen protection conditions throughout the entire process.

[0018] Furthermore, the specific steps of step (2) are as follows: adding acetylaminocyclohexanol to acetic anhydride in an amount of 1.3 to 1.5 times its mass at 20 to 45° C., refluxing for 1 to 5 hours, then removing acetic acid and excess acetic anhydride by reduced pressure distillation to obtain a solid crude product, adding solvent B after cooling, heating and refluxing again until the solid crude product is completely dissolved, cooling to 10 to 15° C. and maintaining for 1.5 to 2.5 hours, filtering, and obtaining acetylaminocyclohexanol acetate.

[0019] Furthermore, the solvent B is acetone.

[0020] Furthermore, the specific steps of step (3) are as follows: add trans-p-acetylaminocyclohexanol acetate to a 20% sodium hydroxide solution with a mass fraction of 2 to 3 times its mass, heat and reflux for 14 to 16 hours, cool the hydrolyzate, transfer it to a continuous extraction device, and continuously extract it with chloroform for 18 to 24 hours. The organic phase is dried with magnesium sulfate, filtered, concentrated under reduced pressure, and vacuum dried to obtain trans-p-aminocyclohexanol.

[0021] By adopting the above technical solution, the present invention has the following beneficial effects:

[0022] (1) The present invention prepares a cis-trans mixture of acetaminocyclohexanol by mixing acetaminophenol as a reaction raw material with a solvent A, an additive and a catalyst A, and then performing hydrogenation reaction at a certain reaction pressure and reaction temperature, filtering and crystallizing. The yield of the prepared acetaminocyclohexanol is high, and the proportion of trans-acetaminocyclohexanol in the cis-trans mixture of acetaminocyclohexanol is relatively high, up to 91.3%.

[0023] (2) The solvent A of the present invention is dimethylformamide. Compared with the traditional methanol solvent, dimethylformamide has a stronger polarity. The transition state of forming trans-p-acetylaminocyclohexanol is more easily absorbed by polar solvents than the transition state of forming cis-p-acetylaminocyclohexanol, which is more conducive to the formation of trans-p-acetylaminocyclohexanol.

[0024] (3) Sodium or potassium carbonate or sulfate is also added during the hydrogenation reaction of the present invention. The addition of sodium or potassium carbonate or sulfate tends to enhance the electron donating property of the catalyst surface, prolonging the residence time of the reactant 4-acetylaminocyclohexanol and hydrogen on the catalyst surface, thereby facilitating the reaction process to be thermodynamically controlled to form stable trans-4-acetylaminocyclohexanol.

[0025] (4) The weight parts of acetaminophenol, solvent A, additive and catalyst A of the present invention are respectively: 250-350 parts by weight of acetaminophenol, 550-650 parts by weight of solvent A, 38-40 parts by weight of additive and 2.5-3 parts by weight of catalyst A, and the proportion of trans-4-acetylaminocyclohexanol obtained is higher.

[0026] (5) The reaction pressure of the present invention is: 1-1.2 MPa; the reaction temperature is 98-102° C.; the reaction time is controlled at 6.5-7.5 h, the reaction is relatively gentle, the reaction temperature and reaction pressure are greatly reduced, and the proportion of the generated trans-4-acetylaminocyclohexanol is higher.

[0027] (6) The hydrogenation reaction of the present invention is carried out under hydrogen protection conditions throughout the entire process, which can avoid the situation in which, when there is no hydrogen protection, the hydrogen adsorbed on the catalyst surface is easily reacted with oxygen in the air to deactivate the catalyst due to the intense stirring of the catalyst and the reaction liquid, thereby leading to the formation of the by-product 4-acetylaminocyclohexanone and affecting the product yield.

[0028] (7) The present invention uses acetic anhydride to esterify acetylaminocyclohexanol and then recrystallize and separate it. Compared with directly fractionating and crystallizing acetylaminocyclohexanol, the yield of trans-acetylaminocyclohexanol acetate is higher. DETAILED DESCRIPTION

[0029] In order to better understand the above technical solution, the above technical solution is described in detail below.

[0030] The following embodiments are only used to more clearly illustrate the technical solutions of the present invention, and are not intended to limit the protection scope of the present invention.

[0031] Analysis method: Gas chromatography was used to analyze the product components of each step.

[0032] (Overall Embodiment)

[0033] A synthesis process of trans-p-aminocyclohexanol, the process steps are as follows:

[0034] (1) First, a high-pressure hydrogenation kettle is purged with hydrogen for 4 to 5 minutes, and then 250 to 350 parts by weight of acetaminophenol, 550 to 650 parts by weight of solvent A, 38 to 40 parts by weight of additives, and 2.5 to 3 parts by weight of catalyst A are placed in the high-pressure hydrogenation kettle, and hydrogenation is performed at a reaction pressure of 1 to 1.2 MPa and a reaction temperature of 98 to 102° C. until hydrogen absorption is complete, and the reaction is kept warm for 6.5 to 7.5 hours, and the temperature is lowered to 9 to 11° C., and the filtrate is filtered, and the filtrate is crystallized to obtain acetaminocyclohexanol; the above hydrogenation reaction is performed under hydrogen protection conditions throughout the process.

[0035] (2) adding acetylaminocyclohexanol to acetic anhydride in an amount of 1.3 to 1.5 times the mass of acetylaminocyclohexanol at 20 to 45° C., and subjecting the mixture to reflux reaction for 1 to 5 hours. Subsequently, removing acetic acid and excess acetic anhydride by distillation under reduced pressure to obtain a solid crude product. After cooling, adding solvent B in an amount of 2 to 4 times the mass of acetylaminocyclohexanol, and heating and refluxing again until the solid crude product is completely dissolved, cooling to 10 to 15° C. and maintaining for 1.5 to 2.5 hours, and filtering to obtain trans-acetylaminocyclohexanol acetate;

[0036] (3) Add trans-p-acetylaminocyclohexanol acetate to a 20% sodium hydroxide solution of 2 to 3 times its mass, heat to reflux for 14 to 16 hours, cool and transfer to a continuous extraction device, extract with chloroform for 18 to 24 hours, dry the organic phase with magnesium sulfate, filter, concentrate under reduced pressure, and dry in vacuo to obtain trans-p-aminocyclohexanol in a yield of 92%.

[0037] The solvent A is dimethylformamide;

[0038] The solvent B is acetone;

[0039] The catalyst used is 5% palladium carbon catalyst

[0040] The additive is a sodium or potassium carbonate or sulfate, such as potassium (sodium) carbonate, potassium (sodium) bicarbonate, sodium (potassium) sulfate, sodium (potassium) bisulfate, and sodium (potassium) bisulfite.

[0041] (Example 1)

[0042] A synthesis process of trans-p-aminocyclohexanol, the process steps are as follows:

[0043] (1) firstly purge the high-pressure hydrogenation autoclave with hydrogen for 4 minutes, then put 250 parts by weight of acetaminophenol, 550 parts by weight of solvent A, 38 parts by weight of additives, and 2.5 parts by weight of catalyst A into the high-pressure hydrogenation autoclave, hydrogenate until hydrogen absorption is complete at a reaction pressure of 1 MPa and a reaction temperature of 98° C., keep the temperature for 6.5 hours, cool to 9° C., filter, and crystallize the filtrate to obtain acetaminocyclohexanol; the above hydrogenation reaction is carried out under hydrogen protection conditions throughout the process; wherein the yield of acetaminocyclohexanol is 99.8%; wherein the yields of cis-acetaminocyclohexanol acetate and trans-acetaminocyclohexanol acetate are 7.5% and 92.3%, respectively;

[0044] (2) adding acetylaminocyclohexanol to acetic anhydride in an amount of 1.3 times its mass at 20° C., and refluxing for 1 hour. Then, removing acetic acid and excess acetic anhydride by distillation under reduced pressure to obtain a solid crude product. After cooling, adding solvent B in an amount of 2 times the mass of acetylaminocyclohexanol, and heating and refluxing again until the solid crude product is completely dissolved. Cooling to 10° C. and maintaining for 1.5 hours, filtering, and obtaining trans-acetylaminocyclohexanol acetate;

[0045] (3) Add trans-p-acetylaminocyclohexanol acetate to a 20% sodium hydroxide solution with a mass fraction twice that of the ester, heat to reflux for 14 hours, cool and transfer to a continuous extraction device, extract with chloroform for 18 hours, dry the organic phase with magnesium sulfate, filter, concentrate under reduced pressure, and dry in vacuo to obtain trans-p-aminocyclohexanol with a yield of 90.8%.

[0046] The solvent A is dimethylformamide;

[0047] The solvent B is acetone;

[0048] The catalyst used is 5% palladium carbon catalyst

[0049] The additive is potassium bicarbonate.

[0050] (Example 2)

[0051] A synthesis process of trans-p-aminocyclohexanol, the process steps are as follows:

[0052] (1) firstly purge the high-pressure hydrogenation autoclave with hydrogen for 5 minutes, then put 300 parts by weight of acetaminophenol, 600 parts by weight of solvent A, 39 parts by weight of additives, and 2.8 parts by weight of catalyst A into the high-pressure hydrogenation autoclave, and hydrogenate until hydrogen absorption is complete at a reaction pressure of 1.1 MPa and a reaction temperature of 100° C., keep the temperature for 7 hours, cool to 10° C., filter, and crystallize the filtrate to obtain acetaminocyclohexanol; the above hydrogenation reaction is carried out under hydrogen protection conditions throughout the process, wherein the yield of acetaminocyclohexanol is 99.9%; wherein the yields of cis-acetaminocyclohexanol acetate and trans-acetaminocyclohexanol acetate are 7.2% and 92.7%, respectively;

[0053] (2) adding acetylaminocyclohexanol to acetic anhydride in an amount 1.4 times its mass at 30° C., and subjecting the mixture to reflux reaction for 3 h. Subsequently, removing acetic acid and excess acetic anhydride by distillation under reduced pressure to obtain a solid crude product. After cooling, adding solvent B in an amount 3 times its mass, and heating and refluxing again until the solid crude product is completely dissolved, cooling to 13° C. and maintaining for 2 h, and filtering to obtain trans-acetylaminocyclohexanol acetate;

[0054] (3) Add trans-p-acetylaminocyclohexanol acetate to a 20% sodium hydroxide solution with a mass fraction of 2.5 times its mass, heat to reflux for 15 hours, cool and transfer to a continuous extraction device, extract with chloroform for 20 hours, dry the organic phase with magnesium sulfate, filter, concentrate under reduced pressure, and dry in vacuum to obtain trans-p-aminocyclohexanol with a yield of 91.3%.

[0055] The solvent A is dimethylformamide;

[0056] The solvent B is acetone;

[0057] The catalyst used is 5% palladium carbon catalyst

[0058] The additive is sodium bisulfite.

[0059] (Example 3)

[0060] A synthesis process of trans-p-aminocyclohexanol, the process steps are as follows:

[0061] (1) firstly purge the high-pressure hydrogenation autoclave with hydrogen for 5 minutes, then put 350 parts by weight of acetaminophenol, 650 parts by weight of solvent A, 40 parts by weight of additives, and 3 parts by weight of catalyst A into the high-pressure hydrogenation autoclave, and hydrogenate until hydrogen absorption is complete at a reaction pressure of 1.2 MPa and a reaction temperature of 102° C., keep the temperature for 7.5 hours, cool to 11° C., filter, and crystallize the filtrate to obtain acetaminocyclohexanol; the above hydrogenation reaction is carried out under hydrogen protection conditions throughout the process, wherein the yield of acetaminocyclohexanol is 99.7%; wherein the yields of cis-acetaminocyclohexanol acetate and trans-acetaminocyclohexanol acetate are 7.8% and 91.9%, respectively;

[0062] (2) adding acetylaminocyclohexanol to acetic anhydride in an amount 1.5 times its mass at 45° C., and reacting under reflux for 5 hours. Then, removing acetic acid and excess acetic anhydride by distillation under reduced pressure to obtain a solid crude product. After cooling, adding solvent B in an amount 4 times its mass, and heating under reflux again until the solid crude product is completely dissolved. Then, cooling to 15° C. and maintaining for 2.5 hours, filtering, and obtaining trans-acetylaminocyclohexanol acetate;

[0063] (3) Add trans-p-acetylaminocyclohexanol acetate to a 20% sodium hydroxide solution with a mass fraction three times its mass, heat to reflux for 16 hours, cool and transfer to a continuous extraction device, extract with chloroform for 24 hours, dry the organic phase with magnesium sulfate, filter, concentrate under reduced pressure, and dry in vacuo to obtain trans-p-aminocyclohexanol with a yield of 90.7%.

[0064] The solvent A is dimethylformamide;

[0065] The solvent B is acetone;

[0066] The catalyst is a 5% palladium-carbon catalyst;

[0067] The additive is sodium bicarbonate.

[0068] (Comparative Example 1)

[0069] A synthesis process of trans-p-aminocyclohexanol, the process steps are as follows:

[0070] (1) firstly purge the high-pressure hydrogenation autoclave with hydrogen for 5 minutes, then put 300 parts by weight of acetaminophenol, 600 parts by weight of solvent A, 39 parts by weight of additives, and 2.8 parts by weight of catalyst A into the high-pressure hydrogenation autoclave, and hydrogenate at a reaction pressure of 1.1 MPa and a reaction temperature of 100° C. until hydrogen absorption is complete, keep the temperature for 7 hours, cool to 10° C., filter, and crystallize the filtrate to obtain acetaminocyclohexanol; the above hydrogenation reaction is carried out under hydrogen protection conditions throughout the process, wherein the yield of acetaminocyclohexanol is 99.8%; wherein the yields of cis-acetaminocyclohexanol acetate and trans-acetaminocyclohexanol acetate are 9.8% and 90.0%, respectively;

[0071] (2) adding acetylaminocyclohexanol to acetic anhydride in an amount 1.4 times its mass at 30° C., and subjecting the mixture to reflux reaction for 3 h. Subsequently, removing acetic acid and excess acetic anhydride by distillation under reduced pressure to obtain a solid crude product. After cooling, adding solvent B in an amount 3 times its mass, and heating and refluxing again until the solid crude product is completely dissolved, cooling to 13° C. and maintaining for 2 h, and filtering to obtain trans-acetylaminocyclohexanol acetate;

[0072] (3) Add trans-p-acetylaminocyclohexanol acetate to a 20% sodium hydroxide solution with a mass fraction of 2.5 times its mass, heat to reflux for 15 hours, cool and transfer to a continuous extraction device, extract with chloroform for 20 hours, dry the organic phase with magnesium sulfate, filter, concentrate under reduced pressure, and dry in vacuum to obtain trans-p-aminocyclohexanol with a yield of 88.9%.

[0073] The solvent A is methanol;

[0074] The solvent B is acetone;

[0075] The catalyst used is 5% palladium carbon catalyst.

[0076] The additive is sodium bisulfite.

[0077] (Comparative Example 2)

[0078] A synthesis process of trans-p-aminocyclohexanol, the process steps are as follows:

[0079] (1) firstly purge the high-pressure hydrogenation autoclave with hydrogen for 5 minutes, then put 300 parts by weight of acetaminophenol, 600 parts by weight of solvent A, and 2.8 parts by weight of catalyst A into the high-pressure hydrogenation autoclave, and hydrogenate at a reaction pressure of 1.1 MPa and a reaction temperature of 100° C. until hydrogen absorption is complete, keep the temperature for 7 hours, cool to 10° C., filter, and crystallize the filtrate to obtain acetaminocyclohexanol; the above hydrogenation reaction is carried out under hydrogen protection conditions throughout the process, wherein the yield of acetaminocyclohexanol is 99.8%; wherein the yields of cis-acetaminocyclohexanol acetate and trans-acetaminocyclohexanol acetate are 17.2% and 82.6%, respectively;

[0080] (2) adding acetylaminocyclohexanol to acetic anhydride in an amount 1.4 times its mass at 30° C., and subjecting the mixture to reflux reaction for 3 h. Subsequently, removing acetic acid and excess acetic anhydride by distillation under reduced pressure to obtain a solid crude product. After cooling, adding solvent B in an amount 3 times its mass, and heating and refluxing again until the solid crude product is completely dissolved, cooling to 13° C. and maintaining for 2 h, and filtering to obtain trans-acetylaminocyclohexanol acetate;

[0081] (3) Add trans-p-acetylaminocyclohexanol acetate to a 20% sodium hydroxide solution with a mass fraction of 2.5 times its mass, heat to reflux for 15 hours, cool and transfer to a continuous extraction device, extract with chloroform for 20 hours, dry the organic phase with magnesium sulfate, filter, concentrate under reduced pressure, and dry in vacuum to obtain trans-p-aminocyclohexanol with a yield of 81.3%.

[0082] The solvent A is dimethylformamide;

[0083] The solvent B is acetone;

[0084] The catalyst used is 5% palladium carbon catalyst.

[0085] (Comparative Example 3)

[0086] A synthesis process of trans-p-aminocyclohexanol, the process steps are as follows:

[0087] (1) 300 parts by weight of acetaminophenol, 600 parts by weight of solvent A, 39 parts by weight of additives, and 2.8 parts by weight of catalyst A are placed in a high-pressure hydrogenation reactor, and hydrogenated at a reaction pressure of 1.1 MPa and a reaction temperature of 100° C. until hydrogen absorption is complete, and the reaction is kept warm for 7 hours, cooled to 10° C., filtered, and the filtrate is crystallized to obtain acetaminocyclohexanol; wherein the yield of acetaminocyclohexanol is 95.9%; wherein the yields of cis-acetaminocyclohexanol acetate and trans-acetaminocyclohexanol acetate are 12.6% and 83.3%, respectively;

[0088] (2) adding acetylaminocyclohexanol to acetic anhydride in an amount 1.4 times its mass at 30° C., and subjecting the mixture to reflux reaction for 3 h. Subsequently, removing acetic acid and excess acetic anhydride by distillation under reduced pressure to obtain a solid crude product. After cooling, adding solvent B in an amount 3 times its mass, and heating and refluxing again until the solid crude product is completely dissolved, cooling to 13° C. and maintaining for 2 h, and filtering to obtain trans-acetylaminocyclohexanol acetate;

[0089] (3) Add trans-p-acetylaminocyclohexanol acetate to a 20% sodium hydroxide solution with a mass fraction of 2.5 times its mass, heat to reflux for 15 hours, cool and transfer to a continuous extraction device, extract with chloroform for 20 hours, dry the organic phase with magnesium sulfate, filter, concentrate under reduced pressure, and dry in vacuum to obtain trans-p-aminocyclohexanol with a yield of 82.7%.

[0090] The solvent A is dimethylformamide;

[0091] The solvent B is acetone;

[0092] The catalyst used is 5% palladium carbon catalyst

[0093] The additive is sodium bisulfite.

[0094] (Comparative Example 4)

[0095] A synthesis process of trans-p-aminocyclohexanol, the process steps are as follows:

[0096] (1) firstly purge the high-pressure hydrogenation autoclave with hydrogen for 5 minutes, then put 300 parts by weight of acetaminophenol, 600 parts by weight of solvent A, 39 parts by weight of additives, and 2.8 parts by weight of catalyst A into the high-pressure hydrogenation autoclave, and hydrogenate until hydrogen absorption is complete at a reaction pressure of 1.1 MPa and a reaction temperature of 100° C., keep the temperature for 7 hours, cool to 10° C., filter, and crystallize the filtrate to obtain acetaminocyclohexanol; the above hydrogenation reaction is carried out under hydrogen protection conditions throughout the process, wherein the yield of acetaminocyclohexanol is 99.8%; wherein the yields of cis-acetaminocyclohexanol acetate and trans-acetaminocyclohexanol acetate are 10.5% and 89.3%, respectively;

[0097] (2) adding acetylaminocyclohexanol to acetic anhydride in an amount 1.4 times its mass at 30° C., and subjecting the mixture to reflux reaction for 3 h. Subsequently, removing acetic acid and excess acetic anhydride by distillation under reduced pressure to obtain a solid crude product. After cooling, adding solvent B in an amount 3 times its mass, and heating and refluxing again until the solid crude product is completely dissolved, cooling to 13° C. and maintaining for 2 h, and filtering to obtain trans-acetylaminocyclohexanol acetate;

[0098] (3) Add trans-p-acetylaminocyclohexanol acetate to a 20% sodium hydroxide solution with a mass fraction of 2.5 times its mass, heat to reflux for 15 hours, cool and transfer to a continuous extraction device, extract with chloroform for 20 hours, dry the organic phase with magnesium sulfate, filter, concentrate under reduced pressure, and dry in vacuum to obtain trans-p-aminocyclohexanol with a yield of 87.6%.

[0099] The solvent A is dimethylformamide;

[0100] The solvent B is acetone;

[0101] The catalyst is Raney nickel;

[0102] The additive is sodium bisulfite.

[0103] (Comparative Example 5)

[0104] A synthesis process of trans-p-aminocyclohexanol, the process steps are as follows:

[0105] (1) firstly purge the high-pressure hydrogenation autoclave with hydrogen for 5 minutes, then put 300 parts by weight of acetaminophenol, 600 parts by weight of solvent A, 39 parts by weight of additives, and 2.8 parts by weight of catalyst A into the high-pressure hydrogenation autoclave, and hydrogenate until hydrogen absorption is complete at a reaction pressure of 1.1 MPa and a reaction temperature of 100° C., keep the temperature for 7 hours, cool to 10° C., filter, and crystallize the filtrate to obtain acetaminocyclohexanol; the above hydrogenation reaction is carried out under hydrogen protection conditions throughout the process, wherein the yield of acetaminocyclohexanol is 99.9%; wherein the yields of cis-acetaminocyclohexanol acetate and trans-acetaminocyclohexanol acetate are 7.3% and 92.6%, respectively;

[0106] (2) adding 2.5 times the mass of p-acetylaminocyclohexanol to a 20% sodium hydroxide solution, heating and reflux for 15 hours, cooling and transferring to a continuous extraction device, extracting with chloroform for 20 hours, drying the organic phase with magnesium sulfate, filtering, concentrating under reduced pressure, and drying in vacuo to obtain p-aminocyclohexanol;

[0107] (3) At 30° C., p-aminocyclohexanol was added to acetone (2.1 times its mass), refluxed for 5 h, cooled, filtered, and vacuum dried to obtain trans-p-aminocyclohexanol in a yield of 74.08%.

[0108] The solvent A is dimethylformamide;

[0109] The solvent B is acetone;

[0110] The catalyst used is 5% palladium carbon catalyst

[0111] The additive is sodium bisulfite.

[0112] The yield obtained by the embodiment of the present invention is higher than that obtained by the aforementioned embodiment and comparative example.

[0113] The specific embodiments described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A synthesis process for trans-p-aminocyclohexanol, characterized in that: The process steps include: (1) taking acetaminophenol as a reaction raw material, mixing it with solvent A, additives and catalyst A, hydrogenating it under a certain reaction pressure and reaction temperature, filtering it, and crystallizing it to obtain acetaminocyclohexanol; (2) esterifying acetylaminocyclohexanol with acetic anhydride, recrystallizing and separating to obtain trans-acetylaminocyclohexanol acetate; (3) Separating trans-p-acetylaminocyclohexanol acetate to obtain trans-p-aminocyclohexanol.

2. The synthesis process of trans-p-aminocyclohexanol according to claim 1, characterized in that: The solvent A is dimethylformamide.

3. The synthesis process of trans-p-aminocyclohexanol according to claim 1, characterized in that: The additive is a carbonate or sulfate of sodium or potassium.

4. The synthesis process of trans-p-aminocyclohexanol according to claim 1, characterized in that: The catalyst used is 5% palladium carbon catalyst.

5. The synthesis process of trans-p-aminocyclohexanol according to any one of claims 1 to 4, characterized in that: In terms of weight fractions, the weight parts of acetaminophenol, solvent A, additives and catalyst A in step (1) are respectively: 250-350 parts by weight of acetaminophenol, 550-650 parts by weight of solvent A, 38-40 parts by weight of additives and 2.5-3 parts by weight of catalyst A.

6. The synthesis process of trans-p-aminocyclohexanol according to claim 5, characterized in that: The reaction pressure is 1-1.2 MPa; the reaction temperature is 98-102° C.; and the reaction time is controlled at 6.5-7.5 h.

7. The synthesis process of trans-p-aminocyclohexanol according to claim 5, characterized in that: The hydrogenation reaction in step (1) is carried out under hydrogen protection conditions throughout the entire process.

8. The synthesis process of trans-p-aminocyclohexanol according to claim 1, characterized in that: The specific steps of step (2) are as follows: adding acetylaminocyclohexanol to acetic anhydride in an amount of 1.3 to 1.5 times its mass at 20 to 45° C., refluxing for 1 to 5 hours, then removing acetic acid and excess acetic anhydride by distillation under reduced pressure to obtain a solid crude product, adding solvent B after cooling, heating and refluxing again until the solid crude product is completely dissolved, cooling to 10 to 15° C. and maintaining for 1.5 to 2.5 hours, filtering, and obtaining acetylaminocyclohexanol acetate.

9. The synthesis process of trans-p-aminocyclohexanol according to claim 1, characterized in that: The solvent B is acetone.

10. The synthesis process of trans-p-aminocyclohexanol according to claim 1, characterized in that: The specific steps of step (3) are as follows: adding trans-p-acetylaminocyclohexanol acetate to a 20% sodium hydroxide solution with a mass fraction of 2 to 3 times its mass, heating and reflux for 14 to 16 hours, cooling the hydrolyzate, transferring it to a continuous extraction device, and continuously extracting it with chloroform for 18 to 24 hours. The organic phase is dried with magnesium sulfate, filtered, concentrated under reduced pressure, and vacuum dried to obtain trans-p-aminocyclohexanol.