Search

CN-122011053-A - Benzyloxycarbonyl deprotection reaction method and application

CN122011053ACN 122011053 ACN122011053 ACN 122011053ACN-122011053-A

Abstract

The application relates to a method for deprotection reaction of benzyloxycarbonyl and application thereof, belonging to the technical field of catalytic chemistry. Dissolving Cbz epoxy as a raw material in ethanol, carrying out high-temperature reflux stirring treatment, transferring the obtained product into a reaction kettle, adding Raney nickel, charging nitrogen, discharging air in the kettle, charging hydrogen again, keeping the final pressure of the hydrogen in the reaction kettle at 1-2 MPa, filtering the Raney nickel to obtain a reaction liquid after the room-temperature reaction is finished, dripping water for crystallization, carrying out suction filtration and drying to obtain the product, recycling the filtered Raney nickel at least 10 times after the high-temperature treatment, and replacing the new Raney nickel, thereby realizing triangular balance of catalytic performance, economic cost and process stability, reducing the production cost on the premise of not influencing the reaction effect, realizing recycling and application of the used Raney nickel after proper treatment, further reducing the production cost, and having good economic benefit.

Inventors

  • ZHAO BO
  • LI DONGXU
  • GU CHENGLONG
  • LIN ZHIHAO
  • QIU CAIYUN
  • SHAN GUOYANG
  • HUANG QIUBO
  • ZHOU ZHIKUI
  • QIU JIAJUN

Assignees

  • 浙江国邦药业有限公司
  • 国邦医药集团股份有限公司

Dates

Publication Date
20260512
Application Date
20260211

Claims (8)

  1. 1. A method for deprotection reaction of carbobenzoxy includes dissolving Cbz epoxy as raw material in alcohol, reflux stirring, transferring the resultant to reactor, adding Raney nickel, charging nitrogen gas, discharging air, charging hydrogen again, holding the final pressure of hydrogen in reactor below 2MPa, filtering out Raney nickel to obtain reaction liquid, dropping water for crystallizing, suction filtering and baking, activating Raney nickel, recovering for at least 10 times, and exchanging Raney nickel, and features that the weight ratio of raw material to Raney nickel is 1:0.1-0.15.
  2. 2. The method for deprotection reaction of benzyloxycarbonyl group according to claim 1, wherein the temperature of the reflux stirring treatment is 60 to 70 ℃.
  3. 3. The method for deprotection reaction of benzyloxycarbonyl group according to claim 1, wherein the duration of the reflux stirring treatment is 1 to 2 hours.
  4. 4. The method for deprotection reaction of benzyloxycarbonyl group according to claim 1, wherein the final pressure of hydrogen in the reaction vessel is 1-2 MPa.
  5. 5. The method for deprotection reaction of benzyloxycarbonyl group according to claim 1, wherein the recovery time of Raney nickel is 10 to 20 times.
  6. 6. The method for protecting the benzyloxycarbonyl group according to claim 1 is characterized in that the specific method for activating treatment is that filtered Raney nickel is firstly washed by stirring with water and then washed by stirring with absolute ethyl alcohol, so that activated Raney nickel is obtained, the temperature of the water stirring washing is 70-80 ℃ for 1-2 hours, the temperature of the absolute ethyl alcohol stirring washing is 20-30 ℃ for 1-2 hours.
  7. 7. Use of the method of any one of claims 1-6 in a tylosin deprotected epoxide synthesis reaction.
  8. 8. The use according to claim 7, characterized by the steps of: Adding Cbz epoxy solid obtained by epoxidation reaction into ethanol, stirring and dissolving, refluxing and stirring, and transferring the obtained product into a reaction kettle; Step two, adding Raney nickel into the reaction kettle, charging and discharging nitrogen, discharging air in the kettle, and then charging and discharging hydrogen again, and keeping the final pressure of the hydrogen in the reaction kettle below 2MPa, and reacting at room temperature; step three, filtering out Raney nickel to obtain a reaction liquid after the room temperature reaction is finished, dripping water for crystallization of the reaction liquid, and carrying out suction filtration and drying to obtain a product; step four, the filtered Raney nickel is used as a catalyst recovery sleeve for the step two after being activated; And (3) after the catalyst to be activated is recycled and reused for at least 10 times, replacing the Raney nickel with new Raney nickel, and repeating the steps.

Description

Benzyloxycarbonyl deprotection reaction method and application Technical Field The application relates to a method for deprotection reaction of benzyloxycarbonyl and application thereof, belonging to the technical field of catalytic chemistry. Background The macrolide medicines are widely used at present, namely tylosin and tilmicosin, and the two medicines have good effects, but have different degrees of drug resistance in a plurality of areas along with the extension of the use time, and generally adopt a mode of mixing materials or drinking water for administration, and the drug effect can be exerted by repeated administration for a plurality of times. The tulathromycin is mainly used for preventing and treating respiratory infectious diseases of cattle and pigs caused by sensitive bacteria and infectious keratoconjunctivitis of cattle caused by Moraxella bovis. The medicine effect of the preparation is stronger than that of tylosin and tilmicosin, and the preparation has a plurality of advantages of special animal use, small dosage, one-time administration, high bioavailability, ultra-long elimination half-life, low residue and the like which are superior to other macrolide antibiotics. The synthesis of tulathromycin has been reported in the literature, which includes a one-step benzyloxycarbonyl (Cbz) deprotection synthesis reaction, wherein benzyloxycarbonyl groups are generally used to protect the non-reactive sites and functional groups such as amino and hydroxyl groups, so as to avoid the reaction of various functional groups present in the organic macromolecule with other functional groups to generate more byproducts. The raw material catalytic hydrogenation method is a common method for deprotection of benzyloxycarbonyl, and the catalyst in the method is mainly a palladium-carbon catalyst, and palladium cannot be well dispersed due to weaker interaction of a carbon carrier on palladium, the overall particle size is larger, and the utilization rate of palladium atoms is lower, so that the palladium-carbon catalyst with high load is needed during use, the palladium-carbon catalyst is difficult to apply to industrial production, and the production cost is greatly increased. Therefore, how to realize low cost and multi-cycle use of the catalyst in the deprotection reaction of the benzyloxycarbonyl and ensure high conversion rate and yield is a key for reducing the deprotection cost of the benzyloxycarbonyl and promoting industrialization of the benzyloxycarbonyl. Disclosure of Invention In view of the above, the application provides a benzyloxycarbonyl deprotection reaction method, which processes raw materials by a special method and is matched with Raney nickel as a catalyst, so that the dosage of Raney nickel of the catalyst is halved, the catalyst is recycled for multiple times, 100% conversion rate and more than 90% yield can be realized, the production cost is effectively reduced, and the production efficiency is improved. Specifically, the application is realized by the following scheme: A method for deprotection reaction of carbobenzoxy comprises the following steps: Dissolving Cbz epoxy (CAS number: 217649-77-9) as a raw material in ethanol, refluxing and stirring, transferring into a reaction kettle, adding Raney nickel into the reaction kettle according to the weight ratio of raw materials (1:0.1-1:0.15), charging and discharging nitrogen, discharging air in the kettle, charging and discharging hydrogen again, keeping the final pressure of hydrogen in the reaction kettle below 2MPa, filtering Raney nickel after the stirring reaction at room temperature is finished, dripping water for crystallization, and performing suction filtration and drying to obtain a product. The reaction conversion rate and the yield are obtained through HPLC detection, and 100% conversion rate and more than 90% yield can be realized. And the filtered Raney nickel is recycled and reused for at least 10 times after being treated at high temperature, and new Raney nickel is replaced. Further, as preferable: the temperature of the reflux stirring treatment is 60-70 ℃. And the duration of the reflux stirring treatment is 1-2 hours. The final pressure of hydrogen in the reaction kettle is 1-2 MPa. The recycling time of Raney nickel is 10-20 times. The specific method of the activation treatment comprises the steps of firstly stirring and washing filtered Raney nickel with water, then stirring and washing the Raney nickel with absolute ethyl alcohol to obtain activated Raney nickel, wherein the temperature of the water stirring and washing is 70-80 ℃ for 1-2 hours, and the temperature of the absolute ethyl alcohol stirring and washing is 20-30 ℃ for 1-2 hours. The method for deprotection reaction of benzyloxycarbonyl group can be applied to synthesis reaction of tulathromycin deprotection epoxide and the like. The specific application steps are as follows: Adding Cbz epoxy solid obtained by epoxidation reaction into ethan