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CN-115232020-B - Method for synthesizing N, N-diethyl-2-hydroxyphenylacetamide and analogues thereof and application thereof

CN115232020BCN 115232020 BCN115232020 BCN 115232020BCN-115232020-B

Abstract

The invention provides a method for synthesizing N, N-diethyl-2-hydroxyphenylacetamide and analogues thereof, which comprises the following reaction routes: The method comprises the steps of 1) reacting a compound shown in a formula (III) with a compound shown in a formula (IV) in a solvent A under the action of a condensing agent and alkali for a certain time to obtain a reaction solution containing the compound shown in the formula (II), 2) adding a reducing agent into the reaction solution containing the compound shown in the formula (II) obtained in the step 1), reacting for a certain time, monitoring the reaction, spin-drying the solvent after the reaction is finished, separating and drying to obtain a crude product of the compound shown in the formula (I), and 3) purifying the crude product obtained in the step 2) to obtain a pure product of the compound shown in the formula (I), wherein R1 and R2 are independently hydrogen, alkyl or aryl, and A is substituted or unsubstituted aryl or heteroaryl.

Inventors

  • LIU JUNYI
  • WANG XIAOWEI
  • SHENG TAO

Assignees

  • 百新(北京)药业科技有限责任公司

Dates

Publication Date
20260505
Application Date
20210422

Claims (20)

  1. 1. A method for synthesizing N, N-diethyl-2-hydroxyphenylacetamide, which comprises the following reaction scheme: The method comprises the following steps: 1) Reacting a compound of formula (III) with a compound of formula (IV) in a solvent A under the action of a condensing agent and a base for a certain time to obtain a reaction solution containing a compound of formula (II); 2) Adding a reducing agent into the reaction solution containing the compound of the formula (II) obtained in the step 1), reacting for a certain time, monitoring the reaction, spin-drying the solvent after the reaction is finished, separating and drying to obtain a crude product of the compound of the formula (I); 3) Purifying the crude product obtained in the step 2) to obtain a pure product of the compound of the formula (I); wherein R 1 and R 2 are both ethyl, A is phenyl; wherein, in step 1), the solvent A is acetonitrile; in step 2), the reducing agent is sodium borohydride or lithium borohydride.
  2. 2. The process of claim 1, wherein in step 1) the condensing agent is selected from HBTU, HATU, HOBT, pyBOP and TBTU.
  3. 3. The process of claim 2, wherein the condensing agent is HBTU.
  4. 4. The process according to claim 1, wherein in step 1), the molar ratio of the compound of formula (III) to the condensing agent is from 1:1 to 1:1.2.
  5. 5. The process according to claim 4, wherein in step 1), the molar ratio of the compound of formula (III) to the condensing agent is 1:1.2.
  6. 6. The process according to claim 1, wherein in step 1) the molar ratio of the compound of formula (III) to the compound of formula (IV) is from 1:1 to 1:3.
  7. 7. The process according to claim 6, wherein in step 1), the molar ratio of the compound of formula (III) to the compound of formula (IV) is 1:1.5.
  8. 8. The process according to claim 1, wherein in step 1) the base is a nitrogen-containing organic base.
  9. 9. The process according to claim 8, wherein in step 1) the base is selected from triethylamine, DMAP, DIPEA and pyridine.
  10. 10. The process according to claim 9, wherein in step 1) the base is triethylamine.
  11. 11. The process according to claim 1, wherein in step 1) the molar ratio of the compound of formula (III) to the base is from 1:1 to 1:3.
  12. 12. The process according to claim 11, wherein in step 1), the molar ratio of the compound of formula (III) to the base is 1:3.
  13. 13. The method according to claim 1, wherein in step 1), the reaction is carried out for a period of time of 4 to 6 hours.
  14. 14. The method of claim 13, wherein in step 1), the reacting for a period of time is 5 hours.
  15. 15. The process according to claim 1, wherein in step 2) the molar ratio of the compound of formula (III) to the reducing agent is from 1:1 to 1:3.
  16. 16. The process according to claim 15, wherein in step 2) the molar ratio of the compound of formula (III) to the reducing agent is 1:3.
  17. 17. The method according to claim 1, wherein in step 2), the reaction is carried out for a period of time ranging from 18 to 24 hours.
  18. 18. The method of claim 17, wherein in step 2), the reaction time is 20 hours.
  19. 19. The method of claim 1, wherein in step 2) the method of monitoring the reaction is selected from the group consisting of ultraviolet spectrophotometry, infrared spectrophotometry, nuclear magnetic resonance, thin layer chromatography, gas chromatography, and high performance liquid chromatography.
  20. 20. The method of claim 19, wherein in step 2) the method of monitoring the reaction is high performance liquid chromatography.

Description

Method for synthesizing N, N-diethyl-2-hydroxyphenylacetamide and analogues thereof and application thereof Technical Field The invention relates to the field of pharmaceutical chemistry, in particular to a method for synthesizing N, N-diethyl-2-hydroxyphenylacetamide and analogues thereof and application thereof. Background N, N-diethyl-2-hydroxyphenylacetamide (MANDELIC ACID N, N-DIETHYLAMIDE, DEM) having good insect repellent activity is reported in Swedish patent SE 409808B published in 1979. Various synthetic methods have been developed in the prior art to produce DEM. However, the existing methods for synthesizing DEM all use mandelic acid as a substrate, and have the disadvantages of more synthesis steps, low overall yield and low purity. For example, in the existing method for preparing the DEM by adopting mandelic acid, after the DEM crude product is obtained, the anhydrous calcium chloride is adopted, and the principle of removing impurities by complexing calcium ions is utilized for carrying out post-treatment purification. However, the skilled person found in practice that when 1g of crude DEM having a purity of 95% was purified by complexation with calcium chloride, only 0.64g of product was obtained with little change in purity, and that this post-treatment significantly reduced the yield with insignificant improvement in purity. Disclosure of Invention Aiming at the defects in the prior art, the invention provides a method for synthesizing N, N-diethyl-2-hydroxyphenylacetamide (DEM) and analogues thereof with high efficiency and high yield by using benzoyl formic acid and analogues thereof as synthesis substrates through a one-pot method. It is therefore an object of the present invention to provide a process for the synthesis of N, N-diethyl-2-hydroxyphenylacetamide and analogues thereof. It is another object of the present invention to provide the use of the above process for the preparation of N, N-diethyl-2-hydroxyphenylacetamide and analogues thereof. The technical scheme for realizing the purpose of the invention is as follows: in one aspect, the present invention provides a method (i.e., method one) for synthesizing N, N-diethyl-2-hydroxyphenylacetamide and analogs thereof, the method comprising the following reaction scheme: The method comprises the following steps: 1) Reacting a compound of formula (III) with a compound of formula (IV) in a solvent A under the action of a condensing agent and a base for a certain time to obtain a reaction solution containing a compound of formula (II); 2) Adding a reducing agent into the reaction solution containing the compound of the formula (II) obtained in the step 1), reacting for a certain time, monitoring the reaction, spin-drying the solvent after the reaction is finished, separating and drying to obtain a crude product of the compound of the formula (I); 3) Purifying the crude product obtained in the step 2) to obtain a pure product of the compound of the formula (I); Wherein R 1 and R 2 are independently hydrogen, alkyl or aryl, and A is substituted or unsubstituted aryl or heteroaryl. In the above-mentioned method, the method comprises, Preferably, in step 1), the solvent a includes, but is not limited to, tetrahydrofuran, dichloromethane, acetonitrile, ethyl acetate, N-dimethylformamide or mixtures thereof, more preferably acetonitrile; Preferably, in step 1), the condensing agent includes, but is not limited to HBTU, HATU, HOBT, pyBOP, TBTU, etc., more preferably HBTU; preferably, in step 1), the molar ratio of the compound of formula (III) to the condensing agent is about 1:1 to 1:1.2, more preferably 1:1.2; preferably, in step 1), the molar ratio of the compound of formula (III) to the compound of formula (IV) is about 1:1 to 1:3, more preferably 1:1.5; preferably, in step 1), the base is a nitrogen-containing organic base, further preferably, the base includes, but is not limited to, triethylamine, DMAP, DIPEA, pyridine, etc., more preferably triethylamine; Preferably, in step 1), the molar ratio of the compound of formula (III) to the base is about 1:1 to 1:3, more preferably 1:3; preferably, in step 1), the reaction is carried out for a period of time ranging from 4 to 6 hours, more preferably 5 hours; preferably, in step 2), the reducing agent is a selective reducing agent, further preferably, the reducing agent includes, but is not limited to, sodium borohydride, lithium borohydride, sodium cyanoborohydride, DIBAL-H, LTBA, red-Al, etc., more preferably, the reducing agent is sodium borohydride; Preferably, in step 2), the molar ratio of compound of formula (III) to reducing agent is about 1:1 to 1:3, more preferably 1:3; Preferably, in step 2), the reaction is carried out for a period of time ranging from 18 to 24 hours, more preferably 20 hours; preferably, in step 2), the method of monitoring the reaction is selected from the group consisting of ultraviolet spectrophotometry, infrared spectrophotometry, nuclear magnetic resonanc