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CN-121990931-A - Method for synthesizing multi-deuterium substituted amine by photocatalysis

CN121990931ACN 121990931 ACN121990931 ACN 121990931ACN-121990931-A

Abstract

The invention discloses a method for synthesizing multi-deuterium substituted amine by photocatalysis, and relates to the technical field of chemical synthesis. The method comprises the steps of reacting carbonyl compounds with amine compounds in the presence of deuterium-containing reagents, thiol catalysts and reducing agents under the conditions of a photocatalyst and illumination to obtain the multi-deuterium substituted amine. The method of the invention realizes the repeated introduction of deuterium atoms at alpha-carbon sites of target amine products through a serial free radical mechanism initiated by photo-generated carriers, thereby directly converting simple and easily obtained raw materials into multi-deuterium substituted amine. The invention solves the problems that only one deuterium atom can be introduced into the nitrogen alpha-position, the synthesis route is long, the operation steps are complex and expensive deuterium sources or metal catalysts are relied on, which are commonly existed in the existing deuterated amine synthesis technology, and provides a new multi-deuterium substituted amine synthesis strategy which has simple steps, mild conditions, high atom economy and easy scale.

Inventors

  • OU WEI
  • LIAO ZHENGWU
  • SU CHENLIANG

Assignees

  • 深圳大学

Dates

Publication Date
20260508
Application Date
20260128

Claims (10)

  1. 1. A method for synthesizing multi-deuterium substituted amine by photocatalysis is characterized by comprising the following steps of reacting carbonyl compounds with amine compounds in the presence of deuterium-containing reagents, thiol catalysts and reducing agents under the conditions of photocatalysis and illumination to obtain the multi-deuterium substituted amine.
  2. 2. The method of claim 1, wherein the photocatalyst is selected from 4CzIPN, 4DPAIPN, 5CzBN, poly-4CzIPN, or Poly-5CzBN.
  3. 3. The process according to claim 1, wherein the thiol catalyst is selected from thiophenols, alkyl thiols or mercaptoalkane sulfonates.
  4. 4. A method according to claim 3, wherein the mercaptoalkane sulfonate is sodium 2-mercaptoethane sulfonate.
  5. 5. The method of claim 1, wherein the reducing agent is formate and the deuterium containing agent is heavy water or deuterated alcohol.
  6. 6. The process according to claim 1, wherein the reaction is carried out under light having a wavelength in the range of 400 to 450 nm and/or the reaction is carried out under inert atmosphere protection.
  7. 7. The method of claim 1, wherein the reaction further comprises a solvent selected from one or more of ethanol, methanol, cyclohexane, N-hexane, N-pentane, N-heptane, petroleum ether, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, ethyl acetate, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, acetonitrile, and the like.
  8. 8. The method according to claim 1, wherein the carbonyl compound is aldehyde or ketone, and the structural formula is shown in formula (1), and the amine compound is primary amine or secondary amine, and the structural formula is shown in formula (2); (1)、 (2); Wherein R1 and R3 are each independently aryl, substituted aryl, polycyclic aryl, heterocyclic aryl, substituted polycyclic aryl, C 1-18 -chain alkyl, C 1-10 -cycloalkyl; R2 and R4 are each independently hydrogen, C 1-18 alkyl, C 1-10 cycloalkyl.
  9. 9. Use of the method of photocatalytic synthesis of a polydeutero-substituted amine as described in any one of claims 1-8 for the preparation of a polydeutero-substituted drug molecule or biomass derivative.
  10. 10. A method of synthesizing a multi-deuterium substituted drug molecule or biomass derivative, characterized in that deuteration is performed using the method of any one of claims 1-8.

Description

Method for synthesizing multi-deuterium substituted amine by photocatalysis Technical Field The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing multi-deuterium substituted amine by photocatalysis. Background In drug development, strategies for selectively introducing deuterium atoms at key metabolic sites, i.e., deuteration modification, have become an important research direction for improving the metabolic properties of drugs. The mechanism of this strategy is based on the fact that carbon-deuterium bonds have a higher bond energy than carbon-hydrogen bonds and can produce a significant Kinetic Isotope Effect (KIE), thus slowing down the rate at which drug molecules are catalytically cleaved in vivo by metabolic enzymes such as cytochrome P450 oxidase. Amine structures are widely present in drug molecules and are one of the common pharmacophores. In such structures, the carbon-hydrogen bond at the alpha position of the nitrogen atom is prone to oxidative metabolic reactions, such as N-dealkylation, leading to loss of pharmaceutical activity. If deuterium atoms are introduced at this position, the stability of the chemical bond can be enhanced, thereby slowing down the progress of the relevant metabolic pathway. The reductive amination process is one of the important methods for synthesizing amines, and it is counted that about one quarter of the carbon-nitrogen bonds (C-N) in the pharmaceutical industry are built by reductive amination, wherein deuterated reduced imines (c=n) are efficient routes for precisely obtaining a-deuterated amines. However, existing methods are generally limited to the introduction of a single deuterium atom at the nitrogen α -position, and it is difficult to achieve the introduction of multiple deuterium atoms in the same molecule, and thus are limited in applications requiring multiple deuterium substitutions to further modulate the metabolic properties of the drug. Therefore, it is needed to develop a general method for efficiently and selectively synthesizing multi-deuterium substituted amine under mild conditions, so as to overcome the problems of single deuteration site, complex synthesis steps, high cost and the like in the prior art. Disclosure of Invention The invention aims to solve the technical problem of how to introduce a plurality of deuterium atoms into the same molecule to realize the synthesis of the multi-deuterium substituted amine. In order to solve the problems, the invention provides the following technical scheme: A process for preparing multi-deuterium substituted amine by photocatalysis includes such steps as reacting carbonyl compound with amine compound in the presence of deuterium-contained reagent, thiol catalyst and reducer under the condition of photocatalyst and light. It is understood that the multi-deuterium substituted amine of the present invention refers to a compound in which at least one hydrogen atom of the carbon site (nitrogen alpha position, beta position, etc.) of the amine group is substituted with a deuterium atom in the amine compound. Preferably, the photocatalyst is selected from 4CzIPN, 4DPAIPN, 5CzBN, poly-4CzIPN or Poly-5CzBN. Compared with a small molecule catalyst, the polymer skeleton can provide stable photoactive sites, can effectively separate photo-generated charges, and is insoluble and convenient to recycle after reaction. Preferably, the thiol catalyst is selected from thiophenols, alkyl thiols or mercaptoalkane sulfonates. The sulfur free radical generated after the mercapto (-SH) in the mercaptoalkane sulfonate is oxidized is a key medium for initiating Hydrogen Atom Transfer (HAT), and drives a reducing agent (such as formate) to generate CO 2-, and the mercaptoalkane sulfonate can also quickly exchange hydrogen and deuterium with a deuterium-containing reagent to generate deuterated mercaptan (R-SD) which is used as a direct deuterium source for subsequent Deuterium Atom Transfer (DAT) reaction. The sulfydryl alkyl acid salt, especially the water-soluble sulfydryl alkyl sulfonate or sulfydryl alkyl carboxylate, is favorable for being uniformly dispersed in a reaction system due to the good solubility, has good compatibility with deuterium-containing reagents and polar solvents, and thus, the reaction efficiency is obviously improved. The mercaptoalkanoates of the present invention include, but are not limited to, mercaptoethane sulfonate, mercaptopropane sulfonate, and the like. Preferably, the mercaptoalkane sulfonate comprises sodium 2-mercaptoethane sulfonate. Preferably, the reducing agent is formate. In the HAT reaction initiated by the sulfur radical, the formate radical (HCOO -) loses one hydrogen atom and is efficiently converted into a carbon dioxide radical anion (CO 2-). The free radicals have a moderate reduction potential and are capable of selectively reducing the imine intermediate to form critical alpha-amino carbon free radicals without ov