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CN-122011013-A - Azepine-2-ketone derivative and synthetic method and application thereof

CN122011013ACN 122011013 ACN122011013 ACN 122011013ACN-122011013-A

Abstract

The invention discloses aza-2-ketone derivatives, a synthesis method thereof and application thereof in preparing medicaments. The invention can take alpha-carbonyl acyl silane compounds as raw materials, and generate [5+2] cycloaddition reaction with vinyl aziridine compounds under illumination, thereby simply and efficiently synthesizing a series of aza-2-ketone derivatives with different structures. The aza-2-ketone derivative of the invention can be further converted into drug molecules such as kappa-opioid receptor selective agonist molecules. The method has the advantages of easily available raw materials, simple and convenient operation, mild reaction conditions and diversity of functional groups.

Inventors

  • Wang quannan
  • LI XIUHUI
  • DENG WEIPING
  • YAO LINGYUN

Assignees

  • 浙江师范大学

Dates

Publication Date
20260512
Application Date
20260414

Claims (10)

  1. 1. An aza-2-ketone derivative, which is characterized by having a molecular structure as shown in formula 1: R 1 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, wherein the substituent is selected from one or more than two of halogen atoms, alkyl, alkoxy, alkoxycarbonyl, phenyl, alkoxyphenyl and pyrrolidinyl; R 2 is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted alkoxy, a halogen atom, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, wherein the substituents are one or more than two of halogen atoms, alkyl, alkoxy, alkoxycarbonyl, phenyl, alkoxyphenyl and pyrrolidinyl, and the heteroatoms in the heterocycloalkyl and heteroaryl are one or more than two of N, O, S; R 3 is a silicon protecting group.
  2. 2. The azepin-2-one derivative according to claim 1, wherein the alkyl group is a C1-C6 alkyl group; The cycloalkyl is a three-membered to ten-membered ring; the heterocycloalkyl group is a three-membered to ten-membered ring; the alkoxy is C1-C6 alkoxy; The aryl is phenyl or naphthyl; The heteroaryl is furyl or thienyl; The silicon protecting group is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl or triisopropylsilyl.
  3. 3. A method for the synthesis of an azepin-2-one derivative according to claim 1 or 2, The synthesis method comprises the step of generating [5+2] cycloaddition reaction of the compound 2 and the compound 3 under illumination to generate the azepine-2-ketone derivative with the molecular structure shown in the formula 1.
  4. 4. A synthetic method according to claim 3, wherein the molar ratio of compound 2 to compound 3 is (3:1) - (1:3).
  5. 5. A synthetic method according to claim 3, characterized in that the reaction is carried out in the presence of a solvent; The solvent comprises one or more than two of 1, 4-dioxane, dimethyl sulfoxide, acetonitrile, toluene and tetrahydrofuran.
  6. 6. A synthetic method according to claim 3, characterized in that the temperature of the reaction is 0-40 ℃; the reaction time is 0.5-6 hours; the atmosphere of the reaction comprises one or more than two of air, nitrogen and argon.
  7. 7. A method of synthesizing according to claim 3, wherein the light is of a wavelength of 390 to 760 nm; The light source used for illumination comprises an LED light source; The power of the light source used for illumination is 1-30 watts.
  8. 8. Use of an azepine-2-one derivative according to claim 1 or 2 or a synthetic method according to any one of claims 3-7 for the preparation of a medicament.
  9. 9. The use according to claim 8, wherein the medicament is for the treatment and/or prevention of kappa-opioid receptor mediated diseases.
  10. 10. The use according to claim 8, wherein the medicament comprises a kappa-opioid receptor selective agonist.

Description

Azepine-2-ketone derivative and synthetic method and application thereof Technical Field The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to an azepine-2-ketone derivative, a synthesis method and application thereof. Background The aza-2-ketone belongs to a typical seven-membered nitrogen-containing heterocyclic ring (epsilon-lactam) skeleton, and the ring of the aza-2-ketone is provided with a nitrogen atom and a carbonyl functional group, and the unique seven-membered ring structure endows the molecule with excellent flexible conformation and is a dominant pharmacophore which is concerned in the design and development of medicine molecules. Such frameworks are widely available in various marketed drugs and bioactive molecules (curr. Org. Chem. 2021, 25, 449-506), such as benzothiazepine such as diltiazem, clenbuterol and the like, which have been used in the treatment of central nervous system related diseases, and angiotensin converting enzyme inhibitors such as cilazapril, benazepril and the like, which have also been widely used in the clinical treatment of hypertension and congestive heart failure. Meanwhile, azepine-2-one derivatives have important application potential in a plurality of innovative medicine research and development fields (J. Med. Chem. 2003, 46, 2973-2984), and the molecules are taken orally to show remarkable analgesic activity in rodent models as novel kappa-opioid receptor agonists, and are expected to become a core skeleton of a new generation of peripheral limiting analgesic drugs (Bio. Med. Chem. Lett. 2004, 14, 5693-5697). Therefore, the development of an efficient and convenient azepine-2-one synthesis method, in particular to a technology for constructing the framework in a stereoselective way, has important theoretical research value and industrial application value. Currently, for the construction of aza-2-one backbones, reported synthetic strategies fall largely into three general categories, the ring-expanding strategy, the ring-closing metathesis (RCM) strategy and the cycloaddition strategy (Molecules 2020, 25, 3147; chem. Rev. 2021, 121, 8926-8947; chem. Sci. 2020, 11, 2876-2881). Among them, the ring expansion strategy is a classical method for early construction of seven-membered lactam rings, typified by Beckmann rearrangement, schmidt reaction (Schmidt reaction) (eur. J. Org. Chem. 2023, 26, e 202300754). The Ring Closing Metathesis (RCM) strategy typically requires the preparation of a diene amide intermediate containing a diene structure followed by a Grubbs catalyst (Grubbs catalyst) mediated olefin ring closing metathesis reaction to effect the construction of a seven membered lactam ring. However, the two synthesis methods generally have obvious defects, namely complex reaction steps, poor substrate universality and high synthesis cost, are difficult to realize large-scale production, and limit practical application. In addition, the cycloaddition strategy is an important way for constructing the azepine-2-one skeleton, the strategy mainly depends on a transition metal catalytic system at present, and most of the constructed azepine-2-one skeleton does not contain quaternary carbon centers, so that the structural diversity and the application range of the skeleton are further limited. In summary, the existing synthesis method of the aza-2-ketone skeleton still has a plurality of defects, and the development of a novel method for constructing the aza-2-ketone skeleton with green, high efficiency and wide substrate application range is still a key technical problem to be solved in the art, and the breakthrough of the method has important practical significance for promoting the research and development and application of drugs with dominant pharmacophores. Disclosure of Invention Aiming at the technical problems and the defects existing in the field, the invention provides an azepine-2-ketone derivative, and a synthesis method and application thereof. The invention can take alpha-carbonyl acyl silane compounds as raw materials, and generate [5+2] cycloaddition reaction with vinyl aziridine compounds under illumination, thereby simply and efficiently synthesizing a series of aza-2-ketone derivatives with different structures. The aza-2-ketone derivative of the invention can be further converted into drug molecules such as kappa-opioid receptor selective agonist molecules. The method has the advantages of easily available raw materials, simple and convenient operation, mild reaction conditions and diversity of functional groups. The specific technical scheme is as follows: In a first aspect, the present invention provides an azepine-2-one derivative having a molecular structure as shown in formula 1: R 1 is a substituted or unsubstituted (chain) alkyl (e.g., methyl, ethyl, propyl, t-butyl, trifluoromethyl, benzyl (Bn), p-methoxybenzyl, etc.) or a substituted or unsubstituted aryl (e.g., phenyl (Ph), o-tolyl