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CN-121990863-A - Chiral thioimine derivative and preparation method and application thereof

CN121990863ACN 121990863 ACN121990863 ACN 121990863ACN-121990863-A

Abstract

The invention discloses a chiral thioimine derivative and a preparation method and application thereof, wherein the preparation method comprises the following steps: dissolving a compound A and a compound B in an organic solvent, adding alkali and a chiral quaternary phosphonium salt catalyst, and reacting to obtain the chiral thioimine derivative. The chiral sulfilimine compound synthesized by the method has high stereoselectivity and excellent separation yield through a novel efficient asymmetric catalytic reaction, the synthetic method has good functional group compatibility, is easy and convenient to operate, is easy to obtain raw materials, is resistant to water and oxygen, and can be used for synthesizing a series of functionalized chiral sulfilimine derivatives in a variety manner. The chiral sulfilimine compound and the derivative thereof provided by the invention have great application potential and development prospect in preparing medicaments for preventing and/or treating acute monocytic leukemia, lung cancer and human osteosarcoma.

Inventors

  • WANG TIANLI
  • Liu Zanjiao
  • Fang Siqiang

Assignees

  • 四川大学

Dates

Publication Date
20260508
Application Date
20241108

Claims (10)

  1. 1. A chiral thioimine derivative is characterized by comprising structural formulas I, II and III and corresponding enantiomer, diastereomer, salt or crystal forms thereof: Wherein R 1 is hydrogen, C 1-20 straight or branched alkyl or substituted C 1-20 straight or branched alkyl, C 3-20 cycloalkyl or substituted C 3-20 cycloalkyl, alkoxy, phenoxy or substituted phenoxy, aryl or substituted aryl, benzyl or substituted benzyl, heterocycle or substituted heterocycle, halogen, ketocarbonyl, ester, amine or substituted amine, wherein aryl or substituted aryl does not include phenyl and substituted phenyl; R 2 is alkyl carboxylate or substituted alkyl carboxylate, arylmethyl or substituted arylmethyl, heterocycle or substituted heterocycle, alkoxy, phenoxy or substituted phenoxy, amino or substituted amino, halogen, ester group, wherein the heterocycle or substituted heterocycle does not include thiophene and substituted thiophene; R 3 is C 1-20 straight or branched alkyl, C 3-20 cycloalkyl, alkyl carboxylate or substituted alkyl carboxylate, aryl or substituted aryl, heterocycle or substituted heterocycle, ester, sulfonyl, arylformyl or substituted arylformyl, wherein aryl or substituted aryl does not include phenyl and substituted phenyl; R 4 is oxygen, amino or substituted amino, amido.
  2. 2. The chiral thioimine derivative according to claim 1, characterized in that R 1 is C 1-20 straight-chain or branched alkyl, C 3-6 cycloalkyl, alkoxy, phenoxy, indole or substituted indole, benzofuran or substituted benzofuran, benzothiophene or substituted benzothiophene, pyrrole or substituted pyrrole, thiophene or substituted thiophene, furan or substituted furan, pyridine or substituted pyridine, naphthyl or substituted naphthyl, amine or substituted amine; R 2 is alkyl carboxylate, phenyl carboxylate, benzyl or substituted benzyl, indolylmethyl or substituted indolylmethyl, benzofuranmethyl or substituted benzofuranmethyl, benzothiophenylmethyl or substituted benzothiophenylmethyl, pyrrolmethyl or substituted pyrrolmethyl, thiophenmethyl or substituted thiophenmethyl, furanmethyl or substituted furanmethyl, picolyl or substituted picolyl, quinolinylmethyl or substituted quinolinylmethyl, naphthylmethyl or substituted naphthylmethyl, alkoxy, phenoxy, amino or substituted amino; R 3 is C 1-20 straight or branched alkyl, C 3-6 cycloalkyl, alkyl carboxylate, phenyl carboxylate, sulfonyl, benzoyl or substituted benzoyl, benzothiophenyl, furoyl, thiophenyl, naphthoyl, pyrrolyl, picolyl, indolyl or substituted indolyl, benzofuranyl, alkylcarbonyl; R 4 is oxygen, amino or substituted amino, amido.
  3. 3. Chiral thioimine derivative according to claim 2, characterized by the following specific structural formula:
  4. 4. The preparation method of the chiral thioimine derivative according to any one of claims 1 to 3, which is characterized by comprising the following steps of dissolving a compound A and a compound B in an organic solvent, adding a chiral quaternary phosphonium salt catalyst and alkali, and reacting to prepare the chiral thioimine derivative I or II, wherein the synthetic route is as follows: wherein LG is halogen or OTs.
  5. 5. The process for producing a chiral thioimine derivative according to claim 4, wherein the organic solvent is methylene chloride, chloroform, 1, 2-dichloroethane, n-hexane, cyclohexane, petroleum ether, tetrahydrofuran, diethyl ether, methyl t-butyl ether, anisole, isopropyl ether, n-butyl ether, ethyl acetate, methanol, ethanol, acetonitrile, toluene, xylene, o-xylene, m-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, bromobenzene, anisole or benzotrifluoride; The base is triethylamine, diisopropylethylamine, DABCO, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate trihydrate, potassium phosphate heptahydrate, sodium phosphate decahydrate, cesium fluoride, sodium phenolate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, cesium hydroxide monohydrate or lithium hydroxide.
  6. 6. The method for preparing chiral sulfilimine derivative according to claim 4, wherein the chiral quaternary phosphonium salt catalyst is: Wherein R 5 is hydrogen, C 1-20 straight-chain or branched alkyl, aryl or substituted aryl, benzyl or substituted benzyl, heterocycle or substituted heterocycle, R 6 is Boc, ts, acyl, ureido, thiourea or substituted thiourea, carbonyl or substituted carbonyl, R 7 is phenyl or substituted phenyl, benzyl or substituted benzyl, naphthyl or substituted naphthyl, X is halogen, PO 4 ,NO 2 ,NO 3 ,BF 4 , OTf, OAc or OBoc.
  7. 7. The method for producing a chiral thioimine derivative according to claim 4, wherein the reaction temperature is-78 to 40 ℃ and the reaction time is 2 to 48 hours.
  8. 8. The preparation method of the chiral thioimine derivative according to any one of claims 4 to 7, which is characterized by comprising the following steps of dissolving the chiral thioimine derivative I or II in an organic solvent, adding an oxidant or an amination agent, and reacting to obtain the chiral thioimine derivative III or IV, wherein the synthetic route is as follows:
  9. 9. the process for preparing chiral sulfilimine derivatives according to claim 8, characterized in that the organic solvent is dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate, methanol, ethanol, acetonitrile, toluene; the oxidant is hydrogen peroxide, m-chloroperoxybenzoic acid, potassium periodate, manganese dioxide and potassium peroxymonosulfonate; the amination agent is sulfonamide or substituted sulfonamide, benzamide or substituted benzamide aryl amine or substituted aryl amine.
  10. 10. Use of a chiral thioimine derivative according to any one of claims 1 to 3 in the preparation of a medicament for the prophylaxis and/or treatment of leukemia or tumor.

Description

Chiral thioimine derivative and preparation method and application thereof Technical Field The invention relates to the technical fields of chemical industry and medicine, in particular to a chiral thioimine derivative, a preparation method and application thereof. Background Chiral thioimines and derivatives thereof are widely applied to natural products and drug molecular structures, and have important biological and pharmacological activities. The compounds are often used for screening and researching pharmacological, biological synthesis, biological activity and medicinal characteristics, and play important roles in anti-cancer and anti-tumor treatment. However, the asymmetric synthesis of the chiral sulfilimine compound still has a plurality of problems that 1) a catalytic system is single and is mostly a metal catalytic system, so that the problem of metal residue in the medicine manufacturing is difficult to avoid, 2) the reaction type is single, the diversity synthesis is limited, 3) the three-dimensional divergency synthesis is not reported so far, and the isomer with opposite configuration is difficult to obtain at the same time, thus preventing the development of related chiral medicines. Therefore, the synthesis of the chiral sulfilimine and the derivatives thereof has high research value, not only can enrich chiral sulfilimine compound families, but also is beneficial to the development and application of the compounds in the aspects of biological activity exploration and drug research and development. Furthermore, it is notable that, although asymmetric synthesis of chiral thioimine compounds has been preliminarily achieved at present by quaternary ammonium salt catalytic systems, the molecular skeleton of the obtained chiral thioimine is very limited and single in configuration due to the relatively rigid structure of the quaternary ammonium salt catalyst, and the nitrogen protecting group thereof is limited to only alkylcarbonyl groups. Therefore, the framework type of the chiral sulfilimine molecule, especially the chiral sulfilimine of N-aryl formyl is widened, and simultaneously the three-dimensional divergence construction is realized, and enantiomers with opposite configurations are directly obtained, so that the method lays a foundation for the development of chiral medicines. Disclosure of Invention In order to solve the defects in the prior art, the invention aims to provide a chiral sulfilimine derivative, a preparation method and application thereof, enrich chiral sulfilimine compound families and construct the chiral sulfilimine compound by a novel efficient asymmetric catalytic reaction in one pot. The technical scheme for solving the technical problems is as follows, and provides a chiral thioimine derivative which comprises a structural general formula I, a structural general formula II, a structural general formula III, a structural general formula IV and corresponding enantiomers, diastereomers, salts or crystal forms thereof: Wherein R 1 is hydrogen, C 1-20 straight or branched alkyl or substituted C 1-20 straight or branched alkyl, C 3-20 cycloalkyl or substituted C 3-20 cycloalkyl, alkoxy, phenoxy or substituted phenoxy, aryl or substituted aryl, benzyl or substituted benzyl, heterocycle or substituted heterocycle, halogen, ketocarbonyl, ester, amino or substituted amino, wherein aryl or substituted aryl does not include phenyl and substituted phenyl, R 2 is alkylcarboxylate or substituted alkylcarboxylate, arylmethyl or substituted arylmethyl, heterocycle or substituted heterocycle, alkoxy, phenoxy or substituted phenoxy, amino or substituted amino, halogen, ester, wherein heterocycle or substituted heterocycle does not include thiophene and substituted thiophene, R 3 is C 1-20 straight or branched alkyl, C 3-20 cycloalkyl, alkylcarboxylate or substituted alkylcarboxylate, aryl or substituted aryl, heterocycle or substituted heterocycle, ester, sulfonyl, arylformyl or substituted arylformyl, wherein aryl or substituted aryl does not include phenyl and substituted phenyl, R 4 is oxo, amino or substituted amino, amide. Based on the technical scheme, the invention can also be improved as follows: Further, R 1 is C 1-20 straight or branched alkyl, C 3-6 cycloalkyl, alkoxy (e.g., methoxy), phenoxy, indole or substituted indole (e.g., methyl substituted indole), benzofuran or substituted benzofuran, benzothiophene or substituted benzothiophene, pyrrole or substituted pyrrole, thiophene or substituted thiophene, furan or substituted furan, pyridine or substituted pyridine, naphthyl or substituted naphthyl, amino or substituted amino (e.g., phenyl substituted amino); R 2 is alkylcarboxylate, phenylcarboxylate, benzyl or substituted benzyl (e.g. halogen, methoxy, methyl, cyano, nitro, phenyl, benzothiophene, isopropyl, biologically active molecule substituted benzyl), indolylmethyl or substituted indolylmethyl, benzofuranmethyl or substituted benzofuranmethyl, benzothiophenylmethy