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CN-122011003-A - Chiral silatetrahydro-1-naphthylamine compound and synthesis method thereof

CN122011003ACN 122011003 ACN122011003 ACN 122011003ACN-122011003-A

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a chiral silatetrahydro-1-naphthylamine compound and a synthesis method thereof. The synthesis method of the chiral silatetrahydro-1-naphthylamine compound comprises the steps of mixing a palladium catalyst, chiral phosphine ligand and an organic solvent under an inert atmosphere, pre-stirring, then adding N-allenamine, cooling to a reaction temperature, adding benzosilacyclobutane for reaction, and separating and purifying after the reaction is finished to obtain the chiral silatetrahydro-1-naphthylamine compound. The raw materials of the benzosilacyclobutane and the N-allenamine can be prepared by a simple method, and the method has the advantages of high selectivity, high yield, mild condition, wide substrate range, simplicity and convenience in operation and the like.

Inventors

  • WANG YIDONG
  • LU RUIQIANG
  • SUN YAN
  • GAO LIUZHOU

Assignees

  • 扬州大学

Dates

Publication Date
20260512
Application Date
20251217

Claims (10)

  1. 1. A method for synthesizing a chiral silatetrahydro-1-naphthylamine compound, which is characterized by comprising the following steps: mixing a palladium catalyst, a chiral phosphine ligand and an organic solvent in an inert atmosphere, pre-stirring, then adding a compound 2 shown in a formula 2, cooling to a reaction temperature, adding a compound 1 shown in a formula 1 for reaction, and separating and purifying after the reaction is finished to obtain a chiral silatetrahydro-1-naphthylamine compound shown in a formula 3; The synthetic route is as follows: ; R is selected from Me, et, n-hex, n-Bu, ph, F, cl, br, I, One of the following; R 1 is selected from Me, et, n-hex, n-Bu, ph, One of the following; r 2 is selected from Me, et, n-hex, n-Bu, ph, One of the following; R 3 is selected from Me, CH 3 (CH 2 ) n CH 2 , ph, bn, boc, , , , , , , , , , , , , , , , , , , , , , , One of the following; PG is selected from , , , , , , , , , One of them.
  2. 2. The synthesis method according to claim 1, wherein the molar ratio of the compound 1, the compound 2, the palladium catalyst and the chiral phosphine ligand is (1.1-3): 1 (0.025-0.1): 0.025-0.1.
  3. 3. The synthesis method according to claim 1, wherein the molar concentration of the compound 2 in the reaction system composed of the compound 1, the compound 2, the palladium catalyst, the chiral phosphine ligand and the organic solvent is 0.1mol/L to 0.2 mol/L.
  4. 4. The synthesis method according to claim 1, wherein the palladium catalyst is selected from one or more of bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, palladium acetate, di-t-butylpalladium, allylpalladium chloride dimer, palladium trifluoroacetate, bis-M-chlorobis [2- [ (dimethylamino) methyl ] phenyl-C, N ] dipalladium, cyclopentadienyl allylpalladium.
  5. 5. The method of synthesis according to claim 1, wherein the chiral phosphine ligand is selected from one of the formulae L1-L12, wherein the formulae L1-L12 are: 。
  6. 6. The synthetic method according to claim 1, wherein the organic solvent is selected from one or more of toluene, benzotrifluoride, o-difluorobenzene, hexafluorobenzene, acetone, tetrahydrofuran, methyl tert-butyl ether, 1, 4-dioxane, ethyl acetate, carbon tetrachloride, methylene chloride, chloroform, and dichloroethane.
  7. 7. The method of claim 6, wherein the organic solvent is a dry solvent.
  8. 8. The synthetic method of claim 1 wherein the reaction temperature is from-20 ℃ to 80 ℃ and the reaction time is from 12 h to 48 h.
  9. 9. The synthetic method of claim 1 wherein the reaction is dosed in the order: Dissolving the palladium catalyst and the chiral phosphine ligand in the organic solvent, then adding the compound 2, adjusting the temperature to the reaction temperature, and finally adding the compound 1; Or, dissolving the palladium catalyst and the chiral phosphine ligand in the organic solvent, then adding the compound 2 and the organic solvent, adjusting the temperature to the reaction temperature, and finally adding the compound 1.
  10. 10. A chiral silatetrahydro-1-naphthylamine compound synthesized according to the method of any one of claims 1-9.

Description

Chiral silatetrahydro-1-naphthylamine compound and synthesis method thereof Technical Field The invention belongs to the technical field of organic synthesis, and particularly relates to a chiral silatetrahydro-1-naphthylamine compound and a synthesis method thereof. Background Chiral tetrahydronaphthylamine backbones are widely known as "dominant structures" in pharmaceutical chemistry due to their rigid and flexible ring system structure and functionalizable sites (e.g., amine groups, aromatic rings). This backbone not only mimics the core of a variety of bioactive natural products, but also exhibits excellent binding potential in drug design due to its unique conformation and spatial orientation. In particular, their derivatives have been shown to be potent 5-hydroxytryptamine reuptake inhibitors, P2X 3 and P2X 2/3 receptor blockers and β 3 -adrenoreceptor antagonists, constituting the cores of lead compounds and clinical drug candidates with significant antidepressant and anti-inflammatory activity (as follows). However, its biological activity is highly dependent on the absolute configuration of the amine group center. Therefore, developing efficient and highly selective methods to stereospecifically synthesize chiral tetrahydronaphthylamines (particularly to control amine chiral centers) is not only a challenge for synthetic chemistry, but also a key strategy to improve such molecular drug-forming parameters (e.g., target selectivity, metabolic stability, reduced off-target toxicity). The manual performance is precisely controlled, and the drug-target interaction is greatly optimized, so that the application depth and the application range of the drug-target interaction in modern drug discovery are remarkably expanded. Silicon heterocycle in silicon-containing functional molecules is one of the most important core frames, and due to the unique physicochemical properties, the silicon heterocycle skeleton has wide application in organic synthesis, material science and biological medicine. In the field of pharmaceutical chemistry, the introduction of silicon atoms into biologically active molecules has attracted considerable attention because silicon-based bioisosteres generally have higher metabolic stability, better lipophilicity and unique three-dimensional structures than their carbon analogs. Of these, silacyclobutane is one of the most important silicon-based synthons, and can be applied to the synthesis of special silicon-containing compounds due to its high cyclic strain force (150 kJ/mol) and special Lewis acidity. The organic nitrogen-containing compounds are also very important compounds, and are applied to various fields such as pesticides, medicines, aerospace and the like. Therefore, the method is of great significance for synthesizing compound molecules with various functions by introducing nitrogen atoms while constructing the silicon heterocyclic compound in a green and efficient way. While these potentials have been demonstrated, the physicochemical properties of chiral silatetrahydronaphthylamine analogs remain poorly understood. This remarkable knowledge gap is mainly due to the persistent limitations of efficient, accurate synthesis methods. Therefore, it is important to develop a simple, effective and efficient synthetic method for constructing excellent stereoselectivity and to mine the undeveloped pharmacological potential. The ring expansion reaction of the benzo silicon hetero compound provides a unique strategy for synthesizing the silicon hetero compound. At present, the strategy is successfully applied to cycloaddition reaction of benzosilacyclobutane, alkene, alkyne, small ring, carbonyl compound and the like to construct 5-7 membered silicon heterocyclic compounds with various structures. Although the problem of the various ring-expanding reactions of benzoazetidines has been overcome, their cycloaddition with dienes remains a great challenge because of the great difficulty in controlling the regio-, chemo-, and configurational selectivities of such reactions. And N-allenamine has unique reactivity and selectivity relative to common allenes. We therefore contemplate that chiral silatetrahydro-1-naphthylamine compounds may be produced by the selective asymmetric cycloaddition of benzosilacyclobutane with N-allenamine. Disclosure of Invention The invention aims to overcome the defects of the prior art and provide a synthesis method of chiral silatetrahydro-1-naphthylamine compound, which has the advantages of high selectivity, high yield, mild condition, wide substrate range, simple operation and the like. In a first aspect of the present invention, there is provided a method for synthesizing a chiral silatetrahydro-1-naphthylamine compound, comprising: mixing a palladium catalyst, a chiral phosphine ligand and an organic solvent in an inert atmosphere, pre-stirring, then adding a compound 2 shown in a formula 2, cooling to a reaction temperature, adding a compound 1 shown in