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CN-122010956-A - Chiral 1, 4-diazabicyclo [3.1.1] heptane derivatives, synthesis and application thereof

CN122010956ACN 122010956 ACN122010956 ACN 122010956ACN-122010956-A

Abstract

The invention discloses chiral 1, 4-diazabicyclo [3.1.1] heptane derivatives, and a synthesis method and application thereof. According to the invention, a 1-azabicyclo [1.1.0] butane derivative is used as a raw material, and is subjected to [3+2] cycloaddition reaction with an N-allyl carbonate derivative under the catalysis of a chiral iridium complex, so that a series of chiral 1, 4-diazabicyclo [3.1.1] heptane frameworks with diversified structures are constructed with high stereoselectivity, and the obtained product has the potential of further derivatization. The method has the advantages of easily available raw materials, mild reaction conditions, simple and convenient operation, good functional group compatibility and the like.

Inventors

  • DENG WEIPING
  • ZHANG JIAN
  • JIN JUNCHENG
  • Zheng Qiguo

Assignees

  • 浙江师范大学

Dates

Publication Date
20260512
Application Date
20260409

Claims (9)

  1. 1. A chiral 1, 4-diazabicyclo [3.1.1] heptane derivative characterized by having a structure represented by formula 1: ; R 1 is selected from hydrogen, hydroxyl, amino, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 alkoxy, C1-C20 alkylamino, C1-C20 alkylthio, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, 3-10 membered saturated or unsaturated heterocyclic group having 1-4 hetero atoms, wherein the hetero atoms are selected from nitrogen atom, oxygen atom and sulfur atom; R 2 is selected from hydrogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 alkoxy, C1-C20 alkylamino, C1-C20 alkylthio, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, 3-10 membered saturated or unsaturated heterocyclic group having 1-4 hetero atoms, wherein the hetero atoms are selected from nitrogen atom, oxygen atom, sulfur atom, acyl, ester group, sulfonyl; The substitution in R 1 、R 2 means that one or more hydrogen atoms on the group are optionally substituted by halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, amino, hydroxy and phenyl.
  2. 2. The method for synthesizing chiral 1, 4-diazabicyclo [3.1.1] heptane derivatives according to claim 1, characterized by comprising: Taking a compound 2 as a raw material, taking a compound 3 as a ternary synthesizer, adding a solvent and alkali under the catalysis of Lewis acid and chiral iridium complex, and generating cycloaddition reaction to generate chiral 1, 4-diazabicyclo [3.1.1] heptane derivatives; ; ; X is selected from alkoxycarbonyl-OC (O) R 3 , acyl-C (O) R 4 , dialkylphosphoryl-P (O) (OR 5 ) 2 ; R 3 、R 4 、R 5 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, substituted or unsubstituted C6-C20 aryl, wherein the substitution means that one or more hydrogen atoms on the group are optionally substituted by halogen, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, amino, hydroxyl and phenyl.
  3. 3. The synthetic method according to claim 2, wherein the lewis acid comprises one or more of gallium triflate, ytterbium triflate, yttrium triflate, indium triflate, scandium triflate, europium triflate, erbium triflate, dysprosium triflate, boron trifluoride diethyl ether, copper triflate, silver triflate, ferrous triflate, zinc bromide, bismuth triflate; The chiral iridium complex comprises one or more than two of [ Ir ] -A, [ Ir ] -B, [ Ir ] -C, [ Ir ] -D, [ Ir ] -E, [ Ir ] -F, [ Ir ] -G, [ Ir ] -H and [ Ir ] -I: , Wherein Ph represents phenyl, OTf represents trifluoromethanesulfonate group, (R a ) -BINOL represents 1,1 '-bi-2-naphthol with R configuration, (R a ) -8H-BINOL represents 5,5', 6', 7',8 '-octahydro-1, 1' -bi-2-naphthol with R configuration, 1-naphth represents 1-naphthyl, 2-OMePh represents 2-methoxyphenyl, 4-OMePh represents 4-methoxyphenyl, and R a ) -SPINOL represents spirocyclic diphenol with R configuration; the solvent comprises one or more than two of tetrahydrofuran, 1, 4-dioxane, cyclopentyl methyl ether, methyl tertiary butyl ether, diethyl ether, methylene dichloride, toluene and acetonitrile; The alkali comprises one or more than two of N, N-diisopropylethylamine, triethylamine, 1, 4-diazabicyclo [2.2.2] octane, potassium carbonate, potassium phosphate, 1, 8-diazabicyclo [5.4.0] undec-7-ene, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium diisopropylamide, N-butyllithium, cesium carbonate, 2, 6-dimethylpyridine, sodium carbonate and sodium bicarbonate.
  4. 4. The synthesis method according to claim 2, wherein the molar ratio of the compound 2 to the compound 3 is (5:1) - (1:5); the molar ratio of the compound 3 to the Lewis acid is (1:0.01) to (1:0.5); The molar ratio of the compound 3 to the chiral iridium complex is (1:0.01) to (1:0.5); The molar ratio of the compound 3 to the alkali is (5:1) - (1:5).
  5. 5. The synthetic method according to claim 2, wherein the cycloaddition reaction temperature is-10-50 ℃; The cycloaddition reaction time is 2-24 hours.
  6. 6. Use of a chiral 1, 4-diazabicyclo [3.1.1] heptane derivative according to claim 1, for the preparation of a bacteriostatic agent.
  7. 7. The use according to claim 6, wherein the object of action of the bacteriostatic agent comprises mycobacterium tuberculosis.
  8. 8. A bacteriostatic agent comprising an effective amount of the chiral 1, 4-diazabicyclo [3.1.1] heptane derivative according to claim 1.
  9. 9. Use of a chiral 1, 4-diazabicyclo [3.1.1] heptane derivative according to claim 1, for the preparation of a medicament for the treatment and/or prevention of mycobacterium tuberculosis infection.

Description

Chiral 1, 4-diazabicyclo [3.1.1] heptane derivatives, synthesis and application thereof Technical Field The invention relates to the field of synthetic chemistry, in particular to chiral 1, 4-diazabicyclo [3.1.1] heptane derivatives, and a synthetic method and application thereof. Background The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art. In recent years, strategies using three-dimensional bicyclic frameworks as bioisosteres to replace aromatic rings have become a hotspot in the field of pharmaceutical research (Nat. Rev. Chem. 2024, 8, 605-627). Chiral nitrogen-containing saturated bridged ring compounds are widely present in natural products and bioactive molecules and are extremely important privileged frameworks in drug development. Among them, 1,4-diazabicyclo [3.1.1] heptane (1, 4-diazabicyclo [3.1.1] heptane) is used as a highly tensile aza-bridged ring system, having unique spatial configuration and rigid structure. The skeleton can effectively increase the three-dimensional characteristic of the molecule and improve the metabolic stability and solubility of the molecule, so that the skeleton has great potential in screening new drug candidate molecules. However, the construction of [3.1.1] bridged ring systems is extremely challenging due to the large geometric tension that they present. At present, methods for synthesizing the frameworks are very limited, and most of the methods have the following defects: 1) The synthesis steps are cumbersome, typically requiring multiple functional group transformations and complex protection/deprotection procedures, resulting in lower overall yields. 2) Atomic economics are low, and some methods rely on pre-functionalized precursors to produce large amounts of quantitative byproducts. 3) The structure is limited, the existing [3.1.1] bridged ring skeleton structure is limited, and 1, 4-diazabicyclo [3.1.1] heptane is not successfully synthesized, so that the further derivatization application of the compound in pharmaceutical chemistry is severely limited. 4) Enantioselectivity control difficulties the one-step construction of [3.1.1] bridged ring frameworks with high chiral purity by catalyzing asymmetric reactions remains a difficulty in synthetic chemistry. 1-Azabicyclo [1.1.0] butane is used as a high-activity electrophile for constructing various azacycles in recent years, but the direct construction of a [3.1.1] heptane system by chiral iridium (Ir) -catalyzed cycloaddition reaction of the 1-azabicyclo [1.1.0] butane and N-allyl carbonate is not yet reported. Therefore, there is a need to develop a method for efficiently constructing structurally diverse chiral 1, 4-diazabicyclo [3.1.1] heptane derivatives with readily available starting materials, mild reaction conditions and high enantioselectivity. Furthermore, the obtained chiral 1, 4-diazabicyclo [3.1.1] heptane can be used as a biological equivalent of pyrazine, can be used for modification of medicines, active molecules and natural products, and provides a new chemical entity for medicine research and development. In particular, the planar symmetrical aza-aromatic ring is replaced by a chiral three-dimensional double-ring skeleton, and the introduction of chiral elements brings new opportunities for drug development. Disclosure of Invention The invention provides chiral 1, 4-diazabicyclo [3.1.1] heptane derivatives, and a synthetic method and application thereof. According to the invention, a 1-azabicyclo [1.1.0] butane derivative is used as a raw material, and is subjected to [3+2] cycloaddition reaction with an N-allyl carbonate derivative under the catalysis of a chiral iridium complex, so that a series of chiral 1, 4-diazabicyclo [3.1.1] heptane frameworks with diversified structures are constructed with high stereoselectivity, and the obtained product has the potential of further derivatization. The method has the advantages of easily available raw materials, mild reaction conditions, simple and convenient operation, good functional group compatibility and the like. The specific technical scheme is as follows: In a first aspect, the present invention provides a class of chiral 1, 4-diazabicyclo [3.1.1] heptane derivatives having the structure shown in formula 1 below: ; R 1 is selected from hydrogen, hydroxyl, amino, substituted or unsubstituted C1-C20 alkyl (including straight chain and branched chain), substituted or unsubstituted C1-C20 alkoxy (including straight chain and branched chain), C1-C20 alkylamino (including straight chain and branched chain), C1-C20 alkylthio (including straight chain and branched chain), substituted or unsubstituted C6-C20 aryl (including phenyl and the like), substituted or unsubstituted C3-C20 heteroaryl