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A kind of axial chiral anilide compound and its preparation method and application

An axial chirality and anilide technology, applied in the field of compound synthesis, can solve problems such as difficulty in generalization, and achieve the effect of high enantioselectivity

Active Publication Date: 2022-04-01
FUDAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Some examples are the formation of axial chirality in the process of C-N bond formation, but it is difficult to generalize because of the rotational barrier. However, there is only one case of atropisomerized anilides prepared by C-terminal functional groups. (10.1021 / jacs.0c09400), but the method in this document is difficult to reproduce in other scenarios, and it is difficult to achieve generalization

Method used

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  • A kind of axial chiral anilide compound and its preparation method and application
  • A kind of axial chiral anilide compound and its preparation method and application
  • A kind of axial chiral anilide compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044]

[0045] The specific operation is: under the protection of nitrogen, add Pd(OAc) to the dry Shrek tube 2 (0.02mmol), organophosphine ligand L19 (0.04mmol) and 2ml of anhydrous ethyl acetate, stirred at room temperature for 1h. Then CuI (0.01 mmol), substrate 1a (0.2 mmol), substrate 2a (0.4 mmol) and cesium acetate (0.4 mmol) were added, and stirred at 5° C. for 60 h. The reaction solution was concentrated, and 95.0 mg of product 3aa was obtained by column chromatography, with a yield of 81%, and 97% ee by HPLC.

[0046] Product characterization data are:

[0047] 1H NMR (400MHz, CDCl 3 )δ=7.74(d,J=1.3,1H),7.65–7.59(m,6H),7.48(t,J=7.5,2H),7.44(d,J=1.2,1H),7.39(t,J =7.3,1H),4.05(dd,J=13.6,7.8,1H),2.99(dd,J=13.6,5.2,1H),2.37(s,3H),2.08(d,J=12.2,1H), 1.85–1.73(m,1H),1.68–1.60(m,2H),1.60–1.50(m,2H),1.16(s,9H),1.14–1.05(m,3H),1.04–0.89(m,2H ). 13 C NMR (101MHz, CDCl 3 )δ178.17,145.76,141.56,140.86,140.18,139.11,133.83,132.09,128.91,127.79,127.12,127.05,125.49,121...

Embodiment 2

[0050]

[0051] The specific operation is: under the protection of nitrogen, add Pd(OAc) to the dry Shrek tube 2 (0.02mmol), organophosphine ligand L19 (0.04mmol) and 2ml of anhydrous ethyl acetate, stirred at room temperature for 1h. Then CuI (0.01 mmol), substrate 1a (0.2 mmol), substrate 2b (0.4 mmol) and cesium acetate (0.4 mmol) were added, and stirred at 5° C. for 60 h. The reaction solution was concentrated, and 84.2 mg of product 3ab was obtained by column chromatography, with a yield of 82%, and 96% ee by HPLC.

[0052] Product characterization data are:

[0053] 1 H NMR (400MHz, CDCl 3 )δ7.73(d,J=1.3Hz,1H),7.55–7.50(m,2H),7.42(d,J=1.2Hz,1H),7.38–7.32(m,3H),4.03(dd,J =13.6,7.9Hz,1H),2.96(dd,J=13.6,5.2Hz,1H),2.36(s,3H),2.04(d,J=12.5Hz,1H),1.85–1.69(m,1H) ,1.67–1.57(m,2H),1.55–1.47(m,2H),1.14(s,9H),1.11–1.02(m,3H),1.02–0.85(m,2H). 13 C NMR (101MHz, CDCl 3 )δ178.11,145.76,140.85,139.09,133.85,131.65,128.86,128.45,125.45,122.40,102.69,94.54,87.25,59.87,41.97,37....

Embodiment 3

[0055]

[0056] The specific operation is: under the protection of nitrogen, add Pd(OAc) to the dry Shrek tube 2 (0.02mmol), organophosphine ligand L19 (0.04mmol) and 2ml of anhydrous ethyl acetate, stirred at room temperature for 1h. Then CuI (0.01 mmol), substrate 1a (0.2 mmol), substrate 2c (0.4 mmol) and cesium acetate (0.4 mmol) were added, and stirred at 5° C. for 60 h. The reaction solution was concentrated, and 86.5 mg of product 3ac was obtained by column chromatography, with a yield of 82%, and 96% ee by HPLC.

[0057] Product characterization data are:

[0058] 1 H NMR (400MHz, CDCl 3 )δ7.69(s,1H),7.42–7.33(m,3H),7.14(d,J=7.9Hz,2H),4.01(dd,J=13.6,7.9Hz,1H),2.92(dd,J =13.6,5.1Hz,1H),2.36(s,3H),2.33(s,3H),2.02(d,J=12.4Hz,1H),1.79–1.68(m,1H),1.66–1.56(m, 2H),1.54–1.45(m,2H),1.11(s,9H),1.09–1.00(m,3H),0.98–0.82(m,2H). 13 C NMR (101MHz, CDCl 3 )δ177.99,145.49,140.48,138.99,138.90,133.62,131.43,129.09,125.54,119.21,102.52,94.72,86.56,59.73,41.83,37.35,32.12,29.7...

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Abstract

The present invention relates to a kind of axial chiral anilide compound and its preparation method and application, its structural formula is: wherein: R 1 For F, Cl, Br, C 1 ~C 12 One of the alkane group, phenyl group and substituted phenyl group; R 2 Is one of cycloalkyl, phenyl, substituted phenyl; R 3 for C 1 ~C 12 One of alkane, alkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, and five-membered heterocyclic groups. Compared with the prior art, this type of compound synthesized by this technical scheme may have potential biological Activity, can be used as a chiral ligand skeleton, and the product obtained by this method has very high enantioselectivity, and has very good application prospects in such demanded drugs, drug intermediates and biological materials; avoids N‑ The catalytic reaction of the terminal functional group establishes a new direction for the preparation of atropisomerized anilide compounds through the catalytic reaction of the C-terminal functional group, which can realize the promotion of industrialization.

Description

technical field [0001] The invention relates to the field of compound synthesis, in particular to a chiral anilide-like compound and its preparation method and application. Background technique [0002] Chirality is one of the basic properties of substances in nature. In recent years, structures with C–N axis chirality frequently appear in the backbones of bioactive molecules, natural products and chiral ligands. In 1994, Curran and his colleagues realized the asymmetric synthesis of axial chiral anilides for the first time (J.Am.Chem.Soc.1994,116,3131). Since then, many of the unique functionalities of axial chiral anilides have been exploited for asymmetric catalysis and the development of bioactive compounds such as alachlor and tinazepine as well as peptoid chemistry (Angew.Chem.Int.Ed. 2009, 48, 6398; J. Med. Chem. 2011, 54, 7005; J. Am. Chem. Soc. 2011, 133, 10910). However, obtaining these useful structures remains a challenge due to the lower rotation barrier of t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/15C07C233/25C07C233/43C07C233/54C07C231/12C07C255/60C07C253/30
CPCC07C233/15C07C233/25C07C233/43C07C233/54C07C231/12C07C255/60C07C253/30C07C2601/14C07C2601/16C07B2200/07
Inventor 张俊良阳斌杨俊锋李志铭
Owner FUDAN UNIV
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