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C-N axis chiral aromatic amine compound and preparation method thereof

A compound and axial chiral technology, which is applied in the field of C-N axial chiral aromatic amine compounds and their preparation, can solve problems such as recrystallization, limited range of substrates, and difficulty in forming C-N bonds

Active Publication Date: 2020-01-14
WENZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis of C-N axis chiral aromatic amines is currently facing great challenges
On the one hand, the C-N axis is more easily flipped, leading to the racemization of the axial chirality; on the other hand, when the ortho bulky hindered substituents are introduced to stabilize the C-N axis chirality, it usually leads to more difficult C-N bond formation
In recent years, the research on the synthesis of C-N axis chiral aromatic amines has made significant progress, but the range of substrates is limited, and the products need further recrystallization or chiral resolution to obtain optically pure products and applications.
Therefore, it is still a huge challenge to develop a method that can obtain optically pure C-N axis chiral aromatic amines with a wide range of substrates.

Method used

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  • C-N axis chiral aromatic amine compound and preparation method thereof
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  • C-N axis chiral aromatic amine compound and preparation method thereof

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Experimental program
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preparation example Construction

[0039] The present invention provides a method for preparing a novel C-N axis chiral aromatic amine compound, wherein the method comprises: in the presence of an achiral catalyst, performing C-H Activated to obtain the axial chiral biaryl compound with the structure shown in formula (2).

[0040]

[0041] Among them, R 1 is substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylbenzyl, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 each independently hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylbenzyl group, wherein, the substituents in substituted alkyl, substituted cycloalkyl, substituted aryl and substituted arylbenzyl are each independently selected from fluorine, chlorine, bromine, nitro, methyl, methoxy , one or more of trifluoromethyl, ...

preparation example 1

[0087] Preparation of secondary amine compounds with structure shown in formula (1-1).

[0088]Step 1: 2-iodo-3-(2-(trimethylsilyl)ethoxymethoxy)phenol (4.78mmol, 1.75g), l-lactate methyl ester (4.78mmol, 497.6mg) triphenyl Phosphine (11.95mmol, 3.13g) was dissolved in tetrahydrofuran (12mL), stirred under ice bath for 10min, then diethyl azodicarboxylate (DIAD, 11.95mmol, 2.46mL) was added dropwise, and the ice bath was removed after the dropwise addition. Stir overnight at room temperature. The solid crude product was obtained after distilling off the solvent under reduced pressure, which was further purified by column chromatography (eluent: a mixture of petroleum ether / ethyl acetate at a volume ratio of 20 / 1) to obtain 2-iodophenyl ether. 2-Iodophenyl ether was dissolved in tetrahydrofuran, while stirring, 2 times the equivalent of lithium hydroxide (9.56mmol, 200mg) was added for hydrolysis, and the reaction was monitored by TLC. After the reaction was completed, the sys...

preparation example 2

[0091] Preparation of secondary amine compounds with structure shown in formula (1-2).

[0092] According to the method of secondary amine preparation example 1 step one;

[0093] According to the method of secondary amine preparation example 1 step 2, the difference is that aniline (147mg, 1.56mmol) is used to replace p-methylaniline in the step, thereby obtaining the compound (new compound) of the structure shown in formula (1-2) , the yield was 65%. [α] 24 D =-40.3(c 0.5in CH 2 Cl 2 ); 1 H NMR (500MHz, CDCl 3 ):δ(ppm) 8.95(s,1H),8.23(d,J=5.0Hz,1H),7.83-7.79(m,2H),7.65(d,J=5.0Hz,1H), 7.45(s, 1H), 7.36-7.33(m, 2H), 7.23(t, J=5.0Hz, 2H), 7.14(s, 1H), 5.01(q, J=6.7 Hz, 1H), 1.77(d, J=5.0 Hz,3H); 13 CNMR (125MHz, CDCl 3 ): δ (ppm) 169.5, 151.1, 137.4, 133.2, 130.7, 129.7, 129.2, 128.3, 128.3, 126.5, 125.4, 124.8, 120.0, 115.8, 110.9, 77.2, 18.9.HRMS(ESI)m / z calcd.forC 19 h 17 BrNO 2 + (M+H) + 370.0437, found 370.0448.

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Abstract

The invention discloses a C-N axis chiral aromatic amine compound and a preparation method thereof, wherein the method comprises the following steps: in the presence of an achiral catalyst, asymmetricBuchwald-Hatwig amination reaction is carried out on a compound with a structure represented by the formula (1) or an optical isomer thereof to prepare a novel C-N axis chiral aromatic amine compounds. According to the invention, high regioselectivity and diastereoselectivity C-N coupling of the central chiral compound with the structure shown by the formula (1) is realized by selecting a suitable compound with the structure shown by the formula (1) as a substrate and a suitable achiral catalyst, thus a new type of C-N axis chiral aromatic amine compound with the structure shown by formula (2) is prepared at low cost. The novel C-N axis chiral aromatic amine compounds can be used as structural blocks of bioactive compounds, chiral drugs and chiral ligands.

Description

technical field [0001] The invention relates to aromatic amine compounds, in particular to a C-N axis chiral aromatic amine compound and a preparation method thereof. Background technique [0002] Axochiral skeletons widely exist in biologically active natural products and drug molecules. For example, Steganacin (Steganacin) exhibits strong antitumor activity. Good anti-malarial activity, and their dimer Michellamine B has excellent anti-HIV activity. There are also chiral biaryl structural units in the widely used clinical vancomycin molecule. Axial chiral biaryl compounds such as BINOLs and their derivatives (such as chiral phosphonic acid, phosphoramidite, etc.) have also been widely reported as chiral ligands with excellent performance in asymmetric synthesis. [0003] Compared with C-C axis chiral compounds, there are very few studies on C-N axis chirality. C-N axis chiral compounds such as axial chiral arylamines widely exist in natural products and medicines, and c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/08C07D265/34
CPCC07F7/083C07F7/0812C07D265/34C07B2200/07Y02A50/30
Inventor 苗婷婷杨骥吴俊吴芬王朝宗童雪怡郑铭雨毛涵轩
Owner WENZHOU UNIVERSITY