Preparation method and application of axially chiral biaryl aminophenol compound

Abstract

The invention discloses a preparation method of an axially chiral biaryl aminophenol compound, which mainly comprises the following steps: adding biaryl amino diphenol, di-tert-butyl dicarbonate ester and a chiral isothiourea catalyst into an organic solvent, cooling to-10 to-30 DEG C for reaction, and after the reaction is completed, separating and purifying to obtain the axially chiral biaryl aminophenol compound. And performing post-treatment to obtain the axially chiral biaryl aminophenol compound. The preparation method can be carried out under mild conditions, is good in stereoselectivity, convenient to operate and simple in post-treatment, and avoids the use of a heavy metal catalyst which may remain in a product; according to the present invention, the reaction raw materials are cheap and easily available, the compatibility of the substrate functional group is good, the amplification treatment can be conveniently performed, the practicability is strong, the diversified axially chiral biaryl aminophenol compound can be designed and synthesized according to the actual requirement, the operation is convenient, and the applicability of the method is widened.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and particularly relates to a method for preparing an axially chiral biaryl aminophenol compound. Background Technology

[0002] Axially chiral biarylaminophenols are a very important and advantageous skeleton in organic synthesis, and compounds with axially chiral biarylaminophenols as basic structural units have wide applications in asymmetric synthesis. For example, compound 1 can be used as a tridentate ligand of titanium(IV) for the asymmetric aldol condensation reaction of methyl or ethyl esters (J. Am. Chem. Soc. 1994, 116, 8837); compound 2 is an important organic photocatalyst for the asymmetric [2+2] cycloaddition reaction of coumarin derivatives (Angew. Chem. Int. Ed. 2014, 53, 5604); and compound 3 can combine with cuprous chloride to catalyze the asymmetric arylation reaction of α-substituted cyanoethyl esters (Angew. Chem. Int. Ed. 2023, 62, e202312383).

[0003]

[0004] Currently, the main methods reported in the literature for obtaining axially chiral biarylaminophenol compounds via catalytic asymmetric synthesis are:

[0005] 1) Direct asymmetric coupling of 2-naphthylamine and 2-naphthol catalyzed by coordination of monovalent copper with spiropyrrolidone (Angew. Chem. Int. Ed. 2021, 60, 7061): The copper catalyst used in this method is a heavy metal and is prone to remain in the product.

[0006] 2) Nucleophilic addition of 2-naphthol to azonaphthalene catalyzed by chiral calcium phosphate (Nat. Catal. 2019, 2, 314): This reaction directly yields hydrazine compounds, which require further cleavage of nitrogen-nitrogen single bonds to obtain biarylaminophenol.

[0007] 3) Kinetic resolution of racemic biaryl aminophenols catalyzed by chiral cinchonaine derivatives (Nat. Commun. 2019, 10, 3061): This method is limited by the characteristics of kinetic resolution, and the yield of the product is only up to 50%.

[0008] 4) Desymmetry of biarylaminodiphenols catalyzed by chiral nitrogen heterocyclic carbene (Nat. Commun. 2019, 10, 3062): The amino group of the starting material used in this reaction needs to be protected beforehand to avoid side reactions.

[0009] In summary, although axially chiral biarylaminophenols are a class of very useful compounds, most current methods suffer from limitations such as low separation efficiency, substrate limitations, the need for toxic and residual heavy metal catalysts, or the requirement for further transformations. Therefore, we have developed a method for the highly stereoselective synthesis of axially chiral biarylaminophenol compounds using a green, environmentally friendly, and readily available chiral isothiourea catalyst under relatively mild conditions. Summary of the Invention

[0010] This invention provides a green and environmentally friendly method for preparing axially chiral biarylaminophenol compounds. This method has good stereoselectivity, is easy to operate, has simple post-processing, and has a wide range of applicable substrates. It also eliminates the need to deal with toxic metal reagents that may remain in the product. Furthermore, this method can be directly scaled up to the gram level, providing potential possibilities for further industrial applications.

[0011] A method for preparing an axially chiral biarylaminophenol compound mainly includes the following steps: adding biarylaminodiphenol, ditert-butyl dicarbonate and a chiral isothiourea catalyst into an organic solvent, cooling to -10 to -30°C for reaction, and after the reaction is complete, post-treatment to obtain the axially chiral biarylaminophenol compound.

[0012] The structure of the biarylaminodiphenol is shown in formula (II):

[0013]

[0014] The structure of the ditert-butyl dicarbonate is shown in formula (III):

[0015]

[0016] The structure of the chiral isothiourea catalyst is shown in formula (IV):

[0017]

[0018] The structure of the axially chiral biarylaminophenol compound is shown in formula (I):

[0019]

[0020] In equations (I) to (II), R 1 The phenyl group is H, C1-C4 alkyl, C3-C6 cycloalkyl, halogen, substituted or unsubstituted phenyl, naphthyl, heterocyclic, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C2-C6 alkenyl, wherein the substituent on the phenyl group is selected from C1-C4 alkoxy or trifluoromethyl, and the substitution position is any position on the benzene ring;

[0021] R2 It is H, C1-C4 alkyl, substituted or unsubstituted phenyl;

[0022] The substituent on the C2-C6 alkynyl group or the C2-C6 alkenyl group is phenyl.

[0023] Wherein, the alkyl group is a substituent formed by removing one hydrogen atom from an alkane molecule, and is more preferably a straight-chain alkyl group.

[0024] The ratio of biarylaminodiphenol: ditert-butyl dicarbonate: chiral isothiourea catalyst is 1:1.1:0.05;

[0025] The reaction formula is as follows:

[0026]

[0027] In the reaction, the chiral isothiourea catalyst (IV) may first activate ditert-butyl dicarbonate (III) to generate a highly active intermediate with a chiral environment. Then, this intermediate undergoes a highly chemoselective and stereoselective oxyacylation reaction with a hydroxyl group of biarylaminodiphenol (II) to finally generate a biarylaminodiphenol compound (I) with axial chirality.

[0028] In this invention, the optional post-processing steps include: concentration, silica gel mixing, and finally purification by column chromatography to obtain the corresponding axially chiral biaryl aminophenol compound. Column chromatography purification is a commonly used technique in this field.

[0029] As a preferred option, R 1 The substituents are 6-methyl, 6-cyclopropyl, 6-bromo, 6-phenyl, 6-p-methoxyphenyl, 6-p-trifluoromethylphenyl, 6-(2-naphthyl), 6-(2-furanyl), 6-(2-thienyl), 6-phenylethynyl, 6-styryl, 6-vinyl, 7-methyl, 7-(2-furanyl), 7-phenylethynyl, 5-methyl, 4-methyl, or 3-methyl. In this case, the biarylaminodiphenol is readily available, and the reaction yield is high with good stereoselectivity. The substituent numbering order is determined according to IUPAC nomenclature.

[0030] As a preferred option, R 2 The solvent is H, methyl, or phenyl. In this case, the biarylaminodiphenol is readily available, and the reaction yield is high with good stereoselectivity.

[0031] The ditert-butyl dicarbonate is inexpensive and readily available. To ensure a more complete reaction, it is used in excess relative to the amount of biarylaminodiphenol. Preferably, the molar ratio of biarylaminodiphenol: ditert-butyl dicarbonate: chiral isothiourea catalyst is 1:1.1:0.05.

[0032] Preferably, the reaction temperature is -20°C. If the reaction temperature is too high, the stereoselectivity will be poor, and if it is too low, it will be difficult to ensure the completeness of the reaction.

[0033] Preferably, the reaction time is 48 hours. A reaction time that is too long increases the reaction cost, while a reaction that is too long makes it difficult to guarantee the completeness of the reaction.

[0034] In this invention, any organic solvent that can fully dissolve the raw materials can enable the reaction to occur, but the reaction efficiency varies greatly. Aprotic solvents are preferred, as they can effectively promote the reaction. Preferably, the aprotic organic solvent is diethyl ether or dichloromethane. More preferably, the organic solvent is diethyl ether, in which case various raw materials can be converted into products with a high conversion rate.

[0035] The amount of organic solvent used should be sufficient to dissolve the raw material well; for example, the amount of organic solvent used for 0.2 mmol of biarylaminodiphenol is approximately 2 mL.

[0036] As a further preferred embodiment, the axially chiral biarylaminophenol compound is one of the compounds shown in formulas (I-1) to (I-12):

[0037]

[0038]

[0039]

[0040] In the above preparation method, the ditert-butyl dicarbonate and the chiral isothiourea catalyst are commercially available products and can be easily obtained from the market. The biarylaminodiphenol can be easily and quickly synthesized from the corresponding 2,6-dimethoxyphenylboronic acid and 1-iodo-2-naphthylamine.

[0041] The present invention also provides an application of the above-described preparation method, comprising:

[0042] (1) The axially chiral biarylaminophenol compound (I-1) was obtained according to the above preparation method;

[0043] (2) The axially chiral biarylaminophenol compound (I-1) obtained in step (1) is subjected to Boc protection, derivatization and deprotection to obtain axially chiral biarylaminophenol derivatives I-14 or I-15.

[0044]

[0045] The derivatization is either methylation or silanization.

[0046] Among them, I-14 (Nat.Commun.2019,10,3062) and I-15 (Angew.Chem.Int.Ed.2022,e202211977) are known compounds that can be used as potential chiral ligands.

[0047] Compared with the prior art, the beneficial effects of the present invention are as follows: the preparation method can be carried out under mild conditions, has good stereoselectivity, is easy to operate, and has simple post-processing, avoiding the use of heavy metal catalysts that may remain in the product; the reaction raw materials are inexpensive and readily available, the substrate functional groups have good compatibility, and a variety of axially chiral biaryl aminophenol compounds can be designed and synthesized according to actual needs, making it highly practical. Attached Figure Description

[0048] Figure 1 The hydrogen NMR spectrum of the product (I-1) obtained in Example 9;

[0049] Figure 2 The carbon NMR spectrum of the product (I-1) obtained in Example 9;

[0050] Figure 3 The lower figure is a high-performance liquid chromatogram of the product (I-1) obtained in Example 9, and the upper figure is the corresponding achiral product obtained according to the method of Example 1, but using a achiral catalyst.

[0051] Figure 4 The high-resolution mass spectrum of the product (I-1) obtained in Example 9 is shown. Detailed Implementation

[0052] The present invention will be further described below with reference to specific embodiments, but it should be emphasized that the present invention is by no means limited to the contents represented by these embodiments.

[0053] Examples 1-21

[0054] According to the raw material ratio in Table 1, chiral isothiourea catalyst (IV), biarylaminodiphenol (II), organic solvent, and di-tert-butyl dicarbonate (III) were added sequentially to a 10 mL Schlenk tube (or a 250 mL round-bottom flask). The mixture was stirred until homogeneous. After the reaction was completed under the reaction conditions in Table 2, the mixture was concentrated, mixed with silica gel, and purified by column chromatography to obtain the corresponding axially chiral biarylaminophenol (I). The reaction process is shown in the following formula:

[0055] Table 1

[0056]

[0057] Table 2

[0058]

[0059]

[0060] In Tables 1 and 2, T represents the reaction temperature, Me represents methyl, CF3 represents trifluoromethyl, Ph represents phenyl, Bn represents benzyl, Naphthyl represents naphthyl, Thienyl represents thienyl, Styryl represents styryl, Phenylethynyl represents phenylethynyl, and ee represents enantiomer excess.

[0061] Structural confirmation data of some compounds prepared in Examples 1-21:

[0062] Nuclear magnetic resonance (NMR) of the axially chiral biarylaminophenol compound (I-1) prepared in Example 9 1 H NMR and 13 The detection data for CNMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC) are as follows:

[0063]

[0064] 1 H NMR (400MHz, CDCl3) δ7.72(t,J=8.8Hz,2H),7.40(t,J=8.4Hz,1H),7.34-7.30(m,1H),7.26-7.2 1(m,2H),7.02(t,J=8.0Hz,2H),6.91(dd,J1=0.8Hz,J2=8.0Hz,1H),3.77(br,3H),1.10(s,9H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ155.1,151.7,150.5,143.6,133.5,130.7,130.1,128.3,128.0,127 .3,123.7,122.8,118.2,116.5,114.6,114.0,107.0,83.1,27.2.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 21 H 22 NO4 +352.1543, found 352.1551. HPLC analysis: 98%ee, [CHIRALPAK OD-H column; 1mL / min; solvent system: i-PrOH / hexane=20 / 80; retention times: 7.8min (major), 12.2min (minor)].

[0065] Nuclear magnetic resonance (NMR) of the axially chiral biarylaminophenol compound (I-2) prepared in Example 10 1 H NMR and 13 The detection data for C NMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC) are as follows:

[0066]

[0067] 1 H NMR(400MHz, CDCl3)δ7.65(d,J=8.4Hz,1H),7.49(s,1H),7.39(t,J=8.0Hz,1H),7.18-7.11(m,2H) ,7.03-6.97(m,2H),6.90(d,J=8.4Hz,1H),5.35(br,1H),3.87(br,2H),2.43(s,3H),1.11(s,9H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ155.1,151.7,150.5,142.8,132.2,131.6,130.1,130.0,129.5,128.5 ,127.0,123.7,118.3,116.7,114.5,114.0,107.2,83.0,27.2,21.3.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 22 H 24 NO4 + 366.1700, found366.1707. HPLC analysis:>99%ee, [CHIRALPAK OD-H column; 1.0mL / min; solventsystem: i-PrOH / hexane=20 / 80; retention times: 7.7min (major), 9.8min (minor)].

[0068] Nuclear magnetic resonance (NMR) of the axially chiral biarylaminophenol compound (I-3) prepared in Example 111 H NMR and 13 The detection data for C NMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC) are as follows:

[0069]

[0070] 1 H NMR (400MHz, CDCl3) δ7.86.(s,1H),7.63(d,J=8.8Hz,1H),7.42-7.36(m,2H),7.09(d,J=9.2H z,1H),7.02(d,J=8.4Hz,2H),6.91(d,J=8.0Hz,1H),5.35(br,1H),4.01(br,2H),1.12(s,9H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ155.0,151.6,150.4,143.9,132.1,130.4,130.3,129.9,129.7,129 .3,125.7,119.2,116.3,115.9,114.8,114.1,107.1,83.2,27.2.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 21 H 21 BrNO4 + 430.0648, found 430.0656. HPLC analysis: 98%ee, [CHIRALPAK OD-H column; 1.0mL / min; solvent system: i-PrOH / hexane=20 / 80; retention times: 9.0min (major), 11.9min (minor)].

[0071] Nuclear magnetic resonance (NMR) of the axially chiral biarylaminophenol compound (I-4) prepared in Example 12 1 H NMR and 13 The detection data for C NMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC) are as follows:

[0072]

[0073] 1H NMR (400MHz, CDCl3) δ7.94(d,J=1.6Hz,1H),7.81-7.75(m,3H),7.69(d,J=8.4Hz,2H),7.58(dd,J1=1.6Hz,J2=8.8Hz,1H),7.42 (t,J=8.4Hz,1H),7.32(d,J=8.8Hz,1H),7.05(d,J=8.8Hz,2H),6.93(d,J=8.0Hz,1H),5.21(br,1H),4.04(br,2H),1.12(s,9H); 13 C{ 1 H}NMR(100MHz, CDCl3)δ155.1,151.7,150.5,144.7,144.2,133.8,133.3,131.2,130.3,129.0(q,J C-F =32.2Hz),128.3,127.3,126.4(d,J C-F =5.2Hz), 125.8(d,J) C-F =3.6Hz),124.7,118.9,116.2,114.8,114.1,106.9,83.2,27.2.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 28 H 25 F3NO4 + 496.1730, found 496.1743. HPLC analysis:>99%ee, [CHIRALPAKOD-H column; 0.8mL / min; solvent system: i-PrOH / hexane=20 / 80; retention times: 12.0min (major), 22.3min (minor)].

[0074] Nuclear magnetic resonance (NMR) of the axially chiral biarylaminophenol compound (I-5) prepared in Example 13 1 H NMR and 13 The detection data for C NMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC) are as follows:

[0075]

[0076] 1H NMR (400MHz, CDCl3) δ8.10(s,1H),8.05(s,1H),7.92-7.79(m,5H),7.73(dd,J1=1.2Hz,J2=8.8Hz,1H),7.51-7.40(m ,3H),7.34(d,J=8.4Hz,1H),7.04(t,J=10.0Hz,2H),6.94(d,J=8.4Hz,1H),5.35(br,1H),4.03(br,2H),1.12(s,9H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ155.1,151.8,150.5,143.8,138.4,135.3,133.9,132.8,132.6,131.1,130.3,128.6,128.5,128.2,127 .7,127.0,126.4,126.3,125.9,125.6,125.5,124.5,118.8,116.4,114.7,114.1,107.0,83.2,27.3.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 31 H 28 NO4 + 478.2013, found 478.2017. HPLC analysis: 98%ee, [CHIRALPAK OD-H column; 0.8mL / min; solvent system: i-PrOH / hexane=20 / 80; retention times: 15.2min (major), 34.1min (minor)].

[0077] Nuclear magnetic resonance (NMR) of the axially chiral biarylaminophenol compound (I-6) prepared in Example 14 1 H NMR and 13 The detection data for C NMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC) are as follows:

[0078]

[0079] 1H NMR (400MHz, CDCl3) δ7.92(d,J=1.6Hz,1H),7.72(d,J=8.8Hz,1H),7.60(dd,J1=2.0Hz,J2=8.8Hz,1H),7.40(t,J=8.4Hz,1H),7.33(dd,J1=0.8Hz,J2= 3.6Hz,1H),7.25(d,J=6.4Hz,2H),7.09-7.07(m,1H),7.04-6.99(m,2H),6. 92(dd,J1=1.2Hz,J2=8.4Hz,1H),5.35(br,1H),3.95(br,2H),1.11(s,9H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ155.1,151.7,150.5,144.7,143.8,132.9,130.8,130.2,128.9,128.4,128.1,125 .8,124.5,124.4,124.3,122.8,118.9,116.3,114.7,114.1,107.2,83.2,27.3.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 25 H 24 NO4S + 434.1421, found 434.1426. HPLC analysis: 99%ee, [CHIRALPAK OD-H column; 1.0mL / min; solvent system: i-PrOH / hexane=20 / 80; retention times: 12.2min (major), 20.4min (minor)].

[0080] Nuclear magnetic resonance (NMR) of the axially chiral biarylaminophenol compound (I-7) prepared in Example 15 1 H NMR and 13 The detection data for C NMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC) are as follows:

[0081]

[0082] 1H NMR (400MHz, CDCl3) δ7.74 (s, 1H), 7.73 (d, J = 8.8Hz, 1H), 7.59-7.52 (m, 3H), 7.43-7.33 (m, 3H), 7.26-7. 19(m,3H),7.11(d,J=16.0Hz,1H),7.05-6.98(m,2H),6.91(d,J=8.0Hz,1H),3.70(br,3H),1.11(s,9H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ155.1,151.7,150.5,143.8,137.6,133.2,131.9,130.9,130.2,128.8,128.7,128.4,127 .8,127.5,126.8,126.5,125.1,124.2,118.6,116.4,114.7,114.1,107.3,83.2,27.2.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 29 H 28 NO4 + 454.2013, found 454.2017. HPLC analysis: 99%ee, [CHIRALPAKOD-H column; 0.8mL / min; solvent system: i-PrOH / hexane=30 / 70; retention times: 11.9min (major), 25.9min (minor)].

[0083] Nuclear magnetic resonance (NMR) of the axially chiral biarylaminophenol compound (I-8) prepared in Example 16 1 H NMR and 13 The detection data for C NMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC) are as follows:

[0084]

[0085] 1 H NMR (400MHz, CDCl3) δ7.68(d,J=8.8Hz,1H),7.61(d,J=8.0Hz,1H),7.40(t,J=8.0Hz,1H),7 .09-7.03(m,2H),6.96-6.90(m,3H),5.13(br,1H),3.90(br,2H),2.33(s,3H),1.14(s,9H); 13 C{1 H}NMR (100MHz, CDCl3) δ155.1,151.8,150.5,143.7,137.0,133.8,130.5,130.0,127.8,126.5 ,125.0,122.8,117.3,116.6,114.7,113.8,106.3,83.1,27.2,22.1.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 22 H 24 NO4 + 366.1700, found 366.1697. HPLC analysis: 97%ee, [CHIRALPAK OD-H column; 1.0mL / min; solvent system: i-PrOH / hexane=20 / 80; retention times: 6.8min (major), 9.7min (minor)].

[0086] Nuclear magnetic resonance (NMR) of the axially chiral biarylaminophenol compound (I-9) prepared in Example 17 1 H NMR and 13 The detection data for C NMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC) are as follows:

[0087]

[0088] 1 H NMR(400MHz, CDCl3)δ7.70(t,J=9.6Hz,2H),7.50(t,J=3.6Hz,2H),7.45-7.30(m,6H) ,7.06-7.00(m,2H),6.93(d,J=8.0Hz,1H),5.14(br,1H),3.96(br,2H),1.15(s,9H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ155.1,151.7,150.5,144.3,133.3,131.7,130.6,130.4,128.3,128.2,128.1,127.6,12 7.1,125.6,123.4,122.0,118.9,116.0,114.8,114.1,106.7,90.4,89.8,83.2,27.3.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 29 H26 NO4 + 452.1856, found452.1858. HPLC analysis:>99%ee, [CHIRALPAK OD-H column; 0.8mL / min; solventsystem: i-PrOH / hexane=30 / 70; retention times: 10.7min (major), 20.3min (minor).].

[0089] Nuclear magnetic resonance (NMR) of the axially chiral biarylaminophenol compound (I-10) prepared in Example 18 1 H NMR and 13 The detection data for C NMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC) are as follows:

[0090]

[0091] 1 H NMR(400MHz, CDCl3)δ7.92(d,J=9.2Hz,1H),7.39(t,J=8.0Hz,1H),7.25-7.19(m,1H),7.10 -7.01(m,4H),6.90(d,J=8.4Hz,1H),5.15(br,1H),3.89(br,2H),2.66(s,3H),1.12(s,9H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ155.1,151.7,150.4,143.3,134.3,133.7,130.0,127.3,127.0,126.9 ,123.9,122.2,117.8,116.8,114.6,113.9,107.5,83.1,27.2,19.5.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 22 H 24 NO4 + 366.1700, found 366.1700. HPLC analysis: 98%ee, [CHIRALPAK ID column; 0.8mL / min; solvent system: i-PrOH / hexane=20 / 80; retention times: 7.8min (minor), 10.1min (major)].

[0092] Nuclear magnetic resonance (NMR) of the axially chiral biarylaminophenol compound (I-11) prepared in Example 19 1 H NMR and 13 The detection data for C NMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC) are as follows:

[0093]

[0094] 1 H NMR (400MHz, CDCl3) δ7.87(d,J=8.4Hz,1H),7.39(t,J=8.4Hz,1H),7.34-7.22(m,3H),7.01(d ,J=8.0Hz,1H),6.89(d,J=8.0Hz,2H),5.22(br,1H),3.85(br,2H),2.66(s,3H),1.11(s,9H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ155.2,151.7,150.6,143.2,137.3,133.7,130.0,127.7,127.0,124.2 ,124.1,122.6,119.1,116.6,114.6,113.8,105.0,83.0,27.2,19.5.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 22 H 24 NO4 + 366.1700, found366.1697. HPLC analysis: 98%ee, [CHIRALPAK OD-H column; 1.0mL / min; solventsystem: i-PrOH / hexane=20 / 80; retention times: 7.0min (major), 11.7min (minor)].

[0095] Nuclear magnetic resonance (NMR) of the axially chiral biarylaminophenol compound (I-12) prepared in Example 20 1 H NMR and 13 The detection data for C NMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC) are as follows:

[0096]

[0097] 1H NMR (400MHz, CDCl3) δ7.73(t,J=8.4Hz,2H),7.67(d,J=7.2Hz,2H),7.46(t,J=7.2Hz,2H),7.40-7. 23(m,5H),7.16(d,J=1.6Hz,1H),7.02(d,J=8.8Hz,1H),5.36(br,1H),4.00(br,2H),1.10(s,9H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ155.2,151.6,150.7,143,7,143.5,139.8,133.5,130.8,128.9,128.3,128.0, 127.4,127.1,123.8,122.9,118.2,115.3,113.5,112.5,107.0,83.1,27.2.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 27 H 26 NO4 + 428.1856, found 428.1860. HPLC analysis: 98%ee, [CHIRALPAK OD-H column; 1.0mL / min; solvent system: i-PrOH / hexane=20 / 80; retention times: 11.3.min (major), 18.8min (minor)].

[0098] The products obtained by this invention can be further deprotected and / or derivatized to obtain other known axially chiral compounds, as can be seen in Application Examples 1 and 2, but are not limited to these two examples.

[0099] Application Example 1:

[0100]

[0101] In a 100 mL dry Schlenk tube, I-1 (351.4 mg, 1 mmol), toluene (20 mL), and di-tert-butyl dicarbonate (327.4 mg, 1.5 mmol) were added sequentially. The mixture was heated to 80 °C and reacted for 48 hours. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The residue was separated by column chromatography (PE / EA = 5 / 1) to obtain product I-13 (383.3 mg, 0.85 mmol, 85% yield, 98% ee).

[0102] I-13 (90.3 mg, 0.2 mmol) and freshly prepared diazonium methyl ether solution (2.4 mL, 1.2 mmol) were added to a 10 mL dry Schlenk tube. After reacting at room temperature for 4 hours, the solvent was removed by rotary evaporation, and the residue was separated by column chromatography (PE / EA = 10 / 1) to obtain the intermediate.

[0103] The intermediate obtained above was dissolved in 4 mL of dichloromethane, and 0.2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with 10 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was separated by column chromatography (PE / EA = 2 / 1) to give the known compound I-14 (32.3 mg, 0.122 mmol, 61% yield, 97% ee in total). 1 H NMR(400MHz, CDCl3)δ7.24(d,J=8.4Hz,2H),7.36-7.20(m,4H),7.04(d,J=8.8Hz,1H), 6.76(d,J=8.0Hz,1H),6.65(d,J=8.4Hz,1H),4.94(br,1H),3.79(br,2H),3.66(s,3H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ158.7,154.9,143.2,133.8,130.3,130.2,128.3,128.2,127 .1,123.7,122.7,118.2,110.6,108.8,108.1,103.6,56.0.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 17 H 16 NO2 + 266.1176, found266.1177. HPLC analysis: 97%ee, [CHIRALPAK AD-H column; 0.8mL / min; solventsystem: i-PrOH / hexane=20 / 80; retention times: 20.2min (minor), 23.1min (major)].

[0104] Application Example 2:

[0105]

[0106] In a 10 mL dry Schlenk tube, I-13 (90.3 mg, 0.2 mmol), imidazole (27.2 mg, 0.4 mmol), N,N-dimethylpyridine (2.4 mg, 0.02 mmol), dichloromethane (2 mL), and tert-butyldimethylchlorosilane (60.3 mg, 0.4 mmol) were added sequentially. After reacting at room temperature for 12 hours, the solvent was removed by rotary evaporation, and the residue was separated by column chromatography (PE / EA = 10 / 1) to obtain the intermediate. The obtained intermediate was dissolved in 4 mL of dichloromethane, and 0.2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, 10 mL of saturated sodium bicarbonate solution was added, followed by extraction three times with 10 mL of ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the residue was separated by column chromatography (PE / EA = 3 / 1) to obtain the known compound I-15 (54.7 mg, 0.15 mmol, 75% yield and 98% ee in total). 1 H NMR (400MHz, CDCl3) δ7.63(d,J=8.4Hz,2H),7.24-7.13(m,4H),6.94(d,J=8.8Hz,1H),6.67(d,J=8.0 Hz,1H),6.51(d,J=8.1Hz,1H),4.86(br,1H),3.75(br,2H),0.36(s,9H),-0.10(s,3H),-0.27(s,3H); 13 C{ 1 H}NMR (100MHz, CDCl3) δ155.2,154.7,143.4,133.9,130.1,139.8,128.3,128.1,126.9,124.0 ,122.5,118.1,114.1,111.9,108.8,108.7,25.0,17.6,-4.4,-4.7.HRMS(ESI-TOF)m / z:[M+H] + calcd.for C 22 H 28 NO2Si + 366.1884, found 366.1887. HPLC analysis: 98%ee, [CHIRALPAK AD-H column; 0.8mL / min; solvent system: i-PrOH / hexane=10 / 90; retention times: 8.1min (minor), 9.4min (major)].

Claims

1. A method for preparing an axially chiral biarylaminophenol compound, characterized in that, The process includes the following steps: adding biarylaminodiphenol, ditert-butyl dicarbonate and chiral isothiourea catalyst into an organic solvent, cooling to -10 to -30°C to carry out the reaction, and after the reaction is complete, post-treatment is performed to obtain the axially chiral biarylaminophenol compound. The structure of the biarylaminodiphenol is shown in formula (II): The structure of the ditert-butyl dicarbonate is shown in formula (III): The structure of the chiral isothiourea catalyst is shown in formula (IV): The structure of the axially chiral biarylaminophenol compound is shown in formula (I): In equations (I) to (II), R 1 It can be H, C1-C4 alkyl, C3-C6 cycloalkyl, halogen, substituted or unsubstituted phenyl, naphthyl, heterocyclic, substituted or unsubstituted C2-C6 alkynyl, or substituted or unsubstituted C2-C6 alkenyl. R 2 It is H, C1-C4 alkyl, substituted or unsubstituted phenyl; The substituents on the phenyl group are selected from C1-C4 alkoxy or trifluoromethyl groups; The substituent on the C2-C6 alkynyl group or the C2-C6 alkenyl group is phenyl.

2. The method for preparing the axially chiral biarylaminophenol compound according to claim 1, characterized in that, R 1 It can be 6-methyl, 6-cyclopropyl, 6-bromo, 6-phenyl, 6-p-methoxyphenyl, 6-p-trifluoromethylphenyl, 6-(2-naphthyl), 6-(2-furanyl), 6-(2-thienyl), 6-phenylethynyl, 6-styryl, 6-vinyl, 7-methyl, 7-(2-furanyl), 7-phenylethynyl, 5-methyl, 4-methyl, or 3-methyl.

3. The method for preparing the axially chiral biarylaminophenol compound according to claim 1, characterized in that, R 2 It can be H, methyl, or phenyl.

4. The method for preparing the axially chiral biarylaminophenol compound according to claim 1, characterized in that, In molar amounts, the ratio of biarylaminodiphenol : ditert-butyl dicarbonate : chiral isothiourea catalyst = 1: 1.0～1.1：0.02～0.05。 5. The method for preparing the axially chiral biarylaminophenol compound according to claim 1, characterized in that, The reaction temperature is -20℃.

6. The method for preparing the axially chiral biarylaminophenol compound according to claim 1, characterized in that, The reaction time is 48 to 96 hours.

7. The method for preparing the axially chiral biarylaminophenol compound according to claim 1, characterized in that, The organic solvent is diethyl ether.

8. The method for preparing the axially chiral biarylaminophenol compound according to claim 1, characterized in that, The axially chiral biarylaminophenol compound is one of the compounds shown in formulas (I-1) to (I-12):

9. The application of the preparation method according to any one of claims 1 to 8, characterized in that, include: (1) A chiral biarylaminophenol compound is obtained by the preparation method according to any one of claims 1 to 8; The axially chiral biarylaminophenol compound is the compound shown in formula (I-1); (2) The axially chiral biarylaminophenol compound obtained in step (1) is subjected to Boc protection, derivatization and deprotection to obtain axially chiral biarylaminophenol derivatives I-14 or I-15. The derivatization is either methylation or silanization.

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