Asymmetric hydrogenation kinetic resolution method of racemic polysubstituted three-membered cyclic imine

Abstract

The invention relates to the field of asymmetric catalytic hydrogenation, in particular to an asymmetric hydrogenation kinetic resolution method of racemic polysubstituted three-membered ring imine, which is characterized by comprising the following steps: in the presence of a chiral diamine metal catalyst, carrying out asymmetric hydrogenation kinetic resolution on racemic polysubstituted three-membered ring imine; the method comprises the following steps: carrying out asymmetric hydrogenation treatment on a mixture containing enantiomers of the multi-substituted three-membered cyclic imine compound by adopting hydrogen to obtain a single optical isomer of the multi-substituted chiral aziridine compound and / or the multi-substituted chiral three-membered cyclic imine compound; wherein the polysubstituted three-membered cyclic imine compound is a compound as shown in a formula (1), and the polysubstituted chiral aziridine compound is a compound as shown in a formula (2). According to the method disclosed by the invention, the resolution of the racemic polysubstituted three-membered cyclic imine compound is realized in an asymmetric hydrogenation manner, and a polysubstituted chiral aziridine compound with certain optical purity and a single optical isomer of the polysubstituted chiral three-membered cyclic imine compound can be obtained at the same time.

Description

Technical Field

[0001] This invention relates to the field of asymmetric catalytic hydrogenation, specifically to an asymmetric hydrogenation kinetic resolution method for racemic multisubstituted three-membered cyclic imines. Background Technology

[0002] Optically pure aziridine skeletons are widely found in natural products and drugs (JBSweeney, Chem. Soc. Rev. 2002, 31, 247; L. Degennaro, P. Trinchera, R. Luisi, Chem. Rev. 2014, 114, 7881; GSSingh, Med. Chem. 2016, 16, 892), and their asymmetric synthesis has attracted widespread attention from scientists. Currently, chiral aziridines can be effectively prepared and chiral three-membered cyclic imines recovered via asymmetric addition kinetics resolution of three-membered cyclic imines, but related reports are very limited (H.Hu, Y.Liu, L.Lin, Y.Zhang, X.Liu, X.Feng, Angew. Chem. Int. Ed. 2016, 55, 10098; D.An, X.Guan, R.Guan, L.Jin, G.Zhang, S.Zhang, Chem. Commun. 2016, 52, 11211; H.Hu, J.Xu, W.Liu ,S. Dong, L. Lin, eng,D.Guo,B.Zhang,L.Liu,J.Wang,Chem.Commun.2020,56,12427;Y.-L.Pan,Y.-B.Shao,J.Wang,Z.Liu,L.Chen,X.Li,ACS Catal. 2021, 11, 13752; F. Xie, J. Zhao, D. Ren, J. Xue, J. Wang, Q. Zhao, L. Liu, X. Liu, Org. Lett. 2023, 25, 8530). Direct asymmetric hydrogenation of three-membered cyclic imines is undoubtedly the most direct and efficient method for preparing chiral aziridines. However, due to the high ring strain of the three-membered ring, ring-opening is easily achieved during metal-involved hydrogenation reactions, resulting in only the yield of enamine byproducts. In the prior art, asymmetric hydrogenation of three-membered cyclic imines has not been reported, and asymmetric hydrogenation of perfluoroalkyl-substituted three-membered cyclic imines with very high bioactive modification properties has even less been reported.

[0003] Therefore, developing a novel, efficient asymmetric synthesis method for chiral azircyclic propanes that does not use expensive chiral starting materials or chiral resolving reagents, is simple to operate, has high product yields, a wide substrate range, and high product optical purity is an urgent problem to be solved in this field. Summary of the Invention

[0004] The purpose of this invention is to provide an efficient asymmetric hydrogenation kinetic resolution method for racemic multisubstituted three-membered cyclic imines, thereby providing a new method for the high enantioselective synthesis of multisubstituted chiral aziridine compounds and corresponding multisubstituted chiral three-membered cyclic imine compounds.

[0005] To achieve the above objectives, the present invention provides an asymmetric hydrogenation kinetic resolution method for racemic multi-substituted three-membered cyclic imines. The method includes: asymmetric hydrogenation treatment of a mixture containing enantiomers of multi-substituted three-membered cyclic imines with hydrogen in the presence of a chiral diamine metal catalyst to obtain a single optical isomer of a multi-substituted chiral aziridine compound and / or a multi-substituted chiral three-membered cyclic imine compound; wherein the multi-substituted three-membered cyclic imine compound is a compound represented by formula (1), and the multi-substituted chiral aziridine compound is a compound represented by formula (2).

[0006]

[0007] Among them, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-Cl o The cycloalkyl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted aryl, and substituted or unsubstituted arylbenzyl; wherein the substituted C1-C 10 Alkyl, substituted C1-C 10 alkoxy groups, substituted C3-C 10 The substituents in the cycloalkyl, substituted heterocyclic aryl, substituted aryl, and substituted aryl benzyl groups are each independently selected from one or more of halogen, nitro, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C2-C6 amide groups.

[0008] A second aspect of the present invention provides a multisubstituted chiral azacyclic propane compound, wherein the multisubstituted chiral azacyclic propane compound is a compound represented by formula (2):

[0009] Among them, R 1 and R 2The choice of functional groups is as described above.

[0010] A third aspect of the present invention provides a multisubstituted chiral three-membered cyclic imine compound, wherein the multisubstituted chiral three-membered cyclic imine compound is a single optical isomer of the multisubstituted three-membered cyclic imine compound shown in formula (1):

[0011] Among them, R 1 and R 2 The choice of functional groups is as described above.

[0012] The method of this invention achieves kinetic resolution of mixtures of enantiomers of multi-substituted three-membered cyclic imine compounds, particularly racemic mixtures of enantiomers of multi-substituted three-membered cyclic imine compounds, through asymmetric hydrogenation catalyzed by a chiral diamine metal catalyst. This method can simultaneously yield single optical isomers of multi-substituted chiral aziridine compounds and multi-substituted chiral three-membered cyclic imine compounds with a certain optical purity. The method of this invention has advantages such as simple and easy operation, mild conditions, high reaction efficiency, high enantioselectivity, and high resolution coefficient. Detailed Implementation

[0013] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0014] The present invention provides an asymmetric hydrogenation kinetic resolution method for racemic multi-substituted three-membered cyclic imines. The method includes: asymmetric hydrogenation treatment of a mixture containing enantiomers of multi-substituted three-membered cyclic imines with hydrogen in the presence of a chiral diamine metal catalyst to obtain a single optical isomer of a multi-substituted chiral aziridine compound and / or a multi-substituted chiral three-membered cyclic imine compound; wherein the multi-substituted three-membered cyclic imine compound is a compound represented by formula (1), and the multi-substituted chiral aziridine compound is a compound represented by formula (2).

[0015]

[0016] Among them, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10The cycloalkyl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted aryl, and substituted or unsubstituted arylbenzyl; wherein the substituted C1-C 10 Alkyl, substituted C1-C 10 alkoxy groups, substituted C3-C 10 The substituents in the cycloalkyl, substituted heterocyclic aryl, substituted aryl, and substituted aryl benzyl groups are each independently selected from one or more of halogen, nitro, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C2-C6 amide groups.

[0017] According to the present invention, preferably, R 1 and R 2 Each of the substituents is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted aryl, and substituted or unsubstituted arylbenzyl; wherein the substituents in the substituted C1-C6 alkyl, substituted C1-C6 alkoxy, substituted C3-C6 cycloalkyl, substituted heterocyclic aryl, substituted aryl, and substituted arylbenzyl are each independently selected from one or more of halogen, nitro, hydroxyl, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C2-C4 amide.

[0018] More preferably, R 1 and R 2 Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, perfluoromethyl, perfluoroethyl, perfluoron-propyl, perfluoron-butyl, cyclopentyl, cyclohexyl, perfluorocyclopentyl, perfluorocyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, substituted or unsubstituted thiophene, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, and substituted or unsubstituted benzyl; wherein, substituted thiophene, substituted phenyl, The substituents in the substituted naphthyl and substituted benzyl groups are each independently selected from one or more of the following: fluorine, chlorine, bromine, iodine, nitro, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -CF3, -CCl3, -CBr3, -CH2CF3, -CH2CCl3, -CH2CBr3, -NH-CO-CH3, and -NH-CO-CH2CH3.

[0019] According to the present invention, in order to prepare multi-substituted chiral aziridine compounds by cooperating with a chiral diamine metal catalyst, preferably, in formula (2), R 1 and R 2 It is a cis substitution.

[0020] According to the present invention, the hydrogenation substrate is a mixture containing enantiomers of a polysubstituted three-membered ring imine compound, wherein the mixture has at least one pair of enantiomers, and in particular the mixture is a racemic mixture. The method of the present invention can resolve a single optical isomer of a polysubstituted chiral three-membered ring imine compound from such a mixture, and simultaneously prepare a polysubstituted chiral aziridine compound.

[0021] According to the present invention, the 2-position in the compound represented by formula (1) can be a chiral carbon site, which can be either R-configuration or S-configuration. The mixture containing enantiomers of polysubstituted three-membered ring imine compounds can be a mixture of 2R-optical configuration and 2S-optical configuration. The above mixture can be a commercially available product or a racemic mixture of enantiomers of polysubstituted three-membered ring imine compounds prepared by conventional methods in the art. The present invention does not have any particular limitation in this regard. For example, it can be prepared using the following synthetic route:

[0022]

[0023] In the above synthetic route, Rz represents a substituted or unsubstituted heterocyclic aryl group and a substituted or unsubstituted aryl group; Rx represents a substituted or unsubstituted alkyl group and a substituted or unsubstituted arylbenzyl group; and Rf represents a perfluoroalkyl group. The specific groups chosen for Rz, Rx, and Rf are the same as those for R in the above synthetic route. 1 and R 2 Maintain consistency.

[0024] According to a preferred embodiment of the present invention, the polysubstituted three-membered ring imine compound represented by formula (1) is selected from the compounds represented by the following formula:

[0025]

[0026]

[0027] According to a preferred embodiment of the present invention, the multisubstituted chiral three-membered cyclic imine compound is a single optical isomer of the multisubstituted three-membered cyclic imine compound shown in formula (1), and is selected from compounds shown in the following formula:

[0028]

[0029]

[0030] According to a preferred embodiment of the present invention, the polysubstituted chiral aziridine compound is selected from compounds represented by the following formula:

[0031]

[0032]

[0033] In these compounds (2-9) to (2-15) and (2-34) to (2-40), the Boc group attached to the N position is only used as a protecting group to maintain the stability of the compound structure. These compounds differ from the structure shown in formula (2) because the Boc group replaces H, but they are still within the range of compounds shown in formula (2).

[0034] According to the present invention, the chiral diamine metal catalyst is selected from one or more compounds with structures shown in formula (4) and formula (5):

[0035]

[0036] In equations (4) and (5), metal M is independently selected from ruthenium, rhodium, and iridium; L1 is independently selected from substituted or unsubstituted η. 6 -Benzene ligand and substituted or unsubstituted η 5 - A cyclohexane ligand, and the substituents present in L1 are each independently selected from C1-C1. 10 One or more of the alkyl groups; L2 is selected from C1-C 10 Oxygen-containing alkylene and sulfur-containing alkylene; X is independently selected from Cl - ,Br - I - CH3COO - NO3 - HSO4 - H2PO4 - BF4 - SbF6 - PF6 - , di(trifluoromethanesulfonyl)imide anion, trifluoromethanesulfonic acid anion, substituted or unsubstituted C 24 -C 32 Tetraarylboron anion, substituted or unsubstituted C 12 -C 36 Diaryl phosphate anions and substituted or unsubstituted C 12 -C 36 The phosphate anion derived from biaryl diol, wherein the substituents optionally present in X are each independently selected from one or more of fluorine, chlorine, bromine, nitro, methyl, ethyl, methoxy, trifluoromethyl, hydroxy and acetamido.

[0037] According to the present invention, the groups in formula (4) and formula (5) are each independently selected from the representations. That is, the groups in formula (4) and formula (5) that are also represented by metals M, L1, X, R' and R” can be the same or different. For example, when X in formula (4) is selected from BF4 - In this case, X in equation (5) can be BF4. - It can also be selected from other groups such as Cl. - SbF6 - PF6 - Examples include bis(trifluoromethanesulfonyl)imide anions and trifluoromethanesulfonic acid anions.

[0038] According to the present invention, the chiral diamine metal catalyst is a ruthenium (Ru), rhodium (Rh), or iridium (Ir) complex with the structure shown in formulas (4) and (5), wherein, as one of the ligands, It is formed by the diamine NHR”-linker arm -NHSO2R', wherein the N at one end of -NHSO2R' forms a covalent bond with the metal M, and the N at one end of NHR”- forms a coordinate bond with the metal M, thereby forming the compounds shown in formula (4) and formula (5). The linker arm in the diamine NHR”-linker arm -NHSO2R' can make the carbon atom connected to the N at the NHR”-end and / or the carbon atom connected to the N at the -NHSO2R' end of the linker arm a chiral center, thereby making the compounds with the structures shown in formula (4) and formula (5) have certain catalytic selectivity, especially the (R,R)-configuration, (S,S)-configuration, (R)-configuration and (S)-configuration of these compounds are suitable for catalyzing the compounds with the structure shown in formula (1). For example, when (R,R) or (R)-chiral diamine NHR”-linker-NHSO2R’ is used as a chiral catalyst, the enantiomeric excess of the compound with the structure shown in (S,S)-formation (2) is usually increased, while when (S,S) or (S)-chiral diamine NHR”-linker-NHSO2R’ is used as a chiral catalyst, the enantiomeric excess of the compound with the structure shown in (R,R)-formation (2) is usually increased. Generally, the catalytic effects of a pair of enantiomeric catalysts are opposite. For example, if the catalytic effect of (R,R)-type catalyst is to increase the product content of (S,S)-type catalyst, then the catalytic effect of (S,S)-type catalyst is to increase the product content of (R,R)-type catalyst.

[0039] According to the present invention, the ligands in equations (4) and (5) are defined For example, equation (6);

[0040] The compounds forming the ligands shown in formula (6) are selected from one or more of the following compounds:

[0041]

[0042] Ar1 and Ar2 are each independently selected from substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl groups; and the substituents optionally present in Ar1 and Ar2 are each independently selected from at least one of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, halogen atom, hydroxyl and carboxyl groups.

[0043] R is selected from C1-C8 alkyl, trifluoromethyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, and the substituents optionally present in R are each independently selected from one or more of C1-C8 alkyl, methoxy, fluorine, chlorine, bromine, nitro and trifluoromethyl.

[0044] R' is selected from C1-C 10 The alkyl, trifluoromethyl, substituted amino, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl groups, wherein the substituents optionally present in R' are each independently selected from C. 1-10 One or more of the following: alkyl, methoxy, fluorine, chlorine, bromine, nitro, and trifluoromethyl;

[0045] R" is selected from H, substituted or unsubstituted benzyl, and C1-C. 10 The alkyl group, and the substituents optionally present in "R" are each independently selected from C1-C2. 10 One or more of the following: alkyl, methoxy, fluorine, chlorine, bromine, nitro, and trifluoromethyl.

[0046] According to the present invention, the compounds with the structure shown in formula (I-1) above are (R,R)-N-monosulfonyl-diarylethylenediamine compounds, and examples of such compounds include:

[0047]

[0048] Compounds with the structure shown in formula (I-2) above are (R,R)-N-monosulfonyl-cyclohexanediamine compounds. Examples of such compounds include:

[0049]

[0050] The compounds with the structure shown in formula (I-3) above are (R,R)-N-monosulfonyl-1-substituted pyrrole-3,4-diamine compounds.

[0051] The compounds with the structure shown in formula (I-4) above are (R)-N-monosulfonyl-2,2'-diamino-1,1'-binaphthyldiamine compounds.

[0052] Compounds with the structure shown in formula (I-5) above are (S,S)-N-monosulfonyl-diarylethylenediamine compounds. Examples of such compounds include:

[0053]

[0054]

[0055] Where iPr represents isopropyl.

[0056] Compounds with the structure shown in formula (I-6) above are (S,S)-N-monosulfonyl-cyclohexanediamine compounds. Examples of such compounds include:

[0057]

[0058] The compounds with the structure shown in formula (I-7) above are (S,S)-N-monosulfonyl-1-substituted pyrrole-3,4-diamine compounds.

[0059] The compounds with the structure shown in formula (I-8) above are (S)-N-monosulfonyl-2,2'-diamino-1,1'-binaphthyldiamine compounds.

[0060] According to the present invention, in the compounds with the structures shown in formulas (4) and (5) above, L1, as another ligand, provides a 6- or 5-coordinated spatial coordination structure for the metal M. Such coordination contributes to the high chemical stability of the compounds with the structure shown in formula (4), thereby helping them to exert efficient and highly enantioselective catalytic activity when used as chiral catalysts of the present invention. Preferably, L1 is independently selected from n. 6 -Benzene ligand, η 6 -1,4-Dimethylbenzene ligand, η 6 -1-Methyl-4-isopropylphenyl ligand, η 6 -1,3,5,-Trimethylbenzene ligand, η 6 -1,2,3,4,5-pentamethylbenzene ligand, η 6 -1,2,3,4,5,6-Hexamethylbenzene ligand, η 5 -Maocene ligand and eta 5 - Pentamethylcyclohexane ligand. More preferably, L1 is selected from η 6 -1-Methyl-4-isopropylphenyl ligand and η 6 -1,2,3,4,5,6-Hexamethylbenzene ligand.

[0061] According to the present invention, in the compound with the structure shown in formula (5), preferably, L2 is selected from C1-C6 oxyalkylene and sulfalkylene. More preferably, L2 is selected from -CH2-O-CH2-CH2-, -CH2-O-CH2-CH2-CH2-CH2- and -CH2-S-CH2-CH2-.

[0062] According to the present invention, in the compounds with the structures shown in formulas (4) and (5), preferably, X is independently selected from Cl. - BF4 - PF6 - SbF6 - , di(trifluoromethanesulfonyl)imide anion, trifluoromethanesulfonic acid anion, substituted or unsubstituted C 24 -C 32 Tetraarylboron anion, substituted or unsubstituted C 12 -C 36 Diaryl phosphate anions and substituted or unsubstituted C 12 -C 36 The phosphate anion derived from biaryl diol, wherein the substituents optionally present in X are each independently selected from one or more of fluorine, chlorine, bromine, nitro, methyl, ethyl, methoxy, trifluoromethyl, hydroxy and acetamido.

[0063] More preferably, X is independently selected from Cl - BF4 - PF6 - SbF6 - The following are anions with structures shown in formulas (II-1) to (II-5): bis(trifluoromethanesulfonyl)imide anion, trifluoromethanesulfonic acid anion, tetraphenylboron anion, tetra(3,5-bis(trifluoromethyl)phenyl)boron anion, diphenyl phosphate anion, di-p-methylphenyl phosphate anion, di(2,4,6-trimethylphenyl) phosphate anion, di-p-methoxyphenyl phosphate anion, di-p-fluoromethylphenyl phosphate anion, di-p-trifluoromethylphenyl phosphate anion, and anions with structures shown in formulas (II-1) to (II-5).

[0064]

[0065]

[0066] Among them, the structure shown in formula (II-1) is 2,2'-biphenyl phosphate anion, the structure shown in formula (II-2) is (R)-2,2'-bidinaphthyl phosphate anion, the structure shown in formula (II-3) is (S)-2,2'-bidinaphthyl phosphate anion, the structure shown in formula (II-4) is (R)-8H-2,2'-bidinaphthyl phosphate anion, and the structure shown in formula (II-5) is (S)-8H-2,2'-bidinaphthyl phosphate anion.

[0067] According to a preferred embodiment of the present invention, the chiral diamine metal catalyst is selected from the structure shown in the following formula:

[0068]

[0069]

[0070] X is selected from trifluoromethanesulfonic acid anions and BF4. - PF6 - SbF6 - The anions are: bis(trifluoromethanesulfonyl)imide, tetra(3,5-bis(trifluoromethyl)phenyl)boron, diphenyl phosphate, 2,2'-biphenyl phosphate, (R)-2,2'-bidinaphthyl phosphate and (S)-2,2'-bidinaphthyl phosphate.

[0071] According to the present invention, in the above preferred embodiment, the trifluoromethanesulfonic acid anion is defined as α,BF4. - b, PF6 - c, SbF6 - If d is the bis(trifluoromethanesulfonyl)imide anion, e is the tetrakis(3,5-bis(trifluoromethyl)phenyl)boron anion, f is the diphenyl phosphate anion, g is the 2,2'-biphenyl phosphate anion, h is the (R)-2,2'-bidinaphthyl phosphate anion, i is the (S)-2,2'-bidinaphthyl phosphate anion, and j is the (S)-2,2'-bidinaphthyl phosphate anion, then the chiral diamine metal catalyst of the above preferred embodiment can be obtained by selecting one or more of the following compounds:

[0072] (R,R)-4a、(R,R)-4b、(R,R)-4c、(R,R)-4d、(R,R)-4e、(R,R)-4f、(R,R)-4g、(R,R)-4h、(R,R)-4i、(R,R)-4j、(R,R)-5a、(R,R)-5b、(R,R)-5c、(R,R)-5d、(R,R)-5e、(R,R)-5f、(R,R)-5g、(R,R)-5h、(R,R)-5i、(R,R)-5j、(R,R)-6a、(R,R)-6b、(R,R)-6c、(R,R)-6d、(R,R)-6e、(R,R)-6f、(R,R)-6g、(R,R)-6h、(R,R)-6i、(R,R)-6j、(R,R)-7a、(R,R)-7b、(R,R)-7c、(R,R)-7d、(R,R)-7e、(R,R)-7f、(R,R)-7g、(R,R)-7h、(R,R)-7i、(R,R)-7j、(R,R)-8a、(R,R)-8b、(R,R)-8c、(R,R)-8d、(R,R)-8e、(R,R)-8f、(R,R)-8g、(R,R)-8h、(R,R)-8i、(R,R)-8j、(R,R)-9a、(R,R)-9b、(R,R)-9c、(R,R)-9d、(R,R)-9e、(R,R)-9f、(R,R)-9g、(R,R)-9h、(R,R)-9i、(R,R)-9j、(R,R)-10a、(R,R)-10b、(R,R)-10c、(R,R)-10d、(R,R)-10e、(R,R)-10f、(R,R)-10g、(R,R)-10h、(R,R)-10i、(R,R)-10j、(R,R)-11a、(R,R)-11b、(R,R)-11c、(R,R)-11d、(R,R)-11e、(R,R)-11f、(R,R)-11g、(R,R)-11h、(R,R)-11i、(R,R)-11j、(R,R)-12a、(R,R)-12b、(R,R)-12c、(R,R)-12d、(R,R)-12e、(R,R)-12f、(R,R)-12g、(R,R)-12h、(R,R)-12i、(R,R)-12j、(R,R)-13a、(R,R)-13b、(R,R)-13c、(R,R)-13d、(R,R)-13e、(R,R)-13f、(R,R)-13g、(R,R)-13h、(R,R)-13i、(R,R)-13j、(R,R)-14a、(R,R)-14b、(R,R)-14c、(R,R)-14d、(R,R)-14e、(R,R)-14f、(R,R)-14g、(R,R)-14h、(R,R)-14i、(R,R)-14j、(R,R)-15a、(R,R)-15b、(R,R)-15c、(R,R)-15d、(R,R)-15e、(R,R)-15f、(R,R)-15g、(R,R)-15h、(R,R)-15i、(R,R)-15j、(R,R)-16a、(R,R)-16b、(R,R)-16c、(R,R)-16d、(R,R)-16e、(R,R)-16f、(R,R)-16g、(R,R)-16h、(R,R)-16i、(R,R)-16j、(R,R)-17a、(R,R)-17b、(R,R)-17c、(R,R)-17d、(R,R)-17e、(R,R)-17f、(R,R)-17g、(R,R)-17h、(R,R)-17i、(R,R)-17j、(R,R)-18a、(R,R)-18b、(R,R)-18c、(R,R)-18d、(R,R)-18e、(R,R)-18f、(R,R)-18g、(R,R)-18h、(R,R)-18i、(R,R)-18j、(R,R)-19a、(R,R)-19b、(R,R)-19c、(R,R)-19d、(R,R)-19e、(R,R)-19f、(R,R)-19g、(R,R)-19h、(R,R)-19i、(R,R)-19j、20a、20b、20c、20d、20e、20f、20g、20h、20i、20j、(S,S)-4a、(S,S)-4b、(S,S)-4c、(S,S)-4d、(S,S)-4e、(S,S)-4f、(S,S)-4g、(S,S)-4h、(S,S)-4i、(S,S)-4j、(S,S)-5a、(S,S)-5b、(S,S)-5c、(S,S)-5d、(S,S)-5e、(S,S)-5f、(S,S)-5g、(S,S)-5h、(S,S)-5i、(S,S)-5j、(S,S)-6a、(S,S)-6b、(S,S)-6c、(S,S)-6d、(S,S)-6e、(S,S)-6f、(S,S)-6g、(S,S)-6h、(S,S)-6i、(S,S)-6j、(S,S)-7a、(S,S)-7b、(S,S)-7c、(S,S)-7d、(S,S)-7e、(S,S)-7f、(S,S)-7g、(S,S)-7h、(S,S)-7i、(S,S)-7j、(S,S)-8a、(S,S)-8b、(S,S)-8c、(S,S)-8d、(S,S)-8e、(S,S)-8f、(S,S)-8g、(S,S)-8h、(S,S)-8i、(S,S)-8j、(S,S)-9a、(S,S)-9b、(S,S)-9c、(S,S)-9d、(S,S)-9e、(S,S)-9f、(S,S)-9g、(S,S)-9h、(S,S)-9i、(S,S)-9j、(S,S)-10a、(S,S)-10b、(S,S)-10c、(S,S)-10d、(S,S)-10e、(S,S)-10f、(S,S)-10g、(S,S)-10h、(S,S)-10i、(S,S)-10j、(S,S)-11a、(S,S)-11b、(S,S)-11c、(S,S)-11d、(S,S)-11e、(S,S)-11f、(S,S)-11g、(S,S)-11h、(S,S)-11i、(S,S)-11j、(S,S)-12a、(S,S)-12b、(S,S)-12c、(S,S)-12d、(S,S)-12e、(S,S)-12f、(S,S)-12g、(S,S)-12h、(S,S)-12i、(S,S)-12j、(S,S)-13a、(S,S)-13b、(S,S)-13c、(S,S)-13d、(S,S)-13e、(S,S)-13f、(S,S)-13g、(S,S)-13h、(S,S)-13i、(S,S)-13j、(S,S)-14a、(S,S)-14b、(S,S)-14c、(S,S)-14d、(S,S)-14e、(S,S)-14f、(S,S)-14g、(S,S)-14h、(S,S)-14i、(S,S)-14j、(S,S)-15a、(S,S)-15b、(S,S)-15c、(S,S)-15d、(S,S)-15e、(S,S)-15f、(S,S)-15g、(S,S)-15h、(S,S)-15i、(S,S)-15j、(S,S)-16a、(S,S)-16b、(S,S)-16c、(S,S)-16d、(S,S)-16e、(S,S)-16f、(S,S)-16g、(S,S)-16h、(S,S)-16i、(S,S)-16j、(S,S)-17a、(S,S)-17b、(S,S)-17c、(S,S)-17d、(S,S)-17e、(S,S)-17f、(S,S)-17g、(S,S)-17h、(S,S)-17i、(S,S)-17j、(S,S)-18a、(S,S)-18b、(S,S)-18c、(S,S)-18d、(S,S)-18e、(S,S)-18f、(S,S)-18g, (S,S)-18h, (S,S)-18i, (S,S)-18j, (S,S)-19a, (S,S)-19b, (S,S)-19c, ( S,S)-19d, (S,S)-19e, (S,S)-19f, (S,S)-19g, (S,S)-19h, (S,S)-19i, (S,S)-19j. ,

[0073] The above compound formulas are illustrated by example. For instance, (R,R)-4a refers to a compound having the above (R,R)-4 structure and wherein X is a trifluoromethanesulfonic acid anion.

[0074] According to the present invention, in order to improve the hydrogenation conversion rate of the compound shown in formula (1), preferably, in the compound shown in the above simplified formula, X is selected from a, b, c, d, f and g. In order to simultaneously improve the hydrogenation conversion rate and enantiomeric excess value of the compound with the structure shown in formula (1), preferably, X is selected from g, wherein, particularly preferably, one or more of (R,R)-4g, (R,R)-5g, and their enantiomeric counterparts (S,S)-4g, (S,S)-5g are used as the chiral diamine metal catalyst of the present invention.

[0075] According to the present invention, the chiral diamine metal catalyst can be prepared by conventional methods in the art, such as those disclosed in CN105111208A and CN103080118B, and the present invention does not have any particular limitation thereto.

[0076] According to the present invention, in the asymmetric hydrogenation process, the amounts of the chiral diamine metal catalyst and the compound shown in formula (1) can be selected within a wide range. In order to optimize the catalytic activity of the chiral diamine metal catalyst on the compound shown in formula (1), preferably, the amount of the compound shown in formula (1) relative to 1 mol of the chiral diamine metal catalyst can be 10-2000 mol, preferably 20-500 mol, more preferably 50-200 mol, for example, 55 mol, 90 mol, 120 mol and 195 mol and any value between them.

[0077] According to the present invention, the reaction conditions for the asymmetric hydrogenation treatment can be selected within a wide range. To better complement the catalytic effect of the chiral diamine metal catalyst on the substrate and thus improve the hydrogenation conversion rate, the conditions for the asymmetric hydrogenation treatment preferably include: a hydrogen pressure of 1-100 atm, preferably 5-80 atm, for example, values ​​such as 8 atm, 26 atm, 55 atm, and 76 atm, and any range thereof; a temperature of -10°C to 100°C, preferably 0°C to 60°C, for example, values ​​such as 5°C, 22°C, 47°C, and 58°C, and any range thereof; and a time of 0.5-72 h, preferably 0.5-20 h, for example, values ​​such as 0.8 h, 6 h, 11 h, and 19 h, and any range thereof.

[0078] According to the present invention, the reaction solvent for the asymmetric hydrogenation treatment can be selected from a wide range. To improve the dissolution of the reaction substrate and facilitate the reaction process and post-treatment, the solvent for the asymmetric hydrogenation treatment is preferably selected from [BMIM]PF6, dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, tetrahydrofuran, benzene, toluene, xylene, chlorobenzene, diethyl ether, dioxane, acetone, and C1-C4. 10 One or more of the monohydric alcohols, preferably one or more of methanol, ethanol, isopropanol, n-butanol, dichloromethane, tetrahydrofuran, toluene, ethyl acetate and acetone.

[0079] According to another preferred embodiment of the present invention, the solvent may also be selected from at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, benzene, toluene, xylene, chlorobenzene, and C1-C4. 10 The mixed solvent of monohydric alcohols may be selected, for example, a mixed solvent of isopropanol and toluene in a volume ratio of 1-2:1 and a mixed solvent of isopropanol and dichloromethane in a volume ratio of 1-2:1.

[0080] According to the present invention, in order to improve the reaction efficiency of asymmetric hydrogenation, it is necessary to control the concentration of the hydrogenation substrate. Preferably, the amount of the compound shown in formula (1) is 0.1-1 mmol, preferably 0.1-0.6 mmol, relative to 1 mL of the solvent. For example, it can be 0.2 mmol, 0.32 mmol, 0.48 mmol and 0.57 mmol, or any value between these values.

[0081] A second aspect of the present invention provides a multisubstituted chiral azacyclic propane compound, wherein the multisubstituted chiral azacyclic propane compound is a compound represented by formula (2):

[0082] Among them, R 1 and R2 The choice of functional groups is as described above, and the specific compounds are as described above, so they will not be repeated here.

[0083] A third aspect of the present invention provides a multisubstituted chiral three-membered cyclic imine compound, wherein the multisubstituted chiral three-membered cyclic imine compound is a single optical isomer of the multisubstituted three-membered cyclic imine compound shown in formula (1):

[0084] Among them, R 1 and R 2 The choice of functional groups is as described above, and the specific compounds are as described above, so they will not be repeated here.

[0085] The technical solution of this invention can obtain polysubstituted chiral aziridines with an enantiomeric excess of up to 98% and a diastereomer excess of over 99%. Furthermore, this invention can also obtain polysubstituted chiral three-membered cyclic imines with an enantiomeric excess of over 99% and a diastereomer excess of over 99%. The technical solution of this invention fills the gap in the prior art and has the advantages of simple and easy operation, mild conditions, high reaction efficiency, high enantioselectivity, and high resolution coefficient.

[0086] The present invention will be described in detail below through embodiments.

[0087] In the following examples:

[0088] The conversion rate of the reaction = [converted reactants] / ([converted reactants] + [unconverted reactants]) × 100%. The conversion rate of the asymmetric catalytic hydrogenation reaction of the compound represented by formula (1) of this invention is obtained by directly performing a hydrogen nuclear magnetic resonance spectrum (HMR) on the mixture of asymmetric catalytic hydrogenation reaction products before purification. 1 In the H-NMR analysis, the peak area of ​​the characteristic peak of the unreacted compound represented by formula (1) and the peak area of ​​the characteristic peak of the converted product are regarded as the concentration (weight percentage) of the unreacted reactant and the converted reactant, respectively, and the conversion rate is calculated according to the above formula.

[0089] For hydrogenated products with two chiral centers, trans / cis refers to the ratio of diastereomers in the reaction product, calculated as [(S,S)+(R,R)] / [(S,R)+(R,S)]. For products with more trans, the enantiomer excess (the absolute value of ee, representing the excess of one enantiomer over another in the reaction product, usually expressed as a percentage) is calculated as: ee = [(S,S)-(R,R)] / [(S,S)+(R,R)]) × 100%. For products with more cis, the enantiomer excess (the absolute value of ee) is calculated as: ee = [(S,R)-(R,S)] / [(S,R)+(R,S)] × 100%.

[0090] The chiral diamine metal catalysts were all prepared according to the preparation methods disclosed in CN105111208A and CN103080118B.

[0091] The multi-substituted three-membered ring imine compounds shown in formula (1) are all prepared by the following methods, and the compounds prepared by the following methods are all racemic versions of the compounds shown in formula (1):

[0092]

[0093] The specific preparation method is as follows:

[0094] Synthetic route a (synthesis of the 2,3-diaryl tricyclic imine compound shown in Formula 1-a):

[0095] Arylbenzyl ketone was dissolved in a mixed solvent of methanol and water (methanol to water volume ratio 20:1), with the solvent volume resulting in a arylbenzyl ketone concentration of 0.25 mol / L. Hydroxylamine hydrochloride and NaOAc were added sequentially, with the molar ratio of arylbenzyl ketone to hydroxylamine hydrochloride to NaOAc being 1:1.5:3. The dehydration condensation reaction was carried out at room temperature under a nitrogen atmosphere until the reaction was complete as monitored by TLC. Methanol was removed by rotary evaporation, the aqueous phase was extracted with dichloromethane, the combined organic phases were washed with saturated sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude oxime product, which could be directly proceeded to the next reaction without further purification.

[0096] At 0°C, the above intermediate oxime was dissolved in dry tetrahydrofuran, with the solvent used to achieve an oxime concentration of 0.2 mol / L. Triethylamine was added, followed by the addition of a tetrahydrofuran solution of methanesulfonyl chloride. After reacting for 1 hour, a tetrahydrofuran solution of DBU was added. The molar ratio of oxime to triethylamine to methanesulfonyl chloride to DBU was 1:1.5:1.5:1.5. The reaction was carried out at room temperature under a nitrogen atmosphere until complete as monitored by TLC. After filtration, the filtrate was evaporated to dryness to obtain the crude product, which was then purified by column chromatography to obtain the 2,3-diaryl tricyclic imine compound represented by formula 1-a.

[0097] Synthetic route b (synthesis of the 2-alkyl-3-aryl tricyclic imine compound shown in Formula 1-b):

[0098] Sodium azide was dissolved in acetonitrile, with the amount of solvent used to achieve a sodium azide concentration of 3.0 mol / L. After cooling to -20°C, a dichloromethane solution of iodine monochloride was added dropwise. After the addition was complete and the mixture was stirred for 30 min, a dichloromethane solution of 1-alkyl-2-arylethylene was added dropwise, with the amount of solvent used to achieve a 1.5 mol / L 1-alkyl-2-arylethylene concentration. The molar ratio of 1-alkyl-2-arylethylene to sodium azide to iodine monochloride was 1:2.5:2. After continuing the reaction for 1 h, a saturated sodium thiosulfate solution was added dropwise to quench the reaction until the color completely disappeared. The organic phase was separated, and the aqueous phase was extracted with dichloromethane and separated. The combined organic phases were dried over anhydrous sodium sulfate, and most of the solvent was removed by rotary evaporation under reduced pressure (complete rotary evaporation is dangerous). The crude product was directly used for the next reaction.

[0099] The intermediate was dissolved in diethyl ether, with the solvent volume adjusted to a concentration of 0.25 mol / L. Potassium tert-butoxide was added at 0°C, with a molar ratio of intermediate to potassium tert-butoxide of 1:1.5. The reaction was continued until complete as monitored by TLC. The reaction was quenched with ammonia, and the pH was adjusted to approximately 9. The organic phase was separated, and the aqueous phase was extracted with toluene. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude alkenyl azide product. The crude product was used directly in the next reaction without purification.

[0100] The obtained crude alkenyl azide product was placed in toluene, with the solvent amount adjusted to a concentration of 0.25 mol / L. The reaction was refluxed until complete as monitored by TLC. After cooling to room temperature, the toluene solvent was removed by rotation to obtain a liquid crude product, which was then purified by column chromatography to obtain the 2-alkyl-3-aryl tricyclic imine compound represented by formula 1-b.

[0101] Synthetic route c (synthesis of the 2-aryl-3-alkyl tricyclic imine compound shown in formula 1-c):

[0102] Sodium azide was dissolved in methanol, with the solvent volume adjusted to a sodium azide concentration of 0.5 mol / L. Sodium iodide and 1-alkyl-2-arylene were added, with a molar ratio of 1:1:1 between 1-alkyl-2-arylene and sodium azide / sodium iodide. The mixture was cooled to 0°C, and a methanol solution of CAN was added dropwise, with the solvent volume adjusted to a CAN concentration of 0.5 mol / L. The reaction was allowed to proceed until complete as monitored by TLC. The reaction was quenched with saturated sodium bisulfite solution, and the organic phase was separated. The aqueous phase was extracted with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. Most of the solvent was removed by rotary evaporation under reduced pressure (complete rotary evaporation is dangerous). The resulting crude alkenyl azide product was used directly in the next reaction step.

[0103] The obtained crude alkenyl azide product was dissolved in toluene, with the solvent amount adjusted to a concentration of 0.25 mol / L. The reaction was refluxed until complete as monitored by TLC. After cooling to room temperature, the toluene solvent was removed by rotation to obtain a liquid crude product, which was then purified by column chromatography to obtain a 2-aryl-3-alkyl tricyclic imine compound with the structure shown in Formula 1-c.

[0104] Synthetic route d (synthesis of the 3-aryl-2-perfluoroalkyl tricyclic imine compound shown in Formula 1-d):

[0105] Arylyne and perfluoroalkyl iodide were dissolved in ethylene glycol dimethyl ether, with the amount of solvent used to achieve a concentration of 0.25 mol / L for the arylyne compound. TPPB, TMSN3, and Fe(OAc)3 were added, with a molar ratio of arylyne compound to TPPB to TMSN3 to Fe(OAc)3 of 1:2:2:0.05. A free radical addition reaction was carried out at room temperature under a nitrogen atmosphere. After 1 h of reaction, the ethylene glycol dimethyl ether was removed under reduced pressure using a water pump. Toluene was then added under a nitrogen atmosphere, and the mixture was refluxed at 120 °C for 3 h, with the amount of toluene used to achieve a concentration of 0.25 mol / L for the arylyne compound. After cooling to room temperature and evaporating to dryness, a crude product was obtained. Purification by column chromatography yielded a 3-aryl-2-perfluoroalkyl tricyclic imine compound with the structure shown in Formula 1-d.

[0106] The substrates in the following embodiments were prepared using the synthetic routes described above, wherein the starting materials refer to the initial raw materials in each of the synthetic routes described above, including... and R f I. The specific details are shown in the table below:

[0107]

[0108]

[0109]

[0110] Examples 1-12

[0111] This embodiment illustrates an asymmetric hydrogenation kinetics method for resolving mixtures of enantiomers of the 2-phenyl-3-naphthyl tricyclic imine compound represented by formula (1-1).

[0112] In a high-pressure reactor, a chiral diamine metal catalyst and 0.2 mmol of the racemic mixture of 2-phenyl-3-naphthyl tricyclic imine compound were dissolved in 1 mL of solvent. After replacing the air with nitrogen, 50 atm of hydrogen was introduced, and the reaction was stirred at 25 °C for a certain period of time. The resulting reaction solution was subjected to silica gel column chromatography (eluent was dichloromethane) to remove the chiral diamine metal catalyst, and chiral 2-naphthyl-3-phenylazacyclopropane and chiral 2-phenyl-3-naphthyl tricyclic imine of formula (3-1) were obtained. The ee values ​​of the chiral compounds prepared in the test examples were tested. The ee values ​​and the calculated reaction yields are shown in Table 1.

[0113] Table 1

[0114]

[0115] Note: The unit x mol% for chiral catalyst dosage refers to the percentage of the molar amount of chiral catalyst relative to the molar amount of the racemic 2-phenyl-3-naphthyl tricyclic imine compound.

[0116] Examples 13-20

[0117] This embodiment illustrates an asymmetric hydrogenation kinetics method for resolving mixtures of enantiomers of the 2,3-diaryl tricyclic imine compound shown in Formula 1-a.

[0118] In a high-pressure reactor, 0.04 mmol of chiral diamine metal catalyst (R,R)-4 g and 0.2 mmol of racemic 2,3-diaryl tricyclic imine compound were dissolved in 1 mL of dichloromethane. After replacing the air with nitrogen, 50 atm of hydrogen was introduced, and the reaction was stirred at 25 °C for a certain period of time. The resulting reaction solution was subjected to silica gel column chromatography (eluent was dichloromethane) to remove the chiral diamine metal catalyst, and chiral 2,3-diarylazacyclopropane and chiral 2,3-diaryl tricyclic imine as shown in formula (2) and formula (3) were obtained. The ee values ​​of the chiral compounds prepared in each example were tested, and the ee values ​​and calculated reaction yields are shown in Table 2.

[0119]

[0120] Examples 21-27

[0121] This embodiment illustrates the asymmetric hydrogenation kinetics resolution method for a mixture of enantiomers of 2-alkyl-3-aryl tricyclic imine compounds represented by Formula 1-b and a mixture of enantiomers of 2-aryl-3-alkyl tricyclic imine compounds represented by Formula 1-c.

[0122] In a high-pressure reactor, 0.04 mmol of chiral diamine metal catalyst (R,R)-4 g and 0.2 mmol of racemic 2-alkyl-3-aryl tricyclic imine compound or racemic 2-aryl-3-alkyl tricyclic imine compound were dissolved in 1 mL of dichloromethane. After replacing the air with nitrogen, 50 atm of hydrogen was introduced, and the reaction was stirred at 25 °C for a certain period of time. The resulting reaction solution was subjected to silica gel column chromatography (eluent was dichloromethane) to remove the chiral diamine metal catalyst, and chiral 2-alkyl-3-arylazicyclopropane or 2-aryl-3-alkylazicyclopropane as shown in formula (2) and chiral 2-alkyl-3-aryl tricyclic imine or 2-aryl-3-alkyl tricyclic imine as shown in formula (3) were obtained. The ee values ​​of the chiral compounds prepared in each example were tested, and the ee values ​​and calculated reaction yields are shown in Table 3.

[0123] Table 3

[0124]

[0125] Examples 28-37

[0126] This embodiment illustrates the asymmetric hydrogenation kinetics resolution method for a mixture of enantiomers of the 3-aryl-2-perfluoroalkyl tricyclic imine compound represented by Formula 1-d of the present invention.

[0127] In a high-pressure reactor, 0.04 mmol of the chiral diamine metal catalyst (R,R)-19f and 0.2 mmol of the racemic 3-aryl-2-perfluoroalkyl tricyclic imine compound were dissolved in 1 mL of tert-amyl alcohol. After replacing the air with nitrogen, 50 atm of hydrogen was introduced, and the reaction was stirred at 25 °C for a certain period of time. The resulting reaction solution was subjected to silica gel column chromatography (eluent was dichloromethane) to remove the chiral diamine metal catalyst, and chiral 3-aryl-2-perfluoroalkyl aziridine and 3-aryl-2-perfluoroalkyl tricyclic imine as shown in formula (2) and formula (3) were obtained. The ee values ​​of the chiral compounds prepared in each example were tested, and the ee values ​​and calculated reaction yields are shown in Table 4.

[0128] Table 4

[0129]

[0130]

[0131] To intuitively illustrate the properties and characterization process of the multisubstituted chiral aziridine compounds and multisubstituted chiral three-membered ring imine compounds prepared by the asymmetric hydrogenation kinetic resolution method of racemic multisubstituted three-membered ring imines of the present invention, the present invention provides, exemplarily, the identification results and processes of the chiral compounds prepared in Examples 13-41, as shown in Table 5.

[0132] Table 5

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. An asymmetric hydrogenation kinetic resolution method for racemic multisubstituted three-membered cyclic imines, characterized in that, The method includes: asymmetric hydrogenation of a mixture containing enantiomers of a multisubstituted three-membered ring imine compound with hydrogen in the presence of a chiral diamine metal catalyst to obtain a single optical isomer of a multisubstituted chiral aziridine compound and / or a multisubstituted chiral three-membered ring imine compound; wherein the multisubstituted three-membered ring imine compound is the compound shown in formula (1), and the multisubstituted chiral aziridine compound is the compound shown in formula (2); Equation (1) Equation (2) Among them, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 The cycloalkyl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted aryl, and substituted or unsubstituted arylbenzyl; wherein the substituted C1-C 10 Alkyl, substituted C1-C 10 alkoxy groups, substituted C3-C 10 The substituents in the cycloalkyl, substituted heterocyclic aryl, substituted aryl, and substituted aryl benzyl groups are each independently selected from one or more of halogen, nitro, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C2-C6 amide groups.

2. The method according to claim 1, wherein, R 1 and R 2 Each of the substituents is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted aryl, and substituted or unsubstituted arylbenzyl; wherein the substituents in the substituted C1-C6 alkyl, substituted C1-C6 alkoxy, substituted C3-C6 cycloalkyl, substituted heterocyclic aryl, substituted aryl, and substituted arylbenzyl are each independently selected from one or more of halogen, nitro, hydroxyl, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C2-C4 amide. Preferably, R 1 and R 2 Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, perfluoromethyl, perfluoroethyl, perfluoron-propyl, perfluoron-butyl, cyclopentyl, cyclohexyl, perfluorocyclopentyl, perfluorocyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, substituted or unsubstituted thiophene, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, and substituted or unsubstituted benzyl; wherein, substituted thiophene, substituted phenyl, The substituents in the substituted naphthyl and substituted benzyl groups are each independently selected from one or more of the following: fluorine, chlorine, bromine, iodine, nitro, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -CF3, -CCl3, -CBr3, -CH2CF3, -CH2CCl3, -CH2CBr3, -NH-CO-CH3, and -NH-CO-CH2CH3; Preferably, in formula (2), R 1 and R 2 It is a cis substitution.

3. The method according to claim 1 or 2, wherein, The polysubstituted three-membered cyclic imine compounds are selected from compounds shown in the following formula:

4. The method according to any one of claims 1-3, wherein, The multisubstituted chiral three-membered cyclic imine compounds are selected from one or more of the compounds shown in the following formula:

5. The method according to any one of claims 1-4, wherein, The polysubstituted chiral aziridine compounds are selected from one or more compounds shown in the following formula:

6. The method according to any one of claims 1-5, wherein, The chiral diamine metal catalyst is selected from one or more compounds with the structures shown in formula (4) and formula (5): Equation (4) Equation (5) In equations (4) and (5), metal M is independently selected from ruthenium, rhodium, and iridium; L1 is independently selected from substituted or unsubstituted η. 6 -Benzene ligand and substituted or unsubstituted η 5 - A cyclohexane ligand, and the substituents present in L1 are each independently selected from C1-C1. 10 One or more of the alkyl groups; L2 is selected from C1-C 10 Oxygen-containing alkylene and sulfur-containing alkylene; X is independently selected from Cl - ,Br - I - CH3COO - NO3 - HSO4 - H2PO4 - BF4 - SbF6 - PF6 - , di(trifluoromethanesulfonyl)imide anion, trifluoromethanesulfonic acid anion, substituted or unsubstituted C 24 -C 32 Tetraarylboron anion, substituted or unsubstituted C 12 -C 36 Diaryl phosphate anions and substituted or unsubstituted C 12 -C 36 The phosphate anion derived from biaryl diol, wherein the substituents optionally present in X are each independently selected from one or more of fluorine, chlorine, bromine, nitro, methyl, ethyl, methoxy, trifluoromethyl, hydroxy and acetamido.

7. The method according to claim 6, wherein, Define the ligands in equations (4) and (5) Equation (6); The compounds forming the ligands shown in formula (6) are selected from one or more of the following compounds: Formula (I-1) Formula (I-2) Formula (I-3) Formula (I-4) Formula (I-5) Formula (I-6) Formula (I-7) Formula (I-8) Ar1 and Ar2 are each independently selected from substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl groups, and the substituents optionally present in Ar1 and Ar2 are each independently selected from at least one of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, halogen atom, hydroxyl and carboxyl groups. R is selected from C1-C8 alkyl, trifluoromethyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, and the substituents optionally present in R are each independently selected from one or more of C1-C8 alkyl, methoxy, fluorine, chlorine, bromine, nitro and trifluoromethyl. R' is independently selected from C1-C 10 The alkyl, trifluoromethyl, substituted amino, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl groups, wherein the substituents optionally present in R' are each independently selected from C. 1-10 One or more of the following: alkyl, methoxy, fluorine, chlorine, bromine, nitro, and trifluoromethyl; R" is independently selected from H, substituted or unsubstituted benzyl, and C1-C. 10 The alkyl group, and the substituents optionally present in "R" are each independently selected from C1-C2. 10 One or more of the following: alkyl, methoxy, fluorine, chlorine, bromine, nitro, and trifluoromethyl.

8. The method according to claim 6 or 7, wherein, In equations (4) and (5), L1 is independently selected from η. 6 -Benzene ligand, η 6 -1,4-Dimethylbenzene ligand, η 6 -1-Methyl-4-isopropylphenyl ligand, η 6 -1,3,5,-Trimethylbenzene ligand, η 6 -1,2,3,4,5-pentamethylbenzene ligand, η 6 -1,2,3,4,5,6-Hexamethylbenzene ligand, η 5 -Maocene ligand and eta 5 - Pentamethylcenyl ligand; L2 is selected from C1-C6 oxyalkylene and sulfalkylene groups; X is independently selected from Cl - BF4 - PF6 - SbF6 - , di(trifluoromethanesulfonyl)imide anion, trifluoromethanesulfonic acid anion, substituted or unsubstituted C 24 -C 32 Tetraarylboron anion, substituted or unsubstituted C 12 -C 36 Diaryl phosphate anions and substituted or unsubstituted C 12 -C 36 The phosphate anion derived from biaryl diol, wherein the substituents optionally present in X are each independently selected from one or more of fluorine, chlorine, bromine, nitro, methyl, ethyl, methoxy, trifluoromethyl, hydroxy and acetamido.

9. The method according to claim 8, wherein, In equations (4) and (5), L1 is independently selected from η. 6 -Benzene ligand, η 6 -1-Methyl-4-isopropylphenyl ligand and η 6 -1,2,3,4,5,6-Hexamethylbenzene ligand; L2 is selected from -CH2-O-CH2-CH2-, -CH2-O-CH2-CH2-CH2-CH2-, and -CH2-S-CH2-CH2-; X is independently selected from Cl - BF4 - PF6 - SbF6 - The following are listed: bis(trifluoromethanesulfonyl)imide anion, trifluoromethanesulfonic acid anion, tetraphenylboron anion, tetra(3,5-bis(trifluoromethyl)phenyl)boron anion, diphenyl phosphate anion, di-p-methylphenyl phosphate anion, di(2,4,6-trimethylphenyl) phosphate anion, di-p-methoxyphenyl phosphate anion, di-p-fluoromethylphenyl phosphate anion, di-p-trifluoromethylphenyl phosphate anion, 2,2'-biphenyl phosphate anion, (R)-2,2'-bi-naphthyl phosphate anion, (S)-2,2'-bi-naphthyl phosphate anion, (R)-8H-2,2'-bi-naphthyl phosphate anion, and (S)-8H-2,2'-bi-naphthyl phosphate anion.

10. The method according to any one of claims 6-9, wherein, The chiral diamine metal catalyst is selected from one or more of the following compounds: Where X is independently selected from Cl - BF4 - PF6 - SbF6 - The anions are: bis(trifluoromethanesulfonyl)imide, trifluoromethanesulfonic acid, tetra(3,5-bis(trifluoromethyl)phenyl)boron, diphenyl phosphate, 2,2'-biphenyl phosphate, (R)-2,2'-bidinaphthyl phosphate, and (S)-2,2'-bidinaphthyl phosphate.

11. The method according to any one of claims 1-10, wherein, In the asymmetric hydrogenation process, the amount of the compound shown in formula (1) relative to 1 mol of the chiral diamine metal catalyst can be 10-2000 mol, preferably 20-500 mol, and more preferably 50-200 mol; Preferably, the conditions for the asymmetric hydrogenation treatment include: a hydrogen pressure of 1-100 atm, preferably 5-80 atm; a temperature of -10℃ to 100℃, preferably 0℃ to 60℃; and a time of 0.5-72h, preferably 0.5-20h. Preferably, the solvent for the asymmetric hydrogenation treatment is selected from [BMIM]PF6, dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, tetrahydrofuran, benzene, toluene, xylene, chlorobenzene, diethyl ether, dioxane, acetone, and C1-C4. 10 One or more of the monohydric alcohols, preferably one or more of methanol, ethanol, isopropanol, n-butanol, dichloromethane, tetrahydrofuran, toluene, ethyl acetate and acetone; Preferably, during the asymmetric hydrogenation process, the amount of the compound represented by formula (1) is 0.1-1 mmol, more preferably 0.1-0.6 mmol, relative to 1 mL of the solvent.

12. A multi-substituted chiral azacyclopropane compound, characterized in that, The multisubstituted chiral azacyclopropane compounds are those shown in formula (2): Equation (2) Among them, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 The cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted arylbenzyl; wherein the substituted C1-C 10 Alkyl, substituted C1-C 10 alkoxy groups, substituted C3-C 10 The substituents in the cycloalkyl, substituted aryl, and substituted aryl benzyl groups are each independently selected from one or more of halogens, nitro groups, hydroxyl groups, C1-C6 alkyl groups, C1-C6 hydroxyalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C2-C6 amide groups.

13. A multi-substituted chiral three-membered cyclic imine compound, characterized in that, The multisubstituted chiral three-membered cyclic imine compound is a single optical isomer of the multisubstituted three-membered cyclic imine compound shown in formula (1): Equation (1) Among them, R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 The cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted arylbenzyl; wherein the substituted C1-C 10 Alkyl, substituted C1-C 10 alkoxy groups, substituted C3-C 10 The substituents in the cycloalkyl, substituted aryl, and substituted aryl benzyl groups are each independently selected from one or more of halogens, nitro groups, hydroxyl groups, C1-C6 alkyl groups, C1-C6 hydroxyalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, and C2-C6 amide groups.

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