阅读说明：本技术 消旋多取代二氢异喹啉的不对称氢化动力学拆分方法 (Asymmetric hydrogenation kinetic resolution method of racemic polysubstituted dihydroisoquinoline ) 是由 范青华 张珊珊 陈飞 何艳梅 于 2020-05-18 设计创作，主要内容包括：本发明涉及不对称催化氢化领域,具体涉及消旋多取代二氢异喹啉的不对称氢化动力学拆分方法。该方法包括：在手性二胺金属催化剂存在下,采用氢气对含多取代二氢异喹啉类化合物对映异构体的混合物进行不对称氢化处理,得到多取代手性四氢异喹啉类化合物和多取代手性二氢异喹啉类化合物的单一光学异构体；其中,所述多取代二氢异喹啉类化合物为式(1)所示的化合物；所述多取代手性四氢异喹啉类化合物为式(2)所示的化合物。本发明的方法,通过不对称加氢的方式,实现消旋多取代二氢异喹啉类化合物的拆分,可同时获得具有一定光学纯度的多取代手性四氢异喹啉类化合物和多取代手性二氢异喹啉类化合物的单一光学异构体。(The invention relates to the field of asymmetric catalytic hydrogenation, in particular to an asymmetric hydrogenation kinetic resolution method of racemic polysubstituted dihydroisoquinoline. The method comprises the following steps: in the presence of a chiral diamine metal catalyst, adopting hydrogen to carry out asymmetric hydrogenation treatment on a mixture containing the enantiomers of the polysubstituted dihydroisoquinoline compound to obtain a single optical isomer of the polysubstituted chiral tetrahydroisoquinoline compound and the polysubstituted chiral dihydroisoquinoline compound; wherein the polysubstituted dihydroisoquinoline compound is a compound shown as a formula (1); the polysubstituted chiral tetrahydroisoquinoline compound is a compound shown as a formula (2). The method of the invention is realized by asymmetric hydrogenationThe resolution of the racemic polysubstituted dihydroisoquinoline compounds can simultaneously obtain a single optical isomer of polysubstituted chiral tetrahydroisoquinoline compounds and polysubstituted chiral dihydroisoquinoline compounds with certain optical purity.)

1. A process for the asymmetric hydrogenation kinetic resolution of a mixture of enantiomers of a polysubstituted dihydroisoquinoline class of compounds comprising: in the presence of a chiral diamine metal catalyst, adopting hydrogen to carry out asymmetric hydrogenation treatment on a mixture containing the enantiomers of the polysubstituted dihydroisoquinoline compound to obtain a single optical isomer of the polysubstituted chiral tetrahydroisoquinoline compound and the polysubstituted chiral dihydroisoquinoline compound; wherein the polysubstituted dihydroisoquinoline compound is a compound shown as a formula (1); the polysubstituted chiral tetrahydroisoquinoline compound is a compound shown as a formula (2);

formula (1)Formula (2)

Wherein R is¹、R²And R³Each independently is substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group and R³Can be hydrogen, R⁴、R⁵And R⁶Each independently hydrogen, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group, or R⁵And R⁴Or R⁶Ring-synthesizing to form a ring, wherein the substituents for the substituted alkyl, the substituted cycloalkyl, the substituted aryl and the substituted arylbenzyl are respectively and independently selected from halogen, nitro, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkylOne or more of oxy, C1-C6 haloalkyl, and C2-C6 amido.

2. The method of claim 1, wherein R¹、R²And R³Each independently is substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group and R³Can be hydrogen, R⁴、R⁵And R⁶Each independently hydrogen, halogen, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group, or R⁵And R⁴Or R⁶Synthesizing a 3-8 membered ring; wherein, the substituents for the substituted alkyl, the substituted cycloalkyl, the substituted aryl and the substituted arylbenzyl are respectively and independently selected from one or more of halogen, nitryl, hydroxyl, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkyl and C2-C4 amido;

preferably, R¹、R²And R³Each independently being methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl and R is³Can be hydrogen, R⁴、R⁵And R⁶Each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, or R⁵And R⁴Or R⁶Synthesizing 6-8 membered aromatic ring; wherein the substituents for the substituted phenyl and substituted benzyl groups are each independently selected from fluorine, chlorine, bromine, iodine, nitro, hydroxyMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -CF₃、-CCl₃、-CBr₃、-CH₂CF₃、-CH₂CCl₃、-CH₂CBr₃、-NH-CO-CH₃and-NH-CO-CH₂CH₃One or more of;

preferably, the formulae (1) and (2), R²And R³Is cis-substituted.

3. The method according to claim 1 or 2, wherein the polysubstituted dihydroisoquinoline type compound is selected from the group consisting of compounds represented by the following formulae:

4. the method of claim 3, wherein the single optical isomer of the polysubstituted dihydroisoquinoline compound is selected from the group consisting of compounds represented by the following formulas:

5. the method according to any one of claims 1 to 4, wherein the polysubstituted chiral tetrahydroisoquinoline compound is selected from the group consisting of compounds represented by the following formulae:

6. the method of any one of claims 1-5, wherein the chiral diamine metal catalyst is at least one of a compound having a structure represented by formula (4):

formula (4)

Wherein, in the formula (4),

m is selected from the metals ruthenium, rhodium or iridium;

L₁selected from substituted or unsubstituted eta⁶-phenyl ligand, substituted or unsubstituted eta⁵-a metallocene ligand;

and L is₁Each of the substituents optionally present in (a) is independently at least one selected from the group consisting of C1-C10 alkyl;

x is selected from Cl^-、Br^-、I^-、CH₃COO^-、NO₃ ^-、HSO₄ ^-、H₂PO₄ ^-、BF₄ ^-、SbF₆ ^-、PF₆ ^-Bis (trifluoromethanesulfonyl) imide anion, trifluoromethanesulfonic anion, substituted or unsubstituted C24-C32 tetraarylboron anion, substituted or unsubstituted C12-C36 diarylphosphate anion, substituted or unsubstituted C12-C36 diaryldiphenol-derived phosphate anion; and the substituents optionally present in X are each independently selected from at least one of fluorine, chlorine, bromine, nitro, methyl, methoxy, trifluoromethyl, hydroxy and acetamido.

7. The method according to claim 6, wherein the ligand in formula (4) is defined as a group represented by formula (5),

formula (5)

The compound forming the ligand represented by the formula (5) is selected from at least one 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)

Wherein Ar is₁And Ar₂Each independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl; and Ar₁And Ar₂Wherein the substituents optionally present in (a) are each independently at least one selected from the group consisting of an alkyl group of C1-C3, an alkoxy group of C1-C3, a hydroxyalkyl group of C1-C3, a halogen atom, a hydroxyl group and a carboxyl group;

r is selected from C1-C8 alkyl, trifluoromethyl, substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl; and the substituents optionally present in R are each independently selected from at least one of C1-C8 alkyl, methoxy, fluorine, chlorine, bromine, nitro and trifluoromethyl;

r' is selected from C1-C10 alkyl, trifluoromethyl, substituted amine, substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl; and the substituents optionally present in R' are each independently selected from C_1-10At least one of alkyl, methoxy, fluoro, chloro, bromo, nitro and trifluoromethyl;

r' is selected from hydrogen, substituted or unsubstituted benzyl or C1-C10 alkyl; and the substituents optionally present in R' are each independently selected from at least one of C1-C10 alkyl, methoxy, fluoro, chloro, bromo, nitro and trifluoromethyl.

8. The method according to claim 6 or 7, wherein, in formula (4), L₁Is selected from η⁶-phenyl ligand,. eta.⁶-1, 4-dimethylbenzene ligand, eta⁶-1-methyl-4-isopropylbenzene ligand,. eta.⁶-1,3,5, -trimethylbenzene ligand,. eta.⁶-1,2,3,4, 5-pentamethylbenzene ligand,. eta.⁶-1,2,3,4,5, 6-hexamethylbenzene ligand,. eta.⁵-metallocene ligand or eta⁵-a pentamethylcyclopentadienyl group;

x is selected from Cl^-、BF₄ ^-、PF₆ ^-、SbF₆ ^-Bis (trifluoromethanesulfonyl) imide anion, trifluoromethanesulfonic anion, substituted or unsubstituted C24-C32 tetraarylboron anion, substituted or unsubstituted C12-C36 diarylphosphate anion, or substituted or unsubstituted C12-C36 diaryldiphenol-derived phosphate anion; and the substituents optionally present in X are each independently selected from at least one of fluorine, chlorine, bromine, nitro, methyl, methoxy, trifluoromethyl, hydroxy and acetamido;

preferably, in formula (4), L₁Is selected from η⁶-phenyl ligand,. eta.⁶-1-methyl-4-isopropylbenzene ligand and eta⁶-a 1,2,3,4,5, 6-hexamethylbenzene ligand;

x is selected from Cl^-、BF₄ ^-、PF₆ ^-、SbF₆ ^-Bis (trifluoromethanesulfonyl) imide anions, trifluoromethanesulfonic acid anions, tetraphenylboron anions, tetrakis (3, 5-bis (trifluoromethyl) phenyl) boron anions, diphenylphosphoric acid anions, di-p-methylphenyl phosphate anions, di (2,4, 6-trimethylphenyl) phosphate anions, di-p-methoxyphenyl phosphate anions, di-p-fluoromethylphenyl phosphate anions, di-p-trifluoromethylphenyl phosphate anions, anions of the structures shown in the formulae (II-1) to (II-6);

9. the process of any one of claims 6-8, wherein the chiral diamine metal catalyst is at least one of the following compounds:

wherein X is Cl^-、BF₄ ^-、PF₆ ^-、SbF₆ ^-Bis (trifluoromethanesulfonyl) imide anions, trifluoromethanesulfonic acid anions, tetrakis (3, 5-bis (trifluoromethyl) phenyl) boron anions, diphenylphosphate anions, 2' -biphenylphosphate anions, (R) -2,2' -binaphthyl phosphate anions, or (S) -2,2' -binaphthyl phosphate anions.

10. The method according to any one of claims 1 to 9, wherein the molar ratio of the compound having the structure represented by formula (1) to the amount of the chiral diamine metal catalyst is 10 to 2000: 1, preferably 50 to 200: 1;

preferably, the conditions of the asymmetric hydrogenation treatment include: the pressure of the hydrogen is 1-100atm, preferably 5-80 atm; the temperature is-10 ℃ to 100 ℃, and preferably 0-60 ℃; the time is 0.5 to 72 hours, preferably 0.5 to 10 hours;

preferably, the asymmetric hydrogenation treatment is carried out using a solvent of [ BMIM ]]PF₆Dichloromethane, 1, 2-dichloroethane, chloroform, ethyl acetate, tetrahydrofuran, benzene, toluene, xylene, chlorobenzene, diethyl ether, dioxane, acetone and C₁-C₁₀In a monohydric alcohol ofOne or more of (a); more preferably, the compound having the structure represented by formula (1) is used in a molar amount of 0.1 to 1mmol relative to 1mL of the solvent.

11. A polysubstituted chiral tetrahydroisoquinoline compound is characterized in that the polysubstituted chiral tetrahydroisoquinoline compound is a compound shown as a formula (2);

formula (2)

Wherein R is¹、R²And R³Each independently is substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group and R³Can be hydrogen, R⁴、R⁵And R⁶Each independently hydrogen, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group, or R⁵And R⁴Or R⁶And (3) ring synthesis is carried out, wherein the substituent groups in the substituted alkyl, the substituted cycloalkyl, the substituted aryl and the substituted arylbenzyl are respectively and independently selected from one or more of halogen, nitro, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl and C2-C6 amido.

12. A single optical isomer of polysubstituted chiral dihydroisoquinoline compound is characterized in that the polysubstituted chiral dihydroisoquinoline compound is a compound shown as a formula (1);

formula (1)

Wherein R is¹、R²And R³Each independently of the otherIs substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group and R³Can be hydrogen, R⁴、R⁵And R⁶Each independently hydrogen, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group, or R⁵And R⁴Or R⁶And (3) ring synthesis is carried out, wherein the substituent groups in the substituted alkyl, the substituted cycloalkyl, the substituted aryl and the substituted arylbenzyl are respectively and independently selected from one or more of halogen, nitro, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl and C2-C6 amido.

Technical Field

The invention relates to the field of asymmetric catalytic hydrogenation, in particular to an asymmetric hydrogenation kinetic resolution method of racemic polysubstituted dihydroisoquinoline.

Background

Optically pure tetrahydroisoquinoline skeleton structures are widely present in natural products and drugs (J.D. Scott, R.M. Williams, chem.Rev.2002,102, 1669; M.Chrzanowska, M.D. Rozwawska, chem.Rev.2004,104, 3341; M.Chrzanowska, A.Grajewska, M.D. Rozwawska, chem.Rev.2016,116,12369), and their asymmetric synthesis is of widespread interest to scientists. Dihydroisoquinoline (c.li, j.xiao, j.am.chem.soc.2008,130, 13208; m.chang, w.li, x.zhang, angelw.chem.int.ed.2011, 50,10679) or isoquinoline (s. -m.lu, y. -q.wang, x. -w.han, y. -g.zhou, angelw.chem.int.ed.2006, 45,2260; l.shi, z. -s.ye, l. -l.cao, r. -n.guo, y.hu, y. -g.zhou, angelw.em.ed.2012, 51,8286; z. -s.ye, r. -n.guo, x. -f.cai, m.chen, angel.201m.ed.2012, 52,3685) has been developed only by the most efficient chiral tetrahydroisoquinoline hydrogenation methods, but is not limited to the chiral tetrahydroisoquinoline (s.wo.l., l.q.wang.wang., l.c.c., l.c.c.c.c.c.c.c.c.c.c.c.c.c.c.c.c.c.c.c.c.c.m.m.h.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.3526, z.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.3525, t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t. t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t. t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.t.. There is still a lack of an effective method for the catalytic asymmetric synthesis of chiral trisubstituted tetrahydroisoquinolines. There are only a few reports of synthesis with chiral source reagents, but these methods usually involve complicated synthetic steps, low yields, and large substrate limitations (d.br os zda,Koroniak,M.D.Rozwadowska,Tetrahedron:Asymmetry 2000,11,3017；M.Nicoletti,D.O’Hagan,A.M.Z.Slawin,J.Chem.Soc.Perkin Trans.1,2002,116；T.Saitoh,K.Shikiya,Y.Horiguchi,T.Sano,Chem.Pharm.Bull.2003,51,667；T.Ramanivas,G.Gayatri,D.Priyanka,V.L.Nayak,K.K.Singarapu,A.K.Srivastava,RSC Adv.2015,5,73373；S.G.Davies,A.M.Fletcher,A.B.Frost,M.S.Kennedy,P.M.Roberts,J.E.Thomson,Tetrahedron 2016,72,2139；V.Erdmann,B.R.Lichman,J.Zhao,R.C.Simon,W.Kroutil,J.M.Ward,H.C.Hailes,D.Rother,Angew.Chem.Int.Ed.2017,56,12503)。

therefore, the development of a novel efficient asymmetric synthesis method of chiral polysubstituted tetrahydroisoquinoline, which does not use expensive chiral starting materials or chiral resolution reagents, has simple and easy operation, high product yield and high product optical purity, is a problem to be solved in the field.

Disclosure of Invention

The invention aims to provide a high-efficiency asymmetric hydrogenation kinetic resolution method of racemic polysubstituted dihydroisoquinoline compounds, thereby providing a new method for synthesizing polysubstituted chiral tetrahydroisoquinoline compounds and corresponding polysubstituted chiral dihydroisoquinoline compounds with high enantioselectivity.

In order to achieve the above objects, the present invention provides in a first aspect a process for asymmetric hydrogenation kinetic resolution of a mixture of enantiomers of a polysubstituted dihydroisoquinoline class of compounds, the process comprising: in the presence of a chiral diamine metal catalyst, adopting hydrogen to carry out asymmetric hydrogenation treatment on a mixture containing the enantiomers of the polysubstituted dihydroisoquinoline compound to obtain a single optical isomer of the polysubstituted chiral tetrahydroisoquinoline compound and the polysubstituted chiral dihydroisoquinoline compound; wherein the polysubstituted dihydroisoquinoline compound is a compound shown as a formula (1); the polysubstituted chiral tetrahydroisoquinoline compound is a compound shown as a formula (2);

formula (1)Formula (2)

Wherein R is¹、R²And R³Each independently is substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group and R³Can be hydrogen, R⁴、R⁵And R⁶Each independently hydrogen, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group, or R⁵And R⁴Or R⁶And (3) ring synthesis is carried out, wherein the substituent groups in the substituted alkyl, the substituted cycloalkyl, the substituted aryl and the substituted arylbenzyl are respectively and independently selected from one or more of halogen, nitro, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl and C2-C6 amido.

The second aspect of the invention provides a polysubstituted chiral tetrahydroisoquinoline compound, which is a compound shown in formula (2);

formula (2)Each group is as described above.

The third aspect of the invention provides a single optical isomer of a polysubstituted chiral dihydroisoquinoline compound, which is characterized in that the polysubstituted chiral dihydroisoquinoline compound is a compound shown as a formula (1);

formula (1)Each group is as described above.

According to the method, a chiral diamine metal catalyst is adopted to catalyze asymmetric hydrogenation to realize a mixture containing the enantiomers of the polysubstituted dihydroisoquinoline compounds, particularly a racemic mixture containing the polysubstituted dihydroisoquinoline compounds to realize resolution, so that a single optical isomer of the polysubstituted chiral tetrahydroisoquinoline compounds and the polysubstituted chiral dihydroisoquinoline compounds with certain optical purity can be obtained simultaneously; the method has the advantages of simple and easy operation, mild conditions, high efficiency, high enantioselectivity, high resolution coefficient and the like.

Detailed Description

The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.

The invention provides a method for asymmetric hydrogenation kinetic resolution of a mixture containing multi-substituted dihydroisoquinoline compound enantiomers, which comprises the following steps: in the presence of a chiral diamine metal catalyst, adopting hydrogen to carry out asymmetric hydrogenation treatment on a mixture containing the enantiomers of the polysubstituted dihydroisoquinoline compound to obtain a single optical isomer of the polysubstituted chiral tetrahydroisoquinoline compound and the polysubstituted chiral dihydroisoquinoline compound; wherein the polysubstituted dihydroisoquinoline compound is a compound shown as a formula (1); the polysubstituted chiral tetrahydroisoquinoline compound is a compound shown as a formula (2);

formula (1)Formula (2)

Wherein R is¹、R²And R³Each independently is substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group and R³Can be hydrogen, R⁴、R⁵And R⁶Each independently hydrogen, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₃-C₁₀A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group, or R⁵And R⁴Or R⁶And (3) ring synthesis is carried out, wherein the substituent groups in the substituted alkyl, the substituted cycloalkyl, the substituted aryl and the substituted arylbenzyl are respectively and independently selected from one or more of halogen, nitro, hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 halogenated alkyl and C2-C6 amido.

According to the invention, R is preferably¹、R²And R³Each independently is substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group and R³Can be hydrogen, R⁴、R⁵And R⁶Each independently hydrogen, halogen, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₃-C₆A substituted or unsubstituted aryl group or a substituted or unsubstituted arylbenzyl group, or R⁵And R⁴Or R⁶Synthesizing a 3-8 membered ring; wherein, the substituents for the substituted alkyl, the substituted cycloalkyl, the substituted aryl and the substituted arylbenzyl are respectively and independently selected from one or more of halogen, nitryl, hydroxyl, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkyl and C2-C4 amido;

more preferably, R¹、R²And R³Each independently being methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl and R is³Can be hydrogen, R⁴、R⁵And R⁶Each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, or R⁵And R⁴Or R⁶Synthesizing 6-8 membered aromatic ring; wherein the substituents for the substituted phenyl and substituted benzyl groups are each independently selected from the group consisting of fluoro, chloro, bromo, iodo, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -CF₃、-CCl₃、-CBr₃、-CH₂CF₃、-CH₂CCl₃、-CH₂CBr₃、-NH-CO-CH₃and-NH-CO-CH₂CH₃One or more of (a).

Wherein R is⁵Can be reacted with R⁴Or R⁶Synthesizing a benzene ring structure by a ring.

According to the invention, the hydrogenation substrate is a mixture containing multi-substituted dihydro isoquinoline compound enantiomers, the mixture has at least one pair of enantiomers, particularly the mixture is racemic, and the method can obtain a single optical isomer by resolution from the mixture and simultaneously prepare the multi-substituted chiral tetrahydro isoquinoline compound.

Wherein, 3 and 4 positions in the compound shown in the formula (1) can be chiral carbon positions, the chiral carbon positions can be R-configuration or S-configuration, and the mixture of enantiomers of the polysubstituted dihydroisoquinoline compound can be a mixture of 3R, 4R-optical configuration and 3S, 4S-optical configuration or a mixture of 3R, 4S-optical configuration and 3S, 4R-optical configuration, but the invention does not exclude a small amount of other configurations; or a mixture of 4 configurations.

Formula (1)

Preferably, in the formulae (1) and (2), R²And R³Is cis-substituted.

In a preferred embodiment of the present invention, the polysubstituted dihydroisoquinoline compound is selected from the group consisting of compounds represented by the following formulae:

in another preferred embodiment of the present invention, the single optical isomer of the polysubstituted dihydroisoquinoline compound is selected from the group consisting of compounds represented by the following formulas:

preferably, in the polysubstituted chiral tetrahydroisoquinoline compound, R is¹、R²And R³Is cis-substituted.

In a preferred embodiment of the present invention, the polysubstituted chiral tetrahydroisoquinoline compound is selected from the group consisting of compounds represented by the following formulae:

according to the present invention, the mixture containing the enantiomers of polysubstituted dihydroisoquinoline compounds can be a commercially available product, or can be a racemate of the enantiomer of polysubstituted dihydroisoquinoline compounds prepared by a conventional method in the art, and the present invention is not particularly limited thereto, and can be prepared by one of two synthetic routes shown in the following equation.

(1)

(2)

The chiral diamine metal catalyst is preferably the chiral catalyst disclosed in CN105111208A, wherein the chiral diamine metal catalyst is preferably at least one of the compounds having the structure shown in formula (4):

formula (4)

Wherein, in the formula (4),

m is selected from the metals ruthenium, rhodium or iridium;

L₁selected from substituted or unsubstituted eta⁶-phenyl ligand, substituted or unsubstituted eta⁵-a metallocene ligand;

and L is₁Each of the substituents optionally present in (a) is independently at least one selected from the group consisting of C1-C10 alkyl;

x is selected from Cl^-、Br^-、I^-、CH₃COO^-、NO₃ ^-、HSO₄ ^-、H₂PO₄ ^-、BF₄ ^-、SbF₆ ^-、PF₆ ^-Bis (trifluoromethanesulfonyl) imide anion, trifluoromethanesulfonic anion, substituted or unsubstituted C24-C32 tetraarylboron anion, substituted or unsubstituted C12-C36 diarylphosphate anion, substituted or unsubstituted C12-C36 diaryldiphenol-derived phosphate anion; and the substituents optionally present in X are each independently selected from at least one of fluorine, chlorine, bromine, nitro, methyl, methoxy, trifluoromethyl, hydroxy and acetamido.

According to the invention, the catalyst is a ruthenium (Ru), rhodium (Rh) or iridium (Ir) complex of the structure shown in formula (4), formula (5) as one of the ligands of the complex of the structure shown in formula (4)Is composed of diamine NHR' -linking arm-NHSO₂R' is formed, wherein-NHSO₂N at the end of R 'forms a covalent bond with M, while N at the end of NHR' -forms a coordinate bond with M, thereby forming a ligand represented by formula (4). Wherein, in the chiral catalyst, the diamine NHR' -connecting arm-NHSO₂The linker arm in R' may be such that the carbon atom to which the N at the "terminus of NHR" is attached and/or-NHSO₂The carbon atom connected with N at the end of R' becomes a chiral center, so that the compound with the structure shown as the formula (4) as a chiral catalyst has certain catalytic selectivity, and particularly the compound with the (R, R) -configuration, the (S, S) -configuration, the (R) -configuration or the (S) -configuration is suitable for catalyzing the compound with the structure shown as the formula (1). For example, using (R, R) or (R) -chiral diamines NHR' -linker-NHSO₂When R 'is used as a chiral catalyst, the enantiomeric excess of the compound of formula (5) will generally be increased, whereas when (S, S) or (S) -chiral diamine NHR' -linker-NHSO is used₂When R' is used as a chiral catalyst, it will generally increase the enantiomeric excess of the compound of formula (R, R) -formula (5). However, generally the catalytic effect of the catalyst on the enantiomers is opposite, for example if the catalytic effect of the (R, R) -type catalyst is to increase the content of the (S, S) -type product, then the catalytic effect of the (S, S) -type catalyst is to increase the content of the (R, R) -type product, as will be appreciated by those skilled in the art.

In order to facilitate the catalytic hydrogenation of the racemic polysubstituted dihydroisoquinoline compound having a structure represented by formula (1) of the present invention, it is preferable that the ligand in formula (4) is defined as a group represented by formula (5),

formula (5)

The compound forming the ligand represented by the formula (5) is selected from at least one 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)

Wherein Ar is₁And Ar₂Each independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl; and Ar₁And Ar₂Wherein the substituents optionally present in (a) are each independently at least one selected from the group consisting of an alkyl group of C1-C3, an alkoxy group of C1-C3, a hydroxyalkyl group of C1-C3, a halogen atom, a hydroxyl group and a carboxyl group;

r is selected from C1-C8 alkyl, trifluoromethyl, substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl; and the substituents optionally present in R are each independently selected from at least one of C1-C8 alkyl, methoxy, fluorine, chlorine, bromine, nitro and trifluoromethyl; preferably, R is methyl, p-methylphenyl, p-trifluoromethylphenyl, naphthyl, 2,3, 4-triisopropylphenyl or trifluoromethyl;

r' is selected from C1-C10 alkyl, trifluoromethyl, substituted amine, substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl; and the substituents optionally present in R' are each independently selected from C_1-10At least one of alkyl, methoxy, fluoro, chloro, bromo, nitro and trifluoromethyl; preferably, R' is methyl, p-methylphenyl, naphthyl, 2,3, 4-triisopropylphenyl or trifluoromethyl;

r' is selected from hydrogen, substituted or unsubstituted benzyl or C1-C10 alkyl; and the substituents optionally present in R' are each independently selected from at least one of C1-C10 alkyl, methoxy, fluoro, chloro, bromo, nitro and trifluoromethyl; preferably H.

The compounds having the structure represented by the above formula (I-1) are (R, R) -N-monosulfonyl-diarylethylenediamine compounds, and examples of such compounds include:

formula (R, R) - (I-1-1-1)Formula (R, R) - (I-1-1-2)

Formula (R, R) - (I-1-1-3)Formula (R, R) - (I-1-1-4)

Formula (R, R) - (I-1-1-5)

Formula (R, R) - (I-1-1-6)Formula (R, R) - (I-1-1-7)

Formula (R, R) - (I-1-1-8)

A junction represented by the above formula (I-2)The compounds of formula (I) are (R, R) -N-monosulfonyl-cyclohexanediamines, examples of which include: formula (R, R) - (I-2-1-1)Formula (R, R) - (I-2-1-2)

The compound with the structure shown in the formula (I-3) is a (R, R) -N-monosulfonyl-1-substituted pyrrole-3, 4-diamine compound, and the compound with the structure shown in the formula (I-4) is a (R) -N-monosulfonyl-2, 2 '-diamino-1, 1' -dinaphthalene diamine compound.

The compounds having the structure represented by the above formula (I-5) are (S, S) -N-monosulfonyl-diarylethylenediamine compounds, and examples of such compounds include: formula (S, S) - (I-5-1-1)Formula (S, S) - (I-5-1-2)Formula (S, S) - (I-5-1-3)Formula (S, S) - (I-5-1-4)Formula (S, S) - (I-5-1-5)Formula (S, S) - (I-5-1-6)(S,S)-(I-5-1-7)

The compounds having the structure represented by the above formula (I-6) are (S, S) -N-monosulfonyl-cyclohexanediamines, and examples of such compounds include: formula (S, S) - (I-6-1-1)Formula (S, S) - (I-6-1-2)

The compound with the structure shown in the formula (I-7) is (S, S) -N-monosulfonyl-1-substituted pyrrole-3, 4-diamine compound, and the compound with the structure shown in the formula (I-8) is (S) -N-monosulfonyl-2, 2 '-diamino-1, 1' -dinaphthalene diamine compound

According to the present invention, in the complex having the structure represented by the above formula (4), L as another ligand₁Providing a space coordination structure of 6 coordination or 5 coordination for the metal element M, wherein the coordination can contribute to higher chemical stability of the complex with the structure shown in the formula (4), thereby contributing to the high-efficiency and high-enantioselectivity catalysis of the complex serving as the chiral catalyst of the invention, and preferably, L₁Is eta⁶-phenyl ligand,. eta.⁶-1, 4-dimethylbenzene ligand, eta⁶-1-methyl-4-isopropylbenzene ligand,. eta.⁶-1,3,5, -trimethylbenzene ligand,. eta.⁶-1,2,3,4, 5-pentamethylbenzene ligand,. eta.⁶-1,2,3,4,5, 6-hexamethylbenzene ligand,. eta.⁵-metallocene ligand or eta⁵A pentamethylcyclopentadienyl radical, more preferably eta⁶-1-methyl-4-isopropylphenyl ligand or eta⁶-1,2,3,4,5, 6-hexamethylbenzene ligand.

According to the present invention, in the complex having the structure represented by the above formula (4), the anion X is: OTf^-Refers to the negative ion of trifluoroformic acid, BF₄ ^-Refers to boron tetrafluoride anion, PF₆ ^-Refers to phosphorus hexafluoride anion, SbF₆ ^-Refers to antimony hexafluoride anion, NTf₂ ^-Refers to bis (trifluoromethanesulfonyl) imide anions, the diarylphosphate anions may be, for examplePreferably the diaryl phosphate anion has the formulaThe structure shown; and use BAR₄ ^-Represents a tetraarylboron anion;

wherein, the aryl group in the tetraarylboron anion of the anion X can be, for example, a substituted or unsubstituted phenyl group or a substituted or unsubstituted naphthyl group, and the substituent is a methyl group, an ethyl group, a halogen group or a trifluoromethyl group, preferably, the aryl group in the tetraarylboron anion of the anion X is a phenyl group or a 3, 5-bis (trifluoromethyl) phenyl group; and with BARF^-Tetraarylboron anion with aryl as 3, 5-bis (trifluoromethyl) phenyl, in BPh₄ ^-Represents a tetraarylboron anion with the aryl group being phenyl. Preferably, the biaryl diphenol-derived phosphate anion for X is one of the structures shown in the following formulas:

the structure represented by the formula (II-1) is diphenylphosphate anion, the structure represented by the formula (II-2) is 2,2' -diphenylphosphate anion, the structure represented by the formula (II-3) is (R) -2,2' -binaphthalene phosphate anion, the structure represented by the formula (II-4) is (S) -2,2' -binaphthalene phosphate anion, the structure represented by the formula (II-5) is (R) -8H-2,2' -binaphthalene phosphate anion, and the structure represented by the formula (II-6) is (S) -8H-2,2' -binaphthalene phosphate anion.

In order to obtain a single optical isomer of the polysubstituted chiral tetrahydroisoquinoline compound and the polysubstituted chiral dihydroisoquinoline compound with higher yield and/or higher enantiomeric equivalent, more preferably, X is OTf^-、BF₄ ^-、PF₆ ^-、SbF₆ ^-、BArF^-Or a structure represented by the formula (II-1).

According to the present invention, a typical chiral catalyst has the structure shown in the following formula:

wherein: definition of X ═ OTf^-(a)，BF₄ ^-(b)，PF₆ ^-(c)，SbF₆ ^-(d)，NTf₂ ^-(e)，BArF^-(f) Diphenyl phosphate anion (g), 2,2' -diphenyl phosphate anion (h), (R) -2,2' -binaphthalene phosphate anion (i), (S) -2,2' -binaphthalene phosphate anion (j).

That is, herein, (R, R) -4a refers to a compound having the structure of (R, R) -4 described above and wherein X ═ OTf. That is, the typical chiral catalyst is selected from one or more of the following compounds: (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、18a、18b、18c、18d、18e、18f、18g、18h、18i、18j、(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) -17 j. More preferably, the compound is selected from the group consisting of X ═ OTf^-(a)，BF₄ ^-(b)，PF₆ ^-(c)，SbF₆ ^-(d)，NTf₂ ^-(e)，BArF^-(f) The complex having the structure shown in the case of diphenylphosphoric acid anion (g), 2,2' -diphenylphosphoric acid anion (h), (R) -2,2' -binaphthalene phosphoric acid anion (i), (S) -2,2' -binaphthalene phosphoric acid anion (j) is used as a chiral catalyst. From the viewpoint of improving the hydrogenation conversion rate of the compound of the structure represented by formula (1) of the present invention, it is more preferable to use X ═ OTf^-(a)，BF₄ ^-(b)，PF₆ ^-(c)，SbF₆ ^-(d)，BArF^-(f) The above complexes of diphenylphosphoric acid anion (g) or 2,2' -diphenylphosphoric acid anion (h) serve as the chiral catalyst of the present invention. From the viewpoint of simultaneously improving the hydrogenation conversion rate and the enantiomeric excess of the compound having the structure represented by formula (1) of the present invention, it is more preferable to use the above-mentioned complex of X ═ diphenylphosphoric acid anion (g) as the catalyst of the present invention (particularly, it is preferable to use at least one of (R, R) -4g, (R, R) -5g, and its enantiomer (S, S) -4g, (S, S) -5 g).

The chiral diamine metal catalyst is preferably prepared by the chiral catalyst preparation method disclosed in CN105111208A, and the invention is not particularly limited thereto.

According to the present invention, when a complex having a structure represented by formula (4) is used as a catalyst for addition reaction of a compound having a structure represented by formula (1) with hydrogen, a compound having a structure represented by formula (2) or (3) can be obtained in high yield and in high enantiomeric excess by using a chiral catalyst. However, according to the structural characteristics of the compound having the structure shown in formula (1), in order to optimize the catalytic activity of the chiral catalyst on the compound having the structure shown in formula (1), it is preferable that the molar ratio of the compound having the structure shown in formula (1) to the amount of the chiral catalyst is 10 to 2000: 1, for example, may be 10 to 30: 1. 20-40: 1. 30-50: 1. 45-100 parts of: 1. 50-150: 1. 50-200: 1. 100-250: 1. 100-300: 1. 350-400: 1. 450-500: 1. 500-1000: 1 or 500-1500: 1, more preferably 50 to 1000: 1, more preferably 50 to 500: 1.

the above addition reaction with hydrogen gas may be carried out under the conditions of hydrogen gas catalytic hydrogenation reaction which are conventional in the art, but in order to further match the catalytic action of the chiral catalyst of the present invention on the substrate, the addition reaction preferably comprises the following conditions: the pressure of the hydrogen is 1-100atm, the temperature is-10 to 100 ℃, and the time is 0.5-72 h. The pressure of hydrogen gas as the condition of the above addition reaction may be, for example, 10 to 100atm, 30 to 100atm, 50 to 100atm, 80 to 100atm, 30 to 80atm, 30 to 50atm or 50 to 80atm, more preferably 5 to 80atm, still more preferably 50 to 80 atm. The temperature as the conditions for the above addition reaction may be, for example, -10 to 90 ℃, -10 to 60 ℃, -10 to 40 ℃, -10 to 25 ℃, 25 to 90 ℃, 25 to 60 ℃, 25 to 40 ℃, 40 to 90 ℃, 40 to 60 ℃ or 60 to 90 ℃, more preferably 0 to 60 ℃, and still more preferably 0 to 40 ℃. The time under which the above-mentioned addition reaction is carried out may be, for example, 0.5 to 5 hours, 5 to 10 hours, 11 to 15 hours, 16 to 20 hours or 16 to 20 hours, more preferably 0.5 to 15 hours, still more preferably 0.5 to 5 hours. Wherein the pressure of hydrogen is 1atm means that the reaction system is in an environment where the pressure of hydrogen reaches 1 atm. The addition reaction can be carried out in various reaction vessels, and is preferably carried out in a high-pressure reaction vessel.

According to the present invention, the solvent used for the addition reaction is not particularly limited, and may be water and a conventional organic solvent, for example, imidazole ionic liquid [ BMIM ]]PF₆One or more of water, Dichloromethane (DCM), 1, 2-dichloroethane, chloroform, Ethyl Acetate (EA), Tetrahydrofuran (THF), benzene, toluene, xylene, chlorobenzene, diethyl ether, dioxane, acetone and C1-C10 monohydric alcohols, wherein the C1-C10 monohydric alcohols are preferably one or more of methanol (MeOH), ethanol (EtOH), propanol, n-butanol (n-BuOH) and Isopropanol (IPA). More preferably, the solvent is methanol (MeOH), ethanol (EtOH), iso-ethanolOne or more of propanol (IPA), n-butanol (n-BuOH), Dichloromethane (DCM), Tetrahydrofuran (THF), toluene, Ethyl Acetate (EA), and acetone. Among them, when methanol (MeOH), ethanol (EtOH), Isopropanol (IPA), n-butanol (n-BuOH), Dichloromethane (DCM), Tetrahydrofuran (THF), toluene, Ethyl Acetate (EA), or acetone was used as a solvent, a compound having a structure represented by formula (2) with an ee value of 93% or more and a compound having a structure represented by formula (3) with an ee value of 99% or more were obtained.

Another preferable choice as the above solvent is a mixed solution of at least one of Dichloromethane (DCM), 1, 2-dichloroethane, tetrahydrofuran, benzene, toluene, xylene and chlorobenzene and a monohydric alcohol of C1-C10 as the solvent. For example, a mixed solvent of isopropanol and toluene in a volume ratio of 1-2:1 may be used as the solvent for the addition reaction; alternatively, a mixed solvent of isopropanol and dichloromethane in a volume ratio of 1-2:1 is used as the solvent for the addition reaction.

According to the present invention, the amount of the compound having a structure represented by formula (1) to be used is not particularly limited as long as the compound having a structure represented by formula (2) or formula (3) of the present invention can be obtained, and preferably, the amount of the compound having a structure represented by formula (1) to be used is 0.1 to 1mmol, more preferably 0.1 to 0.6mmol, in terms of moles per 1mL of the solvent.

The method can selectively carry out hydrogenation kinetic resolution on the compound with the structure shown in the formula (1) to obtain the polysubstituted tetrahydroisoquinoline and the corresponding chiral compound of the polysubstituted dihydroisoquinoline, wherein the polysubstituted tetrahydroisoquinoline has chiral carbon atoms.

The second aspect of the invention provides a polysubstituted chiral tetrahydroisoquinoline compound, which is a compound shown in formula (2);

formula (2)Each group is as described above.

The third aspect of the invention provides a single optical isomer of a polysubstituted chiral dihydroisoquinoline compound, which is characterized in that the polysubstituted chiral dihydroisoquinoline compound is a compound shown as a formula (1);

formula (1)Each group is as described above.

The specific compounds are as described above and will not be described in further detail herein.

The invention can obtain polysubstituted chiral tetrahydroisoquinoline with enantiomeric excess of 93 percent and diastereoisomer excess of more than 99 percent. Among them, preferably, the present invention can obtain the enantiomeric excess of more than 99% of the polysubstituted chiral dihydroisoquinoline, diastereoisomers excess more than 99%.

The present invention will be described in detail below by way of examples.

In the following examples

Conversion of reaction ═ conversion reactant]/([ reactant of conversion)]+ [ unconverted reactants)]) X 100%. The conversion rate of the asymmetric catalytic hydrogenation reaction of the compound with the structure shown in the formula (1) is that the product mixture of the asymmetric catalytic hydrogenation reaction before purification is directly subjected to nuclear magnetic resonance hydrogen spectrum (¹H-NMR), wherein the peak area of the characteristic peak of the compound of the structure represented by formula (1) that has not reacted and the peak area of the characteristic peak that has been converted into a product are regarded as the concentrations (weight percentage) of the reactant that has not been converted and the reactant that has been converted, respectively, and the conversion is calculated according to the above formula.

For hydrogenated products with two chiral centers, trans/cis refers to the ratio of diastereomers in the reaction product, calculated by the formula [ (S, S) + (R, R) ]/[ (S, R) + (R, S) ]; where, for trans-greater products, the enantiomeric excess of the product (absolute value of the ee value, which represents the excess of one enantiomer over the other in the reaction product, usually expressed in percent) is calculated by the formula: ee ═ [ (S, S) - (R, R) ]/[ (S, S) + (R, R) ]) x 100%; for the more cis product, the enantiomeric excess (absolute value of ee) of the product is calculated as: ee ═ [ (S, R) - (R, S) ]/[ (S, R) + (R, S) ] × 100%.

The following chiral catalysts were prepared according to the preparation method of chiral catalyst disclosed in CN 105111208A.

The compounds having the structure shown in the formula (1) are prepared by the following method, and the racemates of the compounds having the structure shown in the formula (1) are prepared by the following method:

dissolving the formula (1-a) and the formula (1-b) in an ether solution (the molar ratio of the amount of the compound having the structure represented by the formula (1-a) to the amount of the compound having the structure represented by the formula (1-b) is 1:1.5) so that the concentration of the compound having the structure represented by the formula (1-a) is 1.5 mol/L), and adding Fe₃(CO)₁₂(Compound of the formula (1-a) and Fe₃(CO)₁₂The molar ratio of the used amount of the compound is 1:0.05), carrying out redox neutral 4+2 cycloaddition reaction in a nitrogen atmosphere, cooling to room temperature after the reaction is finished, carrying out spin drying to obtain a crude product, and purifying by using column chromatography to obtain the compound with the structure shown in the formula (1).

Examples 1 to 13

This example illustrates the asymmetric hydrogenation kinetic resolution of a mixture of enantiomers of polysubstituted dihydroisoquinoline compounds of the present invention.

Dissolving 0.01mmol of chiral catalyst (specific selection is shown in table 1) and 0.1mmol of compound raceme with the structure shown in formula (1-1) in 1.0mL of dichloromethane, replacing air with nitrogen, charging 50atm of hydrogen, stirring at 25 ℃ for reaction for a certain time, carrying out silica gel column chromatography on reaction liquid obtained after the reaction to remove the chiral catalyst, obtaining the chiral polysubstituted tetrahydroisoquinoline with the structure shown in formula (2-1) and the chiral polysubstituted dihydroisoquinoline with the structure shown in formula (3-1), and testing the ee value, the ee value and the conversion rate of the obtained compound to be shown in table 1.

TABLE 1

Examples 14 to 20

This example illustrates the asymmetric hydrogenation kinetic resolution of a mixture of enantiomers of polysubstituted dihydroisoquinoline compounds of the present invention.

Dissolving 0.01mmol of chiral catalyst (R, R) -4c and 0.1mmol of compound raceme with a structure shown in a formula (1-1) in 1.0mL of solvent (the specific selection is shown in table 2), replacing air with nitrogen, filling hydrogen of 50atm, stirring at 25 ℃ for reaction for a certain time, carrying out silica gel column chromatography on reaction liquid obtained after the reaction to remove the chiral catalyst, obtaining chiral polysubstituted tetrahydroisoquinoline with a structure shown in a formula (2-1) and chiral polysubstituted dihydroisoquinoline with a structure shown in a formula (3-1), and testing the ee value, the ee value and the conversion rate of the obtained compounds to be shown in table 2.

TABLE 2

Examples 21 to 26

This example illustrates the asymmetric hydrogenation kinetic resolution of a mixture of enantiomers of polysubstituted dihydroisoquinoline compounds of the present invention.

Dissolving a certain amount of chiral catalyst (R, R) -4c and 0.1mmol of compound raceme with the structure shown in the formula (1-1) in 1.0mL of dichloromethane, replacing air with nitrogen, filling a certain amount of hydrogen, stirring and reacting for a certain time at a certain temperature, performing silica gel column chromatography on reaction liquid obtained after the reaction to remove the chiral catalyst to obtain chiral polysubstituted tetrahydroisoquinoline with the structure shown in the formula (2-1) and chiral polysubstituted dihydroisoquinoline with the structure shown in the formula (3-1), and testing the ee value, the ee value and the yield of the obtained compound as shown in the table 3.

TABLE 3

Examples 27 to 48

This example illustrates the asymmetric hydrogenation kinetic resolution of a mixture of enantiomers of polysubstituted dihydroisoquinoline compounds of the present invention.

In an autoclave, 0.01mmol of chiral catalyst (R, R) -4c and 0.1mmol of a racemic compound of the specified structure of formula (1) were dissolved in 1mL of dichloromethane, air was replaced with nitrogen, then 50atm of hydrogen was introduced, and the reaction was stirred at 25 ℃ for a certain period of time, and the resulting reaction solution was subjected to silica gel column chromatography (eluent was dichloromethane) to remove the chiral catalyst. The racemic polysubstituted dihydroisoquinoline derivative with the structure shown in the formula (1) adopted has different structures, the rest is the same as that in the embodiment 23, the chiral polysubstituted tetrahydroisoquinoline compound (2) is obtained, the corresponding chiral polysubstituted dihydroisoquinoline compound (3) is recovered, and the ee value, the ee value and the yield of the chiral compound prepared in each embodiment are specifically shown in the table 4.

TABLE 4

In order to intuitively illustrate the performance and characterization process of the chiral polysubstituted tetrahydroisoquinoline compound and the corresponding chiral 3, 4-dihydroisoquinoline compound prepared by the kinetic resolution method of racemic polysubstituted dihydroisoquinoline compound of the present invention, the present invention exemplarily provides the identification results and processes of the chiral compounds prepared in example 23 and examples 31 to 52, which are specifically shown in table 5.

TABLE 5

The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.