A N6 chiral cyclic compound and its preparation method and application

Abstract

The present invention relates to the field of chemical catalysis and discloses an N6 chiral cyclic compound, its preparation method, and application. The compound is a compound having the structure represented by the following Formula I, or its enantiomers, racemates, diastereomers, or salts. The N6 chiral cyclic compound has abundant coordination sites and weak non-covalent interaction sites, and its synthesis method is simple. When used in the preparation of chiral γ-amino alcohols, the reaction conditions are mild, and both chemoselectivity and enantioselectivity are excellent, significantly increasing the yield of chiral γ-amino alcohols. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of chemical catalysis, and in particular to an N6 chiral cyclic compound, a preparation method and an application thereof. Background Art

[0002] As one of the research subjects of supramolecular chemistry, macrocyclic compounds have attracted much attention at the beginning of the development of supramolecular catalysis because they have recognition sites that can reversibly bind to different guest molecules through non-covalent interactions, simulating the pre-organization process of substrate molecules in enzyme catalysis, and have made gratifying progress in the past two decades.

[0003] On the one hand, macrocyclic molecules can act as microreactors to participate in catalytic reactions. On the other hand, by covalently modifying organic or metal catalytic sites within macrocyclic molecules, novel macrocyclic organocatalysts and macrocyclic ligands can be constructed, enabling supramolecular catalytic reactions with tunable activity and selectivity. One of the main strategies for creating novel macrocyclic ligands is to introduce multiple electron-rich heteroatoms (N / O / P / S, etc.) into the macrocyclic backbone to construct macrocyclic ligands with abundant coordination sites.

[0004] Among them, there have been some specific research reports on chiral nitrogen-containing macrocyclic ligands, such as the application of pyrrole-type chiral multi-N macrocycles developed by Savoia's group in Cu-catalyzed asymmetric Henry reactions, and the application of chiral PN macrocyclic ligands developed by Gao, Mezzeti et al. in Fe-catalyzed asymmetric reduction reactions of aromatic ketones.

[0005] However, due to the flexible backbone structures of existing macrocyclic ligands, truly efficient and highly enantioselective chiral macrocyclic transition metal catalytic systems are rare, especially those based on polynitrogen chiral macrocyclic ligands. Therefore, the development of novel chiral polynitrogen macrocyclic ligands and their application in efficient and highly selective asymmetric transition metal catalysis remains an urgent challenge in this field.

[0006] On the other hand, chiral γ-amino alcohols are important components of many drug molecules or natural products, such as the common antidepressants atomoxetine, fluoxetine and duloxetine, and the anti-HIV drug lopinavir.

[0007] In the traditional preparation method of chiral γ-amino alcohol, it is necessary to first synthesize a chiral alcohol derivative compound, and then modify it to obtain the chiral γ-amino alcohol. The above method has a long synthesis path and poor yield, which is not suitable for large-scale industrial production. In addition, there are also reports of using chiral ruthenium complexes to prepare chiral γ-amino alcohols using a one-pot process. However, this method not only has a low yield, but also, because ruthenium is a precious metal, the economic cost of producing γ-amino alcohols using this method is high, which is also not conducive to large-scale production.

[0008] Therefore, developing a method for preparing chiral γ-amino alcohols with low cost, high yield and simplicity is of great significance and market value. Summary of the Invention

[0009] The present invention aims to address the problems of the prior art by providing an N6 chiral cyclic compound, a preparation method, and applications thereof, as well as a method for preparing chiral γ-amino alcohols. The N6 chiral cyclic compound has abundant coordination sites and weak non-covalent interaction sites, and its synthesis method is simple, making it highly suitable for the preparation of chiral γ-amino alcohols.

[0010] In order to achieve the above-mentioned object, the first aspect of the present invention provides an N6 chiral cyclic compound, wherein the compound is a compound having a structure represented by Formula I or an enantiomer, racemate, diastereomer or salt thereof,

[0011]

[0012] Among them, R 1 、R 2 、R 3 、R 4 Each is independently selected from hydrogen, phenyl, substituted phenyl, furyl, thienyl, pyridyl, 1-naphthyl, 2-naphthyl, C1-10 straight-chain or branched alkyl, and the substituent on the substituted phenyl is selected from one or more of halogen, C1-10 straight-chain or branched alkyl and C1-10 straight-chain or branched alkoxy;

[0013] R 1 、R 2 、R 3 、R 4 Can be the same or different;

[0014] Or, R 1 and R 2 and R 3 and R 4 They can be combined to form a C3-7 aliphatic ring or a substituted C3-7 aliphatic ring, wherein the substituent on the substituted C3-7 aliphatic ring is selected from one or more of phenyl, benzyl, 1-naphthyl, 2-naphthyl, C1-10 straight-chain or branched alkyl and C1-10 straight-chain or branched alkoxy;

[0015] R 5 、R 6Each is independently selected from halogen, nitro, hydroxyl, acetamido, C1-10 straight-chain or branched alkyl, C1-10 straight-chain or branched alkoxy, substituted or unsubstituted C6-20 aryl, substituted or unsubstituted C7-21 arylbenzyl, and the substituents of the substituted C6-20 aryl and substituted C7-21 arylbenzyl are each independently selected from one or more of hydrogen, halogen, nitro, methyl, methoxy, trifluoromethyl, hydroxyl and acetamido;

[0016] R 5 、R 6 Can be the same or different;

[0017] m is an integer of 0-2, and n is an integer of 0-3.

[0018] Preferably, the R 1 、R 2 、R 3 、R 4 Each is independently selected from hydrogen, phenyl, substituted phenyl and C1-6 straight-chain or branched alkyl, and the substituent on the substituted phenyl is selected from one or more of fluorine, chlorine, C1-3 straight-chain alkyl and C1-3 straight-chain alkoxy;

[0019] Alternatively, the R 1 and R 2 、The R 3 and R 4 They can be combined to form C4-6 aliphatic rings.

[0020] Preferably, the R 1 、R 2 、R 3 、R 4 are each independently selected from hydrogen or phenyl, or the R 1 and R 2 、The R 3 and R 4 They can be combined to form C4-6 aliphatic rings.

[0021] Preferably, the R 5 、R 6 Each is independently selected from fluorine, chlorine, nitro, hydroxyl, acetylamino, C1-6 straight chain or branched alkyl, C1-6 straight chain or branched alkoxy; more preferably, the R 5 、R 6 Each is independently selected from fluorine, chlorine or a C1-3 straight-chain alkyl group.

[0022] Preferably, m is 0 and n is 0.

[0023] Preferably, the compound is any one of the compounds having the following structures:

[0024]

[0025] A second aspect of the present invention provides a method for preparing the N6 chiral cyclic compound of the first aspect, the method comprising the following steps: 1) in the presence of a first organic solvent and a reducing agent, subjecting the diamine compound of Formula 1 to a reductive amination reaction with the aldehyde of Formula 2 under reductive amination conditions to obtain a compound of Formula 3;

[0026]

[0027] 2) in the presence of a second organic solvent, condensing the compound represented by Formula 3 with the aldehyde represented by Formula 4 under condensation reaction conditions to obtain a compound represented by Formula 5;

[0028]

[0029] 3) In the presence of a third organic solvent, a catalyst, a ligand, and a first base, a coupling reaction is carried out with the compound represented by Formula 5 and the diamine compound represented by Formula 6 under coupling reaction conditions to prepare a compound represented by Formula I,

[0030]

[0031] Among them, in Formulas 1 to 6 and Formula I,

[0032] R 1 ~R 6 The meaning of is as above;

[0033] R 7 is hydrogen, C1-10 straight-chain or branched alkyl, phenyl, substituted phenyl, furyl, thienyl, pyridyl or benzyl, wherein the substituent on the substituted phenyl is selected from one or more of C1-10 straight-chain or branched alkyl and C1-10 straight-chain or branched alkoxy, and the number of the substituent is 1 to 5;

[0034] X is a halogen or a trifluoromethanesulfonate group; preferably, X is a chlorine, a bromine, an iodine or a trifluoromethanesulfonate group;

[0035] m is an integer of 0-2, and n is an integer of 0-3.

[0036] Preferably, in step 1), the first organic solvent is one or more of dichloromethane, methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane and n-pentane; more preferably, the first organic solvent is one or more of dichloromethane, toluene, methanol and ethanol.

[0037] Preferably, the reducing agent is one or more of lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride; more preferably, the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride.

[0038] Preferably, the molar ratio of the diamine compound represented by Formula 1 to the aldehyde represented by Formula 2 and the reducing agent is 1:2-5:2-10; more preferably, the molar ratio of the diamine compound represented by Formula 1 to the aldehyde represented by Formula 2 and the reducing agent is 1:2-3:4-5.

[0039] Preferably, the amount of the first organic solvent is 50 to 100 mL relative to 1 g of the diamine compound represented by Formula 1; more preferably, the amount of the first organic solvent is 60 to 80 mL relative to 1 g of the diamine compound represented by Formula 1.

[0040] Preferably, the reductive amination conditions include: temperature of -20 to 120° C., and reaction time of 1 to 5 hours; more preferably, the reductive amination conditions include: temperature of 20 to 60° C., and reaction time of 2 to 4 hours.

[0041] Preferably, the reaction in step 1) is carried out in the presence of a first acid.

[0042] Preferably, the first acid is one or more of formic acid, acetic acid, carbonic acid and p-toluenesulfonic acid.

[0043] Preferably, the volume ratio of the first acid to the first organic solvent is 1:50-1000; more preferably, the volume ratio of the first acid to the first organic solvent is 1:50-200.

[0044] Preferably, the reaction in step 1) is carried out in the presence of a first water absorbing agent, which is a molecular sieve and / or anhydrous sodium sulfate.

[0045] Preferably, in step 2), the second organic solvent is one or more of diethyl ether, methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane and n-pentane; more preferably, the second organic solvent is one or more of diethyl ether, tetrahydrofuran and dichloromethane.

[0046] Preferably, the amount of the second organic solvent used is 10 to 50 mL relative to 1 g of the compound represented by Formula 3; more preferably, the amount of the second organic solvent used is 10 to 30 mL relative to 1 g of the compound represented by Formula 3.

[0047] Preferably, the molar ratio of the compound represented by Formula 3 to the aldehyde represented by Formula 4 is 1:1-5; more preferably, the molar ratio of the compound represented by Formula 3 to the aldehyde represented by Formula 4 is 1:1-4.

[0048] Preferably, the condensation reaction conditions include: reaction temperature of -20 to 120° C., and reaction time of 1 to 48 h; more preferably, the condensation reaction conditions include: reaction temperature of 10 to 50° C., and reaction time of 6 to 12 h.

[0049] Preferably, the reaction in step 2) is carried out in the presence of a second water absorbing agent, which is a molecular sieve and / or anhydrous sodium sulfate.

[0050] Preferably, in step 3), the third organic solvent is toluene, diethyl ether, methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane and n-pentane. One or more of; more preferably, the third organic solvent is toluene, xylene and 1,4-dioxane. One or more of.

[0051] Preferably, the catalyst is a transition metal salt and / or a transition metal oxide; more preferably, the catalyst is Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2, Pd(OAc)2, PdCl2(dffp), ( t Bu3P)2Pd, (PCy3)2Pd, Pd(PCy3)2Cl2, Pd-Xphos, Pd- t One or more of BuXphosG3, CuBr, CuI, Cu2O, Cu(acac)2 and Cu(OTf)2; further preferably, the catalyst is Pd2(dba)3, Pd(dba)2, Pd-Xphos and Pd- t One or more of BuXphosG3.

[0052] Preferably, the ligand is one or more of BINAP, Cyclohexyl JohnPhos, DavePhos, XPhos, SPhos, MePhos, RuPhos, BrettPhos, PhDavePHos, tBuXPhos, JohnPhos, TrixiePhos, RockPhos, CPhos, JackiePhos, tBuMePhos, bipyridine, o-phenanthroline, BTMPO, BPMPO, Bn(MNBO), BFMO, BTMO, BHMPO, BPPO and DBO; more preferably, the ligand is one or more of BINAP, XPhos and BrettPhos.

[0053] Preferably, the first base is one or more of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, barium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium fluoride, potassium fluoride, cesium fluoride, LHMDS, triethylamine, N,N-diisopropylethylenediamine and DBU; more preferably, the first base is one or more of sodium tert-butoxide, potassium tert-butoxide and LHMDS.

[0054] Preferably, the molar ratio of the compound represented by Formula 5, the diamine compound represented by Formula 6, the catalyst, the ligand and the first base is 1:1-5:0.001-0.2:0.002-0.4:3-6; more preferably, the molar ratio of the compound represented by Formula 5, the diamine compound represented by Formula 6, the catalyst, the ligand and the first base is 1:1-2:0.02-0.1:0.1-0.2:3-4.

[0055] Preferably, the amount of the third organic solvent used is 10 to 100 mL relative to 1 g of the compound represented by Formula 5; more preferably, the amount of the third organic solvent used is 20 to 50 mL relative to 1 g of the compound represented by Formula 5.

[0056] Preferably, the reaction conditions of the coupling reaction include: reaction temperature of -20 to 120° C., and reaction time of 1 to 48 h; more preferably, the reaction conditions of the coupling reaction include: reaction temperature of 30 to 100° C., and reaction time of 12 to 36 h.

[0057] Preferably, the step 3) further comprises: after the coupling reaction, further performing a deprotection reaction in the presence of a second acid.

[0058] Preferably, the second acid is one or more of hydrochloric acid, sulfuric acid, formic acid, acetic acid, carbonic acid and trifluoroacetic acid; more preferably, the second acid is one or more of hydrochloric acid, formic acid and acetic acid.

[0059] Preferably, the molar ratio of the compound represented by Formula 5 to the second acid is 1:1-5; more preferably, the molar ratio of the compound represented by Formula 5 to the second acid is 1:1-3.

[0060] Preferably, the reaction in step 3) is carried out in the presence of a third water absorbing agent, and the third water absorbing agent is a molecular sieve.

[0061] The third aspect of the present invention provides a method for preparing a chiral γ-amino alcohol, which comprises the steps of reacting racemic allyl alcohol and an alkylamine in the presence of a fourth solvent, a second base and a catalyst composition, wherein the catalyst composition comprises the N6 chiral cyclic compound and a manganese precursor compound described in the first aspect of the present invention, or the catalyst composition comprises a complex formed by the N6 chiral cyclic compound and a manganese precursor compound described in the first aspect of the present invention.

[0062] Preferably, the racemic allyl alcohol has a structure as shown in the following formula II:

[0063]

[0064] Among them, R 8 is phenyl, substituted phenyl, thienyl, pyridyl, furyl, 1-naphthyl, 2-naphthyl or benzothiophene, and the substituent on the substituted phenyl is one or more of halogen, trifluoromethyl, C1-3 straight-chain alkyl and C1-3 straight-chain alkoxy;

[0065] Preferably, the R 8 is phenyl, substituted phenyl, thienyl, 1-naphthyl, 2-naphthyl or benzothiophene.

[0066] Preferably, the substituent on the substituted phenyl group is one or more of fluorine, chlorine, bromine, trifluoromethyl, methyl and methoxy.

[0067] Preferably, the number of the substituents is 1 to 5; more preferably, the number of the substituents is 1 or 2.

[0068] Preferably, the alkylamine may be a cyclic amine or a fatty amine, and the alkylamine has a structure shown in Formula III:

[0069] NHR 9 R 10

[0070] Formula III

[0071] Preferably, the alkylamine is a cyclic amine, R 9 and R 10can be combined to form morpholinyl, thiomorpholinyl, piperazinyl, piperazinyl derivatives, pyrrolyl, piperidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, proline ester, norfloxacin, vortioxetine or amoxapine; more preferably, the alkylamine is a cyclic amine, R 9 and R 10 It can be combined to form morpholinyl, thiomorpholinyl, piperazinyl, piperazinyl derivatives, pyrrolyl or piperidinyl.

[0072] Preferably, the alkylamine is a fatty amine, R 9 is any one of phenyl, benzyl, and C1-C4 alkyl, R 10 It is any one of halogen, C1-C4 alkyl, and C1-C4 alkoxy.

[0073] Preferably, the molar ratio of the racemic allyl alcohol, the alkylamine and the catalyst composition calculated as the N6 chiral cyclic compound is 1-10:1:0.01-0.2; more preferably, the molar ratio of the racemic allyl alcohol, the alkylamine and the catalyst composition calculated as the N6 chiral cyclic compound is 1-5:1:0.02-0.08.

[0074] Preferably, the molar ratio of the racemic allyl alcohol to the second base is 1:0.05-2.0; more preferably, the molar ratio of the racemic allyl alcohol to the second base is 1:0.1-0.4.

[0075] Preferably, the fourth solvent is used in an amount such that the concentration of the second base in the fourth solvent is 0.001 to 10 mol / L; more preferably, the fourth solvent is used in an amount such that the concentration of the second base in the fourth solvent is 0.01 to 1 mol / L.

[0076] Preferably, the second base is one or more of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, barium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium fluoride, potassium fluoride, cesium fluoride, triethylamine, N,N-diisopropylethylenediamine and DBU; more preferably, the second base is one or more of potassium phosphate, potassium tert-butoxide and sodium phosphate; further preferably, the second base is potassium phosphate.

[0077] Preferably, the fourth solvent is one or more of water, methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane and n-pentane; more preferably, the fourth solvent is one or more of isopropanol, toluene and water.

[0078] Preferably, the reaction conditions of the racemic allyl alcohol and alkylamine include: reaction temperature of 0-100°C, reaction time of 1-120h; more preferably, the reaction conditions of the racemic allyl alcohol and alkylamine include: reaction temperature of 20-60°C, reaction time of 10-100h.

[0079] Preferably, the molar ratio of the N6 chiral cyclic compound to the manganese precursor compound in the catalyst composition is 1 to 2:1.

[0080] Preferably, the preparation method of the complex comprises: reacting the N6 chiral cyclic compound with the manganese precursor compound in the presence of a fifth organic solvent at a molar ratio of 1 to 2:1 at -20 to 120° C. for 0.5 to 24 hours.

[0081] Preferably, the manganese precursor compound is Mn(CO)5Br and / or Mn2(CO) 10 .

[0082] Preferably, the fifth organic solvent is one or more of methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane and n-pentane.

[0083] The fourth aspect of the present invention provides use of the N6 chiral cyclic compound described in the first aspect of the present invention in the preparation of chiral γ-amino alcohols.

[0084] The N6 chiral cyclic compound provided by the present invention has abundant coordination sites and non-covalent weak interaction sites, and can form a special chiral cavity with the manganese precursor compound, providing good conditions for achieving chiral induction in the catalytic reaction.

[0085] Furthermore, the synthesis method of the N6 chiral cyclic compound of the present invention is simple, the raw materials are readily available, and the preparation conditions are mild, making it very suitable for large-scale production.

[0086] In addition, when the N6 chiral cyclic compound provided by the present invention is used to prepare chiral γ-amino alcohols, the reaction conditions are mild, the chemical selectivity and enantioselectivity are excellent, and the yield of chiral γ-amino alcohols can be greatly improved. DETAILED DESCRIPTION

[0087] The endpoints of the ranges and any values 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 endpoints of each range, the endpoints of each range and individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0088] The first aspect of the present invention provides an N6 chiral cyclic compound, wherein the compound is a compound having a structure represented by Formula I or an enantiomer, racemate, diastereomer or salt thereof,

[0089]

[0090] In Formula I, R 1 、R 2 can be independently selected from hydrogen, phenyl, substituted phenyl, furyl, thienyl, pyridyl, 1-naphthyl, 2-naphthyl, C1-10 straight or branched alkyl, or the R 1 and R 2 They can be combined to form a C3-7 aliphatic ring or a substituted C3-7 aliphatic ring.

[0091] Here, the substituents on the substituted phenyl group may be selected from one or more of halogen, C1-10 straight-chain or branched alkyl, and C1-10 straight-chain or branched alkoxy; the substituents on the substituted C3-7 aliphatic ring may be selected from one or more of phenyl, benzyl, 1-naphthyl, 2-naphthyl, C1-10 straight-chain or branched alkyl, and C1-10 straight-chain or branched alkoxy.

[0092] In addition, in Formula I, 1 、R 2 Similarly, the R 3 、R 4 They can also be independently selected from hydrogen, phenyl, substituted phenyl, furyl, thienyl, pyridyl, 1-naphthyl, 2-naphthyl, C1-10 straight or branched alkyl, or the R 3 and R 4 They may also be combined to form a C3-7 aliphatic ring or a substituted C3-7 aliphatic ring.

[0093] Here, the substituents on the substituted phenyl group may be selected from one or more of halogen, C1-10 straight-chain or branched alkyl, and C1-10 straight-chain or branched alkoxy; the substituents on the substituted C3-7 aliphatic ring may be selected from one or more of phenyl, benzyl, 1-naphthyl, 2-naphthyl, C1-10 straight-chain or branched alkyl, and C1-10 straight-chain or branched alkoxy.

[0094] Furthermore, the R 1 、R 2 、R 3 、R 4 Can be the same or different.

[0095] In addition, in Formula I, R 5 、R 6 The substituents of the substituted C6-20 aryl group and the substituted C7-21 aryl benzyl group may be independently selected from one or more of hydrogen, halogen, nitro, methyl, methoxy, trifluoromethyl, hydroxyl and acetylamino.

[0096] Furthermore, the R 5 、R 6 Can be the same or different.

[0097] In addition, m may be an integer of 0 to 2, and n may be an integer of 0 to 3. For example, m may be 0, 1, or 2, and n may be 0, 1, 2, or 3.

[0098] In the present invention, preferably, the R 1 and R 2 Each independently selected from hydrogen, phenyl, substituted phenyl and C1-6 straight or branched alkyl, or, the R 1 and R 2 Here, more preferably, the substituent on the substituted phenyl group is selected from one or more of fluorine, chlorine, a C1-3 linear alkyl group, and a C1-3 linear alkoxy group.

[0099] And, preferably, the R 3 and R 4 Each independently selected from hydrogen, phenyl, substituted phenyl and C1-6 straight or branched alkyl, or, the R 3 and R 4 Here, more preferably, the substituent on the substituted phenyl group is selected from one or more of fluorine, chlorine, a C1-3 linear alkyl group, and a C1-3 linear alkoxy group.

[0100] In the present invention, it is further preferred that the R 1 and R 2 The same, are hydrogen or phenyl, or the R 1 and R 2 Can be combined to form C4~6 aliphatic rings.

[0101] More preferably, the R3 and R 4 are the same, are hydrogen or phenyl, or the R 3 and R 4 Can be combined to form C4~6 aliphatic rings.

[0102] In addition, in the present invention, preferably, the R 5 、R 6 Each is independently selected from fluorine, chlorine, nitro, hydroxyl, acetylamino, C1-6 straight chain or branched alkyl, C1-6 straight chain or branched alkoxy; more preferably, the R 5 、R 6 Each is independently selected from fluorine, chlorine or a C1-3 straight-chain alkyl group.

[0103] Furthermore, in the present invention, preferably, m is 0 and n is 0.

[0104] According to the first aspect of the present invention, the compound is any one of the compounds having the following structures:

[0105]

[0106] The second aspect of the present invention provides a method for preparing the N6 chiral cyclic compound according to the first aspect of the present invention, wherein the preparation method comprises the following steps:

[0107] 1) in the presence of a first organic solvent and a reducing agent, subjecting the diamine compound represented by Formula 1 to a reductive amination reaction with the aldehyde represented by Formula 2 under reductive amination conditions to obtain a compound represented by Formula 3;

[0108]

[0109] 2) in the presence of a second organic solvent, condensing the compound represented by Formula 3 with the aldehyde represented by Formula 4 under condensation reaction conditions to obtain a compound represented by Formula 5;

[0110]

[0111] 3) In the presence of a third organic solvent, a catalyst, a ligand, and a first base, a coupling reaction is carried out with the compound represented by Formula 5 and the diamine compound represented by Formula 6 under coupling reaction conditions to prepare a compound represented by Formula I,

[0112]

[0113] Among them, in the above formulas 1 to 6 and formula I, R 1 ~R 6 The meaning of is the same as that described in the first aspect of the present invention and will not be repeated here.

[0114] In the above formulas 4 and 5, R7 It can be hydrogen, a C1-10 straight-chain or branched alkyl group, a phenyl group, a substituted phenyl group, a furyl group, a thienyl group, a pyridyl group or a benzyl group. Here, the substituent on the substituted phenyl group can be selected from one or more of a C1-10 straight-chain or branched alkyl group and a C1-10 straight-chain or branched alkoxy group, and the number of the substituents can be 1 to 5.

[0115] In the above formula 2, formula 3 and formula 5, X may be a halogen or a trifluoromethanesulfonic acid group; preferably, X may be chlorine, bromine, iodine or a trifluoromethanesulfonic acid group.

[0116] Hereinafter, each step in the method for preparing the N6 chiral cyclic compound described in the second aspect of the present invention will be described in detail.

[0117] Step 1) A step of subjecting the diamine compound represented by Formula 1 to a reductive amination reaction with the aldehyde represented by Formula 2.

[0118] The reductive amination reaction is carried out in the presence of a first organic solvent, which is not particularly limited and can be a conventional choice in the art. For example, the first organic solvent can be one or more of dichloromethane, methanol, ethanol, propanol, isopropyl alcohol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane, and n-pentane.

[0119] In the present invention, in order to promote the reaction and improve the reaction efficiency and yield, preferably, the first organic solvent is one or more of dichloromethane, toluene, methanol and ethanol.

[0120] In a particularly preferred embodiment of the present invention, the first organic solvent is dichloromethane.

[0121] To ensure that the reaction proceeds smoothly and fully, the amount of the first organic solvent used can be determined based on the amount of the diamine compound represented by Formula 1. Preferably, the amount of the first organic solvent used is 50 to 100 mL per 1 g of the diamine compound represented by Formula 1; more preferably, the amount of the first organic solvent used is 60 to 80 mL per 1 g of the diamine compound represented by Formula 1.

[0122] In the present invention, in order to further promote the reduction reaction, preferably, the reducing agent is one or more of lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride; more preferably, the reducing agent is one or more of sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride.

[0123] In a particularly preferred embodiment of the present invention, the reducing agent is sodium borohydride, thereby promoting the reduction reaction and improving the yield of the product.

[0124] According to the present invention, in order to improve the reaction efficiency and yield, preferably, the molar ratio of the diamine compound represented by Formula 1 to the aldehyde represented by Formula 2 and the reducing agent is 1:2-5:2-10; more preferably, the molar ratio of the diamine compound represented by Formula 1 to the aldehyde represented by Formula 2 and the reducing agent is 1:2-3:4-5.

[0125] In addition, in the present invention, the reductive amination conditions can be conventionally selected in the art. For example, the reductive amination conditions can include: a temperature of -20 to 120°C and a reaction time of 1 to 5 hours. To further promote rapid reaction, preferably, the reductive amination conditions include: a temperature of 20 to 60°C and a reaction time of 2 to 4 hours.

[0126] In addition, in the present invention, in order to improve the yield, preferably, in step 1), first, in the presence of a first organic solvent, the diamine compound represented by Formula 1 and the aldehyde represented by Formula 2 undergo an amination reaction. After the reaction proceeds to a certain extent (for example, after 1 to 5 hours), the reducing agent is added to the above-mentioned amination reaction system to carry out a reduction reaction.

[0127] In addition, the reductive amination reaction can be carried out in the presence or absence of an acid. In order to accelerate the speed of the reductive amination and improve the yield, preferably, the reaction in step 1) is carried out in the presence of a first acid.

[0128] When the reaction in step 1) is carried out in the presence of the first acid, the first acid is preferably one or more of formic acid, acetic acid, carbonic acid and p-toluenesulfonic acid.

[0129] In addition, the amount of the first acid can be adjusted according to the amount of the first organic solvent. For example, the volume ratio of the first acid to the first organic solvent is 1:50 to 1000; preferably, the volume ratio of the first acid to the first organic solvent is 1:50 to 200.

[0130] In the present invention, in order to promote the rapid forward reaction of step 1) and eliminate the adverse effects of water generated during the reaction on the reaction, a first water absorbing agent may be further used to remove the water generated during the reaction. The first water absorbing agent may be any of various additives commonly used in the art that can absorb water and does not hinder the smooth progress of the reductive amination reaction. Preferably, the first water absorbing agent is a molecular sieve and / or anhydrous sodium sulfate.

[0131] Through the reductive amination reaction described in step 1), the compound represented by formula 3 is obtained.

[0132] In the present invention, in order to improve the purity of the compound represented by Formula 3 and ensure the smooth progress of subsequent reactions, the intermediate product produced in step 1) can be purified by various purification methods conventional in the art, for example, one or more of extraction, washing, drying, distillation, and recrystallization can be used to achieve purification. This is a conventional choice in the art and will not be described in detail here.

[0133] Next, step 2) will be described.

[0134] In step 2), in the presence of a second organic solvent, the compound represented by formula 3 obtained in step 1) is subjected to a condensation reaction with the aldehyde represented by formula 4 under condensation reaction conditions.

[0135] Wherein, the second organic solvent is not particularly limited and can be the conventional selection of this area.For example, the second organic solvent can be ether, methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butyl alcohol, tert-amyl alcohol, tetrahydrofuran, toluene, dimethylbenzene, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, normal heptane, normal hexane and n-pentane One or more.In order to accelerate the progress of the condensation reaction, improve yield, preferably, the second organic solvent is one or more of ether, tetrahydrofuran and dichloromethane.

[0136] In a particularly preferred embodiment of the present invention, the second organic solvent is diethyl ether.

[0137] According to the present invention, to ensure smooth reaction, the amount of the second organic solvent can be determined based on the amount of the compound represented by Formula 3. For example, the amount of the second organic solvent can be 10 to 50 mL relative to 1 g of the compound represented by Formula 3; preferably, the amount of the second organic solvent is 10 to 30 mL relative to 1 g of the compound represented by Formula 3.

[0138] In addition, in step 2), preferably, the molar ratio of the compound represented by formula 3 to the aldehyde represented by formula 4 is 1:1-5; more preferably, the molar ratio of the compound represented by formula 3 to the aldehyde represented by formula 4 is 1:1-4.

[0139] In the present invention, the conditions of the condensation reaction in step 2) are not particularly limited and can be selected conventionally in the art. For example, the conditions of the condensation reaction may include: a reaction temperature of -20 to 120°C and a reaction time of 1 to 48 hours. In order to promote rapid reaction, preferably, the condensation reaction conditions include: a reaction temperature of 10 to 50°C and a reaction time of 6 to 12 hours.

[0140] In addition, in order to promote the condensation reaction in step 2) to proceed quickly in the forward direction and eliminate the adverse effects of water generated during the reaction on the reaction, a second water absorbing agent may be further used in the present invention to remove water generated during the reaction.

[0141] The second water absorbing agent can be any of various additives commonly used in the art that can absorb water and will not hinder the smooth progress of the condensation reaction. Preferably, the second water absorbing agent is molecular sieve and / or anhydrous sodium sulfate.

[0142] Of course, in the present invention, in order to improve the purity of the compound represented by Formula 5 and ensure the smooth progress of the subsequent reaction, the product produced in step 2) can also be subjected to impurity removal and purification treatment by various conventional impurity removal and purification methods in the art. For example, one or more of filtration, washing, distillation, and recrystallization can be used to achieve purification. This is a conventional choice in the art and will not be described in detail here.

[0143] Through step 2), a compound represented by formula 5 is prepared.

[0144] Next, step 3) will be described in detail.

[0145] In step 3), in the presence of a third organic solvent, a catalyst, a ligand and a first base, a coupling reaction is carried out on the compound represented by Formula 5 and the diamine compound represented by Formula 6 under coupling reaction conditions.

[0146] In the present invention, the third organic solvent is not particularly limited and can be a conventional choice in the art. For example, the third organic solvent can be toluene, ether, methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane and n-pentane. In order to improve the progress of the coupling reaction in step 3), preferably, the third organic solvent is one or more of toluene, xylene and 1,4-dioxane.

[0147] In a particularly preferred embodiment of the present invention, the third organic solvent is toluene.

[0148] In the present invention, the amount of the third organic solvent can be determined according to the amount of the compound represented by Formula 5. For example, relative to 1g of the compound represented by Formula 5, the amount of the third organic solvent can be 10 to 100mL; in order to further promote the reaction, preferably, relative to 1g of the compound represented by Formula 5, the amount of the third organic solvent is 20 to 50mL.

[0149] In step 3), the catalyst is used to catalyze the coupling reaction and is not particularly limited. For example, it can be selected from transition metal salts and / or transition metal oxides.

[0150] Wherein, preferably, the catalyst is Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2, Pd(OAc)2, PdCl2(dffp), ( t Bu3P)2Pd, (PCy3)2Pd, Pd(PCy3)2Cl2, Pd-Xphos, Pd- t One or more of BuXphosG3, CuBr, CuI, Cu2O, Cu(acac)2 and Cu(OTf)2; more preferably, the catalyst is Pd2(dba)3, Pd(dba)2, Pd-Xphos and Pd- t One or more of BuXphosG3 can further improve the reaction efficiency.

[0151] In a particularly preferred embodiment of the present invention, the catalyst is Pd2(dba)3. By using Pd2(dba)3 as the catalyst in step 3), the catalytic efficiency can be significantly improved.

[0152] In the present invention, the ligand in step 3) can be one or more of BINAP, Cyclohexyl JohnPhos, DavePhos, XPhos, SPhos, MePhos, RuPhos, BrettPhos, PhDavePHos, tBuXPhos, JohnPhos, TrixiePhos, RockPhos, CPhos, JackiePhos, tBuMePhos, bipyridine, o-phenanthroline, BTMPO, BPMPO, Bn(MNBO), BFMO, BTMO, BHMPO, BPPO, and DBO. Preferably, the ligand is one or more of BINAP, XPhos, and BrettPhos. This can promote the reaction and improve the yield.

[0153] In a particularly preferred embodiment of the present invention, the ligand is BINAP. By using BINAP as the ligand in step 3), the reaction can be significantly promoted and the yield can be greatly improved.

[0154] In addition, in step 3), the first base can be various organic bases and inorganic bases conventionally used in the field for coupling reactions. For example, the first base can be potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, barium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium fluoride, potassium fluoride, cesium fluoride, LHMDS, triethylamine, N,N-diisopropylethylenediamine and DBU. In order to improve the reaction yield and reaction efficiency, preferably, the first base is one or more of sodium tert-butoxide, potassium tert-butoxide and LHMDS.

[0155] In a preferred embodiment of the present invention, the first base is sodium tert-butoxide, which can significantly improve the reaction yield and reaction efficiency.

[0156] In the present invention, in order to ensure the smooth progress of the coupling reaction in step 3) and ensure the product yield, the molar ratio of the compound represented by Formula 5, the diamine compound represented by Formula 6, the catalyst, the ligand and the first base is 1:1-5:0.001-0.2:0.002-0.4:3-6; preferably, the molar ratio of the compound represented by Formula 5, the diamine compound represented by Formula 6, the catalyst, the ligand and the first base is 1:1-2:0.02-0.1:0.1-0.2:3-4.

[0157] In addition, in step 3), the conditions of the coupling reaction are not particularly limited and can be selected conventionally in the art. For example, the reaction conditions of the coupling reaction may include: a reaction temperature of -20 to 120°C and a reaction time of 1 to 48 hours. In order to promote rapid reaction, preferably, the reaction conditions of the coupling reaction include: a reaction temperature of 30 to 100°C and a reaction time of 12 to 36 hours.

[0158] In addition, in the present invention, the coupling reaction is preferably carried out under an inert atmosphere, such as nitrogen, helium, and argon. This is a common choice in the art and will not be described in detail here.

[0159] In addition, in order to further promote the smooth progress of the coupling reaction in step 3), preferably, the reaction in step 3) is carried out in the presence of a third water absorbing agent, and the third water absorbing agent can be a molecular sieve.

[0160] In addition, in the present invention, after the coupling reaction in step 3), further deprotection is required under an acidic environment.

[0161] The deprotection reaction can be completed in the subsequent separation and purification process by column chromatography using the acidic environment. In this case, the compound represented by Formula I can be obtained without a separate deprotection treatment.

[0162] On the other hand, in order to accelerate the deprotection reaction and improve the yield of the compound represented by Formula I, in the present invention, preferably, the step 3) further comprises: after the coupling reaction, further performing a deprotection reaction in the presence of a second acid;

[0163] The second acid can be a conventional choice for deprotection reaction in the art, for example, it can be one or more of hydrochloric acid, sulfuric acid, formic acid, acetic acid, carbonic acid and trifluoroacetic acid; preferably, the second acid is one or more of hydrochloric acid, formic acid and acetic acid.

[0164] Furthermore, in the deprotection reaction, preferably, the molar ratio of the compound represented by Formula 5 to the second acid is 1:1 to 5; more preferably, the molar ratio of the compound represented by Formula 5 to the second acid is 1:1 to 3. This can accelerate the rate of the deprotection reaction and increase the product yield.

[0165] In the present invention, to improve the purity and yield of the compound represented by Formula I, the product obtained in step 3) can be subjected to impurity removal and purification treatments conventional in the art. For example, purification can be achieved by one or more of extraction, washing, drying, column chromatography, etc. This is a conventional option in the art and will not be described in detail here.

[0166] The third aspect of the present invention provides a method for preparing a chiral γ-amino alcohol, wherein the method comprises: a step of reacting racemic allyl alcohol and an alkylamine in the presence of a fourth solvent, a second base and a catalyst composition, wherein the catalyst composition comprises the N6 chiral cyclic compound and a manganese precursor compound described in the first aspect of the present invention, or the catalyst composition comprises a complex formed by the N6 chiral cyclic compound and a manganese precursor compound described in the first aspect of the present invention.

[0167] Next, the preparation method of the chiral γ-amino alcohol described in the third aspect of the present invention is described in detail.

[0168] According to the third aspect of the present invention, the reaction of racemic allyl alcohol and alkylamine to prepare chiral γ-amino alcohol is a hydrogen-Michael addition-asymmetric reduction tandem reaction.

[0169] The hydrogen-Michael addition-asymmetric reduction tandem reaction refers to the following: in the reaction process, racemic allyl alcohol undergoes a hydrogen-borrowing reaction to generate an α,β-unsaturated ketone, then an alkylamine and the α,β-unsaturated ketone undergo a Michael addition reaction to obtain a γ-amino ketone, and finally an asymmetric reduction reaction of the γ-amino ketone occurs to generate a chiral γ-amino alcohol.

[0170] In addition, in the present invention, the racemic allyl alcohol is not particularly limited and can be any of the racemic allyl alcohols commonly used in the art.

[0171] Preferably, the racemic allyl alcohol has a structure as shown in the following formula II:

[0172]

[0173] Among them, R 8 It can be phenyl, substituted phenyl, thienyl, pyridyl, furyl, 1-naphthyl, 2-naphthyl or benzothiophene; preferably, the R 8 is phenyl, substituted phenyl, thienyl, 1-naphthyl, 2-naphthyl or benzothiophene.

[0174] In addition, the substituents on the substituted phenyl group may be one or more of halogen, trifluoromethyl, C1-3 linear alkyl and C1-3 linear alkoxy, and the number of the substituents may be 1-5.

[0175] Preferably, the substituents on the substituted phenyl group may be one or more of fluorine, chlorine, bromine, trifluoromethyl, methyl and methoxy, and the number of the substituents may be 1 or 2.

[0176] In addition, in the present invention, the alkylamine is not particularly limited and may be any of the alkylamines commonly used in the art. For example, the alkylamine may be a cyclic amine or an aliphatic amine.

[0177] Preferably, the alkylamine has a structure shown in Formula III:

[0178] NHR 9 R 10

[0179] Formula III

[0180] When the alkylamine is a cyclic amine, R 9 and R 10 It can be combined to form morpholinyl, thiomorpholinyl, piperazinyl, piperazinyl derivatives, pyrrolyl, piperidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, proline ester, norfloxacin, vortioxetine or amoxapine.

[0181] Preferably, when the alkylamine is a cyclic amine, R 9 and R 10 It can be combined to form morpholinyl, thiomorpholinyl, piperazinyl, piperazinyl derivatives, pyrrolyl or piperidinyl.

[0182] When the alkylamine is a fatty amine, preferably, R 9 is any one of phenyl, benzyl, and C1-C4 alkyl, R 10 It is any one of halogen, C1-C4 alkyl, and C1-C4 alkoxy.

[0183] In the present invention, the fourth solvent can be a conventional choice in the art for carrying out a hydrogen-Michael addition-asymmetric reduction tandem reaction. For example, the fourth solvent can be one or more of water, methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane and n-pentane.

[0184] In the preparation of the chiral γ-amino alcohol described in the third aspect of the present invention, preferably, the fourth solvent is one or more of isopropanol, toluene and water.

[0185] In a particularly preferred embodiment of the present invention, the fourth solvent is isopropanol, thereby achieving a higher reaction rate and increasing the yield of chiral γ-amino alcohol.

[0186] In the present invention, in order to provide suitable reaction conditions, the amount of the fourth solvent can be selected within a wide range according to the amount of the second base described later. For example, the amount of the fourth solvent can make the concentration of the second base in the fourth solvent be 0.001 to 10 mol / L; preferably, the amount of the fourth solvent is such that the concentration of the second base in the fourth solvent is 0.01 to 1 mol / L; more preferably, the amount of the fourth solvent is such that the concentration of the second base in the fourth solvent is 0.01 to 0.05 mol / L.

[0187] In addition, the inventors of the present invention have found that the selection of the second base in the reaction has a great influence on the reaction rate and the yield of the γ-amino alcohol. In order to ensure the smooth progress of the reaction, preferably, the second base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, barium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium fluoride, potassium fluoride, cesium fluoride, triethylamine, N,N-diisopropylethylenediamine and one or more of DBU.

[0188] In order to further improve the reaction efficiency and increase the product yield, more preferably, the second base is one or more of potassium phosphate, potassium tert-butoxide and sodium phosphate.

[0189] In a particularly preferred embodiment of the present invention, the second base is potassium phosphate, thereby significantly improving the reaction efficiency and greatly increasing the yield of the product.

[0190] In the present invention, the amount of the second base can be selected according to the amount of the racemic allyl alcohol. For example, the molar ratio of the racemic allyl alcohol to the second base can be 1:0.05 to 2.0. In order to further promote the rapid progress of the reaction and improve the yield, preferably, the molar ratio of the racemic allyl alcohol to the second base is 1:0.1 to 0.4.

[0191] According to the third aspect of the present invention, the catalyst composition used in the preparation of the chiral γ-amino alcohol can be a mixture of the N6 chiral cyclic compound and the manganese precursor compound described in the first aspect of the present invention, which is directly added to the reaction system. That is, the two can be directly synthesized in situ in the reaction system for generating the chiral γ-amino alcohol to form a complex with catalytic performance without prior preparation, thereby simplifying the preparation process and making it more convenient and quick; or the two can be prepared into a complex in advance and then added to the reaction system, thereby increasing the reaction rate and shortening the reaction time. Those skilled in the art can make specific choices as needed.

[0192] In addition, the preparation method of the complex formed by the N6 chiral cyclic compound and the manganese precursor compound includes: reacting the N6 chiral cyclic compound and the manganese precursor compound in a molar ratio of 1 to 2:1 at -20 to 120° C. for 0.5 to 24 hours in the presence of a fifth organic solvent.

[0193] In the third aspect of the present invention, in order to further improve the catalytic efficiency and yield, the N6 chiral cyclic compound is preferably one or more of the compounds having structures represented by Formulas 1-1 to 1-5 described in the first aspect of the present invention; more preferably one or more of the compounds having structures represented by Formulas 1-1 to 1-4. Particularly preferred are compounds having structures represented by Formulas 1-1 and / or 1-2.

[0194] Here, preferably, the manganese precursor compound is a monovalent manganese precursor compound. More preferably, the manganese precursor compound is Mn(CO)5Br and / or Mn2(CO) 10 .

[0195] Preferably, the fifth organic solvent is one or more of methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane and n-pentane.

[0196] In addition, when the mixture of the N6 chiral cyclic compound and the manganese precursor compound is directly added to the reaction system, the type of the manganese precursor compound and the molar ratio of the N6 chiral cyclic compound to the manganese precursor compound can be the same as those selected when preparing the complex.

[0197] In the present invention, the molar ratio of the racemic allyl alcohol, the alkylamine and the catalyst composition calculated as the N6 chiral cyclic compound is 1-10:1:0.01-0.2; in order to improve the yield and reaction efficiency, preferably, the molar ratio of the racemic allyl alcohol, the alkylamine and the catalyst composition calculated as the N6 chiral cyclic compound is 1-5:1:0.02-0.08.

[0198] In addition, according to the present invention, in order to further ensure the yield and reaction efficiency, more preferably, the molar ratio of the racemic allyl alcohol, the alkylamine and the catalyst composition calculated as the N6 chiral cyclic compound is 2-4:1:0.02-0.05.

[0199] In addition, the preparation of the chiral γ-amino alcohol described in the third aspect of the present invention is preferably carried out under an inert atmosphere, such as nitrogen, helium, and argon. This is a conventional choice in the art and will not be described in detail here.

[0200] The fourth aspect of the present invention provides a use of the N6 chiral cyclic compound described in the first aspect of the present invention in the preparation of chiral γ-amino alcohols.

[0201] The N6 chiral cyclic compound possesses abundant coordination sites and weak non-covalent interaction sites, forming a unique chiral cavity with a monovalent manganese precursor compound. This provides favorable conditions for chiral induction in the catalytic reaction for the preparation of chiral γ-amino alcohols. Therefore, the N6 chiral cyclic compound of the present invention exhibits mild reaction conditions and excellent chemoselectivity and enantioselectivity in the tandem hydrogen-borrowing-Michael addition-asymmetric reduction reaction of racemic allyl alcohols and alkylamines catalyzed by the manganese precursor compound, resulting in high yields of a range of chiral γ-amino alcohol products.

[0202] The present invention will be described in detail below through examples.

[0203] In the following preparation examples and embodiments, unless otherwise specified, the raw materials are conventional commercially available products.

[0204] In the following examples, the yields of the products were analyzed by nuclear magnetic resonance;

[0205] The enantiomeric excess (ee) was analyzed by high performance liquid chromatography.

[0206] Preparation Example 1: Synthesis of the compound represented by Formula 1-1

[0207] The synthesis route of the compound represented by formula 1-1 is as follows:

[0208]

[0209] 1) Compound 2 (9.666 g, 40.94 mmol) and compound 1 (2.337 g, 20.47 mmol) were added sequentially to a 250 mL round-bottom flask, followed by 150 mL of freshly distilled dichloromethane as the reaction solvent. The mixture was refluxed at 45°C for 3 hours. After the reaction, anhydrous sodium sulfate was added to dry the mixture, and the filtrate was collected and spin-dried. The mixture was then recrystallized from methanol / dichloromethane to obtain a white amination intermediate.

[0210] 2) The intermediate was added to 200 mL of freshly distilled methanol, and sodium borohydride (3.102 g, 82 mmol) was added in five portions at 0°C with stirring, each time 5 minutes apart. After the addition was complete, the reaction was continued at 0°C for half an hour, and then the reaction flask was moved to 25°C and reacted for 10 hours. After the reaction was completed, saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered and collected. The solvent was removed under reduced pressure to obtain a crude product, which was then recrystallized from dichloromethane / petroleum ether to obtain the reductive amination product, i.e., compound 3.

[0211] 3) Compound 3 (6.503 g, 11.95 mmol) obtained in step 2) and 5 g of 4A molecular sieves were added to a 250 mL round-bottom flask. 100 mL of ether was added as the reaction solvent, followed by acetaldehyde (1.053 g, 23.89 mmol). The reaction was allowed to proceed at 25°C for 10 h. After completion of the reaction, the insoluble matter was removed by filtration through celite, and the residue was washed with dichloromethane. The filtrates were combined and the solvent was removed under reduced pressure to obtain a crude product, which was then recrystallized from ethyl acetate / petroleum ether to obtain the condensation reaction product, compound 4.

[0212] 4) In a 250 mL round-bottom flask, compound 4 (3.557 g, 6.13 mmol) obtained in step 3), compound 1 (700 mg, 6.13 mmol), Pd2(dba)3 (280 mg, 0.307 mmol), rac-BINAP (281 mg, 0.613 mmol) and t-BuONa (1.778 g, 18.39 mmol) were added, and 125 mL of freshly distilled toluene was added as the reaction solvent. Under nitrogen protection, the reaction was carried out at 87 ° C for 24 hours. After the reaction is completed, the reaction is cooled to 25°C, the insoluble matter is removed by filtration with diatomaceous earth, and the residue is washed with dichloromethane. The filtrates are combined and the solvent is removed under reduced pressure. The resulting solid is added with 15mL of hydrochloric acid in ether (1.0M), followed by 50mL of ether solution, and the reaction is carried out at 25°C for 12 hours. After the reaction is completed, the pH is adjusted to 9 with saturated sodium bicarbonate, and then extracted with dichloromethane, washed with saturated brine, and then the organic phase is dried with anhydrous sodium sulfate and spin-dried. The target product is isolated and purified by continuous column chromatography, and finally recrystallized from dichloromethane / n-hexane to obtain 1.254g of a yellow-green solid, i.e., the compound represented by Formula 1-1, with a yield of 35%.

[0213] mp188-189℃,[α] D 25 =-79.7 (c = 0.31, CHCl3). 1 H NMR (500MHz, CDCl3): δ (ppm) 7.84 (d, J = 8.5Hz, 2H), 7.20 (t, J = 8.0Hz, 2H), 7.15 (d, J = 8.0Hz ,2H),6.89(d,J=8.0Hz,2H),6.78(d,J=7.5Hz,2H),6.72(br,s,2H),4.16(d,J=14.0Hz,2H), 3.89-3.88(m,2H),3.81(d,J=14.0Hz,2H),3.13(br,s,2H),2.59-2.57(m,2H),2.40(d,J=13 .5Hz,2H),2.20(d,J=12.0Hz,2H),1.90-1.79(m,6H),1.51-1.48(m,2H),1.35-1.26(m,4H); 13 C NMR (125MHz, CDCl3): δ (ppm) 156.2, 143.5, 138.4, 136.3, 127.7, 127.0, 120.9, 113.7, 106.9, 61.2, 56.1, 52.1, 32.2, 31.3, 25.7, 25.1. HRMS-ESI exact mass calcd.for C 32 H39 N6 + ([M+H] + ) Calculated value m / z 507.3231, found m / z 507.3233.

[0214] Preparation Example 2: Synthesis of the compound represented by Formula 1-2

[0215] The synthesis route of the compound represented by Formula 1-2 is as follows:

[0216]

[0217] The method described in Preparation Example 1 was followed, except that:

[0218] In step 4), compound 1 is replaced by compound 5.

[0219] As a result, 575 mg of the compound represented by Formula 1-2 was obtained as a yellow solid with a yield of 28%.

[0220] mp132-134℃,[α] D 25 =167.0 (c=0.16, CHCl3). 1 H NMR (500MHz, CDCl3): δ (ppm) 7.93 (d, J = 8.0Hz, 2H), 7.69 (d, J = 7.5Hz, 4H), 7.42 (d, J = 5.5Hz, 2H) ,7.31(t,J=7.5Hz,4H),7.24-7.19(m,4H),7.08(t,J=8.0Hz,2H),6.96(d,J=8.0Hz,2H),6.24(d ,J=7.5Hz,2H),5.13(d,J=5.5Hz,2H),4.32(d,J=15.5Hz,2H),4.08(d,J=15.5Hz,2H),3.05(br, s,2H),2.52(d,J=8.5Hz,2H),2.19(d,J=12.5Hz,2H),1.73(d,J=7.5Hz,2H),1.21-1.07(m,4H); 13 C NMR (125MHz, CDCl3): δ (ppm) 157.3, 143.6, 141.7, 138.1, 136.2, 128.8, 127.5, 1 27.2,126.9,126.9,121.3,114.5,106.8,63.7,60.3,51.5,30.9,25.0.HRMS-ESI exactmass calcd.for C 40 H 41 N6 + ([M+H]+ ) Calculated value m / z 605.3387, found m / z 605.3373.

[0221] Preparation Example 3: Synthesis of the compound represented by Formula 1-3

[0222] The synthesis route of the compound represented by Formula 1-3 is as follows:

[0223]

[0224] Specifically, the method described in Preparation Example 1 was followed, except that:

[0225] In step 4), compound 1 is replaced by compound 6.

[0226] As a result, 251 mg of the compound represented by Formula 1-3 was obtained as a yellow solid with a yield of 38%.

[0227] mp271-272℃,[α] D 25 =-198.8 (c = 0.16, CHCl3). 1 H NMR (500MHz, CDCl3): δ (ppm) 7.96 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 7.8 Hz, 2H), 7.24 (d, J = 8. 0Hz,2H),7.04(d,J=8.5Hz,2H),6.76(d,J=7.5Hz,2H),6.71(s,2H),4.25(d,J=14.0Hz, 2H),3.95(d,J=14.5Hz,2H),3.71(d,J=2.5Hz,4H),3.01(br,s,2H),2.44(d,J=8.5Hz,2 H),2.24(d,J=12.5Hz,2H),1.76(d,J=7.5Hz,2H),1.28-1.20(m,2H),1.16-1.09(m,2H); 13 C NMR (125MHz, CDCl3): δ (ppm) 156.9, 144.0, 138.1, 136.3, 127.6, 127.2, 121.5, 114.2, 105.0, 60.6, 51.9, 41.6, 30.8, 25.2. HRMS-ESI exact mass calcd.for C 28 H 33 N6 + ([M+H] + ) Theoretical value: m / z 453.2761, found: m / z 453.2760.

[0228] Preparation Example 4: Synthesis of the compound represented by Formula 1-4

[0229] The synthesis route of the compound represented by Formula 1-4 is as follows:

[0230]

[0231] Specifically, the method described in Preparation Example 1 was followed, except that:

[0232] In step 4), compound 1 is replaced by compound 7.

[0233] As a result, 176 mg of the compound represented by Formula 1-4 was obtained as a yellow solid with a yield of 31%.

[0234] mp242-243℃,[α] D 25 =83.6 (c = 0.16, CHCl3). 1 H NMR (500MHz, CDCl3): δ (ppm) 7.94 (d, J = 8.5Hz, 2H), 7.33 (t, J = 7.8Hz, 2H), 7.13 (d, J = 8.0Hz, 2H), 7.02 (d ,J=8.0Hz,2H),6.80(br,s,2H),6.78(d,J=7.5Hz,2H),3.87(d,J=13.5Hz,2H),3.69(d,J=7.5Hz,2H),3.6 3(d,J=13.5Hz,2H),2.66(d,J=13.0Hz,2H),2.52(br,s,2H),2.16(d,J=13.0Hz,2H),2.06(d,J=8.0Hz,2H ),1.91(d,J=8.0Hz,2H),1.74(d,J=8.5Hz,2H),1.61-1.49(m,4H),1.27-1.21(m,2H),1.04-0.97(m,2H); 13 C NMR (125MHz, CDCl3): δ (ppm) 156.9, 143.8, 139.0, 136.2, 127.6, 127.1, 121.7, 114.0, 105.4, 58.4, 57.3, 51.4, 32.3, 31.4, 25.3, 24.9. HRMS-ESI exact mass calcd.for C 32 H 39 N6 + ([M+H] + ) Calculated value m / z 507.3231, found m / z 507.3229.

[0235] Preparation Example 5: Synthesis of the compound represented by Formula 1-5

[0236] The synthesis route of the compound represented by Formula 1-5 is as follows:

[0237]

[0238] Specifically, the method described in Preparation Example 1 was followed, except that:

[0239] In step 1), compound 1 is replaced by compound 5;

[0240] Step 2) obtaining compound 8; Step 3) obtaining compound 9;

[0241] In step 4), compound 1 is replaced by compound 5.

[0242] As a result, 67 mg of the compound represented by Formula 1-5 was obtained as a light yellow solid with a yield of 4%.

[0243] mp128-129℃,[α] D 25 =352.7 (c = 0.11, CHCl3). 1 H NMR (500MHz, CDCl3): δ (ppm) 8.02 (d, J = 8.5Hz, 2H), 7.69 (t, J = 8.5Hz, 2H), 7.49 (d, J = 9.5Hz, 2H), 7.32-7.24 (m, 10H), 7.12 (s, 10H), 6.96 -6.89(m,4H),6.38(d,J=7.5Hz,2H),5.25(d,J=9.5Hz,2H),4.88(s,2H),3.66(d,J=13.0Hz,2H),3.46(d,J=13.0Hz,2H),2.93(br,s,2H); 13 C NMR (125MHz, CDCl3): δ (ppm) 160.0, 144.2, 143.0, 140.4, 138.5, 137.0, 128.6, 128.6, 12 8.4,127.3,127.2,127.2,127.0,126.7,119.8,115.7,112.1,65.5,64.6,49.8.HRMS-ESI exact masscalcd.for C 48 H 43 N6 + ([M+H] + ) Theoretical value: m / z 703.3544, found: m / z 703.3532.

[0244] Example 1

[0245] In a 5 mL brown reaction bottle, add racemic allyl alcohol (α-vinylbenzyl alcohol, 0.3mmol), alkylamine (N-phenylpiperazine 0.1 mmol), pentacarbonyl manganese bromide (0.002 mmol), the compound represented by formula 1-2 (0.002 mmol), potassium phosphate (0.04 mmol, 40 mol%) and isopropanol (2 mL) were stirred in a glove box (nitrogen atmosphere) at 40 ° C for 24 hours.

[0246] The reaction product was then separated and purified by column chromatography to obtain a chiral γ-amino alcohol having the following structural formula:

[0247] mp106-107℃,[α] D 25 =-50.7 (c = 0.75, CHCl3); 1 H NMR(400 MHz, CDCl3): δ (ppm) 7.39-7.33 (m, 4H), 7.29-7.23 (m, 3H), 6.93 (d, J = 8.0Hz, 2H), 6.87 (t, J = 7 .2Hz,1H),4.96(t,J=5.8Hz,1H),3.24(t,J=5.0Hz,4H),2.81-2.60(m,6H),1.93-1.88(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 151.2, 144.9, 129.3, 128.4, 127.1, 125.7, 120.1, 116.4, 75.6, 57.2, 53.4, 49.4, 33.9. HRMS-ESIexact mass calcd.for C 19 H 25 ON2 + ([M+H] + ) Theoretical value m / z 297.1961, measured value m / z 297.1956.

[0248] The yield was 97% and the ee value was 90%.

[0249] Example 2

[0250] In a 5 mL brown reaction bottle, add racemic allyl alcohol (α-vinyl-(3-benzothienyl)methanol, 0.3mmol), alkylamine (1-(2-methoxyphenyl)-piperazine 0.1 mmol), pentacarbonyl manganese bromide (0.004 mmol), the compound represented by formula 1-2 (0.004 mmol), potassium phosphate (0.04 mmol, 40 mol%) and isopropanol (2 mL) were stirred in a glove box (nitrogen atmosphere) at 40 ° C for 96 hours.

[0251] The reaction product was then separated and purified by column chromatography to obtain a chiral γ-amino alcohol having the following structural formula:

[0252] [α] D 25 =-63.6 (c = 0.85, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.87 (d, J = 8.0Hz, 1H), 7.82 (d, J = 7.6Hz, 1H), 7.45 (s, 1H), 7.39-7.32 (m ,2H),7.05-6.87(m,4H),5.36(t,J=5.4Hz,1H),3.88(s,3H),3.17-2.70(m,10H),2.21-2.02(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 152.4,141.2,141.1,140.0,137.3,124.3,124.0,123.3,1 23.1,122.1,121.8,121.2,118.4,111.3,71.7,57.2,55.5,53.6,50.8,31.6.HRMS-ESI exact masscalcd.for C 22 H 27 O2N2S + ([M+H] + ) Theoretical value m / z 383.1788, measured value m / z 383.1791.

[0253] The yield was 99% and the ee value was 90%.

[0254] Examples 3 to 11

[0255] The method described in Example 1 was followed, except that

[0256] The types of N6 chiral cyclic compounds and bases used were different, and 0.005 mmol of pentacarbonyl manganese bromide and 0.005 mmol of N6 chiral cyclic compound were used. At the same time, in order to distinguish the difference in reactivity of N6 chiral cyclic compounds with different structures, the reaction time was controlled to 10 hours.

[0257] The specific contents and the corresponding chiral γ-amino alcohol yields and ee values are shown in Table 1.

[0258] Table 1

[0259] Example N6 chiral cyclic compounds alkali NMR yield ee value 3 1-1 <![CDATA[K2CO3]]> 4％ 89％ 4 1-1 t-BuOK 54％ 89％ 5 1-1 KOH 52％ 89％ 6 1-1 <![CDATA[NEt3]]> <5％ - 7 1-1 <![CDATA[K3PO4]]> >99％ 89％ 8 1-2 <![CDATA[K3PO4]]> >99％ 90％ 9 1-3 <![CDATA[K3PO4]]> 73％ 89％ 10 1-4 <![CDATA[K3PO4]]> 64％ 91％ 11 1-5 <![CDATA[K3PO4]]> 12％ 42％

[0260] Examples 12-26

[0261] Proceed as in Example 1, except that:

[0262] The types of racemic allyl alcohol used are different. The specific types of racemic allyl alcohol and the corresponding chiral γ-amino alcohol yields and ee values are shown in Table 2.

[0263] Table 2

[0264]

[0265]

[0266] The spectral data of the compound prepared in Example 12 are:

[0267] [α] D 25 =-46.6 (c = 0.73, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.29-7.25 (m, 4H), 7.16 (d, J = 7.6Hz, 2H), 6.93 (d, J = 8.4Hz, 2H), 6.87 (t, J = 7. 4Hz,1H),4.93(t,J=5.8Hz,1H),3.25(t,J=5.0Hz,4H),2.82-2.60(m,6H),2.34(s,3H),1.91-1.87(m,2H); 13 CNMR (100MHz, CDCl3): δ (ppm) 151.2, 142.0, 136.7, 129.3, 129.1, 125.6, 120.2, 116.4, 75.5, 57.3, 53.4, 49.4, 33.9, 21.2. HRMS-ESI exact mass calcd.for C 20 H 27 ON2 + ([M+H] + ) Theoretical value: m / z 311.2118, found: m / z 311.2125.

[0268] The spectral data of the compound prepared in Example 13 are:

[0269] [α] D25 =-39.9 (c = 0.78, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.29-7.21 (m, 4H), 7.16 (d, J = 7.6Hz, 1H), 7.06 (d, J = 7.2Hz, 1H), 6.93 (d, J = 8.0Hz, 2H), 6 .88(t,J=7.2Hz,1H),4.92(t,J=5.8Hz,1H),3.27(t,J=5.0Hz,4H),2.86-2.64(m,6H),2.36(s,3H),1.95-1.90(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 151.1, 144.7, 138.0, 129.3, 128.3, 127.9, 126.4, 122.8, 120.3, 116.4, 75.3, 57.1, 53.3, 49.2, 33.8, 21.6. HRMS-ESI exactmass calcd.for C 20 H 27 ON2 + ([M+H] + ) Theoretical value m / z 311.2118, measured value m / z 311.2124.

[0270] The spectral data of the compound prepared in Example 14 are:

[0271] [α] D 25 =-65.4 (c = 0.98, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.56 (d, J = 7.6Hz, 1H), 7.29-7.22 (m, 3H), 7.17-7.11 (m, 2H), 6.93 (d, J = 8.0Hz, 2H), 6.8 7(t,J=7.4Hz,1H),5.14(t,J=5.6Hz,1H),3.26(t,J=5.0Hz,4H),2.85-2.62(m,6H),2.32(s,3H),1.87-1.83(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 151.2, 142.7, 134.0, 130.4, 129.3, 126.9, 126.2, 125.6, 120.1, 116.4, 72.4, 57.4, 53.4, 49.4, 32.2, 19.1. HRMS-ESI exactmass calcd.for C 20 H27 ON2 + ([M+H] + ) Theoretical value: m / z 311.2118, found: m / z 311.2125.

[0272] The spectral data of the compound prepared in Example 15 are:

[0273] [α] D 25 =-42.8 (c = 0.90, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.31-7.25 (m, 4H), 6.93-6.85 (m, 5H), 4.91-4.88 (m ,1H),3.79(s,3H),3.24(t,J=5.0Hz,4H),2.82-2.59(m,6H),1.95-1.82(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 158.8, 151.2, 137.1, 129.3, 126.8, 120.1, 116.4, 113.8, 75.2, 57.2, 55.4, 53.3, 49.3, 33.9. HRMS-ESI exact masscalcd.for C 20 H 27 O2N2 + ([M+H] + ) Theoretical value: m / z 327.2067, found: m / z 327.2073.

[0274] The spectral data of the compound prepared in Example 16 are:

[0275] [α] D 25 =-50.1 (c = 0.98, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.46 (d, J = 8.4Hz, 2H), 7.29-7.25 (m, 4H), 6.93 (d, J = 8.0Hz, 2H), 6.88 (t,J=7.4Hz,1H),4.93-4.90(m,1H),3.24(t,J=4.8Hz,4H),2.81-2.60(m,6H),1.91-1.80(m,2H); 13C NMR (100MHz, CDCl3): δ (ppm) 151.1, 144.0, 131.4, 129.3, 127.4, 120.8, 120.2, 116.4, 75.1, 57.1, 53.4, 49.4, 33.7. HRMS-ESI exact mass calcd.for C 19 H 24 ON2Br + ([M+H] + ) Calculated value m / z 375.1067, found m / z 375.1073.

[0276] The spectral data of the compound prepared in Example 17 are:

[0277] [α] D 25 =-53.6 (c = 0.85, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.31-7.25 (m, 6H), 6.94-6.86 (m, 3H), 4.93 (t, J = 5.8Hz, 1H), 3.24 (t, J = 5.0Hz, 4H), 2.81-2.60 (m, 6H), 1.91-1.80 (m, 2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 151.1, 143.5, 132.7, 129.3, 128.5, 127.1, 120.2, 116.4, 75.0, 57.2, 53.4, 49.4, 33.8. HRMS-ESI exact mass calcd.forC 19 H 24 ON2Cl + ([M+H] + ) Calculated value m / z 331.1572, found m / z 331.1578.

[0278] The spectral data of the compound prepared in Example 18 are:

[0279] [α] D 25 =-38.1 (c = 0.83, CHCl3); 1H NMR (400MHz, CDCl3): δ (ppm) 7.36-7.33 (m, 2H), 7.27 (t, J = 8.0Hz, 2H), 7.03 (t, J = 8.6Hz, 2H), 6.93 (d, J = 8.0Hz, 2H),6.88(t,J=7.4Hz,1H),4.93(t,J=5.6Hz,1H),3.24(t,J=5.0Hz,4H),2.82-2.60(m,6H),1.89-1.82(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 162.0 (d, J C-F =243.0Hz),151.2,140.7(d,J C-F =3.0Hz),129.3,127.2(d,J C-F =8.0Hz),120.2,116.4,115.1(d,J C-F =21.0Hz),75.2,57.3,53.4,49.4,33.9.HRMS-ESI exact mass calcd.for C 19 H 24 ON2F + ([M+H] + ) Theoretical value m / z 315.1862, measured value m / z 315.1875.

[0280] The spectral data of the compound prepared in Example 19 are:

[0281] [α] D 25 =-43.9 (c = 0.93, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.60 (d, J = 8.0Hz, 2H), 7.50 (d, J = 8.0Hz, 2H), 7.29-7.25 (m, 2H), 6.93 (d, J = 8.0H) z,2H),6.88(t,J=7.4Hz,1H),5.03-5.00(m,1H),3.26(t,J=4.8Hz,4H),2.84-2.63(m,6H),1.97-1.83(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 151.1, 148.9, 129.3 (q, J C-F =32.0Hz),129.3,125.9,125.3(q,J C-F =4.0Hz),124.4(q,J C-F=270.0Hz),120.3,116.5,75.0,57.1,53.3,49.3,33.6.HRMS-ESI exact mass calcd.for C 20 H 24 ON2F3 + ([M+H] + ) Theoretical value: m / z 365.1835, found: m / z 365.1843.

[0282] The spectral data of the compound prepared in Example 20 are:

[0283] [α] D 25 =-48.8 (c = 0.80, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.59 (t, J = 7.0Hz, 1H), 7.29-7.15 (m, 4H), 7.00 (t, J = 9.2Hz, 1H), 6.93 (d, J = 8.0H z,2H),6.88(t,J=7.2Hz,1H),5.27-5.25(m,1H),3.26(t,J=4.8Hz,4H),2.80-2.61(m,6H),2.04-1.84(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 159.6 (d, J C-F =243.0Hz),151.2,131.9(d,J C-F =13.0Hz),129.3,128.5(d,J C-F =8.0Hz),127.4(d,J C-F =4.0Hz),124.2(d,J C-F =4.0Hz),120.2,116.4,115.2(d,J C-F =22.0Hz),69.8,57.1,53.3,49.4,32.2.HRMS-ESI exact masscalcd.for C 19 H 24 ON2F + ([M+H] + ) Theoretical value m / z 315.1867, measured value m / z 315.1873.

[0284] The spectral data of the compound prepared in Example 21 are:

[0285] [α] D 25=-44.3 (c = 0.80, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.29-7.24 (m, 2H), 6.99 (s, 2H), 6.94-6.85 (m, 4H), 4.89- 4.86(m,1H),3.25(t,J=5.0Hz,4H),2.83-2.61(m,6H),2.32(s,6H),1.96-1.83(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 151.2, 144.8, 137.9, 129.3, 128.8, 123.5, 120.1, 116.4, 75.7, 57.4, 53.4, 49.4, 33.9, 21.5. HRMS-ESIexact mass calcd.for C 21 H 29 ON2 + ([M+H] + ) Theoretical value: m / z 325.2274, found: m / z 325.2280.

[0286] The spectral data of the compound prepared in Example 22 are:

[0287] [α]D25=-54.1(c=0.80,CHCl3); 1H NMR (400MHz, CDCl3): δ (ppm) 7.87-7.81 (m, 4H), 7.48-7.42 (m, 3H), 7.29-7.23 (m, 2H), 6.93 (d, J= 8.0Hz,2H),6.88(t,J=7.2Hz,1H),5.11(t,J=5.6Hz,1H),3.26(t,J=4.8Hz,4H),2.82-2.61(m,6H ), 2.00-1.96 (m, 2H); 13CNMR (100MHz, CDCl3): δ (ppm) 151.2, 142.3, 133.5, 132.9, 129.3, 128.1, 128.1,127.8,126.1,125.7,124.2,124.1,120.2,116.4,75.6,57.1,53.3,49.4,33.7.HRMS-ESI exactmass calcd.for C 23 H 27 ON2 + ([M+H] + ) Theoretical value m / z 347.2118, measured value m / z 347.2125.

[0288] The spectral data of the compound prepared in Example 23 are:

[0289] [α] D 25 =-68.2 (c = 0.83, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 8.04 (d, J = 8.0Hz, 1H), 7.90 (d, J = 7.2Hz, 1H), 7.79 (d, J = 7.6Hz, 2H), 7.55-7.47 (m, 3H), 7.31 (t, J = 8.0H) z,2H),6.97(d,J=8.4Hz,2H),6.91(t,J=7.4Hz,1H),5.77-5.75(m,1H),3.30(t,J=4.8Hz,4H),2.84-2.65(m,6H),2.19-1.99(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 151.2, 140.2, 133.9, 130.3, 129.3, 129.1, 127.6, 125. 9,125.6,125.4,123.1,123.0,120.1,116.4,72.3,57.2,53.4,49.4,32.7.HRMS-ESI exact mass calcd.for C 23 H 27 ON2 + ([M+H] + ) Theoretical value: m / z 347.2118, found: m / z 347.2125.

[0290] The spectral data of the compound prepared in Example 24 are:

[0291] [α] D 25 =-64.1 (c = 0.78, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.87-7.84 (m, 1H), 7.80-7.78 (m, 1H), 7.43 (s, 1H), 7.38-7.24 (m, 4H), 6.93 (d, J = 8. 0Hz,2H),6.88(t,J=7.2Hz,1H),5.35-5.32(m,1H),3.25(t,J=4.8Hz,4H),2.82-2.64(m,6H),2.14-1.99(m,2H); 13C NMR (100MHz, CDCl3): δ (ppm) 151.2, 141.2, 139.9, 137.3, 129.3, 124.3, 124. 0,123.1,122.1,121.9,120.2,116.4,71.7,57.2,53.4,49.4,31.7.HRMS-ESI exact masscalcd.for C 21 H 25 ON2S + ([M+H] + ) Calculated value m / z 353.1682, found m / z 353.1676.

[0292] The spectral data of the compound prepared in Example 25 are:

[0293] [α] D 25 =-26.5 (c = 0.83, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.30-7.21 (m, 4H), 7.04 (d, J = 4.8Hz, 1H), 6.92 (d, J = 8.0Hz, 2H), 6.87 (t,J=7.4Hz,1H),5.04-5.01(m,1H),3.23(t,J=4.8Hz,4H),2.80-2.64(m,6H),2.01-1.90(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 151.2, 146.5, 129.3, 125.9, 125.7, 120.2, 120.1, 116.4, 72.3, 57.1, 53.4, 49.4, 32.9. HRMS-ESI exact mass calcd.for C 17 H 23 ON2S + ([M+H] + ) Theoretical value: m / z 303.1526, found: m / z 303.1531.

[0294] The spectral data of the compound prepared in Example 26 are:

[0295] [α] D 25 =-15.8 (c = 0.85, CHCl3); 1H NMR (400MHz, CDCl3): δ (ppm) 7.29-7.25 (m, 2H), 7.22 (d, J = 5.2Hz, 1H), 6.98 (t, J = 4.2Hz, 1H), 6.92 (d, J = 8.4Hz, 3H),6.87(t,J=7.2Hz,1H),5.21(t,J=5.4Hz,1H),3.23(t,J=5.0Hz,4H),2.81-2.63(m,6H),2.05-2.00(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 151.2, 149.5, 129.3, 126.8, 123.9, 122.5, 120.2, 116.4, 72.1, 56.9, 53.4, 49.4, 33.8. HRMS-ESI exact mass calcd.for C 17 H 23 ON2S + ([M+H] + ) Theoretical value m / z 303.1526, measured value m / z 303.1521.

[0296] Examples 27-38

[0297] Proceed as in Example 1, except that:

[0298] The types of alkylamines used are different. The specific types of alkylamines and the corresponding chiral γ-amino alcohol yields and ee values are shown in Table 3.

[0299] Table 3

[0300]

[0301] The spectral data of the compound prepared in Example 27 are:

[0302] [α]D25=-53.7(c=0.75,CHCl3); 1H NMR (400MHz, CDCl3): δ (ppm) 7.39-7.32 (m, 4H), 7.26-7.23 (m, 1H), 7.08 (d, J = 8.4Hz, 2H), 6.84 (d, J = 8.4Hz 13C NMR (100MHz, CDCl3): δ (ppm) 149.1, 144.9, 129.8, 129.7, 128.4, 127.1, 125.7, 116.7, 75.6, 57.2, 53.4, 50.0, 33.8, 20.6. HRMS-ESI exact mass calcd.for C 20 H 21 ON2 + ([M+H] + ) Theoretical value: m / z 311.2118, found: m / z 311.2115.

[0303] The spectral data of the compound prepared in Example 28 are:

[0304] [α]D25=-49.1(c=0.70,CHCl3); 1H NMR (400MHz, CDCl3): δ (ppm) 7.39-7.33 (m, 4H), 7.27-7.23 (m, 1H), 7.16 (d, J = 7.6Hz, 1H), 6.75-6.69 (m, 13C NMR (100MHz, CDCl3): δ (ppm) 151.3, 144.9, 139.0, 129.1, 128.4, 127.1, 125.7, 121.1, 117.3, 113.5, 75.6, 57.2, 53.4, 49.5, 33.8, 21.9. HRMS-ESI exact mass calcd.for C 20 H 21 ON2 + ([M+H] + ) Theoretical value m / z 311.2118, measured value m / z 311.2111.

[0305] The spectral data of the compound prepared in Example 29 are:

[0306] [α] D 25 =-57.6 (c = 0.68, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.40-7.33 (m, 4H), 7.27-7.23 (m, 1H), 7.19-7.15 (m, 2H), 7.03-6.97 (m, 2H),4.97(t,J=5.6Hz,1H),2.99(t,J=4.4Hz,4H),2.80-2.63(m,6H),2.30(s,3H),1.93-1.88(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 151.3, 145.0, 132.7, 131.2, 128.4, 127.1, 126.8, 125.7, 123.5, 119.2, 75.7, 57.2, 53.9, 51.8, 33.8, 18.0. HRMS-ESI exact mass calcd.for C 20 H 21 ON2 + ([M+H] + ) Theoretical value: m / z 311.2118, found: m / z 311.2109.

[0307] The spectral data of the compound prepared in Example 30 are:

[0308] [α] D 25 =-51.8 (c = 0.88, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.40-7.32 (m, 4H), 7.26-7.23 (m, 1H), 7.03-6.99 (m, 1H), 6.95-6.90 (m, 2H), 6.8 6(d,J=7.6Hz,1H),4.96(t,J=5.6Hz,1H),3.86(s,3H),3.14(br,s,4H),2.84-2.64(m,6H),1.93-1.89(m,2H); 13 CNMR (100MHz, CDCl3): δ (ppm) 152.3, 144.9, 141.0, 128.3, 127.0, 125.6, 123.3, 121.2, 118.4, 111.3, 75.6, 57.2, 55.5, 53.5, 50.7, 33.7. HRMS-ESI exact mass calcd.forC20 H 27 O2N2 + ([M+H] + ) Theoretical value m / z 327.2067, measured value m / z 327.2062.

[0309] The spectral data of the compound prepared in Example 31 are:

[0310] [α] D 25 =-20.6 (c = 0.85, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 8.30 (d, J = 4.8Hz, 2H), 7.40-7.33 (m, 4H), 7.26-7.23 (m, 1H), 6.49 (t, J=4.6Hz,1H),4.96(t,J=5.8Hz,1H),3.88(t,J=4.8Hz,4H),2.76-2.52(m,6H),1.93-1.89(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 161.7, 157.8, 144.9, 128.4, 127.1, 125.7, 110.2, 75.6, 57.3, 53.3, 43.8, 33.9. HRMS-ESI exact mass calcd.for C 17 H 23 ON4 + ([M+H] + ) Calculated value m / z 299.1866, found m / z 299.1874.

[0311] The spectral data of the compound prepared in Example 32 are:

[0312] [α] D 25 =-29.7 (c = 1.00, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.37-7.23 (m, 5H), 4.93 (t, J = 5.6Hz, 1H), 2.74-2.54 (m, 10H), 1.89-1.85 (m, 4H), 1.72-1.46 (m, 7H); 13CNMR (100MHz, CDCl3): δ (ppm) 144.9, 128.4, 127.1, 125.6, 75.5, 67.7, 57.0, 52.8, 52.2, 33.8, 30.2, 24.2. HRMS-ESI exact mass calcd.for C 18 H 29 ON2 + ([M+H] + ) Theoretical value m / z 289.2274, measured value m / z 289.2268.

[0313] The spectral data of the compound prepared in Example 33 are:

[0314] [α] D 25 =-17.9 (c = 0.95, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.38-7.23 (m, 5H), 5.12 (br, s, 1H), 4.97-4.93 (m, 1H), 3.13-3.00 (m, 6H), 2.12-1.94 (m, 6H); 13 C NMR (100MHz, CDCl3): δ (ppm) 144.3, 128.5, 127.4, 125.7, 72.6, 54.0, 53.7, 35.3, 23.5. HRMS-ESI exact mass calcd.for C 13 H 20 ON + ([M+H] + ) Theoretical value m / z 206.1539, measured value m / z 206.1535.

[0315] The spectral data of the compound prepared in Example 34 are:

[0316] [α] D 25 =-26.0 (c = 0.60, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.38-7.31 (m, 4H), 7.27-7.22 (m, 1H), 5.10 (br, s, 1H), 4.93 (t ,J=5.8Hz,1H),2.79-2.57(m,6H),1.95-1.91(m,2H),1.75-1.70(m,4H),1.54-1.47(m,2H); 13C NMR (100MHz, CDCl3): δ (ppm) 144.9, 128.4, 127.1, 125.7, 74.5, 57.1, 54.5, 33.6, 25.3, 23.8. HRMS-ESI exact mass calcd.forC 14 H 22 ON + ([M+H] + ) Theoretical value m / z 220.1696, measured value m / z 220.1690.

[0317] The spectral data of the compound prepared in Example 35 are:

[0318] [α] D 25 =-25.1 (c = 0.95, CHCl3). 1 H NMR (400MHz, CDCl3): δ (ppm) 7.37-7.32 (m, 4H), 7.26-7.23 (m, 1H), 4.92 (t, J = 5.8H z,1H),2.89-2.85(m,2H),2.78-2.73(m,6H),2.68-2.57(m,2H),1.88-1.83(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 144.8, 128.4, 127.1, 125.6, 75.5, 57.9, 55.3, 33.6, 28.2. HRMS-ESI exact mass calcd.for C 13 H 20 ONS + ([M+H] + ) Theoretical value: m / z 238.1260, found: m / z 238.1256.

[0319] The spectral data of the compound prepared in Example 36 are:

[0320] [α] D 25 =-30.8 (c = 1.15, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.38-7.32 (m, 4H), 7.26-7.23 (m, 1H), 4.94 (t, J = 5.6Hz, 1H), 3.75 (t, J = 4.6Hz, 4H), 2.71-2.50 (m, 6H), 1.89-1.85 (m, 2H); 13C NMR (100MHz, CDCl3): δ (ppm) 144.8, 128.4, 127.1, 125.6, 75.6, 67.0, 57.6, 53.8, 33.5. HRMS-ESI exact mass calcd.for C 13 H 20 O2N + ([M+H] + ) Theoretical value m / z 222.1489, measured value m / z 222.1484.

[0321] The spectral data of the compound prepared in Example 37 are:

[0322] [α] D 25 =-47.3 (c = 1.15, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.39-7.32 (m, 4H), 7.24 (t, J = 7.0Hz, 1H), 7.17-7 .09(m,3H),7.04-7.02(m,1H),4.99-4.96(m,1H),3.78(d,J=14.8Hz,1H),3.68 (d, J = 14.8 Hz, 1H), 2.97-2.70 (m, 6H), 2.01-1.92 (m, 2H); 13 C NMR (100 MHz, CDCl3): δ (ppm)145.1,134.1,134.1,128.8,128.3,127.0,126.7,126.5,125.9,125.7,75.6,56.9,56.4,50.8,34.2,29.1.HRMS-ESI exact masscalcd.for C 18 H 22 ON + ([M+H] + ) Calculated value m / z 268.1696, found m / z 268.1694.

[0323] The spectral data of the compound prepared in Example 38 are:

[0324] [α] D 25 =-48.4 (c = 1.20, CHCl3); 1H NMR (400MHz, CDCl3): δ (ppm) 7.36-7.27 (m, 9H), 7.25-7.21 (m, 1H), 4.92-4.89 (m, 1H), 3.65 (d, J = 12.8 Hz,1H),3.48(d,J=12.8Hz,1H),2.85-2.79(m,1H),2.63-2.57(m,1H),2.27(s,3H),1.95-1.85(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 145.0, 137.6, 129.3, 128.6, 128.2, 127.5, 126.9, 125.6, 75.7, 62.8, 56.5, 41.8, 34.5. HRMS-ESI exact mass calcd.for C 17 H 22 ON + ([M+H] + ) Theoretical value: m / z 256.1696, found: m / z 256.1691.

[0325] Examples 39-50

[0326] Proceed as in Example 2, except that:

[0327] α-vinyl-(3-benzothienyl)methanol was replaced with the same molar amount of α-vinyl-(1-naphthyl)methanol In addition, different types of alkylamines were used. The specific types of alkylamines and the corresponding chiral γ-amino alcohol yields and ee values are shown in Table 4.

[0328] Table 4

[0329]

[0330] The spectral data of the compound prepared in Example 39 are:

[0331] [α] D 25 =-69.5 (c = 1.10, CHCl3); 1H NMR (400MHz, CDCl3): δ (ppm) 8.04 (d, J = 8.0Hz, 1H), 7.89 (d, J = 8.0Hz, 1H), 7.79 (d, J = 7.6Hz, 2H), 7.55-7.47 (m, 3H), 7.11 (d, J = 8.4Hz,2H),6.88(d,J=8.4Hz,2H),5.76(d,J=6.4Hz,1H),3.27-3.25(m,4H),2.85-2.67(m,6H),2.31(s,3H),2.19-2.04(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 149.1, 140.2, 133.9, 130.3, 129.8, 129.7, 129.0, 127.6, 1 25.9,125.6,125.4,123.1,123.0,116.7,72.3,57.2,53.4,49.9,32.7,20.6.HRMS-ESI exact mass calcd.for C 24 H 29 ON2 + ([M+H] + ) Calculated value m / z 361.2274, found m / z 361.2274.

[0332] The spectral data of the compound prepared in Example 40 are:

[0333] [α] D 25 =-61.9 (c = 1.13, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 8.04 (d, J = 8.0Hz, 1H), 7.90-7.88 (m, 1H), 7.79 (d, J = 7.6Hz, 2H), 7.55-7.47 (m, 3H), 7.19 (t, J = 7.6Hz,1H),6.79-6.72(m,3H),5.77-5.75(m,1H),3.30(t,J=4.8Hz,4H),2.86-2.65(m,6H),2.35(s,3H),2.20-2.00(m,2H); 13C NMR (100MHz, CDCl3): δ (ppm) 151.3, 140.2, 139.0, 133.9, 130.3, 129.1, 129.1, 127.6, 125.9, 1 25.6,125.4,123.1,123.0,121.1,117.3,113.6,72.3,57.2,53.5,49.5,32.7,21.9.HRMS-ESI exact mass calcd.for C 24 H 29 ON2 + ([M+H] + ) Theoretical value: m / z 361.2274, found: m / z 361.2273.

[0334] The spectral data of the compound prepared in Example 41 are:

[0335] [α] D 25 =-90.2 (c = 0.98, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 8.05 (d, J = 8.0Hz, 1H), 7.91-7.89 (m, 1H), 7.80 (t, J = 7.6Hz, 2H), 7.56-7.47 (m, 3H), 7.22-7.2 0(m,2H),7.09-7.01(m,2H),5.79-5.77(m,1H),3.06(t,J=4.6Hz,4H),2.88-2.69(m,6H),2.34(s,3H),2.21-2.00(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 151.3, 140.3, 133.9, 132.7, 131.2, 130.3, 129.0, 127.6, 126.8, 1 25.9,125.6,125.4,123.5,123.1,123.0,119.3,72.4,57.3,53.9,51.9,32.6,18.0.HRMS-ESI exact mass calcd.for C 24 H 29 ON2 + ([M+H] + ) Calculated value m / z 361.2274, found m / z 361.2274.

[0336] The spectral data of the compound prepared in Example 42 are:

[0337] [α] D25 =-77.2 (c = 0.93, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 8.04 (d, J = 8.0Hz, 1H), 7.90-7.87 (m, 1H), 7.79 (t, J = 6.6Hz, 2H), 7.54-7.46 (m, 3H), 7.06-6.9 3(m,3H),6.89(d,J=8.0Hz,1H),5.77(d,J=5.6Hz,1H),3.88(s,3H),3.20(br,s,4H),2.87-2.67(m,6H),2.18-1.99(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 152.4,141.1,140.3,133.9,130.3,129.0,127.6,125.9,125.6,1 25.4,123.3,123.1,123.0,121.2,118.5,111.4,72.5,57.3,55.5,53.7,50.8,32.6.HRMS-ESI exact mass calcd.for C 24 H 29 O2N2 + ([M+H] + ) Theoretical value: m / z 377.2224, found: m / z 377.2216.

[0338] The spectral data of the compound prepared in Example 43 are:

[0339] [α] D 25 =-48.4 (c = 1.13, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 8.32 (d, J = 4.8Hz, 2H), 8.02 (d, J = 8.0Hz, 1H), 7.89-7.86 (m, 1H), 7.79-7.76 (m, 2H), 7.54 -7.45(m,3H),6.50(t,J=4.6Hz,1H),5.77-5.74(m,1H),3.94(t,J=4.8Hz,4H),2.83-2.59(m,6H),2.19-1.99(m,2H); 13C NMR (100MHz, CDCl3): δ (ppm) 161.7, 157.9, 140.2, 133.9, 130.3, 129.1, 127.6, 1 25.9,125.7,125.4,123.0,123.0,110.2,72.2,57.3,53.3,43.8,32.7.HRMS-ESI exact mass calcd.for C 21 H 25 ON4 + ([M+H] + ) Theoretical value: m / z 349.2023, measured value: m / z 349.2021.

[0340] The spectral data of the compound prepared in Example 44 are:

[0341] [α] D 25 =-66.0 (c = 1.30, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 8.00 (d, J = 7.6Hz, 1H), 7.87-7.85 (m, 1H), 7.75 (t, J = 6.4Hz, 2H), 7 .51-7.44(m,3H),5.71-5.68(m,1H),2.77-2.51(m,11H),2.12-1.84(m,4H),1.75-1.44(m,6H); 13 C NMR (100MHz, CDCl3): δ (ppm) 140.3, 133.9, 130.3, 129.0, 127.5, 125.9, 125.6, 125.4,123.0,123.0,72.2,67.6,57.0,53.0,52.3,32.6,30.3,24.2.HRMS-ESI exact mass calcd.for C 22 H 31 ON2 + ([M+H] + ) Theoretical value: m / z 339.2431, found: m / z 339.2430.

[0342] The spectral data of the compound prepared in Example 45 are:

[0343] [α] D 25 =-53.0 (c = 0.58, CHCl3); 1H NMR (400MHz, CDCl3): δ (ppm) 8.02 (d, J=8.0Hz, 1H), 7.85-7.83 (m, 1H), 7.74 (d, J=8.0Hz, 1H), 7.69 (d, J= 6.8Hz,1H),7.50-7.42(m,3H),5.71(d,J=7.6Hz,1H),3.17-3.07(m,6H),2.29-2.13(m,2H),1.97(s,4H); 13 C NMR (100MHz, CDCl3): δ (ppm) 139.4, 133.8, 130.1, 129.0, 128.0, 126.3, 125.6, 125.6, 123.2, 123.1, 67.8, 53.9, 53.3, 34.1, 23.3. HRMS-ESI exact mass calcd.for C 17 H 22 ON + ([M+H] + ) Theoretical value: m / z 256.1696, found: m / z 256.1694.

[0344] The spectral data of the compound prepared in Example 46 are:

[0345] [α] D 25 =-47.7 (c = 0.65, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 8.01 (d, J = 8.0Hz, 1H), 7.82 (d, J = 8.0Hz, 1H), 7.73-7.68 (m, 2H), 7.49- 7.40(m,3H),5.68(d,J=6.0Hz,1H),3.02-2.84(m,6H),2.24-2.15(m,2H),1.82(s,4H),1.50(s,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 139.8, 133.9, 130.2, 129.0, 127.8, 126.2, 125.6, 125.5, 123.1, 123.1, 69.8, 56.4, 54.1, 32.3, 24.3.23.2. HRMS-ESI exact mass calcd.for C 18 H 24 ON + ([M+H] + ) Theoretical value: m / z 270.1852, found: m / z 270.1851.

[0346] The spectral data of the compound prepared in Example 47 are:

[0347] [α] D 25 =-61.3 (c = 0.75, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 7.99 (d, J = 8.0Hz, 1H), 7.88-7.86 (m, 1H), 7.75 (t, J = 9.0Hz ,2H),7.52-7.45(m,3H),5.71(d,J=6.4Hz,1H),2.92-2.61(m,10H),2.13-1.94(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 140.1, 133.9, 130.2, 129.1, 127.6, 125.9, 125.6, 125.4, 123.0, 122.9, 72.2, 58.0, 55.4, 32.5, 28.1. HRMS-ESI exact mass calcd.for C 17 H 22 ONS + ([M+H] + ) Theoretical value: m / z 288.1417, found: m / z 288.1413.

[0348] The spectral data of the compound prepared in Example 48 are:

[0349] [α] D 25 =-69.9 (c = 0.70, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 8.00 (d, J = 7.6Hz, 1H), 7.89-7.86 (m, 1H), 7.76 (t, J = 7.6Hz, 2H), 7. 52-7.45(m,3H),5.74-5.72(m,1H),3.80(t,J=4.6Hz,4H),2.78-2.57(m,6H),2.15-1.95(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 140.2, 133.9, 130.3, 129.1, 127.6, 125.9, 125.6, 125.4, 123.0, 123.0, 72.4, 67.1, 57.7, 53.9, 32.4. HRMS-ESI exact mass calcd.for C 17 H 22 O2N+ ([M+H] + ) Theoretical value m / z 272.1645, measured value m / z 272.1641.

[0350] The spectral data of the compound prepared in Example 49 are:

[0351] [α] D 25 =-60.7 (c = 1.08, CHCl3); 1 H NMR (400MHz, CDCl3): δ (ppm) 8.04 (d, J = 7.6Hz, 1H), 7.91-7.88 (m, 1H), 7.79 (d, J = 7.6Hz, 2H), 7.55-7.47 (m, 3H), 7.21- 7.08(m,4H),5.80-5.77(m,1H),3.84(d,J=14.8Hz,1H),3.76(d,J=14.8Hz,1H),3.04-2.76(m,6H),2.27-2.05(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 140.4,134.1,134.1,133.9,130.3,129.0,128.8,127.5,126.7,1 26.5,125.9,125.9,125.7,125.4,123.1,123.1,72.3,56.9,56.4,50.8,33.0,29.1.HRMS-ESI exact mass calcd.for C 22 H 24 ON + ([M+H] + ) Theoretical value m / z 318.1852, measured value m / z 318.1846.

[0352] The spectral data of the compound prepared in Example 50 are:

[0353] [α] D 25 =-96.7 (c = 0.68, CHCl3); 1H NMR (400MHz, CDCl3): δ (ppm) 8.00-7.98 (m, 1H), 7.88-7.85 (m, 1H), 7.75 (t, J = 7.4Hz, 2H), 7.51-7.31 (m, 8H), 5.72-5.70 (m, 1H),3.70(d,J=12.8Hz,1H),3.56(d,J=12.8Hz,1H),2.91-2.85(m,1H),2.69-2.63(m,1H),2.34(s,3H),2.18-1.97(m,2H); 13 C NMR (100MHz, CDCl3): δ (ppm) 140.4, 137.8, 133.9, 130.3, 129.5, 129.0, 128.7, 127. 6,127.5,125.8,125.7,125.3,123.1,123.1,72.6,63.0,56.6,42.0,33.4.HRMS-ESI exact mass calcd.for C 21 H 24 ON + ([M+H] + ) Calculated value m / z 306.1852, found m / z 306.1848.

[0354] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. An N6 chiral cyclic compound, characterized in that The compound is a compound having a structure shown in Formula I or an enantiomer, racemate, diastereomer or salt thereof, Among them, the R 1 、R 2 Each is independently selected from hydrogen, phenyl or substituted phenyl, or combined to form a C4~C6 aliphatic ring; The R 3 、R 4 Each is independently selected from hydrogen, phenyl or substituted phenyl, or combined to form a C4~C6 aliphatic ring; The substituent on the substituted phenyl group is selected from one or more of a C1-C3 straight-chain or branched-chain alkyl group and a C1-C3 straight-chain or branched-chain alkoxy group; The R 5 、R 6 Each independently selected from fluorine, chlorine or a C1-C3 straight-chain alkyl group; m is an integer of 0 to 2, and n is an integer of 0 to 3.

2. The compound according to claim 1, wherein The compound is any one of the compounds having the following structures: 。 3. The method for preparing the N6 chiral cyclic compound according to claim 1 or 2, characterized in that: The preparation method comprises the following steps: 1) in the presence of a first organic solvent and a reducing agent, subjecting the diamine compound represented by Formula 1 to a reductive amination reaction with the aldehyde represented by Formula 2 under reductive amination conditions to obtain a compound represented by Formula 3; 2) in the presence of a second organic solvent, condensing the compound represented by Formula 3 with the aldehyde represented by Formula 4 under condensation reaction conditions to obtain a compound represented by Formula 5; 3) in the presence of a third organic solvent, a catalyst, a ligand, and a first base, conducting a coupling reaction with the compound represented by Formula 5 and the diamine compound represented by Formula 6 under coupling reaction conditions, and after the coupling reaction, conducting a deprotection reaction in the presence of a second acid to prepare a compound represented by Formula I, ， Among them, in Formulas 1 to 6 and Formula I, R 1 ~R 6 The meaning as defined in claim 1 or 2; R 7 is hydrogen, a C1~C10 straight or branched chain alkyl group; X is a halogen or a trifluoromethanesulfonic acid group; m is an integer of 0 to 2, and n is an integer of 0 to 3.

4. The preparation method according to claim 3, wherein In step 1), the first organic solvent is one or more of dichloromethane, methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane and n-pentane; The reducing agent is one or more of lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride; The molar ratio of the diamine compound represented by Formula 1 to the aldehyde represented by Formula 2 and the reducing agent is 1:2-5:2-10; The amount of the first organic solvent is 50-100 mL relative to 1 g of the diamine compound represented by Formula 1; The reductive amination conditions include: temperature of -20 to 120°C, reaction time of 1 to 5 hours; Step 1) the reaction is carried out in the presence of a first acid; The first acid is one or more of formic acid, acetic acid, carbonic acid and p-toluenesulfonic acid; The volume ratio of the first acid to the first organic solvent is 1:50-1000.

5. The preparation method according to claim 3, wherein In step 2), the second organic solvent is one or more of diethyl ether, methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane and n-pentane; The amount of the second organic solvent is 10-50 mL relative to 1 g of the compound represented by Formula 3; The molar ratio of the compound represented by Formula 3 to the aldehyde represented by Formula 4 is 1:1 to 5; The condensation reaction conditions include: reaction temperature of -20 to 120° C., and reaction time of 1 to 48 hours.

6. The method according to claim 3, wherein: In step 3), the third organic solvent is one or more of toluene, diethyl ether, methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane and n-pentane; The catalyst is Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, Pd(PPh3)2Cl2, PdCl2, Pd(OAc)2, PdCl2(dffp), ( t Bu3P)2Pd, (PCy3)2Pd, Pd(PCy3)2Cl2, Pd-Xphos, Pd- t One or more of BuXphosG3, CuBr, CuI, Cu2O, Cu(acac)2, and Cu(OTf)2; The ligand is BINAP, Cyclohexyl JohnPhos, DavePhos, XPhos, SPhos, MePhos, RuPhos, BrettPhos, PhDavePHos, t BuXPhos, JohnPhos, TrixiePhos, RockPhos, CPhos, JackiePhos, t One or more of BuMePhos, bipyridine, o-phenanthroline, BTMPO, BPMPO, Bn(MNBO), BFMO, BTMO, BHMPO, BPPO and DBO; The first base is one or more of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, barium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium fluoride, potassium fluoride, cesium fluoride, LHMDS, triethylamine, N,N-diisopropylethylenediamine and DBU; The molar ratio of the compound represented by Formula 5, the diamine compound represented by Formula 6, the catalyst, the ligand and the first base is 1:1-5:0.001-0.2:0.002-0.4:3-6; The amount of the third organic solvent used is 10-100 mL relative to 1 g of the compound represented by Formula 5; The reaction conditions of the coupling reaction include: reaction temperature of -20 to 120°C, reaction time of 1 to 48 hours; The second acid is one or more of hydrochloric acid, sulfuric acid, formic acid, acetic acid, carbonic acid and trifluoroacetic acid; The molar ratio of the compound represented by Formula 5 to the second acid is 1:1-5.

7. A method for preparing a chiral γ-amino alcohol, characterized in that: The method comprises the steps of reacting racemic allyl alcohol and alkylamine in the presence of a fourth solvent, a second base and a catalyst composition, Wherein, the catalyst composition comprises the N6 chiral cyclic compound according to claim 1 or 2 and a manganese precursor compound, and the manganese precursor compound is Mn(CO)5Br; The second base is one or more of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, barium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium fluoride, potassium fluoride, cesium fluoride, N,N-diisopropylethylenediamine and DBU; The racemic allyl alcohol has the structure shown in the following formula II: Among them, R 8 is phenyl, substituted phenyl, thienyl, pyridyl, furyl, 1-naphthyl, 2-naphthyl or benzothiophene, The substituent on the substituted phenyl group is one or more of halogen, trifluoromethyl, C1-C3 straight-chain alkyl and C1-C3 straight-chain alkoxy. The alkylamine has a structure shown in Formula III: The alkylamine is a cyclic amine, N, H, R 9 and R 10 Combined into morpholine, thiomorpholine, piperazine, pyrrole, piperidine, tetrahydroisoquinoline, tetrahydroquinoline, 、 、 、 、 or ; Alternatively, R in the alkylamine 9 is any one of phenyl, benzyl, and C1-C4 alkyl, R 10 It is any one of halogen, C1-C4 alkyl, and C1-C4 alkoxy.

8. The preparation method according to claim 7, wherein The R 8 is phenyl, substituted phenyl, thienyl, 1-naphthyl, 2-naphthyl or benzothiophene; The substituent on the substituted phenyl group is one or more of fluorine, chlorine, bromine, trifluoromethyl, methyl and methoxy; The number of the substituents is 1 or 2.

9. The preparation method according to claim 7, wherein The alkylamine is a cyclic amine, N, H, R 9 and R 10 Combined into morpholine, thiomorpholine, piperazine, pyrrole, piperidine, 、 、 、 、 or .

10. The preparation method according to claim 7, wherein The second base is one or more of potassium phosphate, potassium tert-butoxide and sodium phosphate.

11. The preparation method according to any one of claims 7 to 10, wherein The molar ratio of the racemic allyl alcohol, the alkylamine and the catalyst composition calculated as the N6 chiral cyclic compound is 1-10:1:0.01-0.2; The molar ratio of the racemic allyl alcohol to the second base is 1:0.05-2.0; The fourth solvent is used in an amount such that the concentration of the second base in the fourth solvent is 0.001 to 10 mol / L; The fourth solvent is one or more of water, methanol, ethanol, propanol, isopropanol, butanol, n-butanol, tert-butanol, tri-amyl alcohol, tetrahydrofuran, toluene, xylene, ethylene glycol dimethyl ether, methyl tert-butyl ether, ethyl ether, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, n-heptane, n-hexane and n-pentane; The reaction conditions of the racemic allyl alcohol and alkylamine include: reaction temperature of 0-100° C., reaction time of 1-120 h; The molar ratio of the N6 chiral cyclic compound to the manganese precursor compound in the catalyst composition is 1-2:

1.

12. Use of the N6 chiral cyclic compound according to claim 1 or 2 in the preparation of chiral γ-amino alcohols.

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