CN118620007A - A chiral tetradentate phosphine ligand compound and its preparation method and application - Google Patents

Abstract

The present invention discloses a chiral tetradentate phosphine ligand compound and a preparation method and application thereof. The chiral tetradentate phosphine ligand compound provided by the present invention has the advantages of simple synthesis route, low cost and air stability. After the chiral tetradentate phosphine ligand provided by the present invention forms a complex with a transition metal, it is applied to the efficient asymmetric hydrogenation of various prochiral ketones; during the reaction process, it exhibits excellent reaction activity and enantioselectivity, and has broad application prospects.

Description

A chiral tetradentate phosphine ligand compound and its preparation method and application

Technical Field

The invention relates to the technical field of asymmetric catalysis, and specifically provides a chiral tetradentate phosphine ligand compound, a preparation method and application thereof in asymmetric hydrogenation reactions and similar reactions.

Background Art

Chiral compounds are widely found in natural products, bioactive molecules, and clinical drug molecules (or their key intermediates). In the field of new drug research, 820 of the more than 1,200 drugs under development are chiral molecules, accounting for nearly 70%. The research on chiral drugs has been very rapid in recent years, and major drug research and development companies have developed small molecule drugs. The proportion of single chiral compounds has gradually increased. The importance of chiral research is self-evident. Among all chiral compounds, chiral alcohols belong to a common class of chiral molecules, which are widely used in the fields of small molecule drugs, pesticides, natural compounds and functional materials. The asymmetric hydrogenation reaction catalyzed by organometallics has the advantages of mild reaction conditions, high efficiency and selectivity, and a wide range of substrates, and has received extensive attention and in-depth research. However, the core factor affecting the efficiency of asymmetric catalytic hydrogenation is the catalyst, which is composed of a metal center and a ligand. Due to the limitations of the periodic table, the types of transition metals available are limited. Therefore, the development of new chiral ligands has in fact become the most fundamental research topic in the field of asymmetric hydrogenation, running through the entire history of asymmetric hydrogenation.

In asymmetric hydrogenation reactions, the structure of chiral ligands has an important influence on the activity and stereoselectivity of the reaction, so chemists can achieve fine control of the reaction through reasonable ligand electrical properties and steric hindrance design. However, no ligand can solve all problems, so the development of chiral ligands and asymmetric catalytic systems with high efficiency, high selectivity and a wide range of substrates will be an eternal theme. Although chiral phosphine ligands are now very rich in both types and numbers, each ligand has its own unique properties. Therefore, the development of new chiral multidentate phosphine ligands is of great significance.

Summary of the invention

The present invention aims to provide a chiral tetradentate phosphine ligand compound and its preparation method and application. After the chiral tetradentate phosphine ligand provided by the present invention forms a complex with a transition metal, it is applied to the efficient asymmetric hydrogenation of various prochiral ketones (especially aromatic ketone compounds), and the reaction achieves excellent reactivity and enantioselectivity at a high conversion number. During the reaction process, it exhibits excellent reactivity and enantioselectivity, and has broad application prospects. The chiral tetradentate phosphine ligand provided by the present invention is simple to synthesize, the raw materials are easily available, it is relatively stable in an air atmosphere, has high catalytic activity, high stereoselectivity, and is easy to realize industrial production.

To achieve the above object, the technical solution of the present invention is as follows:

In one aspect, the present invention provides a chiral tetradentate phosphine ligand compound (abbreviated as: f-thiophamidol), the structure of which is shown in formula (I):

wherein each R ¹ is independently an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group or a heteroaryl group, or two R ¹ together with the connected P atom form a heterocyclic group;

^L1 and ^L2 are each independently selected from ^-NR2 -C(=O)-, -C(=O) ^-NR2- , -C(=O)-C(=O)-, -((C( ^R3 ) ₂ ) _q -C(=O)) _x- , -C(=O)-(C( ^R3 ) ₂ ) _q ) _x- or -(C( ^R3 ) ₂ ) _q ) _x- ;

q and x are independently selected from 0, 1, 2, 3, 4, 5 or 6;

Each R ³ is independently H, -F, -Cl, -Br, -I, -CN, -CHO, nitro, alkoxy, alkylthio, haloalkyl, alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl or heteroaryl; or R ³ on two adjacent carbon atoms can form a C _3-6 cycloalkyl or aryl group together with the connected C;

Each ^R2 is independently H or alkyl;

Each of R ¹ , R ² and R ³ is independently further substituted or polysubstituted by the same or different substituents; the substituents are selected from hydrogen, -F, -Cl, -Br, -I, -NH ₂ , -CN, -CHO, nitro, C _1-6 alkoxy, C _1-6 alkylthio, C _3-12 cycloalkyl, C _4-12 heterocycloalkyl, C _6-12 aryl, C _5-12 heteroaryl or C _1-6 alkyl. The substituents of the present invention may be further substituted or polysubstituted by -F, -Cl, -Br, -I, -NH ₂ , -CN, -CHO, nitro, C _1-6 alkoxy, C _1-6 alkylthio, C _3-12 cycloalkyl, C _4-12 heterocycloalkyl, C _6-12 aryl, C _5-12 heteroaryl or C _1-6 alkyl.

Further, each R ¹ is independently C _1-6 alkyl, C _3-12 cycloalkyl, C 2-12 heterocyclyl, C _6-12 aryl, C _6-12 arylC _1-6 alkyl or C _1-12 heteroaryl, or two R ¹ together with the connected P atom form _{a C 2-12 heterocyclyl} . Further, each R ¹ is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidyl or phenylmethyl, etc.; each R ¹ is independently further substituted or polysubstituted by the same or different substituents; the substituents are selected from hydrogen, -F, -Cl, -Br, -I, -NH ₂ , -CN, -CHO, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butoxy, tert-butoxy, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidyl, etc.

Further, each ^R3 is independently H, -F, -Cl, -Br, -I, -CN, -CHO, nitro, _C1-6 alkoxy, C1-6 alkylthio, _C1-6 haloalkyl, _C1-6 alkyl, _C3-12 cycloalkyl, _C2-12 heterocyclyl, _C6-12 aryl, _{C6-12 arylC1-6} alkyl or _C1-12 heteroaryl; or ^R3 on two adjacent carbon atoms can form _{a C3-6 cycloalkyl} or _C6-12 aryl together with the connected C. Further, each R ³ is independently H, -F, -Cl, -Br, -I, -CN, -CHO, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl or phenylmethyl, etc.

Further, each R ² is independently H or C _1-6 alkyl. Further, each R ² is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.

Further, ^L1 and ^L2 are each independently selected from the following substructures:

Furthermore, the present invention provides a chiral tetradentate phosphine ligand compound, the structure of which is shown in formula (II):

Wherein, each of ^R1 and ^R3 has the meaning as defined in the present invention.

Furthermore, the present invention provides a chiral tetradentate phosphine ligand compound, the structure of which is shown in formula (III):

Wherein, each of ^R1 and ^R3 has the meaning as defined in the present invention.

Furthermore, the compound of the present invention is selected from one of the following structures:

On the other hand, the present invention provides a method for preparing a chiral tetradentate phosphine ligand compound, the specific steps of which are as follows:

S1, condensing compound 1 and compound 5 at high temperature to obtain compound 2;

S2, reacting compound 2 with sodium hydroxide and acetic acid in sequence to remove the ester protecting group to obtain compound 3;

S3, condensing compound 3 and compound 4 to obtain a compound represented by formula (I);

Herein, each of R ¹ , L ¹ , L ² and R ³ has the meaning as defined in the present invention.

On the other hand, the present invention provides a method for preparing a chiral tetradentate phosphine ligand compound, the specific steps of which are as follows:

S1, condensing compound 1 with methyl thioglycolate at high temperature to obtain compound 6;

S2, reacting compound 6 with sodium hydroxide and acetic acid in sequence to remove the ester protecting group to obtain compound 7;

S3, condensing compound 7 with chiral amino alcohol 8 to obtain a compound represented by formula (III);

Wherein, each of ^R1 and ^R3 has the meaning as defined in the present invention.

Furthermore, in S1, compound 1, methyl thioglycolate and tetrahydrofuran are added to a sealed tube equipped with a magnetic stirrer, and the mixture is heated in an oil bath at 120°C overnight. After the reaction is completed, the solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, half-saturated brine is added, and then extracted with ethyl acetate, the organic phases are combined, backwashed with half-saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by flash column chromatography to obtain a yellow solid, which is compound 6.

Further, step S2 is: adding compound 6, sodium hydroxide, ethanol and water to a flask equipped with a magnetic stirrer, reacting at room temperature for 2 hours, and then dripping excess acetic acid into the flask until the system is acidic. Dissolve the residue in ethyl acetate, add semi-saturated brine, and then extract with ethyl acetate, combine the organic phases, backwash with semi-saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain a yellow oil as compound 7.

Further, step S3 is: dissolving compound 7 in anhydrous dichloromethane, adding triethylamine, chiral amino alcohol and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) at room temperature, and reacting at room temperature for 12 hours. After the reaction is completed, the reaction solution is concentrated and separated by column chromatography to obtain a light yellow solid as the compound represented by formula (III).

In another aspect, the present invention provides a chiral catalyst, wherein the chiral catalyst is a complex formed by the chiral tetradentate phosphine ligand compound of the present invention and a transition metal salt. Further, the transition metal is selected from Ru, Rh, Pd, Ir, Fe, Co, Ni, Cu, Sc, Ti, V, Cr, Mn, Ag and Re. The transition metal salt used may be _RuX3 , RuHX(L) ₂ (diphosphine), _RuX2 (L) ₂ (diphosphine), Ru(arene) _X2 (diphosphine), Ru(ary1group) _X2 , Ru(RCOO) ₂ (diphsphine), Ru(methallyl) ₂ (diphine), Ru(ary1group) _X2 ( _PPh3 ) ₃ , Ru(COD)(COT), Ru(COD)(COT)X, _RuX2 (cymene), Ru(COD)n, Ru(arylgroup) _X2 (diphosphine), RuCl2(COD), [Ru(COD) ₂ ]X, _RuX2 (diphosphine ₎ , _RuCl2 (=CHR)( _PR'3 ) ₂ , Ru(ArH) _Cl2 , Ru(COD)(methallyl) ₂ , Rh(CO) _2Cl2 , or ₂ , [Rh(NBD) ₂ ]BF ₄ , [Rh(NBD)C1] ₂ , [Rh(COD)C1] ₂ , [Rh(COD) ₂ ] 3) ₄ , Pd(allyl)Cl, IrX ₃ , [Ir(NBD) ₂ )C1] ₂ , _[ Ir(COD) _{C1 ] 2 , Ir} (COD _{)X, FeX 2, FeX 3 , Ni(acac) 2, NiX 2 , [ Ni (} allyl)X] ₂ , Ni(COD) ₂ , CuX, _{CuX 2} , MoO ₂ (acac) ₂ , ScX ₂ , Ti(OiPr) ₄ , VO(acac) ₂ , CrX ₂ , CrX ₃ , MnX ₂ , Mn(acac) ₂ , MeReO ₃ .

In another aspect, the present invention provides a use of the chiral tetradentate phosphine ligand compound of the present invention in the preparation of a chiral catalyst.

In another aspect, the present invention provides an application of the chiral tetradentate phosphine ligand compound of the present invention and the catalyst prepared therefrom in catalyzing an asymmetric catalytic reaction. Further, the asymmetric reaction is an asymmetric hydrogenation reaction of a prochiral ketone compound for synthesizing chiral alcohols. The asymmetric reactions include asymmetric hydrogenation, asymmetric transfer hydrogenation, asymmetric hydroamination, asymmetric hydrocyanation, asymmetric hydrosilylation, asymmetric hydroboration, asymmetric allylic alkylation, asymmetric coupling, asymmetric cyclization, asymmetric Michael addition, asymmetric epoxidation, asymmetric Aldol reaction, asymmetric Mannich reaction, asymmetric Diels-Alder reaction, asymmetric cycloisomerization, hydroformylation, hydrosilylation, hydroboration, hydrohydroxylation, hydroamination, hydrocyanation, isomerization formylation, hydroaminomethylation, transfer hydrogenation, allylation, olefin metathesis, cycloisomerization, asymmetric coupling, Michael addition, asymmetric epoxidation, kinetic resolution and [m+n] cyclization. The prochiral ketone compounds include simple aryl alkyl ketones, conjugated enones, α-hydroxyaryl alkyl ketones, α-aminoaryl alkyl ketones, α-chloroaryl alkyl ketones, β-keto acid esters, aryl (hetero) aryl ketones, and the like.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

Substituted phenyl refers to a phenyl group having at least one substituent, and the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The ligand disclosed in the present invention is a novel chiral tetradentate phosphine ligand, which has the advantages of simple synthesis, easy modification, good stability, etc. The metal complex of this type of ligand exhibits very excellent catalytic activity and extremely high enantioselectivity in the asymmetric hydrogenation reaction of ketones, and can efficiently reduce prochiral ketones such as α, β-unsaturated ketones, simple aryl alkyl ketones, α-hydroxyaryl alkyl ketones, α-aminoaryl alkyl ketones, α-chloroaryl alkyl ketones, β-ketoesters, aryl (hetero) aryl ketones to corresponding chiral alcohols, and has important industrial application value.

The ligands have the following advantages: 1. Simple synthesis. Most chiral ligands can be prepared in only 4 to 6 steps of reaction with high yield; 2. Stable ligands. This series of ligands is insensitive to water and oxygen, and is convenient for storage and use; 3. The ligands are easy to modify. Through the combination and replacement of connecting units, a series of structurally rich chiral tetradentate ligands can be quickly and efficiently synthesized, and steric hindrance and electrical regulation can be achieved. 4. High catalytic activity and good selectivity. This type of catalyst exhibits extremely high catalytic activity and excellent stereoselectivity in the asymmetric hydrogenation of ketones.

The present invention provides a chiral tetradentate phosphine ligand and a preparation method and application thereof. The present invention constructs a chiral tetradentate phosphine ligand based on a ferrocene skeleton as a ligand and in-situ complexes with metal iridium to prepare a chiral catalyst in one step. The metal complex is applied to asymmetric catalytic reactions, especially to asymmetric hydrogenation of ketones. Experimental results show that asymmetric hydrogenation reactions with high reaction activity and high stereoselectivity can be achieved at a higher conversion number.

The tetradentate ligand developed by the present invention has excellent performance in the asymmetric hydrogenation of a series of prochiral ketones, can efficiently prepare a series of chiral alcohols, and has high enantioselectivity, high yield and high turnover number (TON). Most ketone substrates can achieve a conversion rate of more than 99% and an ee value of more than 99% when the catalyst dosage is 0.01 mol% (S/C=10000). This type of ligand and the corresponding catalytic hydrogenation method can be used in the synthesis of key chiral fragments of drugs such as Ezetimine, Duloxetine, Aprepitant, Crizotinib, bepotastine besilate, carbinoxamine, orphenadine, neobenodine, etc., and has important application value and broad industrial application prospects.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. NMR spectrum of ligand L2

Figure 2. NMR spectrum of ligand L8

The present invention will be further described below in conjunction with specific examples. These examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

DETAILED DESCRIPTION

The present invention is further described in detail below through specific implementation methods in conjunction with the accompanying drawings. In the following implementation methods, many detailed descriptions are intended to enable the present application to be better understood. However, those skilled in the art can easily recognize that some of the features may be omitted in different situations, or may be replaced by other materials or methods. In some cases, some operations related to the present application are not shown or described in the specification. This is to avoid the core part of the present application being overwhelmed by too much description. For those skilled in the art, it is not necessary to describe these related operations in detail. They can fully understand the related operations based on the description in the specification and the general technical knowledge in the field.

In addition, the features, operations or characteristics described in the specification can be combined in any appropriate manner to form various implementations. At the same time, the steps or actions in the method description can also be interchanged or adjusted in a manner that is obvious to those skilled in the art. Therefore, the various sequences in the specification and the drawings are only for the purpose of clearly describing a certain embodiment and are not meant to be a required sequence, unless otherwise specified that a certain sequence must be followed.

The serial numbers assigned to the components in this article, such as "first", "second", etc., are only used to distinguish the objects described and do not have any order or technical meaning.

The technical problem to be solved by the present invention is to provide a chiral tetradentate phosphine ligand and a preparation method and application thereof. The chiral tetradentate phosphine ligand provided by the present invention forms a catalyst with metal iridium and is applied to the asymmetric hydrogenation of ketones. The reaction achieves excellent reaction activity and enantioselectivity at a higher conversion number.

The catalyst of the present invention is used in catalyzing the asymmetric hydrogenation reaction of aromatic ketone compounds, and the reaction formula is as follows:

In one embodiment, the compound of structural formula a may be at least one of a1 to a14:

In one embodiment, the chiral alcohol represented by structural formula b may be at least one of b1 to b14:

In one embodiment, a method for preparing a catalyst may include: mixing a transition metal precursor and a ligand f-thiophamidol in a solvent to obtain a catalyst.

In one embodiment, the asymmetric hydrogenation reaction can be carried out in an alcohol solvent.

In one embodiment, the amount of the basic compound added is 5.0-10.0% molar equivalent of the compound represented by structural formula a.

In one embodiment, the strong alkaline condition can be formed by adding at least one of potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium methoxide, sodium methoxide and potassium hydroxide to the aprotic solvent.

In one embodiment, the pressure of hydrogen during the reaction may be 30-50 atm.

In one embodiment, the amount of the catalyst used may be 0.01 molar equivalent of the compound represented by structural formula A. Preferably, the amount of the catalyst used is 5×10 ^-5 molar equivalent of the compound represented by structural formula I.

In one embodiment, the reaction time may be 12-48 hours.

In one embodiment, the reaction is carried out in an oxygen-free environment.

In one embodiment, the oxygen-free environment is an inert gas atmosphere.

In one embodiment, the inert gas is at least one of nitrogen, helium, neon, argon, krypton, and xenon. Preferably, the inert gas is nitrogen.

It should be noted that the main purpose of introducing inert gas into the reaction system in the present application is to form an anaerobic environment. If an anaerobic environment can be ensured, inert gas may not be used. In one implementation of the present application, even if inert gas is used, most of the entire reaction environment is still hydrogen, for example, more than 99% is hydrogen and the rest is inert gas.

The present application discloses a chiral alcohol obtained according to the preparation method of the present invention.

The present application uses the f-thiophamidol ligand to reduce alkyl aryl ketone compounds by a highly efficient asymmetric catalytic hydrogenation method, and divergently synthesizes chiral alcohol derivatives shown in structural formula b. The obtained products have high optical purity and can be used as intermediates for a variety of biologically active compounds.

The present application is further described in detail below through specific examples. The following examples are only used to further illustrate the present application and should not be construed as limiting the present application.

Ligand preparation example, taking ligand L2 as an example:

S1: Add compound 1 (335 mg, 1 mmol), methyl thioglycolate (212 mg, 2 mmol) and tetrahydrofuran (2 mL) into a sealed tube equipped with a magnetic stirrer, and heat in an oil bath at 120°C overnight. After the reaction is completed, remove the solvent by distillation under reduced pressure, dissolve the residue in ethyl acetate (5 mL), add half-saturated brine (10 mL), and then extract with ethyl acetate (10 mL), combine the organic phases, backwash with half-saturated brine (10 mL), dry with anhydrous sodium sulfate (3 g), concentrate, and separate by flash column chromatography to obtain a yellow solid, which is compound 6 (413 mg, 75% yield).

S2: Add compound 6 (413 mg), sodium hydroxide (200 mg), ethanol (3 mL) and water (3 mL) to a flask equipped with a magnetic stirrer. After reacting at room temperature for 2 hours, add excess acetic acid to the flask until the system is acidic (3-4). Dissolve the residue in ethyl acetate (5 mL), add half-saturated brine (10 mL), and then extract with ethyl acetate (10 mL). Combine the organic phases, backwash with half-saturated brine (10 mL), dry with anhydrous sodium sulfate, and concentrate to obtain a yellow oily compound 7 (369 mg, 93% yield), which can be directly used for the next step without purification.

Further, the step S3 is: dissolving compound 7 (369 mg) in anhydrous dichloromethane (2 mL), adding triethylamine (202 μL), L-tert-leucine alcohol (117 mg) and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) (380 mg) at room temperature, and reacting at room temperature for 12 hours. After the reaction is completed, the reaction solution is concentrated and separated by column chromatography to obtain a light yellow solid as compound L2 (316 mg, 71% yield).

The following are some of the product ligand NMR data:

The NMR data of product L2 are ¹ H NMR (600 MHz, CDCl ₃ ) δ7.60 (t, J = 8.0 Hz, 2H), 7.40 (d, J = 7.4 Hz, 3H), 7.22 (d, J = 5.4 Hz, 3H), 7.19–7.13 (m, 2H), 6.89 (d, J = 8.8 Hz, 1H), 4.46 (s, 1H), 4.39 (d, J = 7.8 Hz, 2H), 4.05 (s, 1H), 3.89 (s, 5H) ,3.81(dd,J＝11.3,3.2Hz,1H),3.73(dd,J＝17.0,3.2Hz,1H),3.49(dd,J＝11.3,8.2Hz,1H),3.14(d,J＝16.9Hz,1H),3.04(d,J＝16.9Hz,1H),1.76(d,J＝6.9Hz, 3H),0.97(s,9H).

The NMR data of product L6 are ¹ H NMR (600 MHz, CDCl ₃ ) δ7.37 (d, J=11.8 Hz, 1H), 7.21 (s, 1H), 7.19–7.12 (m, 2H), 7.06 (m, 1H), 7.03 (s, 1H), 6.75 (d, J=7.9 Hz, 1H), 4.44 (d, J=2.8 Hz, 1H), 4.40–4.32 (m, 2H), 4.03 (s, 1H), 3.89 (s, 5H), 3.81 (dd, J= 11.3,3.2Hz,1H),3.72(dd,J＝17.0,3.2Hz,1H),3.48(dd,J＝11.3,8.2Hz,1H),3.14(d,J＝16.9Hz,1H),3.04(d,J＝16.9Hz,1H),2.33(s,6H),2.20(s,6H),1 .72(d,J=6.9Hz,3H),0.97(s,9H).

The NMR data of product L8 are ¹ H NMR (600 MHz, CDCl ₃ ) δ7.60 (ddd, J=9.5, 5.8, 2.1 Hz, 2H), 7.44–7.37 (m, 3H), 7.21 (h, J=2.2 Hz, 3H), 7.15 (td, J=7.2, 2.2 Hz, 2H), 7.06 (d, J=8.1 Hz, 1H), 4.48 (q, J=2.0 Hz, 1H), 4.40 (t, J=2.6 Hz, 1H), 4.35 (qd, J=6.8, 3.2 Hz, 1H), 4.06 (dt, J=2.4, 1.0 Hz, 1H) ,3.87(s,5H),3.69(dt,J＝11.4,3.7Hz,1H),3.59(dt,J＝11.1,5.3Hz,1H),3.56–3.49(m,1H),3.21(d,J＝17.1Hz,1H),3.04(d,J＝17.1Hz,1H),2.73(d, J＝5.8Hz,1H),1.76(d,J＝6.9Hz,3H),0.97(d,J＝6.8Hz,3H),0.94(d,J＝6.8Hz,3H).

Application Examples

(1) Synthesis of chiral alcohol represented by structural formula b

Under nitrogen atmosphere, add 0.2mmol of acetophenone derivative of compound shown in structural formula a to hydrogenation bottle, then add metal precursor [Ir(COD)Cl] ₂ 0.001mmol, ligand L2 0.002mmol, potassium tert-butoxide 0.002mmol, deoxyisopropanol 1.0mL, and then transfer to autoclave, the inert gas in the reaction chamber is nitrogen, more than 99% of the reaction atmosphere is hydrogen, set hydrogen pressure 30atm, react at 25°C for 12h. Then slowly release hydrogen, add 10.0mL of dichloromethane to dilute, quench with 8.0mL of water, separate the organic phase, wash the aqueous phase twice with 10.0mL of dichloromethane, then combine the organic phases, dry with anhydrous sodium sulfate, concentrate to obtain a crude product, and then separate and purify by column chromatography to obtain a clean chiral alcohol shown in structural formula b.

(3) Product structure, yield and enantioselectivity detection

The structure of the hydrogenation product was determined by ¹ H NMR and ¹³ C NMR spectra, the ee value (enantioselectivity) of the product was determined by HPLC (high performance liquid chromatography), the yield was analyzed by hydrogen nuclear magnetic resonance spectrum, and the optical rotation value of the product was determined by a polarimeter.

This example specifically synthesized chiral alcohols b1 to b14, and the structures of the products and their yields and enantioselectivities are as follows:

The specific synthesis steps of some products and their product structures, yields and enantioselectivity detection and analysis data are schematically listed in this example, as follows:

a) Synthesis of chiral cyclic alcohol shown in b1

Under an inert gas atmosphere, 24.0 mg of acetophenone shown in b1, i.e. 0.2 mmol, 6.7 mg of metal precursor [Ir(COD)Cl] ₂ , i.e. 0.001 mmol, 12.6 mg of ligand L2, i.e. 0.002 mmol, 2.2 mg of potassium tert-butoxide, i.e. 0.002 mmol, and 1.0 mL of deoxyisopropanol were added to the hydrogenation bottle, and then transferred to a pressure autoclave. The inert gas in the reaction chamber was nitrogen, and more than 99% of the reaction atmosphere was hydrogen. The hydrogen pressure was set to 10 atm, and the reaction was carried out at 25° C. for 12 hours. Subsequently, hydrogen was slowly released, 10.0 mL of dichloromethane was added for dilution, 8.0 mL of water was used for quenching, the organic phase was separated, the aqueous phase was washed twice with 10.0 mL of dichloromethane, and then the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was subsequently separated and purified by column chromatography to obtain a clean chiral alcohol shown in structural formula b1.

The results of nuclear magnetic resonance analysis showed that the product b1 was colorless oil, 23.9 mg, 99% yield, 98% ee; the nuclear magnetic resonance data of the product b1 were ¹ H NMR (400 MHz, CDCl ₃ ) δ7.37–7.29 (m, 4H), 7.28–7.21 (m, 1H), 4.84 (q, J=6.4 Hz, 1H), 2.15 (s, 1H), 1.46 (dd, J=6.5, 1.1 Hz, 3H). ¹³ C NMR (101 MHz, CDCl 3 ) δ145.9, 128.5, 127.5, 125.4, 70.4, 25.2. [α] D ₂₀ ＝+50.15 (c＝1.0, CHCl ₃ ).

ee was measured by chiral GC (Supelco β-DEXTM 120, df = 0.25 mm i.d. × 30 cm, fused silica capillary column) carrier gas, N2 (flow rate 1.2 mL/min); injection temperature, 220°C; initial column temperature, 80°C; progress, 2.0°C/min; final column temperature was 120°C, and this temperature was maintained for 20 minutes; detector temperature, 240°C; tR(R) = 23.73 minutes (main), tR(S) = 25.03 minutes.

b) Synthesis of chiral cyclic alcohols shown in b1 at high turnover

Under an inert gas atmosphere, 0.005 mmol of the metal precursor [Ir(COD)Cl] ₂ and 0.01 mmol of the ligand L2 were dissolved in 5 mL of isopropanol solution and stirred at room temperature for 2 h until they were completely dissolved.

Add 2.4 g of acetophenone shown in b1, i.e. 20 mmol, 0.5 mL of the above catalyst solution, 448.8 mg of potassium tert-butoxide, i.e. 0.4 mmol, and 10.0 mL of deoxyisopropanol to the hydrogenation bottle, and then transfer to a pressure autoclave. The inert gas in the reaction chamber is nitrogen, and more than 99% of the reaction atmosphere is hydrogen. Set the hydrogen pressure to 50 atm, and react at 25°C for 48 hours. Then slowly release the hydrogen, add 30.0 mL of dichloromethane to dilute, quench with 20.0 mL of water, separate the organic phase, wash the aqueous phase twice with 30.0 mL of dichloromethane, then combine the organic phases, dry with anhydrous sodium sulfate, and concentrate to obtain a crude product, which is subsequently separated and purified by column chromatography to obtain a clean chiral alcohol shown in structural formula b1.

In summary, this embodiment uses the acetophenone derivatives shown in a1 to a14 to synthesize the chiral alcohols shown in b1 to b14 respectively. The synthesis method of this embodiment has cheap and easily available raw materials, simple operation steps, and has the advantages of high catalytic efficiency, high yield, and high product enantioselectivity.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A chiral tetradentate phosphine ligand compound or an isomer thereof, characterized in that the structure is as shown in formula (I): wherein each R ¹ is independently an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group or a heteroaryl group, or two R ¹ together with the connected P atom form a heterocyclic group; ^L1 and ^L2 are each independently selected from ^-NR2 -C(=O)-, -C(=O) ^-NR2- , -C(=O)-C(=O)-, -((C( ^R3 ) ₂ ) _q -C(=O)) _x- , -C(=O)-(C( ^R3 ) ₂ ) _q ) _x- or -(C( ^R3 ) ₂ ) _q ) _x- ; q and x are independently selected from 0, 1, 2, 3, 4, 5 or 6; Each R ³ is independently H, -F, -Cl, -Br, -I, -CN, -CHO, nitro, alkoxy, alkylthio, haloalkyl, alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl or heteroaryl; or R ³ on two adjacent carbon atoms can form a C _3-6 cycloalkyl or aryl group together with the connected C; Each ^R2 is independently H or alkyl; Each of R ¹ , R ² and R ³ is independently further substituted or polysubstituted by the same or different substituents; the substituents are selected from hydrogen, -F, -Cl, -Br, -I, -NH ₂ , -CN, -CHO, nitro, C _1-6 alkoxy, C _1-6 alkylthio, C _3-12 cycloalkyl, C _4-12 heterocycloalkyl, C _6-12 aryl, C _1-12 heteroaryl or C _1-6 alkyl. 2. The chiral tetradentate phosphine ligand compound according to claim 1, characterized in that each R ¹ is independently C _1-6 alkyl, C _3-12 cycloalkyl, C _2-12 heterocyclic group, C _6-12 aryl, C _6-12 aryl C _1-6 alkyl or C _1-12 heteroaryl, or two R ^1s together with the connected P atom form a C _2-12 heterocyclic group; preferably, each R ¹ is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidyl or phenylmethyl; each R ¹ is independently further substituted or polysubstituted by the same or different substituents; the substituents are selected from hydrogen, -F, -Cl, -Br, -I, -NH ₂ , -CN, -CHO, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidyl; Each R ³ is independently H, -F, -Cl, -Br, -I, -CN, -CHO, nitro, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkyl, C _1-6 alkyl, C _3-12 cycloalkyl, C _2-12 heterocyclyl, C _6-12 aryl, C _6-12 arylC _1-6 alkyl or C _1-12 heteroaryl; or R ³ on two adjacent carbon atoms can form a C _3-6 cycloalkyl or C _6-12 aryl together with the connected C; preferably, each R ³ is independently H, -F, -Cl, -Br, -I, -CN, -CHO, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl or phenylmethyl; Each R ² is independently H or C _1-6 alkyl; preferably, each R ² is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl. 3. The chiral tetradentate phosphine ligand compound according to claim 1, characterized in that ^L1 and ^L2 are each independently selected from one of the following substructures: 4. The chiral tetradentate phosphine ligand compound according to claim 1, characterized in that the structure is as shown below: wherein each of R ¹ and R ³ has the meaning as defined in claim 1. 5. The chiral tetradentate phosphine ligand compound according to claim 1, characterized in that the compound is selected from one of the following structures: 6. A method for preparing the chiral tetradentate phosphine ligand compound according to any one of claims 1 to 5, comprising the following steps: S1, condensing compound 1 and compound 5 at high temperature to obtain compound 2; S2, reacting compound 2 with sodium hydroxide and acetic acid in sequence to remove the ester protecting group to obtain compound 3; S3, condensing compound 3 and compound 4 to obtain a compound represented by formula (I); wherein each of R ¹ , L ¹ , L ² and R ³ has the meaning as defined in claim 1 . 7. A method for preparing the chiral tetradentate phosphine ligand compound according to any one of claims 1 to 5, comprising the following steps: S1, condensing compound 1 with methyl thioglycolate at high temperature to obtain compound 6; S2, reacting compound 6 with sodium hydroxide and acetic acid in sequence to remove the ester protecting group to obtain compound 7; S3, condensing compound 7 with chiral amino alcohol 8 to obtain a compound represented by formula (III); wherein each of R ¹ and R ³ has the meaning as defined in claim 1. 8. A chiral catalyst, characterized in that the chiral catalyst is a complex formed by the complexation of the chiral tetradentate phosphine ligand compound according to any one of claims 1 to 5 with a transition metal salt; preferably, the transition metal is selected from Ru, Rh, Pd, Ir, Fe, Co, Ni, Cu, Sc, Ti, V, Cr, Mn, Ag and Re. 9. Use of the chiral tetradentate phosphine ligand compound according to any one of claims 1 to 5 in the preparation of a chiral catalyst. 10. Use of the chiral tetradentate phosphine ligand compound according to any one of claims 1 to 5 and a catalyst prepared therefrom in catalytic asymmetric hydrogenation reactions.