Electron-rich diphosphine ligand, and preparation therefor and use thereof

Abstract

The present invention relates to the technical field of asymmetric hydrogenation. Particularly disclosed is an electron-rich chiral diphosphine ligand. The ligand is particularly L1-L5. Further disclosed are synthesis routes of the ligands L1-L5 and intermediate compounds 1-5 in the synthesis routes. In the present invention, L1-L7 are used to complex with different transition metal precursors, such as [Rh(COD)2]BArF 4, [Rh(NBD)2]BF4, [Rh(NBD)Cl]2, Rh(acac)(CO)2, Rh(ethylene)2(acac) and [Rh(ethylene)2Cl]2, so as to obtain a series of catalysts which are stable in terms of properties, simple to prepare and low in terms of cost. The catalysts can be used for asymmetric hydrogenation and particularly can be used for an asymmetric hydrogenation step in an N-Boc amino alcohol synthesis path, thereby effectively overcoming the steric effect under different conditions of amino protecting groups. Under the participation of the catalysts, the technical defect of dangerous articles being used in the prior art is overcome by the asymmetric hydrogenation step in the N-Boc amino alcohol synthesis path, such that the production safety coefficient is improved, and the asymmetric yield and selectivity both satisfy the industrial production requirements under the participation of the catalysts.

Description

Electron-rich biphosphine ligand, preparation and use thereof TECHNICAL FIELD

[0001] The present application relates to the field of chemical catalysts, in particular to an electron-rich chiral biphosphine ligand, preparation and use thereof. BACKGROUND

[0002] Mammalian endogenous atrial natriuretic peptide (ANP) also known as atriopeptin (ANF) has diuretic, natriuretic and vasodilatory functions. The natural ANF peptide is inactivated by metabolism, particularly by a degrading enzyme believed to be equivalent to NEP, which also causes the metabolic inactivation of enkephalins.

[0003] Sacubitril (AHU-377) is one of the main components of the anti-heart failure drug LCZ696 (CAS: 936623-90-4) developed by Novartis. The anti-heart failure drug is a supramolecular complex (complex) formed by the non-covalent combination of valsartan and sacubitril (AHU-377), which has the dual effects of angiotensin receptor blockade and neutral endopeptidase inhibition, reduces the risk of cardiovascular disease, and is mainly used for the treatment of heart failure, and can also be used for hypertension.

[0004] Sacubitril (AHU-377) is usually prepared through the key intermediate N-Boc amino alcohol [formula (10-a)], which is chemically named as tert-butyl N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl] carbamate (CAS: 1426129-50-1); its structural formula is:

[0005] There are many patent documents in the prior art about the synthesis method of sacubitril intermediate N-Boc amino alcohol, such as patents WO 2013 / 026773 and CN 103764624 disclose a method for preparing sacubitril intermediate amino alcohol by using p-phenylbenzaldehyde as raw material, and the key synthesis steps are as follows:

[0006] The route has the advantage of high yield in synthesizing compound 6a relative to the currently reported path, but in the process, a large amount of asymmetric catalyst is used in the step of synthesizing compound 4a from compound 3a, which leads to high process cost, and the use of lithium aluminum hydride in the process to reduce the ester group and the protecting group Bz increases the risk of operation, so the preparation of the key chiral intermediate N-Boc amino alcohol (10-a) of sacubitril is limited by raw materials, reaction reagents, post-treatment process and the like on the one hand, and the synthetic route is long, the diastereoisomer ratio is low, the environment is not friendly and the like on the other hand, which leads to high production cost and complicated operation, and is not conducive to industrialization. Therefore, it is of great significance to develop a more simple, economical and convenient production route for the key chiral intermediate N-Boc amino alcohol (10-a). SUMMARY

[0007] In the synthesis path of N-Boc amino alcohol in the prior art, there is steric hindrance in asymmetric hydrogenation, low diastereoisomer ratio, environmental unfriendliness, use of unstable hazardous chemicals, increase in operation risk and related production personnel safety risk, which leads to high production cost, complicated operation and non-conducive to industrialization. The present application proposes an electron-rich chiral diphosphine ligand, which can be complexed with various metal transition metal precursors to form a metal complex catalyst for use in the asymmetric hydrogenation step.

[0008] The first aspect proposes an electron-rich chiral diphosphine ligand having the structure of formula (I),

[0009] The * represents a chiral center;

[0010] Each of the plurality of carbon chiral centers is independently in R configuration or S configuration;

[0011] The -X1- is -(CH2) n , the n is selected from 1-5, preferably 1-3, and particularly preferably 1, or, optionally, any one of the methylene units in -(CH2) n is optionally and independently replaced by -NR5-, -O-, -S- and -C(O)-, and the R5 is selected from H, alkyl, alkenyl, alkynyl or halogenated alkyl;

[0012] The R2 and R3 together with the atoms to which they are attached form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heterocycloalkenyl;

[0013] The R4 is selected from a substituted or unsubstituted alkyl;

[0014] each of said plurality of R1is independently selected from the group consisting of substituted or unsubstituted linear alkane, substituted or unsubstituted branched alkane, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted adamantyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylthio,

[0015] or,

[0016] said plurality of R1together with the atoms to which they are attached form a substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted heteroaryl;

[0017] In some embodiments of the electron-rich chiral diphosphine ligand, said R1is selected from linear alkane, said linear alkane comprising 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1, 2, or 4 carbon atoms.

[0018] In some embodiments of the electron-rich chiral diphosphine ligand, said R1is selected from branched alkane, said branched alkane comprising 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, more preferably 3, 4, 5 carbon atoms.

[0019] In some embodiments of the electron-rich chiral diphosphine ligand, said R1is selected from cycloalkyl, said cycloalkyl comprising 1 to 10 carbon atoms, preferably 5 to 7 carbon atoms, more preferably 6 carbon atoms.

[0020] In some embodiments of the electron-rich chiral diphosphine ligand, said R1is selected from aryl, said aryl comprising monocyclic aryl or fused ring aryl.

[0021] In some embodiments of the electron-rich chiral diphosphine ligand, said R1is selected from sec-butyl, tert-butyl.

[0022] In some embodiments of the electron-rich chiral diphosphine ligand, said R1is selected from alkylaryl, said alkylaryl containing monocyclic aryl, said monocyclic aryl having any of its hydrogens replaced by alkyl comprising 3 to 5 carbon atoms.

[0023] In some embodiments of the electron-rich chiral diphosphine ligand, R1 is selected from the group consisting of straight-chain alkane, branched alkane, cycloalkyl, aryl, alkylaryl, and in some embodiments of R1, the hydrogens are optionally substituted with R6, which is independently selected at each occurrence from the group consisting of alkoxy, aryloxy, n-butyl, sec-butyl, t-butyl, halogen, nitro, cyano, alkanoyl.

[0024] In some embodiments of the electron-rich chiral diphosphine ligand, the hydrogens on the ligand are optionally substituted with D, up to complete deuteration.

[0025] In some embodiments of the electron-rich chiral diphosphine ligand, the ligand of formula (I) is specifically L1-L5, and the ligands L1-L5 are specifically as follows:

[0026] The second aspect of the present application provides a method for preparing a ligand, which is used for preparing the ligand of formula (I) or L1-L5 of the first aspect, and comprises steps S1-S4:

[0027] In M1, X2 is selected from the group consisting of M1 is specifically

[0028] In M2, X2 is selected from the group consisting of M2 is specifically

[0029] In M3, X2 is selected from the group consisting of M3 is specifically

[0030] In M4, X2 is selected from the group consisting of M4 is specifically

[0031] In M5, X2 is selected from the group consisting of M5 is specifically

[0032] In which S1: NaBH4 is added in batches to the alcohol solution of compound 2 to obtain compound 3;

[0033] S2: Br2 and PPh3 are added in sequence to the container, and then dissolved with an organic solvent, stirred, and compound 3 is added dropwise to the dissolved solution, and stirred to obtain compound 4;

[0034] S3: corresponding LiP(Ad)2, LiP(Ph)2, LiP(tBu)2, LiP(Cy)2 or LiP(DTBM)2 is mixed with compound 4, and then DMF is added to the reaction, and stirred to obtain corresponding M1-M5;

[0035] S4: M1~M3 respectively independently mixed with P(NMe2)3, heating to obtain corresponding L1~L3, specifically M1 alone mixed with P(NMe2)3, heating to obtain L1, M2 alone mixed with P(NMe2)3, heating to obtain L2, M3 alone mixed with P(NMe2)3, heating to obtain L3,

[0036] Alternatively, M4~M5 respectively independently mixed with Si2Cl6, heating to obtain corresponding L4~L5, specifically M4 alone mixed with Si2Cl6, heating to obtain L4, M5 alone mixed with Si2Cl6, heating to obtain L5;

[0037] The third aspect of the present application proposes a catalyst preparation method, which is that the structural ligand of formula (I) and the transition metal precursor participate in the complexation reaction in the organic solvent, the structural ligand of formula (I) and the transition metal precursor are both the substrates of the complexation reaction, and the catalyst is obtained by the complexation reaction;

[0038] Alternatively, any one of L1~L5 and the transition metal precursor participate in the complexation reaction in the organic solvent, any one of L1~L5 and the transition metal precursor are both the substrates of the complexation reaction, and the catalyst is obtained by the complexation reaction;

[0039] Alternatively, any one of L6~L7 and the transition metal precursor participate in the complexation reaction in the organic solvent, any one of L6~L7 and the transition metal precursor are both the substrates of the complexation reaction, and the catalyst is obtained by the complexation reaction.

[0040] In some specific embodiments of the catalyst preparation method of the third aspect, the organic solvent is selected from a mixed solvent of DCM and THF.

[0041] In some specific embodiments of the catalyst preparation method of the third aspect, the transition metal precursor is selected from [Rh(COD)2]BAr F 4、[Rh(NBD)2]BF4、[Rh(NBD)2]X;[Rh(NBD)Cl]2;Rh(acac)(CO)2;[Rh(COD)Cl]2;Rh(ethylene)2(acac);[Rh(ethylene)2Cl]2;[Rh(COD)2]X;

[0042] The X is a negative anion, which is selected from Cl - 、Br - 、I - 、BF4 - 、ClO4 - 、SbF6 - 、PF6- , TfO - , RCOO - or B(Ar)4 - any one of.

[0043] The fourth aspect of the present application provides a metal complex catalyst prepared by the method of the third aspect.

[0044] The fifth aspect of the present application provides the use of the metal complex catalyst of the fourth aspect in asymmetric hydrogenation.

[0045] The sixth aspect of the present application provides a method for preparing a sacubitril intermediate, characterized in that, comprising:

[0046] The * represents a chiral center, and the chiral carbon atom is in R configuration or S configuration;

[0047] The R7 is selected from any amino protecting group.

[0048] In some specific embodiments of the method for preparing a sacubitril intermediate, the R7 is selected from Cbz, Boc, Fmoc, Alloc, Teoc, Pht, Tfa, Trt, Dmb, Bn.

[0049] In some specific embodiments of the method for preparing a sacubitril intermediate, the R7 is selected from alkanoyl.

[0050] In some specific embodiments of the method for preparing a sacubitril intermediate, the R7 is selected from arylacyl.

[0051] In some specific embodiments of the method for preparing a sacubitril intermediate, the R7 is selected from any one of.

[0052] The seventh aspect of the present application provides an intermediate or a deuterated compound thereof, the intermediate having a structure as described in formula (III):

[0053] The * represents a chiral center, and each of the plurality of carbon chiral centers is independently in R configuration or S configuration;

[0054] The -X1- is -(CH2) n -, and the n is selected from 1-5, preferably 1-3, and particularly preferably 1, or, any one of the methylene units in -(CH2) n is optionally and independently replaced by -NR5-, -O-, -S-, and -C(O)-, and the R5 is selected from H, alkyl, alkenyl, alkynyl, or halogenated alkyl;

[0055] R2and R3together with the atom to which they are attached form a substituted or unsubstituted C5-C7carbocyclic group, a 3- to 7-membered heterocyclic group;

[0056] X2is selected from the group consisting of hydroxyl, halogen, each of a, b is independently selected from 1, 2, 3;

[0057] each of R1is independently selected from the group consisting of hydrogen, C1-C 10 linear alkanes, C3-C 10 branched alkanes, monocyclic aryl, fused ring aryl, cycloalkyl, adamantyl, hydrogen on R1optionally substituted with R8, each occurrence of R8is independently selected from the group consisting of alkoxy, sec-butyl, t-butyl, halogen, nitro, cyano, alkanoyl;

[0058] Abbreviations / Chemical Names / Structure Lookup Table:

[0059] L1is written as where Ad represents an adamantyl group;

[0060] L2is written as where Ph represents a phenyl group;

[0061] L3is written as where tBu represents a t-butyl group;

[0062] L4is written as where Cy represents a cyclohexane group;

[0063] L5is written as where DTBM is

[0064] L6is written as represents ZhangPhos;

[0065] L7is written as represents MeO-POP;

[0066] Glossary:

[0067] The term "degrees" in the present invention, in the absence of a specific designation, is degrees Celsius.

[0068] In the absence of a specified temperature and pressure, all measurements in the present invention are made at standard atmospheric pressure;

[0069] "room temperature" means a temperature from about 10 °C to about 40 °C. In some embodiments, "room temperature" means a temperature from about 20 °C to about 30 °C; in other embodiments, "room temperature" means 20 °C, 22.5 °C, 25 °C, 27.5 °C, etc.

[0070] "Cycloalkyl" refers to a saturated monocyclic hydrocarbon group, the carbocyclic ring of which can contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms, excluding the case where the carbon atoms are arranged in a connection such as adamantyl;

[0071] "Aryl" is any C5-C26 carbocyclic aromatic, heteroaromatic, fused heteroaromatic, or fused heteroaromatic group. For example, "aryl" can include 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered monocyclic aromatic groups, including but not limited to benzene. "Aryl" also encompasses polycyclic systems having two or more rings in which two or more carbons are shared by two adjacent rings (i.e., "fused aromatic rings"), where at least one ring is aromatic, for example, another ring or additional rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocycle.

[0072] "Alkoxy," "Aroxy" or "Aryloxy" refers to the group -OR x of the compounds shown, wherein R x include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, polyaryl, polyheteroaryl, arylalkyl, heteroalkyl, alkylaryl, alkylheteroaryl, arylalkyl, carbonyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, t-butoxy, and the like.

[0073] "Alkylaryl" refers to an aryl group in which any hydrogen is replaced by R c , wherein R c is an alkyl group, an alkene, or an alkyne, R c is an alkane when the carbon number can contain 1-10 carbon atoms, R c is an alkene or alkyne when the carbon number can contain 3-6 carbon atoms, more preferably 4 carbon atoms, exemplary including m R c , each independently, replaces a hydrogen on the phenyl ring, m is the number of hydrogens on the phenyl ring replaced by R c , m is selected from 1-5, further 2, and further exemplary R c is t-butyl, m is 2, and the number of t-butyl groups is 2;

[0074] "Arylalkyl" refers to an alkyl group in which any hydrogen is replaced by R d , wherein R d is selected from monocyclic aryl, or fused ring aryl, exemplary including

[0075] "Arylacyl" refers to a group of the formula -COR e R f or a group of the formula -COR f wherein R e is -(CH2) p - wherein p is selected from the group consisting of positive integers from 1 to 10, and R f may optionally be a monocyclic aryl group, a monocyclic aryl group includes 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered monocyclic aromatic groups, including but not limited to benzene, R f may also be a fused aryl group, a fused aryl group includes a polycyclic system of two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is aromatic, for example, another ring or additional rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocycle. An exemplary arylacyl group is

[0076] The reagents of the present application are purchased from Sigma-Aldrich, Sinopharm Chemical Reagent Co., Ltd., and XiLong Reagent Co., Ltd., and the purity can be any of AR, GR, or HPLC, and the reagents have not been further purified.

[0077] "ee" is the enantiomeric excess, in the present application, that is, in chiral synthesis, the percentage content of (a) minus the percentage content of (b) .

[0078] The number of catalyst cycles is the number of times the catalyst is used until the yield (%) is less than 95% of the yield of the first catalytic reaction, or the enantiomeric excess ee% is less than 95% of the enantiomeric excess of the first catalytic reaction.

[0079] "S / C" is the molar ratio of the substrate to the catalyst.

[0080] The present application has the following advantages:

[0081] The various electron-rich chiral diphosphine ligands prepared by the present application can be complexed with various transition metal precursors, and the catalysts obtained after complexation can be used in the synthesis of N-Boc amino alcohols, and the catalysis of the asymmetric hydrogenation step. The ligand and transition metal complex have strong stability, high catalyst yield, and in the case of various transition metal precursor raw materials and various ligands available for selection, inexpensive raw materials can be used, thereby reducing production costs.

[0082] The catalyst used in the application is also applied to reaction substrates with various amino protecting groups, and high yield and selectivity are obtained. The yield and selectivity are high under different amino protecting groups, the structural adaptability to the reaction substrate is good, the steric hindrance effect is avoided, the activity decay degree is low after multiple cycles, the work burden of production personnel is reduced, and the reactivation frequency in production is reduced.

[0083] Under the participation of the catalyst prepared from the ligand, the selectivity and yield of asymmetric hydrogenation in the N-Boc amino alcohol path meet the requirements of industrial production, and the disadvantages of the prior art, such as environmental unfriendliness, use of unstable hazardous chemicals, increased operation danger, safety risk to related production personnel, complicated production operation, high cost and being not conducive to industrialization, are overcome. DETAILED DESCRIPTION

[0084] The further features, advantages and effects of the application will be more clearly and thoroughly understood by the person skilled in the art through the further detailed description of the embodiments of the application in conjunction with the accompanying drawings and specific embodiments.

[0085] The technical solutions of the embodiments of the application will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the application, rather than all the embodiments. Based on the embodiments in the application, all other embodiments obtained by the person skilled in the art without creative labor fall within the protection scope of the application.

[0086] Example 1: Synthesis of compound 2

[0087] A magnetic stirrer was placed in a 250 ml schlenk reaction bottle, the reaction bottle was heated with an electric gun and then cooled under vacuum, and then dry nitrogen was supplemented, and the gas exchange was repeated for 3 times. Under the protection of nitrogen, a mixed solution system of 3.9 ml TMEDA and 45 ml ether was added, and the system was stirred at-78℃ for 10-15 minutes. 22.4 ml of sec-butyl lithium (1.16M, 26 mmol) was then added dropwise into the reaction system, and stirred at-78℃ for 30 minutes. 5 g of reactant 1 (21.7 mmol) was dissolved in 32.5 ml of dry toluene, and then added dropwise into the reaction system with a syringe, and then stirred at the temperature for 5 hours. 8.4 ml of DMF was added into the reaction system, and stirred for 5 minutes, and then the temperature was raised to room temperature and stirred overnight. The reaction system was extracted with saturated NH4Cl aqueous solution, and extracted with ether or ethyl acetate. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed under vacuum. The white solid product compound 2 was separated by silica gel column chromatography, and the yield was 4.936 g, 88%.

[0088] 1H NMR (400 MHz, CDC13) δ 9.64 (d, J = 3.7 Hz, 1H), 2.70 (ddd, J = 12.6, 9.2, 3.7 Hz, 1H), 2.60 (ddd, J = 14.9, 6.9, 1.6 Hz, 1H), 2.32 (qdd, J = 11.6, 3.5, 1.7 Hz, 1H), 2.03 - 1.89 (m, 2H), 1.89 - 1.74 (m, 3H), 1.65 (s, 1H), 1.40 - 1.24 (m, 12H), 1.05 (qd, J = 12.5, 3.4 Hz, 1H).

[0089] 13 C NMR (101 MHz, CDC13) δ 200.21, 54.91 (d, J = 37.3 Hz), 44.89 (d, J = 6.6 Hz), 44.42, 38.75 (d, J = 46.2 Hz), 34.73 (d, J = 42.7 Hz), 33.26 (d, J = 14.5 Hz), 31.44 (d, J = 12.4 Hz), 25.69, 25.51, 24.49 (d, J = 2.5 Hz).

[0090] 31 P NMR (162 MHz, CDC13) δ 77.56.

[0091] Example 2: Synthesis of compound 3

[0092] Compound 2 (18.57 mmol) and a magnetic stir bar were added to a 250 ml round bottom flask, 100 ml of ethanol was added, then the reaction temperature was reduced to 0 °C and stirred for 10-15 minutes, 1.5 g of NaBH4 was gradually added to the reaction system in three times, the reaction temperature was raised to room temperature, and the reaction was monitored by TLC (usually 1-2 hours). After the reaction was completed, water was gradually added dropwise at 0 °C to remove excess NaBH4, then the system was concentrated under vacuum to remove most of the ethanol, the aqueous phase was extracted with ethyl acetate, then anhydrous sodium sulfate was added to the organic phase to dry, concentrated, and the remaining solid was filtered through a short silica gel column to obtain the clean white solid product compound 3, (18.03 mmol), 97% yield.

[0093] 1H NMR (400 MHz, CDC13) δ 3.98 (dt, J = 20.8, 6.0 Hz, 2H), 2.50 (ddd, J = 14.9, 6.4, 3.2 Hz, 1H), 2.06 - 1.88 (m, 3H), 1.78 (s, 2H), 1.72 - 1.51 (m, 4H), 1.25 (m, 11H), 1.19 - 1.09 (m, 1H), 1.09 - 0.96 (m, 1H).

[0094] 13 C NMR (101 MHz, CDC13) δ 59.97 (d, J = 2.7 Hz), 44.68 (d, J = 7.5 Hz), 44.21 (d, J = 3.1 Hz), 37.53, 37.07, 33.94, 33.46 (d, J = 14.0 Hz), 31.17 (d, J = 13.4 Hz), 25.93 (d, J = 2.0 Hz), 25.61, 24.91 (d, J = 2.0 Hz).

[0095] 31 P NMR (162 MHz, CDC13) δ 77.68. HRMS (ESI-MS): calc. 260.1364 [M] + , found 261.1439 [M + H] + .

[0096] Example 3: Synthesis of compound 4

[0097] In a 50 ml dry reaction flask, Br2and PPh3compound (5.54 mmol) were added successively, dissolved in 16 ml dry acetonitrile. The reaction system was stirred at -30 °C for 10 minutes, compound 3 (3.96 mmol) was dissolved in 8 ml dry acetonitrile, then added dropwise into the reaction system, the reaction system was stirred for 5 minutes, then raised to room temperature and stirred overnight for 12 hours. The saturated aqueous sodium thiosulfate solution was added to the reaction to remove the liquid bromine, and after the liquid bromine was completely removed, ethyl acetate was added to extract, the organic phase was dried with anhydrous sodium sulfate, concentrated, and then separated by silica gel column chromatography (TLC PE:EA = 10:1) to obtain 3.71 mmol of pure white solid product compound 4, with a yield of 93.7%.

[0098] 1H NMR (400 MHz, CDC13) δ 3.95 (ddd, J = 13.2, 11.0, 5.2 Hz, 1H), 3.42 (ddd, J = 14.0, 11.0, 5.9 Hz, 1H), 2.56 (ddd, J = 14.8, 6.6, 2.9 Hz, 1H), 2.35 (dd, J = 12.2, 3.2 Hz, 1H), 2.18 (ddt, J = 11.6, 7.6, 5.6 Hz, 1H), 1.97 - 1.89 (m, 1H), 1.87 - 1.72 (m, 2H), 1.61 (ddd, J = 16.5, 14.8, 12.1 Hz, 1H), 1.49 - 1.38 (m, 1H), 1.28 - 1.06 (m, 14H).

[0099] 13 C NMR (101 MHz, CDC13) δ 50.43 (d, J = 7.7 Hz), 44.38 (d, J = 42.2 Hz), 43.48 (d, J = 1.8 Hz), 37.60 (d, J = 47.4 Hz), 33.92 (d, J = 42.5 Hz), 33.47 (d, J = 14.1 Hz), 31.99 (d, J = 12.6 Hz), 30.12 (d, J = 4.5 Hz), 25.82 (d, J = 2.1 Hz), 25.68, 25.11 (d, J = 2.0 Hz).

[0100] 31 P NMR (162 MHz, CDC13) δ 81.69. HRMS (ESI-MS): calc. 322.0520 [M] + , found 323.0595 [M + H] + .

[0101] Example 4: Synthesis of compound 5

[0102] A 50 ml schlenk reaction tube was charged with a magnetic stir bar, dried under vacuum with heating by an electric heating gun, and then transferred into a glove box under argon atmosphere. 5 mmol of HPAd2, 10 mL of THF, and then 8 mL of n-BuLi solution in n-hexane (1.3 M) were added. The reaction system was taken out of the glove box, heated at 80 °C for 2 hours, and then cooled. The solvent was removed under vacuum, and the remaining solid material was washed with ice-cold n-hexane three times and filtered to obtain LiPAd2 (white solid product, yield > 79%).

[0103] A 10 ml reaction tube was charged with a magnetic stir bar, dried under vacuum with a heat gun, then transferred into a dry argon-filled glovebox, where LiPAd2(2.33 mmol) and compound 4 (1.55 mmol) were weighed into the reaction tube. The reaction tube was sealed with a rubber septum, then removed from the glovebox and cooled to -78 °C. After 10-15 min, 4 ml of dry DMF was added to the reaction while slowly warming. The reaction was stirred overnight at room temperature. The reaction was quenched with water, then extracted with n-hexane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give compound 5 (1.14 mmol) as a white solid. Compound 5 is defined as compound M1, 73.5% yield.

[0104] 1 H NMR (600 MHz, CDC13) δ 2.63-2.52 (m, 2H), 2.12 (td, J = 17.0, 7.9 Hz, 1H), 2.02-1.96 (m, 3H), 1.94-1.85 (m, 17H), 1.85-1.80 (m, 1H), 1.71 (d, J = 9.8 Hz, 14H), 1.47-1.38 (m, 1H), 1.30 (d, J = 15.9 Hz, 9H), 1.26-1.17 (m, 4H), 1.14-0.98 (m, 2H).

[0105] 13 C NMR (151 MHz, CDC13) δ 51.60 (dd, J = 8.0, 4.0 Hz), 43.74 (d, J = 2.6 Hz), 41.37 (dd, J = 41.4, 20.6 Hz), 40.86 (dd, J = 10.6, 8.0 Hz), 38.19 (d, J = 47.1 Hz), 37.06, 37.01 (d, J = 4.0 Hz), 36.87 (d, J = 2.8 Hz), 33.94, 33.84 (d, J = 4.1 Hz), 33.55, 33.28 (dd, J = 13.6, 8.7 Hz), 28.63 (dd, J = 7.8, 5.6 Hz), 26.29-25.74 (m), 16.39 (d, J = 25.7 Hz).

[0106] 31 P NMR (243 MHz, CDC13) δ 85.65 (d, J = 14.7 Hz), 16.83 (d, J = 15.8 Hz).

[0107] HRMS (ESI-MS): calc. 544.3421 [M] + , found 545.3497 [M + H]+ .

[0108] Example 5: Synthesis of Ligand L1

[0109] In a 10 ml Schlenk sealed reaction tube, compound 5 (1.10 mmol), 4 ml P(NMe2)3, the system was degassed by freeze-pump-thaw, the tube was sealed and then heated to 130 °C, the reaction was monitored by 31 P NMR, after the reaction was completed, the system was cooled to room temperature, the excess P(NMe2)3was removed under high vacuum, the remaining oily mixture was filtered through a short plug of silica gel, dried and crystallized in ethanol to give the pure white solid product compound L1 (0.99 mol) with a yield of 90%.

[0110] 1 H NMR (400 MHz, CDC13) δ 1.97 - 1.81 (m, 15H), 1.81 - 1.75 (m, 1H), 1.74 - 1.61 (m, 12H), 1.61 - 1.50 (m, 1H), 1.50 - 1.20 (m, 6H), 1.10 (d, J = 11.4 Hz, 9H), 1.02 - 0.76 (m, 10H).

[0111] 13 C NMR (101 MHz, CDC13) δ 55.16 (d, J = 6.7 Hz), 47.34, 43.53 (dd, J = 20.1, 15.5 Hz), 40.90 (dd, J = 17.9, 11.0 Hz), 37.12 (d, J = 4.2 Hz), 36.75 (d, J = 24.0 Hz), 36.10 (d, J = 22.1 Hz), 34.82 (d, J = 2.7 Hz), 32.96 (t, J = 4.6 Hz), 30.09 (t, J = 6.8 Hz), 29.85 - 29.55 (m), 29.50 (d, J = 4.7 Hz), 28.62 (dd), 26.26 (d, J = 25.8 Hz), 11.94.

[0112] 31 P NMR (162 MHz, CDC13) δ 23.34 (d, J = 17.4 Hz), 17.22 (d, J = 16.2 Hz). m / z (ESI-MS): calc. 512.3701 [M] + , found 513.3773 [M+H] + .

[0113] Example 6: Synthesis of Compound 6

[0114] A 50 ml schlenk tube was charged with a magnetic stir bar, dried and evacuated under vacuum with heating from an electric heater. The tube was then transferred into a dry argon filled glove box. 5 mmol of HPPh2, 10 mL of THF, followed by 8 mL of nBuLi in n-hexane (1.3 M) were added to the tube, which was sealed and removed from the glove box. The reaction mixture was heated at 80 °C for 1 h. The solvent was removed under vacuum and the remaining solid was washed with ice-cold n-hexane three times and filtered to obtain LiPPh2(white solid, >82% yield).

[0115] A 10 ml schlenk tube was charged with a magnetic stir bar, dried and evacuated under vacuum with heating from an electric heater. The tube was then transferred into a dry argon filled glove box. LiPPh2(0.8 mmol) and compound 4 (0.4 mmol) were weighed into the tube, which was sealed and removed from the glove box. The reaction mixture was cooled to -78 °C for 10-15 min, followed by the addition of 3 mL of dry DMF. The reaction mixture was allowed to warm up to room temperature with stirring overnight. The reaction mixture was quenched with water, followed by extraction with n-hexane. The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to obtain compound 6 (0.273 mmol) as a white solid, 68% yield.

[0116] 1 H NMR (400 MHz, CDC13) δ 7.48 (ddd, J = 8.7, 5.5, 1.9 Hz, 2H), 7.41 (dq, J = 7.2, 3.0 Hz, 2H), 7.37 - 7.31 (m, 3H), 7.28 (td, J = 3.5, 1.8 Hz, 3H), 2.75 (ddd, J = 16.9, 14.3, 5.0 Hz, 1H), 2.51 (ddd, J = 14.9, 6.6, 3.3 Hz, 1H), 2.35 - 2.23 (m, 1H), 2.14 (dddd, J = 14.7, 12.3, 6.8, 2.6 Hz, 1H), 1.91 - 1.83 (m, 1H), 1.80 - 1.50 (m, 4H), 1.47 - 1.33 (m, 1H), 1.19 - 1.11 (m, 3H), 1.01 (d, J = 15.9 Hz, 10H), 0.92 - 0.76 (m, 1H).

[0117] 13C NMR (151MHz, CDCl3) δ139.14 (d, J = 15.1Hz), 138.18 (d, J = 13.8Hz), 133.32 (d, J = 18.6Hz), 132.9 6(d,J=18.5Hz),128.75(d,J=3.4Hz),128.54,128.48(d,J=3.6Hz),128.43,51.52(dd,J=7.7,3. 2Hz),43.57(d,J=2.3Hz),37.71(d,J=15.3Hz),37.68(d,J=47.3Hz),37.42(d,J=15.6Hz),33.75 (d,J=27.9Hz),33.56,32.44(dd,J=14.0,9.2Hz),28.08(d,J=15.5Hz),26.24-25.75(m),25.22.

[0118] 31 P NMR(162MHz, CDCl3)δ83.53(d,J=21.2Hz),-17.81(d,J=21.3Hz).m / z(ESI-MS):calc.428.1856[M] + ,found429.1935[M+H] + .

[0119] Example 7: Synthesis of Compound L2

[0120] In a 10 ml Schlenk sealed reaction tube, compound 6 (1.63 mmol) and 4 ml P(NMe2)3 were added, and the air in the system was removed by freeze-pump-thaw. The sealed tube was then heated to 130 ° C. The reaction was completed. 31 P NMR monitoring. After the reaction, the system was cooled to room temperature, and the excess P(NMe2)3 was removed under high vacuum. The remaining oily mixture was filtered through a short silica gel plug, dried, and crystallized in ethanol to obtain a clean white solid product, compound L2 (1.55 mmol), with a yield of 95%.

[0121] 1H NMR (400 MHz, CDC13) δ 7.47 (ddd, J = 8.2, 5.1, 1.8 Hz, 2H), 7.44 - 7.39 (m, 2H), 7.36 - 7.31 (m, 3H), 7.31 - 7.26 (m, 3H), 2.51 (td, J = 15.4, 5.9 Hz, 1H), 2.39 (dd, J = 15.0, 7.0 Hz, 1H), 2.16 (d, J = 12.0 Hz, 1H), 1.85 (d, J = 12.8 Hz, 1H), 1.76 - 1.58 (m, 4H), 1.36 - 1.22 (m, 2H), 1.07 - 0.73 (m, 14H).

[0122] 13 C NMR (101 MHz, CDC13) δ 140.20 (d, J = 15.1 Hz), 138.99 (d, J = 14.0 Hz), 133.28 (d, J = 19.1 Hz), 132.72 (d, J = 17.9 Hz), 128.40 (d, J = 5.7 Hz), 128.31, 128.27 (d, J = 5.0 Hz), 53.75 (d, J = 6.7 Hz), 47.04 (d, J = 3.6 Hz), 39.68 (dd, J = 14.9, 12.4 Hz), 34.68 (d, J = 2.5 Hz), 33.86 (dd, J = 32.3, 13.7 Hz), 32.53 (t, J = 4.9 Hz), 28.75, 28.60, 28.58, 28.35 (dd, J = 13.5, 2.2 Hz), 26.09 (d, J = 11.3 Hz).

[0123] 31 P NMR (162 MHz, CDC13) δ 20.15 (d, J = 41.3 Hz), -19.82 (d, J = 41.1 Hz). m / z (ESI-MS): calc. 396.2136 [M] + , found 397.2204 [M+H] + .

[0124] Example 8: Synthesis of compound 7

[0125] A 50 ml schlenk reaction tube was charged with a magnetic stir bar, dried under vacuum with heating by an electric heating gun, and then transferred into a glove box under argon. 5 mmol of HP tBu2, 10 mL THF, followed by 8 mL of nBuLi in n-hexane (1.3 M), sealed, removed from the glove box, heated at 80 °C for 1 h, cooled, solvent removed under vacuum, remaining solid material washed with ice-cold n-hexane three times, filtered to give LiP t Bu2 (white solid product, >85% yield).

[0126] A 25 mL schlenk tube was charged with a magnetic stir bar, dried under vacuum with heating from an electric heater, then transferred into a glove box under dry argon, LiP t Bu2 (6.2 mmol) and compound 4 (3.1 mmol) were added to the reaction tube, sealed with a rubber septum, removed from the glove box, cooled to -78 °C for 10-15 min, then 8 mL of dry DMF was added to the reaction while slowly warming, stirring was initiated, the reaction was allowed to warm to room temperature and stirred overnight. 500 mg of powdered sulfur was then added to the reaction under inert gas protection, stirred for 5 h, the reaction was quenched with water, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the pure white solid product, compound 7 (1.97 mmol), was isolated by silica gel column chromatography, compound 7 was defined as M3, 63.5% yield.

[0127] 1 H NMR (600 MHz, CDC13) δ 3.35 (dddd, J = 25.1, 16.7, 8.9, 5.0 Hz, 1H), 2.70 (ddd, J = 21.8, 10.7, 5.1 Hz, 1H), 2.64 (ddd, 1H), 2.28 (d, J = 8.6 Hz, 1H), 1.97 - 1.91 (m, 1H), 1.87 - 1.80 (m, 1H), 1.79 - 1.67 (m, 2H), 1.66 - 1.60 (m, 1H), 1.44 - 1.27 (m, 28H), 1.25 - 1.13 (m, 4H), 1.04 (qd, J = 12.6, 3.6 Hz, 1H).

[0128] 13C NMR (151 MHz, CDCI3) δ 54.02 (dd, J = 8.5, 5.0 Hz), 42.83 (d, J = 2.7 Hz), 39.01, 38.72, 38.45, 38.37, 38.05, 37.52 (dd, J = 40.0, 2.9 Hz), 35.20 (d, J = 41.5 Hz), 34.04 (d, J = 14.2 Hz), 32.68 (d, J = 13.0 Hz), 28.04 (d, J = 20.6 Hz), 26.27 (d, J = 2.0 Hz), 25.74 (d, J = 2.2 Hz), 21.50 (dd, J = 39.2, 2.8 Hz).

[0129] 31 P NMR (243 MHz, CDCI3) δ 87.85 (d, J = 18.1 Hz), 81.17 (d, J = 16.7 Hz). m / z (ESI-MS): calc. 420.2203 [M] + , found 421.2278 [M + H] + .

[0130] Example 9: Synthesis of compound L3

[0131] In a 10 ml Schlenk sealed reaction tube, compound 7 (1.90 mmol), 4 ml of P(NMe2)3, the system was degassed by freeze-pump-thaw, the sealed tube was then heated to 130 °C, the reaction was monitored by 31 P NMR, after the reaction was completed, the system was cooled to room temperature, the excess P(NMe2)3 was removed under high vacuum, the remaining oily mixture was separated and purified by a silica gel column to give the product compound L3 (1.51 mmol, 80% yield) as colorless oil.

[0132] 1 H NMR (400 MHz, CDCI3) δ 1.16 - 1.02 (m, 27H), 1.01 - 0.72 (m, 15H).

[0133] 13C NMR (101 MHz, CDC13) δ 55.03 (d, J = 7.6 Hz), 47.32 (d, J = 3.6 Hz), 43.40 (dd, J = 20.2, 15.7 Hz), 37.10, 34.84 (d, J = 2.4 Hz), 31.93, 30.08 (d, J = 9.3 Hz), 29.90 (d, J = 4.5 Hz), 29.79, 29.72 (d, J = 3.4 Hz), 29.53 (d, J = 4.7 Hz), 29.39 (d, J = 4.8 Hz), 28.89 (d, J = 13.6 Hz), 28.55 (d, J = 18.3 Hz), 26.24 (d, J = 22.5 Hz).

[0134] 31 P NMR (162 MHz, CDC13) δ 22.93 (d, J = 17.7 Hz), 20.53 (d, J = 18.2 Hz). m / z (ESI-MS): calc. 356.2762 [M] + , found 357.2829 [M + H] + .

[0135] Example 10: Synthesis of compound 8

[0136] A 50 ml schlenk tube was charged with a magnetic stir bar, dried under vacuum with heating from an electric heating gun, and then transferred into a glove box under argon. 5 mmol of HPCy2, 10 mL of THF, and then 8 mL of n-BuLi in n-hexane (1.3 M) were added. The reaction system was taken out of the glove box, heated at 80 °C for 1 h, and then cooled. The solvent was removed under vacuum, and the remaining solid was washed with ice-cold n-hexane three times, and then filtered to obtain LiPCy2 (all white solid products, yield > 80%).

[0137] In a 25 ml schlenk reaction tube, a magnetic stirrer was added, and after the electric gun heating, it was dried under vacuum condition, and then the reaction tube was transferred into the glove box protected by dry argon, and the pre-prepared LiPCy2(6.2 mmol) and compound 4(3.1 mmol) were weighed and added into the reaction tube, sealed with a rubber plug, and then taken out of the glove box, cooled to-78℃, 10-15 minutes, then 6 ml of dry DMF was added to the reaction, and the stirring was started, and the reaction system was raised to room temperature and stirred overnight for 12 hours. 500 mg of sulfur powder was then added to the reaction system under inert gas protection, and stirred for 5 hours, and then the reaction system was extracted with water, and then extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain the pure white solid product compound 8, compound 8 was defined as M4(2.16 mmol), 69.5% yield.

[0138] 1 H NMR (600 MHz, CDCl3) δ 3.14-2.94 (m, 1H), 2.89-2.71 (m, 1H), 2.60 (ddd, J = 14.8, 6.4, 3.2 Hz, 1H), 2.10 (d, J = 11.3 Hz, 2H), 2.03-1.67 (m, 14H), 1.59-1.53 (m, 2H), 1.47 (dq, J = 14.4, 6.7 Hz, 2H), 1.38-1.15 (m, 22H), 1.03 (qd, J = 12.4, 3.6 Hz, 1H).

[0139] 13 C NMR (101 MHz, CDCl3) δ 52.45 (dd, J = 8.0, 6.4 Hz), 43.16 (d, J = 2.0 Hz), 39.41 (d, J = 22.2 Hz), 38.94 (d, J = 22.4 Hz), 37.75 (d, J = 47.9 Hz), 35.78 (dd, J = 42.6, 1.9 Hz), 34.83 (d, J = 42.8 Hz), 33.53 (d, J = 14.2 Hz), 31.36 (d, J = 13.4 Hz), 27.00-26.69 (m), 26.69 (d, J = 1.6 Hz), 26.56 (d, J = 2.4 Hz), 26.43 (d, J = 3.7 Hz), 26.13 (d, J = 3.2 Hz), 26.00, 25.89 (d, J = 1.7 Hz), 25.80 (dd, J = 4.8, 1.9 Hz), 25.71 (d, J = 2.0 Hz), 22.30 (dd, J = 45.7, 2.5 Hz).

[0140] 31P NMR (243 MHz, CDC13) δ 84.83 (d, J = 14.6 Hz), 61.63 (d, J = 14.6 Hz). m / z (ESI-MS): calc. 472.2516 [M] + , found 473.2596 [M + H] + .

[0141] Example 11: Synthesis of Ligand L4

[0142] A 100 ml three necked flask was fitted with a magnetic stirrer, and a reflux condenser. The apparatus was heated with an electric gun and dried under vacuum. Compound 8 (1.06 mmol) was then added to the apparatus, and the system was flushed with nitrogen three times. Freshly distilled dry toluene (25 ml) and Si2Cl6(3 ml, 5 g, 10 eq.) were then added. The reaction was heated to 130 °C for 20 hours. The reaction was cooled, and 50 ml of 30% aqueous NaOH was added. The reaction was heated to 50 °C until the aqueous phase became clear. The aqueous phase was extracted three times with 30 ml of degassed benzene. The organic phase was dried over anhydrous Na2S04and concentrated under vacuum. The remaining colorless oily mixture was purified by filtration through a short column of silica gel to give the pure colorless oily product, compound L4 (0.72 mol), 68.0% yield, which solidified into a solid after drying overnight. 31 P NMR (243 MHz, CDC13) δ 84.83 (d, J = 14.6 Hz), 61.63 (d, J = 14.6 Hz). m / z (ESI-MS): calc. 472.2516 [M]

[0143] 1 H NMR (400 MHz, CDC13) δ 1.93 - 1.61 (m, 4H), 1.39 - 1.10 (m, 26H), 1.10 - 1.02 (m, 3H), 0.99 - 0.71 (m, 13H).

[0144] 13C NMR (101 MHz, CDC13) δ 53.84 (d, J = 7.0 Hz), 47.11 (d, J = 3.3 Hz), 42.57 - 41.31 (m), 39.45 (d, J = 5.8 Hz), 34.72 (d, J = 6.5 Hz), 34.49 (d, J = 9.9 Hz), 33.83 (d, J = 14.8 Hz), 30.33, 30.11, 29.99 (d, J = 5.0 Hz), 29.54 - 29.31 (m), 28.95 (d, J = 2.8 Hz), 28.81 (d, J = 2.8 Hz), 28.57 (d, J = 5.0 Hz), 28.01, 27.53 (d, J = 8.8 Hz), 27.16 (d, J = 2.6 Hz), 26.74 (d, J = 12.4 Hz), 26.22 (d, J = 8.3 Hz).

[0145] 31 P NMR (162 MHz, CDC13) δ 19.90 (d, J = 34.3 Hz), -9.57 (d, J = 34.5 Hz). m / z (ESI-MS): calc. 408.3075 [M] + , found 409.3143 [M + H] + .

[0146] Example 12: Synthesis of compound 9

[0147] A 50 ml schlenk reaction tube was charged with a magnetic stir bar, dried under vacuum with heating from an electric heating gun, and then transferred into a glovebox under an argon atmosphere. 5 mmol of HPAr2 (CAS: 1173023-24-9) and 10 mL of THF were added, followed by 4 mL of n-BuLi in n-hexane (1.3 M). The reaction tube was sealed and removed from the glovebox. The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and the remaining solid was washed with ice-cold n-hexane three times and filtered to give LiPAr2 (Ar = DTBM, light yellow solid, yield > 95%).

[0148] In a 25 ml schlenk reaction tube, a magnetic stirrer was added, and after the electric gun heating, it was dried under vacuum condition, and then the reaction tube was transferred into the glove box protected by dry argon, LiPAr2(10 mmol) and compound 4 (4 mmol) were weighed and added into the reaction tube, and then the rubber plug was sealed and taken out of the glove box, cooled to -78℃, 10-15 minutes, then 10 ml of dry DMF was added to the reaction, and the stirring was started, and the reaction system was raised to room temperature and stirred overnight. 500 mg of sulfur powder was then added to the reaction system under inert gas protection, and stirred for 5 hours, and then the reaction system was extracted with water, and then extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain the pure white solid product compound 9 (3.12 mmol), compound 9 is defined as M5, 78% yield.

[0149] 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 13.5 Hz, 2H), 7.69 (d, J = 13.6 Hz, 2H), 3.68 (d, J = 1.8 Hz, 6H), 3.62-3.44 (m, 1H), 3.07-2.90 (m, 1H), 2.58 (ddd, J = 14.3, 6.2, 3.4 Hz, 2H), 2.40-2.25 (m, 1H), 1.96-1.81 (m, 1H), 1.72-1.48 (m, 5H), 1.40 (d, J = 8.1 Hz, 37H), 1.16 (d, J = 16.1 Hz, 9H), 1.11-0.96 (m, 3H).

[0150] 13 C NMR (101 MHz, CDCl3) δ 162.52, 144.28, 144.19 (d, J = 12.7 Hz), 144.02, 130.55 (d, J = 11.7 Hz), 130.31 (d, J = 12.0 Hz), 129.60 (d, J = 12.4 Hz), 64.64 (d, J = 12.1 Hz), 64.51, 51.41-51.60 (m), 43.19, 36.25 (d, J = 5.4 Hz), 36.21, 34.79, 34.37, 32.14-31.79 (m), 26.02 (d, J = 22.7 Hz), 25.06 (d, J = 1.8 Hz).

[0151] 31 P NMR (162 MHz, CDCl3) δ 84.02 (d, J = 32.7 Hz), 45.76 (d, J = 32.5 Hz). m / z (ESI-MS): calc. 744.4292 [M] +found 767.4180 [M+Na] + .

[0152] Example 13: Synthesis of Ligand L5

[0153] A 25 ml Schlenk flask was charged with a magnetic stir bar, the reaction apparatus was heated with an electric gun and dried under vacuum. Compound 9 (1.4 mmol) was then weighed into the reaction apparatus, the system was degassed and purged with an inert gas atmosphere three times, 7 ml of freshly distilled dry benzene and Si2Cl6(5.65 mmol) were added. The reaction was heated to 80°C for 15 hours, cooled and 50 ml of a 30% aqueous NaOH solution was added. The reaction was heated to 50°C until the aqueous phase became clear, the aqueous phase was extracted three times with 30 ml of degassed benzene and the organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum and the remaining colourless oily mixture was purified by filtration through a short column of silica gel to give the ligand compound L5 (1.26 mmol) as a white solid in 90% yield. 31 P NMR monitoring of the reaction end point. The reaction system was then cooled to 0°C, 50 ml of a 30% aqueous NaOH solution was added, the reaction was heated to 50°C until the aqueous phase became clear, the aqueous phase was extracted three times with 30 ml of degassed benzene and the organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum and the remaining colourless oily mixture was purified by filtration through a short column of silica gel to give the ligand compound L5 (1.26 mmol) as a white solid in 90% yield.

[0154] 1 H NMR (400 MHz, C6D6) δ 7.79 (d, J = 7.3 Hz, 2H), 7.67 (d, J = 7.3 Hz, 2H), 3.38 (d, J = 12.0 Hz, 6H), 2.89 - 2.58 (m, 2H), 2.37 (d, J = 7.3 Hz, 1H), 1.94 - 1.73 (m, 2H), 1.72 - 1.54 (m, 4H), 1.45 (d, J = 13.4 Hz, 36H), 1.40 - 1.31 (m, 3H), 0.99 (m, J = 11.2 Hz, 10H), 0.94 - 0.78 (m, 2H).

[0155] 13C NMR (101 MHz, C6D6) δ 160.51 (d, J = 16.7 Hz), 143.80 (d, J = 6.7 Hz), 143.64 (d, J = 6.7 Hz), 134.76 (d, J = 14.2 Hz), 133.08 (d, J = 12.5 Hz), 132.24 (d, J = 9.8 Hz), 132.03 (d, J = 9.4 Hz), 128.07 (d, J = 24.5 Hz), 64.15 (d, J = 5.8 Hz), 54.19 (m), 47.56, 40.43 (m), 36.10 (d, J = 6.5 Hz), 35.05, 33.34 (m), 32.33 (d, J = 6.1 Hz), 29.07 (d, J = 10.2 Hz), 28.89 (d, J = 13.6 Hz), 28.70 (d, J = 14.0 Hz), 26.58 (d, J = 11.3 Hz).

[0156] 31 P NMR (162 MHz, C6D6) δ 19.75 (d, J = 36.6 Hz), -19.39 (d, J = 36.3 Hz).

[0157] Example 14:

[0158] 1 eq of electron-rich chiral diphosphine ligand L1-L7 was in situ complexed with 1.02 eq of transition metal precursor in a 1:1 volume ratio of DCM / THF mixed solvent, the reaction was detected by P NMR after 3 hours, then the solvent was removed under vacuum, the remaining orange solid was washed with n-hexane three times, the orange solid could be recrystallized by dichloromethane-n-hexane mixed solvent to obtain 1 eq of a series of catalysts. 31 P NMR (162 MHz, C6D6) δ 19.75 (d, J = 36.6 Hz), -19.39 (d, J = 36.3 Hz).

[0159] Example 14-1:

[0160] Compound a hydrogenation reaction step: in the glove box under argon protection, 0.05 mmol of compound (A) was weighed into a 1 ml ampoule, a small magnetic stirrer was added, 0.5 ml of alcohol was added, and finally the catalyst was added. The reaction mixture was added to a dry high-pressure reaction kettle, then taken out of the glove box, and after the high-pressure kettle was connected to the hydrogen cylinder, it was replaced three times, and finally the pressure in the kettle was kept at 10 bar. The reaction was stirred at room temperature for 3 hours, and after the pressure was released, the ampoule was taken out, the solvent was dried under vacuum, and the remaining solid was filtered through a short silica gel column to remove the metal catalyst. The organic phase was dried under vacuum to obtain a white solid product. The chemical reaction formula is as follows:

[0161] The yield (%) and enantiomeric excess ee (%) of the hydrogenation product were detected, and the results are shown in Table 1:

[0162] Table 1 Asymmetric hydrogenation of formula (A)

[0163] The above described embodiments are only used to illustrate the technical solutions of the present application, but not limit the present application; although the present application has been described in detail with reference to the foregoing embodiments, those ordinarily skilled in the art should understand: the technical solutions recorded in the foregoing embodiments can still be modified, or some technical features can be replaced by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application, and should be included in the protection scope of the present application.

Claims

1. An electron-rich chiral diphosphine ligand characterized in that, having the structure of formula (I): said * represents a chiral center; each of said plurality of carbon chiral centers is independently in the R or S configuration; said -X1- is -(CH2) n - said n is selected from 1 to 5, preferably 1 to 3, especially preferably 1, or, optionally, any one of the methylene units in -(CH2) n - is optionally and independently replaced by -NR5-, -0-, -S-, and -C(O)-, said R5being selected from H, alkyl, alkenyl, alkynyl, or haloalkyl; said R2 and R3 together with the atoms to which they are attached form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heterocycloalkenyl; said R4 is selected from a substituted or unsubstituted alkyl; each of said plurality of R1 is independently selected from a substituted or unsubstituted straight chain alkane, a substituted or unsubstituted branched chain alkane, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted alkylaryl, a substituted or unsubstituted adamantyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted alkylthio, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocycloalkenyl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted aryloxy, a substituted or unsubstituted arylthio, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkylheteroaryl, a substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted heteroaryloxy, a substituted or unsubstituted heteroarylthio, or, said plurality of R1 together with and the atoms to which they are attached form a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted heterocycloalkenyl, a substituted or unsubstituted heteroaryl.

2. The ligand of claim 1, wherein said R1 is selected from a straight chain alkane comprising 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1, 2, or 4 carbon atoms, or, said R1 is selected from a branched chain alkane comprising 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, more preferably 3, 4, 5 carbon atoms, or, said R1 is selected from a cycloalkyl comprising 1 to 10 carbon atoms, preferably 5 to 7 carbon atoms, more preferably 6 carbon atoms, or, said R1 is selected from an aryl comprising a monocyclic aryl or a fused ring aryl, or, said R1 is selected from a sec-butyl, a tert-butyl, or, said R1 is selected from an alkylaryl comprising a monocyclic aryl, said monocyclic aryl having any of its hydrogens replaced by an alkyl comprising 3 to 5 carbon atoms. said hydrogen of the above R1 is optionally replaced by R6, said R6 is independently selected at each occurrence from an alkoxy, an aryloxy, a n-butyl, a sec-butyl, a tert-butyl, a halogen, a nitro, a cyano, an alkanoyl; said hydrogen on the ligand is optionally replaced by D, up to complete deuteration.

3. An electron-rich chiral bisphosphine ligand, wherein the ligands L1 to L5 are specifically as follows:

4. A process for the preparation of an electron-rich chiral diphosphine ligand, characterized in that, comprising: wherein, in M1, the X2is selected from In M2, said X2is selected from In M3, the X2is selected from In M4, said X2is selected from In M5, the X2 is selected from S1 : NaBH4 is added in batches to an alcohol solution of compound 2 to obtain compound 3; S2: Br2 and PPh3 are dissolved in an organic solvent to obtain a solution, compound 3 in an organic solvent is added dropwise to the solution to obtain compound 4; S3: corresponding LiP(Ad)2, LiP(Ph)2, LiP(tBu)2, LiP(Cy)2 or LiP(DTBM)2 is mixed with compound 4, followed by adding DMF to the reaction, stirring to obtain corresponding M1 to M5; S4: M1-M3 are each independently mixed with P(NMe2)3 and heated to give L1-L3, respectively; or, M4-M5 are each independently mixed with Si2Cl6 and heated to give L4-L5, respectively; 5. A method for preparing a catalyst, characterized in that, the ligand of claim 1 is involved in a complexation reaction of a transition metal precursor in an organic solvent, which complexation reaction forms the catalyst; or, at least one ligand of L1-L5 of claim 2 is involved in a complexation reaction of a transition metal precursor in an organic solvent, which complexation reaction forms the catalyst; 6. The method of claim 5, wherein, The organic solvent is selected from a mixture of DCM and THF, and / or the transition metal precursor is selected from [Rh(COD)2]BAr F 4, [Rh(NBD)2]BF4, [Rh(NBD)2]X; [Rh(NBD)Cl]2; Rh(acac)(CO)2; [Rh(COD)Cl]2; Rh(ethylene)2(acac); [Rh(ethylene)2Cl]2; [Rh(COD)2]X; X is a negative anion selected from the group consisting of CI - , Br - , I - , BF4 - , CIO4 - , SbF6 - , PF6 - , TfO - , RCOO - , or B(Ar)4 - any one of.

7. A catalyst prepared by the method of any one of claims 5 or 6.

8. Use of the catalyst of claim 7 in asymmetric hydrogenation.

9. A process for the preparation of a sacubitril intermediate, characterized by, including: the * represents a chiral center, and the chiral carbon atom is in the R or S configuration; said R7is selected from any amino protecting group, or, said R7is selected from Cbz, Boc, methoxycarbonyl, ethoxycarbonyl, Alloc, Trt, Bn, or, said R7is selected from alkanoyl, or, said R7is selected from arylacyl, or, said R7is selected from any one of a compound of formula (A) is asymmetrically hydrogenated to form a compound of formula (B) in the presence of the catalyst cata; the catalyst cata is prepared by a complexation reaction, any one of the ligands of formula (I) of claim 1 or its deuterated compound and any one of the metal precursors of claim 6 are involved as substrates in the complexation reaction; or, the catalyst cata is prepared by a complexation reaction, any one of the ligands L1-L5 of claim 2 and any one of the metal precursors of claim 6 are involved as substrates in the complexation reaction; or, the catalyst cata is prepared by a complexation reaction, any one of the ligands L6, L7 and any one of the metal precursors of claim 6 are involved as substrates in the complexation reaction; The L6 and L7 are as follows:

10. An intermediate or a deuterated compound thereof, wherein the intermediate has the structure of formula (III): the * represents a chiral center, and the chiral carbon atom is in the R or S configuration; said -X1- is -(CH2) n -, said n is selected from 1 to 5, preferably 1 to 3, especially preferred 1, or, any one of the methylene units in -(CH2) n - is optionally and independently replaced by -NR5-, -0-, -S-, and -C(O)-, said R5is selected from H, alkyl, alkenyl, alkynyl or haloalkyl; R2 and R3, together with the atoms to which they are attached, form a substituted or unsubstituted C5-C7 carbocyclic group, a 3-7 membered heterocyclic group; said X2is selected from the group consisting of hydroxyl, halogen, any one of, the a, b are each independently selected from any one of 1, 2, 3; each of said plurality of R1is independently selected from the group consisting of hydrogen, C1-C 10 linear alkanes, C3-C 10 branched alkanes, monocyclic aryl, fused ring aryl, cycloalkyl, adamantyl, said hydrogen on R1optionally substituted with R8, said R8independently selected at each occurrence from the group consisting of alkoxy, sec-butyl, t-butyl, halogen, nitro, cyano, alkanoyl.

Images