A chiral multidentate ligand and its application in asymmetric hydrogenation

Abstract

The present invention discloses a chiral multidentate ligand and its application in asymmetric hydrogenation. This type of ligand is flexible and variable, has strong adjustability of stereostructure and electrical properties, and is more universal; its synthesis can start from cheap and readily available raw materials, the steps are simple, and it is relatively stable in an air atmosphere. In particular, in the application of asymmetric hydrogenation reactions, the catalyst formed by the chiral multidentate ligand and metal disclosed in the invention has high catalytic activity and high stereoselectivity. Specifically, it has important applications in the synthesis of some drug intermediates, such as the synthesis of drug intermediates such as phenylephrine, mirabegron, ticagrelor, and benazepril, showing broad prospects for industrial production and extremely high commercial value.

Description

Technical Field

[0001] The invention relates to a chiral multidentate ligand and application thereof in an asymmetric hydrogenation reaction, and belongs to the field of fine chemicals. Background Art

[0002] Chiral molecules exist in large quantities in nature. Amino acids, proteins, and sugars required for human life activities are all chiral compounds. The "Thalidomide Incident" that occurred in the West in the early 1960s led to the birth of about 12,000 deformed babies worldwide, commonly known as "seal babies". The culprit behind it was the drug thalidomide, which is composed of two very similar chemicals, just like our left and right hands. Among them, the right-handed compound (R-configuration) has the activity of inhibiting pregnancy reactions, while the left-handed compound (S-configuration) is teratogenic. With the development of science and technology and the improvement of living standards, chiral compounds are increasingly widely used in the fields of pesticides, medicines, food, materials, and fine chemicals. Therefore, it is of great significance for scientists to study chirality and explore more efficient and simple methods to synthesize optically pure chiral molecules.

[0003] Asymmetric catalytic reaction is the most economical and efficient method for synthesizing chiral compounds. A large amount of chiral products can be obtained by using a catalytic amount of chiral catalyst. Among them, metal-catalyzed asymmetric hydrogenation reactions have attracted great attention from chemists due to their unique high atom economy, high enantioselectivity and environmental friendliness, and have been greatly developed. The first homogeneous catalytic hydrogenation reaction was reported by Professor Wilkinson in 1965 [Chem. Commun. 1965, 17.], and the first asymmetric homogeneous catalytic hydrogenation reaction was reported by Professor Knowles in 1968 [Chem. Commun. 1968, 1445.]. More and more asymmetric hydrogenation reactions are being commercialized, such as the synthesis of L-dopamine by Monsanto, the synthesis of L-menthol by Takasago, and the synthesis of (S)-isopropylamine by Novartis. In particular, in 2012, BASF successfully achieved the synthesis of 10,000 tons of L-menthol using asymmetric hydrogenation reactions.

[0004] In asymmetric hydrogenation reactions, chiral ligands have an important influence on the activity and stereoselectivity of the reaction. Researchers achieve fine control of the reaction by designing the appropriate electrical properties and steric hindrance of the ligand. Since the discovery of the Noyori ruthenium-bisphosphine-bisamine system and the in-depth study of the bifunctionalization mechanism of metal-ligand cooperative catalysis, ligands containing NH groups have been widely studied and used for asymmetric catalytic hydrogenation of ketones. In 1998, Professor Zhang Xumu designed and synthesized a class of tridentate ligands (ph-ambox) containing a bisoxazoline ring and an NH functional group, and successfully applied it to the highly stereoselective asymmetric transfer hydrogenation of aromatic ketones [J.Am.Chem.Soc.1998,120,3817.]. Later, his research group designed and synthesized the indan-ambox with greater steric hindrance based on the previous one, and successfully used it in the asymmetric hydrogenation of simple ketones [Chem.Commun.2010,46,3979.]. In 2011, Professor Zhou Qilin introduced pyridine into the bidentate Spiro-AP ligand to obtain the tridentate Spiro-PAP ligand. The iridium complex of this ligand is more stable in catalytic hydrogenation and can efficiently and selectively reduce simple aromatic ketones to obtain 96%-99.9% ee value and reach 4550000 TON [Angew.Chem.Int.Ed.2011,50,7329.].

[0005] The ruthenium-bisphosphine-bisamine system and several representative asymmetric hydrogenation catalytic tridentate ligands are as follows:

[0006]

[0007] In 2016, Professor Zhang Xumu designed and synthesized a new type of ferrocenyl chiral tridentate PNN ligand (f-amphox) based on the Ambox ligand, which showed super high activity and stereoselectivity in the asymmetric hydrogenation of aromatic ketones [Org. Lett. 2016, 18, 2938.]. Subsequently, a series of new ferrocenyl chiral ligands were developed, which showed excellent activity and stereoselectivity in the asymmetric hydrogenation of aromatic ketones, greatly enriching the types of ligand libraries.

[0008] A series of novel ferrocenyl-based chiral tridentate ligands are as follows:

[0009]

[0010] Since substrates are diverse in reality, it is still of great significance to develop different ligands to meet the needs of different substrates. Compared with the existing catalytic systems and tridentate ligands, the present invention proposes a new type of multi-dentate chiral ligand with cheap and easy-to-obtain raw materials, simple synthesis route, simple process, easy large-scale preparation, and easy-to-adjust structure and electrical properties. The ligand exhibits ultra-high activity and stereoselectivity in asymmetric hydrogenation reactions and has broad industrial application prospects. Summary of the invention

[0011] The invention discloses a novel chiral multidentate ligand and a synthesis method thereof, as well as an application in asymmetric hydrogenation reaction. The ligand is easy to synthesize, the raw materials are readily available, it is relatively stable in an air atmosphere, has high catalytic activity, high stereoselectivity, and is easy to realize industrial production.

[0012] The present invention is achieved through the following technical solutions. First, the general structural formula (I) of the chiral multidentate ligand proposed in the present invention is as follows:

[0013]

[0014] In the general formula (I): R1 and R2 are independently an alkyl group or an aryl group; R3 and R4 are independently an alkyl group, an aryl group or a hydrogen atom; R5 and R6 are independently an alkyl group or an aryl group, and R5 and R6 may form a ring or not.

[0015] As a preferred embodiment of the present invention, the alkyl group is selected from C1-6 alkyl groups, and the C1-6 alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl. The aryl group is selected from phenyl.

[0016] As a preferred embodiment of the present invention, the multidentate chiral ligands are L1-L10, each of which contains two enantiomers, and the specific structures are as follows:

[0017]

[0018] Preferred are L1, L2, L3, and L10; more preferred are L3 or its enantiomer L10.

[0019] The present invention further provides a method for preparing the multidentate ligand, and the synthesis route is as follows:

[0020]

[0021] Furthermore, the following technical solution can be used to achieve the above, including the following steps:

[0022] 1) N-protected glycine (M1) and chiral amino alcohol (M2) undergo condensation reaction under certain conditions to obtain an amide intermediate (M3), and compound M3 is deamino protected to obtain amino alcohol compound M4; wherein, when the nitrogen protecting group is Boc, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc. are used as deprotection agents, preferably trifluoroacetic acid and hydrochloric acid; when the nitrogen protecting group is Cbz, it is removed by Pd / C or Pd(OH)2 / C under a hydrogen atmosphere;

[0023] 2) Starting from (R) or (S)-Ugi's amine (1), a simple butyl lithium deprotonation and phosphine addition are performed to obtain an intermediate chiral aminophosphine (2), and then the dimethylamino group is replaced by an acetoxy group to obtain an intermediate acetate (3);

[0024] 3) Acetate (3) reacts with the corresponding amino alcohol compound M4 in the presence of triethylamine to obtain the corresponding chiral multidentate ligands L1-L9. The enantiomer L10 of L3 can be synthesized from the corresponding chiral raw materials by the same method.

[0025] The present invention further provides a series of catalysts, wherein the obtained novel chiral multidentate ligand can form a complex with a transition metal, i.e., a catalyst, and the transition metal is selected from Ru, Rh, Ir, Fe, Co, Ni, Mn, Cu, etc.

[0026] Among them, suitable transition metal precursors include [Ir(NBD)Cl]2; [Ir(NBD)2]X; [Ir(COD)Cl]2; [Ir(COD)2]X; [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; RhCl(PPh3)3; Ru(aryl group)X2; RuX2(L)2(diphosphine); Ru(arene)X2(diphosphine); Ru(methallyl)2(diphosphine); hine); Ru(ArH)Cl2; Ru(COD)(methallyl)2; (Ni(allyl)X)2; Ni(acac)2; Ni(COD)2; NiX2; Mn X2; Mn(acac)2; CoX2; FeX2; CuX; CuX2; AgX; [Pd(allyl)Cl]2; PdCl2; Pd(OAc)2; Pd(CF3COO)2.

[0027] In the above transition metal precursors, R represents an alkyl group, an alkoxy group or a substituted alkyl group, aryl represents an aromatic group, and X represents a negative anion, such as Cl - ,Br - , I - , BF4 - , ClO4 - , SbF6 - , PF6 - , TfO - ,RCOO - ,B(Ar)4 - , wherein Ar can be 3,5-ditrifluoromethylbenzene or fluorobenzene. L is a solvent molecule, such as CH3CN, DMF, etc.

[0028] The present invention further provides application of the catalyst in asymmetric hydrogenation reaction.

[0029] The catalyst obtained above exhibits excellent activity and stereoselectivity in the asymmetric hydrogenation of ketones. Specifically, the metal precursor and the multidentate ligand of the present invention are complexed and reacted in a suitable solvent for a certain period of time to obtain several catalysts for catalyzing asymmetric hydrogenation, and then the complex is mixed with the substrate ketone and added to the corresponding solvent, and a catalytic amount of a base-activated catalyst is added, the reaction liquid is transferred to a stainless steel autoclave, and after being replaced with hydrogen three times, a certain amount of hydrogen is filled, and the reaction is carried out at room temperature or under heating for several hours, and the gas is slowly and carefully released, and the reaction liquid is filtered through a thin layer of silica gel, and then the chiral product alcohol is obtained by spin drying.

[0030] As a preferred technical solution of the present invention, the solvent in the asymmetric hydrogenation reaction is preferably one of isopropanol, ethanol, toluene, and n-hexane, or a mixture thereof in any proportion, more preferably isopropanol, toluene, or a mixture thereof in any proportion; the base is one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate, or a mixture thereof in any proportion, more preferably one of potassium tert-butoxide, potassium hydroxide, sodium hydroxide, and potassium carbonate, or a mixture thereof in any proportion.

[0031] As a preferred technical solution of the present invention, the hydrogen pressure is preferably 10-80 atm, more preferably 20-50 atm; the reaction temperature is preferably 20-80°C, more preferably 20-50°C.

[0032] This type of catalyst can efficiently catalyze the asymmetric hydrogenation of ketones, and in particular, has important applications in the synthesis of some drug intermediates, such as phenylephrine, mirabegron, ticagrelor, benazepril and other drug intermediates. The reaction formula is:

[0033]

[0034] The present invention further provides a compound, the compound structure of which is as follows:

[0035]

[0036] Wherein, the "*" in the compound of formula M4-3 indicates that it includes two configurations, R and S;

[0037]

[0038] Wherein, P represents an amino protecting group, specifically selected from benzyloxycarbonyl (Cbz) and tert-butyloxycarbonyl (Boc), and the "*" in the compound of formula M4-3 represents two configurations including R and S.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] 1) The present invention successfully develops a chiral multidentate ligand and a synthesis method. This type of ligand is flexible and variable, has strong adjustability of stereostructure and electrical properties, and is more universal. Its synthesis can start from cheap and readily available raw materials, the steps are simple, and it is more suitable for industrial production.

[0041] 2) Through a large number of experimental studies, it was found that the catalytic system formed by this type of ligand and metallic iridium has a very high reaction activity in asymmetric hydrogenation reactions, with a catalyst turnover number (TON) as high as one million (1,000,000) and a stereoselectivity of >99.9% ee.

[0042] 3) The present invention has the advantages of simple operation, strong stability, good applicability, low cost, and environmental friendliness. It has good industrialization prospects, can bring huge economic benefits, and has extremely high commercial value. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 , Compound M3-3 (R = t Bu, P = Cbz) H NMR spectrum;

[0044] Figure 2 , Compound M3-3 (R = t Bu, P = Boc) H NMR spectrum;

[0045] Figure 3 , Compound M4-3 (R = t Bu) H NMR spectrum;

[0046] Figure 4 , H NMR spectrum of ligand L1;

[0047] Figure 5 , H NMR spectrum of ligand L2;

[0048] Figure 6 , H NMR spectrum of ligand L3;

[0049] Figure 7 , H NMR spectrum of ligand L4;

[0050] Figure 8 , H NMR spectrum of ligand L5;

[0051] Fig. 9 , H NMR spectrum of ligand L6;

[0052] Fig.10 , H NMR spectrum of ligand L7;

[0053] Fig.11 , H NMR spectrum of ligand L8;

[0054] Fig.12 , H NMR spectrum of ligand L9. DETAILED DESCRIPTION

[0055] The present application is further described in detail below in conjunction with examples, but the implementation methods of the present application are not limited thereto.

[0056] Example 1 Intermediate (S C ,R P Synthesis of )-2

[0057]

[0058] 0℃, N2, 30mL n-BuLi hexane solution (2.3mol / L, 1.2equiv.) was added dropwise to 15g (S)-1 (58mmol, 1.0equiv.) anhydrous ether (145mL) solution under stirring, and the temperature was naturally raised to room temperature and stirred for 4.0h after the addition was completed. Then Ar2PCl (70mmol, 1.2equiv.) was added dropwise to the reaction solution under reflux, and the reflux was continued for about 4h, and TLC was monitored. After the reaction was completed, water was added to quench, and the organic phase was extracted with ether. The organic phase was dried with anhydrous sodium sulfate, filtered, and spun to dryness to obtain a red oily liquid, and a certain amount of ether was added to slurry to obtain an orange-yellow solid product (S C ,R P )-2 (65%-83% yield).

[0059] Example 2 Intermediate (S C ,R P Synthesis of )-3

[0060]

[0061] Under nitrogen protection, (S C ,R P A mixture of 2-(30 mmol)-2 and acetic anhydride (24 mL) was heated at 100°C for about 1.0 h. After the reaction was completed, the acetic anhydride was dried under reduced pressure to obtain an orange-red solid with a yield of >95%, which was used directly in the next step without purification.

[0062] Example 3 Synthesis of Intermediate M3

[0063]

[0064] N-protected glycine (M1) (1.2 equivalents) and chiral amino alcohol (M2) (1.0 equivalents) were dissolved in dichloromethane and condensed under the action of condensation agent DCC (1.5 equivalents). After the reaction was completed, the by-product solid N,N'-dicyclohexylurea was filtered to obtain a crude amide intermediate (M3). The pure product M3 was separated and purified by column with a yield of 76%-88%.

[0065] M3-3(R= t Bu, P = Cbz) characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.31-7.26 (m, 5H), 6.72 (d, J = 9.6Hz, 1H), 6.24 (s, 1H), 5.07 (s, 2H), 3.93 (dd,J=16.6,6.0Hz,1H),3.82-3.73(m,3H),3.40(t,J=10.3Hz,1H),3.06(br,1H),0.85(s,9H). 13 CNMR(101MHz, CDCl3)δ170.75,157.04,136.10,128.46,128.14,127.98,67.05,61.62,59.54,44.53,33.45,26.59.

[0066] M3'-3(R= t Bu, P = Boc) characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ6.58 (d, J = 9.1Hz, 1H), 5.62 (s, 1H), 3.89-3.69 (m, 4H), 3.49 (s, 1H), 3.30 (s, 1H), 1.44 (s, 9H), 0.93 (s, 9H). 13 CNMR (101MHz, CDCl3) δ170.98,156.53,80.40,62.37,59.72,44.78,33.46,28.26,26.74.

[0067] Example 4 Synthesis of Intermediate M4

[0068]

[0069] Compound M3 (P = Boc) was dissolved in trifluoroacetic acid / dichloromethane (V:V = 1:1) and reacted at room temperature for 4 hours. The reaction was completed by TLC monitoring. The solvent and excess trifluoroacetic acid were dried, and the residue was neutralized with a saturated sodium bicarbonate solution. The product was extracted with dichloromethane (3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered to obtain M4. The crude yield was >90%, and it was directly used in the next step without purification.

[0070] Compound M3' (P = Cbz) was dissolved in methanol, and 5% Pd / C was added. The reaction suspension was placed in a high-pressure reactor, and the nitrogen was replaced 3 times, and then the hydrogen was replaced 3 times. 5-10atm hydrogen was filled and reacted at room temperature for 12 hours. The hydrogen was released slowly and carefully, and the Pd / C was filtered out to obtain M4. The crude yield was >98%, and it was directly used in the next step without purification.

[0071] M4-3(R= t Bu) Characterization data are as follows: 1 H NMR (400MHz, CDCl3) δ7.59 (d, J=8.9Hz, 1H), 3.85 (dd, J=11.2, 3.2Hz, 1H), 3.76 (td, J= 8.9,3.2Hz,1H),3.50(dd,J=11.2,8.6Hz,1H),3.37(s,2H),2.39(s,3H),0.94(s,9H). 13 C NMR (101MHz, CDCl3) δ174.07,62.99,59.74,44.56,33.35,26.82.

[0072] Example 5 Synthesis of ligand L1

[0073]

[0074] In a 50 mL reaction tube, 0.91 g (2.0 mmol) of acetate 3a and 0.29 g (2.2 mmol) of M4-1 were added. After replacing N2, 0.41 g (4 mmol, 2 equiv) of triethylamine and 20 mL of anhydrous methanol were added in sequence. After stirring at room temperature for 2 h, the mixture was heated under reflux and reacted overnight. The mixture was concentrated by rotary evaporation and column chromatography to obtain a light yellow foamy solid L1 with a mass of 0.63 g and a yield of 61%.

[0075] 1 H NMR (400MHz, CDCl3) δ7.53-7.49(m,2H),7.37-7.35(m,3H),7.24-7.18(m,5H),4.42(s,1H),4.29(s,1H),4.16-4.09(m,1H),3.96(s,5H) ,3.85-3.76(m,2H),3.51-3.43(m,1H),3.41-3.34(m,1H),2.86(dd,J=16.0Hz,60.0Hz,2H),1.37(d,J=8.2Hz,3H),1.04(d,J=4.3Hz,3H); 13C NMR (101MHz, CDCl3) δ173.61, 140.10 (d, J = 9.2Hz), 136.88 (d, J = 9.2Hz), 134.9 6,134.81,132.51(d,J=18.5Hz),129.31,128.48(d,J=2.0Hz),128.49,128.28( d,J=8.2Hz),96.53,96.29,75.23(d,J=8.2Hz),71.73(d,J=4.3Hz),69.77,69. 58(d,J=4.3Hz),69.24,67.62,51.73(d,J=8.2Hz),48.62,48.08,19.00,16.80; 31 PNMR (101MHz,CDCl3)δ-24.85.

[0076] Example 6 Synthesis of ligand L2

[0077]

[0078] In a 50 mL reaction tube, 0.91 g (2.0 mmol) of acetate 3a and 0.35 g (2.2 mmol) of M4-2 were added. After replacing N2, 0.41 g (4 mmol, 2 equiv) of triethylamine and 20 mL of anhydrous methanol were added in sequence. After stirring at room temperature for 2 h, the mixture was heated under reflux and reacted overnight. The mixture was concentrated by rotary evaporation and column chromatography to obtain a light yellow foamy solid L2 with a mass of 0.61 g and a yield of 55%.

[0079] 1 H NMR (400MHz, CDCl3) δ7.54-7.50(m,2H),7.44-7.37(m,4H),7.27-7.20(m,4H ),4.43(s,1H),4.30(s,1H),4.20-4.16(m,1H),3.98(s,5H),3.83(s,1H),3.6 3-3.58(m,1H),3.53-3.41(m,2H),2.87(dd,J=17.0Hz,66.7Hz,2H),1.88-1.7 6(m,1H),1.43(d,J=8.2Hz,3H),0.92(d,J=8.2Hz,3H),0.88(d,J=8.2Hz,3H); 13C NMR (101MHz, CDCl3) δ173.89, 140.13 (d, J = 10.4Hz), 136.99 (d, J = 8.5Hz), 135. 01,134.81,132.52(d,J=18.1Hz),129.32,128.51(d,J=1.9Hz),128.19(d,J=7. 1Hz),96.58,96.28,75.21(d,J=8.2Hz),71.72(d,J=4.2Hz),69.76,69.60,69.4 9,69.20,64.61,57.79,51.64(d,J=8.2Hz),48.39,28.77,19.59,19.12,19.05; 31 P NMR (101 Hz, CDCl3) δ-24.73.

[0080] Example 7 Synthesis of ligand L3

[0081]

[0082] In a 50 mL reaction tube, 0.91 g (2.0 mmol) of acetate 3a and 0.38 g (2.2 mmol) of M4-3 were added. After replacing N2, 0.41 g (4 mmol, 2 equiv) of triethylamine and 20 mL of anhydrous methanol were added in sequence. After stirring at room temperature for 2 h, the mixture was heated under reflux and reacted overnight. The mixture was concentrated by rotary evaporation and column chromatography to obtain a light yellow foamy solid L3 with a mass of 0.58 g and a yield of 51%.

[0083] 1 H NMR (400MHz, CDCl3) δ7.50-7.47(m,3H),7.25-7.21(m,3H),7.21-7.13(m,4H),4.41(s,1H),4.30(s,1H),4.20-4.18(m,1H),3.99(s, 5H),3.80-3.74(m,2H),3.62-3.60(m,1H),3.40-3.35(m,1H),2.82(dd,J=17.5Hz,117.2Hz,2H),1.38(d,J=6.7Hz,3H),0.89(s,9H); 13C NMR (101MHz, CDCl3) δ174.09, 139.70 (d, J = 9.7Hz), 136.74 (d, J = 8.6Hz), 134.81, 134.67,132.54(d,J=19.1Hz),129.20,128.66,128.50(d,J=6.3Hz),128.18(d,J =7.7Hz),96.28(d,J=23.7Hz),75.18(d,J=7.6Hz),71.57(d,J=4.2Hz),69.70,69 .59,69.56,69.14,63.78,60.30,51.43(d,J=8.5Hz),48.06,33.32,26.94,19.18; 31 PNMR (101MHz,CDCl3)δ-25.04.

[0084] in, Figure 1 , Compound M3-3 (R = t Bu, P = Cbz) H NMR spectrum; Figure 2 , Compound M3-3 (R = t Bu, P = Boc) H NMR spectrum; Figure 3 , Compound M4-3 (R = t Bu) H NMR spectrum; Figure 4 , H NMR spectrum of ligand L1.

[0085] Example 8 Synthesis of Ligand L4

[0086]

[0087] In a 50 mL reaction tube, 0.91 g (2.0 mmol) of acetate 3a and 0.46 g (2.2 mmol) of M4-4 were added. After replacing N2, 0.41 g (4 mmol, 2 equiv) of triethylamine and 20 mL of anhydrous methanol were added in sequence. After stirring at room temperature for 2 h, the mixture was heated under reflux and reacted overnight. The mixture was concentrated by rotary evaporation and column chromatography to obtain a light yellow foamy solid L4 with a mass of 0.74 g and a yield of 61%.

[0088] 1H NMR (400MHz, CDCl3) δ7.55-7.51(m,2H),7.43-7.29(m,4H),7.30-7.16(m,9H),4.40(s,1H),4.32(s,1H),4.13-4.05(m,1H), 3.98(s,5H),3.95-3.82(m,1H),3.81(s,1H),3.59-3.53(m,1H),3.48-3.41(m,1H),2.90-2.67(m,4H),1.19(d,J=8.0Hz,3H); 13 C NMR(101MHz, CDCl3) δ173.63,140.14(d,J=9.6Hz),137.88,136.99(d,J=8.2Hz),134 .98,134.78,132.45(d,J=18.1Hz),129.28,129.24,128.57,128.49,128.42,128.20 (d,J=8.2Hz),126.60,96.50(d,J=24.0Hz),75.10(d,J=7.7Hz),71.69(d,J=4.3Hz), 69.69,69.52,69.43,69.19,65.05,53.58,51.45(d,J=8.5Hz),48.29,36.80,18.73; 31 PNMR (101MHz,CDCl3)δ-24.93.

[0089] Example 9 Synthesis of ligand L5

[0090]

[0091] In a 50 mL reaction tube, 0.91 g (2.0 mmol) of acetate 3a and 0.43 g (2.2 mmol) of M4-5 were added. After replacing N2, 0.41 g (4 mmol, 2 equiv) of triethylamine and 20 mL of anhydrous methanol were added in sequence. After stirring at room temperature for 2 h, the mixture was heated under reflux and reacted overnight. The mixture was concentrated by rotary evaporation and column chromatography to obtain a light yellow foamy solid L5 with a mass of 0.68 g and a yield of 58%.

[0092] 1H NMR (400MHz, CDCl3) δ7.93-7.88(m,1H),7.54-7.49(m,2H),7.41-7.32(m, 5H),7.33-7.27(m,1H),7.26-7.23(m,6H),4.97-4.84(m,1H),4.40(s,1H) ,4.32(d,J=4.3Hz,1H),4.23-4.10(m,1H),4.02(s,5H),3.78(s,1H),3.73 (d, J=8.7Hz, 2H), 2.92 (dd, J=18.1Hz, 56.0Hz, 2H), 1.34 (d, J=4.0Hz, 3H); 13 C NMR (101MHz, CDCl3) δ173.40, 139.89 (d, J = 9.5Hz), 138.93, 136.82 (d, J = 9.5Hz), 134. 89,134.75,132.50(d,J=18.1Hz),129.30,128.78,128.61(d,J=7.5Hz),128.50,128. 19(d,J=8.0Hz),127.80,126.91,96.32(d,J=23.5Hz),75.21(d,J=7.7Hz),71.71(d,J =4.0Hz),69.79,69.72,69.59,69.23,67.03,56.28,51.65(d,J=8.0Hz),48.51,18.98; 31 P NMR (101MHz,CDCl3)δ-24.95.

[0093] Example 10 Synthesis of ligand L6

[0094]

[0095] In a 50 mL reaction tube, 0.97 g (2.0 mmol) of acetate 3a and 0.38 g (2.2 mmol) of M4-3 were added. After replacing N2, 0.41 g (4 mmol, 2 equiv) of triethylamine and 20 mL of anhydrous methanol were added in sequence. After stirring at room temperature for 2 h, the mixture was heated under reflux and reacted overnight. The mixture was concentrated by rotary evaporation and column chromatography to obtain a light yellow foamy solid L6 with a mass of 0.68 g and a yield of 57%.

[0096] 1HNMR (400MHz, CDCl3) δ7.60-7.54(m,1H),7.41(t,J=8.5Hz,2H),7.20(d,J=7.9Hz ,2H),7.15-7.04(m,4H),4.38(s,1H),4.28(t,J=2.4Hz,1H),4.30-4.18(m,1H),4. 00(s,5H),3.82-3.78(m,2H),3.66-3.58(m,1H),3.46-3.39(m,1H),2.82(dd,J=1 8.0Hz, 80.2Hz, 2H), 2.39 (s, 3H), 2.30 (s, 3H), 1.40 (d, J = 4.3Hz, 3H), 0.89 (s, 9H); 13 C NMR(101MHz,CDCl3)δ173.88,139.23,138.60,136.26(d,J=8.5Hz),134.85,134 .62,133.40(d,J=8.5Hz),132.51(d,J=19.2Hz),129.42,129.34,129.08(d,J=8. 5Hz),95.80(d,J=23.4Hz),75.81(d,J=8.0Hz),71.71,69.78,69.62,69.56,69. 14,63.61,60.35,51.55(d,J=9.7Hz),47.93,33.40,27.00,21.42,21.35,19.23; 31 PNMR (101MHz,CDCl3)δ-27.50.

[0097] Example 12 Synthesis of ligand L7

[0098]

[0099] In a 50 mL reaction tube, 1.02 g (2.0 mmol) of acetate 3c and 0.38 g (2.2 mmol) of M4-3 were added. After replacing N2, 0.17 mL (1.2 mmol, 3 equiv) of triethylamine and 20 mL of anhydrous methanol were added in sequence. After stirring at room temperature for 2 h, the mixture was heated under reflux and reacted overnight. The mixture was concentrated by rotary evaporation and column chromatography to obtain 0.66 g of a light yellow foamy solid in a yield of 53%.

[0100] 1H NMR(600MHz, CDCl3) δ7.50(d,J=8.3Hz,1H),7.14(d,J=8.4Hz,2H),7.02(s,1H),6.89(s,1H),6.8 3(d,J=7.6Hz,2H),4.40(s,1H),4.30(s,1H),4.21(tt,J=6.5,3.3Hz,1H),4.02(s,5H),3.81(s,1 H),3.78(d,J=2.7Hz,1H),3.62(td,J=8.4,2.7Hz,1H),3.42(dd,J=11.1,8.5Hz,1H),2.92(d,J=1 7.5Hz,1H),2.68(d,J=17.5Hz,1H),2.32(s,6H),2.21(s,6H),1.40(d,J=6.7Hz,3H),0.91(s,9H). 13 CNMR (151MHz, CDCl3) δ174.21, 139.16 (d, J = 8.9Hz), 137.92 (d, J = 6.8Hz), 137.49 (d, J = 8. 0Hz),136.31(d,J=7.9Hz),132.33(d,J=20.4Hz),130.84,130.56,130.38(d,J=19.5Hz),9 5.80(d,J=22.9Hz),75.83(d,J=7.8Hz),71.67(d,J=4.0Hz),69.69,69.37(d,J=3.5Hz),6 8.83,63.82,60.46,51.23(d,J=8.8Hz),47.67,33.29,26.89,21.31(d,J=13.0Hz),18.93. 31 PNMR (243MHz,CDCl3)δ-25.07.

[0101] Example 13 Synthesis of ligand L8

[0102]

[0103] In a 50 mL reaction tube, 1.36 g (2.0 mmol) of acetate 3d and 0.38 g (2.2 mmol) of M4-3 were added. After replacing N2, 0.41 g (4 mmol, 2 equiv) of triethylamine and 20 mL of anhydrous methanol were added in sequence. After stirring at room temperature for 2 h, the mixture was heated under reflux and reacted overnight. The mixture was concentrated by rotary evaporation and column chromatography to obtain 0.75 g of a light yellow foamy solid in a yield of 47%.

[0104] 1H NMR (600MHz, CDCl3) δ7.72(d,J=8.1Hz,1H),7.42(s,1H),7.40(dd,J=8.6,1.6Hz,2H),7.32(s,1H),7.21(dd ,J=8.1,1.6Hz,2H),4.37(s,1H),4.27(t,J=2.2Hz,1H),4.13(dd,J=6.6,2.6Hz,1H),4.06(s,5H),3.80(dd,J =11.1,2.7Hz,1H),3.72(s,1H),3.59(td,J=8.3,2.6Hz,1H),3.43(dd,J=11.0,8.4Hz,1H),2.71(d,J=17.7Hz ,1H),2.55(d,J=17.7Hz,1H),1.67(br,3H),1.35(d,J=6.6Hz,3H),1.30(s,18H),1.22(s,18H),0.90(s,9H). 13 C NMR (151MHz, CDCl3) δ174.44, 150.79 (d, J = 6.7Hz), 150.26 (d, J = 7.2Hz), 138.14 (d, J = 7.9Hz), 135.01(d,J=7.5Hz),128.80(d,J=20.9Hz),127.65(d,J=20.7Hz),122.99,122.73,95.47(d,J= 21.7Hz),77.39(d,J=6.8Hz),71.23(d,J=3.8Hz),69.65,69.08(d,J=3.7Hz),68.58,64.17,60 .61,51.96(d,J=8.9Hz),48.65,34.88(d,J=9.8Hz),33.22,31.41(d,J=14.6Hz),26.89,19.03. 31 PNMR (243MHz,CDCl3)δ-23.86.

[0105] Example 14 Synthesis of ligand L9

[0106]

[0107] In a 50 mL reaction tube, 1.48 g (2.0 mmol) of acetate 3e and 0.38 g (2.2 mmol) of M4-3 were added. After replacing N2, 0.41 g (4 mmol, 2 equiv) of triethylamine and 2 mL of anhydrous methanol were added in sequence. After stirring at room temperature for 2 h, the mixture was heated under reflux and reacted overnight. The mixture was concentrated by rotary evaporation and column chromatography to obtain 0.77 g of a light yellow foamy solid in a yield of 45%.

[0108] 1 H NMR (600MHz, CDCl3) δ7.77(d,J=8.1Hz,1H),7.39(d,J=8.3Hz,2H),7.22(d,J=7.7Hz,2H),4.37(s,1H), 4.28(s,1H),4.14(dd,J=6.6,2.5Hz,1H),4.05(s,5H),3.81(dd,J=11.1,2.6Hz,1H),3.71(s,3H),3.69 (s,1H),3.60(dd,J=8.1,2.6Hz,1H),3.58(s,3H),3.44(dd,J=11.0,8.5Hz,1H),2.76(d,J=17.7Hz,1H) ,2.57(d,J=17.7Hz,1H),1.67(br,3H),1.40(s,18H),1.35(d,J=6.6Hz,3H),1.31(s,18H),0.91(s,9H). 13 C NMR (151MHz, CDCl3) δ174.38, 160.51, 160.36, 143.76 (d, J = 6.9Hz), 143.19 (d, J = 7.7Hz), 132.97 (d ,J=21.8Hz),132.63(d,J=5.9Hz),131.77(d,J=21.5Hz),129.57(d,J=5.9Hz),95.40(d,J=21.8Hz), 77.76(d,J=6.9Hz),71.07(d,J=3.6Hz),69.59,69.17(d,J=3.7Hz),68.61,64.36(d,J=2.4Hz),64.1 5, 60.61, 51.91 (d, J = 8.5Hz), 48.56, 35.84 (d, J = 3.3Hz), 33.24, 32.04 (d, J = 12.9Hz), 26.89, 18.97. 31 PNMR (243MHz,CDCl3)δ-26.53.

[0109] Example 15 Synthesis of ligand L10

[0110]

[0111] In a 50 mL reaction tube, add 0.91 g (2.0 mmol) of acetate (R C , S P)-3a and 0.38g (2.2mmol) (R)-M4-3, after replacing N2, 0.41g (4mmol, 2equiv) of triethylamine and 20mL of anhydrous methanol were added in sequence. After stirring at room temperature for 2h, the mixture was heated under reflux to react overnight. The mixture was concentrated by rotary evaporation and column chromatography to obtain a light yellow foamy solid L10 with a mass of 0.58g and a yield of 51%.

[0112] 1 H NMR (400MHz, CDCl3) δ7.53-7.48(m,3H),7.28-7.22(m,3H),7.22-7.12(m,4H),4.44(s,1H),4.32(s,1H),4.23-4.19(m,1H),4.02(s, 5H),3.84-3.73(m,2H),3.63-3.59(m,1H),3.43-3.38(m,1H),2.84(dd,J=17.5Hz,117.2Hz,2H),1.39(d,J=6.7Hz,3H),0.90(s,9H); 13 C NMR (101MHz, CDCl3) δ174.12, 139.72 (d, J = 9.7Hz), 136.77 (d, J = 8.6Hz), 134.83, 134.68,132.58(d,J=19.1Hz),129.24,128.70,128.54(d,J=6.3Hz),128.20(d,J =7.7Hz),96.29(d,J=23.7Hz),75.21(d,J=7.6Hz),71.59(d,J=4.2Hz),69.73,69 .63,69.59,69.17,63.80,60.32,51.48(d,J=8.5Hz),48.03,33.30,26.96,19.20; 31 PNMR (101MHz,CDCl3)δ-25.08.

[0113] Example 16-25 Asymmetric catalytic hydrogenation of simple aromatic ketones (S / C = 10,000)

[0114] In a glove box filled with argon, the catalyst precursor [Ir(COD)Cl]2 (1.4 mg, 2.0×10 -3 mmol) and different ligands L1-L10 (4.2×10 -3 mmol) were added to a 4.0 mL reaction bottle, and then 2 mL of dry iPrOH solvent dissolved, the mixture was stirred at 25 ° C for 2.0 h, the solution turned from yellow to orange and then the stirring was stopped. Anhydrous K2CO3 (10 μL, c = 0.02 mmol / mL) and freshly distilled acetophenone (0.2 mmol) were added to a 5.0 mL hydrogenation bottle, followed by 1.0 mL of dry i PrOH is dissolved, and then the newly prepared complex solution (10 μL) is added dropwise to the reaction system using a microsyringe. The hydrogenation reaction bottle is carefully placed in the autoclave, and the autoclave is tightened. The autoclave is removed from the glove box, and the autoclave body is replaced with 10 atmospheres of H2 three times. Then, 20 atm H2 is filled into the autoclave body and the air inlet valve is closed, and the reaction is stirred at room temperature for 4 hours. After the reaction is completed, the air release valve is opened to slowly release the hydrogen in the autoclave body. The reaction liquid in the hydrogenation bottle is directly subjected to rapid silica gel column chromatography using ethyl acetate as an eluent to remove the metal complex. The solvent is spin-dried to obtain the product chiral alcohol, and then the reaction mixture is purified by 1 H NMR and 13 The compound structure was determined by C NMR, the ee value of the product was determined by chiral HPLC and chiral gas chromatography, and the optical rotation value of the product was measured. The results are shown in Table 1.

[0115] Table 1 Ligand screening for asymmetric catalytic hydrogenation of acetophenone

[0116]

[0117] Example 26-39 Asymmetric catalytic hydrogenation of simple aromatic ketones

[0118] Using L3 as the ligand, the conditions of the hydrogenation reaction were optimized according to the above-mentioned operation method. The results are shown in Table 2:

[0119] Table 2 Optimization of conditions for asymmetric catalytic hydrogenation of acetophenone

[0120]

[0121]

[0122] Example 40 Asymmetric catalytic hydrogenation of simple aromatic ketones

[0123] In the hydrogenation of simple aromatic ketones, we expanded the substrate using L3 as ligand, sodium tert-butoxide as base, and isopropanol as solvent. The reaction equation is shown below and the results are shown in Table 3.

[0124]

[0125] Table 3 Results of asymmetric catalytic hydrogenation of simple aromatic ketones

[0126]

[0127] Example 41 Asymmetric catalytic hydrogenation of α-amino ketone

[0128] Furthermore, we applied this system to the asymmetric hydrogenation of amino ketones, and the results showed that it has good substrate universality and application value. The reaction equation is shown below and the results are shown in Table 4.

[0129]

[0130] Table 4 Results of asymmetric catalytic hydrogenation of α-aminoketones

[0131]

[0132] Example 42 Asymmetric catalytic hydrogenation of chloroketone

[0133] In order to solve the challenging substrates, we applied this system to the asymmetric hydrogenation of chloroketones. After optimizing the conditions, potassium carbonate was used as the base, and toluene and isopropanol (volume ratio of 10:1) were used as solvents. The reaction equation is shown below and the results are shown in Table 4. The results show that this system has good universality in the asymmetric hydrogenation of chloroketones and has industrial application prospects.

[0134]

[0135] Table 5 Results of asymmetric catalytic hydrogenation of chloroketones

[0136]

[0137] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A chiral multidentate ligand, characterized in that: The ligand is selected from L1-L10:

2. A method for preparing the ligand according to claim 1, characterized in that: The synthetic route is as follows: The following steps are involved: 1) N-protected glycine M1 and chiral amino alcohol M2 undergo condensation reaction under certain conditions to obtain amide intermediate M3, and compound M3 is deamino protected to obtain amino alcohol compound M4; wherein, when the nitrogen protecting group is Boc, trifluoroacetic acid is used as a deprotection agent; when the nitrogen protecting group is Cbz, it is removed by Pd / C or Pd(OH)2 / C under a hydrogen atmosphere; 2) Starting from (S)-1, the intermediate (S C ,R p )-2, and then the dimethylamino group is replaced by acetoxy to obtain the intermediate acetate (S C ,R p )-3; 3) Acetate (S C ,R p )-3 reacts with the corresponding amino alcohol compound M4 in the presence of triethylamine to obtain the corresponding chiral multidentate ligands L1-L9, and the enantiomer L10 of L3 is synthesized from the corresponding chiral raw materials by the same method.

3. A catalyst, characterized in that The ligand according to claim 1 forms a complex with a transition metal, i.e., a catalyst, wherein the transition metal precursor is selected from [Ir(NBD)Cl]2; [Ir(NBD)2]X; [Ir(COD)Cl]2; [Ir(COD)2]X, where X is Cl - ,Br - , I - , BF4 - .

4. Use of the catalyst according to claim 3 in the asymmetric hydrogenation of ketones.

5. The use according to claim 4, characterized in that: The asymmetric catalytic hydrogenation reaction of the ketone comprises: The transition metal precursor and the multidentate ligand are complexed and reacted in a solvent for a certain period of time to obtain several catalysts for catalytic asymmetric hydrogenation, and then the complex is mixed with the substrate ketone and added to the corresponding solvent, and a catalytic amount of a base-activated catalyst is added, the reaction liquid is transferred to a stainless steel autoclave, and after being replaced with hydrogen three times, a certain amount of hydrogen is filled, and the reaction is carried out at room temperature or under heating for several hours, and the gas is slowly and carefully released, and the reaction liquid is filtered through a thin layer of silica gel, and then the chiral product alcohol is obtained by spin drying; Wherein, the solvent is selected from one of isopropanol, ethanol, toluene, n-hexane or a mixture thereof in any proportion; The base is one or a mixture of any proportion of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate; the pressure of hydrogen is 10-80 atm; and the reaction temperature is 20-80°C.

6. The use according to claim 4, characterized in that: The catalyst is used for the synthesis of drug intermediates, including phenylephrine, mirabegron, ticagrelor and benazepril.

7. A compound, characterized in that The compound structure is as follows M3-3: Wherein, P represents an amino protecting group, specifically selected from benzyloxycarbonyl Cbz and tert-butyloxycarbonyl Boc, and the "*" in the compound of formula M3-3 represents two configurations including R and S.

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