A kind of C 2 Symmetric chiral bisphosphine ligand and its application in asymmetric hydrogenation reaction

Abstract

The present invention discloses a C2-symmetric chiral bisphosphine ligand and its application in asymmetric hydrogenation reactions. The synthesis of this new type of chiral bisphosphine ligand can be prepared starting from the chiral raw material Ugi's amine, through deprotonation, followed by a tandem reaction with phosphine chloride and Grignard reagent. The synthesis method is simple, with variable structures and easy to control. At the same time, the present invention discloses a catalyst formed by this new type of chiral bisphosphine ligand and metal, which exhibits excellent catalytic activity and stereoselectivity in asymmetric hydrogenation and can be applied to the preparation of chiral drugs such as ibuprofen, naproxen, and alfloprofen.

Description

Technical Field

[0001] The present invention relates to a C 2 2-symmetric chiral bisphosphine ligand and its application in asymmetric hydrogenation reaction, belonging to the field of fine chemical industry. Background Art

[0002] Transition metal-catalyzed asymmetric reactions have the characteristics of high atom economy, high enantioselectivity and environmental friendliness, and play an important role in people's lives. Among them, chiral ligands have a key influence on the activity and stereoselectivity of the reaction. Scientific researchers achieve fine regulation of the reaction by designing appropriate electrical properties and steric hindrance of the ligands. Although hundreds of chiral ligands and corresponding patented technologies have been reported at present, however, in asymmetric catalytic reactions, no chiral catalyst is universal, and different types of reactions often require different types of ligands. Therefore, it is of great significance to develop effective, easily synthesized and practically useful chiral ligands.

[0003] Ferrocene-type chiral bisphosphine ligands have been widely reported, and the representative phosphine ligands are shown in the following formula. These ligands all have C-chirality and facial chirality, and have excellent chiral induction effects. These ligands show very excellent enantioselectivity in some asymmetric catalytic reactions.

[0004]

[0005] Based on the excellent chiral induction effect of the chiral ferrocene skeleton, the present invention reports a new type of C2-symmetric chiral bisphosphine ligand based on the ferrocene skeleton, and its structure is shown in the following formula. This type of chiral bisphosphine ligand has a brand-new ligand skeleton and is a brand-new chiral phosphine ligand.

[0006] Summary of the Invention

[0007] The present invention discloses a new type of C2-symmetric chiral bisphosphine ligand based on the ferrocene skeleton and its application in asymmetric hydrogenation. This type of chiral bisphosphine ligand has a brand-new ligand skeleton and is a brand-new chiral phosphine ligand. This type of ligand is easy to synthesize, its structure can be adjusted, and it is easy to derivatize; during the catalytic reaction process, the dimethylamino group in the ligand has a secondary interaction at the same time, which can interact with the reaction substrate to increase the reaction activity of the substrate, and has high enantioselectivity in asymmetric hydrogenation reactions; in addition, this type of ligand shows very good stability in the air. The general structural formula (I) of this type of chiral bisphosphine ligand is as follows:

[0008]

[0009] In the general formula (I), R is an alkyl group, an aryl group, etc.

[0010] As a preferred embodiment of the present invention, the chiral bisphosphine ligands L1-L6 have the following specific structures:

[0011]

[0012] The present invention also discloses a method for synthesizing such chiral bisphosphine ligands, and the route is as follows:

[0013]

[0014] Specifically, starting from chiral Ugi's amine, after lithiation, reacting with 1,2-bis(dichlorophosphino)ethane, and then reacting with the corresponding Grignard reagent or lithium reagent, the target ligand can be obtained after simple post-treatment such as quenching with water.

[0015] The present invention also provides a catalyst formed by complexing such chiral bisphosphine ligands with metal complexes and their applications in asymmetric hydrogenation and related reactions. The metal atoms in the metal complexes are selected from Ru, Rh, Ir, Fe, Co, Ni, Mn, Cu, etc. Suitable transition metal precursors include [Rh(NBD) 2 X; [Rh(NBD)Cl] 2 , Rh(acac)(CO) 2 , [Rh(COD)Cl] 2 , Rh(ethylene) 2 (acac), [Rh(ethylene) 2 Cl] 2 , [Rh(COD) 2 X and RhCl(PPh 3 ) 3 , where X is a negative anion, such as Cl - , Br - , I - , BF 4 - , ClO 4 - , SbF 6 - , PF 6 - , TfO - , RCOO - , B(Ar) 4 - , etc.

[0016] Taking metal Rh as an example, the catalytic reaction is achieved according to the following steps and methods:

[0017] (1) Under the protection of inert gas, a certain proportion of chiral bisphosphine ligand and Rh(COD) 2BF 4 and stirred at room temperature for 30 min in trifluoroethanol as a solvent to obtain a clear yellow catalyst solution;

[0018] (2) In a hydrogenation flask, the reaction substrate, isopropanol and acetic acid were successively added, and then a certain amount of the above catalyst solution was added. After the addition was completed, the hydrogenation flask was placed in a hydrogenation reaction device and sealed. A certain pressure of hydrogen was charged into the reaction device, and then the reaction device was heated to a certain temperature. After the reaction was completed, the gas in the reaction device was slowly released completely, the reaction solution was concentrated, and the metal was filtered off. The reaction mixture was analyzed by HPLC.

[0019] After the chiral bisphosphine ligand forms a catalyst with the metal, the synthesis of chiral drugs ibuprofen, naproxen and esflurbiprofen can be achieved through the following reaction.

[0020]

[0021] Among them, the ligand L can be any one of L1-L6.

[0022] In addition, the catalyst made of the chiral bisphosphine ligand of the present invention is used for the synthesis of the chiral synthon methyl 3-hydroxyisobutyrate (Roche Ester).

[0023] Description of the Drawings

[0024] Figure 1 , synthesis of the chiral bisphosphine ligand;

[0025] Figure 2 , 1H NMR spectrum of ligand L1;

[0026] Figure 3 , 13C NMR spectrum of ligand L1;

[0027] Figure 4 , 1H NMR spectrum of ligand L2;

[0028] Figure 5 , 13C NMR spectrum of ligand L2;

[0029] Figure 6 , 1H NMR spectrum of ligand L3;

[0030] Figure 7 , 13C NMR spectrum of ligand L3;

[0031] Figure 8 , 1H NMR spectrum of ligand L4;

[0032] Figure 9 , 13C NMR spectrum of ligand L4;

[0033] Figure 10 , 1H NMR spectrum of ligand L5;

[0034] Figure 11 , 13C NMR spectrum of ligand L5;

[0035] Figure 12 , 1H NMR spectrum of ligand L6;

[0036] Figure 13 , 13C NMR spectrum of ligand L6. Detailed implementation manners

[0037] The present application will be further described in detail below in conjunction with embodiments, but the implementation manners of the present application are not limited thereto.

[0038] Example 1 Synthesis of ligand L1

[0039]

[0040] Under a nitrogen atmosphere, (R)-2-dimethylamino-ethyl ferrocene (1.03 g, 4 mmol) and 20 mL of anhydrous diethyl ether were successively added to a 100 mL Schlenk flask. At 0 °C, a 1.3 M solution of tert-butyllithium in pentane (4.42 mmol, 3.4 mL) was added dropwise, and then the reaction was allowed to proceed at room temperature for 2 h. After cooling the reaction solution to -78 °C, 1,2-bis(dichlorophosphino)ethane (0.46 g in 4 mL Et 2 O, 2 mmol) was added dropwise, and the resulting reaction solution was allowed to warm to room temperature and react for 4 h. The reaction solution was cooled to -78 °C again, phenylmagnesium chloride (1.0 M in THF, 6 mL) was added, and the reaction was slowly warmed to room temperature and allowed to react overnight. 10 mL of water was added to quench the reaction, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target product L1, a yellow solid, 44% yield.

[0041] 1 1H NMR (600 MHz, CDCl 3 ) δ 7.69 - 7.63 (m, 2H), 7.43 - 7.38 (m, 3H), 4.18 (s, 1H), 4.14 - 4.09 (m, 1H), 4.05 - 4.02 (m, 1H), 3.80 (s, 5H), 3.70 (s, 1H), 2.04 - 1.99 (m, 1H), 2.01 (s, 6H), 1.84 - 1.76 (m, 1H), 1.24 (d, J = 7.3 Hz, 3H); 13 13C NMR (151 MHz, CDCl 3) δ137.12 (dd, J = 5.5Hz, 5.5Hz), 134.86 (dd, J = 9.8Hz, 10.9Hz), 129.29, 128.16 (dd, J = 4.4Hz, 3.3Hz), 96.47, 78.89 (dd, J = 6.5Hz, 7.6Hz), 70.79, 69.61, 69.04, 67.98, 57.02 (dd, J = 4.4Hz, 4.4Hz), 39.55, 25.84 (d, J = 4.4Hz), 9.01; 31 P NMR (243MHz, CDCl 3 ) δ - 28.34 (s).

[0042] Among them, Figure 2 , the 1H NMR spectrum of ligand L1; Figure 3 , the 13C NMR spectrum of ligand L1.

[0043] Synthesis of Ligand L2 in Example 2

[0044]

[0045] Under a nitrogen atmosphere, (R)-2-dimethylamino-ethylferrocene (1.03 g, 4 mmol) and 20 mL of anhydrous diethyl ether were successively added to a 100 mL Schlenk flask. At 0 °C, a 1.3 M solution of tert-butyllithium in pentane (4.42 mmol, 3.4 mL) was added dropwise, and then the reaction mixture was allowed to warm to room temperature and react for 2 h. After cooling the reaction mixture to -78 °C, 1,2-bis(dichlorophosphino)ethane (0.46 g in 4 mL Et 2 O, 2 mmol) was added dropwise, and the resulting reaction mixture was allowed to warm to room temperature and react for 4 h. The reaction mixture was cooled to -78 °C again, methylmagnesium chloride (1.0 M in THF, 6 mL) was added, and the reaction mixture was slowly warmed to room temperature and reacted overnight. 10 mL of water was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography to obtain the target product L2, a yellow solid, 36% yield.

[0046] 1 1H NMR (400 MHz, CDCl 3 ) δ 4.24 - 4.22 (m, 1H), 4.15 (t, J = 2.4 Hz, 1H), 4.08 - 4.04 (m, 2H), 4.03 (s, 5H), 2.05 (s, 6H), 1.72 - 1.64 (m, 1H), 1.39 - 1.29 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H), 1.23 - 1.21 (m, 3H); 1313C NMR (151 MHz, CDCl 3 ) δ 97.09 (dd, J = 10.9 Hz, 12.0 Hz), 78.90 (dd, J = 4.4 Hz, 8.7 Hz), 69.60, 69.19, 68.57 (dd, J = 2.2 Hz, 3.3 Hz), 67.60, 56.96 (dd, J = 3.3 Hz, 4.3 Hz), 39.70, 27.10 (d, J = 3.3 Hz), 9.00 (dd, J = 4.4 Hz, 7.6 Hz), 8.59; 31 31P NMR (162 MHz, CDCl 3 ) δ -48.48 (s).

[0047] Among them, Figure 4 , the 1H NMR spectrum of ligand L2; Figure 5 , the 13C NMR spectrum of ligand L2.

[0048] Synthesis of Ligand L3 in Example 3

[0049]

[0050] Under a nitrogen atmosphere, (R)-2-dimethylamino-ethylferrocene (1.03 g, 4 mmol) and 20 mL of anhydrous diethyl ether were successively added to a 100 mL Schlenk flask. At 0 °C, a 1.3 M solution of tert-butyllithium in pentane (4.42 mmol, 3.4 mL) was added dropwise, and then the reaction mixture was warmed to room temperature and reacted for 2 h. After cooling the reaction mixture to -78 °C, 1,2-bis(dichlorophosphino)ethane (0.46 g in 4 mL Et 2 2O, 2 mmol) was added dropwise, and the resulting reaction mixture was warmed to room temperature and reacted for 4 h. The reaction mixture was cooled to -78 °C again, benzylmagnesium chloride (1.0 M in THF, 6 mL) was added, and the mixture was slowly warmed to room temperature and reacted overnight. 10 mL of water was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the target product L3, a yellow solid, 31% yield.

[0051] 1 1H NMR (400 MHz, CDCl 3) δ 7.26 - 7.16 (m, 4H), 7.15 - 7.07 (m, 1H), 4.22 (d, J = 8.5 Hz, 2H), 4.13 (s, 1H), 4.06 - 3.93 (m, 1H), 3.99 (s, 5H), 3.13 (d, J = 13.2 Hz, 1H), 2.95 (d, J = 13.2 Hz, 1H), 1.89 (s, 6H), 1.66 - 1.50 (m, 1H), 1.48 - 1.32 (m, 1H), 1.19 (d, J = 6.8 Hz, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 139.94 (dd, J = 5.5 Hz, 5.5 Hz), 129.57 (dd, J = 3.3 Hz, 3.3 Hz), 128.60, 125.73, 97.10 (dd, J = 10.9 Hz, 10.9 Hz), 77.95 (d, J = 17.4 Hz), 69.70, 69.62, 69.15, 67.85, 56.79 (d, J = 3.3 Hz, 4.4 Hz), 39.52, 32.59 (d, J = 12.0 Hz), 23.57 (dd, J = 6.6 Hz, 18.5 Hz), 8.31; 31 P NMR (162 MHz, CDCl 3 ) δ -26.58 (s).

[0052] Among them, Figure 6 , the proton NMR spectrum of ligand L3; Figure 7 , the carbon NMR spectrum of ligand L3.

[0053] Example 4 Synthesis of Ligand L4

[0054]

[0055] Under a nitrogen atmosphere, (R)-2-dimethylamino-ethyl ferrocene (1.03 g, 4 mmol) and 20 mL of anhydrous diethyl ether were successively added to a 100 mL Schlenk flask. At 0 °C, a 1.3 M solution of tert-butyllithium in pentane (4.42 mmol, 3.4 mL) was added dropwise, and then the reaction mixture was allowed to warm to room temperature and stirred for 2 h. After cooling the reaction mixture to -78 °C, 1,2-bis(dichlorophosphino)ethane (0.46 g in 4 mL Et 2O (2 mmol), and the resulting reaction solution was allowed to warm to room temperature and react for 4 h. The reaction solution was cooled to -78 °C again, and o-methoxyphenylmagnesium chloride (1.0 M in THF, 6 mL) was added. It was slowly warmed to room temperature and reacted overnight. 10 mL of water was added to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain the target product L4, a yellow solid, 36% yield.

[0056] 1 H NMR (600 MHz, CDCl 3 ) δ 7.53 - 7.49 (m, 1H), 7.39 - 7.33 (m, 1H), 6.96 (t, J = 7.4 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 4.18 (s, 1H), 4.16 - 4.10 (m, 1H), 4.07 - 4.04 (m, 1H), 3.87 (s, 1H), 3.841 (s, 3H), 3.835 (s, 5H), 2.10 - 2.02 (m, 1H), 2.02 (s, 6H), 1.87 - 1.79 (m, 1H), 1.28 (d, J = 6.7 Hz, 3H); 13 C NMR (151 MHz, CDCl 3 ) δ 162.80 (dd, J = 7.6 Hz, 7.6 Hz), 135.30 (t, J = 3.3 Hz), 130.56, 124.92 (dd, J = 7.6 Hz, 8.7 Hz), 120.46, 110.44, 96.46, 78.63 (t, J = 8.3 Hz), 71.34, 70.48, 69.96, 69.60, 68.93, 67.97, 56.80, 55.44, 39.80, 24.97 (d, J = 4.4 Hz), 10.17; 31 P NMR (243 MHz, CDCl 3 ) δ -42.78 (s).

[0057] Among them, Figure 8 , the 1H NMR spectrum of ligand L4; Figure 9 , the 13C NMR spectrum of ligand L4.

[0058] Example 5 Synthesis of Ligand L5

[0059]

[0060] In a nitrogen atmosphere, (R)-2-dimethylaminoethylferrocene (1.03 g, 4 mmol) and 20 mL of anhydrous diethyl ether were successively added to a 100 mL Schlenk flask. At 0 °C, a 1.3 M solution of tert-butyllithium in pentane (4.42 mmol, 3.4 mL) was added dropwise, and then the reaction mixture was allowed to warm to room temperature and stirred for 2 h. After cooling the reaction mixture to -78 °C, 1,2-bis(dichlorophosphino)ethane (0.46 g in 4 mL Et 2 O, 2 mmol) was added dropwise. The resulting reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was cooled to -78 °C again, and magnesium chloride m-anisyl (1.0 M in THF, 6 mL) was added. The reaction mixture was slowly warmed to room temperature and stirred overnight. 10 mL of water was added to quench the reaction, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the target product L5 as a yellow solid, with a yield of 42%.

[0061] 1 1H NMR (600 MHz, CDCl 3 ) δ 7.32 (t, J = 7.7 Hz, 1H), 7.27 - 7.21 (m, 2H), 6.95 (dd, J = 2.6 Hz, 8.1 Hz, 1H), 4.19 (s, 1H), 4.14 - 4.08 (m, 1H), 4.05 (t, J = 2.5 Hz, 1H), 3.81 (s, 3H), 3.81 (s, 5H), 3.76 (s, 1H), 2.07 - 1.96 (m, 1H), 2.01 (s, 6H), 1.84 - 1.76 (m, 1H), 1.24 (d, J = 6.6 Hz, 3H); 13 13C NMR (151 MHz, CDCl 3 ) δ 159.09 (dd, J = 4.3 Hz, 4.9 Hz), 138.28 (dd, J = 6.0 Hz, 6.0 Hz), 128.86 (dd, J = 3.8 Hz, 4.4 Hz), 126.69 (dd, J = 9.8 Hz, 9.8 Hz), 119.59 (dd, J = 12.0 Hz, 12.5 Hz), 115.0, 96.14, 78.36 (dd, J = 6.5 Hz, 6.6 Hz), 70.55 (dd, J = 2.7 Hz, 2.7 Hz), 69.59, 69.36, 68.80, 67.73, 65.85, 56.75, 55.23, 39.28, 25.76 (d, J = 4.9 Hz), 8.77; 31 31P NMR (243 MHz, CDCl 3 ) δ -26.75 (s).

[0062] Among them, Figure 10 , the 1H NMR spectrum of ligand L5; Figure 11 , the 13C NMR spectrum of ligand L5.

[0063] Example 6 Synthesis of Ligand L6

[0064]

[0065] Under a nitrogen atmosphere, (R)-2-dimethylamino-ethylferrocene (1.03 g, 4 mmol) and 20 mL of anhydrous diethyl ether were successively added to a 100 mL Schlenk flask. At 0 °C, a 1.3 M solution of tert-butyllithium in pentane (4.42 mmol, 3.4 mL) was added dropwise, and then the reaction mixture was allowed to warm to room temperature and react for 2 h. After cooling the reaction mixture to -78 °C, 1,2-bis(dichlorophosphino)ethane (0.46 g in 4 mL Et 2 O, 2 mmol) was added dropwise, and the resulting reaction mixture was allowed to warm to room temperature and react for 4 h. The reaction mixture was cooled to -78 °C again, and p-methoxyphenylmagnesium chloride (1.0 M in THF, 6 mL) was added. The mixture was slowly warmed to room temperature and reacted overnight. 10 mL of water was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography to give the target product L6, a yellow solid, 45% yield.

[0066] 1 1H NMR (600 MHz, CDCl 3 ) δ 7.50 - 7.53 (m, 2H), 6.99 - 6.92 (m, 2H), 4.19 - 4.15 (m, 1H), 4.13 - 4.09 (m, 1H), 4.02 (t, J = 2.4 Hz, 1H), 3.88 (s, 3H), 3.80 (s, 5H), 3.70 - 3.67 (m, 1H), 2.07 - 1.97 (m, 1H), 2.04 (s, 6H), 1.75 - 1.66 (m, 1H), 1.25 (d, J = 6.6 Hz, 3H); 13 13C NMR (151 MHz, CDCl 3) δ 160.5, 162.80 (dd, J = 7.6 Hz, 7.6 Hz), 135.96 (dd, J = 10.9 Hz, 11.5 Hz), 127.54 (dd, J = 3.8 Hz, 5.1 Hz), 113.48 (dd, J = 4.4 Hz, 4.4 Hz), 96.01 (dd, J = 10.9 Hz, 12.0 Hz), 79.25 (dd, J = 6.5 Hz, 6.6 Hz), 70.37 (dd, J = 2.2 Hz, 2.7 Hz), 69.91, 69.28, 68.71 (dd, J = 2.2 Hz, 2.2 Hz), 68.64, 67.62, 56.73 (dd, J = 3.8 Hz, 4.4 Hz), 55.24, 39.33, 25.95 (d, J = 6.0 Hz), 8.93; 31 P NMR (243 MHz, CDCl 3 ) δ -30.42 (s).

[0067] Among them, Figure 12 , the 1H NMR spectrum of ligand L6; Figure 13 , the 13C NMR spectrum of ligand L6.

[0068] Example 7 Screening of Asymmetric Hydrogenation Conditions for α-Phenylacrylic Acid

[0069] Under the protection of inert gas, in a glove box, successively add bisphosphine ligand L1 (8.3 mg, 0.011 mmol), metal precursor Rh(COD) 2 BF 4 (4.1 mg, 0.01 mmol) and trifluoroethanol (1 mL) into a 2.5 mL reaction flask, stir at room temperature for complexation for 30 min to obtain a clear yellow catalyst solution. In another hydrogenation flask, successively add the reaction substrate α-phenylacrylic acid (0.2 mmol), reaction solvent (1 mL) and additive (added as appropriate), and then add the above catalyst solution (0.2 mL, 0.002 mmol, S / C = 100). After adding the materials, place the hydrogenation flask in a hydrogenation reaction device and seal it. Fill the reaction device with 50 atm of hydrogen, heat to 35 °C, and react for 24 h. After the reaction is completed, slowly release all the gas in the reaction device, concentrate the reaction solution, dissolve the residue in ethyl acetate again, wash away the water-soluble impurities with water, filter the metal from the ethyl acetate solution of the crude product through a short silica gel column, analyze the conversion rate of the reaction by 1H NMR, and derivatize the crude product in situ with TMSCHN 2 , and determine its ee value by chiral HPLC analysis.

[0070] To obtain the optimal solvent and other conditions for this reaction, we used α-phenylacrylic acid 1a as the standard substrate and screened the solvents. The results are shown in Table 1. The results indicate that the optimal conditions for this reaction are the solvent TFE / i PrOH(1 / 5), the additive is acetic acid in a two-fold equivalent amount to the substrate, the reaction temperature is 35 °C, and the hydrogen pressure is 50 atm.

[0071] Table 1 Screening of Asymmetric Hydrogenation Conditions for α-Phenylacrylic Acid

[0072]

[0073]

[0074] a Add 2 equivalents of HOAc (0.4 mmol).

[0075] Example 8 Substrate Applicability of Asymmetric Hydrogenation of 2-Arylacrylic Acids

[0076] Under inert gas protection, in a glove box, in a 2.5 mL reaction flask, sequentially add the bisphosphine ligand L1 (8.3 mg, 0.011 mmol), the metal precursor Rh(COD) 2 BF 4 (4.1 mg, 0.01 mmol) and trifluoroethanol (1 mL), stir at room temperature for complexation for 30 min to obtain a clear yellow catalyst solution. In another hydrogenation flask, sequentially add the reaction substrate 2-arylacrylic acid (0.2 mmol), isopropanol (1 mL) and acetic acid (0.4 mmol), and then add the above catalyst solution (0.2 mL, 0.002 mmol, S / C = 100). After adding the materials, place the hydrogenation flask in the hydrogenation reaction device and seal it. Fill the reaction device with 50 atm of hydrogen, heat to 35 °C, and react for 24 h. After the reaction is completed, slowly release all the gas in the reaction device, concentrate the reaction solution, dissolve the residue in ethyl acetate again, wash away the water-soluble impurities with water, and filter the metal from the ethyl acetate solution of the crude product through a short silica gel column. Analyze the conversion rate of the reaction by 1H NMR, and derivatize the crude product in situ with TMSCHN 2 After in-situ derivatization, determine its ee value by chiral HPLC analysis.

[0077] Using the above optimal reaction conditions, we extended the substrate applicability of 2-arylacrylic acid substrates. The results are shown in Table 2. The results indicate that this reaction has good substrate generality. In particular, the chiral drugs ibuprofen, naproxen, and esflurbiprofen can be synthesized through this reaction.

[0078] Table 2 Substrate Applicability of Asymmetric Hydrogenation of Ligand L1 in 2-Arylacrylic Acid

[0079]

[0080] Example 9 Ligand Screening for Asymmetric Hydrogenation of 2-Benzylacrylic Acid

[0081] Using the above optimal reaction conditions, we investigated the applicability of 2-alkylacrylic acids. Taking 2-benzylacrylic acid 1r as the standard substrate, we screened the conditions and ligands, and the results are shown in Table 3. The results indicate that L4 has the best stereoselectivity for 2-benzylacrylic acid, and there is no need to add acetic acid as an additive additionally.

[0082] Table 3 Ligand Screening for Asymmetric Hydrogenation of 2-Benzylacrylic Acid

[0083]

[0084]

[0085] a Add 2 equivalents of HOAc (0.4 mmol).

[0086] Example 10 Substrate Applicability of Asymmetric Hydrogenation of 2-Alkylacrylic Acid

[0087] Under inert gas protection, in a glove box, sequentially add bisphosphine ligand L4 (26.9 mg, 0.033 mmol), metal precursor Rh(COD) 2 BF 4 (12.2 mg, 0.03 mmol) and trifluoroethanol (2 mL) to a 5 mL reaction flask, stir at room temperature for complexation for 30 min to obtain a clear yellow catalyst solution. In another hydrogenation flask, sequentially add the reaction substrate 2-alkylacrylic acid (0.3 mmol) and isopropanol (1 mL), and then add the above catalyst solution (0.2 mL, 0.003 mmol, S / C = 100). After adding the materials, place the hydrogenation flask in a hydrogenation reaction device and seal it. Charge 50 atm of hydrogen into the reaction device, heat to 35 °C, and react for 24 h. After the reaction is completed, slowly release all the gas in the reaction device, concentrate the reaction solution, dissolve the residue in ethyl acetate again, wash away the water-soluble impurities with water, filter the metal from the ethyl acetate solution of the crude product through a short silica gel column, analyze the conversion rate of the reaction by 1H NMR, and determine the ee value of the crude product by chiral HPLC after in-situ derivatization to the corresponding p-methoxybenzamide.

[0088] Using the above optimal reaction conditions, we extended the applicability of 2-alkylacrylic acid, and the results are shown in Table 4. The results indicate that the reaction has good substrate generality. In particular, 2w or its derivatives can be synthesized by asymmetric hydrogenation and subsequent esterification for use in the chiral synthon methyl 3-hydroxyisobutyrate (Roche Ester).

[0089] Table 4 Substrate generality of the asymmetric hydrogenation of ligand L4 in 2-alkylacrylic acid

[0090]

[0091] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A C 2 symmetric chiral diphosphine ligand, It is characterized in that The structural general formula (I) is as follows: In general formula (I), each R is one of phenyl, methyl, benzyl, o-methoxyphenyl, p-methoxyphenyl, and m-methoxyphenyl.

2. The ligand according to claim 1, It is characterized in that The ligand is specifically as follows:

3. The synthesis method of the chiral bisphosphine ligand according to claim 1 or 2, It is characterized in that The route is as follows: Starting from chiral Ugi's amine, after lithiation, reacting with 1,2-bis(dichlorophosphino)ethane, then reacting with the corresponding Grignard reagent, and quenching with water to obtain the target ligand.

4. The application of the chiral bisphosphine ligand according to claim 1 or 2 in the catalytic asymmetric hydrogenation reaction, It is characterized in that The chiral bisphosphine ligand forms a catalyst after complexing with a metal complex, and the metal is selected from Rh.

5. The application according to claim 4, It is characterized in that The chiral bisphosphine ligand is selected from L1 and L4.

6. The application according to claim 4, wherein the metal complex is Rh(COD) 2 BF 4 , Rh(NBD) 2 BF 4 , [Rh(NBD)Cl] 2 , Rh(acac)(CO) 2 , [Rh(COD)Cl] 2 , Rh(ethylene) 2 (acac), [Rh(ethylene) 2 Cl] 2 , RhCl(PPh 3 ) 3 .

7. The application according to claim 4, It is characterized in that The catalytic reaction is achieved by the following method: (1) Under the protection of inert gas, a certain proportion of chiral bisphosphine ligand and Rh(COD) 2 BF 4 were successively added, and the mixture was stirred at room temperature for complexation for 30 min in trifluoroethanol as a solvent to obtain a clear yellow catalyst solution; (2) In a hydrogenation flask, successively add the reaction substrate, isopropanol and acetic acid, then add a certain amount of the above catalyst solution. After the addition is complete, place the hydrogenation flask in a hydrogenation reaction device and seal it. Charge a certain pressure of hydrogen into the reaction device, then heat the reaction device to a certain temperature. After the reaction is completed, slowly release all the gas in the reaction device, concentrate the reaction solution, filter out the metal, and analyze the reaction mixture by HPLC.

8. The application according to claim 4, It is characterized in that The catalyst made of the chiral bisphosphine ligand according to claim 1 or 2 is used for the synthesis of chiral drugs ibuprofen, naproxen and alfloprofen.

9. The application according to claim 4, It is characterized in that The catalyst made of the chiral bisphosphine ligand according to claim 1 or 2 is used for the synthesis of methyl (R)-3-hydroxyisobutyrate.

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