A chiral bisphosphine ligand with a ferrocene skeleton, its preparation method and application

Abstract

The present invention discloses a chiral bisphosphine ligand with a ferrocene skeleton, its preparation method and application. The preparation process of the chiral bisphosphine ligand is as follows: under nitrogen protection, a bisphosphine-substituted ferrocene-α-ethylamine derivative shown in formula (II) and an aromatic carbonyl isocyanate or aromatic carbonyl isothiocyanate shown in formula (III) are added to an organic solvent, and the reaction is carried out at 0-40 °C for 1-24 hours. TLC is used to monitor the reaction until it is complete. The solvent is recovered by reduced pressure concentration, and the residue is separated by column chromatography to obtain the chiral bisphosphine ligand with a ferrocene skeleton shown in formula (I). The catalyst formed by complexing the chiral bisphosphine ligand provided by the present invention with a transition metal can efficiently catalyze the asymmetric hydrogenation reaction of α,β-unsaturated lactam, thereby developing an asymmetric synthesis process of brivaracetam, which has the advantages of a short synthesis route, high yield, good stereoselectivity, etc., and has good economic and social benefits.

Description

Technical Field

[0001] The present invention belongs to the technical field of asymmetric catalysis, and particularly relates to a chiral bisphosphine ligand with a ferrocene skeleton, a preparation method thereof, and an application thereof. Background Art

[0002] Especially in the clinical application of drugs, chiral drugs often have unique curative effects on diseases. The methods for obtaining chiral compounds mainly include chiral resolution method, chiral source synthesis method, asymmetric synthesis method, etc. In the asymmetric synthesis method, asymmetric hydrogenation has become a relatively mature chiral catalytic technology in current industrial production due to its good atom economy, high selectivity, and green and clean process characteristics. The catalysts used in asymmetric hydrogenation are mainly complexes of transition metals and chiral ligands, and the ligand is the core and key to determining the catalytic efficiency and selectivity of the catalyst. Therefore, the design and synthesis of novel chiral ligands have always been a research hotspot in asymmetric synthesis.

[0003] In the field of asymmetric catalysis, small molecule (thio)urea structural units are common functional groups for forming intermolecular (intramolecular) hydrogen bonds, and the ferrocene skeleton is a dominant skeleton in chiral ligands. However, there are few reports on connecting (thio)urea structural units and ferrocene skeletons to the same ligand structure (Org. Biomol. Chem., 2014, 12, 2423–2426; Catal. Commun., 2019, 121, 78–83; Org. Lett., 2013, 15, 4014-4017). To date, countless chiral ligands have been reported, and many of them also exhibit high stereoselectivity. However, due to reasons such as complex synthesis, difficult modification, and high price, their industrial applications are limited. The present invention provides a class of chiral bisphosphine ligands with a ferrocene skeleton that are simple to synthesize, stable to water and air, and easy to prepare on a large scale. This ligand exhibits high activity and high selectivity in the asymmetric hydrogenation of α,β-unsaturated lactams and has potential industrial application prospects. Summary of the Invention

[0004] Aiming at the above problems existing in the prior art, the purpose of the present invention is to provide a chiral bisphosphine ligand with a ferrocene skeleton, a preparation method thereof, and an application thereof. The ligand provided by the present invention has the characteristics of simple synthesis, stability to water and air, and the catalyst composed of the ligand and a noble metal precursor has high activity and high selectivity in the asymmetric hydrogenation reaction of α,β-unsaturated amides.

[0005] The chiral bisphosphine ligand with a ferrocene skeleton is shown in the general structural formula (I):

[0006]

[0007] In formula (I): R 1 、R2 Each independently selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, aryloxy or hydrogen atom, R 1 , R 2 may optionally form a ring or not; R 3 is hydrogen or methyl; X is S or O; R 4 is aryl, a five- or six-membered heteroaryl containing at least one S, O or N atom or C1-C6 alkyl.

[0008] Furthermore, in the said R 1 , R 2 , the aryl is phenyl or substituted phenyl, the number of substituents on the benzene ring of the substituted phenyl is 1-3, and is selected from C1-C4 alkyl; in the said R 4 , the aryl is phenyl or substituted phenyl, the number of substituents on the benzene ring of the substituted phenyl is 1-3, and is selected from C1-C4 alkyl or C1-C4 haloalkyl.

[0009] Furthermore, a chiral bisphosphine ligand with a ferrocene skeleton provided by the present application includes one of 10 ligands, and each ligand corresponds to two isomers. The structural formulas of the 10 ligands are as follows:

[0010]

[0011] The preparation method of the said chiral bisphosphine ligand with a ferrocene skeleton includes the following steps: Under nitrogen protection, a bisphosphine-substituted ferrocene-α-ethylamine derivative shown in formula (II) and an arylcarbonyl isocyanate or arylcarbonyl isothiocyanate shown in formula (III) are added to an organic solvent, and stirred and reacted at 0-40 °C for 1-24 hours. TLC is used to track until the reaction is complete, the solvent is recovered by reduced pressure concentration, and the residue is separated by column chromatography (the eluent is petroleum ether: ethyl acetate = 5-20:1, volume ratio) to obtain the chiral bisphosphine ligand with a ferrocene skeleton shown in formula (I);

[0012]

[0013] R 1 , R 2 , R 3 in formula (II) are the same as those in formula (I), and R 4 in formula (III) is the same as that in formula (I).

[0014] Furthermore, the molar ratio of the bisphosphine-substituted ferrocene-α-ethylamine derivative shown in formula (II) to the arylcarbonyl isocyanate or arylcarbonyl isothiocyanate shown in formula (III) is 1:1.0-2.0; the reaction temperature is 20-30 °C, and the reaction time is 1-5 hours.

[0015] Furthermore, the organic solvent is dichloromethane, acetone or acetonitrile, and the concentration of the bisphosphine-substituted ferrocene-α-ethylamine derivative shown in formula (II) in the organic solvent is 0.02 - 0.1 mol / L, preferably 0.05 - 0.07 mol / L.

[0016] A noble metal catalyst is a complex obtained by complexing a chiral bisphosphine ligand with a ferrocene skeleton provided by the present invention with a transition metal precursor, and the transition metal is any one of Ru, Rh, Ir or Pd.

[0017] Specific transition metal precursors are selected from any one of: Pd(COD)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dba)2, Pd(OAc)2, [Rh(NBD)2]BF4, [Rh(NBD)Cl]2, [Rh(COD)Cl]2, [Rh(acac)(CO)]2, Rh(ethylene)2(acac), Rh(ethylene)2Cl2, RhCl(PPh3)3, Rh(CO)2Cl2, RuCl2(COD), [Ru(COD)2]Cl, [Ir(NBD)2Cl]2, Ir(NBD)2)BF4, [Ir(COD)Cl]2 or [Ir(COD)2]BF4.

[0018] Furthermore, the molar ratio of the chiral bisphosphine ligand with a ferrocene skeleton to the transition metal precursor is 1:0.8 - 1.2.

[0019] The noble metal catalyst can be applied to an asymmetric hydrogenation reaction, specifically applied to the asymmetric synthesis of brivaracetam, and the reaction general formula is as follows:

[0020]

[0021] By adopting the above technologies, a novel chiral bisphosphine ligand with a ferrocene skeleton provided by the present invention has the characteristics of simple synthesis, stability to water and air, high activity and high selectivity, easy realization of industrial production, etc. Moreover, the ligand can regulate the steric hindrance and electric property of the ligand by simple group changes, is suitable for large-scale preparation, has good industrial application prospects, and can be applied to the asymmetric hydrogenation synthesis of the drug brivaracetam. Specific Embodiments

[0022] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0023] Example 1: Synthesis of Ligand L2

[0024]

[0025] (1) Dissolve (R)-Ugi amine 1 (5.14 g, 20 mmol) in 50 mL of diethyl ether. Under nitrogen protection and at 0 °C, add n-butyllithium (10 mL, 2.5 mol / L) dropwise to the reaction flask. After the addition is complete, keep the reaction at this temperature for 3 hours. Then slowly add n-butyllithium (12 mL, 2.5 mol / L) and N,N,N,N-tetramethylethylenediamine (TMEDA) (3.95 g, 30 mmol) dropwise to the reaction flask. After the addition is complete, keep the reaction mixture stirring at this temperature for 5 hours. Then add chlorodiphenylphosphine (17.65 g, 80 mmol) dropwise. After the addition, slowly raise the temperature to room temperature and stir the reaction for 12 hours. Quench the reaction with saturated ammonium chloride solution, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (petroleum ether:ethyl acetate:triethylamine = 2:1:0.01, v / v) to obtain compound 2a (6.3 g, yield 52%).

[0026]

[0027] (2) Mix compound 2a (6.3 g, 10 mmol) with 15 mL of acetic anhydride and react at 100 °C for 3 hours. Concentrate under reduced pressure to remove the excess acetic anhydride and low-boiling substances. Add 50 mL of 40% aqueous methylamine solution to the residue. After displacing the nitrogen, react at 100 °C for 12 h. After the reaction is complete, cool the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (petroleum ether:ethyl acetate:triethylamine = 1:1:0.01, v / v) to obtain compound IIa (3.2 g, yield 53%).

[0028]

[0029] (3) Add compound IIa (611.5 mg, 1 mmol), compound IIIb (310 mg, 1.5 mmol), and 15 mL of dichloromethane to a 50 mL reaction flask and react at 25 °C for 2 hours. After the reaction is complete, extract with dichloromethane, dry over anhydrous sodium sulfate, and separate by column chromatography (petroleum ether:ethyl acetate = 10:1, v / v) to obtain the yellow ligand L2 (0.52 g, yield 63.6%).

[0030] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.25 (m, 20H), 6.83 (q, J = 7.6 Hz, 1H), 4.51 (s, 2H), 4.23 (d, J = 3.3 Hz, 2H), 4.02 (s, 1H), 3.74 (s, 1H), 3.38 (s, 1H), 2.27 (s, 3H), 2.18 (s, 6H), 1.92 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H). 1313C NMR (100 MHz, DMSO-d6) δ 180.51, 175.51, 140.21 (d, J = 10.1 Hz), 139.80 (d, J = 10.1 Hz), 139.51 (d, J = 10.1 Hz), 137.14 (d, J = 9.1 Hz), 135.62 (d, J = 21.1 Hz), 134.13 (d, J = 20.1), 133.75 (d, J = 19.1 Hz), 133.02 (d, J = 19.1 Hz), 132.78, 131.89, 131.56, 130.34, 129.91, 129.52, 129.37, 128.75 (d, J = 6 Hz), 128.51 (d, J = 6 Hz), 128.41, 128.12, 127.51, 93.11 (d, J = 24.5 Hz), 77.86 (d, J = 16.4 Hz), 77.62 (d, J = 14.5 Hz), 75.61 (d, J = 18.9 Hz), 74.54 (d, J = 4.6 Hz), 74.11 (d, J = 10.4 Hz), 73.81 (d, J = 2.1 Hz), 73.54 (d, J = 9.9 Hz), 72.15 (d, J = 2.1 Hz), 71.61 (d, J = 2.1 Hz), 68.61 (d, J = 9.1 Hz), 35.80, 21.37, 20.54, 18.61. 31 31P NMR (162 MHz, DMSO-d6) δ -17.72, -25.43. HRMS (ESI): [M+H + Calc. C 48 H 47 FeN2OP2S 817.2235, found 817.2243。

[0031] Example 2: Synthesis of Ligand L3

[0032]

[0033] Add compound IIa (611.5 mg, 1 mmol) and compound IIIc (412.5 mg, 1.5 mmol) and 15 mL of dichloromethane to a 50 mL reaction flask, and react at 25 °C for 2 hours. After the reaction is completed, extract with dichloromethane, dry with anhydrous sodium sulfate, and perform column chromatography (petroleum ether: ethyl acetate = 10:1, v / v) to obtain yellow ligand L3 (0.49 g, yield 54.8%).

[0034] 11H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.45–7.17 (m, 23H), 6.45 (q, J = 7.6 Hz, 1H), 4.47 (s, 2H), 4.15 (d, J = 3.3 Hz, 2H), 3.89 (s, 1H), 3.54 (s, 1H), 3.38 (s, 1H), 1.88 (s, 3H), 1.43 (d, J = 6.8 Hz, 3H), 1.32 (s, 18H). 13 13C NMR (100 MHz, DMSO-d6) δ 182.51, 173.67, 141.22, 138.42 (d, J = 9.9 Hz), 137.26 (d, J = 5.4 Hz), 137.03 (d, J = 9.7 Hz), 136.73, 135.42 (d, J = 21.1 Hz), 134.13 (d, J = 20.1), 133.84 (d, J = 20.4 Hz), 133.64 (d, J = 21.2 Hz), 133.32 (d, J = 19.1 Hz), 132.86 (d, J = 18.9 Hz), 132.78, 132.08 (d, J = 17.5 Hz), 131.89, 131.56, 130.34 129.91, 129.52, 129.37, 129.27 (d, J = 17.7 Hz), 95.11 (d, J = 24.5 Hz), 77.68 (d, J = 16.4 Hz), 77.45 (d, J = 14.5 Hz), 75.51 (d, J = 18.9 Hz), 74.84 (d, J = 4.6 Hz), 74.11 (d, J = 10.4 Hz), 73.61 (d, J = 2.1 Hz), 73.54 (d, J = 9.9 Hz), 72.15 (d, J = 2.1 Hz), 71.61 (d, J = 2.1 Hz), 68.61 (d, J = 9.1 Hz), 36.87 (s), 35.75, 30.46, 20.57. 31 31P NMR (162 MHz, DMSO-d6) δ -17.72, -25.43. HRMS (ESI): [M+H + Calc. C 53 H 57 FeN2OP2S, 887.3018, found 887.3026。

[0035] Example 3: Synthesis of Ligand L7

[0036]

[0037] In a 50 mL reaction flask, compound IIa (611.5 mg, 1 mmol) and compound IIId (220.7 mg, 1.5 mmol) were added, along with 15 mL of dichloromethane, and the reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was extracted with dichloromethane, dried over anhydrous sodium sulfate, and separated by column chromatography (petroleum ether: ethyl acetate = 10:1, v / v) to obtain yellow solid L7 (0.42 g, yield 51%).

[0038] 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 7.40–7.24 (m, 20H), 7.23–7.18 (m, 5H), 6.71 (q, J = 7.7 Hz, 1H), 4.51 (s, 2H), 4.21 (d, J = 3.3 Hz, 2H), 3.92 (s, 1H), 3.64 (s, 1H), 3.22 (s, 1H), 2.17 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 181.51, 175.51, 141.89 (d, J = 10.1 Hz), 139.56 (d, J = 10.1 Hz), 139.51 (d, J = 10.1 Hz), 138.14 (d, J = 9.1 Hz), 136.82 (d, J = 21.1 Hz), 135.13 (d, J = 20.1 Hz), 133.75 (d, J = 19.1 Hz), 133.42 (d, J = 19.1 Hz), 132.38, 131.79, 131.56, 130.34, 129.91, 129.52, 129.37, 128.75 (d, J = 6 Hz), 128.51 (d, J = 6 Hz), 128.41, 128.12, 127.5196.88 (d, J = 24.1 Hz), 75.39 (d, J = 22.6 Hz), 73.95 (d, J = 5.3 Hz), 73.65 (d, J = 5.6 Hz), 72.98 (d, J = 6.8 Hz), 72.81, 72.56 (d, J = 3.7 Hz), 72.16 (d, J = 3.6 Hz), 71.61 (d, J = 2.1 Hz), 67.84. 31 PNMR (100 MHz, DMSO-d6) δ -18.71, -26.73. HRMS (ESI): [M+H + Calc. C 45 H 40 FeN2O2P2, 759.1987, found 759.1979。

[0039] Example 4: Synthesis of ligand L8:

[0040]

[0041] Compound IIb can be prepared with reference to the synthesis method of IIa in Example 1: Replace 50 mL of 40% methylamine aqueous solution in step (2) of Example 1 with 50 mL of 40% ammonia aqueous solution to obtain Compound IIb.

[0042] Add Compound IIb (611.5 mg, 1 mmol), Compound IIIb (226.8 mg, 1.5 mmol) and 15 mL of dichloromethane into a 50 mL reaction flask, and react at 25 °C for 2 hours. After the reaction is completed, extract with dichloromethane, dry with anhydrous sodium sulfate, and perform column chromatography (petroleum ether: ethyl acetate = 10:1, v / v) to obtain yellow solid L8 (0.52 g, yield 63%).

[0043] 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (d, J = 7.0 Hz, 1H), 8.30 (s, 1H), 7.40–7.24 (m, 20H), 6.83 (s, 2H), 5.59 (p, J = 7.1 Hz, 1H), 4.51 (s, 2H), 4.23 (d, J = 3.3 Hz, 2H), 4.02 (s, 1H), 3.74 (s, 1H), 3.38 (s, 1H), 2.27 (s, 3H), 2.18 (s, 6H), 1.63 (d, J = 6.8 Hz, 3H). 1313C NMR (400 MHz, DMSO-d6) δ 184.32, 175.11, 140.82, 138.32 (d, J = 9.9 Hz), 137.56 (d, J = 5.4 Hz), 137.03 (d, J = 9.7 Hz), 136.13 (s), 135.62 (d, J = 21.1 Hz), 134.13 (d, J = 20.1), 133.84 (d, J = 20.4 Hz), 133.64 (d, J = 21.2 Hz), 133.42 (d, J = 19.1 Hz), 132.76 (d, J = 18.9 Hz), 132.78, 132.08 (d, J = 17.5 Hz), 131.89, 131.56, 130.34 129.91, 129.52, 129.37, 129.27 (d, J = 17.7 Hz), 93.11 (d, J = 24.5 Hz), 77.86 (d, J = 16.4 Hz), 77.62 (d, J = 14.5 Hz), 75.61 (d, J = 18.9 Hz), 74.54 (d, J = 4.6 Hz), 74.11 (d, J = 10.4 Hz), 73.81 (d, J = 2.1 Hz), 73.54 (d, J = 9.9 Hz), 72.15 (d, J = 2.1 Hz), 71.61 (d, J = 2.1 Hz), 68.61 (d, J = 9.1 Hz), 51.84, 24.43, 20.57. 31 31P NMR (162 MHz, DMSO-d6) δ -18.22, -26.13. HRMS (ESI): [M+H + Calc. C 47 H 44 FeN2OP2S, 803.2072, found 803.2066。

[0044] Example 5: Synthesis of Ligand L9

[0045]

[0046] Compound IIc can be prepared by referring to the synthesis method of IIa in Example 1. The preparation steps are repeated as in Example 1, except that "chlorodiphenylphosphine (80 mmol) in step (1) is replaced by chloro-bis(3,5-dimethylphenyl)phosphine (80 mmol)", and then Compound IIc is obtained.

[0047] In a 50 mL reaction flask, compound IIc (723.5 mg, 1 mmol), compound IIIb (310 mg, 1.5 mmol) and 15 mL of dichloromethane were added, and the reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was extracted with dichloromethane, dried over anhydrous sodium sulfate, and column chromatography (petroleum ether: ethyl acetate = 10:1, volume ratio) gave yellow solid L9 (0.53 g, yield 56.8%).

[0048] 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.40–7.25 (m, 12H), 6.83 (q, J = 7.6 Hz, 1H), 4.31 (s, 2H), 4.23 (d, J = 3.3 Hz, 2H), 3.98 (s, 1H), 3.74 (s, 1H), 3.28 (s, 1H), 2.27 (s, 3H), 2.18 (s, 24H), 2.08 (s, 6H), 1.92 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 180.51, 175.51, 140.62, 138.12 (d, J = 9.9 Hz), 137.56 (d, J = 5.4 Hz), 137.03 (d, J = 9.7 Hz), 136.13 (s), 135.62 (d, J = 21.1 Hz), 134.13 (d, J = 20.1), 133.84 (d, J = 20.4 Hz), 133.64 (d, J = 21.2 Hz), 133.42 (d, J = 19.1 Hz), 132.76 (d, J = 18.9 Hz), 132.78, 132.08 (d, J = 17.5 Hz), 131.89, 131.56, 130.34 129.91, 129.52, 129.37, 129.27 (d, J = 17.7 Hz), 96.88 (d, J = 24.1 Hz), 77.68 (d, J = 16.4 Hz), 77.45 (d, J = 14.5 Hz), 75.51 (d, J = 18.9 Hz), 74.84 (d, J = 4.6 Hz), 74.11 (d, J = 10.4 Hz), 73.61 (d, J = 2.1 Hz), 73.54 (d, J = 9.9 Hz), 72.15 (d, J = 2.1 Hz), 71.61 (d, J = 2.1 Hz), 68.61 (d, J = 9.1 Hz), 37.87, 24.43, 23.54, 22.78, 21.21 20.57. 31PNMR (162 MHz, DMSO-d6) δ -18.72 (s), -24.43 (s). HRMS (ESI): [M + H + Calc. C 56 H 62 FeN2OP2S, 929.3481, found 929.3489。

[0049] Example 6: Preparation of Noble Metal Catalyst and Asymmetric Synthesis of Brivaracetam

[0050] (1) Ligand L2 (8.98 mg, 0.011 mmol) and metal precursor Rh(NBD)2BF4 (3.4 mg, 0.01 mmol) were added to a reaction flask. 1 mL of dichloromethane was added under an argon atmosphere, and the mixture was stirred at 25 °C for 1 hour to obtain a Rh catalyst solution.

[0051] (2) Substrate S1 (225.3 mg, 1 mmol) and 0.5 mL of dichloromethane were added to an autoclave. The Rh catalyst solution prepared in step (1) (1 mL, 0.01 mmol) was added. The air was displaced with nitrogen three times, and then H2 was charged to 6.0 MPa. The reaction was carried out at 35 °C for 48 hours. After the reaction was completed, the hydrogen was released, and the reaction solution was filtered through silica gel to obtain 226 mg of intermediate S2, with a yield of 99%, an HPLC purity of 99%, and an ee value of 91%.

[0052] (3) Intermediate S2 (225.3 mg, 1 mmol) and 3 mL of 7 M ammonia in methanol solution were added to a pressure-resistant tube. The reaction was carried out at 90 °C for 5 hours. After the reaction was completed, the solvent was concentrated to remove, and 205 mg of brivaracetam S3 was obtained, with a yield of 96.5%, an HPLC purity of 98%, and an ee value of 91%.

[0053] Example 7: Preparation of Noble Metal Catalyst and Asymmetric Synthesis of Brivaracetam

[0054] (1) Ligand L9 (10.22 mg, 0.011 mmol) and metal precursor Rh(NBD)2BF4 (3.4 mg, 0.01 mmol) were added to a reaction flask. 1 mL of dichloromethane was added under an argon atmosphere, and the mixture was stirred at 25 °C for 1 hour to obtain a Rh catalyst solution.

[0055] (2) Add the substrate S1 (1 mmol, 225.3 mg), 0.5 mL of dichloromethane, and the Rh catalyst solution prepared in step (1) (1 mL, 0.01 mmol) into an autoclave. Replace the air with nitrogen three times, and then fill it with H2 to 6.0 MPa. React at 35 °C for 48 hours. After the reaction is completed, release the hydrogen. The reaction solution is filtered through silica gel to obtain 227 mg of intermediate S2, with a yield of 99%, an HPLC purity of 99%, and an ee value of 95%.

[0056] (3) Add the intermediate S2 (227 mg, 1 mmol) and 3 mL of 7 M ammonia in methanol solution into a pressure-resistant tube. React at 90 °C for 5 hours. After the reaction is completed, concentrate to remove the solvent to obtain 200 mg of bucindolol S3, with a yield of 94.2%, an HPLC purity of 99%, and an ee value of 95%.

[0057] Example 8: Preparation of a noble metal catalyst and asymmetric synthesis of bucindolol

[0058] (1) Add the ligand L7 (8.34 mg, 0.011 mmol) and metal Rh(COD)2BF4 (3.4 mg, 0.01 mmol) into a reaction flask. Add 1 mL of dichloromethane under an argon atmosphere and stir at 25 °C for 1 hour to prepare the Rh catalyst solution.

[0059] (2) Add the substrate S1 (1 mmol, 225.3 mg), 0.5 mL of dichloromethane, and the Rh catalyst solution prepared in step (1) (1 mL, 0.01 mmol) into an autoclave. Replace the air with nitrogen three times, and then fill it with H2 to 6.0 MPa. React at 35 °C for 48 hours. After the reaction is completed, release the hydrogen. The reaction solution is filtered through silica gel to obtain 225.3 mg of intermediate S2, with a yield of 96%, an HPLC purity of 99%, and an ee value of 81.4%.

[0060] (3) Add the intermediate S2 (225.3 mg, 0.99 mmol) and 3 mL of 7 M ammonia in methanol solution into a pressure-resistant tube. React at 90 °C for 5 hours. After the reaction is completed, concentrate to remove the solvent to obtain 203 mg of bucindolol S3, with a yield of 96.6%, an HPLC purity of 97%, and an ee value of 81.4%.

[0061] Example 9: Preparation of a noble metal catalyst and asymmetric synthesis of bucindolol

[0062] The experimental procedure of Example 9 was repeated for Example 6, except that "the ligand L2 (0.011 mmol) was replaced with other ligand (0.011 mmol)", and finally brivaracetam S3 was prepared. Different other ligands were used in Example 9, and the corresponding experimental results of the brivaracetam S3 product were summarized in Table 1.

[0063] Table 1

[0064]

[0065] The content described in this specification is only a list of the implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as limited to the specific forms stated in the embodiments.

Claims

1. A chiral bisphosphine ligand with a ferrocene backbone, characterized in that The general structural formula thereof is shown as formula (I): The chiral bisphosphine ligand with a ferrocene skeleton specifically includes one of 10 ligands, and each ligand corresponds to two isomers. The structural formulas of the 10 ligands are as follows:

2. The preparation method of a chiral bisphosphine ligand with a ferrocene skeleton according to claim 1, characterized in that It includes the following steps: Under nitrogen protection, the bisphosphine-substituted ferrocene-α-ethylamine derivative shown in formula (II) and the aromatic carbonyl isocyanate or aromatic carbonyl isothiocyanate shown in formula (III) are added to an organic solvent, and stirred and reacted at 0 - 40 °C for 1 - 24 hours. TLC is used to track until the reaction is complete. The solvent is recovered by concentration under reduced pressure, and the residue is separated by column chromatography to obtain the chiral bisphosphine ligand with a ferrocene skeleton shown in formula (I); R in formula (II) 1 , R 2 , R 3 are the same as those in formula (I), and R 4 in formula (III) is the same as that in formula (I).

3. The preparation method of a chiral bisphosphine ligand with a ferrocene skeleton according to claim 2, characterized in that The molar ratio of the bisphosphine-substituted ferrocene-α-ethylamine derivative shown in formula (II) to the aromatic carbonyl isocyanate or aromatic carbonyl isothiocyanate shown in formula (III) is 1:1.0 - 2.0; the reaction temperature is 20 - 30 °C, and the reaction time is 1 - 5 hours; The organic solvent is dichloromethane, acetone or acetonitrile, and the concentration of the bisphosphine-substituted ferrocene-α-ethylamine derivative shown in formula (II) in the organic solvent is 0.02 - 0.1 mol / L.

4. The preparation method of a chiral diphosphine ligand with a ferrocene skeleton according to claim 3, characterized in that The concentration of the bisphosphine-substituted ferrocene-α-ethylamine derivative shown in formula (II) in the organic solvent is 0.05 - 0.07 mol / L.

5. A noble metal catalyst, characterized in that It is a complex obtained by complexing the chiral bisphosphine ligand with a ferrocene skeleton described in claim 1 with a transition metal precursor.

6. The noble metal catalyst according to claim 5, characterized in that The transition metal is any one of Ru, Rh, Ir or Pd.

7. A noble metal catalyst according to claim 5 or 6, characterized in that The transition metal precursor is selected from any one of: Pd(COD)Cl2, Pd(PPh3)4, PdCl2(PPh3)2, Pd(dba)2, Pd(OAc)2, [Rh(NBD)2]BF4, [Rh(NBD)Cl]2, [Rh(COD)Cl]2, [Rh(acac)(CO)]2, Rh(ethylene)2(acac), Rh(ethylene)2Cl2, RhCl(PPh3)3, Rh(CO)2Cl2, RuCl2(COD), [Ru(COD)2]Cl, [Ir(NBD)2Cl]2, Ir(NBD)2)BF4, [Ir(COD)Cl]2 or [Ir(COD)2]BF4; The molar ratio of the chiral bisphosphine ligand with a ferrocene skeleton to the transition metal precursor is 1:0.8 - 1.

2.

8. Application of the noble metal catalyst as described in claim 5 in an asymmetric hydrogenation reaction.

9. The application according to claim 8, wherein The noble metal catalyst is used to catalyze the asymmetric hydrogenation reaction to synthesize boceprevir.

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