Metal complex and preparation method and application thereof

Abstract

The application discloses a metal complex and a preparation method and application thereof. Specifically, the metal complex catalyst is prepared by complexing a chiral tetradentate ligand with a metal precursor, the catalyst can realize asymmetric hydrogenation of a ketone, and through comparison of different preparation catalyst processes, an easy-to-prepare and simple-to-operate method is determined, the metal complex catalyst prepared by the method is stable in property, has certain tolerance to water and oxygen, can greatly improve catalytic efficiency, is suitable for industrial production, has a wide substrate application range, and has important practical value and industrialization prospect.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric synthesis technology, specifically relating to a metal complex, its preparation method, and its application. Background Technology

[0002] With the improvement of human understanding of the microscopic world and the improvement of living standards, people's demand for optically pure chiral drugs, pesticides, fragrances and other fine chemicals is increasing. Asymmetric catalysis technology has always been a research hotspot and has made great progress.

[0003] Asymmetric catalytic hydrogenation, in particular, utilizes hydrogen gas to directly achieve the asymmetric reduction of proximal chiral substrates under the action of a catalyst. It is a simple and effective method for constructing chiral substrates. Asymmetric catalytic hydrogenation offers advantages such as high efficiency, high selectivity, high atom economy, and environmental friendliness. The core issue determining the success of asymmetric hydrogenation technology is the catalyst. The stability, high activity, and high selectivity of the catalyst have always been challenges in the industrial application of asymmetric catalytic hydrogenation. High catalyst activity leads to decreased stability and extreme sensitivity to water and oxygen, thus limiting its application. In practical production applications, it is very inconvenient to use, requiring more stringent operating procedures or increased equipment investment, thereby raising production costs.

[0004] Some typical industrial applications of asymmetric hydrogenation reactions include: 1) The synthesis of L-DOPA by Monsanto, which uses the asymmetric hydrogenation of dehydrogenated amino acids with Rh-DIPAMP complex as the catalyst, achieving 94% ee and 2000 TON (TON: turnover number); 2) The synthesis of L-Menthol by Takasago, using Rh-BINAP complex as the catalyst, achieving 98% ee and 300,000 TON; 3) The synthesis of (S)-metolachlor by Norvatis, using Ir-ferrocene skeleton phosphine ligand complex as the catalyst, achieving 80% ee and 1,000,000 TON; 4) In 2012, BASF successfully synthesized 10,000 tons of L-Menthol using asymmetric hydrogenation reaction.

[0005] As can be seen from the above examples of commercial applications of asymmetric catalytic hydrogenation, the catalyst is the key to the entire process. Therefore, the preparation of highly active, highly stable, and highly selective metal complex catalysts is of paramount importance.

[0006] Chiral alcohols and amines are widely present in drug molecules, such as the antidepressant duloxetine, atomoxetine for treating attention deficit hyperactivity disorder in children and adolescents, phenylephrine for anaphylactic shock, rivastigmine for treating mild to moderate Alzheimer's disease, Montelukast for preventing and treating asthma, and ezetimibe, a cholesterol absorption inhibitor. Nicotine, also known as L-nicotine, is a chiral amine alkaloid containing pyridine and tetrahydropyrrole rings, possessing unique physiological activity due to its special structure. It can be used in smoking cessation products, and further research shows that nicotine acts on acetylcholine receptors, potentially making it an effective drug for treating Alzheimer's disease, Parkinson's disease, schizophrenia, depression, and other central nervous system disorders.

[0007]

[0008] The aforementioned drugs can be obtained through the asymmetric catalytic hydrogenation of the relevant ketones and further derivatization. Currently, two systems have been reported to achieve TON (total oxygen) in the millions during the asymmetric catalytic hydrogenation of ketones. One is the ruthenium-bisphosphine diamine system reported by the Noyori group in 1998, where the asymmetric catalytic hydrogenation of acetophenone achieved 80% ee, 2,400,000 TON, and 63S. - 1 TOF (Angew. Chem. Int. Ed. 1998, 37, 1703.); another is the iridium-SpiroPAP tripentate ligand catalytic system reported by Zhou Qilin's group in 2011, in which the asymmetric catalytic hydrogenation of acetophenone can achieve 98% ee and 4,550,000 TON (Angew. Chem. Int. Ed. 2011, 50, 7329.).

[0009]

[0010] To enrich the asymmetric catalytic system of ketones while maintaining high efficiency and selectivity, and to address the challenges of ligand and catalyst synthesis, this invention discloses a method for forming highly stable metal complexes by complexing tetradentate ligands with metals using a simple and easily scalable process. These complexes exhibit high activity and selectivity in drug synthesis and industrial applications, demonstrating broad commercial potential. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to provide a method for preparing a metal complex catalyst that can efficiently and selectively perform asymmetric catalytic hydrogenation of ketones and can be successfully applied to drug synthesis and industrialization.

[0012] This invention provides a metal complex as shown in Formula 1 or 2:

[0013]

[0014] Wherein, the * mark position represents the chiral center;

[0015] The metal complexes represented by Formula 1 or 2 are monoisomers, racemates, enantiomers in any proportion, or diastereomers in any proportion.

[0016] In the metal complexes shown in Formula 1 or 2, R1 and R2 are independently alkyl and aryl, respectively; R3 and R4 are independently alkyl, aryl, or hydrogen atoms; R5 and R6 are independently alkyl, aryl, or oxygen atoms, respectively, and R5 and R6 may be cyclic or non-cyclic.

[0017] M1 represents a transition metal selected from ruthenium (Ru), rhodium (Rh), iridium (Ir), palladium (Pd), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), and manganese (Mn).

[0018] M2 represents an alkali metal, selected from lithium (Li), sodium (Na), potassium (K), and cesium (Cs);

[0019] X represents OH, OR7, NH2, NHPG; Y represents O or NPG; where R7 represents C1-C6 aliphatic alkanes, and PG represents a nitrogen protecting group selected from p-toluenesulfonyl (Ts), trifluoromethanesulfonyl (Tf), and nitrobenzenesulfonyl (Ns).

[0020] This invention discloses a method for preparing metal complexes as shown in Formula 1 and Formula 2, comprising the following steps:

[0021] Under anhydrous and oxygen-free conditions, the ligand compound and the metal precursor are thoroughly and uniformly complexed in a suitable solvent. The mixture is then stirred at room temperature for 2 hours under a hydrogen atmosphere. After careful release of hydrogen, the mixture is concentrated under reduced pressure to obtain a yellow solid, which is the metal complex catalyst of formula 1.

[0022]

[0023] Under anhydrous and oxygen-free conditions, the ligand compound and the metal precursor are thoroughly and uniformly complexed in a suitable solvent, and a certain amount of alkali is added. The mixture is then stirred at room temperature for 2 hours under a hydrogen atmosphere. After carefully releasing the hydrogen, the mixture is concentrated under reduced pressure to obtain a yellow solid, which is the metal complex catalyst of formula 2.

[0024]

[0025] As a preferred embodiment of the present invention, the ligand of formula 3 in the metal complex as shown in formula 1 or 2 is represented as follows:

[0026]

[0027] Wherein, the * mark position represents the chiral center;

[0028] In the ligands described in Formula 3, R1 and R2 are independently alkyl and aryl, respectively; R3 and R4 are independently alkyl, aryl, or hydrogen atoms; R5 and R6 are independently alkyl, aryl, or oxygen atoms, respectively, and R5 and R6 may be cyclic or non-cyclic.

[0029] X represents OH, OR7, NH2, NHPG; Y represents O or NPG; where R7 represents C1-C6 aliphatic alkanes, and PG represents a nitrogen protecting group selected from p-toluenesulfonyl (Ts), trifluoromethanesulfonyl (Tf), and nitrobenzenesulfonyl (Ns).

[0030] Preferably, the ligand of formula 3 in the preparation of the metal complex of formula 1 or formula 2 is selected from the following structures:

[0031]

[0032] or any enantiomer thereof; preferably L3 or any enantiomer thereof.

[0033] In this invention, the transition metal M1 in the metal complex of formula 1 or 2 is represented as a transition metal selected from ruthenium (Ru), rhodium (Rh), iridium (Ir), palladium (Pd), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), and manganese (Mn).

[0034] Suitable metal precursors for this invention are selected from [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); sphine); Ru(ArH)Cl2; Ru(COD)(methallyl)2; (Ni(allyl)X)2; Ni(acac)2; Ni(COD)2; NiX2; MnX2; Mn(acac)2; CoX2; FeX2; CuX; CuX2; [Pd(allyl)Cl]2; PdCl2;

[0035] In the above transition metal precursors, R represents alkyl, alkoxy, or substituted alkyl, aryl represents aryl, and X represents an anion, such as Cl. - , Br - I - BF4 - ClO4 - SbF6 - PF6 - TfO - RCOO - B(Ar)4 - Ar can be 3,5-difluoromethylbenzene or fluorobenzene. L is a solvent molecule, such as CH3CN or DMF.

[0036] The base used in Formula 2 for preparing the metal complex catalyst is selected from one or a mixture of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate in any proportion.

[0037] As a preferred embodiment of the present invention, the transition metal is selected from iridium (Ir), and the preferred structure of the metal complex is represented by formula 1a or formula 2a:

[0038]

[0039] In the metal-iridium complexes shown in Formula 1a or Formula 2a, M2 represents an alkali metal selected from lithium (Li), sodium (Na), potassium (K), and cesium (Cs).

[0040] As a preferred embodiment of the present invention, when M2 represents sodium, its advantageous structure is shown in the following formula 2a-1:

[0041]

[0042] This metal complex increases the stability of the iridium complex by introducing an anion donor to coordinate with the iridium metal center, and also greatly enhances the acidity of the iridium hydrogen, thereby improving the reactivity and selectivity of the iridium metal complex catalyst. Similar to sodium borohydride compared to borane, the acidity is greatly enhanced through the interaction of the negative hydrogen atom with the boron atom.

[0043]

[0044] In this invention, using a metal complex of formula 1a as a catalyst precursor and sodium tert-butoxide as a base in isopropanol solvent, an active metal complex catalyst of formula 2a-1 is produced for the asymmetric hydrogenation of acetophenone. This process exhibits excellent high activity and selectivity, achieving a result of 99% ee and 13,425,000 TON. This TON value is the highest reported in current literature and patents, and it is also the first artificially synthesized catalyst to reach the tens of millions of TON level.

[0045] Furthermore, this metal complex catalyst achieves a TOF (turnover frequency) of 253 s⁻¹ in the asymmetric catalytic hydrogenation of acetophenone. -1 It can rival the TOF catalysis of biological enzymes, while the limiting TON of the in-situ complexed catalyst in the asymmetric catalytic hydrogenation of acetophenone is 1,000,000 (Green Synthesis and Catalysis 2022, 3, 175-178).

[0046]

[0047] The metal complex catalysts of formula 1a or 2a-1 disclosed in this invention can be used for the synthesis of drug intermediates such as duloxetine, atomoxetine, phenformin, rivastigmine, montelukast sodium, ezetimibe, and nicotine. The reaction formulas are as follows:

[0048]

[0049] Asymmetric catalytic hydrogenation of reaction I to prepare duloxetine

[0050]

[0051] Asymmetric catalytic hydrogenation of reaction II to prepare atomoxetine

[0052]

[0053] Asymmetric catalytic hydrogenation of reaction III to prepare benzyl benzoate

[0054]

[0055] Reactive IV asymmetric catalytic hydrogenation for the preparation of rivastigmine

[0056]

[0057] Reactive V-asymmetric catalytic hydrogenation for the preparation of montelukast

[0058] Reactive VI asymmetric catalytic hydrogenation to prepare ezetimibe

[0059]

[0060] Asymmetric catalytic hydrogenation of nicotine using reaction VII

[0061] The present invention has the following advantages over the prior art:

[0062] (1) This invention provides a method for preparing a metal complex catalyst, which is simple to operate and easy to carry and store;

[0063] (2) The metal complex catalyst disclosed in this invention exhibits excellent high activity and high selectivity in the asymmetric catalytic hydrogenation reaction of acetophenone, achieving a result of 99% ee, 13,425,000 TON (TON: turnover number), and 253S. -1 TOF (turnover frequency); this is the highest TON reported in current literature and patents, and also the first artificially synthesized catalyst to reach tens of millions of TON; the catalyst's TOF reaches 253 s. -1 It is comparable to time-of-flight (TOF) catalyzed by biological enzymes;

[0064] (3) The metal complex catalyst disclosed in this invention can be applied to the synthesis of drug intermediates such as duloxetine, atomoxetine, phenylephrine, rivastigmine, montelukast sodium, ezetimibe, and nicotine. The process exhibits advantages such as stable operation, low cost, and environmental friendliness, and has extremely high industrialization value. Detailed Implementation

[0065] The following further discloses some non-limiting examples and figures to further illustrate the present invention, but the present invention is not limited thereto. Experimental methods in the embodiments that do not specify specific conditions are generally performed under conventional conditions and conditions described in the manual, or according to the manufacturer's recommendations; the materials, reagents, etc. used, unless otherwise specified, are commercially available.

[0066] Example 1: Preparation of metal complex catalyst precursor of formula 1a

[0067]

[0068] Under nitrogen protection, in a 50 mL high-pressure hydrogenation reactor, 1.15 g of ligand L3 and 0.67 g of metal precursor [Ir(COD)Cl]2 were dissolved in 30 mL of isopropanol and fully complexed at 25-30 °C for 2 hours. Then, 20 atm of hydrogen was introduced and stirred at 25-30 °C for 2 hours. After carefully releasing the hydrogen, the mixture was concentrated under reduced pressure to obtain a yellow solid, which is the metal complex catalyst of formula 1a.

[0069] Example 2: Preparation of metal complex catalyst of formula 2a-1

[0070]

[0071] Under nitrogen protection, in a 50 mL high-pressure hydrogenation reactor, 240 mg of ligand L3 and 134 mg of metal precursor [Ir(COD)Cl]2 were dissolved in 10 mL of isopropanol and fully complexed at 25-30 °C for 2 hours. Then, 20 atm of hydrogen was introduced and stirred at 25-30 °C for 2 hours. After carefully releasing the hydrogen, the mixture was concentrated under reduced pressure to obtain a yellow solid, which is the metal complex catalyst of formula 2a-1.

[0072] Example 3: Asymmetric catalytic hydrogenation of acetophenone (S / C = 2,000,000)

[0073] Under nitrogen protection, 3.2 mg (0.004 mmol) of pre-prepared catalyst formula 1a was weighed and added to a 20 mL vial. 10 mL of anhydrous isopropanol was added, and the mixture was stirred at room temperature for half an hour to obtain a catalyst solution. 80 mmol of acetophenone and 0.1 mmol of sodium tert-butoxide were added to a 30 mL hydrogenation vial, followed by 2 mL of isopropanol. The mixture was stirred until homogeneous. 100 μL of the prepared catalyst solution was then drawn using a microsyringe and placed in the hydrogenation vessel. The vessel was sealed, purged with hydrogen three times, and then purged with hydrogen to 80 bar. The reaction was carried out at room temperature for 16 hours. After the reaction was completed, samples were taken to monitor the conversion rate and ee value, which were >99% conv. and >99% ee, respectively. The results are shown in Table 1 (entry 1). Subsequently, under the same operation as in entry 1, the metal complex catalyst 1a was changed to 2a-1. In comparison, the ee value remained unchanged, but its conversion rate decreased to 92%. The presumed reason is that the metal complex 2a-1 is a real active catalyst with active properties, which may deteriorate during the transfer process. On the other hand, the metal complex 1a, as a catalyst precursor, can generate catalyst 2a-1 in situ in the reaction solution, avoiding the premature deactivation caused by using the catalyst directly. This makes the catalytic properties relatively more stable, thereby ensuring that the reaction can proceed smoothly and is more conducive to operation.

[0074] Furthermore, using metal complex formula 1a as a catalyst precursor, the results obtained by changing other conditions such as catalyst dosage, substrate dosage, reaction time, and pressure are shown in Table 1. The data show that metal complex formula 1a as a catalyst precursor forms catalyst formula 2a-1 in situ, and its TON can reach as high as 13,425,000 in the asymmetric catalytic hydrogenation of acetophenone.

[0075] Table 1

[0076]

[0077]

[0078] [a]Reaction conditions: acetophenone (80mmol) in 2.0mL iPrOH and 0.125mol% NaOtBu (0.1mmol) at RT under 80bar H2. H2.[c]acetophenone(800mmol)in 20.0mL iPrOH and 0.125mol%NaOtBu(1mmol)at RT under80bar H2.[d]acetophenone(80mmol)in 2.0mL iPrOH and 0.125mol%NaOtBu(0.1mmol)at RT under 100bar H2.[e]acetophenone(800mmol)in 20.0mL iPrOH and 0.125mol% NaOtBu (1mmol) at RT under 100bar H2.Conversion was determined by 1H NMRanalysis, ee was determined by HPLC with a chiral stationary phase.

[0079] Example 4: Experiment on the control factors of ligand OH / NH in the asymmetric catalytic hydrogenation of acetophenone

[0080] Modification via ligand L3(f-phamidol) yielded the following ligands: L3a(f-phamidol-N-Me), L3b(f-phamidol-OMe), and L3c(f-phamidol-Nacl-Me). Following the procedure in Example 1, L3a-L3c were prepared into corresponding metal complex catalysts, and asymmetric catalytic hydrogenation of acetophenone was performed according to the procedure in Example 3, yielding the following results: 1) L3a(f-phamidol-N-Me): 95% ee, 10,000 TON; 2) L3b(f-phamidol-OMe): 76% ee, 10,000 TON; 3) L3c(f-phamidol-Nacl-Me): 35% ee, 7,000 TON. Controlled experimental results indicate that the influence of OH / NH at different positions on the metal complex varies significantly.

[0081]

[0082] Example 5: Preparation of duloxetine intermediate compound 5 (kg, S / C = 200,000)

[0083]

[0084] Under an argon atmosphere, 1.5 g of intermediate 4 and 5 L of isopropanol were added to a 10 L hydrogenation reactor, along with 46 g of potassium tert-butoxide. After thorough mixing, 33 mg of the enantiomer of the metal complex catalyst precursor prepared according to Example 1, ent-1a, was added. The reactor was sealed, purged with nitrogen three times, and hydrogen was introduced at 40 atm. The internal temperature was maintained at 25-30 °C until hydrogen evolution ceased (48 h). HPLC analysis showed a conversion rate >99.5% and an ee value >99%. The solvent was concentrated, washed with water, and extracted with ethyl acetate. After concentration, duloxetine intermediate 5 was obtained in 1.49 kg, with a yield of 99%. 1 H NMR (400MHz, CDCl3): δ7.23 (dd, J=5.2Hz, 0.8Hz, 1H), 6.99-6.92 (m, 1H), 6.93 (d, J=3.6Hz, 1H), 5.22 (dd,J=7.2Hz,4.0Hz,1H),2.72-2.65(m,1H),2.59-2.54(m,1H),2.30(s,6H),1.99-1.91(m,2H)ppm.

[0085] Example 6: Preparation of atomoxetine intermediate compound 7 (100g scale, S / C = 500,000)

[0086]

[0087] Under an argon atmosphere, 500 g of intermediate 6 and 3 L of isopropanol were added to a 10 L hydrogenation reactor, along with 8.5 g of potassium methoxide. After thorough mixing, 3.9 mg of the metal complex catalyst precursor 1a prepared according to Example 1 was added. The reactor was sealed, purged with nitrogen three times, and hydrogen was introduced at 80 atm. The internal temperature was maintained at 25-30 °C until hydrogen evolution ceased (48 h). HPLC analysis showed a conversion rate >99.5% and an ee value >99%. The solvent was concentrated, washed with water, and extracted with ethyl acetate. After concentration, 7,485 g of atomoxetine intermediate was obtained, with a yield of 97%. 1 H NMR (400MHz, CDCl3): δ7.35–7.21(m,5H),5.07(br s,1H),4.75(t,1H,J=7.30Hz),4.10(s,3H),3.65–3.44(m,1H),3.27–3.17(m,1H),1.91–1.81(m,2H)ppm.

[0088] Example 7: Preparation of phenylphosphine intermediate compound 9 (ten kilograms, S / C = 200,000)

[0089]

[0090] Under an argon atmosphere, 10.2 kg of intermediate 8 and 50 L of isopropanol were added to a 100 L hydrogenation reactor, followed by 8.0 kg of sodium tert-butoxide. After thorough mixing, 137 mg of the enantiomer of the metal complex catalyst precursor prepared according to Example 1 (ent-1a) was added. The reactor was sealed, purged with nitrogen three times, and hydrogen was introduced at 80 atm. The internal temperature was maintained at 40-50 °C until hydrogen evolution ceased (48 h). HPLC analysis showed a conversion rate >99.5% and an ee value >99%. The reaction solvent was concentrated, extracted with ethyl acetate, washed with water, and dried to obtain 9.7 kg of phenylphosphine intermediate 9, with a yield of 95%. 1 H NMR (400MHz, CDCl3): δ7.39-7.27(m,5H),7.15(t,J=7.6Hz,1H),6.89(s,1H),6.83(d,J=8.0Hz,1H),6.72(dd,J=8.0Hz,2.0 Hz,1H),4.73(dd,J=6.0Hz,4.0Hz,1H),3.75(d,J=13.6Hz,1H),3.55(d,J=12.8Hz,1H),2.63-2.51(m,3H),2.34(s,3H)ppm.

[0091] Example 8: Preparation of rivastigmine intermediate compound 11 (kg, S / C = 200,000)

[0092]

[0093] Under an argon atmosphere, 1.0 kg of intermediate 10 and 4 L of isopropanol were added to a 10 L hydrogenation reactor, along with 0.78 kg of sodium tert-butoxide. After thorough mixing, the enantiomer of the metal complex catalyst precursor, ent-1a (29.4 mg), prepared according to Example 1, was added. The reactor was sealed, purged with nitrogen three times, and hydrogen was introduced at 80 atm. The internal temperature was maintained at 40-50 °C until hydrogen evolution ceased (48 h). HPLC analysis showed a conversion rate >99.5% and an ee value >99%. The reaction solvent was concentrated, extracted with ethyl acetate, washed with water, and dried to obtain 0.96 kg of rivastigmine intermediate 11, with a yield of 96%. 1H NMR (400MHz, CDCl3): δ8.14(s,1H),7.12(t,J=7.6Hz,1H),6.90(s,1H),6.81(d,J=7.6Hz,1H),6. 66(dd,J=8.4Hz,2.4Hz,1H),4.80-4.72(m,1H),4.08(d,J=3.2Hz,1H),1.35(d,J=6.0Hz,3H)ppm.

[0094] Example 9: Preparation of Montelukast intermediate compound 13 (kilograms, S / C = 100,000)

[0095]

[0096] Under an argon atmosphere, 1.2 kg of intermediate 12 and 6 L of isopropanol were added to a 10 L hydrogenation reactor, along with 13 g of sodium tert-butoxide. After thorough mixing, 21 mg of the enantiomer of the metal complex catalyst precursor prepared according to Example 1, ent-1a, was added. The reactor was sealed, purged with nitrogen three times, and hydrogen was introduced at 60 atm. The internal temperature was maintained at 40 °C until hydrogen evolution ceased (48 h). HPLC analysis showed a conversion rate >99.5% and an ee value >99%. The solvent was concentrated, washed with water, and extracted with ethyl acetate. After concentration, 1.16 kg of montelukast intermediate 13 was obtained, with a yield of 98%. 1 H NMR (400MHz, CDCl3) δ = 8.10 (d, J = 8.2Hz, 1H), 8.07 (d, J = 1.6Hz, 1H), 7.71-7.58 (m ,4H),7.38-7.19(m,8H),7.14(td,J=7.4,2.0Hz,1H),4.75-4.71(m,1H),3.33(br s,1H),3.30-3.18(m,2H),3.18-3.11(m,1H),2.54(br s,1H),2.21-2.05(m,2H),1.71(s,3H),1.66(s,3H)ppm.

[0097] Example 10: Preparation of ezetimibe intermediate compound 15c (100g, S / C = 50,000)

[0098]

[0099] Under an argon atmosphere, 150 g of intermediate 14c and 500 mL of isopropanol were added to a 1 L hydrogenation reactor, along with 1.7 g of potassium tert-butoxide. After thorough mixing, 4.8 mg of the enantiomer of the metal complex catalyst precursor prepared according to Example 1, ent-1a, was added. The reactor was sealed, purged with nitrogen three times, and hydrogen was introduced at 80 atm. The internal temperature was maintained at 25-30 °C until hydrogen evolution ceased (48 h). HPLC analysis showed a conversion rate >99.5% and an ee value >99%. The solvent was concentrated, washed with water, and extracted with ethyl acetate. After concentration, 141 g of nicotine hydrogenation intermediate 15c was obtained, with a yield of 94%. 1 HNMR (400MHz, CDCl3): δ7.45-7.20(m,11H),7.05-6.92(m,6H),5.04(s,2H),4.70(br s,1H),4.58(d,J=2.1Hz,1H),3.11-3.03(m,1H),2.33(d,J=3.6Hz,1H),2.03-1.88(m,4H)ppm.

[0100] Example 11 Preparation of nicotine intermediate compound 17 (100g scale, S / C = 1,000,000)

[0101]

[0102] Under an argon atmosphere, 210 g of intermediate 16 and 500 mL of isopropanol were added to a 1 L hydrogenation reactor, along with 2.8 g of potassium methoxide. After thorough mixing, 6.4 mg of the metal complex catalyst precursor 1a prepared according to Example 1 was dissolved in 10 mL to prepare a catalyst solution. 1.0 mL of this solution was then added to the above reaction solution. The reactor was sealed, purged with nitrogen three times, and hydrogen was introduced at 80 atm. The internal temperature was maintained at 25-30 °C until hydrogen evolution ceased (48 h). HPLC analysis showed a conversion rate >99.5% and an ee value >99%. The solvent was concentrated, extracted with ethyl acetate, washed with water, and concentrated to obtain 206 g of nicotine hydrogenation intermediate 17, with a yield of 98%. 1 H NMR (600MHz, CDCl3) δ8.22(s,1H),8.14(d,J=4.4Hz,1H),7.53(d,J=7.7Hz,1H),7.06–7.04(m,1H),5.61(br,1H),5.24(br,1H), 4.53–4.51(m,1H),2.93–2.90(m,2H),1.60–1.56(m,1H),1.54–1.49(m,1H),1.45–1.38(m,1H),1.34–1.32(m,1H),1.22(s,9H).

[0103] Example 12: Industrial production of nicotine intermediate compound 19 (500 kg, S / C = 100,000)

[0104]

[0105] Under an argon atmosphere, 500 kg of intermediate 18 and 1000 L of isopropanol were added to a 2000 L hydrogenation reactor, along with 10 kg of potassium tert-butoxide. After thorough mixing, 14 g of the metal complex catalyst precursor 1a prepared according to Example 1 was added. The reactor was sealed, purged with nitrogen three times, and hydrogen was introduced at 60 atm. The internal temperature was maintained at 30-40 °C until hydrogen evolution ceased. HPLC analysis showed a conversion rate >99.5% and an ee value >99%. The concentrate yielded nicotine hydrogenation intermediate 19, which was directly used for the next conversion step without further purification. 1 HNMR (400MHz, CDCl3): δ9.27-9.08(m,1H),8.84-8.72(m,1H),8.30-8.16(m,1H),7.50-7.38(m, 1H),3.36(t,J=6.8Hz,2H),3.03(t,J=7.0Hz,2H),2.88(s,3H),2.07-1.92(m,2H),1.42(s,9H).

[0106] 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 changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A metal complex, characterized in that: The metal complex is selected from formula 1a or formula 2a: ； ； In the iridium complex shown in Formula 2a, M2 represents an alkali metal selected from lithium, sodium, potassium or cesium.

2. The metal complex according to claim 1, characterized in that, The metal complex is of formula 2a-1: 。 3. A method for preparing the metal complex as described in claim 1, characterized in that, Includes the following steps: Under anhydrous and oxygen-free conditions, in a suitable solvent, ligand compound 3 and metal precursor [M1] were thoroughly and uniformly complexed. The mixture was then stirred at room temperature for 2 h under a hydrogen atmosphere. After careful release of hydrogen, the mixture was concentrated under reduced pressure to obtain a yellow solid, which is the metal complex catalyst of formula 1. ； or, Under anhydrous and oxygen-free conditions, in a suitable solvent, ligand compound 3 and metal precursor [M1] were thoroughly and uniformly complexed, and a certain amount of alkali was added. The mixture was then stirred at room temperature for 2 h under a hydrogen atmosphere. After carefully releasing the hydrogen, the mixture was concentrated under reduced pressure to obtain a yellow solid, which is the metal complex catalyst of formula 2. ； Metal complex catalyst of formula 1 is ; Metal complex catalyst formula 2 is In the iridium complex shown in Formula 2a, M2 represents an alkali metal selected from lithium, sodium, potassium, or cesium. The ligand compound 3 is selected from the following structures: , or any of its enantiomers; The metal precursor [M1] in the metal complexes prepared by formula 1 or 2 is selected from [Ir(NBD)Cl]2; [Ir(NBD)2]X'; [Ir(COD)Cl]2; [Ir(COD)2]X'; X' is a negative anion, selected from Cl... - ,Br - I - BF4 - ClO4 - SbF6 - PF6 - TfO - Or B(Ar)4 - .

4. The method according to claim 3, characterized in that: The base used in Formula 2 for preparing the metal complex catalyst is selected from one or a mixture of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate in any proportion.

5. The use of the metal complex according to any one of claims 1 and 2 or the metal complex prepared by the method according to any one of claims 3 and 4 in synthesis, characterized in that, It is used in the synthesis of drug intermediates for duloxetine, montelukast sodium, phenformin, rivastigmine, atomoxetine, nicotine, and ezetimibe.

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