A process for the preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline

Abstract

This invention belongs to the field of active pharmaceutical ingredient intermediates, specifically disclosing a method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. The method includes: placing a solution containing 1-phenyl-3,4-dihydroisoquinoline and a chiral ferrocene bisphosphine-thiourea ligand / iridium precursor in a reaction vessel under inert gas protection; replacing the inert gas in the vessel with H2; and reacting for 10-40 hours at H2 concentrations of 1-100 atm and temperatures of 0-60°C to obtain (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. This method requires no additional acid or base additives, and the reaction temperature is below 60°C. Product purification is simple, and the yield reaches over 90%. Importantly, the ee value of the product obtained using this method can reach 99%. Therefore, this invention has advantages such as mild reaction conditions, high yield, and good stereoselectivity, and can be applied to new process routes for the synthesis of sofosmin.

Description

Technical Field

[0001] This invention belongs to the field of active pharmaceutical ingredient intermediates, specifically relating to a method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, which can be used as a raw material for preparing sofinacin. Background Technology

[0002] Solifenacin, developed by Astellas Pharma Inc. of Japan, is a selective muscarinic M3 receptor antagonist primarily used to treat overactive bladder symptoms such as urinary urgency and frequency. The chemical name of solifenacin is (3R)-1-azabicyclo[2,2,2]octane-3-yl(1S)-1-phenyl-1,4-dihydroisoquinoline-2-(1H)-carboxylic acid ester, and its structural formula is shown below. It contains two chiral centers, one located in the isoquinoline (I) structural unit and the other in the quininecyclool (III) structural unit. Therefore, the synthesis of solifenacin is usually based on (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline as shown in formula (I) and quininecyclool as shown in formula (III).

[0003]

[0004] It is evident that (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline is a key intermediate in the preparation of sofosina. Currently, the main methods for preparing this intermediate are as follows:

[0005] (1) Chiral resolution method: Chinese patent CN108329309A, entitled "Synthesis Process of Solifenacin Succinate API", discloses the preparation of racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline by reduction with sodium borohydride, followed by chiral resolution to obtain optically pure I. This is a commonly used method for preparing chiral drugs, but the resolution process is cumbersome and the product has poor optical purity, requiring multiple purifications.

[0006] (2) Asymmetric catalytic synthesis: Generally, it is prepared by asymmetric hydrogenation of imine catalyzed by noble metals. For example, in 2011, Zhang Xumu's research group reported the asymmetric hydrogenation of 1-phenyl-3,4-dihydroisoquinoline(II) catalyzed by Ir-(S,S)-(f)-Binaphane (Angew. Chem. Int. Ed. 2011, 50, 10679). When 10 mol% I2 was used as an additive, the ee value of the reaction was 95%.

[0007] Chinese Patent CN 107540606 A, entitled "A Method for Bidirectional Enantioselective Synthesis of Chiral Tetrahydroisoquinoline Catalyzed by Ir-(R)-BINAP", discloses the asymmetric hydrogenation of 1-phenyl-3,4-dihydroisoquinoline (II) catalyzed by Ir-(R)-BINAP. This method uses NBS as an additive, and by adjusting the amount of NBS, it is the first reported method for biantioselective synthesis of chiral tetrahydroisoquinoline. However, it can only obtain two enantiomers with enantioselectivity of 86% ee(S) and 92% ee(R).

[0008] Chinese patent CN110041255 A, entitled "A Method for Preparing a Solifenac Intermediate," discloses a method using Ir / (R... c ,S Fc ,S ax Using 1-Josiphos-Type Binaphane as a catalyst and 40% hydrobromic acid as an additive, an asymmetric hydrogenation reaction of 1-phenyl-3,4-dihydroisoquinoline(II) was carried out at a hydrogen pressure of 50 atm. Although high conversion (>99%) and high enantioselectivity (99% ee) were achieved, the use of hydrobromic acid increased the difficulty of post-processing.

[0009] Asymmetric catalytic synthesis is becoming an important method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. However, current methods still suffer from problems such as low catalyst activity, high reaction pressure, the need for additives, and poor stereoselectivity. Therefore, developing an asymmetric synthesis method for (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline with mild reaction conditions (such as lower hydrogen pressure), no need for any additives, high yield, and high stereoselectivity is of great significance. Summary of the Invention

[0010] To address the aforementioned problems, this invention provides a method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, using 1-phenyl-3,4-dihydroisoquinoline as a raw material, in formulas (L1) to (L... 10 Using the chiral ferrocene bisphosphine-thiourea ligand / iridium precursor as a catalyst, (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline can be asymmetrically hydrogenated to obtain (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, which can be used as a starting material for the synthesis of sofinacin. This preparation method has advantages such as mild reaction conditions, high yield, and good stereoselectivity. Among them, (L1)~(L 10 The chiral ferrocene bisphosphine-thiourea ligand shown can be prepared according to the method disclosed in Chinese Patent CN 115536708A, entitled "A chiral bisphosphine ligand with a ferrocene framework and its preparation method".

[0011] The technical solution of the present invention is as follows:

[0012] This invention provides a method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, the reaction formula of which is shown below, including the following steps:

[0013]

[0014] (1) Under the protection of an inert gas, a mixture of 1-phenyl-3,4-dihydroisoquinoline as shown in formula (II) and formulas (L1) to (L) is prepared. 10 The chiral ferrocene bisphosphine-thiourea ligand / metallic iridium precursor solution shown in the figure is placed in a reaction vessel. First, the inert gas in the reaction vessel is replaced with H2 to completely remove the inert gas from the reaction vessel and fill the reaction vessel with H2.

[0015] (2) The reaction was stirred for 10 to 40 h at H2 of 1 to 100 atm and at 0 to 60 °C to obtain (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline as shown in formula (I).

[0016]

[0017] In one embodiment of the present invention, the preferred metallic iridium precursor is one or more of [Ir(COD)Cl]2, [Ir(NBD)Cl]2, [Ir(NBD)2]X, or [Ir(COD)2]X, wherein X is BF4. - ClO4 - SbF6 - PF6 - CF3SO3 - or B(Ar)4 - More preferably, the metallic iridium precursor is [Ir(COD)Cl]2.

[0018] In one embodiment of the present invention, it is preferable to further include, before the reaction, preparing the chiral ferrocene bisphosphine-thiourea ligand / iron metal precursor solution, comprising the following steps: under inert gas protection, reacting the solutions of formulas (L1) to (L... 10 The chiral ferrocene bisphosphine-thiourea ligand and the aforementioned metallic iridium precursor were added to dichloromethane and reacted with stirring at 20–30 °C for 0.5–2 h to obtain the product.

[0019] In one embodiment of the present invention, preferably, formulas (L1) to (L) are used. 10 The molar ratio of the chiral ferrocene bisphosphine-thiourea ligand to the iridium metal precursor shown is 1.1:0.5-1.

[0020] In one embodiment of the present invention, preferably, in step (1), 1-phenyl-3,4-dihydroisoquinoline of formula (II) reacts with formulas (L1) to (L2).10 The molar ratio of the chiral ferrocene bisphosphine-thiourea ligands shown is 1:0.0001 to 0.01.

[0021] In one embodiment of the present invention, preferably, in step (1), 1-phenyl-3,4-dihydroisoquinoline of formula (II) reacts with formulas (L1) to (L2). 10 The reaction solvent used in the chiral ferrocene bisphosphine-thiourea ligand / iridium precursor solution reaction shown is one or more of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, isopropanol or toluene; more preferably, the reaction solvent used is dichloromethane or toluene.

[0022] In one embodiment of the present invention, preferably, in step (2), the reaction temperature is set to 25-40°C, and the reaction time can be further shortened to 25-35h as the reaction temperature increases.

[0023] In one embodiment of the present invention, preferably, in step (2), the reaction vessel is a high-pressure vessel, and the asymmetric hydrogenation reaction of 1-phenyl-3,4-dihydroisoquinoline can be completed with H2 at 1 atm.

[0024] In one embodiment of the present invention, preferably, the inert gas in steps (1) and (2) can be nitrogen or the like.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] The present invention provides a method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, using 1-phenyl-3,4-dihydroisoquinoline as a raw material, in formulas (L1) to (L... 10 (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline can be asymmetrically hydrogenated under the catalysis of the chiral ferrocene bisphosphine-thiourea ligand / iridium precursor shown in the figure. This method requires no additional acid or base additives, the reaction temperature is below 60°C, product purification is simple, and the yield exceeds 90%. Most importantly, the ee value of the product obtained using this method can reach 99%. Therefore, the method of this invention has the advantages of mild reaction conditions, high yield, and good stereoselectivity, and can be applied to a new process route for the synthesis of sofosmin. Attached Figure Description

[0027] Figure 1 The (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I) of Example 3 of this invention 1 H NMR spectrum;

[0028] Figure 2 The (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I) of Example 3 of this invention 13C NMR spectrum;

[0029] Figure 3 The HPLC spectrum of the racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline of Example 3 of the present invention is shown below.

[0030] Figure 4 The HPLC spectrum of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (Ⅰ) in Example 3 of this invention is shown. Detailed Implementation

[0031] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

[0032] Numerous specific details are set forth in the following description to provide a full understanding of the invention. However, the invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0033] Example 1: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0034] (1) Under a nitrogen atmosphere, ligand L1 (16.3 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution, namely a chiral ferrocene bisphosphine-thiourea ligand / metal iridium precursor solution;

[0035] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added to an autoclave according to formula (II). The gas in the autoclave was replaced with hydrogen three times, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25 °C for 30 hours. The reaction solution was then filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove dichloromethane, thus obtaining 196.1 mg of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline product (I), which was white, with a melting point of 80-82 °C; the yield was 94%, and the ee value was 97.2% as determined by HPLC.

[0036] Example 2: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0037] (1) Under a nitrogen atmosphere, ligand L2 (19.1 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution, namely a chiral ferrocene bisphosphine-thiourea ligand / metallic iridium precursor solution.

[0038] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added sequentially to an autoclave. The gas in the autoclave was replaced with hydrogen three times, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25 °C for 30 hours. The catalyst was removed by silica gel filtration, and the filtrate was concentrated under reduced pressure to remove dichloromethane, yielding 190.3 mg of white solid (I), melting point: 80-82 °C; yield: 91%, ee value: 97.6%.

[0039] Example 3: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0040] (1) Under a nitrogen atmosphere, ligand L3 (17.1 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution, namely a chiral ferrocene bisphosphine-thiourea ligand / metallic iridium precursor solution;

[0041] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added sequentially to a high-pressure reactor. The gas in the high-pressure reactor was replaced three times with hydrogen, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25°C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove dichloromethane, yielding 196.8 mg of white solid (I), melting point: 80-82°C; yield 94%, ee value 99.4%. Figures 3-4 As shown. 1 H NMR (400MHz, CDCl3) δ7.35–7.25(m,5H),7.16–7.12(m,2H),7.06–7.02(m,1H),6.76(d ,J=8.0Hz,1H),5.11(s,1H),3.31–3.24(m,1H),3.13–3.01(m,2H),2.88–2.81(m,1H), such as Figure 1 As shown; 13C NMR (100MHz, CDCl3) δ 144.8, 138.2, 135.5, 129.1, 129.0, 128.5, 128.1, 127.4, 126.3, 125.7, 62.1, 42.3, 29.8. (e.g.) Figure 2 As shown.

[0042] Example 4: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0043] (1) Under a nitrogen atmosphere, ligand L4 (17.4 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution, namely a chiral ferrocene bisphosphine-thiourea ligand / metallic iridium precursor solution;

[0044] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced with hydrogen three times, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25°C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove dichloromethane, yielding 188.3 mg of white solid (I), melting point: 80-82°C; yield: 90%, ee value: 93.4%.

[0045] Example 5: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0046] (1) Under a nitrogen atmosphere, ligand L5 (16.8 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution, namely a chiral ferrocene bisphosphine-thiourea ligand / metallic iridium precursor solution;

[0047] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added sequentially to an autoclave. The gas in the autoclave was replaced three times with hydrogen, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25°C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove dichloromethane, yielding 194.4 mg of white solid (I), melting point: 80-82°C; yield 93%, ee value 92.3%.

[0048] Example 6: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0049] (1) Under a nitrogen atmosphere, ligand L6 (18.6 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution, namely a chiral ferrocene bisphosphine-thiourea ligand / metallic iridium precursor solution;

[0050] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced with hydrogen three times, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25°C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove dichloromethane, yielding 190.3 mg of white solid (I), melting point: 80-82°C; yield: 91%, ee value: 91.5%.

[0051] Example 7: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0052] (1) Under a nitrogen atmosphere, ligand L7 (18.8 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution, namely a chiral ferrocene bisphosphine-thiourea ligand / metallic iridium precursor solution;

[0053] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced three times with hydrogen, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25°C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove dichloromethane, yielding 190.6 mg of white solid (I), melting point: 80-82°C; yield 91%, ee value 94.4%.

[0054] Example 8: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0055] (1) Under a nitrogen atmosphere, ligand L8 (16.8 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution, namely a chiral ferrocene bisphosphine-thiourea ligand / metallic iridium precursor solution;

[0056] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced with hydrogen three times, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25°C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove dichloromethane, yielding 190.6 mg of white solid (I), melting point: 80-82°C; yield 91%, ee value 95.3%.

[0057] Example 9: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0058] (1) Under a nitrogen atmosphere, ligand L9 (19.5 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution, namely a chiral ferrocene bisphosphine-thiourea ligand / metallic iridium precursor solution;

[0059] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added sequentially to an autoclave. The gas in the autoclave was replaced three times with hydrogen, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25°C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove dichloromethane, yielding 192.4 mg of white solid (I), melting point: 80-82°C; yield 92%, ee value 99.1%.

[0060] Example 10: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0061] (1) Under a nitrogen atmosphere, ligand L 10(23.2 mg, 0.021 mmol), the metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) was dissolved in dichloromethane (1.0 mL), and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution, namely a chiral ferrocene bisphosphine-thiourea ligand / metallic iridium precursor solution.

[0062] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added sequentially to an autoclave. The gas in the autoclave was replaced three times with hydrogen, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25°C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove dichloromethane, yielding 193.1 mg of white solid (I), melting point: 80-82°C; yield 92%, ee value 99.0%.

[0063] Example 11: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0064] (1) Under a nitrogen atmosphere, ligand L3 (19.5 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution, namely a chiral ferrocene bisphosphine-thiourea ligand / metallic iridium precursor solution;

[0065] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced with hydrogen three times, and then H2 was introduced to 10.0 atm. The reaction was carried out at 25°C for 24 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove dichloromethane, yielding 194.5 mg of white solid (I), melting point: 80-82°C; yield 93%, ee value 99.3%.

[0066] Example 12: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0067] (1) Under a nitrogen atmosphere, ligand L3 (19.5 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution, namely a chiral ferrocene bisphosphine-thiourea ligand / metallic iridium precursor solution;

[0068] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), tetrahydrofuran (2.0 mL), and the iridium catalyst solution prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced with hydrogen three times, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25°C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove the solvent, yielding 193.1 mg of white solid (I), melting point: 80-82°C; yield: 93%, ee value: 90.7%.

[0069] Example 13: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0070] (1) Under a nitrogen atmosphere, ligand L3 (19.5 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution. The dichloromethane was removed by vacuum concentration to obtain solid iridium catalyst.

[0071] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), isopropanol (2.0 mL), and the iridium catalyst solid prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced with hydrogen three times, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25°C for 30 hours. After the reaction was completed, hydrogen was released. The reaction solution was concentrated under reduced pressure and dissolved in dichloromethane. The catalyst was removed by silica gel filtration. The filtrate was concentrated under reduced pressure to remove isopropanol, yielding 198.5 mg of white solid I, melting point: 80-82°C; yield 95%, ee value 93.8%.

[0072] Example 14: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0073] (1) Under a nitrogen atmosphere, ligand L3 (19.5 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution. The dichloromethane was removed by vacuum concentration to obtain solid iridium catalyst.

[0074] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), toluene (2.0 mL), and the iridium catalyst solid prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced with hydrogen three times, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25 °C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove toluene, yielding 194.7 mg of white solid (I), melting point: 80-82 °C; yield 93%, ee value 99.2%.

[0075] Example 15: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0076] (1) Under a nitrogen atmosphere, ligand L3 (19.5 mg, 0.021 mmol) and metal precursor [Ir(COD)Cl]2 (6.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution. The dichloromethane was removed by vacuum concentration to obtain solid iridium catalyst.

[0077] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), toluene (2.0 mL), and the iridium catalyst solid prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced three times with hydrogen, and then H2 was introduced to 1.0 atm. The reaction was carried out at 60 °C for 20 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove toluene, yielding 198.2 mg of white solid (I), melting point: 80-82 °C; yield 95%, ee value 97.8%.

[0078] Example 16: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0079] (1) Under a nitrogen atmosphere, ligand L3 (4.3 mg, 0.0053 mmol) and metal precursor [Ir(COD)Cl]2 (1.7 mg, 0.0025 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution. The dichloromethane was removed by vacuum concentration to obtain solid iridium catalyst.

[0080] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (518.0 mg, 2.5 mmol), toluene (2.5 mL), and the iridium catalyst solid prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced with hydrogen three times, and then H2 was introduced to 10.0 atm. The reaction was carried out at 25°C for 48 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove toluene, yielding 495.9 mg of white solid (I), melting point: 80-82°C; yield 95%, ee value 99.4%.

[0081] Example 17: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0082] (1) Under a nitrogen atmosphere, ligand L3 (9.0 mg, 0.011 mmol) and metal precursor [Ir(COD)2BF4] (4.9 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution. The dichloromethane was removed by vacuum concentration to obtain solid iridium catalyst.

[0083] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), toluene (2.0 mL), and the iridium catalyst solid prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced with hydrogen three times, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25 °C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove toluene, yielding 196.6 mg of white solid (I), melting point: 80-82 °C; yield 94%, ee value 99.4%.

[0084] Example 18: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0085] (1) Under a nitrogen atmosphere, ligand L3 (19.5 mg, 0.021 mmol) and metal precursor [Ir(NBD)Cl]2 (7.0 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution. The dichloromethane was removed by vacuum concentration to obtain solid iridium catalyst.

[0086] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), toluene (2.0 mL), and the iridium catalyst solid prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced three times with hydrogen, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25 °C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove toluene, yielding 192.3 mg of white solid (I), melting point: 80-82 °C; yield: 92%, ee value: 93.3%.

[0087] Example 19: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0088] (1) Under a nitrogen atmosphere, ligand L3 (9.0 mg, 0.011 mmol) and metal precursor [Ir(COD)2B(di-3,5-CF3-Ph)4] (12.7 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution. The dichloromethane was removed by vacuum concentration to obtain solid iridium catalyst.

[0089] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), toluene (2.0 mL), and the iridium catalyst solid prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced three times with hydrogen, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25 °C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove toluene, yielding 194.5 mg of white solid (I), melting point: 80-82 °C; yield: 93%, ee value: 94.6%.

[0090] Example 20: Preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I)

[0091] (1) Under a nitrogen atmosphere, ligand L3 (9.0 mg, 0.011 mmol) and metal precursor [Ir(NBD)2]BF4 (4.5 mg, 0.01 mmol) were dissolved in dichloromethane (1.0 mL) and stirred at 25 °C for 1 hour to obtain an orange iridium catalyst solution. The dichloromethane was removed by vacuum concentration to obtain solid iridium catalyst.

[0092] (2) Under a nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol), toluene (2.0 mL), and the iridium catalyst solid prepared in step (1) were added sequentially to an autoclave according to formula (II). The gas in the autoclave was replaced three times with hydrogen, and then H2 was introduced to 1.0 atm. The reaction was carried out at 25 °C for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was filtered through silica gel to remove the catalyst. The filtrate was concentrated under reduced pressure to remove toluene, yielding 194.8 mg of white solid (I), melting point: 80-82 °C; yield 93%, ee value 91.4%.

[0093] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. A kind (S) The method for preparing -1-phenyl-1,2,3,4-tetrahydroisoquinoline is characterized by, The reaction formula is shown below, including the following steps: (1) Under the protection of an inert gas, 1-phenyl-3,4-dihydroisoquinoline of formula (II) and formula (L1)~(L 10 The chiral ferrocene bisphosphine-thiourea ligand / iridium precursor solution shown is placed in a reaction vessel, and the inert gas in the reaction vessel is replaced with H2. The iridium precursor is one or more of [Ir(COD)Cl]2, [Ir(NBD)Cl]2, [Ir(NBD)2]X, or [Ir(COD)2]X, where X is BF4. ⁻ ClO4 ⁻ SbF6 ⁻ PF6 ⁻ CF3SO3 ⁻ or B(Ar)4 ⁻ ; (2) The reaction was stirred for 10 to 40 h at H2 concentrations of 1 to 100 atm and temperatures of 0 to 60 °C to obtain the product shown in formula (I). (S) -1-Phenylacetyl-1,2,3,4-Tetrahydroisoquinoline; 。 2. As described in claim 1 (S) The method for preparing -1-phenyl-1,2,3,4-tetrahydroisoquinoline is characterized by, The iridium precursor is [Ir(COD)Cl]2.

3. As described in claim 1 (S) The method for preparing -1-phenyl-1,2,3,4-tetrahydroisoquinoline is characterized by, The method also includes preparing the chiral ferrocene bisphosphine-thiourea ligand / iridium precursor solution, comprising the following steps: under inert gas protection, mixing formulas (L1) to (L... 10 The chiral ferrocene bisphosphine-thiourea ligand and the aforementioned metallic iridium precursor were added to dichloromethane and reacted with stirring at 20–30 °C for 0.5–2 h to obtain the product.

4. The method according to claim 3 (S) The method for preparing -1-phenyl-1,2,3,4-tetrahydroisoquinoline is characterized by, Equation (L1) ~ (L 10 The molar ratio of the chiral ferrocene bisphosphine-thiourea ligand to the iridium metal precursor shown is 1.1:0.5-1.

5. The method according to claim 1 (S) The method for preparing -1-phenyl-1,2,3,4-tetrahydroisoquinoline is characterized by, In step (1), the 1-phenyl-3,4-dihydroisoquinoline shown in formula (II) reacts with formula (L1) ~ (L 10 The molar ratio of the chiral ferrocene bisphosphine-thiourea ligands shown is 1:0.0001 to 0.

01.

6. The method according to claim 1 (S) The method for preparing -1-phenyl-1,2,3,4-tetrahydroisoquinoline is characterized by, In step (1), the 1-phenyl-3,4-dihydroisoquinoline shown in formula (II) reacts with formula (L1) ~ (L 10 The reaction solvent used in the chiral ferrocene bisphosphine-thiourea ligand / iridium precursor solution reaction shown is one or more of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, isopropanol, or toluene.

7. The method according to claim 6 (S) The method for preparing -1-phenyl-1,2,3,4-tetrahydroisoquinoline is characterized by, In step (1), the reaction solvent used is dichloromethane or toluene.

8. The method according to claim 1 (S) The method for preparing -1-phenyl-1,2,3,4-tetrahydroisoquinoline is characterized by, In step (2), the reaction temperature is 25-40 °C and the reaction time is 25-35 h.

9. The method according to claim 1 (S) The method for preparing -1-phenyl-1,2,3,4-tetrahydroisoquinoline is characterized by, In step (1), the reactor is a high-pressure reactor and the H2 concentration is 1 atm.

Images