Preparation method of (S)-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline

Abstract

The invention belongs to the technical field of bulk drug intermediates, and particularly discloses a preparation method of (S)-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline, which comprises the following steps: under the protection of inert gas, putting a solution mixed with 1-phenyl-3, 4-dihydroisoquinoline and chiral ferrocene diphosphine-thiourea ligand / metal iridium precursor into a reaction kettle, and replacing the inert gas in the kettle with H2; the preparation method comprises the following steps: taking (S)-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline as a raw material, reacting for 10-40 hours under the conditions that H2 is 1-100 atm and the temperature is 0-60 DEG C to obtain (S)-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline. According to the method, other acid-base substances do not need to be additionally added, the reaction temperature is lower than 60 DEG C, the product purification treatment is simple and convenient, the yield reaches 90% or above, and more importantly, the ee value of the product obtained by using the method can reach 99%. Therefore, the method has the advantages of mild reaction conditions, high yield, good stereoselectivity and the like, and can be applied to a process route for synthesizing solifenacin.

Description

Technical Field

[0001] The invention belongs to the technical field of raw material drug intermediates, and specifically relates to a method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. The (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline can be used as a raw material for preparing solifenacin drugs. Background Art

[0002] Solifenacin was developed by Astellas Pharmaceuticals of Japan. It is a selective muscarinic M3 receptor antagonist and is mainly used to treat overactive bladder with symptoms of urgency and frequency of urination. The chemical name of solifenacin is (3R)-1-azabicyclo[2,2,2]octan-3-yl(1S)-1-phenyl-1,4-dihydroisoquinoline-2-(1H)-carboxylate. Its structural formula is shown below. It contains two chiral centers, one of which is located in the isoquinoline (I) structural unit and the other is located in the quinuclidinol (III) structural unit. Therefore, the synthesis of solifenacin is usually prepared using (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline as shown in formula (I) and quinuclidinol as shown in formula (III) as raw materials.

[0003]

[0004] It can be seen that (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline is a key intermediate for preparing solifenacin. Currently, there are mainly the following methods for preparing this intermediate:

[0005] (1) Chiral resolution method: In Chinese patent CN108329309A, the invention name is a process for synthesizing the raw material of solifenacin succinate, which discloses the use of sodium borohydride reduction to prepare the racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline, and then chiral resolution to obtain optically pure I. This is a common method for preparing chiral drugs, but the resolution process is relatively complicated, and the optical purity of the product is poor, requiring multiple purifications.

[0006] (2) Asymmetric catalytic synthesis: It is generally prepared by asymmetric hydrogenation of imine catalyzed by precious metals. For example, in 2011, Zhang Xumu's research group reported the use of Ir-(S,S)-(f)-Binaphane to catalyze the asymmetric hydrogenation of 1-phenyl-3,4-dihydroisoquinoline (II) (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, the invention name is a method for the bidirectional enantioselective synthesis of chiral tetrahydroisoquinoline catalyzed by iridium, discloses the asymmetric hydrogenation of 1-phenyl-3,4-dihydroisoquinoline (II) catalyzed by Ir-(R)-BINAP. The method uses NBS as an additive and adjusts the dosage of NBS. It is the first reported method for the bidirectional enantioselective synthesis of chiral tetrahydroisoquinoline, but only two enantiomers with enantioselectivity of 86% ee (S) and 92% ee (R) can be obtained.

[0008] Chinese patent CN110041255 A, the invention name is a method for preparing a solifenacin intermediate, which discloses a method for preparing a solifenacin intermediate by using Ir / (R c ,S Fc ,S ax )-Josiphos-Type Binaphane was used as a catalyst and 40% hydrobromic acid was used as an additive to carry out asymmetric hydrogenation of 1-phenyl-3,4-dihydroisoquinoline (II) at a hydrogen pressure of 50 atm. Although high conversion rate (>99%) and high enantioselectivity (99% ee) were achieved, the use of hydrobromic acid increased the difficulty of post-treatment.

[0009] Asymmetric catalytic synthesis is becoming an important method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. However, there are still problems such as low catalyst activity, high reaction pressure, the need for additives, and poor stereoselectivity. Therefore, it is of great significance to develop an asymmetric synthesis of (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. Summary of the invention

[0010] In order to solve the above problems, 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, 10 ) as a catalyst, asymmetric hydrogenation can be performed to obtain (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, which can be used as a raw material for synthesizing solifenacin. The preparation method has the advantages of mild reaction conditions, high yield, good stereoselectivity, etc. Among them, the relevant (L1)~(L 10 The chiral ferrocene bisphosphine-thiourea ligand shown in ) can be prepared according to the method disclosed in Chinese patent CN 115536708A, the invention name of which is a chiral bisphosphine ligand with a ferrocene skeleton and its preparation method and application.

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

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

[0013]

[0014] (1) Under the protection of an inert gas, a mixture of 1-phenyl-3,4-dihydroisoquinoline represented by formula (II) and a mixture of formula (L1) to (L 10 ) is placed in a reaction vessel, and the inert gas in the reaction vessel is first replaced with H2, and the inert gas in the reaction vessel is completely exhausted to fill the reaction vessel with H2;

[0015] (2) Stirring the reaction at 1 to 100 atm of H2 and 0 to 60°C for 10 to 40 hours to obtain (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by formula (I).

[0016]

[0017] In one embodiment of the present invention, the metal iridium precursor is preferably 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 metal iridium precursor is [Ir(COD)Cl]2.

[0018] In one embodiment of the present invention, it is preferred that the method further comprises preparing the chiral ferrocenyl diphosphine-thiourea ligand / metal iridium precursor solution before the reaction, comprising the following steps: under the protection of an inert gas, 10 ) and the metal iridium precursor are added to dichloromethane and stirred at 20-30°C for 0.5-2h to obtain the product.

[0019] In one embodiment of the present invention, preferably, the formula (L1) to (L 10 ) The molar ratio of the chiral ferrocenyl diphosphine-thiourea ligand to the metal iridium precursor is 1.1:0.5~1.

[0020] In one embodiment of the present invention, preferably, in step (1), 1-phenyl-3,4-dihydroisoquinoline represented by formula (II) and formula (L1) to (L10 ) The feeding molar ratio of the chiral ferrocene diphosphine-thiourea ligand shown in FIG. 1 is 1:0.0001 to 0.01.

[0021] In one embodiment of the present invention, preferably, in step (1), 1-phenyl-3,4-dihydroisoquinoline represented by formula (II) and formula (L1) to (L 10 ) The reaction solvent used in the reaction of the chiral ferrocenyl diphosphine-thiourea ligand / metal iridium precursor solution shown in ) 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 as the reaction temperature increases, the reaction time can be further shortened to 25-35 h.

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

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

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The preparation method of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline of the present invention uses 1-phenyl-3,4-dihydroisoquinoline as a raw material, and 10 ) is catalyzed by a chiral ferrocenyl diphosphine-thiourea ligand / metal iridium precursor, and asymmetric hydrogenation can be performed to obtain (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. This method does not require the addition of other acids and bases, and the reaction temperature is less than 60°C. The product purification process is simple and convenient, and the yield is more than 90%. More importantly, the ee value of the product obtained by this method can reach 99%. Therefore, the method of the present invention has the advantages of mild reaction conditions, high yield, good stereoselectivity, etc., and can be applied to the process route for synthesizing solifenacin. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

[0030] Figure 4 This is the HPLC spectrum of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (I) of Example 3 of the present invention. DETAILED DESCRIPTION

[0031] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below with reference to the accompanying drawings.

[0032] Many specific details are set forth in the following description to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar generalizations without violating the connotation of the present invention, so the present invention is not limited to the specific implementation disclosed below.

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

[0034] (1) Under 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, i.e., a chiral ferrocenylbisphosphine-thiourea ligand / metal iridium precursor solution;

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

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

[0037] (1) Under 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, i.e., a chiral ferrocenylbisphosphine-thiourea ligand / metal iridium precursor solution.

[0038] (2) Under nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol) of formula (II), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added to an autoclave in sequence, the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. The reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove dichloromethane to obtain 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 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, i.e., a chiral ferrocenylbisphosphine-thiourea ligand / metal iridium precursor solution;

[0041] (2) Under the protection of nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol) of formula (II), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added to the autoclave in sequence, and the gas in the autoclave was replaced with hydrogen three times, and then H2 was filled to 1.0 atm, and 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, and 196.8 mg of white solid (I) was obtained, with a melting point of 80-82°C; a yield of 94%, and an ee value of 99.4%. Figures 3-4 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 (100 MHz, 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. Figure 2 shown.

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

[0043] (1) Under 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, i.e., a chiral ferrocenylbisphosphine-thiourea ligand / metal iridium precursor solution;

[0044] (2) Under the protection of nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol) of formula (II), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added to the autoclave in sequence, and the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove dichloromethane, thereby obtaining 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 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, i.e., a chiral ferrocenylbisphosphine-thiourea ligand / metal iridium precursor solution;

[0047] (2) Under nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol) of formula (II), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added to the autoclave in sequence, the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove dichloromethane, thereby obtaining 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 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, i.e., a chiral ferrocenylbisphosphine-thiourea ligand / metal iridium precursor solution;

[0050] (2) Under nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol) of formula (II), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added to the autoclave in sequence, and the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove dichloromethane, thereby obtaining 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 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, i.e., a chiral ferrocenylbisphosphine-thiourea ligand / metal iridium precursor solution;

[0053] (2) Under nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol) of formula (II), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added to the autoclave in sequence, the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove dichloromethane, thereby obtaining 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 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, i.e., a chiral ferrocenylbisphosphine-thiourea ligand / metal iridium precursor solution;

[0056] (2) Under the protection of nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol) of formula (II), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added to the autoclave in sequence, and the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove dichloromethane, thereby obtaining 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 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, i.e., a chiral ferrocenylbisphosphine-thiourea ligand / metal iridium precursor solution;

[0059] (2) Under the protection of nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol) of formula (II), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added to the autoclave in sequence, the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove dichloromethane, thereby obtaining 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 nitrogen atmosphere, ligand L 10(23.2 mg, 0.021 mmol), 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, i.e., a chiral ferrocenyl diphosphine-thiourea ligand / metal iridium precursor solution;

[0062] (2) Under nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol) of formula (II), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added to the autoclave in sequence, and the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove dichloromethane, thereby obtaining 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 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, i.e., a chiral ferrocenylbisphosphine-thiourea ligand / metal iridium precursor solution;

[0065] (2) Under the protection of nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol) of formula (II), dichloromethane (1.0 mL), and the iridium catalyst solution prepared in step (1) were added to the autoclave in sequence, and the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 10.0 atm, and the reaction was carried out at 25° C. for 24 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove dichloromethane, thereby obtaining 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 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, i.e., a chiral ferrocenylbisphosphine-thiourea ligand / metal iridium precursor solution;

[0068] (2) Under the protection of nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol) of formula (II), tetrahydrofuran (2.0 mL), and the iridium catalyst solution prepared in step (1) were added to the autoclave in sequence, the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove the solvent, thereby obtaining 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 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), stirred at 25°C for 1 hour to obtain an orange iridium catalyst solution, and the dichloromethane was removed by concentration under reduced pressure to obtain an iridium catalyst solid;

[0071] (2) Under 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 to the autoclave in sequence, and the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, and the reaction solution was concentrated under reduced pressure to dissolve in dichloromethane, and the catalyst was removed by filtration through silica gel. The filtrate was concentrated under reduced pressure to remove isopropanol, and 198.5 mg of white solid I was obtained, with a melting point of 80-82° C., a yield of 95%, and an ee value of 93.8%.

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

[0073] (1) Under 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 concentration under reduced pressure to obtain an iridium catalyst solid.

[0074] (2) Under 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 to the autoclave in sequence, the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove toluene, thereby obtaining 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 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 concentration under reduced pressure to obtain an iridium catalyst solid.

[0077] (2) Under 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 to the autoclave in sequence, the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 60° C. for 20 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove toluene, thereby obtaining 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 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 concentration under reduced pressure to obtain an iridium catalyst solid.

[0080] (2) Under 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 to the autoclave in sequence, and the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 10.0 atm, and the reaction was carried out at 25° C. for 48 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove toluene, thereby obtaining 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 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 concentration under reduced pressure to obtain an iridium catalyst solid.

[0083] (2) Under 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 to the autoclave in sequence, the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove toluene, thereby obtaining 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 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 concentration under reduced pressure to obtain an iridium catalyst solid.

[0086] (2) Under 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 to the autoclave in sequence, the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove toluene, thereby obtaining 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 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 concentration under reduced pressure to obtain an iridium catalyst solid.

[0089] (2) Under the protection of nitrogen atmosphere, 1-phenyl-3,4-dihydroisoquinoline (207.3 mg, 1.0 mmol) of formula (II), toluene (2.0 mL) and the iridium catalyst solid prepared in step (1) were added to the autoclave in sequence, the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25°C for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove toluene, thereby obtaining 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 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 concentration under reduced pressure to obtain an iridium catalyst solid.

[0092] (2) Under 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 to the autoclave in sequence, the gas in the autoclave was replaced with hydrogen three times, and then H2 was charged to 1.0 atm, and the reaction was carried out at 25° C. for 30 hours. After the reaction was completed, hydrogen was released, the reaction solution was filtered through silica gel to remove the catalyst, and the filtrate was concentrated under reduced pressure to remove toluene, thereby obtaining 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 only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, characterized in that: The following steps are involved: (1) Under the protection of an inert gas, a mixture of 1-phenyl-3,4-dihydroisoquinoline represented by formula (II) and a mixture of formula (L1) to (L 10 ) is placed in a reaction vessel, and the inert gas in the reaction vessel is replaced by H2; (2) Stirring the reaction at 1 to 100 atm of H2 and 0 to 60°C for 10 to 40 hours to obtain (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline represented by formula (I).

2. The method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline according to claim 1, characterized in that: The metal 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 - .

3. The method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline according to claim 2, characterized in that: The metal iridium precursor is [Ir(COD)Cl]2.

4. The method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline according to claim 1, characterized in that: The method also includes preparing the chiral ferrocenyl diphosphine-thiourea ligand / metal iridium precursor solution, comprising the following steps: under the protection of an inert gas, 10 ) and the metal iridium precursor are added to dichloromethane and stirred at 20-30°C for 0.5-2h to obtain the product.

5. The method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline according to claim 4, characterized in that: Formula (L1)~(L 10 ) The molar ratio of the chiral ferrocenyl diphosphine-thiourea ligand to the metal iridium precursor is 1.1:0.5~1.

6. The method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline according to claim 1, characterized in that: In step (1), 1-phenyl-3,4-dihydroisoquinoline represented by formula (II) and formula (L1) to (L 10 ) The feeding molar ratio of the chiral ferrocene diphosphine-thiourea ligand shown in FIG. 1 is 1:0.0001 to 0.

01.

7. The method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline according to claim 1, characterized in that: In step (1), 1-phenyl-3,4-dihydroisoquinoline represented by formula (II) and formula (L1) to (L 10 ) The reaction solvent used in the chiral ferrocenyl diphosphine-thiourea ligand / metal iridium precursor solution is one or more of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, isopropanol or toluene.

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

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

10. The method for preparing (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline according to claim 1, characterized in that: In step (2), the reactor is an autoclave and the H2 is 1 atm.

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