Preparation method and application of chiral 1, 4-dihydroquinoline

Abstract

The invention discloses a preparation method and application of chiral 1, 4-dihydroquinoline. According to the method, 4-substituted-quinoline-3-carboxylic ester is subjected to asymmetric catalytic hydrogenation by adopting a chiral Ir-SpiroPAP catalyst, and a series of chiral 1, 4-dihydroquinoline with high enantioselectivity are obtained. The reaction has a wide substrate application range, the dosage of the catalyst can be as low as 0.05 mol%, and the obtained chiral 1, 4-dihydroquinoline has enantioselectivity as high as 99% ee. The obtained optically active 1, 4-dihydroquinoline containing a three-dimensional center is used as a key chiral raw material and is respectively applied to asymmetric synthesis of a Melatonin MT2 receptor and an ABCB1 inhibitor.

Description

Technical Field

[0001] The invention relates to the technical field of asymmetric synthesis, and in particular to a preparation method of chiral 1,4-dihydroquinoline and application thereof. Background Art

[0002] Chiral 1,4-dihydroquinoline nitrogen-containing heterocyclic compounds, as an important heterocyclic structure, have significant biological activity and interesting biological properties, and are widely present in bioactive molecules and natural products. In addition, chiral 1,4-dihydroquinoline derivatives are an important research direction in drug discovery and synthetic chemistry. Although asymmetric hydrogenation reactions of quinoline compounds catalyzed by iridium, ruthenium, manganese, borane, etc. have been developed, the final compounds are limited to chiral tetrahydroquinoline, not chiral 1,4-dihydroquinoline. Even if dihydroquinoline intermediates are detected during the reaction, the hydrogenation reaction cannot be stopped at the dihydroquinoline product.

[0003] In 1984, Meyers et al. found that quinoline containing a chiral oxazoline auxiliary group at the 3-position undergoes nucleophilic addition with naphthyl lithium to obtain 1,4-dihydroquinoline with 76% ee (Meyers, AI et al. J. Am. Chem. Soc. 1984, 106, 1135–1136). In 2007, Yamada et al. studied the asymmetric addition reaction of quinoline containing a chiral oxazoline auxiliary group at the 3-position to obtain chiral 1,4-dihydroquinoline with a de value of 78% (Yamada, S. et al. Org. Lett. 2007, 9, 1477–1480). Recently, Coldham et al. used the kinetic resolution of racemic 2-aryldihydroquinolines to obtain enantiomerically enriched 2-aryldihydroquinolines and chiral 1,4-dihydroquinolines (Yeo, S.-H. et al. Chem. Eur. J. 2023, 29, e202300815). Wang Wei, Kim et al. developed an aza-Michael / aldol tandem reaction or Michael / aza-cyclization tandem reaction of aldehydes or ketones with 2-amino-β-nitro unsaturated aromatic ketones catalyzed by small organic catalytic molecules to obtain chiral 1,4-dihydroquinolines with up to 99% ee (Zhang, X. et al. Angew. Chem. Int. Ed. 2012, 51, 7282–7286; Kim, S.-G. et al. J. Org. Chem. 2014, 79, 8234-8243; Kim, S.-G. et al. Tetrahedron. Lett. 2015, 56, 4159–4162; Kim, S.-G. et al. Adv. Synth. Catal. 2015, 357, 1545–1550). In addition, Aggarwal et al. reported the asymmetric addition reaction of quinoline-3-carboxamide with chiral boron reagents to generate chiral 1,4-dihydroquinoline (Mohiti, M. et al. Chem. Sci., 2014, 5, 602–607). Schneider et al. successfully applied chiral phosphoric acid to the asymmetric addition cyclization reaction of enamine or ethyl 3-oxobutyrate with o-methylenequinone (Kretzschmar, M. et al. Angew. Chem. Int. Ed. 2016, 55, 9788–9792; Hodík, T. et al. Org. Biomol. Chem. 2017, 15, 3706–3716). Li Can et al. reported an organic base-catalyzed asymmetric [4+2] cycloaddition reaction of benzyl mercaptan and malononitrile to produce chiral 1,4-dihydroquinoline, achieving an enantioselectivity of 93% ee (Liu, X. et al. Chem. Commun. 2019, 55, 2668-2671).In addition, Harutyunyan et al. discovered the existence of chiral 1,4-dihydroquinoline when studying the nucleophilic dearomatization reaction mechanism of quinoline, but dihydroquinoline is difficult to retain under the reaction conditions (Yan, X. et al. J. Am. Chem. Soc. 2020, 142, 20247-20256). Unfortunately, Liu Qiang et al. recently reported the manganese-catalyzed regioselective hydroboration of quinoline, but obtained racemic 1,4-dihydroquinoline (Wang, Y. et al. CCS Chem. 2023, 10.31635 / ccschem.023.202303289).

[0004] It can be found that the developed asymmetric addition reaction of chiral oxazoline auxiliary groups to synthesize 1,4-dihydroquinoline has low enantioselectivity, and the aza-Michael / aldol tandem reaction or Michael / aza-cyclization tandem reaction catalyzed by small organic catalytic molecules usually requires 20 mol% of catalyst or two steps to obtain chiral 1,4-dihydroquinoline, and the substrate range is narrow; the asymmetric cycloaddition reaction catalyzed by chiral phosphoric acid to synthesize 1,4-dihydroquinoline has good enantioselectivity, but the catalyst dosage is usually 5 mol%, and the substrate application range is narrow. Therefore, the synthesis of optically active 1,4-dihydroquinoline compounds by asymmetric catalysis is very limited. Summary of the invention

[0005] In order to solve the problems existing in the prior art, an object of the present invention is to provide a method for preparing chiral 1,4-dihydroquinoline by asymmetric catalytic hydrogenation with a wide substrate range, low catalyst dosage and high enantioselectivity.

[0006] Another object of the present invention is to provide an application of the chiral 1,4-dihydroquinoline compound prepared by the above method in synthesizing Melatonin MT2 receptor.

[0007] Another object of the present invention is to provide a use of the chiral 1,4-dihydroquinoline compound prepared by the above method in the synthesis of Melatonin MT2 receptor and ABCB1 inhibitors.

[0008] To this end, the present invention adopts the following technical solutions:

[0009] A method for preparing chiral 1,4-dihydroquinoline comprises the following steps:

[0010] In the presence of a hydrogen atmosphere, a chiral Ir-SpiroPAP catalyst, a base and a solvent, 4-substituted quinoline-3-carboxylate is subjected to asymmetric catalytic hydrogenation to obtain a chiral 1,4-dihydroquinoline compound, and the reaction formula is as follows:

[0011]

[0012] Wherein, R is a C1-C20 alkyl, aryl, heteroaryl or alkenyl aryl; or, R has the following structure:

[0013]

[0014] Among them, R 1 is aryl or heteroaryl; R 2 is hydrogen, methyl;

[0015] X is hydrogen, alkyl, alkoxy, or halogen;

[0016] The structural formula of the chiral Ir-SpiroPAP catalyst is:

[0017] or its enantiomer (S)-1,

[0018] Wherein, Y is hydrogen or alkyl, alkoxy, or halogen.

[0019] Preferably, the chiral Ir-SpiroPAP catalyst has the structural formula:

[0020] or its enantiomer (S)-1a.

[0021] When the catalyst is (R)-1a, the reaction formula is:

[0022]

[0023] When the catalyst is (S)-1a, the reaction formula is:

[0024]

[0025] In the above reaction, the concentration of the 4-substituted-quinoline-3-carboxylate is 0.01-2.0 mmol / mL; the molar ratio of the 4-substituted-quinoline-3-carboxylate to the chiral Ir-SpiroPAP catalyst is (100-5000):1; the pressure of the hydrogen is 1-100 atm; the concentration of the base is 0.01-1.0 mmol / mL; the time for asymmetric catalytic hydrogenation is 24-168 hours; and the reaction temperature is 0-50°C.

[0026] Preferably, the hydrogen pressure is 50 atm; the reaction temperature is room temperature to 50°C; the molar ratio of 4-substituted-quinoline-3-carboxylate to chiral Ir-SpiroPAP catalyst is 200:1, the concentration of 4-substituted-quinoline-3-carboxylate is 0.05-1.0 mmol / mL; and the concentration of the base is 0.05-0.5 mmol / mL.

[0027] The base is an alkali metal salt of an alcohol, an alkali metal hydroxide or an alkali metal carbonate, wherein: the alkali metal salt of the alcohol is lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, potassium isopropoxide or sodium isopropoxide; the alkali metal hydroxide is potassium hydroxide or sodium hydroxide; the alkali metal carbonate is potassium carbonate, sodium carbonate or cesium carbonate.

[0028] The solvent is one of alcohol solvents, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide or a mixture of several thereof; the alcohol solvent is methanol, ethanol, n-propanol, isopropanol or butanol.

[0029] In the above reaction formula:

[0030] When R is an alkyl group, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;

[0031] When R is an aryl group, the aryl group is an aryl group with hydrogen, alkyl, alkoxy, halogen, ethoxycarbonyl, nitro or amino on the benzene ring;

[0032] When R is a heteroaryl group, the heteroaryl group is furan, thiophene, benzofuran, benzothiophene, indole, pyridin-2 / 3 / 4-yl, or alkyl or halogen-substituted pyridin-2 / 3 / 4-yl;

[0033] When R is an alkenyl aryl group, the alkenyl aryl group is a styryl group, a vinyl pyridin-2 / 3 / 4-yl group, a vinyl thiophene group, or a vinyl aryl group substituted with an alkyl group, an alkoxy group or a halogen group;

[0034] The R 1 When it is an aryl group, the aryl group is an aryl group substituted by an alkyl group, an alkoxy group, a fluorine group, a chlorine group or a bromine group; R 1 When it is a heteroaryl group, the heteroaryl group is pyridine and thiophene.

[0035] The above reaction products include:

[0036]

[0037]

[0038] The present invention also protects the application of the above method in preparing Melatonin MT2 receptor, and the reaction process is as follows:

[0039]

[0040] In the reaction of preparing compound (R)-3a by asymmetric hydrogenation of substrate 2a, the molar ratio of 4-phenyl-quinoline-3-carboxylate to Ir-SpiroPAP catalyst (R)-1a is (200-5000):1; the concentration of 4-phenyl-quinoline-3-carboxylate is 0.01-1.0 mmol / mL; the pressure of hydrogen is 1-100 atm; the concentration of lithium tert-butoxide is 0.01-1.0 mmol / mL; the time of asymmetric catalytic hydrogenation is 24-168 hours; the reaction temperature is 30-50°C;

[0041] The product (R)-3a obtained by the hydrogenation reaction was stirred with methyl iodide and sodium hydride in tetrahydrofuran solvent for 3-12 hours, and then simply post-treated and purified by column chromatography. The product was transferred to the inner tube of the hydrogenation reaction via methanol, Raney Ni was added, and hydrogen was filled at 1-100 atm. The enamine was reduced at room temperature to obtain the chiral product (R,R)-4, wherein the equivalent ratio of (R)-3a to sodium hydride was 1:(1.0-5.0); the equivalent ratio of (R)-3a to methyl iodide was 1:(1.0-5.0), and the mass ratio of (R)-3a to Raney Ni was 1:(1.0-10.0); the hydrogen pressure was 1-50 atm;

[0042] The chiral compound (R,R)-4 was dissolved in tetrahydrofuran, and lithium aluminum hydride was added in batches under ice bath conditions. The reaction was stirred at room temperature for 3-12 hours, and water was added to quench the reaction. After filtration through diatomaceous earth, the primary alcohol intermediate was obtained. No further purification was required and the next step of Mitsunobu reaction was directly carried out.

[0043] To a tetrahydrofuran solution of the primary alcohol intermediate obtained in the previous step is added diphenylphosphoryl azide (DPPA), diethyl azodicarboxylate and triphenylphosphine at 0°C, and the mixture is heated to room temperature for 3–12 hours to obtain an azide compound (R,R)-5; wherein the equivalent ratio of (R,R)-4 to lithium aluminum hydride is 1:(1.0–10.0); the equivalent ratio of (R,R)-4 to diphenylphosphoryl azide is 1:(1.0–5.0); the equivalent ratio of (R,R)-4 to diethyl azodicarboxylate is 1:(1.0–5.0); and the equivalent ratio of (R,R)-4 to triphenylphosphine is 1:(1.0–5.0).

[0044] The azide compound (R,R)-5 was transferred to a hydrogenation reactor via ethanol, and the azide was reduced to an amine under Pd / C / hydrogen conditions, and the reaction was carried out at room temperature for 3-12 hours. After the hydrogen pressure was released, the amine intermediate was obtained by filtration through diatomaceous earth, and was directly used in the next reaction without purification.

[0045] Then, triethylamine and propionic anhydride are added to the tetrahydrofuran solution of the amine intermediate, and the mixture is reacted at room temperature for 1-5 hours. After simple post-treatment, the mixture is purified by silica gel column chromatography to obtain an oily substance, Melatonin MT2 receptor (R,R)-6; wherein the mass ratio of (R,R)-5 to Pd / C is (1.0-100.0):1; the hydrogen pressure of the reaction is 1-100 atm; the equivalent ratio of (R,R)-5 to triethylamine is 1:(1.0-5.0); and the equivalent ratio of (R,R)-5 to propionic anhydride is 1:(1.0-10.0).

[0046] The present invention also protects the use of the above method in preparing an ABCB1 inhibitor, which is characterized in that the reaction equation is:

[0047]

[0048] In the reaction of preparing compound (R)-3f by asymmetric hydrogenation of substrate 2f, the molar ratio of 4-(4-methoxyphenyl)-quinoline-3-carboxylate to Ir-SpiroPAP catalyst (R)-1a is (200-5000):1; the concentration of 4-(4-methoxyphenyl)-quinoline-3-carboxylate is 0.01-1.0 mmol / mL; the pressure of hydrogen is 1-100 atm; the concentration of lithium tert-butoxide is 0.01-1.0 mmol / mL; the time of asymmetric catalytic hydrogenation is 24-168 hours; and the reaction temperature is 30-50°C.

[0049] At 0°C, sodium hydride and benzyl bromide were added to the N,N-diformamide solution of the hydrogenated product (+)-3f, and the mixture was stirred at room temperature for 1-5 hours. After simple post-treatment and purification by column chromatography, the chiral product ABCB1 inhibitor (+)-7 was obtained; the equivalent ratio of the hydrogenated product (+)-3f to sodium hydride was 1:(1.0-5.0); the equivalent ratio of (+)-3f to benzyl bromide was 1:(1.0-5.0).

[0050] Compared with the prior art, the present invention has the following beneficial effects:

[0051] 1. The method of the present invention increases the polarity of the carbon-carbon double bond at the C3-C4 position by introducing an ester group at the C-3 position of quinoline, so that the chiral Ir-SpiroPAP catalyst chemically selectively hydrogenates the polar carbon-carbon double bond at the C3-C4 position of quinoline, and then a base-promoted isomerization process occurs due to the presence of the C-3 electron-withdrawing group, and a series of chiral 1,4-dihydroquinolines are obtained with a maximum yield of 95% and an enantioselectivity of 99% ee. In addition, the gram-scale asymmetric hydrogenation reaction shows that the asymmetric hydrogenation reaction in the method of the present invention can be carried out at a catalyst dosage of 0.05 mol%, and both the yield and enantioselectivity can be maintained.

[0052] 2. The optically active chiral 1,4-dihydroquinoline obtained by the method of the present invention has a wide range of substrate applicability, and the substituent at the 4-position of quinoline can be an aryl group, a heteroaryl group, an alkyl group, an alkenyl aryl group, etc.; when the ester group at the 3-position is replaced by a nitrile group, the corresponding product can be obtained with an enantioselectivity of up to 98% ee.

[0053] 3. The optically active chiral 1,4-dihydroquinoline obtained by the method of the present invention can be used for the asymmetric synthesis of melatonin MT2 receptor and ABCB1 inhibitors. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 This is the X-ray single crystal diffraction result of chiral 1,4-dihydroquinoline (R)-3a prepared in Example 1;

[0055] Figure 2 This is the X-ray single crystal diffraction result of compound (R,R)-8 prepared in Example 37. DETAILED DESCRIPTION

[0056] The preparation method and application of the present invention are described in detail below in conjunction with the embodiments and drawings.

[0057] Unless otherwise specified, the structural formula of the spiropyridine aminophosphine-iridium catalyst (Ir-SpiroPAP catalyst, hereinafter referred to as "iridium catalyst") used in the following examples is as follows:

[0058] or its enantiomer (S)-1a.

[0059] Among them, Ar is 3,5-(tBu)2C6H3.

[0060] Example 1

[0061]

[0062] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-phenylquinoline-3-carboxylic acid ethyl ester 2a (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (R)-3a. 130mg, 93% yield, 95% ee, 1H NMR (400MHz, CDCl3): δ = 7.57 (d, J = 6.0Hz, 1H), 7.29–7.26 (m, 2H), 7.25–7.18 (m, 2H), 7.14–7.03 (m, 3H), 6.93– 6.86(m,1H),6.74–6.69(m,1H),6.31(d,J=5.8Hz,1H),5.14(s,1H),4.17–4.01(m,2H),1.19(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.6,148.2,136.2,135.5,130.3,128.2,127.6,127.0 ,126.1,125.0,123.5,115.0,103.0,59.6,42.3,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 18 H 18 NO2 280.1332; Found 280.1333. HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 4.98min; t R (minor) = 6.56min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0063] (+)-3a (20 mg) was dissolved in 0.5 mL of dichloromethane and 0.5 mL of n-hexane, and the solvent was slowly evaporated at room temperature to obtain a single crystal of compound (+)-3a. The X-ray single crystal diffraction result is shown in the figure. Figure 1 .

[0064] Table Single crystal data of compound (+)-3a (CCDC 2336186)

[0065]

[0066]

[0067] Example 2

[0068]

[0069] Under argon protection, iridium catalyst (R)-1b (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-phenylquinoline-3-carboxylic acid ethyl ester 2a (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40℃ for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL saturated ammonium chloride was added to quench, and a short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (R)-3a. 90mg, 65% yield, 86% ee.

[0070] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 106 bar; t R (major) = 4.92min; t R (minor) = 6.50min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0071] Example 3

[0072]

[0073] Under argon protection, iridium catalyst (R)-1c (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-phenylquinoline-3-carboxylic acid ethyl ester 2a (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40℃ for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL saturated ammonium chloride was added to quench, and a short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (R)-3a. 106mg, 76% yield, 88% ee.

[0074] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 4.94min; t R (minor) = 6.51min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0075] Example 4

[0076]

[0077] Under argon protection, iridium catalyst (R)-1d (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-phenylquinoline-3-carboxylic acid ethyl ester 2a (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40℃ for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL saturated ammonium chloride was added to quench, and a short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (R)-3a. 118mg, 85% yield, 88% ee.

[0078] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 4.94min; t R (minor) = 6.52min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0079] Example 5

[0080]

[0081] Under argon protection, iridium catalyst (R)-1e (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-phenylquinoline-3-carboxylic acid ethyl ester 2a (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40℃ for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL saturated ammonium chloride was added to quench, and a short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (R)-3a. 100mg, 72% yield, 83% ee.

[0082] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 4.91min; tR (minor) = 6.52min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0083] Example 6

[0084]

[0085] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(4-fluoro-phenyl)quinoline-3-carboxylic acid ethyl ester 2b (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3b. 141mg, 95% yield, 95% ee, 1 H NMR (400MHz, CDCl3): δ = 7.56 (d, J = 6.0Hz, 1H), 7.25–7.19 (m, 2H), 7.11–7.01 (m, 2H), 6.95–6.85 (m, 3H) ),6.73(d,J=7.9Hz,1H),6.34(d,J=6.0Hz,1H),5.13(s,1H),4.18–4.01(m,2H),1.20(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.7,161.2(d, 1 J C-F =244.0Hz),144.2(d, 4 J C-F =3.2Hz),136.4,135.4,130.2,128.9(d, 3 J C-F =7.8Hz),127.1,124.8,123.5,115.1,114.9(d, 2 J C-F =21.2Hz),102.4,59.7,41.6,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 18 H 17 FNO2298.1238; Found 298.1232.

[0086] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 4.88min; t R (minor) = 6.56min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0087] Example 7

[0088]

[0089] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(4-chloro-phenyl)quinoline-3-carboxylic acid ethyl ester 2c (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3c. 145mg, 93% yield, 93% ee, 1 H NMR (400MHz, CDCl3): δ = 7.55 (d, J = 6.0Hz, 1H), 7.23–7.14 (m, 4H), 7.09–6.99 (m, 2H), 6.9 3–6.86(m,1H),6.73–6.60(m,2H),5.12(s,1H),4.18–4.01(m,2H),1.20(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.5,146.7,136.3,135.3,131.8,130.2,128.9,128.4,12 7.2,124.5,123.7,115.1,102.5,59.7,41.8,26.9,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 18 H 17 ClNO2 314.0943; Found 314.0947.

[0090] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 86 bar; t R (major) = 5.02min; t R (minor) = 6.38min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0091] Example 8

[0092]

[0093] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(4-methyl-phenyl)quinoline-3-carboxylic acid ethyl ester 2e (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3e. 138mg, 94% yield, 92% ee, 1 H NMR (400MHz, CDCl3): δ=7.51 (d, J=6.0Hz, 1H), 7.20–7.12 (m, 2H), 7.08–6.96 (m, 4H), 6.86 (t, J=7 .4Hz,1H),6.74–6.60(m,2H),5.10(s,1H),4.19–4.00(m,2H),2.23(s,3H),1.19(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.7,145.5,136.3,135.5,135.5,130.2,128.9,127.3,12 6.9,125.2,123.5,115.0,102.8,59.6,41.9,20.9,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 19 H 20 NO2 294.1489; Found294.1491.

[0094] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 4.92min; t R (minor) = 6.01min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0095] Example 9

[0096]

[0097] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(4-methoxy-phenyl)quinoline-3-carboxylic acid ethyl ester 2f (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3f. 140mg, 91% yield, 93% ee, 1 H NMR (400MHz, CDCl3): δ = 7.51 (d, J = 6.0Hz, 1H), 7.22–7.16 (m, 2H), 7.06–6.93 (m, 3H), 6.86 (t, J = 7.3Hz, 1H), 6 .78–6.71(m,2H),6.64(d,J=7.9Hz,1H),5.10(s,1H),4.18–4.01(m,2H),3.67(s,3H),1.19(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.8,157.7,141.0,136.3,135.4,130.1,128.4,126.8,12 5.2,123.3,115.0,113.5,102.5,59.5,55.0,41.4,14.3.HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 19 H 19 NO3Na332.1257; Found 332.1255.

[0098] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 6.44min; t R (minor) = 10.48min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0099] Example 10

[0100]

[0101] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(4-ethoxycarbonyl-phenyl)quinoline-3-carboxylic acid ethyl ester 2g (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3g. 149mg, 91% yield, 92% ee, 1 H NMR (400MHz, CDCl3): δ=7.98–7.86(m,2H),7.59(d,J=6.0Hz,1H),7.40–7.33(m,2H),7.16–6.95(m,3H),6.90–6.83(m,1H), 6.72(d,J=7.9Hz,1H),5.21(s,1H),4.32(q,J=7.1Hz,2H),4.16–4.00(m,2H),1.34(t,J=7.1Hz,3H),1.18(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.5,166.7,153.2,136.7,135.4,130.2,129.7,128.2,127.5,1 27.3,124.1,123.5,115.3,101.9,60.7,59.6,42.5,14.3,14.2.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 21 H 22 NO4352.1544;Found 352.1545.

[0102] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 8.35min; t R (minor) = 18.93min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0103] Embodiment 11

[0104]

[0105] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(3-chloro-phenyl)quinoline-3-carboxylic acid ethyl ester 2h (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3h. 142mg, 91% yield, 90% ee, 1 HNMR (400MHz, CDCl3): δ = 7.56 (d, J = 6.0Hz, 1H), 7.24 (s, 1H), 7.20–7.11 (m, 2H), 7.11–7.00 (m, 3 H),6.93–6.86(m,1H),6.74–6.58(m,2H),5.13(s,1H),4.19–4.02(m,2H),1.20(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.4,150.1,136.4,135.3,134.1,130.2,129.5,127.8,127.3 ,126.3,125.8,124.2,123.7,115.2,102.3,59.7,42.2,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 18 H 17 ClNO2 314.0943; Found 314.0942.

[0106] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 4.84min; t R (minor) = 6.06min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0107] Example 12

[0108]

[0109] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(3-bromo-phenyl)quinoline-3-carboxylic acid ethyl ester 2i (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3i. 162mg, 91% yield, 92% ee, 1 H NMR (400MHz, CDCl3): δ=7.57(d,J=6.0Hz,1H),,7.39(t,J=1.8Hz,1H),7.27–7.19(m,2H),7.12–7.02(m,3H),6.91(td,J=7 .5,1.2Hz,1H),6.73(dd,J=7.9,1.3Hz,1H),6.45(d,J=6.1Hz,1H),5.11(s,1H),4.19–4.01(m,2H),1.21(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.3,150.3,136.2,135.3,130.7,130.3,129.8,129.3,127.4 ,126.3,124.3,123.7,122.5,115.2,102.6,59.7,42.2,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 18 H 17BrNO2 358.0437,360.0417; Found 358.0435,360.0413.

[0110] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 86 bar; t R (major) = 5.09min; t R (minor) = 6.03min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0111] Embodiment 13

[0112]

[0113] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(3-methyl-phenyl)quinoline-3-carboxylic acid ethyl ester 2j (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3j. 129mg, 88% yield, 90% ee, 1 H NMR (400MHz, CDCl3): δ=7.54(d,J=6.0Hz,1H),7.13–7.00(m,5H),6.95–6.90(m,1H),6.88(td,J=7.5,1.2Hz,1H ),6.68(dd,J=7.9,1.2Hz,1H),6.48(s,1H),5.09(s,1H),4.18–4.00(m,2H),2.26(s,3H),1.19(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.6,148.2,137.7,136.1,135.5,130.3,128.3,128.1,126.9 ,125.2,124.6,123.5,115.0,103.1,59.6,42.3,21.5,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 19H 20 NO2 294.1489; Found 294.1490.

[0114] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 4.98min; t R (minor) = 6.56min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0115] Embodiment 14

[0116]

[0117] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(3,4-dioxa-phenyl)quinoline-3-carboxylic acid ethyl ester 2l (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3l. 134mg, 83% yield, 89% ee, 1 H NMR (400MHz, CDCl3): δ = 7.54 (d, J = 6.0Hz, 1H), 7.09–7.03 (m, 2H), 6.94–6.87 (m, 1H), 6.80–6.73 (m, 2H), 6.7 2–6.63(m,2H),6.53–6.42(m,1H),5.87–5.80(m,2H),5.06(s,1H),4.20–4.02(m,2H),1.22(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.5,147.6,145.8,142.6,135.9,135.3,130.2,127.0,125.1,123.6 ,120.3,115.0,108.2,107.8,103.2,100.7,59.6,42.0,26.9,14.4.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C19 H 18 NO4 324.1231; Found 324.1230.

[0118] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 7.76min; t R (minor) = 11.88min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0119] Embodiment 15

[0120]

[0121] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(3,4-dichloro-phenyl)quinoline-3-carboxylic acid ethyl ester 2m (0.5mmol) and ethanol (2.0mL) were added to the inner tube of the hydrogenation reaction in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3m. 161mg, 93% yield, 94% ee, 1 H NMR (400MHz, CDCl3): δ = 7.57 (d, J = 6.1Hz, 1H), 7.34 (s, 1H), 7.30–7.23 (m, 1H), 7.16–7.05 (m, 2H), 7.01 (d, J=7.6Hz,1H),6.95–6.87(m,1H),6.78–6.65(m,2H),5.12(s,1H),4.21–4.01(m,2H),1.22(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.3,148.3,136.5,135.3,132.2,130.2,130.0,129.6, 127.5,127.0,123.8,115.3,102.0,59.8,41.7,14.3.HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H15 Cl2NO2Na370.0372; Found 370.0366.

[0122] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 4.79min; t R (minor) = 5.63min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0123] Example 16

[0124]

[0125] Under argon protection, iridium catalyst (R)-1a (0.005mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 7-methoxy-4-(phenyl)quinoline-3-carboxylic acid ethyl ester 2q (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 48 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3q. 134mg, 87% yield, 93% ee, 1 H NMR (400MHz, CDCl3): δ = 7.52 (d, J = 6.0Hz, 1H), 7.30–7.18 (m, 4H), 7.14–7.06 (m, 1H), 6.95 (d, J = 8.4Hz, 1H), 6 .54–6.42(m,2H),6.24(d,J=2.5Hz,1H),5.07(s,1H),4.17–4.00(m,2H),3.71(s,3H),1.18(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.6,158.6,148.5,136.3,136.0,131.2,128.2,127.5,12 6.0,117.7,109.3,103.6,100.5,59.6,55.2,41.7,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 19 H 20NO3310.1438; Found 310.1438.

[0126] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 5.87min; t R (minor) = 7.20min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0127] Embodiment 17

[0128]

[0129] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 7-methyl-4-(phenyl)quinoline-3-carboxylic acid ethyl ester 2r (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3r. 138mg, 88% yield, 90% ee, 1 H NMR (400MHz, CDCl3): δ=7.59(d,J=6.0Hz,1H),7.36–7.30(m,2H),7.30–7.22(m,2H),7.19–7.12(m,1H),6.99(d,J=7.7 Hz,1H),6.75(d,J=7.8Hz,1H),6.60–6.48(m,2H),5.15(s,1H),4.23–4.05(m,2H),2.28(s,3H),1.24(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.7,148.5,136.8,136.2,135.3,130.1,128.2,127.5,12 6.0,124.5,122.3,115.5,103.0,59.5,42.0,21.0,14.3.HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 19 H 19NO2Na 316.1308; Found 316.1310.

[0130] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 102 bar; t R (major) = 4.16min; t R (minor) = 5.82min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0131] Embodiment 18

[0132]

[0133] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 8-methoxy-4-(phenyl)quinoline-3-carboxylic acid ethyl ester 2t (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3t. 134mg, 87% yield, 97% ee, 1 H NMR (400MHz, CDCl3): δ = 7.61 (d, J = 6.0Hz, 0H), 7.30–7.25 (m, 2H), 7.24–7.18 (m, 2H), 7.14–7.06 (m, 1H), 6.89– 6.78(m,2H),6.66(dd,J=12.2,7.9Hz,2H),5.14(s,1H),4.17–3.99(m,2H),3.87(s,3H),1.18(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.5,148.2,146.3,135.6,128.2,127.6,126.1,125.5 ,122.9,122.0,107.8,102.9,59.5,55.6,42.3,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 19 H 20NO3 310.1438; Found 310.1438. HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 107 bar; t R (major) = 6.35min; t R (minor) = 7.12min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0134] Embodiment 19

[0135]

[0136] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(6-methylpyridin-3-yl)-quinoline-3-carboxylic acid ethyl ester 2v (0.5mmol) and ethanol (2.0mL) were added to the inner tube of the hydrogenation reaction in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3v. 132mg, 90% yield, 91% ee, 1 H NMR (400MHz, CDCl3): δ=8.42(s,1H),7.61–7.56(s,1H),7.45(d,J=7.7,1H),7.12–6.98(m,3H),6.95–6 .88(m,1H),6.73(d,J=8.0Hz,1H),5.14(s,1H),4.17–4.03(m,2H),2.47(s,3H),1.21(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3): δ=167.3,155.9,148.0,140.7,136.4,135.7,135.6,130.2,127.3 ,124.1,123.7,123.1,115.2,102.1,59.7,39.7,23.9,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 18 H 19 N2O2295.1441; Found 295.1440.

[0137] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 90:10; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 8.52min; t R (minor) = 13.66min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0138] Embodiment 20

[0139]

[0140] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(6-chloropyridin-3-yl)-quinoline-3-carboxylic acid ethyl ester 2w (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3w. 145mg, 92% yield, 91% ee, 1 H NMR (400MHz, CDCl3): δ=8.32(d,J=2.5Hz,1H),7.65–7.49(m,2H),7.18(d,J=8.2Hz,1H),7.15–7.05(m,2H),7.0 2–6.97(m,1H),6.96–6.89(m,1H),6.77(d,J=7.9Hz,1H),5.19(s,1H),4.19–4.03(m,2H),1.22(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.1,148.9,148.5,142.5,138.4,136.7,135.6,130.2,12 7.7,124.2,123.9,123.2,115.4,101.5,59.8,39.4,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 17 H 16 ClN2O2 315.0895; Found 315.0895.

[0141] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 106 bar; t R (major) = 10.07min; t R (minor) = 13.89min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0142] Embodiment 21

[0143]

[0144] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(2-methylpyridin-4-yl)-quinoline-3-carboxylic acid ethyl ester 2x (0.5mmol) and ethanol (2.0mL) were added to the inner tube of the hydrogenation reaction. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3x. 135mg, 92% yield, 92% ee, 1 H NMR (400MHz, CDCl3): δ = 8.34 (d, J = 5.2Hz, 1H), 8.21–8.05 (m, 1H), 7.63 (d, J = 6.1Hz, 1H), 7.13–7.00 (m, 4H), 6 .94–6.87(m,1H),6.77(d,J=7.9Hz,1H),5.14(s,1H),4.19–4.03(m,2H),2.49(s,3H),1.20(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.3,158.1,157.0,148.7,137.1,135.8,130.0,127.5,123.5 ,123.3,122.5,120.2,115.4,100.7,59.6,42.0,24.2,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 18 H 19 N2O2 295.1441; Found 295.1443.

[0145] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 90:10; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 100 bar; t R (major) = 6.91min; t R (minor) = 8.11min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0146] Embodiment 22

[0147]

[0148] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(2-chloropyridin-4-yl)-quinoline-3-carboxylic acid ethyl ester 2y (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3y. 144mg, 92% yield, 91% ee, H NMR (400MHz, CDCl3): δ = 8.22 (d, J = 5.1Hz, 1H), 7.61 (d, J = 6.1Hz, 1H), 7.21 (s, 1H), 7.18–7.10 (m, 2H), 7.05–7.00 (m, 1H) ),6.99–6.93(m,1H),6.78(d,J=8.0Hz,1H),6.51–6.42(m,1H),5.16(s,1H),4.20–4.04(m,2H),1.22(t,J=7.1Hz,3H); 13 CNMR (101MHz, CDCl3): δ=167.1,159.7,151.4,149.3,137.4,135.5,130.0,127.9,12 3.8,123.3,122.3,121.8,115.6,100.1,59.8,41.9,14.2.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 17 H 16 ClN2O2 315.0895; Found315.0900.

[0149] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 90:10; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 105 bar; t R (major) = 5.70min; t R (minor) = 7.68min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0150] Embodiment 23

[0151]

[0152] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(benzothiophene-2-yl)-quinoline-3-carboxylic acid ethyl ester 2ab (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3ab. 154mg, 92% yield, 87% ee, 1 H NMR (400MHz, CDCl3): δ=7.64(d,J=7.9Hz,1H),7.60–5.51(m,2H),7.26–7.12(m,3H),7.08–7.01(t,J=7.6 Hz,1H),7.00–6.86(m,3H),6.66(d,J=7.9Hz,1H),5.51(s,1H),4.25–4.10(m,2H),1.24(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.5,152.5,139.8,139.6,136.9,135.5,130.1,127.6,123.9,123.6 ,123.4,123.3,123.2,122.2,119.5,115.2,101.3,59.9,38.0,14.4.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 20 H 18 NO2S 336.1053;Found 336.1058.

[0153] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 106 bar; t R (major) = 7.35min; t R (minor) = 8.31min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0154] Embodiment 24

[0155]

[0156] Under argon protection, iridium catalyst (R)-1a (0.001mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-methyl-quinoline-3-carboxylic acid ethyl ester 2ae (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 24 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (–)-3ae. 96mg, 89% yield, 83% ee, 1 H NMR (400MHz, CDCl3): δ = 7.40 (d, J = 6.0Hz, 1H), 7.12 (d, J = 7.5Hz, 1H), 7.06 (td, J = 7.6, 1.5Hz, 1H), 6.96 (td, J = 7.4, 1.3Hz, 1H), 6 .65(d,J=7.6Hz,1H),6.55–6.35(m,1H),4.28–4.14(m,2H),4.00(q,J=6.8Hz,1H),1.30(t,J=7.1Hz,3H),1.25(d,J=6.7Hz,3H); 13 C NMR (101MHz, CDCl3): δ = 167.8, 136.4, 136.0, 129.0, 127.1, 126.7, 123.3, 114.4, 103.6, 59.5, 31.1, 25.8, 14.5. HRMS (ESI) m / z: [MH] + Calculate for C 13 H 14 NO2 216.1030; Found 216.1028.

[0157] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 86 bar; t R (major) = 4.01min; t R (minor) = 4.59 min; (the ee value was determined by protecting the amine group with tert-butyloxycarbonyl).

[0158] Embodiment 25

[0159]

[0160] Under argon protection, iridium catalyst (R)-1a (0.001mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-ethyl-quinoline-3-carboxylic acid ethyl ester 2af (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40℃ for 24 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (–)-3af. 104mg, 90% yield, 72% ee, 1 HNMR (400MHz, CDCl3): δ = 7.50 (d, J = 6.0Hz, 1H), 7.12–7.04 (m, 2H), 6.97 (td, J = 7.5, 1.2Hz, 1H), 6.74–6.48 (m, 2H),4.27–4.13(m,2H),3.97(t,J=5.2Hz,1H),1.71–1.50(m,2H),1.29(t,J=7.1Hz,3H),0.74(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3): δ = 167.9, 137.4, 137.1, 129.3, 126.6, 124.8, 123.0, 114.3, 101.5, 59.5, 36.9, 31.1, 14.4, 9.2. HRMS (ESI-TOF) m / z: [M+H] + Calculate for C 14 H 18 NO2 231.1259; Found 232.1330.

[0161] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 108 bar; t R (major) = 3.87min; t R (minor) = 4.83min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0162] Embodiment 26

[0163]

[0164] Under argon protection, iridium catalyst (R)-1a (0.001mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-phenylene-quinoline-3-carboxylic acid ethyl ester 2ai (0.5mmol) and ethanol (2.0mL) were added to the inner tube of the hydrogenation reaction in sequence. The reaction kettle was sealed, filled with hydrogen to 20atm, and stirred at 40°C for 24 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3ai. 138mg, 90% yield, 99% ee, 1 HNMR (400MHz, CDCl3): δ = 7.49 (d, J = 6.1Hz, 1H), 7.30–7.26 (m, 2H), 7.25–7.20 (m, 3H), 7.19–7.07 (m, 3H), 6.98 (td, J = 7.4, 1.2Hz, 1H) ,6.69(dd,J=7.9,1.2Hz,1H),6.45–6.35(m,1H),6.31–6.18(m,2H),4.75(d,J=6.2Hz,1H),4.27–4.12(m,2H),1.28(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3): δ=167.5,137.4,136.6,136.1,133.1,130.3,128.3,128.1,127.3,12 7.0,126.3,123.5,123.2,114.8,100.8,59.7,39.5,26.9,14.5.HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 20 H 19NO2Na 328.1308; Found 328.1310.

[0165] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 107 bar; t R (major) = 5.26min; t R (minor) = 6.79min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0166] Embodiment 27

[0167]

[0168] Under argon protection, iridium catalyst (R)-1a (0.001mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(4-methyl-styrene)-quinoline-3-carboxylic acid ethyl ester 2ak (0.5mmol) and ethanol (2.0mL) were added to the inner tube of the hydrogenation reaction in sequence. The reaction kettle was sealed, filled with hydrogen to 20atm, and stirred at 40°C for 24 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3ak. 145mg, 91% yield, 99% ee, 1 H NMR (400MHz, CDCl3): δ=7.48(d,J=6.0Hz,1H),7.21–7.15(m,3H),7.11(td,J=7.6,1.5Hz,1H),7.06–7.02(m,2H),6.99(td,J=7.4,1.2 Hz,1H),6.69(dd,J=7.9,1.2Hz,1H),6.29–6.12(m,3H),4.73(d,J=5.1Hz,1H),4.27–4.12(m,2H),2.28(s,3H),1.28(t,J=7.1Hz,3H); 13 CNMR (101MHz, CDCl3): δ=167.7,136.8,136.7,136.1,134.5,132.2,130.2,128.99,127.8,1 27.1,126.2,123.4,123.2,114.8,100.5,59.6,39.5,21.1,14.5.HRMS(ESI-TOF)m / z:[M+Na]+ Calculate for C 21 H 21 NO2Na 342.1462; Found342.1462.

[0169] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 118 bar; t R (major) = 5.13min; t R (minor) = 6.88min; (the ee value was determined by protecting the amine group with tert-butyloxycarbonyl).

[0170] Embodiment 28

[0171]

[0172] Under argon protection, iridium catalyst (R)-1a (0.001mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(3-chloro-phenylethylene)quinoline-3-carboxylic acid ethyl ester 2am (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 20atm, and stirred at 40°C for 24 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3am. 151mg, 89% yield, 99% ee, 1 H NMR (400MHz, CDCl3): δ=7.50(d,J=6.1Hz,1H),7.19–7.07(m,5H),7.03–6.96(m,1H),6.71(d,J=7.9Hz,1H),6.53(s,1 H),6.28(dd,J=15.7,6.9Hz,1H),6.20–6.08(m,1H),4.75(d,J=7.0Hz,1H),4.27–4.12(m,2H),1.29(t,J=7.1Hz,1H); 13C NMR (101MHz, CDCl3): δ=167.4,139.3,136.8,136.1,134.6,134.2,130.2,129.5,127.4,126.9, 126.8,126.2,124.6,123.6,122.8,114.9,100.4,59.7,39.5,14.5.HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 20 H 18 ClNO2Na362.0918; Found 362.0920.

[0173] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 107 bar; t R (major) = 5.25min; t R (minor) = 6.18min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0174] Embodiment 29

[0175]

[0176] Under argon protection, iridium catalyst (R)-1a (0.001mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(3-methyl-phenylethylene)-quinoline-3-carboxylic acid ethyl ester 2an (0.5mmol) and ethanol (2.0mL) were added to the inner tube of the hydrogenation reaction in sequence. The reaction kettle was sealed, filled with hydrogen to 20atm, and stirred at 40°C for 24 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3an. 141mg, 88% yield, 99% ee, 1H NMR (400MHz, CDCl3): δ=7.49(d,J=6.0Hz,1H),7.18(d,J=7.5Hz,1H),7.15–7.06(m,4H),7.02–6.93(m,2H),6.70(d,J=7.9H z,1H),6.32–6.22(m,2H),6.21–6.15(m,1H),4.74(d,J=6.5Hz,1H),4.28–4.12(m,2H),2.28(s,3H),1.28(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.5,137.8,137.3,136.6,136.1,133.0,130.3,128.2,128.1,127.8,127 .2,127.0,123.51,123.45,123.2,114.8,100.8,59.7,39.5,21.3,14.5.HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 21 H 21 NO2Na 342.1462; Found 342.1466.

[0177] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 107 bar; t R (major) = 4.76min; t R (minor) = 5.80min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0178] Embodiment 30

[0179]

[0180] Under argon protection, iridium catalyst (R)-1a (0.001mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(2-(pyridin-2-yl-vinyl)-quinoline-3-carboxylic acid ethyl ester 2ao (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 20atm, and stirred at 40°C for 24 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and a short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3ao. 132mg, 87% yield, 97% ee, 1 H NMR (400MHz, CDCl3): δ=8.47–8.39(m,1H),8.09–7.97(m,1H),7.57(td,J=7.7,1.8Hz,1H) ,7.48(d,J=6.1Hz,1H),7.29–7.24(m,2H),7.14(dd,J=7.4,1.7Hz,1H),7.08–7.03(m,1H) ,7.00–6.89(m,2H),6.78(dd,J=15.7,7.1Hz,1H),6.60(dd,J=7.7,1.5Hz,1H),6.32(dd,J =15.7,1.1Hz,1H),4.79(dd,J=7.1,1.1Hz,1H),4.35–4.02(m,2H),1.27(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.5,156.1,148.9,138.2,137.4,136.5,136.4,129.8,127.6,12 7.3,123.2,122.5,121.7,121.6,114.9,99.1,59.5,39.4,14.5.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 19 H 19 N2O2 307.1441; Found307.1443.

[0181] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 90:10; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 114 bar; t R (major) = 7.99min; tR (minor) = 13.33min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl)

[0182] Embodiment 31

[0183]

[0184] Under argon protection, iridium catalyst (R)-1a (0.001mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-(2-(thiophene-2-yl)-vinyl)-quinoline-3-carboxylic acid ethyl ester 2ap (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 20atm, and stirred at 40°C for 24 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3ap. 150mg, 90% yield, 98% ee, 1 H NMR (400MHz, CDCl3): δ = 7.48 (d, J = 6.1Hz, 1H), 7.16 (d, J = 7.5Hz, 1H), 7.13–7.07 (m, 1 H),7.04(d,J=5.1Hz,1H),6.98(td,J=7.5,1.2Hz,1H),6.90–6.85(m,1H),6.85–6.81( m,1H),6.70(d,J=7.8Hz,1H),6.54(d,J=6.0Hz,1H),6.33(d,J=15.5Hz,1H),6.10(dd ,J=15.6,7.0Hz,1H),4.71(d,J=7.0Hz,1H),4.28–4.12(m,2H),1.28(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3): δ=167.7,142.6,137.1,137.0,136.0,133.0,130.1,127.2,127.1 ,125.1,123.4,122.8,121.4,115.0,99.8,59.7,39.3,14.4.HRMS(ESI-TOF)m / z:[M+Na] + Calculate for C 18 H 17 NO2NaS 334.0872; Found 334.0874.

[0185] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 107 bar; t R (major) = 5.71min; t R (minor) = 7.40min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0186] Embodiment 32

[0187]

[0188] Under argon protection, iridium catalyst (R)-1a (0.0025mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-phenyl-quinoline-3-carbonitrile 2ar (0.5mmol) and ethanol (2.0mL) were added to the inner tube of the hydrogenation reaction in sequence. The reaction kettle was sealed, filled with hydrogen to 50atm, and stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3ar. 105mg, 90% yield, 96% ee, 1 H NMR (400MHz, CDCl3): δ=7.34–7.17(m,5H),7.10–7.02(m,1H),6.95–6.78(m,4H),6.65(d,J=7.9Hz,1H),4.88(s,1H); 13 C NMR (101MHz, CDCl3): δ = 145.7, 138.1, 134.7, 130.1, 128.7, 127.8, 127.7, 127.1, 123.8, 122.2, 121.3, 115.4, 82.3, 43.3. HRMS (ESI-TOF) m / z: [M+H] + Calculate for C 16 H 13 N2233.1073; Found 233.1070.

[0189] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 82 bar; t R(major) = 4.93min; t R (minor) = 5.50min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0190] Embodiment 33

[0191]

[0192] Under argon protection, iridium catalyst (R)-1a (0.001mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-phenylene-quinoline-3-carbonitrile 2as (0.5mmol) and ethanol (2.0mL) were added to the inner tube of the hydrogenation reaction in sequence. The reaction kettle was sealed, filled with hydrogen to 20atm, and stirred at 40°C for 24 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL of saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3as. 116mg, 90% yield, 98% ee, 1 H NMR (400MHz, CDCl3): δ=7.42–7.33(d,J=7.1Hz,2H),7.29(t,J=7.4Hz,2H),7.25–7.18(m,1H),7.17–7.07(m,2H),6.99(t,J=7.5H z,1H),6.93(d,J=5.9Hz,1H),6.66(d,J=8.1Hz,1H),6.46(d,J=15.7Hz,1H),6.26(dd,J=15.6,8.0Hz,2H),4.50(d,J=8.1Hz,1H); 13 C NMR (101MHz, CDCl3): δ=138.3,136.5,134.7,131.1,130.0,129.9,128.5,128.0, 127.6,126.6,124.0,121.1,120.8,115.3,81.5,41.1.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 18 H 15 N2 259.1230; Found 259.1227.

[0193] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 93 bar; tR (major) = 4.63min; t R (minor) = 4.93min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0194] Embodiment 34

[0195]

[0196] Under argon protection, iridium catalyst (R)-1a (0.001mmol) and lithium tert-butoxide (16.0mg, 0.2mmol), 4-phenylethynyl-quinoline-3-carboxylic acid ethyl ester 2ar (0.5mmol) and ethanol (2.0mL) were added to the hydrogenation reaction tube in sequence. The reaction kettle was sealed, filled with hydrogen to 20atm, and stirred at 40℃ for 24 hours. After the hydrogenation reaction was completed, hydrogen was released, 0.5mL saturated ammonium chloride was added to quench, and the short silica gel column was filtered and dried under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain (+)-3ai. 135mg, 88% yield, 98% ee.

[0197] HPLC separation conditions: Chiralcel AD-3 column (25 cm × 0.46 cm ID); n-hexane / isopropanol = 95:5; temperature: 26 ° C; flow rate: 1.0 mL / min; UV detection wavelength: 254 nm; column pressure: 107 bar; t R (major) = 5.25min; t R (minor) = 6.76min; (the ee value of the product was measured after the amino group was protected by tert-butyloxycarbonyl).

[0198] Embodiment 35

[0199] The enantiomeric excess value of the above hydrogenation product is determined by high performance liquid chromatography (HPLC) testing after N-acyl protection of the hydrogenation product; the N-acylation reaction equation of the hydrogenation product is as follows:

[0200]

[0201] Under argon, di-tert-butyl carbonate (Boc2O) (131 mg, 140 μL, 0.6 mmol) was added dropwise to a dichloromethane solution (3.0 mL) of DMAP (12 mg, 0.1 mmol), triethylamine (90 μL, 65 mg, 0.6 mmol) and hydrogenation product 3, and the mixture was stirred at room temperature for at least 15 hours. After direct concentration under reduced pressure, the mixture was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to obtain an N-acylated derivative with an equivalent yield, and the enantiomeric excess value of the hydrogenation product 3 was tested by high performance liquid chromatography (HPLC).

[0202] Embodiment 36

[0203] According to the asymmetric hydrogenation method of the present invention, the (R)-3a compound prepared by asymmetric hydrogenation of 2a is used to prepare the intermediate (R,R)-7, which is further used to prepare the Melatonin MT2 receptor. The reaction equation is:

[0204]

[0205] Gram-scale asymmetric hydrogenation reactions:

[0206] In a glove box, chiral spirocyclic pyridine aminophosphine-iridium catalyst (R)-1a (4.9 mg, 0.005 mmol), 4-phenyl-quinoline-3-carboxylic acid ethyl ester 2a (2.77 g, 10.0 mmol) and lithium tert-butoxide (160.0 mg, 2.0 mmol) were weighed into a 60 mL hydrogenation inner tube, and the inner tube was sealed with a sealing film and the kettle was taken out. After argon replacement, ethanol (20.0 mL) was added, and then hydrogen was filled at 50 atm and released to purge the reactor. After repeating three times, hydrogen was filled at 60 atm again and the reactor was placed in a 40 ° C oil bath for 5 days. After releasing the hydrogen pressure, 0.5 mL of saturated ammonium chloride solution was added to quench, and the short silica gel column was filtered (eluent: ethyl acetate), and the solvent was removed under reduced pressure to obtain a residue. Purification by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1-5:1) gave the hydrogenated product (+)-3a, 2.56 g, 92% yield, 94% ee.

[0207] N-Alkylation and Raney Ni Reduction:

[0208]

[0209] Under argon, NaH (144 mg, 6.0 mmol) was added in batches to a solution of (+)-3a (1.40 g, 5.0 mmol) in THF (30 mL) in an ice-water bath. After stirring for 0.5 hours, iodomethane (1.06 g, 7.50 mmol) was added dropwise to the reaction system, and the mixture was returned to room temperature and the reaction was continued for 12 hours. After the reaction was completed, water (20 mL) was added to quench the mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 3), the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification was performed by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain an N-methylated product, 1.45 g, 99% yield. Next, the N-methylated compound (295 mg, 1.00 mmol) was added to a 25 mL hydrogenation inner tube, dissolved in methanol (5.0 mL), and then Raney Ni (3.0 g, rinsed with methanol) was added, and the reactor was installed. After argon replacement, hydrogen was filled at 50 atm and released to purge the reactor. After three times, hydrogen was filled at 50 atm again and reacted at room temperature for 24 hours. After releasing the hydrogen pressure, the product was filtered through diatomaceous earth (eluent: ethyl acetate) and the solvent was removed under reduced pressure to obtain a residue. Silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) was used for purification to obtain (R,R)-4 as a colorless oil, 184 mg, 62% yield, 1 HNMR (400MHz, CDCl3): δ=7.23–7.12(m,4H),7.02–6.95(m,1H),6.91(d,J=6.8Hz,1H),6.72(d,J=8.3Hz,1H),6.59(t,J=7.3 Hz,1H),4.57(d,J=4.9Hz,1H),4.14–3.98(m,2H),3.51–3.41(m,1H),3.30–3.18(m,2H),3.03(s,3H),1.20(t,J=7.2Hz,3H); 13 C NMR (101MHz, CDCl3): δ=171.7,145.7,142.5,130.1,129.3,128.0,127.9,126.7,1 23.3,116.4,110.8,60.4,46.5,45.5,43.3,39.0,14.1.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 19 H 22 NO9296.1645; Found 296.1641.

[0210] Reduction of esters with Mitsunobu reaction:

[0211]

[0212] Under argon atmosphere, LiAlH4 (184 mg, 4.60 mmol) was added in batches to a solution of (R,R)-4 (270 mg, 0.915 mmol) in tetrahydrofuran (20 mL) at 0°C, and the mixture was allowed to react at room temperature for 10 hours. After the reaction, water (2 mL) was added to quench the mixture, and the mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, and concentrated under reduced pressure to obtain 230 mg of a colorless oily primary alcohol intermediate with a yield of 99%, which was used directly in the next step without purification.

[0213] Under argon atmosphere, add DPPA (467 mg, 1.70 mmol), DEAD (296 mg, 1.70 mmol), PPh3 (445 mg, 1.70 mmol) to the tetrahydrofuran (25 mL) solution of the first step primary alcohol intermediate (215 mg, 0.85 mmol) under ice bath, and return to room temperature to react for 10 hours. After the reaction is completed, add ammonium chloride (20 mL) to quench, the aqueous phase is extracted with ethyl acetate (20 mL x 3), the organic phases are combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain (R,R)-5 as a colorless oil, 185 mg, 78% yield. 1 H NMR (400MHz, CDCl3): δ=7.29–7.23(m,2H),7.22–7.11(m,2H),7.08–7.01(m,2H),6.89(dd,J=7.5,1.7Hz,1H),6.71(d,J=8.2Hz ,1H),6.58(td,J=7.3,1.2Hz,1H),4.22(d,J=5.0Hz,1H),3.21–3.07(m,3H),3.01(s,3H),2.97–2.90(m,1H),2.54–2.40(m,1H); 13 C NMR (101MHz, CDCl3): δ=145.82,141.88,130.19,129.63,128.14,127.93,126.60,12 3.70,116.42,110.82,52.27,49.49,45.74,38.94,36.82.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 17 H 19 N4 279.1604; Found 279.1606.

[0214] Azide reduction and N-propionyl protection:

[0215]

[0216] (R,R)-5 (170 mg, 0.61 mmol) was weighed into a 25 mL hydrogenation inner tube, and Pd / C (17 mg) and ethanol (3 mL) were added. After the hydrogenation kettle was installed, argon was replaced, and hydrogen was filled at 50 atm and released to purge the reactor. After repeating three times, hydrogen was filled at 20 atm again and reacted at room temperature for 12 hours. After releasing the hydrogen pressure, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain an amine intermediate, which was directly used in the next step without purification.

[0217] Under argon atmosphere, Et3N (75 mg, 0.73 mmol) and propionic anhydride (96 mg, 0.73 mmol) were added to the tetrahydrofuran (4 mL) solution of the amine intermediate, and the reaction was continued at room temperature for 1 hour. After the reaction was completed, water (5 mL) was added to quench, the aqueous phase was extracted with ethyl acetate (10 mL x 3), the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1–5:1) gave a colorless oil (R,R)-6, 135 mg, 72% yield, 1 H NMR (400MHz, CDCl3): δ=7.28–7.22(m,2H),7.21–7.16(m,1H),7.15-7.08(m,1H),7.08–7 .00(m,2H),6.86(dd,J=7.5,1.7Hz,1H),6.69(d,J=8.2Hz,1H),6.56(td,J=7.3,1.2Hz,1H ),5.45–5.20(m,1H),4.13(d,J=5.1Hz,0H),3.30–3.20(m,1H),3.15–3.07(m,2H),2.98(s ,3H),2.95–2.89(m,1H),2.48–2.36(m,1H),2.07(q,J=7.6Hz,2H),1.05(t,J=7.6Hz,3H); 13 C NMR (101MHz, CDCl3): δ=173.7,145.9,142.8,130.1,129.4,128.2,127.8,126.5,124 .1,116.2,110.8,49.9,46.6,40.6,39.0,37.3,29.6,9.8.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 20 H 25N2O 309.1962;Found 309.1959.

[0218] Embodiment 37

[0219] In order to confirm the absolute configuration of the two adjacent chiral centers of (–)-4a obtained by Raney Ni reduction, ester reduction and primary alcohol mesylation were performed. The reaction equation is as follows:

[0220]

[0221] Under argon atmosphere, lithium aluminum hydride (0.44 g, 11.0 mmol) was added to a solution of (–)-4a (0.65 g, 2.20 mmol) in tetrahydrofuran (20 mL) in an ice bath in batches, and the mixture was allowed to react at room temperature for 10 hours. After the reaction was completed, water (2 mL) was added to quench the mixture, the mixture was filtered through diatomaceous earth, rinsed with ethyl acetate, and concentrated under reduced pressure to obtain a colorless oily primary alcohol intermediate, which was directly used in the next step without purification. Under argon atmosphere, methanesulfonyl chloride (0.51 g, 13.52 mmol), DMAP (27 mg, 0.22 mmol) and pyridine (0.26 g, 3.3 mmol) were added to a solution of the primary alcohol intermediate in CH2Cl2 (20 mL), and the reaction was continued at room temperature for 10 hours. After the reaction was completed, water (15 mL) was added to quench the mixture, the aqueous phase was extracted with ethyl acetate (20 mL x 3), the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) gave a white solid (-)-8, 590 mg, 81% yield. White solid, 1 H NMR (400MHz, CDCl3): δ=7.31–7.17(m,3H),7.17–7.11(M,1H),7.06–7.00(m,2H),6.88(d,J=7.4Hz,1H),6.72(d,J=8.3Hz,1H),6.59(t,J=7.3Hz,1H ), 4.26 (d, J = 5.2Hz, 1H), 4.06 (dd, J = 9.9, 6.3Hz, 1H), 3.79 (dd, J = 9.8, 8. 4Hz,1H),3.30–3.12(m,2H),3.01(s,3H),2.95(s,3H),2.75–2.64(m,1H); 13C NMR (101MHz, CDCl3): δ=145.7,141.5,130.1,129.4,128.3,128.0,126.8,123. 2,116.6,110.9,69.8,48.4,45.0,39.0,37.3,36.7.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 18 H 22 NO3S 332.1315;Found332.1315

[0222] (–)-8 (20 mg) was dissolved in 0.5 mL of dichloromethane and 0.5 mL of n-hexane, and the solvent was slowly evaporated at room temperature to obtain a single crystal of compound (–)-8. The X-ray single crystal diffraction results of (R,R)-8 are shown in the figure. Figure 1 .

[0223] Single crystal data of compound (–)-8 (CCDC 2336189)

[0224]

[0225] The test results show that the compound (–)-8 obtained in this example is of (R,R)-configuration; based on this, it is inferred that the compound (–)-4a is also of (R,R)-configuration.

[0226] Embodiment 38

[0227] According to the asymmetric hydrogenation method mentioned in the present invention, the (R)-3f compound prepared by asymmetric hydrogenation of 2f is used to prepare an ABCB1 inhibitor, and the reaction equation is:

[0228]

[0229] In a glove box, chiral spirocyclic pyridine aminophosphine ligand iridium catalyst (R)-1a (4.9 mg, 0.005 mmol), 4-phenyl-quinoline-3-carboxylic acid ethyl ester 2f (3.07 g, 10.0 mmol) and lithium tert-butoxide (160.0 mg, 2.0 mmol) were weighed into a 60 mL hydrogenation inner tube, and the inner tube was sealed with a sealing film and the kettle was taken out. After argon replacement, ethanol (20.0 mL) was added, and then hydrogen was filled at 50 atm and released to purge the reactor. After repeating three times, hydrogen was filled at 60 atm again and the reactor was placed in a 40 ° C oil bath for 7 days. After releasing the hydrogen pressure, 0.5 mL of saturated ammonium chloride solution was added to quench, and the short silica gel column was filtered (eluent: ethyl acetate), and the solvent was removed under reduced pressure to obtain a residue. The product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1-5:1) to give the hydrogenated product (R)-3f, 2.78 g, 90% yield, 94% ee.

[0230] Under ice bath conditions, sodium hydride (60wt%, 40mg, 1.0mmol) was added to a DMF (10mL) solution of (R)-3f (155mg, 0.50mmol), and then bromine (256mg, 1.5mmol) was added dropwise to the reaction system and returned to room temperature for 3 hours. After the reaction was completed, water was added to quench, and the aqueous phase was extracted three times with ether (10mLx3), and the organic phases were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to obtain (+)-7, which is an ABCB1 inhibitor. 180mg, 90% yield, yellow oil, 1 H NMR(400MHz, CDCl3)δ7.59(s,1H),7.38–7.23(m,5H),7.23–7.13(m,2H),7.12–7.05(m,1H),7.01–6.93(m,1H),6.87(t, J=7.4Hz,1H),6.79–6.72(m,3H),5.16(s,1H),4.97–4.80(m,2H),4.18–4.02(m,2H),3.71(s,3H),1.20(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ167.4,157.8,141.5,140.7,136.8,136.5,130.5,128.9,128.5,127.6,127.1 ,126.9,126.2,123.5,113.6,113.6,103.1,59.6,55.1,55.0,41.7,14.3.HRMS(ESI-TOF)m / z:[M+H] + Calculate for C 26 H 26 NO3400.1907;Found 400.1902.

Claims

1. A method for preparing chiral 1,4-dihydroquinoline, characterized in that The following steps are involved: In the presence of a hydrogen atmosphere, a chiral Ir-SpiroPAP catalyst, a base and a solvent, 4-substituted quinoline-3-carboxylate is subjected to asymmetric catalytic hydrogenation to obtain a chiral 1,4-dihydroquinoline compound, and the reaction formula is as follows: in: R is a C1-C20 alkyl, aryl, heteroaryl or alkenyl aryl; or, R has the following structure: Among them, R 1 is aryl or heteroaryl; R 2 is hydrogen or methyl; X is hydrogen, alkyl, alkoxy or halogen; The structural formula of the chiral Ir-SpiroPAP catalyst is: or its enantiomer (S)-1, Wherein, Y is hydrogen, alkyl, alkoxy or halogen.

2. The preparation method according to claim 1, characterized in that: The chiral Ir-SpiroPAP catalyst structural formula is: or its enantiomer (S)-1a.

3. The preparation method according to claim 1, characterized in that: The concentration of the 4-substituted-quinoline-3-carboxylate is 0.01-2.0 mmol / mL; the molar ratio of the 4-substituted-quinoline-3-carboxylate to the chiral Ir-SpiroPAP catalyst is (100-5000):1; the pressure of the hydrogen is 1-100 atm; the concentration of the base is 0.01-1.0 mmol / mL; the time for asymmetric catalytic hydrogenation is 24-168 hours; and the reaction temperature is 0-50°C.

4. The preparation method according to claim 3, characterized in that: The hydrogen pressure is 50 atm; the reaction temperature is room temperature to 50° C.; the molar ratio of 4-substituted-quinoline-3-carboxylate to chiral Ir-SpiroPAP catalyst is 200:1; the concentration of 4-substituted-quinoline-3-carboxylate is 0.05–1.0 mmol / mL; and the concentration of the base is 0.05–0.5 mmol / mL.

5. The preparation method according to claim 1, characterized in that: The base is an alkali metal salt of an alcohol, an alkali metal hydroxide or an alkali metal carbonate, wherein: the alkali metal salt of the alcohol is lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, potassium isopropoxide or sodium isopropoxide; the alkali metal hydroxide is potassium hydroxide or sodium hydroxide; the alkali metal carbonate is potassium carbonate, sodium carbonate or cesium carbonate.

6. The preparation method according to claim 1, characterized in that: The solvent is one of alcohol solvents, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide or a mixture of several thereof; the alcohol solvent is methanol, ethanol, n-propanol, isopropanol or butanol.

7. The preparation method according to claim 1, characterized in that: When R is an alkyl group, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl; When R is an aryl group, the aryl group is an aryl group with hydrogen, alkyl, alkoxy, halogen, ethoxycarbonyl, nitro or amino on the benzene ring; When R is a heteroaryl group, the heteroaryl group is furan, thiophene, benzofuran, benzothiophene, indole, pyridin-2 / 3 / 4-yl, or alkyl or halogen-substituted pyridin-2 / 3 / 4-yl; When R is an alkenyl aryl group, the alkenyl aryl group is a styryl group, a vinyl pyridin-2 / 3 / 4-yl group, a vinyl thiophene group, or a vinyl aryl group substituted with an alkyl group, an alkoxy group or a halogen group; The R 1 When it is an aryl group, the aryl group is an aryl group substituted by an alkyl group, an alkoxy group, a fluorine group, a chlorine group or a bromine group; R 1 When it is a heteroaryl group, the heteroaryl group is pyridine and thiophene.

8. Application of the preparation method according to claim 1 in the preparation of melatonin MT2 receptor, characterized in that The reaction process is as follows: In the reaction of preparing compound (R)-3a by asymmetric hydrogenation of substrate 2a, the molar ratio of 4-phenyl-quinoline-3-carboxylate to Ir-SpiroPAP catalyst (R)-1a is (200-5000):1; the concentration of 4-phenyl-quinoline-3-carboxylate is 0.01-1.0 mmol / mL; the pressure of hydrogen is 1-100 atm; the concentration of lithium tert-butoxide is 0.01-1.0 mmol / mL; the time of asymmetric catalytic hydrogenation is 24-168 hours; the reaction temperature is 30-50°C; The product (R)-3a obtained by the hydrogenation reaction was reacted with iodomethane and sodium hydride in tetrahydrofuran solvent with stirring for 3-12 hours, and then simply post-treated and purified by column chromatography, and then transferred to a hydrogenation reaction tube via methanol, Raney Ni was added, and hydrogen was filled at 1-100 atm. The enamine was reduced at room temperature to obtain the chiral product (R,R)-4; The chiral compound (R,R)-4 was dissolved in tetrahydrofuran, and lithium aluminum hydride was added in batches under ice bath conditions. The reaction was stirred at room temperature for 3-12 hours, and water was added to quench the reaction. After filtration through diatomaceous earth, the primary alcohol intermediate was obtained. No further purification was required and the next step of Mitsunobu reaction was directly carried out. At 0°C, diphenylphosphoryl azide (DPPA), diethyl azodicarboxylate and triphenylphosphine were added to the tetrahydrofuran solution of the primary alcohol intermediate obtained in the previous step, and the mixture was heated to room temperature for 3–12 hours to obtain azide compound (R,R)-5; The azide compound (R,R)-5 was transferred to a hydrogenation reactor via ethanol, and the azide was reduced to an amine under Pd / C / hydrogen conditions, and the reaction was carried out at room temperature for 3-12 hours. After the hydrogen pressure was released, the amine intermediate was obtained by filtration through diatomaceous earth, and was directly used in the next reaction without purification. Then, triethylamine and propionic anhydride are added to the tetrahydrofuran solution of the amine intermediate, and the mixture is reacted at room temperature for 1-5 hours. After simple post-treatment, the mixture is purified by silica gel column chromatography to obtain an oily substance, Melatonin MT2 receptor (R,R)-6.

9. The use according to claim 8, characterized in that: In the reaction of preparing chiral product (R,R)-4 from product (R)-3a, the equivalent ratio of (R)-3a to sodium hydride is 1:(1.0–5.0); the equivalent ratio of (R)-3a to methyl iodide is 1:(1.0–5.0), and the mass ratio of (R)-3a to Raney Ni is 1:(1.0–10.0); the hydrogen pressure is 1–50 atm; Preferably, in the reaction for preparing the azide compound (R,R)-5, the equivalent ratio of (R,R)-4 to lithium aluminum hydride is 1:(1.0-10.0); the equivalent ratio of (R,R)-4 to diphenylphosphoryl azide is 1:(1.0-5.0); the equivalent ratio of (R,R)-4 to diethyl azodicarboxylate is 1:(1.0-5.0); the equivalent ratio of (R,R)-4 to triphenylphosphine is 1:(1.0-5.0); Preferably, in the reaction for preparing the oily Melatonin MT2 receptor (R,R)-6, the mass ratio of (R,R)-5 to Pd / C is (1.0-100.0):1; the hydrogen pressure of the reaction is 1-100 atm; the equivalent ratio of (R,R)-5 to triethylamine is 1:(1.0-5.0); and the equivalent ratio of (R,R)-5 to propionic anhydride is 1:(1.0-10.0).

10. Use of the preparation method according to claim 1 in the preparation of ABCB1 inhibitors, characterized in that The reaction equation is: In the reaction of preparing compound (R)-3f by asymmetric hydrogenation of substrate 2f, the molar ratio of 4-(4-methoxyphenyl)-quinoline-3-carboxylate to Ir-SpiroPAP catalyst (R)-1a is (200-5000):1; the concentration of 4-(4-methoxyphenyl)-quinoline-3-carboxylate is 0.01-1.0 mmol / mL; the pressure of hydrogen is 1-100 atm; the concentration of lithium tert-butoxide is 0.01-1.0 mmol / mL; the time of asymmetric catalytic hydrogenation is 24-168 hours; the reaction temperature is 30-50°C; At 0°C, sodium hydride and benzyl bromide are added to a N,N-diformamide solution of the hydrogenated product (+)-3f, and the mixture is heated to room temperature and stirred for reaction for 1-5 hours. After simple post-treatment and purification by column chromatography, a chiral product ABCB1 inhibitor (+)-7 is obtained; preferably, the equivalent ratio of the hydrogenated product (+)-3f to sodium hydride is 1:(1.0-5.0); the equivalent ratio of (+)-3f to benzyl bromide is 1:(1.0-5.0).

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