Process for the preparation of chiral 1,4-dihydroquinolines and use thereof

Abstract

The application discloses a preparation method and application of chiral 1,4-dihydroquinoline. The method adopts a chiral Ir-SpiroPAP catalyst to perform asymmetric catalytic hydrogenation on 4-substituted-quinoline-3-carboxylate, and a series of chiral 1,4-dihydroquinoline with high enantioselectivity is obtained. The reaction has a wide substrate application range, the catalyst consumption can be as low as 0.05 mol%, and the obtained chiral 1,4-dihydroquinoline has an enantioselectivity as high as 99% ee. The optical active 1,4-dihydroquinoline with one stereogenic center is used as a key chiral raw material and applied to asymmetric synthesis of Melatonin MT2 receptor and ABCB1 inhibitor respectively.

Description

TECHNICAL FIELD

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

[0002] Chiral 1,4-dihydroquinoline is an important heterocyclic compound with nitrogen-containing heterocyclic ring, has significant biological activity and interesting biological properties, and is widely present in bioactive molecules and natural products. In addition, chiral 1,4-dihydroquinoline derivatives are an important research direction of drug discovery and synthetic chemistry. Although asymmetric hydrogenation reactions of quinoline compounds catalyzed by iridium, ruthenium, manganese, borane and the like have been developed, the final obtained compounds are limited to chiral tetrahydroquinoline, but not chiral 1,4-dihydroquinoline, even if a dihydroquinoline intermediate is detected in the reaction process, 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 underwent nucleophilic addition with naphthyllithium to give 1,4-dihydroquinoline with 76% ee (Meyers, A. I. et al. J. Am. Chem. Soc. 1984, 106, 1135-1136). In 2007, Yamada et al. studied the asymmetric addition of quinoline containing a chiral oxazoline auxiliary group at the 3-position to give chiral 1,4-dihydroquinoline with 78% de value (Yamada, S. et al. Org. Lett. 2007, 9, 1477-1480). Recently, Coldham et al. obtained enantiomerically enriched 2-aryl dihydroquinoline and chiral 1,4-dihydroquinoline by kinetic resolution of racemic 2-aryl dihydroquinoline (Yeo, S.-H. et al. Chem. Eur. J. 2023, 29, e202300815). Wang Wei and Kim et al. developed organocatalytic small molecule-catalyzed aza-Michael / aldol cascade reaction or Michael / aza-cyclization cascade reaction of aldehyde or ketone with 2-amino-β-nitro unsaturated aryl ketone to give chiral 1,4-dihydroquinoline 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 of quinoline-3-carboxamide with chiral boron reagent 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-oxobutanoate with o- quinone methide (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 the asymmetric [4+2] cycloaddition of benzyl mercaptan and malononitrile catalyzed by organic base to generate chiral 1,4-dihydroquinoline with 93% ee enantioselectivity (Liu, X. et al. Chem. Commun. 2019, 55, 2668-2671).In addition, Harutyunyan et al. found the presence of chiral 1,4-dihydroquinoline in the study of the mechanism of nucleophilic de-aromatization of quinoline, but it is difficult to retain dihydroquinoline under the reaction conditions (Yan, X. et al. J. Am. Chem. Soc. 2020, 142, 20247-20256). Unfortunately, Liu et al. recently reported the manganese-catalyzed regioselective borohydration of quinoline, but racemic 1,4-dihydroquinoline was obtained (Wang, Y. et al. CCS Chem. 2023, 10.31635 / ccschem.023.202303289).

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

[0005] In order to solve the problems existing in the prior art, one object of the present application is to provide a method for preparing chiral 1,4-dihydroquinoline by asymmetric catalytic hydrogenation, which has a wide substrate range, a small amount of catalyst, and high enantioselectivity.

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

[0007] Still another object of the present application is to provide an application of the chiral 1,4-dihydroquinoline compound prepared by the above method in the synthesis of Melatonin MT2 receptor and ABCB1 inhibitor.

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

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

[0010] In the presence of hydrogen atmosphere, chiral Ir-SpiroPAP catalyst, base and solvent, 4-substituted quinoline-3-carboxylate is subjected to asymmetric catalytic hydrogenation to obtain 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 group; or R has the following structure:

[0013]

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

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

[0016] The chiral Ir-SpiroPAP catalyst has the following structure:

[0017] or an enantiomer thereof (S)-1,

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

[0019] Preferably, the chiral Ir-SpiroPAP catalyst has the following structure:

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

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

[0022]

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

[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 gas is 1-100 atm; the concentration of the base is 0.01-1.0 mmol / mL; the time of the asymmetric catalytic hydrogenation is 24-168 hours; and the reaction temperature is 0-50°C.

[0026] Preferably, the pressure of the hydrogen gas is 50 atm; the reaction temperature is room temperature-50°C; the molar ratio of the 4-substituted-quinoline-3-carboxylate to the chiral Ir-SpiroPAP catalyst is 200:1; the concentration of the 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 alcohol, alkali metal hydroxide or alkali metal carbonate, wherein: the alkali metal salt of 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 or a mixture of several of alcohol solvent, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N, N-dimethylformamide, dimethyl sulfoxide; 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 a benzene ring;

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

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

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

[0035] The above reaction product includes:

[0036]

[0037]

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

[0039]

[0040] In the reaction of preparing compound (R)-3a from substrate 2a by asymmetric hydrogenation, the molar ratio of 4-phenyl-quinoline-3-carboxylic acid ester to Ir-SpiroPAP catalyst (R)-1a is (200-5000):1; the concentration of 4-phenyl-quinoline-3-carboxylic acid ester 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℃.

[0041] The product (R)-3a obtained by hydrogenation is stirred with methyl iodide and sodium hydride in tetrahydrofuran solvent for 3-12 hours, and then subjected to simple post-treatment and column chromatography purification. The methanol is transferred into the hydrogenation reactor, Raney Ni is added, and the enamine is reduced under the condition of hydrogen gas pressure of 1-100 atm and room temperature to obtain a chiral product (R,R)-4, wherein 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); and the hydrogen gas pressure is 1-50 atm.

[0042] The chiral compound (R,R)-4 is dissolved in tetrahydrofuran, lithium aluminum hydride is added in batches under ice bath condition, and the stirring reaction is carried out at room temperature for 3-12 hours. After quenching by adding water and then performing diatomite suction filtration, a primary alcohol intermediate is obtained, which is directly subjected to the next Mitsunobu reaction without further purification.

[0043] Diphenyl phosphorazide (DPPA), diethyl azodicarboxylate and triphenylphosphine are added to the tetrahydrofuran solution of the primary alcohol intermediate obtained in the previous step under the condition of 0℃, and then the reaction is carried out at room temperature for 3-12 hours to obtain an azido 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 diphenyl phosphorazide 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 azido compound (R,R)-5 is transferred into a hydrogenation reactor by ethanol, and azide reduction to amine is carried out under the condition of Pd / C / hydrogen, and the stirring reaction is carried out at room temperature for 3-12 hours. After releasing the hydrogen gas pressure, diatomite suction filtration is carried out to obtain an amine intermediate, which is directly used in the next step reaction without purification.

[0045] Then triethylamine, propionic anhydride are added to the tetrahydrofuran solution of the amine intermediate, and the reaction is carried out at room temperature for 1-5 hours, and after simple post-treatment, the oil Melatonin MT2 receptor (R,R)-6 is obtained by silica gel column chromatography purification; 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 application also protects the use of the above method in the preparation of an ABCB1 inhibitor, characterized in that the reaction equation is:

[0047]

[0048] In the reaction of preparing compound (R)-3f from substrate 2f by asymmetric hydrogenation, 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 hydrogen pressure 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 are added to the N,N-dimethylamide solution of hydrogenation product (+)-3f, and the reaction is stirred at room temperature for 1-5 hours, and after simple post-treatment and column chromatography purification, the chiral product ABCB1 inhibitor (+)-7 is obtained; wherein the equivalent ratio of hydrogenation product (+)-3f to sodium hydride is 1:(1.0-5.0); and the equivalent ratio of (+)-3f to benzyl bromide is 1:(1.0-5.0).

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

[0051] 1. The method of the application increases the polarity of the C3-C4 carbon-carbon double bond by introducing an ester group at the C-3 position of quinoline, so that the chiral Ir-SpiroPAP catalyst can selectively hydrogenate the polar C3-C4 carbon-carbon double bond of quinoline, and then an alkali-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 yield of up to 95% and an enantioselectivity of 99% ee. In addition, the asymmetric hydrogenation reaction in the method of the application can be carried out at a catalyst dosage of 0.05 mol%, and the yield and enantioselectivity can be maintained.

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

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

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

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

[0056] The preparation method and application of the present application are described in detail below in combination with examples and drawings.

[0057] The structure of the spirocyclic pyridyl amine phosphine-iridium catalyst (Ir-SpiroPAP catalyst, hereinafter referred to as "iridium catalyst") used in the following examples is as follows, unless otherwise specified:

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

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

[0060] Example 1

[0061]

[0062] Under argon protection, the iridium catalyst (R)-1a (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) were sequentially added to the inner tube of the hydrogenation reaction, and 4-phenylquinoline-3-carboxylic acid ethyl ester 2a (0.5 mmol) and ethanol (2.0 mL) were added. The reaction kettle was sealed, hydrogen was filled to 50 atm, and the reaction was stirred at 40°C for 36 hours. After the hydrogenation reaction was completed, the hydrogen was released, 0.5 mL of saturated ammonium chloride was added for quenching, and the short silica gel column was extracted 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. 130 mg, 93% yield, 95% ee, 1H NMR (400 MHz, CDC13): δ = 7.57 (d, J = 6.0 Hz, 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 = 5.8 Hz, 1H), 5.14 (s, 1H), 4.17-4.01 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 18 H 18 NO2 280.1332; Found 280.1333. High performance liquid chromatography separation condition: Chiralcel AD-3 column (25 cm x 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) = 4.98 min; t R (minor) = 6.56 min; (the ee value of the product was determined after the tert-butyloxycarbonyl protection of the amine group).

[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, and the X-single crystal diffraction result is shown in FIG. 1. Figure 1 .

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

[0065]

[0066]

[0067] Example 2

[0068]

[0069] Under argon, the inner tube of the hydrogenation reactor was charged with iridium catalyst (R)-1b (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 4-phenylquinoline-3-carboxylate 2a (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and charged with hydrogen to 50 atm. The reaction was stirred at 40 °C for 36 h. After the hydrogenation was complete, the hydrogen was released and the reaction was quenched with 0.5 mL of saturated ammonium chloride. The reaction was filtered through a short plug of silica gel and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (R)-3a. 90 mg, 65% yield, 86% ee.

[0070] High performance liquid chromatography separation conditions: Chiralcel AD-3 column (25 cm x 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) = 4.92 min; t R (minor) = 6.50 min; (ee value of product was determined after the amine group was protected with tert-butyloxycarbonyl).

[0071] Example 3

[0072]

[0073] Under argon, the inner tube of the hydrogenation reactor was charged with iridium catalyst (R)-1b (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 4-phenylquinoline-3-carboxylate 2a (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and charged with hydrogen to 50 atm. The reaction was stirred at 40 °C for 36 h. After the hydrogenation was complete, the hydrogen was released and the reaction was quenched with 0.5 mL of saturated ammonium chloride. The reaction was filtered through a short plug of silica gel and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (R)-3a. 90 mg, 65% yield, 86% ee.

[0074] High performance liquid chromatography separation conditions: Chiralcel AD-3 column (25 cm x 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) = 4.92 min; t R (minor) = 6.50 min; (ee value of product was determined after the amine group was protected with tert-butyloxycarbonyl).

[0075] Example 4

[0076]

[0077] Into the inner tube of the hydrogenation reactor, iridium catalyst (R)-1d (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) were added successively under argon atmosphere, followed by 4-phenylquinoline-3-carboxylic acid ethyl ester 2a (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and charged with hydrogen gas to 50 atm. The reaction was stirred at 40 °C for 36 h. After the hydrogenation was completed, the hydrogen gas was released and the reaction was quenched by the addition of 0.5 mL of saturated ammonium chloride. The mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (R)-3a. 118 mg, 85% yield, 88% ee.

[0078] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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) = 4.94 min; t R (minor) = 6.52 min; (ee value of the product was determined after the amino group was protected with tert-butyloxycarbonyl).

[0079] Example 5

[0080]

[0081] Into the inner tube of the hydrogenation reactor, iridium catalyst (R)-1d (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) were added successively under argon atmosphere, followed by 4-phenylquinoline-3-carboxylic acid ethyl ester 2a (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and charged with hydrogen gas to 50 atm. The reaction was stirred at 40 °C for 36 h. After the hydrogenation was completed, the hydrogen gas was released and the reaction was quenched by the addition of 0.5 mL of saturated ammonium chloride. The mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (R)-3a. 118 mg, 85% yield, 88% ee.

[0082] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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) = 4.91 min; tR (minor) = 6.52 min; (determined product ee value after protecting amine group with tert-butyloxycarbonyl).

[0083] Example 6

[0084]

[0085] To the inner tube of hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol), lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 4-(4-fluoro-phenyl)quinoline-3-carboxylate 2b (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed and hydrogenated to 50 atm, stirred at 40 °C for 36 h. After the hydrogenation was completed, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and the mixture 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 give (+)-3b. 141 mg, 95% yield, 95% ee, 1 H NMR (400 MHz, CDC13): δ = 7.56 (d, J = 6.0 Hz, 1H), 7.25 - 7.19 (m, 2H), 7.11 - 7.01 (m, 2H), 6.95 - 6.85 (m, 3H), 6.73 (d, J = 7.9 Hz, 1H), 6.34 (d, J = 6.0 Hz, 1H), 5.13 (s, 1H), 4.18 - 4.01 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): δ = 167.7, 161.2 (d, 1 J C-F = 244.0 Hz), 144.2 (d, 4 J C-F = 3.2 Hz), 136.4, 135.4, 130.2, 128.9 (d, 3 J C-F = 7.8 Hz), 127.1, 124.8, 123.5, 115.1, 114.9 (d, 2 J C-F = 21.2 Hz), 102.4, 59.7, 41.6, 14.3. HRMS (ESI-TOF) m / z: [M + H] + calcd for C 18 H 17 FNO 298.1238; Found 298.1232.

[0086] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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) = 4.88 min; t R (minor) = 6.56 min; (the ee value of the product was determined after the amino group was protected with tert-butyloxycarbonyl).

[0087] Example 7

[0088]

[0089] To the inner tube of the hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) under argon protection, ethyl 4-(4-chloro-phenyl)quinoline-3-carboxylate 2c (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and hydrogenated to 50 atm, stirred at 40 °C for 36 h. After the hydrogenation was completed, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and the mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3c. 145 mg, 93% yield, 93% ee, 1 H NMR (400 MHz, CDC13): δ = 7.55 (d, J = 6.0 Hz, 1H), 7.23 - 7.14 (m, 4H), 7.09 - 6.99 (m, 2H), 6.93 - 6.86 (m, 1H), 6.73 - 6.60 (m, 2H), 5.12 (s, 1H), 4.18 - 4.01 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): δ = 167.5, 146.7, 136.3, 135.3, 131.8, 130.2, 128.9, 128.4, 127.2, 124.5, 123.7, 115.1, 102.5, 59.7, 41.8, 26.9, 14.3. HRMS (ESI-TOF) m / z: [M + H] + calcd for C 18 H 17 ClNO2 314.0943; Found 314.0947.

[0090] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 5.02 min; t R (minor) = 6.38 min; (the ee value of the product was determined after the amino group was protected with tert-butyloxycarbonyl).

[0091] Example 8

[0092]

[0093] Into the inner tube of the hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol), lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 4-(4-methyl-phenyl)quinoline-3-carboxylate 2e (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed and hydrogenated to 50 atm, and stirred at 40 °C for 36 h. After the hydrogenation was completed, the hydrogen was released, 0.5 mL of saturated ammonium chloride was added to quench, and the mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3e. 138 mg, 94% yield, 92% ee, 1 H NMR (400 MHz, CDC13): δ = 7.51 (d, J = 6.0 Hz, 1H), 7.20 - 7.12 (m, 2H), 7.08 - 6.96 (m, 4H), 6.86 (t, J = 7.4 Hz, 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 = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDC13): δ = 167.7, 145.5, 136.3, 135.5, 135.5, 130.2, 128.9, 127.3, 126.9, 125.2, 123.5, 115.0, 102.8, 59.6, 41.9, 20.9, 14.3. HRMS (ESI-TOF) m / z: [M + H] + calcd for C 19 H 20 NO2 294.1489; Found 294.1491.

[0094] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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) = 4.92 min; t R (minor) = 6.01 min; (the ee value of the product was determined after the amino group was protected by tert-butyloxycarbonyl).

[0095] Example 9

[0096]

[0097] Into the inner tube of the hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 4-(4-methoxy-phenyl)quinoline-3-carboxylate 2f (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed, charged with hydrogen gas to 50 atm, and stirred at 40 °C for 36 h. After the hydrogenation reaction was completed, the hydrogen gas was released, 0.5 mL of saturated ammonium chloride was added for quenching, and the mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3f. 140 mg, 91% yield, 93% ee, 1 H NMR (400 MHz, CDC13): δ = 7.51 (d, J = 6.0 Hz, 1H), 7.22 - 7.16 (m, 2H), 7.06 - 6.93 (m, 3H), 6.86 (t, J = 7.3 Hz, 1H), 6.78 - 6.71 (m, 2H), 6.64 (d, J = 7.9 Hz, 1H), 5.10 (s, 1H), 4.18 - 4.01 (m, 2H), 3.67 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): δ = 167.8, 157.7, 141.0, 136.3, 135.4, 130.1, 128.4, 126.8, 125.2, 123.3, 115.0, 113.5, 102.5, 59.5, 55.0, 41.4, 14.3. HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 19 NO3Na 332.1257; Found 332.1255.

[0098] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 6.44 min; t R (minor) = 10.48 min; (the ee value of the product was determined after the amino group was protected with tert-butyloxycarbonyl).

[0099] Example 10

[0100]

[0101] To the inner tube of the hydrogenation reactor, was added successively under argon atmosphere, iridium catalyst (R)-la (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 4-(4-ethoxycarbonyl-phenyl)quinoline-3-carboxylate 2g (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed, charged with hydrogen gas to 50 atm, and stirred at 40 °C for 36 h. After the hydrogenation was completed, the hydrogen gas was released, 0.5 mL of saturated ammonium chloride was added to quench, and the mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3g. 149 mg, 91% yield, 92% ee, 1 H NMR (400 MHz, CDC13): δ = 7.98 - 7.86 (m, 2H), 7.59 (d, J = 6.0 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.16 - 6.95 (m, 3H), 6.90 - 6.83 (m, 1H), 6.72 (d, J = 7.9 Hz, 1H), 5.21 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.16 - 4.00 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): δ = 167.5, 166.7, 153.2, 136.7, 135.4, 130.2, 129.7, 128.2, 127.5, 127.3, 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] + calcd for C 21 H 22 NO 4352.1544; Found 352.1545.

[0102] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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 (minor) = 18.93 min; (the ee value of the product was determined after the amino group was protected by tert-butyloxycarbonyl). R (minor) = 18.93 min; (the ee value of the product was determined after the amino group was protected by tert-butyloxycarbonyl).

[0103] Example 11

[0104]

[0105] Into the inner tube of the hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol), lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 4-(3-chloro-phenyl)quinoline-3-carboxylate 2h (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed and hydrogenated to 50 atm, stirred at 40 °C for 36 h. After the hydrogenation was completed, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and the mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3h. 142 mg, 91% yield, 90% ee, 1 HNMR (400 MHz, CDC13): δ = 7.56 (d, J = 6.0 Hz, 1H), 7.24 (s, 1H), 7.20-7.11 (m, 2H), 7.11-7.00 (m, 3H), 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 = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 18 H 17 ClNO2 314.0943; Found 314.0942.

[0106] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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) = 4.84 min; t R (minor) = 6.06 min; (the ee value of the product was determined after the amino group was protected by tert-butyloxycarbonyl).

[0107] Example 12

[0108]

[0109] Into the inner tube of the hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol), lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 4-(3-bromo-phenyl)quinoline-3-carboxylate 2i (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed and charged with hydrogen gas to 50 atm, and stirred at 40 °C for 36 h. After the hydrogenation reaction was completed, the hydrogen gas was released, 0.5 mL of saturated ammonium chloride was added to quench, and the mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3i. 162 mg, 91% yield, 92% ee, 1 H NMR (400 MHz, CDC13): δ = 7.57 (d, J = 6.0 Hz, 1H),, 7.39 (t, J = 1.8 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.12 - 7.02 (m, 3H), 6.91 (td, J = 7.5, 1.2 Hz, 1H), 6.73 (dd, J = 7.9, 1.3 Hz, 1H), 6.45 (d, J = 6.1 Hz, 1H), 5.11 (s, 1H), 4.19 - 4.01 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 18 H 17BrNO2 358.0437, 360.0417; Found 358.0435, 360.0413.

[0110] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 5.09 min; t R (minor) = 6.03 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl).

[0111] Example 13

[0112]

[0113] To the inner tube of hydrogenation reaction, iridium catalyst (R)-la (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) were added successively under argon protection, followed by 4-(3-methyl-phenyl)quinoline-3-carboxylic acid ethyl ester 2j (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and hydrogenated to 50 atm, and stirred at 40 °C for 36 h. After the hydrogenation reaction was completed, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and then the mixture 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. 129 mg, 88% yield, 90% ee, 1 H NMR (400 MHz, CDC13): δ = 7.54 (d, J = 6.0 Hz, 1H), 7.13 - 7.00 (m, 5H), 6.95 - 6.90 (m, 1H), 6.88 (td, J = 7.5, 1.2 Hz, 1H), 6.68 (dd, J = 7.9, 1.2 Hz, 1H), 6.48 (s, 1H), 5.09 (s, 1H), 4.18 - 4.00 (m, 2H), 2.26 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 19H 20 NO2 294.1489; Found 294.1490.

[0114] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 4.98 min; t R (minor) = 6.56 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl).

[0115] Example 14

[0116]

[0117] To the inner tube of hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) under argon protection, ethyl 4-(3,4-dioxa-phenyl)quinoline-3-carboxylate 2l (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and hydrogenated to 50 atm, stirred at 40 °C for 36 hours. After the completion of hydrogenation, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and the mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3l. 134 mg, 83% yield, 89% ee, 1 H NMR (400 MHz, CDC13): δ = 7.54 (d, J = 6.0 Hz, 1H), 7.09 - 7.03 (m, 2H), 6.94 - 6.87 (m, 1H), 6.80 - 6.73 (m, 2H), 6.72 - 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 = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C19 H 18 NO4 324.1231;Found 324.1230.

[0118] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 7.76 min; t R (minor) = 11.88 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl).

[0119] Example 15

[0120]

[0121] To the inner tube of hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol), lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 4-(3,4-dichloro-phenyl)quinoline-3-carboxylate 2m (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed and hydrogenated to 50 atm, stirred at 40 °C for 36 h. After the hydrogenation was completed, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and the mixture 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 give (+)-3m. 161 mg, 93% yield, 94% ee, 1 H NMR (400 MHz, CDC13): δ = 7.57 (d, J = 6.1 Hz, 1H), 7.34 (s, 1H), 7.30-7.23 (m, 1H), 7.16-7.05 (m, 2H), 7.01 (d, J = 7.6 Hz, 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 = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 18 H15 Cl2NO2Na 370.0372; Found 370.0366.

[0122] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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) = 4.79 min; t R (minor) = 5.63 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl).

[0123] Example 16

[0124]

[0125] To the inner tube of hydrogenation reaction, lithium tert-butoxide (16.0 mg, 0.2 mmol) and ethyl 7-methoxy-4-(phenyl)quinoline-3-carboxylate 2q (0.5 mmol) were added successively under argon atmosphere. The reaction vessel was sealed and charged with hydrogen gas to 50 atm. The reaction was stirred at 40 °C for 48 h. After the hydrogenation reaction was completed, the hydrogen gas was released and 0.5 mL of saturated ammonium chloride was added to quench the reaction. The mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3q. 134 mg, 87% yield, 93% ee, 1 H NMR (400 MHz, CDC13): δ = 7.52 (d, J = 6.0 Hz, 1H), 7.30 - 7.18 (m, 4H), 7.14 - 7.06 (m, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.54 - 6.42 (m, 2H), 6.24 (d, J = 2.5 Hz, 1H), 5.07 (s, 1H), 4.17 - 4.00 (m, 2H), 3.71 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): δ = 167.6, 158.6, 148.5, 136.3, 136.0, 131.2, 128.2, 127.5, 126.0, 117.7, 109.3, 103.6, 100.5, 59.6, 55.2, 41.7, 14.3. HRMS (ESI-TOF) m / z: [M + H] + calcd for C 19 H 20NO 3310.1438; Found 310.1438.

[0126] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 5.87 min; t R (minor) = 7.20 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl).

[0127] Example 17

[0128]

[0129] To the inner tube of hydrogenation reaction, iridium catalyst (R)-la (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) were added successively under argon protection, followed by ethyl 7-methyl-4-(phenyl)quinoline-3-carboxylate 2r (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and hydrogenated to 50 atm, and stirred at 40 °C for 36 h. After the completion of hydrogenation, the hydrogen was released, 0.5 mL of saturated ammonium chloride was added to quench, and the mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3r. 138 mg, 88% yield, 90% ee, 1 H NMR (400 MHz, CDC13): δ = 7.59 (d, J = 6.0 Hz, 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 = 7.8 Hz, 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 = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): δ = 167.7, 148.5, 136.8, 136.2, 135.3, 130.1, 128.2, 127.5, 126.0, 124.5, 122.3, 115.5, 103.0, 59.5, 42.0, 21.0, 14.3. HRMS (ESI-TOF) m / z: [M + Na] + calcd for C 19 H 19NO2Na 316.1308; Found 316.1310.

[0130] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 4.16 min; t R (minor) = 5.82 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl).

[0131] Example 18

[0132]

[0133] To the inner tube of hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol), lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 8-methoxy-4-(phenyl)quinoline-3-carboxylate 2t (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed and hydrogenated to 50 atm, stirred at 40 °C for 36 h. After the hydrogenation was completed, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and the mixture 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 give (+)-3t. 134 mg, 87% yield, 97% ee, 1 H NMR (400 MHz, CDC13): δ = 7.61 (d, J = 6.0 Hz, 0 H), 7.30 - 7.25 (m, 2 H), 7.24 - 7.18 (m, 2 H), 7.14 - 7.06 (m, 1 H), 6.89 - 6.78 (m, 2 H), 6.66 (dd, J = 12.2, 7.9 Hz, 2 H), 5.14 (s, 1 H), 4.17 - 3.99 (m, 2 H), 3.87 (s, 3 H), 1.18 (t, J = 7.1 Hz, 3 H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 19 H 20HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 6.35 min; t R (minor) = 7.12 min; (product ee value was determined after the amino group was protected with tert-butyloxycarbonyl).

[0134] Example 19

[0135]

[0136] Into the inner tube of the hydrogenation reactor, was added sequentially iridium catalyst (R)-la (0.0025 mmol), lithium tert-butoxide (16.0 mg, 0.2 mmol), 4-(6-methylpyridin-3-yl)- quinoline-3-carboxylic acid ethyl ester 2v (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed, charged with hydrogen gas to 50 atm, and stirred at 40 °C for 36 h. After the hydrogenation reaction was completed, the hydrogen gas was released, 0.5 mL of saturated ammonium chloride was added to quench, and the mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3v. 132 mg, 90% yield, 91% ee, 1 H NMR (400 MHz, CDC13): 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 = 8.0 Hz, 1H), 5.14 (s, 1H), 4.17-4.03 (m, 2H), 2.47 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDC13): 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] + calcd for C 18 H 19 N2O2295.1441; Found 295.1440.

[0137] High performance liquid chromatography separation condition: Chiralcel AD-3 column (25 cm x 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 (minor) = 13.66 min; (the ee value of the product was determined after the amino group was protected by tert-butyloxycarbonyl). R (minor) = 13.66 min; (the ee value of the product was determined after the amino group was protected by tert-butyloxycarbonyl).

[0138] Example 20

[0139]

[0140] Into the inner tube of the hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) under argon protection, 4-(6-chloropyridin-3-yl)-quinoline-3-carboxylic acid ethyl ester 2w (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and hydrogenated to 50 atm, stirred at 40 °C for 36 h. After the hydrogenation reaction was completed, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and then the mixture 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 give (+)-3w. 145 mg, 92% yield, 91% ee, 1 H NMR (400 MHz, CDC13): δ = 8.32 (d, J = 2.5 Hz, 1H), 7.65 - 7.49 (m, 2H), 7.18 (d, J = 8.2 Hz, 1H), 7.15 - 7.05 (m, 2H), 7.02 - 6.97 (m, 1H), 6.96 - 6.89 (m, 1H), 6.77 (d, J = 7.9 Hz, 1H), 5.19 (s, 1H), 4.19 - 4.03 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): δ = 167.1, 148.9, 148.5, 142.5, 138.4, 136.7, 135.6, 130.2, 127.7, 124.2, 123.9, 123.2, 115.4, 101.5, 59.8, 39.4, 14.3. HRMS (ESI-TOF) m / z: [M + H] + calcd for C 17 H 16 ClN2O2 315.0895; Found 315.0895.

[0141] High performance liquid chromatography separation condition: Chiralcel AD-3 column (25 cm x 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 (minor) = 13.89 min; (the ee value of the product was determined after the amino group was protected by tert-butyloxycarbonyl). R (minor) = 13.89 min; (the ee value of the product was determined after the amino group was protected by tert-butyloxycarbonyl).

[0142] Example 21

[0143]

[0144] Under argon protection, the iridium catalyst (R)-la (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) were added into the inner tube of the hydrogenation reactor, followed by 4-(2-methylpyridin-4-yl)-quinoline-3-carboxylic acid ethyl ester 2x (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and hydrogenated to 50 atm, and stirred at 40 °C for 36 h. After the hydrogenation reaction was completed, the hydrogen was released, 0.5 mL of saturated ammonium chloride was added to quench, and then the mixture 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. 135 mg, 92% yield, 92% ee, 1 H NMR (400 MHz, CDC13): δ = 8.34 (d, J = 5.2 Hz, 1H), 8.21 - 8.05 (m, 1H), 7.63 (d, J = 6.1 Hz, 1H), 7.13 - 7.00 (m, 4H), 6.94 - 6.87 (m, 1H), 6.77 (d, J = 7.9 Hz, 1H), 5.14 (s, 1H), 4.19 - 4.03 (m, 2H), 2.49 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 18 H 19 N2O2 295.1441; Found 295.1443.

[0145] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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) = 6.91 min; t R (minor) = 8.11 min; (the ee value of the product was determined after the amino group was protected by tert-butyloxycarbonyl).

[0146] Example 22

[0147]

[0148] Into the inner tube of the hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol), lithium tert-butoxide (16.0 mg, 0.2 mmol), 4-(2-chloropyridin-4-yl)-quinoline-3-carboxylic acid ethyl ester 2y (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed and hydrogenated to 50 atm, and stirred at 40 °C for 36 h. After the hydrogenation was completed, the hydrogen was released, 0.5 mL of saturated ammonium chloride was added to quench, and the mixture 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 give (+)-3y. 144 mg, 92% yield, 91% ee, H NMR (400 MHz, CDC13): δ = 8.22 (d, J = 5.1 Hz, 1H), 7.61 (d, J = 6.1 Hz, 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 = 8.0 Hz, 1H), 6.51 - 6.42 (m, 1H), 5.16 (s, 1H), 4.20 - 4.04 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H); 13 CNMR (101 MHz, CDC13): δ = 167.1, 159.7, 151.4, 149.3, 137.4, 135.5, 130.0, 127.9, 123.8, 123.3, 122.3, 121.8, 115.6, 100.1, 59.8, 41.9, 14.2. HRMS (ESI-TOF) m / z: [M + H] + calcd for C 17 H 16 ClN2O2 315.0895; Found 315.0900.

[0149] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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) = 5.70 min; t R (minor) = 7.68 min; (the ee value of the product was determined after the amino group was protected by tert-butyloxycarbonyl).

[0150] Example 23

[0151]

[0152] Into the inner tube of the hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) under argon protection, ethyl 4-(benzothiophen-2-yl)-quinoline-3-carboxylate 2ab (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and hydrogenated to 50 atm, stirred at 40 °C for 36 h. After the hydrogenation was completed, the hydrogen was released, 0.5 mL of saturated ammonium chloride was added to quench, and the mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3ab. 154 mg, 92% yield, 87% ee, 1 H NMR (400 MHz, CDC13): δ = 7.64 (d, J = 7.9 Hz, 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 = 7.9 Hz, 1H), 5.51 (s, 1H), 4.25 - 4.10 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 20 H 18 NO2S 336.1053; Found 336.1058.

[0153] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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 (minor) = 8.31 min; (the ee value of the product was determined after the amino group was protected with tert-butyloxycarbonyl). R (minor) = 8.31 min; (the ee value of the product was determined after the amino group was protected with tert-butyloxycarbonyl).

[0154] Example 24

[0155]

[0156] Into the inner tube of the hydrogenation reactor, was added successively iridium catalyst (R)-la (0.001 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 4-methyl-quinoline-3-carboxylate 2ae (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed and charged with hydrogen gas to 50 atm, and stirred at 40 °C for 24 h. After the hydrogenation reaction was completed, the hydrogen gas was released, 0.5 mL of saturated ammonium chloride was added to quench, and the mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (–)-3ae. 96 mg, 89% yield, 83% ee, 1 H NMR (400 MHz, CDC13): δ = 7.40 (d, J = 6.0 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.06 (td, J = 7.6, 1.5 Hz, 1H), 6.96 (td, J = 7.4, 1.3 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.55 - 6.35 (m, 1H), 4.28 - 4.14 (m, 2H), 4.00 (q, J = 6.8 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.25 (d, J = 6.7 Hz, 3H); 13 C NMR (101 MHz, CDC13): 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: [M-H] + calcd for C 13 H 14 NO2 216.1030; Found 216.1028.

[0157] High performance liquid chromatography separation condition: Chiralcel AD-3 column (25 cm x 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) = 4.01 min; t R (minor) = 4.59 min; (amine group protected with tert-butyloxycarbonyl group to determine ee value).

[0158] Example 25

[0159]

[0160] To the inner tube of hydrogenation reactor, was added successively iridium catalyst (R)-la (0.001 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) under argon protection, ethyl 4- ethyl-quinoline-3-carboxylate 2af (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and hydrogenated to 50 atm, stirred at 40 °C for 24 hours. After the completion of hydrogenation, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and the mixture 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 give (–)-3af. 104 mg, 90% yield, 72% ee, 1 HNMR (400 MHz, CDC13): δ = 7.50 (d, J = 6.0 Hz, 1H), 7.12-7.04 (m, 2H), 6.97 (td, J = 7.5, 1.2 Hz, 1H), 6.74-6.48 (m, 2H), 4.27-4.13 (m, 2H), 3.97 (t, J = 5.2 Hz, 1H), 1.71-1.50 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.74 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 14 H 18 NO2 231.1259; Found 232.1330.

[0161] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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) = 3.87 min; t R (minor) = 4.83 min; (the ee value of the product was determined after the amino group was protected with tert-butyloxycarbonyl).

[0162] Example 26

[0163]

[0164] Into the inner tube of the hydrogenation reactor, was added successively iridium catalyst (R)-la (0.001 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol), 4-styryl-quinoline-3-carboxylic acid ethyl ester 2ai (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed and hydrogenated to 20 atm, and stirred at 40 °C for 24 hours. After the hydrogenation was completed, the hydrogen was released, 0.5 mL of saturated ammonium chloride was added to quench, and the mixture 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 give (+)-3ai. 138 mg, 90% yield, 99% ee, 1 HNMR (400 MHz, CDC13): δ = 7.49 (d, J = 6.1 Hz, 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, 1.2 Hz, 1H), 6.69 (dd, J = 7.9, 1.2 Hz, 1H), 6.45-6.35 (m, 1H), 6.31-6.18 (m, 2H), 4.75 (d, J = 6.2 Hz, 1H), 4.27-4.12 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDC13): δ = 167.5, 137.4, 136.6, 136.1, 133.1, 130.3, 128.3, 128.1, 127.3, 127.0, 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] + calcd for C 20 H 19NO2Na 328.1308; Found 328.1310.

[0165] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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 (minor) = 6.79 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl). R (minor) = 6.79 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl).

[0166] Example 27

[0167]

[0168] To the inner tube of hydrogenation reactor, was added successively iridium catalyst (R)-la (0.001 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) under argon protection, ethyl 4-(4-methyl-styrene)-quinoline-3-carboxylate 2ak (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and hydrogenated to 20 atm, stirred at 40 °C for 24 hours. After the completion of hydrogenation, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and the mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3ak. 145 mg, 91% yield, 99% ee, 1 H NMR (400 MHz, CDC13): δ = 7.48 (d, J = 6.0 Hz, 1H), 7.21 - 7.15 (m, 3H), 7.11 (td, J = 7.6, 1.5 Hz, 1H), 7.06 - 7.02 (m, 2H), 6.99 (td, J = 7.4, 1.2 Hz, 1H), 6.69 (dd, J = 7.9, 1.2 Hz, 1H), 6.29 - 6.12 (m, 3H), 4.73 (d, J = 5.1 Hz, 1H), 4.27 - 4.12 (m, 2H), 2.28 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13 CNMR (101 MHz, CDC13): δ = 167.7, 136.8, 136.7, 136.1, 134.5, 132.2, 130.2, 128.99, 127.8, 127.1, 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]+ C 21 H 21 NO2Na 342.1462; Found 342.1462.

[0169] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 5.13 min; t R (minor) = 6.88 min; (amine group protected with tert-butyloxycarbonyl group to determine ee value).

[0170] Example 28

[0171]

[0172] Into the inner tube of the hydrogenation reactor, was added sequentially iridium catalyst (R)-la (0.001 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) under argon protection, ethyl 4-(3-chloro-styryl)quinoline-3-carboxylate 2am (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and charged with hydrogen gas to 20 atm, stirred at 40 °C for 24 hours. Upon completion of the hydrogenation, the hydrogen gas was released, 0.5 mL of saturated ammonium chloride was added to quench, and the mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3am. 151 mg, 89% yield, 99% ee, 1 H NMR (400 MHz, CDC13): δ = 7.50 (d, J = 6.1 Hz, 1H), 7.19 - 7.07 (m, 5H), 7.03 - 6.96 (m, 1H), 6.71 (d, J = 7.9 Hz, 1H), 6.53 (s, 1H), 6.28 (dd, J = 15.7, 6.9 Hz, 1H), 6.20 - 6.08 (m, 1H), 4.75 (d, J = 7.0 Hz, 1H), 4.27 - 4.12 (m, 2H), 1.29 (t, J = 7.1 Hz, 1H); 13C NMR (101 MHz, CDC13): 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] + calcd for C 20 H 18 ClNO2Na 362.0918; Found 362.0920.

[0173] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 5.25 min; t R (minor) = 6.18 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl).

[0174] Example 29

[0175]

[0176] Into the inner tube of the hydrogenation reactor, was added sequentially iridium catalyst (R)-la (0.001 mmol), lithium tert-butoxide (16.0 mg, 0.2 mmol), 4-(3-methyl-styrene)-quinoline-3-carboxylic acid ethyl ester 2an (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed, charged with hydrogen gas to 20 atm, stirred at 40 °C for 24 hours. After the hydrogenation reaction was completed, the hydrogen gas was released, 0.5 mL of saturated ammonium chloride was added to quench, and the mixture was filtered through a short silica gel column and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3an. 141 mg, 88% yield, 99% ee, 1H NMR (400 MHz, CDC13): δ = 7.49 (d, J = 6.0 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 7.15 - 7.06 (m, 4H), 7.02 - 6.93 (m, 2H), 6.70 (d, J = 7.9 Hz, 1H), 6.32 - 6.22 (m, 2H), 6.21 - 6.15 (m, 1H), 4.74 (d, J = 6.5 Hz, 1H), 4.28 - 4.12 (m, 2H), 2.28 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 21 H 21 NO2Na 342.1462; Found 342.1466.

[0177] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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) = 4.76 min; t R (minor) = 5.80 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl).

[0178] Example 30

[0179]

[0180] Under argon, to the inner tube of hydrogenation reactor was added successively iridium catalyst (R)-la (0.001 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 4-(2-(pyridin-2-yl-vinyl)-quinoline-3-carboxylate 2ao (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed, charged with hydrogen to 20 atm, stirred at 40 °C for 24 h. After the hydrogenation was completed, the hydrogen was released, 0.5 mL of saturated ammonium chloride was added to quench, and the mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3ao. 132 mg, 87% yield, 97% ee, 1 H NMR (400 MHz, CDC13): δ = 8.47 - 8.39 (m, 1H), 8.09 - 7.97 (m, 1H), 7.57 (td, J = 7.7, 1.8 Hz, 1H), 7.48 (d, J = 6.1 Hz, 1H), 7.29 - 7.24 (m, 2H), 7.14 (dd, J = 7.4, 1.7 Hz, 1H), 7.08 - 7.03 (m, 1H), 7.00 - 6.89 (m, 2H), 6.78 (dd, J = 15.7, 7.1 Hz, 1H), 6.60 (dd, J = 7.7, 1.5 Hz, 1H), 6.32 (dd, J = 15.7, 1.1 Hz, 1H), 4.79 (dd, J = 7.1, 1.1 Hz, 1H), 4.35 - 4.02 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDC13): δ = 167.5, 156.1, 148.9, 138.2, 137.4, 136.5, 136.4, 129.8, 127.6, 127.3, 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] + calcd for C 19 H 19 N2O2 307.1441; Found 307.1443.

[0181] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 7.99 min; tR (minor) = 13.33 min; (ee value of the product determined after tert-butyloxycarbonyl protection of the amino group)

[0182] Example 31

[0183]

[0184] Under argon protection, iridium catalyst (R)-1a (0.001 mmol), lithium tert-butoxide (16.0 mg, 0.2 mmol), ethyl 4-(2-(thiophen-2-yl)-vinyl)-quinoline-3-carboxylate 2ap (0.5 mmol), and ethanol (2.0 mL) were added sequentially to the inner tube of the hydrogenation reaction. The reactor was sealed, purged with hydrogen to 20 atm, and stirred at 40 °C for 24 hours. After the hydrogenation reaction was complete, hydrogen was released, quenched with 0.5 mL of saturated ammonium chloride, filtered through a short silica gel column, and evaporated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give (+)-3ap. 150 mg, 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] + calcd for C 18 H 17 NO2NaS 334.0872; Found 334.0874.

[0185] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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) = 5.71 min; t R (minor) = 7.40 min; (the ee value of the product was determined after the amino group was protected by tert-butyloxycarbonyl).

[0186] Example 32

[0187]

[0188] Into the inner tube of the hydrogenation reactor, was added successively iridium catalyst (R)-la (0.0025 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) under argon protection, 4-phenyl-quinoline-3-carbonitrile 2ar (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and hydrogenated to 50 atm, stirred at 40 °C for 36 h. After the hydrogenation was completed, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and the mixture 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 give (+)-3ar. 105 mg, 90% yield, 96% ee, 1 H NMR (400 MHz, CDC13): δ = 7.34 - 7.17 (m, 5H), 7.10 - 7.02 (m, 1H), 6.95 - 6.78 (m, 4H), 6.65 (d, J = 7.9 Hz, 1H), 4.88 (s, 1H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 16 H 13 N 2233.1073; Found 233.1070.

[0189] HPLC separation condition: Chiralcel AD-3 column (25 cm x 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) = 4.93 min; t R (minor) = 5.50 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl).

[0190] Example 33

[0191]

[0192] To the inner tube of hydrogenation reactor, was added successively iridium catalyst (R)-la (0.001 mmol) and lithium tert-butoxide (16.0 mg, 0.2 mmol) under argon protection, 4-styryl-quinoline-3-carbonitrile 2as (0.5 mmol) and ethanol (2.0 mL). The reactor was sealed and hydrogenated to 20 atm, stirred at 40 °C for 24 h. After the hydrogenation was completed, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and then the mixture 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 give (+)-3as. 116 mg, 90% yield, 98% ee, 1 H NMR (400 MHz, CDC13): δ = 7.42 - 7.33 (d, J = 7.1 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H), 7.25 - 7.18 (m, 1H), 7.17 - 7.07 (m, 2H), 6.99 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 5.9 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 6.46 (d, J = 15.7 Hz, 1H), 6.26 (dd, J = 15.6, 8.0 Hz, 2H), 4.50 (d, J = 8.1 Hz, 1H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 18 H 15 N2 259.1230; Found 259.1227.

[0193] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 4.63 min; t R (minor) = 4.93 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl).

[0194] Example 34

[0195]

[0196] To the inner tube of hydrogenation reactor, was added successively iridium catalyst (R)-la (0.001 mmol), lithium tert-butoxide (16.0 mg, 0.2 mmol), 4-phenylacetylene-quinoline-3-carboxylic acid ethyl ester 2ar (0.5 mmol) and ethanol (2.0 mL) under argon protection. The reactor was sealed and hydrogenated to 20 atm, and stirred at 40 °C for 24 h. After the hydrogenation was completed, the hydrogen was released, 0.5 mL saturated ammonium chloride was added to quench, and the mixture 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 give (+)-3ai. 135 mg, 88% yield, 98% ee.

[0197] HPLC separation conditions: Chiralcel AD-3 column (25 cm x 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) = 5.25 min; t R (minor) = 6.76 min; (ee value of product was determined after protecting the amine group with tert-butyloxycarbonyl).

[0198] Example 35

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

[0200]

[0201] To a solution of hydrogenation product 3 (2.0 g, 6.0 mmol) in dichloromethane (30.0 mL) was added DMAP (12 mg, 0.1 mmol), triethylamine (90 μL, 65 mg, 0.6 mmol) and di-tert-butyl carbonate (Boc20) (131 mg, 140 μL, 0.6 mmol) dropwise under argon. The reaction was stirred at room temperature for at least 15 h. After direct concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20:1, v / v) to give the N-acylated derivative, which was ready for high performance liquid chromatography (HPLC) test for the enantiomeric excess value of hydrogenation product 3.

[0202] Example 36

[0203] According to the asymmetric hydrogenation method of the present application, the (R)-3a compound prepared from 2a by asymmetric hydrogenation reaction was used to prepare intermediate (R,R)-7, which was further used to prepare Melatonin MT2 receptor, and the reaction equation was as follows:

[0204]

[0205] Asymmetric hydrogenation reaction on a gram scale:

[0206] In a glove box, chiral spirocyclic pyridyl amine phosphine-iridium catalyst (R)-la (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 charged into a 60 mL hydrogenation inner tube, which was sealed with a septum and removed from the glove box. After replacement with argon, ethanol (20.0 mL) was added, followed by hydrogenation at 50 atm and release to purge the reactor, which was repeated three times. Then the reactor was charged with hydrogen at 60 atm and placed in a 40 °C oil bath for 5 days. After release of the hydrogen pressure, the reaction was quenched by the addition of 0.5 mL of saturated ammonium chloride solution and short silica gel column filtration (eluent: ethyl acetate). The solvent was removed under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1 - 5:1) to give hydrogenation product (+)-3a, 2.56 g, 92% yield, 94% ee.

[0207] N-alkylation and Raney Ni reduction:

[0208]

[0209] To a solution of (+)-3a (1.40 g, 5.0 mmol) in THF (30 mL) in an ice water bath was added NaH (144 mg, 6.0 mmol) in portions under argon and stirred for 0.5 h. Then iodomethane (1.06 g, 7.50 mmol) was added dropwise to the reaction mixture. The reaction was allowed to warm to room temperature and continue for 12 h. After the reaction was completed, water (20 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Purification by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) gave the N-methylation product, 1.45 g, 99% yield. Then, the N-methylation compound (295 mg, 1.00 mmol) was dissolved in methanol (5.0 mL) in a 25 mL hydrogenation inner tube, followed by the addition of Raney Ni (3.0 g, methanol-rinsing), and the reaction vessel was assembled. After argon replacement, the reaction vessel was charged with hydrogen gas at 50 atm and released to purge the reaction vessel, which was repeated three times. Then, the reaction vessel was charged with hydrogen gas at 50 atm and allowed to react at room temperature for 24 h. After the hydrogen pressure was released, the reaction mixture was filtered through celite (eluent: ethyl acetate), and the solvent was removed under reduced pressure to give a residue. Purification by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) gave (R,R)-4 as a colorless oil, 184 mg, 62% yield, 1 HNMR (400 MHz, CDC13): δ = 7.23-7.12 (m, 4H), 7.02-6.95 (m, 1H), 6.91 (d, J = 6.8 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.59 (t, J = 7.3 Hz, 1H), 4.57 (d, J = 4.9 Hz, 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 = 7.2 Hz, 3H); 13 C NMR (101 MHz, CDC13): δ = 171.7, 145.7, 142.5, 130.1, 129.3, 128.0, 127.9, 126.7, 123.3, 116.4, 110.8, 60.4, 46.5, 45.5, 43.3, 39.0, 14.1. HRMS (ESI-TOF) m / z: [M + H] + calcd for C 19 H 22 NO9296.1645; Found 296.1641.

[0210] Reduction of ester and Mitsunobu reaction:

[0211]

[0212] To a solution of (R,R)-4 (270 mg, 0.915 mmol) in THF (20 mL) was added LiAlH4(184 mg, 4.60 mmol) in portions at 0 °C under argon atmosphere, and the reaction was allowed to warm to room temperature for 10 h. After completion of the reaction, the reaction was quenched by the addition of water (2 mL) and filtered through celite, rinsing with EtOAc. The filtrate was concentrated under reduced pressure to give the primary alcohol intermediate as a colorless oil (230 mg, 99% yield) which was used in the next step without further purification.

[0213] To a solution of the primary alcohol intermediate (215 mg, 0.85 mmol) in THF (25 mL) was added DPPA (467 mg, 1.70 mmol), DEAD (296 mg, 1.70 mmol), PPh3(445 mg, 1.70 mmol) at 0 °C under argon atmosphere, and the reaction was allowed to warm to room temperature for 10 h. After completion of the reaction, the reaction was quenched by the addition of NH4CI (20 mL) and the aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the crude product. Purification by column chromatography on silica gel (eluent: petroleum ether / EtOAc = 20:1) gave (R,R)-5 as a colorless oil (185 mg, 78% yield). 1 H NMR (400 MHz, CDC13): 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, 1.7 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.58 (td, J = 7.3, 1.2 Hz, 1H), 4.22 (d, J = 5.0 Hz, 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 (101 MHz, CDC13): δ = 145.82, 141.88, 130.19, 129.63, 128.14, 127.93, 126.60, 123.70, 116.42, 110.82, 52.27, 49.49, 45.74, 38.94, 36.82. HRMS (ESI-TOF) m / z: [M + H] + calcd for C 17 H 19 N4 279.1604; Found 279.1606.

[0214] azide reduction and N-propionyl protection:

[0215]

[0216] Into a 25 mL hydrogenation inner tube, (R,R)-5 (170 mg, 0.61 mmol) was charged with Pd / C (17 mg) and ethanol (3 mL), the hydrogenation cell was assembled and purged with argon, charged with hydrogen gas at 50 atm and released to purge the cell, repeated three times, then charged with hydrogen gas at 20 atm and reacted at room temperature for 12 hours. After releasing the hydrogen pressure, the mixture was filtered through celite and concentrated under reduced pressure to give the amine intermediate, which was used in the next step without purification.

[0217] Into the solution of the amine intermediate in tetrahydrofuran (4 mL) was added Et3N (75 mg, 0.73 mmol), propionic anhydride (96 mg, 0.73 mmol) and continued to react 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 combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. Purification by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1-5:1) gave (R,R)-6 as colorless oil, 135 mg, 72% yield, 1 H NMR (400 MHz, CDC13): 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, 1.7 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.56 (td, J = 7.3, 1.2 Hz, 1H), 5.45-5.20 (m, 1H), 4.13 (d, J = 5.1 Hz, 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 = 7.6 Hz, 2H), 1.05 (t, J = 7.6 Hz, 3H); 13 C NMR (101 MHz, CDC13): 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] + calcd for C 20 H 25N2O 309.1962; Found 309.1959.

[0218] Example 37

[0219] To confirm the absolute configuration of the two adjacent chiral centers of the reduced (-)-4a by Raney Ni, the ester reduction and primary alcohol mesylation were carried out, as shown in the following reaction equation:

[0220]

[0221] To a solution of (-)-4a (0.65 g, 2.20 mmol) in THF (20 mL) was added LiAlH4(0.44 g, 11.0 mmol) portionwise under argon atmosphere at ice bath condition, and the reaction was allowed to warm to room temperature for 10 h. After the reaction was completed, the reaction was quenched by the addition of water (2 mL), and the mixture was filtered through celite, rinsing with EtOAc, and concentrated under reduced pressure to give the primary alcohol intermediate as a colorless oil, which was used in the next step without further purification. To a solution of the above primary alcohol intermediate in CH2Cl2(20 mL) was added methanesulfonyl chloride (0.51 g, 13.52 mmol), DMAP (27 mg, 0.22 mmol), and pyridine (0.26 g, 3.3 mmol) under argon atmosphere, and the reaction was allowed to continue at room temperature for 10 h. After the reaction was completed, the reaction was quenched by the addition of water (15 mL), and the aqueous phase was extracted with EtOAc (20 mL x 3), and the combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. Purification by silica gel column chromatography (eluent: petroleum ether / EtOAc = 20: 1) gave (-)-8 as a white solid, 590 mg, 81% yield. White solid, 1 H NMR (400 MHz, CDC13): δ = 7.31 - 7.17 (m, 3H), 7.17 - 7.11 (M, 1H), 7.06 - 7.00 (m, 2H), 6.88 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 6.59 (t, J = 7.3 Hz, 1H), 4.26 (d, J = 5.2 Hz, 1H), 4.06 (dd, J = 9.9, 6.3 Hz, 1H), 3.79 (dd, J = 9.8, 8.4 Hz, 1H), 3.30 - 3.12 (m, 2H), 3.01 (s, 3H), 2.95 (s, 3H), 2.75 - 2.64 (m, 1H); 13C NMR (101 MHz, CDC13): 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] + calcd for C 18 H 22 NO3S 332.1315; Found 332.1315

[0222] A single crystal of compound (–)-8 was obtained by dissolving (–)-8 (20 mg) in 0.5 mL of dichloromethane and 0.5 mL of n-hexane, and slowly evaporating the solvent at room temperature. The X-ray single crystal diffraction result of (R,R)-8 is shown in Figure 1. Figure 1 .

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

[0224]

[0225] The test results prove that the compound (–)-8 obtained in this embodiment is in (R,R)-configuration; accordingly, it is inferred that the compound (–)-4a is also in (R,R)-configuration.

[0226] Example 38

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

[0228]

[0229] In a glove box, chiral spirocyclic pyridyl amine phosphine 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 tube was sealed with a septum. After argon replacement, 20.0 mL of ethanol was added, followed by hydrogen charging of 50 atm and release to purge the reactor, which was repeated three times. Then the reactor was charged with hydrogen again at 60 atm and 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 for quenching, and the mixture was filtered through a short silica gel column (eluent: ethyl acetate). 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 hydrogenation product (R)-3f, 2.78 g, 90% yield, 94% ee.

[0230] To a solution of (R)-3f (155 mg, 0.50 mmol) in DMF (10 mL) was added sodium hydride (60 wt%, 40 mg, 1.0 mmol) under ice-bath condition, followed by dropwise addition of benzyl bromide (256 mg, 1.5 mmol) into the reaction system, and the reaction was allowed to warm to room temperature for 3 h. After the reaction was completed, the reaction was quenched by the addition of water, and the aqueous phase was extracted with diethyl ether (10 mL x 3) three times, and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 20: 1) to give (+)-7, which is an ABCB1 inhibitor. 180 mg, 90% yield, yellow oil, 1 H NMR (400 MHz, CDC13) δ 7.59 (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 = 7.4 Hz, 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 = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 167.4, 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] + calcd for C 26 H 26 NO3400.1907; Found 400.1902.

Claims

1. A process for the preparation of chiral 1,4-dihydroquinolines, characterized in that The method comprises the following steps: Asymmetrically catalyzing hydrogenation of 4-substituted quinoline-3-carboxylate in the presence of hydrogen, chiral Ir-SpiroPAP catalyst, base and solvent to obtain chiral 1,4-dihydroquinoline compound, and the reaction formula is as follows: Wherein: R is C1-C20 alkyl, aryl, heteroaryl or alkenyl aryl; or R has the following structure: wherein R 1 is aryl or heteroaryl; R 2 is hydrogen or methyl; X is hydrogen, alkyl, alkoxy or halogen; When R is alkyl, the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl; When R is aryl, the aryl is aryl with hydrogen, alkyl, alkoxy, halogen, ethoxycarbonyl, nitro or amino on the benzene ring; When R is heteroaryl, the heteroaryl is furan, thiophene, benzofuran, benzothiophene, indole, pyridine-2 / 3 / 4-yl, or alkyl, halogen-substituted pyridine-2 / 3 / 4-yl; When R is alkenyl aryl, the alkenyl aryl is styryl, vinyl pyridine-2 / 3 / 4-yl, vinyl thiophene, or alkyl, alkoxy or halogen-substituted vinyl aryl; R 1 When R is aryl, the aryl is alkyl, alkoxy, fluoro, chloro, or bromo substituted aryl; R 1 When R is heteroaryl, the heteroaryl is pyridine and thiophene; The chiral Ir-SpiroPAP catalyst has the following structure: or an enantiomer thereof (S)-1a.

2. The method of claim 1, wherein: 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 of the asymmetric catalytic hydrogenation is 24-168 hours; and the reaction temperature is 0-50 DEG C.

3. The method of claim 2, wherein: The pressure of the hydrogen is 50 atm; the reaction temperature is room temperature-50 DEG C; the molar ratio of the 4-substituted quinoline-3-carboxylate to the chiral Ir-SpiroPAP catalyst is 200:1; the concentration of the 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.

4. The method of claim 1, wherein: The base is alkali metal salt of alcohol, alkali metal hydroxide or alkali metal carbonate, wherein the alkali metal salt of 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; and the alkali metal carbonate is potassium carbonate, sodium carbonate or cesium carbonate.

5. The method of claim 1, wherein: The solvent is one or a mixture of several of alcohol solvent, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N,N-dimethylformamide and dimethyl sulfoxide; and the alcohol solvent is methanol, ethanol, n-propanol, isopropanol or butanol.

6. Use of the preparation method of claim 1 for the preparation of Melatonin MT2 receptors, characterized in that The reaction process is as follows: In the reaction of preparing compound (R)-3a from substrate 2a by asymmetric hydrogenation, the molar ratio of 4-phenyl-quinoline-3-carboxylic acid ester to Ir-SpiroPAP catalyst (R)-1a is (200-5000):1; the concentration of 4-phenyl-quinoline-3-carboxylic acid ester 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℃; The product (R)-3a obtained by hydrogenation is stirred with methyl iodide and sodium hydride in tetrahydrofuran solvent for 3-12 hours, and after simple post-treatment and column chromatography purification, it is transferred into the hydrogenation reactor tube with methanol, Raney Ni is added, hydrogen is filled at 1-100 atm, and the enamine is reduced at room temperature to obtain the chiral product (R,R)-4; The chiral compound (R,R)-4 is dissolved in tetrahydrofuran, lithium aluminum hydride is added in batches under ice bath condition, and stirring reaction is carried out at room temperature for 3-12 hours; after quenching with water and then being filtered with diatomite, the primary alcohol intermediate is obtained, which is directly used for the next Mitsunobu reaction without further purification; Diphenyl phosphorazide (DPPA), diethyl azodicarboxylate and triphenylphosphine are added to the tetrahydrofuran solution of the primary alcohol intermediate obtained in the previous step under 0℃, and the reaction is carried out at room temperature for 3-12 hours to obtain the azido compound (R,R)-5; The azido compound (R,R)-5 is transferred into the hydrogenation reactor tube with ethanol, and azido reduction to amine is carried out under Pd / C / hydrogen condition, and the reaction is carried out at room temperature for 3-12 hours; after releasing the hydrogen pressure, the amine intermediate is obtained by diatomite filtration, which is directly used for the next reaction without purification; Then, triethylamine and propionic anhydride are added to the tetrahydrofuran solution of the amine intermediate, and the reaction is carried out at room temperature for 1-5 hours; after simple post-treatment, the oil Melatonin MT2 receptor (R,R)-6 is obtained by silica gel column chromatography.

7. The use according to claim 6, wherein: In the reaction of preparing the chiral product (R,R)-4 from the 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; In the reaction of preparing the azido 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 diphenyl phosphorazide 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). In the reaction of preparing oil 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).

8. Use of the production process according to claim 1 for the production of an ABCB1 inhibitor, characterized in that The reaction equation is as follows: In the reaction of preparing compound (R)-3f from substrate 2f through asymmetric hydrogenation, 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 hydrogen pressure 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℃. Under the condition of 0℃, sodium hydride and benzyl bromide are added to a solution of hydrogenation product (+)-3f in N, N-dimethylformamide, and the reaction is stirred at room temperature for 1-5 hours, followed by simple post-treatment and column chromatography purification to obtain chiral product ABCB1 inhibitor (+)-7; wherein the equivalent ratio of the hydrogenation product (+)-3f to sodium hydride is 1:(1.0-5.0); and the equivalent ratio of (+)-3f to benzyl bromide is 1:(1.0-5.0).

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