N-substituted-4-quinolone-2-carboxylic acid (ester) compounds, their reduced derivatives, and methods of making and using the same

Abstract

The application relates to a class of N-substituted-4-quinoione-2-carboxylic acid (ester) and a reduced derivative, a preparation method and application. Based on the research of high-pressure catalytic hydrogenation, especially the asymmetric catalytic hydrogenation field, the selective reduction of the quinolone skeleton is carried out, a high-efficiency and high-selectivity synthesis method is developed, a series of quinolone compounds with potential medicinal value and the reduced derivatives, chiral N-substituted-2,3-dihydro-4-quinoione-2-carboxylic acid compounds and N-substituted-5,6,7,8-tetrahydro-4-quinoione-2-carboxylic acid ethyl ester compounds are constructed, and novel molecular skeletons and chemical spaces are provided for new drug creation.

Description

Technical Field

[0001] This invention belongs to the field of compound technology and relates to a class of N-substituted-4-quinolone-2-carboxylic acid (ester) compounds, their reduced derivatives, preparation methods, and applications. Specifically, it relates to drug-like skeletons N-substituted-4-quinolone-2-carboxylic acid and esters, their selective reduction products, chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds, and N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylic acid ethyl ester compounds, their preparation methods, and applications. Background Technology

[0002] Quinolones are widely used and highly effective scaffolds in medicinal chemistry, and their precise structural modification and efficient derivatization are crucial for discovering novel bioactive molecules and advancing innovative drug development. Chiral 2,3-dihydro-4-quinolones and 5,6,7,8-tetrahydroquinolones, as two high-value quinolone derivatives, are widely found in various bioactive natural products and drug lead structures, and are therefore of great significance. However, current synthetic methods for these two scaffolds still have significant limitations, failing to meet the demands of modern drug development for efficient, highly selective, and versatile chemical spaces.

[0003] In the synthesis of chiral 2-substituted-2,3-dihydro-4-quinolones, existing methods have significant shortcomings: the theoretical yield limit of traditional chiral resolution is only 50%, the substrate universality is poor, and it is difficult to achieve large-scale preparation; although asymmetric conjugation addition can construct a chiral center at the C2 position, it can only introduce a limited number of substituents such as alkyl, aryl, and alkynyl, which limits the space for subsequent structural derivation and is not conducive to the rapid establishment of a diverse compound library; in addition, some catalytic systems have harsh conditions and high catalyst consumption, which further restricts their practical application value.

[0004] The synthesis of 5,6,7,8-tetrahydroquinolone skeletons presents even greater challenges, and a systematic and efficient construction method is still lacking. The most direct method for constructing this skeleton is through the selective reduction of the quinolone benzene ring; however, in the 4-quinolone molecule, the pyridone heterocycle has weak aromaticity and the nitrogen atom is sp. 3 Hybridized and unstable, fused benzene rings exhibit strong aromaticity, thermodynamic stability, and high reactivity, resulting in significant differences in their reducing activities. Compared to substrates such as quinolines and isoquinolines, which readily achieve selective reduction of the benzene ring, 4-quinolones struggle to achieve specific reduction of the benzene ring while preserving the heterocycle, leaving a gap in highly selective catalytic systems.

[0005] Catalytic hydrogenation has outstanding advantages such as high atom economy, high reaction efficiency, simple post-processing, and green environmental protection, and is one of the most widely used reaction types in drug synthesis. Summary of the Invention

[0006] To overcome the shortcomings of the prior art, the present invention aims to provide a class of N-substituted-4-quinolone-2-carboxylic acid (ester) compounds, their reduced derivatives, preparation methods, and applications, adapted to a precise selective catalytic hydrogenation system for quinolone skeletons. By controlling the reaction conditions, the selective reduction of quinolone heterocycles and benzene rings can be achieved, respectively, to construct novel drug-like skeletons with chiral 2,3-dihydro-4-quinolones and 5,6,7,8-tetrahydro-4-quinolones at the C2 position.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] A method for preparing a class of N-substituted-4-quinolone-2-carboxylic acid ethyl esters includes the following steps:

[0009] Step 1: Weigh K2CO3 and o-aminoacetophenone separately, add them to a three-necked flask, and replace them with argon gas three times;

[0010] Step 2: Add anhydrous DMF. First, stir the reaction solution at room temperature for 30 minutes, then slowly add anhydrous DMF solution of haloalkanes. After the addition is complete, heat the reaction to 60°C and stir overnight.

[0011] Step 3: After the reaction is completed by TLC monitoring, the reaction mixture is washed with water, extracted with DCM, the organic phases are combined, dried with anhydrous Na2SO4, concentrated by rotary evaporation, and purified by column chromatography to obtain the intermediate.

[0012] Step 4: Under argon protection, place bis(trimethylsilylamine) lithium LiHMDS at -78°C and slowly add anhydrous THF solution of the intermediate obtained in step 3) to the bis(trimethylsilylamine) lithium LiHMDS, stirring for 30 min.

[0013] Step 5: Slowly add anhydrous THF solution of diethyl oxalate to the above reaction solution, stir for 30 min, allow to rise naturally to room temperature, then heat to reflux, and monitor the reaction by TLC;

[0014] Step 6: After the reaction was monitored by TLC, a sufficient amount of saturated NH4Cl solution was added to quench the reaction. The mixture was extracted with EA, the organic phases were combined, dried with anhydrous Na2SO4, concentrated by rotary evaporation, and purified by column chromatography to obtain the final product N-substituted-4-quinolone-2-carboxylic acid ethyl ester.

[0015] Furthermore, the N-substituted 4-quinolone-2-carboxylic acid ethyl ester compounds include: 4-quinolone-2-carboxylic acid ethyl ester, N-methyl-4-quinolone-2-carboxylic acid ethyl ester, N-ethyl-4-quinolone-2-carboxylic acid ethyl ester, N-propyl-4-quinolone-2-carboxylic acid ethyl ester, N-n-butyl-4-quinolone-2-carboxylic acid ethyl ester, 1,5-dimethyl-4-quinolone-2-carboxylic acid ethyl ester, or 1,7-dimethyl-4-quinolone-2-carboxylic acid ethyl ester.

[0016] Furthermore, the preparation steps for a class of N-substituted-4-quinolone-2-carboxylic acids are as follows:

[0017] Step 1: Dissolve N-substituted-4-quinolone-2-carboxylic acid ethyl ester in methanol and dilute with H2O in the reaction flask;

[0018] Step 2: Add 15 mL of 1M NaOH, heat to 70℃, and react for 2 hours; after the reaction is completed by TLC monitoring, evaporate and concentrate to remove MeOH;

[0019] Step 3: Adjust the pH to 2-3 with 1 M HCl in an ice bath. A solid precipitates out. After filtration under reduced pressure, the target product N-substituted-4-quinolone-2-carboxylic acid is obtained.

[0020] Furthermore, the aforementioned class of N-substituted-4-quinolone-2-carboxylic acid compounds includes: 1-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 4-oxo-1-propyl-1,4-dihydroquinoline-2-carboxylic acid, 1-butyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-benzyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, and 1-(4-methylbenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid. Acids, 1-(4-chlorobenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-(4-chlorobenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-(3-chlorobenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-(2-bromobenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-methyl-4-oxo-8-phenyl-1,4-dihydroquinoline-2-carboxylic acid, 1,5-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1,6-dimethyl -4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 6-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1,7-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1,8-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1,5,6-trimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1,6,7-trimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 5-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 6 -Fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 8-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 6-bromo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 6-methoxy-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1,5,8-trimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 5,7-difluoro-1-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid or 1-methyl-4-oxo-1,4-dihydrobenzo[g]quinoline-2-carboxylic acid.

[0021] A method for preparing a class of chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds includes the following steps:

[0022] Step 1: Weigh the chiral ligand and metal precursor in the glove box and add them to the reaction vial. Add solvent to the reaction vial and stir for 30 min to form an in-situ coordinated metal complex.

[0023] Step 2: Use a syringe to transfer the in-situ coordinated metal complex to an ampoule containing N-substituted-4-quinolone-2-carboxylic acid and a stir bar. Then place the ampoule into the high-pressure reactor, tighten the reactor, and transfer it out of the glove box.

[0024] Step 3: Replace the argon gas in the autoclave with hydrogen three times, then introduce hydrogen gas at the required pressure. Stop the reaction after stirring at room temperature for 24 hours. Release the hydrogen gas in a fume hood, transfer the reaction mixture to a small reaction flask, and concentrate it using a rotary condenser. 1 H-NMR analysis determined the conversion rate of the reaction, and a small amount of the reaction mixture was concentrated by rotation to obtain the crude product;

[0025] Step 4: The crude product was further purified by column chromatography to obtain pure chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid product;

[0026] Step 5: The chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid product was refluxed in toluene for 12 h to obtain stable chiral 4-hydroxy-1-substituted-1,2-dihydroquinoline-2-carboxylic acid compounds.

[0027] Furthermore, the chiral ligands include:

[0028] ;

[0029]

[0030] .

[0031] Furthermore, the chiral ligand is a BPE-type ligand L16, namely (R,R)-Ph-BPE.

[0032] Furthermore, the metal precursors include the following: Ru(2-methylally)COD, [Ru(p-cymene)Cl]2, [Ir(COD)Cl]2, Rh(COD)2OTf, Rh(COD)2SbF6, Rh(NBD)2BF4, [(CF3COO)2Rh]2, [[CH3(CH2)6CO2]2Rh]2, RhCp*(OAc)2, or Rh(OAc)3.

[0033] Furthermore, the metal precursor is Rh(COD)2OTf.

[0034] Furthermore, the solvent is MeOH, EtOH, i-PrOH, t-BuOH, CF3CH2OH, (CF3)2CHOH, DCM, EtOAc, Toluene, or THF.

[0035] Furthermore, the solvent is tert-butanol (t-BuOH).

[0036] Furthermore, the optimal reaction conditions, using 1.1 mol% (R,R)-Ph-BPE as the chiral ligand and 1.0 mol% Rh(COD)₂OTf as the coordinating metal precursor, with the two coordinating in situ to form a complex as the catalyst, and t-BuOH as the reaction solvent, resulted in a diverse range of chiral 4-hydroxy-1-substituted-1,2-dihydroquinoline-2-carboxylic acid compounds after reacting at 40 atm H₂ and 80 °C for 24 h, including:

[0037] .

[0038] Furthermore, using the method described above, with ethyl 4-quinolone-2-carboxylate as the template substrate and the complex formed by the in-situ coordination of ligand L27 with Rh(NBD)2BF4 as the catalyst, N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylate compounds were synthesized by reacting at room temperature in anhydrous EtOH at 80 °C and 40 atm for 24 h.

[0039] Furthermore, the N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylic acid ethyl ester comprises:

[0040] .

[0041] A class of non-natural chiral amino acids or esters and their preparation methods, wherein the non-natural chiral amino acids or esters are chiral 4-oxo-1,2,3,4-tetrahydroquinoline-2-carboxylic acid (ester).

[0042] A method for preparing a class of chiral 4-oxo-1,2,3,4-tetrahydroquinoline-2-carboxylic acids (esters) includes the following steps:

[0043] Step 1: Dissolve the chiral product 7h (0.1 mmol) in dry THF under ice bath conditions, and slowly add trimethylsilyldiazomethane (0.12 mmol). After the addition is complete, react at room temperature for 2h.

[0044] Step 2: After the reaction is complete, THF is removed by rotary evaporation and the resulting product is dissolved in methanol after 10 hours. 10% Pd / C is added, and the reaction is carried out at 1 atm hydrogen pressure for 6 hours.

[0045] Step 3: After the reaction is complete, filter Pd / C, concentrate by rotary evaporation to remove methanol, and then purify by column chromatography to obtain chiral 4-oxo-1,2,3,4-tetrahydroquinoline-2-carboxylate 11h.

[0046] The beneficial effects of this invention are:

[0047] In heterocyclic asymmetric selective reduction, this invention focuses on the efficient construction of a novel class of chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds with potential pharmaceutical value. These parent nuclei are widely found in bioactive natural products and drug candidates with antitumor, antiviral, antibacterial, and anti-inflammatory properties. However, traditional synthetic routes generally suffer from drawbacks such as lengthy reaction steps, difficulty in controlling chirality, and limited space for subsequent derivatization. This invention uses N-substituted-4-quinolone-2-carboxylic acid as a template substrate and, through systematic screening of catalytic systems and reaction parameters, has for the first time successfully constructed an asymmetric catalytic hydrogenation system using (R,R)-Ph-BPE as a chiral ligand, Rh(COD)₂OTf as a metal precursor, and t-BuOH as a reaction solvent. Based on this optimized system, 26 structurally diverse C2-chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds were efficiently synthesized, with product yields reaching up to 99% and stereoselectivity up to 99% ee. X-ray single-crystal diffraction characterization confirmed that the absolute configuration of the products was (R)-. Furthermore, the carboxyl group introduced at the C2 position serves as a multifunctional synthetic "handle," readily converting to various functional groups such as amides, esters, and amino groups. It also allows for further derivatization modifications such as cyclization and cross-coupling, enabling the rapid construction of a high-throughput chiral compound library. This provides solid methodological support for the structure-activity relationship analysis and drug lead structure optimization of this type of skeleton.

[0048] In this invention on the selective reduction of aromatic rings, the present invention tackles the synthetic challenge of selective dearomatization of the benzene ring in 4-quinolones. Compared to classic heterocyclic substrates such as quinolines and isoquinolines, which are easily subjected to selective reduction of aromatic rings, the pyridine ring nitrogen atom in the 4-quinolone structure is sp... 3 Hybridized and heterocyclic rings exhibit weak aromaticity and poor stability, while fused benzene rings possess strong aromaticity and high reactivity. The significant differences in thermodynamic stability and kinetic activity between these two types of rings make it difficult to achieve directional reduction of the benzene ring while preserving the sensitive pyridinone structure, a persistent technical challenge in this field. Through extensive catalyst screening, this invention discovered that a novel catalytic system formed by the in-situ complexation of the chiral PN ligand L27 and Rh(NBD)2BF4, independently developed by our research group, can effectively balance the reactivity differences between the two types of unsaturated ring systems. Under 40 atm hydrogen atmosphere and 80 °C, using ethanol as a solvent, the selective catalytic hydrogenation of the 4-quinolone benzene ring was achieved for the first time, successfully constructing a novel N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylate (cyclohexanopyridone) skeleton. Although the system has not yet achieved stereoselectivity control, this method is the first to break through the selective reduction barrier of the full-carbon aromatic ring of quinolones under mild conditions, expanding the field of medicinal chemistry with a new type of heterocyclic structural unit with unique three-dimensional spatial configuration and potential biological activity.

[0049] In summary, this invention addresses the core scientific problem of selective reduction of the quinolone skeleton, achieving systematic and innovative results at both the heterocyclic and aromatic ring modification levels. The heterocyclic asymmetric hydrogenation strategy solves a key challenge in the efficient and highly enantioselective synthesis of chiral 2,3-dihydro-4-quinolones, providing abundant molecular resources for screening chiral lead compounds. The aromatic ring selective hydrogenation achieves, for the first time, the directional dearomatization of the 4-quinolone benzene ring, opening a new pathway for constructing novel cyclohexanopyridone skeletons. Although the two inventions target different parts of the quinolone skeleton, they share a common chemical concept of precisely modifying the structure of this "dominant skeleton": the former imparts chiral characteristics to the molecule through asymmetric catalysis, while the latter reshapes the three-dimensional structure of the molecule through regioselective reduction, effectively expanding the chemical space of the quinolone core and laying a theoretical and material foundation for subsequent structure-activity relationship inventions and innovative drug development. Attached Figure Description

[0050] Figure 1 Preparation of N-substituted 4-quinolone-2-carboxylic acid ethyl ester;

[0051] Figure 2 Preparation of N-substituted-4-quinolone-2-carboxylic acid;

[0052] Figure 3 Preparation of N-methyl-4-quinolone-2-carboxylic acid;

[0053] Figure 4 This is an asymmetric hydrogenation reaction;

[0054] Figure 5 For deuteration experiments;

[0055] Figure 6 To control the experiment;

[0056] Figure 7 Screening of reaction ligands for N-substituted-4-quinolone-2-carboxylic acid compounds;

[0057] Figure 8 For screening ligands;

[0058] Figure 9 Screening for metal precursors for the reaction of N-substituted-4-quinolone-2-carboxylic acid compounds;

[0059] Figure 10 Screening of reaction solvents for N-substituted-4-quinolone-2-carboxylic acid compounds;

[0060] Figure 11 Investigation of catalyst loading for the reaction of N-substituted-4-quinolone-2-carboxylic acid compounds;

[0061] Figure 12Synthesis of a series of chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds;

[0062] Figure 13 The single-crystal diffraction pattern of product 7a;

[0063] Figure 14 For deuteration experiments;

[0064] Figure 15 To control the experiment;

[0065] Figure 16 For the synthesis of N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylate compounds;

[0066] Figure 17 Ligand selection for the synthesis of ethyl 5,6,7,8-tetrahydro-4-quinolone-2-carboxylate;

[0067] Figure 18 For screening ligands;

[0068] Figure 19 It is an N-substituted ethyl 5,6,7,8-tetrahydro-4-quinolone-2-carboxylate compound;

[0069] Figure 20 Preparation of chiral 4-oxo-1,2,3,4-tetrahydroquinoline-2-carboxylate 11h, a non-natural chiral amino ester. Detailed Implementation

[0070] The present invention will be further described below with reference to the embodiments, but the present invention is not limited to the following embodiments.

[0071] 1. Instruments and equipment

[0072] Nuclear magnetic resonance spectrometer (Bruker Advance 400, TMS as internal standard); high performance liquid chromatography (Agilent 1260); Daicel Chiralcel OD-H, OB-H, and OJ-H chiral columns; Anton Paar MCP4100 automatic polarimeter; electric thermostatic drying oven (DGG-9140A); rotary evaporator (EYELA N-1300); Yuhua circulating water vacuum pump (SHZ-DⅢ); IKARCT-digital magnetic stirrer; Kanghe ZF-C type three-purpose ultraviolet analyzer; Shaanxi Aixin 5 / -40℃ low-temperature thermostatic reaction bath; Shanghai Optical Instrument Factory X-5 precision micro melting point apparatus; high resolution mass spectrometer (Agilent 6545 Q-TOF); SLM-N500 high-pressure reactor.

[0073] 2. Chemical reagents

[0074] Reagents used in the experiment were purchased from J&K Chemical, Admas, Sigama-Aldrich, Energie Chemicals, and Innocare. Unless otherwise specified, none of the reagents required further purification.

[0075] 3. Preparation of N-substituted 4-quinolone-2-carboxylic acid ethyl ester:

[0076] K₂CO₃ (6.64 g, 48 mmol) and o-aminoacetophenone 1 (5.8 mL, 48 mmol) were weighed separately and added to a 250 mL three-necked flask. After purging with argon three times, anhydrous DMF (50 mL) was added. The reaction mixture was stirred at room temperature for 30 min, and then an anhydrous DMF solution of haloalkanes (48 mmol) (30 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was heated to 60 °C and stirred overnight. After the reaction was completed by TLC monitoring, the reaction mixture was washed with water and extracted with DCM (5 × 50 mL). The organic phases were combined, dried over anhydrous Na₂SO₄, concentrated by rotary evaporation, and purified by column chromatography to obtain intermediate 2.

[0077] Under argon protection, LiHMDS (33 mmol) was kept at -78℃. Anhydrous THF solution of intermediate 2 (22 mmol) was slowly added dropwise to LiHMDS and stirred for 30 min. Then, anhydrous THF solution of diethyl oxalate (4.8 mL, 55 mmol) was slowly added dropwise to the above reaction solution and stirred for 30 min. The mixture was then allowed to rise naturally to room temperature and then heated under reflux. After the reaction was completed by TLC monitoring, a sufficient amount of saturated NH4Cl solution was added to quench the reaction. The mixture was extracted with EA (3 × 50 mL), and the organic phases were combined. After drying with anhydrous Na2SO4, the mixture was concentrated by rotary evaporation and purified by column chromatography to obtain the final product N-substituted-4-oxo-1,4-dihydroquinoline-2-carboxylate 3.

[0078] 4. Preparation of N-substituted 4-quinolone-2-carboxylic acid compounds:

[0079] The N-substituted 4-quinolone-2-carboxylic acid ethyl ester obtained above can be hydrolyzed to yield the corresponding formic acid compounds. The experimental method is as follows:

[0080] Ester 3 was dissolved in 10 mL of methanol, and 20 mL of H2O was added to dilute it in the reaction flask. Then, 15 mL of 1 M NaOH was added, and the mixture was heated to 70 °C and reacted for 2 h. After the reaction was completed by TLC monitoring, the MeOH was removed by evaporation and concentration. The pH was adjusted to 2-3 with 1 M HCl under ice bath conditions, and a solid precipitated out. After filtration under reduced pressure, the target product N-substituted-4-quinolone-2-carboxylic acid 4 was obtained.

[0081] Preparation of aromatic ring-substituted N-methyl-4-quinolone-2-carboxylic acid compounds:

[0082] K₂CO₃ (48 mmol) and substituted aniline 5 (48 mmol) were weighed separately and added to a 250 mL three-necked flask. After purging with argon three times, 50 mL of anhydrous DMF was added. The reaction mixture was stirred at room temperature for 30 min, and then an anhydrous DMF solution of iodomethane (48 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was heated to 60 °C and reacted for 24 h. After the reaction was completed by TLC monitoring, the reaction mixture was washed with water, extracted with DCM (5 × 50 mL), and the organic phases were combined. After drying with anhydrous Na₂SO₄, the mixture was concentrated by rotary evaporation and purified by silica gel column chromatography to obtain aromatic amine intermediate 6.

[0083] Aromatic amine 6 (10 mmol) and diethyl butynedioate (15 mmol) were mixed in DCM and stirred at room temperature. The reaction progress was observed by thin-layer chromatography (TLC). After the reaction was complete, the reaction mixture was dissolved in 10 mL of polyphosphoric acid (PPA), and then heated to 90 °C and reacted for 12 h. After the reaction was complete, the reaction mixture was cooled and poured into 100 mL of water. A solid precipitated out, which was filtered under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate 3.

[0084] The above intermediate product was dissolved in 10 mL of methanol, and 20 mL of H2O was added to dilute it in the reaction flask. Then, 15 mL of 1 M NaOH solution was added, and the mixture was heated to 70 °C and reacted for 2 h. After the reaction was completed, the MeOH was removed by evaporation and concentration. The pH was adjusted to 2-3 with 1 M HCl under ice bath conditions, and a solid precipitated out. After filtration under reduced pressure, the corresponding target product, N-methyl-4-quinolone-2-carboxylic acid compound 4, was obtained.

[0085] Using the above synthetic method, a total of 27 N-substituted 4-quinolone-2-carboxylic acid ethyl ester compounds were prepared in this invention. Among them, 7 compounds were used in the aromatic ring regioselective hydrogenation reaction of this paper, and their structures were confirmed by NMR and HRMS. The structural and qualitative data of these 7 compounds are as follows:

[0086]

[0087] 4-Quinolone-2-carboxylic acid ethyl ester (3a): yellow solid, yield 80%, melting point: 214-216℃. 1H NMR (400MHz, CDCl3)δ 8.38 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 5.1 Hz, 2H), 7.48 (dt, J= 8.1, 3.8 Hz, 1H), 7.21 (t, J = 2.0 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.45(t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 179.61, 162.91, 139.13, 136.64, 133.15, 126.37, 126.27, 124.58, 118.18, 111.54, 63.36, 14.09, known compound.

[0088]

[0089] N-Methyl-4-quinolone-2-carboxylic acid ethyl ester (3b): yellow solid, yield 45%, melting point: 109-115℃. 1 H NMR(400 MHz, CDCl3)δ 8.38 (dd, J = 8.0, 1.7 Hz, 1H), 7.70 (ddd, J = 8.7, 6.9,1.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 6.63 (s,1H), 4.42 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). 13 C NMR(101 MHz, CDCl3)δ 178.13, 163.64, 144.14, 141.88, 133.12, 127.09, 126.65,124.18, 116.07, 112.38, 62.96, 37.25, 14.05. HRMS (ESI): m / z for C 13 H 13 NO3[M+H] + Calcd 232.0968, found 232.0978.

[0090]

[0091] N-Ethyl-4-quinolone-2-carboxylic acid ethyl ester (3c): brown solid, yield 40%, melting point: 86-88℃. 1 H NMR(400 MHz, CDCl3)δ 8.43 (dd, J = 8.0, 1.7 Hz, 1H), 7.71 (ddd, J = 8.7, 6.9,1.7 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.39 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.59 (s, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.54 (t, J= 7.1 Hz, 3H), 1.43 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ 177.89,163.77, 144.12, 140.43, 133.03, 127.45, 126.96, 124.05, 116.06, 111.97,62.91, 44.73, 14.66, 14.04. HRMS (ESI): m / z for C 14 H 15 NO3[M+H] + calcd 246.1125, found 246.1135.

[0092]

[0093] N-propyl-4-quinolone-2-carboxylic acid ethyl ester (3d): yellow oily liquid, yield 55%. 1 H NMR (400 MHz, CDCl3) δ 8.44 (dd, J = 8.1, 1.7 Hz, 1H), 7.71 (ddd, J = 8.7, 7.0, 1.7 Hz,1H), 7.54 (d, J = 8.7 Hz, 1H), 7.40 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.60 (s,1H), 4.45 (q, J = 7.2 Hz, 2H), 4.27-4.16 (m, 2H), 2.02-1.87 (m, 2H), 1.43 (t,J = 7.2 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3)δ 177.91,163.85, 144.28, 140.66, 132.98, 127.43, 126.93, 124.09, 116.23, 111.98,62.92, 50.74, 22.36, 14.04, 10.98. HRMS (ESI): m / z for C 15 H 17 NO3[M+H] + calcd260.1281, found 260.1290.

[0094]

[0095] N-Butyl-4-quinolone-2-carboxylic acid ethyl ester (3e): brown solid, yield 40%, melting point: 65-66℃. 1 HNMR (400 MHz, CDCl3)δ 8.37 (dd, J = 8.0, 1.7 Hz, 1H), 7.67 (ddd, J = 8.8,7.0, 1.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.34 (ddd, J = 8.0, 7.0, 0.9 Hz,1H), 6.55 (s, 1H), 4.24-4.13 (m, 2H), 3.94 (s, 3H), 1.91-1.76 (m, 2H), 1.36(h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ177.83, 164.24, 143.94, 140.61, 133.06, 127.35, 126.86, 124.14, 116.28,111.96, 53.54, 49.18, 30.98, 19.89, 13.62. HRMS (ESI): m / z for C 16 H 19 NO3[M+H] + Calcd 274.1238, found 274.2750.

[0096]

[0097] 1,5-Dimethyl-4-quinolone-2-carboxylic acid ethyl ester (3f): yellow solid, yield 60%, melting point: 128-131℃.1 HNMR (400 MHz, CDCl3)δ 7.53 (dd, J = 8.7, 7.3 Hz, 1H), 7.35 (d, J = 8.7 Hz,1H), 7.11 (dt, J = 7.3, 0.9 Hz, 1H), 6.58 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.76 (s, 3H), 2.92 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ 180.54, 163.80, 143.87, 142.84, 141.88, 132.00, 127.00, 125.73, 114.28,113.92, 62.82, 37.98, 24.03, 14.07. HRMS (ESI): m / z for C 14 H 15 NO3[M+H] + calcd246.1125, found 246.1105.

[0098]

[0099] 1,7-Dimethyl-4-quinolone-2-carboxylic acid ethyl ester (3g): white solid, yield 50%, melting point: 91-93℃. 1 HNMR (400 MHz, CDCl3)δ 8.30 (d, J = 8.2 Hz, 1H), 7.32 (s, 1H), 7.24 (dd, J =8.2, 1.4 Hz, 1H), 6.66 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 2.53(s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ 177.97, 163.75,144.12, 143.93, 142.12, 126.59, 125.98, 125.07, 115.78, 112.40, 62.93, 37.26,22.39, 14.06. HRMS (ESI): m / z for C 14 H 15 NO3[M+H] +calcd 246.1125, found246.1105.

[0100] The hydrogenation reaction substrate is N-substituted-4-quinolone-2-carboxylic acid.

[0101] Using the above synthetic method, a total of 26 N-substituted-4-quinolone-2-carboxylic acid compounds were prepared in this invention, and their structures were confirmed by NMR, HRMS, etc. The structural and qualitative data are as follows:

[0102]

[0103] 1-Methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4b): white solid, yield: 45%, melting point: 215-216℃. 1 H NMR (400 MHz, MeOD)δ 8.34 (dt, J = 7.6, 1.1 Hz, 1H), 7.89-7.79 (m, 2H),7.50 (ddd, J = 8.0, 5.2, 2.8 Hz, 1H), 6.37 (s, 1H), 3.96 (s, 3H). 13 C NMR (101MHz, MeOD) δ 180.22, 170.22, 157.22, 142.34, 134.08, 127.29, 126.70, 125.30,117.99, 106.95, 38.03. HRMS (ESI): m / z for C 11 H9NO3[M+H] + calcd 204.0655, found 204.0597.

[0104]

[0105] 1-Ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4c): white solid, yield: 15%, melting point: 209-210℃. 1 H NMR (400 MHz, MeOD)δ 8.36 (dd, J = 8.1, 1.6 Hz, 1H), 7.89 (dt, J = 8.8,0.9 Hz, 1H), 7.86-7.80 (m, 1H), 7.48 (ddd, J = 8.0, 6.7, 1.1 Hz, 1H), 6.32(s, 1H), 4.52 (q, J = 7.1 Hz, 2H), 1.53 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, MeOD)δ 180.02, 170.31, 157.14, 140.90, 134.00, 127.67, 126.99, 125.17,118.18, 106.81, 45.91, 14.91. HRMS (ESI): m / z for C 12 H 11 NO3[M+H] + calcd218.0812, found 218.0739.

[0106]

[0107] 4-Oxo-1-propyl-1,4-dihydroquinoline-2-carboxylic acid (4d): white solid, yield: 10%, melting point: 218-220℃. 1 H NMR (400 MHz, MeOD)δ 8.39-8.28 (m, 1H), 7.88-7.74 (m, 2H), 7.45 (ddd, J= 8.0, 6.0, 1.9 Hz, 1H), 6.31 (s, 1H), 4.46-4.31 (m, 2H), 2.01-1.84 (m, 2H),1.01 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, MeOD)δ 180.00, 170.34, 157.21,141.23, 133.96, 127.59, 126.93, 125.17, 118.30, 106.98, 52.21, 23.50, 11.25.HRMS (ESI): m / z for C 13 H 13 NO3[M+H] + Calcd 232.0968, found 232.0896.

[0108]

[0109] 1-Butyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4e): white solid, yield: 55%, melting point: 198-201℃. 1H NMR (400 MHz, MeOD)δ 8.40-8.32 (m, 1H), 7.86-7.81 (m, 2H), 7.48 (ddd, J= 8.0, 5.3, 2.6 Hz, 1H), 6.34 (s, 1H), 4.54-4.39 (m, 2H), 2.00-1.85 (m, 2H), 1.49 (h, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, MeOD)δ180.00, 170.27, 157.23, 141.22, 133.93, 127.64, 126.95, 125.15, 118.26,107.03, 50.56, 32.26, 20.99, 14.04. HRMS (ESI): m / z for C 14 H 15 NO3[M+H] + calcd246.1125, found 246.1046.

[0110]

[0111] 1,5-Dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4f): white solid, yield: 13%, melting point: 218-220℃. 1 H NMR (400 MHz, MeOD)δ 7.63-7.54 (m, 2H), 7.16 (q, J = 4.8 Hz,1H), 6.23 (s, 1H), 3.85 (s, 3H), 2.89 (s, 3H). 13 C NMR (101 MHz, MeOD)δ182.94, 170.59, 155.49, 144.16, 142.05, 133.00, 128.08, 126.05, 115.75,108.75, 38.61, 24.45. HRMS (ESI): m / z for C 12 H 11 NO3[M+H] + Calcd 218.0812, found 218.0754.

[0112]

[0113] 1,7-Dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4g): white solid, yield: 10%, melting point: 198-200℃. 1 H NMR (400 MHz, MeOD)δ 8.19 (d, J = 8.3 Hz, 1H), 7.66-7.61 (m, 1H), 7.35-7.29 (m, 1H), 6.30 (s, 1H), 3.92 (s, 3H), 2.56 (s, 3H). 13 C NMR (101 MHz, MeOD)δ 180.09, 170.32, 157.02, 145.42, 142.51, 127.01, 126.61, 125.17,117.57, 106.73, 38.02, 22.21. HRMS (ESI): m / z for C 12 H 11 NO3[M+H] + calcd218.0812, found 218.0756.

[0114]

[0115] 1-Benzyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4h): white solid, yield: 50%, melting point: 208-210℃. 1 H NMR (400 MHz, MeOD)δ 8.34-8.29 (m, 1H), 7.65-7.57 (m, 2H), 7.39 (ddd, J= 8.0, 5.7, 2.2 Hz, 1H), 7.32-7.19 (m, 5H), 6.44 (s, 1H), 5.74 (s, 2H). 13 CNMR (101 MHz, MeOD)δ 180.36, 170.14, 157.73, 141.52, 137.76, 133.72, 129.85,128.63, 127.75, 127.58, 126.76, 125.25, 119.31, 107.36, 54.04. HRMS (ESI): m / z for C 17 H 13 NO3[M+H] + Calcd 280.0968, found 280.0893.

[0116]

[0117] 1-(4-methylbenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4i): white solid, yield: 65%, melting point: 218-220℃. 1 H NMR (400 MHz, MeOD)δ 8.33 (dd, J = 8.2, 1.5 Hz, 1H), 7.69 -7.58 (m, 2H), 7.40 (ddd, J = 8.0, 6.4, 1.4 Hz, 1H), 7.21-7.09 (m, 4H), 6.45 (s,1H), 5.71 (s, 2H), 2.28 (s, 3H). 13 C NMR (101 MHz, MeOD)δ 180.35, 170.16,157.78, 141.53, 138.49, 134.69, 133.63, 130.43, 127.77, 127.60, 126.72,125.19, 119.38, 107.33, 53.92, 21.09. HRMS (ESI): m / z for C 18 H 15 NO3[M+H] + calcd294.1125, found 294.1051.

[0118]

[0119] 1-(4-chlorobenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4j): white solid, yield: 55%, melting point: 211-212℃. 1 H NMR (400 MHz, MeOD)δ 8.34 (dd, J = 8.1, 1.6 Hz, 1H), 7.72 -7.57(m, 2H), 7.48-7.39 (m, 1H), 7.29 (q, J = 8.7 Hz, 4H), 6.45 (s, 1H), 5.73 (s,2H). 13 C NMR (101 MHz, MeOD)δ 180.39, 170.00, 157.62, 141.42, 136.64, 134.43,133.86, 129.89, 129.35, 127.77, 126.87, 125.32, 119.07, 107.47, 53.36. HRMS(ESI): m / z for C 17 H 12ClNO3[M+H] + Calcd 314.0578, found 314.0591.

[0120]

[0121] 1-(3-methylbenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4k): white solid, yield: 66%, melting point: 210-212℃. 1 H NMR (400 MHz, MeOD)δ 8.33 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 5.7Hz, 2H), 7.45-7.36 (m, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.14-7.02 (m, 3H), 6.46 (s, 1H), 5.72 (s, 2H), 2.28 (s, 3H). 13 C NMR (101 MHz, MeOD)δ 180.36, 170.12,157.79, 141.58, 139.80, 137.70, 133.66, 129.76, 129.33, 128.08, 127.76,126.73, 125.21, 124.66, 119.35, 107.35, 54.08, 21.42. HRMS (ESI): m / z forC 18 H 15 NO3[M+H] + Calcd 294.1125, found 294.1046.

[0122]

[0123] 1-(3-chlorobenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4l): white solid, yield: 81%, melting point: 220-222℃. 1 H NMR (400 MHz, MeOD)δ 8.35 (dd, J = 8.1, 1.5 Hz, 1H), 7.72 -7.57(m, 2H), 7.42 (ddd, J = 8.0, 6.7, 1.2 Hz, 1H), 7.37-7.17 (m, 4H), 6.47 (d, J= 0.9 Hz, 1H), 5.75 (s, 2H). 13C NMR (101 MHz, MeOD)δ 180.43, 169.95, 157.58,141.43, 140.26, 135.80, 133.92, 131.38, 128.78, 127.75, 126.91, 126.07,125.36, 119.01, 107.57, 53.39. HRMS (ESI): m / z for C 17 H 12 ClNO3[M+H] + calcd314.0578, found 314.0511.

[0124]

[0125] 1-(2-bromobenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4m): white solid, yield: 55%, melting point: 232-234℃. 1 H NMR (400 MHz, MeOD)δ 8.37 (dd, J = 8.2, 1.6 Hz, 1H), 7.65 (ddd,J = 11.3, 5.9, 2.2 Hz, 2H), 7.44 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.7 Hz,1H), 7.25-7.15 (m, 2H), 6.85-6.76 (m, 1H), 6.48 (s, 1H), 5.76 (s, 2H). 13 C NMR(101 MHz, MeOD)δ 180.49, 169.72, 157.59, 141.41, 136.41, 134.08, 133.95,130.39, 129.13, 128.84, 127.72, 127.02, 125.42, 122.58, 118.59, 107.68,54.35. HRMS (ESI): m / z for C 17 H 12 BrNO3[M+H] + Calcd 358.0073, found 357.9991.

[0126]

[0127] 1-Methyl-4-oxo-8-phenyl-1,4-dihydroquinoline-2-carboxylic acid (4n): white solid, yield: 25%, melting point: 219-220℃. 1H NMR (400 MHz, MeOD)δ 8.36 (dt, J = 8.1, 1.2 Hz, 1H), 7.67 (dt, J= 7.3, 1.3 Hz, 1H), 7.54-7.41 (m, 6H), 6.45 (s, 1H), 3.29 (s, 3H). 13 C NMR(101 MHz, MeOD)δ 180.46, 170.23, 159.66, 143.11, 142.39, 138.22, 134.77,130.26, 129.88, 129.11, 128.88, 126.17, 124.94, 107.87, 44.47. HRMS (ESI): m / z for C 17 H 13 NO3[M+H] + Calcd 280.0968, found 280.0887.

[0128]

[0129] 1,6-Dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4o): white solid, yield: 20%, melting point: 217-218℃. 1 H NMR (400 MHz, MeOD)δ 8.17-8.10 (m, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 8.9, 2.1 Hz, 1H), 6.34 (s, 1H), 3.95 (s, 3H), 2.52 (s, 3H). 13 CNMR (101 MHz, MeOD) δ 179.99, 170.28, 156.80, 140.48, 135.57, 135.48, 127.21,125.95, 117.95, 106.77, 37.98, 20.98. HRMS (ESI): m / z for C 12 H 11 NO3[M+H] + calcd218.0812, found 218.0743.

[0130]

[0131] 6-Isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4p): brown solid, yield: 5%, melting point: 190-192℃. 1 H NMR (400 MHz, MeOD)δ 8.19 (d, J = 2.1 Hz, 1H), 7.82-7.71 (m, 2H), 6.33(s, 1H), 3.94 (s, 3H), 3.09 (hept, J = 6.7 Hz, 1H), 1.33 (d, J = 6.9 Hz, 6H). 13 C NMR (101 MHz, MeOD)δ 180.13, 170.29, 156.78, 146.45, 140.70, 133.30,127.22, 123.26, 118.11, 106.72, 38.02, 34.98, 24.33. HRMS (ESI): m / z forC 14 H 15 NO3[M+H] + Calcd 246.1125, found 246.1051.

[0132]

[0133] 1,8-Dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4q): white solid, yield: 35%, melting point: 218-220℃. 1 H NMR (400 MHz, MeOD)δ 8.15 (dd, J = 8.2, 1.7 Hz, 1H), 7.60 (d, J =7.2 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 6.40 (s, 1H), 3.98 (s, 3H), 2.79 (s,3H). 13 C NMR (101 MHz, MeOD)δ 180.81, 170.36, 159.73, 144.85, 138.23, 129.42,128.92, 125.33, 124.82, 107.86, 43.89, 23.97. HRMS (ESI): m / z for C 12 H 11 NO3[M+H] + Calcd 218.0812, found 218.0743.

[0134]

[0135] 1,5,6-Trimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4r): white solid, yield: 20%, melting point: 247-248℃. 1 H NMR (400 MHz, MeOD)δ 7.57-7.46 (m, 2H), 6.23 (s, 1H), 3.83 (s,3H), 2.86 (s, 3H), 2.38 (s, 3H). 13 C NMR (101 MHz, MeOD)δ 183.18, 170.64,154.88, 142.67, 139.54, 135.50, 134.23, 126.05, 114.86, 108.73, 38.44, 20.51,18.50. HRMS (ESI): m / z for C 13 H 13 NO3[M+H] + Calcd 232.0968, found 232.0898.

[0136]

[0137] 1,6,7-Trimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4s): white solid, yield 20%, melting point: 218-220℃. 1 H NMR (400 MHz, MeOD)δ 8.04 (s, 1H), 7.61 (s, 1H), 6.29 (s, 1H), 3.91 (s, 3H), 2.49 (s, 3H), 2.41 (s, 3H). 13 C NMR (101 MHz, MeOD)δ 179.85,170.41, 156.54, 144.75, 140.89, 135.14, 126.35, 125.47, 118.07, 106.58,37.99, 20.80, 19.52. HRMS (ESI): m / z for C 13 H 13 NO3[M+H] + calcd 232.0968, found 232.0894.

[0138]

[0139] 5-Fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4t): brown solid, yield: 16%, melting point: 200-201℃. 1 H NMR (400 MHz, MeOD)δ 8.63 (ddd, J = 9.2, 5.9, 1.2 Hz, 1H), 8.20 -8.11(m, 1H), 7.78-7.68 (m, 1H), 7.37 (d, J = 1.2 Hz, 1H), 4.35 (d, J = 1.2 Hz, 3H). 19 F NMR (376 MHz, MeOD)δ -98.64. HRMS (ESI): m / z for C 11 H8FNO3[M+H] + calcd222.0561, found 222.0508.

[0140]

[0141] 6-Fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4u): brown solid, yield: 15%, melting point: 214-215℃. 1 H NMR (400 MHz, MeOD)δ 8.01-7.90 (m, 2H), 7.64 (dddd, J = 9.2, 7.8, 3.1,1.2 Hz, 1H), 6.34 (d, J = 1.1 Hz, 1H), 3.97 (d, J = 1.3 Hz, 3H). 13 C NMR (101MHz, MeOD)δ 179.30, 179.27, 169.95, 162.10, 159.67, 157.21, 139.01, 128.81,128.74, 122.51, 122.26, 121.02, 120.94, 110.95, 110.72, 106.53, 38.34. 19 F NMR (376 MHz, MeOD) δ -119.28. HRMS (ESI): m / z for C 11 H8FNO3[M+H] + calcd 222.0561,found 222.0448.

[0142]

[0143] 8-Fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4v): brown solid, yield: 20%, melting point: 200-201℃. 1 H NMR (400 MHz, DMSO)δ 7.97 (dd, J = 8.1, 1.6 Hz, 1H), 7.55 (ddd, J = 15.2,7.8, 1.6 Hz, 1H), 7.31 (td, J = 7.9, 4.2 Hz, 1H), 5.86 (s, 1H), 3.86 (d, J =8.7 Hz, 3H). 13 C NMR (101 MHz, DMSO)δ 175.26, 165.09, 159.17, 130.43, 129.13,123.16, 123.08, 121.39, 121.36, 118.75, 118.52, 105.22, 48.43, 40.74, 40.58.HRMS (ESI): m / z for C 11 H8FNO3[M+H] + Calcd 222.0561, found 222.0491.

[0144]

[0145] 6-Bromo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4w): brown solid, yield: 5%, melting point: 232-233℃. 1 H NMR (400 MHz, MeOD)δ 8.44 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 9.2, 2.5 Hz,1H), 7.80 (d, J = 9.2 Hz, 1H), 6.35 (s, 1H), 3.94 (s, 3H). 13 C NMR (101 MHz, MeOD)δ 178.83, 169.86, 157.43, 141.24, 136.74, 129.13, 128.73, 120.47,118.91, 107.46, 38.14. HRMS (ESI): m / z for C 11 H8BrNO3[M+H] + calcd 281.9760,found 281.9685.

[0146]

[0147] 6-Methoxy-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4x): white solid, yield: 26%, melting point: 230-232℃. 1 H NMR (400 MHz, MeOD)δ 7.81 (d, J = 9.5 Hz, 1H), 7.76 (d, J = 3.0 Hz,1H), 7.45 (dd, J = 9.4, 3.0 Hz, 1H), 6.36 (s, 1H), 3.97 (s, 3H), 3.94 (s,3H). 13 C NMR (101 MHz, MeOD)δ 179.38, 170.33, 158.20, 156.05, 136.97, 128.47,124.37, 119.82, 106.34, 105.98, 56.18, 38.18. HRMS (ESI): m / z for C 12 H 11 NO3[M+H] + Calcd 234.0761, found 234.0692.

[0148]

[0149] 1,5,8-Trimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4y): white solid, yield: 30%, melting point: 216-219℃. 1 H NMR (400 MHz, MeOD)δ 7.57 (d, J = 7.5 Hz, 1H), 7.22 (d, J = 7.5Hz, 1H), 6.88 (s, 1H), 3.93 (s, 3H), 2.84 (s, 3H), 2.69 (s, 3H). 13 C NMR (101MHz, MeOD) δ 181.45, 165.41, 151.14, 148.81, 139.22, 138.54, 129.70, 128.09,126.67, 113.07, 46.09, 24.09, 23.20. HRMS (ESI): m / z for C 13 H 13 NO3[M+H] + calcd232.0968, found 232.0890.

[0150]

[0151] 5,7-Difluoro-1-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (4z): brown solid, yield: 20%, melting point: 208-210℃. 1 H NMR (400 MHz, MeOD)δ 7.42 (dt, J = 11.3, 2.0 Hz, 1H), 7.03 (ddd, J = 11.6, 9.0, 2.3 Hz, 1H), 6.24 (s, 1H), 3.85 (s, 3H). 13 C NMR (101MHz, MeOD)δ 180.42, 179.14, 178.94, 170.00, 169.55, 167.19, 167.03, 165.54,165.29, 164.85, 164.70, 164.54, 162.93, 162.71, 156.69, 156.29, 155.41,146.23, 145.74, 145.68, 145.50, 114.81, 114.48, 111.71, 111.62, 109.49,109.07, 108.31, 101.55, 101.28, 101.20, 101.02, 100.95, 100.60, 100.56, 100.34, 100.29, 96.51, 96.48, 95.85, 95.61, 39.03, 38.96, 38.84. 19 F NMR (376MHz, MeOD)δ -103.23, -103.27, -108.41, -108.44. HRMS (ESI): m / z for C 11 H8F2NO3[M+H] + Calcd 240.0467, found 240.0395.

[0152]

[0153] 1-Methyl-4-oxo-1,4-dihydrobenzo[g]quinoline-2-carboxylic acid (4aa): white solid, yield: 23%, melting point: 200-201℃. 1H NMR (400 MHz, MeOD)δ 10.40-10.29 (m, 1H), 8.20 (d, J = 9.4 Hz,1H), 7.97 (dd, J = 8.0, 1.5 Hz, 1H), 7.90 (d, J = 9.5 Hz, 1H), 7.72 (ddd, J =8.6, 6.9, 1.5 Hz, 1H), 7.63 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 6.62 (s, 1H), 4.06 (s, 3H). 13 C NMR (101 MHz, MeOD)δ 182.09, 170.37, 153.78, 143.25, 135.84,132.51, 131.42, 129.49, 129.20, 128.43, 127.42, 120.76, 116.78, 111.94,39.32. HRMS (ESI): m / z for C 15 H 11 NO3[M+H] + Calcd 254.0812, found 254.0748.

[0154] Asymmetric catalytic hydrogenation synthesis of chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds:

[0155] Weigh out 0.0022 mmol of chiral ligand and 0.002 mmol of metal precursor in a glove box and add them to a 5 mL reaction vial. Add 1 mL of t-BuOH to the reaction vial and stir for 30 min to form an in-situ coordinated metal complex. Transfer the complex to an ampoule containing 0.2 mmol of N-substituted-4-quinolone-2-carboxylic acid and a stir bar using a 1 mL syringe. Place the ampoule into an autoclave, tighten the autoclave, and remove it from the glove box. Replace the argon gas in the autoclave with hydrogen three times, then fill it with hydrogen at the required pressure. After stirring the reaction at room temperature for 24 h, stop the reaction. Release the hydrogen in a fume hood, transfer the reaction mixture to a 5 mL reaction vial, and concentrate by rotary evaporation. 1 H-NMR analysis determined the conversion rate of the reaction. The crude product was further purified by column chromatography to obtain pure N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid product 7, and the chemical yield was calculated. The obtained pure product was reacted with trimethylsilyldiazomethane (1.1 eq) in THF to give the corresponding methyl ester. After rapid purification by a neutral Al2O3 column, the ee value of the product was determined by chiral HPLC, and the absolute configuration of the product was determined by single-crystal diffraction.

[0156] Furthermore, the obtained hydrogenation product N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid 7 is unstable and readily forms a thermodynamically stable enol structure in air. To facilitate yield calculation in subsequent experiments, the hydrogenation product 7 was refluxed in toluene for 12 hours, which completely converted it into the thermodynamically stable enol structure 8. Unless otherwise specified, the yields of subsequent experiments were calculated based on the separation yields of the final converted enol products.

[0157] Deuteration experiments such as Figure 5 :

[0158] To investigate the source of hydrogen atoms in the reaction products, a deuteration tracer experiment was designed and conducted. Under optimal reaction conditions, the following three gas / solvent combinations were used for the hydrogenation reaction: (1) H2 / t-BuOD, (2) D2 / t-BuOD, and (3) D2 / t-BuOH. After the reaction, the target product (R)-4-hydroxy-1-methyl-1,2-dihydroquinoline-2-carboxylic acid was obtained after post-processing and column chromatography purification. The incorporation of deuterium atoms in the product was determined by ¹H NMR (using MeOD-d4 as solvent) to trace the hydrogen atom transfer pathway during the reaction.

[0159] Controlled experiments such as Figure 6 :

[0160] To investigate the effect of the 2-position substituent on the reactivity and selectivity, and further explore the role of the carboxyl group in the reaction, the 2-position carboxyl group of the substrate was replaced with a methyl group and an ethyl formate group, respectively. Hydrogenation was carried out under optimized reaction conditions. The formation of the target product was analyzed by monitoring the reaction progress, and its separation yield and enantioselectivity excess were determined. The reaction efficiency was compared with that of carboxyl-substituted substrates to evaluate the effect of different substituents on the conversion process.

[0161] Screening of hydrogenation reaction conditions:

[0162] To establish an optimal preparation method for chiral N-substituted-4-quinolone-2-carboxylic acid compounds, this invention uses a series of synthesized N-substituted-4-quinolone-2-carboxylic acid compounds as hydrogenation substrates and systematically investigates the key parameters of their asymmetric hydrogenation reactions. By screening different types of ligands, coordination metal precursors, reaction solvents, and catalyst dosages, the reaction conditions are optimized to achieve efficient construction of the target chiral products.

[0163] Ligand screening:

[0164] Using N-methyl-4-quinolone-2-carboxylic acid 4b as a template substrate, and Rh(NBD)2BF4 as a metal precursor, suitable catalysts for the asymmetric catalytic hydrogenation of this type of substrate were explored by screening chiral ligands. The reaction is as follows. Figure 7 As shown in Table 1, the data is as follows: ligand screening and... Figure 8 Ligand structure.

[0165] Table 1

[0166]

[0167] Note: a All reactions involved 0.2 mmol of N-methyl-4-quinolone-2-carboxylic acid, 1.0 mol% of the in-situ coordinated Ligand / Metal (1.1:1) complex, reacted in 1 mL of anhydrous EtOH at 80 °C for 24 h. b through 1 Obtained by H NMR. c The ee value was obtained by HPLC using a chiral column, Chiralcel OJ-H.

[0168] Initial screening revealed that Josiphos-type bisphosphine ligands exhibited generally poor catalytic performance in this reaction. While most ligands catalyzed the reaction and yielded the product in moderate yields, their enantioselectivity was generally low (Table 1, entries 1-15). Ligands L3, L9, L12, and L13 yielded the target product in moderate yields, but their enantioselectivity was only about 30% (entries 3, 9, 12, 13). Subsequently, we screened other commercially available chiral bisphosphine ligands, such as BPE, FcPhos, DuPhos, DIOP, and BDPP. Among these, bisphosphine ligands L17-L22 catalyzed the reaction and yielded 63%-92% yields, but their enantioselectivity remained low (entries 17-22); while BPE-type ligand L16 showed more ideal reactivity and higher enantioselectivity (92% yield, 77% ee) (entry 16). In addition, we screened for the chiral PN ligand L23, but only obtained the racemic product (entry 23) in 32% yield.

[0169] Metal precursor screening, such as Figure 9 And as shown in Table 2;

[0170] Table 2

[0171]

[0172] Note: aAll reactions involved 0.2 mmol of N-methyl-4-quinolone-2-carboxylic acid, 1.0 mol% of the in-situ coordinated Ligand / Metal (1.1:1) complex, reacted in 1 mL of anhydrous EtOH at 80 °C for 24 h. b through 1 Obtained by H NMR. c The ee value was obtained by HPLC using a chiral column, Chiralcel OJ-H.

[0173] After determining (R, R)-Ph-BPE as the optimal chiral ligand, the effects of three metal precursors—Ru, Rh, and Ir—on the reaction were further investigated. Experimental results showed that when [Ir(COD)Cl]₂ was used as the metal precursor, although the yield was as high as 97%, the enantioselectivity was only 63% ee (Table 2, entry 3). When using Ru as the metal precursor, the reaction could occur, but enantioselectivity was completely lost, yielding only the racemic product (entry 1). When Rh(COD)₂OTf was used as the metal precursor, the enantioselectivity was optimal (78% ee), and the conversion was comparable to the previous results (84%) (entry 4). When using other Rh metal precursors (entries 5-10) to catalyze the reaction, although the target product could be obtained at different conversion rates, the enantioselectivity decreased to varying degrees. Based on the above screening results, Rh(COD)₂OTf was determined to be the optimal metal precursor. In summary, the complex formed by (R,R)-Ph-BPE and Rh(COD)2OTf was identified as the optimal catalyst for this asymmetric hydrogenation reaction.

[0174] Solvent screening, such as Figure 10 And as shown in Table 3:

[0175] Table 3

[0176]

[0177] Note: a All reactions involved 0.2 mmol of N-methyl-4-quinolone-2-carboxylic acid and 1.0 mol% of in-situ coordinated (R,R)-Ph-BPE / Rh(COD)2OTf (1.1:1) complex, reacted in 1 mL of anhydrous solvent at 80 °C for 24 h. b through 1 Obtained by H NMR. c The ee value was obtained by HPLC using a chiral column, Chiralcel OJ-H.

[0178] Solvents play a crucial role in asymmetric catalytic reactions. After determining the catalyst, a comprehensive investigation of the solvents was conducted. Experimental results show that protic polar solvents favor this reaction. As the acidity of the protic solvent decreases, the yield and ee both increase to varying degrees (Table 3, entries 1-4). The best reaction results were obtained when tert-butanol was used as the solvent (95% yield, 92% ee, entry 4). However, when using strongly acidic protic solvents such as trifluoroethanol and hexafluoroisopropanol, only trace amounts of reaction occurred, and the ee values ​​of the products were only 32% and 41% (entries 5, 6), indicating that acidic protic solvents are unfavorable for this reaction. When dichloromethane was used as the solvent, only a 34% yield and 49% ee were obtained (entry 7). Ethyl acetate and toluene also yielded ideal high enantioselectivity (entries 8, 9), but the chemical conversion rates were not as high as when tert-butanol was used. When using the ether solvent tetrahydrofuran, the highest ee of 97% can be obtained, but its functional group selectivity is poor, and a small amount of double reduction byproduct (entry 10) will be generated. Therefore, after comprehensive comparison, tert-butanol was selected as the optimal solvent for the reaction.

[0179] Catalyst loading considerations Figure 11 And as shown in Table 4:

[0180] Table 4

[0181]

[0182] Note: a All reactions involved 0.2 mmol of N-methyl-4-quinolone-2-carboxylic acid and 1.0 mol% of in-situ coordinated (R,R)-Ph-BPE / Rh(COD)2OTf (1.1:1) complex, reacted in 1 mL of tert-butanol at 80 °C for 24 h. b through 1 Obtained by H-NMR. c The ee value was obtained by HPLC using a chiral column, Chiralcel OJ-H.

[0183] The conversion number (TON) of a catalyst often determines the efficiency and practical application value of asymmetric catalytic reactions in synthesis. Therefore, after establishing the optimal conditions for asymmetric catalytic hydrogenation, this invention further investigated the effect of catalyst dosage on the reaction. Experimental results show that as the catalyst dosage gradually decreases, the conversion rate of the reaction remains above 90%, however, the enantioselectivity shows a continuous downward trend. When the catalyst dosage is 0.5 mol% (S / C = 200), the stereoselectivity of the product is only 37% ee (Table 4, entry 2). Further reducing the catalyst dosage to 0.01 mol% still yields a 90% yield (entry 7), but unfortunately, the product is a racemic mixture. The above results indicate that in this catalytic system, although reducing the catalyst dosage can basically maintain the catalytic activity, it leads to a significant decrease in enantioselectivity.

[0184] After a systematic investigation of the reaction conditions, the optimal reaction conditions were obtained: 1.1 mol% (R,R)-Ph-BPE as the chiral ligand, 1.0 mol% Rh(COD)2OTf as the coordinating metal precursor, the two coordinate in situ to form a complex as the catalyst, tert-butanol as the reaction solvent, and the reaction was carried out at 40 atm H2 and 80℃ for 24 h.

[0185] Synthesis of a series of chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds:

[0186] After obtaining the above-mentioned optimal reaction conditions, the applicability of this catalytic system was further investigated to verify whether it could be used for the construction of diverse chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds. The results are as follows: Figure 12 As shown, all reactions involved 1.0 mmol of N-substituted-4-quinolone-2-carboxylic acid and 1.0 mol% of in-situ coordinated (R,R)-Ph-BPE / Rh(COD)2OTf (1.1:1) complex, reacted in 1 mL of t-BuOH at 80 °C for 24 h.

[0187] The results of this invention demonstrate that all 26 N-substituted-4-quinolone-2-carboxylic acid substrates containing various types of substituents can react under optimal reaction conditions, achieving moderate to high yields (40%-99%) and stereoselectivity up to 99% ee, to N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid products. Based on the template substrates, we first investigated the effect of substituents on the nitrogen atom on the reaction. Replacing the substituents on the nitrogen atom with various alkanes (8b-e) did not significantly alter the reaction yield and stereoselectivity; replacing the methyl group with a benzyl group (8h) also facilitated the reaction. We then investigated the effect of substituents on the benzyl group on the reaction. We found that when the benzyl group at the para position is electron-withdrawing, such as when it is substituted with a chlorine atom (8j), the reaction result is better than that of the electron-donating methyl substituent (8i). This indicates that the electron-withdrawing substituent at the para position favors the reaction. When the benzyl group at the meta position contains a substituent (8k, 8l), the electron-donating substituent is more favorable to the reaction. The electronic effect of the benzyl group at the ortho position has no effect on the stereoselectivity of the reaction (8m). We then systematically investigated the effect of substituents on the aromatic ring of N-methyl-4-quinolone-2-carboxylic acid on the reaction. When there is a single electron-donating substituent on the aromatic ring, the position of the substituent has a significant effect on the stereoselectivity of the reaction. Only substrates with a methyl group at the 8-position can obtain the product with excellent enantioselectivity (8q). Similarly, when there is a single electron-withdrawing substituent on the aromatic ring, the enantioselectivity of the reaction product obtained by the substituent at the ortho and meta positions (8t, 8v) is significantly better than that obtained by the para substituent (8u). When a double electron-donating group (8r, 8s, 8y) or a double electron-withdrawing group (8z) is attached to the aromatic ring, the corresponding product can be successfully converted under this catalytic system. When a benzene ring (8n) or a naphthalene ring (8aa) is attached to the aromatic ring, the reaction can also occur, and moderate to excellent yields and high stereoselectivity (92%-99% ee) can be obtained.

[0188] Furthermore, this invention also cultivated single crystals of the keto reaction product 7b using N-methyl-4-quinolone-2-carboxylic acid 4b as a substrate, and determined its absolute configuration to be (R)-type by X-ray single-crystal diffraction. Based on this result, the absolute configurations of all reaction products were determined, such as... Figure 13 As shown:

[0189] The structures and corresponding qualitative data of the chiral 4-hydroxy-1-substituted-1,2-dihydroquinoline-2-carboxylic acid compounds synthesized in this paper are as follows:

[0190]

[0191] (R)-4-hydroxy-1-methyl-1,2-dihydroquinoline-2-carboxylic acid (8b): yellow solid, 95% yield, 92% ee, melting point: 85-88℃. = +15.60 (c=0.25 in MeOH). 1 H NMR (400 MHz, CDCl3)δ 8.47 (dt, J= 8.3, 1.8 Hz, 1H), 7.73 (ddd, J = 8.6, 7.0, 1.5 Hz, 1H), 7.61 (d, J = 7.5Hz, 1H), 7.45 (ddd, J = 10.7, 6.0, 2.1 Hz, 2H), 6.42 (d, J = 7.5 Hz, 1H), 3.86 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 178.51, 163.50, 144.31, 140.52,132.68, 126.96, 126.51, 124.31, 115.47, 109.53, 40.96. HRMS (ESI): m / z forC 11 H 11 NO3[M+H-HCOOH] + Calcium cd 160.0757, found 160.0742. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, detection wavelength 245 nm, t R =19.43 min for minor isomer, and t R =22.56 min for major isomer.

[0192]

[0193] (R)-1-Ethyl-4-hydroxy-1,2-dihydroquinoline-2-carboxylic acid (8c): Brown oily liquid, 95% yield, 82% ee. = +1.600 (c=0.25 in MeOH). 1H NMR (400 MHz, MeOD)δ 8.34 (d, J = 8.1 Hz,1H), 8.06 (d, J = 7.3 Hz, 1H), 7.78 (d,J = 4.5 Hz, 2H), 7.52-7.39 (m, 1H),6.33 (d, J = 7.4 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.46 (t,J = 7.1 Hz, 3H). 13 C NMR (101 MHz, MeOD) δ 179.88, 164.58, 146.02, 140.95, 134.00, 127.72,127.19, 125.40, 117.69, 110.08, 14.90. HRMS (ESI): m / z for C 12 H 13 NO3[M+H-HCOOH] - Calculation result: 174.0913, found: 174.0915. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, detection wavelength 254 nm. R =14.78 min for minor isomer, and t R =17.63 min for major isomer.

[0194]

[0195] (R)-4-Hydroxy-1-propyl-1,2-dihydroquinoline-2-carboxylic acid (8d): Brown oily liquid, 90% yield, 89% ee, melting point: = +1.500 (c=0.125 in MeOH). 1H NMR (400 MHz, MeOD)δ 8.40- 8.29(m, 1H), 8.04 (d, J = 7.4 Hz, 1H), 7.84-7.71 (m, 2H), 7.45 (ddd, J = 8.0,6.1, 1.7 Hz, 1H), 6.31 (d, J = 7.4 Hz, 1H), 4.27 (t, J = 7.3 Hz, 2H), 1.87 (h, J = 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, MeOD)δ179.92, 164.57, 146.62, 141.16, 133.93, 127.72, 127.16, 125.38, 117.82,109.69, 55.87, 23.41, 11.20. HRMS (ESI): m / z for C 13 H 15 NO3[M+H-HCOOH] + calcd 188.1070, found 190.0890. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cmID), hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, detection wavelength 254 nm, t R =12.07 minfor minor isomer, and t R =13.24 min for major isomer.

[0196]

[0197] (R)-1-Butyl-4-hydroxy-1,2-dihydroquinoline-2-carboxylic acid (8e): Brown oily liquid, 95% yield, 83% ee. Melting point: = +5.20 (c=0.25 in MeOH). 1H NMR (400 MHz, MeOD)δ 8.40-8.33 (m,1H), 8.0d, J = 7.5 Hz, 1H), 7.86-7.78 (m, 2H), 7.49 (ddd, J = 8.1, 5.7, 2.2Hz, 1H), 6.34 (d, J = 7.5 Hz, 1H), 4.36 (t,J = 7.4 Hz, 2H), 1.92-1.80 (m,2H), 1.43 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, MeOD)δ 180.03, 164.52, 146.59, 141.19, 133.95, 127.80, 127.21, 125.38,117.83, 109.77, 54.25, 32.24, 20.85, 14.02. HRMS (ESI): m / z for C 14 H 17 NO3[M+H-HCOOH] + Calculation result 202.1226, found 202.1217. HPLC detection conditions: Chiralcel OD-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 80:20, flow rate = 1.0 mL / min, detection wavelength 254 nm. R =12.95 min for major isomer, and t R =16.04 min for minor isomer.

[0198]

[0199] (R)-4-hydroxy-1,5-dimethyl-1,2-dihydroquinoline-2-carboxylic acid (8f): white solid, yield 83%, 30% ee, melting point: 149-151℃. = +1.60 (c=0.25 in MeOH). 1H NMR (400 MHz, MeOD)δ 8.09(s, 1H), 7.85 (d,J = 7.4 Hz, 1H), 7.59 (dd,J = 8.6, 7.3 Hz, 1H), 7.49 (d, J =8.6 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.19 (d, J = 7.4 Hz, 1H), 3.84 (s, 3H), 2.89 (s, 3H). 13 C NMR (101 MHz, MeOD)δ 182.62, 164.54, 145.56, 143.84,142.27, 132.98, 128.28, 126.11, 115.49, 111.45, 41.94, 24.43. HRMS (ESI): m / zfor C 12 H 13 NO3[M+H-HCOOH] + Calculation result: 174.0913, found: 174.0891. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 93:7, flow rate = 0.7 mL / min, detection wavelength 245 nm. R =27.40 min for minor isomer, and t R =30.53 min for majorisomer.

[0200]

[0201] (R)-4-hydroxy-1,7-dimethyl-1,2-dihydroquinoline-2-carboxylic acid (8g): white solid, yield 77%, 44% ee, melting point: 208-210℃. = +2.00 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ 8.18(d, J = 8.3 Hz, 1H), 7.93 (d,J = 7.5 Hz, 1H), 7.50 (s, 1H), 7.30 (dd, J =8.3, 1.4 Hz, 1H), 6.24 (d, J = 7.5 Hz, 1H), 3.89 (s, 3H), 2.54 (s, 3H). 13CNMR (101 MHz, MeOD) δ 180.02, 146.79, 145.32, 142.32, 127.20, 126.76, 125.37,117.23, 109.57, 41.32, 22.14. HRMS (ESI): m / z for C 12 H 13 NO3[M+H-HCOOH] + calcd174.0913, found 174.0904. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cmID), hexane / 2-propanol=93:7, flow rate=0.7 mL / min, detection wavelength 245 nm, t R =29.29 minfor minor isomer, and t R =36.21 min for major isomer.

[0202]

[0203] (R)-1-Benzyl-4-hydroxy-1,2-dihydroquinoline-2-carboxylic acid (8h): brown solid, yield 76%, 97% ee, melting point: 50-54℃. = +1.00 (c=0.075 in MeOH). 1 H NMR (400 MHz, MeOD)δ 8.39 -8.30(m, 1H), 8.21 (d, J = 7.4 Hz, 1H), 7.69-7.58 (m, 2H), 7.41 (ddd, J = 8.0,6.1, 1.7 Hz, 1H), 7.32 (dd, J = 8.1, 6.3 Hz, 2H), 7.29-7.23 (m, 1H), 7.22-7.15 (m, 2H), 6.40 (d, J = 7.4 Hz, 1H), 5.56 (s, 2H). 13 C NMR (101 MHz, MeOD)δ180.25, 164.47, 147.26, 141.52, 137.22, 133.84, 130.15, 129.19, 127.87,127.42, 127.10, 125.51, 118.56, 110.08, 57.55. HRMS (ESI): m / z for C 17 H15 NO3[M+H-HCOOH] + calcd 236.1070, found 236.1081. HPLC detection conditions: Chiralcel OD-H column (25cm × 0.46 cm ID), hexane / 2-propanol = 80:20, flow rate = 1.0 mL / min, detection wavelength 254 nm, t R =12.95 min for major isomer, and t R =16.04 min for minor isomer.

[0204]

[0205] (R)-4-hydroxy-1-(4-methylbenzyl)-1,2-dihydroquinoline-2-carboxylic acid (8i): white solid, yield 83%, 60% ee, melting point: 152-154℃. = +5.20 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ8.35 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.73-7.60 (m, 2H), 7.43(ddd, J = 8.0, 5.4, 2.5 Hz, 1H), 7.21-7.06 (m, 4H), 6.41 (d, J = 7.5 Hz, 1H), 5.53 (s, 2H), 2.30 (s, 3H). 13 C NMR (101 MHz, MeOD) δ 180.29, 164.58, 147.15,141.54, 139.19, 134.12, 133.77, 130.72, 127.90, 127.46, 127.07, 125.45,118.59, 110.04, 57.41, 21.09. HRMS (ESI): m / z for C 18 H 17 NO3[M+H-HCOOH] +calcd250.1226, found 250.1199. HPLC detection conditions: Chiralcel OD-H column (25 cm × 0.46 cmID), hexane / 2-propanol = 80:20, flow rate = 1.0 mL / min, detection wavelength 365 nm, t R =9.89 minfor minor isomer, and t R =10.92 min for major isomer.

[0206]

[0207] (R)-4-hydroxy-1-(4-chlorobenzyl)-1,2-dihydroquinoline-2-carboxylic acid (8j): white solid, yield 91%, 96% ee, melting point: 162-168℃. = +10.40 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ 8.22(dd, J = 8.2, 1.5 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.61-7.41 (m, 2H), 7.36-7.26 (m, 1H), 7.26-7.14 (m, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.28 (d, J = 7.5Hz, 1H), 5.44 (s, 2H). 13 C NMR (101 MHz, MeOD) δ 180.29, 147.14, 141.41,136.10, 134.97, 133.93, 130.21, 129.09, 127.92, 127.19, 125.55, 118.39,110.27, 56.80. HRMS (ESI): m / z for C 17 H 14 ClNO4[M+H-HCOOH] - Calcium 270.0680, found 270.0686. HPLC detection conditions: Chiralcel OD-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 80:20, flow rate = 1.0 mL / min, detection wavelength 365 nm, t R =11.89 min for minorisomer, and tR =12.50 min for major isomer.

[0208]

[0209] (R)-4-hydroxy-1-(3-methylbenzyl)-1,2-dihydroquinoline-2-carboxylic acid (8k): white solid, 99% yield, 95% ee, melting point: 140-145℃. = +11.60 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ8.23 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 7.3 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.30 (t, J = 6.8 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.92 (s, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.28 (d, J = 7.3 Hz, 1H), 5.40 (s, 2H), 2.16 (s, 3H). 13 C NMR (101 MHz, MeOD) δ 180.34, 147.19, 141.56, 140.15,137.17, 133.78, 130.06, 129.89, 127.98, 127.09, 125.44, 124.48, 118.56,110.08, 57.55, 21.43. HRMS (ESI): m / z for C 18 H 17 NO3[M+H-HCOOH] + Calcium 250.1226, found 250.1213. HPLC detection conditions: Chiralcel OD-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 80:20, flow rate = 1.0 mL / min, detection wavelength 365 nm, t R =10.23 min for majorisomer, and t R =11.44 min for minor isomer.

[0210]

[0211] (R)-4-hydroxy-1-(3-chlorobenzyl)-1,2-dihydroquinoline-2-carboxylic acid (8l): white solid, yield 80%, 70% ee, melting point: 153-155℃. = -293.99 (c=0.25 in MeOH). 13 C NMR (101 MHz, MeOD)δ180.34, 147.10, 141.41, 139.79, 136.02, 133.98, 131.73, 129.24, 127.99,127.46, 127.27, 125.75, 125.51, 118.32, 110.48, 56.74. HRMS (ESI): m / z forC 17 H 14 ClNO4[M+H-HCOOH] + Calcium 270.0680, found 270.0681. HPLC detection conditions: Chiralcel OD-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 80:20, flow rate = 1.0 mL / min, detection wavelength 365 nm, t R =12.70 min for major isomer, and t R =16.78 min for minor isomer.

[0212]

[0213] (R)-4-hydroxy-1-(2-bromobenzyl)-1,2-dihydroquinoline-2-carboxylic acid (8m): white solid, yield 93%, 21% ee, melting point: 116-120℃. = +6.80 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ 8.36(dd, J = 8.1, 1.6 Hz, 1H), 8.12-8.07 (m, 1H), 7.73-7.58 (m, 2H), 7.47-7.30(m, 2H), 7.25 -7.16 (m, 2H), 6.75-6.66 (m, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.55 (s, 2H). 13C NMR (101 MHz, MeOD)δ 180.31, 164.50, 146.95, 141.46, 135.90,134.46, 134.09, 130.99, 129.34, 128.61, 127.87, 127.32, 125.62, 123.22,118.01, 110.52, 57.58. HRMS (ESI): m / z for C 17 H 14 BrNO3[M+H-HCOOH] + calcd 314.0175, found 314.0181. HPLC detection conditions: Chiralcel OD-H column (25 cm × 0.46 cmID), hexane / 2-propanol = 80:20, flow rate = 1.0 mL / min, detection wavelength 365 nm, t R =12.09 minfor minor isomer, and t R =12.99 min for major isomer.

[0214]

[0215] (R)-4-hydroxy-1-methyl-8-phenyl-1,2-dihydroquinoline-2-carboxylic acid (8n): White solid, yield 82%, 95% ee, melting point: 130-132℃. = +32.00 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ8.43 (dd, J = 8.0, 1.7 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.63 (dd, J = 7.2,1.7 Hz, 1H), 7.55 -7.46 (m, 4H), 7.45-7.38 (m, 2H), 6.36 (d, J = 7.6 Hz, 1H), 3.34 (s, 3H). 13 C NMR (101 MHz, MeOD)δ 179.99, 149.77, 142.98, 141.04, 138.11,134.30, 130.66, 129.57, 129.19, 129.05, 126.75, 124.82, 109.93, 47.27, 28.13.HRMS (ESI): m / z for C17 H 15 NO3[M+H-HCOOH] - Calculation result: 236.1070, found: 236.1057. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, detection wavelength 365 nm. R =16.78 min for major isomer, and t R =19.57 minfor minor isomer.

[0216]

[0217] (R)-4-hydroxy-1,6-dimethyl-1,2-dihydroquinoline-2-carboxylic acid (8o): white solid, yield 99%, 37% ee, melting point: 140-141℃. = +2.40 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ 7.98(d, J = 7.4 Hz, 1H), 7.68-7.62 (m, 2H), 6.29 (d, J = 7.5 Hz, 1H), 3.93 (s,3H), 2.50 (d, J = 0.9 Hz, 3H). 13 C NMR (101 MHz, MeOD)δ 179.81, 164.59,146.61, 140.31, 135.85, 135.44, 127.30, 126.05, 117.68, 109.45, 41.36, 21.09.HRMS (ESI): m / z for C 12 H 13 NO3[M+H-HCOOH] + Calculation result: 174.0913, found: 174.0891. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, detection wavelength 245 nm. R =14.65 min for minor isomer, and t R=16.81 minfor major isomer.

[0218]

[0219] (R)-4-hydroxy-6-isopropyl-1,2-dihydroquinoline-2-carboxylic acid (8p): white solid, yield 81%, 41% ee, melting point: 115-117℃. = +2.40 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ 8.19 (s,1H), 7.94 (d, J = 7.4 Hz, 1H), 7.82-7.56 (m, 2H), 6.26 (d, J = 7.4 Hz, 1H), 3.90 (s, 3H), 1.32 (d, J = 7.0 Hz, 6H). 13 C NMR (101 MHz, MeOD) δ 180.01,146.63, 146.55, 140.54, 133.23, 127.39, 123.39, 117.82, 109.49, 41.35, 35.01,24.34. HRMS (ESI): m / z for C 12 H 13 NO3[M+H-HCOOH] + calcd 202.1226, found201.0388. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 93:7, flow rate = 0.7 mL / min, detection wavelength 245 nm, t R =17.30 min for minorisomer, and t R =22.72 min for major isomer.

[0220]

[0221] (R)-4-hydroxy-1,8-dimethyl-1,2-dihydroquinoline-2-carboxylic acid (8q): white solid, yield 91%, 97% ee, melting point: 125-128℃. = -2.00 (c=0.25 in MeOH). 1H NMR (400 MHz, MeOD)δ 8.21(d, J = 8.1 Hz, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 7.1 Hz, 1H), 7.31(t, J = 7.6 Hz, 1H), 6.26 (d, J = 7.4 Hz, 1H), 4.16 (s, 3H), 2.85 (s, 3H).HRMS (ESI): m / z for C 12 H 13 NO3[M+H-HCOOH] - Calcium 174.0913, found 174.0900. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 93:7, flow rate = 0.7 mL / min, detection wavelength 245 nm, t R =22.50 min for minor isomer, and t R =23.97 minfor major isomer.

[0222]

[0223] (R)-4-hydroxy-1,5,6-trimethyl-1,2-dihydroquinoline-2-carboxylic acid (8r): white solid, yield 44%, 99% ee, melting point: 147-150℃. = +8.00 (c=0.075 in MeOH). 1 H NMR (400 MHz, MeOD)δ 7.76(d, J = 7.5 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.14(d, J = 7.5 Hz, 1H), 3.79 (s, 3H), 2.83 (s, 3H), 2.36 (s, 3H). 13 C NMR (101MHz, MeOD) δ 182.96, 144.77, 142.33, 139.73, 135.37, 134.37, 126.11, 114.54,111.40, 41.74, 30.80, 20.59, 18.47. HRMS (ESI): m / z for C 13 H 15NO3[M+H-HCOOH] + Calculation result: 188.1070, found: 188.1049. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 93:7, flow rate = 0.7 mL / min, detection wavelength 245 nm. R =21.46 minfor major isomer, and t R =23.89 min for minor isomer.

[0224]

[0225] (R)-4-hydroxy-1,6,7-trimethyl-1,2-dihydroquinoline-2-carboxylic acid (8s): white solid, yield 83%, 96% ee, melting point: 228-230℃. = +1.60 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ 7.99(s, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.43 (s, 1H), 6.21 (d, J = 7.4 Hz, 1H), 3.86 (s, 3H), 2.44 (s, 3H), 2.38 (s, 3H). 13 C NMR (101 MHz, MeOD) δ 179.77,146.22, 144.63, 140.69, 135.30, 126.42, 125.64, 117.70, 109.31, 41.27, 20.73,19.60. HRMS (ESI): m / z for C 13 H 15 NO3[M+H-HCOOH] + calcd 188.1070, found188.1059. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, detection wavelength 254 nm, t R =15.44 min for minorisomer, and t R =21.73 min for major isomer.

[0226]

[0227] (R)-5-fluoro-4-hydroxy-1-methyl-1,2-dihydroquinoline-2-carboxylic acid (8t): yellow solid, yield 55%, 87%ee, melting point: 147-155℃. = +1.20 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ 8.37(dd, J = 9.1, 6.4 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.49 (dd, J = 10.8, 2.3Hz, 1H), 7.27 (td, J = 8.6, 2.3 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 3.90 (s,3H). 13 C NMR (101 MHz, MeOD) δ 179.48, 167.90, 165.41, 164.49, 147.53, 143.92,143.80, 130.23, 130.12, 124.32, 114.27, 114.03, 110.13, 103.84, 103.57,41.45. 19 F NMR (376 MHz, MeOD) δ -106.16. HRMS (ESI): m / z for C 11 H 10 NO3[M+H-HCOOH] + Calculation result: 178.066; Found value: 178.0652. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 93:7, flow rate = 0.7 mL / min, detection wavelength 245 nm. R =17.49 min for minor isomer, and t R =30.12 min for major isomer.

[0228]

[0229] (R)-6-fluoro-4-hydroxy-1-methyl-1,2-dihydroquinoline-2-carboxylic acid (8u): yellow solid, yield 76%, 62% ee, melting point: 150-152℃. = +1.20 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ 8.01(d, J = 7.4 Hz, 1H), 7.92 (dd, J = 9.1, 3.0 Hz, 1H), 7.81 (dd, J = 9.4, 4.3Hz, 1H), 7.60 (td, J = 8.8, 2.8 Hz, 1H), 6.28 (d, J = 7.4 Hz, 1H), 3.95 (s, 3H). 13 C NMR (101 MHz, MeOD)δ 179.21, 164.51, 162.08, 159.64, 147.04, 138.87,128.88, 128.81, 122.56, 122.31, 120.70, 120.62, 111.08, 110.85, 109.21,41.64. 19 F NMR (376 MHz, MeOD) δ -118.50. HRMS (ESI): m / z for C 11 H 10 NO3[M+H-HCOOH] + Calculation result: 178.0663, found: 178.0649. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, detection wavelength 254 nm. R =18.66 min for minor isomer, and t R =20.82 min for major isomer.

[0230]

[0231] (R)-8-fluoro-4-hydroxy-1-methyl-1,2-dihydroquinoline-2-carboxylic acid (8v): white solid, yield 75%, 98% ee, melting point: 150-152℃. = +1.60 (c=0.25 in MeOH). 1H NMR (400 MHz, MeOD)δ 8.12– 8.07 (m, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 14.7, 7.7 Hz, 1H), 7.38 (td, J = 7.9, 4.2 Hz, 1H), 6.25 (d, J = 7.4 Hz, 1H), 4.08 (d, J = 8.5Hz, 3H). 13 C NMR (101 MHz, MeOD) δ 178.63, 164.51, 155.22, 152.75, 149.05,131.79, 131.72, 130.15, 125.57, 125.49, 122.99, 122.95, 120.37, 120.14,110.01, 45.97, 45.81. 19 F NMR (376 MHz, MeOD) δ -80.04, -122.89. HRMS (ESI):m / z for C 11 H 10 NO3[M+H-HCOOH] + Calculation result: 178.0663, found: 178.0649. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 93:7, flow rate = 0.7 mL / min, detection wavelength 245 nm. R =25.15 min for major isomer, and t R =27.67 min for minorisomer.

[0232]

[0233] (R)-6-bromo-4-hydroxy-1-methyl-1,2-dihydroquinoline-2-carboxylic acid (8w): white solid, yield 75%, 7%ee, melting point: 150-152℃. = +0.8 (c=0.25 in MeOH). 1H NMR (400 MHz, MeOD)δ 8.43(d, J = 2.3 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.91 (dd, J = 9.1, 2.3 Hz,1H), 7.70 (d, J = 9.0 Hz, 1H), 6.32 (d, J = 7.5 Hz, 1H), 3.94 (s, 3H). 13 C NMR (101 MHz, MeOD) δ 178.79, 164.49, 147.42, 141.05, 136.70, 129.31, 128.82, 120.17, 119.04, 110.26, 41.43. 13 C NMR (101 MHz, MeOD) δ 178.79, 164.49,147.42, 141.05, 136.70, 129.31, 128.82, 120.17, 119.04, 110.26, 41.43. HRMS(ESI): m / z for C 11 H 10 BrNO3[M+H-HCOOH] + Calculation result: 237.9862; Found result: 237.9834. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, detection wavelength 365 nm. R =20.01 min for minor isomer, and t R =24.64 minfor major isomer.

[0234]

[0235] (R)-4-hydroxy-6-methoxy-1-methyl-1,2-dihydroquinoline-2-carboxylic acid (8x): white solid, 90% yield, 30% ee, melting point: 210-212℃. = +6.0 (c=0.25 in MeOH). 1H NMR (400 MHz, MeOD)δ7.98 (d, J = 7.4 Hz, 1H), 7.78 -7.69 (m, 2H), 7.45 (dd, J = 9.3, 3.0 Hz, 1H), 6.30 (d, J = 7.3 Hz, 1H), 4.02 -3.87 (m, 6H). 13 C NMR (101 MHz, MeOD) δ179.42, 158.33, 145.81, 136.96, 128.67, 124.52, 119.54, 108.84, 105.87,56.15, 41.52. HRMS (ESI): m / z for C 12 H 13 NO4[M+H-HCOOH] + Calcium 190.0863, found 190.0844. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, detection wavelength 365 nm, t R =22.22 min for minorisomer, and t R =27.50 min for major isomer.

[0236]

[0237] (R)-4-hydroxy-1,5,8-trimethyl-1,2-dihydroquinoline-2-carboxylic acid (8y): white solid, yield 70%, 96% ee, melting point: 175-178℃. = -1.60 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ 7.73(d, J = 7.0 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.15(d, J = 7.6 Hz, 1H), 3.99 (s, 3H), 2.82 (s, 3H), 2.71 (s, 3H). 13C NMR (101MHz, MeOD)δ 148.14, 145.41, 139.97, 137.30, 128.39, 126.14, 111.39, 46.86,24.71, 24.33. HRMS (ESI): m / z for C 13 H 15 NO3[M+H-HCOOH] + calcd 188.1070, found188.1051. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 93:7, flow rate = 0.6 mL / min, detection wavelength 220 nm, t R =16.19 min for minorisomer, and t R =16.98 min for major isomer.

[0238]

[0239] (R)-5,7-difluoro-4-hydroxy-1-methyl-1,2-dihydroquinoline-2-carboxylic acid (8z): white solid, 95% yield, 96% ee, melting point: 206-208℃. = -235.19 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ6.41 (dt, J = 12.1, 1.9 Hz, 1H), 6.25 (ddd, J = 11.7, 9.2, 2.3 Hz, 1H), 4.43(dd, J = 7.3, 2.2 Hz, 1H), 3.13 (s, 3H), 2.92 (dd, J = 16.4, 2.2 Hz, 1H). 13 CNMR (101 MHz, MeOD) δ 190.94, 173.69, 170.21, 170.04, 167.70, 167.53, 167.00,166.84, 164.38, 164.21, 155.63, 155.57, 155.49, 155.43, 106.92, 106.86,96.95, 96.92, 96.69, 96.65, 94.47, 94.21, 93.94, 63.74, 41.61, 40.28. HRMS(ESI): m / z for C11 H9F2NO3[M+H-HCOOH] + Calculation result: 194.0568, found: 196.0582. HPLC detection conditions: Chiralcel OJ-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, detection wavelength 365 nm. R =26.84 min for minor isomer, and t R =29.87 minfor major isomer.

[0240]

[0241] (R)-4-hydroxy-1-methyl-1,2-dihydrobenzo[g]quinoline-2-carboxylic acid (8aa): white solid, yield 81%, 99% ee, melting point: 204-207℃. = +14.00 (c=0.25 in MeOH). 1 H NMR (400 MHz, MeOD)δ10.31 (d, J = 8.6 Hz, 1H), 8.21-8.04 (m, 2H), 8.00-7.85 (m, 2H), 7.72 (ddd, J= 8.6, 6.9, 1.5 Hz, 1H), 7.68-7.57 (m, 2H), 6.47 (d, J = 7.3 Hz, 1H), 3.93(s, 3H). 13 C NMR (101 MHz, MeOD)δ 181.70, 164.59, 143.62, 142.88, 135.73,132.44, 131.49, 129.54, 129.32, 128.33, 127.47, 120.73, 116.43, 114.56,42.55. HRMS (ESI): m / z for C 17 H 15 NO3[M+H-HCOOH] - calcd 210.0913, found210.0902. HPLC detection conditions: Chiralcel OD-H column (25 cm × 0.46 cm ID), hexane / 2-propanol = 80:20, flow rate = 1.0 mL / min, detection wavelength 365 nm, t R=13.56 min for minorisomer, and t R =23.22 min for major isomer.

[0242] Deuteration experiments such as Figure 14 As shown:

[0243] Since the direct reduction product 7 is thermodynamically unstable and readily tautomerizes to an enol structure 8, this invention uses 4b as the analytical object and investigates the hydrogen source and its transport pathway in this asymmetric hydrogenation reaction through deuteration tracer experiments. Three reaction conditions were set up in the experiment: (1) H2 / deuterated tert-butanol (t-BuOD); (2) D2 / deuterated butanol (t-BuOH); (3) D2 / deuterated tert-butanol (t-BuOD). After the reaction, product 8b was separated, and the deuteration rate of its 2- and 3-position hydrogen atoms was determined by ¹H NMR.

[0244] Experimental results show that under H2 / t-BuOD conditions, no significant deuterium incorporation was detected at the C2 and C3 sites of product 8b, indicating that deuterium in the solvent did not directly participate in the reduction process. Under D2 / t-BuOH conditions, the deuteration rate at the C2 site reached 86%, while that at the C3 site was only 20%. Under D2 / t-BuOD conditions, the deuteration rate at the C2 site further increased to over 95%, while that at the C3 site was 24%.

[0245] The results reveal the following key information: First, the hydrogen source for this hydrogenation reaction mainly originates from hydrogen molecules, rather than from a protic solvent; second, the lower deuteration rate at the C3 position and its variation under different conditions indicate that the reaction may have undergone an enol-keto tautomerism equilibrium—that is, the deuterium atom at the C3 position is partially replaced by protons in the solvent during the tautomerism process, resulting in a significantly lower deuteration rate at the C3 position than at the C2 position in the final product. These experimental results provide important experimental evidence for further understanding the reaction mechanism and optimizing the catalytic system.

[0246] Controlled experiments such as Figure 15 As shown:

[0247] To evaluate the application potential of the aforementioned asymmetric catalytic hydrogenation system in the synthesis of chiral 2-substituted quinolone compounds, we further prepared 2-methyl and ester-substituted quinolone substrates and investigated their performance in the hydrogenation reaction. Unfortunately, neither type of substrate underwent hydrogenation under optimal reaction conditions. This result indicates that the carboxyl group on the substrate plays an important role in this reaction and participates in the catalytic cycle.

[0248] Based on deuterium labeling experiments, substituent-controlled experiments, and previous findings on the enantioselective reduction mechanism of α,β-unsaturated carboxylic acids catalyzed by transition metals, we propose a possible catalytic cycle for this reaction. First, the catalyst precursor reacts with t-BuOH and hydrogen to generate an Rh(III) species, which then forms a complex with substrate 4b. Intramolecular rearrangement occurs, generating a hydride intermediate; this step is stereochemically determinant. Subsequently, the hydride at the metal center migrates and inserts into the double bond of the substrate, forming an alkyl hydride species. A reductive elimination reaction between the metal hydride and the substrate releases product 7b and an Rh(I) species. 7b undergoes tautomerism to the thermodynamically more stable final product 8b, while the Rh(I) species undergoes an oxidative addition reaction with hydrogen to regenerate the Rh(III) species, thus completing the catalytic cycle.

[0249] Catalytic hydrogenation reaction to synthesize N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylic acid ethyl ester, such as Figure 16 As shown:

[0250] Weigh out 0.0022 mmol of the ligand and 0.002 mmol of the metal precursor and add them to a 5 mL reaction vial. In a glove box, add 1 mL of EtOH to the reaction vial and stir for 30 min to form an in-situ coordinated metal complex. Transfer the complex to an ampoule containing 0.2 mmol of N-substituted 4-quinolone-2-carboxylic acid ester 3 and a stir bar using a 1 mL syringe. Place the ampoule in an autoclave, tighten the autoclave, and remove it from the glove box. Replace the argon gas in the autoclave with hydrogen three times, then purge with hydrogen to the required pressure. Stop the reaction by stirring at 80 °C for 24 h. After releasing the hydrogen in a fume hood, transfer the reaction mixture to a 5 mL reaction vial and concentrate by rotary evaporation. 1 ¹H NMR analysis determined the conversion rate of the reaction. The crude product was further purified by rapid column chromatography to obtain pure N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylate 9, and its chemical yield was calculated.

[0251] Synthesis of N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylic acid ethyl ester by catalytic hydrogenation:

[0252] After obtaining a series of N-substituted-4-quinolone-2-carboxylate compounds 3, N-methyl-4-quinolone-2-carboxylate 3a was used as a template substrate to screen and optimize parameters of the hydrogenation reaction, such as ligands, coordination metals, and reaction temperature, in order to obtain the optimal reaction conditions for the preparation of N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylate 9.

[0253] First, using Rh(NBD)₂BF₄ as a metal precursor, the catalytic effect of JosiPhos series bisphosphine ligands in this reaction was investigated. Experimental results showed that these ligands failed to catalyze the reaction. Subsequently, the bisphosphine ligands L24-BINAP and L25-SegPhos were tried, but they also failed to achieve catalytic conversion, indicating that the bisphosphine ligand system is not suitable for this reaction. Based on this result, we switched to using the chiral PN ligand L26, and detected a small amount of the target product, confirming that the PN ligand can catalyze this reaction. Further evaluation using novel chiral PN ligands L27 and L28, independently developed by our research group, revealed that L27 achieved a 60% product yield.

[0254] Subsequently, using L27 as the best-performing ligand, the effects of different rhodium metal precursors on the catalytic results were systematically investigated. The results showed that the highest reaction yield was obtained when using Rh(NBD)₂BF₄, while the yields of Rh(NBD)₂OTf and Rh(COD)₂SbF₆ were both relatively low. At room temperature, the yields of each catalytic system remained at a moderate level; after raising the reaction temperature to 80℃, the feedstock could be completely converted into the target product 9a. In summary, through the screening of the above ligands and metal precursors, the optimal conditions for this reaction were determined to be: using the in-situ complex formed by the novel PN ligand L27 and Rh(NBD)₂BF₄ as the catalyst, and reacting at 80℃ and 40 atm H₂ for 24 hours. The screening of reaction conditions is as follows: Figure 17 , 18 And as shown in Table 5:

[0255] Table 5

[0256]

[0257] Note: a All reactions were carried out in 1 mL of anhydrous EtOH at room temperature for 24 h, using 0.2 mmol of 4-quinolone-2-carboxylate and 1.0 mol% of the in-situ coordinated Ligand / Metal (1.1:1) complex. b through 1 ¹H NMR was obtained, c No response.

[0258] Synthesis of a series of N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylic acid ethyl esters:

[0259] After obtaining the optimal reaction conditions, the substrate suitability of this reaction was investigated, and the results are as follows: Figure 19 As shown, all reactions involved 0.2 mmol of 4-quinolone-2-carboxylate, 1.0 mol% of the in-situ coordinated Ligand / Metal (1.1:1) complex, reacted in 1 mL of anhydrous EtOH at room temperature for 24 h.

[0260] The results of this invention indicate that the reaction proceeds smoothly when different alkyl substituents are replaced on the nitrogen atom. However, the reaction yield gradually decreases with the increase of the alkyl carbon chain (9a-d), suggesting that the increase in the size of the substituent has an adverse effect on the reaction, possibly due to the enhanced steric hindrance effect. Substrates with methyl substitutions at different positions on the benzene ring can also react under standard conditions, achieving selective reduction of the aromatic ring, but the products obtained are all racemic mixtures (9f, 9g). When the substituent on the nitrogen atom is benzyl, the reaction can occur, but the benzyl group is removed during the process, ultimately yielding product 9a.

[0261]

[0262] 5,6,7,8-Tetrahydro-4-quinolone-2-carboxylic acid ethyl ester (9a): white solid, yield 99%, melting point: 56-58℃. 1 HNMR (400 MHz, CDCl3)δ 7.03 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 2.68 (t, J =6.2 Hz, 2H), 2.57 (t, J = 6.2 Hz, 2H), 1.90-1.74 (m, 4H), 1.38 (t, J = 7.1Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ 179.61, 162.91, 139.13, 136.64, 133.15,126.37, 126.27, 124.58, 118.18, 111.54, 63.36, 14.09. HRMS (ESI): m / z forC 12 H 14 NO3[M+H] + calcd 222.1125, found 222.1112. HRMS (ESI): m / z for C 12 H 15 NO3[M+H] + Calcd 222.1281, found 222.1260.

[0263]

[0264] N-Methyl-5,6,7,8-tetrahydro-4-quinolone-2-carboxylic acid ethyl ester (9b): white solid, yield 86%, melting point: 60-62℃. 1H NMR (400 MHz, CDCl3)δ 6.73 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.60 (s,3H), 2.68-2.53 (m, 4H), 1.87-1.79 (m, 2H), 1.73-1.64 (m, 2H), 1.36 (t, J =7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ 177.53, 163.53, 147.80, 141.17, 128.68,117.66, 62.55, 36.78, 27.37, 22.78, 22.44, 20.95, 14.01. HRMS (ESI): m / z forC 13 H 17 NO3[M+H] + Calcd 236.1281, found 236.1265.

[0265]

[0266] N-Ethyl-5,6,7,8-Tetrahydro-4-quinolone-2-carboxylic acid ethyl ester (9c): White solid, yield 70%, melting point: 95-98℃. 1 H NMR (400 MHz, CDCl3)δ 6.70 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.13 (q,J = 7.2 Hz, 2H), 2.80-2.52 (m, 4H), 1.91-1.78 (m, 2H), 1.76-1.62 (m, 2H),1.35 (dt, J = 13.8, 7.0 Hz, 6H). 13 C NMR (101 MHz, CDCl3)δ 163.71, 146.69,140.82, 62.58, 43.34, 29.70, 26.57, 22.96, 22.57, 21.05, 16.36, 14.02. HRMS(ESI): m / z for C 14 H 19 NO3[M+H] + Calcd 250.1438, found 250.1416.

[0267]

[0268] N-propyl-5,6,7,8-tetrahydro-4-quinolone-2-carboxylic acid ethyl ester (9d): white solid, yield 43%, melting point: 75-77℃. 1 H NMR (400 MHz, CDCl3)δ 6.66 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 4.02-3.91 (m, 2H), 2.61 (t, J = 6.3 Hz, 2H), 2.53 (t, J = 6.4 Hz, 2H), 1.83-1.73(m, 2H), 1.68-1.56 (m, 4H), 1.31 (t, J = 7.1 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 177.44, 163.71, 146.92, 141.01, 128.89,117.80, 62.54, 49.39, 26.72, 24.43, 22.98, 22.56, 21.02, 13.99, 10.89. HRMS(ESI): m / z for C 15 H 21 NO3[M+H] + Calcd 264.1594, found 264.1575.

[0269]

[0270] N-Butyl-5,6,7,8-tetrahydro-4-quinolone-2-carboxylic acid ethyl ester (9e): Yellow oily liquid, yield 36%. 1 HNMR (400 MHz, CDCl3)δ 6.69 (s, 1H), 4.07-3.95 (m, 2H), 3.85 (s, 3H), 2.62 (t,J = 6.3 Hz, 2H), 2.54 (t, J = 6.5 Hz, 2H), 1.78 (ddt, J = 8.8, 6.4, 4.1 Hz,2H), 1.68-1.60 (m, 2H), 1.56 (qd, J = 7.0, 4.0 Hz, 2H), 1.27 (h, J = 7.3 Hz,2H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3)δ 164.17, 147.08,140.62, 117.95, 53.33, 47.93, 33.16, 26.76, 22.99, 22.57, 21.00, 19.83,13.64. HRMS (ESI): m / z for C 16 H 23 NO3[M+H] + Calcd 278.1751, found 278.1748.

[0271]

[0272] 1,5-Dimethyl-5,6,7,8-tetrahydro-4-quinolone-2-carboxylic acid ethyl ester (9f): white solid, yield 80%, melting point: 80-82℃, racemic. 1 H NMR (400 MHz, CDCl3)δ 6.73 (s, 1H), 4.47-4.30 (m, 2H), 3.61 (s, 3H), 3.22 (d, J = 6.6 Hz, 1H), 2.69 (dt, J = 17.2, 3.9 Hz, 1H), 2.59-2.48 (m, 1H), 1.90 (dt, J = 9.1, 4.2 Hz, 2H), 1.74-1.53 ​​(m, 3H), 1.38(t, J = 7.1 Hz, 3H), 1.18 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ177.13, 163.53, 147.69, 141.19, 133.04, 118.26, 77.36, 77.10, 76.78, 62.52,36.85, 28.08, 27.35, 26.26, 19.05, 17.58, 13.99. HRMS (ESI): m / z for C 14 H 19 NO3[M+H] + Calcium 250.1418, found 250.1416. HPLC detection conditions: Chiralcel OJ-H column (25cm × 0.46cm ID), hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, detection wavelength 254 nm, t R=24 minfor minor isomer, and t R =52 min for major isomer.

[0273]

[0274] 1,7-Dimethyl,5,6,7,8-Tetrahydro-4-quinolone-2-carboxylic acid ethyl ester (9 g): white solid, yield 80%, melting point: 80-82℃, racemic. 1 H NMR (400 MHz, CDCl3)δ 6.76 (s, 1H), 4.38 (q, J = 7.0 Hz,2H), 3.63 (s, 3H), 2.86 (d, J = 19.3 Hz, 1H), 2.73 (dd, J = 17.0, 4.4 Hz,1H), 2.43 (dd, J = 14.8, 8.4 Hz, 1H), 2.20 (dd, J = 16.6, 10.2 Hz, 1H), 1.84 (d, J = 25.7 Hz, 4H), 1.44-1.32 (m, 4H), 1.12 (d, J = 6.4 Hz, 4H). 13 C NMR(101 MHz, CDCl3)δ 177.13, 163.53, 147.69, 141.19, 133.04, 118.26, 62.52,36.85, 28.08, 27.35, 26.26, 19.05, 17.58, 13.99. HRMS (ESI): m / z for C 14 H 19 NO3[M+H] + Calcium 250.1438, found 250.1420. HPLC detection conditions: Chiralcel OJ-H column (25cm × 0.46cm ID), hexane / 2-propanol = 90:10, flow rate = 1.0 mL / min, detection wavelength 254 nm, t R =24 minfor minor isomer, and t R =52 min for major isomer.

[0275] A class of non-natural chiral amino acids or esters and their preparation methods, such as Figure 20 .

[0276] Under ice bath conditions, the chiral product 7h (0.1 mmol) was dissolved in dry THF, and trimethylsilyldiazomethane (0.12 mmol) was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature for 2h. After the reaction was completed, the THF was removed by rotary evaporation and the resulting product 10h was dissolved in methanol. 10% Pd / C was added, and the reaction was carried out at 1 atm hydrogen pressure for 6h. After the reaction was completed, the Pd / C was filtered off, the methanol was removed by rotary evaporation, and the chiral 4-oxo-1,2,3,4-tetrahydroquinoline-2-carboxylate 11h was obtained after separation and purification by column chromatography.

[0277]

[0278] (2R)-4-hydroxy-1,2,3,4-tetrahydroquinoline-2-carboxylate (11h): colorless oily liquid, yield 95%, 92% ee. = +1.00 (c=0.25 in MeOH). 1 H NMR (400 MHz, CDCl3)δ 7.04-6.94 (m, 2H),6.65 (td, J = 7.4, 1.2 Hz, 1H), 6.59 (dd, J = 8.0, 1.2 Hz, 1H), 4.36 (s, 1H),4.05 (dd, J = 8.9, 3.8 Hz, 1H), 3.78 (s, 3H), 2.79 (dqd, J = 21.9, 10.9, 4.7Hz, 2H), 2.29 (dtd, J = 12.9, 5.6, 3.8 Hz, 1H), 2.00 (dtd, J = 12.9, 9.1, 5.2Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 173.74, 142.89, 137.40, 130.37, 129.14, 127.59, 127.06, 120.58, 117.73, 114.58, 53.81, 52.38, 25.78, 24.67. HPLC detection conditions: Chiralcel OD-H column (25 cm × 0.46 cm ID), hexane / 2-propanol / Et2NH=90:10:0.1, flow rate=1.0 mL / min, detection wavelength 254 nm, t R =8.83 min for minor isomer, and t R =13.53min for major isomer.

Claims

1. A method for preparing a class of N-substituted-4-quinolone-2-carboxylic acid ethyl esters, characterized in that, Includes the following steps: Step 1: Weigh K2CO3 and o-aminoacetophenone separately, add them to a three-necked flask, and replace them with argon gas three times; Step 2: Add anhydrous DMF. First, stir the reaction solution at room temperature for 30 minutes, then slowly add anhydrous DMF solution of haloalkanes. After the addition is complete, heat the reaction to 60°C and stir overnight. Step 3: After the reaction is completed by TLC monitoring, the reaction mixture is washed with water, extracted with DCM, the organic phases are combined, dried with anhydrous Na2SO4, concentrated by rotary evaporation, and purified by column chromatography to obtain the intermediate. Step 4: Under argon protection, place bis(trimethylsilylamine) lithium LiHMDS at -78°C and slowly add anhydrous THF solution of the intermediate obtained in step 3) to the bis(trimethylsilylamine) lithium LiHMDS, stirring for 30 min. Step 5: Slowly add anhydrous THF solution of diethyl oxalate to the above reaction solution, stir for 30 min, allow to rise naturally to room temperature, then heat to reflux, and monitor the reaction by TLC; Step 6: After the reaction was monitored by TLC, a sufficient amount of saturated NH4Cl solution was added to quench the reaction. The mixture was extracted with EA, the organic phases were combined, dried with anhydrous Na2SO4, concentrated by rotary evaporation, and purified by column chromatography to obtain the final product N-substituted-4-quinolone-2-carboxylic acid ethyl ester.

2. The method for preparing a class of N-substituted-4-quinolone-2-carboxylic acid ethyl esters according to claim 1, characterized in that, The N-substituted 4-quinolone-2-carboxylic acid ethyl ester includes: 4-quinolone-2-carboxylic acid ethyl ester, N-methyl-4-quinolone-2-carboxylic acid ethyl ester, N-ethyl-4-quinolone-2-carboxylic acid ethyl ester, N-propyl-4-quinolone-2-carboxylic acid ethyl ester, N-n-butyl-4-quinolone-2-carboxylic acid ethyl ester, 1,5-dimethyl-4-quinolone-2-carboxylic acid ethyl ester, or 1,7-dimethyl-4-quinolone-2-carboxylic acid ethyl ester.

3. A method for preparing a class of N-substituted-4-quinolone-2-carboxylic acids, characterized in that, Includes the following steps: Step 1: Dissolve the N-substituted-4-quinolone-2-carboxylic acid ethyl ester obtained as described in claim 1 in methanol, and add H2O to the reaction flask for dilution; Step 2: Add 15 mL of 1M NaOH, heat to 70℃, and react for 2 hours; after the reaction is completed by TLC monitoring, evaporate and concentrate to remove MeOH; Step 3: Adjust the pH to 2-3 with 1 M HCl in an ice bath. A solid precipitates out. After filtration under reduced pressure, the target product N-substituted-4-quinolone-2-carboxylic acid is obtained.

4. The method for preparing a class of N-substituted-4-quinolone-2-carboxylic acids according to claim 3, characterized in that, The N-substituted 4-quinolone-2-carboxylic acid includes: 1-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-ethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 4-oxo-1-propyl-1,4-dihydroquinoline-2-carboxylic acid, 1-butyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-benzyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-(4-methylbenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-(4-chlorobenzyl) 1-(4-chlorobenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-(3-chlorobenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-(2-bromobenzyl)-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1-methyl-4-oxo-8-phenyl-1,4-dihydroquinoline-2-carboxylic acid, 1,5-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1,6-dimethyl-4-oxo- 1,4-Dihydroquinoline-2-carboxylic acid, 6-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1,7-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1,8-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1,5,6-trimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1,6,7-trimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 5-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 6-fluoro- 4-Oxo-1,4-dihydroquinoline-2-carboxylic acid, 8-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 6-bromo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 6-methoxy-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1,5,8-trimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 5,7-difluoro-1-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, or 1-methyl-4-oxo-1,4-dihydrobenzo[g]quinoline-2-carboxylic acid.

5. A method for preparing a class of chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds, characterized in that, Includes the following steps: Step 1: Weigh the chiral ligand and metal precursor in the glove box and add them to the reaction vial. Add solvent to the reaction vial and stir for 30 min to form an in-situ coordinated metal complex. Step 2: Use a syringe to transfer the in-situ coordinated metal complex to an ampoule containing N-substituted-4-quinolone-2-carboxylic acid and a stir bar. Then place the ampoule into the high-pressure reactor, tighten the reactor, and transfer it out of the glove box. Step 3: Replace the argon gas in the autoclave with hydrogen three times, then purge with hydrogen to the required pressure. Stop the reaction after stirring at room temperature for 24 hours. Release the hydrogen in a fume hood, transfer the reaction mixture to a small reaction flask, concentrate by rotation, and then... 1 H-NMR analysis determined the conversion rate of the reaction, and a small amount of the reaction mixture was concentrated by rotation to obtain the crude product; Step 4: The crude product was further purified by column chromatography to obtain pure chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid product; Step 5: The chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid product is refluxed in toluene for 12 h to obtain a stable enol product, namely a chiral 4-hydroxy-1-substituted-1,2-dihydroquinoline-2-carboxylic acid compound.

6. The method for preparing a class of chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds according to claim 5, characterized in that, The chiral ligands include: ； ； 。 7. The method for preparing a class of chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds according to claim 6, characterized in that, The chiral ligand is the BPE-type ligand L16, namely (R,R)-Ph-BPE.

8. The method for preparing a class of chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds according to claim 5, characterized in that, The metal precursors include the following: Ru(2-methylally)COD, [Ru(p-cymene)Cl]2, [Ir(COD)Cl]2, Rh(COD)2OTf, Rh(COD)2SbF6, Rh(NBD)2BF4, [(CF3COO)2Rh]2, [[CH3(CH2)6CO2]2Rh]2, RhCp*(OAc)2, or Rh(OAc)3.

9. The method for preparing a class of chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds according to claim 8, characterized in that, The metal precursor is Rh(COD)2OTf.

10. The method for preparing a class of N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds according to claim 5, characterized in that, The solvent is MeOH, EtOH, i-PrOH, t-BuOH, CF3CH2OH, (CF3)2CHOH, DCM, EtOAc, Toluene, or THF.

11. The method for preparing a class of N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds according to claim 10, characterized in that, The solvent is tert-butanol (t-BuOH).

12. The method for preparing a class of chiral N-substituted-2,3-dihydro-4-quinolone-2-carboxylic acid compounds according to claim 5, characterized in that, The optimal reaction conditions were as follows: using 1.1 mol% (R,R)-Ph-BPE as the chiral ligand, 1.0 mol% Rh(COD)₂OTf as the metal precursor, and the two coordinated in situ to form a complex as a catalyst; t-BuOH as the reaction solvent; and reacting at 40 atm H₂ and 80 °C for 24 h, followed by reflux in toluene for 12 h to obtain a stable enol product. This yielded a diverse range of chiral 4-hydroxy-1-substituted-1,2-dihydroquinoline-2-carboxylic acid compounds, including: 。 13. A method for preparing a class of N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylic acid ethyl esters, characterized in that, Using the method described in claim 5, with ethyl 4-quinolone-2-carboxylate as the template substrate and the in-situ complex formed by ligand L27 and Rh(NBD)2BF4 as the catalyst, N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylate was synthesized by reacting at room temperature for 24 h at 80 °C and 40 atm in anhydrous EtOH.

14. The method for preparing a class of N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylic acid ethyl esters according to claim 13, characterized in that, The N-substituted-5,6,7,8-tetrahydro-4-quinolone-2-carboxylic acid ethyl ester comprises: 。 15. A class of non-natural chiral amino acids or esters and a method for preparing the same, characterized in that, The non-natural chiral amino acid or ester mentioned is chiral 4-oxo-1,2,3,4-tetrahydroquinoline-2-carboxylic acid (ester).

16. The method for preparing a type of chiral 4-oxo-1,2,3,4-tetrahydroquinoline-2-carboxylic acid (ester) according to claim 15, characterized in that, Includes the following steps: Step 1: Dissolve the chiral product 7h (0.1 mmol) in dry THF under ice bath conditions, and slowly add trimethylsilyldiazomethane (0.12 mmol). After the addition is complete, react at room temperature for 2h. Step 2: After the reaction is complete, THF is removed by rotary evaporation and the resulting product is dissolved in methanol after 10 hours. 10% Pd / C is added, and the reaction is carried out at 1 atm hydrogen pressure for 6 hours. Step 3: After the reaction is complete, filter Pd / C, concentrate by rotary evaporation to remove methanol, and then purify by column chromatography to obtain chiral 4-oxo-1,2,3,4-tetrahydroquinoline-2-carboxylate 11h.

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