Preparation method of chiral α-chlorocarbonyl compounds

Abstract

This application relates to the field of synthetic chemistry, and in particular to a method for preparing a chiral α-chlorocarbonyl compound, comprising the following steps: chlorinating an α-carbonyl-substituted thioonium salt compound of Formula I and a chlorinated salt of Formula II under catalytic conditions to obtain a chiral α-chlorocarbonyl compound of Formula III. This preparation method is characterized by simple and practical operation, high selectivity, few side reactions, low cost, and environmental friendliness, and has a promising application prospect in the field of synthetic chemistry.

Description

Technical Field

[0001] This application belongs to the field of synthetic chemistry technology, and in particular relates to a method for preparing chiral α-chlorocarbonyl compounds. Background Technology

[0002] Chiral α-chlorocarbonyl compounds are a class of compounds containing a chiral chloro center at the α-position of the carbonyl group. These compounds are not only closely related to medicinal chemistry but also serve as widely used building blocks in organic synthesis. Their good stereostructural stability and known highly stereospecific synthetic transformation modes give them great application potential and value in synthetic chemistry.

[0003] However, the current synthetic methods for these chiral α-chlorocarbonyl compounds are quite complex, and controlling the regioselectivity and stereoselectivity during their synthesis is very challenging. Summary of the Invention

[0004] The purpose of this application is to provide a method for preparing chiral α-chlorocarbonyl compounds, aiming to solve the technical problem of how to prepare chiral α-chlorocarbonyl compounds simply, rapidly, and efficiently. To achieve the above objective, the technical solution adopted in this application is as follows:

[0005] This application provides a method for preparing a chiral α-chlorocarbonyl compound, comprising the following steps:

[0006] The α-carbonyl-substituted thioonium salt compound of Formula I and the chlorinated salt of Formula II were subjected to chlorination under catalytic conditions to obtain the chiral α-chlorocarbonyl compound of Formula III.

[0007]

[0008] in,

[0009] R 1 Selected from aromatic groups, heteroaromatic groups, substituted aromatic groups, and aromatic groups (C1-C2). 20 )alkyl, aromatic oxygen (C1-C 20 At least one of the alkyl groups;

[0010] R 2 Selected from C1-C 20 Alkyl, C1-C 20 Heteroalkyl, C3-C 20 cycloalkyl, C3-C 20 Heterocyclic alkyl, C1-C 20 Alkyloxy (C1-C) 20 )alkyl, aromatic (C1-C 20 )alkyl, aromatic oxygen (C1-C 20)alkyl, aromatic amide (C1-C 20 At least one of the alkyl groups;

[0011] R 3 R 4 Each is independently selected from aromatic groups, heteroaromatic groups, substituted aromatic groups, and aromatic groups (C1-C2). 20 )alkyl, aromatic oxygen (C1-C 20 At least one of the alkyl groups;

[0012] A is selected from at least one of tetrafluoroborate, hexafluorophosphate, sulfonate, carboxylate, sulfate, and carbonate.

[0013] M is selected from at least one of sodium ion, lithium ion, potassium ion, cesium ion, ammonium ion, and quaternary ammonium cation.

[0014] The method for preparing chiral α-chlorocarbonyl compounds provided in this application starts from chemically stable α-carbonyl-substituted thioonium salts. Under the action of a chiral catalyst, and using readily available chlorine-containing salts as nucleophilic chlorine sources, a highly selective phase-transfer chlorination reaction is employed to rapidly and effectively prepare chiral α-chlorocarbonyl compounds. This method overcomes the difficulties in the direct catalytic synthesis of α-chlorocarbonyl compounds in the fields of chemical and pharmaceutical synthesis. It features simple and practical reaction operation, high selectivity, few side reactions, low cost, and environmental friendliness, and has excellent application prospects in the field of synthetic chemistry. Detailed Implementation

[0015] To make the technical problems, technical solutions, and beneficial effects of this application clearer, the following detailed description is provided in conjunction with embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of this application.

[0016] The compounds and their derivatives involved in the embodiments of this invention are all named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, located in Columbus, Ohio) nomenclature systems. Therefore, the compound groups specifically involved in the embodiments of this invention are described and explained as follows:

[0017] "alkyl" refers to a straight-chain or branched saturated aliphatic chain, including but not limited to methyl, ethyl, propyl (e.g., isopropyl), butyl (e.g., isobutyl), pentyl (e.g., isopentyl), hexyl, and other similar groups. "Heteroalkyl" refers to a straight-chain or branched saturated aliphatic chain containing at least one heteroatom, wherein at least one carbon atom has been replaced by a heteroatom such as nitrogen, oxygen, or sulfur, for example, but not limited to methylaminoethyl, propyloxyethyl, and other similar groups. "Cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and other similar groups. "Heterocyclic alkyl" refers to a saturated monocyclic or polycyclic alkyl group, wherein at least one carbon atom has been replaced by a heteroatom such as nitrogen, oxygen, or sulfur. "Aromatic group" refers to a cyclic aromatic hydrocarbon, including monocyclic, polycyclic, or fused-ring aromatic hydrocarbons, for example, but not limited to phenyl, naphthyl, anthraceneyl, phenanthrene, and other similar groups. "Heteroaryl" refers to a monocyclic, polycyclic, or fused-ring aromatic hydrocarbon in which one or more carbon atoms have been replaced by heteroatoms such as nitrogen, oxygen, or sulfur. If a heteroaryl group contains more than one heteroatom, these heteroatoms may be the same or different. Heteroaryl groups include, but are not limited to, benzofuranyl, benzothiopheneyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzopyranyl, furanyl, imidazolyl, indazole, inazinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridineyl, purine, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroleyl, quinazinyl, quinolinyl, quinoxolinyl, thiadiazolyl, thiatriazolyl, thiazolyl, thiopheneyl, triazinyl, and other similar groups. "Substitution" refers to the independent replacement of one or more hydrogen atoms in a group with the same or different substituents.

[0018] This application provides a method for preparing a chiral α-chlorocarbonyl compound, comprising the following steps: subjecting an α-carbonyl-substituted thioonium salt compound of Formula I and a chlorinated salt of Formula II to a chlorination reaction under catalytic conditions to obtain a chiral α-chlorocarbonyl compound of Formula III;

[0019]

[0020] Among them, R 1 Selected from aromatic groups, heteroaromatic groups, substituted aromatic groups, and aromatic groups (C1-C2). 20 )alkyl, aromatic oxygen (C1-C 20 At least one of the alkyl groups; R 2 Selected from C1-C 20 Alkyl, C1-C 20 Heteroalkyl, C3-C 20 cycloalkyl, C3-C 20 Heterocyclic alkyl, C1-C 20Alkyloxy (C1-C) 20 )alkyl, aromatic (C1-C 20 )alkyl, aromatic oxygen (C1-C 20 )alkyl, aromatic amide (C1-C 20 At least one of the alkyl groups; R 3 R 4 Each is independently selected from aromatic groups, heteroaromatic groups, substituted aromatic groups, and aromatic groups (C1-C2). 20 )alkyl, aromatic oxygen (C1-C 20 At least one of the alkyl groups; A is selected from at least one of tetrafluoroborate, hexafluorophosphate, sulfonate, carboxylate, sulfate, and carbonate; M is selected from at least one of sodium ion, lithium ion, potassium ion, cesium ion, ammonium ion, and quaternary ammonium cation.

[0021] α-Carbonyl-substituted thioonium salts are a class of chemically stable and readily available reaction raw materials. This application utilizes these α-carbonyl-substituted thioonium salts and chloride-containing salts as raw materials. Under the action of a chiral catalyst and with readily available chloride-containing salts as nucleophilic chlorine sources, a highly selective phase-transfer chlorination reaction is employed to rapidly and effectively prepare chiral α-chlorocarbonyl compounds. Using sodium chloride as the chloride-containing salt represented by Formula II, and CTU representing the catalyst, the reaction principle is as follows:

[0022]

[0023] Among them, the catalyst CTU can be a chiral thiourea catalyst based on amino acids or a chiral squamamide catalyst based on amino acids, R 1 R 2 R 3 R 4 A represents the anion contained in the aforementioned optional α-carbonyl-substituted thioonium salt compound. In the above process: a chiral thiourea catalyst or a chiral squaramide catalyst captures chloride ions in the aqueous phase, generating the corresponding chiral anionic complex. Simultaneously, this chiral anionic complex combines with the thioonium cation to form a pair of diastereomeric ion pairs (Formula IV and Formula V) and enters the organic phase. Through racemization of the unstable α-chiral center, the aforementioned diastereomeric isomers can interconvert during the reaction and reach a rapid equilibrium state. Subsequently, the chloride ion undergoes an asymmetric nucleophilic substitution reaction with the dominant intermediate to generate the product. The above preparation method improves the economy, convenience, and practicality of the reaction by using a dynamic kinetic resolution strategy, and exhibits excellent enantioselectivity. Furthermore, this preparation method uses inexpensive aqueous solutions of chlorinated inorganic salts or quaternary ammonium salts as chlorination reagents, making it low-cost, environmentally friendly, safe, and easily industrialized, demonstrating high application value.

[0024] In the above preparation method, R in the α-carbonyl-substituted thioonium salt compound represented by Formula I 1 and R 2 The corresponding R in the chiral α-chlorocarbonyl compound shown in Formula III 1 and R 2 .

[0025] Chiral thiourea catalysts based on amino acids or chiral squaramide catalysts based on amino acids can catalyze the efficient and highly selective asymmetric chlorination reaction of α-carbonyl-substituted thioonium salts of Formula I and chlorinated salts of Formula II to obtain chiral α-chlorocarbonyl compounds of Formula III.

[0026] In some embodiments, in the structure shown in Formula I or Formula III, R 1 Selected from at least one of aromatic groups, heteroaromatic groups, and substituted aromatic groups; R 2 Selected from C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Alkyloxy (C1-C) 10 )alkyl, aromatic (C1-C 10 )alkyl, aromatic amide (C1-C 10 At least one of the alkyl groups.

[0027] In some embodiments, in the structure shown in Equation I, R 3 R 4 Each is independently selected from aromatic groups.

[0028] Specifically, when R 1 R 3 Or R 4 When selected from aromatic groups, the aromatic group includes, but is not limited to, at least one of phenyl, naphthyl, phenanthryl, anthraceneyl, acenaphthene, fluorenyl, pyrene, and fluoranthracene; when R 1 R 3 Or R 4 When selected from heteroaryl groups, the heteroaryl group includes, but is not limited to, at least one of pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzopyrazolyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, and purinel.

[0029] Specifically, when R 1 R 3 Or R 4 When selected from substituted aromatic groups, the substituents in the substituted aromatic groups include, but are not limited to, (C1-C1) substituents. 10 )alkyl, halosubstituted (C1-C 10 )alkyl, (C1-C10 )alkoxy, (C1-C 10 )alkylsilyl, (C1-C 10 At least one of alkylsiloxy, halogen, phenyl, and nitro groups. The substituted aromatic group includes, but is not limited to, at least one of phenyl, naphthyl, phenanthryl, anthraceneyl, acenaphthene, fluorenyl, pyrene, and fluoranthracene.

[0030] Additionally, for R 1 R 2 R 3 Or R 4 In this context, the aromatic groups involved (C1-C) 20 )alkyl, aromatic oxygen (C1-C 20 )alkyl, aromatic amide (C1-C 20 )alkyl, wherein the aromatic group includes, but is not limited to, at least one of phenyl, naphthyl, phenanthryl, anthraceneyl, acenaphthene, fluorenyl, pyreneyl and fluoranthyl.

[0031] In some embodiments, R 1 Selected from at least one of phenyl, biphenyl, halophenyl, (C1-C5)alkylphenyl, halo(C1-C5)alkylphenyl, (C1-C5)alkoxyphenyl, tri(C1-C5)alkylsilylphenyl, tri(C1-C5)alkylsiloxyphenyl, 3-benzo[1,3]-m-dioxocyclopentyl, 3-thiophene; R 2 Selected from C1-C 10 Alkyl groups, heterooxygen-containing C1-C 10 Heteroalkyl, phenyl (C1-C) 10 )alkyl, 9-phthalamide (C1-C 10 ) group, 9-acetoxy (C1-C 10 At least one of the following: R 3 and R 4 All are phenyl.

[0032] In one embodiment, the chloride-containing salt represented by Formula II can be a chloride-containing inorganic salt or a quaternary ammonium salt. For the chloride-containing inorganic salt, M is selected from sodium ions, lithium ions, potassium ions, cesium ions, and ammonium ions; for the chloride-containing quaternary ammonium salt, M is selected from quaternary ammonium cations and can be represented as [NR4]Cl, where R is (Cl-C) 10 )alkyl.

[0033] In one embodiment, the chiral catalyst is selected from at least one of an amino acid-based chiral thiourea catalyst (structural formula VI below) or an amino acid-based chiral squaramide catalyst (structural formula VII below).

[0034]

[0035] Wherein, *R is selected from groups containing chiral structures, such as any group with a chiral carbon atom; Ar is selected from aromatic groups, heteroaromatic groups, substituted aromatic groups, and aromatic groups (C1-C2). 20 )alkyl, aromatic oxygen (C1-C 20 At least one of the alkyl groups. The aromatic group includes, but is not limited to, at least one of phenyl, naphthyl, phenanthryl, anthracene, acenaphthene, fluorenyl, pyrene, and fluoranthyl, and the substituents in the substituted aromatic group include, but are not limited to, (C1-C2) alkyl groups. 10 )alkyl, halosubstituted (C1-C 10 )alkyl, (C1-C 10 )alkoxy, (C1-C 10 )alkylsilyl, (C1-C 10 At least one of alkylsiloxy, halogen, phenyl, and nitro groups. Heteroaryl groups include, but are not limited to, at least one of pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzothiophene, benzofuranyl, benzopyrazolyl, benzoimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, and purine.

[0036] The above-mentioned amino acid-based chiral catalysts, when used with (S)-type chiral catalysts, produce products with stereoconfigurations opposite to those produced by (R)-type chiral catalysts of the same structure. The amount of the chiral catalyst used is 5-20 mol%.

[0037] In some embodiments, the chiral thiourea catalyst is CTU 1, with the specific chemical structure shown below:

[0038]

[0039] In one embodiment, the chlorination reaction is carried out in a mixed solvent consisting of an organic solvent and water, wherein the organic solvent is selected from at least one of dichloromethane, 1,2-dichloroethane, trichloromethane, tetrachloromethane, diethyl ether, n-hexane, chlorobenzene, fluorobenzene, toluene, xylene, and trifluorotoluene. The chlorination reaction is carried out at a temperature of –15 to 40°C.

[0040] Specifically, in one embodiment, the chiral α-chlorocarbonyl compound was prepared as follows: At room temperature (25–27°C), 0.5 mmol of α-carbonyl thioonium salt and 0.05 mmol of chiral catalyst CTU 1 (structural formula below) were sequentially added to 5 mL of o-xylene solvent, and the mixture was cooled in a –15°C cold bath. 5 mL of a saturated chloride-containing salt solution (using an aqueous solvent) pre-cooled to the same temperature was rapidly added to the reaction solution, and the mixture was stirred at –15°C for the appropriate time. The reaction was monitored by TLC. After the reaction was complete, the organic phase and aqueous phase were separated by standing at –15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain a high-yield, high-optical-purity chiral α-chlorocarbonyl compound III. The specific reaction formula is as follows:

[0041]

[0042] This application has undergone multiple experiments, and some of the experimental results are presented here for reference to further describe the application in detail. The following is a detailed description in conjunction with specific embodiments.

[0043] Example 1

[0044]

[0045] A method for preparing a chiral α-chlorocarbonyl compound IIIa: using R in formula I 1 It is 4-methylphenyl, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0046] At room temperature, 0.5 mmol of α-carbonyl thioonium salt and 0.05 mmol of chiral thiourea catalyst CTU 1 were sequentially added to 5 mL of o-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution (aqueous solvent), pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 120 hours. The reaction equation is as follows:

[0047]

[0048] After the reactants reacted completely, the organic and aqueous phases were separated by standing at –15°C. The aqueous phase was extracted three times with 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solution was separated by column chromatography to obtain 79.2 mg of the target product IIIa as a white solid, with a calculated yield of 87%.

[0049] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0050] 1. Specific rotation [α] measured by the D line at 23℃ D 23 +35.0 (c=1.0, CH2Cl2).

[0051] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel OD-H column; 5% i-PrOH in hexanes; 1.0 mL / min; retention times: 4.9 min (minor), 5.4 min (major). The calculated ee was 92%.

[0052] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0053] 1 H NMR (400MHz, CDCl3) δ7.95–7.87(m,2H),7.28(d,J=8.0Hz,2H),5.24(q,J=6.6Hz,1H),2.41(s,3H),1.73(d,J=4.0Hz,3H).

[0054] 13 C NMR (100MHz, CDCl3) δ193.2,144.7,131.5,129.4,129.0,52.8,21.7,20.0.

[0055] HRMS(CI+) Calculated for C 10 H 12 ClO[M+H] + :183.0571,found:183.0576.

[0056] Example 2

[0057]

[0058] A method for preparing a chiral α-chlorocarbonyl compound IIIb: using R in formula I 1 It is a phenyl group, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0059] At room temperature, 0.25 mmol of α-carbonylthioonium salt and 0.1 mmol of chiral thiourea catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonylthioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 61.9 mg of the target product IIIb as a colorless oily liquid, with a calculated yield of 74%.

[0060] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0061] 1. Specific rotation [α] measured by the D line at 22℃ D 22 +14.3 (c=1.0, CH2Cl2).

[0062] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AS-H column; 5% i-PrOH in hexanes; 1.0 mL / min; retention times: 6.2 min (minor), 6.6 min (major). Calculated result: 90% ee

[0063] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0064] 1 H NMR (400MHz, CDCl3) δ8.06–7.98(m,2H),7.64–7.55(m,1H),7.54–7.44(m,2H),5.26(q,J=6.6Hz,1H),1.74(d,J=6.7Hz,3H).

[0065] 13 C NMR (100MHz, CDCl3) δ193.6,134.0,133.7,128.9,128.7,52.7,19.9.

[0066] HRMS(CI+) Calcd for C9H10 ClO[M+H] + :169.0415,found:169.0423.

[0067] Example 3

[0068]

[0069] A method for preparing a chiral α-chlorocarbonyl compound IIIc: using R in formula I 1 It is 4-(trimethylsilyl)phenyl, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0070] At room temperature, 0.25 mmol of α-carbonylthioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonylthioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 117.6 mg of the target product IIIc white solid, with a calculated yield of 98%.

[0071] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0072] 1. Specific rotation [α] measured by the D line at 21℃ D 21 +27.3 (c=1.0, CH2Cl2).

[0073] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AD-H column; 0.7% i-PrOH in hexanes; 1.0 mL / min; retention times: 7.8 min (minor), 8.6 min (major). The calculated ee was 91%.

[0074] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0075] 1 H NMR (400MHz, CDCl3) δ7.98 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 5.27 (q, J = 6.7 Hz, 1H), 1.75 (d, J = 4.0 Hz, 3H), 0.31 (s, 9H).

[0076] 13 C NMR (100MHz, CDCl3) δ193.7,148.2,134.0,133.6,127.8,52.8,19.9,–1.4.

[0077] HRMS(CI+) Calculated for C 12 H 18 ClOSi[M+H] + :241.0810,found:241.0811.

[0078] Example 4

[0079]

[0080] A method for preparing a chiral α-chlorocarbonyl compound IIId: using R in formula I 1 It is 4-phenylphenyl, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0081] At room temperature, 0.25 mmol of α-carbonylthioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonylthioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 107.0 mg of the target product IIId as a white solid, with a calculated yield of 88%.

[0082] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0083] 1. Specific rotation [α] measured by the D line at 21℃ D 21 +57.4 (c=1.0, CH2Cl2).

[0084] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AD-H column; 3% i-PrOH in hexanes; 1.0 mL / min; retention times: 9.9 min (minor), 11.8 min (major). The calculated ee was 92%.

[0085] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0086] 1 H NMR (400MHz, CDCl3) δ8.11–8.09(m,2H),7.73–7.71(m,2H),7.65–7.63(m,2H),7.51–7.40(m,3H),5.29(q,J=6.7Hz,1H),1.78(d,J=6.7Hz,3H).

[0087] 13 C NMR (100MHz, CDCl3) δ193.2,146.4,139.6,132.7,129.6,129.0,128.4,127.4,127.3,52.8,20.0.

[0088] HRMS(CI+) Calculated for C 15 H 14 ClO[M+H] + :245.0728,found:245.0724.

[0089] Example 5

[0090]

[0091] A method for preparing a chiral α-chlorocarbonyl compound IIIe: using R in formula I 1 It is 4-fluorophenyl, R 2 For methyl, R 3 and R 4The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0092] At room temperature, 0.5 mmol of α-carbonyl thioonium salt and 0.05 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of o-xylene solvent, and the mixture was cooled in a –15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at –15°C for 120 hours. After the starting materials had reacted completely, the organic and aqueous phases were separated by standing at –15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 79.6 mg of the target product IIIe, a green oily liquid, with a calculated yield of 86%.

[0093] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0094] 1. Specific rotation [α] measured by the D line at 22℃ D 22 +20.0 (c=1.0,CH2Cl2).

[0095] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AS-H column; 5% i-PrOH in hexanes; 1.0 mL / min; retention times: 6.6 min (minor), 7.5 min (major). Calculated result: 90% ee

[0096] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0097] 1 H NMR (400MHz, CDCl3) δ8.06–8.01(m,2H),7.17–7.11(m,2H),5.18(q,J=6.6Hz,1H),1.72(d,J=6.6Hz,3H).

[0098] 13 C NMR (100MHz, CDCl3) δ192.0, 166.0 (d, J = 256.2Hz), 131.7 (d, J = 9.5Hz), 130.4 (d, J = 3.0Hz), 115.9 (d, J = 22.0Hz), 52.6, 19.8.

[0099] 19 F NMR(376MHz, CDCl3)δ–103.7.

[0100] HRMS(CI+)Calcd for C9H9ClFO[M+H] + :187.0320,found:187.0321.

[0101] Example 6

[0102]

[0103] A method for preparing a chiral α-chlorocarbonyl compound IIIf: using R in formula I 1 It is 4-chlorophenyl, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0104] At room temperature, 0.5 mmol of α-carbonyl thioonium salt and 0.05 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of o-xylene solvent, and the mixture was cooled in a –15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at –15°C for 48 hours. After the starting materials had reacted completely, the organic and aqueous phases were separated by standing at –15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 87.2 mg of the target product IIIf, a green oily liquid, with a calculated yield of 86%.

[0105] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0106] 1. Specific rotation [α] measured by the D line at 23℃ D 23 +31.3 (c=1.0, CH2Cl2).

[0107] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AS-H column; 3% i-PrOH in hexanes; 1.0 mL / min; retention times: 7.0 min (minor), 8.5 min (major). Calculated result: 90% ee

[0108] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0109] 1 H NMR (400MHz, CDCl3) δ7.97–7.94(m,2H),7.48–7.44(m,2H),5.18(q,J=6.6Hz,1H),1.74(d,J=6.6Hz,3H).

[0110] 13 C NMR (100MHz, CDCl3) δ192.3,140.2,132.3,130.4,129.0,52.5,19.7.

[0111] HRMS(CI+)Calcd for C9H9Cl2O[M+H] + :203.0025,found:203.0039.

[0112] Example 7

[0113]

[0114] A method for preparing a chiral α-chlorocarbonyl compound IIIg: using R in formula I 1 It is 4-bromophenyl, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0115] At room temperature, 0.5 mmol of α-carbonyl thioonium salt and 0.05 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of o-xylene solvent, and the mixture was cooled in a –15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at –15°C for 120 hours. After the starting materials had reacted completely, the organic and aqueous phases were separated by standing at –15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 115.3 mg of the target product III as a white solid, with a calculated yield of 94%.

[0116] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0117] 1. Specific rotation [α] measured by the D line at 23℃ D 23 +31.9 (c=1.0, CH2Cl2).

[0118] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AS-H column; 5% i-PrOH in hexanes; 1.0 mL / min; retention times: 6.6 min (minor), 7.9 min (major). The calculated ee was 92%.

[0119] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0120] 1 H NMR (400MHz, CDCl3) δ7.92–7.84(m,2H),7.68–7.59(m,2H),5.17(q,J=6.6Hz,1H),1.74(d,J=6.6Hz,3H).

[0121] 13 C NMR (100MHz, CDCl3) δ192.6,132.8,132.1,130.5,129.0,52.6,19.7.

[0122] HRMS(CI+)Calcd for C9H9BrO[M–Cl] + :210.9753,found:210.9749.

[0123] Example 8

[0124]

[0125] A method for preparing a chiral α-chlorocarbonyl compound IIIh: using R in formula I 1 It is 4-trifluoromethylphenyl, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0126] At room temperature, 0.5 mmol of α-carbonyl thioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of o-xylene solvent, and the mixture was cooled in a –15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at –15°C for 120 hours. After the starting materials had reacted completely, the organic and aqueous phases were separated by standing at –15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 96.7 mg of the target product IIIh, a green oily liquid, with a calculated yield of 82%.

[0127] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0128] 1. Specific rotation [α] measured by the D line at 22℃ D 22 +12.9 (c=1.0, CH2Cl2).

[0129] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AD-H column; 3% i-PrOH in hexanes; 1.0 mL / min; retention times: 5.6 min (minor), 6.1 min (major). The calculated ee was 89%.

[0130] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0131] 1 H NMR (400MHz, CDCl3) δ8.12(d,J=8.2Hz,2H),7.75(d,J=8.2Hz,2H),5.22(q,J=6.6Hz,1H),1.73(d,J=6.6Hz,3H).

[0132] 13 C NMR (100MHz, CDCl3) δ192.6, 136.9, 134.9 (q, J = 32.7Hz), 129.4, 125.8 (q, J = 3.8Hz), 123.4 (q, J = 271.1Hz), 52.7, 19.6.

[0133] 19 F NMR (376MHz, CDCl3) δ–63.3.

[0134] HRMS(CI+) Calculated for C 10 H9ClF3O[M+H] + :237.0289,found:237.0289.

[0135] Example 9

[0136]

[0137] A method for preparing a chiral α-chlorocarbonyl compound IIIi: using R in formula I 1 It is 4-methoxyphenyl, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0138] At room temperature, 0.5 mmol of α-carbonyl thioonium salt and 0.05 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of o-xylene solvent, and the mixture was cooled in a –15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at –15°C for 120 hours. After the starting materials had reacted completely, the organic and aqueous phases were separated by standing at –15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 79.2 mg of the target product IIIi as a white solid, with a calculated yield of 80%.

[0139] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0140] 1. Specific rotation [α] measured by the D line at 23℃ D 23 +51.1 (c=1.0,CH2Cl2).

[0141] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AD-H column; 5% i-PrOH in hexanes; 1.0 mL / min; retention times: 8.6 min (minor), 9.6 min (major). Calculated result: 92% ee

[0142] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0143] 1 H NMR (400MHz, CDCl3) δ8.03–7.94(m,2H),6.99–6.90(m,2H),5.21(q,J=6.6Hz,1H),3.86(s,3H),1.72(d,J=6.7Hz,3H).

[0144] 13 C NMR (100MHz, CDCl3) δ192.1,163.9,131.3,126.8,113.9,55.5,52.6,20.0.

[0145] HRMS(CI+) Calculated for C 10 H 12 ClO2[M+H] + :199.0520,found:199.0526.

[0146] Example 10

[0147]

[0148] A method for preparing a chiral α-chlorocarbonyl compound IIIj: using R in formula I 1 It is 4-triisopropylsiloxyphenyl, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0149] At room temperature, 0.25 mmol of α-carbonyl thioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonyl thioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had reacted completely, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 155.6 mg of the target product IIIj, a pale green oily liquid, with a calculated yield of 91%.

[0150] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0151] 1. Specific rotation [α] measured by the D line at 21℃ D 21 +33.9 (c=1.0, CH2Cl2).

[0152] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel IC column; 1% i-PrOH in hexanes; 1.0 mL / min; retention times: 5.6 min (major), 6.7 min (minor). The calculated ee was 86%.

[0153] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0154] 1 H NMR (400MHz, CDCl3) δ7.98–7.90(m,2H),6.97–6.88(m,2H),5.21(q,J=6.6Hz,1H),1.71(d,J=8.0Hz,3H),1.35–1.22(m,3H),1.12–1.09(m,18H).

[0155] 13 C NMR (100MHz, CDCl3) δ192.1,161.2,131.3,127.1,119.9,52.5,20.1,17.8,12.6.

[0156] HRMS(ES+)Calcd for C 18 H 29 ClNaO2Si[M+Na] + :363.1518,found:363.1523.

[0157] Example 11

[0158]

[0159] A method for preparing a chiral α-chlorocarbonyl compound IIIk: using R in formula I 1 It is 3-methoxyphenyl, R 2 For methyl, R 3 and R 4The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0160] At room temperature, 0.5 mmol of α-carbonyl thioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of o-xylene solvent, and the mixture was cooled in a –15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at –15°C for 120 hours. After the starting materials had reacted completely, the organic and aqueous phases were separated by standing at –15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 92.8 mg of the target product IIIk as a green oily liquid, with a calculated yield of 94%.

[0161] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0162] 1. Specific rotation [α] measured by the D line at 22℃ D 22 +12.2 (c=1.0,CH2Cl2).

[0163] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AS-H column; 10% i-PrOH in hexanes; 1.0 mL / min; retention times: 7.0 min (minor), 7.7 min (major). Calculated result: 85% ee

[0164] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0165] 1 H NMR (400MHz, CDCl3) δ7.61–7.49(m,2H),7.38(t,J=7.9Hz,1H),7.17–7.09(m,1H),5.23(q,J=6.7Hz,1H),3.84(s,3H),1.72(d,J=6.7Hz,3H).

[0166] 13 C NMR (100MHz, CDCl3) δ193.4,159.8,135.3,129.7,121.3,120.1,113.3,55.4,52.8,20.0.

[0167] HRMS(CI+) Calculated for C 10 H 11 ClO2[M] + :198.0442,found:198.0450.

[0168] Example 12

[0169]

[0170] A method for preparing a chiral α-chlorocarbonyl compound IIIl: using R in formula I 1 It is 3-chlorophenyl, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0171] At room temperature, 0.25 mmol of α-carbonyl thioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonyl thioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 95.6 mg of the target product IIIl, a green oily liquid, with a calculated yield of 95%.

[0172] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0173] 1. Specific rotation [α] measured by the D line at 21℃ D 21 +19.9 (c=1.0, CH2Cl2).

[0174] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel OD-H column; 2% i-PrOH in hexanes; 1.0 mL / min; retention times: 5.7 min (minor), 8.1 min (major). Calculated result: 85% ee.

[0175] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0176] 1 H NMR (400MHz, CDCl3) δ8.01–7.95(m,1H),7.93–7.85(m,1H),7.61–7.53(m,1H),7.48–7.39(m,1H),5.18(q,J=6.6Hz,1H),1.74(d,J=8.0Hz,3H).

[0177] 13 C NMR (100MHz, CDCl3) δ192.3,135.6,135.1,133.6,130.0,129.0,127.0,52.6,19.7.

[0178] HRMS(CI+)Calcd for C9H9Cl2O[M+H] + :203.0025,found:203.0031.

[0179] Example 13

[0180]

[0181] A method for preparing a chiral α-chlorocarbonyl compound IIIm: using R in formula I 1 It is 3-benzo[1,3]-m-dioxocyclopentyl, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0182] At room temperature, 0.25 mmol of α-carbonylthioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonylthioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 98.3 mg of the target product IIIm, a green oily liquid, with a calculated yield of 93%.

[0183] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0184] 1. Specific rotation [α] measured by the D line at 21℃ D 21 +39.0 (c=1.0,CH2Cl2).

[0185] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel OD-H column; 5% i-PrOH in hexanes; 1.0 mL / min; retention times: 12.2 min (minor), 12.9 min (major). Calculated result: 90% ee.

[0186] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0187] 1 H NMR (400MHz, CDCl3) δ7.61–7.58(m,1H),7.44(d,J=1.8Hz,1H),6.84(d,J=8.2Hz,1H),6.03(s,2H),5.16(q,J=6.6Hz,1H),1.68(d,J=6.7Hz,3H).

[0188] 13 C NMR (100MHz, CDCl3) δ191.7,152.2,148.2,128.5,125.3,108.6,107.9,102.0,52.5,20.0.

[0189] HRMS(CI+) Calculated for C 10 H 10 ClO3[M+H] + :213.0313,found:213.0315.

[0190] Example 14

[0191]

[0192] A method for preparing a chiral α-chlorocarbonyl compound IIIn: using R in formula I 1 It is 2-thienyl, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0193] At room temperature, 0.25 mmol of α-carbonylthioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonylthioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 83.0 mg of the target product IIIn, a pale green oily liquid, with a calculated yield of 95%.

[0194] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0195] 1. Specific rotation [α] measured by the D line at 21℃ D 21 +46.1 (c=1.0,CH2Cl2).

[0196] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AS-H column; 3% i-PrOH in hexanes; 1.0 mL / min; retention times: 9.0 min (minor), 9.8 min (major). Calculated result: 92% ee.

[0197] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0198] 1 H NMR (400MHz, CDCl3) δ7.88–7.82(m,1H),7.74–7.68(m,1H),7.20–7.13(m,1H),5.09(q,J=6.7Hz,1H),1.74(d,J=6.8Hz,3H).

[0199] 13 C NMR (100MHz, CDCl3) δ187.0,140.8,135.0,133.3,128.3,54.1,20.3.

[0200] HRMS(CI+)Calcd for C7H8ClOS[M+H] + :174.9979,found:174.9985.

[0201] Example 15

[0202]

[0203] A method for preparing a chiral α-chlorocarbonyl compound IIIo: using R in formula I 1 It is 3-thienyl, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0204] At room temperature, 0.25 mmol of α-carbonyl thioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonyl thioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 51.4 mg of the target product IIIo, a green oily liquid, with a calculated yield of 59%.

[0205] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0206] 1. Specific rotation [α] measured by the D line at 21℃ D 21 +36.6 (c=1.0, CH2Cl2).

[0207] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AS-H column; 3% i-PrOH in hexanes; 1.0 mL / min; retention times: 10.1 min (minor), 11.5 min (major). Calculated result: 86% ee.

[0208] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0209] 1 H NMR (400MHz, CDCl3) δ8.21(dd,J=2.9,1.3Hz,1H),7.60(dd,J=5.1,1.3Hz,1H),7.38–7.32(m,1H),5.04(q,J=6.7Hz,1H),1.73(d,J=7.1Hz,3H).

[0210] 13 C NMR (100MHz, CDCl3) δ188.0,138.7,133.6,127.5,126.5,54.5,20.0.

[0211] HRMS(CI+)Calcd for C7H8ClOS[M+H] + :174.9979,found:174.9985.

[0212] Example 16

[0213]

[0214] A method for preparing a chiral α-chlorocarbonyl compound IIIp: using R in formula I 1 It is 4-methoxyphenyl, R 2 For propyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0215] At room temperature, 0.25 mmol of α-carbonylthioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonylthioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 83.4 mg of the target product IIIp green solid, with a calculated yield of 74%.

[0216] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0217] 1. Specific rotation [α] measured by the D line at 21℃ D 21 +33.0 (c=1.0,CH2Cl2).

[0218] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel IC-3 column; 3% i-PrOH in hexanes; 1.0 mL / min; retention times: 12.0 min (major), 13.5 min (minor). Calculated result: 91% ee.

[0219] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0220] 1 H NMR (400MHz, CDCl3) δ8.02–7.93(m,2H),6.98–6.90(m,2H),5.09(dd,J=8.2,5.7H z,1H),3.86(s,3H),2.14–1.90(m,2H),1.63–1.37(m,2H),0.96(t,J=7.4Hz,3H).

[0221] 13 C NMR (100MHz, CDCl3) δ192.2,163.9,131.2,127.3,113.9,57.3,55.5,35.7,19.6,13.5.

[0222] HRMS(CI+) Calculated for C 12 H 16 ClO2[M+H] + :227.0833,found:227.0838.

[0223] Example 17

[0224]

[0225] A method for preparing a chiral α-chlorocarbonyl compound IIIq: using R in formula I 1 It is 4-methoxyphenyl, R 2 It is 2-phenylethyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0226] At room temperature, 0.25 mmol of α-carbonylthioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonylthioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 123.5 mg of the target product IIIq, a pale green solid, with a calculated yield of 86%.

[0227] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0228] 1. Specific rotation [α] measured by the D line at 21℃ D 21 +0.6 (c=1.0,CH2Cl2).

[0229] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel OD-H column; 7% i-PrOH in hexanes; 1.0 mL / min; retention times: 9.3 min (major), 11.1 min (minor). Calculated result: 86% ee.

[0230] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0231] 1 H NMR (400MHz, CDCl3) δ7.92–7.84(m,2H),7.36–7.19(m,5H),6.97–6.88(m,2H ),5.02(q,J=4.0Hz,1H),3.87(s,3H),2.93–2.77(m,2H),2.48–2.25(m,2H).

[0232] 13 C NMR (100MHz, CDCl3) δ191.9,164.0,140.3,131.3,128.6(2C),127.2,126.3,114.0,56.6,55.5,35.2,32.2.

[0233] HRMS(ES+)Calcd for C 17 H 17 ClNaO2[M+Na] + :311.0809,found:311.0815.

[0234] Example 18

[0235]

[0236] A method for preparing a chiral α-chlorocarbonyl compound IIIr: using R in formula I 1 It is 4-trifluoromethylphenyl, R 2 For propyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0237] At room temperature, 0.25 mmol of α-carbonylthioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonylthioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 114.8 mg of the target product IIIr, a green oily liquid, with a calculated yield of 87%.

[0238] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0239] 1. Specific rotation [α] measured by the D line at 21℃ D 21 +0.9 (c=1.0, CH2Cl2).

[0240] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AD-H column; 3% i-PrOH in hexanes; 1.0 mL / min; retention times: 4.8 min (minor), 5.7 min (major). Calculated result: 79% ee.

[0241] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0242] 1 H NMR (400MHz, CDCl3) δ8.14–8.07(m,2H),7.78–7.71(m,2H),5.08(dd,J=8.2,5.6Hz,1H),2.17–1.93(m,2H),1.66–1.38(m,2H),0.98(t,J=7.4Hz,3H).

[0243] 13 C NMR (100MHz, CDCl3) δ192.6, 137.3, 134.8 (q, J = 32.9Hz), 129.2, 125.8 (q, J = 3.7Hz), 123.4 (q, J = 271.0Hz), 57.5, 35.2, 19.5, 13.5.

[0244] 19 F NMR (376MHz, CDCl3) δ–63.3.

[0245] HRMS(ES–)Calcd for C 12 H 11 ClF3O[M–H] - :263.0456,found:263.0447.

[0246] Example 19

[0247]

[0248] A method for preparing a chiral α-chlorocarbonyl compound IIIs: using R in formula I 1 It is 4-methoxyphenyl, R 2 It is decyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0249] At room temperature, 0.25 mmol of α-carbonylthioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonylthioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 124.0 mg of the target product IIIs, a pale green solid, with a calculated yield of 77%.

[0250] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0251] 1. Specific rotation [α] measured by the D line at 21℃ D 21 +13.3 (c=1.0, CH2Cl2).

[0252] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AD-H column; 7% i-PrOH in hexanes; 1.0 mL / min; retention times: 5.4 min (minor), 7.0 min (major). Calculated result: 90% ee.

[0253] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0254] 1 H NMR (400MHz, CDCl3) δ8.02–7.95(m,2H),6.99–6.92(m,2H),5.07(dd,J=8.1,5.8Hz,1H),3. 88(s,3H),2.16–2.05(m,1H),2.05–1.91(m,1H),1.58–1.16(m,16H),0.87(t,J=6.8Hz,3H).

[0255] 13C NMR (100MHz, CDCl3) δ192.2,163.9,131.3,127.4,113.9,57.6,55.5,33.8,31.9,29.53,29.47,29.4,29.3,29.1,26.3,22.7,14.1.

[0256] HRMS(ES+)Calcd for C 19 H 29 ClNaO2[M+Na] + :347.1748,found:347.1754.

[0257] Example 20

[0258]

[0259] A method for preparing a chiral α-chlorocarbonyl compound IIIt: using R in formula I 1 It is 4-methoxyphenyl, R 2 It is 9-methoxynonyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0260] At room temperature, 0.25 mmol of α-carbonylthioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonylthioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 128.2 mg of the target product IIIt, a red oily liquid, with a calculated yield of 75%.

[0261] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0262] 1. Specific rotation [α] measured by the D line at 21℃ D 21+15.0 (c=1.0, CH2Cl2).

[0263] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AD-H column; 10% i-PrOH in hexanes; 1.0 mL / min; retention times: 7.1 min (minor), 12.2 min (major). Calculated result: 86% ee.

[0264] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0265] 1 H NMR (400MHz, CDCl3) δ8.00–7.96(m,2H),6.97–6.93(m,2H),5.06(q,J=4.0Hz ,1H),3.87(s,3H),3.36–3.31(m,5H),2.14–1.93(m,2H),1.56–1.28(m,14H).

[0266] 13 C NMR (100MHz, CDCl3) δ192.2,163.9,131.2,127.4,114.0,72.9,58.5,57.6,55.5,33.7,29.6,29.4(2C),29.2,29.1,26.3,26.1.

[0267] HRMS(ES+)Calcd for C 19 H 29 ClNaO3[M+Na] + :363.1697,found:363.1702.

[0268] Example 21

[0269]

[0270] A method for preparing a chiral α-chlorocarbonyl compound IIIu: using R in formula I 1 It is 4-methoxyphenyl, R 2 It is 9-phthalamidononyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0271] At room temperature, 0.25 mmol of α-carbonylthioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonylthioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 122.2 mg of the target product IIIu, a pale green solid, with a calculated yield of 54%.

[0272] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0273] 1. Specific rotation [α] measured by the D line at 21℃ D 21 +13.3 (c=1.0, CH2Cl2).

[0274] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel OD-3 column; 5% i-PrOH in hexanes; 1.0 mL / min; retention times: 20.5 min (minor), 22.2 min (major). Calculated result: 90% ee.

[0275] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0276] 1 H NMR(400MHz, CDCl3)δ8.00–7.96(m,2H),7.83–7.80(m,2H),7.71–7.68(m,2H),6.97–6.93(m,2H),5.08–5 .04(m,1H),3.87(s,3H),3.66(t,J=7.3Hz,2H),2.13–1.92(m,2H),1.68–1.61(m,2H),1.52–1.27(m,12H).

[0277] 13C NMR (100MHz, CDCl3) δ192.2,168.4,163.9,133.8,132.1,131.2,127.3,123.1 ,113.9,57.6,55.5,38.0,33.7,29.23,29.21,29.02,29.00,28.5,26.7,26.2.

[0278] HRMS(ES+)Calcd for C 26 H 30 ClNNaO4[M+Na] + :478.1756,found:478.1760.

[0279] Example 22

[0280]

[0281] A method for preparing a chiral α-chlorocarbonyl compound IIIv: using R in formula I 1 It is 4-methoxyphenyl, R 2 It is 9-acetoxynonyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is a tetrafluoroborate α-carbonyl thioonium salt) and sodium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0282] At room temperature, 0.25 mmol of α-carbonylthioonium salt and 0.1 mmol of chiral catalyst CTU 1 were sequentially added to 5 mL of m-xylene solvent, and the mixture was cooled in a -15°C cold bath. 5 mL of saturated sodium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at -15°C for 72 hours. After the reaction was complete, 0.25 mmol of α-carbonylthioonium salt and 5 mL of m-xylene at -15°C were rapidly added to the reaction system, and the mixture was stirred at -15°C for another 72 hours. After the starting materials had completely reacted, the organic and aqueous phases were separated by standing at -15°C. The aqueous phase was extracted three times using 4 mL of a hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). The combined organic phase solutions were separated by column chromatography to obtain 115.7 mg of the target product IIIv, a pale green solid, with a calculated yield of 63%.

[0283] After this preparation step was completed, in order to further verify that the purified compound was indeed the target product to be prepared in this embodiment, the obtained product was analyzed. The analytical methods included determining specific rotation, high-performance liquid chromatography (HPLC) to determine the ee value, and nuclear magnetic resonance (NMR). The analysis results are as follows:

[0284] 1. Specific rotation [α] measured by the D line at 21℃ D21 +14.2 (c=1.0,CH2Cl2).

[0285] 2. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AD-H column; 15% i-PrOH in hexanes; 1.0 mL / min; retention times: 8.3 min (minor), 12.3 min (major). Calculated result: 88% ee.

[0286] 3. Proton, carbon and high-resolution mass spectrometry of nuclear magnetic resonance analysis.

[0287] 1 H NMR (400MHz, CDCl3) δ8.02–7.95(m,2H),6.99–6.92(m,2H),5.11–5.02(m,1H ),4.04(t,J=6.7Hz,2H),3.88(s,3H),2.16–1.93(m,5H),1.64–1.20(m,14H).

[0288] 13 C NMR (100MHz, CDCl3) δ192.2,171.2,164.0,131.3,127.4,114.0,64.6,57.6,55.5,33.7,29.3,29.2,29.14,29.07,28.6,26.3,25.8,21.0.

[0289] HRMS(ES+)Calcd for C 20 H 29 ClNaO4[M+Na] + :391.1647,found:391.1650.

[0290] Example 23

[0291]

[0292] A method for preparing a chiral α-chlorocarbonyl compound IIIa: using R in formula I 1 It is a phenyl group, R 2 For methyl, R 3 and R 4 The reaction proceeds using a phenyl group (A is an α-carbonyl thioonium salt of tetrafluoroborate) and potassium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0293] At room temperature, 0.05 mmol of α-carbonyl thioonium salt and 0.005 mmol of chiral thiourea catalyst CTU 1 were sequentially added to 0.5 mL of xylene solvent. 0.5 mL of saturated potassium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at room temperature for 8 hours. After the reactants had reacted completely, the organic and aqueous phases were separated by standing. The aqueous phase was extracted three times using a 2 mL hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). NMR analysis of the combined organic phase solutions yielded a 95% yield of the target product IIIa.

[0294] After this preparation step is completed, in order to further verify that the purified compound is indeed the target product to be prepared in this embodiment, the obtained product is analyzed. The analytical method used is high-performance liquid chromatography (HPLC) to determine the ee value. The analysis results are as follows:

[0295] 1. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AS-H column; 5% i-PrOH in hexanes; 1.0 mL / min; retention times: 6.2 min (minor), 6.6 min (major). Calculated result: 85% ee.

[0296] Example 24

[0297]

[0298] A method for preparing a chiral α-chlorocarbonyl compound IIIa: using R in formula I 1 It is a phenyl group, R 2 For methyl, R 3 and R 4 The reaction proceeds using an α-carbonyl thioonium salt of phenyl group A and tetrafluoroborate group A, and ammonium chloride as reactants, and a chiral thiourea as a catalyst. The specific implementation process is as follows:

[0299] At room temperature, 0.05 mmol of α-carbonyl thioonium salt and 0.005 mmol of chiral thiourea catalyst CTU 1 were sequentially added to 0.5 mL of xylene solvent. 0.5 mL of saturated ammonium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at room temperature for 8 hours. After the reactants had reacted completely, the organic and aqueous phases were separated by standing. The aqueous phase was extracted three times using a 2 mL hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). NMR analysis of the combined organic phase solutions yielded a 95% yield of the target product IIIa.

[0300] After this preparation step is completed, in order to further verify that the purified compound is indeed the target product to be prepared in this embodiment, the obtained product is analyzed. The analytical method used is high-performance liquid chromatography (HPLC) to determine the ee value. The analysis results are as follows:

[0301] 1. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AS-H column; 5% i-PrOH in hexanes; 1.0 mL / min; retention times: 6.2 min (minor), 6.6 min (major). Calculated result: 88% ee.

[0302] Example 25

[0303]

[0304] A method for preparing a chiral α-chlorocarbonyl compound IIIa: using R in formula I 1 It is a phenyl group, R 2 For methyl, R 3 and R 4 The reaction proceeds using an α-carbonyl thioonium salt of phenyl group A and tetrafluoroborate group A, and lithium chloride as reactants, with chiral thiourea as a catalyst. The specific implementation process is as follows:

[0305] At room temperature, 0.05 mmol of α-carbonyl thioonium salt and 0.005 mmol of chiral thiourea catalyst CTU 1 were sequentially added to 0.5 mL of xylene solvent. 0.5 mL of saturated lithium chloride solution, pre-cooled to the same temperature, was rapidly added to the reaction solution, and the mixture was stirred at room temperature for 8 hours. After the reactants had reacted completely, the organic and aqueous phases were separated by standing. The aqueous phase was extracted three times using a 2 mL hexane-diethyl ether mixture (hexane:diethyl ether = 2:1). NMR analysis of the combined organic phase solutions yielded a 95% yield of the target product IIIa.

[0306] After this preparation step is completed, in order to further verify that the purified compound is indeed the target product to be prepared in this embodiment, the obtained product is analyzed. The analytical method used is high-performance liquid chromatography (HPLC) to determine the ee value. The analysis results are as follows:

[0307] 1. High-performance liquid chromatography (HPLC) analysis for determining ee value: chiral column Daicel AS-H column; 5% i-PrOH in hexanes; 1.0 mL / min; retention times: 6.2 min (minor), 6.6 min (major). Calculated result: 72% ee.

[0308] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for preparing a chiral α-chlorocarbonyl compound, characterized in that, Includes the following steps: The α-carbonyl-substituted thioonium salt compound of Formula I and the chlorinated salt of Formula II were subjected to chlorination under catalytic conditions to obtain the chiral α-chlorocarbonyl compound of Formula III. in, R 1 Selected from at least one of phenyl, biphenyl, halophenyl, C1-C5 alkylphenyl, haloC1-C5 alkylphenyl, C1-C5 alkoxyphenyl, triC1-C5 alkylsilylphenyl, triC1-C5 alkylsiloxyphenyl, 3-benzo[1,3]-m-dioxocyclopentyl, thiophene, R 2 Selected from C1-C 10 Alkyl groups, heterooxygen-containing C1-C 10 Heteroalkyl, phenyl C1-C 10 Alkyl, 9-phthalamide C9-C 10 9-acetoxy C9-C 10 At least one of the bases, R 3 and R 4 All are phenyl; A is selected from at least one of tetrafluoroborate, hexafluorophosphate, sulfonate, carboxylate, sulfate, and carbonate. M is selected from at least one of sodium ion, lithium ion, potassium ion, cesium ion, ammonium ion, and quaternary ammonium cation; The catalyst comprises a chiral thiourea catalyst with the following structure: ； The amount of catalyst added is 5% to 20% of the molar amount of the α-carbonyl-substituted thioonium salt compound; the chlorination reaction is carried out at a temperature of -15 to 40°C in a mixed solvent consisting of an organic solvent and water, wherein the organic solvent is selected from at least one of dichloromethane, 1,2-dichloroethane, chloroform, tetrachloromethane, diethyl ether, n-hexane, chlorobenzene, fluorobenzene, toluene, xylene, and trifluorotoluene.

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