A chiral metal complex, its preparation method and its use as a catalyst for the synthesis of chiral imidazoline derivatives

Abstract

The present invention belongs to the field of pharmaceutical technology and specifically relates to a chiral metal complex, its preparation method, and its use as a catalyst for the synthesis of chiral imidazoline derivatives. The chiral metal complex of the present invention is shown in Formula I. The chiral metal complex of the present invention is used as a synthesis catalyst to achieve high yield and high stereoselectivity in the synthesis of chiral imidazoline compounds. Thus, the present invention provides a novel method for preparing chiral imidazoline compounds, which has the advantages of high efficiency, mild conditions, high atom economy (100%), and wide substrate compatibility, and has excellent application prospects. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a chiral metal complex, a preparation method thereof and use thereof as a catalyst for synthesizing chiral imidazoline derivatives. Background Art

[0002] Imidazolines are an important class of organic compounds with a wide range of uses and applications in medicine and organic synthesis. Compounds containing imidazoline skeletons exhibit a variety of important physiological activities. Among them, imidazoline quaternary ammonium salts are common cationic surfactants with bactericidal, antifungal, and anti-inflammatory effects. They are commonly used to treat a variety of bacterial and fungal infections and can also be used as anti-inflammatory drugs to effectively inhibit inflammatory responses and reduce pain. Imidazoline compounds are important organic synthesis intermediates and precursors of functional materials and are widely used in organic synthesis. In addition, chiral imidazolines can be used as chiral auxiliary groups, organic catalysts, and chiral ligands in asymmetric synthesis.

[0003] At present, there have been many studies on the synthesis of imidazoline compounds. For example, the document "Angew. Chem. Int. Ed. 2015, 54, 14452–14456" reports a method for synthesizing imidazoline compounds using rare earth metal catalysts. The specific reaction is as follows:

[0004]

[0005] However, in this method, there is no selectivity for the chirality of the product. And the chirality of many drug molecules has a significant impact on its biological activity and toxic side effects. In addition, imidazoline, as an organic catalyst and chiral ligand, shows huge development potential in asymmetric catalysis. The synthetic method of existing chiral imidazoline is usually obtained by multi-step conversion from chiral raw materials, and synthesis efficiency and atom utilization rate are not high. Therefore, this area is in the urgent need of developing new synthetic catalysts and synthetic methods, to prepare various imidazoline compounds with chirality. Summary of the Invention

[0006] In view of the problems of the prior art, the present invention provides a chiral metal complex, a preparation method thereof and use thereof as a catalyst for the synthesis of chiral imidazoline derivatives.

[0007] The compound represented by formula I or formula II, or a stereoisomer thereof, or a salt thereof:

[0008]

[0009] wherein M is selected from La, Y, Ce, Pr, Nd, Gd or Sm;

[0010] R 1 Selected from C1-C 10Alkyl, C3-C 10 Cycloalkyl, C6-C 10 aryl;

[0011] R 2 Selected from hydrogen, C1-C 10 Alkyl, C1-C 10 Cycloalkyl, C6-C 10 aryl;

[0012] R 3 Selected from trimethylsilane.

[0013] Preferably, the M is selected from La;

[0014] The R 1 Selected from C1-C4 alkyl, C 10 Cycloalkyl or phenyl;

[0015] The R 2 Selected from hydrogen, C1-C4 alkyl, C 10 Cycloalkyl or phenyl;

[0016] The R 3 Selected from trimethylsilane.

[0017] Preferably, the M is selected from La.

[0018] Preferably, the R 1 is selected from tert-butyl, adamantyl or phenyl.

[0019] Preferably, the R 2 is selected from hydrogen or phenyl.

[0020] Preferably, the R 3 Selected from trimethylsilane.

[0021] Preferably, the compound represented by formula I is one of the following compounds:

[0022]

[0023] The present invention also provides a method for preparing the above-mentioned compound, or its stereoisomer, or its salt, which is characterized by comprising the steps of:

[0024]

[0025] Reacting raw material A with raw material B to obtain a compound of formula I or formula II;

[0026] Among them, M, R 1 、R 2 、R 3 As mentioned above.

[0027] Preferably, the solvent of the reaction is selected from toluene or tetrahydrofuran;

[0028] And / or, the reaction temperature is raised from -30°C to 25°C.

[0029] The present invention also provides use of the above compound or its salt as a catalyst for synthesizing chiral imidazoline derivatives.

[0030] The present invention also provides a method for preparing a chiral imidazoline derivative, comprising the following steps:

[0031]

[0032] Reacting raw material C with raw material D to obtain a compound represented by formula III, wherein the reaction uses the above compound, or a stereoisomer thereof, or a salt thereof as a catalyst;

[0033] in,

[0034] R 1 Selected from substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkenyl, wherein the substituent is selected from C6-C 10 Aryl, halogen, cyano, C1-C 10 alkoxy;

[0035] R 2 Selected from hydrogen, substituted or unsubstituted C1-C 10 Alkyl, wherein the substituent is selected from halogen, cyano, C1-C 10 alkoxy;

[0036] R 3 Selected from hydrogen, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted benzyl, wherein the substituent is selected from C1-C 10 Alkyl, halogen, cyano, C1-C 10 alkoxy;

[0037] R 4 Selected from substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 5- to 10-membered heterocycloalkyl, substituted or unsubstituted C9-C 18 Spiroalkyl, substituted or unsubstituted 9 to 18-membered hetero-spiroalkyl, wherein the substituent is selected from C1-C 10 Alkyl, C1-C 10 Haloalkyl, halogen, cyano, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C1-C 10 Amine, C6-C10 Aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C6-C 10 Cycloalkyl, PPh2, OTBS, Among them, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl may be further substituted, and the substituent is selected from C1-C 10 Alkyl, halogen, cyano.

[0038] Preferably, the amount of the catalyst is 2.5-5 mol%;

[0039] and / or, the solvent of the reaction is selected from tetrahydrofuran or toluene;

[0040] And / or, the reaction is carried out under the protection of an inert gas;

[0041] and / or, the reaction temperature is 25° C.;

[0042] and / or, R 1 is selected from substituted or unsubstituted methyl, C3 alkenyl, wherein the substituent is selected from phenyl;

[0043] and / or, R 2 is selected from hydrogen, methyl;

[0044] and / or, R 3 Selected from hydrogen, substituted or unsubstituted C6-C 10 Aryl, benzyl, wherein the substituent is selected from methyl, methoxy, F, Cl, Br;

[0045] and / or, R 4 Selected from substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 9-membered heterocycloalkyl, substituted or unsubstituted C 17 -C 18 Spiroalkyl, 18-membered hetero-spiroalkyl, wherein the substituent is selected from C1-C6 alkyl, trifluoromethyl, halogen, cyano, C1-C8 alkoxy, methylthio, C2-C5 amino, phenyl, 5-heteroaryl, 5- to 9-membered heterocycloalkyl, C6 cycloalkyl, PPh2, OTBS, Among them, the aryl group, heterocycloalkyl group, and cycloalkyl group may be further substituted, and the substituents are selected from C1-C4 alkyl and F.

[0046] Preferably, the compound represented by formula III is one of the following compounds:

[0047]

[0048]

[0049]

[0050]

[0051] Wherein, Ar is 4-CF3C6H4.

[0052] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0053] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0054] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0055] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.

[0056] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may optionally be substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. Alkyl groups can also be part of other groups, such as C1-C6 alkoxy.

[0057] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spirocyclic systems). For polycyclic systems with aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8,-tetrahydronaphthalene-5-yl) is used when the point of attachment is located at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, etc. Two such bicycloalkyl polycyclic structures are exemplified and named below: Biscyclohexyl and Bicyclohexyl. "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms, and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms, and having at least one site of vinyl unsaturation (>C=C<). For example, (C-C)alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0058] "Alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon groups having one triple bond and one double bond. For example, (C2-C6)alkynyl is intended to include ethynyl, propynyl, and the like.

[0059] "Halogen" is fluorine, chlorine, bromine or iodine.

[0060] "Halogenalkyl" means that the hydrogen atoms in the alkyl group may be replaced by one or more halogen atoms. 1～4 The halogenalkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms.

[0061] "Heterocycle" and "heterocycloalkyl" refer to saturated or non-aromatic unsaturated rings containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0062] "Aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom;

[0063] "Alkoxy" refers to an alkyl group attached to the site of attachment through an oxygen atom, for example, methoxy refers to -OCH3;

[0064] "Alkylthio" refers to an alkyl group attached to the site of attachment through a sulfur atom, for example, methylthio refers to -SCH3;

[0065] "Circular lines" represent delocalized conjugated systems, e.g.

[0066] In the present invention, the abbreviations of the groups involved are as follows:

[0067] Me: methyl, Et: ethyl, i Pr: isopropyl, t Bu: tert-butyl, n Pen: n-pentyl, n Hex: n-hexyl, Oct: octyl, Ph: phenyl, Bn: benzyl, OTBS: tert-butyldimethylsilyl, TMS: trimethylsilyl.

[0068] Previous studies in this field have shown that the opposite configuration of chiral catalysts generally have similar catalytic properties, and the use of chiral catalysts with opposite configurations (such as their left-handed and right-handed enantiomers) can generally produce products with different stereoconfigurations.

[0069] The present invention provides a chiral metal complex that can be used as a catalyst for the synthesis of chiral imidazolines, achieving high-yield, high-stereoselectivity synthesis of chiral imidazoline compounds. Furthermore, using the chiral metal complex as a catalyst, the synthesis method for chiral imidazolines has the advantages of mild conditions, high atom economy (100%), and wide substrate compatibility. Therefore, the present invention has promising application prospects.

[0070] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0071] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0072] In the following examples and experimental examples, reagents and raw materials not otherwise specified are commercially available.

[0073] Example 1 Synthesis of Chiral Metal Complexes

[0074]

[0075] The specific preparation method is as follows: In a glove box, weigh M(HMDS)3 (1 mmol) and pour it into a 25 mL pre-dried Shrek bottle. Add toluene (5 mL, 0.2 M) and cool to –30°C. Slowly add a pre-prepared oxazoline toluene solution (0.2 M) at –30°C to the Shrek bottle, slowly warm to room temperature, and react overnight. Wherein, M is selected from La.

[0076] The solvent was removed under reduced pressure, n-hexane solution (5 mL) was added, and the mixture was dried. Then n-hexane solution (5 mL) was added, and the mixture was filtered in a glove box, washed and filtered, and the solvent was removed under reduced pressure to obtain the target catalyst.

[0077] Get the product:

[0078]

[0079] 0.38(s,36H). 13 C{ 1H} NMR (101 MHz, deuterated benzene) δ 172.7, 74.8, 68.0, 57.5, 34.6, 26.9, 4.7.

[0080] Example 2 Synthesis of Chiral Metal Complexes

[0081] The preparation method and conditions of the chiral metal complex of this embodiment are the same as those of Example 1, except that the corresponding raw materials are replaced according to the different metal ions or substituents.

[0082] Get the product:

[0083]

[0084] 3.1Hz, 2H), 3.85 (dd, J=8.8, 3.1Hz, 2H), 3.77 (t, J=8.5Hz, 2H), 1.61 (s, 15H), 1.36 (s, 15H), 0.39 (s, 36H). 13 C{ 1 H} NMR (101 MHz, deuterated benzene) δ 173.6, 74.7, 66.5, 57.7, 38.9, 38.6, 37.1, 36.9, 31.7, 30.2, 28.4, 23.1, 5.0.

[0085] Example 3 Synthesis of Chiral Metal Complexes

[0086] The preparation method and conditions of the chiral metal complex of this embodiment are the same as those of Example 1, except that the corresponding raw materials are replaced according to the different metal ions or substituents.

[0087] Get the product:

[0088]

[0089] 3.68(dd,J=9.0,2.9Hz,2H),3.61(t,J=8.7Hz,2H),0.85(s,18H),0.37(s,36H). 13 C{ 1 H} NMR (101 MHz, deuterated benzene) δ 172.5, 138.9, 133.2, 125.5, 75.4, 73.7, 67.9, 35.2, 26.4, 4.9.

[0090] Example 4 Synthesis of Chiral Metal Complexes

[0091] The preparation method and conditions of the chiral metal complex of this embodiment are the same as those of Example 1, except that the corresponding raw materials are replaced according to the different metal ions or substituents.

[0092] Get the product:

[0093]

[0094] 6.90(m,9H),6.90–6.85(m,5H),6.84(s,2H),5.68(d,J=8.2Hz,2H),5.56(d,J=8.2Hz,2H),5.25(s,1H),0.21(s,36H). 13 C{ 1 H} NMR (101 MHz, deuterated benzene) δ 174.4, 139.0, 136.3, 128.7, 128.5, 126.6, 84.8, 72.3, 58.6, 4.0.

[0095] Example 5 Synthesis of Chiral Metal Complexes

[0096] The preparation method and conditions of the chiral metal complex of this embodiment are the same as those of Example 1, except that the corresponding raw materials are replaced according to the different metal ions or substituents.

[0097] Get the product:

[0098]

[0099] 2H),3.83–3.73(m,4H),0.84(s,18H),0.38(s,36H).

[0100] 13 C{ 1 H} NMR (101 MHz, deuterated benzene) δ 174.4, 174.4, 74.2, 68.4, 58.5, 34.9, 26.3, 6.1

[0101] Example 6 Synthesis of Chiral Metal Complex

[0102] The preparation method and conditions of the chiral metal complex of this embodiment are the same as those of Example 1, except that the corresponding raw materials are replaced according to the different metal ions or substituents.

[0103] Get the product:

[0104]

[0105] confirmed by single crystal diffractometry.

[0106] Example 7 Synthesis of Chiral Metal Complex

[0107] The preparation method and conditions of the chiral metal complex of this embodiment are the same as those of Example 1, except that the corresponding raw materials are replaced according to the different metal ions or substituents.

[0108] Get the product:

[0109]

[0110] Example 8 Synthesis of Chiral Imidazoline

[0111] The general formula of the synthesis method is:

[0112]

[0113] Among them, R 1 、R 2 、R 3 and R 4 The structure can be determined according to the specific structure of the product.

[0114] The specific method is:

[0115] In the glove box, weigh M-BOX- t Bu (2.5 mol%, 3.4 mg) was poured into a pre-dried catalytic test tube, and raw material D (0.30 mmol) and solvent (tetrahydrofuran or toluene) were added. Raw material C (0.20 mmol) was added, and the mixture was reacted at 25°C under argon protection. The product was obtained by silica gel column chromatography.

[0116] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0117] Get the product:

[0118] 0.64, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =8.90min,t minor =7.36min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.57–7.45 (m, 2H), 7.43–7.29 (m, 3H), 4.21–4.00 (m, 1H), 3.62–3.51 (m, 1H), 3.00–2.93 (m, 1H), 2.75 (s, 3H), 1.30 (d, J = 6.6 Hz, 3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 165.7, 130.4, 128.8, 127.3, 60.0, 58.7, 35.4, 21.2. HRMS (FTMS+c ESI) calculated for C 11 H15 N2 + ([M]+H) + =175.1230, Found 175.1228; IR(film,cm -1 ).3386,2965,1605,1567,1449,1383,1282,1025,798.

[0119] Example 9 Synthesis of Chiral Imidazoline

[0120] In the glove box, weigh Pr-BOX- t Bu (5 mol%, 3.7 mg) was poured into a pre-dried catalytic test tube, and raw material D (0.15 mmol) and solvent (tetrahydrofuran or toluene) were added. Raw material C (0.10 mmol) was added, and the mixture was reacted at 25°C under argon protection. The product was obtained by silica gel column chromatography.

[0121] In this embodiment, the catalyst is Pr-BOX- t Bu, the solvent is toluene.

[0122] Get the product:

[0123]

[0124] Response time: 12 h. Oily liquid, 25.0 mg, >99% yield, 74% ee; [α] D 25 = +33.0 (c = 0.44, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel ODH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =6.19min,t minor =7.37min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.51–7.40 (m, 2H), 7.36–7.27 (m, 3H), 7.24–7.16 (m, 4H), 7.15–7.09 (m, 1H), 4.36–4.23 (m, 1H), 3.38–3.26 (m, 1H), 3.19–3.00 (m, 2H), 2.72–2.63 (m, 1H), 2.60 (s, 3H). 13 C{ 1H} NMR (101 MHz, deuterated chloroform) δ 167.1, 138.9, 131.3, 129.8, 129.5, 128.3, 126.2, 65.7, 58.1, 42.3, 36.2. HRMS (FTMS+c ESI) calculated for C 17 H 19 N2 + ([M]+H) + =251.1543, Found 251.1543; IR(film,cm -1 ):2922,1594,1570,1496,1448,1385,1260,1060,1024,775,700,506.

[0125] Example 10 Synthesis of Chiral Imidazoline

[0126] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 9, except that the corresponding raw materials are replaced according to the different substituents.

[0127] In this embodiment, the catalyst is Pr-BOX- t Bu, the solvent is toluene.

[0128] Get the product:

[0129]

[0130] Prepared according to the chiral imidazoline synthesis method, reaction time: 12h. White solid 31.8 mg, >99% yield, 93% ee; [α] D 28 = +10.9 (c = 0.58, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicelchiralcel ODH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =5.91min,t minor =7.49min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.66–7.53 (m, 4H), 7.29–7.11 (m, 5H), 4.40–4.26 (m, 1H), 3.44–3.31 (m, 1H), 3.17–3.04 (m, 2H), 2.74–2.65 (m, 1H), 2.59 (s, 3H). 13 C{ 1H} NMR (101 MHz, deuterated chloroform) δ 138.5, 134.8, 131.7 (q, J = 32.7 Hz), 129.4, 128.7, 128.3, 126.3, 125.3 (q, J = 3.8 Hz), 123.9 (q, J = 272.4 Hz). 19 F{ 1 H}NMR (376 MHz, deuterated chloroform) δ–62.84 (s, 3F). HRMS (FTMS+c ESI) calculated for C 18 H 18 F3N2 + ([M]+H) + =319.1417,Found 319.1414;IR(film,cm -1 ):2926,1601,1408,1167,1126,1070,1017,851,701.MP86–88℃

[0131] Example 11 Synthesis of Chiral Imidazoline

[0132] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0133] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0134] Get the product:

[0135]

[0136] Time: 132h. Oily liquid, 36.2 mg, 96% yield, 91% ee; [α] D 28 = +39.8 (c = 0.66, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =5.98min,t minor =5.28min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.31–7.23 (m, 2H), 7.22–7.15 (m, 2H), 4.22–4.06 (m, 1H), 3.60–3.50 (m, 1H), 3.03–2.93 (m, 1H), 2.58 (s, 3H), 2.32 (s, 3H), 1.33 (d, J = 6.6 Hz, 3H).13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 166.0, 136.3, 131.6, 130.2, 129.1, 128.6, 125.7, 60.0, 59.9, 34.7, 34.6, 22.3, 19.3. HRMS (FTMS+c ESI) calcd for C 12 H 17 N2 + ([M]+H) + =

[0137] 189.1386, Found 189.1387; IR(film,cm -1 ):3367,2968,2922,1616,1593,1497,1450,1387,1344,1306,1270,1235,1107,1036,766,732.

[0138] Example 12 Synthesis of Chiral Imidazoline

[0139] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0140] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0141] Get the product:

[0142]

[0143] Time: 132 h. Oily liquid, 37.6 mg, >99% yield, 91% ee;

[0144] [α] D 28 = +46.6 (c = 0.70, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicelchiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min), retention time: t major =7.15min,t minor =6.29min. 1H NMR(400MHz,Chloroform-d)δ7.39(s,1H),7.34–7.24(m,2H),7.23–7.18(m,1H),4.20–4.07(m,1 H),3.57(t,J=9.5Hz,1H),2.98(t,J=8.7Hz,1H),2.78(s,3H),2.36(s,3H),1.32(d,J=6.6Hz,3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 166.8, 138.0, 131.3, 130.4, 129.0, 128.1, 125.2, 61.0, 59.7, 36.4, 22.2, 21.3. HRMS (FTMS+c ESI) calculated for C 12 H 17 N2 + ([M]+H) + =189.1386, Found 189.1386; IR(film,cm -1 ):3304,2962,2923,1645,1578,1483,1450,1385,1308,1275,1226,796,722.

[0145] Example 13 Synthesis of Chiral Imidazoline

[0146] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0147] In this embodiment, the catalyst is Y-BOX- t Bu (5 mol%), the solvent is tetrahydrofuran.

[0148] Get the product:

[0149]

[0150] Reaction time: 108 h. Oily liquid, 37.3 mg, 99% yield, 90% ee; [α] D 28 = +30.4 (c = 0.56, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicelchiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =8.32min,t minor =6.44min. 1H NMR (400 MHz, deuterated chloroform) δ 7.42 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 4.19–4.02 (m, 1H), 3.56 (t, J = 9.5 Hz, 1H), 2.96 (t, J = 8.7 Hz, 1H), 1.31 (d, J = 6.5 Hz, 3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 166.7, 139.7, 128.9, 128.2, 61.1, 59.6, 22.2. HRMS (FTMS+c ESI) calculated for C 12 H 17 N2 + ([M]+H) + =189.1386, Found 189.1387; IR(film,cm -1 ):3307,2962,2923,1597,1563,1450,1386,1307,1273,1217,1049,825,734.

[0151] Example 14 Synthesis of Chiral Imidazoline

[0152] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0153] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0154] Get the product:

[0155] 88% ee; [α] D 28 = +46.1 (c = 0.74, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicelchiralcel ODH, n-hexane (0.1% diethylamine) / isopropanol = 95 / 5, flow rate 1.0 mL / min) retention time: t major =6.80min,t minor =6.02min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.13 (s, 2H), 7.01 (s, 1H), 4.18–3.98 (m, 1H), 3.59–3.47 (m, 1H), 3.05–2.89 (m, 1H), 2.76 (s, 3H), 2.30 (s, 6H), 1.29 (d, J = 6.6 Hz, 3H). 13C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 167.0, 137.8, 131.2, 131.2, 126.0, 61.0, 59.6, 36.5, 22.2, 21.2. HRMS (FTMS+c ESI) calcd for C 13 H 19 N2 + ([M]+H) + =203.1543,Found 203.1544;IR(film,cm -1 ):2961,2920,1450,1389,1253,1079,856,729.

[0156] Example 15 Synthesis of Chiral Imidazoline

[0157] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0158] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0159] Get the product:

[0160] midazole(C8)(C 13 H 18 N2), the compound was prepared according to the chiral imidazoline synthesis method, reaction time: 24h. Oily liquid, 37.2 mg, 92% yield, 88% ee; [α] D 28 = +38.1 (c = 0.68, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =6.27min,t minor =5.17min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.45 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 4.20–4.03 (m, 1H), 3.56 (t, J = 9.4 Hz, 1H), 2.98 (t, J = 8.7 Hz, 1H), 2.78 (s, 3H), 2.66 (q, J = 7.6 Hz, 2H), 1.31 (d, J = 6.6 Hz, 3H), 1.23 (t, J = 7.6 Hz, 3H). 13 C{1 H} NMR (101 MHz, deuterated chloroform) δ 166.9, 146.2, 128.7, 128.4, 127.9, 61.2, 59.8, 36.6, 28.9, 22.4, 15.5. HRMS (FTMS+c ESI) calcd for C 13 H 19 N2 + ([M]+H) + =203.1543,Found 203.1544;IR(film,cm -1 ):3365,2964,2927,1618,1597,1566,1516,1387,1346,1307,1049,1018,839,544.

[0161] Example 16 Synthesis of Chiral Imidazoline

[0162] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0163] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0164] Get the product:

[0165]

[0166] Prepared by a synthetic method, reaction time: 24h. Oily liquid, 43.2 mg, >99% yield, 90% ee; [α] D 28 = +53.4 (c = 0.80, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel AZH, n-hexane (0.1% diethylamine) / isopropanol = 95 / 5, flow rate 1.0 mL / min) retention time: t major =14.03min,t minor =13.48min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.45 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 4.15–4.04 (m, 1H), 3.54 (t, J = 9.5 Hz, 1H), 2.97 (t, J = 8.6 Hz, 1H), 2.94–2.85 (m, 1H), 2.77 (s, 3H), 1.29 (d, J = 6.6 Hz, 3H), 1.22 (d, J = 7.0 Hz, 6H). 13 C{1 H} NMR (101 MHz, deuterated chloroform) δ 166.7, 150.6, 128.7, 128.3, 126.3, 61.0, 59.6, 36.5, 34.0, 23.9, 22.2. HRMS (FTMS+c ESI) calcd for C 14 H 21 N2 + ([M]+H) + =217.1699, Found 217.1698; IR(film,cm -1 ):2960,2925,2870,1597,1562,1514,1457,1385,1306,1272,1217,1017,839,559.

[0167] Example 17 Synthesis of Chiral Imidazoline

[0168] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0169] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0170] Get the product:

[0171]

[0172] Prepared by phenoxyethylene synthesis method, reaction time: 72h. Oily liquid, 45.6 mg, 99% yield, 91% ee; [α] D 28 = +55.6 (c = 0.86, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =4.39min,t minor =3.93min. 1 H NMR (400 MHz, deuterated chloroform) δδ7.50–7.42 (m, 2H), 7.40–7.34 (m, 2H), 4.18–4.03 (m, 1H), 3.53 (dd, J = 10.0, 9.0 Hz, 1H), 2.97 (dd, J = 9.0, 8.1 Hz, 1H), 2.77 (s, 3H), 1.35–1.21 (m, 12H). 13 C{ 1H} NMR (101 MHz, deuterated chloroform) δ 166.6, 152.8, 128.3, 128.0, 125.2, 61.0, 59.6, 36.5, 34.7, 31.2, 22.2. HRMS (FTMS+c ESI) calculated for C 15 H 23 N2 + ([M]+H) + =231.1856,Found231.1857;IR(film,cm -1 ):2961,2868,1596,1509,1462,1396,1365,1307,1267,1109,1049,1016,838,799,701,567,499.

[0173] Example 18 Synthesis of Chiral Imidazoline

[0174] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 1, except that the corresponding raw materials are replaced according to the different substituents.

[0175] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0176] Get the product:

[0177]

[0178] g, 99% yield, 94% ee; [α] D 28 = +40.5 (c = 0.76, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol = 80 / 20, flow rate 1.0 mL / min) retention time: t major =7.68min,t minor =6.26min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.47 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.17–3.98 (m, 1H), 3.80 (s, 3H), 3.54 (dd, J = 9.9, 9.0 Hz, 1H), 2.95 (dd, J = 9.0, 8.3 Hz, 1H), 2.76 (s, 3H). 13 C{ 1H} NMR (101 MHz, deuterated chloroform) δ 166.4, 160.7, 129.8, 123.6, 113.6, 61.1, 59.5, 55.3, 36.6, 22.3. HRMS (FTMS+c ESI) calculated for C 12 H 17 N2O + ([M]+H) + =205.1335, Found 205.1335; IR(film,cm -1 ):2962,1613,1515,1438,1388,1304,1176,1027,839,604.

[0179] Example 19 Synthesis of Chiral Imidazoline

[0180] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0181] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0182] Get the product:

[0183]

[0184] e(C12)(C 11 H 13 ClN2), the compound was prepared according to the chiral imidazoline synthesis method, reaction time: 12 h. Oily liquid, 37.6 mg, 90% yield, 94% ee; [α] D 28 = +58.0 (c = 0.70, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel ODH, hexane / i PrOH=90 / 10, flow rate 1.0 mL / min) retention time: t maj o r =5.32 min,t min o r =5.02 min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.36–7.15 (m, 4H), 4.19–4.05 (m, 1H), 3.60–3.49 (m, 1H), 2.99–2.87 (m, 1H), 2.57 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H). 13 C{ 1H}NMR (101 MHz, deuterated chloroform) δ163.6, 132.8, 131.3, 130.5, 130.4, 129.5, 126.8, 60.2, 59.8, 34.1, 22.1. HRMS (FTMS+c ESI) calculated for C 11 H 14 35 ClN2+([M]+H)+=209.0840,Found209.0842,calcd for C 11 H 14 37 ClN2+([M]+H)+=211.0811, Found 211.0810; IR(film,cm- 1 ):2963,2923,1615,1585,1495,1472,1440,1394,1345,1307,1273,1111,1076,1034,761.

[0185] Example 20 Synthesis of Chiral Imidazoline

[0186] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0187] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0188] Get the product:

[0189]

[0190] Rate, 92%ee; [α] D 28 = +46.4 (c = 0.74, in CH2Cl2), dissolved in n-hexane for HPLC;

[0191] HPLC (Daicel chiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t maj o r =6.77 min,t min o r =5.45 min. 1H NMR (400 MHz, deuterated chloroform) δ 7.59–7.53 (m, 1H), 7.46–7.29 (m, 3H), 4.21–4.06 (m, 1H), 3.59 (t, J = 9.5 Hz, 1H), 2.99 (t, J = 8.8 Hz, 1H), 2.77 (s, 3H), 1.32 (d, J = 6.6 Hz, 3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 165.3, 134.3, 133.2, 129.8, 129.6, 128.5, 126.4, 61.0, 59.9, 36.3, 36.3, 22.1. HRMS (FTMS+c ESI) calcd for C 11 H 14 35 ClN2 + ([M]+H) + =209.0840,Found 209.0841,calcd for C 11 H 14 37 ClN2 + ([M]+H) + =211.0811, Found 211.0809; IR(film,cm -1 ):2963,1650,1609,1591,1561,1482,1448,1401,1308,1273,1092,1049,1014,835,734.

[0192] Example 21 Synthesis of Chiral Imidazoline

[0193] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0194] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0195] Get the product:

[0196]

[0197] Prepared by a synthetic method, reaction time: 12h. Oily liquid, 41.4 mg, >99% yield, 93% ee; [α] D 28= +56.5 (c = 0.72, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel IG, hexane / i PrOH=90 / 10, flow rate 1.0mL / min) retention time: t major =17.29min,t minor =16.70min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.54–7.44 (m, 2H), 7.39–7.33 (m, 2H), 4.19–4.06 (m, 1H), 3.57 (t, J = 9.5 Hz, 1H), 2.96 (t, J = 8.8 Hz, 1H), 2.74 (s, 3H), 1.30 (d, J = 6.6 Hz, 3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 165.6, 135.7, 129.9, 129.7, 128.6, 61.0, 59.9, 36.4, 36.4, 22.1. HRMS (FTMS+c ESI) calcd for C 11 H 14 35 ClN2 + ([M]+H) + =209.0840,Found 209.0842,calcd forC 11 H 14 37 ClN2 + ([M]+H) + =211.0811,Found 211.0810;IR(film,cm -1 ):2963,2924,1650,1606,1587,1482,1449,1401,1347,1307,1272,1091,1014,835,734.

[0198] Example 22 Synthesis of Chiral Imidazoline

[0199] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0200] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0201] Get the product:

[0202]

[0203] ole(C15)(C 11 H 13 FN2), this compound was prepared according to the chiral imidazoline synthesis method, reaction time: 12h. Oily liquid, 38.0 mg, 99% yield, 87% ee; [α] D 28 = +43.9 (c = 0.70, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol = 95 / 5, flow rate 1.0 mL / min) retention time: t major =13.98min,t minor =10.16min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.62–7.47 (m, 2H), 7.16–6.99 (m, 2H), 4.19–4.02 (m, 1H), 3.56 (dd, J = 10.0, 9.0 Hz, 1H), 2.96 (t, J = 8.8 Hz, 1H), 2.74 (s, 3H), 1.30 (d, J = 6.6 Hz, 3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 165.7, 163.5 (d, J = 249.2 Hz), 130.3 (d, J = 8.5 Hz), 127.4 (d, J = 3.3 Hz), 115.3 (d, J = 21.7 Hz), 61.0, 59.7, 36.4, 22.2. 19 F NMR (376 MHz, deuterated chloroform) δ–110.97 (s, 1F). HRMS (FTMS+c ESI) calculated for C 11 H 14 FN2 + ([M]+H) + =193.1136, Found 193.1134; IR(film,cm -1 ):3380,2964,1611,1580,1513,1483,1388,1225,1158,1048,1015,844,818,596.

[0204] Example 23 Synthesis of Chiral Imidazoline

[0205] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0206] In this embodiment, the catalyst is Y-BOX-t Bu, the solvent is toluene.

[0207] Get the product:

[0208] 92% ee; [α] D 25 =(c=, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicelchiralcel ODH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =5.82min,t minor =5.40min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.38–7.28 (m, 2H), 7.28–7.23 (m, 1H), 7.23–7.17 (m, 2H), 7.17–7.10 (m, 2H), 7.05–6.95 (m, 3H), 4.24 (d, J = 3.2 Hz, 2H), 2.68–2.28 (m, 1H), 1.36 (d, J = 7.5 Hz, 3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 144.6, 135.7, 131.4, 129.8, 128.4, 127.9, 127.2, 125.1, 25.4, 16.4. HRMS (FTMS+c ESI) calculated for C 11 H 14 79 BrN2 + ([M]+H) + =253.0335, Found 253.0334; C 11 H 14 81 BrN2 + ([M]+H) + =255.0314, Found 255.0310; IR(film,cm -1 ):3371,2962,2921,2832,1614,1582,1466,1438,1493,1343,1306,1269,1070,1027,760.

[0209] Example 24 Synthesis of Chiral Imidazoline

[0210] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0211] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0212] Get the product:

[0213]

[0214] Prepared by imidazoline synthesis method, reaction time: 24h. Oily liquid, 44.0 mg, >99% yield, 92% ee; [α] D 28 = +56.7 (c = 0.82, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel AZH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =22.04min,t minor =19.17min. 1 H NMR (400 MHz, deuterated chloroform): 7.49–7.38 (m, 2H), 7.25–7.16 (m, 2H), 4.17–3.99 (m, 1H), 3.66–3.45 (m, 1H), 3.00–2.90 (m, 1H), 2.75 (s, 3H), 2.46 (s, 3H), 1.29 (d, J = 6.6 Hz, 3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 166.2, 140.7, 128.7, 127.7, 125.7, 36.5, 22.2, 15.3. HRMS (FTMS+c ESI) calcd for C 12 H 17 N2S + ([M]+H) + =221.1107, Found 221.1106; IR(film,cm -1 ):2962,2922,1593,1498,1435,1400,1307,1273,1096,1048,827,737,531.

[0215] Example 25 Synthesis of Chiral Imidazoline

[0216] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0217] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0218] Get the product:

[0219]

[0220] in CH2Cl2), dissolved in n-hexane and subjected to HPLC; HPLC (Daicel chiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol = 99.7 / 0.3, flow rate 1.0 mL / min) retention time: t major =13.69min,t minor =16.52min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.67–7.54 (m, 8H), 7.49 (d, 2H), 7.24–7.17 (m, 2H), 4.18–4.02 (m, 1H), 3.52 (t, J = 9.5 Hz, 1H), 2.93 (t, J = 8.7 Hz, 1H), 2.75 (s, 3H), 2.58 (t, J = 7.8 Hz, 2H), 1.67–1.50 (m, 2H), 1.37–1.21 (m, 7H), 0.93–0.77 (m, 3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 166.4, 142.4, 142.0, 140.5, 138.9, 137.9, 130.2, 128.9, 128.8, 127.4, 127.4, 126.9, 126.8, 61.1, 59.8, 36.5, 35.6, 31.6, 31.2, 22.6, 22.3, 14.1. HRMS (FTMS+c ESI) calcd for C 28 H 33 N2 + ([M]+H) + =397.2638, Found 397.2639; IR(film,cm -1 ):2956,2925,2867,1595,1491,1387,1305,1271,1115,1053,752,517.MP179–181℃

[0221] Example 26 Synthesis of Chiral Imidazoline

[0222] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 1, except that the corresponding raw materials are replaced according to the different substituents.

[0223] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0224] Get the product:

[0225]

[0226] [α] D 25 = +29.8 (c = 1.50, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicelchiralcel OZH, n-hexane (0.1% diethylamine) / isopropanol = 97 / 3, flow rate 1.0 mL / min) retention time: t major =16.59min,t minor =20.65min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.63–7.55 (m, 4H), 7.55–7.49 (m, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.20–4.07 (m, 1H), 4.01–3.90 (m, 2H), 3.63–3.52 (m, 1H), 3.03–2.94 (m, 1H), 2.80 (s, 3H), 1.85–1.73 (m, 2H), 1.52–1.40 (m, 2H), 1.38–1.22 (m, 11H), 0.94–0.80 (m, 3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 166.5, 159.0, 142.1, 132.6, 129.4, 128.7, 128.1, 126.4, 114.8, 68.1, 61.1, 59.7, 36.5, 31.8, 29.4, 29.3, 29.3, 26.1, 22.7, 22.2, 14.1. HRMS (FTMS+c ESI) calculated for C 25 H 33 N2O2 + ([M]+H) + =379.2744, Found 379.2743; IR(film,cm -1 ):2924,2855,1601,1528,1499,1468,1388,1347,1288,1251,1198,1123,1053,751,532.MP68–71℃

[0227] Example 27 Synthesis of Chiral Imidazoline

[0228] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0229] In this embodiment, the catalyst is Y-BOX- t Bu, solvent is tetrahydrofuran, raw material D (0.2 mmol), raw material C (2.5 equiv).

[0230] Get the product:

[0231] g,>99% yield,>99%ee;[α] D 25 = +64.8 (c = 0.96, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel ODH, n-hexane (0.1% diethylamine) / isopropanol = 95 / 5, flow rate 1.0 mL / min) retention time: t major =24.41min,t minor =18.41min,20.16min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.70–7.64 (m, 1H), 7.56–7.49 (m, 2H), 7.42–7.33 (m, 1H), 4.15–4.00 (m, 2H), 3.60–3.51 (m, 2H), 2.95–2.86 (m, 2H), 2.71 (s, 6H), 1.26 (d, J = 6.6 Hz, 6H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 166.1, 131.5, 129.5, 128.4, 128.2, 60.9, 59.6, 36.3, 36.3, 22.1. HRMS (FTMS+cESI) calculated for C 16 H 23 N4 + ([M]+H) + =271.1917, Found 271.1917; IR(film,cm -1 ):3363,2963,2924,1570,1493,1450,1390,1347,1301,1052,984,814,716.

[0232] Example 28 Synthesis of Chiral Imidazoline

[0233] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0234] In this embodiment, the catalyst is Y-BOX- tBu, solvent is tetrahydrofuran, raw material D (0.2 mmol), raw material C (2.5 equiv).

[0235] Get the product:

[0236] 51.2 mg, >99% yield, >99% ee, dl / meso=91 / 9; [α] D 25 =31.1 (c=0.98, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel ADH, n-hexane (0.1% diethylamine) / isopropanol=90 / 10, flow rate 1.0 mL / min) retention time: t major =8.55min,t minor =12.43min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.51 (s, 4H), 4.20–4.00 (m, 2H), 3.53 (t, J = 9.6 Hz, 2H), 2.93 (t, J = 8.8 Hz, 2H), 2.69 (s, 6H), 1.25 (d, J = 6.6 Hz, 6H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 166.0, 132.5, 128.3, 60.9, 59.6, 36.1, 22.1. HRMS (FTMS+c ESI) calculated for C 16 H 23 N4 + ([M]+H) + =271.1917, Found 271.1918; IR(film,cm -1 ):3371,2952,1590,1516,1483,1449,1393,1347,1306,1263,1504,1154,1017,860,798.

[0237] Example 29 Synthesis of Chiral Imidazoline

[0238] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0239] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0240] Get the product:

[0241]

[0242] 55.2 mg, 70% yield, 92:8 dr; [α] D 25 = +38.6 (c = 1.04, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =11.99min,t minor =8.62min. 1 HNMR (400 MHz, deuterated chloroform) δ7.33–7.16 (m, 3H), 4.20–4.06 (m, 1H), 4.01–

[0243] 3.81(m,4H),3.62–3.48(m,1H),3.01–2.94(m,1H),2.91–2.84(m,2H),2. 80(s,3H),2.38–2.25(m,2H),2.13–1.96(m,1H),1.98–1.71(m,4H),1.72–

[0244] 1.60(m,1H),1.60–1.28(m,8H),0.89(s,3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 166.7, 142.2, 136.9, 136.9, 129.0, 128.8, 128.8, 128.2, 128.2, 125.3, 125.3, 125.1, 119.4, 65.2, 64.6, 61.0, 59.4, 49.5, 46.1, 44.1, 38.7, 36.5, 34.2, 30.7, 29.4, 29.4, 26.8, 25.8, 22.4, 22.2, 14.3. HRMS (FTMS+c ESI) calculated for C 25 H 35 N2O2 + ([M]+H) + =395.2693, Found 395.2694; IR(film,cm -1 ):2936,2870,1596,1559,1453,1381,1344,1307,1275,1221,1160,1106,1047,960,901,845.

[0245] Example 30 Synthesis of Chiral Imidazoline

[0246] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 1, except that the corresponding raw materials are replaced according to the different substituents.

[0247] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0248] Get the product:

[0249]

[0250] [α] D 25 = +6.6 (c = 0.10, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicelchiralcel ODH, n-hexane (0.1% diethylamine) / isopropanol = 97 / 3, flow rate 1.0 mL / min) retention time: t major =19.01min,24.44min,t minor =28.72min,.35.04min 1 H NMR (400 MHz, deuterated chloroform) δ 7.55–7.38 (m, 4H), 7.38–7.22 (m, 1H), 7.05–6.92 (m, 2H), 5.23–5.09 (m, 2H), 4.24–4.08 (m, 1H), 3.67–3.55 (m, 1H), 3.09–3.00 (m, 1H), 2.80 (d, J = 1.2 Hz, 3H), 2.34–2.08 (m, 10H), 1.59–1.41 (m, 1H), 1.38–1.22 (m, 4H). 13 C{ 1 H}NMR (101 MHz, deuterated chloroform)

[0251] δ166.3,166.3,161.8(d,J=245.5Hz),146.0,140.7(d,J=3.2Hz),139.5,130.4,127.8,127.8,126.9(d,J =8.0Hz),121.8,121.4,115.0(d,J=21.2Hz),71.7,60.9,59.6,59.2,59.2,45.3,39.2,36.3,22.1,22.1. 19 F{ 1 H}NMR (376 MHz, deuterated chloroform) δ–116.19 (s, 1F). HRMS (FTMS+c ESI) calculated for C 24 H 30 FN3O +([M]+H) + =396.2446, Found 396.2446; IR(film,cm -1 ):3384,2956,2860,1599,1573,1506,1450,1387,1274,1224,1032,835,589.

[0252] Example 31 Synthesis of Chiral Imidazoline

[0253] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0254] In this embodiment, the catalyst is Y-BOX- t Bu (5 mol%), the solvent is tetrahydrofuran.

[0255] Get the product:

[0256]

[0257] HPLC; HPLC (Daicel chiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol =

[0258] 99.7 / 0.3, flow rate 1.0mL / min) retention time: t major =8.54min,t minor =6.18min. 1 HNMR (400 MHz, deuterated chloroform) δ7.44–7.31 (m, 2H), 7.27–7.12 (m, 6H), 7.10–

[0259] 7.03(m,2H),4.38–4.01(m,2H),3.59–3.35(m,1H),3.29–3.00(m,2H),1.90–1.80(m,1H),1.63–1.40(m,1H),1.20(d,J=6.7Hz,3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 158.2, 138.0, 137.8, 128.6, 128.6, 128.4, 128.0, 127.2, 127.0, 55.6, 49.1, 44.6, 28.9, 23.5. HRMS (FTMS+c ESI) calcd for C 17 H 19 N2 + ([M]+H) +=251.1543, Found 251.1543; IR(film,cm -1 ):2962,1594,1570,1496,1450,1401,1260,1074,1027,799,737,699.

[0260] Example 32 Synthesis of Chiral Imidazoline

[0261] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 9, except that the corresponding raw materials are replaced according to the different substituents.

[0262] In this embodiment, the catalyst is Pr-BOX- t Bu, the solvent is toluene.

[0263] Get the product:

[0264]

[0265] oromethyl)phenyl)-4,5-dihydro-1H-imidazole(C50)(C 19 H 19 F3N2O), this compound was prepared according to the chiral imidazoline synthesis method, reaction time: 12h. Oily liquid, 34.8 mg, >99% yield, 95% ee; [α] D 25 = +35.8 (c = 0.62, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel OJH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =8.66min,t minor =12.49min. 1 H NMR (400 MHz, deuterated chloroform) δ7.80–7.55 (m, 4H), 7.28–7.17 (m, 2H), 7.01–6.79 (m, 2H), 4.57–

[0266] 4.37(m,1H),3.84(s,3H),3.48–3.34(m,1H),3.30–3.13(m,2H),2.71(s,4H). 13 C{ 1H} NMR (101 MHz, deuterated chloroform) δ 165.8, 157.9, 135.1, 131.8 (q, J = 32.3 Hz), 131.1, 128.9, 127.7, 127.3, 125.4 (q, J = 3.9 Hz), 124.0 (q, J = 273.7 Hz), 120.4, 110.5, 64.7, 58.5, 55.3, 36.8, 36.3. 19 F{ 1 H}NMR (376 MHz, deuterated chloroform) δ-62.81 (s, 3F). HRMS (FTMS+c ESI) calculated for C 19 H 20 F3N2O + ([M]+H) + =

[0267] 349.1522, Found 349.1523; IR(film,cm -1 ):2940,1601,1493,1408,1243,1167,1124,1071,1018,851.

[0268] Example 33 Synthesis of Chiral Imidazoline

[0269] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 9, except that the corresponding raw materials are replaced according to the different substituents.

[0270] In this embodiment, the catalyst is Pr-BOX- t Bu, the solvent is toluene.

[0271] Get the product:

[0272]

[0273] ee; [α] D 25 = +31.5 (c = 0.60, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicelchiralcel ODH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =5.97min,t minor =7.63min. 1H NMR (400 MHz, deuterated chloroform) δ 165.9, 137.0, 134.8, 132.1, 131.8 (q, J = 32.6 Hz), 130.8, 128.7, 128.4, 125.4 (q, J = 3.7 Hz), 123.8 (q, J = 272.4 Hz), 65.6, 58.0, 41.4, 36.0. 13 C{ 1 H}

[0274] NMR (101 MHz, deuterated chloroform) δ 165.9, 137.0, 134.8, 132.1, 131.8 (q, J = 32.6 Hz), 130.8, 128.7, 128.4, 125.4 (q, J = 3.7 Hz), 123.8 (q, J = 272.4 Hz), 65.6, 58.0, 41.4, 36.0. 19 F{ 1 H}NMR (376 MHz, deuterated chloroform) δ-62.84 (s, 3F). HRMS (FTMS+c ESI) calculated for C 18 H 17 35 ClF3N2 + ([M]+H) + =353.1027,Found 353.1028,calcd for C 18 H 17 37 ClF3N2 + ([M]+H) + =355.0997,Found 355.0994;IR(film,cm -1 ):2925,1601,1491,1408,1166,1126,1071,1016,850.

[0275] Example 34 Synthesis of Chiral Imidazoline

[0276] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 9, except that the corresponding raw materials are replaced according to the different substituents.

[0277] In this embodiment, the catalyst is Pr-BOX- t Bu, the solvent is toluene.

[0278] Get the product:

[0279]

[0280] 33.2 mg, >99% yield, 86% ee; [α]D 25 = -32.2 (c = 0.60, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel ODH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =6.08min,t minor =5.61min. 1 HNMR (400 MHz, deuterated chloroform) δ7.62–7.46 (m, 4H), 7.22–7.10 (m, 5H), 3.28 (d, J = 9.4 Hz, 1H), 3.04 (d, J = 9.4 Hz, 1H), 2.90 (d, J = 13.2 Hz, 1H), 2.69 (d, J = 13.2 Hz, 1H), 2.40 (s, 3H), 1.34 (s, 3H). (4 00MHz,Chloroform-d)δ7.62–7.46(m,4H),7.22–7.10(m,5H),3.28(d,J=9.4Hz,1H),3.04( d,J=9.4Hz,1H),2.90(d,J=13.2Hz,1H),2.69(d,J=13.2Hz,1H),2.40(s,3H),1.34(s,3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 163.9, 138.2, 135.1, 131.7 (q, J =

[0281] 32.5Hz),130.7,128.9,127.9,126.4,125.4(q,J=3.9Hz),124.0(q,J=272.7Hz),68.7,62.7,47.6,35.7,28.5. 19 F{ 1 H}NMR (376 MHz, deuterated chloroform) δ–62.81 (s, 3F). HRMS (FTMS+c ESI) calculated for C 19 H 20 F3N2 + ([M]+H) + =333.1573,Found

[0282] 333.1573; IR(film,cm -1 ):3024,2925,1602,1408,1168,1127,1069,1018,851,701.

[0283] Example 35 Synthesis of Chiral Imidazoline

[0284] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 9, except that the corresponding raw materials are replaced according to the different substituents.

[0285] In this embodiment, the catalyst is Y(HMDS)3, the solvent is toluene, the raw material D (0.1 mmol) and the raw material C (0.2 mmol).

[0286] Get the product:

[0287] 12h. White solid 34.0 mg, 99% yield, >19:1dr; [α] D 25 = +65.5 (c = 0.60, in CH2Cl2), dissolved in n-hexane for HPLC; HPLC (Daicel chiralcel ODH, n-hexane (0.1% diethylamine) / isopropanol = 90 / 10, flow rate 1.0 mL / min) retention time: t major =5.91min,t minor =6.77min. 1 H NMR (400 MHz, deuterated chloroform) δ 7.44–7.40 (m, 1H), 7.40–7.35 (m, 1H), 7.34–7.29 (m, 1H), 7.27–7.18 (m, 2H), 7.05–6.96 (m, 1H), 3.21–3.06 (m, 4H), 3.04–2.91 (m, 2H), 2.66–2.45 (m, 6H), 2.38–2.23 (m, 2H), 1.07 (d, J = 6.7 Hz, 3H). 13 C{ 1 H} NMR (101 MHz, deuterated chloroform) δ 162.9, 152.4, 147.9, 147.3, 144.9, 130.4, 128.3, 127.3, 127.1, 127.0, 126.9, 125.4, 117.4, 107.8, 61.7, 58.8, 41.6, 38.7, 34.7, 31.0, 30.8, 21.9. HRMS (FTMS+c ESI) calculated for C 23 H 24 N3 + ([M]+H) + =342.1965, Found342.1965; IR(film,cm -1):3026,2939,2911,2226,1612,1585,1493,1449,1391,1031,1273,1110,996,750.MP122–124℃

[0288] Example 36 Synthesis of Chiral Imidazoline

[0289] The preparation method and conditions of the chiral imidazoline in this example are the same as those in Example 8, except that the corresponding raw materials are replaced according to the different substituents.

[0290] In this embodiment, the catalyst is Y-BOX- t Bu, the solvent is tetrahydrofuran.

[0291] Get the product:

[0292] HPLC (Daicel chiralcel IG, n-hexane (0.1% diethylamine) / isopropanol = 95 / 5, flow rate 1.0 mL / min) retention time: t major =15.94min,t minor =18.45min. 1 H NMR(400MHz,Chloroform-d)δ7.41–7.22(m,13H),7.08–6.95(m,1H),4.06–3.88(m,1H),3.43–3.30(m,1H),2.84–2.75(m,1H),2.47(s,3H),1.15(d ,J=6.6Hz,3H).7.41–7.22(m,13H),7.08–6.95(m,1H),4.06–3.88(m,1H), 3.43–3.30(m,1H),2.84–2.75(m,1H),2.47(s,3H),1.15(d,J=6.6Hz,3H). 13 C{ 1 H}NMR(101MHz,Chloroform-d)δ165.2(d,J=2.0Hz),137.6(d,J=17.9Hz),137.3,137.2,137.1,136.9,136.9,134.3(d,J=10.4Hz),134. 1(d,J=10.1Hz),133.6,132.1,129.1,129.0(d,J=5.2Hz),128.7,128.6,128.5,128.4(d,J=7.0Hz),60.1,59.8,34.9(d,J=3.7Hz),21.8. 31 P{ 1H}NMR(162MHz,Chloroform-d)δ-11.18.HRMS(FTMS+c ESI)calcd for C 23 H 23 N2P + ([M]+H) + =359.1672, Found 359.1668; IR(film,cm- 1 ):3050,3024,2961,2919,1609,1582,1480,1435,1389,1343,1305,1272,1184,1117,1031,745,545,504.

[0293] The technical solution of the present invention is further illustrated by experiments below.

[0294] Experimental Example 1 Chiral Imidazoline Compounds I. Experimental Method

[0295] Cell characteristics:

[0296] Hepatocellular carcinoma cell lines HCCLM3 (obtained from Procell) and MHCC97 (obtained from Shanghai Zhongqiao Xinzhou Biotechnology Co., Ltd.) were cultured in Dulbecco's modified Eagle's medium (DMEM; Hyclone, Utah) supplemented with 10% (v / v) FBS (Gibco, New York) and 1% (v / v) penicillin / streptomycin (Beyotime, Shanghai). All cells were cultured in a 37°C, 5% CO2 incubator.

[0297] Cell test method:

[0298] Cells were cultured in 96-well plates at a density of 2 x 10⁴ cells per well. After overnight culture, cells were treated with 1% DMSO (negative control) and test compounds at various concentrations for 24 hours. FBS-containing DMEM supplemented with 10% (v / v) CCK-8 (Selleck, Houston) was not added to each well and incubated at 37°C for 1 hour. Absorbance was measured at 450 nm to calculate cell viability (%).

[0299] The test compounds were the compounds prepared in Example 31 and Example 32:

[0300] (R is n Hex or n OctO).

[0301] 2. Experimental Results

[0302] The half-inhibitory concentration test is as follows:

[0303]

[0304] The above experimental results show that the chiral imidazoline compound prepared by the present invention has a good inhibitory effect on liver cancer and lung cancer cells. Therefore, the chiral imidazoline compound of the present invention has the potential to be used for the preparation of anti-tumor drugs and has a good application prospect.

[0305] As can be seen from the above embodiments and experimental examples, the present invention provides a chiral metal complex that, when used as a synthesis catalyst, can achieve high yield and high stereoselectivity in the synthesis of chiral imidazoline compounds. Thus, the present invention provides a novel method for preparing chiral imidazoline compounds, which has the advantages of high efficiency, mild conditions, high atom economy (100%), and wide substrate compatibility, and has promising application prospects.

Claims

1. The use of a compound represented by formula I or formula II as a catalyst for the synthesis of chiral imidazoline derivatives, characterized in that: Formula I Formula II wherein M is selected from Y; R 1 Selected from C1-C 10 alkyl; R 2 Selected from hydrogen, C1-C 10 alkyl; R 3 Selected from trimethylsilane; The preparation method of the chiral imidazoline derivative comprises the following steps: Reacting raw material C with raw material D to obtain a compound represented by formula III, wherein the reaction uses a compound represented by formula I or formula II as a catalyst; in, R 1’ Selected from substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkenyl, wherein the substituent is selected from C6-C 10 Aryl, halogen, cyano, C1-C 10 alkoxy; R 2’ Selected from hydrogen, substituted or unsubstituted C1-C 10 Alkyl, wherein the substituent is selected from halogen, cyano, C1-C 10 alkoxy; R 3’ selected from hydrogen; R 4 Selected from substituted or unsubstituted C6-C 10 Aryl, wherein the substituent is selected from C1-C 10 Alkyl, C1-C 10 Haloalkyl, halogen, cyano, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C1-C 10 Amine, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C6-C 10 Cycloalkyl, OTBS, among which C6-C 10 Aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C6-C 10 The cycloalkyl group may be further substituted with a substituent selected from C1-C 10 Alkyl, halogen, cyano.

2. The use according to claim 1, characterized in that: The M is selected from Y; The R 1 Selected from C1-C4 alkyl; The R 2 Selected from hydrogen, C1-C4 alkyl.

3. The use according to claim 1, characterized in that: The M is selected from Y; The R 1 selected from tert-butyl; The R 2 Selected from hydrogen.

4. The use according to claim 1, characterized in that: The compound represented by formula I is one of the following compounds: 。 5. The use according to claim 1, characterized in that The compound represented by formula III is one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 6. A method for preparing a chiral imidazoline derivative, characterized in that: The steps include: Reacting raw material C with raw material D to obtain a compound represented by formula III, wherein the reaction uses a compound represented by formula I or formula II as a catalyst; Formula I Formula II in, M is selected from Pr; R 1 Selected from C1-C 10 alkyl; R 2 Selected from hydrogen, C1-C 10 alkyl; R 3 Selected from trimethylsilane; R 1’ Selected from substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C1-C 10 Alkenyl, wherein the substituent is selected from C6-C 10 Aryl, halogen, cyano, C1-C 10 alkoxy; R 2’ Selected from hydrogen, substituted or unsubstituted C1-C 10 Alkyl, wherein the substituent is selected from halogen, cyano, C1-C 10 alkoxy; R 3’ Selected from substituted or unsubstituted C6-C 10 Aryl, wherein the substituent is selected from C1-C 10 Alkyl, halogen, cyano, C1-C 10 alkoxy; R 4 Selected from substituted or unsubstituted C6-C 10 Aryl, wherein the substituent is selected from C1-C 10 Alkyl, C1-C 10 Haloalkyl, halogen, cyano, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C1-C 10 Amine, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C6-C 10 Cycloalkyl, OTBS, among which C6-C 10 Aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C6-C 10 The cycloalkyl group may be further substituted with a substituent selected from C1-C 10 Alkyl, halogen, cyano.

7. The preparation method according to claim 6, characterized in that: The amount of the catalyst is 2.5-5 mol%; and / or, the solvent of the reaction is selected from tetrahydrofuran or toluene; And / or, the reaction is carried out under the protection of an inert gas; And / or, the reaction temperature is 25 ; and / or, R 1’ is selected from substituted or unsubstituted methyl, C3 alkenyl, wherein the substituent is selected from phenyl; and / or, R 2’ is selected from hydrogen, methyl; and / or, R 3’ Selected from substituted or unsubstituted C6-C 10 Aryl, wherein the substituent is selected from methyl, methoxy, F, Cl, Br; and / or, R 4 Selected from substituted or unsubstituted C6-C 10 Aryl, wherein the substituent is selected from C1-C6 alkyl, trifluoromethyl, halogen, cyano, C1-C8 alkoxy, methylthio, C2-C5 amino, phenyl, 5-membered heteroaryl, 5- to 9-membered heterocycloalkyl, C6 cycloalkyl, OTBS, wherein the 5- to 9-membered heterocycloalkyl and C6 cycloalkyl may be further substituted, and the substituent is selected from C1-C4 alkyl, F.

8. The preparation method according to claim 6, characterized in that The compound represented by formula III is one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 ； Wherein, Ar is 4-CF3C6H4.

9. The preparation method according to claim 6, characterized in that: The compound shown in formula I is the following compound: 。

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