A method for preparing a chiral α,α,α,4(5H)-oxazolone

Abstract

The present invention discloses a method for preparing a chiral α - tetrasubstituted oxazol - 4(5H) - one. Under a protective atmosphere, a bromide is reacted with an oxazol - 4(5H) - one derivative in the presence of a palladium catalyst, a chiral phosphine ligand, a base, and a solvent to obtain the chiral α - tetrasubstituted oxazol - 4(5H) - one. By selecting the reaction substrates and under the action of a specific chiral ligand and a palladium catalyst, the present invention can synthesize a chiral α - tetrasubstituted oxazol - 4(5H) - one with an ee value of up to 93%, and the reaction has a high yield. The above - mentioned synthesis method is easy to operate, does not require the addition of extra additives, the reaction is simple and efficient, and the substrate has a wide range of applicability and strong functional group compatibility, and can be used to prepare different types of chiral α - tetrasubstituted oxazol - 4(5H) - ones.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly to a method for preparing chiral α - tetrasubstituted oxazol - 4(5H) - one. Background Art

[0002] α - Aryl - α - hydroxy carboxylic acids are structures widely present in natural products and pharmacologically active molecules [(a) Chem. Soc. Rev., 2009, 38, 2093. (b) Org. Biomol. Chem., 2007, 5, 406]. At present, the stereoselective synthesis of such structures mainly focuses on the nucleophilic addition reactions of carbonyl compounds, such as α - cyanation of ketones [J. Am. Chem. Soc., 2001, 123, 6195], aldol condensation reactions of α - keto esters and carbonyl compounds [J. Am. Chem. Soc., 2008, 130, 5654], nucleophilic addition of Grignard reagents to carbonyl compounds controlled by chiral auxiliary reagents [Tetrahedron Lett., 2006, 47, 7067], reductive carboxylation of ketones [Chem. Commun., 2009, 2009, 7297], etc. However, so far, no strategy for directly realizing the asymmetric α - arylation reaction of α - hydroxy carboxylic acid derivatives has been reported.

[0003] Oxazol - 4(5H) - one derivatives can be used as nucleophiles in such reaction strategies, and 5,5 - disubstituted oxazol - 4 - one compounds can be obtained through asymmetric α - arylation reactions. Such compounds can be converted into optically active α - hydroxy carboxylic acid derivatives in one step under mild conditions. Previously, the α - position modification of such substrates mainly focused on reactions such as alkylation, allylation, benzylation, etc. [(a) Adv. Syn. Catal., 2014, 356, 3777. (b) J. Org. Chem., 2016, 81, 11916. (c) Adv. Syn. Catal., 2013, 355, 1505. (d) Angew. Chem. Int. Ed., 2012, 51, 6480. (e) Chem. Sci., 2015, 6, 4912]. However, so far, no strategy for the asymmetric α - arylation reaction of such substrates has been reported. Summary of the Invention

[0004] The present invention provides a method for preparing chiral α - tetrasubstituted oxazol - 4(5H) - one. By selecting reaction substrates and under the action of specific chiral ligands and palladium catalysts, chiral α - tetrasubstituted oxazol - 4(5H) - one with an ee value of up to 93% can be synthesized, and the reaction yield is high.

[0005] To solve the above technical problems, the present invention provides the following technical solutions:

[0006] The present invention provides a method for preparing a chiral α - tetrasubstituted oxazol - 4(5H) - one. Under a protective atmosphere, a compound represented by formula (I) and a compound represented by formula (II) are reacted in the presence of a palladium catalyst, a chiral phosphine ligand, a base, and a solvent to obtain the chiral α - tetrasubstituted oxazol - 4(5H) - one represented by formula (III);

[0007] The structures of the above - mentioned formula (I) to formula (III) are as follows:

[0008]

[0009] Among them, A is selected from one of a substituted or unsubstituted phenyl group, a substituted or unsubstituted thiophenyl group, a substituted or unsubstituted naphthyl group, and a substituted or unsubstituted indolyl group;

[0010] R 1 is selected from one of a substituted or unsubstituted C 1-6 alkyl group and a substituted or unsubstituted benzyl group;

[0011] Ar 1 is a substituted or unsubstituted phenyl group;

[0012] Substituted or unsubstituted means that the group is substituted or unsubstituted by one or more substituents, and the substituents are selected from one of a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a trifluoromethyl group, a ketone carbonyl group, and an aryl group.

[0013] The chiral phosphine ligand is selected from one of the following structures:

[0014]

[0015] Furthermore, under a protective atmosphere, the palladium catalyst and the chiral phosphine ligand are first mixed in a solvent to form a catalyst [Pd] / L * solution, and then the compound represented by formula (I), the compound represented by formula (II), and the base are added to the catalyst [Pd] / L * solution for reaction to obtain the chiral α - tetrasubstituted oxazol - 4(5H) - one; the protective atmosphere is composed of nitrogen and / or argon.

[0016] Furthermore, A is more preferably one of a phenyl group, a phenyl group substituted by a halogen, a phenyl group substituted by a C 1-6 alkyl group, a thiophenyl group, a naphthyl group, and an indolyl group substituted by a ketone carbonyl group, and R 1 is more preferably a C 1-6 alkyl group.

[0017] Further, the chiral phosphine ligand is more preferably the compound shown in formula X1 and / or the compound shown in formula X2.

[0018] Further, the palladium catalyst is selected from one or more of palladium acetate, palladium trifluoroacetate, palladium dichloro(dicyanoethane), palladium chloride, and palladium adamantane carboxylate; more preferably palladium acetate.

[0019] Further, the base is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, and potassium phosphate; more preferably rubidium carbonate.

[0020] Further, the solvent is selected from one or more of dichloromethane, 2-methyltetrahydrofuran, tetrahydrofuran, benzotrifluoride, toluene, mesitylene, chlorobenzene, ethyl acetate, n-hexane, methyl tert-butyl ether, anisole, isopropyl ether, n-butyl ether, and diethyl ether; more preferably mesitylene.

[0021] In some preferred embodiments of the present invention, the palladium catalyst is palladium acetate, the base is rubidium carbonate, and the solvent is mesitylene.

[0022] Further, the molar ratio of the compound shown in formula (I) to the compound shown in formula (II), palladium catalyst, chiral phosphine ligand, and base is 1:1 - 2:0.025 - 0.1:0.03 - 0.2:1 - 2.5.

[0023] Further, the reaction temperature of the reaction is 20 - 100 °C, more preferably 20 - 50 °C, and the reaction time is 6 - 60 h.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] By selecting the reaction substrates and under the action of specific chiral ligands and palladium catalysts, the present invention can synthesize chiral α-tetrasubstituted oxazol-4(5H)-ones with an ee value of up to 93%, and the reaction yield is high; the above synthesis method is easy to operate, does not require the addition of extra additives, the reaction is simple and efficient, and the substrate scope is wide and the functional group compatibility is strong. It can be used to prepare different types of chiral α-tetrasubstituted oxazol-4(5H)-ones, and these chiral α-tetrasubstituted oxazol-4(5H)-ones can be directly converted into optically active α-hydroxy carboxylic acid derivatives in one step. Description of the Drawings

[0026] Figure 1 HPLC chart of the product 3a prepared in Example 2;

[0027] Figure 2 HPLC chart of the product 3b prepared in Example 3;

[0028] Figure 3 HPLC chart of the product 3c prepared in Example 4;

[0029] Figure 4 HPLC chromatogram of product 3d prepared in Example 5;

[0030] Figure 5 HPLC chromatogram of product 3e prepared in Example 6;

[0031] Figure 6 HPLC chromatogram of product 3f prepared in Example 7;

[0032] Figure 7 HPLC chromatogram of product 3g prepared in Example 8;

[0033] Figure 8 HPLC chromatogram of product 3h prepared in Example 9;

[0034] Figure 9 HPLC chromatogram of product 3i prepared in Example 10;

[0035] Figure 10 HPLC chromatogram of product 3j prepared in Example 11. Detailed implementation manners

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this invention belongs. The terms used in the description of this invention herein are for the purpose of describing specific embodiments only and are not intended to limit the invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items. The "including" or "comprising" as used in this invention means that in addition to the components described, it may also include or comprise other components. The "including" or "comprising" as used in this invention may also be replaced by the closed "consisting of" or "composed of".

[0037] The present invention will be further described below in conjunction with specific embodiments, so that those skilled in the art can better understand the present invention and be able to implement it, but the examples given are not intended to limit the present invention.

[0038] Example 1

[0039] This example relates to the preparation of chiral phosphine ligands X1 to X7, wherein X1 to X6 are prepared with reference to Chinese patents with patent application numbers 201910831293.0, 201510107308.0, and 201310671902.3 and the literature [(a) Angew. Chem. Int. Ed. 2020, 59, 4421. (b) Chem. Sci., 2020, 11, 6283], and X7 is directly purchased. The structures of chiral phosphine ligands X1 to X7 are shown as follows:

[0040]

[0041] The reaction process for preparing the above chiral phosphine ligand X3 is as follows:

[0042]

[0043] The specific preparation process is as follows:

[0044] Under nitrogen protection, a magnetic stir bar, magnesium chips (72 mg, 3.0 mmol, 3.0 equiv.), and dry tetrahydrofuran (5 mL) were added to a dried 100 mL three-necked flask. Then, the corresponding aryl bromide (2.0 mmol, 2.0 equiv.) and initiator 1,2-dibromoethane were added dropwise to the system at 65 °C. After the Grignard reagent was completely initiated, the system was continuously stirred at 65 °C for two hours. Then, a magnetic stir bar, the compound shown in Formula 4 (1.0 mmol, 1.0 equiv.), and dry tetrahydrofuran (5 mL) were added to another dried 100 mL three-necked flask. The Grignard reagent was added dropwise to the system at -40 °C, and the system was slowly warmed to room temperature and continuously stirred for 8 hours. After the reaction was completed as detected by TLC, the reaction was quenched by adding saturated ammonium chloride solution (10 mL), and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the target compound shown in Formula 5 was obtained by column chromatography.

[0045] Under nitrogen protection, a magnetic stir bar, the compound shown in Formula 5 (0.5 mmol, 1.0 equiv.), and dry tetrahydrofuran (5 mL) were added to a dried 100 mL three-necked flask. n-Butyllithium (0.3 mL, 0.75 mmol, 1.5 equiv., 2.5 M n-hexane solution) was added dropwise to the system at -78 °C, and the system was continuously stirred at -78 °C for 1 hour. Then, iodomethane (142 mg, 1.0 mmol, 2.0 equiv.) was added dropwise to the reaction system, and the reaction solution was continuously stirred at 0 °C for 15 minutes. After the reaction was completed as detected by TLC, the reaction was quenched by adding saturated ammonium chloride solution (10 mL), and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the target chiral phosphine ligand X3 (which has been disclosed in the literature (a)) was obtained by column chromatography.

[0046] The chiral phosphine ligands X1, X2, X4, and X5 can be prepared by changing the above aryl bromide.

[0047] The test characterization data of the prepared chiral phosphine ligand X1 are as follows:

[0048] 11H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 4.0 Hz, 1H), 7.52 - 7.37 (m, 11H), 7.26 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 2.71 (s, 3H), 2.03 - 2.00 (m, 3H), 1.91 - 1.86 (m, 6H), 1.75 - 1.52 (m, 21H), 1.15 (s, 9H).

[0049] 13 13C NMR (100 MHz, CDCl3) δ 149.9, 145.9, 140.8, 140.5, 140.3, 140.0, 133.7, 132.9, 131.5, 130.3, 128.2, 127.6, 126.7, 125.8, 125.7, 125.3, 124.2, 124.0, 119.6, 110.7, 77.2, 71.7, 71.3, 58.9, 56.1, 55.9, 41.9, 41.8, 41.7, 37.9, 37.6, 36.8, 36.8, 31.3, 28.8, 28.7, 24.3.

[0050] 31 31P NMR (162 MHz, CDCl3) δ 15.64.

[0051] HRMS (ESI): m / z: [M + H] + Calcd for C 60 H 69 NO3PS: 914.4736, found 914.4736.

[0052] [α]D 20 = 42.577 (c = 0.5, CHCl3).

[0053] The melting point is 121.4 - 122.0 °C.

[0054] The test characterization data of the prepared chiral phosphine ligand X2 are as follows:

[0055] 11H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 4.0 Hz, 1H), 7.51 (s, 1H), 7.37 (s, 2H), 7.23 (s, 1H), 6.96 (d, J = 12.0 Hz, 1H), 6.64 (d, J = 4.0 Hz, 4H), 6.47 - 6.46 (m, 2H), 4.02 (s, 3H), 3.91 (s, 3H), 3.82 (s, 12H), 2.70 (s, 3H), 2.02 - 1.99 (m, 3H), 1.90 - 1.86 (m, 6H), 1.68 - 1.59 (m, 10H), 1.50 - 1.36 (m, 11H), 1.09 (s, 9H).

[0056] 13 13C NMR (100 MHz, CDCl3) δ 161.0, 150.0, 146.0, 143.5, 141.3, 141.2, 141.0, 130.4, 124.7, 124.5, 124.4, 119.5, 110.7, 105.5, 99.2, 71.4, 71.0, 58.9, 56.2, 56.0, 55.4, 42.0, 41.8, 41.7, 37.9, 37.7, 36.9, 36.9, 36.8, 36.6, 31.2, 28.8, 28.8, 28.7, 28.7, 24.3.

[0057] 31 31P NMR (162 MHz, CDCl3) δ 15.94.

[0058] HRMS (ESI): m / z: [M + H] + Calcd for C 56 H 73 NO7PS: 934.4845, found 934.4846.

[0059] [α]D 20 = 32.298 (c = 0.5, CHCl3).

[0060] The melting point is 145.6 - 145.8 °C.

[0061] The test characterization data of the prepared chiral phosphine ligand X4 are as follows:

[0062] 11H NMR (400 MHz, CDCl3) δ 7.66 - 7.63 (m, 1H), 7.58 - 7.56 (m, 1H), 7.53 - 7.51 (m, 4H), 7.44 - 7.40 (m, 6H), 7.36 - 7.32 (m, 2H), 7.27 - 7.26 (m, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.02 (s, 3H), 3.93 (s, 3H), 2.71 (s, 3H), 2.04 - 2.00 (m, 3H), 1.91 - 1.88 (m, 6H), 1.69 - 1.65 (m, 10H), 1.59 - 1.35 (m, 11H), 1.10 (s, 9H).

[0063] 13 13C NMR (100 MHz, CDCl3) δ 149.9, 146.0, 141.5, 141.4, 141.3, 141.2, 141.0, 130.0, 128.8, 127.2, 127.2, 124.8, 119.4, 71.3, 58.9, 56.2, 55.9, 42.0, 41.8, 41.8, 37.9, 37.6, 37.0, 36.8, 31.0, 28.8, 28.8, 28.7, 24.4, 22.8.

[0064] 31 31P NMR (162 MHz, CDCl3) δ 16.11.

[0065] HRMS (ESI): m / z: [M + H] + Calcd for C 52 H 65 NO3PS: 814.4423, found 814.4423.

[0066] [α]D 20 = 43.457 (c = 0.5, CHCl3).

[0067] The melting point is 118.0 - 118.9 °C.

[0068] The test characterization data of the prepared chiral phosphine ligand X5 are as follows:

[0069] 11H NMR (400 MHz, CDCl3) δ 7.55 - 7.54 (m, 1H), 7.21 (s, 1H), 6.78 - 6.75 (m, 1H), 6.71 (s, 2H), 6.60 (s, 1H), 4.19 - 4.10 (m, 4H), 4.00 (s, 3H), 3.91 (s, 3H), 2.60 (s, 3H), 2.00 - 1.97 (m, 3H), 1.88 - 1.84 (m, 6H), 1.69 - 1.66 (m, 10H), 1.57 - 1.46 (m, 11H), 1.09 (s, 9H).

[0070] 13 13C NMR (100 MHz, CDCl3) δ 149.8, 145.8, 142.6, 142.4, 141.9, 141.6, 133.4, 125.1, 124.1, 121.0, 119.4, 116.2, 110.8, 70.6, 70.2, 64.4, 64.3, 58.7, 56.1, 56.0, 41.9, 41.8, 41.8, 41.7, 37.8, 37.6, 36.9, 36.9, 36.6, 30.8, 28.9, 28.8, 28.8, 28.7, 24.5.

[0071] 31 31P NMR (162 MHz, CDCl3) δ 15.91.

[0072] HRMS (ESI): m / z: [M + H] + Calcd for C 42 H 59 NO5PS: 720.3852, found 720.3851.

[0073] [α]D 20 = 64.676 (c = 0.5, CHCl3).

[0074] The melting point is 111.3 - 111.4 °C.

[0075] Chiral phosphine ligand X6: Prepared according to the method described in reference (b).

[0076] Example 2

[0077] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 4(5H) - one of formula 3a, and the reaction equation is as follows:

[0078]

[0079] The specific preparation process is as follows:

[0080] In a glove box filled with N2, Pd(OAc)2 (6.6 mg, 0.03 mmol, 10 mol%), chiral phosphine ligand X1 (33.0 mg, 0.036 mmol, 12 mol%) and dry mesitylene (3 mL) were added into a 10 mL Schlenk tube and pre-stirred at room temperature for 1 h. Then, the compound shown in Formula 1a (47.1 mg, 0.3 mmol, 1.0 equiv), the compound shown in Formula 2a (91.4 mg, 0.45 mmol, 1.5 equiv) and Rb2CO3 (138.6 mg, 0.6 mmol, 2.0 equiv) were added into the sealed tube in the glove box. Under the protection of N2, the reaction system was stirred in an oil bath at 40 °C for 48 h, and TLC was used to determine that the raw materials had completely reacted. The solvent was rotary evaporated, and the crude product was purified by flash column chromatography on silica gel (using PE / EA as the eluent) to obtain the target product shown in Formula 3a, with a yield of 76% and an ee value of 93%.

[0081] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0082] 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.0 Hz, 2H), 7.72 (t, J = 8.0 Hz, 1H), 7.59 - 7.55 (m, 4H), 7.40 - 7.34 (m, 3H), 1.95 (s, 3H).

[0083] 13 C NMR (100 MHz, CDCl3) δ 191.9, 185.1, 137.0, 135.3, 130.1, 129.0, 128.7, 128.6, 125.8, 124.5, 87.4, 24.9.

[0084] HRMS (EI): m / z: [M]+ Calcd for C 16 H 13 NO2: 251.0946, found 251.0941.

[0085] [α]D 20 = -105.316 (c = 0.5, CHCl3).

[0086] HPLC test conditions: Daicel Chiralpak ODH chromatographic column; n-hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 7.65 min (main peak), tr = 8.51 min (sub-peak).

[0087] Example 3

[0088] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 4(5H) - one shown in Formula 3b, and the reaction equation is as follows:

[0089]

[0090] The specific preparation process is as follows:

[0091] In a glove box filled with N2, Pd(OAc)2 (6.6 mg, 0.03 mmol, 10 mol%), chiral phosphine ligand X1 (33.0 mg, 0.036 mmol, 12 mol%) and dry mesitylene (3 mL) were added into a 10 mL Schlenk tube and pre - stirred at room temperature for 1 h. Then, the compound shown in Formula 1b (69.9 mg, 0.3 mmol, 1.0 equiv), the compound shown in Formula 2a (91.4 mg, 0.45 mmol, 1.5 equiv) and Rb2CO3 (138.6 mg, 0.6 mmol, 2.0 equiv) were added into the sealed tube in the glove box. Under N2 protection, the reaction system was stirred in an oil bath at 40 °C for 48 h, and TLC was used to determine that the raw materials had completely reacted. The solvent was evaporated to dryness, and the crude product was purified by flash column chromatography on silica gel (using PE / EA as the eluent) to obtain the target product shown in Formula 3b, with a yield of 86% and an ee value of 91%.

[0092] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0093] 1 H NMR(400 MHz, CDCl3) δ 8.36 (d, J = 8.0 Hz, 2H), 7.76 - 7.56 (m, 9H), 7.44 (t, J = 8.0 Hz, 2H), 7.37 - 7.33 (m, 1H), 2.36 - 2.21 (m, 2H), 1.46 - 1.38 (m, 2H), 0.95 (t, J = 8.0 Hz, 3H).

[0094] 13 C NMR(100 MHz, CDCl3) δ 191.6, 185.4, 141.4, 140.3, 135.4, 135.3, 130.1, 129.0, 128.8, 127.5, 127.4, 127.1, 125.8, 125.0, 90.5, 41.0, 17.0, 13.8.

[0095] HRMS(EI): m / z: [M]+ Calcd for C 24 H 21 NO2: 355.1572, found 355.1568.

[0096] [α]D20 = -155.368 (c = 0.5, CHCl3).

[0097] The melting point is 142.0 - 142.9 °C.

[0098] HPLC test conditions: Daicel Chiralpak OZ-3 chromatographic column; n-hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 8.00 min (minor peak), tr = 8.88 min (major peak).

[0099] Example 4

[0100] This example provides the preparation of a chiral α-tetrasubstituted oxazol-4(5H)-one shown in Formula 3c, and the reaction equation is as follows:

[0101]

[0102] The specific preparation process is as follows:

[0103] In a glove box filled with N2, Pd(OAc)2 (6.6 mg, 0.03 mmol, 10 mol%), chiral phosphine ligand X1 (33.0 mg, 0.036 mmol, 12 mol%) and dry mesitylene (3 mL) were added to a 10 mL Schlenk tube and pre-stirred at room temperature for 1 h. Then, the compound shown in Formula 1c (51.3 mg, 0.3 mmol, 1.0 equiv), the compound shown in Formula 2a (91.4 mg, 0.45 mmol, 1.5 equiv) and Rb2CO3 (138.6 mg, 0.6 mmol, 2.0 equiv) were added to the sealed tube in the glove box. Under N2 protection, the reaction system was stirred and reacted in an oil bath at 40 °C for 48 h, and TLC was used to determine that the raw materials had completely reacted. The solvent was evaporated to dryness, and the crude product was purified by flash column chromatography on silica gel (using PE / EA as the eluent) to obtain the target product shown in Formula 3c, with a yield of 82% and an ee value of 89%.

[0104] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0105] 1 1H NMR (400 MHz, CDCl3) δ 8.34 - 8.31 (m, 2H), 7.74 - 7.70 (m, 1H), 7.59 - 7.55 (m, 2H), 7.48 - 7.46 (m, 2H), 7.18 (d, J = 8.0 Hz, 2H), 2.33 (s, 3H), 2.27 - 2.18 (m, 2H), 1.39 - 1.33 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H).

[0106] 13 13C NMR (100 MHz, CDCl3) δ 191.8, 185.3, 138.3, 135.2, 133.5, 130.1, 129.3, 129.0, 125.9, 124.5, 90.6, 41.0, 21.0, 16.9, 13.8.

[0107] HRMS (EI): m / z: [M]+ Calcd for C 19 H 19 NO2: 293.1416, found 293.1410.

[0108] [α]D 20 = -165.229 (c = 0.5, CHCl3).

[0109] HPLC test conditions: Daicel Chiralpak OJH chromatographic column; n-hexane / isopropanol = 92 / 8, 0.6 mL / min, 254 nm; tr = 13.28 min (main peak), tr = 16.23 min (secondary peak).

[0110] Example 5

[0111] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 4(5H)-one shown in Formula 3d, and the reaction equation is as follows:

[0112]

[0113] In a glove box filled with N2, Pd(OAc)2 (6.6 mg, 0.03 mmol, 10 mol%), chiral phosphine ligand X1 (33.0 mg, 0.036 mmol, 12 mol%) and dry mesitylene (3 mL) were added into a 10 mL Schlenk tube and pre - stirred at room temperature for 1 h. Then, the compound shown in Formula 1d (51.3 mg, 0.3 mmol, 1.0 equiv), the compound shown in Formula 2a (91.4 mg, 0.45 mmol, 1.5 equiv) and Rb2CO3 (138.6 mg, 0.6 mmol, 2.0 equiv) were added into the sealed tube in the glove box. Under N2 protection, the reaction system was stirred in an oil bath at 40 °C for 48 h, and TLC was used to determine that the raw materials had completely reacted. The solvent was rotary - evaporated, and the crude product was purified by flash column chromatography on silica gel (using PE / EA as the eluent) to obtain the target product shown in Formula 3d, with a yield of 85% and an ee value of 92%.

[0114] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0115] 11H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.0 Hz, 2H), 7.85 (s, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.61 - 7.56 (m, 6H), 7.48 - 7.43 (m, 3H), 7.38 - 7.35 (m, 1H), 2.34 - 2.27 (m, 2H), 1.44 - 1.38 (m, 2H), 0.95 (t, J = 8.0 Hz, 3H).

[0116] 13 13C NMR (100 MHz, CDCl3) δ 191.5, 185.3, 141.8, 140.6, 137.0, 135.3, 130.1, 129.0 (overlap), 128.8, 127.5, 127.3, 127.2, 125.7, 123.4, 123.3, 90.5, 41.3, 16.9, 13.7.

[0117] HRMS (EI): m / z: [M]+ Calcd for C 24 H 21 NO2: 355.1572, found 355.1566.

[0118] [α]D 20 = -125.222 (c = 0.5, CHCl3).

[0119] The melting point is 122.4 - 122.9 °C.

[0120] HPLC test conditions: Daicel Chiralpak OZ - 3 chromatographic column; n - hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 7.08 min (minor peak), tr = 9.08 min (major peak).

[0121] Example 6

[0122] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 4(5H) - one shown in Formula 3e, and the reaction equation is as follows:

[0123]

[0124] In a glove box filled with N2, Pd(OAc)2 (6.6 mg, 0.03 mmol, 10 mol%), chiral phosphine ligand X1 (33.0 mg, 0.036 mmol, 12 mol%) and dry mesitylene (3 mL) were added into a 10 mL Schlenk tube and pre-stirred at room temperature for 1 h. Then, the compound shown in Formula 1e (56.1 mg, 0.3 mmol, 1.0 equiv), the compound shown in Formula 2a (91.4 mg, 0.45 mmol, 1.5 equiv) and Rb2CO3 (138.6 mg, 0.6 mmol, 2.0 equiv) were added into the sealed tube in the glove box. Under N2 protection, the reaction system was stirred in an oil bath at 40 °C for 48 h, and TLC was used to determine that the raw materials had completely reacted. The solvent was evaporated to dryness, and the crude product was purified by flash column chromatography on silica gel (using PE / EA as the eluent) to obtain the target product shown in Formula 3e with a yield of 81% and an ee value of 91%.

[0125] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0126] 1 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.0 Hz, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.57 - 7.49 (m, 4H), 6.89 (d, J = 8.0 Hz, 2H), 3.77 (s, 3H), 2.23 - 2.16 (m, 2H), 1.38 - 1.32 (m, 2H), 0.90 (t, J = 8.0 Hz, 3H).

[0127] 13 13C NMR (100 MHz, CDCl3) δ 191.9, 185.2, 159.6, 135.2, 130.0, 128.9, 128.4, 125.9, 125.8, 114.0 (overlap), 90.4, 55.2, 40.8, 16.8, 13.7.

[0128] HRMS (EI): m / z: [M]+ Calcd for C 19 H 19 NO3: 309.1365, found 309.1362. [α]D20 = -149.555 (c = 0.5, CHCl3).

[0129] HPLC test conditions: Daicel Chiralpak ODH chromatographic column; n-hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 7.54 min (main peak), tr = 8.04 min (secondary peak).

[0130] Example 7

[0131] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 4(5H) - one shown in Formula 3f, and the reaction equation is as follows:

[0132]

[0133] In a glove box filled with N2, Pd(OAc)2 (6.6 mg, 0.03 mmol, 10 mol%), chiral phosphine ligand X1 (33.0 mg, 0.036 mmol, 12 mol%) and dry mesitylene (3 mL) were added into a 10 mL Schlenk tube and pre - stirred at room temperature for 1 h. Then, the compound shown in Formula 1f (62.1 mg, 0.3 mmol, 1.0 equiv), the compound shown in Formula 2a (91.4 mg, 0.45 mmol, 1.5 equiv) and Rb2CO3 (138.6 mg, 0.6 mmol, 2.0 equiv) were added into the sealed tube in the glove box. Under N2 protection, the reaction system was stirred in an oil bath at 40 °C for 48 h, and TLC was used to determine that the raw materials had completely reacted. The solvent was rotary - evaporated, and the crude product was purified by silica gel flash column chromatography (using PE / EA as the eluent) to obtain the target product shown in Formula 3f, with a yield of 71% and an ee value of 87%.

[0134] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0135] 1 H NMR(400MHz,CDCl3)δ8.39(d,J=8.0Hz,2H),8.07(s,1H),7.89 - 7.82(m,3H),7.76 - 7.71(m,2H),7.61 - 7.57(m,2H),7.49 - 7.48(m,2H),2.38 - 2.31(m,2H),1.46 - 1.39(m,2H),0.94(t,J=8.0Hz,3H).

[0136] 13 C NMR(100MHz,CDCl3)δ191.7,185.5,135.4,133.8,133.1,133.0,130.2,129.1,128.7,128.3,127.7,126.6,126.6,125.9,123.8,122.4,90.7,41.2,17.1,13.9.

[0137] HRMS(EI):m / z:[M] + Calcd for C 22 H 19NO2: 329.1416, found 329.1411.

[0138] [α]D 20 = -136.272 (c = 0.5, CHCl3).

[0139] HPLC test conditions: Daicel Chiralpak ODH chromatographic column; n-hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 7.28 min (main peak), tr = 8.16 min (secondary peak).

[0140] Example 8

[0141] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 4(5H)-one represented by Formula 3g, and the reaction equation is as follows:

[0142]

[0143] In a glove box filled with N2, Pd(OAc)2 (6.6 mg, 0.03 mmol, 10 mol%) and chiral phosphine ligand X1 (33.0 mg, 0.036 mmol, 12 mol%) and dry mesitylene (3 mL) were added to a 10 mL Schlenk tube and pre - stirred at room temperature for 1 h. Then, the compound represented by Formula 1g (48.9 mg, 0.3 mmol, 1.0 equiv), the compound represented by Formula 2a (91.4 mg, 0.45 mmol, 1.5 equiv) and Rb2CO3 (138.6 mg, 0.6 mmol, 2.0 equiv) were added to the sealed tube in the glove box. Under N2 protection, the reaction system was stirred in an oil bath at 40 °C for 48 h, and TLC was used to determine that the raw materials had completely reacted. The solvent was rotary - evaporated, and the crude product was purified by flash column chromatography on silica gel (using PE / EA as the eluent) to obtain the target product represented by Formula 3f, with a yield of 64% and an ee value of 89%.

[0144] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0145] 1 1H NMR (400 MHz, CDCl3) δ 8.31 - 8.28 (m, 2H), 7.74 - 7.70 (m, 1H), 7.58 - 7.54 (m, 2H), 7.41 - 7.40 (m, 1H), 7.35 - 7.33 (m, 1H), 7.24 - 7.22 (m, 1H), 2.30 - 2.15 (m, 2H), 1.42 - 1.32 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H).

[0146] 1313C NMR (100 MHz, CDCl3) δ 191.3, 185.4, 137.0, 135.3, 130.1, 129.0, 126.7, 125.8, 124.8, 121.6, 89.6, 40.4, 16.8, 13.7.

[0147] HRMS (EI): m / z: [M] + Calcd for C 16 H 15 NO2S: 285.0823, found 285.0820.

[0148] [α]D 20 = -143.291 (c = 0.5, CHCl3).

[0149] HPLC test conditions: Daicel Chiralpak ODH column; n - hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 7.51 min (minor peak), tr = 8.16 min (major peak).

[0150] Example 9

[0151] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 4(5H) - one shown by Formula 3h, and the reaction equation is as follows:

[0152]

[0153] In a glove box filled with N2, Pd(OAc)2 (6.6 mg, 0.03 mmol, 10 mol%) and chiral phosphine ligand X1 (43.5 mg, 0.045 mmol, 15 mol%) and dry mesitylene (3 mL) were added into a 10 mL Schlenk tube, and pre - stirred at room temperature for 1 h. Then, the compound shown by Formula 1h (88.8 mg, 0.3 mmol, 1.0 equiv), the compound shown by Formula 2a (91.4 mg, 0.45 mmol, 1.5 equiv) and Rb2CO3 (138.6 mg, 0.6 mmol, 2.0 equiv) were added into the sealed tube in the glove box. Under N2 protection, the reaction system was stirred in an oil bath at 40 °C for 48 h, and TLC was used to determine that the raw materials had completely reacted. The solvent was rotary - evaporated, and the crude product was purified by silica gel flash column chromatography (using PE / EA as the eluent) to obtain the target product shown by Formula 3h, with a yield of 71% and an ee value of 85%.

[0154] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0155] 11H NMR (400 MHz, CDCl3) δ 8.37 - 8.35 (m, 2H), 8.15 - 8.13 (m, 1H), 7.79 - 7.79 (m, 1H), 7.75 - 7.71 (m, 1H), 7.61 - 7.54 (m, 4H), 6.57 - 6.56 (m, 1H), 2.36 - 2.20 (m, 2H), 1.66 (s, 9H), 1.43 - 1.34 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H).

[0156] 13 13C NMR (100 MHz, CDCl3) δ 192.1, 185.3, 149.5, 135.2, 135.0, 130.8, 130.6, 130.2, 129.0, 126.8, 125.9, 120.8, 117.2, 115.4, 107.4, 90.9, 84.0, 41.4, 28.1, 17.0, 13.8.

[0157] HRMS (EI): m / z: [M] + Calcd for C 25 H 26 N2O4: 418.1893, found 318.1362.

[0158] [α]D 20 = -135.592 (c = 0.5, CHCl3).

[0159] HPLC test conditions: Daicel Chiralpak OZ - 3 chromatographic column; n - hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 6.99 min (minor peak), tr = 8.77 min (major peak).

[0160] Example 10

[0161] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 4(5H) - one of formula 3i, and the reaction equation is as follows:

[0162]

[0163] In a glove box filled with N2, Pd(OAc)2 (6.6 mg, 0.03 mmol, 10 mol%), chiral phosphine ligand X1 (43.5 mg, 0.045 mmol, 15 mol%) and dry mesitylene (3 mL) were added to a 10 mL Schlenk tube and pre-stirred at room temperature for 1 h. Then, in the glove box, the compound shown in Formula 1a (47.1 mg, 0.3 mmol, 1.0 equiv), the compound shown in Formula 2b (78.8 mg, 0.45 mmol, 1.5 equiv) and Rb2CO3 (138.6 mg, 0.6 mmol, 2.0 equiv) were added to the sealed tube. Under N2 protection, the reaction system was stirred in an oil bath at 40 °C for 48 h, and TLC was used to determine that the raw materials had completely reacted. The solvent was rotary evaporated, and the crude product was purified by silica gel flash column chromatography (using PE / EA as the eluent) to obtain the target product shown in Formula 3i with a yield of 83% and an ee value of 91%.

[0164] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0165] 1 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.0 Hz, 2H), 7.72 (t, J = 8.0 Hz, 1H), 7.59 - 7.55 (m, 4H), 7.40 - 7.34 (m, 3H), 1.95 (s, 3H).

[0166] 13 13C NMR (100 MHz, CDCl3) δ 191.9, 185.1, 137.0, 135.3, 130.1, 129.0, 128.7, 128.6, 125.8, 124.5, 87.4, 24.9.

[0167] HRMS (EI): m / z: [M] + Calcd for C 16 H 13 NO2: 251.0946, found 251.0941.

[0168] [α]D 20 = -105.316 (c = 0.5, CHCl3).

[0169] HPLC test conditions: Daicel Chiralpak ODH chromatographic column; n-hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 7.65 min (main peak), tr = 8.51 min (secondary peak).

[0170] Example 11

[0171] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 4(5H) - one shown in Formula 3j, and the reaction equation is as follows:

[0172]

[0173] In a glove box filled with N2, Pd(OAc)2 (6.6 mg, 0.03 mmol, 10 mol%), chiral phosphine ligand X1 (43.5 mg, 0.045 mmol, 15 mol%) and dry mesitylene (3 mL) were added to a 10 mL Schlenk tube and pre - stirred at room temperature for 1 h. Then, in the glove box, the compound shown in Formula 1a (47.1 mg, 0.3 mmol, 1.0 equiv), the compound shown in Formula 2d (85.1 mg, 0.45 mmol, 1.5 equiv) and Rb2CO3 (138.6 mg, 0.6 mmol, 2.0 equiv) were added to the sealed tube. Under N2 protection, the reaction system was stirred in an oil bath at 40 °C for 48 h, and TLC was used to determine that the raw materials had completely reacted. The solvent was rotary - evaporated, and the crude product was purified by flash column chromatography on silica gel (using PE / EA as the eluent) to obtain the target product shown in Formula 3j, with a yield of 75% and an ee value of 92%.

[0174] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0175] 1 H NMR (400 MHz, CDCl3) δ 8.35 - 8.33 (m, 2H), 7.72 (t, J = 8.0 Hz, 1H), 7.62 - 7.56 (m, 4H), 7.40 - 7.33 (m, 3H), 2.31 (q, J = 8.0 Hz, 2H), 0.95 (t, J = 8.0 Hz, 3H).

[0176] 13 C NMR (100 MHz, CDCl3) δ 191.5, 185.4, 136.2, 135.2, 130.0, 129.0, 128.6, 128.4, 125.7, 124.5, 90.8, 32.3, 7.8.

[0177] HRMS (EI): m / z: [M] + Calcd for C 17 H 15 NO2: 265.1103, found 265.1098.

[0178] [α]D 20 =-149.531 (c = 0.5, CHCl3).

[0179] HPLC test conditions: Daicel Chiralpak ODH chromatographic column; n-hexane / isopropanol = 95 / 5, 0.5 mL / min, 254 nm; tr = 17.33 min (main peak), tr = 18.51 min (secondary peak).

[0180] The yields and ee values of the chiral α - tetrasubstituted oxazol - 4(5H)-ones prepared using the chiral phosphine ligand X1 in Examples 2 - 11 above are shown in Table 1 below:

[0181] Table 1

[0182] Serial number Product Palladium salt Solvent Base Yield ee value Example 2 3a Palladium acetate Mesitylene Rubidium carbonate 76％ 93％ Example 3 3b Palladium acetate Mesitylene Rubidium carbonate 86％ 91％ Example 4 3c Palladium acetate Mesitylene Rubidium carbonate 82％ 89％ Example 5 3d Palladium acetate Mesitylene Rubidium carbonate 85％ 92％ Example 6 3e Palladium acetate Mesitylene Rubidium carbonate 81％ 91％ Example 7 3f Palladium acetate Mesitylene Rubidium carbonate 71％ 87％ Example 8 3g Palladium acetate Mesitylene Rubidium carbonate 64％ 89％ Example 9 3h Palladium acetate Mesitylene Rubidium carbonate 71％ 85％ Example 10 3i Palladium acetate Mesitylene Rubidium carbonate 83％ 91％ Example 11 3j Palladium acetate Mesitylene Rubidium carbonate 75％ 92％

[0183] Examples 12 - 17

[0184] The compounds shown in Formula 3i were prepared using different chiral phosphine ligands X2 - X7. The specific preparation steps refer to Example 10. The yields and enantioselectivities (ee values) measured by NMR are shown in Table 2 below:

[0185] Table 2

[0186] Serial number Ligand L* Palladium salt Solvent Base Yield ee value Example 12 X2 Palladium acetate Mesitylene Rubidium carbonate 77％ 89％ Example 13 X3 Palladium acetate Mesitylene Rubidium carbonate 66％ 68％ Example 14 X4 Palladium acetate Mesitylene Rubidium carbonate 75％ 78％ Example 15 X5 Palladium acetate Mesitylene Rubidium carbonate 78％ 59％ Example 16 X6 Palladium acetate Mesitylene Rubidium carbonate 49％ 53％ Example 17 X7 Palladium acetate Mesitylene Rubidium carbonate 18％ 57％

[0187] Comparative Examples 1 - 8

[0188] The compounds shown in Formula 3i were prepared using the known chiral phosphine ligands L1 - L8. The specific preparation steps refer to Example 10. The structures of the chiral phosphine ligands L1 - L8 are shown below:

[0189]

[0190] The yields and enantioselectivities (ee values) measured by NMR are shown in Table 3 below:

[0191] Table 3

[0192] Serial number Ligand L* Palladium salt Solvent Base Yield ee value Comparative Example 1 L1 Palladium acetate Mesitylene Rubidium carbonate 0％ - Comparative Example 2 L2 Palladium acetate Mesitylene Rubidium carbonate 0％ - Comparative Example 3 L3 Palladium acetate Mesitylene Rubidium carbonate 0％ - Comparative Example 4 L4 Palladium acetate Mesitylene Rubidium carbonate 0％ - Comparative Example 5 L5 Palladium acetate Mesitylene Rubidium carbonate 0％ - Comparative Example 6 L6 Palladium acetate Mesitylene Rubidium carbonate 0％ - Comparative Example 7 L7 Palladium acetate Mesitylene Rubidium carbonate 0％ - Comparative Example 8 L8 Palladium acetate Mesitylene Rubidium carbonate 0％ -

[0193] As can be seen from Tables 1 - 3 above, by selecting the reaction substrates and under the action of specific chiral phosphine ligands X1 - X7 and palladium catalysts, the present invention can synthesize chiral α - tetrasubstituted oxazol - 4(5H)-ones. Among them, the products prepared using chiral phosphine ligands X1 and X2 have high yields and high ee values. In the above synthesis system, chiral α - tetrasubstituted oxazol - 4(5H)-ones cannot be prepared using chiral phosphine ligands L1 - L8.

[0194] The above-described embodiments are merely preferred embodiments cited to fully illustrate the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or transformations made by those skilled in the art on the basis of the present invention are within the protection scope of the present invention. The protection scope of the present invention is subject to the claims.

Claims

1. A method for preparing a chiral α - tetrasubstituted oxazol - 4(5 H ) - one, characterized in that, Under a protective atmosphere, the compound represented by formula (I) is reacted with the compound represented by formula (II) in the presence of a palladium catalyst, a chiral phosphine ligand, a base and a solvent to obtain a chiral α,α,α,α-tetrasubstituted oxazol-4(5 H )-one; The structures of the above formulas (I) - (III) are as follows: 、 、 ， Among them, A is selected from one of substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted naphthyl, and substituted or unsubstituted indolyl; R 1 selected from one of substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted benzyl; Ar 1 is a substituted or unsubstituted phenyl group; Substituted or unsubstituted means that the group is substituted or unsubstituted by one or more substituents selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, and trifluoromethyl; The chiral phosphine ligand is selected from one of the following structures: ； The palladium catalyst is selected from one or more of palladium acetate, palladium trifluoroacetate, palladium dichloride diacetonitrile, palladium chloride, and palladium adamantane carboxylate; The base is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, rubidium carbonate, and potassium phosphate; The solvent is selected from one or more of dichloromethane, 2-methyltetrahydrofuran, tetrahydrofuran, trifluorotoluene, toluene, mesitylene, chlorobenzene, ethyl acetate, n-hexane, methyl tert-butyl ether, anisole, isopropyl ether, n-butyl ether, and diethyl ether.

2. The preparation method according to claim 1, characterized in that, A is selected from one of phenyl, halogen-substituted phenyl, C 1-6 alkyl-substituted phenyl, thienyl, and naphthyl, and R 1 is C 1-6 alkyl.

3. The preparation method according to claim 1, characterized in that, The chiral phosphine ligand is the compound shown in formula X1 and / or the compound shown in formula X2.

4. The preparation method according to claim 1, characterized in that, The palladium catalyst is palladium acetate, the base is rubidium carbonate, and the solvent is mesitylene.

5. The preparation method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (I) to the compound shown in formula (II), palladium catalyst, chiral phosphine ligand, and base is 1:1 - 2:0.025 - 0.1:0.03 - 0.2:1 - 2.

5.

6. The preparation method according to claim 1, characterized in that, The reaction temperature of the reaction is 20 - 100 °C, and the reaction time is 6 - 60 h.

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