Method for preparing chiral α - tetrasubstituted oxazol - 5(4H)-one

Abstract

The present invention discloses a method for preparing chiral α - tetrasubstituted oxazol - 5(4H) - one. Under a protective atmosphere, a bromide is reacted with an oxazol - 5(4H) - 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 - 5(4H) - one. 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 - 5(4H) - one. The above - mentioned synthesis method has a wide range of substrate applicability, strong functional group compatibility, simple and efficient reaction, easy separation and purification of products, high enantioselectivity of the prepared products, the ee value can be as high as 95%, and the reaction yield is high, which is suitable for the efficient preparation of chiral α - tetrasubstituted oxazol - 5(4H) - one.

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 - 5(4H) - ones. Background Art

[0002] Quaternary carbon centers are widely present in the skeletal structures of natural products and drug molecules, but their synthesis remains a major challenge in the field of chemical synthesis, especially the synthesis of highly enantioselective quaternary carbon centers [Chem. Rev., 1993, 93, 2037]. The asymmetric α - arylation of carbonyl compounds catalyzed by transition metals can effectively construct C(sp 3 ) - C(sp 2 ) bonds and can efficiently synthesize α - quaternary carbon chiral centers through the regulation of chiral ligands [Synlett, 2012, 23, 1999], so it has been widely studied by scientists.

[0003] Oxazol - 5(4H) - one compounds can be hydrolyzed in one step to obtain the corresponding amino acid derivatives. Therefore, the modification of such substrates can obtain a series of unnatural amino acids, which have high synthetic value [(a) J. Am. Chem. Soc. 2003, 125, 13368; (b) Chem. Soc. Rev., 2007, 36, 1432. (c) Chem. Eur. J., 2016, 22, 10294]. The present invention envisions that through the asymmetric α - arylation reaction of transition metals involving such compounds, unnatural amino acids with α - quaternary carbon chiral centers can be effectively synthesized. This strategy is simple and efficient, extremely significant in the field of organic synthesis, and has not been reported yet. Summary of the Invention

[0004] The present invention provides a method for preparing chiral α - tetrasubstituted oxazol - 5(4H) - ones. By selecting reaction substrates and under the action of specific chiral ligands and palladium catalysts, chiral α - tetrasubstituted oxazol - 5(4H) - ones with an ee value of up to 95% can be synthesized, and the reaction yield is high.

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

[0006] The present invention provides a method for preparing chiral α - tetrasubstituted oxazol - 5(4H) - ones. Under a protective atmosphere, the compound shown in formula (I) and the compound shown in 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 - 5(4H) - one shown in 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 substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl;

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

[0011] Ar 1 is substituted or unsubstituted phenyl;

[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 halogen, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl, aryl, and ketone carbonyl.

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

[0014]

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

[0016] Furthermore, A is selected from one of phenyl, phenyl substituted by C 1-6 alkyl, phenyl substituted by C 1-6 alkoxy, and phenyl substituted by trifluoromethyl, and R 1 is more preferably C 1-6 alkyl.

[0017] Furthermore, the chiral phosphine ligand is more preferably the compound shown in formula X1 and / or the compound shown in formula X2; in some preferred embodiments of the present invention, when the chiral phosphine ligand is the compound shown in formula X1, the ee value of the prepared product is not less than 90%.

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

[0019] Furthermore, 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, trifluorotoluene, toluene, mesitylene, chlorobenzene, ethyl acetate, n-hexane, methyl tert-butyl ether, anisole, isopropyl ether, n-butyl ether, and diethyl ether; more preferably toluene.

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

[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, for example 1:1.5:0.1:0.12:2.

[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-5(4H)-ones. The substrates of the above synthesis method have a wide range of applicability, strong functional group compatibility, simple and efficient reactions, and easy separation and purification of products. The prepared products have high enantioselectivity, with an ee value up to 95%, and high reaction yields, and are suitable for the efficient preparation of chiral α-tetrasubstituted oxazol-5(4H)-ones. In addition, such chiral α-tetrasubstituted oxazol-5(4H)-ones can be used for one-step hydrolysis to prepare unnatural amino acids with α-quaternary carbon chiral centers, which have great application value. Description of the Drawings

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

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

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

[0029] Figure 4 It is the HPLC chart of the product 3d prepared in Example 5;

[0030] Figure 5 It is the HPLC chart of the product 3e prepared in Example 6;

[0031] Figure 6HPLC 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 mode

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those 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" described in this invention means that in addition to the components described, it may also include or contain other components. The "including" or "comprising" described in this invention can also be replaced by the closed "consisting of" or "consisting 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 embodiments cited are not intended to limit the present invention.

[0038] Example 1

[0039] This example relates to the preparation of chiral phosphine ligands X1 - X5, wherein X1 - X4 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.], and X5 is directly purchased. The structures of chiral phosphine ligands X1 - X5 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 detected to be complete 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 separation.

[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 detected to be complete 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 separation.

[0046] The chiral phosphine ligands X1, X2, and X4 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 7.68 (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).

[0049] 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.

[0050] 31 31P NMR (162 MHz, CDCl3) δ 15.94.

[0051] HRMS (ESI): m / z: [M + H] + Calcd for C 56 H 73 NO7PS: 934.4845, found 934.4846.

[0052] [α]D 20 = 32.298 (c = 0.5, CHCl3).

[0053] The melting point is 145.6 - 145.8 °C.

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

[0055] 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).

[0056] 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.

[0057] 31 31P NMR (162 MHz, CDCl3) δ 15.64.

[0058] HRMS (ESI): m / z: [M + H] + Calcd for C 60 H 69 NO3PS: 914.4736, found 914.4736.

[0059] [α]D 20 = 42.577 (c = 0.5, CHCl3).

[0060] The melting point is 121.4 - 122.0 °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] Example 2

[0076] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 5(4H) - one represented by Formula 3a, and the reaction equation is as follows:

[0077]

[0078] The specific preparation process is as follows:

[0079] 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 toluene (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 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 silica gel flash column chromatography (using PE / EA as the eluent) to obtain the target product shown in Formula 3a with a yield of 80% and an ee value of 90%.

[0080] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0081] 1 H NMR (400 MHz, CDCl3) δ 8.13 - 8.12 (m, 2H), 7.71 - 7.70 (m, 2H), 7.62 - 7.58 (m, 1H), 7.54 - 7.50 (m, 2H), 7.40 - 7.36 (m, 2H), 7.34 - 7.30 (m, 1H), 2.62 - 2.56 (m, 1H), 0.96 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H).

[0082] 13 C NMR (100 MHz, CDCl3) δ 179.1, 160.1, 138.0, 132.7, 128.8, 128.4, 128.1, 128.0, 126.0, 125.9, 77.9, 38.6, 17.2, 16.8.

[0083] HRMS (EI): m / z: [M] + Calcd for C 18 H 17 NO2: 279.1259, found 279.1256.

[0084] [α]D 20 = -154.347 (c = 0.5, CHCl3).

[0085] HPLC test conditions: Daicel Chiralpak IA chromatographic column; n-hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 4.43 min (secondary peak), tr = 6.62 min (main peak).

[0086] Example 3

[0087] This example provides the preparation of a chiral α-quaternary substituted oxazol-5(4H)-one shown in Formula 3b, and the reaction equation is as follows:

[0088]

[0089] The specific preparation process is as follows:

[0090] 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%) were added to a 10 mL Schlenk tube, and dry toluene (3 mL) was added, and pre-stirred at room temperature for 1 h. Then, the compound shown in Formula 1b (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 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 79% and an ee value of 91%.

[0091] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0092] 1 H NMR (400 MHz, CDCl3) δ 8.12 - 8.10 (m, 2H), 7.61 - 7.49 (m, 5H), 7.19 (d, J = 8.0 Hz, 2H), 2.62 - 2.51 (m, 1H), 2.35 (s, 3H), 0.95 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H).

[0093] 13 C NMR (100 MHz, CDCl3) δ 179.3, 160.0, 137.7, 135.0, 132.6, 129.1, 128.7, 128.0, 126.0, 125.9, 77.8, 38.3, 21.0, 17.2, 16.8.

[0094] HRMS (EI): m / z: [M] + Calcd for C 19 H 19 NO2: 293.1416, found 293.1411.

[0095] [α]D 20 = -137.135 (c = 0.5, CHCl3).

[0096] HPLC test conditions: Daicel Chiralpak IA column; n-hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 4.54 min (minor peak), tr = 10.41 min (major peak).

[0097] Example 4

[0098] This example provides the preparation of a chiral α,α,α,α -tetrasubstituted oxazol - 5(4H)-one represented by Formula 3c, and the reaction equation is as follows:

[0099]

[0100] The specific preparation process is as follows:

[0101] 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 toluene (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 1c (63.9 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 3c, with a yield of 70% and an ee value of 93%.

[0102] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0103] 11H NMR (400 MHz, CDCl3) δ 8.17 - 8.15 (m, 2H), 7.69 - 7.67, (m, 2H), 7.64 - 7.60 (m, 1H), 7.57 - 7.53 (m, 2H), 7.46 - 7.44 (m, 2H), 2.67 - 2.60 (m, 1H), 1.37 (s, 9H), 1.02 (d, J = 4.5 Hz, 3H), 1.00 (d, J = 4.6 Hz, 3H).

[0104] 13 13C NMR (100 MHz, CDCl3) δ 179.2, 159.9, 150.8, 134.9, 132.6, 128.7, 128.0, 126.0, 125.7, 125.3, 77.8, 38.3, 34.4, 31.3, 17.2, 16.9.

[0105] HRMS (EI): m / z: [M] + Calcd for C 22 H 25 NO2: 335.1885, found 335.1880.

[0106] [α]D 20 = -124.394 (c = 0.5, CHCl3).

[0107] HPLC test conditions: Daicel Chiralpak IA chromatographic column; n - hexane / isopropanol = 92 / 8, 0.6 mL / min, 254 nm; tr = 3.89 min (minor peak), tr = 5.10 min (major peak).

[0108] Example 5

[0109] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 5(4H) - one shown in Formula 3d, and the reaction equation is as follows:

[0110]

[0111] 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 toluene (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 (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 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 silica gel flash column chromatography (using PE / EA as the eluent) to obtain the target product shown in Formula 3d, with a yield of 77% and an ee value of 94%.

[0112] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0113] 1 H NMR (400 MHz, CDCl3) δ 8.16 - 8.13 (m, 2H), 7.79 - 7.76 (m, 2H), 7.63 - 7.59 (m, 5H), 7.55 - 7.51 (m, 2H), 7.47 - 7.42 (m, 2H), 7.38 - 7.34 (m, 1H), 2.66 - 2.59 (m, 1H), 1.00 (d, J = 2.6 Hz, 3H), 0.98 (d, J = 2.7 Hz, 3H).

[0114] 13 C NMR (100 MHz, CDCl3) δ 179.2, 160.2, 140.8, 140.5, 137.0, 132.7, 128.8 (overlap), 128.1, 127.4, 127.1, 127.1, 126.5, 126.0, 77.8, 38.5, 17.2, 16.9.

[0115] HRMS (EI): m / z: [M] + Calcd for C 24 H 21 NO2: 355.1572, found 355.1569.

[0116] [α]D 20 = -120.214 (c = 0.5, CHCl3).

[0117] HPLC test conditions: Daicel Chiralpak IA chromatographic column; n-hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 6.77 min (secondary peak), tr = 9.56 min (main peak).

[0118] Example 6

[0119] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 5(4H)-one represented by Formula 3e, and the reaction equation is as follows:

[0120]

[0121] 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 toluene (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 1e (56.1 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 evaporated to dryness, and the crude product was purified by silica gel flash column chromatography (using PE / EA as the eluent) to obtain the target product represented by Formula 3e, with a yield of 66% and an ee value of 90%.

[0122] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0123] 1 H NMR (400 MHz, CDCl3) δ 8.12 - 8.09 (m, 2H), 7.61 - 7.57 (m, 1H), 7.53 - 7.49 (m, 2H), 7.30 - 7.25 (m, 3H), 6.87 - 6.84 (m, 1H), 3.82 (s, 3H), 2.60 - 2.53 (m, 1H), 0.95 (d, J = 4.0 Hz, 3H), 0.93 (d, J = 4.0 Hz, 3H).

[0124] 13 C NMR (100 MHz, CDCl3) δ 179.4, 159.6, 159.3, 132.6, 130.1, 128.8, 128.0, 127.2, 126.1, 113.8, 77.5, 55.3, 38.4, 17.2, 16.8.

[0125] HRMS (EI): m / z: [M] + Calcd for C 19 H 19 NO3: 309.1365, found 309.1359.

[0126] [α]D 20 = -141.252 (c = 0.5, CHCl3).

[0127] HPLC test conditions: Daicel Chiralpak IA column; n-hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 6.07 min (minor peak), tr = 12.62 min (major peak).

[0128] Example 7

[0129] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 5(4H)-one shown in Formula 3f, and the reaction equation is as follows:

[0130]

[0131] 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 toluene (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 (67.5 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 3f, with a yield of 81% and an ee value of 95%.

[0132] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0133] 1 H NMR (400 MHz, CDCl3) δ 8.13 - 8.11 (m, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.65 - 7.59 (m, 3H), 7.55 - 7.51 (m, 2H), 2.60 - 2.53 (m, 1H), 0.96 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H).

[0134] 13 13C NMR (100 MHz, CDCl3) δ 178.6, 160.5, 141.9, 133.0, 130.3 (q, 2JC-F = 32.0 Hz), 128.8, 128.1, 126.6, 125.7, 125.4 (q, 3JC-F = 3.0 Hz), 124.0 (q, 1JC-F = 267.0 Hz), 77.7, 39.0, 17.2, 16.8.

[0135] 19 19F NMR (376 MHz, CDCl3) δ -62.6 (s).

[0136] HRMS (EI): m / z: [M] + Calcd for C 19 H 16 FNO2: 347.1133, found 347.1128.

[0137] [α]D 20 = -140.130 (c = 0.5, CHCl3).

[0138] HPLC test conditions: Daicel Chiralpak IA column; n-hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 4.18 min (minor peak), tr = 6.56 min (major peak).

[0139] Example 8

[0140] This example provides the preparation of a chiral α,α,α,α-tetrasubstituted oxazol-5(4H)-one of formula 3g, and the reaction equation is as follows:

[0141]

[0142] 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 toluene (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 1g (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 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 silica gel flash column chromatography (using PE / EA as the eluent) to obtain the target product shown in Formula 3f with a yield of 74% and an ee value of 90%.

[0143] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0144] 1 H NMR (400 MHz, CDCl3) δ 8.14 - 8.12 (m, 2H), 7.63 - 7.60 (m, 1H), 7.55 - 7.51 (m, 2H), 7.32 - 7.28 (m, 3H), 6.89 - 6.86 (m, 1H), 3.85 (s, 3H), 2.62 - 2.55 (m, 1H), 0.98 (d, J = 4.0 Hz, 3H), 0.96 (d, J = 4.0 Hz, 3H).

[0145] 13 C NMR (100 MHz, CDCl3) δ 179.1, 160.0, 159.6, 139.6, 132.7, 129.4, 128.8, 128.1, 126.0, 118.4, 113.2, 112.1, 77.8, 55.3, 38.6, 17.2, 16.9.

[0146] HRMS (EI): m / z: [M] + Calcd for C 22 H 25 NO3: 335.1885, found 335.1880.

[0147] [α]D 20 = -109.294 (c = 0.5, CHCl3).

[0148] HPLC test conditions: Daicel Chiralpak IA chromatographic column; n-hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 4.48 min (minor peak), tr = 5.48 min (major peak).

[0149] Example 9

[0150] This example provides the preparation of a chiral α-tetrasubstituted oxazol-5(4H)-one shown in Formula 3h, and the reaction equation is as follows:

[0151]

[0152] 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%) were added to a 10 mL Schlenk tube, and dry toluene (3 mL) was added, 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 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 in the glove box. Under N2 protection, the reaction system was stirred in an oil bath at 30 °C for 60 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 3h, with a yield of 81% and an ee value of 90%.

[0153] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0154] 1 H NMR (400 MHz, CDCl3) δ 8.12 - 8.10 (m, 2H), 7.68 - 7.65 (m, 2H), 7.62 - 7.58 (m, 1H), 7.54 - 7.50 (m, 2H), 7.42 - 7.32 (m, 3H), 1.90 (s, 3H).

[0155] 13 C NMR (100 MHz, CDCl3) δ 179.2, 160.2, 138.8, 132.8, 128.8, 128.7, 128.2, 128.0, 125.9, 125.4, 70.6, 27.0.

[0156] HRMS (EI): m / z: [M] + Calcd for C 16 H 13NO2: 251.0946, found 251.0944.

[0157] [α]D 20 = -95.316 (c = 0.5, CHCl3).

[0158] HPLC test conditions: Daicel Chiralpak IA chromatographic column; n-hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 4.92 min (secondary peak), tr = 6.24 min (main peak).

[0159] Example 10

[0160] This example provides the preparation of a chiral α-tetrasubstituted oxazol-5(4H)-one represented by Formula 3i, and the reaction equation is as follows:

[0161]

[0162] 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%) were added to a 10 mL Schlenk tube, and dry toluene (3 mL) was added. The mixture was pre-stirred at room temperature for 1 h. Then, the compound represented by Formula 1a (47.1 mg, 0.3 mmol, 1.0 equiv), the compound represented by Formula 2c (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 in the glove box. Under N2 protection, the reaction system was stirred in an oil bath at 30 °C for 60 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 represented by Formula 3i, with a yield of 74% and an ee value of 90%.

[0163] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0164] 1 1H NMR (400 MHz, CDCl3) δ 8.14 - 8.12 (m, 2H), 7.73 - 7.70 (m, 2H), 7.62 - 7.59 (m, 1H), 7.54 - 7.51 (m, 2H), 7.42 - 7.32 (m, 3H), 2.27 (q, J = 8.0 Hz, 2H), 0.96 (t, J = 8.0 Hz, 3H).

[0165] 1313C NMR (100 MHz, CDCl3) δ 178.8, 160.1, 138.2, 132.7, 128.8, 128.6, 128.1, 128.0, 125.9, 125.6, 74.9, 34.3, 8.5.

[0166] HRMS (EI): m / z: [M] + Calcd for C 17 H 15 NO2: 265.1103, found 265.1098.

[0167] [α]D 20 = -128.192 (c = 0.5, CHCl3).

[0168] HPLC test conditions: Daicel Chiralpak IA column; n - hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 4.75 min (minor peak), tr = 6.30 min (major peak).

[0169] Example 11

[0170] This example provides the preparation of a chiral α - tetrasubstituted oxazol - 5(4H) - one represented by Formula 3j, and the reaction equation is as follows:

[0171]

[0172] 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 toluene (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 1a (47.1 mg, 0.3 mmol, 1.0 equiv), the compound represented by Formula 2d (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 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, 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 3j, with a yield of 69% and an ee value of 90%.

[0173] The product prepared in this example was tested and characterized, and the characterization results are as follows:

[0174] 11H NMR (400 MHz, CDCl3) δ 8.11 - 8.09 (m, 2H), 7.70 - 7.68 (m, 2H), 7.62 - 7.58 (m, 1H), 7.53 - 7.50 (m, 2H), 7.40 - 7.36 (m, 2H), 7.34 - 7.30 (m, 1H), 2.22 - 2.16 (m, 2H), 1.37 - 1.31 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H).

[0175] 13 13C NMR (100 MHz, CDCl3) δ 179.0, 160.1, 138.5, 132.8, 128.8, 128.6, 128.1, 128.0, 125.9, 125.6, 74.5, 43.2, 17.6, 13.8.

[0176] HRMS (EI): m / z: [M] + Calcd for C 17 H 15 NO2: 265.1103, found 265.1098.

[0177] [α]D 20 = -105.354 (c = 0.5, CHCl3).

[0178] HPLC conditions: Daicel Chiralpak IA column; hexane / 2 - propanol = 90 / 10, 1.0 mL / min, 254 nm. tr = 4.60 min (minor), tr = 5.81 min (major)

[0179] HPLC test conditions: Daicel Chiralpak IA column; hexane / isopropanol = 90 / 10, 1.0 mL / min, 254 nm; tr = 4.60 min (minor peak), tr = 5.81 min (major peak).

[0180] The yields and ee values of the chiral α - tetrasubstituted oxazol - 5(4H) - ones prepared using the chiral phosphine ligand X1 in Examples 2 - 11 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 Toluene Rubidium carbonate 80％ 90％ Example 3 3b Palladium acetate Toluene Rubidium carbonate 79％ 91％ Example 4 3c Palladium acetate Toluene Rubidium carbonate 70％ 93％ Example 5 3d Palladium acetate Toluene Rubidium carbonate 77％ 94％ Example 6 3e Palladium acetate Toluene Rubidium carbonate 66％ 90％ Example 7 3f Palladium acetate Toluene Rubidium carbonate 81％ 95％ Example 8 3g Palladium acetate Toluene Rubidium carbonate 74％ 90％ Example 9 3h Palladium acetate Toluene Rubidium carbonate 81％ 90％ Example 10 3i Palladium acetate Toluene Rubidium carbonate 74％ 90％ Example 11 3j Palladium acetate Toluene Rubidium carbonate 69％ 90％

[0183] Examples 12 - 15

[0184] The compounds shown in Formula 3h were prepared using different chiral phosphine ligands X2 - X5. For the specific preparation steps, refer to Example 9. The yields and enantioselectivities (ee values) were measured by NMR and 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 Toluene Rubidium carbonate 82％ 81％ Example 13 X3 Palladium acetate Toluene Rubidium carbonate 71％ 62％ Example 14 X4 Palladium acetate Toluene Rubidium carbonate 75％ 74％ Example 15 X5 Palladium acetate Toluene Rubidium carbonate 31％ 51％

[0187] Comparative Examples 1 - 8

[0188] The compounds shown in Formula 3h were prepared using known chiral phosphine ligands L1 - L8. For the specific preparation steps, refer to Example 9. The structures of 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 Toluene Rubidium carbonate 0％ - Comparative Example 2 L2 Palladium acetate Toluene Rubidium carbonate 0％ - Comparative Example 3 L3 Palladium acetate Toluene Rubidium carbonate 0％ - Comparative Example 4 L4 Palladium acetate Toluene Rubidium carbonate 0％ - Comparative Example 5 L5 Palladium acetate Toluene Rubidium carbonate 0％ - Comparative Example 6 L6 Palladium acetate Toluene Rubidium carbonate 0％ - Comparative Example 7 L7 Palladium acetate Toluene Rubidium carbonate 0％ - Comparative Example 8 L8 Palladium acetate Toluene 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 - X5 and palladium catalysts, the present invention can synthesize chiral α - tetrasubstituted oxazol - 5(4H) - ones. Among them, the products prepared using chiral phosphine ligands X1 and X2 have high yields and high ee values. In particular, the yields of the products prepared using chiral phosphine ligand X1 are all above 90%. In the above - mentioned synthesis system, chiral α - tetrasubstituted oxazol - 5(4H) - ones cannot be prepared using chiral phosphine ligands L1 - L8.

[0194] The above - mentioned embodiments are only preferred embodiments given 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 all 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 - 5(4 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-5(4 H )-one; the structures of the above formula (I) to formula (III) are as follows: 、 、 ， Among them, A is selected from one of substituted or unsubstituted phenyl and substituted or unsubstituted naphthyl; R 1 selected from one of substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted phenyl, and 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, dichlorodicyanopalladium, palladium chloride, and palladium adamantaneformate; 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, C 1-6 alkyl-substituted phenyl, C 1-6 alkoxy-substituted phenyl, and trifluoromethyl-substituted phenyl, 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 by formula X1 and / or the compound shown by 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 toluene.

5. The preparation method according to claim 1, characterized in that, The molar ratio of the compound shown by formula (I) to the compound shown by 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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