Chiral pyran ring compound as well as synthesis method and application thereof

Abstract

The invention discloses a chiral pyran ring compound as well as a synthesis method and application thereof, sulfur ylide shown in a formula (I) and a vinyl-containing carbonate compound shown in a formula (II) are used as reaction raw materials, under the action of a catalyst and chiral phosphoric acid, a molecular sieve is added, a reaction is performed in an organic solvent, and the chiral pyran ring compound is obtained. The chiral pyran ring compound shown in the formula (III) is obtained through treatment after reaction, and in the formula # imgabs0, R is selected from benzene ring, substituted phenyl, furan, thiophene or naphthalene ring during substitution, and the substituent group of the substituted phenyl is tert-butyl, halogen or trifluoromethyl; during substitution, R1 is selected from a benzene ring, substituted phenyl or thiophene, and a substituent group of the substituted phenyl is methyl, methoxyl, halogen or trifluoromethyl. The method has the advantages of high yield and high selectivity; the reaction conditions are mild; the reaction raw materials are easy to obtain, stable in character, free of pungent smell and environmentally friendly.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a chiral pyran ring compound, a synthesis method thereof and an application thereof. Background Art

[0002] Dihydropyran compounds are widely present in many natural products and drug molecules with important biological significance. Because the olefin functional group of dihydropyran compounds provides convenience for structural changes, they can also be used as general starting materials for many other important six-membered oxygen-containing heterocyclic compounds (such as tetrahydropyran and pyranone). Due to the synthetic and medicinal value of these molecules, methods for their preparation have been actively pursued in society. Drugs with chiral pyran rings are as follows:

[0003]

[0004] Currently, methods for asymmetric construction of chiral pyran rings can be mainly divided into two categories. The first is the [4+2] hetero-Diels-Alder reaction of carbonyl compounds with 1,3-dienes, and the second is the [5+1] Prins-type cyclization reaction of carbonyl compounds with 4-hydroxyvinylsilanes. However, both of these methods usually require the use of active aldehydes, glyoxylates or ketonates as substrates, which substantially limits the scope of the reaction. In this regard, it is necessary to develop a more general cyclization strategy to conveniently synthesize such oxygen-containing heterocyclic compounds. Summary of the Invention

[0005] Aiming at the above problems, the purpose of the present invention is to provide a chiral pyran ring compound, a synthesis method thereof and an application thereof.

[0006] To achieve the above purpose, the following technical solutions are proposed:

[0007] A chiral pyran ring compound, whose structure is shown in formula (Ⅲ),

[0008]

[0009] In the formula, when substituted, R is selected from a benzene ring, a substituted phenyl group, furan, thiophene or a naphthalene ring, and the substituent of the substituted phenyl group is a tert-butyl group, a halogen or a trifluoromethyl group; when substituted, R 1 is selected from a benzene ring, a substituted phenyl group or thiophene, and the substituent of the substituted phenyl group is a methyl group, a methoxy group, a halogen or a trifluoromethyl group.

[0010] A method for synthesizing a chiral pyran ring compound, using a sulfonium ylide shown in formula (I) and a vinyl-containing carbonate compound shown in formula (II) as reaction raw materials, adding molecular sieves, and under the action of a catalyst and chiral phosphoric acid, reacting at room temperature in an organic solvent for 18 - 36 h. After the reaction is completed, the chiral pyran ring compound shown in formula (III) is obtained through silica gel column chromatography separation and purification. The reaction formula is as follows:

[0011]

[0012] In the formula, when substituted, R is selected from a benzene ring, a substituted phenyl group, furan, thiophene or a naphthalene ring, and the substituent of the substituted phenyl group is a tert-butyl group, a halogen or a trifluoromethyl group; when substituted, R 1 is selected from a benzene ring, a substituted phenyl group or thiophene, and the substituent of the substituted phenyl group is a methyl group, a methoxy group, a halogen or a trifluoromethyl group.

[0013] Further, the catalyst used is Pd(PPh 3 ) 4 , and the dosage is 1 - 5 mol% of the dosage of the compound shown in formula (I).

[0014] Further, the chiral phosphoric acid is (S)-(+)-binaphthol phosphate, (R)-3,3'-bis(2,4,6-trimethylphenyl)-1,1'-binaphthol phosphate, (R)-3,3'-bis(1-naphthyl)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthol phosphate, (R)-3,3'-bis(3,5-diphenylphenyl)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthol phosphate, (11bS)-2,6-di-9-anthryl-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxo-binaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphole, (R)-spirobiphenol phosphonate or (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate.

[0015] Further, the molecular sieve is molecular sieve, molecular sieve or molecular sieve.

[0016] Further, the organic solvent is dichloromethane, 1,2-dichloroethane, isopropanol, ethanol, carbon tetrachloride, chloroform, chlorobenzene, toluene, dimethylacetamide or tetrahydrofuran.

[0017] Further, the molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1.0:1.0 - 1.0:2.0.

[0018] Further, after the reaction is completed, the specific operation process of silica gel column chromatography separation and purification is as follows: after the reaction is completed, the reaction solution is concentrated, subjected to column chromatography, a mixed solution of petroleum ether and ethyl acetate is used as the eluent, the eluent containing the target compound is collected, concentrated, distilled and dried to obtain the compound shown in formula (III), and the volume ratio of the mixed solution of petroleum ether and ethyl acetate is 10:1 - 20:1.

[0019] Preferably, the catalyst is Pd(PPh 3 ) 4 , the dosage is 3 mol% of the dosage of the compound shown in formula (I), the chiral phosphoric acid is (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate, the molecular sieve is molecular sieve, the organic solvent is 1,2-dichloroethane, and the molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1.0:1.5.

[0020] Use of a chiral pyran ring compound in the preparation of an anti-inflammatory drug.

[0021] The beneficial effects of the present invention are as follows:

[0022] The present invention has a high yield and high selectivity; the reaction conditions are mild; the reaction raw materials are simple, easy to obtain, have stable properties, no pungent smell, and are environmentally friendly. In addition, the prepared chiral pyran ring compound can potentially be applied in the fields of organic synthesis, medicine, materials, etc. Biological anti-inflammatory activity experiments were carried out on some of the obtained compounds, and all showed good anti-inflammatory activity. Therefore, the present invention has great potential in the preparation of anti-inflammatory drugs. Description of the Drawings

[0023] Figure 1 Effects of compounds at different concentrations on nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages;

[0024] Figure 2 Effects of compounds at different concentrations on reactive oxygen species (ROS) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Detailed Embodiments

[0025] Combined with the following specific embodiments, the present invention will be further described in detail. The protection scope of the present invention is not limited to the following embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that those skilled in the art can think of are included in the present invention, and the scope of protection is defined by the appended claims. The processes, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the specifically mentioned content below, are all common knowledge and well-known common sense in the art, and the present invention has no special limiting content. The data given in the following embodiments include specific operations, reaction conditions and products, and the product purity is identified by nuclear magnetic resonance.

[0026] Example 1

[0027] Synthesis of Compound 3aa:

[0028]

[0029] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2a (0.15 mmol, 28.8 mg, 1.5 equiv.) were added to a reaction tube, Pd(PPh 3 ) 4 (0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3aa was directly purified by column chromatography (yield 80%, enantioselectivity 92%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 1H NMR (400 MHz, CDCl 3 ) δ 8.08 - 8.01 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.39 - 7.27 (m, 5H), 6.29 -

[0030] 6.21 (m, 1H), 5.01 (dd, J = 9.9, 4.0 Hz, 1H), 4.83 - 4.65 (m, 2H), 2.75 - 2.61 (m, 1H), 2.56 - 2.46 (m, 1H). 13 13C NMR (101 MHz, CDCl 3 ) δ 197.8, 137.8, 135.9, 135.1, 133.6, 129.1, 128.8, 128.7, 127.9, 125.0, 120.3, 75.5, 67.4, 28.0.

[0031] Example 2

[0032] Synthesis of Compound 3ab:

[0033]

[0034] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2b (0.15 mmol, 30.6 mg, 1.5 equiv.) were added to a reaction tube, Pd(PPh3 ) 4 (0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ab was directly purified by column chromatography (yield 50%, enantioselectivity 90%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 1H NMR (400 MHz, CDCl 3 ) δ 8.04 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 6.27 - 6.14 (m, 1H), 4.98 (dd, J = 9.9, 4.0 Hz, 1H), 4.83 - 4.56 (m, 2H), 2.79 - 2.59 (m, 1H), 2.57 - 2.42 (m, 1H), 2.35 (s, 3H). 13 13C NMR (101 MHz, CDCl 3 ) δ 197.9, 137.7, 135.7, 135.2, 134.9, 133.6, 129.4, 129.1, 128.8, 124.9, 119.4, 75.6, 67.4, 27.9, 21.3.

[0035] Example 3

[0036] Synthesis of compound 3ac:

[0037]

[0038] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2c (0.15 mmol, 33.0 mg, 1.5 equiv.) were added to a reaction tube, Pd(PPh 3 ) 4 (0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ac was directly purified by column chromatography (yield 43%, enantioselectivity 89%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (d, J = 7.4 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.33 - 7.20 (m, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.22 - 6.07 (m, 1H), 4.97 (dd, J = 9.9, 4.0 Hz, 1H), 4.79 - 4.58 (m, 2H), 3.81 (s, 3H), 2.74 - 2.59 (m, 1H), 2.53 - 2.42 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 197.9, 159.4, 135.3, 135.2, 133.6, 130.4, 129.1, 128.8, 126.1, 118.6, 114.1, 75.7, 67.4, 55.4, 27.9.

[0039] Example 4

[0040] Synthesis of compound 3ad:

[0041]

[0042] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2d (0.15 mmol, 31.2 mg, 1.5 equiv.), Pd(PPh 3 ) 4 (0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ad was directly purified by column chromatography (yield 60%, enantioselectivity 92%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400 MHz, CDCl 3)δ8.01(d, J = 7.4 Hz, 2H), 7.57(t, J = 7.4 Hz, 1H), 7.47(t, J = 7.7 Hz, 2H), 7.26(dd, J = 8.5, 5.4 Hz, 2H), 7.01(t, J = 8.7 Hz, 2H), 6.21 - 6.11(m, 1H), 4.96(dd, J = 9.7, 4.0 Hz, 1H), 4.75 - 4.57(m, 2H), 2.71 - 2.60(m, 1H), 2.53 - 2.43(m, 1H). 13 C NMR(101 MHz, CDCl 3 )δ197.5, 162.2(d, J = 263.3 Hz), 135.0, 134.9, 133.8(d, J = 3.2 Hz), 133.5, 129.0, 128.7, 126.6(d, J = 7.9 Hz), 120.2, 115.5(d, J = 21.5 Hz), 75.3, 67.1, 27.7. 19 F NMR(376 MHz, CDCl 3 )δ - 114.44.

[0043] Example 5

[0044] Synthesis of Compound 3ae:

[0045]

[0046] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2e (0.15 mmol, 33.6 mg, 1.5 equiv.), Pd(PPh 3 ) 4 (0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL) were added to a reaction tube. The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ae was directly purified by column chromatography (yield 76%, enantioselectivity 89%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR(400 MHz, CDCl 3)δ8.10 - 8.04 (m, 2H), 7.66 - 7.60 (m, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.37 - 7.32 (m, 2H), 7.31 - 7.25 (m, 2H), 6.34 - 6.20 (m, 1H), 5.01 (dd, J = 9.7, 4.1 Hz, 1H), 4.80 - 4.60 (m, 2H), 2.79 -

[0047] 2.65 (m, 1H), 2.60 - 2.43 (m, 1H). 13 C NMR (101 MHz, CDCl 3 )δ197.6, 136.2, 135.1, 134.9, 133.6, 129.1, 129.1, 128.9, 128.8, 126.3, 120.9, 75.4, 67.1, 27.8.

[0048] Example 6

[0049] Synthesis of Compound 3af:

[0050]

[0051] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2f (0.15 mmol, 40.2 mg, 1.5 equiv.), Pd(PPh 3 ) 4 (0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiaryl phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL) were added to the reaction tube. The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3af was directly purified by column chromatography (yield 62%, enantioselectivity 90%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400 MHz, CDCl 3 )δ8.04 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.55 - 7.42 (m, 4H), 7.18 (d, J = 8.5 Hz, 2H), 6.30 - 6.20 (m, 1H), 4.98 (dd, J = 9.6, 4.1 Hz, 1H), 4.77 - 4.60 (m, 2H), 2.76 - 2.59 (m, 1H), 2.59 - 2.40 (m, 1H). 13 C NMR (101 MHz, CDCl3 ) δ 197.6, 136.7, 135.2, 134.9, 133.7, 131.9, 129.1, 128.8, 126.6, 121.8, 121.0, 75.4, 67.0, 27.8.

[0052] Example 7

[0053] Synthesis of Compound 3ag

[0054]

[0055] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2g (0.15 mmol, 38.7 mg, 1.5 equiv.), Pd(PPh 3 ) 4 (0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL) were added to a reaction tube. The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ag was directly purified by column chromatography (yield 74%, enantioselectivity 86%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 1H NMR (400 MHz, CDCl 3 ) δ 8.09 - 8.01 (m, 2H), 7.61 (dd, J = 10.3, 4.4 Hz, 3H), 7.49 (t, J = 7.6 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 6.39 - 6.32 (m, 1H), 5.00 (dd, J = 9.5, 4.1 Hz, 1H), 4.79 - 4.64 (m, 2H), 2.78 - 2.67 (m, 1H), 2.60 - 2.50 (m, 1H). 13 13C NMR (101 MHz, CDCl 3 ) δ 197.5, 141.3, 135.1, 134.9, 133.7, 129.8 (q, J = 32.6 Hz), 129.1, 128.8, 125.9 - 125.4 (m), 125.2, 122.9, 122.6, 75.3, 67.0, 27.7. 19 19F NMR (376 MHz, CDCl 3 ) δ -62.6.

[0056] Example 8

[0057] Synthesis of Compound 3ah:

[0058]

[0059] Under a nitrogen atmosphere, 1a (0.1 mmol, 30.4 mg, 1.0 equiv.), 2h (0.15 mmol, 29.4 mg, 1.5 equiv.), Pd(PPh 3 ) 4 (0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiaryl phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL) were added to a reaction tube. The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ah was directly purified by column chromatography (yield 80%, enantioselectivity 90%). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 1H NMR (400 MHz, CDCl 3 ) δ 8.15 - 7.94 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.31 (dd, J = 5.1, 2.9 Hz, 1H), 7.21 (dd, J = 5.1, 1.1 Hz, 1H), 7.06 (d, J = 1.7 Hz, 1H), 6.33 - 6.17 (m, 1H), 4.97 (dd, J = 9.7, 4.0 Hz, 1H), 4.81 - 4.55 (m, 2H), 2.76 - 2.61 (m, 1H), 2.56 - 2.41 (m, 1H). 13 13C NMR (101 MHz, CDCl 3 ) δ 197.7, 138.8, 135.2, 133.6, 131.4, 129.1, 128.8, 126.1, 124.6, 119.3, 118.7, 75.7, 67.0, 27.6.

[0060] Example 9

[0061] Synthesis of Compound 3ba:

[0062]

[0063] Under a nitrogen atmosphere, 1b (0.1 mmol, 36.0 mg, 1.0 equiv.), 2a (0.15 mmol, 28.8 mg, 1.5 equiv.), Pd(PPh 3 ) 4(0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ba was directly purified by column chromatography (yield 80%, enantioselectivity 97%). (Eluent polarity: petroleum ether / ethyl acetate 10:1), 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.38 - 7.26 (m, 5H), 6.30 - 6.19 (m, 1H), 4.98 (dd, J = 9.9, 4.0 Hz, 1H), 4.84 - 4.64 (m, 2H), 2.74 - 2.62 (m, 1H), 2.56 - 2.46 (m, 1H), 1.36 (s, 9H). 13 C NMR (101 MHz, CDCl 3 ) δ 196.3, 156.4, 136.9, 134.9, 131.5, 128.0, 127.7, 126.8, 124.7, 124.0, 119.4, 74.5, 66.4, 34.3, 30.2, 27.0.

[0064] Example 10

[0065] Synthesis of compound 3ca:

[0066]

[0067] Under a nitrogen atmosphere, 1c (0.1 mmol, 32.2 mg, 1.0 equiv.), 2a (0.12 mmol, 23.0 mg, 1.2 equiv.), Pd(PPh 3 ) 4 (0.005 mmol, 5.8 mg, 5 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 36 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ca was directly purified by column chromatography (yield 67%, enantioselectivity 89%). (Eluent polarity: petroleum ether / ethyl acetate 10:1), 1 H NMR (400 MHz, CDCl 3)δ8.10 (dd, J = 8.4, 5.6 Hz, 2H), 7.40 - 7.23 (m, 5H), 7.16 (t, J = 8.5 Hz, 2H), 6.29 - 6.22 (m, 1H), 4.92 (dd, J = 9.8, 3.9 Hz, 1H), 4.80 - 4.64 (m, 2H), 2.76 - 2.64 (m, 1H), 2.55 - 2.43 (m, 1H). 13 CNMR(101MHz, CDCl 3 )δ196.3, 166.0 (d, J = 255.4 Hz), 137.7, 135.8, 131.9 (d, J = 9.3 Hz), 131.5 d, J = 3.0 Hz), 128.8, 127.9, 125.0, 120.2, 115.9 (d, J = 21.9 Hz), 75.7, 67.3, 27.7. 19 FNMR(376MHz, CDCl 3 )δ - 104.29.

[0068] Example 11

[0069] Synthesis of Compound 3da:

[0070]

[0071] Under a nitrogen atmosphere, 1d (0.1 mmol, 33.8 mg, 1.0 equiv.), 2a (0.12 mmol, 23.0 mg, 1.2 equiv.), Pd(PPh 3 ) 4 (0.005 mmol, 5.8 mg, 5 mol%), (R)-6,6'-bis(9-anthryl)spirobiaryl phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL) were added to the reaction tube. The reaction system was reacted at room temperature for 36 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3da was directly purified by column chromatography (yield 40%, enantioselectivity 96%). (Eluent polarity: petroleum ether / ethyl acetate 10:1) 1 H NMR(400MHz, CDCl 3 )δ8.01 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.39 - 7.28 (m, 5H), 6.35 - 6.16 (m, 1H), 4.90 (dd, J = 9.7, 4.0 Hz, 1H), 4.79 - 4.62 (m, 2H), 2.83 - 2.60 (m, 1H), 2.57 - 2.42 (m, 1H). 13¹³C NMR (101 MHz, CDCl 3 ) δ 196.7, 140.0, 137.7, 135.8, 133.5, 130.7, 129.08, 128.8, 127.9, 125.0, 120.2, 75.8, 67.3, 27.6.

[0072] Example 12

[0073] Synthesis of Compound 3ea:

[0074]

[0075] Under a nitrogen atmosphere, 1e (0.1 mmol, 38.4 mg, 1.0 equiv.), 2a (0.15 mmol, 28.8 mg, 1.5 equiv.), Pd(PPh 3 ) 4 (0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL) were added to a reaction tube. The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ea was directly purified by column chromatography (yield 36%, enantioselectivity 96%). (Eluent polarity: petroleum ether / ethyl acetate 10:1), 1 ¹H NMR (400 MHz, CDCl 3 ) δ 7.93 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.43 - 7.28 (m, 5H), 6.33 - 6.14 (m, 1H), 4.90 (dd, J = 9.6, 4.0 Hz, 1H), 4.79 - 4.61 (m, 2H), 2.80 - 2.62 (m, 1H), 2.55 - 2.33 (m, 1H). 13 ¹³C NMR (101 MHz, CDCl 3 ) δ 196.9, 137.7, 135.8, 133.9, 132.1, 130.7, 128.8, 128.8, 127.9, 125.0, 120.1, 75.8, 67.3, 27.6.

[0076] Example 13

[0077] Synthesis of Compound 3fa:

[0078]

[0079] Under a nitrogen atmosphere, 1f (0.1 mmol, 43.0 mg, 1.0 equiv.), 2a (0.15 mmol, 28.8 mg, 1.5 equiv.) were added to a reaction tube, Pd(PPh 3 ) 4 (0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3fa was directly purified by column chromatography (yield 24%, enantioselectivity 92%). (Eluent polarity: petroleum ether / ethyl acetate 10:1), 1 1H NMR (400 MHz, CDCl 3 ) δ 7.86 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.39 - 7.27 (m, 5H), 6.27 - 6.21 (m, 1H), 4.89 (dd, J = 9.6, 3.9 Hz, 1H), 4.79 - 4.62 (m, 2H), 2.75 - 2.63 (m, 1H), 2.55 - 2.43 (m, 1H). 13 13C NMR (101 MHz, CDCl 3 ) δ 197.1, 137.9, 137.6, 135.7, 134.3, 130.4, 128.61, 127.8, 124.9, 120.0, 101.5, 75.6, 67.2, 27.5.

[0080] Example 14

[0081] Synthesis of compound 3ga:

[0082]

[0083] Under a nitrogen atmosphere, 1g (0.1 mmol, 37.2 mg, 1.0 equiv.), 2a (0.15 mmol, 28.8 mg, 1.5 equiv.) were added to a reaction tube, Pd(PPh 3 ) 4 (0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), Molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ga was directly purified by column chromatography (yield 36%, enantioselectivity 96%). (Eluent polarity: petroleum ether / ethyl acetate 10:1), 1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.38 - 7.29 (m, 5H), 6.35 - 6.16 (m, 1H), 4.94 (dd, J = 9.6, 4.1 Hz, 1H), 4.79 - 4.60 (m, 2H), 2.81 - 2.61 (m, 1H), 2.60 - 2.38 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 197.0, 137.8, 137.5, 135.7, 134.4 (dd, J = 50.4, 17.6 Hz), 129.4, 128.6, 127.8, 125.6 (q, J = 3.7 Hz), 124.9, 119.9, 75.83, 67.2, 27.2. 19 F NMR (376 MHz, CDCl 3 ) δ -63.20 (s).

[0084] Example 15

[0085] Synthesis of compound 3ha:

[0086]

[0087] Under a nitrogen atmosphere, 1h (0.1 mmol, 35.4 mg, 1.0 equiv.), 2a (0.12 mmol, 23.0 mg, 1.2 equiv.), Pd(PPh 3 ) 4 (0.005 mmol, 5.8 mg, 5 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL) were added to the reaction tube. The reaction system was reacted at room temperature for 36 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ha was directly purified by column chromatography (yield 54%, enantioselectivity 91%). (Eluent polarity: petroleum ether / ethyl acetate 10:1), 1 H NMR (400 MHz, CDCl 3)δ8.60(s,1H),8.08(dd,J=8.6,1.5Hz,1H),7.99(d,J=8.0Hz,1H),7.95 - 7.86(m,2H),7.65 - 7.54(m,2H),7.41 - 7.27(m,5H),6.35 - 6.21(m,1H),5.15(dd,J=9.7,4.0Hz,1H),4.90 - 4.65(m,2H),2.83 - 2.67(m,1H),2.64 - 2.48(m,1H). 13 C NMR(101MHz,CDCl 3 )δ197.8,137.8,135.9,132.6,132.5,130.9,129.8,128.8,128.7,128.6,127.9,127.8,127.0,125.0,124.6,120.3,75.6,67.4,28.1.

[0088] Example 16

[0089] Synthesis of Compound 3ia:

[0090]

[0091] Under a nitrogen atmosphere, 1i (0.1 mmol, 29.4 mg, 1.0 equiv.), 2a (0.12 mmol, 23.0 mg, 1.2 equiv.), Pd(PPh 3 ) 4 (0.005 mmol, 5.8 mg, 5 mol%), (R)-6,6'-bis(9-anthryl)spirobiaryl phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL) were added to a reaction tube. The reaction system was reacted at room temperature for 36 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ia was directly purified by column chromatography (yield 51%, enantioselectivity 79%). (Eluent polarity: petroleum ether / ethyl acetate 10:1) 1 1H NMR(400MHz,CDCl 3 )δ7.65(s,1H),7.48(d,J=3.5Hz,1H),7.39 - 7.27(m,5H),6.58(d,J=2.0Hz,1H),6.27 - 6.19(m,1H),4.83 - 4.73(m,2H),4.69 - 4.61(m,1H),2.72 - 2.50(m,2H). 13 13C NMR(101MHz,CDCl 3)δ185.7,149.8,146.1,136.8,134.9,127.7,126.9,124.0,119.1,119.0,111.5,75.2,66.4,27.1.

[0092] Example 17

[0093] Synthesis of Compound 3ja:

[0094]

[0095] Under a nitrogen atmosphere, 1j (0.1 mmol, 31.0 mg, 1.0 equiv.), 2a (0.15 mmol, 28.8 mg, 1.5 equiv.) were added to a reaction tube, Pd(PPh 3 ) 4 (0.003 mmol, 3.5 mg, 3 mol%), (R)-6,6'-bis(9-anthryl)spirobiphenol phosphate (0.01 mmol, 6.6 mg, 10 mol%), molecular sieve (100 mg) and 1,2-dichloroethane (1.0 mL). The reaction system was reacted at room temperature for 18 h, and the reaction was monitored by TLC. After the reaction was completed, the product 3ja was directly purified by column chromatography (yield 72%, enantioselectivity 82%). (Eluent polarity: petroleum ether / ethyl acetate 10:1), 1 1H NMR (400 MHz, CDCl 3 )δ8.05 (d, J = 3.6 Hz, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.52 - 7.28 (m, 5H), 7.17 (t, J = 4.2 Hz, 1H), 6.36 -

[0096] 6.18 (m, 1H), 4.92 - 4.61 (m, 3H), 2.77 - 2.62 (m, 1H), 2.62 - 2.47 (m, 1H). 13 13C NMR (101 MHz, CDCl 3 )δ191.1, 141.0, 137.8, 135.8, 134.7, 134.1, 128.7, 128.2, 127.9, 125.0, 120.3, 77.3, 67.3, 28.2.

[0097] Example 18

[0098] Synthesis of Compound 4ba:

[0099]

[0100] Under a nitrogen atmosphere, 3ba (0.1 mmol, 36.0 mg, 1.0 equiv.) and ultradry methanol were added to a reaction tube. NaBH 4 (0.15 mmol, 5.7 mg, 1.5 equiv.) was added at -40 °C, and the reaction system was reacted at this temperature for 8 h. The reaction was monitored by TLC. After the reaction was completed, the product 4ba was directly purified by column chromatography (yield 99%, enantioselectivity 96%, diastereoselectivity ratio 2.5:1). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400 MHz, CDCl 3 ) δ 7.46 - 7.26 (m, 9H), 6.31 - 6.01 (m, 1H), 5.01 (d, J = 3.5 Hz, 1H), 4.87 - 4.46 (m, 2H), 3.84 (dt, J = 10.5, 3.5 Hz, 1H), 2.59 (s, 1H), 2.57 - 2.46 (m, 1H), 2.03 - 1.80 (m, 1H), 1.36 (s, 9H). 13 C NMR (101 MHz, CDCl 3 ) δ 150.5, 138.1, 137.0, 135.3, 128.5, 127.4, 126.1, 125.2, 124.8, 121.4, 76.7, 74.9, 67.7, 34.5, 31.4, 24.2.

[0101] Example 19

[0102] Synthesis of compound 5ao:

[0103]

[0104] Under a nitrogen atmosphere, 3ba (0.1 mmol, 36.0 mg, 1.0 equiv.) and ultradry tetrahydrofuran (1 mL) were added to a reaction tube. A 0.5 mol / L solution of ethynylmagnesium bromide in tetrahydrofuran (0.3 mmol, 0.6 mL, 3 equiv.) was added dropwise at 0 °C, and the reaction system was reacted at 0 °C for 12 h. The reaction was monitored by TLC. After the reaction was completed, the product 5ba was directly purified by column chromatography (yield 90%, enantioselectivity 96%, diastereoselectivity ratio >20:1). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR (400 MHz, CDCl 3)δ 7.51 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.28 - 7.15 (m, 5H), 6.01 (d, J = 4.2 Hz, 1H), 4.80 - 4.35 (m, 2H), 3.82 (dd, J = 10.6, 2.8 Hz, 1H), 3.12 (s, 1H), 2.58 (s, 1H), 2.37 - 2.21 (m, 1H), 1.88 - 1.63 (m, 1H), 1.27 (s, 9H). 13 C NMR(101MHz, CDCl 3 )δ 151.1, 137.9, 137.2, 135.3, 128.6, 127.6, 125.8, 125.2, 124.9, 121.2, 86.3, 79.6, 73.7, 73.0, 68.4, 34.6, 31.4, 25.0.

[0105] Example 20

[0106] Synthesis of Compound 5ao:

[0107]

[0108] Under a nitrogen atmosphere, 3ba (0.1 mmol, 36.0 mg, 1.0 equiv.) and ultra-dry tetrahydrofuran (1 mL) were added to a reaction tube. A 1.0 mol / L solution of vinylmagnesium bromide in tetrahydrofuran (0.3 mmol, 0.3 mL, 3 equiv.) was added dropwise at -78 °C. The reaction system was reacted at -78 °C for 12 h. The reaction was monitored by TLC. After completion of the reaction, the product 6ba was directly purified by column chromatography (yield 99%, enantioselectivity 96%, diastereoselectivity ratio >20:1). (Eluent polarity: petroleum ether / ethyl acetate 10:1). 1 H NMR(400MHz, CDCl 3 )δ 7.43 - 7.33 (m, 4H), 7.33 - 7.20 (m, 5H), 6.37 (dd, J = 17.2, 10.7 Hz, 1H), 6.17 - 6.00 (m, 1H), 5.34 (dd, J = 69.7, 13.9 Hz, 2H), 4.82 - 4.49 (m, 2H), 3.94 (dd, J = 10.7, 3.2 Hz, 1H), 2.76 (s, 1H), 2.53 - 2.29 (m, 1H), 1.77 - 1.58 (m, 1H), 1.31 (s, 9H). 13 C NMR(101MHz, CDCl 3)δ149.9, 143.1, 139.2, 138.1, 135.09, 128.7, 127.5, 125.3, 125.2, 124.9, 121.9, 113.8, 78.0, 77.5, 68.1, 34.6, 31.5, 25.1.

[0109] Example 21

[0110] Anti-inflammatory test:

[0111] The compounds 3ba, 3ag, 3ga, 3ea and 3fa in the above examples were subjected to anti-inflammatory tests. When evaluating the anti-inflammatory activity of the synthesized compounds, the levels of inflammatory factors in RAW264.7 cells were monitored. The concentrations of two key pro-inflammatory mediators, nitric oxide (NO) and reactive oxygen species (ROS), play a crucial role in the organism's response to inflammatory stimuli. Studies have shown that elevated levels of NO and ROS significantly affect the pathogenesis of various inflammatory diseases. Therefore, the concentrations of these two key pro-inflammatory mediators were detected in RAW264.7 cells. Figure 1 and Figure 2 show the effects of different concentrations of the compounds on the production of nitric oxide (NO) and reactive oxygen species (ROS) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages, respectively. Con. is the negative control group without induced inflammation (blank experiment). It can be found from the figure that the compounds 3ba, 3ag, 3ga, 3ea and 3fa have a certain inhibitory effect on NO. Especially when the compound concentration is 30 μM, the effect of compound 3ba at a concentration of 30 μM is equivalent to that of 10 μM dexamethasone (DEX.). While compounds 3ga and 3fa have a weak inhibitory effect on ROS secretion at a concentration of 30 μM, and the effect is equivalent to that of 10 μM DEX.

Claims

1. A chiral pyran ring compound, characterized in that: Its structure is shown in formula (III), In the formula, when substituted, R is selected from a benzene ring, a substituted phenyl ring, furan, thiophene or a naphthalene ring, and the substituent of the substituted phenyl ring is a tert-butyl group, a halogen group or a trifluoromethyl group; when substituted, R 1 It is selected from a benzene ring, a substituted phenyl group or thiophene, and the substituent of the substituted phenyl group is methyl, methoxy, halogen or trifluoromethyl.

2. A method for synthesizing a chiral pyran ring compound as claimed in claim 1, characterized in that: The sulfur ylide shown in formula (I) and the carbonate compound containing vinyl group shown in formula (II) are used as reaction raw materials, molecular sieves are added, and the reaction is carried out in an organic solvent at room temperature for 18-36 hours under the action of a catalyst and chiral phosphoric acid. After the reaction is completed, the chiral pyran ring compound shown in formula (III) is obtained by separation and purification by silica gel column chromatography. The reaction formula is shown below: In the formula, when substituted, R is selected from a benzene ring, a substituted phenyl ring, furan, thiophene or a naphthalene ring, and the substituent of the substituted phenyl ring is a tert-butyl group, a halogen group or a trifluoromethyl group; when substituted, R 1 It is selected from a benzene ring, a substituted phenyl group or thiophene, and the substituent of the substituted phenyl group is methyl, methoxy, halogen or trifluoromethyl.

3. The synthesis method according to claim 2, characterized in that The catalyst used is Pd(PPh3)4, and the amount used is 1 to 5 mol% of the amount of the compound represented by formula (I).

4. The synthesis method according to claim 2, characterized in that Chiral phosphoric acid is (S)-(+)-binaphthol phosphate, (R)-3,3'-bis(2,4,6-trimethylphenyl)-1,1'-binaphthol phosphate, (R)-3,3'-bis(1-naphthyl)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthol phosphate, (R)-3,3'-bis(3,5-diphenylphenyl)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthol phosphate, (11bS)-2,6-di-9-anthracenyl -8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxidized-binaphthyl[2,1-d:1',2'-f][1,3,2]dioxaphosphine, (R)-spirocyclic diphenol phosphonate or (R)-6,6'-di(9-anthryl)spirocyclic diphenol phosphate.

5. The synthesis method according to claim 2, characterized in that Molecular sieves are Molecular sieves, Molecular sieve or Molecular sieve.

6. The synthesis method according to claim 2, characterized in that The organic solvent is dichloromethane, 1,2-dichloroethane, isopropanol, ethanol, carbon tetrachloride, chloroform, chlorobenzene, toluene, dimethylacetamide or tetrahydrofuran.

7. The synthesis method according to claim 2, characterized in that The molar ratio of the compound represented by formula (I) to the compound represented by formula (II) is 1.0:1.0-1.0:2.

0.

8. The synthesis method according to claim 2, characterized in that After the reaction is completed, the specific operation process of separation and purification by silica gel column chromatography is as follows: after the reaction is completed, the reaction solution is concentrated and subjected to column chromatography, a mixture of petroleum ether and ethyl acetate is used as an eluent, the eluate containing the target compound is collected, concentrated, distilled and dried to obtain a compound as shown in formula (III), and the volume ratio of the mixture of petroleum ether and ethyl acetate is 10:1-20:

1.

9. The synthesis method according to claim 2, characterized in that The catalyst is Pd(PPh3)4, the amount of which is 3 mol% of the compound shown in formula (I), the chiral phosphoric acid is (R)-6,6'-di(9-anthryl)spirocyclic diphenol phosphate, and the molecular sieve is Molecular sieve, the organic solvent is 1,2-dichloroethane, and the molar ratio of the compound represented by formula (I) to the compound represented by formula (II) is 1.0:1.

5.

10. Use of the chiral pyran ring compound according to claim 1 in the preparation of anti-inflammatory drugs.

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