CN117683026A - 3-tetrahydrofuran chromone compound and diastereoisomeric divergent preparation method and application thereof - Google Patents

3-tetrahydrofuran chromone compound and diastereoisomeric divergent preparation method and application thereof Download PDF

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CN117683026A
CN117683026A CN202311687113.9A CN202311687113A CN117683026A CN 117683026 A CN117683026 A CN 117683026A CN 202311687113 A CN202311687113 A CN 202311687113A CN 117683026 A CN117683026 A CN 117683026A
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phenyl
substituted phenyl
chromone
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黄慧才
陈佳佳
詹若挺
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Guangzhou University of Traditional Chinese Medicine
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Guangzhou University of Traditional Chinese Medicine
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Abstract

The invention discloses a 3-tetrahydrofuran chromone compound, a diastereoisomeric divergent preparation method and application thereof. A 3-tetrahydrofuran chromone derivative having the structure shown below:wherein R is 1 Phenyl, substituted phenyl or naphthyl; r is R 2 Methyl, ethyl or cyano; r is R 3 Is phenyl, substituted phenyl or aromatic five-membered ring containing hetero atom; the heteroatom in the aromatic five-membered ring containing the heteroatom is S. The 3-tetrahydrofuran chromone compound disclosed by the invention has a certain inhibition effect on human non-small cell lung cancer cells H1299, is basically nontoxic to RAW 264.7 cells, and has good anti-inflammatory activity.

Description

3-tetrahydrofuran chromone compound and diastereoisomeric divergent preparation method and application thereof
Technical Field
The invention relates to the field of asymmetric organic chemical drug synthesis, in particular to a 3-tetrahydrofuran chromone compound, a diastereoisomeric divergent preparation method and application thereof.
Background
The presence of multiple stereocenters in natural and synthetic compounds is a very common phenomenon. Since the configuration of the stereocenters in a compound is generally critical to its physiological and pharmacological properties, the development of diastereoisomeric syntheses is highly desirable for compounds containing multiple stereocenters because it allows the selective synthesis of more than one diastereomer of a given molecule from the same starting material.
Chromones and their derivatives are an important class of heterocyclic compounds, which are widely found in natural products as well as in pharmaceutical molecules. The heterocycle has various pharmacological characteristics, and has excellent anti-inflammatory, antibacterial, antioxidant and anticancer activities, and a large number of researches prove that the efficient construction of the heterocycle has important significance for drug research and development. In addition, tetrahydrofuran ring is a ubiquitous structural group in many natural molecules, providing potential development space for various research fields. It has been reported that 3-tetrahydrofuranyl chromone backbone compounds can be extracted from g.parvifolia plants, but there is currently little research on such compounds.
The wide application prospect of chiral 3-tetrahydrofuran chromone compounds promotes us to develop a diastereoisomeric divergent synthesis strategy which starts from simple and easily available raw materials and realizes structural diversity with high yield and high stereoselectivity under mild conditions.
Disclosure of Invention
In order to overcome the problems in the prior art, the invention provides a 3-tetrahydrofuran chromone compound, and a diastereoisomeric divergent preparation method and application thereof.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the first aspect of the invention provides a 3-tetrahydrofuran chromone derivative, which has the following structure:
wherein R is 1 Phenyl, substituted phenyl or naphthyl;
R 2 methyl, ethyl or cyano;
R 3 is benzeneA group, a substituted phenyl group or an aromatic five-membered ring containing a heteroatom; the heteroatom in the aromatic five-membered ring containing the heteroatom is S.
Preferably, in the compound of formula I, R 1 The phenyl is phenyl, substituted phenyl or naphthyl, wherein the substituent in the substituted phenyl is any one of fluorine atom, chlorine atom, bromine atom, methoxy group, hydroxyl group and methyl group; r is R 3 The aromatic five-membered ring is phenyl, substituted phenyl or aromatic five-membered ring containing heteroatom S, wherein the substituent in the substituted phenyl is any one of chlorine atom, bromine atom, trifluoromethyl, methoxy, methyl, ethyl and phenyl;
in the compound of formula II, R 1 The phenyl is phenyl or substituted phenyl, wherein the substituent in the substituted phenyl is any one of fluorine atom and methoxy; r is R 2 Is methyl or ethyl; r is R 3 The aromatic five-membered ring is phenyl, substituted phenyl or aromatic five-membered ring containing heteroatom S, wherein the substituent in the substituted phenyl is any one of bromine atom, trifluoromethyl, methoxy, methyl and phenyl.
Further preferably, the 3-tetrahydrofuran chromone derivative has the following structural formula:
in a second aspect, the present invention provides a method for preparing the 3-tetrahydrofuran chromone compound in a diastereoisomeric divergent manner, comprising the steps of:
s1, reacting a compound shown in a formula (1) with dimethylformamide in a phosphorus oxychloride reagent to obtain a compound shown in a formula (2); reacting a compound of formula (2) with a cyano compound in the presence of a catalyst potassium carbonate, wherein the solvent is acetic anhydride, so as to obtain a compound of formula (3);
wherein R is 1 Phenyl, substituted phenyl or naphthyl; r is R 2 Methyl, ethyl or cyano;
s2, reacting the compound shown in the formula (4) with triphenylphosphine in toluene to obtain a compound shown in the formula (5); reacting the compound of formula (5) with glycolaldehyde dimer in anhydrous tetrahydrofuran to obtain a compound of formula (6);
wherein R is 3 Is phenyl, substituted phenyl or aromatic five-membered ring containing hetero atom; the heteroatom in the aromatic five-membered ring containing the heteroatom is S;
s3, mixing the compound of the formula (3) and the compound of the formula (6), adding a chiral catalyst of the formula (V) or the formula (VI), reacting in a first reaction solvent at 0 ℃, and purifying by column chromatography to obtain the compound of the formula (I) or the formula (III); after the reaction for generating the compounds of the formulas (I) and (III) is finished, directly spin-drying the reaction solvent, adding a base catalyst and a second reaction solvent, reacting at room temperature, and purifying by column chromatography to obtain the compound of the formula (I) or (IV);
the chiral catalyst has the following structural formulas:
wherein ar=3, 5- (CF) 3 ) 2 C 6 H 3 -。
Preferably, in step S1, the compound of formula (1) and dimethylformamide are stirred in phosphorus oxychloride reagent under ice bath condition for 0.8-1.2h, then transferred to room temperature and stirred for 22-26h, and reacted to obtain the compound of formula (2).
Preferably, in step S1, the reaction of the compound of formula (2) to prepare the compound of formula (3) is carried out at room temperature for 5-7 hours.
Preferably, in step S2, the compound of formula (4), triphenylphosphine and toluene are mixed, and then heated at 110-130 ℃ under reflux for 10-14h, the solid is obtained by suction filtration, the solid is dissolved in a solution of methanol and dichloromethane, a saturated sodium hydroxide solution is added, the mixed solution is stirred at room temperature for 0.9-1.1h, the dichloromethane is used for extraction, an organic layer is collected, and the organic layer is dried by spinning, thus obtaining the compound of formula (5).
Preferably, in step S2, after the compound of formula (5), glycolaldehyde dimer and tetrahydrofuran are mixed, reflux heating is performed at 64-68 ℃ for 2.5-3.5h, the solvent is dried by spin, and the compound of formula (6) is obtained by column chromatography purification.
Preferably, in step S3, the first reaction solvent is at least one of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, chlorobenzene, benzene, toluene, and ethyl acetate; the base catalyst is at least one of tetramethyl guanidine, dicycloamidine, lithium diisopropylamide, sodium bis (trimethylsilyl) amide, sodium hydroxide and potassium hydroxide; the second reaction solvent is at least one of dichloromethane, 1, 2-dichloroethane, chlorobenzene, benzene, toluene, ethyl acetate, acetonitrile, methanol, ethanol and isopropanol.
The third aspect of the invention provides application of the 3-tetrahydrofuran chromone compound in preparing anti-inflammatory drugs and/or anti-tumor drugs.
Preferably, when the 3-tetrahydrofuran chromone compound is applied to the preparation of antitumor drugs, the 3-tetrahydrofuran chromone compound has the following structural formula:
preferably, when the 3-tetrahydrofuran chromone compound is used for preparing anti-inflammatory drugs, the 3-tetrahydrofuran chromone compound has the following structural formula: further preferably, the 3-tetrahydrofuranThe structural formula of the chromone compound is as follows:
compared with the prior art, the invention has the beneficial effects that:
the 3-tetrahydrofuran chromone compound disclosed by the invention has a certain inhibition effect on human non-small cell lung cancer cells H1299, is basically nontoxic to RAW 264.7 cells, and has good anti-inflammatory activity.
The preparation method of the compound has the advantages of simplicity, convenience, mild condition, high yield, strong stereoselectivity, good biological activity and new drug development potential, and wide application prospect.
Drawings
FIG. 1 is a graph showing the effect of compound 25. Mu.M on H1299 cell survival at drug delivery concentration;
FIG. 2 is the effect of compounds on RAW 264.7 cell activity at a 25. Mu.M dosing concentration;
FIG. 3 is the effect of compound 25. Mu.M on the level of NO release from RAW 264.7 cells at the concentration of the compound administered.
Detailed Description
The following describes the invention in more detail. The description of these embodiments is provided to assist understanding of the present invention, but is not intended to limit the present invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.
The experimental methods in the following examples, unless otherwise specified, are conventional, and the experimental materials used in the following examples, unless otherwise specified, are commercially available.
The preparation method of the catalyst of the formula (V) and the formula (VI) comprises the following steps:
s1. quinidine/quinine (QD/QN) (1.0 eq.) and triphenylphosphine (1.2 eq.) were dissolved in dry tetrahydrofuran (0.2M) at room temperature, after which the reaction was cooled to 0 ℃, diisopropyl azodicarboxylate (1.2 eq.) was added and diphenyl azide phosphate (1.2 eq.) dissolved in dry tetrahydrofuran was added dropwise at 0℃and the reaction stirred at room temperature for 12h. Then, the reaction was heated at 50 ℃ for 2 hours, after which triphenylphosphine (1.3 eq.) was added, and stirring was continued for 2 hours, 1-2mL water was added, and stirring was continued overnight (TLC detects progress of the reaction);
note that: preparation of QNNH 2 When the reaction is required to be cooled to room temperature, 1-2mL of water is added, and the mixture is stirred for 3 hours;
spin-drying the reaction solvent, dissolving in dichloromethane, adding saturated hydrochloric acid solution to adjust pH to 1, and extracting the aqueous phase with dichloromethane for 3 times; then adding saturated sodium hydroxide aqueous solution into the water phase to adjust pH to 13, extracting with dichloromethane for 3 times, mixing the obtained organic phases, drying with anhydrous sodium sulfate, spin-drying the reaction solvent, and purifying by column chromatography to obtain yellow oily substance (QDNH) 2 /QNNH 2 )；
S2, dissolving 3, 5-bis (trifluoromethyl) aniline (1.0 eq.) and dimethyl squarate (1.0 eq.) in methanol at room temperature, stirring for 48h, and carrying out suction filtration to obtain white solid squaramide;
s3, QDNH is carried out 2 /QNNH 2 (1.0 eq.) and square amide in methanol, stirring at room temperature for 48h, spin-drying the reaction solvent, and purifying by column chromatography to give a yellow solid as a catalyst of formula (V)/formula (VI).
Example 1
The synthetic route for compound I-a is shown in the following formula:
step S1: in a round bottom flask, o-hydroxyacetophenone of formula (1) (20 mmol,1.0 eq.) was added, dissolved in dimethylformamide (12 mL), phosphorus oxychloride (60 mmol,3.0 eq.) was added dropwise in an ice bath, the reaction was stirred in an ice bath for 1h, then stirred at room temperature for 24h, quenched with ice water, filtered off with suction, and the solid was washed 2-3 times with water to give the crude product, which was recrystallized from methanol to give 3-formylchromanone of formula (2).
In a round bottom flask, ethyl cyanoformate (15 mmol,1.5 eq.), potassium carbonate (1 mmol,0.1 eq.) and acetic anhydride (10 mL) were added, after stirring well, the compound of formula (2) (10 mmol,1.0 eq.) was added and reacted at room temperature for 6h (thin layer chromatography monitoring the progress of the reaction), filtered off with suction and the solid was washed 2-3 times with cyclohexane to give the compound of formula (3).
Step S2: in a round bottom flask, triphenylphosphine (50 mmol,1.0 eq.) and toluene (200 mL) were added, after stirring well, the compound of formula (4) (50 mmol,1.0 eq.) was added, heated under reflux at 120 ℃ for 12h, suction filtration afforded a white solid, the solid was dissolved in a system solution of methanol and dichloromethane (10 mL:100 mL), saturated sodium hydroxide solution (100 mL) was added, the mixed solution was stirred at room temperature for 1h, extracted 3 times with dichloromethane, the organic layer was collected, and dried by spinning to give the compound of formula (5).
In a round bottom flask, the compound of formula (5) (12 mmol,1.2 eq.) and anhydrous tetrahydrofuran (50 mL) were added, after stirring well, glycolaldehyde dimer (10 mmol,1.0 eq.) was added, heated under reflux at 66 ℃ for 3h, the solvent was dried by spinning, and purified by column chromatography to give the compound of formula (6).
Step S3: in a reaction tube, the compound of formula (3) (0.1 mmol,1.0 eq.) was added sequentially, the squaric amide derivative catalyst (V) (0.01 mmol,0.1 eq.) and chloroform (1 mL), the compound of formula (6) (0.11 mmol,1.1 eq.) were stirred at 0deg.C until the reaction was complete (thin layer chromatography for detecting the progress of the reaction, reaction time of I-a was 72 h), the reaction solvent was dried by spin-drying, and the compound I-a was obtained by column chromatography purification. The structural formula is as follows:
white solid, yield 94%, dr 92:8, ee 95%.
1 H NMR(400MHz,CDCl 3 )δ8.22–8.16(m,2H),7.93(d,J＝7.6Hz,2H),7.72–7.66(m,1H),7.60(t,J＝7.3Hz,1H),7.49(dt,J＝10.6,5.8Hz,3H),7.41(t,J＝7.5Hz,1H),5.49(s,1H),4.60(dd,J＝8.7,6.6Hz,1H),3.93(s,3H),3.71(m,1H),3.53(m,2H),3.17–3.07(m,1H). 13 CNMR(100MHz,CDCl 3 )δ196.6,176.5,167.7,156.7,153.7,136.1,134.2,133.9,128.9,128.1,125.8,125.6,123.5,121.3,118.5,118.1,82.0,72.7,56.6,54.0,47.7,37.0.
Synthesis of Compound I-b: the synthesis method is the same as that of the compound I-a, and only needs to change the o-hydroxyacetophenone of the formula (1) into 5-fluoro-2-hydroxyacetophenone. The structural formula is as follows:
white solid, yield 98%, dr 95:5, ee 94%.
1 H NMR(400MHz,CDCl 3 )δ8.20(d,J＝1.1Hz,1H),7.93(d,J＝7.4Hz,2H),7.82(dd,J＝8.1,3.0Hz,1H),7.60(t,J＝7.4Hz,1H),7.55–7.46(m,3H),7.45–7.39(m,1H),5.49–5.46(m,1H),4.60(dd,J＝8.8,6.6Hz,1H),3.92(s,3H),3.71(m,1H),3.58–3.47(m,2H),3.17–3.08(m,1H). 13 C NMR(100MHz,CDCl 3 )δ196.6,175.8,175.8,167.6,161.0,158.5,153.9,153.0,153.0,136.1,133.9,128.9,128.1,124.6,124.6,122.7,122.5,120.8,120.7,120.6,118.0,110.8,110.6,81.9,72.8,56.5,54.1,47.6,37.0.
Synthesis of Compounds I-c: the synthesis method is the same as that of the compound I-a, and only needs to change the o-hydroxyacetophenone of the formula (1) into 5-chloro-2-hydroxyacetophenone. The structural formula is as follows:
white solid, yield83%, dr 90:10, ee 94%.
1 H NMR(400MHz,CDCl 3 )δ8.17(dd,J＝12.7,1.9Hz,2H),7.95–7.90(m,2H),7.66–7.58(m,2H),7.51–7.45(m,3H),5.47(d,J＝1.2Hz,1H),4.60(dd,J＝8.9,6.6Hz,1H),3.92(s,3H),3.71(m,1H),3.57–3.47(m,2H),3.17–3.08(m,1H). 13 C NMR(100MHz,CDCl 3 )δ196.6,175.4,167.6,155.0,153.9,136.1,134.5,133.9,131.6,129.0,128.1,125.3,124.4,121.5,120.2,118.0,81.9,72.8,56.5,54.1,47.6,37.0.
Synthesis of Compounds I-d: the synthesis method is the same as that of the compound I-a, and only needs to change the o-hydroxyacetophenone of the formula (1) into 5-bromo-2-hydroxyacetophenone. The structural formula is as follows:
white solid, yield 83%, dr 89:11, ee 96%.
1 H NMR(400MHz,CDCl 3 )δ8.32(d,J＝2.4Hz,1H),8.19(d,J＝1.4Hz,1H),7.95–7.91(m,2H),7.77(dd,J＝8.9,2.5Hz,1H),7.63–7.58(m,1H),7.49(t,J＝7.7Hz,2H),7.41(d,J＝8.9Hz,1H),5.47(d,J＝1.3Hz,1H),4.60(dd,J＝8.9,6.6Hz,1H),3.93(s,3H),3.71(m,1H),3.57–3.47(m,2H),3.17–3.07(m,1H). 13 C NMR(100MHz,CDCl 3 )δ196.6,175.3,167.6,155.5,153.9,137.3,136.1,133.9,129.0,128.5,128.1,124.7,121.6,120.4,119.1,118.0,81.9,72.8,56.5,54.1,47.6,37.0.
Synthesis of Compounds I-e: the synthesis method is the same as that of the compound I-a, and only needs to change the o-hydroxyacetophenone of the formula (1) into 4-bromo-2-hydroxyacetophenone. The structural formula is as follows:
white solid, yield 73%, dr 94:6, ee 94%.
1 H NMR(400MHz,CDCl 3 )δ8.14(d,J＝1.4Hz,1H),8.03(d,J＝8.5Hz,1H),7.94–7.89(m,2H),7.69(d,J＝1.7Hz,1H),7.63–7.56(m,1H),7.55–7.45(m,3H),5.45(d,J＝1.2Hz,1H),4.59(dd,J＝8.8,6.6Hz,1H),3.91(s,3H),3.72(m,1H),3.57–3.45(m,2H),3.16–3.06(m,1H). 13 C NMR(100MHz,CDCl 3 )δ196.4,175.7,167.5,156.6,153.6,136.0,133.8,129.2,128.8,128.5,128.0,127.1,122.2,121.7,121.5,117.9,81.7,72.7,56.4,53.9,47.5,36.8.
Synthesis of Compounds I-f: the synthesis method is the same as that of the compound I-a, and only needs to change the o-hydroxyacetophenone of the formula (1) into 2-hydroxy-5-methoxyacetophenone. The structural formula is as follows:
white solid, yield 98%, dr 92:8, ee 96%.
1 H NMR(400MHz,CDCl 3 )δ8.17(d,J＝1.3Hz,1H),7.92(d,J＝8.5Hz,2H),7.60(t,J＝7.4Hz,1H),7.54(d,J＝3.1Hz,1H),7.48(t,J＝7.7Hz,2H),7.43(d,J＝9.2Hz,1H),7.28(dd,J＝9.6,3.5Hz,1H),5.50(d,J＝1.2Hz,1H),4.60(dd,J＝8.9,6.5Hz,1H),3.94(s,3H),3.87(s,3H),3.74–3.67(m,1H),3.57–3.47(m,2H),3.16–3.07(m,1H). 13 C NMR(100MHz,CDCl 3 )δ196.6,176.4,167.7,157.2,153.4,151.6,136.1,133.9,128.9,128.1,124.5,124.1,120.5,119.9,118.1,104.7,82.0,72.7,56.6,56.0,54.0,47.7,36.9.
Synthesis of Compound I-g: the synthesis method is the same as that of the compound I-a, and only needs to change the o-hydroxyacetophenone of the formula (1) into 2-hydroxy-6-methoxyacetophenone. The structural formula is as follows:
white solid, yield 88%, dr 88:12, ee 94%.
1 H NMR(400MHz,CDCl 3 )δ8.03(d,J＝1.3Hz,1H),7.92(d,J＝8.5Hz,2H),7.62–7.53(m,2H),7.48(t,J＝7.7Hz,2H),7.05(d,J＝8.4Hz,1H),6.80(d,J＝8.3Hz,1H),5.46(d,J＝1.1Hz,1H),4.56(dd,J＝8.8,6.5Hz,1H),3.94(s,6H),3.68(t,J＝9.3Hz,1H),3.52–3.45(m,2H),3.08(dd,J＝19.0,10.1Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ196.6,176.3,167.8,160.1,158.7,151.8,136.1,134.3,133.9,128.9,128.1,122.6,118.2,114.3,110.4,106.7,82.0,72.4,56.6,54.0,47.8,36.6.
Synthesis of Compounds I-h: the synthesis method is the same as that of the compound I-a, and only needs to change the o-hydroxyacetophenone of the formula (1) into 2, 5-dihydroxyacetophenone. The structural formula is as follows:
white solid, yield 70%, dr 92:8, ee 95%.
1 H NMR(400MHz,CDCl 3 )δ8.19(d,J＝1.4Hz,1H),7.95–7.91(m,2H),7.88(d,J＝2.8Hz,1H),7.60(t,J＝7.4Hz,1H),7.53(d,J＝9.1Hz,1H),7.48(t,J＝7.7Hz,2H),7.44(dd,J＝9.1,2.8Hz,1H),5.47(d,J＝1.2Hz,1H),4.60(dd,J＝8.9,6.6Hz,1H),3.91(s,3H),3.71(t,J＝9.2Hz,1H),3.59–3.48(m,2H),3.17–3.09(m,1H). 13 C NMR(100MHz,CDCl 3 )δ196.6,175.9,169.2,167.6,154.2,153.9,147.9,136.1,133.9,128.9,128.5,128.1,124.2,121.0,119.9,118.0,117.8,81.9,72.8,56.6,54.0,47.6,37.0,21.1.
Synthesis of Compound I-i: the synthesis method is the same as that of the compound I-a, and only needs to change the o-hydroxyacetophenone of the formula (1) into 2, 6-dihydroxyacetophenone. The structural formula is as follows:
white solid, yield 83%, dr 89:11, ee 84%.
1 H NMR(400MHz,CDCl 3 )δ11.95(s,1H),8.17(d,J＝1.3Hz,1H),7.96–7.91(m,2H),7.61(t,J＝6.9Hz,1H),7.56(t,J＝8.4Hz,1H),7.49(t,J＝7.7Hz,2H),6.95(d,J＝8.4Hz,1H),6.82(d,J＝8.8Hz,1H),5.44(d,J＝1.2Hz,1H),4.63–4.58(m,1H),3.89(s,3H),3.71(t,J＝9.2Hz,1H),3.60–3.49(m,2H),3.19–3.09(m,1H). 13 C NMR(100MHz,CDCl 3 )δ196.6,181.3,167.6,160.8,156.9,154.8,136.1,136.0,133.9,129.0,128.2,120.0,118.0,111.8,110.7,107.6,81.5,72.9,56.5,54.1,47.7,37.1.
Synthesis of Compound I-j: the synthesis method is the same as that of the compound I-a, and only needs to change the o-hydroxyacetophenone of the formula (1) into 2-hydroxy-5-methylacetophenone. The structural formula is as follows:
white solid, yield 97%, dr 93:7, ee 99%.
1 H NMR(400MHz,CDCl 3 )δ8.17(d,J＝1.3Hz,1H),8.00–7.96(m,1H),7.95–7.91(m,2H),7.60(t,J＝7.4Hz,1H),7.52–7.46(m,3H),7.40(d,J＝8.6Hz,1H),5.49(d,J＝1.2Hz,1H),4.60(dd,J＝8.9,6.6Hz,1H),3.93(s,3H),3.71(t,J＝9.1Hz,1H),3.58–3.47(m,2H),3.17–3.08(m,1H),2.44(s,3H). 13 C NMR(100MHz,CDCl 3 )δ196.6,176.6,167.7,155.0,153.5,136.1,135.6,135.5,133.8,128.9,128.1,125.1,123.1,121.1,118.2,118.1,82.0,72.7,56.6,54.0,47.6,37.0,21.0.
Synthesis of Compounds I-k: the synthesis method is the same as that of the compound I-a, and only needs to change the o-hydroxyacetophenone of the formula (1) into 2-acetyl-1-naphthol. The structural formula is as follows:
white solid, yield 95%, dr 92:8, ee 96%.
1 H NMR(400MHz,CDCl 3 )δ8.52–8.48(m,1H),8.37(d,J＝1.4Hz,1H),8.11(d,J＝8.7Hz,1H),7.95–7.89(m,3H),7.76(d,J＝8.8Hz,1H),7.69(pd,J＝7.0,1.4Hz,2H),7.60(t,J＝7.4Hz,1H),7.48(t,J＝7.7Hz,2H),5.56(s,1H),4.64(dd,J＝8.8,6.7Hz,1H),3.96(s,3H),3.78–3.71(m,1H),3.61–3.49(m,2H),3.19–3.10(m,1H). 13 C NMR(100MHz,CDCl 3 )δ196.6,176.2,167.7,154.4,152.8,136.1,136.1,133.8,129.7,128.9,128.2,128.1,127.4,125.8,124.0,122.8,122.5,120.5,119.8,118.1,82.0,72.8,56.6,54.0,47.7,37.0.
Synthesis of Compound I-l: the synthesis method is the same as that of the compound I-a, and only needs to change the o-hydroxyacetophenone of the formula (1) into 1-acetyl-2-naphthol. The structural formula is as follows:
white solid, yield 91%, dr 85:15, ee 94%.
1 H NMR(400MHz,CDCl 3 )δ9.94(d,J＝8.6Hz,1H),8.24(d,J＝1.4Hz,1H),8.10(d,J＝9.1Hz,1H),7.97–7.93(m,2H),7.90(d,J＝7.8Hz,1H),7.73(ddd,J＝8.5,7.0,1.4Hz,1H),7.64–7.59(m,2H),7.54(d,J＝9.1Hz,1H),7.50(t,J＝7.7Hz,2H),5.58(d,J＝1.3Hz,1H),4.63(dd,J＝8.9,6.6Hz,1H),3.99(s,3H),3.74(t,J＝9.2Hz,1H),3.60–3.52(m,2H),3.20–3.12(m,1H). 13 C NMR(100MHz,CDCl 3 )δ196.7,178.1,167.9,158.1,151.3,136.2,136.0,133.9,130.8,130.5,129.4,129.0,128.3,128.2,127.4,126.9,124.1,118.2,117.8,117.0,82.4,72.8,56.7,54.0,47.7,37.0.
Example 2
Synthesis of Compound I-m: the synthesis method is similar to the compound I-a, wherein the compound of formula (2) is synthesized by the method of the compound of formula (3):
in a round bottom flask, the compound of formula (2) (10 mmol,1.0 eq.) and malononitrile (10 mmol,1.0 eq.) were added, water (100 mL) was heated to reflux for 45min, suction filtered and the solid recrystallized from ethanol to give the compound of formula (3).
The structural formula of the compound I-m is as follows:
white solid, 43% yield, dr 74:26, ee 84%.
1 H NMR(400MHz,CDCl 3 )δ8.29(dd,J＝8.0,1.4Hz,1H),8.19(d,J＝1.1Hz,1H),8.05–7.99(m,2H),7.74(ddd,J＝8.6,7.3,1.6Hz,1H),7.63(t,J＝7.4Hz,1H),7.56–7.44(m,4H),5.49–5.43(m,1H),4.74(dd,J＝9.4,6.6Hz,1H),3.78–3.64(m,2H),3.57–3.41(m,2H). 13 CNMR(100MHz,CDCl 3 )δ195.8,176.1,156.6,154.6,135.7,134.6,134.3,129.1,128.3,126.1,126.1,123.5,119.6,118.5,114.0,113.2,81.7,72.7,46.7,44.7,38.3.
Synthesis of Compounds I-n: the synthesis method is the same as that of the compound I-a, and only the ethyl cyanoformate in the step S1 is required to be replaced by ethyl cyanoacetate. The structural formula is as follows:
white solid, yield 95%, dr 93:7, ee 95%.
1 H NMR(400MHz,CDCl 3 )δ8.19(dd,J＝7.6,1.4Hz,2H),7.95–7.91(m,2H),7.69(ddd,J＝8.6,7.2,1.6Hz,1H),7.60(t,J＝7.4Hz,1H),7.51–7.46(m,3H),7.43–7.38(m,1H),5.51(d,J＝1.1Hz,1H),4.60(dd,J＝8.9,6.5Hz,1H),4.41(qq,J＝7.5,3.6Hz,2H),3.70(t,J＝9.2Hz,1H),3.57–3.48(m,2H),3.18–3.08(m,1H),1.38(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ196.5,176.4,167.1,156.7,153.6,136.1,134.2,133.8,128.9,128.1,125.8,125.5,123.5,121.4,118.4,118.2,81.8,72.7,63.5,56.6,47.6,36.9,14.3.
Synthesis of Compound I-o: the synthesis method is the same as that of the compound I-a, and only 2-bromoacetophenone of the formula (4) is required to be replaced by 2-bromo-4' -chloroacetophenone. The structural formula is as follows:
white solid, yield 92%, dr 92:8, ee 97%.
1 H NMR(400MHz,CDCl 3 )δ8.18(td,J＝4.1,1.5Hz,2H),7.87(d,J＝8.5Hz,2H),7.72–7.66(m,1H),7.50(d,J＝8.4Hz,1H),7.45(d,J＝8.5Hz,2H),7.41(t,J＝7.6Hz,1H),5.47(d,J＝1.0Hz,1H),4.62–4.55(m,1H),3.92(s,3H),3.70(t,J＝9.1Hz,1H),3.57–3.44(m,2H),3.14–3.04(m,1H). 13 C NMR(100MHz,CDCl 3 )δ195.4,176.5,167.6,156.7,153.7,140.4,134.4,134.2,129.5,129.3,125.8,125.6,123.4,121.2,118.5,118.0,82.0,72.7,56.5,54.1,47.5,37.0.
Synthesis of Compound I-p: the synthesis method is the same as that of the compound I-a, and only 2-bromoacetophenone of the formula (4) is required to be replaced by 2,4' -dibromoacetophenone. The structural formula is as follows:
white solid, yield 91%, dr 94:6, ee 99%.
1 H NMR(400MHz,CDCl 3 )δ8.18(q,J＝3.3Hz,2H),7.79(d,J＝8.4Hz,2H),7.69(t,J＝7.8Hz,1H),7.62(d,J＝8.5Hz,2H),7.50(d,J＝8.5Hz,1H),7.41(t,J＝7.6Hz,1H),5.47(s,1H),4.58(m,1H),3.91(s,3H),3.70(t,J＝9.1Hz,1H),3.57–3.43(m,2H),3.13–3.04(m,1H). 13 CNMR(100MHz,CDCl 3 )δ195.7,176.5,167.6,156.7,153.7,134.8,134.2,132.3,129.6,129.1,125.8,125.6,123.4,121.2,118.5,118.0,82.0,72.7,56.5,54.1,47.5,37.0.
Synthesis of Compounds I-q: the synthesis method is the same as that of the compound I-a, and only 2-bromoacetophenone of the formula (4) is required to be replaced by 2-bromo-4' - (trifluoromethyl) acetophenone. The structural formula is as follows:
white solid, yield 88%, dr 93:7, ee 96%.
1 H NMR(400MHz,CDCl 3 )δ8.21–8.17(m,2H),8.04(d,J＝8.2Hz,2H),7.76(d,J＝8.3Hz,2H),7.70(ddd,J＝8.6,7.2,1.6Hz,1H),7.51(d,J＝8.4Hz,1H),7.42(t,J＝7.6Hz,1H),5.48(d,J＝1.2Hz,1H),4.60(dd,J＝9.0,6.5Hz,1H),3.92(s,3H),3.73(t,J＝9.0Hz,1H),3.60–3.52(m,2H),3.19–3.11(m,1H). 13 C NMR(100MHz,CDCl 3 )δ195.9,176.5,167.6,156.7,153.7,138.7,134.3,128.5,126.1,126.1,126.0,126.0,125.8,125.6,123.5,121.1,118.5,118.0,82.1,72.7,56.6,54.1,47.4,37.5. 19 F NMR(376MHz,CDCl 3 )δ-63.21.
Synthesis of Compound I-r: the synthesis method is the same as that of the compound I-a, and only 2-bromoacetophenone of the formula (4) is required to be replaced by 2-bromo-4' -methoxyacetophenone. The structural formula is as follows:
white solid, yield 92%, dr 92:8, ee 94%.
1 H NMR(400MHz,CDCl 3 )δ8.19(dd,J＝6.9,1.2Hz,2H),7.91(m,2H),7.72–7.66(m,1H),7.50(d,J＝8.3Hz,1H),7.41(t,J＝7.3Hz,1H),6.94(d,J＝8.9Hz,2H),5.49(d,J＝1.0Hz,1H),4.59(dd,J＝8.8,6.9Hz,1H),3.93(s,3H),3.87(s,3H),3.70(t,J＝9.3Hz,1H),3.57–3.41(m,2H),3.06(dd,J＝17.4,8.5Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ195.0,176.5,167.7,164.1,156.7,153.7,134.2,130.5,129.2,125.9,125.6,123.5,121.4,118.5,118.1,114.1,81.9,72.8,56.6,55.7,54.0,47.8,36.5.
Synthesis of Compound I-s: the synthesis method is the same as that of the compound I-a, and only 2-bromoacetophenone of the formula (4) is required to be replaced by 2-bromo-4' -methylacetophenone. The structural formula is as follows:
white solid, yield 92%, dr value 90:10, ee value 99%.
1 H NMR(400MHz,CDCl 3 )δ8.22–8.16(m,2H),7.82(d,J＝8.2Hz,2H),7.69(ddd,J＝8.6,7.2,1.6Hz,1H),7.50(d,J＝8.3Hz,1H),7.44–7.38(m,1H),7.28(s,1H),7.26(s,1H),5.49(d,J＝1.2Hz,1H),4.59(dd,J＝8.8,6.7Hz,1H),3.93(s,3H),3.70(t,J＝9.2Hz,1H),3.58–3.43(m,2H),3.09(dd,J＝17.4,8.2Hz,1H),2.42(s,3H). 13 C NMR(100MHz,CDCl 3 )δ196.2,176.6,167.7,156.7,153.7,144.8,134.2,133.7,129.6,128.2,125.9,125.6,123.5,121.3,118.5,118.1,81.9,72.8,56.6,54.0,47.7,36.8,21.8.
Synthesis of Compound I-t: the synthesis method is the same as that of the compound I-a, and only 2-bromoacetophenone of the formula (4) is required to be replaced by 2-bromo-2' -methylacetophenone. The structural formula is as follows:
white solid, 96% yield, 87:10:3 dr, 94% ee.
1 H NMR(400MHz,CDCl 3 )δ8.22–8.16(m,2H),7.69(m,1H),7.64(d,J＝7.8Hz,1H),7.50(d,J＝8.4Hz,1H),7.43–7.38(m,2H),7.30–7.25(m,2H),5.49(d,J＝1.3Hz,1H),4.59(dd,J＝8.8,6.9Hz,1H),3.91(s,3H),3.71(t,J＝9.3Hz,1H),3.52(m,1H),3.42(dd,J＝17.7,6.1Hz,1H),3.06(dd,J＝17.7,8.1Hz,1H),2.51(s,3H). 13 C NMR(100MHz,CDCl 3 )δ200.0,176.5,167.7,156.7,153.6,138.8,136.6,134.2,132.4,132.1,128.8,126.0,125.8,125.5,123.5,121.3,118.4,118.1,82.0,72.7,56.5,54.0,47.9,39.5,21.6.
Synthesis of Compound I-u: the synthesis method is the same as that of the compound I-a, and only 2-bromoacetophenone of the formula (4) is required to be replaced by 2-bromo-4' -ethylacetophenone. The structural formula is as follows:
white solid, yield 91%, dr 92:8, ee 99%.
1 H NMR(400MHz,CDCl 3 )δ8.20(dd,J＝6.9,1.4Hz,2H),7.85(d,J＝8.2Hz,2H),7.69(m,1H),7.50(d,J＝8.4Hz,1H),7.41(t,J＝7.6Hz,1H),7.30(d,J＝8.2Hz,2H),5.50(d,J＝1.1Hz,1H),4.59(dd,J＝8.8,6.7Hz,1H),3.94(s,3H),3.70(t,J＝9.2Hz,1H),3.57–3.45(m,2H),3.14–3.05(m,1H),2.72(q,J＝7.6Hz,2H),1.26(t,J＝7.6Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ196.2,176.6,167.7,156.7,153.7,151.0,134.2,133.9,128.4,128.4,125.9,125.6,123.5,121.4,118.5,118.1,81.9,72.8,56.6,54.0,47.8,36.8,29.1,15.3.
Synthesis of Compounds I-v: the synthesis method is the same as that of the compound I-a, and only 2-bromoacetophenone of the formula (4) is required to be replaced by 2-bromo-4-phenylacetophenone. The structural formula is as follows:
white solid, yield 91%, dr 93:7, ee 95%.
1 H NMR(400MHz,CDCl 3 )δ8.20(m,2H),8.01(d,J＝8.4Hz,2H),7.73–7.67(m,3H),7.65–7.61(m,2H),7.52–7.45(m,3H),7.41(t,J＝7.2Hz,2H),5.51(d,J＝1.2Hz,1H),4.66–4.58(m,1H),3.95(s,3H),3.73(t,J＝9.1Hz,1H),3.62–3.51(m,2H),3.20–3.12(m,1H). 13 CNMR(100MHz,CDCl 3 )δ196.2,176.5,167.7,156.7,153.7,146.5,139.7,134.8,134.2,129.1,128.7,128.5,127.5,127.4,125.8,125.6,123.5,121.3,118.5,118.1,82.0,72.8,56.6,54.0,47.7,37.0.
Synthesis of Compound I-w: the synthesis method is the same as that of the compound I-a, and only 2-bromoacetophenone of the formula (4) is required to be replaced by 2- (bromoacetyl) thiophene. The structural formula is as follows:
white solid, yield 94%, dr 90:10, ee 99%.
1 H NMR(400MHz,CDCl 3 )δ8.19(m,2H),7.73–7.67(m,3H),7.50(d,J＝8.3Hz,1H),7.44–7.39(m,1H),7.15(dd,J＝4.8,3.9Hz,1H),5.49(d,J＝1.1Hz,1H),4.58(dd,J＝8.9,6.8Hz,1H),3.94(s,3H),3.72(t,J＝9.3Hz,1H),3.55–3.40(m,2H),3.07(dd,J＝17.2,8.7Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ189.2,176.4,167.5,156.6,153.5,143.0,134.5,134.1,132.4,128.3,125.7,125.5,123.4,121.2,118.4,117.9,81.9,72.5,56.4,53.9,47.5,37.3.
Example 3
Synthesis of Compound II-a: the synthesis method of step S1 and step S2 is the same as that of the compound I-a, and the synthesis method of step S3 is as follows:
step S3: in a reaction tube, the compound of formula (3) (0.1 mmol,1.0 eq.) was added sequentially, the squaric amide derivative catalyst (v) (0.01 mmol,0.1 eq.), chloroform (1 mL), the compound of formula (6) (0.11 mmol,1.1 eq.) was stirred at 0 ℃ until the reaction was complete (thin layer chromatography detects the progress of the reaction), the reaction solvent was dried by spinning, isopropanol (2 mL) was added, and bicyclic amidine (DBU) (0.02 mmol,0.2 eq.) was stirred at room temperature until the reaction was complete (thin layer chromatography detects the progress of the reaction), and the compound ii-a was obtained by column chromatography purification. The structural formula is as follows:
white solid, yield 95%, dr value97:2:1, ee 96%.
1 H NMR(400MHz,CDCl 3 )δ8.24–8.16(m,2H),7.98–7.93(m,2H),7.69(m,1H),7.59(t,J＝7.4Hz,1H),7.52–7.45(m,3H),7.41(t,J＝7.6Hz,1H),5.49(d,J＝1.2Hz,1H),4.61(t,J＝7.8Hz,1H),3.96(s,3H),3.89–3.76(m,2H),3.52(dd,J＝18.2,5.2Hz,1H),3.36(m,1H). 13 CNMR(100MHz,CDCl 3 )δ196.6,176.2,166.6,156.6,154.5,136.0,134.2,133.9,128.9,128.2,125.8,125.6,123.5,120.5,118.4,115.4,80.7,72.2,59.9,54.2,45.1,39.6.
Synthesis of Compound II-b: the synthesis method is the same as that of the compound II-a, and only needs to change the o-hydroxyacetophenone in the formula (1) into 5-fluoro-2-hydroxyacetophenone. The structural formula is as follows:
white solid, yield 94%, dr 62:32:6, ee 96%.
1 H NMR(400MHz,CDCl 3 )δ8.22(d,J＝1.2Hz,1H),7.99–7.95(m,2H),7.82(dd,J＝8.1,3.1Hz,1H),7.60(m,1H),7.54–7.46(m,3H),7.43(m,1H),5.49(d,J＝1.2Hz,1H),4.62(t,J＝7.8Hz,1H),3.96(s,3H),3.90–3.78(m,2H),3.52(dd,J＝18.2,5.2Hz,1H),3.36(m,1H). 13 CNMR(100MHz,CDCl 3 )δ196.6,175.5,166.6,161.0,158.6,154.8,152.8,136.0,133.9,128.9,128.2,124.7,124.6,122.7,122.4,120.7,120.6,120.1,115.3,110.8,110.6,80.6,72.3,59.9,54.3,45.1,39.6.
Synthesis of Compounds II-c: the synthesis method is the same as that of the compound II-a, and only needs to change the o-hydroxyacetophenone in the formula (1) into 2-hydroxy-5-methoxyacetophenone. The structural formula is as follows:
white solid, yield 98%, dr 75:19:6, ee 96%.
1 H NMR(400MHz,CDCl 3 )δ8.20(d,J＝1.1Hz,1H),8.00–7.93(m,2H),7.60(m,1H),7.53(d,J＝3.1Hz,1H),7.51–7.42(m,3H),7.28(dd,J＝9.2,3.1Hz,1H),5.51(d,J＝1.1Hz,1H),4.60(t,J＝7.9Hz,1H),3.97(s,3H),3.89(s,3H),3.87–3.72(m,2H),3.52(dd,J＝18.2,5.1Hz,1H),3.36(dd,J＝18.1,8.5Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ196.7,176.1,166.8,157.3,154.3,151.5,136.0,133.9,128.9,128.2,124.4,124.1,119.9,119.8,115.4,104.8,80.9,76.8,72.3,59.9,56.1,54.3,45.1,39.6.
Synthesis of Compounds II-d: the synthesis method is the same as that of the compound II-a, and only the ethyl cyanoformate in the step S1 is required to be replaced by ethyl cyanoacetate. The structural formula is as follows:
white solid, yield 95%, dr 93:4:3, ee 99%.
1 H NMR(400MHz,CDCl 3 )δ8.24–8.16(m,2H),7.99–7.94(m,2H),7.70(m,1H),7.62–7.57(m,1H),7.52–7.45(m,3H),7.44–7.39(m,1H),5.51(d,J＝1.2Hz,1H),4.65–4.58(m,1H),4.42(m,2H),3.89–3.78(m,2H),3.56–3.48(m,1H),3.40–3.30(m,1H),1.34(t,J＝7.2Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ196.7,176.1,166.0,156.6,154.5,136.0,134.2,133.9,128.9,128.2,125.8,125.6,123.6,120.6,118.5,115.5,80.5,72.2,63.7,60.1,45.0,39.6,14.1.
Synthesis of Compound II-e: the synthesis method is the same as that of the compound II-a, and only 2-bromoacetophenone of the formula (4) is required to be replaced by 2,4' -dibromoacetophenone. The structural formula is as follows:
white solid, yield 91%, dr 98:2, ee 92%.
1 H NMR(400MHz,CDCl 3 )δ8.22–8.15(m,2H),7.82(m,2H),7.69(m,1H),7.44–7.39(m,1H),5.48(d,J＝1.2Hz,1H),4.58(t,J＝7.9Hz,1H),3.95(s,3H),3.89–3.75(m,2H),3.47(dd,J＝18.2,5.3Hz,1H),3.31(dd,J＝18.2,8.4Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ195.7,176.2,166.6,156.5,154.5,134.7,134.2,132.2,129.7,129.2,125.8,125.6,123.5,120.4,118.4,115.3,80.7,72.1,59.9,54.3,44.9,39.6.
Synthesis of Compounds II-f: the synthesis method is the same as that of the compound II-a, and only 2-bromoacetophenone in the formula (4) is required to be replaced by 2-bromo-4' - (trifluoromethyl) acetophenone. The structural formula is as follows:
white solid, yield 84%, dr 99:1, ee 95%.
1 H NMR(400MHz,CDCl 3 )δ8.22–8.16(m,2H),8.07(d,J＝8.2Hz,2H),7.77–7.67(m,3H),7.50(d,J＝8.4Hz,1H),7.42(t,J＝7.5Hz,1H),5.49(d,J＝1.2Hz,1H),4.60(t,J＝7.8Hz,1H),3.96(s,3H),3.90–3.77(m,2H),3.54(dd,J＝18.4,5.5Hz,1H),3.37(dd,J＝18.3,8.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ195.8,176.2,166.6,156.6,154.5,138.6,134.2,128.6,126.1,126.0,126.0,125.9,125.8,125.6,123.5,120.4,118.4,115.3,80.8,72.1,59.9,54.3,44.9,40.1. 19 FNMR(376MHz,CDCl 3 )δ-63.20.
Synthesis of Compound II-g: the synthesis method is the same as that of the compound II-a, and only 2-bromoacetophenone of the formula (4) is required to be replaced by 2-bromo-4' -methoxyacetophenone. The structural formula is as follows:
white solid, 93% yield, dr 87:9:4, ee 94%.
1 H NMR(400MHz,CDCl 3 )δ8.23–8.16(m,2H),7.97–7.92(m,2H),7.70(m,1H),7.50(d,J＝8.0Hz,1H),7.45–7.39(m,1H),6.96–6.92(m,2H),5.49(d,J＝1.3Hz,1H),4.60(t,J＝7.9Hz,1H),3.96(s,3H),3.88(s,3H),3.85(m,1H),3.84–3.76(m,1H),3.47(dd,J＝17.9,5.1Hz,1H),3.30(dd,J＝17.9,8.7Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ195.0,176.2,166.7,164.1,156.6,154.5,134.2,130.6,129.1,125.9,125.6,123.5,120.6,118.4,115.4,114.0,80.7,72.3,60.0,55.7,54.2,45.2,39.2.
Synthesis of Compounds II-h: the synthesis method is the same as that of the compound II-a, and only the 2-bromoacetophenone shown in the formula (4) is required to be replaced by 2-bromo-2' -methylacetophenone. The structural formula is as follows:
white solid, yield 91%, dr 92:7:1, ee 95%.
1 H NMR(400MHz,CDCl 3 )δ8.23–8.15(m,2H),7.70(m,2H),7.50(d,J＝8.3Hz,1H),7.44–7.38(m,2H),7.30–7.24(m,2H),5.49(d,J＝1.2Hz,1H),4.59(t,J＝8.2Hz,1H),3.96(s,3H),3.90–3.76(m,2H),3.45(dd,J＝18.1,5.7Hz,1H),3.30(dd,J＝18.1,8.2Hz,1H),2.51(s,3H). 13 C NMR(100MHz,CDCl 3 )δ200.0,176.2,166.8,156.6,154.5,138.9,136.4,134.2,132.4,132.2,129.0,126.0,125.9,125.6,123.5,120.6,118.4,115.4,80.8,77.5,72.2,59.9,54.2,45.3,42.2,21.7.
Synthesis of Compound II-i: the synthesis method is the same as that of the compound II-a, and only 2-bromoacetophenone of the formula (4) is required to be replaced by 2-bromo-4-phenylacetophenone. The structural formula is as follows:
white solid, 91% yield, dr 56:37:7, ee 93%.
1 H NMR(400MHz,CDCl 3 )δ8.23(d,J＝1.3Hz,1H),8.19(dd,J＝8.0,1.6Hz,1H),8.06–8.02(m,2H),7.73–7.68(m,3H),7.65–7.61(m,2H),7.52–7.45(m,3H),7.42(m,2H),5.51(d,J＝1.3Hz,1H),4.66–4.59(m,1H),3.98(s,3H),3.92–3.80(m,2H),3.56(m,1H),3.43–3.35(m,1H). 13 C NMR(100MHz,CDCl 3 )δ196.2,176.3,166.7,156.6,154.6,146.6,139.8,134.7,134.2,129.1,128.9,128.5,127.5,127.4,125.9,125.6,123.6,120.6,118.5,115.4,80.8,72.3,60.0,54.3,45.1,39.7.
Synthesis of Compound II-j: the synthesis method is the same as that of the compound II-a, and only the 2-bromoacetophenone shown in the formula (4) is required to be replaced by 2- (bromoacetyl) thiophene. The structural formula is as follows:
white solid, yield95% and 93:6:1, 96% ee.
1 H NMR(400MHz,CDCl 3 )δ8.23–8.15(m,2H),7.80–7.74(m,1H),7.73–7.66(m,2H),7.50(d,J＝8.5Hz,1H),7.42(m,1H),7.18–7.12(m,1H),5.49(s,1H),4.61–4.54(m,1H),3.95(d,J＝1.4Hz,3H),3.92–3.85(m,1H),3.84–3.76(m,1H),3.50–3.41(m,1H),3.34–3.23(m,1H). 13 C NMR(100MHz,CDCl 3 )δ189.3,176.2,166.5,156.6,154.5,143.1,134.6,134.2,132.8,128.5,125.9,125.6,123.5,120.5,118.4,115.3,80.7,72.1,59.8,54.3,45.0,39.8.
Synthesis of Compound III: the synthesis process is the same as that of the compound I-a, and only the catalyst (V) is replaced by the catalyst (VI). The structural formula is as follows:
white solid, yield 98%, dr 88:12, ee 96%.
1 H NMR(400MHz,CDCl 3 )δ8.19(m,2H),7.95–7.91(m,2H),7.69(m,1H),7.61(m,1H),7.52–7.46(m,3H),7.43–7.38(m,1H),5.49(d,J＝1.2Hz,1H),4.60(m,1H),3.93(s,3H),3.74–3.67(m,1H),3.58–3.47(m,2H),3.17–3.08(m,1H). 13 C NMR(100MHz,CDCl 3 )δ196.6,176.5,167.7,156.7,153.7,136.1,134.2,133.9,128.9,128.1,125.8,125.6,123.5,121.3,118.5,118.1,82.0,72.7,56.6,54.0,47.7,37.0.
Synthesis of Compound IV: the synthesis method is the same as that of the compound II-a, and only the catalyst (V) is needed to be replaced by the catalyst (VI). The structural formula is as follows:
white solid, yield 98%, dr 90:8:2, ee 96%.
1 H NMR(400MHz,CDCl 3 )δ8.23–8.17(m,2H),7.99–7.95(m,2H),7.70m,1H),7.62–7.57(m,1H),7.52–7.45(m,3H),7.45–7.40(m,1H),5.50(d,J＝1.3Hz,1H),4.61(m,1H),3.96(s,3H),3.90–3.78(m,2H),3.52(dd,J＝18.2,5.1Hz,1H),3.40–3.32(m,1H). 13 C NMR(100MHz,CDCl 3 )δ196.7,176.2,166.7,156.6,154.6,136.0,134.2,133.9,128.9,128.3,125.9,125.6,123.6,120.6,118.5,115.4,80.7,72.3,59.9,54.3,45.1,39.7.
The advantageous effects of the present invention will be specifically described below by way of test examples.
Test example 1: anti-tumor study
1. Experimental tumor cell lines
H1299 human non-small cell lung cancer cells were purchased from cell banks of the institute of biochemistry and cell biology, academy of sciences of china.
2. Test method
2.1 preparation and treatment of cells
Culturing cells in 1640 medium containing 10% Fetal Bovine Serum (FBS) and 1% green streptomycin double antibody mixture, taking logarithmic growth H1299, digesting the cells with 0.25% pancreatin to prepare single cell suspension, inoculating into 96-well plate with volume of 100 μl of 3000 cells per well, 3 multiple wells, placing the cells at 37deg.C, 5% CO 2 Incubator, incubate overnight. The next day, the test compound is diluted to 50 mu M with cell complete medium as working solution, and 100 mu L of compound working solution (namely, the final administration concentration is 25 mu M) is added into a 96-well plate; the blank group and the control group are added with the same amount of culture solution. 37 ℃,5% CO 2 Incubator, incubate for 48h. 10. Mu.L of MTT solution was added to each well, and after 4 hours of incubation, the supernatant was discarded, and 100. Mu.L of DMSO solution was added to each well. The absorbance values for each well were measured at 490nm wavelength on a microplate reader.
2.2 determination of cell viability
Cell viability was calculated according to the following formula: cell viability (%) = (experimental OD value-blank OD value)/(control OD value-blank OD value) ×100%.
3. Test results
The effect of the compound of the invention on H1299 cell survival at a 25. Mu.M dosing concentration is shown in FIG. 1.
Experimental results show that the compound has a certain effect on human non-small cell lung cancer cells H1299, wherein the compounds I-f, I-j and I-v have better inhibition effect on H1299.
Test example 2: anti-inflammatory study
1. Experimental cell strain
RAW 264.7 mouse mononuclear macrophage leukemia cells were purchased from Shanghai cell bank.
2. Test method
2.1CCK-8 assay for the Effect of Compounds on RAW 264.7 cell Activity
Culturing cells in DMEM medium containing 10% Fetal Bovine Serum (FBS) and 1% green streptomycin double-antibody mixture, taking logarithmic growth RAW 264.7, preparing single cell suspension, inoculating 4 ten thousand cells per well in a volume of 100 μl into 96-well plates, 3 multiple wells, placing cells at 37deg.C and 5% CO 2 Incubator, incubate overnight. The next day, the test compound is diluted to 50 mu M with cell complete medium as working solution, and 100 mu L of compound working solution (namely, the final administration concentration is 25 mu M) is added into a 96-well plate; the blank group and the control group are added with the same amount of culture solution. 37 ℃,5% CO 2 Incubator, incubate for 24h. After adding 10. Mu.L of CCK-8 solution to each well and culturing for 1 hour, the absorbance value of each well is measured at the wavelength of 450nm of an enzyme labeling instrument, and the cell viability is calculated.
2.2Griess assay for determining NO levels
Culturing cells in DMEM medium containing 10% Fetal Bovine Serum (FBS) and 1% green streptomycin double-antibody mixture, taking logarithmic growth RAW 264.7, preparing single cell suspension, inoculating 4 ten thousand cells per well in a volume of 100 μl into 96-well plates, 3 multiple wells, placing cells at 37deg.C and 5% CO 2 Incubator, incubate overnight. Setting a control group, a model group (LPS) and a dosing group (positive drug is dexamethasone), diluting a compound to be tested to 50 mu M with a cell complete culture medium to serve as working solution, and adding 100 mu L of compound working solution (namely, the final dosing concentration is 25 mu M) into a 96-well plate; equal amounts of culture medium were added to the control and model groups. After that, the model group and the administration group were stimulated with LPS (1.0. Mu.g/mL), 50. Mu.L of each supernatant was taken after 24 hours, 50. Mu. L Griess Reagent I and 50. Mu. L Griess Reagent II were sequentially added, and the absorbance value of each well was measured at a wavelength of 540nm in an ELISA reader. The NO content of the sample was determined from the measured standard curve.
3. Test results
The effect of CCK-8 on RAW 264.7 cell activity at 25. Mu.M is shown in FIG. 2.
Experimental results show that compounds with the RAW 264.7 cell survival rate higher than 80% have I-b, I-g, I-M, II-g and II-h at the administration concentration of 25 mu M, which indicate that the compounds are basically nontoxic to RAW 264.7 cells, so that subsequent experiments are carried out to determine the influence of the compounds I-b, I-g, I-M, II-g and II-h on the NO release level of RAW 264.7 cells.
The effect of compound 25 μm on the level of NO release from RAW 264.7 cells at the dosing concentration is shown in fig. 3.
Experimental results show that the compounds I-b, I-g, I-m, II-g and II-h have certain anti-inflammatory activity, the capacity of inhibiting NO release of the compounds I-m and II-g is better than that of positive control dexamethasone, wherein the anti-inflammatory activity of the compound I-m is optimal, and the IC is measured 50 ＝11.08μM。
The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, and yet fall within the scope of the invention.

Claims (9)

1. A 3-tetrahydrofuran chromone derivative, characterized by the following structure:
wherein R is 1 Phenyl, substituted phenyl or naphthyl;
R 2 methyl, ethyl or cyano;
R 3 is phenyl, substituted phenyl or aromatic five-membered ring containing hetero atom; the heteroatom in the aromatic five-membered ring containing the heteroatom is S.
2. 3-tetrahydrofuran-chromone derivatives according to claim 1, characterized in that in the compounds of formula I, R 1 The phenyl is phenyl, substituted phenyl or naphthyl, wherein the substituent in the substituted phenyl is any one of fluorine atom, chlorine atom, bromine atom, methoxy group, hydroxyl group and methyl group; r is R 3 The aromatic five-membered ring is phenyl, substituted phenyl or aromatic five-membered ring containing heteroatom S, wherein the substituent in the substituted phenyl is any one of chlorine atom, bromine atom, trifluoromethyl, methoxy, methyl, ethyl and phenyl;
in the compound of formula II, R 1 The phenyl is phenyl or substituted phenyl, wherein the substituent in the substituted phenyl is any one of fluorine atom and methoxy; r is R 2 Is methyl or ethyl; r is R 3 The aromatic five-membered ring is phenyl, substituted phenyl or aromatic five-membered ring containing heteroatom S, wherein the substituent in the substituted phenyl is any one of bromine atom, trifluoromethyl, methoxy, methyl and phenyl.
3. A process for the diastereoisomeric divergent preparation of a 3-tetrahydrofuran chromone compound according to claim 1 or 2, characterized by comprising the steps of:
s1, reacting a compound shown in a formula (1) with dimethylformamide in a phosphorus oxychloride reagent to obtain a compound shown in a formula (2); reacting a compound of formula (2) with a cyano compound in the presence of a catalyst potassium carbonate, wherein the solvent is acetic anhydride, so as to obtain a compound of formula (3);
wherein R is 1 Phenyl, substituted phenyl or naphthyl; r is R 2 Methyl, ethyl or cyano;
s2, reacting the compound shown in the formula (4) with triphenylphosphine in toluene to obtain a compound shown in the formula (5); reacting the compound of formula (5) with glycolaldehyde dimer in anhydrous tetrahydrofuran to obtain a compound of formula (6);
wherein R is 3 Is phenyl, substituted phenyl or aromatic five-membered ring containing hetero atom; the heteroatom in the aromatic five-membered ring containing the heteroatom is S;
s3, mixing the compound of the formula (3) and the compound of the formula (6), adding a chiral catalyst of the formula (V) or the formula (VI), reacting in a first reaction solvent at 0 ℃, and purifying by column chromatography to obtain the compound of the formula (I) or the formula (III); after the reaction for generating the compounds of the formulas (I) and (III) is finished, directly spin-drying the reaction solvent, adding a base catalyst and a second reaction solvent, reacting at room temperature, and purifying by column chromatography to obtain the compound of the formula (I) or (IV);
the chiral catalyst has the following structural formulas:
wherein ar=3, 5- (CF) 3 ) 2 C 6 H 3 - 。
4. The process for diastereoisomeric divergent preparation of 3-tetrahydrofuranyl chromone compound according to claim 3, wherein in step S1, the compound of formula (1) is reacted with dimethylformamide in phosphorus oxychloride reagent under ice bath conditions for 0.8-1.2h, and then transferred to room temperature for stirring for 22-26h, to obtain the compound of formula (2).
5. A process for the diastereoisomeric preparation of 3-tetrahydrofuranyl chromone compounds according to claim 3, wherein in step S1 the reaction of the compound of formula (2) to the compound of formula (3) is carried out at room temperature for 5-7h.
6. The process for diastereoisomeric divergent preparation of 3-tetrahydrofuranyl chromone compound of claim 3, wherein in step S2, the compound of formula (4), triphenylphosphine and toluene are mixed, and then heated at 110-130 ℃ under reflux for 10-14h, the solid is obtained by suction filtration, the solid is dissolved in methanol and dichloromethane solution, saturated sodium hydroxide solution is added, the mixed solution is stirred at room temperature for 0.9-1.1h, the dichloromethane is used for extraction, the organic layer is collected, and the compound of formula (5) is obtained by spin drying.
7. The process for diastereoisomeric divergent preparation of 3-tetrahydrofuranyl chromone compound of claim 3, wherein in step S2, the compound of formula (5), glycolaldehyde dimer and tetrahydrofuran are mixed, heated at 64-68 ℃ under reflux for 2.5-3.5h, the solvent is dried by spin-drying, and the compound of formula (6) is purified by column chromatography.
8. The method for diastereoisomeric divergent preparation of 3-tetrahydrofuranyl chromone compound according to claim 3, wherein in step S3, the first reaction solvent is at least one of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, chlorobenzene, benzene, toluene, ethyl acetate; the base catalyst is at least one of tetramethyl guanidine, dicycloamidine, lithium diisopropylamide, sodium bis (trimethylsilyl) amide, sodium hydroxide and potassium hydroxide; the second reaction solvent is at least one of dichloromethane, 1, 2-dichloroethane, chlorobenzene, benzene, toluene, ethyl acetate, acetonitrile, methanol, ethanol and isopropanol.
9. Use of a 3-tetrahydrofuranyl chromone compound according to claim 1 or 2 for the preparation of an anti-inflammatory and/or an anti-tumour agent.
CN202311687113.9A 2023-12-11 2023-12-11 3-tetrahydrofuran chromone compound and diastereoisomeric divergent preparation method and application thereof Pending CN117683026A (en)

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