Chiral dihydrofurocumarin compounds, synthesis method and application thereof

Abstract

The application discloses a kind of chiral dihydrofuranocoumarin compounds, its synthesis method and application, belong to organic chemistry synthesis and medical field;The structure of the compound is with C3 position amino methyl substitution chiral center dihydrofuranocoumarin as skeleton, its synthesis method is: at room temperature, copper salt and chiral ligand (L) are dissolved in organic solvent and stirred, then 4-ethynyl cyclic carbamic acid ester (I), 4-hydroxycoumarin (II) are sequentially added, after stirring reaction is completed, direct separation and purification are obtained;The compound provided by the application can be efficiently converted into other novel furanocoumarin compounds by simple reaction, and has good potential application value in antitumor drug research;The synthesis method of the application has the advantages of novelty, simple operation, mild reaction condition, good substrate universality, high yield, high stereoselectivity and the like.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to chiral dihydrofuranocoumarin compounds, their synthesis methods and applications. Background Technology

[0002] Dihydrofuranocoumarins and their skeletons are key structures in many natural products and bioactive compounds. Compounds containing dihydrofuranocoumarins and their skeletons often exhibit a wide variety of biological activities, such as anti-inflammatory, antitumor, anticoagulant, and antibacterial activities (New J. Chem. 2022, 46, 22353; Org. Biomol. Chem. 2017, 15, 6837; Nat. Prod. Rep. 2015, 32, 1472; J. Med. Chem. 2004, 47, 5816; J. Org. Chem. 2000, 65, 5644). These dihydrofuranocoumarin derivatives are an important source for developing new drugs. Furthermore, different enantiomers of the same compound not only have different optical properties but also different biological activities. In many drugs containing chiral centers, often only one configuration has therapeutic effects, while other configurations are ineffective or even have toxic side effects. Therefore, the development of efficient methods for synthesizing furanocoumarins and high-optical-purity dihydrofuranocoumarin derivatives has attracted widespread attention from organic chemists and medicinal chemists.

[0003] Through literature review, the inventors discovered that there are currently no reports on the highly stereoselective construction of aminomethyl-modified chiral dihydrofuranocoumarin structural skeletons using 4-ethynyl cyclic carbamate and 4-hydroxycoumarin as raw materials. Given the important role of the chiral dihydrofuranocoumarin skeleton in new drug development, constructing novel chiral dihydrofuranocoumarin compounds through asymmetric catalysis is of great significance. Summary of the Invention

[0004] One of the objectives of this invention is to provide a class of high-optical-purity aminomethyl-modified chiral dihydrofuranocoumarin compounds, providing a sufficient and reliable pool of candidate molecules for new drug development.

[0005] The high optical purity aminomethyl-modified chiral dihydrofuranocoumarin compound provided by this invention has the structure shown in the following structural formula (Ⅲ):

[0006]

[0007] In the above structural formula, R 1 The substituent is selected from aryl, alkyl, and hydrogen; R 2The substituent is selected from one of hydrogen, alkyl, aryl, acyl, sulfonyl, alkoxycarbonyl, and phosphonoacyl; R 3 The substituent is selected from one of alkyl, halogen, cyano, alkoxy, aryl, alkylthio, and amino.

[0008] This invention provides a class of high optical purity chiral dihydrofuranocoumarin compounds, which have a dihydrofuranocoumarin core structural unit with a quaternary carbon stereocenter containing an aminomethyl group at position 3.

[0009] This invention not only synthesizes chiral dihydrofuranocoumarin derivatives with a single configuration through asymmetric catalysis, but also starts from the source by modifying the structure of chiral dihydrofuranocoumarins to improve the pharmacological properties of this type of compound, thereby facilitating the discovery of new drugs.

[0010] The application value of the compounds of this invention lies in:

[0011] 1. Many chiral dihydrofuranocoumarin compounds possess excellent biological activity. For example, the paper "An efficient one-pot approach for the regio-an diastereoselective synthesis of trans-dihydrofuran derivatives: cytotoxicity and DNA-binding studies" (Org. Biomol. Chem., 2017, 15, 6837-6853) reported that the dihydrofuranocoumarin compound (V) shown below exhibits good cytotoxicity against human lung cancer cells, human prostate cancer cells, human cervical cancer cells, and human breast cancer cells, especially showing excellent cytotoxicity against human breast cancer cells. The novel compound provided by this invention has a parent ring similar to that of compound (V), namely, a dihydrofuranocoumarin skeleton. Therefore, it is reasonable to predict that a large class of novel compounds provided by this invention also possess potential biological activity, thus providing a sufficient source of compounds for new drug screening and an important source for new drug development.

[0012]

[0013] 2. In vitro activity tests showed that the chiral indolinoquinazolinone polycyclic compound containing a dihydronaphthofuran structure provided by this invention exhibits significant anti-human lung cancer cell activity. This result corroborates the prediction that the compound provided by this invention possesses good biological activity and also demonstrates the application potential of this invention in the field of drug development.

[0014] The second objective of this invention is to provide a method for synthesizing the above-mentioned compound (Ⅲ), the technical solution of which includes the following steps:

[0015] At room temperature, copper salt and chiral ligand (L) are stirred in an organic solvent for 0.5-2.0 h, then 4-ethynyl cyclic carbamate (I) and 4-hydroxycoumarin (II) are added sequentially, and the reaction is stirred at -40 to 50 °C for 0.5-5 h. After the reaction is complete, the mixture is directly separated and purified to obtain the final product.

[0016] The 4-ethynyl cyclic carbamate (Ⅰ) has the following structure:

[0017]

[0018] The 4-hydroxycoumarin(II) has the following structure:

[0019]

[0020] The chiral ligand (L) has the following structure:

[0021]

[0022] The synthetic route is as follows:

[0023]

[0024] The present invention uses the above-described synthetic method to synthesize a series of novel chiral dihydrofuranocoumarin derivatives.

[0025] As a preferred technical solution, the organic solvent is selected from one or a mixture of more than one of dichloromethane, chloroform, toluene, mesitylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, methanol, ethanol, hexafluoroisopropanol, and N,N-dimethylformamide.

[0026] Tetrahydrofuran was further preferred as the solvent because it yielded the highest reaction rate and exhibited the best stereoselectivity.

[0027] As a preferred technical solution, the copper salt is selected from at least one of copper acetate, copper trifluoromethanesulfonate, copper sulfate, copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, cuprous chloride, cuprous bromide, cuprous iodide, and copper acetylacetonate.

[0028] Copper acetate was further preferred as a copper salt catalyst because it yielded the highest reaction rate and exhibited the best stereoselectivity.

[0029] As a preferred technical solution: the minimum amount of copper salt used is 5 mol% of 4-hydroxycoumarin (II).

[0030] As a preferred technical solution, the chiral ligand (L) has the following structure:

[0031]

[0032] In the above structural formula, R 4 The substituent is selected from one of aryl, alkyl, hydrogen, carbonyl, and silyl groups; R 5 The substituent is selected from aryl, alkyl, and hydrogen.

[0033] More preferably, the chiral ligand is one of the following chiral tridentate oxazoline ligands: L1, L2, L3, L4, L5:

[0034]

[0035] L1 was further preferred as the chiral ligand because it yielded the highest reaction and exhibited the best stereoselectivity.

[0036] As a preferred technical solution: the minimum amount of the 4-ethynyl cyclic carbamate (Ⅰ) is 100 mol of 4-hydroxycoumarin (Ⅱ).

[0037] A further preferred amount is 1.5 equivalents because it results in a high reaction yield and good stereoselectivity.

[0038] As a preferred technical solution: the minimum amount of the chiral ligand is 5 mol% of 4-hydroxycoumarin (II).

[0039] As a preferred technical solution, the reaction temperature is any temperature between -40 and 50°C.

[0040] 30°C is further preferred because it yields the highest reaction rate and exhibits the best stereoselectivity.

[0041] As a preferred technical solution, the separation and purification method is one or more of pulping, recrystallization, and column chromatography separation.

[0042] Column chromatography separation is further preferred because it yields high product purity.

[0043] As a preferred technical solution: the solvent for separation and purification is selected from one or more of the following: petroleum ether, n-hexane, dichloromethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, N,N-dimethylformamide, and dimethyl sulfoxide.

[0044] Petroleum ether, n-hexane, dichloromethane, and ethyl acetate are further preferred because of their high purity.

[0045] The third objective of this invention is to provide an application of the above-mentioned compound (Ⅲ) in chemical synthesis, and the technical solution adopted is as follows:

[0046] Compound (III) was dissolved in an organic solvent, and then a catalyst was added. The mixture was stirred at reflux temperature for 5–12 h. After the reaction was complete, the compound (IV) with a furanocoumarin skeleton was directly separated and purified.

[0047] Compound (Ⅲ) has the following structure:

[0048]

[0049] The furanocoumarin compound (Ⅳ) has the following structure:

[0050]

[0051] The synthetic route is as follows:

[0052]

[0053] The present invention uses the above-described synthetic method to synthesize a series of novel furanocoumarin compounds.

[0054] As a preferred technical solution, the organic solvent is selected from one or a mixture of more than one of dichloromethane, chloroform, toluene, mesitylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate, methanol, ethanol, hexafluoroisopropanol, and N,N-dimethylformamide.

[0055] Toluene was further preferred as the solvent because it yielded the highest reaction rate.

[0056] As a preferred technical solution, the catalyst is selected from at least one or a mixture of multiple of phosphoric acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, and boron trifluoride ether.

[0057] p-Toluenesulfonic acid was further preferred because it yielded the highest reaction rate.

[0058] As a preferred technical solution, the minimum amount of catalyst used is 10 mol%.

[0059] As a preferred technical solution, the separation and purification method is one or more of pulping, recrystallization, and column chromatography separation.

[0060] Column chromatography separation is further preferred because it yields high product purity.

[0061] The furanocoumarin compound (Ⅳ) provided by this invention shares a similar parent ring, namely the furanocoumarin skeleton, with the novel tanshinone (Ⅵ) exhibiting anti-human breast cancer cell activity (as shown below) (J.Med.Chem.2004,47,5816-5819). Therefore, it is reasonable to predict that this new compound (Ⅳ) provided by this invention also possesses potential biological activity, providing a sufficient source of compounds for new drug screening. Furthermore, in vitro activity tests show that the furanocoumarin compound provided by this invention exhibits significant anti-human lung cancer cell activity. This result corroborates the prediction that the compound provided by this invention possesses good biological activity and also demonstrates the application potential of this invention in the field of drug development.

[0062]

[0063] A fourth objective of this invention is to provide the use of the above-mentioned compounds (III and IV) in the preparation of antitumor drugs.

[0064] Specifically, the application value of the compounds (III and IV) disclosed in this invention lies in the following: preliminary cell activity experiments show that these compounds have a good killing effect on human leukemia cells K562, and the cell activity study results are shown in Table 1. Therefore, through further research, these compounds are expected to become lead compounds for anti-tumor drugs.

[0065] Specific experimental procedures: 5000 human leukemia cells (K562) were seeded into 96-well cell culture plates and allowed to grow for 24 hours; then, certain concentrations of compounds III-a, III-b, III-c, III-d, III-e, and IV (described in the later examples), as well as the known compound Va(R), were added. 6 =Phenylacetyl, R 7 =4-methoxyphenyl) and VI, with the antitumor drug cisplatin as a control, were treated for 48 h; then the mean 50% inhibitory concentration (IC50) of all compounds was determined. 50 Each concentration was repeated at least 3 times, and all experiments were repeated 3 times. The average results are shown in Table 1.

[0066] As shown in Table 1, under the same testing conditions, some compounds of the present invention exhibit better anti-K562 activity against leukemia cells than known compounds Va and neotanshinone VI. Furthermore, these compounds of the present invention possess anti-K562 activity comparable to or even better than cisplatin. This indicates that these compounds hold promise as lead compounds for the treatment of leukemia.

[0067] Table 1: Results of cell viability assays for different compounds

[0068]

[0069] The advantages of this invention are as follows: This invention utilizes a copper salt-catalyzed decarboxylation cyclization reaction of 4-ethynyl cyclic carbamates with 4-hydroxycoumarin to synthesize a series of chiral dihydrofuranocoumarin compounds with high yield and high enantioselectivity. Furthermore, this invention also efficiently synthesizes furanocoumarin derivatives through a simple method. This invention enriches the variety of dihydrofuranocoumarins and furanocoumarin compounds, and these compounds have initially shown certain antitumor activity, thus providing a sufficient source of compounds for screening lead compounds and drug candidates. This method has the advantages of mild reaction conditions, commercially available catalysts, simple operation, wide substrate applicability and good generality, high yield (up to 99%), and excellent stereoselectivity (up to 99% ee). Attached Figure Description

[0070] Figure 1 The 1H NMR spectrum of Ⅲ-a obtained in Example 1;

[0071] Figure 2 The carbon NMR spectrum of Ⅲ-a obtained in Example 1;

[0072] Figure 3 The high performance liquid chromatogram (racemic) of Ⅲ-a obtained in Example 1 is shown.

[0073] Figure 4 The high-performance liquid chromatogram (chiral) of Ⅲ-a obtained in Example 1 is shown.

[0074] Figure 5 The hydrogen nuclear magnetic resonance spectrum of N4 prepared in Example 6;

[0075] Figure 6 The image shows the carbon NMR spectrum of sample IV obtained in Example 6. Detailed Implementation

[0076] The invention will now be further described with reference to the accompanying drawings.

[0077] Example 1: Synthesis of compound (Ⅲ-a)

[0078]

[0079] Synthesis of compound III-a:

[0080]

[0081] In a dry reaction tube, copper acetate and chiral ligand L were dissolved in 2 mL of solvent and stirred for 2 hours at room temperature under an argon atmosphere. Then, 4-ethynyl cyclic carbamate Ia (0.15 mmol) and 4-hydroxycoumarin II-a (0.1 mmol) were added sequentially. The reaction was then stirred at a certain temperature. After the reaction was complete, the solvent was removed by vacuum distillation, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 1:1) to obtain compound III-a.

[0082] Table 2 shows some different reaction conditions based on the process and conditions shown in the above reaction formula:

[0083] Table 2: Yields and stereoselectivity under different reaction conditions

[0084]

[0085]

[0086] As can be seen from Table 2, chiral ligands have a significant impact on the stereoselectivity of the reaction, with ligand L1 showing the best effect. In addition, temperature, solvent, and catalyst dosage also have a significant impact on the reaction.

[0087] The results showed that using copper acetate as the copper source, L1 as the ligand, 5 mol% catalyst, tetrahydrofuran as the solvent, and a reaction temperature of 30℃ was a more preferred scheme.

[0088] Under the above optimal scheme, the obtained Ⅲ-a was a white solid with a yield of 87%; the enantiomeric excess percentage was 98% (ee); [α] D 20 =+10(c=1.0g / 100mL, CH2Cl2);

[0089] The ee value was determined by HPLC: Chiralpak IA column; mobile phase: 70 / 30 n-hexane / isopropanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major =19.0min,t minor =17.1min.

[0090] Structural assessment: 1H NMR(300MHz,DMSO-d6)δ7.90-7.81(m,1H),7.81-7.71(m,2H),7.71-7.60(m,2H),7.58-7.44(m,2H ),7.41-7.22(m,7H),5.16(d,J=3.9Hz,1H),4.57(d,J=3.8Hz,1H),3.82-3.57(m,2H),2.35(s,3H);

[0091] 13 C NMR(101MHz,DMSO-d6)δ165.5,163.7,157.5,155.1,142.7,140.4,137.9,133.4,129 .6,128.8,127.5,126.4,126.4,124.6,122.7,116.9,111.1,106.1,91.8,56.0,47.7;

[0092] HRMS(ESI)m / z:[M+Na] + calcd.For C 26 H 21 NNaO5S 482.1033,found:482.1032;

[0093] The 1H NMR spectrum, 1C NMR spectrum, and HPLC chromatogram of Ⅲ-a are shown below. Figure 1-4 As shown.

[0094] Example 2: Synthesis of compound (Ⅲ-b)

[0095]

[0096] In a dry reaction tube, copper acetate (0.005 mmol) and chiral ligand L1 (0.005 mmol) were dissolved in 2 mL of solvent. After stirring for 2 hours at room temperature under an argon atmosphere, 4-ethynyl cyclic carbamate Ib (0.15 mmol) and 4-hydroxycoumarin II-a (0.1 mmol) were added sequentially. The reaction was then stirred at 30 °C. After the reaction was complete, the solvent was removed by vacuum distillation, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 1:1) to give compound III-b.

[0097] Compound III-b was a white solid in 99% yield; enantiomeric excess was 98% (ee); [α] D 20 =-12.6(c=1.0g / 100mL, CH2Cl2);

[0098] The ee value was determined by HPLC: Chiralpak IA column; mobile phase: 70 / 30 n-hexane / isopropanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major =22.5min,t minor =17.7min.

[0099] Structural assessment: 1 H NMR (300MHz, DMSO-d6) δ7.88-7.82(m,1H),7.82-7.73(m,2H),7.65(d,J=8.2Hz,2H),7.58-7.44(m,2 H),7.41-7.32(m,6H),5.18(d,J=4.1Hz,1H),4.59(d,J=3.9Hz,1H),3.79-3.54(m,2H),2.36(s,3H);

[0100] 13 C NMR(101MHz,DMSO-d6)δ165.1,163.8,157.4,155.1,142.7,139.3,137.9,133.5,132.3, 129.6,128.6,128.5,126.4,124.6,122.8,116.9,111.1,105.8,92.1,55.6,47.6,21.0;

[0101] HRMS(ESI)m / z:[M+Na] + calcd.for C 26 H 20 ClNNaO5S 516.0648,found:516.0633.

[0102] Example 3: Synthesis of compound (Ⅲ-c)

[0103]

[0104] In a dry reaction tube, copper acetate (0.005 mmol) and chiral ligand L1 (0.005 mmol) were dissolved in 2 mL of solvent. After stirring for 2 hours at room temperature under an argon atmosphere, 4-ethynyl cyclic carbamate Ic (0.15 mmol) and 4-hydroxycoumarin II-a (0.1 mmol) were added sequentially. The reaction was then stirred at 30 °C. After the reaction was complete, the solvent was removed by vacuum distillation, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 1:1) to give compound III-c.

[0105] Compound III-c was a white solid in 72% yield; enantiomeric excess was 97% (ee); [α] D 20 =+26.5(c=1.0g / 100mL, CH2Cl2);

[0106] The ee value was determined by HPLC: Chiralpak IA column; mobile phase: 70 / 30 n-hexane / isopropanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major =22.9min,t minor =17.8min.

[0107] Structural assessment: 1 H NMR (300MHz, CDCl3) δ7.78-7.69(m,1H),7.69-7.53(m,3H),7.42-7.30(m,2H),7.26-7.10(m,4H),7.01-6.89(m,1H),5.48-5.3 3(m,1H),5.29(d,J=4.0Hz,1H),4.82(d,J=4.0Hz,1H),4.03(dd,J=12.9,7.7Hz,1H),3.55(dd,J=12.9,5.8Hz,1H),2.35(s,3H);

[0108] 13 C NMR (151MHz, CDCl3) δ164.5,164.4,158.7,155.3,143.5,143.0,136.9,133.6,129.7,1 27.5,127.1,125.6,125.5,124.6,123.2,117.2,111.2,106.1,93.2,53.8,50.1,21.6;

[0109] HRMS(ESI)m / z:[M+Na] + calcd.for C 24 H 19 NNaO5S2488.0602,found:488.0590.

[0110] Example 4: Synthesis of compound (Ⅲ-d)

[0111]

[0112] In a dry reaction tube, copper acetate (0.005 mmol) and chiral ligand L1 (0.005 mmol) were dissolved in 2 mL of solvent. After stirring for 2 hours at room temperature under an argon atmosphere, 4-ethynyl cyclic carbamate Ia (0.15 mmol) and 4-hydroxycoumarin II-b (0.1 mmol) were added sequentially. The reaction was then stirred at 30 °C. After the reaction was complete, the solvent was removed by vacuum distillation, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 1:1) to give compound III-d.

[0113] Compound III-d was a white solid in 97% yield; enantiomeric excess was 97% (ee); [α] D 20 =+25.5(c=1.0g / 100mL, CH2Cl2);

[0114] The ee value was determined by HPLC: Chiralpak IA column; mobile phase: 70 / 30 n-hexane / isopropanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major =29.5min,t minor =22.6min.

[0115] Structural assessment: 1 H NMR (300MHz, CDCl3) δ7.79-7.50(m,3H),7.42-7.25(m,5H),7.20(d,J=8.1Hz,2H),6.98-6.87(m,1H),6.87-6.75(m,1H),5.55-5.36(m, 1H),5.18(d,J=3.8Hz,1H),4.61(d,J=3.9Hz,1H),4.08(dd,J=12.5,7.8Hz,1H),3.89(s,3H),3.53(dd,J=12.7,4.7Hz,1H),2.35(s,3H);

[0116] 13 C NMR (101MHz, CDCl3) δ165.4,165.0,164.3,159.7,157.5,143.4,139.3,136.9,129.7,129 .1,128.0,127.1,126.6,124.1,113.3,104.4,103.7,101.0,92.5,56.1,55.7,49.4,21.6;

[0117] HRMS(ESI)m / z:[M+Na] + calcd.for C27 H 23 NNaO6S 512.1144,found:512.1122.

[0118] Example 5: Synthesis of compound (Ⅲ-e)

[0119]

[0120] In a dry reaction tube, copper acetate (0.005 mmol) and chiral ligand L1 (0.005 mmol) were dissolved in 2 mL of solvent. After stirring for 2 hours at room temperature under an argon atmosphere, 4-ethynyl cyclic carbamate Ia (0.15 mmol) and 4-hydroxycoumarin II-c (0.1 mmol) were added sequentially. The reaction was then stirred at 30 °C. After the reaction was complete, the solvent was removed by vacuum distillation, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1 to 1:1) to give compound III-e.

[0121] Compound III-e was a white solid in 64% yield; enantiomeric excess was 97% (ee); [α] D 20 =+5.1(c=1.0g / 100mL, CH2Cl2);

[0122] The ee value was determined by HPLC: Chiralpak IA column; mobile phase: 70 / 30 n-hexane / isopropanol; flow rate: 1.0 mL / min; detection wavelength λ = 254 nm; retention time t major =45.1min,t minor =19.2min.

[0123] Structural assessment: 1 H NMR (300MHz, DMSO-d6) δ8.45-8.36(m,1H),8.17-8.08(m,1H),7.97(d,J=8.7Hz,1H),7.84-7.74(m,4H),7.66(d,J=8.2Hz,2 H),7.41(d,J=7.0Hz,2H),7.38-7.26(m,5H),5.20(d,J=3.9Hz,1H),4.62(d,J=3.9Hz,1H),3.86-3.66(m,2H),2.26(s,3H);

[0124] 13C NMR (101MHz, CDCl3) δ165.5,159.2,153.5,143.4,139.1,137.0,135.7,129.67,129.65,129.1, 128.3,128.1,127.8,127.1,126.7,124.9,123.1,118.0,106.5,106.2,92.7,56.1,49.5,21.4;

[0125] HRMS(ESI)m / z:[M+Na] + calcd.for C 30 H 23 NNaO5S 532.1195,found:532.1185.

[0126] Example 6: Synthesis of Compound IV

[0127]

[0128] In a dry reaction tube, compound III-e (0.1 mmol) was dissolved in 2 mL of toluene, and then p-toluenesulfonic acid (0.01 mmol) was added. The mixture was refluxed at 110 °C for 8 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the crude product residue was purified by column chromatography (petroleum ether: methyl tert-butyl ether = 15:1) to obtain compound IV.

[0129] Compound IV is a brown solid with a yield of 94%.

[0130] Structural assessment: 1 H NMR (300MHz, CDCl3) δ8.60(d,J=8.9Hz,1H),7.96-7.82(m,2H),7.75(d,J=8.6Hz,1H),7.66-7.36(m,7H),2.56(s,3H);

[0131] 13 C NMR (101MHz, CDCl3) δ157.7,157.3,151.6,149.1,134.1,130.0,129.4,128.7,12 8.3,128.0,127.8,127.3,124.6,123.4,122.6,120.5,117.0,109.3,108.0,12.7;

[0132] HRMS(ESI)m / z:[M+Na] + calcd.for C 22 H 14NaO3349.0835,found:349.0835.

[0133] The above description is only a partial embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The use of chiral dihydrofuranocoumarin compounds in the preparation of antitumor drugs, characterized in that, The chiral dihydrofuranocoumarin compounds have the following structures: ， ， ， ， ； The tumor is leukemia.

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