CN113149948B - Preparation method and application of 3-methylene cyclopentano [ b ] chromone compound - Google Patents

Preparation method and application of 3-methylene cyclopentano [ b ] chromone compound Download PDF

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CN113149948B
CN113149948B CN202110123462.2A CN202110123462A CN113149948B CN 113149948 B CN113149948 B CN 113149948B CN 202110123462 A CN202110123462 A CN 202110123462A CN 113149948 B CN113149948 B CN 113149948B
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韩文勇
朱文庆
张紫薇
方雨辰
杨萍
李林强
陈永正
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Zunyi Medical University
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Abstract

The present invention provides 3-methylenecyclopenta [ b ]]A preparation method and application of chromone compounds, relating to the technical field of chemistry. The 3-subMethylcyclopentano [ b ] methyl ester]Preparation method of chromone compound to prepare 3-methylene cyclopentano [ b ] with structural formula as below]The chromone compound 4a is taken as an example, and the used raw materials and the preparation method are as follows:
Figure DDA0002924333890000011
3-iodo-chromone (0.2mmol), N-Ts-aziridine (0.28mmol), norbornene (0.8mmol,75.3mg), Pd [ (allyl) Cl]2(0.02mmol,7.3mg)，P(4‑F‑C6H4)3(0.04mmol,18.7mg)，Cs2CO3(0.4mmol,130.3mg)，H2O (0.6mmol, 10.8. mu.l), 2.0mL of ultra-dry toluene was added to a 4mL reaction flask and reacted at 100 ℃ for 24 h. The compound of the invention has important biological activity, and the cytotoxicity test of two strains of tumor cells, namely human breast cancer cell (MCF-7) and human cervical cancer cell (HeLa) in vitro shows that: such 3-methylenecyclopenta [ b]The chromone compound has the inhibiting effect on the growth of tumor cells and can be developed into a novel medicine for preventing and treating tumors.

Description

Preparation method and application of 3-methylene cyclopentano [ b ] chromone compound
Technical Field
The invention relates to the field of chemistry, in particular to a preparation method and application of a 3-methylene cyclopentano [ b ] chromone compound.
Background
Aziridine is used as a ternary heterocyclic compound with biological activity, and is used as an important synthetic building block to realize the design and synthesis of various heterocyclic compounds due to the high tension of the three-membered ring, so that the aziridine has special antibacterial and antitumor pharmacological activity. Therefore, how to rapidly and efficiently synthesize a diversity of heterocyclic compounds has been important in the field of medicinal chemistry.
The reactions currently involved in aziridines are largely divided into two groups:
1. the three-membered ring of aziridine is cleaved by a C-N bond, which serves as a hetero 3C synthon, and undergoes cycloaddition reactions such as [3+1], [3+2], [3+3], to thereby construct other heterocyclic compounds;
2. aziridine reacts with other reagents through C-N bond cleavage and ring opening to obtain a non-cyclic organic amine compound;
although chemical reactions involving aziridines have been rapidly developed, they are currently limited to the above two types of reactions, i.e., the introduction of a continuous C-N chain into a target molecule by C-N bond cleavage or the introduction of a continuous C-N-C chain into a target molecule by C-C bond cleavage, which greatly limits the applications of aziridine compounds in the fields of organic synthesis and pharmaceutical chemistry.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a method for introducing a vinyl unit into a target molecule through two C-N bond fractures, and provides a preparation method and application of a 3-methylene cyclopentano [ b ] chromone compound, and provides a candidate drug molecule for treating human breast cancer and human cervical carcinoma.
(II) technical scheme
In order to achieve the purpose, the invention is realized by the following technical scheme: a preparation method of 3-methylene cyclopentano [ b ] chromone compounds takes 3-methylene cyclopentano [ b ] chromone compounds 4a with the structural formula as follows as an example, and the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000021
3-iodochromone (0.2mmol), N-Ts aziridine (0.28mmol), norbornene (0.8mmol,75.3mg), Pd [ (allyl) Cl]2(0.02mmol,7.3mg)， P(4-F-C6H4)3(0.04mmol,18.7mg)，Cs2CO3(0.4mmol,130.3mg)， H2O (0.6mmol, 10.8. mu.l), 2.0mL of ultra-dry toluene were added to a 4mL reaction flask and reacted at 100 ℃ for 24hAfter the reaction is finished, cooling to room temperature, and separating and purifying by silica gel column chromatography (ethyl acetate/petroleum ether is 50: 1-30: 1) (the separation method is column chromatography) to obtain a white solid 4a, wherein the yield is 37.5mg, the yield is 71%, the melting point is 124.6-125.3 ℃, and the spectrum data is as follows:1H NMR(400MHz,CDCl3)δ8.22(dd, J＝8.0,1.6Hz,1H),7.66–7.57(m,1H),7.47(d,J＝8.4 Hz,1H),7.37(t,J＝7.6Hz,1H),5.77(d,J＝2.4Hz,1H), 5.32(d,J＝1.8Hz,1H),3.06(d,J＝6.4Hz,1H),2.75(d, J＝6.0Hz,1H),2.57(d,J＝3.6Hz,1H),2.20(d,J＝3.6Hz, 1H),1.71–1.62(m,1H),1.62–1.53(m,1H),1.50–1.40 (m,1H),1.37–1.29(m,1H),1.17(d,J＝10.4Hz,1H),1.05 (d,J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ177.0,164.7, 156.4,148.5,133.3,126.5,125.9,124.9,118.2,110.5,110.1, 48.0,46.8,43.7,38.5,32.3,29.4,28.5；HRMS(ESI-TOF):calcd. for C18H17O2[M+H]+265.1223；found 265.1232。
the 3-methylene cyclopentano [ b ] chromone compound is applied to tumor treatment.
(III) advantageous effects
The invention provides a preparation method and application of a 3-methylene cyclopentano [ b ] chromone compound. The method has the following beneficial effects:
the compound of the invention has important biological activity, and the cytotoxicity test of two strains of tumor cells, namely human breast cancer cell (MCF-7) and human cervical cancer cell (HeLa) in vitro shows that: the 3-methylene cyclopentano [ b ] chromone compounds have the inhibiting effect on the growth of tumor cells and can be developed into new medicaments for preventing and treating tumors.
Drawings
FIG. 1 is a schematic single crystal-X-ray diffraction diagram of Compound 4a of the present invention;
FIG. 2 is a NMR spectrum of Compound 4a of the present invention;
FIG. 3 is a NMR carbon spectrum of Compound 4a of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
Example 1:
the embodiment of the invention provides a preparation method of a 3-methylene cyclopentano [ b ] chromone compound, taking 3-methylene cyclopentano [ b ] chromone compound 4a with the structural formula as the example, the used raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000041
3-iodochromone (0.2mmol), N-Ts aziridine (0.28mmol), norbornene (0.8mmol,75.3mg), Pd [ (allyl) Cl]2(0.02mmol,7.3mg)， P(4-F-C6H4)3(0.04mmol,18.7mg)，Cs2CO3(0.4mmol,130.3mg)， H2Adding O (0.6mmol,10.8 mu l) and 2.0mL of ultra-dry toluene into a 4mL reaction bottle, reacting at 100 ℃ for 24 hours, cooling to room temperature after the reaction is finished, and separating and purifying by silica gel column chromatography (ethyl acetate/petroleum ether is 50: 1-30: 1) (the separation method is column chromatography) to obtain a white solid 4a, wherein the yield is 37.5mg, the yield is 71%, the melting point is 124.6-125.3 ℃, and the spectral data is as follows:1H NMR(400MHz,CDCl3)δ8.22(dd, J＝8.0,1.6Hz,1H),7.66–7.57(m,1H),7.47(d,J＝8.4 Hz,1H),7.37(t,J＝7.6Hz,1H),5.77(d,J＝2.4Hz,1H), 5.32(d,J＝1.8Hz,1H),3.06(d,J＝6.4Hz,1H),2.75(d, J＝6.0Hz,1H),2.57(d,J＝3.6Hz,1H),2.20(d,J＝3.6Hz, 1H),1.71–1.62(m,1H),1.62–1.53(m,1H),1.50–1.40 (m,1H),1.37–1.29(m,1H),1.17(d,J＝10.4Hz,1H),1.05 (d,J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ177.0,164.7, 156.4,148.5,133.3,126.5,125.9,124.9,118.2,110.5,110.1, 48.0,46.8,43.7,38.5,32.3,29.4,28.5；HRMS(ESI-TOF):calcd. for C18H17O2[M+H]+265.1223；found 265.1232。
example 2
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4b with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000051
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-5-methoxy chromone and the other steps were the same as in example to give white solid 4b with 37.9mg yield, 64% yield, melting point 119.5-120.8 ℃, and spectral data:1H NMR(400MHz, CDCl3)δ7.49(t,J＝8.4Hz,1H),7.03(d,J＝8.4Hz,1H), 6.77(d,J＝8.4Hz,1H),5.68(d,J＝2.4Hz,1H),5.26(d, J＝1.8Hz,1H),3.95(s,3H),3.00(d,J＝6.4Hz,1H),2.71 (d,J＝5.8Hz,1H),2.59(d,J＝3.6Hz,1H),2.16(d,J＝3.4 Hz,1H),1.68–1.59(m,1H),1.59–1.50(m,1H),1.47– 1.37(m,1H),1.35–1.26(m,1H),1.15(d,J＝10.4Hz,1H), 1.02(d,J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ177.2, 162.6,160.3,158.7,148.5,133.3,127.7,115.5,110.5,109.7, 106.4,56.5,48.1,47.0,43.6,38.3,32.3,29.4,28.6；HRMS (ESI-TOF):calcd.for C19H19O3[M+H]+295.1329；found 295.1335。
example 3
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4c with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000061
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-5-fluoro chromone and the other steps were the same as in example to give white solid 4c with a yield of 33.0mg, 58% yield, melting point 146.1-147.4 ℃ and spectral data:1H NMR(400MHz, CDCl3)δ7.54(td,J＝8.4,5.6Hz,1H),7.26(d,J＝8.4,1H), 7.00(dd,J＝10.8,8.4Hz,1H),5.74(d,J＝2.4Hz,1H),5.32 (d,J＝2.0Hz,1H),3.03(d,J＝6.4Hz,1H),2.73(d,J＝6.2 Hz,1H),2.57(d,J＝3.8Hz,1H),2.18(d,J＝3.6Hz,1H), 1.70–1.61(m,1H),1.60–1.52(m,1H),1.47–1.39(m, 1H),1.35–1.28(m,1H),1.15(d,J＝10.4Hz,1H),1.05(d, J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ175.5,163.1(d, J＝109.2Hz,1C),159.9,157.6(d,J＝3.8Hz,1C),148.1,133.2 (d,J＝10.8Hz,1C),127.3,115.2(d,J＝10.0Hz,1C),114.2 (d,J＝4.4Hz,1C),112.0(d,J＝21.2Hz,1C),110.8,48.0, 46.8,43.6,38.3,32.3,29.3,28.5；HRMS(ESI-TOF):calcd.for C18H16FO2[M+H]+283.1129；found 283.1131。
example 4
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4d with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000071
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-6-methylchromone and the other steps were the same as in example, to give 4d as a white solid with a yield of 34.0mg, 61% yield, melting point 161.8-162.9 ℃, and spectral data:1H NMR(400MHz, CDCl3)δ8.01(dd,J＝1.6,0.4Hz,1H),7.43(dd,J＝8.4, 2.2Hz,1H),7.36(d,J＝8.4Hz,1H),5.76(d,J＝2.4Hz,1H), 5.31(d,J＝2.0Hz,1H),3.06(d,J＝6.4Hz,1H),2.75(d, J＝6.4Hz,1H),2.57(d,J＝4.0Hz,1H),2.44(s,3H),2.19 (d,J＝3.8Hz,1H),1.71–1.62(m,1H),1.61–1.53(m,1H), 1.50–1.41(m,1H),1.37–1.29(m,1H),1.19–1.13(m, 1H),1.07–1.02(m,1H)；13C NMR(100MHz,CDCl3)δ177.2, 164.7,154.7,148.7,134.9,134.5,126.5,125.4,124.5,118.0, 110.3,48.1,46.9,43.8,38.5,32.3,29.5,28.6,21.0；HRMS (ESI-TOF):calcd.for C19H19O2[M+H]+279.1380；found 279.1381。
example 5
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4e with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000081
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-6-methoxy chromone and the other steps were the same as in example, to give 4e as a yellow solid in 36.6mg yield, 62% yield, melting point 125.8-126.9 ℃, and spectral data:1H NMR(400MHz, CDCl3)δ7.57(d,J＝2.6Hz,1H),7.37(d,J＝9.2Hz,1H), 7.19(dd,J＝8.8,2.4Hz,1H),5.73(s,1H),5.28(s,1H),3.86 (s,3H),3.04(d,J＝6.4Hz,1H),2.72(d,J＝6.2Hz,1H), 2.55(d,J＝2.6Hz,1H),2.17(d,J＝2.6Hz,1H),1.70–1.60 (m,1H),1.59–1.49(m,1H),1.48–1.37(m,1H),1.35– 1.26(m,1H),1.14(d,J＝10.4Hz,1H),1.02(d,J＝10.3Hz, 1H)；13C NMR(100MHz,CDCl3)δ176.8,164.6,156.8,151.1, 148.5,125.8,125.4,123.1,119.5,110.3,105.3,56.0,48.1, 46.8,43.7,38.4,32.2,29.4,28.5；HRMS(ESI-TOF):calcd.for C19H19O3[M+H]+295.1329；found 295.1332。
example 6
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4f with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000091
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-6-isopropyl chromone and the other steps were the same as in example to give white solid 4f with 37.0mg yield, 60% yield, melting point 113.9-115.4 ℃, and spectral data:1H NMR(400MHz, CDCl3)δ8.04(d,J＝2.4Hz,1H),7.48(dd,J＝8.6,2.4Hz, 1H),7.37(d,J＝8.6Hz,1H),5.73(d,J＝2.4Hz,1H),5.28 (d,J＝1.8Hz,1H),3.04(d,J＝6.4Hz,1H),2.99(dd,J＝ 13.8,6.8Hz,1H),2.71(d,J＝6.4Hz,1H),2.55(d,J＝3.8 Hz,1H),2.16(d,J＝3.8Hz,1H),1.69–1.59(m,1H),1.58 –1.50(m,1H),1.48–1.39(m,1H),1.35–1.28(m,1H), 1.26(d,J＝6.8Hz,6H),1.13(d,J＝10.4Hz,1H),1.01(d, J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ177.2,164.5,154.8, 148.6,145.7,132.1,126.3,124.5,122.6,118.0,110.2,48.0, 46.8,43.7,38.4,33.8,32.2,29.4,28.5,24.1,24.0；HRMS (ESI-TOF):calcd.for C21H23O2[M+H]+307.1693；found 307.1703。
example 7
Taking 4g of 3-methylene cyclopentano [ b ] chromone compound with the structural formula as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000101
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-6-fluoro chromone and the other steps were the same as in example, to give 4g of a white solid with a yield of 30.0mg, a yield of 53%, a melting point of 138.1-139.0 ℃, and spectral data:1H NMR(400MHz, CDCl3)δ7.86(dd,J＝8.4,3.2Hz,1H),7.48(dd,J＝9.2, 4.2Hz,1H),7.35(ddd,J＝9.2,7.6,3.2Hz,1H),5.78(d,J ＝2.4Hz,1H),5.35(d,J＝2.0Hz,1H),3.06(d,J＝6.6Hz, 1H),2.77(d,J＝6.2Hz,1H),2.56(d,J＝3.8Hz,1H),2.21 (d,J＝3.8Hz,1H),1.69–1.63(m,1H),1.62–1.53(m,1H), 1.50–1.41(m,1H),1.38–1.30(m,1H),1.16(d,J＝10.4 Hz,1H),1.06(d,J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ 176.2,165.1,159.6(d,J＝246.2Hz,1C),152.6,148.4,126.1 (d,J＝8.6Hz,1C),126.0,121.3(d,J＝25.4Hz,1C),120.2 (d,J＝8.0Hz,1C),111.0(d,J＝2.4Hz,1C),110.8,48.1, 46.8,43.8,38.5,32.3,29.4,28.6；HRMS(ESI-TOF):calcd.for C18H16FO2[M+H]+283.1129；found 283.1134。
example 8
Taking 4h as an example for preparing the 3-methylene cyclopentano [ b ] chromone compound with the structural formula as follows, the used raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000111
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-6-chloro chromone and the other steps were the same as in example, to give a white solid 4h with a yield of 36.0mg, a yield of 60%, a melting point of 141.7-142.6 ℃, and spectral data:1H NMR(400MHz, CDCl3)δ8.17(d,J＝2.4Hz,1H),7.57(dd,J＝8.8,2.6Hz, 1H),7.43(d,J＝8.8Hz,1H),5.78(d,J＝2.4Hz,1H),5.35 (d,J＝1.4Hz,1H),3.06(d,J＝6.6Hz,1H),2.76(d,J＝6.4 Hz,1H),2.56(d,J＝3.6Hz,1H),2.20(d,J＝3.6Hz,1H), 1.71–1.62(m,1H),1.62–1.53(m,1H),1.50–1.41(m, 1H),1.38–1.29(m,1H),1.15(d,J＝10.4Hz,1H),1.06(d, J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ175.8,165.0,154.8, 148.3,133.5,130.9,126.6,125.9,125.4,119.9,111.1,48.1, 46.8,43.8,38.5,32.3,29.4,28.5；HRMS(ESI-TOF):calcd.for C18H16ClO2[M+H]+299.0833；found 299.0843。
example 9
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4i with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000121
in example 1, the 3-iodochromone used was replaced with equimolar 3-iodo-6-bromochromone and the other steps were the same as in example, to give 4i as a white solid with a yield of 27.6.0mg, a yield of 40%, a melting point of 155.2-156.2 ℃, and spectral data as follows:1H NMR(400MHz, CDCl3)δ8.34(d,J＝2.4Hz,1H),7.71(dd,J＝8.8,2.4Hz, 1H),7.37(d,J＝8.8Hz,1H),5.78(d,J＝2.4Hz,1H),5.35 (d,J＝2.0Hz,1H),3.06(d,J＝6.6Hz,1H),2.77(d,J＝6.4 Hz,1H),2.56(d,J＝4.0Hz,1H),2.21(d,J＝3.9Hz,1H), 1.72–1.62(m,1H),1.62–1.53(m,1H),1.50–1.41(m, 1H),1.38–1.30(m,1H),1.18–1.12(m,1H),1.09–1.04 (m,1H)；13C NMR(100MHz,CDCl3)δ175.7,165.0,155.2,148.3, 136.2,128.6,126.7,126.3,120.2,118.4,111.1,48.1,46.9, 43.8,38.5,32.3,29.4,28.6；HRMS(ESI-TOF):calcd.for C18H16BrO2[M+H]+343.0328；found 343.0338。
example 10
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4j with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000131
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-6-cyano chromone and the other steps were the same as in example to give 4j as a white solid with a yield of 25.2mg, a yield of 44%, a melting point of 166.0-167.2 ℃, and spectral data:1H NMR(400MHz, CDCl3)δ8.55(d,J＝2.0Hz,1H),7.86(dd,J＝8.6,2.2Hz, 1H),7.59(d,J＝8.8Hz,1H),5.82(d,J＝2.4Hz,1H),5.40 (d,J＝1.8Hz,1H),3.07(d,J＝6.4Hz,1H),2.79(d,J＝6.0 Hz,1H),2.55(s,1H),2.22(s,1H),1.72–1.64(m,1H),1.63 –1.54(m,1H),1.50–1.40(m,1H),1.39–1.29(m,1H), 1.16(d,J＝10.6Hz,1H),1.08(d,J＝9.6Hz,1H)；13C NMR(100 MHz,CDCl3)δ175.1,165.2,158.2,147.9,135.7,131.6,127.3, 125.3,119.9,117.8,112.0,109.2,48.0,46.8,43.7,38.5,32.4, 29.4,28.5；HRMS(ESI-TOF):calcd.for C19H16NO2[M+H]+290.1176； found 290.1184。
example 11
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4k with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000141
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-7-methyl chromone and the other steps were the same as in example to give 4k as a white solid in yield30.0mg, a yield of 54%, a melting point of 106.6 to 107.7 ℃, and spectral data:1H NMR(400MHz, CDCl3)δ8.11(d,J＝8.0Hz,1H),7.28(s,1H),7.19(d,J ＝8.2Hz,1H),5.75(d,J＝2.4Hz,1H),5.31(d,J＝1.6Hz, 1H),3.06(d,J＝6.4Hz,1H),2.75(d,J＝5.8Hz,1H),2.57 (s,1H),2.48(s,3H),2.20(s,1H),1.72–1.63(m,1H),1.62 –1.52(m,1H),1.50–1.41(m,1H),1.38–1.30(m,1H), 1.17(dd,J＝10.6,1.0Hz,1H),1.05(dd,J＝10.4,1.2Hz, 1H)；13C NMR(100MHz,CDCl3)δ177.2,164.5,156.6,148.7, 144.7,126.5,126.4,125.7,122.6,118.1,110.2,48.1,46.9, 43.8,38.5,32.3,29.5,28.6,21.9；HRMS(ESI-TOF):calcd.for C19H19O2[M+H]+279.1380；found 279.1391。
example 12
Taking 4l as an example for preparing 3-methylene cyclopentano [ b ] chromone compounds with the structural formula as follows, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000151
in example 1, the 3-iodochromone used was replaced with equimolar 3-iodo-7-methoxychromone and the other steps were the same as in example, giving 4l as a yellow solid in 36.9mg yield, 63% yield, melting point 138.9-140.2 ℃, and spectral data:1H NMR(400MHz, CDCl3)δ8.11(d,J＝8.8Hz,1H),6.93(dd,J＝8.8,2.4Hz, 1H),6.87(d,J＝2.4Hz,1H),5.71(d,J＝2.4Hz,1H),5.28 (d,J＝1.8Hz,1H),3.89(s,3H),3.03(d,J＝6.4Hz,1H), 2.73(d,J＝6.2Hz,1H),2.56(d,J＝3.8Hz,1H),2.18(d, J＝3.8Hz,1H),1.69–1.61(m,1H),1.61–1.52(m,1H), 1.49–1.39(m,1H),1.36–1.28(m,1H),1.17(d,J＝10.4 Hz,1H),1.04(d,J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ 176.6,164.3,163.9,158.2,148.6,127.2,126.5,118.8,114.0, 109.8,100.7,55.9,48.1,46.8,43.7,38.5,32.3,29.5,28.6； HRMS(ESI-TOF):calcd.for C19H19O3[M+H]+295.1329；found 295.1333。
example 13
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4m with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000161
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-7-fluoro chromone and the other steps were the same as in example, to give 4m as a white solid with a yield of 32.2mg, a yield of 57%, a melting point of 90.8-92.4 ℃, and spectral data:1H NMR(400MHz, CDCl3)δ8.23(dd,J＝8.8,6.4Hz,1H),7.15(dd,J＝9.2, 2.2Hz,1H),7.10(td,J＝8.6,2.2Hz,1H),5.75(d,J＝2.4 Hz,1H),5.33(d,J＝1.6Hz,1H),3.05(d,J＝6.4Hz,1H), 2.76(d,J＝5.8Hz,1H),2.56(d,J＝3.2Hz,1H),2.20(d, J＝3.0Hz,1H),1.71–1.62(m,1H),1.62–1.52(m,1H), 1.50–1.40(m,1H),1.37–1.29(m,1H),1.16(d,J＝10.4 Hz,1H),1.06(d,J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ 176.2,166.8,164.6(d,J＝70Hz,1C),157.4(d,J＝13.2Hz, 1C),148.3,128.3(d,J＝10.6Hz,1C),126.7,121.7(d,J＝ 2.4Hz,1C),113.6(d,J＝22.6Hz,1C),110.8,105.0(d,J＝ 25.4Hz,1C),48.1,46.8,43.7,38.5,32.3,29.4,28.5；HRMS (ESI-TOF):calcd.for C18H16FO2[M+H]+283.1129；found 283.1136。
example 14
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4n with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000171
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-7-chloro chromone and the other steps were the same as in example, to give 4n as a white solid with a yield of 31.6mg, a yield of 53%, a melting point of 149.4-150.1 ℃, and spectral data as follows:1H NMR(400MHz, CDCl3)δ8.16(d,J＝8.4Hz,1H),7.51(d,J＝1.8Hz,1H), 7.34(dd,J＝8.4,1.8Hz,1H),5.76(d,J＝2.4Hz,1H),5.34 (d,J＝1.8Hz,1H),3.05(d,J＝6.4Hz,1H),2.76(d,J＝6.2 Hz,1H),2.56(d,J＝3.8Hz,1H),2.21(d,J＝3.8Hz,1H), 1.72–1.65(m,1H),1.62–1.53(m,1H),1.50–1.41(m, 1H),1.38–1.30(m,1H),1.16(d,J＝10.4Hz,1H),1.10– 1.04(m,1H)；13C NMR(100MHz,CDCl3)δ176.2,164.8,156.6, 148.3,139.3,127.3,126.9,125.8,123.5,118.4,110.9,48.1, 46.9,43.8,38.5,32.3,29.5,28.6；HRMS(ESI-TOF):calcd.for C18H16ClO2[M+H]+299.0833；found 299.0842。
example 15
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4o with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000181
in example 1, the 3-iodochromone used was replaced with equimolar 3-iodo-7-bromochromone and the other steps were the same as in example, to give 4o as a white solid with a yield of 28.3mg, a yield of 41%, a melting point of 143.6-144.7 ℃, and spectral data as follows:1H NMR(400MHz, CDCl3)δ8.08(dd,J＝8.4,3.2Hz,1H),7.68(s,1H),7.54 –7.46(m,1H),5.76(s,1H),5.34(s,1H),3.05(d,J＝6.4 Hz,1H),2.76(d,J＝4.6Hz,1H),2.56(s,1H),2.21(s,1H), 1.71–1.62(m,1H),1.62–1.54(m,1H),1.50–1.40(m, 1H),1.38–1.30(m,1H),1.16(d,J＝10.4Hz,1H),1.07(d, J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ；13C NMR(100MHz, CDCl3)δ176.3,164.7,156.5,148.3,128.6,127.5,127.4, 126.9,123.8,121.4,111.0,48.1,46.8,43.7,38.5,32.3,29.4, 28.5；HRMS(ESI-TOF):calcd.for C18H16BrO2[M+H]+343.0328； found 343.0338。
example 16
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4p with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000191
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-8-methyl chromone and the other steps were the same as in example to give 4p as a white solid with a yield of 34.5mg, a yield of 62%, a melting point of 110.0 to 111.1 ℃, and spectral data as follows:1H NMR(400MHz, CDCl3)δ8.07(d,J＝8.0Hz,1H),7.50–7.42(m,1H),7.26 (t,J＝7.6Hz,1H),5.77(d,J＝2.4Hz,1H),5.33(d,J＝1.8 Hz,1H),3.07(d,J＝6.4Hz,1H),2.76(d,J＝5.8Hz,1H), 2.58(d,J＝3.2Hz,1H),2.51(s,3H),2.20(d,J＝3.2Hz, 1H),1.71–1.62(m,1H),1.62–1.53(m,1H),1.50–1.41 (m,1H),1.38–1.30(m,1H),1.18(d,J＝10.4Hz,1H),1.05 (dd,J＝10.4,1.2Hz,1H)；13C NMR(100MHz,CDCl3)δ177.4, 164.4,154.8,148.8,134.4,127.6,126.3,124.7,124.5,123.6, 110.2,48.1,46.9,43.7,38.5,32.3,29.4,28.6,15.7；HRMS (ESI-TOF):calcd.for C19H19O2[M+H]+279.1380；found 279.1386。
example 17
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4q with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000201
in example 1, the 3-iodochromone used was replaced with equimolar 3-iodo-8-chlorochromone and the other steps were the same as in example, giving 4q as a white solid with a yield of 30.2mg, 51% yield, melting point 99.9-101.1 ℃, and spectral data:1H NMR(400MHz, CDCl3)δ8.12(dd,J＝8.0,1.6Hz,1H),7.68(dd,J＝7.6, 1.6Hz,1H),7.30(t,J＝7.8Hz,1H),5.87(d,J＝2.4Hz,1H), 5.37(d,J＝1.8Hz,1H),3.06(d,J＝6.4Hz,1H),2.77(d, J＝6.2Hz,1H),2.56(d,J＝3.8Hz,1H),2.21(d,J＝3.8Hz, 1H),1.72–1.62(m,1H),1.62–1.53(m,1H),1.49–1.40 (m,1H),1.37–1.29(m,1H),1.17(d,J＝10.4Hz,1H),1.06 (d,J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ176.3,164.7, 152.0,148.0,133.7,126.5,126.3,125.0,124.6,123.4,111.5, 48.0,46.9,43.7,38.4,32.3,29.4,28.5；HRMS(ESI-TOF):calcd. for C18H16ClO2[M+H]+299.0833；found 299.0834。
example 18
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4r with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000211
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-8-nitro chromone and the other steps were the same as in example, to give 4r as a yellow solid in 25.6mg yield, 41% yield, melting point 139.6-140.9 ℃, and spectral data:1H NMR(400MHz, CDCl3)δ8.51(dd,J＝8.0,1.8Hz,1H),8.29(dd,J＝8.0, 1.8Hz,1H),7.49(t,J＝8.0Hz,1H),5.90(d,J＝2.4Hz,1H), 5.42(d,J＝2.0Hz,1H),3.09(d,J＝6.6Hz,1H),2.81(d, J＝6.4Hz,1H),2.57(d,J＝3.8Hz,1H),2.24(d,J＝3.8Hz, 1H),1.73–1.65(m,1H),1.64–1.56(m,1H),1.50–1.42 (m,1H),1.39–1.32(m,1H),1.20(d,J＝10.6Hz,1H),1.10 (d,J＝10.6Hz,1H)；13C NMR(100MHz,CDCl3)δ174.9,165.0, 148.7,147.4,139.2,131.9,129.5,126.9,126.8,124.2,112.8, 48.0,47.0,43.7,38.5,32.4,29.4,28.5；HRMS(ESI-TOF):calcd. for C18H16NO4[M+H]+310.1074；found 310.1085。
example 19
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4s with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000221
in example 1, 3-iodochromone was used in equimolar amountsThe same procedure as in example except for the replacement of 3-iodo-6, 7-dimethylchromone gave 4s as a white solid in 42.0 mg yield at 72% melting point of 110.1-110.8 ℃ and spectral data:1H NMR(400 MHz,CDCl3)δ7.90(s,1H),7.20(s,1H),5.69(d,J＝2.4Hz, 1H),5.25(d,J＝1.8Hz,1H),3.02(d,J＝6.4Hz,1H),2.70 (d,J＝6.0Hz,1H),2.55(d,J＝3.6Hz,1H),2.33(s,3H), 2.30(s,3H),2.16(d,J＝3.6Hz,1H),1.68–1.59(m,1H), 1.59–1.50(m,1H),1.47–1.39(m,1H),1.34–1.26(m, 1H),1.13(d,J＝10.4Hz,1H),1.01(d,J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ177.1,164.3,154.9,148.7,143.6, 134.0,126.3,125.5,122.6,118.3,109.9,48.0,46.8,43.7, 38.4,32.2,29.4,28.5,20.4,19.3；HRMS(ESI-TOF):calcd.for C20H21O2[M+H]+293.1536；found 293.1545。
example 20
Taking 4t as an example for preparing 3-methylene cyclopentano [ b ] chromone compounds with the structural formula as follows, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000231
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-6, 8-dimethylchromone and the other steps were the same as in example, to give 4t of white solid with a yield of 35.8 mg, a yield of 61%, a melting point of 142.6-143.8 ℃, and spectral data as follows:1H NMR(400 MHz,CDCl3)δ7.85(s,1H),7.29(s,1H),5.75(d,J＝2.4Hz, 1H),5.31(d,J＝2.0Hz,1H),3.07(d,J＝6.6Hz,1H),2.76 (d,J＝6.2Hz,1H),2.58(d,J＝3.6Hz,1H),2.47(s,3H), 2.40(s,3H),2.20(d,J＝3.6Hz,1H),1.69–1.62(m,1H), 1.62–1.54(m,1H),1.49–1.42(m,1H),1.37–1.30(m, 1H),1.17(d,J＝10.4Hz,1H),1.05(d,J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3)δ177.5,164.3,153.1,149.0,135.7, 134.3,127.3,126.2,124.4,123.0,109.9,48.1,46.9,43.8, 38.5,32.3,29.5,28.6,21.0,15.6；HRMS(ESI-TOF):calcd.for C20H21O2[M+H]+293.1536；found 293.1540。
example 21
Taking 4u as an example for preparing 3-methylene cyclopentano [ b ] chromone compounds with the structural formula as follows, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000241
in example 1, the 3-iodo chromone used was replaced with equimolar 3-iodo-6-chloro-7-methyl chromone and the other steps were the same as in example, to give 4u as a white solid with a yield of 37.2mg, a yield of 60%, a melting point of 132.8-133.4 ℃, and spectral data as follows:1H NMR (400MHz,CDCl3)δ8.17(s,1H),7.37(s,1H),5.75(d,J＝ 2.3Hz,1H),5.33(d,J＝1.8Hz,1H),3.05(d,J＝6.4Hz,1H), 2.76(d,J＝6.0Hz,1H),2.56(d,J＝3.2Hz,1H),2.49(s, 3H),2.20(d,J＝3.2Hz,1H),1.71–1.63(m,1H),1.59– 1.54(m,1H),1.49–1.42(m,1H),1.38–1.30(m,1H),1.16 (d,J＝10.5Hz,1H),1.06(d,J＝10.4Hz,1H)；13C NMR(100 MHz,CDCl3)δ175.9,164.8,154.7,148.5,142.4,131.6,126.5, 125.7,124.0,120.1,110.7,48.1,46.9,43.8,38.5,32.3,29.5, 28.6,20.9；HRMS(ESI-TOF):calcd.for C19H18ClO2[M+H]+313.0990； found 313.0989。
example 22
Taking 4v as an example for preparing 3-methylene cyclopentano [ b ] chromone compounds with the structural formula as follows, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000251
in example 1, 3-iodochromone was used in equimolar amounts with 3-iodo-4H-benzo [ H ]]Chromen-4-one substitution, otherwise identical to example, gave 4v as a yellow solid in 33.5mg yield of 53% with a melting point of 135.4-136.5 ℃ and spectral data:1H NMR (400MHz,CDCl3)δ8.53(d,J＝8.0Hz,1H),8.19(d,J＝8.8 Hz,1H),7.91(d,J＝7.2Hz,1H),7.75(d,J＝8.8Hz,1H), 7.72–7.62(m,2H),5.92(s,1H),5.39(s,1H),3.14(d,J ＝6.4Hz,1H),2.82(d,J＝5.8Hz,1H),2.66–2.61(m,1H), 2.27–2.22(m,1H),1.72–1.66(m,1H),1.65–1.56(m, 1H),1.53–1.46(m,1H),1.40–1.33(m,1H),1.23(d,J＝ 15.8Hz,1H),1.09(d,J＝10.4Hz,1H)；13C NMR(100MHz,CDCl3) δ177.0,164.0,153.6,148.7,136.0,129.1,128.2,127.9, 127.1,125.1,124.4,122.4,121.2,121.1,110.0,48.3,47.0, 43.8,38.5,32.4,29.5,28.6；HRMS(ESI-TOF):calcd.for C22H19O2 [M+H]+315.1380；found 315.1387。
example 23
Taking the preparation of 3-methylene cyclopentano [ b ] chromone compound 4w with the structural formula as follows as an example, the raw materials and the preparation method are as follows:
Figure RE-GDA0003095833970000261
in example 1, the 3-iodochromone used was equimolar with 2-iodo-1H-benzo [ f]Chromen-1-one substitution, otherwise identical to example, gave 4w as a white solid in a yield of 26.6mg, 42% yield, melting point 161.7-162.4 ℃ and spectral data:1H NMR (400MHz,CDCl3)δ10.15(d,J＝7.8Hz,1H),8.06(d,J＝8.6 Hz,1H),7.89(d,J＝6.6Hz,1H),7.80–7.69(m,1H),7.65 –7.51(m,2H),5.79(s,1H),5.34(s,1H),3.16(s,1H),2.82 (s,1H),2.68(s,1H),2.24(s,1H),1.75–1.66(m,1H),1.66 –1.58(m,1H),1.50(d,J＝11.0Hz,1H),1.36(d,J＝10.2 Hz,1H),1.22(d,J＝10.2Hz,1H),1.09(d,J＝10.6Hz,1H)；13C NMR(100MHz,CDCl3)δ179.4,162.4,157.7,148.4,135.2, 131.2,130.8,129.2,129.1,128.2,127.2,126.5,118.0,109.8, 48.4,47.2,43.7,38.5,32.4,29.5,28.6；HRMS(ESI-TOF):calcd. for C22H19O2[M+H]+315.1380；found 315.1388。
pharmacological example 1:
cytotoxicity of Compounds 4a, 4g, 4j, 4l, 4m, 4n, 4o, 4q, 4s or 4u on MCF-7 cells
For MCF-7 cellsThe culture medium RPMI-1640 is cultured, and the culture medium contains 10% of fetal bovine serum, 100U/mL of penicillin and 100U/mL of streptomycin. Cells were added to 96 wells at a concentration of 5000 cells per well and 5% CO at 37 deg.C2Incubate in a humidified air incubator for 72 hours.
The cell viability was determined by the modified MTT method. After 72 hours incubation of the cells, a solution of the newly formulated compound 4a, 4g, 4j, 4L, 4m, 4n, 4o, 4q, 4s or 4u in dimethylsulfoxide was added to each well in a concentration gradient such that the final concentration of the compound in the wells was 1.11, 3.33 and 10. mu. mol/L, respectively. After 72 hours, 10. mu.L of MTT (5mg/mL) in phosphate buffer was added to each well, and after further incubation at 37 ℃ for 4 hours, the unconverted MTT was removed by centrifugation for 5 minutes, and 150. mu.L of dimethyl sulfoxide was added to each well. The OD value was measured at 490 nm wavelength with a microplate reader by dissolving reduced MTT crystal formazan (formazan).
Wherein the half inhibitory concentration IC50 of compound 4a, 4g, 4j, 4l, 4m, 4n, 4o, 4q, 4s or 4u on MCF-7 cells was analyzed by the sps software (version 19). The IC50 of the compound 4a on MCF-7 tumor cells is 49.6 mu mol/L; the IC50 of compound 4g to MCF-7 tumor cells was 45.2. mu. mol/L; the IC50 of compound 4j on MCF-7 tumor cells was 21.3. mu. mol/L; the IC50 of the compound 4L on MCF-7 tumor cells is more than 50.0 mu mol/L; the IC50 of the compound 4m on MCF-7 tumor cells is 2.5 mu mol/L; the IC50 of compound 4n on MCF-7 tumor cells was 45.5. mu. mol/L; the IC50 of the compound 4o on MCF-7 tumor cells is 15.9 mu mol/L; IC50 of compound 4q to MCF-7 tumor cells is >50.0 μmol/L; the IC50 of the compound 4s on MCF-7 tumor cells is 6.2 mu mol/L; the IC50 of the compound 4u to MCF-7 tumor cells is more than 50.0 mu mol/L; while the positive control cisplatin had an IC50 of 3.5. mu. mol/L for MCF-7 tumor cells.
And (4) experimental conclusion: MCF-7 cells are an effective tool and an index for evaluating the cytotoxicity of test compounds on tumor cells. The experiment shows that the 3-methylene cyclopentano [ b ] chromone compound has certain cytotoxicity to MCF-7 cells and is likely to be developed into a new medicine with anti-tumor effect.
Pharmacological example 2: cytotoxicity of Compounds 4a, 4g, 4j, 4l, 4m, 4n, 4o, 4q, 4s or 4u on HeLa cells
HeLa cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100U/mL penicillin and 100U/mL streptomycin. Cells were added to 96 wells at a concentration of 5000 cells per well and incubated for 72 hours in an incubator containing 5% CO2 humidified air at 37 ℃.
The cell viability was determined by the modified MTT method. After 72 hours incubation of the cells, a solution of the newly formulated compound 4a, 4g, 4j, 4L, 4m, 4n, 4o, 4q, 4s or 4u in dimethylsulfoxide was added to each well in a concentration gradient such that the final concentration of the compound in the wells was 1.11. mu. mol/L, 3.33. mu. mol/L and 10. mu. mol/L, respectively. After 72 hours, 10. mu.L of MTT (5mg/mL) in phosphate buffer was added to each well, and after further incubation at 37 ℃ for 4 hours, the untransformed MTT was removed by centrifugation for 5 minutes, and 150. mu.L of dimethyl sulfoxide was added to each well. The OD value was measured at 490 nm wavelength with a microplate reader by dissolving reduced MTT crystal formazan (formazan). Wherein compounds 4a, 4g, 4j, 4l, 4m, 4n, 4o, 4q, 4s or 4u were analyzed by the sps software (version 19) for HeLa cell half inhibitory concentration IC 50.
The IC50 of compound 4a on HeLa tumor cells was 45.9. mu. mol/L; the IC50 of compound 4g to HeLa tumor cells was 40.1. mu. mol/L; the IC50 of compound 4j on HeLa tumor cells was 10.5. mu. mol/L; the IC50 of compound 4L to HeLa tumor cells was 38.8. mu. mol/L; the IC50 of compound 4m on HeLa tumor cells was 4.6. mu. mol/L; the IC50 of compound 4n to HeLa tumor cells was 38.0. mu. mol/L; the IC50 of compound 4o on HeLa tumor cells was 44.1. mu. mol/L; IC50 of compound 4q to HeLa tumor cells is >50.0 μmol/L; IC50 of compound 4s to HeLa tumor cells is more than 50.0 mu mol/L; IC50 of compound 4u to HeLa tumor cells is >50.0 μmol/L; while the IC50 of the positive control cisplatin for HeLa tumor cells was 3.7. mu. mol/L.
And (4) experimental conclusion: HeLa cells are an effective tool and evaluation index for testing the cytotoxicity of compounds on tumor cells. The experiment shows that the 3-methylene cyclopentano [ b ] chromone compound has certain cytotoxicity to HeLa cells and is likely to be developed into a new drug with anti-tumor effect.
From the above pharmacological examples, we can see that the compounds show certain cytotoxicity to the two tumor cells. Therefore, the compounds have the potential of being developed into antitumor drugs and are worthy of further research
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (2)

1. A process for the preparation of 3-methylenecyclopenta [ b ] chromones of the formula:
Figure FDA0003651864320000011
the raw materials and the preparation method are as follows: 0.2mmol of 3-iodochromone, 0.28mmol of N-Ts aziridine, 0.8mmol of norbornene, 0.02mmol of Pd [ (allyl) Cl]20.04mmol of P (4-F-C)6H4)30.4mmol of Cs2CO30.6mmol of H2O, 2.0mL of ultra-dry toluene is added into a 4mL reaction bottle, the reaction is carried out for 24h at 100 ℃, after the reaction is finished, the reaction product is cooled to room temperature, and the white solid 4a is obtained by silica gel column chromatography separation and purification.
2. Use of a 3-methylenecyclopentano [ b ] chromone compound as claimed in claim 1, in the preparation of a medicament for the treatment of tumours, wherein: the tumor is breast tumor or cervical tumor.
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