CN111454275B - Sesquiterpene lactone-cinnamic acid derivative and salt thereof, pharmaceutical composition and application thereof - Google Patents

Sesquiterpene lactone-cinnamic acid derivative and salt thereof, pharmaceutical composition and application thereof Download PDF

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CN111454275B
CN111454275B CN201910046842.3A CN201910046842A CN111454275B CN 111454275 B CN111454275 B CN 111454275B CN 201910046842 A CN201910046842 A CN 201910046842A CN 111454275 B CN111454275 B CN 111454275B
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陈悦
张泉
丁亚辉
戈伟智
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Luoyang Shangde Pharmaceutical Margin Technology Co ltd
Nankai University
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Abstract

The invention provides application of sesquiterpene lactone-cinnamic acid derivatives and salts thereof in preparing medicines for treating cancers and auxiliary medicines for treating cancers.

Description

Sesquiterpene lactone-cinnamic acid derivative and salt thereof, pharmaceutical composition and application thereof
Technical Field
The invention relates to a sesquiterpene lactone-cinnamic acid derivative and a pharmaceutical composition for treating cancer or assisting in treating cancer, which take the sesquiterpene lactone-cinnamic acid derivative and salt thereof as active ingredients, and application of the pharmaceutical compound and the pharmaceutical composition in preparing anticancer or assisting in anticancer drugs, belonging to the field of pharmaceutical chemistry.
Background
Breast Cancer is the most common Cancer in the world and is also the second leading cause of Cancer-related death in women [ H.A.Wahba, H.A.El-Hadaad, current approaches in treatment of triple-negative breast Cancer, cancer bio.med.,12 (2015) 106-116]. It is estimated that 100 to 130 tens of thousands of breast cancer cases are diagnosed annually worldwide. Triple Negative Breast Cancer (TNBC) is characterized by a lack of expression of human epidermal growth factor receptor 2 (HER-2), estrogen Receptor (ER), and progestogen receptor, TNBC is the most aggressive tumor in the breast cancer subtype, with high recurrence rate and strong drug resistance [ R.Dent, M.Trudeau, K.I.Pritchard, W.M.Hanna, H.K.Kahn, C.A.Sawka, L.A.Lickley, E.Rawlinson, P.Sun, S.A.Narod, triple-negative breast cancer: clinical features and patterns of recurrence, clin. Cancer Res.,13 (2007) 4429-4434 ]. Parthenolide (PTL) is a typical germacrane sesquiterpene lactone with good anticancer properties. However, PTL also suffers from drawbacks such as poor oral bioavailability, instability under chemical and physiological conditions, poor water solubility [ Q.Zhang, Y.Lu, etl.Y.Chen, guaianolide sesquiterpene lactones, a source to discover agents that selectively inhibit acute myelogenous leukemia stern and progenitor cells, j.med.chem.,55 (2012) 8757-8769 ]. The PTL original drug DMAPT effectively improves water solubility and oral bioavailability, and has entered phase I clinical trials of acute myeloid leukemia treatment. Cinnamic Acid (CA) is a natural aromatic fatty acid, is formed by substituting acrylic acid groups with benzene rings, and has a long history of plant spices and plant seasonings; cinnamic Acid (CA) and Cinnamic Acid Derivatives (CADs) are present in large numbers in many plants and foods and exhibit a wide range of biological activities including anti-cancer, anti-oxidant, antibacterial, antiviral, liver protecting and hypolipidemic. CA scaffolds exist in a variety of registered drugs, such as Panobunostat (anti-tumor drug), cinanserin and tranilast (anti-allergic drug). The anticancer potential of CADs has been known for over a century. The cinnamic acid ester derivative has obvious anti-tumor activity.
Disclosure of Invention
The invention provides a pharmaceutical composition for treating cancers or a composition with other anticancer drugs of sesquiterpene lactone-cinnamic acid derivatives or salts thereof and pharmaceutically acceptable carriers, a preparation method thereof, and application of the sesquiterpene lactone-cinnamic acid derivatives or salts thereof of formula (I) and pharmaceutical compositions thereof in preparing medicaments for treating cancers.
Figure BDA0001949486420000021
Wherein P is the following structure:
Figure BDA0001949486420000022
R 1 is hydrogen, alkyl, alkylaryl, cyanoA base; r is R 2 Phenyl, substituted phenyl, furyl, thienyl, pyridyl, naphthyl, methylenedioxyphenyl; r is R 3 R being a hydrogen atom 4 Amino groups which are hydrogen atoms or one or more substituents, wherein the substituents comprise methyl, ethyl and propyl chain substituents and can also be cyclic substituents such as cyclopentyl and cyclohexyl; r is R 3 ，R 4 Is a single bond.
Pharmaceutically acceptable salts thereof with inorganic or organic acids, including quaternary ammonium salts with compounds of formula (i), including hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, phosphorous acid, sulfurous acid, carbonic acid, boric acid, phosphomolybdic acid, selenious acid, methanesulfonic acid, substituted methanesulfonic acid, benzenesulfonic acid, substituted benzenesulfonic acid, fumaric acid, citric acid, maleic acid, tartaric acid, oxalic acid, D-malic acid, L-malic acid, DL-lactic acid, D-lactic acid, DL-lactic acid, formic acid, substituted formic acid, acetic acid, propionic acid, butyric acid, valeric acid, oleic acid, lauric acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, phthalic acid, malonic acid, succinic acid, glycolic acid, thioalkyd, glycine, sarcosine, sulfonic acid, nicotinic acid, picolinic acid, isonicotinic acid, dichloroacetic acid, benzoic acid, substituted benzoic acid.
Figure BDA0001949486420000031
Figure BDA0001949486420000041
Figure BDA0001949486420000051
Figure BDA0001949486420000061
Figure BDA0001949486420000071
Figure BDA0001949486420000081
The invention also provides the use of a compound of formula 3-24 in the manufacture of a medicament for the treatment of cancer, wherein the cancer is breast cancer.
The invention also provides the use of a compound of formula 3-24 in the manufacture of a medicament for the adjuvant treatment of cancer, wherein the cancer is breast cancer.
The invention also provides a pharmaceutical composition for treating cancer, which comprises an effective amount of the compound of the formula 3-24 and a pharmaceutically acceptable carrier or a composition with other anticancer drugs.
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FIG. 1 preparation of sesquiterpene lactone- cinnamic acid derivatives 3,4a-4x,5a-5b
FIG. 2 preparation of sesquiterpene lactone-cinnamic acid derivatives 6a-6g
FIG. 3 preparation of sesquiterpene lactone-cinnamic acid derivatives 7a-7m
FIG. 4 preparation of sesquiterpene lactone-cinnamic acid derivatives 10a-10l,12a-12c,14
FIG. 5 preparation of sesquiterpene lactone- cinnamic acid derivatives 16,17a-17b,18a-18b,19a-19b,20a-20b,21a-21b
FIG. 6 preparation of sesquiterpene lactone-cinnamic acid derivative 24
Detailed Description
The invention is further illustrated by the following examples for the understanding of the invention, which are not intended to limit the scope of the invention.
Example 1:
the parthenolide (compound 1) is oxidized by selenium dioxide to obtain compound 2, and the compound 2 and various substituted cinnamic acids are esterified under EDCI/DMAP or triphenylphosphine and DIAD conditions to obtain compounds 3,4a-4x,7a-7m. The compound 2 is esterified with other heterocyclic ring acid instead of benzene ring to obtain compounds 6a-6g, compound 8 is taken as raw material to obtain some column-substituted double bond acid through the Knaowian condensation reaction, and then the compound is esterified with compound 2 to obtain compounds 10a-10l,12a-12c,14. Reducing the compound 2 by sodium borohydride to obtain a compound 15, and esterifying the compound 15 with 2, 5-dimethoxy cinnamic acid and 2, 6-dimethoxy cinnamic acid to obtain compounds 20a-20b;2, 5-dimethoxy cinnamic acid and 2, 6-dimethoxy cinnamic acid are reduced by palladium carbon hydrogen to obtain acids 18a-18b, and then are esterified with a compound 2 to obtain 21a-21b. Acids 18a-18b give methyl esters 19a-19b in thionyl chloride methanol. The compound 2 is reacted with 2, 6-dimethoxybenzoic acid to give compound 16.
Synthesis of Compound 2:
PTL (1.0 g,4.3 mmol) was dissolved in 20ml DCM and selenium dioxide (324 mg,2.4 mmol) and t-BuOOH (70% in H) previously dried over anhydrous sodium sulfate were added 2 O,1.48mL,10.8 mmol). The mixture was stirred at room temperature overnight. After the reaction, DCM (20 mL) was added to dilute the mixture, saturated sodium thiosulfate was added to quench the reaction, methylene chloride was extracted three times, the organic phase was saturated brine, dried over anhydrous sodium sulfate and concentrated, and purified by silica gel column chromatography to give Compound 2 (810 mg, 72%) 1 H NMR(400MHz,CDCl 3 )δ6.15(d,J＝3.5Hz,1H),5.60(t,J＝8.2Hz,1H),5.52(d,J＝3.2Hz,1H),4.05(dd,J＝32.1,12.9Hz,2H),3.81(t,J＝9.4Hz,1H),2.87–2.75(m,2H),2.48–2.29(m,4H),2.28–2.04(m,3H),1.65–1.56(m,1H),1.49(s,3H),1.03(t,J＝12.4Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.9,139.5,138.8,126.8,120.4,81.4,65.4,63.3,60.4,42.7,36.8,25.5,24.0,23.6,18.0.hrms (ESI) calculated C 15 H 20 NaO 4 [M+Na] + 287.1254, experimental 287.1258.
Synthesis of Compounds 3,4a-4 x:
in a reaction flask, compound 2 (53 mg,0.2 mmol), EDCI (115 mg,0.6 mmol), DMAP (1.2 mg,0.01 mmol) and the corresponding cinnamic acid (0.3 mmol,1.5 eq) were added sequentially. 2mL of anhydrous DCM was added and triethylamine (83.4. Mu.L, 0.6 mmol) was added with zero degree stirring. The reaction solution is stirred at room temperature overnight, saturated sodium bicarbonate is added to quench the reaction, the reaction is basically completed, the extraction is carried out three times by methylene dichloride, the reaction solution is dried by anhydrous sodium sulfate, and the solid 3,4a-4x is obtained by filtration and concentration and purification by silica gel column chromatography.
(3) White solidBody (yield: 86%). 1 H NMR(400MHz,CDCl 3 )δ7.68(d,J＝16.0Hz,1H),7.54–7.46(m,2H),7.45–7.34(m,3H),6.41(d,J＝16.0Hz,1H),6.22(d,J＝3.5Hz,1H),5.72(t,J＝8.2Hz,1H),5.55(d,J＝3.1Hz,1H),4.77(d,J＝12.5Hz,1H),4.59(d,J＝12.5Hz,1H),3.85(t,J＝9.3Hz,1H),3.01–2.91(m,1H),2.87(d,J＝9.4Hz,1H),2.49–2.11(m,6H),1.72–1.64(m,1H),1.54(s,3H),1.10(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.5,145.4,138.6,134.8,133.9,130.6,130.5,128.8,128.0,120.2,117.2,80.9,66.8,63.2,59.9,42.5,36.5,25.7,24.4,23.7,17.9.Hrms (ESI) calculated value C 24 H 30 NO 5 [M+NH 4 ] + 412.2118, experimental 412.2122.
(4a) White solid (yield: 92%). 1 H NMR(400MHz,CDCl 3 )δ8.05(d,J＝15.8Hz,1H),7.67(d,J＝7.9Hz,2H),7.56(t,J＝7.5Hz,1H),7.47(t,J＝7.6Hz,1H),6.38(d,J＝15.8Hz,1H),6.19(d,J＝3.4Hz,1H),5.72(t,J＝8.2Hz,1H),5.54(d,J＝3.4Hz,1H),4.75(d,J＝12.5Hz,1H),4.63(d,J＝12.5Hz,1H),3.85(t,J＝9.3Hz,1H),2.91(t,J＝9.0Hz,1H),2.85(d,J＝9.4Hz,1H),2.51–2.09(m,6H),1.69(dd,J＝16.5,8.6Hz,1H),1.52(s,3H),1.08(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.3,165.5,140.7,138.6,134.7,132.8,132.1,130.7,129.7,128.6(q,J＝30.3Hz),127.7,126.0(d,J＝5.5Hz),123.8(d,J＝274.1Hz),121.6,120.1,80.9,66.9,63.1,59.7,42.5,36.4,25.5,24.3,23.7,17.8. 19 F NMR(376MHz,CDCl 3 ) Delta-58.8(s). HRMS (ESI) calculated C 25 H 29 F 3 NO 5 [M+NH 4 ] + 480.1992, experimental 480.1993.
(4b) White solid (yield: 98%); 1 H NMR(400MHz,CDCl 3 )δ7.77(d,J＝16.2Hz,1H),7.48(t,J＝7.4Hz,1H),7.33(dd,J＝13.2,7.0Hz,1H),7.13(t,J＝7.5Hz,1H),7.10–7.03(m,1H),6.49(d,J＝16.2Hz,1H),6.19(d,J＝2.0Hz,1H),5.70(t,J＝8.2Hz,1H),5.53(d,J＝2.0Hz,1H),4.76(d,J＝12.5Hz,1H),4.57(d,J＝12.5Hz,1H),3.84(t,J＝9.3Hz,1H),2.92(t,J＝9.1Hz,1H),2.85(d,J＝9.4Hz,1H),2.50–2.05(m,6H),1.74–1.60(m,1H),1.51(s,3H),1.07(t,J＝12.9Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.2,166.2,161.2(d,J＝254.1Hz),138.6,137.9(d,J＝2.3Hz),134.8,131.9(d,J＝8.8Hz),130.6,129.0(d,J＝2.6Hz),124.4(d,J＝3.5Hz),122.0(d,J＝11.5Hz),120.1,119.8(d,J＝6.7Hz),116.0(d,J＝21.8Hz),80.9,66.8,63.1,59.8,42.5,36.4,25.6,24.3,23.7,17.8. 19 F NMR(376MHz,CDCl 3 ) Delta-114.2 (ddd, j=10.6, 7.5,3.7 hz.) HRMS (ESI) calculated C 24 H 29 FNO 5 [M+NH 4 ] + 430.2024, experimental 430.2019.
(4c) White solid (yield: 96%). 1 H NMR(400MHz,CDCl 3 )δ8.08(d,J＝16.0Hz,1H),7.57(dd,J＝7.4,1.7Hz,1H),7.38(dd,J＝7.7,1.2Hz,1H),7.28(m,2H),6.39(d,J＝16.0Hz,1H),6.19(d,J＝3.4Hz,1H),5.72(t,J＝8.2Hz,1H),5.54(d,J＝3.1Hz,1H),4.76(d,J＝12.5Hz,1H),4.60(d,J＝12.5Hz,1H),3.84(t,J＝9.3Hz,1H),3.04–2.89(m,1H),2.85(d,J＝9.4Hz,1H),2.47–2.08(m,6H),1.67(m,1H),1.52(s,3H),1.08(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.1,141.3,138.7,135.0,134.9,132.3,131.3,130.9,130.2,127.6,127.2,120.4,119.9,81.0,67.0,63.3,59.9,42.7,36.6,25.8,24.5,23.8,18.0.hrms (ESI) calculated value C 24 H 29 ClNO 5 [M+NH 4 ] + 446.1729, experimental 446.1723.
(4d) White solid (yield: 72%). 1 H NMR(400MHz,CDCl 3 )δ8.04(d,J＝15.9Hz,1H),7.57(dd,J＝11.2,4.5Hz,2H),7.31(t,J＝7.5Hz,1H),7.21(td,J＝7.9,1.4Hz,1H),6.35(d,J＝15.9Hz,1H),6.20(d,J＝3.4Hz,1H),5.73(t,J＝8.3Hz,1H),5.54(d,J＝3.4Hz,1H),4.76(d,J＝12.5Hz,1H),4.61(d,J＝12.5Hz,1H),3.85(t,J＝9.3Hz,1H),2.98–2.90(m,1H),2.86(d,J＝9.4Hz,1H),2.49–2.10(m,6H),1.68(dd,J＝12.8,8.6Hz,1H),1.53(s,3H),1.09(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,165.8,143.6,138.6,134.7,134.0,133.3,131.4,130.7,127.7,127.6,125.2,120.2,120.1,80.9,66.9,63.1,59.8,42.6,36.5,25.6,24.4,23.7,17.9.hrms (ESI) calculated value C 24 H 29 BrNO 5 [M+NH 4 ] + 490.1224, experimental 490.1214.
(4e) White solid (yield: 94%). 1 H NMR(400MHz,CDCl 3 )δ7.99(d,J＝15.9Hz,1H),7.52(d,J＝7.3Hz,1H),7.29–7.24(m,1H),7.20(t,J＝7.0Hz,2H),6.34(d,J＝15.9Hz,1H),6.22(d,J＝3.5Hz,1H),5.73(t,J＝8.3Hz,1H),5.55(d,J＝3.2Hz,1H),4.77(d,J＝12.6Hz,1H),4.60(d,J＝12.6Hz,1H),3.86(t,J＝9.3Hz,1H),3.00–2.91(m,1H),2.87(d,J＝9.4Hz,1H),2.53–2.11(m,9H),1.68(dd,J＝13.2,8.8Hz,1H),1.54(s,3H),1.10(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.5,143.1,138.6,137.6,134.9,132.9,130.7,130.4,130.2,126.3,126.2,120.2,118.2,80.9,66.7,63.1,59.8,42.5,36.5,25.6,24.4,23.7,19.6,17.9.hrms (ESI) calculated C 25 H 32 NO 5 [M+NH 4 ] + 426.2275, experimental 426.2281.
(4f) White solid (yield: 89%). 1 H NMR(400MHz,CDCl 3 )δ7.98(d,J＝16.1Hz,1H),7.46(d,J＝7.4Hz,1H),7.35(t,J＝7.7Hz,1H),7.00–6.87(m,2H),6.50(d,J＝16.1Hz,1H),6.21(d,J＝3.3Hz,1H),5.72(t,J＝8.0Hz,1H),5.54(d,J＝2.9Hz,1H),4.75(d,J＝12.4Hz,1H),4.59(d,J＝12.5Hz,1H),3.96–3.79(m,4H),3.00(t,J＝8.8Hz,1H),2.89(d,J＝9.4Hz,1H),2.54–2.09(m,6H),1.67(t,J＝11.1Hz,1H),1.54(s,3H),1.11(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.4,167.1,158.3,141.0,138.6,135.0,131.7,130.7,129.1,122.9,120.6,120.3,117.7,111.1,81.0,66.8,63.2,59.9,55.4,42.6,36.5,25.8,24.6,23.8,17.9.hrms (ESI) calculated C 25 H 32 NO 6 [M+NH 4 ] + 442.2224, experimental 442.2232.
(4g) White solid (yield: 89%). 1 H NMR(400MHz,CDCl 3 )δ8.03(d,J＝16.1Hz,1H),7.48(d,J＝7.6Hz,1H),7.33(t,J＝7.8Hz,1H),6.97–6.89(m,2H),6.52(d,J＝16.1Hz,1H),6.29–6.19(m,1H),5.74(t,J＝8.0Hz,1H),5.55(d,J＝2.9Hz,1H),4.76(d,J＝12.6Hz,1H),4.62(d,J＝12.6Hz,1H),4.10(q,J＝6.9Hz,2H),3.86(t,J＝9.3Hz,1H),2.99(dd,J＝14.5,5.9Hz,1H),2.90(dd,J＝9.4,2.2Hz,1H),2.53–2.12(m,6H),1.72–1.63(m,1H),1.55(s,3H),1.47(t,J＝6.9Hz,3H),1.12(t,J＝12.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.3,167.0,157.5,140.9,138.5,134.9,131.6,130.1Calculated C for HRMS (ESI) values of 128.7,122.7,120.3,120.1,117.3,111.9,80.8,66.5,63.7,63.0,59.8,42.4,36.4,25.5,24.3,23.6,17.7,14.5 26 H 34 NO 6 [M+NH 4 ] + 456.2381, experimental 456.2380.
(4h) White solid (yield: 69%). 1 H NMR(400MHz,CDCl 3 )δ7.80–7.60(m,4H),7.53(t,J＝7.7Hz,1H),6.49(d,J＝16.0Hz,1H),6.26(d,J＝3.3Hz,1H),5.75(t,J＝8.2Hz,1H),5.57(d,J＝2.9Hz,1H),4.80(d,J＝12.5Hz,1H),4.62(d,J＝12.5Hz,1H),3.87(t,J＝9.3Hz,1H),2.93(dd,J＝15.1,6.0Hz,1H),2.88(d,J＝9.4Hz,1H),2.56–2.14(m,6H),1.76–1.64(m,1H),1.56(s,3H),1.13(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.3,166.0,143.7,138.7,134.9,134.8,131.5(d,J＝32.3Hz),131.1,130.8,129.5,126.9(d,J＝3.7Hz),124.6(d,J＝3.8Hz),123.7(d,J＝273.30),120.3,119.3,81.0,66.9,63.3,59.9,42.7,36.6,25.7,24.4,23.8,18.0. 19 F NMR(376MHz,CDCl 3 ) Delta-62.89(s). HRMS (ESI) calculated C 25 H 29 F 3 NO 5 [M+NH 4 ] + 480.1992, experimental 480.1992.
(4i) White solid (yield: 76%). 1 H NMR(400MHz,CDCl 3 )δ7.63(d,J＝16.0Hz,1H),7.35(dd,J＝13.8,7.8Hz,1H),7.27(d,J＝6.8Hz,1H),7.19(d,J＝9.5Hz,1H),7.08(t,J＝8.2Hz,1H),6.40(d,J＝16.0Hz,1H),6.23(d,J＝3.4Hz,1H),5.73(t,J＝8.2Hz,1H),5.55(d,J＝3.4Hz,1H),4.78(d,J＝12.5Hz,1H),4.59(d,J＝12.5Hz,1H),3.86(t,J＝9.3Hz,1H),2.93(dd,J＝14.8,5.8Hz,1H),2.87(d,J＝9.4Hz,1H),2.50–2.11(m,6H),1.70(m,1H),1.54(s,3H),1.11(m,1H). 13 C NMR(100MHz,CDCl 3 )δ169.3,166.1,162.9(d,J＝247.0Hz),144.0(d,J＝2.5Hz),138.7,136.2(d,J＝7.7Hz),134.8,130.7,130.5(d,J＝8.2Hz),124.1(d,J＝2.7Hz),120.2,118.7,117.3(d,J＝21.4Hz),114.3(d,J＝22.0Hz),80.9,66.8,63.2,59.9,42.6,36.5,25.7,24.4,23.8,17.9. 19 F NMR(376MHz,CDCl 3 ) Delta-112.3 (dd, j=14.8, 8.9 hz.) HRMS (ESI) calculated C 24 H 29 FNO 5 [M+NH 4 ] + 430.2024, experimental 430.2024.
(4j) White solid(yield: 69%). 1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝16.0Hz,1H),7.46(s,1H),7.37-7.30(m,3H),6.40(d,J＝16.0Hz,1H),6.21(d,J＝3.2Hz,1H),5.71(t,J＝8.2Hz,1H),5.54(d,J＝2.8Hz,1H),4.76(d,J＝12.5Hz,1H),4.59(d,J＝12.6Hz,1H),3.85(t,J＝9.3Hz,1H),2.91(dd,J＝14.7,5.8Hz,1H),2.85(d,J＝9.4Hz,1H),2.50–2.09(m,6H),1.73–1.62(m,1H),1.53(s,3H),1.09(t,J＝13.0Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.2,166.0,143.7,138.6,135.8,134.8,134.7,130.6,130.2,130.1,127.7,126.2,120.2,118.8,80.9,66.8,63.1,59.9,42.5,36.5,25.6,24.3,23.7,17.9.hrms (ESI) calculated value C 24 H 29 ClNO 5 [M+NH 4 ] + 446.1729, experimental 446.1723.
(4k) White solid (yield: 89%). 1 H NMR(400MHz,CDCl 3 )δ7.62(s,1H),7.57(d,J＝16.0Hz,1H),7.48(d,J＝7.9Hz,1H),7.40(d,J＝7.8Hz,1H),7.27–7.22(m,1H),6.39(d,J＝16.0Hz,1H),6.21(d,J＝3.4Hz,1H),5.71(t,J＝8.2Hz,1H),5.54(d,J＝3.4Hz,1H),4.76(d,J＝12.6Hz,1H),4.58(d,J＝12.6Hz,1H),3.84(t,J＝9.3Hz,1H),2.97–2.88(m,1H),2.85(d,J＝9.4Hz,1H),2.50–2.10(m,6H),1.73–1.63(m,1H),1.52(s,3H),1.08(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.2,166.0,143.5,138.6,136.0,134.7,133.1,130.6,130.5,130.4,126.6,122.8,120.1,118.8,80.9,66.8,63.1,59.8,42.5,36.4,25.5,24.3,23.7,17.8.hrms (ESI) calculated value C 24 H 29 BrNO 5 [M+NH 4 ] + 490.1224, experimental 490.1218.
(4 l) white solid (yield: 88%). 1 H NMR(400MHz,CDCl 3 )δ7.67(d,J＝16.0Hz,1H),7.36–7.27(m,3H),7.21(d,J＝7.2Hz,1H),6.42(d,J＝16.0Hz,1H),6.24(d,J＝3.5Hz,1H),5.74(t,J＝8.2Hz,1H),5.57(d,J＝3.1Hz,1H),4.78(d,J＝12.5Hz,1H),4.61(d,J＝12.5Hz,1H),3.87(t,J＝9.3Hz,1H),3.02–2.94(m,1H),2.89(d,J＝9.4Hz,1H),2.54–2.13(m,9H),1.75–1.66(m,1H),1.56(s,3H),1.12(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.2,166.5,145.5,138.6,138.4,134.8,133.9,131.2,130.4,128.7,128.6,125.1,120.1,117.0,80.9,66.7,63.1,59.8,42.5,36.4,25.6,24.4,23.7,21.1,17.8HRMS (ESI) calculated C 25 H 32 O 5 [M+NH 4 ] + 426.2275，found 426.2283.
(4 m) white solid (yield: 92%). 1 H NMR(400MHz,CDCl 3 )δ7.63(d,J＝16.0Hz,1H),7.29(d,J＝7.9Hz,1H),7.08(d,J＝7.7Hz,1H),7.00(s,1H),6.92(dd,J＝8.2,2.1Hz,1H),6.39(d,J＝16.0Hz,1H),6.22(d,J＝3.5Hz,1H),5.72(t,J＝8.2Hz,1H),5.54(d,J＝3.1Hz,1H),4.76(d,J＝12.5Hz,1H),4.58(d,J＝12.5Hz,1H),3.85(t,J＝9.3Hz,1H),3.80(s,3H),3.00–2.91(m,1H),2.86(d,J＝9.4Hz,1H),2.51–2.10(m,6H),1.73–1.63(m,1H),1.53(s,3H),1.09(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.4,159.8,145.3,138.7,135.3,134.8,130.6,129.8,120.7,120.2,117.5,116.3,112.8,80.9,66.8,63.2,59.9,55.2,42.6,36.5,25.7,24.4,23.7,17.9.hrms (ESI) calculated C 25 H 32 NO 6 [M+NH 4 ] + 442.2224, experimental 442.2229.
(4 n) white solid (yield: 72%). 1 H NMR(400MHz,CDCl 3 )δ7.66(d,J＝16.0Hz,1H),7.63–7.56(m,4H),6.47(d,J＝16.0Hz,1H),6.19(d,J＝3.5Hz,1H),5.72(t,J＝8.2Hz,1H),5.53(d,J＝3.1Hz,1H),4.77(d,J＝12.5Hz,1H),4.60(d,J＝12.5Hz,1H),3.85(t,J＝9.3Hz,1H),2.93(dd,J＝14.9,5.9Hz,1H),2.86(d,J＝9.4Hz,1H),2.51–2.09(m,6H),1.73–1.65(m,1H),1.52(s,3H),1.08(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.2,165.9,143.4,138.7,137.4,134.6,131.6(q,J＝32.6Hz),130.7,128.1,125.7(d,J＝3.8Hz),123.6(d,J＝272.3Hz),120.1,119.9,80.9,66.9,63.1,59.8,42.5,36.4,25.5,24.3,23.7,17.8. 19 F NMR(376MHz,CDCl 3 ) Delta-62.9(s). HRMS (ESI) calculated C 25 H 29 F 3 NO 5 [M+NH 4 ] + 480.1992, experimental 480.2000.
(4 o) white solid (yield: 93%). 1 H NMR(400MHz,CDCl 3 )δ7.63(d,J＝16.0Hz,1H),7.55–7.43(m,2H),7.06(t,J＝8.6Hz,2H),6.32(d,J＝16.0Hz,1H),6.21(d,J＝3.5Hz,1H),5.72(t,J＝8.2Hz,1H),5.54(d,J＝3.5Hz,1H),4.76(d,J＝12.5Hz,1H),4.58(d,J＝12.5Hz,1H),3.85(t,J＝9.3Hz,1H),3.01–2.90(m,1H),2.87(d,J＝9.4Hz,1H),2.51–2.10(m,6H),1.73–1.64(m,1H),1.53(s,3H),1.10(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.3,166.4,163.9(d,J＝251.9Hz),144.1,138.7,134.8,130.6,130.3(d,J＝3.2Hz),129.9(d,J＝8.6Hz),120.2,117.0,116.0(d,J＝22.0Hz),80.9,66.8,63.2,59.9,42.6,36.5,25.7,24.4,23.7,17.9. 19 F NMR(376MHz,CDCl 3 ) Delta-109.0(s). HRMS (ESI) calculated C 24 H 29 FNO 5 [M+NH 4 ] + 430.2024, experimental 430.2026.
(4 p) white solid (yield: 90%). 1 H NMR(400MHz,CDCl 3 )δ7.61(d,J＝16.0Hz,1H),7.42(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),6.37(d,J＝16.0Hz,1H),6.21(d,J＝3.5Hz,1H),5.72(t,J＝8.2Hz,1H),5.54(d,J＝3.2Hz,1H),4.76(d,J＝12.5Hz,1H),4.58(d,J＝12.5Hz,1H),3.85(t,J＝9.3Hz,1H),3.00–2.89(m,1H),2.86(d,J＝9.4Hz,1H),2.52–2.10(m,6H),1.72–1.63(m,1H),1.53(s,3H),1.09(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.2,143.9,138.7,136.3,134.8,132.5,130.7,129.2,129.1,120.2,117.9,80.9,66.8,63.2,59.9,42.6,36.5,25.7,24.4,23.7,17.9.Hrms (ESI) calculated value C 24 H 29 ClNO 5 [M+NH 4 ] + 446.1729, experimental 446.1732.
(4 q) white solid (yield: 86%). 1 H NMR(400MHz,CDCl 3 )δ7.59(d,J＝16.0Hz,1H),7.49(d,J＝8.4Hz,2H),7.35(d,J＝8.4Hz,2H),6.39(d,J＝16.0Hz,1H),6.21(d,J＝3.5Hz,1H),5.72(t,J＝8.2Hz,1H),5.53(d,J＝3.1Hz,1H),4.76(d,J＝12.5Hz,1H),4.58(d,J＝12.5Hz,1H),3.85(t,J＝9.3Hz,1H),2.93(m,1H),2.86(d,J＝9.4Hz,1H),2.51–2.11(m,6H),1.73–1.63(m,1H),1.53(s,3H),1.09(t,J＝12.7Hz,1H). 13 C NMR(101MHz,CDCl 3 ) Delta 169.3,166.2,144.0,138.6,134.7,132.9,132.1,130.7,129.4,124.7,120.2,118.0,80.9,66.8,63.1,59.9,42.5,36.5,25.6,24.4,23.7,17.9.Hrms (ESI) calculated value C 24 H 29 BrNO 5 [M+NH 4 ] + 490.1224, experimental 490.1221.
(4 r) white solid (yield: 62%). 1 H NMR(400MHz,CDCl 3 )δ7.66(d,J＝16.0Hz,1H),7.40(d,J＝8.0Hz,2H),7.19(d,J＝7.9Hz,2H),6.36(d,J＝16.0Hz,1H),6.23(d,J＝3.5Hz,1H),5.73(t,J＝8.2Hz,1H),5.55(d,J＝3.1Hz,1H),4.77(d,J＝12.5Hz,1H),4.59(d,J＝12.5Hz,1H),3.86(t,J＝9.3Hz,1H),3.01–2.92(m,1H),2.88(d,J＝9.4Hz,1H),2.52–2.12(m,9H),1.68(dd,J＝12.8,8.5Hz,1H),1.55(s,3H),1.11(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.7,145.5,141.0,138.7,135.0,131.3,130.6,129.6,128.1,120.3,116.1,81.0,66.7,63.2,59.9,42.6,36.5,25.8,24.5,23.8,21.4,17.9.hrms (ESI) calculated value C 25 H 32 NO 5 [M+NH 4 ] + 426.2275, experimental 426.2281.
(4 s) white solid (yield: 71%). 1 H NMR(400MHz,CDCl 3 )δ7.66(d,J＝16.0Hz,1H),7.43(d,J＝8.1Hz,2H),7.23(d,J＝8.1Hz,2H),6.36(d,J＝16.0Hz,1H),6.22(d,J＝3.5Hz,1H),5.72(t,J＝8.2Hz,1H),5.55(d,J＝3.1Hz,1H),4.76(d,J＝12.5Hz,1H),4.58(d,J＝12.5Hz,1H),3.86(t,J＝9.3Hz,1H),2.93(m,3H),2.51–2.10(m,6H),1.68(dd,J＝12.9,8.8Hz,1H),1.54(s,3H),1.23(d,J＝6.9Hz,6H),1.10(t,J＝13.2Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.7,151.8,145.4,138.6,134.9,131.6,130.5,128.1,126.9,120.2,116.2,80.9,66.7,63.1,59.9,42.5,36.5,33.9,25.7,24.4,23.7,23.6,17.9.hrms (ESI) calculated C 27 H 36 NO 5 [M+NH 4 ] + 454.2588, experimental 454.2594.
(4 t) white solid (yield: 77%). 1 H NMR(400MHz,CDCl 3 )δ7.63(d,J＝15.9Hz,1H),7.45(d,J＝8.7Hz,2H),6.89(d,J＝8.7Hz,2H),6.27(d,J＝15.9Hz,1H),6.23(d,J＝3.5Hz,1H),5.72(t,J＝8.2Hz,1H),5.55(d,J＝3.1Hz,1H),4.76(d,J＝12.5Hz,1H),4.57(d,J＝12.5Hz,1H),3.89–3.83(m,1H),3.82(s,3H),2.97(dd,J＝14.8,5.8Hz,1H),2.88(d,J＝9.4Hz,1H),2.51–2.12(m,6H),1.67(dd,J＝12.7,8.6Hz,1H),1.54(s,3H),1.10(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.9,161.5,145.1,138.7,135.0,130.5,129.7,126.7,120.3,114.6,114.3,81.0,66.7,63.2,59.9,55.3,42.6,36.5,25.8,24.5,23.8,17.9.hrms (ESI) calculated value C 25 H 32 NO 6 [M+NH 4 ] + 442.2224, experimental 442.2230.
(4 u) white solid (yield: 90%). 1 H NMR(400MHz,CDCl 3 )δ7.61(d,J＝15.9Hz,1H),7.42(d,J＝8.6Hz,2H),6.86(d,J＝8.7Hz,2H),6.25(d,J＝15.9Hz,1H),6.21(d,J＝3.4Hz,1H),5.70(s,1H),5.54(d,J＝3.2Hz,1H),4.74(d,J＝12.5Hz,1H),4.56(d,J＝12.5Hz,1H),4.03(q,J＝6.9Hz,2H),3.84(t,J＝9.3Hz,1H),2.95(t,J＝8.9Hz,1H),2.86(d,J＝9.4Hz,1H),2.49–2.10(m,6H),1.66(t,J＝10.7Hz,1H),1.53(s,3H),1.39(t,J＝7.0Hz,3H),1.09(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.8,160.9,145.1,138.6,135.0,130.3,129.7,126.5,120.2,114.7,114.4,80.9,66.6,63.5,63.1,59.8,42.5,36.5,25.7,24.4,23.7,17.8,14.6.hrms (ESI) calculated value C 26 H 34 NO 6 [M+NH 4 ] + 456.2381, experimental 456.2390.
(4 v) white solid (yield: 78%). 1 H NMR(400MHz,CDCl 3 )δ7.63(d,J＝16.0Hz,1H),7.50(d,J＝8.6Hz,2H),7.10(d,J＝8.6Hz,2H),6.35(d,J＝16.0Hz,1H),6.20(d,J＝3.4Hz,1H),5.70(t,J＝8.2Hz,1H),5.53(d,J＝3.1Hz,1H),4.75(d,J＝12.5Hz,1H),4.57(d,J＝12.5Hz,1H),3.84(t,J＝9.3Hz,1H),2.92(dd,J＝14.8,5.8Hz,1H),2.85(d,J＝9.4Hz,1H),2.50–2.09(m,9H),1.71–1.62(m,1H),1.51(d,J＝4.5Hz,3H),1.08(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,169.0,166.3,152.1,144.2,138.6,134.8,131.6,130.5,129.1,122.1,120.2,117.4,80.9,66.7,63.1,59.8,42.5,36.4,25.6,24.3,23.7,21.0,17.8.hrms (ESI) calculated value C 26 H 32 NO 7 [M+NH 4 ] + 470.2173, experimental 470.2171.
(4 w) white solid (yield: 53%). 1 H NMR(400MHz,CDCl 3 )δ8.24(d,J＝8.7Hz,2H),7.71(d,J＝16.1Hz,1H),7.66(d,J＝8.7Hz,2H),6.54(d,J＝16.0Hz,1H),6.24(d,J＝3.5Hz,1H),5.75(t,J＝8.2Hz,1H),5.56(d,J＝3.1Hz,1H),4.80(d,J＝12.5Hz,1H),4.63(d,J＝12.5Hz,1H),3.87(t,J＝9.3Hz,1H),3.00–2.91(m,1H),2.88(d,J＝9.4Hz,1H),2.35(m,6H),1.76–1.66(m,1H),1.55(s,3H),1.12(t,J＝12.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.3,165.6,148.6,142.5,140.1,138.7,134.6,131.1,128.7,124.2,121.6,120.2,81.0,67.1,63.2,59.9,42.6,36.5,25.7,24.4,23.8,17.9.HRMS (ESI) calculated C 24 H 29 N2O 7 [M+NH 4 ] + 457.1969, experimental 457.1970.
(4 x) white solid (yield: 82%). 1 H NMR(400MHz,CDCl 3 )δ7.73–7.57(m,5H),6.50(d,J＝16.0Hz,1H),6.26(d,J＝3.5Hz,1H),5.76(t,J＝8.1Hz,1H),5.56(d,J＝3.1Hz,1H),4.80(d,J＝12.5Hz,1H),4.62(d,J＝12.6Hz,1H),3.87(t,J＝9.3Hz,1H),3.01–2.92(m,1H),2.88(d,J＝9.4Hz,1H),2.56–2.14(m,6H),1.77–1.67(m,1H),1.56(s,3H),1.13(t,J＝12.6Hz,1H). 13 C NMR(101MHz,CDCl 3 ) Delta 169.4,165.9,143.3,138.9,138.5,134.8,132.9,131.3,128.6,121.1,120.4,118.4,113.8,81.1,67.3,63.4,60.1,42.8,36.7,25.9,24.7,24.0,18.1.hrms (ESI) calculated value C 25 H 29 N2O 5 [M+NH 4 ] + 437.2071, experimental 437.2074.
Synthesis of Compounds 5a-5 b:
compound 2 (264.3 mg,1.0mmol,1 eq) was added in sequence to a 20mL reaction flask, PPh 3 (393.5 mg,1.5 mmol) and the corresponding substituted cinnamic acid (1.5 mmol,1.5 eq), displacing the gas, adding anhydrous THF (10 mL) to dissolve, and adding DIAD (297. Mu.L, 1.5mmol,1.5 eq) with zero degree stirring. The reaction solution is reacted overnight at room temperature, saturated ammonium chloride is added to quench the reaction, ethyl acetate is added to extract three times after the reaction is basically finished, the organic phase is combined, saturated saline is washed three times, anhydrous sodium sulfate is dried, filtered and concentrated in a spin-drying way, and oily matters are obtained and purified by silica gel column chromatography [ PE/EA=2:1-1:2]Compounds 5a-5b were obtained.
(5a) White solid (yield: 76%). 1 H NMR(400MHz,CDCl 3 )δ7.62(d,J＝15.9Hz,1H),7.38(d,J＝8.5Hz,2H),7.13-6.99(m,1H),6.87(d,J＝8.4Hz,2H),6.26(d,J＝8.9Hz,1H),6.23(d,J＝3.6Hz,1H),5.72(t,J＝7.9Hz,1H),5.57(d,J＝3.3Hz,1H),4.76(d,J＝12.5Hz,1H),4.59(d,J＝12.5Hz,1H),3.89(t,J＝9.3Hz,1H),2.98(t,J＝9.1Hz,1H),2.91(d,J＝9.4Hz,1H),2.51–2.11(m,6H),1.73–1.64(m,1H),1.55(s,3H),1.12(t,J＝12.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.9,167.3,158.6,145.7,138.Calculated values C for HRMS (ESI) of 5,134.9,130.6,130.1,126.3,120.8,116.0,114.1,81.2,66.8,63.3,60.3,42.6,36.5,25.8,24.5,23.8,17.9.HRMS (ESI) 24 H 30 NO 6 [M+NH 4 ] + 428.2068, experimental 428.2067.
(5b) White solid (yield: 55%). 1 H NMR(400MHz,CDCl 3 )δ7.62(d,J＝15.9Hz,1H),7.07(dd,J＝8.2,1.8Hz,1H),7.00(d,J＝1.8Hz,1H),6.92(d,J＝8.2Hz,1H),6.25(dd,J＝9.7,6.2Hz,2H),5.88(s,1H),5.75(t,J＝8.3Hz,1H),5.56(d,J＝3.2Hz,1H),4.78(d,J＝12.4Hz,1H),4.60(d,J＝12.5Hz,1H),3.94(s,3H),3.88(t,J＝9.3Hz,1H),3.09–2.98(m,1H),2.91(d,J＝9.4Hz,1H),2.55–2.14(m,6H),1.70(dd,J＝16.9,9.1Hz,1H),1.56(s,3H),1.14(t,J＝12.6Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.4,166.8,148.2,146.8,145.6,138.8,135.0,130.8,126.6,123.2,120.3,114.7,114.6,109.2,81.0,66.9,63.3,60.0,55.9,42.7,36.6,25.8,24.7,23.8,18.0.hrms (ESI) calculated C 25 H 29 O 7 [M+H] + 441.1908, experimental 441.1910.
Synthesis of Compounds 6c-6 e:
the corresponding acid (0.6 mmol,1.2 eq) was added to the reaction flask and dissolved in anhydrous DCM (6 mL), oxalyl chloride (51. Mu.L, 0.6mmol,1.2 eq) was added under ice-water bath, then a drop of anhydrous DMF was added and the reaction was stirred at room temperature for 1.5h. The solvent was dried to give the acid chloride, dissolved in home anhydrous DCM, and the reaction mixture of Compound 2 (132 mg,0.5mmol,1 eq) and TEA (83. Mu.L, 0.6mmol,1.2 eq) was added and stirred at room temperature for 2h to substantially complete the reaction, and the solvent was purified directly by silica gel column chromatography [ PE: EA=2:1 to 1:1] to give a white solid 6c-6e.
(6c) White solid (yield: 77%). 1 H NMR(400MHz,CDCl 3 )δ8.65(d,J＝3.7Hz,1H),7.71(dd,J＝19.0,11.6Hz,2H),7.42(d,J＝7.7Hz,1H),7.29(d,J＝5.2Hz,1H),6.93(d,J＝15.7Hz,1H),6.25(d,J＝2.9Hz,1H),5.74(t,J＝7.9Hz,1H),5.56(d,J＝2.3Hz,1H),4.78(d,J＝12.5Hz,1H),4.63(d,J＝12.6Hz,1H),3.86(t,J＝9.3Hz,1H),3.00–2.84(m,2H),2.29(dddd,J＝33.1,26.7,14.1,4.8Hz,6H),1.69(t,J＝10.3Hz,1H),1.55(s,3H),1.16–1.07(m,1H). 13 C NMR(100MHz,CDCl 3 )δ169.6,166.6,152.8,150.4,144.4,138Calculated C for HRMS (ESI) values 8,137.1,135.1,130.8,124.8,124.7,121.8,120.7,81.2,67.1,63.5,60.2,42.9,36.8,26.0,24.6,24.1,18.2 23 H 26 NO 5 [M+H] + 396.1805, experimental 396.1800.
(6d) White solid (yield: 71%). 1 H NMR(400MHz,CDCl 3 )δ8.69(d,J＝49.3Hz,2H),7.83(d,J＝6.6Hz,1H),7.69(d,J＝15.7Hz,1H),7.35(s,1H),6.50(d,J＝15.9Hz,1H),6.27(s,1H),5.76(s,1H),5.57(s,1H),4.81(d,J＝12.0Hz,1H),4.62(d,J＝12.2Hz,1H),3.88(t,J＝9.1Hz,1H),3.03–2.79(m,2H),2.54–2.14(m,6H),1.71(dd,J＝18.5,7.7Hz,1H),1.56(s,3H),1.13(t,J＝13.2Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.5,166.1,151.3,149.8,141.9,138.7,134.8,134.3,131.0,123.8,120.4,119.5,81.0,67.0,63.3,59.9,42.7,36.6,29.7,25.7,24.4,23.9,18.0.hrms (ESI) calculated value C 23 H 26 NO 5 [M+H] + 396.1805, experimental 396.1802.
(6e) White solid (yield: 67%). 1 H NMR(400MHz,CDCl 3 )δ8.63(d,J＝5.0Hz,2H),7.58(d,J＝16.1Hz,1H),7.34(d,J＝5.6Hz,2H),6.57(d,J＝16.1,1H),6.22(d,J＝3.4Hz,1H),5.72(t,J＝8.2Hz,1H),5.54(d,J＝3.0Hz,1H),4.78(d,J＝12.5Hz,1H),4.60(d,J＝12.5Hz,1H),3.85(t,J＝9.3Hz,1H),2.91(dd,J＝15.1,6.0Hz,1H),2.85(d,J＝9.4Hz,1H),2.47–2.13(m,6H),1.73–1.64(m,1H),1.53(s,3H),1.09(t,J＝12.9Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,165.6,150.4,142.4,141.3,138.6,134.5,131.0,122.1,121.8,120.3,80.9,67.1,63.2,59.9,42.5,36.4,25.6,24.3,23.7,17.9.hrms (ESI) calculated value C 23 H 26 NO 5 [M+H] + 396.1805, experimental 396.1802.
Synthesis of Compounds 6a-6b, 6f-6g and 7a-7m
Reaction procedure same as for preparation of Compound 3
(6a) White solid (yield: 82%). 1 H NMR(400MHz,CDCl 3 )δ7.48(s,1H),7.42(d,J＝15.7Hz,1H),6.62(d,J＝3.3Hz,1H),6.47(dd,J＝3.2,1.7Hz,1H),6.28(d,J＝15.7Hz,1H),6.24(d,J＝3.4Hz,1H),5.72(t,J＝8.2Hz,1H),5.55(d,J＝3.1Hz,1H),4.75(d,J＝12.6Hz,1H),4.58(d,J＝12.6Hz,1H),3.86(t,J＝9.3Hz,1H),3.01–2.91(m,1H),2.88(d,J＝9.4Hz,1H),2.47–2.13(m,6H),1.72–1.63(m,1H),1.54(s,3H),1.11(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.6,150.5,145.0,138.6,134.9,131.6,130.5,120.3,115.3,114.8,112.3,80.9,66.7,63.2,59.9,42.6,36.5,25.7,24.4,23.7,17.9.Hrms (ESI) calculated value C 22 H 28 NO 6 [M+NH 4 ] + 402.1911, experimental 402.1910.
(6b) White solid (yield: 95%). 1 H NMR(400MHz,CDCl 3 )δ7.76(d,J＝15.7Hz,1H),7.37(d,J＝5.0Hz,1H),7.24(d,J＝3.4Hz,1H),7.03(dd,J＝4.9,3.8Hz,1H),6.22(d,J＝3.5Hz,1H),6.18(d,J＝15.7Hz,1H),5.70(t,J＝8.2Hz,1H),5.54(d,J＝3.1Hz,1H),4.75(d,J＝12.5Hz,1H),4.56(d,J＝12.5Hz,1H),3.85(t,J＝9.3Hz,1H),2.99–2.90(m,1H),2.86(d,J＝9.4Hz,1H),2.48–2.11(m,6H),1.73–1.60(m,1H),1.53(s,3H),1.09(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.3,139.1,138.6,137.8,134.9,131.3,130.6,128.8,128.1,120.2,115.9,80.9,66.8,63.2,59.9,42.6,36.5,25.7,24.4,23.7,17.9.Hrms (ESI) calculated value C 22 H 28 NO 5 S[M+NH 4 ] + 418.1683, experimental 418.1678.
(6f) White solid (yield: 93%). 1 H NMR(400MHz,CDCl 3 )δ7.95–7.81(m,5H),7.65(d,J＝8.5Hz,1H),7.53(dd,J＝8.9,4.5Hz,2H),6.53(d,J＝16.0Hz,1H),6.27(d,J＝3.3Hz,1H),5.77(t,J＝8.2Hz,1H),5.58(d,J＝3.3Hz,1H),4.81(d,J＝12.5Hz,1H),4.63(d,J＝12.5Hz,1H),3.88(t,J＝9.3Hz,1H),2.99(t,J＝9.1Hz,1H),2.91(d,J＝9.4Hz,1H),2.55–2.15(m,6H),1.70(m,1H),1.57(s,3H),1.14(t,J＝12.9Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.4,166.7,145.6,138.7,135.0,134.3,133.2,131.6,130.8,130.2,128.8,128.6,127.8,127.4,126.8,123.3,120.4,117.4,81.0,66.9,63.3,59.9,42.7,36.6,25.8,24.6,23.9,18.0.hrms (ESI) calculated value C 28 H 32 NO 5 [M+NH 4 ] + 462.2275, experimental 462.2283.
(6g) White solid (yield: 94%). 1 H NMR(400MHz,CDCl 3 )δ7.58(d,J＝15.9Hz,1H),6.98(d,J＝9.1Hz,2H),6.80(d,J＝7.9Hz,1H),6.24(d,J＝3.0Hz,1H),6.22(d,J＝9.1Hz,1H),6.00(s,2H),5.72(t,J＝8.2Hz,1H),5.55(d,J＝3.1Hz,1H),4.76(d,J＝12.5Hz,1H),4.57(d,J＝12.6Hz,1H),3.86(t,J＝9.3Hz,1H),3.00–2.90(m,1H),2.87(d,J＝9.4Hz,1H),2.51–2.12(m,6H),1.68(dd,J＝12.8,8.5Hz,1H),1.54(s,3H),1.11(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.7,149.8,148.3,145.2,138.7,135.0,130.5,128.4,124.6,120.3,115.1,108.5,106.4,101.6,81.0,66.7,63.2,59.9,42.6,36.5,25.7,24.4,23.8,17.9.hrms (ESI) calculated C 25 H 30 NO 7 [M+NH 4 ] + 456.2017, experimental 456.2022.
(7a) White solid (yield: 89%). 1 H NMR(400MHz,CDCl 3 )δ7.99(d,J＝16.2Hz,1H),7.13–7.07(m,1H),7.03(t,J＝8.0Hz,1H),6.97–6.89(m,1H),6.44(d,J＝16.2Hz,1H),6.20(d,J＝3.4Hz,1H),5.71(t,J＝8.2Hz,1H),5.54(d,J＝3.1Hz,1H),4.75(d,J＝12.5Hz,1H),4.58(d,J＝12.6Hz,1H),3.87–3.81(m,7H),3.00–2.89(m,1H),2.86(d,J＝9.4Hz,1H),2.51–2.09(m,6H),1.71–1.62(m,1H),1.52(s,3H),1.08(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.5,166.8,153.1,148.5,140.3,138.8,135.1,130.6,128.2,124.3,120.4,119.2,118.6,114.2,81.1,66.8,63.3,61.3,60.0,55.9,42.7,36.6,25.8,24.5,23.9,18.0.hrms (ESI) calculated C 26 H 34 NO 7 [M+NH 4 ] + 472.2330, experimental 472.2332.
(7b) White solid (yield: 94%). 1 H NMR(400MHz,CDCl 3 )δ7.90(d,J＝16.1Hz,1H),7.41(d,J＝8.6Hz,1H),6.50(dd,J＝8.6,2.3Hz,1H),6.45(d,J＝2.3Hz,1H),6.41(d,J＝16.1Hz,1H),6.23(d,J＝3.5Hz,1H),5.74(t,J＝8.2Hz,1H),5.55(d,J＝3.2Hz,1H),4.76(d,J＝12.5Hz,1H),4.59(d,J＝12.5Hz,1H),3.91–3.81(m,7H),3.10–3.00(m,1H),2.92(d,J＝9.4Hz,1H),2.29(dd,J＝87.9,29.8Hz,6H),1.68(t,J＝11.2Hz,1H),1.56(s,3H),1.14(t,J＝12.6Hz,1H). 13 C NMR (100 MHz, CDCl 3) delta 169.4,167.6,162.9,160.0,141.0,138.7,135.3,130.8,130.7,120.4,116.2,115.0,105.3,98.3,81.0,66.8,63.3,60.0,55.4,53.4,42.7,36.6,26.0,24.8,23.8,18.0.HRMS (ESI) calculated C 26 H 31 O 7 [M+H] + 455.2064, experimental 455.2061.
(7c) White solid (yield: 83%). 1 H NMR(400MHz,CDCl 3 )δ7.95(d,J＝16.1Hz,1H),6.99(d,J＝3.0Hz,1H),6.90(dd,J＝9.0,3.0Hz,1H),6.83(d,J＝9.0Hz,1H),6.46(d,J＝16.1Hz,1H),6.20(d,J＝3.4Hz,1H),5.72(t,J＝8.1Hz,1H),5.53(d,J＝3.1Hz,1H),4.75(d,J＝12.5Hz,1H),4.58(d,J＝12.5Hz,1H),3.86(d,J＝9.3Hz,1H),3.82(s,3H),3.76(s,3H),3.00(dd,J＝14.8,5.8Hz,1H),2.88(d,J＝9.4Hz,1H),2.52–2.11(m,6H),1.66(dd,J＝13.1,9.1Hz,1H),1.53(s,3H),1.10(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.9,153.3,152.8,140.7,138.6,135.0,130.7,123.3,120.2,117.9,117.4,113.2,112.3,80.9,66.8,63.2,59.9,55.9,55.7,42.6,36.5,25.8,24.6,23.8,17.9.Hrms (ESI) calculated C 26 H 34 NO 7 [M+NH 4 ] + 472.2330, experimental 472.2328.
(7d) White solid (yield: 84%). 1 H NMR(400MHz,CDCl 3 )δ8.14(d,J＝16.3Hz,1H),7.25(t,J＝8.4Hz,1H),6.82(d,J＝16.3Hz,1H),6.53(d,J＝8.4Hz,2H),6.17(d,J＝3.4Hz,1H),5.71(t,J＝8.1Hz,1H),5.52(d,J＝3.4Hz,1H),4.72(d,J＝12.4Hz,1H),4.57(d,J＝12.4Hz,1H),3.88–3.81(m,7H),3.10–3.01(m,1H),2.89(d,J＝9.4Hz,1H),2.48–2.10(m,6H),1.68–1.59(m,1H),1.53(s,3H),1.09(t,J＝12.6Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.4,168.2,159.9,138.5,136.3,135.2,131.5,130.6,120.3,119.2,111.6,103.5,80.9,66.8,63.2,59.9,55.6,42.6,36.5,25.9,24.8,23.7,17.9.hrms (ESI) calculated value C 26 H 34 NO 7 [M+NH 4 ] + 472.2330, experimental 472.2329.
(7e) White solid (yield: 56%). 1 H NMR(400MHz,CDCl 3 )δ7.61(d,J＝15.9Hz,1H),7.08(dd,J＝8.3,1.7Hz,1H),7.01(d,J＝1.6Hz,1H),6.86(d,J＝8.3Hz,1H),6.26(d,J＝15.9Hz,1H),6.23(d,J＝3.5Hz,1H),5.73(t,J＝8.1Hz,1H),5.54(d,J＝3.1Hz,1H),4.76(d,J＝12.5Hz,1H),4.58(d,J＝12.5Hz,1H),3.96–3.82(m,7H),3.07–2.95(m,1H),2.89(d,J＝9.4Hz,1H),2.53–2.11(m,6H),1.68(dd,J＝13.3,9.0Hz,1H),1.54(s,3H),1.11(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,166.7,151.3,149.2,145.4,138.8,135.0,130.7,127.0,122.8,120.2,114.9,111.0,109.4,81.0,66.8,63.2,59.9,55.9,55.8,42.7,36.6,25.8,24.6,23.8,17.9.Hrms (ESI) calculated value C 26 H 34 NO 7 [M+NH 4 ] + 472.2330, experimental 472.2333.
(7f) White solid (yield: 73%). 1 H NMR(400MHz,CDCl 3 )δ7.57(d,J＝15.9Hz,1H),6.62(d,J＝2.1Hz,2H),6.47(t,J＝2.0Hz,1H),6.36(d,J＝15.9Hz,1H),6.21(d,J＝3.4Hz,1H),5.71(t,J＝8.2Hz,1H),5.54(d,J＝3.4Hz,1H),4.76(d,J＝12.5Hz,1H),4.57(d,J＝12.5Hz,1H),3.84(dd,J＝16.7,7.4Hz,1H),3.78(s,6H),3.00–2.91(m,1H),2.86(d,J＝9.4Hz,1H),2.49–2.10(m,6H),1.73–1.62(m,1H),1.53(s,3H),1.09(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.2,166.3,160.9,145.3,138.7,135.8,134.8,130.7,120.1,117.8,105.8,102.7,80.9,66.9,63.2,59.8,55.3,42.6,36.5,25.7,24.5,23.7,17.8.hrms (ESI) calculated value C 26 H 34 NO 7 [M+NH 4 ] + 472.2330, experimental 472.2328.
(7g) White solid (yield: 92%). 1 H NMR(400MHz,CDCl 3 )δ7.85(d,J＝16.1Hz,1H),7.20(d,J＝8.8Hz,1H),6.66(d,J＝8.8Hz,1H),6.35(d,J＝16.1Hz,1H),6.18(d,J＝3.4Hz,1H),5.69(t,J＝8.2Hz,1H),5.52(d,J＝3.1Hz,1H),4.73(d,J＝12.5Hz,1H),4.56(d,J＝12.6Hz,1H),3.87(s,3H),3.85(s,3H),3.83(d,J＝4.8Hz,4H),2.96(dd,J＝14.8,5.8Hz,1H),2.85(d,J＝9.4Hz,1H),2.50–2.08(m,6H),1.71–1.60(m,1H),1.51(s,3H),1.07(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,167.0,155.6,153.1,142.1,140.4,138.6,135.0,130.3,123.2,120.9,120.1,115.9,107.5,80.9,66.5,63.1,61.2,60.7,59.8,55.9,42.5,36.4,25.7,24.5,23.7,17.8.hrms (ESI) calculated value C 27 H 36 NO 8 [M+NH 4 ] + 502.2435, experimental 502.2444.
(7h) White solid (yield: 84%). 1 H NMR(400MHz,CDCl 3 )δ7.91(d,J＝16.1Hz,1H),6.92(s,1H),6.45(s,1H),6.28(d,J＝16.0Hz,1H),6.14(d,J＝3.5Hz,1H),5.68(t,J＝8.1Hz,1H),5.49(d,J＝3.5Hz,1H),4.70(d,J＝12.4Hz,1H),4.54(d,J＝12.4Hz,1H),3.86(d,J＝9.1Hz,3H),3.84–3.78(m,7H),3.05–2.95(m,1H),2.85(d,J＝9.4Hz,1H),2.47–2.06(m,6H),1.63(dd,J＝13.1,9.2Hz,1H),1.50(s,3H),1.06(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,167.1,153.9,152.2,143.0,140.2,138.6,135.0,130.5,120.0,114.4,114.2,110.6,96.5,80.9,66.6,63.1,59.8,56.2,56.0,55.9,42.5,36.4,25.7,24.6,23.6,17.8.hrms (ESI) calculated value C 27 H 36 NO 8 [M+NH 4 ] + 502.2435, experimental 502.2442.
(7i) White solid (yield: 77%); 1 H NMR(400MHz,CDCl 3 )δ8.09(d,J＝16.2Hz,1H),6.68(d,J＝16.2Hz,1H),6.17(d,J＝3.2Hz,1H),6.08(s,2H),5.71(t,J＝8.1Hz,1H),5.52(d,J＝3.2Hz,1H),4.71(d,J＝12.4Hz,1H),4.57(d,J＝12.4Hz,1H),3.84(m,10H),3.14–3.03(m,1H),2.91(d,J＝9.4Hz,1H),2.48–2.11(m,6H),1.70–1.60(m,1H),1.53(s,3H),1.11(t,J＝12.6Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.5,168.6,163.0,161.3,138.6,136.4,135.4,130.6,120.3,116.0,105.3,90.2,81.0,66.8,63.2,59.9,55.6,55.3,42.7,36.5,26.0,24.9,23.8,17.9.hrms (ESI) calculated C 27 H 36 NO 8 [M+NH 4 ] + 502.2435, experimental 502.2444.
(7j) White solid (yield: 73%). 1 H NMR(400MHz,CDCl 3 )δ7.53(d,J＝15.9Hz,1H),6.68(s,2H),6.27(d,J＝15.9Hz,1H),6.16(d,J＝3.4Hz,1H),5.69(t,J＝8.2Hz,1H),5.50(d,J＝3.0Hz,1H),4.72(d,J＝12.5Hz,1H),4.55(d,J＝12.5Hz,1H),3.82(m,10H),2.97(dd,J＝14.8,5.8Hz,1H),2.84(d,J＝9.4Hz,1H),2.49–2.07(m,6H),1.66(dd,J＝16.7,9.1Hz,1H),1.50(s,3H),1.06(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.2,166.3,153.2,145.1,134.0,138.7,134.8,130.7,129.4,120.0,116.4,105.0,80.85,66.9,63.1,60.7,59.8,55.9,42.5,36.4,25.6,24.5,23.6,17.8.hrms (ESI) calculated value C 27 H 36 NO 8 [M+NH 4 ] + 502.2435, experimental 502.2445.
(7k) White solid (yield: 97%). 1 H NMR(400MHz,CDCl 3 )δ7.77(d,J＝16.4Hz,1H),7.37–7.27(m,1H),6.93(t,J＝8.6Hz,2H),6.70(d,J＝16.4Hz,1H),6.23(d,J＝3.4Hz,1H),5.74(t,J＝8.3Hz,1H),5.56(d,J＝3.4Hz,1H),4.79(d,J＝12.5Hz,1H),4.60(d,J＝12.5Hz,1H),3.85(t,J＝9.3Hz,1H),2.97–2.89(m,1H),2.87(d,J＝9.4Hz,1H),2.51–2.11(m,6H),1.68(dd,J＝12.8,9.0Hz,1H),1.54(s,3H),1.11(t,J＝12.9Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.3,166.4,161.6(dd,J＝255.8,6.6Hz),160.4,160.3,138.6,134.8,131.7–131.2(m),130.9,123.3(t,J＝8.8Hz),120.3,112.4–111.4(m),80.9,67.1,63.2,59.9,42.6,36.5,25.8,24.5,23.8,17.9. 19 F NMR(376MHz,CDCl 3 ) Delta-109.9- -110.1 (m.) HRMS (ESI) calculated C 24 H 28 F 2 NO 5 [M+NH 4 ] + 448.1930, experimental 448.1929.
(7 l) white solid (yield: 91%). 1 H NMR(400MHz,CDCl 3 )δ7.72(d,J＝16.4Hz,1H),7.27(d,J＝8.1Hz,2H),7.12(t,J＝8.0Hz,1H),6.51(d,J＝16.4Hz,1H),6.14(d,J＝3.4Hz,1H),5.68(t,J＝8.2Hz,1H),5.49(d,J＝2.4Hz,1H),4.71(d,J＝12.5Hz,1H),4.56(d,J＝12.5Hz,1H),3.79(t,J＝9.3Hz,1H),2.87(t,J＝9.1Hz,1H),2.80(d,J＝9.4Hz,1H),2.44–2.04(m,6H),1.69–1.57(m,1H),1.47(s,3H),1.03(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.2,165.7,138.7,138.5,134.8,134.6,131.3,131.0,130.0,128.7,125.8,120.2,80.8,67.1,63.1,59.8,42.5,36.4,25.6,24.4,23.7,17.8.hrms (ESI) calculated value C 24 H 28 Cl 2 NO 5 [M+NH 4 ] + 480.1339, experimental 480.1338.
(7 m) white solid (yield: 87%). 1 H NMR(400MHz,CDCl 3 )δ7.68(d,J＝16.3Hz,1H),7.58(d,J＝8.0Hz,2H),7.03(t,J＝8.0Hz,1H),6.39(d,J＝16.3Hz,1H),6.23(d,J＝3.4Hz,1H),5.76(t,J＝8.2Hz,1H),5.57(d,J＝3.4Hz,1H),4.79(d,J＝12.5Hz,1H),4.65(d,J＝12.5Hz,1H),3.86(t,J＝9.3Hz,1H),2.93(dd,J＝14.7,5.8Hz,1H),2.88(d,J＝9.4Hz,1H),2.52–2.13(m,6H),1.70(t,J＝10.8Hz,1H),1.55(s,3H),1.12(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.3,165.5,143.1,138.6,135.2,134.7,132.5,131.1,130.6,126.1,123.7Calculated C of 120.4,80.9,67.2,63.2,59.9,42.7,36.5,25.8,24.6,23.8,18.0.HRMS (ESI) 24 H 28 Br 2 NO 5 [M+NH 4 ] + 570.0308, experimental 570.0300.
Synthesis of Compounds 10a-10 h:
in a 50mL reaction flask, compound 8a (610 mg,3.67mmol,1 eq) and phenylacetic acid (3.67 mmol,1 eq) of the different substituents were added, acetic anhydride (20 mL) and triethylamine (1 mL) were added, and heated under reflux for 4-9h. After the reaction was substantially completed, the reaction mixture was cooled to room temperature and the pH was adjusted to 2-3 with 35% aqueous hydrochloric acid. Filtration gave a filter cake which was washed with (PE: ea=10:1). Dissolving the filter cake with 1N NaOH, acidifying and filtering again to obtain a filter cake, drying the filter cake to obtain the compounds 9a-9h, and directly putting the compound into the next step. In a reaction flask, compound 2 (53 mg,0.2mmol,1 eq), EDCI (115 mg,0.6mmol,2 eq), DMAP (1.2 mg,0.01mmol,0.05 eq) and the acid 9a-9h (0.3 mmol,1.5 eq) obtained in the previous step were added in succession, and dissolved in anhydrous DCM (2 mL) under an ice-water bath and Et was added 3 N (83.4. Mu.L, 0.6mmol,2 eq). The reaction solution is stirred at room temperature overnight, the reaction is quenched by adding saturated sodium bicarbonate solution for three times after the reaction is completed, the organic phases are combined, the organic phases are washed with saturated common salt and dried by anhydrous sodium sulfate, filtered and concentrated to obtain oily matter, and the oily matter is subjected to silica gel column chromatography to obtain the compounds 10a-10h.
(10a) White solid (yield: 86%); 1 H NMR(400MHz,CDCl 3 )δ8.16(s,1H),7.33(dd,J＝16.1,8.9Hz,3H),7.19(d,J＝7.0Hz,2H),6.75(q,J＝9.0Hz,2H),6.22(s,1H),6.14(d,J＝2.7Hz,1H),5.66(t,J＝7.2Hz,1H),5.45(s,1H),4.73–4.61(m,2H),3.88–3.75(m,4H),3.23(s,3H),2.83(d,J＝8.4Hz,1H),2.76(d,J＝9.3Hz,1H),2.47–2.08(m,6H),1.64–1.54(m,1H),1.51(s,3H),1.07(t,J＝12.4Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,167.4,152.8,152.4,138.8,136.0,135.3,134.8,131.6,130.7,129.7,128.6,127.7,123.3,120.0,117.6,114.1,111.8,80.7,67.2,63.1,59.9,56.0,55.0,42.6,36.5,25.7,24.9,23.7,17.9.hrms (ESI) calculated value C 32 H 38 NO 7 [M+NH 4 ] + 548.2643, experimental 548.2642.
(10b) White solid (yield: 65%) 1 H NMR(400MHz,CDCl 3 )δ8.20(s,1H),7.61(d,J＝8.1Hz,2H),7.35(d,J＝8.1Hz,2H),6.82–6.73(m,2H),6.16(d,J＝3.4Hz,1H),6.09(s,1H),5.68(t,J＝7.9Hz,1H),5.48(d,J＝3.0Hz,1H),4.75–4.65(m,2H),3.86–3.78(m,4H),3.24(s,3H),2.91(ddd,J＝12.0,9.2,3.1Hz,1H),2.83(d,J＝9.4Hz,1H),2.48–2.11(m,6H),1.70–1.59(m,1H),1.53(s,3H),1.08(t,J＝12.5Hz,1H). 13 C NMR(100MHz,CDCl3)δ169.26,166.69,152.79,152.50,140.01,138.64,136.95,133.90,131.85(d,J＝137.5Hz),130.79,130.48,130.23,127.07,125.44(d,J＝3.7Hz),121.17(d,J＝313.5Hz),120.28,118.06,114.76(d,J＝14.8Hz),114.08,111.95,111.50,80.83,67.40,63.22,59.94,55.99,54.95,42.69,36.56,25.68,24.73,23.78,17.97. 19 F NMR(376MHz,CDCl 3 ) Delta-62.6(s). HRMS (ESI) calculated C 33 H 33 F 3 NaO 7 [M+Na] + 621.2071, experimental 621.2073.
(10c) White solid (yield: 70%). 1 H NMR(400MHz,CDCl 3 )δ8.14(s,1H),7.18(dd,J＝8.4,5.5Hz,2H),7.04(t,J＝8.4Hz,2H),6.81–6.74(m,2H),6.22(s,1H),6.17(d,J＝3.0Hz,1H),5.69(t,J＝7.8Hz,1H),5.47(d,J＝3.0Hz,1H),4.74–4.64(m,2H),3.87–3.79(m,4H),3.33(s,3H),2.98–2.87(m,1H),2.84(t,J＝8.2Hz,1H),2.48–2.12(m,6H),1.68–1.59(m,1H),1.53(s,3H),1.10(t,J＝12.5Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.3,167.2,162.2(d,J＝247.5Hz),152.7,152.5,138.7,136.0,134.8,131.8,131.7(d,J＝8.0Hz),130.7,130.6,123.3,120.2,117.4,115.6(d,J＝21.4Hz),114.4,111.8,80.8,67.3,63.2,59.9,56.0,55.1,42.7,36.6,25.7,24.8,23.8,17.9. 19 F NMR(376MHz,CDCl 3 ) Delta-113.8 (dq, j=8.7, 5.5 hz.) HRMS (ESI) calculated C 32 H 37 FNO 7 [M+NH 4 ] + 566.2549, experimental 566.2548.
(10d) White solid (yield: 77%). 1 H NMR(400MHz,CDCl 3 )δ8.14(s,1H),7.34–7.28(m,2H),7.14(d,J＝8.4Hz,2H),6.80–6.74(m,2H),6.19(d,J＝8.7Hz,1H),6.16(d,J＝3.4Hz,1H),5.68(t,J＝7.9Hz,1H),5.47(d,J＝3.0Hz,1H),4.74–4.60(m,2H),3.89–3.77(m,4H),3.33(s,3H),2.96–2.86(m,1H),2.82(d,J＝9.4Hz,1H),2.46–2.11(m,6H),1.67–1.59(m,1H),1.53(s,3H),1.09(dd,J＝15.4,9.8Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.2,166.9,152.7,152.4,138.6,136.2,134.7,134.3,133.7,131.3,130.7,130.4,128.7,123.1,120.2,117.4,114.3,111.8,80.8,67.3,63.1,59.9,56.0,55.0,42.6,36.5,25.6,24.7,23.7,18.0.hrms (ESI) calculated value C 32 H 37 ClNO 7 [M+NH 4 ] + 582.2253, experimental 582.2246.
(10e) White solid (yield: 84%); 1 H NMR(400MHz,CDCl 3 )δ8.14(s,1H),7.46(d,J＝8.2Hz,2H),7.08(d,J＝8.2Hz,2H),6.79(d,J＝17.3Hz,2H),6.19(s,1H),6.16(d,J＝3.2Hz,1H),5.67(t,J＝7.7Hz,1H),5.47(d,J＝2.7Hz,1H),4.72–4.62(m,2H),3.87–3.75(m,4H),3.32(s,3H),2.89(t,J＝8.7Hz,1H),2.82(d,J＝9.4Hz,1H),2.48–2.10(m,6H),1.63(m,1H),1.52(s,3H),1.08(t,J＝12.5Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.2,166.8,152.7,152.4,138.6,136.2,134.8,134.7,131.6,130.7,130.4,123.0,121.8,120.2,117.5,114.3,111.8,80.8,67.3,63.1,59.9,55.9,55.0,42.6,36.5,25.6,24.7,23.7,17.9.hrms (ESI) calculated value C 32 H 37 BrNO 7 [M+NH 4 ] + 626.1748, experimental 626.1749.
(10f) White solid (yield: 93%). 1 H NMR(400MHz,CDCl 3 )δ8.12(s,1H),7.09(dd,J＝30.5,7.7Hz,4H),6.78–6.69(m,2H),6.25(s,1H),6.12(d,J＝3.0Hz,1H),5.66(t,J＝7.9Hz,1H),5.43(d,J＝2.5Hz,1H),4.64(dd,J＝27.6,12.4Hz,2H),3.80(s,3H),3.76(d,J＝9.3Hz,1H),3.24(s,3H),2.80(t,J＝8.8Hz,1H),2.73(d,J＝9.4Hz,1H),2.44–2.33(m,1H),2.32(s,3H),2.27–2.09(m,5H),1.63–1.53(m,1H),1.50(s,3H),1.06(t,J＝12.5Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.2,167.5,152.7,152.3,138.8,137.5,135.0,134.8,132.8,131.6,130.8,129.5,129.2,123.5,119.9,117.3,114.1,111.7,80.6,67.2,63.0,59.8,55.9,54.8,42.5,36.5,25.7,25.0,23.6,21.1,17.9.hrms (ESI) calculated value C 33 H 40 NO 7 [M+NH 4 ] + 562.2799, experimental 562.2797.
(10g) White solid (yield: 83%). 1 H NMR(400MHz,CDCl 3 )δ8.10(s,1H),7.11(d,J＝8.7Hz,2H),6.86(d,J＝8.6Hz,2H),6.83–6.70(m,2H),6.30(d,J＝2.4Hz,1H),6.15(d,J＝3.4Hz,1H),5.69(t,J＝7.9Hz,1H),5.45(d,J＝3.0Hz,1H),4.66(q,J＝12.4Hz,2H),3.80(m,7H),3.31(s,3H),2.91–2.82(m,1H),2.77(d,J＝9.4Hz,1H),2.46–2.11(m,6H),1.66–1.56(m,1H),1.52(s,3H),1.08(t,J＝12.4Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,167.7,159.1,152.7,152.4,138.8,135.1,134.9,131.3,131.0, 127.9,123.7,120.1,117.2,114.3,114.0,111.8,80.7,67.3,63.1,59.9,56.0,55.2,55.1,42.6,36.6,25.8,25.1,23.7,18.0.hrms (ESI) calculated value C 33 H 40 NO 8 [M+NH 4 ] + 578.2748, experimental 578.2742.
(10h) White solid (yield: 84%). 1 H NMR(400MHz,CDCl 3 )δ8.09(s,1H),7.09(d,J＝8.6Hz,2H),6.85(d,J＝8.6Hz,2H),6.80–6.70(m,2H),6.32(d,J＝2.4Hz,1H),6.15(d,J＝3.4Hz,1H),5.69(t,J＝7.9Hz,1H),5.46(d,J＝3.0Hz,1H),4.72–4.61(m,2H),4.02(q,J＝6.6Hz,2H),3.86–3.76(m,4H),3.31(s,3H),2.93–2.83(m,1H),2.79(d,J＝9.4Hz,1H),2.43–2.12(m,6H),1.66–1.56(m,1H),1.52(s,3H),1.40(t,J＝6.9Hz,3H),1.09(dd,J＝15.6,9.0Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,167.7,158.5,152.7,152.4,138.8,135.0,134.9,131.4,131.0,130.8,127.7,123.7,120.1,117.2,114.6,114.2,111.8,80.8,67.3,63.4,63.1,59.9,56.0,55.1,42.6,36.6,25.8,25.0,23.7,18.0,14.8.hrms (ESI) calculated value C 34 H 38 NaO 8 [M+Na] + 597.2459, experimental 597.2462.
(10i) White solid (yield: 90%). 1 H NMR(400MHz,CDCl 3 )δ8.13(d,J＝15.5Hz,1H),7.18(t,J＝12.7Hz,2H),7.10(d,J＝8.1Hz,2H),6.78–6.71(m,2H),6.26(s,1H),6.14(d,J＝3.2Hz,1H),5.67(t,J＝7.8Hz,1H),5.45(d,J＝2.8Hz,1H),4.65(q,J＝12.5Hz,2H),3.85–3.75(m,4H),3.29(s,3H),2.85(dd,J＝15.5,8.8Hz,1H),2.76(d,J＝9.4Hz,1H),2.47(d,J＝7.3Hz,3H),2.42–2.08(m,6H),1.61(dd,J＝19.2,7.5Hz,1H),1.51(s,3H),1.07(t,J＝12.4Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.2,167.3,152.7,152.4,138.7,138.3,135.5,134.7,132.3,131.0,130.8,130.2,126.3,123.3,120.1,117.4,114.1,111.7,80.7,67.2,63.0,59Calculated C for HRMS (ESI) values of 8,56.0,55.0,42.5,36.5,25.6,24.9,23.7,17.9,15.4 33 H 40 NO 7 S[M+NH 4 ] + 594.2520, experimental 594.2516.
Synthesis of Compounds 12a-12 c:
aldehyde 8a (498 mg,3.0mmol,1 eq) and malonic acid of different substituents (6.0 mmol,2 eq) were added to a 100mL reaction flask and pyridine (30 mL) and piperidine (0.5 mL) were added to dissolve. The reaction solution is heated and refluxed for 8 hours, cooled to room temperature after the reaction is basically finished, added into 6N hydrochloric acid in an ice water bath, yellow solid is separated out, and the filter cake is filtered and collected and dried in vacuum to obtain the compounds 11a-11c, and then the compound is directly put into the next step. In a reaction flask, compound 2 (53 mg,0.2mmol,1 eq), EDCI (115 mg,0.6mmol,2 eq), DMAP (1.2 mg,0.01mmol,0.05 eq) and acids 11a-11c (0.3 mmol,1.5 eq) were added sequentially. Anhydrous DCM (2 mL) was added and triethylamine (83.4. Mu.L, 0.6mmol,2 eq) was added dissolved in an ice-water bath. The reaction was stirred at room temperature overnight and the spot plate was essentially complete. The reaction dichloromethane was quenched with saturated sodium bicarbonate solution to extract three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give an oil which was chromatographed on a silica gel column to give compounds 12a-12c.
(12a) White solid (yield: 95%). 1 H NMR(400MHz,CDCl 3 )δ7.77(s,1H),6.92–6.75(m,3H),6.15(d,J＝3.1Hz,1H),5.72(t,J＝8.1Hz,1H),5.51(d,J＝2.7Hz,1H),4.72(d,J＝12.5Hz,1H),4.61(d,J＝12.5Hz,1H),3.84(t,J＝9.3Hz,1H),3.77(s,3H),3.75(s,3H),2.96(t,J＝9.0Hz,1H),2.88(d,J＝9.4Hz,1H),2.51–2.10(m,6H),2.03(s,3H),1.67(dd,J＝16.2,8.2Hz,1H),1.53(s,3H),1.09(t,J＝12.9Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.2,168.0,152.8,151.8,138.6,135.0, 130.4,128.0,125.0,120.2,115.9,114.4,111.3,80.8,66.9,63.1,59.9,55.8,55.6,42.6,36.5,25.7,24.6,23.7,17.9,14.1.hrms (MALDI) calculated value C 27 H 32 NaO 7 [M+Na] + 491.2040, experimental 491.2045.
(12b) White solid (yield: 73%). 1 H NMR(400MHz,CDCl 3 )δ7.75(s,1H),6.91–6.79(m,3H),6.19(d,J＝3.5Hz,1H),5.75(t,J＝8.2Hz,1H),5.53(d,J＝3.1Hz,1H),4.77(d,J＝12.5Hz,1H),4.63(d,J＝12.6Hz,1H),3.86(t,J＝9.3Hz,1H),3.78(d,J＝6.0Hz,6H),3.02–2.93(m,1H),2.91(d,J＝9.4Hz,1H),2.55–2.14(m,8H),1.74–1.65(m,1H),1.56(s,3H),1.20–1.08(m,4H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,167.7,153.0,151.8,138.6,135.1,134.9,134.4,130.5,125.1,120.4,115.3,114.5,111.4,80.9,66.9,63.3,60.0,56.0,55.7,42.7,36.6,25.8,24.7,23.8,21.1,18.0,14.0.hrms (MALDI) calculated value C 28 H 34 NaO 7 [M+Na] + 505.2197, experimental 505.2198.
(12c) White solid (yield: 54%). 1 H NMR(400MHz,CDCl 3 )δ7.76(s,1H),6.88-6.81(m,J＝8.8,6.1,3.1Hz,3H),6.19(d,J＝3.4Hz,1H),5.74(t,J＝8.3Hz,1H),5.52(d,J＝3.1Hz,1H),4.75(d,J＝12.6Hz,1H),4.63(d,J＝12.6Hz,1H),3.86(t,J＝9.3Hz,1H),3.78(d,J＝6.0Hz,6H),3.02–2.93(m,1H),2.90(d,J＝9.4Hz,1H),2.53–2.14(m,8H),1.75–1.64(m,1H),1.60–1.49(m,5H),1.13(t,J＝12.7Hz,1H),0.94(t,J＝7.3Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.3,167.9,153.0,151.9,138.6,135.2,135.1,133.1,130.3,125.1,120.3,115.1,114.8,111.5,80.9,66.9,63.3,60.0,56.0,55.7,42.7,36.6,29.9,25.8,24.7,23.8,22.7,18.0,14.2.hrms (ESI) calculated value C 29 H 36 NaO 7 [M+Na] + 519.2353, experimental 519.2358.
Synthesis of Compound 14:
the preparation method is the same as that of the compound 12 a. (yield 83%). 1 H NMR(400MHz,CDCl 3 )δ8.73(s,1H),7.26(s,1H),7.10(dd,J＝9.1,3.0Hz,1H),6.90(d,J＝9.2Hz,1H),6.22(d,J＝3.4Hz,1H),5.78(t,J＝8.3Hz,1H),5.56(d,J＝3.0Hz,1H),4.78(q,J＝12.4Hz,2H),3.95–3.84(m,4H),3.81(s,3H),2.93(dd,J＝15.6,6.4Hz,1H),2.87(d,J＝9.4Hz,1H),2.52–2.14(m,6H),1.78–1.67(m,1H),1.55(s,3H),1.12(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.2,162.6,154.1,153.3,150.0,138.5,134.1,131.4,122.9,120.4,120.3,115.8,112.5,111.9,101.0,80.9,68.3,63.2,59.9,56.2,55.8,42.6,36.5,25.5,24.3,23.8,17.9.hrms (ESI) calculated value C 27 H 29 NNaO 7 [M+Na] + 5052.1836, experimental 5052.1840.
Synthesis of Compound 15:
compound 2 (400 mg,1.51 mmol) was added to a reaction flask and dissolved in EtOH (12 mL) and NaBH was added in portions under an ice-water bath 4 (63 mg,1.67 mmol) and the reaction was vented, the reaction was stirred under ice-water bath for 4h to substantially complete the reaction, quenched with saturated ammonium chloride solution, extracted with EA three times, combined with saturated brine for three times, dried over anhydrous sodium sulfate, filtered and concentrated to give an oil which was purified by silica gel column chromatography to give 15t (311 mg, 77% yield) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ5.62(t,J＝7.8Hz,1H),4.08(q,J＝12.5Hz,2H),3.83(t,J＝9.5Hz,1H),2.75(d,J＝9.4Hz,1H),2.50–2.08(m,7H),1.90(td,J＝12.1,2.5Hz,1H),1.68–1.46(m,5H),1.25(d,J＝6.9Hz,3H),1.07(t,J＝12.5Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 178.0,139.9,127.3,81.3,65.9,63.7,60.0,46.6,41.6,37.1,26.8,24.3,23.7,18.0,13.2.hrms (ESI) calculated C 15 H 22 NaO 4 [M+Na] + 289.1410, experimental 289.1413.
Synthesis of Compound 16:
in a reaction flask, compound 2 (82.6 mg,0.31 mmol), EDCI (89.9 mg,0.47 mmol), DMAP (3.8 mg,0.03 mmol) and 2, 6-dimethoxybenzoic acid (85.5 mg,0.47 mmol) were added sequentially. 2mL of anhydrous DCM was added for dissolution, and triethylamine (65 uL,0.47 mmol) was added with zero degree stirring. The reaction mixture was stirred at room temperature overnight, the reaction was quenched with saturated sodium bicarbonate, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and filtered and concentrated to give compound 16 (71 mg, 83%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ7.29(d,J＝8.4Hz,1H),6.55(d,J＝8.4Hz,2H),6.11(d,J＝2.9Hz,1H),5.81(t,J＝7.9Hz,1H),5.41(s,1H),5.11(d,J＝12.4Hz,1H),4.54(d,J＝12.3Hz,1H),3.90–3.72(m,7H),2.99(t,J＝9.0Hz,1H),2.90(d,J＝9.4Hz,1H),2.33(dddd,J＝52.9,29.1,17.7,6.8Hz,6H),1.63(t,J＝10.6Hz,1H),1.55(s,3H),1.13(t,J＝12.7Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.7,166.3,157.4,138.7,135.3,131.4,131.2,120.3,112.8,104.1,81.3,68.0,63.5,60.1,56.1,42.7,36.8,26.0,24.7,24.1,18.2.hrms (ESI) calculated value C 24 H 28 NaO 7 [M+Na] + 451.1727, experimental 451.1732.
Synthesis of Compounds 17a-17 b:
preparation method and preparation process of Compound 11a
(17a) White solid (yield: 67%). 1 H NMR(400MHz,DMSO-d6)δ12.34(s,1H),7.80(d,J＝16.1Hz,1H),7.25(s,1H),7.07–6.93(m,2H),6.55(d,J＝16.1Hz,1H),3.80(s,3H),3.74(s,3H). 13 C NMR (100 MHz, DMSO-d 6) delta 167.9,153.2,152.1,138.4,123.0,119.6,117.5,113.0,112.6,56.1,55.6.HRMS (ESI) calculated C 11 H 11 O 4 [M–H] – 207.0663, experimental 207.0660.
(17b) White solid (yield: 57%). 1 H NMR(400MHz,DMSO-d6)δ12.17(s,1H),7.94(d,J＝16.3Hz,1H),7.34(t,J＝8.4Hz,1H),6.71(dd,J＝12.4,6.4Hz,3H),3.85(s,6H). 13 C NMR (100 MHz, DMSO-d 6) delta 168.9,159.54 134.7,131.9,120.9,110.9,104.1,56.0.HRMS (ESI) calcd C 11 H 12 NaO 4 [M+Na] + 231.0628, experimental 231.0631.
Synthesis of Compounds 19a-19 b:
compound 17a or 17b (320 mg,1.54 mmol) was dissolved in 15mL anhydrous DCM and oxalyl chloride 3.0mL at 75deg.C was added at reflux for 2h. The redundant oxalyl chloride is screwed off to obtain acyl chloride, 10mL of anhydrous DCM is added for dissolving, 10mL of methanol is added for reacting for 1h, and after the basic reaction is finished, the spin-dry solvent is purified by silica gel column chromatography to obtain the compounds 19a-19b
(19a) White solid (yield: 75%) 1 H NMR(400MHz,CDCl 3 )δ7.97(d,J＝16.2Hz,1H),7.03(d,J＝2.7Hz,1H),6.90(dd,J＝9.0,2.8Hz,1H),6.83(d,J＝9.0Hz,1H),6.49(d,J＝16.2Hz,1H),3.83(s,3H),3.79(s,3H),3.77(s,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 167.7,153.4,152.7,139.9,123.8,118.4,117.0,113.2,112.3,56.0,55.7,51.6.Hrms (ESI) calculated C 12 H 15 O 4 [M+H] + 223.0965, experimental 223.0966.
(19b) White solid (yield: 81%) 1 H NMR(400MHz,CDCl 3 )δ8.14(d,J＝16.3Hz,1H),7.27(t,J＝8.4Hz,1H),6.89(d,J＝16.3Hz,1H),6.56(d,J＝8.4Hz,2H),3.88(s,6H),3.79(s,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 169.2,160.2,135.8,131.4,120.4,112.3,103.8,55.9,51.6.HRMS (ESI) calculated C 12 H 14 NaO 4 [M+Na] + 245.0784, experimental 245.0788.
Synthesis of Compounds 20a-20 b:
in a reaction flask, compound 15 (53 mg,0.2 mmol), EDCI (115.0 mg,0.6 mmol), DMAP (1.2 mg,0.01 mmol) and 17a or 17b (63 mg,0.15 mmol) were added sequentially. Anhydrous DCM (2 mL) was added and TEA (83. Mu.L, 0.6 mmol) was added dissolved in an ice-water bath. The reaction mixture was stirred at room temperature overnight, and after the reaction was quenched with saturated sodium bicarbonate solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography to give solids 20a-20b.
(20a) White solid (yield: 77%). 1 H NMR(400MHz,CDCl 3 )δ7.96(d,J＝16.1Hz,1H),7.01(d,J＝2.9Hz,1H),6.90(dd,J＝9.0,2.9Hz,1H),6.83(d,J＝9.0Hz,1H),6.49(d,J＝16.1Hz,1H),5.67(t,J＝8.2Hz,1H),4.77(d,J＝12.5Hz,1H),4.52(d,J＝12.6Hz,1H),3.87–3.79(m,4H),3.76(s,3H),2.76(d,J＝9.4Hz,1H),2.52–2.41(m,1H),2.35–2.08(m,6H),2.06–1.96(m,1H),1.63–1.55(m,1H),1.53(s,3H),1.27(d,J＝6.9Hz,3H),1.06(t,J＝13.1Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 177.8,166.9,153.3,152.8,140.6,135.2,129.8,123.4,118.0,117.2,113.3,112.3,81.0,66.1,63.3,59.7,55.9,55.6,46.1,41.3,36.7,26.6,24.4,23.6,17.8,13.0.hrms (ESI) calculated C 26 H 32 NaO 7 [M+Na] + 479.2040, experimental 479.2046.
(20b) White solid (yield: 84%) 1 H NMR(400MHz,CDCl 3 )δ8.16(d,J＝16.3Hz,1H),7.31–7.21(m,1H),6.87(d,J＝16.3Hz,1H),6.54(d,J＝8.4Hz,2H),5.68(t,J＝8.0Hz,1H),4.76(d,J＝12.5Hz,1H),4.51(d,J＝12.5Hz,1H),3.91–3.79(m,7H),2.79(d,J＝9.3Hz,1H),2.50–2.40(m,1H),2.36–2.01(m,7H),1.62–1.50(m,4H),1.27(d,J＝6.7Hz,3H),1.07(t,J＝13.0Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ178.0,168.3,160.2,136.4,135.6,131.7,130.0,119.7,111.9,103.7,81.2,66.2,63.5,59.9,55.8,46.3,41.6,36.9,26.9,24.8,23.8,18.0,13.1HRMS (ESI) calculated C 26 H 32 NaO 7 [M+Na] + 479.2040, experimental 479.2045.
Synthesis of Compounds 21a-21 b:
acid (400 mg,1.92 mmol) and 10% Pd/C in methanol (20 mL) were added to the flask and dissolved, argon was replaced three times and hydrogen was replaced three times, and the mixture was stirred at room temperature overnight to substantially complete the reaction. The mixture was subjected to a short silica gel column chromatography to give acids 18a-18b which were directly fed to the next step. Acid 18a or 18b (167 mg,0.79 mmol), compound 2 (140 mg,0.53 mmol), EDCI (153 mg,0.79 mmol) and DMAP (0.6 mg,0.053 mmol) were added sequentially to the reaction flask and dissolved in 5mL anhydrous DCM. Triethylamine (110. Mu.L, 0.79 mmol) was added under an ice-water bath. The reaction mixture was stirred at room temperature overnight, and after the reaction was quenched with saturated sodium bicarbonate solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography to give solids 21a-21b.
(21a) White solid (yield: 85%). 1 H NMR(400MHz,CDCl 3 )δ6.78–6.66(m,3H),6.20(d,J＝3.5Hz,1H),5.61(t,J＝8.0Hz,1H),5.50(d,J＝3.5Hz,1H),4.62(d,J＝12.4Hz,1H),4.40(d,J＝12.4Hz,1H),3.80(t,J＝9.3Hz,1H),3.75(s,3H),3.71(s,3H),2.89(m,2H),2.84–2.79(m,1H),2.77(d,J＝9.4Hz,1H),2.60(t,J＝7.5Hz,2H),2.42–2.08(m,6H),1.59(td,J＝12.1,3.1Hz,1H),1.51(s,3H),1.05(t,J＝12.5Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 172.82,169.30,153.14,151.54,138.62,134.76,130.54,129.48,120.13,116.34,111.18,110.90,80.85,66.63,63.09,59.84,55.62,55.47,42.46,36.42,33.93,26.13,25.61,24.37,23.67,17.85.Hrms (ESI) calculated value C 26 H 36 NO 7 [M+NH 4 ] + 474.2486, experimental 474.2484.
(21b) White solid (yield: 83%). 1 H NMR(400MHz,CDCl 3 )δ7.13(t,J＝8.3Hz,1H),6.51(d,J＝8.3Hz,2H),6.21(d,J＝3.5Hz,1H),5.64(t,J＝8.0Hz,1H),5.52(d,J＝3.1Hz,1H),4.61(d,J＝12.4Hz,1H),4.46(d,J＝12.4Hz,1H),3.82(t,J＝9.4Hz,1H),3.79(s,6H),3.02–2.91(m,2H),2.87(ddd,J＝14.5,7.4,4.5Hz,1H),2.81(d,J＝9.4Hz,1H),2.51–2.44(m,2H),2.44–2.11(m,6H),1.68–1.57(m,1H),1.53(s,3H),1.09(t,J＝12.4Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 173.5,169.5,158.3,138.9,135.1,130.7,127.5,120.3,116.4,103.6,81.1,66.9,63.3,60.0,55.7,42.7,36.7,33.5,26.0,24.8,23.9,18.8,18.1.hrms (ESI) calculated value C 26 H 32 NaO 7 [M+Na] + 479.2040, experimental 479.2045.
Synthesis of Compound 23:
compound 2 (1.1 g,4.16 mmol) was added to the reaction flask and a 2N solution of dimethylamine in tetrahydrofuran (20.8 mL) was added under an ice water bath. The reaction was stirred for 1h in an ice water bath, the solvent was dried after disappearance of the starting material, and purified directly by silica gel column chromatography (DCM: meoh=50:1) to give compound 22 as a white solid (1.2,93%), 1 H NMR(400MHz,CDCl 3 )δ5.58(t,J＝7.9Hz,1H),4.10(dd,J＝30.7,13.1Hz,2H),3.85(t,J＝9.2Hz,1H),3.38(s,1H),2.81(d,J＝9.4Hz,1H),2.73(dd,J＝12.9,5.1Hz,1H),2.61(dd,J＝12.9,5.4Hz,1H),2.51–2.38(m,4H),2.30–2.18(m,7H),2.17–2.06(m,2H),1.67–1.55(m,1H),1.52(s,3H),1.12–1.02(m,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 177.0,141.2,127.5,81.7,66.3,64.2,60.0,57.6,45.8,44.3,42.1,37.2,27.7,26.0,23.9,18.1.hrms (ESI) calculated C 17 H 28 N 2 O 4 [M+H] + 310.2013, experimental 310.2015.
In a reaction flask, compound 17b (710 mg,3.42 mmol), compound 22 (704 mg,2.28 mmol), EDCI (655.6 mg,3.42 mmol) and DMAP (27.8 mg,0.228 mmol) were added sequentially, 25mL of anhydrous CH 2 Cl 2 Dissolving in ice water bath, adding Et 3 N (0.45 mL,3.42 mmol). The reaction mixture was stirred at room temperature overnight, quenched with saturated sodium bicarbonate solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated through silica gel column chromatography [ DCM: meoh=50:1]Purification gave compound 23 (987.2 mg, 86%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ8.16(d,J＝16.3Hz,1H),7.28(d,J＝8.7Hz,1H),6.89(d,J＝16.3Hz,1H),6.56(d,J＝8.4Hz,2H),5.67(t,J＝7.8Hz,1H),4.84(d,J＝12.8Hz,1H),4.66(d,J＝12.8Hz,1H),3.97–3.80(m,7H),2.84(d,J＝9.3Hz,1H),2.73(d,J＝4.3Hz,1H),2.65(d,J＝5.9Hz,1H),2.58–2.26(m,6H),2.23(s,6H),2.15(d,J＝12.5Hz,2H),1.58(d,J＝20.6Hz,4H),1.10(t,J＝12.8Hz,1H). 13 C NMR(100MHz,CDCl 3 ) Delta 177.2,168.3,160.2,136.3,136.1,131.6,128.5,120.2,112.2,103.8,81.3,66.2,64.0,60.0,58.5,55.9,45.9,44.7,43.3,37.1,27.2,25.0,23.9,18.1.hrms (ESI) calculated value C 28 H 38 NO 7 [M+H] + 500.2643, experimental 500.2644.
Synthesis of Compound 24:
compound 23 (1.15 g,2.3 mmol) was dissolved in 23mL of methanol and fumaric acid (267 mg,2.3 mmol) was added in portions and the reaction stirred at room temperature for 6.5h. Spin-drying the solvent afforded compound 24 (1.3 g, 92% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.95(s,2H),8.00(d,J＝16.3Hz,1H),7.37(t,J＝8.4Hz,1H),6.78(d,J＝16.3Hz,1H),6.72(d,J＝8.4Hz,2H),6.61(s,2H),5.59(t,J＝7.6Hz,1H),4.79(d,J＝12.7Hz,1H),4.57(d,J＝12.6Hz,1H),4.03(t,J＝9.5Hz,1H),3.86(s,6H),2.77–2.54(m,4H),2.39–2.23(m,4H),2.18(s,6H),2.10(dd,J＝24.6,10.8Hz,3H),1.65(t,J＝11.4Hz,1H),1.48(s,3H),0.94(t,J＝12.3Hz,1H). 13 C NMR (100 MHz, DMSO). Delta.177.07, 167.16,166.24,159.62,135.82,135.17,134.15,132.20,128.13,119.42,110.67,104.13,80.41,66.03,63.16,59.78,57.87,55.97,45.20,43.28,42.60,36.56,25.63,24.18,23.14,17.46.HRMS (ESI) calculated C 28 H 38 NO 7 [M+H] + 500.2643, experimental 500.2645.
Example 2: pharmacological action of sesquiterpene lactone-cinnamic acid derivative or its salt
Preparing various cancer cells into 2×10 5 adding/mL cell suspension into 24-well plate round bottom cell culture plate, adding sesquiterpene lactone-cinnamic acid derivative or its salt, respectively, each measuring 5-well concentration, placing at 37deg.C and 5% CO 2 Culturing for 18 hours under the saturated humidity condition, measuring absorbance (A) value at 570nm wavelength of an enzyme-linked detector by using an MTT method, and calculating the inhibition effect of the compound to the tested cancer cells.
TABLE 1 inhibitory Activity of sesquiterpene lactone-cinnamic acid derivatives on MDA-MB-231 of breast cancer cell lines (IC) 50 ，μM)
Figure BDA0001949486420000341
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Figure BDA0001949486420000342
Figure BDA0001949486420000351
Wherein MDA-MB-231 is a human breast cancer cell line.
TABLE 2 inhibitory Activity of sesquiterpene lactone-cinnamic acid derivatives on MDA-MB-231 of breast cancer cell lines (IC) 50 ，μM)
Figure BDA0001949486420000352
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Figure BDA0001949486420000353
Figure BDA0001949486420000361
TABLE 3 inhibitory Activity of sesquiterpene lactone-cinnamic acid derivatives on MDA-MB-231 of breast cancer cell lines (IC) 50 ，μM)
Figure BDA0001949486420000362
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Figure BDA0001949486420000363
Figure BDA0001949486420000371
TABLE 4 sesquiInhibitory Activity of terpene lactone-cinnamic acid derivatives on mammary cancer cell line MDA-MB-231 (IC) 50 ，μM)
Figure BDA0001949486420000372
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Figure BDA0001949486420000373
Table 5 inhibitory Activity of sesquiterpene lactone-cinnamic acid derivatives against mammary cancer cell line MDA-MB-231 (IC 50 ，μM)
Figure BDA0001949486420000374
Figure BDA0001949486420000381
The results of the activity test show that the compounds screened show inhibitory activity against the cells tested. The test compounds thus have utility for the treatment of cancer.
The compounds, uses and methods of the invention have been described by way of specific examples. Those skilled in the art can appropriately change the links of the raw materials, the process conditions and the like to achieve the corresponding other objects by referring to the content of the present invention, and all the similar substitutions and modifications are obvious to those skilled in the art without departing from the content of the present invention, and are considered to be included in the scope of the present invention.

Claims (3)

1. The use of sesquiterpene lactone-cinnamic acid derivatives of formula (I) and salts thereof in the manufacture of a medicament for the treatment of breast cancer,
wherein the sesquiterpene lactone-cinnamic acid derivative represented by formula (I) is selected from:
Figure FDA0004277175010000011
2. the use of sesquiterpene lactone-cinnamic acid derivatives of formula (I) and salts thereof in the preparation of adjuvant drugs for the treatment of breast cancer,
wherein the sesquiterpene lactone-cinnamic acid derivative represented by formula (I) is selected from:
Figure FDA0004277175010000012
Figure FDA0004277175010000021
3. the use according to claim 1 or 2, wherein the salt is a pharmaceutically acceptable salt of a compound of formula (I) with an inorganic or organic acid selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, phosphorous acid, sulfurous acid, carbonic acid, boric acid, phosphomolybdic acid, selenious acid, methanesulfonic acid, phenylsulfonic acid, fumaric acid, citric acid, maleic acid, tartaric acid, oxalic acid, D-malic acid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid, DL-lactic acid, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, oleic acid, lauric acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, phthalic acid, malonic acid, succinic acid, glycolic acid, thioic acid, glycine, sarcosine, sulfonic acid, nicotinic acid, picolinic acid, isonicotinic acid, dichloroacetic acid, benzoic acid.
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