CN111454275A - Sesquiterpene lactone-cinnamic acid derivatives and salts thereof, pharmaceutical compositions and uses thereof - Google Patents

Sesquiterpene lactone-cinnamic acid derivatives and salts thereof, pharmaceutical compositions and uses thereof Download PDF

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CN111454275A
CN111454275A CN201910046842.3A CN201910046842A CN111454275A CN 111454275 A CN111454275 A CN 111454275A CN 201910046842 A CN201910046842 A CN 201910046842A CN 111454275 A CN111454275 A CN 111454275A
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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 an application of sesquiterpene lactone-cinnamic acid derivatives shown in formula (I) and salts thereof in preparing medicaments for treating cancers and auxiliary medicaments for treating the cancers.

Description

Sesquiterpene lactone-cinnamic acid derivatives and salts thereof, pharmaceutical compositions and uses thereof
Technical Field
The invention relates to a pharmaceutical composition for treating cancer or assisting in treating cancer, which takes sesquiterpene lactone-cinnamic acid derivatives and salts thereof as active ingredients, and application of the pharmaceutical compound and the pharmaceutical composition in preparing anti-cancer or assisting anti-cancer 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 female Cancer-related death [ h.a. wahba, h.a. el-Hadaad, Current apoache in molecular of Triple-negative breast Cancer (TNBC) is estimated to be characterized by human epidermal growth factor receptor 2(HER-2), Estrogen Receptor (ER), progesterone receptor expression deficiency, TNBC is the most invasive tumor of breast Cancer subtypes, recurrence rate is high, drug resistance is strong [ r.dent, m.truduuu, k.i. pritchard, w.m. hanna, h.k.k.k.k.o.c. wauka, & t. p. prt. c.p. prt. c. w.m. hanna, h.k.k.k.c. a. wauk. t. c. wo. t. c. wo. c. w. t. c. t. c. t. c. t. c. t. c. t. c. t. a. c. t. c. a. c. a. c. a. c. a. c. a.
Disclosure of Invention
The invention provides a pharmaceutical composition of sesquiterpene lactone-cinnamic acid derivatives or salts thereof and a pharmaceutically acceptable carrier for treating cancer or a composition of sesquiterpene lactone-cinnamic acid derivatives or salts thereof and other anti-cancer drugs, a preparation method thereof, and application of sesquiterpene lactone-cinnamic acid derivatives or salts thereof in preparation of drugs for treating cancer.
Figure BDA0001949486420000021
Wherein, P is the following structure:
Figure BDA0001949486420000022
R1hydrogen, alkyl, alkylaryl, cyano; r2Phenyl, substituted phenyl, furyl, thienyl, pyridyl, naphthyl, methylenedioxyphenyl; r3R being a hydrogen atom4The amino group is hydrogen atom or one or more substituent groups, and the substituent groups comprise methyl, ethyl and propyl chain substituent groups and can also be cyclic substituent groups such as cyclopentyl and cyclohexyl; r3，R4Is a single bond.
Pharmaceutically acceptable salts thereof with inorganic or organic acids, including quaternary ammonium salts with compounds of formula (i), including hydrofluoric, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, nitric, phosphorous, sulfurous, carbonic, boric, phosphomolybdic, selenious, methanesulfonic, substituted methanesulfonic, phenylsulfonic, substituted phenylsulfonic, fumaric, citric, maleic, tartaric, oxalic, D-malic, L-malic, D L-malic, L-lactic, D L-lactic, formic, substituted formic, acetic, propionic, butyric, valeric, oleic, lauric, p-toluenesulfonic, 1-naphthalenesulfonic, 2-naphthalenesulfonic, phthalic, malonic, succinic, glycolic, thiolanic, glycine, sarcosine, sulfonic, nicotinic, picolinic, isonicotinic, dichloroacetic, benzoic, substituted benzoic.
Figure BDA0001949486420000031
Figure BDA0001949486420000041
Figure BDA0001949486420000051
Figure BDA0001949486420000061
Figure BDA0001949486420000071
Figure BDA0001949486420000081
The invention also provides the use of a compound of formulae 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 formulae 3-24 in the manufacture of an adjuvant medicament for the 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 shown in the formula 3-24 and a pharmaceutically acceptable carrier or a composition with other anti-cancer 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 derivatives 24
Detailed Description
In order to understand the present invention, the following examples are further illustrative, but not limiting the scope of the present invention.
Example 1:
feverfew (compound 1) is oxidized by selenium dioxide to obtain compound 2, and compound 2 is esterified with various substituted cinnamic acids under EDCI/DMAP or triphenylphosphine, DIAD to obtain compound 3,4a-4x,7a-7 m. Esterifying compound 2 with other heterocycle to obtain 6a-6g, performing clairvoyance condensation reaction on compound 8 to obtain a series of double bond-substituted acids, and esterifying with compound 2 to obtain 10a-10l,12a-12c, and 14. Reducing the compound 2 with sodium borohydride to obtain a compound 15, and esterifying the compound 15 with 2, 5-dimethoxycinnamic acid and 2, 6-dimethoxycinnamic acid to obtain a compound 20a-20 b; 2, 5-dimethoxy cinnamic acid and 2, 6-dimethoxy cinnamic acid are reduced by palladium carbon hydrogen to obtain acid 18a-18b, and then esterified with compound 2 to obtain 21a-21 b. Acids 18a-18b in thionyl chloride methanol give methyl esters 19a-19 b. The compound 2 reacts with 2, 6-dimethoxybenzoic acid to obtain a compound 16.
Synthesis of Compound 2:
PT L (1.0g,4.3mmol) was dissolved in 20ml DCM, and selenium dioxide (324mg,2.4mmol) and t-BuOOH (70% in H) previously dried over anhydrous sodium sulfate were added2O,1.48m L, 10.8mmol) of the mixture was stirred at room temperature overnight after the reaction was substantially complete, DCM (20m L) was added to dilute the reaction, saturated sodium thiosulfate was added to quench the reaction, dichloromethane was extracted three times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate was concentrated and purified by silica gel column chromatography to give compound 2(810mg, 72%) as a white solid1H NMR(400MHz,CDCl3)6.15(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).13C NMR(100MHz,CDCl3)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 value C15H20NaO4[M+Na]+287.1254, Experimental value 287.1258.
Synthesis of Compounds 3,4a-4 x:
adding compound 2(53mg,0.2mmol), EDCI (115mg,0.6mmol), DMAP (1.2mg,0.01mmol) and corresponding cinnamic acid (0.3mmol,1.5eq) into a reaction bottle in sequence, adding anhydrous DCM2m L for dissolution, adding triethylamine (83.4 mu L, 0.6mmol) under zero-degree stirring, stirring at room temperature overnight, adding saturated sodium bicarbonate to quench the reaction after the reaction is almost finished, extracting with dichloromethane three times, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by silica gel column chromatography to obtain solid 3,4a-4 x.
(3) White solid (yield: 86%).1H NMR(400MHz,CDCl3)7.68(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).13C NMR(100MHz,CDCl3)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 C24H30NO5[M+NH4]+412.2118, Experimental value 412.2122.
(4a) White solid (yield: 92%).1H NMR(400MHz,CDCl3)8.05(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).13C NMR(100MHz,CDCl3)169.3,165.5,140.7,138.6,134.7,132.8,132.1,130.7,129.7,128.6(q,J＝30.3Hz),127.7,126.0(d,J＝5.5Hz),123.8(d,J＝274.1Hz),121.6,120.1,80.9,66.9,63.1,59.7,42.5,36.4,25.5,24.3,23.7,17.8.19F NMR(376MHz,CDCl3) Calculation of C58.8(s) HRMS (ESI)25H29F3NO5[M+NH4]+480.1992, Experimental value 480.1993.
(4b) White solid (yield: 98%);1H NMR(400MHz,CDCl3)7.77(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).13C NMR(100MHz,CDCl3)169.2,166.2,161.2(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),80.9,66.8,63.1,59.8,42.5,36.4,25.6,24.3,23.7,17.8.19F NMR(376MHz,CDCl3) -114.2 (ddd, J ═ 10.6,7.5,3.7Hz). hrms (esi) calculated value C24H29FNO5[M+NH4]+430.2024, Experimental value 430.2019.
(4c) White solid (yield: 96%).1H NMR(400MHz,CDCl3)8.08(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).13C NMR(100MHz,CDCl3)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 C24H29ClNO5[M+NH4]+446.1729, Experimental value 446.1723.
(4d) White solid (yield: 72%).1H NMR(400MHz,CDCl3)8.04(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).13C NMR(100MHz,CDCl3)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 C24H29BrNO5[M+NH4]+490.1224, Experimental value 490.1214.
(4e) White solid (yield: 94%).1H NMR(400MHz,CDCl3)7.99(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).13C NMR(100MHz,CDCl3)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 C25H32NO5[M+NH4]+426.2275, Experimental value 426.2281.
(4f) White solid (yield: 89%).1H NMR(400MHz,CDCl3)7.98(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).13CNMR(100MHz,CDCl3)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 C25H32NO6[M+NH4]+442.2224, Experimental value 442.2232.
(4g) White solid (yield: 89%).1H NMR(400MHz,CDCl3)8.03(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).13C NMR(100MHz,CDCl3)169.3,167.0,157.5,140.9,138.5,134.9,131.6,130.1,128.7,122.7,120.3,120.1,117.3,111.9,80.8,66.5,63.7,63.0,59.8,42.4,36.4,25.5,24.3,23.6,17.7,14.5 HRMS (ESI) calculated C26H34NO6[M+NH4]+456.2381, Experimental value 456.2380.
(4h) White solid (yield: 69%).1H NMR(400MHz,CDCl3)7.80–7.60(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).13C NMR(100MHz,CDCl3)169.3,166.0,143.7,138.7,134.9,134.8,131.5(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),120.3,119.3,81.0,66.9,63.3,59.9,42.7,36.6,25.7,24.4,23.8,18.0.19F NMR(376MHz,CDCl3) Calculated value C of 62.89(s) HRMS (ESI)25H29F3NO5[M+NH4]+480.1992, Experimental value 480.1992.
(4i) White solid (yield: 76%).1H NMR(400MHz,CDCl3)7.63(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).13C NMR(100MHz,CDCl3)169.3,166.1,162.9(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),80.9,66.8,63.2,59.9,42.6,36.5,25.7,24.4,23.8,17.9.19F NMR(376MHz,CDCl3) -112.3 (dd, J ═ 14.8,8.9 Hz.) hrms (esi) calculated value C24H29FNO5[M+NH4]+430.2024, Experimental value 430.2024.
(4j) White solid (yield: 69%).1H NMR(400MHz,CDCl3)7.59(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).13C NMR(100MHz,CDCl3)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 C24H29ClNO5[M+NH4]+446.1729, Experimental value 446.1723.
(4k) White solid (yield: 89%).1H NMR(400MHz,CDCl3)7.62(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).13C NMR(100MHz,CDCl3)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 C24H29BrNO5[M+NH4]+490.1224, Experimental value 490.1218.
(4l) white solid (yield: 88%).1H NMR(400MHz,CDCl3)7.67(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).13C NMR(100MHz,CDCl3)169.2,166.5,145.5,138.6,138.4,134.8,133.9,131.2,130.4,128.7,128.6,125.1,120.1,117.0,80.9,66.7,63.1,59.8,42.5,36.4,25.6,24.4,23.7,21.1,17.8 HRMS (ESI) calculated C25H32O5[M+NH4]+426.2275，found 426.2283.
(4m) white solid (yield: 92%).1H NMR(400MHz,CDCl3)7.63(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).13C NMR(100MHz,CDCl3)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 C25H32NO6[M+NH4]+442.2224, Experimental value 442.2229.
(4n) white solid (yield: 72%).1H NMR(400MHz,CDCl3)7.66(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).13C NMR(100MHz,CDCl3)169.2,165.9,143.4,138.7,137.4,134.6,131.6(q,J＝32.6Hz),130.7,128.1,125.7(d,J＝3.8Hz),123.6(d,J＝272.3Hz),120.1,119.9,80.9,66.9,63.1,59.8,42.5,36.4,25.5,24.3,23.7,17.8.19F NMR(376MHz,CDCl3) Calculated value C of 62.9(s) HRMS (ESI)25H29F3NO5[M+NH4]+480.1992, Experimental value 480.2000.
(4o) white solid (yield: 93%).1H NMR(400MHz,CDCl3)7.63(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).13C NMR(100MHz,CDCl3)169.3,166.4,163.9(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),80.9,66.8,63.2,59.9,42.6,36.5,25.7,24.4,23.7,17.9.19F NMR(376MHz,CDCl3) -109.0(s) HRMS (ESI) calcd for C24H29FNO5[M+NH4]+430.2024, Experimental value 430.2026.
(4p): white solid (yield: 90%).1H NMR(400MHz,CDCl3)7.61(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).13C NMR(100MHz,CDCl3)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 C24H29ClNO5[M+NH4]+446.1729, Experimental value 446.1732.
(4q) white solid (yield: 86%).1H NMR(400MHz,CDCl3)7.59(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).13C NMR(101MHz,CDCl3)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 C24H29BrNO5[M+NH4]+490.1224, Experimental value 490.1221.
(4r) white solid (yield: 62%).1H NMR(400MHz,CDCl3)7.66(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).13C NMR(100MHz,CDCl3)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 C25H32NO5[M+NH4]+426.2275, Experimental value 426.2281.
(4s): white solid (yield: 71%).1H NMR(400MHz,CDCl3)7.66(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).13C NMR(100MHz,CDCl3)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 C27H36NO5[M+NH4]+454.2588, Experimental value 454.2594.
(4t) white solid (yield: 77%).1H NMR(400MHz,CDCl3)7.63(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).13C NMR(100MHz,CDCl3)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 C25H32NO6[M+NH4]+442.2224, Experimental value 442.2230.
(4u) white solid (yield: 90%).1H NMR(400MHz,CDCl3)7.61(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).13C NMR(100MHz,CDCl3)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 C26H34NO6[M+NH4]+456.2381, Experimental value 456.2390.
(4v): white solid (yield: 78%).1H NMR(400MHz,CDCl3)7.63(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).13CNMR(100MHz,CDCl3)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 C26H32NO7[M+NH4]+470.2173, experimentValue 470.2171.
(4w) white solid (yield: 53%).1H NMR(400MHz,CDCl3)8.24(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).13C NMR(100MHz,CDCl3)169.3,165.6,148.6,142.5,140.1,138.7,134.6,131.1,128.7,124.2,121.6,120.2,81.0,67.1,63.2,59.9,42.6,36.5,25.7,24.4,23.8,17.9 HRMS (ESI) calculated value C24H29N2O7[M+NH4]+457.1969, Experimental value 457.1970.
(4X) white solid (yield: 82%).1H NMR(400MHz,CDCl3)7.73–7.57(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).13C NMR(101MHz,CDCl3)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 C25H29N2O5[M+NH4]+437.2071, Experimental value 437.2074.
Synthesis of Compounds 5a-5 b:
compound 2(264.3mg,1.0mmol,1eq), PPh were added sequentially to a 20m L reaction flask3(393.5mg,1.5mmol) and corresponding substituted cinnamic acid (1.5mmol,1.5eq), replacing gas, adding anhydrous THF (10m L) for dissolving, adding DIAD (297 mu L,1.5 mmol,1.5eq) under zero-degree stirring, reacting at room temperature overnight, adding saturated ammonium chloride to quench the reaction, extracting with ethyl acetate three times, combining organic phases, washing with saturated common salt water three times, drying with anhydrous sodium sulfate, filtering, spin-drying, concentrating to obtain an oil, and purifying by silica gel column chromatography [ PE/EA is 2: 1-1: 2 ═ 2%]Compounds 5a-5b are obtained.
(5a) White solid (yield: 76%).1H NMR(400MHz,CDCl3)7.62(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).13CNMR(100MHz,CDCl3)169.9,167.3,158.6,145.7,138.5,134.9,130.6,130.1,126.3,120.8,116.0,114.1,81.2,66.8,63.3,60.3,42.6,36.5,25.8,24.5,23.8,17.9 HRMS (ESI) calculated value C24H30NO6[M+NH4]+428.2068, Experimental value 428.2067.
(5b) White solid (yield: 55%).1H NMR(400MHz,CDCl3)7.62(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).13C NMR(100MHz,CDCl3)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 value C25H29O7[M+H]+441.1908, Experimental value 441.1910.
Synthesis of Compounds 6c-6 e:
the corresponding acid (0.6mmol,1.2eq) was added to the reaction flask and dissolved in anhydrous DCM (6m L), oxalyl chloride (51 μ L, 0.6mmol,1.2eq) was added followed by a drop of anhydrous DMF under ice water bath, the reaction solution was stirred at room temperature for 1.5h, the solvent was spun dry to give the acid chloride, dissolved in anhydrous DCM at home, compound 2(132mg,0.5mmol,1eq) and TEA (83 μ L, 0.6mmol,1.2eq) were added and stirred at room temperature for 2h to essentially complete the reaction, and the spun dry solvent was purified directly by silica gel column chromatography [ PE: EA 2:1to 1:1] to give a white solid 6c-6 e.
(6c) White solid (yield):77％).1H NMR(400MHz,CDCl3)8.65(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).13C NMR(100MHz,CDCl3)169.6,166.6,152.8,150.4,144.4,138.8,137.1,135.1,130.8,124.8,124.7,121.8,120.7,81.2,67.1,63.5,60.2,42.9,36.8,26.0,24.6,24.1,18.2 HRMS (ESI) calculated value C23H26NO5[M+H]+396.1805, Experimental value 396.1800.
(6d) White solid (yield: 71%).1H NMR(400MHz,CDCl3)8.69(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).13C NMR(100MHz,CDCl3)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 C23H26NO5[M+H]+396.1805, Experimental value 396.1802.
(6e) White solid (yield: 67%).1H NMR(400MHz,CDCl3)8.63(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).13C NMR(100MHz,CDCl3)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 C23H26NO5[M+H]+396.1805, Experimental value 396.1802.
Synthesis of Compounds 6a-6b, 6 f-6 g and 7a-7m
Reaction step preparation of Compound 3
(6a) White solid (yield: 82%).1H NMR(400MHz,CDCl3)7.48(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).13C NMR(100MHz,CDCl3)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 C22H28NO6[M+NH4]+402.1911, Experimental value 402.1910.
(6b) White solid (yield: 95%).1H NMR(400MHz,CDCl3)7.76(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).13C NMR(100MHz,CDCl3)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 C22H28NO5S[M+NH4]+418.1683, Experimental value 418.1678.
(6f) White solid (yield: 93%).1H NMR(400MHz,CDCl3)7.95–7.81(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).13C NMR(100MHz,CDCl3)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 C28H32NO5[M+NH4]+462.2275, Experimental value 462.2283.
(6g) White solid (yield: 94%).1H NMR(400MHz,CDCl3)7.58(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).13CNMR(100MHz,CDCl3)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 value C25H30NO7[M+NH4]+456.2017, Experimental value 456.2022.
(7a) White solid (yield: 89%).1H NMR(400MHz,CDCl3)7.99(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).13C NMR(100MHz,CDCl3)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 C26H34NO7[M+NH4]+472.2330, Experimental value 472.2332.
(7b) White solid (yield: 94%).1H NMR(400MHz,CDCl3)7.90(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).13C NMR (100MHz, CDCl3)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) calcd for C26H31O7[M+H]+455.2064, Experimental value 455.2061.
(7c) White solid (yield: 83%).1H NMR(400MHz,CDCl3)7.95(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).13C NMR(100MHz,CDCl3)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 C26H34NO7[M+NH4]+472.2330, Experimental value 472.2328.
(7d) White solid (yield: 84%).1H NMR(400MHz,CDCl3)8.14(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).13C NMR(100MHz,CDCl3)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 C26H34NO7[M+NH4]+472.2330, Experimental value 472.2329.
(7e) White solid (yield: 56%).1H NMR(400MHz,CDCl3)7.61(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).13C NMR(100MHz,CDCl3)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 C26H34NO7[M+NH4]+472.2330, Experimental value 472.2333.
(7f) White solid (yield: 73%).1H NMR(400MHz,CDCl3)7.57(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).13CNMR(100MHz,CDCl3)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 C26H34NO7[M+NH4]+472.2330, Experimental value 472.2328.
(7g) White solid (yield: 92%).1H NMR(400MHz,CDCl3)7.85(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).13C NMR(100MHz,CDCl3)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 C27H36NO8[M+NH4]+502.2435, Experimental value 502.2444.
(7h) White solid (yield: 84%).1H NMR(400MHz,CDCl3)7.91(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).13C NMR(100MHz,CDCl3)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 C27H36NO8[M+NH4]+502.2435, Experimental value 502.2442.
(7i) White solid (yield: 77%);1H NMR(400MHz,CDCl3)8.09(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).13C NMR(100MHz,CDCl3)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 value C27H36NO8[M+NH4]+502.2435, Experimental value 502.2444.
(7j) White solid (yield: 73%).1H NMR(400MHz,CDCl3)7.53(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).13C NMR(100MHz,CDCl3)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 C27H36NO8[M+NH4]+502.2435, Experimental value 502.2445.
(7k) White solid (yield: 97%).1H NMR(400MHz,CDCl3)7.77(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).13C NMR(100MHz,CDCl3)169.3,166.4,161.6(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),80.9,67.1,63.2,59.9,42.6,36.5,25.8,24.5,23.8,17.9.19F NMR(376MHz,CDCl3) Calculated values C of-109.9-110.1 (m) HRMS (ESI)24H28F2NO5[M+NH4]+448.1930, Experimental value 448.1929.
(7l) white solid (yield: 91%).1H NMR(400MHz,CDCl3)7.72(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).13C NMR(100MHz,CDCl3)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 C24H28Cl2NO5[M+NH4]+480.1339, Experimental value 480.1338.
(7m) white solid (yield: 87%).1H NMR(400MHz,CDCl3)7.68(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).13C NMR(100MHz,CDCl3)169.3,165.5,143.1,138.6,135.2,134.7,132.5,131.1,130.6,126.1,123.7,120.4,80.9,67.2,63.2,59.9,42.7,36.5,25.8,24.6,23.8,18.0 HRMS (ESI) calculated value C24H28Br2NO5[M+NH4]+570.0308, Experimental value 570.0300.
Synthesis of Compounds 10a-10 h:
adding compound 8a (610mg,3.67mmol,1eq) and phenylacetic acid (3.67mmol,1eq) with different substituents into a 50m L reaction flask, heating and refluxing for 4-9 h, after the reaction is basically finished, cooling the reaction solution to room temperature, adjusting the pH to 2-3 with 35% hydrochloric acid aqueous solution, filtering to obtain a filter cake, (PE: EA ═ 10:1) washing the filter cake, dissolving the filter cake with 1N NaOH, acidifying again, filtering to obtain a filter cake, drying to obtain compound 9a-9h, and directly feeding the next step, adding compound 2(53mg,0.2mmol,1eq), EDCI (115mg,0.6mmol,2eq), DMAP (1.2mg,0.01mmol,0.05eq) and Et obtained in the previous step into the reaction flask in turn, adding DCM (2 m) to dissolve in water bath, and adding DCM) to dissolve in water bath under ice-cold condition3N (83.4 mu L, 0.6mmol,2 eq.) the reaction solution is stirred at room temperature overnight, the reaction solution is spotted on a plate, saturated sodium bicarbonate solution is added after the basic reaction is finished to quench the reaction, dichloromethane is used for extraction for three times, organic phases are combined, saturated common salt solution is used for washing, anhydrous sodium sulfate is used for drying, filtering and concentrating, and the oily substance is used for silica gel column chromatography to obtain the compound 10a-10 h.
(10a) White solid (yield: 86%);1H NMR(400MHz,CDCl3)8.16(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).13C NMR(100MHz,CDCl3)169.3167.4,152.8,152.4,138.8,136.0,135.3,134.8,131.6,130.7,129.7,128.6,127.7,123.3,120.0,117.6,114.1,111.8,80.7,67.2,63.1,59.9,56.0,55.0,42.6,36.5,25.7,24.9,23.7,17.9 HRMS (ESI) calcd for C32H38NO7[M+NH4]+548.2643, Experimental value 548.2642.
(10b) White solid (yield: 65%)1H NMR(400MHz,CDCl3)8.20(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).13C NMR(100MHz,CDCl3)169.26,166.69,152.79,152.50,140.01,138.64,136.95,133.90,131.85(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),114.08,111.95,111.50,80.83,67.40,63.22,59.94,55.99,54.95,42.69,36.56,25.68,24.73,23.78,17.97.19F NMR(376MHz,CDCl3) Calculated value C of 62.6(s) HRMS (ESI)33H33F3NaO7[M+Na]+621.2071, Experimental value 621.2073.
(10c) White solid (yield: 70%).1H NMR(400MHz,CDCl3)8.14(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).13C NMR(100MHz,CDCl3)169.3,167.2,162.2(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),114.4,111.8,80.8,67.3,63.2,59.9,56.0,55.1,42.7,36.6,25.7,24.8,23.8,17.9.19F NMR(376MHz,CDCl3) -113.8 (dq, J ═ 8.7,5.5Hz). hrms (esi) calculated value C32H37FNO7[M+NH4]+566.2549, Experimental value 566.2548.
(10d) White solid (yield: 77%).1H NMR(400MHz,CDCl3)8.14(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).13C NMR(100MHz,CDCl3)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 C32H37ClNO7[M+NH4]+582.2253, Experimental value 582.2246.
(10e) White solid (yield: 84%);1H NMR(400MHz,CDCl3)8.14(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).13C NMR(100MHz,CDCl3)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 C32H37BrNO7[M+NH4]+626.1748, Experimental value 626.1749.
(10f) White solid (yield: 93%).1H NMR(400MHz,CDCl3)8.12(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).13C NMR(100MHz,CDCl3)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 C33H40NO7[M+NH4]+562.2799, Experimental value 562.2797.
(10g) White solid (yield: 83%).1H NMR(400MHz,CDCl3)8.10(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).13C NMR(100MHz,CDCl3)169.3,167.7,159.1,152.7,152.4,138.8,135.1,134.9,131.3,131.0,131.0,127.9,123.7,120.1,117.2,114.3,114.0,111.8,80.7,67.3,63.1,59.9,56.0,55.2,55.1,42.6,36.6,25.8,25.1,23.7,18.0 HRMS (ESI) calculated value C33H40NO8[M+NH4]+578.2748, Experimental value 578.2742.
(10h) White solid (yield: 84%).1H NMR(400MHz,CDCl3)8.09(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).13C NMR(100MHz,CDCl3)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 C34H38NaO8[M+Na]+597.2459, Experimental value 597.2462.
(10i) White solid (yield: 90%).1H NMR(400MHz,CDCl3)8.13(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).13C NMR(100MHz,CDCl3)169.2,167.3,152.7,152.4,138.7,138.3,135.5,134.7,132.3,131.0,130.8,130.2,126.3,123.3,120.1,117.4,114.1,111.7,80.7,67.2,63.0,59.8,56.0,55.0,42.5,36.5,25.6,24.9,23.7,17.9,15.4 HRMS (ESI) calculated value C33H40NO7S[M+NH4]+594.2520, Experimental value 594.2516.
Synthesis of Compounds 12a-12 c:
adding aldehyde 8a (498mg,3.0mmol,1eq) and malonic acid (6.0mmol,2eq) with different substituents into a 100m L reaction bottle to dissolve the aldehyde 8a and pyridine (30m L) and piperidine (0.5m L), heating and refluxing the reaction liquid for 8h, cooling to room temperature after the reaction is basically finished, adding the cooled reaction liquid into hydrochloric acid in a 6N ice water bath to separate out yellow solid, filtering, collecting a filter cake, drying in vacuum to obtain compounds 11a-11c, directly adding the compounds 2(53mg,0.2mmol,1eq), EDCI (115mg,0.6mmol,2eq), DMAP (1.2mg,0.01mmol,0.05eq) and acids 11a-11c (0.3mmol,1.5eq), adding anhydrous DCM (2m L), dissolving the triethylamine (83.4 mu L, 0.6 eq, 2eq) in ice, adding saturated sodium bicarbonate solution, filtering, drying the reaction liquid after the saturated sodium bicarbonate solution is added, filtering, adding saturated sodium bicarbonate solution, and concentrating the reaction liquid after the saturated sodium bicarbonate solution is added with saturated sodium bicarbonate solution and the saturated sodium bicarbonate solution is added.
(12a) White solid (yield: 95%).1H NMR(400MHz,CDCl3)7.77(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).13C NMR(100MHz,CDCl3)169.2,168.0,152.8,151.8,138.6,135.0,135.0,130.4,128.0,125.0,120.2,115.9,114.4,111.3,80.8,66.9,63.1,59.9,55.8,55.6,42.6,36.5,25.7,24.6,23.7,17.9,14.1 HRMS (MA L DI) calcd for C27H32NaO7[M+Na]+491.2040, Experimental value 491.2045.
(12b) White solid (yield: 73%).1H NMR(400MHz,CDCl3)7.75(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).13C NMR(100MHz,CDCl3)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 (MA L DI) calcd for C28H34NaO7[M+Na]+505.2197, Experimental value 505.2198.
(12c) White solid (yield: 54%).1H NMR(400MHz,CDCl3)7.76(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).13C NMR(100MHz,CDCl3)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 C29H36NaO7[M+Na]+519.2353, Experimental value 519.2358.
Synthesis of compound 14:
preparation method is used for preparing compound 12 a. (yield 83%).1H NMR(400MHz,CDCl3)8.73(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).13C NMR(100MHz,CDCl3)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 C27H29NNaO7[M+Na]+5052.1836, Experimental value 5052.1840.
Synthesis of compound 15:
compound 2(400mg,1.51mmol) is added to a reaction flask, dissolved in EtOH (12m L), and NaBH is added in portions in an ice-water bath4(63mg,1.67mmol), discharging the reaction gas, stirring the reaction solution in an ice water bath for 4 hours to basically finish the reaction, adding a saturated ammonium chloride solution to quench the reaction, extracting by EA for three times, combining organic phases, washing by saturated salt solution for three times, drying by anhydrous sodium sulfate, filtering, concentrating to obtain an oily substance, and purifying by silica gel column chromatography to obtain 15t (311mg, 77 percent of yield) of a white solid compound.1H NMR(400MHz,CDCl3)5.62(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).13C NMR(100MHz,CDCl3)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 C15H22NaO4[M+Na]+289.1410, Experimental value 289.1413.
Synthesis of compound 16:
compound 2(82.6mg,0.31mmol), EDCI (89.9mg,0.47mmol), DMAP (3.8mg,0.03mmol) and 2, 6-dimethoxybenzoic acid (85.5mg,0.47mmol) were added to a reaction flask in this order, anhydrous DCM2m L was added to dissolve, triethylamine (65u L, 0.47mmol) was added under zero degree stirring, the reaction was stirred at room temperature overnight, the reaction was quenched with saturated sodium bicarbonate after the reaction was almost complete, dichloromethane was extracted three times, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography to give compound 16(71mg, 83%) as a white solid.1H NMR(400MHz,CDCl3)7.29(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).13C NMR(100MHz,CDCl3)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 C24H28NaO7[M+Na]+451.1727, Experimental value 451.1732.
Synthesis of Compounds 17a-17 b:
method for producing Compound 11a
(17a) White solid (yield: 67%).1H NMR(400MHz,DMSO-d6)12.34(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).13C NMR (100MHz, DMSO-d6)167.9,153.2,152.1,138.4,123.0,119.6,117.5,113.0,112.6,56.1,55.6.HRMS (ESI) calcd C11H11O4[M–H]–207.0663, Experimental value 207.0660.
(17b) White solid (yield: 57%).1H NMR(400MHz,DMSO-d6)12.17(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).13C NMR (100MHz, DMSO-d6)168.9,159.54134.7,131.9,120.9,110.9,104.1, 56.0 HRMS (ESI) calcd for C11H12NaO4[M+Na]+231.0628, Experimental value 231.0631.
Synthesis of Compounds 19a-19 b:
dissolving compound 17a or 17b (320mg,1.54mmol) in 15m L anhydrous DCM, adding oxalyl chloride at 3.0m L75 deg.C under reflux for 2h, removing excess oxalyl chloride to obtain acid chloride, dissolving in 10m L anhydrous DCM, adding 10ml methanol, reacting for 1h, and purifying the solvent by silica gel column chromatography to obtain compounds 19a-19b
(19a) White solid (yield: 75%)1H NMR(400MHz,CDCl3)7.97(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).13C NMR(100MHz,CDCl3)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 C12H15O4[M+H]+223.0965, Experimental value 223.0966.
(19b) White solid (yield: 81%)1H NMR(400MHz,CDCl3)8.14(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).13C NMR(100MHz,CDCl3)169.2,160.2,135.8,131.4,120.4,112.3,103.8,55.9,51.6 HRMS (ESI) calcd for C12H14NaO4[M+Na]+245.0784, Experimental value 245.0788.
Synthesis of Compounds 20a-20 b:
compound 15(53mg,0.2mmol), EDCI (115.0mg,0.6mmol), DMAP (1.2mg,0.01mmol) and 17a or 17b (63mg,0.15mmol) are added in sequence to a reaction flask, anhydrous DCM (2m L) is added to dissolve in an ice-water bath, TEA (83. mu. L, 0.6mmol) is added to the reaction solution under stirring overnight at room temperature, the reaction is quenched with saturated sodium bicarbonate solution after the reaction is almost completed, dichloromethane is extracted three times, anhydrous sodium sulfate is dried, filtered, concentrated and purified by silica gel column chromatography to obtain solid 20a-20 b.
(20a) White solid (yield: 77%).1H NMR(400MHz,CDCl3)7.96(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).13C NMR(100MHz,CDCl3)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 value C26H32NaO7[M+Na]+479.2040, Experimental value 479.2046.
(20b) White solid (yield: 84%)1H NMR(400MHz,CDCl3)8.16(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).13C NMR(100MHz,CDCl3)178.0,168.3,160.2,136.4,135.6,131.7,130.0,119.7,111.9,103.7,81.2,66.2,63.5,59.9,55.8,46.3,41.6,36.9,26.9,24.8,23.8,18.0,13.1HRMS (ESI) calculated value C26H32NaO7[M+Na]+479.2040, experimental value 479.2045.
Synthesis of Compounds 21a-21 b:
adding acid (400mg,1.92mmol) and 10% Pd/C into a reaction bottle, adding methanol (20m L) for dissolution, replacing argon for three times and replacing hydrogen for three times, stirring the mixture at room temperature overnight to basically complete the reaction, performing short silica gel column chromatography on the mixture to obtain acid 18a-18b, directly feeding the acid 18a-18b into the reaction bottle, sequentially adding acid 18a or 18b (167mg,0.79mmol), compound 2(140mg,0.53mmol), EDCI (153mg,0.79mmol) and DMAP (0.6mg,0.053mmol), adding 5m L of anhydrous DCM for dissolution, adding triethylamine (110 mu L, 0.79mmol) under ice water bath, stirring at room temperature overnight to basically complete the reaction, adding saturated sodium bicarbonate solution for quenching reaction, extracting dichloromethane for three times, drying anhydrous sodium sulfate, filtering, concentrating, and performing silica gel column chromatography to obtain solid 21a-21 b.
(21a) White solid (yield: 85%).1H NMR(400MHz,CDCl3)6.78–6.66(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).13C NMR(100MHz,CDCl3)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) calcd for C26H36NO7[M+NH4]+474.2486, Experimental value 474.2484.
(21b) White solid (yield: 83%).1H NMR(400MHz,CDCl3)7.13(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).13C NMR(100MHz,CDCl3)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 C26H32NaO7[M+Na]+479.2040, Experimental value 479.2045.
Synthesis of compound 23:
compound 2(1.1g,4.16mmol) was added to a reaction flask in an ice-water bath and 2N dimethylamine tetrahydrofuran solution (20.8m L) was added, the reaction stirred for 1h in an ice-water bath, the solvent was spun off after disappearance of starting material and purified directly by silica gel column chromatography (DCM: MeOH ═ 50:1) to give compound 22(1.2, 93%) as a white solid,1H NMR(400MHz,CDCl3)5.58(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).13C NMR(100MHz,CDCl3)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 value C17H28N2O4[M+H]+310.2013, Experimental value 310.2015.
Compound 17b (712mg,3.42mmol), compound 22(705mg,2.28mmol), EDCI (655.6mg,3.42mmol) and DMAP (27.8mg,0.228mmol) were added sequentially to a reaction flask, and 25m L anhydrous CH was added2Cl2Dissolving in ice water bath, adding Et3N (0.45m L, 3.42 mmol). reaction solution was stirred at room temperature overnight, quenched with saturated sodium bicarbonate solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated and chromatographed on silica gel column [ DCM: MeOH 50: 1]]Purification yielded compound 23 as a white solid (987.2mg, 86%).1H NMR(400MHz,CDCl3)8.16(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).13CNMR(100MHz,CDCl3)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 C28H38NO7[M+H]+500.2643, Experimental value 500.2644.
Synthesis of compound 24:
compound 23(1.15g,2.3mmol) was dissolved in 23m L methanol and fumaric acid (267mg,2.3mmol) was added in portions and the reaction solution was stirred at room temperature for 6.5 h.1HNMR(400MHz,DMSO-d6)12.95(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).13C NMR (100MHz, DMSO)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 C28H38NO7[M+H]+500.2643, Experimental value 500.2645.
Example 2: pharmacological action of sesquiterpene lactone-cinnamic acid derivative or its salt
Various cancer cells were assigned 2 × 105Adding cell suspension of/m L into 24-well round-bottom cell culture plate, adding sesquiterpene lactone-cinnamic acid derivative or its salt at each concentration of 5 wells, standing at 37 deg.C and 5% CO2Culturing for 18 hours under the condition of saturated humidity, measuring the absorbance (A) value by an MTT method at the wavelength of 570nm of an enzyme-linked detector,the inhibitory effect of the compounds of the present invention on the test cancer cells was calculated.
TABLE 1 inhibitory Activity of sesquiterpene lactone-cinnamic acid derivatives on breast cancer cell line MDA-MB-231 (IC)50，μM)
Figure BDA0001949486420000341
Figure BDA0001949486420000342
Figure BDA0001949486420000351
Wherein the MDA-MB-231 is a human breast cancer cell line.
TABLE 2 inhibitory Activity of sesquiterpene lactone-cinnamic acid derivatives on breast cancer cell line MDA-MB-231 (IC)50，μM)
Figure BDA0001949486420000352
Figure BDA0001949486420000353
Figure BDA0001949486420000361
TABLE 3 inhibitory Activity of sesquiterpene lactone-cinnamic acid derivatives on breast cancer cell line MDA-MB-231 (IC)50，μM)
Figure BDA0001949486420000362
Figure BDA0001949486420000363
Figure BDA0001949486420000371
TABLE 4 inhibitory Activity of sesquiterpene lactone-cinnamic acid derivatives on breast cancer cell line MDA-MB-231 (IC)50，μM)
Figure BDA0001949486420000372
Figure BDA0001949486420000373
TABLE 5 inhibitory Activity of sesquiterpene lactone-cinnamic acid derivatives on breast cancer cell line MDA-MB-231 (IC)50，μM)
Figure BDA0001949486420000374
Figure BDA0001949486420000381
The results of the activity test show that the screened compounds show inhibitory activity against the test cells. The test compounds therefore have utility for the treatment of cancer.
The compounds, uses and methods of the invention have been described by specific examples. The invention can be used for other purposes by those skilled in the art by appropriately changing the raw materials, the process conditions and the like without departing from the content of the invention, and all similar substitutes and modifications obvious to those skilled in the art are deemed to be included in the scope of the invention.

Claims (4)

1. Sesquiterpene lactone-cinnamic acid derivatives of formula (I) and their salts,
Figure FDA0001949486410000011
wherein, P is the following structure:
Figure FDA0001949486410000012
R1、hydrogen, alkyl, alkylaryl, cyano; r2Phenyl, substituted phenyl, furyl, thienyl, pyridyl, naphthyl, methylenedioxyphenyl; when R is3When it is a hydrogen atom, R4The amino group is hydrogen atom or one or more substituent groups, and the substituent groups comprise methyl, ethyl and propyl chain substituent groups and can also be cyclic substituent groups such as cyclopentyl and cyclohexyl; when R is3，R4Is a single bond.
Pharmaceutically acceptable salts thereof with inorganic or organic acids, including quaternary ammonium salts with compounds of formula (i), including hydrofluoric, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, nitric, phosphorous, sulfurous, carbonic, boric, phosphomolybdic, selenious, methanesulfonic, substituted methanesulfonic, phenylsulfonic, substituted phenylsulfonic, fumaric, citric, maleic, tartaric, oxalic, D-malic, L-malic, D L-malic, L-lactic, D L-lactic, formic, substituted formic, acetic, propionic, butyric, valeric, oleic, lauric, p-toluenesulfonic, 1-naphthalenesulfonic, 2-naphthalenesulfonic, phthalic, malonic, succinic, glycolic, thiolanic, glycine, sarcosine, sulfonic, nicotinic, picolinic, isonicotinic, dichloroacetic, benzoic, substituted benzoic.
2. The compound of claim 1, wherein the compound is 3-24
Figure FDA0001949486410000021
Figure FDA0001949486410000031
Figure FDA0001949486410000041
Figure FDA0001949486410000051
Figure FDA0001949486410000061
Figure FDA0001949486410000071
3. The invention also provides the use of a compound of formulae 3-24 in the manufacture of a medicament for the treatment of cancer, wherein the cancer is breast cancer.
4. The invention also provides the use of a compound of formulae 3-24 in the manufacture of an adjuvant medicament for the treatment of cancer, wherein the cancer is breast cancer.
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CN112047953A (en) * 2019-06-06 2020-12-08 天津尚德药缘科技股份有限公司 Parthenolide-benzenesulfonyl furazan derivative and salt thereof, preparation method and application
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