CN112691099B - Application of organic compound in preparation of medicine for treating colon cancer - Google Patents
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Abstract
The invention discloses an application of an organic compound in preparing a medicament for treating colon cancer, wherein the organic compound is represented by R 1 Radical, R radicalGroup and R 2 The groups are connected in sequence to form the compound, and the molecular structural general formula of the compound is shown as formula 1: formula 1; wherein R is 1 The radical structural formula is 2, R 3 Selected from-H, -OAc, -OH, halo, -F 3 Any one of CO or a benzenesulfonyloxy group-containing group, R 4 Any one selected from-H, -OAc or-OH; r 2 The radicals being selected from alkyl or the formula 3, R 5 Selected from C or N, R 6 Selected from any one of hydrogen, alkyl, halogen or trifluoromethyl, R 7 Selected from any one of hydrogen, halogen, cyano, nitro or trifluoromethoxy, R 8 Selected from hydrogen or halo. The invention also provides a pharmaceutical composition containing the organic compound as an active ingredient. The organic compound provided by the invention has a colon cancer cell inhibition rate of 0.27-0.8 mu m.
Description
The technical field is as follows:
the invention relates to the technical field of medicaments for treating colon cancer, in particular to application of an organic compound in preparing a medicament for treating colon cancer.
Background art:
colon cancer is one of the common cancers in the world at present, the early symptoms are not obvious, and the late symptoms show general symptoms such as anemia, weight loss and the like. The incidence and mortality of the disease are high. By far, the most common clinical diagnosis is colonoscopy. However, the misdiagnosis rate of rectal cancer is 30% according to statistics. The treatment methods for rectal cancer are surgery and radiotherapy. However, surgical radiation therapy is performed with recurrence, metastasis and great pain. Therefore, the development of more effective diagnostics and minimally invasive treatments is not always feasible.
At present, various combination therapies, such as chemotherapy/photothermal therapy (CT/PTT), photothermal/photodynamic therapy (PTT/PDT) and photothermal/chemodynamic therapy (PTT/CDT), etc., have been widely used in the research of cancer treatment, but have defects, such as that PTT not only kills tumor tissues but also harms surrounding normal tissue cells, and sometimes is accompanied by a series of inflammation problems after treatment; PDT is limited by hypoxia of tumor cells; CT often presents problems of recurrence and metastasis after treatment.
The invention content is as follows:
the invention aims to provide application of an organic compound in preparing a medicament for treating colon cancer.
The invention provides an organic compound represented by the general formula R 1 Group, R group and R 2 The groups are connected in sequence to form the compound, and the molecular structural general formula of the compound is shown as formula 1:
R 1 the structural formula of the radical is
R 3 Selected from-H, -OAc, -OH, halo, -F 3 CO or containing benzene sulfonic acid
Any of the radicals of acyloxy, R 4 Any one selected from-H, -OAc or-OH; r is a group
R 2 The radicals being selected from alkyl or
R 5 Selected from C or N, R 6 Selected from hydrogen, alkyl, halo or tri
Any one of fluoromethyl, R 7 Selected from any one of hydrogen, halogen, cyano, nitro or trifluoromethoxy, R 8 Selected from hydrogen or halo.
In one embodiment according to the present invention, when R in said formula 2 4 When not-H, R 3 Selected from-OAc, -OH, halo, -F 3 CO or phenylsulfonyloxy.
In one embodiment according to the present invention, in said formula 3, when R is 5 When is N, R 5 Selected from the group consisting of 6 And R 7 Selected from-H or alkyl.
In one embodiment according to the invention, R 1 Selected from the structural formulas
In one embodiment according to the invention, said R 2 Selected from the structural formulas
-OH、
Any one of the substituent groups.
In one embodiment according to the invention, the organic compound is selected from (E) -4- (3- (3-cyanophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester, (E) -4- (3-oxo-3- (p-tolyloxy) prop-1-en-1-yl) -1, 2-phenylenediacetic acid ester, (E) -4- (3- (4-isopropylphenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester, (E) -4- (3- (3-fluorophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester, (E) -3-fluorophenyl 3- (4-acetoxyphenyl) acrylate, (E) -4- (trifluoromethyl) phenyl 3- (4-acetoxyphenyl) acrylate, (E) -3,4-difluorophenyl 3- (4-acetoxyphenyl) acrylate, (E) -4-fluorophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate, (E) -4-methylbenzyl 3- (4- (trifluoromethoxy) phenyl) acrylate, (E) -4- (trifluoromethyl) phenyl 3- (4-hydroxyphenyl) acrylate, and mixtures thereof, (E) -3-cyanophenyl 3- (3,4-dihydroxyphenyl) acrylate, (E) -4-methylbenzyl 3- (3,4-dihydroxyphenyl) acrylate, (E) -3,4-difluorophenyl 3- (4- (toluenesulfonyloxy) phenyl) acrylate or (E) -3-fluorophenyl 3- (4-hydroxyphenyl) acrylate.
In one embodiment according to the present invention, the organic compound is any one selected from the group consisting of (E) -3-fluorophenyl 3- (4-acetoxyphenyl) acrylate, (E) -3,4-difluorophenyl 3- (4-acetoxyphenyl) acrylate, (E) -3-cyanophenyl 3- (3,4-dihydroxyphenyl) acrylate, (E) -4-fluorophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate, (E) -3,4-difluorophenyl 3- (4- (toluenesulfonyloxy) phenyl) acrylate, and (E) -4- (trifluoromethyl) phenyl 3- (4-hydroxyphenyl) acrylate.
The present invention further provides a pharmaceutical composition for the treatment of colon cancer, the active ingredient of which comprises a dose of an organic compound.
In one embodiment according to the present invention, the organic compound is any one selected from the group consisting of (E) -3-fluorophenyl 3- (4-acetoxyphenyl) acrylate, (E) -3,4-difluorophenyl 3- (4-acetoxyphenyl) acrylate, (E) -3-cyanophenyl 3- (3,4-dihydroxyphenyl) acrylate, (E) -4-fluorophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate, (E) -3,4-difluorophenyl 3- (4- (toluenesulfonyloxy) phenyl) acrylate, and (E) -4- (trifluoromethyl) phenyl 3- (4-hydroxyphenyl) acrylate.
In one embodiment according to the present invention, the IC of the organic compound 50 Is 0.25-0.8 μm.
The invention has the beneficial effects that:
the organic compound is used for treating colon cancer for the first time, experiments prove that the organic compound has obvious effect on colon cancer, and part of the organic compound has IC on colon cancer cells 50 Reaching 0.2-0.8 μm.
The specific implementation mode is as follows:
the following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more readily understand the advantages and features of the present invention and to clearly define the scope of the invention.
EXAMPLE 13 Synthesis of- (trifluoromethoxy) phenylcinnamate
3- (trifluoromethoxy) phenyl cinnamate (3- (trifluoromethyl) cinnamate) having the following chemical formula:
product(s) 1 H NMR(500MHz,CDCl 3 )δ7.87(d,J＝16.0Hz,1H),7.60–7.58(m,2H),7.47–7.39(m,3H),7.25(d, J＝2.5Hz,2H),7.22–7.16(m,2H),6.61(d,J＝16.0Hz,1H). 13 C NMR(101MHz,MeOD)δ164.32,161.04, 152.35,147.93,135.22,130.15,129.76,127.94,128.76,128.64,128.57,128.45,115.56,113.93,111.15,107.75. [M+H] + ＝309.0733.
The synthetic route is as follows:
cinnamic acid (200mg, 1.5mmol), p-trifluoromethoxyphenol (160.3mg, 0.9mmol), EDCI (345mg,1.8mmol), DMAP (5.5mg,0.045mmol) were weighed out at room temperature and dissolved in 6mL dichloromethane, triethylamine (0.25mL,1.8mmol) was added with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 92% yield.
EXAMPLE 2 Synthesis of (E) -4- (3- (3-cyanophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic ester
(E) -4- (3- (3-cyanophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E)-4-(3-(3-cyanophenoxy)-3-oxoprop-1-en-1-yl)-1,2-phenylene diacetate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.83(d,J＝16.0Hz,1H),7.62–7.50(m,3H),7.50–7.41(m,3H),7.30– 7.27(m,1H),6.56(d,J＝16.0Hz,1H),2.32(d,J＝3.6Hz,6H). 13 C NMR(101MHz,MeOD)δ169.14,169.03, 164.33,152.06,147.92,143.27,142.54,131.27,129.83,129.02,126.45,125.97,125.23,123.87,122.99,118.62, 115.54,113.25,20.39,20.32.[M+H] + ＝366.0973.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution at 0 ℃ and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate is concentrated
After the condensation, the concentrate (300mg, 1.06mmol), m-cyanophenol (83mg, 0.7mmol), EDCI (268mg, 1.4mmol) and DMAP (4.3mg, 0.035mmol) were weighed out and dissolved in 6mL of dichloromethane, and triethylamine (0.19mL, 1.4mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 80% yield.
EXAMPLE 3 Synthesis of (E) -4- (3- (3-Nitrophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E) -4- (3- (3-nitrophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E)-4-(3-(3-nitrophenoxy)-3-oxoprop-1-en-1-yl)-1,2-phenylene diacetate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ8.15–8.13(m,1H),8.09(t,J＝2.1Hz,1H),7.85(d,J＝16.0Hz,1H),7.60 (t,J＝8.1Hz,1H),7.55–7.53(m,1H),7.51–7.43(m,2H),7.29(d,J＝8.3Hz,1H),6.58(d,J＝16.0Hz,1H),2.33 (d,J＝4.0Hz,6H). 13 C NMR(101MHz,MeOD)δ169.14,169.03,164.35,152.23,148.37,147.95,143.27,142.52, 131.25,130.06,127.71,126.48,123.85,122.99,120.74,117.22,115.58,20.39,20.32.[M+H] + ＝386.0870.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution at 0 ℃ and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. Concentrating the filtrate, and weighing concentrate (300mg, 1.06mmol), m-nitrophenol (97mg, 0.7mmol), EDCI (268mg, 1.4mmol),
DMAP (4.3mg, 0.035mmol) was dissolved in 6mL of dichloromethane, triethylamine (0.19mL, 1.4mmol) was added with stirring, and the mixture was stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. Concentrating the filtrate, and separating by column chromatographyPurification by ionization with EtOAc, eluent, petroleum ether 1:15, afforded the compound as a white powder in 81% yield.
Example 4(E) -4- (3- ((4-methylbenzyl) oxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E) -4- (3- ((4-methylbenzyl) oxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E)-4-(3-((4-methylbenzyl)oxy)-3-oxoprop-1-en-1-yl)-1,2-phenylene diacetate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.64(d,J＝16.0Hz,1H),7.39(dd,J＝8.4,2.0Hz,1H),7.34(d,J＝1.9Hz, 1H),7.30(d,J＝7.9Hz,2H),7.20(dd,J＝9.5,8.4Hz,3H),6.41(d,J＝16.0Hz,1H),5.20(s,2H),2.36(s,3H),2.30 (d,J＝2.7Hz,6H).
13 C NMR(101MHz,MeOD)δ169.14,169.03,166.57,143.63,143.25,142.52,137.36,133.17,131.22,129.35, 129.27,127.01,127.12,126.47,123.84,122.98,118.02,65.98,21.36,20.34.[M+H] + ＝369.1335.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution at 0 ℃ and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. After the filtrate was concentrated, the concentrate (300mg, 1.06mmol), 4-methylbenzyl alcohol (85.5mg, 0.7mmol), EDCI (268mg, 1.4mmol), and DMAP (4.3mg, 0.035mmol) were weighed out and dissolved in 6mL of a dichloromethane solution, and triethylamine (0.19mL, 1.4mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the combined organic phases were washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 81% yield.
EXAMPLE 5 Synthesis of (E) -4- (3-oxo-3- (p-tolyloxy) prop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E) -4- (3-oxo-3- (p-tolyloxy) prop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E)-4-(3-oxo-3-(p-tolyloxy)prop-1-en-1-yl)-1,2-phenylene diacetate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.79(d,J＝16.0Hz,1H),7.46(dd,J＝8.4,1.6Hz,1H),7.42(d,J＝1.5Hz, 1H),7.28–7.23(m,1H),7.20(d,J＝8.2Hz,2H),7.05(d,J＝8.3Hz,2H),6.57(d,J＝16.0Hz,1H),2.36(s,3H), 2.31(d,J＝4.1Hz,6H).
13 C NMR(101MHz,MeOD)δ169.14,169.03,164.35,148.32,147.97,143.22,142.57,135.24,131.24,129.43, 129.26,126.43,123.88,122.95,121.56,121.39,115.54,21.37,20.39,20.32.[M+H] + ＝355.1176.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution at 0 ℃ and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. After concentrating the filtrate, the concentrate (300 mg) was weighed1.06mmol), 4-methylphenol (76mg, 0.7mmol), EDCI (268mg, 1.4mmol), DMAP (4.3mg, 0.035mmol) were dissolved in 6mL of a dichloromethane solution, and triethylamine (0.19mL, 1.4mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 81% yield.
Example 6 Synthesis of (E) -4- (3- (4-isopropylphenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetate
(E) -4- (3- (4-isopropylphenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E)-4-(3-(4-isopropylphenoxy)-3-oxoprop-1-en-1-yl)-1,2-phenylene diacetate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.79(d,J＝16.0Hz,1H),7.46(d,J＝8.4Hz,1H),7.42(s,1H),7.26(s,1H), 7.25(d,J＝2.3Hz,2H),7.08(d,J＝8.4Hz,2H),6.57(d,J＝16.0Hz,1H),2.95–2.90(m,1H),2.32(d,J＝3.7Hz, 6H),1.26(d,J＝6.9Hz,6H). 13 C NMR(101MHz,MeOD)δ169.14,169.03,164.35,148.58,147.93,145.24,143.27, 142.58,131.23,126.55,126.49,126.41,123.88,122.95,121.33,115.55,33.28,23.34,23.25,20.37,20.28.
[M+H] + ＝383.1490.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution at 0 ℃ and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Make ice cubesThe reaction mixture was placed in a reaction system, adjusted to pH 2 with 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. After the filtrate was concentrated, the concentrate (300mg, 1.06mmol), 4-isopropylphenol (95mg, 0.7mmol), EDCI (268mg, 1.4mmol) and DMAP (4.3mg, 0.035mmol) were weighed out and dissolved in 6mL of dichloromethane, and triethylamine (0.19mL, 1.4mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 83% yield.
Example 7(E) -4- (3- (3-fluorophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E) -4- (3- (3-fluorophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E)-4-(3-(3-fluorophenoxy)-3-oxoprop-1-en-1-yl)-1,2-phenylene diacetate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.80(d,J＝16.0Hz,1H),7.47(d,J＝8.4Hz,1H),7.43(s,1H),7.36(dd,J＝ 15.1,7.5Hz,1H),7.27(d,J＝8.1Hz,1H),6.96(dd,J＝15.1,8.9Hz,3H),6.55(d,J＝16.0Hz,1H),2.32(d,J＝3.8 Hz,6H). 13 C NMR(101MHz,MeOD)δ169.14,169.03,164.34,163.36,152.93,147.97,143.28,142.52,131.26, 129.42,126.46,123.87,122.93,117.22,115.57,112.38,109.71,20.37,20.28.[M+H] + ＝359.0924.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution at 0 ℃ and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. After the filtrate was concentrated, the concentrate (300mg, 1.06mmol), m-fluorophenol (78.5mg, 0.7mmol), EDCI (268mg, 1.4mmol) and DMAP (4.3mg, 0.035mmol) were weighed out and dissolved in 6mL of a dichloromethane solution, and triethylamine (0.19mL, 1.4mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 82% yield.
EXAMPLE 8 Synthesis of (E) -4- (3- (2-methylpyridin-4-yl) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E) -4- (3- (2-methylpyridin-4-yl) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E)-4-(3-(2-methylpyridin-4-yl)-3-oxoprop-1-en-1-yl)-1,2-phenylene diacetate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ8.39(d,J＝2.1Hz,1H),7.82(d,J＝16.0Hz,1H),7.47(dd,J＝15.6,8.9Hz, 3H),7.28(s,1H),7.23(d,J＝8.4Hz,1H),6.57(d,J＝16.0Hz,1H),2.60(s,3H),2.32(d,J＝3.8Hz,6H). 13 C NMR (101MHz,MeOD)δ169.14,169.03,164.36,152.02,149.47,147.92,143.22,142.57,131.23,131.12,126.76,126.47, 123.85,123.76,122.91,115.57,23.97,20.37,20.28.[M+H] + ＝356.1140.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were added to a 1.4mL pyridine solution at 0 deg.C, and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. After the filtrate was concentrated, the concentrate (300mg, 1.06mmol), 3-hydroxy-6-methylpyridine (76.4mg, 0.7mmol), EDCI (268mg, 1.4mmol), and DMAP (4.3mg, 0.035mmol) were weighed out and dissolved in 6mL of a dichloromethane solution, and triethylamine (0.19mL, 1.4mmol) was added thereto under stirring, followed by stirring overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 80% yield.
Example 9 Synthesis of (E) -3-cyanophenyl 3- (3,4-dihydroxyphenyl) acrylate
(E) -3-cyanophenyl 3- (3,4-dihydroxyphenyl) acrylate (E) -3-cyanophenyl 3- (3,4-dihydroxyphenyl) acrylate
Product(s) 1 H NMR(400MHz,MeOD)δ7.79(d,J＝15.9Hz,1H),7.69–7.58(m,3H),7.56–7.49(m,1H),7.15(d, J＝2.0Hz,1H),7.06(dd,J＝8.2,2.0Hz,1H),6.84(d,J＝8.2Hz,1H),6.50(d,J＝15.8Hz,1H). 13 C NMR(101 MHz,MeOD)δ165.46,151.32,148.89,148.14,145.57,130.36,129.14,126.81,126.02,125.33,122.21,117.52, 115.19,114.03,112.89,112.01.[M+H] + ＝282.0770.
The synthetic route is as follows:
caffeic acid (200mg, 1.11mmol), m-cyanophenol (88mg, 0.74mmol), EDCI (284mg, 1.48mmol) and DMAP (4.5mg, 0.037mmol) were weighed out at room temperature and dissolved in 6mL of dichloromethane, and triethylamine (0.2mL, 1.48mmol) was added with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 88% yield.
EXAMPLE 10 Synthesis of (E) -4-methylbenzyl 3- (3,4-dihydroxyphenyl) acrylate
(E) -4-methylbenzyl 3- (3,4-dihydroxyphenyl) acrylate (E) -4-methylbenzyl 3- (3,4-dihydroxyphenyl) acrylate
Product(s) 1 H NMR(400MHz,MeOD)δ7.57(d,J＝15.9Hz,1H),7.29(d,J＝8.0Hz,2H),7.19(d,J＝7.9Hz,2H), 7.04(d,J＝2.0Hz,1H),6.94(dd,J＝8.2,2.0Hz,1H),6.77(d,J＝8.2Hz,1H),6.29(d,J＝15.9Hz,1H),5.16(s, 2H),2.34(s,3H). 13 C NMR(101MHz,MeOD)δ169.29,149.84,147.33,147.02,139.32,134.99,130.35,129.56, 127.90,123.21,116.69,115.33,115.22,67.32,21.43.[M+H] + ＝285.1120.
The synthetic route is as follows:
caffeic acid (200mg, 1.11mmol), p-methylbenzyl alcohol (90mg, 0.74mmol), EDCI (284mg, 1.48mmol), DMAP (4.5mg, 0.037mmol) were weighed and dissolved at room temperatureTo 6mL of the dichloromethane solution was added triethylamine (0.2mL, 1.48mmol) with stirring, and the mixture was stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:10 to give the compound as a white powder in 91% yield.
EXAMPLE 11 Synthesis of (E) -3-fluorophenyl 3- (4-acetoxyphenyl) acrylate
(E) -3-fluorophenyl 3- (4-acetoxyphenyl) acrylate (E) -3-fluoropentyl 3- (4-acetoxyphenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.85(d,J＝16.0Hz,1H),7.61(d,J＝8.1Hz,2H),7.37(dd,J＝15.2,7.6Hz, 1H),7.17(d,J＝8.0Hz,2H),7.03-6.90(m,3H),6.57(d,J＝16.0Hz,1H),2.33(s,3H). 13 C NMR(101MHz,MeOD) δ169.24,164.37,163.34,152.92,150.56,147.94,132.02,129.68,129.55,129.47,121.53,121,46,117.28,115.59, 112.34,109.78,20.34.[M+H] + ＝301.0880.
The synthetic route is as follows:
4-Hydroxycinnamic acid (300mg,1.83mmol) and DMAP (22mg,0.18mmol) were placed in 1.5mL of pyridine solution at 0 ℃ and acetic anhydride (0.22mL,2.28mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated, and the concentrate (373mg,1.83mmol), m-fluorophenol (134.5mg,1.2mmol), EDCI (460mg,2.4mmol), DMAP (7.4mg,0.06mmol) were weighed out) Dissolve in 8mL of dichloromethane, add triethylamine (0.33mL,2.4mmol) with stirring, and stir overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the compound as a white powder in 83% yield.
EXAMPLE 12 Synthesis of (E) -4-fluorophenyl 3- (4-acetoxyphenyl) acrylate
(E) -4-fluorophenyl 3- (4-acetoxyphenyl) acrylate (E) -4-fluoropentyl 3- (4-acetoxyphenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.84(d,J＝16.0Hz,1H),7.61(d,J＝8.5Hz,2H),7.19-7.05(m,6H),6.57 (d,J＝16.0Hz,1H),2.33(s,3H). 13 C NMR(101MHz,MeOD)δ169.24,164.35,159.76,150.53,147.93,146.97, 132.08,129.67,129.56,123.26,123.14,121.57,121,48,115.95,115.87,115.56,20.35.[M+H] + ＝301.0870.
The synthetic route is as follows:
4-Hydroxycinnamic acid (300mg,1.83mmol) and DMAP (22mg,0.18mmol) were placed in 1.5mL of pyridine solution at 0 ℃ and acetic anhydride (0.22mL,2.28mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated, and the concentrate (373mg,1.83mmol), 4-fluorophenol (134.5mg,1.2mmol), EDCI (460mg,2.4mmol), and DMAP (7.4mg,0.06mmol) were weighed out and dissolved in 8mL of dichloromethane with stirringTriethylamine (0.33mL,2.4mmol) was added and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the compound as a white powder in 81% yield.
Example 13 Synthesis of (E) -4- (trifluoromethyl) phenyl 3- (4-acetoxyphenyl) acrylate
(E) -4- (trifluoromethyl) phenyl 3- (4-acetoxyphenyl) acrylate (E) -4- (trifluoromethyl) phenyl 3- (4-acetoxyphenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.87(d,J＝16.0Hz,1H),7.68(d,J＝8.5Hz,2H),7.62(d,J＝8.6Hz,2H), 7.31(d,J＝8.6Hz,2H),7.18(d,J＝8.5Hz,2H),6.59(d,J＝16.0Hz,1H),2.33(s,3H). 13 C NMR(101MHz,MeOD) δ169.23,164.35,154.63,150.56,147.97,132.03,129.67,129.59,127.83,127.65,127.53,124.15,121.94,129.87, 121.57,121.48,115.52,20.36.[M+H] + ＝351.0841.
The synthetic route is as follows:
4-Hydroxycinnamic acid (300mg,1.83mmol) and DMAP (22mg,0.18mmol) were put in 1.5mL of a pyridine solution at 0 ℃ and acetic anhydride (0.22mL,2.28mmol) was added and the mixture was stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated, and the concentrate (373mg,1.83mmol), p-trifluoromethylphenol (194.5mg,1.2mmol), EDCI (460mg,2.4mmol), DMAP (7.4mg,0.0 mmol) were weighed out6mmol) was dissolved in 8mL of dichloromethane, triethylamine (0.33mL,2.4mmol) was added with stirring, and the mixture was stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the compound as a white powder in 85% yield.
EXAMPLE 14 Synthesis of (E) -2-chloro-4-fluorophenyl 3- (4-acetoxyphenyl) acrylate
(E) -2-chloro-4-fluorophenyl 3- (4-acetoxyphenyl) acrylate (E) -2-chloro-4-fluorophenonyl 3- (4-acetoxyphenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.89(d,J＝16.0Hz,1H),7.62(d,J＝8.5Hz,2H),7.25–7.14(m,4H),7.06 –6.99(m,1H),6.61(d,J＝16.0Hz,1H),2.33(s,3H).
13 C NMR(101MHz,MeOD)δ169.25,164.35,161.12,150.56,147.92,143.06,132.03,131.58,129.64,129.35, 124.63,121.56,121.48,118.26,115.58,114.09,20.34.[M+H] + ＝335.0485.
The synthetic route is as follows:
4-Hydroxycinnamic acid (300mg,1.83mmol) and DMAP (22mg,0.18mmol) were put in 1.5mL of a pyridine solution at 0 ℃ and acetic anhydride (0.22mL,2.28mmol) was added and the mixture was stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. After the filtrate was concentrated, the concentrate (373mg,1.83mmol) and 2-chloro-4-fluorophenol (175.9mg, 1mmol) were weighed2mmol), EDCI (460mg,2.4mmol), DMAP (7.4mg,0.06mmol) were dissolved in 8mL of dichloromethane, triethylamine (0.33mL,2.4mmol) was added with stirring, and the mixture was stirred overnight. Saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:12 to give the compound as a white powder in 86% yield.
Example 15 Synthesis of (E) -3,4-difluorophenyl 3- (4-acetoxyphenyl) acrylate
(E) -3,4-difluorophenyl 3- (4-acetoxyphenyl) acrylate (E) -3,4-difluorophenyl 3- (4-acetoxyphenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.84(d,J＝16.0Hz,1H),7.61(d,J＝8.5Hz,2H),7.19(dd,J＝18.6,8.8Hz, 3H),7.10–7.02(m,1H),6.95–6.89(m,1H),6.55(d,J＝16.0Hz,1H),2.33(s,3H). 13 C NMR(101MHz,MeOD)δ 169.23,164.34,150.52,149.96,148.57,147.93,146.37,132.08,129.64,126.27,121.55,121.38,118.85,117.59, 115.53,111.34,20.33.[M+H] + ＝319.0780.
The synthetic route is as follows:
4-Hydroxycinnamic acid (300mg,1.83mmol) and DMAP (22mg,0.18mmol) were placed in 1.5mL of pyridine solution at 0 ℃ and acetic anhydride (0.22mL,2.28mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated, and the concentrate (373mg,1.83mmol) and 3, 4-difluoro-l-e were weighedPhenol (156mg,1.2mmol), EDCI (460mg,2.4mmol), DMAP (7.4mg,0.06mmol) were dissolved in 8mL of dichloromethane, triethylamine (0.33mL,2.4mmol) was added with stirring, and the mixture was stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the combined organic phases were washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give the compound as a white powder in 80% yield.
EXAMPLE 16 Synthesis of (E) -4-fluorophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate
(E) -4-fluorophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate (E) -4-fluorophenyl 3- (4- (trifluoromethyloxy) phenyl) acrylate
Product(s) 1 H NMR(400MHz,CDCl 3 )δ7.64(d,J＝8.7Hz,2H),7.58–7.50(m,3H),7.48(d,J＝16.0Hz,1H),7.47 –7.43(m,1H),7.28(d,J＝8.4Hz,2H),6.31(d,J＝16.0Hz,1H). 13 C NMR(101MHz,MeOD)δ164.34,159.72, 149.86,147.93,146.94,130.24,130.08,129.74,127.54,123.25,123.11,115.95,115.67,115.57,114.22,114.05.
[M+H] + ＝327.0642.
The synthetic route is as follows:
p-trifluoromethoxycinnamic acid (200mg, 0.86mmol), 4-fluorophenol (64mg, 0.57mmol), EDCI (220mg, 1.15mmol) and DMAP (3.5mg, 0.029mmol) were weighed out and dissolved in 6mL of dichloromethane at room temperature, and triethylamine (0.16mL, 1.15mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), organic phases are combined and then saturated with waterAnd aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:50 to give the compound as a white powder in 90% yield.
EXAMPLE 17 Synthesis of (E) -4-methylbenzyl 3- (4- (trifluoromethoxy) phenyl) acrylate
(E) -4-methylbenzyl 3- (4- (trifluoromethoxy) phenyl) acrylate (E) -4-methyllbenzyl
3-(4-(trifluoromethoxy)phenyl)acrylate
Product(s) 1 H NMR(400MHz,CDCl 3 )δ7.68(d,J＝16.0Hz,1H),7.55–7.52(m,2H),7.31(d,J＝8.0Hz,2H),7.21 (t,J＝8.7Hz,4H),6.44(d,J＝16.0Hz,1H),5.21(s,2H),2.37(s,3H). 13 C NMR(101MHz,CDCl 3 )δ166.52, 150.44,143.27,138.26,133.01,132.91,129.52,129.33,128.54,121.67,121.16,121.16,119.10,118.99,66.52,21.23. [M+H] + ＝337.1046.
The synthetic route is as follows:
p-trifluoromethoxycinnamic acid (263mg, 1.13mmol), 4-methylbenzyl alcohol (92mg, 0.75mmol), EDCI (288mg, 1.5mmol) and DMAP (4.6mg, 0.038mmol) were weighed out at room temperature, dissolved in 6mL of dichloromethane, and triethylamine (0.2mL, 1.5mmol) was added with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:50 to give the compound as a white powder in 88% yield.
EXAMPLE 18 Synthesis of (E) -3-cyanophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate
(E) -3-cyanophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate (E) -3-cyanophenyl
3-(4-(trifluoromethoxy)phenyl)acrylate
Product(s) 1 H NMR(400MHz,CDCl 3 )δ7.87(d,J＝16.0Hz,1H),7.64(d,J＝8.7Hz,2H),7.58–7.50(m,3H),7.47 –7.43(m,1H),7.28(d,J＝8.4Hz,2H),6.59(d,J＝16.0Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ164.38,150.99, 150.97,150.84,145.92,132.39,130.44,129.94,129.60,126.63,125.42,121.65,121.27,119.08,117.88,117.25, 113.53.[M+H] + ＝334.0690.
The synthetic route is as follows:
p-trifluoromethoxycinnamic acid (200mg, 0.86mmol), m-cyanophenol (68mg, 0.57mmol), EDCI (220mg, 1.15mmol) and DMAP (3.5mg, 0.029mmol) were weighed out and dissolved in 6mL of dichloromethane at room temperature, and triethylamine (0.16mL, 1.15mmol) was added under stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:50 to give the compound as a white powder in 91% yield.
EXAMPLE 19 Synthesis of (E) -4-fluorophenyl 3- (4-fluorophenyl) acrylate
(E) -4-fluorophenyl 3- (4-fluorophenyl) acrylate (E) -4-fluoropentyl 3- (4-fluoropentyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.72(d,J＝8.2Hz,2H),7.48(d,J＝15.9Hz,1H),7.21(d,J＝8.3Hz,2H), 7.19(d,J＝8.3Hz,2H),7.27(d,J＝8.2Hz,2H),6.31(d,J＝15.9Hz,1H). 13 C NMR(101MHz,MeOD)δ164.33, 162.14,159.71,147.95,146.92,130.86,130.44,130.28,123.24,123.16,115.94,115.74,115.53,115.45,115.27.
[M+H] + ＝261.0730.
The synthetic route is as follows:
p-fluorocinnamic acid (210mg, 1.26mmol), 4-fluorophenol (94mg, 0.84mmol), EDCI (323mg, 1.685mmol) and DMAP (5.1mg, 0.042mmol) were weighed out and dissolved in 6mL of dichloromethane at room temperature, and triethylamine (0.23mL, 1.68mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:80 to give the compound as a white powder in 94% yield.
EXAMPLE 20 Synthesis of 4-methylbenzyl (E) -4- (3-fluorophenyl) acrylate
(E) 4-methylbenzyl (E) -4-methylb enzyl 3- (4-fluorophenyl) acrylate-4- (3-fluorophenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.72(d,J＝8.0Hz,2H),7.48(d,J＝15.9Hz,1H),7.21(d,J＝8.3Hz,2H), 7.19(d,J＝8.3Hz,2H),7.16(d,J＝8.0Hz,2H),6.31(d,J＝15.9Hz,1H),5.16(s,2H),2.34(s,3H). 13 C NMR(101 MHz,MeOD)δ166.52,162.15,143.62,137.32,133.16,130.87,130.44,130.27,129.24,129.09,127.05,126.78, 118.02,115.43,115.29,115,18,65.97,21.34.[M+H] + ＝271.1130.
The synthetic route is as follows:
p-fluorocinnamic acid (210mg, 1.26mmol), 4-methylbenzyl alcohol (103mg, 0.84mmol), EDCI (323mg, 1.685mmol) and DMAP (5.1mg, 0.042mmol) were weighed out at room temperature and dissolved in 6mL of a dichloromethane solution, and triethylamine (0.23mL, 1.68mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:50 to give the compound as a white powder in 89% yield.
EXAMPLE 21 Synthesis of (E) -3-cyanophenyl 3- (4-fluorophenyl) acrylate
(E) -3-cyanophenyl 3- (4-fluorophenyl) acrylate (E) -3-cyanophenyl 3- (4-fluorophenyl) acrylate
Product(s) 1 H NMR(400MHz,CDCl 3 )δ7.87(d,J＝16.0Hz,1H),7.64(d,J＝8.7Hz,2H),7.58–7.50(m,3H),7.47 –7.43(m,1H),7.28(d,J＝8.4Hz,2H),6.31(d,J＝16.0Hz,1H). 13 C NMR(101MHz,MeOD)δ164.34,162.12, 152.05,147.92,130.86,130.45,130.27,129.83,129.07,125.93,125.27,118.62,115.57,115.43,115.13,113.0.
[M+H] + ＝268.0774.
The synthetic route is as follows:
p-fluorocinnamic acid (213mg, 1.28mmol), m-cyanophenol (101mg, 0.85mmol), EDCI (325mg, 1.7mmol) and DMAP (5.2mg, 0.042mmol) were weighed out and dissolved in 6mL of dichloromethane at room temperature, and triethylamine (0.24mL, 1.7mmol) was added with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder in 90% yield.
EXAMPLE 22 Synthesis of (E) -2-chloro-4-fluorophenyl 3- (4-hydroxyphenyl) acrylate
(E) -2-chloro-4-fluorophenyl 3- (4-hydroxyphenyl) acrylate (E) -2-chloro-4-fluorophenyl 3- (4-hydroxyphenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.89(d,J＝16.0Hz,1H),7.62(d,J＝8.5Hz,2H),7.25–7.14(m,4H),7.06 –6.99(m,1H),6.61(d,J＝16.0Hz,1H). 13 C NMR(101MHz,MeOD)δ164.33,161.15,157.72,147.97,143.02, 131.55,130.64,130.38,127.87,124.64,118.29,115.85,115.67,115.53,114.08.[M+H] + ＝293.0381.
The synthetic route is as follows:
taking 4-hydroxy cinnamon at 0 DEG CThe acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL DMF and t-butyldimethylsilyl chloride (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (380mg,1.36mmol), 2-chloro-4-fluorophenol (132mg, 0.9mmol), EDCI (345mg,1.8mmol) and DMAP (5.5mg,0.045mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.25mL,1.8mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (297mg,0.73mmol) was dissolved in 5mL THF at 0 deg.C, acetic acid (0.045mL,0.8mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (253.3mg,0.8mmol) was added, and the mixture was allowed to cool to room temperature for 1 hour. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (3X 20mL), combined organic phases and washed with saturated aqueous NaCl (2X 20mL), filtered and then with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give the compound as a white solid in 82% yield.
Example 23 Synthesis of (E) -4- (trifluoromethyl) phenyl 3- (4-hydroxyphenyl) acrylate
(E) -4- (trifluoromethyl) phenyl 3- (4-hydroxyphenyl) acrylate (E) -4- (trifluoromethylphenyl) phenyl 3- (4-hydroxyphenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.84(d,J＝15.9Hz,1H),7.68(d,J＝8.3Hz,2H),7.51(d,J＝8.3Hz,2H), 7.30(d,J＝8.2Hz,2H),6.88(d,J＝8.2Hz,2H),6.49(d,J＝15.9Hz,1H). 13 C NMR(101MHz,MeOD)δ164.36, 157.74,154.67,147.94,130.65,130.48,127.85,127.69,127.63,127.38,124.17,121.96,121.69,115.82,115.68, 115.54.[M+H] + ＝309.0742.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL of DMF at 0 ℃ and stirred with tert-butyldimethylchlorosilane (918mg,6.1mmol) for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (380mg,1.36mmol), 4-trifluoromethylphenol (146mg, 0.9mmol), EDCI (345mg,1.8mmol) and DMAP (5.5mg,0.045mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.25mL,1.8mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (195mg,0.46mmol) was dissolved in 4mL THF at 0 deg.C, acetic acid (0.029mL,0.5mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (160mg,0.5mmol) was added, and the mixture was allowed to stand at room temperature for 1 hour. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (3X 20mL), combined organic phases and saturatedAqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give the compound as a white solid in 78% yield.
EXAMPLE 24 Synthesis of (E) -4-fluorophenyl 3- (4-hydroxyphenyl) acrylate
(E) -4-fluorophenyl 3- (4-hydroxyphenyl) acrylate (E) -4-fluorophenyl 3- (4-hydroxyphenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.81(d,J＝15.9Hz,1H),7.50(d,J＝8.3Hz,2H),7.14–7.04(m,4H),6.87 (d,J＝8.3Hz,2H),6.47(d,J＝15.9Hz,1H). 13 C NMR(101MHz,MeOD)δ164.35,159.73,157.76,147.93,146.93, 130.65,130.47,127.86,123.26,123.11,115.95,115.89,115.83,115.67,115.52.[M+H] + ＝259.0772.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL of DMF at 0 ℃ and tert-butyldimethylsilyl chloride (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (290mg,1mmol), 4-fluorophenol (77mg,0.69mmol), EDCI (266mg,1.39mmol), and DMAP (4.2mg,0.034mmol) were weighed out and dissolved in 8mL of a dichloromethane solution, triethylamine (0.2mL, 1.39mmol) was added thereto with stirring, and the mixture was stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL) was extracted,the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (243mg,0.65mmol) was dissolved in 5mL THF at 0 deg.C, acetic acid (0.041mL,0.72mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (226mg,0.72mmol) was added further, and the mixture was allowed to stand at room temperature for 1 hour. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (3X 20mL), combined organic phases and washed with saturated aqueous NaCl (2X 20mL), filtered and then with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the compound as a white solid in 83% yield.
EXAMPLE 25 Synthesis of (E) -3-fluorophenyl 3- (4-hydroxyphenyl) acrylate
(E) -3-fluorophenyl 3- (4-hydroxyphenyl) acrylate (E) -3-fluorophenyl 3- (4-hydroxyphenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.81(d,J＝15.9Hz,1H),7.50(d,J＝8.3Hz,2H),7.36(dd,J＝14.8,7.9Hz, 1H),7.00–6.91(m,3H),6.87(d,J＝8.4Hz,2H),6.47(d,J＝15.9Hz,1H). 13 C NMR(101MHz,MeOD)δ164.34, 163.36,157.72,152.97,147.92,130.65,130.28,129.43,127.86,117.22,115.86,115.65,115.57,112.31,109.76.
[M+H] + ＝59.0773.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL of DMF at 0 ℃ and tert-butyldimethylsilyl chloride (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing the ice blocks in the reverse directionThe reaction system was extracted with ethyl acetate (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl solution (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (290mg,1mmol), m-fluorophenol (77mg,0.69mmol), EDCI (266mg,1.39mmol) and DMAP (4.2mg,0.034mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.2mL, 1.39mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (185mg,0.5mmol) was dissolved in 4mL THF at 0 deg.C, acetic acid (0.031mL,0.55mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (172mg,0.55mmol) was added, and the mixture was allowed to stand at room temperature for 1 hour. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (3X 20mL), combined organic phases washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the compound as a white solid in 78% yield.
Example 26 Synthesis of 4-methylbenzyl (E) -3- (4-hydroxyphenyl) acrylate
(E) 4-methylbenzyl (E) -4-methylidenyl 3- (4-hydroxyphenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.65(d,J＝16.0Hz,1H),7.42(d,J＝8.3Hz,2H),7.31(d,J＝7.6Hz,2H), 7.19(d,J＝7.5Hz,2H),6.83(d,J＝8.2Hz,2H),6.33(d,J＝15.9Hz,1H),5.20(s,2H),2.36(s,3H). 13 C NMR(101 MHz,MeOD)δ166.53,157.77,143.63,137.34,133.17,130.64,130.28,129.28,129.01,127.88,127.03,126.84, 118.03,115.84,115.67,65.96,21.38.[M+H] + ＝269.1177.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL of DMF at 0 ℃ and stirred with tert-butyldimethylchlorosilane (918mg,6.1mmol) for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5, to give an oily concentrate. The concentrate (340mg,1.22mmol), 4-methylbenzyl alcohol (98mg, 0.8mmol), EDCI (310.6mg,1.62mmol) and DMAP (5mg,0.04mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.23mL,1.62mmol) was added with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:50 to give the compound as a white powder. The product (247mg,0.65mmol) was dissolved in 5mL THF at 0 deg.C, acetic acid (0.04mL,0.71mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (224mg,0.71mmol) was added, and the mixture was allowed to stand at room temperature for 1 hour. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (3X 20mL), combined organic phases and washed with saturated aqueous NaCl (2X 20mL), filtered and then with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the compound as a white solid in 79% yield.
EXAMPLE 27 Synthesis of (E) -3-cyanophenyl 3- (4-hydroxyphenyl) acrylate
(E) -3-cyanophenyl 3- (4-hydroxyphenyl) acrylate (E) -3-cyanophenyl 3- (4-hydroxyphenyl) acrylate
Product(s) 1 H NMR(400MHz,CDCl 3 )δ7.83(d,J＝15.9Hz,1H),7.58–7.48(m,5H),7.46–7.41(m,1H),6.93– 6.85(m,2H),6.47(d,J＝15.9Hz,1H). 13 C NMR(101MHz,DMSO)δ165.42,160.95,151.23,147.98,131.39, 130.25,128.04,126.29,125.32,118.47,116.38,112.90,112.73.[M+H] + ＝266.0818.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL of DMF at 0 ℃ and stirred with tert-butyldimethylchlorosilane (918mg,6.1mmol) for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (340mg,1.22mmol), m-cyanophenol (95.3mg, 0.8mmol), EDCI (310.6mg,1.62mmol) and DMAP (5mg,0.04mmol) were weighed out and dissolved in 8mL of dichloromethane, triethylamine (0.23mL,1.62mmol) was added with stirring, and the mixture was stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (188mg,0.5mmol) was dissolved in 5mL THF at 0 deg.C, acetic acid (0.031mL,0.54mmol) was added dropwise, and tetrabutylammonium fluoride trihydrate was added(172mg,0.54mmol) and allowed to move to room temperature for 1 hour. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (3X 20mL), combined organic phases washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography using EtOAc, petroleum ether 1:2 to give a white solid compound in 84% yield.
EXAMPLE 28 Synthesis of (E) -3,4-difluorophenyl 3- (4- (toluenesulfonyloxy) phenyl) acrylate
(E) -3,4-difluorophenyl 3- (4- (tosyloxy) phenyl) acrylate (E) -3,4-difluorophenyl 3- (4- (tosyloxy) phenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.79(d,J＝16.0Hz,1H),7.73(d,J＝8.1Hz,2H),7.51(d,J＝8.4Hz,2H), 7.33(d,J＝8.0Hz,2H),7.19(dd,J＝18.7,9.2Hz,1H),7.09-7.02(m,3H),6.91(d,J＝8.9Hz,1H),6.53(d,J＝16.0 Hz,1H),2.46(s,3H).
13 C NMR(101MHz,DMSO)δ164.92,150.98,150.82,149.17,148.51,148.37,146.48,145.73,133.44,131.75, 130.91,130.78,128.74,123.10,119.31,118.29,118.26,118.07,112.72,112.53,21.65.[M+H] + ＝431.0760.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL of DMF at 0 ℃ and tert-butyldimethylsilyl chloride (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na 2 SO 4 And (5) drying. Concentrating the filtrate, and separating and purifying by column chromatography to obtain eluentEtOAc, petroleum ether 1:5, gave an oily concentrate. The concentrate (540mg,1.94mmol), 3, 4-difluorophenol (168mg, 1.29mmol), EDCI (496.5mg,2.59mmol) and DMAP (7.9mg,0.065mmol) were weighed out and dissolved in 8mL of dichloromethane, triethylamine (0.36mL,2.59mmol) was added under stirring, and the mixture was stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (673mg,1.72mmol) was dissolved in 10mL THF at 0 deg.C, acetic acid (0.11mL,1.9mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (598mg,1.9mmol) was added, and the mixture was allowed to stand at room temperature for 1 hour. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (3X 20mL), combined organic phases and washed with saturated aqueous NaCl (2X 20mL), filtered and then with anhydrous Na 2 SO 4 And (5) drying. The filtrate is concentrated and purified by column chromatography, the eluent is EtOAc: petroleum ether 1:6, and concentrated. The concentrate (165mg,0.6mmol) was dissolved in 5mL of dichloromethane at room temperature, triethylamine (0.17mL,1.2mmol) was added dropwise, p-toluenesulfonyl chloride (121mg,1.2mmol) was added dropwise, and the mixture was stirred for 8 hours. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with dichloromethane (3X 20mL), the organic phases combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying.
The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:7 to give a white powder in 73% yield.
Example 29(E) -4- (trifluoromethyl) phenyl 3- (4- (toluenesulfonyloxy) phenyl) acrylate
(E) -4- (trifluoromethyl) phenyl 3- (4- (toluenesulfonyloxy) phenyl) acrylate (E) -4- (trifluoromethylphenyl) phenyl
3-(4-(tosyloxy)phenyl)acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.82(d,J＝16.0Hz,1H),7.73(d,J＝8.2Hz,2H),7.68(d,J＝8.4Hz,2H), 7.52(d,J＝8.4Hz,2H),7.34(d,J＝8.0Hz,2H),7.29(d,J＝8.3Hz,2H),7.07(d,J＝8.5Hz,2H),6.56(d,J＝16.0 Hz,1H),2.47(s,3H).
13 C NMR(101MHz,DMSO)δ164.79,153.85,151.00,146.47,145.86,133.44,132.14,131.74,130.94,130.77, 130.70,128.74,128.66,128.55,127.42,127.39,127.15,126.83,125.85,123.39,123.10,122.17,118.33,21.65.
[M+H] + ＝463.0829.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL of DMF at 0 ℃ and tert-butyldimethylsilyl chloride (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (380mg,1.36mmol), 4-trifluoromethylphenol (146mg, 0.9mmol), EDCI (345mg,1.8mmol) and DMAP (5.5mg,0.045mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.25mL,1.8mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO 3 Quench the reaction with aqueous solution (20mL), CH 2 Cl 2 (3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. Concentrating the filtrate, and separating by column chromatographyPurification with EtOAc: peloleum ether ═ 1:20 afforded the compound as a white powder. The product (195mg,0.46mmol) was dissolved in 4mL THF at 0 deg.C, acetic acid (0.029mL,0.5mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (160mg,0.5mmol) was added, and the mixture was allowed to stand at room temperature for 1 hour. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (3X 20mL), combined organic phases and washed with saturated aqueous NaCl (2X 20mL), filtered and then with anhydrous Na 2 SO 4 And (5) drying. The filtrate is concentrated and separated and purified by column chromatography, the eluent is EtOAc, petroleum ether 1:5, and concentrated. The concentrate (123mg,0.4mmol) was dissolved in 5mL of dichloromethane at room temperature, triethylamine (0.11mL,0.8mmol) was added dropwise, p-toluenesulfonyl chloride (152.5mg,0.8mmol) was added dropwise, and the mixture was stirred for 8 hours. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with dichloromethane (3X 20mL), combined organic phases washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na 2 SO 4 And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, peleveleumer 1:10 to give a white powder in 77% yield.
Example 30(E) Synthesis of methyl 3- (4-hydroxyphenyl) acrylate
(E) Methyl 3- (4-hydroxyphenyl) acrylate (E) -methyl 3- (4-hydroxyphenyl) acrylate
Product(s) 1 H NMR(500MHz,CDCl 3 )δ7.64(d,J＝16.0Hz,1H),7.43(d,J＝8.6Hz,2H),6.84(d,J＝8.5Hz,2H), 6.30(d,J＝15.9Hz,1H),5.18(s,1H),3.80(s,3H).
13 C NMR(101MHz,DMSO)δ166.52,157.76,143.64,130.68,130.48,127.83,115.89,115.68,115.17,52.05. [M+H] + ＝179.0703.
Reacting 4-hydroxyCinnamic acid (1mmol,164mg) was dissolved in anhydrous methanol (5mL), sulfuric acid (1 drop) was added with stirring at room temperature, and the reaction was heated to reflux for 24 h. The mixture was cooled and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (30mL) and washed with saturated aqueous sodium bicarbonate (20mL) and saturated aqueous NaCl (2X 20 mL). Filtering, adding anhydrous Na 2 SO 4 Drying, concentrating the filtrate, and separating and purifying by column chromatography, wherein the eluent is EtOAc, petroleum ether 1:5, to obtain the compound as a white solid with the yield of 87%.
Example 31 Colon cancer cell proliferation assay
Colon cancer HCT-116 cells (5X 10 per well) 3 ) Plating into 96-well plates. Cultured in media containing the organic compounds prepared according to examples 1-30, respectively, for 72 hours. Then, the medium was removed and the wells were washed with Phosphate Buffered Saline (PBS). mu.L of 3- (4, 5-dimethylthiazol-2) -2, 5-diphenyltetrazolium bromide (MTT) was added to each well at a working concentration of 5 mg/mL. After 4 hours of incubation, the media was removed and 150 μ l of LDMSO was added to each well to dissolve formazan crystals. Absorbance was measured at 490nm on a microplate reader. The half inhibitory concentration of the compound on tumor cells was calculated by absorbance (IC 50). The positive control is tripterine, and the IC is determined 50 It was 1.86 μm.
TABLE 1 inhibitory Activity of TRPV inhibitors described in examples 1-30 on colon cancer
| Compound numbering | IC 50 (μm) | Compound numbering | IC 50 (μm) | Compound numbering | IC 50 (μm) |
| 1 | 2.83 | 11 | 0.43 | 21 | 2.42 |
| 2 | 1.62 | 12 | 1.39 | 22 | 2.05 |
| 3 | 3.1 | 13 | 1.48 | 23 | 0.78 |
| 4 | 3.77 | 14 | 1.94 | 24 | 2.84 |
| 5 | 1.34 | 15 | 0.73 | 25 | 1.85 |
| 6 | 1.82 | 16 | 0.37 | 26 | 3.58 |
| 7 | 1.65 | 17 | 1.59 | 27 | 4.02 |
| 8 | 2.67 | 18 | 2.48 | 28 | 0.27 |
| 9 | 0.4 | 19 | 1.89 | 29 | 3.01 |
| 10 | 1.4 | 20 | 2.47 | 30 | 1.28 |
The inhibitory activity of the organic compounds prepared according to examples 1 to 30 on colon cancer is shown in table 1, and it can be seen that most of the organic compounds according to the present invention have significant therapeutic effects on colon cancer, and particularly, the therapeutic effects of the organic compounds prepared according to examples 2,5, 6, 7, 9, 10, 11, 12, 13, 15, 16, 17, 23, 25, 28 and 30 are significantly stronger than that of tripterine, and have broad application prospects in clinical treatment of colon cancer.
The above summary and the detailed description are intended to demonstrate the practical application of the technical solutions provided by the present invention, and should not be construed as limiting the scope of the present invention. Various modifications, equivalent substitutions, or improvements may be made by those skilled in the art within the spirit and principles of the invention. The scope of the invention is to be determined by the appended claims.
Claims (4)
1. Use of an organic compound for the manufacture of a medicament for the treatment of colon cancer, wherein said organic compound is represented by R 1 Group, R group and R 2 The groups are connected in sequence to form the compound, and the molecular structural general formula of the compound is shown as formula 1:
R 1 the structural formula of the radical is
R 3 Selected from-H, -OAc, -OH, halo, -F 3 Any one of CO or a benzenesulfonyloxy group-containing group, R 4 Any one selected from-H, -OAc or-OH; the structural formula of the R group is
R 2 The radicals being selected from alkyl or
R 5 Selected from C or N, R 6 Selected from any one of hydrogen, alkyl, halogen or trifluoromethyl, R 7 Selected from any one of hydrogen, halogen, cyano, nitro or trifluoromethoxy, R 8 Selected from hydrogen or halo;
the organic compound is selected from (E) -4- (3- (3-cyanophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester, (E) -4- (3-oxo-3- (p-tolyloxy) prop-1-en-1-yl) -1, 2-phenylenediacetic acid ester, (E) -4- (3- (4-isopropylphenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester, (E) -4- (3- (3-fluorophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester, (E) -3-fluorophenyl 3- (4-acetoxyphenyl) acrylate, (E) -4- (trifluoromethyl) phenyl 3- (4-acetoxyphenyl) acrylate, (E) -3,4-difluorophenyl 3- (4-acetoxyphenyl) acrylate, (E) -4-fluorophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate, (E) -4-methylbenzyl 3- (4- (trifluoromethoxy) phenyl) acrylate, (E) -4- (trifluoromethyl) phenyl 3- (4-hydroxyphenyl) acrylate, and the like, (E) -3-cyanophenyl 3- (3,4-dihydroxyphenyl) acrylate, (E) -4-methylbenzyl 3- (3,4-dihydroxyphenyl) acrylate, (E) -3,4-difluorophenyl 3- (4- (toluenesulfonyloxy) phenyl) acrylate or (E) -3-fluorophenyl 3- (4-hydroxyphenyl) acrylate.
2. The use according to claim 1, the organic compound is any one selected from (E) -3-fluorophenyl 3- (4-acetoxyphenyl) acrylate, (E) -3,4-difluorophenyl 3- (4-acetoxyphenyl) acrylate, (E) -3-cyanophenyl 3- (3,4-dihydroxyphenyl) acrylate, (E) -4-fluorophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate, (E) -3,4-difluorophenyl 3- (4- (toluenesulfonyloxy) phenyl) acrylate, and (E) -4- (trifluoromethyl) phenyl 3- (4-hydroxyphenyl) acrylate.
3. A pharmaceutical composition for the treatment of colon cancer, wherein the active ingredient of the pharmaceutical composition comprises a dose of an organic compound;
the organic compound is represented by R 1 Group, R group and R 2 The groups are connected in sequence to form the compound, and the molecular structural general formula of the compound is shown as formula 1:
R 1 the structural formula of the radical is
R 3 Selected from-H, -OAc, -OH, halo, -F 3 Any one of CO or a phenylsulfonyloxy-containing group, R 4 Any one selected from-H, -OAc or-OH; the structural formula of the R group is
R 2 The radicals being selected from alkyl or
R 5 Selected from C or N, R 6 Selected from any one of hydrogen, alkyl, halogen or trifluoromethyl, R 7 Selected from any one of hydrogen, halogen, cyano, nitro or trifluoromethoxy, R 8 Selected from hydrogen or halo;
the organic compound is any one selected from (E) -3-fluorophenyl 3- (4-acetoxyphenyl) acrylate, (E) -3,4-difluorophenyl 3- (4-acetoxyphenyl) acrylate, (E) -3-cyanophenyl 3- (3,4-dihydroxyphenyl) acrylate, (E) -4-fluorophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate, (E) -3,4-difluorophenyl 3- (4- (toluenesulfonyloxy) phenyl) acrylate, and (E) -4- (trifluoromethyl) phenyl 3- (4-hydroxyphenyl) acrylate.
4. The pharmaceutical composition of claim 3, wherein the IC of the organic compound is 50 Is 0.25-0.8 μm.
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