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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Caffeic acid is a hydroxycinnamic acid, a naturally occurring organic compound isolated and purified from the herb of Boehmeria siamensis Craib., with antioxidant, antineoplastic, anti-HIV, choleretic, hepatotropic, and is a strong inhibitor of neutrophil elastase.
Synonyms: 3,4-Dihydroxycinnamic Acid
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Enhancing the anticancer effects of Apiaceae spice phytochemicals.
Scott, Jared Lee ;
Abstract: Breast cancer (BC) is the second greatest contributor to the death of women, second only to heart disease, and is the most common type of cancer. BC treatments involve the administration of adjuvant chemotherapies which often have side effects that prevent patients from completing the full course of drugs or the refusal to take these potentially lifesaving treatments. Many chemotherapy drugs are developed from plants, and some plant extracts can exhibit significant anticancer activities while also having less toxic side effects. However, these potential "plant therapeutics" suffer from poor oral bioavailability. The Apiaceae plant family consists of several species that are used as culinarily spices including anise, celery, cumin, and coriander, all of which have demonstrated antioxidant, chemopreventive, and anticancer activities. One method to improve the systemic distribution of anticancer phytochemicals is their encapsulation in naturally produced membrane bound nanoparticles known as exosomes. Exosomes are produced by most eukaryotic organisms, as well as some prokaryotes, and are involved in cell-to-cell communication through the delivery of proteins, nucleic acids, and small molecules from one cell to another. Exosomes are found in many extracellular fluids including blood, urine, and milk. Bovine milk exosomes represent a scalable source of exosomes that are already present in the human diet and have been explored as a drug delivery system that can increase effectiveness and improve bioavailability. To enhance the loading potential and anticancer bioactivity of Apiaceae phytochemicals, an acid hydrolysis (AH) of the glycoside compounds present in ethanolic spice extracts was performed on eight ethanolic spice extracts. The antiproliferative effects of AH extracts and exosomal formulations were assayed with three model types of BC cells. Cumin was characterized in greater detail as these extracts had the highest concentration of terpenoids and alkaloids while also having significant concentrations of phenolics and responded well to AH with increased antiproliferative activity and exosomal loading. Extracts and exosomal formulations exhibited broad antiproliferative effects with lower IC50s in the extracts delivered with exosomes. The phytochemical contents of AH-cumin extracts and exosomal formulations were assayed with HPLC-DAD, LC-MS/MS, and GC-MS, while the potential anticancer mechanisms of these treatments were investigated in triple negative BC (TNBC). AHcumin extracts were determined to have numerous phenolic compounds, many of which have known anticancer mechanisms, in addition to several alkaloids and lipid compounds, some of which have activities that could contribute to the anticancer effects observed. Mechanistically, AH-cumin extracts and exosomal formulations were shown to interact with multidrug resistance proteins and inhibit lipid metabolism in TNBC cells. These results indicate that acid hydrolyzed cumin extracts delivered through exosome nanoparticles represent a possible avenue towards the development of novel treatments for TNBC, the hardest type of BC to treat.
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CAS No. : | 331-39-5 |
Formula : | C9H8O4 |
M.W : | 180.16 |
SMILES Code : | O=C(O)/C=C/C1=CC=C(O)C(O)=C1 |
Synonyms : |
3,4-Dihydroxycinnamic Acid
|
MDL No. : | MFCD00004392 |
InChI Key : | QAIPRVGONGVQAS-DUXPYHPUSA-N |
Pubchem ID : | 689043 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335-H351-H361 |
Precautionary Statements: | P261-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With ytterbium(III) triflate; In nitromethane; at 120℃; for 0.666667h;Catalytic behavior; | To a mixture of caffeic acid fine powder (1.0 g, 5.56 mmol, 1.0 equiv.),alcohol (5.56 mmol, 1.0 equiv.) in nitromethane (125 mL) was addedytterbium triflate (34.4 mg, 0.056 mmol, 0.01 equiv.). After 5 min inan ultrasonic bath the mixture without protective gas was stirred ona 120 C oil bath for a given time. The reaction mixture was cooled toroom temperature, washed with deionised water (30 mL), 2% NaHCO3(30 mL) and brine, dried over anhydrous Na2SO4 and evaporated underreduced pressure to give the crude product, which was purified on asilica gel column to give the compounds 1-5 and 8-30.2-Phenethyl (E)-3-(3,4-dihydroxyphenyl) acrylate (1): Whitesolid; yield 758 mg, 48.0%; m.p. 128-130 C (lit.20 116-123 C);IR (KBr) numax 3480, 3328, 1683, 1601, 1362, 1301, 1279, 1182 cm-1;1H NMR (400 MHz, DMSO-d6) deltaH 7.46 (1H, d, J = 16 Hz, CH=CHCO),7.34-7.18 (5H, m, C6H5), 7.05 (1H, s, 2-ArH), 6.99 (1H, d, J = 8.0 Hz,6-ArH), 6.77 (1H, d, J = 8.0 Hz, 5-ArH), 6.24 (1H, d, J = 16 Hz,CH=CHCO), 4.32 (2H, t, J = 6.8 Hz, OCH2), 2.94 (2H, t, J = 6.8 Hz,OCH2CH2) ppm; 13C NMR (100 MHz, DMSO-d6) deltaC 166.4, 148.3,145.4, 145.1, 138.0, 128.8, 128.3, 126.3, 125.4, 121.4, 115.7, 114.7, 113.8,64.3, 34.4 ppm; HRMS-ESI C17H16O4 calcd [M-H]- 283.0970, found283.0966. |
48% | With ytterbium(III) triflate; In nitromethane; at 120℃; | General procedure: To a mixture of caffeic acid fine powder (1.0 g, 5.56 mmol), various phenethyl alcohols (5.56 mmol) in CH3NO2 (125 mL) was added Yb(OTf)3 (34.4 mg, 0.056 mmol). After 5 min of ultrasonic shake, the mixture was stirred on a 120 C oil bath for 40-120 min. The reaction mixture was cooled to room temperature, washed with 2% NaHCO3 (30 mL) and brine, dried over anhydrous Na2SO4, and concentrated to give crude products, which were purified by column chromatography to give the compounds 1-26 in 18-61% yields. Phenethyl (E)-3-(3,4-dihydroxyphenyl) acrylate (CAPE). White solid (48% yield for esterification reaction); Mp 128-130 C; 1H NMR (400 MHz, DMSO-d6) deltaH 7.46 (1H, d, J = 16.0 Hz, CH=CHCO), 7.34-7.18 (5H, m, C6H5), 7.05 (1H, s, 2-ArH), 6.99 (1H, d, J = 8.0 Hz, 5-ArH), 6.77 (1H, d, J = 8.0 Hz, 6-ArH), 6.24 (1H, d, J = 16.0 Hz, CH=CHCO), 4.32 (2H, t, J = 6.8 Hz, OCH2), 2.94 (2H, t, J = 6.8 Hz, CH2C6H5) ppm; 13C NMR (100 MHz, DMSO-d6) deltaC 166.4, 148.3, 145.4, 145.1, 138.0, 128.8, 128.3, 126.3, 125.4, 121.4, 115.7, 114.7, 113.8, 64.3, 34.4 ppm; HRMS-ESI C17H16O4 calcd [M-H]- 283.0970, found 283.0966. |
9% | With ytterbium(III) triflate; In nitromethane; for 1.5h;Reflux; | Caffeic acid (0.5 g, 2.78 mmol) and 2-phenylethanol (0.35 mL,2.78 mmol) were dissolved in nitromethane (62.5 mL). Yb(OTf)3(0.017 g, 0.028 mmol) was added, and the suspension was stirredfor 5 min in an ultrasonic bath followed by an additional 1.5 hstirring under reflux [4]. The reaction mixture was stirred at roomtemperature overnight and washed with NaHCO3-solution (2%,15 mL) and brine (15 mL). The organic phase was dried over Na2SO4and concentrated under reduced pressure. The crude product waspurified by column chromatography (silica gel; chloroform/methanol,99:1), and compound 17 was obtained as a white solid (0.07 g,9%); RF 0.04 (silica gel; chloroform/methanol, 99:1); m.p.128-130 C (lit.: [19]: 126-128 C); IR (KBr): nu 3480s, 1685m,1636m, 1602s, 1535w, 1442w, 1363w, 1302m, 1279s, 1182s cm1;UV-vis (CHCl3): lambda (log epsilon) 250 (4.06), 320 (4.21), 353 (4.28) nm; 1HNMR (500 MHz, CDCl3): delta 7.56 (d, J 15.9 Hz, 1H, 3-H), 7.34-7.30(m, 2H, 2-H), 7.27-7.22 (m, 3H, 3-H4-H), 7.07 (d, J 2.0 Hz, 1H, 50-H), 7.01 (dd, J 8.2, 2.0 Hz, 1H, 20-H), 6.87 (d, J 8.2 Hz, 1H, 60-H),6.25 (d, J 15.9 Hz, 1H, 2-H), 4.42 (t, J 7.1 Hz, 2H, 1-H), 3.01 (t,J 7.1 Hz, 2H, 2-H); 13C NMR (125 MHz, CDCl3): delta 167.8 (C-1),146.5 (C-40), 145.2 (C-30), 143.9 (C-3), 138.0 (C-1), 129.1 (C-3), 128.7(C-2), 127.7 (C-10), 126.8 (C-4), 122.7 (C-60), 115.7 (C-2), 115.6 (C-50),144.6 (C-20), 65.3 (C-1), 35.4 (C-2) ppm; MS (ESI, MeOH): m/z(%) 285.0 ([MH], 45), 302.2 ([MNH4], 23), 307.1 ([MNa],100), 446.1 ([3 MKH]2, 44), 580.1 ([4 MNaH]2, 23), 588.0([4MKH]2, 50), 590.8 ([2MNa], 42), 599.9 ([4MZn]2, 48);analysis calcd for C17H16O4 (284.31): C 71.82, H 5.67; found: C 71.69,H 5.83. |
With toluene-4-sulfonic acid; In benzene; | Synthesis of Cinnamic Acid Analogues. The synthesis of cinnamic acid analogues was achieved by straight forward application of literature techniques. Two general approaches, designated "method A" and "method B" were utilized: Method A: Synthesis of Caffeic acid beta-phenylethyl ester (CAPE, 67H-42-A). A solution of 1.80 g (10.0 mmol) of caffeic acid, 17.9 mL (150 mmol) of beta-phenylethyl alcohol and 100 mg of p-toluenesulfonic acid in benzene (100 mL) were stirred overnight at reflux with a Dean Stark trap. Solvent and excess alcohol were removed by distillation and residue purified by silica gel chromatography (petroleum ether/CHCl3). Product was crystallized (ether/petroleum ether) to provide 67H-42-A as snow-white crystals, 1.0 g (35%): mp 128.0 C. 126-128 C.) (Grunberger, D. et al., Experimentia, (1988) 44:230-2). | |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 48h; | General procedure: Cinnamicacid esters (13-22) were synthesized according to a modified previous procedure.31) To a mixture of cinnamic acid derivatives (Ia-d, 3.0 mmol) and the appropriate alcohol (2.0 mmol)in dry tetrahydrofuran (6mL) were added triphenylphosphine (3.0 mmol) and diisopropyl azodicarboxylate (DIAD(3.0mmol). The reaction mixture was stirred for 48h at room temperature and the whole mixture was extracted with AcOEt and saturated NaHCO3 solution, and the organic extract was washed with brine.The organic layer was dried overNa2SO4 and the solvent was evaporated under reduced pressure. The residue was then purified by silica gel column chromatography (hexane:AcOEt=2:1)to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Nua2CO3 (126 mg, 1.19 mmol) wasadded and stirring continued for 30 min. At the end of this period, thecorresponding bromide (1.14 mmol) was added to the reaction mixture followed bya catalytic amount of potassium iodide. The mixture was stirred at room temperaturefor 48 h, after which EtOAc (30 ml) and HCl 0.5 N (5 mL) were added. Theorganic phase was washed with brine, dried over Na2SO4,filtered and concentrated under reduced pressure. The crude product waspurified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Caffeic acid (140.7 mg, 0.78 mmol) was dissolved in CH2Cl2/DMF (1:3, 3.0 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDC) (247 mL, 147 mmol) and 1-hydroxy-benzotriazole(HOBt) (75.4 mg, 0.56 mmol) were added to the solution. After themixture was cooled in an ice-water bath for 15 min, Et3N (156 mL,1.12 mmol) and compound a (138.3 mg, 0.56 mmol) were added tothe mixture. After stirring at room temperature for 19 h, the mixturewas poured into H2O (50 mL), extracted with EtOAc (50 mL 3), washed with 5% NaHCO3 (150 mL) and brine (150 mL), driedover MgSO4, filtered, and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (CHCl3:MeOH =9:1) to afford clovamide methyl ester (clovamide-Me, 10, 84.7 mg,40%) as a yellow powder: 1H NMR (CD3OD) d 7.36 (1H, d, J = 15.7Hz, H-70), 6.99 (1H, d, J = 1.9 Hz, H-2), 6.89 (1H, dd, J = 8.2, 1.9 Hz,H-6), 6.75 (1H, d, J = 8.2 Hz, H-5), 6.64 (1H, d, J = 1.9 Hz, H-20),6.67 (1H, d, J = 8.1 Hz, H-50), 6.53 (1H, dd, J = 8.1, 1.9 Hz, H-60),6.41 (1H, d, J = 15.7 Hz, H-80), 4.69 (1H, m, H-8), 3.68 (3H, s,MeO-90), 3.02 (1H, dd, J = 13.9, 5.9 Hz, H-7a), 2.93 (1H, dd, J =13.9, 6.6 Hz, H-7b); 13C NMR (CD3OD) d 174.6 (C, C-9), 169.8(C, C-90), 149.5 (C, C-40), 147.3 (C, C-30), 146.8 (C, C-3), 145.9(C, C-4), 143.8 (CH, C-70), 130.2 (C, C-1), 128.9 (C, C-10), 123.1(CH, C-60), 122.4 (CH, C-6), 118.4 (CH, C-80), 118.0 (CH, C-2),117.2 (CH, C-5), 117.1 (CH, C-50), 115.9 (CH, C-20), 56.5 (CH, C-8),53.4 (CH3, CO-9) 39.1 (C, C-7); UV kmax (MeOH) nm (e): 208(12400), 220 (12100), 291 (9700), 324 (10700); HR-ESI-MS (negativeion) m/z: 372.1100 [MH] (calcd for C19H18NO7, 372.1083);[a]D20 +20 (c = 1.0, MeOH). | |
33.2% | General procedure: To a solution of the corresponding substitutedacid (1 eq, 2.02 mmol) in dichloromethane-N,N-dimethylformamide(DMF) (3 : 1, 20 mL) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) (1 eq, 2.02 mmol),N,N-diisopropylethylamine (DIEA) (1 eq, 2.02 mmol) andN-hydroxybenzotriazole (HOBt) (1 eq, 2.02 mmol). After themixture was stirred at room temperature for 30 min, correspondingamine (1 eq, 2.02 mmol) and triethylammoniumacetate (TEA) (3 eq, 6.06 mmol) was added. The solution wasstirred at room temperature for 4 h and then extracted withdichloromethane. The organic layer was washed with 1 N HClsolution, saturated NaHCO3 solution, water and brine, driedover Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (ethylacetate-hexane, 1 : 2) to obtain the title compound. | |
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; | General procedure: As shown in Scheme 1, the synthetic route of the analogues (1-7) involved a two-step sequence viamethyl esterification of L-amino acidand amide condensation. 100 muL SOCl2was added in portions to 4 mL methanol at -10 C,then 1 mmol L-amino acid was addedand the mixture was warmed to room temperature and stirred overnight. After thesolvent was removed, 5 mL CH3CN, 500 muL DIPEA (N,N-Diisopropyl ethylamine), 1.1 mmolcorresponding substituted acid and 1.1 mmol HBTU (O-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluorophosphate)was added into the residue. The mixture was stirred for 1 h at room temperatureto finish condensation. The reaction solution was added 20 mL 1 M HCl, andextracted with ethyl acetate (4 × 20 mL). The combined organic phasewas dried over anhydrous Na2SO4 and finally evaporated invacuum. The residue was purified by silica-gel chromatography using mixtures ofPE/EtOAcas eluent to afford compounds 1-7.At this stage, all compounds were fully analyzed and characterized by nuclearmagnetic resonance (NMR), high resolution massspectrum (HRMS). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 100% | at 50.0℃; for 48.0h; | General procedure: As a resin that is a solid catalyst, PK208LH manufactured by Mitsubishi Chemical Corporation was used. In this system, conditions without using a solvent were adopted, and therefore, a homogeneous phase was formed by setting the reaction temperature to 50 C. so as to dissolve a cinnamic acid (1) and an alcohol (2). Here, ferulic acid was used as the cinnamic acid, and methanol (MeOH) was used as the alcohol (2), and these components were mixed by setting the cinnamic acid (1): the alcohol (2) to 1:20 (molar ratio). Incidentally, the resin is of H+ type (?99 mol %) showing a catalytic activity, however, it is in a swollen state with water that is a reaction by-product of esterification at the time of factory shipment, and therefore, it was swollen with the alcohol that is a reactant, and thereafter used in the experiment. The swelling was performed by packing the resin in a glass column with an inner diameter of 11 mm and allowing the alcohol (2) to pass through the column at 2.5 cm/min until the water content of the washing liquid was decreased to less than 10 mass %.In this experiment (batch type), 20 g of the reaction solution obtained by homogeneously dissolving by preheating in advance so that the reaction temperature was 50 C. was placed in a glass reactor, and the resin in an alcohol-swollen state preheated in the same manner was fed thereto in an amount of 33 mass % with respect to the total reaction system, followed by shaking at a stirring rate of 150 spm. During the reaction, a small amount was collected from the reaction solution at predetermined time intervals and appropriately diluted with methanol, and the yield of the reaction was traced and determined using an HPLC (Waters Corp., Milford, Mass., USA) system. The yield when the reaction time was 12 hours was 100% (conversion rate: 100%). |
81% | With sulfuric acid; for 2.0h;Reflux; | General procedure: Caffeic acid (0.5 g, 2.77 mmol) was dissolved in dry appropriate aliphatic alcohol (20 mL) and H2SO4 (0.5 mL, 96%, v/v) was added. Reaction mixture was reuxed for 2 h. After cooling at room temperature, the solution was diluted with ethyl acetate (100 mL) and washed with an aqueous solution of NaHCO3 (5% w/v) until neutral pH. The organic layer was then washed with distilled water and dried over anhydrous MgSO4, and the solvent was removed under vacuum. The residue was then puried by silica gel circula rchromatography to afford the required ester derivative. 5.1.2.5. Compound 4: procedure 1. Ester 4 (382 mg, 81%) was obtained after silica gel circular chromatography (40% EtOAc-hexane) as a white solid; mp 128-140 C; 1H NMR (400 MHz, DMSO-d6, 25 C) delta (ppm): 9.58 (br s, 1H, OH), 9.14 (br s, 1H, OH), 7.47 (d, J = 15.93 Hz, 1H, CHCar), 7.05 (s, 1H, Har), 7.00 (dd, J = 8.24, 1.16 Hz, 1H, Har), 6.76 (d, J = 8.12 Hz, 1H, Har), 6.26 (d, J = 15.89 Hz, 1H, CHCO), 4.16 (q, J = 7.04 Hz, 2H, CH2CH3), 1.24 (t, J = 7.08 Hz, 3H, CH2CH3); 13C NMR (101 MHz, DMSO-d6, 25 C) delta (ppm): 167.01, 148.83, 146.02, 145.45, 125.97, 121.80, 116.19, 115.26, 114.51, 60.15, 14.73; HRMS m/z calcd for C10H12O4+(H+): 209.0808; found: 209.0811. |
With sulfuric acid; at 100.0℃; for 0.116667h;Microwave irradiation; | General procedure: Briefly, the acid (2 g) with the appropriate aromatic pattern, ethanol (2.5 mL) and H2SO4 (3 drops) were put together in a glass vial (2-5 mL) sealed with a cap and heated in the MW reactor cavity under mechanical stirring at 100 C for 7 min. After cooling to room temperature, the solvent was removed and the compounds were purified by flash chromatography (silica gel; hexane with increasing ethyl acetate gradient) and recrystallized from diethyl ether/petroleum ether. |
With sulfuric acid; | General procedure: As recently reported (Sanderson et al., 2013), alkyl esters 6-12 were prepared by esterification with selected alcohol and commercially available caffeic acid (4) in the presence of sulfuric acid. | |
With sulfuric acid;Reflux; | General procedure: A mixture of caffeic acid (0.25 g, 1.39 mmol) and alcohol (50 ml) was heated under reflux in the presence of sulfuric acid (0.4 ml) until completion of the reaction (5-21 hours)and verified by a single spot in TLC. The alcohol was then removed under reduced pressure, and the solution was diluted with 20 ml of water. The product was extracted with ethyl acetate (15 ml). The organic phase was neutralized successively with 5% sodium bicarbonate and water, dried over anhydrous sodium sulfate, and filtered. After evaporation under reduced pressure, this phase yielded the ester derivatives [44]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; at 60℃; for 3.0h; | General procedure: Compounds 1 (1mg), 2 (1.5mg), 9 (1.9mg), 14 (2.5mg), 15 (2.0mg), and 17 (7.6mg) were separately hydrolyzed with 2N HCl (0.5mL) at 60C for 3h. Each reaction mixture was neutralized using an Amberlite IRA400 column (Sigma-Aldrich Co. LLC., St. Louis, MO, USA), and each eluate was concentrated. Residues were individually stirred with l-cysteine methyl ester (5mg) and O-tolyl isothiocyanate (20muL) in pyridine (0.5mL), using the procedure reported by Tanaka and colleagues (Tanaka et al., 2007). (0047) Each of the mixtures was analyzed by HPLC (column, Cosmosil 5C18-AR II column, 4.6×250mm, Nacalai tesque; mobile phase, CH3CN-0.2% TFA in H2O (25:75), 1.0mL/min; detector, UV at 210nm) at 20C. d-Glucose (tR 16.4min) was identified as the glycosidic moiety of 1, 2, 9, and 14 in comparison with the authentic samples of d-glucose derivatives (tR 16.4min) and l-glucose derivatives (tR 15.3min). d-Glucuronic acid (tR 16.2min) was identified as the glycosidic moiety of 15 and 17 by comparison with authentic samples of d-glucuronic acid derivatives (tR 16.2min) and l-glucuronic acid derivatives (using d-cysteine methyl ester and d-glucuronide, tR 15.1min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With ytterbium(III) triflate; In nitromethane; at 120℃; | General procedure: To a mixture of caffeic acid fine powder (1.0 g, 5.56 mmol), various phenethyl alcohols (5.56 mmol) in CH3NO2 (125 mL) was added Yb(OTf)3 (34.4 mg, 0.056 mmol). After 5 min of ultrasonic shake, the mixture was stirred on a 120 °C oil bath for 40-120 min. The reaction mixture was cooled to room temperature, washed with 2percent NaHCO3 (30 mL) and brine, dried over anhydrous Na2SO4, and concentrated to give crude products, which were purified by column chromatography to give the compounds 1-26 in 18-61percent yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With ytterbium(III) triflate; In nitromethane; at 120℃; | General procedure: To a mixture of caffeic acid fine powder (1.0 g, 5.56 mmol), various phenethyl alcohols (5.56 mmol) in CH3NO2 (125 mL) was added Yb(OTf)3 (34.4 mg, 0.056 mmol). After 5 min of ultrasonic shake, the mixture was stirred on a 120 °C oil bath for 40-120 min. The reaction mixture was cooled to room temperature, washed with 2percent NaHCO3 (30 mL) and brine, dried over anhydrous Na2SO4, and concentrated to give crude products, which were purified by column chromatography to give the compounds 1-26 in 18-61percent yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With ytterbium(III) triflate; In nitromethane; at 120℃; | General procedure: To a mixture of caffeic acid fine powder (1.0 g, 5.56 mmol), various phenethyl alcohols (5.56 mmol) in CH3NO2 (125 mL) was added Yb(OTf)3 (34.4 mg, 0.056 mmol). After 5 min of ultrasonic shake, the mixture was stirred on a 120 C oil bath for 40-120 min. The reaction mixture was cooled to room temperature, washed with 2% NaHCO3 (30 mL) and brine, dried over anhydrous Na2SO4, and concentrated to give crude products, which were purified by column chromatography to give the compounds 1-26 in 18-61% yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.16% | With triethanolamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 16.5h; | Place L-dopa methyl hydrochloride (9.99 mmol, 2.47 g) in a round bottom flask, add DMF (10 mL) to dissolve,Place in an ice bath (0-5 C) and stir for 10 minutes, and then add the prepared caffeic acid (8.33 mmol, 1.50 g) in dichloromethane (20 mL) dropwise.After the dropwise addition, PyBOP (8.33 mmol, 4.33 g) was added in portions, and triethanolamine (24.98 mmol, 3.33 mL) was added at the same time.After 30 minutes of reaction, stir at room temperature for 16 h.The reaction was monitored by TLC (developing solvent: n-hexane-ethyl acetate-methanol, 5: 4: 1), and the reaction was complete.The solvent was recovered under reduced pressure, and the mixture was allowed to cool and extracted with ethyl acetate (3 × 25 mL). The organic phases were combined, followed by 1 M hydrochloric acid solution,10% sodium bicarbonate solution, water, saturated sodium chloride (3 × 25 mL), dried over anhydrous sodium sulfate, spin-dried,Column chromatography (eluent: n-hexane: ethyl acetate: methanol = 60: 35: 5), dried under reduced pressure,A light yellow powder (I-1) (1.87 g) was obtained.The yield was 60.16%. Mp: 162.1-162.8 |
Tags: Caffeic acid | TRP Channel | Lipoxygenase | Endogenous Metabolite | Transient receptor potential channels | LOX | TRPV1 ion channel inhibitor | 5-Lipoxygenase inhibitor | 5-LO inhibitor | 331-39-5
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