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CAS No. : | 102-32-9 | MDL No. : | MFCD00004338 |
Formula : | C8H8O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CFFZDZCDUFSOFZ-UHFFFAOYSA-N |
M.W : | 168.15 | Pubchem ID : | 547 |
Synonyms : |
3,4-Dihydroxyphenylacetic Acid;NSC 73191;DOPAC
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 42.03 |
TPSA : | 77.76 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.63 cm/s |
Log Po/w (iLOGP) : | 0.8 |
Log Po/w (XLOGP3) : | 0.98 |
Log Po/w (WLOGP) : | 0.72 |
Log Po/w (MLOGP) : | 0.47 |
Log Po/w (SILICOS-IT) : | 0.59 |
Consensus Log Po/w : | 0.71 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.74 |
Solubility : | 3.07 mg/ml ; 0.0183 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.2 |
Solubility : | 1.06 mg/ml ; 0.00629 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.02 |
Solubility : | 16.1 mg/ml ; 0.0957 mol/l |
Class : | Soluble |
PAINS : | 1.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.27 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
96.9% | With hydrogenchloride; acetic acid In water at 80℃; for 6h; | 1.1 (1) Add 520 g of a 10% by mass aqueous solution of dilute hydrochloric acid to the reaction vessel.Add 100g of 3,4-dimethoxyphenylacetic acid with stirring at room temperatureAnd 1.53g of glacial acetic acid;After the addition is completed, the reaction is carried out at 80 ° C for 6 h;Sampling, HPLC detection of the complete reaction of the raw materials;The reaction solution was lowered to 60 ° C, and water was distilled off under reduced pressure.Add 200 mL of isopropyl ether to the remaining oil.Then it was frozen in a refrigerator (0 ° C) overnight, a white solid precipitated, and filtered.The filter cake was washed with isopropyl ether.Drying at 55 ° C to obtain pure 3,4-dihydroxyphenylacetic acid,83.5 g, the yield was 96.9%. |
With phosphorus; hydrogen iodide | ||
With boron dimethyl-trifluoro sulphide In dichloromethane at 20℃; for 24h; Darkness; Cooling with ice; | 2-(3,4-dihydroxyphenyl)acetic acid (34) To an ice-cold solution of 2-(3,4-dimethoxyphenyl)acetic acid (10.2 mmol, 2.0 g) in dry CH2C12 (40 mL), BF3S(CH3)2 (101.9 mmol, 10.7 mL) was added dropwise. The reaction mixture was then stirred at ambient temperature, in the dark, for 24 h. Upon completion of the reaction, the solvent was evaporated under nitrogen flow. The desired product 34 was obtained as a yellowoil and used to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrogenchloride; water; at 65℃; for 16.0h; | A mixture of <strong>[1126-62-1](3,4-dihydroxyphenyl)acetonitrile</strong> (75 mg, 0.5 mmol, prepared according toexample 4) and concentrated aqueous hydrochloric acid (0.5 ml) was stirred at 65 C for 16 h.The mixture was diluted with brine (5 ml), extracted with AcOEt (3 ml), and iBu3PO4 (0.04ml, 0.146 mmol) was added as NMR standard. Analysis by 1H NMR of a concentrated sampleindicated, that (3,4-dihydroxyphenyl)acetic acid had been formed in 70% yield.1H NMR (DMSO, 400 MHz) delta = 6.64 (m, 2H), 6.48 (m, 2H), 3.34 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sulfuric acid In diethyl ether at 20℃; for 24h; Inert atmosphere; | |
46% | With sulfuric acid at 75℃; for 1.5h; | Preparation of 2a-2c General procedure: Gallic acid (1a, 7.53 g, 40 mmol) and acetic anhydride (22.7 mL, 240 mmol) were combined in a 100 mL round-bottom flask. The slurry was stirred with a magnetic stirrer and catalytic amount of sulfuric acid (500 lL) was added. The reaction mixture was stirred at 75 C for 1.5 h, and the slurry became a clear yellow solution. The mixture was further stirred for 20 min at room temperature, and 60 mL of water was added. After stirring for 2.5 h, a white crystalline product was isolated by filtration and washed with water (20 mL 9 3). The product was dried in a vacuum drying oven overnight to obtain the acetyl-protected gallic acid 2a (8.7 g). 2b, 2c were synthesized using similar method as 2a. |
With pyridine at 20℃; |
at 20℃; for 18h; | 41 PREPARATIVE EXAMPLE 41 PREPARATION OF [3,4-BIS(ACEYLOXY)PHENYL]ACETIC ACIDTo a solution of 3,4-dihydroxy-phenyl acetic acid (1.0 g, 5.95 mmols) in Ac2O (5.0 mL) at r.t., was added cone. H2SO4 (0.1 mL), The mixture was stirred at r.t., for 18hrs. The reaction mixture was partitioned between EtOAc and D.I, H2O and washed with brine. The extract was dried over Na2SO4 and filtered. 50193-253 . 21908PVThe filtrate was concentrated in vacuo. The crude mixture was purified using silica gel chromatography( 10% MeOH-DCM) to give 160 mg of product. . . ..1H NMR (500 MHz, dβ-acetone) δ (ppm): 7.2 (m, 3H), 3.6 (s, 2H), 2.2 (d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sulfuric acid for 2h; Reflux; Darkness; Inert atmosphere; | |
100% | With thionyl chloride at 50℃; for 5h; Inert atmosphere; | |
98.4% | With hydrogenchloride In water monomer at 56℃; for 1h; | 1.2 (2) adding 100 mL of methanol to a reaction vessel,83.5 g of 3,4-dihydroxyphenylacetic acid was added with stirring at room temperature, after it was completely dissolved,4.98 g of concentrated hydrochloric acid (mass fraction 36%) was added;After the addition is completed, the reaction is carried out at 56 ° C for 1 h;Sampling, HPLC detection of the complete reaction of the raw materials;The reaction solution was cooled to room temperature, and concentrated under reduced pressure to recover methanol.Add 100 mL of water to the remaining oil.Then extracted with methyl tert-butyl ether,Collecting organic layers and drying the organic layer,Concentration to dryness gave methyl 3,4-dihydroxyphenylacetate, 89.5 g, yield 98.4%. |
97% | With sulfuric acid for 3h; Heating; | |
96% | With sulfuric acid for 1.5h; Heating; | |
95% | With thionyl chloride at 50℃; for 5h; | |
94% | With thionyl chloride at 0 - 20℃; for 9h; | DOPAC methyl ester (2) 30 mmol of DOPAC (5 g) was dissolved inanhydrous methanol (60 ml) under stirring at 0 °C in the presence of40 mmol of SOCl2 (3 ml) as acid catalyst. The mixture was stirred atroom temperature for 9 h. After solvent was evaporated under lowpressure, desired compound 2 (94% yield) was isolated as colorless oilby silica gel column chromatography using petroleum ether/ ethyl acetate (3:1, v/v) as eluent. Analytical data were as reported in Zhanget al. (2010). |
91.2% | With thionyl chloride at 0 - 20℃; | |
84% | With sulfuric acid for 2h; Inert atmosphere; Darkness; Reflux; | |
56% | With sulfuric acid for 24h; Reflux; | General procedure for the synthesis of compounds 9-12 and 21-29 General procedure: After dissolving the carboxylic acid in the alcohol, three drops of H2SO4 95% were added to the solution and the mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure and water was added to the crude mixture. The pH of the aqueous layer was adjusted to 7 adding drops of a saturated solution of NaHCO3 and brine was added in the mixture. The aqueous layer was extracted three times with ethyl acetate; the organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure yielding the final compound. Further purification step was made when it was necessary. |
With sulfuric acid | ||
With sulfuric acid for 3h; Heating; | ||
With acetyl chloride for 1h; | ||
With thionyl chloride | ||
With sulfuric acid Heating; | ||
With sulfuric acid for 2h; Heating; | ||
With sulfuric acid Heating / reflux; | 24 Ciompound 24 2-{3,4-Bis[(4-methoxybenzyl)oxy]phenyl}-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl) acetoamide 3,4-Dihydroxyphenylacetic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(3,4-dihydroxyphenyl)acetate. | |
With sulfuric acid In water monomer for 13h; Heating / reflux; | 10.a Example 10 2-[3,4-Bis(octyloxy)phenyl]-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 10) (a) 3,4-Dihydroxyphenylacetic acid (4.00g, 23.79mmol) was dissolved in methanol (48ml), and sulfuric acid (1.3ml) was added thereto. The mixture was refluxed for 13 hours, and then the solvent was evaporated out. The residue was diluted with water, neutralized with sodium hydrogencarbonate, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over MgSO4, and then the solvent was evaporated out. | |
With hydrogenchloride for 4h; Reflux; | ||
With sulfuric acid Reflux; | ||
With thionyl chloride at 0℃; | ||
With thionyl chloride at 20℃; for 8h; | ||
140 mg | With acetyl chloride at 20℃; | 4 We started our hydroxytyrosol synthesis from 3,4-dihydroxylphenylacetic ester. It was prepared by the following procedure. The reaction mixture of 3,4-dihydroxylphenylacetic acid 168 mg in CH3OH was treated with Acetyl chloride and CH3OH mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography. A total of 140 mg of oily compound was obtained |
With toluene-4-sulfonic acid for 3h; Reflux; Darkness; | A.A.1.a Step a): Synthesis In Situ of Hydroxytyrosol from Dihydroxyphenylacetic Acid Dihydroxyphenylacetic acid is dissolved in methanol and esterified at reflux over 3 hours with catalysis by para-toluenesulfonic acid, in the absence of light. The methanol is evaporated and methyltetrahydrofuran (methylTHF) is added. The resulting solution is washed with sodium bicarbonate and with brine. Following evaporation of the solvent, the residue is taken up in tetrahydrofuran and lithium aluminum hydride is added to the mixture. The whole mixture is refluxed for 2 hours. 5N HCl solution is added to the mixture, which is subsequently extracted with methylTHF. | |
With acetyl chloride at 0 - 20℃; for 3h; Inert atmosphere; | ||
With sulfuric acid for 3h; Heating / reflux; | 1.1; 2.1; 3.1; 4.1; 5.2 3,4-Dihydroxyphenylacetic acid (13 g, 77.3 mmol) was heated with methanol (260 mL) and concentrated sulfuric acid (6.5 mL) at reflux for about 3 hours. The solvent was removed in vacuo, and the resulting residue was dissolved in anhydrous dimethylformamide (50 mL). Dichloromethane (19.5 mL, 304 mmol) and cesium fluoride (60 g, 395 mmol) were then added, and the mixture was heated to about 90 0C for about 12 hours. After cooling to ambient temperature, standard extractive workup was performed with dichloromethane, and the crude product was then purified by column chromatography on silica gel (5x20 cm, petroleum ether/ethyl acetate=10/l elution) to yield the title product (6.3 g, 42%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.77-6.69 (m, 3H), 5.93 (s, 2H), 3.69 (s, 3H), 3.53 (s, 2H); LC-MS: m/z=195(MH)+.; 2-Dichloromethane (15 mL, 228.8 mmol) and cesium fluoride (98 g, 644.7 mmol) were then added, and the mixture was heated at about 100 0C for about 12 hours. After cooling to ambient temperature, strandard extractive workup was performed with dichloromethane, and the resulting crude product was then purified by flash column chromatography on silica gel (4 x 15 cm, petroleum ether/ethyl acetate= 10/1 elution) to yield the title product as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.79-6.71 (m, 3H), 3.71 (s, 3H), 3.55 (s, 2H); LC-MS: m/z= 197 (MH) +.; | |
With sulfuric acid for 3h; Reflux; | ||
With sulfuric acid at 65℃; for 2h; Darkness; | Methyl 2-(3,4-dihydroxyphenyl)acetate (35) To a solution of 34 (10.2 mmol) in methanol (140 mL) conc. H2S04 was added (10 drops). The reaction mixture was then refluxed, in the dark, for 2 h. Uponcompletion of the reaction, the mixture was cooled to ambient temperature and evaporated in vacuo almost to dryness. The residue was diluted with ethyl acetate and washed with sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried over anhydrous Na2 SO4 and evaporated to dryness. The desired product 35 was obtained as a dark yellow oil which was used to the next step without further purification.‘H NMR (300 MHz, CD3OD): 6 6.70 -6.68 (m, 2H, Ar), 6.56 (dd, J 8.1, 1.9 Hz, 1H, Ar), 3.66 (s, 3H,OCH3), 3.46 (s, 2H, CH2) | |
With sulfuric acid at 60℃; for 1h; | Preparation of Methyl Ester 20 from 19 A solution of 3,4-dihydroxyphenylacetic acid (19, 238 mg, 1.41 mmol) in MeOH (4.0 mL) with conc. H2SO4 (0.1 mL) was stirred for 1 h at 60°C. After cooling to room temperature, EtOAc was added to reaction mixture, then the whole was washed with saturated aqueous NaHCO3 and brine, sequentially. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to yield a crude product. To a solution of the crude product in CH2Cl2 (4.0 mL) were added pyridinium p-toluenesulfonate (PPTS, 35.5 mg, 0.14 mmol) and 3,4-dihydro-2H-pyran (DHP, 2.2 mL, 25.4 mmol) at room temperature. After stirring for 12 h at room temperature, the reaction was quenched by adding brine. The mixture was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n-hexane-EtOAc=10 : 1 to 5 : 1) to give 20 (498 mg, quant.). The obtained products was identified by the previously reported spectroscopic data.10) | |
With sulfuric acid at 75℃; for 6h; Inert atmosphere; | 2.2.1. Synthetic procedure of compound 7 To a solution of 3,4-dihydroxyphenylacetic acid 6 (5.65 g, 33.6mmol) in MeOH (100 mL), H2SO4 (98%, 10 drops) was slowly added in atmosphere of argon, followed by further refluxing for 6 h. After the reaction was completed, the solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), and the solution was washed with saturated NaHCO3 solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3), washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, and evaporated in vacuo to give the crude product 7, which was directly used in the next step without further purification. | |
With sulfuric acid at 70℃; for 12h; | 2.1.1 Methyl-2-(3,4-dihydroxyphenyl) acetate (5) A commercially available 3,4-dihydroxyphenylacetic acid (4, 7g, 41.6mmol) in methanol was added concentrated sulfuric acid, and the reaction was refluxed for 12h, 70°C. After completion of the reaction, it was quenched by adjusting pH to 7.0 with the additional imidazole (10g) and was stirred for another 30min. Then the mixture was concentrated under vacuum to furnish the residue as crude product (5, 7.2g, 39.52mmol, 80%) [12]. HRESIMS m/z 183.0652 [M+H]+ (calcd. for C9H11O4, 183.0651). 1H NMR (400MHz, CD3OD): δH 6.67 (d, J=8.0Hz, 1H), 6.65 (s, 1H), 6.52 (dd, J=2.0, 8.0Hz, 1H), 3.59 (s, 3H), 3.41 (s, 2H). 13C NMR (100MHz, CD3OD): δC 174.6, 146.3, 145.5, 136.3, 121.6, 117.4, 116.3, 52.4, 41.1. | |
With sulfuric acid at 70℃; for 12h; | 2.1.1 Methyl-2-(3,4-dihydroxyphenyl) acetate (5) A commercially available 3,4-dihydroxyphenylacetic acid (4, 7g, 41.6mmol) in methanol was added concentrated sulfuric acid, and the reaction was refluxed for 12h, 70°C. After completion of the reaction, it was quenched by adjusting pH to 7.0 with the additional imidazole (10g) and was stirred for another 30min. Then the mixture was concentrated under vacuum to furnish the residue as crude product (5, 7.2g, 39.52mmol, 80%) [12]. HRESIMS m/z 183.0652 [M+H]+ (calcd. for C9H11O4, 183.0651). 1H NMR (400MHz, CD3OD): δH 6.67 (d, J=8.0Hz, 1H), 6.65 (s, 1H), 6.52 (dd, J=2.0, 8.0Hz, 1H), 3.59 (s, 3H), 3.41 (s, 2H). 13C NMR (100MHz, CD3OD): δC 174.6, 146.3, 145.5, 136.3, 121.6, 117.4, 116.3, 52.4, 41.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.7% | With ascorbic acid In aq. phosphate buffer at 25℃; | 2.5. Reaction to produce 3,4-dihydroxyphenylacetic acid (DHPAA) from 4-hydroxyphenylacetic acid (HPAA) A typical reaction was started by addition of 15.0 mg of tyrosinaseCLEAs into 20.0 mL of Na phosphate buffer (50 mM, pH 6.0) containing10.0mM HPAA and 15.0mM L-ascorbic acid in a 50 mL conical flask,which was placed in a shaking incubator with agitation of 200 rpm at25 °C. Periodically, a 0.15 mL sample was taken which was then fourtimes diluted with the buffer before subjected to HPLC analysis as describedbelow. |
98% | With Agaricus bisporus; oxygen In aq. phosphate buffer; dichloromethane at 25℃; for 24h; | 4.8 Oxidation of phenols and esters derivatives General procedure: The reactions were performed under both homogeneous and heterogeneous conditions in CH2Cl2/buffer. As a general procedure, phenol (0.05mmol), tyrosinase (600IU) and the optimal amount of the Na-phosphate buffer 0.1M, pH 7 (CH2Cl2/buffer ratio ca. 1:0.1) were suspended in CH2Cl2 (2.5mL) at 25°C for 24h, and the mixture stirred under O2 atmosphere. The reactions were monitored by thin layer chromatography (TLC, n-hexane/EtOAc=2.0:1.0). After the disappearance of the substrate, the organic layer was recovered (eventually after filtration for immobilized enzyme), and evaporated under reduced pressure. The crude was treated with Na2S2O4 in equal volume of H2O and THF (2.0mL) with stirring for 5min. The mixture was diluted with EtOAc (4.0mL) and separated from H2O. The organic layer was dried on anhydrous Na2SO4 and evaporated under reduced pressure. When necessary the crude was purified by flash-chromatography. The products were characterized by 1H and 13C NMR, GC-MS (after silylation) and Elemental Analysis. GC-MS analysis was performed on a GC-MS QP5050 Shimadzu apparatus using an SPB column (25m×0.25mm and 0.25mm film thickness) and an isothermal temperature profile of 100°C for 2min, followed by a 10°Cmin-1 temperature gradient to 280°C for 25min. The injector temperature was 280°C. Chromatography-grade helium was used as the carrier gas with a flow of 2.7 mL×min-1. Mass spectra were recorded with an electron beam of 70eV. Quantitative analyses were performed by using dodecane as the internal standard. MS values are referred to full silylated derivatives with the only exception of 3c and 3d. |
91% | With sodium dihydrogenphosphate at 25℃; for 0.25h; Glovebox; |
88% | With Agaricus bisporus tyrosinase; oxygen; ascorbic acid In water at 20℃; for 24h; Na-phosphate buffer; Enzymatic reaction; | 4.10. Phenols oxidation General procedure: A panel of phenols (Fig. 7) were oxidized, including para-cresol 1, 4-ethyl phenol 2, 4-tert-butyl phenol 3, 4-sec-butyl phenol 4, 2,4-di-tert-butyl phenol 5, meta-cresol 6, 3,4-dimethyl phenol 7, 4-chloro phenol 8, 4-chloro-2-methyl phenol 9, 2-methoxy-4-methyl phenol 10, 2-methoxy phenol 11, 3-(4-hydroxyphenyl)propionic acid 12, 4-hydroxyphenylacetic acid 13, bis(4-hydroxyphenyl)methane 14 and tyrosol 15. As a general procedure phenol (0.05 mmol), tyrosinases (263-526 IU) and AA (1.5 equiv) were placed in 0.1 M Na-phosphate buffer pH 7.0 (5.0 mL) in vigorous stirring at room temperature. For insoluble aqueous phenols 3, 5, 14 substrates were dissolved in CH3CN (1.0 mL) and then added to the buffer solutions. Oxidations were performed using homogeneous and heterogeneous conditions. Reactions were monitored by thin layer chromatography (TLC). After the disappearance of the substrate, the reaction mixture was acidified with a solution of HCl 1.0 N and extracted twice with EtOAc. The organic extracts were treated with a saturated solution of NaCl and dried over anhydrous Na2SO4, then filtered and concentrated under vacuum to yield a colored crude. In the case of immobilized enzyme, biocatalyst was first recovered by filtration and the solution was subjected to the same work up described above. The obtained colored residue was treated with pyridine, HMDS and TMCS (HMDS-TMCS, 2:1 v/v) under vigorous stirring at room temperature for 30 min, then allowed to stand for 5 min.50 All products were identified by 1H NMR, 13C NMR and GC-MS. 1H NMR and 13C NMR were recorded on a Bruker 200 MHz spectrometer using CDCl3 as solvent. All chemical shift are expressed in parts per million (δ scale). GC-MS analysis were performed on a GCMS-QP5050 Shimadzu apparatus using a SPB column (25 m × 0.25 mm and 0.25 mm film thickness) and an isothermal temperature profile of 100 °C for 2 min, followed by a 10 °C/min temperature gradient to 280 °C for 25 min. The injector temperature was 280 °C. Chromatography-grade helium was used as the carrier gas with a flow of 2.7 mL/min. Mass spectra were recorded with an electron beam of 70 eV. |
56% | With oxygen; ascorbic acid In aq. buffer at 30℃; for 4.4h; Enzymatic reaction; | 2.6.2. Production of DHPAA without in situ adsorption To examine the tyrosinase catalyzed production of DHPAA, dif-ferent amounts (0.1-0.9 g) of various matrix capsules (17-83 mgcdw/g, d = 0.9-1.3 mm) were incubated in 9 ml substrate solution(5 mM HPAA, 0-25 mM ascorbic acid, 0.1 M MES with pH 6 adjustedto with NaOH) under stirring and aeration at 30C. At certain timeintervals samples of the solution were withdrawn and the concen-trations of HPAA and DHPAA were quantified by HPLC. The yieldof DHPAA in these experiments was determined as the percent-age ratio of the amount of DHPAA in the reaction medium and theamount of HPAA initially used. |
In various solvent(s) at 30℃; for 170h; biosynthesis by Trichosporon cutaneum strains, other incubation times; | ||
With mushroom tyrosinase In N,N-dimethyl-formamide at 25℃; aq. phosphate buffer; Enzymatic reaction; | ||
With HpaB from Escherichia coli; sodium formate; flavin adenine dinucleotide; NADH; sodium chloride In aq. buffer at 35℃; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (C4H9)NBH4 In tetrahydrofuran; dichloromethane at 20℃; for 2h; | |
90% | With lithium aluminium hydride In tetrahydrofuran at 0 - 60℃; for 8h; | 7 Example 7 Lithium aluminum hydride (2.00 g, 135 mmol, 3 equiv) was placed in a dry single-mouth bottle.After adding 125 mL of anhydrous tetrahydrofuran, it was dissolved by stirring at 0 °C.Weigh 3,4-dihydroxyphenylacetic acid (3.0 g, 45 mmol, 1.0 equiv),Add the above solution in batches, remove the ice bath after low temperature feeding, react at 60 ° C for 8 h, place the reaction solution at 0 ° C, slowly add water and 2 M hydrochloric acid solution.After the dropwise addition, multiple extractions were carried out with ethyl acetate, which contained 8.9 Å of N-phenylpyrrolidine and 1.3 Å of dimethyl carbonate.The organic phase was combined, washed with a saturated aqueousA pale yellow oil was obtained, which was hydroxytyrosol, and the purity was 97% and the yield was 90% by high performance liquid chromatography. |
79% | With lithium aluminium hydride In tetrahydrofuran for 2h; Heating; |
79% | With tetra-N-butylammonium borohydride; iodomethane In tetrahydrofuran; dichloromethane at -5 - 20℃; for 2h; | To the reaction flask was added tetrabutylammonium borohydride in dichloromethane (preparation method J. Agric. Food Chem. 2000, 48, 4087-4090) 0.1 mol,Cool down to -5 °C.Further, 3,4-dihydroxyphenylacetic acid (8.4 g, 0.05 mol) was dissolved in 20 ml of tetrahydrofuran.Dropped into the reaction bottle,Keep the temperature -5 ~ 5 ° C, drop,Iodomethane (3.1 ml, 0.05 mol) was added dropwise at this temperature.After the dropwise addition was completed, the reaction was carried out for 2 hours at room temperature.To the reaction solution, about 80 ml of 1N hydrochloric acid was added dropwise, and the mixture was stirred.The dichloromethane layer was extracted with water (40 ml x 3).The combined aqueous phases were extracted with ethyl acetate (100 ml×3), and ethyl acetate and brine.Dry over anhydrous sodium sulfate, filter,The solvent was evaporated under reduced pressure to give a pale yellow oil hydroxytyrosol 6.1g. The yield was 79% and the content was >98% (HPLC area normalization method). |
66% | With lithium aluminium hydride In tetrahydrofuran for 6h; Heating; | |
59% | With lithium aluminium hydride In tetrahydrofuran for 22h; Heating; | |
45% | With lithium aluminium hydride In tetrahydrofuran for 2h; Reflux; | |
42% | With D-glucose In aq. phosphate buffer at 30℃; for 29h; Enzymatic reaction; | 2.10. Reduction with whole cell biocatalyst General procedure: Glucose (22.2 mM), E. coli BL21(DE3)/pETDuet-1-PPTase-CAR (wet cells, 10 g), and the substrate (20a, 5.0 mM) were mixed in the sodium phosphate buffer (100 mL, 100 mM, pH 8). The resulting mixture was incubated at 200 rpm in a rotary shaker at 30°C, and the reaction was monitored by GC. After 29 h, the pH of the reaction mixture was adjusted to 2-3 with 2 M HCl and the mixture was filtered through a Celite pad to remove the biomass. The resulting aqueous solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was puriedby a silica gel column to give the product. |
88 mg | With lithium aluminium hydride In diethyl ether for 24h; Ambient temperature; | |
With lithium aluminium hydride | ||
With lithium aluminium hydride | ||
With lithium aluminium hydride In tetrahydrofuran | ||
Multi-step reaction with 4 steps 1: conc. H2SO4 / 2 h / Heating 2: 2.99 g / camphorsulfonic acid / CHCl3 / 8 h / Heating 3: 95 percent / LiAlH4 / tetrahydrofuran / 3 h / Heating 4: 97 percent / Amberlyst 15 / methanol / 3 h / Heating | ||
Multi-step reaction with 3 steps 3: LiAlH4 | ||
With lithium aluminium hydride In tetrahydrofuran at 0℃; for 6.33333 - 6.5h; Heating / reflux; | 4 Tetrahydrofuran (THF, 200 ml) and lithium aluminum hydride LiAlH4 (5.12 g:0.13 mol) were cooled to 0° C., and 3,4-dihydroxyphenylacetic acid (7.6 g:0.045 mol) was added thereto over a period of 20 to 30 minutes under agitation. Afterward, the temperature was gradually elevated, and reflux was performed for 6 hours. After the reaction solution was allowed to stand to cool, the reaction was stopped by adding ice water (100 ml) and 10% hydrochloric acid (100 ml). Next, an extraction operation was repeated 3 to 4 times with ethyl acetate (100 ml), and the ethyl acetate layer thus obtained was dried with anhydrous magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure, to thereby produce a dried product. The dried product was purified by silica gel column chromatography, to thereby produce DPE (4.5 g). | |
With lithium aluminium hydride | ||
Stage #1: 3,4-dihydroxyphenylacetate With sulfuric acid In ethanol for 3h; Reflux; Stage #2: With sodium tetrahydridoborate In ethanol; water monomer at 20℃; for 8h; | ||
29.2 mg | With ethylenediaminetetraacetic acid; oxygen; coenzyme A||CoA; NADPH; magnesium(II) chloride; DL-threo-1,4-dimercapto-2,3-butanediol In aq. phosphate buffer; toluene at 28℃; for 5h; Enzymatic reaction; | |
Multi-step reaction with 2 steps 1: thionyl chloride / 8 h / 20 °C 2: lithium aluminium hydride / tetrahydrofuran / 8 h / 0 °C | ||
Multi-step reaction with 2 steps 1: acetyl chloride / 20 °C 2: lithium aluminium hydride / tetrahydrofuran / 2 h / 0 °C | ||
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / 3 h / Reflux; Darkness 2: lithium aluminium hydride / tetrahydrofuran / 2 h / Reflux | ||
With D-glucose; magnesium(II) sulfate; magnesium(II) chloride In aq. buffer at 28℃; for 24h; Microbiological reaction; | ||
Multi-step reaction with 4 steps 1: sulfuric acid / 2 h / Inert atmosphere; Darkness; Reflux 2: toluene-4-sulfonic acid / dichloromethane / 8 h / Inert atmosphere; Darkness; Reflux 3: lithium aluminium hydride / diethyl ether / 3 h / 0 °C / Inert atmosphere 4: Amberlyst 15 / methanol / 8 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 12 h / 70 °C 2: lithium aluminium hydride / tetrahydrofuran / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With formic acid; phosphoric acid; sodium hydrogensulfite In water at 100℃; for 9h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium hydrogencarbonate In N,N-dimethyl-formamide Heating; | |
78% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: benzyl bromide With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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 |
---|---|---|
100% | With sulfuric acid for 4h; Heating; | |
100% | With sulfuric acid for 4h; Inert atmosphere; | |
90% | With sulfuric acid for 2h; Inert atmosphere; Reflux; |
89.8% | In ethanol for 3h; Heating / reflux; | a a) Ethyl 2-(3,4-dihydroxyphenyl)acetate To the flask was added EtOH (15 ml) followed by starting material (1.07 g, 6.36 mmol) and sulfuric acid (catalytic amount). The mixture was refluxed for 3 hrs then cooled to room temperature. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:1) as eluant. Colorless oil, yield: 89.8%. |
With sulfuric acid | ||
With thionyl chloride at 20℃; for 8h; | ||
With sulfuric acid for 2h; Reflux; | 1 [0185] ethyl 2-(3,4-dihydroxyphenyl)acetate. To a stirred solution of (3,4-dihydroxyphenyl)acetic acid (2.00 g, 11.9 mmol) in ethanol (10 mL) was added 3 drops of cone. H2SO4 and the reaction was heated at reflux for 2 h. The ethanol was removed under vacuum and the resulting residue was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with aqueous NaHCCL (2 x 50 mL) and water (50 mL), dried (Na2S04) and evaporated under vacuum to afford the ester (2.10 g, 10.7 mmol, 90%) as a colorless oil. This compound was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: conc. H2SO4 / 2 h / Heating 2: 2.99 g / camphorsulfonic acid / CHCl3 / 8 h / Heating 3: 95 percent / LiAlH4 / tetrahydrofuran / 3 h / Heating | ||
With sodium hydroxide In tetrahydrofuran; water; acetone; benzene | P.4 2,2-Dimethyl-5-(2-hydroxyethyl)-1,3-benzodioxole STR245 Preparative Example 4 2,2-Dimethyl-5-(2-hydroxyethyl)-1,3-benzodioxole STR245 1.7 g of 3,4-dihydroxyphenylacetic acid, a catalytic amount of p-toluenesulfonic acid, 10 ml of acetone and 10 ml of benzene were heated under reflux for 18 h. The reflux solution was dehydrated with Molecular Sieve 4A. The reaction mixture was concentrated and the obtained dark brown oil was dissolved in 20 ml of tetrahydrofuran. The solution was added to a suspension of 0.8 g of lithium aluminum hydride in 30 ml of tetrahydrofuran under cooling with ice. The mixture was stirred at room temperature for 1 h and then cooled with ice/water. 0.8 ml of water, then 0.8 ml of a 15% aqueous sodium hydroxide solution and finally 2.4 ml of water were added thereto and an insoluble substance was filtered off. The filtrate was concentrated and treated according to silica gel column chromatography (ethyl acetate/ n-hexane=1:1) to obtain 1.1 g of the intended compound in the form of a colorless oil. . 1 H-NMR(90MHz,CDCl3) δ;1.67 (s,6H), | |
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / toluene / 24 h / Reflux; Dean-Stark 2: sodium tetrahydroborate; iodine / tetrahydrofuran / 24 h / 4 °C / Reflux |
Multi-step reaction with 3 steps 1: sulfuric acid / 2 h / 65 °C / Darkness 2: camphor-10-sulfonic acid / dichloromethane / 24 h / 65 °C / Darkness 3: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 0 - 20 °C | ||
Multi-step reaction with 3 steps 1: sulfuric acid / 2 h / Inert atmosphere; Darkness; Reflux 2: toluene-4-sulfonic acid / dichloromethane / 8 h / Inert atmosphere; Darkness; Reflux 3: lithium aluminium tetrahydride / diethyl ether / 3 h / 0 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: conc. H2SO4 / Heating 2: pyridinium p-tosylate / CH2Cl2 / 1 h 3: 52 percent / DIBALH / toluene / 0.5 h / -78 °C 4: 50 percent / Amberlite-H+ / H2O; tetrahydrofuran / 4 h | ||
With glycerol-3-Phosphate Dehydrogenase; D-glucose; NADP<SUP>+</SUP>; Nocardia PPTase; Segniliparus CAR; ATP; coenzyme A; magnesium chloride In dimethyl sulfoxide at 35℃; for 16h; Enzymatic reaction; | 2.4. Standard reduction procedure General procedure: The His-CAR (1.5 mg) was incubated with His-PPTase (295 g) in the presence of CoA (1 mM) as a cofactor for 1 h at 28°C in a final volume of 600 L of sodium phosphate buffer (100 mM, pH 7.5) containing 10 mM of MgCl2. The resulting enzyme mixture (holo-CAR, 50 g) was mixed with NADP+ (0.9 mM), GDH (1 U, one unitcorresponds to the amount of enzyme which could reduce 1 molNADP+ to NADPH per minute), glucose (60 mM), MgCl2 (10 mM), substrate (5 or 10 mM, from 1 M stock solution in DMSO), and ATP (15 mM) in Tris-HCl buffer (100 mM, pH 9) with a nal volume of 1 mL. The reaction mixture was incubated at 100 rpm in a rotaryshaker at 35C for 16 h, and extracted with 1 mL of ethyl acetateafter the pH was adjusted to 2-3 with 1 M HCl solution. The organicextracts were dried over anhydrous sodium sulfate and analyzedby gas chromatography (GC) and gas chromatography-mass spec-trometry (GC-MS) to determine the amount of substrate (a) andproducts (aldehyde b, alcohol c) in the mixture. All experimentswere conducted in triplicate. | |
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / Reflux 2: N-ethyl-N,N-diisopropylamine; sulfur trioxide pyridine complex / dichloromethane; dimethyl sulfoxide / 1.5 h / -15 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With barium dihydroxide In water at 20 - 40℃; for 4h; | II EXAMPLE II; 3,4-diethoxy-phenylacetic acid 0.8 g of 3,4-dihydroxy-phenylacetic acid and 6.9 g of barium hydroxide octahydrate are dissolved in 50 ml of water and at ambient temperature 2.9 ml of diethylsulphate are added dropwise.. The solution is stirred for 2 hours at ambient temperature and for 2 hours at 40° C. After this time the solution is acidified with saturated potassium hydrogen sulphate solution, mixed with ethyl acetate and the suspension is filtered through Celite. The phases are separated and the ethyl acetate phase is dried over sodium sulphate and concentrated by evaporation.. The residue obtained is purified through a silica gel column with toluene/ethyl acetate/ethanol (4:2:1) as eluant. Yield: 0.5 g (42% of theory), Rf value: 0.5 (silica gel, toluene/ethyl acetate/ethanol=4:2:1) C12H16O4 ESI mass spectrum: m/z=223 [M-H-] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.4% | With sulfuric acid In benzene | 3.1 (1) (1) Synthesis of isopropyl (3,4-dihydroxyphenyl)acetate In dry benzene, 20.0 g of 3,4-dihydroxyphenylacetic acid were dissolved. The solution was added with 2 ml of concentrated sulfuric acid and 200 ml of isopropyl alcohol. The resulting mixture was refluxed for 10 hours under an argon stream while being dried through molecular sieves. The reaction mixture was extracted with ether. The organic layer was washed with water, shaken together with a saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The solvent was distilled off, whereby 32.5 g of black crude oil were obtained. The crude oil thus obtained was purified by column chromatography (crude oil: 32.5 g, silica gel: MERCK 9385, 615 g, column: 100 mm across*171 mm long, N2 pressure 0.3 kg/cm2, developer: chloroform:methanol=40:1), whereby 24.6 g of isopropyl (3,4-dihydroxyphenyl)acetate were obtained as colorless oil (yield: 98.4%). IR (NaCl)νmax cm-1: 3380, 1708, 1522, 1448, 1374, 1286, 1194, 1148, 1104. 1 H-NMR (CDCl3) δ [200 MHz] ppm: 1.24(6H,d,J=6.4 Hz), 3.46(2H,s), 5.02(1H,Sept., J=6.4 Hz), 6.62(1H,d,J=2.0,8.1 Hz), 6.72(1H,d, J=8.1 Hz), 6.73(1H,d,J=2.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate In acetonitrile for 16h; Reflux; | 3 Synthesis of benzyl 2-(3,4-bis(benzyloxy)phenyl)acetate 3,4-Dihydroxyphenylacetic acid (10 g, 65 mmol), benzyl bromide (30.88 mL, 260 mmol), and potassium carbonate (35.86 g, 260 mmol) in 200 mL acetonitrile were refluxed for 16 hrs. The reaction solution was cooled to room temperature and the solvent was removed under vacuum. Ethyl acetate (300 mL), hexanes (300 mL), and water (100 mL) were added to the residue. The organic layer was retained, washed with water (100 mL) twice, dried over MgS04and evaporated. The resulting solid was recrystallized in THF/Hexane to yield a pure product (19.28 g, 74.0% yield).XH NMR (400 MHz, CDCI3, 22 °C): δ 7.36 (m, 15H, H of -OCH2PhAY), 6.89 (m, 2H, H of phenylacetate), 6.78 (m, 1H, H of phenylacetate), 5.11 (m, 6H, -OCAY2PhH), 3.56 (s, 2H, H of acetate). |
With potassium carbonate In N,N-dimethyl-formamide | R.4.i REFERENCE EXAMPLE 4 STR58 i) To a solution of 3,4-dihydroxyphenylacetic acid (10 g) in N,N-dimethylformamide (50 ml), potassium carbonate (74 g) and benzyl bromide (37 g) were added, followed by stirring at 40° C. for 6 hours. The solvent was distilled off and the resultant was extracted with dichloromethane. The dichloromethane extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain as colorless crystal benzyl 3,4-dibenzyloxy phenylacetate (16.0 g). M.p. 71.5°-72.5° C. Elemental analysis for C29 H26 O4: Calcd. C: 79.43; H: 5.98. Found C: 79.42; H: 5.86. | |
With potassium carbonate In acetone at 75℃; Inert atmosphere; | General procedure: Compound 1a (1.00 g, 7.24 mmol) was dissolved indry acetone (30 mL), benzyl bromide (1.73 g mL,14.55 mmol), and potassium carbonate (3.00 g mL,21.74 mol) were added, stirred, and refluxed overnight at75 °C under the nitrogen atmosphere, and the reactionprocess was monitored by TLC. The stirring was stoppedafter the end of reaction, and the solution was cooled toroom temperature. The filtrate was filtered by a Brinellfunnel and decompressed to remove organic solvents on arotary evaporator. The residue was dissolved in ethylacetate, washed with saturated sodium carbonate solution(30 mL × 2) and saturated sodium chloride solution(30 mL × 2), dried with anhydrous sodium sulfate, filteredand concentrated under vacuum. The white solid 2a (1.85 g) was obtained by column chromatography (petroleumether-ethyl acetate, 15:1). The yield was 80.23%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In diethyl ether at 20℃; for 24.0833h; | 2.17 Compound 17. Butyric acid 2-butyryloxy-5-[4-(4-chloro-phenyl)-thiazol-2-ylcarbamoyl]-methyl}-phenyl ester (B240819) Butyric acid 2-butyryloxy-5-carboxymethyl-phenyl ester (B240810) 3,4-Dihydroxyphenylacetic acid (1.0 g, 6.0 mmol) was mixed with butyric acid anhydride (6 mL), followed by addition of H2SO4 (0.1 mL). After stirring for 5 min, it became a dark gray solution. Ether (20 mL) was added to it. The reaction was continued for 24 hours at RT. The mixture was poured into 50 mL of ice-water. It was extracted with EtOAc (2×50 mL). The EtOAc solution was dried over Na2SO4. After filtration and concentration, the oily residue was purified by chromatography (CHCl3-3% MeOH in CHCl3, Si) to afford a redish syrup (1.45 g, Y=78%). The structure of the compound was confirmed by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With boron trifluoride diethyl ether complex In N,N-dimethyl-formamide at 120℃; for 0.166667h; | |
With boron trifluoride diethyl ether complex at 110℃; for 2h; Inert atmosphere; | ||
With boron trifluoride diethyl ether complex at 80℃; Inert atmosphere; |
With boron trifluoride diethyl ether complex at 110℃; for 2h; Inert atmosphere; | ||
With boron trifluoride diethyl ether complex at 120℃; for 0.166667h; | 2.1 General processes for the synthesis of SIFs General procedure: The scheme of the synthetic procedure is shown in Fig. 1. The details concerning the synthesis of SIFs are described in the previous investigation (Goto et al., 2009). The mixture of compound 1 (7.8mmol), compound 2 (7.3mmol), and boron trifluoride-diethyl etherate (2.2ml) was heated at 120°C for 10min and cooled to room temperature. Then, N,N-dimethylformamide (9.9ml) was incorporated into the reaction mixture at 50°C for 10min. After adding methanesulfonyl chloride (5.9g), the mixture was heated at 80°C for 30min. After cooling to room temperature, cold water (240ml) was added. The product was extracted with diethylene and washed by brine and sodium bicarbonate. The sample was further purified with silica gel column chromatography to produce SIFs. The synthesized compounds included SIF-1 (3′,4′,7,8-tetrahydroxyisoflavone), SIF-2 (4′,7,8-trihydroxyisoflavone, 8-hydroxydaidzein), SIF-3 (3′,4′,7-trihydroxyisoflavone), SIF-4 (7,8-dihydroxy-3′,4′-dimethoxyisoflavone), SIF-5 (4′,7-dihydroxyisoflavone, daidzein), SIF-6 (7-hydroxy-3′,4′-dimethoxyisoflavone, cladrin), and SIF-7 (7-hydroxy-4′-methoxyisoflavone, formononetin, methoxy daidzein) (Fig. 1). The elucidation of SIF structures was established by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, and the data were in accordance with those reported earlier (Goto et al., 2009; Frasinyuk et al., 2015). The NMR spectra of SIFs were shown in Suppl. Material 1. The profiles and data about infrared (IR) spectrophotometry, ultraviolet (UV) spectrophotometry, NMR, and purity are depicted in Suppl. Material 2. The purity of SIF analogs was determined by high-performance liquid chromatography (HPLC). | |
With boron trifluoride diethyl ether complex at 120℃; for 0.166667h; | 2.1 General processes for the synthesis of SIFs General procedure: The scheme of the synthetic procedure is shown in Fig. 1. The details concerning the synthesis of SIFs are described in the previous investigation (Goto et al., 2009). The mixture of compound 1 (7.8mmol), compound 2 (7.3mmol), and boron trifluoride-diethyl etherate (2.2ml) was heated at 120°C for 10min and cooled to room temperature. Then, N,N-dimethylformamide (9.9ml) was incorporated into the reaction mixture at 50°C for 10min. After adding methanesulfonyl chloride (5.9g), the mixture was heated at 80°C for 30min. After cooling to room temperature, cold water (240ml) was added. The product was extracted with diethylene and washed by brine and sodium bicarbonate. The sample was further purified with silica gel column chromatography to produce SIFs. The synthesized compounds included SIF-1 (3′,4′,7,8-tetrahydroxyisoflavone), SIF-2 (4′,7,8-trihydroxyisoflavone, 8-hydroxydaidzein), SIF-3 (3′,4′,7-trihydroxyisoflavone), SIF-4 (7,8-dihydroxy-3′,4′-dimethoxyisoflavone), SIF-5 (4′,7-dihydroxyisoflavone, daidzein), SIF-6 (7-hydroxy-3′,4′-dimethoxyisoflavone, cladrin), and SIF-7 (7-hydroxy-4′-methoxyisoflavone, formononetin, methoxy daidzein) (Fig. 1). The elucidation of SIF structures was established by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, and the data were in accordance with those reported earlier (Goto et al., 2009; Frasinyuk et al., 2015). The NMR spectra of SIFs were shown in Suppl. Material 1. The profiles and data about infrared (IR) spectrophotometry, ultraviolet (UV) spectrophotometry, NMR, and purity are depicted in Suppl. Material 2. The purity of SIF analogs was determined by high-performance liquid chromatography (HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With boron trifluoride diethyl ether complex In N,N-dimethyl-formamide at 120℃; for 0.166667h; | |
With boron trifluoride diethyl ether complex at 120℃; for 0.166667h; | 2.1 General processes for the synthesis of SIFs General procedure: The scheme of the synthetic procedure is shown in Fig. 1. The details concerning the synthesis of SIFs are described in the previous investigation (Goto et al., 2009). The mixture of compound 1 (7.8mmol), compound 2 (7.3mmol), and boron trifluoride-diethyl etherate (2.2ml) was heated at 120°C for 10min and cooled to room temperature. Then, N,N-dimethylformamide (9.9ml) was incorporated into the reaction mixture at 50°C for 10min. After adding methanesulfonyl chloride (5.9g), the mixture was heated at 80°C for 30min. After cooling to room temperature, cold water (240ml) was added. The product was extracted with diethylene and washed by brine and sodium bicarbonate. The sample was further purified with silica gel column chromatography to produce SIFs. The synthesized compounds included SIF-1 (3′,4′,7,8-tetrahydroxyisoflavone), SIF-2 (4′,7,8-trihydroxyisoflavone, 8-hydroxydaidzein), SIF-3 (3′,4′,7-trihydroxyisoflavone), SIF-4 (7,8-dihydroxy-3′,4′-dimethoxyisoflavone), SIF-5 (4′,7-dihydroxyisoflavone, daidzein), SIF-6 (7-hydroxy-3′,4′-dimethoxyisoflavone, cladrin), and SIF-7 (7-hydroxy-4′-methoxyisoflavone, formononetin, methoxy daidzein) (Fig. 1). The elucidation of SIF structures was established by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, and the data were in accordance with those reported earlier (Goto et al., 2009; Frasinyuk et al., 2015). The NMR spectra of SIFs were shown in Suppl. Material 1. The profiles and data about infrared (IR) spectrophotometry, ultraviolet (UV) spectrophotometry, NMR, and purity are depicted in Suppl. Material 2. The purity of SIF analogs was determined by high-performance liquid chromatography (HPLC). | |
With boron trifluoride diethyl ether complex at 120℃; for 0.166667h; | 2.1 General processes for the synthesis of SIFs General procedure: The scheme of the synthetic procedure is shown in Fig. 1. The details concerning the synthesis of SIFs are described in the previous investigation (Goto et al., 2009). The mixture of compound 1 (7.8mmol), compound 2 (7.3mmol), and boron trifluoride-diethyl etherate (2.2ml) was heated at 120°C for 10min and cooled to room temperature. Then, N,N-dimethylformamide (9.9ml) was incorporated into the reaction mixture at 50°C for 10min. After adding methanesulfonyl chloride (5.9g), the mixture was heated at 80°C for 30min. After cooling to room temperature, cold water (240ml) was added. The product was extracted with diethylene and washed by brine and sodium bicarbonate. The sample was further purified with silica gel column chromatography to produce SIFs. The synthesized compounds included SIF-1 (3′,4′,7,8-tetrahydroxyisoflavone), SIF-2 (4′,7,8-trihydroxyisoflavone, 8-hydroxydaidzein), SIF-3 (3′,4′,7-trihydroxyisoflavone), SIF-4 (7,8-dihydroxy-3′,4′-dimethoxyisoflavone), SIF-5 (4′,7-dihydroxyisoflavone, daidzein), SIF-6 (7-hydroxy-3′,4′-dimethoxyisoflavone, cladrin), and SIF-7 (7-hydroxy-4′-methoxyisoflavone, formononetin, methoxy daidzein) (Fig. 1). The elucidation of SIF structures was established by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, and the data were in accordance with those reported earlier (Goto et al., 2009; Frasinyuk et al., 2015). The NMR spectra of SIFs were shown in Suppl. Material 1. The profiles and data about infrared (IR) spectrophotometry, ultraviolet (UV) spectrophotometry, NMR, and purity are depicted in Suppl. Material 2. The purity of SIF analogs was determined by high-performance liquid chromatography (HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium acetate; at 160℃; for 6h;Inert atmosphere; | General procedure: A mixture of benzaldehyde (2a-d) (20 mmol), phenylacetic acids (3a-c) (20 mmol), and sodium acetate (50 mmol) was stirred in 40 mL acetic anhydride at 160 C under N2 atmosphere for 6 h. On reaction completion, the mixture was poured into ice-cold water (200 mL). The crude product was filtered and recrystallized from ethanol. 6,7-Dimethoxy-3-(3',4'-diacetoxyphenyl)coumarin (4a). A mixture of <strong>[14382-91-3]2-hydroxy-4,5-dimethoxybenzaldehyde</strong> (2a) (3.6 g, 20 mmol), 3,4-dihydroxyphenylacetic acid (3a) (3.4 g, 20 mmol), and sodium acetate (4.1 g, 50 mmol) in acetic anhydride (40 mL) was treated as described above to yield 4a (7.7 g, 97 %). M.p.: 206 C, lit. 207-208 C [32]. 1H NMR (400 MHz, CDCl3, 25 C): delta = 2.29 (s, 6H, COCH3), 3.89 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.85 (s, 1H), 6.93 (s, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.64 (dd, J = 8.2, 2 Hz, 1H), 7.59 (d, J = 2 Hz, 1H), 7.81 (s, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With toluene-4-sulfonic acid In toluene at 100℃; for 24h; | |
94% | With toluene-4-sulfonic acid In toluene for 24h; Reflux; | 1 3,4-(dimethylmethylenedioxy)phenylacetic acid methyl ester Reference Example 1 3,4-(dimethylmethylenedioxy)phenylacetic acid methyl ester Dihydroxyphenylacetic acid (11.9 mmol), p-toluenesulfonic acid (1.2 mmol), 2,2-dimethoxypropane (69.2 mmol) and toluene (30 mL) were added in a round-bottom flask equipped with a Dean-Stark apparatus and a magnetic stirrer. The mixture was stirred for 24 hours under reflux temperature. The organic phase was washed twice with distilled water and once with brine and evaporated to dryness. The product was purified by flash chromatography column using ethyl acetate/hexane as an eluent. The product was obtained as a transparent oil with a yield of 94%. 1H NMR (400 MHz, CDCl3) δ ppm 1.66 (s, 6H); 3.52 (s, 2H); 3.69 (s, 3H); 6.64-6.71 (m, 3H). 13C NMR (101 MHz, CDCl3) δ ppm 25.85; 40.80; 52.01; 108.04; 109.44; 117.94; 121.70; 146.61; 147.55; 172.25, IR (KBr): ν cm-1=2890, 2952, 1740, 1498, 1255, 981, 838. |
94% | With toluene-4-sulfonic acid In toluene for 24h; Reflux; Dean-Stark; | 1 3,4-(dimethylmethylenedioxy)phenylacetic acid methyl ester Reference example 1 3,4-(dimethylmethylenedioxy)phenylacetic acid methyl ester Dihydroxyphenylacetic acid (11.9 mmol), p-toluenesulfonic acid (1.2 mmol), 2,2-dimethoxypropane (69.2 mmol) and toluene (30 mL) were added in a round-bottom flask equipped with a Dean-Stark apparatus and a magnetic stirrer. The mixture was stirred for 24 hours under reflux temperature. The organic phase was washed twice with distilled water and once with brine and evaporated to dryness. The product was purified by flash chromatography column using ethyl acetate/hexane as an eluent. The product was obtained as a transparent oil with a yield of 94%. 1H NMR (400 MHz, CDCl3) δ ppm 1.66 (s, 6H); 3.52 (s, 2H); 3.69 (s, 3H); 6.64-6.71 (m, 3H). 13C NMR (101 MHz, CDCl3) δ ppm 25.85; 40.80; 52.01; 108.04; 109.44; 117.94; 121.70; 146.61; 147.55; 172.25. IR (KBr): ν cm-1= 2890, 2952, 1740, 1498, 1255, 981, 838. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 12.5h; Inert atmosphere; | 3.2.3. General procedure to obtain the conjugates derivatives General procedure: To a solution of 29 (383 mg, 0.77 mmol) and TEA (215 μL, 1.5 mmol) in dry DMF (15 mL) were added at 0 °C the opportune phenolic acid (caffeic acid or 3,4-dihydoxyphenilacetic acid respectively (0.77 mmol) and BOP (340 mg, 0.77 mmol). The reaction mixture was stirred under argon atmosphere at 0 °C for 30 min and then at room temperature for further 12 h. After evaporation of the solvent, the residue was dissolved in AcOEt and washed with HCl 1N, sat.d aq. NaHCO3 solution and H2O. The organic phase was dried, filtered and evaporated to give a crude residue purified by chromatography over silica gel to afford the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 12.5h; Inert atmosphere; | 3.1.25. General procedure to obtain the methionine-phenolic acids conjugates General procedure: To a solution of Methionine methyl ester (400 mg, 2 mmol) and TEA (700 μL, 5 mmol) in dry DMF (15 mL) were added at 0 °C the selected phenolic acid (caffeic acid or 3,4-dihydroxyphenil-acetic acid) (2 mmol) and BOP (1.3 g, 2.5 mmol). The reaction mixture was stirred under argon atmosphere for 30 min at 0 °C and then at room temperature for further 12 h. After the evaporation of the solvents, the residue was diluted with AcOEt and washed with HCl 1N, sat.d aq. NaHCO3 and H2O. The organic phase was dried, filtered and evaporated to give a crude residue purified by chromatography over silica gel to afford the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 12.5h; Inert atmosphere; | 3.1.28. General procedure to obtain the conjugates tyrosine-phenolic acids General procedure: To a solution of tyrosine methyl ester (500 mg, 2.6 mmol) and TEA (1.3 mL, 5.1 mmol) in dry DMF (15 mL) were added at 0 °C the selected phenolic acid (caffeic acid or 3,4-dihydroxyphenil-acetic acid) (2.6 mmol) and BOP (1.1 g, 2.6 mmol). The reaction mixture was stirred under argon atmosphere for 30 min at 0 °C and then at room temperature for 12 h. After the evaporation of the solvents, the residue was diluted with AcOEt and washed with HCl 1N, sat.d aq. NaHCO3 and H2O. The organic phase was dried, filtered and evaporated to give a crude residue purified by chromatography over silica gel to afford the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 12.5h; Inert atmosphere; | 3.1.5. General procedure to obtain the conjugates cysteine-phenolic acids General procedure: To a solution of 5[38] (370 mg, 1 mmol) and TEA (350 μL, 2 mmol) in dry DMF (10 mL) were added the opportune phenolic acid (caffeic acid, syringic, p-coumaric, o-coumaric, 3,4-dihydoxyphenil-acetic, sinapic, m-coumaric, homovanillic or ferulic respectively) (1 mmol) and BOP (442 mg, 1 mmol). The reaction mixture was stirred at 0 °C for 30 min and then for 12 h at room temperature under argon atmosphere. After evaporation of the solvent, the residue was dissolved in AcOEt and washed with HCl 1N, sat.d aq. NaHCO3 solution and H2O. The organic phase was dried, filtered and evaporated to give a crude residue purified by chromatography over silica gel to afford the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | Stage #1: N-(3-aminopropyl)-1,4-diaminobutane; 3,4-dihydroxyphenylacetate With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 22h; Inert atmosphere; Stage #2: trifluoroacetic acid In methanol; water | General procedure for preparation of amide analogues 1-21 General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | Stage #1: N-(2-Aminoethyl)-1,3-propanediamine; 3,4-dihydroxyphenylacetate With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 22h; Inert atmosphere; Stage #2: trifluoroacetic acid In methanol; water | General procedure for preparation of amide analogues 1-21 General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 22h; Inert atmosphere; | General procedure for preparation of amide analogues 1-21 General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 28.6 A mixture of benzyl 3-(piperidin-4-yl)benzylcarbamate (100 mg, 0.3 mmol), 3,4-dimethoxyphenylacetic acid (52 mg, 0.3 mmol), EDCI (88 mg, 0.45 mmol), HOBt (60 mg, 0.45 mmol), DIEA (0.08 mL, 0.6 mmol) in CH2Cl2 (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 and washed with water, brine, dried over Na2SO4, concentrated and purified by column chromatography 0-5% MeOH in CHCl3 as eluent to yield benzyl 3-(1-(2-(3,4-dihydroxyphenyl)acetyl)piperidin-4-yl)benzylcarbamate (46 mg, 61%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water at 37℃; for 1h; | 5 Synthesis of sarar-DOP Example 5 - Synthesis of sarar-DOP Sarar-DOP (N-(4-((8-amino-3,6, 10, 13, 16, 19-hexaaza-bicyclo[6,6,6]icosan- 1 - ylamino)methyl)phenyl)-2-(3,4-dihydroxyphenyl)acetamide) can be synthesised in the following maner. To SarAr (54.9 mg; 0.13 mmol) in water (1 mL) was added a solution of 3,4- dihydroxyphenylacetic acid (21.9 mg; 0.13 mmol; in 200 water) and N-(3- dimethylaminopropyl)-iV-ethylcarbodiimide hydrochloride (EDC) (75.4 mg; 0.39 mmol in 200 i water). The mixture was left to stir for 1 hour at 37 °C. The desired compound was purified from unreacted reagent by reverse-phase HPLC using a water :methanol gradient [20min 100% water; followed 70% methanol for water]. The desired compound was eluted from the column at 47 mins. The methanol was evaporated under reduced pressure and the aqueous phase containing the product was lyophilised overnight. The white residue was analysed by NMR and MS. .H NMR (D20): 3.02 (s, 12H, NCH2CH2N); 3.22 (s, 6H, NCCH2N); 3.24 (έ, 6Η, NCCH2NCCH2); 3.64 (s, 2H, ArCH2); 3.80 (s, 2Η, ArCH2-CO); 6.81 (m, 1Η, Ar-H); 6.91 (m, 2Η, Ar-H); 7.34 (d, 2Η, Ar-H); 7.39 (d, 2Η, Ar-H). ESI/MS, mlz = 570.4 [M + Η]+· |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 48h; Inert atmosphere; | 17 Preparation method of 3,4-dihydroxyphenylacetic acid-4-hydroxyphenethyl ester: 0.57 g (4 mmol) of tyrosol was weighed under N2 protection and placed in a reaction flask.Then 1.08 g (4 mmol) of triphenylphosphine was added.Subsequently, 0.71 g (4 mmol) of 3,4-dihydroxyphenylacetic acid was added.Add 10 mL of tetrahydrofuran,0.81 mL (4 mmol) of diisopropyl azodicarboxylate was added dropwise with stirring at 0 ° C.After the dropwise addition, the reaction was carried out at room temperature for 48 hours, and after the reaction was completed, the reaction solution was evaporated to dryness.After adding 150 mL of ethyl acetate to dissolve, it was washed three times with 150 mL of a saturated aqueous solution of sodium hydrogencarbonate, and washed three times with 150 mL of a saturated aqueous solution of sodium chloride.Dry over anhydrous sodium sulfate, remove the salt by suction filtration, distill off the solvent under reduced pressure, and then purify by gel column chromatography.A white solid is obtained as the target compound in a yield of 82%. |
50% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 48h; chemoselective reaction; | 5.4.1 Chemoselective esterification of tyrosol using Mitsunobu reaction General procedure: To a cooled (0 °C) solution of freshly prepared tyrosol (138 mg, 1 mM) and phenolic acids (1 mM equiv) in dry THF (3.5 mL) were added triphenylphosphine (280 mg, 1 mM) and diisopropylazodicarboxylate (208 μL, 1 mM). After stirring for 48 h at rt, the reaction was worked up by removal of the solvent, and the residue was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified on Sephadex LH-20 (35 mL after CH2Cl2 swelling) using CH2Cl2 to remove the Mitsunobu byproducts, followed by normal phase chromatography to isolate the esters 4-10. |
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In ethylene glycol at 120℃; for 4.5h; Inert atmosphere; | 120.1 Step 1. 2-(2,3-dihydrobenzo[b][1,4]dioxacyclohexene-6-yl)acetic acid (GEN1-159-1) 1,2-dibromoethane (1.13 g, 6.0 mmol) was added to a solution of 2-(3,4-dihydroxyphenyl)acetic acid (500 mg, 3.0 mmol) and K2CO3 (1.24 g, 9.0 mmol) in ethylene glycol (5.0 mL). The resulting mixture was stirred at 120°C for 4.5 hours under a N2 atmosphere. The reaction mixture was cooled to room temperature and diluted with water (40 mL). EtOAc (40 mL) was added and the mixture was stirred for 5 minutes. The organic layer was discarded, and the aqueous layer was acidified with 2M HCl to pH <1. The aqueous layer was extracted with EA (60 mL*3). The combined organic layer was washed with water (150 mL), brine (150 mL), dried over Na2SO4 and it was concentrated to obtain a black oil. The crude product was purified by silica gel column chromatography and eluted with (EA/(PE + EA)=60%) to obtain the desired compound (495 mg, yield 85%) as a black oil. MS (ESI): Rt = 1.01 min, m/z 217 [M+Na]+, Purity: 100% 254 nm, 100% 214 nm. |
52% | With potassium carbonate In ethylene glycol at 120℃; for 4.5h; | 7 3,4-Ethylenedioxyphenylacetic acid (11) and 3,4-propylenedioxyphenylacetic acid (12) To a solution of 3,4-dihydroxyphenylacetic acid (500mg, 3.0mmol) and either 1,2-dibromoethane (1.13g, 6.0mmol) or 1,3-dibromopropane (1210mg, 6.0mmol) in ethylene glycol (5mL) was added anhydrous K2CO3 (1240mg, 9.0mmol). After heating at 120°C for 4.5h, the mixtures were cooled, diluted with H2O (50mL), acidified to pH N HCl), and extracted with EtOAc (3×20mL). The organic layers were concentrated under reduced pressure, and residues were purified by column chromatography (EtOAc/ Hexane=50:50 for 11; 40:60 for 12) to give 1144 (301mg, 52%) or 1245 (260mg, 42%). 11 1H NMR: (300MHz, CDCl3, δ) 3.56 (s, 2H, CH2), 4.23 (s, 4H, CH2), 6.75-6.87 (m, 3H, CH), 11.64 (br s, 1H, -COOH). 12 1H NMR: (250MHz, CDCl3, δ) 2.19 (app p, 2H, J=7.5Hz, CH2), 3.55 (s, 2H, CH2), 4.21 (m, 4H, CH2), 6.81-6.95 (m, 3H, CH), 10.50 (br s, 1H, -COOH). |
With potassium carbonate | 120.1 Step 1. Step 1. 2-(2,3-dihydrobenzo[b][1,4]dioxacyclohexene-6-yl)acetic acid (GEN1-159-1) 1,2-dibromoethane (1.13 g, 6.0 mmol) was added to a solution of 2-(3,4-dihydroxyphenyl)acetic acid (500 mg, 3.0 mmol) and K2CO3 (1.24 g, 9.0 mmol) in ethylene glycol (5.0 mL). The resulting mixture was stirred at 120°C for 4.5 hours under a N2 atmosphere. The reaction mixture was cooled to room temperature and diluted with water (40 mL). EtOAc (40 mL) was added and the mixture was stirred for 5 minutes. The organic layer was discarded, and the aqueous layer was acidified with 2M HCl to pH <1. The aqueous layer was extracted with EA (60 mL*3). The combined organic layer was washed with water (150 mL), brine (150 mL), dried over Na2SO4 and it was concentrated to obtain a black oil. The crude product was purified by silica gel column chromatography and eluted with (EA/(PE + EA)=60%) to obtain the desired compound (495 mg, yield 85%) as a black oil. MS (ESI): Rt = 1.01 min, m/z 217 [M+Na]+, Purity: 100% 254 nm, 100% 214 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate In ethylene glycol at 120℃; for 4.5h; | 7 3,4-Ethylenedioxyphenylacetic acid (11) and 3,4-propylenedioxyphenylacetic acid (12) To a solution of 3,4-dihydroxyphenylacetic acid (500mg, 3.0mmol) and either 1,2-dibromoethane (1.13g, 6.0mmol) or 1,3-dibromopropane (1210mg, 6.0mmol) in ethylene glycol (5mL) was added anhydrous K2CO3 (1240mg, 9.0mmol). After heating at 120°C for 4.5h, the mixtures were cooled, diluted with H2O (50mL), acidified to pH N HCl), and extracted with EtOAc (3×20mL). The organic layers were concentrated under reduced pressure, and residues were purified by column chromatography (EtOAc/ Hexane=50:50 for 11; 40:60 for 12) to give 1144 (301mg, 52%) or 1245 (260mg, 42%). 11 1H NMR: (300MHz, CDCl3, δ) 3.56 (s, 2H, CH2), 4.23 (s, 4H, CH2), 6.75-6.87 (m, 3H, CH), 11.64 (br s, 1H, -COOH). 12 1H NMR: (250MHz, CDCl3, δ) 2.19 (app p, 2H, J=7.5Hz, CH2), 3.55 (s, 2H, CH2), 4.21 (m, 4H, CH2), 6.81-6.95 (m, 3H, CH), 10.50 (br s, 1H, -COOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 6.5 mg 2: 5.5 mg | With sodium bromide; calcium bromide In methanol; water; N,N-dimethyl-formamide at 29℃; for 336h; Microbiological reaction; | Microbial Transformation of 2-(3,4-Dihydroxyphenyl)-acetic Acid (1). A two-stage culture protocol9 was used to obtain metabolites 2 and 3 on a preparative scale. The SS medium consisting of soytone (0.1%), soluble starch (1.0%), and seawater (100%) was autoclaved at 121 °C for 15 min after addition of NaBr and CaBr2 (each 50 mM).14,15 The preparative culture (stage 1) was incubated in1 L sterile medium in a 3 L culture flask on a rotary shaker (130 rpm) at 29 °C for 1 week. A 10% inoculum derived from the 1-week-old preparative culture was used to initiate the stage II culture (1 L), which was incubated for a further 24 h under the same conditions before addition of 20.0 mg of compound 1 in 1.0 mL of N,N-dimethyl formamide (DMF)-MeOH (3:1 v/v). Incubation was continued for two weeks in the same manner as described above. The substrate control consisted of sterile medium and substrate incubated under the same conditions, but without microorganisms. The culture control consisted of the microorganism grown under the same condition, but without substrate. After three weeks, each control was harvested and analyzed by TLC. TLC analyses showed that the composition of the extract differed from those derived from two controls. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 3,4-dihydroxyphenylacetate; allyl bromide With potassium carbonate In ethanol at 20℃; for 5h; Stage #2: With potassium hydroxide In ethanol for 12h; | 3,4-Bis(2-propenyloxy) benzeneacetic Acid (3g): General procedure: According to the procedure for the preparation of compound (3f), 3,4-dihydroxyphenylacetic acid (3i, 6.8 g, 50 mmol) and allylbromide (24.2 g, 200 mmol) were treated with K2CO3 (41 g, 300 mol) followed by KOH (11.2 g, 200 mmol) to give the title compound (3g) in 92% yield. Colorless semisolid. 1H-NMR (CDCl3, 400 MHz) δ: 6.86-6.75 (3H, m, aromatic), 6.06 (2H, m, -CH=CH2), 5.40 (2H, m, -CH=CH2), 5.27 (2H, m, -CH=CH2), 4.59 (4H, m, CH2), 3.56 (2H, s, CH2). HR-MS m/z: Calcd for C14H16O4(M+): 248.1049; Found: 248.1028. |
88% | With potassium carbonate In acetone for 2h; Inert atmosphere; Reflux; | General procedure for the preparation of 3,4-bis(allyloxy)phenylacetic acid (10a) and 3,4-bis(allyloxy)cinnamic acid (11a) A mixture of acid (1.0equiv), allyl bromide (2.0equiv per phenolic OH), and K2CO3 (5.0equiv) in acetone was stirred under reflux for 12h. The solids were filtered out and acetone was evaporated. To this residue was added methanol/ NaHCO3 (sat.) (1:1). The mixture was heated under reflux for 2h. After it was cooled down, the pH value of the mixture was adjusted to 6 with HCl (aq. 1M). The precipitation was collected and further purified by recrystallization from EtOAc/petroleum ether to give the product. Compound 10a was prepared from compound 10 as white solids (88% yield): 1H NMR (400MHz, CDCl3) δ 6.89-6.86 (m, 2H), 6.83 (dd, J=1.9Hz, 8.2Hz, 1H), 6.15-6.05 (m, 2H), 5.47-5.41 (m, 2H), 5.31-5.29 (m, 2H), 4.63-4.62 (m, 4H), 3.60 (s, 2H); 13C NMR (100MHz, CDCl3) δ 177.2, 148.6, 148.0, 133.5, 133.4, 126.2, 122.0, 117.6, 117.5, 115.5, 114.4, 70.1, 70.0, 40.5; MS (m/z): calcd for C14H16O4: 248, found: 248 [M] +. Anal. Calcd for C14H16O4 (%) C, 67.73; H, 6.50; found C, 67.51; H, 6.75. Compound 11a was prepared from compound 11 as white solids (80% yield): 1H NMR (400MHz, CDCl3) δ 7.70 (d, J=15.9Hz, 1H), 7.12-7.10 (m, 2H), 6.88 (d, J=8.1Hz, 1H), 6.28 (d, J=15.9Hz, 1H), 6.08 (m, 2H), 5.47-5.41 (m, 2H), 5.33-5.29 (m, 2H), 4.66-4.64 (m, 4H); 13C NMR (100MHz, CDCl3) δ 172.5, 151.1, 148.6, 146.9, 133.0, 132.8, 127.2, 123.1, 118.0, 117.9, 114.9, 113.4, 112.9, 70.0, 69.7; ESI-HRMS [M+H]+ calcd for C15H17O4 261.1121, found 261.1121. |
88% | With potassium carbonate In acetone for 12h; Reflux; | 1 Synthesis of 3,4-diallyloxyphenylacetic acid (10a) and 3,4-diallyl oxycinnamic acid (11a) In a 250 ml round bottom flask, acid compound 10 or compound 11 (1.0 equiv) was added,Allyl bromide (4.0 equiv), anhydrous K2CO3 (5.0 equiv) and anhydrous acetone, and heated under reflux for 12 h with stirring.The insoluble material was filtered off and concentrated. The residue was added directly to saturated aqueous NaHCO3 solution and methanol (1: 1)Stir for 1 hour. The reaction solution was cooled to room temperature and adjusted to pH 6 with 1 mol / L hydrochloric acid.And filtered under reduced pressure to give a yellow solid. And further recrystallized from a mixed solvent of petroleum ether and ethyl acetate to give a white solid.Compound 10a was prepared from compound 10 in a yield of 88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium dihydrogenphosphate at 25℃; for 0.25h; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium acetate at 160℃; for 6h; Inert atmosphere; | |
65% | With sodium acetate at 160℃; for 6h; Inert atmosphere; | General procedure for synthesis of o-diacetoxy-3-phenylchromenones (4a-f) General procedure: A mixture of benzaldehyde (2a-d) (20 mmol), phenylacetic acids (3a-c) (20 mmol), and sodium acetate (50 mmol) was stirred in 40 mL acetic anhydride at 160 °C under N2 atmosphere for 6 h. On reaction completion, the mixture was poured into ice-cold water (200 mL). The crude product was filtered and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; | Synthesis of bifunctional linker 12: To a solution of 3,4-dihydroxyphenylacetic acid (200 mg, 1.19 mmol) in DMF (2 mL) was added subsequentlyBOP (526 mg, 1.19 mmol), DIPEA (414 mL, 2.38 mmol) and O-(2-aminoethyl)-O’-(2-azidoethyl)ethylene glycol (249 mg,1.43 mmol). After stirring for 16 h at rt the mixture was concentrated in vacuo and the residue was purified by columnchromatography (column 1: MeOH/acetone/DCM/toluene, 0.1/2/8/1, column 2: MeOH/EA, 1/19) which afforded theproduct (281 mg, 73 %) as an oil. Rf 0.32 (MeOH/EA, 1/19). 1H NMR (CDCl3, 400 MHz): δ 6.76-6.72 (m, 2H), 6.58 (d,J = 7.9 Hz, 1H), 6.37 (t, J = 5.1 Hz, 1H), 3.64-3.57 (m, 6H), 3.52 (t, J = 5.0 Hz, 2H), 3.44-3.41 (m, 4H), 3.37-3.35 (m,2H). 13C NMR (CDCl3, 125 MHz): δ 173.3, 144.7, 144.0, 126.5, 121.4, 116.4, 115.8, 70.5, 70.2, 70.0, 69.6, 50.7, 42.8,39.7. HRMS (ESI) m/z for C14H20N4NaO5: (M + Na+), calcd: 347.1331, found: 347.1340. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With boric acid In 5,5-dimethyl-1,3-cyclohexadiene for 16h; Reflux; | 19 General procedure to synthesis of compounds 3a-y and 5 General procedure: To a stirred solution of benzene-1,2-diamine 1 (1.85 mmol)in xylenes (10 mL) were added carboxylic acid 2 (2.77 mmol)and boric acid (0.185 mmol). The resulting solution wasrefluxed for 16 h. After cooling to room temperature, the reactionwas concentrated under reduced pressure and diluted withEtOAc (50 mL). The organic phase was washed with saturatedNaHCO3 solution (2 50 mL), dried over anhydrous Na2SO4and then concentrated under reduced pressure. The residuewas purified by silica gel flash column chromatography (elutingwith 10-15% Ethyl acetate in hexanes) to afford the title compounds3a-y and 5.6.2.19 4-((1H-Benzo[d]imidazol-2-yl)methyl)benzene-1,2-diol (3s) Yield 60%; Off white solid; mp 258-260 °C; IR (KBr) 3258, 3248, 1512, 1439, 1248, 1026, 812, 738 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 12.17 (br s, 1H), 8.87 (s, 1H), 8.75 (s, 1H), 7.45 (br s, 2H), 7.06-7.14 (m, 2H), 6.62-6.71 (m, 2H), 6.52-6.60 (m, 1H), 3.96 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 154.4, 145.4, 144.1, 128.5, 121.3, 119.6, 116.2, 115.6, 34.4; HRMS calcd for C14H12N2O2 m/z 240.0935, found 240.0931. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dihydrogen peroxide In water at 24.84℃; Green chemistry; | 2.3. Phenyl acetic acid conversion Phenylacetic acid oxidation was carried out in a 100 mlPyrex reactor equipped with a magnetic stirrer. The solidcatalystwas introduced into 50mL of PAA aqueous solution(500 mg L1), under continuous stirring. The desiredquantity of H2O2 (0.02 M) was added indicating the start ofthe reaction. During the experiments, aliquots were withdrawnat regular intervals with the purpose of monitoringthe conversion of PAA to p-HPAA and then to 3,4-DHPAAafter being immediately filtered to completely removecatalyst particles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.9% | With sodium hydroxide In N,N-dimethyl-formamide at 45℃; for 3h; | General procedure for synthesis of 2-phenyl-benzo[d]oxazole-7-carboxamide 8 and 9 General procedure: To asolution of compound 7(0.258 mmol), amines(0.774 mmol) and sodium hydroxide (31mg, 0.774 mmol) in DMF (3 mL) were addedand the reaction was heated to 45 oC and stirred for 3 h. Then themixture was poured into H2O (20 mL) and EtOAc(15 mL), the organiclayer was washed by water (20 mL), saturatedsodium bicarbonate solution (20 mL), brine (10 mL), and finally dried byanhydrous Na2SO4. The organic layer was concentratedunder vacuum and residue was purified by silica gel column eluting with dichloromethane / methanol (100:1) to give compound8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.1% | With sodium hydroxide In N,N-dimethyl-formamide at 45℃; | General procedure for synthesis of 2-phenyl-benzo[d]oxazole-7-carboxamide 8 and 9 General procedure: To asolution of compound 7(0.258 mmol), amines(0.774 mmol) and sodium hydroxide (31mg, 0.774 mmol) in DMF (3 mL) were addedand the reaction was heated to 45 oC and stirred for 3 h. Then themixture was poured into H2O (20 mL) and EtOAc(15 mL), the organiclayer was washed by water (20 mL), saturatedsodium bicarbonate solution (20 mL), brine (10 mL), and finally dried byanhydrous Na2SO4. The organic layer was concentratedunder vacuum and residue was purified by silica gel column eluting with dichloromethane / methanol (100:1) to give compound8 |
31.1% | With sodium hydroxide In N,N-dimethyl-formamide at 50℃; for 3h; | 28 4-(7-(isopropylcarbamoyl)benzo[d]oxazol-2-yl)benzyl 2-(3,4-dihydroxyphenyl)acetate (I-21) 100mg 2- (4- (bromomethyl) phenyl) -N- isopropylbenzofuran [d] oxazole-7-carboxamide, 48mg 3,4- dihydroxyphenyl acetic acid and 14mg of sodium hydroxide dissolved in 2mL N, N- dimethylformamide, the reaction was heated to 3h 50 , were added 10mL of water and 10mL of ethyl acetate, and the organic layer was washed with 10mL water. 3 times, dried over anhydrous sodium sulfate was added, the organic layer was concentrated to methanol: dichloromethane = 1: 25 by column chromatography to give 37mg as a pale yellow solid, yield 31.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.4% | With sodium hydroxide In N,N-dimethyl-formamide at 45℃; | General procedure for synthesis of 2-phenyl-benzo[d]oxazole-7-carboxamide 8 and 9 General procedure: To asolution of compound 7(0.258 mmol), amines(0.774 mmol) and sodium hydroxide (31mg, 0.774 mmol) in DMF (3 mL) were addedand the reaction was heated to 45 oC and stirred for 3 h. Then themixture was poured into H2O (20 mL) and EtOAc(15 mL), the organiclayer was washed by water (20 mL), saturatedsodium bicarbonate solution (20 mL), brine (10 mL), and finally dried byanhydrous Na2SO4. The organic layer was concentratedunder vacuum and residue was purified by silica gel column eluting with dichloromethane / methanol (100:1) to give compound8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.2% | With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 3h; | General procedure: To a solution of intermediate IIa (200 mg, 0.496 mmol) inDMF (10 mL), NaOH (99.2 mg, 2.48 mmol) and benzoic acid(302.6 mg, 2.48 mmol) was added and stirred at room temperature for 3 h before H2O (10 mL) was added. The resulting solid was filtered, washed with ethyl acetate and 95% ethanol, and recrystallized in DMF/H2O to give compound Ia-1 as white solid (150 mg,71.5% yield); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With dipotassium peroxodisulfate In water at 90℃; for 12h; Green chemistry; | General Procedure for the preparation of Aldehydes and Ketones from Aryl acetic acids General procedure: In an oven dried tube containing a mixture of 4-methyl phenyl acetic acid 1a (200 mg, 1.33mmol) and potassium persulfate (360 mg, 2.66 mmol), water (2 mL) was added and heated at 90 °C for 12 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature (24°C) and it was extracted with ethyl acetate (3 x 5 mL). The crude product was purified by column chromatography to furnish compound 2a as colorless liquid (136 mg, 85% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 60℃; for 2h; Inert atmosphere; | 4.6.4. Allyl (3,4-dihydroxyphenyl)acetate (8) To a mixture of (3,4-dihydroxyphenyl)acetic acid (7, 1.01 g,6.02 mmol), EDCI (1.38 g, 7.21 mmol) and DMAP (73.4 mg,0.60 mmol) was added allyl alcohol (4.5 mL) at room temperature,then heated at 60 °C for 2 h. The resulting mixture was quenchedwith 2 N HCl and extracted with AcOEt. The combined organicphases were washed with sat. NaHCO3, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel(acetoneen-hexane) (1:5 v/v) to give a title compound (1.11 g, 89%)as a yellow oil. IRν : 3389, 1706, 1606, 1281, 988, 961, 795 cm-1. 1HNMR (500 MHz, acetone-d6): δ 6.77 (d, 1H, J = 2.2 Hz), 6.73 (d, 1H,J = 8.2 Hz), 6.59 (dd, 1H, J = 2.2, 8.2 Hz), 5.93-5.85 (m, 1H), 5.24 (dq,1H, J = 1.6, 17.3 Hz), 5.13 (dq, 1H, J = 1.6, 10.6 Hz), 4.52 (dt, 2H,J = 1.6, 5.5 Hz), 3.47 (s, 2H). 13C NMR (125 MHz, acetone-d6): δ 171.8,145.6, 144.8, 133.5, 126.7, 121.5, 117.7, 117.1, 115.9, 65.4, 40.8. HighresolutionMS calcd for C11H12O4 (M): 208.0736. Found: 208.0727. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.1% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; | 4.1.3. General procedure for the synthesis of the compound 5a-5n,7a-7h General procedure: To a solution of the corresponding compound 4a-4g, 6a-6h(0.5 mmol), triethylamine (1.2 mmol), and PyBOP (0.6 mmol) inDMF (8 mL) was added the appropriated compound 3b-3c(0.5 mmol). The reaction mixture was stirred at room temperatureovernight, and DMF was then evaporated to dryness under reducedpressure. The residue was dissolved in CH2Cl2 (10 mL) andconsecutively washed with a 10% aqueous NaHCO3 solution(3 10 mL) and H2O (10 mL). The organic phase was dried oversodium sulfate and evaporated to dryness under reduced pressure.The residue was purified on a silica gel column using CH2Cl2 aseluent, obtaining the corresponding compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.9% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; | 4.1.3. General procedure for the synthesis of the compound 5a-5n,7a-7h General procedure: To a solution of the corresponding compound 4a-4g, 6a-6h(0.5 mmol), triethylamine (1.2 mmol), and PyBOP (0.6 mmol) inDMF (8 mL) was added the appropriated compound 3b-3c(0.5 mmol). The reaction mixture was stirred at room temperatureovernight, and DMF was then evaporated to dryness under reducedpressure. The residue was dissolved in CH2Cl2 (10 mL) andconsecutively washed with a 10% aqueous NaHCO3 solution(3 10 mL) and H2O (10 mL). The organic phase was dried oversodium sulfate and evaporated to dryness under reduced pressure.The residue was purified on a silica gel column using CH2Cl2 aseluent, obtaining the corresponding compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 40h; | 7 EXAMPLE 7 α-Asaronol 3,4-dihydroxyphenylacetate Into a 100 mL single-necked flask, α-Asaronol 1.68 g (7.5 mmol), 3,4-dihydroxy phenylacetic acid 1.90 g (11.3 mmol), tetrahydrofuran (30 mL), triphenylphosphine 1.97 g (7.5 mmol), and diisopropyl azodicarboxylate 1.52 g (7.5 mmol) were added at 0° C. The mixture was stirred at room temperature for 40 hours. The reaction was monitored by TLC. After the completion of the reaction of raw materials, the mixture was extracted with ethyl acetate/water system, and washed three times. The organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure. The resulting crude product was isolated by silica gel column to obtain 1.23 g of a yellow solid in 44% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.6% | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In acetonitrile at 20℃; for 4h; Cooling with ice; | 4.2.1.1 General procedure for the synthesis of the methyl esters of N-phenoyl and N-catechoyl serine, phenylserine and alanine General procedure: To a solution of the phenolic or catecholic acid in acetonitrile (0.0100moldm-3), 1.1 equiv. of HOBt was added, followed by 1.1 equiv. of HBTU, 1.1 equiv. of the methyl ester of the amino acid hydrochloride and 2.2 equiv. of NEt3 in an ice bath. After stirring for 4h at room temperature, the solvent was evaporated at reduced pressure. The residue was dissolved in ethyl acetate (100cm3) and washed with KHSO4 (1moldm-3), NaHCO3 (1moldm-3) and brine (3 times 25cm3 each). The organic layer was dried with MgSO4 and the solvent evaporated at reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.7% | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In acetonitrile at 20℃; for 4h; Cooling with ice; | 4.2.1.1 General procedure for the synthesis of the methyl esters of N-phenoyl and N-catechoyl serine, phenylserine and alanine General procedure: To a solution of the phenolic or catecholic acid in acetonitrile (0.0100moldm-3), 1.1 equiv. of HOBt was added, followed by 1.1 equiv. of HBTU, 1.1 equiv. of the methyl ester of the amino acid hydrochloride and 2.2 equiv. of NEt3 in an ice bath. After stirring for 4h at room temperature, the solvent was evaporated at reduced pressure. The residue was dissolved in ethyl acetate (100cm3) and washed with KHSO4 (1moldm-3), NaHCO3 (1moldm-3) and brine (3 times 25cm3 each). The organic layer was dried with MgSO4 and the solvent evaporated at reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With boron trifluoride diethyl etherate at 90℃; for 1.5h; Inert atmosphere; | General procedure for the preparation of deoxybenzoines(3a-d) General procedure: In a two-neck round-bottom flask a mixture of 3,5-dimethoxyphenol (1) (6 mmol, 1.00 equiv.), 3,4-disubstitutedphenyl acetic acid (2a-d) (6 mmol, 1.00 equiv.) and BF3*Et2O(48 mmol, 8.00 equiv.) was stirred at 90 °C for 90 min under argon. The reaction mixturewas poured into 10% aqueous NaOAc (100 mL)and allowed to stir at room temperature for 24 h, forming a brown precipitate. The precipitate was filtered and washed with H2O(2 x 20 mL). The precipitate was resuspended with EtOAc, driedover Na2SO4 and finally concentrated in vacuo. The residue waspurified by FC using a mixture of Petroleum Ether/EtOAc as eluent,to obtain the corresponding deoxybenzoin (3a-d) (Supplementary Material). |
17% | With boron trifluoride diethyl etherate at 75℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-(3,4-dihydroxyphenyl)ethan-1-one With morpholine; toluene-4-sulfonic acid; sulfur at 120℃; Stage #2: With tetrabutylammomium bromide; sodium hydroxide In ethanol; water at 100℃; for 4h; | ||
Stage #1: 1-(3,4-dihydroxyphenyl)ethan-1-one With morpholine; toluene-4-sulfonic acid; sulfur at 120℃; Stage #2: With tetrabutylammomium bromide; sodium hydroxide at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: 1-phenyl-2-bromoethane With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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. |
58% | Stage #1: 3,4-dihydroxyphenylacetate With sodium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide for 0.5h; Inert atmosphere; Stage #2: 1-phenyl-2-bromoethane With potassium iodide In N,N,N,N,N,N-hexamethylphosphoric triamide at 0℃; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: methyl iodide With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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 |
---|---|---|
71% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: ethyl bromide With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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 |
---|---|---|
83% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: propyl bromide With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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 |
---|---|---|
81% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: 1-bromo-butane With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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 |
---|---|---|
83% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: 1-Bromopentane With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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 |
---|---|---|
83% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: 1-bromo-hexane With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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 |
---|---|---|
87% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: 1-bromo-octane With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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 |
---|---|---|
87% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: hexadecanyl bromide With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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 |
---|---|---|
87% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: allyl bromide With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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 |
---|---|---|
71% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: propargyl bromide With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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 |
---|---|---|
73% | Stage #1: 3,4-dihydroxyphenylacetate With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium carbonate for 0.5h; Stage #2: 1-bromocyclohexane With potassium iodide at 20℃; for 48h; | General esterification method A (compounds 3-15, 26-27,34, 35, 42,43). General procedure: To a stirredsolution of the acid (1 mmol) in dry hexamethyl phosphoramide (5 mL), Νa2CO3 (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 |
---|---|---|
25% | Stage #1: 3,4-dihydroxyphenylacetate With thionyl chloride In 1,2-dimethoxyethane at 70℃; for 4h; Stage #2: 2-(4-nitrophenyl)ethanol In 1,2-dimethoxyethane at 70℃; for 16h; | General esterification method B (compounds 16, 17, 28,29, 36, 37, 44, 45). General procedure: To a mixture of the acid (1 mmol) in 3 mL anhydrous 1,2-dimethoxyethane,thionyl chloride (6 mmol) was added. The mixture was heated to 70oCfor 4 h and then evaporated under vacuum to remove the excess thionyl chloridecompletely. The intermediate was redissolved with 3 mL anhydrous DME, and tothis solution the alcohol (1 mmol) was added. This mixture was heated to 70oCfor 16 h before evaporation. The residue was purified by column chromatographyto give target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: 3,4-dihydroxyphenylacetate With thionyl chloride In 1,2-dimethoxyethane at 70℃; for 4h; Stage #2: 2-(4-Fluorophenyl)ethanol In 1,2-dimethoxyethane at 70℃; for 16h; | General esterification method B (compounds 16, 17, 28,29, 36, 37, 44, 45). General procedure: To a mixture of the acid (1 mmol) in 3 mL anhydrous 1,2-dimethoxyethane,thionyl chloride (6 mmol) was added. The mixture was heated to 70oCfor 4 h and then evaporated under vacuum to remove the excess thionyl chloridecompletely. The intermediate was redissolved with 3 mL anhydrous DME, and tothis solution the alcohol (1 mmol) was added. This mixture was heated to 70oCfor 16 h before evaporation. The residue was purified by column chromatographyto give target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 24.17h; | General amide synthesis method C (compounds 19-21, 31,32, 39, 40). General procedure: A mixture of the acid (1 mmol), amine (1 mmol), HOBtH2O (1mmol) in CH2Cl2 (5 mL) and drops of DMF, if necessary, tomake a clear solution, was cooled to 0oC. Then EDCHCl (1 mmol) wasadded and the reaction mixture was stired at 0oC for 10 min and atroom temperature for 24 h. EtOAc (50 mL) and HCl 0.5 N (5 mL) were added, theorganic phase was succesfuly washed with H2O, brine, dried over Na2SO4and concentrated under reduced pressure. The crude product was purifiedby column chromatography to give the pure amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 24.17h; | General procedure: A mixture of the acid (1 mmol), amine (1 mmol), HOBtH2O (1mmol) in CH2Cl2 (5 mL) and drops of DMF, if necessary, tomake a clear solution, was cooled to 0oC. Then EDCHCl (1 mmol) wasadded and the reaction mixture was stired at 0oC for 10 min and atroom temperature for 24 h. EtOAc (50 mL) and HCl 0.5 N (5 mL) were added, theorganic phase was succesfuly washed with H2O, brine, dried over Na2SO4and concentrated under reduced pressure. The crude product was purifiedby column chromatography to give the pure amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 24.17h; | General procedure: A mixture of the acid (1 mmol), amine (1 mmol), HOBtH2O (1mmol) in CH2Cl2 (5 mL) and drops of DMF, if necessary, tomake a clear solution, was cooled to 0oC. Then EDCHCl (1 mmol) wasadded and the reaction mixture was stired at 0oC for 10 min and atroom temperature for 24 h. EtOAc (50 mL) and HCl 0.5 N (5 mL) were added, theorganic phase was succesfuly washed with H2O, brine, dried over Na2SO4and concentrated under reduced pressure. The crude product was purifiedby column chromatography to give the pure amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: 3,4-dihydroxyphenylacetate With thionyl chloride at 50℃; for 3h; Stage #2: 1-amino-2-propene With triethylamine In dichloromethane at 20℃; for 16h; | General amide synthesis method D (22-24). General procedure: The acid (1 mmol) was dissolved in thionyl chloride (2mL) and the solution was stirred at 50oC for 3 h. The volatiles wereremoved, the residue was dissolved in CH2Cl2 (3 mL) andwas added to a solution of of allylamine (1 mmol), Et3N (2 mmol) inCH2Cl2. The solution was stirred at room temperature for 16h, then concentrated in vacuo and theresidue was purified by column chromatography to give target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: 3,4-dihydroxyphenylacetate With thionyl chloride at 50℃; for 3h; Stage #2: SEC-BUTYLAMINE With triethylamine In dichloromethane at 20℃; for 16h; | General amide synthesis method D (22-24). General procedure: The acid (1 mmol) was dissolved in thionyl chloride (2mL) and the solution was stirred at 50oC for 3 h. The volatiles wereremoved, the residue was dissolved in CH2Cl2 (3 mL) andwas added to a solution of of allylamine (1 mmol), Et3N (2 mmol) inCH2Cl2. The solution was stirred at room temperature for 16h, then concentrated in vacuo and theresidue was purified by column chromatography to give target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: 3,4-dihydroxyphenylacetate With thionyl chloride at 50℃; for 3h; Stage #2: cyclohexylamine With triethylamine In dichloromethane at 20℃; for 16h; | General amide synthesis method D (22-24). General procedure: The acid (1 mmol) was dissolved in thionyl chloride (2mL) and the solution was stirred at 50oC for 3 h. The volatiles wereremoved, the residue was dissolved in CH2Cl2 (3 mL) andwas added to a solution of of allylamine (1 mmol), Et3N (2 mmol) inCH2Cl2. The solution was stirred at room temperature for 16h, then concentrated in vacuo and theresidue was purified by column chromatography to give target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With triethylamine at 120℃; for 3h; | 3.2.1. General Procedure for the Synthesis of Acetyloxy Coumarins (3a-3o) General procedure: A mixture of the appropriate phenylacetic acid (2.83 mmol) and the appropriate2-hydroxyacetophenone (2.97 mmol) in acetic anhydride (3.1 mL) in the presence of triethylamine(8.77 mmol) was refluxed for 3 h. Water was then added, and the mixturewas extracted with dichloromethane, dried over anhydrous Na2SO4, filtered, and concentratedin vacuo to afford the crude products, which on recrystallization from methanol anddichloromethane gave the purified products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With triethylamine at 120℃; for 3h; | 3.2.1. General Procedure for the Synthesis of Acetyloxy Coumarins (3a-3o) General procedure: A mixture of the appropriate phenylacetic acid (2.83 mmol) and the appropriate2-hydroxyacetophenone (2.97 mmol) in acetic anhydride (3.1 mL) in the presence of triethylamine(8.77 mmol) was refluxed for 3 h. Water was then added, and the mixturewas extracted with dichloromethane, dried over anhydrous Na2SO4, filtered, and concentratedin vacuo to afford the crude products, which on recrystallization from methanol anddichloromethane gave the purified products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With triethylamine at 120℃; for 3h; | 3.2.1. General Procedure for the Synthesis of Acetyloxy Coumarins (3a-3o) General procedure: A mixture of the appropriate phenylacetic acid (2.83 mmol) and the appropriate2-hydroxyacetophenone (2.97 mmol) in acetic anhydride (3.1 mL) in the presence of triethylamine(8.77 mmol) was refluxed for 3 h. Water was then added, and the mixturewas extracted with dichloromethane, dried over anhydrous Na2SO4, filtered, and concentratedin vacuo to afford the crude products, which on recrystallization from methanol anddichloromethane gave the purified products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine at 120℃; for 3h; | 3.2.1. General Procedure for the Synthesis of Acetyloxy Coumarins (3a-3o) General procedure: A mixture of the appropriate phenylacetic acid (2.83 mmol) and the appropriate2-hydroxyacetophenone (2.97 mmol) in acetic anhydride (3.1 mL) in the presence of triethylamine(8.77 mmol) was refluxed for 3 h. Water was then added, and the mixturewas extracted with dichloromethane, dried over anhydrous Na2SO4, filtered, and concentratedin vacuo to afford the crude products, which on recrystallization from methanol anddichloromethane gave the purified products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.9% | With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; for 8h; | 4.2.2. N-(3,5-dimethylphenyl)-4-hydroxybenzamide (12b) General procedure: To a stirring solution of 4-hydroxybenzoic acid 11b (0.73 g, 6 mmol), EDCl (1.44 g,7.5 mmol) and HOBT (0.81 g, 6 mmol) in dry DCM (20 mL) at room temperature was added3,5-dimethylaniline 10a (0.73 g, 6 mmol) for 8 h. Upon completion, the mixture was washedwith water (3 20 mL) and dried over anhydrous sodium sulfate before concentrationin vacuo. The crude product was purified with silica gel column chromatography usingpetroleum ether (PE)/ethyl acetate (EA) (5:1 to 3:1) as eluent to afford 12b as a white solid(0.53 g, 44%). |
Tags: 102-32-9 synthesis path| 102-32-9 SDS| 102-32-9 COA| 102-32-9 purity| 102-32-9 application| 102-32-9 NMR| 102-32-9 COA| 102-32-9 structure
A1267665[ 1189915-73-8 ]
3,4-Dihydroxyphenylacetic Acid-13C,18O2
Reason: Stable Isotope
[ 1131-94-8 ]
2-(3-Hydroxy-4-methoxyphenyl)acetic acid
Similarity: 0.91
[ 621-54-5 ]
3-(3-Hydroxyphenyl)propanoic acid
Similarity: 0.90
[ 1131-94-8 ]
2-(3-Hydroxy-4-methoxyphenyl)acetic acid
Similarity: 0.91
[ 621-54-5 ]
3-(3-Hydroxyphenyl)propanoic acid
Similarity: 0.90
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Code | Phrase |
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P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
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P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
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Response | |
Code | Phrase |
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P306 | IF ON CLOTHING: |
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P321 | |
P322 | |
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P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
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P374 | Fight fire with normal precautions from a reasonable distance. |
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P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
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P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
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P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
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P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
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P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
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P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
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P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
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P422 | |
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Disposal | |
Code | Phrase |
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Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
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H221 | Flammable gas |
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H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
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H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
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H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
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H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
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H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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