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CAS No. : | 99-50-3 | MDL No. : | MFCD00002509 |
Formula : | C7H6O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YQUVCSBJEUQKSH-UHFFFAOYSA-N |
M.W : | 154.12 | Pubchem ID : | 72 |
Synonyms : |
3,4-Dihydroxybenzoic acid;NSC 16631;PCA
|
Chemical Name : | 3,4-Dihydroxybenzoic acid |
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 37.45 |
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 : | Yes |
Log Kp (skin permeation) : | -6.42 cm/s |
Log Po/w (iLOGP) : | 0.66 |
Log Po/w (XLOGP3) : | 1.15 |
Log Po/w (WLOGP) : | 0.8 |
Log Po/w (MLOGP) : | 0.4 |
Log Po/w (SILICOS-IT) : | 0.26 |
Consensus Log Po/w : | 0.65 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.86 |
Solubility : | 2.14 mg/ml ; 0.0139 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.38 |
Solubility : | 0.646 mg/ml ; 0.00419 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.6 |
Solubility : | 38.3 mg/ml ; 0.248 mol/l |
Class : | Soluble |
PAINS : | 1.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.07 |
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 |
---|---|---|
89% | at 40 - 80℃; for 10 h; | 3,4-dihydroxybenzoic acid (5.0 g, 32.0 mmol) was placed in a reaction flask, 40 mL of ethanol was added, and the temperature was raised to 40 ° C, and 5 mL of concentrated sulfuric acid was added dropwise. After the dropwise addition, the temperature was raised to 80 ° C and refluxed for 10 h. Cooled to room temperature, add 10M potassium hydroxide solution to adjust the pH to neutral. The solvent was evaporated under reduced pressure to precipitate a solid which was washed with a small amount of water to give ethyl 3,4-dihydroxybenzoate. Ethyl 3,4-dihydroxybenzoate: white solid; 89percent yield; |
86.8% | Reflux | 15.4 g (0.1 mol) of 3,4-dihydroxybenzoic acid and 200 mL of absolute ethanol were added to a 500 mL flask,In the constant stirring slowly dropping 5mL 98percent concentration of concentrated sulfuric acid.The mixture was heated to reflux, the TLC was followed by the reaction, 80percent by volume of solvent was distilled off under reduced pressure,Diluted with 30 mL of ethyl acetate and 25 mL of water, and the aqueous layer was extracted with 300 mL of ethyl acetate,The organic layers were combined, washed with saturated aqueous NaHCO3, saturated brine,Anhydrous Na2SO4 dry, filtered, decompression,To obtain 15.8 g of ethyl 3,4-dihydroxybenzoate in 86.8percent yield. |
70% | at 0℃; Reflux; Inert atmosphere | General procedure: Thionyl chloride (1.16 g, 1.5 equiv) was added drop-wise to a solution of acid (1.0 g, 1.0 equiv) in the corresponding alcohol (15 ml) at 0&d eg;C. The solution was refluxed under a nitrogen atmosphere until all starting material was consumed (TLC monitoring). Then the solvent was removed under vacuo and the residue was purified by silica gel column chromatography eluting with ethyl acetate/n-hexane to afford the corresponding carboxylic esters.#10; |
15.8 g | for 4 h; Reflux | To a solution of 3,4-dihydroxybenzoic acid (15.4g, 0.1mol) in absolute ethanol (200mL) was added 5mL concentrated sulfuric acid. This mixture was heated at reflux for 4h. After cooling to ambient temperature, water (100mL) was slowly introduced over a period of 10min. The mixture was extracted with EtOAc, washed with diluted HCl followed by water, dried with Na2SO4. Then solvent was removed under reduced pressure, the yellow powder as ethyl 3,4-dihydroxybenzoate was used without further disposal. Yield 15.8g, 86.8percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride Heating; | |
100% | With sulfuric acid for 8h; Reflux; | |
100% | With sulfuric acid Reflux; | 5.1 Step 1. Synthesis of compound 107-B To a solution of compound 107-A (CAS No.99-50-3) (50 g, 0.325 mol) in MeOH (300 mL) was added conc.H2SO4 (50 mL) slowly. Then, the mixture was heated to reflux for overnight. The solvent was removed. The residue wasdiluted with water (500 mL), extracted with EA (300 mL2), washed with brine (300 mL2), dried and concentrated togive the product 107-B as white solid (54.5 g, 100%).1H NMR (300 MHz, DMSO) δ 9.77 (s, 1H), 9.34 (s, 1H), 7.35 - 7.29 (m, 2H), 6.80 (d, J= 8.2 Hz, 1H), 3.76 (s, 3H). |
98% | With sulfuric acid Heating; | |
98% | With sulfuric acid for 12h; Reflux; | |
98% | With sulfuric acid at 80℃; for 5h; | 1.1 To the mixture of 3,4-dihydrobenzoic acid (20 g, 129.7 mmol) in MeOH (260 mL) wasadded concentrated sulfuric acid (13.8 mL, 259.5 mmol). The reaction mixture wasstirred at 80 ° C for 5 hours. The resulting mixture was concentrated in vacuo. The crude product was washed with H2O and dried under high vacuum to give the titlecompound (21.5 g, 98%). |
98% | With thionyl chloride at 0 - 20℃; for 16h; | |
97% | With thionyl chloride at 0 - 50℃; for 13h; Inert atmosphere; | |
96% | With sulfuric acid for 9h; Heating; | |
96% | With sulfuric acid for 4h; Reflux; | 2.1 A solution of 3,4-dihydroxybenzoic acid (5.0 g, 32 mmol) in methanol (80 mL) containing c-H2SO4 (3 mL) was heated at reflux for 4 hrs and cooled to room temperature. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate and washed successively with water, saturated NaHCO3, and brine. The organic fraction was dried over MgSO4 and concentrated to give 3,4-dihydroxybenzoic acid methyl ester (5.2 g, 96%). 1H NMR (DMSO-(I6, 600 MHz) δ 9.77 (s, IH), 9.35 (s, IH), 7.35 (s, IH), 7.30 (d, IH, J=7.8 Hz), 6.79 (d, IH, J=7.8 Hz), 3.78 (s, 3H). |
96% | With thionyl chloride at 20℃; for 12h; | |
95% | With thionyl chloride for 2h; Reflux; | |
95% | With thionyl chloride at 0 - 20℃; for 12h; Inert atmosphere; | |
94% | With sulfuric acid Heating; | |
93% | With toluene-4-sulfonic acid for 2h; Inert atmosphere; Reflux; | 1-1 Example 1-1 Synthesis of Methyl Protocatechuate Under the protection of nitrogen gas, a magnet, 15.4g of protocatechuic acid (0.1mol) and 81mL of methanol were added to the dry three-necked flask.Then 77 mg of p-toluenesulfonic acid was added.Warm up to reflux temperature and react for 2 hours, cool to room temperature, distill to remove excess methanol,The remaining solid was recrystallized with water and dried in a vacuum drying oven to obtain methyl protocatechuate with a yield of 93%. |
93% | With sulfuric acid for 6h; Reflux; | |
91% | With sulfuric acid at 65℃; for 24h; | |
90% | With hydrogenchloride at 80℃; for 12h; | |
90% | With thionyl chloride for 12h; Heating; | |
90% | With sulfuric acid for 8h; Reflux; | Protocatechuic acid in accordance with the following procedure, was used by methyl esterification. Protocatechuic acid 14g, the methanol 50mL was mixed with 100mL eggplant type flask, was added to concentrated sulfuric acid 1mL, the mixture was heated and stirred under reflux for 8 hours. After the reaction, the methanol was evaporated and the resulting solid was dissolved in ethyl acetate, addition of ion-exchanged water, the aqueous layer was separated until neutral. Thereafter, the organic layer was separated, to give a solid by evaporation the organic layer. The solid was dried under reduced pressure to obtain methyl protocatechuic acid in 13.7g (90% yield). |
90.7% | With sulfuric acid Heating; | 1.A; 2.A Step A: Methyl 3,4-dihydroxybenzoate (Intermediate 100B) Sulfuric acid (138.0 mL, 2.60 mol, 2.0 eq.) was added to stirred a solution of 3,4-dihydroxy benzoic acid (100A) (200.0 g, 1.30 mol, 1.0 eq.) in methanol (2.0 L). The reaction mixture was stirred at 80° C. for 15 h. The progress of the reaction was monitored by TLC (50% EtOAc in n-hexane). The solvent was removed by distillation under vacuum then DMW (1500 mL) was added and the product was extracted with ethyl acetate (3*1.5 L). The combined organic extract was washed with saturated solution of sodium bicarbonate (2000 mL) brine (1500 mL), dried over sodium sulfate and concentrated under vacuum to obtained the intermediate 100B (198.0 g, 90.70%) as an off white solid. 1H NMR (300 MHz, DMSO): δ 9.78 ppm (s, 1H), 9.37 ppm (s, 1H), 7.36-7.23 ppm (m, 2H), 6.81 ppm (d, J=8.2 Hz, 1H), 3.76 ppm (s, 3H). |
88% | With sulfuric acid In tetrahydrofuran at 45 - 65℃; for 120 - 240h; Molecular sieve; Darkness; | 4.1 Chemical synthesis General procedure: PA esters were synthesized as described by Reis et al. (2010). Modifications to the general procedure were made to allow the use of fatty alcohols with a longer carbon chain and facilitate the purification step. Briefly, 1 g (6.49 mmol) of protocatechuic acid was solubilized in 3 mL of THF. Then, 3 M equivalents (19.47 mmol) of the corresponding alcohol (from methanol to octadecanol, C1 to C18, respectively) were added. Sulfuric acid was used as catalyst (4%, v/v of the final reaction mixture volume) and the reaction mixtures were incubated in an orbital shaker (250 rpm) at temperatures varying from 45 to 65 °C, depending on the alcohol used, for approximately 5-10 days, protected from light. To remove water generated during the reaction, molecular sieves were added to the medium (40 mg/mL of final volume). At different time intervals, samples were withdrawn from the reaction mixture, and then analyzed by reversed-phase HPLC (Section 2.3). The reaction was stopped by the addition of 2 mL of sodium carbonate (1 M). The mixture was dissolved in approximately 100 mL of acetonitrile and filtrated (150 mm standard pleated filter, Grosseron, Saint-Herblain, France). The resulting solution was stocked at 4 °C until purification. In the case of the esters with an alkyl chain length from 14 to 18 carbons (solids at room temperature), it was necessary to wash the filter using heated acetonitrile. |
86.5% | With hydrogenchloride In lithium hydroxide monohydrate for 12h; | 11.A Example 11; 3,4-dihydroxy- N-(2-oxo-2,3-dihydro-l H-benzo [d]imidazol-5-yl)benzamide (referred to as DC-0051-B3).; 3,4-Dihydroxybenzoic acid was converted to its methyl ester by refluxing in methanol in presence of acid. The dihydroxy group was protected as its benzyl ether by treating with benzyl bromide and potassium carbonate. Hydrolysis of the ester using sodium hydroxide provided the acid which was coupled to 5-amino-2,3- dihydro-1H-benzoimidazol-5-one using N, N-1,3-diisopropylcarbodiimide in presence of 1-hydroxybenzotriazole to provide the amide. The amide was debenzylated by hydrogenation in presence of palladium on carbon. A) 3, 4-Dihydroxy benzoic acid methyl ester; A solution of 3, 4-dihydroxy benzoic acid (2.8 g) in methanol (150 ml) was refluxed in presence of concentrated hydrochloric acid (0.5 ml) for 12 hrs. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate (150 ml) and washed with water (50 ml) 10 % sodium bicarbonate solution (50 ml), brine solution (50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 2.64 g of 3,4-dihydroxybenzoic acid methyl ester. (Yield = 86.5 %). 'H NMR CDC13 7.7 (1H, s) 7.63 (1H, d, J 8Hz) 6.92 (1H, d, J 8Hz) 5.7 (2H, 3.92 (3H, s) |
86% | With hydrogenchloride Inert atmosphere; | |
85% | With toluene-4-sulfonic acid for 72h; Heating; | |
85% | With thionyl chloride at 0℃; Reflux; Inert atmosphere; | 5.2. General procedure for preparation of esters General procedure: Thionyl chloride (1.16 g, 1.5 equiv) was added drop-wise to a solution of acid (1.0 g, 1.0 equiv) in the corresponding alcohol (15 ml) at 0&d eg;C. The solution was refluxed under a nitrogen atmosphere until all starting material was consumed (TLC monitoring). Then the solvent was removed under vacuo and the residue was purified by silica gel column chromatography eluting with ethyl acetate/n-hexane to afford the corresponding carboxylic esters. |
82% | With sulfuric acid for 18h; Reflux; | |
81% | With sulfuric acid at 20℃; for 120h; | |
80% | With sulfuric acid Reflux; | |
76% | With hydrogenchloride In lithium hydroxide monohydrate at 80℃; | |
73% | With sulfuric acid for 168h; Heating; | |
24% | With sulfuric acid for 24h; Reflux; | |
With hydrogenchloride | ||
With hydrogenchloride | ||
3.5 g | With sulfuric acid for 5h; Heating; | |
With sulfuric acid | ||
With trichlorophosphate Heating; | ||
With hydrogenchloride at 20℃; | ||
With sulfuric acid | ||
With sulfuric acid Heating; | ||
With sulfuric acid | 102 3,4-Dihydroxy benzoic acid methyl ester EXAMPLE 102 3,4-Dihydroxy benzoic acid methyl ester A mixture of 100 g of 3,4-dihydroxy benzoic acid, 600 ml methyl alcohol and 10 ml of concentrated sulfuric acid is heated at reflux for 18 hours. The reaction mixture is cooled to room temperature, poured into water and extracted with methylene chloride. The organic layer is washed with saturated sodium bicarbonate and sodium chloride, dried and concentrated in vacuo to give 50.6 g of the desired product. MP 130°-131° C. EI-MS:m/z 168 (M+). | |
With hydrogenchloride for 4h; Reflux; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid | ||
With sulfuric acid at 40℃; for 2h; | ||
With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h; | ||
With sulfuric acid at 90℃; for 8h; | General procedure for the preparation of compounds 2. Protocatechuic acid (1 mmol) in methanol (30 ml) was treated with concentrated sulfuric acid (0.5 ml) under 90 oC overnight. The sovlent was removed leaving oil which was dissovled in ethyl acetate (20 ml) and extracted with water (40 ml). After drying the organic layer with anhydrous Na2SO4 and evaporating the solvent under reduced pressure a solid appeared. The solid was recyrstallized from ethanol to obtain the compound 2. | |
With sulfuric acid Reflux; | ||
With thionyl chloride at 0 - 50℃; for 8h; | ||
With thionyl chloride at 20℃; for 8h; | ||
With sulfuric acid at 90℃; for 8h; | 4.1.1 General procedure for the preparation of compound 2 Protocatechuic acid (1mmol) in methanol (30mL) was treated with concentrated sulfuric acid (0.5mL) under 90°C overnight. The sovlent was removed leaving oil which was dissolved in ethyl acetate (20mL) and extracted with water (40mL). After drying the organic layer with anhydrous Na2SO4 and evaporating the solvent under reduced pressure a solid appeared. The solid was recrystallized from ethanol to obtain the compound 2. | |
With sulfuric acid for 8h; Reflux; | ||
With sulfuric acid Reflux; | 1.1 example 1 (1) the 3,4-dihydroxy benzoic acid, concentrated sulfuric acid, methanol reflux reaction, TLC detection until the raw material disappeared, the obtained solid product; 3,4-dihydroxybenzoic acid, the amount of the concentrated sulfuric acid and methanol is the proportion of 1 : 0.1: 5, wherein 3,4-dihydroxy benzoic acid to mmol meter, concentrated sulfuric acid, in terms of ml of methanol. | |
With thionyl chloride at 60℃; for 10h; Inert atmosphere; | 3,4-Dibenzyloxybenzoic acid (9b) To a solution of 8b (15.0 g, 97.4 mmol) in MeOH (360 mL) was added SOCl2 (7.9 mL, 48.7 mmol) fordropwise at 60 °C. The reaction mixture was stirred at 60 °C for 10 h. Then, the reaction mixture wasevaporated under reduced pressure. The crude mixture was applied to following reaction without furtherpurification.To a mixture of crude residue and K2CO3 (40.4 g, 0.292 mol) in DMF (162 mL) was added benzylbromide (29.0 mL, 0.244 mol) at 100 °C. The reaction mixture was stirred at 100 °C for 16 h. Then, thereaction mixture was filtered through a pad of Celite, diluted with H2O, and extracted with EtOAc. Theorganic layer was washed with water and brine, dried over anhydrous MgSO4, and evaporated underreduced pressure. The crude mixture was applied to following reaction without further purification.To a stirred solution of crude residue in MeOH/THF (1/1, 324 mL) were added 4 M NaOH aq. (85 mL,0.34 mol) at 80 °C. The reaction mixture was stirred at same temperature for 1 h. Then, the reactionmixture was quenched with 6 M HCl aq., filtered and washed with H2O to give 9b (32.2 g, 96.3 mmol,99%) as a white solid.Spectral data for 9b were in good agreement with those reported in reference.16 | |
Heating; | 4.1.1. General procedure for the preparation of methyl 3,4-dihydroxybenzoate(1) To a stirred solution of 3,4-dihydroxybenzoic acid (1 mmol) inmethanol (30 mL) was added thionyl chloride (1 mL) dropwiseover 1 h at 0 C. The mixture was further stirred overnight at50 C. The solution was cooled to room temperature, and dilutedwith water (25 mL). Excess methanol was distilled out and the pH was adjusted to 6 with saturation sodium bicarbonate. Then,the mixture was extracted with ethyl acetate and washed withbrine. After drying the organic layer with anhydrous sodium sulfateand evaporating the solvent under reduced pressure a solidappeared. The crude product was recrystallized from ethanol togive compound 1. The completion of the reaction was monitoredon TLC by using and ethyl acetate petroleum ether (1:1) andobserved in UV light. | |
With sulfuric acid at 63℃; | Synthesis of the ligand. Protocatechuic acid (0.0973 mol, 15 g) was dissolved in methanol (100 ml) with stirring,catalyzed by concentrated sulfuric acid. The mixture was stirred for about 20 h at 63°C and evaporated. The concentratedsolution was poured into 200 ml of ethyl acetate and 100 ml of water and stilled. The ethyl acetate solvent was evaporated togive white powdered compound 1. | |
With thionyl chloride | ||
With thionyl chloride for 1h; Reflux; | Synthesis of compounds 7a-7e General procedure: In a dry round-bottomed flask, protocatechuic acid (2 mmol, 0.308 g) and the respective alcohol(MeOH, n-propanol, n-butanol, n-pentanol, or n-hexanol-10 mL) were added. Immediately,2 mL of SOCl2 were added dropwise. The system was kept under reflux for 1 h and thevolatiles were evaporated under reduced pressure. The residue was dissolved in 25 mL ofEtOAc, washed with 2 x 15 mL aqueous NaHCO3, and with 3 x 25 mL of H2O. The organicphase was dried with anhydrous Na2SO4 and partially evaporated. The crude material waspurified over silica gel column chromatography eluted with n-hexane:EtOAc 1:1 to afford 7a-7e (for NMR and ESI-HRMS spectral data, see S1 File). | |
With sulfuric acid at 100℃; for 2h; | 2.1 Step 1. General procedure: Add compound 1a (18mmol) to 19mL methanol MeOH solution, stir, and then add 0.45mL H2SO4 with a mass fraction of 98.3%. The reaction mixture is refluxed at 100°C for 2 hours, distilled under reduced pressure, and the residue is dissolved in water , And extracted with dichloromethane (DCM), the organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1b (2.68g); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With aluminium(III) iodide; diisopropyl-carbodiimide In acetonitrile at 80℃; for 18h; | Hydroxychavicol (4-Allylbenzene-1,2-diol, 2); General Procedure General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in hot CH3CN (40 mL) were added sequentially DIC (0.379 g, 3 mmol, 0.6 equiv) and eugenol (1, 0.821 g, 5.0 mmol). The mixture was stirred for 18 h at 80 °C, and then it was cooled to r.t., acidified with HCl (2 mol/L, 10 mL), and extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with sat. aq Na2S2O3 (10 mL) and brine (10 mL), and was dried (MgSO4). The solvent was removed on a rotary evaporator and the residue was purified by flash column chromatography (PE/EtOAc, 4:1) to afford 2 (0.750 g, 99%) as a white solid |
100% | With aluminium(III) iodide; diisopropyl-carbodiimide In acetonitrile at 80℃; for 18h; | 28 Example 28 (vanillic acid demethylation) To a 100 ml eggplant flask were added aluminum triiodide (2.253 g), acetonitrile (40 ml), DIC (0.379 g) and Vanillic acid (0.838 g), heated to 80 ° C, and the reaction was stopped after stirring for 18 hours. Cold to room temperature after the eggplant bottle by adding 2mol / L dilute hydrochloric acid (lml) acidification, Extracted with ethyl acetate (50 ml X3) and the combined organic phases were washed first with a saturated aqueous solution of sodium thiosulfate (10 ml) Washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness with a rotary evaporator, The residue was washed with dichloromethane (50 ml) and dried to dry weight, 0.768 g of protocatechuic acid white solid, yield 100%) was obtained. |
77% | With 1,4-dithio-D,L-threitol; phosphite dehydrogenase; phosphite ion; iron(II) sulfate; NADH In dimethyl sulfoxide at 30℃; for 7h; Enzymatic reaction; |
70% | With pyridinium hydrobromide perbromide In xylene for 1.5h; Heating; | |
65% | With pyridine; aluminium(III) iodide In acetonitrile at 80℃; for 18h; | General procedure: To a solution of AlI3 (36.6 mmol, 1.1 equiv) in MeCN (100 mL)was added dropwise a solution of pyridine (12.2 g, 154.2 mmol,4.6 equiv) and eugenol (5.4 g, 33.0 mmol). The mixture wasstirred at 80 °C for 18 h. After cooling to room temperature, themixture was quenched with aq HCl (2 mol/L, 50 mL), and wasextracted with EtOAc (4 × 50 mL). The combined organic phaseswere washed with brine and dried by MgSO4. After evaporationof solvents by a rotary evaporator, the residue was purifiedthrough flash column chromatography to afford 5 as a whitesolid (4.9 g, 99%). |
65% | Stage #1: 3-methoxy-4-hydroxybenzoic acid With pyridine; iodine; aluminium In acetonitrile for 18h; Reflux; Stage #2: With hydrogenchloride In water; acetonitrile at 20℃; | 12 Example 12 (vanillic acid demethylation) To a 100 ml eggplant flask were added iodine (2.100 g), aluminum powder (0.464 g) and acetonitrile (50 ml)Heated to reflux, stirring for 2 hours to the purple red of iodine disappears.Pyridine (1.622 g) and vanillic acid (0.844 g) were added and the reaction was continued for 18 hours. Stop stirring,After cooling to room temperature, 2 mol / L dilute hydrochloric acid (10 ml) was added to the reaction solution,Extracted with ethyl acetate (50 ml x 3). The organic phases were combined and dried over anhydrous sodium sulfate. filter,The filtrate was evaporated to dryness with a rotary evaporator,The residue was purified by flash column chromatography (mobile phase ethyl acetate: petroleum ether = 1: 1,Volume ratio) to give the protocatechinic acid (white solid, 0.510 g, 65% yield). |
With hydrogenchloride at 150 - 160℃; im geschlossenen Rohr; | ||
With Pseudomonas fluorescens B56 (IFO 12055) at 30℃; for 8h; non-growing conditions; | ||
15.28 g | With aluminum (III) chloride; sodium iodide In dichloromethane at 30℃; for 5h; | 3.S2; 4.S2; 5.S2 S2: Add 15g of sodium iodide and 13g of aluminum chloride to the crude 4-hydroxy-3-methoxybenzoic acid solution, stir at 30°C for 5 hours,After the reaction, it was returned to room temperature, then poured into cold water, extracted with ethyl acetate, and the extract was rotary evaporated to obtain 15.28 g of protocatechuic acid with a yield of 99.2% and a product purity of 99.2% |
With 3-mercaptopropionic acid ethyl ester In aq. buffer at 30℃; for 24h; Inert atmosphere; Glovebox; Enzymatic reaction; | ||
With tetrahydrofuran; L-homocysteine; recombinant methionine synthase from Catharanthus roseus; recombinant O-demethylase from Sphingobium sp. SYK-6 In aq. buffer at 30℃; for 8h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In ethanol; | (1) To a suspension of 3,4-dihydroxybenzoic acid (25.4 g, 0.17 mle) in ethanol (250 ml), 5N NaOH aq. (270 ml) and benzyl chloride (102 g, 0.81 mole) were added. The resulting mixture was reacted with stirring for 6 hours under reflux. The reaction mixture was cooled to room temperature, allowed to stand at same temperature overnight and acidified with conc. hydrochloric acid (40 ml). The precipitate was filtered, washed with hot ethanol and dried under reduced pressure to give 38.2 g of 3,4-dibenzyloxybenzoic acid as pale yellow crystals having a m.p. of 184°-186° C. 1 H-NMR delta ppm (DMSO-d6): 3.38 (1H, bs, OH), 5.18 and5.22 (each 2H, each s, each ARCH2 O-), 7.16(1H, d, J=8.8Hz, Ar 5-H), 7.30 - 7.57 (12H,m, ArH). IR (KBr-disk) nu cm-1: 1679 (C=O). | |
With sodium hydroxide; In ethanol; | (1) To a suspension of 3,4-dihydroxybenzoic acid (25.4 g, 0.17 mole) in ethanol (250 ml), 5N NaOH aq. (270 ml) and benzyl chloride (102 g, 0.81 mole) were added, and the mixture was reacted with stirring for 6 hours under reflux. The reaction mixture was cooled to room temperature, allowed to stand at same temperature overnight and acidified with conc. hydrochloric acid (40 ml). The precipitate was filtered, washed with hot ethanol and dried under reduced pressure to give 38.2 g of 3,4-dibenzyloxybenzoic acid as pale yellow crystals having a m.p. of 184-186°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium hydroxide In water at 260℃; for 0.75h; | 3.1. PA Synthesis Protocatechuic acid was obtained by the caustic fusion of vanillin. In a nickel crucible potassiumhydroxide (33 g, 0.588 mol) is added with a small volume of water (4 mL). A crucible is placed inan oil bath, and an overhead mechanical stirrer is installed. Heating is set to 260 C and stirring isset to ca. 100 rpm. After a few minutes, the salt mixture becomes a homogeneous viscous mixture.Vanillin (12 g, 0.079 mol) is then carefully added into the solution. After 45 min, the reaction is stoppedand allowed to cool down. The reaction mixture is dissolved in water (200 mL), and the product isthen recovered by acidification/precipitation with hydrochloric acid. Filtration in a Buchner funnelyields 9.5 g of protocatechuic acid (0.061 mol). The aqueous phase is further extracted three times withdiethyl ether (50 mL). The organic phase in then dried over anhydrous MgSO4 and evaporated underreduced pressure to recover an additional 2.1 g of protocatechuic acid (0.013 mol, 94% yield). 1H-NMR(400 MHz, d6-DMSO): 7.32 (s, H, ArH), 7.27 (d, 1H, ArH), 6.79 (d, 1H, ArH). |
With potassium carbonate durch Schmelzen; | ||
With potassium hydroxide durch Schmelzen; |
With potassium hydroxide at 250℃; | ||
With tetrahydrofuran; L-homocysteine; water; recombinant methionine synthase from Catharanthus roseus; recombinant O-demethylase from Sphingobium sp. SYK-6; xanthine oxidase from bovine serum milk; catalase from bovine liver In aq. buffer at 30℃; for 8h; Enzymatic reaction; | ||
Multi-step reaction with 2 steps 1: water; catalase from bovine liver; tetrahydrofuran; xanthine oxidase from bovine serum milk; recombinant O-demethylase from Sphingobium sp. SYK-6; recombinant methionine synthase from Catharanthus roseus; L-homocysteine / aq. buffer / 30 °C / pH 8 / Enzymatic reaction 2: tetrahydrofuran; recombinant O-demethylase from Sphingobium sp. SYK-6; recombinant methionine synthase from Catharanthus roseus; L-homocysteine / aq. buffer / 8 h / 30 °C / pH 8 / Enzymatic reaction | ||
Multi-step reaction with 2 steps 1: water; catalase from bovine liver; xanthine oxidase from bovine serum milk / aq. buffer / 2 h / 30 °C / pH 8 / Enzymatic reaction 2: tetrahydrofuran; recombinant O-demethylase from Sphingobium sp. SYK-6; recombinant methionine synthase from Catharanthus roseus; L-homocysteine / aq. buffer / 8 h / 30 °C / pH 8 / Enzymatic reaction |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In neat (no solvent) at 80℃; for 4h; | General procedure: General procedure: An organic acid (1 g), alcohol (excess) and catalyst (0.1 g) mixture was heated in a round bottomed flask. The completion of reaction is indicated by the total disappearance of acid. Then after, the catalyst was separated by filtration and reused. Sodium bicarbonate solution was added to the filtrate and removed with ether. With anhydrous sodium sulphate, the extract was dried and solvent was removed. Using ethyl acetate and petroleum ether, the pure product was isolated by column chromatography. |
73% | With thionyl chloride at 0℃; Reflux; Inert atmosphere; | 5.2. General procedure for preparation of esters General procedure: Thionyl chloride (1.16 g, 1.5 equiv) was added drop-wise to a solution of acid (1.0 g, 1.0 equiv) in the corresponding alcohol (15 ml) at 0&d eg;C. The solution was refluxed under a nitrogen atmosphere until all starting material was consumed (TLC monitoring). Then the solvent was removed under vacuo and the residue was purified by silica gel column chromatography eluting with ethyl acetate/n-hexane to afford the corresponding carboxylic esters. |
51.8% | With sulfuric acid at 0 - 80℃; |
With hydrogenchloride | ||
With sulfuric acid | ||
With thionyl chloride at 20℃; for 8h; | ||
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sulfuric acid for 2h; Inert atmosphere; Reflux; | 1-2 Example 1-1 Synthesis of Methyl Protocatechuate General procedure: Under the protection of nitrogen gas, a magnet, 15.4g of protocatechuic acid (0.1mol) and 81mL of methanol were added to the dry three-necked flask.Then 77 mg of p-toluenesulfonic acid was added.Warm up to reflux temperature and react for 2 hours, cool to room temperature, distill to remove excess methanol,The remaining solid was recrystallized with water and dried in a vacuum drying oven to obtain methyl protocatechuate with a yield of 93%. |
93% | With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h; | |
82% | With sulfuric acid In tetrahydrofuran at 45 - 65℃; for 120 - 240h; Darkness; Molecular sieve; | 4.2 Chemical synthesis General procedure: PA esters were synthesized as described by Reis et al. (2010). Modifications to the general procedure were made to allow the use of fatty alcohols with a longer carbon chain and facilitate the purification step. Briefly, 1 g (6.49 mmol) of protocatechuic acid was solubilized in 3 mL of THF. Then, 3 M equivalents (19.47 mmol) of the corresponding alcohol (from methanol to octadecanol, C1 to C18, respectively) were added. Sulfuric acid was used as catalyst (4%, v/v of the final reaction mixture volume) and the reaction mixtures were incubated in an orbital shaker (250 rpm) at temperatures varying from 45 to 65 °C, depending on the alcohol used, for approximately 5-10 days, protected from light. To remove water generated during the reaction, molecular sieves were added to the medium (40 mg/mL of final volume). At different time intervals, samples were withdrawn from the reaction mixture, and then analyzed by reversed-phase HPLC (Section 2.3). The reaction was stopped by the addition of 2 mL of sodium carbonate (1 M). The mixture was dissolved in approximately 100 mL of acetonitrile and filtrated (150 mm standard pleated filter, Grosseron, Saint-Herblain, France). The resulting solution was stocked at 4 °C until purification. In the case of the esters with an alkyl chain length from 14 to 18 carbons (solids at room temperature), it was necessary to wash the filter using heated acetonitrile. |
64% | With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; | |
With hydrogenchloride | ||
With sulfuric acid | ||
With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h; | ||
With sulfuric acid | ||
With thionyl chloride for 1h; Reflux; | Synthesis of compounds 7a-7e General procedure: In a dry round-bottomed flask, protocatechuic acid (2 mmol, 0.308 g) and the respective alcohol(MeOH, n-propanol, n-butanol, n-pentanol, or n-hexanol-10 mL) were added. Immediately,2 mL of SOCl2 were added dropwise. The system was kept under reflux for 1 h and thevolatiles were evaporated under reduced pressure. The residue was dissolved in 25 mL ofEtOAc, washed with 2 x 15 mL aqueous NaHCO3, and with 3 x 25 mL of H2O. The organicphase was dried with anhydrous Na2SO4 and partially evaporated. The crude material waspurified over silica gel column chromatography eluted with n-hexane:EtOAc 1:1 to afford 7a-7e (for NMR and ESI-HRMS spectral data, see S1 File). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sulfuric acid In tetrahydrofuran at 45 - 65℃; for 120 - 240h; Darkness; Molecular sieve; | 4.4 Chemical synthesis General procedure: PA esters were synthesized as described by Reis et al. (2010). Modifications to the general procedure were made to allow the use of fatty alcohols with a longer carbon chain and facilitate the purification step. Briefly, 1 g (6.49 mmol) of protocatechuic acid was solubilized in 3 mL of THF. Then, 3 M equivalents (19.47 mmol) of the corresponding alcohol (from methanol to octadecanol, C1 to C18, respectively) were added. Sulfuric acid was used as catalyst (4%, v/v of the final reaction mixture volume) and the reaction mixtures were incubated in an orbital shaker (250 rpm) at temperatures varying from 45 to 65 °C, depending on the alcohol used, for approximately 5-10 days, protected from light. To remove water generated during the reaction, molecular sieves were added to the medium (40 mg/mL of final volume). At different time intervals, samples were withdrawn from the reaction mixture, and then analyzed by reversed-phase HPLC (Section 2.3). The reaction was stopped by the addition of 2 mL of sodium carbonate (1 M). The mixture was dissolved in approximately 100 mL of acetonitrile and filtrated (150 mm standard pleated filter, Grosseron, Saint-Herblain, France). The resulting solution was stocked at 4 °C until purification. In the case of the esters with an alkyl chain length from 14 to 18 carbons (solids at room temperature), it was necessary to wash the filter using heated acetonitrile. |
55% | With sulfuric acid In tetrahydrofuran at 100℃; for 1h; Microwave irradiation; | 2.3. Synthesis of compound 2d In a microwave flask, 1.5 mmol of 3,4-dihydroxybenzoic acid and 1 mmol of 1-octanol were dissolved in 3 mL of tetrahydrofuran and then 0.2 mL of concentrated sulfuric acid was added (Scheme 2). The reaction proceeded in a microwave reactor (Discovery, CEM Inc.) for 1 h at 100 °C. Solvent was removed and the residue dissolved in 15 mL of CH2Cl2 and washed with 5x15 mL of NaHCO3 saturated solution. The organic layer was dried over anhydrous Na2SO4 and evaporated to give the product 2d with adequate purity. Octyl 3,4-dihydroxybenzoate (2d). 0.231 g of 3,4-dihydroxybenzoic acid and 0.1301 g of 1-octanol yielded 55% of the ester as a white powder (mp 94-96 °C). 1H NMR (300 MHz, CDCl3): δ=7.67 (d, J=1.7 Hz, 1H), 7.57 (dd, J=8.3, 1.7 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.21 (br.s, 1H), 6.05 (br.s, 1H), 4.28 (t, J=6.6 Hz, 2H), 184-164 (m, 2H), 1.47-1.18 (m, 10H), 0.88 (t, J=6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ=167.22, 148.90, 143.20, 123.71, 122.70, 116.67, 114.81, 65.36, 31.80, 29.30, 29.20, 28.69, 26.04, 22.65, 14.09. |
36% | With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; |
With dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 20h; | ||
With sulfuric acid at 110℃; for 5h; | ||
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 20℃; | ||
With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h; | ||
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sulfuric acid In tetrahydrofuran at 45 - 65℃; for 120 - 240h; Molecular sieve; Darkness; | 4.3 Chemical synthesis General procedure: PA esters were synthesized as described by Reis et al. (2010). Modifications to the general procedure were made to allow the use of fatty alcohols with a longer carbon chain and facilitate the purification step. Briefly, 1 g (6.49 mmol) of protocatechuic acid was solubilized in 3 mL of THF. Then, 3 M equivalents (19.47 mmol) of the corresponding alcohol (from methanol to octadecanol, C1 to C18, respectively) were added. Sulfuric acid was used as catalyst (4%, v/v of the final reaction mixture volume) and the reaction mixtures were incubated in an orbital shaker (250 rpm) at temperatures varying from 45 to 65 °C, depending on the alcohol used, for approximately 5-10 days, protected from light. To remove water generated during the reaction, molecular sieves were added to the medium (40 mg/mL of final volume). At different time intervals, samples were withdrawn from the reaction mixture, and then analyzed by reversed-phase HPLC (Section 2.3). The reaction was stopped by the addition of 2 mL of sodium carbonate (1 M). The mixture was dissolved in approximately 100 mL of acetonitrile and filtrated (150 mm standard pleated filter, Grosseron, Saint-Herblain, France). The resulting solution was stocked at 4 °C until purification. In the case of the esters with an alkyl chain length from 14 to 18 carbons (solids at room temperature), it was necessary to wash the filter using heated acetonitrile. |
63% | With dicyclohexyl-carbodiimide In tetrahydrofuran for 20h; | |
33% | With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 20℃; | ||
With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h; | ||
With sulfuric acid | ||
With thionyl chloride for 1h; Reflux; | Synthesis of compounds 7a-7e General procedure: In a dry round-bottomed flask, protocatechuic acid (2 mmol, 0.308 g) and the respective alcohol(MeOH, n-propanol, n-butanol, n-pentanol, or n-hexanol-10 mL) were added. Immediately,2 mL of SOCl2 were added dropwise. The system was kept under reflux for 1 h and thevolatiles were evaporated under reduced pressure. The residue was dissolved in 25 mL ofEtOAc, washed with 2 x 15 mL aqueous NaHCO3, and with 3 x 25 mL of H2O. The organicphase was dried with anhydrous Na2SO4 and partially evaporated. The crude material waspurified over silica gel column chromatography eluted with n-hexane:EtOAc 1:1 to afford 7a-7e (for NMR and ESI-HRMS spectral data, see S1 File). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sulfuric acid In tetrahydrofuran at 45 - 65℃; for 120 - 240h; Darkness; Molecular sieve; | 4.6 Chemical synthesis General procedure: PA esters were synthesized as described by Reis et al. (2010). Modifications to the general procedure were made to allow the use of fatty alcohols with a longer carbon chain and facilitate the purification step. Briefly, 1 g (6.49 mmol) of protocatechuic acid was solubilized in 3 mL of THF. Then, 3 M equivalents (19.47 mmol) of the corresponding alcohol (from methanol to octadecanol, C1 to C18, respectively) were added. Sulfuric acid was used as catalyst (4%, v/v of the final reaction mixture volume) and the reaction mixtures were incubated in an orbital shaker (250 rpm) at temperatures varying from 45 to 65 °C, depending on the alcohol used, for approximately 5-10 days, protected from light. To remove water generated during the reaction, molecular sieves were added to the medium (40 mg/mL of final volume). At different time intervals, samples were withdrawn from the reaction mixture, and then analyzed by reversed-phase HPLC (Section 2.3). The reaction was stopped by the addition of 2 mL of sodium carbonate (1 M). The mixture was dissolved in approximately 100 mL of acetonitrile and filtrated (150 mm standard pleated filter, Grosseron, Saint-Herblain, France). The resulting solution was stocked at 4 °C until purification. In the case of the esters with an alkyl chain length from 14 to 18 carbons (solids at room temperature), it was necessary to wash the filter using heated acetonitrile. |
81% | With dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 20h; | |
33% | With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; |
With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h; | ||
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With toluene-4-sulfonic acid In methanol for 120h; Heating; | |
80% | With thionyl chloride In methanol at 0℃; for 16h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sulfuric acid In tetrahydrofuran at 45 - 65℃; for 120 - 240h; Darkness; Molecular sieve; | 4.5 Chemical synthesis General procedure: PA esters were synthesized as described by Reis et al. (2010). Modifications to the general procedure were made to allow the use of fatty alcohols with a longer carbon chain and facilitate the purification step. Briefly, 1 g (6.49 mmol) of protocatechuic acid was solubilized in 3 mL of THF. Then, 3 M equivalents (19.47 mmol) of the corresponding alcohol (from methanol to octadecanol, C1 to C18, respectively) were added. Sulfuric acid was used as catalyst (4%, v/v of the final reaction mixture volume) and the reaction mixtures were incubated in an orbital shaker (250 rpm) at temperatures varying from 45 to 65 °C, depending on the alcohol used, for approximately 5-10 days, protected from light. To remove water generated during the reaction, molecular sieves were added to the medium (40 mg/mL of final volume). At different time intervals, samples were withdrawn from the reaction mixture, and then analyzed by reversed-phase HPLC (Section 2.3). The reaction was stopped by the addition of 2 mL of sodium carbonate (1 M). The mixture was dissolved in approximately 100 mL of acetonitrile and filtrated (150 mm standard pleated filter, Grosseron, Saint-Herblain, France). The resulting solution was stocked at 4 °C until purification. In the case of the esters with an alkyl chain length from 14 to 18 carbons (solids at room temperature), it was necessary to wash the filter using heated acetonitrile. |
73% | With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h; | |
36% | With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; |
With dicyclohexyl-carbodiimide In 1,4-dioxane at 5℃; for 48h; | ||
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | To a stirred solution of 3,4-dihydroxybenzoic acid (10 g, 64.88 mmol) in DMF (100 mL) was added potassium carbonate (35.86 g, 259.5 mmol) followed by benzyl bromide (23.89 mL, 201 .1 mmol). The resulting suspension was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with brine (1x), brine:water (2x) and brine (1 x). The organic phase was dried, filtered and concentrated in vacuo giving an amber oil which slowly solidified. The residue was stirred in hexanes and filtered to give the desired product as a white solid (22g, 81 %). [See Australian Journal of Chemistry, 70(1 ), 52-60; 2017]. |
57.3% | With potassium carbonate; In acetonitrile; for 18.0h;Reflux; | The first step involves mixing 3,4-dihydroxy benzoic acid (5 g, 32.44 mmol), benzyl bromide (15.41 mL, 129.76 mmol), and potassium carbonate (17.93 g, 129.73 mmol) in 100 mL of acetonitrile (MeCN or ACN) under reflux for 18 h. The reaction solution was cooled to room temperature and the salts were filtered out. The solution was concentrated down to about 20 mL and diluted with 100 mL of hexane. A solid was formed which was removed by filtration. The solid was recrystallized out of tetrahydrofuran (THF)/Hexane to yield a pure product (7.88 g, 57.3% yield). ^ N MR (400 MHz, CDCI3, 22 C): delta 7.70-7.68 (m, 2H, -COOCCH-), 7.47-7.28 (m, 15H, -CH2C6H5), 6.96- 6.93 (m, 1H, -COOCCHCCHC-), 5.34 (s, 2H, -COOCAY2C6H5), 5.25-5.21 (d, J = 20 Hz, 4H, - C2COCH2C6H5). |
57.3% | With potassium carbonate; In acetonitrile; for 18.0h;Reflux; | The first step involves mixing of 3,4-dihydroxy benzoic acid (5 g, 32.44 mmol), benzyl bromide (15.41 mL, 129.76 mmol), and potassium carbonate (17.93 g, 129.73 mmol) in 100 mL of acetonitrile under refluxed for 18 h. The reaction solution was cooled to room temperature and the salts were filtered out. The solution was then concentrated down to 20 mL and diluted with 100 mL of hexanes. A solid was formed, and harvested by filtration. The solid was then recrystallized out of THF/hexanes to yield a pure product (7.88 g, 57.3% yield). 1H NMR (400 MHz, CDCl3, 22 C.): delta7.70-7.68 (m, 2H, -COOCCH-), 7.47-7.28 (m, 15H, -CH2C6H5), 6.96-6.93 (m, 1H, -COOCCHCCHC-), 5.34 (s, 2H, -COOCH2C6H5), 5.25-5.21 (d, J=20 Hz, 4H, -C2CO(CH2C6H5)2. |
With potassium carbonate; In N,N-dimethyl-formamide;Inert atmosphere; | General procedure: A solution of hydroxy benzoic acid (1.0 equiv), BnBr (3-5 equiv) and K2CO3 (10-15 equiv) in DMF was stirred overnight under argon. After filtration, the solution was concentrated in vacuo to afford the crude product. The crude product was dissolved in methanol and an aqueous solution of NaOH (75 equiv) was added. The mixture was stirred at room temperature overnight and the solution concentrated in vacuo to remove the methanol. The residue was acidified with 10 % HCl to pH 2 and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by recrystallization from CH2CH2 / MeOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | 3,4-Dihydroxy-N-(2-(1H-indol-2-yl)-phenyl)-benzamide Prepared from 2-(2-aminophenyl) indole and 3,4-dihydroxybenzoic acid in 54% yield following procedure 1. The product was chromatographed on silica. 100% Purity by LC/MS (230 DAD), Mass-spec (M+H+)=345.83, 1H NMR (MeOH-d4): 6.645 s (1H), 6.80 d, 8 Hz (1H), 7.02 t, 8 Hz (1H), 7.12 td, 8, 1 Hz (1H), 7.23 dd, 8, 1 Hz (1H), 7.33-7.36 m (2H), 7.39-7.42 m (2H), 7.52 d, 7 Hz (1H), 7.65 dd, 8, 1 Hz (1H), 7.94 d, 8 Hz (1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; dimethyl sulfate; In ethyl acetate; acetone; | (a) Schemes of Synthesis Compounds of the present inventions were synthesised from commercially available 3,4-dihydroxybenzoic acid (1) and 4-bromo-3,4-dihydroxybenzoic acid (10) following the route, outlined in Scheme 1 or 2: Procedure A (Methylation). Alcohol or acid (1 g, 1 eq) was added to a well stirred acetone solution (100 ml) containing dimethyl sulfate (2 eq. for each hydroxyl or carboxylic group) and K2CO3 (5 eq. for each hydroxyl or carboxylic group). This solution was refluxed for 12 hours. After filtration, solvent acetone was evaporated under reduced pressure, the residue was dissolved in EtOAc (50 mL). The EtOAc solution was washed with water (50 mL*2), saturated aqueous NaCl (50 mL), dried over Na2SO4, evaporated under reduced pressure to offer syrup which was purified by silica column chromatography (Hexanes/EtOAc=4:1). When PO(OEt)3 is substituted with triphenylphosphate, cis-derivatives are synthesised. | |
With potassium carbonate; dimethyl sulfate; In ethyl acetate; acetone; | (a) Schemes of Synthesis. Compounds of the present inventions were synthesised from commercially available 3,4-dihydroxybenzoic acid (1A) and 4-bromo-3,4-dihydroxybenzoic acid (10A) following the route, outlined in Scheme 4 and Scheme 5. Procedure A (Methylation). Alcohol or acid (1 g, 1 eq) was added to a well stirred acetone solution (100 ml) containing dimethyl sulfate (2 eq. for each hydroxyl or carboxylic group) and K2CO3 (5 eq. for each hydroxyl or carboxylic group). This solution was refluxed for 12 hours. After filtration, solvent acetone was evaporated under reduced pressure, the residue was dissolved in EtOAc (50 mL). The EtOAc solution was washed with water (50 mL*2), saturated aqueous NaCl (50 mL), dried over Na2SO4, evaporated under reduced pressure to offer syrup which was purified by silica column chromatography (Hexanes/EtOAc=4:1). When PO(OEt)3 is substituted with triphenylphosphate, cis-derivatives are synthesised. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In tetrahydrofuran; ethyl acetate | 3 N-α-(3,4-dihydroxybenzoyl)-N-ε-t-BOC-lysine methyl ester N-α-(3,4-dihydroxybenzoyl)-N-ε-t-BOC-lysine methyl ester 3,4-dihydroxybenzoic acid (820 mg, 5.3 mmole) and N-ε-t-BOC-lysine methyl ester (1.38 g, 5.31 mmole) were dissolved in 50 mL EtOAc/THF (1/1, anhydrous). Dicyclohexylcarbodiimde (1.24 g, 6 mmole) was added to the solution. The reaction mixture was stirred for 24 hours, filtered, and the solvent was evaporated. The solid obtained was dissolved in EtOAc (50 mL) and extracted with phosphate buffer (200 mM, pH=6.5) 2*50 mL. The ethyl acetate solution was washed with brine, separated, dried with Na2SO4, and evaporated to produce 1.89 g of solid (90% yield). The compound was pure by TLC and used as is for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound 12 was prepared according a procedure reported by Tranchimand et al.33 and spectral data were in accordance with literature. Briefly, benzyl bromide (14 mL, 117 mmol) and K2CO3 (10.7 g, 78 mmol) were added over a solution of 3,4-dihydroxybenzoic acid (11) (2.00 g, 13 mmol) in dry DMF (30 mL) under an argon atmosphere and heated to 60 °C for 20 h. The reaction mixture was cooled to room temperature, filtered and the solvent was removed under reduced pressure. The residue was dissolved in AcOEt (10 mL) and washed with 1 M HCl (3 x 5 mL) and brine (5 x 5 mL). The combined organic extracts were dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was dissolved in CH3OH (38 mL), and treated with 2.3 MNaOH (14 mL) and the mixture was heated under reflux for 1 h. Then, solvents were evaporated under reduced pressure and the residue was treated with H2O (5 mL) and then extracted with Et2O (3 6 mL). The aqueous phase was made acidic (pH 1?2) with 1 M HCl and extracted with AcOEt (3 x 5 mL). The organic extracts were dried over MgSO4, filtered and the solvent was removed under reduced pressure. Mp 187?188 °C as reported inliterature.33 | ||
With potassium carbonate; In acetonitrile; for 18h;Reflux; | Preparation of 3,4-bis(benzyloxy)benzoic acid (0175) 3,4-Dihydroxy benzoic acid, benzyl bromide, and potassium carbonate were dissolved in acetonitrile, and the solution was refluxed for 18 hours. The reaction solution was then cooled to room temperature and filtered. The solution was then concentrated and diluted with hexanes, resulting in a solid that was collected by filtration. The solid was then recrystallized in the mixture of THF and hexanes, giving rise to a pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere; | PRO-04-35 Anhydrous potassium carbonate (10.9 g, 79.5 mmol) was added to a solution of 3, 4- Dihydroxybenzoic acid (3.5 g, 22.7 mmol) in anhydrous DMF (100 ml followed by benzyl chloride (8.8 g, 69.2 mmol). The resulting suspension was stirred under argon at 60 C overnight. The reaction mixture was poured in water (150ml) and extracted with ethyl acetate (3x 50 ml). The combined organic extract was washed with water, brine solution (50 ml each) dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. Yield = 9.4 g, 98% yield. |
98% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere; | Anhydrous potassium carbonate (10.9 g, 79.5 mmol) was added to a solution of 3,4-Dihydroxybenzoic acid (3.5 g, 22.7 mmol) in anhydrous DMF (100 ml followed by benzyl chloride (8.8 g, 69.2 mmol). The resulting suspension was stirred under argon at 60 C. overnight. The reaction mixture was poured in water (150 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extract was washed with water, brine solution (50 ml each) dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. Yield=9.4 g, 98% yield. PRO-04-35. |
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 85℃; for 12.0h;Inert atmosphere; | Take 1g3,4- dihydroxybenzoic acid (6.49 mmol) was dissolved in 20mL of dry N, N- dimethylformamide was stirred under dry potassium carbonate 2.96g was added, at room temperature was added dropwise 2.98mL of benzyl chloride and stirring was continued for 10min, then the reaction under nitrogen 85 12h.Completion of the reaction was cooled to room temperature, 100mL water and extracted three times with chloroform (3 × 100mL).The combined organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure.The residue was separated by silica gel column to give a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | Stage #1: 3,4-Dihydroxybenzoic acid With 1,2-dichloro-ethane In acetonitrile at 20℃; for 1h; Inert atmosphere; Stage #2: N-(3-aminopropyl)-1,4-diaminobutane In acetonitrile Inert atmosphere; Stage #3: trifluoroacetic acid | Generalprocedure for the generation of the amide analogues A solution of a benzoic acid derivative (0.5 mmol) and EDC (0.6 mmol) in dry MeCN (1 mL) werestirred at room temperature for 1 h under nitrogen gas, and to this was added an amine (0.6 mmol) in dry MeCN (1mL). The reaction mixture was stirred overnight before being quenched with H2O(500 µL) then extracted with CH2Cl2 (3 × 10 mL). Thecombined organic extracts were dried over anhydrous sodium sulfate, filteredand evaporated to dryness to afford a crude product that was purified bysemi-preparative reversed phase C18 HPLC using the isolation conditionsdescribed above to give the desired amide product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: In an ice-bath, 1.60 mmol of the opportune acid has been dissolved in DMF (2 mL) then 0.4 mL of aqueous 0.4 M sodium hydroxyde were added. The mixture was stirred for 20 min and then <strong>[20782-91-6]2-(bromomethyl)-5-nitrofuran</strong> (1.6 mmol) was slowly added. After the addition was complete, the mixture was allowed to reach ambient temperature for 20 h and afterward it was stirred for 2 h at 50 C. The reaction mixture was treated with H2O and AcOEt (3:1). The ethyl acetate layer was separated and the aqueous layer extracted with ethyl acetate (20 mL). The combined ethyl acetate extracts were washed with water (30 mL), saturated sodium hydrogen carbonate solution (30 mL), water (30 mL) and with saturated sodium chloride solution (30 mL) and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified with column chromatography using silica gel and AcOEt/n-hexane as eluent to give a yellow solid which was crystallized from toluene (yield 40-50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In methanol; at 20℃; for 168h; | General procedure: The synthesis of the co-crystals was carried out in solution crystallization experiments. Co-crystal 1 was obtained by the following procedure: stoichiometric amounts of PZA (0.5 mmol, 61.5 mg) and MHBA (0.5 mmol, 69.1 mg) were dissolved separately in a beaker with 10 ml of methanol solution, then combined and slowly evaporated at room temperature. A week later, we got club-shaped colorless crystals (yield 91 % based on MHBA). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With human-soluble catechol O-methyltransferase; disodium ethylenediamine tetraacetic acid; magnesium chloride; Cleland's reagent In aq. buffer at 37℃; for 14h; Enzymatic reaction; | 1.5 General Procedure for determination of the meta/para alkylation ratio General procedure: Reactions were carried out with purified hsCOMT (1.0 mg/mL, 40 μM, 0.02 eq), catechols (2 mM, 1.0 eq), allyl-SAM/SAM (3 mM, 1.5 eq) at 37 °C in reaction buffer (50 mM Tris, pH 8.0, 100 μM MgCl2, 100 μM DTT, 10 μM EDTA.2Na). A fast ultrafiltration was carried out onto the reaction mixture after 14 h incubation using Millipore’s Amicon Ultra-0.5 10K centrifugal filter device. The filter liquor part for 1c was concentrated under reduced pressure and went for NMR directly after adding CD3OD. 1d reaction mixture was treated in the same way except the additional acidification with 1 M HCl after ultrafiltration and CDCl3 was used as the NMR detecting solvent. The meta/para methylation ratio of 1c and 1d was 2.1:1 and 3:1 by comparison with reported 1.3~1.6:1 and 4.2:15-6, respectively. Ratio determined by HPLC was calculated by the peak area of each generated isomers in the filter liquor part. The mobile phase composition differed slightly depending on the substrate. In the case of 1e, the solvent system consisted of a mixture of 30% methanol, 1 mM 1-heptane sulfonic acid sodium salt and 50 mM Na2HPO4 at pH 2.5. For the Boc group protected dopamine 1f, the solvent system consisted of water (A) and methanol (B). The gradient used was 40% A, 60% B in 8 min, a linear gradient to 100% B in 12 min. For 1g, the mobile phase was 45% 50 mM Na2HPO4 at pH 5.2 and 55% methanol. For 1h, the mobile phase was 50% 50 mM Na2HPO4 at pH 5.2 and 50% methanol. For 1i, the mobile phase was 65% 50 mM Na2HPO4 at pH 5.2 and 35% methanol. | |
With ethylenediaminetetraacetic acid; magnesium(II); Niastella koreensis catechol O-methyltransferase Enzymatic reaction; regiospecific reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.4% | In ethanol at 50℃; for 0.666667h; | Protocatechuic acid (PA, 1.54 g, 0.01mol) was dissolved in absolute ethyl alcohol (7.5 mL)and ligustrazine (TMP, 0.68 g, 0.005 mol) was dissolved in absolute ethyl alcohol (3.5 mL) at40°C. The solution of ligustrazinewas added into the solution of protocatechuic acid, and thenthemixture was refluxed for 40min at 50°C.After cooling, the crude productwas precipitated.The crystal of the complex (II) was obtained after crystallization in 100 mL water-ethanol(1:1) solvent system at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 31% 2: 64% | With aluminium(III) iodide; diisopropyl-carbodiimide In acetonitrile at 40℃; for 18h; | Hydroxychavicol (4-Allylbenzene-1,2-diol, 2); General Procedure General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in hot CH3CN (40 mL) were added sequentially DIC (0.379 g, 3 mmol, 0.6 equiv) and eugenol (1, 0.821 g, 5.0 mmol). The mixture was stirred for 18 h at 80 °C, and then it was cooled to r.t., acidified with HCl (2 mol/L, 10 mL), and extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with sat. aq Na2S2O3 (10 mL) and brine (10 mL), and was dried (MgSO4). The solvent was removed on a rotary evaporator and the residue was purified by flash column chromatography (PE/EtOAc, 4:1) to afford 2 (0.750 g, 99%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With aluminium(III) iodide; diisopropyl-carbodiimide; In acetonitrile; at 80℃; for 18h; | General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in hot CH3CN (40 mL) were added sequentially DIC (0.379 g, 3 mmol, 0.6 equiv) and eugenol (1, 0.821 g, 5.0 mmol). The mixture was stirred for 18 h at 80 C, and then it was cooled to r.t., acidified with HCl (2 mol/L, 10 mL), and extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with sat. aq Na2S2O3 (10 mL) and brine (10 mL), and was dried (MgSO4). The solvent was removed on a rotary evaporator and the residue was purified by flash column chromatography (PE/EtOAc, 4:1) to afford 2 (0.750 g, 99%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 72% 2: 14% | With aluminium(III) iodide; ethyl acetate; diisopropyl-carbodiimide In acetonitrile at 80℃; for 5h; | |
1: 31% 2: 64% | With aluminium(III) iodide; diisopropyl-carbodiimide In acetonitrile at 40℃; for 18h; Overall yield = 89 %; Overall yield = 0.684 g; | 30 Example 29 (methyl vanillate demethylation) To a 100 ml eggplant flask were added aluminum triiodide (2.247 g), Acetonitrile (40 ml) DIC (0.378 g) and vanillic acid methyl ester (0.909 g), heated to 40 ° C, After stirring for 18 hours, the mixture was stirred, cooled to room temperature and then acidified with 2 mol / L dilute hydrochloric acid (10 ml) And extracted with ethyl acetate (50 ml X). The combined organic phases were washed first with a saturated aqueous solution of sodium thiosulfate (10 ml), washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated Instrument evaporated, The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 3: 7, volume ratio) 0.260 g of methyl catecholate (white solid, 31% yield) and unreacted starting material (2 mg) were obtained. The polarity of the eluent was increased to ethyl acetate / petroleum ether = 1: 1 (volume ratio) To give 0.496 g of protocatechuic acid (white solid, 64% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.33% | :[0177]A suspension of 3, 4-dihydroxybenzoic acid (1.0 g, 6.49 mmol) , TBAI (239.67 mg, 0.65 mmol) and K2CO3(3.59 g, 25.98 mmol) in N, N-dimethylformamide (DMF) (10 mL) was heated to 100 for 1 h. The mixture was allowed to cool to 50 before 1-chloro-2-methoxyethane (2.45g, 25.92 mmol) was added. The resulting mixture was stirred at 85 for 15 h before cooled to room temperature. It was filtered and concentrated, the residue was solved by THF (40mL) /H2O (10 mL) , and KOH (1.09 g, 19.5mmol ) was added. The resulting solution was stirred at room temperature for 5 h before it was quenched by 1N HCl. Extracted by ethyl acetate (30mL, 3times) , the organic phase was washed by brine (15mL) , dried over Na2SO4, filtered and concentrated to give 3, 4-bis (2-methoxyethoxy) benzoic acid (Intermediate 1) as a clear oil (1.32g, yield 75.33) .1H NMR (400 MHz, CDCl3) delta 7.48 (d, J 8.4Hz, 1H) , 7.65 (s, 1H) , 6.94 (d, J8.4Hz, 1H) , 4.24-4.16 (m, 4H) , 3.82-3.76 (m, 4H) , 3.47 (s, 6H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; for 1.66667h; | General procedure: The TN salts/molecular salts was preparedby grinding an equimolar mixture containing 200mg (1 mmol) of TN and 1mmol of correspondingcarboxylic acids/PTSA wetted with few drops of waterwas manually grounded in an agate mortar for 100minutes until a dried powder was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With potassium carbonate; In acetone; at 62℃; for 6.0h; | 2,3,4-trihydroxyacetophenone (1 g, 5.95 mmol) was added to the reaction flask followed by the addition of 20 mL of acetone and the mixture was stirred to dissolve. Then methyl iodide (0.93 mL, 14.94 mmol) and potassium carbonate (3.3 g, 23.88 mmol) and refluxed at 62 C for 6h. The reaction mixture was directly filtered off with suction and extracted with dichloromethane (3 × 50 mL). The organic phases were combined and washed with 3% diluted hydrochloric acid (100 mL), saturated sodium bicarbonate (100 mL) and saturated brine (100 mL) Each wash 1 times, anhydrous sodium sulfate drying. The solvent was removed by rotary evaporation,The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to give 0.24 g of a white solid,The reaction yield was 21%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
480 mg | In acetonitrile;Reflux; | 500mg tenofovir alafenamide free base were mixed at room temperature with lOmi of acetonitrile. 170mg of 3,4-dihydroxybenoic acid (1,OSeq) were added and the mixture washeated to reflux until a solution was observed. The hot solution was filtered and allowed to cool to room temperature and further stored at 2-8°C in a fridge. The precipitate was filtered and dried under vacuum to yield 480mg of tenofovir alafemamide 3,4-dihydroxybenoic acid form. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.1% | With benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine; at 60 - 80℃; for 4h; | To 10 mL of DMF were added 0.5 g of protocatechuic acid, 0.68 g of EDC, 0.48 g of HOBt, 1.4 mL of TEA and 0.55 g of homosystein thiolactone hydrochloride, and the mixture was stirred at 60 to 80C for 4 hours. 10 mL of EtOAc and 10 mL of purified water were added to the reaction mixture and the layers were separated. The aqueous layer was extracted once with 10 mL of EtOAc and the aqueous layer was discarded. The organic layer was washed three times with 10 mL of purified water, dried over Na2SO4, and filtered. The filtrate was concentrated by distillation under reduced pressure and purified by flash column chromatography to obtain 0.28 g of the title compound as a white solid. Yield: 34.1% 1H NMR(400MHz, DMSO-d6) 9.52(brs, 1H), 9.17(brs, 1H), 8.42(d, J=8.0, 1H), 7.29(d, J=2.0, 1H), 7.20(dd, J=2.0 and 8.4, 1H), 6.77(d, J=8.8, 1H), 4.79(sex, J=7.6, 1H), 3.47?3.29(m, 2H), 2.46?2.22(m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With tert.-butylhydroperoxide; methanesulfonic acid; iron(II) phthalocyanine; acetic acid; In acetonitrile; for 0.0833333h;Cooling with ice; | Dissolve 101 mg of S2 in acetonitrile.Add 154 mg of 3,4-dihydroxybenzoic acid,Add 7 mg under ice bath Iron phthalocyanine, 30 mg of acetic acid,4.8 mg of methanesulfonic acid and 135 mg of tert-butyl hydroperoxide. The reaction system is under the same conditions After stirring for 5 minutes, after monitoring the reaction, it was diluted with 20 mL of ethyl acetate and extracted with 20 mL of H2O, then combined. The organic layer was washed with 20 mL of saturated brine, dried over anhydrous Na2SO4, filtered and evaporated. Silica gel chromatography The crude product was purified (PE/EtOAc = 2:1).Obtaining 101 mg of compound 2,The reaction yield is 57%.The product was a white solid at room temperature.Physical state: white solid; melting point: 149.6-151.9 C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With tert.-butylhydroperoxide; methanesulfonic acid; iron(II) phthalocyanine; acetic acid; In acetonitrile; for 0.0833333h;Cooling with ice; | Dissolve 103 mg of S4 in acetonitrile and add 154 mg of 3,4-dihydroxybenzoic acid.Add 7 mg of iron phthalocyanine and 30 mg of acetic acid under ice bath conditions.4.8 mg of methanesulfonic acid and 135 mg of tert-butyl hydroperoxide, Stir the reaction under the same conditions 5After a minute, after monitoring the reaction,Dilute with 20 mL of ethyl acetate and extract 20 mL of H2O.Then merge the organic The layer was washed with 20 mL of saturated brine.Dry with anhydrous Na2SO4,Filtered,Spin dry.By silica gel chromatography (PE/EtOAc) = 2:1) Purify the crude product,158 mg of compound 4 are obtained,The reaction yield was 89% and the product was a white solid at room temperature.Physical state: white solid; melting point: 112.2-115.1 C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With tert.-butylhydroperoxide; methanesulfonic acid; iron(II) phthalocyanine; acetic acid; In acetonitrile; for 0.0833333h;Cooling with ice; | Dissolve 125 mg of S6 in acetonitrile.Add 154 mg of 3,4-dihydroxybenzoic acid,Add 7 mg under ice bath Iron phthalocyanine, 30 mg of acetic acid,4.8 mg of methanesulfonic acid and 135 mg of tert-butyl hydroperoxide, After stirring the reaction for 5 minutes under the same conditions,After monitoring the reaction,Dilute with 20 mL of ethyl acetate and extract 20 mL of H2O.The combined organic layers were then washed with 20 mL of saturated brine.Dry with anhydrous Na2SO4, filter and spin dry.By silica gel chromatography (PE/EtOAc) = 2:1) Purify the crude product,127 mg of compound 6,The reaction yield is 64%.The product was a white solid at room temperature.Physical state: white solid; melting point: 149.1-150.2 C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tert.-butylhydroperoxide; methanesulfonic acid; iron(II) phthalocyanine; acetic acid In acetonitrile for 0.25h; Cooling with ice; | 1 Example 1; Preparation of Compound 1 86 mg of S1 was dissolved in acetonitrile,Add 154 mg of 3,4-dihydroxybenzoic acid and add in ice bath7 mgIron phthalocyanine,30 mg of acetic acid,4.8 mg of methanesulfonic acid and 135 mgof tert-butyl hydroperoxide after the reaction system was stirred for 15 minutes under the same conditions,After monitoring the reaction,Dilute with 20 mL of ethyl acetate.Wash with 20 mL of saturated brine.Dry with anhydrous Na2SO4, filter and spin dry.The crude product was purified by silica gel chromatography (PE /EtOAc = 3:1)146 mg of compound 1,The reaction yield was 91%; the product was a yellow oil at room temperature. Physical State: Yellow oil; Melting point: 96.9-100.4 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-benzyl-N,N,N-triethylammonium chloride at 100 - 120℃; for 12h; Inert atmosphere; | 3 Synthesis Example 1 Synthesis of Compound (X-1)] After 57.2 g of the epoxy compound (E-X1), 42.8 g of the carboxylic acid compound (C-X1), and 300 g of 2-methoxy-1-propanol were made to a uniform solution at the liquid temperature of 100° C. under a nitrogen atmosphere, 10.0 g of benzyl triethyl ammonium chloride was added to this solution; and the resulting mixture was stirred at the liquid temperature of 120° C. for 12 hours. After the reaction solution was cooled to room temperature, 1,000 g of methyl isobutyl ketone was added to it, and then, the organic phase was washed with 200 g of pure water for 5 times. The organic phase was evaporated to dryness under reduced pressure to obtain the compound (X-1). From the GPC measurement, the weight average molecular weight (Mw) of 780 and the dispersibility (Mw/Mn) of 1.04 were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With dihydrogen peroxide; In water; at 20℃; for 24h; | A mixture of <strong>[603-36-1]triphenylantimony</strong> (0.2 g, 0.57 mmol)and 3,4-dihydroxybenzoic acid (0.09 g, 0.57 mmol) was dissolved in diethyl ether (30 ml) and 30% aqueous solution of hydrogen peroxide (0.096 g, 0.86 mmol) was added. The mixure was kept at room temperature for 24 h, then diethyl ether was evaporated and the precipitate was recrystallized from o-xylene. Evaporation of the solvent afforded 0.205 g (71%) of compound 1 as yellow crystals, mp 145 C. IR (n/cm-1): 1641 (C=O), 457 (Sb-O). 1H NMR (DMSO-d6) d: 7.12 [d, 3H, O2C3H3C(O)O, J 2.7 Hz], 7.14 [d, 3H, O2C3H3C(O)O, J 2.7 Hz], 7.19[d, 3H, O2C3H3C(O)O, J 2.7 Hz], 7.28 [d, 24H, m-protons, Sb-C(Ph),J 3 Hz], 7.32 [s, 12H, p-protons, Sb-C(Ph)], 7.67 [s, 24H, o-protons,Sb-C(Ph)]. 13C NMR (DMSO-d6) d: 112.92; 113.12, 121.15 [12C,O2C3H3C(O)O], 119.81 (4C, C-COOH), 134.56 [24C, o-carbons,Sb-C(Ph)], 130.09 [12C, p-carbons, Sb-C(Ph)], 129.26 [24C, m-carbons,Sb-C(Ph)], 154.18, 148.62 (8C, C-OH), 168.34 (s, 4C, C=O). Found (%):C, 59.50; H, 3.57. Calc. for C100H76O16Sb4 (%): C, 59.44; H, 3.80. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.7% | With iron(III) chloride hexahydrate for 3h; Reflux; | Add 3,4-dihydroxybenzoic acid, 2 to 5% ferric chloride hexahydrate and 1-penten-3-ol into a three-necked flask equipped with a water trap, a thermometer and a reflux condenser, of which 3,4 -The molar ratio of dihydroxybenzoic acid to 1-penten-3-ol is 1:4, heated until 3,4-dihydroxybenzoic acid is dissolved, shake well, take a sample for analysis; then add 1 dropwise to the water separator -Penten-3-ol, heated and refluxed for 3 hours, cooled for 10 minutes, and then sampled and analyzed. The conversion rate was determined to be 85.7%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-methyltransferase gene from Eriobotrya japonica mutant I133S/L138V/L342V strain expressed in E.coli In aq. phosphate buffer at 30℃; for 18h; Enzymatic reaction; |
Tags: 99-50-3 synthesis path| 99-50-3 SDS| 99-50-3 COA| 99-50-3 purity| 99-50-3 application| 99-50-3 NMR| 99-50-3 COA| 99-50-3 structure
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H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
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 |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
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 |
Sorry,this product has been discontinued.
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