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CAS No. : | 89-86-1 | MDL No. : | MFCD00002451 |
Formula : | C7H6O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UIAFKZKHHVMJGS-UHFFFAOYSA-N |
M.W : | 154.12 | Pubchem ID : | 1491 |
Synonyms : |
|
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) : | -6.08 cm/s |
Log Po/w (iLOGP) : | 0.75 |
Log Po/w (XLOGP3) : | 1.63 |
Log Po/w (WLOGP) : | 0.8 |
Log Po/w (MLOGP) : | 0.4 |
Log Po/w (SILICOS-IT) : | 0.26 |
Consensus Log Po/w : | 0.77 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.16 |
Solubility : | 1.07 mg/ml ; 0.00692 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.88 |
Solubility : | 0.205 mg/ml ; 0.00133 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.6 |
Solubility : | 38.3 mg/ml ; 0.248 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.1 |
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 |
---|---|---|
92% | for 15 h; Reflux | Methyl 2,5-dihydroxybenzoate (19) To a solution of 2,4-dihydroxybenzoic acid (20.0 g, 0.13 mol) in MeOH (200 mL) was added concentrated H2SO4 (8.52 mL, 0.16 mol). The resulting mixture was then heated at reflux for 15 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue taken up in Et2O (200 mL). The organic extract was then washed with H2O (3 x 200 mL), brine (200 mL) and the solvent removed under reduced pressure to afford 20.0 g (92percent) of 19 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sulfuric acid for 72h; Heating; | |
100% | With sulfuric acid In water for 120h; Reflux; Inert atmosphere; | |
99% | With sulfuric acid for 20h; Reflux; |
99% | With sulfuric acid | 1; 3.3 2,4-dihydroxybenzoic acid (5) was treated with sulfuric acid in methanol to obtain 2,4-dihydroxybenzoate (6) at a yield of 99%. |
98% | With sulfuric acid at 65℃; for 16h; | |
90.5% | With sulfuric acid at 70℃; for 24h; | |
90% | With sulfuric acid for 24h; Reflux; | 4.1.2. Methyl 2,4-dihydroxybenzoate (2) [60] To a stirred solution of 2,4-dihydroxybenzoicacid (1, 10.00 g,64.93 mmol) in methanol (100 mL) was added catalytic amount ofCon.H2SO4 (0.35 mL, 6.49 mmol) and stirred at reflux for 24 h. Aftercompletion of the reaction methanolwas evaporated and quenchedwith ice water and basified into pH 8 using aq.Na2CO3 solution.Then precipitated solid was filtered off, washed with ice water andthen dried. The title compound 2 (9.80 g, 90%) was obtained as palebrown solid. This is pure enough for further step. M.p. 118-120° C. |
89% | With sulfuric acid for 96h; Reflux; Inert atmosphere; | |
89.3% | With sulfuric acid for 20h; Reflux; | |
88% | With sulfuric acid Reflux; | |
86% | With sulfuric acid at 100℃; for 24h; Inert atmosphere; | 4.1.1 Methyl 2,4-dihydroxybenzoate (6) 2,4-Dihydroxybenzoic acid (10g, 64.88mmol) and sulfuric acid (5mL) in MeOH (40mL) was stirred at 100°C for 24h, equipped with a refluxing condenser under argon. After cooling at room temperature, the mixture was concentrated under reduced pressure and added water at 0°C. To filter the resulting white solid was dissolved in ethyl acetate washed with saturated NaHCO3 solution. The organic layer was dried over Na2SO4, concentrated under reduced pressure to afford compound 6 in 86% yield. 1H NMR (500MHz, CD3OD) 7.56 (d, J=9Hz, 1H), 6.24 (dd, J=8.8Hz, 2.0Hz, 1H), 6.21 (d, J=2.5Hz, 1H), 3.78 (s, 3H). 13C NMR (125MHz, CD3OD) δ 171.7, 165.7, 164.9, 132.7, 109.1, 105.5, 103.4, 52.3. |
86% | With sulfuric acid at 100℃; for 12h; Inert atmosphere; | 1. Synthesis of Compound 6 Compound 6 was synthesized in the same manner as in Scheme 1.2,4-Dihydroxyacetophenone (10.2 g, 66.0 mmol) and 5 mL of sulfuric acid were placed in 40 mL of methanol and stirred in a reflux condenser under argon at 100 ° C for 12 hours.The mixture was cooled at room temperature, concentrated under reduced pressure, and then 40 mL of H 2 O was poured in an ice water bath and filtered to obtain a white solid.The solid was dissolved in ethyl acetate and washed with saturated NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain Compound 6 in 86% yield. |
86% | With sulfuric acid at 100℃; for 12h; Inert atmosphere; | 1.1 1. Synthesis of methyl-2,4-dihydroxybenzoate (Compound 4) To proceed all synthetic reactions, 2,4-dihydroxybenzoic acid (Compound 3) was purchased from Aldrich and prepared.Methanol (100 mL), 5 mL of sulfuric acid and 10.2 g (66.0 mmol) of the 2,4-dihydroxybenzoic acid were put in a reflux condenser under argon, and the mixture was stirred at 100 ° C for 12 hours. The mixture was cooled at room temperature, concentrated under reduced pressure, and the concentrate was poured into an icebath with 40 mL of water. To filter the product of the reaction, the white solid was dissolved in ethyl acetate and washed with saturated sodium hydrogencarbonate (NaHCO3) solution. Thereafter, the organic layer was dried in the presence of sodium sulfate (Na2SO4) and concentrated under reduced pressure to obtain compound 4 at a yield of 86%.NMR spectra of synthesized Compound 4 were measured using a JEOL 500 MHz NMR spectrometer. Rf = 0.20 (2: 8 ethyl acetate: hexane). |
85% | With sulfuric acid for 4h; Reflux; | |
84% | With sulfuric acid for 4h; Heating; | |
81% | With sulfuric acid for 22h; Heating; | |
80% | 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. |
78% | With sulfuric acid at 100℃; for 12h; | Methyl 2,4-dihydroxybenzoate (P) To a stirred solution of 2,4-dihydroxybenzoic acid (100 g, 649.35 mmol) in methanol (400 mL) was added concentrated H2SO4 (50 mL) at room temperature. The reaction mixture was heated to 100°C and stirred for 12 h. The resulting solution was concentrated under vacuum and poured into water (500 mL). The resulting precipitate was collected by filtration and dried under high vacuum yielding methyl 2, 4-dihydroxybenzoate (P) as an off white solid (170 g, 78%). This material was used for the next step without any further purification. [00196] LCMS (Method C): 4.24 min, MS: ES+ 169. 19(M+1); 1H NMR (CDCl3, 400 MHz) d 3.39 (s, 3H), 5.72 (br. s, 1H), 6.38 - 6.42 (m, 2H), 7.74 (d, J = 8.8Hz, 1H), 11.02 (s, 1H). |
75% | With sulfuric acid | |
36% | With sulfuric acid for 16h; Reflux; | Synthesis of Methyl 2,4-dihydroxybenzoate (10). A solution of 2,4-dihydroxybenzoic acid (9) (20.00g, 129.77mmol) in dry methanol (100mL) and concentrated sulfuric acid (2.6mL) was stirred under reflux for 16h. After reaction completion, the solvent was removed under reduced pressure and the residue was taken up with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. Further purification was done with silica gel column chromatography with a mobile phase of n-hexane and ethyl acetate (ratio of 4:1). The desired compound was obtained as a white solid (7.76g, 36%). 1H NMR (250MHz, DMSO-d6): δ 10.70 (s, 1H, OH), 10.44 (s, 1H, OH), 7.64 (d, J=8.7Hz, PhH), 6.37 (dd, J=8.8, 2.4Hz, 1H, PhH), 6.29 (d, J=2.3Hz, 1H, PhH), 3.84 (s, 3H, OCH3) ppm. |
26% | With sulfuric acid In dichloromethane Heating; | |
With hydrogenchloride | ||
With sulfuric acid | ||
With hydrogenchloride Heating; | ||
With thionyl chloride | ||
With trichlorophosphate | ||
With sulfuric acid Heating; | ||
With sulfuric acid Heating; | ||
With sulfuric acid at 0℃; Reflux; | 1 Preparation of intermediate 4 To a stirred solution of 2,4-dihydroxybenzoic acid (20.00 g, 129.77 mmol) in MeOH (100 ml) was added dropwise at 0 °C a solution of sulfuric acid (96%) in MeOH (290 ml). The reaction mixture was refluxed overnight. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents. The product fractions were collected and the solvent was evaporated.LCMS method 1 : MH+ = 169, RT = 0.660 min | |
With sulfuric acid at 0℃; Reflux; | 1 Preparation of Intermediate 4 Preparation of Intermediate 4 [0724] [0725] To a stirred solution of 2,4-dihydroxybenzoic acid (20.00 g, 129.77 mmol) in MeOH (100 ml) was added dropwise at 0° C. a solution of sulfuric acid (96%) in MeOH (290 ml). The reaction mixture was refluxed overnight. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents. The product fractions were collected and the solvent was evaporated. [0726] LCMS method 1: MH+=169, RT=0.660 min | |
With sulfuric acid | ||
With sulfuric acid at 100℃; for 24h; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid Reflux; | Synthesis of esters (2) from aromatic carboxylic acids (1) General procedure: The mixture of corresponding carboxylic acid (2 mmol),methanol (15 ml) in the presence of concentration sulfuricacid (2 mmol) were refluxed until monitoring by TLCindicated the end of the reaction. The excess of alcohol wasdistilled off under reduced pressure. The reaction mixture issolidified by cooling to room temperature. After filtering offthe crystal and washing with distilled water to remove thesulfuric acid, the residue was recrystallized from ethanoland distilled water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With Eaton′s Reagent at 80℃; for 1h; | 1,3,6-Trihydroxy-9H-xanthen-9-one (4) General procedure: Eaton's reagent (P2O5-CH3SO3H) (10 mL) was added slowly to a mixture of 2,4-dihydroxybenzoic acid (1; 155 mg, 1 mmol) and phloroglucinol (3; 126 mg, 1 mmol). The resulting mixture was stirred for 1 h at 80 °C, cooled to rt, and poured onto ice. After vigorous stirring at ambient temperature for 2 h, thin slurry formed. The solid was collected by filtration, washed with water to adjust the pH to approximately 6, and dried under vacuum at 50 °C. The residue was chromatographed on silica gel and eluted successively with hexane-EtOAc (2:3) to give the desired product (225 mg, 92%) as a yellow solid. Mp: 158-160 °C; 1H NMR (CD3OD, 300 MHz): δ 6.13 (1H, d, J = 2.1 Hz), 6.26 (1H, d, J = 2.4 Hz), 6.72 (1H, d, J = 2.4 Hz), 6.81 (1H, dd, J = 2.3, 8.9 Hz), 7.97 (1H, d, J = 9.0 Hz). |
84% | With zinc(II) chloride; trichlorophosphate at 75℃; Microwave irradiation; | 8 5.2.3. Synthesis of 1,3-dihydroxyxanthones (2a ~ i) General procedure: The synthesis refers to a procedure described in the literature [43]. To a 50-mL flask 8mL phosphorus oxychloride (POCl3) and anhydrous zinc chloride (6.8g, 0.05mol) were added. The suspension was stirred at 70°C until ZnCl2 was completely dissolved into phosphorus oxychloride. The mixture was then cooled down to room temperature (r.t.). Afterwards, salicylic acids (1a-i) (l.0mmol) and 1,3,5-trihydroxybenzene (1.1mmol) were added, respectively, and the mixture was heated with microwave reactor with a programmed procedure of 75°C for 30min, where the power was 200W. Then the mixture was cooled down to r. t. and pulled into ice water stirring for 20min. The mixed solution was filtered, washed with cold water. The solid residues were collected and purified by flash column liquid chromatography. |
81% | With tin(ll) chloride at 140℃; for 0.0138889h; Microwave irradiation; regioselective reaction; | 4.1. General procedures for the synthesis of hydroxyxanth General procedure: To an equimolar mixture of phenolic acids and phenol derivatives, anhydrous AlCl3, ZnCl2, TiCl4 or SnCl2 was added. The reaction mixture was heated at 140 °C for 50 s in CEM microwave. The contents were poured into ice and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The product thus obtained was purified by silica gel column chromatography. |
74% | With eaton’s reagent at 80℃; for 0.5h; | |
69% | With methanesulfonic acid; phosphorus pentoxide at 90℃; for 0.583333h; | |
66% | With Eaton’s reagent at 80℃; for 1h; | |
61% | With phosphorus pentoxide In methanesulfonic acid at 70℃; for 1h; | 1,3,6-Trihydroxyxanthone(1) A mixture of 2,4-dihydroxybenzoic acid (0.77 g, 5.00mmol) andphloroglucinol(0.76 g, 6.00mmol) was added slowly to 12 mL of Eaton's reagent (mass ratio ofmethanesulfonicacid to P2O5is 10:1), the mixture was heated at 70°C for 1 h, under stirring. After cooling it to room temperature, the reaction mixture was poured onto crushed ice and stirred for 2 h. The resulting solid was collected by filtration and dried. The dried solid was purified on a silica gel column with a mixture of petroleum ether-ethyl acetate (4:1) as eluent to give compound1as a yellowish green solid,yeild61%. |
60% | With Eaton’s reagent at 60℃; | |
55% | Stage #1: 3,5-dihydroxyphenol; 4-hydroxysalicylic acid With methanesulfonic acid; phosphorus pentoxide at 80℃; for 2h; Stage #2: at 20℃; for 2h; Cooling with ice; | 2.3. General procedure for the preparation of polyoxygenated xanthones (9-12)2 General procedure: To a mixture of the commercially available corresponding phenol derivative (1.0 equiv.) and thecorresponding salicylic acid (1.0 equiv.), 10 mL of phosphorus pentoxide-methanesulfonic acid (v/v =1:10) was added slowly. The mixture was stirred at 80 °C for 2 h. The mixture was cooled to roomtemperature, and poured onto ice. After vigorous stirring at room temperature for 2 h, the solid wascollected by filtration, washed with water, and dried at 60 °C. The crude product was purified by silicagel column chromatography using chloroform/methanol, to give the polyoxygenated xanthones (9-12). |
42% | With zinc(II) chloride; trichlorophosphate at 65℃; for 3h; Inert atmosphere; | |
25% | With PPA at 80 - 140℃; microwave irradiation; | |
With acetic anhydride at 260℃; zuletzt unter vermindertem Druck.; | ||
With zinc(II) chloride; trichlorophosphate | ||
With zinc(II) chloride; trichlorophosphate at 55 - 70℃; | Synthesis of di and tri-hydroxy xanthones General procedure: A mixture of o-hydroxy benzoic acid or 2, 4 dihydroxy benzoic acid, a phenol (such as catechol,pyrogallol, resorcinol, etc.), freshly fused zinc chloride (ZnCl2) and phosphorous oxychloride(POCl3) was heated on a water bath or on heating mantle (maintaining the temperature 55-70C) for 1.5-2 hr, cooled and poured into ice water carefully in order to avoid polymerization(Grover et al., 1955). The product was filtered off, washed with 2% sodium hydrogen carbonate solution (if needed) and water, dried and crystallized from suitable solvents. The recrystallization of compounds from appropriate solvents furnished analytically pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 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. |
62% | With thionyl chloride Inert atmosphere; Reflux; | |
57% | With sulfuric acid for 18h; Reflux; |
55.4% | With sulfuric acid at 60℃; for 12.5h; Reflux; | |
With sulfuric acid | ||
With hydrogenchloride | ||
With hydrogenchloride Heating; | ||
With sulfuric acid for 24h; Heating; Yield given; | ||
With sulfuric acid Heating; | ||
11.5 g | With sulfuric acid Dean-Stark; Reflux; | 12 In a flask equipped with a Dean-Stark apparatus, (I-12a) 10.0 g (0.065 mol), ethanol 100 mL, Concentrated sulfuric acid (1 mL) was added, and heating and refluxing was carried out for 10 hours while adding ethanol while removing the reaction solution. The solvent was distilled off, the solution was redissolved in ethyl acetate, and the solution was washed with brine. The solvent was distilled off to obtain 11.5 g (0.063 mol) of the compound represented by the formula (I-12b). |
With sulfuric acid | ||
With sulfuric acid Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid Behandeln des Reaktionsprodukts mit Brom; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.25% | With nitric acid; acetic acid; at 5 - 90℃;Large scale; | Add 8.166kg glacial acetic acid and 10.18kg nitric acid to 20L in turn.The four-necked flask was mechanically stirred and mixed uniformly, and the internal temperature of the mixed solution was lowered to 5-10 C.An average of 2000 g of 2,4-dihydroxybenzoic acid was added in three portions.After the first feeding (one third), the ice bath was removed and the reaction system was intensely exothermic.The temperature control of the ice bath is below 90 C, when the reaction system is no longer exothermic,Re-cool down to 5-10 C and add one-third of 2,4-dihydroxybenzoic acid again.Repeat the above steps until all the ingredients have been added.The reaction was stirred at 20-30 C overnight (central control 1).After the reaction was completed, the reaction solution was poured into 20 L of ice water to quench the reaction, and filtered.The filter cake was washed with water (1 L x 5) until the pH was equal to 7.Obtained a pink solid with a wet weight of 2.3kg.Drying at 60 C (12 h) gave 1.5 kg of crude product.The crude product was beaten with 10 L of dichloromethane at 20-30 C for 1.5 h, and filtered.The filter cake was dried in a forced air oven at 60 C for 2-3 h.Obtained 1.43 kg of 5-nitro 2,4-dihydroxybenzoic acid as a pink solid.(Central Control 2) HPLC purity 98.21%,The yield was 55.25%. |
51.84% | With nitric acid; In acetonitrile; at 35 - 50℃; for 3.5h; | In a 250 mL four-necked flask equipped with a thermometer, add 7.5 g (0.05 mol) in sequence.2,4-dihydroxybenzoic acid, 60 mL of acetonitrile, and 8 mL of concentrated nitric acid (containing 0.12 mol of nitric acid) was added dropwise., Stir and control the temperature 35 50 , stop the reaction for 3.5h, pour the reaction solution into a beaker containing 300mL of distilled water or 100g crushed ice to quench the precipitated product, filter, filter cake, dry and grind to get pale yellow Solid, HPLC analysis mass fraction 99.79%,The yield based on 2,4-dihydroxybenzoic acid was 51.84%. |
With nitric acid; In water; acetic acid; at 0 - 20℃; for 18h; | To an ice cold stirred solution of nitric acid (70%, 28 mL) and AcOH (30 mL), is added portionwise 2,4-dihydroxybenzoic acid (7.7 g, 49.9 mmol). The mixture is stirred at 00C for 15 min and then slowly warmed to room temperature. The reaction becomes very exothermic and is cooled again in an ice bath to keep the mixture at approximately room temperature. The mixture is stirred at room temperature for 18 h. The resulting precipitate <n="108"/>is filtered, washed with water, air dried, then washed with DCM and dried under reduced pressure to afford 2,4-dihydroxy-5-nitrobenzoic acid as a solid: (M-H)" = 198.1. |
With nitric acid; acetic acid; | FIG. 5A shows the synthesis of 2,4-dihydroxy-5-nitrobenzoic acid from the commercially available 2,4-dihydroxybenzoic acid. The acid is then esterified and alkylated in high yields. The alkylation reaction is quite general, since methyl, ally, iso-butyl, octyl, and decyl bromides all have resulted in corresponding products with high yields (>95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With bromine; acetic acid at 20℃; regioselective reaction; | |
94% | With bromine; acetic acid at 20℃; regioselective reaction; | |
90% | With bromine; acetic acid | 2,4-Dihydroxybenzoic acid S9(3 g, 19.6 mmol) was dissolvedin acetic acid (21 mL) before bromine (1.1 mL, 23.3 mmol) dissolved in aceticacid (18 mL) was added dropwise and stirred overnight. The mixture was dilutedwith water (100 mL) and quenched with saturated aqueous Na2S2O3. The mixturewas extracted rigorously with EtOAc until the extracts showed no sign ofproduct. The combined EtOAc layers were dried over Na2SO4, filtered, andconcentrated to afford the product 5-bromo-2,4-dihydroxybenzoic acid S10as a light yellow solid (4.11 g, 90%). 1H NMR (300 MHz, DMSO-d6) δ 11.27 (s,1H), 7.82 (s, 1H), 6.48 (s, 1H).MS (ESI, negative) : m/z 230.9,232.9(M-H).Retention time of 2.06 min,>99% pure. |
89.2% | With bromine In chloroform at 0 - 20℃; for 4h; | 5-Bromo-2,4-hydroxybenzoic acid (2) A solution of bromine in chloroform was added dropwise to a solution of 1 (1 eq.) in chloroform at 0 °C (250 mL). The resulting mixture was stirred at room temperature for 4 h before quenching with 10% aqueous solution of sodium thiosulfate (200 mL). The organic layer was washed with saturated sodium bicarbonate solution (2 x 200 mL) and saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (Si02, 1 :9 ethyl acetate/hexanes) to afford 2 (89.2 %) as a yellow solid. 1H- NMR (400 MHz, CDC13) δ 16.47 (s, 1H), 12.4 (s, 1H), 9.98 (s, 1H), 8.05 (s, 1H), 6.37 (3, 1H).13C- NMR (100 MHz, CDC13) δ 171.8, 162.6, 160.09, 136.6, 110.3, 106.3, 105.7. |
80% | With bromine; acetic acid for 4h; | |
73% | With N-benzyl-N,N-dimethyl anilinium peroxodisulfate; potassium bromide In acetonitrile for 6h; Reflux; regioselective reaction; | |
66% | With bromine; acetic acid at 15 - 20℃; for 24h; | 2.1 EXAMPLE 2 The synthesis of "C1" can be carried out as follows: 2.1 5-Bromo-2,4-dihydroxybenzoic acid (1) 3.55 kg of 2,4-dihydroxybenzoic acid are dissolved in 30 l of glacial acetic acid. A solution of 1060 ml of bromine in 10 l of glacial acetic acid is subsequently added dropwise at 15° C. over a period of 8 h. Stirring is then continued at 20° C. for 16 h, the mixture is evaporated in vacuo, and the crystalline residue is slurried in 20 l of dichloromethane and stirred for 1 h. Filtration and drying in air gives 4.9 kg of white crude product. Recrystallisation from 30 l of toluene/acetonitrile (1:1) and drying gives 3.549 kg (66% yield) of 5-bromo-2,4-dihydroxybenzoic acid (m.p. 210-211.5° C.; MW 233.0). |
66% | With bromine; acetic acid at 15 - 20℃; | 5-Bromo-2,4-dihydroxybenzoic acid (1): 3.55 kg of 2,4-dihydroxybenzoic acid are dissolved in 30 l of glacial acetic acid. A solution of 1060 ml of bromine in 10 l of glacial acetic acid is subsequently added dropwise over a period of 8 h at 15° C. Stirring is then continued overnight at 20° C., the mixture is evaporated in vacuo, and the crystalline residue is suspended in 20 l of dichloromethane and stirred for 1 h. Filtration and drying in air gives 4.9 kg of white crude product. Recrystallisation from 30 l of toluene/acetonitrile (1:1) gives, after drying, 3.549 kg (66% yield) of 5-bromo-2,4-dihydroxybenzoic acid (m.p. 210-211.5°; MW 233.0). |
65% | With benzyltriphenylphosphonium peroxodisulfate; potassium bromide In acetonitrile for 6h; Heating; | |
64.6% | With bromine; acetic acid at 20℃; for 4h; | 16.a A) Bromo (1.1 mL, 23.3 mmol)Dissolved in 18mL acetic acid,A solution of 2,4-dihydroxybenzoic acid (compound 3A, 3 g, 19.6 mmol)Of acetic acid (21 mL)Followed by stirring at room temperature for 4 hours.After the reaction mixture was diluted with water,And extracted with ethyl acetate.The organic layer was washed with water (50 mL)Dried over anhydrous sodium sulfate,filter,Concentrated to give a white solid.Recrystallization (acetonitrile / toluene, 1: 1) gave white needles (5-bromo-2,4-dihydroxybenzoic acid, compound 3B, 2.93 g, 64.6% yield). |
With acetic acid at 30 - 35℃; durch Bromierung; | ||
With diethyl ether; bromine | ||
With bromine; acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.4% | With thionyl chloride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 8.5h; | 1-2 Example 2: Preparation of 2,4-dihydroxybenzoyl chloride: Add 1541 mg of 2,4-dihydroxybenzoic acid to the reactor, add 30 ml of tetrahydrofuran, stir, and add 0.5 ml of N,N-dimethylformamide at room temperature then, the mixture was stirred at room temperature for 0.5 hour, and 3 g of thionyl chloride was added dropwise, followed by stirring at room temperature for 8 hours. After completion of the reaction, the compound 2,4-dihydroxybenzoyl chloride was obtained by post-treatment and purification, and the yield was 90.4%. |
With thionyl chloride | ||
With thionyl chloride In chloroform Heating; |
With thionyl chloride for 4h; Heating; | ||
With thionyl chloride | ||
With thionyl chloride; N,N-dimethyl-formamide at 20℃; for 2h; | 2,4- and 3,4-dihydroxybenzoic chloro anhydrides (b). General procedure: Ten grams (64.8 mmol) of dihydroxybenzoic acid was placed into a single-necked round-bottom flask. Three drops of DMF and 15 mL of freshly distilled thionyl chloride were then added, and the reaction mixture was stirred at room temperature for 2 h. Finally, the excess SOCl2 was driven away using the rotor evaporator at reduced pressure. Yields were not determined at this stage. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With Iodine monochloride; acetic acid at 20℃; for 4h; | |
91% | With Iodine monochloride In acetic acid at 20℃; for 5h; | |
69% | With Iodine monochloride; acetic acid for 4h; |
With diethyl ether; Iodine monochloride | ||
With Iodine monochloride In acetic acid at 20℃; | 1.a; 1.2.2.1; 2.a Using Formula 5 as a starting point, various sets of compounds were derived and screened. The results of some of these tests are represented in Tables 2-8. mPTPB inhibitors (Formula 5) were prepared using the methods outlined in FIG. 1. Commercially available compound 4-hydroxysalicylic acid reacted with iodine monochloride to afford compound 1 in good yield. The compound 1 was selectively protected in the presence of acetone and TFAA/TFA to finish dioxanone 2 in modest yield. Then dioxanone 2 reacted with Mel at room temperature in the presence of K2CO3/DMSO to give the methylation product 3 with quantitative yield. Compound 3 coupled with Y-containing acetylene in the presence of catalytic amounts of Pd(PPh3)2Cl2 and Cul to furnish 4 which was then subjected to I2 induced cyclization. Cyclization of 4 proceeded exceedingly well and afforded 5 in high yield on a multigram scale. The efficiency and operational simplicity of this key cyclization make this project successful and this approach has the potential to easily prepare a large number of different 2, 3-disubstituted benzofuran from a common intermediate 5. Once the key compounds 5 is made various side chains are introduced a the 3 -position of compound 5. The iodination product 5 is coupled with substituted acetylene to give compound 6. After deprotection of 6 in the presence KOH/THF/H20, 6-hydroxy-benzofuran-5-carboxylic acid 7 (Formula 5) were obtained in a high yield. Hydrogenation of the alkyne 7 produced 8 (Formula 6) and 9 (Formula 7). When Y = 0(CH2)nCOOH in Formula 5, the compound 7 (FIG. 1) was further reacted with amines to release sets Formula 10, 11. When Ri contain a carboxylic acid group in Formula 5, it was further reacted with amines to release set Formula 12, 13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sulfuryl dichloride; acetic acid at 20℃; for 1h; | |
With sulfuryl dichloride; diethyl ether | ||
With chlorine; acetic acid |
With chlorine; acetic acid | ||
With tert-butylhypochlorite In ethyl acetate | R.50.1 Production of 3,5-dichloro-2,4-dihydroxybenzoic acid Step 1 Production of 3,5-dichloro-2,4-dihydroxybenzoic acid 2,4-Dihydroxybenzoic acid (25.0 g) was dissolved in ethyl acetate (400 mL), tert-butyl hypochlorite (61.9 g) was added dropwise under ice-cooling, and the mixture was stirred for 2 hrs. The reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was crystallized from ethyl ether-n-hexane to give the title compound (11.88 g) as a solid. | |
With tert-butylhypochlorite In ethyl acetate at 0℃; for 2h; | 50.1 Production of (3,5-dichloro-2,4-dihydroxyphenyl)-(2,3-dihydrobenzo[1,4]oxazin-4-yl)-methanone Step 1 Production of 3,5-dichloro-2,4-dihydroxybenzoic acid 2,4-Dihydroxybenzoic acid (25.0 g) was dissolved in ethyl acetate (400 mL), tert-butyl hypochlorite (61.9 g) was added dropwise under ice-cooling, and the mixture was stirred for 2 hrs. The reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was crystallized from ethyl ether-n-hexane to give the title compound (11.88 g) as a solid. | |
With tert-butylhypochlorite In ethyl acetate at 0℃; for 2h; | 50.1 Step 1 Production of 3,5-dichloro-2,4-dihydroxybenzoic acid 2,4-Dihydroxybenzoic acid (25.0 g) was dissolved in ethyl acetate (400 mL), tert-butyl hypochlorite (61.9 g) was added dropwise under ice-cooling, and the mixture was stirred for 2 hrs. The reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was crystallized from ethyl ether-n-hexane to give the title compound (11.88 g) as a solid. | |
With hydrogenchloride; dihydrogen peroxide; acetic acid at 65℃; for 2h; | 3,5-dichloro-2,4-dihydroxybenzoic acid (2) 2,4-dihydroxybenzoic acid 1 (32.4mmol) and HCl (c, 194.6mmol) were dissolved in CH3COOH (10ml) and 10ml 30% H2O2 was added through the dropping funnel within 1h. The mixed solution was stirred at 65°C for 2h and then cooled down to 4°C. The precipitation was filtrated and washed with cold water, followed by recrystallization (v(H2O): v(CH3CH2OH)=2:1) to obtain 3,5-dichloro-2,4-dihydroxybenzoic acid 2 as white solid. 1H NMR (400MHz, DMSO): δ 7.66(1H Ar-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine; dmap at 20℃; for 24h; | |
93% | With dmap; triethylamine In tetrahydrofuran at 20℃; for 4h; | |
80% | With sulfuric acid at 65℃; for 0.5h; | 1.1 Step 1 2,4-bis(acetyloxy)benzoic acid Step 12,4-bis(acetyloxy)benzoic acidTo a stirred suspension of 2,4-dihydrobenzoic acid (40g, 259.5 mmol) in acetic anhydride (85 mL) was added cone. H2S04 (20 drops) and then the mixture was warmed to 65 °C for 30mins. Analysis by LCMS and TLC indicated formation of the desired product. The reaction mixture was cooled to ambient temperature and then poured onto a mixture of ice and water (1 :1) (1700 mL) with rapid stirring. Stirring was continued for 30 mins. The solid was collected via filtration, washed well with water and then iso-hexane, before drying in vacuo at 40 °C overnight to afford the desired product (49.4g, 80%) as a colourless solid. LC/MS (method B): RT = 0.93 min; m/z = 256 [M+NH4]+. Total run time 1.90 mins.1H NMR (d6DMSO): δ 2.24 (s, 3H), 2.29 (s, 3H), 7.09 (d, 1 H, J = 2.3 Hz), 7.18 (dd, 1 H, J = 8.8, 2.3 Hz), 7.98 (d, 1 H, J = 8.6 Hz), 13.17 (brs, 1 H). |
80% | With sulfuric acid at 65℃; for 0.5h; | 2,4-bis(acetyloxy)benzoic acid To a stirred suspension of 2,4-dihydrobenzoic acid (40g, 259.5 mmol) in acetic anhydride (85 mL) was added conc. H2S04 (20 drops) and then the mixture was warmed to 65°C for 30mins.Analysis by LCMS and TLC indicated formation of the desired product. The reaction mixture was cooled to ambient temperature and then poured onto a mixture of ice and water (1:1) (1700 mL) with rapid stirring. Stirring was continued for 30mins. The solid was collected via filtration, washed well with water and then iso-hexane, before drying in vacuo at 40°C overnight to affordthe desired product (49.4g, 80%) as a colourless solid. LC/MS (method B): RT = 0.93 mm; m/z = 256 [M+NH4]. Total run time 1.90 mins. 1H NMR (d6 DMSO): o 2.24 (5, 3H), 2.29 (5, 3H), 7.09 (d, IH, J= 2.3 Hz), 7.18 (dd, IH, J= 8.8, 2.3 Hz), 7.98 (d, IH, J= 8.6 Hz), 13.17 (brs, IH). |
80% | With sulfuric acid at 65℃; for 0.5h; | |
70% | With sulfuric acid | |
56% | With dmap; triethylamine In tetrahydrofuran at 20℃; for 3h; | Synthesis of 2,4-Dihydroxy-N-(3-hydroxy-phenyl)-benzamide (3c). Acetic anhydride (8.26 g, 80.9 mmol)was added to a solution of 2,4-dihydroxy benzoic acid(5.20 g, 33.7 mmol), triethyl amine (8.19 g, 80.9 mmol),and 4-(dimethylamino)pyridine (cat) in tetrahydrofuran(60 mL). The reaction mixture was stirred at room tempera-ture for 3 h and then solvent was removed at reduced pres-sure. The residue was dissolved in dichloromethane andwashed three times with NaCl (5%) solution. The organiclayer was dried with anhydrous MgSO 4 and concentrated invacuo. The residual solid was puri ed by crystallizationfrom dichloromethane-hexane to give a 2,4-diacetoxy ben-zoic acid 5 (4.50 g) in 56% yields.2,4-Diaceoxy benzoic acid (3.00 g, 12.6 mmol) wasadded to a solution of SOCl 2 (20 mL) at 0C. The mixturewas re uxed for 1 h and concentrated in vacuo. The result-ing crude acid chloride 6 was dissolved in CH 2 Cl 2(15 mL). Prepared acid chloride was added to a solution of3-hydroxyaniline (1.37 g, 12.6 mmol) and triethyl amine(2.54 g, 25.1 mmol) in N, N-dimethylformamide (10ml) atroom temperature. The reaction mixture was stirred for 3 hand concentrated in vacuo. The residue was dissolved inethyl acetate (150 mL) and washed three times with water.The organic layer was dried with anhydrous MgSO 4 andconcentrated in vacuo. The residual solid was puri edby crystallization from ethyl acetate-hexane to give 2,4-diacetoxy benzamide 7 (1.86 g) in 45% yields.N-(3-Hydroxy-phenyl)-2,4-diacetoxy benzamide7 (1.86 g, 5.64 mmol) was added to a solution of KOH(0.5 M). The mixture was heated to 50C and stirred for1 h. After obtaining clear solution, the mixture wasquenched with HCl (1 M) solution. The reaction mixturewas extracted with ethyl acetate (100 mL). The organiclayer was dried with anhydrous MgSO 4 and concentrated invacuo. The residual solid was puri ed by crystallizationfrom ethyl acetate-hexane to give 2,4-dihydroxy-N-(3-hydroxy-phenyl)-benzamide 3c (1.03 g) in 75% yields.1H NMR (300 MHz, DMSO - d 6 ): δ 12.2 (s, 1H), 10.1 (s,1H), 10.0 (s, 1H), 9.40 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.20(s, 1H), 7.13 - 7.01 (m, 2H), 6.51 - 6.30 (m, 3H).13C NMR(125 MHz, DMSO - d 6 ): δ 176.1, 162.5, 161.5, 157.6, 139.3,130.4, 129.4, 111.8, 111.1, 108.2, 108.0, 107.5, 102.8. |
56% | With sulfuric acid for 3h; Inert atmosphere; | |
24% | With sulfuric acid at 60℃; | 1.1 Step 1: 2,4-diacetoxybenzoic acid Acetic anhydride (16 mL, 168.5 mmol) was added to 2,4-dihydroxybenzoic acid (5.2 g, 33.7 mmol), followed by sulfuric acid at 60°C.The reaction was terminated immediately after adding sulfuric acid, followed by extraction with EA and 1 N HCl.After removing the solvent of the obtained organic layer under reduced pressure, it was washed with ether to obtain 2,4-dihydroxybenzoic acid (1.92 g, 24% yield). |
With zinc(II) chloride | ||
With pyridine | ||
With sulfuric acid | ||
With pyridine at 20℃; for 4h; | ||
With dmap; triethylamine In tetrahydrofuran | ||
With sodium hydroxide In water at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate | |
With potassium hydroxide at 50℃; | ||
With potassium hydroxide |
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 70 - 115℃; for 10.5h; | 9 Reference Example 9 50 g of 2,4-dihydroxybenzoic acid, 269 g of potassium carbonate, 123 ML of dimethyl sulfate, and 500 ML of N,N-dimethylformamide were suspended together, and this suspension was stirred for 6.5 hours at 70 to 80°C. Further, 90 g of potassium carbonate and 61 ML of dimethyl sulfate were added to this suspension, which was stirred for another 4 hours at 110 to 115°C. This reaction mixture was added to a mixture of ethyl acetate and water, and adjusted to PH 2 with 6M hydrochloric acid, and then the organic phase was separated therefrom.. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure.. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:2] to yield 54 g of methyl 2,4-dimethoxybenzoate as yellow oil. NMR(90MHz,CDCl3) δ value: 3.85(6H,s), 3.89(3H,s), 6.42-6.55(2H,m), 7.85(1H,d,J=9.3Hz) | |
With potassium carbonate In acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With zinc(II) chloride; trichlorophosphate at 65℃; for 3h; Inert atmosphere; | |
With zinc(II) chloride; trichlorophosphate | ||
With zinc(II) chloride at 125 - 140℃; |
With zinc(II) chloride; trichlorophosphate at 70℃; for 2.5h; | ||
Stage #1: 4-hydroxysalicylic acid; recorcinol With zinc(II) chloride; trichlorophosphate at 70℃; for 2.5h; Stage #2: With water at 4℃; for 24h; Cooling with ice; | ||
With phosphoric acid; zinc(II) chloride; trichlorophosphate | ||
With toluene-4-sulfonic acid In Trichloroethylene at 105 - 110℃; for 2h; Large scale; | 1.1-1.2; 2.1-2.2; 3.1-3.2; 4.1-4.2 (1) Add 65.0 kg of trichloroethylene, a halogenated hydrocarbon solvent, into the reactor, Compound catalyst diatomaceous earth 10.0kg, p-toluenesulfonic acid 10.0kg, stir and mix uniformly, heat up to 105-110, then add 10.0kg 2,4-dihydroxybenzoic acid and 9.0kg resorcinol to the mixture, stir Dissolve, keep the reaction for 2 hours. After the reaction is complete, filter the catalyst while it is hot to recover the catalyst graphite. Add 100L tap water to the filtrate, heat to 100°C, stir to dissolve completely, stand for layering, distill the organic layer to recover the solvent, and cool the water layer to 10~ At 15°C, a large number of red crystals were precipitated, filtered with suction and washed with water to obtain 16.8 kg of crude BP-2 product, and the purity of the crude product was 83.6%; (2) The method of refining the crude BP-2 product obtained in the above step (1) is to dissolve it in hot water, then add activated carbon for decolorization, boil it for 60 minutes, filter it while it is hot, and cool to crystallize to obtain light yellow-green crystals. Absorbent BP-2 product, the melting point of the product is 199200; the obtained ultraviolet absorber BP-2 product is tested by liquid chromatography, and the product purity is 99.5%; in the above process, the temperature of hot water used to dissolve the crude product At 90°C, the dosage is 5 times the quality of the crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.7% | With hydrogenchloride; CO2; potassium carbonate In water | 3 Example 3 Example 3 92.5g (0.84 mole) of resorcinol and 200.2 g (1.45 mole) of potassium carbonate are added to the filtrate obtained in Example 2 and reacted together at 95-105°C, for 2 hours maintaining 5 atm of CO2. The reaction mixtures are filtered at this temperatures, the filtered precipitates are dissolved in 380 g of water, and neutralized by 180 g of concentrated HCl. The white solid thus obtained is 125.2 g (0.81 mole, yield 96.7%) of 2,4-dihydroxybenzoic acid, having a melting point of from 224 to 226°c. |
With potassium dicarbonate; water | ||
With sodium hydrogencarbonate anschliessendes Einleiten von Kohlendioxid; |
With ethylmagnesium iodide; diethyl ether Umsetzen des Reaktionsprodukts mit CO2 bei 250-270grad; | ||
Multi-step reaction with 3 steps 1: 82 percent / acetic acid / 0.25 h / Heating 2: 63 percent / acetic acid / 12 h / Heating 3: aq. NaOH / 0.08 h / Heating | ||
With hydrogenchloride; sodium hydrogencarbonate; potassium hydrogencarbonate In carbon dioxide; water | 5 EXAMPLE 5 EXAMPLE 5 A 35-1 solids mixer was charged with 10 kg of sodium bicarbonate, 5 kg of potassium bicarbonate and 3.3 kg of resorcinol and heated with mixing to 120° C. in a stream of carbon dioxide. After 3 hours the contents were cooled down with mixing, and 28 l of water were added. The hot suspension at 60° C. was then discharged and brought to pH 3 at room temperature with 20 kg of concentrated hydrochloric acid. The suspension was cooled to 10-15° C. and filtered on a filter press, and the filter residue was washed with water and dried, leaving 4.1 kg (81%) of 2,4-dihydroxybenzoic acid; purity (HPLC): 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With trifluoroacetic anhydride In diethyl ether at 65℃; for 2h; | 2,4-Dihydroxyphenylbenzoate (6) Phenol (6.1 g,.065 mol), 2,4-dihydroxy-benzoic acid (11 g) and trifluoroacetic anhydride (20 g) were mixed in ether (50 mL) and it was heated to refluxed at 65 °C for 2 hours. 200 mL ether was added to the solution and ether layer was shaken well with saturated bicarbonate, brine solutions and concentrated. The crude product was treated with Norit in toluene and filtered. Hexane was added to it to get a white powder that was free of phenol. The compound was purified by crystalization from toluene-hexane mixture (6:4, v/v) provided white prisms (10.2 g, 67%). m.p: 147-149 °C . Proton-NMR (CDCl3) δ : 10.73 (OH at C-2), 7.95 (Ar-H), 7.43 (Ar-H), 7.28 (Ar-H), 7.18 (Ar-H), 6.43 (m, 2H), 6.09 (bs, 1H, OH); MS (C13H10O4) calcd. 230.058 found MH+ 231.2. |
45% | With trichlorophosphate In toluene for 2.5h; Heating; | |
28% | With trichlorophosphate In toluene at 110℃; Sealed tube; |
27% | With trichlorophosphate In o-xylene at 100℃; for 1.5h; | |
With trichlorophosphate | ||
With trifluoroacetic anhydride | ||
With thionyl chloride In <i>N</i>-methyl-acetamide; cyclohexane; toluene | 13.a ethyl 4-{4,6-bis[4-(2-ethylhexyloxy)phenyl]-s-triazin-2-yl}-3-hydroxyphenoxy)acetate a) A 1.5 l sulfonating flask equipped with stirrer, condenser, dropping funnel and gas outlet is charged with 154.1 g (1.0 mol) of 2,4-dihydroxybenzoic acid, 141.2 g (1.5 mol) of phenol, 500 ml of toluene and 1 ml of dimethylformamide. 178.5 g (1.5 mol) of thionyl chloride are then added dropwise at an internal temperature of 100°-105° C. over a period of 2.5 hours. The reddish clear solution is then refluxed overnight (110°-15° C.). The toluene and the phenol are distilled off in vacuo, the highly viscous residue (271.5 g) is stirred in 300 ml of 7:3 toluene/cyclohexane, and the product is allowed to crystallize overnight. The precipitate is filtered off with suction while cold (10° C.) and washed with 3*50 ml of 73 toluene/cyclohexane. It is dried at 80° C. in vacuo to give 125.5 g (54.4% of theory) of phenyl 2,4-dihydroxybenzoate (m.p. 135°-137° C.). | |
With thionyl chloride In <i>N</i>-methyl-acetamide; cyclohexane; toluene | 13.a Ethyl 2-{4,6-bis[4-(2-ethylhexyloxy)phenyl]-s-triazin-2-yl}-(3-hydroxyphenoxy)acetate a) 154.1 g (1.0 mol) of 2,4-dihydroxybenzoic acid, 141.2 g (1.5 mol) of phenol, 500 ml of toluene and 1 ml of dimethylformamide are placed in a 1.5 l sulfonating flask fitted with stirrer, condenser, dropping funnel and gas outlet. 178.5 g (1.5 mol) of thionyl chloride are added dropwise over the course of 2.5 hours at an internal temperature of 100-105 C. The reddish, clear solution is then refluxed overnight (110-115 C.). Toluene and phenol are distilled off in vacuo, the highly viscous residue (271.5 g) is stirred in 300 ml of toluene/cyclohexane (7/3) and the mixture is left overnight to crystallize. The precipitate is filtered off with suction under cold conditions (10 C.) and the solid product is washed with 3*50 ml of toluene/cyclohexane (7/3) and then dried at 80 C. in vacuo, to give 125.5 g (54.4% of theory) of phenyl 2,4-dihydroxybenzoate (m.p. 135-137 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate In N,N-dimethyl-formamide at 20 - 50℃; | B001 Preparation of intermediate B001: [B0001] 2,4-bis(benzyloxy)benzoic acid Preparation of intermediate B001:[B0001] 2,4-bis(benzyloxy)benzoic acid2,4-dihydroxybenzoic acid (29.3 g, 0.19 mol) was stirred in DMF (500mL) and potassium carbonate (105 g, 0.76mol) was added. To this stirred mixture was added benzyl bromide (99.2 g, 69 mL, 0.58mol) in DMF (100 mL) drop-wise at RT and the reaction was stirred at ambient temperature overnight. A further 7 mL of benzyl bromide was added and the reaction mixture heated at 50°C for 2 hours to give complete conversion to the tris-benzylated product. When complete an aqueous solution of potassium hydroxide (17 g, 0.3 mol) in water (200 mL) was added followed by methanol (300 mL) and the mixture heated at reflux until complete hydrolysis of the benzyl ester. When complete, the mixture was cooled and poured carefully into 1 N HCI (2000 mL) and was then extracted with ethyl acetate (4 x 500mL). The combined extracts were washed with brine (5 x 800mL), water (800mL), dried (MgS04) and concentrated in vacuo. The resultant solid material was washed with petroleum ether and diethyl ether and dried to yield 2,4-bis(benzyloxy)benzoic acid (63.53 g, 96%).LC/MS (method A): RT = 2.63 min; m/z = 333 [M-H] Total run time 3.75 mins. |
79% | Stage #1: 4-hydroxysalicylic acid; benzyl bromide With potassium carbonate In N,N-dimethyl-formamide at 20℃; Stage #2: With water; sodium hydroxide In tetrahydrofuran; methanol at 80℃; | |
With sodium hydroxide; sodium hydride Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In N,N-dimethyl-formamide at 20 - 90℃; for 13h; Inert atmosphere; | |
98% | With potassium carbonate In acetonitrile at 70℃; for 5h; | Benzyl 2,4-bis(benzyloxy)benzoate (33)[32] A mixture of 2,4-dihydroxybenzoic acid (3.0 g, 19.47 mmol, 1.0 eq.), benzyl bromide (6.94 mL, 58.40 mmol, 3.0 eq.) and K2CO3 (8.07 g, 58.40 mmol, 3.0 eq.) in anhydrous acetonitrile (50 mL) was heated at 70 °C. After 5 hours, the solvent was removed and residue dissolved in ethyl acetate (150 mL) before it was washed with water (30 mL). The organic layer was separated, washed with brine (30 mL), dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The resulting residue was washed with diethyl ether, hexane and dried under vacuum to afford 2,4-bis(benzyloxy) benzoate as a colorless solid (8.1 g, 98 %): 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 1H), 7.46 - 7.43 (m, 2H), 7.40 - 7.38 (m, 7H), 7.35 - 7.29 (m, 6H), 6.61 (d, J = 2.3 Hz, 1H), 6.58 (dd, J = 8.7, 2.3 Hz, 1H), 5.32 (s, 2H), 5.12 (s, 2H), 5.06 (s, 2H). |
98% | With potassium carbonate In N,N-dimethyl-formamide at 20 - 90℃; for 13h; Inert atmosphere; | 1-5 Synthesis of Benzyl 2,4-Bis(Benzyloxy)Benzoate (12) The starting material 2,4-dihydroxy benzoic acid (20 g, 130 mmol) was dissolved in 200 ml of DMF in a 2L round-bottom flask. Benzyl bromide (62 ml, 519 mmol) and potassium carbonate (72 g, 519 mmol) were added to the reaction flask at room temperature. After stirring at room temperature for 12 hours, the reaction temperature was increased to 90°C., followed by stirring for 1 hour. Ethyl acetate and 1N HCl were added to the reaction residue. The mixture was separated into two layers, and the aqueous phase was extracted three times with ethyl acetate. The obtained organic layer was dried with anhydrous Na2SO4, concentrated, and then purified by recrystallization from MeOH. The yield was 98%. FIG. 8 shows the 400 MHz 1H-NMR spectrum (in CD3OD) of the compound of Formula 12, and FIG. 9 shows the 101 MHz 13C-NMR spectrum (in CD3OD) of the compound of Formula 12.1H NMR (400 MHz, CDCl3) δ=7.91 (d, J=8.6, 1H), 7.40-7.26 (m, 15H), 6.61 (d, J=2.4, 1H), 6.57 (dd, J=2.4, 8.6, 1H), 5.32 (s, 2H), 5.12 (s, 2H), 5.06 (s, 2H); 13C NMR (101 MHz, CDCl3) δ=165.6, 163.3, 160.3, 136.4, 136.3, 134.1, 128.7, 128.5, 128.4, 128.2, 128.1, 127.8, 127.5, 127.0, 113.1, 106.0, 101.3, 70.6, 70.2, 66.3; HRMS (ESI-TOF) m/z calculated for C28H25O4 [M+H]+: 425.1753, found: 425.1740. |
77% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 16h; | |
63.4% | With sodium hydride In N,N-dimethyl-formamide 1.) 0 deg C, 1 h 2.) r.t., overnight; | |
57% | With potassium carbonate; sodium iodide In acetone for 16h; Reflux; | |
With sodium hydride In N,N-dimethyl-formamide; paraffin for 12h; Ambient temperature; | ||
With potassium carbonate In acetone for 24h; Heating; | ||
With potassium carbonate In acetone for 24h; Reflux; | 3 4.3 2,4-Bis(benzyloxy)benzoic acid (9) A solution of 2,4-dihydroxybenzoic acid (3.00 g, 19.5 mmol), benzyl bromide (20.00 g, 117.0 mmol), and K2CO3 (16.50 g, 119.0 mmol) in acetone (90 mL) was refluxed for 24 h. After filtration, the solution was concentrated in vacuo to give the crude product as a clear oil, which was then dissolved in methanol (80 mL) and an aqueous solution of 5 N NaOH (20 mL) was added. The mixture was refluxed for 12 h and the solution was concentrated in vacuo to remove the methanol. The residue was dissolved in water and extracted with petroleum ether (5×40 mL). Then the water phase was acidified with 3 N HCl to pH 2 and filtered to give the product 9 as a white solid (6.47 g, quantitative): mp 124-126 °C (lit.5 120-121 °C). IR (neat): ν 3301, 1726, 1678, 1574, 1385, 1257, 1173, 1026, 835, 734, 696 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J=8.8 Hz, 1H, Ar-H), 7.48-7.30 (m, 10H, 2× -Ar), 6.73 (dd, J=8.8, 2.1 Hz, 1H, Ar-H), 6.68 (d, J=2.1 Hz, 1H, Ar-H), 5.21 (s, 2H, -OCH2Ar), 5.10 (s, 2H, -OCH2Ar). | |
125.8 g | With potassium carbonate In acetonitrile at 85℃; | Step 1 benzyl 2,4-bis(benzyloxy)benzoate 2,4-dihydroxybenzoic acid (46 g, 0.298 mol) was stirred in acetonitrile (400mL) and potassium carbonate (200 g, 1 .45 mol) was added. To this stirred mixturewas added benzyl bromide (110 ml) drop-wise at RT and the reaction was heated at 85°C overnight. The reaction mixture was allowed to cool to ambienttemperature then poured into water (1200 mL). The resulting solids were filtered and washed with water (2 x 400 mL) then hexane (400 mL) to afford a white powder which was dried in vacuo at 40°C, affording benzyl 2,4- bis(benzyloxy)benzoate as white powder (125.8 g). |
With potassium carbonate In N,N-dimethyl-formamide at 20 - 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With phosphorus trichloride In toluene for 4h; Heating; | |
63% | With phosphoric acid at 150℃; for 4h; | |
61% | With polyphosphoric acid at 250℃; for 4h; | 2.4 Synthesis of (1H-benzo[d]thiazole-2-yl) benzene-1,3-diol (3) 2,4-Dihydroxybenzoic acid 1 (10g, 64.9mmol), and o-amino thiophenol 2 (7.07g, 64.9mmol) were mixed in polyphosphoric acid (121.94g). The mixture was stirred at 250°C for 4h and then it was allowed to cool to room temperature, poured into 1200ml ice-cold water with continuous stirring. A dark brown precipitate was obtained. It was filtered and dissolved in a cold solution of 10% Na2CO3 (140mL) acidified with 10% HCl (40mL) up to pH 2 at 10°C. This solution was kept overnight at 0°C to give 3 with good yield (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate In acetone for 16h; Heating; | |
With potassium carbonate In thiophene; water | R.5.v 2-benzyloxy-4-methoxybenzoic acid, respectively, there were prepared: (b)(v) The 2-benzyloxy-4-methoxybenzoic acid used as a starting material was prepared as follows: Methyl 2,4-dihydroxybenzoate (prepared from 2,4-dihydroxybenzoic acid by the general method of Brunner (Monatsh. 1913, 34, 916) (12 g) was treated with methyl iodide (12.2 g) and anhydrous potassium carbonate (4.95 g) in dry sulpholane (140 ml) at 60°-70° C. After 8 hours, further methyl iodide (12.2 g) was added and heating was continued for 14 hours. The excess of methyl iodide was evaporated and the mixture was poured into a mixture of ice and water (1 liter) and the mixture was acidified with aqueous acetic acid (2N). The separated solid was filtered off and washed with water to give methyl 2-hydroxy-4-methoxybenzoate (10.8 g), m.p. 47°-50° C. [a sample of which, purified by chromatography on silica gel (eluding with chloroform), had the melting point 49°-51° C.]. | |
With potassium carbonate In acetone for 6h; Inert atmosphere; Reflux; |
With potassium carbonate In acetone for 16h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
nachfolgend Bromieren in waessr. Loesung; |
Yield | Reaction Conditions | Operation in experiment |
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59% | With trifluoroacetic acid; trifluoroacetic anhydride at 0 - 25℃; for 72h; | 16.1; 17.1; 18.1 Step 1. Synthesis of 7-hydroxy-2, 2-dimethyl-4H-1, 3-benzodioxin-4-one (C50) Trifluoroacetic anhydride (300 mL) and acetone (150 mL) were added drop-wise to a 0° C. suspension of 2,4-dihydroxybenzoic acid (55.0 g, 357 mmol) in trifluoroacetic acid (500 mL) and the reaction mixture was stirred at 25° C. for 3 days. Volatiles were removed in vacuo, the residue was added to saturated aqueous sodium bicarbonate solution (500 mL), and the resulting mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed sequentially with water (500 mL) and with saturated aqueous sodium chloride solution (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Trituration with dichloromethane (200 mL) provided the product as a white solid. Yield: 41.0 g, 211 mmol, 59%. LCMS m/z 194.7 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.73 (d, J=8.5 Hz, 1H), 6.58 (dd, J=8.5, 2.0 Hz, 1H), 6.35 (d, J=2.0 Hz, 1H), 1.69 (s, 6H). |
53% | With trifluoroacetic acid; trifluoroacetic anhydride at 0 - 20℃; for 24h; | |
47% | With trifluoroacetic anhydride In trifluoroacetic acid at 20℃; for 24h; |
23% | With trifluoroacetic acid; trifluoroacetic anhydride at 0 - 20℃; for 24h; | |
With trifluoroacetic acid; trifluoroacetic anhydride at 0℃; for 24h; | Preparation of Intermediate 7-Hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (I-1a): A suspension of 2,4-dihydroxybenzoic acid (85.0 g) in trifluoroacetic acid (800 mL) was cooled in an ice/water bath as trifluoroacetic anhydride (500 mL) followed by the addition of acetone (100 mL). After the addition was complete, the ice/water bath was removed and the reaction mixture stirred for 24 hours before the volatiles were removed under vacuum using a rotary evaporator. The residue was cautiously added to a water/sodium bicarbonate suspension to afford a neutralized mixture. The mixture was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with dichloromethane to afford the product (I-1a) as an off-white solid. 1H NMR (CDCl3): δ 1.71 (s, 6H), 6.41 (d, 1H, J=2.5 Hz), 6.59 (dd, 1H, J=8.7, 2.5 Hz), 7.82 (d, 1H, J=8.2 Hz). | |
With trifluoroacetic acid; trifluoroacetic anhydride for 24h; Cooling with ice; | 3.5 7-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one Step 5 7-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one A suspension of 2,4-dihydroxybenzoic acid (85.0 g) in trifluoroacetic acid (800 mL) was cooled in an ice/water bath. Trifluoroacetic anhydride (500 mL) was added followed by acetone (100 mL). After the addition was complete, the ice/water bath was removed and the reaction mixture stirred for 24 hours before the volatiles were removed under vacuum using a rotary evaporator. The residue was cautiously added to a water/sodium bicarbonate suspension to afford a neutralized mixture. The mixture was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with dichloromethane to afford the product as an off-white solid (50 g). | |
With dmap; thionyl chloride In 1,2-dimethoxyethane at 20℃; | ||
With dmap; thionyl chloride In 1,2-dimethoxyethane at 0 - 20℃; for 24h; | 53.a To a cold mixture of 2,4-dihydroxybenzoic acid (25.9 g, 168.1 mmol), acetone (12.7 g,218.5 mmol) and DMAP (1.03 g, 8.4 mmol) in 1 ,2-dimethoxyethane (DME) (96 mL) in an ice bath was added thionyl chloride (26.0 g, 218.5 mml) slowly. Resulting mixture was stirred at 0 0C for 1 h and then at rt for 23 h. Reaction mixture was quenched at 0 0C with saturated NaHCO3 solution (slowly with caution). After 200 mL of saturated NaHCO3 solution was added, NaHCO3 solid was added in small portion to the mixture until pH reaches 7-8. It was diluted with water (200 mL) and extracted with EtOAc (2 x 200 mL). Organic layers were combined and washed with brine, dried over MgSO/i, filtered and concentrated. Crude residue was triturated with CH2Cl2 (100 mL). Solid was collected and dried to provide the title compound (10.4 g). 1H NMR (200 MHz, DMSO-d6): δ (ppm) = 7.66 (d, J = 7.8 Hz, 1 H), 6.59 (d, J = 7.8 Hz, 1 H), 6.36 (s, 1 H), 1.65 (s, 6 H). | |
With trifluoroacetic anhydride In trifluoroacetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: conc. H2SO4 / Heating 2: N2H4*H2O / ethanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; trifluoroacetic anhydride; In acetone; | 2,4-dihydroxyphenol is stirred in trifluoroacetic acid, and this mixture is treated with acetone and trifluoroacetic anhydride. After stirring until completion, the mixture is partitioned between neutral buffer and ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; sulfuric acid; dimethyl sulfoxide; In methanol; water; ethyl acetate; | EXAMPLE 1 Synthesis of methyl 2-hydroxy-4-(2-chloro-4-trifluoromethylphenoxy)benzoate: A mixture of 45.5 parts of 85% KOH, 250 parts by volume of methanol and 13 parts of water was added to a solution of 50.8 parts of 2,4-dihydroxybenzoic acid in 300 parts by weight of methanol. The mixture was stirred at room temperature for 30 minutes, and then concentrated to dryness under reduced pressure. To the residue were added 71 parts of <strong>[328-84-7]3,4-dichlorobenzotrifluoride</strong> and 250 parts by volume of dimethyl sulfoxide, and the mixture was heated with stirring at 150 to 160 C. for about 20 hours. After cooling, water was added, and the unreacted matter was extracted by using ether. The aqueous layer was acidified with HCl, and the precipitated crystals were collected by filtration. Methanol (400 parts by volume) and 0.1 part by volume of concentrated sulfuric acid were added to 20 parts of the crystals, and the mixture was refluxed. About 10 hours later, methanol was removed by concentration under reduced pressure. Ethyl acetate was added to the residue, and the solution was washed twice with 1N aqeuous NaOH solution. The organic layer was washed with water and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure to give 18 parts of the captioned compound. | |
With potassium hydroxide; sulfuric acid; dimethyl sulfoxide; In methanol; water; ethyl acetate; | EXAMPLE 1 Synthesis of methyl 2-hydroxy-4-(2-chloro-4-trifluoromethylphenoxy)benzoate:- A mixture of 45.5 parts of 85% KOH, 250 parts by volume of methanol and 13 parts of water was added to a solution of 50.8 parts of 2,4-dihydroxybenzoic acid in 300 parts by weight of methanol. The mixture was stirred at room temperature for 30 minutes, and then concentrated to dryness under reduced pressure. To the residue were added 71 parts of <strong>[328-84-7]3,4-dichlorobenzotrifluoride</strong> and 250 parts by volume of dimethyl sulfoxide, and the mixture was heated with stirring at 150 to 160C for about 20 hours. After cooling, water was added, and the unreacted matter was extracted by using ether. The aqueous layer was acidified with HCl, and the precipitated crystals were collected by filtration. Methanol (400 parts by volume) and 0.1 part by volume of concentrated sulfuric acid were added to 20 parts of the crystals, and the mixture was refluxed. About 10 hours later, methanol was removed by concentration under reduced pressure. Ethyl acetate was added to the residue, and the solution was washed twice with 1N aqeuous NaOH solution. The organic layer was washed with water and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure to give 18 parts of the captioned compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 4-hydroxysalicylic acid With sodium hydride In DMF (N,N-dimethyl-formamide) at 20℃; for 0.5h; Stage #2: With Trimethyl borate In DMF (N,N-dimethyl-formamide) at 20℃; for 1h; Stage #3: 2,2,3,3,3-pentafluoropropyl triflate In DMF (N,N-dimethyl-formamide) at 100℃; | 6.A.b b) Title compound To a mixture of 95% NaH (1.43 [G,] 56.64 [MMOL)] in DMF (12 mL) under argon, a solution of 2,4-dihydroxybenzoic acid (3.00 g, 18.88 [MMOL)] in DMF (18 mL) was added. The resulting suspension was stirred at room temperature for 30 min. Next, B [(OCH3)] 3 (6.3 mL, 56.64 [MMOL)] was added dropwise and the reaction mixture was stirred for one hour more at room temperature. Then, the compound obtained in the preceding section (5.0 mL, 28.32 [MMOL)] was added dropwise and the resulting mixture was stirred at 100 [°C] overnight. The mixture was cooled to room temperature and acidified with 1 N HCI to pH 1. The solution thus obtained was extracted with EtOAc and the organic phase was washed with H20 and brine, dried over [NA2SO4] and concentrated to dryness. The crude product obtained was recrystallized in [ACOH] (4 times, 3 mL [ACOH] each time), affording the title compound as a slightly coloured solid (66% yield). M. [P.] [= 147-148 °C] ['H] NMR (200 MHz, [CDC13)] [8] (TMS): 4.42 (t, J = 12.4 Hz, 2H), 6.45 (d, J = 2.2 Hz, [1] H), 6.50 (d, J = 2.6 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sulfuric acid; for 15h;Reflux; | Methyl 2,5-dihydroxybenzoate (19) To a solution of 2,4-dihydroxybenzoic acid (20.0 g, 0.13 mol) in MeOH (200 mL) was added concentrated H2SO4 (8.52 mL, 0.16 mol). The resulting mixture was then heated at reflux for 15 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue taken up in Et2O (200 mL). The organic extract was then washed with H2O (3 x 200 mL), brine (200 mL) and the solvent removed under reduced pressure to afford 20.0 g (92%) of 19 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In nitromethane; for 120h;Sealed vial; | [0563 Example 2. 1:1 <strong>[90098-04-7]Rebamipide</strong> 2, ~0illiy roiiy benzoic AcM CocrystalfOS7] 2.1 Preparation of a 1:1 <strong>[90098-04-7]Rebamipide</strong> 2,4-DihydroKyben2oic Acid Cocrystal[058] <strong>[90098-04-7]Rebamipide</strong> (200mg) and 2,4-dlhydroxybenzbic acid (S3 mg) were weighed into a glass vial.Nitromethane (2.0 ml) was added and the vial sealed. The resulting slurry was placed in a shaker and matured for 5 days (RT to 50 C on an 8 hour cycle, heatin to 50 C for 4 hours and then cooiing to RT for 3 further 4 hours), The product was then filtered under vacuum and dried in a vacuum oven at SO aC overnight |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.5% | With zinc(II) chloride; trichlorophosphate at 75℃; for 0.5h; Microwave irradiation; | 5.2.2. Synthesis of xanthones (3-1~3-33) General procedure: The synthesis refers to a procedure described in literature [32].To a 50-mL flask 8 mL phosphorus oxychloride (POCl3) and anhydrouszinc chloride (6.8 g, 0.05 mol) were added. The suspensionwas stirred at 70 °C until ZnCl2 was completely dissolved intophosphorus oxychloride. The mixture was then cooled down toroom temperature (r.t.). Afterwards, salicylic acids (1a-l) (l.0 mmol)and phenolics (2a-d) (1.1 mmol) were added, respectively, and themixture was heated with microwave reactor with a programmedprocedure of 75 °C for 30 min. Then the mixture was cooled downto r.t. and pulled into ice water stirring for 20 min. The mixed solutionwasfiltered,washed with coldwater. The solid residues werecollected and purified by flash column liquid chromatography. |
43% | With Eaton’s acid at 80℃; for 3h; | General procedure for the synthesis ofcompounds 3,6-dihydroxy-9H-xanthen-9-one (26)and 3,4,6-trihydroxy-9H-xanthen-9-one (27) General procedure: A mixture of 2,4-dihydroxybenzoic acid (5mmol) and resorcinol or pyrogallol (5 mmol) wasstirred in Eaton’s acid (5 ml) and heated to 80 °Cfor 3 h. After the completion of reaction (monitoredby TLC), the product was poured into an ice waterand the precipitate formed was fltered, washedwith water and 5% NaHCO3. The dried productwas purifed by silica gel column chromatographywith n-hexane/ethyl acetate (gradient 0-30% ethylacetate) to afford compound 26 and 27. 3,6-dihydroxy-9H-xanthen-9-one (26).Reddish crystals, yield 43%, mp 247 °C; 1H-NMR(500 MHz, CDCl3) d (ppm): 7.37 (d, J = 8.5 Hz,2H), 6.37 (d, J = 8.4 Hz, 2H), 6.35 (s, 2H). HRESIMS calcd. for C13H8O4, [M+H]+ 229.0522, found229.0517. |
Multi-step reaction with 2 steps 1: trichlorophosphate; zinc(II) chloride / 3 h / 65 °C / Inert atmosphere 2: sodium acetate / water / 0.13 h / 120 °C / Microwave irradiation |
Stage #1: 4-hydroxysalicylic acid; recorcinol With methanesulfonic acid; phosphorus pentoxide at 70℃; Stage #2: With water for 2h; Cooling with ice; | Synthesis Synthesis of all the designed compounds (B1-B9) involves three steps reactions. All the targeted compounds were synthesized using laboratory grade chemicals and solvents without further purification. Eaton’s reagent was prepared by dissolving phosphorus pentoxide in methanesulphonic acid in 1:10 ratio i.e. 10 g phosphorus pentoxide was dissolved in 100 mL methane sulphonic acid. 100 mL of Eaton’s reagent was added slowly to a mixture of resorcinol (60 mmol) and 2,4-dihydroxybenzoic acid (60 mmol). The mixture was warmed up to 70 °C for 35 min under stirred. Then cooled to room temperature and the reaction was poured into an ice bath and stirred for 2 h. The resulting solid collected by filtration, washed with water until pH 6 and dried at 60 °C. | |
With zinc(II) chloride; trichlorophosphate at 55 - 70℃; | Synthesis of di and tri-hydroxy xanthones General procedure: A mixture of o-hydroxy benzoic acid or 2, 4 dihydroxy benzoic acid, a phenol (such as catechol,pyrogallol, resorcinol, etc.), freshly fused zinc chloride (ZnCl2) and phosphorous oxychloride(POCl3) was heated on a water bath or on heating mantle (maintaining the temperature 55-70C) for 1.5-2 hr, cooled and poured into ice water carefully in order to avoid polymerization(Grover et al., 1955). The product was filtered off, washed with 2% sodium hydrogen carbonate solution (if needed) and water, dried and crystallized from suitable solvents. The recrystallization of compounds from appropriate solvents furnished analytically pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 4-hydroxysalicylic acid With dmap In dichloromethane for 0.0833333h; Reflux; Stage #2: With acetic anhydride; triethylamine In dichloromethane at 40℃; for 2h; Stage #3: m-Hydroxyaniline Further stages; | 3 [Example 2] Preparation of 2-Hydroxy-N-(3-hydroxyphenyl)benzamide General procedure: 2-Hydroxybenzoic acid (100 g, 0.72 mol) was dissolved in 1000 mL of dichloromethane, then a catalytic amount (8.8 g, 0.072 mol) of dimethylaminopyridine was added and the mixture was refluxed for 5 minutes. Triethylamine (146 g, 1.44 mol) Drop it. Acetic anhydride (147 g, 1.44 mol) was slowly added dropwise thereto and refluxed at a reaction temperature of 40 ° C for 2 hours.After the reaction was completed, dichloromethane (1000 ml) was added dropwise to the reaction solution, which was then diluted. 1000 ml of water was added to wash the reaction mixture, which was then washed with 500 ml of 1M HCl solution, dried over anhydrous manganese (100 g) Crystallization with hexane followed by filtration gave 108 g (yield = 83%). This compound (100 g, 0.55 mol) was dissolved in tetrahydrofuran (1500 mL), triethylamine (56.1 g, 0.55 mol) was added dropwise thereto, and 1.3 equivalents of ethyl chloroformate (77.6 g, 0.715 mol) After stirring for 30 minutes, 3-hydroxyaniline (60 g, 0.55 mol) and triethylamine (56.1 g, 0.55 mol) were dissolved in 1500 ml of N, N-dimethylformamide by heating and then slowly added dropwise And further stirred for 3 hours.After completion of the reaction, the reaction mixture was filtered, and the reaction mixture was concentrated. The residue was dissolved in dichloromethane (1500 ml), washed with distilled water (500 ml), washed with saturated sodium hydrogencarbonate (500 ml), dried over anhydrous manganese (100 g) Crystallization with hexane followed by filtration gave 155 g (yield = 79%). This compound (100 g, 0.36 mol) was dissolved in 1500 ml of tetrahydrofuran and methanol (1: 1) solvent, followed by the addition of 15% potassium hydroxide, 100 ml and stirring for 30 minutes.After completion of the reaction, the reaction mixture was neutralized by addition of acid, and the reaction mixture was concentrated. 1500 ml of ethyl acetate was added to dissolve the reaction mixture. The reaction mixture was washed with water (1000 ml), filtered and concentrated. The residue was crystallized from hexane and filtered to obtain 77.7 g As a pale yellow solid. |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetone for 12h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In nitromethane; at 20 - 50℃; for 120h; | <strong>[73963-72-1]Cilostazol</strong> (300 mg) and 2,4-dihydroxybenzoic acid (125 mg) were weighed into a glass vial. Nitromethane (1.5 ml) was added to the vial. The resulting slurry was matured for 5 days (RT to 50 C. on an 8 hour cycle, heating to 50 C. for 4 hours and then cooling to RT for a further 4 hours). The product was then filtered under vacuum for ca. 1 hour before being allowed to dry under ambient conditions overnight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine; potassium iodide In N,N-dimethyl-formamide at 20℃; | 1 2-[5-Methyl-2-(propan-2-yl)phenoxy]-2-oxoethyl 2,4-dihydroxybenzoate (4c) General procedure: A mixture of thymol chloroacetyl derivative (2) (0.01 mol), hydroxysubstituted benzoic acids (3aee) (0.01 mol), triethyl amine(0.01 mol), potassium iodide (0.01 mol) in dimethyl formamide(25 mL)was stirred overnight at room temperature (Scheme 1). Thereaction mixture was poured into finely crushed ice with stirringand extracted with ethyl acetate (4 25 mL). The combined organiclayer was washed with 5% HCl, 5% sodium hydroxide and finallywith aqueous NaCl solution. The organic layer was dried overanhydrous magnesium sulfate, filtered and the solvent wasremoved under reduced pressure to afford the crude products(4aee). The title compounds (4aee) were purified by silica gel column chromatography (n-hexane: ethyl acetate 4:1). The sameprocedure was used for the preparation of compounds (6a-c) Scheme 2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dihydrogen peroxide In aq. buffer at 30℃; | Catalytic oxidation of morin A set volume of catalyst, 300 L of AgDENs (0.49 M,1.47 × 10-6mmol) or 400 L of AuDENs (0.62 M,1.86 × 10-6mmol), was used to evaluate the catalytic oxida-tion of morin. A UV-vis spectrophotometer was used to monitorthe process by recording the absorbance at 410 nm, the max-imum morin absorbance, for three hours. Exactly, 180 L ofhydrogen peroxide (24 mM, 4.32 × 10-3mmol) was used as oxidant. A volume of 300 L of carbonate buffer solution (50 mM,0.15 mmol) was used to assure the stability of hydrogen peroxideby maintaining the pH at 10 [27]. A freshly prepared solution of1 mM morin was diluted to 0.05-0.15 mM for all evaluations. Arequired volume of deionized water was added unto each cuvetteto the total of 3 mL. At least 15 min were allocated for temperatureequilibration of the reactants into the UV-vis compartmentsand morin solution was added last. For the uncatalyzed reac-tion, the nanoparticle solution was replaced with a dendrimersolution of the same concentration. The stability of the colloidalcatalysts was investigated by three recycle runs of 5 mL of bothsilver and gold nanoparticles, (0.49 M, 2.45 × 10-6mmol) and(0.62 M, 3.10 × 10-6mmol) respectively. The catalyst solutionswere dialyzed against 50 mL of aqueous solution of all reactants(morin (0.05 mM, 2.5 × 10-3mmol), hydrogen peroxide (24 mM,1.2 mmol), and carbonate buffer (50 mM, 2.5 mmol)) at roomtemperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate at 120℃; for 5.7h; | 1 Resorcinol 55g (0.50 mol) were charged in a 300ml four-necked flask,The temperature was raised to 120 after the replacement with carbon dioxide. 120 , potassium carbonate, while the carbon dioxide is circulated in 100ml / min. At a rate of atmospheric pressure 13.8gIt was added to the flask over a period of 40 minutes while stirring (0.20 mol as K).After reacting for 5 hours with stirring at 120 ,The distribution of carbon dioxide to complete the reaction was stopped and dissolved water was added to precipitate the end of the reaction solution. After sampling the reaction solution, analysis after acid treatment by HPLC (high performance liquid chromatography) (absolute calibration method)As a result, 2,6-dihydroxybenzoic acid /2,4-dihydroxybenzoic acid /4,6-dihydroxy isophthalic acid generation ratio1 / 0.10 / 0.005,The existence yield of 2,6-dihydroxybenzoic acid to the potassium of potassium carbonateThe rate was 49.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine; potassium iodide In N,N-dimethyl-formamide at 20℃; for 24h; | Synthesis of carvacrol derivatives(4a-f) and (6a-d). General procedure: The hydroxy substituted benzoicacids 3a-f (0.01mole), triethyl amine (0.01 mol), potassium iodide (0.01 mol) in dimethylformamide (25 mL) and intermediate 2 (0.01 mol)were stirred overnight at room temperature.After the completion of reaction the mixture was poured into finely crushed ice with stirring and extracted with ethyl acetate (4×25 mL). The combined organic layer was washed with 5%HCl, 5% sodium hydroxide and finally with aqueous NaCl solution. The organic layer wasdried over anhydrous magnesium sulphate, filtered and the solvent was removed underreduced pressure to afford the crude products 4a-4f. The title compounds 4a-f were purifiedby silica gel column chromatography (n-hexane: ethyl acetate 4:1). The same procedure wasused for the preparation of compounds 6a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; for 3h;Reflux; | All materials were purchased from commercial suppliersand were used without further purification. Equimolar quantitiesof both pyrimethamine and 2,4-dihydroxybenzoic acid were mixed in a round-bottomed flask and refluxed for 3 h inmethanol. Rod-like colourless crystals were obtained after afew days. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cobalt(II,III) oxide; dihydrogen peroxide | ||
With dihydrogen peroxide In water; acetic acid at 25℃; | ||
With C18H12N5(1-)*Fe(3+)*2Cl(1-); dihydrogen peroxide at 25℃; | 2.2. Description of the catalytic bleaching Bleaching experiments were carried out as describedpreviously for 1,3-bis(20-Ar-imino)isoindoline manganesecomplexes to allow comparison of the twosystems. Kinetics of morin bleach were monitored onan Agilent 8453 diode-array spectrophotometer usingthermostated quartz cells equipped with a magneticstirring unit. The initial absorbance of morin inbuffer solution was measured, and its bleaching reactionwas followed as the decrease in absorbance at 410 nm. In a typical experiment, the cuvette (l 1 cm) was filled with 3 mL buffer solution containing0.62 M catalyst, 160 M morin, and the bleachingreaction initiated by adding 10 mM H2O2 intothe reaction mixture (Tables 1 and 2). The pH wasadjusted by 50 mM sodium carbonate-bicarbonate(CO23 /HCO3 ) buffer (pH 10) or 25 mM borax buffer(pH 8.5), respectively. First-order rate constants werecalculated using Biochemical Analysis Software forAgilent ChemStation software. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; Inert atmosphere; | General Procedure for Synthesis of FTY720 Derivatives 2-10 General procedure: EDCI (3 eq), N,N-dimethyl-4-aminopyridine (DMAP) (0.5 eq), and the acid intermediates (1.5 eq) were added to a stirred solution of 4-n-octylaniline (100 mg, 0.49 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred under nitrogen for 12 h. The solvent was removed in vacuo and the resulting residue was purified by flash column chromatography to afford the desired products 2-10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With acetic anhydride; triethylamine; for 4.0h;Heating; | <strong>[15441-10-8]3-sulfamoylpropionic acid</strong> (Compound 1) (15.0 g, 97.94 mmol) and 2,4-dihydroxybenzoic acid (Compound 2)(10.2 g, 66.18 mmol) was dissolved in acetic anhydride (22.6 mL), and triethylamine (13.2 mL) was carefully added to the mixture, and the mixture was heated for 4 hr. After the reaction, it was cooled and diluted with water. The precipitated product was filtered and washed with aqueous methanol.(7-Hydroxy-2-oxo-2H-chromen-3-yl)methanesulfonamide (Compound 3), 21.2 g, yield 85%. |
85% | With acetic anhydride; triethylamine; for 4.0h;Heating; | <strong>[15441-10-8]3-sulfamoylpropionic acid</strong> (Compound 1) (15.0 g, 97.94 mmol) and 2,4-dihydroxybenzoic acid (Compound 2) (10.2 g, 66.18 mmol) were dissolved in acetic anhydride (22.6 mL). triethylamine (13.2 mL) was carefully added to the mixture, and the mixture was heated for 4 hr. After the reaction, it was cooled and diluted with water.The precipitated product was filtered and washed with aqueous methanol. (7-Hydroxy-2-oxo-2H-chromen-3-yl)methanesulfonamide (compound 3), 21.2 g, yield 85% |
85% | With acetic anhydride; triethylamine; for 4.0h;Heating; | <strong>[15441-10-8]3-sulfamoylpropionic acid</strong> (Compound 1) (15.0 g, 97.94 mmol) and 2,4-dihydroxybenzoic acid (Compound 2)(10.2 g, 66.18 mmol) was dissolved in acetic anhydride (22.6 mL).Carefully added triethylamine (13.2 mL) to the mixture.The mixture was heated for 4 hours. After the reaction, it was cooled and diluted with water.The precipitated product was filtered and washed with aqueous methanol.(7-Hydroxy-2-oxo-2H-chromen-3-yl)methanesulfonamide (Compound 3), 21.2 g, yield 85%. |
85% | With triethylamine; In acetic anhydride; for 4.0h;Heating; | <strong>[15441-10-8]3-sulfamoylpropionic acid</strong> (Compound 1) (15.0 g, 97.94 mmol) and 2,4-dihydroxybenzoic acid (Compound 2)(10.2 g, 66.18 mmol) were dissolved in acetic anhydride (22.6 mL). Triethylamine (13.2 mL) was carefully addedto the mixture, andthe mixture was heated for 4 hr.After the reaction, it was cooled and diluted with water.The precipitated product was filtered and washed with aqueous methanol togive (7-hydroxy-2-oxo-2H-chromen-3-yl)methanesulfonamide (Compound 3), 21.2 g, yield 85%. |
85% | With triethylamine; In acetic anhydride; for 4.0h;Heating; | <strong>[15441-10-8]3-sulfamoylpropionic acid</strong> (Compound 1) (15.0 g, 97.94 mmol) and 2,4-dihydroxybenzoic acid (Compound 2)(10.2 g, 66.18 mmol) was dissolved in acetic anhydride (22.6 mL), and triethylamine (13.2 mL) was carefully added to the mixture, andThe mixture was heated for 4 hours. After the reaction, it was cooled and diluted with water. The precipitated product was filtered and washed with aqueous methanol.(7-Hydroxy-2-oxo-2H-chromen-3-yl)methanesulfonamide (Compound 3), 21.2 g, yield 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | In methanol; Isopropyl acetate; at 23℃; | Finasteride (2.3 g; 6.2 mmol) and 2,4-dihydroxybenzoic acid (0.95 g; 6.2 mmol) were added to methanol (2 ml) under stirring at 23C, wherein a thick white suspension was obtained. Under further stirring, isopropyl acetate(2 ml) was added and the mixture was filtered under suction, washed with cold isopropyl acetate (3 ml) and dried at 23C in a vacuum oven (20 mbar) to yield 2.05 g (63%) of <strong>[98319-26-7]finasteride</strong> 2,4-dihydroxybenzoic acid cocrystal. |
63% | In methanol; at 23℃; | Finasteride (2.3 g; 6.2 mmol) and 2,4-dihydroxybenzoic acid (0.95 g; 6.2 mmol) were added to methanol (2 ml) under stirring at 23C, wherein a thick whitesuspension was obtained. Under further stirring, isopropyl acetate (2 ml) was added and the mixture was filtered under suction, washed with cold isopropyl acetate (3 ml) and dried at 23C in a vacuum oven (20 mbar) to yield 2.05 g (63%) of <strong>[98319-26-7]finasteride</strong> 2,4-dihydroxybenzoic acid cocrystal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 48h; Schlenk technique; Inert atmosphere; | Synthesis of Target Compounds 3g-3p General procedure: Tyrosol (1, 0.4 mmol, 1.0 equiv), organic acids 2g-2p (0.4 mmol, 1.0 equiv),and TPP (0.4 mmol, 1.0 equiv) were placed in a dry standard Schlenk tube under N2. Dry THF (1.0 mL) was added, followedby the addition of DIAD (0.4 mmol, 1.0 equiv) at 0 ° C. The reaction mixture was stirred at room temperature for 48 h, and thereaction was monitored with TLC. The crude reaction mixture was purified by column chromatography on Sephadex LH-20 toafford the corresponding product. |
65% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 48h; Inert atmosphere; | 4 Continuously introducing nitrogen into the reactor to protect the reaction.6 mmol of tyrosol, 8 mmol of triphenylphosphine and 6 mmol of 2,4-dihydroxybenzoic acid were added in sequence.Then add 12 mL of tetrahydrofuran,6 mmol of diisopropyl azodicarboxylate was added dropwise at 0 ° C.After the completion of the dropwise addition, the ice bath was removed, and the mixture was warmed to room temperature, and the reaction was stirred for 48 hours.After the reaction is completed, the reaction solution is evaporated and dried.Dissolved in ethyl acetate and washed 3 times with saturated aqueous sodium hydrogencarbonate solution.Then washed 3 times with a saturated aqueous solution of sodium chloride,Drying with anhydrous sodium sulfate, removing the salt by suction filtration, and concentrating to obtain a concentrate;The concentrate is subjected to column chromatography using methanol as a solvent.2,4-dihydroxybenzoic acid-4-hydroxyphenethyl ester is isolated,The yield is 65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate / Reflux | ||
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide; thionyl chloride / 2 h / 20 °C 2: 0.5 h / 0 °C 3: hydrazine hydrate / ethanol / 9 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone at 20 - 25℃; for 10 - 20h; | 7 Example 7.- Preparation of a cocrystal of ubiquinone:2,4-dihvdroxybenzoic acid A saturated solution of 2,4-dihydroxybenzoic acid (100 mg) in acetone (0.15 ml.) was prepared at room temperature. Then, ubiquinone (56 mg) was added until a suspension was formed. The suspension was stirred at room temperature overnight. The solid was filtered and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 8h; | 4.3. General procedure for the preparation of 1-9, 11-14, 16,19-20, 22-27 General procedure: To a solution of tryptamine derivatives (0.62 mmol) indichloromethane (3 mL), EDCIHCl (144 mg, 0.75 mmol) and HOBT(110 mg, 0.81 mmol), Et3N (0.22 mL, 1.56 mmol), salicylic acid derivatives(0.69 mmol) were added at room temperature and stirredfor 8 h. After completion of the reaction detected by TLC, the reactionliquid was removed by rotary evaporation under reducedpressure. Then the resulting residue was purified by silica gel flashcolumn chromatography to afford the desired product as a solid(70%-90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.1% | With tetramethyl ammoniumhydroxide In dichloromethane; water at 20℃; for 0.5h; | Production Example of Compound (D0-1) 2,4-dihydroxybenzoic acid (compound B1) (1.3 g, 8.4 mmol) and the compound A1 (2.9 g, 8.4 mmol) were dissolved in dichloromethane (35 g), and a 5% tetramethylammonium hydroxide (TMAH) aqueous solution (15.3 g) was added thereto for the reaction at room temperature for 30 minutes. After the reaction, the water phase was removed, and the organic phase was washed with ultrapure water (10 g) 10 times. The organic phase was concentrated and dried using a rotary evaporator to obtain a compound (D0-1) (2.7 g, yield=77.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine; potassium iodide In N,N-dimethyl-formamide at 20℃; for 24h; | 3.2. General Procedure for the Synthesis of Title Compounds (Ph1-Ph5) and (Ph6-Ph10) General procedure: The intermediate 2-(4-methoxyphenyl)ethan-1-aminechloroacetate (2) was synthesizedby following the Sidhu et al., method with some modifications [51]. The 2-(4-methoxyphenyl) ethan-1-amine (1) (0.01 mol) was dissolved in anhydrous dichloromethane(DCM) (25 mL) and triethylamine (C2H5)3N (0.01 mol) was added slowly. The resultingsolution was then cooled in an ice salt mixture to 0 to 5 C. The chloroacetyl chloride(0.01 mol) in dry DCM was added drop-wise to the reaction mixture with constant stirringover a period of 1h maintaining the temperature constant. The reaction mixture wasthen stirred at room temperature for a further 5 h, washed with 5% HCl, and 5% sodiumMolecules 2021, 26, 2477 9 of 17hydroxide solution. The organic layer was washed with saturated aqueous NaCl, driedover anhydrous magnesium sulfate, filtered and the solvent was removed under reducedpressure. The crude product was purified by silica gel column to afford the corresponding2-(4-methoxyphenyl)ethan-1-aminechloroacetate (2).The substituted benzoic acids (3a-e) (0.01 mol), triethylamine (0.01 mol) and potassiumiodide (KI) (0.01 mol) were mixed in dimethyl formamide (DMF) (25 mL) and stirred atroom temperature. The 2-(4-methoxyphenyl)ethan-1-amine chloroacetate intermediate (2)was then added to the reaction mixture slowly and stirred the reaction mixture at the sametemperature overnight (Scheme 1). The final products (Ph1-Ph5) were then extracted withethyl acetate (3 25 mL). The combined ethyl acetate layer was then washed with 5%HCl, 5% sodium carbonate and finally with brine solution. The organic layer was driedover anhydrous magnesium sulfate, filtered and the solvent was removed under reducedpressure to afford the crude products (Ph1-Ph5). The title compounds (Ph1-Ph5) werepurified by silica gel column chromatography (n-hexane: ethyl acetate 3:1). The sameprocedure was used for the preparation of compounds (Ph6-Ph10) Scheme 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.7% | With potassium hydroxide In water monomer at 60℃; for 0.25h; | The synthetic process of complex I was as follows: 2,4- dihydroxybenzoic acid (7.705 g, 0.05 mol) was dispersed in 25 mL of water at 60 o C, then the solution of KOH (3.366 g in 5 mL of water) was added into the above solution. The mixture was then stirred for 15 min at 60 o C and filtered. The filtrate was stayed at room temperature. After 2 days, colorless stick crystals formed ( Fig. 1 a), then were filtered, washed with ethanol and dried un- der vacuum. The yield was 7.2 g (64.7%). IR (KBr) (cm -1 ) (Fig. S1): 2357 (O -H), 1618 (C = O), 1510 (C -C), 1355 (C -O). Elemental Anal. Calc. (%): C, 39.99; H, 3.36; Found: C, 39.98; H, 3.38. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.1% | With sodium hydroxide In water monomer at 60℃; for 0.25h; | The synthetic process of complex I was as follows: General procedure: 2,4- dihydroxybenzoic acid (7.705 g, 0.05 mol) was dispersed in 25 mL of water at 60 o C, then the solution of KOH (3.366 g in 5 mL of water) was added into the above solution. The mixture was then stirred for 15 min at 60 o C and filtered. The filtrate was stayed at room temperature. After 2 days, colorless stick crystals formed ( Fig. 1 a), then were filtered, washed with ethanol and dried un- der vacuum. The yield was 7.2 g (64.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-(trifluoromethyl)benzenesulfonamide; 4-hydroxysalicylic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With 4-dimethylaminopyridine In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere; | 4.1.3. 2-Hydroxy-N-((2S, 3R)-3-hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamido)-1-phenylbutan-2-yl)benzamide (15a) General procedure: To a stirred solution of 2-hydroxybenzoic acid (14a, 0.14 g, 1.0mmol) and 11 (0.44 g, 1.05 mmol) in 3 mL anhydrous N, N-dimethylformamidewas added N-(3-dimethylaminopropyl)-N′ -ethylcarbodiimidehydrochloride (EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt, 0.15 g, 1.1 mmol) in batches at 0 Cunder an argon atmosphere. The slurry was stirred at 0 C or 10 min andthen warmed to 25 C for another 1 h until the reaction turned yellowishclarified. A catalytic amount of 4-dimethylaminopyridine (DMAP,0.024 g, 0.20 mmol) was added and stirred for 2 h at 25 C. Afterremoval of the solvent under reduced pressure, 5 mL water was added tothe residue and extracted with dichloromethane (3 × 5 mL). The combinedorganic solution was dried over Na2SO4, and then evaporated. Thecrude residue was purified via a reverse-phase C18 flash column chromatographby gradient elution with initial mobile phase methanol-water(55: 45) to furnish 15a as a white branch shape crystallite (yield:0.54 g, 89%): 1H NMR (500 MHz, CD3OD) δ 8.19 (d, J = 8.5 Hz, 2H),7.93 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5 Hz,1H), 7.26 - 7.19 (m, 4H), 7.13 (t, J = 7.0 Hz, 1H), 6.89 (t, J = 7.5 Hz,2H), 4.21 (dd, J = 11.5, 5.0 Hz, 1H), 3.89 (t, J = 7.5 Hz, 1H), 3.43 (d, J= 15.0 Hz, 1H), 3.27 - 3.19 (m, 2H), 3.09 (dd, J = 15.0, 9.0 Hz, 1H),2.95 (dd, J = 13.5, 6.5 Hz, 1H), 2.83 (dd, J = 13.5, 11.0 Hz, 1H), 2.08 -2.01 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H); 13C NMR(151 MHz, CD3OD) δ 170.2, 160.5, 151.3, 146.4, 139.7, 134.8, 130.4,129.8, 129.4, 129.3, 127.3, 125.2, 120.3, 118.3, 117.3, 73.6, 58.3, 55.4,53.5, 36.7, 27.7, 20.3; HRMS (ESI) m/z calcd. for C27H30N3O7S ([M -H]-): 540.1799, found 540.1816. |
82% | Stage #1: N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-(trifluoromethyl)benzenesulfonamide; 4-hydroxysalicylic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With 4-dimethylaminopyridine In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere; | 4.1.3. 2-Hydroxy-N-((2S, 3R)-3-hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamido)-1-phenylbutan-2-yl)benzamide (15a) General procedure: To a stirred solution of 2-hydroxybenzoic acid (14a, 0.14 g, 1.0mmol) and 11 (0.44 g, 1.05 mmol) in 3 mL anhydrous N, N-dimethylformamidewas added N-(3-dimethylaminopropyl)-N′ -ethylcarbodiimidehydrochloride (EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt, 0.15 g, 1.1 mmol) in batches at 0 Cunder an argon atmosphere. The slurry was stirred at 0 C or 10 min andthen warmed to 25 C for another 1 h until the reaction turned yellowishclarified. A catalytic amount of 4-dimethylaminopyridine (DMAP,0.024 g, 0.20 mmol) was added and stirred for 2 h at 25 C. Afterremoval of the solvent under reduced pressure, 5 mL water was added tothe residue and extracted with dichloromethane (3 × 5 mL). The combinedorganic solution was dried over Na2SO4, and then evaporated. Thecrude residue was purified via a reverse-phase C18 flash column chromatographby gradient elution with initial mobile phase methanol-water(55: 45) to furnish 15a as a white branch shape crystallite (yield:0.54 g, 89%): 1H NMR (500 MHz, CD3OD) δ 8.19 (d, J = 8.5 Hz, 2H),7.93 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5 Hz,1H), 7.26 - 7.19 (m, 4H), 7.13 (t, J = 7.0 Hz, 1H), 6.89 (t, J = 7.5 Hz,2H), 4.21 (dd, J = 11.5, 5.0 Hz, 1H), 3.89 (t, J = 7.5 Hz, 1H), 3.43 (d, J= 15.0 Hz, 1H), 3.27 - 3.19 (m, 2H), 3.09 (dd, J = 15.0, 9.0 Hz, 1H),2.95 (dd, J = 13.5, 6.5 Hz, 1H), 2.83 (dd, J = 13.5, 11.0 Hz, 1H), 2.08 -2.01 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H); 13C NMR(151 MHz, CD3OD) δ 170.2, 160.5, 151.3, 146.4, 139.7, 134.8, 130.4,129.8, 129.4, 129.3, 127.3, 125.2, 120.3, 118.3, 117.3, 73.6, 58.3, 55.4,53.5, 36.7, 27.7, 20.3; HRMS (ESI) m/z calcd. for C27H30N3O7S ([M -H]-): 540.1799, found 540.1816. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 4-hydroxysalicylic acid; N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-4-fluoro-N-isobutylbenzenesulfonamide With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With 4-dimethylaminopyridine In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere; | 4.1.3. 2-Hydroxy-N-((2S, 3R)-3-hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamido)-1-phenylbutan-2-yl)benzamide (15a) General procedure: To a stirred solution of 2-hydroxybenzoic acid (14a, 0.14 g, 1.0mmol) and 11 (0.44 g, 1.05 mmol) in 3 mL anhydrous N, N-dimethylformamidewas added N-(3-dimethylaminopropyl)-N′ -ethylcarbodiimidehydrochloride (EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt, 0.15 g, 1.1 mmol) in batches at 0 Cunder an argon atmosphere. The slurry was stirred at 0 C or 10 min andthen warmed to 25 C for another 1 h until the reaction turned yellowishclarified. A catalytic amount of 4-dimethylaminopyridine (DMAP,0.024 g, 0.20 mmol) was added and stirred for 2 h at 25 C. Afterremoval of the solvent under reduced pressure, 5 mL water was added tothe residue and extracted with dichloromethane (3 × 5 mL). The combinedorganic solution was dried over Na2SO4, and then evaporated. Thecrude residue was purified via a reverse-phase C18 flash column chromatographby gradient elution with initial mobile phase methanol-water(55: 45) to furnish 15a as a white branch shape crystallite (yield:0.54 g, 89%): 1H NMR (500 MHz, CD3OD) δ 8.19 (d, J = 8.5 Hz, 2H),7.93 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5 Hz,1H), 7.26 - 7.19 (m, 4H), 7.13 (t, J = 7.0 Hz, 1H), 6.89 (t, J = 7.5 Hz,2H), 4.21 (dd, J = 11.5, 5.0 Hz, 1H), 3.89 (t, J = 7.5 Hz, 1H), 3.43 (d, J= 15.0 Hz, 1H), 3.27 - 3.19 (m, 2H), 3.09 (dd, J = 15.0, 9.0 Hz, 1H),2.95 (dd, J = 13.5, 6.5 Hz, 1H), 2.83 (dd, J = 13.5, 11.0 Hz, 1H), 2.08 -2.01 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H); 13C NMR(151 MHz, CD3OD) δ 170.2, 160.5, 151.3, 146.4, 139.7, 134.8, 130.4,129.8, 129.4, 129.3, 127.3, 125.2, 120.3, 118.3, 117.3, 73.6, 58.3, 55.4,53.5, 36.7, 27.7, 20.3; HRMS (ESI) m/z calcd. for C27H30N3O7S ([M -H]-): 540.1799, found 540.1816. |
88% | Stage #1: 4-hydroxysalicylic acid; N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-4-fluoro-N-isobutylbenzenesulfonamide With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With 4-dimethylaminopyridine In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere; | 4.1.3. 2-Hydroxy-N-((2S, 3R)-3-hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamido)-1-phenylbutan-2-yl)benzamide (15a) General procedure: To a stirred solution of 2-hydroxybenzoic acid (14a, 0.14 g, 1.0mmol) and 11 (0.44 g, 1.05 mmol) in 3 mL anhydrous N, N-dimethylformamidewas added N-(3-dimethylaminopropyl)-N′ -ethylcarbodiimidehydrochloride (EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt, 0.15 g, 1.1 mmol) in batches at 0 Cunder an argon atmosphere. The slurry was stirred at 0 C or 10 min andthen warmed to 25 C for another 1 h until the reaction turned yellowishclarified. A catalytic amount of 4-dimethylaminopyridine (DMAP,0.024 g, 0.20 mmol) was added and stirred for 2 h at 25 C. Afterremoval of the solvent under reduced pressure, 5 mL water was added tothe residue and extracted with dichloromethane (3 × 5 mL). The combinedorganic solution was dried over Na2SO4, and then evaporated. Thecrude residue was purified via a reverse-phase C18 flash column chromatographby gradient elution with initial mobile phase methanol-water(55: 45) to furnish 15a as a white branch shape crystallite (yield:0.54 g, 89%): 1H NMR (500 MHz, CD3OD) δ 8.19 (d, J = 8.5 Hz, 2H),7.93 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5 Hz,1H), 7.26 - 7.19 (m, 4H), 7.13 (t, J = 7.0 Hz, 1H), 6.89 (t, J = 7.5 Hz,2H), 4.21 (dd, J = 11.5, 5.0 Hz, 1H), 3.89 (t, J = 7.5 Hz, 1H), 3.43 (d, J= 15.0 Hz, 1H), 3.27 - 3.19 (m, 2H), 3.09 (dd, J = 15.0, 9.0 Hz, 1H),2.95 (dd, J = 13.5, 6.5 Hz, 1H), 2.83 (dd, J = 13.5, 11.0 Hz, 1H), 2.08 -2.01 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H); 13C NMR(151 MHz, CD3OD) δ 170.2, 160.5, 151.3, 146.4, 139.7, 134.8, 130.4,129.8, 129.4, 129.3, 127.3, 125.2, 120.3, 118.3, 117.3, 73.6, 58.3, 55.4,53.5, 36.7, 27.7, 20.3; HRMS (ESI) m/z calcd. for C27H30N3O7S ([M -H]-): 540.1799, found 540.1816. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 4-hydroxysalicylic acid; N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzenesulfonamide With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With 4-dimethylaminopyridine In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere; | 4.1.3. 2-Hydroxy-N-((2S, 3R)-3-hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamido)-1-phenylbutan-2-yl)benzamide (15a) General procedure: To a stirred solution of 2-hydroxybenzoic acid (14a, 0.14 g, 1.0mmol) and 11 (0.44 g, 1.05 mmol) in 3 mL anhydrous N, N-dimethylformamidewas added N-(3-dimethylaminopropyl)-N′ -ethylcarbodiimidehydrochloride (EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt, 0.15 g, 1.1 mmol) in batches at 0 Cunder an argon atmosphere. The slurry was stirred at 0 C or 10 min andthen warmed to 25 C for another 1 h until the reaction turned yellowishclarified. A catalytic amount of 4-dimethylaminopyridine (DMAP,0.024 g, 0.20 mmol) was added and stirred for 2 h at 25 C. Afterremoval of the solvent under reduced pressure, 5 mL water was added tothe residue and extracted with dichloromethane (3 × 5 mL). The combinedorganic solution was dried over Na2SO4, and then evaporated. Thecrude residue was purified via a reverse-phase C18 flash column chromatographby gradient elution with initial mobile phase methanol-water(55: 45) to furnish 15a as a white branch shape crystallite (yield:0.54 g, 89%): 1H NMR (500 MHz, CD3OD) δ 8.19 (d, J = 8.5 Hz, 2H),7.93 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5 Hz,1H), 7.26 - 7.19 (m, 4H), 7.13 (t, J = 7.0 Hz, 1H), 6.89 (t, J = 7.5 Hz,2H), 4.21 (dd, J = 11.5, 5.0 Hz, 1H), 3.89 (t, J = 7.5 Hz, 1H), 3.43 (d, J= 15.0 Hz, 1H), 3.27 - 3.19 (m, 2H), 3.09 (dd, J = 15.0, 9.0 Hz, 1H),2.95 (dd, J = 13.5, 6.5 Hz, 1H), 2.83 (dd, J = 13.5, 11.0 Hz, 1H), 2.08 -2.01 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H); 13C NMR(151 MHz, CD3OD) δ 170.2, 160.5, 151.3, 146.4, 139.7, 134.8, 130.4,129.8, 129.4, 129.3, 127.3, 125.2, 120.3, 118.3, 117.3, 73.6, 58.3, 55.4,53.5, 36.7, 27.7, 20.3; HRMS (ESI) m/z calcd. for C27H30N3O7S ([M -H]-): 540.1799, found 540.1816. |
90% | Stage #1: 4-hydroxysalicylic acid; N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-4-nitrobenzenesulfonamide With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With 4-dimethylaminopyridine In N,N-dimethyl-formamide at 25℃; for 2h; Inert atmosphere; | 4.1.3. 2-Hydroxy-N-((2S, 3R)-3-hydroxy-4-(N-isobutyl-4-nitrophenylsulfonamido)-1-phenylbutan-2-yl)benzamide (15a) General procedure: To a stirred solution of 2-hydroxybenzoic acid (14a, 0.14 g, 1.0mmol) and 11 (0.44 g, 1.05 mmol) in 3 mL anhydrous N, N-dimethylformamidewas added N-(3-dimethylaminopropyl)-N′ -ethylcarbodiimidehydrochloride (EDCI, 0.29 g, 1.5 mmol) and 1-hydroxybenzotriazole (HOBt, 0.15 g, 1.1 mmol) in batches at 0 Cunder an argon atmosphere. The slurry was stirred at 0 C or 10 min andthen warmed to 25 C for another 1 h until the reaction turned yellowishclarified. A catalytic amount of 4-dimethylaminopyridine (DMAP,0.024 g, 0.20 mmol) was added and stirred for 2 h at 25 C. Afterremoval of the solvent under reduced pressure, 5 mL water was added tothe residue and extracted with dichloromethane (3 × 5 mL). The combinedorganic solution was dried over Na2SO4, and then evaporated. Thecrude residue was purified via a reverse-phase C18 flash column chromatographby gradient elution with initial mobile phase methanol-water(55: 45) to furnish 15a as a white branch shape crystallite (yield:0.54 g, 89%): 1H NMR (500 MHz, CD3OD) δ 8.19 (d, J = 8.5 Hz, 2H),7.93 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5 Hz,1H), 7.26 - 7.19 (m, 4H), 7.13 (t, J = 7.0 Hz, 1H), 6.89 (t, J = 7.5 Hz,2H), 4.21 (dd, J = 11.5, 5.0 Hz, 1H), 3.89 (t, J = 7.5 Hz, 1H), 3.43 (d, J= 15.0 Hz, 1H), 3.27 - 3.19 (m, 2H), 3.09 (dd, J = 15.0, 9.0 Hz, 1H),2.95 (dd, J = 13.5, 6.5 Hz, 1H), 2.83 (dd, J = 13.5, 11.0 Hz, 1H), 2.08 -2.01 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H); 13C NMR(151 MHz, CD3OD) δ 170.2, 160.5, 151.3, 146.4, 139.7, 134.8, 130.4,129.8, 129.4, 129.3, 127.3, 125.2, 120.3, 118.3, 117.3, 73.6, 58.3, 55.4,53.5, 36.7, 27.7, 20.3; HRMS (ESI) m/z calcd. for C27H30N3O7S ([M -H]-): 540.1799, found 540.1816. |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
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 |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
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: |
P370 + P380 | In case of fire: Evacuate area. |
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. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
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 |
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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