Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 490-78-8 | MDL No. : | MFCD00002343 |
Formula : | C8H8O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WLDWSGZHNBANIO-UHFFFAOYSA-N |
M.W : | 152.15 | Pubchem ID : | 10279 |
Synonyms : |
DHAP;2-Acetylhydroquinone;Quinacetophenone;2',5'-Dihydroxyacetophenone
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 40.68 |
TPSA : | 57.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.06 cm/s |
Log Po/w (iLOGP) : | 1.39 |
Log Po/w (XLOGP3) : | 1.65 |
Log Po/w (WLOGP) : | 1.3 |
Log Po/w (MLOGP) : | 0.51 |
Log Po/w (SILICOS-IT) : | 1.19 |
Consensus Log Po/w : | 1.21 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.16 |
Solubility : | 1.05 mg/ml ; 0.00691 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.47 |
Solubility : | 0.514 mg/ml ; 0.00338 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.57 |
Solubility : | 4.13 mg/ml ; 0.0272 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.04 |
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 |
---|---|---|
40% | at 20℃; | To a suspension of 2’,5’-dihydroxyacetophenone (100 mg, 0.66 mmol) and potassium carbonate (95 mg, 0.69 mmol) was added dimethyl sulfate (87 mg, 0.69 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure. The resultant residue was treated with 2N NaOH and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane-EtOAc (10:1) to give 2’-hydroxy-5’-methoxyacetophenone in 40percent yield as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 11.9 (s, 1H), 7.18 (d, J = 2.8 Hz, 1H), 7.12 (dd, J = 8.8, 2.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 2.63 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 18-crown-6 ether; potassium carbonate; potassium iodide In toluene at 115℃; for 14 h; | The second alternate way consists in making at first the protection of the OH function with a benzylic group by involving the same conditions as for the previous O-alkylation reaction to furnish the acetophenone derivative (1-6) in a very good yield (95percent). To form the product (1- 7), beforehand synthesized by the other methodology, acetophenone derivative (1-6) was submitted to VilsmeierHaack reaction using standard conditions (70percent). Knoevenagel condensation of the resulting product (1-7) with diethyl malonate provided in an ultimate stage the expected diester (1-8) in high yield (94percent). In view of these results (Scheme 2), we can notice that in priori both ways can be used to synthesize the intermediate (1-7) in an overall yield of 42percent and 66percent, respectively, from the dihydroxy-acetophenone (1-4) as the raw material; with however the second way more effective in term of yield. |
75.6% | With potassium carbonate In 4-methyl-2-pentanone at 60℃; for 20 h; | 1-[2-hydroxy-5-(phenylmethoxy)-phenyl]-ethanone: 20 kg (131.4 mol) 2-acetyl-hydroquinone 6a are dissolved in 150 l methylisobutylketone and combined with 19.98 kg (144.6 mol) potassium carbonate. At 60° C., 22.48 kg (131.5 mol) benzyl bromide are added. The reaction mixture is stirred for 20 hours at 60° C. The reaction mixture is cooled to 25° C. and the solid is filtered off. The filtrate is washed twice with a solution of 0.96 kg (11.8 mol) sodium hydroxide solution (50percent) and 60 l water at 25° C. The methylisobutylketone is largely distilled off in vacuo, and the residue is dissolved in 80 l methanol at 60° C. The solution is cooled to 0° C. and stirred for 1 hour at this temperature to complete the crystallisation. Yield (5a): 24.07 kg (75.6percent), chemical purity according to HPLC: 99.2percent. |
75.6% | With potassium carbonate In 4-methyl-2-pentanone at 60℃; for 20 h; Industry scale | 1-[2-hydroxy-5-(phenylmethoxy)-phenyl]-ethanone: 20 kg (131.4 mol) 2-acetyl-hydroquinone 6a are dissolved in 150 L methylisobutylketone and combined with 19.98 kg (144.6 mol) potassium carbonate. At 60° C., 22.48 kg (131.5 mol) benzyl bromide are added. The reaction mixture is stirred for 20 hours at 60° C. The reaction mixture is cooled to 25° C. and the solid is filtered off. The filtrate is washed twice with a solution of 0.96 kg (11.8 mol) sodium hydroxide solution (50percent) and 60 L water at 25° C. The methylisobutylketone is substantially distilled off in vacuo, and the residue is dissolved in 80 L methanol at 60° C. The solution is cooled to 0° C. and stirred for 1 hour at this temperature to complete the crystallisation.Yield (5a): 24.07 kg (75.6percent), chemical purity according to HPLC: 99.2percent. |
82% | With potassium carbonate In acetone | EXAMPLE 9 Stage A: 5-Benzyloxy-2-hydroxyacetophenone A mixture of 2,5-dihydroxyacetophenone (6.10 g = 40 mM), benzyl bromide (5 ml = 42 mM) and anhydrous potassium carbonate (5,6 g = 40 mM in anhydrous acetone (120 ml)) is heated under reflux for 5 hours. Then, the mixture is concentrated under reduced pressure, the residue is taken up with 1N HCl (120 ml) and extracted with ethyl ether. The combined extracts are washed with water and with a saturated ammonium sulfate solution, anhydrated (Na2SO4) and concentrated to give a crude solid compound that is then purified by flash-chromatography (4:1, n-hexane: ethyl acetate as the eluent) to give 8 g (82percent) of a yellow solid, m.p. 63-65°C. |
49 g | With potassium carbonate In acetone for 16 h; Reflux | 1000 ml three-neck bottle , the compound 1 - 4 (44 g, 290 mmol), potassium carbonate (44 g, 319 mmol) dissolved in acetone (750 ml), heated to 60 °C, continue adding benzyl bromide (57.7 g, 304.5 mmol), reflux reaction 16 h. Cooling the reaction liquid to room temperature, the solid in filtering system, concentrated, continue adding ethyl acetate (400 ml), sequentially for cold aqueous solution of sodium hydroxide (1 M, 50 ml), water (200 ml) and saturated salt water (200 ml).The organic phase drying, filtering, concentrated and methanol recrystallization to obtain a yellow solid product 49 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.3% | With potassium iodide In acetone for 6 h; Reflux | 2 ', 5'-hydroxyacetophenone (7.60g, 0.05mol),Anhydrous potassium carbonate (8.00g, 0.06 mol),Potassium iodide (1.00g, 0.006mol),100mL of acetone is placed in a 250mL eggplant-shaped bottle.Stir at room temperature.Benzyl chloride (7.87 g, 0.06 mol) was diluted with 10 mL of acetone and dropped into the reaction solution at a constant rate. The addition was completed in about 10 minutes. The reaction was heated at reflux for 6 h and the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature and the organic solvent was distilled off under reduced pressure to give yellow crystals.Recrystallization from 50 mL of ethanol gave 9.84 g of yellow crystals with a yield of 81.3percent. |
81.3% | With potassium carbonate; potassium iodide In acetone for 6 h; Reflux | The 2',5'-dihydroxyacetophenone(7.60g, 0.05mol),Anhydrous potassium carbonate (8.00g, 0.06mol), potassium iodide (1.00g, 0.006mol),100 mL of acetone was placed in a 250 mL eggplant-shaped flask and stirred at room temperature.Benzyl chloride (7.87g, 0.06mol) was diluted with 10mL of acetone and dropped into the reaction solution at a constant rate.About 10 minutes after the completion of the drop. The reaction was heated at reflux for 6 h and the reaction was monitored by TLC.After the reaction was completed, it was cooled to room temperature and the organic solvent was distilled off under reduced pressure to give yellow crystals.Recrystallization from 50 mL of ethanol gave 9.84 g of yellow crystals with a yield of 81.3percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | for 0.116667h; microwave irradiation; | |
85% | Stage #1: benzene-1,4-diyl diacetate With aluminum (III) chloride; sodium chloride at 140 - 195℃; for 0.15h; Stage #2: With hydrogenchloride; water for 0.5h; Reflux; | |
76.6% | Stage #1: benzene-1,4-diyl diacetate With aluminum (III) chloride; sodium chloride at 180℃; for 3h; Stage #2: With hydrogenchloride In methanol Reflux; | 4.1.3. 2',5'-Dihydroxyacetophenone (3) A mixture of 1,4-diacetoxybenzene (2) (10.0 g, 51.1 mmol), NaCl (10 g) and anhydrous aluminum chloride (15.0 g, 0.112 mol) was heated for 3 h at 180 °C in an oil bath. The reaction mixture was cooled to room temperature and then was added 15 mL of concentrated hydrochloric acid and 200 mL of ice water to produce a precipitate. The precipitate was collected, washed with water, and dried. Then the dark product was stirred for 1 h with 4 mL of hydrogen chloride in 100 mL of methanol. The resulting solution was poured, with stirring, into ice water, the solid was filtered, and washed with water. The crude product was recrystallized from ethanol to give a dark-green crystal of 6.0 g of 2',5'-dihydroxyacetophenone (3) with a yield of 76.6%, mp 198-200 °C. MS (EI): m/z = 152. |
64% | With aluminum (III) chloride at 110 - 165℃; for 3.5h; | |
60% | With aluminum (III) chloride at 110 - 165℃; for 3.5h; | |
54.4% | With aluminium trichloride at 180℃; for 3h; | |
50% | With hydrogen fluoride supported on silica gel In neat (no solvent) at 55℃; for 4h; Green chemistry; | 3.4. General Procedure for Synthesis of Hydroxyaryl Ketones General procedure: A mixture of aryl ester (25 mmol), HFSiO2 (2 g), and EtOAc (5 mL) was charged in a 50 ml flask and stirred for 5min. EtOAc was used for homogenization of the reactionmixture in this step. The solvent was evaporated under vacuumand the residue was heated with the classical method for 4 h at 55°C for aryl acetates and at 75°C for aryl benzoates(Table 1). After cooling, the reaction mixture was extractedwith EtOAc (3 × 10 mL) and the solvent was removed under vacuum. The residue was subjected to short column chromatography (EtOAc/hexane; 1:5) on silica gel to obtain pureproducts. All the isolated hydroxyaryl ketones successfullygave the related spectral data of IR, 1H NMR, 13C NMR andMS spectrometers (see the Supporting Information, Fig. 12S-39S) and comparison with authentic samples prepared byreported methods [33-36]. |
With aluminium trichloride at 165℃; | ||
With aluminium trichloride at 135℃; dann auf 160grad; | ||
Fries rearrangement; | ||
With aluminium trichloride | ||
With aluminum (III) chloride Heating; | ||
With aluminum (III) chloride | ||
With Fluoro Flash In neat (no solvent) at 80℃; for 4h; Green chemistry; | 4.2 General procedure for Fries rearrangement and catalyst preparation General procedure: Catalyst (FSG) was purchased from Fluorous Technologies Inc. and used without further purification. Its synthesis procedure is reported by Curran et al. [24]. General procedure for Fries rearrangement was done by adding FSG to aryl ester at the ambient temperatures. Before adding FSG to reaction mixture, aryl esters were obtained by in situ formation through the reaction of acyl chloride derivatives and phenol derivatives. Thus, to a 100ml round bottom flask stirring by a magnetic bar 10mmol of phenols was added and then, 10mmol of acyl chloride derivatives (for catechols 20mmol) was added dropwise and allowed to react at room temperature. After 30min, temperature was raised to remove HCl from reaction mixture. Then 1g of FSG was added to reaction mixture at ambient temperature. After 4h heating at appropriate temperature in oil bath, the reaction mixture was cooled to room temperature and washed with dichloromethane. The catalyst was separated by filtration. The solvent was removed by rotary evaporator and resulting mixture was separated by column chromatography (stationary phase: silica-gel, eluent:hexane:ethyl acetate) and purified by recrystallization. All isolated products successfully gave related spectral data of IR, NMR, and mass spectrometers. | |
With aluminum (III) chloride at 160 - 165℃; | ||
With aluminum (III) chloride at 160 - 165℃; | ||
21 g | With zinc(II) chloride In dichloromethane for 16h; Reflux; | 1.2 2) Synthesis of 1- (2,5-dihydroxyphenyl) ethanone 60 g of phenylethyl acetate was added to 550 ml of methylene chloride, followed by addition of 27 g of zinc chloride. The mixture was heated under reflux for 16 hours, cooled to room temperature, and the reaction solution was slowly poured into water. The extract was separated and the organic phase was collected , Dried, concentrated, and the residue was separated on a silica gel column to give 21 g of 1- (2,5-dihydroxyphenyl) ethanone |
With aluminum (III) chloride Heating; | ||
With aluminum (III) chloride | ||
With aluminum (III) chloride Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminium trichloride at 190 - 200℃; | ||
Stage #1: benzene-1,4-diyl diacetate With aluminium trichloride; sodium chloride at 195℃; for 0.15h; Stage #2: With hydrogenchloride In water for 12h; Further stages. Title compound not separated from byproducts.; | ||
Stage #1: benzene-1,4-diyl diacetate With aluminum (III) chloride; sodium chloride at 140 - 195℃; for 0.15h; Stage #2: With hydrogenchloride; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 2,5-Dihydroxyacetophenone With lithium hydroxide monohydrate In methanol at 5℃; for 0.166667h; Stage #2: benzaldehyde In methanol at 20℃; for 144h; | General procedures for synthesis of flavanones General procedure: Flavanone (1) and 6-hydroxyflavanone (2) were synthesized as previously described by Zeraik et al. [17], withminor modifications. In a 30-mL vial, the appropriated acetophenone (2.5 mmol) and lithium hydroxide monohydrate (0.5 mmol) were dissolved in methanol (10 mL), andthe mixture was stirred at 5 C for 10 min followed by the addition of benzaldehyde (2.70 mmol). The reaction mixture was stirred at room temperature and monitored byTLC using hexanes/ethyl acetate (9:1) as the mobile phase.The reaction was quenched after 6 days by pouring into100 mL of stirring ice cold water, and a stick mass was observed in the aqueous solution after quenching. Thus, theproduct was extracted by ethyl acetate (3 9 100 mL),dried over sodium sulfate and concentrated under reduced pressure. The crude products were purified by flash chromatographyusing hexanes/ethyl acetate as the solvent system in increasing the order of polarity. (±)-Flavanone(1) and its hydroxylated derivative (2) were identified by1H and 13C NMR spectra data obtained from a VarianDRX-500 spectrometer (11.7 T). Chemical shifts (d) wereexpressed in ppm. Coupling constants (J) were expressedin Hz, and splitting patterns are described as follows:s = singlet; d = doublet; m = multiplet; dd = doublet ofdoublets (Fig. 1). |
With potassium hydroxide (+-)-6-hydroxy-2-phenyl-chroman-4-one; | ||
4.3 g | With potassium hydroxide In methanol; water at 20℃; for 72h; | Synthesis of 9A, 9B, 9C; general procedure Method (c2) General procedure: A mixture of compound 7 (0.02 mol) and compound 8 (0.022 mol) were dissolved in methanol (20 mL), and 40% aqueous KOH (100 mL) was added dropwise at approximately 0 °C. The solution was vigorously stirred for 72 h at room temperature. Then the reaction mixture was neutralised to pH 5 with 37% aqueous HCl. The precipitate was filtered off, washed with water and recrystallised from ethanol to give compound 9. 6-Hydroxyflavanone (9A): White solid (4.3 g), yield: 89%, m.p.214-215 °C (lit.28 213-214 °C) 1H NMR (500 MHz, DMSO-d6) (δ,ppm): 7.49-7.31 (m, 5H, ArH), 7.09-6.51 (m, 3H, ArH), 5.43 (dd, 1H,CH), 4.96 (s, 1H, OH), 3.07 (dd, 1H, CH2), 2.87 (dd, 1H, CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.3% | With potassium iodide; In acetone; for 6h;Reflux; | 2 ', 5'-hydroxyacetophenone (7.60g, 0.05mol),Anhydrous potassium carbonate (8.00g, 0.06 mol),Potassium iodide (1.00g, 0.006mol),100mL of acetone is placed in a 250mL eggplant-shaped bottle.Stir at room temperature.Benzyl chloride (7.87 g, 0.06 mol) was diluted with 10 mL of acetone and dropped into the reaction solution at a constant rate. The addition was completed in about 10 minutes. The reaction was heated at reflux for 6 h and the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature and the organic solvent was distilled off under reduced pressure to give yellow crystals.Recrystallization from 50 mL of ethanol gave 9.84 g of yellow crystals with a yield of 81.3%. |
81.3% | With potassium carbonate; potassium iodide; In acetone; for 6h;Reflux; | The 2',5'-dihydroxyacetophenone(7.60g, 0.05mol),Anhydrous potassium carbonate (8.00g, 0.06mol), potassium iodide (1.00g, 0.006mol),100 mL of acetone was placed in a 250 mL eggplant-shaped flask and stirred at room temperature.Benzyl chloride (7.87g, 0.06mol) was diluted with 10mL of acetone and dropped into the reaction solution at a constant rate.About 10 minutes after the completion of the drop. The reaction was heated at reflux for 6 h and the reaction was monitored by TLC.After the reaction was completed, it was cooled to room temperature and the organic solvent was distilled off under reduced pressure to give yellow crystals.Recrystallization from 50 mL of ethanol gave 9.84 g of yellow crystals with a yield of 81.3% |
80.7% | With potassium carbonate; In acetone; at 56 - 60℃; for 5h; | General procedure: In a 250 ml round-bottomed flask were placed 2?,4?-dihydroxyacetophenone or 2?,5?-dihydroxyacetophenone (0.10 mol), benzylchloride(0.105 mol), potassium iodide (0.01 mol), anhydrous potassium carbonate (1 mol) and 100 ml dry acetone. The mixture was refluxed for 5 h at 56-60 C in oil bath. After reaction was finished, the reaction liquid was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain the crude. The solid was recrystallized from 100 ml ethanol to obtain 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.6% | With potassium carbonate In hexane; water; ethyl acetate; N,N-dimethyl-formamide | 259 1-[2',5'-bis(phenylmethoxy)phenyl]ethanone (Compound 259) Example 259 1-[2',5'-bis(phenylmethoxy)phenyl]ethanone (Compound 259) 15 g (9.86*10-2 mol) of 2',5'-dihydroxyacetophenone was dissolved in 150 ml of DMF, into which 32.71 g (2.37*101 mol) of potassium carbonate and 29.96 g (2.37*10-1 mol) of benzylchloride were added, and the mixture was refluxed for three hours. Following this, water was added and extraction was carried out with benzene. After removal of the solvent under reduced pressure, recrystallization of the residue was carried out using ethyl acetate/n-hexane, and 28.11 g (yield=87.6%) of the desired compound 259 was obtained. 1 H-NMR (CDCl3, δ-TMS) 7.30~7.60 (m, 13H), 5.10 (s,2H), 5.01 (s,2H), 2.58 (s, 3H) |
75% | With potassium carbonate In ethanol for 18h; Heating; | |
With potassium carbonate; acetophenone at 140 - 150℃; |
With potassium carbonate In butanone for 5h; Heating / reflux; | 4.a Example 4. Intermediate; 2-(2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-nitropyridine; a) 1-[2,5-Bis(benzyloxy) phenyl]ethanone A mixture of 1- (2, 5-dihydroxyphenyl) ethanone (3.16 g), benzyl chloride (7.04 g), potassium carbonate (12.4 g) and 18-Crown-6 (30 mg) in 2-butanone (50 ml) was heated under reflux for 5 hrs. After cooling the precipitate was filtered off. The filtrate was evaporated to dryness under reduced pressure and ether (50 ml) was added to it. The solution was washed twice with dilute sodium hydroxide solution, twice with dilute hydrochloric acid, dried over sodium sulphate and substantially evaporated to dryness under reduced pressure. The residue was triturated with cold n- heptane (30 ml), and the precipitate was filtered off with suction filtration giving after drying 2.85 g of 1- [2, 5-bis (benzyloxy) phenyl] ETHANONE. 1H NMR (400 MHz, DMSO-d6) 5 : 2.50 (s, 3H), 5.08 (s, 2H), 5.18 (s, 2H), 7.20-7. 50 (m, 13H). | |
With 18-crown-6 ether; potassium carbonate In butanone for 5h; Heating / reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With phosgene In ethanol at 20℃; for 6h; | |
With potassium hydroxide; ethanol | ||
With thionyl chloride In ethanol at 20℃; for 6h; | 3.2. General Procedure for the Synthesis of Compounds 1-3 General procedure: To a stirred mixture of 20,50-dihydroxyacetophenone (0.30 g, 1.97 mmol) and the appropriatealdehydes (1 eq.) in absolute ethanol (2 mL), thionyl chloride (120 μL) was added dropwise over 5 min.The reaction was stirred at room temperature for 6 h. Ethanol and excess of thionyl chloride were removed under reduced pressure on a rotary evaporator. Column chromatography was carried out topurify the desired product (eluent system: cyclohexane/ethyl acetate 9.8/0.2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate In acetone for 18h; Heating; | |
86% | With potassium carbonate; sodium iodide In acetone for 15h; Heating; | |
86% | With potassium carbonate In acetone for 18h; Inert atmosphere; Reflux; | 3.2. 1-(5-Allyloxy-2-hydroxyphenyl)ethanone 2,5-Dihydroxyacetophenone (8.00 g, 52.6 mmol) was dissolved in Me2CO (300 mL) in a round-bottom flask (500 mL) equipped with a reflux condenser and a magnetic stirrer bar. Allyl bromide (8.28 g, 68.4 mmol) and anhydrous K2CO3 (9.45 g, 68.4 mmol) were added to the solution, which was then heated at reflux for 18 h under a N2(g) atmosphere. The mixture was then allowed to cool to rt, filtered through a bed of Celite, and the solvent was removed in vacuo. The residue was purified by column chromatography (20% EtOAc/hexane) to afford 1-(5-allyloxy-2-hydroxyphenyl)ethanone (8.69 g, 86%) as a yellow crystalline solid; Rf=0.79 (20% EtOAc/hexane); mp=60-61 °C; 1H NMR (300 MHz, CDCl3) δH=11.84 (1H, s, OH), 7.16 (1H, d, J 3.0, H-6'), 7.08 (1H, dd, J 9.0, 3.0, H-4'), 6.86 (1H, d, J 9.0, H-3'), 6.02 (1H, ddt, J 17.2, 10.5, 5.3, OCH2CHCH2), 5.38 (1H, dt, J 17.2, 3.6, one of OCH2CHCH2), 5.28 (1H, dd, J 10.5, 1.3, one of OCH2CHCH2), 4.47 (2H, dt, J 5.3, 1.3, OCH2CHCH2), 2.56 (3H, s, COCH3); 13C NMR (75 MHz, CDCl3) δC=204.0 (CO), 156.8, 150.6, 133.1 (OCH2CHCH2), 124.9 (C-3'), 119.2, 119.1 (C-6'), 117.8 (OCH2CHCH2), 114.9 (C-4'), 69.8 (OCH2CHCH2), 26.6 (COCH3).12 The spectroscopic data agreed with that reported in the literature. |
52% | With potassium carbonate In butanone for 72h; Heating; | |
With potassium carbonate; acetone | ||
11.2 gm (97%) | With potassium carbonate In hexane; ethyl acetate; acetone | 10.a (a) (a) Preparation of 2-hydroxy-5-allyloxyacetophenone A mixture of 2,5-dihydroxyacetophenone (7.6 gm; 50mmoles), potassium carbonate (6.9 gm; 50 mmoles) and allyl bromide (6.0 gm; 50mmoles) in acetone (100 mL) was refluxed for a period of 18 hours. The reaction mixture was cooled, filtered through Celite (diatomaceous earth) and concentrated in vacuo. The residue was chromatographed on silica gel using 20% ethylacetate in hexane as eluent to yield 11.2 gm (97%) of 2-hydroxy-5-allyloxyacetophenone, mp. 51°-53° C. 1 H NMR 2.60 (s, 3H, CH3), 4.52 (d,J=6Hz, 2H,OCH2), 5.30 (m, 1H, CH), 6.00 (m, 2H, CH2, 6.83 (d, J=9 Hz, 1H, proton ortho to hydroxyl), 7.13 (m, 2H, proton ortho to allyloxy). Anal. Calcd for C11 H12 O3: C, 68.75; H, 6.25. Found: C, 68.74: H, 6.53. |
With potassium carbonate In acetone Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminium trichloride; 1,2-dichloro-benzene at 130 - 150℃; | ||
With aluminium trichloride; nitrobenzene at 45 - 95℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate; at 20℃; | To a suspension of 2?,5?-dihydroxyacetophenone (100 mg, 0.66 mmol) and potassium carbonate (95 mg, 0.69 mmol) was added dimethyl sulfate (87 mg, 0.69 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure. The resultant residue was treated with 2N NaOH and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane-EtOAc (10:1) to give 2?-hydroxy-5?-methoxyacetophenone in 40% yield as a colorless oil. 1H NMR (400 MHz, CDCl3): delta 11.9 (s, 1H), 7.18 (d, J = 2.8 Hz, 1H), 7.12 (dd, J = 8.8, 2.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 2.63 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With manganese(IV) oxide In dichloromethane for 0.25h; Ambient temperature; | |
88% | With oxygen In chloroform; lithium hydroxide monohydrate at 20℃; for 6h; | |
84% | With ammonium hexanitratocerate(IV); mesoporous silica In dichloromethane for 0.25h; |
70% | With oxygen; mesoporous silica In dichloromethane at 25℃; for 10h; | 3.3. General Procedure for P1/Silica-gel Combined Catalyst Catalyzed Aerobic Oxidation of Various Dihydroxy Arenes General procedure: In a two-neck 100 ml round bottomed flask connected tomolecular oxygen balloon (1.0 atm) and containing dihydroxyarene (0.1 mmol), P1 (100 mg, 0.1 mmol/g loading)and 250 mg silica-gel, a 3.0 mL of CH2Cl2 was injected and the reaction mixture was stirred at room temperature and followed by TLC until the starting material had completely converted to quinone. The quinone product was extracted with CH2Cl2 or ether and was obtained under reduced pressure.The further purification of most of the quinone product was not necessary. The P1/silica-gel combined catalyst was washed several times with ether or CH2Cl2 until it became completely clean and dried under vacuum to be ready for the next cycle. |
69% | With Sodium sulfate [anhydrous]; silver(I) oxide In toluene for 21h; | |
With silver(I) oxide | ||
With magnesium(II) sulfate; silver(I) oxide In benzene | ||
With manganese(IV) oxide | ||
With Sodium sulfate [anhydrous]; silver(I) oxide In diethyl ether for 3h; Ambient temperature; | ||
With silver(I) oxide | ||
With citrate-phosphate buffer; Myceliophthora thermophila fungal laccase; oxygen at 20℃; Enzymatic reaction; | ||
With manganese(IV) oxide; magnesium(II) sulfate In dichloromethane at 20℃; for 0.5h; | ||
With manganese(IV) oxide In dichloromethane at 20℃; | ||
With silver(I) oxide In dichloromethane | ||
With manganese(IV) oxide In benzene | ||
With silver(I) oxide | EXPERIMENTAL 2-Acetyl-1,4-benzoquinone was prepared via oxidation of 2,5-dihydroxyacetophenone by Ag2O [9].2-(Methoxycarbonyl)-1,4-benzoquinone was prepared in two steps from 2,5-dihydroxybenzoic acid (first, methylation bydiazomethane; second, oxidation by Ag2O [9]). Physicochemical data for the synthesized quinones agreed with those in theliterature. We used Pinus sylvestris pine tar containing ~30% levopimaric acid that was collected in spring 2012 near NizhniiNovgorod. The levopimaric acid content in the pine tar was determined using GC and the ratio of methyl esters of totalresinous acids that were produced by methylating pine tar with an excess of diazomethane. The product yields were calculatedper starting quinone. | |
With silver(I) oxide In dichloromethane | ||
With magnesium(II) sulfate; silver(I) oxide In dichloromethane at 20℃; for 0.5h; | Preparation of 3-Acyl-2,5-bis(phenylamino)-1,4-benzoquinones 2a-q, General Procedure. General procedure: Suspensions of the acylhydroquinones 1a-q (1 equiv.),Ag2O(2.0 equiv.) andMgSO4 anhydrous (300mg) in dichloromethane (30mL)were leftwith stirring for 30min at roomtemperature (rt). Themixtureswere filtered, the solidswerewashedwith dichloromethane (3 25mL), and the filtrateswere evaporatedunder reduced pressure. The residues were dissolved in ethanol, the phenylamines (2 equiv.) wereadded to the solutions, and the mixtures were left with stirring at rt for 24 h. The solvents were removedunder reduced pressure and the residues were column-chromatographed over silica gel (petroleumether/EtOAc) to yield the corresponding pure 3-acyl-2,5-bis(phenylamino)- 1,4-benzoquinones 2a-q. | |
With manganese(IV) oxide Inert atmosphere; | ||
With manganese(IV) oxide at 0℃; | 4.1. General procedure for the synthesis of 1-(indol-2-yl)-phenoxazine derivative. (1-14) General procedure: A suspension of quinacetophenone I (0.152 g,1 mmol) and MnO2(0.860 g, 10 mmol) is cooled in an ice bath to 0 °C under constantstirring. Anilines II (0.182 mL, 2.0 mmol) in anhydrous chloroformand triethylamine (0.068 mL, 0.5 mmol) were added and stirred atrt for 6 h. The mixture was filtered through celite. Removal of thesolvent under reduced pressure followed by column chromatography(5% EtOAc/Hexane) yielded pure 1-(indol-2-yl)-phenoxazines(PI) in moderate to good yields. 4.2. 1-(3H-indol-2-yl)-10H-phenoxazin-2-ol (1) Orange solid, Yield (45%), m. p. 165-167 °C, Rf 0.5 (30:70 Ethylacetate: Hexane);1H NMR (500 MHz, CDCl3): δ 8.19 (s, 1H),7.43-7.35 (m, 4H), 7.30-7.21 (m, 4H), 7.13 (d, J 7.5 Hz, 2H), 6.04 (s,1H), 2.65 (s, 2H). 13C NMR (125 MHz, CDCl3): δ 178.58, 177.88,146.43, 139.22, 137.06, 129.71, 129.05, 127.05, 126.17, 124.28, 122.79,107.80, 99.14, 32.61. IR (neat, cm-1): 3291, 3046, 2804, 1649, 1626,1615, 1509, 1233, 1156. HRMS m/z calculated for C20H14N2O3[M H2O H] : 333.1239 found: 333.1238. | |
With silver(I) oxide In dichloromethane at 20℃; | Procedure to synthesize naphthalenones 1-3 A mixture of acetyl hydroquinone (1 equiv) and Ag2O (2.5 equiv) in 20-30 mL of dichloromethane was vigorously stirred by 1-2 h. at RT, yielding the corresponding quinone. This mixture was filtered through celite, and added dropwise, to a solution of the corresponding enamine at 0°C, and was allowed to reach rt in a time of 30-60 min, being monitored by thin-layer chromatography. Then, the solvent is evaporated under reduced pressure. The residue was dissolved in a mixture of ethanol and hydrochloric acid and refluxed by 3 h. After was poured on ice/water mixture. The product was filtered, dried and purified by flash chromatography with 6:1 hexane/ethyl acetate as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; | |
91% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 4h; | Protection of the phenolic group General procedure: The appropriate dihydroxyacetophenones (3.0 equiv.) were dissolved in dichloromethane and stirred at room temperature. Pyridinium p-toluene sulfonate was added followed by the dropwise addition of 3,4-dihydro-2H-pyran (3.0 equiv.) in dichloromethane. The reaction mixture was stirred at room temperature for 4 hours. For work up, the reaction mixture was washed with saturated aqueous sodium bicarbonate and extracted thrice with dichloromethane. The organic fractions were combined and dried using anhydrous sodium sulphate, evaporated in vacuo and purified using flash chromatography eluting with n-hexanes and ethyl acetate to yield the pure intermediates I and II 1-(2-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)phenyl)ethanone (II) Colourless oil (353 mg, 91 %) Rf (EtOAc: Hexane 1:4) 0.52 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 2.9 Hz, 1H, H-6’), 7.23 (dd, J = 9.0, 2.9 Hz, 1H, H-4’), 6.89 (d, J = 9.0 Hz, 1H, H-3’), 5.29 (t, J = 3.2 Hz, 1H, H-2”), 3.96 - 3.86 (m, 1H, H-6”), 3.64 - 3.56 (m, 1H, H-6”), 2.59 (s, 3H, CH3), 2.04 - 1.90 (m, 1H, THP-H), 1.86 (m, 1H, THP-H), 1.73 - 1.55 (m, 4H, THP-H). 13C NMR (101 MHz, CDCl3) δ 203.8, 157.5, 148.9, 126.7, 119.3, 119.0, 117.6, 97.7, 62.1, 30.5, 26.7, 25.2, 18.8 |
87% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 5h; | 5.5.1 1-(2-Hydroxy-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (14) Compound 9 (3mmol, 456mg) was dissolved in dichloromethane (15mL) and stirred at room temperature. Pyridinium p-toluene sulfonate (1mmol, 251mg) was added followed by the dropwise addition of 3,4-dihydro-2H-pyran (3mmol, 273μL) in dichloromethane (2mL). The reaction mixture was stirred at room temperature for 5h. The reaction mixture was washed with saturated aqueous sodium bicarbonate and extracted with dichloromethane (15mL×3). The organic fractions were combined and dried over anhydrous sodium sulfate, evaporated in vacuo, and purified by flash chromatography eluting with n-hexanes and ethyl acetate to yield compound 14 (yellow oil, 584mg, 87%). 1H NMR (500MHz, CDCl3) δ 11.89 (s, 1H), 7.41 (s, 1H), 7.24 (s, 1H), 6.91 (d, J=9.0Hz, 1H), 5.31 (s, 1H), 3.93 (t, J=11.0Hz, 1H), 3.62 (d, J=11.0Hz, 1H), 2.61 (s, 3H), 1.86-1.55 (m, 6H). |
83% | With pyridinium p-toluenesulfonate In dichloromethane for 1.5h; Heating; | |
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; | ||
With toluene-4-sulfonic acid | 20.1 Step 1: Step 1: Preparation of 2-hydroxy-5-(tetrahydropyran-2-yloxy)acetophenone 14.89 g of 2,5-dihydroxy acetophenone, 25.18 g of dihydropyran and 100 mg of p-toluenesulfonic acid are stirred together at room temperature overnight. The resulting mixture is dissolved in 1 1 of ether and the ether solution washed with sodium bicarbonate solution, water and brine, then dried over sodium sulfate and concentrated in vacuo to give 2-hydroxy-5-(tetrahydropyran-2-yloxy)acetophenone as an oil, which is used directly in the next step. | |
With toluene-4-sulfonic acid | 20.1 Step 1 Step 1 Preparation of 2-hydroxy-5-(tetrahydropyran-2-yloxy)acetophenone 14.89g of 2,5-dihydroxy acetophenone, 25.18g of dihydropyran and 100 mg of p-toluenesulfonic acid are stirred together at room temperature overnight. The resulting mixture is dissolved in 1 1 of ether and the ether solution washed with sodium bicarbonate solution, water and brine, then dried over sodium sulfate and concentrated in vacuo to give 2-hydroxy-5-(tetrahydropyran-2-yloxy)acetophenone as an oil, which is used directly in the next step. | |
With toluene-4-sulfonic acid In 1,4-dioxane at 20℃; for 19h; | 119.1 (1) 1-[2-Hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)phenyl]ethanone 2',5'-Dihydroxyacetophenone (5 g) was dissolved in 1,4-dioxane (100 mL) in a nitrogen atmosphere. p-Toluenesulfonic acid monohydrate (70 mg) and 3,4-dihydro-2H-pyrane (6 mL) were sequentially added to the solution, and the mixture was stirred at room temperature for 15 hours. p-Toluenesulfonic acid monohydrate (70 mg) and 3,4-dihydro-2H-pyrane (1 mL) were further added to the mixture, followed by stirring at room temperature for four hours. Concentrated aqueous ammonia was added to the reaction mixture under ice-cooling and then water was added, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried over magnesium sulfate. The drying agent was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to obtain the title compound (7.47 g). 1H-NMR (400 MHz, CDCl3) δ(ppm): 1.52-1.76 (m, 3H), 1.82-2.05 (m, 3H), 2.61 (s, 3H), 3.58-3.65 (m, 1H), 3.88-3.96 (m, 1H), 5.30 (dd, J=3.2 Hz, 3.2 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 7.23 (dd, J=2.8 Hz, 8.8 Hz, 1H), 7.40 (d, J=2. Hz, 1H), 11.88 (s, 1H). | |
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; | 31.1 Step 1. l-(2-Hydroxy-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone Step 2: Selecti -protection of phenol(s) z = 0 or 1 [00380] 3,4-Dihydro-2H-pyran (5.0 equiv) was added to a mixture of dihydroxyaryl ketone (1 equiv) and pyridinium -toluene sulfonate (0.20 equiv) in DCM (0.25M) at room temperature . The resulting mixture was stirred at this temperature for 2-24h. The mixture was washed with water, washed with saturated aqueous NaHC03, dried over Na2S04 (or MgSC^), filtered, and concentrated to afford the crude product. This crude product was then purified by silica gel chromatography to give the corresponding THP -protected hydroxyarylketone. Step 1. l-(2-Hydroxy-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone [00440] The title compound was prepared from l-(2,5-dihydroxyphenyl)ethanone following general procedure C, step 2. 1H NMR (400 MHz, DMSO-d6): δ 11.4 (s, 1H), 7.47 (d, 1H), 7.26 (dd, 1H), 6.90 (d, 1H), 5.40 (t, 1H), 3.79 (ddd, 1H), 3.55 (ddd, 1H), 2.62 (s, 3H), 1.90-1.70 (m, 3H), 1.65-1.50 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.2% | Stage #1: 2,5-Dihydroxyacetophenone With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 0.166667h; Stage #2: 3,4-dihydro-2<i>H</i>-pyran In dichloromethane at 20℃; | |
With pyridinium p-toluenesulfonate In dichloromethane Ambient temperature; | ||
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 4.5h; |
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 40h; | ||
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 4h; | ||
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 4h; | ||
With pyridium para-toluenesulfonate at 20℃; | ||
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 4h; | ||
Stage #1: 2,5-Dihydroxyacetophenone With pyridinium p-toluenesulfonate In dichloromethane for 0.5h; Stage #2: 3,4-dihydro-2<i>H</i>-pyran In dichloromethane at 20℃; for 4h; | i; 4.4A 3,4-Dichloro-2',5'-dihydroxychalcone (Compound 4) 2,5-Dihydroxyacetophenone (3.8 g, 25 mmol) and pyridinium P-toluenesulfonate (0.15 g, 0.6 mmol) were stirred in methylene chloride (80 ML) for 0.5 hr, and 3,4-dihydro-α-pyran in methylene chloride (13 ML in 20 ML) was then added dropwise.The resultant reaction mixture was stirred at room temperature for 4 hrs.Thereafter, the reaction mixture was washed twice with water, dried, and evaporated in vacuo.The obtained residue yielded crude 2',5'-bis(tetrahydropyran-2-yloxy)acetophenone (compound 4a), and a part of the crude compound 4a was eluted through a silica-gel column with n-hexane/CH2Cl2 (2:1) to give a product as a yellowish oil, which was identified with various spectral data and compared with those of authentic sample (i.e. compound (3a) reported in H. K. Hsieh et at. (1998), Pharm. Res., 15, 39-46). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: acetic anhydride; hydroquinone In 1,2-dichloro-ethane at 100℃; for 4h; Stage #2: With boron trifluoride diethyl etherate In 1,2-dichloro-ethane at 120℃; for 3h; | 2,5-Dihydroxyacetophenone (7) 1,4-Dihydroxybenzene (5.5 g, 0.05 mol) and dichloroethane (10 mL) were placed in a dry roundbottomed flask, then Ac2O (10 mL, 0.1 mol) was slowly added. The solution was stirred for 4 h at 100 °C until TLC showed that 1,4-dihydroxybenzene had disappeared. BF3-Et2O (9 mL, 0.07 mol) was then added dropwise and the reaction mixture was heated to 120 °C and stirred for another 2-3 h. H2O (40 mL) was then added andthe reaction mixture was extracted with ethyl acetate (50 mL × 2). The combined extracts were washed sequentially with H2O (100 mL × 2), saturated sodium bicarbonate (100 mL × 2) and H2O (100 mL × 1) and then dried with anhydrous sodium sulfate overnight. Removal of the solvent in vacuo to give a solid residue, which was recrystallised from ethanol to give compound 7 as yellow crystals (7.0 g), yield: 92%, m.p.195-198 °C (lit.27 197-199 °C) 1H NMR (500 MHz, DMSO-d6) (δ,ppm): 2.6 (s, 3H, CH3), 6.9 (s, 1H, OH), 7.2-7.3 (m, 3H, ArH), 11.8 (s, 1H, OH). |
76% | at 145 - 150℃; for 0.25h; | |
26.3% | With boron trifluoride diethyl etherate In ethyl acetate at 50℃; for 12h; | 4.2. General Procedure for Preparation of 2-Hydroxyacetophenone Derivatives (I) General procedure: The synthesis of 5-9 was conducted according to literature [9]. Thus, phenol derivatives(1-4) (13.2 mmol) dissolved in acetic anhydride (Ac2O) (3 mL, 30 mmol) were addedin ethyl acetate (AcOEt) (5 mL). Then, boron trifluoride-diethyl ether (BF3-Et2O, 800 L,6.4 mmol) was slowly added to the reaction mixtures, a reflux setup allowed the mixturesto be heated in a controlled manner at 50 °C for 12 h without the loss of solvent. Thework-up process was performed using 100 mL of water, neutralization with NaHCO3, andextraction with CH2Cl2 (3 x 100 mL). The organic phase was brought to dryness and theresulting solid was eluted on a silica gel 60 columns using hexane:ethyl acetate (Hex:AcOEt)(2:1) (v:v). The synthesis of 5-9 was achieved in an overall yield of 16.5-56%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 18-crown-6 ether; potassium carbonate; potassium iodide; In toluene; at 115℃; for 14h; | The second alternate way consists in making at first the protection of the OH function with a benzylic group by involving the same conditions as for the previous O-alkylation reaction to furnish the acetophenone derivative (1-6) in a very good yield (95%). To form the product (1- 7), beforehand synthesized by the other methodology, acetophenone derivative (1-6) was submitted to VilsmeierHaack reaction using standard conditions (70%). Knoevenagel condensation of the resulting product (1-7) with diethyl malonate provided in an ultimate stage the expected diester (1-8) in high yield (94%). In view of these results (Scheme 2), we can notice that in priori both ways can be used to synthesize the intermediate (1-7) in an overall yield of 42% and 66%, respectively, from the dihydroxy-acetophenone (1-4) as the raw material; with however the second way more effective in term of yield. |
88.3% | With sodium hydrogencarbonate; In ethanol; at 0 - 10℃; for 3.33333h; | [0168] 152 g (1.0 mol) of 2,5-dihydroxy acetophenone was added to a 1L three-necked flask. 400 mL of absolute ethanol was added, stirred for dissolution. 92.4 g (1.1 mol) of sodium bicarbonate was added at room temperature and stirred for 5 minutes. The temperature of the reaction mixture was kept at 0-10 C. 180 g (1.05 mol) of benzyl bromide was added dropwise, and the addition was completed within 20 minutes. At this temperature, the reaction was continued with stirring for 3 hours, and thin layer detection showed that the raw material 2,5-dihydroxyacetophenone was reacted completely. The solvent was removed under reduced pressure. The residue was dissolved with 400 mL of dichloromethane, and washed with saturated citric acid aqueous solution 3 times (3150 mL). The the dichloromethane solution was dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was removed by filtration. Dichloromethane was removed from the solution under reduced pressure. The residue was dissolved in 300 mL of absolute ethanol which is cooled and crystallized to obtain 213.7 g of 2-hydroxy-5-benzyloxy acetophenone as a white solid with a yield of 88.3%. The chemical purity was 99.0% (HPLC). |
75.6% | With potassium carbonate; In 4-methyl-2-pentanone; at 60℃; for 20h; | 1-[2-hydroxy-5-(phenylmethoxy)-phenyl]-ethanone: 20 kg (131.4 mol) 2-acetyl-hydroquinone 6a are dissolved in 150 l methylisobutylketone and combined with 19.98 kg (144.6 mol) potassium carbonate. At 60 C., 22.48 kg (131.5 mol) benzyl bromide are added. The reaction mixture is stirred for 20 hours at 60 C. The reaction mixture is cooled to 25 C. and the solid is filtered off. The filtrate is washed twice with a solution of 0.96 kg (11.8 mol) sodium hydroxide solution (50%) and 60 l water at 25 C. The methylisobutylketone is largely distilled off in vacuo, and the residue is dissolved in 80 l methanol at 60 C. The solution is cooled to 0 C. and stirred for 1 hour at this temperature to complete the crystallisation. Yield (5a): 24.07 kg (75.6%), chemical purity according to HPLC: 99.2%. |
75.6% | With potassium carbonate; In 4-methyl-2-pentanone; at 60℃; for 20h;Industry scale; | 1-[2-hydroxy-5-(phenylmethoxy)-phenyl]-ethanone: 20 kg (131.4 mol) 2-acetyl-hydroquinone 6a are dissolved in 150 L methylisobutylketone and combined with 19.98 kg (144.6 mol) potassium carbonate. At 60 C., 22.48 kg (131.5 mol) benzyl bromide are added. The reaction mixture is stirred for 20 hours at 60 C. The reaction mixture is cooled to 25 C. and the solid is filtered off. The filtrate is washed twice with a solution of 0.96 kg (11.8 mol) sodium hydroxide solution (50%) and 60 L water at 25 C. The methylisobutylketone is substantially distilled off in vacuo, and the residue is dissolved in 80 L methanol at 60 C. The solution is cooled to 0 C. and stirred for 1 hour at this temperature to complete the crystallisation.Yield (5a): 24.07 kg (75.6%), chemical purity according to HPLC: 99.2%. |
8 g (82%) | With potassium carbonate; In acetone; | EXAMPLE 9 Stage A: 5-Benzyloxy-2-hydroxyacetophenone A mixture of 2,5-dihydroxyacetophenone (6.10 g = 40 mM), benzyl bromide (5 ml = 42 mM) and anhydrous potassium carbonate (5,6 g = 40 mM in anhydrous acetone (120 ml)) is heated under reflux for 5 hours. Then, the mixture is concentrated under reduced pressure, the residue is taken up with 1N HCl (120 ml) and extracted with ethyl ether. The combined extracts are washed with water and with a saturated ammonium sulfate solution, anhydrated (Na2SO4) and concentrated to give a crude solid compound that is then purified by flash-chromatography (4:1, n-hexane: ethyl acetate as the eluent) to give 8 g (82%) of a yellow solid, m.p. 63-65C. |
49 g | With potassium carbonate; In acetone; for 16h;Reflux; | 1000 ml three-neck bottle , the compound 1 - 4 (44 g, 290 mmol), potassium carbonate (44 g, 319 mmol) dissolved in acetone (750 ml), heated to 60 C, continue adding benzyl bromide (57.7 g, 304.5 mmol), reflux reaction 16 h. Cooling the reaction liquid to room temperature, the solid in filtering system, concentrated, continue adding ethyl acetate (400 ml), sequentially for cold aqueous solution of sodium hydroxide (1 M, 50 ml), water (200 ml) and saturated salt water (200 ml).The organic phase drying, filtering, concentrated and methanol recrystallization to obtain a yellow solid product 49 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In acetone for 18h; Heating; | |
94% | With potassium carbonate In acetone for 24h; Reflux; | |
93% | Stage #1: 2,5-Dihydroxyacetophenone In 1,2-dimethoxyethane at 80℃; Inert atmosphere; Stage #2: benzyl bromide In 1,2-dimethoxyethane; N,N-dimethyl-formamide for 12h; |
92% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 16 To a solution of 2,5-dihydroxyacetophenone (15.0 g, 98.59 mmol, 1 eq) in DMF (150 mL), potassium carbonate (40.88 g, 295.76 mmol, 3 eq) and benzyl bromide (32.5 mL, 295.76 mL, 3 eq) were added under argon at room temperature. The mixture was allowed to stir at room temperature overnight. The reaction mixture was poured with stirring onto chilled water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aq NaCl, dried over MgSO4, filtrated and concentrated under vacuum. The crude product purified by recrystallization in EtOH/ water (5:95) to afford 29.96 g (92%) of a cream solid 21a.Molecular Weight: 332.40 (C22H20O3).1H-NMR δ (CDCl3, 250 MHz) ppm (Jin Hz): 2.61 (s, 3H, CH3CO), 5.05 (s, 2H, CH2Ph), 5.12 (s, 2Η, CH2Ph), 6.96 (d, 1Η, J=9.0, Η-3'), 7.08 (dd, IH, J=3.2, 9.0, H-4'), 7.28-7.46 (m, HH, 2 x Ph, H-6'). |
88% | With potassium carbonate In acetone for 24h; Heating; | |
With potassium carbonate In dimethyl sulfoxide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In butanone for 16h; Heating; | ||
With potassium carbonate In dichloromethane; butanone | 11 2-Cyclopentyl-6-[6-(4-Hydroxypiperidyl)hexoxy1-4H-1-benzopyran-4-one hydrochloride EXAMPLE 11 2-Cyclopentyl-6-[6-(4-Hydroxypiperidyl)hexoxy1-4H-1-benzopyran-4-one hydrochloride A mixture of 2',5'-dihydroxyacetophenone (150 g), 1-bromo-6-chlorohexane (186 g), and potassium carbonate (186 g) in 2500 mL of 2-butanone was refluxed for 16 hours. The solvent was removed in vacuo and the residue was stirred with 1000 mL of methylene chloride. After filtration, the filtrate was washed with 10% KOH (250 mL), water (250 mL), and brine (250 mL). The solution was dried over magnesium sulfate and the solvent was removed to give an oil which solidified overnight to give 210 g of 5'-(6-chlorohexoxy)-2'-hydroxyacetophenone as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With pyrrolidine; 3 A molecular sieve In ethanol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 89% 2: 9% | With boron trifluoride for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 35% 2: 40% | With boron trifluoride diethyl etherate In benzene for 0.5h; microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 20% 2: 50% | With boron trifluoride diethyl etherate In benzene for 0.5h; microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 35% 2: 45% | With boron trifluoride diethyl etherate In benzene for 0.5h; microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 25% 2: 60% | With boron trifluoride diethyl etherate In benzene for 0.5h; microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With piperidine for 0.166667h; Neat (no solvent); Microwave irradiation; | |
82% | With pyrrolidine In acetonitrile at 45℃; for 8h; | |
81% | With Amberlite IRA 400 basic resin for 0.166667h; Microwave irradiation; Neat (no solvent); |
77% | With pyrrolidine In ethanol Reflux; | |
76% | With piperidine; pyridine for 96h; Heating / reflux; | 2 Example 2; Preparation of 6-Hydroxy-2, 2-dimethyl-chroman-4-one (3) To a 250 mL, 2-necked round bottom flask equipped with a magnetic stir bar and a WATER-JACKETED condenser capped with a balloon was added 2', 5'- dihydroxyacetophenone (2,8. 00 g, 52.6 MMOL), reagent grade acetone (19.45 mL, 263 MMOL), piperidine (5.2 mL, 52.6 MMOL) and freshly distilled pyridine (50 mL). The mixture was heated to a vigorous reflux with stirring under a nitrogen atmosphere for 2 d. The solvent was evaporated and the concentrate was dried under high vacuum. Reagent grade acetone (19.45 mL, 263 MMOL), piperidine (5.2 mL, 52.6 MMOL) and freshly distilled pyridine (50 mL) were added, and vigorous reflux with stirring under a nitrogen atmosphere was continued for 2d more. The solvent was evaporated, ethyl acetate (30 mL) and 30% aqueous CuS04 (30mL) were added to the concentrate. The organic phase was washed with brine (1X30 mL), dried over MGSO4, filtered, concentrated and dried under high vacuum. The dry crude product was passed through a silica gel column using 2: 1 HEXANES/ETHYL acetate as eluent (RF= 0. 3). The product gives off a purple color on an analytical silica gel plate illuminated with a short wave UV lamp. The fractions containing the pure product were transferred to a pre-weighed flask, the solvent was evaporated and the concentrate was dried under high vacuum. The reaction furnished 7.65 g of 3 (76 %) as a brown SOLID. H NMR (300 MHZ, CDCI3) : 6 7.32 (m, 1 H), 7.04 (m, 1 H), 6.82 (m, 1 H), 5.48 (bs, 1 H), 2.68 (s, 2H), 1.42 (s, 6H). 13C NMR (75.5 MHZ, CDCI3) : No. 193.8, 154.4, 149.9, 125.2, 120.0, 119.6, 110.7, 79.0, 48.7, 26.5 ; HRMS (El+) : calculated for C,, [M+] m/z 192.0786, found 192. 0788. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With kiwi juice In water at 20℃; for 0.0833333h; Sonication; Green chemistry; | Coumarin-3-carboxylic andcinnamic acids synthesis. General procedure General procedure: 2-Hydroxybenzaldehyde (acetophenone, or benzaldehydes) (1.0 mmol) and Meldrum’s acid (1.01 mmol) were suspended in the aqueous medium (juice or waste water) (2 mL). The resulting mixture was subjected to ultrasound irradiation at room temperature for 5 min (15 min). The precipitate so formed was filtrated under vacuum. Structural assignments (NMR) was made by comparison of the recorded analytical data with those of commercially available sample or those already reported for the same compounds.2-6 The aqueous medium (juice or waste water) was recovered by filtration and re-used as such to perform further processes. |
83% | With lithium perchlorate for 0.0194444h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrogenchloride In ethanol for 12h; | |
65% | With toluene-4-sulfonic acid In benzene for 48h; Reflux; | General method for the synthesis of chalcones and flavanones General procedure: 2,5-Dihydroxyacetophenone (50 mg, 0.3 mmol) and nitrobenzaldehyde (45 mg, 0.3 mmol) were dissolved in hot dry benzene (20 mL). Then p-Toluene sulfonic acid (5 mg, 0.03 mmol) was added. The resulting reaction mixture was refluxed for 48 h.The reaction was monitored with TLC. After completion of the reaction, benzene was removed under vacuum and residue was purified on silica gel column using hexane-ethyl acetate (4:1) as eluent. In case of 3-nitrobenzaldehyde and 4-nitrobenzaldehyde, corresponding flavanones were also isolated along with chalcones. Whereas with 2-nitrobenzaldehyde only a novel chalcone (2a) was obtained. 2.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.1% | With N-ethyl-N,N-diisopropylamine In dichloromethane at -10 - 0℃; | 1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)ethanone, 9 General procedure: The starting material 2’4’6’-trihydroxyacetophenone trihydrate (930 mg, 5 mmol) was dissolved in DCM (20 mL), and MOMCl (0.94 mL, 12.5 mmol) was added at -10°C. After 10 mins stirring, DIEA (2.2mL, 12.5mmol) was added slowly and the suspension heated to 0°C. Saturated sodium bicarbonate (20 mL) was added to quench reaction after 1h. The dichloromethane layer was separated, then the aqueous phase was extracted with dichloromethane (20 mL). The organic phase was merged, then washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/acetone = 20:1) to give 9 as white solids (1.1 g, 85.9%). |
79% | With N-ethyl-N,N-diisopropylamine In dichloromethane for 4.5h; | General synthesis of compounds 12a-12d General procedure: To a solution of dihydroxyphenylacetaldehyde (350 mg, 2.30 mmol) in anhydrous dichloromethan (20 mL), Hünig’ base (0.76 mL, 4.60 mmol) and methoxylmethyl chloride (0.26 mL, 3.45mmol) were added at -10 °C. The solution was stirred for 4.5h at this temperature before it was diluted with 20 mL of ethyl acetate. Then reaction mixture was washed with saturated NaHCO3 (aq., 30 mL), H2O (30 mL) and saline (30 mL) subsequently. The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The crude products were then purified on silica gel columns to afford the products 12a-12d. |
72.8% | With N-ethyl-N,N-diisopropylamine In dichloromethane for 1h; Heating; |
66.5% | With potassium carbonate In acetone at 30℃; for 2h; | 4.1.4. 2'-Hydroxy-5'-(methoxymethoxy)acetophenone (4) To a mixture of 2',5'-dihydroxyacetophenone (3, 7.0 g, 46.05 mmol) and anhydrous K2CO3 (20 g) in dry acetone (100 mL) was added dropwise chloromethyl methyl ether (4 mL, 53.6 mmol). The mixture was heated for 2 h at 30 °C in an oil bath, cooled to room temperature, filtered, washed with acetone and the solvent wad evaporated. The resulting yellowish oil was purified using flash column chromatography (petroleum ether/ethyl acetate 9:1) to give 2'-hydroxy-5'-(methoxymethoxy)acetophenone (4) as a low melting white solid. Yield: 6.0 g (66.5%). |
61% | With potassium carbonate In acetone at 30℃; for 12.17h; | |
52% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | Gereral procedure for MOM protected acetophenones General procedure: To a solution of 2’,4’-dihydroxyacetophenone (150 mg, 0.99 mmol) in dichloromethane (1.7 mL) were added N,N-diisopropylethylamine (0.5 mL, 3.0 mmol) and chloromethyl methyl ether (0.075 mL, 1.0 mmol), and the mixture was stirred at room temperature. After the reaction was complete, the mixture wasextracted with chloroform. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane-EtOAc (5:1) to give 2’-hydroxy-4’-(methoxymethoxy)acetophenone1 (178 mg, 0.91 mmol) in 92% yield as a colorless solid. |
With potassium carbonate In acetone at 0 - 20℃; regioselective reaction; | ||
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | ||
With N-ethyl-N,N-diisopropylamine In dichloromethane at -10℃; for 4.5h; Inert atmosphere; | 1.1 (1) Preparation of 2-hydroxy-5-methoxymethoxymethoxy-acetophenone Under argon protection,2,5-dihydroxyacetophenone (350 mg, 2.30 mmol),Soluble in 20mL anhydrous dichloromethane,Cool to -10 ° C,DIEA (0.76 mL, 4.60 mmol) and MOMCl (0.26 mL, 3.45 mmol),Stir for 4.5 hours.Add 20 mL of ethyl acetate,Wash with 30 mL each of saturated sodium bicarbonate, water and saturated brine.The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1) LDA / 1) THF, HMPT 2: H+ | ||
In acetone; acetonitrile | 105.a 4-(N-Ethylsulfonyl-N-methyl)amino-6-methoxy-2,2-dimethylchroman a) 6-Hydroxy-2,2-dimethyl-4-chromanone is obtained analogously to the procedure indicated in Example 18 b) from 2,5-dihydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as solvent. Crystalline compound, melting point 147-149° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With sodium In ethanol at 20 - 80℃; for 12h; Inert atmosphere; | 27.1 Step 1: Synthesis of ethyl 6-hydroxy-4-oxo-4H-chromene-2-carboxylate (2) A solution of 1-(2,5-dihydroxyphenyl)ethan-1-one 1 (10 g, 65.79 mmol) in diethyloxalate (80 mL) was added to NaOEt solution (prepared by slow addition of Na metal (18.16 g, 789.47 mmol) in EtOH (500 mL)) at RT under argon. The reaction mixture was stirred and heated at 80 °C for 12 h. The mixture was cooled to RT then quenched with ice cold water (150 mL). The aqueous layer was acidified with 6 N HC1 solution (to pH 4) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in EtOH (500 mL) and 6 N HC1 (100 mL) was added at RT. The reaction mixture was refluxed for 3 h. The mixture was diluted with EtOAc (150 mL) and washed with water (100 mL). The separated organic layer was washed with brine (50 mL), dried over Na2 SO4, filtered and concentrated under reduced pressure. The residue was purified (silica gel; using 20% EtOAc/hexanes), to afford compound 2(4.2 g, 33%) as pale yellow solid. ‘HNMR(SOOIVIHz, DMSO-d6): = 10.18 (br s, 1H), 7.63 (d, J= 9.8 Hz, 1H), 7.30 (dd, J= 4.8, 2.2 Hz, 2H), 6.87 (s, 1H), 4.39 (q, J 7.2 Hz, 2H), 1.34 (t, J 7.1 Hz, 3H). |
Stage #1: oxalic acid diethyl ester; 2,5-Dihydroxyacetophenone With sodium In ethanol at 80℃; for 3h; Stage #2: With hydrogenchloride In ethanol; water at 90℃; for 0.5h; | 1 Beispiel 1; Herstellung von 6-hydroxy-2[3-(4-tert-butylphenyl)-1,2,4-oxadiazol-5-yl]chromone 1.1 3,25 g Natrium werden portionsweise unter Rhren in 300 ml Ethanol gelst. Anschlieend wird eine Lsung von 4,3 g 2,5-Dihydroxyacetophenon und 15,5 ml Oxalsurediethylester in 25 ml Ethanol zugetropft. Danach wird das Reaktionsgemisch 3 Stunden auf 80 erhitzt. Man khlt auf Raumtemperatur ab und tropft 10 ml 32 %ige HCl zu. Man erhitzt 30 Minuten bei 90, khlt ab, und entfernt das Lsungsmittel. Nach blicher Aufarbeitung erhlt man 5,9 g 6-Hydroxy-2-ethoxycarbonyl-chromon ("AA"). 1.2 Eine Lsung von 2,0 g "AA" in 30 ml Essigsure und 20 ml 32 %iger HCl wird unter Rckflu erhitzt. Man khlt ab, giet auf Eis, filtriert ab und kristallisiert aus Ethanol um. Man erhlt 1,5 g 6-Hydroxy-2-carbonsure-chromon ("AB"). 1.3 Zu einer Lsung von 150 mg "AB" in 10 ml THF gibt man unter Stickstoffatmosphre und bei -10 0,51 ml Triethylamin und 0,14 ml Isobutylchloroformiat. Man rhrt eine Stunde nach und gibt danach eine Lsung von 280 mg 4-tert.-Butylbenzamidoxim in THF zu. Man rhrt 30 Minuten bei Raumtemperatur, 90 Minuten unter Rckflu, arbeitet wie blich auf und erhlt 123 mg 6-Hydroxy-2-[3-(4-tert.-butylphenyl)-[1,2,4]-oxadiazol-5-yl]-chromon; EI MS (m/z) 362 (M+), 347 (M-Me+) UV-vis (iPrOH): ?max (Abs): 359 (0,12), 262.50 (1.02), 203.50 (1.08) | |
Stage #1: With ethanol; sodium Stage #2: oxalic acid diethyl ester; 2,5-Dihydroxyacetophenone In ethanol at 80℃; for 3h; Stage #3: With hydrogenchloride In ethanol; water at 90℃; for 0.5h; | 1 Beispiel 1; Herstellung von 6-Hydroxy-2-(1-methyl-1H-imidazol-2-carbonyl)-chromen-4-on 1.1 3,8 g Natrium werden portionsweise unter Rühren in 300 ml Ethanol gelöst. Anschließend wird eine Lösung von 5,0 g 2,5-Dihydroxyacetophenon und 17,8 ml Oxalsäurediethylester in 25 ml Ethanol zugetropft. Danach wird das Reaktionsgemisch 3 Stunden auf 80° erhitzt. Man kühlt auf Raumtemperatur ab und tropft 10 ml 32 %ige HCl zu. Man erhitzt 30 Minuten bei 90°, kühlt ab, und entfernt das Lösungsmittel. Nach üblicher Aufarbeitung erhält man 5,6 g 6-Hydroxy-2-ethoxycarbonyl-chromen-4-on ("AA"). 1.2 Zu einer auf -78° abgekühlten Lösung von 0,3 ml 1-Methyl-1H-imidazol in 5 ml THF gibt man unter N2-Atmosphäre 2,4 ml einer 1,6 M n-BuLi-Lösung und rührt 30 Minuten nach. Anschließend gibt man eine Lösung von 300 mg "AA" in 5 ml THF zu und rührt 1 Stunde nach. Man arbeitet wie üblich auf und erhält 303 mg 6-Hydroxy-2-(1-methyl-1H-imidazol-2-carbonyl)-chromen-4-on.1H NMR (DMSO-d6) δ 4.02 (s, 3H), 7.32 (m, 3H), 7.59 (s, 1H), 7.62 (dd, J= 9.6, 2.0 Hz, 1H), 7.74 (s, 1H), 10.21(s, 1H).13C NMR (DMSO-d6) δ 36.1, 107.2, 115,3, 120.3, 124.2, 124.6, 129.7, 129.9, 141.1, 149.2, 155.2, 156.0, 174.8, 177.4. EI MS (m/z) 267 (M+), 239, 211 UV-Vis (iPrOH): λmax. (lg. ε): |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyrrolidine In methanol at 60℃; for 48h; | 14 A solution of 1-(2,5-dihydroxyphenyl)ethanone (3.82 g, 25.1 mmol),), tert-butyl 4-oxopiperidine-1- carboxylate (5.0 g, 25.1 mmol) and pyrrolidine (2.1 mL, 25.1 mmol) in methanol (100 mL). The mixture was heated at 600C for 2 days before concentrating and purifying by Biotage chromatography to provide tert-butyl 6-hydroxy-4-oxo-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1 '-carboxylate as a yellow solid (7.80 g, 93%).A mixture of tert-butyl 6-hydroxy-4-oxo-3,4-dihydro-1 'H-spiro[chromene-2,4'-piperidine]-1 '-carboxylate (1.00 g, 3.00 mmol), acetone (5.0 mL), isopropyl iodide (3.06 g, 1.80 mL, 18 mmol), and K2CO3 (1.24 g, 9.0 mmol) was heated in a sealed tube at 70 0C overnight. The solids were removed by vacuum filtration and the filtrate was concentrated. The residue was purified by Biotage chromatography to provide tert- butyl 6-isopropoxy-4-oxo-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1 '-carboxylate (890 mg, 79%).A mixture of tert-butyl 6-isopropoxy-4-oxo-3,4-dihydro-1'H-spiro[chromene-2,4'-piperidine]-1'- carboxylate (890 mg, 2.37 mmol), methanol (5.0 mL), and cone. HCI was stirred at room temperature overnight to provide 6-isopropoxyspiro[chromene-2,4'-piperidin]-4(3H)-one hydrochloride (750 mg, 100%). |
87% | With pyrrolidine In methanol for 18h; Reflux; | |
82% | With pyrrolidine In methanol for 23h; Reflux; | 17.1 A solution of 2,5-dihydroxyacetophenone (15 g, 98 mmol), 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (20 g, 100 mmol) and pyrrolidine (21 mL, 260 mmol) in methanol (146 mL) was stirred at reflux for 23 h and concentrated under vacuum to produce a red oily crude material. The oily crude material was purified by ISCO (330 g column) chromatography using 27 to 80% ethyl acetate in hexane to afford the product of step 1 (27 g, 82%), mp 72-74 0C (ethyl acetate, ether and hexane), MS m/z = 332 (M - H). |
82% | With pyrrolidine In methanol for 23h; Reflux; | |
75% | With pyrrolidine at 20 - 70℃; for 48.5h; | 2A EXAMPLE 2A; Preparation of 2.2; Pyrrolidine (104 mL, 1.256 mol, 2.0 eq) was added at room temperature to 1.2 (125.2 g, 0. 628 mol, 1.0 eq) and 2.1 (95.6 g, 0.628 mol, 1.0 eq). The solution was stirred at 70°C for 30 min and then cooled to room temperature and stirred for 48h. The mixture was then concentrated under reduced pressure and ethyl acetate (800 mL) was added. The organic mixture was washed with a IN aqueous solution of hydrochloric acid, water, brine and dried over sodium sulfate. Diethyl ether (500 mL) was added to the organics and the mixture was stirred overnight at room temperature. The resulting precipitate was collected by filtration, washed with hexane and used for the next step without further purification. Yield: 75% 'H NMR (400MHZ, CDC13) 8 7.31 (d, 1H), 7.08 (m, 1H), 6.87 (d, 1H), 6.06 (s, 1H), 3.86 (br s, 2H), 3.19 (br s, 2H), 2.69 (s, 2H), 2.02 (M, 2H), 1. 58 (M, 2H), 1.47 (s, 9H) Mass Spectral Analysis m/z = 332.4 (M-H)- |
75% | With pyrrolidine at 20 - 70℃; | |
75% | With pyrrolidine at 20 - 70℃; for 48.5h; | 2A.2.1 Preparation of 2.2: Pyrrolidine (104 mL, 1.256 mol, 2.0 eq) was added at room temperature to 1.2 (125.2 g, 0.628 mol, 1.0 eq) and 2.1 (95.6 g, 0.628 mol, 1.0 eq). The solution was stirred at 7O0C for 30 min and then cooled to room temperature and stirred for 48h. The mixture was then concentrated under reduced pressure and ethyl acetate (800 mL) was added. The organic mixture was washed with a IN aqueous solution of hydrochloric acid, water, brine and dried over sodium sulfate. Diethyl ether (500 mL) was added to the organics and the mixture was stirred overnight at room temperature. The resulting precipitate was collected by filtration, washed with hexane and used for the next step without further purification.Yield: 75%1H NMR (400MHz, CDCl3) δ 7.31 (d, IH), 7.08 (m, IH), 6.87 (d, IH), 6.06 (s, IH), 3.86 (br s, 2H), 3.19 (br s, 2H), 2.69 (s, 2H), 2.02 (m, 2H), 1.58 (m, 2H), 1.47 (s, 9H) Mass Spectral Analysis m/z = 332.4 (M-H)-. |
72% | With pyrrolidine In isopropyl alcohol for 24h; Reflux; | 6.2. General procedure for the synthesis of compounds 2a to 2f General procedure: To a stirred solution of 2-hydroxyacetophenone derivative (1 eq)and Boc-4-piperidone (1.5 eq) in Isopropanol (10 mL for 1 mmol ofsubstrate), pyrrolidine (2 eq) was added drop wise at RT and stirred for15 min. Reaction mass heated to reflux for 24 h. TLC showed completionof starting material. The reaction mixture was cooled to RT andconcentrated under reduced pressure. The crude compound was dilutedwith water, pH adjusted to ~6 using 1 N HCl and extracted with ethylacetate. Combined organic layer washed with brine, dried over Na2SO4,filtered and concentrated to get crude compound. The crude compoundwas purified by flash column chromatography using 10-30% (v/v)ethyl acetate in pet ether as eluent to get desired compound 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With pyrrolidine In methanol at 70℃; for 16h; | 10.1 To a solution of 4-oxo-butyric acid tert-butyl ester (53 mg; 0.335 mmol) in MeOH (3 mL) were added 2',5'-dihydroxyacetophenone (51 mg; 0.335 mmol) and pyrrolidine (28 μL; 0.335 mmol). The reaction mixture was heated to 70° C. for 16 h. The mixture was cooled, concentrated in vacuo and the residue was purified by FCC (silica gel; elution with 3:1 hexanes:EtOAc) to afford 76 mg (78%) of 10-1. |
78% | With pyrrolidine In methanol at 70℃; for 16h; | 10.1 Example 10; Step 1; [00101] To a solution of 4-oxo-butyric acid tert-butyl ester (53 mg; 0.335 rnmol) in MeOH (3 mL) were added 2',5'- dihydroxyacetophenone (51 mg; 0.335 rnmol) and pyrrolidine (28 μL; 0.335 mmol). The reaction mixture was heated to 70 0C for EPO 16 h. The mixture was cooled, concentrated in vacuo and the residue was purified by FCC (silica gel; elution with 3:1 hexanes:EtOAc) to afford 76 mg (78%) of 10-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 4-Fluorobenzyl bromide; 2,5-Dihydroxyacetophenone With potassium carbonate In acetonitrile at 20℃; for 3h; Heating / reflux; Stage #2: With ammonium chloride; water | C.10 (C-10) To a suspension of 2', 5'-dihydroxyacetophenone (23.1g, 152mmol) and powder potassium carbonate (23.1g, 167mmol) in acetonitrile (400ml), was added 4-fluorobenzylbromide (18.9ml, 152mmol) at room temperature and the mixture was refluxed for 3 hours.. The solution cooled to room temperature was filtered and the obtained solid products were washed with ethyl acetate.. The filtrate and the ethyl acetate solution after washing were combined and concentrated under reduced pressure, to which was added an ammonium chloride aqueous solution, followed by extraction with ethyl acetate.. The extract was washed and dried, then active carbon (10g) was added thereto, followed by filtration and concentration under reduced pressure.. The residue was crystallized from methyl alcohol (100ml) to give 1-[5-(4-fluorobenzyloxy)-2-hydroxyphenyl]etanone (30.3g, yield: 77%). Melting point: 88.89°C NMR(CDCl3)δ: 2.60(3H, s), 5.00(2H, s), 6.90-7.45(7H, m), 11.87(1H, s). 10 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; acetonitrile; Petroleum ether | 1 (+-)-trans-N-(6-Benzyloxy-3-hydroxy-2,2-dimethylchroman-4-yl)-N-methylmethanesulfonamide STR16 a) 2,2-Dimethyl-6-hydroxychroman-4-one EXAMPLE 1 (+-)-trans-N-(6-Benzyloxy-3-hydroxy-2,2-dimethylchroman-4-yl)-N-methylmethanesulfonamide STR16 a) 2,2-Dimethyl-6-hydroxychroman-4-one A reaction mixture of 100 g (0.65 mol) of 2,5-dihydroxyacetophenone in 1 l of acetonitrile, 130 ml (1.55 mol) of pyrrolidine and 290 ml (3.95 mol) of acetone was heated at 45° C. for 8 h. The sol. were then removed i. vac. and the residue was dissolved in 1 l of EA. The organic phase was washed twice with dilute hydrochloric acid, stirred with activated carbon and dried over magnesium sulfate and substantially concentrated. The residue was stirred with petroleum ether and the precipitate was filtered off with suction giving 102 g of 2,2-dimethyl-6-hydroxychroman-4-one, m.p. 161° C. | |
In ethyl acetate; acetone; acetonitrile | 3 Preparation of 6-hydroxy-2,2-dimethylchroman-4-one (Ih) Example 3 Preparation of 6-hydroxy-2,2-dimethylchroman-4-one (Ih) 2,5-Dihydroxyacetophenone (5 g, 33 mmol) and acetone (15 ml, 204 mmol) are initially introduced suspended in acetonitrile (50 ml), and pyrrolidine (6.5 ml) is subsequently added. The solution is left to stir at an internal temperature of 45-50° C. for about 8 h. The solvent is subsequently distilled off, and the residue is taken up in 200 ml of ethyl acetate and washed twice with 2N hydrochloric acid and subsequently washed with NaCl solution. Drying over Na2SO4, removal of the solvent by distillation and drying gives 6-hydroxy-2,2-dimethylchroman-4-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In sodium hydroxide; hexane; ethyl acetate; acetone; | PREPARATION 1 5-Benzyloxy-2-hydroxyacetophenone To 2,5-dihydroxyacetophenone (30 g, 0.197 mol) dissolved in 600 ml acetone was added benzyl bromide (24.64 ml, 1.05 equiv) and K2 CO3 (68.0 g, 0.492 mol). The mixture was heated at reflux under N2 for 2 days, then cooled to room temperature, filtered and stripped of solvent in vacuo. The residue was taken up in 500 ml ethyl acetate, washed 3* with ice cold IN NaOH, 2* with H2 O and 2* with brine, dried (Na2 SO4), stripped to solids, and chromatographed on silica gel using 9:1 hexane:ethyl acetate as eluant to yield 35 g of purified title product. A portion was recrystallized as needles from hexane; mp 68-70 C.; Anal. C 74.37, H 5.69, calcd. C 74.36, H 5.82, 1 H-NMR (300 MHz, CDCl3) delta (ppm) 2.6 (s, 3H), 5.05 (s, 2 H), 6.9 (d, 1H), 7.1-7.45 (m, 7H), 11.85 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.7% | In dichloromethane; | Referential Example 10 2-Hydroxy-5-(2-tetrahydropyranyloxy)acetophenone II -6 A solution of 5 g of 2,5-dihydroxyacetophenone a-3 , 4.15 g of 2,3-dihydropyran and 100 mg of pyridine p-toluenesulfonate dissolved in 50 ml of CH2Cl2 was stirred for 1.5 hr. at room temperature. The reaction mixture was made alkaline with saturated aqueous NaHSO3 solution and extracted with CH2Cl2. The extract was washed with water, dried over Na2SO4, and the solvent was distilled off. The residue was recrystallized from isopropyl ether and filtered to give 6.42 g of Compound II -6 (yield: 82.7 %). m.p.: 66.5-67.5 C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 2,5-Dihydroxyacetophenone With pyridine; water; potassium carbonate In acetone at 60℃; for 0.25h; Stage #2: 4-methoxy-benzoyl chloride In acetone Reflux; | General procedure for preparation of flavones16a-16e, 19a-19e, 22a-22e, 25a-25d. To a solutionof acetophenone (1 mmol) in wet acetone (containing1% w/w water) (20 mL/mmol) was added potassiumcarbonate (8 equiv.) and then pyridine (4 equiv.). Thesolution was stirred at 60°C for 15 min and aroylchloride (2 equiv.) was slowly added. The reactionmixture was stirred upon refluxing for 24-48 h. Aftercooling down to room temperature, acetone wasevaporated. Acetic acid (10%) was added, the solutionwas stirred till it stopped bubbling. The residue wasfiltered off, washed with water (2×50 mL) to make itneutral, vacuum-dried, and then crystallized fromacetone (20 mL) to produce pure products. |
With hydrogenchloride; lithium hydroxide; sulfuric acid In tetrahydrofuran; acetic acid | 5 EXAMPLE 5 EXAMPLE 5 Dry, pulverulent lithium hydroxide (19.7 mmol, 3 equivalents) is added in one portion to a well-stirred solution of 2',5'-dihydroxyacetophenone (6.4 mmol) in dry THF (5 ml) under an argon atmosphere at -78° C. The reaction mixture is stirred at -78° C. for one hour and subsequently at -10° C. for two hours. After the mixture has been re-cooled to -78° C., a solution of 4-methoxybenzoyl chloride (6.5 mmol) in THF (10 ml) is added in one portion. The mixture is stirred at -78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied into a mixture of ice (150 g) and concentrated HCl (5 ml) and extracted with chloroform (3*50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (30 ml) and sulfuric acid (0.2 ml) are added to the residue, and the mixture is heated at 95-100° C. for from 30 minutes to one hour under an argon atmosphere. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallized in methanol, giving 4'-methoxy-6-hydroxyflavone. 1H NMR (250 MHz, d6-DMSO): δ=3.73 (s, 3H), 6.6-8.5 (m, 8H), 12.5 (s, 10H); NMR (250 MHz, d6-DMSO): δ=56 (s), 94.9 (s), 114.0 (s), 117.6 (s), 118.9 (s), 122.2 (s), 126.6 (s), 127.2 (s), 150.5 (s), 152.0 (s), 161.2 (s), 168.8 (s), 187.0 (s) EI-MS (70 eV) m/e (rel. abund.)=268; UV (2-propanol): λ=254 nm, 323 nm. | |
Stage #1: 4-methoxy-benzoyl chloride; 2,5-Dihydroxyacetophenone With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene for 8h; Reflux; Stage #2: With sodium hydroxide In 1,4-dioxane; methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With hydroxylamine hydrochloride In ethanol for 16h; Heating; Reflux; | 1.D Step D: Preparation of 1-(2,5-dihydroxyphenyl)ethanone oxime: To a solution of 1-(2,5-dihydroxyphenyl)ethanone (10.0 g, 65.73 mmol) in ethanol (200 mL) was added hydroxylamine hydrochloride (13.7 g, 197.2 mmol). After heating to reflux for 16 hours, the solvent was reduced under reduced pressure. Ethyl acetate (200 mL) and water were added and the mixture was extracted with ethyl acetate (3 X). The combined organic layers were dried and concentrated to provide the product (10 g, 91%) as yellow solid. |
86.4% | With hydroxylamine hydrochloride In ethanol for 16h; Reflux; | 80 Synthesis of Compound 2 Compound 1 (100 g, 657 mmol) and NH2OH.HCl (137 g, 1973 mmol) were added to EtOH (1.5 L). The reaction mixture was refluxed for 16 h. The reaction mixture was concentrated. The residue was recrystallized from DCM/PE (4:1), afforded compound 2 (95 g, 86.4% yield). |
4.63 g | With pyridine; hydroxylamine monohydrate at 20℃; | 6 A solution of 2,5-dihydroxyacetophenone (compound 6-1) (4.5 g, 30 mmol) in pyridine (17 ml) was added in portions NH20H.H20 (2.1 g, 30 mmol), stirred at room temperature overnight, and the reaction was complete by TLC The organic layer was washed successively with water, 0.2 M HC1 solution, concentrated to dryness under reduced pressure, added with toluene, concentrated under reduced pressure and dried to give the solid compound 6-2 (4.63 g).Will 2,5-dihydroxyacetophenone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium hydroxide In ethanol at 25℃; | |
85% | With potassium hydroxide In ethanol at 25℃; | |
57% | Stage #1: 2,5-Dihydroxyacetophenone With potassium hydroxide In ethanol at 20℃; for 0.5h; Stage #2: 4-hydroxy-benzaldehyde In ethanol for 2h; Heating; | 1-(2,5-Dihydroxyphenyl)-3-(4-hydroxyphenyl)-propenone 9 1-(2,5-Dihydroxyphenyl)-3-(4-hydroxyphenyl)-propenone 9KOH (60%, 8 mL) was added to a solution of 5-hydroxy-2-methyl-benzoic acid (1 g, 6.57 mmol) in EtOH (1 mL) andthe mixture was then stirred at room temperature for 30 min.4-Hydroxybenzaldehyde (785.6 mg, 6.40 mmol) was addedto the reaction mixture, which was then stirred at 100 °C for2 h. The reaction mixture was cooled and quenched with icewater (6 mL), acidified to pH = 5 by the addition of aqueousHCl solution (2.6 mL). Afterward, the reaction mixture waswashed with water (25 mL) and filtrated to afford compound9 (986.0 mg, 3.84 mmol, 57%) as a yellow solid. Rf = 0.35(methanol/chloroform = 2 : 1); 1H-NMR (400 MHz, CD3OD)7.85 (1H, d, J = 15.6 Hz), 7.64 (2H, d, J = 8.4 Hz), 7.59 (1H,d, J = 15.6 Hz), 7.42 (1H, d, J = 2.4 Hz), 7.03 (1H; dd; J = 8.8,2.4 Hz), 6.86 (2H, d, J = 8.4 Hz), 6.82 (1H, d, J = 8.8 Hz);13C-NMR (100 MHz, CD3OD) δ: 195.1,161.9, 157.6, 150.6,146.9, 132,0, 127.6, 125.5, 119.6, 118.2, 117.0, 115.4.6-Hydroxy-2-(4-hyroxyphenyl)chroman-4-one 10 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With pyrrolidine In ethanol at 60℃; for 20h; Molecular sieve; Inert atmosphere; | 5 l,l-Dimethoxypropan-2-one (8.6 niL, 72.30 mmol, 1.1 eq), 3 A molecular sieves (10 g) and pyrrolidine (16.3 mL, 197.17 mmol, 3 eq) were added to 2',5'-dihydroxyacetophenone (10.0 g, 65.72 mmol, 1 eq) in absolute EtOH (66 mL) under argon. The reaction mixture was heated at 600C for 20 h. The reaction mixture was then quenched with H2O (200 mL) and the pH was adjusted to 3 with HCl IN. The aqueous phase was extracted 3 times with CH2Cl2 (3*200 mL). The combined organic layers were washed with HCl IN, with H2O, dried over MgSO4 and concentrated in vacuo. The red oil was purified by silica gel flash chromatography (heptanes / AcOEt: 7/3) to afford 14.59 g (88%) of a white solid 9a.Molecular Weight: 252.26 (Ci3Hi6O5).1H-NMR δ (CDCl3, 300 MHz) ppm (Jin Hz): 1.36 (s, 3H, H-2a), 2.61 (d, IH, J=16.8, H-3), 3.00 (d, 1H, J=16.8, H-3), 3.48 (s, 3H, MeO), 3.51 (s, 3H, MeO), 4.27 (s, IH, H-I '), 6.84 (d, 1H, J=8.9, H-8), 7.04 (dd, 1H, J=8.9, 3.1, H-7), 7.32 (d, 1H, J=3.1, H-5).13C-NMR δ (CDCl3, 75 MHz) ppm: 19.8 (C-2a), 42.6 (C-3), 57.8 (MeO), 58.0 (MeO), 82.9 (C-2), 108.4 (C-5), 110.6 (C-I '), 119.2 (C-8), 120.4 (C-4a), 124.8 (C-7), 150.0 (C-8a), 153.6 (C-6), 192.8 (C-4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With pyrrolidine In ethanol at 60℃; Molecular sieve; Inert atmosphere; | 1 14-hydroxy-tetradecan-2-one (0.30 g, 1.31 mmol, 1 eq), 3 A molecular sieves (0.18 g) and pyrrolidine (0.33 mL, 3.94 mmol, 3 eq) were added to 2',5'-dihydroxyacetophenone (0.20 g, 1.31 mmol, 1 eq) in absolute EtOH (3 mL) under argon. The reaction mixture was heated at 600C overnight then quenched with aqueous HCl IN (20 mL) and extracted 3 times with AcOEt (3*20 mL). The combined organic layers were washed with H2O, dried over MgSO4 and concentrated in vacuo. The brown residue was purified by silica gel flash chromatography (heptanes / AcOEt: 6/4) to afford 0.33 g (70%) of a yellow solid Ia.Molecular Weight: 362.50 (C22H34O4).1H-NMR δ (CDCl3, 300 MHz) ppm (Jin Hz): 1.23 (s large, 18H, H-2' to H-IO'), 1.38 (s, 3H, H-2a), 1.52 to 1.75 (m, 4H, H-I ',11 '), 2.64 (d, 1H, J=16.6, H-3), 2.73 (d, 1H, J=16.6, H-3), 3.66 (t, 2H, J=6.6, H-12'), 6.82 (d, 1H, J=8.8, H-8), 7.04 (dd, 1H, J=8.8, 3.1, H-7), 7.28 (d, lH, J=3.1, H-5).13C-NMR δ (CDCl3, 75 MHz) ppm: 23.3 (C-2'), 24.1 (C-2a), 25.7 (C-IO'), 29.2 to 29.5 (C-3' to C-9'), 32.7 (C-I l '), 38.7 (C-I '), 47.5 (C-3), 63.2 (C-12'), 81.0 (C-2), 110.6 (C-5), 119.6 (C-8), 120.4 (C-4a), 149.7 (C-8a), 154.2 (C-6), 193.2 (C-4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium hydroxide In ethanol at 25℃; | |
With potassium hydroxide In ethanol at 50℃; for 15h; | 2.2.1. Synthesis of the chalcones (step 1) General procedure: Substituted 2′-hydroxyacetophenone (10 mmol) and the substituted aldehyde (10 mmol) were dissolved in ethanol (100 ml) and potassium hydroxide (1.12 g, 20 mmol) was added and the mixture was stirred at 50 °C for 15h. After this time the pH was adjusted to 1-2 by the addition of HCl(c) and the precipitate formed was filtered under vacuum to obtain the target chalcone as a yellow solid. | |
2.3 g | With sodium hydroxide In ethanol at 20℃; for 72h; | 13 2,5-dihydroxyacetophenone taking 2g (13.2mmol), benzaldehyde 2.1g (20mmol), were added to 10mlEthanol was added 20% NaOH1ml, the reaction was stirred at room temperature for 72h. The reaction mixture was poured onto iceWater, with dilute hydrochloric acid, then stirred for 1h, filtered and the resulting solid was recrystallized from ethanol and dryingCrystal, to give 2 ', 5'-hydroxy chalcone 2.3g. |
With sodium hydroxide In ethanol; water for 3h; | Synthesis of Compound 4 Sodium hydroxide (1.00 g) and water (5 mL) were added into a 100 mL beaker and stirred todissolve. Then 2,5-dihydroxyacetophenone (1.75 g) and ethanol (2.5 mL) were added. The lattermethod is the same as 3.2.1, and finally the target product 6-hydroxyflavanone was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42%; 39% | With ammonium acetate; acetic acid; for 8h;Reflux; | Example A[0137] (E)-1-(2,5-Dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone and 2-(5-fluoro-pyridin-3-yl)-6-hydroxy-chroman-4-one <strong>[39891-04-8]5-fluoro-pyridine-3-carbaldehyde</strong> (3.1 g, 24.6 mmol, 1.1 eq) and ammonium acetate (2.2 g, 29.1 mmol, 1.3 eq) were suspended in acetic acid (100%, 70 ml) and heated to reflux for 8 h. The solution was allowed to reach room temperature. The volume of the resulting suspension was reduced to half of the volume under reduced pressure. The mixture was poured on ice water and neutralized with caution using sodium carbonate. The aqueous layer was washed with ethyl acetate and the remaining precipitate filtered. Solid (E)-1-(2,5-dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone (2.4 g, 42%) was obtained as a brownish solid and used in the cyclization reaction without further purification. The remaining aqueous solution was extracted with ethyl acetate and the combined organic layers dried with sodium sulfate, filtered, the solvent removed under reduced pressure and the resulting solid digested with few dichloromethane. 2-(5-Fluoro-pyridin-3-yl)-6-hydroxy-chroman-4-one was obtained as a brown solid (2.3 g, 39%) and used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39%; 42% | With ammonium acetate; acetic acid; for 8h;Reflux; | Example A (E)-1-(2,5-Dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone and 2-(5-fluoro-pyridin-3-yl)-6-hydroxy-chroman-4-one 2,5-Dihydroxy-acetophenone (3.4 g, 22.4 mmol), <strong>[39891-04-8]5-fluoro-pyridine-3-carbaldehyde</strong> (3.1 g, 24.6 mmol, 1.1 eq) and ammonium acetate (2.2 g, 29.1 mmol, 1.3 eq) were suspended in acetic acid (100%, 70 ml) and heated to reflux for 8 h. The solution was allowed to reach room temperature. The volume of the resulting suspension was reduced to half of the volume under reduced pressure. The mixture was poured on ice water and neutralized with caution using sodium carbonate. The aqueous layer was washed with ethyl acetate and the remaining precipitate filtered. Solid (E)-1-(2,5-dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone (2.4 g, 42%) was obtained as a brownish solid and used in the cyclization reaction without further purification. The remaining aqueous solution was extracted with ethyl acetate and the combined organic layers dried with sodium sulfate, filtered, the solvent removed under reduced pressure and the resulting solid digested with few dichloromethane. 2-(5-Fluoro-pyridin-3-yl)-6-hydroxy-chroman-4-one was obtained as a brown solid (2.3 g, 39%) and used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.2% | With 1H-imidazole In N,N-dimethyl-formamide at 50℃; for 16h; Inert atmosphere; | 1-(2,5-Bis(tert-butyldimethylsilyloxy)phenyl)ethanone (19a) A solution of 1-(2,5-dihydroxyphenyl)ethanone(3.00 g, 19.7 mmol), TBDMSCl (6.69 g, 44.4 mmol) and IMZ (4.03 g, 59.2 mmol) inDMF (anhydrous, 50.0 mL) were heated under an N2 atmosphere to 50 °Cfor 16 hrs. The solution was poured into H2O (100 mL), the aqueousand organic layers separated and the aqueous layer extracted with ether (100mL). The combined organic layers were washed with brine (100 mL), dried overMgSO4 and concentrated invacuo to yield protected ketone 19a (6.99 g, 93.2 %) as a colourlessoil; 1H NMR (400 MHz, CDCl3) δ=0.19(18H, s), 0.96 (12H, s), 2.50 (3H, s), 6.51 (1H, t, J=2.15), 7.02 (2H, d,J=2.27); 13C NMR (400 MHz, CDCl3) δ=-4.5,25.7, 26.6, 108.9,, 111.6, 112.3, 113.3,116.7; IR vmax (NaCl) 1690.8,2931.2 cm-1; MS(ES+) m/z 381.14 (MH+, 100%); HRMS (ES+)C20H37O3Si2 calcd: 381.2276, obsd: 381.2274. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium acetate; acetic acid; for 8h;Reflux; | Example A(E)-1 -(2,5-Dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone and 2-(5-fluoro- pyridin-3-yl)-6-hydroxy-chroman-4-one2,5-Dihydroxy-acetophenone (3.4 g, 22.4 mmol), <strong>[39891-04-8]5-fluoro-pyridine-3-carbaldehyde</strong> (3.1 g, 24.6 mmol, 1 .1 eq) and ammonium acetate (2.2 g, 29.1 mmol, 1 .3 eq) were suspended in acetic acid (100%, 70 ml) and heated to reflux for 8 h. The solution was allowed to reach room temperature. The volume of the resulting suspension was reduced to half of the volume under reduced pressure. The mixture was poured on ice water and neutralized with caution using sodium carbonate. The aqueous layer was washed with ethyl acetate and the remaining precipitate filtered. Solid (E)-1 -(2,5- dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone (2.4 g, 42%) was obtained as a brownish solid and used in the cyclization reaction without further purification. The remaining aqueous solution was extracted with ethyl acetate and the combined organic layers dried with sodium sulfate, filtered, the solvent removed under reduced pressure and the resulting solid digested with few dichloromethane. 2-(5-Fluoro- pyridin-3-yl)-6-hydroxy-chroman-4-one was obtained as a brown solid (2.3 g, 39%) and used in the next step without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium hydroxide In ethanol; water at 20℃; | General procedure for synthesis of chalcones via Claisen-Schmidt condensation General procedure: To a solution of 2,4,5-trimethoxy benzaldehyde (4mmol) and appropriate acetophenone (4mmol) in C2H5OH (25ml), 40% of aqueous KOH (2mmol) was added. The reaction mixture was stirred at r.t. till completion of reaction (monitored by TLC). Then the reaction mass was poured into ice water and neutralized with aqueous 10% HCl solution. The precipitate was filtered, washed with excess of water, dried and recrystallized from methanol to obtain pure chalcones. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With acetic acid In ethanol Reflux; | General Procedure for the Synthesis of Compounds 1-25 General procedure: Benzophenone hydrazone derivatives 1-25 were synthesized by refluxing a mixture of benzophenone hydrazone (3 mmol) and substituted benzaldehyde (3 mmol) in the presence of HPLC grade ethanol and 1-2 drops of acetic acid for 2-3 h. Completion of reaction was monitored by TLC. After completion of reaction, the crystalline powder of benzophenone hydrazone derivatives were collected and washed with hexane and dried to afford compounds 1-25 in high yields. Recrystallization from methanol afforded pure crystals. The structures of synthetic compounds 1-25 were confirmed by 1H NMR, EI mass spectroscopy, and elemental analysis. |
With acetic acid In ethanol Reflux; | ||
With acetic acid In methanol Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium hydroxide In methanol; water at 20℃; for 72h; | Synthesis of 9A, 9B, 9C; general procedure Method (c2) General procedure: A mixture of compound 7 (0.02 mol) and compound 8 (0.022 mol) were dissolved in methanol (20 mL), and 40% aqueous KOH (100 mL) was added dropwise at approximately 0 °C. The solution was vigorously stirred for 72 h at room temperature. Then the reaction mixture was neutralised to pH 5 with 37% aqueous HCl. The precipitate was filtered off, washed with water and recrystallised from ethanol to give compound 9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium hydroxide In methanol; water at 20℃; for 72h; | Synthesis of 9A, 9B, 9C; general procedure Method (c2) General procedure: A mixture of compound 7 (0.02 mol) and compound 8 (0.022 mol) were dissolved in methanol (20 mL), and 40% aqueous KOH (100 mL) was added dropwise at approximately 0 °C. The solution was vigorously stirred for 72 h at room temperature. Then the reaction mixture was neutralised to pH 5 with 37% aqueous HCl. The precipitate was filtered off, washed with water and recrystallised from ethanol to give compound 9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With potassium <i>tert</i>-butylate In butan-1-ol at 50℃; Inert atmosphere; | 13 Embodiment 13: compound 8 preparation of In 20 ml flask is added in the compound 2 - 2 (300 mg, 1 . 97 mmol), furfural (322 mg, 3 . 35 mmol, 1.7 eq), potassium tertiary butyl alcohol (885 mg, 7 . 89 mmol, 4.0 eq), butanol 10 ml, replace the nitrogen, heating to 50 °C reaction, TLC detection reaction process for, until the disappearance of the raw material (10 h). After the reaction is completed in the steaming and removing solvent, adding 2 M hydrochloric acid to regulate acid stirring 10 min, the generated mixed solution is extracted with ethyl acetate (3 × 20 ml). The combined organic phase, dried with anhydrous sodium sulfate, the mixture is filtered, the solvent is removed in the steaming and on, for the crude product is purified by silica gel column, the proportion of the eluant: ethyl acetate/petroleum ether=40%. Be brown all kinds solid compound 8 (164 mg, yield: 36%). |
With sodium hydroxide In ethanol at 10℃; | 2.3 Preparation, purification and characterizationof 6th substituted 2-(furan-2-yl)-3-hydroxy-4Hchromen-4-one General procedure: For the preparation of 2-(furan-2-yl)-3-hydroxy-4H-chromen-4-one and its derivatives by substitution at the 6th position with those of -CH3, -OH, -NO2,-Cl, (0.03 mole) of appropriately substituted 2’-hydroxyacetophenones were condensed with 2.88 g (0.03 mole) of furan-2-carboxaldehyde in the presence 3.6 g (0.09 mole) of sodium hydroxide in ethanol at 10± 5C (scheme 1). The reaction mixture which turned deep red in colour after 30 min was stirred further for 7-8 h. Thereafter, it was poured over ice, neutralised with dilute HCl and then the solid mass so obtained was crystallized from methanol to afford orange yellow needles of chalcone.The chalcone thus obtained was subjected to A.F.O. (Algar Flynn Oyamada) reaction conditions in sodium hydroxide and ethanol stirred at 10 ± 5C with dropwise addition of 30% (w/v) H2O2 over an hour. This mixture was further stirred for 5-6 h and the resulting reaction mixture on neutralization with dilute HCl, gave a yellow mass which was crystallised twice from appropriate solvents for different compounds. Purity of the compounds was checked from the sharp M.p. single spot on TLC plate and sharp peaks in the UV-Vis spectrum. The structures have been confirmed by their IR and 1H NMR spectra. | |
With sodium hydroxide In ethanol at 10℃; | Preparation, purification and characterization of variously substituted 2-(furan-2'-yl)-3-hydroxy-4H-chromen-4-one General procedure: 2-(Furan-2'-yl)-3-hydroxy-4H-chromen-4-one (FHC) and its derivatives have been synthesized by two step synthesis scheme already reported [12]. First step is preparation of chalcone from 0.03 mole of furan-2-carboxaldehyde and 0.03 mol of 2'-hydroxyacetophenone in the presence of 0.09 mol of sodium hydroxide in ethanol at 10 ± 0.5 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 48h; chemoselective reaction; | 4.3.1. Preparation of analogs 5-9 and 13-47 by chemoselective Mitsunobu esterification General procedure: Triphenylphosphine (TPP) (280 mg, 1.07 mmol) was added in portions to a freshly prepared solution of the designated alcohol (1.0 mmol) and the specified phenolic acid (1.0 mmol equivalent) in anhydrous THF (3.5 mL) at 0 °C. Diisopropylazodicarboxylate (DIAD) (208 mL, 1.0 mmol) was then added dropwise to the mixture. The reaction mixture was stirred at 0 °C for 30 min. The mixture was then warmed and stirring was continued for 48 h at rt [19]. Reactions were monitored till completion by TLC. The reaction mixture was then worked up by removal of the solvent under reduced pressure, saturated solution of NaHCO3 (10 mL) was added, and then the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to dryness. The crude product was collected and purified by column chromatography(CC) on Sephadex LH-20 using isocratic CH2Cl2 followed by chromatography on Si gel 60 using n-hexane-EtOAc system, gradient elution, to afford 5-9 and 13-47 (Supplementary Information). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 48h; chemoselective reaction; | 4.3.1. Preparation of analogs 5-9 and 13-47 by chemoselective Mitsunobu esterification General procedure: Triphenylphosphine (TPP) (280 mg, 1.07 mmol) was added in portions to a freshly prepared solution of the designated alcohol (1.0 mmol) and the specified phenolic acid (1.0 mmol equivalent) in anhydrous THF (3.5 mL) at 0 °C. Diisopropylazodicarboxylate (DIAD) (208 mL, 1.0 mmol) was then added dropwise to the mixture. The reaction mixture was stirred at 0 °C for 30 min. The mixture was then warmed and stirring was continued for 48 h at rt [19]. Reactions were monitored till completion by TLC. The reaction mixture was then worked up by removal of the solvent under reduced pressure, saturated solution of NaHCO3 (10 mL) was added, and then the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to dryness. The crude product was collected and purified by column chromatography(CC) on Sephadex LH-20 using isocratic CH2Cl2 followed by chromatography on Si gel 60 using n-hexane-EtOAc system, gradient elution, to afford 5-9 and 13-47 (Supplementary Information). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.2% | Stage #1: 2,5-Dihydroxyacetophenone With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: 4-(bromomethyl)-2-fluoropyridine In tetrachloromethane at 60℃; for 16h; | 2.2 Step -2 To a stirred solution of 2,5-dihydroxy acetophenone (0.6 g, 3.94 mmol, 1 eq), in acetone (15 mL), was added K2C03 (0.54 g, 3.9 mmol, 0.99 eq). After stirring at room temperature for 30 minutes, 4-(bromomethyl)-2-fluoropyridine (0.74 g, 3.90 mmol,0.99 eq) was added drop wise. The reaction mixture was heated to reflux at 60° C for 16h. Reaction progress was monitored by TLC (2:8, ethyl acetate: pet ether). After completion of reaction, the reaction mixture was cooled to room temperature mixed with aq. NaHCO3 solution (30 mL) and extracted with ethyl acetate (4 x 50 mL). The combined organic layer was washed with saturated NaC1 (100 mL) solution, dried overanhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (60-120 mesh silica gel) using 13% Ethyl acetate in pet ether as eluent to yield 1-(5-((2-fluopyridin-4-yl)methoxy)-2-hydroxyphenyl)ethanone (0.5 g, 48.2%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.9% | To a stirred solution of 2,5-dihydroxyacetophenone (1.48 g, 9.78 mmol) in dry Acetone (30 mL) was added K2C03 (0.36 g, 1.33 mmol). After stirring at ambient temperature for 30 minutes, a solution of <strong>[182924-36-3]5-(bromomethyl)-2-chloropyridine</strong> (2 g, 9.68 mmol) inacetone (15 mL) was added dropwise. The reaction mixture was heated to 60 C for14h. The progress of the reaction was monitored by TLC (3:7, Ethyl acetate: pet. ether).After completion of the reaction the reaction mixture was cooled to room temperatureand quenched with aqueous 10% NaHCO3 solution (50 ml) and stirred for 15 minutes.The yellow solid appeared was filtered under suction. The solid obtained wassuspended in EtOAc (70 ml) and inorganic was filtered under suction. The EtOAc layer was dried over anhydrous sodium sulfate and removed under reduced pressure. The crude was purified by column chromatography (60-120 mesh silica gel) using 14% Ethyl acetate in pet ether as eluent to yield pure 1-(5-((6-chloropyridin-3-yl)methoxy)- 2-hydroxyphenyl)ethan- 1-one (1 .15 g, 42.9%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.21 g | With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 5h; | <strong>[25812-30-0]Gemfibrozil</strong> lg, dicyclohexylcarbodiimide 1. 07 g, 2,4-dihydroxyacetophenone 0.608 g Dichloromethane 60ml placed in 100ml single-mouth bottle, room temperature reaction for 5 hours, evaporated to dryness solvent, ethanol recrystallization of compound a2 1. 21g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.13 g | With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 5h; | <strong>[41859-67-0]Bezafibrate</strong>L, dicyclohexylcarbodiimide 0. 74g, 2,4-dihydroxyacetophenone 0. 638g and dichloromethane 60ml were placed in a 100ml single-necked flask and allowed to react at room temperature for 5 hours. The solvent was evaporated to dryness and the column layer To give the compound a71.13g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.33 g | With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 5h; | <strong>[49562-28-9]fenofibrate</strong> lg,0.843 g of dicyclohexylcarbodiimide, 0. 58 g of 2,5-dihydroxyacetophenone, and dichloromethane60ml placed in 100ml single-mouth bottle, room temperature for 5 hours, evaporated to dryness solvent, column chromatography compound a6 1. 33 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.9% | With sulfuric acid In dichloromethane at 0℃; Inert atmosphere; Reflux; | 2 Example 2: 2,5-Dihydroxy-3- (1-adamantyl) -acetophenone Under nitrogen, in a dry two neck flask2,5-dihydroxyacetophenone (6.08 g, 40 mmol),1-adamantanol (6.68 g, 44 mmol) and dry dichloromethane (100 mL)Stirring to make it fully dissolved;Concentrated sulfuric acid (240 μL, 4.4 mmol) diluted in dichloromethane (50 mL) was slowly added dropwise to the reaction system under ice-cooling at 0 ° C. After completion of the dropwise addition,Ice bath environment to continue the reaction 30min;Then the reaction system slowly heated back,Stirring reflux 18h, a large number of white solid,The reaction was terminated by TLC.After the reaction solution was cooled to room temperature,The pH was adjusted to 7 with saturated NaHCO3 solution,And extracted with ethyl acetate (150 mL x 3)The combined organic phases were dried over anhydrous Na2SO4 overnight,The organic phase was concentrated under reduced pressure and the resulting residue was separated by silica gel column chromatography (eluent: petroleum ether:Ethyl acetate = 10: 1),To give 10.81 g of 5-dihydroxy-3- (1-adamantyl) -acetophenone as a white solid. Yield 94.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 2,5-Dihydroxyacetophenone With pyridine; water; potassium carbonate In acetone at 60℃; for 0.25h; Stage #2: 4-fluorobenzoyl chloride In acetone Reflux; | General procedure for preparation of flavones16a-16e, 19a-19e, 22a-22e, 25a-25d. To a solutionof acetophenone (1 mmol) in wet acetone (containing1% w/w water) (20 mL/mmol) was added potassiumcarbonate (8 equiv.) and then pyridine (4 equiv.). Thesolution was stirred at 60°C for 15 min and aroylchloride (2 equiv.) was slowly added. The reactionmixture was stirred upon refluxing for 24-48 h. Aftercooling down to room temperature, acetone wasevaporated. Acetic acid (10%) was added, the solutionwas stirred till it stopped bubbling. The residue wasfiltered off, washed with water (2×50 mL) to make itneutral, vacuum-dried, and then crystallized fromacetone (20 mL) to produce pure products. |
Stage #1: 4-fluorobenzoyl chloride; 2,5-Dihydroxyacetophenone With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene for 8h; Reflux; Stage #2: With sodium hydroxide In 1,4-dioxane; methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With ammonium acetate; acetic acid; for 8h;Reflux; | 2,5-Dihydroxy-acetophenone (3.4 g, 22.4 mmol), <strong>[39891-04-8]5-fluoro-pyridine-3-carbaldehyde</strong> (3.1 g, 24.6 mmol, 1.1 eq) and ammonium acetate (2.2 g, 29.1 mmol, 1.3 eq) were suspended in acetic acid (100%, 70 ml) and heated to reflux for 8 h. The solution was allowed to reach room temperature. The volume of the resulting suspension was reduced to half of the volume under reduced pressure. The mixture was poured on ice water and neutralized with caution using sodium carbonate. The aqueous layer was washed with ethyl acetate and the remaining precipitate filtered. Solid (E)-1-(2,5-dihydroxy-phenyl)-3-(5-fluoro-pyridin-3-yl)-propenone (2.4 g, 42%) was obtained as a brownish solid and used in the cyclization reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate In N,N-dimethyl-formamide; acetonitrile at 80℃; for 30h; | 7.1.5. General synthetic procedure for the preparation ofcompounds 12 General procedure: To a stirred solution of the corresponding dihydroxy acetophenone11 (19.736 mmol) and K2CO3 (21.71 mmol) in CH3CN/DMF(1:1) (30 mL), the corresponding alkyl bromide (21.71 mmol) wasadded. The resulting solution was heated at 80 °C until completeconversation of the starting material (~30 h). After cooling toambient temperature, the reaction mixture was concentrated underreduced pressure and diluted with ethyl acetate. The organicphasewas washed withwater, brine solution, dried over anhydrousNa2SO4, and then concentrated under reduced pressure. The residuewas subjected to flash silica gel (230e400 mesh) columnchromatography (eluting with 0-5% ethyl acetate in hexanes) toafford the title compounds 12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate In N,N-dimethyl-formamide; acetonitrile at 80℃; for 30h; | 7.1.5. General synthetic procedure for the preparation ofcompounds 12 General procedure: To a stirred solution of the corresponding dihydroxy acetophenone11 (19.736 mmol) and K2CO3 (21.71 mmol) in CH3CN/DMF(1:1) (30 mL), the corresponding alkyl bromide (21.71 mmol) wasadded. The resulting solution was heated at 80 °C until completeconversation of the starting material (~30 h). After cooling toambient temperature, the reaction mixture was concentrated underreduced pressure and diluted with ethyl acetate. The organicphasewas washed withwater, brine solution, dried over anhydrousNa2SO4, and then concentrated under reduced pressure. The residuewas subjected to flash silica gel (230e400 mesh) columnchromatography (eluting with 0-5% ethyl acetate in hexanes) toafford the title compounds 12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.6 g | With sulfuric acid; In cyclohexene; for 60h;Dean-Stark; Reflux; | In a reaction vessel equipped with a Dean-Stark apparatus and a condenser, 10.0 g of the compound represented by the formula (C-7-1)9.5 g of the compound represented by the formula (C-7-2)200 mL of cyclohexane and 0.4 g of concentrated sulfuric acid were added,And heated under reflux for 60 hours while removing water.After cooling, the solid was filtered and dispersed and washed with water.And dried to obtain 14.6 g of a compound represented by the formula (C-7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 2,5-Dihydroxyacetophenone With pyridine; water; potassium carbonate In acetone at 60℃; for 0.25h; Stage #2: benzoyl chloride In acetone Reflux; | General procedure for preparation of flavones16a-16e, 19a-19e, 22a-22e, 25a-25d. To a solutionof acetophenone (1 mmol) in wet acetone (containing1% w/w water) (20 mL/mmol) was added potassiumcarbonate (8 equiv.) and then pyridine (4 equiv.). Thesolution was stirred at 60°C for 15 min and aroylchloride (2 equiv.) was slowly added. The reactionmixture was stirred upon refluxing for 24-48 h. Aftercooling down to room temperature, acetone wasevaporated. Acetic acid (10%) was added, the solutionwas stirred till it stopped bubbling. The residue wasfiltered off, washed with water (2×50 mL) to make itneutral, vacuum-dried, and then crystallized fromacetone (20 mL) to produce pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 2,5-Dihydroxyacetophenone With pyridine; water; potassium carbonate In acetone at 60℃; for 0.25h; Stage #2: 4-chloro-benzoyl chloride In acetone Reflux; | General procedure for preparation of flavones16a-16e, 19a-19e, 22a-22e, 25a-25d. To a solutionof acetophenone (1 mmol) in wet acetone (containing1% w/w water) (20 mL/mmol) was added potassiumcarbonate (8 equiv.) and then pyridine (4 equiv.). Thesolution was stirred at 60°C for 15 min and aroylchloride (2 equiv.) was slowly added. The reactionmixture was stirred upon refluxing for 24-48 h. Aftercooling down to room temperature, acetone wasevaporated. Acetic acid (10%) was added, the solutionwas stirred till it stopped bubbling. The residue wasfiltered off, washed with water (2×50 mL) to make itneutral, vacuum-dried, and then crystallized fromacetone (20 mL) to produce pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 2,5-Dihydroxyacetophenone With pyridine; water; potassium carbonate In acetone at 60℃; for 0.25h; Stage #2: 4-methyl-benzoyl chloride In acetone Reflux; | General procedure for preparation of flavones16a-16e, 19a-19e, 22a-22e, 25a-25d. To a solutionof acetophenone (1 mmol) in wet acetone (containing1% w/w water) (20 mL/mmol) was added potassiumcarbonate (8 equiv.) and then pyridine (4 equiv.). Thesolution was stirred at 60°C for 15 min and aroylchloride (2 equiv.) was slowly added. The reactionmixture was stirred upon refluxing for 24-48 h. Aftercooling down to room temperature, acetone wasevaporated. Acetic acid (10%) was added, the solutionwas stirred till it stopped bubbling. The residue wasfiltered off, washed with water (2×50 mL) to make itneutral, vacuum-dried, and then crystallized fromacetone (20 mL) to produce pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium In methanol at 0℃; for 4h; Reflux; | 1.1 Step 1: Synthesis of Compound 2 Add Na (23 g, 1000 mmol) to 0 ° C in methanol (1 L), and when no H2 is evolved, add compound 1 (30.4 g, 200 mmol) and dimethyl oxalate (118 g, 1000 mmol), and warm to reflux for 4 h, cold To room temperature, concentrated hydrochloric acid (100 mL) was added, and the mixture was heated to reflux for 1 h.Cool to room temperature,Pour into ice water,filter,The solid is washed with cold methanol.And dried to give a gray-green solid (34.5g, 78%),I.e., Compound 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; potassium iodide In acetonitrile at 165℃; for 96h; | 3.1.1. General Procedure for Synthesis of Benzofuran Derivatives 3a-c under ConventionalTH Conditions General procedure: To a mixture of dihydroyacetophenone derivatives (5 mmol, 0.761 g), potassium carbonate(10 mmol, 1.382 g) and potassium iodide (a spatula tip) in 100 mL acetonitrile, methylchloroacetatewere added (10 mmol, 0.88 mL) at room temperature. Under conventional TH, the solution wasthen refluxed at 165 C for four days on an oil bath. After the completion of the reaction (TLC), theobtained solution was cooled at room temperature; water was added and then the compounds wereextracted with chloroform (3 50 mL), washed with a solution of sodium hydroxide (10%), dried andevaporated, with precipitate formation. The purification of the crude product was done by columnchromatography on silica gel (eluted with dichloromethane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate; potassium iodide In acetonitrile at 165℃; for 6h; Microwave irradiation; | 3.1.2. General Procedure for Syntheses of Benzofuran Derivatives 3a-c and 4a-c underMicrowave Irradiation General procedure: Under MW irradiation, the mixture of reagents were dissolved in 40 mL acetonitrile, placed in thereaction vessel (borosilicate), and exposed to microwave irradiation (for 3±6 h; see Table 1). Using MWirradiation, the best results were obtained using a temperature control method. The temperaturecontrol” method ensures a constant temperature (in this case 165 C) and the power and pressure arekept constant. This method takes place in three stages. In the first step the temperature is raised asquickly as possible (within less than 1 min) by applying the maximum power. In the second step thereaction mixture is kept at a constant temperature with the control of the magnetron power. In the laststep the reaction tube is cooled to 55 C by stopping the irradiation and blowing the reaction vial withcompressed air. Once the heating cycle is completed, the reaction vial is removed from the reactor, andprocessed as indicated for TH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; potassium iodide In acetonitrile at 165℃; for 15h; Microwave irradiation; | 3.1.2. General Procedure for Syntheses of Benzofuran Derivatives 3a-c and 4a-c underMicrowave Irradiation General procedure: Under MW irradiation, the mixture of reagents were dissolved in 40 mL acetonitrile, placed in thereaction vessel (borosilicate), and exposed to microwave irradiation (for 3±6 h; see Table 1). Using MWirradiation, the best results were obtained using a temperature control method. The temperaturecontrol” method ensures a constant temperature (in this case 165 C) and the power and pressure arekept constant. This method takes place in three stages. In the first step the temperature is raised asquickly as possible (within less than 1 min) by applying the maximum power. In the second step thereaction mixture is kept at a constant temperature with the control of the magnetron power. In the laststep the reaction tube is cooled to 55 C by stopping the irradiation and blowing the reaction vial withcompressed air. Once the heating cycle is completed, the reaction vial is removed from the reactor, andprocessed as indicated for TH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With perchloric acid In water at 20 - 100℃; for 1.08333h; | 1.a Example 1: Synthesis of Compound of Formula (1) First step a): HC(OEt)3, 70% HClO4-1) room temperature, 1 hour; 2) 100° C., 5 minutes in water, then room temperature (yield: 95%);Second step b): H2, Pd/C, 40° C., 8 hours, 5 bar (yield: 56%).The procedure is described by J. C. Jaen, L. D. Wise, T. G. Heffner, T. A. Pugsley, L. T. Meltzer: “Dopamine autoreceptor agonists as potential antipsychotics. 2. (Aminoalkoxy)-4H-1-benzopyran-4-ones.” in J. Med. Chem. 1991, 34, 248-256. It is followed for the first step a), which furnishes the intermediate in high yield and good selectivity. The crude intermediate enone is then hydrogenated using Pd/C in a second step b), furnishing chroman-6-ol in 53% yield over two steps. |
78% | With perchloric acid at 20℃; for 1.5h; | |
30.55% | With perchloric acid at 20℃; for 2h; | 4.7. General Procedure for Preparation of Chromones (II and V) General procedure: The series of compounds 5-9 and 19-22 (1 mmol) were suspended in triethyl orthoformate(TEOF) (0.5 mL), the resulting solutions were treated with 70% HClO4 (0.01 mL,0.17 mmol) slowly [15]. The mixtures were then stirred at room temperature for 2 h, andether (200 mL) was added, subsequently, the solution was filtered and the solid was purifiedby column chromatography with silica gel 60, eluting Hex:AcOEt (2:1) (v/v). Thesynthesis of chromones (10-13) and prenylated chromones (23-26) was achieved in anoverall yield of 30.4-70.2% and 8.21-40.1% respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 4h; Inert atmosphere; | 3.1.1. Synthesis of 5-(3-chloropropoxy)-2-hydroxy-acetophenone (1) 2,5-Dihydroxyacetophenone (2.0 g, 0.013 mol) was dissolved in dry DMF (13 mL). Then, K2CO3(1 eq, 1.8 g, 0.013 mol) and 1-bromo-3-chloropropane (1.1 eq, 1.4 mL, 0.0145 mol) were added.The reaction mixture was stirred under a nitrogen atmosphere heating at 80 C for 4 h. The solutionbecame dark. After cooling, it was diluted with water and extracted with ethyl acetate (three times).The combined organic layers were dried over anhydrous sodium sulfate, filtered and the solventevaporated under reduced pressure. The obtained dark oil was purified by flash columnchromatography in silica gel (hexane: ethyl acetate, 98:2) to produce compound 1 as a light-yellowsolid (1.13 g, 0.005 mol). Yield 38%. 1H-NMR (400 MHz, CDCl3): 2.16 (m, 2H), 2.55 (s, 3H), 3.70(t, 2H), 4.03 (t, 2H), 6.86 (1, 2H), 7.05 (dd, 1H), 7.14 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With pyrrolidine In ethanol at 45℃; for 24h; Molecular sieve; Inert atmosphere; | 1.3.a [0203] (a) Synthesis of benzopyran-4-one: 2,5-dihydroxyacetophenone (0.5 g, 3.28 mmol), ethyl levulinate (0.46 mL, 3.28 mmol) and pyrrolidine (0.87 mL, 9.86 mmol), were dissolved in absolute EtOH (10 mL) with a 3-Å (100 mg) molecular sieve.6 The mixture was shaken at 45°C for 24 h under a N2 atmosphere. Then the reaction mixture was filtered and the filtrate was diluted with CH2Cl2 (100 mL) and washed with HCI 1N (3 x 50 mL), H2O (3 x 50 mL) and brine (3 x 50 mL), dried on anhydrous Na2SO4 and evaporated in the rotary evaporator. The residue was purified by silica gel column chromatography (hexane-AcOEt, 70:30) to obtain the benzopyran-4-one (729 mg, 2.62 mmol, 80%) as a yellowish oil. NMR 1H (400 MHz, CDCl3) 7.34 (d, J= 3.0 Hz, H-5), 7.07 (dd, J= 8.9, 3.0 Hz, H-7), 6.80 (d, J= 8.9 Hz, H-8), 4.14 (q, J= 7.1Hz, 2H, COOCH2CH3), 2.78 (d, J= 16.7 Hz, 1H, CH2a-3), 2.63 (d, J= 16.7 Hz, 1H, CH2b-3), 2.53-2.46 (m, 2H, CH2-2'), 2.1 (m, 2H, CH2-1'), 1.38 (s, 3H, CH3-4'), 1.25 (t, J= 7.1Hz, 3H, COOCH2CH3); 13C NMR (100 MHz, CDCl3) 193.0 (C-4), 173.3 (COOCH2CH3-3'), 153.7 (C-8a), 150.2 (C-6), 125.2 (CH-7), 120.1 (C-4a), 119.5 (CH-8), 110.6 (CH-5), 79.8 (C-2), 60.8 (COOCH2CH3), 47.2 (CH2-3), 34.1 (CH2-1'), 28.7 (CH2-2'), 23.3 (CH3-4'), 14.1 (COOCH2CH3); EIMS m/z 278 [M: C15H18O5]+ (35), 233 (25), 177 (100), 137 (75); HREIMS (%) m/z 278.11408 [M]+ (278.11542 calc for C15H18O5). |
80% | With pyrrolidine In ethanol at 60℃; for 24h; Molecular sieve; |
[ 1990-24-5 ]
1-(2-Hydroxy-5-propylphenyl)ethanone
Similarity: 0.98
[ 876-02-8 ]
4'-Hydroxy-3'-methylacetophenone
Similarity: 0.95
[ 13494-10-5 ]
1-(2,3-Dihydroxyphenyl)ethanone
Similarity: 0.93
[ 1818-27-5 ]
1-(2,4,5-Trihydroxyphenyl)ethanone
Similarity: 0.93
[ 1990-24-5 ]
1-(2-Hydroxy-5-propylphenyl)ethanone
Similarity: 0.98
[ 876-02-8 ]
4'-Hydroxy-3'-methylacetophenone
Similarity: 0.95
[ 13494-10-5 ]
1-(2,3-Dihydroxyphenyl)ethanone
Similarity: 0.93
[ 1818-27-5 ]
1-(2,4,5-Trihydroxyphenyl)ethanone
Similarity: 0.93
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.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :