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CAS No. : | 122-99-6 | MDL No. : | MFCD00002857 |
Formula : | C8H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QCDWFXQBSFUVSP-UHFFFAOYSA-N |
M.W : | 138.16 | Pubchem ID : | 31236 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 38.9 |
TPSA : | 29.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.32 cm/s |
Log Po/w (iLOGP) : | 1.78 |
Log Po/w (XLOGP3) : | 1.16 |
Log Po/w (WLOGP) : | 1.06 |
Log Po/w (MLOGP) : | 1.21 |
Log Po/w (SILICOS-IT) : | 1.54 |
Consensus Log Po/w : | 1.35 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.67 |
Solubility : | 2.93 mg/ml ; 0.0212 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.37 |
Solubility : | 5.85 mg/ml ; 0.0423 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.34 |
Solubility : | 0.627 mg/ml ; 0.00454 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.16 |
Signal Word: | Danger | Class: | N/A |
Precautionary Statements: | P501-P261-P270-P271-P264-P280-P301+P312+P330-P304+P340+P312-P305+P351+P338+P310-P403+P233-P405 | UN#: | N/A |
Hazard Statements: | H302-H318-H335-H336 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.8% | With benzenesulfonyl chloride In 1-methyl-pyrrolidin-2-one at 20 - 100℃; for 0.5 h; | At room temperature, 2.5 mL of N-methylpyrrolidone (NMP), 1.38 g (10 mmol) of 2-benzeneOxyethanol and 1.5 mL (11 mmol) of benzenesulfonyl chloride. Mixed uniformly, and reacted at 100 ° C for 30 min under stirring. stopAfter the reaction mixture was cooled to room temperature, 30 mL of dichloromethane and 30 mL of water were added, and the mixture was thoroughly mixed,The organic layer was washed with saturated brine, driedThe crude product was obtained by evaporation of methylene chloride. Further chromatography afforded 1.52 g of colorless liquid, and the yield was 96.8percent. |
94% | With pyridine; thionyl chloride In toluene at 10 - 80℃; Large scale | 10233] In to clean, dry, nitrogen flushed 750 1 GER, charged toluene (150 E), 2-phenoxyethanol (15 kg, 0.108 mol) and pyridine (1.2 kg, 0.162 mol, 0.15 equiv). reaction mass was cooled to 10-15° C., added thionyl chloride (19.3 kg, 0.162 mol, 1.5 equiv) over 90 mm. The reaction mixture was then heated to reflux and maintained for 10-12 h. After the reaction completion, it was cooled to 10-15° C. andquenched with water (500 L). The aqueous phase was separated and discarded. The washing procedure was repeated one more time before the vessel was set for vacuum distillation and heated at less than 60° C. until toluene (500L) had been removed. The residue was then cooled to 30-35° C. before being transferred to a smaller vessel (16 kg, 94percent, 95.89percent HPLC purity).10234] ‘H NMR (400 MHz, DMSO-d6): ö 7.27-7.31 (t, 2H), 6.94-6.96 (t, 3H), 4.22-4.25 (t, 2H), 3.95-4.0 (t, 2H); HPLC: 95.89percent at 210 nm. |
83% | With pyridine; thionyl chloride; sodium sulfate In toluene | a. Preparation of 1-Chloro-2-phenoxyethane To a flask was added 41.5 grams (g.) (0.3 mole) of 2-phenoxyethanol, 50 ml of toluene and 3.93 g. of pyridine, then 39.3 g. (0.33 mole) of thionyl chloride dropwise while stirring at room temperature. The exothermic reaction was heated at 50°-60° C. for two hours. After cooling to room temperature, the resulting salt was filtered and washed with methylene chloride. The filtrate was washed several times with aqueous sodium bicarbonate, dried using sodium sulfate, and then concentrated to obtain 39 g. of the 1-chloro-2-phenoxyethane as a yellow oil (83percent yield). |
66.8% | With thionyl chloride In N,N-dimethyl-formamide at 50℃; for 5 h; | Plus phenoxyethanol(7a, 4.5 mmol), THF (5 mL), SOCl2 (1 mL), DMF (2 drops), and the reaction was carried out at 50C for 5 h. reaction The reaction solution was concentrated under reduced pressure to dryness to give crude product. Column chromatography (petroleum ether / ethyl acetate 20/1, V / V) gave a colorless liquid, yield 66.8percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hydroxide; chlorine; sodium hydrogensulfite In hydrogenchloride; methanol; water | EXAMPLE 1 Preparation of 2-(2,4,6-trichlorophenoxy)-ethanol: in the presence of hydrogen chloride (Stage I (a) Into a three-necked, round-bottomed 1-liter flask fitted with a stirrer, thermometer, reflux condenser, and a gas sparger are added 70 g of 2-phenoxyethanol dissolved in 125 ml of HCl (32percent). The reaction mixture is cooled with stirring to 0°-25° C. and chlorine gas is added at a rate sufficient to keep the temperature at 0° C. 5° C. cooling when necessary. During the reaction a second liquid phase appears. After adding two thirds of the chlorine (about 7 hours) the temperature is raised to 25° C. and the remaining chlorine is added at a slower rate (additional 8 hours) where a total of 125 g of chlorine are added. The stirring is stopped and the lower organic layer is poured into 100 ml of 20percent stirred solution of sodium bisulfite kept at a temperature of 70° C. A 10percent sodium hydroxide solution is added until a pH of 7.5 is reached, the stirring is stopped, the lower organic layer is separated, dissolved in 150 ml methanol and 50 ml water kept at 45° C. The resulting solution is cooled to 0°-5° C. to precipitate the crystalline product. The crystals are filtered, washed with water, and dried to yield 2-(2,4,6-trichlorophenoxy)-ethanol in a yield of 88percent having a purity of 98-99percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.2% | at 130℃; for 4 h; Inert atmosphere | Example 12 A reaction was carried out by (a) adding 80.0 g (0.444 mol) of fluorenone, 613.5 g (4.44 mol) of 2-phenoxyethanol, and 2.0 g of tungstophosphoric acid [(H3PW12O40).nH2O] serving as a catalyst to a glass reactor vessel equipped with a stirrer, a nitrogen-blowing tube, a thermometer and a T-tube and (b) allowing a mixture to react for 4 hours under a reduced pressure of 2.0.x.103 Pa at 130° C. The content of multimers in a reaction mixture obtained after completion of the reaction was 3.9percent. To the reaction mixture thus obtained, 800.0 g of toluene was added. The reaction mixture was neutralized with a sodium hydroxide aqueous solution and washed with water. Thereafter an organic phase was separated. Toluene and excess 2-phenoxyethanol were removed from an obtained organic phase by concentration under reduced pressure. To an obtained concentrate, 560.0 g of toluene was added, and the mixture was heated and stirred at 80° C. for 1 hour and thereafter directly cooled to 70° C. Thereafter, 0.4 g of crystals of 9,9-bis(4-(2-hydroxyethoxy)phenyl)fluorene serving as seed crystals were added, and a mixture was incubated at 70° C. for 2 hours and thereafter directly cooled to 20° C. Then, precipitated crystals were subjected to filtration and drying to obtain 78.0 g of white crystals of 9,9-bis(4-(2-hydroxyethoxy)phenyl)fluorene (yield: 90.2percent, purity: 99.2percent). The 9,9-bis(4-(2-hydroxyethoxy)phenyl)fluorene thus obtained had a melting point of 163° C. |
85.4% | at 50℃; for 18 h; Inert atmosphere | A thermometer, a stirrer, 2 - neck flask equipped with condenser 4 544.7 g phenoxyethanol (3.94mol) as raw materials, the reaction vessel was replaced with nitrogen after, at 40 °C 840.7 g was added methanesulfonic acid (8.75mol). Then, 3.8 g of β - mercaptopropionic acid were added at 50 °C, 2 - phenoxyethanol is 9 - fluorenone (1.93mol) dissolved therein (3.78mol) 521.9 g 347.9 g was added dropwise over 1 hour at 50 °C solution after the reaction. After the completion of the dropping, stirring was carried out at 50 °C 17 hours. By using high-performance liquid chromatography analysis of the reaction solution as a result of calibration curve, 9, 9 - bis (4 - (2 - hydroxyethoxy) phenyl) fluorene in the reaction liquid is present in the yield of 85.4percent. After completion of the reaction, stirring 1287.2 g toluene, 50 °C 890.9 g water was added followed by order, standing water layer 1664 g being pulled. In 48percent aqueous methanesulfonic acid concentrations, the recovery rate was 95percent. Thereafter heated to 80 °C, 16percent sodium hydroxide aqueous solution was added 3 hours 1042.4 g. After stirring, the aqueous layer was extracted after standing, 75percent phosphoric acid aqueous solution was added to the neutralizing aqueous 347.9 g and 14.3 g. After that, the water layer to settle out, water is added after stirring at 80 °C 347.9 g oil, water washing operation was performed twice to remove isolation layer 2. Oil obtained from toluene, 2 - phenoxyethanol was removed by vacuum distillation of the excess. After distillation of the residual liquid is added to the homogeneous solution after toluene 2435.3 g, 2 hours to precipitate out at 65 °C, 25 °C gradually cooled filtrate the deposited crystal, drying the crude crystal 630.4 g was obtained. The 97.6percent purity by analytical high-performance liquid chromatography was. 60.0 g of crude crystals were obtained with a thermometer, a stirrer, a cooling pipe 4 neck flask equipped with a charge and, after nitrogen substitution, addition of 1 - butanol 120.0 g, 78 °C temperature raised to dissolve. Thereafter, 9, 9 - bis [4 - (2 - hydroxyethoxy) phenyl] fluorene is 75 °C at high melting point crystalline seed crystal was added, 1 hour at 55 °C crystalline precipitate. After heated up to 65 °C, gradually cooling the precipitated crystal was filtered off 25 °C. The resulting crystals under vacuum, dried and heated to 80 °C, 9, 9 - bis [4 - (2 - hydroxyethoxy) phenyl] fluorene 52.8 g was obtained. 88percent yield for crude crystals which, 98.7percent purity by analytical high-performance liquid chromatography was. Fig. 1 shows the data obtained from DSC crystal. An endothermic maximum temperature: (differential scanning calorimetry) 121.1 °C |
75.1% | for 12 h; Inert atmosphere; Reflux | Example 3: Production of crude product Into a glass reactor equipped with a stirrer, a nitrogen blowing tube, a thermometer and a water separator with cooling tube was added 86.4 g (0.48 mol) of fluorenone, 397.9 g (2.88 mol) of phenoxyethanol, 350 g of toluene and 4.3 g of phosphotungstic acid [(H3PW12O40)] which had been dried under reduced pressure at 100°C to remove crystal water, and the mixture was stirred for 12 hours while removing generated water out of the system, under toluene reflux. The resultant reaction liquid was analyzed by high performance liquid chromatography to find generation of 197.3 g (0.45 mol) of 9,9-bis(4-(2-hydroxyethoxy)phenyl)fluorene. To this reaction liquid was added 300 g of toluene, and water-washed at 80°C using 100 g of water. The resultant organic layer was cooled gradually, to find initiation of deposition of a crystal at 12°C, and the organic layer was cooled down to 10°C without any other procedure, and stirred for 12 hours. The deposited crystal was taken out by filtration, and the crystal was dried to obtain 158.0 g (yield: 75.1percent, LC purity: 99.9percent) of a white crystal of a crude product of 9,9-bis(4-(2-hydroxyethoxy)phenyl)fluorene. The resultant crystal had a melting point (melt endotherm maximum by differential scanning calorimetry) of 109°C, and a bulk density of 0.24 g/cm3. |
104.5 g | at -40 - 80℃; for 17 h; Autoclave; Inert atmosphere | 500 ml stainless steel reactor was added fluorenone 50 g (0.277), ethylene glycol monophenyl ether, 172.5 g, 0.6 g 3-mercaptopropionic acid, sealed reactor, pressure tested with nitrogen, the reactor sealed after confirmation, system was purged twice with nitrogen, the autoclave was cooled to -40 ~ -50 ° C , slow flow of anhydrous hydrogen fluoride gas is condensed to a liquid hydrogen fluoride in a reactor, to the reactor 150 g weight gain, hydrogen fluoride was stopped.The reaction vessel was heated to 70 ~ 80 ° Creaction for 17 hours.The reaction system was cooled to 40 ~ 50 ° C, slowly open the exhaust valve, exhaust gas is hydrogen fluoride, hydrogen fluoride gas recovery after a condenser to condense the hydrogen fluoride until the basic system is discharged to the reaction vessel purged with nitrogen, the remaining hydrogen fluoride rush out, stop nitrogen.Was slowly added to the kettle 6percent potassium bicarbonate 150 g, was heated to 70 ~ 80 ° C, stirred for 15 minutes, 150 g of toluene was added, stirred for 20 minutes, allowed to stand, the organic phase was separated, the aqueous phase with 60 g of toluene extracted once, and the combined organic phase was washed with pure water twice the amount of 60 grams.The organic phase cooling crystallization, filtration, washing, drying dryness to give 9,9-bis [(4-hydroxy) phenyl]fluorene 104.5 g, 99.2percent purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.5 g | Stage #1: at 70℃; for 3 h; Inert atmosphere Stage #2: at 110℃; for 9 h; Inert atmosphere |
mixer,Nitrogen blowing tube,23.5 g (0.17 mol) of 2-phenoxyethanol was charged in a glass reactor equipped with a thermometer and a cooling tube,After replacing the reaction vessel with nitrogen,A mixed solution of 10.0 g (0.0425 mol) of 9,9-dichloro-9H-fluorene and 11.7 g (0.08 mol) of 2-phenoxyethanol was added dropwise at 70 ° C. over 1 hour with stirring.After completion of the dropwise addition,After stirring at 70 ° C. for 2 hours,4.1 g (0.04 mol) of methanesulfonic acid was added and stirred at 110 ° C. for 9 hours. As a result of analyzing the obtained reaction solution by high performance liquid chromatography,The composition value of 9,9-bis [4- (2-hydroxyethoxy) phenyl] fluorene was 72.5percent (area percentage / 2-phenoxyethanol excluded). From the composition value, formation of 13.5 g of 9,9-bis [4- (2-hydroxyethoxy) phenyl] fluorene was confirmed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 35 - 40℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 2-Phenoxyethanol With di-isopropyl azodicarboxylate; N-hydroxyphthalimide resin; triphenylphosphine In dichloromethane at 20℃; for 24h; Stage #2: With methylamine In methanol; chloroform at 20℃; for 2h; | |
With chloroamine; diethyl ether; sodium weiteres Reagens: Benzol; | ||
Multi-step reaction with 2 steps 1: 72 percent / diethyl azodicarboxylate, triphenylphosphine / tetrahydrofuran / 16 h / Ambient temperature 2: 63 percent / hydrazine monohydrate / methanol / 4 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.8% | With benzenesulfonyl chloride; In 1-methyl-pyrrolidin-2-one; at 20 - 100℃; for 0.5h; | At room temperature, 2.5 mL of N-methylpyrrolidone (NMP), 1.38 g (10 mmol) of 2-benzeneOxyethanol and 1.5 mL (11 mmol) of benzenesulfonyl chloride. Mixed uniformly, and reacted at 100 C for 30 min under stirring. stopAfter the reaction mixture was cooled to room temperature, 30 mL of dichloromethane and 30 mL of water were added, and the mixture was thoroughly mixed,The organic layer was washed with saturated brine, driedThe crude product was obtained by evaporation of methylene chloride. Further chromatography afforded 1.52 g of colorless liquid, and the yield was 96.8%. |
96% | With 1-methyl-pyrrolidin-2-one; benzenesulfonyl chloride; In 1,2-dichloro-ethane; at 80℃; for 1.5h; | General procedure: In a round-bottom flask, benzylic alcohol 1a (10 mmol, 2.0 equiv.), benzenesulfonyl chloride 2a (13 mmol, 1.3 equiv.) and NMP (2.5 equiv.). Then, DCE (3 mL) were added. The mixture was stirred at 80 C for 1.5 h. After completion of the reaction (monitoredby TLC), water (10 mL) was added and the mixture was extracted with ethyl acetate (3*10 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel to give the desired alkyl chlorides 3. |
94% | With pyridine; thionyl chloride; In toluene; at 10 - 80℃;Large scale; | 10233] In to clean, dry, nitrogen flushed 750 1 GER, charged toluene (150 E), 2-phenoxyethanol (15 kg, 0.108 mol) and pyridine (1.2 kg, 0.162 mol, 0.15 equiv). reaction mass was cooled to 10-15 C., added thionyl chloride (19.3 kg, 0.162 mol, 1.5 equiv) over 90 mm. The reaction mixture was then heated to reflux and maintained for 10-12 h. After the reaction completion, it was cooled to 10-15 C. andquenched with water (500 L). The aqueous phase was separated and discarded. The washing procedure was repeated one more time before the vessel was set for vacuum distillation and heated at less than 60 C. until toluene (500L) had been removed. The residue was then cooled to 30-35 C. before being transferred to a smaller vessel (16 kg, 94%, 95.89% HPLC purity).10234] ?H NMR (400 MHz, DMSO-d6): oe 7.27-7.31 (t, 2H), 6.94-6.96 (t, 3H), 4.22-4.25 (t, 2H), 3.95-4.0 (t, 2H); HPLC: 95.89% at 210 nm. |
83% | With pyridine; thionyl chloride; sodium sulfate; In toluene; | a. Preparation of 1-Chloro-2-phenoxyethane To a flask was added 41.5 grams (g.) (0.3 mole) of 2-phenoxyethanol, 50 ml of toluene and 3.93 g. of pyridine, then 39.3 g. (0.33 mole) of thionyl chloride dropwise while stirring at room temperature. The exothermic reaction was heated at 50-60 C. for two hours. After cooling to room temperature, the resulting salt was filtered and washed with methylene chloride. The filtrate was washed several times with aqueous sodium bicarbonate, dried using sodium sulfate, and then concentrated to obtain 39 g. of the 1-chloro-2-phenoxyethane as a yellow oil (83% yield). |
66.8% | With thionyl chloride; In N,N-dimethyl-formamide; at 50℃; for 5h; | Plus phenoxyethanol(7a, 4.5 mmol), THF (5 mL), SOCl2 (1 mL), DMF (2 drops), and the reaction was carried out at 50C for 5 h. reaction The reaction solution was concentrated under reduced pressure to dryness to give crude product. Column chromatography (petroleum ether / ethyl acetate 20/1, V / V) gave a colorless liquid, yield 66.8% |
With pyridine; thionyl chloride; In chloroform; at 60 - 65℃; | General procedure: To a solution of 0.85 g of freshly distilled thionyl chloridein 15 mL of anhydrous chloroform precooled to 0-5C was successively added 0.56 g of anhydrous pyridine. Next a solution of 12.7 g of 2-(2-fluorophenoxy)ethanol 6b in 15 mL of anhydrous chloroform was added dropwise with vigorous stirring within 1 h, maintaining the temperature of the reaction mixture below 10C. The resulting mixture was slowly heated in a water bath to 60-65C and kept at this temperature until gas evolution ceased. After distilling off the volatiles, the residue was treated with 20 mL of water and 20 mL of benzene, and the organic layer was separated and dried over calcium chloride. Benzene was distilled off, the residue was distilled, collecting the fraction with bp 124-127C (35 mmHg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With pyridine at 20℃; for 12h; | |
70% | With triethylammonium acetate at 20℃; for 3h; | Typical Procedure General procedure: To a stirred solution of 2-naphthol (0.2 mmol) in TEAA(2 ml), was added acetic anhydride (0.22 mmol). The solutionwas stirred for 3 hours at room temperature. After consumptionof starting material (TLC monitoring, ethyl acetate/hexane, 2:8), the product formed was diluted with 1 mlH2O and extracted with 3 x 2 ml ether. The combined organiclayer was separated, dried (Na2SO4), and evaporatedunder reduced pressure to afford the desired product. 1H and13C NMR spectra were in full accordance with the structureproposed. The water in the aqueous layer was distilled under reduced pressure leaving behind the TEAA which was furtherrecycled. |
at 150℃; im Druckrohr; |
exothermic; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dmap; oxo[hexa(trifluoroacetato)]tetrazinc In neat (no solvent) at 80℃; for 24h; Inert atmosphere; Schlenk technique; chemoselective reaction; | |
With toluene-4-sulfonic acid; hydroquinone Entfernen des entstehenden Methanols; | ||
With sulfuric acid; hydroquinone Entfernen des entstehenden Methanols; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; hydroquinone Entfernen des entstehenden Aethanols; | ||
With toluene-4-sulfonic acid; hydroquinone Entfernen des entstehenden Aethanols; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In water; at 70℃; for 6h; | 85.8 g of water were added to 33.0 g of sodium phenolate trihydrate, and the mixture was stirred until dissolved. A solution of 15.6 g of 2-chloroethanol in12.9 g water was prepared separately. The aqueous solution of sodium phenolate trthydrate was heated to 70C and the aqueous solution of 2-chloroethanol was added to the solution dropwise continuously during a 1 hour time period while maintaining the temperature at 70C. The reaction was performed for 5 hours at the temperature of 70C. After the reaction mixture was allowed to cool to room temperature, theproduct was extracted with methylene chloride to form an organic phase. The organic phase was washed twice with a 5% aqueous solution of sodium hydroxide, and the solvent was distilled off. Phenoxyethano 1 was fractionally distilled under decreased pressure in an apparatus comprising a packed column, where a fraction with a boiling point within the range of 95C to 120C was collected. 22.0 g ofphenoxyethanol were obtained, which is 82% w/w of the theoretical yield.[0033j The phenoxyethanol was analyzed by mass spectrum (MS) analysis, infrared (IR) spectroscopy analysis, and 1H-NMR spectroscopy analysis, as shown in FIGS. 2-4. The MS spectrum of FIG. 2 evidences C - 68.78% (theoretic 69.52); H - 7.39% (theoretic 7.3 1%). TheIR spectrum evidences 0-H at 3340 cm1, C-Haromatic at 3062 cm1 and 3040 cm1, CH2 at 2930 cm1 and 2873 cm1, C=C at 1597 cm1, 1587 cm1, and 1495 cm1, aryl-0-C at 1241 cm1 and 1040 cm1, CH2-OH at 1078 cm1, C-H aromatic at 750 cm1, and C=C aromatic at 690 cm1. |
In water; at 60℃; for 2h; | In 500 ml container add 10mol/L phenol sodium aqueous solution 100 ml, 2-chlorohydrin 67.1 ml, copper chloride and ferric chloride mixed solid 17.05g (copper chloride and ferric chloride mass ratio is 3:1), heating to 60 C start timing reflux reaction 2 hours, cooled to room temperature after the reaction to collect organic layer, the organic layer used for quality concentration is 3% aqueous sodium hydroxide solution of washing 2 times to obtain 2- phenoxyethyl alcohol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In tetrahydrofuran | ||
With triethylamine In acetonitrile | 156 Methylsulfamic acid 2-phenoxyethyl ester EXAMPLE 156 Methylsulfamic acid 2-phenoxyethyl ester This compound was prepared according to the procedure used in Example 112. Thus, a mixture of 14.8 g (0.1 mole) of 2-phenoxyethanol (Matheson, Coleman, and Bell), 15.6 g (0.12 mole) of methylsulfamoyl chloride and 12.3 g (0.12 mole) of triethylamine in 150 ml of acetonitrile gave a viscous oil that solidified upon standing. The solid was recrystallized from benzene-petroleum ether (30°-60° C.) to yield 15.4 g (67%) of shiny, white flakes, mp 66°-68° C. Analysis: Calculated for C9 H13 NO4 S: C, 46.74; H, 5.67; N, 6.06; Found: C, 46.68; H, 5.75; N, 6.07. | |
With triethylamine In acetonitrile | 114 Methylsulfamic acid 2-phenoxyethyl ester EXAMPLE 114 Methylsulfamic acid 2-phenoxyethyl ester This compound was prepared according to the procedure used in Example 112. Thus, a mixture of 14.8 g (0.1 mole) of 2-phenoxyethanol (Matheson, Coleman, and Bell), 15.6 g (0.12 mole) of methylsulfamoyl chloride and 12.3 g (0.12 mole) of triethylamine in 150 ml of acetonitrile gave a viscous oil that solidified upon standing. The solid was recrystallized from benzene-petroleum ether (30°-60° C.) to yield 15.4 g (67%) of shiny, white flakes, mp 66°-68° C. Analysis: Calculated for C9 H13 NO4 S: C, 46.74; H, 5.67; N, 6.06. Found: C, 46.68; H, 5.75; N, 6.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | at 0℃; for 8h; | |
With copper(I) chloride; sodium carbonate In benzene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tungstophosphoric acid-modified zirconia; In toluene; at 110℃; for 14h; | General procedure: testIn all the reactions, a 25 cm3round-bottomed flask, at thereaction temperature and connected with a water jacketed con-denser, was used. In a typical experience, the reactor was loadedwith a mixture of 1 mmol of 2-phenylethanol (122 mg), 5 mmolof acetic acid (300 mg), 5 cm3of toluene and 100 mg of the cata-lyst. The mixture was stirred at 700 rpm. Samples were withdrawnfrom the organic phase at different intervals (1, 3, 5, 7, 10 and14 h). Each sample volume was approximately 10 mm3and wasdiluted with 2 cm3of acetonitrile. The concentration of substrateswas calculated with the corresponding areas, using a ShimadzuHP2010 gas chromatography instrument (Chromopack CP Sil 8 CB,30 m × 0.32 mm ID). A similar procedure was followed with theother studied alcohols and phenols.After 14 h of reaction, the solution was concentrated undervacuum, and the residue was purified by column chromatogra-phy employing silica gel as the stationary phase and a mixtureof hexane-ethyl acetate as the elution solvent. The reaction prod-ucts were identified by chromatographic comparison with standardsamples. The conversion was expressed as the ratio of moles ofproducts to moles of initial alcohol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.7% | With sodium hydroxide; In water; at 90℃; for 12h; | General procedure: Phenol or phenol derivatives (10 mmol) was dissolved in NaOH aqueous solution (25 mL, 15 mmol), 2-bromoethanol (1.06 mL, 15 mmol) was added. Then heating to 90 for 12h. When cooled to room temperature, dilution with 15 mL water. The mixture was extracted with CH2Cl2(50 mL), The organic layer was washed with 10% NaOH (30 mL), water (30 mL) and brine (30 mL), dried over sodium sulfate. The solvent was evaporated in vacuo to afford the products.2-phenoxy ethanolColorless oil, 66.7%.1H-NMR (400 MHz, CDCl3) delta 7.26-7.32 (m,J= 8.7, 7.4 Hz, 2H), 6.91-6.99 (m, 3H), 4.07-4.09 (m, 2H), 3.94-3.98 (m,J= 9.1, 4.9 Hz, 2H), 2.15-2.18 (t,J= 5.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With [ReOCl2(1,2-bis(diphenylphosphino)ethane)]; hydrogen; potassium tetraphenylborate; In tetrahydrofuran; at 160℃; under 30003 Torr; for 24h;Autoclave; Inert atmosphere; | General procedure: By the following method, it went 3-reduction of phenylpropionic acid (hydrogenation).Put a stir bar in a dry glass tube (25mL), further, 3-phenylpropionic acid (75.09mg, 0.5mmol), the rhenium complex 4 (7.07mg, 0.010mmol), potassium tetraphenylborate (17.92mg , accommodates 0.05 mmol), the tubes containing this mixture, was inserted into the autoclave. Then, after replacing the inside of the autoclave in an argon gas atmosphere was added while continuing flow of argon gas dehydration toluene (4.0mL). This autoclave through a stainless steel tube by introducing hydrogen gas from a hydrogen gas cylinder connected, the inside of the autoclave was replaced with hydrogen gas, then disconnect the hydrogen gas pressure from the leak valve. This operation - was repeated (substituted de substitution) five times. Finally, the hydrogen gas pressure in the autoclave was set to 4 MPa, using a constant temperature bath, and allowed to react for 12 hours at 180 C. After completion of the reaction, the autoclave was cooled by immersion in an ice bath, almost to room temperature. Then, carefully release the hydrogen gas that is inside in the draft. After removing the solvent, the reaction product was analyzed by 1H NMR using mesitylene (60.1 mg, 0.5 mmol) as an internal standard substance. As a result, 3-phenylpropyl alcohol, and 3-phenylpropionic acid 3-phenylpropyl The yield was 98% and 1%, respectively. In the above Examples 6-1,Substrate (carboxylic acid compounds), and hydrogenation conditions (hydrogen pressure),Except that to adopt the conditions described in Table 7-9,It has been reduced (hydrogenated) in the same manner as in Example 6-1.However,The entry 19-26 in Table 9,Using tetrahydrofuran (THF) as a solvent.The results are shown in Tables 7 to 9. |
94% | With strain of the zygomycete fungus S. racemosum MUT 770; In dimethyl sulfoxide; for 72h;Enzymatic reaction; | 2.3. Biotransformation experimentsFungal strains were pre-grown in Petri dishes containing maltextract solid medium (MEA: 20 g L-1 glucose, 20 g L-1 malt extract,20 g L-1 agar, 2 g L-1 peptone) from which the inoculum for liquidcultures was set up. The fungus was inoculated as conidia suspen-sion (1 106 conidia/mL) in 50 mL asks containing 40 mL of maltextract liquid medium. Flasks were incubated at 25 C and weremaintained under agitation (110 rpm).After 2 days of pre-growth, a 500 mM solution of the substratein DMSO was added, to a starting substrate concentration (c0) of1-5 mM. For each substrate, three biological replicates were run.The experiment was run for 3 days after the addition of the sub-strates, during which time 1 mL samples were taken, at speciedintervals (usually 24, 48, and 72 h). Each sample was extractedwith EtOAc (500 L), the organic phase was dried over anhydrousNa2SO4 and analysed by means of GC/MS. In some cases (see Section2.4) the isolation of the reduced product has been carried out.For each set of biotransformations, one ask was used to mea-sure the initial biomass and pH before the addition of the substrate.These parameters were also evaluated at the end of the experimentfor all the asks. The liquid media was separated from the biomassby ltration and was used for pH measurement while the myceliawere dried at 60 C for 24 h to measure the biomass dry weight. 2-Phenoxyethanol: from phenoxyacetic acid (25.9 mg, 94%) andfrom methyl phenoxyacetate (26.4 mg, 96%). 1H NMR (400 MHz,CDCl3, TMS): = 7.28 (m, 2H, aromatic hydrogens), 6.93 (3H, m,aromatic hydrogens), 4.08 (m, 2H, PhOCH2CH2OH), 3.94 (m, 2H,PhOCH2CH2OH). 13C NMR (100 MHz, CDCl3, TMS): = 158.6, 129.4,121.0, 114.6, 69.2, 61.2. GC/MS: tR = 11.82 min, m/z 138 (M+, 27), 94(100), 77 (32). |
88% | With 1,1,3,3-Tetramethyldisiloxane; copper(II) bis(trifluoromethanesulfonate); In toluene; at 80℃; for 16h;sealed tube; | General procedure: In a sealed tube, 29 mg Cu(OTf)2 (0.08 mmol, 8 mol %) and 0.7 mL TMDS (537 mg, 4 mmol, 8 Si-H mol/mol substrate) were introduced to a solution of aliphatic carboxylic acid (1 mmol) in 1.5 mL toluene. After stirring 16 h at 80 C, the reaction mixture was cooled to room temperature and quenched with 4 mL H2O. The organic layer was extracted with CH2Cl2, dried with anhydrous MgSO4, and evaporated under reduced pressure. The crude was purified by silica gel column chromatography to obtain the alcohol. |
75% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 4h; | Plus lithium tetrahydrate(0.35 g, 9.15 mmol),Anhydrous tetrahydrofuran (THF, 10 mL),Stir,A solution of phenoxyacetic acid (4 c, 6.1 mmol) in THF (10 mL) was slowly added dropwise. After completion of the drop, room temperature reaction 4h. The reaction was terminated, the remaining LiAlH4 was extracted with a small amount of water, and the appropriate amount of ethyl acetate was added. The mixture was filtered and the solid was filtered off. The solution was concentrated to dryness under reduced pressure to give a colorless transparent liquid in 75% |
99.6%Chromat. | With cobalt(II) oxide; hydrogen; In 1,4-dioxane; at 179.84℃; under 15001.5 Torr; for 7h;Autoclave; | General procedure: The hydrogenation of carboxylic acids or other substrates was performed in a high-pressure stainless-steel autoclave (Xinyuan Chemical Machinery, Series CJK, 300 mL) with a maximum stirring rate of 1500 r/min. In a typical experiment, 0.2 g of catalyst (or without catalyst for the control experiment), 3 mmol of the substrate, and 100 mL alkane solvent (n-hexane, n-heptane, i-octane, or n-dodecane) were well mixed in the autoclave and purged with pure nitrogen at room temperature. The gas supply and discharge were carried out manually through needle valves. The autoclave was rapidly heated to the desired temperature and hydrogen was introduced at 2 MPa to initiate the reaction. The reaction pressure was kept at 2 MPa with a small negative deviation (?0.2 MPa) owing to the consumption of hydrogen. Samples of the liquid phase were continuously taken through a sampling tube with a filter at certain intervals. The stirring rate was kept at 750 r/min during the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.7% | With pyridine; In dichloromethane; at 0 - 20℃; for 1h; | General procedure: Substituted phenyl ethanol(5 mmol) was dissolved in CH2Cl2(30 mL), then cooled to 0. Bromoacetyl bromide (0.53 mL, 6 mmol) was added and followed by addition of pyridine (0.48 mL, 6 mmol). The mixture was stirred at room temperature for 1h. The reaction was quenched by addition of water (30 mL). The organic layer was separated, washed with water (20 mL) and brine (20 mL), dried over sodium sulfate. The solvent was evaporated in vacuo to afford the products.2-bromoacetic acid-2-phenoxy ethyl esterColorless oil, 80.7%.1H-NMR (400 MHz, CDCl3) delta 7.28-7.32 (m,J= 8.7, 7.4 Hz, 2H), 6.96-7.00 (m,J= 7.4 Hz, 1H), 6.90-6.92 (m,J= 7.8 Hz, 2H), 4.53-4.56 (m, 2H), 4.19-4.22 (m, 2H), 4.11 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | General procedure: The starting material, 2-(3,4-dimethoxyphenyl)-ethan-1-ol (521 mg, 2.86 mmol, 1.0 equiv) was dissolved in dichloromethane (20 mL) and imidazole (583 mg, 8.58 mmol, 3.0 equiv) was added. The mixture was stirred for 5 minutes. tert-Butyldimethylsilyl chloride (518 mg, 3.43 mmol, 1.2 equiv) was added and the reaction mixture was stirred at room temperature for 1 hr. Water (20 mL) and dichloromethane (20 mL) were added and the mixture was shaken in a separating funnel. The aqueous layer was separated and washed with dichloromethane (2 x 5 mL). The combined organic layers were washed with water (20 mL), brine (20 mL) and dried over MgSO4. Following filtration, the solvent was removed under reduced pressure. The crude material was purified by column chromatography on silica gel (eluting with a gradient from petroleum ether to 1:1 petroleum ether : ether) to afford 820mg of 1a (97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.1% | A mixture of phenol (9.41g, 100mmol) and NaOH (8.00g, 200mmol) in water (40mL) was stirred for 10min. 2-Chloroethanol (8.53g, 106mmol) was added dropwise and refluxed for 40h. The aqueous layer was extracted three times with dichloromethane (3×40mL), and the combined organic portions were washed with H2O (3×30mL). The resulting residue was dried over MgSO4 and filtered. The removal of solvent at reduced pressure gave the desired product 1L1 as colorless oil (7.33g, yield=53.1%). | |
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 6 - 10h; | To 150 mL of N, N-dimethylformamide were added 0.1 mol of substituted phenol (ArOH), 0.2 mol of Cl(CH2)pOH and 0.2 mol of anhydrous potassium carbonate and the resulted mixture was kept at 110C for 6-10h. Then the solvent was distilled, and a small amount of water was added. After being extracted with methylene chloride, the solution was washed with dilute sodium hydroxide, then washed with water to neutral, dried. The solution was evaporated to give ArO (CH2)POH which was used directly in the next reaction. To 150 mL of methylene chloride were added 0.1 mol of ArO(CH2)POH or Ar(CH2)POH and 0.2 mol of pyridine, and then a solution of 0.11 mol ofmethylsulfonyl chloride in 150 mL of methylene chloride was added dropwise below 10C after the temperature was cooled to -5C by ice-salt bath. After stirring at 5-10C for 12-18h, the solvent was poured into 100 mL of water, and the organic phase was washed with water to neutral, dried, and evaporated to give the methylsulfonyl ester of ArO(CH2)POH or Ar(CH2)POH which was used directly in the next reaction. To 200 mL of absolute ethanol were added 0.1 mol of the methylsulfonyl ester of ArO(CH2)POH or Ar(CH2)pOH and 0.13 mol of potassium thioacetate. After stirring at 50-60C for 6-12h, the mixture was added to a small amount of water, and then extracted with methylene chloride, washed with water, dried, and evaporated to give [Show Image] which was used directly in the next reaction. When q is 0, [Show Image] was hydrolyzed in the solution of potassium hydroxide in methanol. 0.1 mol of [Show Image] was added to methanol, and then the solution was cooled to 0.5 C. After a solution of 0.11 mol of potassium hydroxide in methanol was added below 5C, the mixture was stirred at 0-5C until that TLC indicated the reaction was complete. The solution was poured into a small amount of water, extracted with ethyl acetate, washed with water, dried, and evaporated to give Ar-(CH2)p-SH which was used directly in the next reaction. When q is 1, Ar-O-(CH2)p-SH is obtained by the reduction of [Show Image] with lithium aluminium hydride. To the suspension of 0.1 mol of lithium aluminium hydride in diethyl ether was added dropwise the solution of 0.1 mol of [Show Image] in absolute diethyl ether, the reaction temperature kept at 20-25C. Then I mol/L hydrochloride acid was added dropwise after the solution was stirred for 0.5-4h. The organic phase was separated, washed with water, dried, evaporated to give Ar-O-(CH2)p-SH which was used directly in the next reaction. | |
With potassium carbonate; In dimethyl sulfoxide; at 150℃; for 5h; | 97g 98.5% phenol, 81g 99% chloroethanol, 145g 99% potassium carbonate,300 g of DMSO was added to the reactor, and the temperature was raised to 150 C for 5 hours.Cool to room temperature, then remove the salt by filtration, and wash the filter cake twice with fresh DMSO.Then, the mixed filtrate is subjected to rectification treatment to obtain phenoxyethanol.139.6 g (1 mol) of phenoxyethanol, 300 g of water, and 28 g of silicawere added.Pass 32g of ozone and heat up to about 120 C for 12 hours.Check the phenoxyethanol content, when the phenoxyethanol content is less than 0.1%.Cool down to about 80 C, add 1.5g of formamide, add 270g of sulfuryl chloride, add the time to control after 2 to 5 hours to be chlorinated,The temperature was lowered, filtered, and dried to obtain 217.4 g of 2,4-dichlorophenoxyacetic acid, the purity was 98.1%, and the yield was 96.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | With 3-mercaptopropionic acid; In chlorobenzene; at 115℃; for 2h; | With a stirrer,a thermometer and a three-necked flask with a condenser,Add 3.6g of 9-fluorenone,6.3 g phenoxyethanol,0.3 g 3-mercaptopropionic acid,The SO42-/ZrO2-Fe2O3-SiO2 solid composite super acid catalyst recovered in Example 1 (used after activation at 115 C for 2 hours) and the recovered phenoxyethanol and chlorobenzene solution;The operation is the same as in the first embodiment,To give 8.1g of white solid 9,9-bis [4- (2-hydroxyethoxy) phenyl] fluorene,The yield is 92.5%.The measured melting point is 163.2~164.8 C,The HPLC purity was 99.5%. |
90.2% | tungstophosphoric acid; In toluene; at 130℃; under 15.0015 Torr; for 4h;Inert atmosphere;Product distribution / selectivity; | Example 12 A reaction was carried out by (a) adding 80.0 g (0.444 mol) of fluorenone, 613.5 g (4.44 mol) of 2-phenoxyethanol, and 2.0 g of tungstophosphoric acid [(H3PW12O40).nH2O] serving as a catalyst to a glass reactor vessel equipped with a stirrer, a nitrogen-blowing tube, a thermometer and a T-tube and (b) allowing a mixture to react for 4 hours under a reduced pressure of 2.0×103 Pa at 130 C. The content of multimers in a reaction mixture obtained after completion of the reaction was 3.9%. To the reaction mixture thus obtained, 800.0 g of toluene was added. The reaction mixture was neutralized with a sodium hydroxide aqueous solution and washed with water. Thereafter an organic phase was separated. Toluene and excess 2-phenoxyethanol were removed from an obtained organic phase by concentration under reduced pressure. To an obtained concentrate, 560.0 g of toluene was added, and the mixture was heated and stirred at 80 C. for 1 hour and thereafter directly cooled to 70 C. Thereafter, 0.4 g of crystals of 9,9-bis(4-(2-hydroxyethoxy)phenyl)fluorene serving as seed crystals were added, and a mixture was incubated at 70 C. for 2 hours and thereafter directly cooled to 20 C. Then, precipitated crystals were subjected to filtration and drying to obtain 78.0 g of white crystals of 9,9-bis(4-(2-hydroxyethoxy)phenyl)fluorene (yield: 90.2%, purity: 99.2%). The 9,9-bis(4-(2-hydroxyethoxy)phenyl)fluorene thus obtained had a melting point of 163 C. |
85.4% | With methanesulfonic acid; 3-(tritylthio) propanoic acid; at 50℃; for 18h;Inert atmosphere; | A thermometer, a stirrer, 2 - neck flask equipped with condenser 4 544.7 g phenoxyethanol (3.94mol) as raw materials, the reaction vessel was replaced with nitrogen after, at 40 C 840.7 g was added methanesulfonic acid (8.75mol). Then, 3.8 g of beta - mercaptopropionic acid were added at 50 C, 2 - phenoxyethanol is 9 - fluorenone (1.93mol) dissolved therein (3.78mol) 521.9 g 347.9 g was added dropwise over 1 hour at 50 C solution after the reaction. After the completion of the dropping, stirring was carried out at 50 C 17 hours. By using high-performance liquid chromatography analysis of the reaction solution as a result of calibration curve, 9, 9 - bis (4 - (2 - hydroxyethoxy) phenyl) fluorene in the reaction liquid is present in the yield of 85.4%. After completion of the reaction, stirring 1287.2 g toluene, 50 C 890.9 g water was added followed by order, standing water layer 1664 g being pulled. In 48% aqueous methanesulfonic acid concentrations, the recovery rate was 95%. Thereafter heated to 80 C, 16% sodium hydroxide aqueous solution was added 3 hours 1042.4 g. After stirring, the aqueous layer was extracted after standing, 75% phosphoric acid aqueous solution was added to the neutralizing aqueous 347.9 g and 14.3 g. After that, the water layer to settle out, water is added after stirring at 80 C 347.9 g oil, water washing operation was performed twice to remove isolation layer 2. Oil obtained from toluene, 2 - phenoxyethanol was removed by vacuum distillation of the excess. After distillation of the residual liquid is added to the homogeneous solution after toluene 2435.3 g, 2 hours to precipitate out at 65 C, 25 C gradually cooled filtrate the deposited crystal, drying the crude crystal 630.4 g was obtained. The 97.6% purity by analytical high-performance liquid chromatography was. 60.0 g of crude crystals were obtained with a thermometer, a stirrer, a cooling pipe 4 neck flask equipped with a charge and, after nitrogen substitution, addition of 1 - butanol 120.0 g, 78 C temperature raised to dissolve. Thereafter, 9, 9 - bis [4 - (2 - hydroxyethoxy) phenyl] fluorene is 75 C at high melting point crystalline seed crystal was added, 1 hour at 55 C crystalline precipitate. After heated up to 65 C, gradually cooling the precipitated crystal was filtered off 25 C. The resulting crystals under vacuum, dried and heated to 80 C, 9, 9 - bis [4 - (2 - hydroxyethoxy) phenyl] fluorene 52.8 g was obtained. 88% yield for crude crystals which, 98.7% purity by analytical high-performance liquid chromatography was. Fig. 1 shows the data obtained from DSC crystal. An endothermic maximum temperature: (differential scanning calorimetry) 121.1 C |
75.1% | phosphotungstic acid; In toluene; for 12h;Inert atmosphere; Reflux;Product distribution / selectivity; | Example 3: Production of crude product Into a glass reactor equipped with a stirrer, a nitrogen blowing tube, a thermometer and a water separator with cooling tube was added 86.4 g (0.48 mol) of fluorenone, 397.9 g (2.88 mol) of phenoxyethanol, 350 g of toluene and 4.3 g of phosphotungstic acid [(H3PW12O40)] which had been dried under reduced pressure at 100C to remove crystal water, and the mixture was stirred for 12 hours while removing generated water out of the system, under toluene reflux. The resultant reaction liquid was analyzed by high performance liquid chromatography to find generation of 197.3 g (0.45 mol) of 9,9-bis(4-(2-hydroxyethoxy)phenyl)fluorene. To this reaction liquid was added 300 g of toluene, and water-washed at 80C using 100 g of water. The resultant organic layer was cooled gradually, to find initiation of deposition of a crystal at 12C, and the organic layer was cooled down to 10C without any other procedure, and stirred for 12 hours. The deposited crystal was taken out by filtration, and the crystal was dried to obtain 158.0 g (yield: 75.1%, LC purity: 99.9%) of a white crystal of a crude product of 9,9-bis(4-(2-hydroxyethoxy)phenyl)fluorene. The resultant crystal had a melting point (melt endotherm maximum by differential scanning calorimetry) of 109C, and a bulk density of 0.24 g/cm3. |
104.5 g | With hydrogen fluoride; 3-mercaptopropionic acid; at -40 - 80℃; for 17h;Autoclave; Inert atmosphere; | 500 ml stainless steel reactor was added fluorenone 50 g (0.277), ethylene glycol monophenyl ether, 172.5 g, 0.6 g 3-mercaptopropionic acid, sealed reactor, pressure tested with nitrogen, the reactor sealed after confirmation, system was purged twice with nitrogen, the autoclave was cooled to -40 ~ -50 C , slow flow of anhydrous hydrogen fluoride gas is condensed to a liquid hydrogen fluoride in a reactor, to the reactor 150 g weight gain, hydrogen fluoride was stopped.The reaction vessel was heated to 70 ~ 80 Creaction for 17 hours.The reaction system was cooled to 40 ~ 50 C, slowly open the exhaust valve, exhaust gas is hydrogen fluoride, hydrogen fluoride gas recovery after a condenser to condense the hydrogen fluoride until the basic system is discharged to the reaction vessel purged with nitrogen, the remaining hydrogen fluoride rush out, stop nitrogen.Was slowly added to the kettle 6% potassium bicarbonate 150 g, was heated to 70 ~ 80 C, stirred for 15 minutes, 150 g of toluene was added, stirred for 20 minutes, allowed to stand, the organic phase was separated, the aqueous phase with 60 g of toluene extracted once, and the combined organic phase was washed with pure water twice the amount of 60 grams.The organic phase cooling crystallization, filtration, washing, drying dryness to give 9,9-bis [(4-hydroxy) phenyl]fluorene 104.5 g, 99.2% purity. |
First four-port first with capacity of 1,000 mL In a glass reactor, phenoxyethanol (Purity 99.8%) and 100 g of dichloroethane were introduced. After completion of installation, 1st The interior of the glass reactor was returned to atmospheric pressure, and fluorenone (Purity 99.8%) 100 g The content of the first glass reactor was heated to 40 C. under stirring, Take the contents over 2 hours And completely dissolved. After confirming the dissolution of contents visually, The contents were cooled to 20 C. 1.56 g of beta-mercaptopropionic acid was added to the cooled contents, And the mixture was stirred for 20 minutes. Next, 60 g of 36% hydrochloric acid was added dropwise over 3 hours, After completion of the dropwise addition, 60 g of 90% sulfuric acid was added dropwise over 6 hours. After completion of the dropwise addition of sulfuric acid, Maintain the temperature of the contents at 18 to 20 C, The reaction was allowed to proceed until the fluorenone concentration in the reaction system became 0.1% or less. The time required for the reaction was 24 hours. The volume and mass of the reaction solution at the end of the reaction are, They were 400 mL and 520 g respective | ||
200 g of phenoxyethanol (purity 99.8%) and 100 g of dichloroethane were introduced into a 4-necked first glass reactor having a capacity of 1,000 mL, under reduced pressure. After the introduction was completed, the inside of the first glass reactor was returned to atmospheric pressure and 100 g of fluorenone (purity 99.8%) was charged from the sample input port, and the content of the first glass reactor was heated to 40 C under stirring, and the contents were completely dissolved for 2 hours. After confirming the dissolution of contents visually, the contents were cooled to 20 C. 1.56 g of beta-mercapto propionic acid was added to the cooled contents, and the mixture was stirred for 20 minutes. Next, 60 g of 36% hydrochloric acid was added dropwise over 3 hours, and after completion of the dropwise addition, 60 g of 90% sulfuric acid was added dropwise over 6 hours. After completion of the dropwise addition of sulfuric acid, the temperature of the contents was maintained at 18 to 20 C and was reacted until the concentration of fluorenone in the reaction system became 0.1% or less. The time required for the reaction was 24 hours. The volume and mass of the reaction solution at the end of the reaction were 400 mL and 520 g respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium 1.) THF, methylcyclohexane, -65 deg C to rt, 2.) THF, methylcyclohexane, rt, 2 h; Yield given; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With toluene-4-sulfonic acid; In methanol; dichloromethane; at 20 - 25℃; for 0.333333h;Flow reactor; | General procedure: The system (Figure 4) was primed with solvent (DCM and 0.3 M aqueous NaOH) prior to the introduction of the substrates. Substrates were present as 0.034 M solutions (20 mL) in glass vials. These were placed in a square 4 x 4 rack. Following initiation of the computer-vision system (and checking to make sure the aqueous-out tap was opening/closing properly), activation of the autosampler/liquid-handling schedule was initiated by pressing ?s? on the computer keyboard. The outlet of the flow stream for each product was then collected until the autosampler moved to the waste position between each run. 5 mL of substrate was taken up during each run, 4 mL of which entered the holding loop (the line between the autosampler and 3-way-valve 1 was 1 mL in volume). Outlet collection flasks were changed manually. The products were isolated by removing solvent under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | General procedure: To a suspension of lithium aluminum hydride (0.249 g, 6.55 mmol) in anhydrous THF (40 mL) was added during 15 min a solution of the corresponding beta-oxoester derivative (11A) or (11B) (3.12 mmol) in anhydrous THF (20 mL). After 4 h, the excess of reductive agent was quenched with methanol (1 mL) and 10% aqueous NaOH solution (1 mL) until formation of aluminum hydroxide, which was neutralized with 10% aqueous hydrochloric acid solution (ca. 2 mL). The obtained mixture was extracted with ethyl acetate (3 × 25 mL) and the combined organic extracts were washed with brine and concentrated at reduced pressure after drying with anhydrous sodium sulfate. The residue was separated by chromatography on silica gel eluted with chloroform to give the corresponding primary alcohols (12A) and (12B), as described in Supplementary Material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 6-oxoheptanoic acid With thionyl chloride In N,N-dimethyl-formamide at 30℃; for 1h; Stage #2: 2-Phenoxyethanol In pentane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: Ph3P; diisopropyl azodicarboxylate / tetrahydrofuran / 20 °C 2: aq. NaOH / methanol; tetrahydrofuran / 1 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: SOCl2 / 1 h / Heating 2: pyridine / 160 °C 3: 84 percent / trifluoroacetic anhydride / 72 h 4: tetrahydrofuran / -50 °C 5: conc. HCl / aq. ethanol / Heating 6: 97 percent / ethanol / 4 h / 100 °C / 1034.3 Torr | ||
Multi-step reaction with 3 steps 1.1: thionyl chloride; pyridine / toluene / 1 h / Reflux; Large scale 2.1: trifluoroacetic anhydride / 1,2-dichloro-ethane / 25.5 h / 14 - 33 °C / Large scale 3.1: n-butyllithium / hexane; toluene / 0.88 h / -67 - -54 °C / Large scale 3.2: 78 °C / Large scale 3.3: 16 h / 40 - 83 °C / Large scale | ||
Multi-step reaction with 3 steps 1.1: thionyl chloride; pyridine / toluene / 1 h / Reflux; Large scale 2.1: carbon disulfide; aluminum (III) chloride / 2 h / 20 - 25 °C / Inert atmosphere 3.1: 1,2-bis-(diphenylphosphino)ethane; zinc; titanium tetrachloride / 1,4-dioxane / 2.5 h / 20 °C / Inert atmosphere; Reflux 3.2: 18 h / Reflux; Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In n-heptane; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate; | Step 1 Phenoxyacetaldehyde At -78 C., a solution of dimethylsulphoxide (5.11 ml, 72 mmol) in DCM (50 ml) was added dropwise to a solution of oxalyl chloride (6.12 ml, 72 mmol) in DCM (150 ml). The reaction mixture was stirred for 10 min at -78 C. A solution of 2-phenoxyethanol (10.0 g, 72 mmol) in DCM (70 ml) was added dropwise. The reaction mixture was stirred at -78 C. for 10 min. A solution of triethylamine (50 ml, 360 mmol) in DCM (50 ml) was added dropwise. The reaction mixture was stirred for 10 min at -78 C. It was warmed to room temperature. The reaction mixture was washed with a 10% aqueous solution of sodium hydrogensulphate (2*200 ml) and subsequently with brine (2*200 ml). It was dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using ethyl acetate/heptane (1:3) as eluent, to give 2.73 g of phenoxyacetaldehyde. 1H NMR (CDCl3): delta 4.55 (s, 2 H); 7.00 (m, 3 H); 7.30 (m, 2 H); 9.90 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In 1,4-dioxane; | Step 3: (2R)-Methyl-1-[3-(2-phenoxyethoxy)-2-pyrazinyl]piperazine, Hydrochloride. KO-t-Bu (0.52 g, 4.66 mmol) was added to a solution of 2-phenoxyethanol (0.42 g, 3.0 mmol) in dioxane (15 mL) and the mixture was stirred at room temperature for 15 minutes. 4-tert-Butoxycarbonyl-(2R)-methylpiperazine (0.73 g, 2.33 mmol; from |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In dichloromethane; at 0℃; for 2h; | To a solution of 2-phenoxyethanol (10.0 mL, 80.0 mmol) and triethylamine (13.5 mL, 96.9 mmol) in anhydrous CH2Cl2 (250 mL) at 0 C. is added methanesulfonyl chloride (6.80 mL, 87.9 mmol). The resulting cloudy mixture is stirred at 0 C. for 2 h. The mixture is diluted with water (75 mL) and extracted. The organic layer is washed with 1N HCl (75 mL) then saturated NaHCO3/brine (1:1; 75 mL) dried (Na2SO4), filtered, and concentrated. The residue is dried to constant weight under reduced pressure to provide the title compound as a pale yellow oil (17.1 g, 99%). This material is used in the next step without further purification. 1H NMR (400 MHz, CDCl3): delta 7.31-7.27 (m, 2H), 7.01-6.96 (m, 1H), 6.91-6.87 (m, 2H), 4.58-4.55 (m, 2H), 4.24-4.22 (m, 2H), 3.08 (s, 3H). |
95.3% | Triethylamine (6.00mL, 43.0mmol) was added to 1L1 (5.53g, 40.0mmol) in dichloromethane (30mL) at 0C and stirred for 10min. Methanesulfonyl chloride (3.70mL, 47.8mmol) was then added dropwise via cannula at 0C. The reaction mixture was warmed to room temperature and stirred for 3h. The reaction was stopped by the addition of water (50mL) and the organic portion was separated. The aqueous layer was extracted three times with dichloromethane (3×50mL) and the combined organic portions were dried over MgSO4 and filtered. The removal of solvent at reduced pressure gave the desired product 1L2 (8.24g, yield=95.3%) as a yellow oil. | |
90% | With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere; | General procedure: To a solution of corresponding alcohol (12A-B) or (15A-B) or (17A-B) or (19A-B) or (23A-B) (2.14 mmol) and triethylamine (0.36 mL, 2.59 mmol) in anhydrous dichloromethane (6 mL), kept to 0 C, was added mesyl chloride (0.18 mL, 2.31 mmol). The reaction was maintained at 0 C during the first hour, followed by warming to room temperature, under vigorous stirring and nitrogen atmosphere for 3 h. At the end of this time the solution was extracted with dichloromethane (3 × 30 mL) and the combined organic extracts were washed with a 10% aqueous hydrochloric acid solution, brine, dried over sodium sulfate and evaporated. The obtained residue was separated by chromatography on silica gel eluted with dichloromethane, followed by chloroform to give the desired O-mesylated derivatives, as described in Supplementary Material. |
With triethylamine; In dichloromethane; | (1) Synthesis of 1-methanesulfonyloxy-2-(phenoxy)ethane To a solution of 2-(phenoxy)ethanol (1.35 g, 9.78 mmoles) and triethylamine (2.04 ml, 14.7 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.91 ml, 12 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction solution was washed with water and the aqueous layer was extracted with methylene chloride (30 ml*3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography [eluent: hexane/methyl (1:1)] to obtain crude 1-methanesulfonyloxy-2-(phenoxy)ethane as a pale yellow oily product. | |
With pyridine; In dichloromethane; at -5 - 10℃; for 12 - 18h; | To 150 mL of N, N-dimethylformamide were added 0.1 mol of substituted phenol (ArOH), 0.2 mol of Cl(CH2)pOH and 0.2 mol of anhydrous potassium carbonate and the resulted mixture was kept at 110C for 6-10h. Then the solvent was distilled, and a small amount of water was added. After being extracted with methylene chloride, the solution was washed with dilute sodium hydroxide, then washed with water to neutral, dried. The solution was evaporated to give ArO (CH2)POH which was used directly in the next reaction. To 150 mL of methylene chloride were added 0.1 mol of ArO(CH2)POH or Ar(CH2)POH and 0.2 mol of pyridine, and then a solution of 0.11 mol ofmethylsulfonyl chloride in 150 mL of methylene chloride was added dropwise below 10C after the temperature was cooled to -5C by ice-salt bath. After stirring at 5-10C for 12-18h, the solvent was poured into 100 mL of water, and the organic phase was washed with water to neutral, dried, and evaporated to give the methylsulfonyl ester of ArO(CH2)POH or Ar(CH2)POH which was used directly in the next reaction. To 200 mL of absolute ethanol were added 0.1 mol of the methylsulfonyl ester of ArO(CH2)POH or Ar(CH2)pOH and 0.13 mol of potassium thioacetate. After stirring at 50-60C for 6-12h, the mixture was added to a small amount of water, and then extracted with methylene chloride, washed with water, dried, and evaporated to give [Show Image] which was used directly in the next reaction. When q is 0, [Show Image] was hydrolyzed in the solution of potassium hydroxide in methanol. 0.1 mol of [Show Image] was added to methanol, and then the solution was cooled to 0.5 C. After a solution of 0.11 mol of potassium hydroxide in methanol was added below 5C, the mixture was stirred at 0-5C until that TLC indicated the reaction was complete. The solution was poured into a small amount of water, extracted with ethyl acetate, washed with water, dried, and evaporated to give Ar-(CH2)p-SH which was used directly in the next reaction. When q is 1, Ar-O-(CH2)p-SH is obtained by the reduction of [Show Image] with lithium aluminium hydride. To the suspension of 0.1 mol of lithium aluminium hydride in diethyl ether was added dropwise the solution of 0.1 mol of [Show Image] in absolute diethyl ether, the reaction temperature kept at 20-25C. Then I mol/L hydrochloride acid was added dropwise after the solution was stirred for 0.5-4h. The organic phase was separated, washed with water, dried, evaporated to give Ar-O-(CH2)p-SH which was used directly in the next reaction. | |
With triethylamine; In tetrahydrofuran; at 0 - 25℃; for 20h; | To a solution of 2-phenoxyethan-l-ol (1 g, 7.24 mmol) and TEA (3.03 mL, 21.71 mmol) in THF (20 mL) was added dropwise Ms-Cl (0.846 mL, 10.86 mmol)at 0 C. The reaction mixture was stirred for 20 hours at 25 C. LCMS showed that SM was consumed completely. The reaction mixture was poured into water (20 mL), extracted by EtOAc (30 mL), washed with 1M HC1 (5 ml), sat NaHCCh, (10 ml) and brine (10 ml). The organic layer was dried over Na2S04, filtered and concentrated to give 2-phenoxy ethyl methanesulfonate (900 mg, 4.16 mmol, 57.5 % yield) as a brown oil which was used in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
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88% | With sodium hydroxide; chlorine; sodium hydrogensulfite; In hydrogenchloride; methanol; water; | EXAMPLE 1 Preparation of 2-(2,4,6-trichlorophenoxy)-ethanol: in the presence of hydrogen chloride (Stage I (a) Into a three-necked, round-bottomed 1-liter flask fitted with a stirrer, thermometer, reflux condenser, and a gas sparger are added 70 g of 2-phenoxyethanol dissolved in 125 ml of HCl (32%). The reaction mixture is cooled with stirring to 0-25 C. and chlorine gas is added at a rate sufficient to keep the temperature at 0 C. 5 C. cooling when necessary. During the reaction a second liquid phase appears. After adding two thirds of the chlorine (about 7 hours) the temperature is raised to 25 C. and the remaining chlorine is added at a slower rate (additional 8 hours) where a total of 125 g of chlorine are added. The stirring is stopped and the lower organic layer is poured into 100 ml of 20% stirred solution of sodium bisulfite kept at a temperature of 70 C. A 10% sodium hydroxide solution is added until a pH of 7.5 is reached, the stirring is stopped, the lower organic layer is separated, dissolved in 150 ml methanol and 50 ml water kept at 45 C. The resulting solution is cooled to 0-5 C. to precipitate the crystalline product. The crystals are filtered, washed with water, and dried to yield 2-(2,4,6-trichlorophenoxy)-ethanol in a yield of 88% having a purity of 98-99%. |
With chlorine; urea; In tetrachloromethane; water; | EXAMPLE 2 Preparation of 2-(2,4,6-trichlorophenoxy)-ethanol in the presence of urea (Stage I(b) Into a three-necked, round-bottomed 1-liter flask fitted with a stirrer, a dip-pipe to convey gas, a thermometer and a reflux condenser, 140 g 2-phenoxy ethanol, 250 ml carbon tetrachloride, 25 ml water and 10 g urea were introduced. Chlorine gas was then added while stirring and keeping the temperature at 20 C. via cooling. When the temperature reached about 55 C. the rate of chlorine addition was lowered so that the cooling kept the temp. at 55 C. in spite of the exotherm. Chlorine gas was added until the solution became yellow. The rate of chlorine addition was further lowered until the yellow color disappeared. At this stage it became necessary to heat the reaction mixture to keep the temperature at 55 C. The end of the reaction was determined by GLC. Addition of chlorine was stopped and the mixture washed with NaHSO3 (10%) and then with water. The mixture was then washed with a bicarbonate solution until a pH of 8 was reached and then with additional water. Cooling the organic phase to 5 C. with a gentle stirring caused the precipitation of white crystals to afford 135 g of 2-(2,4,6-trichlorophenoxy)-ethanol at a concentration of 96%. The mother liquor was recycled as solvent for subsequent batches of chlorination, purging about 15%. The overall yield after several runs of chlorination reaches 80%. |
Yield | Reaction Conditions | Operation in experiment |
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57% | With triethylamine; In toluene; | EXAMPLE 1.1 Preparation of 2-chloro-5-(2-phenoxyethoxycarbonyl)-4-trifluoromethyl-thiazole STR12 6.3 g (0.045 mol) of 2-phenoxyethanol are added slowly while stirring to a solution of 11 g (0.44 mol) of 2-chloro-5-chlorcarbonyl-4-trifluoromethyl-thiazole in 100 ml of absolute toluene. The solution is then cooled to 0-5 and 3.6 g (0.045 mol) of triethylamine are added dropwise while stirring. Triethylamine-hydrochloride precipitates from the reaction mixture. After everything is added, the suspension is stirred for 20 hours at room temperature and then poured onto ice-water. The organic phase is separated, dried over sodium sulfate and concentrated in a rotatory evaporator. The residue cristallizes. In order to purify it, the crystals are suspended in petrol-ether, filtered and dried. In this manner 8.7 g (57% of the theoreticl yield) of the title compound are obtained, m.p. 70-72. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; tetrabutylammomium bromide; In methanol; toluene; | EXAMPLE 1 29.3 g of the quinazolone of formula STR24 are reacted with 16 g of phosphoroxy chloride at 85-90 C. in 70 g of toluene. The reaction mixture is stirred for 1 hour at this temperature to form a dark red solution of the 4-chloro-2-(4'-diethylaminophenyl)quinazoline of formula STR25 The solution is added dropwise to a suspension of 13.8 g of 2-phenoxyethanol, 10 g of a 50% solution of sodium hydroxide and 2 g of tetrabutylammonium bromide. The suspension is then stirred for 11/2 hours at 100-108 C. and subsequently extracted with 100 ml of water at 90 C. The toluene phase is separated and washed repeatedly with hot water. The toluene is removed by distillation and the residue is stirred into 320 g of methanol. The crystalline precipitate so formed is isolated by filtration at 15-20 C., washed with methanol and water and dried, affording 24 g of a quinazoline of formula STR26 with a melting point of 116-119 C. This readily soluble and sublimation-fast colour former develops on acid clay a strong greenish yellow colour of good lightfastness. Following the procedure described in this Example, the quinazolines listed in the table are obtained using the appropriate starting materials. |
Yield | Reaction Conditions | Operation in experiment |
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I EXAMPLE I EXAMPLE I 139 Parts of phosgene are introduced through 150 parts of 2-phenoxyethanol at room temperature (exothermic reaction: cooling on a water-bath is necessary). The reaction mixture is poured onto ice-water. The organic phase is separated, dried, filtered and evaporated. The residue is distilled, yielding 106 parts of 2-phenoxyethyl chloroformate; bp. 135°-140° C. (water-jet). |
Yield | Reaction Conditions | Operation in experiment |
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In benzene | 2 (Compound No. 23) EXAMPLE 2 β-phenoxyethylacrylate (Compound No. 23) This compound was prepared according to a known process (Chemical Abstracts Vol. 59, 11323a). Namely, acrylic acid-chloride (5g) was added slowly under ice cooling into the mixture of β-phenoxyethylalcohol (6.75g), sodium-carbonate (2.9g), cuprous chloride (0.2g) and benzene (50ml) with stirring. The mixture was allowed to stand 15 hours at room temperature and then refluxed for 4 hours. The reaction mixture was treated according to the above mentioned known process, giving a crude product (6.6g). The crude product on fractionation gave a fraction (4.7g), b.p. 88.0° C./0.1mmHg, of β-phenoxy-ethyl acrylate. |
Yield | Reaction Conditions | Operation in experiment |
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To a 16 mm test tube was added; 0.5 mmol of the appropriate alcohol or thiol0.4 mmol of the appropriate 6-chloro 5-trifluoromethyl-2-piperazinylpyridine in DMSO (0.5 mL) 0.65 mmol of K-t-BuO in DMSO (1.0 mL) The reactions were stirred at room temperature for two hours followed by addition of HOAc (1.25 mmol, 75 L). The solvent was evaporated at reduced pressure over night (Speed Vac). The remaining solids were dissolved in water/acetonitrile/HOAc, filtered, and the products were purified with preparative HPLC. Mass detection was obtained by a Micro Mass LCP with electrospray positive ionization mode. The analytical HPLC-chromatograms were performed on a Hewlett Packard 1100 with a 504.6 mm Grom-SIL 100 ODS 0 AB, 3 m column and a 504.6 mm YMC-AQ 5 m column. Different gradients of 0.1% TFA in water and acetonitrile were used and the peaks were detected at 254 nm. The area % under the largest peak was reported as the purity. |
Yield | Reaction Conditions | Operation in experiment |
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41% | With triethylamine;dmap; In dichloromethane; at 20℃; for 16h; | Triethylamin (0.33 mL) and DMAP (20 mg) were added to a solution of 2-Phenoxy- ethanol (66 mg, 1 eg) and 3-Tridecafluorohexyl-benzenesulfonyl chloride (261 mg, 1.1 eg) in dichloromethane (5 mL). The reaction mixture was stirred for 16 h at room temperature. The solution was diluted with dichloromethane and carefully neutralized with 5% sodium bicarbonate solution. The phases were separated and the organic layer was washed with water and brine. The solution was dried over sodium sulfate and filtered. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate = 9.5/0.5) to afford 117 mg (41 %) 3-tridecafluorohexyl- benzenesulfonic acid 2-phenoxy-ethyl ester as white solid. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine In dichloromethane at 23℃; Cooling with ice; | 1.1 Preparation of Examples 1-6 and Comparative Example 1Example 1Step 12-Phenoxyethanol (34.5 g) and acetyl chloride 19.5 g) were added to 200 ml of methylene chloride in a 500 mL flask. The mixture was stirred at ice bath temperature while triethyl amine (25 g) was added dropwise. On completion of the addition, the mixture was allowed to warm to about 23° C. and subsequently was poured into 1 liter of water. The organic layer was separated, washed twice with 100 mL portions of water, and the solvent removed on a rotary evaporator. The resulting product, 1-acetoxy-2-phenoxyethane, had crystallized in the flask. The solid was suction filtered, washed with two 50 mL portions of hexane and dried to yield 32 g of product that was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With caesium carbonate at 125℃; for 19h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With caesium carbonate at 125℃; for 15h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99 %Chromat. | With steapsin lipase In hexane at 55℃; for 24h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
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83% | To a solution of 2-phenoxyethanol (4.81 g, 34.8 mmol) in DMF (20 mL) was added sodium hydride (60% suspension in mineral oil, 0.70 g, 17.4 mmol) in portions and the reaction mixture was stirred at room temperature for 1 hour. To this mixture was added 2-(2,6-dimethylpyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (0.50 g, 1.74 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water (1 mL) was added, neutralized to pH approximatley 6-7 with acetic acid, concentrated, dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (eluted with 50% ethyl acetate in hexanes, then 5% methanol in DCM) to give 2-(2,6-dimethylpyridin-4-yl)-7-fluoro-5-(2-phenoxyethoxy)-3H-quinazolin-4-one as a light yellow solid. Yield: 0.59 g (83%) | |
83% | To a solution of 2-phenoxyethanol (4.81 g, 34.8 mmol) in DMF (20 mL) was added sodium hydride (60% suspension in mineral oil, 0.70 g, 17.4 mmol) in portions and the reaction mixture was stirred at room temperature for 1 hour. To this mixture was added 2-(2,6-dimethylpyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (0.50 g, 1.74 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water (1 mL) was added, neutralized to pH approximately 6-7 with acetic acid, concentrated, dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (eluted with 50% ethyl acetate in hexanes, then 5% methanol in DCM) to give 2-(2,6-dimethylpyridin-4-yl)-7-fluoro-5-(2-phenoxyethoxy)-3H-quinazolin-4-one as a light yellow solid. Yield: 0.59 g (83%). |
Yield | Reaction Conditions | Operation in experiment |
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95% | With triethylamine; In dichloromethane; at 0 - 20℃; | <strong>[122-99-6]2-Phenoxyethanol</strong> (50 g, 0.362 mol) was dissolved in dichloromethane (500 ml) and the solution was cooled to 0-5 C. Triethylamine (101 ml, 0.724 mol) was added to the cooled solution followed by pivaloyl chloride (53.5 ml, 0.434 mol) maintaining the temperature below 5 C. After additions the mixture was stirred at 5 C for 30 min and at room temperature for 12 h. The reaction was quenched by addition of lM HCl-solution (300 ml) and stirred vigorously. The phases were separated and organic phase was washed with saturated NaHC03-solution (2 x 150. ml), water (1 x 100 ml) and brine (1 x 100 ml). After drying (Na2S04) and filtration the solvent was evaporated yielding the tile compound (76.78 g, 0.345 mol, 95 %) as a yellow oil. -NMR (400 MHz, DMSO- l6) S (ppm): 7.3 1 -7.27 (2H, m, ArH), 6.96-6.93 (3Eta, m, ArH), 4.34 (2Eta, m, CH2CH2OPiv), 4. 19 (2Eta, m, ArOCH2CH2), 1. 13 (9H, s, 3 x Me). C-NMR (100 MHz, DMSO-c delta (ppm): 177.7, 158.7, 130.1, 121 . 1 , 1 14.9, 66. 1 , 62.9, 38.5, 27.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; In dichloromethane; at -78 - 20℃; for 0.5h; | Synthesis of 2-phenoxyethyl triflate: To a solution of 2-phenoxyethanol (0.327 g, 2.367 mmol) in dry DCM (5 mL) was added pyridine (0.25 mL, 1.3 eq.) at RT. The solution was cooled to -78 C. and 667 mg Tf2O was added dropwise. After the addition, the reaction was stirred at RT for 30 min. The mixture was washed with 0.5M HCl, sated. NaHCO3, dried over anhydrous MgSO4 and evaporated on a rotary evaporator to give 0.646 g (quantitative yield). 1H NMR (300 MHz, CDCl3): delta 7.35 (dt, J=2.1, 7.8 Hz, 2H), 7.05 (t, J=7.2 Hz, 1H), 6.95 (dt, J=2.1, 7.8 Hz, 2H), 4.86 (dd, J=4.2, 6.0 Hz, 2H), 4.33 (dd, J=4.2, 6.0 Hz, 2H) |
With 2,6-dimethylpyridine; In dichloromethane; at 0 - 20℃; for 1.5h;Inert atmosphere; | To a mixture of C8Hi0O2(0.151 g, 1.093 mmol, 1.6 eq) and 2,6-lutidine (0.167 mL, 1.434 mmol, 2.10 eq) in dry DCM (5 mL) was added a solution of triflic anhydride (0.195 mL, 1.161 mmol, 1.70 eq) in dry DCM (2.5 mL) dropwise at 0 C under an inert atmosphere. The resulting light pink solution was stirred at 0 C for 30 min and at room temperature for 60 min. The mixture was again cooled down to 0 C. To this, solution of (1R,2R)TSDPEN (0.250 g, 0.683 mmol, 1.0 eq) and TEA (0.228 mL, 1.639 mmol, 2.4 eq) into dry DCM (2.5 mL) was added dropwise at 0 C.The resulting yellow coloured mixture was stirred at 0 C for 30 min and then at room temperature for 17 h. The reaction mixture was diluted with DCM (20 mL) and washed with sat. NaHC03 solution (3 x 25 mL).The organic layer was separated, washed with H20 (2 x 15 mL), brine (25 mL), dried over anhy. Na2S04, filtered and concentrated to give crude compound. The crude compound was purified by column chromatography over silica gel using EtOAc: Pet. ether (25:75) as an eluent to give a residue. The residue was triturated in n-pentane (to remove traces of 2,6-lutidine) to give a solid. The solid was filtered, washed with n-pentane and dried under vacuum to give pure compound as white solid (0.250 g, 0.514 mmol, 75%). Mp 130- 132 C; [a]D = -6.21 (c 0.515 in CHC13); vmax 3344, 3297, 3064, 3029, 2940, 1600, 1491, 1454, 1433, 1303, 1248, 1159, 807, 754, 696, 668 cm"1; deltaEta (300 MHz, CDC13) 7.36 (2H, d, / 8.4, -CH of -S02C6H4CH3), 7.30-7.24 (2H, m, -CH of phenyl), 7.16-7.11 (3Eta, m, -CH of phenyl), 7.09-7.02 (3Eta, m, -CH of phenyl), 6.99- 6.93 (7Eta, m, -CH of phenyl), 6.80 (2Eta, d, J 7.8, -CH of phenyl), 6.18(1H, br s, -NHTs), 4.28 (1Eta, d, / 7.3, -CHNHTs), 4.01-3.87 (2H, m, -CH2CH2OC6H5), 3.73 (1H, d, / 7.3, - CHNHCH2-), 2.84-2.76 (1H, m, -CHHCH2OC6H5), 2.69-2.62 (1H, m, -C HHCH2OC6H5), 2.30 (3H, s, -CH3), 1.79 (1Eta, br s, -NHCH2-); 5c (75 MHz, CDC13) 157.92(C), 142.06(C), 138.30(C), 137.70(C), 136.37(C), 128.84(2CH), 128.47(2CH), 127.75(2CH), 127.36(2CH), 126.95(CH), 126.87(2CH), 126.82(2CH), 126.71(CH), 126.46(2CH), 120.34(CH), 113.90(2CH), 67.00(CH), 66.38(CH2), 62.47(CH), 45.52(CH2), 20.80(CH3); m/z ESI-MS [M+H]+ 487.1 ; HRMS found 487.2051 (C29H30N2O3S H+ requires 487.2050, error = -0.2 ppm). |
Yield | Reaction Conditions | Operation in experiment |
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71% | Step 14-bromo-1-nitro-2-(2-phenoxyethoxy)benzene<strong>[122-99-6]2-Phenoxyethanol</strong> (345 mg, 2.500 mmol) was added to a suspension of potassium tertbutoxide (306 mg, 2.73 mmol) in tetrahydrofuran (10 mL). The suspension was stirred for 10 minutes, then 4-bromo-2-fluoronitrobenzene (500 mg, 2.273 mmol) was added, and stirring was continued at room temperature for 41 hours. The mixture was concentrated under vacuum, and the residue was diluted with water (15 mL) and extracted with ethyl acetate (2x30 mL). The combined extract was dried (MgSO4), concentrated under vacuum and purified by flash chromatography (silica gel eluted with hexanes-ethyl acetate, 100:0-90:10) to provide the titled compound (546 mg, 7 1%). ?H NMR (300 MHz, DMSO-d6) 5 ppm 4.354.42 (m, 2H), 4.44 - 4.50 (m, 2H), 6.91 - 6.95 (m, 2H), 6.96 - 7.02 (m, 1H), 7.21 (dd, J = 8.8,1.7 Hz, 1H), 7.27 - 7.35 (m, 2H), 7.38 (d, J = 1.7 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H). | |
71% | Step 1 4-bromo-1-nitro-2-(2-phenoxyethoxy)benzene <strong>[122-99-6]2-Phenoxyethanol</strong> (345 mg, 2.500 mmol) was added to a suspension of potassium tert-butoxide (306 mg, 2.73 mmol) in tetrahydrofuran (10 mL). The suspension was stirred for 10 minutes, then 4-bromo-2-fluoronitrobenzene (500 mg, 2.273 mmol) was added, and stirring was continued at room temperature for 41 hours. The mixture was concentrated under vacuum, and the residue was diluted with water (15 mL) and extracted with ethyl acetate (2*30 mL). The combined extract was dried (MgSO4), concentrated under vacuum and purified by flash chromatography (silica gel eluted with hexanes-ethyl acetate, 100:0-90:10) to provide the titled compound (546 mg, 71%). 1H NMR (300 MHz, DMSO-d6) delta ppm 4.35-4.42 (m, 2H), 4.44-4.50 (m, 2H), 6.91-6.95 (m, 2H), 6.96-7.02 (m, 1H), 7.21 (dd, J=8.8, 1.7 Hz, 1H), 7.27-7.35 (m, 2H), 7.38 (d, J=1.7 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium fluoride; 18-crown-6 ether In tetrahydrofuran at -20℃; for 12h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | l-Oxido-4-(2-phenoxyethoxy)pyridin-l-ium (G): To a solution of 2-phenoxyethanol (F) (1.24 mL, 10.0 mmol, 1.0 eq) in THF (50 mL) was added a 60% dispersion of sodium hydride in mineral oil (440 mg, 11.0 mmol, 1.1 eq) at 0 C. The solution was allowed to warm to room temperature and stirred for 30 minutes before adding 4-nitropyridine N-oxide (E) (1.40 g, 10.0 mmol, 1.0 eq). The reaction was then heated to 100 C overnight. The solvent was removed in vacuo, and the crude product was purified by flash chromatography on silica gel using 0-10% methanol in DCM to afford 1.87 g (81%) of the title compound. ES-MS [M+l]+: 232.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.36% | With 10H-phenothiazine at 130℃; for 7h; | 1-15; 1-2 Example 9 Under stirring, add 183.22g methyl methacrylate, 45.59g ethylene glycol phenyl ether, 6.86g potassium hydroxide/magnesium-zinc composite solid base catalyst, and 0.41g phenothiazine into a 500mL four-neck flask, and seal the magnetic force. Stir, condense and reflux, heat the oil bath to a set temperature, cool and discharge after the reaction, to obtain the ethylene glycol phenyl ether methacrylate product (EPHMA).The molar ratio of the reaction raw materials is MMA:EPH=5.5:1, the amount of catalyst is 3.0% of the total mass of the raw materials, the amount of polymerization inhibitor is 0.18% of the total mass of the raw materials, the reaction temperature is 130°C, the reaction time is 7h, and the conversion of EPH is It was 94.44%, and the yield of EPHMA was 91.36%. |
89% | With dmap; oxo[hexa(trifluoroacetato)]tetrazinc In neat (no solvent) at 80℃; for 24h; Inert atmosphere; Schlenk technique; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.3%; 87.7% | With potassium hydroxide; In dimethyl sulfoxide; at 100℃; under 300.03 Torr; for 3h;Inert atmosphere; | Namely, 100.0 g (0.72 mol) of 2-phenoxyethanol, 400.0 g (5.11 mol) of dimethylsulfoxide ),8.8 g (0.14 mol) of potassium hydroxide was placed and the inside of the system was replaced with nitrogen gas while stirring at 600 rpm.Subsequently, after the temperature of the reaction solution was brought to 100 C.,The inside of the system was replaced with acetylene gas,While supplying acetylene continuously so as to be constant at a pressure of 0.04 MPa,The reaction was carried out at 100 C. for 3 hours.As a result of gas chromatographic analysis of the reaction solution,The conversion of raw material was 99.1%The yield of 2-phenoxyethyl vinyl ether was 87.7%, and the yield of phenyl vinyl ether was 5.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a solution of 2-phenoxyethanol (68, 2.00 g, 14.48 mmol, 1.0 equiv) in DCM (29 mL) and N-ethyl-N-isopropylpropan-2-amine (5.9 mL, 33.8 mmol, 2.3 equiv) at 0 C was added methanesulfonyl chloride (1.34 mL, 17.37 mmol, 1.2 equiv). The reaction was stirred for one hour. The mixture was extracted with water (2 x 25 mL), and the organic layer was concentratedunder reduced pressure. The crude material was then dissolved in DMF (29 ml) and sodium azide (2.82 g, 43.4 mmol, 3.0 equiv) was added. The reaction was stirred at room temperature for 3.5 hours. The reaction was concentrated under reduced pressure and the crude residue was purified by flash chromatography on silica gel (gradient 0-20% EtOAc in DCM), which provided (2-azidoethoxy)benzene (69, 1.88 g, 80% yield over 2 steps). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.5 g | mixer,Nitrogen blowing tube,23.5 g (0.17 mol) of 2-phenoxyethanol was charged in a glass reactor equipped with a thermometer and a cooling tube,After replacing the reaction vessel with nitrogen,A mixed solution of 10.0 g (0.0425 mol) of 9,9-dichloro-9H-fluorene and 11.7 g (0.08 mol) of 2-phenoxyethanol was added dropwise at 70 C. over 1 hour with stirring.After completion of the dropwise addition,After stirring at 70 C. for 2 hours,4.1 g (0.04 mol) of methanesulfonic acid was added and stirred at 110 C. for 9 hours. As a result of analyzing the obtained reaction solution by high performance liquid chromatography,The composition value of 9,9-bis [4- (2-hydroxyethoxy) phenyl] fluorene was 72.5% (area percentage / 2-phenoxyethanol excluded). From the composition value, formation of 13.5 g of 9,9-bis [4- (2-hydroxyethoxy) phenyl] fluorene was confirmed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.3% | With sulfuric acid; In toluene; for 2h;Dean-Stark; Reflux; | The present Example provides a synthesis of 2-Phenoxyethyl 2-(4-hydroxy-3- methoxyphenyl)acetate. 1.82 g (10 mmol) of 2-(4-hydroxy-3-methoxyphenyl) acetic acid and 50 ml oftoluene were added to a one neck, round bottom flask, equipped with a Dean-Stark trap and condenser. While this suspension was stirred at room temperature, 1.38 g (10 mmol) of 2-phenoxyethanol was added followed by 0.10 g (1 mmol) of concentrated sulfuric acid. The mixture was then refluxed for 2 hours and the water formed was collected in the trap. The reaction mixture was then cooled to room temperature, diluted with ethylacetate, and quenched with saturated NaHCO3. Once the phases were separated, the organic phase was washed once more with saturated NaHCO3 and brine. The organic layer was then dried over Mg504, filtered, and concentrated under reduced pressure. The crude product was first isolated by automated silica gel chromatography (Biotage SP1, 12-100% ethyl acetate/hexane) and finally purified via Kugelrohr distillation(100C-120C 0.45 Torr) to afford 2.33 g (77.3%) of 2-phenoxyethyl 2-(4-hydroxy-3- methoxyphenyl)acetate, which crystallized to an off-white solid (mp 56C).?HNMR (400 IVIHz, CDC13) ppm 3.58 (s, 2H) 3.82 (s, 3H) 4.16 (m, 2H) 4.44 (m, 2H) 5.57 (s, 1H) 6.83 (m, 5H) 6.97 (m, 1H) 7.27 (m, 2H). ?3C NMR (101 MHz, CDC13) ppm 40.87, 55.93, 63.30, 65.92, 111.79, 114.44, 114.70, 121.31, 122.25,125.61, 129.62, 144.87, 146.55, 158.53, 171.96. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.2% | Mix phenoxyethanol 139. 6g (lmol), water 300g, 40.5g (1mol) sodium hydroxide and 1.6g of chlorination, add 350g of 10% hydrogen peroxide, and raise the temperature to about 160 C for 12 hours. After the unqualified, the catalyst is removed by filtration to remove the manganese chloride catalyst. The filtrate is directly added with 0.28g of magnesium chloride and 0.3lg of dimethyl phenyl sulfide. The chlorine gas is introduced, and the pH is maintained at about 10 after the chlorination. See hydrochloric acid to adjust the pH to about 1, filter and dry to obtain 216.1 g, purity 98.2%, yield 96.2%. | |
217.4 g | 97g 98.5% phenol, 81g 99% chloroethanol, 145g 99% potassium carbonate,300 g of DMSO was added to the reactor, and the temperature was raised to 150 C for 5 hours.Cool to room temperature, then remove the salt by filtration, and wash the filter cake twice with fresh DMSO.Then, the mixed filtrate is subjected to rectification treatment to obtain phenoxyethanol.139.6 g (1 mol) of phenoxyethanol, 300 g of water, and 28 g of silicawere added.Pass 32g of ozone and heat up to about 120 C for 12 hours.Check the phenoxyethanol content, when the phenoxyethanol content is less than 0.1%.Cool down to about 80 C, add 1.5g of formamide, add 270g of sulfuryl chloride, add the time to control after 2 to 5 hours to be chlorinated,The temperature was lowered, filtered, and dried to obtain 217.4 g of 2,4-dichlorophenoxyacetic acid, the purity was 98.1%, and the yield was 96.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With pyridinium p-toluenesulfonate; In methanol; at 23℃; for 16h; | General procedure: A solution of 23 (1.33 g, 5.27 mmol) in methanol (15 mL) wastreated with pyridinium 4-toluenesulfonate (30 mg). The reactionmixture was stirred at room temperature overnight. Then, water(50 mL) was added and the mixture was extracted with methylenechloride (3×50 mL). The combined organic layers were washed withbrine (3×50 mL), dried (MgSO4), and the solvent was evaporated toproduce 885 mg (100% yield) of pure alcohol 29 as a yellow pale solid:mp=65 C; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(II) acetate monohydrate; potassium carbonate at 110℃; for 20h; Inert atmosphere; | Synthesis of 4a-p; General Procedure B General procedure: To a solution of aromatic amine (1.53 mmol), Cu(OAc)2·H2O (0.13 mmol), K2CO3(3.84 mmol) in DEG (3 mL) were added aryl halides (1.28 mmol). The flask wasevacuated and backfilled with argon (3×), and the resulting mixture was heated in an oilbath with appropriate temperature under rapid stirring for the indicated time. After thecomplete consumption of aryl halide as monitored by TLC, the flask was cooled to r.t.The flask was opened to air, and the reaction mixture (if the product was acidic, themixture was acidified) was extracted with ethyl acetate (3×10 mL), and the organiclayer was washed with water (2×10 mL) and once with brine (10 mL), dried withmagnesium sulfate and concentrated in vacuo. The product was purified by columnchromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With methanol; potassium permanganate; trimethylsulphonium iodide at 25℃; chemoselective reaction; | |
95% | With methanol; potassium permanganate at 25℃; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 54% 2: 16% | With Cs2CO3 In methanol for 1h; Irradiation; |
Tags: 122-99-6 synthesis path| 122-99-6 SDS| 122-99-6 COA| 122-99-6 purity| 122-99-6 application| 122-99-6 NMR| 122-99-6 COA| 122-99-6 structure
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