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CAS No. : | 94-71-3 | MDL No. : | MFCD00002187 |
Formula : | C8H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MOEFFSWKSMRFRQ-UHFFFAOYSA-N |
M.W : | 138.16 | Pubchem ID : | 66755 |
Synonyms : |
Guaethol;Guethol;NSC 180
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 39.76 |
TPSA : | 29.46 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 : | No |
Log Kp (skin permeation) : | -5.95 cm/s |
Log Po/w (iLOGP) : | 2.02 |
Log Po/w (XLOGP3) : | 1.68 |
Log Po/w (WLOGP) : | 1.79 |
Log Po/w (MLOGP) : | 1.48 |
Log Po/w (SILICOS-IT) : | 1.67 |
Consensus Log Po/w : | 1.73 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.07 |
Solubility : | 1.18 mg/ml ; 0.00857 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.91 |
Solubility : | 1.69 mg/ml ; 0.0122 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.33 |
Solubility : | 0.654 mg/ml ; 0.00473 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 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: | H302-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 |
---|---|---|
77% | With sodium hydroxide In water at 25℃; for 48 h; | To a solution of 2-ethoxyphenol 19A (13.82 g, 100.1 mmol) in aqueous NaOH (1.0 N, 300 mL) was added chloroethanol (33.12 mL, 500.1 mmol). After being stirred at 25 °C for 48 h, the reaction mixture was extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over MgSO4(s), filtered, and concentrated under reduced pressure to obtain (ether)benzoxy alcohol 20A (14.02 g, 76.94 mmol) as yellow liquid in 77 percent yield: 1H NMR (CDCl3, 400 MHz) δ 1.44 (t, J = 7.2 Hz, 3 H, OCH2CH3), 3.85 (t, J = 7.2 Hz, 2 H, CH2OH), 4.05-4.12 (m, 4 H, OCH2CH3 + OCH2CH2OH), 6.88-6.97 (m, 4 H, ArH); IR (neat) 3547 (br), 3066 (m), 2977 (s), 2931 (s), 2877 (s), 1739 (m), 1649 (m), 1593 (s), 1503 (s), 1455 (s), 1393 (m), 1324 (m), 1253 (s), 1219 (s), 1123 (s), 1041 (s), 922 (s) cm-1 |
77% | With sodium hydroxide In water at 25℃; for 48 h; | EXAMPLE 8 To a solution of 2-ethoxyphenol 19A (13.82 g, 100.1 mmol) in aqueous NaOH (1.0 N, 300 mL) was added chloroethanol (33.12 mL, 500.1 mmol). After being stirred at 25° C. for 48 h, the reaction mixture was extracted with ethyl acetate (3*100 mL). The organic layer was dried over MgSO4 (s), filtered, and concentrated under reduced pressure to obtain (ether)benzoxy alcohol 20A (14.02 g, 76.94 mmol) as yellow liquid in 77percent yield: 1H NMR (CDCl3, 400 MHz) δ 1.44 (t, J=7.2 Hz, 3 H, OCH2CH3), 3.85 (t, J=7.2 Hz, 2 H, CH2OH), 4.05-4.12 (m, 4 H, OCH2CH3+OCH2CH2OH), 6.88-6.97 (m, 4 H, ArH); IR (neat) 3547 (br), 3066 (m), 2977 (s), 2931 (s), 2877 (s), 1739 (m), 1649 (m), 1593 (s), 1503 (s), 1455 (s), 1393 (m), 1324 (m), 1253 (s), 1219 (s), 1123 (s), 1041 (s), 922 (s) cm-1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In toluene at 115℃; for 24 h; | 2-ethoxyphenols (55.0g, 0.398mol), ethylenecarbonates (70.1g, 0.796mol), andpotassium carbonates (12.1g, 0.088mol) were put into the toluene (550ml) and itmixed reflux in 24 hours 115. After the ethyl acetate (275ml) and saltywater (550ml) were added to the reactant and the organic layer was extractedand the anhydrous sodium sulfate was added to the organic layer and it dried itfiltered and it was the filtrate concentrated under reduced pressure and 2 -(2- ethoxyphenoxy) ethanol was obtained (72.5g, and the yield 100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 30h; | 15.0 g of 2-ethoxyphenol, 18.0 ml of iodoethane and 30.0 g of potassium carbonate were suspended in 150 ml dimethylformamide, and the mixture was stirred at 80 C. for 30 hours. Ethyl acetate was added thereto, and the mixture was washed with water for five times and with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound quantitatively as a red-brown oil. 1H-NMR (400 MHz, CDCl3) delta 1.45 (6H, t, J=7.0 Hz), 4.09 (4H, q, J=7.0 Hz), 6.89 (4H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium hydroxide; In water; at 25℃; for 48h; | To a solution of 2-ethoxyphenol 19A (13.82 g, 100.1 mmol) in aqueous NaOH (1.0 N, 300 mL) was added chloroethanol (33.12 mL, 500.1 mmol). After being stirred at 25 C for 48 h, the reaction mixture was extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over MgSO4(s), filtered, and concentrated under reduced pressure to obtain (ether)benzoxy alcohol 20A (14.02 g, 76.94 mmol) as yellow liquid in 77 % yield: 1H NMR (CDCl3, 400 MHz) delta 1.44 (t, J = 7.2 Hz, 3 H, OCH2CH3), 3.85 (t, J = 7.2 Hz, 2 H, CH2OH), 4.05-4.12 (m, 4 H, OCH2CH3 + OCH2CH2OH), 6.88-6.97 (m, 4 H, ArH); IR (neat) 3547 (br), 3066 (m), 2977 (s), 2931 (s), 2877 (s), 1739 (m), 1649 (m), 1593 (s), 1503 (s), 1455 (s), 1393 (m), 1324 (m), 1253 (s), 1219 (s), 1123 (s), 1041 (s), 922 (s) cm-1 |
77% | With sodium hydroxide; In water; at 25℃; for 48h; | EXAMPLE 8 To a solution of 2-ethoxyphenol 19A (13.82 g, 100.1 mmol) in aqueous NaOH (1.0 N, 300 mL) was added chloroethanol (33.12 mL, 500.1 mmol). After being stirred at 25 C. for 48 h, the reaction mixture was extracted with ethyl acetate (3*100 mL). The organic layer was dried over MgSO4 (s), filtered, and concentrated under reduced pressure to obtain (ether)benzoxy alcohol 20A (14.02 g, 76.94 mmol) as yellow liquid in 77% yield: 1H NMR (CDCl3, 400 MHz) delta 1.44 (t, J=7.2 Hz, 3 H, OCH2CH3), 3.85 (t, J=7.2 Hz, 2 H, CH2OH), 4.05-4.12 (m, 4 H, OCH2CH3+OCH2CH2OH), 6.88-6.97 (m, 4 H, ArH); IR (neat) 3547 (br), 3066 (m), 2977 (s), 2931 (s), 2877 (s), 1739 (m), 1649 (m), 1593 (s), 1503 (s), 1455 (s), 1393 (m), 1324 (m), 1253 (s), 1219 (s), 1123 (s), 1041 (s), 922 (s) cm-1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; tetrabutyl-ammonium chloride; In water; at 40 - 65℃; for 3h; | Example 2 (2R,3S)-3-(2-Ethoxyphenoxy)-2-hydroxy-3-phenylpropanol Sodium hydroxide (49.2 g), tetra n-butylammonium chloride (15.5 g), and 2-ethoxyphenol (169.9 g) were dissolved in water (1080 mL). The solution of (2R,3R)-2,3-epoxy-3-phenylpropanol from Example 1 was added and the mixture was heated to about 40 C. internal temperature and the methylene chloride distilled. The internal temperature was gradually increased to 65 C. as the methylene chloride was distilled and heating continued for three hours after completion of the methylene chloride removal. The reaction mixture was cooled to 30 C. Methyl tert-butyl ether (1.5 L) was added and the mixture was stirred for 30 minutes. The phases were allowed to separate and the aqueous phase was removed. The organic layer was washed with 1 M NaOH (2*1 L), water (1L) and saturated aqueous NaCl solution (1L). The organic solution was dried by refluxing with a Dean-Stark trap until the KF was about 0.9%. The hot solution was filtered through a 0.2 mum filter. Methyl tert-butyl ether (950 mL) was distilled from the filtrate and isooctane (200 mL) was added. An additional 200 mL of solvent was distilled. Isooctane (200 mL) was added and the solution was cooled until crystals started to form. Once crystallization had started, isooctane (700 mL) was added in three portions over about 1 hour. The slurry was stirred for 15 minutes, then cooled to -20 C., and held at -20 C. for 1 hour. The mother liquor was removed with a stick filter and the solids were washed with isooctane (500 mL). The wash was removed with a stick filter. Methyl tert-butyl ether (300 mL) was added to the solids and the mixture was heated to dissolve the solids. The solution was cooled to about 20-25 C. and isooctane (400 mL) was added in a 50 mL portions over about 30 minutes. The slurry was then cooled slowly to -15 C. The slurry was stirred at -15 C. for one hour and filtered. The crystals were washed with isooctane (300 mL) and then dried on a nitrogen press to give 206 g of the title compound. This material assayed at 97% enantiomeric excess. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With aluminium(III) iodide; In dimethyl sulfoxide; acetonitrile; at 80℃; for 18h; | Add aluminum triiodide (2·240 g, 5 · 5 mmol), acetonitrile (40 ml) and DMSO (0.430 g, 5.5 mmol) to a 100 ml eggplant-shaped flask, and heat to 80 C with stirring, and stir for 0.5 hour. Then, 2-ethoxyphenol (0.691 g, 5.0 mmol) was added, and the reaction was further stirred (80 C). After the reaction for 18 hours, the stirring was stopped, and after cooling to room temperature, 2 mol/L of the rarex was added to the eggplant-shaped flask. The organic layer was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. Filtration and evaporation of the filtrate by a rotary evaporator. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1:4, volume ratio) to give 0.527 g of catechol (white solid, Rate 95%). |
95% | With aluminium(III) iodide; dimethyl sulfoxide; In acetonitrile; at 80℃; for 18h; | General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in MeCN was added anhyd DMSO (0.430 g, 5.5 mmol, 1.1 equiv). After stirring for 0.5 h at 80 C, the selected substrate (5 mmol) was added in one portion. The mixture was stirred overnight (18 h) at that temperature before quenching with aq 2 M HCl (10 mL). After extraction with EtOAc (3 50 mL), the organic phases were combined, washed with sat. aq Na2S2O3 and brine, and dried (MgSO4). The solvents were removed on a rotary evaporator, and the residue was purified by column chromatography to give the relevant catechol or phenol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.3 g (53%) | With potassium carbonate; In acetone; | PREPARATION 155 1-Chloro-3-(2-ethoxyphenoxy)propane A mixture of 41.5 g (0.3 mole) of o-ethoxyphenol, 94.4 g (0.6 mole) of 1-bromo-3-chloropropane and 124.4 g (0.9 mole) of anhydrous potassium carbonate in one liter of acetone was heated at reflux for ~20 hr. The mixture was worked-up to give 34.3 g (53%) of clear oil as residue. NMR was perfect for the desired product. Mass Spectra showed m/e=215. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77%; 9% | With hydrogen iodide; at 25℃; for 48.0h;Inert atmosphere; | A 2-way cock with a septum at the tip was attached to a recovery flask containing o-ethoxymethoxybenzene (150 mg, 0.98 mmol) and dried by allowing to stand overnight under reduced pressure in the presence of diphosphorus pentoxide, It was returned to atmospheric pressure with nitrogen. After reducing the pressure with a diaphragm pump again, hydrogen iodide gas (127 mg, 0.99 mmol) was introduced from the septum using a 50 mL syringe and returned to atmospheric pressure by filling with nitrogen and then allowed to stand at 25 C. for 48 hours I put it. After the reaction, the mixture was reduced in pressure by a diaphragm pump to obtain a mixture (139.0 mg) of o-ethoxyphenol, o-methoxyphenol and o-ethoxymethoxybenzene. The yield was determined to be 77%: 9%: 14% o-ethoxyphenol: o-methoxyphenol: o-ethoxymethoxybenzene from the integration ratio of 1 H-NMR using phenanthrene as an internal standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 60℃; for 24h; | A mixture of (S)-3-[(R,S)-hydroxy-phenyl-methyl]-piperidine-1-carboxylic acid tert- butyl ester (1.53 g, 5.24 mmol, Preparation 19), 2-ethoxyphenol (0.83 mL, 6.55 mmol), triphenylphosphine (1.72 g, 6.56 mmol) and diisopropyl azodicarboxylate (1.3 mL, 6.60 <n="53"/>mmol) in 10 mL of THF was heated at 60 C for 24 hours. The sample was cooled, rotary evaporated then suspended into 75 mL of hexanes. The solid that formed was removed by filtration. The filtrate was rotary evaporated and chromatographed (MPLC, silica gel, 100 % CH2CI2 [2L] then 20% EtOAc in hexanes [2L]) to give 0.99 g (46%) of (S)-3-[<2- Ethoxy-phenoxy)-(R,S)-phenyl-methyl]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil. MS (APCI+) m/z 312.2 [M-99, 100%]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.5% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 72h; | EXAMPLE 80 N-(3-{1-[(3S)-3-(2-ETHOXYPHENOXY)-3-PHENYLPROPYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-ethoxyphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 ML) was stirred at room temperature for 3 days.. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.16 mg, 15.5% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) delta 8.06 (s, 1H), 7.52 (s, 1H), 7.40-7.33 (m, 4H), 7.30-7.20 (m, 3H), 6.97 (apparent d, 1H, J=7.7 Hz), 6.88 (m, 2H), 6.68 (m, 2H), 5.21 (m, 1H), 4.11 (q, 2H, J=7.3 Hz), 3.37 (m, 2H), 2.71 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.49 (t, 3H, J=7.3 Hz), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 501.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.4% | With sodium hydroxide; In water; at 20℃; for 16h; | 1.1 Synthesis of intermediate compound A2Put together 2-ethoxyphenol (compound A1) (51.5g, 0.373mol) and 50% glyoxylic acid (37.3ml, 0.34mol, 1eq)and 100ml of distilled water. Add to a 500ml three-mouthed flask. Under ice-cooling, to the three-mouthed flask was added dropwise 10% NaOH solution(29.8gNaOH, 0.745mol, 300ml of distilled water 2eq). At room temperature react for 16 hours. washed with ethyl acetate (4 * 250ml) and the aqueous phase was adjusted pH = 2-3 with aqueous 6N hydrochloric acid , NaCl was added to saturation, and then extracted with ethyl acetate (3 * 200ml), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, andthe solvent under reduced pressure to give 51.4g spin dry brown solid, yield51.4%. |
<strong>[94-71-3]2-Ethoxyphenol</strong> (56.6, 0.401 mol, 1 eq.), glyoxylic acid (50% aqueous solution) (41.0 mL, 0.396 mol, 0.99 eq.), and distilled water (110 mL) were combined. The mixture was cooled in an ice bath, and a solution of 10% NaOH (32.2 g NaOH in 300 mL distilled water, 0.805 mol, 2 eq.) was slowly added via addition funnel. The reaction was allowed to slowly warm to room temperature, and after 18 hours, the solution was washed with ethyl acetate (4×250 mL), then acidified with 6N HCl until pH 3. NaCl was added and the product was then extracted into ethyl acetate (4×200 mL). The organic phase was washed with brine, dried over magnesium sulfate, and solvent was removed under vacuum, giving 51.8 g of intermediate 2 as a light pink solid. [0056] 1H NMR (DMSO-d6, 300 MHz): delta 1.24 (t, 3H), 3.90 (q, 2H), 4.79 (s, 1H), 5.59 (bs, 1H), 6.67 (q, 2H), 6.86 (s, 1H), 8.81 (s, 1H), 12.35 (bs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.8% | With potassium tert-butylate; In tetrahydrofuran; at 25℃; for 1h; | Example 4 Preparation of (R)-2- (2-ethoxyphenoxy)-N- [2- (4-methoxy-3-aminosulfonyl-phenyl)-1 -methyl-ethyl]-acetamide) 1.0 g of (R)-2-bromo-N- [2- (4-methoxy-3-aminosulfonyl-phenyl)-1-methyl-ethyl] - acetamide prepared in Example 2 was added to a stirring solution of 1.25 g of potassium t-butoxide and 1.5 g of 2-ethoxy phenol in 10 ml of tetrahydrofuran and stirred at 25 C for 1 hour. After the reaction was completed, 50 ml of a 10% hydrochloric acid solution and then, 50 ml of ethyl acetate was added to the resultant solution and then, extracted. Next, the organic layer was separated and concentrated. 10 ml of methanol was added to the obtained concentrated residue and stirred for 12 hours. Then, the resultant product was filtered and dried to obtain the title compound as a white solid (0.9 g). Yield : 77.8% NMR (DMSO-d6) : 1.15 (3H, d), 1.25 (3H, t), 2.8 (1 H, m), 3.6 (2H, s) 3.90 (3H, s), 4.05 (2H, q), 6. 9-7. 1 (4H, m), 7.0 (2H, s), 7.1 (1H, d), 7.4 (1H, d), 7.6 (1 H, S), 8.2 (2H, d) [a] 24D =-38. 2 (C=1.0, CH3CN) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In 1,2-dimethoxyethane; at 20℃; for 24h; | To a stirring mixture at room temperature of (S)-2-hydroxymethyl-morpholine-4-carboxylic acid, tert-butyl ester, 2-ethoxyphenol and triphenylphosphine in DME was added dropwise diisopropyl azodicarboxylate. The solution was stirred at room temperature for 24 h, concentrated (to remove most of the DME), then suspended into hexanes. The solid that formed was filtered. The filtrate was concentrated, redissolved into diethyl ether, then washed with 1 N NaOH (2×), sat. KH2PO4 and brine solutions. The organic extract was dried (MgSO4), filtered, concentrated and chromatographed (MPLC, silica gel, 20% EtOAc in hexanes) to give (S)-2-(2-ethoxy-phenoxymethyl)-morpholine-4-carboxylic acid, tert-butyl ester as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | at 160℃; for 20h;Neat (no solvent); | A mixture of 414 g (3 Mol) of guaethol and 255 g (3 Mol) of 2- Methyloxazoline are treated in the same manner as described in Example 1. About 501 g of N-[2-(2-Ethoxy-phenoxy)-ethyl]-acetamide (72%) is obtained. The N-[2-(2-Ethoxy-phenoxy)-ethyl]-acetamide has a melting point of 77-79C and is used for the next step without further purification. EXAMPLE 1 Preparation of N-[2-(2-Methoxy-phenoxy)-ethyl]-acetamide A mixture of 372 g (3 Mol) Guaiacol and 255 g (3 Mol) of 2- Methyloxazoline are heated at 160C for 20h in a three-necked flask equipped with a stirrer, condenser and thermometer. After cooling to 90C the reaction mixture is poured into water and the solid residue obtained is collected, washed with water and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.5% | With ammonia; triphenylphosphine; In tetrahydrofuran; methanol; chloroform; | EXAMPLE 136 N-(3-{1-[(3S)-3-(2-ethoxyphenoxy)-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-ethoxyphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.16 mg, 15.5% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) delta 8.06 (s, 1H), 7.52 (s, 1H), 7.40-7.33 (m, 4H), 7.30-7.20 (m, 3H), 6.97 (apparent d, 1H, J=7.7 Hz), 6.88 (m, 2H), 6.68 (m, 2H), 5.21 (m, 1H), 4.11 (q, 2H, J=7.3 Hz), 3.37 (m, 2H), 2.71 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.49 (t, 3H, J=7.3 Hz), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 501.4 (M+H)+. |
15.5% | With ammonia; triphenylphosphine; In tetrahydrofuran; methanol; chloroform; | EXAMPLE 136 N-(3-{1-[(3S)-3-(2-ETHOXYPHENOXY)-3-PHENYLPROPYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-ethoxyphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.16 mg, 15.5% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) delta 8.06 (s, 1H), 7.52 (s, 1H), 7.40-7.33 (m, 4H), 7.30-7.20 (m, 3H), 6.97 (apparent d, 1H, J=7.7 Hz), 6.88 (m, 2H), 6.68 (m, 2H), 5.21 (m, 1H), 4.11 (q, 2H, J=7.3 Hz), 3.37 (m, 2H), 2.71 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.49 (t, 3H, J=7.3 Hz), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 501.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With sodium hydroxide; sodium chloride; In water; | ED Synthesis This synthesis of 1-ethoxy-2-isopentoxybenzene is representative of the synthesis of the non-commercially available EDs via substitution reactions by salt elimination. 200 mmol of 2-ethoxyphenol was added to a stirring solution of 417 mmol of sodium hydroxide in 90 ml of water. Following the addition of 400 mmol of 1-bromo-3-methylbutane, the mixture was refluxed for 6 hours. The two phase liquid was extracted with hexanes. The organic phase was washed with a sodium hydroxide solution followed by a sodium chloride solution. The organic phase was then dried over magnesium sulfate and distilled. A 38% yield was obtained of the 1-ethoxy-2-isopentoxybenzene product as determined by 1H NMR. |
38% | With sodium hydroxide; sodium chloride; In water; | ED Synthesis This synthesis of 1-ethoxy-2-isopentoxybenzene is representative of the synthesis of the non-commercially available EDs via substitution reactions by salt elimination. 200 mmol of 2-ethoxyphenol was added to a stirring solution of 417 mmol of sodium hydroxide in 90 ml of water. Following the addition of 400 mmol of 1-bromo-3-methylbutane, the mixture was refluxed for 6 hours. The two phase liquid was extracted with hexanes. The organic phase was washed with a sodium hydroxide solution followed by a sodium chloride solution. The organic phase was then dried over magnesium sulfate and distilled. A 38% yield was obtained of the 1-ethoxy-2-isopentoxybenzene product as determined by 1 H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.2 g (58%) | With pyridine; In ethanol; dichloromethane; acetone; | PREPARATION 34 3-(2-Ethoxyphenoxy)-1,2-propanediol A solution of 41.5 g (0.3 mole) of 2-ethoxyphenol, 29.6 g (0.4 mole) of glycidol, 2 ml of pyridine and 150 ml of absolute ethanol was heated at reflux temperature for 18 hr. The mixture was concentrated to a thick oil that crystallized slowly over several days. The crude product was chromatographed on a silica gel column (1.2 kg) using increasing portions of acetone in methylene chloride to elute the product. The desired fractions were combined and concentrated to give a yellow oil that crystallized on standing. The solid was triturated with petroleum ether and the mixture filtered to obtain 41.8 g of solid. Recrystallization from carbon tetrachloride yielded 37.2 g (58%) of white solid, mp 64-65 C. Analysis: Calculated for C11 H6 O4: C, 62.25; H, 7.60. Found: C, 62.34; H, 7.72. |
37.2 g (58%) | With pyridine; In ethanol; dichloromethane; acetone; | Preparation 36 3-(2-Ethoxyphenoxy)-1,2-propanediol. A solution of 41.5 g (0.3 mole) of 2-ethoxyphenol, 29.6 g (0.4 mole) of glycidol, 2 ml of pyridine and 150 ml of absolute ethanol was heated at reflux temperature for 18 hr. The mixture was concentrated to a thick oil that crystallized slowly over several days. The crude product was chromatographed on a silica gel column (1.2 kg) using increasing portions of acetone in methylene chloride to elute the product. The desired fractions were combined and concentrated to give a yellow oil that crystallized on standing. The solid was triturated with petroleum ether and the mixture filtered to obtain 41.8 g of solid. Recrystallization from carbon tetrachloride yielded 37.2 g (58%) of white solid, mp 64-65 C. Analysis: Calculated for C11 H6 O4: C, 62.25; H, 7.60; Found: C, 62.34; H, 7.72. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.4% | In toluene; | EXAMPLE 2 1-(2-Ethoxyphenoxysulfonyl)-3-(4,6-dimethoxy-2-pyrimidyl)urea 38.1 g of 2-ethoxyphenyl N-(2-ethoxyphenoxysulfonyl)carbamate are dissolved in 500 ml of toluene, 15.5 g of 2-amino-4,6-dimethoxypyrimidine are added at room temperature, and the mixture is heated for 2 hours at 100 C. After cooling to 30 C., the precipitate is filtered off and washed with 100 ml of toluene. 38.8 g of the desired product are obtained with a purity of 98.8%, corresponding to a yield of 96.4% of theory. The melting point for the product is 147-149 C. 6.5 g of 2-ethoxyphenol are recovered from the mother liquor by distillation. |
Yield | Reaction Conditions | Operation in experiment |
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91% | In 5,5-dimethyl-1,3-cyclohexadiene; | COMPARISON EXAMPLE 1 Synthesis of 2-ethoxyphenoxysulfonyl isocyanate in xylene following EP-A-342,569 55.2 g of 2-ethoxyphenol are dissolved in 200 ml of xylene and reacted with 67.9 g of chlorosulfonyl isocyanate at 25 C.. The reaction mixture is heated to 140 C. and refluxed for 2.5 hours, during which process HCl is formed. After the solvent has been removed by distillation, 97.2 g of an oil are obtained which has a purity of 91% based on weight, corresponding to a yield of 91% of theory. |
In 5,5-dimethyl-1,3-cyclohexadiene; | EXAMPLE 1 2-Ethoxyphenoxysulfonyl isocyanate 67.9 g (0.48 mol) of chlorosulfonyl isocyanate are added dropwise at 25 C. to a solution of 55.2 g (0.4 mol) of 2-ethoxyphenol in 500 ml of xylene. When the dropwise addition is complete, the temperature is increased slowly to 140 C. and the mixture is refluxed for 2.5 hours. The mixture is cooled, and the solvent as well as excess chlorosulfonyl isocyanate are removed on a rotary evaporator. The yellow oil which remains (97.2 g=100% of theory) is employed without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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85% | With PPA;zinc(II) chloride; at 100℃; for 3h; | A mixture of 2-ethoxyphenol (0.2M), phthalic anhydride (0.1M), polyphosphoric acid (0.25M), and zinc chloride (0.01M), was stirred and heated at 100 C. for 3 hours. The reaction mixture was cooled to room temperature and added to ice-water mixture when the product precipitated. The product was filtered, thoroughly washed with water and dried. Recrystallization from ethanol with charcoal treatment furnished pure 3,3-bis-(4-hydroxy-3-ethoxyphenyl)-1-(3H)-isobenzofuranone in 85% yield. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; In dichloromethane; acetone; benzene; | EXAMPLE 30 Trans-4-(2-ethoxyphenoxy)-1-phenylmethyl-3-pyrrolidinol A mixture of 45.5 g. (0.26 mole) of 1-benzyl-3,4- epoxypyrrolidine (60 g. of 76% epoxide), 48 g. (0.35 mole) of o-ethoxyphenol and 8 drops of concentrated hydrochloric acid was heated at 145 C. for 16 hr. The mixture was cooled, dissolved in methylene chloride and washed with dilute sodium hydroxide solution. The methylene chloride layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on 1 kg. of silica gel using 20% acetone in benzene as the eluent. Two recrystallizations from cyclohexane gave 8.0 g. (10%) of tan needles, m.p. 88.5-90.0 C. Analysis: Calculated for C19 H23 NO3: C,72.82; H,7.40; N,4.47. Found: C,72.64; H,7.39; N,4.56. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; sodium hydroxide; In dichloromethane; | EXAMPLE 51 Trans-4-(2-ethoxypnenoxy)-1-ethyl-3-pyrrolidinol A mixture of 17.0 g. (0.15 mole) of 1-ethyl-3,4-epoxypyrrolidine, 22.1 g. (0.16 mole) of o-ethoxyphenol and 3 drops of concentrted hydrochloric acid was heated on a steam bath overnight. The oil was dissolved in methylene chloride and washed with three 50-ml. portions of 5% sodium hydroxide and one 50-ml. portion of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel to give 8.1 g. (21%) of an oil which crystallized on standing. The solid was recrystallized from cyclohexane to yield a tan solid, m.p. 73-75 C. Analysis: Calculated for C14 H21 NO3: C,66.90; H,8.42; N,5.57; Found: C,66.49; H,8.43; N,5.48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In dichloromethane; acetone; benzene; | EXAMPLE 30 Trans-4-(2-ethoxyphenoxy)-1-phenylmethyl-3-pyrrolidinol A mixture of 45.5 g. (0.26 mole) of <strong>[75390-09-9]1-benzyl-3,4-epoxypyrrolidine</strong> (60 g. of 76% epoxide), 48 g. (0.35 mole) of o-ethoxyphenol and 8 drops of concentrated hydrochloric acid was heated at 145 C. for 16 hr. The mixture was cooled, dissolved in methylene chloride and washed with dilute sodium hydroxide solution. The methylene chloride layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on 1 kg. of silica gel using 20% acetone in benzene as the eluent. Two recrystallizations from cyclohexane gave 8.0 g. (10%) of tan needles, m.p. 88.5-90.0 C. Analysis: Calculated for C19 H23 NO3: C, 72.82; H, 7.40; N, 4.47. Found: C, 72.64; H, 7.39; N, 4.56. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; chloroform; benzene; | EXAMPLE 3 3-[(2-Ethoxyphenoxy)methyl]-1-phenylmethyl-3-pyrrolidinol A stirred mixture of 56.1 g (0.294 mole) of <strong>[97266-84-7]5-benzyl-1-oxa-5-azaspiro[2:4]heptane</strong> and 49.2 g (0.3557 mole) of 2-ethoxyphenol was heated at 100+-2 C. under a nitrogen atmosphere for 2.5 hours. The reaction mixture was cooled to room temperature, dissolved in chloroform (250 ml), extracted with 3N sodium hydroxide (2*125 ml), and the combined basic extracts extracted with chloroform (125 ml). The combined chloroform solutions were extracted with water (250 ml), dried over magnesium sulfate, and evaporated under reduced pressure (94.0 g). The residue was dissolved in benzene and chromatographed on a 1.5 kg column of Florisil packed in benzene. Product was eluted with increasing concentrations of methanol in benzene (1 to 9%). Crystalline solid, 84.6 g was obtained which was recrystallized from isooctane to give 66.0 g crystals (68%), m.p. 56.5-59 C. A portion of the recrystallized product was dried at room temperature and 0.01 mm Hg for 4 hours. Analysis: Calculated for C20 H25 NO3: C,73.37; H,7.70; N,4.28; Found: C,73.47; H,7.70; N,4.25. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogen;palladium; In cyclohexyl propionate; | EXAMPLE 11 A solution of 10 gm. 2-ethoxycyclohexanone in 100 ml. cyclohexylpropionate was refluxed over 400 mg. of palladium on carbon until approximately 75% hydrogen had evolved. The catalyst was removed by filtration. O-ethoxyphenol was obtained in high yield. | |
With hydrogen;palladium; In cyclohexyl propionate; | EXAMPLE 11 A solution of 10 gm. 2-ethoxycyclohexanone in 100 ml. cyclohexylpropionate was refluxed over 400 mg. of palladium on carbon until approximately 75% hydrogen had evolved. The catalyst was removed by filtration. o-Ethoxyphenol was obtained in high yield. |
Yield | Reaction Conditions | Operation in experiment |
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53% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 24h; | To a mixture of alcohol lib (342mg, 1.21mmol, leq), triphenylphosphine (637mg, 2.43mmol, 2eq) and 2-ethoxyrhohenol (28a) (0.31ml, 2.43mmol, 2eq) in 7ml THF at 0C was added diisopropyl azodicarboxylate (0.47ml, 2.43mmol, 2eq). The mixture was allowed to reach RT and stirred for 24h. The crude was concentrated under reduced pressure and purified by flash chromatography on silica gel with EtOAc/hexane (15:85) to provide (S)-2-((S)-(2- ethoxyphenoxy)(phenyl) methyl)-4-benzylmorpholine as a colorless oil (267mg, 53%). The material was dissolved in 5ml of CH2Cl2 and 1Pr2NEt (831 mul, 5eq) and 1-chloroethylchloro- formate (521ml, 5eq) were successively added thereto. The resulting solution was refluxed for 4h. The solvent was evaporated in vacuum and portioned between H2O/AcOEt. The organic phases were washed with H2O and dried over Na2SO4. Evaporation and chromatography (SiO2, CH2Cl2ZMeOH 9/1) of the residue provided 30a as a white solid in 88% yield. NMR 1H (CDCl3), 5=7.47-7.43 (m, 2H, ArH); 7.38-7.27 (m, 3H, ArH); 6.96-6.91 (m,IH3 ArH); 6.89-6.82 (m, 2H, ArH); 6.77-6.71 (m, IH, ArH); 5.26 (d, IH, J=5.5Hz, CHOAr); 4.13-3.97 (m, 4H); 3.77-3.68 (m, IH); 2.98-2.80 (m, 4H); 1.44 (t, 3H, J=7.5Hz, CH3). NMR 13C (MeOH, 125MHz), delta=150.9 (C); 148.7 (C); 138.6 (C); 129.3 (CHAr); 128.6 (CHAr); 123.5 (CHAr); 121.9 (CHAi-); 118.9 (CHAr); 115.5 (CHAr); 83.4 (CHO); 78.8 (CHOAr); 67.0 (CH2O); 65.7 (CH2O); 46.8 (NCH2CH2); 45.1 (NCH2CH); 15.3 (CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; at 0 - 5℃; | 5.00 g (14.5 mmol) of 2,2'-benzidinedisulfonic acid was dissolved in 70 ml of an aqueous 3.3% (w/v) sodium hydroxide solution, followed by stirring at 0 to 5C. While maintaining at the same temperature, 2.10 g (30.5 mmol) of sodium nitrite dissolved in 60 ml of water was added, and then 22 ml of an aqueous 8 N hydrochloric acid solution was slowly added dropwise. After the completion of the dropwise addition, stirring was continued for 3 hours while maintaining the temperature of the reaction solution to prepare a diazonium salt. Then, 4.0 g (29.0 mmol) of 2-ethoxyphenol was dissolved in 140 ml of an aqueous 3.5% (w/v) sodium hydroxide solution, followed by cooling to 0 to 5C, and the diazonium salt mixture obtained by the above method was gradually added dropwise. After the completion of the dropwise addition, stirring was continued for 2.5 hours while maintaining the temperature of the reaction solution. To the reaction solution, 70 g of sodium chloride was added, followed by stirring at room temperature for a while, and the resulting precipitate was removed by filtration to obtain a crude product. The resulting crude product was dried under reduced pressure, washed with heated acetone, and dissolved in 100 ml of heated N,N-dimethylformamide so as to remove insolubles by filtration, and the filtrate was distilled off under reduced pressure to obtain 5.5 g (yield: 55%) of a compound No. A-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | To a stirring mixture consisting of excesses of alcohol derivative and triphenylphosphine in tetrahydrofuran at 0 C. under an inert atmosphere is added dropwise an excess of diisopropyl azodicarboxylate. The mixture is stirred for a time and the limiting reagent, (1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-methanol (Example 1, Compound E) is added. The resultant mixture is agitated at room temperature overnight. The mixture is then concentrated under reduced pressure and the concentrate is dissolved in an organic solvent such as dichloromethane or ethyl acetate. The resultant mixture is washed with aqueous sodium bicarbonate solution. In some experiments, the organic mixture is further washed with water and with brine solution and is then separated. The organic layer is dried over a drying agent such as anhydrous sodium sulfate or anhydrous magnesium sulfate and is filtered and concentrated under reduced pressure. The concentrate is purified by flash silica gel chromatography in which the mobile phase consisted of a hexanes-ethyl acetate mixture to afford the desired synthetic intermediate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium hydroxide; In water; at 70℃; for 6h; | Step 1: A mixture of 2-ethoxyphenol (10 mL, 78 mmol), [(2R,3R)-3-(2-bromophenyl)oxiran-2-yl]methanol (5.95 g, 26 mmol), and sodium hydroxide (1.04 g, 26 mmol) in water (30 mL) were heated to 70 C. for 6 hours. Upon completion, the reaction was poured into saturated aqueous sodium chloride (50 mL) and separated with ether (50 mL). The organic layers were combined and dried with sodium sulfate and the residue purified via silica gel (ISCO 0-100% ethyl acetate/hexane) to give (2R,3S)-3-(2-bromophenyl)-3-(2-ethoxyphenoxy)propane-1,2-diol (6.01 g, 63%). MS (ES) m/z 348.8; HRMS: calculated for C17H19BrO4+Na+, 389.03589; found (ESI, [M+Na]+), 389.0359; |
Yield | Reaction Conditions | Operation in experiment |
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With tetrabutylammomium bromide; potassium hydroxide; In water; at 25℃;Reflux; | Example 7: Preparation of l-(2-chloroethoxy)-2-ethoxy benzene100 gm of 2-ethoxy phenol was added to 150ml of caustic lye dissolved in 450 ml of water at 25-35C. 500 ml of 1,2-dichloroethane and 7 gm of TBAB was added to the above reaction mixture at 25-35C and heated to reflux for about 16 hours. After completion, the reaction mixture was cooled to 25-350C and separated the layers. Aqueous layer was extracted with dichloroethane (2XlOOmI). Total organic layer was washed with 5% caustic lye and distilled off the solvent completely to get residue (140 gm). The residue was further purified by high vacuum distillation to get 112 gm of pure title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran;Reflux; | Example 81 (S)-2-[4-(2-Ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide Hydrochloride To a stirred mixture of 2-ethoxy-phenol (10.3g, 74.5 mmol) and ethyl-2-butynoate (16.80 g, 149.0 mmol) in tetrahydrofuran (60 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene slowly (16.80 g, 149.0 mmol). After addition was complete the mixture was stirred at reflux for 4 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was taken up in diethyl ether and washed with 1N aqueous hydrochloric acid, 10% aqueous sodium hydroxide solution, saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 120 g, 0% to 20% ethyl acetate/hexanes) to afford, (E)-3-(2-ethoxy-phenoxy)-but-2-enoic acid ethyl ester (8.57 g, 46%) as a colorless oil: 1H NMR (300 MHz, CDCl3) delta ppm 1.22 (t, J=7.1 Hz, 3H), 1.37 (t, J=6.9 Hz, 3H), 2.51 (s, 3H), 3.95-4.19 (m, 4H), 4.83 (s, 1H), 6.88-7.08 (m, 3H), 7.09-7.24 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 1: Formation of methyl 2-ethoxyphenoxy acetate (2) A 500 mi three-neck, round bottom flask was charged with 6.25 ml of water and 6.55g of potassium hydroxide. The resulting mixture was gently stirred at ambient temperature to give a clear solution. The resulting mixture was further charged with 250 mi of toluene and 11.5 ml of 2-ethoxyphenol (75 g), then heated to reflux. Water distilled out of the reaction mixture was collected in the Dean-Stark trap. After 3 hours of heating, distillation of water from the reaction mixture had stopped. The reaction mixture was allowed to cool to room temperature. A solution of 11.2 ml of methyl bromoacetate and 12.5 ml of toluene was added to the reaction vessel over a period of 10 minutes, resulting in a white suspension which was allowed to stir vigorously at room temperature for 2 hours. Then, 65 ml of water and 4.86 ml of ethylenediamine were added. The resulting biphasic mixture was stirred vigorously for 60 minutes. The mixture was transferred to a 500 ml separatory funnel and the biphasic layer was separated. The organic layer was collected and washed with diluted HCI solution, followed by water. The organic extract was filtered and the resulting solution was concentrated via atmospheric distillation. This solution of ester 2 in toluene was used"as-is"for the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With bis(trichloromethyl) carbonate; tetrabutylammomium bromide; potassium bromide; In water; ethyl acetate; at 20℃; for 19h; | General procedure: To the solution of anisole (0.50 g, 4.6 mmol), TBAB (0.75 g, 2.3 mmol), KBr (0.83 g, 6.9 mmol), ethyl acetate (3.0 mL) and water (0.050 g, 2.8 mmol) were added and stirred at room temperature. A solution of BTC (1.78 g, 6.0 mmol) in ethyl acetate (6.0 mL) was dropwised to the reaction mixture. After the reaction finished, the reaction mixture was washed with water (10 mL × 2) and evaporated. The product was obtained with 99% purity by HPLC. 1 H NMR (400 MHz, DMSO-d6, ppm): delta 7.46-7.42 (m, 2H), 6.78-6.76 (m, 2H), 3.74 (s, 3H). |
In methanol; dichloromethane; at -78 - 0℃; for 2.5h; | Example 4 Synthesis of 4-Bromo-2-ethoxy-phenol A mixture of 2-ethoxyphenol (30.0 g, 217 mmol) and TBAB [(tri-n-butylamino tribromide) ((n-Bu4)NBr3)](104.7 g, 217 mmol) in a 10:1 mixture of dichloromethane/methanol (385 mL) was allowed to warm from -78 C. to 0 C. over a period of 2.5 hr. The reaction was quenched by the addition of Na2S2O3 (8 g in 80 mL of water) and the reaction mixture was concentrated in vacuo. The residue was extracted with diethyl ether and the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to a volume of 400 mL. The mixture was then warmed slightly and filtered by gravity. The filtrate was concentrated, taken up in diethylether/hexanes (1:2), heated, and the mixture was) filtered while it was hot to remove the inorganic by-product. The filtrate was concentrated to afford 37.04 g of 4-bromo-2-ethoxy-phenol as a slightly colored solid. A second crop of lower purity was isolated from the filtrate, affording an additional 9.41 g of product. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; | To a solution of 100 mg of methyl 4-{2-[5-bromo-6-(bromomethyl)-2-oxopyridin-1(2H)-yl]ethyl}benzoate in 2.0 ml of DMF were added 48 mg of potassium carbonate and 48 mg of 2-ethoxyphenol, followed by stirring at 60C overnight. After leaving to be cooled to room temperature, ethyl acetate and a saturated aqueous ammonium chloride solution were added thereto to carry out a liquid separation operation. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 104 mg of a white solid of the compound. To a mixed solvent of 100 mg of the obtained white solid of the compound in 1.0 ml of THF and 1.0 ml of methanol was added 1.0 ml of a 1 M aqueous sodium hydroxide solution, followed by heating under reflux for 30 minutes. The reaction liquid was acidified by the addition of 1 M hydrochloric acid under ice-cooling, and the precipitated solid was collected by filtration and the obtained solid was washed with methanol-water to obtain 61 mg of 4-(2-{5-bromo-6-[(2-ethoxyphenoxy)methyl]-2-oxopyridin-1(2H)-yl}ethyl)benzoic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of NaH (0.42 g 60% in mineral oil,10.5 mmol) in DMF (8.0 mL) was slowly added 2-ethoxylphenol (1.34 g, 9.7 mmol) in MeCN (4.0 mL) at 0 0C under N2. After the addition, the reaction mixture was allowed to warm up to room temperature for 0.5 hour. 5-bromo-2,4- dichloropyrimidine (2.0 g, 8.8 mmol) in MeCN (16.0 mL) was slowly added and then the resulting reaction mixture was stirred at room temperature for 24 hour. EtOAc (120 mL) was added and washed with NaOH (30 mL, 0.5N) and brine (25x2 mL) . The organic layer was dried with MgSO4, and" concentrated under reduced pressure. The residue was EPO <DP n="203"/>purified by silica gel chromatography (10% to 30% EtOAc in Hexanes, gradient elution) to provide the 5-bromo-2-chloro- 4- (2-ethoxyphenoxy)pyrimidine. MS m/z - 330 [M+l]+. Calc'd for: Ci2H10BrClN2O2: 329 |
Yield | Reaction Conditions | Operation in experiment |
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73% | (iii) R-(~)-N-[2-(3-amino sulfonyl-4-methoxy phenyl)-l -methyl ethyI]-2~(2-ethoxy phenoxy) acetaniide (TV); A solution of 2-ethoxy phenol (431 g, 3.12 mole) in 3-5% aqueous sodium hydroxide solution (3500 niL) was heated at 65-70 C for 15 min. Then R-(-)-N-[2-(3-amino sulfonyl-4-methoxy phenyl)- 1 -methyl ethyl] -2-chloroacetamide (X) (125 g, 0.39 mole) was added to the reaction mixture in parts for 1 hour at 65-70 C. The reaction mixture was acidified with concentrated hydrochloric acid and extracted with 2000 ml of chloroform. The chloroform was separated, washed with dilute sodium hydroxide solution, brine and concentrated to obtain a residue. The residue was treated with 2000 ml of hexane to obtained a solid, filtered and dried. Yield: 120 g (73%), HPLC: 92%. |
Yield | Reaction Conditions | Operation in experiment |
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19% | With nitric acid; In diethyl ether; water; at 20℃; for 3h;Reflux; | Step 1. 2-ethoxy-6-nitrophenolNitric acid (3.89 mL, 60 mmol) was added drop-wise to 2-ethoxy-phenol, (Aldrich, 5.00 mL, 39.4 mmol) in water (20 mL) and diethyl ether (49 mL). The resulting mixture became hot to the point of the reflux of the ether, and then was allowed to cool to RT and stir for 3 h. The reaction mixture was poured into water and was extracted three times with diethyl ether. The extracts were dried over sodium sulfate, decanted and concentrated. The residue was dissolved in a small volume of DCM and hexanes, and what the undissolved material was excluded in loading the silica gel column for flash chromatography. The product was eluted with a gradient from 20-50% chloroform in hexanes, to afford the product as an orange solid (1.36 g, 19%). 1H NMR (300 MHz, CDCl3): delta 10.73 (br s, 1H), 7.68 (dd, 1H), 7.12 (dd, 1H), 6.88 (dd, 1H), 4.14 (q, 2H), 1.50 (t, 3H); LCMS (M+H)+: 183.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With aluminum isopropoxide; at 140℃; for 3h;Inert atmosphere; | General procedure: A two-necked flask equipped with a thermometer and N2 gas inlet was charged with phenols (2 equiv.) and heated up to 140 C and added Al(O-i-Pr)3 (20% mol). After catalyst and phenol were completely dissolved, the solution was treated with isoeugenol (1 equiv.). The reaction was carried out through keeping the temperature at 140 C for 3 h. When the reaction was complete, the mixture was cooled, diluted with ethyl acetate, and treated with HCl solution (5%) to compose the catalyst. Then, the mixture was washed with saturated NaHCO3 solution and water until rinsing was neutral. The organic layer was dried over anhydrous Na2SO4. The solvent was evaporated, and the crude products were purified by column chromatography (on a silica gel column) using n-hexane/EtOAc (9:1) as eluent. The products were crystallized from n-hexane/EtOAc (9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.8% | With potassium hydroxide; In N,N-dimethyl-formamide; at 50℃; | General procedure: Potassium hydroxide (160 mg, 2.8 mmol) was added to a solution of tosylate 3 (485 mg, 0.78 mmol) and phenol (70 mg, 0.72 mmol) in dry DMF (5 mL), and the reaction mixture was heated at 50C overnight. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and EtOAc (20 mL), and the organic phase was separated. The aqueous phase was extracted with EtOAc (3 x 20 mL). All of the organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography on silica gel (EtOAc/hexanes = 1:1), affording target compound 7a (178.8 mg, 74.6% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In 1,2-dimethoxyethane; for 18h;Reflux; | General procedure: A mixture of 2-chloro-phenol (Aldrich) (1.50 g, 11.6 mmol), methyl 2-bromopropionate (1.74 g, 11.6 mmol), and K2CO3 (1.60 g, 11.6 mmol) in DME was refluxed for 18 h. The mixture was cooled and filtered. The solvent was removed under reduced pressure to give a residue, which was taken up in CH2Cl2 and washed with cold 2 N NaOH. Removal of solvent afforded an oil which was purified by flash chromatography eluting with cyclohexane/EtOAc (95:5): 2.23 g (90% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Cyclic sulfate 4 (1.028 g, 2.984 mmol) was dissolved in THF (20 mL). Tetrabutylammonium fluoride (1 M in THF, 3.58 mL, 3.58 mmol) was added and the mixture was stirred at rt for 30 min. Next, NaN3 (0.388 g, 5.973 mmol), THF (34 mL), and H2O (5.4 mL) were added and the mixture was stirred at 70 C for 21 h. The mixture was concentrated and the residue was partitioned between H2O and CHCl3. Extractive work-up (CHCl3-brine), drying (Na2SO4), and concentration yielded the crude epoxide ring-opened product (2.35 g, 2.95 mmol as quantified by NMR with an external standard, 99%).<strong>[94-71-3]2-Ethoxyphenol</strong> (0.68 mL, 5.415 mmol) was treated with NaOH (5.41 mmol) in H2O (4.5 mL). The mixture was stirred at rt for 1 h. The crude intermediate obtained above (2.16 g, 2.70 mmol) and H2O (7 mL) were then added. The mixture was heated at reflux for 5 h. Extractive work-up (CHCl3-brine) was followed by drying (Na2SO4) and concentration. Flash silica column chromatography (hexane-EtOAc 4:1) yielded the desired product 5 as a yellow liquid (0.719 g, 2.294 mmol, 84% from 4). 1H NMR (CDCl3) delta 7.46-7.26 (5H, m, Ar), 6.98-6.71 (4H, m, OAr), 5.05 (1H, d, J = 5.1 Hz, Ph-CH), 4.19-4.04 (3H, m, CH(OH)-CH2, O-CH2-CH3), 3.56 (1H, dd, J = 12.6, 7.8 Hz, CHAHBN3), 3.33 (1H, dd, J = 12.9, 3.3 Hz, CHAHBN3), 3.25 (1H, d, J = 6.9 Hz, OH), 1.51 (3H, t, J = 6.9 Hz, O-CH2-CH3) ppm. IR: 3442(br), 2102(s), 1501(s), 1254(s), 1124(s) cm-1. . HRMS(EI) calcd for C17H19N3O3 [M]+ 313.1426, found 313.1425. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tetrachloromethane; potassium carbonate; In acetonitrile; at 20℃; | General procedure: To a stirred solution of compound 1 (131mg, 0.5 mmol) in CH3CN (3 mL), CCl4 (154mg, 1.0 mmol), phenols (94mg, 1.0 mmol) and K2CO3 (207mg, 1.5 mmol) were successively added. The reaction mixture was stirred at ambient temperature for several hours until the 31P NMR signal of intermediate 2 disappeared. Then the mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by preparative TLC to give 3 as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.9% | With potassium hydroxide; In N,N-dimethyl-formamide; at 50℃; | General procedure: Potassium hydroxide (160 mg, 2.8 mmol) was added to a solution of compound F (485 mg, 0.78 mmol) and 2-propokyphenol (110 mg, 0.72 mmol) in dry DMF (5 mL), and the reaction mixture was heated at 50 C overnight. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and EtOAc (20 mL), and the organic phase was separated. The aqueous phase was extracted with EtOAc (3 * 20 mL). All of the organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography on silica gel (EtOAc/hexanes = 1:1), affording target compound G1 (yield: 20.0%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.6% | With potassium hydroxide; In N,N-dimethyl-formamide; at 50℃; | General procedure: Potassium hydroxide (160 mg, 2.8 mmol) was added to a solution of compound F (485 mg, 0.78 mmol) and 2-propokyphenol (110 mg, 0.72 mmol) in dry DMF (5 mL), and the reaction mixture was heated at 50 C overnight. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and EtOAc (20 mL), and the organic phase was separated. The aqueous phase was extracted with EtOAc (3 * 20 mL). All of the organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography on silica gel (EtOAc/hexanes = 1:1), affording target compound G1 (yield: 20.0%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.0% | With potassium hydroxide; In N,N-dimethyl-formamide; at 50℃; | General procedure: Potassium hydroxide (160 mg, 2.8 mmol) was added to a solution of compound F (485 mg, 0.78 mmol) and 2-propokyphenol (110 mg, 0.72 mmol) in dry DMF (5 mL), and the reaction mixture was heated at 50 C overnight. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and EtOAc (20 mL), and the organic phase was separated. The aqueous phase was extracted with EtOAc (3 * 20 mL). All of the organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography on silica gel (EtOAc/hexanes = 1:1), affording target compound G1 (yield: 20.0%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.1% | With N-benzyl-N,N,N-triethylammonium chloride; sodium hydrogencarbonate; In water; at 60 - 65℃; for 10h;Large scale; | According to the ratio, to the reactor was added 2-ethoxy-phenol 200 Kg, 1,2- dibromoethane 1800 Kg, benzyltriethylammonium chloride 4 Kg, was heated to 60-65 , with one another reactor, preparation of a 15% aqueous sodium bicarbonate 1600 Kg, dropped into the above mixture by the high slot, the drop was completed, the reaction was kept for 10 hours.Cooled to room temperature, layers were separated and the organic phase was collected, vacuum distillation, collecting respectively the excess 1,2-dibromoethane 1028 Kg (-0.08 MPa, 80 ~ 90 ) and crude 2- (2-ethoxy phenoxy) ethyl bromide 336 Kg (-0.1MPa, 130 ~ 140 ); the above-mentioned crude product was transferred to the reaction vessel, was added acetonitrile 340 Kg, water 3400 Kg, was heated to 50 ~ 60 dissolved clarification, slow cooling to 10 .Discharge, centrifugal filtration, and dried to give 2- (2-ethoxy-phenoxy) ethyl bromide pure product 305 Kg, purity 99.1%, the single impurities Finished product packaging and storage. |
With potassium carbonate; In acetonitrile; at 50℃; for 24h;Reflux; | General procedure: K2CO3 (0.02 mol) was suspended in BrCH2CH2Br (30 mL, 0.06 mol), and dropwise added different substituted phenols (0.015 mol) in CH3CN (10 mL) at 50 C, then the mixture was refluxed for 24 h and filtered, the filtrate was concentrated and purified by CC (column chromatography) over silica gel (eluent, PE:EA= 10:1) to give the white solid 3a-3r in 40.28-74.32 % yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 20 - 25℃; for 2h; | To a solution of 2-ethoxyphenol (13.72 g, 99 mmol), tert-butyl (S)-3-hydroxypiperidine-1-carboxylate (20 g, 99 mmol), and triphenylphosphine (29 g, 111 mmol) in toluene (150 mL) at 20-25 C. was added a solution of DIAD (20 mL, 104 mmol) in toluene (50 mL) over 2 hours. After 2 hours, the reaction mixture was filtered and washed with diethyl ether (300 mL). The filtrate was washed with 3N NaOH (150 mL), dried over Na2SO4, and concentrated. The crude residue was purified via column chromatography to afford tert-butyl (R)-3-(2-ethoxyphenoxy)piperidine-1-carboxylate (14.6 g, 45%). MS (ES+) 222.2 (M-100+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
233 g | With 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate; copper(l) chloride; In toluene; at 20 - 119℃; for 20h; | 3-Bromopyridine (224 g, 1.42 mol) and 2-ethoxyphenol (275 g, 1.99 mol) were added to a jacketed reactor vessel containing toluene (2.2 L) at 20 C., and the resulting mixture was stirred until all solids were dissolved. 2,2,6,6-Tetramethylheptane-3,5-dione (118 g, 0.640 mol), copper(I) chloride (71.8 g, 0.71 mol), and cesium carbonate (749 g, 2.27 mol) were added sequentially, and the jacket temperature was raised to 119 C. The mixture became thick, and stirring resumed as the temperature increased. After 20 hours, the mixture was cooled to 30 C. The organic layer was washed sequentially with water (0.75 L) and with aqueous 15% ammonium hydroxide solution (0.70 L), and then was extracted with aqueous 3M hydrochloric acid solution (1.18 L, 3.55 mol). Ethyl acetate (1.8 L) and aqueous 15% ammonium hydroxide solution (0.500 L, 3.60 mol) were then added sequentially to the acidic aqueous phase. The blue aqueous layer was separated, and the resulting organic layer was washed sequentially with aqueous 15% ammonium hydroxide solution (0.50 L) and with 2:1 water:brine solution (0.30 L). The organic layer and Darco G60 activated charcoal (60 g) were stirred at 45 C. for 1 hour, and then were filtered through a pad of Celite, rinsing with ethyl acetate (0.35 L). The filtrate was concentrated under vacuum and the resulting residue was re-concentrated from methanol (0.30 L) to afford 3-(2-ethoxyphenoxy)pyridine (233 g) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) delta 8.25 (s, 2H), 7.34 (dd, 1H), 7.18 (m, 4H), 6.99 (t, 1H), 4.01 (q, 2H), 1.11 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate; In acetonitrile;Reflux; | To a solution 2-ethoxyphenol 17 (414mg, 3mmol) in CH3CN (10mL) was added K2CO3 (620mg, 4.5mmol) at room temperature, followed by a solution of 16 (1200mg, 4.5mmol) in CH3CN (1mL). The reaction mixture was heated to reflux overnight. After cooling to rt, silica gel was added to the reaction mixture and the solvent was removed on the vacuum. The residue was purified by column chromatography to give 18 as a white solid, mp 90-92C; Rf (hexane/EtOAc 4:2) 0.40; yield 381mg, 65%; 1H NMR (600MHz, CDCl3) delta 1.41 (t, J=7.2Hz, 3H), 2.36 (t, J=5.4Hz, 1H), 2.43 (s, 3H), 2.45 (dt, J=11.4 and 3.6Hz, 1H), 3.55 (d, J=11.4Hz, 1H), 3.72 (dt, J=11.4 and 2.4Hz, 1H), 3.80 (d, J=11.4Hz, 1H), 3.93-3.97 (m, 3H), 4.02-4.05 (m, 3H), 6.84-6.89 (m, 3H), 6.92-6.96 (m, 1H), 7.33 (d, J=7.8Hz, 2H), 7.64 (d, J=7.8Hz, 2H); 13C NMR (150MHz, CDCl3) delta 15.0. 21.7, 45.7, 48.0, 64.6, 66.1, 70.5, 73.8, 114.0, 116.1, 121.1, 122.7, 128.0, 129.9, 132.3, 144.1, 148.4, 149.6; IR (KBr, neat) 2924, 2854, 1596, 1504, 1453, 1346, 1256, 1167, 1122, 1041, 961, 754cm-1; HRMS (ESI) calcd for C20H26NO5S (M+H)+ 392.1526, found 392.1536. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.56% | at 150℃; for 4h; | The preparation method of o-ethoxyphenol comprises the following steps: a. 100.13g ortho-ethylvanillin crystals are added into the reaction kettle and heated to melt to form liquid state; b. Start stirring. To the kettle, add 2.0008g of composite metal catalyst (Rh2O3 and RuCl3 mass ratio of 1: 3); c. Heating and raise the temperature to 150 deg.C for 4 hours; d. Pressure filtration to recovery metal catalyst; e. The filtrate undergoes vacuum distillation to obtain product. Product is colorless and transparent liquid 81.23g, the product molar yield 97.56%, as shown in Figure 4, the product GC purity is 99.66%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In toluene; at 115℃; for 24h; | 2-ethoxyphenols (55.0g, 0.398mol), ethylenecarbonates (70.1g, 0.796mol), andpotassium carbonates (12.1g, 0.088mol) were put into the toluene (550ml) and itmixed reflux in 24 hours 115. After the ethyl acetate (275ml) and saltywater (550ml) were added to the reactant and the organic layer was extractedand the anhydrous sodium sulfate was added to the organic layer and it dried itfiltered and it was the filtrate concentrated under reduced pressure and 2 -(2- ethoxyphenoxy) ethanol was obtained (72.5g, and the yield 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.08% | With dinitrogen pentoxide; In 1,2-dichloro-ethane; at 0 - 35℃; for 2h; | (0.1 mol) of o-hydroxyphenylethyl ether and 40 ml of dichloroethane were added to a three-necked flask and the temperature was lowered to0 , slowly dropping 3mol / L of N2O5 / C2H4Cl2 solution 37ml, drop finished 35 reaction 2 hours,The reaction was terminated by adding 13.8 g of water to the reaction solution. After standing, the layers were separated and the organic phase was dried over anhydrous sodium sulfateDried, filtered and the solvent was distilled off to obtain 17.86 g of 2-hydroxy-5-nitrophenylether with an HPLC purity of 98.42%The yield was 96.08%. |
52% | With Iron(III) nitrate nonahydrate; nitric acid; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | General procedure: Nitric acid (10mL, 65%) was added dropwisely into a mixture of 2-ethoxyphenol (10.00g, 72.50mmol) and iron (III) nitrate nonahydrate (900mg, 2.23mmol) in THF (250mL) through a constant pressure dropping funnel at 0C for 30min. Then the mixture was stirred at room temperature for 30min and quenched by water (100mL) and dichloromethane (150mL). The aqueous phase was extracted with dichloromethane (100mL×3), then the combined organic phases were then processed in the usual way and chromatographed to afford compound 3 (6.90g, 52%) as solid. The mixture of compound 3 (5.00g, 27.30mmol), potassium carbonate (15.10g, 109.20mmol) and 1-bromopentane (3.57mL, 28.70mmol) in MeCN (50mL) was refluxed overnight, then the mixture was diluted with EtOAc (200mL), the organic phases were then processed in the usual way and chromatographed to afford compound 4a (5.10g, 74%) as solid. A solution of compound 4a (5.00g, 19.70mmol) in ethanol/water (120mL/120mL) was treated with iron powder (3.32g, 59.30mmol) and ammonium chloride (3.17g, 59.30mmol) and the mixture was heated to reflux overnight. The mixture was then filtered and concentrated under reduced pressure. The resulting oil was partitioned between water and ethyl acetate, and the organic phase was then washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the desired compound 5a (2.87g, 65%) as black oil without purification to use for next step. The mixture of Ethoxymethylenemalonic diethyl ester (EMME, 2.42g, 11.21mmol) and compound 5a (2.50g, 11.21mmol) in EtOH (100mL) was refluxed overnight. After removal of EtOH, the mixture was chromatographed to afford compound 6a (3.01g, 68%) as yellow oil. Diphenyl ether (10mL) was heated to 260C and compound 6a (1.00g, 2.54mmol) was added. The reaction mixture was stirred at 260C for15min, and then cooled to room temperature. EtOAc (25mL) was added to the mixture and the obtained solid was filtrated, washed with EtOAc and dried to obtain 7a (590mg, 67%) as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The reaction kettle fulfill with 7.5 parts of aniline, 22 parts of water, than cooled at 0 C and slowly stirred, the flow 21part of 30 ~ 32% concentrated hydrochloric acid, when flow is completed, than the temperature dropped to 0 C, than flow a stream of sodium nitrite solution (5. 9 parts, water 22 parts), and after finishing the flow continue to react at this temperature at 1h, aniline diazonium salt solution, standby at low temperature; In the reaction kettle added the 11.8 parts of pyrocatechol monoethyl ether, 170 parts of methanol, than with the sodium hydroxide solution to adjust the pH to 8. 5, and stirring at room temperature 1h, at the temperature was lowered to -5 C or lower and the diazonium salt solution of the aniline obtained in Step S1 was added while adjusting pH = 7 with sodium hydroxide solution, after the completion of flow adjust the pH = 7 ~ 8, heated to 8 C, and reaction is continued for 4h, and the methanol in the system is distilled out and recovered to obtain 3-ethoxy-4-hydroxyazobenzene distilling viscous liquid; | ||
In the first reactor, 27.9 kg of aniline was added, 60 L of water was passed into the frozen brine, the temperature was kept at 0 C., and 72 L of concentrated hydrochloric acid was added.After completion of the addition, the temperature dropped below 2 C., and a 25% sodium nitrite solution was added dropwise at 83 kg. During the dropwise addition, the internal temperature was maintained at 5 C. The stirring reaction was continued for 1.5 hours after completion of the dropwise addition to obtain an aniline diazonium salt for use. In the second reactor, 41.4 kg of o-hydroxyphenylethyl ether and ethanol (220 L) were added, and the pH was adjusted to about 7 with saturated sodium carbonate solution.After cooling, the aniline diazonium salt solution prepared in the first reactor is added dropwise to the second reactor. The temperature of the diazonium salt solution is kept below 5 C. during the dropwise addition, and saturated sodium carbonate solution is added dropwise at the same time. Keep the pH of the system at 7-8.The temperature was controlled below 8oC, and the reaction was continued with stirring to obtain a reaction solution containing the intermediate 3-ethoxy-4-hydroxyazobenzene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With molybdenum(VI) oxide; In ethanol; at 280℃; for 4h;Inert atmosphere; | General procedure: 2.0 g of guaiac acid (purchased in Tianjin Guangfu Technology Co., Ltd.), 0.5 g of MOS catalyst and 100 ml of ethanol were placed in a 300 ml reaction vessel, and the air in the reaction vessel was replaced with nitrogen. The temperature was raised to 280 C, and the reaction was stirred for 4 h. After the reaction was completed, the mixture was filtered under suction and rotary evaporated. The liquid product was subjected to qualitative analysis on a gas chromatography-mass spectrometer (GC6890-MS5973, Agilent), and the internal standard was added. Quantitative analysis by gas chromatography. The chromatogram was performed on an HP-5ms, 30m X 0.25mm X 0.25mum capillary column. The conversion of the raw guaiacol is calculated by (initial guaiacol moles - residual guaiacol moles) / (initial guaiacol moles) X100%, and the selectivity of the product hydrocarbyl phenol is (hydrocarbyl phenol) The number of moles / (molar guaiacol moles) X 100 % was calculated. Among the guaiacol conversion products, ethyl phenols include o-ethyl phenol, 2,5-diethyl phenol, 3,5-diethyl phenol, and propyl phenols include 2,6-diisopropyl phenol. , 2,4-diisopropylphenol, 2,4,6-triisopropylphenol, butyl phenols including 2,5-di-sec-butylphenol, 2,6-di-tert-butylphenol, 2, 4-di-tert-butylphenol, 2,6-di-tert-butyl-p-ethylphenol, pentanols include 2,4-di-tert-amylphenol, others include o-ethoxyphenol, o-ethoxybenzene Methyl ether, p-ethyl guaiacol, 2,6-diisopropylanisole). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.1 g | 144g (0.50mol) [[(R)-2-(6-amino-fluoren-9-yl)-1-methyl-ethoxy-]methyl]phosphonic acid, 276 g (2.00 mmol) of o-ethoxyphenol and 390 g of 1-methyl-2-pyrrolidone were added and heated to 85 C. Then 63 g of triethylamine and 309 g (1.50 mmol) of DCC were added and the mixture was stirred under heating at 100 C for 16 hours. The resulting mixture was cooled, and solids were filtered. The filtrate was concentrated under reduced pressure, separated by silica gel (200-300 mesh) column, eluted with a mixed solvent of dichloromethane : methanol (20:1), the required components were collected and evaporated under reduced pressure to obtain [[(R)-2-(6-aminopurin-9-yl)-1-methylethoxy]methyl]phosphonic acid-bis(2-ethoxy-phenol)-ester (tenofovir bis-ethoxyphenol ester, TDP) 62g. 13 g (25.3 mmol) of TDP was dissolved in 50 ml of acetone (water content <0.2%), hydrogen chloride in ether solution was added and the addition rate was controlled for about 5 minutes to a pH of 2-3. The volume of ether and acetone is controlled at (1:5 to 1:30). The resulting mixture was refluxed for 10 min, cooled, a solid was precipitated, filtered, washed with cold crystallization solvent, dried naturally at room temperature for 6 hours, and then vacuum dried at 60 C for 8 hours to obtain I2 13.1g. Melting point 185-186 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 g of DMF was added to a 500 ml flask, and 70 g of anhydrous potassium carbonate, 50 g of o-hydroxyphenylethyl ether and 90 g of bromodecane were respectively added thereto, and the mixture was heated to 70 ± 5 C with stirring, and the reaction and incubation were carried out for 4 to 8 hours. Vacuum distillation (-0.09MPa, less than 90 C) until the material in the bottle is viscous, add 150g of water and 6g of potassium bromide, adjust the pH to 9-10 with 30% sodium hydroxide, add tetrabutylammonium bromide ( or benzyltriethylammonium chloride) 1 gram. Stir for half an hour. The air guiding tube and the constant pressure dropping funnel are installed, the funnel contains 60 g of 30% sodium hydroxide, the temperature inside the stirring bottle is 30-40 C, chlorine gas is introduced, and the tail gas is taken out and absorbed by sodium hydroxide. The sodium hydroxide is added dropwise for 3-6 hours, and the chlorine passing rate is synchronized with the dropping rate of sodium hydroxide to control the pH 8-10. After the completion of the dropwise addition of sodium hydroxide, the chlorine was suspended, and the sample was analyzed and analyzed. There was no bromide ion in the solution.The above solution was transferred to a 1000 ml flask, adjusted to pH 6.5-7 with hydrochloric acid, 300 g of water and 150 g of toluene were thoroughly stirred and separated, and the organic phase was added to a 500 ml flask, and toluene was evaporated under reduced pressure, and then 200 g of DMF was added. After stirring and dissolving, 58 g of self-made potassium phthalimide was added, and the temperature was raised to 50-80 C (preferably 60-80 C, preferably 75 C). After 2 hours of reaction, the salt was removed by filtration. The mother liquor was evaporated to dryness DMF under reduced pressure at 80 C, 300 g of water was added, the temperature was raised to 40 C, pH 10-11 was adjusted with 20% sodium hydroxide, and the aqueous layer was separated and washed three times to obtain the desired product orange liquid: 3-ethoxy-4-decyloxyaniline 82 g with a content of 98.6% and a total yield of 76.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.2 g; 0.26 g | With zinc dibromide; In tetralin; at 240℃; under 7500.75 Torr; for 8h;Autoclave; Green chemistry; | In a 100 mL autoclave, Add 22.0 g (0.2 mol) of catechol, 49 g (50 mL) tetrahydronaphthalene, 1.0 g of cerium oxide and 0.1 g of zinc bromide, Cover the autoclave, Pump out most of the air in the kettle, Start heating and start stirring, when heating to 240 C, The ethylene gas is introduced to bring the pressure in the kettle to 1.0 MPa. Maintaining the reaction at this pressure for 8 hours; After the reaction is cooled to room temperature, Ethylene gas that is not involved in the reaction is released through a pressure reducing valve, The catalyst is recovered by filtration under reduced pressure; Then, most of the solvent tetrahydronaphthalene was removed by distillation under reduced pressure. The residue was separated by column chromatography to recover catechol (12.05 g, Conversion rate of raw materials is 45.2%), By-product o-ethoxyphenylethyl ether (0.26g), The finished o-ethoxyphenol finished product was 11.2 g (purity 99.1%, selectivity 97.7%). |
Tags: 94-71-3 synthesis path| 94-71-3 SDS| 94-71-3 COA| 94-71-3 purity| 94-71-3 application| 94-71-3 NMR| 94-71-3 COA| 94-71-3 structure
[ 104-38-1 ]
1,4-Bis(2-hydroxyethoxy)benzene
Similarity: 0.96
[ 104-38-1 ]
1,4-Bis(2-hydroxyethoxy)benzene
Similarity: 0.96
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P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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