* 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.
Reference：
[1] Organic Process Research and Development, 2007, vol. 11, # 3, p. 468 - 469
2
[ 17178-10-8 ]
[ 74-89-5 ]
[ 38256-93-8 ]
Reference：
[1] Dalton Transactions, 2007, # 13, p. 1309 - 1315
[2] Journal of the American Chemical Society, 1975, vol. 97, p. 6513 - 6521
3
[ 109-86-4 ]
[ 98-59-9 ]
[ 17178-10-8 ]
Yield
Reaction Conditions
Operation in experiment
95%
With tetrabutylammomium bromide; sodium hydroxide In dichloromethane at 20℃; for 24 h;
A solution of 2-methoxyethanol (7.36 mL, 0.10 mol) and a catalytic amount of TBAB (tetra-n-butylammonium bromide) in dichloromethane was stirred, and subsequently NaOH (aq., 30percent, 15 mL) was added. A solution of p-toluenesulfonyl chloride in dichloromethane was added dropwise. The mixturewas stirred for 24 h at room temperature, and then washed with distilled water three times. The product was dried over Na2SO4, the solvent was removed under reduced pressure to give a yellow oil. Yield 95percent. IR (KBr, cm 1) selected bands: 3468 (m), 2938 (s), 2889 (s), 1597 (m), 1455 (m), 1357 (s), 1184 (s), 1130 (m), 1101 (m), 1018 (m), 919 (m), 821 (m). 1H-NMR (400 MHz, CD3COCD3): 3.20 (s, 3H), 3.48 (t, J ¼ 4.6 Hz, 2H), 4.08 (t, J ¼ 4.6 Hz, 2H), 7.71 (d, J ¼ 8.4 Hz, 2H), 7.28 (d, J ¼ 8.4 Hz, 2H), 2.36 (s, 3H). Anal. Calc. for C10H14SO4: C, 52.16; H, 6.13. Found: C, 52.09; H, 6.17.
92%
With triethylamine In dichloromethane at 0℃;
Example 3: Synthesis of IronfflD chloride mgso-tetrakis-2-(N-(2-methoxy)ethγQpyridyl porphyrin; Synthesis of 2-methoxyethyl tosylate; 2-methoxyethanol (0.989 g, 13 mmol) was dissolved in 30 ml dichloromethane, and triethylamine (2.53 g, 25 mmol) was added to the solution. The reaction mixture was set to stir in an ice-water bath, and p-toluenesulfonyl chloride (3.22 g, 17 mmol) was added all at once. The ice was allowed to melt, and the reaction was continued overnight. The reaction mixture was then filtered, to remove all of the triethylamine hydrochloride, and the filtrate was washed with 30 ml saturated NaHCCfyaq), then 30 ml IN KHSψ4(aq), then 30 ml saturated NaHCψ3(aq). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The colorless oily residue was chromatographed on silica gel in 1 :5 ethyl acetate: chloroform, to yield 2.77 g (92percent yield) of 2-methoxyethyl tosylate as a viscous liquid.IH NMR (300 MHz, CDCl3): δ2.4 (s, 3H, ArCH3), 83.3 (s, 3η, -OCH3), 83.6 (m, 2η, - CH2OCH3), 84.1 (m, 2H, -CH2OSO2Ar), 87.3 (d, J = 8.5 Hz, 2H, -SO2CHCHCCH3), 87.8 (d, J = 8.5 Hz, 2H, -SO2CHCHCCH3).
87%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 12 h;
General procedure: Three separate flasks were prepared; flask 1 was composed of p-toluenesulfonylchloride (TsCl) (237.0 mmol) dissolved in THF (74 mL), flask 2 had NaOH (367.0 mmol) dissolved in H2O (74 mL), flask 3 was composed of the alcohol (131.0 mmol) dissolved in THF (74 mL). Flask 2 and 3 were combined and then to an addition funnel flask 3 was added to it and placed over the flask 2 and 3 mixture to be added dropwise for 12h at room temperature, tracked by TLC. The reaction was quenched with water (100 mL) and extracted with DCM (2 x 60 mL) dried over anhydrous Na2S04(s) and filtered through celite. The organic layer was reduced under pressure to afford a clear oil.
81%
With sodium hydroxide In water at 0 - 20℃;
To 150 mL of THF cooled to 0°C was added NaOH (15.8 g in 75 mL H2O), followed byaddition of 2-methoxyethanol (20.0 g, 260 mmol). p-Toluenesulfonyl chloride (50.11 g, 260mmol) was added in 3 portions over 30 min. The reaction was allowed to stir at roomtemperature overnight. The reaction was quenched by the addition of 200 mL H2O. The layerswere allowed to separate and the aqueous layer was extracted twice with CH2Cl2. The organiclayer was washed once with H2O and once with brine, and then was dried over Na2SO4. Rotaryevaporation of the solvent gave the tosylate as a colorless oil (48.5 g, 211 mmol, 81percent). 1H NMR(CDCl3): δ 7.80 (d, J=8.2 Hz, 2H); 7.34 (d, J=8.0 Hz, 2H); 4.16 (m, 2H); 3.58 (m, 2H); 3.31 (s,3H); 2.45 (s, 3H).
71.6%
With triethylamine In dichloromethane at 0 - 20℃;
To a stirred solution of 2-methoxyethan-1-ol (2.0 g, 26.28 mmol, 1.0 eq) in DCM (30mL) at 0 oc was added TEA (14.6 mL, 105.12 mmol, 4.0 eq) followed by paratoluenesulfonylchloride (5.99 g, 31.53 mmol, 1.2 eq). The reaction mixture was changed toroom temperature and stirred for overnight. After completion of the reaction (monitored byTLC), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate25 (2x100 mL). The combined organic layers were washed with water (50 mL) and brinesolution (20 mL). The organic layer was dried over Na2S04, filtered and evaporated underreduced pressure. The residue was purified by silica gel column chromatography by using40percent ethyl acetate in hexane as an eluent to obtain the title compound ( 4.3 g, yield: 71.6percent) asa liquid. 1H NMR (300 MHz, CDCb): 8 ppm 7.80 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.1 Hz,30 2H), 4.15 (t, J = 4.8 Hz, 2H), 3.57 (t, J = 4.8 Hz, 2H), 3.30 (s, 3H), 2.44 (s, 3H); ESI-MS:m/z 252.96 (M+Na)+
39.6%
With dmap; triethylamine In dichloromethane at 0 - 20℃;
To a stirred solution of 2-methoxyethanol (10 g, 131.4mmol, 1.0 eq) in CH2Cl2 (100 ml) at 0°C was added triethyl amine (39.84 g, 394.4 mmol, 3.0 eq), 4- dimethylaminopyridine (4.81 g, 39.44 mmol, 0.3 eq) and /?ara-toluenesulphonylchloride (27.5 g, 144.6 mmol, 1.1 eq). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (200 ml), organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2x200 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using dichloromethane as an eluent to obtain the desired product (12.0 g, 39.6percent yield) as a brown liquid. 1H NMR (300 MHz, CDCl3): δ ppm (d, J = 8.1Hz, 2H), 7.35 (d, J = 8.1Hz, 2H), 4.17-4.14 (m, 2H), 3.59-3.56 (m, 2H), 3.31 (s, 3H), 2.45 (s, 3H); ES Mass: [M+Na]+ 252.96
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[1] Dalton Transactions, 2007, # 13, p. 1309 - 1315
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4
[ 109-86-4 ]
[ 104-15-4 ]
[ 17178-10-8 ]
Yield
Reaction Conditions
Operation in experiment
69%
With triethylamine In dichloromethane at 20℃;
To a solution of 2-methoxyethanol (12-1, 5.00 g, 65.7 mmol) in CH2Cl2 (50.0 rnL) was added triethylamine (18.3 mL, 131.4 mmol) followed by 4-methylbenzene-1-sulfonyl chloride (16.3 mg, 85.4 mmol). The reaction mixture was stirred at room temperature overnight. The solution was added with saturated aqueous Na2CO3 (50.0 mL) and extracted with CH2Cl2. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-methoxyethyl 4-methylbenzenesulfonate (12-2, 10.46 g) as yellow solids in 69percent yield: 1H NMR (500 MHz, CDCl3) 7.80(d, J= 8.3 Hz, 2 H), 7.34 (d, J= 8.3 Hz, 2 H), 4.15-4.16 (m, 2 H), 3.57-3.59 (m, 2 H), 3.31 (s, 3 H), 2.44 (s, 3 H). ESI-MS: m/z 230.8 (M + H)+.
With potassium carbonate In acetonitrile for 6 h; Reflux
EXAMPLE 504-chloro-6,7-bis(2-methoxyethoxy)quinazoline (compound I-1)Ethyl 3,4-dihydroxybenzoate (36.4 g, 0.2 mol), potassium carbonate (82.8 g, 0.6 mol), and 2-methoxyethyl p-toluenesulfonate (72.0 g, 0.4 mol) were dissolved in acetonitrile (200 ml), heated and refluxed for 6 h. The solvent of the reaction mixture was evaporated under vacuum to obtain a residue. The residue was recrystallized with isopropanol, suction filtered, and dried under vacuum to obtain a white powder 3,4-bis (2-methoxyethoxy)ethyl benzoate (53.2 g, 89percent).3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (15.00 g, 0.05 mol) was added into acetic acid (50 ml) to form a mixture, and while the mixture was stirred in an ice water bath, 65-68percent nitric acid (13 ml) was added to the mixture. The mixture then was stirred for 24 h at room temperature. The reaction mixture was transferred into ice water (500 ml), and extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium bicarbonate solution three times, washed with saturated sodium chloride solution, and then dried by anhydrous sodium sulfate. The organic phase was then filtered to obtain a filtrate. The filtrate was concentrated to obtain a brown oily liquid 2-nitro-4,5-bis(2-methoxyethoxy)ethyl benzoate (14.10 g, 82.22percent).2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid ethyl ester (34.3 g, 0.10 mol), ammonium formate (63 g, 1.00 mol), 5percent Pd/C (5.00 g), and formamide (150 ml) were reacted for 7 h at 150° C. The reaction mixture was cooled to room temperature, and a solid precipitated. The precipitate was filtered to obtain a white powder 6,7-bis-(2-methoxyethoxy)-4(3H)quinazolinone (22.1 g, 75percent).Thionyl chloride (14.9 g) was added dropwise slowly to a solution of 6,7-bis-(2-methoxyethoxy)-4 (3H) quinazolinone (14.7 g, 0.15 mol), N,N-dimethylformamide (1 ml), and dichloromethane (150 ml). The reaction mixture was stirred at room temperature, and refluxed for 6 h. The reaction mixture was cooled to room temperature, and the pH of the reaction mixture was adjusted to 7-8 with a sodium hydroxide solution. The reaction mixture was then stirred for 30 min at room temperature, and set aside to allow the organic and aqueous layers to separate. The organic layer was collected, and concentrated under vacuum to obtain a white solid 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline (14.1 g, 89.5percent), [M+H]+=313.
89%
With potassium carbonate In acetonitrile for 6 h; Reflux
Ethyl 3,4-dihydroxybenzoate (36.4 g, 0.2 mol), potassium carbonate (82.8 g, 0.6 mol), and 2-methoxyethyl p-toluenesulfonate (72.0 g, 0.4 mol) were dissolved in acetonitrile (200 ml), heated and refluxed for 6 h. The solvent of the reaction mixture was evaporated under vacuum to obtain a residue. The residue was recrystallized by isopropanol, suction filtered, and dried under vacuum to obtain a white powder 3,4-bis (2-methoxyethoxy)ethyl benzoate (53.2 g, 89percent).
With triethylamine; In dichloromethane; at 25℃; for 12h;
p-Toluenesulfonyl chloride (3.0 g, 15.7 mmol) at 25 CAnd triethylamine (6.65 mL, 47.2 mmol)Add to a 100 mL single-mouth flask,Add dichloromethane (10 mL),Ethylene glycol methyl ether (1.56 g, 20.46 mmol) was added dropwise.Continue the reaction for another 12 hours;Add water (40 mL),Additional dichloromethane (20 mL) was added.Dispensing, collecting organic phase,Dry under reduced pressure,Separation and purification by column chromatography (petroleum ether / ethyl acetate (v / v) = 10/1 ~ 5 / 1)The title compound was obtained as a colorless liquid (3.52 g, 97.1%).
95%
With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; at 20℃; for 24h;
A solution of 2-methoxyethanol (7.36 mL, 0.10 mol) and a catalytic amount of TBAB (tetra-n-butylammonium bromide) in dichloromethane was stirred, and subsequently NaOH (aq., 30%, 15 mL) was added. A solution of p-toluenesulfonyl chloride in dichloromethane was added dropwise. The mixturewas stirred for 24 h at room temperature, and then washed with distilled water three times. The product was dried over Na2SO4, the solvent was removed under reduced pressure to give a yellow oil. Yield 95%. IR (KBr, cm 1) selected bands: 3468 (m), 2938 (s), 2889 (s), 1597 (m), 1455 (m), 1357 (s), 1184 (s), 1130 (m), 1101 (m), 1018 (m), 919 (m), 821 (m). 1H-NMR (400 MHz, CD3COCD3): 3.20 (s, 3H), 3.48 (t, J ¼ 4.6 Hz, 2H), 4.08 (t, J ¼ 4.6 Hz, 2H), 7.71 (d, J ¼ 8.4 Hz, 2H), 7.28 (d, J ¼ 8.4 Hz, 2H), 2.36 (s, 3H). Anal. Calc. for C10H14SO4: C, 52.16; H, 6.13. Found: C, 52.09; H, 6.17.
92%
With triethylamine; In dichloromethane; at 0℃;
Example 3: Synthesis of IronfflD chloride mgso-tetrakis-2-(N-(2-methoxy)ethgammaQpyridyl porphyrin; Synthesis of 2-methoxyethyl tosylate; 2-methoxyethanol (0.989 g, 13 mmol) was dissolved in 30 ml dichloromethane, and triethylamine (2.53 g, 25 mmol) was added to the solution. The reaction mixture was set to stir in an ice-water bath, and p-toluenesulfonyl chloride (3.22 g, 17 mmol) was added all at once. The ice was allowed to melt, and the reaction was continued overnight. The reaction mixture was then filtered, to remove all of the triethylamine hydrochloride, and the filtrate was washed with 30 ml saturated NaHCCfyaq), then 30 ml IN KHStheta4(aq), then 30 ml saturated NaHCtheta3(aq). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The colorless oily residue was chromatographed on silica gel in 1 :5 ethyl acetate: chloroform, to yield 2.77 g (92% yield) of 2-methoxyethyl tosylate as a viscous liquid.IH NMR (300 MHz, CDCl3): delta2.4 (s, 3H, ArCH3), 83.3 (s, 3eta, -OCH3), 83.6 (m, 2eta, - CH2OCH3), 84.1 (m, 2H, -CH2OSO2Ar), 87.3 (d, J = 8.5 Hz, 2H, -SO2CHCHCCH3), 87.8 (d, J = 8.5 Hz, 2H, -SO2CHCHCCH3).
87%
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 12h;
General procedure: Three separate flasks were prepared; flask 1 was composed of p-toluenesulfonylchloride (TsCl) (237.0 mmol) dissolved in THF (74 mL), flask 2 had NaOH (367.0 mmol) dissolved in H2O (74 mL), flask 3 was composed of the alcohol (131.0 mmol) dissolved in THF (74 mL). Flask 2 and 3 were combined and then to an addition funnel flask 3 was added to it and placed over the flask 2 and 3 mixture to be added dropwise for 12h at room temperature, tracked by TLC. The reaction was quenched with water (100 mL) and extracted with DCM (2 x 60 mL) dried over anhydrous Na2S04(s) and filtered through celite. The organic layer was reduced under pressure to afford a clear oil.
81%
With sodium hydroxide; In water; at 0 - 20℃;
To 150 mL of THF cooled to 0C was added NaOH (15.8 g in 75 mL H2O), followed byaddition of 2-methoxyethanol (20.0 g, 260 mmol). p-Toluenesulfonyl chloride (50.11 g, 260mmol) was added in 3 portions over 30 min. The reaction was allowed to stir at roomtemperature overnight. The reaction was quenched by the addition of 200 mL H2O. The layerswere allowed to separate and the aqueous layer was extracted twice with CH2Cl2. The organiclayer was washed once with H2O and once with brine, and then was dried over Na2SO4. Rotaryevaporation of the solvent gave the tosylate as a colorless oil (48.5 g, 211 mmol, 81%). 1H NMR(CDCl3): delta 7.80 (d, J=8.2 Hz, 2H); 7.34 (d, J=8.0 Hz, 2H); 4.16 (m, 2H); 3.58 (m, 2H); 3.31 (s,3H); 2.45 (s, 3H).
71.6%
With triethylamine; In dichloromethane; at 0 - 20℃;
To a stirred solution of 2-methoxyethan-1-ol (2.0 g, 26.28 mmol, 1.0 eq) in DCM (30mL) at 0 oc was added TEA (14.6 mL, 105.12 mmol, 4.0 eq) followed by paratoluenesulfonylchloride (5.99 g, 31.53 mmol, 1.2 eq). The reaction mixture was changed toroom temperature and stirred for overnight. After completion of the reaction (monitored byTLC), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate25 (2x100 mL). The combined organic layers were washed with water (50 mL) and brinesolution (20 mL). The organic layer was dried over Na2S04, filtered and evaporated underreduced pressure. The residue was purified by silica gel column chromatography by using40% ethyl acetate in hexane as an eluent to obtain the title compound ( 4.3 g, yield: 71.6%) asa liquid. 1H NMR (300 MHz, CDCb): 8 ppm 7.80 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.1 Hz,30 2H), 4.15 (t, J = 4.8 Hz, 2H), 3.57 (t, J = 4.8 Hz, 2H), 3.30 (s, 3H), 2.44 (s, 3H); ESI-MS:m/z 252.96 (M+Na)+
39.6%
With dmap; triethylamine; In dichloromethane; at 0 - 20℃;
To a stirred solution of 2-methoxyethanol (10 g, 131.4mmol, 1.0 eq) in CH2Cl2 (100 ml) at 0C was added triethyl amine (39.84 g, 394.4 mmol, 3.0 eq), 4- dimethylaminopyridine (4.81 g, 39.44 mmol, 0.3 eq) and /?ara-toluenesulphonylchloride (27.5 g, 144.6 mmol, 1.1 eq). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (200 ml), organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2x200 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using dichloromethane as an eluent to obtain the desired product (12.0 g, 39.6% yield) as a brown liquid. 1H NMR (300 MHz, CDCl3): delta ppm (d, J = 8.1Hz, 2H), 7.35 (d, J = 8.1Hz, 2H), 4.17-4.14 (m, 2H), 3.59-3.56 (m, 2H), 3.31 (s, 3H), 2.45 (s, 3H); ES Mass: [M+Na]+ 252.96
With pyridine; at 5℃; for 1h;
G1. Toluene-4-sulfonic acid 2-methoxy-ethyl ester; A slurry of p-toluenesulfonyl chloride (205 g, 1.08 mol) and pyridine (150 ml_) is stirred under an argon atmosphere. The temperature is maintained below 5 0C (ice-water bath), while ethylene glycol monomethyl ether (80 ml, 1 mol) is added slowly from a dropping funnel. After the addition is complete, the mixture is stirred for 1 h below 5 0C. The mixture is poured into ice-water (1 L) and is extracted with dichloromethane (1.2 I). The organic layer is washed with ice-cold 6 M HCI (3x350 ml), and is reduced to a minimum volume by evaporation in vacuo.
With pyridine; at 5℃; for 1h;
A slurry of p-toluenesulfonyl chloride (205 g, 1.08 mol) and pyridine (150 ml_) is stirred under an argon atmosphere. The temperature is maintained below 5 0C (ice-water bath), while ethylene glycol monomethyl ether (80 ml, 1 mol) is added slowly from a dropping funnel. After the addition is complete, the mixture is stirred for 1 h below 5 0C. The mixture is poured into ice-water (1 L) and is extracted with dichloromethane (1.2 I). The organic layer is washed with ice-cold 6 M HCI (3x350 ml), and is reduced to a minimum volume by evaporation in vacuo.
With pyridine; at 5℃; for 1h;
A slurry of p-toluenesulfonyl chloride (205 g, 1.08 mol) and pyridine (150 mL) is stirred under an argon atmosphere. The temperature is maintained below 5 0C (ice-water bath), while ethylene glycol monomethyl ether (80 ml, 1 mol) is added slowly from a dropping funnel. After the addition is complete, the mixture is stirred for 1 h below 5 0C. The mixture is poured into ice-water (1 L) and is extracted with dichloromethane (1.2 I). The organic layer is washed with ice-cold 6 M HCI (3x350 ml), and is reduced to a minimum volume by evaporation in vacuo.
With sodium hydroxide; In tetrahydrofuran; water; at 0℃; for 5h;
B Procedure: 6g (0.15mol) of sodium hydroxide was dissolved in 20 mL of water and cooled to room temperature. 2-Methoxyethanol (15.22g, 0.2mol) was added to the solution and stirred for 30 min at 0oC. Tosyl chloride (19.1g, 0.1mol) in 25 mL of dry THF was added to the reaction mixture by dropwise, then the mixture was stirred for 5h at 0oC.The appearing precipitate was filtered and washed with ether, the filtrate was extracted by ether (2×20 mL). The combined organic phases were washed with brine and dried by anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to get 2-methoxyethyl 4-methylbenzenesulfonate. 2-Methoxyethyl 4-methylbenzenesulfonate (2.3g, 0.01mol) in 30mL of dry DMF was added to a 50 mL dry flask. Aloe-emodin (2.7g, 0.01mol) and anhydrous potassium carbonate (6.9 g, 0.05 mol) were added to the solution and stirred for 16h at 80oC. The reaction mixture was cooled to room temperature and poured into 80mL of water. The mixture was extracted with DCM (3×30mL). The combined organic phases were washed with brine and dried by anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to get crude product, which was purified by column chromatography with ethyl acetate in petroleum ether.
With sodium iodide; In acetone; for 3h;Heating / reflux;
F1. 2-Methoxyethyl iodide; The crude <strong>[17178-10-8]2-methoxyethyl tosylate</strong> is dissolved in 1600 ml of acetone and NaI (300 g, 2 mol, 2 equiv) is added. The mixture is heated to reflux and the progress of the reaction is monitored by TLC (toluene-acetone, 9:1 ). After 3 h the mixture is cooled to room temperature and the solid is removed by filtration. The solvent is evaporated, the residue is taken up in dichloromethane (700 ml) and is washed with 10 % aqueous Na2S2O3 and water. The organic layer is dried and the solvent evaporated. The residue is distilled at reduced pressure to yield 108 g (58 %) of 2-methoxyethyl iodide. B. p. 34-36 0C at 30 mbar.
58%
With sodium iodide; In acetonitrile; for 3h;Heating / reflux;
The crude <strong>[17178-10-8]2-methoxyethyl tosylate</strong> is dissolved in 1600 ml of acetone and NaI (300 g, 2 mol, 2 equiv) is added. The mixture is heated to reflux and the progress of the reaction is monitored by TLC (toluene-acetone, 9:1 ). After 3 h the mixture is cooled to room temperature and the solid is removed by filtration. The solvent is evaporated, the residue is taken up in dichloromethane (700 ml) and is washed with 10 % aqueous Na2S2O3 and water. The organic layer is dried and the solvent evaporated. The residue is distilled at reduced pressure to yield 108 g (58 %) of 2- methoxyethyl iodide. B. p. 34-36 0C at 30 mbar.
58%
With sodium iodide; In acetone; for 3h;Heating / reflux;
The crude <strong>[17178-10-8]2-methoxyethyl tosylate</strong> is dissolved in 1600 ml of acetone and NaI (300 g, 2 mol, 2 equiv) is added. The mixture is heated to reflux and the progress of the reaction is monitored by TLC (toluene- acetone, 9:1 v:v). After 3 h the mixture is cooled to room temperature and the solid is removed by filtration. The solvent is evaporated, the residue is taken up in dichloromethane (700 ml) and is washed with 10 % aqueous Na2S2O3 and water. The organic iayer is dried and the solvent evaporated. The residue is distilled at reduced pressure to yield 108 g (58 %) of 2-methoxyethyi iodide. B. p. 34-36 0C at 30 mbar,
EXAMPLE 4 N-(2-Methoxyethyl)diethanolamine Preparation The above named compound was prepared by the procedure described in Example 1 for N-allyldiethanolamine, using 0.5 mol of diethanolamine, 0.55 mol of <strong>[17178-10-8]2-methoxyethyl tosylate</strong> and 29.15 g of sodium carbonate. After workup the crude product was fractionally distilled and the fraction boiling from 90-110 at 0.1 mm was collected. N-(2-Methoxyethyl)diethanolamine, i.e., was obtained (56.6 g, 69%) as an almost colorless oil.
Stage #1: Resorcinol monoacetate; 2-methoxy-ethyl p-toluenesulfonyloxy ester With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 4h;
Stage #2: Further stages.;
With magnesium; In diethyl ether; at 20℃; for 2h;Heating / reflux;
A part of a solution containing 2-bromo-3-methylthiophene CAS14282-76-9 (1.5 g, 8.5 mmol) in dry diethyl ether was added drop-wise to a suspension of magnesium (308 mg, 12.7 mmol, 1.5 equiv.) in dry diethyl ether, until the mixture started to reflux. The remaining solution was added dropwise. A solution of toluene-4-sulfonic acid 2-methoxy-ethyl ester (2.9 g, 12.7 mmol, 1.5 equiv.) in dry diethyl ether was added dropwise at room temp., then the mixture was refluxed for two hours. After cooling down to room temp., the mixture was quenched with ammonium chloride solution saturated and extracted with tert. butylmethyl ether. The combined organic extracts were washed with water and brine, dried over magnesiumsulfate-dihydrate and purified on silica gel with eluent n-heptane and tert.butylmethyl ether. The title compound was obtained as light yellow oil: 490 mg, GC-MS (EI) M=156.
A part of a solution containing 2-bromo-3-methylthiophene CAS 14282-76-9 (1.5 g, 8.5 mmol) in dry diethyl ether was added drop-wise to a suspension of magnesium (308 mg, 12.7 mmol, 1.5 equiv.) in dry diethyl ether,until the mixture started to reflux. The remaining solution was added dropwise. A solution of toluene-4-sulfonic acid 2-methoxy-ethyl ester (2.9 g, 12.7 mmol, 1.5 equiv.) in dry diethyl ether was added dropwise at room temp., then the mixture was refluxed for two hours. After cooling down to room temp., the mixture was quenched with ammonium chloride solution saturated and extracted with tert. butylmethyl ether. The combined organic extracts were washed with water and brine, dried over magnesiumsulfate-dihydrate and purified on silica gel with eluent n-heptane and tert.butylmethyl ether. The title compound was obtained as light yellow oil: 490 mg, GC-MS (EI) M=156.
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 72h;
Example 5; This example illustrates the preparation of 4-{bis [4- (trifluoromethoxy) phenyl] methyl}-4-hydroxy-1-[4-(2- methoxyethoxy) phenyl] methyl} piperidin-1-oxide (Compound 385 in table below); Step A Synthesis of 4- (2-methoxyethoxy) benzaldehyde as an Intermediate; A solution of 5.0 grams (0.041 mole) of 4-hydroxybenzaldehyde, 9.5 grams (0.041 mole) of p-toluene sulfonic acid 2-methoxyethyl ester, and 6.3 grams (0.046 mole) of anhydrous potassium carbonate in 50 mL of dimethylsulfoxide (DMSO) was stirred at ambient temperature for about 72 hours. The reaction mixture was then partitioned between 300 mL of an aqueous mixture of 10% lithium chloride and 100 mL of ethyl acetate. The ethyl acetate portion was washed three times; first, with 100 mL of an aqueous mixture of 10% sodium hydroxide, second, with 100 mL of an aqueous mixture of 10% lithium chloride, and, third, with 100 mL of brine. The resultant organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 7.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
N-(2-methoxyethyl)-2,3,6-trimethylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene;
a. Preparation of the intermediate A solution comprising 595 g (4.4 moles) of 2,3,6-trimethylaniline in 1 liter of toluene is heated to boiling 503 g (2.2 moles) of p-toluenesulfonic-acid-(2-methoxyethyl)-ester is dropped thereto within 6 hrs. The reaction mixture is cooled, poured into 2 liter of isopropylethylether and the solid residue filtered off and washed with diethylether. The combined filtrates are evaporated. After distillation in vacuo 301 g (i.e. 71% theoretical amount) of N-(2-methoxyethyl)-2,3,6-trimethylaniline are obtained, b-p. 141-144 C/14 Torr.
5,10,15,20-tetra-pyridin-2-yl-porphyrine[ No CAS ]
C52H54N8O4(4+)*4Cl(1-)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
Synthesis of «iotaes°-tetrakis-2-(N-(2-methoxy)ethyl)pyridyl porphyrin; In an oven-dried flask under argon, were combined mes°-tetrakis-2-pyridyl porphyrin (2-PyP; 0.091 g, 0.148 mmol) and <strong>[17178-10-8]2-methoxyethyl tosylate</strong> (1.33 g, 5.77 mmol) in 1.37 ml anhydrous DMF. The reaction mixture was heated to 1000C and stirred for 18h 30min. Reaction progress was monitored by reverse-phase HPLC. Once complete, the reaction mixture was cooled to room temperature before being added dropwise to diethyl ether, to precipitate out the product and remove DMF and excess alkylating agent. The porphyrin was filtered onto Celite and washed off with water. The porphyrin was precipitated from water as the hexafluorophosphate salt with saturated NH4PF6^q) added dropwise. The porphyrin was again filtered onto Celite, and washed off with acetone. Saturated tetrabutylammonium chloride (in acetone) was added dropwise to precipitate out the porphyrin as the chloride salt. The gummy precipitate was again filtered onto Celite and washed well with dry acetone, to thoroughly remove any lingering salts, and finally washed off with methanol. The porphyrin <n="39"/>was then chromatographed on Sephadex LH-20 in 1 :1 methanol: water as the eluant, and collection of appropriate fractions yielded /wes°-tetrakis-2-(N-(2-methoxy)ethyl)pyridyl porphyrin in 65% yield. IH NMR (300 MHz, CD3OD): 62.8-3.0 (singlets, 12H, -CH2OCH3), 53.2-3.4 (m, 8eta, -CH2OCH3), 54.5-4.8 (m, 8H, N+CH2), 58.6 (m, 4eta, N+CHCH), 58.8-9.1 (m, 8eta, N+CHCHCH and N+CCH), 58.8-9.4 (br s, 8eta, pyrrole), 59.5 (m, 4H, N+CH). Partial UV-Vis (H2O) (log epsilon): 417 (5.31).
To a solution of 0401 (1.82 g, 10.0 mmol) in N, JV-dimethylformamide (20 mL) was added potassium carbonate (1.38 g, 10.0 mmol). The mixture was stirred for 15 minutes and then a solution of 2-methoxy ethyl 4-methylbenzenesulfonate (2.3O g, 10.0 mmol) in N, N-dimethylformamide (5 mL) was added slowly dropwise. The mixture was stirred 48 hours at room temperature and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate (30 mL) then the organic layer was washed with brine (20 mL><3) and dried over sodium sulfate, filtered and evaporated to give the title product 0402-30 as a white solid (1.2 g, 50%): LCMS: 241 [M+l] +. 1H NMR (DMSO-d6) delta 1.26 ( t, J= 7.5 Hz, 3H), 3.65(m, J = 1.5 Hz, 2H), 4.11 (m, J = 4.5 Hz, 2H), 4.21 ( m, J = 4.5 Hz, 2H), 7.00 (d, J = 9 Hz, IH), 7.37 ( m, J= 2 Hz, 2H), 9.40 (s, IH).
50%
Step 20a. Ethyl 3-hydroxy-4-(2-methoxyethoxy)benzoate (Compound 0402-30) To a solution of 0401 (1.82 g, 10.0 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.38 g, 10.0 mmol). The mixture was stirred for 15 minutes and then a solution of 2-methoxyethyl 4-methylbenzenesulfonate (2.30 g, 10.0 mmol) in N,N-dimethylformamide (5 mL) was added slowly dropwise. The mixture was stirred 48 hours at room temperature and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate (30 mL) then the organic layer was washed with brine (20 mL*3) and dried over sodium sulfate, filtered and evaporated to give the title product 0402-30 as a white solid (1.2 g, 50%): LCMS: 241 [M+1]+. 1H NMR (DMSO-d6) delta 1.26 (t, J=7.5 Hz, 3H), 3.65 (m, J=1.5 Hz, 2H), 4.11 (m, J=4.5 Hz, 2H), 4.21 (m, J=4.5 Hz, 2H), 7.00 (d, J=9 Hz, 1H), 7.37 (m, J=2 Hz, 2H), 9.40 (s, 1H).
50%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 48h;
Example 20Example 1Synthesis of 7-(4-(3-Chloro-4-fluorophenylamino)-7-(2-methoxyethoxy) quinazolin-6-yloxy)-N-hydroxyheptanamide (Compound 30)Step 20a. Ethyl 3-hydroxy-4-(2-methoxyethoxy)benzoate (Compound 0402-30); To a solution of 0401 (1.82 g, 10.0 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.38 g, 10.0 mmol). The mixture was stirred for 15 minutes and then a solution of 2-methoxyethyl 4-methylbenzenesulfonate (2.30 g, 10.0 mmol) in N,N-dimethylformamide (5 mL) was added slowly dropwise. The mixture was stirred 48 hours at room temperature and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate (30 mL) then the organic layer was washed with brine (20 mL×3) and dried over sodium sulfate, filtered and evaporated to give the title product 0402-30 as a white solid (1.2 g, 50%): LCMS: 241 [M+1]+. 1H NMR (DMSO-d6) delta 1.26 (t, J=7.5 Hz, 3H), 3.65 (m, J=1.5 Hz, 2H), 4.11 (m, J=4.5 Hz, 2H), 4.21 (m, J=4.5 Hz, 2H), 7.00 (d, J=9 Hz, 1H), 7.37 (m, J=2 Hz, 2H), 9.40 (s, 1H).
Stage #1: 5,10,15,20-tetra(3-pyridyl)porphyrin; 2-methoxy-ethyl p-toluenesulfonyloxy ester In N,N-dimethyl-formamide for 3.5h;
Stage #2: With FH*F5P*H3N In water
Stage #3: With tetrabutyl-ammonium chloride In diethyl ether; acetone
With potassium carbonate; In acetonitrile; for 6h;Reflux;
EXAMPLE 504-chloro-6,7-bis(2-methoxyethoxy)quinazoline (compound I-1)Ethyl 3,4-dihydroxybenzoate (36.4 g, 0.2 mol), potassium carbonate (82.8 g, 0.6 mol), and 2-methoxyethyl p-toluenesulfonate (72.0 g, 0.4 mol) were dissolved in acetonitrile (200 ml), heated and refluxed for 6 h. The solvent of the reaction mixture was evaporated under vacuum to obtain a residue. The residue was recrystallized with isopropanol, suction filtered, and dried under vacuum to obtain a white powder 3,4-bis (2-methoxyethoxy)ethyl benzoate (53.2 g, 89%).3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (15.00 g, 0.05 mol) was added into acetic acid (50 ml) to form a mixture, and while the mixture was stirred in an ice water bath, 65-68% nitric acid (13 ml) was added to the mixture. The mixture then was stirred for 24 h at room temperature. The reaction mixture was transferred into ice water (500 ml), and extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium bicarbonate solution three times, washed with saturated sodium chloride solution, and then dried by anhydrous sodium sulfate. The organic phase was then filtered to obtain a filtrate. The filtrate was concentrated to obtain a brown oily liquid 2-nitro-4,5-bis(2-methoxyethoxy)ethyl benzoate (14.10 g, 82.22%).2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid ethyl ester (34.3 g, 0.10 mol), ammonium formate (63 g, 1.00 mol), 5% Pd/C (5.00 g), and formamide (150 ml) were reacted for 7 h at 150 C. The reaction mixture was cooled to room temperature, and a solid precipitated. The precipitate was filtered to obtain a white powder 6,7-bis-(2-methoxyethoxy)-4(3H)quinazolinone (22.1 g, 75%).Thionyl chloride (14.9 g) was added dropwise slowly to a solution of 6,7-bis-(2-methoxyethoxy)-4 (3H) quinazolinone (14.7 g, 0.15 mol), N,N-dimethylformamide (1 ml), and dichloromethane (150 ml). The reaction mixture was stirred at room temperature, and refluxed for 6 h. The reaction mixture was cooled to room temperature, and the pH of the reaction mixture was adjusted to 7-8 with a sodium hydroxide solution. The reaction mixture was then stirred for 30 min at room temperature, and set aside to allow the organic and aqueous layers to separate. The organic layer was collected, and concentrated under vacuum to obtain a white solid 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline (14.1 g, 89.5%), [M+H]+=313.
89%
With potassium carbonate; In acetonitrile; for 6h;Reflux;
Ethyl 3,4-dihydroxybenzoate (36.4 g, 0.2 mol), potassium carbonate (82.8 g, 0.6 mol), and 2-methoxyethyl p-toluenesulfonate (72.0 g, 0.4 mol) were dissolved in acetonitrile (200 ml), heated and refluxed for 6 h. The solvent of the reaction mixture was evaporated under vacuum to obtain a residue. The residue was recrystallized by isopropanol, suction filtered, and dried under vacuum to obtain a white powder 3,4-bis (2-methoxyethoxy)ethyl benzoate (53.2 g, 89%).
With caesium carbonate; In acetonitrile; at 20℃; for 50h;
o a solution of 2.44 g (10.0 mmol) 3-iodo-1 H-pyrrolo[2,3-c]pyridine and 2.53 g (1 1 .0 mmol) toluene-4-sulfonic acid 2-methoxy-ethyl ester in 20 ml acetonitrile 3.58 g (1 1 .0 mmol) cesium carbonate were added . The resulting slurry was stirred for 50 hours at room temperature. The reaction mixture was filtered with suction and the residue was washed well with acetonitrile. The filtrate was evaporated and chromatographed on a silica gel column with dichloromethane/methanol as eluent giving two isomers separately:3-lodo-1 -(2-methoxy-ethyl)-1 H-pyrrolo[2,3-c]pyridine as light brown oil, HPLC/MS: 1.22 min, [M+H] 303H NMR (500 MHz, DMSO) delta = 8.88 (s, 1 H), 8.23 (d, J=5.5, 1 H), 7.79 (s, 1 H), 7.25 (dd, J=5.5, 0.8, 1 H), 4.49 (t, J=5.1 , 2H), 3.69 (t, J=5.1 , 2H), 3.23 (s, 3H)..3-lodo-6-(2-methoxy-ethyl)-6H-pyrrolo[2,3-c]pyridine as colourless crystals, HPLC/MS: 1.23 min, [M+H] 3031H NMR (500 MHz, DMSO) delta = 8.71 (s, 1 H), 7.99 (s, 1 H), 7.79 (dd, J=6.7, 1.1 , 1 H), 7.32 (d, J=6.7, 1 H), 4.55 (t, J=5.Q, 2H), 3.75 (t, J=5.0, 2H), 3.23 (s, 3H).
With caesium carbonate; In acetonitrile; at 20℃; for 50h;
1. To a solution of 2.44 g (10.0 mmol) <strong>[956003-24-0]3-iodo-1H-pyrrolo[2,3-c]pyridine</strong> and 2.53 g (11.0 mmol) toluene-4-sulfonic acid 2-methoxy-ethyl ester in 20 ml acetonitrile 3.58 g (11.0 mmol) cesium carbonate were added. The resulting slurry was stirred for 50 hours at room temperature. The reaction mixture was filtered with suction and the residue was washed well with acetonitrile. The filtrate was evaporated and chromatographed on a silica gel column with dichloromethane/methanol as eluent giving two isomers separately:[0339]3-Iodo-1-(2-methoxy-ethyl)-1H-pyrrolo[2,3-c]pyridine as light brown oil, HPLC/MS: 1.22 min, [M+H] 303[0340]1H NMR (500 MHz, DMSO) delta=8.88 (s, 1H), 8.23 (d, J=5.5, 1 H), 7.79 (s, 1H), 7.25 (dd, J=5.5, 0.8, 1H), 4.49 (t, J=5.1, 2H), 3.69 (t, J=5.1, 2H), 3.23 (s, 3H).[0341]3-Iodo-6-(2-methoxy-ethyl)-6H-pyrrolo[2,3-c]pyridine as colourless crystals, HPLC/MS: 1.23 min, [M+H] 303[0342]H NMR (500 MHz, DMSO) delta=8.71 (s, 1H), 7.99 (s, 1H), 7.79 (dd, J=6.7, 1.1, 1H), 7.32 (d, J=6.7, 1H), 4.55 (t, J=5.0, 2H), 3.75 (t, J=5.0, 2H), 3.23 (s, 3H).
tert-butyl (trans-4-((2-methoxyethyl)amino)cyclohexyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 16h;
A mixture of BOC 1,4-trans-diaminocyclohexane.HCl (2.178 g, 8.69 mmol), DIEA (2.275 mL, 13.03 mmol), p-toluenesulfonic acid 2-methoxyethyl ester (1.0 g, 4.34 mmol) in DMSO (20 mL) was heated in 100C oil bath (slightly cloudy colorless suspension) for about 16 hours. The resulting mixture was cooled to room temperature (red solution with solids floating on top), diluted in 200 mL water, added 20 mL 2 M Na2C03 and extracted with EtOAc (2 x 150 mL). To the aqueous layer was added solid NaCl and extracted with EtOAc (1 x 150 mL). The organic extracts were combined, dried over Na2S04, and concentrated to give a dark orange oil (3.2 g). This oil was diluted in 10 mL DCM, filtered off solids (impurity), then concentrated to yield a dark orange oil (3.1 g crude). The crude material was purified by column chromatography (ISCO system, 120 g column, Eluted with 100% DCM for 1 min, then 50% DCM to 100% (solution of 90%DCM/10%MeOH/0.5% NH4OH) over 25 mm, held for 10 mm).Fractions containing pure product were combined and concentrated in vacuo to give 0.956 g (3.51 mmol, 81 % yield) of a dark orange oil that solidified to a yellow solid upon standing. LC/MS (mass only): 273.1 (MH+), retention time =0.50 min.
With caesium carbonate; In butanone; at 70℃; for 16h;Inert atmosphere;
General procedure: The selected intermediate 11a-f (0.101 mmol) was dissolved in MEK (0.591 mL), to which Cs2CO3 (66 mg, 0.201 mmol) and alkylating agent (0.151 mmol) were added. The reaction was heated to 70 C and allowed to stir 16 h. The reaction mixture was diluted with H2O and extracted 2× with EtOAc. The combined organic layers were washed with water and brine, then isolated, dried over MgSO4, vacuum filtered, and concentrated in vacuo. Further purification via flash chromatography in an appropriate solvent system delivered the desired S-alkylated compounds in 24-88% yield.
With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 16h;Inert atmosphere;
The selected phenol intermediate 12a-c (0.622 mmol) was dissolved in DMF (3.66 mL), to which Cs2CO3 (304 mg, 0.933 mmol) and an alkylating agent (0.716 mmol) were added. The resulting suspension was stirred at 25 C to 70 C for 30 min to 16 h until the completion of the reaction. Compounds were purified as indicated in 35-92% yield.
With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 16h;Inert atmosphere;
The selected phenol intermediate 12a-c (0.622 mmol) was dissolved in DMF (3.66 mL), to which Cs2CO3 (304 mg, 0.933 mmol) and an alkylating agent (0.716 mmol) were added. The resulting suspension was stirred at 25 C to 70 C for 30 min to 16 h until the completion of the reaction. Compounds were purified as indicated in 35-92% yield.
With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 16h;Inert atmosphere;
The selected phenol intermediate 12a-c (0.622 mmol) was dissolved in DMF (3.66 mL), to which Cs2CO3 (304 mg, 0.933 mmol) and an alkylating agent (0.716 mmol) were added. The resulting suspension was stirred at 25 C to 70 C for 30 min to 16 h until the completion of the reaction. Compounds were purified as indicated in 35-92% yield.
With potassium hydroxide; In ethanol; at 70℃; for 16h;Inert atmosphere;
General procedure: Compound 5 (100 mg, 0.295 mmol) was combined with base (0.443 mmol) and alkylating agent (0.325 mmol) in ethanol or MEK (1.75 mL). The suspension was warmed to 70 C and allowed to stir for 16 h. The suspension was subsequently diluted with EtOAc and washed with water and brine. The isolated organic layer was then dried over MgSO4, filtered, and concentrated in vacuo. Further purification via flash chromatography (0% to 10% EtOAc/hex) delivered the desired compounds in 72-83% yield.
With caesium carbonate; In butanone; at 70℃; for 16h;Inert atmosphere;
General procedure: The selected intermediate 11a-f (0.101 mmol) was dissolved in MEK (0.591 mL), to which Cs2CO3 (66 mg, 0.201 mmol) and alkylating agent (0.151 mmol) were added. The reaction was heated to 70 C and allowed to stir 16 h. The reaction mixture was diluted with H2O and extracted 2× with EtOAc. The combined organic layers were washed with water and brine, then isolated, dried over MgSO4, vacuum filtered, and concentrated in vacuo. Further purification via flash chromatography in an appropriate solvent system delivered the desired S-alkylated compounds in 24-88% yield.
With potassium carbonate; In acetone; at 20℃; for 3h;
General procedure: To a stirred solution of <strong>[26687-82-1]arctigenin</strong> 1 (180 mg,0.4 mmol) in 3 mL acetone were added K2CO3 (110 mg, 0.8 mmol)and R0X (0.6 mmol) at room temperature. Then the mixture wasstirred at room temperature for 3 h. After completion of the reaction,water (20 mL) was added, and the solution was extractedwith EtOAc (3 20 mL). The combined organic extracts werewashed with brine, dried, filtered, and concentrated under reducedpressure. The crude product was purified by chromatography onsilica gel from (EtOAc/PE = 1/6) to afford the pure product 4a-d.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;
A suspension of 15A (0.50 g, 1.63 mmol), p-toluenesulfonic acid 2-methoxyethyl ester (0.38 g, 1.63 mmol), and K2CO3 (0.68 g, 4.88 mmol) in DMF (5 niL) was heated at 80 C overnight. The reaction was cooled to rt, filtered, and rinsed with EtOAc (3 x 25 mL). The combined filtrate was washed with H20, 1.0 M HCl solution, brine, and dried over Na2S04, filtered, and dry-loaded onto silica gel. Purification by silica gel chromatography afforded a colorless oil (550 mg, 93%) as the desired intermediate. The ester was then dissolved in THF (10 mL) and treated with LiOH (0.205 g, 4.88 mmol) in H20 (3 mL) followed by MeOH (1 mL). After 14 h, the mixture was diluted with H20 and organics concentrated. The remaining aqueous layer was made acidic with 10 % citric acid and extracted with EtOAc (3 x 30 mL). The combined organic extract was washed with H20, brine, dried over Na2S04, filtered, and concentrated give the desired carboxylic acid. This material and tert-butyl 4- aminobenzoate (0.31 g, 1.63 mmol) in pyridine (10 mL) were treated with phosphorus oxychloride (0.15 mL, 1.63 mmol) at -10C. After 2 h, the reaction was quenched with H 0 and extracted with EtOAc. The organic layer was washed with H20, 1.0M HC1 solution, H20, brine, dried over Na2S04, filtered, and concentrated. The residue was treated with 50% TFA/DCM. After stirring for 2 h, the reaction was concentrated to dryness The residue was purified reversed phase HPLC and concentrated in vacuo to give 15B (225 mg, 29%) as an oil. MS (ESI) m/z: 371.3 (M+H)+.
To a solution of 2-methoxyethanol (12-1, 5.00 g, 65.7 mmol) in CH2Cl2 (50.0 rnL) was added triethylamine (18.3 mL, 131.4 mmol) followed by 4-methylbenzene-1-sulfonyl chloride (16.3 mg, 85.4 mmol). The reaction mixture was stirred at room temperature overnight. The solution was added with saturated aqueous Na2CO3 (50.0 mL) and extracted with CH2Cl2. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-methoxyethyl 4-methylbenzenesulfonate (12-2, 10.46 g) as yellow solids in 69% yield: 1H NMR (500 MHz, CDCl3) 7.80(d, J= 8.3 Hz, 2 H), 7.34 (d, J= 8.3 Hz, 2 H), 4.15-4.16 (m, 2 H), 3.57-3.59 (m, 2 H), 3.31 (s, 3 H), 2.44 (s, 3 H). ESI-MS: m/z 230.8 (M + H)+.
With sodium hydride; hydroquinone; In N,N-dimethyl-formamide; at 65.0℃; for 16.0h;
To a solution of 60% sodium hydride (436 mg, 18.2 mmol) in DMF (2.0 mL) was added hydroquinone (1.0 g, 18.2 mmol) in DMF (10.0 mL) dropwisely. The solution was added with 2-methoxyethyl 4-methylbenzenesulfonate (12-2, 2.10 g, 21.8 mmol) dropwisely. The reaction was stirred at 65 C for 16 h. The solution was cooled to room temperature, poured into icy H20, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reducedpressure to give 4-(2-methoxyethoxy)phenol (12-3, 1.0 g), which was used directly for the next step without further purification.
With caesium carbonate; In acetonitrile; at 65℃; for 36h;
0.200 g of 7'-chlorospiro[cyclopentane-1,2'-imidazo[1,2-a]pyrimidin]-5'-one are suspended in 7 mL de CH3CN, 0.62 g of cesium carbonate and 0.49 g of 2-methoxyethyl 4-methylbenzenesulfonate are added. The mixture is heated to 65 C. for 36 h. Water, ethyl acetate are added and then after decantation the organic phase is dried with magnesium sulfate and then evaporated. The crude is purified by flash chromatography on silica gel (CH2CL2/MeOH, 99/1). 0.16 g (yield=41%) of 7'-chloro-1'-(2-methoxyethyl)-spiro[cyclopentane-1,2'-imidazo[1,2-a]pyrimidin]-5'-one are obtained as a brown powder and including the following characteristics: Mass spectrum (method A) ES+/-: Rt: 2.31 min, M/Z=284
To a suspension of sodium hydride (0.228 g, 9.95 mmol, 4.0 eq, 60% dispersion in mineral oil) in THF (10 ml) tert-butyl 4-hydroxypiperidine-1-carboxylate (step 2) (0.500 g, 2.48 mmol, 1.0 eq) was added at 0C. The reaction mixture was stirred at 0C for 30 minutes, 2-methoxyethyl 4-methylbenzenesulfonate (step 3)(0.858 g, 3.73 mmol, 1.5eq) in THF (5 ml) was added and the reaction was allowed to reach to room temperature and heated to reflux for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was quenched with saturated NH4Cl solution (20 ml) and extracted with CH2Cl2 (2x20 ml). The combined organic layers were dried over Na2S04, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using methanol: dichloromethane as an eluent to obtain the desired product (0.340g, 58.9% yield) as a brown liquid. 1H NMR (300 MHz, CDCl3): delta ppm (m, 2H), 3.68-3.39 (m, 5H), 3.39 (s, 3H), 3.07-2.98 (m, 2H), 1.86-1.84 (m, 2H), 1.58- 1.49 (m, 2H), 1.45 (s, 9H); ES Mass: [M+Na]+ 282.03.
2-bromo-4-(2-methoxyethoxy)-1-methylbenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate; In acetone;Reflux;
Phenol 6 (12.0 g, 64 mmol), the tosylate (14.9 g, 64 mmol), K2CO3 (22.2 g, 161 mmol),and acetone (85 mL) were combined and heated at reflux with stirring overnight. After cooling,the mixture was poured into H2O and the organic layer was separated. The aqueous layer wasextracted 3 times with Et2O. The combined organic layers were washed twice with 2M NaOH,once with brine, and finally dried over Na2SO4. Rotary evaporation of the solvent yielded acrude yellow oil that was vacuum distilled to give 7 as a clear oil (13.9 g, 57 mmol, 89%). 1HNMR (CDCl3): delta 7.12 (d, J=2.6 Hz, 1H, H-3); 7.11 (d, J=8.4 Hz, 1H, H-6); 6.79 (dd, J=8.4 Hz,2.6 Hz, 1H, H-5); 4.07 (m, 2H); 3.73 (m, 2H); 3.42 (s, 3H); 2.32 (s, 3H). 13C NMR (CDCl3): delta157.31, 130.91, 129.89, 124.72, 118.28, 113.97, 70.86, 67.55, 59.15, 21.75
3-(hydroxymethyl)-1,8-bis(2-methoxyethoxy)anthracene-9,10-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19.7%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h;
The general procedures for the synthesis of 1, 8-alkoxy substituted aloe-emodin (1-4)
B Procedure: 6g (0.15mol) of sodium hydroxide was dissolved in 20 mL of water and cooled to room temperature. 2-Methoxyethanol (15.22g, 0.2mol) was added to the solution and stirred for 30 min at 0oC. Tosyl chloride (19.1g, 0.1mol) in 25 mL of dry THF was added to the reaction mixture by dropwise, then the mixture was stirred for 5h at 0oC.The appearing precipitate was filtered and washed with ether, the filtrate was extracted by ether (2×20 mL). The combined organic phases were washed with brine and dried by anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to get 2-methoxyethyl 4-methylbenzenesulfonate. 2-Methoxyethyl 4-methylbenzenesulfonate (2.3g, 0.01mol) in 30mL of dry DMF was added to a 50 mL dry flask. Aloe-emodin (2.7g, 0.01mol) and anhydrous potassium carbonate (6.9 g, 0.05 mol) were added to the solution and stirred for 16h at 80oC. The reaction mixture was cooled to room temperature and poured into 80mL of water. The mixture was extracted with DCM (3×30mL). The combined organic phases were washed with brine and dried by anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to get crude product, which was purified by column chromatography with ethyl acetate in petroleum ether.
3-methoxy-17-(2-methoxyethyl)morphinan-6-one trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46.4%
Example 3 Preparation of 3-hydroxy-17-(2-methoxyethyl)morphinan-6-one (3), hydrochloride salt (3) Step 1 : Preparation of 3-Methoxy-17-(2-methoxyethyl)morphinan-6-one trifluoroacetic acid salt 3-Methoxymorphinan-6-one [Zhang et al. (2007) J Med. Chem. 50(11):2747- 2751] (310 mg, 1.14 mmol), 2-methoxy ethyl 4-methylbenzenesulfonate (262 mg, 1.14 mmol) and diisopropylethylamine (177 mg, 1.37 mmol) were dissolved in acetonitrile (2 mL) and allowed to react for 16 hours at 60 C. The solvent was evaporated in vacuo and the residue was purified by reversed phase HPLC to afford 3-methoxy-17-(2-methoxyethyl)morphinan- 6-one trifluoroacetic acid salt (174mg , 46.4%). MS (EI) for C20H27NO3: 330.5 (MH+).
Stage #1: adenosine-2-amine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20 - 100℃; for 1h;
Stage #2: 2-methoxy-ethyl p-toluenesulfonyloxy ester In N,N-dimethyl-formamide; mineral oil at 50℃; for 16.3333h;
tert-butyl (R)-(1-((2-methoxyethyl)thio)propan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
General procedure: Example 31: Preparation of tert-butyl (R)-(1-((2-fluoroethyl)thio)propan-2-yl)carbamate (C157) (0769) (0770) Aqueous sodium hydroxide (2.0 M, 8.5 mL, 17 mmol) was added to a solution of 332 (R)-S-(2-((tert-butoxycarbonyl)amino)propyl) ethanethioate (C58) (2.0 g, 8.5 mmol) in 695 isopropanol at 0 C. After stirring 2 hours, 696 1-fluoro-2-iodoethane (1.76 g, 10.1 mmol) was added and the reaction mixture was left to stir overnight. The reaction mixture was partioned between ethyl acetate and water. The organics were separated, washed with saturated sodium bicarbonate and brine, dried with magnesium sulfate, and concentrated. The resulting residue was purified by flash silica chromatography. The 697 title compound was isolated as a pale yellow liquid (1.55 g 72%): 1H NMR (500 MHz, DMSO-d6) delta 6.80 (d, J=8.2 Hz, 1H), 4.53 (dt, J=47.3, 6.4 Hz, 2H), 3.54 (h, J=6.9 Hz, 1H), 2.81 (dt, J=21.2, 6.4 Hz, 2H), 2.63-2.51 (m, 2H), 1.38 (s, 9H), 1.07 (d, J=6.7 Hz, 3H); 19F NMR (471 MHz, DMSO-d6) delta -211.55 (tt, J=46.9, 21.3 Hz); 13C NMR (126 MHz, DMSO-d6) delta 155.41, 83.20 (d, J=167.3 Hz), 78.02, 46.51, 38.34, 31.84 (d, J=20.5 Hz), 28.72, 20.19; IR (thin film) 3340, 2975, 2931, 1687, 1504 cm-1.
5,11,17,23-tetra(tert-butyl)-25-hydroxy-27-[(4-methylphenyl)sulfonyloxy]-28-propoxy-26-[N-(1-phenylethyl)carbamoylmethoxy]calix[4]arene[ No CAS ]
[ 17178-10-8 ]
C67H85NO8S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
General procedure: To a stirred solution of 1a (or 1b)17 (2.00 g, 1.98 mmol) intetrahydrofuran (30 mL) was added sodium hydride (0.38 g,7.9 mmol) at room temperature. The reaction mixture washeated at reflux for 4 h. Then the <strong>[17178-10-8]2-methoxyethyl tosylate</strong>was added, and the stir was continued for 2 h and quenchedwith hydrocholoric acid (2.00 mol L-1). The aqueous layerwas extracted with dichloromethane, and the combinedorganic layers were washed with saturated brine, dried withanhydrous sodium sulfate. The solvent was removed underreduced pressure to yield product which was further purifiedby silica gel column chromatography (eluent = petroleumether:ethyl acetate, 2:1, v/v). Compound 2a (or 2b) wasobtained as white power.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h;Schlenk technique; Inert atmosphere;
General procedure: 2,5-dibromo-hydroquinone (0.747 mmol), S3a-c (1.87 mmol), and K2CO3 (4.48 mmol) were loaded in a 50 mL flame dried Schlenk flask loaded with a magnetic stirrer. The flask was evacuated to a pressure of 150 mtorr and backfilled with N2(g), repeating this purge procedure 3 times. Anhydrous DMF (4 mL) was added to the flask under N2(g). The solution was stirred and heated to 80 C with stirring for 12 h and tracked by TLC. The reaction was cooled to room temperature and quenched with water (20 mL) and a precipitant was formed. A crystalline white solid was obtained and purified by filtration using a medium porosity glass frit funnel, rinsed with water and dried under vacuum.
methyl 4-chloro-2-(2-methoxyethoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76.3%
With tetrabutylammomium bromide; potassium carbonate; In acetone; for 6h;Reflux;
To a stirred solution of <strong>[22717-55-1]methyl 4-chloro-2-hydroxybenzoate</strong> (2.0 g, 10.718 mmol, 1.05 eq) in acetone (50 mL) was added 2-methoxyethyl4-methylbenzenesulfonate (4.93 g, 21.437mmol, 2.0 eq) followed by potassium carbonate (7.40 g, 53.59 mmol, 5.0 eq) and TBAB(0.690 g, 2.143 mmol, 0.2 eq). The reaction mixture was refluxed for 6 hours. TLC indicatedstarting material was consumed and the desired product was observed. After completion ofthe reaction (monitored by TLC), the reaction mixture was evaporated under reduced10 pressure, diluted with water (200 mL) and extracted with ethyl acetate (2xl00 mL). Thecombined organic extracts were washed with water (50 mL), brine solution (20 mL), driedover sodium sulfate, filtered and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography by using 40% ethyl acetate in hexanes as an eluent toobtain the title compound (2.0 g, yield: 76.3%) as a liquid. 1H NMR (300 MHz, CDCh): 815 ppm 7.83-7.74 (m, lH), 6.99-6.95 (m, 2H), 4.17 (t, J = 4.8 Hz, 2H), 3.87 (s, 3H), 3.80 (t, J =4.5 Hz, 2H), 3.47 (s, 3H); ESI-MS: m/z 266.93 (M+Nat.
(S)-1-(4'-Bromo-biphenyl-4-yloxy)-propan-2-ol[ No CAS ]
[ 17178-10-8 ]
C18H21BrO3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium hydride; In tetrahydrofuran; for 12h;Inert atmosphere; Reflux;
General procedure: NaH (95%, 160 mg, 6.6 mmol) was added to aTHF solution (50 mL) of (R)-8 (1.0 g, 3.3 mmol) and 9 (834 mg,3.63 mmol) under Ar. The mixture was reflux for 12 h and thenallowed to cool to room temperature. After the addition of a smallamount of MeOH, the reaction mixture was diluted with CH2Cl2,washed successively with saturated aqueous NH4Cl and water, driedover MgSO4, and then evaporated to dryness. The residue was subjectedto column chromatography (SiO2, ethyl acetate/hexane, 1/9 v/v) toallow the isolation of (R)-10 as white powder (1.0 g) in 84% yield. 1HNMR (600 MHz, CDCl3) delta (ppm) 7.55 (d, J=8.4 Hz, 2H), 7.49 (d,J=8.6 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.6 Hz, 2H),4.11-4.07 (m, 1H), 3.94 (m, 2H), 3.78 (m, 2H), 3.59 (m, 2H), 3.42 (s,3H), 1.34 (d, J=6.2 Hz, 3H). 13C NMR (151 MHz, CDCl3) delta (ppm)158.70, 139.73, 132.58, 131.80, 128.31, 127.97, 120.80, 115.02,74.45, 72.30, 71.76, 68.84, 59.13, 17.39. MALDI-TOF mass calcd. forC18H21BrO3 [M]+: m/z=364.0669; found: 364.0660.
3-chloro-4-(2-methoxyethoxy)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With barium carbonate; In N,N-dimethyl-formamide; at 100℃; for 14h;
The title compound of this step is prepared by the method described in the second step of Example 1,2-methoxyethyl 4-methylbenzenesulfonate (1.8g, 7.82mmol),Barium carbonate (4.16g, 12.77mmol)Prepared by reacting 3-chloro-4-hydroxybenzaldehyde (1.0 g, 6.38 mmol) in DMF (10 mL).The crude product was purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/v) = 10/1)The title compound was obtained as a pale yellow oil (0.65 g, 47%).
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 14h;
M-hydroxybenzaldehyde (1.5 g, 12.3 mmol),2-methoxyethyl 4-methylbenzenesulfonate (3.4 g, 14.7 mmol)And DMF (10mL) addedInto a 100 mL single-mouth round bottom flask,Add potassium carbonate (3.4 g, 24.6 mmol),The oil bath was reacted at 100 C for 14 hours;Quenched by adding water (50 mL).Additional ethyl acetate (30 mL) was added.Dispensing, collecting organic phase,Dry under reduced pressure,Column chromatography separation and purification(petroleum ether/ethyl acetate (v/v)=8/1)The title compound was obtained as a yellow oil (1.7 g, 77%).
With 1,1'-bis-(diphenylphosphino)ferrocene; sodium metabisulfite; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tin; potassium hydrogenphosphate trihydrate; tetrabutylammomium bromide; In dimethyl sulfoxide; at 100℃; for 10h;Inert atmosphere;
Under nitrogen protection, p-methyliodobenzene (0.1 mmol), sodium metabisulfite (0.2 mmol, 2.0 equiv.), Tin powder (0.3 mmol, 3.0 equiv.), 1,1'-bis (diphenylphosphino) Ferrocene palladium dichloride (0.01 mmol, 10 mol%), 1,1'-bis (diphenylphosphine) ferrocene (0.02 mmol, 20 mol%), dipotassium hydrogen phosphate trihydrate (0.2 mmol, 2.0 equiv .), Tetrabutylammonium bromide (0.15mmol, 1.5equiv.) Was added to the reaction tube containing the magneton,After evacuation three times, add 2-methoxyethyl p-toluenesulfonate(0.3mmol, 3.0equiv.), DMSO (1.0mL), the reaction system was heated to 100 C for 10 hours, and the aryl iodide was completely converted on the spot plate. After the reaction system was cooled to room temperature, diluted with water, ethyl acetate was added. Ester (10 mL * 3) was extracted, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain purified target product 3aa (69%)
Stage #1: 3-hydroxystyrene With potassium <i>tert</i>-butylate In acetonitrile for 1h;
Stage #2: 2-methoxy-ethyl p-toluenesulfonyloxy ester In acetonitrile at 70℃; for 10h; Inert atmosphere;
2 Preparation Example 2: 1-(2-methoxyethoxy)-3-vinylbenzene
55 g of 3-hydroxystyrene prepared in 1) of Preparation Example 1 was put into a 2000 ml round-bottom flask, and 800 ml of acetonitrile was added to dissolve it,41 g of potassium t-butoxide was added dropwise and reacted for 1 hour.Thereafter, 163 g of 2-methoxyethyl 4-methylbenzenesulfonate was slowly added dropwise, followed by stirring at 70° C. for 10 hours under a nitrogen atmosphere.After the solvent is removed under reduced pressure, it is diluted with normal hexane to crystallize the salt. After filtering the crystallized salt, the organic layer is washed with brine. Then, the solvent was removed under reduced pressure to obtain 86 g (85%) of a brown oil (1-(2-methoxyethoxy)-3-vinylbenzene)
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