* 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.
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.5 h; Inert atmosphere Stage #2: at 20℃; for 12 h; Inert atmosphere Stage #3: With sulfuric acid; water In tetrahydrofuran for 3 h; Inert atmosphere; Reflux
General procedure: (Using the synthesis of M-PEG 7 as an example). Under the atmosphere of N2, to a suspension of NaH (1.0 g, 60percent dispersed in mineral oil, 25.0 mmol) in THF (60 mL) at 0 was added a solution of M-PEG 5 (2.0 g, 16.6 mmol) in THF (20 mL). After the addition, the stirring mixture was warmed to rt and stirred for 30 min. Then, a solution of macrocyclic sulfate 8 (5.1 g, 20.0 mmol) in THF (20 mL) was added. The resulting mixture was stirred for 12 h at rt, and concentrated under vacuum. The resulting residue was dissolved in water (50 mL), and washed with CH2Cl2. The aqueous layer was concentrated and then dissolved in THF (100 mL). Then, water (0.6 mL, 33.3 mmol) and H2SO4 (0.4 mL, 8.4 mmol) were added to the reaction mixture and the resulting mixture was refluxed for 3 h. The reaction was neutralized with saturated NaHCO3 solution, extracted with CH2Cl2. The organic layers were dried over anhydrous Na2SO4, concentrated under vacuum, and purified by flash chromatography on silica gel (CH2Cl2/MeOH = 20/1) to give M-OEG 7 as clear oil (4.3 g, 88percent yield).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 22, p. 3502 - 3505
[2] European Journal of Organic Chemistry, 2017, vol. 2017, # 30, p. 4461 - 4468
4
[ 112-35-6 ]
[ 4437-01-8 ]
Reference：
[1] Journal of Mass Spectrometry, 2002, vol. 37, # 7, p. 699 - 708
[2] Patent: CN105732338, 2016, A,
[3] Patent: WO2018/96464, 2018, A1,
5
[ 112-35-6 ]
[ 23778-52-1 ]
Reference：
[1] Macromolecules, 2005, vol. 38, # 23, p. 9509 - 9517
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 5, p. 527 - 536
6
[ 112-35-6 ]
[ 23601-40-3 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 20, p. 7499 - 7508
[2] Organic Letters, 2004, vol. 6, # 4, p. 469 - 472
[3] Chemistry - An Asian Journal, 2011, vol. 6, # 2, p. 452 - 458
[4] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 7, p. 2193 - 2198
[5] Patent: WO2015/143185, 2015, A1,
[6] Patent: WO2016/40891, 2016, A2,
[7] Patent: US2858315, 1957, ,
7
[ 112-35-6 ]
[ 112-27-6 ]
[ 23601-40-3 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1988, vol. 160, p. 331 - 338
8
[ 112-35-6 ]
[ 107-21-1 ]
[ 23783-42-8 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1988, vol. 160, p. 331 - 338
Reference：
[1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 1, p. 186 - 193
[2] Synthesis, 2002, # 6, p. 816 - 824
[3] European Journal of Organic Chemistry, 2001, # 10, p. 1903 - 1915
[4] Journal of the American Chemical Society, 1994, vol. 116, # 12, p. 5057 - 5062
[5] Chemische Berichte, 1980, vol. 113, # 5, p. 1691 - 1707
[6] European Journal of Medicinal Chemistry, 1991, vol. 26, # 4, p. 461 - 467
[7] Chemische Berichte, 1979, vol. 112, p. 1392 - 1399
[8] Patent: US6262029, 2001, B1,
[9] Journal of Molecular Structure, 2011, vol. 990, # 1-3, p. 121 - 131
[10] Journal of Organic Chemistry, 2011, vol. 76, # 15, p. 6271 - 6276
[11] Chemistry - An Asian Journal, 2011, vol. 6, # 1, p. 149 - 156
[12] Chemical Communications, 2011, vol. 47, # 46, p. 12491 - 12493
[13] Journal of the American Chemical Society, 2012, vol. 134, # 2, p. 844 - 847
[14] Macromolecules, 2012, vol. 45, # 12, p. 5151 - 5156
[15] Chemical Communications, 2013, vol. 49, # 45, p. 5177 - 5179
[16] Chemical Communications, 2014, vol. 50, # 54, p. 7139 - 7142
[17] Chemical Communications, 2015, vol. 51, # 32, p. 6948 - 6951
[18] Journal of the American Chemical Society, 2015, vol. 137, # 23, p. 7286 - 7289
[19] Patent: WO2015/143185, 2015, A1,
[20] Molecules, 2015, vol. 20, # 9, p. 16085 - 16102
[21] Patent: WO2015/191433, 2015, A1,
[22] Journal of the American Chemical Society, 2015, vol. 137, # 51, p. 16196 - 16202
[23] Patent: WO2016/40891, 2016, A2,
[24] Journal of Polymer Science, Part A: Polymer Chemistry, 2016, vol. 54, # 20, p. 3294 - 3302
[25] Patent: US2017/65496, 2017, A1,
[26] Journal of the American Chemical Society, 2017, vol. 139, # 17, p. 6234 - 6241
[27] Angewandte Chemie - International Edition, 2017, vol. 56, # 48, p. 15461 - 15465[28] Angew. Chem., 2017, vol. 129, p. 15664 - 15669,6
[29] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 1903 - 1912
[30] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 1903 - 1912
[31] Patent: WO2008/112257, 2008, A1,
12
[ 136918-14-4 ]
[ 112-35-6 ]
[ 74654-07-2 ]
Reference：
[1] European Journal of Inorganic Chemistry, 2011, # 28, p. 4421 - 4428
13
[ 112-35-6 ]
[ 854601-70-0 ]
Reference：
[1] Patent: WO2018/96464, 2018, A1,
14
[ 872-31-1 ]
[ 112-35-6 ]
[ 282540-12-9 ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: With pyridine; copper(l) iodide; potassium <i>tert</i>-butylate In toluene at 20℃; for 0.5 h; Stage #2: at 110℃; for 24 h;
(1) Synthesis of 3- (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) thiophene (compound 9) :[0236]A dry 250 mL two-neck round bottom flask with condenser and magnetic stir bar was charged with potassium tertbutylate (10.5 g, 94 mmol) and cuprous iodide (2.34 g, 12 mmol) . Next, 10 mL pyridine and 100 mL toluene mixture solution was added and stirred until dissolved, and 15 mL triethylene glycol monomethyl ether was added. The reaction mixture was then allowed to stir at room temperature for 30 min. 3-bromothiophene (5.8 mL, 62 mmol) was then added in one portion and the reaction mixture was heated to 110 for 24 h. After cooling to room temperature, the reaction mixture was centrifuged and concentrated under vacuum. 50 mL dichloromethane was added and washed with 5 M HCl (aq) . The aqueous layers were extracted with DCM, and the combined organic portions were dried with MgSO4and concentrated under reduced pressure. The crude material was purified via column chromatography, eluting with 1: 1 ethyl ether in hexanes (v/v) . The desired product was isolated as a yellow tinted oil (10.35 g, 68yield) .[0237]1H-NMR (400 MHz, CDCl3) δ 7.18 (dd, J 5.3, 3.1 Hz, 1H) , 6.79 (dd, J 5.3, 1.5 Hz, 1H) , 6.28 (dd, J 3.1, 1.5 Hz, 1H) , 4.17 –4.10 (m, 2H) , 3.89 –3.83 (m, 2H) , 3.77 –3.72 (m, 2H) , 3.72 –3.64 (m, 4H) , 3.57 (dd, J 5.7, 3.6 Hz, 2H) , 3.40 (s, 3H) .
Reference：
[1] Patent: WO2017/190345, 2017, A1, . Location in patent: Page/Page column 33-34
[2] Journal of the American Chemical Society, 2016, vol. 138, # 32, p. 10252 - 10259
[3] Polymer, 2011, vol. 52, # 17, p. 3704 - 3709
With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hydrogencarbonate; sodium carbonate at 20℃; Electrochemical reaction;
99%
Stage #1: triethylene glucol monomethyl ether With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium carbonate at 20℃; for 2h; aq. buffer; Electroliysis;
Stage #2: With Amberlite IR 120 for 0.5h; aq. buffer;
88%
Stage #1: triethylene glucol monomethyl ether With C29H44Cl2N2Ru; sodium hydroxide In water for 24h; Reflux;
Stage #2: With hydrogenchloride In water
75%
With potassium hydroxide; potassium permanganate In water for 12h; Ambient temperature;
With 4-(benzyloxycarbonyl)-2,2,6,6-tetramethylpiperidine-1-oxyl; acetylcholine chloride; sodium hydrogencarbonate; pyridinium hydrobromide perbromide In TETRAHYDROPYRANE; water at 20℃; for 2h;
Stage #1: triethylene glucol monomethyl ether With 1H-imidazole; triphenylphosphine In tetrahydrofuran at 20℃; for 0.05h; Inert atmosphere;
Stage #2: With iodine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere;
To a solution of triethylene glycol monomethyl ether (3.0×10-3 mol) in THF (20mL) were added triphenylphosphine (0.97g, 3.7×10-3 mol, 1.2 equiv) and imidazole (0.61g, 9.0×10-3 mol, 3.0 equiv). The mixture was stirred under nitrogen atmosphere at room temperature for 3min. Then the reaction mixture was cooled to -20°C and I2 (1.01g, 3.98×10-3 mol, 1.2 equiv) was added. After stirring at this temperature for 15min the cooling bath was removed, and the mixture stirred at room temperature for 2h until the total consumption of triethylene glycol monomethyl ether was verified. This monitoring was carried out by TLC, in an eluent of hexane and ethyl acetate (8:2) (spray reagent: phosphomolybdic acid solution). The reaction was quenched at 0°C with an aqueous saturated solution of NaHCO3 (20mL). The reaction mixture was filtered through out celite several times until all white precipitate formed was removed. The aqueous phase was extracted with diethyl ether and the combined organic phases were washed with a saturated solution of Na2S2O5 (20mL) and brine, dried over Na2SO4 anhydrous, filtered and evaporated. The residue was purified by chromatography on silica gel using as eluent a mixture of hexane and ethyl acetate (8:2), affording 3-{2-[2-(2-methoxyethoxy)ethoxy]ethyl} iodide (0.58g, 77%) as a yellow oil. In a round bottom flask equipped with magnetic stir bar was added 3-{2-[2-(2-methoxyethoxy)ethoxy]ethyl} iodide (0.57g, 2.1×10-3 mol, 1.4 equiv) and the 1,2-dimethylimidazol (0.14g, 1.5×10-3 mol) in dry THF. The reaction mixture was stirred and refluxed for 122h under nitrogen atmosphere until the total consumption of the 1,2-dimethylimidazol was verified. This monitoring was carried out by TLC, in an eluent of dichloromethane/MeOH (95:5) (spray reagent: Dragendorff-Munier solution). The reaction mixture was evaporated and washed with diethyl ether, affording 3-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-1,2-dimethyl-1H-imidazol-3-ium iodide (2e) (0,40g, 75%) as a yellow oil
53%
With 1H-imidazole; iodine; triphenylphosphine In toluene for 4h; Heating;
Multi-step reaction with 2 steps
1: pyridine / CH2Cl2
2: NaI / acetone / 5 h / Heating
Multi-step reaction with 2 steps
1: potassium carbonate / 0.33 h
2: sodium iodide / acetone / 24 h / 20 °C / Inert atmosphere; Darkness
Multi-step reaction with 2 steps
1.1: 0.25 h / 0 °C
1.2: 18 h / 20 °C
2.1: sodium iodide / acetone / 18 h / Reflux
Multi-step reaction with 2 steps
1: tetrahydrofuran / Cooling with ice
2: sodium iodide / acetone / 20 °C
Multi-step reaction with 2 steps
1: potassium hydroxide / tetrahydrofuran; water / 20 °C / Inert atmosphere; Schlenk technique
2: sodium iodide / acetone / 60 °C / Inert atmosphere; Schlenk technique
With carbon tetrabromide; triphenylphosphine In dichloromethane at 0℃; for 5h; Inert atmosphere;
75%
With phosphorus tribromide In methanol; diethyl ether 1.) 0 deg C, 10 min, 2.) RT, 30 min;
70%
With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 50℃; for 12h; Inert atmosphere;
60%
With carbon tetrabromide; triphenylphosphine In dichloromethane at 0℃;
53%
With carbon tetrabromide; triphenylphosphine In dichloromethane at 25℃; for 12h;
21 [0491] Scheme 4: synthesis of 2-(5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-lH-indol-3- yl)ethanamine hydrochloride (KD21)
[0491] Scheme 4: synthesis of 2-(5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-lH-indol-3- yl)ethanamine hydrochloride (KD21)[0492] This compound was prepared by the procedure similar to syntheses of 2-(5-alkoxy- 1H- indol-3-yl) ethanamine hydrochloride.
47%
With sulfurous dibromide In dichloromethane at 20℃; for 18h;
42%
With phosphorus tribromide at 20℃; for 24h;
40%
Stage #1: triethylene glucol monomethyl ether With phosphorus tribromide In diethyl ether at 0℃; for 2h;
Stage #2: In methanol; diethyl ether at 20℃; for 0.5h;
1.1
0.72 ml of phosphorus tribromide was added dropwise to a solution of 2.4 ml of triethylene glycol monomethyl ether in 30 ml of anhydrous ether at 0 ° C. After 2 hours of reaction, the reaction mixture was warmed to room temperature and 2.1 ml of methanol After 0.5 hours, 3.0 ml of water was added to stop the reaction. The reaction mixture was transferred to a separatory funnel and the organic phase was successively washed with 5 wt% NaHCO 3The aqueous solution and the saturated aqueous NaCl solution were each washed once. The aqueous phases were combined and extracted 3-5 times with ethyl acetate. The organic phases are combined, anhydrous MgSO 4Drying, filtering, filtrating, removing the organic solvent under reduced pressure, carrying out silica gel column chromatography with ethyl acetate / petroleum ether system with the volume percent of ethyl acetate of 30-50%, and removing organic Solvent, and dried to give l-bromo-2- (2- (2-methoxyethoxy) ethoxy) ethane. Light yellow liquid, yield 40%.
25%
With phosphorus tribromide In chloroform at 20℃; for 4h;
15
A mixture of triethylene glycol monomethyl ether (71) (9.7 mL, 57.6 mmol) in CHCl3 (20 mL) with PBr3 (10.8 mL, 115.2 mmol) was stirred at room temperature for 4 h. The mixture was poured into ice, and neutralized with Na2CO3. The organic layer was washed with water, dried over Na2SC>4, and concentrated under reduced pressure. Purification of the residue by flash chromatography with petroleum ether-ethyl acetate (65:35) as the eluent gave bromide 8 as a colourless oil (3.3 g, yield 25 %). 1H-NMR (200 MHz, CDCl3): 3.34 (s, 3H), 3.42 (t, J = 6.4, 2H), 3.49-3.53 (m, 2H), 3.59-3.66 (m, 6H), 3.77 (t, J = 6.4,2H). MS (ESI): rø/z 249 (M+Na+).
25%
With phosphorus tribromide
20%
With phosphorus tribromide In methanol; diethyl ether at 0℃; for 0.75h; Inert atmosphere;
Multi-step reaction with 2 steps
1: 78 percent / pyridine / CH2Cl2 / Ambient temperature
2: 92 percent / LiBr / dimethylformamide / Ambient temperature
With carbon tetrabromide; triphenylphosphine In dichloromethane at 0℃; Inert atmosphere;
Multi-step reaction with 2 steps
1: dmap; pyridine / 0 - 25 °C / Inert atmosphere
2: lithium bromide / acetone / 20 °C / Inert atmosphere; Reflux
With carbon tetrabromide; triphenylphosphine In tetrahydrofuran
With phosphorus tribromide In diethyl ether at 0℃; for 2h;
Multi-step reaction with 2 steps
1: pyridine / dichloromethane / 20 °C / Cooling with ice
2: lithium bromide / N,N-dimethyl-formamide / 20 °C / Cooling with ice
With bromine; triphenylphosphine In diethyl ether for 1h;
Multi-step reaction with 2 steps
1: pyridine / dichloromethane / 20 °C / Cooling with ice
2: lithium bromide / N,N-dimethyl-formamide / 20 °C / Cooling with ice
With carbon tetrabromide; triphenylphosphine In dichloromethane
Multi-step reaction with 2 steps
1: triethylamine / dichloromethane / Cooling with ice
2: lithium bromide / acetone / 85 °C
With carbon tetrabromide In acetonitrile at 20℃;
Multi-step reaction with 2 steps
1: triethylamine / dichloromethane / 3 h / 0 - 20 °C
2: tetrabutylammomium bromide / acetonitrile / 3 h / 50 °C
m-PEG-3-SC-carbonate (15) (0148) Into a 100 mL flask was placed mPEG3-OH (14) (2.0 g, 12.1 mmol) and anhydrous dichloromethane (25 mL). The clear solution was cooled to 0 C., and then triethylamine (1.86 mL, 13.4 mmol, 1.1 equivalents) was added slowly. The solution was stirred for 15 minutes at 0 C., and then was added to a second flask containing a suspension of DSC (3.1 g, 12.1 mmol) in dichloromethane (20 mL). The reaction mixture was allowed to equilibrate to room temperature. After approximately 18 hours, the light-yellow reaction mixture was diluted with dichloromethane (60 mL), transferred to a separatory funnel, and partitioned with deionized water (100 mL). The aqueous layer was extracted with dichloromethane (4×80 mL). The combined organics were washed with water, saturated sodium bicarbonate, and saturated sodium chloride. The dried organic layer was filtered, concentrated under reduced pressure and dried overnight under high vacuum, to give 2.79 g (75%) of mPEG3-SC-carbonate as a light yellow oil. 1H NMR (CDCl3) delta 4.40 (m, 2H), 3.80 (m, 2H), 3.70 (bs, 6H), 3.60 (m, 2H), 3.35 (s, 3H), 2.80 (s, 4H); LC/MS=306 (M+1).
55%
With triethylamine; In acetonitrile; at 20℃; for 16.1667h;
Monodispersed branched MPEG3 I (200 mg, 1.21 mmol) was dissolved in acetonitrile (20 mL) and disuccinimidyl carbonate (DSC, II, 0.468 g, 1.82 mmol) was added. Then triethylamine (0.184 g, 1.82 mmol) was added dropwise and after 10 min the reaction mixture became clear. Reaction was stirred overnight at RT. After stirring for ~16 h, the crude reaction was evaporated to dryness and then dissolved in sat. NaHCO3 (20 mL), washed ethyl acetate (2*50 mL), dried MgSO4, and evaporated to dryness. Column chromatography (silica, EtOAc/MeOH, 10:1) afforded the solid III (0.206 g, 55% yield). ESI MS: m/e 306.11 (M+H)+.
20%
With triethylamine; In acetonitrile; at 20℃;
Triethylene glycol monomethyl ether (1.0 g, 6.1 mmol) and <strong>[74124-79-1]N,N'-disuccinimidyl carbonate</strong> (1.87 g, 7.3 mmol) were dissolved in acetonitrile (10 mL). Then triethylamine (1.3 mL, 9.15 mmol) was added and the reaction stirred overnight at room temperature. Crude reaction was evaporated to dryness, dissolved in sat. NaHCO3 (50 mL), washed ethyl acetate (2×50 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate) afforded 1 a clear oil (0.367 g, 20% yield).
naphthalocyaninatogallium methoxytriethyleneoxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: gallium(III) trichloride With sodium methylate In methanol; toluene at 0 - 20℃; for 1h;
Stage #2: triethylene glucol monomethyl ether; 2,3-dicyanonaphthalene at 190℃; for 5h;
1; 1.i
(i) Gallium(III) chloride (5.70 g; 0.032 mol) was dissolved in anhydrous toluene (68 mL) under a slow stream of nitrogen and then the resulting solution was cooled in ice/water. Sodium methoxide (25% in methanol; 23.4 mL) was added slowly with stirring causing a thick white precipitate to form. Upon completion of the addition, the mixture was stirred at room temperature for 1 h and then naphthalene-2,3-dicarbonitrile (22.8 g; 0.128 mol) was added portionwise, followed by triethylene glycol monomethyl ether (65 mL). The thick slurry was distilled for 2 h to remove the methanol and toluene. Once the toluene had distilled off, the reaction mixture became homogeneous and less viscous and stirred readily. Heating was continued for 3 h at 190° C. (internal). The brown/black reaction mixture was cooled to 60° C., diluted with chloroform (150 mL), and filtered under gravity through a sintered glass funnel. The solid residue washed with more chloroform (50 mL) and then a further portion (50 mL) with suction under reduced pressure. The resulting dark green solid was then sequentially washed under reduced pressure with acetone (2×50 mL), DMF (2×50 mL), water (2×50 mL), acetone (2×50 mL), and diethyl ether (2×50 mL). The moist solid was air-dried to a dry powder and then heated under high vacuum at ca. 100° C. for 1 h to complete the drying process. Naphthalocyaninatogallium methoxytriethyleneoxide 3 was obtained as a fine dark green powder (23.14 g; 80%), λmax (NMP) 770 nm.
naphthalocyaninatogallium methoxytriethyleneoxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With gallium(III) trichloride; sodium methylate In methanol; toluene at 0 - 20℃; for 1h;
Stage #2: triethylene glucol monomethyl ether; 2,3-dicyanonaphthalene at 190℃; for 3h;
1.i
(i) Gallium(III) chloride (5.70 g; 0.032 mol) was dissolved in anhydrous toluene (68 mL) under a slow stream of nitrogen and then the resulting solution was cooled in ice/ water. Sodium methoxide (25% in methanol; 23.4 mL) was added slowly with stirring causing a thick white precipitate to form. Upon completion of the addition, the mixture was stirred at room temperature for 1 h and then naphthalene-2,3-dicarbonitrile (22.8 g; 0.128 mol) was added portionwise, followed by Methylene glycol monomethyl ether (65 mL). The thick slurry was distilled for 2 h to remove the methanol and toluene. Once the toluene had distilled off, the reaction mixture became homogeneous and less viscous and stirred readily. Heating was continued for 3 h at 190°C (internal). The brown/black reaction mixture was cooled to 60°C, diluted with chloroform (150 mL), and filtered under gravity through a sintered glass funnel. The solid residue was washed with more chloroform (50 mL) and then a further portion (50 mL) with suction under reduced pressure. The resulting dark green solid was then sequentially washed under reduced pressure with acetone (2'50 mL), DMF (2'50 mL), water (2'50 mL), acetone (2'50 mL), and diethyl ether (2'50 mL). The moist solid was air-dried to a dry powder and then heated under high vacuum at ca. 100°C for 1 h to complete the drying process. Naphthalocyaninatogallium methoxytriethyleneoxide 3 was obtained as a fine dark green powder (23.14 g; 80%),l (NMP) 770 nm. max
naphthalocyaninatogallium methoxytriethyleneoxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; toluene at 20 - 190℃; for 5h; Heating / reflux;
1.i
Examples; 4 quantltavaR = CHaCHzOCHjCWjOCHjGHjOMβScheme 1(i) Galliumαil) chloride (5.70 g; 0.032 mol) was dissolved in anhydrous toluene {68 mL) wnder a slow stream of nitrogen and then the resulting solution was cooled in ice/water. Sodium methoxide (25% in methanol; 23.4 mL) was added alowty with stirring causing a thick white precipitate to form. Upon completion of the addition, the mixture was stifred at room temperature for 1 h and then nφhthalene-2,3- dicarbofljtrile (22.8 g; 0.J28 nW) was added pαrBonwise, followed by Methylene glycol monomethyl ether (65 mL). The thick slurry was distilled for 2 h to remove the methanol and toluene. Once the tojyejje bad distilled off, the reaction mixture became homogeneous and less viscous and stirred readily. Heating was continued for 3 h at 190 °C (internal). The brown/btøck reaction mixture was cooled to 60 0C, diluted with chloroform (ISO mL), and filtered under gravity through a sintered glass funnel. The solid residue was washed with more chloroform (50 mL) and then a further portion (50 mL) with suction under reduced pressure. The resulting dark green solid was then sequentially washed under reduced pressure with acetone (2 x 50 mL), DMF (2 x 50 mL), water (2 x SO mL), acetone (2 x 50 mL), and diethyl ether (2 x 50 mL). The moist solid was air-dried to a dry powder and then bested under high vacuum at ca. 100 "C for I h to complete the drying process. Naphthatooyaninatogsllium methoxymethyleneoxide 3 was obtained as a fine dark green powder (23.X4 g; 80%), λ^ (NMP) 770 pm.
In methanol; toluene at 20 - 190℃; for 5h;
1.i
(i) Gallium(III) chloride (5.70 g; 0.032 mol) was dissolved in anhydrous toluene (68 mL) under a slow stream of nitrogen and then the resulting solution was cooled in ice/water. Sodium methoxide (25% in methanol; 23.4 mL) was added slowly with stirring causing a thick white precipitate to form. Upon completion of the addition, the mixture was stirred at room temperature for 1 h and then naphthalene-2,3-dicarbonitrile (22.8 g; 0.128 mol) was added portionwise, followed by triethylene glycol monomethyl ether (65 mL). The thick slurry was distilled for 2 h to remove the methanol and toluene. Once the toluene had distilled off, the reaction mixture became homogeneous and less viscous and stirred readily. Heating was continued for 3 h at 190° C. (internal). The brown/black reaction mixture was cooled to 60° C., diluted with chloroform (150 mL), and filtered under gravity through a sintered glass funnel. The solid residue was washed with more chloroform (50 mL) and then a further portion (50 mL) with suction under reduced pressure. The resulting dark green solid was then sequentially washed under reduced pressure with acetone (2×50 mL), DMF (2×50 mL), water (2×50 mL), acetone (2×50 mL), and diethyl ether (2×50 mL). The moist solid was air-dried to a dry powder and then heated under high vacuum at ca. 100° C. for 1 h to complete the drying process. Naphthalocyaninatogallium methoxytriethyleneoxide 3 was obtained as a fine dark green powder (23.14 g; 80%), λmax (NMP) 770 nm.
Multi-step reaction with 2 steps
1: sodium hydride / tetrahydrofuran / 12 h / 20 °C
2: formic acid / 2 h / 20 °C
Multi-step reaction with 2 steps
1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C
1.2: 2 h / 0 - 20 °C
2.1: sodium hydroxide / water; acetonitrile / 0.5 h / 20 °C
Multi-step reaction with 2 steps
1: boron trifluoride diethyl etherate / dichloromethane / 3 h / Reflux
2: sodium hydroxide / tetrahydrofuran; water / 12 h / Reflux
Multi-step reaction with 2 steps
1.1: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 2 h / 20 °C
1.2: 12 h / 20 °C
2.1: trifluoroacetic acid; methoxybenzene / dichloromethane / 5 h / 20 °C
Multi-step reaction with 2 steps
1: sodium hydride / tetrahydrofuran / 20 - 25 °C / Cooling with ice
2: trifluoroacetic acid / dichloromethane / 40 °C
With hydrogenchloride; sodium hydrogencarbonate In water
18.A Part A
Part A Preparation of 3,6,9-trioxadecanoic acid (23899IG-154) A 0.5 g quantity of platinum oxide is hydrogenated in 60 ml of water at 25° C. and atmospheric pressure until the uptake of hydrogen ceases. To the resultant mixture is added a mixture of 0.6 g (7.14 mmoles) of sodium bicarbonate and 1.0 g (6.1 mmoles) of triethylene glycol monomethyl ether dissolved in 20 mL of water. Air is bubbled through the above mixture for 4 hr following the consumption of staging material by TLC. The reaction is then filtered though Celite and the Celite washed with water. The combined washes are treated with 7.2 mL (7.2 mmoles) of 1N hydrochloric acid and the resultant solution freeze-dried. The residue is washed with acetone and filtered. The filtrate is evaporated to dryness under vacuum. The residual oil is chromatographed over 100 g of CC-4 silica gel eluted with (50-50)acetone-methylene chloride, collecting 20 mL fractions. Concentration of fractions 11-16 gives 0.92 g of the desired 3,6,9-trioxadecanoic acid. NMR (acetone-d6): δ 3.30 (s, 3H); 3.40-3.75 (m, 8H); 4.12 (s, 2H). TLC: Rf =0.13 in (40-60-2) acetone-hexane-acetic acid.
EXAMPLE 1 methoxytriethylene glycol 3-(3',5'-di-t-butyl-4'-hydroxyphenyl)propionate The aparatus was flushed with nitrogen and charged with 29.2 g of methyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate, 41.1 g of methoxytriethyleneglycol and 10.2 ml of 40% methanol solution of benzyltrimethylammonium methoxide. The reaction was heated for 21/2 hours between 92 and 105 C. at atmospheric pressure and for an additional 1/2 hour at 100 C. at 1 mm pressure. After cooling, the reaction mixture was neutralized with 2.4 ml of glacial acetic acid. The reaction mixture was distilled and the fraction boiling at 200-210 C. at a pressure of 1 to 3 mu was collected as the product. The refractive index of the product at 25 C. was 1.5034. Analysis for C24 H40 O6: % Calculated: C, 67.89; H, 9.50; % Found: C, 68.23; H, 9.36.
naphthalocyaninatogallium methoxytriethyleneoxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; toluene at 190℃; for 5h;
1.i
Gallium(III) chloride (5.70 g; 0.032 mol) was dissolved in anhydrous toluene (68 mL) under a slow stream of nitrogen and then the resulting solution was cooled in ice/water. Sodium methoxide (25% in methanol; 23.4 mL) was added slowly with stirring causing a thick white precipitate to form. Upon completion of the addition, the mixture was stirred at room temperature for 1 h and then naphthalene-2,3-dicarbonitrile (22.8 g; 0.128 mol) was added portionwise, followed by Methylene glycol monomethyl ether (65 mL). The thick slurry was distilled for 2 h to remove the methanol and toluene. Once the toluene had distilled off, the reaction mixture became homogeneous and less viscous and stirred readily. Heating was continued for 3 h at 190 0C (internal). The brown/black reaction mixture was cooled to 60 0C, diluted with chloroform (150 mL), and filtered under gravity through a sintered glass funnel. The solid residue was washed with more chloroform (50 mL) and then a further portion (50 mL) with suction under reduced pressure. The resulting dark green solid was then sequentially washed under reduced pressure with acetone (2 x 50 mL), DMF (2 x 50 mL), water (2 x 50 mL), acetone (2 x 50 mL), and diethyl ether (2 x 50 mL). The moist solid was air-dried to a dry powder and then heated under high vacuum at ca. 100 0C for 1 h to complete the drying process. Naphthalocyaninatogallium methoxytriethyleneoxide 3 was obtained as a fine dark green powder (23.14 g; 80%), λmax (NMP) 770 nm.
2'-({2-[2-(2-methoxyethoxy)ethoxy]ethoxy}carbonyl)-8,12-bis[2-(methoxycarbonyl)ethyl]-2,7,13,17-tetramethyl-18-vinyl-2,21,22,23-tetrahydrobenzo[b]porphyrin-22-carboxylic acid[ No CAS ]
2'-({2-[2-(2-methoxyethoxy)ethoxy]ethoxy}carbonyl)-13,17-bis[2-(methoxycarbonyl)ethyl]-2,7,12,18-tetramethyl-8-vinyl-2,21,22,23-tetrahydrobenzo[b]porphyrin-22-carboxylic acid[ No CAS ]
General procedure: NaH (60% w/w in mineral oil, 3 equiv (for bis-propargylation) or 1.5 equiv (for mono-propargylation)) was added to a solution of appropriate diol 15ba-d or alcohol 19a-d (1 equiv) in anhydrous THF (0.2 M) at 0 C under an N2 atmosphere. A catalytic amount (spatula tip) of Bu4NI (0.05 equiv) and propargyl bromide (3 equiv (for bis-propargylation) or 1.5 equiv (for mono-propargylation)) was added sequentially. The mixture was stirred at rt overnight, before being concentrated under reduced pressure. Purification of the residue by flash column chromatography afforded diynes 16b-e and alkynes 9b-e as pale yellow oils.
82%
With sodium hydroxide; In tetrahydrofuran; at 20℃;Cooling with ice;
General procedure: A dry flask was charged with THF (15 mL), NaOH pellets (2.40 g, 60 mmol), and n-octanol or triethyleneglycol monomethyl ether (15 mmol). The flask was immersed in an ice-bath and the contents stirred for 10 min. before propargyl bromide (2.51 mL, 22.5 mmol) was added dropwise. The reaction mixture was then allowed to stir for 24 h, gradually warming to r.t. The reaction mixture was poured into Et2O (20 mL) and water (50 mL) and the layers were separated. The aqueous layer was further extracted with Et2O (2 × 20 mL), and the combined organic extracts were washed with 10% aq. HCl, followed by sat. NaHCO3 solution and brine, and then dried over MgSO4. Column chromatography (silica gel, Et2O/light petroleum, 10:90) followed by Kulgelrohr distillation gave the desired products.
Stage #1: triethylene glucol monomethyl ether With sodium at 120℃; Inert atmosphere;
Stage #2: chloroacetic acid at 100℃; for 12.3333h; Inert atmosphere;
Stage #1: triethylene glucol monomethyl ether With sodium at 20 - 120℃; Inert atmosphere;
Stage #2: chloroacetic acid at 100℃; for 12h;
1.1 Synthesis of sodium 2,5,8,11-tetraoxatridecan-13-oate (TEGMECH2COO-Na+.
1st Step: Preparation of the Polyethercarboxylic Acid: 15.3 g of Na are dissolved in 260 ml of triethylene glycol monomethyl ether under a protective gas atmosphere while stirring vigorously. The dissolution is firstly carried out at room temperature and the mixture is later heated gradually to about 120° C. After complete dissolution of the Na, the solution is cooled to 100° C. and 30.9 g of chloroacetic acid dissolved in 60 ml of triethylene glycol monomethyl ether are added dropwise. The reaction mixture is then stirred at 100° C. for about 12 hours. Excess triethylene glycol monomethyl ether is then distilled off in an oil pump vacuum (about 10-3 mbar) (boiling point: about 88-90° C.). The cooled residue is subsequently admixed with about 150 ml of water and, after stirring briefly, with 23 ml of 85% strength phosphoric acid. The now clear brown solution is extracted with 3*200 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate. Filtration and removal of the solvent finally gives a dark brown oily liquid. The crude 2,5,8,11-tetraoxatridecan-13-oic acid is purified by distilling it twice in an oil diffusion pump vacuum (about 10-7 mbar; boiling point: 135-145° C.). A colorless viscous liquid is obtained in the end.
Example 1; Example 1 -1; 5.3 g of methallyl dichloride and 11.9 g of tri(ethylene glycol)monomethyl ether) were put into a reactor, and then 60 mL of tetrahydrofuran was added thereto. To the mixture was added dropwise 3.84 g of sodium hydride. The reactor was kept at 65 0C for 12 hr. 5 mL of water was added dropwise to the reactor. The reaction mixture was evaporated under vacuum to remove the tetrahydrofuran. The concentrate was extracted with 100 mL of diethyl ether and 100 mL of water. The organic layer was subjected to column chromatography using ethyl acetate/methanol (100/0-80/20), giving the compound of Formula 12 in a yield of 35%. 1H NMR (250 MHz, CDCl3): delta 5.18 (s, 2H; CH2), 4.01 (s, 4H; CH2(CH2O)2), 3.70-3.58 (m, 24H; OCH2), 3.37 (s, 6H; OCH3)
With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran; dichloromethane at -10 - 20℃;
2.2.3. Synthesis of M-AM4 amide
A solution of MONA (1000 mg, 1.49 mmol), 3,6,9-trioxadecylamine (653 mg, 4.00 mmol) and 1,3-dicyclohexylcarbodiimide (DCC) (515 mg, 2.50 mmol), all dissolved in 25 cm3 dichloromethane and 1-hydroxybenzotriazole (HOBt) (330 mg, 2.44 mmol) dissolved in 10 cm3 tetrahydrofuran were mixed together and stirred at a temperature between 0 °C and -10 °C for 24 h. After this time the reaction mixture was stirred at room temperature for the next 24 h. The solvents were evaporated under reduced pressure to dryness. The residue was dissolved in 2:1 dichloromethane-hexane mixture and filtered off to remove 1,3-dicyclohexylurea as a by-product. The filtrate was evaporated under reduced pressure and purified by chromatography on silica gel (Fluka type 60) to give M-AM4 (778 mg, 64% yield) as a colourless solid glass state.
With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 5h;
4 Example 4: General Procedure for Preparing Acetic Acid-CH2O-[CH2CH2O]n-CH3 (n=3, 6, 12 or 16; Compounds 3-1, 3-2, 3-3 or 3-4)
General procedure: To a solution of CH3O-[CH2CH2O]n-H (n=3, 6, 12 or 16; 12.18 mmol) and bromoacetic acid (13.4 mmol) in THF (24 mL) was added sodium hydride (NaH, 57-63% in oil, 48.72 mmol). The reaction mixture was stirred for 5 h at room temperature. The excess sodium hydride was quenched by the addition of 1N hydrochloric acid (50 mL). The organic solvent was evaporated under reduced pressure. The aqueous solution was extracted with ethyl acetate (30 mL×3). The combined organic layers were dried with MgSO4 and concentrated under reduced pressure to afford acetic acid -CH2O-[CH2CH2O]n-CH3 (n=3, 6, 12 or 16; Compounds 3-1, 3-2, 3-3 or 3-4). (0212) acetic acid -CH2O-[CH2CH2O]3-CH3 (Compound 3-1): 1H NMR (400 MHz, CDCl3) δ 3.37 (s, 3H), 3.55-3.73 (m, 12H), 4.12 (s, 2H).
Sodium hydride (60Wt% in oil, 2.141 g, 53.5 mmol) was added portionwise to a stirring solution of 2-(2-(2-methoxyethoxy)ethoxy)ethanol (8.57 ml, 53.5 mmol) stirring in dioxane (70 mL) at 0C - 5C under N2. This was left to stir for 30 min before 6-fluoropyridin-2- amine (2g, 17.84 mmol) was added in dioxane (10 mL) over 10 min. After addition, reaction was heated to 90C overnight (18h). The reaction was quenched by slow addition of IPA (20 mL) followed by water (50 mL). Dioxane was then removed in vacuo and the residue partitioned between EtOAc and water (100 mL each). The organic phase was washed with saturated brine (2 x 30 mL) and then dried over Na2S04, filtered and concentrated in vacuo to afford the crude product which was purified by chromatography on silica gel (80 g column, DCM:MeOH:NH3, 0 - 10% MeOH to afford a light brown oil. The product was taken up in 1 M HCI (200 mL) and washed with ether (2 x 100 mL). Aqueous was then treated with 2M NaOH to pH 15 and extracted with EtOAc (2 x 100 mL). The organic extracts were combined and washed with saturated brine (1 x 100 mL) and then dried over Na2S04, filtered and concentrated in vacuo affording the sub-title compound (3.52 g). 1 H NMR (DMSO-d6) 400MHz ; δ 7.26 (t, 1 H), 5.97 (d, 1 H), 5.85 (m, 3H), 4.72 (t, 2H), 3.67 (t, 2H), 3.51 (m, 6H), 3.42 (t, 2H), 3.23 (s, 3H). LCMS m/z 258 (M+H)+ (ES+)
Stage #1: triethylene glucol monomethyl ether With sodium
Stage #2: (3-chloropropyl)trimethylsilane With potassium iodide at 90℃;
1S3M3 1S3M3
Triethyleneglycol methyl ether (250g, 1.52 mol) was added to a 1L flask and sodium was slowly added to it in small portions (7.65g, 0.33 mol), each portion was allowed to dissolve completely before adding the next one. Then potassium iodide was added (8g, 0.03 mol), after it was dissolved the mixture was heated to 90°C and chloropropyltrimethylsilane (50g, 0.33 mol) was added and left reacting overnight with strong stirring. The product was extracted with hexane, the hexane was evaporated and the product purified by distillation (111 °C, 0.4 Torr), and then dried with sodium and distilled again.
2-(2-(2-methoxyethoxy)ethoxy)ethyl 2-aminopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With p-toluenesulfonyl chloride In toluene at 126℃; for 4h;
2.1.1 Synthesis of 2-(2-(2-methoxyethoxy)ethoxy)ethyl 2-aminopropanoate
Triethylenglycol methoxy ( 25 ml, 156.21 mmol), L-alanine ( 21.85 g, 245.25 mmol), p-toluene sulfonic acid(32.69 g, 171.83 mmol) and 250 ml of toluene were added in a round bottom flask. The reaction mixture was refluxedat 126 °C for 4h. A solid precipitate was filtered off, and the solvent was evaporated under reduced pressure. Then theproduct was dissolved with 300 ml of chloroform, and the organic layer was extracted three times with NaHCO3 (saturated).Thereafter, the water layer was extracted twice with chloroform. The organic layers were dried with Na2SO4, and thesolvent was evaporated under reduced pressure, obtaining 22.69 g of S6 with a 62% yield.
1-bromo-5-O-mPEG<SUB>3</SUB>-2,3-dichlorobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium hydride; In tetrahydrofuran; at 75℃; for 3.0h;
l -Bromo-2,3-dichloro-5-fluorobenzene (1,4618 g, 5.99 mmol) and mPEG3-OH (1.1097g, 6.76 mmol) was mixed with toluene (25 mL) and removed the solvent. The remaining material was dried under high vacuum for a few minutes. The mixture was dissolved in anhydrous THF (20 mL). 60% Sodium hydride (0.3549 g, 8.87 mmol) was added. The resulting mixture was heated at 75 C for 3 h. The mixture was cooled to room temperature. Saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was concentrated to remove the organic solvent. The remaining mixture was extracted with dichloromethane (3 x 20 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, concentrated. The residue was purified with biotage flash column using 15-100% ethyl acetate/hexane to afford the product (2.057 g, yield: 88%). NMR (500 MHz, Chloroform-i/) delta 7.17 (d, J = 2.9 Hz, 1 H), 7.05 (d, J= 2.8 Hz, IH), 4.16 - 4.07 (m, 2H), 3.89-3.83 (m, 2H), 3.77-3.65 (m, 6H), 3.60-3.55 (m, 2H), 3.41 (s, 3H).
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 48h;
The tetraethylene glycol monomethyl ether (35.4g, 170mmol) and sodium hydride (4g, 170mmol) in anhydrous tetrahydrofuran until no bubbles, and then at 0 3- (methyl tosylate) oxetane (41.2g, 170mmol) was added dropwise to the reaction system, the reaction was added dropwise at room temperature 48 hours after recovery.After the reaction, the reaction solution was diluted with water and extracted by dichloromethane, distilled under reduced pressure to give a colorless liquid.Yield: 70%.
With triethylamine In dichloromethane at 20℃; for 72h;
1.A
10103] To a mixture of cis-5-norbornen-endo-2,3-dicar- boxylic anhydride (1, 16 g, 97.5 mmol) and 2-(2-(2- methoxyethoxy)ethoxy)ethanol (16 g, 97.5 mmol) in dichloromethane (250 mE) at room temp was added slowly triethylamine (14.8 g, 146.2 mmol). The reaction mixture was stirred at room temperature for 3 days. Upon completion of reaction, the mixture was acidified with 6N HC1 (150mE). The organic layer was separated, dried and conc. to getthe product (2) in 90% yield (28.8 g) which was used as suchwithout any further purification. ‘H NMR ((CD3)2C0, 300 MHz): ö 1.35 (m, 2H), 2.03 (m, 1H), 3.08 (s, 2H), 3.27 (s, 3H), 3.31 (m, 2H), 3.46 (m, 2H), 3.56 (m, 8H), 4.03 (m, 2H),6.08 (m, 1H), 6.18 (m, 1H). To a solution of compound (2) (15.43 g, 47 mmol) in dichloromethane (200 mE) was added as meta-chloroperoxybenzioc acid (mCPI3A) (17.3 g, 100 mmol). The reaction mixture was stirred at room tempera-ture for 16 h. After the reaction completion, ethyl acetate (50mE) and water (5 mE) was added to the mixture. The organic layer was separated, washed with dilute NaHCO3 followed by water (50 mE). The organic layer was evaporated to provide white solids. Redissolved the white solids in dichloromethane and passed through silica plug eluting with dichloromethane. The organic part was evaporated to yield the product (3) in 89% yield (14 g). ‘H NMR (CDC13, 300 MHz): ö 1.61 (d, 1H), 2.20 (d, 1H), 2.77 (m, 2H), 3.06 (m, 1H), 3.26 (t, 1H), 3.39 (s, 3H), 3.57 (m, 2H), 3.64 (m, 9H),4.18 (m, 1H), 4.3 (s, 1H), 4.42 (m, 1H), 4.5 (d, 1H). To the solution of compound (3) (20 g, 60 mmol) in acetonitrile (100 mE) was added pyridine (5.24 g, 66 mmol) followed by slow addition of 2-bromo-2,2-difluoroacetyl chloride (11.82 g, 61 mmol). The resulting reaction mixture was stirred overnight at room temp. Upon completion of reaction, solvent was evaporated, the residue was redissolved in dichloromethane (300 mE), washed with iN HC1 (100 mE) followed by Millipore deionized water (100 ml). The organic part was evaporated to yield crude product (4) in 85% yield (25 g) which was used as such without further purification. ‘H NMR (CDC13, 300 MHz): ö 1.39 (d, 1H), 1.72 (d, 1H), 2.53 (m, 2H), 2.79 (m, 1H), 3.0 (m, 4H), 3.26 (m, 2H), 3.28 (m, 8H), 3.94 (m, 2H), 4.31 (d, 1H), 5.14 (s, 1H). ‘9F NMR: ö -61.77.
With potassium carbonate; In toluene; for 96h;Reflux; Inert atmosphere;
0.07 mmol triethylene glycol monomethyl ether solved in1 ml toluene and 300 muL solution added to a mixture of SiPcCl2 (0.087 mmol), sulindac (0.09 mmol) and dry potassiumcarbonate (0.26 mmol) in toluene (30 mL) at the sametime. And then reaction solution refluxed with stirring for4 day under argon atmosphere. After the reaction mixturewas cooled at room temperature, filtered and washed withtoluene. The solvent was evaporated under reduced pressure.The crude product was purified by column chromatographyon aluminium oxide with CH2Cl2:MeOH (200:1) as solventsystem and by preparative TLC on silica with CH2Cl2:MeOH(200:1) as solvent system. At first step of the purificationsymmetric derivative (1) and mixture of asymmetric Pc derivative(2) and symmetric derivative (3) were obtained was columnchromatography. At the second step, 2 and 3 was purelyobtained by preparative TLC on silica with CH2Cl2:Ethylacetate (7:5) as solvent system. Yield of 2 0.010 g(10.8%). IR (ATR) vmax/cm-1: 3062 (Ar-H), 2923-2859(Aliph. C-H), 1684, 1602, 1524, 1467, 1430, 1336, 1290,1196, 1165, 1122, 1081, 949, 912, 760. 1H NMR (CDCl3) (delta ppm): 9.7 (s, 8H, Ar-H), 8.3 (s, 8H, Ar-H), 8.0 (s, 4H, Ar-H),6.7 (m, 1H, Ar-H), 6.3 (s, 1H, Ar-H), 6.0 (m, 1H, Ar-H), 4.4(m, 1H, Ar-H), 3.2 (m, 5H, aliph-H), 2.9 (m, 5H, aliph-H), 2.5(s, 2H, aliph-H), 1.7 (s, 2H, aliph-H), 0.7 (s, 2H, aliph-H), 0.3(s, 2H, aliph-H), 0.2 (s, 3H, aliph-H), -1,8 (s, 2H, aliph-H).ESI-MS (m/z:1061.22 1127.25 g/mol) ESI-MS (m/z) Calc.1061.22 for C59H49FN8O7SSi; Found: 1127.25 [M + 4H +K + Na]+.
ricinoleic acid triethylene glycol methyl ether ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With sodium hydrogensulfate monohydrate; In dichloromethane; at 150℃; for 0.416667h;Microwave irradiation; High pressure;
General procedure: <strong>[141-22-0]Ricinoleic acid</strong> (10.0 mmol) 1a, glycol ethers 2a-2i (12.0 mmol) and DCM (5.0 mL), and NaHSO4 · H2O (0.01% mol) were added into a dry 10.0-mL microwave reaction tube, which was put into a microwave reactor. The desired product was afforded after 25 min at 150 C (Scheme 2). The reaction progress was followed by a thin-layer chromatography and the crude product was purified on column chromatography of silica gel using ethyl acetate-petroleum ether (1:7) as eluent. All products were characterized by 1H NMR, 13C NMR, FTIR, and high resolution mass spectrometer (HRMS), and spectrum data of 3a-3i were listed.
Stage #1: bis(trichloromethyl) carbonate; phenythoin With dmap In tetrahydrofuran at 0℃; for 0.5h;
Stage #2: triethylene glucol monomethyl ether In tetrahydrofuran at 20 - 60℃;
2 Synthesis of mPEGn-Carbamate-Phenyloin Compounds
General procedure: (0192) Briefly, in a 250 mL round bottom flask 5,5-diphenylhydantoin (0.252 g, 0.999 mmol) was dissolved in anhydrous THF (tetrahydrofuran). DMAP (4-dimethylaminopyridine, 0.122 g, 0.999 mmol) was added and the reaction mixture cooled to 0° C. After cooling, triphosgene (0.296 g, 0.999 mmol) was added and the reaction stirred for 30 minutes. The flask was then warmed to room temperature and charged with mPEG3-OH (246 mg, 1.498 mmol). The reaction was allowed to stir overnight at 60° C. HPLC was used to monitor the reaction mixture. Upon reaction completion an additional 150 mL DCM was added. The organic layer was washed with water (100 mL) and dried over Na2SO4. The solvent was removed under reduced pressure. Both LC/MS and NMR confirmed the presence Compound 2a (which was relatively unstable and did decompose upon purification).
4,6-dichloro-2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
Under nitrogen, sodium hydride (1 eq)And 2- (2- (2-methoxyethoxy) ethox y) ethanol (1 eq)Is added to the anhydride THF and stirred for 1 hour in an ice bath.Then, 4,6-dichloro-2-methanesulfonyl-pyrimidine (1.5 eq) is dissolved in THF and stirred overnight. After completion of the reaction, the solvent was dried with a rotary evaporator, and the EA layer was separated from the separatory funnel by using NaHCO 3 solution / EA and dried by drying with MgSO 4. Filter solution was removed by rotary evaporator and column. Yield: white oil 84%.
1,3,6,9,12-pentaoxa-2-thiacyclotetradecane 2,2-dioxide[ No CAS ]
[ 4437-01-8 ]
Yield
Reaction Conditions
Operation in experiment
98%
General procedure: (Using the synthesis of 7e as an example). Under the atmosphere of N2, to a suspension of NaH (750 mg, 60% dispersed in mineral oil, 18.72 mmol, in 60 mL THF) at 0 C was added a solution of monomethoxy M-PEG 7b (1.50 g, 12.48 mmol) in THF (20 mL). After the addition, the stirring mixture was warmed to rt and stirred for 30 min. Then, a solution of macrocyclic sulfate 6a (4.80 g, 18.72 mmol) in THF (20 mL) was added. The resulting mixture was stirred for 12 h at rt, and concentrated under vacuum. The resulting residue was dissolved in water (50 mL), and washed with CH2Cl2. The aqueous layer was concentrated and then dissolved in THF (100 mL). Then, water (0.45 mL, 24.96 mmol) and H2SO4 (0.66 mL, 12.48 mmol) were added and the resulting mixture was refluxed for 3 h. The reaction was neutralized with saturated NaHCO3 solution, extracted with CH2Cl2. The organic layers were dried over anhydrous Na2SO4, concentrated under vacuum, and purified by flash chromatography on silica gel (CH2Cl2/MeOH = 20/1) to give monomethoxy M-PEG 7e as clear oil (3.04 g, 82% yield).
89%
General procedure: (Using the synthesis of M-PEG 7 as an example). Under the atmosphere of N2, to a suspension of NaH (1.0 g, 60% dispersed in mineral oil, 25.0 mmol) in THF (60 mL) at 0 was added a solution of M-PEG 5 (2.0 g, 16.6 mmol) in THF (20 mL). After the addition, the stirring mixture was warmed to rt and stirred for 30 min. Then, a solution of macrocyclic sulfate 8 (5.1 g, 20.0 mmol) in THF (20 mL) was added. The resulting mixture was stirred for 12 h at rt, and concentrated under vacuum. The resulting residue was dissolved in water (50 mL), and washed with CH2Cl2. The aqueous layer was concentrated and then dissolved in THF (100 mL). Then, water (0.6 mL, 33.3 mmol) and H2SO4 (0.4 mL, 8.4 mmol) were added to the reaction mixture and the resulting mixture was refluxed for 3 h. The reaction was neutralized with saturated NaHCO3 solution, extracted with CH2Cl2. The organic layers were dried over anhydrous Na2SO4, concentrated under vacuum, and purified by flash chromatography on silica gel (CH2Cl2/MeOH = 20/1) to give M-OEG 7 as clear oil (4.3 g, 88% yield).
ethyl bis(2-(2-(2-methoxyethoxy)ethoxy)ethyl)phosphate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20.5 g
With triethylamine; In 1,2-dimethoxyethane; at 20℃;
In a 200 mL beaker, 20.6 g of triethylene glycol monomethyl ether, 12.4 g of triethylamine, and 100 g of dimethoxyethane were charged. While stirring, a solution prepared by diluting 10 g of ethyl dichlorophosphate to 50% with 10 g of dimethoxyethane was slowly added dropwise at room temperature. It was verified that heat is gradually generated during dropwise addition, and a white precipitate is precipitated in the system. Thereafter, stirring was performed at room temperature for 1 hour. The white precipitate was then separated into a white solid and a filtrate by performing filtration under reduced pressure. Thereafter, dimethoxyethane was distilled off from the filtrate under reduced pressure. Subsequently, the thus obtained liquid was dissolved by adding dimethoxyethane, and purified by subjecting to flash chromatography using a silica gel to obtain 20.5 g of ethyl bis(2-(2-(2-methoxyethoxy)ethoxy))phosphate as a colorless transparent liquid
1,1'-(4-bromo-1,2-phenylene)bis(2,5,8,11-tetraoxadodecane)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In 1,4-dioxane; at 20℃; for 0.333333h;
4-Bromo-l ,2-bis(bromomethyl)benzene (250 mg) and 2-(2-(2-methoxyethoxy)ethoxy)ethanol (263 mg) were dissolved in dioxane (8 mL). Sodium hydride (60percent, 64.2 mg) was added, and the solution was mixed at ambient temperature. After 20 minutes, the solvent was removed under vacuum. The residue was suspended in ethyl acetate (20 mL), washed with brine (5 mL) and dried over anhydrous sodium sulfate. The solution was concentrated and syringe filtered. The remaining solvent was then removed under vacuum, and the material was utilized without further purification. NMR (500 MHz, dimethylsulfoxide-efe) delta ppm 7.57 (d, IH), 7.48 (dd, IH), 7.33 (d, IH), 4.54 (s, 2H), 4.50 (s, 2H), 3.60- 3.55 (m, 8H), 3.53-3.50 (m, 12H), 3.44-3.40 (m, 4H), 3.24-3.23 (m, 6H). MS (ESI) m/z 526.2 (M+H)+.
2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With diisopropyl (E)-azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 50℃; for 48h;
2-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (8.57 mL) and 2-(2-(2- methoxyethoxy)ethoxy)ethanol (7.58 mL) were added to tetrahydrofuran (200 mL). Triphenylphosphine (1 1.80 g) was added, and the mixture was stirred until it dissolved. (E)-Diisopropyldiazene-l,2- dicarboxylate (8.86 mL) was added, and the mixture was stirred at 50 C for two days. The mixture was cooled, and the solvent was removed under reduced pressure. Diethyl ether (100 mL) and heptanes (50 mL) were added. The mixture was stirred vigorously to precipitate triphenylphosphine oxide. The mixture was filtered, concentrated and purified by flash column chromatography on silica gel using a 30- 60% gradient of ethyl acetate in heptanes to provide the title compound. 'H NMR (400 MHz, DMSO-cfe) delta ppm 7.48 (dd, 1H), 7.40 (td, 1H), 6.95-6.92 (m, 2H), 4.04 (t, 2H), 3.75 (t, 2H), 3.69 (t, 2H), 3.54-3.48 (m, 4H), 3.43-3.41 (m, 2H), 3.23 (s, 3H), 1.22-1.12 (m, 12H).
3,4-dibromo-1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-1H-pyrrole-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52.2%
511 mg (1.95 mmol) of triphenylphosphine was dissolved in 5 mL of anhydrous THF and stirred.0.38 mL (1.95 mmol) of azoxylene diisopropyl ester was added dropwise to the above solution, and stirred at -78 C for 5 min.After 0.25 mL (1.56 mmol) of triethylene glycol monomethyl ether was dissolved in 5 mL of anhydrous THF, the reaction mixture was added dropwise to the azoazolyl diisopropyl ester solution, and stirring was continued at -78 C for 5 min.Thereafter, neopentyl alcohol 121 mg (1.37 mmol) was dissolved in 2 mL of anhydrous THF, added to triethylene glycol monomethyl ether, and stirred at -78 C for 5 min.Finally, 497 mg (1.95 mmol) of <strong>[1122-10-7]dibromomaleimide</strong> was added to the above reaction solution, stirred at -78 C for 10 min, then transferred to room temperature, and magnetically stirred at room temperature for 20 h.The crude product was purified by column chromatography (volume ratio EA:PA=1:10-1:4), and then isolated by medium pressure to obtain the white target product, intermediate 1 325 mg, yield 52.2%.
Stage #1: triethylene glucol monomethyl ether With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1h;
Stage #2: ethyl bromoacetate In tetrahydrofuran; mineral oil at 20℃; for 3h;
Stage #3: With sodium hydroxide In water at 20℃; for 1h;
6 Synthesis of Intermediate 6a
Triethylene glycol monomethyl ether (10 g, 60.9 mmol) was dissolved in tetrahydrofuran (100 mL); and sodium hydride (3.2 g, 60%, 79.17 mmol) in batches was added at 0° C. Afterwards, the mixture was stirred at room temperature for 1 h. Ethyl bromoacetate (20.1 g, 122 mmol) was added dropwise therein; the mixture was reacted at room temperature for 3 h; and water (100 mL) was directly added to the reaction. The reaction was extracted with dichloromethane, and the organic phase was dried using anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Then, water (100 mL) and solid sodium hydroxide (3 g, 73 mmol) were added therein. The mixture was stirred at room temperature for 1 h and extracted 2 times with ethyl acetate. The aqueous phase was adjusted to pH=2 to 3 with diluted HCl and then extracted 5 times with a mixed solvent of dichloromethane/isopropanol (V/V=10:1); and the organic phase was dried using anhydrous sodium sulfate and concentrated to dryness under reduced pressure to yield a crude product. The crude product was purified using silica gel column chromatography (DCM:CH3OH=100:1 to 20:1) to yield compound 6a (yield: 10 g, 74%).
1-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]gallium-naphthalocyanine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41 g
With sodium In methanol; toluene at 170℃; for 5h;
1.a a) l-[2-[2-(2-Meth oxyet h oxy) eth oxy] et h oxy] Ga-naphthalocyanine (C-l)
6.2 g sodium are dissolved in 200 g methanol and slowly added to a solution of 15.0 g gallium chloride in 250 g toluene at room temperature. To the resulting suspension is added a mixture of 62 g naphthalene-2, 3-dicarbonitrile, 240 g triethyleneglycol- monomethylether and 240 g toluene. Toluene and the excess of methanol are distilled off under reduced pressure and the reaction mixture is stirred at 170° C for 5 hours. The suspension is cooled to 80° C, 250 g DMF is added and then further cooled to room temperature. The green solid is collected by filtration, successively washed with DM F, acetone and water and then dried (yield: 41 g; dark green powder). b) 3-[3-[4-[l-[4-(2,3-Dihydroxypropoxy)phenyl]-l-methyI-ethyI]phenoxy]-2-hy- droxy-propoxy] Ga-naphthalocyanine (lh) 5 g of cpd. (C-l) and 15 g 3- [4- [1- [4- (2, 3-dihydroxypropoxy) phenyl] -1-methyl- ethyl] phenoxy]propane-l,2-diol are mixed under nitrogen atmosphere and under stir ring slowly heated up to 150° C. The mixture is kept at that temperature for 18 hours, then allowed to cool down. DMF and water are added and the remaining dark green solid is separated by filtration, washed successively with DMF, acetone and water and dried over night at 60° C in an oven under vacuum (yield 5.3 g; dark green powder).
1-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]gallium-naphthalocyanine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41 g
With methanol; natrium In toluene at 170℃; for 5h;
1.a a) 1-[2-[2-(2-Methoxyethoxy)ethoxy]ethoxy] Ga-naphthalocyanine (cpd. CC-1 (crude))
6.2 g sodium are dissolved in 200 g methanol and slowly added to a solution of 15.0 g gallium chloride in 250 g toluene at room temperature. To the resulting suspension is added a mixture of 62 g naphthalene-2, 3-dicarbonitrile, 240 g triethyleneglycol- monomethylether and 240 g toluene. Toluene and the excess of methanol are distilled off under reduced pressure and the reaction mixture is stirred at 170° C for 5 hours. The suspension is cooled to 80°C, 250 g DMF is added and then further cooled to room temperature. The green solid is collected by filtration, successively washed with DMF, acetone and water and then dried (yield: 41 g; dark green powder). The obtained particles of compound (CC-1) have a number average particle size of 81 nm with standard deviation being 102 nm, D90 = 152.5 nm. The particle size is measured with transmission electron microscopy (TEM).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
