* 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 DMF (N,N-dimethyl-formamide) at 20℃; for 1 h; Stage #2: at 20℃; for 3.5 h;
To a stirred solution of non-polydispersed compound 11 (35.7 mmol) in dry DMF (25.7 ML), under N2 was added in portion a 60percent dispersion of NaH in mineral oil, and the mixture was stirred at room temperature for 1 hour.To this salt 12 was added a solution of non-polydispersed mesylate 9 (23.36) in dry DMF (4 ml) in a single portion, and the mixture was stirred at room temperature for 3.5 hours.Progress of the reaction was monitored by TLC (12percent CH3OH-CHCl3).The reaction mixture was diluted with an equal amount of 1N HCl, and extracted with ethyl acetate (2*20 ml) and discarded.Extraction of aqueous solution and work-up gave non-polydispersed polymer 10 (82-84percent yield).
41%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran for 1.5 h;
To a solution of non-polydispersed tetraethylene glycol (51.5 g, 0.27 mol) in THF (1L) was added potassium t-butoxide (14.8 g, 0.13 mol, small portions over 30 min). The reaction mixture was then stirred for 1 h and then 24 (29.15 g, 0.12 mol) dissolved in THF (90 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, 200 mL) and evaporated to dryness. The oil was then dissolved in HCl (250 mL, 1 N) and washed with ethyl acetate (250 mL) to remove excess 24. Additional washings of ethyl acetate (125 mL) may be required to remove remaining 24. The aqueous phase was washed repetitively with CH2Cl2 (125 mL volumes) until most of the 25 has been removed from the aqueous phase. The first extraction will contain 24, 25, and dicoupled side product and should be back extracted with HCl (125 mL, 1N). The organic layers were combined and evaporated to dryness. The resultant oil was then dissolved in CH2Cl2 (100 mL) and washed repetitively with H20 (50 mL volumes) until 25 was removed. The aqueous fractions were combined, total volume 500 mL, and NaCl was added until the solution became cloudy and then was washed with CH2Cl2 (2.x.500 mL). The organic layers were combined, dried MgSO4, and evaporated to dryness to afford a the non-polydispersed title compound as an oil (16.9 g, 41percent yield). It may be desirable to repeat one or more steps of the purification procedure to ensure high purity.
41%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran for 1.5 h; Stage #3: With hydrogenchloride In water
To a solution of monodispersed tetraethylene glycol (51.5 g, 0.27 mol) in THF (1L) was added potassium t-butoxide (14.8 g, 0.13 mol, small portions over 30 min). The reaction mixture was then stirred for 1 h and then 9 (29.15 g, 0.12 mol) dissolved in THF (90 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, 200 mL) and evaporated to dryness. The oil was then dissolved in HCl (250 mL, 1 N) and washed with ethyl acetate (250 mL) to remove excess 9. Additional washings of ethyl acetate (125 mL) may be required to remove remaining 9. The aqueous phase was washed repetitively with CH2Cl2 (125 mL volumes) until most of the compound 18 has been removed from the aqueous phase. The first extraction will contain 9, 10, and dicoupled side product and should be back extracted with HCl (125 mL, 1N). The organic layers were combined and evaporated to dryness. The resultant oil was then dissolved in CH2Cl2 (100 mL) and washed repetitively with H2O (50 mL volumes) until 10 was removed. The aqueous fractions were combined, total volume 500 mL, and NaCl was added until the solution became cloudy and then was washed with CH2Cl2 (2.x.500 mL). The organic layers were combined, dried MgSO4, and evaporated to dryness to afford the monodispersed compound 10 as an oil (16.9 g, 41percent yield). It may be desirable to repeat one or more steps of the purification procedure to ensure high purity.
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
3
[ 74654-05-0 ]
[ 68999-61-1 ]
[ 4437-01-8 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: at 20℃; for 3.5 h; Stage #2: With hydrogenchloride In water
To a stirred solution of monodispersed tetraethylene glycol (35.7 mmol) in dry DMF (25.7 ML), under N2 was added in portion a 60percent dispersion of NaH in mineral oil, and the mixture was stirred at room temperature for 1 hour.To the resulting sodium salt of the tetraethylene glycol was added a solution of monodispersed mesylate 29 (23.36) in dry DMF (4 ml) in a single portion, and the mixture was stirred at room temperature for 3.5 hours.Progress of the reaction was monitored by TLC (12percent CH3OH-CHCl3).The reaction mixture was diluted with an equal amount of 1N HCl, and extracted with ethyl acetate (2*20 ml) and discarded.Extraction of aqueous solution and work-up gave monodispersed heptaethylene glycol monomethyl ether 30 (82-84percent yield). Oil; Rf 0.46 (methanol:chloroform=3:22); MS m/z calc'd for C15H32O8 340.21 (M++1), found 341.2.
With sodium hydride In tetrahydrofuran at 20℃; for 2 h;
To a solution of hexa(ethylene glycol)(10 g, 35 mmole) and 2-bromoethyl methyl ether (4.9 g, 35 mmole) in THF (100 mL) was slowly added sodium hydride (2.55 g, 106 mmole). The solution was stirred at room temperature for two hours. HPLC indicated that mPEG7-OH was formed in about 54percent yield. The reaction was then stopped by the addition of diluted hydrochloride acid to destroy excess sodium hydride. All solvents were removed using a rotary evaporator to give a brown sticky liquid. Pure mPEG7-OH was obtained as a colorless liquid (4.9 g, 41percent isolated yield) by using semi-preparative HPLC (20 cm.x.4 cm, C18 column, acetonitrile and water as mobile phases). 1H NMR (CDCl3): 2.57 ppm (triplet, 1 H, OH); 3.38 ppm (singlet, 3 H, CH3O); 3.62 ppm (multiplet, 30 H, OCH2CH2).
With sodium chloride In tetrahydrofuran; hydrogenchloride; dichloromethane; ethyl acetate
Example 20 Heptaethylene glycol monomethyl ether (25) To a solution of non-polydispersed tetraethylene glycol (51.5 g, 0.27 mol) in THF (1L) was added potassium t-butoxide (14.8 g, 0.13 mol, small portions over -30 min). The reaction mixture was then stirred for lh and then 24 (29.15 g, 0.12 mol) dissolved in THF (90 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, ~200 mL) and evaporated to dryness. The oil was then dissolved in HCl (250 mL, 1 N) and washed with ethyl acetate (250 mL) to remove excess 24. Additional washings of ethyl acetate (125 mL) may be required to remove remaining 24. The aqueous phase was washed repetitively with CH2Cl2 (125 mL volumes) until most of the 25 has been removed from the aqueous phase. The first extraction will contain 24, 25, and dicoupled side product and should be back extracted with HCl (125 mL, 1N). The organic layers were combined and evaporated to dryness. The resultant oil was then dissolved in CH2Cl2 (100 mL) and washed repetitively with H2O (50 mL volumes) until 25 was removed. The aqueous fractions were combined, total volume 500 mL, and NaCl was added until the solution became cloudy and then was washed with CH2Cl2 (2*500 mL). The organic layers were combined, dried MgSO4, and evaporated to dryness to afford a the non-polydispersed title compound as an oil (16.9 g, 41percent yield). It may be desirable to repeat one or more steps of the purification procedure to ensure high purity.
41%
With sodium chloride In tetrahydrofuran; hydrogenchloride; dichloromethane; ethyl acetate
Example 20 Heptaethylene Glycol Monomethyl Ether (25) To a solution of non-polydispersed tetraethylene glycol (51.5 g, 0.27 mol) in THF (1L) was added potassium t-butoxide (14.8 g, 0.13 mol, small portions over ~30 min). The reaction mixture was then stirred for lh and then 24 (29.15 g, 0.12 mol) dissolved in THF (90 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2,~200 mL) and evaporated to dryness. The oil was then dissolved in HCl (250 mL, 1 N) and washed with ethyl acetate (250 mL) to remove excess 24. Additional washings of ethyl acetate (125 mL) may be required to remove remaining 24. The aqueous phase was washed repetitively with CH2Cl2 (125 mL volumes) until most of the 25 has been removed from the aqueous phase. The first extraction will contain 24, 25, and dicoupled side product and should be back extracted with HCl (125 mL, 1N). The organic layers were combined and evaporated to dryness. The resultant oil was then dissolved in CH2Cl2 (100 mL) and washed repetitively with H2O (50 mL volumes) until 25 was removed. The aqueous fractions were combined, total volume 500 mL, and NaCl was added until the solution became cloudy and then was washed with CH2Cl2 (2*500 mL). The organic layers were combined, dried MgSO4, and evaporated to dryness to afford a the non-polydispersed title compound as an oil (16.9 g, 41percent yield). It may be desirable to repeat one or more steps of the purification procedure to ensure high purity.
Phosphoric acid 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluoro-decyl ester bis-(2-{2-[2-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethyl) ester[ No CAS ]
Phosphoric acid 6,6,7,7,8,8,9,9,10,10,11,11,12,12,13,13,13-heptadecafluoro-tridecyl ester bis-(2-{2-[2-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethyl) ester[ No CAS ]
To a stirred solution of monodispersed tetraethylene glycol (35.7 mmol) in dry DMF (25.7 ML), under N2 was added in portion a 60% dispersion of NaH in mineral oil, and the mixture was stirred at room temperature for 1 hour.To the resulting sodium salt of the tetraethylene glycol was added a solution of monodispersed mesylate 29 (23.36) in dry DMF (4 ml) in a single portion, and the mixture was stirred at room temperature for 3.5 hours.Progress of the reaction was monitored by TLC (12% CH3OH-CHCl3).The reaction mixture was diluted with an equal amount of 1N HCl, and extracted with ethyl acetate (2*20 ml) and discarded.Extraction of aqueous solution and work-up gave monodispersed heptaethylene glycol monomethyl ether 30 (82-84% yield). Oil; Rf 0.46 (methanol:chloroform=3:22); MS m/z calc'd for C15H32O8 340.21 (M++1), found 341.2.
With sodium hydride; In tetrahydrofuran; at 20℃; for 2h;
To a solution of hexa(ethylene glycol)(10 g, 35 mmole) and 2-bromoethyl methyl ether (4.9 g, 35 mmole) in THF (100 mL) was slowly added sodium hydride (2.55 g, 106 mmole). The solution was stirred at room temperature for two hours. HPLC indicated that mPEG7-OH was formed in about 54% yield. The reaction was then stopped by the addition of diluted hydrochloride acid to destroy excess sodium hydride. All solvents were removed using a rotary evaporator to give a brown sticky liquid. Pure mPEG7-OH was obtained as a colorless liquid (4.9 g, 41% isolated yield) by using semi-preparative HPLC (20 cm×4 cm, C18 column, acetonitrile and water as mobile phases). 1H NMR (CDCl3): 2.57 ppm (triplet, 1 H, OH); 3.38 ppm (singlet, 3 H, CH3O); 3.62 ppm (multiplet, 30 H, OCH2CH2).
Example 3 3,6,9,12,15,18,21-Heptaoxadocosanol (10) (m=4) Oil; Rf 0.46 (methanol:chloroform=3:22); MS m/z calc'd for C15H32O8 340.21 (M++1), found 341.2.
Example 3 3,6,9,12,15,18,21-Heptaoxadocosanol (10) (m=4) Oil; Rf 0.46 (methanol: chloroform=3:22); MS m/z calc'd for C15H32O8 340.21 (M++1), found 341.2.
Example 3 3,6,9,12,15,18,21-Heptaoxadocosanol (10) (m=4) Oil; Rf 0.46 (methanol:chloroform=3:22); MS m/z calc'd for C15H32O8 340.21 (M++1), found 341.2.
30
mesylate of triethylene glycol monomethyl ether[ No CAS ]
[ 112-60-7 ]
[ 4437-01-8 ]
Yield
Reaction Conditions
Operation in experiment
41%
With sodium chloride; In tetrahydrofuran; hydrogenchloride; dichloromethane; ethyl acetate;
Example 20 Heptaethylene glycol monomethyl ether (25) To a solution of non-polydispersed tetraethylene glycol (51.5 g, 0.27 mol) in THF (1L) was added potassium t-butoxide (14.8 g, 0.13 mol, small portions over -30 min). The reaction mixture was then stirred for lh and then 24 (29.15 g, 0.12 mol) dissolved in THF (90 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, ~200 mL) and evaporated to dryness. The oil was then dissolved in HCl (250 mL, 1 N) and washed with ethyl acetate (250 mL) to remove excess 24. Additional washings of ethyl acetate (125 mL) may be required to remove remaining 24. The aqueous phase was washed repetitively with CH2Cl2 (125 mL volumes) until most of the 25 has been removed from the aqueous phase. The first extraction will contain 24, 25, and dicoupled side product and should be back extracted with HCl (125 mL, 1N). The organic layers were combined and evaporated to dryness. The resultant oil was then dissolved in CH2Cl2 (100 mL) and washed repetitively with H2O (50 mL volumes) until 25 was removed. The aqueous fractions were combined, total volume 500 mL, and NaCl was added until the solution became cloudy and then was washed with CH2Cl2 (2*500 mL). The organic layers were combined, dried MgSO4, and evaporated to dryness to afford a the non-polydispersed title compound as an oil (16.9 g, 41% yield). It may be desirable to repeat one or more steps of the purification procedure to ensure high purity.
41%
With sodium chloride; In tetrahydrofuran; hydrogenchloride; dichloromethane; ethyl acetate;
Example 20 Heptaethylene Glycol Monomethyl Ether (25) To a solution of non-polydispersed tetraethylene glycol (51.5 g, 0.27 mol) in THF (1L) was added potassium t-butoxide (14.8 g, 0.13 mol, small portions over ~30 min). The reaction mixture was then stirred for lh and then 24 (29.15 g, 0.12 mol) dissolved in THF (90 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2,~200 mL) and evaporated to dryness. The oil was then dissolved in HCl (250 mL, 1 N) and washed with ethyl acetate (250 mL) to remove excess 24. Additional washings of ethyl acetate (125 mL) may be required to remove remaining 24. The aqueous phase was washed repetitively with CH2Cl2 (125 mL volumes) until most of the 25 has been removed from the aqueous phase. The first extraction will contain 24, 25, and dicoupled side product and should be back extracted with HCl (125 mL, 1N). The organic layers were combined and evaporated to dryness. The resultant oil was then dissolved in CH2Cl2 (100 mL) and washed repetitively with H2O (50 mL volumes) until 25 was removed. The aqueous fractions were combined, total volume 500 mL, and NaCl was added until the solution became cloudy and then was washed with CH2Cl2 (2*500 mL). The organic layers were combined, dried MgSO4, and evaporated to dryness to afford a the non-polydispersed title compound as an oil (16.9 g, 41% yield). It may be desirable to repeat one or more steps of the purification procedure to ensure high purity.
mesylate of triethylene glycol monomethyl ether[ No CAS ]
[ 4437-01-8 ]
[ 477775-58-9 ]
Yield
Reaction Conditions
Operation in experiment
44%
With NaH; In methanol; ethyl acetate; toluene;
6-{2-[2-(2-{2-[2-(2-Benzyloxyethoxy)ethoxy]ethoxy}-ethoxy)-ethoxy]-ethoxy}-hexanoic acid ethyl ester (3). Sodium hydride (3.225 g or a 60% oil dispersion, 80.6 mmol) was suspended in 80 ml of anhydrous toluene, placed under a nitrogen atmosphere and cooled in an ice bath. A solution of the monodispersed alcohol 9 (27.3 g, 73.3 mmol) in 80 ml dry toluene was added to the NaH suspension. The mixture was stirred at 0 C. for thirty minutes, allowed to come to room temperature and stirred for another five hours, during which time the mixture became a clear brown solution. The monodispersed mesylate 10 (19.21 g, 80.6 mmol) in 80 ml dry toluene was added to the NaH/alcohol mixture, and the combined solutions were stirred at room temperature for three days. The reaction mixture was quenched with 50 ml methanol and filtered through basic alumina. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, gradient elution: 3/1 ethyl acetate/hexanes to ethyl acetate) to yield the monodispersed compound 3 as a pale yellow oil (16.52 g, 44%). FAB MS: m/e 515 (M+H).
44%
With NaH; In methanol; ethyl acetate; toluene;
6-{2[-2-(2-{2-[2-(2-Benzyloxyethoxy) ethoxy]ethoxy}-ethoxy)-ethoxy]-ethoxy}-hexanoic acid ethyl ester (3). Sodium hydride (3.225 g or a 60% oil dispersion, 80.6 mmol) was suspended in 80 ml of anhydrous toluene, placed under a nitrogen atmosphere and cooled in an ice bath. A solution of the monodispersed alcohol 9 (27.3 g, 73.3 mmol) in 80 ml dry toluene was added to the NaH suspension. The mixture was stirred at 0 C. for thirty minutes, allowed to come to room temperature and stirred for another five hours, during which time the mixture became a clear brown solution. The monodispersed mesylate 10 (19.21 g, 80.6 mmol) in 80 ml dry toluene was added to the NaH/alcohol mixture, and the combined solutions were stirred at room temperature for three days. The reaction mixture was quenched with 50 ml methanol and filtered through basic alumina. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, gradient elution: 3/1 ethyl acetate/hexanes to ethyl acetate) to yield the monodispersed compound 3 as a pale yellow oil (16.52 g, 44%). FAB MS: m/e 515 (M+H).
44%
With NaH; In methanol; ethyl acetate; toluene;
6-{2-[2-(2-{2-[2-(2-Benzyloxyethoxy)ethoxy]ethoxy}-ethoxy)-ethoxy]-ethoxy}-hexanoic acid ethyl ester (3). Sodium hydride (3.225 g or a 60% oil dispersion, 80.6 mmol) was suspended in 80 ml of anhydrous toluene, placed under a nitrogen atmosphere and cooled in an ice bath. A solution of the monodispersed alcohol 9 (27.3 g, 73.3 mmol) in 80 ml dry toluene was added to the NaH suspension. The mixture was stirred at 0 C. for thirty minutes, allowed to come to room temperature and stirred for another five hours, during which time the mixture became a clear brown solution. The monodispersed mesylate 10 (19.21 g, 80.6 mmol) in 80 ml dry toluene was added to the NaH/alcohol mixture, and the combined solutions were stirred at room temperature for three days. The reaction mixture was quenched with 50 ml methanol and filtered through basic alumina. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, gradient elution: 3/1 ethyl acetate/hexanes to ethyl acetate) to yield the monodispersed compound 3 as a pale yellow oil (16.52 g, 44 %). FAB MS: m/e 515 (M+H).
44%
With NaH; In methanol; ethyl acetate; toluene;
6-{2-[2-(2-{2-[2-(2-Benzyloxyethoxy)ethoxy]ethoxy}-ethoxy)-ethoxy]-ethoxy}-hexanoic acid ethyl ester (3). Sodium hydride (3.225 g or a 60% oil dispersion, 80.6 mmol) was suspended in 80 ml of anhydrous toluene, placed under a nitrogen atmosphere and cooled in an ice bath. A solution of the monodispersed alcohol 9 (27.3 g, 73.3 mmol) in 80 ml dry toluene was added to the NaH suspension. The mixture was stirred at 0 C. for thirty minutes, allowed to come to room temperature and stirred for another five hours, during which time the mixture became a clear brown solution. The monodispersed mesylate 10 (19.21 g, 80.6 mmol) in 80 ml dry toluene was added to the NaH/alcohol mixture, and the combined solutions were stirred at room temperature for three days. The reaction mixture was quenched with 50 ml methanol and filtered through basic alumina. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, gradient elution: 3/1 ethyl acetate/hexanes to ethyl acetate) to yield the monodispersed compound 3 as a pale yellow oil (16.52 g, 44%). FAB MS: m/e 515 (M+H).
Heptaethylene glycol mono methyl ether (30). To a stirred solution of monodispersed tetraethylene glycol (35.7 mmol) in dry DMF (25.7 mL), under N2 was added in portion a 60% dispersion of NaH in mineral oil, and the mixture was stirred at room temperature for 1 hour. To the resulting sodium salt of the tetraethylene glycol was added a solution of monodispersed mesylate 29 (23.36) in dry DMF (4 ml) in a single portion, and the mixture was stirred at room temperature for 3.5 hours.
With NaH; In N,N-dimethyl-formamide; mineral oil;
Heptaethylene glycol mono methyl ether (30). To a stirred solution of monodispersed tetraethylene glycol (35.7 mmol) in dry DMF (25.7 mL), under N2 was added in portion a 60% dispersion of NaH in mineral oil, and the mixture was stirred at room temperature for 1 hour. To the resulting sodium salt of the tetraethylene glycol was added a solution of monodispersed mesylate 29 (23.36) in dry DMF (4 ml) in a single portion, and the mixture was stirred at room temperature for 3.5 hours.
With NaH; In N,N-dimethyl-formamide; mineral oil;
Heptaethylene glycol mono methyl ether (30). To a stirred solution of monodispersed tetraethylene glycol (35.7 mmol) in dry DMF (25.7 mL), under N2 was added in portion a 60% dispersion of NaH in mineral oil, and the mixture was stirred at room temperature for 1 hour. To the resulting sodium salt of the tetraethylene glycol was added a solution of monodispersed mesylate 29 (23.36) in dry DMF (4 ml) in a single portion, and the mixture was stirred at room temperature for 3.5 hours.
(b) Amino Heptaethylene Glycol Methyl Ether Methanesulfonic Acid Salt This compound was prepared from <strong>[4437-01-8]heptaethylene glycol monomethyl ether</strong> (Heimann, U.; Voegtle, F. Liebigs Ann. Chem. 1980, 6, 858-862), methanesulfonyl chloride and ammonium hydroxide using methods similar to those described in Example 101a. The crude product was obtained as a white solid and was used without further purification (2.1 g, 96% yield). 1H-NMR (400 MHz, DMSO-d6) delta:7.3 (br s, 3H), 3.60-3.35 (m, 28H), 3.21 (s, 3H), 2.31 (s, 3H).
A 4-nitrobenzenesulfonic acid 3,6,9,12,15,18,21-heptaoxadocos-1-yl ester 6.7 g of triethylamine (TEA) (0.06 mol) are dropwise added, in 10 minutes, to a solution of 20.4 g of 4-nitrobenzenesulfonyl chloride (obtained according to the procedure described by F. Gialdi, R. Ponci, "I1 Farmaco" Vol XIV, 751, 1959) (0.06 mol) and 20.4 g of 3,6,9,12,15,18,21-heptaoxadocosan-1-ol (obtained according to the procedure described in Liebigs Ann. Chem. 1980, 858-862) (0.06 mol) in 60 mL of AcOEt. After 2 h at a temperature of 20 C., the precipitated TEA hydrochloride is washed for three times with 10-mL portion of AcOEt, then filtered off.
35
[ 4437-01-8 ]
[ 7732-18-5 ]
[ 98-74-8 ]
4-nitrobenzenesulfonic acid 3,6,9,12,15,18,21-heptaoxadocos-1-yl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With hydrogenchloride; triethanolamine; In ethyl acetate;
B 4-nitrobenzenesulfonic acid 3,6,9,12,15,18,21-heptaoxadocos-1-yl ester 6.7 g (60 mmol) of TEA are dropwise added, in 10 min, to a solution of 13.3 g (60 mmol) of 4-nitrobenzenesulfonyl chloride (marketed product) and of 20.4 g (60 mmol) of <strong>[4437-01-8]3,6,9,12,15,18,21-heptaoxadocosan-1-ol</strong> (according to Liebigs Ann. Chem. 1980, 858-862) in 60 mL of AcOEt. After 2 h at the temperature of 20 C., the precipitated TEA hydrochloride is filtered off, washing with 10 mL of AcOEt for three times. The filtrates are collected, washed with 30 mL of H2 O, 20 mL of 2N HCl and then with H2 O to reach a neutral pH. The organic phase is evaporated to dryness, to give a thick oil which is directly used in the successive step without a further purification. 25 g (47 mmol) of the desired product are obtained. Yield: 79% 1 H-NMR, 13 C-NMR, IR and MS spectra are consistent with the structure.
To a solution of monodispersed <strong>[4437-01-8]heptaethylene glycol monomethyl ether</strong> (8.51 g, 25 mmol) in THF (250 mL) was added potassium t-butoxide (3.1 g, 27.5 mmol, small portions over 30 min). The reaction mixture was then stirred for 1 h and then II (10 g, 27.5 mol) dissolved in THF (90 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, 200 mL) and evaporated to dryness to afford oil. The crude oil was purified via flash chromatography (silica, gradient elution: 2-5% methanol in CHCl3) to give clear yellow oil IV, 2.48 g (16%).
To a stirred solution of non-polydispersed compound 11 (35.7 mmol) in dry DMF (25.7 ML), under N2 was added in portion a 60% dispersion of NaH in mineral oil, and the mixture was stirred at room temperature for 1 hour.To this salt 12 was added a solution of non-polydispersed mesylate 9 (23.36) in dry DMF (4 ml) in a single portion, and the mixture was stirred at room temperature for 3.5 hours.Progress of the reaction was monitored by TLC (12% CH3OH-CHCl3).The reaction mixture was diluted with an equal amount of 1N HCl, and extracted with ethyl acetate (2*20 ml) and discarded.Extraction of aqueous solution and work-up gave non-polydispersed polymer 10 (82-84% yield).
41%
To a solution of non-polydispersed tetraethylene glycol (51.5 g, 0.27 mol) in THF (1L) was added potassium t-butoxide (14.8 g, 0.13 mol, small portions over 30 min). The reaction mixture was then stirred for 1 h and then 24 (29.15 g, 0.12 mol) dissolved in THF (90 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, 200 mL) and evaporated to dryness. The oil was then dissolved in HCl (250 mL, 1 N) and washed with ethyl acetate (250 mL) to remove excess 24. Additional washings of ethyl acetate (125 mL) may be required to remove remaining 24. The aqueous phase was washed repetitively with CH2Cl2 (125 mL volumes) until most of the 25 has been removed from the aqueous phase. The first extraction will contain 24, 25, and dicoupled side product and should be back extracted with HCl (125 mL, 1N). The organic layers were combined and evaporated to dryness. The resultant oil was then dissolved in CH2Cl2 (100 mL) and washed repetitively with H20 (50 mL volumes) until 25 was removed. The aqueous fractions were combined, total volume 500 mL, and NaCl was added until the solution became cloudy and then was washed with CH2Cl2 (2×500 mL). The organic layers were combined, dried MgSO4, and evaporated to dryness to afford a the non-polydispersed title compound as an oil (16.9 g, 41% yield). It may be desirable to repeat one or more steps of the purification procedure to ensure high purity.
41%
To a solution of monodispersed tetraethylene glycol (51.5 g, 0.27 mol) in THF (1L) was added potassium t-butoxide (14.8 g, 0.13 mol, small portions over 30 min). The reaction mixture was then stirred for 1 h and then 9 (29.15 g, 0.12 mol) dissolved in THF (90 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, 200 mL) and evaporated to dryness. The oil was then dissolved in HCl (250 mL, 1 N) and washed with ethyl acetate (250 mL) to remove excess 9. Additional washings of ethyl acetate (125 mL) may be required to remove remaining 9. The aqueous phase was washed repetitively with CH2Cl2 (125 mL volumes) until most of the compound 18 has been removed from the aqueous phase. The first extraction will contain 9, 10, and dicoupled side product and should be back extracted with HCl (125 mL, 1N). The organic layers were combined and evaporated to dryness. The resultant oil was then dissolved in CH2Cl2 (100 mL) and washed repetitively with H2O (50 mL volumes) until 10 was removed. The aqueous fractions were combined, total volume 500 mL, and NaCl was added until the solution became cloudy and then was washed with CH2Cl2 (2×500 mL). The organic layers were combined, dried MgSO4, and evaporated to dryness to afford the monodispersed compound 10 as an oil (16.9 g, 41% yield). It may be desirable to repeat one or more steps of the purification procedure to ensure high purity.
30 g
The solution of the compound of formula-9 (54.5 gms) in 34 ml of tetrahydrofuran was slowly added to pre-cooled mixture of sodium hydride (5.6 gms) and tetrahydrofuran (170 ml) at 0-5 C under nitrogen atmosphere and stirred the reaction mixture for 45 minutes at the same temperature. To this reaction mixture, the solution of the compound of formula-8a (34 gms) in tetrahydrofuran (34 ml) was added. Heated the reaction mixture to 40-45 C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 25-30C and acidified the reaction mixture using aqueous hydrochloric acid solution. Distilled off the solvent completely from the reaction mixture. To this reaction mixture aqueous sodium chloride solution was added and washed with ethyl acetate. Extracted the compound into dichloromethane from the reaction mixture. Combined the dichloromethane layers and washed with aqueous sodium solution and distilled off the solvent completely from the organic layer to get the title compound. Yield: 30 gms.
With NaH; In N,N-dimethyl-formamide; mineral oil;
Heptaethylene glycol mono methyl ether (30). To a stirred solution of monodispersed tetraethylene glycol (35.7 mmol) in dry DMF (25.7 mL), under N2 was added in portion a 60% dispersion of NaH in mineral oil, and the mixture was stirred at room temperature for 1 hour. To the resulting sodium salt of the tetraethylene glycol was added a solution of monodispersed mesylate 29 (23.36) in dry DMF (4 ml) in a single portion, and the mixture was stirred at room temperature for 3.5 hours.
To a solution of non-polydispersed <strong>[4437-01-8]heptaethylene glycol monomethyl ether</strong> 25 (2.5 g, 7.3 mmol) in tetrahydrofuran (100 mL) was added sodium hydride (0.194 g, 8.1 mmol) and the reaction mixture was stirred for 1 h. Then dropwise addition of mesylate of non-polydispersed 10-hydroxydecanoate 31 (2.4 g, 8.1 mmol), dissolved in tetrahydrofuran (10 mL), was added and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, 200 mL) and evaporated to dryness. The resultant oil was dissolved in ethyl acetate and washed H2O (2×200 mL), dried MgSO4, evaporated to dryness, chromatographed (silica, ethyl acetate/methanol, 10:1), and chromatographed (silica, ethyl acetate) to afford the non-polydispersed title compound as a clear oil (0.570 g, 15% yield).
15%
To a solution of substantially monodispersed <strong>[4437-01-8]heptaethylene glycol monomethyl ether</strong> 10 (2.5 g, 7.3 mmol) in tetrahydrofuran (100 mL) was added sodium hydride (0.194 g, 8.1 mmol) and the reaction mixture was stirred for 1 h. Then dropwise addition of mesylate of monodispersed 10-hydroxydecanoate 16 (2.4 g, 8.1 mmol), dissolved in tetrahydrofuran (10 mL), was added and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, 200 mL) and evaporated to dryness. The resultant oil was dissolved in ethyl acetate and washed H2O (2×200 mL), dried MgSO4, evaporated to dryness, chromatographed (silica, ethyl acetate/methanol, 10:1), and chromatographed (silica, ethyl acetate) to afford the monodispersed compound 17 as a clear oil (0.570 g, 15% yield).
To a solution of the monodispersed compound 10 (3.0 g, 8.8 mmol) in ether (90 mL) was added potassium t-butoxide (1.2 g, 9.6 mmol) and the reaction mixture was stirred for 1 h. Then dropwise addition of the monodispersed compound 11 (2.4 g, 9.6 mmol), dissolved in ether (10 mL), was added and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, 200 mL) and evaporated to dryness. The resultant oil was dissolved in ethyl acetate and washed H2O ( 2×200 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate to ethyl acetate/methanol, 10:1) was performed and afforded the monodispersed compound 12 as a clear oil (0.843 g, 19% yield).
To a solution of the non-polydispersed compound 25 (3.0 g, 8.8 mmol) in ether (90 mL) was added potassium t-butoxide (1.2 g, 9.6 mmol) and the reaction mixture was stirred for 1 h. Then dropwise addition of the non-polydispersed compound 26 (2.4 g, 9.6 mmol), dissolved in ether (10 mL), was added and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed CH2Cl2, 200 mL) and evaporated to dryness. The resultant oil was dissolved in ethyl acetate and washed H2O (2×200 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate to ethyl acetate/methanol, 10:1) was performed and afforded the non-polydispersed title compound as a clear oil (0.843 g, 19% yield).
glycylphenylalanylleusylmalonic ethyl ester[ No CAS ]
[NP(MPEG350)(GlyPheLeuMalEt2)3][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
[NP(MPEG350)(GlyPheLeuMalEt2)]3 (0.5 g, 0.19 mol), which was obtained according to the known method (Youn Soo Sohn et al. Angew. Chem. Int. Edit. 2006, 45 , 6173-6176) by substituting chlorine atoms of hexachlorocyclotriphosphazene with 3 moles of methoxy-poly(ethylene glycol) having molecular weight of 350 (MPEG350) and 3 moles of glycylphenylalanylleusylmalonic ethyl ester, was hy- drolyzed with barium hydroxide (0.22 g, 0.63 mmol) in methanol (20ml) for 12 to 24 hours.[70] The reaction solution was concentrated, to which an excess amount of ethyl ether was added to induce precipitation of the barium salt of cyclotriphosphazene, [NP(MPEG350)(GlyPheLeuMal-Ba)]3. The barium salt was recrystallized from the same solvent system, and dissolved in distilled water (10 ml), to which cis- (amminecyclohexylamine)platinum sulfate (cis- (NH3) (C6H5NH2)PtSO4) (0.23 g, 0.64 mmol) in distilled water (10 ml) was slowly added. The reaction solution was further stirred at room temperature for about 12 hours, and then barium sulfate was removed by filtering. The filtrate was dialyzed in distilled water for 24 hours using a dialysis membrane (molecular weight cutoff: 500) and then freeze-dried to obtain the cyclotri- phosphazene-platinum(II) complex conjugate, (NP(MPEG350) [GlyPheLeuMal-Pt-cis-(NH3)(C6H5NH2)]3in 63% yield.[71] Composition: Ci23H216N2iO45P3Pt3-4H2O[72] Molecular weight: 3,387.34[73] Elementary Analysis (%):[74] Found: C, 37.72; H, 6.85; N, 8.06, Calculated (%): C, 38.68; H, 6.97; N, 7.70.[75] 1H NMR spectra (CD3OD)(delta, ppm): 0.87 (d, 6H, LeU-(CHO2). 1.12 (t, 3H, GIy- <n="12"/>OCH2CfL ), 1.43-1.46 (m, 2H, cyclohexylamine C-4 proton), 1.53-1.78 (m, 2H, cyclo- hexylamine C-6 proton), 1.39-1.49 (m, 4H, cyclohexylamine C-3, C-5 proton), 2.57 (m, IH, cyclohexylamine, 1-C proton), 1.2-1.3 (m, 3H, LeU-CHCH2), 2.95 (dd, 2H, Phe-CH,), 3.2 (s, 3H, PEG35O-OCH3 ), 3.25-3.6 (b, 3OH, PEG350, OCH2CH2), 3.65 (d, 2H, GIy-CH2), 4.1 (dd, IH, Leu-CH), 4.42 (t, IH, Phe-CH), 7.14 (m, Phe- aromatic).[76] 31P-NMR spectra (D2O)(delta, ppm): 22.3
Example 2A Synthesis of 2-cyano-3,3-diphenyl-acrylic acid [Pluriol A350E] ester (27) 63.4 g (189 mmol) of Pluriol A350E (26) were stirred at 150 C. for 30 minutes, nitrogen being passed through by immersion during the entire reaction time. 50.0 g (180 mmol) of Uvinol 3035 (4) and 0.58 g (2 mmol) of titanium(IV) isopropoxide were then added. The reaction mixture was stirred at 155 C. for 24 hours. The ethanol formed was distilled off. The mixture was taken up in 200 ml of methylene chloride, 350 mg (3 mmol) of phosphoric acid 85% were added and the solution was left to stand at 20 C. for 24 hours. The product was purified by flash chromatography with 1 kg of silica gel 60. For this, the solution was introduced on to the flash column and the educt (4) was eluted from the column with methylene chloride, followed by the product (27) with methanol. The methanolic solution was concentrated to dryness on a rotary evaporator. 94 g of an orange viscous liquid (27) were obtained (yield=95%).
95%
63.4 g (189 mMol) Pluriol A350E (2) were stirred for 30 min at 150 C. under nitrogen and 50.0 g (180 mMol) Uvinul 3035 (1) and 0.58 g (2 mMol) titanium(IV) isopropoxid were added. The mixture was stirred at 155 C. for 24 hours and the resulting ethanol distilled off. 200 ml methylene chloride and 350 mg (3 mMol) phosphoric acid 85% were added and the solution was left at 20 C. for 24 h. The product was purified by flash chromatography on silica. 94 g of an orange viscous liquid (3) was obtained (yield 95%).
Example 3B Synthesis of (4-benzoyl-3-hydroxy-phenoxy)-acetic acid [Pluriol A350E] ester (34) Nitrogen was passed through by immersion during the entire reaction time. 61.4 g (192 mmol) of Pluriol A350E (26) and 50.0 g (175 mmol) of (9) were initially introduced into the reaction vessel at RT and the mixture was then stirred at 155 C. for 30 minutes. 0.58 g (2 mmol) of titanium(IV) isopropoxide was then added and the reaction mixture was stirred at 155 C. for 18 hours. The methanol formed was distilled off. The mixture was taken up in 200 ml of methylene chloride, 350 mg (3 mmol) of phosphoric acid 85% were added and the solution was left to stand at 20 C. for 24 hours. The product was purified by flash chromatography with 1 kg of silica gel 60. For this, the solution was introduced onto the flash column and the educt (9) was eluted from the column with methylene chloride, followed by the product (34) with methanol. The methanolic solution was concentrated to dryness on a rotary evaporator. 99 g of an orange viscous liquid (34) were obtained (yield=99%).
Example 1J Synthesis of 2-(5-chloro-2H-benzotriazol-2-yl)-6-tert-butyl-4-hydroxyphenylpropionic acid [Pluriol A350E]ester (15) Nitrogen was passed through by immersion during the entire reaction time. 33 g (103 mmol) of Pluriol A350E (4) were stirred at 150 C. for 30 minutes. Then, 36.4 g (93.8 mmol) (14) and 0.3 g (1 mmol) of titanium(IV) isopropoxide were added. The reaction mixture was stirred at 155 C. for 21 hours. The methanol formed was distilled off. The mixture was taken up in 250 ml of methylene chloride and 173 mg (1.5 mmol) of 85% strength phosphoric acid were added, and the solution was left to stand at 20 C. for 24 hours. The product was purified by flash chromatography on silica gel 60. For this, the solution was introduced onto the flash column and the educt (14) was eluted from the column with methylene chloride followed by the product (15) with methanol. The methanolic solution was concentrated to dryness on a rotary evaporator to obtain 52 g of red viscous liquid (15) (yield=83%).
Example 1C Synthesis of 3-(3-benzotriazol-2-yl-5-tert-butyl-4-hydroxyphenyl)propionic acid [Pluriol A350E]ester (5) Nitrogen was passed through by immersion during the entire reaction time. 59.7 g (187 mmol) of Pluriol A350E (4) were stirred at 150 C. for 30 minutes. Then, 60.0 g (170 mmol) (3) and 0.54 g (2 mmol) of titanium(IV) isopropoxide were added. The reaction mixture was stirred at 155 C. for 18 hours. The methanol formed was distilled off. The mixture was taken up in 100 ml of toluene and 350 mg (3 mmol) of 85% strength phosphoric acid were added, and the solution was left to stand at 20 C. for 24 hours. The product was purified by flash chromatography on silica gel 60. For this, the solution was introduced onto the flash column and the educt (3) was eluted from the column with toluene followed by the product (5) with methanol. The methanolic solution was concentrated to dryness on a rotary evaporator to obtain 106 g of reddish orange viscous liquid (6) (yield=99%).
99%
59.7 g (187 mMol) Pluriol A350E (2) was stirred for 30 Minutes at 150 C. and 60.0 g (170 mMol) compound (4) and 0.54 g (2 mMol) titanium(IV) isopropoxid added. The mixture was stirred at 155 C. for 18 hours. The resulting methanol was distilled off. 100 mL toluene and 350 mg (3 mMol) phosphoric acid 85% were added and the solution was left standing at 20 C. for 24 h. The product was purified by flash chromatography on silica. 106 g of an orange viscous liquid (5) was obtained (yield= 99%).
63.4 g (189 mMol) Pluriol A350E (2) were stirred for 30 min at 150 C. under nitrogen and 50.0 g (180 mMol) Uvinul 3035 (1) and 0.58 g (2 mMol) titanium(IV) isopropoxid were added. The mixture was stirred at 155 C. for 24 hours and the resulting ethanol destilled off. 200 ml methylene chloride and 350 mg (3 mMol) phosphoric acid 85% were added and the solution was left at 20 C. for 24 h. The product was purified by flash chromatography on silica. 94 g of an orange viscous liquid (3) was obtained (yield 95%).
With boron trifluoride diethyl etherate; In diethyl ether; at 20℃; for 24h;
Example 9. Compound of formula 2 wherein n=7.[0078] [0079] Bortrifluoride etherate (124 mul, 1.0 mmol) was added to mPEG(7)-OH (340 mg, 1.0 mmol) and dihydroartemisinin (426 mg, 1.5 mmol) in dry diethyl ether (20 ml) at room temperature. After 4 h, more bortrifluoride etherate (31 mul, 0.25 mmol) was added and the reaction mixture was stirred for another 20 h. Dilute aqueous sodium bicarbonate (2%) was added and the reaction mixture was stirred for another 30 min. The phases were separated and the aqueous phase was saturated with NaCl (s) and then extracted with ethyl acetate (3 x 30 ml). The combined organic phases were dried over sodium sulphate. Filtration and removal of the solvent at reduced pressure followed by column chromatography (EtOAc:THF 4:1) gave 276 mg of the product as a single isomer. HPLC analysis (HPLC-ELSD-C18, 90:10 to 5:95 H2O/ACN in 20 min) displayed the product peak at 21 min. H-NMR (CDCl3); 5.42 (s, 1H); 4.82 (d, 1H); 3.91 (d, 1H); 3.70-3.50 (m, 27 H); 3.36 (s, 3H); 2.60 (m, 1H); 2.35 (m, 1H); 2.10-0.90 (m, 10H); 1.42 (s, 3H); 0.95 (d, 3H); 0.90 (d, 3H)
With pyridine; In dichloromethane; at -78℃; for 3h;
Example 41 [0183] 24-Oxo-2,5,8,11,14,17,20,23,25-nonaoxaheptacosan-26-yl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate [0184] In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Aldrich) was reacted with <strong>[4437-01-8]heptaethylene glycol monomethyl ether</strong> (TCI) and pyridine in methylene chloride at -78 C. for 3 h to give 1-chloroethyl 2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl carbonate. This was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 24-oxo-2,5,8,11,14,17,20,23,25-nonaoxaheptacosan-26-yl-4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C51H68Cl2F2N3O15: [(M+H)+]: 1026, found: 1026.
With pyridine; thionyl chloride; In chloroform; for 3h;Inert atmosphere; Reflux;
Under nitrogen to seven glycol monomethyl ether (24.5g, 72.0mmol) and pyridine (5.70g, 72.0mmol) in CHCl3 (60mL) was slowly dropped into a solution of thionyl chloride (10.95g, 92.0mmol) and CHCl3 (15mL) added and the reaction was stirred at reflux for 3h. Distilled water (300mL), separated, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oil 23.6g, yield 91.3%. Products without purification in the next reaction.
91.3%
With pyridine; thionyl chloride; In chloroform; for 3h;Inert atmosphere; Reflux;
Under a nitrogen atmosphere, a solution of thionyl chloride (10.95 g, 92.0 mmol) in CHCl3 (15 mL) was slowly added dropwise to a solution of <strong>[4437-01-8]heptaethylene glycol monomethyl ether</strong> (24.5 g, 72.0 mmol) and pyridine (5.70 g, 72.0mmol) in CHCl3 (60 mL). The reaction mixture was stirred under reflux for 3 h. Distilled water (300 mL) was added. Afterliquid separation, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressureto obtain a yellow oil (23.6 g, yield: 91.3%), which was used directly in the next reaction without purification.
1.616 g
With thionyl chloride; In chloroform; at 20℃; for 3h;Reflux;
22SOCl2 (900 muL, 12.33 mmol) was added over 5 min to a solution of <strong>[4437-01-8]2,5,8,11,14,17,20-heptaoxadocosan-22-ol</strong> (3.2 g, 9.40 mmol) and pyridine (760 muL, 9.40 mmol) in CHCl3 (20 mL) at rt. The mixture was heated under reflux for 3 h, cooled and evaporated under reduced pressure. The residue was partitioned between EtOAc (200 mL) and water (100 mL), the organic layer washed with sat. aq NaHCO3 (100 mL), dried (MgSO4), filtered and evaporated under reduced pressure to afford the sub-title compound (1.616 g) as an oil. 1H NMR (CDCl3) 400 MHz, delta: 3.77-3.74 (m, 2H), 3.68-3.62 (m, 24H), 3.56-3.54 (m, 2H), 3.38 (s, 3H).
1.616 g
With pyridine; thionyl chloride; In chloroform; at 20℃; for 3h;Reflux;
SOd2 (900 pL, 12.33 mmol) was added over 5mm to a solution of <strong>[4437-01-8]2,5,8,11,14,17,20-heptaoxadocosan-22-ol</strong> (3.2 g, 9.40 mmol) and pyridine (760 pL, 9.40 mmol) in CHCI3 (20mL) at rt. The mixture was heated under reflux for 3h, cooled and evaporated under reduced pressure. The residue was partitioned between EtOAc (200 mL) and water (100 mL), the organic layer washed with sat. aq NaHCO3 (100 mL), dried (MgSO4), filtered and evaporated under reduced pressure to afford the sub-title compound (1.616 g) as an oil.1H NMR (ODd3) 400 MHz, O: 3.77-3.74 (m, 2H), 3.68-3.62 (m, 24H), 3.56-3.54 (m, 2H), 3.38 (5, 3H).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 18h;
(i) 3-(2,5,8,1 1 , 14, 17,20-Heptaoxadocosan-22-yloxy)-5-methoxyaniline DIAD (576 muIota_, 2.96 mmol) was added to a suspension of 3-amino-5-methoxyphenol (275 mg, 1.976 mmol), PPh3 (778 mg, 2.96 mmol) and O-methylheptaethylene glycol (1009 mg, 2.96 mmol) in THF (5 ml_) and the resulting mixture was stirred at rt for 18h. The mixture was cooled and partitioned between water (20 ml_) and ethyl acetate (20 ml_). The organic layer was separated, dried (MgS04), filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by chromatography on silica gel (40 g column, 0-10% MeOH/EtOAc) to afford a clear brown oil. The oil was further purified by chromatography on the Companion (80 g column, 0- 50% acetone/toluene) to afford the sub-title compound (292 mg) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) delta 5.77-5.73 (m, 2H), 5.68 (dd, 1 H), 5.05 (br s, 2H), 3.97- 3.92 (m, 2H), 3.72-3.66 (m, 2H), 3.63 (s, 3H), 3.60-3.48 (m, 22H), 3.45-3.40 (m, 2H), 3.24 (s, 3H). LCMS m/z 462 (M+H)+ (ES+)
The reaction was carried out under strictly dry conditions.To triphenylphosphine (193.9 mg, 0.7 mmol) in THF (5 mL)was added drop-wise diisopropyl azodicarboxylate (145.6 jii,0.7 mmol) at -78 C. The reaction was stirred for 5 mm andPEG300 (200.0 mg, 0.6 mmol) in THF (4 mL) was addeddrop-wise. The reaction was stirred for 5 mm and neopentylalcohol (45.8 mg, 0.5 mmol) in THF (1 ml) was added. Thereaction was stirred for 5 mm and <strong>[1122-10-7]3,4-<strong>[1122-10-7]dibromomaleimide</strong></strong>(189.4mg, 0.7 mmol) in THF (2 ml) was added. The reactionwas stirred for 10 mm, the cold bath removed and stirred for20 h at ambient temperature. The solvent was removed invacuo and the residual material was purified by flash chromatography on silica gel (methanol:dichloromethane, gradientelution from 0.5-5.0% methanol). Fractions containing theproduct were collected and the solvent was removed in vacuo.The still impure product was purified by flash chromatograss phy on silica gel (petroleum ether: ethyl acetate, gradientelution from 7:3 to 2:8) to afford the desired compound as ayellow oil (137 mg, 40%) with 97.5% purity. ?H NMR (500MHz, CDC13): oe=3.76 (t, 2H, J=5.6, N-CH2), 3.64-3.52 (m,24H, 12xCH2-O), 3.49 (t, 2H, J=4.4, N-CH2---CH2), 3.32(s, 3H, O-CH3); ?3C NMR (125 MHz, CDC13): oe=163.8(2xC), 129.5 (2xC), 72.0 (CH2), 70.7-70.5 (9xCH2), 70.1(2xCH2), 67.5 (CH2), 59.1 (CH3), 39.0 (CH2); IR (solid,cm?): 3496 (w), 2869 (m), 1786 (m), 1720(s), 1594 (m); MS(CI) mlz, (%): 580 (8?M+H, 12), 578 (81 79M+H, 23), 576 (79M+H, 12), 279 (100), 84 (61); Mass calc. for C,9H3 ,7913r2O9N[+H]: 576.0444. Found: 576.0437.
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