* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference:
[1] Journal of the Chemical Society, Chemical Communications, 1990, # 13, p. 911 - 912
[2] Journal of the American Chemical Society, 2017, vol. 139, # 34, p. 11998 - 112002
Reference:
[1] Synthesis, 2004, # 7, p. 1007 - 1010
27
[ 4792-15-8 ]
[ 98-59-9 ]
[ 41024-91-3 ]
Yield
Reaction Conditions
Operation in experiment
8.1 mg
With sodium hydroxide In tetrahydrofuran; water for 3 h; Inert atmosphere
Triglycol dichloride (10.8g, 57.8mmol) was added to a stirred mixture of KOH (7.8g, 139.3mmol) in ethylene glycol (60mL) at room temperature under N2. The reaction mixture was stirred at refluxing temperature for 36h. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to yield a viscous oil. To a stirred solution of the above viscous oil and NaOH (4.8g, 120mmol) in THF/H2O (v/v=1/1 40mL) cooled to 0°C under N2 was slowly added portions of p-toluenesulfonyl chloride (22g, 115mmol). After stirring for 3h, water (100mL) was added to the reaction mixture. The product was extracted with CH2Cl2 (20mL×3) and washed with brine (20mL×3). The combined organic layer was dried over MgSO4 and the CH2Cl2 was evaporated off. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give pure product (8.1g) as yellow oil. Yield 27.5percent, 1H NMR (CDCl3, 500MHz) δ 2.44 (3H, s), 3.57 (4H, s), 3.59 (2H, s), 3.67 (2H, t, J=4.8Hz), 4.14 (2H, t, J=4.8Hz), 7.33 (2H, d, J=8.1Hz), 7.78 (2H, d, J=8.2Hz).
Reference:
[1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 14, p. 4841 - 4856
[2] Journal of Organic Chemistry, 1999, vol. 64, # 18, p. 6870 - 6873
[3] Canadian Journal of Chemistry, 2006, vol. 84, # 10, p. 1273 - 1279
[4] Collection of Czechoslovak Chemical Communications, 1987, vol. 52, # 8, p. 2057 - 2060
[5] Russian Journal of Organic Chemistry, 2012, vol. 48, # 10, p. 1345 - 1352[6] Zh. Org. Khim., 2012, vol. 48, # 10, p. 1350 - 1357,8
[7] Chemical Communications, 2016, vol. 52, # 45, p. 7310 - 7313
[8] Organic Letters, 2018, vol. 20, # 2, p. 369 - 372
[9] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 2, p. 265 - 269
[10] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 4, p. 1260 - 1262
[11] Bulletin of the Chemical Society of Japan, 1990, vol. 63, # 4, p. 1260 - 1262
[12] Organic and Biomolecular Chemistry, 2006, vol. 4, # 11, p. 2082 - 2087
[13] Journal of Organic Chemistry, 1984, vol. 49, p. 1408 - 1412
[14] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1985, p. 607 - 624
[15] Liebigs Annalen der Chemie, 1983, # 5, p. 770 - 801
[16] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 1047 - 1052
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[19] Tetrahedron, 2014, vol. 70, # 50, p. 9545 - 9553
Stage #1: Pentaethylene glycol With sodium In tetrahydrofuran Heating;
Stage #2: benzyl bromide In tetrahydrofuran for 5h; Heating;
43%
Stage #1: Pentaethylene glycol With sodium hydride In tetrahydrofuran; paraffin oil at 10℃; for 0.5h;
Stage #2: benzyl bromide In tetrahydrofuran; paraffin oil at 10 - 20℃; for 17.5h;
1 Step 1-1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol
To a stirred solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (10 g, 42 mmol, CAS4792-15-8) in THF (50 mL) was added 60% NaH in paraffin (0.84 g, 21 mmol) at 10° C. The resulting reaction mixture was stirred at the same temperature for 0.5 h. To this reaction mixture benzyl bromide (3.6 g, 21 mmol) in THF (50) was added dropwise at 10° C. over 1.5 h. The resulting reaction mixture was allowed warm to rt and stirred for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (3% MeOH-DCM) to give 1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol as a yellow oil (6 g, 43%). LC-MS (ESI+) m/z 347.4 (M+H2O)+.
19%
Stage #1: Pentaethylene glycol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere;
Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;
1.1 Step 1. 1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (5.0 g, 20.98 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). This was followed by the addition of sodium hydride (920.0 mg, 38.33 mmol, 1.10 equiv), in portions at 0°C in 5 min. To this was added a solution of (bromomethyl)benzene (3.75 g, 21.93 mmol, 1.05 equiv) in N,N-dimethylformamide (5.0 mL) at 0°C in 10 min. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with water (100 mL). The resulting solution was extracted with ethyl acetate (3x100 mL) and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum, ether (1/1). This resulted in 1.3 g (19%) of 1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol as colorless oil.
With sodium hydride In tetrahydrofuran for 12h; Ambient temperature;
Stage #1: Pentaethylene glycol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃;
Stage #2: benzyl chloride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃;
71%
Stage #1: Pentaethylene glycol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h;
Stage #2: benzyl chloride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃;
1-phenyl-2,5,8, 11, 14-pentaoxahexadecan-16-oI (9)
Pentaethylene glycol (9.53 g, 50 mmol, 5 eq.) was added dropwise to a suspension of NaH 60% in mineral oil (800 mg, 20 mmol, 2.5 eq.) in 20 ml of DMF at 0 00 The resulting mixture was stirred at r.tfor lh. The reaction mixture was cooled to 0CC, benzyl chloride (1 ml, 1.1 g,8.72 mmol, 1 eq.) was added. The resulting mixture was stirred 0/N at r.t. The reaction was quenched with a saturated solution of NH4CI and the aqueous phase was extracted with ethyl acetate (x3). The combined organic phases were dried over MgSO4 and evaporated to dryness. The resulting oil was purified by column chromatography (from 0 to 60% of ethyl acetate in heptane) to afford the title compound as an oil. Yield: 2.055 g, 6.25 mmol (71%).1H NMR (400 MHz, ODd3) O 7.28-7.19 (5H, m), 4.50 (2H, 5), 3.66-3.52 (20H, m), 2.50 (1H,5). 13C NMR (101 MHz, ODd3) 138.2, 128.3, 127.8, 127.6, 73.2, 72.7, 70.61, 70.58, 70.53,70.51, 70.2, 69.4, 61.7
With sodium iodide; silver(I) oxide; In dichloromethane; at 0 - 20℃; for 1h;
To a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (10 g, 41.96 mmol, CAS4792-15-8), silver oxide (14.6 g, 62.94 mmol) and NaI (7 g, 46.56 mmol) in DCM (250 mL) was added tosyl chloride (8.5 g, 41.96 mmol) at 0 C. The reaction mixture was then allowed to warm to rt and stirred for 1 h. The reaction mixture was then filtered through celite and the filtrate was washed with 10% NaHCO3 solution (125 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was then evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (3% MeOH-DCM) to give 14-hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate as a yellow oil (13 g, 79%). LC-MS (ESI+) m/z 394.3 (M+H)+.
77%
With potassium iodide; silver(I) oxide; In dichloromethane;Cooling;
To a cold and stirred solution of pentaethylene glycol (1 eq) in DCM (amount×10 mL) were added Ag2O (1.5 eq), TsCl (1.1eq) and KI (0.2 eq). After stirring for 30 to 60 min, the precipitated silver salts were removed by filtration through a pad of Celite and washed thoroughly with EtOAc. The combined filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography to give a colorless oil, yield 77%. LC/MS (ESI) m/z: 393.2 [M+1] +; 1H-NMR (400MHz, CDCl3) d 2.45 (s, 3H), 3.59-3.73 (m, 18H), 4.16 (t, J = 4.8 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H).
75%
With potassium iodide; silver(I) oxide; In dichloromethane; at 0℃; for 0.333333h;
14-Hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate (26) To a chilled (0 C.) solution of pentaethylene glycol (2.13 g, 8.92 mmol) in DCM (89 mL) were added TsCl (1.87 g, 9.81 mmol), Ag2O (3.10 g, 0.134 mmol), and KI (0.296 g, 1.78 mmol). After stirring for 20 min the reaction mixture was filtered through a 4 cm pad of celite and flushed with EtOAc. The resulted filtrate was concentrated under reduced pressure to give a yellow oil. The crude product was purified via silica flash chromatography using 3:2 DCM/acetone as an eluent, providing 26 (2.63 g, 75%): 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.20-4.11 (m, 2H), 3.76-3.54 (m, 18H), 2.44 (s, 3H).
74%
With triethylamine; In dichloromethane; at 0 - 20℃; for 18h;Inert atmosphere;
Protocole 2 A solution of pentaethylene glycol (0.04 mmol ; 25.00 g) in dry CH2Cl2 (15 mL), under argon, was cooled to 0C with an ice bath and triethylamine (0.015 mmol ; 2.10 mL). Subsequently p-toluenesulfonyl chloride (0.0104 mmol ; 1.98 g) was added in the portions to the cooled reaction mixture. After complete addition, the solution was allowed to warm to room temperature and was stirred for 18 h. The mixture was washed with water (3 x 100 mL), the aqueous layers were re-extracted with CH2Cl2 and the combined organic layers washed with 5% citric acid (3 x 25 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel (99% CH2Cl2/MeOH) to give the desired compound 3e as a colorless oil in 74% yield (3.01 g).
69%
To a solution of 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethanol (15 g, 62.95 mmol, 13.27 mL, 2 eq) in tetrahydrofuran (150 mL) was added sodium hydride (1.26 g, 31.48 mmol, 60% purity, 1 eq) at 0 C. The mixture was stirred at 0 C for 0.5 hour. Then p- toluenesulfonyl chloride (6.00 g, 31.48 mmol, 1 eq) was added, the mixture was stirred at 25 C for 2 hours. The mixture was poured into saturated ammonium chloride aqueous solution (100 mL), the water layer was extracted with ethyl acetate (80 mL x 2). Then the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was condensed to get the residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to dichloromathane/methanol = 10/1) to get 2-[2-[2-[2-(2- hydroxyethoxy)ethoxy] ethoxy] ethoxy] ethyl 4-methylbenzenesulfonate (8.62 g, 21.96 mmol, 69% yield) as a light yellow oil.
66%
With triethylamine; In dichloromethane; at 20℃; for 15h;
The compound tetrapentaethylene glycol (6.0 g, 25.2 mmol) was dissolved in 20 mL of dichloromethane, and triethylamine (4.9 g, 48, 4 mmol) was added dropwise while TsCl was placed in dichloromethane. The funnel was slowly added dropwise to the solution and stirred at room temperature for 15 h.The reaction was monitored by thin layer chromatography (EA) and the TsCl portion of the compound remained.The solution was adjusted to pH = 7 with 4M HCl, 10 mL of water was added, and extracted three times with 30 mL of dichloromethane.Column chromatography (EA) gave a product of 6.52 g, yield 66%.
61.22%
With silver(I) oxide; In dichloromethane; at 0 - 20℃; for 2h;
Into a 500-mL round-bottom flask, was placed 3,6,9,12-tetraoxatetradecane-1,14-diol (9.53 g, 39.995 mmol, 1 equiv) in dichloromethane (200 mL), to which was added Ag2O (13.90 g, 59.982 mmol, 1.50 equiv) and TsCl (7.78 g, 40.808 mmol, 1.02 equiv) at 0 in a water/ice bath. Then KI (1.33 g, 8.012 mmol, 0.20 equiv) was added. The resulting mixture was stirred for 2 hr at room temperature. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (12/1). This resulted in 9.61 g (61.22%) of 14-[(4- methylbenzenesulfonyl)oxy]-3,6,9,12-tetraoxatetradecan-1-ol as a light yellow oil. MS (ES+): m/z 392.95[MH+]
51%
With potassium iodide; In dichloromethane; at 20℃;
Into a 250-mL round-bottom flask, was placed a solution of 3,6,9,12-tetraoxatetradecan-1,14-diol (5.0 g, 20.98 mmol, 1.00 equiv) in dichloromethane (100 mL), Ag2O (7.3 g, 31.50 mmol, 1.50 equiv), 4-methylbenzene-1-sulfonyl chloride (4.0 g, 20.99 mmol, 1.00 equiv ), KI (695.0 mg, 4.19 mmol, 0.30 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water (80 mL). The solids were filtered out. The resulting solution was extracted with dichloromethane (60 ml x 3) and the organic layers combined. The resulting mixture was washed with brine (60 ml x 1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1/1). This resulted in 4.2 g (51 %) of 14-[[4-methylbenzenesulfonyl]oxy]-3,6,9,12-tetraoxatetradecan-1-ol as yellow oil.
46%
With triethylamine; In dichloromethane; at 0 - 20℃; for 16h;
The title compound (6.1 g, 46%) was furnished as a colorless oil. It was prepared from 3,6,9,12-tetraoxatetradecane-1,14-diol (8.0 g, 33.57 mmol) following the procedure outlined for Example 2, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.16 (t, J = 4.8 Hz,, 2H), 3.72 - 3.58 (m, 18H), 2.45 (s, 3H).
43%
With N-Trimethylamine hydrochloride; triethylamine; In dichloromethane; for 18h;
A solution of pentaethylene glycol (35g, 147mmol), TEA (41mL, 294mmol) and trimethylamine-HCl (1.4g, 14.7mmol) in CH2C12 (600mL) was treated with tosyl chloride (29.4g, 154mmol). After stirring (18h) the reaction mixture was washed with H20-brine (1 :1), dried (MgS04), filtered, concentrated and subjected to chromatography to yield 82 (24.6g, 43%) as a pale yellow oil. Rf 0.8 (10% CH30H-CH2C12).
43%
With N-Trimethylamine hydrochloride; triethylamine; In dichloromethane; for 18h;
A solution of pentaethylene glycol (35g, 147mmol), TEA (41mL, 294mm ol) and trimethylamine-HCl (1.4g, 14.7mmol) in CH2CI2 (600mL) was treated with tosyl chloride (29.4g, 154mmol). After stirring (18h) the reaction mixture was washed with EbO-brine (1 : 1), dried (MgS04), filtered, concentrated and subjected to chromatography to yield 82 (24.6g, 43%) as a pale yellow oil. Rf 0.8 (10% CH3OH-CH2CI2).
43%
With N-Trimethylamine hydrochloride; triethylamine; In dichloromethane; for 18h;
A solution of pentaethylene glycol (35g, 147mmol), TEA (41mL, 294mmol) and trimethylamine-HCl (1.4g, 14.7mmol) in CH2CI2 (600mL) was treated with tosyl chloride(29.4g, 154mmol). After stirring (18h) the reaction mixture was washed with EhO-brine (1 : 1), dried (MgS04), filtered, concentrated and subjected to chromatography to yield 82 (24.6g, 43%) as a pale yellow oil. Rf 0.8 (10% CH3OH-CH2CI2).
43%
With N-Trimethylamine hydrochloride; triethylamine; In dichloromethane; for 18h;
A solution of pentaethylene glycol (35g, 147mmol), TEA (41mL, 294mmol) and trimethylamine-HCl (1.4g, 14.7mmol) in CH2Cl2 (600mL) was treated with tosyl chloride (29.4g, 154mmol). After stirring (18h) the reaction mixture was washed with H2O-brine (1:1), dried (MgSO4), filtered, concentrated and subjected to chromatography to yield 82 (24.6g, 43%) as a pale yellow oil. Rf 0.8 (10% CH3OH-CH2Cl2).
42%
With triethylamine;
To a stirred solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (70 g, 293.8 mmol) in DCM (500 mL) was added TEA (29.7 g, 293.8 mmol) followed by the addition of a solution of 4- methylbenzene-1-sulfonyl chloride (56.0 g, 293.8 mmol) in DCM (500 mL) over 30 min at room temperature under nitrogen atmosphere. The resulting solution was stirred for an additional 16 h at room temperature. Upon completion, the resulting solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EtOAc to afford 14-[(4-methylbenzenesulfonyl)oxy]-3,6,9,12-tetraoxatetradecan-1-ol (48 g, 42%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) d 7.81 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.17 (t, J = 4.9 Hz, 2H), 3.80-3.56 (m, 18H), 2.50 (d, J = 4.4 Hz, 1H), 2.46 (s, 3H) LC/MS (ESI, m/z): [(M + 1)]+ = 393.00
38%
With potassium iodide; silver(I) oxide; In dichloromethane; at 0 - 20℃; for 16h;
To a solution of 3,6,9,12-tetraoxatetradecan-1,14-diol (0.50 g, 2.1 mmol), potassium iodide (69 mg, 0.42 mmol), and silver oxide (48 mg, 0.21 mmol) in methylene chloride (50 ml) was added p-toluenesulfonyl chloride (0.36 g, 1.9 mmol) at 0 C., and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative TLC (methylene chloride:methanol=10:1) to give Compound (p-2) (0.31 g, 38% yield). (1171) 1H-NMR (CDCl3, 400 MHz) δ: 7.80 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.17-4.15 (m, 2H), 3.71-3.60 (m, 19H), 2.45 (s, 3H).
With triethylamine; In tetrahydrofuran;
FIGURE 36 shows the synthetic scheme used to obtain IBA-GN3. Pentaethylene glycol was treated with tosyl chloride in the presence of base to give the mono-tosylated alcohol, which was then treated with sodium azide at elevated temperature to give the azidoalcohol. This compound was then oxidized using Jones reagent, then reduced with Palladium on carbon under hydrogen atmosphere to give a carboxylic acid-amine. Separately, indole butyric acid was treated with N-hydroxysuccinimide, EDC, and DIPEA to give the NHS-ester indole, which was then reacted with the above carboxylic acid-amine. The product was again reacted with N-hydroxysuccinimide, EDC, and DIPEA to give a NHS ester. This NHS ester was reacted with NH2-GN3, which was prepared as described previously. The subsequent amide was deprotected with NaOMe in MeOH to give compound IBA-GN3.
With sodium hydroxide; In tetrahydrofuran; water monomer; at 0 - 20℃; for 2h;
General procedure: Tetraethylene glycol (10.0g, 51.5mmol) was dissolved in tetrahydrofuran (30mL) at 0C. An aqueous solution of sodium hydroxide (0.3g, 7.7mmol) and TsCl (1.0g, 5.2mmol) were added to the reaction solution, stirred at 0C for 5min, and then stirred at room temperature for 2h. After the completion of the reaction, the reaction solution was filtered, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated and washed twice with 10% NaHCO3 solution. The organic phase was concentrated and dried to obtain 1.7g of a colorless oil V-1 with a yield of 93%.
With sodium hydroxide; In tetrahydrofuran; water monomer; at 0 - 20℃; for 2h;
General procedure: Tetraethylene glycol (10.0g, 51.5mmol) was dissolved in tetrahydrofuran (30mL) at 0C. An aqueous solution of sodium hydroxide (0.3g, 7.7mmol) and TsCl (1.0g, 5.2mmol) were added to the reaction solution, stirred at 0C for 5min, and then stirred at room temperature for 2h. After the completion of the reaction, the reaction solution was filtered, and the filter cake was rinsed with dichloromethane. The filtrate was concentrated and washed twice with 10% NaHCO3 solution. The organic phase was concentrated and dried to obtain 1.7g of a colorless oil V-1 with a yield of 93%.
With potassium <i>tert</i>-butylate In tetrahydrofuran 0 deg C, 1h; rt, 14 h;
73%
Stage #1: Pentaethylene glycol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; Inert atmosphere;
Stage #2: propargyl bromide With tetra-(n-butyl)ammonium iodide In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere;
4.3.1. General procedure for bis-propargylation of diols 15a-d and mono-propargylation of alcohols 19a-d (synthesis of diynes 16b-e and alkynes 9b-e)
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.
60%
With sodium hydroxide In tetrahydrofuran; toluene at 60℃; for 24h;
14%
With caesium carbonate In toluene; acetonitrile at 85℃; for 15h; Inert atmosphere; Reflux;
14%
With caesium carbonate In toluene; acetonitrile at 85℃; for 15h; Inert atmosphere;
32 Preparation of N4-(5-N-(23'-N-(α-3"-propionamido thiomannoside)-3',6',9',12'-15'-18'-hexa-oxa-tricosanamido)aminopentyl)-spermine tetraacetate
EXAMPLE 32 Preparation of N4-(5-N-(23'-N-(α-3"-propionamido thiomannoside)-3',6',9',12'-15'-18'-hexa-oxa-tricosanamido)aminopentyl)-spermine tetraacetate A solution of pentaethylene glycol (5.0 g) in 50 mL of tetrahydrofuran was added to a rapidly stirred suspension of NaH (0.42 g of 60%) in 40 mL of tetrahydrofuran. The reaction mixture was kept under nitrogen and suspended in an ice-water bath and stirred for 0.5 h. A solution of N-CBZ-5-amino-l-bromopentane (3.78 g) in 30 mL of tetrahydrofuran was added and the mixture stirred in the ice-water bath for 1 h, then at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified on silica gel, eluding with a gradient of 2-propanol in chloroform. Fractions containing the product (TLC Rf 0.30, CHCl3/2-propanol 95:5) were combined and the solvent removed to give 3.25 g of N-CBZ-20-amino-3,6,9,12,15-penta-oxa-1-eicosanol as an oil.
Stage #1: Pentaethylene glycol With sodium hydride In 1,4-dioxane; mineral oil for 0.333333h; Inert atmosphere; Cooling with ice;
Stage #2: propargyl bromide In 1,4-dioxane; mineral oil at 20℃; for 4h; Inert atmosphere; Cooling with ice;
a.23 Preparation of compound 33a-3:
NaH (4.7 g, 118.4 mmol, 60% purity) was added in portions to the solution of 33A-2 (46.0 g, 236.8 mmol) in dry dioxane (220.0 mL) under N2and kept stirring for 20 minutes on an ice bath. A solution of 33A-1 (7.7 g, 59.2 mmol) in dry dioxane (30.0 mL) was added to this mixture dropwise over 1 hour. The resulting mixture was stirred for another 3 hours at room temperature and 20.0 ml of water was added slowly and stirred for another 20 minutes. The solvent was removed under vacuum and leftover was dissolved in DCM and washed with brine. Finally, purification using column chromatography was done eluting EA which gave the desired liquid colorless product 33A-3 (12 g, 54.98 mmol, 92.86% yield).1H NMR (400 MHz, CDCl3) δ 4.02 (d, J = 2.4 Hz, 2H), 3.54 - 3.45 (m, 14H), 3.41 (dd, J = 5.5, 3.9 Hz, 2H), 3.20 (s, 1H), 2.38 (t, J = 2.4 Hz, 1H).
61%
Stage #1: Pentaethylene glycol With sodium hydride In N,N-dimethyl-formamide at 0℃; Inert atmosphere;
Stage #2: propargyl bromide In N,N-dimethyl-formamide; toluene at 20℃; for 48h; Inert atmosphere;
General Procedure A: Propargylation of polyethylene glycol
General procedure: Sodium hydride (1.5 eq.) was added under a nitrogen atmosphere to a cooled (0 °C) solution ofpolyethylene glycol 9 (1 eq.) in anhydrous DMF followed by a solution of propargyl bromide intoluene (80% wt, 3 eq.). The reaction mixture was stirred at room temperature for 2 days. It was thenconcentrated in vacuo to give an oil, which was purified by column chromatography (hexane/EtOAc).
60%
Stage #1: Pentaethylene glycol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: propargyl bromide In N,N-dimethyl-formamide at 20℃; for 6h;
45%
With sodium hydride In tetrahydrofuran
41%
Stage #1: Pentaethylene glycol With sodium hydride In tetrahydrofuran at 0 - 10℃; for 0.5h;
Stage #2: propargyl bromide In tetrahydrofuran at 0 - 10℃; for 3.5h;
299a Intermediate 299a: 3,6,9,12,15-pentaoxaoctadec-17-yn-1-ol
Into a 1000-mL 3-necked round-bottom flask, was placed a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (60 g, 251.78 mmol, 0.90 equiv) in tetrahydrofuran (300 mL). This was followed by the addition of sodium hydride (6.7 g, 0.66 equiv, 60%) at 0-10° C. The mixture was stirred for 0.5 h at 0-10° C. To this was added a solution of 3-bromoprop-1-yne (33.32 g, 280.00 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) dropwise with stirring in 1.5 h. The resulting solution was stirred for 2 h at 0˜10° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (4:12:1). This resulted in 32.1 g (41%) of intermediate 299a as light yellow oil.
41%
Stage #1: Pentaethylene glycol With sodium hydride In tetrahydrofuran; mineral oil at 0 - 25℃; for 0.333333h; Inert atmosphere; Schlenk technique;
Stage #2: propargyl bromide In tetrahydrofuran; toluene at 25℃; for 18h; Inert atmosphere; Schlenk technique;
Stage #1: Pentaethylene glycol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: propargyl bromide In N,N-dimethyl-formamide at 20℃; for 6h;
Stage #1: Pentaethylene glycol With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere;
Stage #2: propargyl bromide In tetrahydrofuran at 80℃; for 18h; Inert atmosphere;
4.1.6. The general method for the synthesis of 15 and 17a-d
General procedure: Compounds 15 and 17a-d were prepared following the method as described for 17a. To a suspension of KOt-Bu (116 g, 1 mol) in dry THF (1 L) was added diethylene glycol (2.00 g, 1.9 mmol) at 0 °C under N2 atmosphere. The reaction mixture was allowed to stir at 20 °C for 30 min then propargyl bromide (1.40 g, 0.94 mmol) was added dropwise. The resulting mixture was allowed to stir at 80 °C for 18 h. The mixture was filtered and concentrated under reduced pressure and the resulting residue was purified by column chromatography (Petroleum ether: EtOAc 50/1 to 0:1) furnish 17a(0.40 g, 0.27 mmol, 15% yield) as a yellow oil.
[(2R,3R,4R,5R,6R)-5-acetamido-3,4-diacetoxy-6-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]tetrahydropyran-2-yl]methyl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38.1%
With pyridinium p-toluenesulfonate at 80℃; for 18h;
69 1-O-(14-Hydroxy-3,6,9,12-tetraoxatetradecyl)-3,4,6-tri-O-acetyl-2-acetylamino-2-deoxy-β-D-galactopyranoside (7e)
Example 69 1-O-(14-Hydroxy-3,6,9,12-tetraoxatetradecyl)-3,4,6-tri-O-acetyl-2-acetylamino-2-deoxy-β-D-galactopyranoside (7e) A mixture of compound 5 (1.64 g, 5.0 mmol), anhydrous pentaethyleneglycol (7.15 g, 30.0 mol), and pyridinium p-toluenesulfonate (1.13 g, 4.5 mmol) was heated at 80° C. for 18 h, then distributed between DCM (50 mL) and a 1:1 mixture of brine and 5% aqueous NaHCO3 (25 mL). The organic phase was separated, dried over Na2SO4, and evaporated in vacuo. The product was isolated by column chromatography on silica gel eluted with a step gradient from DCM to a mixture of MeOH and DCM (8:92). Evaporation of the relevant fractions gave the title compound as an off-white solid (1.08 g, 38.1%). ES MS: 568.0 (MK). Calculated for C18H29NO11.H+: 568.2.
Stage #1: Pentaethylene glycol With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h;
Stage #2: 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole In tetrahydrofuran; N,N-dimethyl-formamide at 80℃; for 4h;
4 Step 4: 14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-ol
To a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (270 mg, 1.13 mmol) in THF (10 mL) was added NaH (45 mg, 60%, 1.13 mmol) at 0° C. After stirring at 20° C. for 1 hour, a solution of 7-(6-Fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (150 mg, 0.57 mmol) in DMF (2.0 mL) was added. The resulting solution was stirred at 80° C. for 4 hours. After cooling to room temperature, the reaction was diluted with EA (30 mL), and the mixture was washed with brine. The organic phase was evaporated under reduced pressure. The residue was purified by silica gel column chromatography on silica gel (DCM/MeOH=4/1) to afford the desired product (200 mg. 72.89% yield) as a colorless oil.
72.89%
Stage #1: Pentaethylene glycol With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h;
Stage #2: 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole In tetrahydrofuran; N,N-dimethyl-formamide at 80℃; for 4h;
4 Step 4: 14-((5-(5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)-3,6,9, 12- tetraoxatetradecan- 1 -ol
To a solution of 3,6,9, 12-tetraoxatetradecane-l,14-diol (270mg, 1.13 mmol) in THF (10 mL) was added NaH (45 mg, 60%, 1.13 mmol) at 0°C. After stirring at 20°C for 1 hour, a solution of 7-(6-Fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole (150 mg, 0.57 mmol) in DMF (2.0 mL) was added. The resulting solution was stirred at 80°C for 4 hours. After cooling to room temperature, the reaction was diluted with EA (30 mL), and the mixture was washed with brine. The organic phase was evaporated under reduced pressure. The residue was purified by silica gel column chromatography on silica gel (DCM/MeOH= 4/1) to afford the desired product (200mg.72.89%yield) as a colorless oil.
Stage #1: Pentaethylene glycol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h;
Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 60℃; for 3h;
70.1 1. Step- Synthesis of 1-Phenyl-2,5,8,11-tetraoxatridecan-13-ol
To a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (45 g, 234 mmol) in (1988) DMF(100 mL), was added NaH (60 %, 2.34 g, 58.5 mmol) at 0oC. After stirring at RT 1 h, BnBr (10 g ,58.5 mmol) was added and the mixture was heated to 60oC for 3h. Then the reaction mixture was quenched with water (100 mL) and the resulting reaction mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (hexane : EtOAc1 : 3) to afford the desired product 1-Phenyl-2,5,8,11- tetraoxatridecan-13-ol (15 g, 52.8 mmol, 90%). 1H NMR (400 MHz, CDCl3): δ 7.277.34(m, 5H), 4.57(s, 2H), 3.593.73 (m, 16H),.Chemical Formula: C15H24O5; Molecular Weight: 284.35
With potassium iodide; silver(l) oxide In dichloromethane
With potassium hydroxide; In water; at 20℃; for 0.333333h;
1 part by mole of p-ethylene glycol bis-p-toluenesulfonate, 1.3 parts by mole of pentaethylene glycol, and 2 parts by mole of potassium hydroxide are sequentially added to an industrial microwave reactor.1 mole of water,React at 20 C for 20 minutes,After the reaction is completed, the salt is separated, extracted, and the solvent is distilled off.The crude product was distilled under reduced pressure to give 18-crown ether-6, yield 55%.
14-(4-(naphthalen-2-yl)piperidin-1-yl)-3,6,9,12-tetraoxatetradecan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: Pentaethylene glycol With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; bis[2-(diphenylphosphino)phenyl] ether at 110℃; for 1h; Molecular sieve; Inert atmosphere;
Stage #2: 4-(naphthalen-2-yl)piperidine hydrochloric salt at 110℃; for 18h; Molecular sieve; Inert atmosphere;
With sodium hydride In water at 66℃; for 12h; Cooling with ice;
1-13 Example 1
Under ice water bath, add pentaethylene glycol (1.5 g, 6.3 mmol) to the reaction vessel,Tetrahydrofuran (25 ml), solid sodium hydride (0.25 g, content 60%, 6.3 mmol),Bromotridecane (1.7 g, 6.3 mmol), stir for 10 minutes,Then it was heated to reflux (66°C) in an oil bath, after 6 hours of reaction,Distill off tetrahydrofuran under reduced pressure, add water and mix and extract with ethyl acetate.The resulting organic phase was dried with anhydrous sodium sulfate, and then optionally evaporated to remove ethyl acetate,To get the crude product, add petroleum ether to the crude product,Separate and purify through a suction filter funnel equipped with 200-300 mesh silica gel,The obtained filtrate was passed through a rotary evaporator to remove petroleum ether to obtain the target compound 3,6,9,12,15-pentaoxaoctacosan-1-ol (2.3 g, 5.5 mmol), yield: 87.3%.