* 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.
2-(2-(2-Methoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (Al, 1.0 g, 3.14 mmol) was added with stir to triethylene glycol (2.10 mL, 15.7 mmol). Potassium hydroxide (510 mg, 9.42 mmol) was ground into a powder and added to the reaction and the mixture refluxed at 100°C for 12 hours, upon which the reaction was diluted with water (50 mL) and extracted with DCM. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain 2,5,8,1 l,14,17-hexaoxanonadecan-19-ol as a yellow oil in 69percent yield.
65%
Reflux
The synthesis of compound 3 is shown in Figure 5. Synthesis of compound 3 began by coupling tosylate (6) to triethylene glycol (16) under basic conditions to yield hexaethylene glycol monomethyl ether (17) in 65percent yield. Hexaethylene glycol monomethyl ether (17) was then converted to the corresponding tosylate (18) in 77percent yield, followed by conversion to the azide. The azide was reduced to the corresponding amine (19) via a hydrogenation over activated palladium on carbon in 45percent yield. The amine was coupled to cyanoacetic acid using 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in 80percent yield to give the cyano-acetamide (20). The resulting amide (20) was coupled with previously synthesized piperidine-naphthalene (12) to give compound 3 via Knovenagel condensation in 61percent yield.
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 20, p. 7499 - 7508
[2] Organic Letters, 2004, vol. 6, # 4, p. 469 - 472
[3] Patent: WO2015/143185, 2015, A1, . Location in patent: Paragraph 00819
[4] Patent: WO2016/40891, 2016, A2, . Location in patent: Paragraph 00316
[5] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 7, p. 2193 - 2198
2
[ 125562-28-9 ]
[ 23601-40-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
With hydrogen In tetrahydrofuran for 1.5 h;
D. Hexaethylene Glycol Monomethvl Ether A 50percent wet paste of 10percent palladium on carbon (0.71 g, 5 molpercent) was charged to a nitrogen purged flask. A solution of hexaethylene glycol monomethyl monobenzyl ether ("BnO-6EG-OMe"; 2.66g, 6.88 mmol) in tetrahydrofuran (26.6 mL) was added. The mixture was stirred under an atmosphere of hydrogen for 90 minutes. The mixture was filtered through celite to remove the catalyst. The solids were washed with tetrahydrofuran (20 mL). The filtrate was concentrated to dryness to give hexaethylene glycol monomethyl ether (2.01 g, 99percent theory). 1H NMR (250 MHz, CDCl3, S44238) No.H (CDCl3, ppm from TMS) 3.8-3.5 (24 H, m, CH2 x 12), 3.38 (3 H, s, OCH3), 2.08 (1 H, brs, OH).
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
(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). 1H NMR (400 MHz, CDCl3) δ 3.73-3.70 (m, 2H), 3.70-3.63 (m, 18H), 3.62-3.59 (m, 2H), 3.57-3.55 (m, 2H), 3.39 (s, 3H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 22, p. 3502 - 3505
4
[ 2615-15-8 ]
[ 74-88-4 ]
[ 23601-40-3 ]
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 17, p. 5682 - 5685
[2] Journal of Organometallic Chemistry, 2005, vol. 690, # 24-25, p. 5581 - 5590
[3] Chemical Communications, 2006, # 32, p. 3438 - 3440
[4] Journal of the American Chemical Society, 1995, vol. 117, # 23, p. 6249 - 6253
[5] European Journal of Organic Chemistry, 2008, # 19, p. 3308 - 3313
[6] Dalton Transactions, 2012, vol. 41, # 9, p. 2738 - 2746
5
[ 1134159-69-5 ]
[ 23601-40-3 ]
Reference：
[1] Chemistry - An Asian Journal, 2011, vol. 6, # 2, p. 452 - 458
[2] Journal of Organic Chemistry, 2011, vol. 76, # 3, p. 875 - 881
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, ,
8
[ 112-35-6 ]
[ 112-27-6 ]
[ 23601-40-3 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1988, vol. 160, p. 331 - 338
9
[ 67-56-1 ]
[ 2615-15-8 ]
[ 74-88-4 ]
[ 23601-40-3 ]
Reference：
[1] Patent: US5606038, 1997, A,
10
[ 74654-05-0 ]
[ 112-27-6 ]
[ 23601-40-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 24, p. 10295 - 10300
11
[ 2615-15-8 ]
[ 77-78-1 ]
[ 23601-40-3 ]
Reference：
[1] New Journal of Chemistry, 2008, vol. 32, # 7, p. 1140 - 1152
12
[ 62921-74-8 ]
[ 23601-40-3 ]
Reference：
[1] Chemistry - An Asian Journal, 2011, vol. 6, # 2, p. 452 - 458
13
[ 60221-37-6 ]
[ 23601-40-3 ]
Reference：
[1] Chemistry - An Asian Journal, 2011, vol. 6, # 2, p. 452 - 458
14
[ 112-27-6 ]
[ 23601-40-3 ]
Reference：
[1] Chemistry - An Asian Journal, 2011, vol. 6, # 2, p. 452 - 458
15
[ 111-77-3 ]
[ 23601-40-3 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 9, p. 1357 - 1360
16
[ 5197-62-6 ]
[ 23601-40-3 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 3, p. 875 - 881
17
[ 85539-28-2 ]
[ 23601-40-3 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 3, p. 875 - 881
18
[ 112-60-7 ]
[ 23601-40-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 22, p. 3502 - 3505
19
[ 112-60-7 ]
[ 50586-80-6 ]
[ 23601-40-3 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 9, p. 1357 - 1360
20
[ 75-21-8 ]
[ 109-86-4 ]
[ 23601-40-3 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1973, vol. 46, p. 623 - 626
21
[ 52995-76-3 ]
[ 112-27-6 ]
[ 23601-40-3 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1978, vol. 51, p. 3111 - 3120
22
[ 23601-40-3 ]
[ 27425-92-9 ]
Yield
Reaction Conditions
Operation in experiment
86%
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
3.1 Step 1; Preparation of 2,5,8,11, 14,17-hexaoxanonadecan-19-ol
2-(2-(2-Methoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (Al, 1.0 g, 3.14 mmol) was added with stir to triethylene glycol (2.10 mL, 15.7 mmol). Potassium hydroxide (510 mg, 9.42 mmol) was ground into a powder and added to the reaction and the mixture refluxed at 100°C for 12 hours, upon which the reaction was diluted with water (50 mL) and extracted with DCM. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain 2,5,8,1 l,14,17-hexaoxanonadecan-19-ol as a yellow oil in 69% yield.
69%
With potassium hydroxide at 100℃; for 12h;
3.1 Step 1: Preparation of 2,5,8,11,14,17-hexaoxanonadecan-19-ol
2-(2-(2-Methoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (A1, 1.0 g, 3.14 mmol) was added with stir to triethylene glycol (2.10 mL, 15.7 mmol). Potassium hydroxide (510 mg, 9.42 mmol) was ground into a powder and added to the reaction and the mixture refluxed at 100° C. for 12 hours, upon which the reaction was diluted with water (50 mL) and extracted with DCM. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain 2,5,8,11,14,17-hexaoxanonadecan-19-ol as a yellow oil in 69% yield.
65%
With potassium hydroxide Reflux;
3
The synthesis of compound 3 is shown in Figure 5. Synthesis of compound 3 began by coupling tosylate (6) to triethylene glycol (16) under basic conditions to yield hexaethylene glycol monomethyl ether (17) in 65% yield. Hexaethylene glycol monomethyl ether (17) was then converted to the corresponding tosylate (18) in 77% yield, followed by conversion to the azide. The azide was reduced to the corresponding amine (19) via a hydrogenation over activated palladium on carbon in 45% yield. The amine was coupled to cyanoacetic acid using 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in 80% yield to give the cyano-acetamide (20). The resulting amide (20) was coupled with previously synthesized piperidine-naphthalene (12) to give compound 3 via Knovenagel condensation in 61% yield.
65%
With potassium hydroxide for 12h; Heating;
50%
With sodium at 50 - 100℃; for 49h; Inert atmosphere;
Multi-step reaction with 3 steps
1: Et3N / CH2Cl2 / -10 - 20 °C
2: NaN3, tetrabutylammonium hydrogen sulfate / dimethylformamide / 5 h / 40 °C
3: 61 percent / H2 / Pd/C / methanol / 4 h / 5250.4 Torr
Multi-step reaction with 3 steps
1: 68 percent / triethylamine / tetrahydrofuran / 24 h / Ambient temperature
2: dimethylformamide / 3 h / 120 °C
3: hydrazine / ethanol / 1.5 h / Heating
Multi-step reaction with 3 steps
1.1: pyridine; dmap / dichloromethane / 0.25 h / 0 °C
1.2: 4 h / 20 °C
2.1: sodium azide / water; acetone / 75 °C
3.1: triphenylphosphine / tetrahydrofuran / 5 h / 20 °C
3.2: 80 °C
Multi-step reaction with 3 steps
1.1: triethylamine / dichloromethane / 24 h / 0 - 4 °C
2.1: sodium azide / N,N-dimethyl-formamide / 70 °C
3.1: triphenylphosphine / tetrahydrofuran / 10 h / 0 - 20 °C
3.2: 10 h
Multi-step reaction with 3 steps
1: triethylamine / dichloromethane / 24 h / 0 - 20 °C
2: sodium azide / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere
3: 15% palladium on carbon; hydrogen / ethanol / 4 h / 2585.81 - 3102.97 Torr
Multi-step reaction with 2 steps
1.1: dichloromethane / 24 h / 0 - 20 °C
2.1: N,N-dimethyl-formamide / 12 h / Reflux
2.2: 4 h / 2585.81 Torr
Multi-step reaction with 3 steps
1: triethylamine / dichloromethane / 24 h / 0 - 20 °C
2: sodium azide / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere
3: hydrogen; 15% palladium on carbon / ethanol / 4 h / 2585.81 - 3102.97 Torr
Multi-step reaction with 3 steps
1.1: triethylamine / dichloromethane / 0 - 20 °C
2.1: sodium azide / N,N-dimethyl-formamide / 12 h / 80 °C
3.1: triphenylphosphine / diethyl ether / 2 h / 0 - 20 °C
3.2: 4 h / 20 °C
Multi-step reaction with 3 steps
1: potassium hydroxide / dichloromethane / 8 h
2: sodium azide / N,N-dimethyl-formamide / 5 h / 60 °C / Inert atmosphere
3: platinum(IV) oxide; hydrogen / methanol / 20 °C / 760.05 Torr
Stage #1: hexaethylene glycol monomethyl ether With potassium <i>tert</i>-butylate In tetrahydrofuran at 5℃; for 0.366667h;
Stage #2: triethylene glycol monobenzyl tosyl ether In tetrahydrofuran at 5 - 20℃; for 19.5h;
Stage #3: With potassium <i>tert</i>-butylate; water more than 3 stages;
1.E
E. Nonaethylene Glycol Monobenzyl Monomethyl Ether A solution of potassium tert-butoxide (0.78 g, 6.8 mmol) in tetrahydrofuran (7.5 mL) was cooled to 5 °C. A solution of hexaethylene glycol monomethyl ("MeO-6EG-OH", 1.83 g, 6.19 mmol) in tetrahydrofuran (10 mL) was added dropwise over ten minutes. After 12 minutes, a solution of triethylene glycol monobenzyl ether 4- toluenesulfonate ("BnO-3EG-OTs", 3.17 g, 8.04 mmol) in tetrahydrofuran (7.5 mL) was added over four minutes. The mixture was allowed to warm to room temperature. After 19.5 hours, a solution of potassium tert-butoxide (0.45 g, 4.0 mmol) in tetrahydrofuran (5.0 mL) was added. After 90 minutes more the reaction was quenched with water (15 mL) and the tetrahydrofuran was removed by distillation under reduced pressure. The resulting aqueous layer was washed with diisopropyl ether (3 x 20 mL) then extracted with dichloromethane (2 x 20 mL). The dichloromethane layers were combined and washed with water (2 x 20 mL) then saturated aqueous sodium bicarbonate (4 x 20 mL) then concentrated to dryness to give nonethylene glycol monomethyl monobenzyl ether (2.52 g, 79% theory. ¹H NMR (400 MHz, CDCl3, A11016) No.H (CDCl3, ppm from TMS) 7.4-7.2 (5 H, m, Ar-H), 4.57 (2 H, s, PhCH20-), 3.7-3.6 (34 H, m, CH2 x 17), 3.6-3.5 (2 H, m, CH2), 3.38 (3 H, s, OCH3).
3.36 g of dry MPEG 296 (1.135 102mol) and 0.274 g NaH (1.14 102mol) were placed together in a vacuum glass ampoule closed with Rotao stopcock and attached to the vacuum line. The ampoule was evacuated in the usual way and ~5 mL of THF was distilled in on the vacuumline. Then the ampoule was kept at 35 C for a few hours, until all NaH reacted (no gas evolution (H2)was observed). From time to time the ampoule was evacuated to remove evolved hydrogen. This way MPEG 296 was transformed completely into its alcoholate analog (MPEG-O-, 296). To the fltered solution ~5 mL of THF and 4.85 g of DGNG (2.245 102mol) were added (ratio of [DGNG]0/[MPEG-O-]0=1.98; concentration of reagents: c 45.9 wt%). During this operation dry Ar was passing through the ampoule. The reaction mixture was kept at 25 C (the temperature was chosen low enough in order to have reaction sufciently slow to follow its progress effectively also in the initial stage) and from time to time small samples were taken from the reaction mixture for determination of the progress of reaction by 1H NMR (the content of epoxy groups and the ratio of p-O- and s-O- groups), SEC and MALDI-TOF-ms. Samples were divided into two parts. One part was terminated with 5 vol% CH3COOH/CH3OH mixture and to the second part 2 mol% solution of C2H5ONa/C2H5OH was added and finally after 24 h also terminated with 5 vol% CH3COOH/CH3OH mixture. Before NMR analysis samples were concentrated and dried on the vacuum line. Reactions were completed when no more epoxy groups were detected by 1H NMR in the reaction mixture.When it was necessary the reaction product was purified by ultraltration (cf. Supporting information).
8
[ 23601-40-3 ]
[ 85030-56-4 ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 3 steps
1.1: dmap; pyridine / dichloromethane / 0.25 h / 0 °C
1.2: 6 h / 20 °C
2.1: sodium azide / water; acetone / 75 °C
3.1: triphenylphosphine / tetrahydrofuran / 5 h / 20 °C
1,3,6,9,12-pentaoxa-2-thiacyclotetradecane 2,2-dioxide[ No CAS ]
[ 27425-92-9 ]
Yield
Reaction Conditions
Operation in experiment
86%
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).
85%
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).
With stannous octoate In toluene Reflux; Inert atmosphere;
2.1 Method 1:
In a 100 mL round bottom flask, 1.7787 g (6 mmol) of dried hexaethylene glycol monomethyl ether (5), 1.044 g (9 mmol) of diglycolic anhydride, and 200 mg of tin 2-ethylhexanoate were added.Further, 30 mL of toluene was added, stirred, and heated under reflux with nitrogen to reflux until the reaction was completed.After removing the toluene in the reaction liquid by a rotary evaporator, 20 mL of ethyl acetate was added and stirred.Further, 10 mL of diethyl ether was added to precipitate a white solid, and the solid matter was removed, and the solution was concentrated to 10 mL by a rotary evaporator, and the column was separated to obtain 1.914 g of hexaethylene glycol monomethyl ether diglycolate (6).The yield was 77.5%.
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