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[ CAS No. 112-60-7 ] {[proInfo.proName]}

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Chemical Structure| 112-60-7
Chemical Structure| 112-60-7
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Product Details of [ 112-60-7 ]

CAS No. :112-60-7 MDL No. :MFCD00002879
Formula : C8H18O5 Boiling Point : -
Linear Structure Formula :- InChI Key :UWHCKJMYHZGTIT-UHFFFAOYSA-N
M.W :194.23 Pubchem ID :8200
Synonyms :
Tetraethylene glycol

Calculated chemistry of [ 112-60-7 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 10
Num. H-bond acceptors : 5.0
Num. H-bond donors : 2.0
Molar Refractivity : 46.15
TPSA : 68.15 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -8.61 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.38
Log Po/w (XLOGP3) : -1.58
Log Po/w (WLOGP) : -0.98
Log Po/w (MLOGP) : -1.27
Log Po/w (SILICOS-IT) : 0.49
Consensus Log Po/w : -0.19

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 0.61
Solubility : 793.0 mg/ml ; 4.09 mol/l
Class : Highly soluble
Log S (Ali) : 0.66
Solubility : 882.0 mg/ml ; 4.54 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -1.19
Solubility : 12.4 mg/ml ; 0.064 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 2.48

Safety of [ 112-60-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 112-60-7 ]

* 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.

  • Upstream synthesis route of [ 112-60-7 ]
  • Downstream synthetic route of [ 112-60-7 ]

[ 112-60-7 ] Synthesis Path-Upstream   1~58

  • 1
  • [ 112-60-7 ]
  • [ 33941-15-0 ]
Reference: [1] Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 1, p. 219 - 225
[2] Russian Journal of Organic Chemistry, 2012, vol. 48, # 10, p. 1345 - 1352[3] Zh. Org. Khim., 2012, vol. 48, # 10, p. 1350 - 1357,8
[4] Polyhedron, 2018, vol. 141, p. 385 - 392
  • 2
  • [ 112-60-7 ]
  • [ 98-59-9 ]
  • [ 37860-51-8 ]
  • [ 77544-60-6 ]
YieldReaction ConditionsOperation in experiment
35.9% With triethylamine In acetonitrile at 0 - 25℃; for 1 h; Cooling with ice 20.0 g of triethylene glycol and 10.2 g of triethylamine were charged into a reaction flask, 300 ml of acetonitrile was added thereto, and the mixture was cooled in an ice bathTo 0-5 ° C, 19.0gTsCl dissolved in 100ml acetonitrile slowly dripping into the solution, 1h drops finished, finished after the drop to 20-25Deg.] C for 12-14 h, the solvent was removed by rotary column chromatography, and eluted with n-hexane: ethyl acetate volume ratio= 4: 1 and 1.5: 1 gradient elution, in n-hexane: ethyl acetate volume ratio = 4: 1 eluentTo give 12.9 g of an oily product (compound thirteen) in a yield of 35.9percent in n-hexane: ethyl acetate volume ratio = 1.5: 1To give 5.4 g of an oil (Compound 14) in a yield of 10.4percent.
Reference: [1] Organic Letters, 2002, vol. 4, # 14, p. 2329 - 2332
[2] Journal of Organic Chemistry USSR (English Translation), 1990, vol. 26, # 11, p. 2094 - 2100[3] Zhurnal Organicheskoi Khimii, 1990, vol. 26, # 11, p. 2425 - 2433
[4] Patent: CN105541736, 2016, A, . Location in patent: Paragraph 0044; 0052
[5] Journal of the Chemical Society, Perkin Transactions 2, 2001, # 9, p. 1573 - 1584
[6] Patent: WO2009/108484, 2009, A1, . Location in patent: Page/Page column 22; 23
[7] Patent: US2012/4423, 2012, A1, . Location in patent: Page/Page column 10
  • 3
  • [ 112-60-7 ]
  • [ 98-59-9 ]
  • [ 37860-51-8 ]
YieldReaction ConditionsOperation in experiment
98% With potassium hydroxide In dichloromethane at 0 - 10℃; for 3 h; General procedure: Compounds 2a–c were prepared by a modified procedure known from the literature1. Oligo ethylene glycol(37.7 mmol) and p-toluenesulfonyl chloride (14.4 g, 75.4 mmol, 2 equiv) were dissolved in dichloromethane (36 mL)and this solution was cooled to 0 °C. During permanent stirring, milled potassium hydroxide (17 g, 302 mmol, 8equiv) was added and the solution was then stirred for 3 hours while the temperature was kept from 0 to 10 °C. This reaction was monitored by TLC (UV detection). After warming up to room temperature the reaction mixture was diluted by chloroform and extracted with water (3 × 1:1). Chloroform extracts were collected, dried over magnesium sulfate overnight, filtered and solvents were evaporated under reduced pressure.
98% With potassium hydroxide In dichloromethane for 1.5 h; Cooling with ice The 10mL (0.068mol) of tetraethylene glycol,300ml dichloromethane,25.8g (0.136mol)MethylBenzenesulfonyl chloride,Added to a 500ml round-bottomed flask,Under ice-cooling,Was slowly added 30.4g (0.544mol) of potassium hydroxide,1.5h the reaction is substantially complete.The reaction solution was washed three times with water (3 × 100ml),The organic layer was collected,Dried over anhydrous sodium sulfate.filter,Spin dry solvent,To give the crude product as an oil.Column chromatography (petroleum ether: ethyl acetate = 1:4) to give a pale yellow oily liquid 34g.The yield was 98percent.
95% With 1H-imidazole; triethylamine In dichloromethane at 0 - 20℃; 0-Ditosylate Tetraethylne Glycol (32). Compound 2 (5.00 mL, 28.95 mmol) was added dropwise to a stirred solution of /Moluenesulfonyl chloride (12.15 g, 63.73 mmol), imidazole (0.04 g, 0.65 mmol) and Et3N (16.15 mL, 108.30 mmol) in CH2Cl2 (30 mL) at 0 0C. The reaction mixture was allowed to stir at room temperature (12 h), and then Et2O (80 mL) was added and the reaction washed with H2O (5 x 60 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo, and then the crude product was purified by column chromatography (SiO2; 3/1 EtOAc/hexanes) to yield 13.81 g (95percent) of 32 as a clear oil (Busch et al., 2002): Rf = 0.65 (3/1 EtOAc/hexanes); 1H NMR (CDCl3) δ 2.44 (s, 2 CH3), 3.53-3.59 (m, 2 OCH2CH2O), 3.68 (t, J = 4.8 Hz, OCH2CH2OTs), 4.15 (t, J = 4.8 Hz, OCH2CH2OTs), 7.34 (d, J= 8.4 Hz, 4 ArH), 7.79 (d, J= 8.4 Hz, 4 ArH); 13C NMR (CDCl3) δ 21.7 (CH3), 68.8 , 69.4, 70.6, 70.8 (OCH2CH2O, OCH2CH2OTs), 128.1, 130.1, 133.1, 145.0 (C6H4).
89%
Stage #1: With potassium hydroxide In dichloromethane at 0 - 20℃;
Stage #2: at 20℃; for 10 h;
General procedure: KOH (20 g, 356.5 mmol for 9; and 10 g, 181.5 mmol for 10–11) was added to 300 mL of a CH2Cl2 solution containing the oligoethylene glycol (10 g,94 mmol for 9, 66.6 mmol for 10, and 51.5 mmol for 11) at 0 °C. After stirring for 30 min at room temperature, TsCl (45 g, 236 mmol for 9–11) was added and the resulting solution was stirred for 10 h at room temperature. The resulting solution was filtered and then washed with aq. K2CO3. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The resulting residue was then subjected to silicagel column chromatography (EtOAc:Hex = 1:1) to yield 35 g of 9 (90percent), 27 g of 10 (88percent), and 23 g of 11 (89percent).
74.4% With triethylamine In dichloromethane at 0 - 20℃; To a solution of 2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethan-l-ol (13 g, 67.1 mmol), Et3N (13 mL) in DCM (100 mL) was added TsCl (25.5 g, 134.2 mmol) in portions at 0°C. The resulting mixture was allowed to stir at room temperature overnight. TLC showed the reaction completed. The mixture was partitioned between DCM and H20. The organic phase was washed with brine, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography using with 10-20percent EtOAc in hexane as eluent to afford the desired compound (25.0 g, 74.4percent).
73% With triethylamine In dichloromethane at 25℃; for 12 h; Tetraethylene glycol (3.88 g, 20 mmol) and triethylamine (TEA) (8.0 mL) were dissolved in dichloromethane (60 mL). Then, tosyl-chloride (9.50 g, 50 mmol) was added in one portion. The resulting mixture was stirred at 25 oC for 12 h. After washing with KHSO4 (1 M, 40 mL) and NaHCO3 (5percent, 40 mL), respectively and drying over Na2SO4, the crude product was obtained by evaporation and subsequently purification by column chromatography over silica gel (dichloromethane) to obtain the target product 7 as a colorless oil (7.5 g, 14.6 mmol, 73percent).
73% With potassium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 18 h; Inert atmosphere; Glovebox A 1 L round bottom flask, charged with a magnetic stir bar, THF (400 mL), ptoluenesulfonylchloride(165.6 g, 0.868 mol) and tetraethylene glycol (56.4 g, 0.290 mol). Theflask was cooled to 0°C and a solution of KOH (104.8 g in 100 mL water, 1.87 mol) was addeddropwise through a dropping funnel over the course of 3 h. After addition, the mixture was allowedto stand at ambient temperature for 18 h. At this stage, the reaction mixture had generated a whiteprecipitate. The reaction was poured into 600 mL of water/CH2Cl2 mixture (70/30). The two-phasesolvent system was separated, and the aqueous phase was extracted four times with 100 mLCH2Cl2. Note: Before extraction the aqueous phase is denser than CH2Cl2. The organic phaseswere combined, dried over MgSO4 and solvent was evaporated under reduced pressure to yield acolorless oil. (53.3 g, 73percent). The NMR spectra are consistent with published data.
58% With triethylamine In dichloromethane at 0 - 20℃; for 6 h; Under room temperature, the methyl sulfonyl chloride (29.5g, 155mmol) by adding 2,2 ' - ((oxygen dihydrogenmethylenebisphosphonate (ethane -2,1-diyl)) double (oxy)) b ethanol 20a (10.0g, 51 . 5mmol) in dichloromethane (150 ml) solution, in 0 °C next, add triethylamine (32.6 ml, 232mmol), stirring 5 minutes, to the reaction room temperature for 6 hours. Added to the reaction solution 100 ml water quenching reaction, separation, of sequentially separated organic phase is washed with water (100 ml), saturated salt water washing (100 ml), then dried with anhydrous sodium sulfate, filtered, filtrate concentrated. The resulting residue is purified by silica gel column chromatography [petroleum ether/ethyl acetate (v/v)=10/1], to obtain title compound 20b (15g, pale yellow liquid), yield: 58.0percent.
43% With dmap In dichloromethane at 5 - 20℃; Into a 250-mL 3-necked round-bottom flask, was placed a solution of tetraethylene glycol (10 g, 51 55 mmol, 1 00 equiv) in DCM (100 mL) This was followed by the addition of a solution of 4-methylbenzene-l-sulfonyl chloride (21 4 g, 112 63 mmol, 2 20 equiv) in DCM (50 mL) dropwise with stirring at 5°C To this was added N,N-dimethylpyridin-4-amine (15 7 g, 128 69 mmol, 2 50 equiv) The resulting solution was stirred for 2 h at room temperature at which time it was diluted with 100 mL of water The resulting solution was extracted with 3x100 mL of DCM and the organic layers combined The resulting mixture was washed with 1x100 mL of brine and then concentrated under vacuum The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1 2) to afford H g (43percent) of the title compound as white oil.
21.4 g at 0 - 10℃; for 2 h; Example 4
19.1 g paratoluensulfonyl chloride and 40 mL pyridine are added in 250 mL three-neck flask, and cooled to 0° C. 9.7 g HO-PEG(n=4)-OH is mixed uniformly with 20 mL pyridine, and then dripped in the three-neck flash, and the temperature is controlled between 0 and 10° C. Stirring and reaction is continued at this temperature for two hours. TLC monitors that the reaction is complete. 300 mL cold water and 60 mL concentrated hydrochloric acid are added in the reaction liquid and slowly stirred for half an hour, then the reaction liquid is transferred into a 500 mL separating funnel, acetic ether is added to extract twice (300 mL+200 mL). The organic layers are merged and washed by water to neutrality, dried by anhydrous sodium sulfate for two hours. A rotary evaporator evaporates out solvent to obtain 21.4 g viscous liquid, which will be directly used for next reaction.

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  • 4
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  • 23
  • [ 75-21-8 ]
  • [ 111-46-6 ]
  • [ 112-60-7 ]
  • [ 4792-15-8 ]
  • [ 112-27-6 ]
Reference: [1] Yakugaku Zasshi, 1944, vol. 64, p. 295 - 298[2] Chem.Abstr., 1951, p. 5104
  • 24
  • [ 112-60-7 ]
  • [ 74654-05-0 ]
  • [ 4437-01-8 ]
YieldReaction ConditionsOperation in experiment
82%
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.
Reference: [1] Patent: US2003/228275, 2003, A1, . Location in patent: Page 40
[2] Patent: US2003/228275, 2003, A1, . Location in patent: Page 42
[3] Patent: US2003/229009, 2003, A1, . Location in patent: Page 38
  • 25
  • [ 112-60-7 ]
  • [ 4437-01-8 ]
Reference: [1] Patent: US2003/87808, 2003, A1,
[2] Patent: US2003/69170, 2003, A1,
[3] Patent: US2004/38866, 2004, A1,
[4] Patent: US2003/228652, 2003, A1,
[5] Patent: US6867183, 2005, B2,
[6] Patent: WO2018/96464, 2018, A1,
[7] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 22, p. 3502 - 3505
  • 26
  • [ 112-60-7 ]
  • [ 4437-01-8 ]
YieldReaction ConditionsOperation 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, 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.
Reference: [1] Patent: US2003/27748, 2003, A1,
[2] Patent: US2003/27995, 2003, A1,
  • 27
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  • [ 62921-74-8 ]
  • [ 4437-01-8 ]
Reference: [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 6, p. 1700 - 1707
  • 28
  • [ 112-60-7 ]
  • [ 52995-76-3 ]
  • [ 4437-01-8 ]
Reference: [1] Liebigs Annalen der Chemie, 1980, # 6, p. 858 - 862
[2] Journal of Mass Spectrometry, 2002, vol. 37, # 7, p. 699 - 708
  • 29
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  • [ 57602-02-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 2, p. 636 - 643
  • 30
  • [ 112-60-7 ]
  • [ 6482-24-2 ]
  • [ 23778-52-1 ]
YieldReaction ConditionsOperation in experiment
35%
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.5 h;
Stage #2: at 20℃;
Tetra(ethylene glycol) (55 mmol, 10.7 g) was dissolved in 100 mL of tetrahydrofuran ("THF") and to this solution was added KOtBu (55 mL, 1.0 M in THF) at room temperature. The resulting solution was stirred at room temperature for 30 minutes, followed by dropwise addition of CH3OCH2CH2Br (55 mmol, 5.17 mL in 50 mL THF). The reaction was stirred at room temperature overnight, followed by extraction with H2O (300 mL)/CH2Cl2 (3.x.300 mL). The organic extracts were combined and then dried over anhydrous Na2SO4. After filtering off the solid drying agent and removing the solvent by evaporation, the recovered crude residue was purified by column chromatography using a silica gel column (CH2Cl2:CH3OH=60:140:1) to give pure penta(ethylene glycol) monomethyl ether (yield 35percent). 1H NMR (CDCl3) δ 3.75-3.42 (m, 20 H, OCH2CH2O), 3.39 (s, 3H, MeO).
Reference: [1] Patent: US2005/136031, 2005, A1, . Location in patent: Page/Page column 25
  • 31
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  • [ 110-99-6 ]
  • [ 23243-68-7 ]
  • [ 13887-98-4 ]
Reference: [1] Tetrahedron, 1982, vol. 38, # 22, p. 3299 - 3308
  • 32
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  • [ 23601-40-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 22, p. 3502 - 3505
  • 33
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  • [ 50586-80-6 ]
  • [ 23601-40-3 ]
Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 9, p. 1357 - 1360
  • 34
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  • [ 5617-32-3 ]
Reference: [1] Synthetic Communications, 1986, vol. 16, # 1, p. 19 - 26
[2] Angewandte Chemie - International Edition, 2015, vol. 54, # 12, p. 3763 - 3767[3] Angew. Chem., 2015, vol. 127, # 12, p. 3834 - 3838,5
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  • [ 112-60-7 ]
  • [ 27425-92-9 ]
Reference: [1] Patent: US6355646, 2002, B1, . Location in patent: Page column 12
  • 36
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  • [ 27425-92-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 22, p. 3502 - 3505
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 22, p. 3502 - 3505
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Reference: [1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 24, p. 10295 - 10300
[2] Chemische Berichte, 1981, vol. 114, # 2, p. 477 - 487
[3] Journal of the American Chemical Society, 1981, vol. 103, # 25, p. 7484 - 7489
[4] Journal of Materials Chemistry, 1997, vol. 7, # 7, p. 1147 - 1154
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Reference: [1] Helvetica Chimica Acta, 1984, vol. 67, p. 2128 - 2142
[2] Journal of the Chemical Society, Chemical Communications, 1990, # 13, p. 911 - 912
[3] Angewandte Chemie - International Edition, 2015, vol. 54, # 12, p. 3763 - 3767[4] Angew. Chem., 2015, vol. 127, # 12, p. 3834 - 3838,5
[5] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 22, p. 3502 - 3505
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Reference: [1] Molecular Crystals and Liquid Crystals, 2004, vol. 411, p. 421/[1463]-437/[1479]
[2] RSC Advances, 2014, vol. 4, # 22, p. 11064 - 11072
  • 40
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Reference: [1] Angewandte Chemie - International Edition, 2009, vol. 48, # 7, p. 1248 - 1252
  • 41
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Reference: [1] Molecular Crystals and Liquid Crystals, 2004, vol. 411, p. 421/[1463]-437/[1479]
[2] Journal of the Chemical Society, Chemical Communications, 1990, # 13, p. 911 - 912
  • 42
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Reference: [1] Journal of the American Chemical Society, 2003, vol. 125, # 5, p. 1120 - 1121
[2] Journal of the American Chemical Society, 2001, vol. 123, # 31, p. 7560 - 7563
[3] Journal of Organic Chemistry, 2001, vol. 66, # 13, p. 4494 - 4503
[4] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[5] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[6] Chemistry - A European Journal, 2011, vol. 17, # 6, p. 1828 - 1836
[7] Journal of the American Chemical Society, 2011, vol. 133, # 24, p. 9242 - 9245
[8] Nucleosides, Nucleotides and Nucleic Acids, 2011, vol. 30, # 7-8, p. 490 - 502
[9] Patent: US2012/4423, 2012, A1,
[10] Angewandte Chemie - International Edition, 2012, vol. 51, # 9, p. 2151 - 2154
[11] Chemistry - A European Journal, 2012, vol. 18, # 21, p. 6548 - 6554
[12] Chemistry - A European Journal, 2012, vol. 18, # 33, p. 10419 - 10426
[13] Organic and Biomolecular Chemistry, 2013, vol. 11, # 1, p. 27 - 30
[14] Patent: WO2013/109859, 2013, A1,
[15] European Journal of Organic Chemistry, 2013, # 35, p. 7952 - 7959
[16] Angewandte Chemie - International Edition, 2014, vol. 53, # 3, p. 810 - 814[17] Angew. Chem., 2014, vol. 126, # 3, p. 829 - 833,5
[18] Macromolecular Bioscience, 2015, vol. 15, # 1, p. 63 - 73
[19] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[20] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5
[21] Chemical Communications, 2016, vol. 52, # 6, p. 1154 - 1157
[22] Patent: WO2017/15693, 2017, A1,
[23] Patent: WO2017/50979, 2017, A1,
[24] Bioconjugate Chemistry, 2017, vol. 28, # 9, p. 2284 - 2292
[25] Patent: US2018/44280, 2018, A1,
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Reference: [1] European Journal of Medicinal Chemistry, 2015, vol. 102, p. 153 - 166
  • 44
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  • [ 106984-09-2 ]
Reference: [1] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[2] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[3] Journal of the American Chemical Society, 2011, vol. 133, # 24, p. 9242 - 9245
[4] Patent: US2015/166595, 2015, A1,
[5] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[6] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5
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  • [ 98627-22-6 ]
  • [ 105891-54-1 ]
Reference: [1] Journal of Organic Chemistry, 2006, vol. 71, # 26, p. 9884 - 9886
  • 46
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Reference: [1] Synthetic Communications, 1986, vol. 16, # 1, p. 19 - 26
[2] Synthetic Communications, 1986, vol. 16, # 1, p. 19 - 26
  • 47
  • [ 112-60-7 ]
  • [ 5292-43-3 ]
  • [ 169751-72-8 ]
YieldReaction ConditionsOperation in experiment
72.7% With sodium hydride In dimethyl sulfoxide; mineral oil at 0 - 20℃; for 23 h; Inert atmosphere To a cold (0 °C) stirred solution of tert-butyl 2-bromoacetate (5.4 mL, 36.6 mmol) and 2,2'-((oxybis(ethane-2,l-diyl))bis(oxy))diethanol (35.0 mL, 203 mmol) in DMSO (50 mL) was added NaH (1.6217 g, 40.6 mmol, 60percent in oil) in two portions. The reaction mixture was slowly warmed up to rt, stirred for 23 h, diluted with water (50 mL), saturated with NaCl (50 g), stirred for 5 min, extracted with Et20 (3 x 100 mL), and concentrated. The residue was taken in DCM (50 mL) and water (25 mL), stirred for 5 min. The organic solution was passed through a phase separator, concentrated and purified on a 80 g Si02 cartridge using a gradient of ethyl acetate in hexanes (50- 100percent) to afford the title compound (8.2 g, 72.7percent yield) as a pale yellow oil. Rf = 0.08 (EtOAc). NMR (400 MHz, CDCb) δ 4.02 (d, J = 1.0 Hz, 2H), 3.75 - 3.60 (m, 12H), 1.47 (s, 9H) ppm.LRMS (ESI) m/z: calculated for Ci4H2807 308.3679; found 330.95 (M+Na)+; Found 347.01 (M+K)+.
Reference: [1] Patent: WO2018/200981, 2018, A1, . Location in patent: Paragraph 0209; 0294-0295
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 2, p. 583 - 598
[3] Patent: US2018/177750, 2018, A1, . Location in patent: Paragraph 1106
  • 48
  • [ 112-60-7 ]
  • [ 169751-72-8 ]
Reference: [1] Patent: WO2017/46036, 2017, A1,
  • 49
  • [ 112-60-7 ]
  • [ 101187-40-0 ]
Reference: [1] Journal of the American Chemical Society, 2012, vol. 134, # 1, p. 83 - 86
  • 50
  • [ 112-60-7 ]
  • [ 462100-06-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1105 - 1108
  • 51
  • [ 112-60-7 ]
  • [ 1663-39-4 ]
  • [ 518044-32-1 ]
YieldReaction ConditionsOperation in experiment
82% With sodium In tetrahydrofuran at 20℃; To a solution of tetraethyleneglycol (40.61 mL; 45.64 g; 235 mmol) in abs. THF (125 mL) a piece of sodium (1/4 cm) was added. After the sodium had reacted completely, tert-butylacrylate (1 1.98 mL; 10.57 g; 82.5 mmol) was added dropwise over 20 min and the resulting solution was stirred at rt overnight. The pH was adjusted to 7-8 with NaOH solution (1 N) and the solvents were removed in vacuum. The residue was dissolved in sat. NaCl solution (75 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were dried over MgSO4 and after evaporation of the solvent tert-butyl-15-hydroxy-4,7,10,13-tetraoxapentadecanoate (21.87 g; 67.8 mmol; 82percent based on tert-butylacrylate) was obtained as colorless oil. 1H-NMR (500 MHz, Chloroform-c/, TMS) δ [ppm] = 3.77 - 3.57 (m, 18H; OCH2); 3.01 (bs, 1 H, OH); 2.51 (t, 2H, J = 6.6 Hz, CH2COO'Bu); 1.45 (s, 9H, C(CH3)3); 13C{1H}-NMR (126 MHz, Chloroform-c/, TMS) δ [ppm] = 171.1 (COO); 80.7 (C(CH3)3); 72.6/70.8/70.7/70.6/70.5/67.0 (OCH2); 61.9 (HOCH2); 36.4 (CH2CO); 28.2 (C(CH3)3).
81%
Stage #1: With sodium In tetrahydrofuran at 20℃;
Stage #2: at 20℃;
[00162] Synthesis of tert-butyl l-hydroxy-3,6,9, 12-tetraoxapentadecan-15-oate (2): To a solution of tetraethylene glycol 1 (58.3 g, 300 mmol) in dry THF (200 mL) was added sodium (115 mg), and the mixture was stirred until sodium was consumed. To the resulting solution was then added tert-butyl acrylate (12.8 g, 100 mmol) in dry THF (50 mL) dropwise, and the resulting mixture was stirred overnight. The reaction was quenched with AcOH (0.1 mL) and water (0.5 mL) and stirred for 0.5 h, and was then extracted with ethyl acetate (200 mL χ 3). The combined organics were worked up by a standard procedure to give a clear oil product 2 (26 g, 81percent). ESI m/z: 340 (M+18)+.
81% With sodium In tetrahydrofuran at 20℃; To a solution of tetraethylene glycol (VI-1, 58 g, 0.30 mol) in dry THF (200 mL) was added sodium (0.12 g), and the mixture was stirred until the sodium was consumed. To the resulting solution was then added tert-butyl acrylate (VI-2, 13 g, 0.10 mol) in dry THF (50 mL) dropwise, and the resulting mixture was stirred at RT overnight. The reaction was quenched with acetic acid (0.1 mL) first and then water (0.5 mL), and the resulting mixture was stirred at RT for half an hour, and subsequently was extracted with ethyl acetate (3 x 200 mL). The combined organic solution was washed with water (30 mL) and then brine (3 x 100 mL), dried over sodium sulfate, filtered and concentrated to yield product (VI-3, 26 g, 81percent yield) as colorless oil. ESI m/z: 340 (M + 18)+
80% With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 20 h; To a solution of tetraethylene glycol (20.0 g, 103 mol) in anhydrous THF (54.0 mL) were added NaH (60percent dispersion in mineral oil, 42 mg, 1.05 mmol) and tert-butyl acrylate (5.2 mL, 36.0 mol). The resulting solution was stirred for 20 h at room temperature. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/EtOAc=1/1) to afford 16d-1 as a colorless oil (9.3 g, 80percent). IR (KBr) νmax 3445, 2873, 1729 cm-1. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.65-3.53 (m, 18H), 2.43 (t, J=8.4 Hz, 2H), 1.37 (s, 9H). 13C NMR (100 MHz, CDCl3) δ (ppm) 170.7, 80.3, 72.6, 70.4 (2C), 70.3, 70.2, 70.1, 70.0, 66.7, 61.3, 36.0, 27.9 (3C). MS (ESI) m/z 340.2 [M+NH4]+. HRMS (ESI) m/z calcd for C15H30O7Na [M+Na]+: 345.1883; found, 345.1884.
77%
Stage #1: With sodium In tetrahydrofuran at 20℃; for 2 h;
Stage #2: at 20℃; for 24 h;
To dry tetraethylene glycol (17.2 mL, 0.10 mol) in dry tetrahydrofuran(100 mL), sodium (0.02 g, 0.87 mmol) was added. After 2 h, the sodium had dissolved and tert-butyl acrylate (4.35 mL, 0.03 mol) was added. The solution was stirred under exclusion of moisture for 24 h. After neutralisation with 1 M HCl (0.8 mL), the solvent was evaporated under reduced pressure. The residue was dissolved in brine(100 mL) and extracted three times with ethyl acetate (150 mL). The combined organic layers were washed with water (50 mL) and dried with MgSO4. The solvent was evaporated under reduced pressure to afford 2 as clear, pale yellow liquid; 4.3 g, 77percent; 1H NMR (300 MHz,CDCl3): 3.77–3.52 (m, 18H), 3.06 (s, 1H), 2.41 (t, J = 5.8 Hz, 2H), 1.40(s, 9H); ESI-MS m/z: [M + H]+ 323.20252.
36% With N-benzyl-trimethylammonium hydroxide In methanol at 20℃; To a flask containing PEG4 (3.88 g, 20 mmole) was added triton B (40percent solution in methanol, 1.08 mL, 0.25 mmole) and tert-butyl acrylate (3.62 mL, 24 mmole) followed after 15 min. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel with 1 percent methanol in dichloromethane as eluent to give the title compound as an colorless oil (2.35 g, 36percent). 1H NMR No. 1.45 (s, 9H), 2.5 (t, 2H), 3.65 (m, 18H).
23% With sodium In tetrahydrofuran at 20℃; for 24 h; To a solution of tetra (ethylene glycol) 11-1 (40.6 mL, 235 mmol) in 100 mL of tetrahedrofuran was added 47 mg of sodium. 12 mL of tert-butylacrylate was added after sodium was dissolved. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo and quenched with 2 mL of 1 N HC1. The residue was suspended in brine and extracted with ethyl acetate (100 rriLXl, 50 mL X2). The organic layer was combined and washed with brine, dried over sodium sulfate and concentrated in vacuo to give 6.4 g (23percent) of compound 11-3.
23% at 20℃; for 24 h; Compound 2a: To a solution of tetra (ethylene glycol) (40.6 mL, 235 mmol) in 100 mL of tetrahydrofuran is added 47 mg of sodium. 12 mL of tert-butylacrylate is added after sodium is dissolved. The reaction mixture is stirred at room temperature for 24 hours. The reaction mixture is concentrated in vacuo and quenched with 2 mL of 1 N HCI. The residue is suspended in brine and extracted with ethyl acetate (100 mLX1 , 50 mL X2). The organic layer is combined and washed with brine, dried over sodium sulfate and concentrated in vacuo to give 6.4 g (23percent) of compound 2a.
23% With sodium In tetrahydrofuran at 20℃; for 24 h; Compound 11-3: To a solution of tetra (ethylene glycol) 11-1 (40.6 mL,235 mmol) in 100 mL of tetrahedrofuran was added 47 mg of sodium. 12 mL of tertbutylacrylatewas added after sodium was dissolved. The reaction mixture was stirred at roomtemperature for 24 hours. The reaction mixture was concentrated in vacuo and quenched with mL of 1 N HCI. The residue was suspended in brine and extracted with ethyl acetate (1 00mLXl, 50 mL X2). The organic layer was combined and washed with brine, dried oversodium sulfate and concentrated in vacuo to give 6.4 g (23percent) of compound 11-3.
23% With sodium In tetrahydrofuran at 20℃; for 24 h; To a solution of tetra (ethylene glycol) 11-1 (40.6 mL, 235 mmol) in100 mL oftetrahedrofuran was added 47 mg of sodium. 12 mL oftert-butylacrylate was added aftersodium was dissolved. The reaction mixture was stirred at room temperature for 24 hours. Thereaction mixture was concentrated in vacuo and quenched with 2 mL of 1 N HCl. The residue wassuspended in brine and extracted with ethyl acetate (100 mLXl, 50 mL X2). The organic layer was10 combined and washed with brine, dried over sodium sulfate and concentrated in vacuo to give 6.4 g(23percent) of compound 11-3.

Reference: [1] Synthetic Communications, 2004, vol. 34, # 13, p. 2425 - 2432
[2] Patent: WO2016/146638, 2016, A1, . Location in patent: Page/Page column 20
[3] Patent: WO2017/147542, 2017, A2, . Location in patent: Paragraph 00162
[4] Patent: WO2018/89373, 2018, A2, . Location in patent: Paragraph 0638-0639
[5] Tetrahedron, 2011, vol. 67, # 12, p. 2251 - 2259
[6] Journal of Medicinal Chemistry, 2004, vol. 47, # 20, p. 4802 - 4805
[7] Carbohydrate Research, 2007, vol. 342, # 3-4, p. 541 - 557
[8] Journal of Chemical Research, 2016, vol. 40, # 6, p. 368 - 370
[9] Advanced Synthesis and Catalysis, 2012, vol. 354, # 17, p. 3259 - 3264
[10] Patent: WO2005/112919, 2005, A2, . Location in patent: Page/Page column 150
[11] Patent: WO2012/166560, 2012, A1, . Location in patent: Page/Page column 163; 168
[12] Patent: WO2013/68874, 2013, A1, . Location in patent: Page/Page column 20
[13] Patent: WO2013/192360, 2013, A1, . Location in patent: Paragraph 00458; 00479
[14] Patent: WO2013/185117, 2013, A1, . Location in patent: Paragraph 00444
[15] Synthetic Communications, 2007, vol. 37, # 11, p. 1899 - 1915
[16] Patent: CN107235848, 2017, A, . Location in patent: Paragraph 0021
  • 52
  • [ 112-60-7 ]
  • [ 1663-39-4 ]
  • [ 518044-32-1 ]
YieldReaction ConditionsOperation in experiment
73% With hydrogenchloride In tetrahydrofuran 15-Hydroxy-4,7,10,13-tetraoxapentadecanoic acid tert-butyl ester (9a)
To 300 mL of anhydrous THF was added 80 mg (0.0025 mol) of sodium metal and 128 mL of tetraethylene glycol 4a (0.94 mol) with stirring (Seitz and Kunz, J. Org. Chem., 62:813-826 (1997)).
After the sodium had completely dissolved, tert-butyl acrylate (24 mL, 0.33 mol) was added.
The solution was stirred for 20 hrs at room temperature and neutralized with 8 mL of 1.0 M HCl.
The solvent was removed in vacuo and the residue was suspended in brine (250 mL) and extracted with ethyl acetate (3*125 mL).
The combined organic layers were washed with brine (100 mL) then water (100 mL), dried over sodium sulfate, and the solvent was removed.
The resulting colorless oil was dried under vacuum to give 77.13 g (73percent yield) of product 9a ().
1H NMR: 1.40 (s, 9H), 2.49 (t, 2 H, J=6.4 Hz), 3.59-3.73 (m, 18 H).
Reference: [1] Patent: US2004/1838, 2004, A1,
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[2] Chemical Communications, 2014, vol. 50, # 58, p. 7800 - 7802
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Reference: [1] Patent: WO2012/166560, 2012, A1,
[2] Patent: WO2013/192360, 2013, A1,
[3] Patent: WO2013/185117, 2013, A1,
[4] Journal of Chemical Research, 2016, vol. 40, # 6, p. 368 - 370
[5] Patent: WO2017/147542, 2017, A2,
[6] Patent: CN107235848, 2017, A,
[7] Patent: WO2018/89373, 2018, A2,
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[2] Patent: WO2017/147542, 2017, A2,
[3] Patent: CN107235848, 2017, A,
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