Tetraethylene glycol ditosylate

PROTAC Linker 16 is a polyethylene glycol (PEG)-based PROTAC linker. PROTAC Linker 16 can be used in the synthesis of a series of PROTACs. PROTACs contain two different ligands connected by a linker; one is a ligand for an E3 ubiquitin ligase and the other is for the target protein. PROTACs exploit the intracellular ubiquitin-proteasome system to selectively degrade target proteins[1].

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.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.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.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 EtGeneral 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 CHTo a solution of 2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethan-l-ol (13 g, 67.1 mmol), EtTetraethylene 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).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.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.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.Example 4

Molecular Weight:502.6
XLogP3:2.5
Hydrogen Bond Acceptor Count:9
Rotatable Bond Count:16
Exact Mass:502.13312488
Monoisotopic Mass:502.13312488
Topological Polar Surface Area:131
Heavy Atom Count:33
Complexity:650
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes