Ethanol, 2,2′-oxybis-, 1,1′-bis(4-methylbenzenesulfonate)

Diethylene glycol bis(p-toluenesulfonate) is a PEG-based PROTAC linker that can be used in the synthesis of PROTACs[1].

Diethyleneglycol (1.25 g, 11.8 mmol) was dissolved in water (3.5 mL) and sodium hydroxide (0.768 g, 19.2 mmol) was added. The mixture was stirred at room temperature until a clear solution was obtained. The mixture was cooled to 0°C and a solution of 4-toluene sulfonylchloride (2.27 g, 1 1.9 mmol) in tetrahydrofuran (30 mL) was dropwise added over a period of 20 minutes. After the addition was completed, the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with ethyl acetate (150 mL) and water (40 mL). The organic phase was separated, dried over NaGeneral 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 (0.105mol) of diethylene glycol, 300ml dichloromethane, 40g (0.21mol) of p-toluenesulfonyl chloride was added 500ml round-bottomed flask, under ice-cooling, was slowly added 47g (0.84mol) 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, the crude product was recrystallized from ethanol, to give a white solid 40g, the yield was 95percent. The resulting spectrum is consistent with the reported.Diethyleneglycol (10.61 g, 0.1 mol) was added into triethylamine (100 ml) and stirred with an overhead stirrer. To this mixture, tosylchloride (0.25 mol, 47.7 g) in ether (250 ml) was added slowly in 30 min at 0° C. The reaction mixture was stirred overnight at ambient temperature. The white solid precipitated in the reaction mixture was filtered and washed with water and then with a small amount of ether. The white solid was recrystallized from ethanol to afford compound 4 in 93percent yield. mp: 88-89° C.; General procedure: For ditosylation of the diols, to a solution of oligo ethylene glycol (1 eq, 20 mmol) tetrahydrofuran (15 mL) was added along with sodium hydroxide (3.5 eq, 70 mmol) in HGeneral 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 CHDiethylene glycol (980 mL, 9.4 mmol) and p-toluenesulfonyl chloride (3.58 g, 18.8 mmol) were added to asolution of potassium hydroxide (4.23 g, 75.4 mmol) in dichloromethane (20 mL) at 0°C, and stirred at 0°C for 3 hours.The solution was diluted with water and extraction was carried out with dichloromethane. The organic layer was washedwith water, then dried with anhydrous sodium sulfate, and the solvent was distilled away under a reduced pressure toobtain the title compound (3.38 g, 87percent) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.78 (4H, d, J = 8.4 Hz), 7.35 (4H, d, J = 8.4 Hz), 4.09 (4H, t, J = 4.8 Hz), 3.61 (4H, t, J =4.8 Hz), 2.45 (6H, s).Example 3 [Preparation of Diethylene Glycol Ditosylate 12] [] A 500 mL eggplant-shaped flask was charged with diethylene glycol 13 (15.0 mL, 155 mmol) and pyridine (300 mL), and p-toluenesulfonyl chloride (68.0 g, 351 mmol) was gradually added thereto in an ice bath. The mixture was stirred for 4 hours in the ice bath. Thereafter, a 1-L Erlenmeyer flask containing ice was charged with the reaction solution, and a concentrated hydrochloric acid (220 mL) was added thereto in the ice bath to adjust its pH to 4. The reaction mixture was subjected to suction filtration, and thereafter the residue was dissolved in chloroform. The mixture obtained was dried over anhydrous magnesium sulfate and concentrated, to give a product 12 (54.4 g, 131 mmol) in the form of a white solid (yield: 85percent).1H-NMR (270 MHz, CDCl3, 30°C) δ: 2.45 ppm (6H, s, CH3), 3.61 (4H, t, -CH2-), 4.10 (4H, t, -CH2-), 7.34 (4H, d, J = 8.3 Hz, ArH), 7.78 (4H, d, J = 8.3 Hz, ArH)First Step 0025] The subsequent conversion of amide 5 in thioamide 6 was efficiently achieved in the presence of Lawesson's reagent in 83percent yield. The hydrazinolysis of commercially available methyl 4-phenylbenzoate 7 yielded hydrazide 8 (72percent) that was reacted with thioamide 6 in the presence of mercury (II) acetate, leading to the formation of triazole 9 in 37percent yield. A subsequent treatment in acidic conditions enabled the Boc removal to yield triazole 10, ready to be modified with various N-Boc protected PEG derivatives. As depicted in Scheme 2, these derivatives were obtained in three steps from commercially available diethyleneglycol and tetraethylene glycol. Free alcohols were activated as ditosylated derivatives 11 and 12 with tosyl chloride in basic conditions (62percent and 67percent yield, respectively). The monosubstitution of one tosyl group was achieved by slow addition of di-tert-butyl iminodicarboxylate into an excess of activated PEG derivatives at 0°C, leading to monoactivated derivatives 13 and 14 in 53percent and 67percent yield, respectively. A subsequent treatment with LiBr in DMF enabled the clean conversion of the tosylated derivatives into brominated derivatives 15 and 16 (83percent and 71percent yield, respectively).General procedure: To a stirred solution of diethylene glycol or tetraethylene glycol (1 eq.) in CHDiethylene glycol (2.0 g, 18.9 mmol) and TEA (6.69 g, 66 mmol) were dissolved in DCM (100 mL), to which TsC1 (8.63 g, 45.3 mmol) was added slowly. The reaction mixture was stirred at rt for 18 h, and then washed with 10percent citric acid solution, water, and brine. The organic phase was dried and concentrated to give a white solid 68 (8.0 g), which was used directly for next step. LC-MS (Method 1): R = 2.02 mm; m/z (ES) = 415.1 (M+H).

Molecular Weight:414.5
XLogP3:2.8
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:10
Exact Mass:414.08069538
Monoisotopic Mass:414.08069538
Topological Polar Surface Area:113
Heavy Atom Count:27
Complexity:562
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes