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CAS No. : | 118591-58-5 | MDL No. : | MFCD22574797 |
Formula : | C11H16O5S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KLDLLRZCWYKJBD-UHFFFAOYSA-N |
M.W : | 260.31 | Pubchem ID : | 11253971 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.45 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 62.25 |
TPSA : | 81.21 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.45 cm/s |
Log Po/w (iLOGP) : | 2.68 |
Log Po/w (XLOGP3) : | 0.61 |
Log Po/w (WLOGP) : | 1.79 |
Log Po/w (MLOGP) : | 1.01 |
Log Po/w (SILICOS-IT) : | 1.18 |
Consensus Log Po/w : | 1.45 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.64 |
Solubility : | 6.0 mg/ml ; 0.023 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.89 |
Solubility : | 3.36 mg/ml ; 0.0129 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.24 |
Solubility : | 0.15 mg/ml ; 0.000578 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.84 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: With sodium hydroxide In water at 20℃; Stage #2: at 0℃; for 1.33333 h; |
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 Na2S04, filtered and the solvents were evaporated under reduced pressure. The residue was purified on HP-Sil SNAP cartridges using a Biotage Isolera One purification system employing an dichloromethane/methanol gradient (100/0 ->100/0) to afford the more polar title compound as a colorless oil (1.47 g, 47 percent). The less polar bis-tosyl derivative was discarded. 1H-NMR (400 MHz, CDCI3) δ = 7.80 (d, 2H), 7.35 (d, 2H), 4.22-4.18 (m, 2H), 3.72-3.66 (m, 4H), 3.55-3.51 (m, 2H), 2.45 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium iodide In dichloromethane for 10 h; | Monoprotection of Ethyleneglycol One of the functional OH of the diols (i.e ethylene glycols) is protected selectively before reacting with the aconitic acid. The diol is mono-protected using silver oxide and alkyl halide in quantitative yields.Preparation of Mono-Protected DiolThe diols before reacting with the dendrimer core (aconitic acid) are to the monoprotected. The diols are protected by treatment with (1.0 equivalent) freshly prepared silver oxide (1.5 equivalent) and p-toluene sulfonyl chloride (pTSCl) (1.1 equivalent) in the presence of potassium iodide (KI) (0.2 equivalent) in dichloromethane. The resulting mixture is stirred for 8-10 hours to yield mono-tosyl protected diol in 97-99percent yield. |
87% | Stage #1: With sodium hydroxide In tetrahydrofuran; water at 0℃; for 0.5 h; |
General procedure: Oligo ethylene glycol (2 eq, 40 mmol) was dissolved intetrahydrofuran (20 mL) at 0 oC. Sodium hydroxide (1.5 eq,30 mmol, 1.2 g) in 15 mL H2O was added drop wise to thesolution of oligo ethylene glycol. After stirring for 30 min, ptoluenesulfonylchloride (1 eq, 20 mmol, 3.8 g) was dissolvedin tetrahydrofuran (15 mL) at 0 oC. Oligoethyleneglycol was added drop wise in the solution of ptoluenesulfonylchloride. After the addition was completed,the aqueous solution was treated with HCl 10percent and extractedwith dichloromethane. The organic layer was washedwith distilled water and dried over MgSO4. After the solventwas removed, the residue was purified by column chromatography(ethyl acetate/n-hexane = 1:1 v/v) Diethylene glycol monotosylate (4a): This compoundwas obtained in 87percent yield as colourless oil; ir: 3417 (OH),1353 and 1176 (S=O) cm-1; 1H-NMR (CDCl3): 7.72 (d, J =8.25 Hz, 3H); 7.29 (d, J = 8 Hz, 2H); 4.12 (t, J = 4.5 Hz,2H); 3.63-3.57 (m, 3H); 3.45 (t, J = 4.75 Hz, 2H); 3.18-3.14(m, 2H); 2.38 (s, 3H). 13C-NMR (CDCl3,): 144.9; 132.8;129.8; 128.2; 72.4; 69.3; 68.4; 61.4; 21.5.Anal. calc. forC11H16O5S1: C, 50.75; H, 6.18, S, 12.31. Found: C, 50.73; H,6.21; S, 12.36. |
65% | With potassium hydroxide In tetrahydrofuran at 20℃; for 5 h; Cooling with ice | Compound 1-1 (166 g, 1.57 mol) was dissolved in 500 mL of tetrahydrofuran, potassium hydroxide (32 g, 571 mmol) was added in an ice bath, and then p-toluenesulfonyl chloride 1-2 (100 g, 0.52 mol) was added in batches, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into 1200 mL of water, (400 mL) and extracted twice with ethyl acetate. The extract liquid was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure and purified by silica gel column chromatography, with an eluent (petroleum ether:ethyl acetate=1:1), to obtain the target product 1-3 (55 g, 65percent) as a colorless oil, LC-MS: m/z=261 [M+H]+. |
56% | With potassium iodide; silver(l) oxide In dichloromethane at 20℃; for 12 h; | j00460j A solution of 2,2’-oxybis(ethan-i-ol) 1 (5 g, 47.1 mmol) in DCM (50 mL) wascharged with silver oxide (10.3 g, 70.7 mmol), potassium iodide (1.6 g, 0.09 mmol), and tosyl chloride (9 g, 47.1 mmol) and stirred at room temperature for 12 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo resulting in a crude compound which was purified by chromatography on silica gel, eluting with 5percent methanol in DCM to give 6.9 g, 56percent yield, of the title compound as a colorless thick oil. ‘H NMR (400 MHz, CDC13): ö = 7.81 (d, J= 8.38 Hz, 2H), 7.35 (d, J= 7.94 Hz, 2H), 4.20 (t, J= 4.63 Hz, 2H), 3.65 —3.73 (m, 4H), 3.54 (d, J= 4.41 Hz, 2H), 2.45 (s, 3H), 1.94 (br. s, 1H). |
47% | Stage #1: With sodium hydroxide In water at 0 - 20℃; Stage #2: at 0℃; for 1.33 h; |
(1042) Step A (1043) 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, 11.9 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 Na2SO4, filtered and the solvents were evaporated under reduced pressure. The residue was purified on HP-Sil SNAP cartridges using a Biotage Isolera One purification system employing an dichloromethane/methanol gradient (100/0->100/0) to afford the more polar title compound as a colorless oil (1.47 g, 47percent). The less polar bis-tosyl derivative was discarded. (1044) 1H-NMR (400 MHz, CDCl3) δ=7.80 (d, 2H), 7.35 (d, 2H), 4.22-4.18 (m, 2H), 3.72-3.66 (m, 4H), 3.55-3.51 (m, 2H), 2.45 (s, 3H). |
46% | With triethylamine In dichloromethane at 25℃; for 12 h; | Diethylene glycol (3.18 g, 30 mmol) and triethylamine (TEA) (8.0 mL) were dissolved in dichloromethane (60 mL). Then, tosyl-chloride (5.70 g, 30 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 4 as a colorless oil (3.61 g, 13.8 mmol, 46percent) |
39% | at 16℃; for 18 h; | To a stirred solution of diethylene glycol (compound 3A, 10.0 g, 94.2 mmol), Et3N (2.86 g, 28.3 mmol) in DCM (50 mL) was added a solution of 4-methylbenzenesulfonyl chloride (4.49 g, 23.6 mmol) in DCM (50 mL) slowly at 16 °C. Then the reaction mixture was stirred for 18 hours at 16 °C. TLC (PE:EA=1: 1) showed that the reaction was completed. The reaction mixture was washed with saturated NaHC03(50 mL x 2). The organic layer was dried over anhydrous Na2S04and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (PE:EA=5: 1-1: 1) to give 2-(2-hydroxyethoxy)ethyl 4- methylbenzenesulfonate (compound 3B, 2.4 g, 39percent) as colorless oil. MS: calc'd 278 (M+H20)+, measured 278 (M+H20)+. |
36% | With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere | To a solution of commercially available diethyleneglycol 23 (4.0 g,37.7 mmol) and p-toluenesulfonyl chloride (7.55 g, 39.6 mmol) stirring in anhydrousCH2Cl2 under an Ar atmosphere at 0C was slowly added Et3N (15.8mL,113.1 mmol). After stirring overnight at rt, the reaction was diluted withCH2Cl2 and poured into a saturated aq. NaHCO3 solution. The aq. layer wasextracted three times with CH2Cl2, and the combined organic portions werewashed with brine, dried over MgSO4, and concentrated under reduced pressure.The product mixture was purified by silica gel column chromatography togive 24 (3.56 g, 36percent) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.83–7.76 (d,J = 8.31 Hz, 2H), 7.37–7.30 (d, J = 7.34 Hz, 2H), 4.21–4.15 (m, 2H), 3.70–3.63(m, 4H), 3.54–3.49 (m, 2H), 2.46–2.40 (s, 3H). 13C NMR (100 MHz, CDCl3): δ144.95, 129.84, 127.92, 72.46, 68.54, 61.61, 21.63. |
29.5% | With triethylamine In dichloromethane for 0.5 h; Cooling with ice | Diethylene glycol 69 (20 g, 0.188 mol) was dissolved in CH2Cl2 (500 mL) followed by the addition of TEA (29 mL, 0.207 mol), then cooled with an ice bath. TsCl (20 g, 0.094 mol) in CH2Cl2 (100 mL) was added drop-wise during a period of 30 min. Slowly warmed to room temperature and kept reacting for another 1 hour. The solvent was removed and purified by silica gel chromatography eluting with 20percent EA/hexane, then 66percent EA/hexane to give 14.4 g (29.5percent) of diethylene glycol mono-Ts 70. Then, the obtained compound above diethylene glycol mono-Ts 70 (12.61 g, 44.2 mmol) and N-Boc-hydroxylamine (8.25 g, 62 mmol) were dissolved in CH2Cl2 (400 mL) followed by the addition of DBU (13.5 mL, 88.4 mol). After 48 hours reaction, the reaction was diluted with 400 mL of CH2Cl2, washed with 1N HCl (100 mL, twice), H2O (100 mL) and brine (200 mL), the organic layer was dried over anhydrous MgSO4 and evaporated. The crude was purified by silica gel chromatography eluting with 33percent EA/hexane, then 50percent EA/hexane containing 5percent MeOH to give 1.5 g (16.1percent) of diethylene glycol mono-Ts 71. The product was dissolved in CH2Cl2 (70 mL) followed by the addition of TEA (2.96 mL, 21.3 mmol), then cooled with an ice bath. TsCl (2 g, 9.4 mmol) in CH2Cl2 (20 mL) was added drop-wise during a period of 30 min. Slowly warmed to room temperature and kept reacting for another 1 hour. The solvent was removed and purified by silica gel chromatography eluting with 10percent EA/hexane, then 40percent EA/hexane to give 1.31 g (49percent) of OTs-diethylene glycol hydroxylamine-Boc 72. Finally, OTs-diethylene glycol hydroxylamie-Boc 72 (1.3 g, 3.48 mmol) was dissolved in anhydrous ethanol (50 mL) followed by the addition of sodium azide (680 mg, 10.4 mmol), then refluxed overnight. The solvent was removed, diluted with EA (200 mL), washed with H2O (50 mL) and brine (50 mL), the organic layer was dried over anhydrous MgSO4 and evaporated. The crude was purified by silica gel chromatography eluting with 10percent EA/hexane, then 40percent EA/hexane to give 728 mg (85percent) of Azido-diethylene glycol hydroxylamie-Boc 73. |
22.7 g | at 0 - 20℃; Inert atmosphere | Under the protection of nitrogen, to a 500ml three-necked flask were added 200 mL pyridine, 18.8 g BG01 (1.0eq), stirred and cooled down to 0°C. 35.5g TsCl (1.0eq) was added in batches, stirred for 1h, and then slowly warmed up to room temperature, continuing to stir for 3-4h. After the completion of the reaction, the reaction liquid was poured into the ice-cold solution of dilute hydrochloric acid, with a solid being generated, which was extracted with ethyl acetate. The ethyl acetate layer was washed once with dilute hydrochloric acid, washed with saturated sodium bicarbonate and saturated brine, and dried over anhydrous Na2SO4. The solvents were evaporated off at reduced pressure, and chromatographed in a silica gel column to give 22.7g pure BG02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: With sodium hydroxide In water at 20℃; Stage #2: at 0℃; for 1.33333 h; |
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 Na2S04, filtered and the solvents were evaporated under reduced pressure. The residue was purified on HP-Sil SNAP cartridges using a Biotage Isolera One purification system employing an dichloromethane/methanol gradient (100/0 ->100/0) to afford the more polar title compound as a colorless oil (1.47 g, 47 percent). The less polar bis-tosyl derivative was discarded. 1H-NMR (400 MHz, CDCI3) δ = 7.80 (d, 2H), 7.35 (d, 2H), 4.22-4.18 (m, 2H), 3.72-3.66 (m, 4H), 3.55-3.51 (m, 2H), 2.45 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium iodide;silver(l) oxide; In dichloromethane; for 10h; | Monoprotection of Ethyleneglycol One of the functional OH of the diols (i.e ethylene glycols) is protected selectively before reacting with the aconitic acid. The diol is mono-protected using silver oxide and alkyl halide in quantitative yields.Preparation of Mono-Protected DiolThe diols before reacting with the dendrimer core (aconitic acid) are to the monoprotected. The diols are protected by treatment with (1.0 equivalent) freshly prepared silver oxide (1.5 equivalent) and p-toluene sulfonyl chloride (pTSCl) (1.1 equivalent) in the presence of potassium iodide (KI) (0.2 equivalent) in dichloromethane. The resulting mixture is stirred for 8-10 hours to yield mono-tosyl protected diol in 97-99% yield. |
92% | With potassium iodide; silver(l) oxide; In dichloromethane; at 0 - 20℃; for 0.5h; | To a solution of diethylene glycol (500 ?L, 5.22 mmol) in anhydrous CH2Cl2 (25 mL) at 0 C, Ag2O (928 mg, 3.96 mmol), TsCl (509 mg, 2.64 mmol) and KI (88 mg, 0.53 mmol) were added. After stirring at r.t. for 30 min, the mixture was filtered through celite and the solvent was removed under vacuum. The crude product was purified by chromatography column on silica gel (EtOAc:cyclohexane 2:1) to give 13 (633 mg, 2.43 mmol, 92%) as a colourless oil. |
90.6% | With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 2h;Cooling with ice; | 95.07 g was added to a 500 mL three-necked flask.A solution of diethylene glycol in THF was stirred and cooled in an ice salt bath to obtain a viscous liquid.A NaOH solution (NaOH 5.46 g; water 30 mL) was added and stirred. Under ice water bath, a solution of TsCl in THF (TsCl 16.58 g, THF 70 mL) was added dropwise.After the dropwise addition was completed, stirring was continued for 2 hours in an ice salt bath, followed by stirring at room temperature. After the reaction is completed, the stirring is stopped.The reaction solution was poured into 200 mL of ice water and extracted with CH 2 Cl 2 (100 mL×2).The organic phase was washed with water (50 mL×2) and dried over anhydrous magnesium sulfate.Filtration, rotary evaporation to obtain a transparent viscous liquid, which is Compound A, the yield is 90.6%; |
90.6% | With sodium hydroxide; In tetrahydrofuran; water; at 20℃;Cooling; | Add 95.07 g of diethylene glycol in THF to a 500 mL three-necked flask.The mixture was stirred and cooled under an ice salt bath to obtain a viscous liquid. Add NaOH solution (NaOH 5.46g;Water 30 mL) was stirred. Under ice water bath, a solution of TsCl in THF (TsCl 16.58 g, THF 70 mL) was added dropwise. After the addition was completed, stirring was continued for 2 hours under ice salt bath.Then stir at room temperature. After the reaction is completed, the stirring is stopped.The reaction solution was poured into 200 mL of ice water and extracted with CH 2 Cl 2 (100 mL×2).The organic phase was washed with water (50 mL×2), dried over anhydrous magnesium sulfate and filtered.Rotating to obtain a transparent viscous liquid, which is Compound A, the yield is 90.6%; |
89% | With sodium hydroxide; In tetrahydrofuran; water; for 6h; | In a 250 mL three-necked flask, 92.40 g of diethylene glycol and 5.22 g of 30 mL aqueous NaOH solution were added.THF 100ml, TsCl 16.6g, after 6h reaction,The mixture was poured into ice water, extracted with CH2C12, the organic phase was washed with water, dried over anhydrous magnesium sulfate,Filtration of the compound F 20.29 g was obtained by filtration, yield 89%. |
87% | General procedure: Oligo ethylene glycol (2 eq, 40 mmol) was dissolved intetrahydrofuran (20 mL) at 0 oC. Sodium hydroxide (1.5 eq,30 mmol, 1.2 g) in 15 mL H2O was added drop wise to thesolution of oligo ethylene glycol. After stirring for 30 min, ptoluenesulfonylchloride (1 eq, 20 mmol, 3.8 g) was dissolvedin tetrahydrofuran (15 mL) at 0 oC. Oligoethyleneglycol was added drop wise in the solution of ptoluenesulfonylchloride. After the addition was completed,the aqueous solution was treated with HCl 10% and extractedwith dichloromethane. The organic layer was washedwith distilled water and dried over MgSO4. After the solventwas removed, the residue was purified by column chromatography(ethyl acetate/n-hexane = 1:1 v/v) Diethylene glycol monotosylate (4a): This compoundwas obtained in 87% yield as colourless oil; ir: 3417 (OH),1353 and 1176 (S=O) cm-1; 1H-NMR (CDCl3): 7.72 (d, J =8.25 Hz, 3H); 7.29 (d, J = 8 Hz, 2H); 4.12 (t, J = 4.5 Hz,2H); 3.63-3.57 (m, 3H); 3.45 (t, J = 4.75 Hz, 2H); 3.18-3.14(m, 2H); 2.38 (s, 3H). 13C-NMR (CDCl3,): 144.9; 132.8;129.8; 128.2; 72.4; 69.3; 68.4; 61.4; 21.5.Anal. calc. forC11H16O5S1: C, 50.75; H, 6.18, S, 12.31. Found: C, 50.73; H,6.21; S, 12.36. | |
65% | With potassium hydroxide; In tetrahydrofuran; at 20℃; for 5h;Cooling with ice; | Compound 1-1 (166 g, 1.57 mol) was dissolved in 500 mL of tetrahydrofuran, potassium hydroxide (32 g, 571 mmol) was added in an ice bath, and then p-toluenesulfonyl chloride 1-2 (100 g, 0.52 mol) was added in batches, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into 1200 mL of water, (400 mL) and extracted twice with ethyl acetate. The extract liquid was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure and purified by silica gel column chromatography, with an eluent (petroleum ether:ethyl acetate=1:1), to obtain the target product 1-3 (55 g, 65%) as a colorless oil, LC-MS: m/z=261 [M+H]+. |
60% | With triethylamine; In dichloromethane; at 20℃; | Diethylene glycol (7.0 g, 66.0 mmol) was dissolved in 10 mL of dichloromethane solution, Et3N (13.3 g, 132.2 mmol) was added, and a solution of TsCl (15.1 g, 79.1 mmol) in dichloromethane was added dropwise under ice-cooling. After the completion of the dropwise addition, the mixture was transferred to room temperature and stirred overnight. After adjusting the pH of the solution to 7 with 6 mol/L HCl, 10 mL of water was added, and the mixture was extracted three times with 30 mL of dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. Column chromatography (EA) gave 10 g of a yellow liquid product, yield 60%. |
60% | With triethylamine; In dichloromethane; at 20℃;Cooling with ice; | Diethylene glycol (7.0 g, 66.0 mmol) was dissolved in 10 mL of dichloromethane solution, Et3N (13.3 g, 132.2 mmol) was added, and TsCl (15.1 g, 79.1 mmol) in dichloromethane was added dropwise on ice. .After the completion of the dropwise addition, the mixture was transferred to room temperature and stirred overnight.After adjusting the pH of the solution to 7 with 6 mol/L HCl, 10 mL of water was added, and the mixture was extracted three times with 30 mL of dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate.Column chromatography (EA) gave 10 g of a yellow liquid product, yield 60%. |
56% | With potassium iodide; silver(l) oxide; In dichloromethane; at 20℃; for 12h; | j00460j A solution of 2,2?-oxybis(ethan-i-ol) 1 (5 g, 47.1 mmol) in DCM (50 mL) wascharged with silver oxide (10.3 g, 70.7 mmol), potassium iodide (1.6 g, 0.09 mmol), and tosyl chloride (9 g, 47.1 mmol) and stirred at room temperature for 12 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo resulting in a crude compound which was purified by chromatography on silica gel, eluting with 5% methanol in DCM to give 6.9 g, 56% yield, of the title compound as a colorless thick oil. ?H NMR (400 MHz, CDC13): oe = 7.81 (d, J= 8.38 Hz, 2H), 7.35 (d, J= 7.94 Hz, 2H), 4.20 (t, J= 4.63 Hz, 2H), 3.65 -3.73 (m, 4H), 3.54 (d, J= 4.41 Hz, 2H), 2.45 (s, 3H), 1.94 (br. s, 1H). |
51% | To a solution of 2-(2-hydroxyethoxy)ethanol (55.66 g, 524.53 mmol, 49.70 mL, 2 eq) in tetrahydrofuran (500 mL) was added sodium hydride (6.29 g, 157.27 mmol, 60% purity, 0.6 eq) at 0 C and stirred for 0.5 hour under nitrogen. Then the mixture was added p- toluenesulfonyl chloride (50 g, 262.26 mmol, 1 eq), warmed to 25 C and stirred for 6 hours. The mixture was poured into saturated ammonium chloride solution (200 mL) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with brine (200 mL), dried with anhydrous anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=l0/l to 1/1) to afford 2-(2-hydroxyethoxy)ethyl 4- methylbenzenesulfonate (35 g, 134.46 mmol, 51 % yield) as a yellow oil. LC/MS (ESI) m/z. 261.0 [M+l] +; 1H-NMR (400MHz, CDCb) d 7.76 - 7.72 (m, 2H), 7.28 (d, / = 8.0 Hz, 2H), 4.15 - 4.02 (m, 2H), 3.66 - 3.55 (m, 4H), 3.49 - 3.44 (m, 2H), 2.38 (s, 3H). | |
47% | (1042) Step A (1043) 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, 11.9 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 Na2SO4, filtered and the solvents were evaporated under reduced pressure. The residue was purified on HP-Sil SNAP cartridges using a Biotage Isolera One purification system employing an dichloromethane/methanol gradient (100/0->100/0) to afford the more polar title compound as a colorless oil (1.47 g, 47%). The less polar bis-tosyl derivative was discarded. (1044) 1H-NMR (400 MHz, CDCl3) delta=7.80 (d, 2H), 7.35 (d, 2H), 4.22-4.18 (m, 2H), 3.72-3.66 (m, 4H), 3.55-3.51 (m, 2H), 2.45 (s, 3H). | |
46% | With triethylamine; In dichloromethane; at 25℃; for 12h; | Diethylene glycol (3.18 g, 30 mmol) and triethylamine (TEA) (8.0 mL) were dissolved in dichloromethane (60 mL). Then, tosyl-chloride (5.70 g, 30 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 (5%, 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 4 as a colorless oil (3.61 g, 13.8 mmol, 46%) |
40% | With triethylamine; In dichloromethane; at 25℃; for 16h;Inert atmosphere; | A solution of diethylene glycol (5.01 g, 47.21 mmol), / olucncsulfonyl chloride (4.50 mg, 23.6 mmol) and triethylamine (8.55 mL, 61.37 mmol) in DCM (200 mL) was stirred at 25 C for 16 h. The reaction was added to FLO (30 mL) and extracted with DCM (2 x 50 mL). The organic layer was separated, dried with over Na2S04 and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether :EtO Ac 10:1 to 1 : 1) to afford 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (2.95 g, 40%) as a light yellow oil; LC-MS 283.0 [M+Na]+. |
39% | In dichloromethane; at 16℃; for 18h; | To a stirred solution of diethylene glycol (compound 3A, 10.0 g, 94.2 mmol), Et3N (2.86 g, 28.3 mmol) in DCM (50 mL) was added a solution of 4-methylbenzenesulfonyl chloride (4.49 g, 23.6 mmol) in DCM (50 mL) slowly at 16 C. Then the reaction mixture was stirred for 18 hours at 16 C. TLC (PE:EA=1: 1) showed that the reaction was completed. The reaction mixture was washed with saturated NaHC03(50 mL x 2). The organic layer was dried over anhydrous Na2S04and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (PE:EA=5: 1-1: 1) to give 2-(2-hydroxyethoxy)ethyl 4- methylbenzenesulfonate (compound 3B, 2.4 g, 39%) as colorless oil. MS: calc'd 278 (M+H20)+, measured 278 (M+H20)+. |
36% | With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | To a solution of commercially available diethyleneglycol 23 (4.0 g,37.7 mmol) and p-toluenesulfonyl chloride (7.55 g, 39.6 mmol) stirring in anhydrousCH2Cl2 under an Ar atmosphere at 0C was slowly added Et3N (15.8mL,113.1 mmol). After stirring overnight at rt, the reaction was diluted withCH2Cl2 and poured into a saturated aq. NaHCO3 solution. The aq. layer wasextracted three times with CH2Cl2, and the combined organic portions werewashed with brine, dried over MgSO4, and concentrated under reduced pressure.The product mixture was purified by silica gel column chromatography togive 24 (3.56 g, 36%) as colorless oil. 1H NMR (400 MHz, CDCl3): delta 7.83-7.76 (d,J = 8.31 Hz, 2H), 7.37-7.30 (d, J = 7.34 Hz, 2H), 4.21-4.15 (m, 2H), 3.70-3.63(m, 4H), 3.54-3.49 (m, 2H), 2.46-2.40 (s, 3H). 13C NMR (100 MHz, CDCl3): delta144.95, 129.84, 127.92, 72.46, 68.54, 61.61, 21.63. |
29.5% | With triethylamine; In dichloromethane; for 0.5h;Cooling with ice; | Diethylene glycol 69 (20 g, 0.188 mol) was dissolved in CH2Cl2 (500 mL) followed by the addition of TEA (29 mL, 0.207 mol), then cooled with an ice bath. TsCl (20 g, 0.094 mol) in CH2Cl2 (100 mL) was added drop-wise during a period of 30 min. Slowly warmed to room temperature and kept reacting for another 1 hour. The solvent was removed and purified by silica gel chromatography eluting with 20% EA/hexane, then 66% EA/hexane to give 14.4 g (29.5%) of diethylene glycol mono-Ts 70. Then, the obtained compound above diethylene glycol mono-Ts 70 (12.61 g, 44.2 mmol) and N-Boc-hydroxylamine (8.25 g, 62 mmol) were dissolved in CH2Cl2 (400 mL) followed by the addition of DBU (13.5 mL, 88.4 mol). After 48 hours reaction, the reaction was diluted with 400 mL of CH2Cl2, washed with 1N HCl (100 mL, twice), H2O (100 mL) and brine (200 mL), the organic layer was dried over anhydrous MgSO4 and evaporated. The crude was purified by silica gel chromatography eluting with 33% EA/hexane, then 50% EA/hexane containing 5% MeOH to give 1.5 g (16.1%) of diethylene glycol mono-Ts 71. The product was dissolved in CH2Cl2 (70 mL) followed by the addition of TEA (2.96 mL, 21.3 mmol), then cooled with an ice bath. TsCl (2 g, 9.4 mmol) in CH2Cl2 (20 mL) was added drop-wise during a period of 30 min. Slowly warmed to room temperature and kept reacting for another 1 hour. The solvent was removed and purified by silica gel chromatography eluting with 10% EA/hexane, then 40% EA/hexane to give 1.31 g (49%) of OTs-diethylene glycol hydroxylamine-Boc 72. Finally, OTs-diethylene glycol hydroxylamie-Boc 72 (1.3 g, 3.48 mmol) was dissolved in anhydrous ethanol (50 mL) followed by the addition of sodium azide (680 mg, 10.4 mmol), then refluxed overnight. The solvent was removed, diluted with EA (200 mL), washed with H2O (50 mL) and brine (50 mL), the organic layer was dried over anhydrous MgSO4 and evaporated. The crude was purified by silica gel chromatography eluting with 10% EA/hexane, then 40% EA/hexane to give 728 mg (85%) of Azido-diethylene glycol hydroxylamie-Boc 73. |
24% | With potassium iodide; silver(l) oxide; In dichloromethane; at 0 - 25℃; for 1.66667h;Inert atmosphere; | To a solution of diethyleneglycol (20.0 g, 17.9 ml, 188 mmol) in DCM (200 ml) under argon were added tosyl chloride (53.9 g, 283 mmol) and silver oxide (65.5 g, 283 mmol) and the suspension was cooled to 0-5 C. Then potassium iodide (6.26 g, 37.7 mmol) was added over 10 min in 5 portions. After the addition was completed, the reaction was warmed to 20- 25C and stirred for l.5h. The dark grey suspension was filtered, the cake washed with DCM (100 ml), and the filtrate concentrated under vacuum at 40 C. A yellowish non-transparent emulsion was obtained which was purified by flash chromatography (Si02, Hept/EtOAc 5% to 90%) to obtain the desired product (11.6 g,. 24%) as a colorless oil. LC-MS: m/z = 415.2 [M+H]+. |
22% | With triethylamine; In dichloromethane; at 40℃; for 12h; | General procedure: Ethylene glycol (500 mg, 8.1 mmol) and triethylamine (0.54 mL, 4.0 mmol) were dissolved in 7.5 mL dry CH2Cl2, and then TsCl (384 mg, 2.0 mmol) was added into the mixture. The reaction mixture was stirred 12 h at 40C. The resulting mixture was diluted with CH2Cl2, washed with saturated aqueous NH4Cl , NaHCO3 and NaCl successively, and dried over anhydrous Na2SO4. After concentrated in vacuo, the residue was purified by column chromatography (CH2Cl2/MeOH = 20:1) to give 15a (260mg, 23%) as colorless oil. |
With triethylamine; In dichloromethane; at 25℃; for 1h;Inert atmosphere; | Synthesis of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (Compound 3) Into a 2000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 2-(2-hydroxyethoxy)ethan-l-ol (Compound 2, 42.4 g, 399.55 mmol, 1.00 equiv) in dichloromethane (1000 mL) and triethylamine (27.9 g, 275.72 mmol, 0.25 equiv). To the above was added p-toluenesulfonyl chloride (19.1 g, 100.18 mmol, 0.50 equiv). After stirred for 1 h at 25C, the resulting mixture was washed with 1x500 mL of aq. potassium hydrosulfate (1M) and 1x500 mL of aq. sodium bicarbonate (5%) respectively. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100: 1). This resulted in 2-(2-hydroxyethoxy)ethyl 4- methylbenzenesulfonate (Compound 3) as a colorless oil. | |
With triethylamine; In dichloromethane; at 25℃; for 1h;Inert atmosphere; | Synthesis of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (Compound A3) Into a 2000-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 2-(2-hydroxyethoxy)ethan-l-ol (A2, 42.4 g, 399.55 mmol, 1.00 equiv) in dichloromethane (1000 mL) and triethylamine (27.9 g, 275.72 mmol, 0.25 equiv). To the above was added p-toluenesulfonyl chloride (19.1 g, 100.18 mmol, 0.50 equiv). After stirred for 1 h at 25C, the resulting mixture was washed with 1x500 mL of aq. potassium hydrosulfate (1M) and 1x500 mL of aq. sodium bicarbonate (5%) respectively. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100: 1). This resulted in 2-(2-hydroxyethoxy)ethyl 4- methylbenzenesulfonate (Compound A3) as a colorless oil. | |
With triethylamine; In dichloromethane; at 25℃; for 1h;Inert atmosphere; | Into a 2000-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 2-(2-hydroxyethoxy)ethan-l-ol (2, 42.4 g, 399.55 mmol, 1.00 equiv) in dichloromethane (1000 mL) and triethylamine (27.9 g, 275.72 mmol, 0.25 equiv). To the above was added p-toluenesulfonyl chloride (19.1 g, 100.18 mmol, 0.50 equiv). After stirred for 1 h at 25C, the resulting mixture was washed with 1x500 mL of aq. potassium hydrosulfate (1M) and 1x500 mL of aq. sodium bicarbonate (5%) respectively. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100: 1). This resulted in 2-(2- hydroxyethoxy)ethyl 4-methylbenzenesulfonate (3) as a colorless oil. | |
With pyridine; In dichloromethane; at 0℃; | To a solution of diethylene glycol (270 muL, 2.8 mmol) and pyridine (227.9 muL, 2.8 mmol) in CH2Cl2was added dropwise of a solution of tosyl chloride (805.7 mg, 2.8 mmol) in CH2Cl2at 0 C and stirred overnight. The solvent was removed under pressure to give pale yellow oil which was purified by siliga gel column chromatography with EtOAc as eluent to obtain diethylene glycol monotosylate as a colorless oil. Cassiarin A (60.5 mg, 0.3 mmol) and potassium carbonate (200.8 mg, 1.4 mmol) in DMF was stirred at room temperature for 1 h. The mixture was added diethylene glycol monotosylate (84.6 mg, 0.3 mmol), stirred and refluxed for 2 days and quenched by adding water, then extracted with EtOAc. The organic phase was washed with saturated NaCl, dried over Na2SO4, concentrated under pressure and purified by recrystallization from EtOAc to give5b.The product was characterized by spectroscopic methods. | |
With triethylamine; In dichloromethane; at 25℃; for 1h;Inert atmosphere; | Synthesis of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (Compound A3)Into a 2000-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 2-(2 -hydroxy ethoxy)ethan-l-ol (A2, 42.4 g, 399.55 mmol, 1.00 equiv) in dichloromethane (1000 mL) and triethylamine (27.9 g, 275.72 mmol, 0.25 equiv). To the above was added p-toluenesulfonyl chloride (19.1 g, 100.18 mmol, 0.50 equiv). After stirring for 1 h at 25C, the resulting mixture was washed with 1x500 mL of aq. potassium hydrosulfate (1M) and 1x500 mL of aq. sodium bicarbonate (5%) respectively. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100: 1). This resulted in Compound A3 as an oil. | |
With triethylamine; In dichloromethane; at 25℃; for 1h;Inert atmosphere; | Into a 2000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 2-(2-hydroxyethoxy)ethan-l-ol (A2, 42.4 g,399.55 mmol, 1.00 equiv) in dichloromethane (1000 mL) and triethylamine (27.9 g, 275.72 mmol, 0.25 equiv). To the above was added p-toluenesulfonyl chloride (19.1 g, 100.18 mmol, 0.50 equiv). After stirring for 1 h at 25C, the resulting mixture was washed with lxSOO mL of aq. potassium hydrosulfate (1M) and lxSOO mL of aq. sodium bicarbonate (5%) respectively. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (100:1). This resulted in Compound A3 as an oil. | |
22.7 g | With pyridine; at 0 - 20℃;Inert atmosphere; | Under the protection of nitrogen, to a 500ml three-necked flask were added 200 mL pyridine, 18.8 g BG01 (1.0eq), stirred and cooled down to 0C. 35.5g TsCl (1.0eq) was added in batches, stirred for 1h, and then slowly warmed up to room temperature, continuing to stir for 3-4h. After the completion of the reaction, the reaction liquid was poured into the ice-cold solution of dilute hydrochloric acid, with a solid being generated, which was extracted with ethyl acetate. The ethyl acetate layer was washed once with dilute hydrochloric acid, washed with saturated sodium bicarbonate and saturated brine, and dried over anhydrous Na2SO4. The solvents were evaporated off at reduced pressure, and chromatographed in a silica gel column to give 22.7g pure BG02. |
With triethylamine; In dichloromethane; at 0℃; for 2h;Inert atmosphere; | General procedure: To a stirred solution of substituted ethylene glycol (1.0 eq.) and triethylamine (0.1 eq.) in DCM (500 mL) was added tosyl chloride (0.1 eq.) in DCM (10 vol.) dropwise at 0 C for 2 h under nitrogen atmosphere. Stirring was continued at RT for 20 h and then the reaction mixture was washed with saturated NH4CI solution, water, brine dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash using 10-15% ethyl acetate in n-hexane as eluent to afford title compounds (26ai-26a3 yield: 45-50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In acetonitrile; for 4h;Reflux; | To a solution of 13 (345 mg, 1.33 mmol) in CH3CN (3.3 mL), 4-iodophenol (310 mg, 1.40 mmol) and K2CO3 (222 mg, 1.59 mmol) were added and the mixture was refluxed for 4 h. The mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The resulting residue was purified by chromatography column on silica gel (EtOAc:cyclohexane 1:1) to give 14 (308 mg, 1.00 mmol, 75%) as a colourless oil. |
Yield | Reaction Conditions | Operation in experiment |
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86.91% | With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 2h; | To a solution of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (1 g, 3.84 mmol, 1 eq) in dichloromethane (10 mL) was added 3,4-dihydro-2H-pyran (496 mg, 5.76 mmol, 1.5 eq) and p-toluenesulfonic acid (33 mg, 0.19 mmol, 0.05 eq). The reaction solution was stirred at 20 C for 2 hours. Triethylamine (0.1 mL) was added and the reaction mixture was concentrated under vacuum to get the residue. This residue was purified by silica gel flash chromatography (0-25% ethyl acetate in petroleum ether) to get the product. 2-(2- tetrahydropyran-2-yloxyethoxy)ethyl 4-methylbenzenesulfonate (1.15 g, 3.34 mmol, 86.91% yield) was obtained as a colorless oil. ^-NMR (400MHz, DMSO-ifc) d 7.81 (d, 7=8.3 Hz, 2H), 7.35 (d, 7=8.1 Hz, 2H), 4.62 - 4.58 (m, 1H), 4.20 - 4.16 (m, 2H), 3.90 - 3.77 (m, 2H), 3.74 - 3.69 (m, 2H), 3.64 - 3.59 (m, 2H), 3.57 - 3.46 (m, 2H), 2.46 (s, 3H), 1.88 - 1.77 (m, 1H), 1.75 - 1.67 (m, 1H), 1.57 - 1.48 (m, 4H). |
72.4% | With toluene-4-sulfonic acid; In 1,4-dioxane; at 20℃; for 0.333333h; | Over a period of 5 minutes, dihydropyran(2.5 g, 29.7 mmol) was added drop-wise to a stirred solution of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (compound 3B, 2.40 g, 9.2 mmol) and /7-toluenesulfonic acid monohydrate (125 mg, 0.66 mmol) in anhydrous dioxane (25 mL) at 20 C. After stirring for 20 minutes, saturated Na2C03was added until the solution was slightly basic. The mixture was concentrated under reduced pressure. The residue was dissolved in CH2C12(50 mL), washed with brine (2 x 50 mL), dried over Na2S04andconcentrated in vacuo. The residue was purified by silica gel column chromatography(PE:EA=20: 1-10: 1) to give 2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl 4- methylbenzenesulfonate (compound 3C, 2.3 g, 72.4% ) as a colorless oil. MS: calc'd 262.1 (M+H20)+, 267 (M+Na+); measured 262.2 (M+H20)+, 267 (M+Na+). |
Yield | Reaction Conditions | Operation in experiment |
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64% | With sodium azide; In acetonitrile; at 80℃; for 36h; | A solution of 24 (738 mg, 2.84 mmol) and NaN3 (239 mg, 3.60 mmol) inCH3CN was stirred for 36 h at 80C. A white precipitate was formed and removedby filtration. The precipitate was washed three times with cold CH3CN.The filtrate was evaporated under reduced pressure, diluted with CH2Cl2,poured into a saturated aq. NaHCO3 solution, and extracted three times withCH2Cl2. The combined organic portions were washed with brine, dried overMgSO4, and concentrated under reduced pressure. The remaining residue waspurified by silica gel column chromatography to give 25 (239 mg, 64%) as colorlessoil. 1H NMR (400 MHz, CDCl3): delta 3.75-3.69 (m, 2H), 3.69-3.64 (m, 2H),3.61-3.56 (m, 2H), 3.41-3.36 (m, 2H), 2.59-2.00 (s, 1H). 13C NMR (100 MHz,CDCl3): delta 72.42, 69.99, 61.69, 50.69. |
With sodium azide; In N,N-dimethyl-formamide; at 25 - 100℃; for 5h;Inert atmosphere; | Synthesis of 2-(2-azidoethoxy)ethan-l-ol (Compound 4) Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 2-(2-[[(4- 2-(2-hydroxyethoxy)ethyl 4- methylbenzenesulfonate (Compound 3, 50 g, 192.08 mmol, 1.00 equiv) in N,N- dimethylformamide (250 mL). This was followed by the addition of sodium azide (18.79 g, 289.03 mmol, 1.50 equiv) at 25C. The resulting solution was stirred for 5 h at 100C in an oil bath. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The residual solution was diluted with 1000 mL of dichloromethane and washed with 1x500 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (80: 1). This resulted in 2-(2-azidoethoxy)ethan- 1 -ol (Compound 4) as a colorless oil. 1HNMR (CDCI3, 400 MHz, ppm): 3.42-3.45(t, J= 4.8Hz, 2H), 3.63-3.65(t, J = 4.8Hz, 2H), 3.71-3.74(t, J = 4.8Hz, 2H), 3.71-3.79(m, 2H). | |
With sodium azide; In N,N-dimethyl-formamide; at 25 - 100℃; for 5h;Inert atmosphere; | Synthesis of 2-(2-azidoethoxy)ethan-l-ol (Compound A4) Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 2-(2-[[(4- 2-(2-hydroxyethoxy)ethyl 4- methylbenzenesulfonate (A3, 50 g, 192.08 mmol, 1.00 equiv) in N,N-dimethylformamide (250 mL). This was followed by the addition of sodium azide (18.79 g, 289.03 mmol, 1.50 equiv) at 25C. The resulting solution was stirred for 5 h at 100C in an oil bath. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The residual solution was diluted with 1000 mL of dichloromethane and washed with 1x500 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (80: 1). This resulted in 2-(2-azidoethoxy)ethan-l-ol (Compound A4) as a colorless oil. 1HNMR (CDCls, 400 MHz, ppm): 3.42-3.45(t, J= 4.8Hz, 2H), 3.63-3.65(t, J= 4.8Hz, 2H), 3.71-3.74(t, J= 4.8Hz, 2H), 3.71-3.79(m, 2H). |
With sodium azide; In N,N-dimethyl-formamide; at 25 - 100℃; for 5h;Inert atmosphere; | Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 2-(2-[[(4- 2-(2- hydroxyethoxy)ethyl 4-methylbenzenesulfonate (3, 50 g, 192.08 mmol, 1.00 equiv) in N,N- dimethylformamide (250 mL). This was followed by the addition of sodium azide (18.79 g, 289.03 mmol, 1.50 equiv) at 25C. The resulting solution was stirred for 5 h at 100C in an oil bath. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The residual solution was diluted with 1000 mL of dichloromethane and washed with 1x500 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (80: 1). This resulted in 2-(2-azidoethoxy)ethan-l-ol (4) as a colorless oil. 1HNMR (CDCls, 400 MHz, ppm): 3.42-3.45(t, J= 4.8Hz, 2H), 3.63-3.65(t, J= 4.8Hz, 2H), 3.71-3.74(t, J= 4.8Hz, 2H), 3.71-3.79(m, 2H). | |
With sodium azide; In N,N-dimethyl-formamide; at 25 - 100℃; for 5h;Inert atmosphere; | Synthesis of 2-(2-azidoethoxy)ethan-1-ol (Compound A4)Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 2-(2-[[(4- 2-(2-hydroxyethoxy)ethyl 4- methylbenzenesulfonate (A3, 50 g, 192.08 mmol, 1.00 equiv) in N,N-dimethylformamide (250 mL). This was followed by the addition of sodium azide (18.79 g, 289.03 mmol, 1.50 equiv) at 25C. The resulting solution was stirred for 5 h at 100C in an oil bath. The reaction mixturewas cooled and filtered. The filtrate was concentrated under vacuum. The residual solution was diluted with 1000 mL of dichloromethane and washed with 1x500 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (80: 1). This resulted in Compound A4 as an oil.1HNMR (CDC13, 400 MHz, ppm): 3.42-3.45(t, J= 4.8Hz, 2H), 3.63-3.65(t, J= 4.8Hz, 2H), 3.71-3.74(t, J= 4.8Hz, 2H), 3.71-3.79(m, 2H). | |
With sodium azide; In N,N-dimethyl-formamide; at 25 - 100℃; for 5h;Inert atmosphere; | Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of 2-(2-[[(4- 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (A3, 50 g, 192.08 mmol, 1.00 equiv) in N,N-dimethylformamide (250 mL). This was followed by the addition of sodium azide (18.79 g, 289.03 mmol, 1.50 equiv) at 25C. The resulting solution was stirred for S h at 100C in an oil bath. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The residual solution was diluted with 1000 mL of dichloromethane and washed with 1x500 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (80:1). This resulted5 in Compound A4 as an oil.?HNMR (CDC13, 400 MHz, ppm): 3.42-3.45(t, J= 4.8Hz, 2H), 3.63-3.65(t, J= 4.8Hz, 2H), 3.71-3.74(t, J= 4.8Hz, 2H), 3.71-3.79(m, 2H). | |
With sodium azide; In ethanol; at 90℃; for 6h; | 1004581 A solution of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (6 g, 23.1mmol) in ethanol (50 mL) was charged with sodium azide (12 g, 18.5 mmol) and heated at 90C for 6 h. The reaction mixture was cooled to room temperature, filtered through a pad ofcelite and washed with ethanol (50 mL). The filtrate was concentrated in vacuo resulting in 2.8g of a crude compound as a colorless oil. The crude compound was used in the next stepwithout further purification. ?H NMR (400 MHz, CD3OD): oe = 3.67 (d, J=5.3 Hz, 4H), 3.54 - 3.60 (m, 2H), 3.39 (t, J= 4.8 Hz, 2H). | |
17.1 g | With sodium azide; In dimethyl sulfoxide; at 50℃; for 3h; | To a 500 mL three-necked flask were added 22.7g BG02(1.0eq) and 190mL DMSO, stirred evenly, then added NaN3 11.5 g (2.0 eq), heated to 50C and reacted for 3 hours, cooled down to room temperature. The reaction liquid was poured into water, extracted with ethyl acetate for many times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 17.1g BG03 as a colourless liquid. |
With sodium azide; In N,N-dimethyl-formamide; at 60℃; for 5h; | General procedure: To a stirred solution of compound (26ai-26a3, 1.0 eq.) in DMF (5 vol.) was added sodium azide (1.5 eq.) at RT. Stirring was continued at 60 C for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into water and extracted with ethyl acetate. Organic layer was washed water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to afford title compound (26bi-26b3, yield: 40-50 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-(dimethylamino)pyridinium tosylate; at 20℃; for 10h; | Preparation of Dendrimer G1The generation dendrimer (G1) is prepared by reacting mono-protected diol with aconitic acid by the procedure reported by Moore and Stupp for esterification of aliphatic acids. The mono-protected diol (4 equivalent) (in excess) is treated with aconitic acid (i equivalent) in the presence of DPTS (1.1 equivalent) and EDC (1.2 equivalent) in dichloromethane or DMF. The resulting mixture is stirred for 8-10 hours at room temp to give Dendrimer 1 with protected OH surface groups. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 4h;Inert atmosphere; | General procedure: p-TsCI (1.2 eq.) was added dropwise to a mixture of the appropriate di-alcohol, Et3N (1 eq.), and DMAP (cat.) in dry CH2CI2 (0.01 M) under N2 atmosphere with stirring at 0°C. The stirring was continued at room temperature for 4 hours. The reaction was quenched with saturated NH4CI aqueous solution and the whole was extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and, following solvent evaporation, the crude was purified by flash chromatography. ES154; 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesu Ifonate. It was synthesized from triethylene glycol (1 .000 g, 6.66 mmol). Elution with petroleum etherAcOEt (2:8) afforded ES154 as a waxy solid: 0.450 g (22percent).1H-NMR (CDCI3, 400 MHz)5 2.30 (s, 3H), 2.99 (br s, exchangeable with D20, IH), 3.40-3.63 (m, IOH), 4.02 (t,J=4.8 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H). 13C-NMR (CDCI3, 100MHz) 521.48, 42.73, 61.39, 68.47, 69.24, 70.06, 70.42, 71.12, 72.46, 127.79, 129.81,132.71, 144.87. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of diethylene glycol (270 muL, 2.8 mmol) and pyridine (227.9 muL, 2.8 mmol) in CH2Cl2was added dropwise of a solution of tosyl chloride (805.7 mg, 2.8 mmol) in CH2Cl2at 0 C and stirred overnight. The solvent was removed under pressure to give pale yellow oil which was purified by siliga gel column chromatography with EtOAc as eluent to obtain diethylene glycol monotosylate as a colorless oil. Cassiarin A (60.5 mg, 0.3 mmol) and potassium carbonate (200.8 mg, 1.4 mmol) in DMF was stirred at room temperature for 1 h. The mixture was added diethylene glycol monotosylate (84.6 mg, 0.3 mmol), stirred and refluxed for 2 days and quenched by adding water, then extracted with EtOAc. The organic phase was washed with saturated NaCl, dried over Na2SO4, concentrated under pressure and purified by recrystallization from EtOAc to give5b.The product was characterized by spectroscopic methods. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With caesium carbonate; In acetonitrile; at 70℃; for 16h;Inert atmosphere; | A solution of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (2.50 g, 9.6 mmol), 3-bromophenol (1.99 g, 11.5 mmol), and cesium carbonate (6.26 mg, 19.2 mmol) in MeCN (12 mL) was stirred at 70 C for 16 h. The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (petroleum ether:EtOAc 5:1 to 1 :1) to afford 2-(2-(3-bromophenoxy)ethoxy)ethanol (1.78 g 63%) as a colorless oil; lU NMR (400 MHz, CDCI3) S = 7.20 - 7.14 (m, 1H), 7.14 - 7.07 (m, 2H), 6.94 - 6.82 (m, 1H), 4.18 - 4.12 (m, 2H), 3.92 - 3.86 (m, 2H), 3.88 - 3.71 (m, 2H), 3.73 - 3.66 (m, 2H), 2.18 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 18h; | The title compound from Example 85 (0.08 g, 0.276 mmol) was suspended in tetrahydrofuran (5 mL) and triphenylphosphine (0.178 g, 0.69 mmol) and the title compound from Step A above (0.085 g, 0.345 mmol) was added. After the addition of a solution of diethyl diazodicarboxylate in tetrahydrofuran (0.285 mL, 0.69 mmol), the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure without heating and the residue was purified by chromatography on HP-Sil SNAP cartridges using a Biotage Isolera One purification system employing a dichloromethane/methanol gradient (100/0 -> 50/50). The solvents of the fraction containing the less polar title compound were evaporated under reduced pressure without heating to afford the title compound as a pale yellow glass (0.032 g, 22 percent). The more polar phenol starting material was isolated as a beige solid (0.013 g, 16 percent). 1H-NMR (400 MHz, DMSO-d6): delta = 9.45 (s, 1 H), 9.15 (s, 1 H), 8.41 (d, 1 H), 8.34 (d, 1 H), 7.79- 7.76 (m, 3H), 7.55 (d, 1 H), 7.40 (d, 2H), 7.33-7.30 (m, 1 H), 7.20 (t, 1 H), 6.80 (d, 1 H), 6.52-6.48 (m, 1 H), 4.17-4.15 (m, 2H), 4.08-4.05 (m, 2H), 3.86 (s, 3H), 3.73-3.67 (m, 4H), 2.34 (s, 3H) |
16% | With diethyl diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 18h; | (1045) Step B (1046) The title compound from Example 85 (0.08 g, 0.276 mmol) was suspended in tetrahydrofuran (5 mL) and triphenylphosphine (0.178 g, 0.69 mmol) and the title compound from Step A above (0.085 g, 0.345 mmol) was added. After the addition of a solution of diethyl diazodicarboxylate in tetrahydrofuran (0.285 mL, 0.69 mmol), the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure without heating and the residue was purified by chromatography on HP-Sil SNAP cartridges using a Biotage Isolera One purification system employing a dichloromethane/ methanol gradient (100/0->50/50). The solvents of the fraction containing the less polar title compound were evaporated under reduced pressure without heating to afford the title compound as a pale yellow glass (0.032 g, 22percent). The more polar phenol starting material was isolated as a beige solid (0.013 g, 16percent). (1047) 1H-NMR (400 MHz, DMSO-d6): delta=9.45 (s, 1H), 9.15 (s, 1H), 8.41 (d, 1H), 8.34 (d, 1H), 7.79-7.76 (m, 3H), 7.55 (d, 1H), 7.40 (d, 2H), 7.33-7.30 (m, 1H), 7.20 (t, 1H), 6.80 (d, 1H), 6.52-6.48 (m, 1H), 4.17-4.15 (m, 2H), 4.08-4.05 (m, 2H), 3.86 (s, 3H), 3.73-3.67 (m, 4H), 2.34 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | To a solution of Catechol 5 (1.0 eq, 10 mmol, 1.1 g) inanhydrous acetonitrile (10 ml) was added Cs2CO3 (2 eq, 20mmol, 6.5 g). The mixture was stirred and refluxed for 10minutes under nitrogen. Di (ethylene glycol) mono tosylate4a (2 eq, 20 mmol, 5.2 g) in anhydrous acetonitrile (10 mL)was added by a syringe, and the reaction mixture was stirredfor 12 hours in the presence of nitrogen. After cooling toroom temperature, the mixture was filtered. The combinedfiltrate was evaporated in vacuum and the residue was dissolvedin dichloromethane. The organic layer was washedwith distilled water and dried over magnesium sulfate. Afterthe solvent was evaporated, the residue was purified by columnchromatography (ethyl acetate/n-hexane = 3:1 v/v). 2,2'-(2,2'-(1,2-phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy)diethanol (6a). This compound was obtained in73percent yield as colourless oil. ir: 3355(OH), 1249 and 1126(CO) cm-1; 1H-NMR (CDCl3): 6.90 (s, 4H); 4.16 (t, J = 5 Hz,4H); 3.90 (t, J = 2.5 Hz, 4H); 3.75-3.68 (m, 10H). 13C-NMR(CDCl3): 148.3; 121.4; 113.55; 72.81; 69.3; 68.4; 61.5. Anal.calc. for C14H22O6: C, 58.73; H, 7.73, Found: C, 58.70; H,7.81. MS m/z (C14H22O6, 286) 286 (M+.). | |
73.6% | With potassium carbonate; lithium bromide; In acetonitrile; for 24h;Inert atmosphere; Reflux; | Add catechol 2.61g to a 250mL three-necked flaskAnd K2CO313.12g, by vacuuming for 3 to 5 times in a row,A nitrogen-filled cycle that vents oxygen and moisture from the system.Under nitrogen protection, 12.35 g of diethylene glycol mono-p-toluenesulfonate was added.0.02 g of LiBr and 150 mL of anhydrous acetonitrile solution were heated to reflux for 24 h.After the reaction is completed, the heating is stopped. After cooling, it was filtered, and the filter cake was dissolved with water (100 mL).It was extracted with CH2Cl2 (100 mL×2).The oil was dissolved in 100 mL of CH 2 Cl 2 and washed with a mixed solution (saturated brine: 1percent sodium hydroxide solution = 3:1, 50 mL × 3).Dry over anhydrous magnesium sulfate.Filtration and rotary evaporation gave a light brown powder with a yield of 73.6percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | General procedure: To a solution of Catechol 5 (1.0 eq, 10 mmol, 1.1 g) inanhydrous acetonitrile (10 ml) was added Cs2CO3 (2 eq, 20mmol, 6.5 g). The mixture was stirred and refluxed for 10minutes under nitrogen. Di (ethylene glycol) mono tosylate4a (2 eq, 20 mmol, 5.2 g) in anhydrous acetonitrile (10 mL)was added by a syringe, and the reaction mixture was stirredfor 12 hours in the presence of nitrogen. After cooling toroom temperature, the mixture was filtered. The combinedfiltrate was evaporated in vacuum and the residue was dissolvedin dichloromethane. The organic layer was washedwith distilled water and dried over magnesium sulfate. Afterthe solvent was evaporated, the residue was purified by columnchromatography (ethyl acetate/n-hexane = 3:1 v/v). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 96h;Inert atmosphere; | stirred for 4 days at room temperature in an argon atmosphere.The solvent in the mixture was removed by evaporation at room temperature under reduced pressure. Thereafier, dichloromethane (20 ml) was added thereto, and the resultant mix- tare was filtered. The filtrate was concentrated, and the residual substance obtained was applied to silica gel columnchromatography. As eluents in the silica gel colunm chromatography, first, ethyl acetate containing 0.05percent pyridine was used, and then, a mixture of CR2C12 and CR3OR (CR2C12:CR3OR=9:1) containing 0.05percent pyridine was used. As aresult, Compound 23 in the form of colorless syrup wasobtained (1.15 g, yield: 97percent). The result of NMR analysiswith respect to this compound is shown below.?H-NMR (CDC13): oe7.41-7.45 (m, 2H, Ar?-H), 7.27-7.3 1(m, 6H, Ar?H), 7.17-7.21 (m, 1R, Ar?H), 6.79-6.82 (m,4H, Ar?H), 3.79 (s, 6H, OCR3), 3.60-3.70 (m, 2H), 3.39-3.57 (m, 4H), 3.13-3.27 (m, 3H), 3.07-3.08 (m, 2H), 2.71-2.84 (m, 1R), 2.38-2.46 (m, 1R), 2.14-2.19 (m, 1R), 1.84-1.87 (m, 1R), 1.57-1.76 (m, 8H).(1) DMTr-Amide Rydroxy Ethoxy Ethyl Amino-L-Proline(Compound 23)DMTr-amide-L-proline (Compound 6) (1.00 g, 2.05 mmol), <strong>[118591-58-5]4-toluenesulfonic acid 2-(2-hydroxyethoxy)ethyl ester</strong> (3.10 g, 12.30 mmol), and anhydrous dimethylformamide solution (10 ml) of potassium carbonate (0.85 g, 6.15 mmol) were mixed together, and the resultant mixture was |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 2h; | Step 1: Synthesis of 4-[3-(4-{4-[2-(2-hydroxyethoxy)ethoxy]phenyl}phenyl)-4,4- dimethyl-5-oxo-2-sulfanylideneimidazolidin- 1 -yl] -2-(trifluoromethyl)benzonitrile (BN)[0658] To a stirred solution of 4-{3-[4-(4-hydroxyphenyl)phenyl]-4,4-dimethyl-5-oxo-2- sulfanylideneimidazolidin-l-yl}-2-(trifluoromethyl)benzonitrile (ABM-14, 610.5 mg, 1.27 mmol) in N,N-dimethylformamide (10 mL) was added K2C03(318.46 mg, 2.29 mmol) and 2-{2-[(4- methylbenzenesulfonyl)oxy]ethoxy}ethan-l-ol (L-18, 300 mg, 1.15 mmol) at rt. The resulting mixture was then stirred at 80 °C for 2 hours in an oil bath, LC-MS indicated formation of the desired product. The reaction mixture was cooled down to rt, water (20mL) was added and the resulting mixture was extracted with ethyl acetate (100 mL x 2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (20 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue which was purified by a flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v = 7:3) to give BN (yield: 66percent) as a light yellow oil. LC-MS (ES+): m/z 570, [MH+], tR= 1.60 min (2.0 minute run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With sodium azide; In N,N-dimethyl-formamide; at 50℃; for 12h; | To a solution of compound 4 (3.6 g, 14 mmol) in DMF (85 mL), NaN3 (1.6 g, 25 mmol) was added. The reaction suspension was heated to 50 oC in an oil bath and stirred for 12 h. Then, water (50 mL) was added and the reaction mixture was cooled to room temperature. The product was then extracted using dichloromethane (3 × 80 mL), which was then washed with water (3 × 55 mL) and dried over anhydrous Na2SO4. After removing the solvent, the target product 5 was obtained as a light yellow oil (0.74 g, 6.3 mmol, 45percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (5.7 g, 22 mmol) was dissolved in 1,4-dioxane (60 mL), followed by addition of methoxyethylamine 3-1 (2 g, 27 mmol), and potassium carbonate (3.73 g, 27 mmol) was added under stirring in batches, followed by stirring the reaction overnight at 70° C., TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 3-2 (2.1 g, 58percent) as a pale yellow oil, LC-MS: m/z=164[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (3.5 g, 13.5 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of methoxypropylamine 4-1 (4.81 g, 54 mmol), and potassium carbonate (5.52 g, 40 mmol) was added under stirring in batches, followed by stirring the reaction overnight under at 70° C., TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 4-2 (1.6 g, 67percent) as a pale yellow oil, LC-MS: m/z=178[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (3.5 g, 13.5 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 5-1 (1.9 g, 14.2 mmol), and potassium carbonate (3.7 g, 27 mmol) was added under stirring in batches, followed by stirring the reaction overnight at 70° C., TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product as a pale yellow oil 5-2 (1.2 g, 40percent), LC-MS: m/z=222[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate; In 1,4-dioxane; at 50℃; | Compound 1-3 (5.1 g, 19.6 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of methylamine hydrochloride 1-4 (13.4 g, 196 mmol), and potassium carbonate (13.8 g, 100 mmol) was added under stirring in batches, followed by stirring the reaction overnight under conditions of 50° C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 1-5 (1.2 g, 52percent) as a pale yellow oil, LC-MS: m/z=120[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (40 mL), followed by addition of diethylamine 11-1 (2.2 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70° C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 11-2 (0.68 g, 42percent) as a pale yellow oil, LC-MS: m/z=162[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (40 mL), followed by addition of tetrahydropyrrole 12-1 (2.14 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70° C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 12-2 (0.71 g, 45percent) as a pale yellow oil, LC-MS: m/z=160[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (40 mL), followed by addition of piperidine 13-1 (2.52 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70° C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 13-2 (0.73 g, 42percent) as a pale yellow oil, LC-MS: m/z=174[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.1% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of morpholine 14-1 (2.61 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70° C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 14-2 (1 g, 57.1percent) as a pale yellow oil, LC-MS: m/z=176[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.1% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of N-methylpiperazine 15-1 (3 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70° C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 15-2 (1.45 g, 77.1percent) as a pale yellow oil, LC-MS: m/z=189[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.4% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 16-1 (1 g, 10 mmol), and potassium carbonate (1.38 g, 10 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70° C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 16-2 (0.76 g, 40.4percent) as a pale yellow oil, LC-MS: m/z=189[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.8% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (3.12 g, 12 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of compound 23-1 (1 g, 10 mmol), and under stirring potassium carbonate (1.65 g, 12 mmol) was added, followed by stirring the reaction overnight at 70 C., TLC monitoring showed the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 23-2 (1.2 g, 62.8%) as a pale yellow oil, LC-MS: m/z=192[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (3.5 g, 13.5 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of ethylamine hydrochloride 2-1 (2.2 g, 27 mmol), and carbonate (3.73 g, 27 mmol) was added under stirring potassium in batches, followed by stirring the reaction overnight under at 70° C., TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 2-2 (1.5 g, 83percent) as a pale yellow oil, LC-MS: m/z=134[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 6h; | 5), 2 g of compound 5 and 1.9 g of compound 6 (m = l) were added to N, N-dimethylformamide (DMF) followed byInto 4.lg anhydrous potassium carbonate, at a temperature of 60 ° C under the conditions of reaction 6h, after the end of the reaction, dry dry DMF, then with dichloromethaneAnd water extraction to obtain a crude product, isolated with silica gel column using dichloromethane-methanol as eluent to give compound 7 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Compound 1-1 (24.2 g, 93 mmol) was dissolved in (200 mL)N, N-dimethylformamide (DMF), followed by addition3,6-dihydroxyphthalocyanine 1-2(6 g, 37 mmol) and sodium carbonate(7.8 g, 74 mmol),Heating up to 80 degrees Celsius,Stirred overnight, the solvent was removed under reduced pressure,With tetrahydrofuran (200 mL)The concentrated residue was dispersed and p-toluenesulfonyl chloride was added to the reaction system(19 g, 100 mmol) and potassium hydroxide (5.6 g, 100 mmol)The mixture was stirred at room temperature for 5 hours.500 ml of water and 300 ml of ethyl acetate were added thereto, and the mixture was vigorously stirred for half an hour, allowed to stand, filtered and purified by silica gel column (petroleum ether: ethyl acetate = 1: 1) and dried to give white solid 1-3 (18 g, 75percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With pyridine; In dichloromethane; at 20℃; for 8h;Cooling with ice; | In ice water bath, a compound 1 - 2 (1.2g, 2 . 1mmol), compound 3 - 1 (0.5g, 2 . 4mmol), pyridine (0.8g, 10 . 1mmol) by adding dichloromethane (25 ml), the temperature is raised to room temperature to continue stirring for 8 hours, stopping the reaction, water is added to the reaction solution (100 ml), stirring at a standstill, the collection of organic phase, the organic phase dried with anhydrous sodium sulfate, is distilled under reduced pressure, the crude product for separation and purification of silica gel chromatography, eluting with chloroform/methanol agent is (9:1), getting the oil of bombycinous 3 - 2 (0.85g, 62percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 3h; | To a solution of 1 (300 mg, 0.851 mmol), 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (331 mg, 1.270 mmol) and Cs2CO3(414 mg, 1.270 mmol) were added. The reaction mixturewas stirredat 90 C for 3 h and was subsequently poured into water (250 mL)and extracted 3 times with DCM (75 mL). The combined organiclayers were dried over MgSO4 and evaporated under reducedpressure to give the title compound (357 mg, 0.810 mmol, 95percentyield). 1H NMR (400 MHz, CDCl3): d 9.9 (s, 1H), 8.7 (s, 1H), 8.1 (dd,J 8.1, 1.4 Hz, 1H), 7.4 (t, J 8.1 Hz, 1H), 7.2 (d, J 7.7 Hz, 1H), 4.8 (t,J 4.9 Hz, 2H), 4.0 (s, 3H), 3.8 (t, J 4.9 Hz, 2H), 3.7 (t, J 4.9 Hz,2H), 3.5 (t, J 4.9 Hz, 2H), 2.0e2.2 (m, 9H),1.6e1.8 (m, 6H). 13C NMR(100 MHz, CDCl3): d 176.1, 164.2, 151.1, 150.0, 130.6, 130.2, 125.3,119.6, 114.5, 111.7, 72.9, 70.3, 61.7, 58.3, 56.4, 51.8, 41.9, 36.7, 29.7.HRMS calculated for C25H33N2O5 [MH] 441.2384, found441.2380. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In acetonitrile; for 0.25h;Cooling with ice; Reflux; | 0.83 g (4.5 mmol) of methyl gallate,3.13 g (22.7 mmol) of anhydrous potassium carbonate was dissolved in 50 mL of purified acetonitrile,Then, 4.96 g (18.1 mmol) of compound a was weighed and dissolved with 15 mL of purified acetonitrile,Poured into a constant pressure funnel slowly added dropwise to the above solution,Dropping continued for about 1.5 hours, dropping the ice bath was removed device, refluxed for 24 hours.After cooling, the solvent was spun, washed with water, extracted three times with dichloromethane, dried, filtered, concentrated,Purification by column chromatography (mass ratio of 1:20 ethyl acetate and dichloromethane as eluent)Compound 2a was obtained as a yellow oil, weighing 1.8 g, yield 70percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.1% | Diethylene glycol 69 (20 g, 0.188 mol) was dissolved in CH2Cl2 (500 mL) followed by the addition of TEA (29 mL, 0.207 mol), then cooled with an ice bath. TsCl (20 g, 0.094 mol) in CH2Cl2 (100 mL) was added drop-wise during a period of 30 min. Slowly warmed to room temperature and kept reacting for another 1 hour. The solvent was removed and purified by silica gel chromatography eluting with 20percent EA/hexane, then 66percent EA/hexane to give 14.4 g (29.5percent) of diethylene glycol mono-Ts 70. Then, the obtained compound above diethylene glycol mono-Ts 70 (12.61 g, 44.2 mmol) and N-Boc-hydroxylamine (8.25 g, 62 mmol) were dissolved in CH2Cl2 (400 mL) followed by the addition of DBU (13.5 mL, 88.4 mol). After 48 hours reaction, the reaction was diluted with 400 mL of CH2Cl2, washed with 1N HCl (100 mL, twice), H2O (100 mL) and brine (200 mL), the organic layer was dried over anhydrous MgSO4 and evaporated. The crude was purified by silica gel chromatography eluting with 33percent EA/hexane, then 50percent EA/hexane containing 5percent MeOH to give 1.5 g (16.1percent) of diethylene glycol mono-Ts 71. The product was dissolved in CH2Cl2 (70 mL) followed by the addition of TEA (2.96 mL, 21.3 mmol), then cooled with an ice bath. TsCl (2 g, 9.4 mmol) in CH2Cl2 (20 mL) was added drop-wise during a period of 30 min. Slowly warmed to room temperature and kept reacting for another 1 hour. The solvent was removed and purified by silica gel chromatography eluting with 10percent EA/hexane, then 40percent EA/hexane to give 1.31 g (49percent) of OTs-diethylene glycol hydroxylamine-Boc 72. Finally, OTs-diethylene glycol hydroxylamie-Boc 72 (1.3 g, 3.48 mmol) was dissolved in anhydrous ethanol (50 mL) followed by the addition of sodium azide (680 mg, 10.4 mmol), then refluxed overnight. The solvent was removed, diluted with EA (200 mL), washed with H2O (50 mL) and brine (50 mL), the organic layer was dried over anhydrous MgSO4 and evaporated. The crude was purified by silica gel chromatography eluting with 10percent EA/hexane, then 40percent EA/hexane to give 728 mg (85percent) of Azido-diethylene glycol hydroxylamie-Boc 73. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With sodium hydride; In tetrahydrofuran; at 40℃; for 5h;Cooling with ice; | In an ice bath,Compound c (1.2 g, 2 mmol),2-1 (0.78 g, 3 mmol) was added tetrahydrofuran (30 mL),Sodium hydride (0.15 g, 6.3 mmol) was slowly added to the reaction solution.The reaction solution was heated to 40°C and stirring was continued for 5 hours. The reaction was quenched by adding 5 ml of water slowly.The organic solvent was distilled off under reduced pressure and water (100 mL) and dichloromethane (100 mL) were added.Stir and stand and collect the organic phase. The organic phase is dried over anhydrous sodium sulfate and distilled under reduced pressure.The crude product was purified by chromatography on a silica gel column eluted with chloroform/methanol (10:1).A brown solid was obtained as compound 2-2 (0.55 g, 41percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3h; | Step A: 2-(2-(4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenoxy)ethoxy)ethanol To a solution of 4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenol (500 mg, 1.58 mmol) in dry DMF (5 mL) were added Cs2CO3 (1.55 g, 4.75 mmol) and 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (1.23 g, 4.75 mmol) subsequently. The resulting solution was stirred at 70° C. for 3 hours. After cooling to room temperature, the reaction was quenched with water (20 mL), and the mixture was extracted with EtOAc (20 mL*3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column to afford the desired product (500 mg, 78percent yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): delta 8.69 (s, 2H), 7.91-7.96 (m, 3H), 7.62 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 4.19 (t, J=4.4 Hz, 2H), 3.90 (t, J=4.0 Hz, 2H), 3.78 (t, J=4.8 Hz, 2H), 3.70 (t, J=4.4 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53 mg | Step A: 5-(1-(4-(4-(2-(2 hydroxyethoxy)ethyl)piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydro-1H-inden-1-one To a solution of tert-butyl 4-(4-(4-(1-oxo-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazine-1-carboxylate (200 mg, 0.37 mmol) in MeOH (3 mL) was added 6 M HCl (g) in 1,4-dioxane (1 mL). The resulting solution was stirred at 25° C. for 1 hour. The solvent was removed under vacuum. The residue was diluted with 20 mL DCM, and the pH was adjusted to around 9 by progressively adding NaHCO3 aqueous solution. The mixture was extracted with DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product, which was used directly in next step. To a solution of above intermediate (180 mg crude, 0.37 mmol) in DMF (3 mL) were added 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (194 mg, 0.75 mmol) and K2CO3 (153.2 mg, 1.11 mmol). The resultant solution was stirred at 70° C. for 2 hours. After cooling to room temperature, the reaction was diluted with DCM (20 mL), and the mixture was washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to afford the desired product (53 mg, 27.2percent yield) as a yellow solid. LCMS (ES+): m/z 524.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide;Heating; | A solution of N-(2-chlorobenzyl)-6-(4-(piperazin-1-ylmethyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine (300 mg, 0.693 mmol), 2-(2-hydroxyethoxy)ethyl 4- methylbenzenesulfonate (900 mg, 3.464 mmol), and K2CO3 (478 mg, 3.464 mmol) in DMF (8 mL) was stirred at 75oC overnight. After cooling to rt, the reaction was quenched with water, and the mixture was extracted with ethyl acetate (20 mLx 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford crude title compound 2-(2-(4- (4-(4-((2-Chlorobenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzyl)piperazin-1- yl)ethoxy)ethan-1-ol (250 mg), which was used to next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | To a solution of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (2.7 g, 10.4 mmol) and benzyl piperazine-1-carboxylate (2.3 g, 10.4 mmol) in DMF (10 mL) was added K2CO3 (2.86 g, 20.8 mmol). The solution was stirred at 80oC overnight. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with water (10 mL) and brine (8 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to afford the crude Benzyl 4-(2-(2-hydroxyethoxy)ethyl)piperazine-1-carboxylate (4.5 g), which was used in the next reaction without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | General procedure: Azide solid support 157 [39,40], N3-propargyl pentofuranosyl uracils 158?160 [28] andpropargyl-hexopyranoside 161?163 [27] were previously synthesized. Tosylated diethyleneglycol164a [43] (3.0 g, 11.54 mmol) was co-evaporated three times with dry acetonitrile and thendissolved in dry CH2Cl2 (20 mL). A few molecular beads of molecular sieve (3A) wereadded and diisopropylethylamine (DIEA) (3 mL, 17.3 mmol) under argon. After 15 min,2-cyanoethyl-N,N-diisopropylchlorophosphoramidite (3 g, 12.7 mmol) was added and the solutionwas stirred at room temperature for 3 h. Then water was added (1 mL) and after 10 min dilutedwith 200 mL of CH2Cl2 and washed with a saturated solution of NaHCO3 (2 200 mL), driedwith Na2SO4 and concentrated. The crude product was eluted from a column of silica gel (110 g)with cyclohexane/EtOAc (9:1 to 7:3, containing 4percent of Et3N) to afford tosylated diethyleneglycolphosphoramidite 165a, 4.30 g, 81percent. 1H- NMR (CDCl3, 300 MHz): 1.17 (t, J = 6.8 Hz, 12H, 4 CH3);2.45 (s, 3H, CH3); 2.64 (t, J = 6.0 Hz, 2H, CH2CN); 3.56 (m, 2H, 2 CHMe2); 3.59 (m, 2H, POCH2); 3.89(m, 6H, OCH2 ); 4.15 (t, J = 4.8 Hz, 2H, SO3CH2); 7.35 (d, 2H, J = 8.1 Hz, Ar); 7.79 (d, 2H, J = 8.1 Hz,Ar). 13C-NMR (CDCl3, 75 MHz): .15.08 (CH2CN), 15.17 (CH3Ar), 19.35, 19.40, 19.44 (4 CH3CH),37.80 and 37.93 (CHMe2), 53.17 and 53.41 (POCH2CH2CN), 57.22 and 57.45 (C5, POCH2CH2), 63.42(C7), 64.08 (C8), 66.08 and 66.18 (C6, POCH2CH2), 112.6 (CN), 122.7 and 124.6 (ArH), 127.7 (Ar-S),139.6 (Ar-C). 31P-NMR (CDCl3, 121 MHz): 148.65. HRMS (ESI/Q-TOF): Calcd. for C20H34N2O6PS461.1875 [M + H]+; found 461.1877. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.8% | With potassium carbonate; In acetonitrile; at 80℃; for 12h;Inert atmosphere; | In a 250 mL three-necked flask, 1-naphthol 6.00 g, F 9.75 g, and potassium carbonate 20.70 g were added.The nitrogen gas is circulated for 3 to 5 times by continuous vacuuming, and oxygen and water in the system are discharged to reach a nitrogen atmosphere.Then, 70 mL of anhydrous CH3CN was added as a solvent, and the mixture was stirred at 80 ° C for 12 hours.After the reaction is completed, the reaction is stopped.The temperature of the reaction system was cooled to room temperature.250 mL of water was added to the reaction solution, and the solid was dissolved. Extract with ethyl acetate, with water,Washed with saturated NaHCO3 solution, saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered and evaporated.A pale red wine viscous liquid of 8.25 g was obtained with a yield of 94.8percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.6% | With potassium carbonate; lithium bromide; In acetonitrile; for 24h;Inert atmosphere; Reflux; | 2.21 g of hydroquinone and 13.12 g of K2CO3 were added to a 250 mL three-necked flask.The oxygen and water in the system are discharged by continuously evacuating the vacuum for 3 to 5 times.Under nitrogen protection, 12.35g of diethylene glycol mono-p-toluenesulfonate, 0.02g LiBr and150 mL of anhydrous acetonitrile solution, heated to reflux for 24 h. After the reaction is completed, the heating is stopped.After cooling, it was filtered, and the filter cake was dissolved with water (100mL), and then extracted with CH2Cl2 (100mL×2).The organic phase and the filtrate were combined and evaporated to give a dark brown oil.The oil was dissolved in 100 mL of CH 2 Cl 2 and washed with a mixed solution (saturated brine: 1percent sodium hydroxide solution = 3:1, 50 mL × 3).Dry over anhydrous magnesium sulfate. Filtration and rotary evaporation gave a light brown powder with a yield of 73.6percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With caesium carbonate; In N,N-dimethyl-formamide; for 14h;Reflux; | General procedure: Monotosyl-substituted polyethylene glycol(1 equiv.) or ditosyl-substituted polyethylene glycol (0.5 equiv.) and cesium carbonate (1 equiv.) were added to 6-hydroxy-2-(pyridin-2-yl)benzothiazole (1) (1 equiv.) dissolved in DMF (5 mL). The mixture was refluxed for 14 h (TLC monitoring), the solvent was evaporated at reduced pressure. Water (20 mL) was added to the mixture, which was extracted with ethyl acetate(3×30 mL). The organic phase was dried with anhydrous Na2SO4,the solvent was evaporated at reduced pressure on a rotary evaporator. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 85℃; for 16h;Inert atmosphere; | A mixture of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (3 g, 11.52 mmol, 1 eq) in methanamine (11.93 g, 115.25 mmol, 10 eq) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 85 C for 16 hours under nitrogen. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 2-[2- (methylamino)ethoxy] ethanol (1.37 g, 11.50 mmol, 99% yield) was obtained as a yellow oil. 'H- NMR (400MHz, CDCb) d 3.72 - 3.47 (m, 8H), 2.67 - 2.63 (m, 3H). |
at 70℃; for 12h;Sealed tube; | A solution of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (2.50 g, 9.60 mmol, 1 eq) and methanamine (40.0 mL, 1.00 eq) in sealed tube was stirred at 70 C. for 12 hours. Analysis by TLC indicated 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate was consumed completely. The reaction mixture was concentrated under reduced pressure to remove methanamine (40.0 mL, 1.00 eq) to give 2-[2-(methylamino)ethoxy]ethanol (1.10 g, crude) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 12h; | To a mixture of 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (2 g, 7.29 mmol, 1 eq) and potassium carbonate (3.02 g, 21.9 mmol, 3 eq) in dimethylformamide (10 mL) was added 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (2.09 g, 8.02 mmol, 1.1 eq). The mixture was stirred at 50 C. for 12 hours. The reaction mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate=1/1 to 0:1) to afford 2-(2,6-dioxo-3-piperidyl)-5-[2-(2-hydroxyethoxy)ethoxy]isoindoline-1,3-dione (1.5 g, 54% yield), obtained as a yellow solid. MS (ESI) m/z: 362.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 25℃; for 2h;Inert atmosphere; | To a solution of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (7.64 g, 29.3 mmol) in DCM (115 ml) under Ar was added at 0-5 C diethylaminosulfur trifluoride (14.2 g, 11.6 ml, 88 mmol). The light yellow solution was warmed to 20-25 C and was stirred for 1 h. The reaction mixture was cooled again to 5-10 C and quenched with 1M NaHCCh (200 ml) and solid NaHCCh (11 g) was added to reach pH 7-8. The organic layer was concentrated under vacuum. Due to bad conversion, the crude was dissolved again in DCM (115 ml) under Ar and diethylaminosulfur trifluoride (7.1 g, 5.82 ml, 44 mmol) was added at 0-5 C. The light yellow solution was warmed to 20-25C and stirred for 1 h. The reaction mix was cooled again to 5-lOC and quenched with 1M NaHCCh (200 ml), and solid NaHCCh (3 g) was added to reach pH 7-8. The organic layer was concentrated under vacuum to obtain the crude product as a yellow oil which was purified by MPLC over silica (eluent: heptane/ethyl acetate) to obtain the desired product (3.4 g, 44%) as a light yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) d ppm 1.56 (s, 1 H) 1.90 (t, J=6.l8 Hz, 1 H) 2.45 (s, 3 H) 3.50 - 3.57 (m, 2 H) 3.63 - 3.74 (m, 4 H) 4.16 - 4.25 (m, 2 H) 7.31 - 7.41 (m, 2 H) 7.76 - 7.85 (m, 2 H). LC- MS: m/z = 261.2 [M-H] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With caesium carbonate; In N,N-dimethyl-formamide; at 22 - 70℃; for 3h; | To a suspension of 4-hydroxy-/V-(4-(4-(pyridin-2-yl)piperazin-l-yl)phenyl)benzamide (112 mg, 0.3 mmol) in DMF (2.2 ml) was added at 22 C 2-(2-hydroxyethoxy)ethyl 4- methylbenzenesulfonate (CAS Nr. 118591-58-5) (85.9 mg, 330 m mol) followed by Cs2C03 (108 mg, 330 m mol) and the mixture was stirred at 22 C for 1 h. Then the mixture was warmed to 70 C and stirred for 2 h. The mixture was cooled to 22 C and treated dropwise with H20 (2.2 ml) to give precipitation of a solid. The suspension was stirred for 10 minutes, the solid was filtered off, washed with MeOH/ H20 1:1 (2 x 6 ml) and H20 (2 x 6 ml) and dried. The resulting solid was dissolved in DCM/MeOH 1:1 (10 ml), filtered and the filter washed with DCM/MeOH 1:1 (1 x 2 ml). The filtrate was evaporated and dried under high vacuum to give the title compound (60 mg, 43%) as white solid. LC-MS: m/z = 463.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.6% | With potassium carbonate; lithium bromide; In acetonitrile; for 24h;Reflux; Inert atmosphere; | In a 250 mL three-necked flask, 2.61 g of hydroquinone and 13.12 g of K2CO3 were added, and a vacuum was applied for 3 to 5 times, and a nitrogen-filled cycle was performed.Exhaust oxygen and moisture from the system. Under the protection of nitrogen,12.35 g of diethylene glycol mono-p-toluenesulfonate, 0.02 g of LiBr and 150 mL of anhydrous acetonitrile were added and heated to reflux for 24 h. The reaction is completed,Stop heating. After cooling, it was filtered, and the filter cake was dissolved with water (100 mL).Extracted with CH2Cl2 (100 mL×2), and the organic phase and filtrate were combined.It was steamed to give a dark brown oil. Dissolve the oil with 100 mL of CH 2 Cl 2 ,It was washed with a mixed solution (saturated saline: 1% sodium hydroxide solution = 3:1, 50 mL × 3).Dry over anhydrous magnesium sulfate. Filtered, steamed to a light brown powder,The yield was 73.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In acetonitrile;Reflux; | General procedure: Potassium carbonate (143 mg, 1.0 mmol) was added to a solution of 14 (310 mg, 0.7 mmol) and 15a (223 mg, 1.0 mmol) in CH3CN (4 mL) at room temperature. The reaction mixture was then refluxed overnight. The resulting mixture was poured into ice-water, adjusted to neutral PH with aqueous HCl (5%), and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (CH2Cl2/acetone = 10:1) to give 16a as yellow solid (195 mg, 57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.9% | With tetrabutylammomium bromide; potassium hydroxide; In toluene; at 20℃; | Compound 2a (2.954 g, 11.3 mmol) was dissolved in 10 mL of toluene, TBAB (0.181 g, 0.56 mmol), KOH (1.01 g, 18.1 mmol), tert-butyl bromoacetate (2.7 g, 13.6 mmol) . The reaction was stirred at room temperature overnight. After thin layer chromatography (PE: EA = 1:2), the raw material remained. Toluene was concentrated under reduced pressure, and 5 mL of water was added, and the mixture was extracted three times with 15 mL of dichloromethane. Column chromatography (EA) gave 3.4 g of product, yield 83.9%. |
83.9% | With tetrabutylammomium bromide; potassium hydroxide; In toluene; at 20℃; | Compound 2a (2.954 g, 11.3 mmol) was dissolved in 10 mL of toluene, TBAB (0.181 g, 0.56 mmol), KOH (1.01 g, 18.1 mmol), tert-butyl bromoacetate (2.7 g, 13.6 mmol) .The reaction was stirred at room temperature overnight.After thin layer chromatography (PE: EA = 1:2), the raw material remained.The toluene was concentrated under reduced pressure, and 5 mL of water was added, and the mixture was extracted three times with 15 mL of dichloromethane.Column chromatography (EA) gave 3.4 g of product, yield 83.9percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; for 12h;Reflux; Inert atmosphere; | (1) 2-Methyl-5-bromobenzothiazole (1 mol), p-toluenesulfonic acid diethylene glycol ester (3 mol) was placed in 20 mL of dry toluene, and heated under reflux for 12 hours under nitrogen atmosphere.It was cooled to room temperature, washed with anhydrous diethyl ether and recrystallized from acetone to give a white-yellow solid quaternary ammonium salt (III4d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene;Reflux; Inert atmosphere; | (1) 2-methyl-3-N-ethyl-5-bromobenzimidazole (1 mol), p-toluenesulfonic acid diethylene glycol ester (3 mol) was placed together in 20 mL of dry toluene,The mixture was heated under reflux for 12 hours under nitrogen atmosphere, cooled to room temperature, washed with anhydrous diethyl ether and then recrystallized from acetone to afford white-yellow solid quaternary ammonium salt (IV4d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; for 12h;Reflux; Inert atmosphere; | (1) 2,3,3-trimethyl-5-bromo-3H-indoline (1 mol),P-toluenesulfonic acid diethylene glycol ester (3 mol) was placed together in 20 mL of dry toluene.The mixture was heated to reflux for 12 hours under a nitrogen atmosphere, cooled to room temperature, washed with anhydrous diethyl ether and then recrystallized from acetone to give a white-yellow solid quaternary ammonium salt (I4d) |
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P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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