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CAS No. : | 86259-89-4 | MDL No. : | MFCD28976701 |
Formula : | C20H32O8S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AWIUPDGEVFBSGD-UHFFFAOYSA-N |
M.W : | 432.53 | Pubchem ID : | 13558887 |
Synonyms : |
|
Num. heavy atoms : | 29 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.7 |
Num. rotatable bonds : | 15 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 106.58 |
TPSA : | 97.9 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -7.63 cm/s |
Log Po/w (iLOGP) : | 4.78 |
Log Po/w (XLOGP3) : | 1.84 |
Log Po/w (WLOGP) : | 3.37 |
Log Po/w (MLOGP) : | 0.89 |
Log Po/w (SILICOS-IT) : | 3.09 |
Consensus Log Po/w : | 2.79 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 1.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.84 |
Solubility : | 0.619 mg/ml ; 0.00143 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.52 |
Solubility : | 0.132 mg/ml ; 0.000304 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -5.44 |
Solubility : | 0.00157 mg/ml ; 0.00000362 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.54 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
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 |
---|---|---|
72% | With sodium hydride In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium hydride In N,N-dimethyl-formamide at 60℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.3% | With toluene-4-sulfonic acid In tetrahydrofuran at 20℃; for 36h; Inert atmosphere; | Synthesis of pure monotetrahydropyran-protectedtetraethylene glycol monotosylate (9a) from pure 10a. A 1-L of round bottom flask was charged with pure 10a (200 g, 0.575 mol), dry TsOH (2.0 g,11 mmol) and dry THF (570 mL) and cooled in an ice-water bath followed bydropwise addition of dihydropyran (71.0 mL, 0.776 mol). The resulting mixturewas stirred for 36 h at room temperature. THFand excess of dihydropyran were removed on rotovap, and the mixture wasdissolved in dichloromethane (1 L), washed with aqueous NaCl solution (10%, 3 x300 mL), dried over sodium sulfate and concentrated under vacuum to give pure 9a as a dark red liquid (244 g, 98.3%).1H NMR (500 MHz, CDCl3) δ 7.82 (d, 2H, J = 10 Hz), 7.36 (d, 2H, J = 10 Hz), 4.65 (t, 1H, J = 5Hz), 4.18 (t, 2H, J = 5 Hz), 3.85-3.92 (m, 2H), 3.58-3.75 (m, 13H), 3.52(m, 1H), 2.47 (s, 3H), 1.80-1.90 (m, 1H), 1.68-1.77 (m, 1H), 1.48-1.66 (m, 4H);13C NMR (125 MHz, CDCl3) δ 144.72, 133.08, 129.78, 127.96,98.95, 70.77, 70.65, 70.59, 70.54, 69.20, 68.68, 66.64, 62.23, 30.58, 25.43,21.61, 19.49. |
90% | With pyridinium p-toluenesulfonate In dichloromethane for 2h; Heating; | |
90% | With pyridinium p-toluenesulfonate In dichloromethane for 3h; Heating; |
87% | With toluene-4-sulfonic acid In dichloromethane; water at 20℃; for 2h; Cooling with ice; | 2; 4 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (404) To an ice cold solution of 2-(2-(2-(2-hydroxyethoxyl)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (5.24 g, 15.0 mmol) dissolved in CH2Cl2 (150 mL), 3,4-Dihydro-2H-pyran (1.65 g, 19.7 mmol) was added slowly while stirring, followed by addition of p-toluenesulfonic acid monohydrate (0.69 g, 3.6 mmol). The solution was allowed to warm to room temperature and stirred for 2 hours. H2O (50 mL) was added to the reaction mixture and the organic phase was separated. The organic phase was then washed with additional H2O (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo to yield 404 (5.99 g, 87%) as an oil that did not require further purification. 1H-NMR: (CDCl3): b=1.48-1.93 (m, 6H), 2.45 (s, 3H), 3.48-3.94 (m, 14H), 3.84-3.94 (m, 2H), 4.18 (t, 2H), 4.64 (m, 1H), 7.35 (d, 2H), 7.81 (d, 2H) |
71% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 5h; | 3.1.2. Ethyl 2-[2-(2-{2-[(tetrahydro-2H-pyran-2-yl)oxy]ethoxy}ethoxy)ethoxy]4-methylbenzenesulfonate (6) A mixture of Pyridinium 4-toluenesulfonate (PPTS, 0.73 g, 2.90 mmol) and 3,4-2H-dihydropyran(3.93 mL, 43.11 mmol) in CH2Cl2 (50 mL) was added to a solution of compound 5 (10.0 g, 28.74 mmol)in anhydrous CH2Cl2 (50 mL). The reaction mixture was stirred at room temperature for 5 h. Then,the reaction mixture was diluted with CH2Cl2 and washed with water and saturated brine, dried overanhydrous Na2SO4, and evaporated. The residue was purified by column chromatography on silicagel [EtOAc-petroleum ether (15-50%)] to give the product (8.83 g, 71%) of colorless oil. HPLC analysiswas as follows: 90.1%; 1H-NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H),4.62 (t, J = 3.2 Hz, 1H), 4.18-4.15 (m, 2H), 3.87-3.83 (m, 1H), 3.72-3.47 (m, 15H), 2.45 (s, 3H), 1.86-1.78(m, 1H), 1.75-1.68 (m, 1H), and 1.63-1.49 (m, 4H); 13C-NMR (CDCl3, 100 MHz) δ 144.8, 133.0, 129.8,128.0, 99.0, 70.7, 70.64, 70.58, 70.53, 69.2, 68.7, 66.6, 62.2, 30.6, 25.4, 21.6, and 19.5. |
244 g | With toluene-4-sulfonic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In tetrahydrofuran 1.) reflux, 1 h, 2.) reflux, 36 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydride In tetrahydrofuran; paraffin for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydride In tetrahydrofuran at 50℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In dichloromethane at 0 - 22℃; for 24.25h; | 2.B Step B. Synthesis of 1-tetrahydropyranyloxy-11-tosyloxy-3,6,9-trioxaundecane (n=3) A solution of 1-tetrahydropyranyloxy-3,6,9-trioxaundecan-11-ol (Step A, 5.54 g, 19.9 mmol), tosyl chloride (4.93 g, 25.9 mmol) and triethylamine (3.6 mL, 25.9 mmol) in 60 mL DCM, was stirred at 0° C., under N2 for a period of 15 min and then at room temperature (22° C.) for a period of 24 h Afterwards, the DCM was evaporated and diethyl ether was added to give a precipitate. The reaction mixture was filtered with diethyl ether (70 mL), evaporated and purified by flash chromatography with initially a mixture of hexanes:acetone (9:1) followed by a mixture of hexanes:acetone (3.2). The title compound was obtained as an oil in 85% yield. IR (NaCl, νmax, cm-1): 1600 (C=C), 1360 (SO2), 1125 (C-O). 1H-NMR (CDCl3, δ ppm): 7.80 and 7.35 (4H, 2*d, J=8.2 Hz, 4H aromatic), 4.62 (1H, m, OCHO), 4.16 (2H, m, CH2OTs), 3.91-3.46 (16H, m, 8*CH2O), 3.59 (3H, s, CH3), 1.90-1.20 (6H, m, CH2CH2CH2). MS (m/e), C20H32SO8: no M+, 348 (M+-C5H8O). |
74% | Stage #1: 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethan-1-ol With potassium hydroxide In dichloromethane at 0 - 20℃; Stage #2: p-toluenesulfonyl chloride In dichloromethane at 20℃; for 10h; | Synthesis of tosylate 21-23. General procedure: KOH (0.21 g, 3.7 mmol for18, 0.17 g, 3.0 mmol for 19, 0.14 g, 2.5 mmol for 20) was added dropwise to 40 mL of a CH2Cl2 solution containing the THP-protected alcohol (0.35 g, 1.8 mmol (18), 1.5 mmol(19), 1.3 mmol (20)) was added at 0 °C. After stirring for 30 min at room temperature, TsCl (0.41 g, 2.2 mmol for 18,0.34 g, 1.2 mmol for 19, 0.29 g, 1.5 mmol for 20) was added, and resulting solution was stirred for 10 h at room temperature.The resulting solution was filtered, and the filtrate was washed with aq.K2CO3. The organic layer was dried with MgSO4, filtered,and concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography (diethylether)to yield tosylates 21 (0.54 g, 85%), 22 (0.51 g, 88%), and 23(0.4 g, 74%). |
54% | With triethylamine In dichloromethane at 0 - 20℃; for 3h; | 1 To a stirred solution of 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethan-1-ol 2 (1 g, 4.27 mmol) in DCM (20 mL) was added Et3N (0.8 ml, 5.55 mmol) and p-toluene sulfonyl chloride (1.05 g, 5.55 mmol) at 0 ° C, the reaction mixture and stirred at room temperature for 3 h. After consumption of starting material, the mixture was diluted with ethyl acetate (50 mL) and washed with ice cold water (2 x 20 mL), NaHCO3 solution (2 x 20 mL), brine solution (20 mL), dried over sodium sulfate and concentrated. Crude compound was purified by combi-flash chromatography and eluted with 50 % ethyl acetate in hexanes to afford 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate 3 (1 g, 2.31 mmol, 54 % yield) as pale brown liquid. TLC system: 100 % ethyl acetate - Rf: 0.50; LCMS: m/z = 455.39 (M+Na) + |
54% | With triethylamine In dichloromethane at 0 - 20℃; for 3h; | 1 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl 4- methylbenzenesulfonate (3) To a stirred solution of 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethan-1-ol 2 (1 g, 4.27 mmol) in DCM (20 mL) was added Et3N (0.8 ml, 5.55 mmol) and p-toluene sulfonyl chloride (1.05 g, 5.55 mmol) at 0 ° C, the reaction mixture and stirred at room temperature for 3 h. After consumption of starting material, the mixture was diluted with ethyl acetate (50 mL) and washed with ice cold water (2 x 20 mL), NaHCO3 solution (2 x 20 mL), brine solution (20 mL), dried over sodium sulfate and concentrated. Crude compound was purified by combi-flash chromatography and eluted with 50 % ethyl acetate in hexanes to afford 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate 3 (1 g, 2.31 mmol, 54 % yield) as pale brown liquid. TLC system: 100 % ethyl acetate - Rf: 0.50; LCMS: m/z = 455.39 (M+Na) + |
With sodium hydroxide In tetrahydrofuran at 20℃; for 20h; | ||
With potassium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: p-toluenesulfonic acid monohydrate / CH2Cl2 / 0.5 h / 20 °C 2: aq. NaOH / tetrahydrofuran / 20 h / 20 °C | ||
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid 2: potassium hydroxide | ||
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonic acid / dichloromethane / 0.5 h / 20 °C 1.2: 10 h / 80 °C 2.1: potassium hydroxide / dichloromethane / 0 - 20 °C 2.2: 10 h / 20 °C |
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / dichloromethane / 4 h / 0 - 20 °C 2: triethylamine / dichloromethane / 3 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: p-toluenesulfonyl chloride / dichloromethane / 4 h / 0 - 20 °C 2: triethylamine / dichloromethane / 3 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: p-toluenesulfonic acid monohydrate / CH2Cl2 / 0.5 h / 20 °C 2: aq. NaOH / tetrahydrofuran / 20 h / 20 °C | ||
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid 2: potassium hydroxide | ||
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonic acid / dichloromethane / 0.5 h / 20 °C 1.2: 10 h / 80 °C 2.1: potassium hydroxide / dichloromethane / 0 - 20 °C 2.2: 10 h / 20 °C |
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / dichloromethane / 4 h / 0 - 20 °C 2: triethylamine / dichloromethane / 3 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: p-toluenesulfonyl chloride / dichloromethane / 4 h / 0 - 20 °C 2: triethylamine / dichloromethane / 3 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 75 percent / NaH / tetrahydrofuran / 48 h / 50 °C 2: 92 percent / NaH / tetrahydrofuran / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 75 percent / NaH / tetrahydrofuran / 48 h / 50 °C 2: 92 percent / NaH / tetrahydrofuran / 24 h / 20 °C 3: 40 percent / PdCl2(PPh3)2; CuI; morpholine / 12 h / 75 °C 4: 90 percent / hydrochloric acid / methanol / 0.17 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 75 percent / NaH / tetrahydrofuran / 48 h / 50 °C 2: 92 percent / NaH / tetrahydrofuran / 24 h / 20 °C 3: 40 percent / PdCl2(PPh3)2; CuI; morpholine / 12 h / 75 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 80 percent / NaH / tetrahydrofuran; paraffin / 24 h / Heating 2: 95 percent / p-TsOH*H2O / ethanol / 24 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 80 percent / NaH / tetrahydrofuran; paraffin / 24 h / Heating 2: 95 percent / p-TsOH*H2O / ethanol / 24 h / Heating 3: 10 percent / NaH / tetrahydrofuran; paraffin / 20 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: NaH / tetrahydrofuran / 1.) reflux, 1 h, 2.) reflux, 36 h 2: p-TsOH / aq. ethanol / 38 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 72 percent / NaH / dimethylformamide 2: 100 percent / cc HCl / tetrahydrofuran 3: Zn, NH4Cl, n-propanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 2: 68 percent / H2 / tristriphenylphosphine rhodium chloride / benzene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 72 percent / NaH / dimethylformamide 2: 100 percent / cc HCl / tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 72 percent / NaH / dimethylformamide 2: 100 percent / cc HCl / tetrahydrofuran 3: Zn, NH4Cl, n-propanol 4: pyridine 5: 82 percent / BF3.Et2O / acetic acid 6: 55 percent / NaH / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 72 percent / NaH / dimethylformamide 2: 100 percent / cc HCl / tetrahydrofuran 3: Zn, NH4Cl, n-propanol 4: pyridine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 72 percent / NaH / dimethylformamide 2: 100 percent / cc HCl / tetrahydrofuran 3: Zn, NH4Cl, n-propanol 4: pyridine 5: 82 percent / BF3.Et2O / acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 2: 68 percent / H2 / tristriphenylphosphine rhodium chloride / benzene 3: 85 percent / 10percent HCl / tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 72 percent / NaH / dimethylformamide 2: 100 percent / cc HCl / tetrahydrofuran 3: Zn, NH4Cl, n-propanol 4: pyridine 5: 82 percent / BF3.Et2O / acetic acid 6: 55 percent / NaH / dimethylformamide 7: 84 percent / Tl(NO2)3.3H2O / methanol; tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium iodide In acetone at 60℃; for 10h; | Synthesis of iodo compounds 24-26. General procedure: NaI (0.6 g, 4.0 mmol for 21, 0.57 g, 3.8 mmol for 22, 0.52 g, 3.5 mmol for 23) was added to 20 mL of acetone solution containing tosylate (0.5 g, 1.5 mmol of (21), 1.3 mmol (22), 1.2 mmol (23)), and resulting solution was stirred at 60 °C for 10 h. After the remaining NaI was filtered, the resulting solution was concentratedin vacuo. The residue was extracted with CH2Cl2.The extract was dried with MgSO4, filtered, and concentrated in vacuo to give 24 (0.44 g, 100%), 25 (0.39 g, 91%), and 26(0.43 g, 97%). |
95% | With sodium iodide In acetone at 22℃; for 24h; | 2.C Step C. Synthesis of 11-iodo-1-tetrahydropyranyloxy-3,6,9-trioxaundecane (n=3) A solution of 1-tetrahydropyranyloxy-11-tosyloxy-3,6,9-trioxyundecane (Step B, 3.90 g, 9.0 mmol) and sodium iodide (2.70 g, 18.0 mmol) in dry acetone (40 mL), was stirred for 24 h under N2, at room temperature (22° C.). Then, the acetone was evaporated. The residue was transferred into an extraction funnel with diethyl ether (60 mL) was washed subsequently with a sodium thiosulfate solution (5% w/v, 15 mL) and with water (5*70 mL). The ethereal phase was dried, filtered and concentrated to an oil (95% yield). This material was used as such at the alkylation step (see example 3). IR (NaCl, vmax, cm-1): 1125 (C-O). 1H-NMR (CDCl3, δ ppm): 4.63 (1H, t, J=3.6 Hz, OCHO), 3.87, 3.61 and 3.50 (4H, 3*m, CH2OCHCH2), 3.76 (2H, t, J=6.9 Hz, ICH2CH2O), 3.67 (10H, 2 s, and m, 5*CH2O), 3.26 (2H, t, J=6.9 Hz, ICH2CH2O), 1.90-1.50 (6H, 4*m, CH2CH2CH2). MS (m/e), C13H25IO5: 389 (M++H+), 305 (M++H+-C5H8O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran 2: toluene-4-sulfonic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 20 °C 1.2: 72 h / Inert atmosphere; Reflux 2.1: ethanol; toluene-4-sulfonic acid / 3 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sodium hydride / tetrahydrofuran 2: toluene-4-sulfonic acid 3: potassium iodide; silver(l) oxide / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 20 °C 1.2: 72 h / Inert atmosphere; Reflux 2.1: ethanol; toluene-4-sulfonic acid / 3 h / Reflux 3.1: potassium iodide; silver(l) oxide / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: sodium hydride / tetrahydrofuran 2: toluene-4-sulfonic acid 3: potassium iodide; silver(l) oxide / dichloromethane / 20 °C 4: sodium hydride / tetrahydrofuran / 24 h / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran / 0.5 h / 20 °C 1.2: 72 h / Inert atmosphere; Reflux 2.1: ethanol; toluene-4-sulfonic acid / 3 h / Reflux 3.1: potassium iodide; silver(l) oxide / dichloromethane / 20 °C 4.1: sodium hydride / tetrahydrofuran / 24 h / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 5,11,17,23-tetra-tert-butyl-25,26-dihydroxy-27,28-dipropoxy-calix<4>arene With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate In tetrahydrofuran for 72h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: 3,4-dihydro-2<i>H</i>-pyran; toluene-4-sulfonic acid / dichloromethane / 24 h / 20 °C / Inert atmosphere 1.2: 0 - 20 °C / Inert atmosphere 1.3: 36 h / 20 °C / Inert atmosphere 2.1: toluene-4-sulfonic acid / tetrahydrofuran / 36 h / 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 24 h 2: toluene-4-sulfonic acid / dichloromethane; water / 2 h / 20 °C / Cooling with ice | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 °C 2: pyridinium p-toluenesulfonate / dichloromethane / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3,4-dihydro-2<i>H</i>-pyran; Tetraethylene glycol With toluene-4-sulfonic acid In dichloromethane at 20℃; for 24h; Inert atmosphere; Stage #2: p-toluenesulfonyl chloride With potassium hydroxide In tetrahydrofuran; water at 0 - 20℃; Inert atmosphere; Overall yield = 285 g; | Synthesis of a mixtureof monotetrahydropyran-protected tetraethylene glycol monotosylate (9a) and di-tetrahydropyran-protectedtetraethylene glycol (8a) from a mixture of 7a and 8a. To a 5-L round bottom flask charged with tetraethylene glycol (6a, 1552 g, 8.000 mol), CH2Cl2(3.0 L) and p-toluenesulfonic acidmonohydrate (6.0 g, 32 mmol) was added dihydropyran (174 mL, 1.84 mol) dropwiseand the resulting reaction mixture was stirred for 24 h at room temperature. Abouthalf of solvent was evaporated, and the reaction mixture was washed with water(1 x 3 L), aqueous NaCl solution (6 x 1 L) and dried over anhydrous sodiumsulfate. The organic layer was concentrated and further dried under vacuum toafford a mixture of 7a and 8a as a colorless liquid which was usedfor subsequent reaction without further purification (442 g, 86.3%). The molar ratioof 7a to 8a was found to be 8:1 estimated by 1H NMR analysis. A mixture of 7aand 8a (190 g, ~0.680 mol) preparedabove and THF (500 mL) were added to a 2-L round bottom flask, and theresulting reaction mixture was cooled in an ice-water bath. A solution of KOH(150 g, 2.70 mol) in water (140 mL) was rapidly added and the resulting mixturewas treated with a solution of TsCl (196 g, 1.03 mol) in 300 mL of THF dropwiseat 0 oC while vigorous stirring. The mixture was allowed to warm to roomtemperature and stirred overnight. The resulting mixture was poured into ice-water(500 mL), and the product was extracted with dichloromethane (5 x 200 mL). Theorganic layer was rinsed with aqueous NaCl solution (5 x 500 mL), dried overanhydrous sodium sulfate and concentrated invacuo to afford the required product (a mixture of 9a and 8a) as a lightyellow viscous liquid (285 g, 97.0%). The molar ratio of 9a to 8a was found to be8:1 estimated by 1H NMR analysis. 1H NMR (mixture, 500MHz, CDCl3) δ 7.82 (d, 2H, J= 10 Hz), 7.36 (d, 2H, J = 10Hz), 4.64 (m, 1H), 4.18 (t, 2H, J = 5 Hz), 3.83-3.91 (m, 2H), 3.56-3.74(m, 15H), 3.46-3.53 (m, 1H), 2.47 (s, 3H), 1.80-1.90 (m, 1H), 1.68-1.77 (m,1H), 1.48-1.66 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.3% | Stage #1: 1-phenyl-2,5,8,11-tetraoxatridecan-13-ol With sodium hydride; sodium iodide In tetrahydrofuran; mineral oil at 0℃; for 2h; Inert atmosphere; Stage #2: 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate In tetrahydrofuran; mineral oil for 12h; Reflux; Inert atmosphere; | Synthesis of monotetrahydropyran-protectedocta(ethyleneglycol) monobenzyl ether (11) Pure tetraethylene glycol monobenzyl ether (10b, 71 g, 0.25 mol) in dry THF (200mL) was added to NaH (12.5 g, 60% dispersion in mineral oil, 1.2 equiv.), NaI(2.0 g, 13 mmol) in dry THF (1.3 L) dropwise and stirred for 2 h at 0 oC.A solution of 9a (121.7 g, 0.275 mol,1.1 equiv.) prepared above in THF (300 mL) was added dropwise over 1 h at 0 oCand the resulting reaction mixture was allowed to warm at room temperature andheated slowly to reflux for another 12 h while stirring. After the mixture wasfiltered through Celite 545 to remove the solid, the obtained filtrate was concentratedto remove THF and redissolved in dichloromethane (1 L). After washed withaqueous NaCl/NaOH solution (2 x 300 mL), decolorized by activated charcoal anddried over anhydrous sodium sulfate, the organic layer was concentrated anddried under vacuum to give 11 as areddish viscous liquid (135 g, 99.3%). 1H NMR (500 MHz, CDCl3)δ 7.25-7.37 (m, 5H), 4.64 (t, 1H, J = 5 Hz), 4.58 (s, 2H), 3.83-3.92 (m,2H), 3.59-3.72 (m, 33H), 3.51 (m, 1H), 1.79-1.89 (m, 1H), 1.68-1.77 (m, 1H),1.47-1.66 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 138.26,128.28, 127.66, 127.50, 98.88, 73.18, 70.50-70.61 (br.), 69.41, 66.60, 62.14,30.53, 25.40, 19.43. HRMS(m/z) calcd for C28H48NaO10+,567.3150 [M+Na]+, found 567.3170. |
99.3% | Stage #1: 1-phenyl-2,5,8,11-tetraoxatridecan-13-ol With sodium hydride In tetrahydrofuran Stage #2: 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 g | With methanol; toluene-4-sulfonic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: sodium hydride / tetrahydrofuran 2: methanol; toluene-4-sulfonic acid 3: sodium hydride / tetrahydrofuran 4: hydrogen; palladium on activated charcoal / ethanol / 48 h / 20 °C / 72402.6 Torr / Autoclave 5: potassium hydroxide / tetrahydrofuran; water / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: sodium hydride / tetrahydrofuran 2.1: methanol; toluene-4-sulfonic acid 3.1: sodium hydride / tetrahydrofuran 4.1: hydrogen; palladium on activated charcoal / ethanol / 48 h / 20 °C / 72402.6 Torr / Autoclave 5.1: potassium hydroxide / tetrahydrofuran; water / Cooling with ice 6.1: sodium hydride / tetrahydrofuran; mineral oil / 2 h / 0 - 20 °C 6.2: 96 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1.1: sodium hydride / tetrahydrofuran 2.1: methanol; toluene-4-sulfonic acid 3.1: sodium hydride / tetrahydrofuran 4.1: hydrogen; palladium on activated charcoal / ethanol / 48 h / 20 °C / 72402.6 Torr / Autoclave 5.1: potassium hydroxide / tetrahydrofuran; water / Cooling with ice 6.1: sodium hydride / tetrahydrofuran; mineral oil / 2 h / 0 - 20 °C 6.2: 96 h / Reflux 7.1: trifluoroacetic acid / water; dichloromethane / 72 h 8.1: acetic acid / water / 18 h / Cooling with ice 9.1: sulfuric acid; water / methanol / 24 h / 70 °C / Cooling with ice 9.2: 24 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: sodium hydride / tetrahydrofuran 2: methanol; toluene-4-sulfonic acid 3: sodium hydride / tetrahydrofuran 4: hydrogen; palladium on activated charcoal / ethanol / 48 h / 20 °C / 72402.6 Torr / Autoclave |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: sodium hydride / tetrahydrofuran 2.1: methanol; toluene-4-sulfonic acid 3.1: sodium hydride / tetrahydrofuran 4.1: hydrogen; palladium on activated charcoal / ethanol / 48 h / 20 °C / 72402.6 Torr / Autoclave 5.1: potassium hydroxide / tetrahydrofuran; water / Cooling with ice 6.1: sodium hydride / tetrahydrofuran; mineral oil / 2 h / 0 - 20 °C 6.2: 96 h / Reflux 7.1: trifluoroacetic acid / water; dichloromethane / 72 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: sodium hydride / tetrahydrofuran 2.1: methanol; toluene-4-sulfonic acid 3.1: sodium hydride / tetrahydrofuran 4.1: hydrogen; palladium on activated charcoal / ethanol / 48 h / 20 °C / 72402.6 Torr / Autoclave 5.1: potassium hydroxide / tetrahydrofuran; water / Cooling with ice 6.1: sodium hydride / tetrahydrofuran; mineral oil / 2 h / 0 - 20 °C 6.2: 96 h / Reflux 7.1: trifluoroacetic acid / water; dichloromethane / 72 h 8.1: acetic acid / water / 18 h / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sodium hydride / tetrahydrofuran 2: methanol; toluene-4-sulfonic acid 3: sodium hydride / tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium iodide / acetone / 10 h / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0 - 20 °C 2.2: 10 h / 110 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium iodide / acetone / 10 h / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0 - 20 °C 2.2: 10 h / 110 °C 3.1: hydrogenchloride / methanol; water / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Stage #1: N,N,N'N'-tetramethyl malonamide With sodium hydride In tetrahydrofuran for 0.166667h; Inert atmosphere; Stage #2: 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate In tetrahydrofuran for 16h; Reflux; | 2; 4 N1,N1,N3,N3-tetramethyl-2-(2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)malonamide (406) Sodium hydride (0.391 g, 16.3 mmol) was dissolved in dry THF (100 mL) under N2 in a 3-neck round bottom flask with stir bar. N1,N1,N3,N3-tetramethylmalonamide (2.57 g, 16.2 mmol) dissolved in dry THF (10 mL) was added dropwise over the course of 10 minutes while stirring yielding a cloudy and viscous solution. The monotosylated and protected glycol 404 (5.98 g, 13.8 mmol) dissolved in dry THF (5 mL) was then added dropwise to the solution and the mixture was heated at reflux for 16 hours. A solid precipitate formed upon letting cool to room temperature, which was subsequently removed by filtration. THF was removed by rotary evaporation, and the oil was dissolved in CH2Cl2 (80 mL). The solution was washed with water (100 mL), brine (100 mL), dried with Na2SO4, and concentrated by rotary evaporation. Flash column chromatography (3:2 CH2Cl2/acetone) on silica gel was used to isolate 406 (1.78 g, 31%) as a colorless oil. 1H-NMR (CDCl3): δ=1.48-1.93 (m, 6H), 2.19 (q, 2H), 3.02 (d, 12H), 3.48-3.70 (m, 14H), 3.83-3.94 (m, 2H), 3.98 (t, 1H), 4.64 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N,N,N',N'-tetraethylmalonamide With sodium hydride In tetrahydrofuran Inert atmosphere; Stage #2: 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate In tetrahydrofuran for 20h; Reflux; | 2; 4 N1,N1,N3,N3-tetraethyl-2-(2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)malonamide (408) Sodium hydride (0.362 g, 15.0 mmol) was dissolved in freshly distilled THF (100 mL) under N2. N1,N1,N3,N3-tetraethylmalonamide (2.73 g, 12.7 mmol, dissolved in 5 mL THF) was added dropwise, followed by addition of 404 (4.39 g, 10.6 mmol, dissolved in 10 mL THF). The orange/yellow mixture was heated at reflux for 20 hours. Upon letting cool to room temperature, precipitated material was removed by filtration and THF was removed by rotary evaporation. The crude residue was dissolved in CH2Cl2 (50 mL), washed with deionized water (2*100 mL) and brine (100 mL), dried using Na2SO4 and concentrated. A short silica plug (5:1 CH2Cl2/CH3OH) was used to remove tosylate salts. Further purification was not performed and the crude product 408 was carried on to the THP deprotection step. H-NMR confirmed successful alkylation by presence of a quartet at 2.18 ppm (in CDCl3), typical of methylene protons a to the central carbon of the TMMA functionality |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0.17 h / Inert atmosphere 1.2: 16 h / Reflux 2.1: sulfuric acid / ethanol / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / Inert atmosphere 1.2: 20 h / Reflux 2.1: sulfuric acid / ethanol / 4.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 0.17 h / Inert atmosphere 1.2: 16 h / Reflux 2.1: sulfuric acid / ethanol / 4 h / 20 °C 3.1: phosphorus tribromide / dichloromethane / 19 h / Inert atmosphere; Cooling with ice; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / Inert atmosphere 1.2: 20 h / Reflux 2.1: sulfuric acid / ethanol / 4.5 h / 20 °C 3.1: phosphorus tribromide / dichloromethane / 24 h / Cooling with ice; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran / 0.17 h / Inert atmosphere 1.2: 16 h / Reflux 2.1: sulfuric acid / ethanol / 4 h / 20 °C 3.1: phosphorus tribromide / dichloromethane / 19 h / Inert atmosphere; Cooling with ice; Reflux 4.1: sodium thiosulfate / water; ethanol / 24 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: n-butyl 3,5-di-tert-butyl-4-[(11-hydroxy-3,6,9-oxaundec-1-yl)oxy]benzoate With sodium hydride In tetrahydrofuran; hexane at 0 - 20℃; for 0.5h; Stage #2: 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate In tetrahydrofuran for 24h; Reflux; Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-(2-(2-(2-(((3s,5s,7s)-adamantan-1-yl)oxy)ethoxy)ethoxy)ethoxy)ethan-1-ol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate In tetrahydrofuran; mineral oil at 0 - 20℃; for 5h; | ||
Stage #1: 2-(2-(2-(2-(((3s,5s,7s)-adamantan-1-yl)oxy)ethoxy)ethoxy)ethoxy)ethan-1-ol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate In tetrahydrofuran; mineral oil at 20℃; for 5h; | Synthesis of Compound 6 To a stirred solution of sodium hydride (60 wt % in mineral oil, 497 mg, 12.4 mmol, 1.5 equiv.) in THF (20 mL) at 0° C., Compound 4 (2.72 g, 8.28 mmol, 1.0 equiv.) in THF (10 mL) was slowly added. The resulting mixture was stirred for 30 min, Compound 5 (4.30 g, 9.94 mmol, 1.2 equiv.) in THF (10 mL) was added. The reaction mixture was stirred for 5 h at room temperature. After the desired reaction time, a few drops of water were added to quench the reaction. The reaction mixture was filtered through Celite to remove unwanted solid residue. The organic solution was dried over anhydrous MgSO4 and evaporated under the reduced pressure. The residue was purified by flash column chromatography on silica gel (eluted with EtOAc/MeOH=15/1) to give the THP-protected Compound 6 as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 1.2: 5 h / 0 - 20 °C 2.1: toluene-4-sulfonic acid / methanol / 20 °C 3.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 3.2: 5 h / 0 - 20 °C 4.1: toluene-4-sulfonic acid / methanol / 20 °C 5.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 5.2: 5 h / 0 - 20 °C | ||
Multi-step reaction with 5 steps 1.1: sodium hydride / mineral oil; tetrahydrofuran / 0.5 h / 0 °C 1.2: 5 h / 20 °C 2.1: toluene-4-sulfonic acid / methanol / 20 °C 3.1: sodium hydride / mineral oil; tetrahydrofuran 4.1: toluene-4-sulfonic acid / methanol 5.1: sodium hydride / mineral oil; tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 1.2: 5 h / 0 - 20 °C 2.1: toluene-4-sulfonic acid / methanol / 20 °C 3.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 3.2: 5 h / 0 - 20 °C 4.1: toluene-4-sulfonic acid / methanol / 20 °C 5.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 5.2: 5 h / 0 - 20 °C 6.1: toluene-4-sulfonic acid / methanol / 20 °C | ||
Multi-step reaction with 4 steps 1.1: sodium hydride / mineral oil; tetrahydrofuran / 0.5 h / 0 °C 1.2: 5 h / 20 °C 2.1: toluene-4-sulfonic acid / methanol / 20 °C 3.1: sodium hydride / mineral oil; tetrahydrofuran 4.1: toluene-4-sulfonic acid / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 1.2: 5 h / 0 - 20 °C 2.1: toluene-4-sulfonic acid / methanol / 20 °C 3.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 3.2: 5 h / 0 - 20 °C | ||
Multi-step reaction with 3 steps 1.1: sodium hydride / mineral oil; tetrahydrofuran / 0.5 h / 0 °C 1.2: 5 h / 20 °C 2.1: toluene-4-sulfonic acid / methanol / 20 °C 3.1: sodium hydride / mineral oil; tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 1.2: 5 h / 0 - 20 °C 2.1: toluene-4-sulfonic acid / methanol / 20 °C | ||
Multi-step reaction with 2 steps 1.1: sodium hydride / mineral oil; tetrahydrofuran / 0.5 h / 0 °C 1.2: 5 h / 20 °C 2.1: toluene-4-sulfonic acid / methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 1.2: 5 h / 0 - 20 °C 2.1: toluene-4-sulfonic acid / methanol / 20 °C 3.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C 3.2: 5 h / 0 - 20 °C 4.1: toluene-4-sulfonic acid / methanol / 20 °C | ||
Multi-step reaction with 4 steps 1.1: sodium hydride / mineral oil; tetrahydrofuran / 0.5 h / 0 °C 1.2: 5 h / 20 °C 2.1: toluene-4-sulfonic acid / methanol / 20 °C 3.1: sodium hydride / mineral oil; tetrahydrofuran 4.1: toluene-4-sulfonic acid / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate; 2-(2-(2-(2-(((3s,5s,7s)-adamantan-1-yl)oxy)ethoxy)ethoxy)ethoxy)ethan-1-ol With sodium hydride Stage #2: With toluene-4-sulfonic acid In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 18h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In N,N-dimethyl-formamide at 110℃; for 16h; | 1 2-(2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl) isoindoline-1, 3- dione (4) To a stirred solution of 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate 3 (500 Mg, 1.15 mmol) in DMF (10 mL) was added potassium phthalimide (282 mg, 1.52 mmol) at room temperature then stirred at 110 ° C for 16 h. After completion of reaction as indicated by TLC, to the reaction mixture added ice water (2x 200 mL) and extracted with ethyl acetate (2x 100 mL). Organic layer was washed with brine solution (100 mL), dried over Na2SO4 and concentrated to obtain 2-(2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl) isoindoline-1, 3-dione 4 (400 mg, 9.828 mmol, 84 %) as a pale brown liquid. TLC system: 50 % ethyl acetate in hexanes - Rf: 0.20; LCMS: m/z = 429.97 (M+Na) + |
84% | In N,N-dimethyl-formamide at 20 - 110℃; for 16h; | 1 2-(2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl)isoindoline-1, 3-dione (4) To a stirred solution of 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy)ethoxy) ethyl 4-methylbenzenesulfonate 3 (500 Mg, 1.15 mmol) in DMF (10 mL) was added potassium phthalimide (282 mg, 1.52 mmol) at room temperature then stirred at 110 ° C for 16 h. After completion of reaction as indicated by TLC, to the reaction mixture added ice water (2x 200 mL) and extracted with ethyl acetate (2x 100 mL). Organic layer was washed with brine solution (100 mL), dried over Na2SO4 and concentrated to obtain 2-(2-(2- (2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl) isoindoline-1, 3-dione 4 (400 mg, 9.828 mmol, 84 %) as a pale brown liquid. TLC system: 50 % ethyl acetate in hexanes - Rf: 0.20; LCMS: m/z = 429.97 (M+Na) + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | In ethanol for 12h; Sealed tube; Heating; | 1 To a stirred solution of 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate 1 (500 mg, 1.15 mmol, synthesis of compound-1 is reported in Sidechain-9) in a sealed tube was added 33 % of MeNH2 in ethanol (5 mL) at room temperature then stirred at 60 °C for 12 h. After completion of reaction as indicated by TLC, evaporated organic solvents, sodium bicarbonate solution (20 mL) was added to the residue and extracted with 10 % methanol in dichloromethane (3x 20 mL). The combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SO4 and concentrated to afford N-methyl-2-(2-(2-(2-((tetrahydro- 2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethan-1-amine Sidechain-10 (150 mg, 0.515 mmol, 44 %) as a brown liquid. TLC system: 10 % methanol in dichloromethane - Rf: 0.20 |
44% | In ethanol at 20 - 60℃; for 12h; Sealed tube; | 1 N-methyl-2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethan-1- amine (Sidechain-10) To a stirred solution of 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate 1 (500 mg, 1.15 mmol, synthesis of compound-1 is reported in Sidechain-9) in a sealed tube was added 33 % of MeNH2 in ethanol (5 mL) at room temperature then stirred at 60 °C for 12 h. After completion of reaction as indicated by TLC, evaporated organic solvents, sodium bicarbonate solution (20 mL) was added to the residue and extracted with 10 % methanol in dichloromethane (3x 20 mL). The combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na2SO4 and concentrated to afford N-methyl-2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethoxy) ethan-1-amine Sidechain-10 (150 mg, 0.515 mmol, 44 %) as a brown liquid. TLC system: 10 % methanol in dichloromethane - Rf: 0.20 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 16 h / 110 °C 2: hydrazine hydrate / ethanol / 12 h / 110 °C | ||
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 16 h / 20 - 110 °C 2: hydrazine hydrate / ethanol / 12 h / 110 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate In tetrahydrofuran at 0 - 20℃; | 3.1.3. Tert-butyl 4-{2-[2-(2-{2-[(tetrahydro-2H-pyran-2-yl)oxy]ethoxy}ethoxy)ethoxy]ethoxy}piperidine-1-carboxylate (7) A mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.50 g, 2.49 mmol) and NaH (0.3 g,60%, 7.47 mmol) in THF (35.0 mL) was stirred at 0 °C for 1 h. Then, compound 6 (1.10 g, 2.55 mmol)was slowly added to the reaction, which was stirred at room temperature overnight. The mixturewas diluted with water (30 mL) and extracted with EtOAc (30 mL 3). The combined organic phasewas washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified bycolumn chromatography on silica gel [EtOAc-petroleum ether (30-70%)] to give the product (0.58 g,51%) of colorless oil. HPLC analysis was as follows: 96.8%; 1H-NMR (400 MHz, CDCl3) δ 4.63 (t,J = 3.2 Hz, 1H), 3.90-3.84 (m, 2H), 3.79-3.76 (m, 2H), 3.69-3.63 (m, 15H), 3.51-3.45 (m, 2H), 3.09-3.02(m, 2H), 1.85-1.81 (m, 3H), 1.76-1.68 (m, 1H), 1.63-1.49 (m, 6H), and 1.45 (s, 9H); 13C-NMR (CDCl3,100 MHz) δ 154.8, 98.9, 79.4, 75.1, 70.8, 70.7, 70.6, 70.5, 67.4, 66.6, 62.2, 31.0, 30.6, 28.4, 25.4, and 19.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 5 h / 45 °C 4.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 5.2: 5 h / 45 °C 6.1: triethylamine / dichloromethane / 5 h / 0 - 20 °C 7.1: sodium azide / N,N-dimethyl-formamide / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 5 h / 45 °C 4.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 5.2: 5 h / 45 °C 6.1: triethylamine / dichloromethane / 5 h / 0 - 20 °C 7.1: sodium azide / N,N-dimethyl-formamide / 60 °C 8.1: copper(ll) sulfate pentahydrate; sodium L-ascorbate / dichloromethane; water / 20 °C 9.1: sodium azide / N,N-dimethyl-formamide / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 5 h / 45 °C 4.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 5.2: 5 h / 45 °C 6.1: triethylamine / dichloromethane / 5 h / 0 - 20 °C 7.1: sodium azide / N,N-dimethyl-formamide / 60 °C 8.1: copper(ll) sulfate pentahydrate; sodium L-ascorbate / dichloromethane; water / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 5 h / 45 °C 4.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 5.2: 5 h / 45 °C 6.1: triethylamine / dichloromethane / 5 h / 0 - 20 °C 7.1: sodium azide / N,N-dimethyl-formamide / 60 °C 8.1: copper(ll) sulfate pentahydrate; sodium L-ascorbate / dichloromethane; water / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 5 h / 45 °C 4.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 5.2: 5 h / 45 °C 6.1: triethylamine / dichloromethane / 5 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 5 h / 45 °C 4.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 5 h / 45 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 3.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 3.2: 5 h / 45 °C 4.1: hydrogenchloride / water; methanol / 6 h / 0 - 20 °C 5.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h / 20 °C 5.2: 5 h / 45 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Stage #1: (2S,4R)-2-(tert-butyldimethylsilanyloxymethyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Stage #2: 2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate In tetrahydrofuran; mineral oil at 50℃; for 14h; | 1 Step 1: Preparation of tert-butyl (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(2-(2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethoxy)ethoxy)pyrrolidine-l- carboxylate To a solution of tert-butyl (2S,4R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4- hydroxy-pyrrolidine-l-carboxylate (6 g, 18.10 mmol, 1 eq) in dry tetrahydrofuran (80 mL) (dried by sodium and redistilled) was added sodium hydrogen (1.45 g, 36.20 mmol, 60% purity, 2 eq) at 20 °C. The reaction mixture was stirred at 20 °C for 30 minutes. Then a solution of 2-[2-[2- (2-tetrahydropyran-2-yloxyethoxy)ethoxy] ethoxy] ethyl 4-methylbenzenesulfonate (8.3 g, 19.19 mmol, 1.06 eq) in tetrahydrofuran (40 mL) was added and the reaction mixture was stirred at 50 °C for another 14 hours. Ethyl acetate (40 mL) was added and the mixture was washed with saturated aqueous ammonium chloride (40 mL). The organic layer was dried over sodium sulfate and then concentrated under vacuum to get the residue. The residue was purified by flash chromatography (silica gel, 0-100% ethyl acetate in petroleum ether) to get tert-butyl (2S,4R)-2- [ [tert-butyl(dimethyl) silyl] oxymethyl] -4- [2- [2- [2-(2-tetrahydropyran-2- yloxyethoxy)ethoxy]ethoxy]ethoxy]pyrrolidine-l-carboxylate (3.7 g, 6.25 mmol, 34% yield) as a light yellow oil. 1H-NMR (400MHz, CDCL) d 4.67 - 4.62 (m, 1H), 4.26 - 4.08 (m, 1H), 3.98 (br s, 1H), 3.90 - 3.84 (m, 2H), 3.71 - 3.65 (m, 11H), 3.65 - 3.61 (m, 3H), 3.61 - 3.48 (m, 5H), 3.45 - 3.37 (m, 1H), 2.19 (td, 7=5.4, 12.9 Hz, 1H), 2.09 - 1.94 (m, 1H), 1.89 - 1.69 (m, 2H), 1.62 (br d, 7=4.0 Hz, 1H), 1.66 - 1.60 (m, 1H), 1.58 - 1.49 (m, 3H), 1.46 (s, 9H), 1.30 - 1.24 (m, 1H), 0.88 (s, 9H), 0.07 - -0.03 (m, 6H). |