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CAS No. : | 60221-37-6 | MDL No. : | MFCD28976687 |
Formula : | C11H22O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KUBUREHZQPDYHT-UHFFFAOYSA-N |
M.W : | 234.29 | Pubchem ID : | 13699403 |
Synonyms : |
Thp-peg4
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 9 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 58.38 |
TPSA : | 57.15 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.76 cm/s |
Log Po/w (iLOGP) : | 2.9 |
Log Po/w (XLOGP3) : | -0.04 |
Log Po/w (WLOGP) : | 0.56 |
Log Po/w (MLOGP) : | -0.34 |
Log Po/w (SILICOS-IT) : | 1.58 |
Consensus Log Po/w : | 0.93 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.67 |
Solubility : | 49.7 mg/ml ; 0.212 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.71 |
Solubility : | 45.7 mg/ml ; 0.195 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.86 |
Solubility : | 3.23 mg/ml ; 0.0138 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.76 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | 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 |
---|---|---|
77% | With hydrogenchloride In water at 20℃; | |
74% | With hydrogenchloride for 18h; | |
65% | With hydrogenchloride at 20℃; for 16h; | Synthesis of 2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethanol (10) 2,3-Dihydrophyran (1.82 g, 20 mmol) was added to triethylene glycol 5 (9.01 g, 60 mmol).Then, conc. HCl (9 drops) was added dropwise, and the reaction was stirred at room temperature for 16h. After the completion, the reaction was neutralized using saturated NaHCO3, extracted with EtOAc,and the organic layer washed with brine, dried over anhydrous Na2SO4. Removal of the solvent undervacuum, followed by flash column chromatography (40% EtOAc/hexane) afforded 10 as colorless oil(3.04 g, 13.0 mmol, 65%)1; 1H NMR (400 MHz, CDCl3) δ 4.63 - 4.56 (m, 1H), 3.88 - 3.79 (m, 2H), 3.71 - 3.67 (m, 2H), 3.67 - 3.63 (m, 6H), 3.60 - 3.55 (m, 3H), 3.50 - 3.43 (m, 1H), 1.86 - 1.74 (m,1H), 1.73 - 1.64 (m, 1H), 1.62 - 1.43 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 99.1, 72.7, 70.7, 70.6,70.4, 66.7, 62.4, 61.8, 30.6, 25.5, 19.5. The 1H and 13C spectroscopic data are in good agreement withthose previously reported.1 |
59% | With pyridinium p-toluenesulfonate In dichloromethane at 25℃; for 5h; Inert atmosphere; | |
55% | With toluene-4-sulfonic acid In dichloromethane at 20℃; for 2h; | |
52% | With hydrogenchloride In dichloromethane at 20℃; for 12h; | mono-THP-protected triethylene glycol (12) One drop of HCl was added to triethylene glycol (15 g, 0.1 mmol). To this mixture a solution of 3,4-dihydro-2H-pyran (4.2 g, 0.05 mmol) in 20 mL CH2Cl2 was added slowly. The mixture was stirred at r.t. for 12 h and the solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, PE/EtOAc = 1:2) to afford mono-THP-protected triethylene glycol (12) (12 g, yield: 52%) as a colorless oil. |
50% | With pyridinium p-toluenesulfonate In dichloromethane at 25℃; for 5h; | |
50% | With pyridinium p-toluenesulfonate In chloroform at 20℃; Inert atmosphere; | |
48% | Stage #1: 2,2'-[1,2-ethanediylbis(oxy)]bisethanol With toluene-4-sulfonic acid In dichloromethane at 20℃; for 0.5h; Stage #2: 3,4-dihydro-2<i>H</i>-pyran In dichloromethane at 80℃; for 10h; | Synthesis of THP-protected alcohol 18-20. General procedure: p-TsOH*H2O (0.4 g, 2.4 mmol) was added to 100 mL of a CH2Cl2 solution containing polyethylene glycol (5 g, 47.2 mmol (9), 33.3mmol (10), 25.7 mmol (11)) at room temperature. After stirring for 30 min, DHP (1.3 mL, 14.3 mmol for 9, 0.9 mL, 10mmol for 10, 0.7 mL, 7.7 mmol for 11) was added, and the mixture was stirred for 10 h at 80°. 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 silicagel column chromatography (EtOAc:Hex = 1:3) to yield the THP-protected alcohols 18 (4.4 g, 50%), 19 (3.8 g, 48%), and 20 (3.6 g, 50%). |
10% | With toluene-4-sulfonic acid In dichloromethane at 0 - 20℃; | 1 To a stirred solution of 2,2'-(ethane-1,2-diylbis(oxy))diethanol 1 (50 g, 333.3 mmol) in dichloromethane (1.5 L) was added dihydropyran (20 g, 233.3 mmol) and p-toluene sulfonic acid (6.3 g, 33.33 mmol) at 0 °C, and stirred at room temperature for 4 h. The reaction mixture diluted with water (1000 mL) and extracted with dichloromethane (3 x 800 mL), the combined organic layers were was washed with brine (2 x 200 mL) and dried over sodium sulphate and concentrated. The residue was purified by flash column chromatography (100-200 silica) using 3 % methanol in dichloromethane to afford 2-(2-(2-(tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy) ethanol 2 (3 g, 12.82 mmol, 10 % yield) as a colorless oily liquid. TLC system: 15 % Acetone in dichloromethane; Rf: 0.35 |
10% | With p-toluenesulfonyl chloride In dichloromethane at 0 - 20℃; for 4h; | 1 2-(2-(2-(tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy) ethanol (2) To a stirred solution of 2,2'-(ethane-1,2-diylbis(oxy))diethanol 1 (50 g, 333.3 mmol) in dichloromethane (1.5 L) was added dihydropyran (20 g, 233.3 mmol) and p-toluene sulfonic acid (6.3 g, 33.33 mmol) at 0 °C, and stirred at room temperature for 4 h. The reaction mixture diluted with water (1000 mL) and extracted with dichloromethane (3 x 800 mL), the combined organic layers were was washed with brine (2 x 200 mL) and dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100-200 silica) using 3 % methanol in dichloromethane to afford 2-(2-(2-(tetrahydro-2H- pyran-2-yloxy) ethoxy) ethoxy) ethanol 2 (3 g, 12.82 mmol, 10 % yield) as a colorless oily liquid. TLC system: 15 % Acetone in dichloromethane Rf: 0.35 |
With toluene-4-sulfonic acid In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium hydride In tetrahydrofuran for 21h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 8-(1H-tetrahydropyran-2-yloxy)-3n63-dioxaoctan-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%). |
79% | With pyridine In dichloromethane at 0 - 20℃; | |
59% | With pyridine In dichloromethane for 24h; |
With sodium hydroxide In tetrahydrofuran at 0 - 20℃; for 16h; | 1 To a stirred solution of 2-(2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethan-1-ol 1 (9.5 g, 40.598 mmol, (Synthesis of Cpd-1 was reported in Sidechain-5)) in THF (100 mL) was added NaOH (3.25 g, 81.196 mmol) and p-toluene sulfonyl chloride (9.3 g, 48.718 mmol) at 0 ° C then stirred at room temperature for 16 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), brine solution (20 mL), dried over sodium sulphate and concentrated under reduced pressure to afford 2-(2-(2-((tetrahydro-2H-pyran-2- yl) oxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate 2 (14 g, 36.08 mmol, crude) as a colorless oily liquid. TLC system: 70 % ethyl acetate in pet ether: Rf: 0.50; LCMS: m/z = 305.04 (M-THP) + | |
14 g | With sodium hydroxide In tetrahydrofuran at 0 - 20℃; for 16h; | 1 To a stirred solution of 2-(2-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)ethoxy)ethan-1-ol 1 (9.5 g, 40.598 mmol, (Synthesis of Cpd-1 was reported in Sidechain-5)) in THF (100 mL) was added NaOH (3.25 g, 81.196 mmol) and p-toluene sulfonyl chloride (9.3 g, 48.718 mmol) at 0 ° C then stirred at room temperature for 16 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), brine solution (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 2-(2-(2-((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) ethoxy) ethyl 4-methylbenzenesulfonate 2 (14 g, 36.08 mmol, crude) as a colorless oily liquid. TLC system: 70 % ethyl acetate in pet ether Rf: 0.50; LCMS: m/z = 305.04 (M- THP) + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 83% 2: 7% | With sodium hydride In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 81% 2: 9% | With sodium hydride In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1H-imidazole; iodine; triphenylphosphine In diethyl ether; acetonitrile at 0℃; for 1.5h; | |
Multi-step reaction with 2 steps 1.1: potassium hydroxide / dichloromethane / 0 - 20 °C 1.2: 10 h / 20 °C 2.1: sodium iodide / acetone / 10 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium hydride In tetrahydrofuran at 20 - 65℃; for 12.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 1h; | 14.A 2-(2-(2-(Tetrahydro-2H-pyran-2-yloxy)-ethoxy)-ethylmethanesulfonate (14-1). Methanesulfonyl chloride (1.1 mL, 13.88 mmol) at 0 °C was added to a solution of 2-4B (2.5 g, 10.68 mmol) in THF (22 mL) and triethylamine (3 mL, 21.36 mmol) and stirred at RT for 1 hr. The reaction mixture was diluted with excess DCM (150 mL) and washed with water (100 mL), brine (100 mL) and dried over Na2S04, and the organic phase concentrated under reduced pressure. The crude compound was purified using 100-200 silica gel column chromatography (3% MeOH in DCM) to afford 14-1 (3 g, 9.61 mmol, 91% yield) as a pale yellowish oily liquid. |
88% | With triethylamine In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: 59 percent / pyridine / CH2Cl2 / 24 h 2.1: NaH / dimethylformamide; dioxane / 1 h 2.2: dioxane; dimethylformamide / 80 h 2.3: 1.636 g / 10-camphorsulfonic acid / ethanol / 8 h 3.1: 95 percent / PPh3; DEAD / tetrahydrofuran / 1.5 h 4.1: 1.335 g / aq. hydrazine / tetrahydrofuran / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: 59 percent / pyridine / CH2Cl2 / 24 h 2.1: NaH / dimethylformamide; dioxane / 1 h 2.2: dioxane; dimethylformamide / 80 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: 59 percent / pyridine / CH2Cl2 / 24 h 2.1: NaH / dimethylformamide; dioxane / 1 h 2.2: dioxane; dimethylformamide / 80 h 2.3: 1.636 g / 10-camphorsulfonic acid / ethanol / 8 h 3.1: 95 percent / PPh3; DEAD / tetrahydrofuran / 1.5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: 59 percent / pyridine / CH2Cl2 / 24 h 2.1: NaH / dimethylformamide; dioxane / 1 h 2.2: dioxane; dimethylformamide / 80 h 2.3: 1.636 g / 10-camphorsulfonic acid / ethanol / 8 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 88 percent / triethylamine / tetrahydrofuran / 20 °C 2: 83 percent / NaH / tetrahydrofuran; dimethylsulfoxide / 24 h / 60 °C 3: 88 percent / p-TsOH / methanol / 20 °C | ||
Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran 2: sodium hydride / tetrahydrofuran; dimethyl sulfoxide 3: toluene-4-sulfonic acid / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 88 percent / triethylamine / tetrahydrofuran / 20 °C 2: 83 percent / NaH / tetrahydrofuran; dimethylsulfoxide / 24 h / 60 °C 3: 88 percent / p-TsOH / methanol / 20 °C 4: 91 percent / triethylamine / tetrahydrofuran / 0 - 20 °C 5: 95 percent / NaI / butan-2-one / 4 h / Heating | ||
Multi-step reaction with 5 steps 1: triethylamine / tetrahydrofuran 2: sodium hydride / tetrahydrofuran; dimethyl sulfoxide 3: toluene-4-sulfonic acid / ethanol 5: sodium iodide / butanone / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 88 percent / triethylamine / tetrahydrofuran / 20 °C 2: 83 percent / NaH / tetrahydrofuran; dimethylsulfoxide / 24 h / 60 °C 3: 88 percent / p-TsOH / methanol / 20 °C 4: 91 percent / triethylamine / tetrahydrofuran / 0 - 20 °C | ||
Multi-step reaction with 4 steps 1: triethylamine / tetrahydrofuran 2: sodium hydride / tetrahydrofuran; dimethyl sulfoxide 3: toluene-4-sulfonic acid / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 88 percent / triethylamine / tetrahydrofuran / 20 °C 2: 75 percent / NaH / tetrahydrofuran; dimethylsulfoxide / 24 h / 60 °C 3: 84 percent / p-TsOH / methanol / 20 °C | ||
Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran 2: sodium hydride / tetrahydrofuran; dimethyl sulfoxide 3: toluene-4-sulfonic acid / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 88 percent / triethylamine / tetrahydrofuran / 20 °C 2: 75 percent / NaH / tetrahydrofuran; dimethylsulfoxide / 24 h / 60 °C 3: 84 percent / p-TsOH / methanol / 20 °C 4: 91 percent / triethylamine / tetrahydrofuran / 0 - 20 °C 5: 95 percent / NaI / butan-2-one / 4 h / Heating | ||
Multi-step reaction with 5 steps 1: triethylamine / tetrahydrofuran 2: sodium hydride / tetrahydrofuran; dimethyl sulfoxide 3: toluene-4-sulfonic acid / ethanol 5: sodium iodide / butanone / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 88 percent / triethylamine / tetrahydrofuran / 20 °C 2: 75 percent / NaH / tetrahydrofuran; dimethylsulfoxide / 24 h / 60 °C 3: 84 percent / p-TsOH / methanol / 20 °C 4: 91 percent / triethylamine / tetrahydrofuran / 0 - 20 °C | ||
Multi-step reaction with 4 steps 1: triethylamine / tetrahydrofuran 2: sodium hydride / tetrahydrofuran; dimethyl sulfoxide 3: toluene-4-sulfonic acid / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 88 percent / triethylamine / tetrahydrofuran / 20 °C 2: 83 percent / NaH / tetrahydrofuran; dimethylsulfoxide / 24 h / 60 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran 2: sodium hydride / tetrahydrofuran; dimethyl sulfoxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 88 percent / triethylamine / tetrahydrofuran / 20 °C 2: 65 percent / NaH / tetrahydrofuran; dimethylsulfoxide / 24 h / 60 °C 3: 79 percent / p-TsOH / methanol / 20 °C 4: 86 percent / triethylamine / tetrahydrofuran / 0 - 20 °C 5: 97 percent / NaI / butan-2-one / 4 h / Heating | ||
Multi-step reaction with 5 steps 1: triethylamine / tetrahydrofuran 2: sodium hydride / tetrahydrofuran; dimethyl sulfoxide 3: toluene-4-sulfonic acid / ethanol 5: sodium iodide / butanone / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 88 percent / triethylamine / tetrahydrofuran / 20 °C 2: 65 percent / NaH / tetrahydrofuran; dimethylsulfoxide / 24 h / 60 °C 3: 79 percent / p-TsOH / methanol / 20 °C | ||
Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran 2: sodium hydride / tetrahydrofuran; dimethyl sulfoxide 3: toluene-4-sulfonic acid / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 81 percent / NaH / tetrahydrofuran / 12.25 h / 20 - 65 °C 2: TsOH*H2O / methanol / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 81 percent / NaH / tetrahydrofuran / 12.25 h / 20 - 65 °C 2: TsOH*H2O / methanol / 4 h / 20 °C 3: 12.6 g / pyridine / CH2Cl2 / 12 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: NaH / tetrahydrofuran / 2 h / 80 °C 1.2: tetrahydrofuran / 15 h / Heating 2.1: aq. HCl / ethanol / 3 h / Heating 3.1: Et3N / CH2Cl2 / -5 - 20 °C 4.1: LiBr / acetone / 5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: NaH / tetrahydrofuran / 2 h / 80 °C 1.2: tetrahydrofuran / 15 h / Heating 2.1: aq. HCl / ethanol / 3 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: NaH / tetrahydrofuran / 2 h / 80 °C 1.2: tetrahydrofuran / 15 h / Heating 2.1: aq. HCl / ethanol / 3 h / Heating 3.1: Et3N / CH2Cl2 / -5 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: NaH / tetrahydrofuran / 2 h / 80 °C 1.2: tetrahydrofuran / 15 h / Heating 2.1: aq. HCl / ethanol / 3 h / Heating 3.1: Et3N / CH2Cl2 / -5 - 20 °C 4.1: LiBr / acetone / 5 h / 20 °C 5.1: NaH / tetrahydrofuran / 2 h / 50 °C 5.2: 30 percent / tetrahydrofuran / 24 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 7 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 5 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 4 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 5 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 7 percent / NaH / tetrahydrofuran / 20 °C |
Multi-step reaction with 5 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 8 percent / NaH / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 5 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 5 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 9 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 5 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 4 percent / NaH / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 55 percent / cyclohexene / Pd(OH)2/C / ethanol / 17 h / Heating | ||
Multi-step reaction with 3 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 83 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 88 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 6: 78 percent / Ag2O; KI / CH2Cl2 / Heating 7: 7 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 88 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 6: 78 percent / Ag2O; KI / CH2Cl2 / Heating 7: 3 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 83 percent / NaH / tetrahydrofuran / 20 °C 5: 78 percent / Ag2O; KI / CH2Cl2 / Heating 6: 7 percent / NaH / tetrahydrofuran / 20 °C |
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 83 percent / NaH / tetrahydrofuran / 20 °C 5: 78 percent / Ag2O; KI / CH2Cl2 / Heating 6: 3 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 84 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 6: 78 percent / Ag2O; KI / CH2Cl2 / Heating 7: 7 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 84 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 6: 78 percent / Ag2O; KI / CH2Cl2 / Heating 7: 3 percent / NaH / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 88 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C | ||
Multi-step reaction with 6 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 83 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 6 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 84 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 88 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 6: 78 percent / Ag2O; KI / CH2Cl2 / Heating | ||
Multi-step reaction with 7 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 83 percent / NaH / tetrahydrofuran / 20 °C 5: 78 percent / Ag2O; KI / CH2Cl2 / Heating | ||
Multi-step reaction with 7 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 84 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 6: 78 percent / Ag2O; KI / CH2Cl2 / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 87 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 81 percent / NaH / tetrahydrofuran / 20 °C 5: 80 percent / Ag2O; KI / CH2Cl2 / Heating 6: 81 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 4 steps 1: 81 percent / NaH / tetrahydrofuran / 20 °C 2: 80 percent / Ag2O; KI / CH2Cl2 / Heating 3: 81 percent / NaH / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 55 percent / cyclohexene / Pd(OH)2/C / ethanol / 17 h / Heating 4: 81 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 88 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 6: 78 percent / Ag2O; KI / CH2Cl2 / Heating 7: 80 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 83 percent / NaH / tetrahydrofuran / 20 °C 5: 78 percent / Ag2O; KI / CH2Cl2 / Heating 6: 80 percent / NaH / tetrahydrofuran / 20 °C |
Multi-step reaction with 5 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 81 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 4 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 83 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 4: 81 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 84 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 6: 78 percent / Ag2O; KI / CH2Cl2 / Heating 7: 80 percent / NaH / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 88 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 6: 78 percent / Ag2O; KI / CH2Cl2 / Heating 7: 91 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 83 percent / NaH / tetrahydrofuran / 20 °C 5: 78 percent / Ag2O; KI / CH2Cl2 / Heating 6: 91 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 5 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 85 percent / NaH / tetrahydrofuran / 20 °C |
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 84 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 6: 78 percent / Ag2O; KI / CH2Cl2 / Heating 7: 91 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 4 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / NaH / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 55 percent / cyclohexene / Pd(OH)2/C / ethanol / 17 h / Heating 4: 90 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 4 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 83 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 4: 90 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 5 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 90 percent / NaH / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 88 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 6: 78 percent / Ag2O; KI / CH2Cl2 / Heating 7: 83 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 81 percent / NaH / tetrahydrofuran / 20 °C 3: 84 percent / Ag2O; KI / CH2Cl2 / Heating 4: 83 percent / NaH / tetrahydrofuran / 20 °C 5: 78 percent / Ag2O; KI / CH2Cl2 / Heating 6: 83 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 8 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 84 percent / NaH / tetrahydrofuran / 20 °C 5: 79 percent / CAN / acetonitrile; H2O / 4 h / 0 - 20 °C 6: 78 percent / Ag2O; KI / CH2Cl2 / Heating 7: 83 percent / NaH / tetrahydrofuran / 20 °C |
Multi-step reaction with 7 steps 1: 79 percent / pyridine / CH2Cl2 / 0 - 20 °C 2: 80 percent / NaH / tetrahydrofuran / 20 °C 3: 85 percent / Ag2O; KI / CH2Cl2 / Heating 4: 81 percent / NaH / tetrahydrofuran / 20 °C 5: 83 percent / NaH / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 3 steps 1: 81 percent / NaH / tetrahydrofuran / 20 °C 2: 83 percent / NaH / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium hydride In tetrahydrofuran Reflux; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium hydride In tetrahydrofuran at 20 - 65℃; for 12.25h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With cyanomethylenetributyl-phosphorane In toluene at 80℃; for 1h; Inert atmosphere; | 2a (2a) Ethyl 8-[3-fluoro-4-(2-{2-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]ethoxy}ethoxy)phenyl]-1,6-naphthyridine-2-carboxylate Ethyl 8-(3-fluoro-4-hydroxyphenyl)-1,6-naphthyridine-2-carboxylate (300 mg, 0.961 mmol) synthesized in Example 1 (1a) and 2-{2-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]ethoxy}ethanol (338 mg, 1.44 mmol) were dissolved in toluene (3.0 mL), to which a solution of cyanomethylenetributylphosphorane (348 mg, 1.44 mmol) in toluene (3.0 mL) was added, followed by stirring at 80°C for one hour under a nitrogen atmosphere. The resulting reaction liquid was concentrated under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography (hexane : ethyl acetate, 75 : 25 - 30 : 70, V/V) to give the desired title compound (353 mg, yield 70%). 1H-NMR (CDCl3) δ: 1.48 (3H, t, J = 7.1 Hz), 1.49-1.65 (2H, m), 1.69-1.76 (2H, m), 1.79-1.88 (2H, m), 3.47-3.53 (1H, m), 3.60-3.66 (1H, m), 3.70-3.75 (4H, m), 3.77-3.80 (2H, m), 3.85-3.91 (2H, m), 3.94-3.97 (2H, m), 4.29-4.32 (2H, m), 4.49 (2H, q, J = 7.1 Hz), 4.63-4.66 (1H, m), 7.15 (1H, t, J = 8.7 Hz), 7.60-7.63 (1H, m), 7.88 (1H, dd, J = 12.8, 2.3 Hz), 8.31 (1H, d, J = 8.3 Hz), 8.50 (1H, d, J = 8.3 Hz), 8.93 (1H, s), 9.32 (1H, s). MS (FAB) m/z: 529 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 8-(1H-tetrahydropyran-2-yloxy)-3n63-dioxaoctan-1-ol With sodium hydride In 1,4-dioxane at 20℃; for 3h; Stage #2: (E)-2-chloro-5-(4-nitrostyryl)pyridine In 1,4-dioxane at 20℃; for 12h; | Compound 13 To a solution of mono-THP-protected triethylene glycol (12) (1.83 g, 7.81 mmol) in 16 mL dioxane NaH (312 mg, 7.81 mmol) was added at r.t. The mixture was stirred for 3 h. To the mixture (E)-2-chloro-5-(4-nitrostyryl)pyridine (11) (750 mg, 2.92 mmol) was added. After stirred at r.t. for 12 h, the mixture was poured into water and extracted by EtOAc. The combined organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated under vacuum and the residue was purified by column chromatography (SiO2, PE/AcOEt = 1:1) to afford 13 (1.21 g, yield: 95%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 8-(1H-tetrahydropyran-2-yloxy)-3n63-dioxaoctan-1-ol With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; Stage #2: With lithium bromide In tetrahydrofuran at 50℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 8-(1H-tetrahydropyran-2-yloxy)-3n63-dioxaoctan-1-ol With sodium hydride In 1,4-dioxane at 20℃; for 3h; Stage #2: (E)-5-(4-bromostyryl)-2-chloropyridine In 1,4-dioxane Reflux; | Compound 13 To a solution of mono-THP-protected triethylene glycol (12) (0.40 g, 1.7 mmol) in 16 mL dioxane NaH (136 mg, 3.4 mmol) was added. The mixture was stirred at r.t for 3 h. To the mixture (E)-5-(4-bromostyryl)-2-chloropyridine (11) (0.1 g, 0.34 mmol) was added. The mixture was heated to reflux overnight. After cooling to r.t., the mixture was poured into water and extracted by EtOAc. The combined organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated under vacuum and the residue was purified by column chromatography (SiO2, PE/AcOEt = 1:1) to afford 13 (129 mg, yield: 77%). IR (neat): 3168, 2362, 2334, 2184, 1670, 1605, 1496, 1402, 1290, 1125 cm-1. 1H-NMR (CDCl3): δ 8.17 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 16.4 Hz, 1H), 6.90 (d, J = 16.4 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.63-4.61 (m, 1H), 4.50-4.48 (m, 2H), 3.87-3.83 (m, 4H), 3.71-3.67 (m, 6H), 3.63-3.57 (m, 1H), 3.51-3.46 (m, 1H), 1.85-1.79 (m, 1H), 1.60-1.52 (m, 5H). 13C-NMR (CDCl3): δ 163.3, 145.8, 136.1, 135.3, 131.8, 127.8, 126.6, 126.3, 125.5, 121.3, 111.5, 98.9, 70.7, 70.6, 69.7, 66.6, 65.3, 62.2, 30.5, 25.4, 19.5. HRMS (FAB) calcd for C24H30BrNO5 (MH+): 491.1307; found: 491.1304 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | Stage #1: 8-(1H-tetrahydropyran-2-yloxy)-3n63-dioxaoctan-1-ol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5h; Stage #2: ethyl bromoacetate In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 16h; Inert atmosphere; | 1 Ethyl 2-(2-(2-(2-(tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy) ethoxy) acetate (4) To a stirred solution of 2-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethoxy)ethanol 2 (2.7 g, 11.54 mmol) in N,N-dimethyl formamide (5 mL) was added NaH (554 mg, 23.08 mmol) at 0 °C and stirred at room temperature for 30 min. Then a solution of ethyl 2-bromoacetate 3 (2.3 g, 13.84 mmol) in N, N-dimethyl formamide (5 mL) was added to the above reaction mixture at 0 °C and stirred at room temperature for 16h under nitrogen atmosphere. The reaction mixture was quenched with ice- cold water and extracted with ethyl acetate (3 x 100mL). Combined organic layers were was washed with brine (2 x 100 mL) and dried over Na2SO4, evaporated under reduced pressure. Crude residue was purified by combi-flash chromatography using 40 % ethyl acetate in hexanes to afford ethyl 2-(2- (2-(2-(tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy) ethoxy) acetate 4 (550 mg, 1.7187 mmol, 15 % yield) as a pale yellow oily liquid. TLC system: 70 % ethyl acetate in hexanes; Rf: 0.50 |
15% | Stage #1: 8-(1H-tetrahydropyran-2-yloxy)-3n63-dioxaoctan-1-ol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Stage #2: ethyl bromoacetate In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere; | 1 Ethyl 2-(2-(2-(2-(tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy) ethoxy) acetate (4) To a stirred solution of 2-(2-(2-(tetrahydro-2H-pyran-2- yloxy)ethoxy)ethoxy)ethanol 2 (2.7 g, 11.54 mmol) in N,N-dimethyl formamide (5 mL) was added NaH (554 mg, 23.08 mmol) at 0 °C and stirred at room temperature for 30 min. Then a solution of ethyl 2-bromoacetate 3 (2.3 g, 13.84 mmol) in N, N-dimethyl formamide (5 mL) was added to the above reaction mixture at 0 °C and stirred at room temperature for 16h under nitrogen atmosphere. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3 x 100mL). Combined organic layers were was washed with brine (2 x 100 mL) and dried over Na2SO4, evaporated under reduced pressure. Crude residue was purified by combi-flash chromatography using 40 % ethyl acetate in hexanes to afford ethyl 2-(2-(2-(2-(tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy) ethoxy) acetate 4 (550 mg, 1.7187 mmol, 15 % yield) as a pale yellow oily liquid. TLC system: 70 % ethyl acetate in hexanes Rf: 0.50 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | Stage #1: 8-(1H-tetrahydropyran-2-yloxy)-3n63-dioxaoctan-1-ol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5h; Stage #2: Ethyl 3-bromopropionate In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 16h; Inert atmosphere; | 1 Ethyl 3-(2-(2-(2-(tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy) ethoxy) propionate (3) To a stirred solution of 2-(2-(2-(tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy)ethanol 1 (Synthesis of Cpd-1 was reported in Sidechain-5) (5 g, 21.367 mmol) in N,N-dimethyl formamide (30 mL) was treated with NaH (1.3 g, 53.417 mmol) at 0 °C and stirred at room temperature for 30 minutes. Ethyl 3-bromopropanoate 2 (5.8 g, 32.05 mmol) in N, N-dimethyl formamide (20 mL) was added to above reaction mixture at 0 °C and stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was quenched with ice water and extracted with ethyl acetate (3x 100mL). Combined organic layers were washed with brine (2x 100 mL) and dried over Na2SO4, evaporated under reduced pressure. Crude residue was purified by Combi-flash chromatography using 30% ethyl acetate in hexanes to afford ethyl 3-(2-(2-(2-(tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy) ethoxy) propionate 3 (1 g, 2.994 mmol, 14 % yield) as a pale yellow oily liquid. TLC system: 70% ethyl acetate in hexanes - Rf: 0.60 |
14% | Stage #1: 8-(1H-tetrahydropyran-2-yloxy)-3n63-dioxaoctan-1-ol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Stage #2: Ethyl 3-bromopropionate In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere; | 1 Ethyl 3-(2-(2-(2-(tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy) ethoxy) propionate (3) To a stirred solution of 2-(2-(2-(tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy)ethanol 1 (Synthesis of Cpd-1 was reported in Sidechain-5) (5 g, 21.367 mmol) in N,N-dimethyl formamide (30 mL) was treated with NaH (1.3 g, 53.417 mmol) at 0 °C and stirred at room temperature for 30 minutes. Ethyl 3-bromopropanoate 2 (5.8 g, 32.05 mmol) in N, N-dimethyl formamide (20 mL) was added to above reaction mixture at 0 °C and stirred at room temperature for 16h under nitrogen atmosphere. The reaction mixture was quenched with ice water and extracted with ethyl acetate (3x 100mL). Combined organic layers were washed with brine (2x 100 mL) and dried over Na2SO4, evaporated under reduced pressure. Crude residue was purified by Combi-flash chromatography using 30% ethyl acetate in hexanes to afford ethyl 3-(2-(2-(2-(tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy) ethoxy) propionate 3 (1 g, 2.994 mmol, 14 % yield) as a pale yellow oily liquid. TLC system: 70% ethyl acetate in hexanes - Rf: 0.60 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | Stage #1: 4-(3-phenyl-1H-indol-2-yl)benzoic acid; 8-(1H-tetrahydropyran-2-yloxy)-3n63-dioxaoctan-1-ol With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 3h; Stage #2: With hydrogenchloride In methanol; water at 20℃; for 0.5h; | Synthesis of 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-(3-phenyl-1H-indol-2-yl)benzoate (4) Compound 18 (94 mg, 0.3 mmol), PPh3 (86.6 mg, 0.33 mmol), DIAD (66.8 mg, 0.33 mmol)and 10 (77.3 mg, 0.33 mmol) were dissolved in 0.3 mL THF and stirred at room temperature for 3 h.After the reaction was completed, H2O was added and extracted with EtOAc (3 × 10 mL). The combinedorganic phases were washed with H2O and brine. The organic layer was dried over anhydrous Na2SO4and concentrated. Then, the crude reaction was dissolved in MeOH (1 mL), and 5 drops of 1 M HClwere added dropwise and stirred at room temperature for 30 min. Then, the reaction mixture wasconcentrated, and the pH was adjusted to 7 using saturated NaHCO3. Subsequently, H2O was added,and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with H2O and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated, followedby flash column chromatography (80-100% EtOAc/hexane). Finally, the mixture was further purified by HPLC to afford compound 4 as white solid (30.6 mg, 0.07 mmol, 23%)7; 1H NMR (400 MHz, CDCl3)δ 8.49 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.50 - 7.36 (m, 7H), 7.34 - 7.24 (m,3H), 7.16 (t, J = 7.5 Hz, 1H), 4.51 - 4.45 (m, 2H), 3.86 - 3.80 (m, 2H), 3.73 - 3.66 (m, 6H), 3.62 - 3.58(m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.4, 137.4, 136.4, 134.8, 132.8, 130.3, 130.1, 128.9, 128.8,127.9, 126.7, 123.4, 120.7, 120.1, 116.8, 111.2, 72.6, 70.8, 70.5, 69.4, 64.1, 61.9. HRMS (ESI): calcdfor C27H27NNaO5, [M+Na]+ 468.1781; found: 468.1779. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 8-(1H-tetrahydropyran-2-yloxy)-3n63-dioxaoctan-1-ol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: pentaerythritol tetrabromide In N,N-dimethyl-formamide; mineral oil at 100℃; for 24h; Inert atmosphere; | General Procedure of t-R1-O-THP Synthesis. General procedure: Tetrahydropyranyl(THP) derivative of OH-R1-O-THP (65mmol)was dissolved in DMF (50 mL). NaH (60 wt% dispersion in oil,3.0 g) was added portion-wise. The reaction mixture was stirredfor 30min at room temperature. After adding pentaerythrityltetrabromide (13mmol), the reaction mixture was stirred for24 h at 100 °C under N2 atmosphere. The solvent was removedby evaporation. The residue was dissolved in diethyl ether (150mL) and washed with water (50 mL) using a separation funnel.The organic layer was recovered, dried with MgSO4, filtratedand concentrated with an evaporator. The crude product waspurified by column chromatography (SiO2, Hex/AcOEt = 1/1). |
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P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
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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