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CAS No. : | 19008-71-0 | MDL No. : | MFCD02094315 |
Formula : | C8H19NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WDCOJSGXSPGNFK-UHFFFAOYSA-N |
M.W : | 145.24 | Pubchem ID : | 15919832 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313 | UN#: | N/A |
Hazard Statements: | H315-H319 | 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 |
---|---|---|
30% | With sodium In ethanol Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium hydrogencarbonate In water; acetone for 21h; Ambient temperature; | |
63% | With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 16h; | |
48% | Stage #1: 8-aminooctan-1-ol With methanol; sodium tetrahydroborate at 20℃; for 1h; Inert atmosphere; Stage #2: benzyl chloroformate With sodium hydrogencarbonate In water-d2 at 0 - 20℃; for 16h; |
42% | With triethylamine In methanol at 20℃; for 10h; | |
With TEA In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In dichloromethane at 0 - 20℃; for 1h; | |
94% | With sodium hydrogencarbonate In tetrahydrofuran at 20℃; | 4.1 Step 1. tert-butyl (8-hydroxyoctyl)carbamate (JRW-0896) To a solution of 8-aminooctan-1-ol (1.0 g, 6.9 mmol) in THF (20 mL) was added sodium bicarbonate (saturated solution, 10 mL) and di-tert-butyl dicarbonate (1.8 g, 8.3 mmol). The reaction mixture was stirred overnight at rt, then diluted with ethyl acetate and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, filtered, and concentrated. The crude product was chromotgraphed (DCM/MeOH) to give a white solid (1.6 g, 94%): 1H NMR (400 MHz, CDCl3) δ 4.51 (s, 1H), 3.66 (t, J=6.6 Hz, 2H), 3.18-3.08 (m, 2H), 1.66-1.53 (m, 2H), 1.46 (s, 11H), 1.43-1.26 (m, 8H). |
90% | With triethylamine In methanol Reflux; |
87% | With triethylamine In tetrahydrofuran at 5 - 20℃; for 1h; | 2.1; 40.1; 63.1 Step 1: Preparation of tert-butyl (8-hydroxyoctyl)carbamate To a solution of 8-aminooctane-1-ol (1 g, 6.88 mmol) in THF (20 ml) was added TEA (1.43 ml, 10.32 mmol) and the reaction mixture was cooled to 5-10 °C. Then, di-tert-butyldicarbonate (1.90 ml, 8.26 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and then extracted with EtOAc (50 mL*2). The combined organic layers were dried over MgSO4 and the solvent was removed in vacuo to give an oil. The crude mixture was purified by silica gel column chromatography using (EtOAc/Hx = 40 %) as eluent to give the title compound (1.48 g, 6.03 mmol, 87 %) as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.50 (s, 1H), 3.64 (t, J = 6.6 Hz, 2H), 3.10 (q, J = 6.7 Hz, 2H), 1.64-1.47 (m, 4H), 1.44 (s, 9H), 1.39-1.28 (m, 8H). |
78% | With triethylamine In methanol at 20℃; for 20h; | |
72% | In dichloromethane for 3h; | 3 8-( tert-Butoxycarbonylamino)octyl methanesulfonate To a cooled solution of 8-amino octanol (210 mg, 1.5 mmol) in CH2CI2(5 mL) was added Boc-anhydride (360 mg, 1.65 mmol) in CH2CI2(2.5 mL) and stirred for 3 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (0-60% EtOAc in hexanes) to obtain 8-( tert-butoxycarbony1-amino)octan-1-ol as a white solid (265 mg, 72%). |
66.2% | With triethylamine In tetrahydrofuran; water at 20℃; | 1 3: 35 g, 23.1 mmol) was dissolved in 30 ml of a mixed solvent (THF: H20 = 1: 1)(Boc) 20 (5.04 g, 23.1 mmol) was added, and rhodium was adjusted to 8 with triethylamine and stirred at room temperature. The organic phase was combined, dried over sodium sulfate for about half an hour and filtered, and the ethyl acetate was distilled off. The organic layer was dried over anhydrous sodium sulfate and concentrated in ethyl acetate. The residue was purified by silica gel column chromatography. The eluant: petroleum ether: ethyl acetate = 5: 1 gave 3.74 g of a white solid. The yield of the two steps was 66.2%. |
50% | In dichloromethane at 20℃; for 12.5h; | |
In tetrahydrofuran at 50℃; for 3h; Inert atmosphere; | General Procedure for Preparation of cis-14 General procedure: To a solution of an aminoalcohol (66.6 mmol) in THF (67 mL) was added di-tert-butyl dicarbonate (15.3 g, 66.6 mmol) at 50 °C under an argon atmosphere. After 3 h stirring, the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (EtOAc / hexane, 50:50) to give a N-Boc aminoalcohol. Iodine (12.5 g, 49.3 mmol) was added to a solution of N-Boc aminoalcohol (17.6 mmol), PPh3 (6.92 g, 26.3 mmol) and imidazole (1.79 g, 26.3 mmol) in CH2Cl2 (98 mL) at 0 °C. The mixture was stirred at room temperature for 1 h under an argon atmosphere. The reaction mixture was quenched with saturated aqueous Na2S2O3, diluted with CH2Cl2 and extracted with CH2Cl2. The organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane, 10:90) to afford a N-BOC aminoalkyliodide. To a solution of NaH (60% in oil, 0.673 g, 16.8 mmol) in DMF (15.3 mL) was added dropwise a solution of N-hydroxyphthalimide (2.49 mmol) in DMF (10 mL) at 0 °C under an argon atmosphere. After 15 min of stirring, a solution of the iodide (15.3 mmol) in DMF (10 mL) was added dropwise to the solution and stirred at 70 °C for 12 h. After cooled to 0 °C, the reaction was quenched with H2O and filtrated to afford colorless solid, which was recrystallized to give a N-alkoxyphthalimide 13a-d. | |
With sodium hydroxide In water; acetonitrile at 20℃; Inert atmosphere; | ||
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 5h; | ||
With triethylamine | 1 Step 1: Step 1: Preparation of tert-butyl (8-hydroxyoctyl)carbamate To a solution of 8-aminooctane-1-ol (1 g, 6.88 mmol) in THF (20 ml) was added TEA (1.43 ml, 10.32 mmol) and the reaction mixture was cooled to 5-10 °C. Then, di-tert-butyldicarbonate (1.90 ml, 8.26 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and then extracted with EtOAc (50 mL*2). The combined organic layers were dried over MgSO4 and the solvent was removed in vacuo to give an oil. The crude mixture was purified by silica gel column chromatography using (EtOAc/Hx = 40 %) as eluent to give the title compound (1.48 g, 6.03 mmol, 87 %) as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.50 (s, 1H), 3.64 (t, J = 6.6 Hz, 2H), 3.10 (q, J = 6.7 Hz, 2H), 1.64-1.47 (m, 4H), 1.44 (s, 9H), 1.39-1.28 (m, 8H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In chloroform at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With pyridine In methanol; dichloromethane at 0 - 20℃; Inert atmosphere; | |
52% | With pyridine In methanol at 23℃; for 22h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 5%-palladium/activated carbon; hydrogen In methanol at 24℃; for 1.5h; | 8-Amino-1-octanol (7a) Compound 6a (1.00 g, 5.27 mmol), and a catalytic amount of 5 % Pd/C were dissolved in anhydrous methanol (30 mL) and the reaction mixture was stirred at 24 for 1.5 h under H2 atmosphere, then filtered on Celite545. The filtrate was evaporated to dryness to afford pure compound 7a (0.62 g, 81%). 1H NMR (500 MHz, CDCl3 - CD3OD, 2:1): 1.00 - 1.14 (m, 8 H, OCH2CH2(CH2)4CH2CH2N), 1.18 - 1.32 (m, 4 H, OCH2CH2(CH2)4CH2CH2N), 2.25 - 2.36 (m, 2 H, CH2N), 3.25 - 3.34 (m, 2 H, CH2O). 13 NMR (125 MHz): 26.63, 27.10, 28.44, 28.48, 32.32, 32.93, 41.51, 62.14. MS, m/z: 145.147 [M]+ and 191.126 [M+2Na]+ . Calculated for C8H19NO 145.896 [M]+ and C8H19NNa2O 191.694 [M+2Na]+. |
72% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; | |
With hydrogen In methanol |
With hydrogen In methanol | 26.v v) Cholesteryl 8-hydroxyoctylcarbamate from cholesteryl chloroformate and 8-aminooctan-1-ol. 8-Aminooctan-1-ol is prepared from 8-bromooctan-1-ol and sodium azide in refluxing 95% ethanol, followed by catalytic hydrogenation (10% Pd/C catalyst, 30 psi hydrogen) in methanol. | |
Stage #1: 8-azidooctan-1-ol With triphenylphosphine In N,N-dimethyl-formamide at 20 - 50℃; for 0.333333 - 0.416667h; Stage #2: With ammonia In water; N,N-dimethyl-formamide at 50℃; for 0.5h; | 1 Compound III (310 mg) was mixed into a solution of 520 mg of triphenylphosphine (TPP) in 3 mL of DMF. The mixture was held for 10 min at 200C and then for 10 to 15 min at 500C. Following the incubations, 1.5 mL of ammonium hydroxide was added to the mixture and the incubation continued at 50° for another 30 minutes. The mixture was diluted with 20 mL of 1 M citric acid and extracted with ether. Seven mL of 10 M NaOH were added to the water phase, and the product extracted with ethylacetate (3 x 15 ml). The organic phase was evaporated in vacuo and after the major portion of the solvent was removed the evaporation continued at 70° to remove the traces of DMF. | |
With triphenylphosphine In tetrahydrofuran | ||
Stage #1: 8-azidooctan-1-ol With triphenylphosphine In N,N-dimethyl-formamide at 20 - 50℃; Stage #2: With ammonium hydroxide In N,N-dimethyl-formamide at 50℃; for 0.5h; | 1 Materials and methods Compound IV: Compound III (310 mg) was mixed into a solution of 520 mg of triphenylphosphine (TPP) in 3 mL of DMF. The mixture was held for 10 min at 20° C. and then for 10 to 15 min at 50° C. Following the incubations, 1.5 mL of ammonium hydroxide was added to the mixture and the incubation continued at 50° for another 30 minutes. The mixture was diluted with 20 mL of 1 M citric acid and extracted with ether. Seven mL of 10 M NaOH were added to the water phase, and the product extracted with ethylacetate (3×15 ml). The organic phase was evaporated in vacuo and after the major portion of the solvent was removed the evaporation continued at 70° to remove the traces of DMF. | |
With palladium 10% on activated carbon; hydrogen In methanol | 1 8-amino-1-octanol (Compound No. 2-4-1) Compound 2-3-1 (3.95 g, 23.1 mmol) was added to a hydrogenation tube, dissolved with 10 ml of methanol, 10% Pd / C (0.52 g, 0.489 mmol) was added and catalytic hydrogenation was carried out at 0.4 MPa.TLC monitoring showed that the material disappeared after diatomaceous earth filtration, the filtrate concentrated directly after the next step. | |
With triphenylphosphine In tetrahydrofuran; water at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With lithium aluminium tetrahydride In tetrahydrofuran for 48h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: Et3N; 4-(dimethylamino)pyridine / CH2Cl2 2: sodium azide / dimethylformamide 3: H2 / Pd/C / methanol | ||
Multi-step reaction with 3 steps 1: hydrogen bromide / water; toluene / 96 h / Reflux 2: sodium azide / N,N-dimethyl-formamide / 10 h / 70 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 3000.3 Torr | ||
Multi-step reaction with 2 steps 1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 20 °C / Cooling with ice 2: hydrazine / ethanol; water / 3 h / Reflux |
Multi-step reaction with 3 steps 1: dmap; triethylamine / dichloromethane / 24 h / 20 °C 2: sodium azide / N,N-dimethyl-formamide / 80 °C 3: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 52 percent / pyridine / methanol / 22 h / 23 °C 2: DMSO; SO3*Py; Et3N | ||
Multi-step reaction with 2 steps 1: pyridine / dichloromethane; methanol / 0 - 20 °C / Inert atmosphere 2: pyridinium chlorochromate / dichloromethane / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 52 percent / pyridine / methanol / 22 h / 23 °C 2: DMSO; SO3*Py; Et3N 3: dimethylformamide; methanol / 2 h 4: 28 mg / NaBH4 / dimethylformamide; methanol / 2 h 5: piperidine / dimethylformamide; methanol / 0.5 h 6: diisopropylethylamine; PyBOP; 1-hydroxybenzotriazole / dimethylformamide / 21 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 52 percent / pyridine / methanol / 22 h / 23 °C 2: DMSO; SO3*Py; Et3N 3: dimethylformamide; methanol / 2 h 4: 28 mg / NaBH4 / dimethylformamide; methanol / 2 h 5: piperidine / dimethylformamide; methanol / 0.5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 52 percent / pyridine / methanol / 22 h / 23 °C 2: DMSO; SO3*Py; Et3N 3: dimethylformamide; methanol / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 52 percent / pyridine / methanol / 22 h / 23 °C 2: DMSO; SO3*Py; Et3N 3: dimethylformamide; methanol / 2 h 4: 28 mg / NaBH4 / dimethylformamide; methanol / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium azide / dimethylformamide 2: H2 / Pd/C / methanol | ||
Multi-step reaction with 2 steps 1: sodium azide / N,N-dimethyl-formamide / 80 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 42 percent / triethylamine / methanol / 10 h / 20 °C 2: 88 percent / CBr4; PPh3 / CH2Cl2 / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 42 percent / triethylamine / methanol / 10 h / 20 °C 2: 88 percent / CBr4; PPh3 / CH2Cl2 / 0 - 20 °C 3: 36 percent / diisopropylethylamine / acetonitrile / 192 h / pH 8 / Heating 4: 88 percent / H2 / Pd/C / methanol / 5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 42 percent / triethylamine / methanol / 10 h / 20 °C 2: 88 percent / CBr4; PPh3 / CH2Cl2 / 0 - 20 °C 3: 36 percent / diisopropylethylamine / acetonitrile / 192 h / pH 8 / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 42 percent / triethylamine / methanol / 10 h / 20 °C 2: 88 percent / CBr4; PPh3 / CH2Cl2 / 0 - 20 °C 3: 36 percent / diisopropylethylamine / acetonitrile / 192 h / pH 8 / Heating 4: 88 percent / H2 / Pd/C / methanol / 5 h 5: 24 percent / Et3N / tetrahydrofuran / 28 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 42 percent / triethylamine / methanol / 10 h / 20 °C 2: 88 percent / CBr4; PPh3 / CH2Cl2 / 0 - 20 °C 3: 36 percent / diisopropylethylamine / acetonitrile / 192 h / pH 8 / Heating 4: 88 percent / H2 / Pd/C / methanol / 5 h 5: 24 percent / Et3N / tetrahydrofuran / 28 h / 20 °C 6: 92 percent / CH2Cl2 / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 50 percent / CH2Cl2 / 12.5 h / 20 °C 2: 60 percent / DMAP / CH2Cl2 / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating 4: 33 percent / Cu2O / toluene / 3 h / 40 °C 5: 100 percent / H2O / tetrahydrofuran / 4 h / Heating 6: 1,5-hexadiene, SOBr2 / 1,2-dichloro-ethane / a) 10 deg C, 1 h, b) RT, 1.5 h 7: 17 h / 80 °C / 75.01 Torr 8: 1.) (CH3)3SiBr, 2.) EtOH, 3.) propylene oxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating 4: 33 percent / Cu2O / toluene / 3 h / 40 °C 5: 100 percent / H2O / tetrahydrofuran / 4 h / Heating 6: 1,5-hexadiene, SOBr2 / 1,2-dichloro-ethane / a) 10 deg C, 1 h, b) RT, 1.5 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating 4: 33 percent / Cu2O / toluene / 3 h / 40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating 4: 33 percent / Cu2O / toluene / 3 h / 40 °C 5: 100 percent / H2O / tetrahydrofuran / 4 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating 4: 33 percent / Cu2O / toluene / 3 h / 40 °C 5: 100 percent / H2O / tetrahydrofuran / 4 h / Heating 6: 1,5-hexadiene, SOBr2 / 1,2-dichloro-ethane / a) 10 deg C, 1 h, b) RT, 1.5 h 7: 17 h / 80 °C / 75.01 Torr 8: 1.) (CH3)3SiBr, 2.) EtOH, 3.) propylene oxide 9: 1.) 2N aq. HCl, 2.) propylene oxide / 1.) reflux, 17 h, 2.) EtOH, RT, 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating 4: 33 percent / Cu2O / toluene / 3 h / 40 °C 5: 100 percent / H2O / tetrahydrofuran / 4 h / Heating 6: 1,5-hexadiene, SOBr2 / 1,2-dichloro-ethane / a) 10 deg C, 1 h, b) RT, 1.5 h 7: 17 h / 80 °C / 75.01 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating 4: 33 percent / Cu2O / toluene / 3 h / 40 °C 5: 100 percent / H2O / tetrahydrofuran / 4 h / Heating 6: 1,5-hexadiene, SOBr2 / 1,2-dichloro-ethane / a) 10 deg C, 1 h, b) RT, 1.5 h 7: 17 h / 80 °C / 75.01 Torr 8: 1.) (CH3)3SiBr, 2.) EtOH, 3.) propylene oxide 9: 1.) 2N aq. HCl, 2.) propylene oxide / 1.) reflux, 17 h, 2.) EtOH, RT, 2 h 10: 55 percent / 1 N aq. NaOH / H2O; tetrahydrofuran / 3 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating 4: 33 percent / Cu2O / toluene / 3 h / 40 °C 5: 100 percent / H2O / tetrahydrofuran / 4 h / Heating 6: 1,5-hexadiene, SOBr2 / 1,2-dichloro-ethane / a) 10 deg C, 1 h, b) RT, 1.5 h 7: 17 h / 80 °C / 75.01 Torr 8: 1.) (CH3)3SiBr, 2.) EtOH, 3.) propylene oxide 9: 1.) 2N aq. HCl, 2.) propylene oxide / 1.) reflux, 17 h, 2.) EtOH, RT, 2 h 10: 29 percent / 1 N aq. NaOH / H2O; tetrahydrofuran / 3 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating 4: 33 percent / Cu2O / toluene / 3 h / 40 °C 5: 100 percent / H2O / tetrahydrofuran / 4 h / Heating 6: 1,5-hexadiene, SOBr2 / 1,2-dichloro-ethane / a) 10 deg C, 1 h, b) RT, 1.5 h 7: 17 h / 80 °C / 75.01 Torr 8: 1.) (CH3)3SiBr, 2.) EtOH, 3.) propylene oxide 9: 1.) 2N aq. HCl, 2.) propylene oxide / 1.) reflux, 17 h, 2.) EtOH, RT, 2 h 10: 28 percent / 1 N NaOH / tetrahydrofuran / 23 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating 4: 33 percent / Cu2O / toluene / 3 h / 40 °C 5: 100 percent / H2O / tetrahydrofuran / 4 h / Heating 6: 1,5-hexadiene, SOBr2 / 1,2-dichloro-ethane / a) 10 deg C, 1 h, b) RT, 1.5 h 7: 17 h / 80 °C / 75.01 Torr 8: 1.) (CH3)3SiBr, 2.) EtOH, 3.) propylene oxide 9: 1.) 2N aq. HCl, 2.) propylene oxide / 1.) reflux, 17 h, 2.) EtOH, RT, 2 h 10: 28 percent / 1 N NaOH / tetrahydrofuran / 23 h / Ambient temperature 11: 13 percent / NaI, chloramine-T trihydrate / H2O / 1 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating 4: 33 percent / Cu2O / toluene / 3 h / 40 °C 5: 100 percent / H2O / tetrahydrofuran / 4 h / Heating 6: 1,5-hexadiene, SOBr2 / 1,2-dichloro-ethane / a) 10 deg C, 1 h, b) RT, 1.5 h 7: 17 h / 80 °C / 75.01 Torr 8: 1.) (CH3)3SiBr, 2.) EtOH, 3.) propylene oxide 9: 1.) 2N aq. HCl, 2.) propylene oxide / 1.) reflux, 17 h, 2.) EtOH, RT, 2 h 10: 28 percent / 1 N NaOH / tetrahydrofuran / 23 h / Ambient temperature 11: NaI, chloramine-T trihydrate / H2O / 1 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1: 89 percent / NaHCO3 / acetone; H2O / 21 h / Ambient temperature 2: 1.) oxalyl chloride, DMSO, 2.) N-ethyldiisopropylamine / 1.) CH2Cl2, -60 to -50 deg C, 30 min, 2.) CH2Cl2, -50 deg C, 1 h 3: piperazine, AcOH / H2O / 1 h / Heating 4: 33 percent / Cu2O / toluene / 3 h / 40 °C 5: 100 percent / H2O / tetrahydrofuran / 4 h / Heating 6: 1,5-hexadiene, SOBr2 / 1,2-dichloro-ethane / a) 10 deg C, 1 h, b) RT, 1.5 h 7: 17 h / 80 °C / 75.01 Torr 8: 1.) (CH3)3SiBr, 2.) EtOH, 3.) propylene oxide 9: 1.) 2N aq. HCl, 2.) propylene oxide / 1.) reflux, 17 h, 2.) EtOH, RT, 2 h 10: 28 percent / 1 N NaOH / tetrahydrofuran / 23 h / Ambient temperature 11: NaI, chloramine-T trihydrate / H2O / 1 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 20℃; for 2h; Molecular sieve; | ||
at 20℃; for 2h; Molecular sieve; | 1.d While being cooled in an ice bath and under nitrogen atmosphere, 2.3 ml of thiophosgene was added in drops to a solution of 4.99 g of 4-amino-2-(trifluoromethyl)benzonitrile in 30 ml of N,N-dimethylformamide. The reaction mixture was stirred for one hour at room temperature and then mixed with water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried on sodium sulfate, filtered and concentrated by evaporation in a vacuum. The thus obtained crude isothiocyanate was combined with the cyanamine produced by two hours of stirring of 5.4 ml of acetone cyanohydrin with 4.29 g of the compound produced under 1 c) in the presence of 3 g of molecular sieve 3 at room temperature and boiled for one hour with 7.47 ml of triethylamine in 134 ml of tetrahydrofuran. The crude iminothiohydantoin obtained after concentration by evaporation in a vacuum was stirred with 26.8 ml of 4 molar aqueous hydrochloric acid in 134 ml of methanol overnight at room temperature. The reaction mixture was then poured onto saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried on sodium sulfate, filtered and concentrated by evaporation in a vacuum. Column chromatography on silica gel with a mixture that consists of hexane/ethyl acetate yielded 8.1 g of the title compound as a colorless foam.1H-NMR (300 MHz, CDCl3): δ [ppm]=7.94 d (J=8 Hz, 1H, aryl); 7.89 d (J=2.1 Hz, 1H, aryl); 7.77 dd (J=8 Hz/2.1 Hz, 1H, aryl); 3.67 m (2H, CH2N); 3.65 t (J=6.5 Hz, 2H, CH2OH); 1.83 m (2H, CH2); 1.55 m (2H, CH2); 1.58 s (6H, CH3); 1.37 m (8H, CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With hydrazine hydrate In ethanol at 20℃; for 18h; | |
82% | With hydrazine In ethanol; water for 3h; Reflux; | |
With hydrazine In ethanol; water for 4h; Heating / reflux; |
With water; hydrazine hydrate In ethanol for 4h; Reflux; | 1.c 15.2 ml of 80% aqueous hydrazinium hydroxide was added in drops to a solution of 23 g of the compound, produced under 1b), in 400 ml of ethanol. The reaction mixture was boiled for four hours. The white precipitate was filtered off and rewashed with ethanol. The filtrate was concentrated by evaporation in a vacuum. The residue was taken up in ethyl acetate and irradiated for 30 minutes in an ultrasound bath. The white precipitate was in turn filtered off and rewashed with ethyl acetate. The filtrate was concentrated by evaporation in a vacuum. 8.88 g of the title compound was obtained. 1H-NMR (300 MHz, CDCl3): δ [ppm]=3.62 t (J=7 Hz, 2H, CH2OH); 2.68 t (J=6 Hz, 2H, CH2NH2); 1.56 m (2H, CH2); 1.32 m (10H, CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene | 9 EXAMPLE 9 This product contains as impurities approximately from 5 to 10% by weight of the corresponding compound that is N-benzylated in the 10-position and of the N-(2-hydroxy)propylated compound. The starting material is prepared as follows: In a manner analogous to that described in Example 3,8-(N-benzyloxycarbonylamino)-2-methyleneoctanal is obtained, starting from 8-aminooctan-1-ol, via 8-(N-benzyloxycarbonylamino)octan-1-ol and 8-(N-benzyloxycarbonylamino)octanal. 15.30 g (52.9 mmol) of 8-(N-benzyloxycarbonylamino)-2-methyleneoctanal and 7.37 ml (67.4 mmol) of isocyanoacetic acid ethyl ester are dissolved in 78 ml of toluene and added dropwise under argon, within a period of 75 minutes, to a suspension of 0.30 g of copper(I) oxide in 76 ml of toluene. The mixture is then stirred for 90 minutes at 30°, cooled to room temperature and filtered, and the clear, bright red filtrate is introduced into a column filled with 250 g of silica gel (particle size 0.04-0.063 mm) and eluted with hexane/ethyl acetate (2:1). Concentration of the suitable fractions by evaporation yields 8.15 g of 5-[8-(N-benzyloxycarbonylamino)oct-1-en-2-yl]-oxazoline-4-carboxylic acid ethyl ester in the form of a colourless honey. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In ethanol | 1.5 8-amino-octan-1-ol Step 5 8-amino-octan-1-ol 8-Azido-octan-1-ol (1.99 g, 11.6 mmol) was dissolved in ethanol (25 mL) and Lindlar catalyst (200 mg) was added. The solution was hydrogenated at 50 psi, 30° C. for 2 hours. The catalyst was removed by filtration through Kieselguhr and the solvent was removed in vacuo to give a white solid 1.33 g (79% yield), mp 48°-53° C.; IR (film): 3346, 2927, 2855, 1610, 1597, and 1485 cm-1. NMR (CDCl3): δ 1.32-1.58 (13H, m, CH2 *6, OH), 2.68 (2H, t, J=6.9 Hz, CH2 NH2), 3.62 (2H, t, J=6.6 Hz, CH2 OH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In methanol at 15℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7 % Chromat. | Stage #1: benzoic acid methyl ester; 8-aminooctan-1-ol In di-isopropyl ether for 20h; Heating; Stage #2: di-<i>tert</i>-butyl dicarbonate In dichloromethane Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate In acetonitrile for 2.5h; Reflux; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In methanol at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In methanol at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With pyridine In N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In methanol at 20℃; for 1h; | 8-amino-1-octanol (11.2 mg, 0.077 mmol) was combined with FITC (10 mg, 0.026 mmol) in MeOH (0.3 ml_) and stirred at room-temperature for 1 h. The product was purified by silica gel chromatography (4:1 CH2CI2/MeOH containing 1 % H2O) to yield control compound 6 (13.6 mg, 98%) as an orange solid. 1H (300 MHz, CD3OD): δ 8.12 (d, 1 H, J = 1.7 Hz), 7.74 (dd, 1 H, J = 8.3, 1.6 Hz), 7.15 (d, 1 H, J = 8.2 Hz), 6.77 (d, 2H, J = 8.8 Hz), 6.67 (d, 2H, J = 2.3 Hz), 6.56 (dd, 2H, J = 8.8, 2.2 Hz), 3.60- 3.52 (m, 4H), 1.68-1.63 (m, 4H), 1.56-1.51 (m, 2H), 1.38 (m, 8H); 13C (75 MHz, CD3OD): δ 171.8, 155.2, 142.6, 131.0, 115.3, 112.6, 103.8, 63.2, 63.1 , 33.8, 30.7, 30.6, 30.1 , 28.2, 27.1 ); ESI-MS calcd for C29H30N2O6S [M - H]- : 533.1825 found 533.1846. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 90% 2: 7% | In di-isopropyl ether for 20h; Inert atmosphere; Reflux; | 2 In an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), 8-aminooctan-1-ol (3.6 mmol), Zn4(OCOCF3)6O (1.25 mol% in terms of mole number) and diisopropyl ether (5.0 ml) was heated to reflux for 20 hours, and as a result, 8-aminooctyl benzoate was obtained at a yield of 90%. The yield of 8-benzoylaminooctyl benzoate was 7%. 8-Aminooctyl benzoate: Pale yellow crystal: m.p. 60-62°C 1H-NMR(CDCl3, 35°C) δ 1.3-1.5 (m, 10H, methylene),1.76 (tt, J = 6.9, 6.9 Hz, 2H, OCH2CH2), 2.10 (bs, 2H, NH2),2.68 (t, J = 6.9 Hz, 2H, NH2CH2),4.31 (t, J = 6.9 Hz, 2H, OCH2), 7.4-7.6 (m, 3H, Ph),8.0-8.1 (m, 2H, Ph) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 1H-imidazole In dichloromethane at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | In ethanol for 8h; Reflux; | Synthesis of 6-bromo-2-(8-hydroxyoctyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (3) To a suspension of 4-Bromo-1,8-naphthalic anhydride (1) (1.00 g, 3.61 mmol) in 60 ml abs. EtOH 8-aminooctan-1-ol (2)(0.57 g, 4.33 mmol) was added. The mixture was refluxed for 8 h (reaction monitoring by TLC - hexane:Et2O = 1:4). The solvent was evaporated in vacuo and crude product was purified by columnchromatography (80 g silica gel, phase DCM:Et2O = 10:1) to obtain 1.04 g (71%) of 3 as white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine In dichloromethane at 24℃; for 20h; | Cholest-5-en-3β-yl N-(8-hydroxyoctyl)carbamate Cholesteryl chloroformate 8b (2.04 g, 4.54 mmol) and TEA (1.44 mL, 10.33 mmol) were added to a solution of compound 7a (0.60 g, 4.13 mmol) in anhydrous DCM (20 mL) and the reaction mixture was stirred at 24 for 20 h, diluted with DCM (50 mL), washed with 3 % aq. HCl (1 × 10 mL) and brine (3 × 10 mL). The organic phase was dried over Na2SO4, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with petroleum ether - ethyl acetate (5:1) to afford cholest-5-en-3β-yl N-(8-hydroxyoctyl)carbamate (1.56 g, 71 %). 1H NMR (300 MHz): 0.67 (s, 3 ,C(13)Me), 0.86 (d, 3 , C(25)Me, J = 6.5), 0.86 (d, 3 , C(25)Me, J = 6.5), 0.91 (d, 3 , C(20)Me, J = 6.5), 1.01 (s, 3 , C(10)Me), 0.95 - 1.65 (m, 33 H, Chol, H2(H2)6H2N), 1.72 - 2.07 (m, 5 H, Chol), 2.13 - 2.40 (m, 2 , H2(4) Chol), 3.08 - 3.18 (m, 2 H, NHCH2CH2), 3.63 (t, 2 H, N(CH2)7CH2O, J = 6.5 ), 4.40 - 4.65 (m, 2 , H(3) Chol, NH), 5.30 - 5.41 (m, 1 , H(6) Chol). 13 NMR (75 MHz): 12.00, 18.86, 19.47, 21.20, 22.70, 22.95, 23.99, 24.43, 25.79, 26.79, 28.15, 28.36, 29.33, 29.42, 30.14, 32.05, 32.88, 35.94, 36.34, 36.72, 37.16, 38.74, 39.67, 39.91, 41.06, 42.47, 50.19, 56.31, 56.86, 63.12, 74.34, 122.58, 140.04, 156.33. MS, m/z: 580.528 [M+Na]+ and 596.502 [M+K]+. Calculated for C36H63NNaO3 580.471 [M+ Na]+ and for C36H63KNO3 596.445 [M+K]+ . |
With triethylamine In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 80 %Chromat. 2: 15 %Chromat. | With L-alanin; L-alanine dehydrogenase; ω-transaminase from Chromobacterium violaceum; alcohol dehydrogenase from Bacillus stearothermophilus; pyridoxal 5'-phosphate; NAD; ammonia hydrochloride; sodium hydroxide In 1,2-dimethoxyethane; water monomer at 25℃; for 20h; Enzymatic reaction; | |
With pyridoxal 5'-phosphate; MATITNHMPTAELQALDAAHHLHPFSANNALGEEGTRVITRARGVWLNDSEGEEILDAMAGLWCVNIGYGRDELAEVAARQMRELPYYNTFFKTTHVPAIALAQKLAELAPGDLNHVFFAGGGSEANDTNIRMVRTYWQNKGQPEKTVIISRKNAYHGSTVASSALGGMAGMHAQSGLIPDVHHINQPNWWAEGGDMDPEEFGLARARELEEAILELGENRVAAFIAEPVQGAGGVIVAPDSYWPEIQRICDKYDILLIADEVICGFGRTGNWFGTQTMGIRPHIMTIAKGLSSGYAPIGGSIVCDEVAHVIGKDEFNHGYTYSGHPVAAAVALENLRILEEENILDHVRNVAAPYLKEKWEALTDHPLVGEAKIVGMMASIALTPNKASRAKFASEPGTIGYICRERCFANNLIMRHVGDRMIISPPLVITPAEIDEMFVRIRKSLDEAQAEIEKQGLMKSA; MIKAYAALEANGKLQPFEYDPGALGANEVEIEVQYCGVCHSDLSMINNEWGISNYPLVPGHEVVGTVAAMGEGVNHVEVGDLVGLGWHSGYCMTCHSCLSGYHNLCATAESTIVGHYGGFGDRVRAKGVSVVKLPKGIDLASAGPLFCGGITVFSPMVELSLKPTAKVAVIGIGGLGHLAVQFLRAWGCEVTAFTSSARKQTEVLELGAHHILDSTNPEAIASAEGKFDYIISTVNLKLDWNLYISTLAPQGHFHFVGVVLEPLDLNLFPLLMGQRSVSASPVGSPATIATMLDFAVRHDIKPVVEQFSFDQINEAIAHLESGKAHYRVVLSHSKN; β-nicotinamide adenine dinucleotide phosphate, oxidized form; benzylamine In dimethyl sulfoxide at 37℃; for 24h; Microbiological reaction; Enzymatic reaction; | ||
With benzylamine In aq. phosphate buffer; dimethyl sulfoxide at 30℃; for 24h; Microbiological reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In neat (no solvent) at 20℃; | 4.2 General procedure for the preparation of 3,4-dihydro-2H-1,3-oxazines (3-29 and 35-44) General procedure: 4.2.1 Method A (0026) To a dioxane [15] solution (5 mL) of tocotrienol (4 mmol), the amine (20 mmol) was added. Mixture was cooled in an ice bath and 37% formaldehyde (21 mmol) was added drop wise while stirring. It was then stirred at room temperature for 1 h and then refluxed overnight. Reaction mixture was concentrated under vacuum and the yellow residue obtained was dissolved in ethyl acetate (20 mL), washed several times with saturated NaCl solution, dried over anhydrous MgSO4, and concentrated in vacuum. The residue obtained was subjected to column chromatography using normal phase silica gel as stationary phase and gradient ethyl acetate/n-hexane system as mobile phase (Scheme 1a).4.2.2 Method B (0027) A mixture of tocotrienol [25] (5.0 mmol), paraformaldehyde (5.0 mmol) and amines (5.0 mmol) was stirred and left overnight at rt. The reaction was carried out under solvent-less conditions (few drops of dioxane or ethanol may be added). The residue was purified by flash chromatography directly from the reaction mixture without any work-up (Scheme 1b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In neat (no solvent) at 20℃; | 4.2 General procedure for the preparation of 3,4-dihydro-2H-1,3-oxazines (3-29 and 35-44) General procedure: 4.2.1 Method A (0026) To a dioxane [15] solution (5 mL) of tocotrienol (4 mmol), the amine (20 mmol) was added. Mixture was cooled in an ice bath and 37% formaldehyde (21 mmol) was added drop wise while stirring. It was then stirred at room temperature for 1 h and then refluxed overnight. Reaction mixture was concentrated under vacuum and the yellow residue obtained was dissolved in ethyl acetate (20 mL), washed several times with saturated NaCl solution, dried over anhydrous MgSO4, and concentrated in vacuum. The residue obtained was subjected to column chromatography using normal phase silica gel as stationary phase and gradient ethyl acetate/n-hexane system as mobile phase (Scheme 1a).4.2.2 Method B (0027) A mixture of tocotrienol [25] (5.0 mmol), paraformaldehyde (5.0 mmol) and amines (5.0 mmol) was stirred and left overnight at rt. The reaction was carried out under solvent-less conditions (few drops of dioxane or ethanol may be added). The residue was purified by flash chromatography directly from the reaction mixture without any work-up (Scheme 1b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
129 mg | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 1h; | 70 Intermediate 70: 6-[[3-[(8-Hydroxyoctyl)carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide HATU (116 mg, 0.305 mmol) and DIEA (0.106 mL, 0.61 mmol) were added to a stirring solution of 3-[[3-carbamoyl-4-[(3-methoxyphenyl)amino]-8-methylquinolin-6-yl]sulfonyl]benzoic acid (100 mg, 0.203 mmol) in DMF (2 mL) at rt. After 5 min 8-aminooctanol (0.35 mL, 0.244 mmol) was added and the resulting solution was stirred for an additional 1 h. The reaction mixture was poured into 10% (w/v) citric acid (50 mL) and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with H2O (2×100 mL), brine (100 mL), dried over Na2SO4 (s), and concentrated to give a brown semi-solid (129 mg). Chromatography (9:1, CH2Cl2/MeOH, 0.1% Et3N) afforded the title compound (120 mg, 95%) as a yellow solid. ES/MS calcd. for C33H39N4O6Si+ 619.3. Found m/z=619.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | In tetrahydrofuran at 50℃; for 48h; | 4.11 3-O-[N-(8-Hydroxyoctyl)carbamoyl]-25-ethoxymethyloxyvitamin D3 (28) A solution of vinyl carbonate 25 (45mg, 0.085mmol) in anhydrous THF (1.0mL) was treated with 37mg (0.255mmol) of 8-amino-1-octanol and the mixture was stirred at 50°C until TLC (10% EtOAc/hexane) showed complete consumption of starting material (48h). Then, solvent was evaporated and the residue purified by column chromatography (eluent 30% EtOAc/hexane) to afford 28 in 42% yield. Rf: 0.5 (50% EtOAc/hexane); IR (NaCl): ν 3343, 2931, 2866, 1695, 1539cm-1; 1H NMR (300.13MHz, CDCl3): δ 0.54 (s, 3H, Me18), 0.92 (d, 3H, Me21, J=6.2Hz), 0.96-2.49 (several m), 1.20 (t, 3H, Me3”, J=7.1Hz), 1.21 (s, 6H, Me26+Me27), 2.57 (dd, 1H, J=13.2, 3.2Hz), 2.81 (dd, 1H, J=10.7, 3.3Hz), 3.15 (m, 2H, H2′), 3.61 (q, 2H, H2”, J=7.2Hz), 3.62 (t, 2H, H9′, J=6.6Hz), 4.68 (br s, 1H, NH), 4.75 (s, 2H, H1″), 4.82 (d, 1H, H19, J=2.4Hz), 4.86 (m, 1H, H3), 5.04 (s, 1H, H19), 6.03 and 6.21 (2d, 2H, H6+H7, J=11.3Hz) ppm; 13C NMR (75.5MHz, CDCl3): δ 12.1 (CH3), 15.3 (CH3), 18.9 (CH3), 20.7 (CH2), 22.4 (CH2), 23.7 (CH2), 25.8 (CH2), 26.5 (CH3), 26.6 (CH3), 26.8 (CH2), 27.8 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 30.1 (CH2), 32.2 (CH2), 32.3 (CH2), 32.9 (CH2), 36.3 (CH), 36.6 (CH2), 40.7 (CH2), 41.0 (CH2), 42.4 (CH2), 42.7 (CH2), 46.0 (C), 56.5 (CH), 56.7 (CH), 63.1 (2CH2), 71.8 (CH), 76.3 (C), 89.6 (CH2), 112.6 (CH2), 117.6 (CH), 122.3 (CH), 135.0 (C), 142.3 (C), 145.1 (C), 156.2 (C) ppm; MS (ESI+, m/z): 652 [(M+Na)+, 100%]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | In 1,2-dichloro-ethane at 20℃; | 8 Reagents and conditions: (a) SeO2, dioxane, 50 to 80° C.; (b) N-methylpropagylamine or 2-(piperazin-1-yl) ethanol or NH2(CH2)n-1OH, NaBH(OAc)3, 1,2-dichloroethane, rt. Method: A solution of 8-hydroxy-2-methylquinoline (6.0 g, 37.7 mmol) in dioxane (15 ml) was added to a stirred solution of SeO2 (6.3 g, 56.8 mmol) in dioxane (80 ml) dropwise at 50° C. and the mixture was heated up to 80° C. for further 20 h. The resulting mixture was filtered. The filtrate was concentrated and the residue purified by column chromatography with Hex/EA=(15:1 to 10:1) to give 8-hydroxyquinoline-2-carboxaldehyde (2.45 g, 38%) derivatives as intermediates. Intermediate was converted into N-substituted compounds by reductive amination with aminoalcohol, aminoalkyne or other heterocycles to give series of compounds. 8-alkoxy-2-methyl quinoline were oxidized to give 8-alkoxyquinoline-2-carboxaldehyde derivatives and followed by the same method to give compounds M to O.2-((4-2-hydroxyethyl)piperazin-1-yl)methyl)quinolin-8-ol (M1) YD: 76%. 1H NMR (400 MHz, CDCl3) δ8.02 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.10 (d, J=6.8 Hz, 1H), 3.73 (s, 2H), 3.61 (t, J=6.8 Hz, 2H), 2.51 (t, J=5.6 Hz, 10H); HRMS (ESI): Calcd for [M+Na]+: 310.1526, Found: 310.1527. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: thiophosgene; 8-aminooctan-1-ol In chloroform for 0.0833333h; Cooling with ice; Stage #2: With triethylamine In chloroform | 1 Materials and methods General procedure: ITC Synthesis, Protocol I (The Main Protocol). In an ice bath, and with stirring, 1 mmol of amino compound in 1-2 mL of chloroform was added drop-wise to a mixture of 1.3 mmol of thiophosgene and 3 mL of chloroform. For diamino compounds the amount of thiophosgene was doubled. After 5 minutes, the mixture was supplemented with anhydrous triethylamine (two equivalents per each amino group) in 1-2 mL of chloroform with continuous stirring. The mixture was brought to room temperature and supplemented with water (40 mL). After an extraction, the organic phase was collected and washed with another 40 mL of water, and then evaporated in vacuo. The residue was dissolved in 3-4 mL of acetone and the solution mixed with 6-8 ml of silicagel in a round bottom flask. The silicagel was dried in vacuo and applied on top of silicagel column (20×2.5 sm) equilibrated with a mixture of hexane/acetone (3:1 to 1:1 for different compounds). The product was eluted by the same composition of solvents at an elution rate of 100 ml/h. Fractions containing the product were detected by UV light, combined, and subsequently evaporated under reduced pressure. Most of the residues represented viscose oils, only a few of them being crystals. The products were collected and stored at -20°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: bis(trichloromethyl) carbonate; DMTr-L-Prolinol With N-ethyl-N,N-diisopropylamine In dichloromethane for 1h; Cooling with ice; Inert atmosphere; Stage #2: 8-aminooctan-1-ol In dichloromethane at 20℃; for 20.5h; Cooling with ice; | 4 (4) DMTr-Ureido-L-Prolinol (Compound 8) (4) DMTr-Ureido-L-Prolinol (Compound 8)The DMTr-L-prolinol (Compound 4) (0.50 g, 1.2 mmol) and triphosgene (0.12 g, 0.40 mmol) were dissolved in 8 ml of dichloromethane, and the resultant mixture was stirred in an ice bath under argon. N,N-diisopropylethylamine (0.31 g, 2.4 mmol) was added to the solution, and this was stirred for 1 hour. Then, 8-amino-i -octanol (0.17 g, 1.2 mmol) was further added thereto, and this was stirred for 30 minutes in an ice bath in the same manner as in the above. Then, this was further stirred at room temperature for 20 hours. Dichloromethane was added to the solution, and an organic layer was collected. The collected organic layer was washed with saturated saline, and then dried with anhydrous sodium sulfate. The organic layer was filtered, and the filtrate obtained was vacuum concentrated. The residual substance was purifled by silica gel column chromatography (hexane:ethyl acetate=4: 1, containing 1% triethylamine). Thus, Compound 8 was obtained (0.44 g, yield: 62%). The result of NMR analysis with respect to this compound is shown below.‘H-NMR(CDC13): ö7.40-7.14 (9H, m,Ar-H), 6.82 (4H, m, Ar-H), 3.78 (s, 6H, OCH3), 3.68-3.25 (9H, m, CH2NH, CH2OH, H-2, H-5, H-6), 1.74-1.18(1 6H, m, alkyl, H-3, H-4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: bis(trichloromethyl) carbonate; DMTr-L-Prolinol With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; Stage #2: 8-aminooctan-1-ol With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 49h; | (2) DMTr-Ureido-L-Prolinol (Compound 5) (2) DMTr-Ureido-L-Prolinol (Compound 5)Under argon, triphosgene (2.0 g, 6.7 mmol) was dissolvedin 10 ml of THF, and this was stirred at 0° C. On the otherhand, DMTr-L-prolinol (Compound 3) (1.3 g, 3.2 mmol) and N, N-diisopropylethylamine (16 g, 124 mmol) were dissolved in 10 ml of THF, and this solution was instilled in the THF solution of triphosgene. This reaction solution wasstirred for 1 hour at 0° C. and then for 2 hours at room temperature. Then, 8-amino-1-octanol (2.3 g, 16 mmol) and N, N-diisopropylethylamine (5.0 g, 38 mmol) were dissolved in 30 ml of THF. The reaction solution having been stirred was instilled in this THF solution, and this was stirred for 1hour at 0° C. and then for 48 hours at room temperature. This reaction solution was vacuum concentrated, and the residual substance obtained was dissolved in dichioromethane. This solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline. An organiclayer was collected and dried with anhydrous sodium sulfate. The organic layer was filtered, and the filtrate obtained was vacuum concentrated. The residual substance obtained was purified by applying it to reverse-phase silica gel colunmchromatography. At this time, the eluent used was a mixed solvent of acetone and water, containing 0.1% pyridine, and the mixing ratio between the acetone and water was changed stepwise. Specifically, the molar ratio between the acetone and water (acetone:water) was changed gradually so as to be2:8, 3:7, 4:6, and 5:5 in this order. A fraction containing CompoundS as a target compound was extracted with dichloromethane, and the thus-obtained organic layer was dried with anhydrous sodium sulfate. The organic layer was filtered, and the filtrate obtained was vacuum concentrated.Thus, Compound 5 (prolinol ureido amidite) was obtained (0.9 g, yield: 49%). The result of NMR analysis with respect to this compound is shown below.‘H-NMR (CDC13): ö7.40-7.14 (9H, m, Ar--H), 6.82 (4H,m, Ar-H), 3.78 (s, 6H, OCH3), 3.68-3.25 (9H, m, CH2NH, CH2OH, H-2, H-5, H-6), 1.74-1.18(1 6H, m, alkyl, H-3, H-4);FAI3-MS: 575 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine In dichloromethane at 0℃; Inert atmosphere; | 4.2.1 RRN 44,46,48General procedure for the synthesis of N-Acetylaminols 2c and 4a-b General procedure: To a solution of aminol (2mmol) and TEA (585μL, 4.2mmol) in CH2Cl2 dry (6mL) was added acetyl chloride (149μL, 2.1mmol) at 0°C. The reaction mixture was stirred vigorously at 0°C under N2 until TLC analysis shows complete conversion of the starting materials. The solvent was removed under reduce pressure and the residue was purified by flash column chromatography on silica gel to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / water; tetrahydrofuran / 20 °C / pH 8 2: pyridine / chloroform / 20 °C / Cooling with ice | ||
Multi-step reaction with 2 steps 1: triethylamine / methanol / 20 h / 20 °C 2: triethylamine; dmap / dichloromethane / 20 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / 5 - 20 °C 2: dmap; triethylamine / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium hydroxide In ethanol; water for 18h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 3,4-dimethoxy-trans-cinnamic acid With chloroformic acid ethyl ester; triethylamine In dichloromethane at 20℃; for 2h; Stage #2: 8-aminooctan-1-ol In dichloromethane at 20℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: (E)-3,4,5-trimethoxy-cinnamic acid With chloroformic acid ethyl ester; triethylamine In dichloromethane at 20℃; for 2h; Stage #2: 8-aminooctan-1-ol In dichloromethane at 20℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 8-aminooctan-1-ol With potassium hydroxide In dimethyl sulfoxide at 60℃; for 1h; Stage #2: 4'-Chloro-2,2':6',2''-terpyridine In dimethyl sulfoxide at 60℃; for 48h; | Preparation of 8-(2,2':6′,2″-terpyridin-4′-yloxy)-octanol-1-amine (Terp-NH2) Powdered KOH (280mg, 5mmol) was added to 10mL dry dimethyl sulfoxide (DMSO) and 8-Amino-1-octanol (152.5mg, 1.05mmol) was then added and stirred at 60°C for 1h. Then, 4′-Chloro-2,2':6′,2″-terpyridine (268mg, 1.0mmol) was added, and the resulting mixture was stirred at 60°C for 48h. After cooled to room temperature, the reaction mixture was poured into deionized water (200mL) to yield precipitation, which was collected by filtration. The yellow solid was washed with deionized water, and then dried under vacuum overnight to afford 290mg of the desired product in 77% yield [30]. 1H NMR (400MHz, CDCl3) δ 8.74-8.66 (m, 2H), 8.62 (d, J=8.0Hz, 2H), 8.02 (d, J=9.1Hz, 2H), 7.85 (td, J=7.8, 1.8Hz, 2H), 7.33 (ddd, J=7.5, 4.8, 1.1Hz, 2H), 4.22 (t, J=6.4Hz, 2H), 2.69 (t, J=7.0Hz, 2H), 1.90-1.81 (m, 2H), 1.56-1.28 (m, 10H). HRMS [M+ H]+ calcd for C23H29N4O+ 377.2341; found: 377.2340. Anal Cald for C23H28N4O: C, 73.37; H, 7.50; N, 14.88; Found: C, 73.32; H, 7.85; N, 14.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.6% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 24h; | 3 Preparation of (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-hydroxyoctyl)acetamide (32-2) Preparation of (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-hydroxyoctyl)acetamide (32-2): To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid 32-1 (450 mg, 1.12 mmol) in DMF (2.80 mL ) was added 8-aminooctan-1-ol (244 mg, 1.68 mmol), Diisopropylethylamine (389 µL, 2.24 mmol) and HATU (509 mg, 1.34 mmol), The reaction was stirred for 24 h, at which time the reaction was concentrated and purified by isco (24g column 0-10% MeOH/DCM) to provide (S)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3- hydroxypropyl)acetamide (400 mg, 67.6 %). LCMS ES+ = 529.1 |
67.6% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 24h; | (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)-N-(8-hydroxyoctyl)acetamide (50-2): To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (50-1) (450 mg, 1.12 mmol) in DMF (2.80 mL ) was added 8-aminooctan-1-ol (244 mg, 1.68 mmol), Diisopropylethylamine (389 µL, 2.24 mmol) and HATU (509 mg, 1.34 mmol), The reaction was stirred for 24 h, at which time the reaction was concentrated and purified by isco (24g column 0-10% MeOH/DCM) to provide (S)- 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)- N-(3-hydroxypropyl)acetamide (400 mg, 67.6 %). LCMS ES+ = 529.1 |
67.6% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 24h; | 8.1 Step 1: To a solution of (S)-2-( 4-( 4-chlorophenyl )-2,3 ,9-trimethyl-6H -thieno[3 ,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid 28-1 (450 mg, 1.12 mmol) in DMF (2.80 mL) was added 8-aminooctan-1-ol (244 mg, 1.68 mmol), Diisopropylethylamine (389 J.L, 2.24 mmol)and HATU (509 mg, 1.34 mmol), The reaction was stirred for 24 h, at which time the reaction wasconcentrated and purified by isco (24g column 0-10% MeOH/DCM) to provide (S)-2-( 4-( 4-chlorophenyl )-2,3 ,9-trimethyl-6H -thieno[3 ,2-f] [ 1 ,2, 4 ]triazolo[ 4,3 -a] [ 1, 4 ]diazepin-6-yl )-N -(3-hydroxypropyl)acetamide (400 mg, 67.6 %). LCMS ES+ = 529.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 24 h 2: Dess-Martin periodane / dichloromethane / 1 h / 20 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 24 h 2: Dess-Martin periodane / dichloromethane / 1 h / 20 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 24 h 2: Dess-Martin periodane / dichloromethane / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.3% | With dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2‘-amino-1,1’-biphenyl)]palladium(II) methanesulfonate; lithium hexamethyldisilazane In tetrahydrofuran; 1,4-dioxane Inert atmosphere; Reflux; | Intermediate 210-2. Preparation of 8-((4-(1-Methyl-8-(1-methyl-1H-pyrazol-4- yl)spiro[benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-4,1'-cyclopropan]-6- yl)phenyl)amino)octan-1-ol Brought 6-(4-chlorophenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4- yl)spiro[benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-4,1'-cyclopropane] (209-2) (27 mg, 0.06507 mmol), 8-aminooctan-1-ol (210-1) (11.3 mg, 0.07808 mmol), BrettPhos (3.49 mg, 0.006507 mmol) and Brettphos G3 (5.19 mg, 0.006507 mmol) up in dioxane (433 µL ) and added 1M (in THF) lithium bis(trimethylsilyl)amide (221 µL, 0.2212 mmol) all under Ar. Sealed reaction and heated to reflux overnight. Concentrated onto celite and purified by isco 0-20% MeOH/DCM to give 8-((4-(1-methyl-8-(1-methyl-1H-pyrazol-4-yl)spiro[benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepine-4,1'-cyclopropan]-6-yl)phenyl)amino)octan-1-ol (210-2) (11.0 mg, 0.02100 mmol, 32.3 %) as an oil. LC/MS (ES+): m/z 524.5 [M + H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloroformic acid ethyl ester; triethylamine In dichloromethane | ||
Stage #1: Veratric acid With trichlorophosphate In dichloromethane at 20℃; for 0.5h; Stage #2: 8-aminooctan-1-ol With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Cooling with ice; | A2) General procedure: The appropriate benzoic acid (3,4-dimethoxybenzoic acid(4) or 3,4,5-trimethoxybenzoic acid (5), 1 mmol) was dissolved indichloromethane (15 mL) and POCl3 (1 mmol) was added at roomtemperature. After 30 min, the reactional mixture was cooled (icebath) and 8-aminooctan-1-ol or 10-aminodecan-1-ol (1.2 mmol)and DIPEA (4 mmol) were added. The reaction was stirred for1-2 h at room temperature. The purification conditions aredescribed in literature [15]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloroformic acid ethyl ester; triethylamine In dichloromethane | ||
Stage #1: Eudesmic acid With trichlorophosphate In dichloromethane at 20℃; for 0.5h; Stage #2: 8-aminooctan-1-ol With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Cooling with ice; | A2) General procedure: The appropriate benzoic acid (3,4-dimethoxybenzoic acid(4) or 3,4,5-trimethoxybenzoic acid (5), 1 mmol) was dissolved indichloromethane (15 mL) and POCl3 (1 mmol) was added at roomtemperature. After 30 min, the reactional mixture was cooled (icebath) and 8-aminooctan-1-ol or 10-aminodecan-1-ol (1.2 mmol)and DIPEA (4 mmol) were added. The reaction was stirred for1-2 h at room temperature. The purification conditions aredescribed in literature [15]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: tetrahydrofuran / 3 h / 50 °C / Inert atmosphere 2: iodine; triphenylphosphine; 1H-imidazole / dichloromethane / 1 h / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sodium hydroxide / 1,4-dioxane; water / 5 h / 20 °C 2: triphenylphosphine; 1H-imidazole; iodine / dichloromethane / 20 °C | ||
Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran / 1 h / 5 - 20 °C 2: dmap; triethylamine / 0 - 20 °C 3: sodium iodide / acetone / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.5h; | 7 2-chloroacetyl chloride (57, 0.35 ml, 4.43 mmol) was added to a solution of 8- aminooctan-l-ol (56, 1.9 g, 13.28 mmol) and DIPEA (2.3 ml, 13.28 mmol) in DCM (44 mL) at 0°C. After 30 minutes, complete consumption of the starting material was observed. The reaction mixture was quenched with an aqueous 1M HCl solution and extracted with DCM. The combined organic extracts were dried over MgS04, filtered and concentrated. Purification via silica gel chromatography gave 2-chloro-N-(8-hydroxyoctyl)acetamide (58, 500 mg, 51% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.8% | With N-ethyl-N,N-diisopropylamine In dichloromethane | 7 Example 7 To the solution of (2R,5S,8R, 14S,17R520S,21 S,22S5E)-8-benzyl-20-((E)-but-2-en- 2-yl)-14-((R)-sec-butyl)-2-isobutyl-5,7, 10, 17,21,25-hexamethyl-3,6,9, 12, 15, 18,26-heptaoxo- 1 , 19~dioxa-4,7, 10, 13, 16-pentaazaey clone acos-24-en-22-yi (4-nitrophenyl) carbonate (1.009 μτηο, 1 rng) in DCM (3.11 mmol, 0.2 mL) was added Hiinig's base (0.0103 mmol, 1.8 μΕ) and 8-aminooctan- 1 -ol (0.0103 mmol, 1.5 mg). The mixture was stirred overnight, and the volatile was removed. The residue was purified with RP-flash to afford (2R,5 S,8R, 14S, 17R,2QS,21 S522S,E)-8-benzyl-20-((E)-but-2-en-2-yl)- 14-((R)-sec-butyl)-2- isobutyl-5,7,10,r7,21,25 iexamethyl-3,6,9, 12, 15,18,26-heptaoxo-l, 19"dioxa-4,7, 10,i pentaazacyclohexacos-24-en-22-yl (8-hydroxyoctyl)carbamate (0.3 mg, 29.8%). Observed HRMS (ESI) m/z: 997.6288 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.2% | Stage #1: 8-aminooctan-1-ol; 2-methylthio-2-imidazoline hydroiodide In methanol at 60℃; Stage #2: di-<i>tert</i>-butyl dicarbonate With triethylamine In N,N-dimethyl-formamide at 20℃; Cooling with ice; | 8 Synthesis of tert-butyl 2-(8-hydroxyoctylamino)-4,5-dihydroimidazole-1-carboxylate 2-(methylsulfanyl)-4,5-dihydro-1H-imidazole hydroiodide (4 g) was dissolved in methanol (50 mL). 1-amino-8-octanol (3.57 g) was added to the solution at room temperature. The reaction mixture was heated to 60° C., and stirred at the same temperature overnight. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in N, N-dimethylformamide (50 mL), and triethylamine (9.96 g) and di-tert-butyl dicarbonate (12.52 g) were added thereto under ice-cooling. The reaction mixture was warmed to room temperature and stirred at the same temperature overnight. Water was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The resultant organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.86 g, in a yield of 36.2%). 1NMR (CDCl3): 1.27-1.36 (m, 8H), 1.44-1.58 (m, 17H), 3.07-3.14 (m, 2H), 3.63 (dd, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; | 7.1 Step 1. 2-(2,6-dioxopiperidm-3-yl)-4-((8-hydroxyoctyl)ammo)isomdolme-l^dione (8a) To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione (3c, 172 mg, 0.623 mmol, 1 equiv) in NMP (3.1 mL, 0.2 M) was added DIPEA (325 uL, 1.87 mmol, 3 equiv) and 8-aminooctanol (99 mg, 0.684 mmol, 1 equiv). The reaction mixture was heated to 90 °C overnight and then cooled to room temperature. EtOAc (20 mL) was added. The organic layer was washed with water (20 mL) and brine (3 x 20 mL), dried over Na2S04, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (eluting with 0 to 5% MeOH in CH2CI2) to give the title compound 8a, as a yellow oil (69 mg, 28%). MS (ESI) [M+H]+: 402.4. |
27% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 90℃; | 5.1.1.4. General method D. General procedure: Compound 38/56 (1.0 equiv.), amine (1.2equiv.), and DIPEA (2.0 equiv.) in DMF were stirred at 90 °C overnight. The reaction was cooled to room temperature and poured into water. The resulting mixture was extracted with ethylacetate and the organic layer was washed with water 1, brine 1,dried over anhydrous Na2SO4, filtered, and evaporated to drynessunder vacuum. The residue crude product was purified by column chromatography to afford the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: dicobalt octacarbonyl; 6CO*2Co*C12H21BrF2Si In toluene at 20℃; for 3h; Inert atmosphere; Stage #2: 8-aminooctan-1-ol With 2,6-di-tert-butyl-4-methylpyridine; silver trifluoromethanesulfonate In toluene for 1.5h; Inert atmosphere; Stage #3: acetic anhydride With pyridine In toluene at 20℃; for 1h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 45℃; for 24h; | 1 /V-(3.4-Difluorophenyl)-4-(2-(8-hvdroxyoctylamino)-2-oxoacetyl)-L3.5-trimethyl-lH- pyrrole-2-carboxamide (601 To a solution of 2-(5-((3,4-difluorophenyl) carbamoy 1)- 1,2, 4-trimethyl- lH-pyrrol-3- yl)-2-oxoacetic acid 54 (100 mg, 0.30 mmol) in DMF (4 mL) was added HATU (283 mg, 0.74 mmol), 8-amino- l-octanol 59 (86 mg) and DIPEA (208 pL, 0.59 mmol). After stirring at 45 °C for 24 h, the reaction mixture was poured into a saturated NH4CI (30 mL) and extracted with EtOAc (3 x 50 mL). The organic layers was combined and dried over Na2SC>4, concentrated in vacuo and the residue was purified by Combi-flash chromatography (DCM/MeOH = 100: 1 to 10: 1) to yield 60 (69 mg, 50% yield). NMR (400 MHz, MeOH- di) d 7.83-7.78 (m, 1H), 7.36-7.33 (m, 1H), 7.30-7.23 (m, 1H), 3.67 (s, 3H), 3.57-3.54 (m, 2 H), 3.35-3.31 (m, 2 H), 2.46 (s, 3H), 2.34 (s, 3H), 1.66-1.59 (m, 2H), 1.57-1.52 (m, 2H), 1.38 (brs, 8H); MS (ESI): m/z [M+H] + calcd for C24H32F2N3O4: 464.5, found: 464.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis[dicarbonylcyclopentadienylruthenium(I)] In tetrahydrofuran-d8 at 20℃; for 0.5h; Irradiation; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With propane-1,3-diyl dinitrite In tetrahydrofuran at 70℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With 1,3-(2,2-dimethyl)propanedinitrite In ethyl acetate at 80℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine | 1 Step 1: Step 1: Preparation of tert-butyl (8-hydroxyoctyl) carbamate To a solution of 8-amino octane-1-ol (1.0 g, 6.88 mmol) in THF (30 mL) was added TEA (1.5 mL, 10.32 mmol) and the reaction was cooled to 5-10 °C. BOC anhydride (1.9 mL, 8.25 mmol) is added and the temperature is raised to room temperature. The reaction is stirred for 1 hour. After completion of the reaction, the reaction was quenched with water and extracted with EtOAc, the organic layer was dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography to give the title compound (1.4 g, 85 % yield) as a white solid. 1H NMR: (300 MHz, DMSO) δ 6.75 (s, 1H), 4.32 (t, J = 5.2 Hz, 1H), 3.37 (m, 2H), 2.89 (q, J = 6.6 Hz, 2H), 1.42 (m, 1H), 1.37 (s, 9H), 1.21 (m, 11H). |
With triethylamine | 1 Step 1: Step 1: Preparation of tert-butyl (8-hydroxyoctyl)carbamate To a solution of 8-aminooctane-1-ol (1.00 g, 6.88 mmol) in THF (20 mL) at 0 °C was added BocO (1.90 mL, 8.26 mmol) and TEA (1.44 mL, 10.2 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was quenched and then extracted with EtOAc (2*25 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo. The crude mixture was purified by silica gel column chromatography using EtOAc/Hex (1/1) as eluent to give the title compound (1.19 g, 4.85 mmol, 70 %) as a white solid. 1H NMR (300 MHz, CDCl3) δ4.50 (s, 1H), 3.64 (t, J = 6.3 Hz, 2H), 3.10 (q, J = 6.6 Hz, 2H), 1.66-1.52 (m, 2H), 1.44 (s, 9H), 1.38-1.39-1.21 (m, 10H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With D-glucose; benzylamine; magnesium(II) chloride In aq. phosphate buffer; dimethyl sulfoxide at 30℃; for 24h; Microbiological reaction; | ||
Multi-step reaction with 2 steps 1: magnesium(II) chloride; D-glucose / aq. phosphate buffer / 24 h / 30 °C / pH 7.5 / Microbiological reaction 2: benzylamine / aq. phosphate buffer; dimethyl sulfoxide / 24 h / 30 °C / pH 7.5 / Microbiological reaction |
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P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
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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