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CAS No. : | 89031-84-5 | MDL No. : | MFCD00216589 |
Formula : | C9H21BrOSi | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QGMROEZDWJTIDW-UHFFFAOYSA-N |
M.W : | 253.25 | Pubchem ID : | 607486 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 62.2 |
TPSA : | 9.23 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.02 cm/s |
Log Po/w (iLOGP) : | 3.36 |
Log Po/w (XLOGP3) : | 3.98 |
Log Po/w (WLOGP) : | 3.79 |
Log Po/w (MLOGP) : | 2.99 |
Log Po/w (SILICOS-IT) : | 1.64 |
Consensus Log Po/w : | 3.15 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.59 |
Solubility : | 0.0655 mg/ml ; 0.000258 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.88 |
Solubility : | 0.0338 mg/ml ; 0.000133 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.78 |
Solubility : | 0.042 mg/ml ; 0.000166 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 4.64 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H227-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 |
---|---|---|
93% | at 20℃; for 3 h; Inert atmosphere | Example C: 3-(3-(2,5-Dioxo-4-(3,4,5-trimethoxyphenyl)-2,5-dihydro-1H-pyrrol-3-yl)-1H-indol-1-yl)propyl 2-amino-4-methylpentanoate 3-Bromopropoxy-tert.-butyldimethylsilan A modified procedure of Galka et al. (J. Lab. Comp. Rad. 2005, 48(11): 797-809) was used to prepare the title compound. A mixture of 3-bromopropanol (39.1 mmole; 5.43 g), tert.-butyldimethylsilylchloride (43.2 mmole; 6.47 g) and imidazole (46.7 mmole; 3.20 g) was stirred at RT for 3 hours under inert gas. The reaction was quenched with water, extracted with diethylether, the organic layer dried over MgSO4, filtered and concentrated. The purification was achieved by column chromatography (PE) to yield the title compound (36.4 mmole; 93 percent). 1H NMR (300 MHz, CDCl3) 3.73 (t; 3J = 5.7 Hz; 2H; CH2O); 3.51 (t; 3J = 6.4 Hz; 2H; CH2Br); 2.02 (q; 3J = 5.7 Hz; 3J = 6.4 Hz; 2H; CH2CH2CH2); 0.89 (s; 9H; C(CH3)3); 0.06 (s; 6H; 2xCH3). |
93% | at 20℃; for 3 h; Inert atmosphere | 3-Bromopropoxy-ferf.-butyldimethylsilanA modified procedure of Galka et al. (J. Lab. Comp. Rad. 2005, 48(11): 797-809) was used to prepare the title compound. A mixture of 3-bromopropanol (39.1 mmole; 5.43 g), te/t-butyldimethylsilylchloride (43.2 mmole; 6.47 g) and imidazole (46.7 mmole; 3.20 g) was stirred at RT for 3 hours under inert gas. The reaction was quenched with water, ex- tracted with diethylether, the organic layer dried over MgS04, filtered and concentrated. The purification was achieved by column chromatography (PE) to yield the title compound (36.4 mmole; 93 percent). 1 H NMR (300 MHz, CDCI3) 3.73 (t; 3J = 5.7 Hz; 2H; CH20); 3.51 (t; 3J = 6.4 Hz; 2H; CH2Br); 2.02 (q; 3J = 5.7 Hz; 3J = 6.4 Hz; 2H; CH?CH?CH?); 0.89 (s; 9H; C(CH3)3); 0.06 (s; 6H; 2xCH3). |
81% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 3 h; Inert atmosphere | fresh 3-bromo-1-propanol (2 ml, 22.12 mmol) was dissolved in dry CH2Cl2 (8 ml). Triethylamine (3.39 ml, 24.33 mmol) and 4-(dimethylamino)pyridine (0.29 g, 2.433 mmol) were added under argon with stirring. The solution was cooled to 0 °C under argon, and t-butyldimethylsilyl chloride (3.33 g, 22.12 mmol) was added. The solution was allowed to come to room temperature while stirring for 3 h under argon (monitored by TLC using 15percent ethyl acetate/hexane with anisaldehyde detection). The reaction was quenched with water (5 ml) and allowed to stir for 15 min. The crude product was extracted from the aqueous solution with CH2Cl2, (3 * 10 ml). The combined organic extracts were dried over Na2SO4, filtered, and evaporated. Crude (3-bromopropoxy)-t-butyldimethylsilyl ether was purified on a silica gel column using 15percent ethyl acetate/hexane to yield 4.52 g, 17.85 mmol, 81percent yield, as a yellow oil. 1H NMR (CDCl3) d (ppm): 0.089 (s, 3H, SiCH3); 0.094 (s, 3H, SiCH3); 0.91 (s, 9H, t-Bu); 2.06 (m, 2H, BrCH2CH2CH2O); 3.53 (t, J = 5.7Hz, 2H, BrCH2CH2CH2O); 3.75 (t, J = 5.7 Hz, 2H, BrCH2CH2CH2O). |
40% | With 1H-imidazole In dichloromethane at 20℃; for 3 h; | To lH-imidazole (13.4 g, 197 mmol) in DCM (100 mL) was added 3-bromopropan-l-ol (13.7 g, 99 mmol) followed slowly by fe/ butylchlorodimethylsilane (17.8 g, 118 mmol) in DCM (20 ml). After 3 hr at RT, the reaction was concentrated to ~100 mL and poured in EtOAc (800 mL), washed with 5percent aq citric acid (2 x 200 mL) and brine. The organic layer was dried over MgSCM, filtered and concentrated to yield the title compound (10.0 g, 39.5 mmol, 40 percent yield). *H NMR (400 MHz, chloroform-tf) δ ppm 3.78 (t, 7=5.70 Hz, 2 H), 3.56 (t, 7=6.46 Hz, 2 H), 2.07 (t, 7=5.83 Hz, 2 H), 0.94 (s, 9 H), 0.11 (s, 6 H). |
28% | With 1H-2,2,4-triazole In N,N-dimethyl-formamide at 25℃; for 12 h; Inert atmosphere | Into a 500 ml round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N,N-dimethylformamide (300 ml), 3-bromopropan-1-ol (30 g, 215.84 mmol, 1.21 equiv.), tert-butyl(chloro)dimethylsilane (26.8 g, 177.81 mmol, 1.00 equiv.), 4H- imidazole (36.4 g, 534.69 mmol, 3.01 equiv.). The resulting solution was stirred for 12 h at25 °C. The resulting solution was diluted with 500 ml of ethyl acetate. The resulting mixture was washed with 3x500 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate. This resulted in 12.4 g of the title compound as colorless oil (28percent). ‘H NMR (300 MHz, CDC13) & 3.76-3.73 (m, 2H), 3.67-3.62 (m, 1H), 3.51 (t, 1=6.6Hz, 1H), 2.07-1.9 1 (m, 2H), 0.87 (s, 9H), 0.07 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1H-imidazole In dichloromethane at 20℃; for 0.166667 h; Cooling with ice | 3-Bromopropanol (4.14 g, 30 mmol),Was added to DCM (50 mL), imidazole (2.5 g, 30 mmol) was added, stirred under ice for 10 min, TBDMS (4.5 g, 30 mmol) was added and the reaction was continued at room temperature. The next day, DCM (50 mL) (30 mL X3), dried over anhydrous magnesium sulfate and concentrated to give 7 g of a colorless oil in 92percent yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 1H-imidazole; In dichloromethane; water; at 10℃; for 0.833333h;Industrial scale; | Add 5 liters of dichloromethane to a 10 liter three-neck round bottom flask to control the internal reaction temperature of 10 C, 1.39 kg in sequence.3-Bromopropanol, 748 g of imidazole, after completion, maintain the internal temperature unchanged, continue to stir for 20 minutes, slowly add 1.58 kg of tert-butylAfter the methyl chlorosilane is added, the reaction material is completely disappeared by the spot plate, the reaction is stopped, and water is added to the reaction solution to stir.After two minutes, the aqueous phase was extracted twice with dichloromethane, dried over anhydrous sodium sulfate and evaporated.1, a white solid, yield 99%; |
93% | With 1H-imidazole; at 20℃; for 3h;Inert atmosphere; | Example C: 3-(3-(2,5-Dioxo-4-(3,4,5-trimethoxyphenyl)-2,5-dihydro-1H-pyrrol-3-yl)-1H-indol-1-yl)propyl 2-amino-4-methylpentanoate 3-Bromopropoxy-tert.-butyldimethylsilan A modified procedure of Galka et al. (J. Lab. Comp. Rad. 2005, 48(11): 797-809) was used to prepare the title compound. A mixture of 3-bromopropanol (39.1 mmole; 5.43 g), tert.-butyldimethylsilylchloride (43.2 mmole; 6.47 g) and imidazole (46.7 mmole; 3.20 g) was stirred at RT for 3 hours under inert gas. The reaction was quenched with water, extracted with diethylether, the organic layer dried over MgSO4, filtered and concentrated. The purification was achieved by column chromatography (PE) to yield the title compound (36.4 mmole; 93 %). 1H NMR (300 MHz, CDCl3) 3.73 (t; 3J = 5.7 Hz; 2H; CH2O); 3.51 (t; 3J = 6.4 Hz; 2H; CH2Br); 2.02 (q; 3J = 5.7 Hz; 3J = 6.4 Hz; 2H; CH2CH2CH2); 0.89 (s; 9H; C(CH3)3); 0.06 (s; 6H; 2xCH3). |
93% | With 1H-imidazole; at 20℃; for 3h;Inert atmosphere; | 3-Bromopropoxy-ferf.-butyldimethylsilanA modified procedure of Galka et al. (J. Lab. Comp. Rad. 2005, 48(11): 797-809) was used to prepare the title compound. A mixture of 3-bromopropanol (39.1 mmole; 5.43 g), te/t-butyldimethylsilylchloride (43.2 mmole; 6.47 g) and imidazole (46.7 mmole; 3.20 g) was stirred at RT for 3 hours under inert gas. The reaction was quenched with water, ex- tracted with diethylether, the organic layer dried over MgS04, filtered and concentrated. The purification was achieved by column chromatography (PE) to yield the title compound (36.4 mmole; 93 %). 1 H NMR (300 MHz, CDCI3) 3.73 (t; 3J = 5.7 Hz; 2H; CH20); 3.51 (t; 3J = 6.4 Hz; 2H; CH2Br); 2.02 (q; 3J = 5.7 Hz; 3J = 6.4 Hz; 2H; CH?CH?CH?); 0.89 (s; 9H; C(CH3)3); 0.06 (s; 6H; 2xCH3). |
81% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere; | fresh 3-bromo-1-propanol (2 ml, 22.12 mmol) was dissolved in dry CH2Cl2 (8 ml). Triethylamine (3.39 ml, 24.33 mmol) and 4-(dimethylamino)pyridine (0.29 g, 2.433 mmol) were added under argon with stirring. The solution was cooled to 0 C under argon, and t-butyldimethylsilyl chloride (3.33 g, 22.12 mmol) was added. The solution was allowed to come to room temperature while stirring for 3 h under argon (monitored by TLC using 15% ethyl acetate/hexane with anisaldehyde detection). The reaction was quenched with water (5 ml) and allowed to stir for 15 min. The crude product was extracted from the aqueous solution with CH2Cl2, (3 * 10 ml). The combined organic extracts were dried over Na2SO4, filtered, and evaporated. Crude (3-bromopropoxy)-t-butyldimethylsilyl ether was purified on a silica gel column using 15% ethyl acetate/hexane to yield 4.52 g, 17.85 mmol, 81% yield, as a yellow oil. 1H NMR (CDCl3) d (ppm): 0.089 (s, 3H, SiCH3); 0.094 (s, 3H, SiCH3); 0.91 (s, 9H, t-Bu); 2.06 (m, 2H, BrCH2CH2CH2O); 3.53 (t, J = 5.7Hz, 2H, BrCH2CH2CH2O); 3.75 (t, J = 5.7 Hz, 2H, BrCH2CH2CH2O). |
76% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 6h; | To a solution of 3-bromo-propan-l-ol HHHHH (2.0 g, 14.4 mmol, 1.0 equiv.) in dimethylformamide (40 mL, 0.3M) was added imidazole (1.47 g, 21.6 mmol, 1.5 equiv.) followed by TBS-C1 (3.3 g, 21.6 mmol, 1.5 equiv.). The reaction was stirred at room temperature for 6 hours, or until the reaction was determined to be complete by LCMS or TLC. The reaction was then quenched with water. The aqueous layer was then extracted with diethyl ether. The combined organic layers were washed with brine and dried over sodium sulfate. After filtration, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (hexane/ethyl acetate as eluant) to afford the desired protected alcohol (IIIII, 2.91 g, 10.9 mmol, 76%). |
40% | With 1H-imidazole; In dichloromethane; at 20℃; for 3h; | To lH-imidazole (13.4 g, 197 mmol) in DCM (100 mL) was added 3-bromopropan-l-ol (13.7 g, 99 mmol) followed slowly by fe/ butylchlorodimethylsilane (17.8 g, 118 mmol) in DCM (20 ml). After 3 hr at RT, the reaction was concentrated to ~100 mL and poured in EtOAc (800 mL), washed with 5% aq citric acid (2 x 200 mL) and brine. The organic layer was dried over MgSCM, filtered and concentrated to yield the title compound (10.0 g, 39.5 mmol, 40 % yield). *H NMR (400 MHz, chloroform-tf) delta ppm 3.78 (t, 7=5.70 Hz, 2 H), 3.56 (t, 7=6.46 Hz, 2 H), 2.07 (t, 7=5.83 Hz, 2 H), 0.94 (s, 9 H), 0.11 (s, 6 H). |
40% | With 1H-imidazole; In dichloromethane; at 20℃; for 3h; | To lH-imidazole ( 13.4 g, 197 mmol) in DCM (100 mL) was added 3- bromopropan- l-ol (13.7 g, 99 mmol) followed slowly by fert-butylchlorodimethylsilane (17.8 g, 1 18 mmol) in DCM (20 ml). After 3 hr at RT, the reaction was concentrated to - 100 mL and poured in EtOAc (800 mL), washed with 5% aq citric acid (2 x 200 mL) and brine. The organic layer was dried over MgSCU, filtered and concentrated to yield the title compound ( 10.0 g, 39.5 mmol, 40 % yield). NMR (400 MHz, chloroform- ) delta ppm 3.78 (t, J=5.70 Hz, 2 H), 3.56 (t, J=6.46 Hz, 2 H), 2.07 (t, J=5.83 Hz, 2 H), 0.94 (s, 9 H), 0.1 1 (s, 6 H). |
40% | With 1H-imidazole; In dichloromethane; at 20℃; for 3h; | To 1H-imidazole (13.4 g, 197 mmol) in DCM (100 mL) was added 3-bromopropan-1-ol (13.7 g, 99 mmol) followed slowly by tertbutylchlorodimethylsilane (17.8 g, 118 mmol) in DCM (20 ml). After 3 hr at RT, the reaction was concentrated to ?100 mL and poured in EtOAc (800 mL), washed with 5% aq citric acid (2 x 200 mL) and brine. The organic layer was dried over Mg504, filtered and concentrated to yield the title compound (10.0 g, 39.5 mmol,40 % yield). 1H NMR (400 MHz, chloroform-a) 3 ppm 3.78 (t, 3=5.70 Hz, 2 H), 3.56 (t, J=6.46 Hz, 2 H), 2.07 (t, J=5.83 Hz, 2 H), 0.94 (s, 9 H), 0.11 (s, 6 H). |
40% | With 1H-imidazole; In dichloromethane; at 20℃; for 3h; | To 1H-imidazole (13.4 g, 197 mmol) in DCM (100 mL) was added 3-bromopropan- 1-ol (13.7 g, 99 mmol) followed slowly by tert-butylchlorodimethylsilane (17.8 g, 118 mmol) in DCM (20 ml). After 3 h at room termperature, the reaction was concentrated to ~100 mL and poured in EtOAc (800 mL), washed with 5% aq citric acid (2 x 200 mL) and brine. The organic layer was dried over MgSO4, filtered and concentrated to yield the title compound (10.0 g, 39.5 mmol, 40% yield).1H NMR (400 MHz, chloroform-d) ^ ppm 3.78 (t, J=5.70 Hz, 2 H), 3.56 (t, J=6.46 Hz, 2 H), 2.07 (t, J=5.83 Hz, 2 H), 0.94 (s, 9 H), 0.11 (s, 6 H). |
28% | With 1H-2,2,4-triazole; In N,N-dimethyl-formamide; at 25℃; for 12h;Inert atmosphere; | Into a 500 ml round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N,N-dimethylformamide (300 ml), 3-bromopropan-1-ol (30 g, 215.84 mmol, 1.21 equiv.), tert-butyl(chloro)dimethylsilane (26.8 g, 177.81 mmol, 1.00 equiv.), 4H- imidazole (36.4 g, 534.69 mmol, 3.01 equiv.). The resulting solution was stirred for 12 h at25 C. The resulting solution was diluted with 500 ml of ethyl acetate. The resulting mixture was washed with 3x500 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate. This resulted in 12.4 g of the title compound as colorless oil (28%). ?H NMR (300 MHz, CDC13) & 3.76-3.73 (m, 2H), 3.67-3.62 (m, 1H), 3.51 (t, 1=6.6Hz, 1H), 2.07-1.9 1 (m, 2H), 0.87 (s, 9H), 0.07 (s, 6H). |
2.03 g (80%) | In 1H-imidazole; | (b) 3-Bromo-1-(tert.-butyldimethylsilyloxy)-propane (12). 1.4 g (1 mmol) 3-bromo-1-propanol was dissolved in 5 ml of anhydrous dimethyl formaide and 3.0 g of imidazole, followed by 3.3 g of tert.-butyldimethylsilyl chloride was added at 0 C. with stirring. The mixture was stirred at room temperature for 2 h. Ether was added, and the ether phase washed with water and brine, dried over anh. MgSO4, filtered and evaporated. The residue was passed through a small silica gel column and eluted with hexane to give 2.03 g (80%) pure 12. 1 H NMR (CDCl3, 500 MHz) delta 0.06 (6 H,s, SiMe2), 0.90 (9H, s, Si-t-Bu), 2.03 (2H, ~quint., J~6 Hz, C-CH2 -C), 3.51 (2H, t, J=6.2 Hz, CH2 -O), 3.73 (2H, t, J=5.8 Hz, CH2 -Br). |
With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h; | Separately, 7.0 g (corresponding to 50.4 mmol) of 2-bromopropanol and 6.86 g (corresponding to 101 mmol) of imidazole were dissolved in 50 mL of dimethylformamide, and cooled to 0C. Then, 7.59 g (corresponding to 50.4 mmol) of t-butyldimethylchlorosilane was added thereto. After the reaction mixture was stirred at room temperature for 24 hours, it was supplemented with a saturated sodium chloride solution, and extracted three times with diethyl ether. The combined diethyl ether layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by vacuum distillation (100C, 70 mmHg), to obtain 7.23 g (corresponding to 30.2 mmol) of 1-bromo-3-(t-butyldimethylsiloxy)propane (Fig. 2-10, Step 3). | |
With 1H-imidazole; In dichloromethane; | A flask was charged with 3-bromopropan-1-ol (3.25 mL, 36.0 mmol), 1H-imidazole (4.90 g, 71.9 mmol) and tert-butylchlorodimethylsilane (5.69 g, 37.8 mmol). DCM (100 mL) was added and the reaction was stirred overnight. Water and EtOAc were added to the reaction mixture. The EtOAc layer was dried, and then concentrated in vacuo and purified by silica gel to give the title compound. | |
16.2 g | With 1H-imidazole; In dichloromethane; at 20℃; for 72h; | 3-Bromo-1-propanol (6.5 mL, 71.9 mmol) was dissolved in methylene chloride (250 mL) and imidazole (7.84 g, 115.0 mmol) was added at room temperature and completely dissolved. Tert-butyldimethylsilyl chloride (13.0 g, 86.3 mmol) was added and the mixture was stirred at room temperature for 3 days. The reaction solution was filtered and then concentrated under reduced pressure. The residue was added with diethyl ether (300 mL), washed sequentially with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride solution and dried over anhydrous magnesium sulphate. Following filtration, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane) to obtain the titled compound (16.2 g, 64.0 mmol). 1H-NMR(600MHz,CDCl3)delta(ppm):0.08(s,6H),0.91(s,9H),2.05(quin,J=6.05Hz,2H),3.53(t,J=6 .42Hz,2H),3.75(t,J=5.69Hz,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In benzene; for 72h;Reflux; Inert atmosphere; | (3-bromoprop-oxy)(tert-butyl)dimethylsilane (6.23 g, 24.59 mmol) was diluted in dry benzene (17.6 mL). Triphenylphosphine (7.09 g, 27.05 mmol) was then added. The reaction was fitted with a water condenser and brought to reflux for 72 hours. It was then concentrated to give a hygroscopic foam, which was dried under high vacuum for three days using the apparatus shown in Figure S.1). This cleanly provided 12.6 g (quant.) of 10 as a white solid. Data are: 1H NMR (CDCl3, 500 MHz) delta 7.82-7.79 (m, 9H), 7.72-7.69 (m, 6H), 3.83 (bs, 2H), 3.76-3.71 (m, 2H), 1.89 (d, J=2.5 Hz, 2H), 0.83 (s, 9H), 0.01 (s, 6H); 13C NMR (CDCl3, 125 MHz) delta 135.0, 133.4, 133.3, 130.4, 130.3, 118.4, 117.7, 61.6 (d, J=8.31 Hz), 25.7, 18.97 (d, J=26.25 Hz), 17.9, -5.5. HRMS found 435.2273 [M]+, calcd 435.2268 for [C27H36OPSi]+. |
76% | In toluene; for 16h;Inert atmosphere; Schlenk technique; Reflux; | Commercially available <strong>[89031-84-5](3-bromopropoxy)-tert-butyldimethylsilane</strong> (1.09 g, 4.32 mmol, 1.00 eq.)and PPh3 (1.25 g, 4.75 mmol, 1.10 eq.) in toluene (5.0 mL) were heated to reflux for 16 h. The reactionmixture was cooled to rt and extracted with Et2O (3x 25 mL). The solvent was removed in vacuoto give a white, cloudy liquid. This liquid was purified by column chromatography on silica usingpure dichloromethane as eluent until all excess PPh3 was eluted and there was 7% MeOH in CH2Cl2.The purified product was concentrated in vacuo to aord the title compound as a white solid in 76%yield (1.70 g). All spectroscopic and physical data were in agreement with those reported in theliterature [38]. 1H NMR (400 MHz, CDCl3)delta 7.89-7.75 (m, 9H), 7.74-7.64 (m, 6H), 3.96-3.80 (m, 4H),1.97-1.83 (m, 2H), 0.85 (s, 9H), 0.03 (s, 6H); 13C NMR (101 MHz, CDCl3) delta135.1 (d, 40 JCP = 3.0 Hz),133.9 (d, 30 JCP = 9.9 Hz), 130.6 (d, 20 JCP = 12.5 Hz), 118.6 (d, 10 JCP = 86.1 Hz), 61.9 (d, 3JCP = 16.9 Hz),26.2 (d, 2JCP = 4.1 Hz), 26.1 (3C), 19.1 (d, 1JCP = 52.6 Hz), 18.3, 5.2 (2C); thin layer chromatography(TLC) (MeOH/CH2Cl2 1:20, KMnO4 stain) Rf = 0.18; Mp: 137-139 C. |
69% | In benzene; at 85℃; for 18h; | To a solution of 1-bromo-3-[(tert-butyldimethylsilyl) oxy] propane (2.18 g, 8. 56 mmol) in anhydrous benzene (1.6 mL) was added triphenylphoshine (2.64 g, 10.2 mmol) under argon with stirring. The mixture was heated at 85 C for 18 h and cooled to room temperature. The liquid was decanted and the solid residue was grounded with spatula, filtered and washed several times with ether. Colorless crystals of phosphonium salt B (3.7 g) were purified by silica column chromatography. Pure salt B (3.04 g, 69%) was eluted with CHLOROFORM/METHANOL (96: 4). B : 1H NMR (500 MHz, CDC13) 8 0.039 (6H, s, 2 x SICH3), 0.857 (9H, s, Si-t-Bu), 1.93 (2H, m, CH2-CH2- CH2), 3. 86-3. 94 (4H, br m, CH2-CH2-O and P-CH2),. 7.70, 7.79 and 7.85 (6H, 3H and 6H, each M, AR-H). |
69% | In benzene; at 85℃; for 18h; | To a solution of 1-bromo-3-[(tert-butyldimethylsilyl)oxy]propane (2.18 g, 8.56 mmol) in anhydrous benzene (1.6 mL) was added triphenylphosphine (2.64 g, 10.2 mmol) under argon with stirring. The mixture was heated at 85 C. for 18 hours and cooled to room temperature. The liquid was decanted and the solid residue was grounded with spatula, filtered, and washed several times with ether. Colorless crystals of phosphonium salt B (3.7 g) were purified by silica column chromatography. Pure salt B (3.04 g, 69%) was eluted with chloroform/methanol (96:4). B: 1H NMR (500 MHz, CDCl3) delta0.039 (6H, s, 2×SiCH3), 0.857 (9H, s, Si-t-Bu), 1.93 (2H, m, CH2-CH2-CH2), 3.86-3.94 (4H, br m, CH2-CH2-O and P-CH2), 7.70, 7.79 and 7.85 (6H, 3H and 6H, each m, Ar-H). |
24% | In toluene; at 100℃; for 16h; | A mixture of (3-bromopropoxyl)-(tert-butyl)dimethylsilane (3.0 g, 11.85 mmol) and triphenylphosphine (4.97 g, 18.96 mmol) in anhydrous toluene (25 mL) was stirred at 100C for 16 hr then cooled to r.t. over a period of 25 min and filtered. The solid was washed with PE and EtOAc then dried under high vacuum to give the desired product (1.5 g, 24% yield) as white solid. LC-MS: m/z 435 (M)+. |
In toluene; at 105℃; for 18h; | To 3-(tert-butyldimethylsilanyloxy)propyl-1-bromide is converted to the triphenyl phosphonium salt according to literature precedent (Tetrahedron Letters 1997, 38(20), 3647-3650). To the bromide (25 g, 95 mmol) in toluene (200 mL) is added triphenylphosphine (40 g, 158 mmol). The reaction mixture is stirred at 105 C. for 18 h. The mixture is then allowed to cool to room temperature over the course of an hour. The white solid is filtered off, washed with hexane (50 mL), then washed with ethyl acetate, and dried under vacuum for 24 h. | |
In acetonitrile; for 96h;Heating / reflux; | (i) Production of (3-[tert- butyl (dimethyl) silyl] oxyjpropyl) ( triphenyl ) phosphonium bromide(3-Bromopropoxy) -tert-butyldimethylsilane (3.00 g) was dissolved in acetonitrile (15 mL) .Triphenylphosphine (3.26 g) was added to the solution, and the mixture was stirred for 4 days while heating under reflux. The reaction mixture was concentrated <n="352"/>under reduced pressure. The residue was dissolved in methanol, and extracted with hexane to remove excess triphenylphosphine . The methanol layer was concentrated under reduced pressure, and the precipitate was collected by filtration to give the title compound (5.89 g) as colorless crystals. 1H-NMR (CDCl3) delta: 0.04 (6H, s), 0.86 (9H, s), 1.81-2.01 (2H, m) , 3.79-4.03 (4H, m) , 7.53-8.02 (15H, m) | |
7.69 g | In benzene; at 90℃; | A flask was charged with (3-bromopropoxy)(tert- butyl)dimethylsilane (Example 16.1, 6.40 g, 25.3 mmol) which was azeotroped with toluene. Triphenylphosphine (4.51 mL, 19.44 mmol) was added and the flask was flushed with nitrogen. Benzene (5 mL) was added and the reaction was heated at 90 C overnight. After overnight refluxing and upon cooling, a solid precipitated. The reaction mixture was diluted with hexanes and filtered to yield the title product (7.69 g) as a white solid which was directly used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium iodide In acetone at 60℃; for 0.333333h; Inert atmosphere; | |
With sodium iodide In acetone for 1.5h; Heating; Yield given; | ||
With sodium iodide In acetone for 72h; Ambient temperature; Yield given; |
With sodium iodide In acetone for 7h; Heating; | ||
With sodium iodide In hexane; acetone | 280.a Step 280a. Step 280a. 3-(t-butyldimethylsilyloxy)-1-iodopropane A mixture of 44.28 g (175 mmol) sample of 1-bromo-3-(t-butyldimethylsilyloxy)-propane (prepared according to Wilson and Zucker, J. Org. Chem, 33:2571 (1988)) and 100 g of NaI in 200 mL of acetone was heated at reflux for 20 hours, filtered and concentrated. The residue was dissolved in hexane, re-filtered and concentrated. The residue was distilled in a kugelrohr apparatus (0.2-0.3 mm Hg, 60° C.) to give 46.87 g of the title product. This material was distilled under reduced pressure, and the pure product coming over at 53°-57° C. and 0.3 mm Hg was collected. MS: 301 (M+H)+. 1 H NMR (CDCl3) δ: 0.70 (s, 6H), 0.90 (s, 9H), 1.99 (m, 2H), 3.28 (t, 2H, J=7 Hz), 3.66 (t, 2H, J=6 Hz). | |
With sodium iodide In acetone Heating; | ||
52.8 g | With sodium iodide In acetone for 2h; Reflux; | |
With sodium iodide In acetone at 60℃; for 0.5h; | 1 Preparation of Compound 1-E To a solution of (3-bromopropoxy)(tert-butyl)dimethylsilane (10 g, 39.49 mmol, 1.0 eq) in acetone (30 mL, dried over MgS04) was added Nal (14.80 g, 98.72 mmol, 2.5 eq.). The reaction was heated at 60 °C for 30 minutes. The solution was then diluted with petroleum ether (200 mL) and the solid was removed by filtration. The filtrate was concentrated to give the desired product 1-E as yellow oil, which was used for the next step directly without further purification (12.0 g, crude).^NMR: (400 MHz, CDC13) δ: 3.70 - 3.64 (m, 2 H), 3.29 (t, = 6.6 Hz, 2 H), 2.00 (quin, = 6.0 Hz, 2 H), 0.90 (s, 9 H), 0.08 (s, 6 H). | |
With sodium iodide In acetone at 20℃; for 12h; | 38 To a solution of sodium iodide (42.3 g) in acetone (200 mL) was added(3-bromopropoxy)(tert-butyl)dimethylsilane (10.9 g) at room temperature. The mixture was stirred for 12 hrs (the colorless solution changed to a pale yellow suspention). The white precipitate was filtered off, and the filtrate was concentrated. To the residue was added water and the mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt = 100 / 0 to 95 / 5) to give tert-butyl(3-iodopropoxy)dimethylsilane (12.9 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 3,4-dihydro-2(1H)-quinolone With lithium diisopropyl amide In tetrahydrofuran Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In tetrahydrofuran | |
90% | Stage #1: 3,4-dihydro-2(1H)-quinolone With lithium diisopropyl amide In tetrahydrofuran at -78 - 20℃; for 1.5h; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In tetrahydrofuran at -78 - 20℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: 2-hydroxy-4-nitro-benzoic acid methyl ester With potassium carbonate In N,N-dimethyl-formamide at 20℃; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In N,N-dimethyl-formamide at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In N,N-dimethyl-formamide; | Step 1 To a solution of <strong>[879-37-8]indole-3-acetamide</strong> (2.0 g, 11.5 mmol) in DMF (20 mL) was added sodium hydride (964 mg, 24.1 mmol) at 0C under an argon atmosphere and the mixture was stirred. After 15 minutes, 1-bromo-3-(tert-butyldimethylsilyloxy)propane (3.05 g, 12.1 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent:hexane/ethyl acetate=2/1) to give 1-[3-(tert-butyldimethylsilyloxy)propyl]-1H-indol-3-ylacetamide as a colorless wax (3.39 g, 85% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 70℃; for 3h; | A mixture of Compound 2BA (1.00 g, [3. 30] mmol; prepared as described in Lohse, [O.] Synth. Commun. 1996,26, 2017), DPPA (1. [36] g, 4.95 mmol) and triethylamine (1.4 mL, 10 mmol) in [T-BUOH] (5.5 mL) and toluene (5 mL) was heated at 65 [C] for 1.5 h, then warmed to [100 C] for 4 h. After concentration, the mixture was purified by flash chromatography (EtOAc/hexane) to give Compound 2BB (515 mg, 50%) as a white [SOLID.'H] NMR (300 MHz, [CDC13)] [8] 9.17 (brs, 1H), 8.48 (s, 1H), 7.98 (dd, J= 5.2, 1.5 Hz, 1H), 7.34 (dd, J= 5.2, 1.3 Hz, 1H), 1.56 (s, 9H); MS (ES) m/z: 343 (M+Na). A mixture of Compound 2BB (330 mg, 1.03 mmol), (3-bromopropoxy)-tert- butyldimethylsilane (340 mg, 1.34 mmol) and [CS2CO3] (504 mg, 1.55 mmol) in dry DMF (4 mL) was stirred at [70 C] for 3 h. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (EtOAc/hexane) to provide Compound 2BC (450 mg, 89%) as clear [OIL. 1H] NMR (400 MHz, CDC13) [8] 8.11 (s, [1H),] 8.00 (d, [J=] 5.2 Hz, [1H),] 7. 33 (dd, [J=] 5.2, 1.3 Hz, [1H),] 3.99 (t, [J=] 7.3 Hz, 2H), 3.65 (t, J= 6.3 Hz, 2H), 1.84 [(M,] 2H), 1.52 (s, 9H), 0.87 (s, 9H), 0.02 (s, 6H); MS (ES) m/z: 515 (M+Na). A mixture of Compound 2BC (650 mg, 1.32 mmol), bis (trimethyltin) [(870] mg, 2.66 mmol), tetrakis (triphenylphosphine) palladium (150 mg, 0. [130] mmol), LiCl (170 mg, 4.00 mmol) and 2, [6-DI-TERT-BUTYL-4-METHYLPHENOL] (12 mg, 0.054 mmol) in anhydrous 1,4-dioxane (12 mL) was heated at [90 C FOR] 1.5 h under nitrogen. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (EtOAc/hexane) to give Compound 2BD (590 mg, 84%) as clear [OIL. 1H] NMR (300 MHz, [CDC13)] [6] 8.09 (d, J= 4.7 Hz, [1H),] 7.56 (s, 1H), 7.10 (d, [J=] 4.7 Hz, 1H), 3.97 (t, [J=] 7.2 Hz, 2H), 3.64 (t, [J=] 6.5 Hz, 2H), 1.85 [(M,] 2H), 1.49 (s, 9H), 0.86 (s, 9H), 0.33 (s, 9H), 0.00 (s, 6H); MS (ES) m/z: 527 (M-H+). Anal. Calcd. For [C22H42N203SISN] : C, 49.92 ; H, 8.00 ; N, 5.29. Found: C, 50.32 ; H, 7.88 ; N, 5.20. A mixture of Compound 1C (590 mg, 1.73 mmol), Pd2 (dba) 3 (160 mg, 0.175 mmol), [ASPH3] (424 mg, [1. 39] mmol) and 2, [6-DI-TERT-BUTYL-4-METHYLPHENOL] (24 mg, 0.11 mmol) was degassed under high vacuum and then filled with N2. This process was repeated three times. Toluene (20 [ML)] was added and the mixture was stirred at 20 [C] for about 30 min. A solution of Compound 2BD (915 mg, 1.73 mmol) in toluene (20 mL) was added and the mixture was heated at [100 C FOR] 3.5 h. After removal of solvent, the residue was purified by flash chromatography (EtOAc/hexane) to give Compound 2BE [(895] mg, 77%) as clear [OIL. 1H] NMR (300 MHz, [CDCL3)] [8] 9.05 (s, [1H),] 8.51 (s, [1H),] 8. [48] (d, [J=] 5.1 Hz, [1H),] 7.80 (dd, [J=] 5.2, 1.4 Hz, [1H),] 7.41-7. [39 (M,] [2H),] 7.28-7. 27 [(M,] 1H), 7.16 [(M,] 1H), 4.05 (t, J= 7.3 Hz, 2H), 3.66 (t, J= 6.3 Hz, 2H), 1.87 [(M,] 2H), 1.51 (s, 9H), 1.50 (s, 9H), 0.86 (s, 9H), 0.01 (s, 6H); MS (ES) m/z: 670 (M+H+). CF3COOH (10 mL) was added to a solution of Compound 2BE (1.74 g, 2.59 mmol) in [CH2CL2] (10 mL). After the mixture was stirred at [20 C FOR] 2 h, it was concentrated. Saturated ammonium hydroxide was added to the residue until the pH of the mixture was greater than 7. The precipitated solid was collected through filtration and washed with ice water. The crude product was purified by recrystallization from EtOAc to give Compound 2 (750 mg, [81%)] as a yellow [SOLID. 1H NMR] (300 MHz, [DMSO-D6)] [8] 10.59 (s, [1H), 8.] 92 (s, [1H),] 8.15 (d, J= 6.5 Hz, [1H),] 7.97 (s, [1H),] 7.75 (brs, 1H), 7.43 [(M,] 2H), 7. [30] (d, [J=] 6.5 Hz, [1H),] 7.16 (d, [J=] 6.5 Hz, [1H),] 6.96 (brs, [1H),] 4.52 (brs, [1H),] 3.50 (t, J= 6.3 Hz, [2H),] 3.30 [(M,] 2H), 1.74 [(M,] 2H); MS (ES) m/z: 357 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 70℃; for 23h; | 3-Chloroaniline (29.4 g, 229 mmol) was dissolved in THF (250 mL) at [20 C.] A THF solution (80 mL) of Boc2O (50 g, 229 mmol) was added slowly to the mixture of 3-chloroaniline and THF. The resulting mixture was stirred for 3 days and then concentrated. The crude product was purified by recrystallization from EtOAc/Hexane three times to give Compound 1A (40.4 g, 78%) as a white [SOLID. IH] NMR (300 MHz, [CDCL3)] [5] 7.52 (s, 1H), 7.17 [(M,] 2H), 7.00 (dt, J= 7.4, 1.8 Hz, 1H), 6.49 (s, 1H), 1.52 (s, 9H); MS (ES) [M/Z] : 250 (M+Na). Anal. Calcd. For [CLLHL4NO2CL] : C, 58.03 ; H, 6. 20 ; N, 6.15. Found: C, 58. 14; H, 6.22 ; N, 6.10. THF (150 mL) was added to a mixture of Compound [1A] (5.5 g, 24.2 mmol) and NaH (60% in mineral oil, 2.4 g, 60.6 mmol) at 0 [C] under N2. The mixture was stirred at [20 C] for 1 h and then cooled to [0 C] and Compound 1B (6.2 g, 41.2 mmol; prepared as described in Harris, R. L. N. Synthesis 1981,907) was added. After the mixture was stirred at [20 C] overnight, the solvent was evaporated and the residue was purified by flash chromatography (10% EtOAc in hexanes) to give Compound 1C (4.3 g, 52%) as a white solids NMR (300 MHz, [CDC13)] 8 8.72 (s, 1H), 7.40 (m, 2H), 7.22 (brs, 1H), 7.11 [(M,] [1H),] 1.48 (s, 9H); MS (ES) m/z: 363 (M+Na). Anal. Calcd. For [C14HL4N402CL2] : C, 49.28 ; H, 4.14 ; N, 16.42. Found: C, 49. 52 ; H, 4.13 ; N, 16.41. A mixture of 5-bromonicotinic acid Compound 1D (10 g, 49.5 mmol), [T-BUOH] (100 [ML),] triethylamine (15.2 g, [150] mmol) and DPPA (20.4 g, 74 mmol) in toluene (100 mL) was stirred at [65 C] for 40 min and then warmed to [100 C FOR] 22 h under nitrogen. The mixture was cooled and concentrated under vacuum. The crude product was purified by column chromatography on [SI02] eluting with ethyl acetate/hexane to give Compound [1E] (10.52 g, 78%) as a white [SOLID. LH NMR (300 MHZ, CDCL3) 6 8.] 32 (m, 3H), 6.97 (brs, 1H), 1.53 (s, 9H); MS (ES) [M/Z] : 273,275 [(M+H+).] Anal. Calcd. For [CLOHI3N202BR] : C, 43.98 ; H, 4.80 ; N, 10.26. Found: C, 43. 88 ; H, 4.52 ; N, 10.20. A mixture of Compound [1E] (2.85 g, 10.44 mmol), (3-bromopropoxy)-t- butyldimethylsilane (3.96 g, 15.66 mmol) and [CS2CO3] (10.21 g, 31.3 mmol) in anhydrous DMF (55 mL) was stirred at 70 [C] for 23 h under nitrogen. The mixture was cooled, diluted with water and extracted with ether (3x). The organic phase was dried [(NA2S04)] and concentrated. The product was purified by column chromatography (eluting with EtOAc/hexane) to give Compound IF (4.2 g, 90%) as a yellow [OIL. 1H] NMR (300 MHz, [CDCL3)] [8] 8.45 (brs, 2H), 7.77 (brs, 1H), 3.73 (brt, J= 7.3 Hz, 2H), 3.62 (t, J= 5.9 Hz, 2H), 1.81 [(M,] 2H), 1.45 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H); MS (ES) m/z: 445,447 [(M+H+).] Anal. Calcd. For [CLGH33N203BRSI] : C, 51.23 ; H, 7.47 ; N, 6.29. Found: C, 51.45 ; H, 7.47 ; N, 6.53. [N-BULI] (2.3 [ML,] 2.5 M, 5.65 mmol) was added dropwise to a solution of Compound IF (1.26 g, 2.82 mmol) in anhydrous THF (10 mL) at-78 C and the mixture was stirred for 20 min. Anhydrous zinc chloride (8.47 mL, 1 M in ether, 8.47 mmol) was added dropwise to the THF solution containing Compound IF at-78 [C] and stirred for 10 min before it was warmed to [20 C] by removing the dry-ice bath. A mixture of Compound 1C (640 mg, 1.88 mmol) and [PD (PPH3)] 4 (109 [MG,] 0.094 mmol) in dry THF (8 mL) was added. The resulting mixture was stirred at 20 [C] for 10 min, then at 70 [C] for 22 h and the solvent was removed under vacuum. The residue was partitioned between water and ether and then separated. The aqueous layer was extracted with ether (3x). The combined organic layers were dried [(NA2SO4)] and concentrated. The product (a mixture of bis-Boc-and mono-Boc-protected coupling products) was purified by column chromatography to give 458 mg of yellow foam. The yellow foam was mixed with TFA (5 mL) and the mixture was stirred at [20 C] for 2 h and then concentrated. NH40H was added, followed by water addition until the pH of the aqueous layer reached about 10-11. A yellow solid was formed, collected through filtration and then dried under vacuum. The product was purified by column chromatography to give Compound 1 (208 mg, 73%) as a yellow [SOLID. 1H] NMR (300 MHz, DMSO-d6) 6 10.55 (s, [1H),] 8.89 (s, [1H),] 8.18 (brs, [1H),] 8.06 (s, [1H),] 7.76 (s, 1H), 7.71 (d, [J=] 8.0 Hz, 1H), 7.41 (t, [J= 8. 0 HZ, 1H),] 7.15 (d, [V= 7. 9 HZ, 1H),] 6.19 (brs, 1H), 4.54 (t, [J= 5. 0 HZ,] 1H), 3.55 [(M,] 2H), 3.18 [(M,] 2H), 1.80 [(M,] 2H); MS (ES) [M/Z] : 357 [(M+H+).] Anal. Calcd. For C17H17N6OCl30. 35 [H20] : C, 56.23 ; H, 4.91 ; N, 23.14. Found: C, 56.63 ; H, 4.78 ; N, 22.76. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 2.5h; | A mixture of Compound 3A (220 mg, 1.39 mmol; prepared as described in Sato, N. J. Heterocyc. Chem. 1994,31, 1177), DPPA (575 mg, 2.09 mmol) and triethylamine (0. [39] [ML,] 2. 80 mmol) in [T-BUOH] (3 mL) and toluene (2 mL) was heated at [65 C] for 1.5 h, then at [85 C] for 2 h. After concentration, the mixture was purified by flash chromatography (EtOAc/hexane) to give Compound 3B (180 mg, 57%) as a white [SOLID. 1H NMR] (300 MHz, CDC13) 8 [9. 19 (S,] 1H), 8.26 (s, 1H), 7.17 (brs, 1H), 1.54 (s, 9H). A mixture of Compound 3B (160 mg, 0.697 mmol), [(3-BROMOPROPOXY)-TERT-] butyldimethylsilane (220 mg, 0.870 mmol) and [CS2CO3] (340 mg, 1.04 mmol) in dry DMF (2 mL) was stirred at [60 C] for 2.5 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (EtOAc/hexane) to provide Compound 3C (262 mg, 94%) as clear [OIL. LH NMR (300 MHZ, CDC13) 6 9.] 01 (s, 1H), 8.20 (s, 1H), 4.00 (t, J= 7.4 Hz, 2H), 3. 68 (t, J= [6.] 2 Hz, 2H), 1.87 [(M,] 2H), 1.54 (s, 9H), 0.87 (s, 9H), 0.03 (s, 6H). A mixture of Compound 3C (123 mg, 0.306 mmol), bis [(TRIMETHYLTIN)] (200 mg, 0.611 mmol), tetrakis (triphenylphosphine) palladium (35 mg, 0.030 mmol), LiCl (40 mg, 0.94 mmol) and 2, 6-di-tert-butyl-4-methylphenol (3 mg, 0.014 mmol) in anhydrous 1,4- dioxane (2 [ML)] was refluxed for 4 h under nitrogen. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (EtOAc/hexane) to give Compound 3D (154 mg, 95%) as clear [OIL. 1H NMR] (300 MHz, CDC13) 8 8.79 (s, 1H), 8.21 (s, [1H),] 4.01 (t, J= 7.2 Hz, 2H), 3.67 (t, J= 6.0 Hz, 2H), 1.90 [(M,] 2H), 1.53 (s, 9H), 0. 87 (s, 9H), 0.36 (s, 9H), 0.02 (s, 6H); MS (ES) m/z : 531 (M+H). A mixture of Compound 3D (73 mg, 0.14 [MMOL),] Compound 1C (52 mg, 0.15 mmol), dichlorobis (triphenylphosphine) palladium (15 mg, 0.021 mmol) and LiCl (18 mg, 0.42 mmol) in anhydrous toluene (3 mL) was stirred at [100 C] overnight under nitrogen. The mixture was cooled, concentrated under vacuum and purified by flash chromatography (EtOAc/hexane) to give the coupled product as yellow oil. TFA (1 mL) was added and the mixture was stirred at [20 C] for 4 h. After it was concentrated, saturated NH40H solution and water were added until the mixture turned basic. After the precipitated solid was collected through filtration, it was washed with water and [ET20] and dried under vacuum to provide Compound 3 (1.5 mg, 47%) as a yellow solid. [H NMR] (300 MHz, DMSO-d6) [6] 10.59 (s, 1H), 8.91 (s, 1H), 8.63 (s, 1H), 8.20 (brs, 1H), 8.12 (s, 1H), 7.80 (brs, 1H), 7.39 (t, J= 8.2 Hz, 1H), 7.34 (brs, 1H), 7.13 [(D,] [J=] 7.8 Hz, 1H), 4.60 [(M,] 1H), 3.50 [(M,] 2H), 3.32 [(M,] 2H), 1.76 (t, J= 6.4 Hz, [2H) ;] MS (ES) m/z: 358 [(M+H.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 68℃; for 3h; | Compound 10b (5 g, 28.6 MMOL) was combined with a silyl-protected 3-bromo- 1-propanol Compound 10c (8.33 g, 32.9 MMOL) in the presence OF CS2CO3 (12.11 g, 37 MMOL) in DMF (50 mL) at 68 C for 3 h. The mixture was cooled to rt, water was added and then the mixture was extracted with EtOAc several times. The organic layers were combined and washed with brine, then dried (NA2SO4) and evaporated in vacuo to provide an oil. The oil was purified by flash column chromatography (95: 5: 0.5 ; DCM: MeOH: NH4OH) to give an amide Compound 10D (9.9 g, 100%). H NMR (CDCI3) 8 7.65 (m, 1 H), 7.38 (m, 2H), 7.13 (m, 1H), 6.53 (bd s, 1H), 5.44 (bd s, 1H), 4.44 (t, J = 6.82 Hz, 2H), 3.93 (s, 2H), 3.56 (t, J = 5.73 Hz, 2H), 2.08 (m, 2H), 0.89 (s, 9H), 0.01 (s, 6H). ES-MS m/z 348 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With N-ethyl-N,N-diisopropylamine; sodium iodide In N,N-dimethyl-formamide at 20 - 50℃; | 12 PREPARATIVE EXAMPLE 12 (4S)-I -(3 -Hydroxypropyl)azepan-4-arninium trifluoroacetate. To a solution of tert-Butyl (4S)-azepan-4-ylcarbamate 0028 (108 mg, 0.504 mmol) in anhydrous dimethylformamide (1.5 mL) was added (3-bromopropoxy)-tert- butyldimethylsilane (0.117 mL, 0.504 mmol) and Hunig's Base (0.176 mL, 1.008 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature overnight. LC-MS still showed the presence of starting material so a catalytic amount of sodium iodide was added and the reaction mixture was heated to 50°C and stirred at 50°C overnight. The reaction was partitioned between ethyl acetate and 5% sodium thiosulfate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum to give a yellow oil. The crude intermediate was purified by plate chrom. (1000 micron; 10% methanol/dichloromethane; iodine stain) to afford the intermediate (tert-butyl [(4S)-l-(3-[tert- butyl(dimethyl)silyl]oxy}propyl)azepan-4-yl]carbamate) as a yellow oil (94.4 mg, 48%). This material was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature over the weekend then concentrated under vacuum to afford the crude title compound as a pale orange oil (38 mg, 26%) which was azeotroped from toluene and used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In isopropyl alcohol; for 21h;Heating / reflux; | Example 3: Methyl 4-(2-chlorophenyl)-5-(methoxycarbonyl)-2-methyl-6-[3-(2-oxo (6- hydroquinolyloxy) ) propoxy] [METHYL}-1,] 4-dihydropyridine-3-carboxylate (Compound 7) was synthesized according to Scheme III. SCHEME III [6-R3- (1, 1, 2, 2-TETRAMELHYL-L-SILGPROPOXY) PROPOXYLHYDROQUINOLIN-2-ONE] : (3- [BROMOPROPXYL)-TERT-BUTYLDIMETHYLSILANE] (1.63 g, 1.50 mL, 6.5 mmol) was added drop- wise into a mixture of 6-hydroxyhydroquinolin-2-one (1.04 g, 6.5 mmol), DBU (1.73 g, 1.70 mL, 11.38 mmol) in isopropanol (20 mL). The mixture was refluxed for 21 hours and cooled to room temperature and evaporated to remove the solvent. The residue was extracted with ethyl acetate (EtOAc; 150 mL) and the extracts were washed with water, dried over [NA2S04,] and filtered. The filtrate was concentrated to give the product as an off-white solid (1.6 g, [76%), 1H NMR] (400 MHz; CDC13) : [8] 7.48 [(M,] 1H); 7.36 (d, 1H); 6.79 [(M,] [1H)] ; 6.63 [(M,] [1H)] ; 6.57 (d, [1H)] ; 3.94 [(M,] 2H); 3.79 [(M,] 2H); 1.90 [(M,] 2H); 1.00- 0.08 (overlapping singlets, 15H total). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 90℃; for 1h; | Cesium carbonate (53.48 g, 164.15 mmol) and (3-Bromopropoxy)-tert-butyldimethylsilane (38.14 mL, 164.15 mmol) were added to a DMF solution (100 mL) of a (1H-Pyrrolo[2,3-b]pyridin-3-yl)-acetonitrile Compound 14a (8.6 g, 54.7 mmol; prepared as described in Robison, J. Amer. Chem. Soc., 78, 1956, 1247-1249) and the resulting mixture was stirred at 90 C. After 1 hour the reaction mixture was allowed to cool to 23 C. then filtered through celite, diluted with EtOAc (100 mL) and washed with water (5?100 mL). The organic layer was then dried (MgSO4) and concentrated. The product was purified by column chromatography (SiO2) to give Compound 14b (16.465 g, 92%) as a pale oil. 1H NMR (300 MHz, CDCl3) ? 8.36 (dd, J=4.5, 1.3 Hz, 1H), 7.91 (dd, J=7.9, 1.5 Hz, 1H), 7.28 (s, 1H), 7.11 (dd, J=7.9, 4.7 Hz, 1H), 4.38 (t, J=6.8 Hz, 2H), 3.82 (s, 2H), 3.60 (t, J=5.8 Hz, 2H), 2.06 (m, 2H), 0.93 (s, 9H), 0.05 (s, 6H); MS (ES) m/z: 330 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In acetone for 5h; Heating / reflux; | 5 1- (PHENYLMETHOXY)-2- [3- (1, 1, 2, 2-TETRAMETHYL-1-SILAPROPOXY) PROPOXY] BENZENE. (3- BROMOPROPOXYL)-TERT-BUTYLDIMETHYLSILANE (2.18 g, 2.0 ml, 8.61 mmol) is added to a solution OF 2- (BENZYLOXY) phenol (2.15 g, 1.88 ml, 10.76 mmol) and potassium carbonate (1.48 g, 10.76 mmol) in acetone (20 ml). The resulting mixture is refluxed for 5 hours and then cooled to room temperature. The solvents are removed and the residue is dissolved in EtOAc (150 ml) and water (30 ml). The organic layers are dried over NA2S04 and filtered, and the filtrate is concentrated to give a syrup, which is purified by column chromatography with hexane-5% EtOAc/hexane to give the product (2.90 g, 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | A 50-mL round bottom flask was charged with compound 63 (0.4 g, 1.95 mmol) and compound 64 (0.6 mL, 2.3 mmol; Aldrich) in DMF (6 mL). The mixture was stirred at ambient temperature for 5 minutes, and then NaH (60 mg,60% in mineral oil) was added. The reaction mixture was heated to 7O0C for 4 hours. When the reaction was complete, the mixture was quenched with water (20 mL), transferred to an extraction funnel, and extracted with ethyl acetate (2 x 20 mL). The organic layers were combined and dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash silica column chromatography isocratically (ethyl acetate/ hexanes, 3:100) to give compound 65 as a colorless oil (0.5 g, yield 98%). | |
98% | With sodium hydride; In N,N-dimethyl-formamide; at 70℃; for 4h; | b) A 50-mL round bottom flask was charged with compound 11 (0.4 g, 1.95 mmol) and compound 12 (0.6 mL, 2.3 mmol; Aldrich) in DMF (6 mL). The mixture was stirred at ambient temperature for 5 minutes, and then NaH (60 mg, 60% in mineral oil) was added. The reaction mixture was heated to 7O0C for 4 hours. When the reaction was complete, the mixture was quenched with water (20 mL), transferred to an extraction funnel, and extracted with ethyl acetate (2 x 20 mL). The organic layers were combined and dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash silica column chromatography isocratically (ethyl acetate/ hexanes, 3:100) to give compound 13 as a colorless oil (0.5 g, yield 98%). |
98% | With sodium hydride; In N,N-dimethyl-formamide; at 20 - 70℃; for 4.08h; | b); A 50-mL round bottom flask was charged with compound 29 (0.4 g, 1.95 mmol) and compound 30 (0.6 mL, 2.3 mmol; Aldrich) in DMF (6 mL). The mixture was stirred at ambient temperature for 5 minutes, and then NaH (60 mg, 60% in mineral oil) was added. The reaction mixture was heated to 7O0C for 4 hours. When the reaction was complete, the mixture was quenched with water (20 mL), transferred to an extraction funnel, and extracted with ethyl acetate (2 x 20 mL). The organic layers were combined and dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash silica column chromatography isocratically (ethyl acetate/ hexanes, 3:100) to give compound 31 as a colorless oil (0.5 g, yield 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃; for 19h; | 94 (3-Bomopropoxy)-tert-butyldimethylsilane (17.7 mL 76.2 mmol), K2CO3 (14.0 g, 102 mmol) and n-(tert-butoxycarbonyl)-1-tyrosine methyl ester (15.0 g, 50.8 mmol) were combined in DMF (63 mL and stirred at room temperature for 12 hours and at 80° C. for 7 hours. The mixture was diluted with ether (250 mL) and brine (100 mL) was added. The mixture was passed through a coarse fritted glass funnel. The filtrate was washed with brine (3×100 mL), and the organic layer was dried over sodium sulfate and evaporated to a yellow oil. The oil was soluble in hexane, and was loaded on to a column of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (330 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide (S)-methyl 2-(tert-butoxycarbonyl)-3-(4-(3-(tert-butyldimethylsilyloxy)propoxy)phenyl)propanoate (23.6 g, 100% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.0 (s, 6H), 0.85 (s, 9H) 1.38 (s, 9H) 1.89-1.96 (m, 2H) 2.97 (s, 2H) 3.66 (s, 3H) 3.75 (t, J=5.97 Hz, 2H) 3.99 (t, J=6.26 Hz, 2H) 4.49 (m, 1H) 4.90 (m, 1H) 6.78 (d, J=8.61 Hz, 3H) 6.97 (d, J=8.41 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-fluoro-pyrrolidine dihydrochloride; 3-(tert-butyldimethylsilyloxy)propyl bromide With potassium carbonate In acetontrile at 50℃; Stage #2: With water In acetonitrile | 201.3 Step 3: 1-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-3-fluoro-pyrrolidine.; A solution of 3-Fluoro-pyrrolidine dihydrochloride salt (448 mg, 3.584 mmol) in anhydrous acetonitrile (24 mL) was treated with bromopropoxy-tert-butyldimethyl silane (0.83 mL) and then with K2CO3 (2.5 g, 5 equiv.). The reaction mixture was heated to 50° C. and stirred overnight. The reaction mixture was subsequently diluted with water (75 mL) and extracted with a 6:1 mixture of Hexane and diethyl ether (2×100 mL). The organic layer was washed with NaHCO3(aq) (100 mL) and brine (100 mL) then dried over anhydrous K2CO3. Following filtration and concentration of the filtrate in vacuo the crude product was purified by flash silica gel chromatography (MeOH:EtOAc, 1:20). By 1H NMR the resulting clear oil (0.8 g) was the desired 1-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-3-fluoro-pyrrolidine in a 10:1 ratio with the t-butyldimethylsilanol by-product. This residue was carried on without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 5-chloro-1H-indole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In N,N-dimethyl-formamide at 20℃; for 1.5h; | To a suspension of NaH (0.66 g, 22 mmol, ) in anhydrous DMF (20 mL) was added 5-chloroindole (3 g, 20 mmol) in anhydrous DMF (20 mL). The resultant mixture was stirred at room temperature under Ar for 30 min. 3- (Bromopropoxy)-tert-butyldimethylsilane (4.9 mL, 21 mmol) was then added and the reaction mixture was stirred at r. t. under Ar for 1.5 h. The reaction was quenched with H20 (100 mL) and the aqueous layer was extracted with Et20 (3 x 100 mL). The combined Et20 layers were washed with brine (3 x 100 mL), dried over anhydr. Na2S04 and concentrated to give yield (6.8 g) of the product quantitatively. The product was used in the next step without further purification.'H-NMR (CDC13) 8 7.5 (s, 1H), 7.2 (m, 3H), 6.2 (s, 1H), 4.2 (t, 2 H), 3.5 (t, 2 H), 1. 9 (m, 2 H), 0.8 (s, 9 H), 0.0 (s, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In acetonitrile; at 80℃; for 12h;Inert atmosphere; | Step A: To a solution of 4-hydroxybenzaldehyde (25 g, 205 mmol) and (3-bromopropoxy)(iert4outyl)dimethylsilane (57 g, 225 mmol) in MeCN (200 mL) was added K2C03 (85 g, 614 mmol). The reaction mixture was heated at 80 C for 12 hours. After cooling to room temperation, DCM (50 mL) was added, and the mixture was filtered over Celite. Then the filtrate was concentrated, purified by silica gel column (petroleum ether / EtOAc = 20/1) to afford 4-(3-((ter/4outyldimethylsilyl)oxy)propoxy)benzaldehyde (36 g, 60% yiled) as white solid. |
60% | With potassium carbonate; In acetonitrile; at 80℃; for 12h; | To a solution of 4-hydroxybenzaldehyde (25 g, 205 mmol) and (3-bromopropoxy)(tert-butyl)dimethylsilane (57 g, 225 mmol) in MeCN (200 mL) was added K2C03 (85 g, 614 mmol). The reaction mixture was heated at 80 C for 12 hours. After cooling to room temperature, DCM (50 mL) was added, and the mixture was filtered over Celite. Then the filtrate was concentrated, purified by silica gel column (petroleum ether / EtOAc = 20/1) to afford 4-(3-((ter£-butyldimethylsilyl)oxy)propoxy)benzaldehyde (36 g, 60% yield) as white solid. |
A flask was charged with 4-hydroxybenzaldehyde (0.96 g, 7.9 mmol) andDMF (10 mL). The resulting solution was cooled in an ice bath and treated with NaH (350 mg, 60% in mineral oil, 8.7 mmol). After 5 min, (3-Bromopropoxy)-tert- butyldimethylsilane (2.0 mL, 8.7 mmol) was added dropwise. The reaction was treated with ultrasound for 15 min, and then stirred overnight at room temp. The reaction mixture was partitioned between ethyl acetate (250 mL) and water (10OmL). The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to give the crude TBS-alcohol. The TBS-alcohol was suspended in 120 mL of a 1 :1 mixture of acetonitrile and 1 N HCl. The reaction was stirred at room temp for 1.5 h, and then the solvents were removed in vacuo. The residue was adsorbed onto celite and purified via SiO2 flash chromatography using 1 :1 hexanes:ethyl acetate to give the product alcohol (1.0 g) as a colorless oil. |
Example 933-(4-{5-[2-(2,3-Difluoro-phenyl)-imidazo[4,5-d]pyridazin-5-ylmethyl]-isoxazol-3-yl}-phenoxy)-propan-1-ol (Compound 193)A flask was charged with 4-hydroxybenzaldehyde (0.96 g, 7.9 mmol) and DMF (10 mL). The resulting solution was cooled in an ice bath and treated with NaH (350 mg, 60% in mineral oil, 8.7 mmol). After 5 min, (3-Bromopropoxy)-tert-butyldimethylsilane (2.0 mL, 8.7 mmol) was added dropwise. The reaction was treated with ultrasound for 15 min, and then stirred overnight at room temp. The reaction mixture was partitioned between ethyl acetate (250 mL) and water (100 mL). The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to give the crude TBS-alcohol. The TBS-alcohol was suspended in 120 mL of a 1:1 mixture of acetonitrile and 1 N HCl. The reaction was stirred at room temp for 1.5 h, and then the solvents were removed in vacuo. The residue was adsorbed onto celite and purified via SiO2 flash chromatography using 1:1 hexanes:ethyl acetate to give the product alcohol (1.0 g) as a colorless oil.From 2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine and 3-(4-butyl-2-trifluoromethyl-phenyl)-5-chloromethyl-isoxazole (General Procedure B, from 4-(3-Hydroxy-phenoxy)-benzaldehyde. MS 464.0 (M+H+); H1 NMR (DMSO-d6): delta (ppm) 10.08 (d, 1H), 9.47 (d, 1H), 8.13-8.18 (m, 1H), 7.76 (d, 2H), 7.51-7.60 (m, 1H), 7.31-7.38 (m, 1H), 7.12 (s, 1H), 7.02 (d, 2H), 6.14 (s, 2H), 4.56 (t, 1H), 4.07 (t, 2H), 3.55 (q, 2H), 1.86 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To dimethylformamide solution (50 ml) of 47 (5.00 g, 25.0 mmol), 60% sodium hydride (1.50 g, 37.5 mmol) was added in several portions in argon atmosphere with stirring at room temperature, and stirred for 20 min at room temperature. Then, 88 (12.65 g, 50.0 mmol) was further added, and stirred for 2 hours at room temperature. The reaction mixture was added ice chips, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate/n-hexane = 30/1), to obtain 89 (7.89 g, 85%) of oily colorless substance. APCI-MS m/z 373[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In N,N-dimethyl-formamide; at 60℃; | To a suspension of ethyl 5-oxo-2,5-dihydro-1 H-pyrazole-3-carboxylate (5.47 g, prepared with an analogous procedure to that described in Preparation 1 ) and Na2CO3 (4.46 g) in dry DMF (36 ml_), [(3-bromopropyl)oxy](1 ,1-dimethylethyl)dimethylsilane (8.52 ml.) was added drop wise and the mixture was stirred at 6O0C overnight. [(3-bromopropyl)oxy](1 ,1- dimethylethyl)dimethylsilane (0.8 mL) was added and the mixture was stirred for additional 4h. After cooling, the mixture was diluted with AcOEt, washed with chilly water and brine, dried, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography on silica column eluting with Cy/AcOEt with a gradient of Cy from 100% to 80% to give the title compound as yellow oil (5.63 g).1H NMR (CDCI3) delta: 10.53 (s, 1 H); 6.23 (s, 1 H); 4.38 (q, 2H); 4.27 (t, 2H); 3.79 (t, 2H); 2.0(m, 2H); 1.39 (t, 3H); 0.9 (s, 9H); 0.05 (s, 6H).MS (m/z): 328 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | NaH (55%) (2.14 g, 49.15 mmol) was suspended in 70 ml of dry DMF under a N2 atmosphere. <strong>[698-25-9]6-chloro-indazole</strong> (7.5 g, 49.15 mmol) was added at room temperature. The mixture was stirred for 1 hour before cooling with an ice bath and (3-bromo-propoxy)-tert-butyl-dimethyl-silane (11.4 ml, 49.15 mmol) was added dropwise. After stirring for an additional 15 minutes the mixture was allowed to reach room temperature, stirring was continued for another 8 hours. Subsequently, the mixture was concentrated in vacuo and the residue was dissolved in DCM, the organic layer was then washed with water (3*). The organic layer was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (SiO2, eluent: petroleum ether/diethyl ether 5/1? 4/1) to afford the N1 substituted indazole in 61% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | f) Methyl 4-bromo-3-(3-(tert-butyldimethylsilyloxy)propoxy)benzoateA solution of <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> (2.31 g, 10.0 mmol) in N5N- dimethylformamide (10 niL) was added dropwise to a slurry of sodium hydride (60% in mineral oil, 0.48 g, 12.0 mmol) in N,N-dimethylformamide (30 mL) at 0 0C. The reaction was stirred for 1 h and then (3-bromopropoxy)-tert-butyldimethylsilane (2.55 mL, 11.0 mmol) was added dropwise. The reaction was stirred for 3 h at room temperature, diluted with toluene and washed with diluted hydrochloric acid. The organic phase was dried over magnesium sulfate and evaporated. Purification by column chromatography using dichloromethane, as the eluent gave 46% yield of the title compound. 1H NMR (DMSO-dbeta) delta ppm 7.74 (d, 1 H) 7.53 (d, 1 H) 7.46 (dd, 1 H) 4.18 (t, 2 H) 3.85 (s, 3 H) 3.80 (t, 2 H) 1.90 - 2.00 (m, 2 H) 0.84 (s, 9 H) 0.01 (s, 6 H); MS (ESI) m/z 403, 405 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 14h; | 36.i (3-Bromopropoxy)(tert-butyl)dimethylsilane (6.85 rnL) and K2CO3 (4.09 g, 29.6 mmol) were added to a solution of 4-hydroxy-2-methoxybenzaldehyde (3.00 g) in DMF (30 rnL) and the mixture was stirred for 14 h at r.t. Brine was added, and the mixture was then extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4) and concentrated. The resulting residue was purified by FCC to give the subtitle compound as colourless oil (5.97 g); 1H NMR (CDCl3): 10.29 (IH, s), 7.80 (IH, d), 6.55 (IH, dd), 6.45 (IH, d), 4.15 (2H, t), 3.90 (3H, s), 3.81 (2H, t), 2.00 (2H, tt), 0.89 (9H, s), 0.05 (6H, s). | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; | 1.i The title compound may be prepared by the steps described below:The mixture of 4-hydroxy-2-methoxybenzaldehyde (10.0 g, 65.7 mmol), (3-bromopropoxy)- terr-butyldimethylsilane (25.0 g, 98.6 mmol) and K2C03 (13.6 g, 98.6 mmol) in DMF (100 mL) was stirred at r.t. for 5h. The mixture was diluted with water and extracted with EtOAc. And the combined organic solutions were washed with water and brine, dried (Na2S04), and concentrated. Purification by FCC, eluting with hexane / EtOAc gave 21.3 g of the sub-title compound as a yellow oil [as a mixture with (3-bromopropoxy)-tert-butyldimethylsilane]; LC-MS: m/z = 325 [MH+] (T = 2.68) | |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; | 12.i A mixture of 4-hydroxy-2-methoxybenzaldehyde (10 g), (3-bromopropoxy)-tert-butyl- dimethylsilane (25 g) and K2C03 (13.6 g) in DMF (100 niL) was stirred at RT for 5h. The mixture was then diluted with water and extracted with EtOAc, the combined organic solutions were washed with water and brine, dried (Na2S04) and concentrated. Purification by FCC, eluting with 0-15% EtOAc in hexane, gave the sub-title compound (21.3g) as a yellow oil (as a mixture with (3-bromopropoxy)-tert-butyldimethylsilane); LC-MS: m/z 325 [MH+]. |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; | 8.i (i) 4- [3- (tert-Butyldimethylsilyloxy) propoxy] -2-methoxybenzalde hyde The mixture of 4-hydroxy-2-methoxybenzaldehyde (10.0 g) , ( 3-bromopropoxy) -tert-butyldimethylsilane (25.0 g) , and potassium dicarbonate (13.6 g) in DMF (100 mL) was stirred at RT for 5h. The mixture was diluted with water and extracted with EtOAc. And the combined organic solutions were washed with water and brine, dried and concentrated. The residue was purified by silica gel chromatography eluting with hexane/EtOAc to give 21.3 g of the subtitle compound as a yellow oil [as a mixture with ( 3-bromopropoxy) -tert-butyldimethylsilane] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;Inert atmosphere; | A solution of methyl indole-3-carboxylate (1.87 g, 10.68 mmol), 1-bromo-3-tert-butyldimethylsilyloxypropane (5.0 mL, 21.5 mmol), cesium carbonate (10.43 g, 32 mmol) and anhydrous DMF (90 mL) was heated to 50 C for 16 h under a nitrogen atmosphere. After cooling, the reaction contents were poured into water (90 mL) and extracted with EtOAc (2 × 100 mL). The combined extracts were dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography to yield the N-alkylated indole 3 (3.74 g, 10.68 mmol, 100%) as a colourless oil: Rf 0.24 (9:1 heptane/EtOAc); IR (film) 1696, 1533, 1465, 1375, 1228, 1172, 1088 cm-1; 1H NMR (400 MHz, CDCl3) delta 8.10-8.14 (1H, m), 7.78 (1H, s), 7.33-7.36 (1H, m), 7.19-7.22 (2H, m), 4.22 (2H, t, J = 6.8 Hz), 3.85 (3H, s), 3.49 (2H, t, J = 5.6 Hz), 1.96 (2H, quint., J = 6.2 Hz), 0.88 (9H, s), 0.00 (6H, s); 13C NMR (100.6 MHz, CDCl3) delta 165.5, 136.5, 134.7, 126.7, 122.4, 121.8, 121.7, 110.1, 106.8, 59.1, 50.9, 43.3, 32.5, 26.0, 18.4, -5.5; LC-MS: 100% UV (215 nm), MS 348 (M+1)+ 100%; HRMS M+H+ calcd for C19H30NO3Si 348.1955, found 348.1990. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 3h; | Step 1. Synthesis of 2-(1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indol-3-yl)acetonitrile (25). To a suspension of sodium hydride (0.65 g, 16.36 mmol, 60% in mineral oil) in DMF (30 mL) was added a solution of (1H-indol-3-yl)-acetonitrile (2.128 g, 13.64 mmol) in DMF (10 mL) in a dropwise manner. Once the evolution of gas had stopped the reaction was stirred for another 30 minutes at room temperature, followed by the dropwise addition of (3-bromopropoxy)(tert-butyl)dimethylsilane (3.17 mL, 13.64 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then poured into EtOAc (50 mL) and 1 N HCl (40 mL). The EtOAc layer was separated, washed with aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using flash column chromatography (SiO2, 5% EtOAc in hexanes) to give 2-(1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indol-3-yl)acetonitrile (3.85 g, 86%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 16h; | To a solution of 2-oxo-2,3-dihydro-1 ,3-benzoxazole-6-carbaldehyde (Intermediate 7, 300 mg, 1 .84 mmol) in DMF (10 mL) were added potassium carbonate (633 mg, 4.58 mmol) and (3-bromopropoxy)(ie f-butyl)dimethylsilane (0.47 mL, 2.03 mmol), and the resulting mixture was heated to 75C. Upon complete disappearance of starting material (ca 16 hours), the solvent was removed under reduced pressure and the solid residue was treated with CH2CI2 and stirred for 5 min. The suspension was filtered through Celite and the solid residue washed with additional CH2CI2. The filtrate was concentrated to dryness and the crude was purified by column chromatography over silica gel, eluting with Hexane:Et20 (from 0 to 32% of Et20) to give the title compound as a white solid (550 mg, 89% yield).LRMS (m/z): 336 (M+1 )+. |
550 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 16h; | Intermediate 103.3-(3-[ieri-butyl(dimethyl)silyl]oxy}propyl)-2-oxo-2,3-dihydro-1 ,3-benzoxazole-6- carbaldehydeTo a solution of 2-oxo-2,3-dihydro-1 ,3-benzoxazole-6-carbaldehyde (Intermediate 7, 300 mg, 1 .84 mmol) in DMF (10 mL) were added potassium carbonate (633 mg, 4.58 mmol) and (3-bromopropoxy)(ie f-butyl)dimethylsilane (0.47 mL, 2.03 mmol), and the resulting mixture was heated to 75C. Upon complete disappearance of starting material (ca 16 hours), the solvent was removed under reduced pressure and the solid residue was treated with CH2CI2 and stirred for 5 min. The suspension was filtered through Celite and the solid residue washed with additional CH2CI2. The filtrate was concentrated to dryness and the crude was purified by column chromatography over silica gel, eluting with Hexane:Et20 (from 0 to 32% of Et20) to give the title compound as a white solid (550 mg, 89% yield).LRMS (m/z): 336 (M+1 )+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With cobalt(II) chloride; lithium iodide; isoprene; In tetrahydrofuran; at -78 - 50℃; for 5h;Inert atmosphere; | General procedure: Coupling of Alkyl Halides with t-BuMgCl; Procedure 1 (P1)An alkyl halide (1.0 mmol), decane (63 mg as an internal standard)and LiI (5.3 mg, 0.04 mmol) were added to a dry, nitrogen-flushedtest tube equipped with a rubber septum and a magnetic stir bar.THF (0.8 mL) was added and the solution was cooled to -78 C usinga dry ice/EtOH bath. t-BuMgCl (2a) (1.5 mL, 0.81 M in THF,1.2 mmol) was added slowly followed by isoprene (136.2 mg, 2.0mmol). To this mixture was added CoCl2 [2.6 mg, 0.02 mmol, as apowder or as a THF solution (0.5 mL, 0.04 M)]. (Note 1: CoCl2should be added after isoprene, otherwise the catalytic performancedecreases significantly). The cold bath was removed and the mixturewas warmed to r.t. (ca. over 10 min), and then heated for 5 h bysuspending the reaction vessel in an oil bath kept at 50 C. (Note 2:when the reaction mixture was heated at 30 C during this stage, unidentifiedside reactions occurred resulting in low yields of couplingproducts). The resulting mixture was cooled to 0 C in an ice bathand the reaction was quenched with aq HCl (5 mL, 1 M). The productwas extracted with Et2O (3 × 20 mL). The combined organiclayer dried over Na2SO4, concentrated and analyzed by gas chromatographyto determine the GC yield. The residue was purified by silicagel column chromatography or by GPC. According to P1, 1-bromo-3-[(tert-butyldimethylsilyl)oxy]propane(4e) (253 mg, 1.0 mmol) and t-BuMgCl (2a) (0.81 M in THF, 1.2mmol) were reacted under standard conditions. After aqueouswork-up, purification by GPC (with CHCl3 as the eluent) affordedthe title compound.Yield: 174 mg (76%); yellow oil.IR (Zn/Se-ATR, neat): 2953, 2893, 2858, 1471, 1253, 1100, 1006,940, 834, 814, 773 cm-1.1H NMR (400 MHz, CDCl3): delta = 0.10 (s, 6 H), 0.92 (s, 9 H), 0.94(s, 9 H), 1.21 (m, 2 H), 1.53 (m, 2 H), 3.62 (t, J = 6.8 Hz, 2 H).13C NMR (100 MHz, CDCl3): delta = -5.2, 18.4, 26.0, 28.2, 29.4, 30.0,39.9, 64.2.MS (EI): m/z (%) = 230 (11) [M]+, 215 (42), 200 (36), 185 (35), 173(84), 170 (19), 158 (9), 116 (21).HRMS (EI): m/z [M]+ calcd for C13H30OSi: 230.2066; found:230.2066 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
612 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h; | 1-(3-[tert-butyl(dimethyl)silyl]oxy}propyl)-3 FontWeight="Bold" FontSize="10" 3-difluoropiperidine To a solution of <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (518 mg) in DMF (15 mL) was added cesium carbonate (3.21 g) and (3-bromopropoxy)-tert-butyldimethylsilane (0.838 mL). The resulting reaction mixture was heated to 50C for 1.5 hours before cooling back to room temperature. Water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate (2x). The combined organics were washed with water (2x), brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 0 to 40% ethyl acetate in hexanes with 1% triethylamine) gave the desired product (612 mg). NMR (400 MHz, CDC13): delta (ppm) 4.20 (t, 1H), 3.71-3.64 (m, 2H), 3.46 (t, 1H), 2.62 (t, 1H), 2.50-2.47 (m, 1H), 2.44-2.42 (m, 1H), 2.05-1.98 (m, 1H), 1.91-1.82 (m, 2H), 1.77-1.67 (m, 4H), 0.89 (d, 9H), 0.05 (s, 3H), 0.04 (s, 3H). |
612 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1.5h; | To a solution of <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (518 mg) in DMF (15 mL) was added cesium carbonate (3.21 g) and (3-bromopropoxy)-tert-butyldimethylsilane (0.838 mL). The resulting reaction mixture was heated to 50 C. for 1.5 hours before cooling back to room temperature. Water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate (2×). The combined organics were washed with water (2×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 0 to 40% ethyl acetate in hexanes with 1% triethylamine) gave the desired product (612 mg). 1H NMR (400 MHz, CDCl3): delta (ppm) 4.20 (t, 1H), 3.71-3.64 (m, 2H), 3.46 (t, 1H), 2.62 (t, 1H), 2.50-2.47 (m, 1H), 2.44-2.42 (m, 1H), 2.05-1.98 (m, 1H), 1.91-1.82 (m, 2H), 1.77-1.67 (m, 4H), 0.89 (d, 9H), 0.05 (s, 3H), 0.04 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 g | To a solution of crude 2-(dibenzylamino) ethanol (2.0 g) in DMF (30 mL) was added NaH (purity: 95%, 0.42 g, 16.6 mmol) portionwise at 0 C. The mixture was stirred for 30 minutes, then to the mixture was added 3-bromopropoxy-tert-butyl-dimethyl-silane (3.2 g, 12.5 mmol). The mixture was warmed to 60 C. and stirred at this temperature for 12 hours. After the reaction mixture was cooled to room temperature, the reaction was quenched with saturated aqueous ammonium chloride solution. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give N, N-dibenzyl-2-[3-[tert-butyl (dimethyl) silyl]oxypropoxy]ethanamine (1.0 g). | |
1 g | Step 2: Preparation of N, Lambda-dibenzy 1-2- 13- 1 fc'/Y-buty I (dimethyl)silylj oxypropoxy] ethanamine To a solution of crude 2-(dibenzylamino ) ethanol ( 2.0 g) in DMF (30 niL) was added Nai l (purity: 95%, 0.42 g. 16.6 mmol) portionwise at 0 C. The mixture was st irred for 30 minutes, then to the mixture was added 3-bromopropoxy-feri-butyi-dimethyl-silane (3.2 g, 12.5 mmol). The mixture was warmed to 60 C and st irred at this temperature for 12 hours. After the reaction mixture was cooled to room temperature, the reaction was quenched with saturated aqueous ammonium chloride solution. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous Na2S04 and concentrated. The residue was purified by column chromatography to give N, Lambda - d i be n zy 1 - 2 - [ 3 - [ r rt-b u t y 1 (dimethyl ) silyl j oxypropoxy] ethanaminc (1.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.13.1. di-tert-butyl (3-hydroxypropyl)phosphonate [000576] NaH (60% in mineral oil, 400 mg) was added to di-tert-butylphosphonate (1.93 g) in N,N- dimethylformamide (30 mL), and the reaction was stirred at room temperature for 30 minutes. (3- Bromopropoxy)(tert-butyl)dimethylsilane (2.1 g) was added, and the reaction was stirred overnight. The mixture was diluted with diethyl ether (300 mL), and the solution was washed three times with water, and brine, then dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in 20 mL tetrahydrofuran, and tetrabutyl ammonium fluoride (TBAF, 1M in tetrahydroiuran, 9 mL) was added. The solution was stirred for 20 minutes, and then pH 7 buffer (50 mL) was added. The mixture was taken up in diethyl ether, and separated, and the organic layer was washed with brine, and then concentrated. The crude product was chromatographed on silica gel using 10-100% ethyl acetate in heptanes, followed by 5% methanol in ethyl acetate to provide the title compound. | ||
NaH (60% in mineral oil, 400 mg) was added to di-tert-butylphosphonate (1.93 g) in N,N- dimethylformamide (30 mL), and the reaction was stirred at room temperature for 30 minutes. (3- Bromopropoxy)(tert-butyl)dimethylsilane (2.1 g) was added, and the reaction was stirred overnight. The mixture was diluted with diethyl ether (300 mL), and the solution was washed three times with water, and brine, then dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in 20 mL tetrahydrofuran, and tetrabutyl ammonium fluoride (TBAF, 1M in tetrahydrofuran, 9 mL) was added. The solution was stirred for 20 minutes, and then pH 7 buffer (50 mL) was added. The mixture was taken up in diethyl ether, and separated, and the organic layer was washed with brine, and then concentrated. The crude product was chromatographed on silica gel using 10-100% ethyl acetate in heptanes, followed by 5% methanol in ethyl acetate to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: tert-Butyl N-(4-methyl-pyridin-2-yl)carbamate With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In tetrahydrofuran at -78℃; Inert atmosphere; | |
94% | With n-butyllithium In tetrahydrofuran at -78℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | Stage #1: 2-(tert-butoxycarbonylamino)-6-picoline With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In tetrahydrofuran at -78℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With sodium hydride; In mineral oil; at 20 - 70℃; for 12h;Inert atmosphere; | To a solution of 0.5 g (1.2 mmol) of <strong>[162401-32-3]roflumilast</strong> in DMI (5 mL) were added 139 mg (60% dispersion in oil, 3.5 mmol) of sodium hydride and 0.25 mL (2.9 mmol) of 3-tert-butyldimethylsilyloxypropyl bromide at room temperature under nitrogen stream. The mixture was heated to 70 C. and stirred for 12 hours. To the reaction mixture was added 3 mL of water. The reaction mixture was extracted with ethyl acetate three times. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate) to give 212 mg (0.368 mmol, yield 31%) of the title compound as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.1% | N-Benzyloxycarbonyl-3-oxobutazine (650 mg, 2.78 mmol) was added to DMF (15 mL) under argon,NaH (167 mg, 4.17 mmol) was added at room temperature and stirred at room temperature for 1 h. (3-Bromopropoxy) (tert-butyl) dimethyl(840 mg, 3.34 mmol) was added and the reaction was stirred at room temperature. After 2 h, the reaction was quenched. Water was added and extracted with ethyl acetate (60 mL)The layers were washed with saturated NaCl solution (20 mL X), dried over anhydrous magnesium sulfate and subjected to column chromatography (Epsilon: P = 1: 4, Epsilon: P = 1: 2) to give the product600 mg, yield 53.1% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1H-imidazole; In dichloromethane; at 20℃; for 0.166667h;Cooling with ice; | 3-Bromopropanol (4.14 g, 30 mmol),Was added to DCM (50 mL), imidazole (2.5 g, 30 mmol) was added, stirred under ice for 10 min, TBDMS (4.5 g, 30 mmol) was added and the reaction was continued at room temperature. The next day, DCM (50 mL) (30 mL X3), dried over anhydrous magnesium sulfate and concentrated to give 7 g of a colorless oil in 92% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere; | (3-bromopropoxy)(fe/ butyl)dimethylsilane (7.3 g, 28.8 mmol) was dissolved in dry DMF (75 mL), 4-chloro-3-hydroxy-5-nitrobenzamide (4.8 g, 22.16 mmol) was added followed by K2CO3 (6.13 g, 44.3 mmol) and stirred for 2 hr at 100 C under nitrogen. The reaction was cooled to rt, poured into EtOAc (600 mL), washed with water (600 mL), brine, dried with MgS04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-80% hexanes/EtOAc to afford the title compound (7.43 g, 19.1 mmol, 86% yield). *H NMR (400 MHz, DMSO-cfe) delta ppm 8.29 (br. s., 1 H), 8.05 (d, 7=1.71 Hz, 1 H), 7.89 (d, 7=1.71 Hz, 1 H), 7.77 (br. s., 1 H), 4.30 (t, 7=5.99 Hz, 2 H), 3.80 (t, 7=5.99 Hz, 2 H), 1.98 (quin, 7=5.99 Hz, 2 H), 0.80 - 0.90 (m, 9 H), 0.02 (s, 6 H). LCMS (LCMS Method E): Rt = 1.40 min, [M + H]+ = 389. |
86% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere; | (3-Bromopropoxy)(tert-butyl)dimethylsilane (7.3 g, 28.8 mmol) was dissolved in dry DMF (75 mL), 4-chloro-3-hydroxy-5-nitrobenzamide (4.8 g, 22.16 mmol) was added followed0by K2C03 (6.13 g, 44.3 mmcl) and stirred for 2 hr at 100 C under nitrogen. The reaction was cooled to RT, poured into EtOAc (600 mL), washed with water (600 mL), brine, dried with MgSO4, filtered and concentrated in vacua. The residue was purified by silica gel chromatography eluting with 2080% hexanes/EtOAc to afford the title compound (7.43 g,5 19.1 mmol, 86% yield). 1H NMR (400 MHz, DMSO-d6) 3 ppm 8.29 (br. s., 1 H), 8.05 Cd, J=1.71Hz, 1 H), 7.89 Cd, J=1.71 Hz, 1 H), 7.77 (br. s., 1 H), 4.30 Ct, J=5.99 Hz, 2 H), 3.80 Ct, J=5.99Hz, 2 H), 1.98 (quin, J=5.99 Hz, 2 H), 0.80 - 0.90 (m, 9 H), 0.02 Cs, 6 H). LC-MS (LCMSMethod E): Rt = 1.40 mm, [M + H] = 389. |
86% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere; | (3-bromopropoxy)(tett-butyl)dimethylsilane (7.3 g, 28.8 mmol) was dissolved in dry DMF (75 mL), 4-chloro-3-hydroxy-5-nitrobenzamide (4.8 g, 22.16 mmol) was added followedby K2C03 (6.13 g, 44.3 mmol) and stirred for 2 hr at 100 C under nitrogen. The reaction was cooled to rt, poured into EtOAc (600 mL), washed with water (600 mL), brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-80% hexanes/EtOAc to afford the title compound (7.43 g, 19.1 mmol, 86% yield). 1H NMR (400 MHz, DMSO-d6) 3 ppm 8.29 (br. s., 1 H), 8.05 Cd,3=1.71 Hz, 1 H), 7.89 Cd, 3=1.71 Hz, 1 H), 7.77 (br. s., 1 H), 4.30 Ct, 3=5.99 Hz, 2 H), 3.80 Ct,3=5.99 Hz, 2 H), 1.98 (quin, J=5.99 Hz, 2 H), 0.80 - 0.90 (m, 9 H), 0.02 Cs, 6 H). LCMS (LCMS Method E): Rt = 1.40 mi [M + H] = 389. |
86% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere; | (3-bromopropoxy)(tert-butyl)dimethylsilane (7.3 g, 28.8 mmol) was dissolved in dry DMF (75 mL), 4-chloro-3-hydroxy-5-nitrobenzamide (4.8 g, 22.16 mmol) was added followed by K2CO3 (6.13 g, 44.3 mmol) and stirred for 2 h at 100oC under nitrogen. The reaction was cooled to room temperature, poured into EtOAc (600 mL), washed with water (600 mL), brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-80% hexanes/EtOAc to afford the title compound (7.43 g, 19.1 mmol, 86% yield).1H NMR (400 MHz, DMSO-d6) delta ppm 8.29 (br. s., 1 H), 8.05 (d, J=1.71 Hz, 1 H), 7.89 (d, J=1.71 Hz, 1 H), 7.77 (br. s., 1 H), 4.30 (t, J=5.99 Hz, 2 H), 3.80 (t, J=5.99 Hz, 2 H), 1.98 (quin, J=5.99 Hz, 2 H), 0.80 - 0.90 (m, 9 H), 0.02 (s, 6 H). LCMS [M + H]+= 389. |
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 12h;Sealed tube; | To a suspension of 4-chloro-3-hydroxy-5-nitrobenzamide (211.0 mg, 0.974 mmol), and cesium carbonate (476 mg, 1.461 mmol) in DMF (3247 mul) was added (3-bromopropoxy)(tert-butyl)dimethylsilane (Aldrich, cat No.429066: 271 mul, 1.169 mmol). The reaction was then sealed and heated to 50 C. with stirring for 12 h. After cooling with an ice bath, the product was triturated with cold water, filtered, and dried to provide the desired product as a yellow solid. LC-MS calculated for C16H26ClN2O5Si (M+H)+: m/z=389.1; found 389.1. | |
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 12h;Sealed tube; | To a suspension of 4-chloro-3-hydroxy-5-nitrobenzamide (211.0 mg, 0.974 mmol), and cesium carbonate (476 mg, 1.461 mmol) in DMF (3247 pi) was added (3-bromopropoxy)(tert-butyl)dimethylsilane (Aldrich, cat No.429066: 271 muL, 1.169 mmol). The reaction was then sealed and heated to 50 C. with stirring for 12 h. After cooling with an ice bath, the product was triturated with cold water, filtered, and dried to provide the desired product as a yellow solid. LC-MS calculated for C16H26ClN2O5Si (M+H)+: m/z=389.1; found 389.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.2% | Stage #1: 4-fluoropiperidine With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In tetrahydrofuran at 20℃; for 24h; Stage #3: With ammonia In methanol | 3-(4-Fluoropiperidin-1-yl)propan-1-ol To a solution of 4-fluoropiperidine (2.0 g, 19.39 mmol) in dry tetrahydrofuran (20 ml) at room temperature under nitrogen was added sodium hydride (1 g, 25.00 mmol) then stirred for thirty minutes. (3-Bromopropoxy)(tert-butyl)dimethylsilane (6.77 ml, 29.22 mmol) was added dropwise then allowed to stir for 24 h at room temperature. The reaction mixture was diluted with EtOAc (100 ml), and washed three times with water (3 x 50 ml). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product (silyl). The crude product (silyl) was loaded onto 2 x 50g SCX columns washing with MeOH and then the product was eluted from the column using 2M NH3/MeOH to afford 3-(4-fluoropiperidin-l- yl)propan-l-ol (2.226 g, 71.2 %) as a yellow oil. NMR Spectrum: 1H NMR (500MHz,CDCl3) δ 1.63 - 1.77 (2H, m), 1.87 (4H, dq), 2.42 - 2.7 (6H, m), 3.74 - 3.87 (2H, m), 4.69 (1H, dt). |
2.226 g | Stage #1: 4-fluoropiperidine With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In tetrahydrofuran at 20℃; for 24h; | 12 3 -(4-Fluoropiperidin- 1 -yl)propan- 1 -ol To a solution of 4-fluoropiperidine (2.0 g, 19.39 mmol) in dry tetrahydrofuran (20 mL) at room temperature under nitrogen was added sodium hydride (1 g, 25.00 mmol) then stirred for thirty minutes. (3 -Bromopropoxy)(tert-butyl)dimethylsilane (6.77 mL, 29.22 mmol) was added dropwise then allowed to stir for 24 h at ambient temperature. The reaction mixture was diluted with EtOAc (100 mL), and washed three times with water (3 x 50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product still bearing the silyl protecting group on the alcohol. This material was loadedonto 2 x 50g SCX columns washing with MeOH and the deprotected product eluted from the column using 2M NH3/MeOH to afford the desired material (2.226 g) as a yellow oil. NMR Spectrum: ‘H NMR (500MHz, CDC13) ö 1.63 - 1.77 (2H, m), 1.87 (4H, dq), 2.42 - 2.7 (6H, m), 3.74 - 3.87 (2H, m), 4.69 (1H, dt). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
NaH (60% in mineral oil, 400 mg) was added to di-tert-butylphosphonate (1.93 g) in N,N-25 dimethylformamide (30 mL), and the reaction was stirred at room temperature for 30 minutes. (3-Bromopropoxy)(tert-butyl)dimethylsilane (2.1 g) was added, and the reaction was stirred overnight.The mixture was diluted with diethyl ether (300 mL), and the solution was washed three times withwater, and brine, then dried over sodium sulfate, filtered, and concentrated. The residue wasdissolved in 20 mL tetrahydrofuran, and tetrabutyl ammonium fluoride (TBAF, 1M in30 tetrahydrofuran, 9 mL) was added. The solution was stirred for 20 minutes, and then pH 7 buffer (50mL) was added. The mixture was taken up in diethyl ether, and separated, and the organic layer waswashed with brine, and then concentrated. The crude product was chromatographed on silica gelusing 10-100% ethyl acetate in heptanes, followed by 5% methanol in ethyl acetate to provide thetitle compound. | ||
NaH (60% in mineral oil, 400 mg) was added to di-tert-butylphosphonate (1.93 g) in N,N-dimethylformamide (30 mL), and the reaction was stirred at room temperature for 30 minutes. (3-Bromopropoxy)(tert-butyl)dimethylsilane (2.1 g) was added, and the reaction was stirred overnight. The mixture was diluted with diethyl ether (300 mL), and the solution was washed three times with water, and brine, then dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in 20 mL tetrahydrofuran, and tetrabutyl ammonium fluoride (TBAF, 1M in tetrahydrofuran, 9 mL) was added. The solution was stirred for 20 minutes, and then pH 7 buffer (50 mL) was added. The mixture was taken up in diethyl ether, and separated, and the organic layer was washed with brine, and then concentrated. The crude product was chromatographed on silica gel using 10-100% ethyl acetate in heptanes, followed by 5% methanol in ethyl acetate to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate In acetonitrile at 70℃; for 16h; | 1 Step-1) 2-Bromo-3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-6-iodopyridine To a solution of 2-bromo-6-iodo-pyridin-3-ol (0.50 g) in acetonitrile (8.3 mL) were added potassium carbonate (0.69 g) and (3-bromopropoxy)-tert-butyldimethylsilane (0.77 mL) at room temperature. After stirring for 16 hours at 70 °C, the mixture was allowed to cool to room temperature, quenched with water and stirred, and extracted with EtOAc. The organic extract was concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (0-10 % EtOAc in n-hexane) to give the title compound (0.54 g, 70 % yield) as colorless oil. MS (ESI) m/z : 472 [M+l]. RT = 1.207 min. LCMS condition : C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.7% | To a solution of 4-chloro-lH-pyrrolo-[3,2-c]-pyridine [60290-21-3] (1.0 g, 6.5 mmol) dissolved in DMF (51 mL) at 0C was added portionwise sodium hydride (288 mg, 7.2 mmol). The reaction mixture was allowed to reach rt and stirred 45 min, after which it was re-cooled to 0C and (3-bromopropoxy)-tert-butyldimethylsilane [89031-84-5] (2.5 g, 9.8 mmol) was added dropwise. The mixture was then allowed to reach rt and stirred overnight. NaHCCh sat solution was added and the aqueous phase was extracted with EtOAcThe combined organic extracts were washed with water and brine, then dried over MgS04 and concentrated in vacuo to afford. The residue was purified by column chromatography (silica gel; DCM/MeOH, gradient from 100/0 to 95/5)) to yield 1-31 (2.7 g, 98.7%) as a yellow liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: 1-ethynyl-1-methoxy-cyclohexane With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.5h; Inert atmosphere; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran; hexane at 0 - 20℃; for 22h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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45% | Stage #1: 2-chloro-7,7-dimethyl-6,7-dihydropyrrolo[3,4-b]pyridin-5-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 5℃; for 0.5h; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 3h; | A 6-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one To a stirred solution of 2-chloro-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5- one (250 mg, 1.37 mmol) in N,N-dimethylformamide (3 mL ) was added sodium hydride (99 mg, 2.47 mmol, 60% in mineral oil) at 5 °C. After stirring for 30 min, (3- bromopropoxy)(tert-butyl)dimethylsilane (69 mg, 0.27 mmol) was added to above mixture. The mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated ammonium chloride aqueous solution at 5 °C. The mixture was extracted with ethyl acetate. The combined organic layers was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford 6-(3- ((tert-butyldimethylsilyl )oxy)propyl)-2-chloro-7, 7-dim ethyl-6, 7-dihydro-5H-pyrrolo[3, 4- b]pyridin-5-one (A98) (228 mg, 45%) as a yellow oil. MS m/z 369.2 [M+1]+. 1H NMR (400 MHz, methyl sulfoxide-d6) δ 8.11 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1 H), 3.68 (t, J = 6.4 Hz, 2H), 3.51 - 3.42 (m, 2H), 1.90 - 1.79 (m, 2H), 1.47 (s, 6H), 0.89 (s, 9H), 0.06 (s, 6H). |
45% | Stage #1: 2-chloro-7,7-dimethyl-6,7-dihydropyrrolo[3,4-b]pyridin-5-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 5℃; for 0.5h; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 3h; | A 6-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-chloro-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one To a stirred solution of 2-chloro-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5- one (250 mg, 1.37 mmol) in N,N-dimethylformamide (3 mL ) was added sodium hydride (99 mg, 2.47 mmol, 60% in mineral oil) at 5 °C. After stirring for 30 min, (3- bromopropoxy)(tert-butyl)dimethylsilane (69 mg, 0.27 mmol) was added to above mixture. The mixture was stirred at room temperature for 3 h. The reaction was quenched with saturated ammonium chloride aqueous solution at 5 °C. The mixture was extracted with ethyl acetate. The combined organic layers was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford 6-(3- ((tert-butyldimethylsilyl )oxy)propyl)-2-chloro-7, 7-dim ethyl-6, 7-dihydro-5H-pyrrolo[3, 4- b]pyridin-5-one (A98) (228 mg, 45%) as a yellow oil. MS m/z 369.2 [M+1]+. 1H NMR (400 MHz, methyl sulfoxide-d6) δ 8.11 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1 H), 3.68 (t, J = 6.4 Hz, 2H), 3.51 - 3.42 (m, 2H), 1.90 - 1.79 (m, 2H), 1.47 (s, 6H), 0.89 (s, 9H), 0.06 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: N-Methyl-1,4-dihydro-2,3-quinoxalinedione With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.25h; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In N,N-dimethyl-formamide; mineral oil at 100℃; | 1 Preparation of 1-(3-[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methyl-1,4-dihydroquinoxaline-2,3-dione (7). To a solution of 1-methyl-1,4-dihydroquinoxaline-2,3-dione (4) (100 mg, 0.57 mmol) in DMF (5 mL) was added NaH (114 mg, 2.85 mmol, 60% in oil). After stirring for 15 min, to the mixture was added 3-(tert-butyldimethylsilyloxy)propyl bromide (6) (0.26 mL, 1.14 mmol). The mixture was heated in an oil bath at 100 °C. After overnight, the solvent was removed under reduced pressure. The resulting material was dissolved in DCM (10 mL), silica gel (5 g) was added and the solvent was removed under reduced pressure. The compound was eluted with a gradient of MeOH/CHC13, 0 to 5 %, which generated (7) (128 mg, 64% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: 2-(dibenzylamino)-2-methyl-propan-1-ol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In N,N-dimethyl-formamide at 20℃; | 110.2 Step 2: N,N-Dibenzyl-1-[3-[tert-butyl(dimethyl)silyl]oxypropoxy]-2-methyl-propan-2- amine To a solution of 2-(dibenzylamino)-2-methyl-propan-1-ol (20 g, 74.244 mmol) in dimethylformamide (105 mL) at 0 °C was added sodium hydride (60 % w/w) (4.1 g, 102.51 mmol) portion-wise. After stirring at 0 °C for 30 min, 3-bromopropoxy-tert-butyl- dimethyl-silane (24.046 g, 22 mL, 94.949 mmol) was added to the above solution. To dilute the mixture, dimethylformamide (21 mL) was added. The reaction mixture was stirred overnight at room temperature and quenched with saturated ammonium chloride (200 mL). The mixture was extracted with ethyl acetate (2 X 200 mL) then combined organics were washed with water (2 X 200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography using a gradient from 0 % to 15 % ethyl acetate in heptanes to provide as a colorless oil, N,N-dibenzyl-1-[3-[tert-butyl(dimethyl)silyl]oxypropoxy]-2- methyl-propan-2-amine (16.4 g, 50 %). 1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J = 7.1 Hz, 4H), 7.16 (t, J = 7.5 Hz, 4H), 7.11 - 6.98 (m, 2H), 3.76 (s, 4H), 3.68 (t, J = 6.4 Hz, 2H), 3.38 (t, J = 6.1 Hz, 2H), 3.34 (s, 2H), 1.69 (quin, J = 6.2 Hz, 2H), 1.06 (s, 6H), 0.86 (s, 9H), 0.03 (s, 6H) ppm. ESI-MS m/z calc. 441.3063, found 442.3 (M+1)+; Retention time: 2.17 minutes (LC Method E). |
50% | Stage #1: 2-(dibenzylamino)-2-methyl-propan-1-ol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 3-(tert-butyldimethylsilyloxy)propyl bromide In N,N-dimethyl-formamide at 20℃; | 110.2 Step 2: N,N-Dibenzyl-1-[3-[tert-butyl(dimethyl)silyl]oxypropoxy]-2-methyl-propan-2- amine To a solution of 2-(dibenzylamino)-2-methyl-propan-1-ol (20 g, 74.244 mmol) in dimethylformamide (105 mL) at 0 °C was added sodium hydride (60 % w/w) (4.1 g, 102.51 mmol) portion-wise. After stirring at 0 °C for 30 min, 3-bromopropoxy-tert-butyl- dimethyl-silane (24.046 g, 22 mL, 94.949 mmol) was added to the above solution. To dilute the mixture, dimethylformamide (21 mL) was added. The reaction mixture was stirred overnight at room temperature and quenched with saturated ammonium chloride (200 mL). The mixture was extracted with ethyl acetate (2 X 200 mL) then combined organics were washed with water (2 X 200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography using a gradient from 0 % to 15 % ethyl acetate in heptanes to provide as a colorless oil, N,N-dibenzyl-1-[3-[tert-butyl(dimethyl)silyl]oxypropoxy]-2- methyl-propan-2-amine (16.4 g, 50 %). 1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J = 7.1 Hz, 4H), 7.16 (t, J = 7.5 Hz, 4H), 7.11 - 6.98 (m, 2H), 3.76 (s, 4H), 3.68 (t, J = 6.4 Hz, 2H), 3.38 (t, J = 6.1 Hz, 2H), 3.34 (s, 2H), 1.69 (quin, J = 6.2 Hz, 2H), 1.06 (s, 6H), 0.86 (s, 9H), 0.03 (s, 6H) ppm. ESI-MS m/z calc. 441.3063, found 442.3 (M+1)+; Retention time: 2.17 minutes (LC Method E). |
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P378 | |
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P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
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P401 | |
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Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
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H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
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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 |
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H272 | May intensify fire; oxidizer |
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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 |
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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 |
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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 |
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