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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 13220-33-2 |
Formula : | C5H11NO |
M.W : | 101.15 |
SMILES Code : | OC1CN(C)CC1 |
MDL No. : | MFCD00003176 |
InChI Key : | FLVFPAIGVBQGET-UHFFFAOYSA-N |
Pubchem ID : | 93074 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H227-H315-H319-H335 |
Precautionary Statements: | P305+P351+P338 |
* 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 |
---|---|---|
81% | With dmap; triethylamine; In dichloromethane; at 20℃; for 16h; | (a) 1-Methylpyrrolidin-3-yI methanesulfonate (A 22) 3-Hydroxy-1-methylpyrroldine (0.543 mL, 4.94 mmol) was dissolved in DCM (10 mL)and cooled to 0 C Et3N (0.827 mL, 5.93 mmol), methanesulfonyl chloride (0.421 mL, 5.44 mmol) and DMAP (0.006 g, 0.05 mmol) were added and the mixture was stirred for 16 hours at room temperature. The mixture was diluted with CHCI3 (5 mL) and washed with sat. NaHCO3 (5 mL) and water (2 x 5 mL). The organic layer was concentrated in vacuo to give the title compound A22 as a yellow oil (0.717 g, 81percent yield). 1H NMR (300 MHz, ODd3) O 1.85-2.24 (m, 6H), 2.38- 2.74 (m, 3H), 2.76- 2.91 (m, 3H), 4.95 (m, 1H). |
With triethylamine; In dichloromethane; at -10 - 20℃; for 2.08333h; | A solution of 0.33 cm3 of methanesulfonyl chloride in 7.07 cm3 of dichloromethane is added dropwise to a stirred solution of 0.39 cm3 of <strong>[13220-33-2]1-methyl-3-hydroxypyrrolidine</strong> and 0.62 cm3 of triethylamine in 7.7 cm3 of dichloromethane under a nitrogen atmosphere, at -10° C. The reaction medium is stirred at -10° C. for 5 min and then at a temperature in the region of 20° C. for 2 h, before being concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is taken up with water and ethyl acetate. The solution is stirred for 5 min and is then separated by settling out. The aqueous phase is extracted three times with ethyl acetate. The organic phases are pooled, washed successively with a 5percent aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (2.7 kPa) to give 399 mg of methanesulfonic acid (1-methylpyrrolidin-3-yl) ester in the form of a colorless oil. LCMS (electrospray): m/z 180 (MH+), m/z 84 [MH+-(SO2CH3)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.9% | To 629 mg (2.4 mmol) of PPh3 in 13 mL of dry THF at -20°C was added 378 muL (2.4 mmol) of DEAD dropwise. The solution was allowed to stir 10 min. at -20°C. After 10 min, a solution containing 220 muL (2.0 mmol) of <strong>[13220-33-2]1-methyl-3-hydroxypyrrolidine</strong> and 2 mL of dry THE was added dropwise. The solution was again allowed to stir 10 min at -20°C. After 10 min, to the solution was added 190 mg (2.0 mmol) of 3-hydroxypyridine at once. The solution was allowed to stir at room temperature overnight. Next day, solvent was removed under reduced pressure. The crude product was purified by flash chromatography (9 : 1, CHCl3 : MeOH) to obtain 260 mg (72.9 percent) of a clear oil:1H NMR (300 MHz, CDCl3) delta 8.26 (1H, d, J = 2.6 Hz), 8.20 (1H, d, J = 4.2 Hz), 7.22 - 7.13 (2H, m), 4.85 (1H, m), 2.89 - 2.76 (3H, m), 2.48 -1.95 (3H, m), 2.40 (3H, s); Mass spectrum (ESI) m/z 179.6 (M+H+). | |
260 mg (72.9%) | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; | EXAMPLE 7 3-(1-Methyl-3-pyrrolidinyloxy)-pyridine To 629 mg (2.4 mmol) of PPh3 in 13 mL of dry THF at -20° C. was added 378 muL (2.4 mmol) of DEAD dropwise. The solution was allowed to stir 10 min. at -20° C. After 10 min, a solution containing 220 muL (2.0 mmol) of <strong>[13220-33-2]1-methyl-3-hydroxypyrrolidine</strong> and 2 mL of dry THF was added dropwise. The solution was again allowed to stir 10 min at -20° C. After 10 min, to the solution was added 190 mg (2.0 mmol) of 3-hydroxypyridine at once. The solution was allowed to stir at room temperature overnight. Next day, solvent was removed under reduced pressure. The crude product was purified by flash chromatography (9:1, CHCl3:MeOH) to obtain 260 mg (72.9percent) of a clear oil: 1H NMR (300 MHz, CDCl3) delta 8.26 (1H, d, J=2.6 Hz), 8.20 (1H, d, J=4.2 Hz), 7.22-7.13 (2H, m), 4.85 (1H, m), 2.89-2.76 (3H, m), 2.48-1.95 (3H, m), 2.40 (3H, s); Mass spectrum (ESI) m/z 179.6 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Example 1; 4- (3-Chloro-2-fluoroanilino)-7-methoxy-6- [ (1-methylpyrrolidin-3-yl) oxy] quinazoline; To a suspension of 4- (3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (Reference Example 2,639 mg, 2.0 mmol) in DCM (30 ml) was added 1-methyl-3- pyrrolidinol (658 ul, 6.0 mmol) and triphenyl phosphine (1572 mg, 6.0 mmol). The suspension was cooled to 0°C under a nitrogen atmosphere. Di-tert-butyl azodicarboxylate (1380 mg, 6 mmol) was added as a solution in DCM (20 ml), dropwise over the course of 15 minutes. The resulting light brown solution was allowed to warm to room temperature and was stirred overnight. The solution was evaporated, and the residue purified by chromatography, eluting with 0 to 5percent methanol in DCM. The appropriate fractions were combined and evaporated, and the crude product (230 mg) re-dissolved in 1: 1 methanol/DCM (5 ml). Ethereal HC1 (1M, 1.14 ml) was added, and the mixture evaporated. Crystallisation from ethanol/diethyl ether gave the title product as a hydrochloride salt in the form of a white crystalline solid (154 mg, 16percent) ; 1H NMR (hydrochloride salt) : 2.30 (m, 1H), 2.65-2. 75 (m, 1H), 2.88 (s, 3H), 3.30-3. 80 (m, 3H), 3.85-4. 05 (m, 1H), 4.00 (s, 3H), 5.46 (m, 1H), 7.35 (dd, 1H), 7.45 (s, 1H), 7.51 (dd, 1H), 7.62 (dd, 1H), 8.53 (s, 1H), 8. 72 (s, 1H), 8. 81 (s, 1H) ; Mass Spectrum : 403.3, 405.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium hydroxide;tetrabutylammomium bromide; In water; toluene; at 18 - 60℃; for 18h; | To a solution of 4-Fluoro-2-methoxy-1-nitrobenzene (Apollo Scientific; 4.28 g, 25 mmol) in toluene (20 mL) and 25percent KOH aq. (20 mL), were added at room temperature, <strong>[13220-33-2]1-methyl-3-pyrrolidinol</strong> (5.0 g, 50 mmol) and tetra-n-butylammonium bromide (1.66 g, 5 mmol). The mixture was heated at 60° C. for 18 hrs. The reaction mixture was cooled to room temperature, poured onto ice-water (200 mL) and extracted with Ethyl Acetate (3.x.100 mL). The organic layer was washed with 2 M HCl (250 ml) and then loaded onto a 50 g SCX-2 cartridge, washing with water and eluting with 7 N methanolic ammonia to give the title compound as a yellow oil, which solidified on standing (5.50 g, 87percent).1H NMR (399.902 MHz, DMSO-D6) delta 1.73-1.84 (m, 1H), 2.27 (s, 3H), 2.31-2.37 (m, 2H), 2.65 (dd, 1H), 2.68-2.73 (m, 1H), 2.77 (dd, 1H), 3.92 (s, 3H), 5.02-5.07 (m, 1H), 6.62 (dd, 1H), 6.73 (d, 1H), 7.95 (d, 1H); MS m/z 253.23 [M+H]+. |
87% | With potassium hydroxide;tetrabutylammomium bromide; In water; toluene; at 60℃; for 18h; | l-Methylpyrrolidin-3-ol (4.96 g) and tetra-n-butylammonium bromide (2.26 g) were added to a stirred mixture of 4-fiuoro-2-methoxy-l -nitrobenzene (6.00 g) in toluene (25 mL) and KOH (5.90 g) in water (25 mL). The mixture was heated at 600C for 18h and was then diluted with ice-water (250 mL), EtOAc (400 mL) and toluene (100 mL). The phases were separated. The organic portion was washed with water (200 mL), sat. brine and was then dried (MgSO4). Concentration in vacuo and purification by FCC using 0-10percent MeOH in DCM afforded the title compound (7.70 g, 87 percent) as a yellow gum; 1H NMR: 1.78 (IH, m), <n="90"/>2.26 (3H, s), 2.35 (2H, m), 2.69 (2H, m), 2.77 (IH, m), 3.91 (3H, s), 5.04 (IH, m), 6.62 (IH, dd), 6.72 (IH, d), 7.95 (IH, d); m/z: MH+ 253. |