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With hydrogenchloride; In 1,4-dioxane; at 0 - 20℃; for 1.66667h;
[0358] Part C: To a solution of 1,1-dimethylethyl 3,3-difluoropyrrolidine-1-carboxylate (0.868 g, 4.19 mmol) in 1.5 mL of 1,4-dioxane was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 11 mL, 44 mmol) at 0 C. The mixture was stirred at 0 C. for 40 min, at room temperature for 1 h and was then concentrated to afford 0.65 g (100%) of 3,3-difluoropyrrolidine hydrochloride: 1H-NMR (CD3OD) δ 3.54 (2H, t, J=11.9 Hz), 3.43 (2H, t, J=7.8 Hz), 2.40 (2H, m).
100%
With hydrogenchloride; In 1,4-dioxane; for 2.0h;
To a stirred solution of <strong>[195447-25-7]tert-butyl 3,3-difluoropyrrolidine-1-carboxylate</strong> (step 2, 1.61 g, 7.77 mmol) in dioxane (15 ml), was added 6N HCl in dioxane (20 ml) and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford the desired product (1.11 g, yield: 100%). Next reaction was carried out without any further purification.
With hydrogenchloride; In 1,4-dioxane; for 0.2h;
To a stirred solution of tert-butyl 3,3-difluoropyrrolidine-l-carboxylate (step 2, 1.61 g, 7.77 mmol) in dioxane (15 ml), was added 6N HCl in dioxane (20 ml) and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford the desired product (1.11 g, yield: 100%). Next reaction was carried out without any further purification.
4.1 g
With hydrogenchloride; In water;
DAST (4.03 g, 67.6 mmol, 2.5 eq.) was added to a solution of tert-butyl 3- oxopyrrolidine-l-carboxylate (5 g, 27.0 mmol, 1.0 eq.) in dichloromethane (30 mL). The reaction was stirred for 5 hours at room temperature. The reaction mixture was poured into ice cold sat. NaHCCL solution (100 mL) and extracted with dichloromethane for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude Boc-3,3-difluoropyrrolidine (5.9 g, quantitative yield), which was then treated with 6 N HC1 in dioxane to give 3,3-difluoropyrrolidine hydrochloride (4.1 g, quantitative yield). LC-MS m/z [M+H]+ calc’d for C4H8CIF2N, 110; found, 110.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at -50 - 20℃;
The hydrochloride salt of racemic 3-fluoropyrrolidinc (628 mg, 5mmol) was added to a solution of 2,3-oxoindohne-5-sulfonyl chloride (1.2 g, 4.9 mmol) and diisopropylethyl amine (2.6 mL, 15 mmol) in 1 :1 CH2Cl2ZTHF (50 mL) at -50 C. The solution was warmed to room temperature and slirred at that temperature for 12 hours. The reaction mixture was concentrated, dissolved in CII2CI2. and then washed with saturated NaHCO3 and brine. I he organic layer was dried (MgSO4), filtered, concentrated, and purified by flash chromatography on silica gel (5% MeOH in CH2Cl2) to provide 1.4 g of the product as an orange solid
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at -50 - 20℃;
T he hydrochloride salt of 3,3-difluoropyrrolidine (475 mg, 3,3 mmol) ^as added to a solution of2.3-dioxoiotando.me-5-suifonyl chloride (1 ,0 g, 4, 1 mmol) and diisopropyleth) 1 amine (2 0 ml, 12 mmol) in 1 : 1 CH2Cl2ZTHF (40 mL) at -50 C. The solution was warmed to room temperature and stirred at that temperature for 12 hours The reaction mixture was then concentrated, dissolved in CH2Cl2. and washed with saturated NaHCOj and brine. The organic layer was dried (MgSO4), filtered, concentrated, and purified by flash chromatography on silica gel (5% MeOH in CH2Cl2) to provide 575 mg of the product as an orange solid
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;
General procedure: To a solution of <strong>[22280-60-0]6-chloro-2-methyl-3-nitropyridine</strong> (0.3 g, 1.74 mmol) in DMF (2 mL) was added K2C03 (0.72 g, 5.23 mmol) followed by 3,3-difluoropyrrolidine hydrochloride (0.74 g, 5.23 mmol) and the reaction mixture was heated for 4 h at 80°C. The reaction mixture was then diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-3percent) to afford the title compound (0.2 g, 47percent). LCMS (ES+) 244.05 (M+H)+, RT 3.028 minutes (method 1).
47%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;
Intermediate 51 6-(3,3-Difluoropyrrolidin-1-yl)-2-methyl-3-nitropyridine [0271] To a solution of <strong>[22280-60-0]6-chloro-2-methyl-3-nitropyridine</strong> (0.3 g, 1.74 mmol) in DMF (2 mL) was added K2CO3 (0.72 g, 5.23 mmol) followed by 3,3-difluoropyrrolidine hydrochloride (0.74 g, 5.23 mmol) and the reaction mixture was heated for 4 h at 80° C. The reaction mixture was then diluted with ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, MeOH: DCM 2-3percent) to afford the title compound (0.2 g, 47percent). LCMS (ES+) 244.05 (M+H)+, RT 3.028 minutes (method 1).
Add 3,3-difluoropyrrolidine hydrochloride (3.52g, 24.50mmol) to a 100mL bottle and dissolve it in MeOH (51mL),Add K2CO3 (6.74g, 48.80mmol) under ice bath, stir evenly,Then slowly add di-tert-butyl dicarbonate (6.4mL, 28.00mmol) dropwise,Move to room temperature and react overnight. The insoluble matter was removed by filtration, diluted with water, extracted with EtOAc, combined the organic phases, washed with H2O and saturated NaCl solution, dried with anhydrous Na2SO4, concentrated under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: PE/EtOAc( v/v)=1/10) to obtain a colorless transparent liquid (4.50g, 89%).
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