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Compound 10 2(2-Bromophenyl)pyrrolidine 5-(2-Bromophenyl)-3,4-dihydro-2H-pyrrole (compound 8; 393 mmol, 88 g) was dissolved in methanol (1300 mL), then the acetic acid (330 mL) was added and the solution cooled to -65 C. under a nitrogen atmosphere. Sodium borohydride (589 mmol, 22.28 g) was added portionwise over 1 hour. The reaction was stirred at -65 C. for 30 minutes, then the cooling bath was removed and the reaction mixture temperature was allowed to rise to room temperature. The bulk of the methanol was removed under vacuum then 5N HCl (950 mL) was added and the solution extracted with ether (2×500 mL). The aqueous solution was then basified with sodium hydroxide pellets (310 g) with ice-bath cooling, maintaining the reaction temperature less than 30 C. The basified aqueous was then extracted with ethyl acetate (3×800 mL), the combined organics washed with brine (800 mL), dried with sodium sulfate, evaporated and chromatographed on 1 Kg of silica gel eluting with 19:1 to 9:1 methylene chloride-ethanol to give 2-(2-bromophenyl)pyrrolidine (68.5 g).
With methanol; sodium tetrahydroborate; acetic acid; at -65℃; for 1.5h;Inert atmosphere;
Compound 10; 2-(2-Bromophenyl)pyrrolidine5-(2-Bromophenyl)-3,4-dihydro-2H-pyrrole (compound 8; 393 mmol, 88 g) was dissolved in methanol (1300 ml_), then the acetic acid (330 ml_) was added and the solution cooled to -65 0C under a nitrogen atmosphere. Sodium borohydride (589 mmol, 22.28 g) was added portionwise over 1 hour. The reaction was stirred at -65 0C for 30 minutes, then the cooling bath was removed and the reaction mixture temperature was allowed to rise to room temperature. The bulk of the methanol was removed under vacuum then 5N HCI (950 ml_) was added and the solution extracted with ether (2 x 500 ml_). The aqueous solution was then basified with sodium hydroxide pellets (310 g) with ice-bath cooling, maintaining the reaction temperature less than 30 0C. The basified aqueous was then extracted with ethyl acetate (3 x 800 ml_), the combined organics washed with brine (800 ml_), dried with sodium sulfate, evaporated and chromatographed on 1 Kg of silica gel eluting with 19:1 to 9:1 methylene chloride- ethanol to give 2-(2-bromophenyl)pyrrolidine (68.5 g).
With dmap; triethylamine; In dichloromethane; at 20℃; for 16h;
A mixture solution of 2- (2-bromophenyl) pyrrolidine (1.13 g, 5 mmol), Boc 2O (2.16 g, 10 mmol), TEA (1.01 g, 10 mmol) and DMAP (cat) in DCM (20 mL) was stirred at room temperature for 16hrs. Then the mixture solution was concentrated, and the residue was purified by chromatography on silica-gel (eluting with 100%PE to PE /EA = 5 /1) to give the product (1.6 g, 98.1%) as a colorless oil. MS (ESI, m/e) [M+1] + 270.0, 272.0
In tetrahydrofuran;
Compound 18 tert-Butyl <strong>[129540-24-5]2-(2-bromophenyl)pyrrolidine</strong>-1-carboxylate To a solution of <strong>[129540-24-5]2-(2-bromophenyl)pyrrolidine</strong> (compound 10; 257 mmol, 58 g) in dry tetrahydrofuran (870 mL), cooled with a water bath, was added di-tert-butyl dicarbonate (264 mmol, 57.7 g) in tetrahydrofuran (150 mL) dropwise over 30 minutes. The cooling bath was removed and the reaction stirred at room temperature for two days. The solvent was removed in vacuo and the residue taken up in methylene chloride (1 L), washed with 0.5M Citric acid (400 mL), brine (500 mL) and dried over sodium sulfate. Crystallisation from iso-hexane gave tert-butyl <strong>[129540-24-5]2-(2-bromophenyl)pyrrolidine</strong>-1-carboxylate (42 g) and further tert-butyl <strong>[129540-24-5]2-(2-bromophenyl)pyrrolidine</strong>-1-carboxylate (33 g) was obtained by chromatography of the mother liquors on 800 g silica gel, eluting with heptane-ethyl acetate 9:1 to 3:1.
In tetrahydrofuran; at 20℃;Cooling with water bath;
Compound 18; tert-Butyl <strong>[129540-24-5]2-(2-bromophenyl)pyrrolidine</strong>-1 -carboxylateTo a solution of <strong>[129540-24-5]2-(2-bromophenyl)pyrrolidine</strong> (compound W; 257 mmol, 58 g) in dry tetrahydrofuran (870 ml_), cooled with a water bath, was added di-tert-butyl dicarbo- nate (264 mmol, 57.7 g) in tetrahydrofuran (150 ml.) dropwise over -30 minutes. The cooling bath was removed and the reaction stirred at room temperature for two days. The solvent was removed in vacuo and the residue taken up in methylene chloride (1 L), washed with 0.5M Citric acid (400 ml_), brine (500 ml_) and dried over sodium sulfate. Crystallisation from iso-hexane gave tert-butyl <strong>[129540-24-5]2-(2-bromophenyl)pyrrolidine</strong>-1 -carboxylate (42 g) and further tert-butyl <strong>[129540-24-5]2-(2-bromophenyl)pyrrolidine</strong>-1 -carboxylate (33 g) was obtained by chromatography of the mother liquors on 80Og silica gel, eluting with heptane-ethyl acetate 9:1 to 3:1.
3-{2-[2-(2-bromophenyl)pyrrolidin-1-yl]-2-oxoethyl}-1-[(4-nitrophenyl)methyl]-1-(prop-2-yn-1-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1499 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 18h;
General procedure: Ethyl ester derivatives (1 eq.) were dissolved in a 1 :1 mixture of THF/MeOH and treated with LiOH monohydrate (5 eq.) dissolved in water (Water/THF/MeOH ratio: 1 :2:2). The reaction was kept under stirring at RT for 2 hours, then the reaction mixture was concentrated, diluted with water and washed with DCM. The aqueous phase was treated with 1 N aqueous HCI until acidic pH and extracted several times with EtOAc. The combined ethyl acetate organic phases were dried over MgS04, filtered, and evaporated to afford the desired products, which were used directly in the next step. 2-(2-Bromophenyl)- pyrrolidine (1 eq.), carboxylic acid derivatives (1.1 eq.) and HATU (1.4 eq.) were dissolved in DMF. DIPEA (1.5 eq.) was added and the reaction mixture was stirred at room temperature for 18 hours. After this time, the reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgS04, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with MeOH in DCM. The desired compounds were obtained as an oily product.
3-{2-[2-(2-bromophenyl)pyrrolidin-1-yl]-2-oxoethyl}-1-[(1-methyl-1H-1,2,3-triazol-4-yl)methyl]-1-[(4-nitrophenyl)methyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
311 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 18h;
General procedure: Ethyl ester derivatives (1 eq.) were dissolved in a 1 :1 mixture of THF/MeOH and treated with LiOH monohydrate (5 eq.) dissolved in water (Water/THF/MeOH ratio: 1 :2:2). The reaction was kept under stirring at RT for 2 hours, then the reaction mixture was concentrated, diluted with water and washed with DCM. The aqueous phase was treated with 1 N aqueous HCI until acidic pH and extracted several times with EtOAc. The combined ethyl acetate organic phases were dried over MgS04, filtered, and evaporated to afford the desired products, which were used directly in the next step. 2-(2-Bromophenyl)- pyrrolidine (1 eq.), carboxylic acid derivatives (1.1 eq.) and HATU (1.4 eq.) were dissolved in DMF. DIPEA (1.5 eq.) was added and the reaction mixture was stirred at room temperature for 18 hours. After this time, the reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgS04, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with MeOH in DCM. The desired compounds were obtained as an oily product.
3-{2-[2-(2-bromophenyl)pyrrolidin-1-yl]-2-oxoethyl}-1-[(2-methyl-2H-1,2,3,4-tetrazol-5-yl)methyl]-1-[(4-nitrophenyl)methyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
221 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 18h;
General procedure: Ethyl ester derivatives (1 eq.) were dissolved in a 1 :1 mixture of THF/MeOH and treated with LiOH monohydrate (5 eq.) dissolved in water (Water/THF/MeOH ratio: 1 :2:2). The reaction was kept under stirring at RT for 2 hours, then the reaction mixture was concentrated, diluted with water and washed with DCM. The aqueous phase was treated with 1 N aqueous HCI until acidic pH and extracted several times with EtOAc. The combined ethyl acetate organic phases were dried over MgS04, filtered, and evaporated to afford the desired products, which were used directly in the next step. 2-(2-Bromophenyl)- pyrrolidine (1 eq.), carboxylic acid derivatives (1.1 eq.) and HATU (1.4 eq.) were dissolved in DMF. DIPEA (1.5 eq.) was added and the reaction mixture was stirred at room temperature for 18 hours. After this time, the reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgS04, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with MeOH in DCM. The desired compounds were obtained as an oily product.
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