| 96% |
With triethylamine In dichloromethane at 20℃; for 2h; |
1.2 Preparation of tert-butyl 4-((4-bromophenyl)sulfonyl)piperazine-1-carboxylate (4):
To a solution of 4-bromobenzenesulfonyl chloride (3) (5.1 g, 20 mmol) in dry dichloromethane, N-Boc-piperazine (5.0 g, 27 mmol) and Et3N (5.5 ml, 40 mmol) were added. The mixture was stirred at room temperature for 2 h and monitored by thin layer chromatography. After the reaction is complete. It was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 4 (7.7 g, 96%) as a white solid. |
| 96% |
With triethylamine In dichloromethane at 20℃; for 2h; |
Tert-butyl 4-((4-bromophenyl)sulfonyl)piperazine-1-carboxylate (5).
To the solution of compound 4-bromobenzenesulfonyl chloride (5.1 g, 20 mmol) in dry DCM wasadded N-Boc-piperazine (5.0 g, 27 mmol) and Et3N (5.5 mL,40 mmol). The mixturewas stirred at room temperature for 2 h andmonitored by TLC. After the reaction was complete. The mixturewas evaporated under reduced pressure and purified by silica gelcolumn chromatography to obtain compound 5 (7.7 g, 96%) as awhite solid. 1H NMR (500 MHz, CDCl3) d 7.69 (d, J 8.4 Hz, 2H), 7.61(d, J 8.5 Hz, 2H), 3.54e3.47 (m, 4H), 3.03e2.93 (m, 4H), 1.41 (s,9H). |
| 93% |
With triethylamine In dichloromethane at 20℃; for 2h; |
|
| 92% |
With triethylamine In dichloromethane at 0 - 20℃; for 3h; |
105 Synthesis of 4-(4-bromo-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester
Example 105 Synthesis of 4-(4-bromo-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester To a stirring, 0° C. solution of piperazine-1-carboxylic acid tert-butyl ester (1.17 g, 6.29 mmol, 1.05 equiv) and TEA (1.67 mL, 11.98 mmol, 2.0 equiv) in DCM (10 mL) was added 4-bromo-benzenesulfonyl chloride (1.53 g, 5.99 mmol, 1 equiv). The reaction was allowed to warm to ambient temperature and stir for 3 h. The reaction solvents were evaporated and the resulting solids were dried, washed with water and filtered, yielding a white powder (2.24 g, 92% yield). MS (ESI+): m/z=306.9, LC retention time: 3.17 min. Rf=0.56 (30% EtOAc/hexanes). |
| 92% |
Stage #1: 1-t-Butoxycarbonylpiperazine With triethylamine In tetrahydrofuran at 0 - 20℃;
Stage #2: 4-bromobenzenesulfonyl chloride In tetrahydrofuran for 2h; |
3-1
Triethylamine (0.94 ml_, 6.71 mmol) was added to a stirred reaction mixture of N-tert- butoxycarbonyl piperazine (0.50 g, 2.68 mmol) in tetrahydrofuran (6 ml_) at 0 °C, then the reaction mixture was stirred at room temperature for 15 minutes. A solution of 4-bromo-benzenesulfonyl chloride (0.686 g, 2.68 mmol) in tetrahydrofuran (4 ml_) was added to the reaction mixture and stirring continued for another 2 hours. Tetrahydrofuran was evaporated off under reduced pressure, then the reaction mixture was diluted with ethyl acetate (20 ml_). The inorganic materials were filtered off through a celite bed. The filtrate was washed with 2 N aqueous HCI (5 ml_), dried over anhydrous sodium sulfate and concentrated in vacuo to yield 1.00 g (92%) of 4- (4-bromo-benzenesulfonyl)-piperazine-1 -carboxylic acid terf-butyl ester as a white solid, which was used in the next step without further purification. MS cald. for Ci5H2IBrN2O4S [(M+NH4)+] 422, obsd. 422.1. |
| 91% |
With triethylamine In 1,4-dioxane at 20℃; for 1h; |
To a solution of tert-butyl 1-piperazine-carboxylate (932 mg, 5 mmol) and triethyl amine (836(J,L, 6 mmol) in dioxane (10 mL) was added 4-bromo-benzenesulfonyl chloride (1.28 g, 5 mmol).A white precipitate begins to form almost immediately. The reaction mixture was stirred for 1hour at room temperature and the filtered. The filtrate was concentrated in vacua to yield theproduct as a shiny white solid (1.85 g, 91%). *H NMR (CDC13) 5 1.44 (s, 9H), 3.01 (t, 4H, J =5.1 Hz), 3.53 (t, 4H, J= 5.1 Hz), 7.64 (dt, 2H, /= 2.1, 8.7 Hz), 7.70 (dt, 2H, J = 2.1, 8.7). |
| 83% |
Stage #1: 1-t-Butoxycarbonylpiperazine With triethylamine In tetrahydrofuran at 0℃; for 0.166667h;
Stage #2: 4-bromobenzenesulfonyl chloride In tetrahydrofuran at 20℃; for 0.833333h; |
1 Step 1-Tert-butyl 4-((4-bromophenyl)sulfonyl)piperazine-1-carboxylate
To a solution of tert-butyl piperazine-1-carboxylate (20.1 g, 108 mmol) in THF (250 mL) was added TEA (19.8 g, 196 mmol) at 0° C. The mixture was stirred at 0° C. for 10 minutes, then 4-bromobenzene sulfonylchloride (25.0 g, 97.8 mmol) was added to the reaction mixture. The reaction mixture was then allowed to warm to rt and stirred for 50 minutes. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was washed with water (100 mL) and 10% HCl (50 mL), and then extracted with DCM (2×50 mL). The organic layer was washed with NaHCO3 (50 mL) until the pH=8. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=0:1) to give the title compound (33 g, 83% yield)) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.72-7.70 (m, 2H), 7.64-7.62 (m, 2H), 3.54 (t, J=4.8 Hz, 4H), 3.00 (t, J=4.8 Hz, 4H), 1.43 (s, 9H). |
| 83% |
Stage #1: 1-t-Butoxycarbonylpiperazine With triethylamine In tetrahydrofuran at 0℃; for 0.166667h;
Stage #2: 4-bromobenzenesulfonyl chloride In tetrahydrofuran at 25℃; for 0.833333h; |
22.1 Step 1: tert-butyl 4-((4-bromophenyl)sulfonyl)piperazine-1-carboxylate (3):
To a solution of tert-butyl piperazine-1-carboxylate (20.1 g, 108 mmol) in THF (250 mL) was added TEA (19.8 g, 196 mmol). The mixture was stirred at 0 °C for 10 minutes. Then 4- bromobenzene sulfonylchloride (25.0 g, 97.8 mmol) was added to the reaction mixture, the reaction mixture was stirred at 25 °C for 50 minutes. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was washed with water (100 mL) and 10 % HCl (50 mL), and then extracted with DCM (2 X 50 mL). The organic layer was washed with NaHCO3 (50 mL) to pH = 8. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 0:1) to give the title compound (33 g, 83% yield)) as a white solid. 1H NMR (400MHz, CDCl3) d 7.72 - 7.70 (m, 2H), 7.64 - 7.62 (m, 2H), 3.54 (t, J = 4.8 Hz, 4H), 3.00 (t, J = 4.8 Hz, 4H), 1.43 (s, 9H) |
| 74% |
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 15h; |
33.33(a)
Example 33{a) l-(tert-Butoxycarbonyl)-4-(4-bromo-benzenesulfonyl)-piperazine20 JV-boc-Piperazine (0.5 g, 2.68 mmol) and diisopropyethylamine (0.69 g, 5.36 mmol) were dissolved in CH2Cl2 (50 mL) and cooled to O0C. 4-Bromo-phenylsulphonyl chloride (0.68 g, 2.68 mmol) in CH2Cl2 (10 mL) was added dropwise under vigorous stirring. After stirring for 15h at r.t. the reaction mixture was washed with saturated aqueous NaHCO3 EPO (2x20 mL), brine, then dried (Na2SO4) and concentrated to dryness. The solid residue was recrystallized from heptane/EtOAc mixture (2:1), filtered and washed with cold heptane. The title compound was obtained (0.8 g, 74%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.68 (d, J= 8.4 Hz, 2 H), 7.61 (d, J= 8.4 Hz, 2 H), 3.54-3.47 (m, 4 H), 3.01-2.94 (m, 4 H), 1.41 (s, 9 H). |
| 53% |
With pyridine; dmap at 60℃; for 18h; |
6.a
a) 4-Bromo-1 -[((4-terf-butoxycarbonyl)piperazin-1 -yl)sulfonyl]benzeneTo a solution of 4-bromobenzenesulfonyl chloride (10 g, 39.13 mmol) in pyridine (120 ml_), DMAP (1 mg) and 1 -te/t-butoxycarbonylpiperazine (7.20 g, 39.13 mmol) were added. The mixture was stirred at 60 0C for 18 h. It was cooled until room temperature and evaporated. The residue was washed with a saturated aqueous solution of NaHCO3 and extrated thrice with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was chromatographed over silica gel using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford 8.50 g of the desired compound (53% yield). |
|
With N-ethyl-N,N-diisopropylamine In dichloromethane |
[Referential Example 276] 1-(4-Bromophenylsulfonyl)-4-(tert-butoxycarbonyl)piperazine
[Referential Example 276] 1-(4-Bromophenylsulfonyl)-4-(tert-butoxycarbonyl)piperazine Diisopropylethylamine (4.00 ml) was added to a solution of 4-bromobenzenesulfonyl chloride (3.00 g) and 1-(tert-butoxycarbonyl)piperazine (2.40 g) in methylene chloride (50 ml) at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column (hexane: ethyl acetate = 4:1 → 1:1), followed by reprecipitation in a hexane - methylene chloride system, whereby the title compound (4.47 g) was obtained as a colorless solid. 1H-NMR (CDCl3) δ: 1.41(9H,s), 2.97(4H,t,J=5.1Hz), 3.51(4H,t,J=5.1Hz), 7.61(2H,d,J=8.8Hz), 7.69(2H,d,J=8.8Hz). MS (FAB) m/z: 405 [(M+H)+, Br79], 407 [(M+H)+, Br81], 349 [(M+H-isobutene)+, Br79], 351 [(M+H-isobutene)+, Br81], 305 [(M+H-isobutene-CO2)+, Br79], 307 [(M+H-isobutene-CO2)+, Br81]. |
|
With triethylamine In dichloromethane at 20℃; for 2.5h; |
108
Example 108. 4-(4-Bromo-benzenesuIfonyl)-piperazine-l-carboxylic acid tert-butyl ester (58); [0284] To a solution of 4-bromo-benzenesulfonyl chloride (1.0 g, 3.9 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 5.4 mmol) in dry DCM (15 mL) was added triethylamine (1.6 mL, 11 mmol). The reaction mixture was stirred at room temperature for 2.5 h and then diluted with EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over MgSθ4 and filtered. The filtrate was concentrated to afford the title compound, which was used in the next step without purification. |
|
With triethylamine In dichloromethane at 20℃; for 48h; |
|
|
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; |
3 4-(4-Bromo-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (L-31′)
To a solution of 4-bromobenzenesulfonyl chloride L-31′ (1.000 g; 3.914 mmol) in DCM (10.0 mL), piperazine-1-carboxylic acid tert-butyl ester (0.729 g; 3.914 mmol) and DIPEA (1.347 mL; 7.827 mmol) are added and stirred at RT overnight. The reaction mixture is quenched with water and extracted with DCM (3×50.0 mL). The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure to give the expected product. (0896) HPLC-MS: (M+H-BOC)+=305;307; tRet=0.77 min; method M2 |
|
With triethylamine In dichloromethane |
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