| 84% |
In dichloromethane; at 0 - 20℃; for 4h; |
To a solution of (S)-methylpiperazine (400 mg) in dichloromethane (20 mL) at0 C was added di-tert-butyl dicarbonate (871 mg). The reaction was stirred at room <n="187"/>temperature for 4 h and then quenched with water (20 mL) and extracted into dichloromethane (2 x 40 mL). The combined organics were washed with saturated aqueous brine solution (40 mL), dried (MgSO4) and concentrated to give (S)-3-methyl-piperazine-l- carboxylic acid tert-butyl ester as a white solid (669 mg, 84%). |
| 80% |
With triethylamine; In dichloromethane; for 5h; |
Step B tert-Butyl (3S)-3-methylpiperazine-1-carboxylate To a solution of (2S)-2-methylpiperazine (20.0 g, 0.200 mol) in methylene chloride (300 mL) and triethylamine (20.4 g, 0.202 mol) was added dropwise a solution of di-tert-butyl dicarbonate (44.0 g, 0.202 mol) in CH2Cl2 (100 mL) over 5 hrs. The mixture was washed with water, brine, and then dried over MgSO4 and concentrated. Column chromatography on silica (10-20% MeOH in EtOAc) afforded 32.0 g (80%) of the title compound as an oil. Step C tert-Butyl (3S)-4-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazine-1-carboxylate |
| 76.4% |
With hydrogenchloride; In methanol; water; at 15 - 30℃; for 18h; |
Example 5 (0326) [0227] Compound 154 was prepared according to the reaction scheme in Figures 3 and 4. (0327) [0228] In a first step, compound 40 was prepared from compound 30 as follows: (0328) (0329) 30 40 (0330) [0229] Water (500 g, 5 w/w%) was charged to a reaction flask. Compound 30 (2- methylpiperazine) (100 g, 998.4 mmol, 1 eq.) was charged to the reaction flask with agitation. HC1 (36% aqueous, 102.1 g, 1008 mmol, 1.01 eq.) and methanol (200 g) were charged to the reaction flask with agitation. A solution of Boc20 (222 g, 1008 mmol, 1.01 eq.) in methanol (200 g) was added dropwise to the reaction flask at 15 to 25 C followed by stirring for 18 hours at 20 to 30C. The flask contents were evaporated to dryness in vacuo at 40 to 50C to form a residue. Water (500 g) was added to the residue and the mixture was stirred for 1 hours. The mixture was filtered and the collected solids were washed with water (50 g). The aqueous filtrate was extracted with ethylacetate (500 mL). The extracted aqueous phase was adjusted to a pH in excess of 12 with 30% NaOH and was then extracted with ethylacetate (500 mL) three times. The organic phase was washed with brine (500 g) twice and was then dried with anhydrous Na2S04. The dried mixture was filtered and the collected solids were rinsed with ethylacetate (100 mL). The filtrate was concentrated to dryness in vacuo at 50 to 60C and further concentrated under high vacuum (5 mm Hg) at 65 to 75C for 3 hours to yield compound 40 (tert-butyl 3-methylpiperazine-l-carboxylate). The purity of compound 40 was 97.7 area%, the assay was 95.9% and the yield was 76.4%. |
| 49% |
In dichloromethane; at 0 - 20℃; |
<strong>[74879-18-8](S)-2-methylpiperazine</strong> (5.00 g, 49.9 mmol) was dissolved in DCM (150 mL). A solution of boc anhydride (5.47 g, 25.0 mmol) in DCM (50 mL) was added dropwise at 0 C. The reaction mixture was stirred at rt for 2 h. The solution was filtered and concentrated under reduced pressure. Water (100 mL) was added to the residue and it was filtered again. The filtrate was saturated with K2CO3 and extracted with Et2O (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide 4.92 g title compound (49%) as a solid. 1H NMR (300 MHz, CDCl3) delta ppm 1.03 (d, J=6.3 Hz, 3H) 1.45 (s, 9H) 1.53 (br. s, 1H) 2.38 (t, J=11.8 Hz, 1H) 2.65-2.72 (m, 1H) 2.74-2.76 (m, 2H) 2.92-2.95 (m, 1H) 3.92 (br. s, 2H). |
|
With triethylamine; In methanol; for 17h; |
Triethylamine (2.85 ml) was added to a solution of (S)-2-methyl piperazine (1 g) in methanol (25 ml) followed by portion wise addition of BOC anhydride (2.18 g). The reaction mixture was stirred for 17 h, concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic phase was dried (MgSO4), and then concentrated in vacuo. The residue was purified by chromatography (silica, ethyl acetate as eluent, then 90:10:1 mixture of ethyl acetate: methanol: ammonia) to give the sub-title compound (1.3 g). 1H NMR (CDCl3) delta 4.03-3.85 (2H, m), 2.95 (IH, d), 2.86-2.65 (3H, m), 2.5-2.3 (IH, m), 1.48 (9H, s) and 1.05 (3H, d). |
|
With triethylamine; In hexane; dichloromethane; ethyl acetate; |
Step 1: 3-(S)-Methyl-piperazine-1-carboxylic Acid Tert-Butyl Ester Triethylamine (3 g, 4.2 mL, 30 mmol) was added to a solution of 2-(S)-methyl piperazine (2 g, 20 mmol) in dichloromethane (40 mL) followed by di-tert-butyl-dicarbonate (4.8 g, 22 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The crude product was purified using a short plug of silica gel using hexane/ethyl acetate (1:1). 1H-NMR (CDCl3) delta: 1.03 (3H, d), 1.45 (9H, s), 1.65 (1H, s), 2.35-2.42 (1H, m), 2.66-2.80 (3H, m), 2.92-2.95 (1H, m), 3.92 (2H, br s). ESI-MS m/z: 201(M+1). |
|
With triethylamine; In methanol; for 17h; |
Triethylamine (2.85 ml) was added to a solution of (S)-2-methyl piperazine (1 g) in methanol (25 ml), this was followed by portionwise addition of BOC anhydride (2.18 g). The reaction mixture was stirred for 17 h, then concentrated under reduced pressure. Water was added to the residue and extracted EtOAc (×3), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica (eluent EtOAc, then 9:1:1 EtOAc:MeOH:NH3) to give the sub-title compound as a colourless oil, yield 1.3 g.1H NMR CDCl3: delta 4.04-3.82 (2H, m), 2.95 (1H, d), 2.81-2.66 (3H, m), 2.48-2.32 (1H, m), 1.47 (9H, s), 1.05 (3H, d). |
| 562 mg |
With triethylamine; In dichloromethane; at 0℃; for 2h; |
Description 146(S)-tert-butyl 3-methylpiperazine-1-carboxylate (1)146)NHBocTo a solution of <strong>[74879-18-8](S)-2-methylpiperazine</strong> (500 mg) in DCM (5 mL) was added Et3N (1010 mg) and(Boc)20 (1198 mg) in DCM (3 mL) dropwise. The mixture was stirred at 0C for 2 hours. DCM(10 mL), water (5 mL) and 30% NaHSO4 (10 mL) aqueous solution were added to the reactionmixture. The resulted mixture was stirred for 10 mm, and to the aqueous layer was added saturatedNa2CO3 solution until pH = 8, extracted with isopropyl alcohol: chlorofonn1: 3 (5 x20 mL). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to afford the title compound (562 mg) as pale yellow oil, MS (ESI): C10H20N202 requires 200; found 201 [M+H]. |
|
With triethylamine; In hexane; dichloromethane; |
Step 1 3-(S)-Methyl-piperazine-1-carboxylic acid tert-butyl ester Triethylamine (3 g, 4.2 mL, 30 mmol) was added to a solution of 2-(S)-methyl piperazine (2 g, 20 mmol) in dichloromethane (40 mL) followed by di-tert-butyl-dicarbonate (4.8 g, 22 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The crude product was purified using a short plug of silica gel using hexane/ethyl acetate (1:1). 1H-NMR (CDCl3) delta: 1.03 (3H, d), 1.45 (9H, s), 1.65 (1H, s), 2.35-2.42 (1H, m), 2.66-2.80 (3H, m), 2.92-2.95 (1H, m), 3.92 (2H, br s). ESI-MS m/z: 201 (M+1). |
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