1-tert-Butylpiperazine

The compound of Step 20.2 (1 g, 4.6mmol) is dissolved in ethanol (15 mL). KOH (1.2 g, 201mmol) is added and the reaction is heated to reflux for 12 h. It is allowed to cool to rt and concentrated under reduced pressure. The residue is taken up in EtOAc and washed with brine. Organic layers are dried overNa2SO4, concentrated and dried under high vacuum to give the title compound as a yellow oil. (546 mg, 3.7 mmol, 82 percent).CsH ; MS (ES+), M+H = 143.5;'H-NMR (300 MHz, CDC13) : 2.91-2. 84 (m, 4H), 2.59-2. 48 (m, 4H), 1.02 (s, 9H).The compound of Step 20.2 (1 g, 4.6mmol) is dissolved in ethanol (15 mL). KOH (1.2 g, 201mmol) is added and the reaction is heated to reflux for 12 h. It is allowed to cool to rt and concentrated under reduced pressure. The residue is taken up in EtOAc and washed with brine. Organic layers are dried overNa2SO4, concentrated and dried under high vacuum to give the title compound as a yellow oil. (546 mg, 3.7 mmol, 82 percent).CsH ; MS (ES+), M+H = 143.5;'H-NMR (300 MHz, CDC13) : 2.91-2. 84 (m, 4H), 2.59-2. 48 (m, 4H), 1.02 (s, 9H).Into a 250 ml round-bottom flask was added 20mmol compound (1), 150 ml tetrahydrofuran. At room temperature under stirring slowly drop 20mmol tert-butyl chloride and 50 ml acetonitrile solution. Around 2 hours dropping complete. Continue stirring for 2 hours. Heat to reflux and stir for 5 hours, cooling filter, 10 ml tetrahydrofuran washing, the solid drying to obtain the mono-substituted piperazine acid dihydrochloride (5) (R=tert-butyl). (5) estimate added into 250 ml round bottom flask, add 200 ml tetrahydrofuran and base. Under stirring, heat at reflux and react for 4 hours, cooling to room temperature, filtered, the filtrate solvent and low boiling, rectification collects the product, gain the light yellow oily liquid N-tert butyl piperazine (6) (R=tert-butyl), yield 92percent (tert butyl chlorine idea), General procedure: 1- (5- (trifluoromethyl) pyridin-2-yl) piperazine (13.3 g, 40.0 mmol) was added to 150 mL of a 4N hydrochloric acid-dioxane solution, and the reaction was stirred at room temperature for 3 hours, and the solvent was distilled off under reduced pressure. The residue was adjusted to pH 8-9 with 15% Na2CO3 solution, extracted twice with ethyl acetate, and the organic layers were combined, washed with water and saturated NaCl aqueous solution, and dried with anhydrous Na2SO4 to obtain 8.42 g of A-8, yield 91. %, At room temperature, p-tert-butylpiperazine (2.84 g, 20 mmol), 7-chloro-1-ethyl-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridin-3-carboxylic acid (2.72 g, 10 mmol)Dissolved in 15mL of dimethyl sulfoxide, gradually heated to 120 C, and reacted for 4h.Reduce the temperature to room temperature, and add water (20 mL) to the above reaction system.Extract with ethyl acetate (3 * 15 mL).The organic layers were combined, and the organic layers were sequentially washed with water (2 * 15mL) and saturated brine (15mL).Dry over anhydrous magnesium sulfate. Desolventizing under reduced pressure, column chromatography (eluent: ethyl acetate, A mixture of petroleum ether and formic acid (volume ratio 1: 1: 0.01)) yields 2.26 g of the product, The yield was 60%.A mixture containing 4-nitrobenzoyl chloride (167 mg), 1-(tert-butyl)piperazine (142 mg), triethylamine (1.0 mL)and dichloromethane (10 mL) was stirred at room temperature for 1 hour, and then concentrated under a reduced pressure, the obtained residue was purified through silica gel column chromatography (elution solvent: dichloromethane-ethyl acetate), and thereby 4-(tert-butyl)piperazin-1-yl)(4-nitrophenyl)methanone (246 mg)as a colorless powder was obtained.4-((4-(Chloromethyl)-3-methylbenzyl)amino)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (0.075 g, 0.176 mmol), 1-(tert-butyl)piperazine (0.025 g, 0.176 mmol), and DIEA (0.092 mL, 0.528 mmol) were dissolved in DMF (1.0 mL) and the resulting solution was stirred at ambient temperature for 48 hours. The reaction mixture was purified by standard methods to afford 4-((4-((4-(tert-butyl)piperazin-1-yl)methyl)-3-methylbenzyl)amino)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (56.9 mg, 60.8% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 11.10 (s, 1H), 8.20 (s, 1H), 7.52 (dd, J=8.44, 7.21 Hz, 1H), 7.08-7.20 (m, 4H), 7.00 (dd, J=17.85, 7.83 Hz, 2H), 5.07 (dd, J=12.84, 5.26 Hz, 1H), 4.49 (d, J=6.11 Hz, 2H), 3.35 (s, 3H), 2.84-2.98 (m, 1H), 2.54-2.63 (m, 2H), 2.40-2.48 (m, 3H), 2.32-2.39 (m, 3H), 2.28 (s, 3H), 1.96-2.14 (m, 1H), 0.98 (s, 9H). LCMS (ESI) m/z 532.4 [M+H]+.General procedure: Methane sulfonyl chloride (58 muL, 0.7 mmol) and triethylamine (238 muL) was added to a solution of compound 2 (180 mg, 0.6 mmol) in dichloromethane (5 mL) and stirred at room temperature for 1 h. After completion of the reaction by TLC, ice water was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL×3). The organic layer was washed with brine and dried over Na2SO4. The solid was filtered off, and the filtrate was concentrated under reduced pressure to give the methylsulfonylated product (210 mg, yield 93%). To a solution of the methylsulfonylated product (210mg, 0.6 mmol) in DMF (5 mL) was added K2CO3 (111 mg, 0.8 mmol), morpholine (93 muL, 1.0 mmol). The mixture was stirred at 90 C for 2 h. After completion of the reaction by TLC, The mixture was extracted with dichloromethane (20 mL×3). The organic layer was washed with brine and dried over Na2SO4. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residues were separated by silica gel column chromatography (V petroleum ether: V ethyl acetate = 8:1) to give CH-H-1 (108 mg, yield 53%). Under the same conditions, compounds CH-H-2 to CH-H-16 were obtained.

Molecular Weight:142.24
XLogP3:0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:142.146998583
Monoisotopic Mass:142.146998583
Topological Polar Surface Area:15.3
Heavy Atom Count:10
Complexity:98.3
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes