4-(4-Aminobenzyl)piperazine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (1.100 g, 3.423 mmol), ammonium chloride (0.915 g, 17.114 mmol) and Zn dust (1.119 g, 17.114 mmol) in tetrahydrofuran (20 mL) / water (20 mL) was stirred at the room temperature for 12 hr. The reaction mixture was filtered to remove solids. Then, water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The title compound was used without further purification (tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate, 0.900 g, 90.2 percent, yellow solid).To a solution of tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate derivatives (1 mmol) (compound (ST) with suitable substitution) in ethyl acetate (O.12M ml), tin(ii) chloride dihydrate (5 mmol) was added and the resulting mixture was left stirring at RT overnight.Then, saturated aqueous solution of sodium bicarbonate (20 mL) was addedand vigorously stirred for 1 hour. Solids were removed by filtration throught a celite pad and the organic layer of the filtrate was separated and washed with water (20 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated to give the following compounds of Formula (X).ferf-Butyt 4-(4-nitrobenzyl)piperazine-1-carboxylate (I92) (0.500 g, 1.56 mmol), ethyl acetate (100 mL) and 10percent Pd/C (150 mg) were agitated under a hydrogen atmosphere at 50 psi. After two hours the mixture was filtered through celite and concentrated. The residue was chromatographed (12 g silica cartridge, 0-60percent ethyl acetate/petroleum benzine 40-60 °C) to give the title compound (193) (327 mg, 72percent yield) as a white solid; terf-Butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (192) (0.500 g, 1.58 mmol), ethyl acetate (100 mL) and 10percent Pd/C (150 mg) were agitated under a hydrogen atmosphere at 50 psi. After two hours the mixture was filtered through celite and concentrated. The residue was chromatographed (12 g silica cartridge, 0-60percent ethyl acetate/petroleum benzine 40-60 °C) to give the title compound {193) (327 mg, 72percent yield) as a white solid; A solution of 4-(4-nitro-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (2.82 g, 8.77 mmol) was hydrogenated on an H-Cube apparatus with a 5percent Pd/C cartridge under the following conditions: flow rate=1 mL/min, heating column temperature=30° C., HSynthesis of Compound 5 tert-Butyl 4-[4-(cis-4, 7, 10, 13, 16, 19-docosahexenoyl)amino]benzyl-1-piperazinecarboxylate (5). To compound 3 (0.68 g, 2.1 mmol) in ethyl acetate (100 mL) was added 10% Pd/C (0.1 g), and the reaction mixture was hydrogenated for 2 h under a pressure of 60 lb/inch2. The product was filtered, and solvent was removed in vacuo to afford amine 4 (0.6 g, 97% yield). Without further purification, to amine 4 (0.6 g, 2.06 mmol) dissolved in acetonitrile (90 mL) was added cis-4, 7, 10, 13, 16, 19-docosahexenoic acid (DHA, 0.67 g, 2.0 mmol), 2-(1-benzotriazol-1-yl)-1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HBTU, 0.94 g, 2.5 mmol), and N, N-diisopropylethylamine (2.1 mL). The reaction mixture was stirred overnight. Solvent was removed in vacuo, and the product was purified by column chromatography, eluding with ethyl acetate to afford 5 as an oil (0.91 g, 73% yield). 1H NMR (DMSO-d6): 9.84 (s, 1H, NH), 7.53-7.51 (d, 2H, J=8.80 Hz, Ar-H), 7.19-7.17 (d, 2H, J=8.40 Hz, Ar-H), 5.35-5.31 (m, 12H, CH=CH), 3.40 (s, 2H, CH2), 3.29 (brs, 4H, 2*CH2), 2.83-2.75 (m, 10H, 5*CH2), 2.35 (brs, 4H, 2*CH2), 2.27 (t, 4H, J=4.80 Hz, 2*CH2), 2.04-2.00 (m, 2H, CH2), 1.38 (s, 9H, 3*CH3), 0.91 (t, 3H, J=7.20 Hz, CH3). Anal. (C38H55N3O3.4.1H2O) C, H, NA solution of tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (1.100 g, 3.423 mmol), ammonium chloride (0.915 g, 17.114 mmol) and Zn dust (1.119 g, 17.114 mmol) in tetrahydrofuran (20 mL) / water (20 mL) was stirred at the room temperature for 12 hr. The reaction mixture was filtered to remove solids. Then, water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The title compound was used without further purification (tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate, 0.900 g, 90.2 %, yellow solid).To a solution of tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate derivatives (1 mmol) (compound (ST) with suitable substitution) in ethyl acetate (O.12M ml), tin(ii) chloride dihydrate (5 mmol) was added and the resulting mixture was left stirring at RT overnight.Then, saturated aqueous solution of sodium bicarbonate (20 mL) was addedand vigorously stirred for 1 hour. Solids were removed by filtration throught a celite pad and the organic layer of the filtrate was separated and washed with water (20 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated to give the following compounds of Formula (X).ferf-Butyt 4-(4-nitrobenzyl)piperazine-1-carboxylate (I92) (0.500 g, 1.56 mmol), ethyl acetate (100 mL) and 10% Pd/C (150 mg) were agitated under a hydrogen atmosphere at 50 psi. After two hours the mixture was filtered through celite and concentrated. The residue was chromatographed (12 g silica cartridge, 0-60% ethyl acetate/petroleum benzine 40-60 C) to give the title compound (193) (327 mg, 72% yield) as a white solid; 1H N R (400 MHz, CDCI3) delta 7.11 - 7.05 (m, 2H), 6.67 - 6.61 (m, 2H), 3.62 (s, 2H), 3.43 - 3.37 (m, 6H), 2.40 - 2.30 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 1.80 min; m/z 292.1 [M+H]+terf-Butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (192) (0.500 g, 1.58 mmol), ethyl acetate (100 mL) and 10% Pd/C (150 mg) were agitated under a hydrogen atmosphere at 50 psi. After two hours the mixture was filtered through celite and concentrated. The residue was chromatographed (12 g silica cartridge, 0-60% ethyl acetate/petroleum benzine 40-60 C) to give the title compound {193) (327 mg, 72% yield) as a white solid; 1H N R (400 Hz, CDCI3) delta 7.11 - 7.05 (m, 2H), 6.67 - 6.61 (m, 2H), 3.62 (s, 2H), 3.43 - 3.37 (m, 6H), 2.40 - 2.30 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 1.80 min; m/z 292.1 [M+H]+.A solution of 4-(4-nitro-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (2.82 g, 8.77 mmol) was hydrogenated on an H-Cube apparatus with a 5% Pd/C cartridge under the following conditions: flow rate=1 mL/min, heating column temperature=30 C., H2 pressure=40 bar. The material was passed through the column twice more in order to complete the reaction. Solvents were evaporated in vacuo. Purification of the residue on a 50-g Isolute SPE column on a FlashMaster system with 25-50% EtOAc-hexane afforded the title compound (1.70 g, 67%) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C16H25N3O2, 292.2 (M+H), found 292.1.b. 4-(4-tert.butoxycarbonyl-piperazinomethyl)-aniline Prepared analogously to Example Id by catalytic hydrogenation of 4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene with Raney nickel in ethyl acetate/methanol (1:1). Melting point: 106-107 C. Rf value: 0.6 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)To a solution of compound 78 (35 g, 110 mmol) in a mixture of THF (300 mL)-EtOH (100 mL) was added 50% Raney Nickel (12 g, aqueous slurry), and the mixture was placed on a Parr Shaker and hydrogenated at P0=40 Psi for 16 h. The spent catalyst was filtered off, and the filtrate was concentrated in vacuo. The resultant residue was purified using flash column chromatography on silica gel, eluting with CH2Cl2-MeOH (25:1) to provide compound 79 as a light yellow solid (24.1 g).Compound 3 is synthesized by reacting compound 3-A with 3-B using the conditions indicated above. Compound 3-C is then reacted with compound 3-D using the reaction conditions shown to afford the product 3-E. The amine protecting group is then removed using suitable acidic conditions ( e.g ., TFA or HC1 in dioxane) to afford Compound 3. Purification using standard techniques (e.g., silica gel chromatography or prep-HPLC) as needed.Compound 1 is synthesized by reacting compound l-A with l-B using the conditions indicated above. Compound l-C is then reacted with compound l-D using the reaction conditions shown to afford the product l-E. The amine protecting group is then removed using suitable acidic conditions ( e.g ., TFA or HC1 in dioxane). Purification using standard techniques (e.g., silica gel chromatography or prep-HPLC) as needed.

Molecular Weight:291.39
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:291.19467705
Monoisotopic Mass:291.19467705
Topological Polar Surface Area:58.8
Heavy Atom Count:21
Complexity:338
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes