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[ CAS No. 130636-61-2 ]

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Chemical Structure| 130636-61-2
Chemical Structure| 130636-61-2
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CAS No. :130636-61-2 MDL No. :MFCD03407491
Formula : C16H23N3O4 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W :321.37 g/mol Pubchem ID :23506946
Synonyms :

Safety of [ 130636-61-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 130636-61-2 ]

  • Upstream synthesis route of [ 130636-61-2 ]
  • Downstream synthetic route of [ 130636-61-2 ]

[ 130636-61-2 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 130636-61-2 ]
  • [ 304897-49-2 ]
YieldReaction ConditionsOperation in experiment
97% With hydrogen In ethyl acetate for 2 h; Example 2
Synthesis 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 10percent 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, 97percent 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, 73percent 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, N
90.2% With ammonium chloride; zinc In tetrahydrofuran; water at 20℃; for 12 h; 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).
81% With tin(II) chloride dihdyrate In ethyl acetate at 20℃; 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).
72% With hydrogen In ethyl acetate for 2 h; 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; 1H N R (400 MHz, CDCI3) δ 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]+
72% With palladium 10% on activated carbon; hydrogen In ethyl acetate for 2 h; 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; 1H N R (400 Hz, CDCI3) δ 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]+.
67% at 30℃; 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., 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 25-50percent EtOAc-hexane afforded the title compound (1.70 g, 67percent) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C16H25N3O2, 292.2 (M+H), found 292.1.

Reference: [1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 19, p. 5592 - 5599
[2] Patent: US2004/34033, 2004, A1, . Location in patent: Page/Page column 12; Sheet 1
[3] Patent: WO2017/18803, 2017, A1, . Location in patent: Paragraph 1492; 1493; 1494
[4] Patent: WO2016/146220, 2016, A1, . Location in patent: Page/Page column 26; 27
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 4, p. 1499 - 1518
[6] Patent: WO2012/110773, 2012, A1, . Location in patent: Page/Page column 120; 121
[7] Patent: WO2014/27199, 2014, A1, . Location in patent: Page/Page column 123
[8] Patent: US2007/249649, 2007, A1, . Location in patent: Page/Page column 116
[9] Archiv der Pharmazie, 2000, vol. 333, # 8, p. 267 - 274
[10] Patent: US2003/69299, 2003, A1,
[11] Patent: US2007/167435, 2007, A1, . Location in patent: Page/Page column 47
  • 2
  • [ 100-11-8 ]
  • [ 57260-71-6 ]
  • [ 130636-61-2 ]
YieldReaction ConditionsOperation in experiment
95% With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 4 h; tert-Butyl 4-(4-nitrobenzyl)-1-piperazinecarboxylate (3). To a solution of tert-butyl 1-piperazinecarboxylate, 1 (0.74 g, 4 mmol), and 4-nitrobenzyl bromide, 2 (0.86 g, 4 mmol), in N,N-dimethylformamide (DMF, 5 mL) was added potassium carbonate (3 g), and the reaction mixture was stirred at room temperature for 4 h. The product was extracted with ethyl acetate (50 mL), and the organic phase was washed with water (20 mL.x.3). The solution was dried with sodium sulfate, and solvent was removed in vacuo. The product was purified by column chromatography, eluting with ethyl acetate to afford 3 as a solid (1.22 g, 95percent yield), mp 99-100° C. 1H NMR (DMSO-d6): 8.21-8.19 (d, 2H, J=8.8 Hz, Ar-H), 7.61-7.59 (d, 2H, J=8.0 Hz, Ar-H), 3.63 (s, 2H, CH2), 3.34-3.30 (m, 4H, partially obscured, 2.x.CH2), 2.35-2.32 (m, 4H, 2.x.CH2), 1.39 (s, 9H, 3.x.CH3). Anal. (C16H23N3O4) C, H, N.
95% With triethylamine In acetonitrile at 20℃; for 0.333333 h; A solution of piperazine-1-carboxylic acid tert-butyl ester (1.90 g, 10.2 mmol) and triethylamine (1.55 mL, 11.1 mmol) in CH3CN (9 mL) was treated with 1-bromomethyl-4-nitro-benzene (2.00 g, 9.26 mmol) as a solution in CH3CN (15 mL) at RT for 20 min. The mixture was concentrated in vacuo. The residue was taken up in CH2Cl2 (20 mL) and washed with water (1.x.20 mL). The aqueous layer was extracted with CH2Cl2 (2.x.20 mL), and the combined organic layers were washed with water (1.x.40 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 50-g Isolute SPE column on a FlashMaster system with 10-25percent EtOAc-hexane afforded the title compound (2.82 g, 95percent) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C16H23N3O4, 322.2 (M+H), found 321.9.
95% With sodium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h; 1-(Bromomethyl)-4-nitrobenzene (1 .08 g, 5.00 mmol) was added to a vigorously stirred mixture of fert-butyl piperazine-1 -carboxylate (1 .02 g, 5.50 mmol) and sodium carbonate (0.583 g, 5.50 mmol) in DMF (5 mL) at room temperature and the resulting mixture stirred for two hours. Water (25 mL) was added, and the resulting suspension was allowed to stand for five minutes then filtered. The collected solid was washed with water (25 mL) and air-dried to give the title compound (192) (1 .523 g, 95percent yield); 1H NMR (400 MHz, CDCI3) δ 8.32 - 8.10 (m, 2H), 7.51 (d, J = 8.8 Hz, 2H), 3.59 (s, 2H), 3.52 - 3.39 (m, 4H), 2.43 - 2.34 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 4.58 min, m/z 266.1 [M-tBu+2H]\\ 222.1 [M-Boc+2Hf.
95% With sodium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h; 1-(Bromomethyl)-4-nitrobenzene (1.08 g, 5.00 mmol) was added to a vigorously stirred mixture of ferf-butyi piperazine-1-carboxylate (1.02 g, 5.50 mmol) and sodium carbonate (0.583 g, 5.50 mmol) in DMF (5 mL) at room temperature and the resulting mixture stirred for two hours. Water (25 mL) was added, and the resulting suspension was allowed to stand for five minutes then filtered. The collected solid was washed with water (25 mL) and air-dried to give the title compound (192) (1.523 g, 95percent yield); 1H N R (400 MHz, CDCI3) δ 8.32 - 8.10 (m, 2H), 7.51 (d, J = 8.8 Hz, 2H), 3.59 (s, 2H), 3.52 - 3.39 (m, 4H), 2.43 - 2.34 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 4.58 min, m/z 268, 1 [ -tBu+2H]+, 222.1 [M-Boc+2H].
73.9% With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 5 h; A solution of 1-(bromomethyl)-4-nitrobenzene (1.000 g, 4.629 mmol), N,N-diisopropylethylamine (1.209 mL, 6.943 mmol) and tert-butyl piperazine1-carboxylate (0.948 g, 5.092 mmol) in acetonitrile (50 mL) was stuffed at the room temperature for 5 hr. Then, water was added to the reaction mixture, 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 residue was chromatographed (5i02, 12 g cartridge; ethyl acetate / hexane = 0 percent to 20 percent) to give tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate as yellow oil (1.100 g, 73.9 percent).
71% With triethylamine In dichloromethane at 20℃; for 3 h; 1-(bromomethyl)-4-nitrobenzene (1 mmol) was added to a solution of tert-butyl piperazine-1 -carboxylate derivative (1.2 mmol) (Compound (ST) with suitable substitution) and triethylamine (2 mmol) in DCM. The reaction is slightly exothermic. The resulting mixture was left stirring 3 hours at RT. The reaction was diluted withDCM, washed with water and diluted citric acid, dried and evaporated to give the compounds of examples 1,2,3.

Reference: [1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 19, p. 5592 - 5599
[2] Patent: US2004/34033, 2004, A1, . Location in patent: Page/Page column 12; Sheet 1
[3] Patent: US2007/249649, 2007, A1, . Location in patent: Page/Page column 116
[4] Patent: WO2012/110773, 2012, A1, . Location in patent: Page/Page column 120
[5] Patent: WO2014/27199, 2014, A1, . Location in patent: Page/Page column 122
[6] Patent: WO2017/18803, 2017, A1, . Location in patent: Paragraph 1490; 1491; 1492
[7] Patent: WO2016/146220, 2016, A1, . Location in patent: Page/Page column 25; 26
[8] Journal of Medicinal Chemistry, 2018, vol. 61, # 4, p. 1499 - 1518
  • 3
  • [ 555-16-8 ]
  • [ 57260-71-6 ]
  • [ 130636-61-2 ]
Reference: [1] Patent: US2007/167435, 2007, A1, . Location in patent: Page/Page column 47
  • 4
  • [ 100-14-1 ]
  • [ 57260-71-6 ]
  • [ 130636-61-2 ]
YieldReaction ConditionsOperation in experiment
99% With triethylamine In dichloromethane a.
4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene
10.6 g (57 mmol) of N-tert.butoxycarbonyl-piperazine are dissolved in 100 ml of dichloromethane and combined with 10.7 g (63 mmol) of 4-nitrobenzylchloride and 24 ml (171 mmol) of triethylamine.
The mixture is refluxed for 12 hours.
After cooling to ambient temperature the reaction solution is washed several times with water.
The organic phase is dried over magnesium sulphate and then evaporated to dryness.
Yield: 17 g (99percent) of theory
Melting point: 83-84° C.
Rf value: 0.7 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)
Reference: [1] Patent: US2003/69299, 2003, A1,
[2] Patent: US2003/69299, 2003, A1,
  • 5
  • [ 24424-99-5 ]
  • [ 58198-49-5 ]
  • [ 130636-61-2 ]
Reference: [1] Archiv der Pharmazie, 2000, vol. 333, # 8, p. 267 - 274
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