Structure of 31166-44-6
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Synonyms: 1-Cbz-Piperazine
4.5
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| CAS No. : | 31166-44-6 |
| Formula : | C12H16N2O2 |
| M.W : | 220.27 |
| SMILES Code : | O=C(N1CCNCC1)OCC2=CC=CC=C2 |
| Synonyms : |
1-Cbz-Piperazine
|
| MDL No. : | MFCD00274317 |
| InChI Key : | CTOUWUYDDUSBQE-UHFFFAOYSA-N |
| Pubchem ID : | 643495 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H315-H319-H335 |
| Precautionary Statements: | P261-P305+P351+P338 |
| Num. heavy atoms | 16 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.42 |
| Num. rotatable bonds | 4 |
| Num. H-bond acceptors | 3.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 68.53 |
| TPSA ? Topological Polar Surface Area: Calculated from |
41.57 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.53 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.97 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.31 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.14 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.35 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.26 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-1.83 |
| Solubility | 3.26 mg/ml ; 0.0148 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-1.43 |
| Solubility | 8.17 mg/ml ; 0.0371 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.0 |
| Solubility | 0.222 mg/ml ; 0.00101 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.95 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.17 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 47% | With potassium phosphate;bis(tri-tert-butylphosphine)palladium(0); In ISOPROPYLAMIDE; at 100℃; | A mixture of methyl -bromo-l-benzothiophene-^-carboxylate (60 mg, 0.21 mmol), Cbz- piperazine (0.100 mL, 0.52 mmol) and K3PO4 (220 mg) in DMAc (1 mL) was degassed by the freeze- pump-thaw method. Next, Pd[P(tert-butyl)3]2 (20 mg) was added and the mixture stirred at 100C overnight. The crude mixture was partitioned between EtOAc and sat'd NaCl, the organic layer dried (Na2SO4) and concentrated. Chromatography on SiO2 (EtOAc/CH2Cl2, 0:100 to 10:90) gave 42 mg (47%) of the ethyl ester coupled product. A mixture of this ester in 2: 1: 1 THF/MeOH/water (2 mL) was treated with LiOH (10 mg, 0.24 mmol) and stirred overnight, then partitioned between EtOAc and 1 M citric acid. The organic layer was dried (Na2SO4) and concentrated. The residue was dissolved in DMF (1 mL) and treated with EDC (25 mg, 0.13 mmol), HOBt (15 mg, 0.11 mmol), and 1,2-phenylenediamine (25 mg, 0.23 mmol), then stirred overnight. The reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3, dried (Na2SO4), concentrated and finally triturated with ether to provide the desired product: 1H NMR (600 MHz, DMSO-^6) delta 9.75 (s, 1 H), 8.13 (s, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.45 (d, J = 2.1 Hz, 1 H), 7.36 (m, 5 H), 7.32 (m, 1 H), 7.17 (dd, J = 9.1, 2.3 Hz, 1 H), 6.95 (t, J = 7.8 Hz, 1 H), 6.75 (dd, J = 9.4, 1.2 Hz, 1 H), 6.57 (t, J = 7.6 Hz, 1 H), 5.10 (s, 2 H), 4.93 (s, 2 H), 3.55 (br, 4 H), 3.25 (br, 4 H); MS cal'd 487 (MH+), exp 487 (MH+). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 96% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 70℃; for 16h; | [00199] To a suspension of Intermediate 33 A (50 mg, 0.167 mmol) and Pd2(dba)3 (15.25 mg, 0.017 mmol) in toluene (2 mL) was added xantphos (28.9 mg, 0.050 mmol), benzyl piperazine-l-carboxylate (36.7 mg, 0.167 mmol), followed by sodium tert-butoxide (48.0 mg, 0.500 mmol). The reaction mixture was stirred at 70 C for 16 h, and then filtered. The filtrate was concentrated and purified on ISCO using a 15 min gradient from 0 to 100% EtOAc in hexane to give Intermediate 33B (70 mg,0.159 mmol, 96 % yield). LC-MS (ESI) m/z 440.1 (M+H), RT = 2.27 min (Method B). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 96% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 70℃; for 16h; | To a suspension of Intermediate 10A (50 mg, 0.17 mmol) and Pd2(dba)3 (15 mg, 0.017 mmol) in toluene (2 mL) was added Xantphos (29 mg, 0.050 mmol), benzyl piperazine-l-carboxylate (37 mg, 0.17 mmol), followed by sodium tert-butoxide (48 mg, 0.50 mmol). The reaction mixture was stirred at 70 C for 16 h, and then filtered. The filtrate was concentrated and purified by flash chromatography using a 15 min gradient from 0 to 100% EtOAc in hexanes to give Intermediate 10B (70 mg, 0.16 mmol, 96% yield). LC-MS (ESI) m/z 440.1 (M+H), RT = 2.27 min (Method B). |
[ 31166-44-6 ]
[ 120157-97-3 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | With palladium diacetate; caesium carbonate; XPhos; In toluene; at 105℃;Inert atmosphere; | Into a 100-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was added <strong>[120157-97-3]tert-butyl (4-bromophenethyl)carbamate</strong> (4,00 g, 13.3 mmol) and anhydrous toluene (50 mL). To the resulting solution was added benzyl piperazine-1- carboxylate (3.53 g, 16.0 mmol), Pd(OAc)2 (300 mg, 1.34 mmol), XPhos (1.28 g, 2.69 mmol), and CsiCO, (13.1 g, 40.0 mmol). The reaction mixture was stirred overnight at 105 C in an oil bath and then cooled to RT and quenched by the addition of H20 (200 mL). The resulting mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by FCC eluting with ethyl acetate/petroleum ether (PE/EA=3 : 1) to afford benzyl 4-(4-(2-((fert-butoxycarbonyl)amino)ethyl)phenyl)piperazine-l- carboxylate as a yellow solid (5 g, 85%), LCMS (ESI, m/z) 440 [M+H]+ |
| 85% | With palladium diacetate; caesium carbonate; XPhos; In toluene; at 105℃;Inert atmosphere; | (0937) [00331] Into a 100-mL round-bottom flask, purged and maintained under an inert atmosphere of nitrogen, was added fe/t~buty (4~bromophenethyl)carbarnate (4.00 g, 13.3 mmol) dissolved in anhydrous toluene (50-mL). To the resulting solution was added benzyl piperazine-1- carboxylate (3.53 g, 16.0 mmol), Pd(OAc)2 (0.300 g, 1.34 mmol), XPhos (1.28 g, 2.69 mmol), and CS2CO3 (13.1 g, 40.0 mmol). The reaction mixture was stirred overnight at 105 C in an oil bath and then cooled to RT and quenched with H2O (200 mL). The resulting mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by FCC eluting with ethyl acetate/petroleum ether (PE/EA=3: 1) to afford benzyl 4-(4-(2-((feri-butoxycarbonyl)amino)ethyl)phenyl) piperazine-1- carboxylate as a yellow solid (5 g, 85%), LCMS (ESI, m/z): 440 [M+H]+. |
[ 31166-44-6 ]
[ 118591-58-5 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | To a solution of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (2.7 g, 10.4 mmol) and benzyl piperazine-1-carboxylate (2.3 g, 10.4 mmol) in DMF (10 mL) was added K2CO3 (2.86 g, 20.8 mmol). The solution was stirred at 80oC overnight. The mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with water (10 mL) and brine (8 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to afford the crude Benzyl 4-(2-(2-hydroxyethoxy)ethyl)piperazine-1-carboxylate (4.5 g), which was used in the next reaction without further purification |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 60% | With tetra-(n-butyl)ammonium iodide; potassium carbonate; In 1,4-dioxane; at 100.0℃; for 1.0h; | Combine <strong>[1340506-55-9]tert-butyl 6-chloropyridazine-3-carboxylate</strong> (7b) (0.4g, 1.86mmol), benzyl 1-piperazinecarboxylate (0.4g, 1.82mmol),Potassium carbonate (0.6g, 6mmol) and tetrabutylammonium iodide (0.08g, 0.2mmol) were sequentially added to 10mL 1,4-dioxane and heated to 100 degrees.The reaction was stirred for 1 h and then cooled to room temperature, the solvent was removed under reduced pressure, and 20 mL of DCM and 20 mL of water were added for extraction.After the organic layer was concentrated under reduced pressure, the residue was beaten with 30 mL of dichloromethane/petroleum ether (dichloromethane/petroleum ether (v/v) = 1/2) for 20 min.After filtration, tert-butyl 6-(4-benzyloxycarbonylpiperazin-1-yl)pyridazine-3-carboxylate (8a) (0.45 g, yield: 60%) was obtained. |
[ 31166-44-6 ]
[ 35979-69-2 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 52.7% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 60h; | To a mixture of benzyl piperazine-1-carboxylate (150 mg, 0.681 mmol) and potassium carbonate (188 mg, 1.362 mmol) in DMF (2 mL) at 0 C was added 4-bromo- 2-methylbutan-2-ol (143 mg, 0.858 mmol) in DMF (0.2 mL) in one portion. The mixture was stirred at room temperature for 60 h, diluted with ethyl acetate (10 mL), and filtered through Celite. The filtrate was diluted with ethyl acetate (60 mL), washed with water (2 x 20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The title intermediate (110 mg, 0.359 mmol, 52.7 % yield) was isolated as a white solid by ISCO chromatography (24 g silica gel, solid loading, 1-8% ethyl acetate/hexane). LCMS(M+H)+= 307.4.1H NMR (400 MHz, chloroform-d) δ 7.39-7.29 (m, 5H), 5.13 (s, 2H), 3.55-3.48 (m, 4H), 2.68-2.60 (m, 2H), 2.49 (br s, 4H), 1.66-1.61 (m, 2H), 1.23 (s, 6H). |
| 52.7% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 60h; | To a mixture of benzyl piperazine-1-carboxylate (150 mg, 0.681 mmol) and potassium carbonate (188 mg, 1.362 mmol) in DMF (2 mL) at 0 C was added 4-bromo- 2-methylbutan-2-ol (143 mg, 0.858 mmol) in DMF (0.2 mL) in one portion. The mixture was stirred at room temperature for 60 h, diluted with ethyl acetate (10 mL), and filtered through Celite. The filtrate was diluted with ethyl acetate (60 mL), washed with water (2 x 20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The title intermediate (110 mg, 0.359 mmol, 52.7 % yield) was isolated as a white solid by ISCO chromatography (24 g silica gel, solid loading, 1-8% ethyl acetate/hexane). LCMS(M+H)+= 307.4.1H NMR (400 MHz, chloroform-d) δ 7.39-7.29 (m, 5H), 5.13 (s, 2H), 3.55-3.48 (m, 4H), 2.68-2.60 (m, 2H), 2.49 (br s, 4H), 1.66-1.61 (m, 2H), 1.23 (s, 6H). |
| 52.7% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 60h; | To a mixture of benzyl piperazine-1-carboxylate (150 mg, 0.681 mmol) and potassium carbonate (188 mg, 1.362 mmol) in DMF (2 mL) at 0 C was added 4-bromo- 2-methylbutan-2-ol (143 mg, 0.858 mmol) in DMF (0.2 mL) in one portion. The mixture was stirred at room temperature for 60 h, diluted with ethyl acetate (10 mL), and filtered through Celite. The filtrate was diluted with ethyl acetate (60 mL), washed with water (2 x 20 mL) and brine (20 mL), and dried over anhydrous MgSO4. The title intermediate (110 mg, 0.359 mmol, 52.7 % yield) was isolated as a white solid by ISCO chromatography (24 g silica gel, solid loading, 1-8% ethyl acetate/hexane). LCMS(M+H)+= 307.4.1H NMR (400 MHz, chloroform-d) δ 7.39-7.29 (m, 5H), 5.13 (s, 2H), 3.55-3.48 (m, 4H), 2.68-2.60 (m, 2H), 2.49 (br s, 4H), 1.66-1.61 (m, 2H), 1.23 (s, 6H). |

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