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Chemical Structure| 31166-44-6 Chemical Structure| 31166-44-6

Structure of 31166-44-6

Chemical Structure| 31166-44-6

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Synonyms: 1-Cbz-Piperazine

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Product Details of [ 31166-44-6 ]

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

Safety of [ 31166-44-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 31166-44-6 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

41.57 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.53
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.97
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.31
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.14
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.35
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.26

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.83
Solubility 3.26 mg/ml ; 0.0148 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.43
Solubility 8.17 mg/ml ; 0.0371 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.0
Solubility 0.222 mg/ml ; 0.00101 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.95 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.17

Application In Synthesis of [ 31166-44-6 ]

* 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.

  • Downstream synthetic route of [ 31166-44-6 ]

[ 31166-44-6 ] Synthesis Path-Downstream   1~9

  • 1
  • [ 360576-01-8 ]
  • [ 31166-44-6 ]
  • C22H22N2O4S [ No CAS ]
YieldReaction ConditionsOperation 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+).
  • 2
  • [ 75806-85-8 ]
  • [ 31166-44-6 ]
  • [ 1259313-57-9 ]
  • 3
  • [ 31166-44-6 ]
  • [ 1187932-25-7 ]
  • [ 865-48-5 ]
  • [ 1429187-90-5 ]
YieldReaction ConditionsOperation 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).
  • 4
  • [ 31166-44-6 ]
  • [ 1187932-25-7 ]
  • [ 1429187-90-5 ]
YieldReaction ConditionsOperation 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).
  • 5
  • [ 31166-44-6 ]
  • [ 120157-97-3 ]
  • benzyl 4-(4-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)piperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation 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]+.
  • 6
  • [ 31166-44-6 ]
  • [ 118591-58-5 ]
  • benzyl 4-(2-(2-hydroxyethoxy)ethyl)piperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation 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
  • 7
  • [ 1070-62-8 ]
  • [ 31166-44-6 ]
  • C19H26N2O5 [ No CAS ]
  • 8
  • [ 31166-44-6 ]
  • [ 1340506-55-9 ]
  • C21H26N4O4 [ No CAS ]
YieldReaction ConditionsOperation 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.
  • 9
  • [ 31166-44-6 ]
  • [ 35979-69-2 ]
  • benzyl 4-(3-hydroxy-3-methylbutyl)piperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation 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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