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Structure of 58859-46-4

Chemical Structure| 58859-46-4

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Product Details of [ 58859-46-4 ]

CAS No. :58859-46-4
Formula : C8H16N2O2
M.W : 172.22
SMILES Code : O=C(N1CCC(N)CC1)OCC
MDL No. :MFCD00006484
InChI Key :GQQQULCEHJQUJT-UHFFFAOYSA-N
Pubchem ID :100867

Safety of [ 58859-46-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H227-H315-H319-H335
Precautionary Statements:P305+P351+P338

Computational Chemistry of [ 58859-46-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 0
Fraction Csp3 0.88
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 49.65
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

55.56 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.1
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

0.11
Log Po/w (WLOGP)?

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

0.19
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.

0.24
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

-0.07
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.51

Water Solubility

Log S (ESOL):?

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

-0.78
Solubility 28.6 mg/ml ; 0.166 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.

-0.83
Solubility 25.4 mg/ml ; 0.147 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

-0.49
Solubility 55.5 mg/ml ; 0.322 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.

-7.27 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

1.0
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)

1.92

Application In Synthesis of [ 58859-46-4 ]

* 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 [ 58859-46-4 ]

[ 58859-46-4 ] Synthesis Path-Downstream   1~7

  • 1
  • [ 58859-46-4 ]
  • [ 84946-20-3 ]
  • [ 84501-68-8 ]
YieldReaction ConditionsOperation in experiment
45% In N,N-dimethyl acetamide; at 155℃; for 68h;Inert atmosphere; Compound 3 (0.38 mmol, 100 mg) was dissolved in dimethylacetamide (3 mL), followed by addition of ethyl 4-aminopiperidinecarboxylate (3.8 mmol, 0.65 mL). The reaction mixture was stirred at 155 C in a silicone oil bath for 68 hours and then cooled to room temperature. The reaction mixture was then diluted with ethyl acetate and poured into a 50% saturated brine solution and then extracted with dichioromethane. The crude product was purified by column chromatography on silica gel (hexnne/ethyl acetate; 10:90) to afford Compound 4 (69.5 mg, 45%) as a yellow solid. [00124] 1H NMR (500 MHz, Methanol-d4 σ 7.35 - 7.26 (m, 1 H), 7.15 - 7.09 (m, 2H), 7.06 - 6.98 (m, 4H), 6.93 (ddd, J = 8.1 , 7.3, 1 .1 Hz, 1 H), 5.22 (s, 2H), 4.10 (qd, J = 7.0, 4.0 Hz, 4H), 3.95 (it, J = 11.0, 4.0 Hz, 2H), 2.98 (s, 1 H), 2.10 - 1.98 (m, 2H), 1.45 (dd, J = 11.9, 4.2 Hz, 2H), 1.24 (td, J = 7.1 , 3.3 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) σ 163.56 (d, J = 244.6 Hz), 157.19, 155.18, 142.92, 135.30, 133.75, 129.56, 122.50, 120.86, 116.52, 116.35, 116.08, 109.13, 62.70, 51.43, 45.24, 44.10, 33.11 , 14.96. IR (neat): 3275, 1694, 1220 cm'1, m/z: [(M+H)+ ] calcd for (C22H26FNO2) 397.2040; Found 397.2070. mp 120-123 C.
45% In N,N-dimethyl acetamide; at 155℃; for 68h;Inert atmosphere; Compound 3 (0.38 mmol, 100 mg) was dissolved in dimethylacetamide (3 mL), followed by addition of ethyl 4-aminopiperidinecarboxylate (3.8 mmol, 0.65 mL). The reaction mixture was stirred at 155 C in a silicone oil bath for 68 hours and then cooled to room temperature. The reaction mixture was then diluted with ethyl acetate and poured into a 50% saturated brine solution and then extracted with dichioromethane. The crude product was purified by column chromatography on silica gel (hexnne/ethyl acetate; 10:90) to afford Compound 4 (69.5 mg, 45%) as a yellow solid. [00124] 1H NMR (500 MHz, Methanol-d4 σ 7.35 - 7.26 (m, 1 H), 7.15 - 7.09 (m, 2H), 7.06 - 6.98 (m, 4H), 6.93 (ddd, J = 8.1 , 7.3, 1 .1 Hz, 1 H), 5.22 (s, 2H), 4.10 (qd, J = 7.0, 4.0 Hz, 4H), 3.95 (it, J = 11.0, 4.0 Hz, 2H), 2.98 (s, 1 H), 2.10 - 1.98 (m, 2H), 1.45 (dd, J = 11.9, 4.2 Hz, 2H), 1.24 (td, J = 7.1 , 3.3 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) σ 163.56 (d, J = 244.6 Hz), 157.19, 155.18, 142.92, 135.30, 133.75, 129.56, 122.50, 120.86, 116.52, 116.35, 116.08, 109.13, 62.70, 51.43, 45.24, 44.10, 33.11 , 14.96. IR (neat): 3275, 1694, 1220 cm'1, m/z: [(M+H)+ ] calcd for (C22H26FNO2) 397.2040; Found 397.2070. mp 120-123 C.
34% at 180℃; for 0.0166667h;Microwave irradiation; A mixture of intermediate 1(. 5 g, 1.9 mmol) and 4-amino-1-ethoxycarbonylpiperidine as a colorless oil (0.495 g, 2.8 mmol) was added to the microwave tube, stirred uniformly, microwave 180 C reaction 1min, cooled to room temperature, reddish brown solid, with methanol 15mL and dichloromethane 5mL dissolved after mixing, the column was purified to obtain a white solid, The yield was 34.0%
  • 2
  • [ 437-86-5 ]
  • [ 58859-46-4 ]
  • [ 356072-51-0 ]
  • 3
  • [ 58859-46-4 ]
  • 2-NO2-6-Me-C6H3-X (X: halogen) [ No CAS ]
  • [ 53786-10-0 ]
  • 4
  • [ 58859-46-4 ]
  • [ 84946-20-3 ]
  • [ 75970-99-9 ]
YieldReaction ConditionsOperation in experiment
With 2,3-Lutidine; 1-methyl-pyrrolidin-2-one; sodium hydroxide; In tetrahydrofuran; EXAMPLE 8a To a 25 mL 3-neck flask equipped with a thermometer, reflux consenser and stir bar were added, under a nitrogen atmosphere, 822 mg (4.8 mmol) of Compound XII (Lancaster Synthesis, Inc., Windham, N.H.), and 0.93 mL of lutidine. The mixture was heated to 120 C., whereupon a solution of 1.04 g (4 mmol., 1 eq.) of Compound X (Aldrich Chemical Co., Milwaukee, Wis.), 8 mmol of tetrabutylammonium fluoride (obtained from its 1.0M THF solution by distillation under vacuum with anhydrous toluene) and 4 mL of N-methylpyrrolidinone was added slowly over 2 h. The reaction mixture was allowed to stir at 120 C. for 1 h. High-performance liquid chromatography revealed >95% coversion to Compound XIVa (in free base form). The reaction mixture was allowed to cool to ambient temperature, and slowly poured into a solution of 5% aqueous NaOH while stirring. The resulting suspension was allowed to stir at 0-10 C. for 30 minutes, and the resulting solid product was collected by vacuum filtration, washed with water (3*5 mL), and air dried for 30 minutes under vacuum to afford crude Compound XIVa (in free base form): 1 H NMR (300 MHz, CDCl3) δ7.53 (1H, d, J=7.8 Hz), 7.22-6.92 (7H, m, two groups), 5.12 (2H, s), 4.37 (1H, NH br. d), 4.12 (2H+1H, m overlapped), 4.07 (2H, q, J=7.0 Hz), 2.98 (2H, pseudo t), 2.09 (2H, pseudo d), 1.30 (2H, m overlapped), 1.24 (3H, t, J=7.0 Hz); 13 C NMR (75 MHz, CDCl3) δ164.2 and 161.0 (13 C-19 F coupling), 155.6, 153.3, 142.2, 134.5, 131.4, 128.3, 121.8, 120.0, 116.6, 116.3, 116.1, 107.5, 61.5, 50.1, 45.0, 42.8, 32.6, 14.8. It is to be noted that under the same reaction conditions as above, but without the use of tetrabutylammonium fluoride, only 5% conversion (high-performance liquid chromatography) to Compound XIVa (in free base form) was achieved after 3 h at 120 C. The crude Compound XIVa (in free base form) obtained above was placed in a 50 mL, 3-neck flask equipped with a thermometer, reflux condenser and stir bar. 5 mL of 48% hydrobromic acid was added, and the resulting mixture was heated to 110 C. and allowed to stir at that temperature for 2 h. After the reaction was complete (>98% conversion to norastemizole as shown by high-performance liquid chromatography), the reaction mixture was allowed to cool to room temperature, and 10 mL of toluene and 10 mL of water were added, with stirring.
  • 5
  • [ 67-66-3 ]
  • [ 58859-46-4 ]
  • [ 84946-20-3 ]
  • [ 84501-68-8 ]
YieldReaction ConditionsOperation in experiment
12.1 parts (40.5%) With sodium hydroxide; In water; Example 4 A mixture of 9.8 parts of ethyl 4-amino-1-piperidinecarboxylate and 15 parts of 2-chloro-1-(4-fluorophenylmethyl)-1H-benzimidazole was heated to 120 C. The mixture was stirred at 120 C. during 43 hours. After cooling, 100 parts of trichloromethane were added and the whole was thouroughly stirred. The mixture was washed with water. The aqueous layer was separated and the organic mixture was filtered and evaporated. The collected solid material was dissolved in 100 parts of water and subsequently 100 parts of 20% sodium hydroxide solution were added. The precipitate was filtered and dried in vacuo at 50 C., yielding 12.1 parts (40.5%) of ethyl 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 181 C. (compound 21).
  • 6
  • [ 58859-46-4 ]
  • [ 287730-14-7 ]
  • [ 1352002-42-6 ]
  • 7
  • [ 23779-97-7 ]
  • [ 58859-46-4 ]
  • ethyl 4-((8-(trifluoromethyl)quinolin-4-yl)amino)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
27% With phenol; at 82 - 100℃; for 92h;Sealed tube; 4-Chloro-(8-trifluoromethyl)quinoline (1.50 g, 6.5 mmol), ethyl 4-amino-1-piperidinecarboxylate (1.02 g, 5.9 mmol), and phenol (3.04 g, 32 mol) were heated at 82C in asealed Carius vessel for 20 hours. Additional ethyl 4-amino-1-piperidine carboxylate(0.20 g, 1.2 mmol) was added. The vessel was again sealed and heated for a further 3days at 100C. whereupon TLC indicated that no unreacted quinoline remained. Thereaction mixture was diluted with chloroform (25 mL) and rinsed with 10% 8 soda (5 x10 mL), followed by further rinsing with brine (2 x 10 mL). The organic layer was driedover MgSO4 and concentrated under reduced pressure with warming to yield a thick,brown oil. This was diluted with dichloromethane and adsorbed onto silica, thenpurified by flash chromatography on silica, eluting with a gradient of 100% hexanes to100% ethyl acetate. The desired product was obtained as a beige solid (0.63 g, 27%, Rf =0.4 (silica, ethyl acetate)). The quinoline phenolate was also isolated fromchromatography (a sparkling, white, crystalline solid, 0.94 g, 50%, mp = 175.4-181.0C,Rf = 0.7 (silica, ethyl acetate)).
 

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Technical Information

Categories

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