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Chemical Structure| 139290-70-3

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Product Details of [ 139290-70-3 ]

CAS No. :139290-70-3
Formula : C13H24N2O4
M.W : 272.34
SMILES Code : O=C(N1CCC(C(N(OC)C)=O)CC1)OC(C)(C)C
MDL No. :MFCD07368262
InChI Key :ITCQNWXLNZGEHP-UHFFFAOYSA-N
Pubchem ID :11065582

Safety of [ 139290-70-3 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 139290-70-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 19
Num. arom. heavy atoms 0
Fraction Csp3 0.85
Num. rotatable bonds 6
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 75.19
TPSA ?

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

59.08 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.24
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

1.11
Log Po/w (WLOGP)?

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

1.27
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.

1.18
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

0.23
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.4

Water Solubility

Log S (ESOL):?

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

-1.83
Solubility 4.01 mg/ml ; 0.0147 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.

-1.94
Solubility 3.1 mg/ml ; 0.0114 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

-1.07
Solubility 23.0 mg/ml ; 0.0843 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

Yes
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.

-7.17 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

1.0 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<0.0
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)

2.79

Application In Synthesis of [ 139290-70-3 ]

* 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 [ 139290-70-3 ]

[ 139290-70-3 ] Synthesis Path-Downstream   1~11

  • 2
  • [ 139290-70-3 ]
  • [ 154775-43-6 ]
  • 3
  • [ 139290-70-3 ]
  • [ 162504-75-8 ]
  • 4
  • [ 100-59-4 ]
  • [ 139290-70-3 ]
  • [ 193217-39-9 ]
YieldReaction ConditionsOperation in experiment
59% In tetrahydrofuran; at 0 - 20℃; for 2h; Step 2; To a solution of tert-butyl 4-(methoxy(rnethyl)carbamoyl)piperidine-l-carboxylate (8.0 g, 29.4 mmol) in THF (25 mL) was added PhMgCl (8.0 g, 58.8 mmol) dropwise at 0 0C. After stirring at rt for 2 h, the reaction was quenched with ammonium chloride solution and extracted <n="77"/>with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum to afford tert-butyl 4-benzoylpiperidine-l-carboxylate (5 g, 59% yield) as a pale yellow solid which was used directly in the next step.
  • 5
  • [ 1455-20-5 ]
  • [ 139290-70-3 ]
  • [ 511537-96-5 ]
YieldReaction ConditionsOperation in experiment
67% A solution of the <strong>[1455-20-5]n-butylthiophene</strong> (from Lancaster, 5.0 g, MW 140.26, 1.1 eq) in tetrahydrofuran (80 ml) at 0C was dripped into 1.6 M n-butyllithium in hexanes (from Aldrich, 24 ml, 1.2 EQ). The resulting mixture was stirred at 0C for 0.5 hr under N2. The reaction vessel was then cooled TO-78C. Afterward, a solution OF 4- (METHOXY-METHYL- CARBAMOYL)-PIPERIDINE-L-CARBOXYLIC acid tert-butyl ester (8.7 g, MW 272.34, 1.0 eq) in tetrahydrofuran (30 ml) was slowly added. The dry ice bath was removed, and the mixture was allowed to warm to ambient temperature. After 3 hr, the conversion was complete. The reaction was quenched with water (50 ml). The organic was then removed IRA vacuo. More water (100 ml) was added. The resulting mixture was extracted with diethylether (3X100 ML). Afterward, the organic layers were combined and then washed with water (2x), washed with brine (LX), dried over NA2SO4, and concentrated to afford a brown oil. The oil was chromatographed (ethylacetate: hexanes, 1: 9) to afford 7.5 g of the desired ester as a pale yellow solid (67% crude YIELD). 1H NMR confirmed the presence of the desired ester. The"equivalents"above indicate equivalents relative to charged amount of 4- (METHOXY-METHYL-CARBAMOYL)-PIPERIDINE-1-CARBOXYLIC acid tert-butyl ester.
  • 6
  • [ 27139-97-5 ]
  • [ 139290-70-3 ]
  • [ 1241898-40-7 ]
YieldReaction ConditionsOperation in experiment
INTERMEDIATE 17; (5-Chloro-2-methylphenyl)(piperidin-4-yl)methanone hydrochloride; Step 1 : fert-Butyl 4-(5-chloro-2-methylbenzoyl)piperidine-l-carboxylate; To a solution of rc-butylmagnesium chloride (1.5 mL, 3.0 mmol) in THF (15 mL) stirred at -78 °C, ft-BuLi (3.75 mL, 6.0 mmol) was added drop wise followed by the addition of 2-bromo-4-chloro-l-methylbenzene (2.00 mL, 15.0 mmol) drop wise. The mixture was stirred at -30 °C for 1 h. Then l-Boc-4-(methoxy-methyl-carbamoyl)piperidine (1.36 g, 5.0 mmol) was added and the mixture was stirred at rt overnight. The reaction was worked up by the addition of aqueous citric acid, extracted with ethyl acetate, dried over Na2SO4, and evaporated. The residue was purified by combiflash (0-20percent EtOAc/hexanes) to afford the desired product tert-butyl 4-(5- chloro-2-methylbenzoyl)piperidine-l-carboxylate as clear oil. 1H NMR (500 MHz, DMSO-d6): delta 7.75 (s, IH), 7.48 (d, IH), 7.34 (d, IH), 3.93 (d, 2H), 3.25-3.35 (m, IH), 2.85 (br s, 2H), 2.28 (s, 3H), 1.73 (d, 2H), 1.40 (s, 9H), 1.35 (d, 2H). MS (ESI, Q+) m/z 360 (M+Na)
Step 1:tert-Butyl 4-(5-chloro-2-methylbenzoyl)piperidine-1-carboxylateTo a solution of n-butylmagnesium chloride (1.5 mL, 3.0 mmol) in THF (15 mL) stirred at -78° C., n-BuLi (3.75 mL, 6.0 mmol) was added drop wise followed by the addition of <strong>[27139-97-5]2-bromo-4-chloro-1-methylbenzene</strong> (2.00 mL, 15.0 mmol) drop wise.The mixture was stirred at 30° C. for 1 h.Then 1-Boc-4-(methoxy-methyl-carbamoyl)piperidine (1.36 g, 5.0 mmol) was added and the mixture was stirred at rt overnight.The reaction was worked up by the addition of aqueous citric acid, extracted with ethyl acetate, dried over Na2SO4, and evaporated.The residue was purified by combiflash (0-20percent EtOAc/hexanes) to afford the desired product tert-butyl 4-(5-chloro-2-methylbenzoyl)piperidine-1-carboxylate as clear oil. 1H NMR (500 MHz, DMSO-d6): delta 7.75 (s, 1H), 7.48 (d, 1H), 7.34 (d, 1H), 3.93 (d, 2H), 3.25-3.35 (m, 1H), 2.85 (br s, 2H), 2.28 (s, 3H), 1.73 (d, 2H), 1.40 (s, 9H), 1.35 (d, 2H). MS (ESI, Q+) m/z 360 (M+Na)
  • 7
  • [ 27139-97-5 ]
  • [ 139290-70-3 ]
  • [ 1241898-39-4 ]
  • 8
  • [ 100-58-3 ]
  • [ 139290-70-3 ]
  • [ 193217-39-9 ]
YieldReaction ConditionsOperation in experiment
35.5% In tetrahydrofuran; at 0 - 20℃; To a stirred solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-l- carboxylate (0.5 g, 1.83 mmol) in THF (1.5 mL) was added a 1M solution of phenyl magnesium bromide in THF (3.67 mL, 3.67 mmol) at 0 C. The reaction was stirred overnight at RT. The reaction completion was monitored by TLC and the reaction was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried using Na2S04 and concentrated under reduced pressure to a residue. The residue was purified by column chromatography to obtain tert-butyl 4-benzoylpiperidine-l-carboxylate (0.188 g, 35.5%) LCMS: m/z = 190.1 (M+H) +.
In tetrahydrofuran; diethyl ether; at -78 - 20℃; for 18h;Inert atmosphere; To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1- carboxylate (9.5 g, 34.9 mmol) in THF (100 mL) was added phenylmagnesium bromide (23.25 mL, 69.8 mmol) (3 M in Et2O) at -78 C under N2. The reaction was stirred for 18 h with temperature naturally raised to RT. The reaction was quenched with aq. NH4Cl (50 mL), diluted with H2O (50 mL), extracted by EtOAc (50 mL* 3). The organic layers were collected, washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether:EtOAc=20:1 to 15:1) to give the title compound as an oil.; LCMS m/z [M+Na]+ 312.2.
  • 9
  • [ 139290-70-3 ]
  • [ 887354-02-1 ]
  • 10
  • [ 101335-11-9 ]
  • [ 139290-70-3 ]
  • tert-butyl 4-(2-chloro-4-fluorobenzoyl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
3.41 g To a solution of <strong>[101335-11-9]2-chloro-4-fluoroiodobenzene</strong> (11.6 g) in THF (80 mL) was added dropwise isopropylmagnesium chloride-lithium chloride complex (1.3M THF solution, 34.8 mL) over 20 min at -78 C., and the mixture was stirred at -15 C. for 1.5 hr. To this mixture was added tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (6.16 g), and the mixture was stirred at room temperature for 48 hr. The reaction was quenched with aqueous ammonium chloride solution at 0 C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.41 g). 1H NMR (300 MHz, CDCl3) delta1.46 (9H, s), 1.54-1.71 (2H, m), 1.79-1.94 (2H, m), 2.72-2.94 (2H, m), 3.17-3.31 (1H, m), 4.01-4.19 (2H, m), 7.01-7.09 (1H, m), 7.17 (1H, dd, J=8.5, 2.5 Hz), 7.39 (1H, dd, J=8.6, 5.9 Hz).
  • 11
  • [ 139290-70-3 ]
  • [ 183170-69-6 ]
 

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