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Chemical Structure| 206989-61-9

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Product Details of [ 206989-61-9 ]

CAS No. :206989-61-9
Formula : C12H21NO3
M.W : 227.30
SMILES Code : O=C(N1CCC(C(C)=O)CC1)OC(C)(C)C
MDL No. :MFCD08437655
InChI Key :HNVBBNZWMSTMAZ-UHFFFAOYSA-N
Pubchem ID :10987983

Safety of [ 206989-61-9 ]

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

Computational Chemistry of [ 206989-61-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 0
Fraction Csp3 0.83
Num. rotatable bonds 4
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 66.41
TPSA ?

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

46.61 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.7
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

1.29
Log Po/w (WLOGP)?

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

1.84
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.

1.33
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

1.47
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.73

Water Solubility

Log S (ESOL):?

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

-1.8
Solubility 3.62 mg/ml ; 0.0159 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.

-1.87
Solubility 3.08 mg/ml ; 0.0135 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

-1.62
Solubility 5.49 mg/ml ; 0.0242 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.

-6.77 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)

2.11

Application In Synthesis of [ 206989-61-9 ]

* 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 [ 206989-61-9 ]

[ 206989-61-9 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 206989-61-9 ]
  • [ 301221-79-4 ]
YieldReaction ConditionsOperation in experiment
96% INTERMEDIATE B6 tert-Butyl 4-(bromoacetyl)piperidine-l-carboxylate To a cooled (-78 0C) suspension of tert-butyi 4-acetylpiperidine-l-carboxylate (Intermediate B5; 2.87 g, 12.6 mmol) in THF (30 mL) was added 1 M lithium bis(trimethylsilyl)amide in THF (13.3 mL) over 20 min. The mixture was stirred for 1 h before the addition of trimethylsilyl chloride (1.74 mL, 13.7 mmol). After stirring at 0 0C for 30 min, the solution was cooled to -78 0C and bromine (0.645 mL, 12.6 mmol) was added. The mixture was allowed to reach r.t. and then poured into a solution of 10percent Na2S2O3 (20 mL) and saturated NH4Cl (20 mL). Extraction with EtOAc (2 x 80 mL) gave the title compound. Yield 3.69 g (96percent).
To a cooled (-78 °C) solution of 2.0 M LDA (in HEPTANE/THF/BENZENE, 13.7 mL, 27.3 mmol) in 100 mL THF was added dropwise over 40 min a solution of the methyl ketone prepared as described in Step B (5.17 g, 22.8 mmol) in 40 mL THF. After an additional 25 min, chlorotrimethylsilane (5.79 ML, 45.6 mmol) was added dropwise over 10 minutes. After stirring the for 1 h, the reaction mixture was poured into 300 mL of saturated NAHC03 solution and the resulting mixture was extracted twice with 200 mL of ether. The combined ethereal layers were washed with brine, dried over anhydrous MGS04, filtered, and concentrated to give 7.35 g of TMS-enol ether, which was then redissolved in 120 ML THF, cooled to 0 °C, and treated with sodium bicarbonate (2.87 g, 34.2 mmol), followed by N-BROMOSUCCINIMIDE (4.06 g, 22.8 mmol). The reaction mixture was warmed to rt and stirred for 1 h and 10 min, at which point, it was poured into 200 ML of saturated NAHC03 solution. The resulting mixture was extracted twice with 200 mL of ether and the combined ethereal layers were washed with saturated NAHC03 solution and brine, dried over anhydrous MGS04, filtered, and concentrated to give 7.62 g of crude product which was used without further purification.
Intermediate F: Preparation of tert-butyl 4- 2-bromoacetyl)piperidine-l-carboxylate To a solution of tert-butyl 4-acetylpiperidine-l-carboxylate (2.0 g, 8.8 mmol) in THF (50 mL) was added LHMDS (10.5 mL, 10.5 mmol) at -78 °C. The reaction was stirred at that temperature for 1 h. Then trimethyl chlorosilane (1.45 mL, 11.4 mmol) was added. The mixture was warmed to 0 °C and stirred at that room temperature for 30 min, then cooled to -78 °C again. Br2 (0.45 mL, 8.8 mmol) was added. The reaction mixture was warmed to room temperature and stirred at that room temperature for 30 min. Saturated Na2S03 aqueous solution (30 mL) was added to the reaction vessel and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil (3.2 g) was directly used for the next step without further purification. LCMS [M+H]+ =306.1.
  • 2
  • silyl enolether [ No CAS ]
  • [ 206989-61-9 ]
  • [ 301221-79-4 ]
YieldReaction ConditionsOperation in experiment
With N-Bromosuccinimide; n-butyllithium; triethylamine; diisopropylamine; In tetrahydrofuran; hexane; methyloxirane; Step A 4-Bromoacetyl-1-t-butoxycarbonyl-piperidine To a freshly prepared solution of LDA (from diisopropylamine (0.61 g, 6.0 mmol) and n-BuLi (2.2 ml, 2.5 M soln. in hexane) in 10 ml THF at -78° C. was added a solution of 4-acetyl-1-t-butoxycarbonyl-piperidine (1.0 g, 4.7 mmol) in 2.0 ml THF and the resultant mixture was stirred for 20 min. A mixture of TMSCl and triethylamine (1.37 ml, 10.8 mmol and 2.16 ml, 15.5 mmol) was added and the reaction mixture was gradually warmed to RT and stirred for an additional 1 hr. All the volatiles were removed and the crude silyl enolether was dissolved in 10 mL of THF and the mixture was cooled to 0° C. To this mixture was added in succession propylene oxide (1.0 ml) and NBS (1.0 g) and the mixture was stirred for 15 min, quenched with saturated NaHCO3 solution followed by extraction with CH2Cl2. The CH2Cl2 layer was washed with brine, dried, evaporated and purified by silica column chromatography. Elution with methylene chloride and ether (19:1) gave the title compound (1.11 g) as an yellow solid. 1H-NMR (500MHz, CDCl3): delta 4.16 (s, 2H), 4.12 (m, 2H), 2.79-2.84 (m, 3H), 1.5-2. (m, 4H), 1.47 (s, 9H).
  • 3
  • [ 206989-61-9 ]
  • [ 183170-69-6 ]
YieldReaction ConditionsOperation in experiment
96.6% With sodium tetrahydroborate; In ethanol; at 20℃; for 1h; To a solution of 0.400 g (1.76 mmol) of 4-acetyl-piperidine-l-carboxylic acid ie/ -butyl ester in ethanol (3 mL) is added 0.134 g (3.52 mmol) of sodium borohydride. The mixture is stirred at room temperature for 1 hour then a saturated aqueous solution of ammonium chloride is added to consume excess reactants. The mixture is washed with ethyl acetate and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.390 g (96.6%) of 4-(l-hydroxy-ethyl)- piperidine-l-carboxylic acid ieri-butyl ester as a colorless oil.
Step 3: tert-butyl 4-(l-hydroxyethyl)piperidine-l-carboxylate <n="35"/>tert-Butyl 4-acetylpiperidine-l-carboxylate from the previous step was dissolved in 50 ml methanol. NaBH4 (2.01g, 53 mmol) was added in batches at 0 0C. The resulting reaction mixture was stirred at 0 0C for 30 minutes. The volatiles were removed under vacuum. The residue was partitioned between 150 ml 10% KOH solution and 200 ml ether. The organic layers were washed with 100 ml brine, dried over sodium sulfate and concentrated to give 22.5 g colorless oil, which was azotropically dried by addition of 50 ml toluene and reconcentration under vacuum. This material was used for next step without further purification.1H-NMR (CDCl3): 54.17 (b, 2H), 3.62 (m, IH), 2.69 (b, 2H), 1.85 (m, IH), 1.6 (m, IH), 1.48 (s, 9H), 1.46 (m, IH), 1.24 (m, HH), 1.22 (d, J = 6.2 Hz, 3H).
655 g With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 0.5h; Compound 6 (652 g, 2.87 mol) was dissolved in methanol (1.5 L)Sodium borohydride (108.6 g, 2.87 mol) was added portionwise under ice-cooling and the reaction system temperature was maintained at 0-5 C,And the mixture was stirred at room temperature for 0.5 hour.After the reaction system was concentrated,Water (3 L)And methyl tert-butyl ether (3 L)The aqueous phase was treated with methyl t-butyl ether (1.5 L x 3)The organic phases were combined,Brine washing,Dried over sodium sulfate,And concentrated by filtration to obtain Compound 7 (655 g) as a colorless oil,Without further purification,Directly for the next reaction.
380 mg With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1.66667h; To a stirred solution of tert-butyl 4-acetylpiperidine-l-carboxylate (390 mg, 1.715mmol, 1.0 equiv.) in MeOH (7 mL) was added NaBEL (97 mg, 2.57 mmol, 1.5 equiv.) portion wise at 0 C and stirred for 10 minutes. The reaction mixture was allowed to stir for 1 hour 30 min at RT. Product formation was confirmed by TLC and LCMS. After completion of reaction, reaction mixture was quenched with water and extracted with ethyl acetate (3 x 50 mL). Combined organic extracts were washed with water (2 x 50 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure to obtain tert-butyl 4-(l -hydroxy ethyl) piperidine-l-carboxylate as colorless liquid (380 mg).

 

Historical Records

Technical Information

Categories

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