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Product Details of [ 91419-48-6 ]

CAS No. :91419-48-6
Formula : C11H20N2O3
M.W : 228.29
SMILES Code : O=C(C1CCN(C(OC(C)(C)C)=O)CC1)N
MDL No. :MFCD02180953
InChI Key :YHFUWPUJUMZXBD-UHFFFAOYSA-N
Pubchem ID :2735646

Safety of [ 91419-48-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 91419-48-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 0
Fraction Csp3 0.82
Num. rotatable bonds 4
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 64.31
TPSA ?

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

72.63 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.19
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

0.48
Log Po/w (WLOGP)?

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

0.74
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.

0.62
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

0.26
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.86

Water Solubility

Log S (ESOL):?

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

-1.29
Solubility 11.6 mg/ml ; 0.0508 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.

-1.57
Solubility 6.08 mg/ml ; 0.0266 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

-0.87
Solubility 30.7 mg/ml ; 0.135 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.

-7.35 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)

2.14

Application In Synthesis of [ 91419-48-6 ]

* 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 [ 91419-48-6 ]

[ 91419-48-6 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 91419-48-6 ]
  • [ 214834-18-1 ]
YieldReaction ConditionsOperation in experiment
92% With Lawessons reagent; In 1,2-dimethoxyethane; dichloromethane; at 20℃; To a solution of ferf-butyl-4-carbamoylpiperidine-1-carboxylate (2.65 g, 11.62 mmol) in a DME/DCM 2: 1 mixture (78 ml_), Lawesson reagent (2.35 g, 5.81 mmol, 0.5 eq) was added and the mixture was stirred at r.t. overnight. The solvent was removed and the residue was taken up with ethyl acetate and washed with saturated aqueous K2CO3. The organic layer was separated, dried over Na2S04 and concentrated to dryness. The residue was triturated with diethyl ether and dried to give 2.65 g (92%) of the title compound as a white solid.HPLC: Rt: 5.06 min1H NMR (401 MHz, DMSO-d6) δ ppm 9.39 (br. s., 1 H), 9.09 (br. s., 1 H), 4.00 (d, J = 12.6 Hz, 2 H), 2.77 - 2.61 (m, 3 H), 1.71 - 1.51 (m, 4 H), 1.39 (br. s., 9 H)
92% With Lawessons reagent; In 1,2-dimethoxyethane; dichloromethane; at 20℃; tert-Butyl-4-carbamothioylpiperidine-1-carboxylate, cmpd. of formula 8 [R1=1-tert-butoxycarbonyl-piperidin-4-yl] To a solution of tert-butyl-4-carbamoylpiperidine-1-carboxylate (2.65 g, 11.62 mmol) in a DME/DCM 2:1 mixture (78 mL), Lawesson reagent (2.35 g, 5.81 mmol, 0.5 eq) was added and the mixture was stirred at r.t. overnight. The solvent was removed and the residue was taken up with ethyl acetate and washed with saturated aqueous K2CO3. The organic layer was separated, dried over Na2SO4 and concentrated to dryness. The residue was triturated with diethyl ether and dried to give 2.65 g (92%) of the title compound as a white solid. HPLC: Rt: 5.06 min 1H NMR (401 MHz, DMSO-d6) δ ppm 9.39 (br. s., 1H), 9.09 (br. s., 1H), 4.00 (d, J=12.6 Hz, 2H), 2.77-2.61 (m, 3 H), 1.71-1.51 (m, 4H), 1.39 (br. s., 9H)
82% With Lawessons reagent; In 1,2-dimethoxyethane; dichloromethane; at 20℃; for 1.33333h; Example 2: 4-Thiocarbamoyl-piperidine-l-carboxylic acid tert-butyl ester(Thioamide)[0030] To a suspension of 4-Carbamoyl-piperidine-l-carboxylic acid tert-butyl ester (288 g, 1.26 mol) in dimethoxyethane (2000 mL) and methylene chloride (800 mL) in a 5-lite of three-neck flask was added Lawesson's Reagent (255 g, 0.63 mol). The mixture was stirred at room temperature for 80 min. TLC check there was no starting material left. The solvents were removed under vacuum. The residue was dissolved in ethyl acetate (1500 mL), and washed with half saturated potassium carbonate water solution (500 mL each, two times), 50%> of brine (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dry. The obtained solid was dissolved in ethyl acetate (1000 mL) and filtered at hot to remove insoluble white stuff. To the solution was added heptane (300 mL). After removing most of ethyl acetate, the solid formed was filtrated, washed with hexane-ether (1 : 1), and dried to give 252 g (82%>) of product. TLC: dichloromethane -methanol 90: 10, Rf (product) = 0.37, UV and iodine positive; Rf (starting material) = 0.28, iodine positive.
82% With Lawessons reagent; In 1,2-dimethoxyethane; dichloromethane; at 20℃; for 1.33333h; To a suspension of 4-Carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (288 g, 1.26 mol) in dimethoxyethane (2000 mL) and methylene chloride (800 mL) in a 5-lite of three-neck flask was added Lawesson's Reagent (255 g, 0.63 mol). The mixture was stirred at room temperature for 80 min. TLC check there was no starting material left. The solvents were removed under vacuum. The residue was dissolved in ethyl acetate (1500 mL), and washed with half saturated potassium carbonate water solution (500 mL each, two times), 50% of brine (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dry. The obtained solid was dissolved in ethyl acetate (1000 mL) and filtered at hot to remove insoluble white stuff. To the solution was added heptane (300 mL). After removing most of ethyl acetate, the solid formed was filtrated, washed with hexane-ether (1:1), and dried to give 252 g (82%) of product.TLC: dichloromethane-methanol 90:10, Rf (product)=0.37, UV and iodine positive; Rf (starting material)=0.28, iodine positive.
82.2% With Lawessons reagent; In tetrahydrofuran; at 20℃; for 12h; Dissolve N-Boc-4-piperidinecarboxamide 2 (1.00g, 4.38mmol) in 20mLTetrahydrofuran solution, then add Lawesson's reagent (LR) (1.06g, 2.63mmol),Mechanically stirred at room temperature for 12 hours, TLC monitored until the reaction was complete, and the solutionAdd 20mL ethyl acetate to redissolve, 15mL*2 10% citric acid wash the organic layer, 15mL*2 saturated sodium carbonate wash the organic layer, 15mL water wash the organic layer,The organic layer was dried with anhydrous magnesium sulfate, filtered and desolvated to obtain 0.88 g of white solid.The yield was 82.2%,
78% With Lawessons reagent; In tetrahydrofuran; at 20℃; for 22h;Reflux; To a stirred solution of tert-butyl 4-carbamoylpiperidine-1-carboxylate (1.3 g, 5.7 mmol) in THF (16 mL,), Lawssen's reagent 2.53 g, 6.27 mmol) was added. The reaction mixture was refluxed for 6 h and then stirred at rt for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and was washed with 10% citric acid, 10% sodium bicarbonate, water and brine, dried over anhydrous Na2SO4 and concentrated under vacuum to afford the title compound. Yield: 78% (1.09 g, colorless oil). 1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 9.11 (s, 1H), 4.03-3.97 (m, 1H), 2.66-2.61 (m, 2H), 1.64-1.52 (m, 4H), 1.40 (s, 9H), 1.38-1.34 (m, 2H). LCMS: (Method A) 245.2 (M+H), Rt. 3.38 min, 93.5% (Max).
72% With Lawessons reagent; In 1,2-dimethoxyethane (DME); chloroform; at 20℃; 4-CARBAMOYL-PIPERIDINE-L-CARBOXYLIC acid TERT-BUTYL ester (2) (45.4 g, 0.199 mol), Lawesson's reagent (40.2 g, 0.099 mol, 0.5 equiv), 1,2-dimethoxyethane (DME) (500 mL) and chloroform (200 mL) were combined and stirred at room temperature. The course of the reaction was followed by tlc analysis (30% ethyl ACETATE/HEXANE) and on completion the reaction mixture was evaporated to dryness (glassy solid). The solid was dissolved in ethyl acetate and washed with half saturated potassium carbonate solution, dried (MGSO4), filtered and concentrated to yield the title compound as a colourless solid. The crude product was crystallised from ethyl acetate and hexane to give the title compound (3) (35 g, 0.14 mol, 72%).
62.5% With Lawessons reagent; In 1,2-dimethoxyethane; dichloromethane; at 20℃; Lawson's reagent (12.75 g, 0.032 mol) was added a solution of compound 1(14.4 g, 0.063 mol) in dichloromethane (40 mL) and ethylene glycol dimethyl ether (100 ml). The reaction was stirred at room temperature for 8 h, and monitored by TLC, then concentrated. The residue was diluted with CH2Cl2 (100 mL), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2/MeOH = 100:1) to afford compound 2 (9 g, 62.5 % yield) as a white solid. 1H NMR (400MHz, CDCl3) δ 7.55(s, 1H), 6.99(s, 1H), 4.23(s, 2H), 3.73(q, J = 7.0 Hz, 2H), 2.74-2.65(m, 1H), 1.90(dt, J =13.4 Hz, 2.6 Hz, 2H), 1.72(qd, J = 12.6 Hz, 4.4 Hz, 2H), 1.46(s, 9H).
55% With Lawessons reagent; In toluene; at 20℃; for 1h;Inert atmosphere; To a suspension of compound8(2.2 g, 9.7 mmol) in toluene (100 mL) in a reaction flask was added Lawesson’s reagent (1.9 g, 4.8 mmol). After the reaction mixture was stirred at room temperature for 1 h, the solvents were removed under vacuum. The residue was dissolved in EtOAc and washed with aqueous 1N NaOH solution (2 x 100 mL), 50% of brine (100 mL). The organic phase was dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography using 30% acetone in hexanes as an eluent to afford compound9(1.3 g, 55%)1H-NMR (CDCl3,300 MHz) δ 7.44 (1H, s, NH2), 6.86 (1H, s, NH2), 4.24 (2H, d,J= 11.7 Hz, CH2), 2.78-2.63 (3H, m, CH+CH2), 1.93 (2H, d,J= 14.7 Hz, CH2), 1.73 (2H, dt,J= 15.0 Hz, 6.0 Hz, CH2), 1.46 (9H, s, C(CH3)3).
40.2% With Lawessons reagent; In 1,4-dioxane; at 70℃; for 4h; Dissolve compound 2 (10.2 g, 42.6 mmol) and Lawson's reagent (10.7 g, 26.4 mmol) in 1,4-dioxane (150 mL), heat at 70±5C and stir for 4 h. After the reaction was detected by TLC, the reaction system was cooled to room temperature. Adjust pH=9 with saturated aqueous NaHCO3 solution, extract with DCM (3X100 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the organic phase to obtain crude product, which is purified by silica gel column to obtain 4.1 g of white solid, with a yield of 40.2 %.
With Lawessons reagent; In 1,4-dioxane; at 60℃; for 2h; The amide (20 g, 76.3 mmol) was dissolved in 1,4-dioxane with heating and the clear solution placed in a 60 0C oil bath. Lawesson's Reagent was added (15.43 g, 38.15 mmol) and the solution stirred for 2 hours. The solution was cooled to RT, poured into 8:1 water : saturated NaHCO3, followed by aqueous/EtOAc work-up and silica gel chromatography (EtOAc : hexanes (1:4)) to give the titled compound.
With Lawessons reagent; In 1,4-dioxane; dichloromethane; at 20 - 50℃; for 4h; under room temperature, nitrogen protection, (27.36g, 0 . 12mol, 1eq), laurance reagent (24.26g, 0 . 06mol, 0 . 5eq), mixed, added into the 1,4-dioxane 250 ml, the mixing tabs 50 C, 4h. Quality monitoring, after the reaction is complete. The reaction system can be obtained direct turns on lathe does target product 51. 86g crude product (containing laurance reagent decay product), purity 50%. The crude product of viscosity is very high bombycinous oily liquid.
1 g With Lawessons reagent; In 1,2-dimethoxyethane; dichloromethane; at 20℃; for 16h; To a stirred solution of tert-butyl 4-carbamoylpiperidine-1 -carboxylate (1 .0 g, 4.38 mmol) in a mixture of dimethoxyethane (16 mL) and dichloromethane (8 mL) was added 2,4-bis(4-methoxyphenyl)-,3,2,4-dithiadiphosphetane-2,4-disulfide (885 mg, 2.1 9 mmol). The mixture was stirred at 20 C for 16 h,then concentrated in vacuo. The residue dissolved in ethyl acetate and washed with saturated aqueous potassium carbonate (10 mL x 2). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to give tert-butyl 4-carbamothioylpiperidine-1 -carboxylate (1 .0 g) as a yellow solid. This was used directly without further purification. 1H NMR (400 MHz, DMSO-d6) O 9.45 (br. s., 1 H), 9.17 (br. s., 1H), 4.14-3.98 (m, 2H), 3.91 -3.79 (m, 1H), 2.80-2.66 (m, 2H), 1.74-1.55 (m, 4H), 1.46 (s, 9H).

  • 2
  • phosphorous pentasulfide [ No CAS ]
  • [ 91419-48-6 ]
  • [ 214834-18-1 ]
YieldReaction ConditionsOperation in experiment
In 1,4-dioxane; hexane; Step A 1-t-Butyloxycarbonyl-isonipecot-thioamide To a solution of 500 mg of 1-Boc-isonipecotamide in 5 ml of 1,4-dioxane was added 243 mg of phosphorous pentasulfide. The reaction was stirred at 100 C. for 1 hour. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 30% EtOAc in hexane to give 74 mg of the title compound.
 

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Technical Information

Categories

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