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Structure of 146293-11-0

Chemical Structure| 146293-11-0

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Product Details of [ 146293-11-0 ]

CAS No. :146293-11-0
Formula : C29H35INO2P
M.W : 587.47
SMILES Code : O=C(N1CCC(C[P+](C2=CC=CC=C2)(C3=CC=CC=C3)C4=CC=CC=C4)CC1)OC(C)(C)C.[I-]
MDL No. :MFCD20271861
InChI Key :SXFMQELZEAFAKI-UHFFFAOYSA-M
Pubchem ID :18187633

Safety of [ 146293-11-0 ]

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

Computational Chemistry of [ 146293-11-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 34
Num. arom. heavy atoms 18
Fraction Csp3 0.34
Num. rotatable bonds 8
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 159.51
TPSA ?

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

43.13 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

6.03
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

7.12
Log Po/w (WLOGP)?

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

2.25
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.

5.76
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

5.55
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

5.34

Water Solubility

Log S (ESOL):?

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

-7.83
Solubility 0.00000866 mg/ml ; 0.0000000147 mol/l
Class?

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

Poorly soluble
Log S (Ali)?

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

-7.85
Solubility 0.00000839 mg/ml ; 0.0000000143 mol/l
Class?

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

Poorly 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

-9.21
Solubility 0.000000365 mg/ml ; 0.0000000006 mol/l
Class?

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

Poorly 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

Yes
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

Yes
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.

-4.83 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

2.0
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.

0.17

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

2.0 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<3.0
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)

4.91

Application In Synthesis of [ 146293-11-0 ]

* 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 [ 146293-11-0 ]

[ 146293-11-0 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 146293-11-0 ]
  • [ 33016-47-6 ]
  • tert-butyl 4-[(Z)-2-(1-trityl-1H-imidazol-4-yl)vinyl]piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With potassium tert-butylate; In tetrahydrofuran; for 12.0h; Potassium tert-butoxide (0.21 g) was added to a solution of 1-trityl-1H-imidazole-4-carbaldehyde (Kelly, J. L. et al., J. Med. Chem., 20, 721 (1977)) (0.63 g) and <strong>[146293-11-0](1-tert-butoxycarbonyl-4-piperidinyl)methyl(triphenyl)phosphonium iodide</strong> (WO 99/24421)(1.0 g) in THF (35 mL). After stirred for 12 hours, the reaction solution was poured into a mixture of ethyl acetate and an aqueous saturated ammonium chloride solution to separate an organic layer. The ethyl acetate solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified with a silica gel column to obtain the title compound (0.45 g, 51%). NMR (200 MHz, CDCl3) delta: 1.20-1.36 (2H, m), 1.45 (9H, s), 1.64-1.69 (2H, m), 2.67 (2H, t, J = 12.2), 3.05 (1H, m), 4.01 (2H, d, J = 12.8), 5.32 (1H, dd, J = 9.0, 11.6), 6.16 (1H, d, J = 11.6), 6.69 (1H, s), 7.10-7.20 (6H, m), 7.30-7.36 (9H, m), 7.43 (1H, s).
  • 2
  • [ 146293-11-0 ]
  • [ 112372-06-2 ]
  • 4-(2-furo[2,3-c]pyridin-2-ylvinyl)piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate;18-crown-6 ether; In dichloromethane; for 64.0h; Example 20; 4-(2-Furo[2,3-c]pyridin-2-ylethyl)piperidine-l-carboxylic acid tert-butyl ester; K2CO3 (122 mg, 0.88 mmol) and 18C6 (catalytic amount) were added to a stirred solution of (l-tert-butoxycarbonylpiperidin-4-ylmethyl)triphenylphosphonium iodide (491 mg, 0.88 mmol) and furo[2,3-c]pyridine-2-carbaldehyde (65 mg, 0.44 mmol) in anhydrous CH2Cl2 (10 mL). After 64 h, the reaction mixture was partitioned between CH2Cl2 (50 mL) and H2O (20 mL). The aqueous phase was further extracted with CH2Cl2 (2 x 20 mL), then the combined organic extracts were washed with H2O (20 mL) and brine (20 mL), before being dried (MgSO4). Filtration, solvent evaporation, and flash chromatography (IH-EtOAc, 7:3) afforded 4-(2-furo[2,3-c]pyridin-2-ylvinyl)piperidine-l-carboxylic acid tert-butyl ester: mlz (ES+) = 329.2 [M+ H]+. This alkene (30 mg, 91 mumol) was hydrogenated, as described above in Example 18, to yield the title compound
YieldReaction ConditionsOperation in experiment
Step C ((1-(t-Butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide A solution of triphenylphosphine (6.63 g, 25.3 mmol) and 1-(t-butoxycarbonyl)-4-(iodomethyl)piperidine (7.96 g, 24.5 mmol, from EXAMPLE 155, Step B) in CH3CN (40 mL) was heated to reflux for 72 h. The solution was evaporated to give 13.35 g of white solid. A portion (12.34 g) of this material was dissolved in CH3CN (25 mL) at 65 C. EtOAc (35 mL) was added and the mixture was allowed to cool slowly to RT and then to -20 C. The supernatant was decanted, and the colorless crystals were washed with EtOAc (5*5 mL) and dried under vacuum to give 9.25 g of the title compound. 1H NMR (500 MHz, CD3OD) delta 7.89 (t, J=8, 3H), 7.86 (dd, J=12,8,66H), 7.76 (td, J=8,4,66H), 3.91 (bd, J=13, 2H), 3.44 (dd, J=14, 6, 2H, 2.72-2.58 (m, 2H), 2.08-1.96 (m, 1H), 1.49 (bd, J=12, 2H), 1.41 (s, 9H), 1.43 (qd, J=13, 4, 2H).
  • 4
  • 2,2-difluoro-2-(pyridin-2-yl)-1-methoxyethanol [ No CAS ]
  • aq. NH4Cl [ No CAS ]
  • [ 146293-11-0 ]
  • [ 313513-09-6 ]
YieldReaction ConditionsOperation in experiment
With potassium hexamethylsilazane; In tetrahydrofuran; ethyl acetate; A suspension of <strong>[146293-11-0]((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide</strong> (5.29 g, 9.00 mmol, from EXAMPLE 155, Step C) in THF (70 mL) was stirred at RT for 40 min. A toluene solution of potassium bis(trimethylsilyl)amide (18 mL, 0.5 M, 9.0 mmol) was added, giving an orange suspension. After 40 min., crude 2,2difluoro-2-(2-pyridyl)-1-methoxyethanol (940 mg, 4.97 mmol) was added in THF (20 mL). After an additional 50 min., the mixture was quenched by the addition of saturated aq. NH4Cl (10 mL). The mixture was partitioned between EtOAc (100 mL) and H2O (100 ml), and the aqueous layer was extracted with EtOAc (3*100 mL). The organic layers were washed in succession with saturated aq. NaCl (100 mL), dried (Na2SO4), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluding with 90:10 v/v to 80:20 v/v hexanes/EtOAc, gave 1.18 mg of the title compound (approximately 95:5 cis/trans mixture) as an oil which soldified upon standing. For the title compound: 1H NMR (500 MHz, CDCl3) S 8.68 (d, J=5, 1H), 7.84 (td, J=8, 2, 1H), 7.70 (d, J=8, 1H), 7.39 (dd, J=8, 5, 1H), 5.93 (td, J=14, 11, 1H), 5.70 (ddt, J=11, 10, 2, 1H), 4.17-3.99 (bs, 2H), 2.80-2.62 (m, 3H), 1.58 (d, J=12,22H), 1.46 (s, 9H), 1.26 (qd, J=12, 4, 2H); ESI-MS 339 (M+H); HPLC A: 4.28 min.
 

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