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Structure of 614730-97-1

Chemical Structure| 614730-97-1

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Product Details of [ 614730-97-1 ]

CAS No. :614730-97-1
Formula : C11H20FNO3
M.W : 233.28
SMILES Code : CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
MDL No. :MFCD08062513
InChI Key :BWZOULIMVKCGII-UHFFFAOYSA-N
Pubchem ID :22248400

Safety of [ 614730-97-1 ]

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

Computational Chemistry of [ 614730-97-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 0
Fraction Csp3 0.91
Num. rotatable bonds 4
Num. H-bond acceptors 4.0
Num. H-bond donors 1.0
Molar Refractivity 62.65
TPSA ?

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

49.77 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.56
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

1.14
Log Po/w (WLOGP)?

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

1.76
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.

1.3
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

1.35
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.62

Water Solubility

Log S (ESOL):?

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

-1.74
Solubility 4.24 mg/ml ; 0.0182 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.

-1.78
Solubility 3.88 mg/ml ; 0.0166 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

-1.61
Solubility 5.74 mg/ml ; 0.0246 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.

-6.91 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)

2.27

Application In Synthesis of [ 614730-97-1 ]

* 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 [ 614730-97-1 ]

[ 614730-97-1 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 614730-97-1 ]
  • [ 620611-27-0 ]
  • 2
  • [ 614730-97-1 ]
  • [ 1354961-13-9 ]
  • tert-butyl 4-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)-4-fluoropiperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With caesium carbonate; In dimethyl sulfoxide; at 80℃; for 4h; To a mixture of tert-butyl 4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylate (4.60 g, 19.70 mmol) and tert-butyl 5-chloro-2, 4-difluorobenzoate (4.89 g, 19.70 mmol) in dimethyl sulfoxide (50 mL) was added cesium carbonate (9.65 g, 29.60 mmol) and the reaction mixture was heated at 80 for 4 hours. After cooling to an ambient temperature, water (50 mL) was added, and then extracted with ethyl acetate (3 x 100 mL) . The organic layer was washed with brine (2×50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with gradient of 0-30 ethyl acetate in hexanes to afford the title compound as a colorless gum (6.60 g, 73) :1H NMR (300 MHz, CDCl3) δ 7.82 (d, J7.6 Hz, 1H) , 6.58 (d, J11.8 Hz, 1H) , 3.90-4.10 (m, 3H) , 3.07 (t, J12.4 Hz, 2H) , 1.98-1.89 (m, 3H), 1.84-1.56 (m, 2H) , 1.51 (s, (H) , 1.40 (s, 9H) MS (ES+) m/z 464.1, 462.1 (M+1) .
73% With caesium carbonate; In dimethyl sulfoxide; at 80℃; for 4h;Inert atmosphere; Step 1 Preparation of tert-butyl 4-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)-4-fluoropiperidine-1-carboxylate (0419) tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (3.20 g, 13.7 mmol) and <strong>[1354961-13-9]tert-butyl 5-chloro-2,4-difluorobenzoate</strong> (3.40 g, 13.7 mmol) in dimethyl sulfoxide (50 mL) was added cesium carbonate (8.94 g, 27.5 mmol) and the reaction mixture was heated at 80 C. for 4 h. After cooling to an ambient temperature, added water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed brine (2×50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was concentrated in vacuo and the residue was purified by silica gel column chromatography using gradient of 0-30% ethyl acetate in hexanes as eluent to afford the title compound as a colorless gum (6.6 g, 73% yield): 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=7.6 Hz, 1H), 6.58 (d, J=11.8 Hz, 1H), 3.90-4.10 (m, 3H), 3.07 (t, J=12.4 Hz, 2H), 1.98-1.89 (m, 3H), 1.84-1.56 (m, 2H), 1.51 (s, (H), 1.40 (s, 9H); MS (ES+) m/z 464.1, 462.1 (M+1).
  • 3
  • [ 614731-04-3 ]
  • [ 614730-97-1 ]
YieldReaction ConditionsOperation in experiment
100% With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 5h; 1-(tert-Butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid 13a (5.0 g, 20 mmol) was dissolved in 50 mL of THF.A borane tetrahydrofuran solution (50 mL, 1 M/THF) was added dropwise at 0 C, and the mixture was reacted at room temperature for 5 hours. Slow down in the reaction solution at 0 CThe reaction was quenched by slowly adding 20 mL of methanol. Concentrate under reduced pressure to remove the solvent. Add 50 mL of water and extract with ethyl acetate (50 mL×3).The combined organic layers were washed with EtOAc EtOAc (EtOAc)Fluor-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester 13b (4.7 g, colorless oil), yield: 100%.
98% With borane-THF; In tetrahydrofuran; for 32h;Reflux; To a solution of 1- (tert-butoxycarbonyl) -4-fluoropiperidine-4-carboxylic acid (5.00 g, 20.20 mmol) in tetrahydrofuran (100 mL) was added a solution of borane tetrahydrofuran complex (30.3 mL, 30.30 mmol, 1.0 M solution in tetrahydrofuran) . The reaction mixture was refluxed for 16 hours, and then another 24 mL of borane tetrahydrofuran complex was added and continued to reflux for another 16 hours. After cooling to ambient temperature the reaction mixture poured onto ice-cold water (50 mL) and saturated ammonium chloride (100 mL) , and extracted with ethyl acetate (3 x 100 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford the title compound (4.60 g, 98) . Which was used in the next step without further purification: MS (ES+) m/z 234.1 (M +1) .
With borane-THF; In tetrahydrofuran; for 32h;Reflux; Inert atmosphere; Step 1. Preparation of tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (0341) <strong>[614731-04-3]1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid</strong> (5.00 g, 20.20 mmol) in tetrahydrofuran (100 mL) was added a solution of borane tetrahydrofuran complex (30.3 mL, 30.30 mmol, 1.0 M solution in tetrahydrofuran). The reaction mixture was refluxed for 16 hours, and then another 24 mL of borane tetrahydrofuran complex was added and continued to reflux for another 16 hours. After cooling to ambient temperature the reaction mixture poured onto ice-cold water (50 mL) and saturated ammonium chloride (100 mL), and extracted with ethyl acetate (3×100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford the title compound (4.60 g, 98%). Which was used in the next step without further purification: MS (ES+) m/z 234.1 [M+H]+.
 

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