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Chemical Structure| 1093066-74-0

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Product Details of [ 1093066-74-0 ]

CAS No. :1093066-74-0
Formula : C13H22F2N2O2
M.W : 276.32
SMILES Code : O=C(N1CCC(N2CC(F)(F)C2)CC1)OC(C)(C)C
MDL No. :MFCD18072966
InChI Key :RIGPUFYOEHVLIA-UHFFFAOYSA-N
Pubchem ID :59606191

Safety of [ 1093066-74-0 ]

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

Computational Chemistry of [ 1093066-74-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 19
Num. arom. heavy atoms 0
Fraction Csp3 0.92
Num. rotatable bonds 4
Num. H-bond acceptors 5.0
Num. H-bond donors 0.0
Molar Refractivity 75.85
TPSA ?

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

32.78 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.06
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

2.15
Log Po/w (WLOGP)?

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

2.42
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.

1.97
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

1.68
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.26

Water Solubility

Log S (ESOL):?

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

-2.64
Solubility 0.628 mg/ml ; 0.00227 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-2.47
Solubility 0.935 mg/ml ; 0.00338 mol/l
Class?

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

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

-1.99
Solubility 2.85 mg/ml ; 0.0103 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.

-6.46 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<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)

2.47

Application In Synthesis of [ 1093066-74-0 ]

* 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.

  • Upstream synthesis route of [ 1093066-74-0 ]

[ 1093066-74-0 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 288315-03-7 ]
  • [ 79099-07-3 ]
  • [ 1093066-74-0 ]
YieldReaction ConditionsOperation in experiment
88%
Stage #1: at 20℃; for 0.25 h;
Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane for 17 h;
To a solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) in DCE (50 mL) was added 3,3-difluoroazetidine hydrochloride (712 mg, 5.5 mmol). The mixture was stirred at RT for 15 min, then sodium triacetoxyborohydride (1.59 g, 7.5 mmol) was added and stirring was continued for 17 h. The reaction mixture was diluted with brine and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(3,3- difluoroazetidin-l-yl)-piperidine-l-carboxylic acid tert-butyl ester as a pale yellow solid (1.2 g, 88 percent). To a solution of 4-(3,3-difluoro-azetidin-l-yl)-piperidine-l-carboxylic acid tert- butyl ester (552 mg, 2.0 mmol) in DCM (4 mL) was added TFA (2 mL) and the resulting mixture was stirred at RT for 45 min. The reaction mixture was loaded onto an Isolute.(R). SCX- 2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (271 mg, 77 percent). <n="94"/>1H NMR (400 MHz, CDCl3): δ 1.16-1.27 (m, 2 H), 1.63-1.72 (m, 2 H), 2.14-2.23 (m, 1 H), 2.54-2.62 (m, 2 H), 3.09 (dt, J = 12.7, 3.9 Hz, 2 H) and 3.46-3.57 (m, 4 H).
88%
Stage #1: at 20℃; for 0.25 h;
Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane for 17 h;
Reference Example 254-(3,3-Difluoro-azetidin-l-yl)-piperidineTo a solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) in DCE (50 mL) was added 3,3-difluoroazetidine hydrochloride (712 mg, 5.5 mmol). The mixture was stirred at RT for 15 min, then sodium triacetoxyborohydride (1.59 g, 7.5 mmol) was added and stirring was continued for 17 h. The reaction mixture was diluted with brine and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(3,3- difluoro-azetidin-l-yl)-piperidine-l-carboxylic acid tert-butyl ester as a pale yellow solid (1.2 g, 88 percent). To a solution of 4-(3,3-difluoro-azetidin-l-yl)-piperidine-l-carboxylic acid tert- butyl ester (552 mg, 2.0 mmol) in DCM (4 mL) was added TFA (2 mL) and the resulting <n="69"/>mixture was stirred at RT for 45 min. The reaction mixture was loaded onto an Isolute.(R). SCX- 2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (271 mg, 77 percent).1H NMR (400 MHz, CDCl3): δ 1.16-1.27 (m, 2 H), 1.63-1.72 (m, 2 H), 2.14-2.23 (m, 1 H), 2.54-2.62 (m, 2 H), 3.09 (dt, J = 12.7, 3.9 Hz, 2 H) and 3.46-3.57 (m, 4 H).
88% at 20℃; for 17 h; To a solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) in DCE (50 mL) was added 3,3-difluoroazetidine hydrochloride (712 mg, 5.5 mmol). The mixture was stirred at RT for 15 min, then sodium triacetoxyborohydride (1.59 g, 7.5 mmol) was added and stirring was continued for 17 h. The reaction mixture was diluted with brine and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(3,3- difluoroazetidin-l-yl)piperidine-l-carboxylic acid tert-butyl ester as a pale yellow solid (1.2 g, 88 percent). To a solution of 4-(3,3-difluoroazetidin-l-yl)piperidine-l-carboxylic acid tert-butyl ester (552 mg, 2.0 mmol) in DCM (4 mL) was added TFA (2 mL) and the resulting mixture was stirred at RT for 45 min. The reaction mixture was loaded onto an Isolute.(R). SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (271 mg, 77 percent). 61H NMR (400 MHz, CDCl3): 5 1.16-1.27 (m, 2 H), 1.63-1.72 (m, 2 H), 2.14-2.23 (m, 1 H), 2.54-2.62 (m, 2 H), 3.09 (dt, J = 12.7, 3.9 Hz, 2 H) and 3.46-3.57 (m, 4 H).
43%
Stage #1: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 50℃; for 16 h;
Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In N,N-dimethyl-formamide at 40℃; for 16 h;
A solution of 3,3-difluoroazetidine hydrochloride (300 mg, 2.3 mmol), te/f-butyl 4-oxopiperidine- 1 -carboxylate (461 mg, 2.3 mmol) and DIPEA (0.40 ml_, 2.3 mmol) in DMF (6 mL) was heated to 50 °C for 16 h before cooling to rt, addition of sodium triacetoxyborohydride (1 .23 g, 5.8 mmol) and AcOH (0.13 mL, 2.3 mmol) and further heating at 40 °C for 16 h. The mixture was cooled to rt, quenched by addition of sat. aq. NaHC03 (3 mL) and concentrated in vacuo. The residue was diluted with DCM (15 mL) and washed with sat. aq. NaHC03 (15 mL) and brine (15 mL). Organics were dried (Biotage phase separator) and concentrated in vacuo. The crude residue was purified on silica (Biotage Isolera, SNAP 25 g cartridge, 0 - 10 percent MeOH / DCM and subsequently SNAP 25 g cartridge, 0 - 5 percent MeOH / DCM) to yield te/f-butyl 4-(3,3- difluoroazetidin-1 -yl)piperidine-1 -carboxylate (273 mg, 43 percent) as a white crystalline solid, which was used directly in the next step.

References: [1] Patent: WO2009/53715, 2009, A1, . Location in patent: Page/Page column 92-93.
[2] Patent: WO2009/53716, 2009, A1, . Location in patent: Page/Page column 67-68.
[3] Patent: WO2008/152394, 2008, A1, . Location in patent: Page/Page column 45.
[4] Patent: WO2017/21729, 2017, A1, . Location in patent: Page/Page column 41.
 

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