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Chemical Structure| 193269-78-2 Chemical Structure| 193269-78-2

Structure of 193269-78-2

Chemical Structure| 193269-78-2

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Product Details of [ 193269-78-2 ]

CAS No. :193269-78-2
Formula : C8H16N2O2
M.W : 172.22
SMILES Code : O=C(N1CC(N)C1)OC(C)(C)C
MDL No. :MFCD01861753
InChI Key :WPGLRFGDZJSQGI-UHFFFAOYSA-N
Pubchem ID :1516507

Safety of [ 193269-78-2 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H314
Precautionary Statements:P501-P264-P280-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P405
Class:8
UN#:2735
Packing Group:

Computational Chemistry of [ 193269-78-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 0
Fraction Csp3 0.88
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 49.69
TPSA ?

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

55.56 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.15
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

0.01
Log Po/w (WLOGP)?

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

0.18
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.

0.24
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

-0.25
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.47

Water Solubility

Log S (ESOL):?

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

-0.72
Solubility 33.1 mg/ml ; 0.192 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.

-0.73
Solubility 32.2 mg/ml ; 0.187 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

-0.35
Solubility 76.6 mg/ml ; 0.445 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.

-7.34 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

1.0
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)

2.01

Application In Synthesis of [ 193269-78-2 ]

* 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 [ 193269-78-2 ]

[ 193269-78-2 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 193269-78-2 ]
  • [ 1044733-65-4 ]
  • C20H22ClN5O2 [ No CAS ]
  • 2
  • [ 193269-78-2 ]
  • [ 17794-48-8 ]
  • [ 1228652-17-2 ]
YieldReaction ConditionsOperation in experiment
94% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 30h;Product distribution / selectivity; compound/ Purity d wt. or reagent name (%) MW (g/mL) eq. mol vol. 3 99.0 247.17 1.00 1.00 2.40 600.0 g N-Boc-3- 98.00 172.23 1.38 1.06 2.55 448.0 g (amino) azetidine (4) HOBT 98.00 135.13 1.00 0.117 0.28 37.7 g EDCl 99.00 191.70 1.02 1.42 3.41 660.0 g Tri- 99.0 101.19 0.73 1.30 3.13 0.44 L ethylamine Di- 99.0 84.93 1.32 135.91 8.8 L chloro- methane To a 22-L 4-neck round bottom flask equipped with a thermocouple controller, mechanical stirrer, heating mantle, condenser and a nitrogen inlet adapter was charged with acid 3 as prepared in the previous step (600 g; 2.40 mol), dichloromethane (8.8 L), TEA (440 mL; 3.13 mol), N-Boc-3-(amino)azetidine (4, CNH Technologies, Inc.) (448 g; 2.55 mol) and HOBT (37.7 g; 0.28 mol, AK Scientific), and the mixture was stirred at 20 C. for 5 min, EDCI (506 g; 2.64 mol; 1.1 eq., AK Scientific) was added as one portion. The mixture was stirred at 20 C. for an additional 6 h. More EDCI (120.0 g, 0.626 mol; 0.26 eq) was added and the reaction was stirred at 20 C. for 20 h. EDCI (33.3 g; 0.174 mol; 0.05 eq.) was added again at the 21st h and the reaction was stirred at 20 C. for an additional 4 h. The reaction was washed with saturated NaHCO3 (4 L×2) (aqueous pH=9) and brine (3 L×2), and the separated organic phase was concentrated at 60 C. under house vacuum (120 mmHg) and then high vacuum (20 mmHg) to give crude 5 as a yellowish think syrup.To a 22-L 4-neck round bottom flask equipped with a thermocouple controller, mechanical stirrer, heating mantle, condenser and a nitrogen inlet adapter was charged a warm solution (60 C.) of crude 5 in EtOAc (3.1 L) and the mixture was heated to 73 C. with stirring, while warm (60 C.) heptane (10.0 L) was added as five portions (2 L×5) over 30 min. The resulting slightly white turbid solution was stirred at 73 C. for 10 min. The heating mantle was removed and the mixture was gradually cooled to 20 C. over 3 h, and further to 10 C. in a water bath and stirred for 1 h. The solid was collected by filtration, washed with hexanes (300 mL×2), dried under air-suction and then placed in a drying oven at 50 C. under house vacuum for 20 h to afford pure title compound, 5, as an off-white crystalline solid. The structure of 5 was confirmed by 1H-NMR.
80% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h; General procedure: N-(Azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide TFA salt: 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (1.2 g, 6.97 mmol) and <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (1.57 g, 6.36 mmol) were treated with EDCI (1.57 g, 6.36 mmol), HOBT (1.22 g, 6.36 mmol) in DCM (10 mL) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow oil, which was then purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford 3-[2-(3-trifluoro-methyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butyl ester as white solid, 2.23 g, 80% yield. 1H NMR (400 MHz, CDCl3) d 8.10 (s, 1H), 8.02 (d, J = 6.6 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.56 (t, J = 6.5 Hz, 1H), 4.61 (m, 1H), 4.25 (t, J = 7.2 Hz, 2H), 4.18 (d, J = 5.5 Hz, 2H), 3.82 (t, J = 7.5 Hz, 2H), 1.41 (s, 9H). 3-[2-(3-Trifluoromethyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butyl ester (2.10 g, 5.24 mmol) was dissolved in 1:1 TFA and DCM mixed solution (10 mL) at room temperature. The reaction was stirred for another 2 hours. The solvent was removed and the residue was dried to give N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide as a TFA salt containing extra TFA (colorless oil), ~ 2.5 g, 100% yield. 1H NMR (400 MHz, CDCl3) d 8.10 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.78 (d, J = 6.2 Hz, 1H), 7.55 (m, 2H), 4.78 (m, 1H), 4.15 (d, J = 3.2 Hz, 2H), 3.95 (t, J = 7.0 Hz, 2H), 3.52 (t, J = 7.0 Hz, 2H).8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene (PCT Int. Appl. WO2006064189, 0.292 g, 1.10 mmol), 5-bromobenzo[d][1,3]dioxole (Aldrich, 161 mg, 0.801 mmol), and tetrakis (triphenylphosphino)palladium(0) (Aldrich, 0.048 g, 0.042 mmol) were dissolved in 1,4-dioxane (9 mL), treated with 2M aqueous Na2CO3 (2.0 mL, 4.0 mmol), bubbled with argon for a few minutes, and heated to 100oC under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo to give an orange oil. This was purified by thin layer chromatography on silica gel (EtOAc) to give 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzo[d][1,3]dioxole as a yellow solid (110 mg, 53%). 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzo[d][1,3]dioxole (110 mg, 0.42 mmol) in MeOH (5 mL) was placed in a hydrogenation Par Shaker under 40 psi at room temperature using 5% Pd/C (~ 50 mg) as catalyst for 2 hour. The resulting solution was filtered through a pad of Celite , concentrated and purified by silica gel column on a CombiFlash system to afford 5-(1,4-dioxaspiro[4.5]decan-8-yl)benzo[d][1,3]dioxole as white solid, 91 mg, 82% yield. 5-(1,4-dioxaspiro[4.5]decan-8-yl)benzo[d][1,3]dioxole (91 mg, 0.35 mmol) was treated with 1N HCl ( ~ 2 mL) in acetone (4 mL) at room temperature for 4 hours. The reaction was neutralized with saturate NaHCO3 solution and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow solid, which was then purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford 4-(benzo[d][1,3]dioxol-5-yl)cyclohexanone as white solid, 75 mg, 98% yield.4-(benzo[d][1,3]dioxol-5-yl)cyclohexanone (75 mg, 0.35 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide TFA salt (151 mg, 0.50 mmol) in DCM (2 mL) was treated with TEA (0.1 mL, 0.75 mmol) for 10 min followed by NaBH(OAc)3 (Aldrich, 225 mg, 1.05 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform and IPA "cocktail" (~ 3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford two title compounds as white solids: 8a, less polar isomer (cis), 67 mg, 38% yield; 9a, more polar isomer (trans), 45 mg, 26% yield.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h; A solution of 3-amino-azetidine-1-carboxylic acid tert-butyl ester (BetaPharma, 1.2 g, 6.97 mmol) and <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (Bionet, 1.57 g, 6.36 mmol) in DCM (10 mL) was treated with EDCI (Aldrich, 1.57 g, 6.36 mmol) and HOBT (Aldrich, 1.22 g, 6.36 mmol) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was then purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.10 (s, 1H), 8.02 (d, J=6.6 Hz, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.56 (t, J=6.5 Hz, 1H), 4.61 (m, 1H), 4.25 (t, J=7.2 Hz, 2H), 4.18 (d, J=5.5 Hz, 2H), 3.82 (t, J=7.5 Hz, 2H), 1.41 (s, 9H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h; Step D: 3-[2-(3-Trifluoromethyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tent-butyl ester 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (AstaTech, 1.2 g, 6.97 mmol) and <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (Bionet Building Blocks, 1.57 g, 6.36 mmol) were treated with EDCI (Aldrich, 1.57 g, 6.36 mmol), HOBT (Aldrich, 1.22 g, 6.36 mmol) in DCM (10 mL) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, and purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.10 (s, 1H), 8.02 (d, J=6.6 Hz, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.56 (t, J=6.5 Hz, 1H), 4.61 (m, 1H), 4.25 (t, J=7.2 Hz, 2H), 4.18 (d, J=5.5 Hz, 2H), 3.82 (t, J=7.5 Hz, 2H), 1.41 (s, 9H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h; Step B: 3-[2-(3-Trifluoromethyl-benzoylamino)-acetylamino]azetidine-1-carboxylic acid tent-butyl ester 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (AstaTech, 1.2 g, 6.97 mmol) and <strong>[17794-48-8](3-trifluoromethyl-benzoylamino)-acetic acid</strong> (Bionet Building Blocks, 1.57 g, 6.36 mmol) were treated with EDCI (Aldrich, 1.57 g, 6.36 mmol), HOBT (Aldrich, 1.22 g, 6.36 mmol) in DCM (10 mL) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, and purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.1H NMR (400 MHz, CDCl3) delta 8.10 (s, 1H), 8.02 (d, J=6.6 Hz, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.56 (t, J=6.5 Hz, 1H), 4.61 (m, 1H), 4.25 (t, J=7.2 Hz, 2H), 4.18 (d, J=5.5 Hz, 2H), 3.82 (t, J=7.5 Hz, 2H), 1.41 (s, 9H).

  • 3
  • [ 193269-78-2 ]
  • [ 60211-57-6 ]
  • [ 530-62-1 ]
  • tert-butyl 3-((((3,5-dichlorobenzyl)oxy)carbonyl)amino)azetidine-1-carboxylate [ No CAS ]
  • 4
  • [ 193269-78-2 ]
  • [ 141179-72-8 ]
  • tert-butyl 3-(4-fluoro-2-(trifluoromethyl)benzamido)azetidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 16h;Inert atmosphere; Cooling with ice; General procedure: 4-Fluoro-2-(trifluoromethyl)benzoic acid (1 equiv), amine (1 equiv) and DMAP (0.1 equiv) were added to THF (50mL) under nitrogen. The obtained solution was cooled down on an ice-water bath. EDC·HCl (1.3 equiv) was added to the solution, and the reaction mixture was stirred for 16h while warming at room temperature. The reaction solution was washed with water and extracted with EtOAc, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to yield pure product.
  • 5
  • [ 193269-78-2 ]
  • [ 51991-94-7 ]
  • C15H18N4O4S [ No CAS ]
 

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Technical Information

Categories

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