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Chemical Structure| 181269-69-2 Chemical Structure| 181269-69-2

Structure of 181269-69-2

Chemical Structure| 181269-69-2

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Product Details of [ 181269-69-2 ]

CAS No. :181269-69-2
Formula : C11H19NO3
M.W : 213.27
SMILES Code : O=C(N1CC(C)C(CC1)=O)OC(C)(C)C
MDL No. :MFCD08460962
InChI Key :VWSBNWIPICCWAM-UHFFFAOYSA-N
Pubchem ID :22644642

Safety of [ 181269-69-2 ]

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

Computational Chemistry of [ 181269-69-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 0
Fraction Csp3 0.82
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 61.6
TPSA ?

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

46.61 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.51
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.

1.45
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.

1.05
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

1.23
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.48

Water Solubility

Log S (ESOL):?

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

-1.68
Solubility 4.43 mg/ml ; 0.0208 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.

-1.71
Solubility 4.13 mg/ml ; 0.0194 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

-1.56
Solubility 5.91 mg/ml ; 0.0277 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.

-6.79 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)

2.57

Application In Synthesis of [ 181269-69-2 ]

* 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 [ 181269-69-2 ]

[ 181269-69-2 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 37595-74-7 ]
  • [ 181269-69-2 ]
  • [ 34846-90-7 ]
  • 2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-amine [ No CAS ]
  • N-(isoxazol-3-yl)-2-oxooxazolidine-3-sulfonamide [ No CAS ]
  • (rac)-N-(isoxazol-3-yl)-7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-sulfonamide [ No CAS ]
  • (rac)-N-(isoxazol-3-yl)-5-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-sulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.A 20-mL vial was charged with a mixture of (Rac)-(E)-tert-buty 1 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((lrifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-buty\ 3-(3-methoxy-3-oxoprop-1 -en-1 -yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (716 mg, 1.668 mmol), 2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny 1]-4-amine (Preparation 4h, 352 mg, 1.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (101 mg, 0.174 mmol), cesium carbonate (1.36 g, 4.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.9 mg, 0.07 mmol), and 1,4-dioxane (6.95 mL) then sparged with nitrogen for 10 min. The needle was then removed and the reaction was heated to 100 °C. After 3 h, the reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc (15 mL) and filtered through a Celite® pad. The pad was rinsed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (50-g silica gel Biotage column, eluent: gradient, 0 to 35percent 3:1 EtOAc/EtOH in heptane with DCM as a 10percent additive) to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,r-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-bu\y\ 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (587 mg, 1.17 mmol, 84.0percent) as a brown solid,A 20-mL vial was charged with a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxy late (587 mg, 1.173 mmol) and trifluoroacetic acid (5.86 mL) at ambient temperature. After 30 min, the reaction mixture was concentrated under reduced pressure, dissolved in DCM (15 mL) and carefully poured into saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated and the aqueous layer extracted with additional DCM (3 x 15 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,l'-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (400 mg, 1.00 mmol, 85.0percent) as a tan amorphous solid, which was used without further purification.20-mL vial was charged with a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (400 mg, 1.00 mmol), N-(isoxazol-3-yl)-2-oxooxazol...
  • 2
  • [ 37595-74-7 ]
  • [ 181269-69-2 ]
  • [ 34846-90-7 ]
  • 2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-amine [ No CAS ]
  • (rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate [ No CAS ]
  • (rac)-tert-butyl 5-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.A 20-mL vial was charged with a mixture of (Rac)-(E)-tert-buty 1 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((lrifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-buty\ 3-(3-methoxy-3-oxoprop-1 -en-1 -yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (716 mg, 1.668 mmol), 2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny 1]-4-amine (Preparation 4h, 352 mg, 1.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (101 mg, 0.174 mmol), cesium carbonate (1.36 g, 4.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.9 mg, 0.07 mmol), and 1,4-dioxane (6.95 mL) then sparged with nitrogen for 10 min. The needle was then removed and the reaction was heated to 100 °C. After 3 h, the reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc (15 mL) and filtered through a Celite® pad. The pad was rinsed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (50-g silica gel Biotage column, eluent: gradient, 0 to 35percent 3:1 EtOAc/EtOH in heptane with DCM as a 10percent additive) to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,r-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-bu\y\ 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (587 mg, 1.17 mmol, 84.0percent) as a brown solid,
  • 3
  • [ 37595-74-7 ]
  • [ 181269-69-2 ]
  • [ 34846-90-7 ]
  • 2,3',5'-trifluoro-5-methoxy-[1,1'-biphenyl]-4-amine [ No CAS ]
  • C22H19F3N2O2 [ No CAS ]
  • C22H19F3N2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.A 20-mL vial was charged with a mixture of (Rac)-(E)-tert-buty 1 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((lrifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-buty\ 3-(3-methoxy-3-oxoprop-1 -en-1 -yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (716 mg, 1.668 mmol), 2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny 1]-4-amine (Preparation 4h, 352 mg, 1.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (101 mg, 0.174 mmol), cesium carbonate (1.36 g, 4.17 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.9 mg, 0.07 mmol), and 1,4-dioxane (6.95 mL) then sparged with nitrogen for 10 min. The needle was then removed and the reaction was heated to 100 °C. After 3 h, the reaction mixture was allowed to cool to ambient temperature and was diluted with EtOAc (15 mL) and filtered through a Celite® pad. The pad was rinsed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure and purified by flash column chromatography (50-g silica gel Biotage column, eluent: gradient, 0 to 35percent 3:1 EtOAc/EtOH in heptane with DCM as a 10percent additive) to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,r-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-bu\y\ 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (587 mg, 1.17 mmol, 84.0percent) as a brown solid,A 20-mL vial was charged with a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-trifluoro-5-methoxy-[l,l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxy late (587 mg, 1.173 mmol) and trifluoroacetic acid (5.86 mL) at ambient temperature. After 30 min, the reaction mixture was concentrated under reduced pressure, dissolved in DCM (15 mL) and carefully poured into saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated and the aqueous layer extracted with additional DCM (3 x 15 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to afford a mixture of (Rac)-tert-butyl 7-methyl-2-oxo-l-(2,3',5'-trifluoro-5-methoxy-[l,l'-biphenyl]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate and (Rac)-tert-butyl 5-methy 1-2-oxo-1-(2,3',5'-lrifluoro-5-methoxy-[l, l'-bipheny l]-4-yl)-l,2,7,8-tetrahydro-l,6-naphthyridine-6(5H)-carboxylate (400 mg, 1.00 mmol, 85.0percent) as a tan amorphous solid, which was used without further purification.
  • 4
  • [ 37595-74-7 ]
  • [ 181269-69-2 ]
  • [ 34846-90-7 ]
  • (rac)-(E)-tert-butyl 3-(3-methoxy-3-oxoprop-1-en-1-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
  • (rac)-(E)-tert-butyl 3-(3-methoxy-3-oxoprop-1-en-1-yl)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
A 250-mL round-bottom flask was charged with (Rac)-tert-butyl 3-methy 1-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol) and purged with nitrogen. THF (47.0 ml) was introduced and the reaction mixture was cooled to -78 °C in a dry ice-acetone bath. A solution of potassium /er/-butoxide (1.6 M in THF, 19.0 mL, 29.9 mmol) was added to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to 0 °C in an ice-water bath. After 30 min, the reaction mixture was cooled to -78 °C. Methyl 3 -methoxy aery late (5.29 ml, 49.2 mmol) was added dropwise to the reaction mixture via syringe over 5 min. Following addition, the reaction mixture was allowed to warm to ambient temperature. After 2 h, the resultant red reaction mixture was cooled was cooled to -78 °C. N-phenyl bis-trifluoromethane sulfonamide (13.2 g, 37.0 mmol) was added to the vigorously stirred, cooled reaction mixture in one portion and the reaction mixture was subsequently allowed to warm to 0 °C in an ice-water bath. After 1 h, saturated aqueous sodium bicarbonate solution (100 mL) and EtOAc (100 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography in two portions (100-g silica gel Biotage column, eluent: gradient, 0 to 30percent EtOAc in heptane) to afford a mixture of (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate and (Rac)-(E)-tert-bu\y\ 3-(3-methoxy-3-oxoprop-l-en-l-yl)-2-methy 1-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-l(2H)-carboxylate (11.75 g, 27.4 mmol, 117 percent yield) as a yellow solid.
 

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