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Structure of 478148-62-8

Chemical Structure| 478148-62-8

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Product Details of [ 478148-62-8 ]

CAS No. :478148-62-8
Formula : C8H5NO3
M.W : 163.13
SMILES Code : O=C(C1=CC2=C(OC=C2)C=N1)O
MDL No. :MFCD18255510
InChI Key :BEVAEUJOJMQCIU-UHFFFAOYSA-N
Pubchem ID :22047515

Safety of [ 478148-62-8 ]

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

Computational Chemistry of [ 478148-62-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 9
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 4.0
Num. H-bond donors 1.0
Molar Refractivity 40.97
TPSA ?

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

63.33 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.08
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

1.11
Log Po/w (WLOGP)?

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

1.53
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.

-1.2
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

1.25
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.75

Water Solubility

Log S (ESOL):?

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

-2.04
Solubility 1.49 mg/ml ; 0.00913 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.

-2.03
Solubility 1.51 mg/ml ; 0.00927 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

-2.28
Solubility 0.86 mg/ml ; 0.00527 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.

-6.51 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.

0.56

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)

2.08

Application In Synthesis of [ 478148-62-8 ]

* 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 [ 478148-62-8 ]

[ 478148-62-8 ] Synthesis Path-Downstream   1~20

  • 1
  • [ 478148-61-7 ]
  • [ 478148-62-8 ]
YieldReaction ConditionsOperation in experiment
94% With potassium dihydrogenphosphate; NaClO2; In methanol; water; dimethyl sulfoxide; C17 (850 mg, 5.8 mmol) is dissolved in 10 mL DMSO. KH2PO4 (221 mg, 1.6 mmol) in 3 mL H2O is added and then NaClO2 (920 mg, 8.2 mmol) in 7 mL H2O is added, and the reaction is stirred 3 h at rt. The reaction is diluted with 25 mL water, the pH is adjusted to 10 with 2N NaOH, and the mixture is extracted with 3*20 mL ether. The combined ether layer is discarded. The pH of the aqueous layer is adjusted to 3.5 with 10% aqueous HCl and is extracted with 13*10 mL 10% MeOH/CH2Cl2. The MeOH/CH2Cl2 organic layer is dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to a pale oil. The residual DMSO is removed under a stream of N2 at rt to provide a white paste. The paste is dissolved in MeOH and concentrated to dryness. The white solid is washed with ether and dried to afford crude furo[2,3-c]pyridine-5-carboxylic acid (C18) (94% yield). MS (ESI) for C8H5NO3, 162.8 (M-H)-.
94% With potassium dihydrogenphosphate; NaClO2; In methanol; water; dimethyl sulfoxide; C17 (850 mg, 5.8 mmol) is dissolved in 10 mL DMSO. KH2PO4 (221 mg, 1.6 mmol) in 3 mL water is added and then NaClO2 (920 mg, 8.2 mmol) in 7 mL water is added, and the reaction is stirred 3 h at rt. The reaction is diluted with 25 mL water, the pH is adjusted to 10 with 2N NaOH, and the mixture is extracted with 3*20 mL ether. The combined ether layer is discarded. The pH of the aqueous layer is adjusted to 3.5 with 10% aqueous HCl and is extracted with 13*10 mL 10% MeOH/CH2Cl2. The MeOH/CH2Cl2 organic layer is dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to a pale oil. The residual DMSO is removed under a stream of N2 at rt to provide a white paste. The paste is dissolved in MeOH and is concentrated to dryness. The white solid is washed with ether and dried to afford crude furo[2,3-c]pyridine-5-carboxylic acid (C18) (94% yield). MS (ESI) for C8H5NO3, 162.8 (M-H)-.
94% With sodium chlorite; potassium dihydrogenphosphate; In water; dimethyl sulfoxide; at 20℃; for 3h; C8 (850 mg, 5.8 mmol) is dissolved in 10 mL DMSO. KH2PO4 (221 mg, 1.6 mmol) in 3 mL water is added and then NA102 (920 mg, 8.2 mmol) in 7 mL water is added, and the reaction is stirred 3h at rt. The reaction is diluted with 25 mL water, the pH is adjusted to 10 with 2N NAOH, AND the mixture is extracted with 3 x 20 mL ether. The combined ether layer is discarded. The pH of the aqueous layer is adjusted to 3.5 with 10% aqueous HC1 and is extracted with 13 X 10 mL 10% MEOH/CH2CL2. The MEOH/CH2CL2 organic layer is dried (NA2S04), filtered, and concentrated in vacuo to a pale oil. The residual DMSO is removed under a stream of N2 at rt to provide a white paste. The paste is dissolved in MEOH and is concentrated to dryness. The white solid is washed with ether and dried to afford crude furo [2,3-c] pyridine-5- carboxylic acid C9) (94% YIELD). MS (ESI) FOR CSHSNO3 162.8 (M-H)-.
  • 2
  • [ 478148-62-8 ]
  • [ 6530-09-2 ]
  • [ 478149-53-0 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 2.5h; Acid C9 (1.96 g, 12.0 MMOL), DIEA (6.27 mL, 36.0 mmol), and R- (+)-3- aminoquinuclidine dihydrochloride (2. 42 g, 12.1 mmol) are added to DMF (60 mL), and the reaction is cooled in an ice bath. HATU (4.57 g, 12.0 mmol) is added, the solution allowed to warm to rt over 2.5 h, then CONCENTRATED IN VACUO. The residue is stirred with saturated NAHCO3 (30 mL) for 30 min, then extracted with CHC13 (10 X 50 mL). The combined organic layer is dried (NA2S04) and is concentrated in vacuo. The crude material is chromatographed over 130 g slurry-packed silica gel, eluting with 0.5% ammonium hydroxide in 10% MEOH/CHC13. The appropriate fractions are combined and concentrated to a residue.
  • 9
  • [ 478148-62-8 ]
  • endo-[2.2.1]-3-Amine [ No CAS ]
  • exo-N-(1-azabicyclo[2.2.1]hept-3-yl)furo[2,3-c]pyridine-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; EXAMPLE 1(i-e) (-)-N-[endo-1-azabicyclo[2.2.1]hept-3-yl]furo[2,3-c]pyridine-5-carboxamide To a stirred solution of <strong>[478148-62-8]furo[2,3-c]pyridine-5-carboxylic acid</strong> (400 mg, 0.877 mmol) in anhydrous DMF (10 mL) are added DIEA (626 muL, 3.59 mmol) and endo-[2.2.1]-3-Amine (175 mg, 0.877 mmol). The mixture is cooled to 0 C. in an ice bath, and HATU (333 mg, 0.877 mmol) is added in one portion. The reaction mixture is allowed to warm to rt and stir overnight. The solvent is removed in vacuo, and the residue is partitioned between saturated aqueous K2CO3 solution and CHCl3. The aqueous layer is extracted with CHCl3 (2*). The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 230 mg solid. The racemic mixture is resolved via chromatography using a Chiralcel OJ column. The amides are converted to their fumarate salt forms as described in Step 1b. The (+)-enantiomer ([alpha]25D 31 (c 0.28, MeOH)) gives rise to Example 1-d, and the (-)-enantiomer ([alpha]25D -31 (c 0.30, MeOH)) gives rise to Example 1-e. For Example 1-d: 1H NMR (400 MHz, CD3OD) delta 8.94, 8.46, 8.14, 7.13, 6.71, 4.75-4.70, 3.86-3.79, 3.48-3.42, 3.28-3.21, 2.21-2.03.
  • 10
  • [ 478148-61-7 ]
  • [ 7758-19-2 ]
  • potassium dihydrogen phosphate [ No CAS ]
  • [ 478148-62-8 ]
YieldReaction ConditionsOperation in experiment
890 mg (94%) In methanol; water; dimethyl sulfoxide; Furo[2,3-c]pyridine-5-carbaldehyde (850 mg, 5.8 mmol) is dissolved in 10 ml DMSO. To this solution is added potassium dihydrogen phosphate (221 mg, 1.6 mmol) in 3 ml water followed by sodium chlorite (920 mg, 8.2 mmol) in 7 ml water. The resulting reaction mixture is stirred for 3 h at rt. The reaction is diluted with 25 ml water, the pH is adjusted to 10 with 2N NaOH, and the mixture is extracted with 3*20 ml ether. The pH of the aqueous layer is adjusted to 3.5 with 10% aqueous HCl and is extracted with 13*10 ml 10% MeOH/CH2Cl2. The organic layer is dried over Na2SO4 and is concentrated in vacuo to a pale oil. The residual DMSO is removed under a stream of nitrogen to provide a white paste. The paste is dissolved in MeOH and is concentrated to dryness. The white solid is washed with ether and is dried to give 890 mg (94%) of crude furo[2,3-c]pyridine-5-carboxylic acid. MS for C8H5NO3, (ESI): 162.8 (M-H)-.
  • 11
  • [ 478148-62-8 ]
  • [ 478149-45-0 ]
YieldReaction ConditionsOperation in experiment
92% EXAMPLE 38 N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide Example 38 is obtained (92% yield) as the free base by coupling acid C18 with (S)-(-)-3-aminoquinuclidine according to Method C with omission of the HCl treatment. HRMS (FAB) calculated for C15H17N3O2+H: 272.1399, found 272.1404 (M+H)+.
  • 12
  • [ 478148-62-8 ]
  • 1-azabicyclo[3.2.2]nonan-3-aminobis(4-methylbenzene sulfonate) [ No CAS ]
  • [ 110-17-8 ]
  • [ 1009629-92-8 ]
  • 13
  • [ 478148-62-8 ]
  • exo-6-amino-8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]octane [ No CAS ]
  • tert-butyl exo-6-(furo[2,3-c]pyridine-5-yl-carbonyl)amino-8-azabicyclo[3.2.1]octane 8-carboxylate [ No CAS ]
  • 14
  • [ 478148-62-8 ]
  • (3R,5R)-1-azabicyclo[3.2.1]octane-3-amine dihydrochloride [ No CAS ]
  • [ 508202-22-0 ]
  • 15
  • [ 478148-62-8 ]
  • [ 137661-31-5 ]
  • [ 478149-53-0 ]
YieldReaction ConditionsOperation in experiment
66% With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; for 16.0h; First Step Synthesis of N-(1-Azabicyclo[2.2.2]oct-3(R)-yl)furo[2,3-c]pyridine-5-carboxamide To a solution (10 mL) of <strong>[478148-62-8]furo[2,3-c]pyridine-5-carboxylic acid</strong> (0.16 g, 1.0 mmol) in chloroform, o-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.57 g, 1.5 mmol), diisopropylethylamine (0.70 mL, 4.0 mmol), and (R)-quinuclidine-3-amine hydrochloride (0.20 g, 1.0 mmol) were added, and the resulting mixture was stirred at room temperature. Sixteen hours later, distilled water was added thereto, and the resultant was then extracted with chloroform. The organic layer was washed with brine, then dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (amine silica gel DM1020, Fuji Silysia Chemical Ltd., chloroform alone to chloroform/methanol=98/2) to obtain the title compound (0.18 mg; 66%) as a colorless liquid. 1H-NMR (400 MHz, CDCl3) delta: 1.40-1.55 (1H, m), 1.65-1.74 (2H, m), 1.80-1.90 (1H, m), 2.02-2.06 (1H, m), 2.63-2.70 (1H, m), 2.75-3.00 (4H, m), 3.39-3.46 (1H, m), 4.12-4.20 (1H, m), 6.89-6.92 (1H, m), 7.80 (1H, d, J=2.0 Hz) 8.25-8.35 (1H, m), 8.46-8.49 (1H, m), 8.75-8.78 (1H, m).MS (ESI) [M+H]+272
  • 16
  • [ 478148-62-8 ]
  • [ 137661-31-5 ]
  • PHA-543,613 [ No CAS ]
  • 17
  • [ 478148-62-8 ]
  • N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, hemi-fumarate salt [ No CAS ]
  • 18
  • [ 478148-62-8 ]
  • [ 708261-37-4 ]
  • 19
  • [ 478148-59-3 ]
  • [ 478148-62-8 ]
  • 20
  • [ 441044-90-2 ]
  • [ 478148-62-8 ]
 

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