Structure of 478148-62-8
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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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 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
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 |
63.33 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.08 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.11 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.53 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-1.2 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.25 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.75 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.04 |
Solubility | 1.49 mg/ml ; 0.00913 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.03 |
Solubility | 1.51 mg/ml ; 0.00927 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.28 |
Solubility | 0.86 mg/ml ; 0.00527 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.51 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.08 |
* 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.
Yield | Reaction Conditions | Operation 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)-. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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)-. |
Yield | Reaction Conditions | Operation 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)+. |
Yield | Reaction Conditions | Operation 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 |
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