Structure of 127838-58-8
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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. : | 127838-58-8 |
Formula : | C6H7NO2 |
M.W : | 125.13 |
SMILES Code : | OCC1=CC(=O)NC=C1 |
MDL No. : | MFCD12033137 |
InChI Key : | NVWMXLBVGGYAQW-UHFFFAOYSA-N |
Pubchem ID : | 11094610 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 33.19 |
TPSA ? Topological Polar Surface Area: Calculated from |
53.09 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.12 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-1.13 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.28 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.29 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.36 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.15 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.33 |
Solubility | 58.4 mg/ml ; 0.466 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.51 |
Solubility | 402.0 mg/ml ; 3.21 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.72 |
Solubility | 2.39 mg/ml ; 0.0191 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 |
No |
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 |
-7.87 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 |
0.55 |
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) |
1.4 |
* 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 |
---|---|---|
88% | To a suspension of methyl 2-oxo-1 ,2-dihydro-4-pyridinecarboxylate (1.37 g, 8.98 mmol) in anhydrous tetrahydrofuran (23 ml_) was added dropwise 2 M lithium borohydride/tetrahydrofuran (22.5 ml_, 45 mmol), and the mixture was heated to 550C under a nitrogen atmosphere for 3.5 h. Methanol (15 ml_) and water (3 ml_) were carefully added, and the mixture was stirred at ambient temperature for 30 min. The mixture was concentrated and more methanol (10 ml_) was added carefully. After stirring for 30 min, the mixture was adsorbed on silica gel and placed on top of a silica gel column, eluting with 0 to 30% methanokdichloromethane, to obtain the title compound as an off-white solid (0.99 g, 88%): 1H NMR (400 MHz, DMSOd6) delta ppm 11.29 (br s, 1 H), 7.23 (d, J = 6.7 Hz, 1 H), 6.21 (s, 1 H), 6.03 (dd, J = 6.7, 1.3 Hz, 1 H), 5.27 (t, J = 5.9 Hz, 1 H), 4.28 (d, J = 5.9 Hz, 2H). | |
61.2% | With diisobutylaluminium hydride; In tetrahydrofuran; at 20℃; for 3h; | To a stirred solution of methyl 2-oxo- 1 ,2-dihydropyridine-4-carboxylate (300 mg, 1.96 mmol) in THF (20 mL) was added diisobutylaluminium hydride (1.0 M in THF, 20 mL, 20 mmol). The mixture was stirred at RT for 3h, then MeOH (2 mL) and H20 (1 mL) were added. The mixture was stirred at RT for 20 minutes and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (DCM : MeOH = 8 : 1) to afford 4-(hydroxymethyl)pyridin-2(lH)-one as a white solid (150 mg, 61.2%). MS (ES+) C6H7N02 requires: 125, found: 126 [M+H]+. |
With lithium borohydride; In tetrahydrofuran; methanol; chloroform; water; N,N-dimethyl-formamide; | Step 1 4-Hydroxymethyl-1H-pyridin-2-one 2-Oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester (1.8 g, 12.2 mmol), prepared as described in J. Org. Chem., 26, 428 (1961), was suspended in THF (100 ml). A small amount of DMF was added to help increase solubility. LiBH4 (61 mmol) was added and the reaction was stirred for 18 hours at room temperature. MeOH and H2O are added to quench the reaction. The reaction is then concentrated to yield a yellow oil. Flash chromatography (5% MeOH/CHCl3 to 20% MeOH/CHCl3) yielded 4-hydroxymethyl-1H-pyridin-2-one as a white solid. 1H NMR (400 MHz, CD3OD) delta 7.38-7.36 (1H,d); 6.56 (s, 1H); 6.37-6.36 (d, 1H); 4.50 s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18h; | To a suspension of 4-(hydroxymethyl)-2(1 /-/)-pyridinone (0.98 g, 7.9 mmol) and DMF (10 ml_) was added imidazole (0.64 g, 9.45 mmol) and ferf-butyldimethylsilyl chloride (1.25 g, 8.26 mmol), and the mixture was stirred at ambient temperature under a nitrogen atmosphere for 18 h. The mixture was poured into water (30 ml_), and stirred for 30 min. The solid was filtered, rinsed with water, and air-dried to provide 4-([(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2(1 /-/)-pyridinone as an off-white solid (1.64 g, 88%): 1H NMR (400 MHz, DMSOd6) delta ppm 1 1.34 (br s, 1 H), 7.26 (d, J = 6.6 Hz, 1 H), 6.21 (s, 1 H), 6.01 (dd, J = 6.6, 1.5 Hz, 1 H), 4.5 (s, 2H), 0.88 (s, 9H), 0.05 (s, 6H); EI-LCMS m/z 241 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | Step 2 4-(tert-butyldimethylsilyloxymethyl)-1H-pyridin-2-one 4-Hydroxymethyl-1H-pyridin-2-one from Step 1 (1.3 g, 10.5 mmol) was dissolved in DMF. t-Butyl dimethylsilyl chloride (12.6 mmol, 1.9 g) and imidazole (12.6 mmol, 858 mg) were added and the reaction was stirred for 16 hours. The reaction mixture was diluted with EtOAc and washed with H2O (2*) and brine. The organic layer was dried (MgSO4), filtered and concentrated to yield a yellow oil. Flash chromatography (EtOAC) yielded 4-(tert-butyldimethylsilyloxy-methyl)-1H-pyridin-2-one as an off white solid. 1H NMR (400 MHz, CDCl3) delta 7.30-7.28 (d, 1H); 6.60 (s, 1H); 6.20-6.18 (d, 1H); 4.58 (s, 2H); 0.955 (s, 9H); 0.11 (s, 6H). | |
In N,N-dimethyl-formamide; | Step 2 4-(tert-butyldimethylsilyloxymethyl)-1H-pyridin-2-one 4-Hydroxymethyl-1H-pyridin-2-one from Step 1 (1.3 g, 10.5 mmol) was dissolved in DMF. t-Butyl dimethylsilyl chloride (12.6 mmol, 1.9 g) and imidazole (12.6 mmol, 858 mg) were added and the reaction was stirred for 16 hours. The reaction mixture was diluted with EtOAc and washed with H2 O (2x) and brine. The organic layer was dried (MgSO4), filtered and concentrated to yield a yellow oil Flash chromatography (EtOAC) yielded 4-(tert-butyldimethylsilyloxy-methyl)-1H-pyridin-2-one as an off white solid. 1 H NMR (400 MHz, CDCl3) delta 7.30-7.28 (d, 1H); 6.60 (s, 1H); 6.20-6.18 (d, 1H); 4.58 (s, 2H); 0.955 (s, 9H); 0.11 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium borohydride; In tetrahydrofuran; methanol; chloroform; N,N-dimethyl-formamide; | Step 1 4-Hydroxymethyl-1H-pyridin-2-one 2-Oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester (1.8 g, 12.2 mmol), prepared as described in J. Org. Chem., 26, 428 (1961), was suspended in THF(100 ml). A small amount of DMF was added to help increase solubility. LiBH4 (61 mmol) was added and the reaction was stirred for 18 hours at room temperature. MeOH and H2 O are added to quench the reaction. The reaction is then concentrated to yield a yellow oil. Flash chromatography (5% MeOH/CHCl3 to 20% MeOH/CHCl3) yielded 4-hydroxymethyl-1H-pyridin-2-one as a white solid. 1 H NMR (400 MHz, CD3 OD) delta 7.38-7.36 (1H,d); 6.56 (s, 1H); 6.37-6.36 (d, 1H); 4.50 s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With borane-THF; In tetrahydrofuran; at 0 - 25℃; for 2h; | Preparative Example 4.30 4-[(4-iodo- lH-pyrazol- 1 -yl)methyl]py Step 1 : Borane-THF (29 mL, 1.0 M) was added to a solution of 2-oxo-l,2- dihydropyridine-4-carboxylic acid (1 g, 7.19 mmol) in THF (15 mL) at 0 C. The mixture was stirred at 25 C for 2 hours. Methanol was added and the mixture was concentrated under reduced pressure to afford 4-(hydroxymethyl)pyridin-2(lH)-one. MS ESI calc'd. for C6H8 02 [M + H]+ 126, found 126. XH NMR (400 MHz, CD3OD) delta 7.40 (d, J= 6.8 Hz, 1H), 6.58 (s, 1H), 6.38 (d, J= 6.4 Hz, 1H), 4.52 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With hydrogen bromide; at 110℃; for 16h; | A mixture of 4- (hydroxymethyl)pyridin-2(1H)-one (500 mg, 4.00 mmol) and HBr (1 ml, 8.84 mmol) was heated to 110 C for 16 h. The mixture was concentrated under reduced pressure, the residue was treated with water and the resulting suspension was filtered to give 4-(bromomethyl)pyridin-2(lH)-one as a white solid (368 mg, 49%). MS (ES+) C6H6BrNO requires: 187, found: 188 [M+H]+. |
With hydrogen bromide; at 0 - 110℃; for 3h; | Step 2: Hydrobromic acid (2 mL) was added to a solution of 4-(hydroxymethyl)pyridin- 2(lH)-one (200 mg, 1.6 mmol) was at 0 C. The mixture was stirred at 1 10 C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/MeOH) to afford the 4- (bromomethyl)pyridin-2(lH)-one. MS ESI calc'd. for C6H7BrNO [M + H]+ 188 and 190, found 188 and 190. NMR (400 MHz, DMSO-i) delta 1 1.55 (s, 1H), 7.36 (d, J= 6.8 Hz, 1H), 6.39 (s, 1H), 6.17 (d, J= 6.8 Hz, 1H), 4.45 (s, 2H). | |
With hydrogen bromide; In water; at 100℃; for 16h; | A mixture of 4- (hydroxymethyl)pyridin-2(lH)-one (150 mg, 1.2 mmol) and aqueous hydrogen bromide (48%, 10 mL) was heated to 100C for 16 h. The reaction mixture wascooled to RT and concentrated under reduced pressure to afford 4- (bromomethyl)pyridin-2(lH)-one as a brown solid (225 mg, 100%), which was directly used for next step without further purification. MS (ES+) 06Eta6BetaGammaNuOmicron requires: 188, found: 189 [M+H]+. |
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