Structure of 288385-88-6
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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. : | 288385-88-6 |
Formula : | C9H8FNO |
M.W : | 165.16 |
SMILES Code : | CC(N1)=CC2=C1C=CC(O)=C2F |
MDL No. : | MFCD07368140 |
InChI Key : | UMWRMOYYUHIPDT-UHFFFAOYSA-N |
Pubchem ID : | 10352036 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.11 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 45.25 |
TPSA ? Topological Polar Surface Area: Calculated from |
36.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.72 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.19 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.74 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.65 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.9 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.24 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.8 |
Solubility | 0.263 mg/ml ; 0.00159 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.58 |
Solubility | 0.434 mg/ml ; 0.00263 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.37 |
Solubility | 0.0711 mg/ml ; 0.000431 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) |
Yes |
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 |
-5.75 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) |
1.67 |
* 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 |
---|---|---|
81% | With sodium dithionite; In water; at 0 - 30℃; for 1.0h; | 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one from previous step (50 g, 0.234 mol) was added to 2 liter round bottom flask. Water (1L) was added, and the yellow suspension was stirred at Rt. Sodium dithionite (225 g, 5.5 eq) was added in one portion and the reaction mixture was stirred and kept < 30 C until HPLC analysis indicated no starting material remained (typically less than 1 hour). Upon completion, the reaction mixture was cooled to 0 C and the tan solid product was collected by vacuum filtration. The wet product was dried at <50 C under house vacuum to afford 4-fluoro-2-methyl-1H-indol-5-ol (31.4 g, 81 % yield) which was isolated as a tan crystalline powder. The material had an HPLC purity of >99.8. 1H NMR (CDC3, 400 MHz) delta 7.8 (s, 1H), 6.9-6.7 (m, 2H), 6.2 (s, 1H), 4.7 (s, 1H), 2.4 (s, 3H). 13 C NMR (CDCl3, 100 MHz) delta 145.7, 143.4, 137.5, 136.7, 134.4, 120.1, 112.7, 106.8, 95.4, 13.3 |
68% | With sodium dithionite; potassium carbonate; In water; at 25℃; for 2.0h;Industry scale;Product distribution / selectivity; | Preparation of 4-fluoro-2 -methyl- lH-indol-5-ol (large scale)To a solution of potassium carbonate (79 kg) in water (800 kg) was added l-(2-fluoro-3- hydroxy-6-nitrophenyl)-propan-2-one (61 kg) and the mixture stirred to give a solution. To this solution at 250C was added a solution of sodium dithionite (298 kg) in water (750 kg).The mixture was held at 250C for 2 hours. The product was isolated by filtration, washing the filter cake with water (366 kg). The product was dried under reduced pressure (50 mbar) at350C. Yield: 34 kg, 72%. The crude 4-fluoro-2-methyl-lH-indol-5-ol (33 kg) was dissolved in dichloromethane(880 1) and filtered through silica (33 kg). The filter was washed with dichloromethane (4401). The combined filtrates were distilled, removing 835 1 of distillate. This concentrate was EPO <DP n="43"/>added rapidly to ?hexane (360 kg), resulting in a suspension. The batch was distilled, removing 436 1 of distillate. The batch was cooled to 00C, aged for 1 hour and then filtered. The filter cake was washed with /s°hexane (73 kg). The product was dried under reduced pressure (50 mbar) at 35C. Yield: 31 kg, 68% based on l-(2-fluoro-3-hydroxy-6- s nitrophenyl)-propan-2-one. |
17% | With hydrogen;palladium on activated charcoal; In ethanol; at 20℃; for 8.0h; | Step 3c: 4-Fluoro-2-methyl-1H-indol-5-ol (Compound 304) A mixture of 303 (900 mg, 4.2 mmol), Pd/C (90 mg) and ethanol (20 mL) was stirred under H2 at ambient temperature for 8 h. The solvent was removed and the residue was purified by column chromatography on silica gel (EtOAc/petroleum ether=1/15) to give the title compound 304 as a brown solid (120 mg, 17%): LCMS: 166 [M+1]+; 1H NMR (DMSO-d6): delta 2.34 (s, 3H), 6.05 (s, 1H), 6.64 (t, J=8.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 8.70 (s, 1H), 10.84 (s, 1H). |
With sodium dithionite; potassium carbonate; In water; for 1.5h;Product distribution / selectivity; | Preparation of 4-fluoro-2 -methyl- lH-indol-5-ol (small scale) l-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1 g) was dissolved in a solution of potassium carbonate (1.3g) in water (13 ml). A solution of sodium dithionite (5.24g) in water (12.3 ml) was added dropwise. The mixture was stirred for 1.5 hours, then left to stand overnight. The solid was filtered and washed with water (6 ml). The solid was dried at 35C in a vacuum oven to give crude 4-fluoro-2-methyl-lH-indol-5-ol (0.5 g, 64.5%). EPO <DP n="41"/>The crude solid (250 mg) was dissolved in dichloromethane (6.75 ml) and filtered through a pad of silica (250 mg). The filter pad was washed with dichloromethane (3.4 ml).The combined filtrates were distilled, removing 6 ml of dsitillate. The concentrate was then added dropwise to ohexane (4.25 ml) and the mixture concentrated, removing 3 ml of distillate. The mixture was cooled in an ice-bath and the precipitate filtered and washed with wohexane (0.9 ml). The solid was dried in a vacuum oven at 350C to give 4-fluoro-2-methyl- lH-indol-5-ol (180 mg, 72%)Mass Spectrum [M+eta]+ 166IH NMR Spectrum (400 MHz, DMSO-J6) delta ppm 2.33 (s, 3 H) 6.02 - 6.05 (m, 1 H) 6.64 (t, J=8.41 Hz, 1 H) 6.87 (d, J=8.51 Hz, 1 H) 8.68 (s, 1 H) 10.81 (br. s., 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 24h; | A solution of Compound 10 (739 mg, 3.3 mmol), 4-Fluoro-2-methyl-1H-indol-5-ol (530 mg, 3.3 mmol), and potassium carbonate (920 mg, 6.7 mmol) in dry dimethyl formamide (10 mL) was heated to 100 C. and stirred for 24 hours. The solution was cooled to room temperature and the solvent evaporated by rotary evaporator. Remaining residue was co-evaporated with methanol (20 mL) and dichloromethane/methanol (50 mL). The product residue was precipitated from water (20 mL) and filtered. Solids were washed with water (20 mL), hexanes (20 mL), and diethyl ether (20 mL). Product was dried under high vacuum to give 910 mg of Compound 11 (yield=78%) as a brown powder |
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