Structure of 350-29-8
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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. : | 350-29-8 |
Formula : | C7H5FO3 |
M.W : | 156.11 |
SMILES Code : | O=C(O)C1=CC=C(O)C(F)=C1 |
MDL No. : | MFCD00143161 |
Boiling Point : | No data available |
InChI Key : | IUSDEKNMCOUBEE-UHFFFAOYSA-N |
Pubchem ID : | 160456 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 35.38 |
TPSA ? Topological Polar Surface Area: Calculated from |
57.53 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.04 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.61 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.65 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.42 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.16 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.38 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.16 |
Solubility | 1.08 mg/ml ; 0.00692 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.43 |
Solubility | 0.58 mg/ml ; 0.00372 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.46 |
Solubility | 5.4 mg/ml ; 0.0346 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 |
-6.11 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) |
1.13 |
* 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 |
---|---|---|
87% | With sulfuric acid; at 80℃;Cold solution; | Methyl 3-fluoro-4-hydroxybenzoate (T10.1). To a round bottom flask containing 3-fluoro-4-hydroxybenzoic acid (commercially available from Sigma- Aldrich, St. Louis, MO, USA) (5.03 g, 32.22 mmol) was added a cold solution of MeOH (50.0 mL) and sulfuric acid (2.0 mL). The mixture was heated to 80°C and monitored with TLC. After 20.5 hours, the solvent was removed and the resulting mixture was diluted with diethyl ether. The organic phase was washed carefully two times with saturated aqueous NaHCO3, once with brine, and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to afford TlO.1 as a white solid (4.79 g, 87percent yield). 1H NMR (400 MHz, CDCl3) 7.81 (2 H, m), 7.06 (1 H, t, J=8.4 Hz), 5.62 (1 H, d, J=4.3 Hz), 3.91 (3 H, s). |
87% | With sulfuric acid; at 80℃; for 20.5h; | Methyl 3-fluoro-4-hydroxybenzoate (T25.1). To a round bottom flask containing 3-fluoro-4-hydroxybenzoic acid (5.03 g, 32.22 mmol)(comrnercially available from Aldrich) was added a cold solution of MeOH (50.0 mL) and sulfuric acid (2.0 mL). The mixture was heated to 80°C and monitored with TLC. After 20.5 hours, the solvent was removed and the mixture was diluted with diethyl ether. The organic phase was washed carefully twice with saturated aqueous NaHCO3 and once with brine. The organic phase was then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to afford T25.1 as a white solid (4.79 g, 87percent yield). 1H NMR (400 MHz, CDCl3) delta ppm 7.81 (2 H, m), 7.06 (1 H, t, J=8.4 Hz), 5.62 (1 H, d, J=4.3 Hz), 3.91 (3 H, s). |
85% | sulfuric acid;Heating / reflux; | Hydroxy -aryl- or hydroxy-heteroaryl-carboxylic acid to methyl ester- General procedure4-hydroxy-benzoic acid (usually 24.0 mmol) was dissolved in MeOH (50 mL) and sulfuric acid (1 mL/g substrate) was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCO3 to basic pH. The organic phase was dried and evaporated under reduced pressure, and the product was used without further purification. The yields were between 80 and 90percent.; a) 3-Fluoro-4-hydroxy-ben.sum.oic acid methyl ester3-Fluoro-4-hydroxy-benzoic acid (5 g, 32.0 mmol) was dissolved in-MeOH (50 niL) and catalytic quantity of sulfuric acid (1 mL) was added. The mixture was refluxed overnight, after which the solvent was evaporated under reduced pressure; <n="121"/>the crude was dissolved in DCM and washed with saturated NaHCO3 to basic pH. The organic phase was dried and evaporated under reduced pressure, and the residue was used without further purification (yield 85percent).C8H7FO31H-NMR (dmso-d6): 3.78 (3H, s); 7.00-7.02 (IH, m); 7.61-7.64 (2H5 m); 10.89 (l , br s). |
85% | With sulfuric acid;Reflux; | Hydroxy-aryl- or hydroxy-heteroaryl-carboxylic acid to methyl ester - General procedure; [0157] 4-hydroxy-benzoic acid (usually 24.0 mmol) was dissolved in MeOH (50 mL) and sulfuric acid (1 mL/g substrate) was added. The mixture was re fluxed overnight, after which the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCO3 to basic pH. The organic phase was dried and evaporated under reduced pressure, and the product was used without further purification. The yields were between 80 and 90percent. |
82% | With sulfuric acid; for 48h;Heating / reflux; | A solution of 3-fluoro-4-hydroxybenzoic acid (5.00 g, 32.0 mmol) in 15percent methanolic sulfuric acid solution (50 mL) was heated at reflux over 48 h, then poured upon ice and extracted with ethyl acetate. The organic layer was washed with 1 M aq. sodium carbonate solution and brine, dried (MgSO4), and evaporated to afford 4-fluoro-3-trifluoromethyl-benzoic acid methyl ester (4.48 g, 82percent). Off-white solid, MS (ISP)=169.1 (M-H)-. |
With thionyl chloride; at 0℃; for 2h;Heating / reflux; | Production Example 8-1: Methyl 3-fluoro-4-hydroxybenzenecarboxylate: A commercial product, 3-fluoro-4-hydroxybenzoic acid hydrate (1.1 g) was dissolved in methanol (11 mL), and in an ice bath, thionyl chloride (0.77 mL) was added thereto, and heated under reflux for 2 hours. After the reaction, the reaction liquid was entirely concentrated to obtain the entitled compound (1.1 g). | |
With sulfuric acid; for 10h;Heating / reflux; | Into a 100 mL round-bottomed was added 4-hydroxy-3-fluorobenzoic acid (1 g), methanol (10 mL), and concentrated sulfuric acid (98percent, 0.1 mL). The mixture was heated to reflux for 10 hr. After the reaction was completed, the mixture was poured into 100 mL of ice water, and filtered to yield product A (1 g) as a white solid. | |
With thionyl chloride; at 20℃; for 2h;Heating / reflux; | To a solution of 3-fluoro-4-hydroxybenzoic acid (1.17 g) in methanol (10 mL), thionyl chloride (602 muL) was added at room temperature, and the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure. Water (10 mL) and chloroform (10 mL) were added to the residue for phase separation. The aqueous layer was extracted with chloroform (2 x 10 mL). The organic layers were combined and dried over sodium sulfate anhydrate. The filtrate was concentrated under reduced pressure, whereby the title compound (1.19 g) was yielded. 1H-NMR (CDCl3)delta: 3.90(3H,s),5.85(1H,s),7.04(1H,t,J=8.3Hz),7.79-7.75(2H,m). | |
With sulfuric acid; for 5h;Heating / reflux; | a) 3-Fluoro-4-hydroxybenzoic acid methyl ester To a solution of 3-fluoro-4-hydroxybenzoic acid (3.0 g) in methanol (30 mL) was added conc. sulfuric acid (3 mL), and the mixture was heated for 5 hours under reflux. The reaction solution was allowed to stand for cooling down to room temperature, and then concentrated in vacuo. The residue was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.99 g). | |
21 g | With thionyl chloride; at 0 - 65℃; for 18h; | Intermediate 26: methyl 3-fluoro-4-hydroxybenzoate To a stirred solution of 3-fluoro-4-hydroxybenzoic acid (25 g, 160 mmol, Combiblocks) in methanol (250 mL), was added SOCI2 (25 ml, 343 mmol) at 0 °C and the mixture stirred at 65 °C for 18 h. The solvent was removed under reduced pressure and the residue diluted with diethyl ether (500 ml). The mixture was washed with cold saturated NaHC03 solution (3 x 500 ml), brine solution (2 x 500 ml), dried over anhydrous Na2S04 and the solvent removed under reduced pressure to give the title compound as a brown solid (21 g) which was used in the next step without further purification. (0324) LCMS Method B: m/z [M-H]" 169, tR 0.73 min |
With sulfuric acid; at 50℃; | 3-Fluoro-4-hydroxybenzoic acid (0201-14) (1.0 g, 6.41 mmol, 1.0 equiv)Dissolved in 50 ml of methanol,Concentrated sulfuric acid (3 ml) was slowly added dropwise.The mixture was stirred at 50°C overnight.After the reaction was completed, the solvent was removed, the residue was added to ice water, extracted with ethyl acetate, washed twice with saturated brine, and dried over anhydrous sodium sulfate.Concentration afforded methyl 3-fluoro-4-hydroxybenzoate (1.25 g, crude) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.6% | With sulfuric acid; sodium hydrogencarbonate; In methanol; hexane; | Step i) Production of methyl 3-fluoro-4-hydroxybenzoate 10.0 g (64.1 mM) of 3-fluoro-4-hydroxybenzoic acid, 150 ml of 1,2-dichloroethane, 80 ml of methanol and 10 ml of concentrated sulfuric acid were mixed, followed by refluxing for 5.5 hours under stirring and further stirring for 12 hours at room temperature. After the reaction, a solution of salt was added to the reaction mixture, followed by sufficient shaking to separate the reaction mixture. The organic layer was recovered from the reaction mixture and the water layer was subjected to extraction with methylene chloride to be added thereto. The resultant organic layer was washed with a 5percent-aqueous solution of sodium hydrogencarbonate in a solution of salt and further washed with a solution of salt, followed by drying with anhydrous sodium sulfate. The sodium sulfate was recovered by filtration and the filtrate was condensed into a solid. Hexane was added to the solid and subjected to filtration to obtain 9.98 g of methyl 3-fluoro-4-hydroxybenzoate (Yield: 91.6percent). |
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