Structure of 403-16-7
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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. : | 403-16-7 |
Formula : | C7H4ClFO2 |
M.W : | 174.56 |
SMILES Code : | O=C(O)C1=CC=C(F)C(Cl)=C1 |
MDL No. : | MFCD00042477 |
InChI Key : | PKTSBFXIHLYGEY-UHFFFAOYSA-N |
Pubchem ID : | 520989 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | 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 | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 38.37 |
TPSA ? Topological Polar Surface Area: Calculated from |
37.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.39 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.27 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.6 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.63 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.28 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.23 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.69 |
Solubility | 0.356 mg/ml ; 0.00204 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.69 |
Solubility | 0.356 mg/ml ; 0.00204 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.66 |
Solubility | 0.379 mg/ml ; 0.00217 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 |
-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 |
0.56 |
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) |
1.36 |
* 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 |
---|---|---|
sBuLi (97 mL, 126 mmol) was dissolved in tetrahydrofuran (THF) (200 ml.) at -78 0C and TMEDA (19.02 mL, 126 mmol) was added. 3-chloro-4-fluorobenzoic acid (10 g, 57.3 mmol, commercially available from e.g. Sigma-Aldrich, Fluorochem or Apollo) dissolved in tetrahydrofuran (THF) (50 mL) was added dropwise at -78 0C and the solution stired at this temperature for 30 minutes. Hexachloroethane (54.2 g, 229 mmol) dissolved in tetrahydrofuran (THF) (200 mL) was added dropwise and the solution stirred to room temperature over 4 hours. Water (25 mL) was added and the solution concentrated in vacuo. The residue was partitioned between diethyl ether (300 mL) and saturated sodium bicarbonate solution (50 mL) and extracted with saturated sodium bicarbonate solution (3 x 50 mL). The aqueous phase was acidified to pH1 with 5N hydrochloric acid, extracted with diethyl ether (3 x 200 mL), combined extracts dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a crude solid (9.21 g). The crude solid was recrystalised from heptane/diethyl ether to afford the desired product in 4.91 g. LC/MS = 207/209/211 (M-H)-, retention time = 0.88 minutes (2 minute method). The mother liquors were concentrated in vacuo, washed with heptane and dried to afford a second batch of desired product in 2.62 g LC/MS = 207/209/211 (M-H)-, retention time = 0.88 minutes (2 minute method). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With toluene-4-sulfonic acid; for 48.0h;Heating / reflux; | To a solution of 3-chloro-4-fluoro-benzoic acid (11.75 g, 67.3 [MMOL)] in [ETOH] was added PTSA (1.2 g) and the resulting mixture was heated under reflux for 2 days. On cooling the mixture was poured into water and the aqueous phase was basified with a solution of NaOH 1 N. The product was extracted with CH2CI2 and the organic phase was dried over [NA2SO4] and concentrated under reduced pressure to give the title compound as an oil (13.08g, 96%); [APCI MS] [M/Z] 203 (MH+). |
96% | With toluene-4-sulfonic acid; for 48.0h;Heating / reflux; | To a solution of 3-chloro-4-fluoro-benzoic acid (11.75 g, 67.3 [MMOL)] in EtOH was added PTS (1.2 g) and the resulting mixture was heated under reflux for 2 days. On cooling the mixture was poured into water. The aqueous phase was basified with a solution of [NAOH] 1 N. The product was extracted with [CH2CI2] and the organic phase was dried over [NA2SO4] and concentrated under reduced pressure to give the title compound as an oil (13.08g, 96%); [APCI MS] m/z 203 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sulfuric acid;Heating / reflux; | Preparative Example 29.; A round bottomed flask was charged with 3-chloro-4-fluorobenzoic acid (5.0 g, 28.6 mmol), sulfuric acid (0.84 g, 8.6 mmol), and methanol (60 mL). The solution was heated at reflux overnight. The methanol was removed in vacuo. The residue was extracted with ethyl acetate (5 x), dried over sodium sulfate, filtered and concentrated in vacuo to yield 4.73 g (88%).A round bottomed flask was charged with the ester intermediate (4.73 g, 25 mmol), potassium carbonate (3.45 g, 25 mmol), piperazine-1-carboxylic acid tert-butyl ester (5.59 g, 30 mmol) and acetonitrile (6 mL). The mixture was heated at 650C overnight and the solvent removed in vacuo. The residue was dissolved in ethyl acetate and washed with 0.5 N HCI, 0.5 N NaOH, and brine. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. There was obtained 4.79 g of intermediate 34 which was not purified further. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sulfuric acid; In methanol; for 16h;Reflux; | A round bottomed flask was charged with 3-chloro-4-fluoro-benzoic acid (2.0 g, 11.4 mmol),sulfuric acid (0.33 g, 3.4 mmol), MeOH (20 mL) and refluxed for 16 h (TLC indicatedcomplete consumption of starting material). The volatiles were removed under reducedpressure; the residue was diluted with water (15 mL) and extracted with EtOAc (3 x 50 mL).The combined organic extracts were washed with brine (50 mL), dried over Na2S04 andconcentrated in vacuo to give the crude residue which was purified by columnchromatography (100-200 silica gel, 40 g, 10% EtOAc-hexane) to afford methyl3-chloro-4-fluoro-benzoate ( 1.5 g, 69%) as a light yellow oil. 1H NMR [300 MHz, CDCh]: J 8.08 (dd, J = 6.9, 2.1 Hz, 1H), 7.94-7.89 (m, 1H), 7.18 (t, J =8.7 Hz, 1H), 3.90 (s, 3H). |
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