Structure of 13726-21-1
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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. : | 13726-21-1 |
Formula : | C9H8ClNO |
M.W : | 181.62 |
SMILES Code : | COC1=C(Cl)C=CC(CC#N)=C1 |
MDL No. : | MFCD09907926 |
InChI Key : | XOSGKJSNVLAMGY-UHFFFAOYSA-N |
Pubchem ID : | 20460956 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 47.47 |
TPSA ? Topological Polar Surface Area: Calculated from |
33.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.99 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.81 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.41 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.01 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.77 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.2 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.34 |
Solubility | 0.822 mg/ml ; 0.00453 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.12 |
Solubility | 1.37 mg/ml ; 0.00754 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.63 |
Solubility | 0.0425 mg/ml ; 0.000234 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 |
-6.12 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) |
1.43 |
* 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 |
---|---|---|
48% | In ethanol; at 60℃; | To a solution of <strong>[103347-14-4]4-bromomethyl-1-chloro-2-methoxy-benzene</strong> (68.5 g, 0.290 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). The mixture was stirred at 60 C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) delta 7.36 (d, J=8 Hz, 1H), 6.88-6.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). 13C NMR (100 MHz, CDCl3) delta 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5. |
In ethanol; water; at 20℃; | The 28 g (0.166 mmol) of 38b from the previous step, NaCN (28 g; 0.58 mmol; 3.5 equiv.) and 500 mL of 90% aqueous EtOH were stirred at room temperature overnight. The crude residue was partitioned between EtOAc/H2O (359 mL of each), washed with brine, dried, filtered and evaporated. The crude product was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (100% hexane to 90% hexane) to afford 21 g of 38c. | |
In N,N-dimethyl-formamide; at 20℃; for 2h; | (ii) (4-Chloro-3-methoxyphenyl)acetic acidThe product from step (i), DMF (200 ml) and sodium cyanide (20 g) were charged to a flask and stirred for 2 h at RT. The residue was partitioned between ether and water; the organics were separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. Potassium hydroxide (40 g in water) was added and the mixture heated at reflux for 24 h. The reaction mixture was cooled to RT and extracted with ether. The aq layer was acidified to pH 1 with concentrated HCl and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with isohexane/ether, and then filtered to give the subtitle compound (12.2 g). |
In N,N-dimethyl-formamide; at 20℃; for 2h; | The product from step (i) DMF (200 ml) and sodium cyanide (20 g) were charged to a flask and stirred for 2 h at RT. The residue was partitioned between ether and water; the organics were separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. Potassium hydroxide (40 g in water) was added and the mixture heated at reflux for 24 h. The reaction mixture was cooled to RT and extracted with ether. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with isohexane/ether, and then filtered to give the subtitle compound (12.2 g). | |
In ethanol; water; at 20℃; | The 28 g (0.166 mmol) of 9b from the previous step, NaCN (28 g; 0.58 mmol; 3.5 equiv.) and 500 mL of 90% aqueous EtOH were stirred at room temperature overnight. The crude residue was partitioned between EtOAc/H2O (359 mL of each), washed with brine, dried, filtered and evaporated. Silica gel chromatography and elution with a gradient (100% hexane-90:10 hexane:EtOAc) yielded 21 g of 9c. | |
In ethanol; water; at 20℃; | The 28 g (0.166 mmol) of 9b from the previous step, NaCN (28 g; 0.58 mmol; 3.5 equiv.) and 500 mL of 90% aqueous EtOH were stirred at room temperature overnight. The crude residue was partitioned between EtOAc/H2O (359 mL of each), washed with brine, dried, filtered and evaporated. Silica gel chromatography and elution with a gradient (100% hexane?90:10 hexane:EtOAc) yielded 21 g of 9c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In ethanol; water; for 2h;Reflux; | To a solution of <strong>[103347-14-4]5-(bromomethyl)-3-chloroanisole</strong> (12) (412 g, 1.75 mol) in EtOH (2 L) and H20 (0.5 L) was added NaCN (129 g, 2.63 mol) and the reaction mixture was heated to reflux for 2 h with mechanical stirring. The reaction mixture was cooled and diluted with water (3.5 L). The mixture was extracted with diethyl ether (2 L x 2) and the combined organic layers were washed with aq. 5% HC1 (2.5 L), satd NaHC03 (2.5 L) and brine (2.5 L), dried over anhydrous MgS04, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc = 5: 1) to afford 2-(4-chloro-3-methoxyphenyl)acetonitrile (13) (240 g, 75%) as yellow solid. 1H NMR (400MHz, CDC13): delta 7.35-7.36 (d, 1H), 6.86 (s, 1H), 6.84-6.86 (d, 1H), 3.92 (s, 3H), 3.74 (s, 2H). |
75% | In ethanol; water; for 2h;Reflux; | To a solution of <strong>[103347-14-4]5-(bromomethyl)-3-chloroanisole</strong> (12) (412 g, 1.75 mol) in EtOH (2 L) and H2O (0.5 L) was added NaCN (129 g, 2.63 mol) and the reaction mixture was heated to reflux for 2 h with mechanical stirring. The reaction mixture was cooled and diluted with water (3.5 L). The mixture was extracted with diethyl ether (2 L x 2) and the combined organic layers were washed with aq. 5% HCl (2.5 L), satd NaHCO3 (2.5 L) and brine (2.5 L), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc = 5:1) to afford 2-(4-chloro-3-methoxyphenyl)acetonitrile (13) (240 g, 75%) as yellow solid. 1H NMR (400MHz, CDCl3): delta 7.35-7.36 (d, IH), 6.86 (s, IH), 6.84-6.86 (d, IH), 3.92 (s, 3H), 3.74 (s, 2H). |
48% | In ethanol; at 60℃; | To a solution of <strong>[103347-14-4]4-bromomethyl-1-chloro-2-methoxy-benzene</strong> (68.5 g, 0.290 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). The mixture was stirred at 60 C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) delta 7.36 (d, J=8 Hz, 1H), 6.88-6.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). 13C NMR (100 MHz, CDCl3) delta 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With NaCN; In C2H5OH; water; | 2-(4-Chloro-3-methoxyphenyl)acetonitrile To a solution of <strong>[103347-14-4]4-bromomethyl-1-chloro-2-methoxy-benzene</strong> (68.5 g, 0.290 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). The mixture was stirred at 60 C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL*3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) delta 7.36 (d, J=8 Hz, 1H), 6.88-6.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). 13C NMR (100 MHz, CDCl3) delta 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5. |
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