Structure of 1021871-35-1
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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. : | 1021871-35-1 |
Formula : | C8H6ClNO |
M.W : | 167.59 |
SMILES Code : | N#CC1=CC(CO)=CC(Cl)=C1 |
MDL No. : | MFCD18392447 |
InChI Key : | XNOWXYQLTYKTNC-UHFFFAOYSA-N |
Pubchem ID : | 58369542 |
GHS Pictogram: |
![]() |
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 | 0.12 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 42.29 |
TPSA ? Topological Polar Surface Area: Calculated from |
44.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.77 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.99 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.55 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.44 |
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 |
1.81 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.47 |
Solubility | 0.567 mg/ml ; 0.00339 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.54 |
Solubility | 0.483 mg/ml ; 0.00288 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.92 |
Solubility | 0.201 mg/ml ; 0.0012 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 |
-5.91 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) |
1.66 |
* 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 |
---|---|---|
(Step 2) To a mixed solution of 3-chloro-5-cyanobenzoate (1.13 g) obtained in Step 1 in tetrahydrofuran:ethanol=10:1 (33 ml) was added lithium tetrahydroborate (0.19 g) at 0°C. After stirring at 60°C for 2 hr, the reaction solution was quenched with ice and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by silica gel chromatography (ethyl acetate:hexane=1:1) to give 3-chloro-5-(hydroxymethyl)benzonitrile (0.60 g) as a white solid. 1H-NMR (CDCl3) delta ppm 1.97 (1 H, t, J=5.65 Hz) 4.75 (2 H, d, J=5.84 Hz) 7.56 (2 H, s) 7.61 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; triphenylphosphine; In acetonitrile; at 80℃; for 4.0h; | (Step 3) Triphenylphosphine (0.94 g) was suspended in acetonitrile (20 ml), bromine (0.19 ml) was added, and the mixture was stirred for 30 min. A solution (10 ml) of <strong>[1021871-35-1]3-chloro-5-(hydroxymethyl)benzonitrile</strong> (0.60 g) obtained in Step 2 in acetonitrile was added to the reaction mixture, and the mixture was stirred at 80°C for 4 hr. The reaction solution was quenched with water, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by basic silica gel chromatography (ethyl acetate:hexane=1:2) to give 3-(bromomethyl)-5-chlorobenzonitrile (0.31 g) as a white solid. 1H-NMR (CDCl3) delta ppm 4.42 (2 H, s) 7.58 (2 H, d, J=1.70 Hz) 7.62 (1 H, t, J=1.79 Hz). | |
With phosphorus tribromide; In dichloromethane; for 1.0h; | Toa solution of <strong>[1021871-35-1]5-chloro-3-(hydroxymethyl)benzonitrile</strong> (1.25 g, 7.48 mmol) in DCM(100 mL) was added neat PBr3 (2.43g, 7.48 mmol) and the mixturestirred 1 hr. The mixture was quenched by the addition of saturated NaHC03until the aqueous phase was neutral or slightly basic. The phases wereseparated and the organic phase was washed with brine (20 mL), dried (Na2SC>4),the mixture filtered and the filtrate evaporated to dryness to afford theintermediate bromide as a colourless oil. This was dissolved in acetone (100mL), thioacetic acid (569 mg, 7.48 mmol) and K2C03 (1.55g, 1 1.2 mmol) added and the mixture stirred 1 hr. DCM (100 mL) and saturatedbrine (30 mL) were then added. The phases were separated and the organic phasewas washed with more brine (10 mL), dried (Na2SC>4), the mixturefiltered and the filtrate evaporated to dryness to afford a brown oil,containing the desired title compound (880 mg, 44percent); H NMR (500MHz, CDC13) delta 2.41 (s, 3H), 4.09 (s, 2H), 7.47 - 7.59 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With pyridinium chlorochromate; In dichloromethane; at 20℃; for 2.0h;Celite; | S-Chloro-S-formyl-benzonitrile: To a stirred solution of 3-Chloro-5-hydroxymethyI- benzonitrile (1.43g, 8.53mmol) in dichloromethane (50ml), were added pyridinium chlorochromate (2.76g, 12.8mmol) and celite (2.76g). After stirring for 2hr. at room temperature, the mixture was diluted with ether and filtered through a plug of silica gel. The plug was washed with ether. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane (1 :4)) to afford 1.28g (90percent) of a white solid, m.p. 132-133 0C; 1H- NMR(200MHz, CDCI3) delta 7.89(1H, s), 8.05(1H, s), 8.09(1 H, s), 10.02(1H1 s); m/z (El) 165(M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide; In methanol; | S-Chloro-S-hydroxymethyl-benzonitrile: 3-Chloro-5-methyl-benzonitrile (4.19g, 27.64mmoi) in carbon tetrachloride (60ml) was refluxed with N-bromosuccinimide (4.92g, 27 64mmoi) and benzoyl peroxide (669mg, 2.7deltammol) for 5hr. After cooling to room temperature, the mixture was filtered and evaporated in vacuo The residue was purified by silica gel column chromatography (eiuent, ether hexane (from 1 20 to 1 4)) to give 6 84g of S-Bromomethyi-delta-chloro-benzonitrile as a mixture containing starting material. This mixture was stirred with sodium acetate (4.53g, 55.28mmoi) in DMF (50ml) for overnight at room temperature The mixture was diluted with ether, washed with water three times, dried with MgSO4, filtered, and evaporated in vacuo to give Acetic acid 3-chloro-delta-cyano-benzyl ester. The residue was stirred with ammonium hydroxide (10mi) in methanol (40ml). The mixture was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate: hexane (1 :2)) to afford 1.43g (30percent for 3 steps) of S-Chloro-S-hydroxymethyl-benzonitrile as a white solid, m.p. 110-1 1 1 0C; 1H-NMR(200MHz, CDCI3) delta 2.06(1 H, t, J=5.6Hz), 4.74(2H1 d, J=5.6Hz), 7.55(2H, s), 7.61(1 H1 s); m/z (El) 167(M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; toluene; | Step 4: 3-Chloro-5-cyanobenzyl carbonochloridate <strong>[1021871-35-1]3-Chloro-5-(hydroxymethyl)benzonitrile</strong> (25 g, 145 mmol) was dissolved in THF (200 mL). The resulting yellow solution was cooled to 10° C. in an ice bath and treated dropwise with phosgene in toluene (152 mL, 289 mmol). The reaction mixture was stirred at ambient temperature for 16 hrs. The mixture was concentrated under reduced pressure and the crude material was diluted with toluene (200 ml) and re-concentrated under reduced pressure. The residue was purified by chromatography on silica (Redisep 340 g column on a Biotage system), eluting with EtOAc/iso-hexane to give 3-chloro-5-cyanobenzyl carbonochloridate as an oil. 1H NMR (600 MHz, CDCl3) delta 7.70 (1H, s), 7.66 (1H, s), 7.62 (1H, s), 5.32 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium tetrahydroborate; ethanol; at 20℃; for 1.0h; | General procedure: Toa stirring solution of 4-chloro-3-formylbenzonitrile (5.00 g , 30.2 mmol) inethanol (50 mL), NaBH4 (571 mg, 15.1 mmol) was added batch-wise over 1 minuteunder stirring at room temperature. After 1 hr, the reaction mixture wasconcentrated in vacuo to afford an off-white solid, treated with 2M HC1 (200mL) and DCM (260 mL), effervescence and dissolution occurred. The layers wereseparated, the organic layer was dried over Na2SC>4, the mixturefiltered and concentrated in vacuo to afford the title compound (4.86 g, 96percent)as an off-white solid; H NMR (500 MHz, DMSO) delta 4.58 (d, 2H), 5.63(t, 1H), 7.65 (d, 1H), 7.78 (dd, 1H), 7.85 - 7.94 (m, 1H). |
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