Structure of 21667-62-9
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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. : | 21667-62-9 |
| Formula : | C9H6ClNO |
| M.W : | 179.60 |
| SMILES Code : | C1=C(C(CC#N)=O)C=CC=C1Cl |
| English Name : | 3-(3-Chlorophenyl)-3-oxopropanenitrile |
| MDL No. : | MFCD00067891 |
| InChI Key : | IUDFNNHFARLIPF-UHFFFAOYSA-N |
| Pubchem ID : | 140855 |
| Num. heavy atoms | 12 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.11 |
| Num. rotatable bonds | 2 |
| Num. H-bond acceptors | 2.0 |
| Num. H-bond donors | 0.0 |
| Molar Refractivity | 46.2 |
| TPSA ? Topological Polar Surface Area: Calculated from |
40.86 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.43 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.4 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.44 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.66 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.65 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.11 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.7 |
| Solubility | 0.355 mg/ml ; 0.00198 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.9 |
| Solubility | 0.226 mg/ml ; 0.00126 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.45 |
| Solubility | 0.0636 mg/ml ; 0.000354 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 |
-5.69 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) |
1.27 |
* 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 |
|---|---|---|
| 43% | NaH (0.56 g, 23.44 mmol) was added to a stirred solution of methyl 3- chlorobenzoate (2.0 g, 11.72 mmol) in THF (40 mL) at 0C, and the reaction mixture was heated to 80C. Then MeCN (1.44 g, 35.16 mmol) was added dropwise and the reaction mixture was heated at 80C for 30 min. After completion, THF was removed in vacuo, and the residue was diluted with H2O (100 mL), acidified to pH ~2 with 1N HCl and extracted with EtOAc (3 x 100 mL). Combined organic layers were washed with H2O (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 0.9 g of 3-(3-chlorophenyl)-3- oxopropanenitrile as an off-white solid in 43% yield. 0.45 g of the solid was dissolved in 3 mL of MeOH and methyl hydrazine (0.35g, 7.52 mmol) was added. The resulting mixture was heated at 120C for 1 h under microwave. Then MeOH was removed under reduced pressure, and the crude compound was purified by reverse phase column chromatography to afford Int-31 (0.24 g, 46%) as an off-white solid. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 94% | With hydrazine hydrate In methanol at 150℃; for 0.0833333h; Microwave irradiation; | 1.2. General procedure of microwave synthesis of pyrazoles General procedure: A microwave tube was charged with ketonitrile (2.0 mmol), methanol (1 mL), and hydrazine monohydrate (2.6 mmol) and subjected to microwave irradiation (100 W, 150 °C) for 5 minutes. Volatiles were subsequently removed under reduced pressure. The residue was purified by either trituration with cold methanol or cyclohexane, or by using column chromatography to give the final product. |
| 70% | With hydrazine In ethanol at 80℃; for 15h; | 1 To a stirring solution of 3- (3-clilorophenyl)-3-oxo-propionitrile (2 g, 11.1 mmol) in absolute ethanol (20 mL) was added hydrazine hydrate (3.24 mL, 67 mmol). The reaction mixture was stirred at 80°C for 15 h, cooled to room temperature, concentrated in vacuo, and absorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2C12 as eluent provided 1.53 g (70%) of 5-(3-chloro-phenyl)-2H-pyrazol-3-ylamine as a green solid. 1H NMR (d6-DMSO) No.: 11. 6 and 11. 9 (2 broad s, 1H, NH+tautomer), 7. 69 (s, 1H), 7.60 (d, 1H), 7. 38 (t, 1H), 7.29 (d, 1H), 5.77 (broad s, 1H), 4.98 (broad s, 2H, NH2). To a stirring solution of 5- (3-chloro-phenyl)-2H-pyrazol-3-ylamine (1.53 g, 7.9 mmol) in THF (32 mL) was added N-bromosuccinimide (1.55 g, 8.7 mmol). The reaction mixture was stirred for 5 h at room temperature, then absorbed on silica gel. Purification on silica gel with 0-10% MeOH in CHzClz as eluent provided 1.73 g (80%) of 4-bromo-5- (3- chloro-phenyl)-2H-pyrazol-3-ylamine as a brown solid. 1H NMR (d6-DMSO) No.: 12.2 and 12.4 (2 broad s, 1H, NH+tautomer), 7.77 (s, 1H), 7.73 (broad s, 1H), 7.48 (broad s, 1H), 7.43 (broad s, 1H), 5.30 (broad s, 1H, NH), 4.82 (broad s, 1H, NH) ; HPLC/MS m/z : 272 [MH3+. To a stirring solution of 4-bromo-5-(3-chloro-phenyl)-2H-pyrazol-3-ylamine (50 mg, 0. 183 mmol) in dioxane (1 mL) was added benzoyl isothiocyanate (27 JIL, 0.202 mmol). The reaction mixture was stirred overnight at 90°C, cooled at room temperature, and partitioned between ethyl acetate and sodium bicarbonate. The organic layer was isolated and absorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2C12 as eluent provided 10.8mg (17%) ofN [3- (3-chloro-phenyl)-lH-pyrazolo [3, 4-d] thiazol-5-yl]- benzamide as a white solid NMR (d6-DMSO) d : 13.70 and 13.72 (2 broad s, 1H, NH+tautomer), 12.9 (broad s, 1H, NH), 8.12 (d, 2H), 7.81 and 7. 85 (2 broad s, 1H, tautomers), 7.65-7. 74 (m, 2H), 7.54-7. 62 (m, 3H), 7.45 (m, 1H) ; HPLC/MS m/z : 355 [MH] +. |
| 67% | With hydrazine hydrate In ethanol for 2h; Heating; |
| With hydrazine hydrate In ethanol for 5h; Heating; | ||
| With hydrazine hydrate In ethanol Reflux; | ||
| With hydrazine hydrate In methanol at 160℃; for 0.166667h; Microwave irradiation; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 60% | With [bis(acetoxy)iodo]benzene In dichloromethane for 0.5h; Reflux; | Ethyl (3-chlorophenyl)glyoxylate 3h General procedure: β-Oxo-benzenepropanenitrile 1(1.0 mmol),PIDA (2.2 mmol) were dissolved in EtOH (8 mL) and stirred under refluxing for 0.5h. After the reaction was completed (monitored by TLC), thereaction mixture was concentrated under vacuum. The residue was purified by chromatographyon silica gel (20:1 petroleum ether/EtOAc) to give the product 3a-o .Thesolvent for the synthesis of 3o was MeOH. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With pyridoxal 5'-phosphate; ω-transaminase from Polaromonas sp. JS666; nitrilase from Hoeflea phototrophica DFL-43; water; 3-amino propanoic acid In aq. phosphate buffer; toluene at 37℃; for 24h; Enzymatic reaction; enantioselective reaction; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: 3-chlorobenzoylacetonitrile With sodium hydride In tetrahydrofuran at -5℃; Stage #2: quinoxaline-2-carboxylic acid chloride With benzo<b>thiophene-2-carboxylic acid chloride In tetrahydrofuran at -5 - 25℃; for 13h; | 18.B Step B: Preparation of 3-(3-chlorophenyl)-3-hydroxy-2-(quinoxaline-2-carbonyl)propionitrile In a 100mL round-bottom flask, add 20mL of tetrahydrofuran,then add 3-chlorobenzoylacetonitrile (2.0mmol),then add sodium hydride solid (3.5mmol) in batches,in a low-temperature stirrer at -5,stir and react for 10-20min, then dissolve the acyl chloride (2mmol) obtained in the previous step in 5mL of tetrahydrofuran, and slowly drip into the tetrahydrofuran solution of benzoylacetonitrile with a constant pressure dropping funnel, react at -5 for 5min, and then transfer the reaction system to room temperature 25 for 13h. After the reaction is completed, add citric acid to the reaction system to acidify to pH=2, extract with ethyl acetate, dry with anhydrous sodium sulfate, spin dry the solvent, and add silica gel to mix the sample. Use column chromatography (mobile phase solvents are dichloromethane and methanol) to obtain a light yellow solid. |

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