Structure of 1H-Indazole-5-carbonitrile
CAS No.: 74626-47-4
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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. : | 74626-47-4 |
Formula : | C8H5N3 |
M.W : | 143.15 |
SMILES Code : | N#CC1=CC2=C(NN=C2)C=C1 |
MDL No. : | MFCD04973397 |
InChI Key : | YGBYVNQFNMXDJM-UHFFFAOYSA-N |
Pubchem ID : | 11126384 |
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 | 9 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 40.81 |
TPSA ? Topological Polar Surface Area: Calculated from |
52.47 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.91 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.4 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.43 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.49 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.99 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.25 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.21 |
Solubility | 0.873 mg/ml ; 0.0061 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.11 |
Solubility | 1.12 mg/ml ; 0.00784 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.97 |
Solubility | 0.153 mg/ml ; 0.00107 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 |
-6.18 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 |
---|---|---|
87% | With hydrazine hydrate; at 20℃; for 24h;Inert atmosphere; | <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (25 g, 16.78 mmol) was dissolved in 100 mL of hydrazine hydrate (85percent). The mixture was stirred at room temperature for 24 hours and purified by column chromatography to obtain 1H-indazole-5-carbonitrile (2.1 g, 87percent). 1H NMR (400 MHz, DMSO) delta 13.60 (s, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H); MS m/z (ESI): 144 [M+H]+. |
In dichloromethane; hydrazine hydrate; | Step B 5-Cyanoindazole 5-Cyano-2-fluorobenzaldehyde (512 mg, 3.43 mmol) was dissolved in hydrazine hydrate (25 mL) at room temperature and the solution left to stand overnight. To this reaction mixture was added methylene chloride (30 mL). The mixture was purified by filtration through a pad of silica eluding with methylene chloride, concentrated in vacuo to afford a white solid: 1H NMR (DMSO) delta 8.40 (s, 1H), 8.25 (s, 1H), 7.69 (m, 2H). | |
In dichloromethane; hydrazine hydrate; | Step B 5-Cyanoindazole 5-Cyano-2-fluorobenzaldehyde (512 mg, 3.43 mmol) was dissolved in hydrazine hydrate (25 mL) at room temperature and the solution left to stand overnight. To this reaction mixture was added methylene chloride (30 mL). The mixture was purified by filtration through a pad of silica eluding with methylene chloride, concentrated in vacuo to afford a white solid: 1H NMR (DMSO) delta 8.40 (s, 1H), 8.25 (s, 1H), 7.69 (m, 2H). |
In hydrazine hydrate; | B. 1H-Indazole-5-carbonitrile <strong>[146137-79-3]4-Fluoro-3-formylbenzenecarbonitrile</strong> (4.6 g, 30.85 mmol) was suspended in 20 mL of hydrazine mono-hydrate and the reaction mixture was stirred at room temperature for 48 hours. The title compound was isolated by filtration as a white solid, was washed with small portions of distilled water, and was dried in a vacuum (3.6 g, 81percent yield). The same protocol was used to convert 3.5 g of <strong>[146137-79-3]4-fluoro-3-formylbenzenecarbonitrile</strong> to the title compound and resulted in the isolation of 1.9 g of white solid (80percent yield): 1H NMR (CDCl3) delta 10.45 (br s, 1H), 8.20 (d, 1H), 8.19 (d, 1H), 7.6 (s, 1H); ES-MS 250 [M+1]+. | |
With hydrazine; In water; at 20℃; for 18h; | 2-fluoro-5-cyanobenzaldehyde (1.1 g) is dissolved in hydrazine hydrate (19 ml) and stirred at room temperature for 18 hours. The solution is then distilled and the residue purified by flash column chromatography on silica, eluting with DCM. This gives the title compound (300 mg). | |
With hydrazine hydrate; In N,N-dimethyl-formamide; at 80℃; for 0.416667h;Microwave irradiation; | A solution of <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (1 eq) and hydrazine hydrate (10 eq) in DMF (0.3 M) was heated under microwave irradiation at 80 0C for 25 min.The reaction was partitioned between brine and EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated. Al was obtained by purification through SCX cartridge, eluting with methanol. Volatiles were removed under reduced pressure and the title compound was obtained as a yellow solid.MS (ES) C8H5N3 requires 143, found 144(M+H)+. | |
With hydrazine hydrate; potassium carbonate; In ethanol; at 50℃; for 18h; | A mixture of <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (3.45 g, 23.14 mmol), hydrazine hydrate (32.6 mL, 370 mmol) and potassium carbonate (3.52 g, 25.4 mmol) in ethanol (12 mL) was heated at 50°C overnight (ca. 18 h). The mixture was then cooled and diluted with saturated aqueous ammonium chloride solution (ca. 60 mL) and ethyl acetate (60 mL). The aqueous layer was separated and further extracted with ethyl acetate (5 x 40 mL) and the organics combined, dried over magnesium sulfate, filtered and reduced. The resulting residue was triturated with minimal methanol, ethyl acetate and ether (ca. 15 mL) then filtered. The solid obtained was dried in the vacuum oven to afford the title compound as a pink solid (1.906 g). LCMS (A) m/z: 144 [M+1]+, Rt 0.80 min (acidic). The filtrate was reduced and dried to afford some impure title compound as a reddish pink solid (1.39 g) | |
With potassium carbonate; hydrazine; In ethanol; at 50℃; | Description 29: 1H-Indazole-5-carbonitrileA mixture of <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (3.45 g, 23.14 mmol), hydrazine hydrate (32.6 mL, 370 mmol) and potassium carbonate (3.52 g, 25.4 mmol) in ethanol (12 mL) was heated at 50° C. overnight (ca. 18 h).The mixture was then cooled and diluted with saturated aqueous ammonium chloride solution (ca. 60 mL) and ethyl acetate (60 mL).The aqueous layer was separated and further extracted with ethyl acetate (5*40 mL) and the organics combined, dried over magnesium sulfate, filtered and reduced.The resulting residue was triturated with minimal methanol, ethyl acetate and ether (ca. 15 mL) then filtered.The solid obtained was dried in the vacuum oven to afford the title compound as a pink solid (1.906 g). LCMS (A) m/z: 144 [M+1]+, Rt 0.80 min (acidic).The filtrate was reduced and dried to afford some impure title compound as a reddish pink solid (1.39 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In hydrazine hydrate; | B. 1H-Indazole-5-Carbonitrile <strong>[146137-79-3]4-Fluoro-3-formylbenzenecarbonitrile</strong> (4.6 g, 30.85 mmol) was suspended in mL of hydrazine mono-hydrate and the reaction mixture was stirred at room temperature for 48 hours. The title compound was isolated by filtration as a white solid, was washed with small portions of distilled water, and was dried in a vacuum (3.6 g, 81percent yield). The same protocol was used to convert 3.5 g of<strong>[146137-79-3]4-fluoro-3-formylbenzenecarbonitrile</strong> to the title compound and resulted in the isolation of 1.9 g of white solid (80percent yield): 1H NMR (CDCl3) delta 10.45 (br s, 1H), 8.20 (d, 1H), 8.19 (d, 1H), 7.6 (s, 1H); ES-MS 250 [M+1]+. |
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