Structure of 5975-12-2
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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. : | 5975-12-2 |
Formula : | C5H2Cl2N2O2 |
M.W : | 192.99 |
SMILES Code : | ClC1=NC=CC(=C1[N+](=O)[O-])Cl |
MDL No. : | MFCD09261088 |
InChI Key : | RTXYIHGMYDJHEU-UHFFFAOYSA-N |
Pubchem ID : | 10535773 |
GHS Pictogram: |
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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 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 43.08 |
TPSA ? Topological Polar Surface Area: Calculated from |
58.71 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.15 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.27 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.3 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.49 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.59 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.36 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.8 |
Solubility | 0.303 mg/ml ; 0.00157 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.14 |
Solubility | 0.14 mg/ml ; 0.000725 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.64 |
Solubility | 0.441 mg/ml ; 0.00229 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 |
-5.87 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 |
3.0 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) |
1.93 |
* 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 |
---|---|---|
65% | With sodium acetate; In N,N-dimethyl-formamide; at 120℃; for 5h; | To a solution of 2 , 4-dichloro-3-nitropyridine (100 g, 518 mmol) in N,iV-dimethylformamide (500 mL) was added sodium acetate (106 g, 1295 mmol) at room temperature. The mixture was stirred at 120C for 5 hours. The reaction completion was confirmed by TLC, then the mixture was cooled to room temperature and diluted with water (500 mL) followed by aqueous 2N HC1 solution to adjust the pH < 4. The aqueous layer was extracted with ethyl acetate (5 x 750 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and under vacuum to give a crude product. The crude product was triturated with water, and the resulting solid was collected by filtration, and dried under vacuum to give the title compound (63 g, 65%). MS(ESI)m/z: 175.1 (M+l); XH NMR (400 MHz, DMSO-d6) : delta 7.10 (d, J = 6.0 Hz, 1H) , 8.25 (d, J = 5.6 Hz, 1H) , 13.10 (br s, 1H) . |
60% | With sodium acetate; In N,N-dimethyl-formamide; at 120℃; for 3h; | [0715] To a solution of XIV-2 (10 g, 52.1 mmol) in DMF (60 mL) was added NaOAc (10.3 g, 125 mmol), the reaction mixture was stirred at 120 C. for 3 hrs. The mixture was cooled to rt and poured into water, extracted with EtOAc. Combined organic phase was washed with brine and concentrated under vacuum to afford the crude product. The residue was purified by column chromatography (PE:EA=1:1) to afford XIV-3 as a pale yellow solid (5.4 g, 60% yield). 1HNMR (CD3OD, 300 MHz) delta 8.14 (d, J=6.0 Hz, 1H), 6.98 (d, J=6.0 Hz, 1H). |
60% | With sodium acetate; In N,N-dimethyl-formamide; at 120℃; for 3h; | To a solution of XIV-2 (10 g, 52.1 mmol) in DMF (60 mL) was added NaOAc (10.3 g, 125 mmol), the reaction mixture was stirred at 120C for 3 hrs. The mixture was cooled to rt and poured into water, extracted with EtOAc. Combined organic phase was washed with brine and concentrated under vacuum to afford the crude product. The residue was purified by column chromatography (PE:EA=1:1) to afford XIV-3 as a pale yellow solid (5.4 g, 60% yield). ?HNMR (CD3OD, 300MHz) oe 8.14 (d, J=6.0 Hz, 1H), 6.98 (d, J=6.0Hz, 1H). |
With cesium acetate; In DMF (N,N-dimethyl-formamide); at 80℃; for 2h; | A solution of 2,4-dichloro-3-nitropyridine (6.5 g, 33.7 mmol) and cesium acetate (16.2 g, 84.2 mmol) in 100 mL of DMF was heated at 80 C. for 2 h. The reaction was cooled to room temperature, 50 mL of sat. aq. NH4Cl was added and the mixture was concentrated. The residue was partitioned between 200 mL DCM, 100 mL sat. aq. NH4Cl and 50 mL H2O. The layers were separated and the aqueous layers was backwashed with 200 mL DCM (4×). The combined organics were dried and concentrated (high vacuum) to afford the title compound as a tan solid: 1H NMR (CD3OD) delta6.97 (d, 1H, 5.9 Hz); 8.14 (d, 1H, 5.6 Hz). MS: MH+=174.9. | |
Step-III: Synthesis of 2-chloro-3-nitropyridin-4-ol from 2, 4-dichloro-3-nitro- pyridine; Charged in a R.B. flask dimethylformamide (500 ml), . 2,4-dichlo-3-nitropyridine (100 gm) and sodium acetate (102.4 gm) at 25- 300 C. Heated the reaction mass to 120 to 125C and maintained for 2 hrs. Stopped heating and cooled the reaction mass gradually to 30 to 35C. Charged saturated ammonium chloride solution (800 ml) and stirred for 1045 min. Concentrated the reaction mass at 65 to 7O0C under vacuum to get crude solid product. Charged to the residue saturated ammonium chloride solution (1600 ml) DM water (800 ml) and dichloromethane (1000 ml) and stirred for 15 minutes. Separated the organic layer and extracted the aqueous layer further with dichloromethane (4x500 ml). Combined the organic layer and concentrated under vacuum to get thick solid mass. Charged toluene (1200 ml) to the residue and stirred at 25 - 30C for 30-45 minutes. Filtered the product, washed with cold toluene (400 ml), and dried under vacuum at 40 to 45C to get 2-chloro-3-nitropyridin-4-ol. Dry wt = 45 gm (50%). | ||
With sodium acetate; In N,N-dimethyl-formamide; at 120℃; for 3h;Inert atmosphere; | Compound WX065-1 (35.00 g, 181.36 mmol) and sodium acetate (44.63 g, 544.08 mmol) were dissolved in N,N-dimethylformamide (600.00 mE) at room temperature. The reaction mixture was heated to 120 C. and stirred for 3 hours under nitrogen atmosphere. After the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Ethyl acetate (500 mE) and water (200 mE) were added to the obtained residue. The organic phases were separated and the aqueous phases were extracted with ethyl acetate (200 mEx3). The organic phases were combined, washed with saturated brine (200 mE) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to remove the solvent to obtain the crude product. The obtained crude product was slurried for 30 minutes with the mixture of petroleum ether and ethyl acetate, followed by filtration. The filter cake was dried in vacuum for 30 minutes to obtain the target product WX068- 3. ?H NMR (400 MHz, DMSO_d5) oe: 8.19 (d, J=6.0 Hz, 1H), 7.03 (d, J=6.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 25 - 100℃; | Step-II: Synthesis of 2, 4-dichloro-3-nitropyridine from 4-chloro-3-nitropyridin-2- ol; Charged in a R.B. flask phosphorous oxychloride (81. 0 ml) and 4-chloro-3-nitropyridin- 2-ol (79 gm) in one lot under stirring at 25 - 300C. Charged slowly drop wise diisopropylethylamine (11.5 ml) at 25 - 3O0C. Stirred the reaction mass and raised the temperature to 90 to 100C and maintain for 4 - 6 hrs. Cooled the reaction mass to 10 to 150C and quenched in ice: water mixture. Stirred the reaction mass at 15 to 2O0C for 60 min. Filtered the solid product, wash with cold water, dried well to get 2, 4-dichloro-3- nitropyridine. Dry wt = 50 gm (57.5%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | b) Synthesis of 4-chloro-3-nitro-pyridin-2-ol 2,4-dichloro-3-nitro-pyridine (4.01 g, 20.8 mmol) and cesium acetate (8.0 g, 41.6 mmol) were dissolved in anhydrous N,N-dimethyl formamide (104 ml) under nitrogen atmosphere, and the reaction mixture was heated to 800 and stirred for 18 hours. The reaction mixture was cooled to room temperature the reaction was quenched by adding water. The organic layer was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain pale-yellow solid (1.69 g, 47%). 1H-NMR (DMSO-d6, 300 MHz); δ=8.24 (d, J=5.7 Hz, 1H), 7.09 (d, J=5.7 Hz, 1H). | |
With cesium acetate; In N,N-dimethyl-formamide; at 80℃; for 18h; | Step A: 4-chloro-3-nitropyridin-2-ol A solution of 2,4-dichloro-3-nitropyridine (10 g, 51.8 mmol) and cesium acetate (19.89 g, 104 mmol) in DMF (200 mL) was stirred at 80 C for 18 h. The reaction mixture was cooled to room temperature and the reaction was quenched by adding water. The organic layer was extracted with EtOAc (200 mL*3), and the combined organic layers were washed with water and saturated aq NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4-chloro-3-nitropyridin-2-ol as a solid. NMR (DMSO-ifc, 400 MHz): δ 8.22 (d, J= 5.6 Hz, 1H), 7.92 (s, 1H), 7.06 (d, J= 5.6 Hz, 1H). |
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