Structure of 4-Bromo-2,1,3-benzothiadiazole
CAS No.: 22034-13-5
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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. : | 22034-13-5 |
Formula : | C6H3BrN2S |
M.W : | 215.07 |
SMILES Code : | BrC1=CC=CC2=NSN=C21 |
MDL No. : | MFCD00614355 |
Boiling Point : | No data available |
InChI Key : | KYKBVPGDKGABHY-UHFFFAOYSA-N |
Pubchem ID : | 736492 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 45.11 |
TPSA ? Topological Polar Surface Area: Calculated from |
54.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.02 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.48 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.45 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.42 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.4 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.35 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.4 |
Solubility | 0.0853 mg/ml ; 0.000396 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.26 |
Solubility | 0.118 mg/ml ; 0.000551 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.46 |
Solubility | 0.0753 mg/ml ; 0.00035 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 |
-5.85 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 |
0.0 |
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) |
1.85 |
* 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 |
---|---|---|
49% | With hydrogen bromide; bromine; In water; at 100℃; for 9h; | To a flask equipped with a reflux device, 25.0 g (183.7 mmol) of the compound (a), and 150 mL of 48percent hydrobromic acid were added. After heating to 100° C., 8.5 mL (165.4 mmol) of bromine was dropped, the resultant was stirred at 100° C. for nine hours, and then it was let cool. After a reaction was finished, 200 mL of dichloromethane was added, precipitated solid was dissolved, and further 100 mL of an aqueous sodium sulfate solution was added. An organic layer was collected, washed with a saturated aqueous sodium hydrogen carbonate solution, dried with anhydrous sodium sulfate, and then a solvent was removed under reduced pressure to obtain an unrefined compound (b). The compound (b) was suspended in 200 mL of hexane/ethyl acetate (4:1, volume ratio), remaining solids were filtered to thereby remove 4,7-dibromo-2,1,3-benzothiadiazole being a by-product. The filtrate was condensed again, suspended in 200 mL of hexane, and remaining solids were filtered, to thereby obtain 11.2 g of the compound (b). Further, the filtrate was condensed, and refinement was performed by a column chromatography method using hexane/ethyl acetate (97:3, volume ratio) as a developing solution, to thereby obtain 8.0 g of the compound (b). A sum total was 19.2 g (89.3 mmol), and a yield was 49percent. |
With hydrogen bromide; bromine; at 150℃; for 2h; | In a first step, 10 g (73.52 mmol) of 2,1,3-benzothiadiazole (1) was added to a 100 ml round-Suspended in 50 ml HBr solution (48percent),A solution of 2.8 ml (54.26 mmol) of bromine was added dropwise with vigorous stirring,After all the drops were added, the mixture was heated to 150 ° C and refluxed for 2 hours.After completion of the reaction, the mixture was cooled to room temperature,The reaction mixture was poured into 500 ml of water,The precipitated solid was filtered to give 10.4 g of crude product;The crude product contains a small amount of dibromo substituted product as well as the starting material.The crude product is directly put into the next step.Under nitrogen protection,To a 500 ml two-necked round bottom flask equipped with a condenser tube was added 8.556 g of crude product (assuming all 4-bromo-2,1,3-benzothiadiazole (2), 40 mmol)10.208 g (44 mmol) of 4-formylphenylboronic acid pinacol ester,2.32 g (2.0 mmol) of tetrakis (triphenylphosphine) palladium and 200 ml of THF,Followed by the addition of 200 ml of an aqueous solution of potassium carbonate (11.06 g, 80 mmol), heated to reflux and stirred for 12 h.After completion of the reaction, the mixture was cooled to room temperature and the mixture was extracted three times with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was treated with dichloromethane / petroleum ether (2: 1) as the eluent,Silica gel column chromatography afforded 8.2 g of pale yellow 4-formylphenyl-2,1,3-benzothiadiazole (3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium diacetate; potassium carbonate; In water; N,N-dimethyl-formamide; | In the present invention, 7,7'-dibromo-4,4'-bis (2,1,3-benzothiadiazole) (7,7'-dibromo-4,4'-bis -benzothiadiazole) Was prepared by referring to the previous literature (P. Anant, N. T. Lucas, J. Jacob, Org Letter 10, 5533-5536). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 8h;Heating; | 4-Bromobenzo [c] [1,2,5] thiadiazole (100 g, 0.46 mol),4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi-1,3,2-dioxaborolane(141 g, 0.55 mol), Pd (dppf) Cl2 (32 g, 0.04 mol) and KOAc (90 g, 0.92 mol) were placed in a flask, To this was added 1,4-dioxane (2 L) and dissolved, followed by heating and stirring for 8 hours. After completion of the reaction, Distilled water was added and the organic layer was extracted with ethyl acetate.The obtained organic layer was dried over Na2SO4, distilled under reduced pressure,Purification by column chromatography afforded compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]thiadiazole(72 g, yield 60percent) was obtained as white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In dichloromethane; at 20℃; for 0.5h; | To a clear solution of B(C6F5)3 (0.050 g, 0.098 mmol) in CH2Cl2 (5 mL) was added a colorless solution of <strong>[22034-13-5]4-bromo-benzo[2,1,3]thiadiazole</strong> (0.021 mg, 0.098 mmol) in CH2Cl2 (5 mL). The resulting yellow solution was allowed to stir for 30 minutes at room temperature. The solvent was removed in vacuo and the resulting solid washed with pentanes (2.x.10 mL) and dried under vacuum for 1 hour. The product was collected as a faint yellow solid. Recovered yield, 60 mg (85percent). Crystal's suitable for X-ray diffraction were grown via slow diffusion of pentane into a concentrated solution of 4 in CH2Cl2. Upon addition of excess B(C6F5)3 (3 equivalents total) to 4, no change in the 1H or 19F spectrum was observed from 25 to -50° C. 1H NMR (CD2Cl2): delta 8.02 (d, 3JH-H=8 Hz, 1H, benzothiadiazole-p-CH), 7.71 (dd, 3JH-H=8 Hz, 3JH-H=8 Hz, 1H, benzothiadiazole-m-CH), 7.50 (d, 3JH-H=8 Hz, 1H, benzothiadiazole-o-CH). {1H} NMR (CD2Cl2): delta -5.5 (bs). 13C{1H} NMR (CD2Cl2, -50° C.) partial: 152.79, (s, quaternary), 149.22 (s, quaternary), 148.90 (dm, 1JC-F=250 Hz, CF), 148.22 (dm, 1JC-F=250 Hz, CF), 146.55 (dm, 1JC-F=245 Hz, CF), 141.73 (dm, 1JC-F=245 Hz, CF), 140.85 (dm, 1JC-F=250 Hz, CF), 138.99 (dm, 1JC-F=240 Hz, CF), 137.05 (dm, 1JC-F=245 Hz, CF), 136.74 (s, benzothiadiazole-m-CH), 134.01 (s, benzothiadiazole-p-CH), 131.90 (dm, 1JC-F=250 Hz, CF), 117.22 (quaternary), 116.05 (s, benzothiadiazole-o-CH). 19F NMR (CD2Cl2): delta -125.2 (br, 1F, ortho-C6F5), -131.0 (br, 3F, ortho-C6F5), -135.2 (br, 1F, ortho-C6F5), -137.2 (br, 1F, ortho-C6F5), -154.5 (s, 1F, para-C6F5), -156.5 (br, 2F, para-C6F5), -161.6 (br, 2F, meta-C6F5), 163.8 (br, 4F, meta-C6F5). 19F NMR (CD2Cl2, -50° C.): delta -125.17 (m, 1F, 3JF-F=22 Hz, ortho-C6F5), -130.58 (m, 1F, 3JF-F=21 Hz, ortho-C6F5), -131.42 (m, 2F, 3JF-F=24 Hz, ortho-C6F5), -134.13 (m, 1F, 3JF-F=24 Hz, ortho-C6F5), -137.58 (m, 1F, 3JF-F=24 Hz, ortho-C6F5), -153.99 (m, 1F, 3JF-F=20 Hz, para-C6F5), -155.31 (m, 1F, 3JF-F=20 Hz, para-C6F5), -157.27 (m, 1F, 3JF-F=22 Hz, para-C6F5), -161.28 (m, 1F, 3JF-F=20 Hz, meta-C6F5), -162.91 (m, 1F, 3JF-F=20 Hz, meta-C6F5), -162.74 (m, 1F, 3JF-F=20 Hz, meta-C6F5), -163.33 (m, 1F, 3JF-F=20 Hz, meta-C6F5), -163.77 (m, 1F, 3JF-F=22 Hz, meta-C6F5), -164.03 (m, 1F, 3JF-F=22 Hz, meta-C6F5). UV-vis: lambdamax=355 nm. X-Ray: C24H3B1Br1F15N2S1. Space Group=P-1. Cell: a=10.82(15) , b=11.82(18) , c=12.36(18) , alpha=63.7(3)°, beta=75.1(3)°, gamma=84.1(4)°, V=1369(35) 3. R=0.0432percent, Rw=0.1132percent. GOF=1.027. |
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