Structure of 540516-28-7
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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. : | 540516-28-7 |
Formula : | C8H7BrN2O |
M.W : | 227.06 |
SMILES Code : | OCC1=NC2=CC(Br)=CC=C2N1 |
MDL No. : | MFCD03197450 |
InChI Key : | RXQCVQKHRKONLO-UHFFFAOYSA-N |
Pubchem ID : | 4162824 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 49.92 |
TPSA ? Topological Polar Surface Area: Calculated from |
48.91 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.73 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.33 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.67 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.18 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.51 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.48 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.57 |
Solubility | 0.605 mg/ml ; 0.00266 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.96 |
Solubility | 2.5 mg/ml ; 0.011 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.6 |
Solubility | 0.057 mg/ml ; 0.000251 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 |
-6.74 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) |
1.79 |
* 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 |
---|---|---|
With potassium hydroxide; hydroxylamine-O-sulfonic acid; In water; at 40 - 50℃; for 0.5h; | Example 15. Production of intermediate compounds (l-amino-5-bromo-lH- benzimidazol-2-yl)methanol (compound 17) and (l-amino-6-bromo-lH-benzimidazol-2- yl)methanol (compound 18).The 5(6)-bromo-lH-benzimidazol-2-methanol (16 a, b) (5.2 g, 22.7 mmol), prepared to known methodology, is dissolved in a solution of KOeta (4.8 g, 72.8 mmol) in H2O (40 niL). To the mixture is added under stirring at 400C solution Of NH2OSO3H (6g, 50mmol) in H2O (15 mL), neutralized NaHCO3. Upon the completion of the exothermal reaction the mixture is still incubated at 40-500C for 0.5 h and then cooled to room temperature. The resultant precipitate is filtered and recrystallization is accomplished from water. The mixture of compounds 17 and 18 is obtained in 1 :1 ratio (according to 1H NMR). The mixture of these compounds is crystalline, white.Overall yield: 3.7g (67%). 1H NMR (300 MHz, DMSO-d6): delta ppm 4.73 (4H, s, 2CH2), 5.43 (IH, s, OH), 5.45 (IH, s,OH), 6.01 (2H, s, NH2), 6.03 (2H, s, NH2), 7.31 (IH, d, J- 9Hz, ArH), 7.39 (IH, d, J= 9Hz, ArH), 7.46 (IH, d, J- 9Hz, ArH), 7.53 (IH, d, J= 9Hz, ArH), 7.67 (IH, s, ArH), 7.73 (IH, s, ArH).13C NMR (75 MHz, DMSO-d6): delta ppm 55.81, 55.81, 112.48, 113.46, 114.15, 114.98, 121.46, 122.01, 124.93, 125.36, 135.73, 137.78, 139.62, 141.88, 156.17, 156.48. IR (v, cm"1): 3350, 3313, 3184, 3120 NH2.Analysis (C8H8BrN3O): calcd: C 39.67%, H 3.31 %, N 17.36%; found: C 39.88%, H 3.52%, N 17.46%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25%; 25% | Example 15. Production of intermediate compounds (l-amino-5-bromo-lH- benzimidazol-2-yl)methanol (compound 17) and (l-amino-6-bromo-lH-benzimidazol-2- yl)methanol (compound 18).The 5(6)-bromo-lH-benzimidazol-2-methanol (16 a, b) (5.2 g, 22.7 mmol), prepared to known methodology, is dissolved in a solution of KOeta (4.8 g, 72.8 mmol) in H2O (40 niL). To the mixture is added under stirring at 400C solution Of NH2OSO3H (6g, 50mmol) in H2O (15 mL), neutralized NaHCO3. Upon the completion of the exothermal reaction the mixture is still incubated at 40-500C for 0.5 h and then cooled to room temperature. The resultant precipitate is filtered and recrystallization is accomplished from water. The mixture of compounds 17 and 18 is obtained in 1 :1 ratio (according to 1H NMR). The mixture of these compounds is crystalline, white.Overall yield: 3.7g (67%). 1H NMR (300 MHz, DMSO-d6): delta ppm 4.73 (4H, s, 2CH2), 5.43 (IH, s, OH), 5.45 (IH, s,OH), 6.01 (2H, s, NH2), 6.03 (2H, s, NH2), 7.31 (IH, d, J- 9Hz, ArH), 7.39 (IH, d, J= 9Hz, ArH), 7.46 (IH, d, J- 9Hz, ArH), 7.53 (IH, d, J= 9Hz, ArH), 7.67 (IH, s, ArH), 7.73 (IH, s, ArH).13C NMR (75 MHz, DMSO-d6): delta ppm 55.81, 55.81, 112.48, 113.46, 114.15, 114.98, 121.46, 122.01, 124.93, 125.36, 135.73, 137.78, 139.62, 141.88, 156.17, 156.48. IR (v, cm"1): 3350, 3313, 3184, 3120 NH2.Analysis (C8H8BrN3O): calcd: C 39.67%, H 3.31 %, N 17.36%; found: C 39.88%, H 3.52%, N 17.46%. Example 16. Production of intermediate compounds 3-chloro-6- bromobenzimidazo[l,2-c][l,2,3]thiadiazole (compound 19) and 3-chloro-7- bromobenzimidazo[l,2-c][l,2,3]thiadiazole (compound 20).The mixture of (l-amino-5-brorno-lH-benzimidazol-2-yl)-methanol (compound 17) and (l-amino-6-bromo-lH-benzimidazol-2-yl)-methanol (compound 18) (0.5 g, 2.1 mmol) is refluxed with SOCl2 (5 mL) for 0.5 h. The excess of SOCl2 is evaporated. The residue is washed (NaHCO3ZH2O, H2O). The mixture of products consists of compounds 19 and 20 in proportion 1: 1. The compounds were separated by flash chromatography (dichlormethane: ethy lacetate= 10:1). Overall yield: 0.36 g (60%) (recrystallization is accomplished from methanol).20: Yield: 0.15g (25%), mp 193-1940C. Rf= 0.48 (dichlormethane: ethylacetate=10:l).1H NMR (300 MHz, DMSO-d6): 7.7 (IH, dd, J= 2 and 9Hz, CH(6)), 7.79 (IH, dd, J= 0.5Hz and 9Hz, CH(5)), 8.46 (IH, dd, J= 0.5 and 2Hz, CH(8)). 13C NMR (75 MHz, DMSO-d6): 112.76, 116.24, 123.03, 126.61, 129.36, 131.66, 151.72,152.49.Analysis (C8H3BrClN3S): calcd: C 33.30%, H 1.05 %, N 14.56%; found: C 33.56%, H 1.15%, N 14.63%.3-chloro-6-bromobenzimidazo[l,2-c][l,2,3]thiadiazole (compound 19) yield: 0,15g (25%), mp l53-154C.Rf= 0.59 (dichlormethane: ethylacetate=10:l).1H NMR (300 MHz, DMSO-d6): 7.45 (IH, dd, J= 2 and 9Hz, CH(7)), 8.07 (IH, d, J= 2Hz, CH(5)), 8.19 (IH, d, J= 9Hz, CH(8)).13C NMR (75 MHz, DMSO-d6): 115.36, 121.57, 123.38, 123.77, 127.76, 129.38, 152.77, 154.55.Analysis (C8H3BrClN3S): calc: C 33.30 %, H 1.05 %, N 14.56 %; found: C 33.01 %, H 1.33 %, N 14.36 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 19h; | A 0.1 M solution of 5-Bromo-1H-benzo[d]imidazol-2-yl)methanol (630 mg, 2.8 mmol) in dimethylformamide was stirred with 2.4 equiv of cesium carbonate and (0.3 mL, 1.2 equiv) of cyclopropylmethyl bromide at 50 C. for 19 h. At the end dimethylformamide was evaporated in vacuo. The residue was partitioned between ethyl acetate (70 mL) and water (30 mL). Organic layer was dried (sodium sulfate) and evaporated in vacuo to give 800 mg of crude product which by LC-MS was 75% pure. LC/MS (HPLC method 1): tR=2.1 min, 281(MH)+. Silica gel TLC (ethyl acetate:hexane=4: 1) revealed two major products with Rf=0.29 and 0.20, which without separation were used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; triethylamine; In dichloromethane; at 25℃; for 4h; | Into a 50-mL round-bottom flask, was placed (5-bromo-lH- l,3-benzodiazol-2- yl)methanol (600 mg, 2.64 mmol, 1.00 equiv), dichloromethane (20 mL), Boc20 (1 g, 4.58 mmol, 1.73 equiv), TEA (800 mg, 7.91 mmol, 2.99 equiv), 4- dimethylaminopyridine (32 mg, 0.26 mmol, 0.10 equiv). The resulting solution was stirred for 4 h at 25C. The mixture was diluted with 20 mL of dichloromethane, washed with 3*30 mL of water and 30 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 600 mg (crude) of the title compound as yellow oil. LC-MS (ES, m/z) 429,427[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With potassium permanganate; In water; acetone; | Synthesis of 5-bromo-1H-benzimidazole-2-carboxylic acid hydrochloride 44 was prepared using 5-bromo-1H-benzimidazole-2-yl)-methanol 28 (0.23 g, 1.0 mmol) dissolved in acetone (10 mL) and potassium permanganate (0379, 2.4 mmol) dissolve in water (10 mL). The crude product was recrystallised from water. 5-Bromo-1H-benzimidazole-2-carboxylic acid in Yield 37% was recovered as a creamy white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | N-Methyl-2-methanol 5-bromobenzimidazole 50 was prepared according to the procedure by Gonzlez-Chvez et al. [28]. A solution of 5-bromo-(1H-benzimidazole-2-yl)-methanol 28 (0.60 g, 2.60 mmol), and sodium hydroxide (0.10 g, 2.60 mmol) were stirred in dry acetone (10 mL) for 30 min. Then, iodomethane (0.37 g, 2.60 mmol) was added and the mixture was stirred for 24 h. The reaction mixture was concentrated to a quarter and then poured into ice-cold water. The solid was filtered and washed with 50% HCl. The solid was washed with water (100 mL) and purified by column chromatography (9:1 chloroform/ethanol) to give the desired product (50) as a bright yellow crystals Yield 16%. |
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