Structure of 1206487-35-5
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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. : | 1206487-35-5 |
Formula : | C4H3Br2N3 |
M.W : | 252.90 |
SMILES Code : | NC1=NN=C(Br)C=C1Br |
MDL No. : | MFCD13689240 |
InChI Key : | ZTXKTTUTGHERSF-UHFFFAOYSA-N |
Pubchem ID : | 46238402 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 41.84 |
TPSA ? Topological Polar Surface Area: Calculated from |
51.8 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.64 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.21 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.59 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.36 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.71 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.5 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.66 |
Solubility | 0.549 mg/ml ; 0.00217 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.89 |
Solubility | 3.22 mg/ml ; 0.0127 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.0 |
Solubility | 0.251 mg/ml ; 0.000993 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) |
No |
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 |
-6.98 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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.1 |
* 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 |
---|---|---|
78% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 8.0h;Reflux; | A mixture of crude tert-butyl (1 -{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example lnt-1 -A (5.80 g, 13.1 mmol), <strong>[1206487-35-5]3-amino-4,6-dibromopyridazine</strong> (CAS Registry No. 1206487-35-5, 3.96 g, 15.7 mmol, 1 .2 eq), N,N-diisopropylethylamine (2.3 mL, 13.0 mmol, 1 .0 eq) and powdered activated 3A molecular sieves (1 0 g) in isopropanol (70 mL) was heated at the reflux temperature for 8 h. On cooling, the mixture was filtered through a pad of Celite. The Celite was washed with DCM, and the combined organics were washed with water, dried with sodium sulfate and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 1 00 g SNAP cartridge: 100% hexane 2.0 min., gradient to 75% hexane /25% EtOAc 2.5 min., 75% hexane /25% EtOAc 4.5 min., gradient to 50% hexane /50% EtOAc 2 min., 50% hexane /50% EtOAc 4.5 min., gradient to 100% EtOAc 2.5 min., 100% EtOAc 5.7 min.) to give partially purified tert-butyl (1 -{4-[3-phenyl-6,8-dibromoimidazo[1 ,2-b]pyridazin-2- yl]phenyl}cyclobutyl)carbamate (2.65 g, -82% pure, 28% yield):UPLC-MS (Method 3): RT = 1 .67 min; m/z (rel intensity) 597 (50, (M+H)+). 1 H-NMR (d6-DMSO): delta 1 .00-1 .20 (br s, 3H), 1 .20-1 .37 (br s, 6H), 1 .65-1 .81 (m, 1 H), 1 .85-2.00 (m, 1 H), 2.25-2.38 m, 4H), 3.80 (s, 3H), 6.92 (d, J=9.6 Hz, 1 H), 7.28 (d, J=8.5 Hz, 2H), 7.37-7.59 (m, 8H), 8.50 (d, J=9.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In tetrahydrofuran; at 20 - 125℃;Inert atmosphere; | A mixture comprising 235 g (931 mmol) <strong>[1206487-35-5]4,6-dibromopyridazin-3-amine</strong> which was prepared according to intermediate example 30g, 421 mL (2792 mmol) 2- bromo-1 ,1 -diethoxyethane, 2.93 L water and 227 mL THF was heated at 125C for for h and at rt overnight. The solution was neutralized by addition of solid NaHC03, the precipitate was filtered off, washed with water and dried to give 156 g (80%) of the title compound as a brownish solid. 1 H-NMR (DMSO-d6): delta= 7.81 (1 H), 8.40 (1 H) ppm. |
80% | In tetrahydrofuran; water; at 20 - 125℃; | A mixture comprising 235 g (931 mmol) <strong>[1206487-35-5]4,6-dibromopyridazin-3-amine</strong> which was prepared according to intermediate example 1g, 421 mL (2792 mmol) 2-bromo-1 ,1 - diethoxyethane, 2.93 L water and 227 mL THF was heated at 125 C for for h and at rt overnight. The solution was neutralized by addition of solid NaHC03, the precipitate was filtered off, washed with water and dried to give 156 g (80%) of the title compound as a brownish solid. 1 H-NMR (DMSO-d6): delta= 7.81 (1 H), 8.40 (1 H) ppm. |
80% | In tetrahydrofuran; water; at 20 - 125℃;Inert atmosphere; | Intermediate Example 26f 6,8-dibromoimidazo[1 ,2-b]pyridazine A mixture comprising 235 g (931 mmol) <strong>[1206487-35-5]4,6-dibromopyridazin-3-amine</strong> which was prepared according to intermediate example 26g, 421 mL (2792 mmol) 2- bromo-1 , 1 -diethoxyethane, 2.93 L water and 227 mL THF was heated at 125C for for h and at rt overnight. The solution was neutralized by addition of solid NaHC03, the precipitate was filtered off, washed with water and dried to give 156 g (80%) of the title compound as a brownish solid. 1 H-NMR (DMSO-d6): delta= 7.81 (1 H), 8.40 (1 H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With bromine; sodium hydrogencarbonate; In methanol; at 20℃;Inert atmosphere; | To a mixture comprising 285 g (1638 mmol) 6-bromopyridazin-3-amine which was prepared according to intermediate example 30h,275 g (3276 mmol) NaHCCb and 2815 mL MeOH was dropwise added 85 mL (1638 mmol) bromine at rt and it was stirred at rt overnight. After further addition of 34 mL (655 mmol) bromine and 55 g (655 mmol) NaHC03,the mixture was stirred overnight again. The solvent was reduced to about 1000 mL and the mixture was poured on 5 L of water. The precipitate was filtered off, washed with water and dried give 41 1 g (99%) of the title compound. 1 H-NMR (CDCla): delta= 6.14 (1 H), 9.92 (2H) ppm. |
99% | With bromine; sodium hydrogencarbonate; In methanol; at 20℃; | To a mixture comprising 285 g (1638 mmol) 6-bromopyridazin-3-amine which was prepared according to intermediate example 1 h,275 g (3276 mmol) NaHC03 and 2815 mL MeOH was dropwise added 85 mL (1638 mmol) bromine at rt and it was stirred at rt overnight. After further addition of 34 mL (655 mmol) bromine and 55 g (655 mmol) NaHC03,the mixture was stirred overnight again. The solvent was reduced to about 1000 mL and the mixture was poured on 5 L of water. The precipitate was filtered off, washed with water and dried give 411 g (99%) of the title compound. 1 H-NMR (CDCls): delta= 6.14 (1 H), 9.92 (2H) ppm. |
99% | With bromine; sodium hydrogencarbonate; In methanol; at 20℃;Inert atmosphere; | Intermediate Example 26 6,8-dibromoimidazo[1 ,2-b]pyridazine To a mixture comprising 285 g (1638 mmol) 6-bromopyridazin-3-amine which was prepared according to intermediate example 26h,275 g (3276 mmol) NaHC03 and 2815 mL MeOH was dropwise added 85 mL (1638 mmol) bromine at rt and it was stirred at rt overnight. After further addition of 34 mL (655 mmol) bromine and 55 g (655 mmol) NaHC03,the mixture was stirred overnight again. The solvent was reduced to about 1000 mL and the mixture was poured on 5 L of water. The precipitate was filtered off, washed with water and dried give 411 g (99%) of the title compound. 1 H-NMR (CDCb): delta= 6.14 (1 H), 9.92 (2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; sodium hydrogencarbonate; In methanol; at 20℃; for 16.0h; | Toa mixture of 6-iodopyridazin-3-amine (500 mg, 2.26 mmol), NaHC03(230 mg, 2.71 mmol) in MeOH (5 mL) was added bromine (117 mu, 2.26 mmol)dropwise. The resulting mixture was stirred at room temperature for 16 hrs. Thesolution was filtered and the filtrate concentrated in vacuo. The residue wasdissolved in water, and the product extracted with EtOAc (3 times). The organiclayers were combined, dried ( a2S04) and concentrated invacuo to give a dark red solid which was purified by flash silicachromatography (eluent: 20% EtOAc :Hexane) to give a 60:40 mixture of the titlecompounds as an off white solid (250 mg); H NMR (400 MHz, CDC13) delta5.49 (s, 4H), 7.66 (s, 1H), 7.81 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 20℃; for 72.0h; | A solution of 2-bromo- 1 -((lr,3 r)-3- (quinolin-2-yl)cyclobutyl)ethanone (1.56 g, 4.62 mmol, prepared using themethod described in Example 1, step C) and 4,6-dibromopy-ridazin-3-amine (1.17 g, 4.62 mmol) in DMF (10 mE) wasstirred at rt for 3 days. The reaction mixture was poured intowater (200 mE), and extracted with EtOAc (2x200 mE). The combined organic layers were washed with saturated NaHCO3 and brine, dried over Na2 SO4, filtered, and concentrated. The residue obtained was purified by flash chromatography on silica gel (0-40% EtOAc/heptane) to obtain 2-((lr, 3r)-3-(6,8-dibromoimidazo[ 1 ,2-b]pyridazin-2-yl)cyclobutyl)quinoline as a yellow oil. ?H-NMR (400 MHz, CDC13) oe (ppm): 8.10 (dd, J=8.3, 4.8 Hz, 2H), 7.98 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.47-7.53 (m, 1H), 7.44 (s, 1H), 7.38 (d, J=8.6 Hz, 1H), 4.01-4.10 (m, 1H),3.89-3.99 (m, 1H), 2.96-3.08 (m, 2H), 2.75-2.86 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With bromine; sodium hydrogencarbonate; In methanol; at 0 - 20℃; for 16.0h; | General procedure: To a stirred solution of 6-chloropyridazin-3-amine (20.0 g, 155.02 mmol) in MeOH (100 mL) was added NaHC03 (19.53 g, 232.00 mmol) at RT and stirred for 15 min and then bromine (8.74 mL, 170.52 mmol) was added drop wise to the reaction mixture over period of 1 h at 0 C and stirred for 16 h at RT. After completion of the reaction (monitored by TLC), reaction mixture was quenched with water (100 mL). Dark brown colored solid was precipitated which was filtered and washed with water (50 mL) and dried under vacuum to afford crude title compound. The solid was washed with 20% EtOAc in hexane and diethyl ether to afford pure title compound (15.0 g, 46 %). 1H NMR (400 MHz, DMSO-d6) d 7.99 (s, 1H), 6.97 (bs, 2H); LC-MS: m/z 208.0 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 16.0h;Inert atmosphere; | To a stirred solution of 4-bromo-6-bromopyridazin-3-amine (3a), (0.20 g, 0.79 mmol) in DML (5 mL) were ethyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)acetate hydrochloride (0.278 g, 1.11 mmol ) and DIPEA (0.7 mL, 3.95 mmol) at RT and stirred for 16 h at 90 C under nitrogen atmosphere. Then the reaction mixture was quenched with cold water (20 mL) and the brown solid obtained was washed with diethyl ether, filtered and dried under vacuum. The same procedure was repeated four times to afford pure title compound (0.155 g, Yield : 55 %). 1H NMR (400 MHz, DMSO-d6): d 6.96 (s, 1H), 5.76 (s, 2H), 4.15-4.03 (m, 2H), 3.37-3.29 (m, 2H), 3.19 (s, 2H), 3.16-3.14 (m, 2H), 2.83-2.80 (m, 2H), 1.85 (s, 4H), 1.23-1.13 (m, 3H); LC-MS: m/z 371.1 (M+l)+. |
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