Structure of 766-55-2
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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. : | 766-55-2 |
Formula : | C6H5N3 |
M.W : | 119.12 |
SMILES Code : | C1=CN=C2C=CC=N[N]12 |
MDL No. : | MFCD07782103 |
InChI Key : | VTVRXITWWZGKHV-UHFFFAOYSA-N |
Pubchem ID : | 136599 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
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 | 32.99 |
TPSA ? Topological Polar Surface Area: Calculated from |
30.19 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.35 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.33 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.73 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.56 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.58 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.71 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.53 |
Solubility | 3.54 mg/ml ; 0.0298 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.53 |
Solubility | 35.3 mg/ml ; 0.297 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.66 |
Solubility | 2.59 mg/ml ; 0.0218 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 |
-6.79 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) |
1.69 |
* 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 |
---|---|---|
89% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); at 40 - 45℃; | 2) Add 2g of azobisisobutyronitrile to the reaction solution in the previous step, and add NBS 187g in batches. Pay attention to avoid light reaction. After the addition, control the temperature at 40 ~ 45 C and stir for 5 ~ 6 hours. The prepared 10% sodium bisulfite solution was added to the reaction bottle and stirred for 30 minutes (crack the excess NBS), and the temperature was reduced to -5C with suction to obtain a brown solid.Product II product 176g, yield 89%,The mother liquor can be recovered and applied after being layered. |
75% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; for 2h;Reflux; | The imidazo [1,2-b] pyridazine (6.0g, 50 . 4mmol), NBS (6.0g, 75 . 6mmol) and a catalytic amount of AIBN is added to the 50 ml chloroform, heating to reflux the reaction 2 hours, TLC detection of the reaction process, the raw materials of the reaction after cooling to room temperature stirring under the conditions of the ice bath, a precipitate out, filtered and the filtrate concentrated to get the pure product.The pure product as a pale yellow solid, yield: 75% |
75% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; for 2h;Reflux; | The imidazo [1,2-b] pyridazine (6.0 g, 50.4 mmol), NBS (6.0 g, 75.6 mmol) and a catalytic amount of AIBN were added to 50 mL of chloroform and the reaction was heated to reflux for 2 hours, The reaction solution was cooled to room temperature when the raw material disappeared with the TLC detection of the reaction process, and a precipitate precipitated after the solution stirred in an ice bath. After filtering, the filtrate concentrated under reduced pressure to give the pure product. A pale yellow solid, yield: 75%. 1H NMR (CDCl3, 400 MHz, delta ppm): 8.50 (d, J = 3.6 Hz, 1H), 8.01-7.98 (m, 1H), 7.84 (s, 1H), 7.15-7.12 (m, 1H). ESI-MS m/z : 200.1 [M+H]+. |
74% | With N-Bromosuccinimide; In chloroform; for 0.5h;Reflux; | Example 15 -4 Synthesis of 3-bromo-imidazo[1,2-b]pyridazine To imidazo[1,2-b]pyridazine 1*b (10 g) stirring in chloroform (250 ml) was added N-bromosuccinimide (15.7 g) at 5 C. The cooling bath was removed and the reaction was heated to reflux which was maintained for 30 minutes. After leaving to cool overnight the reaction mixture was concentrated under reduced pressure. The residue was redissolved in ethyl acetate (500 ml), washed with potassium carbonate solution (3 x 200 ml) then brine (100 ml). The organic extract was dried with magnesium sulphate and concentrated in vacuo to give 3-bromo-imidazo[1,2-b]pyridazine 2*b, 12.3 g (74%). 1H-NMR (400MHz, DMSO-D6) : delta = 8.68 (1 H, d, 4.4 Hz, ArH), 8.20 (1 H, d, 9.2 Hz, ArH), 7.95 (1 H, s, ArH), 7.33 (1 H, q, 3.4 Hz, ArH). |
36% | With bromine; acetic acid; at 0 - 20℃; for 1h; | To a stirred solution of imidazo[1,2-bjpyridazine (200 mg, 1.679 mmol) in acetic acid (10 mL) was added bromine (0.2 mL, 3.88 mmol) at 0 C. The reaction mixture was allowed to warm to room temperature and stir for 1 hr. The reaction mixture was neutralized with iN sodium hydroxide, poured into EtOAc (20 mL) and 10% NaHCO3 solution. The layers were separated and the aqueous layer extracted with EtOAC (3x20ml). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated to give 3-bromoimidazo[1,2-bjpyridazine (120 mg, 36%) as light brown solid. ?H NMR (400 MHz, DMSO-d6) oe 8.68 (dd, J=4.52, 1.51 Hz, 1 H) 8.19 (dd, J=9.54, 1.51 Hz, 1 H) 7.94 (s, 1 H) 7.28-7.39 (m, 1 H). |
With bromine; In acetic acid; at 20℃; | EXAMPLE 1; Lambda/-[(l,6i?)-6-Amino-2,2-difluorocyclohexyl]-4-(imidazo[1,2-b]pyridazin-3-yl)-5- methylthiophene-2-carboxamide; 3 -Bromoimidazo [ 1,2-b]pyridazine; Bromine (0.649 mL, 12,6 mmol) was added dropwise to a stirred mixture of Imidazo[1,2- 6]pyridazine (1.0 g, 839 mmol) in acetic acid (42 ml) and the mixture was stirred at room temperature for 1 h. The mixture was neutralized with 1 N sodium hydroxide (100 mL) and solid sodium hydroxide, poured into ethyl acetate and sodium bicarbonate solution, and extracted with ethyl acetate (3 x 200 mL). The combined organics were washed with brine, dried (MgSO,*), and concentrated to afford the title compound. 1H NMR (600 MHz, CD3SOCD3) delta 8.66 (d, 1H); 8.17 (d, 1H); 7.93 (s, 1H); 7.31 (dd, 1H). LRMS (APCI) calc'd for (C6H5BrN3) [M+H]+, 198.0; found 198.0. | |
With N-Bromosuccinimide; In chloroform; for 2h;Reflux; | A mixture of imidazo[1,2-b]pyridazine (2.0 g), N-bromosuccinimide (2.94 g), and chloroform (100 mL) was heated under reflux for 2 hr. Upon cooling, the solution was treated with a saturated aqueous solution of sodium carbonate (200 mL) and shaken. The chloroform layer was separated and concentrated to afford the compound 3-bromoimidazo[1,2-b]pyridazine (IIb). | |
9.9 g | With N-Bromosuccinimide; In chloroform; for 0.5h;Reflux; | theImidazo [1,2-b] pyridazin(50mmol) dissolved in Chloroform (50 ml), Bromosuccinimide(55 mmoles) was slowly added into the reaction . at reflux System was stirredfor 30 minutes. After cooling to room temperature, the pH was adjusted to 8-9 usingsaturated aqueous sodium carbonatesolution and extracted with ethyl acetate. The extract was washed with water andsaturated brine. After dried overanhydrous sodium sulfate and concentrated to give 9.9 g of the title compound. |
9.9 g | With N-Bromosuccinimide; In chloroform; for 0.5h;Reflux; | The imidazo [l, 2_b] pyridazine ¢ .0 g, 50 mmol) was dissolved in chloroform (50 ml), N- bromobutyrate ni imide (NBS) (9.8 g, 55 mmol mol) was slowly added thereto.Was refluxed for 30 minutes.After cooling to room temperature, the PH value was adjusted to 8-9 with saturated sodium carbonate solution, extracted with ethyl acetate.The extract was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 9.9 g. |
With N-Bromosuccinimide; In ethyl acetate; at 95℃; for 2h; | Was added 3-amino-pyridazine in 250 ml single neck round bottom flask (9.51g, 100mmol), 40% aqueous solution of chloroacetaldehyde (chloroacetaldehyde 190mmol) and 81g of ethyl acetate, Start the magnetic stirrer, the mixture of the reaction flask The reaction was stirred at 85 C for 2 hours. TLC, starting material 3-amino-pyridazine completion of the reaction, was added N- bromosuccinimide (17.80g, 100mmol), 95 under stirring for 2 hours,TLC and GC detection to determine the intermediate imidazo [1,2-b] pyridazine was complete. The reaction mixture was suction filtered, the reaction solution was suction filtered, the filter cake with ethyl acetate: n-hexane = 1: 5 to give the pure product recrystallized from 3-bromo-imidazo [1,2-b] pyridazine, the filtrate with ethyl acetate. The pure product was obtained by recrystallization from ethyl acetate: n-hexane = 1: 5 to give the pure product 3-bromoimidazo [1,2-b] pyridazine. After drying, the yield was calculated 88.98%, purity 99% (HPLC). |
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