Structure of 865156-68-9
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CAS No. : | 865156-68-9 |
Formula : | C6H4BrN3 |
M.W : | 198.02 |
SMILES Code : | BrC1=CN2C(N=C1)=NC=C2 |
MDL No. : | MFCD09261434 |
InChI Key : | BQMWMOQCMFLRQQ-UHFFFAOYSA-N |
Pubchem ID : | 26967622 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
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 | 40.69 |
TPSA ? Topological Polar Surface Area: Calculated from |
30.19 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.43 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.8 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.49 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.95 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.2 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.37 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.87 |
Solubility | 0.269 mg/ml ; 0.00136 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.05 |
Solubility | 1.75 mg/ml ; 0.00885 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.57 |
Solubility | 0.533 mg/ml ; 0.00269 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 |
-6.23 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 |
---|---|---|
62% | A suspension of 2-amino-5-bromopyrimidine (3.0 g, 17.2 mmol), bromoacetaldehyde diethyl acetal (3.2 mL, 20.7 mmol) and 48% HBr (1.7 mL) in EtOH was heated was heated to 80 0C in a sealed tube for 16 h. After cooling to rt, the reaction was adjusted to pH ~12 with 6N NaOH and the resultant precipitate was collected by filtration, rinsed with water followed by hexanes and dried to a constant weight to give 2.12 g (62%) of 6-bromoimidazo[l,2-alpha]pyrimidine as a white solid. MS(ES)+ m/e 199.7 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In water; at 25℃; for 24h; | c) 6-Bromo-imidazo[1,2-a]pyrimidine; 50 mmol of 5-bromo-pyrimidin-2-ylamine are dissolved in 200 mi of saturated aqueous sodium hydrogencarbonate solution. 55 mmol of chloroacetaldehyde are added to the reaction mixture and the mixture is stirred for 24 hours at 25C. The mixture is extracted with ethyl acetate (3x300 mi) and the combined extracts are dried over sodium sulphate and evaporated under reduced pressure. Flash chromatography (Si02 60F) of the residue provides the title compound which is identified on the basis of its Rf-value. | |
In ethanol; water; at 20℃; for 16h;Heating / reflux; | Example 9; 211 212 213Part A:To compound 211 (1.00 g, 5.74 mmol) in ethanol (100 ml_) was added chloroacetaldehyde (50 wt% solution in water, 7.34 ml_, 57.5 mmol) at room temperature. The reaction mixture was heated at reflux for 16 hours at which time LC- MS analysis indicated that the reaction was complete. The reaction mixture was concentrated under vacuum. The residue was taken back up in ethyl acetate and saturated sodium bicarbonate. The organic and aqueous layers were separated. The organic layer was washed with brine, dried over anh. sodium sulfate and concentrated to afford compound 212 as a beige solid. 1H NMR (400 MHz, DMSO-d6) delta 9.32 (d, 1 H), 8.56 (d, 1 H), 7.85 (d, 1 H), 7.74 (d, 1 H). | |
With sodium hydrogencarbonate; In water; at 25℃; for 24h; | c) 6-Bromo-imidazof1w2-alPyrimidine; 50 mmol of 5-bromo-pyrimidin-2-ylamine are dissolved in 200 mi of saturated aqueous sodium hydrogencarbonate solution. 55 mmol of chloroacetaldehyde are added to the reaction mixture and the mixture is stirred for 24 hours at 25C. The mixture is extracted with ethyl acetate (3x300 ml) and the combined extracts are dried over sodium sulphate and evaporated under reduced pressure. Flash chromatography (SiO2 60F) of the residue provides the title compound which is identified on the basis of its Rf-value |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In water; | Step 1: 6-Bromoimidazo[l,2-alpha]pyrimidinium hydrobromide. A suspension of 5-bromo-2- aminopyrimidine (6.00 g, 34.5 mmol), bromoacetaldehyde diethylacetal (10.4 mL, 69.0 mmol), 4.0 mL 48% aqueous HBr and 40 mL ethanol was stirred at reflux overnight. Then, the suspension was cooled to room temperature, filtered and dried in vacuo to afford the title compound as an off-white solid. The HBr salt generated above was treated with aqueous NaHCC>3 and the aqueous mixture was extracted with CH2Cl2 to afford after concentration in vacuo pale yellow crystals. 1H NMR (600 MHz, DMSOd6) delta 9.74 (d, IH, J = 2.4 Hz); 9.12 (d, IH, J = 2.4 Hz); 8.28 (d, IH, J = 1.8 Hz); 8.20 (d, IH, J = 1.8 Hz); 6.0 (br s, IH). LCMS (APCI) exact mass calc'd for [M + H]+ (C6H5N3Br) requires mlz 198.0, 200.0 found 197.7, 199.7. EPO <DP n="43"/> |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; methanol; water; at 100℃; | A mixture of 3-cyclobutyl-9-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3,9-diazaspiro[5.5]undecane (60 mg, 0.15 mmol), <strong>[865156-68-9]6-bromoimidazo[1,2-a]pyrimidine</strong> (35 mg, 0.18 mmol), Pd(PPh)4 (18 mg, 0.015) and K2CO3 (138 mg) in dioxane (4 mL) and water (0.5 mL) is heated overnight at 100 C. Water is added and the mixture is extracted with EA (2×10 mL). The combined organic layers are placed directly on an SCX (ion-exchange) column. The column is first washed with EA (discarded to waste) and second with EA/MeOH/TEA (90:10:10) which is collected. The solvent is removed and the crude product is purified by PTLC (5% TEA in EA/MeOH [95:5]) to give the title compound. 1H NMR (300 MHz, CDCl3) delta 8.79 (1H, d), 8.50 (1H, d), 7.82 (1H, d), 7.56 (1H, d), 7.46 (2H, d), 7.03 (2H, d), 3.74-3.24 (4H, m), 2.93 (1H, m), 2.56-2.45 (4H, m), 2.12-2.09 (2H, m), 1.8-1.67 (12H, m). LC-MS (Method 1): 402.13; RT=1.2 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 120℃; for 0.5h;sealed tube; Microwave irradiation; | 670 mul of benzylamine, 2 ml of acetonitrile and 400 mg of <strong>[865156-68-9]6-bromoimidazo[1,2-a]pyrimidine</strong> are charged to a glass tube. The tube is sealed and heated at 120 C. for 30 minutes using microwave radiation. After returning to a temperature in the vicinity of 20 C., the reaction medium is evaporated to dryness by evaporation under reduced pressure and the solid isolated is chromatographed, under argon pressure, on silica gel (eluent dichloromethane/methanol 95/5). 112 mg of N-benzylimidazo[1,2-a]pyrimidin-6-amine are thus obtained in the form of an orange lacquer. MS: method A; [M+H]+ m/z=225; Tr=0.38 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12 ml of ethanol, 920 mg of potassium hydroxide pellets and 1 g of <strong>[865156-68-9]6-bromoimidazo[1,2-a]pyrimidine</strong> are charged to a glass tube. The tube is sealed and heated at 135 C. for 12 minutes using microwave radiation. After returning to a temperature in the vicinity of 20 C., 1.5 ml of bromocyclohexane are added. The tube is again sealed and the combined mixture is heated at 140 C. for 15 minutes using microwave radiation. After returning to a temperature in the vicinity of 20 C., the reaction medium is evaporated to dryness under reduced pressure and the solid isolated is chromatographed, under argon pressure, on silica gel (eluent dichloromethane/methanol 97/3). 75 mg of 6-(cyclohexyloxy)imidazo[1,2-a]pyrimidine are thus obtained in the form of a beige solid. MS: method B; [M+H]+ m/z=218; Tr=2.54 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 120℃; for 0.5h;sealed tube; Microwave irradiation; | EXAMPLE 25c N-cyclohexylimidazo[1,2-a]pyrimidin-6-amine The product can be prepared in the following way: 3.2 g of <strong>[865156-68-9]6-bromoimidazo[1,2-a]pyrimidine</strong>, 5.5 ml of cyclohexylamine and 32 ml of acetonitrile are charged to a glass tube. The tube is sealed and heated at 120 C. for 30 minutes using microwave radiation. After returning to a temperature in the vicinity of 20 C., 100 ml of an aqueous potassium carbonate solution are added and the resulting aqueous phase is extracted with 3 times 150 ml of ethyl acetate and 1 times 150 ml of dichloromethane. The organic phases are combined, washed with 2 times 200 ml of an aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated by evaporation under reduced pressure. The residue obtained is chromatographed on silica gel (eluent dichloromethane/methanol 95/5). 720 mg of N-cyclohexylimidazo[1,2-a]pyrimidin-6-amine are thus obtained in the form of a brown oil. MS: method A; [M+H]+ m/z=217; Tr=0.45 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 150℃; for 0.333333h;sealed tube; Microwave irradiation; | EXAMPLE 23c 6-(3-fluorophenyl)imidazo[1,2-a]pyrimidine The compound can be prepared in the following way: 400 mg of <strong>[865156-68-9]6-bromoimidazo[1,2-a]pyrimidine</strong> (commercially available product), 345 mg of 3-fluorophenylboronic acid, 69 mg of tetrakis(triphenylphosphine)palladium, 2 ml of a 2M aqueous sodium carbonate solution and 8 ml of dimethylformamide are charged to a sealed glass tube. The medium is heated at 150 C. for 20 minutes using microwave radiation. After returning to a temperature in the vicinity of 20 C., the medium is filtered through a bed of Clarcel Flo M and rinsing is carried out with 2 times 2 ml of dimethylformamide and then 2 times 5 ml of methanol. The filtrate is concentrated to dryness by evaporation under reduced pressure. The solid isolated is suspended in 80 ml of distilled water, stirred, filtered off, washed with distilled water, superficially freed from the washing medium and dried under reduced pressure. 430 mg of 6-(3-fluorophenyl)imidazo[1,2-a]pyrimidine are thus obtained in the form of a light brown solid. MS: method A; [M+H]+ m/z=214; Tr=0.38 min. 1H NMR (400 MHz, d6-DMSO) delta ppm 7.28 (td, J=8.5, 2.6 Hz, 1H) 7.51-7.66 (m, 2H) 7.69 (dt, J=10.5, 2.0 Hz, 1H) 7.78 (d, J=1.5 Hz, 1H) 7.92 (d, J=1.5 Hz, 1H) 8.93 (d, J=2.7 Hz, 1H) 9.38 (d, J=2.7 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 g | Under ice cooling, water (20 mL), hydrobromic acid (content 48%, 20 mL) and bromoacetaldehyde diethyl acetal (45 mL) was added to, and stirred for 1 hour 30 minutes at room temperature. After stirring the reaction solution with ice-cold vigorously was added sodium hydrogen carbonate (31 g), the reaction solution was filtered. To the filtrate, ethanol (122 ml) and 2-amino-5-bromopyrimidine (21 g) was added and stirred for 35 min at 85 C. To the reaction solution was ice-cooled, water (244 mL) was added, was neutralized with sodium hydroxide solution of 4M, and stirred for 30 minutes. Collected by filtration resulting suspension, water (60 mL), followed by n- washed with hexane (60 mL), to give after drying the title compound (20 g) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
520 mg | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; at 100℃; for 1h;Inert atmosphere; Microwave irradiation; | The compound of Reference Example 4 (600 mg), 3,4-dichlorophenylboronic acid (635 mg), tetrakis (triphenylphosphine) palladium (175 mg) and sodium carbonate(803 mg) in tetrahydrofuran / water mixed solution (10.1 mL / 5 mL)Were stirred at 100 C. for 1 hour under a nitrogen atmosphere using a microwave reactor. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (520 mg) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EtOH (1.8 mL) was added into a mixture of 4-bromo-3-ethylpyridinehydrobromide (49 mg, 0.18 mmol), B2(OH)4 (49 mg, 0.55 mmol), XPhos-Pd-G2 (14 mg, 0.018 mmol), XPhos (17 mg, 0.037 mmol), and KOAc (54 mg, 0.55 mmol). The reaction was degassed via N2 and stirred at 80C overnight. After cooling to room temperature, solutions of N-(2-(3-bromophenyl)propan-2-yl)-2-(trifluoromethyl)benzenesulfonamide (Intermediate 1J) (100 mg, 0.24 mmol) in EtOH/THF (0.3 mL/0.3 mL) and K2C03 (1.8 M, 0.31 mL, 0.55 mmol) were added respectively into the reaction. The mixture was degassed via N2 again and stirred at 85C overnight. The reaction was cooled to room temperature, filtered through celite, washed with EtOAc (3X), and concentrated in vacuo to give a residue which was dissolved into EtOAc. This solution was washed with brine (IX), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by MS-HPLC to afford the title compound (16 mg, 20%). LCMS (method A): m/z 449.3 (M+H)+. NMR (CDC13) delta 8.54 (s, 1H), 8.46 (d, 1H), 7.83 (d, 1H), 7.79 (d, 1H), 7.59 (t, 1H), 7.47 (t, 1H), 7.31 (m, 2H), 7.21 (t, 1H), 7.11 (dt, 1H), 7.03 (d, 1H), 5.28 (s, 1H), 2.63 (q, 2H), 1.69 (s, 6H), 1.13 (t, 3H). |