Structure of 33696-00-3
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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. : | 33696-00-3 |
Formula : | C7H6BrNO3 |
M.W : | 232.03 |
SMILES Code : | COC1=CC=C(Br)C=C1[N+]([O-])=O |
MDL No. : | MFCD00055529 |
InChI Key : | ORBHQHXVVMZIDP-UHFFFAOYSA-N |
Pubchem ID : | 118533 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 49.46 |
TPSA ? Topological Polar Surface Area: Calculated from |
55.05 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.74 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.68 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.37 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.37 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.35 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.7 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.2 |
Solubility | 0.145 mg/ml ; 0.000624 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.49 |
Solubility | 0.0754 mg/ml ; 0.000325 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.77 |
Solubility | 0.399 mg/ml ; 0.00172 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) |
Yes |
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 |
-5.81 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 |
2.0 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) |
2.15 |
* 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 |
---|---|---|
100% | With ammonium chloride; zinc; In ethanol; at 20℃; for 2h; | [00169] Intermediate 1 1 A. 4-Bromo-l-methoxy-2-nitrobenzene: The mixture of 4- bromo- 1 -methoxy-2 -nitrobenzene (2.00 g, 8.62 mmol), zinc (5.64 g, 86.0 mmol), and ammonium chloride (4.61 g, 86.0 mmol) in ethanol (65 mL) was stirred together at room temperature for 2 h. The reaction was then diluted with EtOAc, filtered through CELITE, and evaporated to give Intermediate 11A (1.74 g, 100%) as a grayish-white solid. LCMS (ESI) m/z 202, 204 (M+H, M+2+H)+, RT = 0.70 min (Method J). |
60% | A mixture of 11d (515 mg, 2.2 mmol) and SnCl2·2H2O (2.1 g, 10 mmol) in absolute ethanol (30 mL) was heated at 70 C under argon for 2 h. The reaction mixture was allowed to cool to room temperature and then poured into ice. The pH was adjusted to 7-8 by addition of 5% aqueous NaHCO3, and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (cyclohexane/EtOAc/Et3N: 85/15/0.5) to give aniline 11e51 as a pink powder (260 mg, 60%). | |
With iron; acetic acid; In acetonitrile; at 0℃; | A solution of 1 (1 eq), acetonitrile, and glacial acetic acid (15 eq) was stirred in an ice bath. Iron powder (7 eq) was added slowly portion-wise. The reaction was left to stir overnight. The reaction solution was filtered, diluted with ethyl acetate, and neutralized with 3N sodium hydroxide. The organic phase was separated and the aqueous phase was washed once more with ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, and the solvent was removed by evaporation under reduced pressure to afford the product as a solid 2. MS: MH+=202 |
With triethylamine;aluminum nickel; In ethanol; | 5-Bromo-2-methoxy-aniline A solution of 4-bromo-2-nitro-anisole (7.7 g, 33.1 mmol), triethylamine (4.6 ml, 33.1 mmol) and Raney Nickel catalyst (4 g) was vigorously stirred in ethanol (300 ml) under an atmosphere of hydrogen for 1 h at 20 C. After this time the theoretical amount of hydrogen had been absorbed (2.5 1), so the catalyst was filtered off and the solvent evaporated to afford the title compound as a light yellow solid (7 g, 104% yield), MS: m/e=201 (M+). intermediates for the preparation of benzylic amines | |
With tin(ll) chloride; In ethanol; at 20℃; | Example 159 2,6-Difluoro-N-(2-(methyloxy)-5-{3-[2-(1,2,3,4-tetrahydro-7-isoquinolinylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)benzamide Step A: N-[5-Bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide; To a solution of 4-bromo-2-nitroanisole (2.0 g, 0.009 mol) in absolute ethanol (100 mL) was added SnCl2.2H2O (11.68 g, 0.051 mol) and the resulting mixture was allowed to stir overnight at ambient temperature. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (100 mL), washed with 1M NaOH (100 mL) and filtered through a celite pad. The organic layer was removed, concentrated by rotary evaporation, and dried under high vacuum. The resulting residue was then dissolved in DCM (150 mL) followed by the addition of triethylamine (5.19 g, 0.051 mol) and trifluoroacetic anhydride (4.52 g, 22 mmol). After overnight stirring, the reaction was washed with 1M HCl (50 mL), organic layer concentrated and purified by column chromatography (1-10% gradient of EtOAc in hexanes) to yield the title compound (1.53 g, 60%) as a white solid. ESIMS (M-H)-=297. | |
With tin(ll) chloride; In ethanol; at 20℃; | Step A: N-[5-Bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide To a solution of 4-bromo-2-nitroanisole (2.0 g, 0.009 mol) in absolute EtOH (100 mL) was added SnCl2.2H2O (11.68 g, 0.051 mol) and the resulting mixture was allowed to stir overnight at rt. The solvent was removed under reduced pressure, residue suspended in EtOAc (100 mL), washed with 1M NaOH (100 mL), and filtered through a celite pad. The organic layer was removed, concentrated by rotary evaporation, and dried under high vacuum. The resulting residue was then dissolved in DCM (150 mL) followed by the addition of TEA (5.19 g, 0.051 mol) and TFAA (4.52 g, 0.022 mol). After overnight stirring, the reaction was washed with 1M HCl (50 mL), organic layer concentrated and purified by column chromatography (1-10% gradient of EtOAc in hexanes) to yield the title compound (1.53 g, 60%) as a white solid. ES-LC/MS m/z=297 [M-H]+. | |
With hydrogenchloride; tin; In ethanol; water; at 20℃; for 5h; | Step 2; Reduction of Nitro Group: Synthesis of 5-bromo-2-methoxyaniline 28.3 To a stirred solution of 28.2 (0.95 g, 4.09 mmol) in ethanol (30 mL) was added concentrated HCl (15 mL) and tin powder (0.95 g, 8 mmol). The reaction was stirred for 5 h. The solvent was then removed in vacuo and the acid was neutralised by the slow addition of 2.5M NaOH solution (13 mL) at 0 C. The aqueous mixture was then extracted with diethyl ether (3*50 mL). The organic fractions were dried over MgSO4, filtered and concentrated in vacuo to yield 28.3 as a brown solid (0.86 g, 100%). The product was not purified further. 1H NMR (CDCl3, 400 MHz) deltaH ppm: 3.85 (3H, s, OMe), 6.65 (1H, dd, J1=2 Hz, J2=10.12 Hz, ArH), 6.83 (1H, dd, J1=2.44 Hz, J2=8.2 Hz, ArH), 6.85 (1H, s, ArH) 13C NMR (CDCl3, 400 MHz) deltac ppm: 55.18 (ArC), 111.14 (ArCH), 112.75 (ArC), 116.87 (ArCH), 117.72 (ArC), 120.23 (ArCH), 137.15 (ArC), 145.90 (ArC); vmax (DCM)/cm-1: 3460.96, 3370.98, 1611.91, 1573.81; HRMS: calculated 201.9862, found 201.9855, molecular formula (C7H9BrNO).; Melting Point: 110 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In n-heptane; water; acetic acid; ethyl acetate; | a) 5-bromo-2-methoxyaniline. A mixture of 4-bromo-1-methoxy-2-nitrobenzene (3.0 g, 12.9 mmol) and glacial acetic acid (25 ml) was heated at 100 C. under an atmosphere of nitrogen. Iron powder (2.2 g, 38.8 mmol) was added and the mixture was stirred for one hour at a temperature of 100 C. The mixture was cooled to ambient temperature then water (100 ml) was added and the mixture was extracted with ethyl acetate (3*25 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3*25 ml) and then brine. The organic solution was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give a residue. Purification of the material by flash chromatography on silica gel using heptane/ethyl acetate (6:4) as an eluent yielded 5-bromo-2-methoxyaniline (2.0 g): 1H NMR (DMSO-d6, 400 MHz) delta 6.76 (s, 1H), 6.71 (d, 1H), 6.61 (d, 1H), 4.99 (bs, 2H), 3.74 (s, 3H); (TLC (heptane/ethyl acetate 1:1) Rf 0.5; RP-HPLC (Hypersil HyPurity Elite C18, 5 mum, 200A, 250*4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=13.33 min.; MS: MH+443. | |
In n-heptane; water; acetic acid; ethyl acetate; | a) 5-bromo-2-methoxyaniline (1) A mixture of 4-bromo-1-methoxy-2-nitrobenzene (3.0 g, 12.9 mmol) and glacial acetic acid (25 ml) was heated at 100 C. under an atmosphere of nitrogen. Iron powder (2.2 g, 38.8 mmol) was added and the mixture was stirred for one hour at a temperature of 100 C. The mixture was cooled to ambient temperature then water (100 ml) was added and the mixture was extracted with ethyl acetate (3*25 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3*25 ml) and then brine. The organic solution was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give a residue. Purification of the material by flash chromatography on silica gel using heptane/ethyl acetate (6:4) as an eluent yielded 5-bromo-2-methoxyaniline (2.0 g): 1H NMR (DMSO-d6, 400 MHz) 6.76 (s, 1H), 6.71 (d, 1H), 6.61 (d, 1H), 4.99 (bs, 2H), 3.74 (s, 3H); (TLC (heptane/ethyl acetate 1:1) Rf 0.5; RP-HPLC (Hypersil HyPurity Elite C18, 5 m, 200A, 250*4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=13.33 min.; MS: MH+443. | |
With hydrogenchloride; sodium hydrogencarbonate; In ethanol; | REFERENCE EXAMPLE 50 5-bromo-2-methoxyaniline A stirred mixture of 4-bromo-2-nitroanisole (98.56 g) and iron powder (113.7 g) in ethanol (1.51) was heated to reflux and treated dropwise with hydrochloric acid (350 ml, 0.5N) over 1 hour. After refluxing for a further 3 hours the reaction mixture was cooled to room temperature then filtered through hyflosupercel. The filtrate was evaporated and the residue was treated with saturated sodium bicarbonate solution (21) then filtered. The solid was washed with water then recrystallized from cyclohexane to give the title compound (61.98 g) as a pale brown solid, m.p. 93-93 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | In ethanol; ethyl acetate; | a. 5-Bromo-2-methoxyaniline To a solution of 4-bromo-2-nitroanisole (500 mg, 2.15 mmol) in anhydrous ethanol (15 ml) was added slowly anhydrous tin chloride (1.6 g, 8.62 mmol). The mixture was refluxed for 1 h, then rotary evaporated to leave a brown oil which was neutralized with aqueous 2N NaOH (5 ml). The resulting solid was filtered and washed with ethyl acetate. The aqueous and ethyl acetate solutions were combined and washed with water. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified column chromatography to give a white solid (46 mg, 11%). 1H NMR (CDCl3): 6.79 (dd, J=2.1, 9.0 Hz, 1H), 6.80 (d, J=1.8 Hz, 1H), 6.61 (d, J=9.3 Hz, 1H), 3.84 (s, 2H), 3.80 (s, 3H). |
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