Structure of 179811-63-3
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CAS No. : | 179811-63-3 |
Formula : | C8H10ClNO |
M.W : | 171.62 |
SMILES Code : | ClC1=CC(C(N)CO)=CC=C1 |
MDL No. : | MFCD12827190 |
Boiling Point : | No data available |
InChI Key : | HLXHAXFWWGYXQW-UHFFFAOYSA-N |
Pubchem ID : | 10953980 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 45.09 |
TPSA ? Topological Polar Surface Area: Calculated from |
46.25 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.65 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.76 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.01 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.53 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.61 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.31 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.65 |
Solubility | 3.8 mg/ml ; 0.0222 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.31 |
Solubility | 8.38 mg/ml ; 0.0489 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.53 |
Solubility | 0.51 mg/ml ; 0.00297 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 |
-6.81 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 |
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) |
1.66 |
* 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% | a) (RS)-2-Amino-2-(3-chloro-phenyl)-ethanolTo a stirred solution of lithium borohydride in THF (10.5 ml, 2 M solution) under an argon atmosphere was added dropwise chlorotrimethylsilane (5.34 ml). The resulting suspension was cooled to 0 0C and amino-(3-chlorophenyl)-acetic acid (2.0 g) was added portionwise. The ice bath was removed and stirring at r.t. was then continued for 16 h. The mixture was quenched by dropwise addition of methanol (15 ml) and then concentrated in vacuo. The residue was suspended in ethyl acetate and washed with 2 N aq NaOH. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated in vacuo to afford (RS)-2-amino-2-(3-chloro-phenyl)-ethanol (1.84 g, quant.) as a yellow viscous oil. MS (ISP): 174.2 ( [{37C1}M+H]+), 172.2 ([{35C1}M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | A solution of 4-(2-methyl-5-(2-methylpyridin-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrrolo[2,3-b]pyridin-3-yl)-lH-pyrrole-2-carboxylic acid (XXVII) (105 mg, 0.227 mmol), 2- amino-2-(3-chlorophenyl)ethanol (XXVIII) (47 mg, 0.272 mmol), HATU (129 mg, 0.340 mmol), and DIEA (88 mg, 0.681 mol) in DMF (5 mL) was stirred at the room temperature overnight. The mixture was diluted with EtOAc (50 mL), washed with H20 (15 mL x 2) and brine (20 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by prep- TLC (DCM/MeOH=20/l) to give the title compound (S)-N-(l-(3-chlorophenyl)-2- hydroxyethyl)-4-(2-methyl-5-(2-methylpyridin-4-yl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- pyrrolo[2,3-b]pyridin-3-yl)-lH-pyrrole-2-carboxamide (XXIX) as a yellow solid (45 mg, yield: 32%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With trimethylaluminum; In toluene; at 100℃; for 1.5h;Microwave irradiation; | To a solution of methyl-1-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate (0.1 g, 0.315 mmol) in toluene (10 mL) was added <strong>[179811-63-3]2-amino-2-(3-chlorophenyl)ethanol</strong> (0.10 g, 0.63 mmol) and trimethylaluminum (2M solution in toluene; 0.78 mL, 1.57 mmol). The resulting mixture was stirred in CEM microwave at 100 C. for 1.5 h. The mixture was cooled, and then quenched with water (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in DCM as eluent to afford N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide as an off-white solid (0.12 g, 86%). 1HNMR (400 MHz, DMSO-d6): delta 8.41 (d, J=7.8 Hz, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.09 (s, 1H), 7.42 (s, 1H), 7.38 (d, J=9.6 Hz, 1H), 7.32-7.27 (m, 3H), 5.05-4.98 (m, 2H), 3.85-3.77 (m, 3H), 3.71 (t, J=4 Hz, 2H), 3.38 (t, J=8 Hz, 2H), 2.16 (s, 3H), 1.80 (d, J=11.2 Hz, 2H), 1.51-1.44 (m, 2H). LC-MS calcd exact mass 456.17, found m/z 457.5 [M+H]+; HPLC purity 99.53%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | To a solution of 1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid (0.04 g, 0.178 mmol) in DCM (6 mL) and DMF (0.2 mL) was added triethylamine (0.053 mL, 0.534 mmol), EDC (0.068 g, 0.356 mmol) and HOBt (0.007 g, 0.053 mmol). The reaction mixture was stirred at RT for 15 min and then <strong>[179811-63-3]2-amino-2-(3-chlorophenyl)ethanol</strong> (0.036 g, 0.213 mmol) was added. The mixture was stirred at RT for 12 h. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in DCM as eluent to afford N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxamide as a colorless solid (0.015 g, 24%). 1HNMR (400 MHz, DMSO-d6): delta 9.17 (s, 1H), 8.45 (s, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.24 (d, J=7.6 Hz, 2H), 7.64 (d, J=7.6 Hz, 2H), 7.42 (s, 1H), 7.32-7.28 (m, 2H), 7.27-7.25 (m, 3H), 7.15 (d, J=5.6 Hz, 1H), 7.02 (s, 1H), 6.92 (t, J=7.2 Hz, 1H), 5.04-4.99 (m, 2H), 3.73 (t, J=5.6 Hz, 2H). LC-MS calcd exact mass 433.13, found m/z 434.2 [M+H]+. HPLC purity 99.52%; mp 130.0 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; | To a stirred solution of 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid (0.035 g, 0.11 mmol) in NMP (1.5 mL) was added EDC (0.065 g, 0.33 mmol), HO t (0.005 g, 0.033 mmol), triethylamine (0.02 mL, 0.22 mmol), and <strong>[179811-63-3]2-amino-2-(3-chlorophenyl)ethanol</strong> (0.022 g, 0.13 mmol). The reaction mixture was stirred at RT overnight. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by preparative TLC using methanol in DCM as eluent to afford 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide as an off-white solid (19 mg, 36% yield). 1HNMR (400 MHz, DMSO-d6): delta 9.44 (s, 1H), 8.41 (s, 1H), 8.38 (d, J=4.0 Hz, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.44 (s, 1H), 7.33-7.30 (m, 2H), 7.29-7.27 (m, 3H), 6.93 (s, 2H), 5.02-5.01 (m, 2H), 3.72 (t, J=5.6 Hz, 2H). LC-MS calcd exact mass 467.09, found m/z 468.1 [M+H]+; HPLC purity 99.88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | To a stirred solution of (S)-1-(2-((1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid (0.07 g, 0.25 mmol) in NMP (3 mL), was added triethylamine (0.076 g, 0.76 mmol), followed by EDC (0.097 g, 0.51 mmol) and HOBt (0.01 g, 0.075 mmol). The mixture was stirred for 20 min at RT, and then <strong>[179811-63-3]2-amino-2-(3-chlorophenyl)ethanol</strong> (0.052 g, 0.30 mmol) was added, and then the reaction mixture was stirred for 12 h at RT. The reaction mixture was quenched with water (25 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure and the residue was purified by gradient column chromatography, eluting with 3% methanol in DCM, to give N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide, as an off-white solid, (15 mg, 14%). 1HNMR (400 MHz, DMSO-d6): delta 8.38 (t, J=7.2 Hz, 2H), 8.18 (s, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.42 (s, 1H), 7.32-7.26 (m, 3H), 6.84 (d, J=5.6 Hz, 1H), 6.74 (s, 1H), 6.36 (d, J=7.6 Hz, 1H), 5.02-4.99 (m, 2H), 4.61 (d, J=5.6 Hz, 1H), 3.81 (s, 1H), 3.71 (t, J=5.6 Hz, 1H), 3.47-3.44 (m, 1H), 3.34-3.27 (m, 1H), 1.67-1.65 (m, 1H), 1.63-1.61 (m, 1H), 1.07 (t, J=7.2 Hz, 1H), 0.87 (t, J=6.8 Hz, 3H). LC-MS calcd exact mass 429.16, found m/z 430.2 [M+H]+; HPLC Purity 99.46%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With trimethylaluminum; In toluene; at 100℃; for 0.75h;Inert atmosphere; Microwave irradiation; | To a solution of methyl 1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylate (90 mg, 0.26 mmol) in toluene (3 mL) was added <strong>[179811-63-3]2-amino-2-(3-chlorophenyl)ethanol</strong> (91 mg, 5.3 mmol) and trimethylaluminum in toluene (2M, 0.26 mL, 2 eq) under a nitrogen atmosphere. The mixture was stirred for 45 min at 100 C. in the CEM microwave. The reaction mixture was poured into ice water and extracted with ethyl acetate. Combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure to give a residue, which was purified by gradient column chromatography using methanol in DCM as eluent to afford N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide as an off-white solid (20 mg, 16%). 1HNMR (400 MHz, DMSO-d6): delta 8.88 (s, 1H), 8.42-8.37 (m, 2H), 8.20-8.16 (m, 2H), 7.51 (s, 1H), 7.42 (s, 1H), 7.32-7.28 (m, 4H), 7.21 (d, J=8.4 Hz, 1H), 7.05 (d, J=4.8 Hz, 1H), 6.88 (s, 1H), 6.8 (d, J=8.4 Hz, 1H), 5.02 (br s, 2H), 4.47 (t, J=8.8 Hz, 2H), 3.72 (s, 2H), 3.15 (t, J=8.4 Hz, 2H). LC-MS calcd exact mass 475.14, found m/z 476.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine; at 85℃; | General procedure: To a mixture of 20 (2.60 mmol) and corresponding amine (2.60 mmol) in MeOH (10 mL) was added Et3N (540.00 mul, 3.90 mmol). The mixture was refluxed for 6h. After completion, the mixture was cooled to 0 oC, and stirred for 30 min, the precipitate was filtered to obtain corresponding product. 2.16.1. 2-(1-(3-chlorophenyl)-2-hydroxyethyl)-6-(2-(methylsulfonyl) pyrimidin-4-yl) isoi-ndolin-1-one (21a) Yield 65%. m.p. 166~167 oC. 1H NMR (300 MHz, CDCl3) delta (ppm): 9.01 (d, J = 5.30 Hz, 1H, ArH), 8.49 (s, 1H, ArH), 8.44 (dd, J = 8.00, 1.50 Hz, 1H, ArH), 8.01 (d, J = 5.30 Hz, 1H, ArH), 7.58 (d, J = 8.00 Hz, 1H, ArH), 7.50-7.31 (m, 3H, ArH), 7.28-7.26 (m, 1H, ArH), 5.40 (dd, J = 7.90, 4.40 Hz, 1H, CHCH2OH), 4.63 (d, J = 17.80 Hz, 1H, CH2), 4.43 - 4.32 (m, 2H, HOCH2CH), 4.28 (dd, J = 11.90, 4.40 Hz, 1H, CH2), 3.49 (s, 3H, SO2CH3 ). |
64.9% | With triethylamine; In methanol; for 6h;Reflux; | Compound VI (9.63 g, 25.0 mmol), <strong>[179811-63-3]2-amino-2-(3-chlorophenyl)ethyl-1-ol</strong> (VII-2) (4.29 g, 25.0 mmol) and triethylamine (10.4 mL, 74.9mmol) dissolved in methanol (100mL), reflux reaction for about 6h, until TLC (dichloromethane: methanol = 20:1) detection of the reaction of the raw materials was completed, cooled to below 10 C in an ice bath, stirred for 30min, solid precipitation, suction filtration ,A white solid 7.2 g was obtained, yield: 64.9% |