Structure of 894852-01-8
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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. : | 894852-01-8 |
Formula : | C9H9BrN2O2 |
M.W : | 257.08 |
SMILES Code : | CC1(C)OC2=CC(Br)=CN=C2NC1=O |
MDL No. : | MFCD11215488 |
InChI Key : | RWDKWNQIMXGFDK-UHFFFAOYSA-N |
Pubchem ID : | 57742040 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 58.41 |
TPSA ? Topological Polar Surface Area: Calculated from |
51.22 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.13 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.42 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.38 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.11 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.12 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.63 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.65 |
Solubility | 0.581 mg/ml ; 0.00226 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.1 |
Solubility | 2.04 mg/ml ; 0.00794 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.88 |
Solubility | 0.0342 mg/ml ; 0.000133 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 |
-6.86 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 |
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) |
2.45 |
* 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 |
---|---|---|
46% | With N-ethyl-N,N-diisopropylamine;palladium diacetate; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; propiononitrile;Heating / reflux; | b) (E)-3 -(2,2-Dimethyl-3 -oxo-3 ,4-dihydro-2H-pyrido[3,2-&] [ 1 ,4]oxazin-7-yl)-iV-methyl-N- (3-methylbenzofuran-2-yhnethyl)acrylamide; A solution of N-methyl-N-(3-methylbenzofuran-2-yhnethyl)acrylamide (0.231 g,1.01 mmol) in propionitrile (4 mL) and DMF (0.8 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.28 mL, 1.64 mmol) and 7- bromo-2,2-dimethyl-4H-rhoyrido[3,2-][l,4]oxazin-3-one (0.200 g, 0.775 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.017 g, 0.078 mmol) and P(o- tol)3 (0.047 g, 0.15 mmol) were then added and the solution was deoxygenated again with Ar for 10 min. The mixture was heated to reflux for 18 h, then allowed to cool. The mixture was diluted with H2O (100 mL). The resulting solids were collected by filtration <n="132"/>and washed with Et2O (50 mL). Residual palladium was removed by silica gel plug (silica gel, 95:5, CH2Cl2/Me0H) the resulting solution concentrated to reveal a light orange solid. The solid was triturated with Et2O and dried to give the title compound (0.14 g, 46%) as a light pink solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-J) delta 11.41 (s, IH), 8.20-8.19 (m, IH), 7.97-7.93 (m, IH), 7.57-7.48 (m, 3H), 7.28-7.23 (m, 3H), 5.00-4.78 (m, 2H), 3.17-2.92 (m, 3H), 2.62 (s, 3H), 1.44 (m, 6H); MS (ESI) m/e 406 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate; In acetone; for 18h;Heating / reflux; | a) 7-Bromo-2,2-dimethyl-4H-pyrido[3,2-] [ 1 ,4]oxazin-3 -one; To a mixture of 2-amino-5-bromopyridin-3-ol (0.500 g, 2.64 mmol) and K2CO3 (1.09 g, 7.93 mmol) in acetone (11.0 niL) was added ethyl bromoisobutyrate (0.50 mL, 3.4 mmol). The solution was stirred under N2 for 18 h and then heated to reflux. After 18 h, the solution was cooled and concentrated. The light-pink, sweet-smelling solid was dissolved in CH2Cl2 (50 mL) and MeOH (5 mL). The solution was diluted with H2O (150 mL) and then washed with CH2Cl2 (3 x 75 mL). The combined organic layers were washed with brine (2 x 100 mL), dried (Na2SO4) and concentrated to yield the title compound (0.57 g, 84percent) as an off-white solid: 1H NMR (300 MHz, DMSO-J,*) delta 11.39 (s, IH), 8.03 (d, J=1.2 Hz, IH), 7.66 (d, 0.9 Hz, IH), 1.43 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | a) 7-Bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-][l,4]oxazine; To a solution of 7-bromo-2,2-dimethyl-4H-pyrido[3,2-][l,4]oxazin-3-one (0.360 g, 1.39 mmol) in TetaF (8.9 mL) at 0 0C was added BH3 (8.43 mL of a 1.0 M solution in THF, 8.43 mmol). The solution was heated to reflux. After 18 h, the solution was cooled to 0 0C and the reaction quenched with MeOH (15 mL). The mixture was concentrated and the resulting off-white solid was dissolved in MeOH (15 mL) and NaOH (10 mL of a 1 N solution). The mixture was heated at reflux to 4 h. The MeOH was removed under reduced pressure. The resulting precipitate was collected by filtration and washed with H2O (10 mL). The white solid was dried to give the title compound (0.260 g, 76%) as white needles: 1H NMR (300 MHz, DMSO-^) delta 7.62 (d, J= 2.1 Hz, IH), 7.10 (d, J = 1.5 Hz, IH), 7.03(br s, IH), 3.14 (d, J= 2.4 Hz, 2H), 1.25 (s, 6H); MS (ESI) m/e 243 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | A dichloroethane (10 mL) solution of 7-bromo-2,2-dimethyl-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one(930 rag, 3.6 mmol) and phosphorus pentachloride (1518 mg, 7.8 mmol) was irradiated in a microwave oven for 10 min at 160 0C. The solution was cooled to -78 0C and NH3 gas was condensed over it. The mixture was slowly let to warm to 21 0C, diluted with CH2Cl2, washed with dilute solution of NaOH, dried and evaporated. Crystallization from CH2Cl2/hexane afforded 602 mg (65%) of the title compound. 1HNMR (300 MHz, CDCl3, delta) 8.06 (d, J=2.0 Hz, IH), 7.24 (d, J=2.0 Hz, IH), 3.73 (s, IH), 1.53 (s, 6H). MS (ESI) m/e 256 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.68 g) in N,N-dimethylformamide (15 mL) was added dropwise a solution of 2-amino- 5- bromopyridin-3-ol (3.22 g) in N,N-dimethylformamide (25 mL) at room temperature over a period of 10 minutes, and the mixture was stirred at room temperature for 20 minutes. To the mixture was added dropwise ethyl alpha-bromoisobutyrate (3.32 g) over a period of 20 minutes, and the reaction mixture was stirred at room temperature for 1 hour and at 80 C for 2 hours. After cooling, to the reaction mixture was added cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively water and brine, dried over magnesium sulfate and concentrated in vacuo by a half volume. The precipitates were collected by filtration to give 7-bromo-2,2- dimethyl-2H-pyrido[3,2-b][l,4]oxazin- 3(4H)-one (0.90 g) was obtained as a powder. MS(APCI) m/z: 257/279 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With bromine; sodium carbonate; In dichloromethane; at 0 - 35℃; for 16h; | Step-(ii): Synthesis of 7-bromo-2.2-dimethyl-2H-pyridor3.2-biri.41oxazin-3(4H)-one (Intermediate- 18) To a stirred solution of 2,2-dimethyl-2H-pyrido[3,2-b][l ,4]oxazin-3(4H)-one (18.1) (2 g, 11.23 mmol) in DCM (20 mL) was added Na2C03 (3.57 g, 33.70 mmol) followed by bromine (0.92 mL, 17.97 mmol) at 0C and the reaction mixture was allowed to stir at 20- 35C for 16 h. Then the reaction mixture was diluted with ice water, obtained solid was filtered and washed with water to get the desired compound as a white solid (1.8 g, 86%); lU NMR (400MHz, DMSO-<) delta 11.39 (s, 1H), 8.04 (d, J=.9 Hz, 1H), 7.66 (d, /=1.4 Hz, 1H), 1.43 (s, 6H); LC-MS: 257.0 (M+l)+. |
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