Structure of 38267-96-8
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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. : | 38267-96-8 |
Formula : | C8H4BrClN2 |
M.W : | 243.49 |
SMILES Code : | BrC2=CC=C1N=CN=C(C1=C2)Cl |
MDL No. : | MFCD01862191 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 10 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 52.25 |
TPSA ? Topological Polar Surface Area: Calculated from |
25.78 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.29 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.19 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.05 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.58 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.25 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.87 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.98 |
Solubility | 0.0257 mg/ml ; 0.000106 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.4 |
Solubility | 0.0963 mg/ml ; 0.000396 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.8 |
Solubility | 0.00384 mg/ml ; 0.0000158 mol/l |
Class? Solubility class: Log S scale |
Moderately 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 |
-5.52 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<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.48 |
* 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 |
---|---|---|
55% | To a solution of trans-4-(morpholin-4-yl)cyclohexan-l-ol, compound 4.1 (364 mg, 1.96 mmol, 1.20 equiv) in distilled THF (10 mL) was added NaHDMS (2.45 mL, 3.00 equiv, 2 M in THF) dropwise via syringe at 0 C under nitrogen. Subsequently a solution of 6-bromo-4- chloroquinazoline (400 mg, 1.64 mmol, 1.00 equiv) in THF (5 mL) was added slowly at 0C and the reaction was stirred for 1 hour at this temperature. The reaction was then quenched with saturated aqueous NH4C1, extracted with 3 x 60 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Crude was purified via flash column chromatography to furnish 357 mg (55%) of 4- ((lr,4r)-4-((6-bromoquinazolin-4-yl)oxy)cyclohexyl)morpholine, 1-4, as a white solid. LCMS (ES, m/z): 393 [M+H]+; 1H NMR (300 MHz, CD3OD) delta 8.75 (s, 1H), 8.30 (d, 1H), 8.02 (dd, 1H), 7.80 (d, 1H), 5.40-5.30 (m, 1H), 3.73 (t, 4H), 2.64 (t, 4H), 2.42-2.35 (m, 3H), 2.12 (d, 2H), 1.78- 1.60 (m, 2H), 1.58-1.49 (m, 2H). | |
With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 18h; | Trans-4-morpholinocyclohexanol (0.134 g, 0.723 mmol) was dissolved in THF (10.95 ml) and added to a slurry of 6-bromo-4-chloroquinazoline (0.16 g, 0.657 mmol) in N,N- dimethylformamide (0.349 mL). The reaction was cooled to 0 C and sodium hydride (0.053 g, 1.31 mmol) was added to the reaction mixture at 0 C and the reaction was allowed to stir at rt for 18 h. The reaction was quenched with saturated aqeuous sodium bicarbonate and the aqueous layer was extracted with 25% IPA/CHCI3 (2x), dried over anhydrous sodium sulfate, filtered and purified by mass triggered reverse phase HPLC (ACN/water with 0.1% NH4OH modifier) to afford the title compound. MS: 392/394 (M + 1). 1H NMR (600 MHz, dmso) delta 8.78 (s, 1H), 8.21 (d, J= 2.2, 1H), 8.04 (dd, J= 2.3, 8.9, 1H), 7.82 (d, J= 8.9, 1H), 5.26 - 5.17 (m, 1H), 3.57 - 3.51 (m, 4H), 2.46 - 2.42 (m, 4H), 2.30 - 2.22 (m, 1H), 2.21 - 2.13 (m, 2H), 1.92 - 1.83 (m, 2H), 1.62 - 1.50 (m, 2H), 1.46 - 1.33 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | In isopropyl alcohol; at 80℃;Inert atmosphere; | To a solution consisting of 6-bromo-4-chloroquinazoline (0.448 g, 1.84 mmol) in 2- propanol (10 mL) was added <strong>[102877-78-1]4-(pyridine-4-yloxy)aniline</strong> (0.360 g, 1.93 mmol). The reaction mixture was heated (80 C) and stirred overnight under a flow of N2. The reaction mixture was cooled to room temperature and then the reaction mixture was filtered over a fritted funnel. The filtered solid was rinsed with excess 2-propanol and dried under high vacuum to afford 6-bromo-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine (3F) as an off-white solid (313 mg, 43% yield,97% purity). MS (ESI + m/z 394.0, ESI - m/z 392.0). Next a solution consisting of 6-bromo-N- (4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine (0.306 g, 0.77 mmol) in anhydrous ethanol (10 mL) was placed in a 20 mL microwave reaction vial containing a stir bar. Next, 3- aminopyridine-5- boronic acid pinacol ester (6, 0.176 g, 0.80 mmol) was added followed bySiliCatDPP-Pd (5 mol %, 0.26mmol/g loading, 0.150 g) and 10% aqueous potassium carbonate solution (2 equivalents, 1.15 mL, 1.6 mmol). The reaction mixture was placed under N2 atmosphere, capped, and then heated at 125 C for one horn in a Biotage Emrys Optimizer microwave. The reaction mixture was allowed to cool to room temperature and then filtered over a fritted funnel to collect SiliCat DPP-Pd. The filtered solid was rinsed with excess ethanoland the filtrate was concentrated under reduced pressure to afford the crude product.Purification of the crude product by Biotage Isolera flash chromatography using a gradient of 4-100% ethyl acetate in heptane, followed by 0-10% methanol in dichloromethane afforded 7F 6-(5-aminopyridin-3-yl)-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4-amine (50 mg, 15% yield,92% purity) as an off-white solid. MS (ESI + m/z 407.1, ESI m/z 405.1). To a roomtemperature solution of 6-(5 -aminopyridin-3 -yl)-N-(4-(pyridin-4-yloxy)phenyl)quinazolin-4- amine (50 mg, 0.12 mmol) in pyridine (3 mL) was added methanesulfonyl chloride (56 mg, 0.5 mmol). The reaction mixture turned dark red which persisted and was stirred for 15 minutes. The reaction mixture was poured into a saturated solution of sodium bicarbonate and the organic material was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The cmde solid was dissolved in methanol and ?dry loaded? on to a silica column eluted with a gradient of 1/9 to 3/7methanol/ethyl acetate to give N-(5-(4-((4-(pyridin-4-yloxy)phenyl)amino)quinazolin-6- yl)pyridin-3-yl)methanesulfonamide (5F, MOL-166, 20 mg, 33% yield, 96% purity) as a solid. ?H NMR (400MHz, DMSO-d6) oe 10.07 (s, 1H), 8.91 (s, 1H), 8.79 (d, J=1.9 Hz, 1H), 8.62 (s, 1H), 8.4-8.5 (m, 3H), 8.15 (dd,J=1.7, 8.6 Hz, 1H), 7.85-8.0(m, 4H), 7.24 (d,J8.9Hz, 2H),6.94 (d, J=4.7 Hz, 2H), 3.08 (s, 3H); MS: (ESI + m/z 485.1, ESI- m/z 483.0). |
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