Structure of 914347-01-6
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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. : | 914347-01-6 |
Formula : | C11H14BrN3O2 |
M.W : | 300.15 |
SMILES Code : | BrC1=CN=C(N=C1)N2CCC(CC2)C(=O)OC |
MDL No. : | MFCD08275691 |
InChI Key : | CCUNQFMNCAFIEV-UHFFFAOYSA-N |
Pubchem ID : | 45036909 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 17 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.55 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 70.08 |
TPSA ? Topological Polar Surface Area: Calculated from |
55.32 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.64 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.7 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.25 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.39 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.59 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.72 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.84 |
Solubility | 0.439 mg/ml ; 0.00146 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.48 |
Solubility | 1.0 mg/ml ; 0.00333 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.06 |
Solubility | 0.259 mg/ml ; 0.000863 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) |
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 |
-6.92 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) |
2.46 |
* 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 |
---|---|---|
A solution of methyl-1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate (0.32 g, 1.05 mmol), bispinacolatodiboron (0.32 g, 1.25 mmol) and KOAc (0.16 g, 1.60 mmol) in 1 ,4-dioxane (5.0 mL) was degassed by flushing with nitrogen for 15 min. Tricyclohexylphosphine (0.036 g, 0.13 mmol) and tris(dibenzyledineacetone) dipalladium (0) (0.05 g, 0.053 mmol) was then added to the reaction mixture, which was again degassed by nitrogen for 15 min. The resulting reaction mixture was heated to 1000C for 4 h. After the completion of the reaction (TLC monitoring), the reaction mixture was filtered through celite bed and the filtrate was concentrated to get the crude residue that was carried forward to the next step without further purification. MS: 348.21 (M+H)+. | ||
900 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 12h;Inert atmosphere; | A mixture of methyl l-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate (1.0 g, 3.33 mmol, 1 eq), bis(pinacolato)diboron (1.69 g, 6.66 mmol, 2 eq), potassium acetate (0.98 g, 10 mmol, 3 eq) and Pd(dppf)C12 (0.24 g, 0.330 mmol, 0.100 eq) in 1,4-dioxane (20 mL) was purged with N2 for 3 times, and the mixture was stirred at 90 C for 12 hours under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Purification by prep-HPLC gave the title compound (900 mg, 2.59 mmol, 77.8% yield) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With tris-(dibenzylideneacetone)dipalladium(0); XPhos; In tetrahydrofuran; at 75℃; for 16h;Inert atmosphere; | Step 2: <strong>[914347-01-6]methyl 1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate</strong> Ex.9a (1 .00 g, 3.33 mmol), freshly prepared tert-butyl 2-(bromozincio)acetate Ex.5a (1 1.7 ml, 9.99 mmol) and dry THF (10 mL) were charged to a flask and the mixture was purged with nitrogen for 5 min. Then Pd2(dba)3 (302 mg, 0.33 mmol) and XPhos (319 mg, 0.67 mmol) were added and the solution was stirred at 75C for Ex.9b 16h. The reaction mixture was concentrated and the residue was diluted with EtOAc and water. After phase separation, the organic layer was washed with brine, dried over MgSO4, filtered and the solution was concentrated to dryness. The crude was purified by flash column chromatography on silica gel eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [50:50]. The desired fractions were combined and concentrate to obtain methyl 1-{5-[2-(tert-butoxy)-2-oxoethyl]pyrimidin-2-yl}piperidine-4-carboxylate Ex.9b (930 mg, 28%) as pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h; | Step 1 : DIPEA (4 mL, 23.20 mmol) was added to 5-bromo-2-chloropyrimidine (3.0 g, 15.50 mmol) in acetonitrile (80 mL). Then, methyl isonipecotate (3.321 g, 23.20 mmol) was added to the solution. The reaction mixture was stirred at rt for Ex.9a 16h. The solvent was concentrated to dryness. Water and EtOAc were added to quench the reaction. The organic layer was separated and concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [0:100]. The product fractions were combined and concentrated to dryness to afford methyl 1-(5-bromopyrimidin-2-yl)piperidine-4-carboxylate Ex.9a (1 .84 mg, 41 %) as white solid. |
To a solution of methyl 4-piperidinecarboxylate (1.0 g, 6.98 mmol, 1 eq) in ethanol (10 mL) was added DIPEA (4.5 g, 34.92 mmol, 5 eq) the mixture was stirred at room temperature for 15 min, then 5-bromo-2-chloropyrimidine (1.35 g, 6.98 mmol, 1 eq) was added and the mixture was stirred at 70 C for 1 hour. The mixture was concentrated to get methyl l-(5-bromopyrimidin-2- yl)piperidine-4-carboxylate (2 g, 6.66 mmol, 95.41% yield) as a yellow solid used directly in the next step. MS m/e: 302 ([M+H+]+). |
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