Structure of 444335-16-4
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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. : | 444335-16-4 |
Formula : | C10H9BrFNO3 |
M.W : | 290.09 |
SMILES Code : | O=C1O[C@@H](CO)CN1C2=CC=C(Br)C(F)=C2 |
MDL No. : | MFCD08166353 |
InChI Key : | UGBKYDASQNOIHP-SSDOTTSWSA-N |
Pubchem ID : | 34177904 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.3 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 61.58 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.77 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.17 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.63 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.95 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.94 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.89 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.92 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.81 |
Solubility | 0.448 mg/ml ; 0.00155 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.29 |
Solubility | 1.5 mg/ml ; 0.00515 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.92 |
Solubility | 0.351 mg/ml ; 0.00121 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 |
-6.91 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) |
2.71 |
* 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 |
---|---|---|
84% | With palladium diacetate; potassium carbonate; triphenylphosphine In 1,4-dioxane at 20℃; Reflux; Inert atmosphere | Under stirring, 1,4-dioxane (400 ml), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (20.0 g, 83.3 mmol, 1.0 equiv), bis(pinacolato)diboron (25.3 g, 100 mmol, 1.2 equivalents), potassium acetate (20.4 g, 208 mmol, 2.5 eq) and bis(triphenylphosphine)palladium dichloride (1.17 g, 1.4 mmol, 0.015 eq) was added in sequence to the reaction vessel. The solution was warmed to reflux under nitrogen and TLC followed 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine for complete reaction. After the reaction is completed, it is cooled to below 20 °C. (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one (21.7 g, 75.0 mmol, 0.9 eq.), potassium carbonate (34.5 g, 250 mmol, 3.0 equiv), palladium acetate (0.14 g, 0.62 mmol, 0.0075 equiv) and triphenylphosphine (0.65 g, 2.5 mmol, 0.03 equiv) was added in sequence to the reaction vessel and nitrogen protected. Warming to reflux, TLC tracks 2-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3-dioxoboran-2-yl)pyridine until reaction is complete. After the reaction was completed, it was cooled to room temperature and stirred for 16 hours. It was filtered under reduced pressure and the cake was rinsed with water (200 ml) and methanol (200 ml). The filter cake was collected and air dried at 80° C. to give 25.8 g (compound I) as an off-white powder in a yield of 84percent. |
78% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; tricyclohexylphosphine In 1,4-dioxane; water for 4 h; Inert atmosphere; Reflux | At room temperature, 1.0 g of the compound of formula I, 1.2 g of the compound of formula II, 0.8 g of potassium carbonate, 60 mgTricyclohexylphosphine and 72 mg of tris (dibenzylideneacetone) dipalladium (Pd2 (dba) 3) catalyst were added followed by 4 mL of water and 15 mL1,4-dioxane, after a vacuum and nitrogen replacement after heating to reflux, insulation in the reflux state SUZUKI coupling anti-When the SUZUKI coupling reaction was complete (about 4 hours), the reaction was terminated, and the reaction solution was filtered while hot with diatomaceous earth so that the collectedCrystallization of the filtrate naturally cool, l. 0g obtained tidiazolamide crystals (off-white solid), HPLC purity of 99.5percent, the molar yield of 78percent. |
63.7% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; toluene for 12 h; Reflux; Inert atmosphere | In 3000 ml of the four port in the round-bottom flask, is provided with the mechanical stirring, reflux condensation tube, thermometer, under the protection of argon is added to the round-bottom flask 1500 ml toluene, 100g (5R) - 3 - (4-bromo-3-fluoro-phenyl) - 5-hydroxy methyl oxazolidine-2-one, 105g2 - (2-methyl -2H-tetrazol-5-yl) pyridine-5-boronic acid frequency ester, 28g two chlorine pairs (triphenyl phosphine) palladium, opening stirring to the solid dissolved, add prepared 140g the potassium carbonate solution dissolving a small amount of water, heating to reflux, the reaction stirred 12 hours, cooling to room temperature. Filtering, the filter cake is washed with water after washing with ethanol mixed solution of methanol used for washing. The filter cake vacuum 45 °C drying 48 hours, shall be 81.3g product. Yield: 63.7percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; bis(pinacol)diborane In dimethyl sulfoxide at 80℃; for 14 h; Inert atmosphere Stage #2: With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate In 1,4-dioxane; water at 70℃; for 3 h; Inert atmosphere |
DMSO (100 ml) was added to a 250 ml reaction flask,(5R) -3- (4-bromo-3-fluorophenyl) -5-hydroxymethyloxazolidin-2-one(10 g, 34.5 mmol), pinacolate (17.52 g, 69 mmol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (1.41 g, 1.73 mmol)And potassium acetate (13.5 g, 138 mmol), and the temperature was raised to 80 ° C under a nitrogen atmosphere,For 14 hours. The heating was stopped, the solution was cooled to room temperature, and extracted with water / ethyl acetate 3 times. The organic layers were combined and the organic layer was washed with saturated waterBrine, dried over anhydrous sodium sulfate and concentrated by suction filtration. The concentrated product of the above step was added to a 250 ml reaction flask,1,4-dioxane (100 ml) was added,5-bromo-2- (2-methyl-2H-tetrazol-5-yl) pyridine(8.28 g, 34.5 mmol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (0.56 g, 0.69 mmol)And cesium carbonate aqueous solution (50 ml, containing 33.72 g of cesium carbonate, 103.5 mmol),Under nitrogen protection,The temperature was raised to 70 ° C,The reaction was carried out for 3 hours,Dichloromethane was added for extraction.The separated organic phase was washed with saturated brine,Anhydrous sodium sulfate dehydration,filter,Concentrated in vacuo and purified by column chromatography,10.6 g of a solid was obtained,The yield was 83.0percentHPLC purity was 98.34percent (area normalization method). |
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