Structure of 480452-05-9
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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. : | 480452-05-9 |
Formula : | C9H20N2O2 |
M.W : | 188.27 |
SMILES Code : | O=C(OC(C)(C)C)NCC(C)CN |
MDL No. : | MFCD06804536 |
InChI Key : | ORDMEFMUSKDHOL-UHFFFAOYSA-N |
Pubchem ID : | 44629801 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.89 |
Num. rotatable bonds | 6 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 52.6 |
TPSA ? Topological Polar Surface Area: Calculated from |
64.35 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.3 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.78 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.11 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.95 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.38 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.1 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.1 |
Solubility | 14.9 mg/ml ; 0.0789 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.71 |
Solubility | 3.65 mg/ml ; 0.0194 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.72 |
Solubility | 3.59 mg/ml ; 0.0191 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 |
-6.89 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) |
2.63 |
* 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 |
---|---|---|
82% | With triethylamine; HATU; In tetrahydrofuran; at 25℃; for 12h; | PP-2-2A FC-1 -4A To a stirred solution of phenylpropiolic acid (156 mg, 1 .1 mmol) in THF (2 mL) was added N-(tert-butoxycarbonyl)-2-methyl-1 , 3-diaminopropane (200 mg, 1.1 mmol), HATU (613 mg, 1 .6 mmol) and TEA (0.3 mL). The reaction mixture was stirred at 25 C for 12 hrs. The analysis of LCMS showed completion of reaction and formation of desired product, it was quenched by addition of H20 (20 mL), extracted with EtOAc (2 x 50 mL), the organic layer was washed with H20, brine dried over Na2S04 and concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH = 10:1 ) to afford the product as a white solid (0.28 g, yield: 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 10 - 35℃; for 16h; | (Step 1) A solution of <strong>[480452-05-9]tert-butyl (3-amino-2-methylpropyl)carbamate</strong> (200 mg, 1.06 mmol), 4-cyanobenzoic acid (156 mg, 1.06 mmol), HATU (525 mg,1.38 mmol) and TEA (0.444 mL, 3.19 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 50% ethyl acetate/hexane) to give tert-butyl (3-(4-cyanobenzamido)-2-methylpropyl)carbamate (311 mg, 0.980 mmol, 92%) as a white powder. 1H-NMR(300MHz,CDCl3) :delta0.83(3H,d,J=6.8Hz), 1.37(9H,s), 1.74-1.93(1H,m), 2.76-3.00(2H,m), 3.05-3.25(2H,m), 6.82(1H,t,J=5.7Hz), 7.93-8.02(4H,m), 8.65(1H,t,J=5.5Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.7% | With triethylamine; In tetrahydrofuran; at 10 - 35℃; for 16h; | (Step 1) To a solution of <strong>[480452-05-9]tert-butyl (3-amino-2-methylpropyl)carbamate</strong> (200 mg, 1.06 mmol) and TEA (0.444 mL, 3.19 mmol) in THF (5 mL) was added 4-cyanobenzene-1-sulfonyl chloride (214 mg, 1.06 mmol), and the mixture was stirred at room temperature for 16 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give tert-butyl (3-(4-cyanophenylsulfonamido)-2-methylpropyl)carbamate (273 mg, 0.772 mmol, 72.7%) as a white powder. 1H-NMR (300MHz, DMSO-d6) :delta0.77(3H,d,J=6.8Hz), 1.34(9H,s), 1.53-1.71(1H,m), 2.52-2.57(1H,m), 2.64-2.89(3H,m), 6.78(1H,t,J=5.8Hz), 7.84(1H,s), 7.90-7.97(2H,m), 8.05-8.12(2H,m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | A mixture of Dl (946 mg, 5.31 mmol) and 5-2 (1.00 g, 5.31 mmol) in CHC13 (53 mL) was stirred at room temperature for 1 hour. A solution of l/2ZnCl2-NaBH3CN (0.3 M MeOH solution, 17.7 mL, 5.31 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 3.25 hours. After quenching the reaction mixture by addition of water, the mixture was extracted with CH2C12. The organic extracts were dried over NaS04, filtered, and then concentrated under reduced pressure. Flash chromatography (CH2Cl2/MeOH/NH4OH = 10: 1 :0.01) of the residue on silica gel gave 5-3 (1.71 g, 92%). 1H NMR (400 MHz, DMSO-< 6) delta 0.87 (d, J = 6.7 Hz, 3H), 1.35 (s, 9H), 1.80- 1.95 (m, 1H), 2.54-2.64 (m, 1H), 2.66-2.76 (m, 1H), 2.81 -2.96 (m, 2H), 3.93 (s, 2H), 4.65 (s, 2H), 6.93 (br, 1H), 7.09 (d, J= 7.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 11.3 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 150℃; for 1.5h;Inert atmosphere; Microwave irradiation; | Step B: tert-Butyl (3-((2-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(hydroxymethyl)pyridin-4-yl)amino)-2-methylpropyl)carbamate A solution of (4-chloro-6-(3-fluoro-4-(trifluoromethoxy)phenyl)pyridin-2-yl)methanol (25 mg, 0.077 mmol), <strong>[480452-05-9]tert-butyl (3-amino-2-methylpropyl)carbamate</strong> (77 mg, 0.39 mmol), potassium phosphate (49 mg, 0.23 mmol), Pd2(dba)3 (6 mg, 0.006 mmol), and rac-BINAP (8 mg, 0.012 mmol) in dioxane (1.1 mL) was heated in the microwave at 150 C. for 1.5 hours then filtered through Celite. Purification by basic prep HPLC (Agilent, Waters XBridge C18 5 um 50*100 mm column, 5-90% MeCN/20 mM NH4OH over 15 min, 80 mL/min) gave the title compound (25 mg, 68%). MS (ESI): mass calcd. for C22H27F4N3O4, 473.2; m/z found, 474.2 [M+H]+. |
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