Structure of 256652-04-7
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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. : | 256652-04-7 |
Formula : | C16H19BO2 |
M.W : | 254.13 |
SMILES Code : | CC1(C)OB(OC1(C)C)C1=CC2=C(C=CC=C2)C=C1 |
MDL No. : | MFCD05663868 |
InChI Key : | SPPZBAGKKBHZRW-UHFFFAOYSA-N |
Pubchem ID : | 10753409 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 19 |
Num. arom. heavy atoms | 10 |
Fraction Csp3 | 0.38 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 80.42 |
TPSA ? Topological Polar Surface Area: Calculated from |
18.46 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
4.16 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.14 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.57 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.9 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.55 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.36 |
Solubility | 0.0111 mg/ml ; 0.0000437 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.26 |
Solubility | 0.0141 mg/ml ; 0.0000555 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.68 |
Solubility | 0.000536 mg/ml ; 0.00000211 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) |
Yes |
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) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-4.9 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 |
1.0 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) |
3.11 |
* 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 (2,2,2-trifluoroethoxy)trimethylsilane; cesium fluoride; dichlorobis(trimethylphosphine)nickel; In tetrahydrofuran; at 100℃; for 2h;Inert atmosphere; Sealed tube; | Under an argon atmosphere,2.8 mg (0.01 mmol) of dichlorobis (trimethylphosphine) nickel,81.5 mg (0.5 mmol) of 2-chloronaphthalene,152 mg (1.0 mmol) of cesium fluoride,140 mg (0.55 mmol) of 4,4,5,5,4 ', 4', 5 ', 5'-octamethyl-2,2'-bi (1,3,2-dioxaborolanyl)180 mg (1.05 mmol) of trimethyl (2,2,2-trifluoroethoxy) silane and 0.5 mL of tetrahydrofuran were added and sealed,Followed by stirring at 100 C. for 2 hours.After the reaction vessel was cooled to room temperature, 1 mL of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted three times with 8 mL of ethyl acetate, and the obtained organic phases were combined.The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: chloroform: ethyl acetate = 16: 4: 0 to 16: 4: 1)104 mg (white solid, yield 82%) of 2- (2-naphthyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane was obtained |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 1h;Heating / reflux; | (2) Synthesis of Exemplified Compound No. 1536 <n="152"/> <n="153"/>Under a nitrogen atmosphere, 0.30 g (0.62 mmol) of the mixture of Intermediate Compounds 4 and 5, 0.11 g (0.62 mmol) of 4 , 4 , 5, 5-tetramethyl-2- (naphthalen-2- yl)-l, 3,2-dioxaborolane, and 0.04 g (0.03 mmol) of tetrakistriphenylphosphinepalladium were suspended in the mixed solvent of 15 mL of toluene, 8 mL of ethanol, and 6 mL of a 10% aqueous solution of sodium carbonate. The resultant solution was stirred under heat and reflux for 1 hour, and the disappearance of Intermediate Compounds 4 and 5 was observed. After that, the resultant was cooled to room temperature, and water was added to the resultant to stop the reaction. An organic layer was separated, and was then washed with water twice. After that, the solvent was removed by distillation. The resultant residue was purified by silica gel column chromatography (toluene : ethyl acetate = 10 : 1), whereby 0.192 g of the mixture of Exemplified Compounds 1536 containing Exemplified Compounds 1536-1 and 1536-2 at a composition ratio of 1 : 1 was obtained.Matrix-assisted laser desorption/ionization time- of-flight mass spectrometry (MALDI-TOF MS) identified 531.9 as the M+ of the compound.Further, NMR measurement identified the structure of the compound (FIG. 9) .The PL spectrum of a solution (1.0 * 10~5 mol/L) of Exemplified Compound 1536 in toluene was measured. <n="154"/>As a result, a blue light emission spectrum having a light emission peak at 439 nm, a half width of 59 nm, and an excellent color purity was shown (FIG. 15) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | (1) Synthesis of Intermediate 1-1 (0232) 20.0 g (20 mmol) of 2-bromonaphthalene was dissolved in 50 mL of tetrahydrofuran (THF), and then 8.8 mL (22.0 mmol) of n-BuLi (2.5 M in hexane) was slowly dropwise added thereto at about -78 C. After the reaction solution was stirred at the same temperature for about 1 hour, 4.65 mL (25.0 mmol) of 2-isoproxy-4,4,5,5,-tetramethyl-1,3,2-dioxaborolane was slowly dropwise added to the reaction solution, stirred at about -78 C. for about 1 hour, and then further stirred at ambient temperature for about 24 hours. After termination of the reaction, 30 mL of a 10% HCl aqueous solution and 30 mL of H2O were added thereto, followed by extraction three times with 50 ml of diethyl ether. An organic phase was collected and dried using magnesium sulfate, followed by evaporating the solvent. The resulting residue was purified by silica gel column chromatography to obtain 3.7 g of Intermediate 1-1 (Yield: 73%). This compound was identified by liquid chromatography-mass spectrometry (LC-MS). C16H19BO2: M+ 255.1 | |
41% | To a 500 mL 3 -necked round bottomed flask, charged were THF (300 mL) and 2-bromonaphthalene (10 g, 48.3 mmol) , and the mixture was chilled to -78C by using liquefied nitrogen. Then, n-BuLi (14.73 g, 53.1 mmol) was slowly added dropwise thereto. After stirring at ambient temperature for 1 hour, 2- isopropoxy-4, 4, 5, 5-tetramethyl- [1, 3, 2] -dioxaborolane (9.87 g) was slowly added dropwise at -78C to the mixture. After 12 hours, water is poured thereto, to quench the reaction. The reaction mixture was extracted with ether, dried over MgSO4 and evaporated by using a rotary evaporator to remove the solvent. The product was isolated via column chromatography (eluent: hexane/EA = 5/1) .Yield: 4.05 g (41%) m.p. : 93 C1H NMR (300 MHz, CDCl3, ppm): 7.81 (d, 4H), 7.29 (t, 3H), 1. 26 (m , 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; toluene; at 90℃; for 24h; | To a 100 mL 2-necked round bottomed flask, charged were 2 , 6-dibromo-9, 10-bis (triisopropyl silyl) acetyl anthracene (Compound 9) (1 g, 1.43 mmol) obtained from Preparation Example 6, and 2 -naphthalene-2 -yl-4 , 4 , 5 , 5-tetramethyl-l, 3,2-dioxaborolane (Compound 13) (0.90 g, 3.57 tnmol) obtained from Preparation Example 10, THF (5 mL) , toluene (30 mL) and 2M- K2CO3 (50 mL) , and the mixture was bubbled with nitrogen. Under nitrogen atmosphere, added was Pd(PPh3)4 (0.1 g) as a catalyst, and the reaction was continued at 90C for 24 hours. Then the reaction mixture was poured to 2N-HC1 to quench the reaction, and the solid produced was filtered, extracted with methanol and toluene by using a soxlet device, and recrystallized from CHCl3.Yield: 0.97 g (86%)1H NMR (300 MHz, CDCl3, ppm) : 8.93 (s, IH), 8.67 (d, IH), 8.21 (d, IH), 7.81-7.98 (m, 5H), 7.41-7.50 (m, 2H), 1.38-1.10 (m, 21H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; N,N-dimethyl-formamide;tetrakis(triphenylphosphine) palladium(0); In water; at 150℃; for 0.133333h;Microwave irradiation; | Step A Methyl 5-[6-chloro-5-(2-naphthyl)-1H-benzimidazol-2-yl]oxy}-2-methylbenzoate. A microwave vial was charged with Intermediate 12 (95 mg, 0.215 mmol), 2-naphthyleneboronic acid pinacol ester (79 mg, 0.311 mmol), Pd(PPh3)4 (37 mg, 0.032 mmol), DMF (2.1 mL), and 1 M aqueous K2CO3 (0.64 mL). The reaction was heated at 150 C. under microwave irradiation for 8 min. The reaction was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. Chromatography over silica eluting with 30% EtOAc/hexanes afforded the desired product as a yellow-orange oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium phosphate tribasic heptahydrate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; XPhos; In ethanol; at 20℃; for 1h; | General procedure: Method (1): Synthesis from 4-tert-butylchlorobenzene as a raw material: K3P04 · 7H20 (3.0 g, 8.85 mmol) and bis-pinacol borate (749 mg, 2.95 mmol) were sequentially added to the reaction flask.The catalyst-chloro (2-dicyclohexyl phosphino-2 ', 4', 6'-tri - triisopropyl-1,1'-biphenyl) (1,1'-biphenyl -2-amino-2'_ -yl)palladium(II) (12 mg, 0.015 mmol) and ligand 2-dicyclohexylphosphine-2',4',6/-triisopropylbiphenyl (4 mg, 0.008 mmol), followed by EtOH (6 mL) The mixture was stirred, and p-tert-butylchlorobenzene (0.5 mL, 2.95 mmol) was added and the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (2 mL) After washing with ethyl acetate (6 mL) in three portions, the filtrate was combined, and the solvent was evaporated to dryness, and the solvent was separated by silica gel (200 to 300 mesh). The eluent was petroleum ether and ethyl acetate. 10~80:1), obtained as a white solid, identified by NMR spectrum as 4-tert-butylphenylboronic acid pinacol ester, yield 98% |
80% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 90℃; | General procedure: Starting material bromobenzene (29.16 g, 185.72 mmol) was dissolved in DMF (930 ml) in a round bottom flask, and Bis(pinacolato)diboron (51.88 g, 204.29 mmol), Pd(dppf)Cl2 (4.55 g, 5.57 mmol), KOAc (54.68 g, 557.16 mmol) were added and stirred at 90 C. When the reaction is complete, the DMF is removed by distillation and extracted with CH2Cl2 and water. The organic layer was dried over MgSO4 and concentrated. The resulting compound was separated by silicagel column chromatography and recrystallized to obtain 31.84 g of the product. (yield: 84%) |
50% | With p-phenylpyridine; potassium methanolate; In tert-butyl methyl ether; at 85℃; for 12h; | General procedure: According to the method described in Scheme 1) above,It is possible to synthesize aryl borates with different aromatic ring substituents (as shown in Table 1).The resulting aryl borates are known compounds, and their characterization data are consistent with those reported in the literature. |
With tetrakis(triphenylphosphine) palladium(0); potassium acetate; In toluene; for 24h; | General procedure: Sub B (1)-2 (4.14g, 20mmol) was dissolved in 48 mL toluene, bis(pinacolato)diboron (5.58g, 22mmol), Pd (dppf) Cl2 catalyst (0.44g, 0.6mmol), KOAc (5.89 g, was added as 60mmol) the sequence after 24 hours with stirring to synthesize a borate compound, and then the resulting compound was separated through a silica gel column and recrystallized to obtain 3.7g to Sub B-2. (Yield: 73%) | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 90 - 100℃; | General procedure: After the bromine compound (1 equivalent) was dissolved in DMF,Bis (pinacolato) diboron (1.1 eq.), Pd (dppf) Cl2 (0.03 mmol)After addition of KOAc (3 eq) And stirred at 90 to 100 C. When the reaction was complete, DMF was removed by distillation and extracted with CH2Cl2 and water.The organic layer was dried over MgSO4 and concentrated. The resulting compound was purified by silicagel column and recrystallized to give product Sub2. |