Structure of 4-(n-Octyl)benzeneboronic acid
CAS No.: 133997-05-4
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CAS No. : | 133997-05-4 |
Formula : | C14H23BO2 |
M.W : | 234.14 |
SMILES Code : | OB(C1=CC=C(CCCCCCCC)C=C1)O |
MDL No. : | MFCD04039034 |
InChI Key : | HUKDAABRKOWPNA-UHFFFAOYSA-N |
Pubchem ID : | 4197992 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 17 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.57 |
Num. rotatable bonds | 8 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 74.88 |
TPSA ? Topological Polar Surface Area: Calculated from |
40.46 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 |
4.87 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.27 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.67 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.26 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.41 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.09 |
Solubility | 0.0189 mg/ml ; 0.0000807 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-5.45 |
Solubility | 0.000822 mg/ml ; 0.00000351 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.52 |
Solubility | 0.00714 mg/ml ; 0.0000305 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) |
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) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-4.27 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<3.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.17 |
* 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 |
---|---|---|
Under nitrogen atmosphere, 10 ml of a solution of 1.6M n-butyl lithium (16 mmol) in hexane is put into a 100 ml three-necked flask cooled at -80 C. After cooling to -80 C., 10 ml of THF is added dropwise thereto using a dropping funnel while the THF is maintained at -60 C. Thereafter, 3.1 g (16 mmol) of 1-bromo-4-n-octylbenzene maintained at -60 C. is added dropwise thereto using a dropping funnel. The resultant mixture is stirred at -40 C. for 1 hour, and a solution of 2.3 g (22 mmol) of trimethyl borate in 10 ml of THF is added dropwise to the mixture using a dropping funnel while the temperature of the added solution is maintained at -40 C. Thereafter, the temperature of the mixture is gradually increased to 10 C. over 2 hours, and 50 ml of a 10% HCl aqueous solution is added thereto at 0 C., and extraction is performed using 100 ml of toluene. The extract is washed with 100 ml of pure water three times, and is dehydrated using sodium sulfate. Toluene is distilled off by reducing the pressure, whereby remaining matter in an amount of 3.3 g is obtained. The remaining matter is washed with a mixed solution of 100 ml pure water/100 ml hexane, whereby 2.0 g of Compound V-a, which is 4-n-octylphenyl borate, is obtained. The obtained compound is identified as the desired product by 1H-NMR and IR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water;Heating / reflux; | Part B: Preparation of 4'-nitro-4-n-octyl-biphenyl <n="43"/>[0115] Tetrakis(triphenylphosphine)palladium (0) (0.30 g, 0.26 mmol) and p-n- octylphenylboronic acid (1.0 g, 4.3 mmol) were sequentially added to a stirred solution of 4-nitroiodobenzene (0.87 g, 3.5 mmol) in 1 ,2-dimethoxyethane (13 mL) and aqueous sodium carbonate (2 M, 13 mL) under dry nitrogen. The stirred mixture was heated under reflux overnight and cooled. Water was added and the product was extracted into ether (30><3 mL) and the combined ethereal extracts were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by chromatography using a short silica gel column (hexane:ethyl acetate - 5: 1 to 2:1] to provide 4'-nitro-4-n-octyl-biphenyl as a yellow oil, which solidified upon standing (1.04 g, 95% yield). The solid was used without further purification.[0116] 1H NMR (CDCl3) delta 0.90 (3H, t), 1.19-1.58 (1OH, m), 1.67 (2H, quint), 2.68 (2 H, t), 7.31(2H, d, J=8.5 Hz), 7.56(2H, d, J=8.5 Hz), 7.73 (2H, d, J=9.0 Hz), 8.29 (2H, d, J=9.0 Hz); GC MS w/z=311 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; water; In tetrahydrofuran; hexanes; for 2h; | Part A: Preparation of p-n-octylphenylboronic acid[0113] n-Butyllithium (BuLi, 1.6 M in hexanes, 2.4 mL, 3.8 mmol) was added dropwise to a stirred solution of p-n-octyliodobenzene (1.0 g, 3.2 mmol) in dry THF (15 mL) at -780C under nitrogen. After stirring for 30 minutes and maintaining the temperature at -780C, trimethylborate (0.4 g, 3.8 mmol) was added dropwise. The system was allowed to return to room temperature after 1 hour and was left stirring under nitrogen overnight. Concentrated HCl (8 mL) and water (15 mL) were then added and stirring was continued for 2 hours. The mixture was extracted with ether (15x3 mL). The ethereal phase was combined and was washed with brine and water (20x2 mL), dried with MgSO4, and the solvent removed in vacuo to give p-n- octylphenylboronic acid as a white solid (0.63 g, 84% yield).[0114] 1H NMR (CDCl3) delta, 0.89 (3H, t), 1.21-1.43 (1OH, m), 1.66 (2H, quint), 2.70 (2H, t), 7.32 (2H, d, J=7.5 Hz), 8.16 (2H, d, J=7.5 Hz); GC MS w/z=234(M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1-methyl-pyrrolidin-2-one; water; at 200℃; for 5h;Inert atmosphere; | Under nitrogen atmosphere, 0.1 g (0.10 mmol) of tetrakistriphenylphosphine palladium(0) is dissolved in 100 ml of NMP in a 300 ml three-necked flask, 1.4 g (3.0 mmol) of Compound IV-a, 9.0 ml of a 2M sodium carbonate aqueous solution, and 1.4 g (6.0 mmol) of 4-n-octylphenyl borate (Compound V-a) are sequentially added, in this order, to the solution in the flask. The resultant mixture is refluxed for 5 hours in an oil bath at 200 C. under stirring by a magnetic stirrer. After the completion of the reaction is confirmed by 1H-NMR, the reaction solution is cooled to 25 C., and the reaction solution is poured into 1 L of pure water in a 2 L beaker. The resultant mixture in the beaker is stirred at 25 C. for 20 minutes using a magnetic stirrer After the completion of the stirring, the precipitated crystal is collected by suction filtration, and washed with 300 ml of pure water. The obtained crystal is further washed with 200 ml of methanol, and then with 100 ml of toluene, and vacuum-dried at 60 C. for 15 hours. The crystal is recrystallized using 200 ml of NMP, followed by purification by sublimation, whereby 0.60 g of Exemplary Compound 4 in the form of an orange crystal is obtained.The IR spectrum and 1H-NMR spectrum of the obtained Exemplary Compound 4 are shown in FIGS. 9 and 10, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1-methyl-pyrrolidin-2-one; water; at 220℃; for 5h;Inert atmosphere; | Under nitrogen atmosphere, 0.10 g (0.080 mmol) of tetrakistriphenylphosphine palladium(0) is dissolved in 100 ml of NMP in a 300 ml three-necked flask. 1.2 g (2.5 mmol) of Compound IV-a, 6.0 ml of a 2M sodium carbonate aqueous solution, and 1.5 g (5.0 mmol) of Compound V-b, which is 4-n-dodecylphenyl borate, are sequentially added, in this order, to the solution in the flask. The resultant mixture is refluxed for 5 hours in an oil bath at 220 C. under stirring by a magnetic stirrer. After the completion of the reaction is confirmed by 1H-NMR, the reaction solution is cooled to 25 C., and the reaction solution is poured into 400 ml of pure water in a 1 L beaker. The resultant mixture in the beaker is stirred at 25 C. for 30 minutes using a magnetic stirrer After the completion of the stirring, the precipitated crystal is collected by suction filtration, and washed with 300 ml of pure water. The obtained crystal is further washed with 200 ml of methanol, and then with 100 ml of toluene, and vacuum-dried at 60 C. for 15 hours. The crystal is recrystallized twice from 200 ml of NMP, followed by purification by sublimation, whereby 0.13 g of Exemplary Compound 5 in the form of an orange crystal is obtained.The IR spectrum (according to the KBr method) of the obtained Exemplary Compound 5 is shown in FIG. 11. The NMR spectrum (H-NMR, solvent: CDCl3) thereof is shown in FIG. 12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; for 12h;Inert atmosphere; Reflux; | Under nitrogen atmosphere, 0.090 g (0.080 mmol) of tetrakistriphenylphosphine palladium (0) is dissolved in 50 ml of THF in a 200 ml three-necked flask. 1.23 g (2.5 mmol) of Compound IV-b, 6.0 ml of a 2M aqueous sodium carbonate solution, and 1.24 g (5.3 mmol) of Compound V-a are added, in this order, to the solution in the flask. The resultant mixture is refluxed for 12 hours under stirring by a magnetic stirrer. After the completion of the reaction is confirmed by 1H-NMR, the reaction solution is cooled to 25 C., and the reaction solution is poured into a 1 L beaker containing 100 ml of a 5% aqueous hydrochloric acid solution and 200 ml of toluene. Then, the contents of the beaker are stirred at 25 C. for 30 minutes using a magnetic stirrer. The toluene layer is taken out, washed with 200 ml of pure water three times, and dehydrated using anhydrous sodium sulfate. Then, the liquid is filtrated, and solvent is removed by distillation under reduced pressure, whereby 1.7 g of an orange solid material is obtained. The orange solid material is subjected to purification by a silica gel column using a mixed solvent of toluene and THF (in a mixing ratio by weight of 1:2), and recrystallized using toluene. The obtained crystal is vacuum-dried for 15 hours, whereby 1.2 g of Exemplary Compound 8 in the form of an orange crystal is obtained (yield: 70%).The IR spectrum (according to the KBr method) of the obtained Exemplary Compound 8 is shown in FIG. 19. The NMR spectrum (1H-NMR, solvent: CDCl3) thereof is shown in FIG. 20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; for 11h;Inert atmosphere; Reflux; | Under nitrogen atmosphere, 0.090 g (0.080 mmol) of tetrakistriphenylphosphine palladium (0) is dissolved in 50 ml of THF in a 200 ml three-necked flask. 1.72 g (2.5 mmol) of Compound VI-d, 6.0 ml of a 2M aqueous sodium carbonate solution, and 1.23 g (5.3 mmol) of Compound V-a are added, in this order, to the solution in the flask. The resultant mixture is refluxed for 11 hours under stirring by a magnetic stirrer. After the completion of the reaction is confirmed by 1H-NMR, the reaction solution is cooled to 25 C., and the reaction solution is poured into a 1 L beaker containing 100 ml of a 5% aqueous hydrochloric acid solution and 200 ml of toluene. Then, the contents of the beaker are stirred at 25 C. for 30 minutes using a magnetic stirrer. The toluene layer is taken out, washed with 200 ml of pure water three times, and dehydrated using anhydrous sodium sulfate. Then, the liquid is filtrated, and solvent is removed by distillation under reduced pressure, whereby 2.8 g of a red solid material is obtained. The red solid material is subjected to purification by a silica gel column using a mixed solvent of toluene and hexane (in a mixing ratio by weight of 1:5), and recrystallized using a mixed solvent of ethanol and hexane (in a mixing ratio by weight of 1:1). The obtained crystal is vacuum-dried for 15 hours, whereby 0.7 g of Exemplary Compound 27 in the form of an orange crystal is obtained (yield: 30%).The IR spectrum (according to the KBr method) of the obtained Exemplary Compound 27 is shown in FIG. 15. The NMR spectrum (1H-NMR, solvent: CDCl3) thereof is shown in FIG. 16. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1-methyl-pyrrolidin-2-one; water; at 100℃; for 6h;Inert atmosphere; | A solution including 1.0 g (0.18 mmol) of the resulting 2,6-bis(5-bromo-2',2-bithiophene-5'-yl)pyrazine, 1.0 g (0.44 mmol) of <strong>[133997-05-4]4-n-octylbenzeneboronic acid</strong> (manufactured by Tokyo Chemical Industry Co., Ltd.), and 0.076 g (0.066 mmol) of tetrakis(triphenylphosphine)palladium(0) in 200 ml of N-methylpyrrolidone is prepared, and a solution including 1.4 g (1.2 mmol) of sodium carbonate (manufactured by Wako Pure Chemical Industries, Ltd.) in 5 ml of water is added thereto. The resulting mixture is stirred at 100 C. for 6 hours in a nitrogen stream.After allowed to cool, the mixture is poured into 800 ml of water, and the resulting precipitate is separated by filtration and washed with water. The precipitate is dried under reduced pressure and then dissolved in toluene. The dissolved precipitate is purified by column chromatography (silica gel) and recrystallized from toluene, so that 0.23 g of compound (II-11) is obtained (16% of the theoretical yield).The resulting compound (II-11) has a melting point of 197.5 C. to 199 C.The infrared absorption spectrum and 1H-NMR spectrum of the resulting compound (II-11) are shown in FIGS. 3 and 4, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; hexane; | Synthesis Example 2 Synthesis of Exemplified Compound 4 <Synthesis of Compound V-a> In a nitrogen atmosphere, 10 ml (16 mmol) of a 1.6 M n-butyllithium/hexane solution is added to a 100-ml three-necked flask cooled to -80 C. This solution is cooled to -80 C., and then 10 ml of THF maintained at -60 C. is added dropwise thereto from a dropping funnel. Subsequently, 3.1 g (16 mmol) of 1-bromo-4-n-octylbenzene maintained at -60 C. is added dropwise to the mixture from a dropping funnel. This mixture is stirred for one hour at -40 C., and then a solution of 2.3 g (22 mmol) of trimethyl borate in THF (10 ml) maintained at -40 C. is added thereto from a dropping funnel. Thereafter, the mixture is slowly heated to 10 C. over 2 hours, and then 50 ml of a 10% aqueous solution of HCl at 0 C. is added thereto. The mixture is extracted with 100 ml of toluene. This extract is washed three times with 100 ml of purified water, and then is dried with sodium sulfate. Toluene is distilled off under reduced pressure, and 3.3 g of a residue is obtained. This residue is further washed with a mixed liquid of 100 ml of purified water and 100 ml of hexane, and thus 2.0 g of the compound V-a, which is 4-n-octylphenylboronic acid, is obtained. It is confirmed by 1H-NMR and IR that the compound is consistent with the intended product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium carbonate; In water; acetonitrile; for 6h;Reflux; | Pd(OAc)2 (0.232 mg, 1.032 mumol), and S-Phos (2.89 mg, 7.03 mumol) were added to a suspension of K2CO3 (243 mg, 1.758 mmol), 5-bromopyrazin-2-amine (61.2 mg, 0.352 mmol), and <strong>[133997-05-4](4-octylphenyl)boronic acid</strong> (107 mg, 0.457 mmol) (prepared according to Ishi-I, T. et al.49) in acetonitrile/water (1.5:1). The suspension was degassed for 5 min and then refluxed for 6 h. The reaction mixture was extracted with EtOAc, washed with brine, dried with MgSO4 and filtered. After evaporation of the organic solvent under reduced pressure, the resulting residue was purified by column chromatography over silica gel (100% hexanes to 50/50 hexanes/EtOAc) to provide an orange solid (95% yield). 1H NMR (400 MHz, CDCl3) delta 8.45 (s, 1H), 8.04 (s, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 4.82 (br s, 1H), 2.64 (t, J = 7.7 Hz, 2H), 1.63 (m, 2H), 1.38-1.20 (m, 8H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) delta 152.8, 143.2, 143.0, 138.4, 134.3, 131.8, 128.9, 125.5, 35.7, 31.9, 31.4, 29.5, 29.3, 29.2, 22.7, 14.1; HRMS (ESI+) m/z calcd for C18H26N3 [M+H]+ 284.2121, found 284.2136.The above amine was dissolved in 10 mL methanol and HCl (g) was bubbled through the solution for one minute. After evaporation of the methanol, diethyl ether was added and the solid filtered. It was washed with cold diethyl ether to yield the title compound as a pale yellow solid (95% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 60℃; for 8h; | 14.3 g (61.0 mmol) of <strong>[133997-05-4]4-octylphenylboronic acid</strong>, 16.7 g (55.5 mmol) of 1-bromo-2-fluoro-4-iodobenzene, 200 ml of dimethoxyethane, 19.4 g (0.183 mol) of sodium carbonate, 200 ml of pure water, 1.0 g (0.86 mmol) of tetrakis(phenylphosphine)palladium (0) were placed in a flask. The resulting mixture was stirred at 60 C. for 8 hours. Pure water was added to the reaction mixture and extracted with dichloromethane. The solvent in an organic phase was removed with hexane, whereby a crude product of compound (o) was obtained.This crude product was purified by column chromatography, whereby 18.2 g (yield: 90%) of compound (o) was obtained. |
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